TW202515566A - Smarca2 degraders and uses thereof - Google Patents

Abstract

The present disclosure provides compounds represented by Formula (A), or a pharmaceutically acceptable salt and/or stereoisomer thereof: wherein R<SP>a</SP>, R<SP>b</SP>, R<SP>c</SP>, R7, R8, R9, R10, X3, W, L, and E are as defined in the specification. Compounds represented by Formula (A) are SMARCA2 protein degraders and are thus useful for treating cancer and other diseases.

Description

SMARCA2 degrading agent and its use

The present disclosure provides proteolysis targeting chimera (PROTAC) compounds and the use of such PROTAC compounds for treating diseases or disorders that depend on SMARCA2 in mammals. Degradation of SMARCA2 can provide, for example, anti-tumor effects. Therefore, the present disclosure provides SMARCA2 degraders and pharmaceutical compositions comprising SMARCA2 degraders for the treatment of cancer. The present disclosure also provides intermediate compounds that can be used to prepare such PROTACs.

Traditional "small molecule" drugs bind reversibly (or sometimes irreversibly) to a target protein as a means of modulating a given biological activity. In contrast, PROTACs bind reversibly to their target proteins, yet result in the degradation of the target protein. Having achieved this effect, PROTACs are theoretically able to repeat the process with another target protein. Accordingly, unlike traditional small molecule inhibitors, PROTAC-driven degradation mechanisms can theoretically operate in a substoichiometric manner - meaning that more modest PROTAC compound exposures can still achieve desired levels of efficacy in vivo . In practice, this means that the degradation potency (DC ₅₀ and D _max ) of a PROTAC can have an improved effect than that reflected by its binding affinity.

PROTAC molecules are described as having three parts - (1) a part that is able to bind to the protein to be degraded, (2) a second part that is able to bind to the E3 ubiquitin ligase, and (3) a linker that connects parts (1) and (2) together. In use, PROTAC binds both the target protein and the E3 ubiquitin ligase simultaneously, forming a ternary complex. The E3 ligase then recruits the E2 ytylase to the ternary complex, which ubiquitinates the target protein. This has the effect of marking the target protein for degradation by the cell's proteasome machinery. The PROTAC can then dissociate from the target protein and catalytically begin another cycle of this process. At the same time, the ubiquitinated target protein is recognized by the cell's proteasome machinery and then degraded by it. This PROTAC-mediated approach may be valuable as a method for treating certain diseases including cancer.

SMARCA4 is frequently mutated in several tumor types, including lung, liver, colorectal, skin, bladder, esophageal, gastric, brain, endometrial, cervical, and ovarian cancers. Furthermore, SMARCA2 has been identified as essential for the growth of tumors harboring such SMARCA4 mutations. Therefore, selective inhibition of SMARCA2 has been proposed as a therapeutic strategy against cancers that may harbor SMARCA4 mutations. Therefore, selective inhibition of SMARCA2 could be used against many cancer types, including lung, liver, colorectal, skin, bladder, esophageal, gastric, brain, endometrial, cervical, and ovarian cancers.

WO 2019/207538 discloses certain PROTAC compounds described as "SMARCA 2/4 degraders", and WO 2020251969 discloses PROTAC compounds that target one or more of SMARCA2, SMARCA4 and PB1. WO 2019/195201 also discloses "bifunctional" compounds described as modulators of SMARCA2. WO 2019/213005 is about compounds that are said to degrade PBRM1. WO 2018/144649 and WO 2021/053495 also disclose certain PROTAC molecules. WO 2021/053555 discloses colloid degrader compounds that bind to the E3 ubiquitin ligase cereblon.

As part of developing PROTACs against cancer, there is a need to develop additional PROTAC compounds with beneficial/improved combinations of properties that make them more suitable for use as therapeutic drugs for human use. Properties of interest during drug discovery and development may involve selectivity characteristics, absorption/bioavailability, distribution, metabolism, elimination, toxicity and side effect characteristics, stability, manufacturability, etc.

In one aspect, the present disclosure provides a PROTAC compound represented by any one of the following formulas (A) and (I)-(V) and a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides any one or more of the PROTAC compounds of the following compound list 1 and a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides any one or more of the PROTAC compounds of the following compound list 2 and a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides any one or more of the PROTAC compounds of the following compound list 3 and a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides any one or more of the PROTAC compounds of the following compound list 4 and a pharmaceutically acceptable salt thereof. Compounds having any one of formula (A) and (I)-(V) and pharmaceutically acceptable salts thereof, as well as compounds of Compound List 1, Compound List 2, Compound List 3 and/or Compound List 4 and pharmaceutically acceptable salts thereof are collectively referred to as "compounds of the present disclosure" or individually referred to as "compounds of the present disclosure". The compounds of the present disclosure exhibit protein degradation activity against SMARCA2. The compounds of the present disclosure may also have beneficial selectivity to minimize certain undesirable off-target degradation activities. Therefore, the compounds of the present disclosure may be used to treat cancer.

The compounds of the present disclosure may also have surprisingly beneficial combinations of properties that are relevant in the context of drug discovery and development. Structural features found in all three regions of PROTACs have the potential (together or in some cases individually) to deliver beneficial combinations and/or balances of such additional beneficial properties. Avoiding off-target activity in drug development is often important to avoid or reduce unwanted toxicity, side effects or other tolerability issues when used in patients.

In addition to being degraders of SMARCA2, the compounds of the present disclosure possess a surprising and beneficial combination of properties such as chemical and metabolic stability (e.g., in human microsomes) and hydrolysis at pH 7.4, and selectivity for SALL4 and/or Ikaros (IKZF1), which is expected to provide an improved safety profile for in vivo use. Without wishing to be bound by any particular theory, it is believed that, among other things, degradation of SALL4 and Ikaros (IKZF1) may have serious adverse effects in humans, such as developmental toxicity or bone marrow toxicity.

Likewise, in this regard, it has been found that molecules that degrade SMARCA2 often also degrade SMARCA4, which is considered an undesirable off-target activity. The compounds disclosed herein can exhibit beneficial selectivity characteristics by achieving an effective degree of degradation for SMARCA2 while having a selectivity margin for SMARCA4 (i.e., relatively low degradation). In a similar manner, in the development of SMARCA2 PROTACs for cancer, it is also considered beneficial to have an effective degree of degradation for SMARCA2 while having a good selectivity margin for PBRM1, i.e., relatively low degradation. The compounds disclosed herein can exhibit beneficial selectivity characteristics between SMARCA2 and PBRM1. Thus, in combination, the compounds of the present disclosure can exhibit high potency against SMARCA2 while achieving beneficial selectivity profiles with respect to SALL4 and/or Ikaros (IKZF1), and in some cases, achieve surprisingly beneficial selectivity margins against SMARCA4 and/or PBRM1.

In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients.

In another aspect, the present disclosure provides a method for degrading human SMARCA2 protein, the method comprising administering an effective amount of a compound of the present disclosure to a human in need thereof.

In another aspect, the present disclosure provides a method for reducing SMARCA2 protein in a human, the method comprising administering an effective amount of a compound of the present disclosure to a human in need thereof.

In another aspect, the present disclosure provides a method for treating cancer in a human, the method comprising administering to a human in need thereof an effective amount of a compound of the present disclosure.

In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in degrading SMARCA2 protein in humans.

In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in reducing SMARCA2 protein in humans.

In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in treating human cancer.

In another aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutical composition thereof in the manufacture of a medicament for degrading SMARCA2 protein in humans.

In another aspect, the present disclosure provides use of the compound of the present disclosure or its pharmaceutical composition in the manufacture of a medicament for reducing human SMARCA2 protein.

In another aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutical composition thereof in the manufacture of a medicament for treating human cancer.

In another aspect, the present disclosure provides methods of preparing the compounds of the present disclosure.

In another aspect, the present disclosure provides intermediates for preparing the compounds of the present disclosure.

Additional embodiments and advantages of the present disclosure will be partially described in the description that follows and will flow from the description, or can be understood by practice of the present disclosure. The embodiments and advantages of the present disclosure will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that both the foregoing summary and the following detailed description are merely exemplary and illustrative and do not limit the invention as claimed.

I. Compounds of the Disclosure

Many embodiments of the present disclosure are described in detail throughout the specification.

In one embodiment, the compound disclosed herein is a compound having formula (A) or a pharmaceutically acceptable salt thereof: (A) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl,

wherein (C ₁ -C ₆ )alkyl is optionally substituted by one, two or three substituents independently selected from halogen or cyano; and 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted by one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -;

or X ³ does not exist;

L is G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; ( _C3 - _C6 )cycloalkylene; -O- _CH2 - _CH2- ; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, cyano or hydroxy; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy or cyano;

^G2 is ( _C1 - _C6 ) alkylene, -C(=O)-, 4- to 6-membered heterocycloalkylene which may be substituted by one, two or three fluorine groups, or a direct bond;

^G3 is -C(=O)-; -C(=O) _-CH2CH2- ; ( _C1 - _C6 )alkylene; _{tetrahydronaphthylene} ; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy or cyano; 7- to 11-membered heterocycloalkyl-C(=O)-; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy or cyano;

G ⁴ is (C ₁ -C ₆ )alkylene; (C ₃ -C ₆ )cycloalkylene; 4- to 6-membered heterocycloalkylene; or a direct bond;

W is -C≡C- or direct key;

R ⁷ is hydrogen; halogen; (C ₁ -C ₆ )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl;

R ⁸ is hydrogen; halogen; (C ₁ -C ₆ )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen; halogen; (C ₁ -C ₆ )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl;

R ¹⁰ is hydrogen; halogen; (C ₁ -C ₆ )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl;

^Ra is hydrogen or a halogen;

R ^b is hydrogen or a halogen; and

R ^c is hydrogen or methyl.

In another embodiment, the compound disclosed herein is a compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or

X ³ does not exist;

L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

G ² is (C ₁ -C ₆ )alkylene or a direct bond;

^G3 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )alkoxy; a cyano group; or a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or a cyano group;

G ⁴ is (C ₁ -C ₆ )alkylene or a direct bond;

W is -C≡C- or direct key;

^R7 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl;

R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which is optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; and

R ¹⁰ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C ₃ -C ₆ )cycloalkyl.

In another embodiment, the compound disclosed herein is a compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or

X ³ does not exist;

L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

G ² is (C ₁ -C ₆ )alkylene or a direct bond;

^G3 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )alkoxy; a cyano group; a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, or cyano; or a 5- to 10-membered heteroaryl group;

G ⁴ is (C ₁ -C ₆ )alkylene, (C ₃ -C ₆ )cycloalkylene, or a direct bond;

W is -C≡C- or direct key;

^R7 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl;

R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which is optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; and

R ¹⁰ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C ₃ -C ₆ )cycloalkyl.

In another embodiment, the compound disclosed herein is a compound having formula (II) or a pharmaceutically acceptable salt thereof: (II), wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , W, L, and E are as defined in the combined formula (I).

In another embodiment, the compound disclosed herein is a compound having formula (III) or a pharmaceutically acceptable salt thereof: (III), wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , W, L, and E are as defined in the combined formula (I).

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein E is E-1.

In another embodiment, the compound disclosed herein is a compound having any one of Formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is hydrogen.

In another embodiment, the compound disclosed herein is a compound of formula (A) or any one of (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is (C ₁ -C ₆ )alkyl optionally substituted with one, two or three substituents independently selected from halogen or cyano.

In another embodiment, the compound disclosed herein is a compound having any one of Formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is methyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is (C ₃ -C ₆ )cycloalkyl.

In another embodiment, the compound disclosed herein is a compound having any one of Formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is cyclopropyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is a 4- to 6-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ )alkyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is cyano.

In another embodiment, the compound of the present disclosure is a compound of any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is aryl optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ )alkyl.

In another embodiment, the compound of the present disclosure is a compound of any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ^5a is a 5- or 6-membered heteroaryl group optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ )alkyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein E is E-2.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein E is E-3.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

R ¹ series: and

^R2 is hydrogen, halogen, (C1-C6) alkyl, or (C1-C6) alkoxy.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, halogen, or (C ₁ -C ₆ )alkyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, fluorine, or methyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein X ¹ is CR ³ .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ³ is a halogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ³ is (C ₁ -C ₆ ) alkyl.

In another embodiment, the compound disclosed herein is a compound having any one of Formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein X ¹ is N.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein X ² is CR ⁴ .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a halogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is (C ₁ -C ₆ )alkyl.

In another embodiment, the compound disclosed herein is a compound having any one of Formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein X ² is N.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein E-1 is: , , , , , , , , , , , ,or .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III), wherein E-1 is: , , , , , , , , , , , , ,or .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein E is: or .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein E-2 is: .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein E-3 is: .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein E is: .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G1 is a 4- to 6-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, or cyano.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G1 is ( _C3 - _C6 ) cycloalkylene; or 4- to 6-membered heterocycloalkylene, which is optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, cyano, or hydroxyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

n is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, or hydroxy;

n is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound of the present disclosure is a compound of any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein each R ¹² is independently fluoro, methyl, methoxy, cyano, or -CHF ₂ ; and n is 0, 1, or 2.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : , , ,or and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : , , , ,or

And the key marked with "*" is attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

X ⁴ series -O-;

each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : or and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having formula (A) or a pharmaceutically acceptable salt thereof, wherein G ¹ is cyclohexylene.

In another embodiment, the compound disclosed herein is a compound having formula (A) or a pharmaceutically acceptable salt thereof, wherein: or and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound of the present disclosure is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G1 is a 7- to 11-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, or cyano.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹³ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

o is 0, 1, 2, or 3;

p, q, r, and s are independently 1, 2, or 3; and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹³ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

o is 0, 1, 2, or 3;

p, q, r, and s are independently 1 or 2;

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

p and q are 1;

r is 1 or 2;

s is 1 or 2; and

R ¹³ is a halogen.

In another embodiment, the compound of the present disclosure is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ¹³ is fluorine and o is 0, 1, or 2.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G1 is: and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

a is 0 or 1;

b is 0 or 1; and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G1 is: , , ,or and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G1 is: or and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G1 is: or and

Keys marked with a "*" are attached to G ² .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ² is a direct bond.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or a pharmaceutically acceptable salt thereof, wherein G ² is -C(=O)-.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ² is (C ₁ -C ₆ )alkylene.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ² is -CH ₂ -.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G3 is a 4- to 6-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, or cyano.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: , , , ,or ;

Each R ¹⁴ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

t is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to G ⁴ .

In another embodiment, the compound of the present disclosure is a compound having any one of Formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is fluoro or methyl and t is 0 or 1.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , ,or .

In another embodiment, the compound of the present disclosure is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^G3 is a 7- to 11-membered heterocycloalkyl group optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, or cyano.

In another embodiment, the compound disclosed herein is a compound having formula (A) or a pharmaceutically acceptable salt thereof, wherein G ³ is: or and

Keys marked with a "*" are attached to ^G4 .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ³ is: and

Keys marked with a "*" are attached to G ⁴ .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ³ is: or and

Keys marked with a "*" are attached to G ⁴ .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: ;

Each R ¹⁵ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

u is 0, 1, 2, or 3;

v, w, x, and y are independently 1, 2, or 3; and

Keys marked with a "*" are attached to G ⁴ .

In another embodiment, the compound of the present disclosure is a compound having any one of Formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein v, w, x, and y are independently 1 or 2.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ is fluorine.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: ;

^xa and ^ya are independently 1, 2, or 3; and

Keys marked with a "*" are attached to G ⁴ .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , , , , , , , , , , , , ,or and

Keys marked with a "*" are attached to G ⁴ .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , , , , , , , , , , , , , , , , ,or and

Keys marked with a "*" are attached to G ⁴ .

In another embodiment, the compound disclosed herein is a compound having formula (A) or a pharmaceutically acceptable salt thereof, wherein G ³ is: ; and the key marked with "*" is attached to G ⁴ .

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ⁴ is (C ₁ -C ₆ )alkylene.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ⁴ is -CH ₂ - or -CH ₂ CH ₂ -.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ⁴ is (C ₃ -C ₆ )cycloalkylene.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ⁴ is: or and

The key marked with "*" is attached to E.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ⁴ is: or and

The key marked with "*" is attached to E.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ⁴ is a direct bond.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein L is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or and

The key marked with "*" is attached to E.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein L is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or and

The key marked with "*" is attached to E.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein L is: , , and

The key marked with "*" is attached to E.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein L is: , , , ,or and

The key marked with "*" is attached to E.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein W is -C≡C-.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein W is a direct bond.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein ^R7 is halogen, ( _C1 - _C6 ) alkyl, cyano, or ( _C3 - _C6 ) cycloalkyl, wherein the ( _C1 - _C6 ) alkyl is optionally substituted with one, two or three halogens.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁷ is halogen or (C ₁ -C ₆ )alkyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁷ is fluoro or methyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁸ , R ⁹ , and R ¹⁰ are H.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halogen or (C ₁ -C ₆ )alkyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is fluoro or methyl.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁹ , and R ¹⁰ are hydrogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁹ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁹ is a halogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁹ is fluorine.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , and R ¹⁰ are hydrogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a halogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is fluorine.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , and R ⁹ are hydrogen.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are hydrogen.

In another embodiment, the compound disclosed herein is a compound having formula (IV) or a pharmaceutically acceptable salt thereof: (IV) where:

each R ¹² is independently fluorine;

n is 0, 1, or 2; and

R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are independently hydrogen, fluorine, or methyl

E is E-1; and

^G3 is as defined in the binding formula (I).

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: , , , , , , ,or and

G ⁴ is a direct bond, -CH ₂ - or -CH ₂ CH ₂ -.

In another embodiment, the compound disclosed herein is a compound having any one of formula (A) or (I)-(III) or a pharmaceutically acceptable salt thereof, wherein G ³ is: or .

In another embodiment, the compound disclosed herein is a compound having formula (V) or a pharmaceutically acceptable salt thereof, (V), where:

Each R ¹² is fluorine or hydroxy;

n is 0, 1, 2, or 3;

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or is absent;

^G3 is tetrahydronaphthyl; 4- to 6-membered heterocycloalkyl, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; 7- to 11-membered heterocycloalkyl-C(=O)-; or 7- to 11-membered heterocycloalkyl, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

^G4 is absent or is a cyclobutylene group;

R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are independently hydrogen, fluorine, methyl, or cyano;

^Ra is hydrogen, chlorine, methyl or fluorine;

R ^b is hydrogen, chlorine, methyl, or fluorine; and

R ^c is hydrogen or methyl.

In another embodiment, the compound disclosed herein is a compound having formula (V) or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: , , , , , , ,or .

In another embodiment, the compound disclosed herein is a compound having formula (V) or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , ,or .

In another embodiment, the compound disclosed herein is a compound having formula (V) or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , , , , , , , , , , , , , , , , ,or .

In another embodiment, the compound disclosed herein is any one or more of the compounds in Compound List 1 or a pharmaceutically acceptable salt thereof. Compound List 1

1-[1-[1-[[7-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-7-azaspiro[3.5]non-2-yl]methyl]-4-piperidinyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]prop-2-ynyl]-7-azaspiro[3.5]non-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-4-piperidinyl]indol-4-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[2-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-4-piperidinyl]-1-methyl-indol-6-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]methyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[(2S)-4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]oxathiapiperidin-2-yl]methyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[2-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]ethyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-(1-(3-((1-(3-(3-(3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4-fluorophenyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undec-9-yl)-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-(5-(7-((1-(5-(-3-(3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione;

(3-(1-(7-((1-(5-(3-(3-amino-6-(2-hydroxyphenyl)tetrahydropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-dioxotetrahydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate; or

1-(1-(2-((1-(5-(-3-(3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione.

In another embodiment, the compound disclosed herein is any one or more of the compounds in Compound List 2 or a pharmaceutically acceptable salt thereof. Compound List 2

1-[1-[1-[[7-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-7-azaspiro[3.5]non-2-yl]methyl]-4-piperidinyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-(1-(3-((1-(3-(3-(3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4-fluorophenyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undec-9-yl)-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

(3-(1-(7-((1-(5-(3-(3-amino-6-(2-hydroxyphenyl)tetrahydropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-dioxotetrahydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate; or

1-(1-(2-((1-(5-(-3-(3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione.

In another embodiment, the compound disclosed herein is any one or more of the compounds in Compound List 3 or a pharmaceutically acceptable salt thereof. Compound List 3

1-[2-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-4-piperidinyl]-1-methyl-indol-6-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]methyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[(2S)-4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]oxathiapiperidin-2-yl]methyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; or

1-(5-(7-((1-(5-(-3-(3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

In another embodiment, the compound disclosed herein is any one or more of the compounds in Compound List 4 or a pharmaceutically acceptable salt thereof. Compound List 4

1-[1-[(6r,9r)-4-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-1-oxa-4-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(1r,3r)-3-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[(2S)-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5r,8r)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[(2R)-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,8-dihydro-5H-imidazo[1,2-a]pyridine-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[(2S)-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[7-[[rel-(3aR,5r*,6aS)-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[7-[[rel-(3aR,5r*,6aS)-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[6-Fluoro-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[6-Fluoro-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-cyclopropyl-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-cyclopropyl-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile;

1-[3-methyl-1-[3-[[rel-(4R*)-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile;

1-[3-methyl-1-[3-[[rel-(4R*)-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5s,8s)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5s,8s)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[rel-(3S*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-Methyl-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione (Isomer 1)

1-[1-[(5s,8s)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5r,8r)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[rel-(3S*)-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[rel-(3R*)-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5r,8r)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]spiro[5.5]undecane-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5s,8s)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(3s,6s)-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(3r,6r)-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(1s,3s)-3-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]cyclobutyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-1-piperidinyl]benzonitrile;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[2-[3-cyclopropyl-5-(2,4-dioxohexahydroxypyrimidin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]-7-azaspiro[3.5]nonan-7-yl]methyl]-1-piperidinyl]benzonitrile;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[(1R,5S,6s)-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hex-6-yl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[(1R,5S,6s)-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hex-6-yl]methyl]-7-azaspiro[3.5]non-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(1s,3s)-3-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[(2R)-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-2-chloro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; or

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione.

In another embodiment, the compound disclosed herein is any one or more of the compounds in Compound List 5 or a pharmaceutically acceptable salt thereof. Compound List 5

1-[1-[1-[[7-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-7-azaspiro[3.5]non-2-yl]methyl]-4-piperidinyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]prop-2-ynyl]-7-azaspiro[3.5]non-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]non-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-4-piperidinyl]indol-4-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[2-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-4-piperidinyl]-1-methyl-indol-6-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]non-2-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]methyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[(2 S )-4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[2-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]ethyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[5-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione;

[3-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]-2,6-dioxo-hexahydropyrimidin-1-yl]methyl dihydrogen phosphate;

1-[1-[2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2-azaspiro[3.5]nonan-7-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(6 r ,9 r )-4-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-1-oxa-4-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(1 r ,3 r )-3-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[(2S)-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[(2 S )-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,8-dihydro- 5H -imidazo[1,2- a ]pyridine-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[[(2 R )-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[7-[[ rel -(3 aR ,5 r *,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3 a ,4,5,6,6 a -hexahydro-1 H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not yet confirmed];

1-[3-methyl-1-[7-[[( 3aR , 5s , 6aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a ,4,5,6,6a- hexahydro - 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[7-[[( 3aR , 5r , 6aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a ,4,5,6,6a- hexahydro - 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[7-[[ rel -(3 aR ,5 r *,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-

3,3a,4,5,6,6a-Hexahydro- 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not yet confirmed];

1-[3-methyl-1-[7-[[( 3aR , 5s , 6aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a ,4,5,6,6a- hexahydro - 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[7-[[( 3aR , 5r , 6aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a ,4,5,6,6a- hexahydro - 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[6-Fluoro-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not yet confirmed];

1-[6-Fluoro-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[6-Fluoro-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[6-Fluoro-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not yet confirmed];

1-[6-Fluoro-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[6-Fluoro-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-cyclopropyl-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not yet confirmed];

1-[3-cyclopropyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-cyclopropyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-Cyclopropyl-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not yet confirmed];

1-[3-cyclopropyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-cyclopropyl-1-[( 3S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[3-[[ rel -(4 R* )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not yet confirmed];

1-[3-methyl-1-[3-[[(4 R )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[3-[[(4 S )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile;

1-[3-methyl-1-[3-[[ rel -(4 R* )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not yet confirmed];

1-[3-methyl-1-[3-[[(4 R )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[3-[[(4 S )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[ rel -(3 S* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not yet confirmed];

1-[3-methyl-1-[( 3S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not yet confirmed];

1-[3-methyl-1-[( 3S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[ rel -(3 S* )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not yet confirmed];

1-[3-methyl-1-[( 3S )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[(3 R )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[ rel -(3 R* )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not yet confirmed];

1-[3-methyl-1-[( 3S )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[(3 R )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]spiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(3 s ,6 s )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(3 r ,6 r )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-1-piperidinyl]benzonitrile;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[2-[3-cyclopropyl-5-(2,4-dioxohexahydroxypyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonan-7-yl]methyl]-1-piperidinyl]benzonitrile;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[(1 R ,5 S ,6 S )-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[(1 R ,5 S ,6 S )-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(1 s ,3 s )-3-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[(2 R )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]non-2-yl]-6-fluoro-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-2-chloro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[8-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[1,2- a ]pyrimidin-3-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(2 S )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(2 R )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(2 S )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-

Diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(2 R )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]-3,8-

[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[(1 s ,4 s )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]cyclohexyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[(1 r ,4 r )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]cyclohexyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(3 r ,6 r )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxazolidin-9-azaspiro[5.5]undecane-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(1 r ,4 r )-4-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]cyclohexyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(1 s ,4 s )-4-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]cyclohexyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(1 r ,3 r )-3-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carbonyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[3-[3-cyclopropyl-5-(2,4-dioxohexahydroxypyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1,5-dioxa-9-azaspiro[5.5]undec-9-yl]methyl]-1-piperidinyl]benzonitrile;

1-[1-[3-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl) pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl) pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[7-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[( 3S )-1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]pyrrolidin-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(3 R )-1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]pyrrolidin-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-ethyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[7-[[ rac -(2 S ,3 aR ,6 aR )-5-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-2,3,3 a ,4,6,6 a -hexahydrofuro[2,3- c ]pyrrol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[3-methyl-1-[7-[[ rac -(2 S ,3 aR ,6 aR )-5-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-2,3,3 a ,4,6,6 a -hexahydrofuro[2,3- c ]pyrrol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(3-chloro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxy-3-methyl-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[( 3S )-4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]-3-methyl-piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[( 3S )-4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]-3-methyl-piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-6-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[2-[4-[2-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]phenoxy]ethyl]piperimide-1-yl]ethyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[2-[4-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]piperimide-1-yl]ethyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]indol-4-yl]hexahydropyrimidine-2,4-dione;

1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[4-[[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]methyl]piperidin-1-carbonyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[4-[[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]phenyl]methyl]piperidin-1-carbonyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[3-[4-[[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]methyl]piperidin-1-yl]-3-oxopropyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione;

1-[1-[1-[3-[4-[[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]methyl]piperidin-1-yl]-3-oxo-propyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is any one or more of the compounds in Compound List 1, Compound List 2, Compound List 3, Compound List 4, and/or Compound List 5, or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound disclosed herein is: , or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients.

The compounds of the present disclosure may possess one or more chiral centers, and it will be recognized that such compounds may be prepared, isolated and/or supplied in the presence or absence of one or more of the other possible mirror image isomers and/or non-mirror image isomers of such compounds, or such isomers may be provided in any relative ratio. Preparation of mirror image isomer-enriched or mirror image isomer-pure and/or non-mirror image isomer-enriched or non-mirror image isomer-pure compounds can be performed by standard techniques of organic chemistry well known in the art, such as by synthesis from mirror image isomer-enriched or mirror image isomer-pure starting materials, and/or by using appropriate mirror image isomer-enriched or mirror image isomer-pure catalysts during synthesis, and/or by resolving racemic or partially enriched stereoisomer mixtures (e.g., by chiral chromatography). The scope of the present disclosure includes mixtures of stereoisomers as well as purified mirror image isomers or mirror image isomer/non-mirror image isomer-enriched mixtures. It should be understood that the present disclosure includes all combinations and subsets of the specific groups defined above.

In one embodiment, the present disclosure provides a composition comprising a compound of the present disclosure and, if desired, one or more of other stereoisomer forms of the compound (if any), wherein the compound of the present disclosure is present in the composition at a non-mirror isomer excess (%de) of ≥ 55%.

In another embodiment, the %de in the above composition is ≥ 90%.

In another embodiment, the %de in the above composition is ≥ 95%.

In another embodiment, the %de in the above composition is ≥ 98%.

In another embodiment, the %de in the above composition is ≥ 99%.

In another embodiment, the present disclosure provides a composition comprising a compound of the present disclosure and, if desired, one or more of other stereoisomer forms of the compound (if any), wherein the compound of the present disclosure is present in the composition with a stereoisomer excess (%ee) of ≥ 55%.

In another embodiment, the %ee in the above composition is ≥ 90%.

In another embodiment, the %ee in the above composition is ≥ 95%.

In another embodiment, the %ee in the above composition is ≥ 98%.

In another embodiment, the %ee in the above composition is ≥ 99%.

In another embodiment, the present disclosure provides a composition comprising a compound of the present disclosure and, if necessary, one or more of other stereoisomeric forms of the compound (if any), wherein the compound of the present disclosure is present in the composition with a mirror image isomer excess (%ee) of ≥ 90% and a non-mirror image isomer excess (%de) of ≥ 90%.

In another embodiment, the present disclosure provides a composition comprising a compound of the present disclosure and, if necessary, one or more of other stereoisomers of the compound (if any), wherein the %ee and %de of the compound of the present disclosure take any combination of values, for example, %ee is ≤ 5% and %de is ≥ 80%; %ee is ≤ 5% and %de is ≥ 90%; %ee is ≤ 5% and %de is ≥ 95%; %ee is ≤ 5% and %de is ≥ 98%; %ee is ≥ 95% and %de is ≥ 95%; %ee is ≥ 98% and %de is ≥ 98%; or %ee is ≥ 99% and %de is ≥ 99%.

The compounds of the present disclosure may be prepared, used or supplied in an amorphous form, a crystalline form, or a semi-crystalline form, and any given compound of the present disclosure may be formed into more than one crystalline/polymorphic form, including hydrated (e.g., hemihydrate, monohydrate, dihydrate, trihydrate or other stoichiometric hydrates) and/or solvated forms. The present disclosure encompasses any and all such solid forms of the compounds of the present disclosure.

The present disclosure encompasses the preparation and use of salts of the compounds of the present disclosure. Pharmaceutically acceptable salts include, among others, those described in Berge, J. Pharm. Sci., 66, 1-19, (1977) or those listed in Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition , ed. , PH Stahl and CG Wermuth Stahl/Wermuth: Wiley- VCH/VHCA (2011) (see http://www.wiley.com/WileyCDA/WileyTitle/productCd-3906390519.html).

Suitable pharmaceutically acceptable salts may include acid or base addition salts.

Such base addition salts can be formed by reacting a compound of the present disclosure with a suitable base, optionally in a suitable solvent such as an organic solvent, to give a salt, which can be isolated by various methods including crystallization and filtration.

Such acid addition salts can be formed by reacting a compound of the present disclosure with a suitable acid, optionally in a suitable solvent such as an organic solvent, to give a salt, which can be isolated by various methods including crystallization and filtration.

Salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure. If a base compound of the compounds of the present disclosure is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic base. Similarly, if a compound of the present disclosure containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic acid.

It should be understood that if the compounds of the present disclosure contain two or more basic moieties, the stoichiometry of the salt formation may include 1, 2 or more equivalents of acid. Such salts will contain 1, 2 or more acid counterions, such as dihydrochlorides.

Stoichiometric and non-stoichiometric forms of pharmaceutically acceptable salts of the compounds of the present disclosure are included within the scope of the present disclosure, including substoichiometric salts, for example, where the counter ion contains more than one acidic proton.

Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, hydrogen sulfate, hydrogen tartrate, butyrate, calcium edetate, camphorate, camphorsulfonate, and the like. ulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclohexylamine sulfonate, digluconate Salt, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (edetate), edetate (ethylenediaminetetraacetic acid salt), edetate (lauryl sulfate), ethane-1,2-disulfonate (ethanedisulfonate), ethanesulfonate (esylate), formate, fumarate, galactosarate (mucate), gentian Acid salts (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamine, glutarate, glycerophosphorate, glycolate, hexylresorcinol, hippurate, hydrabamine ( N , N' -di(dehydroisocyanate)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, apple acid salt, maleate, malonic acid salt, mandelate, methanesulfonate (mesylate), methyl sulfate, mucic acid salt, naphthalene-1,5-disulfonate (naphthalene disulfonate), naphthalene-2-sulfonate (naphthalene sulfonate), niacin, nitrate, oleate, palmitic acid salt, p-aminobenzene Sulfonates, para-aminosalicylate, pamoate (bishydroxynaphthoate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (toluenesulfonate), pyroglutamine, pyruvate, salicylate, sebacate, stearate, hydroxyacetate, succinate, sulfamic acid, sulfate, tannate, tartrate, theocyanate (8-chlorotheoate), thiocyanate, triethyl iodide, undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), arginine, phenethylamine ( N -benzylphenethylamine), benzathine ( N , N' -dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidin, lithium, lysine, magnesium, meglumine ( N -methylglucamine), piperidine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine, tromethamine (tris(hydroxymethyl)aminomethane), and zinc.

The disclosure also includes isotopically labeled compounds, which are identical to the compounds of the disclosure except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I.

Compounds of the present disclosure containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present disclosure. Isotope-labeled compounds of the present disclosure (e.g., those into which radioactive isotopes such as ³ H, ¹⁴ C are incorporated) can be used in drug and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly useful because of their ease of preparation and detectability. ¹¹ C and ¹⁸ F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵ I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all of which can be used for brain imaging. In addition, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be used in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by carrying out the procedures disclosed in the following schemes and/or in the Examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical art). Excipients are acceptable in the sense that they are compatible with the other ingredients of the formulation and are not harmful to the recipient thereof (i.e., the patient). II. Methods of Use

It is known that SMARCA4 mutations may be present in certain tumor/cancer types including lung, liver, colon, skin, bladder, cervical and ovarian tumors/cancers, and SMARCA2 is essential for the growth of tumors containing such SMARCA4 mutations. Therefore, the compounds disclosed herein may have value as anticancer/antitumor agents, particularly against cancer/tumor types known to carry SMARCA4 mutations, such as lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, liver cancer, cervical cancer and ovarian cancer.

The compounds disclosed herein may also be of value against cancer types/tumors that are sensitive to degradation of SMARCA2, such as lung cancer, liver cancer, colorectal cancer, skin cancer, bladder cancer, hepatic cancer, cervical cancer, and ovarian cancer.

The compounds disclosed herein may also have value as antitumor agents, in particular, as selective inhibitors of mammalian cancer cell proliferation, survival, activity, dissemination and invasion, thereby inhibiting tumor growth and survival and inhibiting metastatic tumor growth. In particular, the compounds disclosed herein may have value as antiproliferative and anti-invasive agents in the inhibition and/or treatment of solid tumor diseases.

The compounds disclosed herein can also be used to prevent or treat those tumors that are sensitive to the degradation of SMARCA2 and are involved in signaling steps that lead to tumor cell proliferation and survival and the migration ability and invasiveness that allow tumor cell metastasis. In addition, the compounds disclosed herein can be used to prevent or treat those tumors that are mediated solely or in part by the degradation of SMARCA2, that is, the compounds can be used to produce SMARCA2 degradation in subjects (e.g., warm-blooded animals, such as humans) in need of such treatment.

In one embodiment, the present disclosure provides a compound or a pharmaceutical composition thereof for use in the treatment of cancer.

In another embodiment, the present disclosure provides a compound or a pharmaceutical composition thereof for use in the treatment of solid tumors.

In another embodiment, the present disclosure provides a compound or a pharmaceutical composition thereof for use in the treatment of SMARCA2-sensitive tumor types.

In another embodiment, the present disclosure provides a compound or a pharmaceutical composition thereof for use in the treatment of a tumor type carrying a SMARCA4 mutation.

In another embodiment, the present disclosure provides a compound or a pharmaceutical composition thereof for use in the treatment of lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in the treatment of SMARCA4-mutant cancer.

The amount of a compound of the disclosure that is combined with one or more excipients to produce a single dosage form will necessarily vary, depending upon the subject to be treated and the particular route of administration.

The size of the dose of the disclosed compounds to achieve therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the disease condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known medical principles.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use as a medicament.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in therapy.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in a method of treating a human or animal body by therapy.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in producing an antiproliferative effect in, for example, a warm-blooded animal such as a human.

In another embodiment, the present disclosure provides the use of the compounds of the present disclosure or their pharmaceutical compositions for the manufacture of a medicament for producing an antiproliferative effect in, for example, warm-blooded animals such as humans.

In another embodiment, the present disclosure provides a method for producing an anti-proliferative effect in a warm-blooded animal such as a human in need of such an effect, the method comprising administering to the animal an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof.

In another embodiment, the present disclosure provides a compound or a pharmaceutical composition thereof of the present disclosure for use as an anti-invasive agent for inhibiting and/or treating solid tumor diseases in warm-blooded animals such as humans.

In another embodiment, the present disclosure provides the use of the compound of the present disclosure or its pharmaceutical composition for the manufacture of a medicament for use as an anti-invasive agent for inhibiting and/or treating solid tumor diseases in warm-blooded animals such as humans.

In another embodiment, the present disclosure provides a method for producing an anti-invasive effect in a warm-blooded animal such as a human in need of an anti-invasive effect by inhibiting and/or treating solid tumor diseases, the method comprising administering to the animal an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in the prevention or treatment of cancer in, for example, warm-blooded animals such as humans.

In another embodiment, the present disclosure provides the use of the compound of the present disclosure or its pharmaceutical composition for the manufacture of a medicament for preventing or treating cancer in, for example, warm-blooded animals such as humans.

In another embodiment, the present disclosure provides a method for preventing or treating cancer in a warm-blooded animal such as a human in need of such treatment, the method comprising administering to the animal an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in the prevention or treatment of one or more solid tumors in, for example, warm-blooded animals such as humans.

In another embodiment, the present disclosure provides the use of the compound of the present disclosure or its pharmaceutical composition for the manufacture of a medicament for preventing or treating one or more solid tumors in, for example, warm-blooded animals such as humans.

In another embodiment, the present disclosure provides a method for preventing or treating one or more solid tumors in a warm-blooded animal such as a human in need of such treatment, the method comprising administering to the animal an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in the prevention or treatment of tumor types that are sensitive to degradation of SMARCA2.

In another embodiment, the present disclosure provides the use of the compounds of the present disclosure or their pharmaceutical compositions for the manufacture of a medicament for preventing or treating those tumor types that are sensitive to the degradation of SMARCA2.

In another embodiment, the present disclosure provides a method for preventing or treating those tumor types that are sensitive to the degradation of SMARCA2 in warm-blooded animals such as humans in need of such treatment, the method comprising administering to the animal an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof. Tumor types that are sensitive to the degradation of SMARCA2 include, for example, lung tumors, liver tumors, large intestine tumors, skin tumors, bladder tumors, cervical tumors, and ovarian tumors.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in providing degradation of SMARCA2 in, for example, warm-blooded animals such as humans.

In another embodiment, the present disclosure provides the use of the compounds of the present disclosure or their pharmaceutical compositions for the manufacture of a medicament for providing a degradation effect on SMARCA2, for example in warm-blooded animals such as humans.

In another embodiment, the present disclosure provides a method for providing a degradation effect on SMARCA2 in a warm-blooded animal such as a human in need of such an effect, the method comprising administering to the animal an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in providing a selective degradation effect on SMARCA2, for example in warm-blooded animals such as humans.

In another embodiment, the present disclosure provides the use of the compounds of the present disclosure or their pharmaceutical compositions for the manufacture of a medicament for providing a selective degradation effect on SMARCA2, for example in warm-blooded animals such as humans.

In another embodiment, the disclosure provides a method for providing selective degradation of SMARCA2 in a warm-blooded animal such as a human in need of such an effect, the method comprising administering an effective amount of a compound of the disclosure or a pharmaceutical composition thereof. SMARCA2 has been found to be essential for the growth of tumors containing SMARCA4 mutations, and certain tumor/cancer types are associated with such SMARCA4 mutations.

In another embodiment, the present disclosure provides a compound or a pharmaceutical composition thereof for use in the treatment of a tumor type carrying a SMARCA4 mutation.

In another embodiment, the present disclosure provides the use of the compounds of the present disclosure or their pharmaceutical compositions for the manufacture of medicaments for preventing or treating tumor types carrying SMARCA4 mutations.

In another embodiment, the present disclosure provides a method for preventing or treating those tumor types carrying SMARCA4 mutations in warm-blooded animals such as humans in need of such prevention or treatment, the method comprising administering to the animal an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof. Tumor types known to carry SMARCA4 mutations include lung tumors, liver tumors, large intestine tumors, skin tumors, bladder tumors, cervical tumors, and ovarian tumors, such as lung cancer, liver cancer, large intestine cancer, skin cancer, bladder cancer, cervical cancer, and ovarian cancer.

In another embodiment, the present disclosure provides a compound or a pharmaceutical composition thereof for use in the treatment of lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

In another embodiment, the present disclosure provides the use of the compound or its pharmaceutical composition of the present disclosure for the manufacture of a medicament for treating lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

In another embodiment, the present disclosure provides a method for treating lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer in a warm-blooded animal such as a human in need of such treatment, the method comprising administering to the animal an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof.

In another embodiment of the present invention referring to cancer, the cancer is lung cancer.

In another embodiment of the present invention relating to cancer, the cancer is liver cancer.

In another embodiment of the present invention relating to cancer, the cancer is colorectal cancer.

In another embodiment herein referring to cancer, the cancer is skin cancer.

In another embodiment herein referring to cancer, the cancer is bladder cancer.

In another embodiment of the invention relating to cancer, the cancer is cervical cancer.

In another embodiment herein referring to cancer, the cancer is ovarian cancer.

In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition thereof for use in the treatment of SMARCA4-mutant cancer.

In another embodiment, the present disclosure provides use of the compounds of the present disclosure or their pharmaceutical compositions for the manufacture of a medicament for treating SMARCA4-mutant cancer.

In another embodiment, the present disclosure provides a method for treating SMARCA4-mutant cancer in a warm-blooded animal such as a human in need of such treatment, the method comprising administering an effective amount of a compound of the present disclosure or a pharmaceutical composition thereof. III.      Definitions

As used herein, the term "alkyl" refers to a straight or branched saturated hydrocarbon moiety having a specified number of carbon atoms. The term "(C ₁ -C ₆ )alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl, tertiary butyl, pentyl, and hexyl.

As used herein, the term "alkylene" alone or as part of another group refers to the divalent form of an alkyl group having the specified number of carbon atoms. For example, the term "(C ₁ -C ₆ )alkylene" refers to an alkylene moiety containing from 1 to 6 carbon atoms. The alkylene group may be optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and (C ₁ -C ₆ )alkoxy. Exemplary alkylene groups include, but are not limited to, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ (CH ₂ ) ₂ CH ₂ -, and -CH ₂ (CH ₂ ) ₃ CH ₂ -.

"Alkoxy" refers to a group containing an alkyl group as defined above attached via an oxygen linking atom. The term "(C ₁ -C ₆ )alkoxy" refers to a straight or branched chain alkyl group having at least 1 and at most 6 carbon atoms attached via an oxygen linking atom. Exemplary "(C ₁ -C ₆ )alkoxy" groups useful in the present specification include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, di-butoxy, iso-butoxy, and tertiary butoxy.

As used herein, the term "cycloalkylene" alone or as part of another group refers to the divalent form of a cycloalkyl group having the specified number of carbon atoms in the ring. For example, the term "(C ₃ -C ₆ )cycloalkylene" refers to a cycloalkylene moiety containing from 3 to 6 carbon atoms in the ring. The cycloalkylene group may be optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, cyano, and (C ₁ -C ₆ )alkoxy. Exemplary cycloalkylene groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl: , , ,and .

As used herein, the term "heterocycloalkyl" alone or as part of another group refers to a group or moiety comprising a non-aromatic monovalent, monocyclic, bicyclic, or spirocyclic group, which is saturated or partially unsaturated, having 4 to 11 ring atoms including carbon and one or two heteroatoms independently selected from oxygen, sulfur and/or nitrogen.

As used herein, the term "4- to 6-membered heterocycloalkyl" alone or as part of another group refers to a divalent form of a monocyclic or bicyclic heterocycloalkyl having 4, 5, or 6 ring atoms, including carbon and one or two heteroatoms independently selected from oxygen, sulfur, and/or nitrogen. The 4- to 6-membered heterocycloalkyl may be optionally substituted with one, two, or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₁ -C ₆ )alkoxy. In one embodiment, the 4- to 6-membered heterocycloalkyl is a divalent form of an optionally substituted azacyclobutane. In another embodiment, the 4- to 6-membered heterocycloalkyl is a divalent form of an optionally substituted piperidinyl. In another embodiment, the heterocycloalkylene is a divalent form of an optionally substituted piperidine radical. Exemplary heterocycloalkylene radicals include, but are not limited to: , , , ,and .

As used herein, the term "7- to 11-membered heterocycloalkyl" alone or as part of another group refers to a divalent form of a bicyclic (including bridged bicyclic), fused ring system, or spirocyclic heterocycloalkyl having 7, 8, 9, 10, or 11 ring atoms comprising carbon and one, two, or three heteroatoms independently selected from oxygen, sulfur, and/or nitrogen. Exemplary 7- to 11-membered heterocycloalkyls include, but are not limited to: , , , , , , , , , , ,and .

"Aryl" refers to an optionally substituted monocyclic, fused bicyclic, or fused tricyclic group having 6 to 14 carbon atoms and having at least one aromatic ring that conforms to Huckel's rule. Examples of "aryl" are phenyl, naphthyl, indenyl, dihydroindenyl, anthracenyl, phenanthrenyl, and the like.

"Heteroaryl" means a radical or moiety comprising an aromatic monovalent monocyclic or bicyclic radical containing 5 to 10 ring atoms including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term also encompasses bicyclic heterocyclo-aryl compounds containing an aryl ring portion fused to a heterocycloalkyl ring portion containing 5 to 10 ring atoms including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or bicyclic heterocyclo-heteroaryl compounds containing a heteroaryl ring portion fused to a heterocycloalkyl ring portion containing 5 to 10 ring atoms including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups that can be used in the present specification include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, triazolyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxolyl, benzothiophenyl, indolyl, indolyl, isoindolyl, di ... indolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, quinolinyl, octinyl, phthalinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 5-membered "heteroaryl" include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl. Examples of 6-membered "heteroaryl" include oxo-pyridyl, pyridinyl, pyrimidinyl, pyrimidinyl, and pyrimidinyl. Examples of 6,6-fused "heteroaryl" include quinolyl, isoquinolyl, quinoxalyl, octinyl, phthalidinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of the 6,5-fused "heteroaryl" include benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, indolyl, indolyl, isoindolyl, and indazolyl.

As used herein, the term "5- to 10-membered heteroaryl" alone or as part of another group refers to the divalent form of "heteroaryl". Examples of "5- to 10-membered heteroaryl" include: , ,and .

As used herein, "5- or 6-membered heteroaryl" refers to a group or moiety containing an aromatic monovalent monocyclic group containing 5 or 6 ring atoms, which include at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The selected 5-membered heteroaryl contains one nitrogen, oxygen or sulfur ring heteroatom and optionally contains 1, 2 or 3 additional nitrogen ring atoms. The selected 6-membered heteroaryl contains 1, 2 or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or 6-membered heteroaryl groups that may be used in the present specification include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, and triazinyl.

The terms "halogen" and "halogenated" refer to fluoro, chloro, bromo, or iodo substituents.

As used herein, "hydroxy" alone or as part of a group refers to the group -OH.

The term "cyano" as used herein alone or as part of a group refers to the group -CN.

As used herein, the term "optionally" means that one or more subsequently described events may or may not occur, and includes both one or more events that occur and one or more events that do not occur. Thus, the use of the term "optionally" includes both the case where the feature is present and also the case where the feature is not present. For example, "methyl optionally substituted with one or more F" includes _-CH3 , _-CH2F , _-CHF2 , and _-CF3 .

In the present disclosure, a group such as "A-B-C", where B is defined as a "direct bond", is equivalent to "A-C", i.e., where A and C are directly linked to each other via a covalent bond.

The term "substituted" means that one or more hydrogens on the designated atom or group are replaced with one or more indicated substituents, provided that any atom or atoms bearing such substituents retain their allowed valencies, wherein the skilled artisan understands that the standard valencies of carbon, nitrogen, and oxygen are 4, 3, and 2, respectively.

"Pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

As used herein, the term "treating" refers to alleviating a specified disorder previously suffered from or diagnosed in a patient or subject, eliminating or reducing one or more symptoms of the disorder, slowing or eliminating the progression of the disorder, and delaying the recurrence of the disorder.

The term "effective amount" means that amount of a drug or drug preparation that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for example, by a researcher or clinician.

The term "therapeutically effective amount" means any amount that results in treatment, cure, or improvement of a disease, disorder, or side effect, or a reduction in the rate of development of a disease or disorder, compared to a corresponding subject not receiving the amount. The term also includes within its scope amounts that are effective in enhancing normal physiological function. For use in therapy, a therapeutically effective amount of the compounds of the present disclosure may be administered as a raw chemical. In addition, the active ingredient may be present as a pharmaceutical composition.

The compounds disclosed herein may have asymmetric centers and may therefore give rise to mirror image isomers, non-mirror image isomers and other stereoisomeric forms. The disclosure encompasses the preparation and use of all such possible stereoisomeric forms as well as their racemic and resolved forms and mixtures thereof. According to the disclosure, mirror image isomers and non-mirror image isomers may be separated according to methods known in the art. When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, and unless otherwise stated, they include both E and Z geometric isomers. All tautomeric isomers are also encompassed in the disclosure.

As used herein, the term "stereoisomers" is a general term for all isomers of a single molecule that differ only in the spatial orientation of their atoms. It includes mirror image isomers, atropisomers, and isomers of compounds with more than one chiral center that are not mirror images of each other (non-mirror image isomers).

The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

The terms "mirror image isomer" and "mirror image isomer" refer to molecules that cannot be superimposed on their mirror images and are therefore optically active, wherein the mirror image isomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction. Mirror image isomers can be separated by chiral chromatography using methods well known in the art.

The term "racemic" or "racemate" refers to a mixture of equal parts of mirror image isomers and the mixture is optically inert.

The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, such as R or S.

Unless otherwise indicated, stereochemical terminology and conventions used in this specification are intended to be consistent with those described in Pure & Appl. Chem 68 : 2193 (1996).

The term "mirror image excess" or "ee" refers to a measure of how much of one mirror image isomer is present compared to another. For a mixture of an R mirror image isomer and an S mirror image isomer, the mirror image excess percent is defined as │ R - S │*100, where R and S are the respective mole or weight fractions of the mirror image isomers in the mixture such that R + S = 1. In the case of a known optical rotation of a chiral substance, the mirror image excess percent is defined as ([α] _obs /[α] _max )*100, where [α] _obs is the optical rotation of the mirror image isomer mixture and [α] _max is the optical rotation of the pure mirror image isomer. Various analytical techniques, including NMR spectroscopy, chiral column chromatography, or polarimetry, can be used to determine the excess of mirror image isomers. Racemic compounds of the present disclosure can be separated by chiral HPLC, for example, using a CHIRALPAK IE column. In one embodiment, the ee of the compounds of the present disclosure is about 70% or greater, such as about 80% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, or about 99% or greater.

The term "enantiomerically pure" or "enantiopure" refers to a sample of a chiral substance in which all molecules (within the limits of detection) have the same chirality.

The term "enantiomerically enriched" or "enantioenriched" refers to a sample of a chiral material having an enantiomer ratio greater than 50:50. A compound that is enantiomerically enriched can be enantiomerically pure. Certain compounds of the present disclosure are enantiomerically enriched.

The term "non-mirror image isomer excess" or "de" refers to a measure of how much of one non-mirror image isomer is present compared to another non-mirror image isomer and is defined similarly to the mirror image isomer excess. Non-mirror image isomer excess can be determined using a variety of analytical techniques, including NMR spectroscopy and column chromatography.

The term "non-mirror image-isomer enriched" refers to a sample of a chiral material having a non-mirror image-isomer ratio greater than 50:50. A non-mirror image-isomer enriched compound may be non-mirror image-isomer pure. Certain compounds disclosed herein are non-mirror image-isomer enriched.

As used herein, the term "about" includes ±10% of the stated number. Thus, "about 10" means 9 to 11. IV. Specific Implementation Methods

The present disclosure also provides the following specific implementation methods.

Embodiment 1. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or

X ³ does not exist;

L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

G ² is (C ₁ -C ₆ )alkylene or a direct bond;

^G3 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )alkoxy; a cyano group; or a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or a cyano group;

G ⁴ is (C ₁ -C ₆ )alkylene or a direct bond;

W series -C≡C-, direct bond;

^R7 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl;

R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which is optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; and

R ¹⁰ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C ₃ -C ₆ )cycloalkyl.

Embodiment 2. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or

X ³ does not exist;

L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

G ² is (C ₁ -C ₆ )alkylene or a direct bond;

^G3 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )alkoxy; a cyano group; a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or a 5- to 10-membered heteroaryl group;

G ⁴ is (C ₁ -C ₆ )alkylene, (C ₃ -C ₆ )cycloalkylene, or a direct bond;

W is -C≡C- or direct key;

^R7 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl;

R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which is optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; and

R ¹⁰ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C ₃ -C ₆ )cycloalkyl.

Embodiment 3. The compound according to Embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, having formula (II): (II).

Embodiment 4. The compound or a pharmaceutically acceptable salt thereof as described in claim 1 or 2, having formula (III): (III).

Embodiment 5. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-4, wherein E is E-1.

Embodiment 6. The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is hydrogen.

Embodiment 7. The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is (C ₁ -C ₆ ) alkyl, which is optionally substituted with one, two or three substituents independently selected from halogen or cyano.

Embodiment 8. The compound according to Embodiment 7 or a pharmaceutically acceptable salt thereof, wherein R ^5a is methyl.

Embodiment 9. The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is (C ₃ -C ₆ )cycloalkyl.

Embodiment 10. The compound according to Embodiment 9 or a pharmaceutically acceptable salt thereof, wherein R ^5a is cyclopropyl.

Embodiment 11. The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ )alkyl.

Embodiment 12. The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is cyano.

Embodiment 13. The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is aryl, which is optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ ) alkyl.

Embodiment 14. The compound according to Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ )alkyl.

Embodiment 15. The compound according to any one of Embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, wherein E is E-2.

Embodiment 16. The compound according to any one of Embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, wherein E is E-3.

Embodiment 17. The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 16, wherein:

R ¹ series: and

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy.

Embodiment 18. The compound according to Embodiment 17 or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl.

Embodiment 19. The compound according to Embodiment 18 or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, fluorine, or methyl.

Embodiment 20. The compound according to any one of Embodiments 17 to 19 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen.

Embodiment 21. The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 16, wherein:

R ² series: and

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy.

Embodiment 22. The compound according to Embodiment 21 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl.

Embodiment 23. The compound according to Embodiment 22 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, fluorine, or methyl.

Embodiment 24. The compound according to any one of Embodiments 21 to 23 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen.

Embodiment 25. The compound according to any one of Embodiments 1 to 24 or a pharmaceutically acceptable salt thereof, wherein X ¹ is CR ³ .

Embodiment 26. The compound according to Embodiment 25 or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

Embodiment 27. The compound according to Embodiment 25 or a pharmaceutically acceptable salt thereof, wherein R ³ is a halogen.

Embodiment 28. The compound according to Embodiment 25 or a pharmaceutically acceptable salt thereof, wherein R ³ is (C ₁ -C ₆ ) alkyl.

Embodiment 29. The compound according to any one of Embodiments 1-24 or a pharmaceutically acceptable salt thereof, wherein X ¹ is N.

Embodiment 30. The compound according to any one of Embodiments 1 to 29 or a pharmaceutically acceptable salt thereof, wherein X ² is CR ⁴ .

Embodiment 31. The compound according to Embodiment 30 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

Embodiment 32. The compound according to Embodiment 30 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a halogen.

Embodiment 33. The compound according to Embodiment 30 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is (C ₁ -C ₆ ) alkyl.

Embodiment 34. The compound according to any one of Embodiments 1-29 or a pharmaceutically acceptable salt thereof, wherein X ² is N.

Embodiment 35. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 5, wherein E-1 is: , , , , , , , , , , , ,or .

Embodiment 36. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 15, wherein E-2 is: .

Embodiment 37. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 16, wherein E-3 is: .

Embodiment 38. The compound according to any one of Embodiments 1 to 37 or a pharmaceutically acceptable salt thereof, wherein ^G1 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, or cyano.

Embodiment 39. The compound according to Embodiment 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

n is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to G ² .

Embodiment 40. The compound according to Embodiment 39 or a pharmaceutically acceptable salt thereof, wherein each R ¹² is independently fluoro, methyl, methoxy, cyano, or -CHF ₂ ; and n is 0, 1, or 2.

Embodiment 41. The compound according to Embodiment 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : , , ,or and

Keys marked with a "*" are attached to G ² .

Embodiment 42. The compound according to Embodiment 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

X ⁴ series -O-;

each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; and

Keys marked with a "*" are attached to G ² .

Embodiment 43. The compound according to Embodiment 42 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : or and

Keys marked with a "*" are attached to G ² .

Embodiment 44. The compound according to Embodiment 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : and

Keys marked with a "*" are attached to G ² .

Embodiment 45. The compound according to any one of Embodiments 1-37 or a pharmaceutically acceptable salt thereof, wherein ^G1 is a 7- to 11-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, or cyano.

Embodiment 46. The compound according to Embodiment 45 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹³ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

o is 0, 1, 2, or 3;

p, q, r, and s are independently 1, 2, or 3; and

Keys marked with a "*" are attached to G ² .

Embodiment 47. The compound according to Embodiment 46 or a pharmaceutically acceptable salt thereof, wherein:

p and q are 1;

r is 1 or 2;

s is 1 or 2; and

R ¹³ is a halogen.

Embodiment 48. The compound according to Embodiment 46 or a pharmaceutically acceptable salt thereof, wherein R ¹³ is fluorine and o is 0, 1, or 2.

Embodiment 49. The compound according to Embodiment 46 or a pharmaceutically acceptable salt thereof, wherein ^G1 is: and

Keys marked with a "*" are attached to G ² .

Embodiment 50. The compound according to Embodiment 45 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

a is 0 or 1;

b is 0 or 1; and

Keys marked with a "*" are attached to G ² .

Embodiment 51. The compound according to Embodiment 50 or a pharmaceutically acceptable salt thereof, wherein ^G1 is: or and

Keys marked with a "*" are attached to G ² .

Embodiment 52. The compound according to any one of Embodiments 1-49 or a pharmaceutically acceptable salt thereof, wherein ^G2 is a direct bond.

Embodiment 53. The compound according to any one of Embodiments 1 to 49 or a pharmaceutically acceptable salt thereof, wherein G ² is (C ₁ -C ₆ )alkylene.

Embodiment 54. The compound according to Embodiment 53 or a pharmaceutically acceptable salt thereof, wherein G ² is -CH ₂ -.

Embodiment 55. The compound according to any one of Embodiments 1-54 or a pharmaceutically acceptable salt thereof, wherein G ³ is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano.

Embodiment 56. The compound according to Embodiment 55 or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: , , , ,or ;

Each R ¹⁴ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

t is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to ^G4 .

Embodiment 57. The compound according to Embodiment 56 or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is fluoro or methyl and t is 0 or 1.

Embodiment 58. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 56, wherein ^G3 is: , , ,or .

Embodiment 59. The compound according to any one of Embodiments 1-54 or a pharmaceutically acceptable salt thereof, wherein G ³ is a 7- to 11-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano.

Embodiment 60. The compound according to Embodiment 59 or a pharmaceutically acceptable salt thereof, wherein ^G3 is: and

Keys marked with a "*" are attached to ^G4 .

Embodiment 61. The compound according to Embodiment 59 or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: ;

Each R ¹⁵ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

u is 0, 1, 2, or 3;

v, w, x, and y are independently 1, 2, or 3; and

Keys marked with a "*" are attached to ^G4 .

Embodiment 62. The compound according to Embodiment 61 or a pharmaceutically acceptable salt thereof, wherein v, w, x, and y are independently 1 or 2.

Embodiment 63. The compound according to Embodiment 59 or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: ;

^xa and ^ya are independently 1, 2, or 3; and

Keys marked with a "*" are attached to ^G4 .

Embodiment 64. The compound according to Embodiment 59 or a pharmaceutically acceptable salt thereof, wherein ^G3 is: , , , , , , , , , , , , , ,or ; and the key marked with "*" is attached to G ⁴ .

Embodiment 65. The compound according to any one of Embodiments 1 to 64 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is (C ₁ -C ₆ )alkylene.

Embodiment 66. The compound according to Embodiment 65 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is -CH ₂ - or -CH ₂ CH ₂ -.

Embodiment 67. The compound according to any one of Embodiments 2 to 64 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is (C ₃ -C ₆ )cycloalkylene.

Embodiment 68. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 67, wherein G ⁴ is: or .

Embodiment 69. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments 1-64, wherein G ⁴ is a direct bond.

Embodiment 70. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments 1-37, wherein L is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; and the key marked with "*" is attached to E.

Embodiment 71. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments 2-37, wherein L is: , , and

The key marked with "*" is attached to E.

Embodiment 72. The compound according to any one of Embodiments 1-71 or a pharmaceutically acceptable salt thereof, wherein W is -C≡C-.

Embodiment 73. The compound according to any one of Embodiments 1-71 or a pharmaceutically acceptable salt thereof, wherein W is a direct bond.

Embodiment 74. The compound according to any one of Embodiments 1 to 73 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Embodiment 75. The compound according to Embodiment 74 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is halogen or (C ₁ -C ₆ ) alkyl.

Embodiment 76. The compound according to Embodiment 75 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is fluoro or methyl.

Embodiment 77. The compound according to any one of Embodiments 74-76 or a pharmaceutically acceptable salt thereof, wherein R ⁸ , R ⁹ , and R ¹⁰ are H.

Embodiment 78. The compound according to any one of Embodiments 1 to 76 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Embodiment 79. The compound according to Embodiment 78 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halogen or (C ₁ -C ₆ ) alkyl.

Embodiment 80. The compound according to Embodiment 79 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is fluoro or methyl.

Embodiment 81. The compound according to any one of Embodiments 78 to 80 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁹ , and R ¹⁰ are hydrogen.

Embodiment 82. The compound according to any one of Embodiments 1-76 or 67-69, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Embodiment 83. The compound according to Embodiment 82 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is a halogen.

Embodiment 84. The compound according to Embodiment 83 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is fluorine.

Embodiment 85. The compound according to any one of Embodiments 82-84 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , and R ¹⁰ are hydrogen.

Embodiment 86. The compound according to any one of Embodiments 1-76, 78-80, or 82-84, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Embodiment 87. The compound according to Embodiment 86 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a halogen.

Embodiment 88. The compound according to Embodiment 87 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is fluorine.

Embodiment 89. The compound according to any one of Embodiments 86-88 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , and R ⁹ are hydrogen.

Embodiment 90. The compound according to any one of Embodiments 1-73 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are H.

Embodiment 91. The compound according to any one of Embodiments 1-2, 5-9, or 35, or a pharmaceutically acceptable salt thereof, has formula (IV): (IV) where:

each R ¹² is independently fluorine;

n is 0, 1, or 2; and

R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are independently hydrogen, fluorine, or methyl.

Embodiment 92. The compound according to Embodiment 91 or a pharmaceutically acceptable salt thereof, wherein: G ³ is: , , , , , , ,or and

G ⁴ is a direct bond, -CH ₂ - or -CH ₂ CH ₂ -.

Embodiment 93. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 91, wherein ^G3 is: or .

Embodiment 94. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1, selected from any one or more of the compounds in Compound List 1.

Embodiment 95. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1, selected from any one or more of the compounds in Compound List 2 and/or Compound List 3.

Embodiment 96. The compound or pharmaceutically acceptable salt thereof according to Embodiment 2, selected from any one or more of the compounds in Compound List 4.

Embodiment 97. According to the compound or a pharmaceutically acceptable salt thereof according to Embodiment 94, wherein the compound is: .

Embodiment 98. According to the compound or a pharmaceutically acceptable salt thereof according to Embodiment 94, wherein the compound is: .

Embodiment 99. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 94, wherein the compound is: .

Embodiment 100. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 96, wherein the compound is: .

Embodiment 101. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 96, wherein the compound is: .

Embodiment 102. The compound according to embodiment 96 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Embodiment 103. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 96, wherein the compound is: .

Embodiment 104. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 96, wherein the compound is: .

Embodiment 105. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-104 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Embodiment 106. A method for degrading SMARCA2 protein in humans, the method comprising administering to a person in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-104, or a composition according to Embodiment 105.

Embodiment 107. A method for reducing the level of SMARCA2 activity in a human, the method comprising administering to a human in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-104, or a composition according to Embodiment 105.

Embodiment 108. A method for treating human cancer, comprising administering to a person in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-104, or a composition according to Embodiment 105.

Implementation method 109. According to the method described in implementation method 108, the cancer is a SMARCA2-sensitive cancer.

Embodiment 110. The method according to embodiment 108, wherein the cancer is a SMARCA2 mutation cancer.

Embodiment 111.      The method according to any one of embodiments 108-110, wherein the cancer is a solid tumor.

Embodiment 112. The method according to any one of embodiments 108-110, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

Embodiment 113. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments 1-104, or the composition according to Embodiment 105, is used for degrading SMARCA2 protein in humans.

Embodiment 114. A compound according to any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 105, for use in reducing the level of SMARCA2 activity in humans.

Embodiment 115. A compound according to any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 105, for use in the treatment of human cancer.

Embodiment 116. A compound for use according to embodiment 115, wherein the cancer is a SMARCA2-sensitive cancer.

Embodiment 117. A compound for use according to embodiment 115, wherein the cancer is a SMARCA2 mutation cancer.

Embodiment 118. A compound for use according to any one of embodiments 115-117, wherein the cancer is a solid tumor.

Embodiment 119. A compound for use according to any one of embodiments 115-117, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

Embodiment 120. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-104, or the composition according to Embodiment 105, in the manufacture of a medicament for degrading SMARCA2 protein in humans.

Embodiment 121. Use of a compound according to any one of Embodiments 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to Embodiment 105, in the manufacture of a medicament for reducing the level of SMARCA2 activity in humans.

Embodiment 122. Use of a compound according to any one of embodiments 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment 105, in the manufacture of a medicament for treating human cancer.

Embodiment 123. A compound or a pharmaceutically acceptable salt thereof, for use according to embodiment 122, wherein the cancer is a SMARCA2-sensitive cancer.

Embodiment 124. A compound or a pharmaceutically acceptable salt thereof, for use according to embodiment 122, wherein the cancer is a SMARCA2 mutation cancer.

Embodiment 125. A compound or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 122-124, wherein the cancer is a solid tumor.

Embodiment 126. A compound or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 122-124, wherein the cancer is lung cancer, liver cancer, colorectal cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

The present disclosure also provides the following specific implementation methods.

Embodiment A 1. A compound having formula (A) or a pharmaceutically acceptable salt thereof: (A) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl,

wherein (C ₁ -C ₆ )alkyl is optionally substituted by one, two or three substituents independently selected from halogen or cyano; and 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted by one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -;

or X ³ does not exist;

L is G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; ( _C3 - _C6 )cycloalkylene; -O- _CH2 - _CH2- ; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, cyano or hydroxy; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy or cyano;

^G2 is ( _C1 - _C6 ) alkylene, -C(=O)-, 4- to 6-membered heterocycloalkylene which may be substituted by one, two or three fluorine groups, or a direct bond;

^G3 is -C(=O)-; -C(=O) _-CH2CH2- ; ( _C1 - _C6 )alkylene; _{tetrahydronaphthylene} ; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy or cyano; 7- to 11-membered heterocycloalkyl-C(=O)-; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy or cyano;

G ⁴ is (C ₁ -C ₆ )alkylene; (C ₃ -C ₆ )cycloalkylene; 4- to 6-membered heterocycloalkylene; or a direct bond;

W is -C≡C- or direct key;

R ⁷ is hydrogen; halogen; (C ₁ -C ₆ )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl;

R ⁸ is hydrogen; halogen; (C ₁ -C ₆ )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen; halogen; (C ₁ -C ₆ )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl;

R ¹⁰ is hydrogen; halogen; (C ₁ -C ₆ )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl;

^Ra is hydrogen or a halogen;

R ^b is hydrogen or a halogen; and

R ^c is hydrogen or methyl.

Embodiment A 2. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -;

or X ³ does not exist;

L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

G ² is (C ₁ -C ₆ )alkylene or a direct bond;

^G3 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy or cyano; or a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy or cyano;

G ⁴ is (C ₁ -C ₆ )alkylene or a direct bond;

W is -C≡C- or direct key;

^R7 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl;

R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which is optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; and

R ¹⁰ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C ₃ -C ₆ )cycloalkyl.

Embodiment A 3. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or

X ³ does not exist;

L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

G ² is (C ₁ -C ₆ )alkylene or a direct bond;

^G3 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or a 5- to 10-membered heteroaryl group;

G ⁴ is (C ₁ -C ₆ )alkylene, (C ₃ -C ₆ )cycloalkylene, or a direct bond;

W is -C≡C- or direct key;

^R7 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl;

R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which is optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; and

R ¹⁰ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C ₃ -C ₆ )cycloalkyl.

Embodiment A 4. The compound according to Embodiment A 2 or 3 or a pharmaceutically acceptable salt thereof has formula (II): (II).

Embodiment A 5. The compound according to Embodiment A 2 or 3 or a pharmaceutically acceptable salt thereof, having formula (III): (III).

Embodiment A 6. The compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is hydrogen.

Embodiment A 7. The compound according to Embodiment A1-5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is (C ₁ -C ₆ ) alkyl, which is optionally substituted with one, two or three substituents independently selected from halogen or cyano.

Embodiment A 8. The compound according to Embodiment A 7 or a pharmaceutically acceptable salt thereof, wherein R ^5a is methyl.

Embodiment A 9. The compound according to any one of Embodiments A1-5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is (C ₃ -C ₆ )cycloalkyl.

Embodiment A 10. The compound according to Embodiment A 9 or a pharmaceutically acceptable salt thereof, wherein R ^5a is cyclopropyl.

Embodiment A 11. The compound according to Embodiment A1-5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ )alkyl.

Embodiment A 12. The compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is cyano.

Embodiment A 13. A compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein:

R ¹ series: and

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy.

Embodiment A 14. The compound according to Embodiment A 1-5 or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl.

Embodiment A 15. The compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, fluorine, or methyl.

Embodiment A 16. The compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen.

Embodiment A 17. A compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy; and

R ² series: .

Embodiment A 18. The compound according to Embodiment A 17 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl.

Embodiment A 19. The compound according to Embodiment A 18 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, fluorine or methyl.

Embodiment A 20. The compound according to any one of Embodiments A 17-19 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen.

Embodiment A 21. The compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein X ¹ is CR ³ .

Embodiment A 22. The compound according to Embodiment A 21 or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

Embodiment A 23. The compound according to Embodiment A 21 or a pharmaceutically acceptable salt thereof, wherein R ³ is halogen.

Embodiment A 24. The compound according to Embodiment A 21 or a pharmaceutically acceptable salt thereof, wherein R ³ is (C ₁ -C ₆ ) alkyl.

Embodiment A 25. The compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein X ¹ is N.

Embodiment A 26. The compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein X ² is CR ⁴ .

Embodiment A 27. The compound according to Embodiment A 26 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

Embodiment A 28. The compound according to Embodiment A 26 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is halogen.

Embodiment A 29. The compound according to Embodiment A 26 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is (C ₁ -C ₆ ) alkyl.

Embodiment A 30. The compound according to any one of Embodiments A 1-5 or a pharmaceutically acceptable salt thereof, wherein X ² is N.

Embodiment A 31. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-5, wherein E is: , , , , , , , , , , , , ,or .

Embodiment A 32. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-5, wherein E is: or .

Embodiment A 33. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-5, wherein E is: .

Embodiment A 34. The compound according to any one of Embodiments A1-33 or a pharmaceutically acceptable salt thereof, wherein ^G1 is ( _C3 - _C6 ) cycloalkylene; or 4- to 6-membered heterocycloalkylene, which is optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, cyano, or hydroxyl.

Embodiment A 35. According to embodiment A 34, the compound or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, or hydroxy;

n is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to G ² .

Embodiment A 36. The compound according to Embodiment A 35 or a pharmaceutically acceptable salt thereof, wherein each R ¹² is independently fluoro, methyl, methoxy, cyano, or -CHF ₂ ; and n is 0, 1, or 2.

Embodiment A 37. According to the compound described in Embodiment A 35 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : , , , ,or

And the key marked with "*" is attached to G ² .

Embodiment A 38. According to embodiment A 34, the compound or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Among them, X ⁴ is -O-;

each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; and

Keys marked with a "*" are attached to G ² .

Embodiment A 39. According to the compound described in Embodiment A 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : or and

Keys marked with a "*" are attached to G ² .

Embodiment A 44. According to embodiment A 34, the compound or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : and

Keys marked with a "*" are attached to G ² .

Embodiment A 41. The compound according to Embodiment A1 or a pharmaceutically acceptable salt thereof, wherein ^G1 is a cyclohexylene group.

Embodiment A 42. According to embodiment A 41, the compound or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : or and

Keys marked with a "*" are attached to G ² .

Embodiment A 43. The compound according to any one of Embodiments A1-33 or a pharmaceutically acceptable salt thereof, wherein ^G1 is a 7- to 11-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, or cyano.

Embodiment A 44. According to embodiment A 43, the compound or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹³ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

o is 0, 1, 2, or 3;

p, q, r, and s are independently 1 or 2;

Keys marked with a "*" are attached to G ² .

Embodiment A 45. According to embodiment A 44, the compound or a pharmaceutically acceptable salt thereof, wherein:

p and q are 1;

r is 1 or 2;

s is 1 or 2; and

R ¹³ is a halogen.

Embodiment A 46. The compound according to embodiment A 45 or a pharmaceutically acceptable salt thereof, wherein R ¹³ is fluorine and o is 0, 1, or 2.

Embodiment A 47. The compound according to Embodiment A 44 or a pharmaceutically acceptable salt thereof, wherein ^G1 is: and

Keys marked with a "*" are attached to G ² .

Embodiment A 48. According to the compound described in Embodiment A 43 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

a is 0 or 1;

b is 0 or 1; and

Keys marked with a "*" are attached to G ² .

Embodiment A 49. The compound according to Embodiment A 48 or a pharmaceutically acceptable salt thereof, wherein ^G1 is: , , ,or and

Keys marked with a "*" are attached to G ² .

Embodiment A 50. The compound according to Embodiment A 43 or a pharmaceutically acceptable salt thereof, wherein G ¹ is: or and

Keys marked with a "*" are attached to G ² .

Embodiment A 51. The compound according to any one of Embodiments A 1-50 or a pharmaceutically acceptable salt thereof, wherein G ² is a direct bond.

Embodiment A 52. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiment A 1 or 6-50, wherein G ² is C(=O).

Embodiment A 53. The compound according to any one of Embodiments A 1-50 or a pharmaceutically acceptable salt thereof, wherein G ² is (C ₁ -C ₆ )alkylene.

Embodiment A 54. The compound according to Embodiment A 53 or a pharmaceutically acceptable salt thereof, wherein G ² is -CH ₂ -.

Embodiment A 55. The compound according to any one of Embodiments A1-54 or a pharmaceutically acceptable salt thereof, wherein G ³ is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano.

Embodiment A 56. According to the compound or a pharmaceutically acceptable salt thereof according to Embodiment A 55, wherein:

G ³ Series: , , , ,or ;

Each R ¹⁴ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

t is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 57. The compound according to Embodiment A 56 or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is fluoro or methyl and t is 0 or 1.

Embodiment A 58. The compound according to Embodiment A 56 or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , ,or and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 59. The compound according to any one of Embodiments A1-54 or a pharmaceutically acceptable salt thereof, wherein G ³ is a 7- to 11-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano.

Embodiment A 60. The compound according to Embodiment A 1 or a pharmaceutically acceptable salt thereof, wherein G ³ is: or and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 61. The compound according to Embodiment A 59 or a pharmaceutically acceptable salt thereof, wherein G ³ is: and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 62. The compound according to Embodiment A 59 or a pharmaceutically acceptable salt thereof, wherein G ³ is: or and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 63. According to embodiment A 59, the compound or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: ;

Each R ¹⁵ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

u is 0, 1, 2, or 3;

v, w, x, and y are independently 1, 2, or 3; and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 64. The compound according to embodiment A 63 or a pharmaceutically acceptable salt thereof, wherein v, w, x, and y are independently 1 or 2.

Embodiment A 65. The compound according to Embodiment A 63 or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ is fluorine.

Embodiment A 66. According to embodiment A 59, the compound or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: ;

^xa and ^ya are independently 1 or 2; and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 67. The compound according to Embodiment A 59 or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , , , , , , , , , , , , , , , , ,or and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 68. The compound according to Embodiment A 1 or a pharmaceutically acceptable salt thereof, wherein G ³ is: and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 69. The compound according to any one of Embodiments A 1-68 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is (C ₁ -C ₆ )alkylene.

Embodiment A 70. The compound according to Embodiment A 69 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is -CH ₂ - or -CH ₂ CH ₂ -.

Embodiment A 71. The compound according to Embodiment A1 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is (C ₃ -C ₆ )cycloalkylene.

Embodiment A 72. The compound according to Embodiment A 71 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is: or and

The key marked with "*" is attached to E.

Embodiment A 73. The compound according to Embodiment A 71 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is: or and

Keys marked with a "*" are attached to G ⁴ .

Embodiment A 74. The compound according to any one of Embodiments A 1-68 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is a direct bond.

Embodiment A 75. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-33, wherein L is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or and

The key marked with "*" is attached to E.

Embodiment A 76. The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-33, wherein L is: , , , ,or and

The key marked with "*" is attached to E.

Embodiment A 77. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments A 1-76, wherein W is -C≡C-.

Embodiment A 78. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-76, wherein W is a direct bond.

Embodiment A: The compound according to any one of Embodiments A1-78 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are H.

Embodiment A 80. The compound according to any one of Embodiments A1-78 or a pharmaceutically acceptable salt thereof, wherein ^R7 is halogen, ( _C1 - _C6 ) alkyl, cyano, or ( _C3 - _C6 ) cycloalkyl, wherein the ( _C1 - _C6 ) alkyl is optionally substituted with one, two or three halogens.

Embodiment A 81. The compound according to Embodiment A 80 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is halogen or (C ₁ -C ₆ ) alkyl.

Embodiment A 82. The compound according to Embodiment A 81 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is fluoro or methyl.

Embodiment A 83. The compound according to any one of Embodiments A 80-82 or a pharmaceutically acceptable salt thereof, wherein R ⁸ , R ⁹ , and R ¹⁰ are hydrogen.

Embodiment A 84. The compound according to any one of Embodiments A1-78 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Embodiment A 85. The compound according to Embodiment A 84 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halogen or (C ₁ -C ₆ ) alkyl.

Embodiment A 86. The compound according to Embodiment A 85 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is fluoro or methyl.

Embodiment A 87. The compound according to any one of Embodiments A 84-86 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁹ , and R ¹⁰ are hydrogen.

Embodiment A 88. The compound according to any one of Embodiments A1-78 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Embodiment A 89. The compound according to Embodiment A 88 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is halogen.

Embodiment A 90. The compound according to Embodiment A 89 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is fluorine.

Embodiment A 91. The compound according to any one of Embodiments A 88-90 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , and R ¹⁰ are hydrogen.

Embodiment A 92. The compound according to any one of Embodiments A1-78 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Embodiment A 93. The compound according to Embodiment A 92 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a halogen.

Embodiment A 94. The compound according to Embodiment A 93 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is fluorine.

Embodiment A 95. The compound according to any one of Embodiments A 92-94 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁹ , and R ⁹ are hydrogen.

Embodiment A 96. The compound according to any one of Embodiments A 1-78 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is cyano.

Embodiment A 97. The compound according to Embodiment A 96 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is cyano; and R ⁷ , R ⁸ , and R ⁹ are hydrogen.

Embodiment A 98. A compound having formula (V) or a pharmaceutically acceptable salt thereof, (V), where:

Each R ¹² is fluorine or hydroxy;

n is 0, 1, 2, or 3;

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or is absent;

^G3 is tetrahydronaphthyl; 4- to 6-membered heterocycloalkyl, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; 7- to 11-membered heterocycloalkyl-C(=O)-; or 7- to 11-membered heterocycloalkyl, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

^G4 is absent or is a cyclobutylene group;

R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are independently hydrogen, fluorine, methyl, or cyano;

^Ra is hydrogen, chlorine, methyl or fluorine;

R ^b is hydrogen, chlorine, methyl, or fluorine; and

R ^c is hydrogen or methyl.

Embodiment A 99. According to the compound described in Embodiment A 98 or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: , , , , , , ,or .

Embodiment A 100. The compound according to Embodiment A 98 or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , ,or .

Embodiment A 101. The compound according to Embodiment A 98 or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , , , , , , , , , , , , , , , , , ,or .

Embodiment A 102. According to the compound or a pharmaceutically acceptable salt thereof described in Embodiment A 1, the compound is selected from any one or more of the compounds in Compound List 1, Compound List 2, Compound List 3, Compound List 4, and/or Compound List 5, or a pharmaceutically acceptable salt thereof.

Embodiment A 103. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 104. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 105. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 106. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 107. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 108. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 109. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 110. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 111. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 112. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 113. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 114. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: Embodiment A 115. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 116. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 117. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 118. The compound or a pharmaceutically acceptable salt thereof according to Embodiment A 1 or 102, wherein the compound is: .

Embodiment A 119. A pharmaceutical composition comprising a compound according to any one of Embodiments A 1-118 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Embodiment A 120. A method for degrading SMARCA2 protein in humans, the method comprising administering to a person in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-118, or a composition according to Embodiment A 119.

Embodiment A 121. A method for reducing the level of SMARCA2 activity in a human, the method comprising administering to a human in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-118, or a composition according to Embodiment A 119.

Embodiment A 122. A method for treating human cancer, comprising administering to a person in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-118, or a composition according to Embodiment A 119.

Implementation method A 123. According to the method described in Implementation method A 122, the cancer is a SMARCA2-sensitive cancer.

Implementation method A 124. According to the method described in Implementation method A 122, the cancer is a SMARCA2 mutant cancer.

Implementation method A 125. According to any one of implementation methods A 122-124, the cancer is a solid tumor.

Implementation A 126. The method according to any one of Implementation A 122-124, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

Embodiment A 127. A compound according to any one of embodiments A 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment A 105, is used for degrading SMARCA2 protein in humans.

Embodiment A 128. A compound according to any one of embodiments A 1-118 or a pharmaceutically acceptable salt thereof, or a composition according to embodiment A 119, for use in reducing the level of SMARCA2 activity in humans.

Embodiment A 129. A compound according to any one of Embodiments A 1-118 or a pharmaceutically acceptable salt thereof, or a composition according to Embodiment A 119, for use in the treatment of human cancer.

Embodiment A 130. A compound for use according to embodiment A 129, wherein the cancer is a SMARCA2-sensitive cancer.

Embodiment A 131. A compound for use according to embodiment A 129, wherein the cancer is a SMARCA2 mutation cancer.

Embodiment A 132. A compound for use according to any one of embodiments A 129-131, wherein the cancer is a solid tumor.

Embodiment A 133. A compound for use according to any one of embodiments A 129-131, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

Embodiment A 134. Use of a compound according to any one of Embodiments A 1-118 or a pharmaceutically acceptable salt thereof, or a composition according to Embodiment A 119, in the manufacture of an agent for degrading SMARCA2 protein in humans.

Embodiment A 135. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-118, or a composition according to Embodiment A 119, in the manufacture of a medicament for reducing the level of SMARCA2 activity in humans.

Embodiment A 136. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A 1-118, or a composition according to Embodiment A 119, in the manufacture of a medicament for treating human cancer.

Embodiment A 137. A compound or a pharmaceutically acceptable salt thereof, for use according to embodiment A 136, wherein the cancer is a SMARCA2-sensitive cancer.

Embodiment A 138. A compound or a pharmaceutically acceptable salt thereof, for use according to embodiment A 136, wherein the cancer is a SMARCA2 mutation cancer.

Embodiment A 139. A compound or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments A 136-138, wherein the cancer is a solid tumor.

Embodiment A 140. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments A 136-138, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer. Examples General Experimental Conditions and Abbreviations

The following abbreviations are used: AcOH = acetic acid; aq = aqueous; BINAP = (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc = tert-butyloxycarbonyl; BrettPhos Pd G3 = [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate, palladium(II); t -BuBrettPhos Pd G3 = [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate, palladium(II); ( tBu )PhCphos = 2-[(tert-butyl)phenylphosphino]-2',6'-bis( N , N -dimethylamino)biphenyl; _Cs2CO3 = cesium _carbonate ; CuI = copper(I) iodide; Cphos = 2-dicyclohexylphosphino-2',6'-bis( N,N -dimethylamino)biphenyl; DCE = 1,2-dichloroethane; DCM = dichloromethane; DIBAL-H = diisobutylaluminum hydroxide; DIPEA = N,N -diisopropylethylamine; DMA = N , N -dimethylacetamide; DMAP = 4-dimethylaminopyridine; DMF = N,N -dimethylformamide; DMSO = dimethylsulfoxide; EtOAc = ethyl acetate; EtOH = ethanol; EPhos = =Dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane; EPhos Pd G4 = Palladium catalyst containing EPhos - CAS No. 2132978-44-8; FA = formic acid; FSC = fast silica gel chromatography; g = grams; h = hours; HATU = (dimethylamino)- N , N -dimethyl(3-oxido-1 H -[1,2,3]triazolo[4,5- b ]pyridinyl)methanilinium hexafluorophosphate; HCl = hydrochloric acid; HPLC = high performance liquid chromatography; KO t Bu = potassium tertiary butoxide; K ₃ PO ₄ = potassium triphosphate; LiHMDS = Lithium hexamethyldisilazide; LiOH = lithium hydroxide; M = molar; mg = milligram; min = minute; mL = milliliter; mmol = millimolar; MeCN = acetonitrile; MeOH = methanol; MTBE = methyl tert-butyl ether; N ₂ = nitrogen; Na ₂ CO ₃ = sodium carbonate; Na ₂ SO ₄ = sodium sulfate; NEt ₃ = triethylamine; NH ₄ Cl = ammonium chloride; NH ₄ HCO ₃ = ammonium bicarbonate; NH ₄ OH = ammonium hydroxide; NMP = N -methylpyrrolidone; NMR = nuclear magnetic resonance; Na(OAc) ₃ BH = sodium triacetoxyborohydride; Pd/C = palladium on carbon; PdCl ₂ (PPh ₃ ) ₂ = = bis(triphenylphosphine)palladium(II) dichloride; Pd(dba) ₂ = palladium(0)bis(dibenzylideneacetone); Pd ₂ dba ₃ = tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl ₂ = [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; i PrOH = isopropanol; PyBOP = benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate; rt = room temperature (about 18°C-25°C); RPC = reversed phase chromatography; RP-HPLC = reversed phase high performance liquid chromatography; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhos Pd G3 = Palladium(II) (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate; SFC = supercritical fluid chromatography; SPhos Pd G2 = Palladium(II) chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TsOH = p-toluenesulfonic acid monohydrate; wt% = weight percent; Pd XPhos G3 = (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate Palladium(II).

NMR: Unless otherwise stated, proton NMR ( ^1H NMR) was performed at 300-500 MHz in the temperature range from 15°C to 30°C in deuterated DMSO. Unless otherwise stated, ^19F NMR was performed in DMSO. Standard NMR abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, dd = double of doublets, dt double of triplet, m = multiplet, br = broad.

Analytical methods: The clean apparent fractions containing the desired product are generally identified, pooled together, and then concentrated under reduced pressure. Flash chromatography was performed using: linear phase flash chromatography using C18-flash columns on SP1 ^TM purification or SELEKT ^TM systems from Biotage ^TM , CombiFlash ^TM Rf from ISCO, or on Gilson systems from Thermo Fisher using normal phase silica FLASH+ ^TM (40 M, 25 M, or 12 M), Sfär Silica HC (5 g, 10 g, 25 g, 100 g) or SNAP ^TM KP-Sil cartridges (340, 100, 50, or 10) from Biotage™, Flash Silica-CS columns from Agela, or standard flash chromatography. RP-HPLC was performed using XSelect or XBridge columns.

Generally, all solvents used were commercially available and of analytical grade. Anhydrous solvents were routinely used for the reactions. The phase separator used in these examples was an ISOLUTE® phase separation column.

Concentration of solutions (to partially or completely remove solvents) is usually carried out at or slightly above room temperature under reduced pressure.

The intermediates and examples named below were named using BIOVIA Draw 20.1 or Chem Draw. Starting materials were obtained from commercial sources or prepared by literature routes. Example 1 Intermediate 1a: 7-tert-butyl 2-methyl 7-azaspiro[3.5]nonane-2,7-dicarboxylate

_Cs2CO3 (4.84 g, 14.85 mmol) was added to iodomethane (1.054 g, 7.43 mmol) and 7-(tert-butyloxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid (2 g, 7.43 mmol) in DMF ₍ 10 mL). The resulting mixture was stirred at room temperature for 6 h. 40 mL of water was added and the aqueous layer was extracted with ethyl acetate (2 x 75 mL). The combined organic extracts were dried over _Na2SO4 , filtered and concentrated to provide the title compound (2.0 g, 95%) as _a white solid. ¹ H NMR (DMSO- d6 ) δ 1.32 - 1.42 (11H, m), 1.44 - 1.52 (2H, m), 1.85 - 1.95 (2H, m), 1.95 - 2.05 (2H, m), 3.05 - 3.20 (3H, m), 3.21 - 3.28 (2H, m), 3.58 (3H, s); m/z (ES ⁺ ) [M+H] ⁺ = 284.3. Intermediate 1b: Benzyl 8-(3-bromophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

To a stirred solution of Cs ₂ CO ₃ (5.29 g, 16.24 mmol), sodium(II) acetate (0.182 g, 0.81 mmol) and BINAP (0.506 g, 0.81 mmol) in 1,4-dioxathiocarboxylate (20 mL) at room temperature were added 1,3-dibromobenzene (1.916 g, 8.12 mmol) and benzyl 3,8-diazobicyclo[3.2.1]octane-3-carboxylate (2.0 g, 8.12 mmol). The resulting mixture was stirred at 100°C for 16 h. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (3 x 100 mL), and the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. Purification by FSC (Gradient: 0 to 70% EtOAc in petroleum ether) gave the title compound (1.3 g, 39.9%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.52 (2H, d), 1.83 - 1.93 (2H, m), 2.91 - 3.09 (4H, m), 4.28 (2H, d), 5.05 (2H, d), 6.26 (2H, d), 6.35 (1H, s), 6.97 (1H, t), 7.25 - 7.40 (5H, m); m/z (ES+) [M+H] ⁺ = 366.1. Intermediate 1c: 7-[3-(3-benzyloxycarbonyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl]-7-azaspiro[3.5]nonane-2-carboxylic acid methyl ester

4 M HCl in MeOH (5 mL, 164.57 mmol) was added to intermediate 1a (318 mg, 1.12 mmol). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and a white solid was provided. To the crude product were added RuPhos Pd G3 (94 mg, 0.11 mmol), RuPhos (50.0 mg, 0.11 mmol), Cs ₂ CO ₃ (1096 mg, 3.36 mmol) and intermediate 1b (450 mg, 1.12 mmol) in dioxane (10 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated. Purification by FSC (gradient: 0 to 100% EtOAc in petroleum ether) gave the title compound (530 mg, 94%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.51 - 1.71 (6H, m), 1.83 - 2.07 (6H, m), 2.95 - 3.23 (7H, m), 3.52 - 3.56 (2H, m), 3.59 (3H, s), 4.25 (2H, d), 5.05 (2H, d), 6.21 - 6.42 (3H, m), 6.98 (1H, t), 7.21 - 7.47 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 504.4. Intermediate 1d: Benzyl 8-[3-[2-(dimethoxymethyl)-7-azaspiro[3.5]non-7-yl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

DIBAL-H (169 mg, 1.19 mmol) was added to intermediate 1c (300 mg, 0.60 mmol) in DCM (5 mL) at -50 °C under nitrogen. The resulting mixture was stirred at -50 °C for 1 h. Saturated NH ₄ Cl solution was added to the mixture. The aqueous layer was back extracted with DCM (2 x 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to afford a yellow solid. The product was used directly in the next step without further purification. To the residue were added TsOH (113 mg, 0.60 mmol) and trimethyl orthoformate (190 mg, 1.79 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated. Purification by FSC (Gradient: 0 to 100% EtOAc in petroleum ether) gave the title compound (130 mg, 42.0%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.52 - 1.71 (6H, m), 1.80 - 2.10 (6H, m), 2.95 - 3.27 (5H, m), 3.34 (6H, s), 3.56 (1H, s), 3.61 (4H, s), 4.27 (2H, d), 5.07 (2H, d), 6.28 (2H, d), 6.38 (1H, s), 6.99 (1H, t), 7.18 - 7.46 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 520. Intermediate 1e: 7-[3-(3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl]-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane

Pd/C (11.06 mg, 0.10 mmol) was added to intermediate 1d (270 mg, 0.52 mmol) in MeOH (4 mL) under hydrogen. The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was filtered through celite® and the filtrate was concentrated to provide the title compound (80 mg, 39.9%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ = 386.1. Intermediate 1f: 2-[6-amino-5-[8-[3-[2-(dimethoxymethyl)-7-azaspiro[3.5]non-7-yl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]tathionein-3-yl]phenol

DIPEA (0.095 mL, 0.54 mmol) was added to intermediate 1e (70 mg, 0.18 mmol) and 4-bromo-6-chloropyridinium-3-amine (37.8 mg, 0.18 mmol) in NMP (3 mL). The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 2). The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was used in the next step. To the residue were added Cs ₂ CO ₃ (177 mg, 0.54 mmol), XPhos Pd G3 (15.36 mg, 0.02 mmol), (2-hydroxyphenyl)boronic acid (37.6 mg, 0.27 mmol) in dioxane (1 mL) and water (1 mL). The resulting mixture was stirred at 100° C. for 2 h. The solvent was removed. Purification by RPC (gradient: 0 to 90% MeOH in water containing 0.5% NH ₄ HCO ₃ ) gave the title compound (40.0 mg, 38.6%) as a yellow solid. m/z (ES ⁺ ), [M+H] ⁺ = 571. Intermediate 1g: 4-(5-bromo-3-methyl-indol-1-yl)piperidine-1-carboxylic acid tributyl ester

_Cs2CO3 (16.20 g, 49.72 mmol) was added to _a stirred solution of tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate ₍ 13.90 g, 49.74 mmol) and 5-bromo-3-methyl- 1H -indole (5.50 g, 26.18 mmol) in DMF (30 mL) at room temperature under _N2 . The resulting mixture was stirred at 95 °C for 8.5 h. The mixture was cooled to room temperature, and then tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (14.00 g, 50.10 mmol) and _Cs2CO3 (16.00 g, 49.11 mmol) were _added under N2. The resulting mixture was stirred at 95 °C for 14 h, then cooled to room temperature and diluted with EtOAc (200 mL). The mixture was washed with water (2 x 50 mL) and brine (2 x 50 mL). The organic layer was dried ( _Na2SO4 ) and concentrated. Purification by FSC (gradient: 0-40% DCM in hexanes, then 0-30% EtOAc in hexanes) gave the title compound (5.85 g, 57%) as _a white foam. ¹ H NMR (CDCl ₃ ): δ 1.50 (9H, s), 1.81-1.95 (2H, m), 2.00-2.07 (2H, m), 2.28 (3H, d), 2.82-2.99 (2H, m), 4.21-4.40 (3H, m), 6.95 (1H, s), 7.16-7.24 (1H, m), 7.28-7.30 (1H, m), 7.69 (1H, d); m/z (ES ⁺ ) [M- t Bu+2H] ⁺ = 336.8. Intermediate 1h: 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]piperidine-1-carboxylic acid tributyl ester

1,4-Dihydrogen iodide (100 mL) was added to intermediate 1g (4.20 g, 10.68 mmol), Cs ₂ CO ₃ (6.96 g, 21.36 mmol), Pd ₂ (dba) ₃ (0.885 g, 0.97 mmol), EPhos (1.028 g, 1.92 mmol) and hexahydropyrimidine-2,4-dione (3.66 g, 32.03 mmol) in a degassed flask under argon at room temperature. The mixture was bubbled with argon for five minutes and then stirred at 100°C for 14 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), and filtered through celite®. The filtrate was then concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound as an off-white solid (3.06 g, 67%). ¹ H NMR (CDCl ₃ ): δ 1.52 (9H, s), 1.85-1.97 (2H, m), 2.02-2.09 (2H, m), 2.32 (3H, d), 2.85-2.97 (4H, m), 3.93 (2H, t), 4.26-4.40 (3H, m), 7.02 (1H, s), 7.13 (1H, dd), 7.37 (1H, d), 7.40 (1H, s), 7.48 (1H, s); m/z (ES ⁺ ) [M+Na] ⁺ = 449.2. Intermediate 1i: 1-[3-methyl-1-(4-piperidinyl)indol-5-yl]hexahydropyrimidine-2,4-dione

TFA (0.289 mL, 3.75 mmol) was added to a solution of intermediate 1h (80 mg, 0.19 mmol) in DCM (1.0 mL) at room temperature. After 1 h, the mixture was concentrated. Diethyl ether (2 mL) was added and the resulting mixture was sonicated to produce a solid precipitate. The supernatant was removed and the solid was dried under reduced pressure to give the title compound (83 mg, 100%) as a light pink solid in the form of a trifluoroacetic acid salt. m/z (ES ⁺ ) [M+H] ⁺ = 326.9. 1-[1-[1-[[7-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-7-azaspiro[3.5]non-2-yl]methyl]-4-piperidinyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Formic acid (1 ml, 26.07 mmol) was added to intermediate 1f (35 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 1 h and the solvent was removed under reduced pressure. The crude material was dissolved in DMF (1.0 mL) and DCE (1.0 mL), and intermediate 1i (20.0 mg, 0.06 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (39.0 mg, 0.18 mmol) was added and stirred at room temperature for 1 h. The solvent was removed under reduced pressure. Purification by RPC (gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (5.60 mg, 10.01%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.45 (2H, t), 1.53 - 1.59 (2H, m), 1.65 - 1.71 (2H, m), 1.83 - 2.07 (8H, m), 2.08 - 2.21 (4H, m), 2.23 (3H, s), 2.46 (2H, d), 2.73 (2H, t), 2.91 - 3.04 (4H, m), 3.06 - 3.13 (2H, m), 3.25 (2H, d), 3.77 (3H, t), 4.25 (1H, d), 4.39 (2H, d), 5.95 (2H, s), 6.25 (1H, d), 6.26 (1H, d), 6.43 (1H, s), 6.83 - 6.90 (2H, m), 6.98 - 7.09 (2H, m), 7.19 - 7.26 (1H, m), 7.31 (1H, s), 7.39 (1H, d), 7.43 - 7.50 (2H, m), 7.92 (1H, d), 10.27 (1H, s) (OH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 835.1. Example 2 Intermediate 2a: 2-(5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

A vial was charged with 5-bromo-3-cyclopropyl- 1H -pyrrolo[2,3- b ]pyridine (600 mg, 2.53 mmol) and tributyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (611 mg, 2.53 mmol), 2- (tributyl-15-phosphino)acetonitrile (1222 mg, 5.06 mmol) and m-xylene (15 mL). The reaction was heated to 110 °C for 16 h, then cooled to room temperature and concentrated in vacuo. Purification by RPC (Gradient: 5%-100% MeCN in water containing 0.1% _{NH4HCO3 )} gave the title compound (1000 mg, 86%) as a yellow solid. ¹ H NMR (DMSO- d 6): δ 0.63 - 0.73 (2H, m), 0.82 - 0.90 (2H, m), 1.40 (9H, s), 1.57 - 1.67 (4H, m), 1.91 - 2.02 (1H, m), 2.16 - 2.27 (2H, m), 2.32 - 2.42 (2H, td), 3.21 - 3.34 (4H, m), 5.13 - 5.36 (1H, m), 7.59 (1H, s), 8.20 (1H, d), 8.26 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 460.2. Intermediate 2b: 2-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

A 40 mL vial was charged with hexahydropyrimidine-2,4-dione (873 mg, 7.65 mmol), tBuBrettPhos Pd G3 (327 mg, 0.38 mmol), intermediate 2a (1762 mg, 3.83 mmol) and K ₃ PO ₄ (1625 mg, 7.65 mmol), then the vial was capped and evacuated and backfilled with nitrogen. 1,4-Dihydrogen iodide (20 mL) was added, then the mixture was bubbled with nitrogen for 15 min. The reaction was then heated to 100 °C for 16 h. The reaction was cooled to room temperature, then diluted with EtOAc (50 mL) and filtered through celite®. The filtrate was concentrated under reduced pressure. The resulting residue was purified by FSC (gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) to give the title compound (1446 mg, 77%) as a brown dry film. ¹ H NMR (DMSO- d 6): δ 0.65 - 0.72 (2H, m), 0.84 - 0.92 (2H, m), 1.41 (9H, s), 1.59 - 1.69 (4H, m), 1.91 - 1.98 (1H, m), 2.22 - 2.29 (2H, m), 2.32 - 2.43 (2H, m), 2.72 - 2.80 (2H, m), 3.21 - 3.30 (2H, m), 3.36 (2H, d), 3.78 - 3.87 (2H, m), 5.20 - 5.36 (1H, m), 7.57 (1H, s), 7.96 (1H, d), 8.17 (1H, d), 10.40 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 494.3. Intermediate 2c: 1-[1-(7-Azaspiro[3.5]nonan-2-yl)-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (6.00 mL) was added to a stirred solution of intermediate 2b (1.974 g, 4 mmol) in DCM (24 mL). The resulting solution was stirred for 2 h. The reaction mixture was concentrated. Purification by ion exchange chromatography (Porpak Rxn CX 50 g cartridge) (eluting with 2 N NH ₃ in MeOH) gave the title compound (1.457 g, 93%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.67 - 0.74 (2H, m), 0.82 - 0.90 (2H, m), 1.60 (4H, dt), 1.88 - 2.00 (1H, m), 2.15 - 2.23 (2H, m), 2.30 - 2.38 (2H, m), 2.57 - 2.62 (2H, m), 2.67 - 2.72 (2H, m), 2.77 (2H, t), 3.82 (2H, t), 5.24 (1H, quin), 7.54 (1H, s), 7.95 (1H, d), 8.17 (1H, d), 10.37 (1H, br s) (NH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 394.4. Intermediate 2d: 1-bromo-3-(3,3-diethoxyprop-1-ynyl)benzene

A vial was charged with 3,3-diethoxyprop-1-yne (0.860 ml, 6.00 mmol), 1-bromo-3-iodobenzene (0.765 ml, 6 mmol), PdCl ₂ (PPh ₃ ) ₂ (0.632 g, 0.90 mmol), CuI (0.171 g, 0.90 mmol), DMF (20 ml) and NEt ₃ (10 mL). The reaction was degassed and stirred at room temperature for 1.5 hours. The reaction was diluted with water, extracted with DCM (2 x 20 mL), washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by FCS (0-12% EtOAc in hexanes) gave the title compound (1.272 g, 74.9%) as a colorless oil. ¹ H NMR (CDCl ₃ ): δ 1.28 (6H, t), 3.64 - 3.70 (2H, m), 3.81 (2H, dq), 5.48 (1H, s), 7.18 (1H, t), 7.40 (1H, d), 7.47 (1H, d), 7.63 (1H, s); m/z (ES ⁺ ) [M-OEt] ⁺ = 238.9. Intermediate 2e: 8-[3-(3,3-diethoxyprop-1-ynyl)phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Tributyl (-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.954 g, 4.49 mmol) was added to a stirred solution of intermediate 2d (1.272 g, 4.49 mmol), RuPhos Pd G3 (0.376 g, 0.45 mmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (0.210 g, 0.45 mmol) and cesium carbonate (2.93 g, 8.98 mmol) in 1,4-dioxane (24 mL) under nitrogen. The vial was sealed and flushed with nitrogen for 5 min and heated at 90 °C for 4 hr. h. The reaction was filtered through a plug of celite® and concentrated. Purification by FSC (gradient: 0-50% EtOAc in hexanes) gave the title compound (0.943 g, 50.6%) as a brown viscous oil. ¹ H NMR (CDCl ₃ ): δ 1.30 (6H, t), 1.47 (9H, s), 1.77 - 1.94 (2H, m), 1.98 - 2.07 (2H, m), 3.20 (1H, br d), 3.30 (1H, br d), 3.59 - 3.78 (4H, m), 3.84 (2H, dq), 4.12 - 4.23 (2H, m), 5.50 (1H, s), 6.79 (1H, d), 6.89 (1H, d), 6.92 (1H, s), 7.19 (1H, t); m/z (ES ⁺ ) [M+H] ⁺ = 415.6. Intermediate 2f: 8-[3-(3,3-diethoxyprop-1-ynyl)phenyl]-3,8-diazabicyclo[3.2.1]octane

A vial was charged with intermediate 2e (0.803 g, 1.94 mmol), HCl solution (1.25 M in EtOH, 15.50 mL, 19.37 mmol). The reaction was heated to 40 °C for 2 h. Concentration in vacuo gave the title compound (609 mg, 100%) as a brown film. m/z (ES ⁺ ) [M+H] ⁺ = 315.5. Intermediate 2g: 6-Chloro-4-[8-[3-(3,3-diethoxyprop-1-ynyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

A vial was charged with intermediate 2f (610 mg, 1.94 mmol), 4-bromo-6-chloroindole-3-amine (809 mg, 3.88 mmol), n-butanol (8 mL), and DIPEA (1.694 mL, 9.70 mmol). The reaction was heated to 110 °C for 19 h. Purification by FCS (0-100% EtOAc in hexanes, then 0-25% MeOH in EtOAc) gave a mixture of acetal products. The material was stirred in HCl solution (1.25 M in EtOH, 0.3 mL, 0.4 mmol) and EtOH (10 mL) at 50 °C for 18 h. Concentration in vacuo gave the title compound (351 mg, 40.9%) as a brown solid. ¹ H NMR (DMSO- d 6): δ 1.17 (6H, t), 1.91 - 1.97 (2H, m), 2.04 - 2.14 (2H, m), 3.12 (2H, br d), 3.24 (2H, br d), 3.37 - 3.47 (1H, m), 3.50 - 3.62 (2H, m), 3.66 - 3.72 (2H, m), 4.45 (2H, br s), 5.51 (1H, s), 6.79 (1H, d), 6.95 - 7.05 (3H, m), 7.14 (1H, s), 7.22 (1H, t); m/z (ES ⁺ ) [M+H] ⁺ = 442.3. Intermediate 2h: 2-[6-amino-5-[8-[3-(3,3-diethoxyprop-1-ynyl)phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidine-3-yl]phenol

Intermediate 2g (351 mg, 0.79 mmol) was added to (2-hydroxyphenyl)boronic acid (164 mg, 1.19 mmol), _Cs2CO3 (518 mg, 1.59 mmol) and _XphosPdG3 (67.2 mg, 0.08 mmol) in 1,4-dioxathiocarbamide (7 mL) and water (0.700 mL). The vial was degassed by bubbling _N2 through the solution for 10 min. The vial was sealed and stirred at 100 °C for 30 min. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude residue was partitioned between saturated _NaHCO3 (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (2 x 20 mL) and the combined organic extracts were washed with brine, dried _{( Na2SO4} ), filtered and concentrated. Purification by FSC (Gradient: 0-100% EtOAc in hexanes) gave the title compound (239 mg, 60.2%) as a brown solid. ¹ H NMR (DMSO- d 6): δ 1.14 - 1.21 (6H, m), 1.94 - 1.99 (2H, m), 2.09 - 2.25 (2H, m), 3.08 (2H, br d), 3.22 - 3.31 (2H, m), 3.49 - 3.61 (2H, m), 3.69 (2H, dq), 4.47 (2H, br s), 5.51 (1H, s), 5.94 (2H, s), 6.77 (1H, d), 6.83 - 6.90 (2H, m), 6.95 - 7.00 (2H, m), 7.15 - 7.29 (2H, m), 7.48 (1H, s), 7.92 (1H, d), 14.16 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 500.4. Intermediate 2i: 3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]prop-2-ynal

A vial was charged with intermediate 2h (153 mg, 0.31 mmol) and formic acid (0.5 mL). The reaction was stirred at 40 °C for 10 min. The reaction was concentrated in vacuo and dried by freeze drying. The title compound (121 mg, 93%) was obtained as a brown solid. m/z (ES ⁺ ) [M+H] ⁺ = 426.4. 1-[1-[7-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]prop-2-ynyl]-7-azaspiro[3.5]non-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 2c (59.0 mg, 0.15 mmol), intermediate 2i (63.8 mg, 0.15 mmol) and NMP (1.5 mL). The solution was stirred at room temperature for 30 min. Na(OAc) ₃ BH (95 mg, 0.45 mmol) was added and the reaction was stirred at room temperature for 15 min and then concentrated in vacuo. Purification by RPC (0-50% MeCN in water containing 0.1% FA) gave the title compound (12.12 mg, 9.84%). ¹ H NMR (DMSO- d 6): δ 0.66 - 0.70 (2H, m), 0.83 - 0.89 (2H, m), 1.70 - 1.80 (4H, m), 1.89 - 1.98 (3H, m), 2.14 (2H, br d), 2.20 - 2.28 (2H, m), 2.33 - 2.39 (2H, m), 2.43 - 2.48 (1H, m), 2.54 - 2.58 (1H, m), 2.76 (2H, t), 3.07 (2H, br d), 3.19 - 3.24 (2H, m), 3.45 (2H, s), 3.76 - 3.85 (4H, m), 4.44 (2H, br s), 5.26 (1H, quin), 5.92 (2H, s), 6.72 (1H, d), 6.83 (1H, t), 6.87 (1H, d), 6.89 - 6.96 (2H, m), 7.15 - 7.24 (2H, m), 7.47 (1H, s), 7.55 (1H, s), 7.91 (1H, dd), 7.94 (1H, d), 8.16 (1H, d), 10.37 (1H, s), 13.17 - 15.05 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 803.7. Example 3 Intermediate 3a: 1-(3-bromophenyl)-4-(dibutoxymethyl)piperidine

_A mixture of _Pd2 (dba) ₃ (0.229 g, 0.25 mmol), xantphos (0.289 g, 0.50 mmol) and potassium tert-butoxide (1.122 g, 10.00 mmol), 1-bromo-3-iodobenzene (0.956 mL, 7.50 mmol) and 4-(dibutoxymethyl)piperidine (1.217 g, 5 mmol) and toluene (36 mL) was degassed by bubbling N2 through the solution for 10 min. The reaction was heated to 85 °C for 1.75 h, cooled to room temperature and concentrated under reduced pressure. Purification by FSC (gradient: 0-20% EtOAc in hexanes) gave the title compound (1.758 g, 88%) as a yellow oil. ¹ H NMR (CDCl ₃ ): δ 0.94 (6H, t), 1.35 - 1.49 (6H, m), 1.53 - 1.63 (4H, m), 1.71 - 1.84 (1H, m), 1.87 (2H, br d), 2.65 - 2.73 (2H, m), 3.40 - 3.49 (2H, m), 3.64 (2H, dt), 3.69 (2H, br d), 4.19 (1H, d), 6.84 (1H, dd), 6.89 - 6.95 (1H, m), 7.03 - 7.06 (1H, m), 7.06 - 7.11 (1H, m); m/z (ES ⁺ ) [M+Na] ⁺ = 399.4. Intermediate 3b: 8-[3-[4-(dibutoxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 2e from benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.927 g, 3.77 mmol) and intermediate 3a (1.50 g, 3.77 mmol). Purification by FSC (gradient: 0-50% EtOAc in hexanes) gave the title compound (1.310 g, 61.7%) as a light brown oil. ¹ H NMR (CDCl ₃ ): δ 0.96 (6H, t), 1.39 - 1.54 (6H, m), 1.55 - 1.64 (4H, m), 1.71 - 1.91 (5H, m), 2.00 - 2.06 (2H, m), 2.67 (2H, td), 3.32 - 3.53 (4H, m), 3.62 - 3.74 (6H, m), 3.79 (1H, br d), 4.19 - 4.25 (2H, m), 5.15 (2H, s), 6.29 - 6.35 (1H, m), 6.38 - 6.45 (2H, m), 7.13 (1H, t), 7.30 - 7.39 (5H, m); m/z (ES ⁺ ) [M+Na] ⁺ = 586.7. Intermediate 3c: 8-[3-[4-(dibutoxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octane

Pd/C (100 mg, 0.09 mmol) was added to intermediate 3b (1.3095 g, 2.32 mmol) and ammonium formate (1.465 g, 23.23 mmol) in MeOH (15 mL) and stirred at 50 °C for 30 min. The reaction was cooled to room temperature, filtered through a plug of celite®, eluting with MeOH and EtOAc and concentrated. The resulting residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO ₃ solution (20 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic extracts were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude product was of sufficient purity and was used directly in the next step without subsequent purification to give the title compound as a yellow solid (0.838 g, 84%). ¹ H NMR (DMSO- d 6): δ 0.89 (6H, t), 1.27 - 1.41 (6H, m), 1.45 - 1.55 (4H, m), 1.71 (3H, br d), 1.78 - 1.93 (4H, m), 2.39 (2H, br d), 2.49 - 2.59 (3H, m), 2.95 (2H, br d), 3.39 (2H, dt), 3.56 (2H, dt), 3.63 (2H, br d), 4.04 (2H, br s), 4.19 (1H, d), 6.18 - 6.25 (2H, m), 6.29 (1H, s), 6.96 (1H, t); m/z (ES ⁺ ) [M+Na] ⁺ = 452.2. Intermediate 3d: 6-chloro-4-[8-[3-[4-(dibutoxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

A mixture of intermediate 3c (838.2 mg, 1.95 mmol), 4-bromo-6-chlorotitanium-3-amine (813 mg, 3.90 mmol), DIPEA (9.75 mmol, 1.704 mL) and n-butanol (10 mL) was heated at 110 °C for 8 h. The reaction was cooled to room temperature and concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (657 mg, 60.4%) as a brown solid. ¹ H NMR (DMSO- d 6): δ 0.89 (6H, t), 1.27 - 1.40 (6H, m), 1.44 - 1.53 (4H, m), 1.61 - 1.74 (3H, m), 1.87 - 1.94 (2H, m), 2.05 - 2.11 (2H, m), 2.52 - 2.59 (2H, m), 2.95 (2H, br d), 3.17 (2H, br d), 3.34 - 3.43 (2H, m), 3.56 (2H, dt), 3.66 (2H, br d), 4.19 (1H, d), 4.34 (2H, br s), 5.79 (2H, s), 6.27 (1H, br d), 6.31 (1H, br d), 6.39 (1H, s), 6.85 (1H, s), 7.00 (1H, t); m/z (ES ⁺ ) [M+H] ⁺ = 557.2. Intermediate 3e: 2-[6-amino-5-[8-[3-[4-(dibutyloxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 3d (547 mg, 0.98 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (516 mg, 85%) as a brown solid. ¹ H NMR (DMSO- d 6): δ 0.89 (6H, t), 1.27 - 1.40 (6H, m), 1.45 - 1.51 (4H, m), 1.58 - 1.77 (3H, m), 1.88 - 2.02 (2H, m), 2.10 - 2.18 (2H, m), 2.54 - 2.61 (2H, m), 3.11 (2H, br d), 3.27 (2H, br d), 3.39 (2H, dt), 3.56 (2H, dt), 3.67 (2H, br d), 4.19 (1H, d), 4.39 (2H, br s), 5.97 (2H, br s), 6.28 (1H, br d), 6.35 (1H, br d), 6.43 (1H, s), 6.84 - 6.90 (2H, m), 7.02 (1H, t), 7.23 (1H, t), 7.45 (1H, s), 7.89 (1H, d), 14.05 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 615.4. 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 3e (30.7 mg, 0.05 mmol), intermediate 2b (24.68 mg, 0.05 mmol), and formic acid (0.5 mL). The reaction was stirred at 40 °C for 20 min and then concentrated in vacuo. The resulting film was taken up in DCM (0.5 mL) and iPrOH (0.100 mL) and stirred at room temperature for 30 min. Na(OAc) ₃ BH (21.19 mg, 0.10 mmol) was added and the reaction was stirred at room temperature for 30 min and then concentrated in vacuo. Purification by RPC (0-100% MeCN in water containing 0.1% NH ₄ OH) gave the title compound (11.57 mg, 26.1%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.69 (2H, br d), 0.81 - 0.92 (2H, m), 1.15 - 1.22 (2H, m), 1.24 - 1.31 (2H, m), 1.63 - 1.80 (6H, m), 1.90 - 1.98 (3H, m), 2.09 - 2.26 (6H, m), 2.28 - 2.45 (5H, m), 2.62 (2H, br t), 2.76 (2H, br t), 3.10 (2H, br d), 3.26 (2H, br d), 3.65 (2H, br d), 3.81 (2H, br t), 4.39 (2H, br s), 5.25 (1H, quin), 5.93 (2H, br s), 6.25 - 6.31 (1H, m), 6.34 (1H, br d), 6.42 (1H, br s), 6.81 - 6.92 (2H, m), 7.02 (1H, br t), m/z ( ES ⁺ ) [M+H] ⁺ = 862.6. Example 4 Intermediate 4a: 2-(5-bromo-3-methyl-indol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

A vial was charged with 5-bromo-3-methyl- 1H -indole (525 mg, 2.5 mmol), tributyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (1207 mg, 5.00 mmol), 2-( tributyl -15-phosphino)acetonitrile (1.310 mL, 5.00 mmol) and toluene (12 mL). The reaction was heated to 100 °C for 6 h, cooled to room temperature and concentrated in vacuo. Purification by FCS (0-50% EtOAc in hexanes) gave the title compound (824 mg, 76%) as a yellow solid. ¹ H NMR (CDCl ₃ ): δ 1.48 (9H, s), 1.59 - 1.64 (2H, m), 1.70 - 1.77 (2H, m), 2.16 - 2.22 (2H, m), 2.30 (3H, s), 2.51 - 2.58 (2H, m), 3.31 - 3.39 (2H, m), 3.42 - 3.49 (2H, m), 4.80 (1H, quin), 7.02 (1H, s), 7.14 (1H, d), 7.23 - 7.26 (1H, m), 7.68 (1H, d); m/z (ES ⁺ ) [M- t Bu+2H] ⁺ = 377.1. Intermediate 4b: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

A vial was charged with intermediate 4a (824 mg, 1.90 mmol), hexahydropyrimidine-2,4-dione (651 mg, 5.70 mmol), Cs ₂ CO ₃ (1239 mg, 3.80 mmol), Ephos (102 mg, 0.19 mmol) and Ephos Pd G4 (175 mg, 0.19 mmol). The vial was evacuated and backfilled with nitrogen. 1,4-Dioxathiocarbamide (12 mL) was added, and the reaction mixture was then degassed by bubbling nitrogen through the solution for 10 min. The vial was sealed and the resulting mixture was stirred at 100 °C for 16 h. The solvent was removed. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (727 mg, 82%) as an off-white solid. ¹ H NMR (DMSO- d 6): δ 1.39 (9H, s), 1.53 - 1.59 (2H, m), 1.64 - 1.71 (2H, m), 2.09 - 2.14 (2H, m), 2.24 (3H, s), 2.41 - 2.47 (2H, m), 2.71 (2H, t), 3.19 - 3.27 (2H, m), 3.32 - 3.36 (2H, m), 3.75 (2H, t), 4.98 (1H, quin), 7.03 (1H, dd), 7.36 - 7.43 (3H, m), 10.23 (1H, s); m/z (ES ⁺ ) [M+Na] ⁺ = 489.2. 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting from intermediate 3e (30.7 mg, 0.05 mmol) and intermediate 4b (23.33 mg, 0.05 mmol) in a similar manner to Example 3. Purification by RPC (0-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (11.30 mg, 25.5%) as a light yellow solid. ¹ H NMR (DMSO- d 6): δ 1.15 - 1.28 (6H, m), 1.62 - 1.68 (2H, m), 1.72 - 1.81 (3H, m), 1.89 - 1.97 (2H, m), 2.04 - 2.16 (4H, m), 2.19 - 2.22 (1H, m), 2.24 (3H, s), 2.29 - 2.34 (1H, m), 2.36 - 2.46 (3H, m), 2.61 (2H, br t), 2.71 (3H, br t), 3.08 (2H, br d), 3.25 (2H, br d), 3.64 (2H, br d), 3.75 (2H, br t), 4.38 (2H, br s), 4.88 - 5.01 (1H, m), 5.92 (2H, br s), 6.27 (1H, br d), 6.33 (1H, br d), 6.41 (1H, br s), 6.81 - 6.89 (2H, m), 6.94 - 7.09 (2H, m), 7.21 (1H, br t), 7.34 - 7.49 (4H, m), 7.90 (1H, br d), 10.23 (1H, s), 12.39 - 14.59 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 835.6. Example 5 Intermediate 5a: 4-(4-bromoindol-1-yl)piperidine-1-carboxylic acid tributyl ester

2-(tributyl- 15 -phosphine)acetonitrile (92.0 g, 382.56 mmol) was added to _a stirred solution of tributyl 4-hydroxypiperidine-1-carboxylate (77.0 g, 382.56 mmol) and 4-bromo- 1H -indole (50.0 g, 255.04 mmol) in toluene (500 mL) under N2 at room temperature. The resulting mixture was stirred at 100 ° C. for 18 h, and then cooled to room temperature and concentrated under reduced pressure. Purification by RPC (gradient: 0-70% MeCN in water _containing 0.4% _NH4HCO3 ) gave the title compound (20.0 g, 21%) as a yellow solid. ¹ H NMR (DMSO- d 6): δ 1.44 (9H, s), 1.76-2.00 (4H, m), 2.98 (2H, m), 4.13 (2H, d), 4.60 (1H, m), 6.42 (1H, d), 7.08 (1H, t), 7.23-7.28 (1H, m), 7.58-7.74 (2H, m); m/z (ES ⁺ ) [M+H] ⁺ = 379.1. Intermediate 5b: 4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]piperidine-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4b starting from intermediate 5a (5 g, 13.18 mmol). Purification by FSC (gradient: 0-60% EtOAc in petroleum ether) gave the title compound (5.20 g, 96%) as a yellow solid. ¹ H NMR (CDCl ₃ ): δ 1.52 (9H, s), 1.86-2.01 (2H, m), 2.06-2.14 (2H, m), 2.86-3.00 (4H, m), 3.95 (2H, t), 4.23-4.50 (3H, m), 6.42 (1H, d), 7.06 (1H, d), 7.22-7.27 (2H, m), 7.38 (1H, d), 7.55 (1H, s); m/z (ES ⁺ ) [M+Na] ⁺ = 435.2. Intermediate 5c: 1-[1-(4-piperidinyl)indol-4-yl]hexahydropyrimidine-2,4-dione

Intermediate 5b (7.0 g, 16.97 mmol) was added to AcOH (20 mL). The resulting mixture was stirred at 100 °C for 72 h, and then cooled to room temperature and concentrated under reduced pressure. Purification by RPC (gradient: 0-60% MeCN in water containing 0.4% HCl) gave the title compound as a red solid in the form of the hydrochloride salt (4.50 g, 85%). ¹ H NMR (DMSO- d 6): δ 1.89-2.30 (4H, m), 2.47-2.50 (2H, m), 2.75 (2H, t), 2.99-3.14 (2H, m), 3.76 (2H, t), 4.60-4.77 (1H, m), 6.44 (1H, d), 6.97 (1H, d), 7.16 (1H, t), 7.39 (1H, d), 7.57 (1H, d), 10.33 (1H, s) (NH protons not observed); m/z (ES ⁺ ) [M+H] ⁺ = 313.2. 1-[1-[1-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-4-piperidinyl]indol-4-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 3e (61.5 mg, 0.1 mmol) and intermediate 5c (97 mg, 0.20 mmol) in a similar manner to Example 3. Purification by RPC (0-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (22.30 mg, 26.3%) as a light yellow solid. ¹ H NMR (DMSO- d 6): δ 1.18 - 1.25 (2H, m), 1.61 - 1.72 (1H, m), 1.80 (2H, br d), 1.88 - 2.05 (6H, m), 2.09 - 2.15 (2H, m), 2.19 (2H, br t), 2.26 (2H, br d), 2.62 (2H, br t), 2.75 (2H, t), 3.00 (2H, br d), 3.09 (2H, br d), 3.25 (2H, br d), 3.66 (2H, br d), 3.77 (2H, t), 4.30 - 4.48 (3H, m), 5.92 (2H, s), 6.28 (1H, br d), 6.33 (1H, br d), 6.36 - 6.46 (2H, m), 6.81 - 6.88 (2H, m), 6.93 - 6.97 (1H, m), 7.01 (1H, t), 7.10 - 7.17 (1H, m), 7.21 (1H, t), 7.42 - 7.47 (1H, m), 7.48 - 7.54 (2H, m), 7.90 (1H, br d), 10.31 (1H, s), 12.34 - 14.69 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 781.4. Example 6 Intermediate 6a: 9-(5-Bromo-3-methyl-indol-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

2-(tributyl-15-phosphine)acetonitrile (3.74 mL , 14.28 mmol) was added to tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (2.56 g, 9.52 mmol) and 5-bromo-3-methylindole (1 g, 4.76 mmol) in toluene (20 mL) at room temperature under nitrogen. The resulting mixture was stirred at 120° C. for 16 h. The reaction mixture was poured into water (200 mL), extracted with EtOAc (3 x 200 mL), and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by FSC (gradient: 0 to 20% EtOAc in petroleum ether) gave the title compound (1.900 g, 86%) as a white solid. ¹ H NMR (DMSO- d 6) δ 1.24-1.38 (4H, m), 1.41 (9H, s), 1.58 (2H, t), 1.65-1.97 (7H, m), 2.22 (3H, d), 3.31 (2H, d), 3.34 (1H, s), 4.17-4.34 (1H, m), 7.20 (1H, dd), 7.38 (1H, s), 7.44 (1H, d), 7.64 (1H, d); m/z (ES ⁺ ) [M-tBu+2H] ⁺ = 405.2. Intermediate 6b: 9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Under nitrogen, di-μ-chlorobis[(1,2,3-4)-1-phenyl-2-propenyl]dipalladium(II) (0.057 g, 0.10 mmol) was added to intermediate 6a (1.9 g, 4.12 mmol), hexahydropyrimidine-2,4-dione (1.409 g, 12.35 mmol), Cs ₂ CO ₃ (4.02 g, 12.35 mmol) and 2-(di-tri-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (0.100 g, 0.21 mmol) in dioxane (40 mL). The resulting mixture was stirred at 100°C for 10 h. The reaction mixture was filtered through celite®. The filtrate was poured into water (500 mL), extracted with EtOAc (3 x 500 mL), the combined organic extracts were dried ( _Na2SO4 ), _filtered and evaporated. The crude product was purified by FSC (Gradient: 0 to 10% MeOH in DCM) to give the title compound (1.0 g, 49.1%) as a brown solid. ¹ H NMR (DMSO- d 6): δ 1.41 (13H, s), 1.60 (2H, t), 1.69-2 (6H, m), 2.24 (3H, d), 2.51 (2H, t), 2.73 (2H, t), 3.77 (2H, t), 4.28 (1H, s), 5.76 (2H, s), 7.04 (1H, dd), 7.33-7.42 (2H, m), 7.45 (1H, d), 10.26 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 495.2. Intermediate 6c: 1-[1-(3-azaspiro[5.5]undecane-9-yl)-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

p-Toluenesulfonic acid (0.627 g, 3.64 mmol) was added to intermediate 6b (1.5 g, 3.03 mmol) in MeCN (30 mL) and stirred at 70 °C for 3 h. The product was filtered to afford the title compound as p-toluenesulfonate salt as a white solid (1.0 g, 58.2%). m/z (ES ⁺ ) [M+H] ⁺ = 395.1. Intermediate 6d: 8-(3-bromophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 1b starting from 1,3-dibromobenzene (2.22 g, 9.42 mmol) and tri-butyl (3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2 g, 9.42 mmol). Purification by FSC (gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound as a white solid (2.2 g, 63.6%); m/z (ES ⁺ ) [M+H] ⁺ = 367.0. Intermediate 6e: tri-butyl 8-[3-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

A mixture of RuPhos (0.254 g, 0.54 mmol), RuPhos Pd G3 (0.455 g, 0.54 mmol), Cs ₂ CO ₃ (5.32 g, 16.34 mmol), 4-(dimethoxymethyl)piperidine (0.867 g, 5.45 mmol) and intermediate 6d (2 g, 5.45 mmol) in 1,4-dioxathiol (40 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (3 x 500 mL), and the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. Purification by FSC (gradient: 0 to 40% EtOAc in petroleum ether) gave the title compound as a yellow solid (2.0 g, 82%); m/z (ES ⁺ ) [M+H] ⁺ = 446.2. Intermediate 6f: 6-Chloro-4-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

HCl (10 mL, 40.00 mmol) in MeOH was added to intermediate 6e (1.3 g, 2.92 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to provide the amine. To the crude amine were added 4-bromo-6-chloroindole-3-amine (0.608 g, 2.92 mmol), DIPEA (0.377 g, 2.92 mmol) and MeCN (15 mL) at room temperature. The resulting mixture was stirred at 80 °C for 3 days. The reaction mixture was diluted with water (200 mL), extracted with EtOAc (3 x 200 mL), and the organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated. Purification by RPC (Gradient: 5% to 100% MeCN in water containing 0.1% NH ₄ HCO ₃ ) gave the title compound (0.900 g, 65.2%) as a yellow solid. ¹ H NMR (DMSO- d 6): δ 1.92 (1H, s), 2.29 (3H, s), 3.06-3.21 (8H, m), 3.36 (6H, s), 3.52-3.69 (7H, m), 5.77 (4H, s), 7.13 (2H, d), 7.42-7.53 (2H, m); m/z (ES ⁺ ) [M+H] ⁺ = 473.0. Intermediate 6g: 1-[1-[3-[[1-[3-[3-(3-amino-6-chloro-indole-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Formic acid (1.0 mL) was added to intermediate 6f (100 mg, 0.21 mmol). The resulting mixture was stirred at 40 °C for 30 min. The solvent was removed under reduced pressure to provide the aldehyde. To the crude aldehyde was added intermediate 6c (120 mg, 0.21 mmol) and DCM (1 mL) at room temperature. To the resulting solution was added sodium triacetoxyborohydride (67.2 mg, 0.32 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (25 mL) and washed with saturated NH ₄ HCO ₃ (3 x 25 mL). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and evaporated. Purification by FCS (gradient: 0 to 10% MeOH in DCM) gave the title compound (60.0 mg, 35.2%) as a yellow solid. ¹ H NMR (DMSO- d 6): δ 1.15-1.51 (4H, m), 1.84 (14H, d), 2.09 (2H, d), 2.21-2.32 (5H, m), 2.57-2.77 (5H, m), 2.95 (2H, d), 3.17 (2H, d), 3.66 (3H, d), 3.77 (3H, t), 4.32 (4H, d), 5.82 (2H, s), 6.26-6.46 (3H, m), 6.87 (1H, s), 6.97-7.1 (2H, m), 7.3-7.49 (4H, m), 10.26 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 805.0. 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 2h starting from intermediate 6g (45 mg, 0.06 mmol). Purification by RPC (gradient: 0-50% MeCN in water containing 0.1% FA) gave the title compound (6.80 mg, 14.10%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.12-1.26 (2H, m), 1.29-1.41 (4H, m), 1.67 (3H, s), 1.77 (6H, q), 1.88 (2H, d), 1.92-1.98 (2H, m), 2.17 (4H, dd), 2.23 (3H, d), 2.37 (4H, s), 2.62 (2H, t), 2.73 (2H, t), 3.10 (2H, d), 3.25 (1H, s), 3.27 (1H, d), 3.65 (2H, d), 3.77 (2H, t), 4.26 (1H, t), 4.39 (2H, d), 5.95 (2H, s), 6.25-6.37 (2H, m), 6.43 (1H, t), 6.81-6.91 (2H, m), 6.98-7.08 (2H, m), 7.19-7.27 (1H, m), 7.38 (2H, dd), 7.41-7.49 (2H, m), 7.92 (1H, dd), 8.19 (1H, d), 10.27 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 863.4. Example 7 Intermediate 7a: 1-(5-chloro-2-fluoro-phenyl)-4-(dimethoxymethyl)piperidine

Copper(I) iodide (0.074 g, 0.39 mmol) was added to L -proline (0.045 g, 0.39 mmol), K ₃ PO ₄ (2.483 g, 11.70 mmol), 4-(dimethoxymethyl)piperidine (0.621 g, 3.90 mmol) and 4-chloro-1-fluoro-2-iodobenzene (1 g, 3.90 mmol) in DMF (13 mL) under nitrogen. The resulting mixture was stirred at 100° C. for 16 h. Purification by RPC (gradient: 5% to 100% MeOH in water containing 0.5% NH ₄ HCO ₃ ) gave the title compound (0.470 g, 41.9%) as a grey solid. ¹ H NMR (DMSO- d 6) δ 1.21 - 1.46 (3H, m), 1.64 - 1.78 (3H, m), 2.57 - 2.68 (2H, m), 3.28 (6H, s), 3.43 (1H, s), 4.11 (1H, d), 6.93 - 7.03 (2H, m), 7.10 - 7.19 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 288.3. Intermediate 7b: 8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 2e from tributyl (3,8-diazabicyclo[3.2.1]octane-3-carboxylate (332 mg, 1.56 mmol) and intermediate 7a (450 mg, 1.56 mmol). Purification by RPC (gradient: 5% to 100% MeOH in water containing 0.5% NH ₄ HCO ₃ ) gave the title compound as a yellow solid (410 mg, 56.6%). ¹ H NMR (DMSO- d 6): δ 1.33 - 1.36 (1H, m), 1.33 (10H, m), 1.42 - 1.51 (1H, m), 1.60 - 1.76 (6H, m), 1.82 - 1.91 (2H, m), 2.52- δ 0.14 - 0.13 (2H, m), 0.25 - 0.25 (2H, m), 0.12 - 0.25 (2H, m), 0.25 - 0.25 (2H, m), 0.25 - 0.25 (2H, m); m/z (ES ⁺ ) [M+H] ⁺ = 464.4. Intermediate 7c: 8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane

HCl (6 mL, 197.49 mmol, 4.0 M) in MeOH was added to intermediate 7b (400 mg, 0.86 mmol). The resulting mixture was stirred at room temperature for 3 h. The pH of the reaction mixture was adjusted to 9 with 7 M ammonia methanol solution. The solvent was removed under reduced pressure. The reaction mixture was diluted with MeOH:DCM (1:3) (15 mL) and the solid was filtered off. The filtrate was concentrated under reduced pressure to provide the title compound (300 mg, 87%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.27 - 1.49 (2H, m), 1.67 - 1.75 (3H, m), 1.95 - 2.16 (5H, m), 2.56 - 2.65 (2H, m), 2.88 - 2.95 (3H, m), 2.95 - 3.10 (2H, m ), 3.26 (6H, s), 3.32 - 3.40 (1H, m), 4.12 (1H, d), 4.33 (2H, s), 6.36 - 6.49 (2H, m), 6.91 - 7.03 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 364.2. Intermediate 7d: 6-chloro-4-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

Prepared in analogy to intermediate 3d starting from intermediate 7c (300 mg, 0.83 mmol). Purification by RPC (gradient: 5% to 100% MeCN in water _containing 0.5% _NH4HCO3 ) gave the title compound (200 mg, 45.3%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.50 - 1.60 (2H, m), 1.65 - 1.76 (1H, m), 1.77 - 1.84 (2H, m), 1.91 - 1.96 (2H, m), 2.02 - 2.15 (2H, m), 2.62 - 2.71 (3H, m), 3.02 - 3.18 (4H, m), 3.31 (6H, s), 3.39 - 3.46 (2H, m), 4.05 (1H, d), 4.16 - 4.27 (2H, m), 4.88 - 4.96 (1H, m), 6.31 (1H, s), 6.35 - 674 (2H, m), 6.78 - 6.91 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 492.5. Intermediate 7e: 2-[6-amino-5-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]phthalim-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 7d. Purification by FSC (gradient: 0 to 10% MeOH in DCM) gave the title compound (160 mg, 82%) as a yellow solid. ¹ H NMR (DMSO- d 6) δ 1.23 - 1.27 (2H, m), 1.39 - 1.42 (2H, m), 1.62 - 1.81 (4H, m), 1.91 - 1.97 (3H, m), 2.10 - 2.20 (2H, m), 2.53 - 2.63 (3H, m), 3.05 - 3.13 (2H, m), 3.27 (6H, s), 4.25 - 4.31 (2H, m), 5.95 (2H, s), 6.44 - 6.49 (2H, m), 6.79 - 6.92 (3H, m), 7.02 - 7.27 (1H, m), 7.47 (1H, s), 7.91 (1H, d), 14.19 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 549.7 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 7e (40 mg, 0.07 mmol) and intermediate 2b (28.7 mg, 0.07 mmol) in a similar manner to Example 3. Purification by RPC (gradient: 10%-50% MeCN in water containing 0.1% FA) gave the title compound (11.0 mg, 16.46%) as a white solid. ¹ H NMR (DMSO- d 6) δ 0.66 - 0.73 (2H, m), 0.84 - 0.91 (2H, m), 1.21 - 1.29 (2H, m), 1.66 - 1.83 (7H, m), 1.90 - 1.98 (3H, m), 2.10 - 2.20 (5H, m), 2.19 - 2.36 (2H, m), 2.25 - 2.36 (5H, m), 2.59 - 2.68(2H, m), 2.77 (2H, t), 3.05 - 3.18 (2H, m), 3.21 - 3.29 (2H, m), 3.34 - 3.40 (2H, m), 3.82 (2H, t), 7 - 7.14 (2H, m), 11.7 - 11.9 (1H, s), 7.1 - 7.2 (2H, m), 7.4 - 7.3 (1H, s), 7.6 - 7.4 (1H, s), 7.8 - 7.9 (2H, m), 8.17 (1H, d), 10.40 (1H, s) (OH proton not observed); ¹⁹ F NMR (DMSO- d 6) δ -136.41; m / z (ES ⁺ ) [M + H] ⁺ = 880.6. Example 8 Intermediate 8a: 8-(3-bromo-5-fluoro-phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 1b starting from 1,3-dibromo-5-fluorobenzene (2 g, 7.88 mmol) and tributyl (3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.672 g, 7.88 mmol). Purification by FSC (gradient: 0 to 10% EtOAc in petroleum ether) gave the title compound as a white solid (1.280 g, 42.2%). ¹ H NMR (DMSO- d 6) δ 1.39 (9H, s), 1.61 - 1.72 (2H, m), 1.86 - 1.96 (2H, m), 3.03 (2H, dd), 3.55 (2H, t), 4.33 (2H, s), 6.65 - 6.78 (2H, m), 6.86 - 6.91 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 385. Intermediate 8b: 8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-5-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 6e starting from intermediate 8a (1.28 g, 3.32 mmol). Purification by FSC (gradient: 0 to 40% EtOAc in petroleum ether) gave the title compound (0.790 g, 51.3%) as a yellow solid. ¹ H NMR (DMSO- d 6) δ 1.27 (2H, d), 1.39 (9H, s), 1.60 - 1.72 (5H, m), 1.84 - 1.95 (2H, m), 2.54 - 2.66 (2H, m), 3.06 (2H, dd), 3.27 (6H, s), 3.52 (2H, t), 3.70 (2H, d), 4.08 (1H, d), 4.26 (2H, s), 5.94 - 6.17 (3H, m); m/z (ES ⁺ ) [M+H] ⁺ = 464. Intermediate 8c: 6-chloro-4-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-5-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

Prepared in an analogous manner to intermediate 6f starting from intermediate 8b (490 mg, 1.06 mmol). Purification by RPC (gradient: 3% to 80% MeCN in water containing 0.1% NH ₄ HCO ₃ ) gave the title compound (260 mg, 50.1%) as a yellow solid. ¹ H NMR (DMSO- d 6) δ 1.21 - 1.36 (2H, m), 1.62 - 1.74 (3H, m), 1.87 - 1.95 (2H, m), 2.05 - 2.15 (2H, m), 2.60 (2H, t), 2.93 (2H, d), m/ z (ES ⁺ ) [M+H] ⁺ = 491.2. Intermediate 8d: 2-[6-amino-5-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-5-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 8c (200 mg, 0.41 mmol). Purification by FSC (gradient: 0 to 100% DCM in petroleum ether and 0 to 10% EtOH in DCM) gave the title compound (210 mg, 94%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 0.83 - 0.96 (2H, m), 1.22 - 1.28 (2H, m), 1.64 - 1.73 (3H, m), 1.91 - 2.00 (2H, m), 2.15 (2H, d), 2.61 (2H, t), 3.08 (2H, d), 3.25 (6H, s), 3.71 (2H, d), 4.08 (1H, d), 4.41 (2H, s), 5.96 (2H, s), 6.16 - 6.20 (1H, m), 6.73 - 6.78 (1H, m), 6.84 - 6.90 (2H, m), 7.10 - 7.20 (1H, m), 7.48 (1H, s), 7.89 - 7.96 (1H, m), 9.33 (1H, s), 14.17 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 549. 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 8d (60 mg, 0.11 mmol) and intermediate 2c (51.6 mg, 0.13 mmol) in a similar manner to Example 1. Purification by RPC (gradient: 0-38% MeCN in water containing 0.1% FA) gave the title compound (14.88 mg, 14.72%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.66 - 0.71 (2H, m), 0.84 - 0.90 (2H, m), 1.17 (2H, dtd), 1.60 - 1.80 (6H, m), 1.93 (3H, dp), 2.05 - 2.25 (8H, m), 2.34 (5H, dd), 2.76 (2H, t), 3.09 (2H, d), 3.25 (3H, d), 3.63 (3H, d), 3.81 (2H, t), 4.34 - 4.40 (2H, m), 5.24 (1H, p), 5.94 (2H, s), 6.11 (1H, s), 6.21 (2H, d), 6.82 - 6.89 (2H, m), 7.23 (1H, t), 7.46 (1H, s), 7.56 (1H, s), 7.89 - 7.97 (2H, m), 8.17 (1H, d), 10.41 (1H, s); ¹⁹ F NMR (DMSO- d 6) δ -73.44, -112.18; m/z (ES ⁺ ) [M+H] ⁺ = 880.6. Example 9 Intermediate 9a: 8-(3-bromo-5-methyl-phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 1b starting from 1,3-dibromo-5-methylbenzene (2 g, 8.00 mmol) and tributyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.7 g, 8.00 mmol). Purification by FSC (gradient: 0 to 7% EtOAc in petroleum ether) gave the title compound (2.0 g, 65.5%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.39 (9H, s), 1.59 - 1.73 (2H, m), 1.82 - 1.96 (2H, m), 2.22 (3H, s), 2.92 - 3.19 (2H, m), 3.54 (2H, t), 4.28 (2H, s), 6.64 - 6.70 (2H, m), 6.83 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 381. Intermediate 9b: 8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-5-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 6e starting from intermediate 9a (1 g, 2.62 mmol). Purification by FSC (gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound (0.900 g, 74.7%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.22 - 1.33 (2H, m), 1.39 (9H, s), 1.58 - 1.73 (5H, m), 1.82 - 1.93 (2H, m), 2.16 (3H, s), 2.56 (2H, d), 3.01 (1H, d), 3.15 (1H, d), 3.20 (6H, s), 3.51 (2H, t), 3.64 (2H, d), 4.08 (1H, d), 4.22 (2H, s), 6.07 - 6.21 (3H, m); m/z (ES ⁺ ) [M+H] ⁺ = 460. Intermediate 9c: 6-chloro-4-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-5-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

Prepared in analogy to intermediate 6f starting from intermediate 9b (500 mg, 1.09 mmol). Purification by RPC (gradient: 0 to 70% MeCN in water containing 0.1% FA) gave the title compound (410 mg, 77%). ¹ H NMR (DMSO- d6 ) δ 0.81 - 0.89 (2H, m), 1.22 - 1.36 (3H, m), 1.66 - 1.70 (2H, m), 1.85 - 1.93 (2H, m), 2.04 - 2.10 (1H, m), 2.16 (3H, s), 2.53 - 2.59 (1H, m), 2.94 (2H, d), 3.12 - 3.18 (2H, m), 3.27 (6H, s), 3.60 - 3.69 (2H, m), 4.08 (1H, d), 4.33 (2H, s), 5.81 (2H, s), 6.09 - 6.23 (3H, m), 6.87 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 487.0. Intermediate 9d: 2-[6-amino-5-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-5-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]phthalim-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 9c (200 mg, 0.41 mmol). Purification by FSC (gradient: 0 to 100% DCM in petroleum ether and 0 to 10% MeOH in DCM) gave the title compound (200 mg, 89%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.17 - 1.41 (4H, m), 1.60 - 1.73 (3H, m), 1.85 - 1.97 (2H, m), 2.11 (1H, d), 2.16 (3H, s), 2.55 (2H, d), 3.03 - 3.11 (2H, m), 3.21 (1H, s), 3.25 (6H, s), 3.59 - 3.68 (2H, m), 4.06 (1H, d), 4.35 (2H, s), 5.93 (1H, s), 6.09 (1H, s), 6.19 (2H, d), 6.80 - 6.89 (2H, m), 7.16 - 7.24 (1H, m), 7.44 (1H, s), 7.86 - 7.94 (1H, m), 14.15 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 545. 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 9d (60 mg, 0.11 mmol) and intermediate 2c (52.0 mg, 0.13 mmol) in a similar manner to Example 1. Purification by RPC (gradient: 0-38% MeCN in water containing 0.1% FA) gave the title compound (13.41 mg, 13.28%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.65 - 0.72 (2H, m), 0.83 - 0.91 (2H, m), 1.08 - 1.23 (2H, m), 1.57 - 1.81 (7H, m), 1.89 - 1.99 (3H, m), 2.10 - 2.25 (9H, m), 2.26 - 2.43 (6H, m), 2.59 - 2.70 (2H, m), 2.76 (2H, t), 3.07 (2H, d), 3.24 (2H, d), 3.69 (3H, d), 3.81 (2H, t), 4.41 (2H, d), 5.25 (1H, m), 5.96 (1H, s), 6.00 - 6.08 (1H, m), 6.10 - 6.23 (2H, m), 6.82 - 6.91 (2H, m), 7.19 - 7.26 (1H, m), 7.48 (1H, s), 7.56 (1H, s), 7.90 - 7.97 (2H, m), 8.14 - 8.18 (1H, m), 10.41 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 876.5. Example 10 Intermediate 10a: 8-(3-bromo-4-methyl-phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

₂ -Bromo-4-iodo-1-methylbenzene (2 g, 6.74 mmol) was added to tributyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.430 g, 6.74 mmol), sodium(II) acetate (0.151 g, 0.67 mmol), Cs ₂ CO ₃ (4.39 g, 13.47 mmol) and BINAP (0.419 g, 0.67 mmol) in 1,4-dioxathiocarboxylate (20 mL) under N 2. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with saturated NH ₄ Cl (100 mL x 2) and saturated brine (100 mL x 2). The organic layer was dried ( _Na2SO4 ), filtered and evaporated to provide the crude product. The crude product was purified by FSC (Gradient: 0 to 7% EtOAc in petroleum ether) to give the title compound (2.280 g, 89%) _as a purple solid. ¹ H NMR (DMSO- d6 ) δ 1.39 (9H, s), 1.61 - 1.72 (2H, m), 1.83 - 1.94 (2H, m), 2.22 (3H, s), 2.93 - 3.17 (2H, m), 3.53 (2H, t), 4.25 (2H, s), 6.76 - 6.83 (1H, m), 7.07 (1H, d), 7.11 - 7.17 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 381.3. Intermediate 10b: 8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-4-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 6e starting from intermediate 10a (1 g, 2.62 mmol). Purification by FSC (gradient: 0 to 30% MeCN in water containing 0.1% NH ₄ HCO ₃ ) gave the title compound (750 g, 62.2%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.36 - 1.46 (11H, m), 1.59 - 1.75 (5H, m), 1.81 - 1.92 (2H, m), 2.09 (3H, s), 2.52 - 2.67 (2H, m), 2.95 - 3.10 (3H, m), 3.10 - 3.18 (1H, m), 3.28 (6H, s), 3.52 (2H, t), 4.12 (1H, d), 4.20 (2H, s), 6.44 (2H, d), 6.94 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 460. Intermediate 10c: 6-chloro-4-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-4-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

Prepared in an analogous manner to intermediate 6f starting from intermediate 10b (370 mg, 0.80 mmol). Purification by RPC (gradient: 3% to 80% MeCN in water containing 0.1% NH ₄ HCO ₃ ) gave the title compound (256 mg, 65.3%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.26 - 1.45 (2H, m), 1.61 - 1.77 (3H, m), 1.85 - 1.96 (2H, m), 2.00-2.12 (2H, m), 2.09 (3H, s), 2.53 - 2.64 (2H, m), 2.95 (2H, d), 3.06 (2H, d), 3.16 (2H, d), 3.28 (6H, s), 4.12 (1H, d), 4.30 (2H, s), 5.81 (2H, s), 6.42 - 6.48 (2H, m), 6.86 (1H, s), 6.94 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 487. Intermediate 10d: 2-[6-amino-5-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-4-methyl-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 10c (200 mg, 0.41 mmol). Purification by FSC (gradient: 0 to 40% DCM in petroleum ether) gave the title compound (215 mg, 96%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.32 - 1.46 (2H, m), 1.59 - 1.76 (4H, m), 1.87 - 2.05 (3H, m), 2.10 (3H, s), 2.11 - 2.16 (1H, m), 2.53 - 2.61 (1H, m), 3.00 - 3.13 (4H, m), 3.21 - 3.25 (1H, m), 3.28 (6H, s), 3.43 - 3.61 (1H, m), 4.13 (1H, d), 4.35 (2H, s), 5.95 (1H, s), 6.45 - 6.54 (2H, m), 6.81 - 6.91 (2H, m), 6.93 - 7.03 (2H, m), 7.18 - 7.26 (1H, m), 7.42 - 7.48 (1H, m), 7.91 (1H, d) (OH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 545.3. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 10d (60 mg, 0.11 mmol) and intermediate 2c (52.0 mg, 0.13 mmol) in a similar manner to Example 1. Purification by RPC (gradient: 0-50% MeCN in water containing 0.1% FA) gave the title compound (14.05 mg, 14.23%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.66 - 0.72 (2H, m), 0.83 - 0.91 (2H, m), 1.18 - 1.31 (2H, m), 1.59 - 1.82 (6H, m), 1.89 - 1.98 (3H, m), 2.08 - 2.25 (10H, m), 2.27 - 2.39 (5H, m), 2.53 - 2.63 (2H, m), 2.76 (2H, t), 3.02 - 3.15 (5H, m), 3.25 (3H, d), 3.81 (2H, t), 4.34 (2H, s), 5.23 (1H, q), 5.93 (2H, s), 6.44 - 6.54 (2H, m), 6.86 (2H, t), 6.95 (1H, d), 7.23 (1H, t), 7.45 (1H, s), 7.55 (1H, s), 7.88 - 7.98 (2H, m), 8.17 (1H, d), 10.39 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 877.2. Example 11 Intermediate 11a: 9-(5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2a starting from 5-bromo-3-cyclopropyl- 1H -pyrrolo[2,3- b ]pyridine (593 mg, 2.5 mmol) and tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1010 mg, 3.75 mmol). Purification by FSC (0-50% EtOAc in hexanes) gave the title compound (816 mg, 66.8%) as a colorless dry film. ¹ H NMR (DMSO- d 6): δ 0.58 - 0.67 (2H, m), 0.76 - 0.91 (2H, m), 1.23 - 1.34 (4H, m), 1.39 (9H, s), 1.57 - 1.66 (4H, m), 1.78 (2H, br d), 1.89 - 1.97 (3H, m), 3.29 - 3.33 (4H, m), 4.56 (1H, tt), 7.52 (1H, s), 8.17 (1H, d), 8.24 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 490.2. Intermediate 11b: 9-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 11a (816 mg, 1.67 mmol). Purification by FCS (0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (420 mg, 48.2%) as a brown solid. ¹ H NMR (DMSO- d 6): δ 0.60 - 0.69 (2H, m), 0.79 - 0.90 (2H, m), 1.25 - 1.35 (4H, m), 1.39 (9H, s), 1.59 - 1.69 (4H, m), 1.80 (2H, br d), 1.87 - 1.94 (1H, m), 1.95 - 2.03 (2H, m), 2.75 (2H, t), 3.30 - 3.36 (4H, m), 3.80 (2H, t), 4.60 (1H, tt), 7.49 (1H, s), 7.92 (1H, d), 8.15 (1H, d), 10.35 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 522.7. Intermediate 11c: 1-(5-chloro-2-fluoro-phenyl)-4-(dibutoxymethyl)piperidine

A flask was charged with NaOtBu (27.5 g, 286.47 mmol), 4-(dibutoxymethyl)piperidine (23.24 g, 95.49 mmol), 2-bromo-4-chloro-1-fluorobenzene (20 g, 95.49 mmol), Pd ₂ (dba) ₃ (4.37 g, 4.77 mmol) and BINAP (5.95 m, 9.55) in toluene (300 mL) were added. The resulting mixture was stirred at 60°C under nitrogen for 20 h. The reaction mixture was diluted with EtOAc (500 mL) and washed successively with saturated NH ₄ Cl (500 mL) and saturated brine (500 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FCS (0-5% EtOAc in petroleum ether) gave the title compound (31.7 g, 89%) as a light yellow oil. ¹ H NMR (CDCl ₃ ): δ 0.96 (6H, t), 1.38 - 1.48 (4H, m), 1.49 - 1.65 (6H, m), 1.72 - 1.83 (1H, m), 1.89 (2H, br d), 2.53 - 2.73 (2H, m), 3.41 - 3.54 (4H, m), 3.61 - 3.73 (2H, m), 4.24 (1H, dd), 6.63 - 6.80 (1H, m), 6.88 - 6.99 (1H, m), 7.26 - 7.32 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 372.3. Intermediate 11d: 8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 2e starting from intermediate 11c (16.5 g, 44.36 mmol) and benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate HCl (12.54 g, 44.36 mmol). Purification by FSC (0-25% EtOAc in petroleum ether) gave the title compound (16.88 g, 65.4%) as a red oil. ¹ H NMR (DMSO- d 6): δ 0.89 (6H, t), 1.27 - 1.41 (6H, m), 1.43 - 1.56 (4H, m), 1.58 - 1.77 (5H, m), 1.84 - 1.96 (2H, m), 2.52 - 2.63 (2H, m), 3.07 - 3.28 (2H, m), 3.32 - 3.45 (4H, m), 3.50 - 3.63 (4H, m), 4.15 - 4.29 (3H, m), 5.00 - 5.14 (2H, m), 6.33 - 6.46 (2H, m), 6.85 - 6.98 (1H, dd), 7.24 - 7.48 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 582.4. Intermediate 11e: 8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane

Under hydrogen atmosphere, a flask was charged with intermediate 11d (9.8 g, 16.5 mmol), Pd/C (0.896 g, 0.84 mmol) and MeOH (300 mL). The reaction was stirred at room temperature for 24 h. The solution was filtered and concentrated to give the title compound (7.10 g, 94%) as a brown oil. ¹ H NMR (DMSO- d 6): δ 0.89 (6H, t), 1.29 - 1.42 (6H, m), 1.45 - 1.53 (4H, m), 1.59 - 1.68 (1H, m), 1.68 - 1.76 (2H, m), 1.79 - 1.92 (4H, m), 2.38 (2H, br d), 2.52 - 2.60 (2H, m), 2.94 (2H, br d), 3.32 (2H, br d), 3.36 - 3.44 (2H, m), 3.53 - 3.60 (2H, m), 3.94 - 4.03 (2H, m), 4.22 (1H, d), 6.29 (1H, br d), 6.34 (1H, br d), 6.87 (1H, dd) (NH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 448.3. Intermediate 11f: 6-Chloro-4-[8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

A flask was charged with intermediate 11e (12.7 g, 28.4 mmol), 4-bromo-6-chloroindole-3-amine (6.21 g, 29.79 mmol), DIPEA (14.87 mL, 85.1 mmol) and DMSO (100 mL). The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and washed sequentially with water (2 x 200 mL) and saturated brine (2 x 200 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated. Purification by FSC (gradient: 0-5% MeOH in DCM) gave the title compound (13.49 g, 83%) as a red oil. ¹ H NMR (DMSO- d 6): δ 0.89 (6H, t), 1.30 - 1.42 (6H, m), 1.46 - 1.53 (4H, m), 1.60 - 1.68 (1H, m), 1.73 (2H, br d), 1.88 - 1.94 (2H, m), 2.04 - 2.12 (2H, m), 2.55 - 2.62 (2H, m), 2.95 (2H, br d), 3.16 (2H, br d), 3.33 - 3.43 (4H, m), 3.56 (2H, dt), 4.22 (1H, d), 4.27 - 4.33 (2H, m), 5.76 - 5.82 (2H, m), 6.38 - 6.45 (2H, m), 6.87 (1H, s), 6.91 (1H, dd). m/z (ES ⁺ ) [M-OBu] ⁺ = 501.4. Intermediate 11g: 2-[6-amino-5-[8-[3-[4-(dibutyloxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 11f (281 mg, 0.49 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (202 mg, 65.2%) as a light brown solid. ¹ H NMR (DMSO- d 6): δ 0.88 (6H, t), 1.29 - 1.42 (6H, m), 1.43 - 1.52 (4H, m), 1.58 - 1.68 (1H, m), 1.72 (2H, br d), 1.89 - 1.96 (2H, m), 2.07 - 2.15 (2H, m), 2.58 (2H, br t), 3.08 (2H, br d), 3.24 (2H, br d), 3.32 - 3.43 (4H, m), 3.55 (2H, dt), 4.21 (1H, d), 4.30 - 4.36 (2H, m), 5.92 (2H, s), 6.39 - 6.50 (2H, m), 6.80 - 6.98 (3H, m), 7.21 (1H, t), 7.45 (1H, s), 7.89 (1H, d), 14.15 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 633.6. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 11b (0.092 g, 0.18 mmol), intermediate 11g (0.112 g, 0.18 mmol) and formic acid (2 mL, 52.15 mmol) was added, and the mixture was stirred at 40 °C for 20 min. The reactant was concentrated under reduced pressure. Toluene (12 mL) was added and the reactant was evaporated to dryness. DMF (2 mL) and MgSO ₄ (0.107 g, 0.88 mmol) were added. The mixture was stirred at 40 °C for 30 min. Na(OAc) ₃ BH (0.075 g, 0.35 mmol) was added, and the mixture was stirred at room temperature for 20 min. Purification by RPC (0-50% MeCN in water containing 0.1% FA) gave the title compound (0.067 g, 41.2%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.63 - 0.70 (2H, m), 0.81 - 0.90 (2H, m), 1.21 - 1.35 (4H, m), 1.36 - 1.44 (2H, m), 1.61 - 1.85 (9H, m), 1.89 - 2.04 (5H, m), 2.14 (2H, br d), 2.27 (2H, br d), 2.36 - 2.47 (4H, m), 2.65 (2H, br t), 2.77 (2H, t), 3.11 (2H, br d), 3.27 (2H, br d), 3.36 (2H, br d), 3.82 (2H, t), 4.35 (2H, br s), 4.59 (1H, br t), 5.94 (2H, s), 6.39 - 6.53 (2H, m), 6.83 - 6.98 (3H, m), 7.23 (1H, t), 7.49 (2H, d), 7.87 - 7.96 (2H, m), 8.13 - 8.20 (1H, m), 10.37 (1H, s), 13.30 - 14.81 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 908.7. Example 12 Intermediate 12a: 2-(5-bromoindol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a from tributyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (2.462 g, 10.20 mmol) and 5-bromo- 1H -indole (2 g, 10.20 mmol). Purification by RPC (gradient: 3% to 100% MeOH in MeOH (0.1% _{NH4HCO3 )} ) gave the title compound (4.15 mg, 97%) as an off-white solid. ¹ H NMR (DMSO- d6) δ 1.41 (9H, s), 1.54 - 1.59 (2H, m), 1.66 - 1.72 (2H, m), 2.11 - 2.20 (2H, m), 2.44 - 2.50 (2H, m), 3.22 - 3.27 (2H, m), 3.34 - 3.39 (2H, m), 4.99 - 5.08 (1H, m), 6.48 (1H, d), 7.23 (1H, dd), 7.49 (1H, d), 7.65 (1H, d), 7.73 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 419.2. Intermediate 12b: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4b starting from intermediate 12a (6.7 g, 15.98 mmol). Purification by FSC (gradient: 0 to 5% MeOH in DCM) gave the title compound (6.10 g, 84%) as an off-white solid. ¹ H NMR (DMSO- d6 ) δ 1.41 (9H, s), 1.54 - 1.59 (2H, m), 1.67 - 1.74 (2H, m), 2.12 - 2.20 (2H, m), 2.46 - 2.51 (2H, m), 2.72 (2H, t), 3.23 - 3.29 (2H, m), 3.34 - 3.41 (2H, m), 3.76 (2H, t), 5.01 - 5.09 (1H, m), 6.49 (1H, d), 7.07 (1H, dd), 7.46 (1H, d), 7.50 (1H, d), 7.63 (1H, d), 10.27 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 453.3. Intermediate 12c: 1-[1-(7-azaspiro[3.5]nonan-2-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 6c starting from intermediate 12b (1.1 g, 2.43 mmol). The reaction mixture was diluted with MTBE (10 mL). The resulting mixture was stirred at room temperature for 10 min. The precipitate was collected by filtration, washed with MTBE (10 mL) and dried under vacuum to afford the title compound as an off-white solid in the form of a TsOH salt (1.100 g, 86%). m/z (ES ⁺ ) [M+H] ⁺ = 352.4. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 11g (40 mg, 0.07 mmol) and intermediate 12c (30.8 mg, 0.09 mmol) in a similar manner to Example 1. Purification by RPC (gradient: 0-50% MeCN in water containing 0.1% FA) gave the title compound (8.00 mg, 12.78%) as a white solid. ¹ H NMR (DMSO- d 6) δ 1.17 - 1.29 (3H, m), 1.64 (3H, t), 1.73 - 1.82 (3H, m), 1.90 - 2.01 (2H, m), 2.09 - 2.20 (6H, m), 2.22 - 2.41 (4H, m), 2.45 (2H, t), 2.60 - 2.69 (2H, m), 2.69 - 2.77 (2H, m), 3.10 (2H, d), 3.23 - 3.28 (2H, m), 3.76 (2H, t), 4.35 (2H, d), 4.96 - 5.06 (1H, m), 5.96 (2H, s), 6.40 - 6.45 (1H, m), 6.46 - 6.51 (2H, m), 6.84 - 6.97 (3H, m), 7.04 - 7.09 (1H, m), 7.20 - 7.26 (1H, m), 7.44 - 7.52 (3H, m), 7.62 (1H, d), 7.89 - 7.93 (1H, m), 10.27 (1H, s), 14.19 (1H, s); ¹⁹ F NMR (DMSO- d 6) δ -136.4. m/z (ES ⁺ ) [M+H] ⁺ = 839.5. Example 13 Intermediate 13a: 9-(5-Bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (800 mg, 3.79 mmol) and tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1429 mg, 5.31 mmol). Purification by RPC (gradient: 2% to 80% _MeCN in water containing 0.1% _NH4CO3 ) gave the title compound (910 mg, 51.9%) as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.34 - 1.44 (4 H, m), 1.47 (9 H, s), 1.61 - 1.67 (2 H, m), 1.82 - 1.94 (6 H, m), 2.27 (3 H, d), 3.38 - 3.44 (4 H, m), 4.61 - 4.69 (1 H, m), 7.07 (1 H, s), 7.94 (1 H, d), 8.28 (1 H, d); m/z (ES ⁺ ) [M+H] ⁺ = 462, 464.3. Intermediate 13b: 9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 6b starting from intermediate 13a (530 mg, 1.15 mmol). Purification by FSC (gradient: 0 to 60% EtOAc in petroleum ether) gave the title compound (220 mg, 38.7%) as a yellow solid. ¹ H NMR (CDCl ₃ ) δ 1.39 (3 H, d), 1.47 (9 H, s), 1.62 - 1.71 (3 H, m), 1.83 - 1.95 (6 H, m), 2.30 (3 H, d), 2.87 - 2.93 (2 H, m), 3.38 - 3.45 (4 H, m), 3.87 - 3.94 (2 H, m), 4.74 (1 H, s), 7.15 (1 H, s), 7.53 (1 H, s), 7.80 (1 H, s), 8.22 (1 H, d). m/z (ES ⁺ ) [M+H] ⁺ = 496.5. Intermediate 13c: 1-[1-(3-azaspiro[5.5]undecane-9-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 6c starting from intermediate 168b (190 mg, 0.38 mmol). The solvent was removed under reduced pressure to give the title compound as a white solid in the form of the TsOH salt (152 mg, 100%). m/z (ES ⁺ ) [M+H] ⁺ = 396.5. Intermediate 13d: 1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carbaldehyde

Formic acid (8 mL) was added to intermediate 11 g (300 mg, 0.55 mmol). The resulting mixture was stirred at 40 °C for 1 h. The reaction mixture was evaporated. The reaction was quenched with saturated Na ₂ CO ₃ , extracted with DCM (3 x 1 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to provide the title compound (260 mg, 95%) as a yellow solid. m/z (ES ⁺ ) [M+H] ⁺ = 503.3. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A mixture of intermediate 13d (230 mg, 0.46 mmol) and intermediate 13c (151 mg, 0.38 mmol) was heated in 1,2-dichloroethane (4 mL) and NMP (4.00 mL) at 40 °C for 16 h. The reaction mixture was cooled to room temperature, and then Na(OAc) ₃ BH (405 mg, 1.91 mmol) was added and stirred for 1 h. The reaction mixture was poured into saturated NaHCO ₃ (50 mL), extracted with DCM (3 x 10 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by RPC (Gradient: 2% to 100% MeCN in water containing 0.1% NH ₄ CO ₃ ) gave the title compound (37.4 mg, 11.33%) as a white solid. ¹ H NMR (DMSO- d ₆ ) δ 0.80 - 0.89 (1 H, m), 1.17 - 1.45 (9 H, m), 1.62 - 1.73 (4 H, m), 1.74 - 1.85 (4 H, m), 1.89 - 2.05 (4 H, m), 2.10 - 2.27 (6 H, m), 2.35 (3 H, s), 2.58 - 2.69 (3 H, m), 2.72 - 2.78 (2 H, m), 3.09 (2 H, d), 3.25 (2 H, d), 3.73 - 3.86 (2 H, m), 4.28 - 4.40 (2 H, m), 4.52 - 4.66 (1 H, m), 5.95 (2 H, s), 6.36 - 6.55 (2 H, m), 6.80 - 6.98 (3 H, m), 7.16 - 7.28 (1 H, m), 7.50 (2 H, d), 7.78 - 7.99 (2 H, m), 8.16 (1 H, d), 10.39 (1 H, s), 14.18 (1 H, s); ¹⁹ F NMR (DMSO- d ₆ ) δ: -136.4; m/z (ES ⁺ ), [M+H] ⁺ = 882. Example 14 Intermediate 14a: 2-(5-bromo-6-fluoro-indol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo-6-fluoro- 1H -indole (535 mg, 2.5 mmol), tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (905 mg, 3.75 mmol). Purification by FSC (0-30% EtOAc in hexanes) gave the title compound (826 mg, 76%) as a colorless solid. ¹ H NMR (DMSO- d 6): δ 1.41 (9H, s), 1.54 - 1.59 (2H, m), 1.63 - 1.75 (2H, m), 2.09 - 2.17 (2H, m), 2.45 - 2.49 (2H, m), 3.22 - 3.27 (2H, m), 3.34 - 3.41 (2H, m), 5.03 (1H, quin), 6.50 (1H, d), 7.62 (1H, d), 7.70 (1H, d), 7.84 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 437.1. Intermediate 14b: 2-[5-[(3-ethoxy-3-oxopropyl)amino]-6-fluoro-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Ethyl 3-aminopropionate HCl (435 mg, 2.83 mmol) was added to t- BuBrettPhos Pd G3 (161 mg, 0.19 mmol), intermediate 14a (826 mg, 1.89 mmol) and Cs ₂ CO ₃ (1846 mg, 5.67 mmol) in 1,4-dioxathiocarbamide (10 mL). The vial was capped and evacuated and backfilled with nitrogen. The reaction was heated at 100 °C for 17 h. The reaction was cooled to room temperature and then diluted with EtOAc and filtered through celite®. The filtrate was concentrated under reduced pressure. Purification by FSC (0-70% EtOAc in hexanes) gave the title compound (868 mg, 97%) as a green liquid. ¹ H NMR (DMSO- d 6): δ 1.19 (3H, t), 1.41 (9H, s), 1.49 - 1.60 (2H, m), 1.63 - 1.72 (2H, m), 2.05 - 2.12 (2H, m), 2.42 - 2.48 (2H, m), 2.63 (2H, t), 3.21 - 3.27 (2H, m), 3.30 - 3.34 (2H, m), 3.34 - 3.37 (2H, m), 4.08 (2H, q), 4.81 - 4.95 (2H, m), 6.30 (1H, d), 6.80 (1H, d), 7.28 (1H, d), 7.42 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 474.7. Intermediate 14c: 2-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-6-fluoro-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Intermediate 14b (868 mg, 1.83 mmol) was dissolved in DCM (5 mL) and acetic acid (5 mL). Potassium cyanate (743 mg, 9.16 mmol) was added and the reaction was stirred at room temperature for 20 min. The reaction was diluted with dichloromethane and then washed with water, saturated aqueous NaHCO ₃ solution, and brine solution. The organic layer was separated, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure to provide the crude title compound (945 mg, 100%) as a brown dry film, which was used in the next step without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 517.6. Intermediate 14d: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-6-fluoro-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

A mixture of intermediate 14c (945 mg, 1.83 mmol), ethanol (8 mL) and sodium ethoxide solution (21 wt% in EtOH) (1.366 mL, 3.66 mmol) was stirred at room temperature for 10 min. The reaction mixture was allowed to settle, ethanol (12 mL) was added to suspend the solid, and stirring was continued at room temperature for 1 h. The reaction was quenched with aqueous NH ₄ Cl solution (20 mL) and water (100 mL) was added. The aqueous mixture was extracted with EtOAc (2 x 100 mL), and the organic layer was washed with brine (100 mL). The aqueous layer was extracted with DCM (50 mL), combined with the EtOAc extracts, dried _{( Na2SO4} ), filtered and concentrated. The resulting residue was suspended in ether and sonicated. The suspension was centrifuged and the liquid was decanted (2x this trituration procedure). The resulting solid was dried under vacuum to provide the title compound (526 mg, 61.1%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.41 (9H, s), 1.53 - 1.61 (2H, m), 1.67 - 1.72 (2H, m), 2.09 - 2.18 (2H, m), 2.46 - 2.50 (2H, m), 2.73 (2H, t), 3.22 - 3.29 (2H, m), 3.35 - 3.41 (2H, m), 3.70 (2H, br t), 5.03 (1H, quin), 6.52 (1H, d), 7.50 (1H, d), 7.56 (1H, d), 7.68 (1H, d), 10.41 (1H, s). m/z (ES ⁺ ) [M+Na] ⁺ = 493.2. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 14d (24 mg, 0.05 mmol) and intermediate 11g (32 mg, 0.05 mmol) in a similar manner to Example 11. Purification by RPC (0-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (6.60 mg, 15.23%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.21 - 1.30 (2H, m), 1.64 (3H, br d), 1.73 - 1.83 (4H, m), 1.90 - 1.99 (2H, m), 2.06 - 2.19 (6H, m), 2.20 - 2.34 (2H, m), 2.35 - 2.40 (1H, m), 2.42 - 2.48 (2H, m), 2.53 - 2.56 (1H, m), 2.61 - 2.68 (2H, m), 2.73 (2H, t), 3.10 (2H, br d), 3.26 (2H, br d), 3.34 - 3.38 (2H, m), 3.70 (2H, t), 4.35 (2H, br s), 5.00 (1H, t), 5.96 (2H, s), 6.41 - 6.46 (1H, m), 6.46 - 6.50 (1H, m), 6.51 (1H, d), 6.84 - 6.90 (2H, m), 6.93 (1H, dd), 7.23 (1H, t), 7.47 (1H, s), 7.50 (1H, d), 7.56 (1H, d), 7.66 (1H, d), 7.92 (1H, d), 10.41 (1H, s), 14.20 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 857.6. Example 15 Intermediate 15a: 2-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (3.60 g, 17.06 mmol), tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (6.177 g, 25.60 mmol). Purification by FSC (gradient: 0-50% EtOAc in hexanes) gave the title compound (6.44 g, 87%) as a yellow solid. ¹ H NMR (DMSO- d 6): δ 1.39 (9H, s), 1.56 - 1.66 (4H, m), 2.18 - 2.25 (5H, m), 2.35 - 2.41 (2H, m), 3.21 - 3.25 (2H, m), 3.31 - 3.35 (2H, m), 5.23 (1H, quin), 7.63 (1H, s), 8.14 (1H, d), 8.24 (1H, d); m/z (ES ⁺ ) [M-tBu+2H] ⁺ = 378.4. Intermediate 15b: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 15a (716 mg, 1.65 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (482 mg, 62.5%) as a brown solid. ¹ H NMR (DMSO- d 6): δ 1.41 (9H, s), 1.59 - 1.69 (4H, m), 2.22 - 2.27 (2H, m), 2.27 (3H, s), 2.37 - 2.44 (2H, m), 2.76 (2H, t), 3.23 - m/ z (ES ⁺ ) [M+H] ⁺ = 468.5. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 15b (45.8 mg, 0.10 mmol) and intermediate 11g (63.3 mg, 0.10 mmol) in a similar manner to Example 11. Purification by RPC (0-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (22.1 mg, 25.9%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.08 - 1.32 (3H, m), 1.56 - 1.82 (5H, m), 1.83 - 1.99 (4H, m), 2.07 - 2.16 (3H, m), 2.18 - 2.24 (2H, m), 2.26 (3H, s), 2.44 (4H, br d), 2.51 - 2.69 (3H, m), 2.74 (2H, t), 2.95 - 3.16 (3H, m), 3.25 (2H, br d), 3.33 - 3.38 (2H, m), 3.79 (2H, t), 4.33 (2H, br s), 5.17 - 5.34 (1H, m), 5.92 (2H, s), 6.39 - 6.54 (2H, m), 6.80 - 6.88 (2H, m), 6.92 (1H, br dd), 7.18 - 7.23 (1H, m), 7.41 - 7.50 (1H, m), 7.60 (1H, s), 7.85 - 7.91 (2H, m), 8.16 (1H, d), 10.36 (1H, s), 14.15 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 854.6. Example 16 Intermediate 16a: 2-(5-bromopyrrolo[2,3- b ]pyridin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a starting from 7-tributyloxycarbonyl-7-azaspiro[3.5]nonan-2-ol (500 mg, 2.07 mmol) and 5-bromo- 1H -pyrrolo[2,3- b ]pyridine (408 mg, 2.07 mmol). Purification by FSC (gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound (660 mg, 75%) as a white solid. ¹ H NMR (DMSO-d6): δ 1.39 (9H, s), 1.58-1.66 (4H, m), 2.22-2.29 (2H, m), 2.37-2.44 (2H, m), 3.22-3.25 (2H, m), 3.32 (1H, s), 3.35 (1H, s), 5.22-5.31 (1H, m), 6.50 (1H, d), 7.86 (1H, d), 8.19 (1H, d), 8.28 (1H, d); m/z (ES ⁺ ), [M+H] ⁺ = 420.3. Intermediate 16b: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 6b starting from intermediate 16a (300 mg, 0.71 mmol). Purification by FSC (gradient: 50% to 100% EtOAc in petroleum ether) gave the title compound (172 mg, 45.5%) as a light yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.61-1.70 (4H, m), 2.26-2.36 (2H, m), 2.37-2.48 (2H, m), 2.76 (2H, t), 3.25-3.30 (2H, m), 3.35-3.38 (2H, m), 3.81 (2H, t), 5.27-5.39 (1H, m), 6.54 (1H, d), 7.85 (1H, d), 7.92 (1H, d), 8.21 (1H, d), 10.40 (1H, s). m/z (ES ⁺ ) [M+H] ⁺ = 454.5. Intermediate 16c: 1-[1-(7-azaspiro[3.5]nonan-2-yl)pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 6c starting from intermediate 16b (168 mg, 0.37 mmol). The solvent was removed under reduced pressure to give the title compound as a yellow solid in the form of the 2TsOH salt (246 mg, 94%). m/z (ES ⁺ ) [M+H] ⁺ = 353.4. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]non-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (166 mg, 0.33 mmol) and intermediate 16c (230 mg, 0.33 mmol) in a similar manner to Example 13. Purification by RPC (gradient: 0-50% CH ₃ CN in water containing 0.1% formic acid) gave the title compound (43.0 mg, 14.88%) as a grey solid. ¹ H NMR (DMSO- d6 ): δ 1.21-1.33 (2H, m), 1.62-1.85 (7H, m), 1.90-2.00 (2H, m), 2.09-2.17 (2H, m), 2.22-2.31 (4H, m), 2.32-2.48 (6H, m), 2.60-2.68 (2H, m), 2.76 (2H, t), 3.10 (2H, d), 3.26 (2H, d), 3.36 (2H, d), 3.81 (2H, t), 4.35 (2H, s), 5.27-5.35 (1H, m), 5.95 (2H, s), 6.42-6.50 (2H, m), 6.53 (1H, d), 6.84-6.96 (3H, m), 7.21-7.25 (1H, m), 7.47 (1H, s), 7.84 (1H, d), 7.90-7.92 (2H, m), 8.17-8.23 (2H, m), 10.41 (1H, s). m/z (ES ⁺ ) [M+H] ⁺ = 840.5. Example 17 Intermediate 17a: 1-(3-chloro-2,6-difluorophenyl)-4-(dimethoxymethyl)piperidine

A vial was charged with xantphos (0.211 g, 0.36 mmol), 1-chloro-2,4-difluoro-3-iodobenzene (1 g, 3.64 mmol), 4-(dimethoxymethyl)piperidine (0.696 g, 4.37 mmol), Pd ₂ (dba) ₃ (0.167 g, 0.18 mmol), Cs ₂ CO ₃ (2.374 g, 7.29 mmol) and 1,4-dioxathiol (5 mL). The resulting mixture was stirred at 100 °C under nitrogen for 12 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with saturated NH ₄ Cl (50 mL) and saturated brine (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (gradient: 0 to 40% EtOAc in petroleum ether) gave the title compound (0.700 g, 62.8%) as a light yellow solid. ¹ H NMR (CDCl ₃ ) δ 1.39 - 1.56 (2H, m), 1.69 - 1.82 (3H, m), 3.01 - 3.13 (2H, m), 3.23 - 3.32 (2H, m), 3.37 (6H, s), 4.10 (1H, d), 6.72 - 6.82 (1H, m), 6.90 - 7.01 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 306.1. Intermediate 17b: 8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-2,4-difluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 7b starting from intermediate 17a (650 mg, 2.13 mmol). Purification by FSC (gradient: 0 to 10% MeOH in DCM) gave the title compound (530 mg, 48.4%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.23 - 1.43 (2H, m), 1.55 - 1.74 (5H, m), 1.78 - 1.92 (2H, m), 2.98 (2H, t), 3.07 - 3.23 (4H, m), 3.28 (6H, s), 3.73 (2H, d), 3.98 (2H, s), 4.10 (1H, d), 5.10 (2H, d), 6.59 - 6.71 (1H, m), 6.78 - 6.88 (1H, m), 7.29 - 7.46 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ =516. Intermediate 17c: 8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-2,4-difluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane

Prepared in a similar manner to intermediate 1e starting from intermediate 17b (530 mg, 1.03 mmol). The reaction mixture was filtered and the filtrate was concentrated to afford the title compound as a yellow solid (370 mg, 94%). ¹ H NMR (DMSO- d6 ) δ 1.22 - 1.42 (2H, m), 1.60 - 1.72 (3H, m), 1.72 - 1.86 (4H, m), 2.86 - 3.04 (4H, m), 3.08 - 3.16 (2H, m), 3.17 (2H, s), 3.27 (6H, s), 3.76 (2H, s), 4.10 (1H, d), 6.52 - 6.64 (1H, m), 6.73 - 6.84 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 382.2. Intermediate 17d: 6-chloro-4-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-2,4-difluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

Prepared in an analogous manner to intermediate 11f starting from intermediate 17c (400 mg, 1.05 mmol). Purification by FSC (gradient: 0 to 9% MeOH in DCM) gave the title compound (320 mg, 60.0%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.25 - 1.42 (2H, m), 1.61 - 1.74 (3H, m), 1.81 - 1.92 (2H, m), 1.98 - 2.10 (2H, m), 2.89 - 3.06 (4H, m), 3.16 (2H, m/ z (ES ⁺ ) [M+H] ⁺ = 509. Intermediate 17e: 2-[6-amino-5-[8-[3-[4-(dimethoxymethyl)-1-piperidinyl]-2,4-difluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 17d (200 mg, 0.39 mmol). Purification by FSC (gradient: 0 to 10% MeOH in DCM) gave the title compound (130 mg, 58.4%) as a yellow solid. ¹ H NMR (500 MHz, DMSO- d6 ) δ 1.31 - 1.40 (2H, m), 1.64 - 1.73 (3H, m), 1.86 - 1.95 (2H, m), 2.05 - 2.15 (2H, m), 2.97 - 3.04 (2H, m), 3.10 (2H, d), 3.15 - 3.20 (2H, m), 3.28 (6H, s), 3.34 - 3.39 (2H, m), 4.09 - 4.17 (3H, m), 5.98 (2H, s), 6.69 - 6.77 (1H, m), 6.82 - 6.92 (3H, m), 7.22 - 7.28 (1H, m), 7.55 (1H, s), 7.93 - 7.98 (1H, m), 14.18 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 567.4. 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Formic acid (1 mL, 26.07 mmol) was added to intermediate 17e (108 mg, 0.19 mmol). The resulting mixture was stirred at room temperature for 20 min. The solvent was removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. To the residue were added intermediate 2c (75 mg, 0.19 mmol), NMP (5 ml) and DCE (3 mL). The resulting mixture was stirred at room temperature for 1 h. Na(OAc) ₃ BH (121 mg, 0.57 mmol) was added and the reaction was stirred for 1 h. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO _3. The DCM layers were collected and concentrated. Purification by RPC (Gradient: 0-50% CH ₃ CN in water containing 0.1% FA) gave the title compound (30.0 mg, 17.53%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.64 - 0.74 (2H, m), 0.83 - 0.92 (2H, m), 1.12 - 1.31 (2H, m), 1.60 - 1.81 (7H, m), 1.84 - 1.99 (3H, m), 2.05 - 2.13 (2H, m), 2.17 - 2.45 (10H, m), 2.76 (2H, t), 2.97 - 3.21 (5H, m), 3.46 - 3.27 (3H, s), 3.81 (2H, t), 4.07 - 4.20 (2H, m), 5.17 - 5.34 (1H, m), 5.97 (2H, s), 6.66 - 6.76 (1H, m), 6.78 - 6.95 (3H, m), 7.20 - 7.28 (1H, m), 7.55 (2H, d), 7.91 - 7.99 (2H, m), 8.14 - 8.19 (1H, m), 10.38 (1H, s),(OH proton not observed); ¹⁹ F NMR (282 MHz, DMSO) δ -128.88, -128.89, -130.674, -130.68; m/z (ES ⁺ ) [M+H] ⁺ = 898.4. Example 18 Intermediate 18a: 9-(5-bromopyrrolo[2,3- b ]pyridin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo- 1H -pyrrolo[2,3- b ]pyridine (700 mg, 3.55 mmol) and tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1436 mg, 5.33 mmol). Purification by FSC (gradient: 0-50% EtOAc in hexanes) gave the title compound (900 mg, 56.5%) as a colorless dry film. ¹ H NMR (DMSO- d6 ) δ 1.27 - 1.37 (5H, m), 1.38 - 1.45 (10H, m), 1.60 - 1.65 (2H, m), 1.73 (2H, br d), 1.83 (2H, br d), 1.95 - 2.06 (2H, m), 3.34- 3.40 (2H, m), 4.64 (1H, tt), 6.48 (1H, d), 7.82 (1H, br s), 8.20 (1H, d), 8.29 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 450.2. Intermediate 18b: 9-[5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 6b starting from intermediate 18a (900 mg, 2.01 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (300 mg, 31.0%) as a brown solid. ¹ H NMR (DMSO- d6 ) δ 1.28 - 1.45 (14H, m), 1.57 - 1.67 (2H, m), 1.70 - 1.77 (2H, m), 1.84 (2H, br d), 2.04 (2H, br dd), 2.76 (2H, t), 3.34 - 3.39(3H, m), 3.81 (2H, t), 4.63 - 4.79 (1H, m), 6.50 (1H, d), 7.79 (1H, br d), 7.91 (1H, d), 8.20 (1H, d), 10.40 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 482.3. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting from intermediate 11g (35 mg, 0.06 mmol) and intermediate 18b (26.6 mg, 0.06 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 0-50% CH ₃ CN in water containing 0.1% FA) gave the title compound (17.0 mg, 35.4%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.22 - 1.37 (4H, m), 1.43 (2H, br s), 1.64 - 1.86 (9H, m), 1.91 - 2.06 (4H, m), 2.14 (2H, br d), 2.32 (2H, br d), 2.48 (3H, br s), 2.65 (2H, br t), 2.76 (2H, t), 3.10 (2H, br d), 3.26 (2H, br d), 3.36 - 3.47 (3H, m), 3.81 (2H, t), 4.35 (2H, br s), 4.60 - 4.73 (1H, m), 5.95 (2H, s), 6.37 - 6.52 (3H, m), 6.81 - 6.98 (3H, m), 7.19 - 7.28 (1H, m), 7.47 (1H, s), 7.74 - 7.82 (1H, m), 7.86 - 7.94 (2H, m), 8.12 - 8.24 (1H, m), 10.40 (1H, s), 13.48 - 14.87 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 868.5. Example 19 1-[2-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-4-piperidinyl]-1-methyl-indol-6-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to Example 11, starting from intermediate 11g (38.1 mg, 0.06 mmol) and 1-[1-methyl-2-(4-piperidinyl)indol-6-yl]hexahydropyrimidine-2,4-dione TsOH salt (30 mg, 0.06 mmol) (prepared according to reported patent procedure WO 2022/069520 A1). Purification by RPC (gradient: 0-50% CH ₃ CN in water containing 0.1% FA) gave the title compound (17.0 mg, 34.8%) as a white solid. ¹ H NMR (500 MHz, DMSO- d6 ) δ 1.25 - 1.32 (2H, m), 1.63 - 1.69 (2H, m), 1.79 - 1.85 (2H, m), 1.90 - 1.98 (4H, m), 2.05 - 2.15 (4H, m), 2.23 - 2.27 (2H, m), 2.63 - 2.68 (2H, m), 2.72 - 2.76 (2H, m), 2.76 - 2.84 (1H, m), 2.95 - 3.00 (2H, m), 3.11 (2H, br d), 3.27 (5H, br d), 3.69 (3H, s), 3.79 (2H, t), 4-[3-[4-(dibutyloxymethyl)-1-piperidinyl]-4- ^fluoro - phenyl]piperidin-1-carboxylic ^acid benzyl ester

Prepared in a similar manner to intermediate 7b starting from intermediate 11c (600 mg, 1.63 mmol) and benzyl piperidine-1-carboxylate (359 mg, 1.63 mmol). Purification by FSC (gradient: 0-40% EtOAc in hexanes) gave the title compound (520 mg, 57.4%) as a light yellow solid. ¹ H NMR (DMSO- d6 ) δ 0.90 (6H, t), 1.30 - 1.44 (6H, m), 1.45 - 1.55 (4H, m), 1.73 (3H, br d), 2.58 (2H, s), 3.04 (4H, br d), 3.31 - 3.34 (3H, m), 3.38 - 3.45 (2H, m), 3.50 - 3.62 (6H, m), 4.22 (1H, d), 5.11 (2H, s), 6.40 - 6.51 (1H, m), 6.56 (1H, dd), 6.95 (1H, dd), 7.32 - 7.44 (4H, m); m/z (ES ⁺ ) [M+H] ⁺ = 556.2. Intermediate 20b: 1-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]piperidinium

Pd/C (105 mg, 0.10 mmol) was added to a solution of intermediate 20a (550 mg, 0.99 mmol) in THF (8 mL) under _N2 . The reaction was bubbled with _H2 and stirred under _H2 at room temperature for 6 h. The reaction mixture was filtered through celite® and eluted with ethyl acetate. Concentration in vacuo gave the title compound (398 mg, 95%) as an orange gum. m/z (ES ⁺ ) [M+H] ⁺ = 422.4. Intermediate 20c: 6-Chloro-4-[4-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]piperidin-1-yl]piperidin-3-amine

Prepared in a similar manner to intermediate 3d starting from intermediate 20b (450 mg, 1.07 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound as an orange solid (220 mg, 37.5%). m/z (ES ⁺ ) [M+H] ⁺ = 475.4. Intermediate 20d: 2-[6-amino-5-[4-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]piperidin-1-yl]piperidin-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 20c (120 mg, 0.22 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (70.0 mg, 52.8%) as a light yellow solid. ¹ H NMR (DMSO- d6 ) δ 1.41 (9H, s), 1.52 - 1.69 (2H, m), 1.78 - 1.90 (4H, m), 1.96 (2H, br dd), 2.23 (3H, s), 2.39 (2H, br t), 2.55 - 2.64 (2H,m), 2.64 - 2.65 (1H, m), 2.73 (2H, t), 3.03 (4H, br d), 3.69 - 3.83 (4H, m), 4.27 (1H, br s), 7.05 (1H, dd), 7.32 (1H, s), 7.40 (1H, d), 7.47 (1H, d), 10.24 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 607.6. Example 20 1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 20d (30 mg, 0.05 mmol) and intermediate 2c (19.45 mg, 0.05 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 0-50% CH ₃ CN in water containing 0.1% FA) gave the title compound (17.0 mg, 40.3%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.62 - 0.73 (2H, m), 0.82 - 0.95 (2H, m), 1.28 (2H, q), 1.67 - 1.85 (7H, m), 1.91 - 1.97 (1H, m), 2.18 - 2.46 (8H, m), 2.52- 2.59 (1H, m), 2.66 (2H, br t), 2.77 (2H, t), 3.17 - 3.28 (5H, m), 3.33 - 3.36 (1H, m), 3.34 - 3.45 (4H, m), 3.81 (2H, t), 5.22 - 5.36 (1H, m), 6.36 (2H, br s), 6.51 - 6.67 (2H, m), 6.88 - 6.94 (2H, m), 6.99 (1H, br dd), 7.20 - 7.29 (1H, m), 7.57 (2H, s), 7.89 - 7.99 (2H, m), 8.17 (1H, d), 10.26 - 11.62 (1H, m), 10.41 (1H, s), 13.51 - 14.73 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 854.5. Example 21 1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting from intermediate 20d (30 mg, 0.05 mmol) and intermediate 4b (23.07 mg, 0.05 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 0-50% CH ₃ CN in water containing 0.1% FA) gave the title compound (20.0 mg, 48.9%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.23 - 1.36 (2H, m), 1.69 (3H, br s), 1.81 (4H, br d), 2.13 (2H, br d), 2.25 (3H, s), 2.33 (2H, br d), 2.39 - 2.48 (3H, m), 2.51 - 2.54 (3H, m), 2.54 - 2.60 (1H, m), 2.67 (2H, br t), 2.73 (2H, t), 3.25 - 3.27 (2H, m), 3.28 - 3.43 (7H, m), 3.77 (2H, t), 4.98 (1H, br t), 6.36 (2H, s), 6.50- 6.69 (2H, m), 6.86 - 6.93 (2H, m), 6.95 - 7.10 (2H, m), 7.20 - 7.31 (1H, m), 7.36 - 7.47 (3H, m), 7.58 (1H, s), 7.95 (1H, dd), 10.28 (1H, s), 13.45 - 14.66 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 827.5. Example 22 Intermediate 22a: 2-(5-bromo-4-fluoro-indol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo-4-fluoro- 1H -indole (535 mg, 2.5 mmol) and tributyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (905 mg, 3.75 mmol). Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (963 mg, 88%) as a light yellow dry film. ¹ H NMR (DMSO- d6 ) δ 1.41 (9H, s), 1.55 - 1.60 (2H, m), 1.66 - 1.72 (2H, m), 2.12 - 2.21 (2H, m), 2.46 - 2.49 (1H, m), 3.21 - 3.28 (2H, m), 3.32 - 3.38 (3H, m), 5.07 (1H, quin), 6.59 (1H, d), 7.29 - 7.34 (1H, m), 7.35 - 7.39 (1H, m), 7.73 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 437.1. Intermediate 22b: 2-[5-[(3-ethoxy-3-oxopropyl)amino]-4-fluoro-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 14b starting from intermediate 22a (962 mg, 2.20 mmol). Purification by FCS (gradient: 0-80% EtOAc in hexanes) gave the title compound (953 mg, 91%) as a brown liquid. ¹ H NMR (DMSO- d6 ) δ 1.18 - 1.21 (3H, m), 1.41 (9H, s), 1.53 - 1.58 (2H, m), 1.65 - 1.69 (2H, m), 2.09 - 2.17 (2H, m), 2.42 - 2.49 (2H, m), 2.58 (2H, t), 3.22 - 3.27 (2H, m), 3.33 - 3.39 (4H, m), 4.05 - 4.10 (2H, m), 4.71 (1H, br s), 4.93 (1H, t), 6.34 (1H, d), 6.75 (1H, t), 7.15 (1H, d), 7.47 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 474.8. Intermediate 22c: 2-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-4-fluoro-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 14c starting from intermediate 22b (953 mg, 2.01 mmol). The title compound was obtained as a brown dry film (1038 mg, 100%). m/z (ES ⁺ ) [M+H] ⁺ = 517.6. Intermediate 22d: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-4-fluoro-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 14d starting from intermediate 22c (1038 mg, 2.01 mmol). Trituration with _Et2O gave the title compound as a white solid (581 mg, 61.4%). ¹ H NMR (DMSO- d6 ) δ 1.41 (9H, s), 1.55 - 1.61 (2H, m), 1.64 - 1.77 (2H, m), 2.14 - 2.21 (2H, m), 2.51 - 2.54 (2H, m), 2.74 (2H, t), 3.22 - 3.28 (2H, m), 3.35 - 3.40 (2H, m), 3.71 (2H, t), 5.07 (1H, quin), 6.59 (1H, d), 7.12 (1H, t), 7.38 (1H, d), 7.71 (1H, d), 10.42 (1H, s); m/z (ES ⁺ ) [M- t Bu+2H] ⁺ = 415.4. Example 22 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 22d (0.024 g, 0.05 mmol) and intermediate 11g (0.032 g, 0.05 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 0-50% MeCN in water containing 0.1% FA) gave the title compound (0.022 mg, 48.7%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.17 - 1.28 (2H, m), 1.62 (3H, br t), 1.70 - 1.81 (4H, m), 1.87 - 1.97 (2H, m), 2.07 - 2.18 (6H, m), 2.22 - 2.39 (3H, m), 2.44 (2H, br t), 2.56 - 2.68 (2H, m), 2.72 (2H, t), 3.08 (2H, br d), 3.24 (2H, br d), 3.34 (2H, br d), 3.69 (3H, t), 4.33 (2H, br s), 5.02 (1H, quin), 5.94 (2H, s), 6.37 - 6.49 (2H, m), 6.56 (1H, d), 6.81 - 6.95 (3H, m), 7.06 - 7.14 (1H, m), 7.18 - 7.25 (1H, m), 7.36 (1H, d), 7.45 (1H, s), 7.68 (1H, d), 7.90 (1H, dd), 10.40 (1H, s), 14.16 (1H, br s); m/z (ES ^- ) [MH] ⁺ = 855.6. Example 23 Intermediate 23a: 2-(5-bromo-4-methyl-indol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo-4-methyl- 1H -indole (525 mg, 2.5 mmol) and tributyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (905 mg, 3.75 mmol). Purification by FCS (gradient: 0-30% EtOAc in hexanes) gave the title compound (757 mg, 69.9%) as a light yellow dry film. ¹ H NMR (DMSO- d6 ) δ 1.39 (9H, s), 1.50 - 1.57 (2H, m), 1.64 - 1.70 (2H, m), 2.07 - 2.17 (2H, m), 2.42 - 2.47 (2H, m), 2.48 (3H, s), 3.19 - 3.26 (2H, m), 3.31 - 3.38 (2H, m), 5.00 (1H, quin), 6.56 (1H, d), 7.24 (1H, d), 7.29 (1H, d), 7.62 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 433.2. Intermediate 23b: 2-[5-[(3-ethoxy-3-oxopropyl)amino]-4-methyl-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 14b starting from intermediate 23a (757 mg, 1.75 mmol). Purification by FCS (gradient: 0-100% EtOAc in hexanes) gave the title compound (314 mg, 38.3%) as a brown liquid. ¹ H NMR (CDCl ₃ ): δ 1.29 (3H, t), 1.49 (9H, s), 1.62 (2H, br s), 1.76 (2H, br s), 2.20 - 2.27 (2H, m), 2.35 (3H, s), 2.56 (2H, ddd), 2.62 - 2.70 (2H, m), 3.31 - 3.39 (2H, m), 3.44 - 3.50 (2H, m), 3.50 - 3.57 (2H, m), 3.78 (1H, br s), 4.16 - 4.22 (2H, m), 4.83 (1H, t), 6.44 (1H, dd), 6.78 (1H, d), 7.12 (1H, d), 7.19 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 470.8. Intermediate 23c: 2-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-4-methyl-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 14c starting from intermediate 23b (314 mg, 0.67 mmol). The title compound was obtained as a brown film (343 mg, 100%). m/z (ES ⁺ ) [M+H] ⁺ = 513.6. Intermediate 23d: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 14d starting from intermediate 23c (343 mg, 0.67 mmol). Trituration with _Et2O and hexanes (1:1) gave the title compound (197 mg, 63.0%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.41 (9H, s), 1.55 - 1.60 (2H, m), 1.67 - 1.73 (2H, m), 2.09 - 2.21 (2H, m), 2.31 (3H, s), 2.45 - 2.50 (2H, m), 2.67 - 2.82 (2H, m), 3.23 - 3.28 (2H, m), 3.34 - 3.39 (2H, m), 3.53 (1H, dt), 3.74 (1H, ddd), 5.04 (1H, quin), 6.56 (1H, d), 7.01 (1H, d), 7.35 (1H, d), 7.63 (1H, d), 10.27 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 467.3. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 23d (0.024 g, 0.05 mmol) and intermediate 11g (0.032 g, 0.05 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 0-50% MeCN in water containing 0.1% FA) followed by RPC (0-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (4.10 mg, 9.50%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.21 - 1.27 (2H, m), 1.59 - 1.68 (3H, m), 1.72 - 1.84 (4H, m), 1.88 - 2.01 (2H, m), 2.07 - 2.18 (6H, m), 2.26 (2H, br s), 2.31 (3H, s), 2.34 - 2.48 (4H, m), 2.59 - 2.67 (1H, m), 2.62 - 2.62 (1H, m), 2.68 - 2.82 (2H, m), 3.10 (2H, br d), 3.26 (2H, br d), 3.34 - 3.38 (2H, m), 3.54 (1H, dt), 3.74 (1H, ddd), 4.35 (2H, br s), 5.00 (1H, t), 5.96 (2H, s), 6.40 - 6.45 (1H, m), 6.48 (1H, dd), 6.55 (1H, d), 6.84 - 6.89 (2H, m), 6.93 (1H, dd), 7.00 (1H, d), 7.23 (1H, t), 7.35 (1H, d), 7.47 (1H, s), 7.61 (1H, d), 7.92 (1H, dd), 10.26 (1H, s), 14.20 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 853.5. Example 24 Intermediate 24a:

9-[(5-Bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a starting from 5-bromo-3-cyclopropyl- 1H -pyrrolo[2,3- b ]pyridine (0.593 g, 2.5 mmol) and tributyl 9-(hydroxymethyl)-3-azaspiro[5.5]undecane-3-carboxylate (1.063 g, 3.75 mmol). Purification by FSC (gradient: 0-50% EtOAc in hexanes) gave the title compound (1.202 g, 96%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 0.57 - 0.65 (2H, m), 0.81 - 0.91 (2H, m), 0.94 - 1.03 (2H, m), 1.08 - 1.21 (5H, m), 1.22 - 1.30 (2H, m), 1.37 - 1.39 (10H, m), 1.61 (2H, br d), 1.75 - 1.85 (1H, m), 1.91 - 1.98 (1H, m), 3.21 - 3.29 (4H, m), 4.02 (2H, d), 7.30 (1H, s), 8.19 (1H, s), 8.27 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 504.2. Intermediate 24b: 9-[[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]methyl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 24a (1.202 g, 2.39 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (0.831 g, 64.9%) as a brown solid. ¹ H NMR (DMSO- d6 ) δ 0.57 - 0.68 (2H, m), 0.82 - 0.91 (2H, m), 0.96 - 1.05 (2H, m), 1.06 - 1.23 (5H, m), 1.25 - 1.33 (2H, m), 1.38 (9H, s), 1.40 - 1.43 (1H, m), 1.62 (2H, br d), 1.77 - 1.87 (1H, m), 1.89 - 1.96 (1H, m), 2.76 (2H, t), 3.20 - 3.30 (4H, m), 3.82 (2H, t), 4.04 (2H, br d), 7.28 (1H, s), 7.95 (1H, d), 8.17 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 536.5. 1-[1-[[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]methyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 24b (42.9 mg, 0.08 mmol) and intermediate 11g (50.6 mg, 0.08 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 0-50% MeCN in water containing 0.1% FA) gave the title compound (19.60 mg, 25.6%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.62 (2H, q), 0.84 - 0.90 (2H, m), 0.96 (2H, br t), 1.11 - 1.30 (8H, m), 1.44 - 1.52 (2H, m), 1.56 - 1.66 (3H, m), 1.72 - 1.83 (3H, m), 1.89 - 1.98 (3H, m), 2.10 - 2.16 (2H, m), 2.20 (2H, br d), 2.28 - 2.36 (4H, m), 2.62 (2H, br t), 2.76 (2H, t), 3.09 (2H, br d), 3.25 (2H, br d), 3.33 (2H, br d), 3.82 (2H, t), 4.03 (2H, br d), 4.34 (2H, br s), 5.96 (2H, s), 6.39 - 6.49 (2H, m), 6.83 - 6.94 (3H, m), 7.19 - 7.26 (1H, m), 7.28 (1H, s), 7.46 (1H, s), 7.88 - 7.94 (1H, m), 7.95 (1H, d), 8.17 (1H, d), 10.41 (1H, s), 13.39 - 14.66 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 922.6. Example 25 Intermediate 25a: 4-(8-Benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-3-pyridin-3-amine

Prepared in a similar manner to intermediate 3d starting from 4-bromo-6-chloropyridin-3-amine (6.02 g, 28.89 mmol) and 8-benzyl-3,8-diazabicyclo[3.2.1]octane (4.87 g, 24.07 mmol). Trituration with MeOH and collection by filtration afforded the clean product. The MeOH filtrate contained additional product and was concentrated and purified by FSC (gradient: 0-20% EtOAc in hexanes with 10% DCM additive). The solids were combined to give the title compound (6.81 g, 86%) as an off-white solid. ¹ H NMR (DMSO- d6 ) δ 1.86 - 2.01 (4H, m), 2.81 (2H, br d), 3.17 - 3.23 (4H, m), 3.53 (2H, s), 5.71 - 5.79 (2H, m), 6.89 (1H, s), 7.21 - 7.29 (1H, m), 7.33 (2H, t), 7.37 - 7.41 (2H, m); m/z (ES ⁺ ) [M+H] ⁺ = 330.4. Intermediate 25b: 4-(8-Benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-[2-(methoxymethoxy)phenyl]phthalimide-3-amine

Under _N2 atmosphere, a flask was charged with intermediate 25a (6.81 g, 20.65 mmol) and (2-(methoxy)phenyl)boronic acid (4.70 g, 25.81 mmol), _K2CO3 (5.71 g, 41.29 mmol), _XPhosPdG3 (1.748 g, 2.06 mmol), dioxane (100 ml) and water (20 ml). The reaction was stirred at 100 °C for 1.25 h. The reaction was cooled to room temperature and partially concentrated under reduced pressure to remove excess THF. The reaction mixture was partitioned between DCM (100 mL) and water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with brine, dried _{over Na2SO4} and concentrated under reduced pressure. Trituration with _Et2O gave the title compound as a beige solid (7.48 g, 84%). ¹ H NMR (DMSO- d6 ) δ 1.89 - 2.06 (4H, m), 2.80 (2H, br d), 3.15 - 3.20 (2H, m), 3.21 - 3.25 (2H, m), 3.34 (3H, s), 3.54 (2H, s), 5.21 (2H, s), 5.60 (2H, s), 7.09 (1H, t), 7.18 - 7.21 (2H, m), 7.21 - 7.27 (1H, m), 7.31 - 7.40 (5H, m), 7.62 (1H, dd); m/z (ES ⁺ ) [M+H] ⁺ = 432.5. Intermediate 25c: N- [4-(8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-[2-(methoxymethoxy)phenyl]phthalimide-3-yl] -N -tert-butyloxycarbonyl-carbamic acid tert-butyl ester

A flask was charged with intermediate 25b (7.476 g, 17.32 mmol), DMAP (0.212 g, 1.73 mmol), NEt ₃ (9.48 mL, 69.30 mmol) and DCM (100 mL). The reaction was cooled to 0 °C and di-tributyl carbonate (11.34 g, 51.97 mmol) was added. The reaction was warmed and stirred at room temperature for 1.5 h. The reaction was washed with 0.5 M HCl (2 x 150 mL), brine (150 mL), dried over Na ₂ SO ₄ and concentrated. Trituration with Et ₂ O gave the title compound as a beige solid (10.16 g, 93%). ¹ H NMR (DMSO- d6 ) δ 1.41 (18H, s), 1.90 - 1.98 (2H, m), 2.34 - 2.46 (2H, m), 3.30 (3H, s), 3.51 (2H, br d), 3.80 (2H, br d), 4.02 (2H, br s), 4.24 (2H, br d), 5.26 (2H, s), 7.18 (1H, t), 7.29 (1H, d), 7.44-7.53 (4H, m), 7.62 (1H, s), 7.74-7.84 (3H, m); m/z (ES ⁺ ) [M+H] ⁺ = 632.5. Intermediate 25d: N -tert-butyloxycarbonyl- N- [4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-[2-(methoxymethoxy)phenyl]phthalimide-3-yl]carbamic acid tert-butyl ester

Under _H2 atmosphere, a flask was charged with intermediate 25c (10.156 g, 16.08 mmol), Pd/C (1.711 g, 1.61 mmol), EtOH (100 mL) and DCM (20 mL) for 20 h. The reaction was bubbled with _N2 , filtered through celite®, eluting with DCM and EtOAc. The filtrate was concentrated under reduced pressure, triturated with _Et2O and collected by filtration. The resulting solid was taken up in DCM (200 mL) and washed with _NaHCO3 solution (2 x 100 mL), brine (100 mL), _{dried Na2SO4} and concentrated. The resulting sticky solid was triturated with hexanes to give the title compound as a white solid (6.67 g, 77%). ¹ H NMR (DMSO- d6 ) δ 1.40 (18H, s), 1.68 (4H, br s), 2.99 (2H, br d), 3.29 - 3.32 (4H, m), 3.34 (2H, br d), 3.47 (2H, br s), 5.25 (2H, s), 7.16 (1H, br t), 7.27 (1H, br d), 7.42 - 7.50 (2H, m), 7.74 (1H, br d); m/z (ES ⁺ ) [M+H] ⁺ = 542.6. Intermediate 25e: 4-Fluoro-4-(trifluoromethylsulfonyloxymethyl)piperidine-1-carboxylic acid tributyl ester

To a solution of tributyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (0.100 g, 0.43 mmol) and 2,6-lutidine (0.060 mL, 0.51 mmol) in DCM (0.72 mL) at -5 °C, trifluoromethanesulfonic anhydride (0.076 mL, 0.45 mmol) was added over 3 min. The mixture was stirred at -5 °C for 50 min, then quenched with 1.0 M aqueous NaHSO ₄ solution (5 mL) and diluted with DCM (20 mL). The layers were separated. The organic layer was washed with 1.0 M aqueous NaHSO ₄ solution (5 mL) and then with saturated aqueous NaHCO ₃ solution (10 mL). The organic layer was dried ( _Na2SO4 ) and concentrated to give the title compound (0.142 g, 91%) as _a light brown oil. ^1H NMR (DMSO-d6): δ 1.37-1.45 (9H, m), 1.56-1.76 (2H, m), 1.76-1.90 (2H, m), 2.99 (2H, br s), 3.65-3.96 (2H, m), 4.81-4.96 (2H, m); m/z (ES ⁺ ) [M- tBu +2H] ⁺ = 309.8. Intermediate 25f: 4-[[2-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonan-7-yl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Intermediate 25e (658 mg, 1.80 mmol) was added to intermediate 2c (590 mg, 1.5 mmol) and DIPEA (1.310 mL, 7.50 mmol) in 1,4-dioxathiol (6 mL). The resulting mixture was stirred at 85 °C for 24 h. The reaction was concentrated under reduced pressure. Purification by FSC (gradient: 1%-10% MeOH in DCM containing 0.1% NH ₄ OH) gave the title compound (674 mg, 73.8%) as a beige solid. ¹ H NMR (DMSO- d6 ) δ 0.64 - 0.73 (2H, m), 0.82 - 0.92 (2H, m), 1.41 (9H, s), 1.49 - 1.64 (2H, m), 1.64 - 1.72 (4H, m), 1.75 - 1.82 (2H, m), 1.91 - 1.96 (1H, m), 2.16 - 2.24 (2H, m), 2.27 - 2.35 (2H, m), 2.36 - 2.42 (2H, m), 2.42 - 2.49 (4H, m), 2.76 (2H, t), 2.90 - 3.10 (2H, m), 3.72 (2H, br d), 3.81 (2H, t), 5.24 (1H, quin), 7.56 (1H, s), 7.95 (1H, d), 8.17 (1H, d), 10.40 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 609.6. Intermediate 25g: 1-[3-cyclopropyl-1-[7-[(4-fluoro-4-piperidinyl)methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 25f (670 mg, 1.1 mmol). Purification by ion exchange chromatography (Porpak Rxn CX 5 g cartridge) eluting with 2 N NH ₃ in MeOH gave the title compound (402 mg, 71.8%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.64 - 0.71 (2H, m), 0.84 - 0.87 (2H, m), 1.49 - 1.60 (2H, m), 1.63 - 1.72 (6H, m), 1.89 - 1.95 (1H, m), 2.15 - 2.22 (2H, m), 2.26 - 2.33 (2H, m), 2.33 - 2.48 (6H, m), 2.60 - 2.72 (4H, m), 2.75 (2H, t), 3.80 (2H, t), 5.22 (1H, quin), 7.53 (1H, s), 7.93 (1H, d), 8.15 (1H, d), 10.36 (1H, br s) (amine NH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 509.5. Intermediate 25h: 1-[1-[7-[[1-(5-chloro-2-fluoro-phenyl)-4-fluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 25 g (396 mg, 0.78 mmol), 2-bromo-4-chloro-1-fluorobenzene (190 μl, 1.56 mmol), Pd(dba) ₂ (90 mg, 0.16 mmol), ( t Bu)PhCPhos (94 mg, 0.23 mmol), K ₂ CO ₃ (323 mg, 2.34 mmol), and 1,4-dioxathiocarbamide (7.6 mL). The reaction was stirred at 100 °C for 16 h under N ₂ atmosphere. A second portion of Pd(dba) ₂ (90 mg, 0.16 mmol) and ( t Bu)PhCPhos (94 mg, 0.23 mmol) were added, and the reaction was stirred at 100 °C for an additional 6 h under N ₂ atmosphere. The reaction was cooled to room temperature and concentrated in vacuo and the material was adsorbed onto silica. Purification by FSC (Gradient: 0-6% MeOH in DCM) gave the title compound (341 mg, 68.7%) as a brown solid. ¹ H NMR (DMSO -d6 ) δ 0.67 - 0.72 (2H, m), 0.87 - 0.89 (2H, m), 1.67 - 1.75 (4H, m), 1.76 - 1.88 (2H, m), 1.94 (3H, ddd), 2.17 - 2.25 (2H, m), 2.29 - 2.37 (2H, m), 2.38 - 2.47 (2H, m), 2.48 - 2.58 (4H, m), 2.77 (2H, t), 2.94 (2H, br t), 3.17 - 3.25 (2H, m), 3.82 (2H, t), 5.25 (1H, quin), 6.96 - 7.02 (1H, m), 7.08 (1H, dd), 7.18 (1H, dd), 7.55 (1H, s), 7.95 (1H, d), 8.17 (1H, d), 10.37 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 637.6. Intermediate 25i: N -tert-butyloxycarbonyl- N- [4-[8-[3-[4-[[2-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]non-7-yl]methyl]-4-fluoro-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tert-butyl ester

A vial was charged with intermediate 25d (342 mg, 0.63 mmol), intermediate 25h (335 mg, 0.53 mmol), Cs ₂ CO ₃ (514 mg, 1.58 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (88 mg, 0.11 mmol) and 1,4-dioxathiocarbamide (5.3 ml). The reaction was stirred at 100 °C for 2 h under N ₂ atmosphere. The reaction was cooled to room temperature, partitioned between DCM (25 mL), H ₂ O (10 mL), brine (20 mL) was added, and the phases were separated. The aqueous layer was extracted with DCM (2 x 25 mL). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo. Purification by FSC (gradient: 0-6% MeOH in DCM) gave the title compound (260 mg, 43.3%) as a yellow solid. ¹ H NMR (DMSO- d6 ) δ 0.66 - 0.73 (2H, m), 0.81 - 0.90 (2H, m), 1.40 (18H, s), 1.68 - 1.74 (4H, m), 1.78 - 2.00 (9H, m), 2.18 - 2.25 (2H, m), 2.29 - 2.36 (2H, m), 2.39 - 2.57 (6H, m), 2.77 (2H, t), 2.92 (2H, br t), 3.12 - 3.20 (2H, m), 3.24 - 3.36 (7H, m), 3.82 (2H, t), 4.41 (2H, br s), 5.21 - 5.30 (3H, m), 6.48 (1H, dt), 6.55 (1H, br dd), 6.95 (1H, dd), 7.16 (1H, td), 7.26 (1H, d), 7.46 (1H, td), 7.54 (2H, d), 7.73 (1H, dd), 7.95 (1H, d), 8.17 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 1142.9. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 25i (50 mg, 0.04 mmol), DCM (2 mL) and TFA (0.675 mL, 8.75 mmol). The mixture was stirred at room temperature for 60 min and concentrated under reduced pressure. The crude residue was purified by RPC (gradient: 50% MeCN in water containing 0.1% _NH4OH , then 0-60% MeCN in water containing 0.1% FA). The product-containing fractions were extracted with DCM (3x). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo. The residue was dissolved in DCM (1.5 mL). TFA (0.5 mL) was added and the mixture was stirred at room temperature for 45 minutes. The mixture was diluted with DCM (20 mL), washed with saturated _{aqueous K2CO3} (2 x 20 mL) and saturated aqueous _NH4Cl (20 mL), dried _{over Na2SO4} and concentrated under reduced pressure. Purification by RPC (0-60% MeCN in water containing 0.1% FA) gave the title compound (11.0 mg, 28.0%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.65 - 0.71 (2H, m), 0.82 - 0.90 (2H, m), 1.65 - 1.96 (11H, m), 2.12 (2H, br d), 2.19 (2H, br t), 2.31 (2H, br t), 2.41 (2H, br s), 2.46 - 2.55 (4H, m), 2.75 (2H, t), 2.92 (2H, br t), 3.09 (2H, br d), 3.12 - 3.19 (2H, m), 3.24 (2H, br d), 3.76 - 3.84 (2H, m), 4.36 (2H, br s), 5.23 (1H, quin), 5.92 (2H, s), 6.39 - 6.47 (1H, m), 6.49 - 6.56 (1H, m), 6.81 - 6.89 (2H, m), 6.93 (1H, dd), 7.21 (1H, t), 7.45 (1H, s), 7.53 (1H, s), 7.89 (1H, d), 7.93 (1H, d), 8.15 (1H, d), 10.36 (1H, s), 13.43 - 14.83 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 898.7. Example 26 Intermediate 26a: 4-(5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)piperidine-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 1g starting from 5-bromo-3-cyclopropyl- 1H -pyrrolo[2,3- b ]pyridine (1.10 g, 4.64 mmol). Purification by RPC (gradient: 0-80% MeCN in water _containing 0.05% _NH4HCO3 ) gave the title compound (1.40 g, 72%) as a brown solid. ¹ H NMR (DMSO- d 6): δ 0.46 - 0.58 (2H, m), 0.67 - 0.78 (2H, m), 1.31 (9H, s), 1.64 - 1.88 (5H, m), 2.60 - 3.00 (2H, m), 3.90 - 4.01 (2H, m), 4.60 - 4.71 (1H, m), 7.38 (1H, s), 8.09 (1H, d), 8.15 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 420.0. Intermediate 26b: 4-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]piperidine-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4b starting from intermediate 26a (0.700 g, 1.67 mmol). Purification by FSC (gradient: 0-70% EtOAc in petroleum ether) gave the title compound (0.400 g, 53%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.61 - 0.72 (2H, m), 0.80 - 0.92 (2H, m), 1.44 (9H, s), 1.79 - 2.03 (5H, m), 2.77 (2H, t), 2.80 - 3.00 (2H, m), 3.82 (2H, t), 3.99 - 4.24 (2H, m), 4.75 - 4.85 (1H, m), 7.48 (1H, s), 7.96 (1H, d), 8.18 (1H, d), 10.40 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 454.4. Intermediate 26c: 1-[3-cyclopropyl-1-(4-piperidinyl)pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 6c starting from intermediate 26b (5.6 g, 12.35 mmol). MTBE (100 mL) was added to the reaction mixture and stirred for 0.5 h. The product precipitate was collected by filtration and dried under vacuum to give the title compound as a TsOH salt as a white solid (6.00 g, 92%). m/z (ES ⁺ ) [M+H] ⁺ = 354.3. Intermediate 26d: 4-[[4-[3-Cyclopropyl-5-(2,4-dioxohexahydroxypyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1-piperidinyl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 25f starting from intermediate 26c (0.400 g, 0.76 mmol) and intermediate 25e (0.473 g, 1.29 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.189 g, 43.7%) as a white foam. ¹ H NMR (DMSO -d6 ) 0.62 - 0.68 (2H, m), 0.80 - 0.87 (2H, m), 1.40 (9H, s), 1.50 - 1.67 (2H, m), 1.76 - 1.86 (4H, m), 1.86 - 1.94 (1H, m), 1.99 - 2.10 (2H, m), 2.29 - 2.37 (2H, m), 2.57 (2H, d), 2.75 (2H, t), 2.94 - 3.11 (4H, m), 3.67 - 3.76 (2H, m), 3.80 (2H, t), 4.49 - 4.64 (1H, m), 7.44 (1H, s), 7.93 (1H, d), 8.15 (1H, d), 10.35 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 569.3. Intermediate 26e: 1-[3-cyclopropyl-1-[1-[(4-fluoro-4-piperidinyl)methyl]-4-piperidinyl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 1i starting from intermediate 26d (35 g, 61.6 mmol). Pour the concentrate into cold saturated aqueous NaHCO ₃ solution (1 L), extract with DCM (4 x 1 L) and concentrate the organic layer. The crude solid was triturated with DCM to give a solid which was collected by filtration and dried under vacuum to give the title compound as a 0.75 TF salt as a white solid (24.5 g, 71.4%). m/z (ES ⁺ ) [M+H] ⁺ = 469.3. Intermediate 26f: 1-[1-[1-[[1-(5-chloro-2-fluoro-phenyl)-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 25h starting from intermediate 26e (469 mg, 1 mmol) and 2-bromo-4-chloro-1-fluorobenzene (244 μl, 2 mmol). Purification by FSC (gradient: 0-5% MeOH in DCM) gave the title compound (556 mg, 93%) as an orange solid. ¹ H NMR (CDCl ₃ ): δ 0.59 - 0.67 (2H, m), 0.81 - 0.97 (2H, m), 1.78 - 2.14 (10H, m), 2.47 (2H, td), 2.92 (2H, t), 3.00 - 3.12 (4H, m), 3.28 (2H, br d), 3.93 (2H, t), 4.68 - 4.81 (1H, m), 6.85 - 6.99 (3H, m), 7.11 (1H, s), 7.49 (1H, s), 7.90 (1H, d), 8.23 (1H, d) (NH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 597.4. Intermediate 26g: N -tert-butyloxycarbonyl- N- [4-[8-[3-[4-[[4-[3-cyclopropyl-5-(2,4-dioxohexahydroxypyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1-piperidinyl]methyl]-4-fluoro-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalim-3-yl]carbamic acid tert-butyl ester

Prepared in a similar manner to intermediate 25i starting from intermediate 26e (119 mg, 0.20 mmol) and intermediate 26f (108 mg, 0.20 mmol). Purification by FSC (gradient: 0-3% MeOH in DCM containing 0.1% _NH4OH ) gave the title compound (40.0 mg, 18.14%) as a yellow gum. ¹ H NMR (CDCl ₃ ): δ 0.58 - 0.67 (2H, m), 0.84 - 0.94 (2H, m), 1.46 (18H, s), 1.84 - 2.11 (14H, m), 2.42 - 2.52 (2H, m), 2.56 - 2.65 (2H, m), 2.91 (2H, t), 2.97 - 3.05 (2H, m), 3.10 (2H, br d), 3.23 - 3.30 (2H, m), 3.38 (5H, s), 3.92 (2H, t), 4.22 (2H, br s), 4.74 (1H, br s), 5.17 (2H, s), 6.38 (1H, dt), 6.46 - 6.52 (1H, m), 6.89 - 6.96 (1H, m), 7.10 (1H, s), 7.13 - 7.21 (2H, m), 7.37 - 7.45 (2H, m), 7.57 (1H, s), 7.89 - 7.98 (2H, m), 8.23 (1H, d)(NH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 1102.7. 1-[1-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 26g (34 mg, 0.03 mmol), DCM (2 mL) and TFA (0.4 mL). The reaction was stirred at room temperature for 1.5 h and then concentrated in vacuo. Purification by RPC (Gradient: 50%-100% MeCN in water containing 0.1% NH ₄ OH) gave the title compound (9.80 mg, 37.0%) as a white solid. ¹ H NMR(DMSO -d6 ) δ 0.62 - 0.72 (2H, m), 0.80 - 0.89 (2H, m), 1.75 - 2.03 (9H, m), 2.04 - 2.20 (4H, m), 2.32 - 2.44 (2H, m), 2.58 - 2.69 (2H, m), 2.77 (2H, t), 2.96 (2H, br t), 3.04 - 3.13 (4H, m), 3.16 - 3.23 (2H, m), 3.27 (2H, br d), 3.82 (2H, t), 4.38 (2H, br d), 4.54 - 4.68 (1H, m), 5.94 (2H, s), 6.46 (1H, dt), 6.51 - 6.58 (1H, m), 6.83 - 6.91 (2H, m), 6.96 (1H, dd), 7.20 - 7.27 (1H, m), 7.47 (2H, s), 7.91 (1H, dd), 7.95 (1H, d), 8.18 (1H, d), 10.37 (1H, br s), 14.05 - 14.25 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 858.5. Example 27 Intermediate 27a: 1-(3-bromo-2-fluorophenyl)-4-(dibutoxymethyl)piperidine

A flask was charged with 4-(dibutoxymethyl)piperidine (2.57 g, 10.56 mmol), 1,3-dibromo-2-fluorobenzene (5.36 g, 21.12 mmol), BINAP (0.658 g, 1.06 mmol), Pd ₂ (dba) ₃ (0.483 g, 0.53 mmol), and KO t Bu (1.185 g, 10.56 mmol) in toluene (52.8 ml). The reaction was degassed by bubbling N ₂ through the solution for 5 min. The reaction was heated to 105 °C for 3 h. The reaction was cooled to room temperature and concentrated in vacuo. Purification by FSC (Gradient: 0-10% EtOAc in hexanes) gave the title compound (2.400 g, 54.6%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.91 - 0.96 (6H, m), 1.35 - 1.44 (4H, m), 1.52 - 1.60 (6H, m), 1.67 - 1.75 (1H, m), 1.84 (2H, br d), 2.61 - 2.68 (2H, m), 3.39 - 3.47 (4H, m), 3.61 (2H, dt), 4.19 (1H, d), 6.88 - 6.96 (2H, m), 7.08 - 7.14 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 416.2. Intermediate 27b: 8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-2-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

A vial was charged with a solution of intermediate 27a (1.249 g, 3 mmol), benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.739 g, 3.00 mmol) and SPhos Pd G2 (0.216 g, 0.30 mmol) in THF (6.00 ml), degassed with N ₂ , and LiHMDS solution (9.00 mL, 9.00 mmol, 1 M in THF) was added. The reaction mixture was heated to 60 °C for 2 h. The reaction was cooled to room temperature, diluted with EtOAc (20 mL), and quenched with NH ₄ Cl solution (3 mL). The organic phase was separated, dried over MgSO ₄ , filtered, and concentrated. Purification by FSC (Gradient: 0-30% EtOAc in hexanes) gave the title compound (1.100 g, 63.0%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.90 - 0.95 (6H, m), 1.20 - 1.29 (2H, m), 1.35 - 1.43 (4H, m), 1.43 - 1.51 (2H, m), 1.52 - 1.58 (4H, m), 1.70 - 1.73 (1H, m), 1.73 - 1.78 (2H, m), 1.79 - 1.85 (2H, m), 1.90 - 1.98 (2H, m), 2.60 (2H, br t), 3.34 - 3.40 (2H, m), 3.40 - 3.46 (2H, m), 3.61 (2H, dt), 3.74 - 3.85 (2H, m), 4.02 - 4.11 (2H, m), 4.18 (1H, d), 5.11 (2H, s), 6.49 - 6.56 (2H, m), 6.88 (1H, t), 7.26 - 7.31 (1H, m), 7.33 - 7.36 (4H, m); m/z (ES ⁺ ) [M+H] ⁺ = 582.6. Intermediate 27c: 8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-2-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane

Prepared in a similar manner to intermediate 11e starting from intermediate 27b (1.1 g, 1.89 mmol). The solid was filtered off and the filtrate was concentrated to give the title compound as a black gum (0.500 g, 59.1%). m/z (ES ⁺ ) [M+H] ⁺ = 448.5. Intermediate 27d: 6-Chloro-4-[8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-2-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

Prepared in a similar manner to intermediate 3d starting from intermediate 27c (500 mg, 1.12 mmol) and 4-bromo-6-chlorotitanium-3-amine (233 mg, 1.12 mmol). Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (120 mg, 18.68%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.92 - 0.96 (6H, m), 1.38 - 1.44 (4H, m), 1.52 - 1.58 (6H, m), 1.66 - 1.75 (1H, m), 1.79 - 1.88 (2H, m), 1.96 - 1.99 (2H, m), 2.04 - 2.11 (2H, m), 2.61 (2H, br t), 3.10 (2H, d), 3.27 (2H, dd), 3.36 - 3.46 (4H, m), 3.61 (2H, dt), 4.17 - 4.21 (1H, m), 4.21 - 4.26 (2H, m), 4.68 (2H, s), 6.52 - 6.58 (2H, m), 6.75 (1H, s), 6.89 - 6.93 (1H, m); m/z (ES ⁺ ) [M-OBu] ⁺ = 501.4. Intermediate 27e: 2-[6-amino-5-[8-[3-[4-(dibutyloxymethyl)-1-piperidinyl]-2-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 27d (120 mg, 0.21 mmol). Purification by FSC (gradient: 10%-30% EtOAc in hexanes) gave the title compound (60 mg, 45% yield) as a yellow solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.93 (6H, t), 1.37 - 1.43 (4H, m), 1.46 - 1.51 (2H, m), 1.53 - 1.59 (4H, m), 1.66 - 1.74 (1H, m), 1.81 - 1.87 (2H, m), 1.99 - 2.05 (2H, m), 2.08 - 2.12 (2H, m), 2.58 - 2.66 (2H, m), 3.22 (2H, d), 3.32 - 3.37 (2H, m), 3.38 - 3.47 (4H, m), 3.62 (2H, dt), 4.19 (1H, d), 4.27 (2H, br s), 4.80 (2H, s), 6.57 (2H, t), 6.88 - 6.95 (2H, m), 6.97 (1H, dd), 7.23 - 7.29 (1H, m), 7.36 (1H, s), 7.61 - 7.64 (1H, m), 13.71 - 13.81 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 633.5. 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 27e (32 mg, 0.05 mmol) and intermediate 4b (24 mg, 0.05 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 20%-40% MeCN in water containing 0.1% FA) gave the title compound (15 mg, 35%) as an amorphous white solid. ¹ H NMR (DMSO- d 6) δ 1.20 - 1.30 (2H, m), 1.58 - 1.67 (3H, m), 1.71 - 1.81 (4H, m), 1.91 (2H, br d), 2.05 - 2.12 (4H, m), 2.12 - 2.16 (2H, m), 2.20 - 2.30 (5H, m), 2.30 - 2.43 (4H, m), 2.57 - 2.65 (2H, m), 2.71 (2H, t), 3.08 - 3.12 (2H, m), 3.36 - 3.46 (4H, m), 3.75 (2H, t), 4.22 (2H, br s), 4.95 (1H, quin), 5.94 (2H, s), 6.54 (1H, br t), 6.67 (1H, br t), 6.84 - 6.92 (3H, m), 7.03 (1H, dd), 7.23 (1H, t), 7.36 - 7.44 (3H, m), 7.53 (1H, s), 7.94 (1H, d), 10.22 (1H, s), 13.96 - 14.47 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 853.5. Example 28 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 27e (32 mg, 0.05 mmol) and intermediate 2b (20 mg, 0.05 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 20%-40% MeCN in water containing 0.1% FA) gave the title compound (16 mg, 36%) as an amorphous white solid. ¹ H NMR (DMSO- d 6) δ 0.65 - 0.70 (2H, m), 0.83 - 0.88 (2H, m), 1.20 - 1.30 (2H, m), 1.59 - 1.65 (1H, m), 1.65 - 1.74 (4H, m), 1.74 - 1.82 (2H, m), 1.88 - 1.98 (3H, m), 2.05 - 2.19 (5H, m), 2.19 - 2.24 (2H, m), 2.29 - 2.42 (4H, m), 2.56 - 2.65 (2H, m), 2.75 (2H, t), 3.07 - 3.12 (2H, m), 3.38 - 3.47 (5H, m), 3.80 (2H, t), 4.22 (2H, br s), 5.23 (1H, quin), 5.94 (2H, s), 6.50 - 6.58 (1H, m), 6.68 (1H, br s), 6.82 - 6.96 (3H, m), 7.20 - 7.24 (1H, m), 7.53 (2H, d), 7.91 - 7.96 (2H, m), 8.15 (1H, d), 10.35 (1H, br s), 13.94 - 14.37 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 880.6. Example 29 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 3e (40 mg, 0.07 mmol) and intermediate 15b (30.4 mg, 0.07 mmol) and formic acid (1 mL). The reaction was heated to 40 °C for 30 min. Toluene (2 mL) was added and the solvent was concentrated in vacuo. MeOH (1 mL), DCM (0.2 mL) and DIPEA (0.057 mL, 0.33 mmol) were added to the mixture. Decaborane (3.98 mg, 0.03 mmol) was added and the reaction was stirred at room temperature for 1 h. Acetone (1 mL) was added and stirred for 15 min. DMSO (1 mL) was added and the volatiles were evaporated in vacuo. Purification by RPC (Gradient: 0-80% CH ₃ CN in water containing 0.1% formic acid) gave the title compound (18 mg, 33.1%) as an amorphous off-white solid. ¹ H NMR (DMSO- d 6): δ 1.05 - 1.33 (3H, m), 1.51 - 1.87 (7H, m), 1.87 - 2.02 (2H, m), 2.13 (4H, br d), 2.18 - 2.24 (2H, m), 2.27 (3H, s), 2.35 (4H, br t), 2.62 (2H, br s), 2.76 (2H, t), 3.06 - 3.27 (4H, m), 3.65 (2H, br d), 3.81 (2H, t), 4.39 (2H, br s), 5.14 - 5.37 (1H, m), 6.24 - 6.38 (2H, m), 6.43 (1H, brs), 6.82 - 6.90 (2H, m), 7.02 (1H, t), 7.23 (1H, t), 7.46 (1H, s), 7.61 (1H, s), 7.85 - 7.94 (2H, m), 8.17 (1H, d), 10.38 (1H, s), 14.17 (1H, br s). m/z (ES ⁺ ) [M+H] ⁺ = 836.5. Example 30 Intermediate 30a: (2 R )-2-[(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)methyl]oxoline-4-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a from 5-bromo-3-methyl- 1H -indole (0.500 g, 2.37 mmol), ( S )-2-(hydroxymethyl)oxoline-4-carboxylic acid tributyl ester (0.772 g, 3.55 mmol) and 2-( tributyl -15-phosphinoyl)acetonitrile (0.931 mL, 3.55 mmol). Purification by FSC (gradient: 0 to 50% EtOAc in hexanes) gave the title compound (821 mg, 84%) as an off-white foam. ¹ H NMR (CDCl ₃ ) δ 1.44 (9H, s), 2.27 (3H, s), 2.61 (1H, br s), 2.91 (1H, br s), 3.47 (1H, td), 3.71 - 4.08 (4H, m), 4.16 - 4.42 (2H, m), 7.06 (1H, br d), 7.95 (1H, s), 8.30 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 410.1. Intermediate 30b: ( 2R )-2-[[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]methyl]oxoline-4-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 6b starting from intermediate 30a (0.82 g, 1.99 mmol). The mixture was stirred at 90 °C for 21 h. After cooling to room temperature, the mixture was filtered. The filter cake was washed with DCM. The combined filtrate was concentrated in vacuo. Purification by FSC (first purification, gradient: 0 to 15% MeOH in DCM, second purification, elution gradient: 0 to 100% [3:1 EtOAc/EtOH] in hexanes) gave the title compound (0.66 g, 74%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ) δ 1.36 (9H, s), 2.24 (3H, d), 2.53 - 2.68 (1H, m), 2.75 (2H, t), 2.85 (1H, br s), 3.27 - 3.35 (1H, m), 3.61 - 3.84 (6H, m), 4.27 (2H, br d), 7.33 (1H, d), 7.89 (1H, d), 8.18 (1H, d), 10.37 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 444.4. 1-[1-[[(2 S )-4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]oxathiapiperidin-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Formic acid (1 mL) was added to a mixture of intermediate 11g (30 mg, 0.05 mmol) and intermediate 30b (29 mg, 0.07 mmol). The resulting mixture was stirred at 40 °C for 30 min and concentrated under reduced pressure. The residue was azeotroped with toluene (2 mL). DMF (1 mL) was added and the mixture was stirred at 40 °C for 20 min. After cooling to room temperature, Na(OAc) ₃ BH (20 mg, 0.09 mmol) was added and the mixture was stirred at room temperature for 20 min. Purification by RPC (gradient: 0 to 50% MeCN in water containing 0.1% FA) gave the title compound (14.1 mg, 35%) as a white solid. ¹ H NMR (DMSO-d ₆ ) δ 1.16 - 1.30 (2H, m), 1.60 (1H, ddd), 1.71 - 1.84 (3H, m), 1.89 - 1.96 (2H, m), 1.96 - 2.02 (1H, m), 2.08 - 2.18 (4H, m), 2.23 (3H, s), 2.56 - 2.64 (3H, m), 2.69 - 2.77 (3H, m), 3.08 (2H, br d), 3.24 (2H, br d), 3.30 - 3.34 (2H, m), 3.38 - 3.43 (1H, m), 3.74 - 3.85 (4H, m), 4.24 (2H, br d), 4.33 (2H, br s), 5.93 (2H, s), 6.41 (1H, dt), 6.45 (1H, dd), 6.82 - 6.88 (2H, m), 6.90 (1H, dd), 7.17 - 7.26 (1H, m), 7.32 (1H, s), 7.45 (1H, s), 7.86 - 7.94 (2H, m), 8.17 (1H, d), 10.38 (1H, s), 13.15 - 14.96 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 830.4. Example 31 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 11g (40 mg, 0.07 mmol) and intermediate 4b (40.8 mg, 0.09 mmol) in a similar manner to Example 30. Purification by RPC (gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (3.50 mg, 5.53%) as a white solid. ¹ H NMR (DMSO d6 ) δ 0.85 (1H, d), 1.24 (4H, s), 1.64 (3H, s), 1.78 (4H, d), 1.95 (2H, s), 2.08 (1H, d), 2.12 (1H, d), 2.16 (3H, d), 2.25 (4H, d), 2.31 (1H, s), 2.41 (3H, d), 2.55 (1H, s), 2.63 (1H, d), 2.73 (2H, t), 3.10 (2H, d), 3.26 (3H, d), 3.77 (2H, t), 4.35 (2H, s), 4.92-5.01 (1H, m), 5.96 (2H, s), 6.4-6.51 (2H, m), 6.82-6.98 (3H, m), 7.01-7.08 (1H, m), 7.19-7.27 (1H, m), 7.37-7.5 (4H, m), 7.88-7.95 (1H, m), 10.26 (1H, s), 14.19 (1H, s); ¹⁹ F NMR (DMSO- d6 ) δ -136.411; m/z (ES+) [M+H] ⁺ = 853.1. Example 32 Intermediate 32a: 4-[2-(5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)ethyl]piperidin-1-carboxylic acid tributyl ester

A flask was charged with tributyl 4-(2-bromoethyl)piperidinium-1-carboxylate (500 mg, 1.71 mmol), 5-bromo-3-cyclopropyl- 1H -pyrrolo[2,3- b ]pyridine (270 mg, 1.14 mmol), Cs ₂ CO ₃ (1111 mg, 3.41 mmol) and DMF (10 mL). The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by FSC (gradient: 0 to 100% EtOAc in petroleum ether) gave the title compound (460 mg, 60.5%) as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 0.57 - 0.67 (2 H, m), 0.88 - 0.97 (2 H, m), 1.47 (9 H, s), 1.82 - 1.92 (1 H, m), 2.46 (4 H, s), 2.76 (2 H, s), 3.41 (4 H, s), 4.33 (2 H, s), 7.00 (1 H, s), 8.09 (1 H, d), 8.30 (1 H, d); m/z (ES ⁺ ) [M+H] ⁺ = 449.3. Intermediate 32b: 4-[2-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]ethyl]piperidin-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 6b starting from intermediate 32a (450 mg, 1.00 mmol). Purification by FSC (gradient: 0 to 100% EtOAc in petroleum ether then 0 to 10% MeOH in DCM) gave the title compound (277 mg, 56.5%) as a yellow solid. ¹ H NMR (CDCl ₃ ) δ 0.56 - 0.64 (2 H, m), 0.86 - 0.91 (2 H, m), 1.45 (9 H, s), 1.82 - 1.91 (1 H, m), 2.45 (4 H, s), 2.65 - 2.79 (2 H, m), 2.87 - m /z (ES+) [M+H] ⁺ = 483.3. 1-[1-[2-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]ethyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TsOH (58.9 mg, 0.31 mmol) was added to intermediate 32b (115 mg, 0.24 mmol) in MeCN (2 mL). The resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was evaporated. To the residue were added intermediate 13d (143 mg, 0.29 mmol) and NMP (2.0 mL). The resulting mixture was stirred at 40 °C for 16 h, cooled to room temperature, then Na(OAc) ₃ BH (303 mg, 1.43 mmol) was added and stirred at room temperature for 1 h. The reaction _mixture was poured into saturated _Na2CO3 (20 mL), extracted with DCM (3 x 10 mL), the organic layer was separated, dried _{over Na2SO4} , filtered and concentrated. Purification by RPC (Gradient: 0-70% _CH3CN in water containing _NH4HCO3 + _0.1 % _NH4OH ) gave the title compound (13.00 mg, 6.84%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.55 - 0.65 (2 H, m), 0.82 - 0.91 (2 H, m), 1.12 - 1.31 (3 H, m), 1.59 (1 H, s), 1.75 (2 H, d), 1.86 - 2.00 (3 H, m), 2.04 - 2.19 (4 H, m), 2.32 (4 H, s), 2.45 (3 H, s), 2.56 - 2.68 (4 H, m), 2.71 - 2.80 (2 H, m), 3.09 (2 H, d), 3.25 (2 H, d), 3.40 (2 H, s), 3.76 - 3.85 (2 H, m), 4.21 - 4.38 (4 H, m), 5.94 (2 H, s), 6.37 - 6.52 (2 H, m), 6.80 - 6.98 (3 H, m), 7.18 - 7.26 (1 H, m), 7.32 (1 H, s), 7.46 (1 H, s), 7.86 - 7.98 (2 H, m), 8.17 (1 H, d), 10.39 (1 H, s), 14.17 (1 H, s); ¹⁹ F NMR (DMSO- d6 ) δ: -136.40; m/z (ES ⁺ ) [M+H] ⁺ = 869.5. Example 33 Intermediate 33a: 3-Benzyloxy-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

TsOH (0.19 g, 1.00 mmol) was added to a mixture of 2-benzyloxypropane-1,3-diol (2.01 g, 11.0 mmol) and tributyl 4-oxopiperidine-1-carboxylate (2.00 g, 10.0 mmol) in DCM (49 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was washed with saturated aqueous NaHCO ₃ solution (50 mL), water (50 mL), and brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by FSC (gradient: 0 to 40% EtOAc in hexanes) gave the title compound (2.75 g, 75%) as a colorless oil. ¹ H NMR (DMSO- d 6): δ 1.38 (9H, s), 1.66 - 1.77 (4H, m), 3.28 (4H, br s), 3.42 - 3.49 (1H, m), 3.71 (2H, dd), 3.94 (2H, dd), 4.52 (2H, s), 7.24 - 7.42 (5H, m); m / z (ES ⁺ ) [M+Na] ⁺ = 386.3. Intermediate 33b: 3-Hydroxy-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

EtOAc (50 mL) was added to a mixture of intermediate 33a (2.74 g, 7.54 mmol) and Pd/C (0.80 g, 0.75 mmol). The mixture was bubbled with _H2 for 5 min and stirred under _H2 atmosphere at room temperature for 4 h and at 50 °C for 17 h. After cooling to room temperature, the mixture was filtered through a celite® pad, eluting with EtOAc. The combined filtrate was concentrated under reduced pressure. Purification by FSC (gradient: 0 to 100% EtOAc in hexanes) gave the title compound (1.30 g, 62%) as a white solid. ¹ H NMR (DMSO- d 6) δ 1.39 (9H, s), 1.60 - 1.69 (2H, m), 1.74 - 1.83 (2H, m), 3.26 - 3.33 (4H, m), 3.48 - 3.59 (3H, m), 3.77 - 3.88 (2H, m), 5.00 (1H, br s); m / z (ES ⁺ ) [M- t Bu+2H] ⁺ = 218.0. Intermediate 33c: 3-(5-Bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a using 5-bromo-3-methyl- 1H -indole (1.20 g, 5.66 mmol), intermediate 33b (1.29 g, 4.72 mmol) and 2-(tributyl-λ⁵-phosphine)acetonitrile (1.24 mL, 4.72 mmol). Purification by FSC (gradient: 0 to 50% EtOAc in hexanes) gave the title compound (339 mg, 15%) as an off-white solid. ¹ H NMR (DMSO- d 6) δ 1.41 (9H, s), 1.80 - 1.88 (2H, m), 1.93 - 1.99 (2H, m), 2.27 (3H, d), 3.37 (4H, dt), 3.97 - 4.07 (2H, m), 4.34 (2H, dd), 4.80 (1H, quin), 7.74 (1H, s), 8.21 (1H, d), 8.28 (1H, d); m / z (ES ⁺ ) [M+H] ⁺ = 466.3. Intermediate 33d: 3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 6b using intermediate 33c (334 mg, 0.72 mmol). The mixture was stirred at 95 °C for 23 h. After cooling to room temperature, the mixture was filtered. The filter cake was washed with DCM. The combined filtrate was concentrated under reduced pressure. Purification by FSC (gradient: 0 to 100% [3: 1 EtOAc/EtOH] in hexanes) gave the title compound (207 g, 57%) as an off-white solid. ¹ H NMR (DMSO- d 6) δ 1.40 (9H, s), 1.82 - 1.90 (2H, m), 1.91 - 1.98 (2H, m), 2.27 (3H, d), 2.75 (2H, t), 3.29 - 3.52 (4H, m), 3.80 (2H, t), 3.98 - 4.08 (2H, m), 4.31 (2H, br dd), 4.83 (1H, quin), 7.70 (1H, s), 7.91 (1H, d), 8.18 (1H, d), 10.37 (1H, s); m / z (ES ⁺ ) [M+H] ⁺ = 500.2. Intermediate 33e: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (0.62 mL) was added to a solution of intermediate 33d (199 mg, 0.40 mmol) in DCM (2.4 mL). The resulting mixture was stirred at room temperature for 30 min. The mixture was diluted with DCM-IPA (3:2, ₃₀ mL), washed with saturated aqueous _K2CO3 solution (3 x 30 mL), dried over _Na2SO4 , _filtered , and concentrated under reduced pressure to give the title compound (115 mg, 72%) as an off-white solid. ¹ H NMR (DMSO- d 6) δ 1.81 (2H, br s), 1.89 (2H, br s), 2.28 (3H, s), 2.66 - 2.78 (6H, m), 3.80 (2H, t), 4.01 (2H, dd), 4.26 - 4.35 (2H, m), 4.82 (1H, quin), 7.73 (1H, s), 7.91 (1H, d), 8.19 (1H, d), 9.92 - 10.86 (1H, m), no NH proton observed; m / z (ES ⁺ ) [M+H] ⁺ = 400.4. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

DMF (1 mL) was added to a mixture of intermediate 33e (45 mg, 0.11 mmol) and intermediate 13d (40 mg, 0.08 mmol). The resulting mixture was stirred at room temperature for 3 min. Na(OAc) ₃ BH (34 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 30 min. Purification by RPC (gradient: 40% to 100% MeCN in water containing 0.1% NH ₄ OH) gave the title compound (21.5 mg, 30%) as an amorphous white solid after freeze drying. ¹ H NMR (DMSO- d 6) δ 1.18 - 1.32 (2H, m), 1.56 - 1.67 (1H, m), 1.78 (2H, br d), 1.85 - 2.08 (6H, m), 2.09 - 2.16 (2H, m), 2.19 (2H, br d), 2.27 (3H, s), 2.31 - 2.47 (4H, m), 2.58 - 2.68 (2H, m), 2.75 (2H, t), 3.09 (2H, br d), 3.21 - 3.41 (4H, m), 3.80 (2H, t), 4.00 (2H, dd), 4.25 - 4.41 (4H, m), 4.81 (1H, quin), 5.92 (2H, s), 6.38 - 6.49 (2H, m), 6.81 - 6.97 (3H, m), 7.16 - 7.27 (1H, m), 7.46 (1H, s), 7.72 (1H, s), 7.84 - 7.97 (2H, m), 8.18 (1H, d), 9.85 - 10.91 (1H, m), 13.31 - 14.99 (1H, m); m / z (ES ⁺ ) [M+H] ⁺ = 886.7. Example 34 Intermediate 34a: 8-(5-chloro-2-fluoro-phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.232 g, 5.00 mmol) was added to a suspension of 2-bromo-4-chloro-1-fluorobenzene (1.047 g, 5 mmol), BINAP (0.311 g, 0.50 mmol), Pd ₂ (dba) ₃ (0.229 g, 0.25 mmol) and KO t Bu (1.683 g, 15.00 mmol) in toluene (16 mL). The solution was degassed and purged with N _2. The reaction was heated to 60 °C for 2 h. The reaction was cooled to room temperature and quenched with NH ₄ Cl solution. The organic phase was dried (MgSO 4 ), filtered and concentrated. Purification by FSC (Gradient: 5%-30% EtOAc in hexanes) gave the title compound (1.140 g, 60.8%) as a yellow liquid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.75 - 1.82 (2H, m), 1.94 - 1.99 (2H, m), 3.16 - 3.26 (1H, m), 3.28 - 3.36 (1H, m), 3.76 - 3.86 (2H, m), 4.09 - 4.14 (1H, m), 4.14 - 4.19 (1H, m), 5.08 - 5.12 (2H, m), 6.74 - 6.78 (1H, m), 6.83 (1H, dd), 6.95 (1H, dd), 7.28 - 7.34 (1H, m), 7.34 - 7.39 (4H, m); m/z (ES ⁺ ) [M+H] ⁺ = 375.1. Intermediate: 34b: 8-[5-[4-(dibutoxymethyl)-1-piperidinyl]-2-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Intermediate 34a (1.14 g, 3.04 mmol) was added to 4-(dibutoxymethyl)piperidine (0.740 g, 3.04 mmol), Ruphos Pd G3 (0.254 g, 0.30 mmol) and KO t Bu (0.444 g, 3.95 mmol) in toluene (15 mL). The reaction mixture was degassed and heated at 105 °C under N ₂ for 1 h. The solvent was removed under reduced pressure. Purification by FSC (gradient: 5%-35% EtOAc in hexanes) gave the title compound (0.910 g, 51.4%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ) δ 0.92 (6H, t), 1.37 - 1.41 (4H, m), 1.51 - 1.58 (6H, m), 1.63 - 1.72 (1H, m), 1.73 - 1.85 (4H, m), 1.92 - 2.01 (2H, m), 2.57 (2H, br t), 3.22 - 3.28 (1H, m), 3.29 - 3.36 (1H, m), 3.39 - 3.45 (2H, m), 3.47 - 3.53 (2H, m), 3.57 - 3.63 (2H, m), 3.73 - 3.84 (2H, m), 4.05 - 4.19 (3H, m), 5.11 (2H, s), 6.32 - 6.43 (2H, m), 6.87 (1H, dd), 7.28 - 7.33 (1H, m), 7.33 - 7.38 (4H, m); m/z (ES ⁺ ) [M+H] ⁺ = 582.8. Intermediate: 34c: 8-[5-[4-(dibutoxymethyl)-1-piperidinyl]-2-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane

Prepared in a similar manner to intermediate 20b starting from intermediate 34b (1.2 g, 2.06 mmol). The solid was filtered off and the filtrate was concentrated to give the title compound as a light black gum (0.897 g, 97%). ¹ H NMR (DMSO-d ₆ ): δ 0.87 (6H, t), 1.29 - 1.37 (6H, m), 1.44 - 1.51 (4H, m), 1.59 - 1.65 (1H, m), 1.64 - 1.72 (2H, m), 1.73 - 1.88 (4H, m), 2.40 - 2.48 (3H, m), 2.91 (2H, br d), 3.32 - 3.35 (2H, m), 3.35 - 3.41 (2H, m), 3.50 - 3.57 (4H, m), 3.94 (2H, br s), 4.17 (1H, d), 6.23 - 6.29 (1H, m), 6.39 (1H, dd), 6.86 (1H, dd); m/z (ES ⁺ ) [M+H] ⁺ = 448.6. Intermediate 34d: 6-Chloro-4-[8-[5-[4-(dibutoxymethyl)-1-piperidinyl]-2-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridin-3-amine

Prepared in an analogous manner to intermediate 3d starting from intermediate 34c (0.922 g, 2.06 mmol). Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (0.910 g, 77%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.90 - 0.93 (6H, m), 1.37 - 1.41 (4H, m), 1.50 - 1.57 (6H, m), 1.67 (1H, dtd), 1.82 (2H, br d), 1.95 - 1.99 (2H, m), 2.05 - 2.11 (2H, m), 2.53 - 2.60 (2H, m), 3.08 (2H, d), 3.25 (2H, dd), 3.38 - 3.43 (2H, m), 3.51 (2H, br d), 3.58 - 3.62 (2H, m), 4.16 (1H, d), 4.26 (2H, br s), 4.68 (2H, s), 6.32 - 6.46 (2H, m), 6.73 (1H, s), 6.88 (1H, dd). Intermediate 34e: 2-[6-amino-5-[8-[5-[4-(dibutoxymethyl)-1-piperidinyl]-2-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]phthalim-3-yl]phenol

Prepared in an analogous manner to intermediate 2h starting from intermediate 34d (0.87 g, 1.82 mmol). Purification by FSC (gradient: 10%-30% solvent B in hexanes [solvent B: 10% MeOH in EtOAc]) gave the title compound (0.760 g, 79%) as a yellow solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.91 - 0.94 (6H, m), 1.36 - 1.40 (4H, m), 1.49 - 1.57 (6H, m), 1.68 - 1.73 (1H, m), 1.81 - 1.85 (2H, m), 2.00 - 2.05 (2H, m), 2.09 - 2.16 (2H, m), 2.57 - 2.62 (2H, m), 3.20 - 3.25 (2H, m), 3.31 - 3.37 (2H, m), 3.40 - 3.45 (2H, m), 3.51 - 3.55 (2H, m), 3.58 - 3.63 (2H, m), 4.18 (1H, d), 4.31 (2H, br s), 4.81 (2H, s), 6.34 - 6.43 (1H, m), 6.47 (1H, dd), 6.88 - 6.95 (2H, m), 6.95 - 7.00 (1H, m), 7.26 (1H, ddd), 7.35 (1H, s), 7.62 (1H, dd), 13.66 - 13.92 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 633.7. 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting from intermediate 34e (32 mg, 0.05 mmol) and intermediate 11b (26 mg, 0.05 mmol) in a similar manner to Example 11. Purification by RPC (gradient: 50%-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (21 mg, 46.2%) as an amorphous white solid. ¹ H NMR (DMSO- d 6): 0.62 - 0.66 (2H, m), 0.83 - 0.88 (2H, m), 1.13 - 1.35 (6H, m), 1.37 - 1.47 (2H, m), 1.58 - 1.70 (4H, m), 1.74 - 1.85 (6H, m), 1.88 - 2.05 (6H, m), 2.08 - 2.13 (2H, m), 2.20 - 2.36 (2H, m), 2.51 - 2.64 (4H, m), 2.72 - 2.78 (2H, m), 3.07 - 3.13 (2H, m), 3.48 - 3.60 (2H, m), 3.73 - 3.84 (2H, m), 4.30 (2H, br s), 4.52 - 4.66 (1H, m), 5.94 (2H, s), 6.35 (1H, br d), 6.47 - 6.53 (1H, m), 6.82 - 6.89 (2H, m), 6.90 - 6.99 (1H, m), 7.21 - 7.25 (1H, m), 7.47 - 7.50 (1H, m), 7.50 - 7.55 (1H, m), 7.90 - 7.98 (2H, m), 8.13 - 8.17 (1H, m), 10.35 (1H, s), 14.02 - 14.32 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 908.6. Example 35 Intermediate 35a: 4-(Benzyloxymethyl)-3,3-difluoro-piperidine-1-carboxylic acid tributyl ester

A mixture of tributyl 3,3-difluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.508 g, 6 mmol), DMAP (0.073 g, 0.60 mmol), DCM (25 mL) and DIPEA (3.14 mL, 18.00 mmol). The reaction was cooled to 0 °C. Benzyl chloride (1.381 mL, 12.00 mmol) was added and the reaction was stirred at 0 °C for 5 min and then at room temperature for 2.5 h. The reaction was quenched with saturated aqueous NaHCO ₃ solution (50 mL), extracted with DCM (3 x 50 mL), washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (2.013 g, 94%) as a colorless oil. ¹ H NMR (CDCl ₃ ): δ 1.50 (9H, s), 1.69 (1H, qd), 1.96 (1H, br d), 2.35 - 2.47 (1H, m), 2.73 - 2.93 (1H, m), 2.95 - 3.17 (1H, m), 4.16 - 4.45 (3H, m), 4.67 (1H, dd), 7.47 (2H, t), 7.59 (1H, t), 8.06 (2H, d); m/z (ES ⁺ ) [M- t Bu+2H] ⁺ = 300.1. Intermediate 35b: Benzoic acid (3,3-difluoro-4-piperidinyl) methyl ester

A vial was charged with intermediate 35a (2.013 g, 5.66 mmol), DCM (20 mL) and TFA (4 ml). The reaction was stirred at room temperature for 2.5 h and then concentrated in vacuo. The crude material was purified by ion exchange chromatography (Porpak Rxn CX 5 g cartridge) eluting with 2 N _NH3 in MeOH to give the title compound (1.285 g, 89%) as a light brown oil. ¹ H NMR (DMSO- d 6): δ 1.46 (1H, qd), 1.78 - 1.90 (1H, m), 2.37 - 2.49 (2H, m), 2.52 - 2.56 (1H, m), 2.69 - 2.81 (1H, m), 2.91 (1H, br dd), 3.05 (1H, td), 4.28 (1H, dd), 4.52 (1H, dd), 7.54 (2H, t), 7.67 (1H, t), 7.98 (2H, d); m/z (ES ⁺ ) [M+H] ⁺ = 256.3. Intermediate 35c: Benzoic acid [1-(5-chloro-2-fluoro-phenyl)-3,3-difluoro-4-piperidinyl]methyl ester

Under _N2 , a vial was charged with intermediate 35b (1.2847 g, 5.03 mmol), _Pd2 (dba) ₃ (0.230 g, 0.25 mmol), ( tBu )PhCphos (0.204 g, 0.50 mmol), _Cs2CO3 (4.92 g, 15.10 mmol), 1,4 _- dioxathiocarbamide (20 mL), and 2-bromo-4-chloro-1-fluorobenzene (0.613 mL, 5.03 mmol). The reaction was heated to 100 °C for 1.5 h. The reaction was cooled to room temperature, filtered through celite®, eluted with DCM and concentrated in vacuo. Purification by FSC (0-20% EtOAc in hexanes) gave the title compound (1.675 g, 87%) as a yellow viscous liquid. ¹ H NMR (DMSO- d 6): δ 1.75 (1H, qd), 1.99 - 2.06 (1H, m), 2.52 - 2.64 (1H, m), 2.89 - 2.98 (1H, m), 3.16 - 3.26 (1H, m), 3.47 (1H, br d), 3.65 (1H, td), 4.37 (1H, dd), 4.59 (1H, dd), 7.00 - 7.09 (1H, m), 7.12 (1H, dd), 7.21 (1H, dd), 7.55 (2H, t), 7.66 - 7.70 (1H, m), 8.00 (2H, d); m/z (ES ⁺ ) [M+H] ⁺ = 384.1. Intermediate 35d: [1-(5-chloro-2-fluoro-phenyl)-3,3-difluoro-4-piperidinyl]methanol

A vial was charged with intermediate 35c (1.6751 g, 4.36 mmol), lithium hydroxide (1.045 g, 43.65 mmol), MeOH (15 mL) and water (5 mL). The reaction was heated to 40 °C for 45 min. The reaction was partially concentrated in vacuo to remove excess MeOH. The reaction was quenched with saturated aqueous NH ₄ Cl solution (100 mL) and extracted with DCM (3 x 75 mL). The combined organic extracts were washed with saturated aqueous NaHCO ₃ solution (100 mL) and brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The title compound was obtained as a yellow oil (1.165 g, 95%). ¹ H NMR (DMSO- d 6): δ 1.52 - 1.62 (1H, m), 2.00 - 2.14 (2H, m), 2.87 (1H, br t), 3.07 - 3.17 (1H, m), 3.36 - 3.45 (2H, m), 3.48 - 3.61 (1H, m), 3.81 (1H, dt), 4.72 (1H, t), 7.00 - 7.06 (1H, m), 7.10 (1H, dd), 7.19 (1H, dd); m/z (ES ⁺ ) [M+H] ⁺ = 280.2. Intermediate 35e: 1-(5-chloro-2-fluoro-phenyl)-3,3-difluoro-piperidine-4-carbaldehyde

Dess-Martin periodinane (1943 mg, 4.58 mmol) was added to a stirred solution of intermediate 35d (1165 mg, 4.17 mmol) in DCM (25 mL). The reaction was stirred at room temperature for 1.5 h and quenched with aqueous sodium thiosulfate (50 mL), extracted with DCM (2 x 75 mL). The combined organic extracts were washed with saturated aqueous NaHCO ₃ (100 mL) and brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by FSC (gradient: 0-20% EtOAc in hexanes) gave the title compound (853 mg, 73.7%) as a yellow oil. ¹ H NMR (DMSO- d 6): δ 1.85 - 2.04 (2H, m), 2.89 - 3.00 (1H, m), 3.21 - 3.31 (1H, m), 3.32 - 3.44 (2H, m), 3.59 - 3.67 (1H, m), 7.05 (1H, ddd), 7.13 (1H, dd), 7.21 (1H, dd), 9.87 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 278.0. Intermediate 35f: 1-(5-chloro-2-fluoro-phenyl)-4-(dibutoxymethyl)-3,3-difluoro-piperidine

A mixture of intermediate 35e (853 mg, 3.07 mmol) and TsOH (58.4 mg, 0.31 mmol) in n-butanol (10 mL) was heated at 50 °C for 17 h and then concentrated in vacuo. Purification by FSC (gradient: 0-10% EtOAc in hexanes) gave the title compound (985 mg, 79%) as a light yellow liquid. ¹ H NMR (DMSO- d 6): δ 0.89 (6H, td), 1.31 - 1.41 (4H, m), 1.44 - 1.56 (4H, m), 1.60 - 1.74 (1H, m), 1.83 - 1.91 (1H, m), 2.27 - 2.39 (1H, m), 2.81 - 2.90 (1H, m), 3.06 - 3.16 (1H, m), 3.40 - 3.50 (3H, m), 3.52 - 3.63 (3H, m), 4.66 (1H, d), 7.01 - 7.04 (1H, m), 7.07 (1H, dd), 7.19 (1H, dd).; m/z (ES ⁺ ) [M+H] ⁺ = 408.4. Intermediate 35g: N -tert-butyloxycarbonyl- N- [4-[8-[3-[4-(dibutoxymethyl)-3,3-difluoro-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalim-3-yl]carbamic acid tert-butyl ester

Under an atmosphere of _N2 , a vial was charged with intermediate 35f (938 mg, 2.30 mmol), intermediate 25d (1245 mg, 2.3 mmol), _Cs2CO3 (2248 mg, 6.90 mmol), _RuPhosPdG3 (192 mg, 0.23 mmol) and 1,4-dioxathiol (20 mL). The reaction was heated to 100 °C for 1.5 h. A second portion of RuPhosPdG3 (192 mg, 0.23 mmol) was added and the reaction was heated to 100 °C for 1.5 h. The reaction was cooled to room temperature, filtered through celite®, eluted with DCM and concentrated in vacuo. Purification by FSC (gradient: 0-80% EtOAc in hexanes) gave the title compound (516 mg, 24.59%) as a brown dry film. ¹ H NMR (DMSO- d 6): δ 0.89 (6H, td), 1.31 - 1.41 (22H, m), 1.46 - 1.55 (4H, m), 1.63 - 1.76 (1H, m), 1.78 - 1.90 (3H, m), 1.92 - 1.99 (2H, m), 2.21 - 2.35 (1H, m), 2.76 (1H, br t), 2.97 - 3.10 (1H, m), 3.22 - 3.28 (5H, m), 3.29 - 3.31 (2H, m), 3.36 - 3.53 (4H, m), 3.59 (2H, ddt), 4.41 (2H, br s), 4.66 (1H, d), 5.22 (2H, s), 6.47 - 6.55 (2H, m), 6.97 (1H, dd), 7.12 - 7.19 (1H, m), 7.25 (1H, d), 7.43 - 7.49 (1H, m), 7.52 (1H, s), 7.72 (1H, dd); m/z (ES ⁺ ) [M+H] ⁺ = 913.6. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Intermediate 35g (0.377 g, 0.41 mmol) was added to a stirred solution of sulfuric acid (4.13 mL, 8.26 mmol, 2 M aqueous solution) in THF (4 mL). The mixture was stirred at 50 °C for 2 h. The reaction was quenched with saturated aqueous NaHCO ₃ (50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude aldehyde was dissolved in DCM (4 mL) and added to a vial containing intermediate 2c (0.171 g, 0.43 mmol) and Na(OAc) ₃ BH (0.175 g, 0.83 mmol). The reaction was stirred at room temperature for 20 min. The reaction was quenched with saturated aqueous NaHCO ₃ (50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried (Na ₂ SO ₄ ) and concentrated. Purification by RPC (Gradient: 50%-100% MeCN in water containing 0.1% NH ₄ OH) gave the title compound (0.030 g, 7.83%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.67 - 0.74 (2H, m), 0.83 - 0.91 (2H, m), 1.54 (1H, q), 1.64 - 1.80 (4H, m), 1.88 - 1.99 (3H, m), 2.00 - 2.07 (1H, m), 2.09 - 2.48 (12H, m), 2.73 - 2.86 (3H, m), 3.02 - 3.18 (3H, m), 3.22 - 3.29 (2H, m), 3.33 - 3.37 (1H, m), 3.38 - 3.44 (1H, m), 3.53 - 3.62 (1H, m), 3.82 (2H, t), 5H, s), 4.39 (2H, br s), 5.25 (1H, quin), 5.95 (2H, s), 6.47 - 6.52 (2H, m), 6.85 - 6.90 (2H, m), 6.97 (1H, dd), 7.21 - 7.26 (1H, m), 7.47 (1H, s), 7.56 (1H, s), 7.90 (1H, dd), 7.95 (1H, d), 8.17 (1H, d), 10.38 (1H, s), 14.17 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 916.5 Example 36 Intermediate 36a: 1-[1-(3-Azaspiro[5.5]undecane-9-yl)-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Sulfuric acid (4.22 mL, 8.43 mmol, 2 M aqueous solution) was added to intermediate 11b (220 mg, 0.42 mmol) in THF (4.2 mL). The reaction was heated to 50 °C for 2 h. The crude mixture was cooled to 0 °C and quenched with saturated NaHCO _3. The crude mixture was extracted with 20% IPA/DCM (25 mL x 3). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (178 mg, 100%) as a white solid, which was used in the next step without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 422.5. 1-[1-[3-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Formic acid (1 mL) was added to intermediate 20d (40 mg, 0.07 mmol). The reaction was heated at 40 °C for 30 min. The reaction was concentrated under reduced pressure. Toluene (3 mL) was added to the residue, which was then concentrated and dried under vacuum. The residue was dissolved in DMF (1 mL), and intermediate 36a (27.8 mg, 0.07 mmol) was then added, and the reaction was stirred at room temperature for 20 min. Na(OAc) ₃ BH (27.9 mg, 0.13 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by RPC (0-50% MeCN in water containing 0.1% FA) to give the title compound (15.00 mg, 25.8%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.11-0.88 (1H, m), 0.37 - 0.50 (1H, m), 0.67 (2H, br s), 0.86 (5H, br s), 1.15 - 1.23 (4H, m), 1.39 (2H, br s), 1.60 -1.85 (9H, m), 1.90 - 2.03 (3H, m), 2.15 - 2.24 (2H, m), 2.29 - 2.40 (4H, m), 2.61 - 2.82 (4H, m), 3.25 (5H, br s), 3.82 (2H, br s), 4.51 - 4.71 (1H, m), 6.33 (2H,br s), 6.49 - 6.69 (2H, m), 6.85 - 7.04 (3H, m), 7.25 (1H, br d), 7.46 - 7.63 (2H, m), 7.94 (2H, br s), 8.16 (1H, br s), 10.37 (1H, br s), 14.06 - 14.35 (1H, m); ¹⁹ F NMR (DMSO- d6 ): 133.77; m/z ES ⁺ [M+H] ⁺ = 882.7. Example 37 Intermediate 37a: 2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-benzoyl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tributyl ester

HATU (536 mg, 1.41 mmol) was added to a stirred solution of 3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-benzoic acid (500 mg, 2.01 mmol) (prepared according to the reported patent procedure WO 2022/206924 A1) and DIPEA (1.055 mL, 6.04 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 30 min, and then tributyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (684 mg, 3.02 mmol) in DMF (5 mL) was added. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM:IPA (5:1, 50 mL) and washed with 0.3% _NH4OH (3 x 50 mL), followed by brine (3 x 50 mL). The organic layer was separated, dried ( _Na2SO4 ), filtered and concentrated. Purification by RPC (elution gradient: 0 to 60% _MeCN in water _containing 0.1% _NH4HCO3 ) gave the title compound (760 mg, 83%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.39 (9H, s), 1.57-1.62 (2H, m), 1.65 (4H, t), 2.23 (3H, s), 2.63-2.74 (1H, m), 2.75-2.84 (1H, m), 3.21 (1H, d), 3.47-3.59 (2H, m), 3.76 (2H, s), 3.79-3.87 (1H, m), 4.05 (2H, s), 7.37 (1H, d), 7.51-7.53 (1H, m), 7.56 (1H, d), 10.39 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 457.30. Intermediate 37b: 1-[5-(2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-methyl-phenyl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 37a (300 mg, 0.66 mmol), TsOH (187 mg, 0.99 mmol) and MeCN (5 mL). The resulting mixture was stirred at 70 °C for 2 h. The solvent was removed and the residue was dried under vacuum to afford the title compound (300 mg, 74.3%) as a white solid, which was used directly in the next step without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 357.1. 1-[5-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione

Formic acid (2 mL) was added to intermediate 11g (100 mg, 0.18 mmol). The resulting mixture was stirred at 40 °C for 1 h. The solvent was removed in vacuo. To the residue was added intermediate 37b (65.0 mg, 0.18 mmol) in DCE (2 mL) and NMP (2 mL). The resulting mixture was stirred at 40 °C for 30 min. The reaction was cooled to room temperature and Na(OAc) ₃ BH (193 mg, 0.91 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (50 mL) and washed with saturated NaHCO ₃ (3 x 20 mL), followed by brine (3 x 20 mL). The organic layer was separated, dried ( _Na2SO4 ), _filtered and evaporated. Purification by RPC (elution gradient: 0-40% MeCN in water containing 0.1% FA) gave the title compound (11.00 mg, 6.93%) as a white solid. ¹ H NMR (DMSO- d6) δ 1.13-1.27 (4H, m), 1.57-1.65 (1H, m), 1.69-1.78 (6H, m), 1.91-1.97 (2H, m), 2.1-2.16 (4H, m), 2.23 (3H, s), 2.28 (2H, s), 2.59-2.66 (2H, m), 2.67-2.74 (1H, m), 2.76-2.83 (1H, m), 3.09 (2H, d), 3.24-3.27 (3H, m), 3.49-3.54 (2H, m), 3.73 (2H, s), 3.79-3.88 (1H, m), 4.01 3H, s), 4.34 (2H, d), 5.95 (2H, s), 6.4-6.49 (2H, m), 6.83-6.95 (3H, m), 7.2-7.25 (1H, m), 7.36 (1H, d), 7.46 (1H, s), 7.51-7.56 (2H, m), 7.89-7.92 (1H, m), 8.21 (1H, s), 10.39 (1H, s). No OH protons observed; ¹⁹ F NMR (471 MHz, DMSO) δ -136.42; m/z (ES ⁺ ) [M+H] ⁺ = 843.6. Example 38 Intermediate 38a: 2-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid allyl ester

Allyl chloroformate (0.469 ml, 4.40 mmol) was added to a stirred solution of intermediate 2c (0.787 g, 2 mmol) and NEt ₃ (0.697 ml, 5 mmol) in DCM (20 mL) at 0 °C. The reaction was stirred at 0 °C for 1 h. The reaction was diluted with DCM (20 mL) and washed with saturated NH ₄ Cl solution and Na ₂ CO ₃ solution. The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated. The residue was triturated with diethyl ether (20 mL) to afford the title compound (0.875 g, 92%) as an off-white solid. ¹ H NMR (DMSO- d6 ) δ 0.69 (2H, s), 0.84 - 0.88 (2H, m), 1.66 (4H, dt), 1.85 - 1.99 (1H, m), 2.22 - 2.30 (2H, m), 2.34 - 2.41 (2H, m), 2.75 (2H, t), 3.30 - 3.34 (2H, m), 3.40 - 3.46 (2H, m), 3.80 (2H, t), 4.52 (2H, d), 5.18 (1H, dd), 5.23 - 5.30 (2H, m), 5.83 - 6.01 (1H, m), 7.55 (1H, s), 7.94 (1H, d), 8.16 (1H, d), 10.36 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 478.2. Intermediate 38b: 2-[3-cyclopropyl-5-[3-(di-tri-butyloxyphosphinoyloxymethyl)-2,4-dioxo-hexahydropyrimidin-1-yl]pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid allyl ester

LiHMDS (1.7 ml, 1.7 mmol) was added to a stirred solution of intermediate 38a (0.67 g, 1.40 mmol) and sodium iodide (0.210 g, 1.40 mmol) in THF (10 ml) at 0 °C. Then, di-tributyl (chloromethyl) phosphate (0.726 g, 2.81 mmol) was added in one portion and the reaction was stirred at 50 °C for 30 min. The reaction was cooled to room temperature and diluted with EtOAc (40 mL) and saturated NH ₄ Cl (20 mL) solution. The organic phase was separated, dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by FSC (Gradient: 10%-50% EtOAc in hexanes and 0-10% MeOH in EtOAc) gave the title compound (0.540 g, 55.0%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.65 - 0.70 (2H, m), 0.83 - 0.89 (2H, m), 1.40 - 1.43 (20H, m), 1.62 - 1.71 (4H, m), 1.89 - 1.96 (1H, m), 2.22 - 2.30 (2H, m), 2.35 - 2.42 (2H, m), 2.97 (2H, s), 3.37 - 3.47 (2H, m), 3.82 (2H, s), 4.52 (2H, d), 5.16 - 5.21 (1H, m), 5.23 - 5.32 (2H, m), 5.49 (2H, br d), 5.87 - 6.03 (1H, m), 7.59 (1H, s), 7.97 (1H, d), 8.18 (1H, d); m/z (ES ⁺ ) [2M+2H] ⁺ = 1400. Intermediate 38c: [3-[1-(7-Azaspiro[3.5]non-2-yl)-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]-2,6-dioxo-hexahydropyrimidin-1-yl]methyl phosphate di-tert-butyl ester

A mixture of intermediate 38b (540 mg, 0.77 mmol), 1,3-dimethylhexahydropyrimidine-2,4,6-trione (120 mg, 0.77 mmol) and tetrakis(triphenylphosphine)-palladium(0) (44.6 mg, 0.04 mmol) in DCM (7.7 mL) was stirred under _N2 for 20 min. The solvent was removed under vacuum to give the title compound as a yellow solid (475 mg, 100%), which was used in the next step without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 616.6. Intermediate 38d: [3-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]non-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]-2,6-dioxo-hexahydropyrimidin-1-yl]methyl phosphate dibutyl ester

A mixture of intermediate 11g (443 mg, 0.7 mmol) and TsOH (146 mg, 0.77 mmol) in acetone (6 mL) and water (0.6 mL) was heated at 80 °C in a microwave for 30 min. The solvent was removed and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO ₃ solution. The organic phase was dried (MgSO ₄ ), filtered and concentrated. To the residue was added intermediate 38c (600 mg, 0.77 mmol) and DMF (5 mL). The reaction was stirred at room temperature for 20 min, then Na(OAc) ₃ BH (445 mg, 2.10 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. The reaction was diluted with EtOAc (50 mL), washed with saturated NaHCO ₃ solution and 10% lithium chloride solution. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated. Purification by FSC (elution gradient: 20%-50% EtOAc in hexanes then 10% MeOH in EtOAc) gave the title compound (270 mg, 35.0%) as a colorless foam. ¹ H NMR (DMSO- d6 ) δ 0.68 (2H, dd), 0.83 - 0.88 (2H, m), 1.36 - 1.43 (18H, m), 1.57 - 1.65 (1H, m), 1.65 - 1.73 (4H, m), 1.73 - 1.80 (2H, m), 1.86 - 1.97 (3H, m), 2.06 - 2.15 (4H, m), 2.17 - 2.29 (4H, m), 2.29 - 2.37 (4H, m), 2.59 - 2.67 (2H, m), 2.97 (2H, t), 3.09 (2H, br d), 3.19 - 3.27 (4H, m), 3.33 - 3.39 (2H, m), 3.82 (2H, t), 4.33 (2H, br s), 5.21 - 5.29 (1H, m), 5.49 (2H, d), 5.92 (2H, s), 6.38 - 6.51 (2H, m), 6.81 - 6.95 (3H, m), 7.17 - 7.24 (1H, m), 7.45 (1H, s), 7.57 (1H, s), 7.87 - 7.92 (1H, m), 7.94 - 7.97 (1H, m), 8.17 (1H, d), no OH proton observed; m/z (ES ⁺ ) [M+H] ⁺ = 1103. [3-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]-2,6-dioxo-hexahydropyrimidin-1-yl]methyl dihydrogen phosphate

To intermediate 38d (230 mg, 0.21 mmol) in DCM (4 mL) was added TFA (0.8 mL, 10.43 mmol). The reaction was stirred at room temperature for 2 h, then the solvent was removed under reduced pressure. Purification by RPC (elution gradient: 20%-50% MeCN in water containing 0.1% NH ₄ OH) gave the title compound (151 mg, 73.1%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.66 (2H, br d), 0.80 - 0.90 (2H, m), 1.22 - 1.35 (2H, m), 1.79 - 1.85 (4H, m), 1.85 - 2.00 (4H, m), 2.01 - 2.14 (2H, m), 2.14 - 2.21 (2H, m), 2.25 - 2.37 (2H, m), 2.63 - 2.68 (2H, m), 2.86 - 2.93 (2H, m), 3.07 - 3.11 (2H, m), 3.17 - 3.28 (10H, m), 3.76 - 3.82 (2H, m), 4.30 - 4.38 d), 7.92 - 7.99 (1H, m), 8.16 (1H, d), ^7- (5- bromo -3-methyl- _1H - pyrrolo ^[ 2,3- b ]pyridin-1-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a from 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (0.700 g, 3.31 mmol) and tributyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (1 g, 4.14 mmol) and 2-(tributyl-15-phosphino)acetonitrile (1.303 ml, 4.97 mmol). Purification by FSC (elution gradient: 0-20% EtOAc in hexanes) and RPC (elution gradient: 0-50% MeCN in water containing 0.2% _NH4OH ) afforded the title compound (0.514 g, 35.7%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ) δ 1.47 (9H, s), 1.71 - 1.81 (4H, m), 1.99 - 2.13 (4H, m), 2.30 (3H, s), 3.64 (2H, s), 3.76 (2H, s), 4.64 - 4.73 (1H, m), 7.10 (1H, s), 8.00 (1H, d), 8.29 (1H, d); m/z (ES ⁺ ) [M+2H] ⁺ = 436.3. Intermediate 39b: 7-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-2-azaspiro[3.5]nonane-2-carboxylic acid tributyl ester

A vial was charged with tBuBrettPhos Pd G3 (0.049 g, 0.06 mmol), di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (0.028 g, 0.06 mmol), hexahydropyrimidine-2,4-dione (0.131 g, 1.15 mmol), intermediate 39a (0.25 g, 0.58 mmol), and K ₃ PO ₄ (0.305 g, 1.44 mmol). The solid was evacuated and backfilled with N ₂ , and 1,4-dioxathiol (2.88 mL) was added. The mixture was stirred at 95 °C for 19 h. The reaction mixture was filtered through celite®, washed with EtOAc and MeOH. The filtrate was concentrated. Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (0.149 g, 55.4%) as a tan solid. ¹ H NMR (CD ₂ Cl ₂ ) δ 1.47 (9H, s), 1.72 - 1.84 (4H, m), 2.01 - 2.14 (4H, m), 2.33 (3H, d), 2.89 (2H, t), 3.64 (2H, s), 3.77 (2H, s), 3.91 (2H, t), 4.67 - 4.79 (1H, m), 7.15 (1H, s), 7.68 (1H, s), 7.78 (1H, d), 8.21 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 468.5. 1-[1-[2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2-azaspiro[3.5]nonan-7-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Sulfuric acid solution (0.5 mL, 1.01 mmol, 2.0 M aqueous solution) was added to a solution of intermediate 11 g in THF (0.5 mL) and heated at 40 °C for 1 h, and cooled to room temperature. In a separate reaction vessel, sulphuric acid solution (0.5 mL, 1.01 mmol, 2 M aqueous solution) was added to a suspension of intermediate 39b (28.4 mg, 0.06 mmol) in THF (0.5 mL) at room temperature. The reaction solution was stirred at 50 °C for 2 h. The reaction contents from both deprotections were combined, neutralized by adding saturated aqueous NaHCO ₃ solution while stirring at 0 °C, and diluted with DCM (20 mL) and extracted with DCM/IPA (4:1) (2x). The combined organic phases were dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The resulting solid was dissolved in DCM (1 mL) and stirred at room temperature for 2 min. Na(OAc) ₃ BH (12.86 mg, 0.06 mmol) was added while the mixture was stirred at 0°C for 5 min and at room temperature for 1 h, quenched with saturated aqueous NaHCO ₃ solution, diluted with water and DCM; and the layers were separated. The aqueous layer was extracted with DCM/IPA (4:1) (2 x 25 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered, and concentrated. Purification by FSC (elution gradient: 0-50% MeOH in DCM) and lyophilization gave the title compound (30.3 mg, 70.2%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.22 - 1.35 (2H, m), 1.46 (1H, br s), 1.57 - 1.70 (2H, m), 1.73 - 1.87 (6H, m), 1.90 - 1.99 (2H, m), 2.00 - 2.09 (2H, m), 2.09 - 2.18 (2H, m), 2.25 (3H, s), 2.48 (2H, br s), 2.62 (2H, br t), 2.76 (2H, t), 3.05 (2H, br s), 3.11 (2H, br d), 3.20 (2H, br s), 3.23 - 3.29 (2H, m), 3.35 (2H, br s), 3.81 (2H, t), 4.35 (2H, br s), 4.54 - 4.65 (1H, m), 5.94 (2H, s), 6.40 - 6.52 (2H, m), 6.82 - 6.97 (3H, m), 7.23 (1H, t), 7.46 (2H, d), 7.87 (1H, d), 7.91 (1H, d), 8.17 (1H, d), 10.38 (1H, s), 14.17 (1H, br s); ¹⁹ F NMR (DMSO- d6 ) -136.46; m/z (ES ⁺ ) [M+H] ⁺ = 854.7. Example 40 Intermediate 40a: (4-methylenecyclohexyloxy)methylbenzene

KO t Bu (10.99 mg, 97.91 mmol) was slowly added to methyltriphenylphosphonium bromide (39.6 g, 97.91 mmol) in THF (200 mL). The resulting mixture was stirred at room temperature for 1 h. Then, 4-(benzyloxy)cyclohexane-1-one (10 g, 48.96 mmol) was added dropwise in THF (100 mL) and stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated. Purification by RPC (elution gradient: 2% to 100% MeCN in water containing 0.1% NH ₃ HCO ₃ ) provided the title compound (8.00 g, 81%) as a yellow oil. ¹ H NMR (DMSO-d6): δ 1.42 - 1.57 (2H, m), 1.78 - 1.92 (2H, m), 1.94 - 2.09 (2H, m), 2.21 - 2.35 (2H, m), 3.49 - 3.59 (1H, m), 4.51 (2H, s), 4.60 - 4.66 (2H, m), 7.20 - 7.40 (5H, m). Intermediate 40b: (6 s ,9 s )-9-Benzyloxy-1-oxazolidinone-4-azaspiro[5.5]undecane-4-carboxylic acid tributyl ester

NIS (5.56 g, 24.72 mmol) was added to intermediate 40a (5 g, 24.72 mmol) and tributyl (2-hydroxyethyl)carbamate (3.98 g, 24.72 mmol) in MeCN (100 mL). The resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered and the filtrate was evaporated to afford a crude product, which was used directly in the next step without further purification. NaH (9.89 g, 247.16 mmol) was added to the crude product in DMF (40 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into saturated aqueous _NH4Cl solution (150 mL), extracted with EtOAc (3 x 50 mL), the organic layer was dried over _Na2SO4 , _filtered and evaporated. Purification by FSC (elution gradient: 0 to 80% EtOAc in petroleum ether) gave the title compound (0.600 g, 40.8%) as a yellow gum. ¹ H NMR (CDCl ₃ ): δ 1.20 - 1.32 (2H, m), 1.45 (9H, s), 1.62 - 1.72 (2H, m), 1.76 - 1.84 (2H, m), 1.90 - 2.00 (2H, m), 3.21 (2H, s), 3.35 - 3.46 (3H, m), 3.65 (2H, s), 4.55 (2H, s), 7.23 - 7.29 (1H, m), 7.30 - 7.39 (4H, m); m/z (ES ⁺ ) [M-tBu+H] ⁺ = 306. Intermediate 40c: (6 r ,9 r )-9-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-1-oxa-4-azaspiro[5.5]undecane-4-carboxylic acid tributyl ester

DDQ (628 mg, 2.77 mmol) was added to a solution of intermediate 40b (500 mg, 1.38 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into _saturated aqueous _Na2CO3 solution (50 mL), extracted with DCM ( ₃ x 20 mL), the organic layer was dried over _Na2SO4 , filtered and evaporated to afford the crude product. The product was used directly in the next step without further purification. Under nitrogen, (tributylphosphino)acetonitrile (401 mg, 1.66 mmol) was added to the crude product and 5-bromo-3-methyl- 1H -pyrrolo[2,3 -b ]pyridine (350 mg, 1.66 mmol) in toluene (10 mL). The resulting solution was stirred at 100° C. for 16 h, then cooled to room temperature and concentrated. Purification by FSC (elution gradient: 0 to 70% EtOAc in petroleum ether) gave the title compound (250 mg, 38.9%) as a yellow gum. ¹ H NMR (DMSO- d6 ): δ 1.40 (9H, s), 1.44 - 1.51 (2H, m), 1.79 - 2.01 (6H, m), 2.23 (3H, s), 3.47 - 3.63 (7H, m), 7.32 - 7.62 (1H, m), 8.16 (1H, d), 8.24 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 464. Intermediate 40d: (6 r ,9 r )-9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-4-azaspiro[5.5]undecane-4-carboxylic acid tributyl ester

GPhos Pd G6 TES (40.8 mg, 0.04 mmol) was added to intermediate 40c (200 mg, 0.43 mmol), dihydrouracil (197 mg, 1.72 mmol), EPhos (23.03 mg, 0.04 mmol) and Cs ₂ CO ₃ (421 mg, 1.29 mmol) in 1,4-dioxathiol (4 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution (20 mL), extracted with EtOAc (3 x 10 mL), the organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FCS (elution gradient: 0 to 40% EtOAc in petroleum ether then 0 to 10% MeOH in DCM) gave the title compound (94 mg, 43.9%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.46 - 1.59 (4H, m), 1.86 (2H, d), 1.98 (2H, d), 2.24 (3H, s), 2.73 - 2.78 (2H, m), 3.49 - 3.67 (6H, m), 3.77 - 3.83 (2H, m), 4.63 (1H, s), 7.38 (1H, s), 7.87 (1H, d), 8.16 (1H, s), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 498. 1-[1-[(6 r ,9 r )-4-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-1-oxa-4-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

p-Toluenesulfonic acid monohydrate (30.6 mg, 0.16 mmol) was added to intermediate 40d (80 mg, 0.16 mmol) in MeCN (1.5 mL). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was evaporated and the crude product was used directly in the next step without further purification. Formic acid (3 mL) was added to intermediate 11g (142 mg, 0.23 mmol) and stirred at 40 °C for 20 min. The reaction mixture was evaporated. It was then quenched with saturated aqueous Na ₂ CO ₃ solution (10 mL), extracted with EtOAc (3 x 5 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to provide the crude product. The two crude products were dissolved in DCE (1.00 mL) and NMP (1.00 mL). The resulting mixture was stirred at 40 °C for 2 h. Then, sodium triacetoxyborohydride (136 mg, 0.64 mmol) was added and stirred at room temperature for 2 h. The crude product was purified by RPC (elution gradient: 0-77% ACN in water containing 10 mM NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O) to provide the title compound (32.0 mg, 22.86%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.33 (2H, m), 1.42 - 1.52 (2H, m), 1.74 - 1.86 (5H, m), 1.89 - 1.98 (4H, m), 2.07 - 2.13 (2H, m), 2.14 - 2.28 (8H, m), 2.30 - 2.39 (3H, m), 2.54 (1H, s), 2.63 - 2.69 (2H, m), 2.71 - 2.76 (2H, m), 3.08 (2H, d), 3.24 (2H, d), 3.36 - 3.38 (1H, m), 3.61 - 3.69 (2H, m), 3.75 - 3.82 (2H, m), 4.33 (2H, s), 4.61 - 4.70 (1H, m), 5.93 (2H, s), 6.38 - 6.43 (1H, m), 6.44 - 6.49 (1H, m), 6.81 - 6.95 (3H, m), 7.18 - 19 F ^NMR (DMSO- d6 ) δ -136.33; m/z (ES ⁺ ), [M+H] ⁺ = 884.5. Example 41 Intermediate 41a: 3-(3-benzyloxycyclobutyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester

3-(Benzyloxy)cyclobutan-1-one (6 g, 34.05 mmol) was added to tributyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.95 g, 37.45 mmol) in DCE (50 mL) and NMP (50 mL) at room temperature. The resulting mixture was stirred at 40 °C for 30 min, and then sodium triacetoxyborohydride (28.9 g, 136.20 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (150 mL) and washed successively with saturated aqueous NaHCO ₃ solution (75 mL x 2) and saturated brine (75 mL). The organic layer was separated, dried _{over Na2SO4} , filtered and evaporated. The crude solid was triturated with hexanes, the solid was collected by filtration and dried under vacuum to give the title compound as a yellow solid (8.00 g, 63.1%). ¹ H NMR (DMSO- d6 ): δ 1.40 (9H, s), 1.60 - 1.67 (2H, m), 1.69 - 1.76 (3H, m), 1.87 - 1.94 (2H, m), 2.16 - 2.20 (1H, m), 2.24 - 2.36 (3H, m), 2.55 (1H, d), 2.70 (1H, s), 3.67 - 3.77 (1H, m), 4.03 (2H, s), 4.35 (2H, s), 7.25 - 7.38 (5H, m); m/z (ES ⁺ ), [M+H] ⁺ = 373.3. Intermediate 41b: 3-(3-Hydroxycyclobutyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Under hydrogen atmosphere, potassium hydroxide/carbon powder (1.508 g, 2.15 mmol) was added to intermediate 41a (8 g, 21.48 mmol) in MeOH (300 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through celite®. The filtrate was evaporated to dryness to provide the title compound (6.00 g, 99%) as a yellow solid. ¹ H NMR (CDCl ₃ ): δ 1.44 (9H, s), 1.64 - 1.71 (2H, m), 1.75 - 1.83 (4H, m), 1.96 - 2.05 (2H, m), 2.20 - 2.27 (1H, m), 2.36 (1H, t), 2.39 - 2.46 (2H, m), 2.55 - 2.58 (2H, m), 3.94 - 4.01 (1H, m), 4.13 (2H, d); m/z (ES ⁺ ) [M+H] ⁺ = 283.1. Intermediate 41c: 3-[(1 r ,3 r )-3-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)cyclobutyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a from intermediate 41b (5 g, 17.71 mmol). Purification by FSC (elution gradient: 0 to 100% EtOAc in petroleum ether) gave the title compound (2.5 g) as a mixture of cis-isomers (minor) and trans-isomers. To remove minor isomers, the material was further purified by SFC (column: CHIRALPAK ID, 3 x 25 cm, 5 μm. Mobile phase A: CO ₂ , mobile phase B: (1:1) IPA/(ACN with 0.1% 2 M NH ₃ in MeOH); flow rate: 100 mL/min; gradient: isocratic 45% B). Fractions containing the pure trans isomer were evaporated to dryness to give the title compound (2.0 g, 35.6%). ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.54 - 1.63 (2H, m), 1.73- 1.78 (2H, m), 1.82- 1.86 (2H, m), 1.95 (1H, d), 2.26 (3H, d), 2.39 - 2.47 (3H, m), 2.79 (2H, d), 2.99 - 3.06 (1H, m), 4.06- 4.10 (2H, m), 5.21 - 5.29 (1H, m), 7.67 (1H, d), 8.17 (1H, d), 8.27 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 475.3. Intermediate 41d: 3-[(1 r ,3 r )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]cyclobutyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4b from intermediate 41c (0.500 g, 46.7%). Purification by FSC (elution gradient: 0 to 50% EtOAc in petroleum ether, then 0 to 20% MeOH in DCM) gave the title compound (0.500 g, 46.7%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.42 (9H, s), 1.75 - 1.78 (1H, m), 1.84 - 1.87 (2H, m), 1.93 - 2.00 (2H, m), 2.28 (3H, d), 2.43 - 2.49 (4H, m), 2.72 - 2.82 (4H, m), 3.00 - 3.08 (1H, m), 3.16 - 3.23 (1H, m), 3.81 (2H, t), 4.09 (2H, s), 5.22 - 5.34 (1H, m), 7.63 (1H, d), 7.89 (1H, d), 8.18 (1H, d), 10.40 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 509.6. Intermediate 41e: 1-[1-[(1 r ,3 r )-3-(3,8-diazabicyclo[3.2.1]octan-3-yl)cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 1i from intermediate 41d (500 mg, 0.98 mmol). The crude product was purified by RPC (elution gradient: 5% to 60% MeCN in water containing 0.1% NH ₄ HCO ₃ ). Pure fractions were evaporated to dryness to afford the title compound (300 mg, 74.7%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.54 - 1.66 (2H, m), 1.71 - 1.82 (2H, m), 1.91 (2H, d), 2.27 (3H, s), 2.35 - 2.47 (4H, m), 2.67 - 2.79 (4H, m), 2.95 - 3.04 (1H, m), 3.80 (2H, t), 5.21 - 5.31 (1H, m), 7.63 (1H, s), 7.88 (1H, d), 8.17 (1H, d), 10.21 - 10.56 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 409.2. 1-[1-[(1 r ,3 r )-3-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Formic acid was added to intermediate 11g (81 mg, 0.15 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 1 h. The solvent was removed under reduced pressure. To the residue was added intermediate 41e (60 mg, 0.15 mmol) in DCE (3.00 mL) and NMP (3.00 mL) and then sodium triacetoxyborohydride (187 mg, 0.88 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and washed successively with saturated NaHCO ₃ aqueous solution (10 mL x 2) and saturated brine (10 mL x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by RPC (elution gradient: 0-70% CH ₃ CN in water containing 0.1% NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O) gave the title compound (20.0 mg, 15.21%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.19 - 1.23 (1H, m, 1.25 - 1.31 (1H, m), 1.50 (1H, s), 1.74 (2H, d), 1.75 - 1.80 (2H, m), 1.81 - 1.86 (2H, m), 1.92 - 1.98 (2H, m), 2.04 (2H, d), 2.13 (2H, t), 2.21 (2H, d), 2.25 - 2.29 (3H, m), 2.38 - 2.48 (4H, m), 2.60 - 2.68 (2H, m), 2.70 (2H, d), 2.76 (2H, t), 3.05 (1H, d), 3.08 - 3.15 (4H, m), 3.26 (2H, d), 3.36 -3.39 (2H, m), 3.81 (2H, t), 4.31 -4.36 (2H, m), 5.23 - 5.32 (1H, m), 5.95 (2H, s), 6.39 - 6.55 (2H, m), 6.83 - 6.99 (3H, m), 7.20 - 7.27 (1H, m), 7.47 (1H, s), 7.62 - 7.65 (1H, m), 7.87 - 7.94 (2H, m), 8.18 (1H, d), 10.39 (1H, s), 14.18 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -136.379; m/z (ES ⁺ ), [M+H] ⁺ = 895.7. Example 42 Intermediate 42a: (2 R )-4-(5-chloro-2-fluoro-phenyl) iodine-2-carboxylic acid methyl ester

( R )-methyl iodine-2-carboxylate HCl (0.954 g, 5.25 mmol) was added to a mixture of 2-bromo-4-chloro-1-fluorobenzene (1 g, 4.77 mmol), RuPhos Pd G3 (0.399 g, 0.48 mmol), RuPhos (0.223 g, 0.48 mmol) and Cs ₂ CO ₃ (6.22 g, 19.10 mmol) in 1,4-dioxathiol (20 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (150 mL), extracted with EtOAc (3 x 50 mL), and the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0-20% EtOAc in petroleum ether) gave the title compound (1.700 g, 65.4%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 2.91 - 2.99 (1H, m), 3.06 - 3.15 (2H, m), 3.32 - 3.38 (1H, m), 3.69 (3H, s), 3.70 - 3.76 (1H, m), 3.96 - 4.05 (1H, m), 4.37 - 4.45 (1H, m), 7.01 - 7.09 (2H, m), 7.15 - 7.24 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 274. Intermediate 42b: ( 2R )-4-(5-chloro-2-fluoro-phenyl)-2-(dimethoxymethyl)oxazolidinone

DIBAL-H solution (9.32 mL, 9.32 mmol, 1 M in DCM) was added dropwise to intermediate 42a (1.7 g, 6.21 mmol) in DCM (40 mL) at -60 °C under _N2 . The resulting mixture was stirred at -60 °C for 30 min. The reaction mixture was quenched with saturated aqueous _NH4Cl solution (200 mL), extracted with DCM (3 x 50 mL), and _the organic layer was dried over _Na2SO4 , filtered and evaporated. The crude product was dissolved in MeOH (40.0 mL), followed by the addition of trimethyl orthoformate (1.977 g, 18.63 mmol) and p -TsOH· _H2O (0.118 g, 0.62 mmol). The resulting mixture was stirred at 40 °C for 2 h and quenched with water (5 mL), extracted with EtOAc (3 x 60 mL), the organic layer was dried over _Na2SO4 , _filtered and evaporated. Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound (1.380 g, 77%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 2.58 - 2.67 (1H, m), 2.76 - 2.86 (1H, m), 3.12 - 3.19 (1H, m), 3.24 - 3.30 (1H, m), 3.32 (3H, s), 3.32 (3H, s), 3.60 - 3.70 (2H, m), 3.88 - 3.95 (1H, m), 4.31 (1H, d), 6.99 - 7.05 (2H, m), 7.15 - 7.23 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 290. Intermediate 42c: 8-[3-[(2 R )-2-(dimethoxymethyl)oxazolin-4-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

A vial was charged with RuPhos Pd G3 (188 mg, 0.22 mmol), RuPhos (105 mg, 0.22 mmol), intermediate 42b (650 mg, 2.24 mmol), 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester HCl (698 mg, 2.47 mmol) and Cs ₂ CO ₃ (2924 mg, 8.97 mmol) in 1,4-dioxathiocarbamide (13 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered and poured into water (100 mL), extracted with DCM (3 x 25 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether and 0 to 6% MeOH in DCM) gave the title compound (2.0 g, 89%) as a brown gum. ¹ H NMR (DMSO- d6 ): δ 1.60 - 1.68 (2H, m), 1.80 - 1.95 (2H, m), 2.53 - 2.62 (1H, m), 2.75 - 2.85 (1H, m), 3.05 - 3.16 (2H, m), 3.19 - 3.28 (2H, m), 3.31 (6H, s), 3.32 - 3.33 (2H, m), 3.54 - 3.69 (4H, m), 3.87 - 3.95 (1H, m), 4.23 (2H, d), 5.07 (1H, d), 6.39 - 6.42 (1H, m), 6.42 - 6.45 (1H, m), 6.90 - 6.99 (1H, m), 7.28 - 7.40 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 500. Intermediate 42d: 6-Chloro-4-[8-[3-[(2 R )-2-(dimethoxymethyl)oxazolin-4-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]oxazolidin-3-amine

Pd/C (0.160 g, 0.15 mmol) was added to intermediate 42c (1.5 g, 3.00 mmol) in MeOH (30 mL) under hydrogen. The resulting mixture was stirred at room temperature for 16 h. The catalyst was filtered off and the filtrate was evaporated to afford a crude product. To the crude product were added DIPEA (1.573 mL, 9.01 mmol), 4-bromo-6-chlorotitanium-3-amine (0.688 g, 3.30 mmol) and DMSO (20 mL). The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (100 mL), extracted with EtOAc (3 x 50 mL), and the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0 to 80% EtOAc in petroleum ether) gave the title compound (0.880 g, 59.5%) as a yellow gum. ¹ H NMR (DMSO- d6 ): δ 1.85 - 1.95 (2H, m), 2.08 (2H, d), 2.57 - 2.63 (1H, m), 2.76 - 2.85 (1H, m), 2.90 - 2.99 (2H, m), 3.08 - 3.20 (3H, m), 3.26 (1H, d), 3.31 - 3.32 (6H, m), 3.60 - 3.68 (2H, m), 3.91 (1H, d), 4.26 - 4.36 (3H, m), 5.81 (2H, s), 6.40 - 6.48 (2H, m), 6.87 (1H, s), 6.91 - 6.99 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 493. Intermediate 42e: 2-[6-amino-5-[8-[3-[(2 R )-2-(dimethoxymethyl)oxazolin-4-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]oxazolin-3-yl]phenol

Prepared in an analogous manner to intermediate 2h from intermediate 42d (860 mg, 1.74 mmol). Purification by FSC (elution gradient: 0 to 10% MeOH in DCM) gave the title compound (600 mg, 62.5%) as a yellow gum. ¹ H NMR (DMSO- d6 ): δ 1.90 - 1.97 (2H, m), 2.13 (2H, d), 2.58 - 2.61 (1H, m), 2.78 - 2.85 (1H, m), 3.05 - 3.15 (3H, m), 3.22 - 3.29 (3H, m), 3.32 (6H, s), 3.60 - 3.68 (2H, m), 3.88 - 3.95 (1H, m), 4.31 (1H, d), 4.34 - 4.38 (2H, m), 5.95 (2H, s), 6.43 - 6.52 (2H, m), 6.83 - 6.89 (2H, m), 6.93 - 6.99 (1H, m), 7.19 - 7.26 (1H, m), 7.46 (1H, s), 7.87 - 7.92 (1H, m), 14.17 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 551. Intermediate 42f: 1-[1-(7-Azaspiro[3.5]nonan-2-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

p -TsOH·H2O (177 mg, 1.03 mmol) was added to intermediate 15b (400 mg, 0.86 mmol) in MeCN (10 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with MTBE (200 mL). The solid was filtered and washed with ether, dried under vacuum to give the title compound as a white solid in the form of a TsOH salt (450 mg, 84%). m/z (ES ⁺ ) [M+H] ⁺ = 368.2. 1-[1-[7-[[(2S)-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

p -TsOH·H ₂ O (62.2 mg, 0.33 mmol) was added to intermediate 42e (60 mg, 0.11 mmol) in acetone (1 mL) and water (0.111 mL). The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into saturated aqueous NaHCO ₃ solution (5 mL), extracted with EtOAc (3 x 10 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. To the crude product was added intermediate 42f (22.01 mg, 0.05 mmol) in DCE (0.5 mL) and NMP (0.5 mL). The resulting mixture was stirred at 40 °C for 16 h. Sodium triacetoxyborohydride (69.3 mg, 0.33 mmol) was added to the mixture and stirred at room temperature for 2 h. The reaction mixture was poured into saturated aqueous NaHCO ₃ solution (5 mL), extracted with DCM (3 x 10 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by RPC (elution gradient: 0-70% CH ₃ CN in H ₂ O containing 10 mM NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O) gave the title compound (7.70 mg, 7.70%) as a brown solid. ¹ H NMR (DMSO- d6 ): δ 1.22 - 1.24 (1H, m), 1.61 - 1.74 (4H, m), 1.94 (2H, d), 2.13 (2H, d), 2.16 - 2.22 (2H, m), 2.26 (3H, s), 2.30 - 2.40 (6H, m), 2.43 - 2.48 (2H, m), 2.73 - 2.77 (2H, m), 2.78 - 2.82 (1H, m), 3.06 - 3.13 (2H, m), 3.17 (1H, d), 3.21 - 3.29 (3H, m), 3.62 - 3.69 (1H, m), 3.71 - 3.77 (1H, m), 3.77 - 3.82 (2H, m), 3.88 (1H, d), 4.36 (2H, s), 5.19 - 5.29 (1H, m), 5.94 (2H, s), 6.43 - 6.50 (2H, m), 6.83 - 6.90 (2H, m), 6.92 - 7.00 (1H, m), 7.17 - 7.26 (1H, m), 7.46 (1H, s), 7.60 (1H, s), 7.85 - 7.93 (2H, m), 8.16 (1H, d), 10.38 (1H, s), 14.16 (1H, s); ¹⁹ F NMR (DMSO- d6 ) δ -136.80; m/z (ES ⁺ ) [M+H] ⁺ = 856. Example 43 Intermediate 43a: 7-(5-Chloro-2-fluoro-phenyl)-2,2-dimethoxy-7-azaspiro[3.5]nonane

Tributyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5 g, 20.89 mmol) was added to HCl (30 mL, 120.00 mmol) in MeOH under air. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The reaction mixture was adjusted to pH = 8 with 7 M _NH3 in MeOH. The solvent was removed under reduced pressure. The reaction mixture was diluted with 15 mL 5:1 MeOH/DCM. The reaction mixture was filtered and concentrated under reduced pressure. The crude product (3.6 g, 19.43 mmol) was added to 2-bromo-4-chloro-1-fluorobenzene (4.07 g, 19.43 mmol), Pd ₂ (dba) ₃ (1.778 g, 1.94 mmol), BINAP (1.210 g, 1.94 mmol) and NaO t Bu (5.60 g, 58.29 mmol) in toluene (20 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and washed successively with water (3 x 200 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0-20% EtOAc in petroleum ether) gave the title compound (0.480 g, 7.87%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.63-1.70 (4H, m), 1.91 (4H, s), 2.90-2.96 (4H, m), 3.05 (6H, s), 6.93-7.03 (2H, m), 7.1-7.19 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 314.2. Intermediate 43b: 8-[3-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 42c from intermediate 43a (380 mg, 1.21 mmol). Purification by RPC (elution gradient: 0 to 90% MeOH in water containing 0.1% NH ₄ HCO ₃ ) gave the title compound (560 mg, 88%) as a dark solid. ¹ H NMR (DMSO- d6 ): δ 1.62-1.67 (6H, m), 1.90 (4H, s), 2.85-2.91 (5H, m), 3.04 (6H, s), 3.09-3.26 (3H, m), 3.56-3.62 (2H, m), 4.19-4.26 (2H, m), 5.02-5.13 (2H, m), 6.35-6.4 (1H, m), 6.41-6.45 (1H, m), 6.86-6.95 (1H, m), 7.30-7.40 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 524.3. Intermediate 43c: 7-[5-(3,8-diazabicyclo[3.2.1]oct-8-yl)-2-fluoro-phenyl]-2,2-dimethoxy-7-azaspiro[3.5]nonane

Intermediate 43b (370 mg, 0.71 mmol) was added to Pd/C (75 mg, 0.07 mmol) in DCM (25 mL) under hydrogen. The resulting mixture was stirred at room temperature for 4 h. The reaction was filtered through celite®, the filtrate was collected, and the solvent was removed by reduced pressure to provide the title compound (260 mg, 94%) as a white solid. The product was used directly in the next step without further purification. ¹ H NMR (DMSO- d6 ): δ 1.62-1.69 (4H, m), 1.88-1.93 (4H, m), 1.98-2.11 (4H, m), 2.92 (6H, s), 2.98-3.09 (8H, m), 6.37-6.47 (2H, m), 6.92-7.00 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 390.4. Intermediate 43d: 6-Chloro-4-[8-[3-(2,2-dimethoxy-7-azaspiro[3.5]non-7-yl)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-amine

A mixture of intermediate 43c (250 mg, 0.64 mmol), 4-bromo-6-chloroindole-3-amine (134 mg, 0.64 mmol) and DIPEA (0.336 mL, 1.93 mmol) in DMSO (10 mL) was heated at 100 ° _C for 16 h. The reaction mixture was diluted with DCM (100 mL) and washed with saturated brine (3 x 75 mL), followed by water (3 x 75 mL). The organic layer was dried over _Na2SO4 , filtered and evaporated. Purification by RPC (elution gradient: 0 to 70% MeCN in water (0.1% _{NH4HCO3 )} ) gave the title compound (180 mg, 54.2%) as a brown solid. ¹ H NMR (DMSO- d6 ): δ 1.62-1.68 (4H, m), 1.87-1.93 (6H, m), 2.05-2.11 (2H, m), 2.87-2.91 (4H, m), 2.94 (2H, d), 3.04 (6H, s), m/z (ES ⁺ ) [M+H] ⁺ = 517.1. Intermediate 43e: 2-[6-amino-5-[8-[3-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-yl]phenol

Intermediate 43d (160 mg, 0.31 mmol) was added to (2-hydroxyphenyl)boronic acid (85 mg, 0.62 mmol), Pd(dppf)Cl ₂ •DCM (25.3 mg, 0.03 mmol) and Cs ₂ CO ₃ (302 mg, 0.93 mmol) in 1,4-dioxathiocarbamide (10 mL) and water (1.0 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 8 h. The solvent was removed under reduced pressure. Purification by FSC (elution gradient: 0 to 10% MeOH in DCM) gave the title compound (160 mg, 90%) as a brown solid. ¹ H NMR (DMSO- d6 ): δ 1.63-1.68 (4H, m), 1.89-1.97 (6H, m), 2.11-2.15 (2H, m), 2.88-2.92 (4H, m), 3.04 (6H, s), 3.07-3.11 (2H, m), 3.23-3.28 (2H, m), 4.33-4.37 (2H, m), 5.96 (2H, s), 6.41-6.5 (2H, m), 6.84-6.95 (3H, m), 7.21-7.25 (1H, m), 7.47 (1H, s), 7.9-7.93 (1H, m), 14.19 (1H, s); m/z (ES ⁺ ), [M+H] ⁺ = 575.2. Intermediate 43f: 7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]nonan-2-one

Formic acid (5 mL) was added to intermediate 43e (120 mg, 0.21 mmol). The resulting mixture was stirred at 40 °C for 1 h. The solvent was removed under reduced pressure to provide the title compound (95 mg, 86%) as a brown solid. The product was used directly in the next step without further purification. ¹ H NMR (DMSO- d6 ): δ 1.22-1.26 (2H, m), 1.78 -1.85 (4H, m), 1.92-1.98 (2H, m), 2.07-2.13 (2H, m), 2.84 (4H, s), 2.95-3.01 (4H, m), 3.14-3.23 (2H, m), 4.34 -4.38 (2H, m), 6.13 (2H, d), 6.43-6.48 (1H, m), 6.49-6.52 (1H, m), 6.87-6.98 (3H, m), 7.28 (1H, d), 7.46 (1H, s), 7.80 (1H, s); m/z (ES ⁺ ), [M+H] ⁺ = 529.6. 1-[1-[7-[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Intermediate 43f (90 mg, 0.17 mmol) was added to intermediate 42f (75 mg, 0.20 mmol) in DCE (3 mL) and NMP (3 mL). The resulting mixture was stirred at 40 °C for 1 h, and then sodium triacetoxyborohydride (289 mg, 1.36 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL) and washed successively with saturated aqueous NaHCO ₃ solution (2 x 50 mL) and brine (2 x 50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by RPC (elution gradient: 0-60% ACN in water containing 0.1% FA) gave the title compound (17.89 mg, 11.94%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.51-1.62 (4H, m), 1.63-1.77 (6H, m), 1.91-2.01 (4H, m), 2.10 - 2.14 (3H,mt), 2.18 - 2.24 (3H, m), 2.27 (3H, s), 2.31 - 2.37 (2H, m), 2.57-2.65 (1H, m), 2.76 (2H, t), 2.87 (2H, t), 2.92-2.97 (2H, m), 3.10 (2H, d), 3.25 (2H, d), 3.29 - 3.32 (1H, m), 3.34 - 3.37 (1H, s), 3.80 (2H, t), 4.33 - 4.36 (2H, m), 5.21-5.3 (1H, m), 5.95 (2H, s), 6.39-6.5 (2H, m), 6.84-6.95 (3H, m), 7.2-7.26 (1H, m), 7.47 (1H, s), 7.61 (1H, s), 7.86-7.93 (2H, m), 8.17 (1H, d), 10.40 (1H, s), 14.19 (1H, s); ¹⁹ F NMR (DMSO-d6): δ -136.44; m/z (ES ⁺ ), [M+H] ⁺ = 880.7. Example 44 Intermediate 44a: 8-Hydroxy-2-azaspiro[4.5]decane-2-carboxylic acid tributyl ester

Sodium borohydride (0.164 g, 4.34 mmol) was added portionwise to tributyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate (1 g, 3.95 mmol) in MeOH (10 mL) at 0°C under nitrogen. The resulting mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with saturated aqueous _NH4Cl solution (10 mL), extracted with EtOAc (3 x 30 mL), the organic layer was dried over MgSO4, filtered and evaporated. Purification by FSC (elution gradient: 0 to 100% ethyl acetate in hexanes) gave the title compound (0.850 g, 84%) as a mixture of cis- and trans-isomers as an oil. ¹ H NMR (DMSO- d6 ): δ 1.22 - 1.34 (5H, m), 1.36 - 1.42 (17H, m), 1.48 - 1.72 (11H, m), 2.97 - 2.99 (1H, m), 3.00 - 3.06 (2H, m), 3.26 (3H, br d), 3.41 - 3.51 (1H, m), 4.44 - 4.52 (1H, m); m / z (ES ⁺ ) [M+H] ⁺ = 241.1. Intermediate 44b: 8-(5-Bromo-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl)-2-azaspiro[4.5]decane-2-carboxylic acid tributyl ester

A vial was charged with intermediate 44a (1021 mg, 4.00 mmol), 5-bromo-3-ethyl- 1H -pyrrolo[2,3- b ]pyridine (900 mg, 4.00 mmol) and 2-(tributyl-15-phosphine)acetonitrile (1.572 mL, 6.00 mmol). Toluene (14 mL) was added and the reaction was heated at 80 °C for 16 h. The reaction was concentrated under reduced pressure. Purification by FSC (elution gradient: 0-50% EtOAc/hexanes) gave the title compound (500 mg, 27.0%) as a mixture of cis and trans isomers as an orange solid. ¹ H NMR (DMSO- d6 ): δ 1.25 (4H, t), 1.39 - 1.47 (10H, m), 1.56 (3H, br d), 1.64 - 1.73 (4H, m), 1.75 - 1.87 (3H, m), 1.87 - 1.98 (3H, m), 2.69 (2H, br d), 3.25 - 3.32 (4H, m), 4.54 - 4.72 (1H, m), 7.59 (1H, s), 8.18 (1H, d), 8.26 (1H, d); m / z (ES ⁺ ) [M+H] ⁺ = 462, 464.1. Intermediate 44c: (5 r ,8 r )-8-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-2-azaspiro[4.5]decane-2-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 44b (500 mg, 1.08 mmol). Purification by FSC (elution gradient: 0-100% EtOAc/hexanes) gave the title compound (200 mg, 37.3%) as a brown solid. The isomers were separated by SFC (Chiralcel OJ 21 x 250 mm, 5 μm, CO ₂ with 15% (0.2% NH ₄ OH in methanol), 85 ml/min, 120 bar, 40° C.) to give the title compound (65 mg, 40.6%) as a white solid, which eluted first from the column. Relative stereochemistry was determined by ROESY NMR. ¹ H NMR (CDCl ₃ ): δ 1.33 (3H, br t), 1.48 - 1.55 (9H, m), 1.65 (1H, br s), 1.67 (1H, br d), 1.71 - 1.92 (6H, m), 2.02 (2H, br d), 2.70 - 2.80 (2H, m), 2.92 (2H, t), 3.32 (1H, s), 3.38 - 3.50 (3H, m), 3.92 (2H, t), 4.73 - 4.91 (1H, m), 7.08 - 7.20 (1H, m), 7.54 (1H, br s), 7.80 (1H, br s), 8.23 (1H, br s); m / z (ES ⁺ ) [M+H] ⁺ = 496.4 Intermediate 44d: 1-[1-((5 r ,8 r )-2-azaspiro[4.5]dec-8-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (0.187 mL, 2.42 mmol) was added to a stirred solution of intermediate 44c (60 mg, 0.12 mmol) in DCM (2 mL). The resulting solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column using 7 M NH ₃ /MeOH and the pure fractions were evaporated to dryness to afford the title compound (42.0 mg, 88%) as an orange gum. m / z (ES ⁺ ) [M+H] ⁺ = 396.3. 1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

DCM (1.0 mL) and i -PrOH (0.2 mL) were added to intermediate 44d (27.5 mg, 0.07 mmol) and intermediate 13d (35 mg, 0.07 mmol). The resulting mixture was stirred at room temperature for 10 min, then Na(OAc) ₃ BH (29.5 mg, 0.14 mmol) was added, and the mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure. Purification by RPC (elution gradient: 0 to 60% MeCN in water containing 0.1% formic acid) gave the title compound (33.0 mg, 53.7%) as an amorphous white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.28 (3H, t), 1.38 - 1.46 (2H, m), 1.59 - 1.74 (2H, m), 1.80 - 2.00 (14H, m), 2.08 (2H, br d), 2.67 - 2.80 (6H, m), 3.04 - 3.09 (1H, m), 3.19 - 3.31 (5H, m), 3.41 - 3.44 (1H, m), 3.45 - 3.51 (2H, m), 3.66 - 3.73 (1H, m), 3.81 (3H, br t), 4.38 (2H, br s), 4.64 - 4.74 (1H, m), 6.47 - 6.53 (2H, m), 6.57 (1H, br s), 6.91 - 7.01 (3H, m), 7.34 (1H, br t), 7.45 (1H, s), 7.52 (1H, s), 7.67 (1H, br d), 7.93 (1H, d), 8.18 (1H, d), 9.89 - 9.97 (1H, m), 10.37 - 10.40 (1H, m); ¹⁹ F NMR (DMSO- d6 ): -73.66 (1F, s); m / z (ES ⁺ ) [M+H] ⁺ = 868.6. Example 45 Intermediate 45a: 2-(5-Bromo-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 1b starting from 5-bromo-3-ethyl- 1H -pyrrolo[2,3- b ]pyridine (500 mg, 2.22 mmol) and tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (804 mg, 3.33 mmol). Purification by FSC (elution gradient: 0-50% EtOAc/hexanes) gave the title compound (900 mg, 90%) as a colorless dry film. ¹ H NMR (DMSO- d6 ): δ 1.26 (3H, t), 1.40 (9H, s), 1.63 (4H, dt), 2.21 - 2.30 (2H, m), 2.35 - 2.43 (2H, m), 2.70 (2H, q), 3.21 - 3.27 (2H, m), 3.33 (2H, s), 5.26 (1H, t), 7.66 (1H, s), 8.19 (1H, d), 8.26 (1H, d); m / z (ES ⁺ ) [M+H] ⁺ = 448.4 450.2. Intermediate 45b: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 45a (900 mg, 2.01 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (410 mg, 42.4%) as a brown solid. ¹ H NMR (DMSO- d6 ): δ 1.28 (3H, t), 1.41 (9H, s), 1.60 - 1.71 (4H, m), 2.21 - 2.30 (2H, m), 2.34 - 2.45 (2H, m), 2.66 - 2.83 (4H, m), 3.26 -3.29 (1H, m), 3.30 - 3.41 (3H, m), 3.81 (2H, t), 5.17 - 5.42 (1H, m), 7.63 (1H, s), 7.92 (1H, d), 8.17 (1H, d), 10.40 (1H, s); m / z (ES ⁺ ) [M+H] ⁺ = 481.9. Intermediate 45c: 1-[1-(7-azaspiro[3.5]nonan-2-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 44e starting from intermediate 45b (200 mg, 0.42 mmol) to give the title compound (120 mg, 76%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.28 (3H, t), 1.62 (4H, dt), 2.17 - 2.26 (2H, m), 2.33 - 2.42 (2H, m), 2.58 - 2.65 (2H, m), 2.68 - 2.80 (6H, m), 3.81 (2H, t), 5.26 (1H, br t), 7.60 (1H, s), 7.91 (1H, d), 8.17 (1H, d), 10.24 - 10.69 (1H, m); m / z (ES ⁺ ) [M+H] ⁺ = 382.3. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 11g (50 mg, 0.08 mmol) and intermediate 45c (30.1 mg, 0.08 mmol) in a similar manner to Example 35. Purification by RPC (elution gradient: 0-80% MeCN in water containing 0.1% _NH4OH ) gave the title compound (22.0 mg, 32.1%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.20 - 1.31 (5H, m), 1.59 - 1.85 (8H, m), 1.95 (2H, br d), 2.15 (4H, br dd), 2.24 (4H, br s), 2.36 (4H, br d), 2.62 - 2.68 (2H, m), 2.71 (2H, br d), 2.76 (2H, br s), 3.08 - 3.14 (2H, m), 3.24 - 3.29 (2H, m), 3.34 - 3.37 (2H, m), 3.81 (2H, br t), 4.35 (2H, br s), 5.26 (1H, br t), 5.94 (2H, br s), 6.38 - 6.53 (2H, m), 6.82 - 6.98 (3H, m), 7.20 - 7.27 (1H, m), 7.47 (1H, s), 7.61 (1H, s), 7.86 - 7.95 (2H, m), 10.38 (1H, s), 13.87 - 14.59 (1H, m); m / z (ES ⁺ ) [M+H] ⁺ = 868.6. Example 46 Intermediate 46a: 2-(Benzoyloxymethyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

In a 100 mL flask, tributyl 2-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (1.532 g, 6 mmol) and DMAP (0.073 g, 0.60 mmol) were dissolved in DCM (25 mL). DIPEA (3.14 mL, 18.00 mmol) was added and the reaction was cooled to 0 °C. Benzyl chloride (1.381 mL, 12.00 mmol) was added and the reaction was stirred at 0 °C for 5 min, then warmed to room temperature and stirred for 2.5 h. The reaction was quenched with saturated aqueous NaHCO ₃ solution, extracted with DCM, dried over Na ₂ SO ₄ and concentrated. Purification by FSC (elution gradient: 0-40% EtOAc in hexanes) gave the title compound (1.940 g, 90%) as a yellow oil. ¹ H NMR (CDCl ₃ ): δ 1.45 (9H, s), 1.47 - 1.53 (2H, m), 1.57 - 1.63 (2H, m), 1.64 - 1.70 (2H, m), 1.96 - 2.03 (2H, m), 2.68 - 2.78 (1H, m), 3.26 - 3.31 (2H, m), 3.34 - 3.39 (2H, m), 4.30 (2H, d), 7.45 (2H, t), 7.57 (1H, t), 8.04 (2H, d); m / z (ES ⁺ ) [M- t Bu+2H] ⁺ = 304.1. Intermediate 46b: 7-Azaspiro[3.5]nonan-2-ylmethyl benzoate

Prepared in an analogous manner to intermediate 44e starting from intermediate 46a (1.9396 g, 5.40 mmol) the title compound was obtained as a yellow oil (1.276 g, 91%). ¹ H NMR (CDCl ₃ ): δ 1.48 - 1.53 (2H, m), 1.56 (1H, br s), 1.59 - 1.69 (4H, m), 1.93 - 2.04 (2H, m), 2.67 - 2.76 (3H, m), 2.80 (2H, br t), 4.31 (2H, d), 7.46 (2H, t), 7.57 (1H, t), 8.06 (2H, d); m / z (ES ⁺ ) [M+H] ⁺ = 260.6. Intermediate 46c: Benzoic acid [7-(5-chloro-2-fluoro-phenyl)-7-azaspiro[3.5]non-2-yl]methyl ester

A mixture of Pd ₂ dba ₃ (0.218 g, 0.24 mmol), intermediate 46b (1.2336 g, 4.76 mmol) and Cs ₂ CO ₃ (4.65 g, 14.27 mmol), 2-bromo-4-chloro-1-fluorobenzene (0.580 mL, 4.76 mmol) and t BuPhCphos (0.192 g, 0.48 mmol) and 1,4-dioxathiocarbamide (20 mL) was degassed for 5 min. The reaction was heated to 100 °C for 2.5 h. The reaction was cooled to room temperature, filtered through celite®, eluted with DCM and concentrated. Purification by FSC (elution gradient: 0-30% EOAc/hexanes) gave the title compound (1.673 g, 91%) as a colorless viscous liquid. ¹ H NMR (CDCl ₃ ): δ 1.70 - 1.77 (4H, m), 1.83 - 1.87 (2H, m), 1.99 - 2.12 (2H, m), 2.73 - 2.84 (1H, m), 2.92 - 2.97 (2H, m), 3.00 - 3.05 (2H, m), 4.35 (2H, d), 6.85 - 6.89 (1H, m), 6.90 - 6.99 (2H, m), 7.47 (2H, t), 7.54 - 7.64 (1H, m), 8.08 (2H, d); m / z (ES ⁺ ) [M+H] ⁺ = 388.5. Intermediate 46d: [7-(5-chloro-2-fluoro-phenyl)-7-azaspiro[3.5]nonan-2-yl]methanol

A mixture of intermediate 46c (1.1263 g, 2.90 mmol), LiOH (0.695 g, 29.04 mmol), MeOH (10 mL) and water (5 mL) was heated to 40 °C for 1.5 h. The reaction was quenched with 1 M HCl (50 mL), extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine, dried _{over Na2SO4} , filtered and concentrated. Purification by FSC (elution gradient: 0-50% EtOAc in hexanes) afforded the title compound (0.717 g, 87%) as a colorless oil. ¹ H NMR (CDCl ₃ ): δ 1.55 - 1.63 (2H, m), 1.69 - 1.73 (2H, m), 1.80 - 1.85 (2H, m), 1.94 - 2.00 (2H, m), 2.47 - 2.56 (1H, m), 2.92 - 2.96 (2H, m), 2.99 - 3.05 (2H, m), 3.65 (2H, d), 6.84 - 6.88 (1H, m), 6.90 - 6.96 (2H, m) (OH not observed); m / z (ES ⁺ ) [M+H] ⁺ = 285.2. Intermediate 46e: 7-(5-chloro-2-fluoro-phenyl)-7-azaspiro[3.5]nonane-2-carbaldehyde

To a stirred solution of intermediate 46d (666 mg, 2.35 mmol) in DCM (20 mL) was added dess-Martin periodinane (1095 mg, 2.58 mmol) in one portion. The mixture was stirred at room temperature for 2.5 h. The reaction was quenched with sodium thiosulfate solution, extracted with DCM (2 x 25 mL). The combined organic extracts were washed with saturated aqueous NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 0-30% EtOAc/hexanes) provided the title compound (494 mg, 74.7%) as a white solid. ¹ H NMR (CDCl ₃ ): δ 1.67 - 1.71 (2H, m), 1.81 - 1.86 (2H, m), 2.01 - 2.14 (4H, m), 2.92 - 2.96 (2H, m), 2.99 - 3.03 (2H, m), 3.11 - 3.22 (1H, m), 6.83 - 6.97 (3H, m), 9.79 (1H, d); m / z (ES ⁺ ) [M+H] ⁺ = 282.3. Intermediate 46f: 7-(5-chloro-2-fluoro-phenyl)-2-(dibutoxymethyl)-7-azaspiro[3.5]nonane

A mixture of intermediate 46e (494 mg, 1.75 mmol) and p -TsOH•H ₂ O (33.3 mg, 0.18 mmol) in 1-butanol (5 mL) was stirred at 50° C. for 2.25 h. The reaction was concentrated under reduced pressure. Purification by FSC (elution gradient: 0-10% EtOAc/hexanes) gave the title compound (521 mg, 72.1%) as a colorless liquid. ¹ H NMR (CDCl ₃ ): δ 0.95 (6H, t), 1.41 (4H, sxt), 1.53 - 1.64 (4H, m), 1.67 - 1.73 (4H, m), 1.76 - 1.82 (2H, m), 1.88 - 1.95 (2H, m), 2.56 - 2.65 (1H, m), 2.90 - 2.95 (2H, m), 2.97 - 3.03 (2H, m), 3.45 (2H, dt), 3.58 (2H, dt), 4.43 (1H, d), 6.80 - 6.87 (1H, m), 6.88 - 6.95 (2H, m); m / z (ES ⁺ ) [M+H] ⁺ = 412.6. Intermediate 46g: N -tert-butyloxycarbonyl- N- [4-[8-[3-[2-(dibutoxymethyl)-7-azaspiro[3.5]non-7-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalim-3-yl]carbamic acid tert-butyl ester

A mixture of intermediate 25d (632 mg, 1.17 mmol), intermediate 46f (481 mg, 1.17 mmol), Cs ₂ CO ₃ (1141 mg, 3.50 mmol) and RuPhos Pd G3 (98 mg, 0.12 mmol) in 1,4-dioxathiocarbamide (12 mL) was bubbled with N ₂ for 10 min. The reaction was heated to 100 °C for 1.5 h and the conversion ceased. A second portion of RuPhos Pd G3 (98 mg, 0.12 mmol) was added. The reaction was bubbled with N ₂ for 5 min and stirring was continued at 100 °C for 5 h. The reaction was cooled to room temperature, filtered through celite® and concentrated. Purification by FSC (elution gradient: 0-80% EtOAc/hexanes) gave the title compound (404 mg, 37.7%) as a brown dry film. ¹ H NMR (DMSO- d6 ): δ 0.88 (5H, t), 0.91 - 0.94 (1H, m), 1.29 - 1.37 (5H, m), 1.37 - 1.42 (18H, m), 1.43 - 1.51 (5H, m), 1.55 - 1.64 (4H, m), 1.65 - 1.71 (2H, m), 1.77 - 1.88 (4H, m), 1.93 - 2.00 (2H, m), 2.78 - 2.85 (2H, m), 2.87 - 2.93 (2H, m), 3.21 - 3.30 (5H, m), 3.32 - 3.42 (3H, m), 3.50 (2H, dt), 4.37 - 4.42 (3H, m), 5.14 - 5.27 (2H, m), 6.41 - 6.52 (2H, m), 6.91 (1H, dd), 7.16 (1H, t), 7.25 (1H, d), 7.46 (1H, t), 7.51 (1H, s), 7.73 (1H, dd); m / z (ES ⁺ ) [M+H] ⁺ = 917.7. Intermediate 46h: 1-[3-methyl-1-[[(2 S )-oxo-1-yl]methyl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

HCl solution (4 M in dihydrogen ether, 4.51 mL, 18.04 mmol) was added to a stirred solution of intermediate 30b (400 mg, 0.90 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM/ iPrOH (3:1, 100 mL) and basified with saturated aqueous _NaHCO3 solution (10 mL). The aqueous layer was separated and extracted with DCM/iPrOH mixture (2 x 50 mL). The combined extracts were dried over _Na2SO4 , filtered and concentrated to give the title compound (260 mg, 84%) as _a white solid. The crude material was used in the next step without further purification. m / z (ES ⁺ ) [M+H] ⁺ = 344.3. 1-[1-[[(2 S )-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 46g (50 mg, 0.05 mmol) and intermediate 46h (18.72 mg, 0.05 mmol) in a similar manner to Example 35. Purification by RPC (elution gradient: 0-60% CH ₃ CN/water containing 0.1% formic acid) gave the title compound (10.00 mg, 21.08%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.40 (2H, br t), 1.57 (2H, br s), 1.69 (2H, br s), 1.81 (1H, br t), 1.89 - 1.96 (4H, m), 1.99 - 2.04 (1H, m), 2.10 - 2.16 (2H, m), 2.25 (3H, s), 2.32 - 2.39 (2H, m), 2.41 - 2.45 (1H, m), 2.56 (2H, br s), 2.64 - 2.69 (1H, m), 2.75 (2H, br t), 2.81 - 2.86 (2H, m), 2.93 (2H, br s), 3.06 - 3.13 (2H, m), 3.26 (2H, br d), 3.38 - 3.42 (1H, m), 3.75 - 3.84 (4H, m), 4.19 - 4.27 (2H, m), 4.31 - 4.39 (2H, m), 5.93 (2H, br s), 6.39 - 6.50 (2H, m), 6.81 - 6.97 (3H, m), 7.22 (1H, br s), 7.33 (1H, s), 7.44 - 7.49 (1H, m), 7.85 - 7.93 (2H, m), 8.15 - 8.22 (1H, m), 10.32 - 10.44 (1H, br s), 14.02 - 14.31 (1H, br s); m / z (ES ⁺ ) [M+H] ⁺ = 870.7. Example 47 Intermediate 47a: 2-(5-Bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-7,8-dihydro- 5H -imidazo[1,2- c ]pyrimidine-6-carboxylic acid tributyl ester

A mixture of 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (50 mg, 0.24 mmol), tributyl 2-bromo-5,6-dihydroimidazo[1,2- a ]pyrrolidone-7( 8H )-carboxylate (71.6 mg, 0.24 mmol), copper(I) iodide (9.02 mg, 0.05 mmol), ( 1S , 2S ) -N1 , N2 -dimethylcyclohexane _- 1,2-diamine (13.48 mg, 0.09 mmol) and _K2CO3 (98 mg, 0.71 mmol) in 1,4-dioxathiocarbamide (3 mL) was heated at 100°C for 16 h. The reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate was diluted with DCM and washed with saturated aqueous NaHCO ₃ (20 mL), the organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (70.0 mg, 68.3%) as a light yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.46 (9H, s), 2.31 (3H, d), 3.83 (2H, br d), 4.08 (2H, br d), 4.60 (2H, br s), 7.66 (1H, s), 7.86 (1H, s), 8.29 (1H, d), 8.39 (1H, d); m / z (ES ⁺ ) [M+H] ⁺ = 432.1. Intermediate 47b: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-7,8-dihydro- 5H -imidazo[1,2- c ]pyrimidine-6-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4b starting from intermediate 47a (70 mg, 0.16 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (40.0 mg, 53.1%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.46 (8H, s), 2.32 (3H, d), 2.78 (2H, s), 3.79 - 3.91 (5H, m), 4.09 (3H, br s), 4.59 - 4.62 (3H, m), 7.65 - 7.76 (1H, m),7.84 - 7.90 (1H, m), 7.97 - 8.07 (1H, m), 8.28 - 8.36 (1H, m); m / z (ES ⁺ ) [M+H] ⁺ = 466.0. Intermediate 47c: 1-[3-methyl-1-(5,6,7,8-tetrahydroimidazo[1,2- c ]pyrimidin-2-yl)pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (0.248 mL, 3.22 mmol) was added to a stirred solution of intermediate 47b (50 mg, 0.11 mmol) in DCM (1.5 mL). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated. The crude product was dissolved in MeOH and solid-loaded bicarbonate was added and stirred for 1 h, filtered and concentrated to give the title compound (30.0 mg, 76%) as a gum. The crude product was used in the next step without further purification. m / z (ES ⁺ ) [M+H] ⁺ = 366.1. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,8-dihydro- 5H -imidazo[1,2- a ]pyridine-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 11g (34.6 mg, 0.05 mmol) and intermediate 47c (20 mg, 0.05 mmol) in a similar manner to Example 39. Purification by RPC (elution gradient: 0-80% MeCN in water containing 0.2% _NH4OH ) gave the title compound (15 mg, 32.2%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.32 (2H, br d), 1.72 - 1.79 (1H, m), 1.84 (2H, br d), 1.92 - 1.99 (2H, m), 2.13 (2H, br d), 2.32 (3H, s), 2.46 (2H, br d), 2.69 (2H, br t), 2.78 (2H, br t), 2.90 (2H, br s), 3.11 (2H, br d), 3.27 (2H, br d), 3.38 (2H, br d), 3.65 (2H, s), 3.86 (2H, t), 4.07 (2H, br s), 4.35 (2H, br s), 5.94 (2H, s), 6.38 - 6.54 (2H, m), 6.82 - 6.98 (3H, m), 7.23 (1H, t), 7.47 (1H, s), 7.65 (1H, s), 7.85 (1H, s), 7.91 (1H, br d), 8.00 (1H, d), 8.30 (1H, d), 10.43 (1H, s), 14.17 (1H, br s). m / z (ES ⁺ ) [M+H] ⁺ = 852.4. Example 48 Intermediate 48a: ( 2S )-2-[(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)methyl]oxathioline-4-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a, starting from 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (0.500 g, 2.37 mmol) and ( R )-tert-butyl 2-(hydroxymethyl)iodine-4-carboxylate (0.772 g, 3.55 mmol). Purification by FSC (elution gradient: 0 to 50% EtOAc in hexanes) gave the title compound (0.845 g, 87%) as an off-white foam. ¹ H NMR (CDCl ₃ ): δ 1.44 (9H, s), 2.27 (3H, s), 2.61 (1H, br s), 2.91 (1H, br s), 3.47 (1H, td), 3.71 - 4.08 (4H, m), 4.16 - 4.42 (2H, m), 7.06 (1H, br d), 7.95 (1H, s), 8.30 (1H, d); m / z (ES ⁺ ) [M+H] ⁺ = 410.1, 412.0. Intermediate 48b: ( 2S )-2-[[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]methyl]oxoline-4-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 6b starting from intermediate 48a (0.838 g, 2.04 mmol). Purification by FSC (elution gradient: 0 to 15% MeOH in DCM and 0 to 100% [3:1 EtOAc/EtOH] in hexanes) gave the title compound (0.625 g, 69.0%) as an orange solid. ¹ H NMR (DMSO- d6 ): δ 1.36 (9H, s), 2.24 (3H, d), 2.51 - 2.71 (1H, m), 2.75 (2H, t), 2.78 - 2.92 (1H, m), 3.27 - 3.35 (1H, m), 3.65 (1H, br d), 3.68 - 3.76 (2H, m), 3.80 (3H, t), 4.27 (2H, br d), 7.33 (1H, d), 7.89 (1H, d), 8.18 (1H, d), 10.37 (1H, s); m / z (ES ⁺ ) [M+H] ⁺ = 444.4. Intermediate 48c: 1-[3-methyl-1-[[(2 R )-oxo-2-yl]methyl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 46h starting from intermediate 48b (400 mg, 0.90 mmol). The reaction mixture was concentrated to give the title compound as a white solid (270 mg, 87%). The crude material was used in the next step without further purification. m / z (ES ⁺ ) [M+H] ⁺ = 344.3. 1-[1-[[(2 R )-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 46g (50 mg, 0.05 mmol) and intermediate 48c (18.72 mg, 0.05 mmol) in a similar manner to Example 46. Purification by RPC (elution gradient: 0-60% _CH3CN /water containing 0.1% formic acid) gave the title compound (13.00 mg, 27.4%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.40 (2H, br t), 1.57 (2H, br s), 1.69 (2H, br s), 1.81 (1H, s), 1.87 - 1.97 (4H, m), 1.98 - 2.04 (1H, m), 2.08 (1H, s),2.13 (2H, br d), 2.25 (3H, s), 2.30 - 2.38 (2H, m), 2.40 - 2.46 (1H, m), 2.54 - 2.60 (1H, m), 2.63 - 2.69 (1H, m), 2.75 (2H, t), 2.84 (2H, br s), 2.93 (2H, br s), 3.10 (2H, br d), 3.25 - 3.28 (1H, m), 3.37 - 3.43 (1H, m), 3.74 - 3.85 (4H, m), 4.20 - 4.28 (2H, m), 4.35 (2H, br s), 5.93 (2H, s), 6.40 - 6.50 (2H, m), 6.82 -6.95 (3H, m), 7.22 (1H, t), 7.33 (1H, s), 7.47 (1H, s), 7.89 (2H, d), 8.19 (1H, d), 10.32 - 10.46 (1H, br s), 13.90 - 14.47 (1H, br s) s); m / z (ES ⁺ ) [M+H] ⁺ = 870.7. Example 49 Intermediate 49a: [(3 aR ,6 aS )-1,2,3,3 a ,4,5,6,6 a -octahydrocyclopenta[ c ]pyrrol-5-yl]methanol

( 3aR , 6aS )-5-(Hydroxymethyl)hexahydrocyclopenta[ c ]pyrrole-2( 1H )-carboxylic acid tributyl ester (5 g, 20.72 mmol) was added to 4 M HCl in dihydrogen ether (15 mL, 493.72 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with MTBE to form a precipitate. The solid was collected by filtration and dried in vacuo. The solid was suspended in MeCN (15 mL) and MeOH (6 mL), and _K2CO3 (2 g) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated to provide the title compound (2.30 g, 79%) as _a colorless oil. ¹ H NMR (DMSO- d6 ): δ 0.84 - 0.96 (2H, m), 1.36 - 1.47(1H, m), 1.81 -1.87 (1H, m), 1.88 - 1.94 (2H, m), 2.46 -2.49 (1H, m), 2.63 -2.67 (2H, m), 2.68 -2.74 (2H, m), 3.25 -3.35 (3H, m), 4.69 (1H, brs); m/z (ES ⁺ ) [M+H] ⁺ = 142.2. Intermediate 49b: ( 3aR , 6aS )-2-(5-chloro-2-fluoro-phenyl)-5-(dimethoxymethyl) -3,3a , 4,5,6,6a -hexahydro- 1H -cyclopenta[ c ]pyrrole

DMSO (3.29 mL, 46.34 mmol) was added to oxalyl chloride (3.53 g, 27.80 mmol) in DCM (20 mL) at -78 °C under nitrogen. The resulting mixture was stirred at -78 °C for 30 min, and then a solution of intermediate 49a (2.5 g, 9.27 mmol) in DCM (2 mL) was added. The resulting mixture was stirred at -78 °C for 1 h. Et ₃ N (7.75 mL, 55.61 mmol) was added, and the resulting mixture was stirred at -40 °C for 1 h. The reaction mixture was diluted with DCM (100 mL) and washed with saturated aqueous NH ₄ Cl solution (2 x 50 mL), followed by brine (2 x 50 mL). The organic layer was dried over _Na2SO4 , _filtered and evaporated. To the crude aldehyde was added pTsOH (0.353 g, 1.85 mmol) and trimethoxymethane (1.967 g, 18.54 mmol) in MeOH (30 mL). The resulting mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure. Purification by RPC (elution gradient: 5% to 100% MeCN in water containing _0.5 % _NH4HCO3 ) gave the title compound (2.10 g, 72.2%) as a yellow oil. ¹ H NMR (CDCl ₃ ): δ 1.24 - 1.36 (1H, m), 1.64 - 1.72 (1H, m), 2.04 - 2.15 (1H, m), 2.22 - 2.54 (1H, m), 2.64 - 2.86 (2H, m), 2.99 - 3.08 (1H, m), 3.16 - 3.23 (1H, m), 3.27 - 3.33 (2H, m), 3.34 (6H, s), 3.43 - 3.52 (1H, m), 4.12 - 4.24 (1H, m), 6.63 - 6.72 (2H, m), 6.84 - 6.96 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 314.2. Intermediate 49c: 8-[3-[( 3aR , 6aS )-5-(dimethoxymethyl) -3,3a , 4,5,6,6a- hexahydro - 1H -cyclopenta[ c ]pyrrol-2-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 42c from intermediate 49b (2.1 g, 6.69 mmol) and benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.648 g, 6.69 mmol). Purification by FSC (elution gradient: 0 to 50% EtOAc in petroleum ether) gave the title compound as a yellow oil (3.20 g, 91%, mixture of trans and cis isomers). The mixture was purified by SFC (column: CHIRAL ART Cellulose-SB, 3.0 x 100 mm, 3 μm; mobile phase A: CO ₂ , mobile phase B: MeOH; flow rate: 100 mL/min; gradient: isocratic 15% B; back pressure (bar): 100; wavelength: 220 nm). Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.800 mg, 25.00%) as a dark oil. ¹ H NMR (CDCl ₃ ): δ 1.65 - 1.71 (4H, m), 1.75 - 1..89 (2H, m), 1.97 - 2.07 (2H, m), 2.46 - 2.55 (1H, m), 2.78 - 2.87 (2H, m), 2.95 - 3.02 (2H, m), 3.29 - 3.31 (1H, m), 3.35 (6H, s), 3.38 - 3.43 (1H, m), 3.45 - 3.52 (2H, m), 3.68 - 3.74 (1H, m), 3.76 - 3.82 (1H, m), 4.05 - 4.14 (2H, m), 4.16 (1H, d), 5.15 (2H, s), 6.12 - 6.20 (2H, m), 6.82 - 6.91 (1H, m), 7.31 - 7.40 (5H, m). m/z (ES ⁺ ) [M+H] ⁺ = 524.3. Intermediate 49d: 8-[3-[(3 aR ,6 aS )-5-(dimethoxymethyl)-3,3 a ,4,5,6,6 a -hexahydro-1 H -cyclopenta[ c ]pyrrol-2-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane

Pd/C (10%) (15.24 mg, 0.14 mmol) was added to intermediate 49c (750 mg, 1.43 mmol) in MeOH (25 mL) under nitrogen. The resulting mixture was flushed with hydrogen and stirred under hydrogen atmosphere at room temperature for 16 h. The reaction was filtered through celite®, and the filtrate was concentrated under reduced pressure to provide the title compound (486 mg, 87%) as a colorless gum. ¹ H NMR (DMSO- d6 ): δ 1.48 - 1.61 (4H, m), 1.93 - 2.09 (4H, m), 2.29 - 2.42 (1H, m), 2.67 - 2.76 (2H, m), 2.79 - 2.86 (2H, m), 2.88 - 2.96 (2H, m), 3.01 - 3.05 (2H, m), 3.23 (6H, s), 3.34 - 3.41 (2H, m), 4.11 (1H, d), 4.22 - 4.28 (2H, m), 6.12 - 6.25 (2H, m), 6.85 - 6.94 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 390.4. Intermediate 49e: 4-[8-[3-[( 3aR , 6aS )-5-(dimethoxymethyl) -3,3a , 4,5,6,6a-hexahydro -1H - cyclopenta[ c ]pyrrol-2-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-chloro-3-pyridin-3-amine

Intermediate 49d (476 mg, 1.22 mmol) was added to 4-bromo-6-chloroindole-3-amine (306 mg, 1.47 mmol) and DIPEA (0.640 mL, 3.67 mmol) in DMSO (7 mL). The resulting mixture was stirred at 80 °C for 24 h. The crude product was purified by RPC (elution gradient: 5% to 80% MeCN in water (containing _0.1 % _NH4HCO3 )) to afford the title compound (400 mg, 63.3%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.50 - 1.63 (4H, m), 1.85 - 1.96 (2H, m), 2.03 - 2.12 (2H, m), 2.33 - 2.44 (1H, m), 2.65 - 2.78 (2H, m), 2.89 - 3.01 (4H, m), 3.14 - 3.18 (1H, m), 3.24 (6H, s), 3.35 - 3.43 (2H, m), 4.13 (1H, d), 4.24 - 4.29 (2H, m), 5.80 (2H, s), 6.17 - 6.30 (2H, m), 6.82 - 6.93 (2H, m); m/z (ES ⁺ ) [M+H] ⁺ = 517.2. Intermediate 49f: 2-[5-[8-[3-[(3 aR ,6 aS )-5-(dimethoxymethyl)-3,3 a ,4,5,6,6 a -hexahydro-1 H -cyclopenta[c]pyrrol-2-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-amino-3-indole-1,3-dihydro-phenol

Prepared in an analogous manner to intermediate 2h from intermediate 49e (450 mg, 0.87 mmol). Purification by FSC (elution gradient: 0 to 40% EtOAc in petroleum ether then 0 to 10% MeOH in DCM) gave the title compound (330 mg, 66.0%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 1.51 - 1.60 (4H, m), 1.87 - 1.98 (2H, m), 2.06 - 2.15 (2H, m), 2.32 - 2.43 (1H, m), 2.66 - 2.73 (2H, m), 2.88 - 2.97 (2H, m), 3.04 - 3.12 (2H, m), 3.21 (6H, s), 3.34 - 3.42 (2H, m), 3.22 - 3.27 (2H, m), 4.11 (1H, d), 4.29 - 4.36 (2H, m), 5.92 (2H, s), 6.18 - 6.31 (2H, m), 6.80 - 6.93 (3H, m), 7.17 - 7.26 (1H, m), 7.45 (1H, s), 7.90 (1H, d), 14.17 (1H, s); m/z (ES+) [M+H] ⁺ = 575. 1-[3-Methyl-1-[7-[[ rel -(3 aR ,5 r *,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3 a ,4,5,6,6 a -hexahydro-1 H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration not confirmed] 1-[3-Methyl-1-[7-[[(3 aR ,5 s ,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3 a ,4,5,6,6 a -hexahydro-1 H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[7-[[(3 aR ,5 r ,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a , 4,5,6,6a -hexahydro- 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 49f (100 mg, 0.17 mmol) and formic acid (2 mL). The mixture was stirred at 40 °C for 30 min. The reaction mixture was evaporated to dryness, redissolved in DCM (5 mL), and washed with saturated aqueous NaHCO ₃ solution (2 x 2 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to afford a crude yellow solid. The crude aldehyde was taken up in DCM (6 mL) and LiBH ₄ (7.58 g, 0.35 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness, redissolved in DCM (5 mL), and washed with saturated aqueous NH ₄ Cl solution (2 x 2 mL). The organic layer was dried over _Na2SO4 , _filtered and evaporated to provide a crude yellow solid. The crude alcohol was dissolved in DCM (6 ml), and methanesulfonic anhydride (39.4 mg, 0.23 mmol) and _NEt3 (0.073 ml, 0.52 mmol) were added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness, redissolved in DCM (10 mL), and washed with saturated aqueous _NH4Cl solution (2 x 2 mL). The organic layer was dried over _Na2SO4 , _filtered and evaporated to provide a crude yellow solid. The crude mesylate was dissolved in dihydrogen sulfonate (6 mL), and KI (28.9 mg, 0.17 mmol) and intermediate 42f (63.9 mg, 0.17 mmol) were added. The resulting mixture was stirred at 80 °C for 16 h. The reaction was cooled to room temperature and concentrated. Purification by RPC (elution gradient: 0-70% CH ₃ CN in water containing 0.1% formic acid) gave a mixture of two isomers. The isomers were separated by preparative HPLC (column: Xselect CSH Prep C18 OBD, 19 x 250 mm, 5 μm; mobile phase A: water containing 0.1% FA, mobile phase B: ACN; flow rate: 25 mL/min; gradient: 26% B to 33% B in 10 min). The title compound (8 mg, 4.96%) was obtained as a white solid which eluted first from the column. ¹ H NMR (DMSO- d6 ): δ 1.41 - 1.49 (2H, m), 1.60 - 1.74 (6H, m), 1.90 - 1.98 (2H, m), 2.13 (2H, d), 2.16 - 2.22 (4H, m), 2.25 - 2.28 (4H, m), 2.29 - 2.39 (5H, m), 2.69 - 2.78 (4H, m), 2.91 - 2.98 (2H, m), 3.11 (2H, d), 3.26 (2H, d), 3.51 - 3.53 (3H, m), 3.77 - 3.83 (2H, t), 4.31 - 4.38 (2H, m), 5.20 - 5.29 (1H, m), 5.9 - 5.98 (2H, m), 6.23 - 6.32 (2H, m), 6.84 - 6.92 (3H, m), 7.23 (1H, t), 7.47 (1H, s), 7.60 (1H, s), 7.86 - 7.95 (2H, m), 8.16 (1H, s), 8.30 (1H, s), 10.39 (1H, s) , 14.22 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -136.691. m/z (ES+) [M+H] ⁺ = 880.5. Example 50: 1-[3-methyl-1-[7-[[ rel -(3 aR ,5 r *,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl) phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3a,4,5,6,6a-hexahydro-1 H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not confirmed] 1-[3-methyl-1-[7-[[(3 aR ,5 s ,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3 a ,4,5,6,6 a -hexahydro-1 H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[7-[[(3 aR ,5 r ,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a , 4,5,6,6a -hexahydro- 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

The preparation was started with intermediate 49f (100 mg, 0.17 mmol) in a similar manner to Example 49. Purification by preparative HPLC (column: Xselect CSH Prep C18 OBD, 19 x 250 mm, 5 μm; mobile phase A: water containing 0.1% FA, mobile phase B: ACN; flow rate: 25 mL/min; gradient: 26% B to 33% B in 10 min) gave the title compound (5 mg, 3.04%) as a white solid, which eluted second from the column. ¹ H NMR (DMSO- d6 ): δ 0.97 - 1.08 (2H, m), 1.66 - 1.73 (4H, m), 1.92 - 1.97 (2H, m), 2.06 - 2.15 (5H, m), 2.17 - 2.23(3H, m), 2.22 - 2.30 (6H, m), 2.30 - 2.39 (5H, m), 2.59 -2.64 (2H, m), 2.76 (2H, t), 3.07 - 3.12 (3H, m), 3.21- 3.29 (3H, m), 3.44 - 3.54 (1H, m), 3.78 - 3.80 (2H, m), 4.31 - 4.36 (2H, m), 5.23 - 5.27 (1H, m), 5.95 (2H, s), 6.25 - 6.31 (2H, m), 6.85 - 6.91 (3H, m), 7.23 (1H, t), 7.47 (1H, s), 7.61 (1H, s), 7.87 - 7.93 (2H, m), 8.17 (1H, s), 8.32 (1H, s), 10.39 (1H, s), 14.22 (1H, s); ¹⁹ F NMR (DMSO- d6 ) δ -136.823 1; m/z (ES ⁺ ), [M+H] ⁺ = 880.4. Example 51 Intermediate 51a: 3-(5-bromo-6-fluoro-indol-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a starting from 5-bromo-6-methyl- 1H -indole (0.6 g, 2.80 mmol) and tributyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.37 g, 5.32 mmol). Purification by FSC (elution gradient: 0-70% EtOAc in hexanes) gave the title compound (856 mg, 67%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.47 (9H, s), 1.56 - 1.70 (2H, m, overlapped with residual water), 1.71 - 1.81 (2H, m), 1.99 (1H, dd), 2.43 (1H, dd), 3.37 (2H, ddt), 3.64 (2H, ddt), 4.21 - 4.29 (2H, m), 4.98 - 5.03 (1H, m), 6.50 (1H, d), 7.25 (1H, d), 7.38 (1H, d), 7.80 (1H, d); ¹⁹ F NMR (CD ₂ Cl ₂ ,) δ -115.78 (1F, s); m/z (ES ⁺ ) [M- t Bu+H] ⁺ = 397.1. Intermediate 51b: 3-[5-[(3-ethoxy-3-oxopropyl)amino]-6-fluoro-indol-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 14b starting from intermediate 51a (0.40 g, 0.88 mmol) with addition of tBuBrettPhos (42.8 mg, 0.09 mmol). Purification by FSC (elution gradient: 0-50% EtOAc/hexanes) afforded the title compound (0.361 g, 84%) as a yellow gum. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.29 (3H, t), 1.47 (9H, s), 1.56 - 1.71 (2H, m, overlapped with residual water), 1.75 (2H, br s), 2.00 (1H, dd), 2.39 (1H, dd), 2.69 (2H, t), 3.30 - 3.43 (2H, m), 3.51 (2H, br t), 3.56 - 3.68 (2H, m), 4.05 (1H, br s), 4.18 (3H, q), 4.22 - 4.28 (1H, m), 4.93 - 5.00 (1H, m), 6.39 (1H, d), 6.92 (1H, d), 7.12 (1H, d), 7.23 (1H, d); ¹⁹ F NMR (CD ₂ Cl ₂ ): δ -139.89 (1F, s); m/z (ES ⁺ ) [M+H] ⁺ = 490.6. Intermediate 51c: 3-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-6-fluoro-indol-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 14c starting from intermediate 51b (361 mg, 0.74 mmol) to provide the title compound. The crude product was used in the next step without purification and quantitative yield was assumed. m/z (ES ⁺ ) [M+H] ⁺ = 533.4. Intermediate 51d: 3-[5-(2,4-Dioxohexahydroxypyrimidin-1-yl)-6-fluoro-indol-1-yl]-1-oxahedral-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 14d starting from intermediate 51c (394 mg, 0.74 mmol) to give the title compound (338 mg, 94%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.47 (9H, s), 1.59 (2H, s), 1.72 - 1.83 (2H, m), 1.99 - 2.05 (1H, m), 2.44 (1H, dd), 2.87 (2H, t), 3.33 - 3.43 (2H, m), 3.58 - 3.70 (2H, m), 3.83 (2H, t), 4.21 - 4.32 (2H, m), 5.00 - 5.07 (1H, m), 6.57 (1H, d), 7.25 - 7.30 (1H, m), 7.39 - 7.43 (1H, m), 7.56 (1H, d), 7.63 (1H, s); m/z (ES ⁺ ) [M-tBu+H] ⁺ = 431.2. Intermediate 51e: rel -(3 S * )-3-[5-(2,4-dioxo-hexahydropyrimidin-1-yl)-6-fluoro-indol-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester [* absolute configuration has not been confirmed] (3 S )-3-[5-(2,4-dioxo-hexahydropyrimidin-1-yl)-6-fluoro-indol-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester or (3 R )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-6-fluoro-indol-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Intermediate 51d (0.338 g, 0.69 mmol) was purified by chiral SFC (column: IH 21 mm x 250 5 μm, MeOH/0.2% NH ₄ OH) to give the title compounds: Isomer 1 (136 mg) as an off-white solid which eluted first from the column, and Isomer 2 (133 mg) as a white solid which eluted second from the column. 1-[6-Fluoro-1-[ rel- (3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration not confirmed] 1-[6-Fluoro-1-[(3 R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3- yl] indol-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration not confirmed] )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione or 1-[6-fluoro-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

2 MH ₂ SO ₄ aqueous solution (719 μl, 1.44 mmol) was added to a solution of intermediate 51e, isomer 1 (35 mg, 0.07 mmol) in THF (719 μl), stirred at 50 °C for 2.5 h and cooled to room temperature. The reaction mixture was combined with a solution of intermediate 11g (29 mg, 0.06 mmol) in 1 MH ₂ SO ₄ in THF/H ₂ O (1:1), quenched with saturated aqueous NaHCO ₃ solution and diluted with DCM. The layers were separated and the aqueous layer was extracted with DCM/IPA (4:1). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting solid was dissolved in DCM (1.85 mL) and i PrOH (250 uL) and stirred at room temperature for 5 min. Na(OAc) ₃ BH (14.7 mg, 0.07 mmol) was added and the mixture was stirred at room temperature for 5 min and then kept at 4 °C overnight. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution, diluted with water and DCM, and the layers were separated. The aqueous layer was extracted with 20% IPA in DCM (2 x 20 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. Purification by FSC (elution gradient: 80%-100% MeOH in EtOAc and then 0-25% MeOH in EtOAc) followed by lyophilization gave the title compound (33.4 mg, 66.3%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.19 - 1.31 (2H, m), 1.55 - 1.84 (7H, m), 1.85 - 1.99 (3H, m), 2.09 - 2.22 (4H, m), 2.25 - 2.51 (5H, m, overlapped with residual solvent), 2.64 (2H, br t), 2.74 (2H, t), 3.10 (2H, br d), 3.23 - 3.29 (2H, m), 3.29 - 3.38 (2H, m, overlapped with residual water), 3.67 - 3.75 (2H, m), 4.00 (1H, dd), 4.17 (1H, dd), 4.34 (2H, br s), 5.23 (1H, dt), 5.93 (2H, s), 6.40 - 6.50 (2H, m), 6.52 (1H, d), 6.83 - 6.96 (3H, m), 7.23 (1H, t), 7.47 (1H, s), 7.54 (1H, d), 7.57 (2H, d), 7.91 (1H, d), 10.40 (1H, s), 14.15 (1H, br s); ¹⁹ F NMR (DMSO- d6 ) δ -136.37 (1F, s), -128.92 (1F, s); m/z ES ⁺ [M + H] ⁺ 873.5. Example 52 1-[6-fluoro-1-[ rel- (3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione (Isomer 2) [*Absolute configuration has not been confirmed] 1-[6-fluoro-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione or 1-[6-fluoro-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 51e, isomer 2 (35 mg, 0.07 mmol) and intermediate 11g (28 mg, 0.06 mmol) in a similar manner to Example 51. Purification by FSC (elution gradient: 0-20% MeOH in EtOAc) followed by freeze drying afforded the title compound (36.7 mg, 75%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.19 - 1.32 (2H, m), 1.57 - 1.84 (7H, m), 1.85 - 2.00 (3H, m), 2.13 (2H, br d), 2.17 - 2.29 (2H, m), 2.30 - 2.45 (3H, m), 2.47 - 2.55 (2H, m, overlapped with residual solvent), 2.64 (2H, br t), 2.74 (2H, br t), 3.10 (2H, br d), 3.22 - 3.29 (2H, m, overlapped with residual water), 3.30 - 3.39 (2H, m, with residual water), 3.71 (2H, br t), 4.00 (1H, br dd), 4.17 (1H, dd), 4.34 (2H, br s), 5.23 (1H, dt), 5.93 (2H, s), 6.39 - 6.45 (1H, m), 6.45 - 6.50 (1H, m), 6.52 (1H, d), 6.83 - 6.95 (3H, m), 7.23 (1H, t), 7.46 (1H, s), 7.53 (1H, d), 7.56 (1H, d), 7.58 (1H, s), 7.90 (1H, d), 10.40 (1H, s), 14.15 (1H, br s); ¹⁹ F NMR (DMSO- d6 ) δ -136.37 (1F, s), -128.91 (1F, s ); m/z ES ⁺ [M+H] ⁺ 873.5. Example 53 Intermediate 53a: 3-(5-Bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a starting from 5-bromo-3-cyclopropyl- 1H -pyrrolo[2,3- b ]pyridine (0.6 g, 2.53 mmol) and tributyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.24 g, 4.81 mmol). Purification by FSC (elution gradient: 0-30% EtOAc in hexanes) gave the title compound (1.0911 g, 91%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.61 - 0.70 (2H, m), 0.89 - 0.97 (2H, m), 1.47 (9H, s), 1.56 - 1.64 (1H, m), 1.67 - 1.83 (3H, m), 1.87 - 1.94 (1H, m), 1.98 (1H, dd), 2.43 (1H, dd), 3.33 - 3.46 (2H, m), 3.61 (2H, br d), 4.08 (1H, dd), 4.25 (1H, dd), 5.52 - 5.58 (1H, m), 7.18 (1H, s), 8.13 (1H, d), 8.30 (1H, d); m/z ES ⁺ [M+2H] ⁺ = 478.2. Intermediate 53b: (3 S * )-3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester [*absolute configuration not confirmed] (3 S )-3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester or (3 R )-3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in analogy to intermediate 35b starting from intermediate 53a (410 mg, 0.86 mmol) with addition of tBuBrettPhos (41.7 mg, 0.09 mmol). Purification by FSC (elution gradient: 0 to 100% EtOAc in hexanes and then 0 to 4% MeOH in EtOAc) gave a racemic mixture of the title compound as a tan solid (290 mg, 66.1%). The racemate was further purified by chiral SFC (column: IH 21 mm x 250 5 μm, MeOH/0.2% NH ₄ OH) to give the title compound, isomer 1 (127 mg, 29.0%) as a clear film, which eluted first from the column and turned into a white solid after scraping the side of the vial, and isomer 2 (119 mg, 27.1%) as an off-white solid, which eluted second from the column. Isomer 1: ¹ H NMR (CD ₂ Cl ₂ ): δ 0.64 - 0.71 (1H, m), 0.91 - 0.97 (2H, m), 1.47 (9H, s), 1.57 - 1.65 (1H, m, overlapped with residual water), 1.68 - 1.86 (3H, m), 1.90 - 1.98 (1H, m), 1.94 - 1.94 (1H, m), 2.01 (1H, dd), 2.44 (1H, dd), 2.90 (2H, t), 3.33 - 3.48 (2H, m), 3.61 (2H, br d), 3.92 (2H, t), 4.10 (1H, dd), 4.26 (1H, dd), 5.56 - 5.64 (1H, m), 7.22 (1H, s), 7.60 (1H, br s), 7.92 (1H, d), 8.23 (1H, d); m/z ES ⁺ [M+H] ⁺ = 510.3. Isomer 2: ¹ H NMR (CD ₂ Cl ₂ ): δ 0.63 - 0.73 (2H, m), 0.88 - 0.99 (2H, m), 1.47 (9H, s), 1.56 - 1.65 (1H, m, overlapped with residual water), 1.66 - 1.85 (3H, m), 1.91 - 1.98 (1H, m), 2.01 (1H, dd), 2.44 (1H, dd), 2.90 (2H, t), 3.33 - 3.47 (2H, m), 3.61 (2H, br d), 3.92 (2H, t), 4.10 (1H, dd), 4.26 (1H, dd), 5.57 - 5.64 (1H, m), 7.22 (1H, s), 7.74 (1H, br s), 7.92 (1H, d), 8.23 (1H, d); m/z ES ⁺ [M+H] ⁺ 510.3. Intermediate 53c 1-[3-cyclopropyl-1-[(3 S * )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*The absolute configuration has not been confirmed] 1-[3-cyclopropyl-1-[(3 S )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-cyclopropyl-1-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (360 µl, 4.67 mmol) was added to a solution of intermediate 53b, isomer 2 (119 mg, 0.23 mmol) in DCM (808 µl). The reaction was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was azeotroped with DCM (3x) and dried in vacuo to give the title compound as the penta-TFA salt (243 mg, 107%). Quantitative yield assumed. m/z ES ⁺ [M+H] ⁺ = 410.6. 1-[3-Cyclopropyl-1-[ rel- (3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*Absolute configuration not confirmed] 1-[3-Cyclopropyl-1-[(3 R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3- yl ]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*Absolute configuration not confirmed] )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-cyclopropyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 53c (isomer 2) (65.2 mg, 0.07 mmol) and intermediate 11g (28 mg, 0.06 mmol) in a similar manner to Example 51. Purification by FSC (elution gradient: 80%-100% EtOAc in hexanes and then 0-40% MeOH in EtOAc) followed by freeze drying gave the title compound (38.6 mg, 77%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 0.63 - 0.69 (2H, m), 0.83 - 0.91 (2H, m), 1.17 - 1.30 (2H, m), 1.54 - 1.83 (7H, m), 1.87 - 2.03 (4H, m), 2.10 - 2.20 (4H, m), 2.23 - 2.40 (3H, m), 2.51 (2H, br s), 2.63 (2H, br t), 2.77 (2H, t), 3.10 (2H, br d), 3.23 - 3.29 (2H, m), 3.34 (2H, s), 3.82 (2H, t), 3.95 (1H, dd), 4.13 (1H, dd), 4.34 (2H, br s), 5.43 (1H, quin), 5.93 (2H, s), 6.40 - 6.45 (1H, m), 6.48 (1H, br d), 6.82 - 6.97 (3H, m), 7.23 (1H, t), 7.40 (1H, s), 7.47 (1H, s), 7.90 (1H, d), 7.97 (1H, d), 8.20 (1H, d), 10.39 (1H, s), 14.16 (1H, br s). ¹⁹ F NMR (DMSO-d6) δ -136.36 (1F, s); m/z ES+ [M+H]+ 896.7. Example 54 Intermediate 54a: 2-(5-Bromo-6-fluoro-pyrrolo[2,3- b ]pyridin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a starting from tributyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (1.122 g, 4.65 mmol) and 5-bromo-6-fluoro- 1H -pyrrolo[2,3- b ]pyridine (1 g, 4.65 mmol). Purification by FSC (elution gradient: 0 to 100% EtOAc in petroleum ether) gave the title compound (0.900 g, 44.1%) as a yellow solid. ¹ H NMR (DMSO- d ₆ ): δ 1.41 (9H, s), 1.59 - 1.64 (2H, m), 1.64 - 1.69 (2H, m), 2.24 - 2.29 (2H, m), 2.40 - 2.46 (2H, m), 3.24 - 3.27 (2H, m), 3.34 - 3.36 (2H, m), 5.10 - 5.17 (2H, m), 6.56 (1H, d), 7.84 (1H, d), 8.44 (1H, d): m/z (ES+) [M- t Bu+H] ⁺ = 381.8. Intermediate 54b: 2-[5-[(3-ethoxy-3-oxopropyl)amino]-6-fluoro-pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Under nitrogen, a vial was charged with Cs ₂ CO ₃ (1338 mg, 4.11 mmol), Pd-PEPPS-IheptCl (87 mg, 0.11 mmol), intermediate 54a (600 mg, 1.37 mmol), ethyl 3-aminopropionate HCl (273 mg, 1.78 mmol), and 1,4-dihydrogen iodide (20 mL). The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by RPC (elution gradient: 0 to 100% MeCN in water containing 0.4% NH ₄ HCO ₃ ) gave the title compound (400 mg, 61.6%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.18 (3H, t), 1.40 (9H, s), 1.56 - 1.68 (4H, m), 2.18 - 2.25 (2H, m), 2.35 - 2.41 (2H, m), 2.63 (2H, t), 3.25 (2H, t), 3.30 - 3.36 (4H, m) 4.07 (2H, q), 5.00 - 5.13 (2H, m), 6.35 (1H, d), 7.33 (1H, d), 7.54 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 475.2. Intermediate 54c: 2-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-6-fluoro-pyrrolo[2,3-b]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 14c starting from intermediate 54b (400 mg, 0.84 mmol). Purification by RPC (elution gradient: 0 to 100% MeCN in water _containing 0.4% _NH4HCO3 ) gave the title compound (300 mg, 68.8%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.06 (3H, t), 1.41 (9H, s), 1.62 - 1.69 (4H, m), 2.26 - 2.31 (2H, m), 2.40 - 2.45 (2H, m), 2.47 - 2.51(2H, m), 3.24 -3.29 (2H, m), 3.35 -3.38 (2H, m), 3.90 (2H, q), 5.14 - 5.21 (1H, m), 5.84 (2H, s), 6.57 - 6.62 (1H, m), 7.80 (1H, d), 7.99 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 518.3. Intermediate 54d: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-6-fluoro-pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 14d starting from intermediate 54c (300 mg, 0.58 mmol). The reaction mixture was diluted with EtOAc (25 mL) and washed successively with saturated NH ₄ Cl (10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to afford the title compound (240 mg, 88%) as a yellow solid. The product was used directly in the next step without further purification. ¹ H NMR (DMSO- d6 ): δ 1.39 (9H, s), 1.59 - 1.67 (4H, m), 2.22 - 2.30 (2H, m), 2.39 - 2.45 (2H, m), 2.74 (2H, t), 3.22 - 3.26 (2H, m), 3.31 - 3.35 (2H, m), 3.72 (2H, t), 5.09 - 5.19 (1H, m), 6.58 (1H, d), 7.80 (1H, d), 8.15 (1H, d); m/z (ES ⁺ ) [M- t Bu+H] ⁺ = 416.1. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Step-1- Intermediate 54d (100 mg, 0.21 mmol) was added to p-toluenesulfonic acid (91 mg, 0.53 mmol) in MeCN (4.0 mL). The resulting mixture was stirred at 80°C for 16 h. The solvent was removed under reduced pressure. The crude product was triturated with TBME (50 mL), and the solid was collected by filtration and dried under vacuum to obtain intermediate 1. Step-2- Formic acid (4.0 mL) was added to intermediate 11g (116 mg, 0.21 mmol). The resulting mixture was stirred at 40°C for 30 min. The solvent was removed under reduced pressure. To the residue was added intermediate 1 in NMP (4 mL) and DCE (4.0 mL). The resulting mixture was stirred at 40 °C for 30 min, and then sodium triacetoxyborohydride (225 mg, 1.06 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was diluted with EtOAc (25 mL) and washed successively with saturated NaHCO ₃ (10 mL x 2) and saturated brine (10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by preparative HPLC (column: Sunfire Prep C18 OBD column, 30*150 mm, 5 um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 17% B to 31% B in 8 min) gave the title compound (16.89 mg, 9.09%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.22 - 1.26 (3H, m), 1.60 - 1.85 (7H, m), 1.92 - 1.97 (2H, m), 2.10 - 2.19 (4H, m), 2.23 - 2.27 (3H, m), 2.36 - 3.40 (3H, m), 2.64 (2H, t), 2.75 (2H, t), 3.10 (2H, d), 3.24 - 3.29 (3H, m), 3.33 - 3.37 (2H, m), 3.74 (2H, t), 4.35 (2H, s), 5.08 - 5.19 (1H, m), 5.95 (2H, s), 6.40 - 6.51 (2H, m), 6.59 (1H, d), 6.83 - 6.90 (2H, m), 6.90 - 6.97 (1H, m), 7.23 (1H, t), 7.47 (1H, s), 7.81 (1H, d), 7.91 (1H, d), 8.15 (1H, d), 10.51 (1H, s), 14.18 (1H, s). ⁹ F NMR (DMSO- d6 ): δ -83.288, -136.400; m/z (ES ⁺ ) [M+H] ⁺ = 858.4. Example 55 Intermediate 55a: rel -(3 S * )-3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester (isomer 1) [*The absolute configuration has not been confirmed] 1-[3-cyclopropyl-1-[(3 S )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-cyclopropyl-1-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 53c starting from intermediate 53b, isomer 1 (125 mg, 0.25 mmol) to afford the title compound as a sticky product as a tris-TFA salt (188 mg, 102%). Assuming quantitative yield. m/z ES ⁺ [M+H] ⁺ = 410.3. 1-[3-Cyclopropyl-1-[ rel- (3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration not confirmed] 1-[3-Cyclopropyl-1-[(3 R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3- yl ]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration not confirmed] )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-cyclopropyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 55a (isomer 1) (65.2 mg, 0.07 mmol) and intermediate 11g (28 mg, 0.06 mmol) in a similar manner to Example 51. Purification by FSC (elution gradient: 0-100% MeOH in EtOAc and then 0-40% MeOH in EtOAc) followed by freeze drying gave the title compound (42.3 mg, 85%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 0.63 - 0.70 (2H, m), 0.83 - 0.91 (2H, m), 1.18 - 1.30 (2H, m), 1.56 - 1.81 (7H, m), 1.88 - 2.04 (4H, m), 2.09 - 2.22 (4H, m), 2.26 - 2.40 (3H, m), 2.42 - 2.53 (2H, m, overlapped with residual solvent), 2.64 (2H, br t), 2.77 (2H, t), 3.10 (2H, br d), 3.24 - 3.29 (2H, m), 3.30 - 3.40 (2H, m, with water), 3.82 (2H, t), 3.95 (1H, dd), 4.13 (1H, dd), 4.35 (2H, br s), 5.43 (1H, quin), 5.94 (2H, s), 6.39 - 6.45 (1H, m), 6.48 (1H, br d), 6.82 - 6.96 (3H, m), 7.23 (1H, t), 7.41 (1H, s), 7.47 (1H, s), 7.91 (1H, d), 7.97 (1H, d), 8.20 (1H, d), 10.39 (1H, s), 14.16 (1H, br s). ¹⁹ F NMR (DMSO-d6): δ -136.36 (1F, s); m/z ES ⁺ [M+H] ⁺ = 896.9. Example 56 Intermediate 56a: 9-(5-Bromo-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a starting from 5-bromo-3-ethyl- 1H -pyrrolo[2,3- b ]pyridine (484 mg, 2.15 mmol) and tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1.10 g, 4.09 mmol). Purification by FSC (elution gradient: 0-45% EtOAc in hexanes) gave the title compound (853 mg, 83%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.33 (3H, t), 1.39 - 1.51 (13H, m), 1.64 - 1.72 (2H, m), 1.85 - 2.05 (6H, m), 2.75 (2H, q), 3.39 - 3.48 (4H, m), 4.65 - 4.74 (1H, m), 7.17 (1H, s), 8.03 (1H, d), 8.29 (1H, d); m/z ES ⁺ [M+H] ⁺ = 476.2. Intermediate 56b: 9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 56a (837 mg, 1.76 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes and then 0-5% MeOH in EtOAc) gave the title compound (512 mg, 57.2%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.24 - 1.38 (7H, m), 1.41 (9H, s), 1.61 - 1.67 (2H, m), 1.71 (2H, br d), 1.83 (2H, br d), 1.96 - 2.08 (2H, m), 2.70 (2H, q), 2.76 (2H, t), 3.28 - 3.38 (4H, m, overlapped with residual water), 3.81 (2H, t), 4.63 (1H, ddd), 7.56 (1H, s), 7.90 (1H, d), 8.16 (1H, d), 10.36 (1H, s); m/z ES ⁺ [M+H] ⁺ = 510.4. Intermediate 56c: 1-[1-(3-azaspiro[5.5]undecane-9-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 56b (213 mg, 0.42 mmol). Purification by ion exchange chromatography (PoraPak Rxn CX cartridge) (eluting with 2.9 N _NH3 in MeOH and 2.9 N _NH3 in MeOH/DCM) gave the title compound (187 mg, 100%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.33 (7H, m), 1.62 (2H, br s), 1.69 (2H, br d), 1.84 (2H, br d), 1.97 - 2.08 (2H, m), 2.65 - 2.73 (6H, m), 2.76 (2H, t), 3.81 (2H, t), 4.56 - 4.65 (1H, m), 7.55 (1H, s), 7.90 (1H, d), 8.16 (1H, d), 10.33 (1H, br s); m/z ES ⁺ [M+H] ⁺ = 410.4. Intermediate 56d: 4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Intermediate 56c (186 mg, 0.45 mmol), intermediate 25e (232 mg, 0.64 mmol), DIPEA (238 μl, 1.36 mmol) and 1,4-dihydronaphthalene (2 mL) were stirred together at 95 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by FSC (elution gradient: 15%-100% EtOAc in hexanes and then 0-20% MeOH in EtOAc) gave the title compound (248 mg, 87%) as an orange-brown solid. ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.31 (5H, m), 1.34 - 1.43 (11H, m), 1.48 - 1.73 (6H, m), 1.80 (4H, br d), 1.95 - 2.05 (2H, m), 2.43 - 2.55 (6H, m, overlapped with residual solvent), 2.69 (2H, q), 2.76 (2H, t), 3.03 (2H, br s), 3.71 (2H, br d), 3.80 (2H, t), 4.60 (1H, br t), 7.55 (1H, s), 7.90 (1H, d), 8.16 (1H, d), 10.36 (1H, s); m/z ES ⁺ [M+H] ⁺ = 625.5. Intermediate 56e: 1-[3-ethyl-1-[3-[(4-fluoro-4-piperidinyl)methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (304 μl, 3.97 mmol) was added to a solution of intermediate 56d (248 mg, 0.40 mmol) in DCM (1.3 ml). The reaction was stirred at room temperature for 1.25 h and then concentrated under reduced pressure. Purification by ion exchange chromatography (PoraPak Rxn CX cartridge) (eluting with 2.9 N NH ₃ in MeOH and 2.9 N NH ₃ in MeOH/DCM) gave the title compound (192 mg, 92%) as a tan solid. ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.32 (5H, m), 1.33 - 1.41 (2H, m), 1.49 - 1.64 (2H, m), 1.64 - 1.75 (6H, m), 1.80 (2H, br d), 1.93 - 2.07 (2H, m), 2.42 - 2.50 (6H, m), 2.64 - 2.79 (8H, m), 3.80 (2H, t), 4.55 - 4.65 (1H, m), 7.55 (1H, s), 7.90 (1H, d), 8.16 (1H, d), 10.36 (1H, br s) (NH not observed); m/z ES ⁺ [M+H] ⁺ = 525.4. Intermediate 56f: N -tert-butyloxycarbonyl- N- [4-[8-(3-chloro-4-cyano-phenyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalim-3-yl]carbamic acid tert-butyl ester

Intermediate 25d (0.750 g, 1.38 mmol), CPhos Pd G3 (0.112 g, 0.14 mmol), 4-bromo-2-chlorobenzonitrile (0.450 g, 2.08 mmol) and Cs ₂ CO ₃ (1.128 g, 3.46 mmol) were sealed in a vial. The vial was evacuated and backfilled with nitrogen three times, and toluene (6.9 ml) was added. The resulting suspension was stirred at 100 °C for 18 h and then cooled to room temperature. The reaction mixture was diluted with DCM/MeOH, filtered through Celite® and concentrated under reduced pressure. Purification by FSC (elution gradient: 0-100% EtOAc and then 0-19% MeOH in EtOAc) gave the title compound (0.340 g, 36.3%) as an off-white dry film. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.50 (18H, s), 2.07 - 2.19 (4H, m), 3.27 (2H, d), 3.35 - 3.42 (5H, m), 4.42 (2H, br s), 5.22 (2H, s), 6.74 (1H, dd), 6.88 - 6.92 (1H, m), 7.20 (1H, t), 7.25 (1H, d), 7.42 - 7.49 (2H, m), 7.52 (1H, d), 7.86 - 7.92 (1H, m); m/z ES ⁺ [M+H] ⁺ = 677.5. Intermediate 56g: N -tert-butyloxycarbonyl- N- [4-[8-[4-cyano-3-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undecane-3-yl]methyl]-4-fluoro-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tert-butyl ester

Intermediate 56f (97 mg, 0.14 mmol), intermediate 56e (62.6 mg, 0.12 mmol), K ₂ CO ₃ (49.5 mg, 0.36 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (20.06 mg, 0.02 mmol) were sealed in a vial and evacuated/backfilled with nitrogen three times. Dithionite (955 μl) was added and the reaction mixture was stirred and heated at 100° C. for 15 h. The reaction was diluted with DCM/MeOH, filtered through Celite® and concentrated under reduced pressure. Purification by FSC (elution gradient: 75%-100% EtOAc in hexanes and then 0 to 20% MeOH in EtOAc) gave the title compound (47.8 mg, 34.4%) as a light yellow solid. m/z ES ⁺ [M+H] ⁺ = 1164.6. 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile

2 MH ₂ SO ₄ aqueous solution (820 μL, 1.64 mmol) was added to a stirred solution of intermediate 56g (47.8 mg, 0.04 mmol) in THF (820 μL). The resulting solution was stirred at 50 °C for 4.5 h. The reaction was diluted in DCM (50 mL), quenched with saturated NaHCO ₃ aqueous solution and extracted with DCM/IPA (4:1). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by FSC (elution gradient: 75%-100% EtOAc in hexanes and then 0 to 12% MeOH in EtOAc) followed by lyophilization gave the title compound (18.9 mg, 50.0%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.21 - 1.34 (5H, m), 1.39 (2H, br s), 1.63 - 1.90 (8H, m), 1.99 (6H, br s), 2.21 (2H, br d), 2.48 - 2.62 (6H, m, overlapped with residual solvent), 2.69 (2H, q), 2.76 (2H, t), 2.99 - 3.09 (4H, m), 3.25 - 3.43 (4H, m, overlapped with residual water), 3.81 (2H, t), 4.54 - 4.66 (3H, m), 5.97 (2H, s), 6.51 (1H, s), 6.58 (1H, br d), 6.83 - 6.92 (2H, m), 7.23 (1H, t), 7.44 (1H, d), 7.50 (1H, s), 7.55 (1H, s), 7.87 - 7.92 (2H, m), 8.16 (1H, d), 10.37 (1H, s), 14.13 (1H, br s). ¹⁹ F NMR (DMSO-d6): -155.90 (1F, br s); m/z ES ⁺ [M+H] ⁺ = 921.8. Example 57 Intermediate 57a: N -tert-butyloxycarbonyl- N- [4-[8-(3-chloro-4-fluoro-phenyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalim-3-yl]carbamic acid tert-butyl ester

A vial was charged with intermediate 25d (812 mg, 1.5 mmol), 4-bromo-2-chloro-1-fluorobenzene (0.364 mL, 3.00 mmol), Cs ₂ CO ₃ (1466 mg, 4.50 mmol), Cphos (85 mg, 0.20 mmol), CPhosPdG 3 (157 mg, 0.20 mmol) and toluene (10 mL). The vial was bubbled with N 2 and heated at 100 °C for 3 h. The reaction was cooled to room temperature, filtered through celite®, eluted with EtOAc/DCM and concentrated. Purification by FSC (elution gradient: 0-80% EtOAc in hexanes) gave the title compound (668 mg, 66.5%) as an off-white dry film. ¹ H NMR: δ 1.39 (18H, s), 1.81 - 1.89 (2H, m), 1.94 - 1.99 (2H, m), 3.21 - 3.26 (2H, m), 3.27 (3H, s), 3.29 - 3.31 (2H, m), 4.45 (2H, br s), 5.22 (2H, s), 6.92 (1H, dt), 7.10 - 7.19 (2H, m), 7.21 - 7.29 (2H, m), 7.43 - 7.49 (1H, m), 7.54 (1H, s), 7.72 (1H, dd); m/z (ES ⁺ ) [M+H] ⁺ = 670.3. Intermediate 57b: N -tert-butyloxycarbonyl- N- [4-[8-[3-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tert-butyl ester

Prepared in an analogous manner to intermediate 56f starting with intermediate 57a (97 mg, 0.14 mmol) and intermediate 56e (63.3 mg, 0.12 mmol). Purification by FSC (25%-100% EtOAc in hexanes and then 0-20% MeOH in EtOAc) gave the title compound (56.2 mg, 40.2%) as a light yellow solid. m/z ES ⁺ [M+H] ⁺ = 1158.7. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting with intermediate 57b (49 mg, 0.04 mmol) in an analogous manner to Example 56. Purification by FSC (elution gradient: 0-100% EtOAc in hexanes and then 0 to 20% MeOH in EtOAc) followed by lyophilization afforded the title compound as an off-white solid (7.4 mg, 19.14%). ¹ H NMR (DMSO- d6 ): δ 1.21 - 1.34 (5H, m), 1.39 (2H, br s), 1.71 (4H, br s), 1.75 - 2.07 (10H, m), 2.14 (2H, br d), 2.44 - 2.61 (6H, m, Overlap with residual solvent), 2.70 (2H, q), 2.76 (2H, br t), 2.94 (2H, br t), 3.11 (2H, br d), 3.18 (2H, br d), 3.23 - 3.29 (2H, m), 3.81 (2H, br t), 4.38 (2H, br s), 4.61 (1H, br t), 5.94 (2H, br s), 6.46 (1H, br d), 6.53 (1H, br d), 6.82 - 6.91 (2H, m), 6.95 (1H, br dd), 7.23 (1H, br t), 7.47 (1H, s), 7.56 (1H, s), 7.86 - 7.98 (2H, m), 8.16 (1H, d), 10.37 (1H, s), 14.17 (1H, br s). ¹⁹ F NMR (DMSO- d6 ) δ -155.94 (1F, br s), -136.60 (1F, s); m/z ES ⁺ [M+H] ⁺ = 913.5. Example 58 Intermediate 58a: 1-[1-(3-azaspiro[5.5]undecane-9-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (2.3 mL, 30.26 mmol) was added to a solution of intermediate 13b (1.5 g, 3.03 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. DCM (100 mL), IPA (30 mL) and 5 M K ₂ CO ₃ were added and the phases were separated. The organic layer was washed with saturated aqueous K ₂ CO ₃ (2 x 100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The solid from the remaining aqueous layer of the extraction was filtered, redissolved in MeOH/DCM (1:3), concentrated and combined with the solid from the extraction to give the title compound as a white solid (1.09 g, 91%). ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.34 (4H, m), 1.61 (2H, br s), 1.69 (2H, br d), 1.84 (2H, br d), 1.94 - 2.07 (2H, m), 2.25 (3H, s), 2.70 (4H, br s), 2.76 (2H, t), 3.81 (2H, t), 4.53 - 4.67 (1H, m), 7.54 (1H, s), 7.87 (1H, d), 8.16 (1H, d), 10.37 (1H, br s) (NH not observed); m/z ES ⁺ [M+H] ⁺ = 396.4. Intermediate 58b: 3,3-difluoro-4-(trifluoromethylsulfonyloxymethyl)piperidine-1-carboxylic acid tributyl ester

A 100 mL round-bottom flask was charged with tributyl 3,3-difluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.56 g, 6.21 mmol), 2,6-lutidine (0.863 ml, 7.45 mmol) and DCM (17.33 ml), and the mixture was cooled to 0°C. Trifluoromethanesulfonic anhydride (1.149 ml, 6.83 mmol) was added dropwise over 5 min. The resulting mixture was stirred at 0°C for 2 h and quenched by the slow addition of 1 M aqueous NaHSO ₄ (7 mL). The layers were separated. The organic layer was washed with 1 M aqueous NaHSO ₄ solution (2 x 5 mL), saturated aqueous NaHCO ₃ solution (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (2.40 g, 100%) as a red liquid. ¹ H NMR (CD ₂ Cl ₂ ): 1.48 (9H, s), 1.60 - 1.70 (1H, m), 1.93 - 1.99 (1H, m), 2.39 - 2.53 (1H, m), 2.82 (1H, br s), 3.02 (1H, br s), 4.11 - 4.32 (1H, m), 4.39 (1H, br s), 4.54 (1H, dd), 4.86 (1H, dd). Intermediate 58c: 4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undecane-3-yl]methyl]-3,3-difluoro-piperidine-1-carboxylic acid tributyl ester

Intermediate 58b (750 mg, 1.96 mmol), intermediate 58a (619 mg, 1.57 mmol), DIPEA (820 μl, 4.70 mmol) and 1,4-dihydronaphthalene (7.0 ml) were stirred at 65 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by FSC (0-20% MeOH in DCM) gave the title compound (891 mg, 91%) as a solid. m/z ES ⁺ [M+H] ⁺ = 629.4. Intermediate 58d: rel -(4 R *)-4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-piperidine-1-carboxylic acid tributyl ester [*absolute configuration has not been confirmed] (4 R )-4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-piperidine-1-carboxylic acid tributyl ester or (4 S )-4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-piperidine-1-carboxylic acid tributyl ester

Intermediate 58c (racemic) (664 mg) was purified by chiral SFC (column: OJ-H 30 mm x 250 5 µm, MeOH/0.2% NH ₄ OH) to give the title compounds: Isomer 1 (180 mg) as a solid, which eluted first from the column, and Isomer 2 (193 mg) as a solid, which eluted second from the column. Isomer 1: m/z ES ⁺ [M+H] ⁺ = 629.5. Isomer 2: m/z ES ⁺ [M+H] ⁺ = 629.5. Intermediate 58e: 1-[3-methyl-1-[3-[[ rel -(4 R * )-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*The absolute configuration has not been confirmed] 1-[3-methyl-1-[3-[[(4 R )-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[3-[[(4 S )-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 2c starting from intermediate 58d, isomer 2 (193 mg, 0.31 mmol). Purification by ion exchange chromatography (PoraPak Rxn CX cartridge) (eluting with 2.9 N NH ₃ in MeOH and 2.9 N NH ₃ in MeOH/DCM) gave the title compound (155 mg, 96%) as a white solid. m/z ES ⁺ [M+H] ⁺ = 529.4. Intermediate 58f: N -tert-butyloxycarbonyl- N- [4-[8-[4-fluoro-3-[ rel -(4 R* )-4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalimer-3-yl]carbamic acid tert-butyl ester (isomer 2) [*Absolute configuration has not been confirmed] N -tert-butyloxycarbonyl- N- [4-[8-[4-fluoro-3-[(4 R )-4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tributyl ester or N -tributyloxycarbonyl- N- [4-[8-[4-fluoro-3-[(4 S )-4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tributyl ester

Prepared in an analogous manner to intermediate 56f starting with intermediate 57a (114 mg, 0.17 mmol) and intermediate 58e, isomer 2 (75 mg, 0.14 mmol). Purification by FSC (elution gradient: 50%-100% EtOAc in hexanes and then 0-20% MeOH in EtOAc) gave the title compound (57 mg, 34.6%) as a tan solid. m/z ES ⁺ [M+H] ⁺ = 1162.7. 1-[3-Methyl-1-[3-[[ rel -(4 R* )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*Absolute configuration not confirmed] 1-[3-Methyl-1-[3-[[(4 R )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[3-[[(4 S )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting from intermediate 58f (56 mg, 0.05 mmol) in a similar manner to Example 56. Purification by RP-HPLC (Xselect CSH C18 OBD, 5 μm, 50%-95% ACN/0.2% NH ₄ OH) and freeze drying gave the title compound (22.00 mg, 49.7%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.35 (2H, m), 1.39 (2H, br s), 1.53 (1H, q), 1.61 - 1.74 (4H, m), 1.80 (2H, br s), 1.89 - 2.07 (5H, m), 2.11 - 2.23 (3H, m), 2.23 - 2.33 (5H, m), 2.38 (2H, br t), 2.44 - 2.52 (1H, m, overlapped with residual solvent), 2.52 - 2.59 (1H, m), 2.72 - 2.85 (3H, m), 3.02 - 3.16 (3H, m), 3.22 - 3.29 (2H, m), 3.35 - 3.44 (1H, m, overlapped with residual water), 3.50 - 3.62 (1H, m), 3.81 (2H, t), 4.39 (2H, br s), 4.60 (1H, br t), 5.96 (2H, s), 6.45 - 6.55 (2H, m), 6.84 - 6.91 (2H, m), 6.97 (1H, dd), 7.23 (1H, t), 7.47 (1H, s), 7.55 (1H, s), 7.87 (1H, d), 7.91 (1H, d), 8.17 (1H, d), 10.40 (1H, s), 14.19 (1H, br s); ¹⁹ F NMR (DMSO- d6 ): δ -136.73 (1F, s), -113.73 (1F, br d), -103.22 (1F, br d); m/z ES ⁺ [M+H] ⁺ = 918.6. Example 59: Intermediate 59a: 4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undecane-3-yl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 56d starting with intermediate 54a (440 mg, 1.11 mmol) and intermediate 25e (569 mg, 1.56 mmol). Purification by FSC (elution gradient: 0-20% MeOH in EtOAc with 10% DCM modifier) gave the title compound as a solid (721 mg, 106%). m/z ES ⁺ [M+H] ⁺ = 611.6. Intermediate 59b: 1-[1-[3-[(4-fluoro-4-piperidinyl)methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in analogy to intermediate 2c starting with intermediate 59a (177 mg, 0.29 mmol) in DCM (937 µl). Purification by ion exchange chromatography (PoraPak Rxn CX cartridge) (eluting with 2.9 N NH ₃ in MeOH and 2.9 N NH ₃ in MeOH/DCM) gave the title compound (123 mg, 83%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.34 (2H, m), 1.34 - 1.41 (2H, m), 1.49 - 1.63 (2H, m), 1.64 - 1.74 (6H, m), 1.80 (2H, br d), 1.92 - 2.04 (2H, m), 2.25 (3H, s), 2.42 - 2.50 (6H, m), 2.64 - 2.73 (4H, m), 2.76 (2H, t), 3.81 (2H, t), 4.55 - 4.64 (1H, m), 7.54 (1H, s), 7.87 (1H, d), 8.16 (1H, d), 10.37 (1H, br s) (piperidinyl NH not observed); m/z ES ⁺ [M+H] ⁺ = 511.4. Intermediate 59c: N -tert-butyloxycarbonyl- N- [4-[8-[4-cyano-3-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tert-butyl ester

Prepared in a similar manner to intermediate 56g starting with intermediate 56f (103 mg, 0.15 mmol) and intermediate 59c (65 mg, 0.13 mmol). Purification by FSC (elution gradient: 50%-100% EtOAc in hexanes and then 0-20% MeOH in EtOAc) gave the title compound (67.6 mg, 46.1%) as a tan solid. m/z ES ⁺ [M+H] ⁺ = 1151.8. 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile

Prepared starting with intermediate 59c (67 mg, 0.06 mmol) in an analogous manner to Example 56. Purification by FSC (elution gradient: 25%-100% EtOAc in hexanes and then 0-20% MeOH in EtOAc) and lyophilization afforded the title compound as an off-white solid (27.8 mg, 52.7%). ¹ H NMR (DMSO- d6 ): δ 1.21 - 1.34 (2H, m), 1.39 (2H, br s), 1.69 (4H, br s), 1.75 - 1.91 (4H, m), 1.93 - 2.04 (6H, m), 2.21 (2H, br d), 2.25 (3H, s), 2.47 - 2.62 (6H, m, overlapped with residual solvent), 2.76 (2H, t), 2.99 - 3.09 (4H, m), 3.23 - 3.43 (4H, m, overlapped with residual water), 3.81 (2H, t), 4.59 (3H, br s), 5.98 (2H, br s), 6.51 (1H, s), 6.58 (1H, br d), 6.83 - 6.91 (2H, m), 7.23 (1H, br t), 7.43 (1H, d), 7.50 (1H, s), 7.54 (1H, s), 7.84 - 7.88 (1H, m), 7.90 (1H, br d), 8.12 - 8.19 (1H, m), 10.37 (1H, s), 14.13 (1H, br s); ¹⁹ F NMR (DMSO- d6 ): δ -155.90 (1F, br s); m/z ES+ [M+H] ⁺ = 907.7. Example 60: Intermediate 60a: 1-[3-methyl-1-[3-[[ rel- (4R * )-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration has not been confirmed] 1-[3-methyl-1-[3-[[( 4R )-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[3-[[( 4S )-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 2c starting from intermediate 58d, isomer 1 (129 mg, 0.21 mmol). Purification by ion exchange chromatography (PoraPak Rxn CX cartridge) (eluting with 2.9 N NH ₃ in MeOH and 2.9 N NH ₃ in MeOH/DCM) gave the title compound (109 mg, 100%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.19 - 1.44 (5H, m), 1.62 - 1.74 (4H, m), 1.75 - 1.84 (2H, m), 1.87 (1H, br d), 1.92 - 2.04 (2H, m), 2.04 - 2.18 (1H, m), 2.20 - 2.33 (6H, m), 2.41 - 2.57 (4H, m), 2.63 - 2.80 (3H, m), 2.85 (1H, br dd), 2.95 - 3.04 (1H, m), 3.81 (2H, t), 4.55 - 4.63 (1H, m), 7.54 (1H, s), 7.87 (1H, d), 8.16 (1H, d), 10.37 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -116.39 (1F, br dd), -104.75 (1F, br d); m/z ES ⁺ [M+H] ⁺ = 529.5. Intermediate 60b: 1-[3-methyl-1-[3-[[ rel- ( 4R *)-1-(5-chloro-2-fluoro-phenyl)-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration has not been confirmed] 1-[3-methyl-1-[3-[[( 4R* )-1-(5-chloro-2-fluoro-phenyl)-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[3-[[(4 S )-1-(5-chloro-2-fluoro-phenyl)-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Pd(dba) ₂ (23.49 mg, 0.04 mmol), tBuPhCphos (24.79 mg, 0.06 mmol), intermediate 60a (isomer 1) (108 mg, 0.20 mmol) and K ₂ CO ₃ (85 mg, 0.61 mmol) were sealed in a vial and then evacuated and backfilled with nitrogen three times. 2-Bromo-4-chloro-1-fluorobenzene (49.8 μL, 0.41 mmol) and 1,4-dioxathiazole (1943 μL) were added. The mixture was stirred at 100°C for 15 h and cooled to room temperature. Another portion of Pd(dba) ₂ (11.75 mg, 0.02 mmol) and tBuPhCPhos (12.40 mg, 0.03 mmol) was added, the reaction was sparged with nitrogen, stirring continued at 100 °C for 7 h, and cooled to room temperature. Another portion of Pd(dba) ₂ (11.75 mg, 0.02 mmol), tBuPhCPhos (12.40 mg, 0.03 mmol), and 2-bromo-4-chloro-1-fluorobenzene (50 μL, 0.41 mmol) was added; the reaction was sparged with nitrogen; stirred at 100 °C for another 16 h; and cooled to room temperature. The reaction was concentrated to dryness under reduced pressure, and the crude material was triturated with Et ₂ O and filtered. The solid was suspended in MeOH/DCM and filtered. The solution was mixed with Celite® and concentrated in vacuo. Purification by FSC (elution gradient: 0-20% MeOH in DCM) gave the title compound (54.1 mg, 40.3%) as a solid. ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.36 (3H, m), 1.40 (2H, br s), 1.46 - 1.60 (1H, m), 1.66 - 1.75 (4H, m), 1.81 (2H, br s), 1.94 - 2.08 (3H, m), 2.21 - 2.33 (5H, m), 2.38 (1H, br t), 2.45 - 2.53 (2H, m, overlapped with residual solvent), 2.56 (1H, br d), 2.76 (2H, t), 2.88 (1H, br t), 3.09 - 3.20 (1H, m), 3.37 - 3.45 (1H, m), 3.54 - 3.65 (1H, m), 3.81 (2H, t), 4.55 - 4.66 (1H, m), 7.03 (1H, dt), 7.10 (1H, dd), 7.20 (1H, dd), 7.55 (1H, s), 7.87 (1H, d), 8.17 (1H, d), 10.37 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -124.53 (1F, s), -113.98 (1F, br d), -103.65 (1F, br d); m/z ES ⁺ [M+H] ⁺ = 657.5. Intermediate 60c: N -tert-butyloxycarbonyl- N- [4-[8-[4-fluoro-3-[ rel- (4 R *)-4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalimer-3-yl]carbamic acid tert-butyl ester (isomer 1) [*The absolute configuration has not been confirmed] N -tert-butyloxycarbonyl- N- [4-[8-[4-fluoro-3-[(4 R )-4-[[9-[5-(2,4-dioxohexahydroxypyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalimide-3-yl]carbamic acid tributyl ester or N -tributyloxycarbonyl- N- [4-[8-[4-fluoro-3-[(4 S )-4-[[9-[5-(2,4-dioxohexahydroxypyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b [3-(2-(methoxymethoxy)phenyl)pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-3,3-difluoro-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]carbamic acid tributyl ester

Intermediate 25d (49.5 mg, 0.09 mmol), intermediate 60b, isomer 1 (50 mg, 0.08 mmol), Cs ₂ CO ₃ (18.26 μl, 0.23 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (12.78 mg, 0.02 mmol) were sealed in a vial with a stir bar. The vial was evacuated and backfilled with nitrogen three times. 1,4-Dihydrogen iodide (743 μl) was added and the reaction was stirred at 100°C for 16 h and cooled to room temperature. The crude reaction mixture was diluted with DCM/MeOH, filtered through celite® and concentrated under reduced pressure. Purification by FSC (elution gradient: 75% to 100% EtOAc and then 20% MeOH in EtOAc) gave the title compound (26.8 mg, 30.3%) as a white solid. m/z ES ⁺ [M+H] ⁺ = 1162.8. 1-[3-Methyl-1-[3-[[ rel -(4 R* )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration not confirmed] 1-[3-Methyl-1-[3-[[(4 R* )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[3-[[(4 S )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 60c (27 mg, 0.02 mmol) in a similar manner to Example 56. Purification by RP-HPLC (Xselect CSH C18 OBD, 5 μm, 25%-50% ACN/0.1% FA) and freeze drying gave the title compound as a solid (5.50 mg, 25.8%). ¹ H NMR (DMSO- d6 ): δ 1.25 - 1.34 (2H, m), 1.35 - 1.45 (2H, m), 1.49 - 1.58 (1H, m), 1.65 - 1.74 (4H, m), 1.80 (2H, br s), 1.91 - 2.07 (5H, m), 2.13 (2H, br d), 2.16 - 2.34 (6H, m), 2.35 - 2.42 (1H, m), 2.46 - 2.53 (1H, m, overlapped with residual solvent), 2.54 - 2.60 (1H, m), 2.72 - 2.85 (3H, m), 3.03 - 3.15 (3H, m), 3.22 - 3.29 (2H, m), 3.49 - 3.62 (1H, m, overlapped with water), 3.80 (2H, t), 4.38 (2H, br s), 4.54 - 4.63 (1H, m), 5.93 (2H, s), 6.47 - 6.52 (2H, m), 6.84 - 6.89 (2H, m), 6.97 (1H, dd), 7.23 (1H, t), 7.46 (1H, s), 7.54 (1H, s), 7.87 (1H, d), 7.89 (1H, dd), 8.16 (1H, d), 10.38 (1H, s), 13.22 - 15.00 (1H, m) (two unassigned Hs are broadened around the residual water signal beyond the detection range); ¹⁹ F NMR (DMSO- d6 ): δ -194.42 (1F, s), -190.03 (1F, s), -136.71 (1F, br s), -113.71 (1F, br d), -103.20 (1F, br d); m/z ES ⁺ [M+H] ⁺ = 918.6. Example 61: Intermediate 61a: 9-(5-Bromo-4-methyl-indol-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a from tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (0.914 g, 3.39 mmol), 5-bromo-4-methyl- 1H -indole (0.475 g, 2.26 mmol) and 2-( tributyl -15-phosphino)acetonitrile (0.889 ml, 3.39 mmol). Purification by FSC (elution gradient: 0-12% EtOAc in hexanes) gave the title compound (478 mg, 45.8%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.36 - 1.46 (4H, m), 1.48 (9H, s), 1.63 - 1.69 (2H, m), 1.87 - 2.01 (6H, m), 2.60 (3H, s), 3.40 - 3.46 (4H, m), 4.22 (1H, tt), 6.56 (1H, d), 7.15 (1H, d), 7.29 (1H, d), 7.34 (1H, d); m/z (ES ⁺ ), [M+H] ⁺ = 461.4. Intermediate 61b: 9-[5-[(3-ethoxy-3-oxopropyl)amino]-4-methyl-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester and 9-[5-[(3-methoxy-3-oxopropyl)amino]-4-methyl-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 14b starting from intermediate 61a (250 mg, 0.54 mmol) with addition of tBuBrettPhos (26.3 mg, 0.05 mmol). The reaction was diluted with EtOAc and MeOH, filtered through celite® and concentrated and adsorbed onto Celite® under reduced pressure. Purification by FSC (elution gradient: 0-25% EtOAc in hexanes) gave the title compound (165 mg, 61.2%) as an inseparable mixture of ethyl and methyl esters as a yellow solid. Ethyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 498.6; Methyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 484.6. Intermediate 61c: 9-[5-[aminoformyl-(3-ethoxy-3-oxopropyl)amino]-4-methyl-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester and 9-[5-[aminoformyl-(3-methoxy-3-oxopropyl)amino]-4-methyl-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 14c starting from intermediate 61b (159 mg, 0.32 mmol) to give the title compound as a mixture of ethyl and methyl esters. The material was carried forward to the next step without purification, assuming quantitative yield. Ethyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 541.6; Methyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 527.6. Intermediate 61d: 9-[5-(2,4-Dioxohexahydroxypyrimidin-1-yl)-4-methyl-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 14d starting from intermediate 61c (169 mg, 0.32 mmol). Purification by FSC (elution gradient: 0-10% MeOH in DCM) gave the title compound (125 mg, 79%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.39 - 1.47 (4H, m), 1.48 (9H, s), 1.67 (2H, br t), 1.88 - 2.04 (6H, m), 2.45 (3H, s), 2.81 - 2.93 (2H, m), 3.41 - 3.48 (4H, m), 3.66 - 3.74 (1H, m), 3.81 - 3.88 (1H, m), 4.20 - 4.32 (1H, m), 6.61 (1H, d), 7.04 (1H, d), 7.31 (1H, d), 7.35 (1H, d), 7.54 (1H, s); m/z ES+ [M+H] ⁺ = 495.5. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 61d (28.8 mg, 0.06 mmol) and intermediate 11g (30.7 mg, 0.05 mmol) in a similar manner to Example 51. Purification by FSC (elution gradient: 0-20% MeOH in DCM) and freeze drying gave the title compound (25.07 mg, 58.6%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.10 - 1.53 (7H, m), 1.60 - 1.83 (8H, m), 1.84 - 2.01 (5H, m), 2.14 (2H, br d), 2.18 - 2.49 (8H, m), 2.61 - 2.83 (4H, m), 3.11 (2H, br d), 3.23 - 3.29 (2H, m), 3.30 - 3.40 (2H, m, overlapped with residual water), 3.49 - 3.58 (1H, m), 3.74 (1H, ddd), 4.26 - 4.41 (3H, m), 5.94 (2H, s), 6.39 - 6.50 (2H, m), 6.52 (1H, d), 6.84 - 6.90 (2H, m), 6.93 (1H, dd), 7.00 (1H, d), 7.23 (1H, t), 7.37 (1H, d), 7.47 (1H, s), 7.57 (1H, d), 7.91 (1H, d), 10.24 (1H, s), 14.16 (1H, br s). ¹⁹ F NMR (DMSO- d6 ): -136.38 (1F, s); m/z (ES ⁺ ) [M+H] ⁺ = 881.7. Example 62: Intermediate 62a: 9-(5-bromo-4-fluoro-indol-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a from tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1.05 g, 3.90 mmol), 5-bromo-4-fluoro- 1H -indole (0.556 g, 2.60 mmol) and 2-( tributyl -15-phosphino)acetonitrile (1.090 ml, 4.16 mmol). Purification by FSC (elution gradient: 0-25% EtOAc in hexanes) gave the title compound (285 mg, 23.57%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.37 - 1.46 (4H, m), 1.46 - 1.51 (9H, m), 1.63 - 1.68 (2H, m), 1.87 - 2.03 (6H, m), 3.41 - 3.47 (4H, m), 4.18 - 4.27 (1H, m), 6.61 (1H, d), 7.13 (1H, d), 7.27 - 7.33 (2H, m); ¹⁹ F NMR (CD ₂ Cl ₂ ): δ -116.87 (1F, s); m/z (ES ⁺ ), [M+H] ⁺ = 465.1. Intermediate 62b: 9-[5-[(3-ethoxy-3-oxopropyl)amino]-4-fluoro-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 14b starting from intermediate 62a (250 mg, 0.54 mmol) with addition of tBuBrettPhos (26.0 mg, 0.05 mmol). Purification by FSC (elution gradient: 0-50% EtOAc in hexanes) gave the title compound (211 mg, 78%) as a yellow solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.29 (3H, t), 1.37 - 1.46 (4H, m), 1.48 (9H, s), 1.65 (2H, br s), 1.87 - 2.02 (6H, m), 2.63 (2H, t), 3.40 - 3.46 19 F NMR ₍ CD ₂ Cl ² ): δ -145.81 (1F, s); m/z (ES ⁺ ) [M+H] ⁺ = 502.6. Intermediate 62c: 9-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-4-fluoro-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

The title compound was prepared starting from intermediate 62b (210 mg, 0.42 mmol) in an analogous manner to intermediate 14c. The material was carried forward to the next step without purification, assuming quantitative yield. m/z (ES ⁺ ) [M+H] ⁺ = 545.6. Intermediate 62d: 9-[5-(2,4-Dioxohexahydroxypyrimidin-1-yl)-4-fluoro-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 14d starting from intermediate 62c (229 mg, 0.42 mmol). Purification and concentration by FSC (elution gradient: 0-10% MeOH in DCM) afforded the title compound (184 mg, 88%). ¹ H NMR (CD ₂ Cl ₂ ): δ 1.39 - 1.46 (4H, m), 1.48 (9H, s), 1.64 - 1.69 (2H, m), 1.90 - 2.03 (6H, m), 2.87 (2H, t), 3.41 - 3.47 (4H, m), 3.84 (2H, t), 4.21 - 4.31 (1H, m), 6.66 (1H, d), 7.11 (1H, dd), 7.25 (1H, d), 7.33 (1H, d), 7.61 (1H, s); ¹⁹ F NMR (CD ₂ Cl ₂ ): δ -130.40 (1F, s). m/z (ES ⁺ ) [M+H] ⁺ = 499.5. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 62d (28.4 mg, 0.06 mmol) and intermediate 11g (30 mg, 0.05 mmol) in a similar manner to Example 51. Purification by FSC (elution gradient: 0-20% MeOH in DCM) and freeze drying gave the title compound (22.6 mg, 53.9%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.20 - 1.49 (6H, m), 1.57 - 1.73 (3H, m), 1.78 (6H, br s), 1.87 - 2.04 (5H, m), 2.06 - 2.27 (4H, m), 2.28 - 2.47 (3H, m), 2.65 (2H, br t), 2.74 (2H, t), 3.11 (2H, br d), 3.24 - 3.30 (2H, m), 3.30 - 3.41 (2H, m, overlapped with residual water), 3.72 (2H, t), 4.30 - 4.41 (3H, m), 5.94 (2H, s), 6.39 - 6.51 (2H, m), 6.55 (1H, d), 6.83 - 6.97 (3H, m), 7.11 (1H, t), 7.23 (1H, t), 7.40 (1H, d), 7.47 (1H, s), 7.66 (1H, d), 7.91 (1H, d), 10.39 (1H, s), 14.16 (1H, br s); ¹⁹ F NMR (DMSO- d6 ): δ -136.37 (1F, s), -130.31 (1F, s); m/z (ES ⁺ ) [M+H] ⁺ = 885.7. Example 63: Intermediate 63a: 9-(5-Bromo-6-fluoro-indol-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4a starting from tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (0.959 g, 3.56 mmol) and 5-bromo-6-fluoro- 1H -indole (0.610 g, 2.85 mmol). Purification by FSC (elution gradient: 0-20% EtOAc in hexanes) gave the title compound (380.2 mg, 0.817 mmol, 28.7%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.36 - 1.46 (4H, m), 1.48 (9H, s), 1.62 - 1.69 (2H, m), 1.88 - 2.01 (6H, m), 3.40 - 3.47 (4H, m), 4.09 - 4.18 (1H, m), 6.49 (1H, d), 7.21 (1H, d), 7.30 (1H, d), 7.78 (1H, d); m/z (ES ⁺ ) [M+2H] ⁺ = 467.3. Intermediate 63b: 9-[5-[(3-ethoxy-3-oxopropyl)amino]-6-fluoro-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester and 9-[6-fluoro-5-[(3-methoxy-3-oxopropyl)amino]indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 14b starting from intermediate 63a (200 mg, 0.43 mmol) with addition of tBuBrettPhos (20.83 mg, 0.04 mmol). The reaction mixture was diluted with EtOAc/MeOH, filtered through celite® and concentrated under reduced pressure. Purification by FSC (elution gradient: 0-25% EtOAc in hexanes) gave the title compound (185 mg, 86%) as a solid as an inseparable mixture of ethyl and methyl esters. Ethyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 502.5; methyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 488.5. Intermediate 63c: 9-[5-[aminoformyl-(3-ethoxy-3-oxopropyl)amino]-6-fluoro-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester and 9-[5-[aminoformyl-(3-methoxy-3-oxopropyl)amino]-6-fluoro-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared analogously to intermediate 14c starting from intermediate 63b (185 mg, 0.37 mmol) to give a mixture of the title compounds. Proceeded to the next step without purification, assuming quantitative yield. Ethyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 545.5; Methyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 531.5. Intermediate 63d: 9-[5-(2,4-dioxohexahydroxypyrimidin-1-yl)-6-fluoro-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 14d starting from intermediate 63c (0.37 mmol). Purification by FSC (elution gradient: 0-17% MeOH in DCM) gave the title compound (134 mg, 72.6%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.38 - 1.46 (4H, m), 1.48 (9H, s), 1.63 - 1.69 (2H, m), 1.88 - 2.03 (6H, m), 2.87 (2H, t), 3.39 - 3.48 (4H, m), 3.83 (2H, t), 4.11 - 4.22 (1H, m), 6.56 (1H, d), 7.22 (1H, d), 7.33 (1H, d), 7.50 - 7.62 (2H, m); m/z (ES ⁺ ) [M+Na] ⁺ = 521.2. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 63d (42.5 mg, 0.09 mmol) and intermediate 11g (45 mg, 0.07 mmol) in a similar manner to Example 51. Purification by FSC (elution gradient: 0-20% MeOH in DCM) and freeze drying gave the title compound (34.5 mg, 54.8%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.13 - 1.53 (7H, m), 1.54 - 2.05 (13H, m), 2.10 - 2.27 (4H, m), 2.37 (3H, br s), 2.61 - 2.69 (2H, m), 2.74 (2H, br t), 3.11 (2H, br d), 3.24 - 3.29 (2H, m), 3.30 - 3.39 (2H, m), 3.71 (2H, br t), 4.26 - 4.39 (3H, m), 5.94 (2H, s), 6.39 - 6.52 (3H, m), 6.82 - 6.97 (3H, m), 7.23 (1H, t), 7.47 (1H, s), 7.51 - 7.57 (2H, m), 7.61 (1H, d), 7.91 (1H, br d), 10.38 (1H, s), 14.17 (1H, br s). ¹⁹ F NMR (DMSO- d 6): -136.38 (1F, s), -129.61 (1F, s); m/z (ES ⁺ ) [M+H] ⁺ = 885.7. Example 64: Intermediate 64a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-3-ethyl-pyrrolo[2,3- b ]pyridine

A flask was charged with 5-bromo-3-ethyl- 1H -pyrrolo[2,3- b ]pyridine (2.70 g, 12 mmol, prepared according to literature procedure: WO 2022087634 A1), 1,3-bis(allyloxy)propan-2-ol (3.16 ml, 18.00 mmol) and toluene (48 ml). 2-(tributyl- 15 -phosphine)acetonitrile (4.72 ml, 18.00 mmol) was added. The flask was equipped with a reflux condenser, and the mixture was stirred at 100°C for 2 h, cooled to room temperature and concentrated in vacuo. Purification by FSC (0-20% EtOAc in hexanes) gave the title compound (3.42 g, 75%) as a colorless oil. ¹ H NMR (DMSO- d6 ): δ 1.24 (3H, t), 2.69 (2H, q), 3.74 - 3.81 (2H, m), 3.82 - 3.88 (2H, m), 3.89 - 3.95 (4H, m), 5.06 - 5.18 (5H, m), 5.78 (2H, ddt), 7.49 (1H, s), 8.18 (1H, d), 8.27 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 379.3. Intermediate 64b: 2-(5-Bromo-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl)propane-1,3-diol

A flask was charged with intermediate 64a (3.4234 g, 9.03 mmol), 1,3-dimethylbarbituric acid (2.82 g, 18.05 mmol) and MeOH (90 ml). The solution was bubbled with _N2 for 5 min, then Pd( _PPh3 ) ₄ (0.521 g, 0.45 mmol) was added. The solution was bubbled with _N2 for 5 min and stirred at room temperature for 22 h, then concentrated in vacuo. The crude residue was purified by FSC (0-100% EtOAc in hexanes). The residue was triturated with (5:1) hexanes/DCM and collected by vacuum filtration to give the title compound as a red solid (2.60 g, 96%). ¹ H NMR (DMSO- d6 ): δ 1.25 (3H, t), 2.69 (2H, q), 3.79 (4H, d), 4.79 (1H, quin), 4.90 (2H, br s), 7.46 (1H, s), 8.18 (1H, d), 8.25 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 299.2. Intermediate 64c: 4,4-dimethoxypiperidine-1-carboxylic acid benzyl ester

A flask equipped with a reflux condenser was charged with benzyl 4-oxopiperidine-1-carboxylate (5.83 g, 25 mmol), PPTS (0.314 g, 1.25 mmol) and MeOH (100 mL). The reaction was stirred at 70 °C for 16 h. After cooling to room temperature, the reaction was diluted with DCM (200 mL), washed with saturated aqueous NaHCO ₃ solution (2 x 200 mL), brine (200 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The title compound (6.68 g, 96%) was obtained as a light yellow oil. ¹ H NMR (CDCl ₃ ): δ 1.75 (4H, br s), 3.22 (6H, s), 3.50 - 3.55 (4H, m), 5.15 (2H, s), 7.32 - 7.43 (5H, m). Intermediate 64d: 3-(5-Bromo-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

A flask equipped with a reflux condenser was charged with intermediate 64b (1.3733 g, 4.59 mmol), intermediate 64c (1.966 g, 7.04 mmol), PPTS (0.058 g, 0.23 mmol) and toluene (25 mL). The reaction was stirred at 110 °C for 2 h, then cooled to room temperature and concentrated in vacuo. Purification by FSC (0-75% EtOAc in hexanes, then 0-40% acetone in hexanes) gave the title compound (1.505 g, 63.7%) as a colorless dry film. ¹ H NMR (DMSO- d6 ): δ 1.26 (3H, t), 1.89 (2H, br d), 1.97 - 2.03 (2H, m), 2.72 (2H, q), 3.47 (4H, br d), 4.04 (2H, dd), 4.33 (2H, br d), 4.79-4.84 (1H, m), 5.10 (2H, s), 7.30-7.35 (1H, m), 7.36-7.42 (4H, m), 7.74 (1H, s), 8.23 (1H, d), 8.29 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 513.9. Intermediate 64e: 3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 64d (1.505 g, 2.93 mmol). The crude material was purified by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-20% MeOH in EtOAc). The material was triturated with water to give the title compound as a brown solid (0.664 g, 41.4%). ¹ H NMR (DMSO- d6 ): δ 1.28 (3H, t), 1.89 - 2.02 (4H, m), 2.69 - 2.79 (4H, m), 3.43 - 3.53 (4H, m), 3.82 (2H, t), 4.08 (2H, br dd), 4.32 (2H, br d), 4.87 (1H, quin), 5.10 (2H, s), 7.31 - 7.36 (1H, m), 7.36 - 7.41 (4H, m), 7.72 (1H, s), 7.96 (1H, d), 8.20 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 548.1. Intermediate 64f: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 64e (664 mg, 1.21 mmol), DMF (6 mL) and Pd/C (129 mg, 0.12 mmol). _H2 was bubbled through the mixture for 10 min, and the resulting mixture was stirred under _H2 atmosphere for 4 h. The mixture was bubbled with _N2 , filtered through a pad of celite®, washed with DCM (50 mL) and concentrated in vacuo. The crude residue was dissolved in DCM (3 mL), and hexanes (50 mL) were added to precipitate a solid. The solid was collected by vacuum filtration, washed with _Et2O and dried to give the title compound (380 mg, 76%) as a grey solid. ¹ H NMR (DMSO- d6 ): δ 1.28 (3H, t), 1.78 - 1.92 (4H, m), 2.66 - 2.81 (8H, m), 3.82 (2H, t), 4.04 (2H, dd), 4.29 (2H, dd), 4.83 (1H, quin), 7.74 (1H, s), 7.96 (1H, d), 8.19 (1H, d), 10.38 (1H, br s) (NH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 414.1. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 13d (50.3 mg, 0.1 mmol), intermediate 64f (45.5 mg, 0.11 mmol), DCM (1 mL) and MeOH (0.2 mL). The mixture was stirred at room temperature for 20 min, then Na(OAc) ₃ BH (42.4 mg, 0.20 mmol) was added. The reaction was stirred at room temperature for 10 min, then concentrated in vacuo. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (45.4 mg, 49.2%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.18 - 1.33 (5H, m), 1.56 - 1.70 (1H, m), 1.80 (2H, br d), 1.89 - 2.05 (6H, m), 2.10 - 2.18 (2H, m), 2.22 (2H, br 4.04 (2H, br dd), 4.25 - 4.44 (4H, m), 4.80 - 4.88 (1H, m), 5.94 (2H, s), 6.43 (1H, dt), 6.47 - 6.51 (1H, m), 6.84 - 6.90 (2H, m), 6.93 (1H, dd), 7.21 - 7.26 (1H, m), 7.47 (1H, s), 7.74 (1H, s), 7.91 (1H, dd), 7.96 (1H, d), 8.20 (1H, d), 10.39 (1H, s), 13.13 - 14.96 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 900.5. Example 65: Intermediate 65a: 3,3-dimethoxypyrrolidine-1-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 64c starting from benzyl 3-oxopyrrolidine-1-carboxylate (2.192 g, 10 mmol). The title compound was obtained as a light yellow oil (2.476 g, 93%). ¹ H NMR (CDCl ₃ ) δ 2.07 (2H, q), 3.27 (6H, d), 3.48 - 3.57 (4H, m), 5.15 (2H, s), 7.31 - 7.41 (5H, m).; m/z (ES ⁺ ) [M+Na] ⁺ = 288.2. Intermediate 65b: ( 5s , 8s )-8-(5-bromo-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 64d starting from intermediate 64b (1047 mg, 3.5 mmol) and intermediate 65a (1857 mg, 7.00 mmol). Purification by FCS (0-75% EtOAc in hexanes) isolated the desired non-mirror image isomer, which eluted second from the column. This material was subsequently purified by RPC (elution gradient: 50%-100% MeCN in water containing 0.1% HCOOH) to give the title compound (467 mg, 26.7%) as a colorless dry film. ¹ H NMR (DMSO- d6 ): δ 1.18 - 1.35 (3H, m), 2.28 - 2.40 (2H, m), 2.71 (2H, q), 3.39 - 3.55 (2H, m), 3.65 (2H, br d), 4.10 (2H, dd), 4.27 - 4.40 (2H, m), 4.85 (1H, br dd), 5.10 (2H, d), 7.28 - 7.48 (5H, m), 7.74 (1H, br d), 8.23 (1H, d), 8.28 (1H, br d); m/z (ES ⁺ ) [M+H] ⁺ = 500. Intermediate 65c: ( 5s , 8s )-8-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 65b (467 mg, 0.93 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-20% MeOH in EtOAc) followed by trituration with water afforded the title compound as a beige solid (224 mg, 44.9%). ¹ H NMR (DMSO- d6 ): δ 1.28 (3H, q), 2.27 - 2.38 (2H, m), 2.68 - 2.83 (4H, m), 3.41 - 3.52 (2H, m), 3.68 (2H, br d), 3.82 (2H, t), 4.13 (2H, dd), 4.28 - 4.38 (2H, m), 4.84 - 4.96 (1H, m), 5.11 (2H, br d), 7.28 - 7.35 (1H, m), 7.35 - 7.45 (4H, m), 7.72 (1H, br d), 7.97 (1H, d), 8.20 (1H, br d), 10.39 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 534.7. Intermediate 65d: 1-[1-((5 s ,8 s )-6,10-dioxa-2-azaspiro[4.5]dec-8-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 64f starting from intermediate 65c (223 mg, 0.42 mmol) The title compound was obtained as an off-white solid (119 mg, 71.2%). ¹ H NMR (DMSO- d6 ): δ 1.28 (3H, t), 2.05 (2H, t), 2.68 - 2.81 (4H, m), 2.90 (2H, t), 2.98 (2H, s), 3.82 (2H, t), 4.06 (2H, dd), 4.30 (2H, dd), 4.81 - 4.88 (1H, m), 7.70 (1H, s), 7.97 (1H, d), 8.20 (1H, d), 10.39 (1H, br s) (NH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 400.6. Intermediate 65e: 4-[[(5 s ,8 s )-8-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-6,10-dioxa-2-azaspiro[4.5]dec-2-yl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 25f starting from intermediate 65d (96 mg, 0.24 mmol) and intermediate 25e (105 mg, 0.29 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes, 0-30% MeOH in EtOAc) gave the title compound (115 mg, 78%) as a beige solid. ¹ H NMR (DMSO- d6 ): δ 1.27 (3H, t), 1.40 (9H, s), 1.49 - 1.67 (2H, m), 1.75 - 1.88 (2H, m), 2.13 (2H, br t), 2.60 - 2.68 (2H, m), 2.69 - 2.81 (6H, m), 2.90 (2H, s), 2.97 - 3.10 (2H, m), 3.71 (2H, br d), 3.82 (2H, t), 4.04 (2H, dd), 4.32 (2H, dd), 4.78 - 4.85 (1H, m), 7.67 (1H, s), 7.97 (1H, d), 8.19 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 615.3. Intermediate 65f: 1-[3-ethyl-1-[(5 s ,8 s )-2-[(4-fluoro-4-piperidinyl)methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 65e (114.4 mg, 0.19 mmol). Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2N _NH3 in MeOH gave the title compound (83 mg, 86%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.28 (3H, t), 1.49 - 1.65 (2H, m), 1.66 - 1.77 (2H, m), 2.13 (2H, br t), 2.56 - 2.64 (2H, m), 2.68 - 2.79 (11H, m), 2.89 (2H, s), 3.82 (2H, t), 4.04 (2H, dd), 4.31 (2H, dd), 4.79 - 4.85 (1H, m), 7.68 (1H, s), 7.96 (1H, d), 8.19 (1H, d), 10.38 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 515.1. Intermediate 65g: N -tert-butyloxycarbonyl- N- [4-[8-[3-[4-[[(5 s ,8 s )-8-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-6,10-dioxa-2-azaspiro[4.5]dec-2-yl]methyl]-4-fluoro-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tert-butyl ester

A vial was charged with intermediate 65f (0.083 g, 0.16 mmol), intermediate 57a (0.108 g, 0.16 mmol), K ₂ CO ₃ (0.067 g, 0.48 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (0.027 g, 0.03 mmol) and dihydrogen sulfide (1.6 mL). The vial was bubbled with N ₂ and heated at 100 °C for 22 h. The reaction was cooled to room temperature, filtered through celite®, eluted with EtOAc/DCM and concentrated. Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (0.069 g, 37.0%) as a brown dry film. m/z (ES ⁺ ) [M+H] ⁺ = 1148.7. 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

In a vial, the intermediate 65g (68.5 mg, 0.06 mmol) was dissolved in DCM (2 mL) and TFA (0.4 mL). The reaction was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated aqueous NaHCO ₃ solution. The aqueous layer was extracted with DCM, dried over Na ₂ SO ₄ and concentrated. The resulting residue was suspended in ACN/H ₂ O, frozen, and dried by freeze drying. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (12.50 mg, 22.89%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.27 (3H, t), 1.73 - 2.02 (6H, m), 2.10 - 2.19 (4H, m), 2.66 - 2.81 (8H, m), 2.89 - 3.00 (4H, m), 3.10 (2H, br d), 3.16 - 3.21 (2H, m), 3.26 (2H, br d), 3.82 (2H, t), 4.05 (2H, dd), 4.28 - 4.43 (4H, m), 4.82 (1H, t), 5.93 (2H, s), 6.45 (1H, dt), 6.53 (1H, dd), 6.83 - 6.90 (2H, m), 6.95 (1H, dd), 7.20 - 7.25 (1H, m), 7.47 (1H, s), 7.68 (1H, s), 7.91 (1H, dd), 7.96 (1H, d), 8.20 (1H, d), 10.38 (1H, s), 13.65 - 14.53 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 904.5 Example 66: 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (25.1 mg, 0.05 mmol) and intermediate 65d (19.97 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (23.0 mg, 50.3%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.23 - 1.32 (5H, m), 1.53 - 1.66 (1H, m), 1.82 (2H, br d), 1.91 - 1.98 (2H, m), 2.10 - 2.18 (4H, m), 2.32 (2H, br d), 2.59 - 2.67 (4H, m), 2.68 - 2.79 (5H, m), 2.83 (2H, s), 3.11 (2H, br d), 3.23 - 3.28 (3H, m), 3.82 (2H, t), 4.05 (2H, br dd), 4.30 (2H, br dd), 4.35 (2H, br s), 4.77 - 4.92 (1H, m), 5.94 (2H, s), 6.44 (1H, dt), 6.47 - 6.52 (1H, m), 6.83 - 6.89 (2H, m), 6.93 (1H, dd), 7.21 - 7.26 (1H, m), 7.47 (1H, s), 7.69 (1H, s), 7.91 (1H, d), 7.97 (1H, d), 8.20 (1H, d), 10.38 (1H, s), 13.67 - 14.81 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 886.5. Example 67: Intermediate 67a: 3-(5-Bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (422 mg, 2 mmol) and tributyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (566 mg, 2.20 mmol). Purification by FSC (elution gradient: 0-25% acetone in hexanes) gave the title compound (341 mg, 37.9%) as a colorless dry film. ¹ H NMR (CDCl ₃ ): δ 1.47 (9H, s), 1.55 - 1.64 (1H, m), 1.67 - 1.75 (1H, m), 1.75 - 1.85 (2H, m), 1.96 (1H, dd), 2.28 (3H, d), 2.43 (1H, dd), 3.34 - 3.45 (2H, m), 3.57 - 3.69 (2H, m), 4.08 (1H, dd), 4.24 (1H, dd), 5.52 - 5.59 (1H, m), 7.19 (1H, d), 7.96 (1H, s), 8.30 (1H, d); m/z (ES ⁺ ) [M-tBu+2H] ⁺ = 394.0. Intermediate 67b: rel- (3 S * )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid benzyl ester (isomer 2) [*absolute configuration has not been confirmed] (3 S )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester or (3 R )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 67a (0.341 g, 0.76 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes, then 0-100%) gave the racemic material. The material was purified by chiral SFC (column: Chiralpak IH 21 x 250 mm, 5 µm, mobile phase: 80% CO ₂ , 20% MeOH w/0.2% NH ₄ OH, flow rate: 75 mL/min, BPR: 120 bar, column temperature: 40°C) to provide the title compound (102 mg, 28%) which eluted second from the column. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.52 - 1.62 (1H, m), 1.63 - 1.77 (3H, m), 2.03 (1H, dd), 2.27 (3H, s), 2.41 (1H, dd), 2.76 (2H, t), 3.26 - 3.31 (1H, m), 3.32 - 3.37 (1H, m), 3.42 - 3.50 (2H, m), 3.81 (2H, t), 3.99 (1H, dd), 4.18 (1H, dd), 5.45 - 5.52 (1H, m), 7.48 (1H, s), 7.91 (1H, d), 8.20 (1H, d), 10.39 (1H, s); m/z (ES ⁺ ) [M+Na] ⁺ = 506.1. Intermediate 67c: 1-[3-methyl-1-[ rel- (3S * )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not confirmed] 1-[3-methyl-1-[( 3S )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[( 3R )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 2c starting from intermediate 67b (102 mg, 0.21 mmol). Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2N _NH3 in MeOH gave the title compound (75 mg, 93%) as an off-white solid. ¹ H NMR (DMSO- d6 ): δ 1.54 - 1.61 (2H, m), 1.66 (2H, t), 1.96 (1H, dd), 2.27 (3H, s), 2.32 - 2.45 (1H, m), 2.52 - 2.63 (2H, m), 2.76 (2H, t), 2.85 (2H, dq), 3.21 - 3.46 (1H, m), 3.81 (2H, t), 3.94 (1H, dd), 4.14 (1H, dd), 5.43 - 5.48 (1H, m), 7.47 (1H, s), 7.90 (1H, d), 8.20 (1H, d), 10.08 - 10.76 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 384.6. 1-[3-Methyl-1-[ rel -(3 S* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*Absolute configuration not confirmed] 1-[3-Methyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (99 mg, 0.20 mmol) and intermediate 67c (75.2 mg, 0.20 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (81 mg, 45.5%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.20 - 1.31 (2H, m), 1.59 - 1.84 (7H, m), 1.91 - 2.02 (3H, m), 2.10 - 2.16 (2H, m), 2.23 (2H, br d), 2.27 (3H, s), 2.34 - 2.45 (3H, m), 2.47 - 2.50 (1H, m), 2.53 - 2.57 (1H, m), 2.60 - 2.69 (2H, m), 2.77 (2H, t), 3.10 (2H, br d), 3.20 - 3.30 (1H, m), 3.22 - 3.30 (1H, m), 3.35 3H, 4-nitro-1-ol (1H, 5-nitro-2-ol), 3.81 (2H, t), 3.96 (1H, dd), 4.15 (1H, dd), 4.34 (2H, br s), 5.46 (1H, quin), 5.94 (2H, s), 6.43 (1H, dt), 6.48 (1H, br dd), 6.82 - 6.99 (3H, m), 7.19 - 7.28 (1H, m), 7.47 (2H, s), 7.86 - 7.94 (2H, m), 8.20 (1H, d), 10.39 (1H, s) (phenolic OH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 870.5. Example 68: Intermediate 68a: rel -(3 S * )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester (isomer 1) [*The absolute configuration has not been confirmed] (3 S )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester or (3 R )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 67a (0.341 g, 0.76 mmol). Purification by FCS (0-100% EtOAc in hexanes then 0-100% MeOH in EtOAc) gave the racemic material. The material was purified by chiral SFC (column: Chiralpak IH 21 x 250 mm, 5 µm, mobile phase: 80% CO ₂ , 20% MeOH w/0.2% NH ₄ OH, flow rate: 75 mL/min, BPR: 120 bar, column temperature: 40°C) to afford the title compound (97 mg, 26%) which eluted first from the column. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.52 - 1.62 (1H, m), 1.63 - 1.77 (3H, m), 2.03 (1H, dd), 2.27 (3H, s), 2.41 (1H, dd), 2.76 (2H, t), 3.26 - 3.31 (1H, m), 3.32 - 3.37 (1H, m), 3.42 - 3.50 (2H, m), 3.81 (2H, t), 3.99 (1H, dd), 4.18 (1H, dd), 5.45 - 5.52 (1H, m), 7.48 (1H, s), 7.91 (1H, d), 8.20 (1H, d), 10.39 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 484.1. Intermediate 68b: 1-[3-methyl-1-[ rel- (3S * )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not confirmed] 1-[3-methyl-1-[( 3S )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[( 3R )-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 2c starting from intermediate 68a. Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2N _NH3 in MeOH gave the title compound (72.5 mg, 95%) as an off-white solid. ¹ H NMR (DMSO- d6 ): δ 1.52 - 1.64 (2H, m), 1.66 (2H, t), 1.96 (1H, dd), 2.25 - 2.28 (3H, m), 2.39 (1H, dd), 2.52 - 2.63 (2H, m), 2.72 - 2.81 (2H, m), 2.85 (2H, dq), 3.23 - 3.40 (1H, m), 3.81 (2H, t), 3.95 (1H, dd), 4.14 (1H, dd), 5.42 - 5.49 (1H, m), 7.47 (1H, s), 7.90 (1H, d), 8.20 (1H, d), 10.15 - 10.56 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 384.6. 1-[3-Methyl-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration not confirmed] 1-[3-Methyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (95 mg, 0.19 mmol) and intermediate 68b (72.5 mg, 0.19 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (102 mg, 59.5%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.19 - 1.33 (2H, m), 1.59 - 1.84 (7H, m), 1.91 - 2.03 (3H, m), 2.10 - 2.16 (2H, m), 2.22 (2H, br d), 2.27 (3H, s), 2.32 - 2.43 (3H, m), 2.48 - 2.50 (1H, m), 2.52 - 2.57 (1H, m), 2.64 (2H, br t), 2.76 (2H, t), 3.10 (2H, br d), 3.26 (2H, br d), 3.35 (2H, br d), 3.81 (2H, t), 3.96 (1H, dd), 4.15 (1H, dd), 4.35 (2H, br s), 5.46 (1H, quin), 5.94 (2H, s), 6.40 - 6.45 (1H, m), 6.46 - 6.51 (1H, m), 6.83 - 6.89 (2H, m), m/ z (ES ⁺ ) [M+H] ⁺ = 870.6. Example 69 Intermediate 69a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridine

Prepared in an analogous manner to intermediate 64a starting from bromo-3-cyclopropyl- 1H -pyrrolo[2,3- b ]pyridine (3 g, 12.65 mmol) and 1,3-bis(allyloxy)propan-2-ol (3.34 ml, 18.98 mmol). Purification by FSC (elution gradient: 0-20% EtOAc in hexanes) gave the title compound (4.34 g, 88%) as a yellow oil. ¹ H NMR (DMSO- d6 ): δ 0.59 - 0.64 (2H, m), 0.84 - 0.91 (2H, m), 1.91 - 1.99 (1H, m), 3.73 - 3.78 (2H, m), 3.80 - 3.85 (2H, m), 3.88 - 3.92 (4H, m), 5.04 - 5.17 (5H, m), 5.70 - 5.85 (2H, m), 7.42 (1H, s), 8.20 (1H, d), 8.27 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 391.3. Intermediate 69b: 2-(5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)propane-1,3-diol

Prepared in an analogous manner to intermediate 64b starting from intermediate 69a (4.34 g, 11.09 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (3.02 g, 87%) as a red solid. ¹ H NMR (DMSO- d6 ): δ 0.58 - 0.69 (2H, m), 0.81 - 0.92 (2H, m), 1.87 - 1.98 (1H, m), 3.77 (4H, d), 4.78 (1H, quin), 4.88 (2H, br s), 7.39 (1H, s), 8.18 (1H, d), 8.26 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 311.2. Intermediate 69c: ( 5s , 8s )-8-(5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 64d starting from intermediate 69b (480 mg, 1.54 mmol). The material was purified by FSC (elution gradient: 0-75% EtOAc in hexanes) to give the desired isomer, which eluted second from the column. The title compound was obtained as a brown solid (0.314 g, 39.7%). ¹ H NMR (DMSO- d6 ): δ 0.64 (2H, br s), 0.88 (2H, br d), 1.91 - 1.99 (1H, m), 2.30 (2H, br d), 3.40 - 3.52 (2H, m), 3.66 (2H, br d), 4.09 (2H, br dd), 4.23 - 4.37 (2H, m), 4.84 (1H, br dd), 5.10 (2H, br d), 7.28 - 7.43 (5H, m), 7.64 (1H, br d), 8.24 (1H, br s), 8.29 (1H, br d); m/z (ES ⁺ ) [M+H] ⁺ = 512.3. Intermediate 69d: ( 5s , 8s )-8-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 69c (293 mg, 0.57 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-20% MeOH in EtOAc) followed by trituration with water afforded the title compound as a brown solid (151 mg, 48.4%). ¹ H NMR (DMSO- d6 ): δ 0.60 - 0.69 (2H, m), 0.83 - 0.95 (2H, m), 1.91 - 1.99 (1H, m), 2.26 - 2.34 (2H, m), 2.77 (2H, t), 3.40 - 3.52 (2H, m), 3.68 (2H, br d), 3.83 (2H, t), 4.12 (2H, br dd), 4.22 - 4.36 (2H, m), 4.83 - 4.98 (1H, m), 5.11 (2H, br d), 7.29 - 7.35 (1H, m), 7.39 (4H, br d), 7.62 (1H, br d), 7.99 (1H, br s), 8.20 (1H, br d), 10.39 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 546.1 Intermediate 69e: 1-[3-cyclopropyl-1-((5 s ,8 s )-6,10-dioxa-2-azaspiro[4.5]dec-8-yl)pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 64f starting from intermediate 69d (151 mg, 0.28 mmol). The title compound was obtained as an off-white solid (90 mg, 79%). ¹ H NMR (DMSO- d6 ): δ 0.59 - 0.70 (2H, m), 0.85 - 0.92 (2H, m), 1.92 - 1.99 (1H, m), 2.04 (2H, t), 2.77 (2H, t), 2.87 - 2.92 (2H, m), 2.99 (2H, s), 3.83 (2H, t), 4.05 (2H, dd), 4.26 (2H, dd), 4.82 (1H, quin), 7.61 (1H, s), 7.99 (1H, d), 8.20 (1H, d), 10.38 (1H, br s) (NH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 412.1. 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting from intermediate 13d (25.1 mg, 0.05 mmol) and intermediate 69e (20.6 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (31.3 mg, 68.7%) as a white solid. ¹ H NMR (DMSO- d6 ): δ δ 0.62 - 0.69 (2H, m), 0.83 - 0.93 (2H, m), 1.21 - 1.35 (2H, m), 1.53 - 1.66 (1H, m), 1.82 (2H, br d), 1.90 - 2.00 (3H, m), 2.09 - 2.17 (4H, m), 2.32 (2H, br d), 2.57 - 2.70 (4H, m), 2.77 (2H, t), 2.83 (2H, s), 3.11 (2H, br d), 3.23 - 3.30 (4H, m), 3.83 (2H, t), 4.04 (2H, br dd), 4.26 (2H, br dd), 4.35 (2H, br s), 4.79 - 4.85 (1H, m), 5.94 (2H, s), 6.44 (1H, dt), 6.49 (1H, dd), 6.84 - 6.89 (2H, m), 6.93 (1H, dd), 7.21 - 7.25 (1H, m), 7.47 (1H, s), 7.60 (1H, s), 7.91 (1H, d), 7.99 (1H, d), 8.21 (1H, s), 10.39 (1H, s), 13.83 - 14.53 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 898.5. Example 70 Intermediate 70a: (5 r ,8 r )-8-(5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 64d starting from intermediate 69b (480 mg, 1.54 mmol). Purification by FSC (elution gradient: 0-75% EtOAc in hexanes) gave the desired isomer, which eluted first from the column. Subsequent purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (0.243 g, 30.8%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 0.61 - 0.67 (2H, m), 0.87 - 0.92 (2H, m), 1.94 - 2.02 (1H, m), 2.22 - 2.32 (2H, m), 3.39 - 3.50 (2H, m), 3.70 (2H, br d), 4.10 (2H, dd), 4.26 - 4.34 (2H, m), 4.77 - 4.85 (1H, m), 5.10 (2H, d), 7.30 - 7.42 (5H, m), 7.62 (1H, s), 8.25 (1H, d), 8.30 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 512.0. Intermediate 70b: (5 r ,8 r )-8-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 70a (223 mg, 0.44 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-20% MeOH in EtOAc) gave the title compound (149 mg, 62.8%) as a brown solid. ¹ H NMR (DMSO- d6 ): δ 0.62 - 0.69 (2H, m), 0.85 - 0.95 (2H, m), 1.91 - 1.99 (1H, m), 2.26 - 2.34 (2H, m), 2.77 (2H, t), 3.39 - 3.53 (2H, m), 3.70 (2H, br d), 3.83 (2H, t), 4.13 (2H, dd), 4.25 - 4.34 (2H, m), 4.86 (1H, br d), 5.11 (2H, br d), 7.31 - 7.36 (1H, m), 7.39 (4H, br t), 7.62 (1H, s), 7.99 (1H, d), 8.21 (1H, d), 10.39 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 546.1. Intermediate 70c: 1-[3-cyclopropyl-1-((5 r ,8 r )-6,10-dioxa-2-azaspiro[4.5]dec-8-yl)pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 64f starting from intermediate 70b (149 mg, 0.27 mmol) The title compound was obtained as a grey solid (108 mg, 96%). ¹ H NMR (DMSO- d6 ): δ 0.62 - 0.69 (2H, m), 0.86 - 0.94 (2H, m), 1.90 - 1.99 (1H, m), 2.05 (2H, t), 2.77 (2H, t), 2.85 - 2.92 (2H, m), 3.00 (2H, s), 3.83 (2H, t), 4.09 (2H, dd), 4.16 - 4.24 (2H, m), 4.78 - 4.89 (1H, m), 7.60 (1H, s), 7.99 (1H, d), 8.21 (1H, d), 10.38 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 412.1. 1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (25.1 mg, 0.05 mmol) and intermediate 70c (20.6 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (28.2 mg, 61.5%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 0.62 - 0.69 (2H, m), 0.86 - 0.94 (2H, m), 1.22 - 1.35 (2H, m), 1.53 - 1.64 (1H, m), 1.82 (2H, br d), 1.91 - 2.01 (3H, m), 2.09 - 2.19 (4H, m), 2.32 (2H, br d), 2.56 - 2.71 (4H, m), 2.77 (2H, t), 2.84 (2H, s), 3.11 (2H, br d), 3.25 - 3.31 (4H, m), 3.83 (2H, t), 4.10 (2H, br dd), 4.17 - 4.24 (2H, m), 4.35 (2H, br s), 4.79 - 4.87 (1H, m), 5.94 (2H, s), 6.44 (1H, dt), 6.46 - 6.52 (1H, m), 6.84 - 6.90 (2H, m), 6.93 (1H, dd), 7.21 - 7.26 (1H, m), 7.47 (1H, s), 7.60 (1H, s), 7.89 - 7.93 (1H, m), 7.99 (1H, d), 8.21 (1H, d), 10.39 (1H, s), 13.59 - 14.61 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 898.5. Example 71 Intermediate 71a: 3-(5-Bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-1-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (366 mg, 1.73 mmol), 3-hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester (470 mg, 1.73 mmol). Purification by FSC (elution gradient: 0-25% acetone in hexanes) gave the title compound (241 mg, 30.0%) as a colorless dry film. ¹ H NMR (CDCl ₃ ): δ 1.49 (9H, s), 1.51 - 1.60 (2H, m), 1.62 - 1.75 (2H, m), 1.84 (1H, br d), 2.01 - 2.13 (1H, m), 2.13 - 2.28 (2H, m), 2.29 (2H, d), 2.31 - 2.33 (1H, m), 3.12 - 3.27 (2H, m), 3.73 - 4.00 (4H, m), 4.75 - 4.86 (1H, m), 7.25 (1H, s), 7.97 (1H, d), 8.31 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 464.2. Intermediate 71b: rel -(3 S * )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester (isomer 1) [*The absolute configuration has not been confirmed] (3 S )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester or (3 R )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 71a (0.216 g, 0.47 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the racemic material. The material was purified by chiral SFC (column: ChiralPAK IH 4.6 x 150 mm, 5 µm, mobile phase: phase A: 100% CO ₂ , phase B: methanol containing 0.2% NH ₄ OH, gradient: phase B, from 0 to 5.0 min, 10% to 60%, hold 60% until 5.90 min, and from 5.90 min to 6.00 min, 60% to 10%, flow rate: 4.0 mL/min, diluent: DCM) to give the title compound (48 mg, 20%) as a brown dry film, which eluted first from the column. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.43 - 1.57 (2H, m), 1.58 - 1.68 (2H, m), 1.75 (1H, dt), 1.86 - 1.94 (1H, m), 2.26 (3H, d), 2.27 - 2.33 (2H, m), 2.76 (2H, t), 2.96 - 3.16 (2H, m), 3.59 - 3.70 (2H, m), 3.74 - 3.89 (4H, m), 4.71 - 4.79 (1H, m), 7.60 (1H, s), 7.90 (1H, d), 8.19 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 498.5. Intermediate 71c: 1-[3-methyl-1-[ rel- (3S * )-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration has not been confirmed] 1-[3-methyl-1-[( 3S )-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[( 3R )-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 71b (48 mg, 0.10 mmol). Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2 N _NH3 in MeOH gave the title compound (30 mg, 78%) as an off-white solid. m/z (ES ⁺ ) [M+H] ⁺ = 398.1. 1-[3-Methyl-1-[ rel- (3 S* )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*Absolute configuration not confirmed] 1-[3-Methyl-1-[(3 S )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undecane-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[(3 R )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (37.7 mg, 0.075 mmol) and intermediate 71c (29.8 mg, 0.08 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (44.4 mg, 64.9%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.21 - 1.32 (2H, m), 1.54 - 1.85 (8H, m), 1.87 - 2.00 (3H, m), 2.13 (2H, br d), 2.20 - 2.39 (8H, m), 2.65 (2H, br t), 2.76 (2H, t), 3.11 (2H, br d), 3.24 - 3.38 (6H, m), 3.71 - 3.89 (5H, m), 4.35 (2H, br s), 4.73 (1H, dt), 5.94 (2H, s), 6.40 - 6.52 (2H, m), 6.83 - 6.96 (3H, m), 7.20 - 7.27 (1H, m), 7.47 (1H, s), 7.60 (1H, s), 7.88 - 7.94 (2H, m), 8.19 (1H, s), 10.38 (1H, s), 13.36 - 14.81 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 884.6. Example 72 Intermediate 72a: rel -(3 S * )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester (Isomer 2) [*Absolute configuration has not been confirmed] (3 S )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester or (3 R )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-oxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 71a (0.216 g, 0.47 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the racemic material. The material was purified by chiral SFC (column: ChiralPAK IH 4.6 x 150 mm, 5 µm, mobile phase: phase A: 100% CO ₂ , phase B: methanol containing 0.2% NH ₄ OH, gradient: phase B, from 0 to 5.0 min, 10% to 60%, hold 60% until 5.90 min, and from 5.90 min to 6.00 min, 60% to 10%, flow rate: 4.0 mL/min, diluent: DCM) to give the title compound (48 mg, 20%) as a brown dry film, which eluted second from the column. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.43 - 1.57 (2H, m), 1.58 - 1.68 (2H, m), 1.75 (1H, dt), 1.86 - 1.94 (1H, m), 2.26 (3H, d), 2.27 - 2.33 (2H, m), 2.76 (2H, t), 2.96 - 3.16 (2H, m), 3.59 - 3.70 (2H, m), 3.74 - 3.89 (4H, m), 4.71 - 4.79 (1H, m), 7.60 (1H, s), 7.90 (1H, d), 8.19 (1H, d), 10.38 (1H, s; m/z (ES ⁺ ) [M+H] ⁺ = 498.5. Intermediate 72b: 1-[3-methyl-1-[ rel -(3 S * )-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not confirmed] 1-[3-methyl-1-[(3 S )-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[(3 R )-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 72a (48 mg, 0.10 mmol). Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2N _NH3 in MeOH gave the title compound (38 mg, 99%) as an off-white solid. m/z (ES ⁺ ) [M+H] ⁺ = 398.1 1-[3-methyl-1-[ rel -(3 R* )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*Absolute configuration not confirmed] 1-[3-methyl-1-[(3 S )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undecane-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione or 1-[3-methyl-1-[(3 R )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (50.3 mg, 0.1 mmol) and intermediate 72b (39.7 mg, 0.10 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (56.0 mg, 61.4%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.20 - 1.32 (2H, m), 1.53 - 1.81 (8H, m), 1.85 - 2.00 (3H, m), 2.11 - 2.16 (2H, m), 2.21 - 2.39 (9H, m), 2.65 (2H, br t), 2.76 (2H, t), 3.11 (2H, br d), 3.26 - 3.34 (6H, m), 3.74 (1H, br dd), 3.79 - 3.86 (3H, m), 4.35 (2H, br s), 4.73 (1H, tt), 5.94 (2H, s), 6.41 - 6.51 (2H, m), 6.84 - 6.95 (3H, m), 7.23 (1H, t), 7.47 (1H, s), 7.60 (1H, s), 7.88 - 7.92 (2H, m), 8.19 (1H, s), 10.38 (1H, s), 13.01 - 15.01 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 884.6. Example 73 Intermediate 73a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-3-methyl-pyrrolo[2,3- b ]pyridine

Prepared in an analogous manner to intermediate 64a starting from 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (5 g, 23.69 mmol) and 1,3-bis(allyloxy)propan-2-ol (6.24 ml, 35.53 mmol). Purification by FSC (elution gradient: 0-20% acetone in hexanes) gave the title compound (7.458 g, 86%) as a yellow oil. ¹ H NMR (DMSO- d6 ): δ 2.23 (3H, d), 3.73 - 3.77 (2H, m), 3.79 - 3.84 (2H, m), 3.86 - 3.94 (4H, m), 5.05 - 5.15 (5H, m), 5.77 (2H, ddt), 7.46 (1H, s), 8.15 (1H, d), 8.25 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 365.3. Intermediate 73b: 2-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)propane-1,3-diol

Prepared in a similar manner to intermediate 64b starting from intermediate 73a (2.775 g, 7.60 mmol). Trituration with (2:1) DCM/hexanes followed by _Et2O afforded the title compound as an off-white solid (1.734 g, 80%). ^1H NMR (DMSO- d6 ): δ 2.23 (3H, s), 3.76 (4H, t), 4.76 (1H, quin), 4.85 (2H, t), 7.43 (1H, s), 8.13 (1H, d), 8.23 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 285.0. Intermediate 73c: (5 r ,8 r )-8-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

A vial was charged with intermediate 73b (0.635 g, 2.23 mmol), benzyl 3-oxopyrrolidine-1-carboxylate (0.976 g, 4.45 mmol), TsOH·H ₂ O (0.127 g, 0.67 mmol), and toluene (12 mL). The reaction was heated at 120 °C for 22 h. An additional portion of benzyl 3-oxopyrrolidine-1-carboxylate (0.976 g, 4.45 mmol) and TsOH·H ₂ O (0.127 g, 0.67 mmol) were added, and the reaction was stirred at 110 °C for 6 h. The reaction was cooled to room temperature, quenched with saturated aqueous NaHCO ₃ solution, extracted with DCM, washed with brine, dried over Na ₂ SO ₄ and concentrated. Purification by FSC (elution gradient: 0-100% EtOAc in hexanes, then 0-30% MeOH) gave the title compound (107 mg, 10%) as a brown film, which eluted first from the column. ¹ H NMR (DMSO- d6 ): δ 2.21 - 2.31 (5H, m), 3.37 - 3.52 (2H, m), 3.73 (2H, br d), 4.08 (2H, dd), 4.30 - 4.39 (2H, m), 4.82 (1H, br s), 5.11 (2H, d), 7.30 - 7.36 (1H, m), 7.37 - 7.43 (4H, m), 7.73 (1H, s), 8.22 (1H, d), 8.29 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 486.0. Intermediate 73d: (5 r ,8 r )-8-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 73c (107 mg, 0.22 mmol). Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (71.8 mg, 62.8%) as a brown solid. ¹ H NMR (CDCl ₃ ): δ 2.29 (2H, t), 2.33 (3H, s), 2.90 (2H, t), 3.59 (2H, dt), 3.78 (1H, s), 3.86 (1H, s), 3.91 (2H, t), 4.15 - 4.24 (2H, m), 4.25 - 4.38 (2H, m), 4.91 (1H, br s), 5.17 (2H, s), 7.30 - 7.43 (5H, m), 7.58 - 7.70 (1H, m), 7.71 - 7.84 (2H, m), 8.20 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 520.1. Intermediate 73e: 1-[1-((5 r ,8 r )-6,10-dioxa-2-azaspiro[4.5]dec-8-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 64f starting from intermediate 73d (72 mg, 0.14 mmol). The title compound was obtained as a grey solid (52 mg, 98%). m/z (ES ⁺ ) [M+H] ⁺ = 386.1. 1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (60.3 mg, 0.12 mmol) and intermediate 73e (54.0 mg, 0.14 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (41.8 mg, 39.0%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.22 - 1.34 (2H, m), 1.55 - 1.66 (1H, m), 1.82 (2H, br d), 1.91 - 2.00 (2H, m), 2.10 - 2.17 (4H, m), 2.28 (3H, d), 2.33 (2H, br d), 2.60 (2H, br t), 2.66 (2H, br t), 2.77 (2H, t), 2.86 (2H, s), 3.11 (2H, br d), 3.27 (2H, br d), 3.36 (2H, br d), 3.82 (2H, t), 4.08 (2H, br dd), 4.25 (2H, br dd), 4.35 (2H, br s), 4.83 (1H, quin), 5.94 (2H, s), 6.43 (1H, dt), 6.49 (1H, dd), 6.84 - 6.90 (2H, m), 6.93 (1H, dd), 7.21 - 7.26 (1H, m), 7.47 (1H, s), 7.68 (1H, s), 7.89 - 7.95 (2H, m), 8.20 (1H, d), 10.39 (1H, s), 13.19 - 14.98 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 872.5. Example 74 Intermediate 74a: 9-(5-bromoindol-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2a starting from 5-bromo- 1H -indole (0.588 g, 3 mmol) and tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1.616 g, 6.00 mmol). Purification by FSC (elution gradient: 0-50% EtOAc in hexanes) gave the title compound (1.282 g, 95%) as a colorless dry film. ¹ H NMR (DMSO- d6 ): δ 1.26 - 1.32 (2H, m), 1.33 - 1.39 (2H, m), 1.41 (9H, s), 1.57 - 1.62 (2H, m), 1.71 - 1.84 (4H, m), 1.85 - 1.96 (2H, m), 3.31 - 3.37 (4H, m), 4.34 (1H, tt), 6.44 (1H, d), 7.22 (1H, dd), 7.51 (1H, d), 7.60 (1H, d), 7.72 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 447.1. Intermediate 74b: 9-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 74a (1.002 g, 2.24 mmol). Trituration with EtOAc/hexanes (1:1) followed by water afforded the title compound as a brown solid (0.881 g, 82%). ¹ H NMR (DMSO- d6 ): δ 1.29 - 1.40 (4H, m), 1.41 (9H, s), 1.58 - 1.64 (2H, m), 1.73 - 1.88 (4H, m), 1.89 - 1.99 (2H, m), 2.73 (2H, t), 3.33 - 3.37 (4H, m), 3.77 (2H, t), 4.35 (1H, br t), 6.45 (1H, d), 7.07 (1H, dd), 7.45 (1H, d), 7.52 (1H, d), 7.59 (1H, br d), 10.25 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 481.3. Intermediate 74c: 1-[1-(3-azaspiro[5.5]undecane-9-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 74b (240 mg, 0.5 mmol) and TsOH·H ₂ O (105 mg, 0.55 mmol) and MeCN (2.5 mL). The suspension was stirred at 70 °C for 19.5 h. After cooling to room temperature, the reaction was diluted with Et ₂ O. The solid was collected by vacuum filtration, washed with Et ₂ O and dried to give the title compound as a grey solid as a TsOH salt (208 mg, 73.0%). ¹ H NMR (DMSO- d6 ): δ 1.38 - 1.48 (2H, m), 1.50 - 1.60 (2H, m), 1.77 - 1.97 (8H, m), 2.30 (3H, s), 2.73 (2H, t), 3.09 (4H, br s), 3.77 (2H, t), 4.31 - 4.43 (1H, m), 7.07 (1H, dd), 7.13 (2H, d), 7.46 (1H, d), 7.49 - 7.55 (3H, m), 7.59 (1H, d), 8.33 (2H, br s), 10.26 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 381.4. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (50.3 mg, 0.1 mmol) and intermediate 74c (62.7 mg, 0.11 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 50%-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (49.2 mg, 56.7%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.25 - 1.30 (2H, m), 1.31 - 1.45 (4H, m), 1.58 - 1.71 (3H, m), 1.73 - 1.85 (6H, m), 1.87 - 1.99 (4H, m), 2.11 - 2.17 (2H, m), 2.20 (2H, br d), 2.30 - 2.40 (4H, m), 2.65 (2H, br t), 2.73 (2H, t), 3.11 (2H, br d), 3.23 - 3.29 (2H, m), 3.34 - 3.39 (2H, m), 3.77 (2H, t), 4.28 - 4.40 s), 14.17 (1H, br s; m/z (ES + ) [M+H] ⁺ = 867.6. Example 75 Intermediate 75a: 9- (5-bromo-3-methyl-indol-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ^ester

Prepared in a similar manner to intermediate 2a starting from 5-bromo-3-methyl- 1H -indole (630 mg, 3 mmol) and tributyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (1616 mg, 6.00 mmol). Purification by FSC (elution gradient: 0-30% EtOAc in hexanes) gave the title compound (846 mg, 61.1%) as a colorless dry film. ¹ H NMR (CDCl ₃ ): δ 1.33 - 1.44 (4H, m), 1.48 (9H, s), 1.59 - 1.68 (2H, m), 1.83 - 1.95 (6H, m), 2.24 - 2.32 (3H, m), 3.38 - 3.47 (4H, m), 4.09 - 4.16 (1H, m), 6.99 (1H, s), 7.18 (1H, d), 7.24 - 7.27 (1H, m), 7.68 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 461.1. Intermediate 75b: 9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]-3-azaspiro[5.5]undecane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 75a (0.846 g, 1.83 mmol). Trituration with EtOAc/hexanes (1:1) followed by water afforded the title compound as a brown solid (0.711 g, 78%). ¹ H NMR (DMSO- d6 ): δ 1.24 - 1.40 (4H, m), 1.41 (9H, s), 1.56 - 1.64 (2H, m), 1.74 (2H, br d), 1.79 - 1.97 (4H, m), 2.24 (3H, s), 2.73 (2H, t), 3.32 - 3.37 (4H, m), 3.77 (2H, t), 4.28 (1H, tt), 7.05 (1H, dd), 7.32 - 7.41 (2H, m), 7.45 (1H, d), 10.24 (1H, br s).; m/z (ES ⁺ ) [M+H] ⁺ = 495.4. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 11g (63.3 mg, 0.1 mmol) and intermediate 75b (59.4 mg, 0.12 mmol) in a similar manner to Example 39. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (26.6 mg, 30.0%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.20 - 1.29 (2H, m), 1.30 - 1.41 (4H, m), 1.59 - 1.70 (3H, m), 1.70 - 1.83 (6H, m), 1.83 - 1.91 (2H, m), 1.91 - 1.98 (2H, m), 2.11 - 2.16 (2H, m), 2.20 (2H, br d), 2.24 (3H, s), 2.31 - 2.42 (4H, m), 2.64 (2H, br t), 2.73 (2H, t), 3.11 (2H, br d), 3.26 (2H, br d), 3.37 - 3.41 (2H, m), 3.77 (2H, t), 4.26 (1H, br t), 4.35 (2H, br s), 5.94 (2H, s), 6.41 - 6.50 (2H, m), 6.84 - 6.96 (3H, m), 7.04 (1H, dd), 7.19 - 7.27 (1H, m), 7.35 - 7.40 (2H, m), 7.41 - 7.50 (2H, m), 7.91 (1H, dd), 10.24 (1H, s), 13.75 - 14.57 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 881.6. Example 76 Intermediate 76a: 4-(5-chloro-2-fluoro-phenyl)piperidin-1-carboxylic acid tributyl ester

A vial was charged with Pd ₂ (dba) ₃ (0.229 g, 0.25 mmol), tributyl piperidine-1-carboxylate (0.931 g, 5 mmol), Cs ₂ CO ₃ (4.89 g, 15.00 mmol), 2-bromo-4-chloro-1-fluorobenzene (0.609 mL, 5.00 mmol), BINAP (0.311 g, 0.50 mmol), and 1,4-dioxathiophene (24 mL). The vial was bubbled with N ₂ and heated to 100 °C for 19 h. After cooling to room temperature, the reaction was filtered through celite®, eluted with DCM and EtOAc, and concentrated. Purification by FSC (elution gradient: 0-30% EtOAc in hexanes) gave the title compound (1.429 g, 91%) as a yellow oil. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 2.93 - 3.00 (4H, m), 3.39 - 3.49 (4H, m), 6.99 - 7.05 (2H, m), 7.17 (1H, dd; m/z (ES ⁺ ) [M- t Bu+2H] ⁺ = 259.2. Intermediate 76b: 4-[5-[3-[3-[Bis(tributyloxycarbonyl)amino]-6-[2-(methoxymethoxy)phenyl]piperidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-carboxylic acid tributyl ester

A vial was charged with intermediate 25d (2.383 g, 4.4 mmol), intermediate 76a (1.385 g, 4.40 mmol), Cs ₂ CO ₃ (4.30 g, 13.20 mmol), RuPhos Pd G3 (368 mg, 0.44 mmol) and 1,4-dioxathiol (20 mL). The reaction was bubbled with N ₂ and heated to 100 °C for 1.5 h. A second portion of RuPhos Pd G3 (368 mg, 0.44 mmol) was added and the reaction was stirred at 100 °C for an additional 2.5 h. After cooling to room temperature, the reaction was filtered through celite®, eluted with DCM and EtOAc and concentrated. Purification by FSC (elution gradient: 0-80% EtOAc in hexanes) gave the title compound (714 mg, 19.79%) as a brown dry film. ¹ H NMR (DMSO- d6 ): δ 1.35 - 1.46 (27H, m), 1.80 - 1.89 (2H, m), 1.90 - 1.99 (2H, m), 2.90 - 2.97 (3H, m), 3.22 - 3.34 (8H, m), 3.37 - 3.51 (4H, m), 4.41 (2H, br s), 5.22 (2H, s), 6.49 - 6.55 (2H, m), 6.96 (1H, dd), 7.12 - 7.19 (1H, m), 7.23 - 7.29 (1H, m), 7.46 (1H, t), 7.51 (1H, s), 7.70 - 7.76 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 820.9. Intermediate 76c: 2-[6-amino-5-[8-(4-fluoro-3-piperidin-1-yl-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]phthalimide-3-yl]phenol

A flask was charged with intermediate 76b (0.613 g, 0.75 mmol), DCM (6 mL) and TFA (1.5 mL). The mixture was stirred on a rotovap at 750 mbar with a slight vacuum at room temperature for 3 h to remove the formaldehyde generated during the reaction. The reaction was then completely concentrated in vacuo. Purification by RPC (elution gradient: 40%-100% MeCN in water containing 0.1% NH ₄ OH) gave the title compound (42 mg, 11.8%) as an off-white dry film. ¹ H NMR (CDCl ₃ ): δ 2.03 - 2.10 (2H, m), 2.16 - 2.23 (2H, m), 3.10 (8H, s), 3.23 - 3.34 (4H, m), 4.31 (2H, br s), 4.90 (2H, s), 6.36 - 6.48 (2H, m), 6.87 - 6.99 (2H, m), 7.02 - 7.08 (1H, m), 7.26 - 7.29 (2H, m), 7.53 - 7.59 (1H, m) (NH and OH not observed); m/z (ES ⁺ ) [M+H] ⁺ = 476.2. Intermediate 76d: 9-[tert-butyl(diphenyl)silyl]oxyspiro[5.5]undecane-3-one

A vial was charged with 9-hydroxyspiro[5.5]undecan-3-one (963 mg, 5.28 mmol), imidazole (540 mg, 7.93 mmol), and DCM (20 mL). The reaction was cooled to 0 °C and tributylchlorodiphenylsilane (1.511 mL, 5.81 mmol) was added. The reaction was stirred at 0 °C for 10 min and then warmed to room temperature. After 2.5 h, the reaction was diluted with DCM and washed with 1 M HCl. The aqueous was extracted with DCM and the combined organic extracts were washed with saturated aqueous NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , and concentrated. Purification by FCS (0-15% EtOAc in hexanes) gave the title compound (2142 mg, 96%) as a colorless viscous oil. ¹ H NMR (CDCl ₃ ): δ 1.10 (9H, s), 1.19 - 1.27 (2H, m), 1.53 - 1.69 (6H, m), 1.71 - 1.78 (2H, m), 1.80 (2H, t), 2.32 (4H, dt), 3.75 - 3.83 (1H, m), 7.36 - 7.43 (4H, m), 7.42 - 7.48 (2H, m), 7.65 - 7.75 (4H, m).; m/z (ES ⁺ ) [M+H] ⁺ = 421.3. Intermediate 76e: tert-butyl-[3-(methoxymethylene)spiro[5.5]undec-9-yl]oxy-diphenyl-silane

A flask was charged with (methoxymethyl)triphenylphosphonium chloride (4.96 g, 14.46 mmol). The flask was backfilled with _N2 , THF (15 mL) was added, and the reaction was cooled to -78 °C. A solution of KO t Bu (14.46 mL, 14.46 mmol, 1 M in THF) was added dropwise over 5 min. The solution was stirred at -78 °C for 5 min and then at room temperature for 10 min. A second flask was charged with intermediate 76d (2.028 g, 4.82 mmol) and THF (10 mL) under _N2 . The mixture was cooled to -78 °C and a solution of Wittig reagent was added dropwise over 15 min. The reaction was warmed to room temperature and stirred for 1 h and cooled back to -78 °C. Following the same procedure as above, a second batch of Wittig reagent was prepared from (methoxymethyl)triphenylphosphonium chloride (4.96 g, 14.46 mmol), KOtBu solution (14.46 mL, 14.46 mmol, 1 M in THF) and THF (15 mL). The second batch of Wittig reagent was added dropwise over 15 min, and the reaction was stirred at -78 °C for 10 min, warmed to room temperature and stirred for 2 h. The reaction was quenched with NH4Cl, extracted with DCM, washed with brine, dried _{over Na2SO4} , and concentrated. Purification by FSC (elution gradient: 0-15% EtOAc in hexanes) gave the title compound (1.998 g, 92%) as a colorless liquid. ¹ H NMR (CDCl ₃ ): δ 1.01 - 1.08 (2H, m), 1.09 (9H, s), 1.25 (2H, td), 1.43 - 1.47 (2H, m), 1.50 - 1.59 (4H, m), 1.61 - 1.67 (2H, m), 1.90 - 1.97 (2H, m), 2.13 - 2.21 (2H, m), 3.54 (3H, d), 3.68 - 3.75 (1H, m), 5.76 (1H, d), 7.36 - 7.46 (6H, m), 7.69 - 7.73 (4H, m). Intermediate 76f: tert-butyl-[9-(dibutoxymethyl)spiro[5.5]undec-3-yl]oxy-diphenyl-silane

A vial was charged with intermediate 76e (1.9984 g, 4.45 mmol), TsOH·H ₂ O (0.085 g, 0.45 mmol) and butan-1-ol (20 mL). The reaction was stirred at 70° C. for 17 h and the reaction was concentrated in vacuo. Purification by FSC (elution gradient: 0-12% EtOAc in hexanes) gave the title compound (2.077 g, 83%) as a colorless oil. ¹ H NMR (CDCl ₃ ): δ 0.92 - 0.96 (6H, m), 0.99 - 1.05 (2H, m), 1.08 (9H, s), 1.12 - 1.20 (2H, m), 1.36 - 1.44 (6H, m), 1.50 - 1.65 (12H, m), 1.67 - 1.83 (2H, m), 1.85 - 1.93 (1H, m), 3.42 (2H, dtd), 3.60 (2H, dq), 3.69 - 3.76 (1H, m), 4.14 (1H, d), 7.36 - 7.40 (4H, m), 7.42 - 7.46 (2H, m), 7.66 - 7.71 (4H, m). Intermediate 76g: 9-(dibutoxymethyl)spiro[5.5]undecane-3-ol

A vial was charged with intermediate 76f (1.8381 g, 3.25 mmol) and THF (5 mL). TBAF solution (16.27 mL, 16.27 mmol, 1 M in THF) was added and the reaction was stirred at 60 °C for 1.5 h, then cooled to room temperature and concentrated. Purification by FSC (elution gradient: 0-30% EtOAc in hexanes) gave the title compound (0.948 g, 89%) as a colorless oil. ¹ H NMR (DMSO- d6 ): δ 0.94 (6H, td), 0.89 - 0.90 (1H, m), 0.97 - 1.08 (1H, m), 1.09 - 1.26 (5H, m), 1.33 - 1.66 (17H, m), 1.68 - 1.78 (1H, m), 1.79 - 1.97 (1H, m), 3.42 (2H, dt), 3.55 - 3.69 (2H, m), 4.11 - 4.19 (1H, m) (OH not observed). Intermediate 76h: 5-Bromo-1-[9-(dibutoxymethyl)spiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridine

Prepared in a similar manner to intermediate 4a from intermediate 76g (0.807 g, 2.47 mmol), 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (0.522 g, 2.47 mmol). Purification by FSC (elution gradient: 0-25% EtOAc in hexanes) gave the title compound (0.380 g, 29.6%) as a colorless oil. m/z (ES ⁺ ) [M+H] ⁺ = 519.3. Intermediate 76i: 1-[1-[9-(dibutoxymethyl)spiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 2b starting from intermediate 76h (353 mg, 0.68 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (225 mg, 59.8%) as a brown solid. ¹ H NMR (DMSO- d6 ): δ 0.89 (6H, td), 1.08 - 1.18 (3H, m), 1.18 - 1.26 (2H, m), 1.31 - 1.38 (5H, m), 1.41 - 1.62 (10H, m), 1.69 (2H, br d), 1.87 - 1.98 (1H, m), 1.99 - 2.11 (2H, m), 2.25 (3H, s), 2.76 (2H, t), 3.35 - 3.41 (2H, m), 3.50 - 3.58 (2H, m), 3.81 (2H, t), 4.17 (1H, d), 4.54 - 4.63 (1H, m), 7.55 (1H, s), 7.87 (1H, d), 8.16 (1H, d), 10.37 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 553.5. 1-[1-[9-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]spiro[5.5]undecane-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 76i (27.6 mg, 0.05 mmol), DCM (1 mL), and TFA (0.2 mL). The reaction was stirred at room temperature for 30 min and then concentrated. The crude residue was suspended in Et ₂ O, sonicated, and concentrated. To the residue was added intermediate 76c (23.78 mg, 0.05 mmol) in DCM (1 mL) and MeOH (0.2 mL) followed immediately by Na(OAc) ₃ BH (21.19 mg, 0.10 mmol). The reaction was stirred at room temperature for 15 min. The reaction was then diluted with DMSO and then concentrated to remove volatiles. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (22.0 mg, 49.2%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 0.96 - 1.18 (4H, m), 1.22 - 1.31 (1H, m), 1.32 - 1.38 (1H, m), 1.42 - 1.56 (3H, m), 1.58 - 1.75 (4H, m), 1.86 - 1.99 (3H, m), 2.00 - 2.24 (7H, m), 2.25 (3H, s), 2.46 - 2.50 (4H, m), 2.76 (2H, t), 2.97 - 3.07 (4H, m), 3.11 (2H, br d), 3.24 - 3.27 (2H, m), 3.81 (2H, t), 4.37 (2H, br s), 4.53 - 4.66 (1H, m), 5.94 (2H, s), 6.42 - 6.51 (2H, m), 6.83 - 6.90 (2H, m), 6.94 (1H, dd), 7.21 - 7.26 (1H, m), 7.47 (1H, s), 7.54 (1H, s), 7.87 (1H, d), 7.89 - 7.95 (1H, m), 8.17 (1H, d), 10.37 (1H, s), 13.87 - 14.47 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 882.6. Example 77 Intermediate 77a: ( 5s , 8s )-8-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 73c starting from intermediate 73b (0.635 g, 2.23 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH) gave the title compound (77 mg, 7%) as a brown film which eluted second from the column. ¹ H NMR (DMSO- d6 ): δ 2.27 (3H, d), 2.31 - 2.39 (2H, m), 3.40 - 3.52 (2H, m), 3.64 (2H, br d), 4.07 (2H, dd), 4.30 - 4.41 (2H, m), 4.80 - 4.87 (1H, m), 5.10 (2H, s), 7.30 - 7.35 (1H, m), 7.36 - 7.41 (4H, m), 7.75 (1H, br d), 8.21 (1H, d), 8.28 (1H, br d); m/z (ES ⁺ ) [M+H] ⁺ = 486.0. Intermediate 77b: ( 5s , 8s )-8-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 77a (77 mg, 0.16 mmol). Purification by RPC (elution gradient: 0-80% MeCN in water containing 0.1% HCOOH) gave the title compound (31.0 mg, 37.7%) as a brown solid. ¹ H NMR (CDCl ₃ ): δ 2.29 - 2.42 (5H, m), 2.92 (2H, t), 3.57 - 3.69 (2H, m), 3.74 (1H, s), 3.81 (1H, s), 3.93 (2H, t), 4.13 - 4.24 (2H, m), 4.29 - 4.44 (2H, m), 4.89 - 5.03 (1H, m), 5.18 (2H, s), 7.32 - 7.45 (5H, m), 7.51 - 7.61 (2H, m), 7.81 (1H, d), 8.21 (1H, br d); m/z (ES ⁺ ) [M+H] ⁺ = 520.2. Intermediate 77c: 1-[1-((5 s ,8 s )-6,10-dioxa-2-azaspiro[4.5]dec-8-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 64f starting from intermediate 77b (31 mg, 0.06 mmol). The title compound was obtained as a grey solid (22 mg, 96%). m/z (ES ⁺ ) [M+H] ⁺ = 386.1. 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (30.2 mg, 0.06 mmol) and intermediate 77c (23 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (24.2 mg, 45.5%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.21 - 1.36 (2H, m), 1.54 - 1.64 (1H, m), 1.82 (2H, br d), 1.90 - 1.98 (2H, m), 2.10 - 2.18 (4H, m), 2.28 (3H, s), 2.31 (2H, br d), 2.58 - 2.73 (4H, m), 2.74 - 2.79 (2H, m), 2.82 (2H, s), 3.11 (2H, br d), 3.24 - 3.29 (4H, m), 3.82 (2H, t), 4.03 (2H, br dd), 4.26 - 4.44 (4H, m), 4.83 (1H, br t), 5.94 (2H, s), 6.44 (1H, dt), 6.46 - 6.52 (1H, m), 6.82 - 6.90 (2H, m), 6.93 (1H, dd), 7.21 - 7.25 (1H, m), 7.47 (1H, s), 7.70 (1H, s), 7.90 - 7.95 (2H, m), 8.20 (1H, d), 10.39 (1H, s), 13.96 - 14.41 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 872.5. Example 78 Intermediate 78a: 4-[[9-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 25f starting from intermediate 25e (535 mg, 1.20 mmol) and intermediate 36a (422 mg, 1 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (392 mg, 61.6%) as a beige solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.59 - 0.65 (2H, m), 0.86 - 0.91 (2H, m), 1.32 - 1.38 (2H, m), 1.39 - 1.43 (2H, m), 1.43 - 1.47 (9H, m), 1.55 - 1.65 (2H, m), 1.67 - 1.73 (2H, m), 1.78 - 1.94 (10H, m), 2.48 - 2.55 (5H, m), 2.83 - 2.88 (2H, m), 3.02 - 3.17 (2H, m), 3.79 - 3.90 (4H, m), 4.65 (1H, br d), 7.09 (1H, s), 7.52 (1H, s), 7.86 (1H, d), 8.17 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 637.8. Intermediate 78b: 1-[3-cyclopropyl-1-[3-[(4-fluoro-4-piperidinyl)methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 78a (401 mg, 0.63 mmol). Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2N _NH3 in MeOH gave the title compound (309 mg, 91%) as an off-white solid. m/z (ES ⁺ ) [M+H] ⁺ = 537.6 Intermediate 78c: N -tert-butyloxycarbonyl- N -[4-[8-[3-[4-[[9-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tert-butyl ester

A vial was charged with intermediate 78c (0.081 g, 0.15 mmol), intermediate 57a (0.101 g, 0.15 mmol), K ₂ CO ₃ (0.062 g, 0.45 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (0.025 g, 0.03 mmol) and dihydrogen sulfide (1.5 ml). The vial was bubbled with N ₂ and heated at 100 °C for 22 h. The reaction was cooled to room temperature, filtered through celite®, eluted with EtOAc/DCM and concentrated. Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (0.054 g, 31.0%) as a brown dry film. m/z (ES ⁺ ) [M+H] ⁺ = 1171.1. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 78c (54 mg, 0.05 mmol) and _{CH2Cl2 (} 1 mL), HCl (4 N in dihydrogen ether, 1 ml, 4.00 mmol) was added. The reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. Purification by RPC (elution gradient: 50%-100% _CH3CN in _H2O containing 0.1% _NH4OH ) gave the title compound (22.0 mg, 51.5%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 0.60 - 0.68 (2H, m), 0.79 - 0.89 (2H, m), 1.22 - 1.31 (2H, m), 1.37 (2H, br s), 1.57 - 1.73 (4H, m), 1.72 - 1.83 (3H, m), 1.84 - 2.03 (8H, m), 2.12 (2H, br d), 2.51 - 2.71 (3H, m), 2.75 (2H, t), 2.86 - 2.99 (2H, m), 3.06 - 3.13 (2H, m), 3.16 (2H, br d), 3.25 (2H, br d), 3.80 : 7.77 (2H, d), 7.11 (2H, d), 7.90 (2H, s), 8.47 (2H, d), 7.12 (1H, s), 8.22 (1H, s), 7.14 (1H, d), 10.33 (1H, s), 11.91 (1H, s), 3 protons combined in DMSO; m/z (ES ⁺ ) [M+H] ⁺ = 926.9. Example 79 Intermediate 79a: [2-(5-Bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-3-hydroxy-propyl] 4-methylbenzenesulfonate

A mixture of intermediate 73b (1.29 g, 4.52 mmol), 4-methylbenzenesulfonyl chloride (1.294 g, 6.79 mmol), 4,4,4-trifluoro-1-phenylbutane-1,3-dione (0.196 g, 0.90 mmol), iron(III) chloride (73 mg, 0.45 mmol) and huninine (1.5 ml, 8.60 mmol) in acetonitrile (10 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. Purification by FSC (elution gradient: 10%-50% EtOAc in hexanes) gave the title compound (1.610 g, 81%) as a light grey solid. ¹ H NMR (CD ₂ Cl ₂ ) δ 2.24 (3H, d), 2.37 (3H, s), 4.03 - 4.05 (1H, m), 4.05 - 4.07 (1H, m), 4.42 - 4.47 (1H, m), 4.47 - 4.53 (1H, m), 4.55 - 4.61 (1H, m), 4.91 (1H, dd), 6.98 (1H, s), 7.05 (2H, d), 7.39 (2H, d), 7.94 (1H, d), 8.08 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 439.2. Intermediate 79b: ( 3s , 6s )-3-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

To a stirred solution of intermediate 79a (1.47 g, 3.35 mmol) and tributyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (2.361 g, 10.04 mmol) in DMF (12 mL) at 0 °C was added KO t Bu (1 M in THF, 9 mL, 9.00 mmol). The reaction was allowed to warm to room temperature and stirred for 1 h. LCMS showed both cis and trans isomers. The reaction was diluted with EtOAc and washed with NH ₄ Cl solution. The organic phase was dried over MgSO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 10%-40% EtOAc in hexanes) gave the title compound (0.584 g, 34.7%) which eluted second from the column. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.45 - 1.47 (9H, m), 2.20 (2H, br s), 2.29 (3H, s), 3.48 - 3.56 (2H, m), 3.79 (2H, br t), 4.14 (3H, br d), 4.44 (2H, br d), 5.00 (1H, br s), 7.74 (1H, s), 8.24 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 502.3. Intermediate 79c: ( 3s , 6s )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 79b (0.485 g, 0.97 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-20% MeOH in EtOAc) gave the title compound (0.220 g, 42.5%) as a brown solid. 1H NMR (CD ₂ Cl ₂ ): δ 1.45 - 1.48 (9H, m), 2.20 (2H, br s), 2.32 (3H, s), 2.85 (2H, t), 3.53 (2H, br t), 3.73 - 3.86 (2H, m), 3.88 (2H, t), 4.16 (2H, br d), 4.45 (2H, br d), 5.07 (1H, br s), 7.50 (1H, s), 7.77 - 7.81 (2H, m), 8.17 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 536.7. Intermediate 79d: 1-[1-((3 s ,6 s )-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 79c (220 mg, 0.41 mmol). Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2N _NH3 in MeOH gave the title compound (175 mg, 98%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 2.08 - 2.24 (2H, m), 2.39 - 2.46 (1H, m), 2.65 - 2.73 (2H, m), 2.73 - 2.79 (2H, m), 2.94 (2H, td), 3.27 - 3.33 (3H, m), 3.80 (2H, t), 3.96 (2H, br d), 4.52 - 4.60 (2H, m), 4.87 (1H, br s), 7.81 (1H, s), 7.92 (1H, d), 8.17 (1H, d), 10.37 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 436.6. 1-[1-[(3 s ,6 s )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (12.5 mg, 0.025 mmol) and intermediate 79d (10.9 mg, 0.03 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (10.0 mg, 43.4%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.22 - 1.30 (2H, m), 1.58 - 1.70 (1H, m), 1.77 (2H, br d), 1.91 - 1.97 (2H, m), 2.09 - 2.16 (2H, m), 2.26 - 2.28 (3H, m), 2.28 - 2.33 (2H, m), 2.63 - 2.68 (2H, m), 2.70 - 2.80 (4H, m), 3.09 (2H, br d), 3.18 - 3.28 (4H, m), 3.32 - 3.41 (4H, m), 3.80 (2H, t), 3.98 (2H, br d), 4.34 (2H, br s), 4.57 (2H, br d), 4.88 (1H, br s), 5.92 (2H, s), 6.40 - 6.49 (2H, m), 6.84 - 6.98 (3H, m), 7.22 (1H, t), 7.45 (1H, s), 7.80 (1H, s), 7.88 - 7.94 (2H, m), 8.18(1H, d), 10.37 (1H, s), 14.15 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 923.0. Example 80 Intermediate 80a: (3 r ,6 r )-3-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 79b starting from intermediate 79a (1.47 g, 3.35 mmol). Purification by FSC (elution gradient: 10%-40% EtOAc in hexanes) gave the title compound (0.825 g, 49.1%) which eluted first from the column. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.45 (9H, s), 2.04 (2H, br s), 2.29 (3H, d), 3.49 - 3.56 (2H, m), 3.77 (2H, t), 4.27 (2H, dd), 4.56 (2H, br d), 4.95 (1H, t), 7.42 (1H, s), 8.00 (1H, d), 8.26 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 502.3. Intermediate 80b: (3 r ,6 r )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 80a (0.485 g, 0.97 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-20% MeOH in EtOAc) gave the title compound (0.425 g, 48.3%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.45 - 1.47 (9H, m), 2.07 (2H, br s), 2.32 (3H, s), 2.85 (2H, t), 3.47 - 3.59 (2H, m), 3.71 - 3.84 (2H, m), 3.87 (2H, t), 4.32 (2H, dd), 4.55 (2H, br d), 5.00 (1H, br t), 7.45 (1H, s), 7.61 (1H, s), 7.79 (1H, d), 8.19 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 536.6. Intermediate 80c: 1-[1-((3 r ,6 r )-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 80b (425 mg, 0.79 mmol). Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2N _NH3 in MeOH gave the title compound (321 mg, 93%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 2.10 - 2.22 (2H, m), 2.25 (3H, s), 2.36 - 2.43 (1H, m), 2.69 - 2.80 (4H, m), 2.85 - 3.01 (2H, m), 3.80 (2H, t), 4.22 (2H, dd), 4.29 - 4.35 (2H, m), 4.96 - 5.02 (1H, m), 7.59 (1H, s), 7.92 (1H, d), 8.21 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 436.6. 1-[1-[(3 r ,6 r )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (25.1 mg, 0.05 mmol) and intermediate 80c (28.3 mg, 0.07 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (21 mg, 45.6%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.21 - 1.28 (2H, m), 1.58 - 1.69 (1H, m), 1.70 - 1.80 (2H, m), 1.91 - 1.97 (2H, m), 2.09 - 2.16 (2H, m), 2.22 - 2.27 (4H, m), 2.28 - 2.33 (2H, m), 2.60 - 2.69 (2H, m), 2.71 - 2.84 (4H, m), 3.06 - 3.12 (2H, m), 3.16 - 3.26 (3H, m), 3.31 - 3.39 (4H, m), 3.80 (2H, t), 4.25 (2H, br s), 4.29 - 4.38 (4H, m), 4.97 - 5.03 (1H, m), 5.92 (2H, s), 6.42 (1H, br dd), 6.46 - 6.51 (1H, m), 6.77 - 6.88 (2H, m), 6.88 - 6.95 (1H, m), 7.16 - 7.27 (1H, m), 7.45 (1H, s), 7.61 (1H, s), 7.85 - 7.96 (2H, m), 8.21 (1H, d), 10.38 (1H, s), 14.18 (1H, br d); m/z (ES ⁺ ) [M+H] ⁺ = 923.0. Example 81 Intermediate 81a: 4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

A mixture of intermediate 54a (1317 mg, 3.33 mmol), tributyl 4-fluoro-4-formylpiperidine-1-carboxylate (1925 mg, 8.33 mmol), titanium(IV) isopropoxide (2 ml, 6.66 mmol) in THF (20 mL) was stirred overnight. Na(OAc) ₃ BH (2117 mg, 9.99 mmol) was added and the reaction was stirred for 2 h. The reaction was quenched with NH ₄ OH (2 M, 50 mL) and extracted with CHCl ₃ /IPA (3:1), dried over MgSO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 15%-50% solvent B in _CH2Cl2 , solvent B 10% MeOH _{in CH2Cl2} containing 1% _NH4OH ) gave the title compound (501 mg, 24.63%) as an _off -white solid. ¹ H NMR (DMSO- d6 ): δ 1.24 - 1.33 (2H, m), 1.33 - 1.37 (2H, m), 1.38 - 1.43 (9H, m), 1.49 - 1.63 (2H, m), 1.63 - 1.73 (4H, m), 1.73 - 1.83 (4H, m), 1.94 - 2.05 (2H, m), 2.21 - 2.28 (3H, m), 2.28 - 2.47 (6H, m), 2.69 - 2.77 (2H, m), 2.93 - 3.10 (2H, m), 3.62 - 3.74 (2H, m), 3.79 (2H, s), 4.48 - 4.65 (1H, m), 7.52 (1H, s), 7.85 (1H, d), 8.14 (1H, d), 10.35 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 611.3. Intermediate 81b: 1-[1-[3-[(4-fluoro-4-piperidinyl)methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 2c starting from intermediate 81a (500 mg, 0.82 mmol). Purification by ion exchange chromatography (Porapak Rxn CX 2g cartridge) eluting with 2 N _NH3 in MeOH gave the title compound (391 mg, 94%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ = 511.5. Intermediate 81c: N -tert-butyloxycarbonyl- N- [4-[8-[3-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tert-butyl ester

Prepared in a similar manner to intermediate 78c starting from intermediate 81b (0.184 g, 0.36 mmol), intermediate 57a (0.201 g, 0.3 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (0.14 g, 40.8%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.35 - 1.39 (1H, m), 1.43 - 1.47 (18H, m), 1.53 - 1.62 (2H, m), 1.68 - 1.74 (2H, m), 1.82 - 2.08 (14H, m), 2.28 - 2.32 (3H, m), 2.47 - 2.58 (6H, m), 2.81 - 2.87 (2H, m), 2.92 - 3.00 (2H, m), 3.17 - 3.24 (2H, m), 3.33 - 3.35 (3H, m), 3.36 - 3.37 (2H, m), 3.83 - 3.89 (2H, m), 4.16 - 4.25 (2H, m), 4.62 - 4.72 (1H, m), 5.15 - 5.19 (2H, m), 5.30 - 5.31 (3H, m), 6.35 (1H, br d), 6.43 - 6.47 (1H, m), 6.88 (1H, dd), 7.12 - 7.23 (3H, m), 7.34 - 7.43 (2H, m), 7.63 (1H, s), 7.73 (1H, d), 7.85 (1H, dd), 8.16 (1H, d): m/z (ES ⁺ ) [M+H] ⁺ = 1144.8. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting from intermediate 81c (135 mg, 0.12 mmol) in a similar manner to Example 78. Purification by RPC (elution gradient: 50%-100% CH ₃ CN in water containing 0.1% NH ₄ OH) gave the title compound (55.0 mg, 51.8%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.22 - 1.32 (10H, m), 1.36 - 1.41 (2H, m), 1.66 - 1.73 (4H, m), 1.78 - 1.83 (2H, m), 1.88 - 2.01 (6H, m), 2.08 - 2.16 (2H, m), 2.24 (3H, s), 2.73 - 2.78 (2H, m), 2.89 - 2.96 (2H, m), 3.04 - 3.12 (2H, m), 3.12 - 3.19 (2H, m), 3.20 - 3.26 (2H, m), 3.79 (2H, t), 4.36 (2H, br s), 4.54 - 4.63 (1H, m), 5.88 - 5.97 (2H, m), 6.40 - 6.48 (1H, m), 6.48 - 6.54 (1H, m), 6.80 - 6.90 (2H, m), 6.90 - 6.97 (1H, m), 7.19 - 7.24 (1H, m), 7.45 (1H, s), 7.52 (1H, s), 7.84 - 7.86 (1H, m), 7.86 - 7.93 (1H, m), 8.15 (1H, d), 10.35 (1H, s), 13.98 - 14.28 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 900.8. Example 82 Intermediate 82a: 4-[3-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)cyclobutyl]piperidin-1-carboxylic acid tributyl ester

Tributyl piperidine-1-carboxylate (2.92 g, 15.7 mmol) and MgSO ₄ (1.89 g, 15.7 mmol) were added to a solution of 3-hydroxycyclobutane-1-ol (1.35 g, 15.7 mmol) in DCM (35 mL). The resulting mixture was stirred at room temperature for 30 min. Na(OAc) ₃ BH (4.99 g, 23.5 mmol) was added. The resulting mixture was stirred at room temperature for 200 min. Saturated aqueous K ₂ CO ₃ solution (30 mL) and water (100 mL) were added and the phases were separated. The aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. To the residue were added 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (3.31 g, 15.7 mmol) and 2-(tributyl- l5 -phosphino)acetonitrile (4.11 mL, 15.7 mmol) and toluene (78 mL). The resulting mixture was stirred at 100°C for 18 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. Purification by FSC (elution gradient: 0 to 100% EtOAc in hexane, then 0 to 60% acetone in hexane) gave the title compound (443 mg, 6%). ¹ H NMR (DMSO- d ₆ ): δ 1.39 (9H, s), 2.18 - 2.30 (9H, m), 2.54 - 2.67 (3H, m), 3.32 (4H, br s), 4.87 - 4.98 (1H, m), 7.56 (1H, s), 8.14 (1H, d), 8.25 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 449.3. Intermediate 82b: 4-[3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]cyclobutyl]piperidin-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2b starting from intermediate 82a (402 mg, 0.89 mmol). Purification by FSC (elution gradient: 0 to 100% [3:1 EtOAc/EtOH] in hexanes then 0 to 20% MeOH in DCM) gave the title compound (219 mg, 51%) as a brown solid. ¹ H NMR (DMSO- d ₆ ): δ 1.41 (9H, s), 2.22 - 2.33 (9H, m), 2.57 - 2.70 (3H, m), 2.76 (2H, t), 3.35 (4H, br s), 3.81 (2H, t), 4.92 - 5.05 (1H, m), 7.55 (1H, s), 7.89 (1H, d), 8.18 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 483.5. Intermediate 82c: 1-[3-methyl-1-(3-piperidin-1-ylcyclobutyl)pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

2 MH ₂ SO ₄ aqueous solution (3.00 mL, 6.00 mmol) was added to a solution of intermediate 82b (212 mg, 0.44 mmol) in THF (3 mL). The resulting mixture was stirred at 50 °C for 1 h. The mixture was diluted with DCM-IPA (3:1, 20 mL). Saturated K ₂ CO ₃ aqueous solution (20 mL) was added and the phases were separated. The aqueous layer was extracted with DCM-IPA (3:1, 2 x 20 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (162 mg, 96%) as a beige solid. ¹ H NMR (DMSO- d ₆ ): δ 1.81 - 2.09 (1H, m), 2.12 - 2.40 (9H, m), 2.53 - 2.61 (3H, m), 2.69 (4H, t), 2.74 (2H, t), 3.79 (2H, t), 4.90 - 5.03 (1H, m), 7.54 (1H, s), 7.87 (1H, d), 8.16 (1H, d), 10.37 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 383.4. 1-[1-[3-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

NMP (1 mL) was added to a mixture of intermediate 82c (30 mg, 0.08 mmol) and intermediate 13d (30 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 3 min, and then Na(OAc) ₃ BH (25 mg, 0.12 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. Purification by RPC (elution gradient: 0 to 60% MeCN in water containing 0.1% formic acid) gave the title compound (21.1 mg, 41%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.19 - 1.30 (2H, m), 1.61 (1H, td), 1.76 (2H, br d), 1.86 - 1.96 (2H, m), 2.07 - 2.46 (16H, m), 2.50 - 2.68 (6H, m), 2.74 (2H, t), 3.09 (2H, br d), 3.24 (2H, br d), 3.34 (2H, br d), 3.79 (2H, t), 4.33 (2H, br s), 4.96 (1H, br t), 5.92 (2H, s), 6.37 - 6.49 (2H, m), 6.81 - 6.95 (3H, m), 7.18 - 7.24 (1H, m), 7.45 (1H, s), 7.53 (1H, s), 7.84 - 7.92 (2H, m), 8.16 (1H, d), 10.36 (1H, s), 14.15 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 869.5. Example 83 Intermediate 83a: 4-bromo-2-(4-(dibutoxymethyl)piperidin-1-yl)benzonitrile

4-(Dibutoxymethyl)piperidine (0.730 g, 3.00 mmol) was added to 4-bromo-2-fluorobenzonitrile (0.5 g, 2.50 mmol) in DMSO (3.91 ml) and DIPEA (1.092 ml, 6.25 mmol). The reaction mixture was heated to 120 °C for 3 h. The crude reaction mixture was cooled and diluted with 25 mL of EtOAc and 25 mL of water. The aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were then washed with brine (25 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated in vacuo, and the crude mixture was purified by FSC (Gradient: 0-100% EtOAc/hexanes) to give the title compound (0.475 g, 44.9%) as a yellow oil. ¹ H NMR (DMSO- d 6): δ 0.83 - 0.92 (6H, m), 1.29 - 1.43 (6H, m), 1.44 - 1.53 (4H, m), 1.63 - 1.71 (1H, m), 1.75 (2H, br d), 2.73 - 2.82 (2H, m), 3.36 - 3.43 (2H, m), 3.53 - 3.58 (3H, m), 4.19 - 4.25 (1H, m), 7.20 - 7.23 (1H, m), 7.26 (1H, d), 7.54 - 7.65 (1H, m), 7.58 - 7.59 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 423.4. Intermediate 83b: N -tert-butyloxycarbonyl- N- [4-[8-[4-cyano-3-[4-(dibutoxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalim-3-yl]carbamic acid tert-butyl ester

Intermediate 25d (400 mg, 0.74 mmol), intermediate 83a (375 mg, 0.89 mmol), Cs ₂ CO ₃ (722 mg, 2.22 mmol), RuPhos Pd G3 (61.8 mg, 0.07 mmol) and 1,4-dioxathiocarbamide (7385 μL) were added. The reaction was degassed by bubbling nitrogen for 10 min. The reaction was heated to 100 °C overnight. The reaction was cooled to room temperature, filtered through celite® and concentrated. Purification by FSC (gradient: 0-100% EtOAc/hexanes) gave the title compound (435 mg, 66.6%). ¹ H NMR (DMSO- d 6): δ 0.86 - 0.90 (6H, m), 1.32 - 1.37 (6H, m), 1.38 (17H, s), 1.44 - 1.53 (6H, m), 1.63 - 1.70 (1H, m), 1.74 (2H, br d), 1.85 - 1.91 (2H, m), 1.99 (1H, br d), 2.41 - 2.47 (1H, m), 2.53 - 2.61 (1H, m), 2.65 - 2.71 (2H, m), 3.15 - 3.20 (2H, m), 3.39 (3H, dt), 3.44 - 3.50 (3H, m), 3.51 - 3.58(3H, m), 4.21 - 4.25 (1H, m), 4.56 - 4.61 (2H, m), 5.20 (2H, s), 6.42 - 6.46 (1H, m), 6.56 - 6.60 (1H, m), 7.12 - 7.17 (1H, m), 7.22 - 7.25 (1H, m), 7.40 (1H, d), 7.42 - 7.47 (1H, m), 7.50 - 7.53 (1H, m), 7.67 - 7.71 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 884.3. Intermediate 83c: 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-(4-methyl-1-piperidinyl)benzonitrile

2 MH ₂ SO ₄ aqueous solution (1.131 mL, 2.26 mmol) was added to intermediate 83b (100 mg, 0.11 mmol) in THF (1 mL), and the reaction mixture was heated to 60 °C for 1 h. The mixture was cooled in an ice bath and quenched with saturated NaHCO ₃ aqueous solution (25 mL). The aqueous layer was extracted with DCM (3 x 25 mL), and the combined organic layers were dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the crude material, which was used in the next step without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 510.4. 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-1-piperidinyl]benzonitrile

Prepared from intermediate 83c (28.3 mg, 0.06 mmol) and intermediate 56c (25 mg, 0.06 mmol) in a similar manner to Example 11. Purification by RPC (elution gradient: 0-100% MeCN in water containing 0.1% FA) gave the title compound (18.00 mg, 35.9%) as an amorphous solid. ¹ H NMR (DMSO- d 6): δ 1.24 - 1.30 (5H, m), 1.35 - 1.43 (2H, m), 1.71 (5H, br s), 1.81 (4H, br s), 1.94 - 2.04 (4H, m), 2.22 (4H, br t), 2.37 (4H,br s), 2.53 - 2.64 (1H, m), 2.70 (3H, q), 2.74 - 2.79 (3H, m), 3.02 - 3.09 (1H, m), 3.05 (1H, br d), 3.25 - 3.31 (2H, m), 3.31 - 3.43 (2H, m), 3.46 - 3.54 (1H, m),3.49 - 3.65 (3H, m), 3.81 (2H, br t), 4.56 - 4.66 (2H, m), 5.95 - 6.02 (1H, m), 6.39 - 6.47 (1H, m), 6.52 - 6.60 (1H, m), 6.82 - 6.92 (2H, m),7.20 - 7.27 (1H,m), 7.35 - 7.44 (1H, m), 7.47 - 7.53 (1H, m), 7.53 - 7.57 (1H, m), 7.89 - 7.93 (2H, m), 8.13 - 8.18 (1H, m), 10.23 - 10.45 (1H, m); m/z (ES+) [M+H] ⁺ = 903.6. Example 84 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[2-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]non-7-yl]methyl]-1-piperidinyl]benzonitrile

Prepared from intermediate 83c (57 mg, 0.11 mmol) and intermediate 2c (52.8 mg, 0.13 mmol) in a similar manner to Example 11. Purification by RPC (elution gradient: 0-100% MeCN in water containing 0.1% FA) gave the title compound (50.0 mg, 50.4%) as an amorphous white solid. ¹ H NMR (DMSO- d 6): δ 0.61 -0.74 (2H, m), 0.78 - 0.97 (2H, m), 1.10 - 1.28 (2H, m), 1.64 - 1.76 (5H, m), 1.81 (1H, br s), 1.89 - 2.02 (3H, m), 2.15 - 2.27 (6H, m), 2.29 - 2.43 (5H, m), 2.69 - 2.79 (4H, m), 2.95 - 3.09 (2H, m), 3.27 (2H, br d), 3.49 (3H, br d), 3.80 (3H, br t), 4.46 - 4.66 (2H, m), 5.20 - 5.32 (1H, m), 5.96 (1H, s), 6.42 (1H, s), 6.49 - 6.60 (1H, m), 6.76 - 6.92 (2H, m), 7.16 - 7.25 (1H, m), 7.39 (1H, d), 7.45 - 7.51 (1H, m), 7.53 (1H, s), 7.83 - 7.97 (2H, m), 8.09 - 8.24 (2H, m), 10.22 - 10.44 (1H, m), 10.32 - 10.49 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 887.5. Example 85 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 11g (395 mg, 0.62 mmol), intermediate 56c (281 mg, 0.69 mmol) in a similar manner to Example 11. Purification by RPC (elution gradient: 0-100% MeCN in water containing 0.1% FA) gave the title compound (354 mg, 63.3%) as an amorphous solid. ¹ H NMR (DMSO- d 6): δ 1.20 - 1.32 (7H, m), 1.35 - 1.41 (2H, m), 1.57 - 1.64 (1H, m), 1.65 - 1.72 (4H, m), 1.74 - 1.82 (4H, m), 1.90 - 2.04 (4H, m), 2.08 - 2.15 (2H, m), 2.17 - 2.22 (2H, m), 2.30 - 2.39 (4H, m), 2.61 - 2.70 (4H, m), 2.72 - 2.77 (2H, m), 3.06 - 3.12 (2H, m), 3.21 - 3.27 (1H, m), 3.25 (3H, br d), 3.26 - 3.28 (1H, m), 3.75 - 3.82 (2H, m), 4.26 - 4.41 (2H, m), 4.52 - 4.68 (1H, m), 5.80 - 6.01 (2H, m), 6.37 - 6.52 (2H, m), 6.80 - 6.96 (3H, m), 7.16 - 7.27 (1H, m), 7.38 - 7.58 (2H, m), 7.80 - 7.93 (2H, m), 8.11 - 8.22 (1H, m), 10.35 (1H, s); m/z (ES ⁺ ) [M+Na] ⁺ = 918.49. Example 86 Intermediate 86a: [(1 R , 5 S , 6 r )-3-(5-chloro-2-fluoro-phenyl)-3-azabicyclo[3.1.0]hexan-6-yl]methanol

BINAP (0.595 g, 0.95 mmol) was added to 2-bromo-4-chloro-1-fluorobenzene (2 g, 9.55 mmol), ((1 R ,5 S ,6 r )-3-azabicyclo[3.1.0]hexan-6-yl)methanol (1.189 g, 10.50 mmol), Pd ₂ (dba) ₃ (0.874 g, 0.95 mmol) and NaO t Bu (2.75 g, 28.65 mmol) in toluene (20 mL) under nitrogen. The resulting mixture was stirred at 50 °C for 18 h. The reaction mixture was filtered and concentrated under reduced pressure. Purification by FSC (elution gradient: 0-100% EtOAc in petroleum ether) gave the title compound (0.970 g, 42.0%) as a yellow gum. ¹ H NMR (DMSO- d6 ): δ 0.92 - 0.97 (1H, m), 1.51 - 1.57 (2H, m), 3.25 - 3.28 (2H, m), 3.30 - 3.33 (2H, m), 3.57 - 3.62 (2H, m), 4.52 (1H, t), 6.67 - 6.70 (2H, m), 7.02 - 7.09 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 241.95. Intermediate 86b: (1 R ,5 S ,6 r )-3-(5-chloro-2-fluoro-phenyl)-6-(dimethoxymethyl)-3-azabicyclo[3.1.0]hexane

Methyl N-(triethylammoniumsulfonyl)carbamate (8.87 g, 37.24 mmol) was added to intermediate 86a (1.5 g, 6.21 mmol) in DMSO (20.0 mL). The resulting suspension was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (125 mL) and washed successively with water (3 x 50 mL). The organic layer was dried over Na ₂ SO ₄ and evaporated. To the crude product were added p TsOH •H ₂ O (0.214 g, 1.24 mmol), trimethoxymethane (1.976 g, 18.62 mmol) and MeOH (7 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO ₃ (3 x 50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by RPC (elution gradient: 5% to 100% MeCN in water (0.1% NH ₄ HCO ₃ )) gave the title compound (0.790 g, 44.5%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 0.99 - 1.04 (1H, m), 1.67 - 1.71 (2H, m), 3.25 (6H, s), 3.26 - 3.29 (2H, m), 3.59 - 3.64 (2H, m), 4.18 (1H, d), 6.66 - 6.71 (2H, m), 7.02 - 7.09 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 286.1. Intermediate 86c: 8-[3-[(1 R ,5 S ,6 r )-6-(dimethoxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Prepared in analogy to intermediate 42c starting from intermediate 86b (1 g, 3.50 mmol) and ( 1R , 5S )-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester HCl (0.990 g, 3.50 mmol). Purification by RPC (elution gradient: 5% to 100% MeCN in water (0.1% _{NH4HCO3 )} ) gave the title compound (0.860 g, 49.6%) as a yellow gum. ¹ H NMR (DMSO- d ₆ ): δ 1.04 - 1.10 (1H, m), 1.61 - 1.67 (4H, m), 1.85 - 1.90 (2H, m), 3.12 (1H, d), 3.16 - 3.27 (9H, m), 3.55 - 3.64 (4H, m), 4.14 - 4.23 (3H, m), 5.07 (2H, d), 6.10 - 6.19 (2H, m), 6.82 - 6.88 (1H, m), 7.29 - 7.40 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 496.2. Intermediate 86d: 8-[3-[(1 R , 5 S , 6 r )-6-(dimethoxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane

Under hydrogen atmosphere, potassium hydroxide/carbon powder (244 mg, 0.174 mmol) was added to intermediate 86c (860 mg, 1.74 mmol) in MeOH (10 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was filtered through a celite® pad, and the filtrate was concentrated to afford the title compound (290 mg, 46.2%) as a yellow solid, which was used without further purification. ¹ H NMR (DMSO- d6 ): δ 0.80 - 0.87 (1H, m), 1.04 - 1.10 (1H, m), 1.19 - 1.29 (1H, m), 1.64 - 1.68 (2H, m), 1.77 - 1.89 (5H, m), 2.34 - 2.38 (1H, m), 2.93 (1H, d), 3.16 - 3.20 (2H, m), 3.22 - 3.26 (7H, m), 3.57 - 3.62 (2H, m), 3.94 - 3.97 (1H, m), 4.17 (1H, d), 6.01 - 6.12 (2H, m), 6.77 - 6.85 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 362.3. Intermediate 86e: 6-Chloro-4-[8-[3-[(1 R ,5 S ,6 r )-6-(dimethoxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-amine

Prepared in an analogous manner to intermediate 49e starting from intermediate 86d (200 mg, 0.55 mmol). Purification by RPC (elution gradient: 5% to 100% MeCN in water (0.1% _NH4HCO3 )) gave the title compound (100 mg, _37.0 %) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.03 - 1.09 (1H, m), 1.66 (2H, d), 1.90 (2H, d), 2.08 (2H, d), 2.95 (2H, d), 3.11 - 3.20 (3H, m), 3.21 - 3.25 (7H, m), (7H, s), 3.59 - 3.66 (2H, m), 4.18 (1H, d), 4.26 - 4.29 (2H, m), 5.80 (2H, s), 6.10 - 6.23 (2H, m), 6.81 - 6.90 (2H, m); m/z (ES ^- ) [MH] ^- = 487.4. Intermediate 86f: 2-[6-amino-5-[8-[3-[(1 R ,5 S ,6 r )-6-(dimethoxymethyl)-3-azabicyclo[3.1.0]hex-3-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-yl]phenol

Pd(dppf)Cl ₂ (29.9 mg, 0.04 mmol) was added to (2-hydroxyphenyl)boronic acid (85 mg, 0.61 mmol), Cs ₂ CO ₃ (400 mg, 1.23 mmol) and intermediate 86e (200 mg, 0.41 mmol) in 1,4-dioxathiocarbamide (3.0 mL) and water (0.6 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 20 h. The solvent was removed under reduced pressure. Purification by FSC (elution gradient: 0 to 100% EtOAc in petroleum ether) gave the title compound (110 mg, 49.2%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.00 - 1.09 (1H, m), 1.64 (2H, d), 1.90 - 1.95 (2H, m), 2.10 (2H, d), 3.08 (2H, d), 3.20 - 3.25 (10H, m), 3.57 - 3.66 (2H, m), 4.16 (1H, d), 4.23 - 4.37 (2H, m), 5.93 (2H, s), 6.10 - 6.23 (2H, m), 6.79 - 6.89 (3H, m), 7.21 (1H, t), 7.44 (1H, s), 7.90 (1H, d), 14.18 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 547.3. 1-[1-[3-[[(1 R ,5 S ,6 s )-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

pTsOH •H ₂ O (30.6 mg, 0.16 mmol) was added to intermediate 13b (80 mg, 0.16 mmol) in MeCN (1.5 mL). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was evaporated to provide the crude amine. In a second vial, intermediate 86f (142 mg, 0.23 mmol) was added to formic acid (3 mL) and stirred at 40 °C for 20 min. The reaction mixture was evaporated. The residue was quenched with saturated Na ₂ CO ₃ (10 mL), extracted with EtOAc (3 x 5 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude aldehyde residue was combined with the crude amine in DCE (1.0 mL) and NMP (1.0 mL). The resulting mixture was stirred at 40 °C for 2 h. Then, Na(OAc) ₃ BH (136 mg, 0.64 mmol) was added and stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with DCM/ i PrOH (1: 1) (10 mL) and washed with saturated aqueous NaHCO ₃ solution (2 x 10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by RPC (elution gradient: 0-35% MeCN in water containing 0.1% formic acid) gave the title compound (11.80 mg, 11.78%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.22 - 1.37 (3H, m), 1.38 - 1.45 (2H, m), 1.44 - 1.52 (2H, m), 1.75 (6H, d), 1.89 - 2.05 (4H, m), 2.12 (2H, d), 2.25 (3H, s), 2.33 (2H, d), 2.70 - 2.80 (2H, m), 3.09 (2H, d), 3.23 (5H, d), 3.42 - 3.56 (3H, m), 3.61 - 3.70 (2H, m), 3.76 - 3.85 (2H, m), 4.33 (2H, s), 4.54 - 4.66 (1H, m), 5.95 (2H, s), 6.12 - 6.24 (2H, m), 6.79 - 6.91 (3H, m), 7.16 - 7.28 (1H, m), 7.46 (1H, s), 7.54 (1H, s), 7.87 (1H, d), 7.90 - 7.94 (1H, m), 8.16 (1H, d), 10.40 (1H, s), 13.87 - 14.47 (1H, m); ¹⁹ F NMR (DMSO- d6 ): δ -138.29; m/z (ES ⁺ ), [M+2H] ⁺ /2 = 440.9. Example 87 Intermediate 87a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridine

Prepared in an analogous manner to intermediate 4a from 5-bromo-3-cyclopropyl- 1H -pyrrolo[2,3 -b ]pyridine (2 g, 8.44 mmol). Purification by FSC (elution gradient: 0 to 50% EtOAc in petroleum ether) gave the title compound (3.10 g, 94%) as a yellow liquid. ¹ H NMR (DMSO- d6 ): δ 0.56-0.68 (2H, m), 0.78-0.95 (2H, m), 1.9-1.99 (1H, m), 3.73-3.78 (2H, m), 3.8-3.85 (2H, m), 3.88-3.92 (4H, m), 3.99-4.01 (1H, m), 5.08-5.15 (4H, m), 5.71-5.81 (2H, m), 7.42 (1H, s), 8.20 (1H, d), 8.27 (1H, d); m/z (ES ⁺ ), [M+H] ⁺ = 391.1. Intermediate 87b: 2-(5-bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)propane-1,3-diol

Pd(PPh ₃ ) ₄ (0.443 g, 0.38 mmol) was added to intermediate 87a (3 g, 7.67 mmol) and 1,3-dimethylbarbituric acid (2.394 g, 15.33 mmol) in MeOH (45 mL) under nitrogen over a period of 5 min. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (200 mL), extracted with DCM (3 x 200 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0 to 70% EtOAc in petroleum ether) gave the title compound (2.1 g, 88%) as a yellow liquid. ¹ H NMR (DMSO- d6 ): δ 0.6-0.67 (2H, m), 0.81-0.9 (2H, m), 1.15-1.21 (1H, m), 3.76 (4H, d), 4.73-4.82 (1H, m), 4.86 (2H, s), 7.38 (1H, s), 8.18 (1H, d), 8.25 (1H, d); m/z (ES ⁺ ), [M+H] ⁺ = 311.1. Intermediate 87c: 3-(5-Bromo-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

p-Toluenesulfonic acid (0.221 g, 1.29 mmol) was added to intermediate 87b (2 g, 6.43 mmol) and benzyl 4-oxopiperidine-1-carboxylate (3.00 g, 12.85 mmol) in toluene (30 mL). The resulting mixture was stirred at 100 °C for 20 h. After cooling to room temperature, the mixture was filtered and the filter cake was washed with EtOAc. The combined filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with saturated aqueous NaHCO ₃ solution (2 x 100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 0 to 100% EtOAc in petroleum ether) gave the title compound (3.20 g, 95%) as a yellow liquid. ¹ H NMR (DMSO- d6 ): δ 0.59-0.67 (2H, m), 0.86-0.91 (2H, m), 1.90 (2H, d), 1.94-1.97 (2H, m), 1.98 (1H, d), 3.44-3.48 (4H, m), m/ z (ES ⁺ ) [M+H] ⁺ = 526.2. Intermediate 87d: 3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 6b starting from intermediate 87c (3 g, 5.70 mmol). Purification by FSC (elution gradient: 0 to 5% MeOH in DCM) gave the title compound (1.0 g, 31.4%) as a light brown solid. ¹ H NMR (DMSO- d6 ): δ 0.58-0.68 (2H, m), 0.87-0.95 (2H, m), 1.24 (1H, s), 1.91-2 (5H, m), 2.74-2.8 (2H, m), 3.45-3.49 (4H, m), 3.79-3.86 (2H, m), 4.04-4.11 (2H, m), 4.25 (1H, d), 4.81-4.89 (1H, m), 5.10 (2H, s), 7.31-7.43 (5H, m), 7.63 (1H, s), 7.99 (1H, d), 8.20 (1H, d), 10.40 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 560.1. Intermediate 87e: 1-[3-cyclopropyl-1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Pd-C (60 mg, 0.56 mmol) was added to intermediate 87d (350 mg, 0.63 mmol) in DMF (10 mL) under nitrogen. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. The catalyst was filtered through celite® and the filtrate was evaporated to afford the title compound (250 mg, 94%) as a light grey solid. The crude product was used directly in the next step without further purification. ¹ H NMR (DMSO- d6 ): δ 0.60-0.67 (2H, m), 0.86-0.91 (2H, m), 1.16 (1H, d), 1.8-1.89 (4H, m), 1.92-2 (1H, m), 2.68-2.75 (4H, m), 2.75-2.8 (2H, m), 3.79-3.86 (2H, m), 4-4.11 (2H, m), 4.2-4.33 (2H, m), 4.78-4.88 (1H, m), 7.64 (1H, s), 7.94-8.04 (1H, m), 8.20 (1H, d), 10.40 (1H, s); m/z (ES ⁺ ), [M+H] ⁺ = 426.2. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 11g (65 mg, 0.10 mmol) and intermediate 87e (43.7 mg, 0.10 mmol) in a similar manner to Example 40. Purification by RPC (elution gradient: _0-72 % MeCN in water containing _NH4HCO3 + 0.05% _{NH3H2O )} gave the title compound (18.30 mg, 19.53%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 0.61-0.67 (2H, m), 0.86-0.92 (2H, m), 1.26 (3H, d), 1.63 (1H, s), 1.80 (2H, d), 1.86-1.99 (6H, m), 2.08 (1H, s), 2.1-2.17 (2H, m), 2.21 (2H, s), 2.32 (1H, s), 2.43 (4H, s), 2.62-2.67 (2H, m), 2.74-2.81 (2H, m), 3.11 (2H, d), 3.26 (2H, d), 3.78-3.86 (2H, m), 4-4.09 (2H, m), 4.2-4.3 (2H, m), 4.35 (2H, s), 4.78-4.87 (1H, m), 5.95 (2H, s), 6.41-6.46 (1H, m), 6.46-6.52 (1H, m), 6.83-6.9 (2H, m), 19 ^F NMR (DMSO- d6 ): δ -136.401; m/z (ES ⁺ ) [M+H] ⁺ = 912.5. Example 88 1-[1-[7-[[(1 R ,5 S ,6 S )-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hex-6-yl]methyl]-7-azaspiro[3.5]non-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 86f (40 mg, 0.07 mmol) and intermediate 42f (32.3 mg, 0.09 mmol) in a similar manner to Example 41. Purification by RPC (elution gradient: ₅₀ % to 63% MeCN in water containing 10 mmol/ _{L NH4HCO3} + 0.05% _NH3H2O ) gave the title compound (7.94 mg, 12.74%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 0.88 (2H, d), 1.24 (1H, s), 1.48 (2H, s), 1.71 (2H, s), 1.75 (2H, d), 1.95 (2H, d), 2.13 (2H, d), 2.22 (3H, t), 2.27 (4H, s), 2.37 (4H, s), 2.76 (2H, t), 3.10 (2H, d), 3.24 (4H, d), 3.64 - 3.69 (2H, m), 3.81 (2H, t), 4.33 (2H, s), 5.24 - 5.29 (1H, m), 5.94 (2H, s), 6.15 - 6.24 (2H, m), 6.83 - 6.89 (3H, m), 7.19 - 7.24 (1H, m), 7.47 (1H, s), 7.62 (1H, s), 7.89 (1H, d), 7.90 - 7.93 (1H, m), 8.17 (1H, d), 10.39 (1H, s), 14.19 (1H, s); ¹⁹ F NMR (DMSO): δ -138.32; m/z (ES ⁺ ) [M+H] ⁺ = 852.4. Example 89 Intermediate 89a: 8-(3-Benzyloxycyclobutyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 41a starting from 3-(benzyloxy)cyclobutan-1-one (8 g, 45.40 mmol) and ( 1R , 5S )-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester (11.57 g, 54.48 mmol). Purification by RPC (elution gradient: 0 to 80% _MeCN in water containing 0.1% _NH4HCO3 ) gave the title compound (11.79 g, 69.7%) as a yellow gum. ¹ H NMR (DMSO d6 ): δ 1.39 (9H, d), 1.42 (2H, d), 1.61-1.68 (2H, m), 1.71-1.78 (2H, m), 1.98-2.06 (1H, m), 2.35-2.41 (1H, m), 2.43-2.49 (1H, m), 2.78 (1H, d), 2.88-2.97 (1H, m), 3-3.17 (2H, m), 3.49-3.64 (2H, m), 3.69-3.76 (1H, m), 4.36 (2H, d), 7.26-7.37 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 373.3. Intermediate 89b: 8-(3-Hydroxycyclobutyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 41b starting from intermediate 89a (11 g, 29.53 mmol). The precipitate was filtered through celite®, washed with MeOH (50 mL) and dried under vacuum to afford the title compound (8.00 g, 96%) as a brown gum which was used without further purification. ¹ H NMR (DMSO- d6 ): δ 1.36 (9H, s), 1.52 - 1.60 (1H, m), 1.66 - 1.76 (2H, m), 1.78 - 2.04 (1H, m), 2.25 - 2.39 (2H, m), 2.75 (1H, d), 2.82 - 2.94 (1H, m), 3.03 (2H, d), 3.16 (2H, s), 3.45 - 3.65 (2H, m), 3.73 (1H, d), 4.06 - 4.26 (1H, m), 4.93 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 283.3. Intermediate 89c: 8-[(1 s ,3 s )-3-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)cyclobutyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in analogy to intermediate 41c starting from intermediate 89a (5 g, 17.71 mmol) and 5-bromo-3-methyl-1H-pyrrolo[2,3- b ]pyridine (3.74 g, 17.71 mmol). Purification by RPC (elution gradient: 0 to 100% MeCN in water containing 0.1% NH ₄ HCO ₃ ) gave the title compound (0.600 g, 7.13%) as a brown solid. ¹ H NMR (CDCl ₃ ): δ 1.46 (9H, s), 1.60 - 1.71 (3H, m), 1.82 - 1.93 (2H, m), 2.28 (3H, s), 2.67 - 2.77 (2H, m), 2.79 - 2.90 (1H, m), 2.96 - 3.24 (5H, m), 3.63 (1H, d), 3.77 (1H, d), 4.98 - 5.11 (1H, m), 7.32 (1H, s), 7.93 (1H, d), 8.27 (1H, d); m/z (ES ⁺ ) [M+H]+ = 477.4. Intermediate 89d: 8-[(1 s ,3 s )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]cyclobutyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 41d starting from intermediate 89c (250 mg, 0.53 mmol). Purification by RPC (elution gradient: 0 to 70% MeOH in water containing 0.1% NH ₄ HCO ₃ ) gave the title compound (45.0 mg, 16.83%) as a white solid. ¹ H NMR (CDCl ₃ ): δ 1.48 (9H, s), 1.62 - 1.70 (2H, m), 1.86 - 1.94 (2H, m), 2.19 - 2.23 (2H, m), 2.33 (3H, s), 2.72 - 2.79 (2H, m), 2.83 - 2.88 (1H, m), 2.92 (2H, t), 2.99 - 3.12 (2H, m), 3.14 - 3.26 (2H, m), 3.65 (1H, d), 3.79 (1H, d), 3.92 (2H, t), 5.06 - 5.16 (1H, m), 7.39 (1H, s), 7.55 (1H, s), 7.78 (1H, d), 8.22 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 509.3. Intermediate 89e: 1-[1-[(1 s ,3 s )-3-(3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 89d (40 mg, 0.08 mmol) in a similar manner to intermediate 1i. The crude product was evaporated to dryness to afford the title compound (25.00 mg, 78%) as a brown gum. The product was used directly in the next step without further purification. ¹ H NMR (DMSO- d6 ): δ 2.16 -2.22 (2H, m), 2.27 (3H, s), 2.33 - 2.38 (2H, m), 2.74 - 2.81 (5H, m), 2.88 - 2.95 (2H, m), 3.47 -3.56 (2H, m), 3.61 -3.67 (2H, m), 3.70 -3.84 (3H, m), 4.18 - 4.22 (2H, m), 5.10 - 5.18 (1H, m), 7.65 (1H, s), 7.94 (1H, d), 8.21 (1H, d), 10.41 (1H, s); m/z (ES+) [M+H]+ = 409.1. 1-[1-[(1 s ,3 s )-3-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 89e (25 mg, 0.06 mmol) and intermediate 11g (40.3 mg, 0.07 mmol) in a similar manner to Example 41. Purification by RPC (elution gradient: 43% to 57% MeCN in water containing 10 mmol/ _{L NH4HCO3 +} 0.05% _NH3H2O ) gave the title compound (8.0 mg, 14.6%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.20 - 1.27 (3H, m), 1.55 - 1.61 (1H, m), 1.65 - 1.72 (2H, m), 1.73 - 1.83 (4H, m), 1.90 - 1.98 (2H, m), 2.06 - 2.24 (8H, m), 2.28 (3H, s), 2.54 - 2.67 (7H, m), 2.76 (2H, t), 2.84 - 2.91 (1H, m), 3.10 (2H, d), 3.14 - 3.19 (2H, m), 3.26 (2H, d), 3.81 (2H, t), 4.35 (2H, d), 4.90 - 4.99 (1H, m), 5.95 (2H, s), 6.41 - 6.50 (2H, m), 6.84 - 6.96 (3H, m), 7.23 (1H, t), 7.53 (2H, d), 7.87 - 7.93 (2H, m), 8.18 (1H, t), 10.39 (1H, s), 14.18 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -136.45; m/z (ES ⁺ ) [M+H] ⁺ = 895.7. Example 90 Intermediate 90a: (2 S )-4-(5-chloro-2-fluoro-phenyl) iodine-2-carboxylic acid methyl ester

Prepared in an analogous manner to intermediate 42a starting from methyl ( S )-iodine-2-carboxylate (2 g, 13.78 mmol) and 2-bromo-4-chloro-1-fluorobenzene (2.89 g, 13.78 mmol). Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound (1.470 g, 39.0%) as a white liquid. ¹ H NMR (DMSO- d ₆ ): δ 2.92 - 2.99 (1H, m), 3.08 - 3.14 (2H, m), 3.33 - 3.37 (1H, m), 3.69 (3H, s), 3.71 - 3.76 (1H, m), 3.98 - 4.05 (1H, m), 4.40 - 4.44 (1H, m), 7.04 - 7.07 (1H, m), 7.07 - 7.10 (1H, m), 7.18 - 7.23 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 274.1. Intermediate 90b: (2 S )-4-(5-chloro-2-fluoro-phenyl)-2-(dimethoxymethyl)thiophene

Prepared in an analogous manner to intermediate 42b starting from intermediate 90a (1.47 g, 5.37 mmol). Purification by FSC (elution gradient: 0 to 50% EtOAc in petroleum ether) gave the title compound (0.810 g, 52.1%) as a yellow liquid. ¹ H NMR (DMSO- d6 ): δ 2.60 - 2.66 (1H, m), 2.76 - 2.85 (1H, m), 3.14 - 3.19 (1H, m), 3.25 - 3.30 (1H, m), 3.33 (6H, d), 3.61 - 3.69 (2H, m), 3.89 - 3.95 (1H, m), 4.32 (1H, d), 6.99 - 7.06 (2H, m), 7.14 - 7.23 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 290.1. Intermediate 90c: 8-[3-[( 2S )-2-(dimethoxymethyl)oxazolin-4-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 42c starting from intermediate 90b (800 mg, 2.76 mmol) and benzyl ( 1R , 5S )-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (816 mg, 3.31 mmol). Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound (1220 mg, 88%) as a yellow oil. ¹ H NMR (DMSO- d6 ): δ 1.62 - 1.69 (2H, m), 1.86 - 1.93 (2H, m), 2.59 (1H, dd), 2.76 - 2.83 (1H, m), 3.07 - 3.15 (2H, m), 3.20 - 3.28 (2H, m), 3.33 (6H, s), 3.54 - 3.67 (4H, m), 3.88 - 3.93 (1H, m), 4.20 - 4.29 (2H, m), 4.31 (1H, d), 5.06 - 5.09 (2H, m), , 6.40 - 6.46 (2H, m), 6.92 - 6.98 (1H, m), 7.16 - 7.63 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 500.4. Intermediate 90d: (2 S )-4-[5-(3,8-diazabicyclo[3.2.1]oct-8-yl)-2-fluoro-phenyl]-2-(dimethoxymethyl)oxazolidine

Prepared in a similar manner to intermediate 88d starting from intermediate 90c (1.2 g, 2.40 mmol).The reaction mixture was filtered through celite® and the filtrate was collected and evaporated to afford the title compound (0.670 g, 76%) as a yellow oil. ¹ H NMR (DMSO- d6 ): δ 1. 73 - 1.95 (4H, m), 2.34 - 2.43 (2H, m), 2.5 -2.60 (1H, m), 2.75 -2.82 (1H, m), 2.94 (1H, d), 3.06 - 3.11(1H, m), 3.23 -3.27 (1H, m), 3.30(6H, s) 3.59 - 3.69 (2H, m), 3.91 (1H, d), 3.96 - 4.05 (1H, m), 4.15 - 4.18(1H, m), 4.27 - 4.33 (1H, m), 6.30 - 6.42 (2H, m), 6.87 - 6.96 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 366.3. Intermediate 90e: 6-Chloro-4-[8-[3-[(2 S )-2-(dimethoxymethyl)oxazolin-4-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]oxazolidin-3-amine

Prepared in a similar manner to intermediate 49e starting from intermediate 90d (670 mg, 1.83 mmol) and 4-bromo-6-chlorotitanium-3-amine (420 mg, 2.02 mmol). Purification by FSC (elution gradient: 0 to 20% EtOAc in petroleum ether then 0 to 10% MeOH in DCM) gave the title compound (650 mg, 71.9%) as a grey gum. ¹ H NMR (DMSO- d6 ): δ 1.92 - 1.96 (2H, m), 2.11 - 2.15 (2H, m), 2.59 (1H, t), 2.78 - 2.86 (1H, m), 3.08 - 3.14 (3H, m), 3.24 - 3.29 (3H, m), 3.62 - 3.68 (2H, m), 3.89 - 3.94 (1H, m), 4.31 (1H, d), 4.34 - 4.38 (2H, m), 5.95 (2H, s), 6.47 - 6.49 (2H, m), 6.87 - 6.88 (2H, m), 6.95 - 6.99 (1H, m), 7.20 - 7.25 (1H, m), 7.46 (1H, s), 7.88 - 7.93 (1H, m), 14.17 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 493.3. Intermediate 90f: 2-[6-amino-5-[8-[3-[(2 S )-2-(dimethoxymethyl)oxazolin-4-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]oxazolin-3-yl]phenol

Prepared in a similar manner to intermediate 2h starting from intermediate 90e (640 mg, 1.30 mmol) and (2-hydroxyphenyl)boronic acid (358 mg, 2.60 mmol). Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether then 0 to 10% MeOH in DCM) gave the title compound (530 mg, 74.1%) as a grey solid. ¹ H NMR (DMSO- d6 ) δ 0.81 - 0.89 (1H, m), 0.91 - 0.96 (1H, m), 1.07 - 1.12 (1H, m), 1.19 - 1.29 (1H, m), 1.89 - 2.17 (4H, m), 2.53 - 2.65 (2H, m), 2.80 - 2.87 (1H, m), 3.07 - 3.19 (2H, m), 3.22 - 3.32 (4H, m), 3.46 - 3.57 (1H, m), 3.61 - 3.70 (2H, m), 3.89 - 3.96 (1H, m), 4.32 (1H, d), 4.34 - 4.42 (2H, m), 6.13 - 6.23 (1H, m), 6.28 - 6.41 (1H, m), 6.46 - 6.53 (2H, m), 6.83 - 6.94 (2H, m), 6.94 - 7.06 (2H, m), 7.18 - 7.48 (2H, m), 8.00 - 8.18 (1H, m); m/z (ES+) [M+H] ⁺ = 551.4. 1-[1-[7-[[(2 R )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 90f (40 mg, 0.07 mmol) and intermediate 42f (26.7 mg, 0.07 mmol) in a similar manner to Example 42. Purification by RPC (elution gradient: 18% to 33% MeCN in water containing 0.1% formic acid) gave the title compound (4.48 mg, 6.79%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.65 - 1.73 (4H, m), 1.94 - 1.98 (2H, d), 2.14 - 2.17 (2H, d), 2.20 (2H, t), 2.25 - 2.29 (2H, m), 2.34 - 2.40 (5H, m), 2.45 - 2.48 (1H, m), 2.73 - 2.79 (3H,m), 3.10 (2H, t), 3.14 - 3.20 (2H, m), 3.25 - 3.30 (3H, m), 3.34 (2H, d), 3.63 - 3.70 (2H, m), 3.73 - 3.77 (1H, m), 3.80 (2H, t), 3.87 - 3.92 (1H, m), 4.34 - 4.40 (2H, m), 5.21 - 5.30 (1H, m), 5.98 (2H, s), 6.45 - 6.50 (2H, m), 6.87 (2H, t), 6.94 - 7.00 (1H, m), 7.21 - 7.26 (1H, m), 7.47 (1H, s), 7.61 (1H, s), 7.87 - 7.93 (2H, m), 8.17 (1H, d), 8.26 - 8.31 (1H, m), 10.39 (1H, s), 14.15 (1H, s); ¹⁹ F NMR (DMSO): δ -136.815; m/z (ES+) [M+H] ⁺ = 856.3. Example 91 Intermediate 91a: 2-(5-Bromo-6-fluoro-3-methyl-indol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4a starting from 5-bromo-6-fluoro-3-methyl- 1H -indole (400 mg, 1.75 mmol) and tributyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (508 mg, 2.10 mmol). Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound (560 mg, 70.7%) as a yellow oil. ¹ H NMR (CDCl ₃ ): δ 1.47 (9 H, s), 1.57 - 1.64 (2 H, m), 1.69 - 1.76 (2 H, m), 2.12 - 2.21 (2 H, m), 2.27 (3 H, s), 2.49 - 2.58 (2 H, m), 3.31 - 3.38 (2 H, m), 3.41 - 3.48 (2 H, m), 4.65 - 4.76 (1 H, m), 6.98 - 7.00 (1 H, m), 7.02 (1 H, d), 7.66 (1 H, d); m/z (ES ⁺ ) [M- t Bu+H] ⁺ = 395. Intermediate 91b: 2-[5-[(3-ethoxy-3-oxopropyl)amino]-6-fluoro-3-methyl-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Pd ₂ (dba) ₃ (46.7 mg, 0.05 mmol) was added to intermediate 91a (230 mg, 0.51 mmol), ethyl 3-aminopropionate (65.7 mg, 0.56 mmol), CPhos (22.25 mg, 0.05 mmol) and Cs ₂ CO ₃ (664 mg, 2.04 mmol) in 1,4-dioxathiocarbamide (5 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (20 mL), extracted with EtOAc (3 x 20 mL), and the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound (200 mg, 80%) as a yellow oil. ¹ H NMR (DMSO- d6 ): δ 1.16 - 1.22 (3H, m), 1.40 (9H, s), 1.50 - 1.57 (2H, m), 1.62 - 1.69 (2H, m), 2.00 - 2.09 (2H, m), 2.19 (3H, s), 2.36 - 2.44 (2H, m), 2.60 - 2.68 (2H, m), 3.18 - 3.27 (2H, m), 3.32 - 3.41 (4H, m), 4.01 - 4.13 (2H, m), 4.72 - 4.89 (2H, m), 6.69 (1H, d), 7.16 - 7.26 (2H, m); m/z (ES ⁺ ) [M+H] ⁺ = 488. Intermediate 91c: 2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-6-fluoro-3-methyl-indol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tributyl ester

Potassium cyanate (59.9 mg, 0.74 mmol) was added to intermediate 91b (180 mg, 0.37 mmol) in DCM (2 mL) and acetic acid (2 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution (10 mL), extracted with DCM (3 x 5 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. To the crude product were added NaOH (29.5 mg, 0.74 mmol) and EtOH (4 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution (20 mL), extracted with EtOAc (3 x 20 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether then 0 to 6% MeOH in DCM) gave the title compound (70.0 mg, 39.1%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.40 (9H, s), 1.51 - 1.60 (2H, m), 1.64 - 1.71 (2H, m), 2.05 - 2.14 (2H, m), 2.24 (3H, s), 2.40 - 2.48 (2H, m), 2.68 - 2.78 (2H, m), 3.20 - 3.27 (2H, m), 3.33 - 3.39 (2H, m), 3.65 - 3.74 (2H, m), 4.90 - 5.03 (1H, m), 7.40 - 7.46 (2H, m), 7.49 (1H, d), 10.39 (1H, s); m/z (ES ⁺ ); m/z (ES ⁺ ) [M-tBu+H] ⁺ = 429. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 91c (60 mg, 0.12 mmol) and intermediate 11g (90 mg, 0.16 mmol) in a similar manner to Example 86. Purification by RPC (elution gradient: ₆₂ % to 80% MeCN in water containing 10 mmol/ _{L NH4HCO3} + 0.1% _NH3H2O ) gave the title compound (25 mg, 25%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.17 - 1.31 (3H, m), 1.62 (3H, s), 1.70 - 1.82 (4H, m), 1.89 - 1.99 (2H, m), 2.01 - 2.09 (2H, m), 2.09 - 2.17 (4H, m), 2.24 (4H, s), 2.31 - 2.45 (4H, m), 2.58 - 2.68 (2H, m), 2.70 - 2.78 (2H, m), 3.10 (2H, d), 3.25 (2H, d), 3.34 - 3.40 (2H, m), 3.65 - 3.75 (2H, m), 4.34 (2H, s), 4.86 - 5.00 (1H, m), 5.95 (2H, s), 6.38 - 6.51 (2H, m), 6.81 - 6.98 (3H, m), 7.18 - 7.26 (1H, m), 7.38 - 7.54 (4H, m), 7.88 - 7.93 (1H, m), 10.39 (1H, s), 14.18 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -129.64, -136.40; m/z (ES ⁺ ) [M+H] ⁺ = 871. Example 92 Intermediate 92a: 8-(3-bromo-4-chloro-phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Under nitrogen, a flask was charged with NaO t Bu (0.606 g, 6.30 mmol), rac -BINAP (0.785 g, 1.26 mmol), (1 R ,5 S )-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (1.552 g, 6.30 mmol), 2-bromo-1-chloro-4-iodobenzene (2 g, 6.30 mmol), and Pd ₂ (dba) ₃ (0.577 g, 0.63 mmol) in toluene (20 mL). The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous NaHCO ₃ solution (100 mL) and brine (100 mL). The organic layer was dried over _Na2SO4 , _filtered and evaporated. Purification by FSC (elution gradient: 0 to 20% EtOAc in petroleum ether) gave the title compound (1.0 g, 36.4%) as a brown oil. ^1H NMR (DMSO- _d6 ): δ 1.68 (2H, t), 1.91 (2H, td), 3.13 (2H, dd), 3.49 - 3.70 (2H, m), 4.25 - 4.42 (2H, m), 5.08 (2H, d), 6.90 (1H, dd), 7.23 (1H, d), 7.28 - 7.42 (6H, m); m/z (ES ⁺ ) [M+H] ⁺ = 435. Intermediate 92b: Benzyl 8-[4-chloro-3-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Under nitrogen, a flask was charged with Cs ₂ CO ₃ (2.243 g, 6.88 mmol), 4-(dimethoxymethyl)piperidine (0.365 g, 2.29 mmol), intermediate 92a (1 g, 2.29 mmol), Ruphos (0.107 g, 0.23 mmol) and RuphosPd G3 (0.192 g, 0.23 mmol) in 1,4-dioxathiocarbamide (10 mL). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc and the solvent was removed under reduced pressure. Purification by RPC (elution gradient: 0 to 60% MeCN in water containing 0.04% NH ₄ HCO ₃ ) gave the title compound (0.500 g, 42.4%) as a brown solid. ¹ H NMR (DMSO- d ₆ ): δ 1.38 (2H, qd), 1.61 - 1.76 (6H, m), 1.85 - 1.94 (2H, m), 3.11 (1H, d), 3.28 (10H, s), 3.59 (2H, d), 4.12 (1H, d), 4.28 (2H, d), 5.07 (2H, d), 6.46 - 6.57 (2H, m), 7.14 (1H, d), 7.28 - 7.42 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 514. Intermediate 92c: 6-Chloro-4-[8-[4-chloro-3-[4-(dimethoxymethyl)-1-piperidinyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-amine

Under hydrogen, a vial was charged with intermediate 92b (0.5 g, 0.97 mmol) and 10% Pd/C (0.058 g, 0.49 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through celite® and the filtrate was concentrated. The white solid (0.30 g) was dissolved in DMSO (3 mL), and then DIPEA (0.510 mL, 2.92 mmol) and 4-bromo-6-chloropyridinium-3-amine (223 mg, 107 mmol) were added under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with DCM (50 mL) and washed with water (10 mL) and brine (10 mL) in sequence. The organic layer was dried over _Na2SO4 , _filtered and evaporated. Purification by FSC (elution gradient: 0 to 10% MeOH in DCM) gave the title compound (0.170 g, 42.4%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.18 (1H, t), 1.24 (1H, s), 1.39 (2H, qd), 1.64 - 1.76 (3H, m), 1.88 - 1.96 (2H, m), 2.11 (2H, q), 2.58 (2H, td), 2.94 (2H, d), 3.12 - 3.20 (2H, m), 3.27 - 3.38 (6H, m), 4.13 (1H, d), 4.36 (2H, t), 5.82 (2H, s), 6.50 - 6.57 (2H, m), 6.88 (1H, s), 7.14 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 507. Intermediate 92d: 1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-chloro-phenyl]piperidine-4-carboxaldehyde

Under nitrogen, a vial was charged with Pd(dppf)Cl ₂ (0.029 g, 0.04 mmol), (2-hydroxyphenyl)boronic acid (0.065 g, 0.47 mmol), Cs ₂ CO ₃ (0.385 g, 1.18 mmol) and intermediate 92c (0.17 g, 0.39 mmol) in water (0.50 mL) and 1,4-dioxathiocarbamide (5 mL). The resulting mixture was stirred at 80 °C for 4 h. The solvent was removed under reduced pressure. A brown solid was obtained by FSC (elution gradient: 0 to 80% EtOAc in petroleum ether) and the fractions containing the product were concentrated. The brown solid was dissolved in formic acid (0.5 mL). The resulting mixture was stirred at 40 °C for 1 h. The solvent was evaporated to dryness to afford the title compound as a white solid (0.060 g, 34.5%). The product was used directly in the next step without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 519. 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-2-chloro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A vial was charged with intermediate 92d (52.8 mg, 0.10 mmol) and intermediate 2c (40 mg, 0.10 mmol), DCE (1 mL) and NMP (1.0 mL). The resulting solution was stirred at 40 °C for 0.5 h. Then, Na(OAc) ₃ BH (129 mg, 0.61 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was diluted with DCE (20 mL) and washed successively with saturated aqueous NaHCO ₃ solution (5 mL) and brine (5 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated. Purification by preparative HPLC (mobile phase A: water containing 10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 65% B to 90% B) gave the title compound (5.09 mg, 5.47%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 0.62 - 0.72 (2H, m), 0.81 - 0.91 (2H, m), 1.25 (3H, d), 1.71 (5H, s), 1.74 - 1.83 (2H, m), 1.88 - 2.01 (3H, m), 2.17 (4H, dd), 2.22 (2H, d), 2.28 - 2.40 (5H, m), 2.62 (2H, t), 2.76 (2H, t), 3.09 (2H, d), 3.28 (4H, d), 3.81 (2H, t), 4.41 (2H, s), 5.25 (1H, p), 5.97 (2H, s), 6.52 - 6.61 (2H, m), 6.81 - 6.90 (2H, m), 7.15 (1H, d), 7.23 (1H, td), 7.47 (1H, s), 7.56 (1H, s), 7.87 - 7.97 (2H, m), 8.17 (1H, d), 10.40 (1H, s), 14.20 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 896. Example 93 Intermediate 93a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-3-methyl-indole

Prepared in a similar manner to intermediate 64a, using 5-bromo-3-methyl- 1H -indole (15.0 g, 71.4 mmol) and 1,3-bis(allyloxy)propan-2-ol (18.5 g, 107.1 mmol), stirring at 100 °C for 16 h. Purification by FSC (elution gradient: 0 to 100% DCM in petroleum ether) gave the title compound (18.0 g, 69%) as a yellow liquid. ¹ H NMR (DMSO- d ₆ ): δ 2.22 (3H, d), 3.73 - 3.79 (4H, m), 3.88 - 3.93 (4H, m), 4.79 (1H, p), 5.08 - 5.12 (2H, m), 5.13 - 5.18 (2H, m), 5.73 - 5.84 (2H, m), 7.19 - 7.22 (1H, m), 7.30 (1H, d), 7.46 (1H, d), 7.65 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 363.9. Intermediate 93b: 2-(5-bromo-3-methyl-indol-1-yl)propane-1,3-diol

Tetrakis(triphenylphosphine)palladium(0) (2.86 g, 2.47 mmol) was added to intermediate 93a (18.0 g, 49.4 mmol) and 1,3-dimethylbarbituric acid (15.4 g, 98.8 mmol) in MeOH (50 mL) under nitrogen. The resulting mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. Purification by RPC (elution gradient: 5% to 100% MeCN in water _containing 0.1% _NH4HCO3 ) gave the title compound (9.40 g, 66%) as a yellow gum. ¹ H NMR (DMSO- d ₆ ): δ 2.24 (3H, d), 3.69 - 3.83 (4H, m), 4.37 - 4.45 (1H, m), 4.88 (2H, t), 7.19 - 7.23 (1H, m), 7.30 (1H, d), 7.41 (1H, d), 7.65 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 283.9. Intermediate 93c: 3-(5-Bromo-3-methyl-indol-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Pyridinium p-toluenesulfonate (0.354 g, 1.41 mmol) was added to 93b (1 g, 3.52 mmol) and tributyl 4-oxopiperidine-1-carboxylate (2.104 g, 10.56 mmol) in toluene (10 mL) under nitrogen at 25 °C. The resulting mixture was stirred at 100 °C for 2 days. The solvent was removed under reduced pressure. Purification by RPC (elution gradient: 5% to 100% _MeCN in water containing 0.1% _NH4HCO3 ) gave the title compound (0.700 g, 42%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.84 (2H, t), 1.93 (2H, t), 2.25 (3H, d), 3.34 - 3.41 (4H, m), 3.93 - 4.01 (2H, m), 4.24 - 4.31 (2H, m), 4.51 - 4.57 (1H, m), 7.21 - 7.25 (1H, m), 7.45 (1H, d), 7.59 - 7.61 (1H, m), 7.68 (1H, d); m/z (ES+) [M- t Bu+H] ⁺ = 408.9. Intermediate 93d: 3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 4b starting from intermediate 93c (620 mg, 1.33 mmol). Purification by FSC (elution gradient: 0-10% MeOH in DCM) gave the title compound (488 mg, 73%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.42 (9H, s), 1.84-1.95 (4H, m), 2.26 (3H, s), 2.73 (2H, t), 3.34 - 3.42 (4H, m), 3.78 (2H, t), 3.96 - 4.03 (2H, m), 4.20 - 4.31 (2H, m), 4.50 - 4.60 (1H, m), 7.05 - 7.11 (1H, m), 7.39 - 7.50 (2H, m), 7.58 (1H, s), 10.27 (1H, s); m/z (ES ⁺ ), [M- tBu +H] ⁺ = 443.1. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

TFA (0.300 mL) was added to intermediate 93d (100 mg, 0.20 mmol) in DCM (1.0 mL). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give the intermediate deprotected amine. Formic acid (1.0 mL) was added to intermediate 11g (127 mg, 0.20 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 20 min. The solvent was removed under reduced pressure. The reaction mixture was diluted with DCM (5 mL) and washed successively with saturated aqueous NaHCO ₃ solution (5 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. To the residue was added the intermediate deprotected amine produced from intermediate 93d and DCE (0.50 mL) and NMP (0.50 mL). The resulting mixture was stirred at 40 °C for 40 min, and then sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM and IPA (3:1, 15 mL) and washed with saturated aqueous NaHCO ₃ solution (10 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by RPC (elution gradient: 5% to 100% MeCN in water (0.1% NH ₄ HCO ₃ )) and lyophilization gave the title compound (16.0 mg, 8.8%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.20 - 1.31 (2H, m), 1.54 - 1.67 (1H, m), 1.73 - 1.83 (2H, m), 1.85 - 2.05 (6H, m), 2.11 - 2.16 (2H, m), 2.21 (2H, d), 2.26 (3H, s), 2.41 (4H, s), 2.59 - 2.69 (2H, m), 2.69 - 2.77 (2H, m), 3.11 (2H, d), 3.26 (2H, d), 3.36 (2H, d), 3.73 - 3.82 (2H, m), 3.92 - 4.01 (2H, m), 4.18 - 4.30 (2H, m), 4.30 - 4.41 (2H, m), 4.47 - 4.57 (1H, m), 5.95 (2H, s), 6.39 - 6.51 (2H, m), 6.82 - 6.98 (3H, m), 7.05 - 7.10 (1H, m), 7.20 - 7.27 (1H, m), 7.40 - 7.50 (3H, m), 7.60 (1H, s), 7.91 (1H, d), 10.27 (1H, s), 14.20 (1H, s); ¹⁹ F NMR (DMSO- d6 ) δ-136.38; m/z (ES ⁺ ) [M+H] ⁺ = 885.4. Example 94 Intermediate 94a: 5-bromo-2-(3,3-dimethoxypropyl)pyrimidine

Iodine (5.55 g, 21.85 mmol) was added to zinc (14.29 g, 218.53 mmol) in DMF (30 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 15 min, and then 3-bromo-1,1-dimethoxypropane (20 g, 109.26 mmol) in DMF (70 mL) was added. The resulting mixture was stirred at 80°C for 4 h. The reaction mixture was filtered and the filtrate was collected. 5-Bromo-2-iodopyrimidine (34.2 g, 120.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.63 g, 10.93 mmol) were added to the filtrate. The resulting mixture was stirred at 80°C for 12 h. The solvent was removed under reduced pressure. Purification by FSC (elution gradient: 0-100% EtOAc in petroleum ether) gave the title compound (10.90 g, 38%) as a colorless oil. ¹ H NMR (CDCl ₃ ): δ 2.05 - 2.24 (2H, m), 2.92 - 3.05 (2H, m), 3.32 (6H, s), 4.45 (1H, t), 8.69 (2H, s); m/z (ES ⁺ ) [M+H] ⁺ = 261.0. Intermediate 94b: 3-bromopyrrolo[1,2-a]pyrimidine

Formic acid (2 mL, 52.15 mmol) was added to intermediate 94a (10 g, 38.30 mmol). The resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure. The residue was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO ₃ solution (50 mL) and brine (50 mL) successively. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. To the residue was added Burgess reagent (36.5 g, 153.19 mmol) in THF (100 mL) under nitrogen. The resulting mixture was stirred at room temperature for 20 min. The solvent was removed under reduced pressure. Purification by FSC (elution gradient: 0 to 20% EtOAc in petroleum ether) gave the title compound as a yellow solid (1.6 g, 21%). ¹ H NMR (CDCl ₃ ): δ 6.61 - 6.73 (1H, m), 6.95 - 7.01 (1H, m), 7.16 - 7.23 (1H, m), 8.06 (1H, d), 8.31 - 8.36 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 197.0. Intermediate 94c: 3-Bromo-6-chloro-pyrrolo[1,2- a ]pyrimidine

NCS (1.084 g, 8.12 mmol) was added to intermediate 94b (1.6 g, 8.12 mmol) in THF (10 mL). The resulting mixture was stirred at -10 °C for 20 min. The solvent was removed under reduced pressure. Purification by FSC (elution gradient: 0 to 30% EtOAc in petroleum ether) gave the title compound (0.430 g, 22.9%) as a yellow solid. ¹ H NMR (CDCl ₃ ): δ 6.70 - 6.74 (1H, m), 6.92 (1H, d), 8.09 (1H, d), 8.33 - 8.38 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 230.9. Intermediate 94d: 9-(3-bromo-6-chloro-pyrrolo[1,2- a ]pyrimidin-8-yl)-3-azaspiro[5.5]undec-9-ene-3-carboxylic acid tributyl ester

_POCl3 (0.260 mL, 2.79 mmol) was added to a mixture of intermediate 94c (430 mg, 1.86 mmol) and tributyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (993 mg, 3.72 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (25 mL) and washed with saturated aqueous _NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was separated, dried over _Na2SO4 , filtered and evaporated. Purification by FSC (elution gradient: 0 to 30% DCM in petroleum ether) gave the title compound (250 mg, 28%) as _a yellow solid. ¹ H NMR (CDCl ₃ ): δ 1.35 - 1.40 (14H, m), 1.60 (2H, t), 2.07 - 2.13 (2H, m), 2.46 - 2.54 (2H, m), 3.22 - 3.33 (2H, m), 3.37 - 3.49 (2H, m), 6.40 - 6.46 (1H, m), 6.81 (1H, s), 7.92 (1H, d), 8.17 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 480.0. Intermediate 94e: 9-[6-chloro-3-[3-[(2,4-dimethoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]pyrrolo[1,2- a ]pyrimidin-8-yl]-3-azaspiro[5.5]undec-9-ene-3-carboxylic acid tributyl ester

3-[(2,4-dimethoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (91 mg, 0.34 mmol) was added to ( 1S , 2S )-cyclohexane-1,2-diamine (10.69 mg, 0.09 mmol), K3PO4 (199 mg, 0.94 mmol), copper(I) iodide (17.82 mg, 0.09 mmol) and intermediate 94d (150 mg, 0.31 mmol) in _dioxane (5 mL) under _nitrogen . The resulting mixture was stirred at 90°C for 16 h. Purification by FSC (elution gradient: 0 to 5% MeOH in DCM) gave the title compound (110 mg, 53%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.33 - 1.37 (3H, m), 1.40 (9H, s), 1.61 (2H, t), 2.07 - 2.15 (2H, m), 2.53 - 2.60 (2H, m), 3.26 - 3.31 (2H, m), 3.37 - 3.45 (2H, m), 3.75 (3H, s), 3.81 (3H, s), 3.93 (2H, t), 4.79 (2H, s), 6.43 - 6.52 (2H, m), 6.56 (1H, d), 6.93 (1H, d), 7.20 (1H, s), 8.14 (1H, d), 8.61 (1H, d)); m/z (ES ⁺ ) [M+H] ⁺ = 608.2. Intermediate 94f: 1-[8-(3-azaspiro[5.5]undec-9-en-9-yl)-6-chloro-pyrrolo[1,2- a ]pyrimidin-3-yl]hexahydropyrimidine-2,4-dione

Methanesulfonic acid (159 mg, 1.66 mmol) was added to intermediate 94e (110 mg, 0.17 mmol) in TFA (1 mL). The resulting mixture was stirred at 80 °C for 1 h. The solvent was removed under reduced pressure. Purification by RPC (elution gradient: 0 to 50% MeCN in water) gave the title compound (40.0 mg, 58%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.37 - 1.44 (4H, m), 1.61 (2H, t), 2.08 - 2.15 (2H, m), 2.53 - 2.59 (2H, m), 2.73 - 2.72 (6H, m), 3.80 - 3.88 (2H, m), 6.44 - 6.49 (1H, m), 7.19 (1H, s), 8.14 (1H, d), 8.56 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 414.2. 1-[8-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]pyrrolo[1,2- a ]pyrimidin-3-yl]hexahydropyrimidine-2,4-dione

Pd-C (5 mg, 0.05 mmol) was added to intermediate 94f (35 mg, 0.08 mmol) in DMF (2.00 mL) under nitrogen. The resulting mixture was stirred at 40 °C for 10 h. The reaction mixture was filtered through celite® and the filtrate was concentrated to give the free amine. Formic acid (1 mL, 26.07 mmol) was added to intermediate 11g (53.5 mg, 0.08 mmol). The resulting mixture was stirred at 40 °C for 1 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with DCM (5 mL) and washed with saturated aqueous NaHCO ₃ (2 mL) and brine (2 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. To the crude aldehyde was added the free amine in DMF (2.00 mL). Sodium triacetoxyborohydride (35.8 mg, 0.17 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (5 mL) and washed with saturated aqueous NaHCO ₃ (2 mL) and brine (2 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by RPC (elution gradient: 53%-74% MeCN in water containing 10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O) gave the title compound (0.56 mg, 0.7%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.54 - 1.31(6H, m), 1.34 - 1.41 (2H, m), 1.50 - 1.83 (11H, m), 1.91 - 1.98 (2H, m), 2.10 - 2.22 (4H, m), 2.29 - 2.40 (3H, m), 2.64 (3H, t), 2.75 (2H, t), 2.90 - 2.98 (1H, m), 3.10 (2H, d), 3.23 - 3.29 (2H, m), 3.79 (2H, t), 4.31 - 4.38 (2H, m), 5.95 (2H, s), 6.38 - 6.52 (2H, m), 6.84 - 6.97 (4H, m), 7.21 - 7.27 (1H, m), 7.37 (1H, d), 7.47 (1H, s), 7.89 - 7.93 (1H, m), 7.97 (1H, d), 8.63 (1H, d), 10.51 (1H, s), 14.18 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -136.38 ; m/z (ES ⁺ ) [M+H] ⁺ = 868.4. Example 95 Intermediate 95a: Tributyl 5-(2,4-dioxohexahydropyrimidin-1-yl)indoline-1-carboxylate

Tributyl 5-bromoindoline-1-carboxylate (3 g, 10.06 mmol) was added to hexahydropyrimidine-2,4-dione (2.296 g, 20.12 mmol), Cs ₂ CO ₃ (9.83 g, 30.18 mmol), GPhos (0.378 g, 0.70 mmol) and GPhos Pd G6 (0.665 g, 0.70 mmol) in 1,4-dioxathiocarbamide (30 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated. The residue was dissolved in DCM (100 mL) and washed with saturated aqueous K ₂ CO ₃ solution (75 mL). The organic layer was separated, dried _{over Na2SO4} , filtered and evaporated. Purification by FSC (elution gradient: 0 to 50% EtOAc in petroleum ether then 0 to 5% MeOH in DCM) gave the title compound (1.8 g, 54%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.49 - 1.54 (9H, s), 2.67 - 2.71 (2H, t), 3.04 - 3.09 (2H, t), 3.69 - 3.73 (2H, t), 3.90 - 3.96 (2H, t), 7.06 - 7.09 (1H, m), 7.17 (1H, d), 7.47 - 7.69 (1H, m), 10.31 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 331.9. Intermediate 95b: 1-Indolin-5-ylhexahydropyrimidine-2,4-dione

p-Toluenesulfonic acid (1.122 g, 6.52 mmol) was added to intermediate 95a (1.8 g, 5.43 mmol) in MeOH (15 mL). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. Purification by FSC (elution gradient: 5% to 40% MeCN in water containing 0.1% NH ₄ HCO ₃ ) gave the title compound (800 mg, 63%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 2.64 - 2.68 (2H, t), 2.88 - 2.93 (2H, t), 3.41 - 3.45 (2H, t), 3.64 (2H, t), 5.53 (1H, s), 6.47 (1H, d), 6.80 - 6.83 (1H, m), 6.96 (1H, d), 10.20 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 232.1. Intermediate 95c: 1-[1-(6-bromotetrahydronaphthalen-2-yl)indolin-5-yl]hexahydropyrimidine-2,4-dione

6-Bromo-3,4-dihydronaphthalen-2( 1H )-one (759 mg, 3.37 mmol) was added to intermediate 95b (780 mg, 3.37 mmol) in acetic acid (7 mL). The resulting mixture was stirred at room temperature for 10 min. Then sodium triacetyloxyborohydride (2145 mg, 10.12 mmol) was added and stirred for 30 min. The reaction mixture was evaporated. The residue was dissolved in DCM (75 mL) and washed with saturated aqueous _NaHCO3 solution (50 mL). The organic layer was separated, dried _{over Na2SO4} , filtered and evaporated to provide the title compound (1.0 g, 67%) as a brown solid. The product was used directly in the next step without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 440.1. Intermediate 95d: 1-[1-(6-bromotetrahydronaphthalen-2-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

Manganese(IV) oxide (1.974 g, 22.71 mmol) was added to a stirred solution of intermediate 95c (1 g, 2.27 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate was concentrated to provide the title compound (0.830 g, 83%) as a brown solid. m/z (ES ⁺ ) [M+H] ⁺ = 438.0. Intermediate 95e: 1-[1-[6-(Hydroxymethyl)tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

XPhos Pd G2 (0.090 g, 0.11 mmol) was added to intermediate 95d (1 g, 2.28 mmol) and (tributylmethyltinyl)methanol (0.366 g, 1.14 mmol) in 1,4-dioxathione (10 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 16 h. The reaction was quenched with saturated aqueous KF solution (20 mL). The mixture was extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 0 to 50% EtOAc in petroleum ether then 0 to 5% EtOH in DCM) gave the title compound (0.430 g, 48%) as a white solid. ¹ H NMR (DMSO- d6 ) δ 2.13 - 2.19 (1H, m), 2.22 - 2.30 (1H, m), 2.71 - 2.75 (2H, m), 2.85 - 2.91 (1H, m), 3.02 - 3.10 (1H, m), 3.19 (2H, d), 3.77 (2H, t), 4.48 (2H, d), 4.82 - 4.89 (1H, m), 5.13 (1H, t), 6.49 (1H, d), 7.08 - 7.13 (4H, m), 7.49 (1H, d), 7.52 (1H, d), 7.60 (1H, d), 10.29 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 390.0. Intermediate 95f and Intermediate 95g: (2 R )-2-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]tetrahydronaphthalene-6-carboxaldehyde and (2 S )-2-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]tetrahydronaphthalene-6-carboxaldehyde

MnO ₂ (938 mg, 10.78 mmol) was added to intermediate 95e (420 mg, 1.08 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated. The mirror image isomers were purified by preparative chiral HPLC (column: CHIRALPAK SB 2 x 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2 M NH ₃ -MeOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: isocratic 30% mobile phase A and 70% mobile phase B; wavelength: 220/254 nm; RT1: 14.16 min; RT2: 18.935 min; sample solvent: EtOH). Intermediate 95f (40.0 mg, 9%) was obtained as a grey solid, which eluted first from the column (ee = 100%, *absolute configuration not confirmed). ¹ H NMR (DMSO- d6 ): δ 2.18 - 2.22 (1H, m), 2.28 - 2.35 (1H, m), 2.74 (2H, t), 3.01 - 3.06 (1H, m), 3.12 - 3.20 (1H, m), 3.28 -3.32(2H, m), 3.79 (2H, t), 4.91 - 4.97 (1H, m), 6.51 (1H, d), 7.08 - 7.11 (1H, m), 7.39 (1H, d), 7.49 (1H, d), 7.55 (1H, d), 7.63 (1H, d), 7.69 - 7.72 (1H, m), 7.75 (1H, d), 9.98 (1H, s), 10.28 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 388.1. The intermediate 95 g (60.0 mg, 14%) was obtained as a grey solid, which eluted second from the column (ee = 97.5%, *absolute configuration not confirmed). ¹ H NMR (DMSO- d6 ): δ 2.17 - 2.24 (1H, m), 2.28 - 2.36 (1H, m), 2.70 - 2.76 (3H, m), 3.01 - 3.06 (1H, m), 3.13 - 3.20 (2H, m), 3.79 (2H, t), 4.91 - 4.97 (1H, m), 6.51 (1H, d), 7.09 (1H, d), 7.39 (1H, d), 7.49 (1H, s), 7.55 (1H, d), 7.63 (1H, d), 7.69 - 7.72 (1H, m), 7.75 (1H, s), 9.98 (1H, s), 10.28 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 388.15. Intermediate 95h: 4-(5-chloro-2-fluoro-phenyl)piperidin-1-carboxylic acid tributyl ester

NaO t Bu (5.51 g, 57.29 mmol) was added to tributyl 1-piperidincarboxylate (3.56 g, 19.10 mmol), 2-bromo-4-chloro-1-fluorobenzene (4 g, 19.10 mmol), Pd ₂ dba ₃ (0.874 g, 0.95 mmol) and BINAP (1.189 g, 1.91 mmol) in toluene (40 mL). The resulting mixture was stirred at 50 °C under nitrogen for 20 h. The reaction mixture was poured into water (250 mL), extracted with EtOAc (3 x 250 mL), and the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0 to 40% EtOAc in petroleum ether) gave the title compound as a yellow solid (5.30 g, 88%). ¹ H NMR (DMSO- d6 ): δ 1.43 (9H, s), 2.96-3.01 (4H, m), 3.44-3.49 (4H, m), 7-7.08 (2H, m), 7.19-7.22 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 315.2. Intermediate 95i: 8-[3-(4-tributyloxycarbonylpiperidin-1-yl)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.939 g, 3.81 mmol) was added to intermediate 95h (1 g, 3.18 mmol), Ruphos Pd G3 (0.266 g, 0.32 mmol), RuPhos (0.148 g, 0.32 mmol) and Cs ₂ CO ₃ (3.11 g, 9.53 mmol) in 1,4-dioxathiocarbamide (20 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was concentrated and diluted with EtOAc (150 mL) and washed with saturated aqueous NH ₄ Cl solution (150 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0 to 60% EtOAc in petroleum ether) gave the title compound (1.40 g, 84%) as a yellow liquid. ¹ H NMR (DMSO- d6 ): δ 1.42 (9H, s), 1.63 - 1.68 (2H, m), 1.87 - 1.92 (2H, m), 2.92 - 2.95 (4H, m), 3.09 - 3.12 (1H, m), 3.22 - 3.25 (1H, m), 3.41 - 3.48 (4H, m), 3.55 - 3.60 (2H, m), 4.23 - 4.27 (2H, m), 5.05 - 5.09 (2H, m), 6.42-6.47 (2H, m), 6.93-6.98 (1H, m), 7.32-7.39 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 525.4. Intermediate 95j: 4-[5-(3,8-diazabicyclo[3.2.1]oct-8-yl)-2-fluoro-phenyl]piperidin-1-carboxylic acid tributyl ester

10% Pd/C (200 mg, 0.19 mmol) was added to intermediate 95i (1.3 g, 2.48 mmol) in MeOH (50 mL) under nitrogen. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was filtered through celite® and the filtrate was concentrated to give the title compound (0.870 g, 90%) as a yellow liquid. ¹ H NMR (DMSO- d6 ): δ 1.42 (9H, s), 1.78 -1.95 (4H, m), 2.35 - 2.42 (2H, m), 2.89 - 2.99 (6H, m), 3.41 - 4.50 (4H, m), 3.98 - 4.07 (2H, m), 6.28-6.41 (2H, m), 6.87-6.96 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 391.1. Intermediate 95k: 4-[5-[3-(3-amino-6-chloro-indole-4-yl)-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]piperidin-1-carboxylic acid tributyl ester

4-Bromo-6-chloropyridinium-3-amine (499 mg, 2.39 mmol) was added to intermediate 95j (850 mg, 2.18 mmol) and DIPEA (1.141 mL, 6.53 mmol) in DMSO (10 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 24 h. The reaction mixture was diluted with EtOAc (125 mL) and washed with saturated aqueous NH ₄ Cl solution (125 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0 to 20% EtOAc in petroleum ether, then 0 to 10% MeOH in DCM) gave the title compound (930 mg, 82%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.40 (9H, s), 1.88 - 2.02 (2H, m), 2.07 - 2.11 (2H, m), 2.88 - 2.98 (6H, m), 3.11 - 3.16 (2H, m), 3.27 - 3.33 (4H, m), 4.29 - 4.34 (2H, m), 5.80 (2H, s), 6.4-6.49 (2H, m), 6.85 (1H, s), 6.88-7.0 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 518.3. Intermediate 951: 4-[5-[3-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]piperidin-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 6f starting from intermediate 95k (910 mg, 1.76 mmol). Purification by FSC (elution gradient: 0 to 100% EtOAc in petroleum ether) gave the title compound (620 mg, 61%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.42 (9H, s), 1.91 - 1.96 (2H, m), 2.11 - 2.17 (2H, m), 2.92-3.01 (4H, m), 3.09 - 3.12 (2H, m), 3.22 - 3.27 (2H, m), 3.43 - 3.51 (4H, m), 4.35 - 4.40 (2H, m), 5.96 (2H, s), 6.45-6.52 (2H, m), 6.82-6.9 (2H, m), 6.94-7.0 (1H, m), 7.19-7.26 (1H, m), 7.46 (1H, s), 7.87-7.93 (1H, m), 14.18 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 576.3. Intermediate 95m: 2-[6-amino-5-[8-(4-fluoro-3-piperidin-1-yl-phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]phthalimide-3-yl]phenol

4 M HCl in 1,4-dioxathiocarbamide (20 mL, 80 mmol) was added to intermediate 95l (600 mg, 1.04 mmol). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with petroleum ether. The solid was collected and dried to provide the title compound (400 mg, 81%) as a yellow solid. The product was used directly in the next step without further purification. ¹ H NMR (DMSO- d6 ): δ 1.90 - 2.08 (4H, m), 3.14 - 3.29 (8H, m), 3.31 - 3.40 (2H, m), 4.01 - 4.05 (2H, m), 4.39 - 4.45 (2H, m), 6.53 - 6.56 (2H, m), 6.94 - 7.07 (2H, m), 7.12 (1H, d), 7.34 - 7.48 (2H, m), 7.50 (1H, d), 9.38 (2H, s), 14.74 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 476.2. 1-[1-[(2 S )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione or 1-[1-[(2 R )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Sodium triacetoxyborohydride (32.8 mg, 0.15 mmol) was added to a stirred solution of intermediate 95f (20 mg, 0.05 mmol) and intermediate 95m (49.1 mg, 0.10 mmol) in DMF (2 mL). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated _{aqueous Na2CO3} solution (5 mL). The organic layer was dried over _Na2SO4 , _filtered and evaporated. Purification by preparative HPLC (Xbridge Prep Shield RP18 OBD, 30 x 150 mm, 5 μm; mobile phase A: water (containing 10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O); mobile phase B: ACN, gradient: 57% B to 70% B) gave the title compound (10.0 mg, 22%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.92 - 1.98 (2H, m), 2.11 - 2.20 (3H, m), 2.27 - 2.32 (1H, m), 2.52 - 2.56 (4H, m), 2.73 (2H, t), 2.89 - 2.95 (1H, m), 2.99 - 3.14 (7H, m), 3.18 - 3.28 (4H, m), 3.47 - 3.52 (2H, m), 3.78 (2H, t), 4.35 - 4.38 (2H, m), 4.85 - 4.90 (1H, m), 5.95 (2H, s), 6.43 - 6.51 (3H, m), 6.84 - 6.89 (2H, m), 6.91 - 6.97 (1H, m), 7.07 - 7.15 (4H, m), 7.21 - 7.26 (1H, m), 7.45 - 7.50 (2H, m), 7.54 (1H, d), 7.61 (1H, d), 7.91 (1H, d), 10.28 (1H, s), 14.19 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -136.59; m/z (ES ⁺ ) [M+H] ⁺ = 847.3. Example 96 1-[1-[(2 S )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione or 1-[1-[(2 R )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Intermediate 95g (30 mg, 0.08 mmol) was added to intermediate 95m (73.6 mg, 0.15 mmol) in DCE (2 mL) and NMP (2 mL). The resulting mixture was stirred at 50 °C for 4 h. Then, sodium triacetoxyborohydride (49.2 mg, 0.23 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL) and washed successively with saturated aqueous NaHCO ₃ solution (2 x 2 mL). The organic layer was dried over Na ₂ SO 4 , filtered and evaporated. Purification by preparative HPLC (column: Xbridge Prep Shield RP18 OBD, mobile phase A: water (containing 10 mmol/L NH ₄ HCO ₃ + 0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 40% B to 58% B in 8 min) gave the title compound (15.0 mg, 22%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.90 - 1.98 (2H, m), 2.10 - 2.19 (3H, m), 2.22 - 2.30 (1H, m), 2.52 - 2.54 (1H, m), 2.73 (2H, t), 2.87 - 2.94 (1H, m), 2.99 - 3.13 (6H, m), 3.15 - 3.21 (5H, m), 3.22 - 3.26 (2H, d), 3.45 - 3.53 (2H, m), 3.78 (2H, t), 4.07 - 4.13 (1H, m), 4.32 - 4.39 (2H, m), 4.83 - 4.91 (1H, m), 5.95 (2H, s), 6.42 - 6.51 (3H, m), 6.82 - 6.89 (2H, m), 6.91 - 6.97 (1H, m), 7.03 - 7.15 (4H, m), 7.20 - 7.26 (1H, m), 7.43 - 7.50 (2H, m), 7.53 (1H, d), 7.61 (1H, d), 7.90 (1H, d), 10.27 (1H, s), 14.18 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -136.59; m/z (ES ⁺ ) [M+H] ⁺ = 847.3. Example 97 and Example 98 Intermediate 97a: 4-(5-chloro-2-fluoro-phenyl)cyclohex-3-ene-1-carboxylic acid ethyl ester

1,1'-Bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane adduct (0.780 g, 0.95 mmol) was added to 2-bromo-4-chloro-1-fluorobenzene (4 g, 19.10 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (5.35 g, 19.10 mmol) and Cs ₂ CO ₃ (18.67 g, 57.29 mmol) in 1,4-dioxadiazole (80 mL) under nitrogen. The resulting solution was stirred at 50°C for 16 h. The reaction mixture was poured into water (300 mL), extracted with EtOAc (3 x 50 mL), the organic layer was dried over _Na2SO4 , _filtered and evaporated. Purification by FSC (elution gradient: 0 to 70% EtOAc in petroleum ether) gave the title compound (4.0 g, 74%) as a yellow oil. ¹ H NMR (DMSO- d6 ): δ 1.19 (3H, t), 1.62 - 1.75 (1H, m), 1.95 - 2.09 (1H, m), 2.22 - 2.46 (4H, m), 2.55 - 2.65 (1H, m), 4.06 - 4.15 (2H, m), 5.96 -5.98 (1H, m), 7.14 - 7.25 (1H, m), 7.29 - 7.36 (2H, m). Intermediate 97b: 8-[3-(4-ethoxycarbonylcyclohexen-1-yl)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 6e starting from intermediate 97a (2 g, 7.07 mmol). Purification by FSC (elution gradient: 0 to 40% EtOAc in petroleum ether then 0 to 10% MeOH in DCM) gave the title compound as a yellow solid (1.4 g, 40%). ¹ H NMR (DMSO- d6 ): δ 1.17 - 1.22 (3H, m), 1.61 - 1.73 (3H, m), 1.85 - 1.91 (2H, m), 1.99 - 2.07 (1H, m), 2.28 - 2.46 (4H, m), 2.57 - 2.64 (1H, m), 3.08 - 3.12 (1H, m), 3.20 - 3.23 (1H, m), 3.59 (2H, d), 4.06 - 4.13 (2H, m), 4.25 (2H, d), 5.07 (2H, d), 5.88 (1H, s), 6.68 - 6.71 (1H, m), 6.72 - 6.77 (1H, m), 6.94 - 7.00 (1H, m), 7.29 - 7.39 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 493.4. Intermediate 97c: 8-[3-[4-(dimethoxymethyl)cyclohexen-1-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

DIBAL-H (1 M in DCM) (1.523 mL, 1.52 mmol) was added dropwise to a solution of intermediate 97b (500 mg, 1.02 mmol) in DCM (10 mL) under nitrogen at -60 °C. The resulting mixture was stirred at -60 °C for 30 min. The reaction mixture was quenched with saturated aqueous NH ₄ Cl solution (50 mL), extracted with DCM (3 x 50 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. To the crude residue were added trimethyl orthoformate (323 mg, 3.05 mmol) and p TsOH•H ₂ O (19.31 mg, 0.10 mmol) in MeOH (10 mL). The resulting mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated. Purification by FSC (elution gradient: 0 to 40% EtOAc in petroleum ether then 0 to 10% MeOH in DCM) gave the title compound (300 mg, 59%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.29 - 1.40 (1H, m), 1.61 - 1.68 (2H, m), 1.81 - 1.99 (5H, m), 2.19 (1H, d), 2.25 - 2.42 (2H, m), 3.10 (1H, d), 3.22 (1H, d), 3.28 (6H, s), 3.58 (2H, d), 4.15 (1H, d), 4.20 - 4.32 (2H, m), 5.07 (2H, d), 5.84 - 5.87(1H, m), 6.67 - 6.77 (2H, m), 6.93 - 7.00 (1H, m), 7.28 - 7.42 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 495.4. Intermediate 97d: 6-chloro-4-[8-[3-[(1 s ,4 s )-4-(dimethoxymethyl)cyclohexyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]phthalimide-3-amine and intermediate 97e: 6-chloro-4-[8-[3-[(1 r ,4 r )-4-(dimethoxymethyl)cyclohexyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]phthalimide-3-amine

Pd/C (200 mg, 0.188 mmol) was added to intermediate 97c (580 mg, 1.17 mmol) in DCM (50 mL) under hydrogen. The resulting mixture was stirred at room temperature for 5 days. The reaction mixture was filtered through celite® and the filtrate was concentrated to afford the crude product. To the residue were added DIPEA (0.491 mL, 2.81 mmol), 4-bromo-6-chloropyridinium-3-amine (215 mg, 1.03 mmol) and DMSO (7 mL). The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3 x 20 mL), and the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by FSC (elution gradient: 0-30% EtOAc in petroleum ether, then 0 to 10% MeOH in DCM) gave a mixture of trans and cis isomers as a yellow gum. The mixture was purified by preparative chiral HPLC on column: CHIRALPAK IF 2 x 25 cm, 5 μm; mobile phase A: MTBE (containing 0.5% NH ₃ in MeOH), mobile phase B: EtOH; flow rate: 11 mL/min; gradient: isocratic 10% mobile phase B; wavelength: 220/254 nm) to give the cis isomer intermediate 97d as a yellow solid (60.0 mg, 13.05%). ¹ H NMR (DMSO- d6 )L δ 1.38 - 1.96 (13H, m), 2.05 - 2.10 (2H, m), 2.72 - 2.77 (1H, m), 2.91 - 2.95 (2H, m), 3.16 - 3.19 (2H, m), 3.26 (6H, s), 4.67 (1H, d), 5.78 (2H, s), 6.62 - 6.99 (4H, m); m/z (ES ⁺ ) [M+H] ⁺ = 490.5. The trans-isomer intermediate 97e (110 mg, 23.93%) was obtained as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.10 (1H, s), 1.11 - 1.26 (2H, m), 1.40 - 1.99 (10H, m), 2.08 (2H, d), 2.57 - 2.70 (1H, m), 2.93 (2H, d), 3.17 (2H, d), 3.25 (6H, s), 4.02 (1H, d), 5.80 (2H, s), 6.61 - 6.97 (4H, m); m/z (ES ⁺ ) [M+H] ⁺ = 490.4. 1-[1-[3-[[(1 s ,4 s )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]cyclohexyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (Example 97) and 1-[1-[3-[[(1 r ,4 r )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]cyclohexyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (Example 98)

_PdCl2 (dppf) (6.42 mg, 8.78 μmol) was added to intermediate 97d (43 mg, 0.09 mmol), _Cs2CO3 (86 mg, 0.26 mmol) and (2- _{hydroxyphenyl} )boronic acid (24.21 mg, 0.18 mmol) in water (0.5 mL) and dihydrogen hydride (5 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 h. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 5% MeOH) to provide 2-(6-amino-5-(8-(3-(4-(dimethoxymethyl)cyclohexyl)-4-fluorophenyl)-3,8-diaza-bicyclo[3.2.1]octan-3-yl)thiazol-3-yl)phenol as a yellow solid. Due to the low yield, the material was used directly in the next step. To the residue was added formic acid (1 mL, 26.07 mmol). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with DCM (20 mL) and washed successively with saturated _{aqueous Na2CO3} solution (2 x 10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. To the crude material were added intermediate 58a (34.7 mg, 0.09 mmol), NMP (2.000 ml) and DCE (2.00 mL). The resulting mixture was stirred at 60 °C for 2 h. Then sodium triacetoxyborohydride (55.8 mg, 0.26 mmol) was added. The resulting mixture was stirred at 40 °C for 1 h. During the reductive amination, some cis isomers were epimerized to trans isomers. The reaction mixture was diluted with DCM (20 mL) and washed successively with saturated Na ₂ CO ₃ (10 mL x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. To separate the non-mirror isomers, the crude product was purified by preparative HPLC (column: Xselect CSH Prep C18 OBD, 30 x 150 mm, 5 um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 29% B to 34% B in 10 min; wavelength: 254 nm/220 nm nm; RT1 8.57 min, RT2 9.23 min). Fractions containing the desired compound were evaporated to dryness to provide cis-isomer Example 97 (4.10 mg, 5%). ¹ H NMR (DMSO- d6 ): δ 0.94 - 1.03 (2H, m), 1.26 - 1.35 (2H, m), 1.37 - 1.41 (2H, m), 1.51 - 1.63 (3H, m), 1.63 - 1.73 (4H, s), 1.73 - 1.83 (4H, m), 1.84 - 1.91 (2H, m), 1.91 - 2.04 (4H, m), 2.09 - 2.19 (4H, m), 2.25 (3H, s), 2.31 - 2.40 (4H, m), 2.67 - 2.72 (1H, m), 2.74 - 2.78 (2H, m), 3.06 - 3.11 (2H, m), 3.26 -3.29 (2H, m), 3.81 (2H, t), 4.37 - 4.42 (2H, m), 4.57 - 4.63 (1H, m), 5.95 (2H, s), 6.70 - 6.75 (1H, m), 6.78 - 6.82 (1H, m), 6.85 - 6.90 (2H, m), 6.93 - 6.98 (1H, m), 7.21 - 7.25 (1H, m), 7.46 (1H, s), 7.55 (1H, s), 7.87 (1H, d), 7.89 - 7.92 (1H, m), 8.17 (1H, s), 10.39 (1H, s), 14.17 (1H, s); ¹⁹ F NMR (DMSO- d6 ): δ -133.61. m/z (ES ⁺ ) [M+H] ⁺ = 881.7. and trans isomer Example 98 (5.00 mg, 6%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.29 - 1.35(2H, m), 1.37 - 1.42(2H, m), 1.53 - 1.68 (4H, m), 1.68 - 1.75 (8H, m), 1.78 - 1.84 (2H, m), 1.93 - 2.05 (5H, m), 2.11 - 2.18 (2H, m), 2.25 (3H, s), 2.40 - 2.43 (5H, m), 2.68 - 2.73 (1H, m), 2.73 - 2.79 (2H, m), 3.06 - 3.12 (2H, m), 3.28 (3H, m), 3.81 (2H, t), 4.39 - 4.43 (2H, m), 4.56 - 4.64 (1H, m), 5.95 (2H, s), 6.69 - 6.76 (1H, m), 6.77 - 6.83 (1H, m), 6.83 - 6.91 (2H, m), 6.92 - 6.99 (1H, m), 7.20 - 7.27 (1H, m), 7.47 (1H, s), 7.55 (1H, s), 7.87 (1H, d), 7.89 - 7.94 (1H, m), 8.17 (1H, d), 8.28 (1H, s), 10.39 (1H, s),14.12 (1H, s). ¹⁹ F NMR (DMSO- d6 ): δ -133.23. m/z (ES ⁺ ) [M+H] ⁺ = 881.4. Example 99 Intermediate 99a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-indole

1,3-Bis(allyloxy)propan-2-ol (6.16 ml, 35.03 mmol) and 2-(tributyl- l 5-phosphino)acetonitrile (9.18 ml, 35.03 mmol) were added to a solution of 5-bromo- 1H -indole (4.579 g, 23.36 mmol) in toluene (78 mL). The resulting mixture was stirred at 100°C for 19 h. 1,3-Bis(allyloxy)propan-2-ol (6.16 ml, 35.03 mmol) and 2-(tributyl- l 5-phosphino)acetonitrile (9.18 ml, 35.03 mmol) were further added and stirring was continued at 100°C for 23 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. Purification by FSC (1st purification: elution gradient: 0 to 25% EtOAc in hexanes; 2nd purification: elution gradient: 10 to 100% DCM in hexanes) gave the title compound as a colorless oil. ¹ H NMR (DMSO- d6 ): δ 3.72 - 3.84 (4H, m), 3.86 - 3.95 (4H, m), 4.87 (1H, quin), 5.03 - 5.19 (4H, m), 5.77 (2H, ddt), 6.45 (1H, d), 7.21 (1H, dd), 7.48 - 7.57 (2H, m), 7.71 (1H, d); m/z ES ⁺ [M+H] ⁺ = 350.2. Intermediate 99b: 2-(5-bromoindol-1-yl)propane-1,3-diol

Pd(PPh3)4 (0.867 g, 0.75 mmol) was added to a suspension of intermediate 99a (5.254 g, 15.00 mmol) and 1,3-dimethylbarbituric acid (4.68 g, 30.00 mmol) in MeOH (75 ml) under argon. The flask was evacuated and backfilled with argon (3x). The resulting mixture was stirred at 35 °C for 3.5 h and concentrated under reduced pressure. Purification by FSC (1st purification: elution gradient: 0 to 80% acetone in hexanes, 2nd purification: elution gradient: 0 to 60% acetone in hexanes) gave the title compound (4.13 g, 102%) as a red oil. The product contained about 37 mol%/11 wt% EtOAc and a small amount of other impurities. The material was used directly in the next step without further purification. ¹ H NMR (DMSO- d6 ): δ 3.69 - 3.87 (4H, m), 4.45 (1H, br t), 4.87 (2H, br t), 6.42 (1H, d), 7.16 - 7.24 (1H, m), 7.45 (1H, br d), 7.50 (1H, d), 7.65 - 7.77 (1H, m); m/z ES ⁺ [M+H] ⁺ = 270.1. Intermediate 99c: [2-(5-Bromoindol-1-yl)-3-hydroxy-propyl] 4-methylbenzenesulfonate

To a solution of intermediate 99b (2.93 g, 10.85 mmol), 4-methylbenzenesulfonyl chloride (2.482 g, 13.02 mmol), 4,4,4-trifluoro-1-phenylbutane-1,3-dione (0.469 g, 2.17 mmol) and iron(III) chloride (0.063 mL, 1.09 mmol) in acetonitrile (25 mL) was added DIPEA (3.60 mL, 20.62 mmol). The reaction was stirred at room temperature for 2 h. The solvent was removed. Purification by FSC (elution gradient: 10%-50% EtOAc in hexanes) gave the title compound (4.32 g, 94%) as a light orange solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.81 - 1.92 (1H, m), 2.40 (3H, s), 3.98 - 4.06 (2H, m), 4.40 (2H, d), 4.66 (1H, quin), 6.45 (1H, d), 7.11 (1H, d), 7.17 - 7.26 (4H, m), 7.54 (2H, d), 7.70 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 424.1. Intermediate 99d: (3 r ,6 r )-3-(5-bromoindol-1-yl)-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

A solution of intermediate 99c (2.12 g, 5 mmol) and tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (3.52 g, 15.00 mmol) in DMF (5 mL) was stirred at 0 °C. A 1 M solution of potassium tert-butoxide in THF (15 mL, 15.00 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with EtOAc and washed with saturated aqueous NH ₄ Cl solution. The organic phase was dried over MgSO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 10%-40% EtOAc in hexanes) gave the title compound (891 mg, 36.6%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.44 - 1.48 (9H, m), 1.94 - 2.00 (2H, m), 3.49 - 3.55 (2H, m), 3.78 (2H, t), 4.18 (2H, br d), 4.60 (3H, br s), 6.52 (1H, d), 7.19 - 7.25 (1H, m), 7.30 (1H, d), 7.56 (1H, br s), 7.76 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 487.1. Intermediate 99e: (3 r ,6 r )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid tributyl ester

A solution of intermediate 99d (0.852 g, 1.75 mmol), hexahydropyrimidine-2,4-dione (0.399 g, 3.50 mmol), K ₃ PO ₄ (0.742 g, 3.50 mmol) and t BuBrettPhos Pd G3 (0.299 g, 0.35 mmol) in dihydrogen ether (10 mL) was evacuated and backfilled with nitrogen. The reaction was stirred at 95° C. for 24 h. The reaction was cooled to room temperature, diluted with DCM (30 mL), washed with water, dried over MgSO 4 , filtered and concentrated. Purification by FSC (elution gradient: 20%-100% EtOAc in hexanes then 10% MeOH in EtOAc) gave the title compound (0.502 g, 55.2%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.45 (9H, s), 2.00 (2H, br s), 2.82 (2H, t), 3.49 - 3.55 (2H, m), 3.74 - 3.83 (2H, m), 3.86 (2H, t), 4.20 (2H, dd), 4.59 - 4.69 (3H, m), 6.58 (1H, d), 7.14 (1H, dd), 7.36 (1H, d), 7.49 - 7.56 (2H, m), 7.58 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 521.3. Intermediate 99f: 1-[1-((3 r ,6 r )-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

To a solution of intermediate 99e (505 mg, 0.97 mmol) in DCM (4 mL) was added TFA (1.5 ml, 19.40 mmol). The reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in MeOH (10 mL), and carbonate resin (1 g, 2.5-3.5 mmol/g) was added. The reaction was stirred at room temperature for 1 h, and the resin was filtered off and the filtrate was concentrated to give the title compound (205 mg, 50.3%) as a white solid. ¹ H NMR (DMSO- d 6): δ 2.38 - 2.47 (2H, m), 2.62 - 2.75 (2H, m), 3.12 - 3.20 (2H, m), 3.66 - 3.73 (2H, m), 3.74 - 3.79 (2H, m), 4.20 - 4.30 (2H, m), 4.30 - 4.43 (2H, m), 4.76 - 4.98 (1H, m), 6.53 (1H, d), 7.07 - 7.13 (1H, m), 7.46 - 7.49 (1H, m), 7.60 (1H, d), 7.67 (1H, d), 10.25 (1H, s), NH proton not observed; m/z (ES ⁺ ) [M+H] ⁺ = 421.1. 1-[1-[(3 r ,6 r )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (25.1 mg, 0.05 mmol) and intermediate 99f (21.02 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 20% to 60% MeCN in water containing 0.1% FA) gave the title compound, trans isomer (30.0 mg, 66.2%) as a white solid after lyophilization. ¹ H NMR (DMSO-d6) δ 1.24 (2H, br d), 1.58 - 1.69 (1H, m), 1.72 - 1.83 (4H, m), 1.90 - 1.99 (2H, m), 2.06 - 2.21 (4H, m), 2.29 (2H, br d), 2.61- 2.68 (2H, m), 2.68 - 2.83 (4H, m), 3.09 (2H, br d), 3.20 - 3.26 (2H, m), 3.35 - 3.41 (2H, m), 3.75 (2H, t), 4.19 (2H, br dd), 4.33 (4H, br d), 4.83 (1H, br s),5.92 (2H, s), 6.41 (1H, br d), 6.44 - 6.50 (1H, m), 6.51 (1H, d), 6.79 - 6.88 (2H, m), 6.91 (1H, dd), 7.09 (1H, dd), 7.19 - 7.24 (1H, m), 7.42 - 7.50 (2H, m), 7.57 (1H, d), 7.70 (1H, d), 7.89 (1H, d), 10.25 (1H, s), 14.03 - 14.23 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 907.5. Example 100 Intermediate 100a: 3-(4-Hydroxycyclohexyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester

To a solution of 4-hydroxycyclohexan-1-one (1.14 g, 10 mmol) and tributyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.12 g, 10.00 mmol) in THF (45 mL) was added DIPEA (5.2 mL, 30.00 mmol) and MgSO ₄ (0.722 g, 6.00 mmol). The reaction was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (4.24 g, 20.00 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed, and the residue was partitioned between NaHCO ₃ solution (40 mL) and DCM (80 mL). The organic phase was separated and dried over MgSO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 20%-100% EtOAc in hexanes, then 10% MeOH in EtOAc containing 1% NH ₄ OH) gave the title compound (2.25 g, 72.5%) as a mixture of cis- and trans-isomers as a colorless gum. (NMR showed a ratio of 39:61). ¹ H NMR (DMSO- d 6): δ 1.04 - 1.16 (2H, m), 1.28 - 1.45 (11H, m), 1.51 - 1.84 (8H, m), 2.04 - 2.33 (3H, m), 2.51 - 2.68 (2H, m), 3.30 - 3.64 (1H, m), 3.95 - 4.01 (2H, m), 4.23 - 4.48 (1H, m). The expected mass was not detected. Intermediate 100b: 3-[(1 r ,4 r )-4-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)cyclohexyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester and intermediate 100c: 3-[( 1s , 4s)-4-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)cyclohexyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester

To a solution of intermediate 100a (2.18 g, 7.02 mmol) and 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (1.482 g, 7.02 mmol) in toluene (20 mL) was added 2-(tributyl - 15-phosphino)acetonitrile (1.8 mL, 7.02 mmol). The reaction was stirred at 100°C overnight. The reaction was concentrated under reduced pressure. Purification by FSC (elution gradient: 0-50% EtOAc in hexanes) gave the trans isomer, intermediate 100b (0.302 g, 8.54%) as a solid. ¹ H NMR (DMSO- d 6): δ 1.45 - 1.47 (9H, m), 1.53 - 1.60 (2H, m), 1.72 (2H, br s), 1.84 - 1.90 (2H, m), 1.94 - 1.98 (2H, m), 2.07 - 2.17 (6H, m), 2.28 (4H, s), 2.82 - 2.86 (2H, m), 4.19 (2H, br s), 4.70 - 4.78 (1H, m), 7.11 (1H, s), 7.96 (1H, d), 8.24 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 503.3. and the cis isomer, intermediate 100c (0.760 g, 21.50%) as a solid. ¹ H NMR (DMSO- d 6): δ 1.44 - 1.46 (9H, m), 1.52 - 1.57 (2H, m), 1.73 - 1.85 (6H, m), 1.96 (2H, br d), 2.08 (2H, br d), 2.26 (3H, s), 2.32 - 2.43 (1H, m), 2.52 (2H, br s), 2.58 - 2.64 (2H, m), 4.13 (2H, br s), 4.58 - 4.66 (1H, m), 7.09 (1H, s), 7.95 (1H, d), 8.24 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 503.3. Intermediate 100d: 3-[(1 r ,4 r )-4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]cyclohexyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 100b (331 mg, 0.66 mmol) to give the title compound (225 mg, 63.8%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.39 - 1.44 (10H, m), 1.43 - 1.55 (2H, m), 1.60 - 1.71 (2H, m), 1.75 - 1.86 (2H, m), 1.91 - 1.97 (2H, m), 1.97 - 2.05 (4H, m), 2.14 - 2.22 (2H, m), 2.24 - 2.30 (3H, m), 2.70 - 2.79 (2H, m), 2.80 - 2.88 (2H, m), 3.79 (2H, t), 4.04 - 4.12 (2H, m), 4.67 (1H, br s), 7.30 (1H, s), 7.86 (1H, d), 8.14 (1H, d), 10.35 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 537.6. Intermediate 100e: 1-[1-[(1 r ,4 r )-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)cyclohexyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 1i starting from intermediate 100d (220 mg, 0.41 mmol) to afford the title compound as a white solid in free base form (145 mg, 81%). m/z (ES ⁺ ) [M+H] ⁺ = 437.3. 1-[1-[(1 r ,4 r )-4-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]cyclohexyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 100e (32.7 mg, 0.08 mmol) and intermediate 13d (25.1 mg, 0.05 mmol) in a manner analogous to Example 64. Purification by RPC (elution gradient: 45%-100% MeCN in water containing 0.1% NH ₄ OH) and then by FSC (20%-100% solvent B in DCM; solvent B: 10% MeOH in DCM containing 1% NH ₄ OH) gave the title compound (18 mg, 39%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.27 (2H, br d), 1.42 - 1.56 (3H, m), 1.56 - 1.68 (2H, m), 1.80 - 2.15 (16H, m), 2.15 - 2.25 (3H, m), 2.25 - 2.29 (3H, m), 2.57 - 2.69 (2H, m), 2.69 - 2.78 (4H, m), 2.98 - 3.19 (4H, m), 3.21 - 3.28 (2H, m), 3.33 - 3.40 (2H, m), 3.80 (2H, t), 4.33 (2H, br s), 4.60 - 4.75 (1H, m), 5.92 (2H, s), 6.38 - 6.50 (2H, m), 6.81 - 6.96 (3H, m), 7.19 - 7.23 (1H, m), 7.28 (1H, s), 7.45 (1H, s), 7.84 - 7.91 (2H, m), 8.15 (1H, d), 10.36 (1H, s), 14.15 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 923.8. Example 101 Intermediate 101a: 3-[( 1s , 4s )-4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]cyclohexyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 100c (744 mg, 1.48 mmol) to give the title compound (451 mg, 56.9%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.39 - 1.42 (9H, m), 1.43 - 1.50 (2H, m), 1.68 - 1.77 (4H, m), 1.82 - 1.90 (4H, m), 1.91 - 1.98 (2H, m), 2.23 (3H, s), 2.34 - 2.38 (1H, m), 2.39 - 2.44 (2H, m), 2.61 (2H, br d), 2.74 (2H, t), 3.79 (2H, t), 3.99 - 4.06 (2H, m), 4.57 (1H, br s), 7.42 (1H, s), 7.85 (1H, d), 8.16 - 8.17 (1H, m), 10.35 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 537.6 Intermediate 101b: 1-[1-[(1 s ,4 s )-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)cyclohexyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 1i starting from intermediate 101a (450 mg, 0.84 mmol) to give the title compound (315 mg, 86%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ = 437.3. 1-[1-[(1 s ,4 s )-4-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]cyclohexyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 101b (22 mg, 0.05 mmol) and intermediate 13d (25.1 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (gradient: 20% to 60% MeCN in water containing 0.1% FA) gave the title compound (14.2 mg, 30.8%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.18 - 1.34 (2H, m), 1.37 - 1.56 (3H, m), 1.59 - 1.69 (2H, m), 1.70 - 1.77 (2H, m), 1.77 - 2.01 (11H, m), 2.04 - 2.27 (8H, m), 2.28 - 2.36 (1H, m), 2.51 - 2.58 (2H, m), 2.59 - 2.68 (2H, m), 2.68 - 2.78 (2H, m), 3.00 - 3.16 (4H, m), 3.18 - 3.26 (2H, m), 3.32 - 3.35 (2H, m), 3.35 - 3.38 (1H, m), 3.79 (2H, t), 4.33 (2H, br s), 4.59 (1H, br s), 5.92 (2H, s), 6.31 - 6.48 (2H, m), 6.73 - 6.94 (3H, m), 7.17 - 7.25 (1H, m), 7.45 (1H, s), 7.83 - 7.90 (2H, m), 8.15 (1H, d), 10.36 (1H, s), 14.15 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 923.8. Example 102 Intermediate 102a: 4-[[(1 r ,3 r )-3-[3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]cyclobutyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 25f starting from intermediate 41e (172 mg, 0.42 mmol) and intermediate 25e (0.473 g, 1.29 mmol). Purification by SFC (elution gradient: 10%-60% EtOAc in hexanes then 10% MeOH in EtOAc) gave the title compound (241 mg, 92%) as an off-white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.42 - 1.48 (10H, m), 1.59 - 1.74 (2H, m), 1.78 - 1.90 (6H, m), 2.07 - 2.15 (2H, m), 2.30 - 2.35 (3H, m), 2.37 - 2.48 (4H, m), 2.51 - 2.58 (2H, m), 2.70 (2H, br d), 2.85 (2H, br t), 3.02 - 3.13 (4H, m), 3.13 - 3.18 (1H, m), 3.87 (4H, br t), 7.30 (1H, s), 7.45 (1H, br s), 7.75 (1H, s), 8.17 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 624.6. Intermediate 102b: 1-[1-[(1 r ,3 r )-3-[8-[(4-fluoro-4-piperidinyl)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 1i starting from intermediate 102a (242 mg, 0.39 mmol). The reaction was alkalized with solid supported bicarbonate resin, the resin was filtered off, and the filtrate was concentrated to give the title compound as a white solid in free base form (195 mg, 96%). m/z (ES ⁺ ) [M+H] ⁺ = 524.4. Intermediate 102c: N -tert-butyloxycarbonyl- N- [4-[8-[3-[4-[[3-[3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]cyclobutyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methyl]-4-fluoro-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalim-3-yl]carbamic acid tert-butyl ester

A solution of intermediate 102b (79 mg, 0.15 mmol), intermediate 57a (101 mg, 0.15 mmol) _{, K2CO3} (62.2 mg, 0.45 mmol) and Pd-PEPPSI-IPentCl (25.2 mg, 0.03 mmol) in dihydrogen ether (1.5 mL) was degassed for 5 min and backfilled with _N2 . The reaction was heated at 100 °C overnight. The solvent was removed. Purification by FSC (elution gradient: 10%-50% EtOAc in hexanes, then 10% MeOH in EtOAc) gave the title compound (41.0 mg, 23.62%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ = 1157.8. 1-[1-[(1 r ,3 r )-3-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

To a solution of intermediate 102c (41 mg, 0.04 mmol) in DCM (1 mL) was added HCl (4 N in dihydrogen ether, 1 mL, 4 mmol). The reaction was stirred at room temperature for 4 h. The solvent was removed. Purification by RPC (elution gradient: 45%-100% MeCN in water containing 0.1% NH ₄ OH) gave the title compound (11.00 mg, 34.0%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.18 - 1.22 (2H, m), 1.70 - 1.80 (4H, m), 1.80 - 1.90 (2H, m), 1.90 - 2.00 (4H, m), 2.02 - 2.09 (2H, m), 2.09 - 2.17 (2H, m), 2.25 (3H, s), 2.36 - 2.46 (4H, m), 2.65 - 2.71 (2H, m), 2.74 (2H, t), 2.87 - 2.97 (2H, m), 3.01 - 3.06 (1H, m), 3.09 (2H, br d), 3.12 - 3.26 (6H, m), 3.79 (2H, t), 4.36 (2H, br s), 5.18 - 5.32 (1H, m), 5.92 (2H, s), 6.39 - 6.47 (1H, m), 6.47 - 6.55 (1H, m), 6.82 - 6.89 (2H, m), 6.93 (1H, m/ z (ES ^- ) [MH] ^- = 913.6. Example 103 Intermediate 103a: 2-[6-amino-5-[8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-yl]-4-fluoro-phenol

Intermediate 11f (225 mg, 0.39 mmol) was added to a solution of (5-fluoro-2-hydroxyphenyl)boronic acid (61.0 mg, 0.39 mmol), XPhos Pd G3 (33.1 mg, 0.04 mmol), and K ₂ CO ₃ (162 mg, 1.17 mmol) in 1,4-dioxathiol (2.1 mL) and water (0.5 mL) under nitrogen atmosphere. The reaction was bubbled with nitrogen for 5 min and then heated at 105 °C for 2 h. The reaction mixture was cooled to room temperature. The aqueous layer was removed and the organic layer was concentrated. Purification by FSC (elution gradient: 10%-30% EtOAc in hexanes then 10% MeOH in EtOAc) gave the title compound (235 mg, 92%) as a yellow solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.90 - 0.96 (6H, m), 1.32 - 1.41 (4H, m), 1.50 - 1.59 (6H, m), 1.65 - 1.75 (1H, m), 1.79 - 1.89 (2H, m), 2.01 - 2.08 (2H, m), 2.12 - 2.19 (2H, m), 2.57 - 2.69 (2H, m), 3.17 - 3.28 (4H, m), 3.40 - 3.50 (4H, m), 3.56 - 3.67 (2H, m), 4.14 - 4.22 (1H, m), 4.25 - 4.33 (2H, m), 4.76 - 4.92 (2H, m), 6.27 - 6.50 (2H, m), 6.86 - 7.01 (3H, m), 7.18 (1H, s), 7.30 (1H, dd), 13.40 - 13.69 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 651.3. Intermediate 103b: 1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carboxaldehyde

A solution of intermediate 103a (260 mg, 0.4 mmol) and p-toluenesulfonic acid monohydrate (76 mg, 0.40 mmol) in a mixture of acetone (1.8 mL) and water (0.2 mL) in a microwave tube was heated at 80 °C for 30 min. The solvent was removed and the residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution, the organic phase was separated, dried over MgSO ₄ , filtered and concentrated to provide the title compound as a yellow solid (195 mg, 96%). m/z (ES ⁺ ) [M+H] ⁺ = 521.4. 1-[1-[3-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 103b (36 mg, 0.07 mmol) and intermediate 56c (29 mg, 0.07 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 50%-100% MeCN in water containing 0.1% FA) gave the title compound (31.0 mg, 48.4%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.20 - 1.30 (4H, m), 1.34 - 1.42 (2H, m), 1.44 - 1.61 (4H, m), 1.69 - 1.79 (3H, m), 1.80 - 1.89 (2H, m), 1.91 - 2.10 (7H, m), 2.21 - 2.32 (1H, m), 2.34 - 2.43 (1H, m), 2.65 - 2.72 (4H, m), 2.72 - 2.79 (2H, m), 3.02 - 3.12 (4H, m), 3.29 - 3.44 (6H, m), 3.47 - 3.58 (2H, m), 3.76 - 3.82 (2H, m), 4.34 - 4.40 (2H, m), 4.59 - 4.68 (1H, m), 6.48 (2H, br t), 6.97 - 7.08 (3H, m), 7.14 - 7.29 (2H, m), 7.46 (2H, br t), 7.56 (1H, s), 7.91 (1H, d), 8.15 (1H, d), 10.39 (1H, s) (OH proton not observed); m/z (ES ⁺ [M+H] ⁺ = 914.5. Example 104 Intermediate 104a: 2-[6-amino-5-[8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-yl]-4,6-difluoro-phenol

Prepared in analogy to intermediate 103a starting from intermediate 11f (250 mg, 0.43 mmol) and (3,5-difluoro-2-hydroxyphenyl)boronic acid (76 mg, 0.43 mmol). Purification by FSC (elution gradient: 10%-40% EtOAc in hexanes then 10% MeOH in EtOAc) gave the title compound (241 mg, 83%) as a yellow solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.88 - 0.95 (6H, m), 1.37 - 1.43 (4H, m), 1.51 - 1.59 (10H, m), 1.64 - 1.77 (1H, m), 1.78 - 1.88 (2H, m), 2.02 - 2.08 (2H, m), 2.12 - 2.19 (2H, m), 2.58 - 2.65 (2H, m), 3.18 - 3.26 (4H, m), 3.59 - 3.64 (2H, m), 4.17 - 4.20 (1H, m), 4.29 (2H, br s), 4.83 - 4.91 (2H, m), 6.32 - 6.38 (1H, m), 6.43 (1H, dd), 6.85 - 6.94 (2H, m), 7.10 - 7.18 (2H, m), 13.89 - 14.10 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 669.3. Intermediate 104b: 1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carboxaldehyde

Prepared in a similar manner to intermediate 103b starting from intermediate 104a (268 mg, 0.4 mmol) to give the title compound as a yellow solid (192 mg, 89%). m/z (ES ⁺ ) [M+H] ⁺ = 539.6. 1-[1-[3-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to Example 64 starting from intermediate 104b (38 mg, 0.07 mmol) and intermediate 56c (29 mg, 0.07 mmol) to give the title compound (18 mg, 27.6%) as a white solid after freeze drying. ¹ H NMR (DMSO- d 6): δ 1.24 - 1.31 (4H, m), 1.33 - 1.43 (2H, m), 1.44 - 1.62 (4H, m), 1.70 - 1.80 (3H, m), 1.81 - 1.88 (2H, m), 1.91 - 1.97 (3H, m), 1.97 - 2.05 (2H, m), 2.05 - 2.12 (2H, m), 2.22 - 2.29 (1H, m), 2.34 - 2.42 (1H, m), 2.66 - 2.73 (4H, m), 2.73 - 2.79 (2H, m), 3.01 - 3.14 (4H, m), 3.22 - 3.31 (2H, m), 3.34 - 3.45 (6H, m), 3.79 (2H, t), 4.36 (2H, br s), 4.63 (1H, br t), 6.43 - 6.52 (2H, m), 6.73 - 6.90 (2H, m), 6.94 - 7.00 (1H, m), 7.37 - 7.42 (1H, m), 7.46 - 7.52 (2H, m), 7.55 (1H, s), 7.90 (1H, d), 8.15 (1H, d), 10.36 (1H, s) (OH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 932.5. Example 105 Intermediate 105a: 2-[6-amino-5-[8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-yl]-6-fluoro-phenol

Prepared in analogy to intermediate 103a starting from intermediate 11f (230 mg, 0.4 mmol) and (3,5-difluoro-2-hydroxyphenyl)boronic acid (62 mg, 0.4 mmol). Purification by FSC (elution gradient: 10%-30% EtOAc in hexanes then 10% MeOH in EtOAc) gave the title compound (231 mg, 89%) as a yellow solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.90 - 0.95 (6H, m), 1.33 - 1.43 (4H, m), 1.44 - 1.54 (6H, m), 1.64 - 1.77 (1H, m), 1.79 - 1.88 (2H, m), 1.98 - 2.08 (2H, m), 2.08 - 2.22 (2H, m), 2.61 (2H, br t), 3.17 - 3.33 (4H, m), 3.43 (4H, br d), 3.57 - 3.64 (2H, m), 4.18 (1H, br d), 4.29 (2H, br s), 4.77 - 4.90 (2H, m), 6.35 (1H, br d), 6.40 - 6.45 (1H, m), 6.72 - 6.85 (1H, m), 6.89 (1H, br dd), 7.09 (1H, br t), 7.27 (1H, s), 7.39 (1H, br d), 14.14 - 14.43 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 651.3. Intermediate 105b: 1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)thiazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carbaldehyde

Prepared in a similar manner to intermediate 103b starting from intermediate 105a (260 mg, 0.4 mmol) to give the title compound as a yellow solid (185 mg, 89%). m/z (ES ⁺ ) [M+H] ⁺ = 521.5. 1-[1-[3-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 105b (31 mg, 0.06 mmol) and intermediate 56c (25 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 20% to 60% MeCN in water containing 0.1% FA) gave the title compound (21 mg, 38.3%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.19 - 1.30 (4H, m), 1.34 - 1.44 (2H, m), 1.45 - 1.62 (4H, m), 1.70 - 1.79 (3H, m), 1.80 - 1.88 (2H, m), 1.90 - 2.09 (7H, m), 2.19 - 2.31 (1H, m), 2.31 - 2.43 (1H, m), 2.64 - 2.73 (4H, m), 2.73 - 2.79 (2H, m), 3.01 - 3.12 (4H, m), 3.24 - 3.32 (2H, m), 3.34 - 3.38 (2H, m), 3.43 - 3.51 (2H, m), 3.74 - 3.85 (2H, m), 4.32 - 4.39 (2H, m), 4.57 - 4.71 (1H, m), 6.41 - 6.52 (2H, m), 6.78 - 6.99 (4H, m), 7.30 - 7.37 (2H, m), 7.41 - 7.47 (3H, m), 7.55 (1H, s), 7.90 (1H, d), 8.16 (1H, d), 10.36 (1H, s) (OH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 914.6. Example 106 Intermediate 106a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-3-methyl-indole

Under nitrogen atmosphere, 2-( tributyl -15-phosphine)acetonitrile (3.24 mL, 12.38 mmol) was added dropwise to a stirred solution of 5-bromo-3-methyl- 1H -indole (2 g, 9.52 mmol) and 1,3-bis(allyloxy)propan-2-ol (2.132 g, 12.38 mmol) in toluene (20 mL). The reaction mixture was heated to 100° C. overnight. The reaction mixture was concentrated under reduced pressure and purified by FSC (elution gradient: 0-30% EtOAc in hexane) to give the title compound (1.800 g, 51.9%) as an orange oil. ¹ H NMR (CDCl ₃ ): δ 2.30 (3H, s), 3.84 (4H, dd), 3.97 - 3.99 (4H, m), 4.59 - 4.67 (1H, m), 5.18 - 5.27 (4H, m), 5.79 - 5.91 (2H, m), 7.19 - 7.30 (3H, m), 7.64 - 7.71 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 364.1, 366.1. Intermediate 106b: 2-(5-bromo-3-methyl-indol-1-yl)propane-1,3-diol

Pd(PPh ₃ ) ₄ (0.422 g, 0.37 mmol) and 1,3-dimethylbarbituric acid (1.629 g, 10.43 mmol) were added to a solution of intermediate 106a (1.9 g, 5.22 mmol) in methanol (20 mL). The flask was evacuated and backfilled with nitrogen (3x). The resulting mixture was stirred at room temperature for 24 h and concentrated under reduced pressure. Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (1.0 g, 67.5%) as an orange gum. ¹ H NMR (DMSO- d6 ): δ 2.23 (3H, d), 3.69 - 3.80 (4H, m), 4.39 (1H, s), 4.55 - 5.00 (2H, br.s), 7.19 (1H, dd), 7.29 (1H, s), 7.40 (1H, d), 7.63 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 286.0. Intermediate 106c: (5 s ,8 s )-8-(5-bromo-3-methyl-indol-1-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 64d starting from intermediate 106b (920 mg, 3.24 mmol) and intermediate 65a (1288 mg, 4.86 mmol). Purification by FSC (elution gradient: 0 to 100% EtOAc in hexanes) gave the title compound as an orange gum, the cis isomer (600 mg, 38.2%), which eluted second from the column. ¹ H NMR (DMSO- d6 ): δ 2.24 (3H, s), 2.32 (2H, br t), 3.44 (1H, br t), 3.48 (1H, br t), 3.70 (2H, br s), 4.00 - 4.05 (2H, m), 4.30 (2H, br s), 4.56 - 4.63 (1H, m), 5.10 (2H, s), 7.22 - 7.25 (1H, m), 7.32 - 7.34 (1H, m), 7.38 (4H, br d), 7.46 (1H, br t), 7.57 - 7.63 (1H, m), 7.68 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 485.1, 487.0. Intermediate 106d: (5 s ,8 s )-8-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 2b using intermediate 106c (650 mg, 1.34 mmol). Purification by FSC (elution gradient: 0 to 100% EtOAc in hexanes) gave the title compound (470 mg, 67.7%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 2.26 (3H, s), 2.32 (2H, br t), 2.73 (2H, t), 3.44 (1H, br t), 3.49 (1H, br t), 3.66 (2H, s), 3.78 (2H, t), 4.01 - 4.08 (2H, m), 4.26 - 4.36 (2H,m), 4.58 - 4.64 (1H, m), 5.10 (2H, s), 7.08 (1H, dd), 7.33 (1H, br d), 7.39 (4H, br d), 7.43 (1H, d), 7.47 (1H, br t), 7.58 (1H, br d), 10.25 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 519.3. Intermediate 106e: 1-[1-((5 s ,8 s )-6,10-dioxa-2-azaspiro[4.5]dec-8-yl)-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 64f starting from intermediate 106d (500 mg, 0.96 mmol). Purification by FSC (elution gradient: 0 to 100% [0.5% _NH4OH in MeOH] in DCM) gave the title compound (240 mg, 64.7%) as an off-white solid. ¹ H NMR (DMSO- d6 ): δ 2.05 (2H, t), 2.26 (3H, s), 2.74 (2H, t), 2.89 (2H, t), 2.98 (2H, s), 3.78 (2H, t), 4.00 (2H, dd), 4.26 (2H, dd), 4.55 (1H, br t), 7.08 (1H, dd), 7.43 (1H, d), 7.45 (1H, d), 7.55 (1H, s), 10.25 (1H, br s), no NH proton observed; m/z (ES ⁺ ) [M+H] ⁺ = 385.4. 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 13d (60 mg, 0.12 mmol) and intermediate 106e (45.9 mg, 0.12 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-80% MeCN in water containing 0.1% HCOOH) gave the title compound (57.0 mg, 54.1%) as a white solid after freeze drying. ¹ H NMR (DMSO-d6): δ 1.20 - 1.34 (2H, m), 1.56 - 1.67 (1H, m), 1.81 (2H, br d), 1.91 - 1.98 (2H, m), 2.10 - 2.16 (4H, m), 2.26 (3H, s), 2.31 (2H, br d), 2.59 - 2.70 (4H, m), 2.74 (2H, t), 2.82 (2H, s), 3.11 (2H, br d), 3.26 (2H, br d), 3.36 (2H, br d), 3.78 (2H, t), 3.98 (2H, br dd), 4.25 (2H, br dd), 4.35 (2H, br s), 4.52 - 4.59 (1H, m), 5.94 (2H, s), 6.43 (1H, br d), 6.49 (1H, dd), 6.84 - 6.96 (3H, m), 7.08 (1H, dd), 7.21 - 7.26 (1H, m), 7.43 (1H, d), 7.44 - 7.48 (2H, m), 7.55 (1H, s), 7.89 - 7.94 (1H, m), 10.26 (1H, s), 13.33 - 14.77 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 871.8. Example 107 Intermediate 107a: 1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]piperidine-4-carboxaldehyde

Prepared in analogy to intermediate 83c starting from intermediate 3e (150 mg, 0.24 mmol) the title compound was obtained as an orange solid (90 mg, 76%). The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 485.4. 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 107a (25 mg, 0.05 mmol) and intermediate 36a (21.75 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% formic acid) gave the title compound (12.00 mg, 26.1%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 0.65 (2H, dd), 0.82 - 0.90 (2H, m), 1.12 - 1.33 (4H, m), 1.39 (2H, br s), 1.64 - 1.82 (8H, m), 1.88 - 2.03 (5H, m), 2.13 (2H, br d), 2.24 (2H, br d), 2.41 (4H, br s), 2.62 (2H, br t), 2.76 (2H, t), 3.09 (2H, br d), 3.25 (2H, br d), 3.64 (3H, br d), 3.81 (2H, t), 4.38 (2H, br s), 4.58 (1H, br s), 5.93 (2H, s), 6.28 (1H, br d), 6.34 (1H, br d), 6.42 (1H, s), 6.80 - 6.90 (2H, m), 7.01 (1H, t), 7.16 - 7.27 (1H, m), 7.47 (2H, d), 7.86 - 8.00 (2H, m), 8.13 - 8.24 (1H, m), 10.37 (1H, s), 15.43 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 890.5. Example 108 Intermediate 108a: 1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carboxylic acid

Potassium peroxymonosulfate (Oxone) (0.278 mL, 0.50 mmol) was added to a stirred solution of intermediate 13d (250 mg, 0.50 mmol) in DMF (4 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated. Purification by RPC (elution gradient: 25%-50% MeCN in water containing 0.1% formic acid) gave the title compound (50.0 mg, 19.38%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.70 (2H, br d), 1.87 - 1.99 (4H, m), 2.13 (2H, br d), 2.30 - 2.41 (1H, m), 2.72 (2H, br t), 3.10 (2H, br d), 3.26 (2H, br d), 3.32 (2H, br d), 4.36 (2H, br s), 5.93 (2H, s), 6.40 - 6.53 (2H, m), 6.80 - 7.01 (3H, m), 7.18 - 7.29 (1H, m), 7.47 (1H, s), 7.91 (1H, br d), 12.61 - 14.63 (1H, m), (COOH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 519.3. 1-[1-[7-[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carbonyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

HATU (12.10 mg, 0.03 mmol) was added to a stirred solution of intermediate 108a (15 mg, 0.03 mmol), intermediate 2c (11.38 mg, 0.03 mmol) and DIPEA (10.10 μl, 0.06 mmol) in DMF (1 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by RPC (elution gradient: 0-80% MeCN in water containing 0.1% NH ₄ OH) to give the title compound (10.0 mg, 38.7%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 0.70 (2H, br d), 0.88 (2H, br d), 1.60 - 1.81 (8H, m), 1.91 - 2.01 (3H, m), 2.14 (2H, br d), 2.29 (2H, br s), 2.41 (2H, br s), 2.77 (5H, br t), 3.11 (2H, br d), 3.26 (2H, br d), 3.40 (4H, br d), 3.53 (2H, br s), 3.82 (2H, br t), 4.36 (2H, br s), 5.24 - 5.37 (1H, m), 5.94 (2H, br s), 6.42 - 6.52 (2H, m), 6.83 - 6.90 (2H, m), 6.94 (1H, br dd), 7.23 (1H, br t), 7.47 (1H, s), 7.58 (1H, br s), 7.91 (1H, br d), 7.96 (1H, d), 8.18 (1H, d), 10.38 (1H, br s), 14.16 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 894.7. Example 109 1-[1-[3-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 107a (25 mg, 0.05 mmol) and intermediate 56c (21.13 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% formic acid) gave the title compound (12.00 mg, 26.5%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.13 - 1.33 (7H, m), 1.38 (2H, br s), 1.59 - 1.83 (9H, m), 1.91 - 2.06 (4H, m), 2.08 - 2.24 (4H, m), 2.35 (4H, br s) s), 2.56 - 2.72 (4H, m), 2.75 (2H, t), 3.09 (2H, br d), 3.25 (2H, br d), 3.64 (2H, br d), 3.80 (2H, t), 4.39 (2H, br s), 4.54 - 4.65 (1H, m), 5.92 (2H, s), 6.24 - 6.29 (1H, m), 6.34 (1H, br d), 6.42 (1H, s), 6.81 - 6.89 (2H, m), 7.01 (1H, t), 7.18 - 7.27 (1H, m), 7.45 (1H, s), 7.54 (1H, s), 7.87 - 7.94 (2H, m), 8.15 (1H, d), 10.36 (1H, s), 13.85 - 14.76 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 878.7. Example 110 1-[1-[9-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 107a (25 mg, 0.05 mmol) and intermediate 87e (21.95 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% formic acid) gave the title compound (14.00 mg, 30.4%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 0.58 - 0.68 (2H, m), 0.84 - 0.95 (2H, m), 1.11 - 1.28 (2H, m), 1.77 (2H, br d), 1.89 - 2.02 (7H, m), 2.09 - 2.23 (4H, m), 2.40 (4H, br s), 2.54 (1H, s), 2.61 (2H, br t), 2.76 (2H, t), 3.09 (2H, br d), 3.25 (2H, br d), 3.62 - 3.67 (2H, m), 3.81 (2H, t), 4.03 (2H, br dd), 4.23 (2H, br dd), 4.38 (2H, br s), 4.81 (1H, br t), 5.92 (2H, s), 6.28 (1H, br d), 6.33 (1H, br d), 6.42 (1H, s), 6.81 - 6.91 (2H, m), 7.01 (1H, t), 7.18 - 7.27 (1H, m), 7.45 (1H, s), 7.63 (1H, s), 7.91 (1H, dd), 7.97 (1H, d), 8.19 (1H, d), 10.38 (1H, s), 13.30 - 15.40 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 894.5. Example 111 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1,5-dioxa-9-azaspiro[5.5]undec-9-yl]methyl]-1-piperidinyl]benzonitrile

Prepared from intermediate 83c (20 mg, 0.04 mmol) and intermediate 87e (20.04 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-100% MeCN in water containing 0.1% formic acid) gave the title compound (15.0 mg, 41.6%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 0.62 - 0.68 (2H, m), 0.87 - 0.91 (2H, m), 1.21 - 1.32 (4H, m), 1.64 - 1.70 (1H, m), 1.81 - 1.84 (1H, m), 1.93 - 2.01 (5H, m), 2.18 - 2.25 (3H, m), 2.74 - 2.81 (6H, m), 3.05 (4H, br d), 3.56 (5H, br s), 3.83 (3H, br t), 4.05 (2H, br dd), 4.25 (2H, br d), 4.56 - 4.60 (2H, m), 4.80 - 4.85 (1H, m), 5.76 (2H, s), 5.97 -6.01 (1H, m), 6.51 (2H, s), 6.54 - 6.60 (1H, m), 6.85 - 6.90 (1H, m), 7.19 - 7.26 (1H, m), 7.37- m/ z (ES ⁺ ) [M+H] ⁺ = 919.8. Example 112 1-[1-[3-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 103b (21 mg, 0.04 mmol) and intermediate 36a (20 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (22.0 mg, 59.4%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.60 - 0.69 (2H, m), 0.80 - 0.89 (2H, m), 1.20 - 1.31 (4H, m), 1.33 - 1.40 (2H, m), 1.57 - 1.71 (5H, m), 1.73 - 1.84 (4H, m), 1.89 - 2.01 (5H, m), 2.08 - 2.14 (2H, m), 2.16 - 2.23 (2H, m), 2.33 (4H, br s), 2.62 (2H, br t), 2.75 (2H, br t), 3.07 - 3.13 (2H, m), 3.20 - 3.26 (2H, m), 3.27 - 3.33 (2H, m), 3.80 (2H, br t), 4.33 (2H, br s), 4.57 (1H, br t), 6.01 (2H, br s), 6.34 - 6.53 (2H, m), 6.82 - 6.95 (2H, m), 7.05 (1H, td), 7.48 (2H, d), 7.81 - 7.87 (1H, m), 7.92 (1H, d), 8.14 (1H, d), 10.39 (1H, s), 13.50 - 14.56 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 926.5. Example 113 Intermediate 113a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-4-methyl-indole

A mixture of 5-bromo-4-methyl- 1H -indole (0.61 g, 2.90 mmol), 1,3-bis(allyloxy)propan-2-ol (0.77 mL, 4.36 mmol) and 2-(tributyl- 1-5 -phosphino)acetonitrile (1.14 mL, 4.36 mmol) in toluene (9.7 mL) was stirred at 70°C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. Purification by FSC (1st purification: 0-10% acetone in hexanes; 2nd purification: 30%-100% DCM in hexanes) gave the title compound (0.34 g, 33%) as a yellow oil. ¹ H NMR (DMSO- d ₆ ): δ 2.49 (3H, s), 3.72 - 3.83 (4H, m), 3.85 - 3.94 (4H, m), 4.79 - 4.89 (1H, m), 5.04 - 5.11 (2H, m), 5.11 - 5.18 (2H, m), 5.69 - 5.84 (2H, m), 6.55 (1H, d), 7.24 (1H, d), 7.34 (1H, d), 7.50 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 364.0. Intermediate 113b: 2-(5-bromo-4-methyl-indol-1-yl)propane-1,3-diol

Prepared in an analogous manner to intermediate 64b using intermediate 113a (338 mg, 0.93 mmol). Purification by FSC (elution gradient: 0-80% acetone in hexanes) and trituration with DCM-hexanes (1:1) gave the title compound as a red solid (153 mg, 58%). ¹ H NMR (DMSO- d ₆ ) δ 2.49 (3H, s), 3.67 - 3.86 (4H, m), 4.34 - 4.51 (1H, m), 4.86 (2H, t), 6.51 (1H, d), 7.20 - 7.24 (1H, m), 7.25 - 7.29 (1H, m), 7.47 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 284.2. Intermediate 113c: 3-(5-Bromo-4-methyl-indol-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 64d using intermediate 113b (737 mg, 2.59 mmol). Purification by FSC (1st purification: 0-30% acetone in hexanes; 2nd purification: 0-15% EtOAc in DCM) gave the title compound (836 mg, 65%) as a white foam. ¹ H NMR (DMSO- d ₆ ): δ 1.83 (2H, br s), 1.98 (2H, br s), 2.43 - 2.55 (3H, m), 3.44 (4H, br s), 3.98 (2H, br dd), 4.31 (2H, br d), 4.56 (1H, br t), 5.08 (2H, s), 6.57 (1H, d), 7.23 - 7.41 (7H, m), 7.78 (1H, d).; m/z (ES ⁺ ) [M+H] ⁺ = 499.2. Intermediate 113d: 3-[5-[(3-ethoxy-3-oxopropyl)amino]-4-methyl-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

A 40 mL vial was charged with intermediate 113c (0.84 g, 1.67 mmol), ethyl 3-aminopropionate hydrochloride (0.39 g, 2.51 mmol), Cs ₂ CO ₃ (1.96 g, 6.03 mmol), Pd ₂ (dba) ₃ (0.08 g, 0.08 mmol) and CPhos (0.09 g, 0.20 mmol). 1,4-Dihydrogen 2-nitrogen (11 mL) was added. Argon was bubbled through the mixture for 5 min. The resulting mixture was stirred at 85 °C for 5 h. After cooling to room temperature, the mixture was filtered through a celite® pad and eluted with DCM. The filtrate was concentrated under reduced pressure. Purification by FSC (1st purification: 0-40% acetone in hexanes; 2nd purification: 0-80% EtOAc in hexanes) gave the title compound (0.52 g, 57%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.17 (3H, t), 1.85 (2H, br s), 1.93 (2H, br s), 2.20 (3H, s), 2.57 (2H, t), 3.31 - 3.36 (2H, m), 3.38 - 3.50 (4H, m), 3.98 (2H, br dd), 4.06 (2H, q), 4.17 - 4.34 (3H, m), 4.39 - 4.48 (1H, m), 5.08 (2H, s), 6.32 (1H, d), 6.63 (1H, d), 7.15 (1H, d), 7.26 - 7.42 (5H, m), 7.58 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 536.2. Intermediate 113e: 3-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-4-methyl-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Potassium cyanate (382 mg, 4.71 mmol) was added to a solution of intermediate 113d (505 mg, 0.94 mmol) in DCM (3.1 mL) and acetic acid (3.1 mL). The resulting mixture was stirred at room temperature for 25 min. The mixture was diluted with DCM (20 mL), washed with water (25 mL), saturated aqueous NaHCO ₃ solution (25 mL), and brine-saturated aqueous NaHCO ₃ solution (1:1, 25 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound as a light yellow foam, which was used in the next step without further purification. Quantitative yield assumed. m/z (ES ⁺ ) [M+H] ⁺ = 579.2. Intermediate 113f: 3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

21 wt% sodium ethoxide in EtOH (0.71 mL, 1.89 mmol) was added to a solution of intermediate 113e (546 mg, 0.94 mmol) in EtOH (8.7 mL). The resulting mixture was stirred at room temperature for 60 min. Water (40 mL), saturated NH ₄ Cl (40 mL), and DCM (30 mL) were added, and the phases were separated. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Trituration with Et ₂ O gave the title compound (405 mg, 81%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.86 (2H, br s), 1.97 (2H, br s), 2.31 (3H, s), 2.65 - 2.84 (2H, m), 3.38 - 3.57 (5H, m), 3.68 - 3.78 (1H, m), 4.00 (2H, td), 4.30 (2H, br d), 4.51 - 4.67 (1H, m), 5.08 (2H, s), 6.56 (1H, d), 7.01 (1H, d), 7.26 - 7.46 (6H, m), 7.77 (1H, d), 10.23 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 533.2. Intermediate 113g: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 64f starting from intermediate 113f (400 mg, 0.75 mmol) to afford the title compound (281 mg, 94%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.71 - 1.81 (2H, m), 1.82 - 1.93 (2H, m), 2.07 (1H, br s), 2.31 (3H, s), 2.61 - 2.83 (6H, m), 3.52 (1H, dt), 3.68 - 3.79 (1H, m), 3.96 (2H, td), 4.28 (2H, br dd), 4.50 - 4.60 (1H, m), 6.55 (1H, d), 7.01 (1H, d), 7.34 (1H, d), 7.78 (1H, d), 10.23 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 399.1. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to Example 64 using intermediate 113g (30 mg, 0.08 mmol) and intermediate 13d (32 mg, 0.06 mmol). Purification by RPC (elution gradient: 20%-45% MeCN in water containing 0.1% HCOOH) gave the title compound (31.6 mg, 55%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.13 - 1.31 (2H, m), 1.54 - 1.67 (1H, m), 1.78 (2H, br d), 1.84 - 2.05 (6H, m), 2.08 - 2.16 (2H, m), 2.20 (2H, br d), 2.31 (3H, s), 2.41 (4H, br d), 2.57 - 2.82 (4H, m), 3.09 (2H, br d), 3.25 (2H, br d), 3.29 - 3.39 (2H, m), 3.52 (1H, dt), 3.73 (1H, ddd), 3.92 - 4.03 (2H, m), 4.24 - 4.39 (4H, m), 4.55 (1H, br t), 5.92 (2H, s), 6.41 (1H, dt), 6.47 (1H, dd), 6.55 (1H, d), 6.82 - 6.96 (3H, m), 7.01 (1H, d), 7.22 (1H, ddd), 7.34 (1H, d), 7.45 (1H, s), 7.79 (1H, d), 7.89 (1H, dd), 10.23 (1H, s), 12.03 - 15.85 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 885.5. Example 114 Intermediate 114a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-pyrrolo[2,3- b ]pyridine

A mixture of 5-bromo- 1H -pyrrolo[2,3- b ]pyridine (3.94 g, 20.0 mmol), 1,3-diallyloxypropan-2-ol (4.52 mL, 26.0 mmol) and 2-(tributyl- 1-5 -phosphino)acetonitrile (6.81 mL, 26.0 mmol) in toluene (100 mL) was stirred at 100°C for 20 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. Purification by FSC (elution gradient: 0-20% EtOAc in hexanes) gave the title compound (5.00 g, 71%) as a light yellow oil. ¹ H NMR (DMSO- d ₆ ): δ 3.85 - 3.96 (4H, m), 3.99 (4H, d), 5.14 - 5.29 (5H, m), 5.79 - 5.89 (2H, m), 6.42 (1H, d), 7.52 (1H, d), 8.03 (1H, d), 8.33 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 351.2. Intermediate 114b: 2-(5-bromopyrrolo[2,3- b ]pyridin-1-yl)propane-1,3-diol

Prepared in an analogous manner to intermediate 64b using intermediate 114a (5.00 g, 14.2 mmol). Trituration with DCM-hexanes (1:1) gave the title compound as a white solid (3.52 g, 91%). ¹ H NMR (DMSO- d ₆ ) δ 3.81 (4H, t), 4.84 (1H, quin), 4.90 (2H, t), 6.46 (1H, d), 7.68 (1H, d), 8.20 (1H, d), 8.28 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 270.9. Intermediate 114c: 3-(5-bromopyrrolo[2,3- b ]pyridin-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 64d using intermediate 114b (4.00 g, 14.8 mmol) at 110 °C with stirring for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ (2x) and brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Trituration with hexane-acetone gave the title compound as a white solid (5.72 g, 80%). ¹ H NMR (DMSO- d6 ): δ 1.85 (2H, br s), 2.03 (2H, br s), 3.40 - 3.53 (4H, m), 4.00 - 4.08 (2H, m), 4.39 (2H, br d), 4.85 (1H, br t), 5.10 (2H, s), 6.53 (1H, d), 7.32 - 7.41 (5H, m), 7.98 (1H, d), 8.24 - 8.28 (1H, m), 8.32 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 486.1. Intermediate 114d: 3-[5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

A 250 mL flask was charged with intermediate 114c (7.30 g, 15.0 mmol), hexahydropyrimidine-2,4-dione (3.42 g, 30.0 mmol), tBuBrettPhos (0.72 g, 1.50 mmol), [Pd(cinnamyl)Cl] ₂ (0.39 g, 0.75 mmol), and K ₃ PO ₄ (6.37 g, 30.0 mmol). The flask was evacuated and backfilled with nitrogen (3x). The solid was suspended in 1,4-dioxane (85 mL). The flask was evacuated and backfilled with nitrogen (3x). The resulting mixture was stirred at 90 °C for 6 h. After cooling to room temperature, the mixture was diluted with EtOAc (85 mL) and filtered through a pad of celite®. The filtrate was washed with saturated aqueous NH ₄ Cl, water, and brine. The combined aqueous layers were back extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Trituration with DCM-hexanes gave the title compound (5.50 g, 71%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.89 (2H, br s), 1.97 - 2.06 (2H, m), 2.76 (2H, t), 3.48 (4H, br s), 3.82 (2H, t), 4.01 - 4.14 (2H, m), 4.38 (2H, br d), 4.90 (1H, br t), 5.10 (2H, s), 6.55 (1H, d), 7.31 - 7.36 (1H, m), 7.36 - 7.41 (4H, m), 7.93 - 7.99 (2H, m), 8.23 (1H, d), 10.39 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 520.3. Intermediate 114e: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 64f starting from intermediate 114d (39 mg, 0.08 mmol). The residue was filtered through a pad of celite® eluting with DCM -iPrOH (3:1). The filtrate was concentrated under reduced pressure and lyophilized from water-MeCN to give the title compound as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.74 - 1.86 (2H, m), 1.93 (2H, br s), 2.75 (6H, br t), 3.80 (2H, br t), 4.02 (2H, br dd), 4.34 (2H, br d), 4.80 - 4.93 (1H, m), 6.52 (1H, d), 7.88 - 7.98 (2H, m), 8.21 (1H, s), 10.38 (1H, br s), (one NH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 386.1. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared using intermediate 114e (27 mg, 0.06 mmol) and intermediate 13d (32 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 20%-45% MeCN in water containing 0.1% HCOOH) gave the title compound (39.4 mg, 68%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.17 - 1.34 (2H, m), 1.53 - 1.68 (1H, m), 1.78 (2H, br d), 1.86 - 1.96 (4H, m), 2.02 (2H, br s), 2.08 - 2.16 (2H, m), 2.21 (2H, br d), 2.35 - 2.48 (4H, m), 2.63 (2H, br t), 2.75 (2H, t), 3.09 (2H, br d), 3.25 (2H, br d), 3.34 (2H, br d), 3.80 (2H, t), 4.02 (2H, dd), 4.29 - 4.39 (4H, m), 4.79 - 4.96 (1H, m), 5.92 (2H, s), 6.41 (1H, dt), 6.47 (1H, dd), 6.52 (1H, d), 6.82 - 6.96 (3H, m), 7.16 - 7.26 (1H, m), 7.45 (1H, s), 7.89 (1H, dd), 7.92 - 7.98 (2H, m), 8.21 (1H, d), 10.38 (1H, s), 11.87 - 15.76 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 872.5. Example 115 1-[1-[9-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 103b (21 mg, 0.04 mmol) and intermediate 87e (20 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (21.0 mg, 56.4%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.58 - 0.67 (2H, m), 0.81 - 0.93 (2H, m), 1.11 - 1.37 (2H, m), 1.54 - 1.66 (1H, m), 1.74 - 1.83 (2H, m), 1.86 - 2.01 (7H, m), 2.09 - 2.16 (2H, m), 2.16 - 2.24 (2H, m), 2.29 - 2.45 (4H, m), 2.57 - 2.68 (2H, m), 2.71 - 2.79 (2H, m), 3.04 - 3.12 (2H, m), 3.19 - 3.25 (2H, m), 3.27 - 3.34 (2H, m), 3.78 - 3.84 (2H, m), 4.02 (2H, br dd), 4.16 - 4.28 (2H, m), 4.33 (2H, br s), 4.74 - 4.87 (1H, m), 6.01 (2H, br s), 6.37 - 6.50 (2H, m), 6.82 - 6.94 (2H, m), 7.05 (1H, td), 7.47 (1H, s), 7.63 (1H, s), 7.84 (1H, dd), 7.97 (1H, d), 8.16 - 8.20 (1H, m), 10.40 (1H, s), 13.46 - 14.75 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 930.7. Example 116 Intermediate 116a: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

TFA (2.0 mL) was added to a stirred solution of intermediate 93d (300 mg, 0.60 mmol) in DCM (6 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The reaction mixture was adjusted to pH 8 with DIPEA. The solvent was removed under reduced pressure. Purification by RPC (elution gradient: 5% to 100% MeCN in water containing _0.5 % _NH4HCO3 ) gave the title compound (130 mg, 54.2%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.73 - 1.94 (4H, m), 2.26 (3H, s), 2.62 - 2.80 (6H, m), 3.78 (2H, t), 3.91 - 4.02 (2H, m), 4.20 - 4.32 (2H, m), 4.46 - 4.59 (1H, m), 7.02 - 7.10 (1H, m), 7.38 - 7.49 (2H, m), 7.59 (1H, s), 10.27 (1H, s). m/z (ES ⁺ ) [M+H] ⁺ = 399.2. 1-[1-[9-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 103b (21 mg, 0.04 mmol) and intermediate 116a (19 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (19.2 mg, 53.2%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.17 - 1.30 (2H, m), 1.54 - 1.67 (1H, m), 1.74 - 1.81 (2H, m), 1.88 - 2.00 (6H, m), 2.07 - 2.15 (2H, m), 2.18 - 2.22 (2H, m), 2.22 - 2.27 (3H, m), 2.30 - 2.45 (4H, m), 2.58 - 2.67 (2H, m), 2.68 - 2.75 (2H, m), 3.05 - 3.11 (2H, m), 3.17 - 3.25 (2H, m), 3.29 - 3.35 (2H, m), 3.74 - 3.80 (2H, m), 3.91 - 3.99 (2H, m), 4.15 - 4.29 (2H, m), 4.29 - 4.40 (2H, m), 4.51 (1H, br s), 6.01 (2H, br s), 6.37 - 6.50 (2H, m), 6.83-6.94 (2H, m), 7.02-7.08 (2H, m), 7.37-7.48 (3H, m), 7.58 (1H, s), 7.84 (1H, dd), 10.26 (1H, s), 13.13-14.84 (1H, m) ; (ES ⁺ ) [M+H] ⁺ = 903.5. Example 117 1-[1-[9-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione Prepared from intermediate 105b (21 mg, 0.04 mmol) and intermediate 116a (19 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (16.2 mg, 44.8%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.16 - 1.31 (2H, m), 1.60 (1H, br s), 1.74 - 1.81 (2H, m), 1.89 - 2.01 (6H, m), 2.09 - 2.15 (2H, m), 2.15 - 2.20 (2H, m), 2.23 - 2.28 (3H, m), 2.30 - 2.44 (4H, m), 2.59 - 2.67 (2H, m), 2.70 - 2.74 (2H, m), 3.07 - 3.13 (2H, m), 3.23 - 3.27 (2H, m), 3.30 - 3.35 (2H, m), 3.74 - 3.79 (2H, m), 3.91 - 3.98 (2H, m), 4.19 - 4.29 (2H, m), 4.33 (2H, br s), 4.44 - 4.57 (1H, m), 6.05 (2H, br s), 6.38 - 6.51 (2H, m), 6.75 - 6.86 (1H, m), 6.91 (1H, dd), 7.05 (1H, dd), 7.18 (1H, dd), 7.38 - 7.45 (2H, m), 7.45 - 7.51 (1H, m), 7.58 (1H, s), 7.75 (1H, br d), 10.26 (1H, s), 14.29 - 15.83 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 903.6. Example 118 1-[1-[9-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 105b (21 mg, 0.04 mmol) and intermediate 87e (20 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (20.5 mg, 55.1%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.62 (2H, br d), 0.83 - 0.91 (2H, m), 1.14 - 1.30 (2H, m), 1.51 - 1.67 (1H, m), 1.74 - 1.82 (2H, m), 1.82 - 2.03 (7H, m), 2.03 - 2.16 (2H, m), 2.16 - 2.22 (2H, m), 2.28 - 2.47 (4H, m), 2.58 - 2.69 (2H, m), 2.71 - 2.81 (2H, m), 3.04 - 3.13 (2H, m), 3.18 - 3.26 (2H, m), 3.28 - 3.34 (2H, m), 3.78 - 3.86 (2H, m), 3.99 - 4.07 (2H, m), 4.16 - 4.29 (2H, m), 4.33 (2H, br s), 4.80 (1H, br s), 6.05 (2H, br s), 6.37 - 6.50 (2H, m), 6.74 - 6.87 (1H, m), 6.91 (1H, br dd), 7.14 - 7.21 (1H, m), 7.48 (1H, s), 7.63 (1H, s), 7.75 (1H, br d), 7.97 (1H, d), 8.15 - 8.22 (1H, m), 10.40 (1H, s), 14.29 - 15.71 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 930.7. Example 119 1-[1-[9-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 104b (22 mg, 0.04 mmol) and intermediate 116a (19 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (19.5 mg, 52.9%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.23 (2H, q), 1.60 (1H, br s), 1.73 - 1.81 (2H, m), 1.87 - 1.98 (6H, m), 2.07 - 2.16 (2H, m), 2.16 - 2.22 (2H, m), 2.23 - 2.27 (3H, m), 2.31 - 2.44 (4H, m), 2.62 (2H, br t), 2.72 (2H, br t), 3.08 - 3.14 (2H, m), 3.23 - 3.28 (2H, m), 3.33 - 3.37 (2H, m), 3.74 - 3.80 (2H, m), 3.92 - 3.99 (2H, m), 4.24 (2H, br d), 4.33 (2H, br s), 4.45 - 4.56 (1H, m), 6.12 (2H, br s), 6.37 - 6.50 (2H, m), 6.92 (1H, dd), 7.02 - 7.08 (1H, m), 7.21 - 7.28 (1H, m), 7.38 - 7.45 (2H, m), 7.49 (1H, s), 7.58 (1H, s), 7.77 (1H, br d), 10.26 (1H, s), 14.02 - 15.51 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 921.6. Example 120 1-[1-[9-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 104b (22 mg, 0.04 mmol) and intermediate 87e (20 mg, 0.05 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (19.5 mg, 51.4%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.58 - 0.67 (2H, m), 0.79 - 0.93 (2H, m), 1.19 - 1.28 (2H, m), 1.60 (1H, br s), 1.72 - 1.83 (2H, m), 1.85 - 2.05 (7H, m), 2.08 - 2.23 (4H, m), 2.29 - 2.46 (4H, m), 2.57 - 2.69 (2H, m), 2.71 - 2.80 (2H, m), 3.07 - 3.14 (2H, m), 3.21 - 3.26 (2H, m), 3.28 - 3.35 (2H, m), 3.79 - 3.85 (2H, m), 4.00 - 4.07 (2H, m), 4.16 - 4.28 (2H, m), 4.33 (2H, br s), 4.65 - 4.95 (1H, m), 6.12 (2H, br s), 6.38 - 6.49 (2H, m), 6.91 (1H, dd), 7.16 - 7.33 (1H, m), 7.49 (1H, s), 7.63 (1H, s), 7.77 (1H, br d), 7.97 (1H, d), 8.18 (1H, d), 10.40 (1H, s), 14.32 - 15.52 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 948.5. Example 121 1-[1-[3-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 105b (36 mg, 0.07 mmol) and intermediate 36a (35 mg, 0.08 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (41 mg, 63.2%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.59 - 0.69 (2H, m), 0.79 - 0.88 (2H, m), 1.18 - 1.30 (4H, m), 1.32 - 1.42 (2H, m), 1.59 - 1.73 (5H, m), 1.74 - 1.84 (4H, m), 1.85 - 2.03 (6H, m), 2.12 (2H, br d), 2.24 (2H, br d), 2.31 - 2.47 (4H, m), 2.55 - 2.66 (2H, m), 2.75 (2H, t), 3.06 - 3.13 (2H, m), 3.23 - 3.29 (2H, m), 3.32 - 3.38 (2H, m), 3.77 - 3.83 (2H, m), 4.33 (2H, br s), 4.57 (1H, br t), 6.03 (2H, br s), 6.37 - 6.50 (2H, m), 6.91 (1H, dd), 7.17 (1H, dd), 7.48 (2H, d), 7.74 (1H, br d), 7.92 (1H, d), 8.12 - 8.17 (1H, m), 10.36 (1H, s),(no OH proton observed); m/z (ES ⁺ ) [M+H] ⁺ = 926.7. Example 122 1-[1-[3-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 104b (38 mg, 0.07 mmol) and intermediate 36a (35 mg, 0.08 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (36 mg, 54.5%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.59 - 0.69 (2H, m), 0.78 - 0.90 (2H, m), 1.17 - 1.32 (4H, m), 1.35 - 1.45 (2H, m), 1.58 - 1.73 (5H, m), 1.73 - 1.85 (4H, m), 1.87 - 2.02 (5H, m), 2.11 (2H, br d), 2.16 - 2.29 (2H, m), 2.29 - 2.45 (4H, m), 2.63 (2H, br t), 2.75 (2H, t), 3.08 - 3.13 (2H, m), 3.23 - 3.27 (2H, m), 3.33 - 3.38 (2H, m), 3.77 - 3.86 (2H, m), 4.33 (2H, br s), 4.57 (1H, br t), 6.10 (2H, br s), 6.37 - 6.50 (2H, m), 6.91 (1H, dd), 7.19 - 7.29 (1H, m), 7.49 (2H, d), 7.76 (1H, br d), 7.92 (1H, d), 8.09 - 8.16 (1H, m), 10.36 (1H, s), 14.32 - 15.21 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 944.6. Example 123 Intermediate 123a: 4-bromo-2-(2,2-diethoxyethoxy)-1-fluorobenzene

A mixture of 5-bromo-2-fluorophenol (1.910 g, 10 mmol), 2-bromo-1,1-diethoxyethane (1.971 g, 10.00 mmol), K ₂ CO ₃ (1.38 g, 10 mmol) and NaI (0.150 g, 1.00 mmol) in DMF (8 mL) was heated at 120° C. overnight. The reaction was cooled to room temperature. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with 10% LiCl solution, dried over MgSO ₄ and concentrated. Purification by FSC (elution gradient: 0-10% EtOAc in hexanes) gave the title compound (1.650 g, 53.7%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ) δ 1.18 - 1.24 (6H, m), 3.58 - 3.64 (2H, m), 3.68 - 3.77 (2H, m), 4.01 (2H, d), 4.81 (1H, t), 6.97 (1H, dd), 7.02 - 7.06 (1H, m), 7.16 (1H, dd). Intermediate 123b: 8-[3-(2,2-diethoxyethoxy)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

A mixture of intermediate 123a (1.347 g, 4.38 mmol), benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.08 g, 4.38 mmol), RuPhosPdG3 (0.183 g, 0.22 mmol) and KOtBu (0.738 g, 6.58 mmol) in toluene (20 mL) was degassed for 5 min and backfilled with nitrogen. The mixture was stirred at 105 °C under nitrogen for 2 h. The reaction was cooled to room temperature and filtered through celite®. The filtrate was concentrated. Purification by FSC (elution gradient: 0-30% EtOAc in hexanes) gave the title compound (1.60 g, 77%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.17 - 1.23 (6H, m), 1.74 - 1.86 (2H, m), 1.93 - 2.00 (2H, m), 3.21 - 3.28 (1H, m), 3.28 - 3.40 (1H, m), 3.57 - 3.65 (2H, m), 3.65 - 3.78 (4H, m), 4.00 (2H, d), 4.01 - 4.07 (1H, m), 4.09 - 4.14 (1H, m), 4.81 (1H, t), 5.10 (2H, s), 6.30 (1H, dt), 6.45 (1H, dd), 6.93 (1H, dd), 7.29 - 7.37 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 473.6. Intermediate 123c: 8-[3-(2,2-diethoxyethoxy)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane

Intermediate 123b (1.6 g, 3.39 mmol) and Pd/C (50% wet basis) (0.180 g, 0.17 mmol) in THF (40 mL) were degassed and flushed with hydrogen. The reaction was stirred at room temperature under hydrogen atmosphere for 2 h. The catalyst was filtered off through celite® and the filtrate was concentrated to give the title compound (1.10 g, 96%) as a black gum. The crude material was used in the next step. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.21 (6H, t), 1.89 - 2.05 (4H, m), 2.50 - 2.58 (2H, m), 3.14 (2H, d), 3.58 - 3.67 (2H, m), 3.74 (2H, dq), 3.95 - 4.03 (4H, m), 4.81 (1H, t), 6.26 (1H, dt), 6.41 (1H, dd), 6.91 (1H, dd); (NH protons not observed); m/z (ES ⁺ ) [M+H] ⁺ = 339.5. Intermediate 123d: 6-chloro-4-[8-[3-(2,2-diethoxyethoxy)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidine-3-amine

Prepared in an analogous manner to intermediate 3c starting from intermediate 123c (1.147 g, 3.39 mmol) and 4-bromo-6-chloro-indole-3-amine (0.707 g, 3.39 mmol). Purification by FSC (elution gradient: 10%-80% EtOAc in hexanes then 10% MeOH in EtOAc) gave the title compound (1.180 g, 74.7%) as a brown gum. ¹ H NMR (CD ₂ Cl ₂ ) δ 1.19 - 1.22 (6H, m), 2.00 - 2.04 (2H, m), 2.09 - 2.19 (2H, m), 3.06 - 3.12 (2H, m), 3.17 (2H, dd), 3.62 (2H, dq), 3.75 (2H, dq), 4.00 - 4.03 (2H, m), 4.23 (2H, br s), 4.68 (2H, s), 4.78 - 4.85 (1H, m), 6.33 (1H, dt), 6.49 (1H, dd), 6.70 (1H, s), 6.95 (1H, dd); m/z (ES ⁺ ) [M+H] ⁺ = 466.5. Intermediate 123e: 2-[6-amino-5-[8-[3-(2,2-diethoxyethoxy)-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]phthalimide-3-yl]phenol

Prepared from intermediate 123d (1.18 g, 2.53 mmol) in a similar manner to intermediate 2h. The reaction mixture was cooled to room temperature and partitioned between water (50 mL) and EtOAc (100 mL). The organic phase was separated, dried over _MgSO4 , filtered and concentrated. The residue was triturated in MeOH, the product precipitated, and the solid was filtered and dried to give the title compound as a yellow solid (0.820 g, 61.8%). ¹ H NMR (CD ₂ Cl ₂ ): δ 1.20 - 1.24 (6H, m), 2.04 - 2.09 (2H, m), 2.12 - 2.19 (2H, m), 3.17 - 3.29 (5H, m), 3.58 - 3.63 (2H, m), 3.76 (3H, dq), 4.03 (2H, d), 4.28 (2H, br s), 4.78 - 4.85 (3H, m), 6.36 (1H, dt), 6.52 (1H, dd), 6.85 - 6.92 (1H, m), 6.92 - 7.01 (2H, m), 7.24 - 7.30 (2H, m), 7.60 (1H, d), 13.75 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 524.6. 1-[1-[3-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A mixture of intermediate 123e (26.2 mg, 0.05 mmol) and p-toluenesulfonic acid monohydrate (9.5 mg, 0.05 mmol) in acetone (1 mL) and water (0.1 mL) was heated at 60 °C overnight. The solvent was removed and the residue was partitioned between _{CH2Cl2 (} 20 mL) and saturated aqueous _NaHCO3 solution (10 mL). The organic phase was separated, dried over _MgSO4 , filtered and concentrated to give the crude aldehyde. To the residue was added intermediate 58a (24 mg, 0.06 mmol) in NMP (2.0 mL). The reaction was stirred at room temperature for 2 h and then sodium triacetoxyborohydride (21 mg, 0.10 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated. Purification by RPC (elution gradient: 20%-50% MeCN in water containing 0.1% FA) gave the title compound (12.0 mg, 29.0%) as a white solid. ¹ H NMR (DMSO-d6): δ 1.25 - 1.32 (2H, m), 1.35 - 1.42 (2H, m), 1.64 - 1.73 (4H, m), 1.76 - 1.85 (2H, m), 1.91 - 1.99 (4H, m), 2.09 - 2.15 (2H, m), 2.23 - 2.26 (3H, m), 2.31 - 2.43 (2H, m), 2.51 - 2.57 (2H, m), 2.69 - 2.80 (4H, m), 3.08 - 3.12 (2H, m), 3.18 - 3.24 (2H, m), 3.79 (2H, t), 4.17 (2H, br s), 4.39 (2H, br s), 4.54 - 4.63 (1H, m), 5.93 (2H, s), 6.37 - 6.43 (1H, m), 6.65 - 6.71 (1H, m), 6.82 - 6.89 (2H, m), 7.00 (1H, dd), m /z ( ES ⁺ ) [M+H] ⁺ = 829.5. Example 124 Intermediate 124a: 1-[1-(7-azaspiro[3.5]nonan-2-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in analogy to intermediate 2c starting from intermediate 15b (826 mg, 1.77 mmol). Purification by ion exchange chromatography (PoraPak Rxn CX cartridge) eluting with 1.5 N NH ₃ in MeOH gave the title compound (631 mg, 97%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ = 368.3. 1-[1-[7-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 123e (26 mg, 0.05 mmol) and intermediate 124a (22 mg, 0.06 mmol) in a similar manner to Example 123. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (4 mg, 10%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.67 (2H, br t), 1.71 (2H, br s), 1.91 - 1.98 (2H, m), 2.11 - 2.16 (2H, m), 2.16 - 2.23 (2H, m), 2.24 - 2.27 (3H, m), 2.30 - 2.47 (6H, m), 2.62 - 2.70 (2H, m), 2.74 (2H, t), 3.10 (2H, br d), 3.19 - 3.25 (2H, m), 3.79 (2H, t), 4.14 (2H, t), 4.39 (2H, br s), 5.24 (1H, quin), 5.93 (2H, s), 6.39 (1H, dt), 6.67 (1H, dd), 6.82 - 6.87 (2H, m), 6.99 (1H, dd), 7.19 - 7.23 (1H, m), 7.45 (1H, s), 7.58 (1H, s), 7.84 - 7.90 (2H, m), 8.15 (1H, d), 10.35 (1H, s), 14.05 - 14.20 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 801.5. Example 125 Intermediate 125a: 2-(5-bromo-2-fluoro-phenoxy)ethoxy-tributyl-dimethyl-silane

A solution of di-(tri-butyl)azodicarboxylate (1.900 g, 8.25 mmol) in DCM (7 mL) was added dropwise to a solution of 5-bromo-2-fluorophenol (1.432 g, 7.5 mmol), 2-((tri-butyldimethylsilyl)oxy)ethan-1-ol (1.322 g, 7.50 mmol) and triphenylphosphine (2.361 g, 9.00 mmol) in DCM (30 mL) at room temperature. The resulting solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. Purification by FSC (elution gradient: 0-5% EtOAc in hexanes) gave the title compound (2.120 g, 81%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.09 (6H, s), 0.90 (9H, s), 3.95 - 4.00 (2H, m), 4.07 - 4.11 (2H, m), 6.92 - 6.99 (1H, m), 6.99 - 7.07 (1H, m), 7.17 (1H, dd). Intermediate 125b: N -tert-butyloxycarbonyl- N- [4-[8-[3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tributyl ester

Intermediate 125a (0.524 g, 1.5 mmol), intermediate 25d (0.813 g, 1.50 mmol), RuPhos Pd G3 (0.125 g, 0.15 mmol) and KO t Bu (0.252 g, 2.25 mmol) in toluene (7.50 mL) were degassed and backfilled with nitrogen. The mixture was stirred at 105 ° C for 2 h under nitrogen. The reaction was cooled to room temperature, filtered through celite® and the filtrate was concentrated. Purification by FSC (elution gradient: 0-30% EtOAc in hexanes) gave the title compound (0.516 g, 42.5%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 0.09 - 0.13 (6H, m), 0.90 - 0.92 (9H, m), 1.44 - 1.47 (18H, m), 1.94 - 1.99 (2H, m), 2.02 - 2.10 (2H, m), 3.35 - 3.36 (3H, m), 3.37 - 3.38 (3H, m), 3.92 - 4.01 (3H, m), 4.04 - 4.07 (2H, m), 4.21 (2H, br s), 5.18 (2H, s), 6.33 (1H, br d), 6.49 (1H, dd), 6.94 (1H, dd), 7.14 - 7.19 (1H, m), 7.19 - 7.24 (1H, m), 7.39 - 7.45 (2H, m), 7.85 (1H, dd); m/z (ES ⁺ ) [M+H] ⁺ = 811.0. Intermediate 125c: N -tert-butyloxycarbonyl- N -[4-[8-[4-fluoro-3-(2-hydroxyethoxy)phenyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]-6-[2-(methoxymethoxy)phenyl]thiazol-3-yl]carbamic acid tert-butyl ester

Intermediate 125b (440 mg, 0.54 mmol) in THF (1 mL) was cooled to 0 °C. Then, TBAF (0.6 ml, 0.6 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was diluted with EtOAc and washed with water. The organic phase was dried over MgSO ₄ , filtered and concentrated to give the title compound (369 mg, 98%) as a brown gum. m/z (ES ⁺ ) [M+H] ⁺ = 696.3. Intermediate 125d: Methanesulfonic acid 2-[5-[3-[3-[bis(tert-butyloxycarbonyl)amino]-6-[2-(methoxymethoxy)phenyl]phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl ester

Intermediate 125c (376 mg, 0.54 mmol) and DIPEA (141 μl, 0.81 mmol) in DCM (5 ml) were cooled to 0 °C and a solution of methanesulfonic anhydride (141 mg, 0.81 mmol) in DCM (1 ml) was added. The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was diluted with DCM and washed with NaHCO ₃ solution followed by brine. The organic phase was dried over MgSO ₄ and concentrated. Purification by SFC (gradient: 15%-90% EtOAc in hexanes) gave the title compound (270 mg, 64.6%) as a white foam. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.40 - 1.46 (18H, m), 1.94 - 2.00 (2H, m), 2.04 - 2.11 (2H, m), 3.08 (3H, s), 3.33 - 3.42 (7H, m), 4.19 - 4.25 (2H, m), 4.27 - 4.31 (2H, m), 4.52 - 4.57 (2H, m), 5.19 (2H, s), 6.40 (1H, br d), 6.50 (1H, dd), 6.98 (1H, dd), 7.13 - 7.24 (2H, m), 7.39 - 7.45 (2H, m), 7.86 (1H, dd); m/z (ES ⁺ ) [M+H] ⁺ = 774.8. Intermediate 125e: 4-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)piperidine-1-carboxylic acid tributyl ester

Tributyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.59 g, 23.59 mmol) and Cs ₂ CO ₃ (11.5 g, 35.4 mmol) were added to a solution of 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (4.98 g, 23.6 mmol) in DMF (79 mL), and the mixture was heated to 75 °C. After 4 h and 7 h, more tributyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.59 g, 23.59 mmol) and Cs ₂ CO ₃ (7.69 g, 23.6 mmol) were added. Stirring was continued at 75 °C for 16 h after the last addition. The mixture was partially concentrated under reduced pressure, diluted with EtOAc (100 mL), washed with brine (2 x 150 mL), _dried over _Na2SO4 , filtered, and concentrated under reduced pressure. Purification by FSC (elution gradient: 0 to 30% EtOAc in hexanes) gave the title compound (7.27 g, 78%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.43 (9H, s), 1.80 - 1.94 (4H, m), 2.23 (3H, s), 2.93 (2H, br s), 4.10 (2H, br s), 4.69 - 4.92 (1H, m), 7.51 (1H, s), 8.16 (1H, d), 8.26 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 394.2. Intermediate 125f: 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]piperidine-1-carboxylic acid tributyl ester

1,4-Dioxathiocarbamide (82 mL) was added to a mixture of intermediate 125e (5.48 g, 13.9 mmol), hexahydropyrimidine-2,4-dione (3.17 g, 27.8 mmol), K ₃ PO ₄ (5.90 g, 27.8 mmol), [Pd(cinnamyl)Cl] ₂ (0.36 g, 0.69 mmol) and t BuBrettPhos (0.67 g, 1.39 mmol). The flask was evacuated and backfilled with nitrogen (5x). The mixture was stirred at 90°C for 15 h. After cooling to room temperature, saturated aqueous NH ₄ Cl solution (150 mL) was added, and the mixture was extracted with DCM (3 x 200 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was triturated with hexanes/DCM (5:1), _H2O , and hexanes to give the title compound (4.61 _g , 78%) as a grey solid. ¹ H NMR (DMSO- d 6): δ 1.42 (9H, s), 1.77 - 1.98 (4H, m), 2.23 (3H, s), 2.75 (2H, t), 2.94 (2H, br d), 3.79 (2H, t), 4.10 (2H, br d), 4.71 - 4.87 (1H, m), 7.49 (1H, s), 7.87 (1H, d), 8.16 (1H, d), 10.36 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 428.4. Intermediate 125g: 1-[3-methyl-1-(4-piperidinyl)pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (5.41 mL, 70.2 mmol) was added to a solution of intermediate 125f (1.50 g, 3.51 mmol) in DCM (17 mL). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. DCM (100 mL), IPA (30 mL), and saturated aqueous K ₂ CO ₃ solution (100 mL) were added, and the phases were separated. The organic layer was washed with saturated aqueous K ₂ CO ₃ solution (100 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give the title compound as a pale yellow salt (1.17 g, 102%, 92% purity), which was used in the next step without further purification. ¹ H NMR (DMSO- d 6): δ 1.72 - 1.93 (4H, m), 2.26 (3H, s), 2.61 - 2.71 (2H, m), 2.76 (2H, t), 3.07 (2H, br d), 3.81 (2H, t), 4.63 - 4.72 (1H, m), 7.45 (1H, s), 7.88 (1H, d), 8.17 (1H, d), 10.38 (1H, br s), (one NH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 328.2. Intermediate 125h: 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-piperidinyl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 25f using intermediate 25e (3.71 g, 10.2 mmol) and intermediate 125g (1.66 g, 5.08 mmol) and stirring at 85° C. for 23 h. Purification by FSC (elution gradient: 0 to 15% MeOH in DCM) gave the title compound (1.42 g, 51%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.40 (9H, s), 1.51 - 1.69 (2H, m), 1.77 - 1.89 (4H, m), 1.98 - 2.10 (2H, m), 2.24 (3H, s), 2.34 (2H, br t), 2.52 - 2.64 (2H, m), 2.74 (2H, t), 3.02 (4H, br d), 3.68 - 3.76 (2H, m), 3.79 (2H, t), 4.58 (1H, tt), 7.48 (1H, s), 7.86 (1H, d), 8.16 (1H, d), 10.36 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 543.5. Intermediate 125i: 1-[1-[1-[(4-fluoro-4-piperidinyl)methyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (4.0 mL) was added to a solution of intermediate 125h (1.42 g, 2.61 mmol) in DCM (12.1 mL). The resulting mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was azeotroped with DCM (3x) and dried in vacuo. DCM (90 mL), IPA (30 mL), saturated aqueous K ₂ CO ₃ solution (50 mL), and water (20 mL) were added, and the phases were separated. The organic layer was washed with saturated aqueous K ₂ CO ₃ solution (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (1.01 g, 78%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.55 - 1.70 (2H, m), 1.73 - 1.88 (4H, m), 2.04 (2H, qd), 2.24 (3H, s), 2.33 (2H, br t), 2.51 - 2.58 (2H, m), 2.68 - 2.85 (6H, m), 3.02 (2H, br d), 3.79 (2H, t), 4.58 (1H, tt), 7.48 (1H, s), 7.86 (1H, d), 8.16 (1H, d), 10.36 (1H, br s), (one NH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 443.4. 1-[1-[1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

A mixture of intermediate 125d (28.0 mg, 0.04 mmol), intermediate 125i (16 mg, 0.04 mmol) and DIPEA in DMF (0.2 mL) was stirred at 80 °C overnight. The alkylated product was purified by RPC (elution gradient: 20%-60% MeCN in water containing 0.1% FA). The alkylated product was dissolved in DCM (0.5 mL) and HCl (4 N in dihydrogen ether, 0.5 ml) was added. The mixture was stirred at room temperature for 30 min. The solvent was removed and the material was dissolved in MeOH and carbonate resin was added and stirred for 1 h. The resin was filtered off and the filtrate was concentrated. Purification by RPC (elution gradient: 5%-35% MeCN in water containing 0.1% FA) gave the title compound (10.40 mg, 32.8%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.57 - 1.77 (2H, m), 1.79 - 1.88 (4H, m), 1.90 - 1.98 (2H, m), 2.00 - 2.10 (2H, m), 2.10 - 2.16 (2H, m), 2.21 - 2.25 (3H, m), 2.29 - 2.39 (4H, m), 2.70 - 2.78 (6H, m), 2.99 - 3.05 (2H, m), 3.06 - 3.11 (2H, m), 3.17 - 3.24 (4H, m), 3.78 - 3.82 (2H, m), 4.12 - 4.18 (2H, m), 4.37 - 4.43 (2H, m), 4.55 - 4.63 (1H, m), 5.93 (2H, s), 6.40 (1H, dt), 6.67 (1H, dd), 6.82 - 6.89 (2H, m), 7.00 (1H, dd), 7.19 - 7.23 (1H, m), 7.45 (1H, s), 7.48 (1H, s), 7.85 - 7.91 (2H, m), 8.13 - 8.17 (1H, m), 10.35 (1H, s), 13.75 - 14.58 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 876.4. Example 126 Intermediate 126a: ( 3S )-3-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)pyrrolidine-1-carboxylic acid tributyl ester

5-Bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (1 g, 4.74 mmol) was added to ( R )-3-hydroxypyrrolidine-1-carboxylic acid tributyl ester (0.887 g, 4.74 mmol) and 2-(tributyl-λ⁵-phosphine)acetonitrile (1.372 g, 5.69 mmol) in toluene (10 mL) under nitrogen. The resulting mixture was stirred at 100°C for 24 h. The reaction mixture was concentrated under reduced pressure. Purification by RPC (elution gradient: 5% to 100% MeCN in water _containing 0.1% _NH4HCO3 ) gave the title compound (1.0 g, 56%) as a brown gum. ¹ H NMR (DMSO- d ₆ ): δ 1.38 - 1.42 (9H, s), 2.24 (3H, s), 2.29 - 2.33 (2H, m), 3.40 - 3.49 (2H, m), 3.50 - 3.54 (1H, m), 3.75 - 3.79 (1H, m), 5.28 - 5.35 (1H, m), 7.44 (1H, d), 8.20 (1H, d), 8.30 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 380.1. Intermediate 126b: ( 3S )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]pyrrolidine-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 114d starting from intermediate 126a (900 mg, 2.37 mmol). Purification by FSC (elution gradient: 0 to 50% EtOAc in petroleum ether then 0 to 10% MeOH in DCM) gave the title compound (600 mg, 61%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, d), 2.26 (3H, d), 2.29 - 2.35 (2H, m), 2.76 (2H, t), 3.38 - 3.50 (2H, m), 3.52 - 3.57 (1H, m), 3.76 - 3.81 (1H, m), 3.83 (2H, t), 5.31 - 5.39 (1H, m), 7.42 (1H, d), 7.92 (1H, d), 8.21 (1H, d), 10.41 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 414.2. Intermediate 126c: 1-[3-methyl-1-[( 3S )-pyrrolidin-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 6c starting from intermediate 126b (600 mg, 1.45 mmol). The mixture was concentrated under reduced pressure. MTBE (3 mL) was added. The solid was collected by filtration, washed with MTBE (1 mL), and dried in vacuo to give the title compound as a yellow solid as a TsOH salt (690 mg, 98%), which was used without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 314.1. Intermediate 126d: 4-[[( 3S )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]pyrrolidin-1-yl]methyl]-4-fluoro-piperidine-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 25f starting from intermediate 25e (1224 mg, 3.35 mmol) and intermediate 126c (700 mg, 2.23 mmol). Purification by FSC (elution gradient: 0 to 10% MeOH in DCM) gave the title compound (580 mg, 49%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.56 - 1.68 (3H, m), 1.80 - 1.92 (3H, m), 2.27 (3H, s), 2.38 - 2.42 (1H, m), 2.53 - 2.57 (1H, m), 2.69 - 2.72 (1H, m), 2.74 - 2.78 (3H, m), 2.86 (1H, d), 2.99 - 3.10 (3H, m), 3.72 - 3.77 (2H, m), 3.81 (2H, t), 5.37 - 5.41 (1H, m), 7.47 (1H, s), 7.89 (1H, d), 8.16 (1H, s), 10.39 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 529.3. Intermediate 126e: 1-[1-[(3 S )-1-[(4-fluoro-4-piperidinyl)methyl]pyrrolidin-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 1i starting from intermediate 126d (570 mg, 1.08 mmol). The crude residue was triturated with MTBE (5 mL) and dried in vacuo to afford the title compound as a white solid as a TFA salt (300 mg, 65%). m/z (ES ⁺ ) [M+H] ⁺ = 429.2. 1-[1-[(3 S )-1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]pyrrolidin-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 125d (40 mg, 0.05 mmol) and intermediate 126e (22 mg, 0.05 mmol) in a similar manner to Example 125. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (11.8 mg, 26.7%) as a white solid. ¹ H NMR (DMSO- d 6) δ 1.60 - 1.76 (2H, m), 1.79 - 1.91 (3H, m), 1.92 - 2.01 (2H, m), 2.10 - 2.20 (2H, m), 2.20 - 2.27 (3H, m), 2.33 - 2.43 (3H, m), 2.52 - 2.56 (1H, m), 2.63 - 2.67 (1H, m), 2.67 - 2.79 (8H, m), 2.80 - 2.86 (2H, m), 3.01 - 3.13 (4H, m), 3.20 - 3.24 (2H, m), 3.77 - 3.81 (2H, m), 4.13 - 4.19 (2H, m), 4.35 - 4.42 (2H, m), 5.33 - 5.41 (1H, m), 6.39 (1H, dt), 6.66 (1H, dd), 6.81 - 6.90 (2H, m), 6.99 (1H, dd), 7.15 - 7.24 (1H, m), 7.46 (2H, d), 7.85 - 7.91 (2H, m), 8.16 (1H, d), 10.36 (1H, s), 13.78 - 14.48 (1H, m); m/z (ES ⁺ [M+H] ⁺ = 862.4. Example 127 Intermediate 127a: (3 R )-3-(5-bromo-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl)pyrrolidine-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 114a, starting from 5-bromo-3-methyl- 1H -pyrrolo[2,3- b ]pyridine (0.939 g, 4.45 mmol) and ( 3S )-3-hydroxypyrrolidine-1-carboxylic acid tributyl ester (1 g, 5.34 mmol). Purification by RPC (elution gradient: 5% to 100% MeCN in water _containing 0.5% _NH4HCO3 ) gave the title compound (1.0 g, 59%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, d), 2.28 - 2.39 (3H, m), 2.31 (2H, q), 3.38 - 3.57 (3H, m), 3.73 - 3.79 (1H, m), 5.26 - 5.37 (1H, m), 7.44 (1H, d), 8.20 (1H, d), 8.30 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 324.1. Intermediate 127b: (3 R )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]pyrrolidine-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 4b starting from intermediate 127a (900 mg, 2.37 mmol).

Purification by FSC (elution gradient: 0 to 10% MeOH in DCM) gave the title compound (500 mg, 51.1%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.42 (9H, d), 2.29 - 2.37 (3H, m), 2.77 (2H, t), 3.45 - 3.58 (3H, m), 3.78 (1H, t), 3.82 (2H, t), 5.28 - 5.39 (1H, m), 7.42 (1H, d), 7.92 (1H, d), 8.21 (1H, d), 10.41 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 414.2. Intermediate 127c: 1-[3-methyl-1-[(3 R )-pyrrolidin-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 6c starting from intermediate 127b (490 mg, 1.19 mmol) the title compound was obtained as a yellow solid in the form of the TsOH salt (540 mg, 69.3%). The crude product was used in the next step without further purification. m/z (ES ⁺ ) [M+H] ⁺ = 314. Intermediate 127d: 4-[[( 3R )-3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]pyrrolidin-1-yl]methyl]-4-fluoro-piperidine-1-carboxylate

Prepared in a similar manner to intermediate 25f starting from intermediate 127c (530 mg, 1.09 mmol) and intermediate 25e (479 mg, 1.31 mmol). Purification by FSC (elution gradient: 0 to 10% MeOH in DCM) gave the title compound (300 mg, 52.0%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.41 (9H, s), 1.57 - 1.71 (2H, m), 1.80 - 1.93 (3H, m), 2.27 (3H, s), 2.52 - 2.59 (1H, m), 2.70 (1H, d), 2.76 (3H, t), 2.83 - 2.89 (2H, m), 3.12 - 3.17 (2H, m), 3.59 - 3.66 (2H, m), 3.74 (2H, d), 3.81 (2H, t), 5.34 - 5.45 (1H, m), 7.47 (1H, s), 7.89 (1H, d), 8.18 (1H, d), 10.40 (1H, s); m/z (ES ⁺ ), [M+H] ⁺ = 529.0 Intermediate 127e: 1-[1-[(3 R )-1-[(4-fluoro-4-piperidinyl)methyl]pyrrolidin-3-yl]-3-methyl-pyrrolo[2,3 -b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 1i starting from intermediate 127d (70 mg, 0.16 mmol).

Purification by RPC (elution gradient: 5% to 70% MeCN in water containing 0.5% NH ₄ HCO ₃ ) gave the title compound (30.0 mg, 42.9%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.53 - 1.67 (2H, m), 1.69 - 1.81 (2H, m), 1.84 - 1.95 (1H, m), 2.26 (3H, s), 2.36 - 2.45 (1H, m), 2.53 - 2.58 (1H, m), 2.63 - 2.68 (1H, m), 2.69 - 2.74 (4H, m), 2.76 (3H, t), 2.83 - 2.89 (2H, m), 3.05 - 3.11 (1H, m), 3.81 (2H, t), 5.32 - 5.43 (1H, m), 7.49 (1H, s), 7.89 (1H, d), 8.18 (1H, d), 10.39 (1H, s); m/z (ES ⁺ ), [M+H] ⁺ = 429. 1-[1-[(3 R )-1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]pyrrolidin-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 125d (29 mg, 0.04 mmol) and intermediate 127e (16 mg, 0.04 mmol) in a similar manner to Example 125. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (6.7 mg, 20.82%) as a white solid. ¹ H NMR (DMSO- d 6) δ 1.58 - 1.76 (2H, m), 1.77 - 1.91 (3H, m), 1.92 - 1.99 (2H, m), 2.09 - 2.19 (2H, m), 2.19 - 2.25 (3H, m), 2.31 - 2.38 (2H, m), 2.53 - 2.56 (1H, m), 2.62 - 2.68 (1H, m), 2.69 - 2.79 (7H, m), 2.82 - 2.88 (2H, m), 3.01 - 3.15 (4H, m), 3.20 - 3.24 (2H, m), 3.77 - 3.81 (2H, m), 4.13 - 4.19 (2H, m), 4.37 - 4.43 (2H, m), 5.34 - 5.40 (1H, m), 5.93 (2H, s), 6.39 (1H, dt), 6.66 (1H, dd), 6.80 - 6.89 (2H, m), 6.99 (1H, dd), 7.18 - 7.24 (1H, m), 7.42 - 7.49 (2H, m), 7.84 - 7.91 (2H, m), 8.16 (1H, d), 10.36 (1H, s), 13.38 - 14.98 (1H, m); m/z (ES ⁺ [M+H] ⁺ = 862.4. Example 128 1-[1-[3-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 125d (26 mg, 0.05 mmol) and intermediate 36a (31 mg, 0.06 mmol) in a similar manner to Example 125. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (4 mg, 9.36%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.64 (2H, dd), 0.82 - 0.86 (2H, m), 1.21 - 1.32 (3H, m), 1.33 - 1.39 (2H, m), 1.62 - 1.71 (4H, m), 1.74 - 1.82 (2H, m), 1.87 - 2.01 (6H, m), 2.11 - 2.16 (2H, m), 2.69 - 2.73 (2H, m), 2.73 - 2.77 (2H, m), 3.08 - 3.13 (2H, m), 3.20 - 3.26 (3H, m), 3.77 - 3.83 (2H, m), 4.13 - 4.18 (2H, m), 4.37 - 4.42 (2H, m), 4.55 - 4.61 (1H, m), 5.91 - 5.96 (2H, m), 6.38 - 6.42 (1H, m), 6.66 - 6.69 (1H, m), 6.82 - 6.88 (2H, m), 6.97 - 7.03 (1H, m), 7.19 - 7.24 (1H, m), 7.43 - 7.47 (1H, m), 7.49 (1H, s), 7.87 (1H, s), 7.92 (2H, d), 8.14 (1H, d), 10.35 (1H, s), 13.96 - 14.35 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 855.6. Example 129 Intermediate 129a: 3-(5-bromoindol-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

A 250 mL flask was charged with intermediate 99b (4.12 g, 15.3 mmol) and intermediate 64c (5.54 g, 19.8 mmol). PPTS (0.19 g, 0.76 mmol) and toluene (76 mL) were added. The resulting mixture was stirred at 110 °C for 15 h. After cooling to room temperature, the mixture was washed with saturated aqueous NaHCO ₃ solution (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by FSC (1st purification: 0-30% acetone in hexanes; 2nd purification: 0-50% EtOAc in hexanes) gave the title compound (5.06 g, 68%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.83 (2H, br s), 1.98 (2H, s), 3.37 - 3.53 (4H, m), 3.94 - 4.01 (2H, m), 4.32 (2H, br d), 4.59 (1H, br t), 5.08 m/ z (ES ⁺ ) [M+H] ⁺ = 485.2. Intermediate 129b: 3-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

A 250 mL flask was charged with intermediate 129a (4.04 g, 8.32 mmol), K ₃ PO ₄ (5.30 g, 25.0 mmol), hexahydropyrimidine-2,4-dione (1.42 g, 12.5 mmol) and t BuBrettPhos Pd G3 (0.71 g, 0.83 mmol). The flask was evacuated and backfilled with argon (2x). 1,4-Dihydrogen iodide (49 mL) was added. The flask was evacuated and backfilled with argon (3x). The resulting mixture was stirred at 100 °C for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. Water (70 mL) and EtOAc (70 mL) were added. The resulting suspension was stirred at room temperature for 15 min. The mixture was filtered. The filter cake was washed with EtOAc (2 x 20 mL) and dried in vacuo to give 2.90 g of a gray solid. The filtrate was concentrated under reduced pressure. EtOAc-MeOH (9: 1, 20 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and filtered. The solid was washed with EtOAc-MeOH (9: 1, 10 mL) and dried in vacuo to give 0.72 g of an off-white solid. The two filter cakes were combined and purified by FSC (0-12% MeOH in EtOAc) to give the title compound (2.98 g, 69%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.88 (2H, br s), 1.99 (2H, br s), 2.73 (2H, t), 3.47 (4H, br s), 3.77 (2H, t), 4.02 (2H, br dd), 4.33 (2H, br d), 4.54 - 4.72 (1H, m), 5.10 (2H, s), 6.50 (1H, d), 7.09 (1H, dd), 7.27 - 7.43 (5H, m), 7.46 - 7.56 (2H, m), 7.81 (1H, d), 10.29 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 519.2. Intermediate 129c: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

A 40 mL vial was charged with intermediate 129b (100 mg, 0.19 mmol) and Pd/C (41 mg, 0.04 mmol, 10 wt% Pd). DMF (3.9 mL) was added. Hydrogen was bubbled through the mixture for 5 min. The resulting mixture was stirred under hydrogen atmosphere for 2 h. The mixture was filtered through a celite® pad and eluted with DMF. The filtrate was concentrated under reduced pressure. Lyophilization from water-MeCN gave the title compound as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.63 - 2.12 (5H, m), 2.62 - 2.77 (6H, m), 3.76 (2H, t), 3.97 (2H, dd), 4.29 (2H, dd), 4.53 - 4.59 (1H, m), 6.47 (1H, d), 7.07 (1H, dd), 7.44 - 7.52 (2H, m), 7.80 (1H, d), 10.24 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 385.3. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared using intermediate 129c (31 mg, 0.08 mmol) and intermediate 13d (34 mg, 0.07 mmol) in a similar manner to Example 64. Purification by RPC (0-40% MeCN in water containing 0.1% HCOOH) gave the title compound (31.9 mg, 53%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.16 - 1.30 (2H, m), 1.61 (1H, br s), 1.78 (2H, br d), 1.83 - 2.06 (6H, m), 2.12 (2H, br d), 2.20 (2H, br d), 2.33 - 2.47 (4H, m), 2.63 (2H, br t), 2.71 (2H, t), 3.09 (2H, br d), 3.25 (2H, br d), 3.34 (2H, br d), 3.76 (2H, t), 3.94 - 4.01 (2H, m), 4.24 - 4.41 (4H, m), 4.53 - 4.61 (1H, m), 5.92 (2H, s), 6.38 - 6.44 (1H, m), 6.44 - 6.51 (2H, m), 6.81 - 6.96 (3H, m), 7.08 (1H, dd), 7.18 - 7.27 (1H, m), 7.42 - 7.51 (3H, m), 7.80 (1H, d), 7.89 (1H, br d), 10.24 (1H, s), 13.97 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 871.5. Example 130 Intermediate 130a: 3-[3-bromo-5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

NBS ₍ 177 mg, 0.99 mmol) was added to a solution of intermediate 129b (491 mg, 0.95 mmol) in DCM (19 mL). The resulting mixture was stirred at room temperature for 12 min. The mixture was washed with _saturated aqueous _Na2S2O3 (2 x 20 mL) and saturated aqueous _NaHCO3 (20 mL), dried over _Na2SO4 , filtered, and _concentrated under reduced pressure to give the title compound (529 mg, 94%) as a brown solid. ¹ H NMR (DMSO- d ₆ ): δ 1.81 - 1.91 (2H, m), 1.97 (2H, br s), 2.73 (2H, t), 3.36 - 3.55 (4H, m), 3.79 (2H, t), 4.02 (2H, br dd), 4.24 - m/z (ES ⁺ ) [M+H] ⁺ = 597.2. Intermediate 130b: 3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

A 20 mL vial was charged with intermediate 130a (243 mg, 0.41 mmol), cyclopropylboronic acid (87 mg, 1.02 mmol), PdCl ₂ (dtbpf) (27 mg, 0.04 mmol) and K ₃ PO ₄ (259 mg, 1.22 mmol). Toluene (3.7 mL) and water (0.37 mL) were added. Argon was bubbled through the mixture for 5 min. The resulting mixture was stirred at 70 °C for 6 h. After cooling to room temperature, DCM (30 mL), saturated aqueous NaHCO ₃ solution (10 mL) and brine (15 mL) were added. The phases were separated. The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. Purification by FSC (1st purification: 80%-100% EtOAc in hexanes, then 0-10% MeOH in EtOAc; 2nd purification: 0-6% MeOH in EtOAc) gave the title compound (157 mg, 69%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 0.48 - 0.65 (2H, m), 0.78 - 0.93 (2H, m), 1.78 - 2.03 (5H, m), 2.72 (2H, t), 3.45 (4H, br s), 3.77 (2H, t), 4.00 (2H, br dd), 4.20 (2H, br d), 4.51 - 4.60 (1H, m), 5.08 (2H, s), 7.06 (1H, dd), 7.26 - 7.41 (5H, m), 7.41 - 7.49 (2H, m), 7.51 (1H, d), 10.23 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 559.3. Intermediate 130c: 1-[3-cyclopropyl-1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 129c starting from intermediate 130b (153 mg, 0.27 mmol) to give the title compound (116 mg, 100%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 0.53 - 0.61 (2H, m), 0.81 - 0.88 (2H, m), 1.74 - 1.84 (4H, m), 1.86 - 1.93 (1H, m), 2.18 (1H, br s), 2.64 - 2.76 (6H, m), 3.77 (2H, t), 3.96 (2H, dd), 4.18 (2H, dd), 4.47 - 4.54 (1H, m), 7.01 - 7.09 (1H, m), 7.40 - 7.48 (2H, m), 7.49 - 7.53 (1H, m), 10.23 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 425.4. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared using intermediate 130c (30 mg, 0.07 mmol) and intermediate 13d (30 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (23.6 mg, 43%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 0.54 - 0.60 (2H, m), 0.82 - 0.88 (2H, m), 1.24 (2H, q), 1.60 (1H, br s), 1.73 - 1.81 (2H, m), 1.84 - 2.01 (7H, m), 2.08 - 2.15 (2H, m), 2.19 (2H, br d), 2.33 - 2.47 (4H, m), 2.59 - 2.67 (2H, m), 2.72 (2H, t), 3.09 (2H, br d), 3.25 (2H, br d), 3.34 (2H, br d), 3.77 (2H, t), 3.97 (2H, dd), 4.18 (2H, br dd), 4.33 (2H, br s), 4.47 - 4.54 (1H, m), 5.92 (2H, s), 6.37 - 6.44 (1H, m), 6.45 - 6.50 (1H, m), 6.82 - 6.93 (3H, m), 7.03 - 7.09 (1H, m), 7.18 - 7.25 (1H, m), 7.41 - 7.49 (3H, m), 7.49 - 7.54 (1H, m), 7.78 - 8.01 (1H, m), 10.24 (1H, s), 14.07 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 911.5. Example 131 Intermediate 131a: 3-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-vinyl-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

A 20 mL vial was charged with intermediate 130a (226 mg, 0.38 mmol), K ₃ PO ₄ (241 mg, 1.13 mmol) and PdCl ₂ (dtbpf) (25 mg, 0.04 mmol). Toluene (3.3 mL), water (0.3 mL) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane cyclopentane (0.16 mL, 0.95 mmol) were added. Argon was bubbled through the mixture for 5 min. The resulting mixture was stirred at 70 °C for 135 min and at 100 °C for 90 min. After cooling to room temperature, saturated aqueous NaHCO ₃ solution (20 mL) was added. The mixture was extracted with DCM (3 x 20 mL). The combined organic layers were dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. Purification by FSC (elution gradient: 0-6% MeOH in EtOAc) and RPC (elution gradient: 40%-70% MeCN in water containing 0.1% _NH4OH ) gave the title compound (51 mg, 25%) as a white solid in an 8:1 mixture with intermediate 130a. ¹ H NMR (DMSO- d ₆ ): δ 1.83 - 1.92 (2H, m), 1.94 - 2.02 (2H, m), 2.73 (2H, t), 3.40 - 3.54 (4H, m), 3.78 (2H, t), 4.01 (2H, dd), 4.31 (2H, br d), 4.56 - 4.62 (1H, m), 5.02 - 5.15 (3H, m), 5.62 (1H, br d), 6.86 (1H, dd), 7.08 - 7.15 (1H, m), 7.30 - 7.40 (5H, m), 7.46 - 7.57 (1H, m), 7.76 (1H, s), 7.93 (1H, s), 10.29 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 545.3. Intermediate 131b: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-3-ethyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in analogy to intermediate 129c starting from intermediate 131a (49 mg, 0.09 mmol). Purification by RPC (elution gradient: 0-90% MeCN in water containing 0.1% _NH4OH ) gave the title compound (29 mg, 78%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.25 (3H, t), 1.83 (4H, br d), 2.64 - 2.77 (8H, m), 3.76 (2H, t), 3.97 (2H, br dd), 4.22 (2H, dd), 4.47 - 4.57 (1H, m), 7.05 (1H, dd), 7.38 - 7.48 (2H, m), 7.58 (1H, s), 10.26 (1H, br s), (one NH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 413.4. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-ethyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared using intermediate 131b (28 mg, 0.07 mmol) and intermediate 13d (28 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-50% MeCN in water containing 0.1% HCOOH) gave the title compound (23.6 mg, 43%) as an off-white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.19 - 1.30 (5H, m), 1.57 - 1.65 (1H, m), 1.78 (2H, br d), 1.85 - 2.02 (6H, m), 2.08 - 2.15 (2H, m), 2.20 (2H, br d), 2.33 - 2.47 (4H, m), 2.59 - 2.75 (6H, m), 3.09 (2H, br d), 3.25 (2H, br d), 3.34 (2H, br d), 3.76 (2H, br t), 3.97 (2H, br dd), 4.23 (2H, br d), 4.30 - 4.38 (2H, m), 4.52 (1H, br d), 5.92 (2H, br s), 6.38 - 6.43 (1H, m), 6.44 - 6.49 (1H, m), 6.82 - 6.88 (2H, m), 6.91 (1H, dd), 7.03 - 7.08 (1H, m), 7.22 (1H, t), 7.41 - 7.47 (3H, m), 7.57 (1H, s), 7.89 (1H, br d), 10.23 (1H, s), 14.04 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 899.5. Example 132 Intermediate 132a 3-allyl-4-hydroxy-pyrrolidine-1-carboxylic acid tributyl ester

Under nitrogen, tributyllithium borohydride solution (11.3 ml, 11.3 mmol, 1 M in THF) was slowly added to a stirred solution of tributyl 3-allyl-4-oxopyrrolidine-1-carboxylate (2.31 g, 10.25 mmol) in 2-methyltetrahydrofuran (37.9 ml) cooled to 0°C. The resulting mixture was stirred while slowly warming to room temperature. The reaction was stirred at room temperature for 17 h. An additional portion of tributyllithium borohydride (2.05 ml, 2.05 mmol, 1 M in THF) was added and the reaction was stirred for an additional 15 min. The reaction mixture was diluted with EtOAc and quenched with saturated aqueous NH ₄ Cl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 0 to 100% EtOAc in hexanes) provided the title compound (1.10 g, 47.2%) as a light yellow oil. ¹ H NMR (CDCl ₃ ): δ 1.48 (9H, s), 2.08 - 2.29 (2H, m), 2.34 (1H, dt), 3.07 - 3.16 (1H, m), 3.40 - 3.55 (2H, m), 3.61 (1H, br t), 4.28 (1H, br s), 5.01 - 5.10 (1H, m), 5.15 (1H, br d), 5.74 - 5.90 (1H, m). Intermediate 132b: rac- (2 R ,3a R ,6a R )-2-(bromomethyl)-2,3,3 a ,4,6,6 a -hexahydrofuro[2,3- c ]pyrrole-5-carboxylic acid tributyl ester and intermediate 132c: rac- ( 2S , 3aR , 6aR )-2-(bromomethyl) -2,3,3a , 4,6,6a -hexahydrofuro[2,3- c ]pyrrole-5-carboxylic acid tributyl ester

NBS (0.941 g, 5.28 mmol) was added in one portion to a stirred solution of intermediate 132a (1.09 g, 4.80 mmol) in DCM (24.0 ml) under air. The resulting mixture was stirred at room temperature for 20 h. The reaction was quenched with saturated _{aqueous Na2SO3} . The reaction was diluted with EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over _Na2SO4 , _filtered , and concentrated. Purification by FSC (elution gradient: 0 to 61% EtOAc in hexanes) gave the title compound intermediate 132b (0.581 g, 39.5%) and intermediate 132c (0.346 g, 23.5%).

The compound is a racemic mixture of image isomers, but non-image isomers are known. The relative stereochemistry of non-image isomers was evaluated by comparison of the spectra of analogous products and derivatives. Intermediate 132b: ¹ H NMR (CD ₂ Cl ₂ ): δ 1.46 (9H, s), 1.94 - 2.03 (1H, m), 2.04 - 2.11 (1H, m), 2.91 - 3.03 (1H, m), 3.17 (1H, dd), 3.40 (1H, dd), 3.47 (2H, d), 3.55 - 3.63 (2H, m), 4.42 (1H, dq), 4.65 (1H, t). Intermediate 132c: ¹ H NMR (CD ₂ Cl ₂ ): δ 1.47 (9H, s), 1.54 - 1.68 (1H, m), 2.30 - 2.41 (1H, m), 2.84 - 2.95 (1H, m), 3.31 (1H, br s), 3.39 (1H, br dd), 3.46 - 3.55 (3H, m), 3.63 (1H, d), 4.11 - 4.20 (1H, m), 4.53 (1H, t). Intermediate 132d: rac- ( 2S , 3aR , 6aR )-2-[[2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]non-7-yl]methyl] -2,3,3a , 4,6,6a -hexahydrofuro[2,3- c ]pyrrole-5-carboxylic acid tributyl ester

DIPEA (282 μl, 1.62 mmol) was added in one portion to a stirred mixture of intermediate 132c (198 mg, 0.54 mmol) and intermediate 124a (248 mg, 0.81 mmol) in DMF (3767 μl). The resulting suspension was stirred at 100 °C for 15 h and cooled to room temperature. Purification by RPC (elution gradient: 10%-100% water containing 0.1% formic acid in MeOH) gave the title compound (152 mg, 47%) as a solid. ¹ H NMR (DMSO- d6 ): δ 1.40 (9H, s), 1.64 - 1.77 (4H, m), 2.20 (3H, br s), 2.27 (3H, s), 2.31 - 2.50 (7H, m), 2.76 (3H, br t), 3.15 (1H, br dd), 3.24 - 3.36 (2H, m), 3.36 - 3.47 (3H, m), 3.80 (2H, t), 4.00 (1H, br s), 4.34 (1H, br s), 5.25 (1H, quin), 7.61 (1H, s), 7.88 (1H, d), 8.17 (1H, s), 10.40 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 593.5. Intermediate 132e 1-[1-[7-[[ rac- (2 S ,3a R ,6a R )-3,3 a ,4,5,6,6 a -hexahydro-2 H -furo[2,3- c ]pyrrol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 2c starting from intermediate 132d (149 mg, 0.25 mmol). Purification by ion exchange chromatography (PoraPak Rxn CX cartridge) (eluting with 1.5 N NH ₃ in MeOH and 1.5 N NH ₃ in MeOH/DCM) gave the title compound (109 mg, 88%) as a yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.58 - 1.76 (4H, m), 2.09 - 2.23 (3H, m), 2.23 - 2.47 (12H, m), 2.53 - 2.70 (2H, m), 2.72 - 2.79 (2H, m), 2.87 (1H, br d), 3.17 (1H, br s), 3.69 - 3.86 (3H, m), 4.31 (1H, br d), 5.25 (1H, br t), 7.61 (1H, s), 7.88 (1H, s), 8.16 (1H, s), 10.40 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 493.3. Intermediate 132f: N- [4-[8-[3-[ rac- ( 2S , 3aR , 6aR )-2-[[2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]non-7-yl]methyl] -2,3,3a ,4,6,6a - hexahydrofuro[2,3- c ]pyrrol-5-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]phthalim-3-yl]-N- t -butyloxycarbonyl-carbamic acid t-butyl ester

Prepared in a similar manner to intermediate 56f starting with intermediate 57a (148 mg, 0.22 mmol) and intermediate 132e (109 mg, 0.22 mmol). Purification by FSC (elution gradient: 75%-100% EtOAc in hexanes and then 0-100% MeOH in EtOAc) gave the title compound (63.7 mg, 25.6%) as a yellow solid. m/z : ES+ [M+H] ⁺ = 1126.8. 1-[3-methyl-1-[7-[[ rac- ( 2S , 3aR , 6aR )-5-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -2,3,3a , 4,6,6a -hexahydrofuro[2,3- c ]pyrrol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

2 M sulfuric acid in water (1.12 mL, 2.24 mmol) was added to a stirred solution of intermediate 132f (63 mg, 0.06 mmol) in THF (1.12 mL). The resulting solution was stirred at 50 °C for 2.5 h. The reaction was diluted with DCM (20 mL) and basified with saturated aqueous NaHCO ₃ solution. The aqueous layer was extracted with additional DCM/IPA (4:1). The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated. Purification by FSC (elution gradient: 0-100% MeOH in EtOAc) gave the title compound (16.9 mg, 34.3%) as an off-white solid. ¹ H NMR (DMSO- d6 ): δ 1.33 - 1.47 (1H, m), 1.66 (4H, br d), 1.94 (2H, br s), 2.08 - 2.21 (4H, m), 2.26 (5H, s), 2.33 (3H, br s), 2.36 - 2.50 (5H, m), 2.76 (2H, br t), 2.85 (1H, br s), 3.04 - 3.15 (4H, m), 3.21 - 3.29 (2H, m), 3.48 - 3.60 (1H, m), 3.80 (2H, br t), 3.89 - 3.99 (1H, m), 4.35 (2H, br s), 4.43 - 4.51 (1H, m), 5.24 (1H, br t), 5.95 (2H, br s), 6.25 (1H, br d), 6.29 (1H, br d), 6.81 - 6.96 (3H, m), 7.22 (1H, br t), 7.47 (1H, s), 7.60 (1H, s), 7.88 (1H, s), 7.91 (1H, br d), 8.16 (1H, s), 10.41 (1H, br s), 14.14 (1H, br s). 19F NMR (DMSO-d6) δ -137.23 (1F, s); m/z (ES ⁺ ) [M+H] ⁺ = 882.5. Example 133 Intermediate 133a: rac- ( 2R , 3aR , 6aR )-2-[[2-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]non-7-yl]methyl] -2,3,3a , 4,6,6a -hexahydrofuro[2,3- c ]pyrrole-5-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 132d starting with intermediate 132b (240 mg, 0.65 mmol) and intermediate 124a (300 mg, 0.98 mmol). Purification by RPC (elution gradient: 10%-100% MeOH in water containing 0.1% formic acid) gave the formate salt of the title compound as a tan solid (144 mg, 34.4%). ¹ H NMR (DMSO- d6 ): δ 1.39 (9H, s), 1.65 - 1.77 (5H, m), 1.91 (1H, br dd), 2.17 - 2.24 (2H, m), 2.26 (3H, s), 2.34 (2H, br d), 2.40 - 2.64 (5H, m, overlapped with residual solvent), 2.72 - 2.78 (2H, m), 2.81 - 2.93 (1H, m), 3.05 (1H, br s), 3.25 - 3.56 (4H, m, overlapped with residual water), 3.80 (2H, br t), 4.25 (1H, br s), 4.48 (1H, br t), 5.25 (1H, quin), 7.61 (1H, s), 7.88 (1H, d), 8.14 - 8.17 (2H, m), 10.40 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 593.5. Intermediate 133b: 1-[1-[7-[[ rac- (2 R ,3a R ,6a R )-,3 a ,4,5,6,6 a -hexahydro-2 H -furo[2,3- c ]pyrrol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 132e starting from intermediate 133a (143 mg, 0.24 mmol) to give the title compound (112 mg, 94%) as an off-white solid. ¹ H NMR (DMSO- d6 ): δ 1.61 - 1.76 (6H, m), 2.14 - 2.23 (2H, m), 2.24 - 2.47 (11H, m), 2.59 - 2.69 (3H, m), 2.71 - 2.83 (4H, m), 3.80 (2H, m/z (ES + ) ^[ M+ H ] ⁺ = 493.4 Intermediate 133c: N -[4-[8-[3-[ rac- ( 2R , 3aR , 6aR )-,2-[[2-[5-(2,4-dioxohexahydroxypyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]non-7-yl]methyl] -2,3,3a , 4,6,6a -hexahydrofuro[2,3- c ]pyrrol-5-yl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl] -N -tributyloxycarbonyl-carbamic acid tributyl ester

Prepared in an analogous manner to intermediate 56f starting with intermediate 57a (152 mg, 0.23 mmol) and intermediate 133b (112 mg, 0.23 mmol). Purification by FSC (elution gradient: 0-50% MeOH in EtOAc) gave the title compound (93 mg, 36.5%) as a yellow solid. m/z (ES ⁺ ) [M+H] ⁺ = 1126.6. 1-[3-methyl-1-[7-[[ rac- ( 2S , 3aR , 6aR )-5-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -2,3,3a , 4,6,6a -hexahydrofuro[2,3- c ]pyrrol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared starting from intermediate 133c (35 mg, 0.03 mmol) in an analogous manner to Example 132. Purification by RPC (elution gradient: 10%-100% MeOH in water containing 0.1% _NH4OH ) gave the title compound (5.6 mg, 20.43%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.59 - 1.80 (5H, m), 1.85 - 2.01 (3H, m), 2.09 - 2.23 (4H, m), 2.27 (3H, s), 2.29 - 2.50 (7H, m, some slight overlap with residual solvent), 2.76 (2H, br t), 2.93 (1H, br s), 3.07 - 3.15 (2H, m), 3.17 - 3.31 (5H, m), 3.39 - 3.47 (2H, m), 3.80 (2H, br t), 4.22 (1H, br s), 4.36 (2H, br s), 4.64 (1H, br t), 5.25 (1H, quin), 5.96 (2H, br s), 6.24 (1H, br d), 6.30 (1H, br d), 6.81 - 6.96 (3H, m), 7.23 (1H, br t), 7.48 (1H, s), 7.61 (1H, s), 7.85 - 7.90 (1H, m), 7.92 (1H, br d), 8.13 - 8.20 (1H, m), 10.41 (1H, br s), 14.20 (1H, br s). ¹⁹ F NMR (DMSO- d6 ): δ -137.39 (1F, s); m/z (ES ⁺ ) [M+H] ⁺ = 882.5. Example 134 Intermediate 134a: 2-[6-amino-5-[8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-yl]-6-chloro-phenol

Prepared in a similar manner to intermediate 2h from (3-chloro-2-hydroxyphenyl)boronic acid (71.9 mg, 0.42 mmol) and intermediate 11f (200 mg, 0.35 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (83 mg, 35.8%) as an orange solid. ¹ H NMR (DMSO- d6 ): δ 0.89 (6H, t), 1.33 - 1.43 (6H, m), 1.47 - 1.53 (4H, m), 1.61 - 1.70 (1H, m), 1.73 (2H, br d), 1.89 - 1.99 (2H, m), 2.13 (2H, br d), 2.60 (2H, br t), 3.12 (2H, br d), 3.27 (2H, br d), 3.35 - 3.43 (4H, m), 3.53 - 3.60 (2H, m), 4.22 (1H, d), 4.35 (2H, br s), 6.08 (2H, s), 6.45 (2H, br dd), 6.84 - 6.98 (2H, m), 7.36 - 7.43 (1H, m), 7.52 (1H, s), 7.94 (1H, br d), 15.69 (1H, br s); ); m/z (ES ⁺ ) [M+H] ⁺ = 667.5. Intermediate 134b: 1-[5-[3-[3-amino-6-(3-chloro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carboxaldehyde

Prepared in an analogous manner to intermediate 83c from intermediate 134a (80 mg, 0.12 mmol) to afford the title compound as a solid (60.0 mg, 93%). The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 537.3. 1-[1-[9-[[1-[5-[3-[3-amino-6-(3-chloro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 134b (37.9 mg, 0.07 mmol) and intermediate 87e (30 mg, 0.07 mmol) in a manner similar to Example 64. Purification by RPC (elution gradient: 0-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (28.0 mg, 42.0%) as a light yellow solid after lyophilization. ¹ H NMR (DMSO- d6 ): δ 0.64 (2H, br d), 0.89 (2H, br d), 1.13 - 1.31 (4H, m), 1.57 - 1.68 (1H, m), 1.79 (2H, br d), 1.95 (6H, br s), 2.14 (2H, br d), 2.21 (2H, br d), 2.42 (4H, br s), 2.65 (2H, br t), 2.77 (2H, br t), 3.07 - 3.17 (2H, m), 3.28 (2H, br d), 3.37 (1H, br s), 3.83 (2H, br t), 4.05 (2H, br dd), 4.24 (2H, br d), 4.35 (2H, br s), 4.83 (1H, br s), 6.09 (2H, br s), 6.40 - 6.50 (2H, m), 6.86 (1H, br t), 6.93 (1H, br dd), 7.40 (1H, br d), 7.52 (1H, s), 7.64 (1H, s), 7.94 (1H, br d), 7.99 (1H, s), 8.20 (1H, s), 10.39 (1H, s), 15.69 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 946.8. Example 135 Intermediate 135a: 2-[6-amino-5-[8-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-3-yl]-6-methyl-phenol

Prepared in a similar manner to intermediate 2h from (2-hydroxy-3-methylphenyl)boronic acid (63.4 mg, 0.42 mmol) and intermediate 11f (200 mg, 0.35 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (105 mg, 46.7%) as an orange solid. ¹ H NMR (DMSO- d6 ): δ 0.89 (6H, t), 1.36 (6H, dt), 1.45 - 1.54 (4H, m), 1.60 - 1.68 (1H, m), 1.73 (2H, br d), 1.91 - 1.99 (2H, m), 2.13 (2H, br d), 2.19 (3H, s), 2.60 (2H, br t), 3.10 (2H, br d), 3.26 (2H, br d), 3.35 - 3.45 (4H, m), 3.56 (2H, dt), 4.22 (1H, d), 4.34 (2H, br s), 5.94 (2H, s), 6.45 (2H, br dd), 6.76 (1H, t), 6.92 (1H, dd), 7.13 (1H, br d), 7.45 (1H, s), 7.74 (1H, br d), 14.58 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 647.6. Intermediate 135b: 1-[5-[3-[3-amino-6-(2-hydroxy-3-methyl-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carboxaldehyde

Prepared in an analogous manner to intermediate 83c from intermediate 135a (100 mg, 0.15 mmol) to afford the title compound as a solid (73.0 mg, 91%). The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 517.4. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxy-3-methyl-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 135b (30.4 mg, 0.06 mmol) and intermediate 87e (25 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (20.00 mg, 36.8%) as a white solid after lyophilization. ¹ H NMR (DMSO- d6 ): δ 0.65 (2H, br d), 0.89 (2H, br d), 1.25 (2H, br d), 1.62 (1H, br s), 1.79 (2H, br d), 1.95 (6H, br s), 2.13 (2H, br d), 2.20 (5H, br s), 2.42 (4H, br s), 2.65 (2H, br t), 2.77 (2H, br t), 3.11 (2H, br d), 3.27 (2H, br d), 3.36 (3H, br d), 3.83 (2H, br t), 4.05 (2H, br d), 4.24 (2H, br d), 4.35 (2H, br s), 4.83 (1H, br s), 5.94 (2H, br s), 6.39 - 6.54 (2H, m), 6.77 (1H, br t), 6.87 - 7.01 (1H, m), 7.13 (1H, br m/z ( ^ES + ) [ M +H] ⁺ = 926.8. Example 136 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 103b (20 mg, 0.04 mmol) and intermediate 106e (22.15 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% formic acid) gave the title compound (9.00 mg, 26.4%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.27 (2H, q), 1.60 (1H, br s), 1.81 (2H, br d), 1.90 - 2.00 (2H, m), 2.13 (4H, br d), 2.26 (3H, s), 2.31 (2H, br d), 2.57 - 2.70 (4H, m), 2.74 (2H, br t), 2.82 (2H, s), 3.12 (2H, br d), 3.26 (2H, br d), 3.36 (2H, br d), 3.78 (2H, t), 3.98 (2H, br dd), 4.25 (2H, br d), 4.35 (2H, br s), 4.55 (1H, br s), 6.01 (2H, br s), 6.39 -6.55 (2H, m), 6.85 - 6.98 (2H, m), 7.03 - 7.10 (2H, m), 7.41 - 7.51 (3H, m), 7.55 (1H, s), 7.85 (1H, dd), 10.26 (1H, s), 13.35 - 14.84 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 889.5. Example 137 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 105b (20 mg, 0.04 mmol) and intermediate 106e (21.41 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% formic acid) gave the title compound (8.0 mg, 23.4%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.27 (2H, q), 1.60 (1H, br s), 1.81 (2H, br d), 1.95 (2H, br d), 2.13 (4H, br d), 2.26 (3H, s), 2.31 (2H, br d), 2.58 - 2.70 (4H, m), 2.74 (2H, br t), 2.82 (2H, s), 3.12 (2H, br d), 3.27 (2H, br d), 3.36 (2H, br d), 3.78 (2H, br t), 3.98 (2H, br dd), 4.25 (2H, br d), 4.35 (2H, br s), 4.55 (1H, br s), 6.05 (2H, br s), 6.38 - 6.55 (2H, m), 6.78 - 6.87 (1H, m), 6.93 (1H, br dd), 7.08 (1H, br d), 7.15 - 7.26 (1H, m), 7.41 - 7.51 (3H, m), 7.55 (1H, s), 7.77 (1H, br d), 10.25 (1H, s), 14.35 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 889.6. Example 138 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 104b (20 mg, 0.04 mmol) and intermediate 106e (21.41 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% formic acid) gave the title compound (10.00 mg, 29.7%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.27 (2H, q), 1.60 (1H, br s), 1.81 (2H, br d), 1.92 - 1.99 (2H, m), 2.09 - 2.17 (4H, m), 2.26 (3H, s), 2.31 (2H, br d), 2.58 - 2.70 (4H, m), 2.74 (2H, t), 2.82 (2H, s), 3.13 (2H, br d), 3.26 (2H, br d), 3.36 (2H, br d), 3.78 (2H, br t), 3.98 (2H, br dd), 4.25 (2H, br d), 4.35 (2H, br s), 4.55 (1H, br s), 6.12 (2H, br s), 6.41 - 6.51 (2H, m), 6.93 (1H, dd), 7.08 (1H, br d), 7.22 - 7.29 (1H, m), 7.43 (1H, s), 7.46 (1H, d), 7.51 (1H, s), 7.55 (1H, s), 7.78 (1H, br d), 10.25 (1H, s), 14.01 (1H, br.s); m/z (ES ⁺ ) [M+H] ⁺ = 907.7. Example 139 Intermediate 139a: ( 2S )-4-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-2-methyl-piperidin-1-carboxylic acid benzyl ester

A mixture of [Pd(allylCl] ₂ (4.92 mg, 0.01 mmol), Xphos (25.6 mg, 0.05 mmol), benzyl ( 2S )-2-methylpiperidinium-1-carboxylate (378 mg, 1.61 mmol), intermediate 11c (500 mg, 1.34 mmol) and _Cs2CO3 (1095 mg, 3.36 mmol) in dihydrogen ether (6.5 mL) was degassed for 5 min and heated to 90 °C under nitrogen for ₄ h. The reaction mixture was diluted with EtOAc (50 mL) and filtered through celite®. The filtrate was concentrated. Purification by FSC (elution gradient: 0-30% ethyl acetate in hexanes) gave the title compound as an orange gum (570 mg, 74.4%). ¹ H NMR (DMSO -d6 ): δ 0.90 (6H, t), 1.24 (3H, d), 1.30 - 1.44 (6H, m), 1.45 - 1.54 (4H, m), 1.66 (1H, dt), 1.73 (2H, br d), 2.54 - 2.64 (3H, m), 2.77 (1H, dd), 3.18 - 3.28 (1H, m), 3.32 - 3.44 (5H, m), 3.49 (1H, br d), 3.56 (2H, dt), 3.88 (1H, br d), 4.22 (1H, d), 4.29 (1H, br d), 5.06 - 5.20 (2H, m), 6.39 - 6.59 (2H, m), 6.95 (1H, dd), 7.30 - 7.44 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 570.6. Intermediate 139b: (3 S )-1-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-3-methyl-piperidinol

Pd/C (213 mg, 0.20 mmol) was added to a solution of intermediate 139a (570 mg, 1.00 mmol) in THF (10 mL). The reaction was bubbled with hydrogen and stirred under hydrogen at room temperature overnight. The reaction was filtered through a plug of celite®, eluting with EtOAc and MeOH. The filtrate was concentrated to give the title compound (390 mg, 89%) as an orange gum. The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 436.4. Intermediate 139c: 6-Chloro-4-[( 2S )-4-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-2-methyl-piperidin-1-yl]piperidin-3-amine

A mixture of 4-bromo-6-chlorotitanium-3-amine (215 mg, 1.03 mmol), intermediate 139b (450 mg, 1.03 mmol) and potassium fluoride (120 mg, 2.07 mmol) in DMSO (4 mL) was heated at 130 °C for two days. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 25 mL). The combined extracts were dried over _Na2SO4 , _filtered and concentrated. Purification by FSC (elution gradient: 0-100% ethyl acetate in hexanes) gave the title compound (150 mg, 25.8%) as an orange gum. ¹ H NMR (DMSO- d6 ): δ 0.90 (6H, t), 0.99 (3H, d), 1.31 - 1.45 (6H, m), 1.46 - 1.54 (4H, m), 1.66 (1H, dt), 1.74 (2H, br d), 2.60 (2H, br t), 2.75 - 2.84 (1H, m), 2.96 - 3.04 (2H, m), 3.08 - 3.13 (1H, m), 3.33 - 3.44 (6H, m), 3.57 (2H, dt), 3.77 (1H, br dd), 4.23 (1H, d), 6.21 (2H, s), 6.50 (1H, dt), 6.56 (1H, dd), 6.93 - 7.01 (1H, m), 7.07 (1H, s). Intermediate 139d: 2-[6-amino-5-[(2 S )-4-[3-[4-(dibutoxymethyl)-1-piperidinyl]-4-fluoro-phenyl]-2-methyl-piperidin-1-yl]piperidin-3-yl]phenol

Prepared in an analogous manner to intermediate 2h from intermediate 139c (150 mg, 0.27 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes) gave the title compound (75 mg, 45.4%) as an orange solid. ¹ H NMR (DMSO- d6 ): δ 0.90 (7H, t), 1.02 (3H, d), 1.32 - 1.43 (7H, m), 1.47 - 1.52 (4H, m), 1.75 (2H, br d), 2.58 - 2.66 (2H, m), 2.85 - 2.93 (1H, m), 3.01 (1H, br dd), 3.15 - 3.23 (1H, m), 3.37 - 3.50 (6H, m), 3.57 (2H, dt), 3.84 - 3.91 (1H, m), 4.23 (1H, d), 6.38 (2H, s), 6.54 (1H, dt), 6.57 - δ 0.61 (1H, m), 6.88 - 6.94 (2H, m), 6.98 (1H, dd), 7.23 - 7.29 (1H, m), 7.70 (1H, s), 7.93 - 7.98 (1H, m), 14.12 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 621.5. Intermediate 139e 1-[5-[(3 S )-4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]-3-methyl-piperidin-1-yl]-2-fluoro-phenyl]piperidine-4-carboxaldehyde

Prepared in an analogous manner to intermediate 83c from intermediate 139d (75 mg, 0.12 mmol) to give the title compound as a solid (55.0 mg, 93%). The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 491.4. 1-[1-[3-[[1-[5-[( 3S )-4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]-3-methyl-piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 139e (20 mg, 0.04 mmol) and intermediate 36a (21.41 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% formic acid) gave the title compound (15.00 mg, 41.1%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 0.66 (2H, br d), 0.86 (2H, br d), 1.03 (3H, br d), 1.23 - 1.35 (4H, m), 1.41 (2H, br s), 1.63 - 1.74 (5H, m), 1.80 (4H, br d), 1.89 - 2.04 (3H, m), 2.27 (2H, br d), 2.43 (4H, br s), 2.67 (2H, br d), 2.77 (2H, br t), 2.86 - 2.95 (1H, m), 3.01 (1H, br dd), 3.20 (1H, br d), 3.36 (3H, br d), 3.44 - 3.52 (2H, m), 3.82 (2H, br t), 3.88 (1H, br d), 4.60 (1H, br t), 6.38 (2H, br s), 6.50 - 6.66 (2H, m), 6.89 - 7.05 (3H, m), 7.26 (1H, t), 7.50 (1H, s), 7.70 (1H, s), 7.88 - 8.00 (2H, m), 8.15 - 8.19 (1H, m), 10.38 (1H, s), 15.66 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ ₌ 896.8. Example 140 1-[1-[9-[[1-[5-[( 3S )-4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]-3-methyl-piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 139e (20 mg, 0.04 mmol) and intermediate 87e (21.41 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-100% MeCN in water containing 0.1% _NH4OH ) gave the title compound (17.00 mg, 46.3%) as a white solid after lyophilization. ¹ H NMR (DMSO- d6 ): δ 0.64 (2H, q), 0.83 - 0.94 (2H, m), 1.03 (3H, d), 1.22 - 1.25 (3H, m), 1.25 - 1.33 (2H, m), 1.64 (1H, br s), 1.81 (2H, br d), 1.96 (4H, br d), 2.22 (2H, br d), 2.42 (3H, br d), 2.67 (2H, br d), 2.77 (2H, t), 2.87 - 2.93 (1H, m), 3.01 (1H, br dd), 3.16 - 3.23 (1H, m), 3.36 (2H, br d), 3.42 - 3.50 (2H, m), 3.83 (2H, t), 3.86 -3.92 (1H, m), 4.05 (2H, br dd), 4.25 (2H, br dd), 4.79 - 4.88 (1H, m), 6.38 (2H, br s), 6.51 - 6.57 (1H, m), 6.57 - 6.63 (1H, m), 6.88 - 6.94 (2H, m), 6.98 (1H, dd), 7.26 (1H, t), 7.65 (1H, s), 7.71 (1H, s), 7.90 - 8.00 (2H, m), 8.20 (1H, d), 10.39 (1H, s), 14.12 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 900.7. Example 141 Intermediate 141a: 4-[[9-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-hydroxy-piperidine-1-carboxylic acid tributyl ester

A mixture of intermediate 36a (527 mg, 1.25 mmol), tributyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (533 mg, 2.50 mmol) and DIPEA (437 μl, 2.50 mmol) in n BuOH (0.5 ml) was heated at 85 °C for 6 h. The solvent was removed and the residue was partitioned between DCM and water. The organic phase was dried over MgSO ₄ , filtered and concentrated. The residue was triturated in ether to give the title compound as a solid (601 mg, 76%). ¹ H NMR (DMSO- d 6): δ 0.64 (2H, br s), 0.82 - 0.88 (2H, m), 1.20 - 1.27 (2H, m), 1.30 - 1.48 (18H, m), 1.65 (4H, br s), 1.77 (2H, br d), 1.88 - 2.01 (4H, m), 2.23 (2H, s), 2.75 (2H, t), 2.98 - 3.15 (2H, m), 3.61 (2H, br d), 3.80 (2H, t), 4.10 (1H, s), 4.52 - 4.63 (1H, m), 7.48 (1H, s), 7.92 (1H, d), 8.14 (1H, d), 10.35 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 635.5. Intermediate 141b: 1-[3-cyclopropyl-1-[3-[(4-hydroxy-4-piperidinyl)methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

TFA (1.5 ml, 18.93 mmol) was added to a stirred solution of intermediate 141a (601 mg, 0.95 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 h. The solvent was removed, and the residue was triturated with ether, and the solid was collected by filtration. The solid was dissolved in MeOH (20 mL), and carbonate resin (2.5-3.5 mmol/g, 1 g) was added. The reaction was stirred at room temperature for 2 h. The resin was filtered off to give the title compound (495 mg, 98%) as a beige solid. ¹ H NMR (DMSO- d 6): δ 0.60 - 0.68 (2H, m), 0.80 - 0.88 (2H, m), 1.24 - 1.32 (2H, m), 1.32 - 1.39 (2H, m), 1.54 - 1.59 (2H, m), 1.63 - 1.73 (6H, m), 1.73 - 1.81 (2H, m), 1.87 - 1.92 (1H, m), 1.96 - 2.02 (1H, m), 2.27 (2H, s), 2.75 (2H, t), 2.99 - 3.11 (4H, m), 3.23 - 3.35 (6H, m), 3.80 (2H, t), 4.38 - 4.50 (1H, m), 4.57 (1H, br t), 7.47 (1H, s), 7.92 (1H, d), 8.14 (1H, d), 10.35 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 535.5 Intermediate 141c: N -tert-butyloxycarbonyl- N -[4-[8-[3-[4-[[9-[3-cyclopropyl-5-(2,4-dioxohexahydroxypyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-hydroxy-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tributyl ester

Prepared in a similar manner to intermediate 56f starting with intermediate 141b (96 mg, 0.18 mmol) and intermediate 57a (101 mg, 0.15 mmol). Purification by FSC (elution gradient: 10%-50% MeOH in EtOAc) followed by RPC (elution gradient: 25%-60% MeCN in water containing 0.1% FA) gave the title compound (17.0 mg, 9.7%) as a brown gum. m/z (ES ⁺ ) [M+H] ⁺ = 1168.6. 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

To intermediate 141c (17 mg, 0.01 mmol) in DCM (0.5 mL) was added HCl (4 N in dihydrogen ether) (0.5 mL, 2.00 mmol). The reaction was stirred at room temperature for 2 h. The solvent was removed, the HCl salt was alkalized by dissolving in MeOH (2 mL), and quenched by adding carbonate resin. The resin was filtered off and the filtrate was concentrated. Purification by RPC (elution gradient: 25%-60% MeCN in water containing 0.1% FA) gave the title compound (5.0 mg, 37%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.64 (2H, br d), 0.84 (2H, br d), 1.26 (2H, br t), 1.31 - 1.43 (2H, m), 1.53 (2H, br d), 1.63 - 1.81 (8H, m), 1.81 - 2.02 (6H, m), 2.12 (2H, br d), 2.32 (2H, br s), 2.54 - 2.59 (3H, m), 2.75 (2H, br t), 2.94 - 3.01 (2H, m), 3.03 - 3.11 (4H, m), 3.21 - 3.26 (2H, m), 3.77 - 3.81 (2H, m), 4.30 - 4.36 (2H, m), 4.57 (1H, br t), 5.91 (2H, br s), 6.36 - 6.44 (1H, m), 6.49 (1H, br d), 6.82 - 6.94 (3H, m), 7.21 (1H, br t), 7.47 (2H, br d), 7.87 - 7.95 (2H, m), 8.15 (1H, s), 10.35 (1H, s), (two OH protons not observed); m/z (ES ⁺ ) [M+H] ⁺ = 924.6. Example 142 Intermediate 142a: ( 5s , 8s )-8-(5-bromoindol-1-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 64d starting from intermediate 99b (2.1 g, 7.77 mmol) and intermediate 65a (2.475 g, 9.33 mmol). Purification by FSC (elution gradient: 0 to 100% ethyl acetate in hexanes) gave the title compound as an orange gum, the cis isomer (1.260 g, 34.4%), which eluted second from the column. ¹ H NMR (DMSO- d6 ): δ 2.29 - 2.37 (2H, m), 3.38 - 3.52 (2H, m), 3.59 (2H, s), 4.00 - 4.06 (2H, m), 4.27 - 4.38 (2H, m), 4.63 (1H, br s), 5.07 (2H, s), 6.47 (1H, br s), 7.20 - 7.27 (1H, m), 7.28 - 7.34 (1H, m), 7.36 (4H, d), 7.50 (1H, br t), 7.75 (1H, d), 7.80 (1H, br d); m/z (ES ⁺ ) [M+H] ⁺ = 471.3. Intermediate 142b: ( 5s , 8s )-8-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 2b starting from intermediate 142a (943 mg, 2 mmol).

Purification by FSC (elution gradient: 10%-60% MeOH in DCM containing 1% _NH4OH ) gave the title compound (496 mg, 49.2%) as a white solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 2.28 - 2.38 (2H, m), 2.75 - 2.85 (2H, m), 3.54 - 3.60 (2H, m), 3.63 - 3.75 (2H, m), 3.83 - 3.88 (2H, m), 4.10 - 4.17 (2H, m), 4.31 - 4.42 (2H, m), 4.44 - 4.59 (1H, m), 5.12 (2H, s), 6.56 (1H, br s), 7.13 (1H, br d), 7.27 - 7.40 (6H, m), 7.49 - 7.56 (1H, m), 7.60 - 7.76 (2H, m); m/z (ES ⁺ ) [M+H] ⁺ = 505.4. Intermediate 142c: 1-[1-((5 s ,8 s )-6,10-dioxa-2-azaspiro[4.5]dec-8-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 139b starting from intermediate 142b (492 mg, 0.98 mmol) to afford the title compound as an off-white solid (295 mg, 82%). m/z (ES ⁺ ) [M+H] ⁺ = 371.6. 1-[1-[( 5s , 8s )-2-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 105b (21 mg, 0.04 mmol) and intermediate 142c (22 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (18 mg, 51.4%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.26 (2H, q), 1.62 (1H, br s), 1.80 (2H, br d), 1.90 - 1.96 (2H, m), 2.04 - 2.13 (2H, m), 2.14 - 2.24 (2H, m), 2.26 - 2.47 (2H, m), 2.59 - 2.79 (6H, m), 2.80 - 3.00 (2H, m), 3.10 (2H, br d), 3.18 - 3.26 (2H, m), 3.34 - 3.44 (2H, m), 3.76 (2H, t), 4.01 (2H, br dd), 4.22 - 4.41 (4H, m), 4.60 (1H, br s), 6.03 (2H, s), 6.39 - 6.52 (3H, m), 6.81 (1H, td), 6.91 (1H, dd), 7.08 (1H, br d), 7.14 - 7.20 (1H, m), 7.44 - 7.52 (3H, m), 7.73 - 7.78 (2H, m), 10.24 (1H, s), 13.75 - 15.20 (1H, m); m/z (ES ⁺ [M+H] ⁺ = 875.5. Example 143 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 103b (21 mg, 0.04 mmol) and intermediate 142c (22 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (21 mg, 60%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.26 (2H, q), 1.60 (1H, br s), 1.79 (2H, br d), 1.87 - 1.99 (2H, m), 2.08 - 2.22 (4H, m), 2.24 - 2.43 (2H, m), 2.55 - 2.70 (4H, m), 2.70 - 2.76 (2H, m), 2.76 - 2.93 (2H, m), 3.10 (2H, br d), 3.20 - 3.25 (2H, m), 3.33 - 3.41 (2H, m), 3.76 (2H, t), 4.00 (2H, br dd), 4.24 - 4.38 (4H, m), 4.60 (1H, br s), 5.99 (2H, s), 6.38 - 6.52 (3H, m), 6.84 - 6.95 (2H, m), 7.03 - 7.10 (2H, m), 7.43 - 7.53 (3H, m), 7.76 (1H, d), 7.83 (1H, dd), 10.24 (1H, s), 13.45 - 14.88 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 875.5. Example 144 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 104b (22 mg, 0.04 mmol) and intermediate 142c (22 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (26 mg, 72.8%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.18 - 1.33 (2H, m), 1.59 (1H, br s), 1.79 (2H, br d), 1.88 - 1.98 (2H, m), 2.07 - 2.19 (4H, m), 2.27 - 2.39 (2H, m), 2.59 - 2.68 (4H, m), 2.71 (2H, br t), 2.82 (2H, br s), 3.11 (2H, br d), 3.19 - 3.26 (2H, m), 3.33 - 3.41 (2H, m), 3.76 (2H, t), 4.00 (2H, br dd), 4.24 - 4.37 (4H, m), 4.59 (1H, br s), 6.10 (2H, s), 6.37 - 6.51 (3H, m), 6.91 (1H, dd), 7.08 (1H, br d), 7.19 - 7.28 (1H, m), 7.43 - 7.54 (3H, m), 7.73 - 7.79 (2H, m), 10.24 (1H, s), 14.14 - 15.30 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 893.5. Example 145 Intermediate 145a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-6-methyl-indole

Prepared in an analogous manner to intermediate 113a using 5-bromo-4-fluoro- 1H -indole (1.00 g, 4.67 mmol). Purification by FSC (1st purification: 0-10% acetone in hexanes; 2nd purification: 30%-100% DCM in hexanes) gave the title compound (0.62 g, 36%) as a yellow oil. ¹ H NMR (DMSO- d ₆ ): δ 2.42 (3H, s), 3.73 - 3.82 (4H, m), 3.90 (4H, d), 4.82 (1H, quin), 5.05 - 5.11 (2H, m), 5.11 - 5.18 (2H, m), 5.70 - 5.85 (2H, m), 6.39 (1H, d), 7.44 (1H, d), 7.56 (1H, s), 7.73 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 364.2. Intermediate 145b: 2-(5-bromo-6-methyl-indol-1-yl)propane-1,3-diol

Prepared in an analogous manner to intermediate 64b using intermediate 145a (613 mg, 1.68 mmol). Purification by FSC (1st purification: elution gradient: 0-80% acetone in hexanes; 2nd purification: 50%-100% EtOAc in hexanes) gave the title compound (398 mg, 83%) as a red solid. ¹ H NMR (DMSO- d ₆ ): δ 2.43 (3H, s), 3.68 - 3.86 (4H, m), 4.42 (1H, quin), 4.85 (2H, br s), 6.36 (1H, d), 7.42 (1H, d), 7.47 (1H, s), 7.73 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 284.0. Intermediate 145c: 3-(5-Bromo-6-methyl-indol-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 64d using intermediate 145b (496 mg, 1.78 mmol). Purification by FSC (elution gradient: 0-15% EtOAc in DCM) gave the title compound (469 mg, 69%) as a white foam. ¹ H NMR (DMSO- d ₆ ): δ 1.81 - 1.90 (2H, m), 1.94 - 1.99 (2H, m), 2.42 (3H, s), 3.34 - 3.55 (4H, m), 3.98 (2H, dd), 4.23 - 4.36 (2H, m), 4.50 - 4.61 (1H, m), 5.08 (2H, s), 6.42 (1H, d), 7.26 - 7.40 (5H, m), 7.52 (1H, s), 7.73 (1H, d), 7.77 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 499.0. Intermediate 145d: 3-[5-[(3-ethoxy-3-oxopropyl)amino]-6-methyl-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 113d using intermediate 145c (467 mg, 0.94 mmol). Purification by FSC (1st purification: elution gradient: 0-100% EtOAc in hexanes; 2nd purification: 0-40% acetone in hexanes) gave the title compound (352 mg, 70%) as a yellow wax. ¹ H NMR (DMSO- d ₆ ): δ 1.18 (3H, t), 1.82 - 1.89 (2H, m), 1.89 - 1.96 (2H, m), 2.17 (3H, s), 2.63 (2H, t), 3.27 - 3.35 (2H, m), 3.44 (4H, br s), 3.97 (2H, br dd), 4.08 (2H, q), 4.23 (2H, br d), 4.31 - 4.39 (1H, m), 4.40 - 4.50 (1H, m), 5.08 (2H, s), 6.23 (1H, d), 6.66 (1H, s), 7.15 (1H, s), 7.28 - 7.40 (5H, m), 7.48 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 536.3. Intermediate 145e: 3-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-6-methyl-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 113e using intermediate 145d (0.34 g, 0.64 mmol) to afford the title compound as a light yellow foam which was used in the next step without further purification. Quantitative yield assumed. m/z (ES ⁺ ) [M+H] ⁺ = 579.4. Intermediate 145f: 3-[5-(2,4-Dioxohexahydropyrimidin-1-yl)-6-methyl-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 113f using intermediate 145e (0.37 g, 0.64 mmol) to give the title compound as an orange solid (0.27 g, 81%). ¹ H NMR (DMSO- d ₆ ): δ 1.83 - 1.90 (2H, m), 1.96 (2H, br s), 2.26 (3H, s), 2.64 - 2.79 (2H, m), 3.39 - 3.58 (5H, m), 3.69 - 3.80 (1H, m), 3.96 - 4.05 (2H, m), 4.30 (2H, br d), 4.53 - 4.60 (1H, m), 5.08 (2H, s), 6.43 (1H, d), 7.27 - 7.40 (6H, m), 7.43 (1H, s), 7.72 (1H, d), 10.24 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 533.3. Intermediate 145g: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-6-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 129c starting from intermediate 145f (262 mg, 0.49 mmol) to give the title compound (182 mg, 93%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.80 (2H, br s), 1.84 - 1.93 (2H, m), 2.26 (3H, s), 2.69 - 2.76 (6H, m), 3.53 (1H, dt), 3.70 - 3.80 (1H, m), 3.91 - 4.02 (2H, m), 4.27 (2H, dd), 4.50 - 4.57 (1H, m), 6.42 (1H, d), 7.38 (1H, s), 7.43 (1H, s), 7.72 (1H, d), 10.24 (1H, br s), one nitrogen-bound proton not observed; m/z (ES ⁺ ) [M+H] ⁺ = 399.3. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-6-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to Example 64 using intermediate 145g (25 mg, 0.06 mmol) and intermediate 13d (26 mg, 0.05 mmol). Purification by RPC (elution gradient: 10%-40% MeCN in water containing 0.1% HCOOH) gave the title compound (26.8 mg, 57%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.18 - 1.32 (2H, m), 1.61 (1H, br s), 1.72 - 1.81 (2H, m), 1.83 - 2.05 (6H, m), 2.08 - 2.15 (2H, m), 2.20 (2H, d), 2.26 (3H, s), 2.33 - 2.47 (4H, m), 2.63 (2H, t), 2.67 - 2.81 (2H, m), 3.09 (2H, d), 3.25 (2H, d), 3.34 (2H, br d), 3.50 - 3.57 (1H, m), 3.72 - 3.79 (1H, m), 3.91 - 4.02 (2H, m), 4.24 - 4.30 (2H, m), 4.33 (2H, br s), 4.48 - 4.60 (1H, m), 5.92 (2H, br s), 6.37 - 6.52 (3H, m), 6.82 - 6.88 (2H, m), 6.91 (1H, dd), 7.22 (1H, t), 7.38 (1H, s), 7.43 (1H, s), 7.45 (1H, s), 7.73 (1H, d), 7.89 (1H, br d), 10.24 (1H, s), 14.12 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 885.5. Example 146 Intermediate 146a: 4-[2-(3-bromophenoxy)ethyl]piperidin-1-carboxylic acid benzyl ester

Di-tri-butyl azodicarboxylate (1.900 g, 8.25 mmol) in DCM (5 mL) was added dropwise to a solution of 3-bromophenol (1.298 g, 7.5 mmol), benzyl 4-(2-hydroxyethyl)piperidinium-1-carboxylate (1.982 g, 7.50 mmol) and triphenylphosphine (2.361 g, 9.00 mmol) in DCM (30 ml) at room temperature. The resulting solution was stirred at room temperature for 2 h. The solvent was concentrated. Purification by FSC (elution gradient: 10%-20% MeOH in DCM containing 1% NH ₄ OH) gave the title compound (2.74 g, 87%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 2.51 (4H, br s), 2.78 (2H, br t), 3.50 (4H, br s), 4.02 - 4.12 (2H, m), 5.10 (2H, s), 6.83 - 6.87 (1H, m), 7.05 - 7.11 (2H, m), 7.12 - 7.19 (1H, m), 7.29 - 7.41 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 419.2. Intermediate 146b: 8-[3-[2-(4-benzyloxycarbonylpiperidin-1-yl)ethoxy]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

A mixture of intermediate 146a (1.677 g, 4 mmol), tributyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.849 g, 4.00 mmol), RuPhosPdG3 (0.167 g, 0.20 mmol) and KOtBu (0.673 g, 6.00 mmol) in toluene (20 mL) was flushed with nitrogen and backfilled with nitrogen. The mixture was stirred at 105 °C for 2 h under nitrogen and then cooled to room temperature, filtered through celite®, and the filtrate evaporated. Purification by FSC (elution gradient: 0-10% MeOH in EtOAc) gave the title compound (1.670 g, 76%) as a light yellow solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.42 (9H, s), 1.80 (2H, br d), 1.95 - 2.00 (2H, m), 2.51 (4H, br s), 2.76 (2H, br t), 3.14 (1H, br d), 3.20 - 3.31 (1H, m), 3.47 - 3.53 (4H, m), 3.57 (1H, br d), 3.67 (1H, br d), 4.01 - 4.06 (2H, m), 4.10 - 4.19 (2H, m), 5.10 (2H, s), 6.24 - 6.30 (1H, m), 6.32 (1H, s), 6.40 (1H, br d), 7.11 (1H, t), 7.26 - 7.38 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 551.6. Intermediate 146c: Benzyl 4-[2-[3-(3,8-diazabicyclo[3.2.1]oct-8-yl)phenoxy]ethyl]piperidin-1-carboxylate

To intermediate 146b (1.48 g, 2.69 mmol) in DCM (10 ml) was added TFA (4 ml, 53.75 mmol). The reaction was stirred at room temperature for 1 h. The solvent was removed and the residue was partitioned between CHCl ₃ /IPA (3:1) (70 mL) and washed with saturated Na ₂ CO ₃ solution. The organic phase was separated, dried over MgSO ₄ , filtered and concentrated to give the title compound (1.320 g, 109%) as a beige gum. ¹ H NMR (DMSO- d6 ): δ 1.85 - 1.95 (4H, m), 2.40 - 2.46 (4H, m), 2.50 - 2.57 (2H, m), 2.68 (2H, br t), 2.96 (2H, br d), 3.72 - 3.80 (2H, m), 3.96 - 4.08 (2H, m), 4.13 (2H, br s), 4.31 (2H, br s), 5.06 (2H, s), 6.22 (1H, br d), 6.28 - 6.34 (1H, m), 6.37 (1H, br d), 7.04 (1H, t), 7.27 - 7.41 (5H, m), (NH protons not observed); m/z (ES ⁺ ) [M+H] ⁺ = 451.4. Intermediate 146d: 4-[2-[3-[3-(3-amino-6-chloro-piperidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]phenoxy]ethyl]piperidin-1-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 3c starting from intermediate 146c (1.172 g, 2.6 mmol). Purification by FSC (elution gradient: 5%-30% MeOH in DCM then 10% MeOH in DCM containing 1% _NH4OH ) gave the title compound as a light yellow solid (1.090 g, 72.5%). ¹ H NMR (CD ₂ Cl ₂ ): δ 2.01 - 2.05 (2H, m), 2.09 - 2.20 (2H, m), 2.31 - 2.74 (4H, m), 2.77 - 3.01 (2H, m), 3.04 - 3.12 (2H, m), 3.12 - 3.21 (2H, m), 3.34 - 3.77 (4H, m), 4.07 - 4.21 (2H, m), 4.31 (2H, br s), 4.61 - 4.77 (2H, m), 5.11 (2H, s), 6.28 - 6.35 (1H, m), 6.37 (1H, br s), 6.44 (1H, br d), 6.69 (1H, s), 7.14 (1H, t), 7.26 - 7.42 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 578.4. Intermediate 146e: 4-[2-[3-[3-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]phenoxy]ethyl]piperidin-1-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 2h starting from intermediate 146d (0.504 g, 0.87 mmol). Purification by FSC (elution gradient: 0-10% MeOH in DCM containing 1% _NH4OH ) gave the title compound as a beige solid (0.294 g, 53.0%). ¹ H NMR (DMSO- d6 ): δ 1.91 - 1.97 (2H, m), 2.13 (2H, br d), 2.41 - 2.45 (2H, m), 2.69 (2H, br t), 3.07 (2H, br d), 3.20 - 3.25 (2H, m), 3.26 - 3.29 (2H, m), 3.39 (4H, br s), 4.02 - 4.08 (2H, m), 4.39 (2H, br s), 5.06 (2H, s), 5.89 - 5.95 (2H, m), 6.25 (1H, br d), 6.40 - 6.46 (1H, m), 6.48 (1H, br d), 6.77 - 6.92 (2H, m), 7.07 (1H, t), 7.15 - 7.26 (1H, m), 7.29 - 7.37 (5H, m), 7.44 (1H, s), 7.89 (1H, d), 14.14 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 636.4. Intermediate 146f: 2-[6-amino-5-[8-[3-(2-piperidin-1-ylethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-yl]phenol

Prepared in a similar manner to intermediate 123c starting from intermediate 146e (309 mg, 0.49 mmol) to give the title compound as a beige solid (261 mg, 107%). ¹ H NMR (CD ₂ Cl ₂ ) δ 2.05 - 2.13 (2H, m), 2.12 - 2.19 (2H, m), 2.52 (4H, br s), 2.74 (2H, br t), 2.88 (4H, br t), 3.23 (4H, s), 4.06 (2H, br t), 4.36 (2H, br s), 4.82 (2H, br s), 6.27 - 6.37 (1H, m), 6.41 (1H, br s), 6.46 (1H, br d), 6.81 - 6.94 (1H, m), 6.94 - 6.98 (1H, m), 7.15 (1H, br t), 7.25 (2H, br t), 7.59 (1H, br d); m/z (ES ⁺ ) [M+H] ⁺ = 502.2. Intermediate 146g: 1-[1-[1-(2-chloroethyl)-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Intermediate 125g (327 mg, 1 mmol) and 2-chloroacetaldehyde (50% w in water) (314 mg, 2.00 mmol) in DCM (5 mL) were stirred at room temperature for 30 min. Sodium triacetoxyborohydride (424 mg, 2.00 mmol) was added and the mixture was stirred at room temperature for 30 min. The reaction was partitioned between saturated aqueous NaHCO ₃ solution and DCM (50 mL). The organic phase was dried over MgSO ₄ , filtered, and concentrated. The residue was triturated with ether, and the solid was filtered and dried to give the title compound (315 mg, 81%) as a light yellow solid. ¹ H NMR (DMSO- d6 ): δ 1.85 (2H, br d), 1.97 - 2.06 (2H, m), 2.23 - 2.32 (5H, m), 2.70 - 2.77 (4H, m), 3.04 (2H, br d), 3.71 (2H, br t), 3.79 (2H, t), 4.53 - 4.67 (1H, m), 7.49 (1H, s), 7.87 (1H, d), 8.16 (1H, d), 10.36 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 390.2. 1-[1-[1-[2-[4-[2-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]phenoxy]ethyl]piperimide-1-yl]ethyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Intermediate 146f (25 mg, 0.05 mmol), intermediate 146g (23 mg, 0.06 mmol), NaI (7.5 mg, 0.05 mmol) and NaHCO ₃ (12.60 mg, 0.15 mmol) in DMF (500 μl) were heated at 75°C overnight. The reaction was partitioned between 10% LiCl solution and CHCl ₃ /IPA (3:1). The organic phase was separated, dried over MgSO ₄ , filtered and concentrated. Purification by RPC (elution gradient: 35%-70% MeCN in water containing 0.1% NH ₄ OH) gave the title compound (15.00 mg, 35.1%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.78 - 1.86 (2H, m), 1.92 - 1.98 (2H, m), 1.98 - 2.08 (2H, m), 2.08 - 2.19 (4H, m), 2.21 - 2.26 (3H, m), 2.27 - 2.47 (10H, m), 2.51 - 2.61 (2H, m), 2.63 - 2.68 (2H, m), 2.72 - 2.78 (2H, m), 2.95 - 3.03 (2H, m), 3.03 - 3.10 (2H, m), 3.17 - 3.24 (2H, m), 3.76 - 3.83 (2H, m), 4.02 (2H, br t), 4.40 (2H, br s), 4.58 (1H, br t), 5.92 (2H, s), 6.25 (1H, br d), 6.40 - 6.51 (2H, m), 6.80 - 6.89 (2H, m), 7.07 (1H, t), 7.21 (1H, br t), 7.45 (2H, br d), 7.85 - 7.88 (1H, m), 7.90 (1H, br d), 8.16 (1H, d), 10.36 (1H, s), 13.79 - 14.63 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 855.7. Example 147 Intermediate 147a: 4-[2-(5-bromo-2-fluoro-phenoxy)ethyl]piperidin-1-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 146a starting from 5-bromo-2-fluorophenol (1.432 g, 7.5 mmol) and benzyl 4-(2-hydroxyethyl)piperidinium-1-carboxylate (1.982 g, 7.50 mmol). Purification by FSC (elution gradient: 0-10% MeOH in DCM containing 1% _NH4OH ) gave the title compound (2.87 g, 88%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 2.52 (4H, br s), 2.81 (2H, br t), 3.50 (4H, br s), 4.09 - 4.15 (2H, m), 5.10 (2H, s), 6.93 - 7.01 (1H, m), 7.01 - 7.07 (1H, m), 7.15 (1H, dd), 7.24 - 7.40 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 437.2. Intermediate 147b: 8-[3-[2-(4-benzyloxycarbonylpiperidin-1-yl)ethoxy]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 146b starting from a mixture of intermediate 147a (1.749 g, 4 mmol) and tributyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.849 g, 4.00 mmol). Purification by FSC (elution gradient: 0-10% MeOH in EtOAc) gave the title compound (1.56 g, 68.6%) as a light yellow solid. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.42 (9H, s), 1.80 (2H, br d), 1.90 - 2.00 (2H, m), 2.53 (4H, br s), 2.67 - 2.93 (2H, m), 3.08 - 3.19 (1H, m), 3.24 (1H, br d), 3.41 - 3.56 (4H, m), 3.57 - 3.65 (1H, m), 3.69 (1H, br d), 4.06 - 4.18 (4H, m), 5.11 (2H, s), 6.29 (1H, br d), 6.42 (1H, br d), 6.93 (1H, dd), 7.25 - 7.40 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 569.5. Intermediate 147c: 4-[2-[5-(3,8-diazabicyclo[3.2.1]oct-8-yl)-2-fluoro-phenoxy]ethyl]piperidin-1-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 146c starting from intermediate 147b (1.46 g, 2.57 mmol) the title compound was obtained as a beige gum (1.26 g, 105%) with some residual solvent remaining. ¹ H NMR (DMSO- d6 ): δ 1.79 - 1.92 (4H, m), 2.38 - 2.43 (2H, m), 2.43 - 2.47 (4H, m), 2.71 (2H, t), 2.93 (2H, br d), 3.72 - 3.81 (2H, m), 4.02 - 4.07 (2H, m), 4.10 (2H, t), 4.31 (2H, br s), 5.06 (2H, s), 6.23 - 6.29 (1H, m), 6.52 (1H, dd), 6.94 (1H, dd), 7.29 - 7.38 (5H, m), (NH peak not observed); m/z (ES ⁺ ) [M+H] ⁺ = 469.4. Intermediate 147d: 4-[2-[5-[3-(3-amino-6-chloro-piperidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenoxy]ethyl]piperidin-1-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 3c starting from intermediate 147c (1.218 g, 2.6 mmol). Purification by FSC (elution gradient: 5%-30% solvent B in DCM, solvent B: 10% MeOH in DCM containing 1% _NH4OH ) gave the title compound as a light yellow solid (1.1 g, 71%). ¹ H NMR (CD ₂ Cl ₂ ): δ 2.01 - 2.07 (2H, m), 2.09 - 2.17 (2H, m), 2.43 - 2.75 (4H, m), 2.78 - 2.97 (2H, m), 3.04 - 3.14 (2H, m), 3.18 (2H, br d), 3.55 (4H, br s), 4.11 - 4.21 (2H, m), 4.21 - 4.27 (2H, m), 4.62 - 4.77 (2H, m), 5.11 (2H, s), 6.33 (1H, br d), 6.47 (1H, br d), 6.70 (1H, s), 6.92 - 6.98 (1H, m), 7.26 - 7.39 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 596.4. Intermediate 147e: 4-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]piperidin-1-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 2h starting from intermediate 147d (0.494 g, 0.83 mmol). Purification by FSC (elution gradient: 20%-60% solvent B in DCM, solvent B: 10% MeOH in DCM containing 1% _NH4OH ) gave the title compound as a beige solid (0.304 g, 56.1%). ¹ H NMR (DMSO- d6 ): δ 1.87 - 1.96 (2H, m), 2.13 (2H, br d), 2.42 - 2.47 (2H, m), 2.73 (2H, br t), 3.09 (2H, br d), 3.19 - 3.25 (2H, m), 3.26 - 3.30 (2H, m), 3.39 (4H, br s), 4.15 (2H, br t), 4.38 (2H, br s), 5.06 (2H, s), 5.89 - 5.96 (2H, m), 6.39 (1H, br d), 6.65 (1H, br d), 6.82 - 6.88 (2H, m), 6.96 - 7.02 (1H, m), 7.17 - 7.25 (1H, m), 7.28 - 7.37 (5H, m), 7.45 (1H, s), 7.88 (1H, br d), 14.13 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 654.4. Intermediate 147f: 2-[6-amino-5-[8-[4-fluoro-3-(2-piperidin-1-ylethoxy)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]indole-3-yl]phenol

Prepared in an analogous manner to intermediate 123c starting from intermediate 147e (305 mg, 0.47 mmol) the title compound was obtained as a beige solid (255 mg, 105%) with some residual solvent remaining. ¹ H NMR (CD ₂ Cl ₂ ): δ 2.03 - 2.09 (2H, m), 2.59 (5H, br s), 2.80 (2H, t), 2.93 (4H, br t), 3.18 - 3.28 (5H, m), 4.14 (2H, t), 4.29 (2H, br s), 4.80 (2H, s), 6.36 (1H, br d), 6.50 (1H, br d), 6.86 - 6.91 (1H, m), 6.94 - 6.99 (2H, m), 7.23 - 7.31 (2H, m), 7.60 (1H, br d), (OH and NH protons not observed); m/z (ES ⁺ ) [M+H] ⁺ = 520.2. 1-[1-[1-[2-[4-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]piperidin-1-yl]ethyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 147f (26 mg, 0.05 mmol) and intermediate 146g (24 mg, 0.06 mmol) in a similar manner to Example 146. Purification by RPC (elution gradient: 35%-70% MeCN in water containing 0.1% _NH4OH ) gave the title compound (19.00 mg, 43.5%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.76 - 1.86 (2H, m), 1.93 - 1.98 (2H, m), 1.98 - 2.06 (2H, m), 2.09 - 2.17 (4H, m), 2.23 (3H, s), 2.28 - 2.46 (9H, m), 2.46 - 2.47 (1H, m), 2.51 - 2.62 (2H, m), 2.66 - 2.72 (2H, m), 2.73 - 2.78 (2H, m), 2.95 - 3.02 (2H, m), 3.05 - 3.12 (2H, m), 3.20 - 3.25 (2H, m), 3.79 (2H, t), 4.13 (2H, br t), 4.38 (2H, br s), 4.58 (1H, br t), 5.93 (2H, s), 6.39 (1H, br d), 6.66 (1H, br d), 6.81 - 6.90 (2H, m), 6.99 (1H, dd), 7.19 - 7.19 (1H, m), 7.45 (2H, d), 7.83 - 7.91 (2H, m), 8.13 - 8.18 (1H, m), 10.36 (1H, s), 13.74 - 14.48 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 873.6. Example 148 Intermediate 148a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-5-bromo-4-fluoro-indole

Prepared in an analogous manner to intermediate 113a using 5-bromo-4-fluoro- 1H -indole (1.00 g, 4.67 mmol). Purification by FSC (elution gradient: 1st purification: 0-100% DCM in hexanes; 2nd purification: 30%-100% DCM in hexanes) gave the title compound (1.01 g, 59%) as a yellow oil. ¹ H NMR (DMSO- d ₆ ): δ 3.74 - 3.85 (4H, m), 3.85 - 3.95 (4H, m), 4.84 - 4.95 (1H, m), 5.05 - 5.09 (2H, m), 5.10 - 5.17 (2H, m), 5.70 - 5.83 (2H, m), 6.56 (1H, d), 7.25 - 7.31 (1H, m), 7.41 (1H, d), 7.58 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 368.0. Intermediate 148b: 2-(5-bromo-4-fluoro-indol-1-yl)propane-1,3-diol

Prepared in an analogous manner to intermediate 64b using intermediate 148a (1.01 g, 2.73 mmol). Purification by FSC (elution gradient: 1st purification: 0-80% acetone in hexanes; 2nd purification: 50%-100% EtOAc in hexanes) and trituration with DCM-hexanes (1:1) gave the title compound (0.51 g, 64%) as a reddish solid. ¹ H NMR (DMSO- d ₆ ): δ 3.69 - 3.88 (4H, m), 4.47 (1H, quin), 4.89 (2H, t), 6.53 (1H, d), 7.23 - 7.30 (1H, m), 7.30 - 7.36 (1H, m), 7.54 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 288.0. Intermediate 148c: 3-(5-bromo-4-fluoro-indol-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 64d using intermediate 148b (501 mg, 1.74 mmol). Purification by FSC (elution gradient: 0-15% EtOAc in DCM) gave the title compound (797 mg, 91%) as a white foam. ¹ H NMR (DMSO- d ₆ ): δ 1.76 - 1.88 (2H, m), 1.98 - 2.05 (2H, m), 3.35 - 3.57 (4H, m), 3.98 (2H, dd), 4.34 (2H, br d), 4.58 - 4.66 (1H, m), 5.08 (2H, s), 6.59 (1H, d), 7.19 - 7.48 (7H, m), 7.85 (1H, d); (mass not observed). Intermediate 148d: 3-[5-[(3-ethoxy-3-oxopropyl)amino]-4-fluoro-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

A 40 mL vial was charged with intermediate 148c (0.79 g, 1.57 mmol), ethyl 3-aminopropionate hydrochloride (0.36 g, 2.35 mmol), tBuBrettPhos Pd G3 (0.13 g, 0.16 mmol) and Cs ₂ CO ₃ (1.84 g, 5.65 mmol). 1,4-Dihydrogen iodide (9.4 mL) was added. Argon was bubbled through the mixture for 5 min. The resulting mixture was stirred at 100 °C for 15 h. After cooling to room temperature, the mixture was filtered through a celite® pad and eluted with DCM. The filtrate was concentrated under reduced pressure. Purification by FSC (elution gradient: 0-40% acetone in hexanes) gave the title compound (0.53 g, 63%) as a yellow oil. ¹ H NMR (DMSO- d ₆ ): δ 1.17 (3H, t), 1.76 - 1.89 (2H, m), 1.91 - 2.01 (2H, m), 2.56 (2H, t), 3.35 (2H, q), 3.39 - 3.53 (4H, m), 3.97 (2H, br dd), 4.05 (2H, q), 4.29 (2H, br d), 4.41 - 4.53 (1H, m), 4.69 (1H, br t), 5.08 (2H, s), 6.34 (1H, d), 6.75 (1H, t), 7.15 (1H, d), 7.28 - 7.45 (5H, m), 7.64 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 540.3. Intermediate 148e: 3-[5-[aminomethyl-(3-ethoxy-3-oxopropyl)amino]-4-fluoro-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 113e using intermediate 148d (0.52 g, 0.97 mmol) to afford the title compound as a light yellow foam which was used in the next step without further purification. Quantitative yield assumed. m/z (ES ⁺ ) [M+H] ⁺ = 583.3. Intermediate 148f: 3-[5-(2,4-Dioxohexahydropyrimidin-1-yl)-4-fluoro-indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in a similar manner to intermediate 113f using intermediate 148e (0.57 g, 0.97 mmol) to give the title compound as a white solid (0.42 g, 81%). ¹ H NMR (DMSO- d ₆ ): δ 1.79 - 1.91 (2H, m), 1.92 - 2.04 (2H, m), 2.73 (2H, t), 3.35 - 3.56 (4H, m), 3.70 (2H, t), 4.00 (2H, br dd), 4.34 (2H, br d), 4.56 - 4.68 (1H, m), 5.08 (2H, s), 6.59 (1H, d), 7.13 (1H, t), 7.25 - 7.46 (6H, m), 7.84 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 537.2. Intermediate 148g: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 129c starting from intermediate 148f (420 mg, 0.78 mmol) to give the title compound (29 mg, 29%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.68 - 1.82 (2H, m), 1.84 - 1.96 (2H, m), 2.67 - 2.76 (6H, m), 3.70 (2H, t), 3.96 (2H, br dd), 4.32 (2H, br dd), 4.54 - 4.64 (1H, m), 6.58 (1H, d), 7.12 (1H, t), 7.37 (1H, d), 7.85 (1H, d), 10.13 - 10.66 (1H, m), one nitrogen-bound proton was not observed; m/z (ES ⁺ ) [M+H] ⁺ = 403.3. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to Example 64 using intermediate 148g (20 mg, 0.05 mmol) and intermediate 13d (21 mg, 0.04 mmol). Purification by RPC (elution gradient: 10%-40% MeCN in water containing 0.1% HCOOH) gave the title compound (24.1 mg, 64%) as a white solid. ¹ H NMR (DMSO- d ₆ ): δ 1.16 - 1.32 (2H, m), 1.55 - 1.66 (1H, m), 1.71 - 2.06 (8H, m), 2.12 (2H, br d), 2.16 - 2.23 (2H, m), 2.33 - 2.48 (4H, m), 2.63 (2H, br t), 2.73 (2H, br t), 3.09 (2H, br d), 3.25 (2H, br d), 3.34 (2H, br d), 3.70 (2H, t), 3.97 (2H, br dd), 4.27 - 4.39 (4H, m), 4.59 (1H, br s), 5.92 (2H, s), 6.37 - 6.44 (1H, m), 6.44 - 6.50 (1H, m), 6.59 (1H, d), 6.81 - 6.95 (3H, m), 7.12 (1H, t), 7.22 (1H, t), 7.37 (1H, d), 7.45 (1H, s), 7.85 (1H, d), 7.89 (1H, br d), 10.38 (1H, s), 12.79 - 15.29 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 889.5. Example 149 Intermediate 149a: 1-[2-allyloxy-1-(allyloxymethyl)ethyl]-4-bromo-indole

Prepared in an analogous manner to intermediate 113a using 4-bromo- 1H -indole (1.960 g, 10 mmol). Purification by FSC (elution gradient: 0-15% EtOAc in hexanes) gave the title compound (1.520 g, 43.4%) as a colorless oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 3.85 (4H, d), 3.96 (4H, dd), 4.70 (1H, quin), 5.12 - 5.23 (4H, m), 5.79 - 5.89 (2H, m), 6.54 (1H, d), 7.06 (1H, t), 7.25 (1H, d), 7.37 (1H, d), 7.44 (1H, d); m/z (ES ⁺ ) [M+H] ⁺ = 350.2. Intermediate 149b: 2-(4-bromoindol-1-yl)propane-1,3-diol

Prepared in an analogous manner to intermediate 64b using intermediate 149a (1.22 g, 3.48 mmol). Purification by FSC (elution gradient: 20%-40% solvent B in hexanes, solvent B: 10% MeOH in EtOAc) gave the title compound (0.798 g, 85%) as a yellow oil. ¹ H NMR (CD ₂ Cl ₂ ): δ 1.72 - 1.90 (2H, m), 4.03 - 4.10 (4H, m), 4.59 (1H, quin), 6.60 (1H, d), 7.08 (1H, t), 7.28 (1H, d), 7.38 (1H, d), 7.41 - 7.46 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 270.1. Intermediate 149c: Benzyl 3-(4-bromoindol-1-yl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylate

Prepared in a similar manner to intermediate 64d using intermediate 149b (800 mg, 2.96 mmol) and intermediate 64c (910 mg, 3.26 mmol). The residue was triturated with ether, the solid was filtered and dried to give the title compound as a white solid (1.2 g, 84%). ¹ H NMR (CD ₂ Cl ₂ ): δ 1.83 (2H, br s), 1.99 (2H, br s), 3.45 (4H, br s), 4.00 (2H, br dd), 4.34 (2H, br d), 4.61 (1H, br s), 5.05 - 5.10 (2H, m), 6.45 (1H, d), 7.07 (1H, t), 7.26 (1H, d), 7.30 - 7.38 (5H, m), 7.54 (1H, d), 7.86 - 7.91 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 485.1. Intermediate 149d: 3-[4-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylic acid benzyl ester

Prepared in an analogous manner to intermediate 4b using intermediate 149c (1.1 g, 2.27 mmol). Purification by FSC (elution gradient: 0 to 10% MeOH in DCM) gave the title compound (0.812 g, 69.1%) as a light beige solid. ¹ H NMR (DMSO- d6 ): δ 1.85 (2H, br s), 1.98 (2H, br s), 2.75 (2H, t), 3.45 (4H, br s), 3.74 - 3.79 (1H, m), 3.78 (1H, s), 4.02 (2H, br dd), 4.33 (2H, br d), 4.61 (1H, br d), 5.08 (2H, s), 6.44 (1H, d), 6.95 - 7.00 (1H, m), 7.15 (1H, t), 7.34 - 7.39 (5H, m), 7.46 (1H, d), 7.77 (1H, d), 10.31 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 519.3. Intermediate 149e: 1-[1-(1,5-dioxa-9-azaspiro[5.5]undecane-3-yl)indol-4-yl]hexahydropyrimidine-2,4-dione

Prepared in a similar manner to intermediate 129c starting from intermediate 149d (810 mg, 1.56 mmol) to give the title compound as a yellow solid (630 mg, 105%). m/z (ES ⁺ ) [M+H] ⁺ = 385.3. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]indol-4-yl]hexahydropyrimidine-2,4-dione

Prepared using intermediate 149e (55 mg, 0.06 mmol) and intermediate 13d (30 mg, 0.06 mmol) in a similar manner to Example 64. Purification by RPC (elution gradient: 20%-50% MeCN in water containing 0.1% FA) gave the title compound (24.0 mg, 45.9%) as a white solid. ¹ H NMR (DMSO- d 6): δ 1.26 (2H, q), 1.65 (1H, br s), 1.78 (2H, br d), 1.92 (4H, br s), 2.01 - 2.10 (2H, m), 2.10 - 2.18 (2H, m), 2.27 - 2.42 (2H, m), 2.51 - 2.59 (4H, m), 2.61 - 2.69 (2H, m), 2.76 (2H, br t), 3.09 (2H, br d), 3.18 - 3.25 (2H, m), 3.35 - 3.45 (2H, m), 3.77 (2H, br t), 4.00 (2H, br d), d), 10.32 (1H, s), 12.43 - 15.19 (1H, m); m/z (ES + ^[ M+H] ^{+ )} = 871.6. Example 150 Intermediate 150a : 4-[[3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1,5-dioxa-9-azaspiro[5.5]undec-9-yl]methyl]-4-hydroxy-piperidine-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 141a starting from intermediate 87e (740 mg, 1.74 mmol) and tributyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (742 mg, 3.48 mmol) to afford the title compound (950 mg, 86%) as a beige solid. ¹ H NMR (DMSO- d 6): δ 0.62 (2H, q), 0.79 - 0.91 (2H, m), 1.26 - 1.39 (9H, m), 1.39 - 1.44 (4H, m), 1.82 - 2.01 (5H, m), 2.25 (2H, s), 2.52 - 2.63 (4H, m), 2.75 (2H, t), 2.95 - 3.15 (2H, m), 3.60 (2H, br d), 3.81 (2H, t), 4.01 (2H, br dd), 4.11 - 4.17 (1H, m), 4.21 (2H, br dd), 4.80 (1H, br s), 7.62 (1H, s), 7.96 (1H, d), 8.18 (1H, d), 10.36 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 639.5. Intermediate 150b: 1-[3-cyclopropyl-1-[9-[(4-hydroxy-4-piperidinyl)methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared in an analogous manner to intermediate 141b starting from intermediate 150a (0.95 g, 1.49 mmol) to give the title compound as a beige solid (0.751 g, 94%). ¹ H NMR (DMSO- d6 ): δ 0.62 (2H, br d), 0.87 (2H, br d), 1.33 - 1.40 (2H, m), 1.40 - 1.48 (2H, m), 1.92 (5H, br d), 2.23 (2H, s), 2.51 - 2.60 (4H, m), 2.63 (2H, br d), 2.71 - 2.81 (4H, m), 3.76 - 3.86 (2H, m), 3.88 - 3.95 (1H, m), 3.99 - 4.05 (2H, m), 4.21 (2H, br dd), 4.80 (1H, br s), 7.62 (1H, s), 7.97 (1H, d), 8.18 (1H, d), 10.18 - 10.53 (1H, m), (one NH proton not observed); m/z (ES ⁺ ) [M+H] ⁺ = 539.4. Intermediate 150c: N -tert-butyloxycarbonyl- N- [4-[8-[3-[4-[[3-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-1,5-dioxa-9-azaspiro[5.5]undec-9-yl]methyl]-4-hydroxy-1-piperidinyl]-4-fluoro-phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]indole-3-yl]carbamic acid tert-butyl ester

Prepared in an analogous manner to intermediate 141c starting from intermediate 150b (194 mg, 0.36 mmol). Purification by FSC (elution gradient: 10%-50% hexanes in solvent B. Solvent B = 10% MeOH in EtOAc) followed by RPC (elution gradient: 20%-60% MeCN in water containing 0.1% FA) gave the title compound (29 mg, 8.25%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ = 1172.6. 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 150c (30 mg, 0.03 mmol) in a similar manner to Example 141. Purification by RPC (elution gradient: 20%-50% MeCN in water containing 0.1% FA) gave the title compound (11.0 mg, 46.3%) as a white solid. ¹ H NMR (DMSO- d 6): δ 0.63 (2H, br d), 0.82 - 0.93 (2H, m), 1.55 (2H, br d), 1.63 - 1.75 (2H, m), 1.87 - 2.03 (7H, m), 2.12 (2H, br d), 2.32 (2H, s), 2.53 - 2.55 (1H, m), 2.55 - 2.68 (4H, m), 2.75 (2H, br t), 2.97 - 3.04 (2H, m), 3.04 - 3.14 (4H, m), 3.21 - 3.30 (2H, m), 3.81 (2H, br t), 4.02 (2H, br dd), 4.22 (2H, br d), 4.34 (2H, br s), 4.72 - 4.88 (1H, m), 5.92 (2H, s), 6.36 - 6.45 (1H, m), 6.49 (1H, br d), 6.81 - 6.94 (3H, m), 7.21 (1H, t), 7.46 (1H, s), 7.62 (1H, s), 7.85 - 7.94 (1H, m), 7.95 - 7.99 (1H, m), 8.15 - 8.21 (1H, m), 10.37 (1H, s), 13.63 - 15.01 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 928.6. Example 151 Intermediate 151a: 4-[(5-bromo-2-fluoro-phenyl)methyl]piperidinium-1-carboxylic acid tributyl ester

Sodium triacetoxyborohydride (1.566 g, 7.39 mmol) was added to a stirred solution of 5-bromo-2-fluorobenzaldehyde (1 g, 4.93 mmol) and tributyl piperidine-1-carboxylate (0.917 g, 4.93 mmol) in DCM (15 mL). The resulting solution was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc (60 mL) and washed with saturated aqueous NaHCO ₃ solution (40 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by FSC (elution gradient: 0-50% EtOAc in hexanes) to give the title compound (1.350 g, 73.4%) as an oil. ¹ H NMR (DMSO- d6 ): δ 1.39 (9H, s), 2.34 (4H, br t), 3.31 (4H, br s), 3.54 (2H, s), 7.19 (1H, t), 7.46 - 7.55 (1H, m), 7.57 - 7.64 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 373.1, 375.1. Intermediate 151b: 8-[3-[(4-tributyloxycarbonylpiperidin-1-yl)methyl]-4-fluoro-phenyl]-3,8-diazobicyclo[3.2.1]octane-3-carboxylic acid benzyl ester

A 40 mL vial was charged with benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.924 g, 3.75 mmol), intermediate 151a (1.4 g, 3.75 mmol), [Pd(allylCl] ₂ (0.014 g, 0.04 mmol), Xphos (0.072 g, 0.15 mmol) and _Cs2CO3 (3.06 g, 9.38 mmol) and _dioxane (15 mL). The reaction mixture was degassed for 5 min and heated to 90 °C under nitrogen overnight. The reaction mixture was filtered through celite® and washed with EtOAc (100 mL). The filtrate was concentrated. The product was purified by FSC (elution gradient: 0-80% in hexanes). EtOAc) to give the title compound (1.420 g, 70.3%) as an oil. ¹ H NMR (DMSO- d6 ): δ 1.38 (9H, s), 1.66 (2H, br d), 1.82 - 1.99 (2H, m), 2.33 (4H, br s), 3.06 - 3.27 (2H, m), 3.31 (4H, br d), 3.47 (2H, s), 3.61 (2H, br d), 4.23 (2H, br d), 5.08 (2H, br d), 6.74 - 6.90 (2H, m), 6.95 - 7.08 (1H, m), 7.30 - 7.45 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 539.6. Intermediate 151c: 4-[[5-(3,8-diazabicyclo[3.2.1]oct-8-yl)-2-fluoro-phenyl]methyl]piperidin-1-carboxylic acid tributyl ester

Pd/C (0.277 g, 0.26 mmol) was added to a solution of intermediate 151b (1.4 g, 2.60 mmol) in MeOH (20 mL). The reaction was bubbled with _H2 (g) overnight while stirring under _H2 at room temperature. The reaction was filtered through a plug of celite® eluting with MeOH and EtOAc. The filtrate was concentrated to give the title compound (0.950 g, 90%) as an oil. The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 405.3. Intermediate 151d: 4-[[5-[3-(3-amino-6-chloro-indole-4-yl)-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]methyl]piperidin-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 3c starting from intermediate 151c (920 mg, 2.27 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (1050 mg, 87%) as a brown solid. ¹ H NMR (DMSO- d6 ): δ 1.38 (9H, s), 1.85 - 1.95 (2H, m), 2.09 (2H, br d), 2.34 (4H, br s), 2.95 (2H, br d), 3.13 - 3.23 (2H, m), 3.26 - 3.31 (4H, m), 3.48 (2H, s), 4.31 (2H, br s), 5.81 (2H, s), 6.77 - 6.89 (3H, m), 7.00 (1H, t); m/z (ES ⁺ ) [M+H] ⁺ = 532.4. Intermediate 151e: 4-[[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]methyl]piperidin-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 2h starting from intermediate 151d (500 mg, 0.94 mmol). Purification by FSC (elution gradient: 0 to 100% EtOAc in hexanes) gave the title compound (470 mg, 85%) as a brown solid. ¹ H NMR (DMSO-d6) δ 1.37 (9H, s), 1.93 - 1.98 (2H, m), 2.15 (2H, br d), 2.35 (4H, br s), 3.09 (2H, br d), 3.23 - 3.31 (6H, m), 3.49 (2H, s), 4.36 (2H, br s), 5.95 (2H, br s), 6.83 - 6.91 (4H, m), 7.01 (1H, t), 7.23 (1H, br t), 7.46 (1H, s), 7.89 (1H, br d), 14.14 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 590.5. Intermediate 151f: 2-[6-amino-5-[8-[4-fluoro-3-(piperidin-1-ylmethyl)phenyl]-3,8-diazobicyclo[3.2.1]oct-3-yl]phthalimide-3-yl]phenol

TFA (0.901 mL, 11.70 mmol) was added to a stirred solution of intermediate 151e (460 mg, 0.78 mmol) in DCM (6 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was alkalized with saturated sodium bicarbonate (20 mL) and extracted with DCM-IPA (2:1, 2 x 50 mL). The phases were separated. The combined organic layers were dried over _Na2SO4 , filtered, and concentrated to give the title compound (320 mg, 84%) as _a white solid. The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 490.3. Intermediate 151g: 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]piperidine-1-carbonyl chloride

Triphosgene (181 mg, 0.61 mmol) was dissolved in DCM (5 mL), the resulting solution was cooled to -78 °C, and then DIPEA (0.533 mL, 3.05 mmol) was added. The reaction mixture was stirred for 5 min, and intermediate 125g (200 mg, 0.61 mmol) was added in three portions over 15 min. After the addition of the amine was complete, the mixture was warmed to room temperature and stirred at room temperature for 15 min. The reaction mixture was diluted with DCM (20 mL) and washed with saturated aqueous NH ₄ Cl solution. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (205 mg, 86%) as a light yellow solid. The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 390.2 1-[1-[1-[4-[[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]methyl]piperidin-1-carbonyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Intermediate 151g (23.89 mg, 0.06 mmol) in DMF (1.0 mL) was added to a stirred solution of intermediate 151f (30 mg, 0.06 mmol) and DIPEA (0.032 mL, 0.18 mmol) in DMF (1.5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was directly purified by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) to give the title compound (20.0 mg, 38.7%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.82 - 2.06 (6H, m), 2.15 (2H, br d), 2.24 (3H, s), 2.42 (4H, br s), 2.77 (2H, br t), 2.95 (2H, br t), 3.10 (2H, br d), 3.21 - 3.45 (6H, m), 3.51 (2H, br s), 3.72 (2H, br d), 3.81 (2H, br t), 4.37 (2H, br s), 4.80 (1H, br t), 5.95 (2H, br s), 6.81 - 6.96 (4H, m), 7.02 (1H, br t), 7.23 (1H, br t), 7.47 (2H, br d), 7.89 (2H, br d), 8.18 (1H, s), 10.38 (1H, s), 13.79 - 14.47 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 843.4. Example 152 Intermediate 152a: 4-[(3-bromophenyl)methyl]piperidinium-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 151a starting from 3-bromobenzaldehyde (1 g, 5.40 mmol). Purification by FSC (elution gradient: 0-50% EtOAc in hexanes) gave the title compound as an oil (1.270 g, 66.1%). ¹ H NMR (DMSO- d6 ): δ 1.39 (9H, s), 2.31 (4H, br t), 3.29 - 3.36 (4H, m), 3.48 (2H, s), 7.26 - 7.37 (2H, m), 7.46 (1H, br d), 7.49 - 7.54 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 355.1, 357.1. Intermediate 152b: Benzyl 8-[3-[(4-tributyloxycarbonylpiperidin-1-yl)methyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Prepared in an analogous manner to intermediate 151b starting from intermediate 152a (1.2 g, 3.38 mmol). Purification by FSC (elution gradient: 0-80% EtOAc in hexanes) gave the title compound (1.280 g, 72.8%) as an oil. ¹ H NMR (DMSO- d6 ): δ 1.39 (9H, s), 1.67 (2H, br d), 1.85 - 1.95 (2H, m), 2.30 (4H, br s), 3.06 - 3.25 (2H, m), 3.32 (4H, s), 3.40 (2H, s), 3.61 (2H, br d), 4.28 (2H, br d), 5.08 (2H, br d), 6.63 (1H, br d), 6.73 - 6.83 (2H, m), 7.08 - 7.18 (1H, m), 7.29 - 7.41 (5H, m); m/z (ES ⁺ ) [M+H] ⁺ = 521.7. Intermediate 152c: 4-[[3-(3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl]methyl]piperidin-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 151c starting from intermediate 152b (1.2 g, 2.30 mmol) the title compound was obtained as an oil (0.820 g, 92%). The crude product was used in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 387.3. Intermediate 152d: 4-[[3-[3-(3-amino-6-chloro-piperidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]methyl]piperidin-1-carboxylic acid tributyl ester

Prepared in a similar manner to intermediate 3c starting from intermediate 152c (800 mg, 2.07 mmol). Purification by FSC (elution gradient: 0-100% EtOAc in hexanes then 0-30% MeOH in EtOAc) gave the title compound (702 mg, 66.0%) as an orange solid. ¹ H NMR (DMSO- d6 ): δ 1.39 (9H, s), 1.86 - 1.95 (2H, m), 2.10 (2H, br d), 2.30 (4H, br s), 2.95 (2H, br d), 3.19 (2H, br d), 3.27 - 3.31 (4H, m), 3.41 (2H, s), 4.36 (2H, br s), 5.76 - 5.88 (2H, m), 6.63 (1H, br d), 6.75 - 6.82 (2H, m), 6.84 (1H, s), 7.10 - 7.20 (1H, m); m/z (ES ⁺ ) [M+H] ⁺ = 514.3. Intermediate 152e: 4-[[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]phenyl]methyl]piperidin-1-carboxylic acid tributyl ester

Prepared in an analogous manner to intermediate 2h starting from intermediate 152d (400 mg, 0.78 mmol). Purification by FSC (elution gradient: 0 to 100% EtOAc in hexanes) gave the title compound (300 mg, 67.4%) as a brown solid. ¹ H NMR (DMSO-d6): δ 1.38 (9H, s), 1.90 - 2.03 (2H, m), 2.15 (2H, br d), 2.31 (4H, br s), 3.09 (2H, br d), 3.26 - 3.31 (6H, m), 3.42 (2H, s), 4.41 (2H, br s), 5.95 (2H, s), 6.63 (1H, br d), 6.79 - 6.90 (4H, m), 7.16 (1H, t), 7.23 (1H, t), 7.45 (1H, s), 7.90 (1H, br d), 14.15 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 572.4. Intermediate 152f: 2-[6-amino-5-[8-[3-(piperidin-1-ylmethyl)phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]phthalimide-3-yl]phenol

Prepared in a similar manner to intermediate 151f starting from intermediate 152e (300 mg, 0.52 mmol) to give the title compound as a light orange solid (220 mg, 89%). m/z (ES ⁺ ) [M+H] ⁺ = 472.4. 1-[1-[1-[4-[[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]phenyl]methyl]piperidin-1-carbonyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 152f (30 mg, 0.06 mmol) and intermediate 151g (24.80 mg, 0.06 mmol) in a similar manner to Example 151. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (18.00 mg, 34.3%) as a white solid. ¹ H NMR (DMSO- d6 ): δ 1.83 - 2.03 (6H, m), 2.16 (2H, br d), 2.24 (3H, s), 2.39 (4H, br s), 2.76 (2H, br t), 2.95 (2H, br t), 3.10 (2H, br d), 3.20 (4H, br s), 3.28 (2H, br d), 3.44 (2H, br s), 3.73 (2H, br d), 3.81 (2H, br t), 4.41 (2H, br s), 4.80 (1H, br t), 5.95 (2H, br s), 6.65 (1H, br d), 6.78 - 6.92 (4H, m), 7.14 - 7.27 (2H, m), 7.46 (2H, br d), 7.85 - 7.92 (2H, m), 8.18 (1H, d), 10.39 (1H, s), 13.66 - 14.68 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 825.4. Example 153 Intermediate 153a: 3-[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-piperidinyl]propionic acid tributyl ester

A mixture of tributyl 3-bromopropanoate (153 mg, 0.73 mmol), intermediate 125g (200 mg, 0.61 mmol) and DIPEA (0.427 mL, 2.44 mmol) in DMF (5 mL) was heated at 90 ° C overnight. The mixture was concentrated under reduced pressure. The crude material was purified by FSC (0-60% EtOAc in MeOH). The pure fractions were concentrated to give the title compound (165 mg, 59.3%) as an orange solid. ¹ H NMR (DMSO- d6 ): δ 1.43 (9H, s), 1.83 - 1.91 (2H, m), 2.00 (2H, br s), 2.12 - 2.20 (2H, m), 2.25 (3H, s), 2.37 - 2.44 (2H, m), 2.58 - 2.66 (2H, m), 2.75 (3H, br d), 2.99 (1H, br d), 3.81 (2H, t), 4.56 - 4.69 (1H, m), 7.46 (1H, s), 7.88 (1H, d), 8.17 (1H, d), 10.38 (1H, s); m/z (ES ⁺ ) [M+H] ⁺ = 456.4. Intermediate 153b: 3-[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-1-piperidinyl]propanoic acid

TFA (0.761 mL, 9.88 mmol) was added to a stirred solution of intermediate 153a (150 mg, 0.33 mmol) in DCM (4 mL). The resulting solution was stirred for 1 h. The solvent was removed under reduced pressure to give the title compound (200 mg, 97%) as a light orange solid. m/z (ES ⁺ ) [M+H] ⁺ = 400.3. 1-[1-[1-[3-[4-[[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]methyl]piperidin-1-yl]-3-oxopropyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

HATU (15.53 mg, 0.04 mmol) was added to a stirred solution of intermediate 151f (20 mg, 0.04 mmol), intermediate 153b (25.6 mg, 0.04 mmol) and DIPEA (0.029 mL, 0.16 mmol) in DMF (1.5 mL). The resulting solution was stirred for 1 h. The reaction mixture was directly purified by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) to give the title compound (14.00 mg, 39.3%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.84 (2H, br d), 1.90 - 2.06 (4H, m), 2.10 - 2.18 (4H, m), 2.26 (3H, s), 2.33 - 2.44 (4H, m), 2.46 - 2.50 (2H, m), 2.55 - 2.63 (2H, m), 2.76 (2H, t), 2.99 (2H, br d), 3.09 (2H, br d), 3.27 (2H, br d), 3.33 - 3.50 (6H, m), 3.81 (2H, t), 4.35 (2H, br s), 4.59 (1H, br t), 5.95 (2H, s), 6.79 - 6.93 (4H, m), 7.01 (1H, t), 7.23 (1H, t), 7.46 (2H, s), 7.86 - 7.93 (2H, m), 8.18 (1H, d), 10.38 (1H, s), 13.86 - 14.54 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 871.7. Example 154 1-[1-[1-[3-[4-[[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]phenyl]methyl]piperidin-1-yl]-3-oxo-propyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione

Prepared from intermediate 152f (20 mg, 0.04 mmol) and intermediate 153b (26.5 mg, 0.04 mmol) in a similar manner to Example 153. Purification by RPC (elution gradient: 0-60% MeCN in water containing 0.1% FA) gave the title compound (15.0 mg, 41.5%) as a white solid after freeze drying. ¹ H NMR (DMSO- d6 ): δ 1.85 (2H, br d), 1.93 - 2.06 (4H, m), 2.10 - 2.19 (4H, m), 2.26 (3H, s), 2.29 - 2.41 (4H, m), 2.57 - 2.64 (2H, m), 2.76 (2H, t), 3.00 (2H, br d), 3.09 (2H, br d), 3.28 (2H, br d), 3.34 (2H, br s), 3.46 (6H, br d), 3.81 (2H, t), 4.41 (2H, br s), 4.60 (1H, br t), 5.95 (2H, s), 6.65 (1H, br d), 6.76 - 6.91 (4H, m), 7.16 (1H, t), 7.23 (1H, t), 7.46 (2H, br d), 7.86 - 7.94 (2H, m), 8.18 (1H, d), 10.33 - 10.48 (1H, m), 14.01 - 14.32 (1H, br s); m/z (ES ⁺ ) [M+H] ⁺ = 853.7. SMARCA2, SMARCA4 and PBRM1 degradation assay

A high-throughput immunofluorescence assay was used to measure changes in SMARCA2, SMARCA4, and PBRM1 protein levels following compound treatment. 5,000 Hela cells were seeded into 30 μL RPMI + 10% FBS per well of a 384-well plate. Cells were incubated with increasing concentrations of compound (10-point dose reactions from 1 nM to 31.7 μM, 0.3% final DMSO) for 24 h and then fixed for analysis. Cells were incubated with paraformaldehyde (2% final concentration) for 20 minutes at room temperature. The plates were then aspirated using a Biotek plate washer and 30 μL ice-cold MeOH was added to permeabilize the cells. After incubation in MeOH for 5 min at room temperature, the plates were washed once with PBS and incubated with blocking solution (PBS + 1% BSA + 0.3% Triton-X100) for 1 h at room temperature. After blocking, the plates were aspirated again and 20 μL of primary antibody dilution (SMARCA2, Cell Signaling #11966, 1:1000; SMARCA4, Cell Signaling #52251, 1:1000; PBRM1, Bethyl A700-019, 1:200, diluted in blocking solution) was added to each well, and the plates were kept incubated at room temperature for 2 h. The plates were then washed and aspirated, and 20 μL of secondary antibody dilution (goat-anti-rabbit, Invitrogen #A-11034; goat-anti-mouse, Invitrogen #A-11032; Hoechst 33342; 1:1000 in blocking solution) was added and the plates were incubated for 1 h at room temperature in the dark. After the final wash, the plates were read on an Operetta CLS imager using the appropriate channel. The percentage of degradation was calculated as F _compound /F _DMSO x 100% (F: fluorescence intensity). Endogenous SALL4 degradation assay:

The neuroblastoma cell line Kelly was used to monitor the degradation of endogenous SALL4 protein using SDS-PAGE assay. Kelly cells were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. Cells were split at a 1/10 ratio every 4 days. Cells that were passaged less than 10 times were used for experiments.

For this experiment, cells were seeded at 500,000 cells per well in a 12-well plate in a final volume of 1 mL of medium. The next day, different compounds were added to the cells at 1 µM and/or 10 µM. After 24 h of treatment, cells were lysed in RIPA buffer plus protease cocktail inhibitor (100 µL/well) on ice for 20 min. Lysates were collected and centrifuged at 10,000 g for 5 min. Supernatants were collected and mixed with sample buffer 4X (25 μL) containing sample reducing agent and then boiled at 85°C for 5 min. Lysates were stored at -20°C.

For SDS-PAGE analysis, samples were loaded onto precast gels (4%-12%), run at a constant 150 V on ice, and transferred to membranes using the P0 program from a fast transfer iBlot2 device (Thermo Fisher Scientific). The membranes were then incubated in LI-COR blocking solution (Intercept) for 30 min and then incubated with primary antibodies overnight at 4°C. The membranes were then washed with TBS-tween 0.1% for at least 30 min and incubated with secondary antibodies for LI-COR detection (1 h, diluted 1/10000). After several washes in PBS-Tween 0.1%, the membranes were analyzed by the Li-COR Odyssey CLx imaging system for protein level detection. GAPDH was used as a loading control. Reagent List Reagent Source Catalog Number Kelly Cell Sigma-Aldrich 92110411 RPMI 1640 with glutamine Thermo Fisher Scientific 11875093 RIPA lysis and extraction buffer Thermo Fisher Scientific 89900 Halt™ Protease Inhibitor Cocktail (100X) Thermo Fisher Scientific 78430 NuPAGE™ LDS Sample Buffer (4X) Thermo Fisher Scientific NP0007 NuPAGE™ Sample Reducing Agent (10X) Thermo Fisher Scientific NP0004 NuPAGE™ 4%-12% Bis-Tris Protein Gel, 1.5 mm, 15-well Thermo Fisher Scientific NP0336BOX iBlot™ 2 Transfer Stack, C-Nitrate, Regular Size Thermo Fisher Scientific IB23001 Intercept ^TM Occlusion Buffer LI-COR 927-60001 SALL4 Antibody Proteintech 24500-1-AP GAPDH Antibody Protein Technology Company 60004-1-Ig IRDye ^TM 800CW Donkey anti-rabbit IgG secondary antibody LI-COR 926-32213 IRDye ^TM 800CW Donkey anti-mouse IgG secondary antibody LI-COR 926-32212 Endogenous Ikaros 1 (IKZF1) degradation assay:

Leukemia cell line NB4 was used to monitor the degradation of endogenous IKZF1 protein using SDS-PAGE assay. NB4 cells were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. Then, cells were split at a 1/10 ratio every 3 days. Cells that were passaged less than 10 times were used for experiments.

For this experiment, cells were seeded at 1,000,000 cells per well in a 12-well plate in a final volume of 1 mL of medium. The next day, different compounds were added to the cells at 1 µM and/or 10 µM. After 24 h of treatment, cells were lysed in RIPA buffer plus protease cocktail inhibitor (100 µL/well) on ice for 20 min. Then, the lysate was collected and spun at 10,000 g for 5 min. Then, the supernatant was collected and mixed with sample buffer 4X (25 μL) containing sample reducing agent and then boiled at 85°C for 5 min. The lysate was stored at -20°C. For SDS-PAGE analysis, samples were loaded onto precast gels (4%-12%), run at a constant 150 V on ice, and transferred to membranes using the P0 program from a fast transfer iBlot2 device (Thermo Fisher Scientific). The membranes were then incubated in LI-COR blocking solution (Intercept) for 30 min and then incubated with primary antibodies overnight at 4°C. The membranes were then washed with TBS-tween 0.1% for at least 30 min and incubated with secondary antibodies for LI-COR detection (1 h, diluted 1/10000). After several washes in PBS-Tween 0.1%, the membranes were analyzed by the Li-COR Odyssey CLx imaging system for protein level detection. GAPDH was used as a loading control. Reagent List Reagent Source Catalog Number NB4 cells DSMZ ACC-207 RPMI 1640 with glutamine Thermo Fisher Scientific 11875093 RIPA lysis and extraction buffer Thermo Fisher Scientific 89900 Halt™ Protease Inhibitor Cocktail (100X) Thermo Fisher Scientific 78430 NuPAGE™ LDS Sample Buffer (4X) Thermo Fisher Scientific NP0007 NuPAGE™ Sample Reducing Agent (10X) Thermo Fisher Scientific NP0004 NuPAGE™ 4%-12% Bis-Tris Protein Gel, 1.5 mm, 15-well Thermo Fisher Scientific NP0336BOX iBlot™ 2 Transfer Stack, C-Nitrate, Regular Size Thermo Fisher Scientific IB23001 Intercept ^TM Occlusion Buffer LI-COR 927-60001 IKZF1 Antibody Cellular Communications 14859 GAPDH Antibody Protein Technology Company 60004-1-Ig IRDye ^TM 800CW Donkey anti-rabbit IgG secondary antibody LI-COR 926-32213 IRDye ^TM 800CW Donkey anti-mouse IgG secondary antibody LI-COR 926-32212 Clearance determination: Metabolic stability assessment using human liver microsomes (HLM)

The stability of controls (phenacetin, verapamil, diclofenac, imipramine, benzydamine, and metoprolol) and test compounds was evaluated using 1 mg/mL HLM (150 mixed-sex donor pool) containing 1 mM NADPH and 1 μM test compound/control. 222.5 μL of the HLM mixture containing 1.12 mg/mL HLM in phosphate buffer pH 7.4 was mixed with 25 μL of 10 mM NADPH and preheated at 37°C for 8 minutes before adding 2.5 μL of 100 μM test compound/control prepared in DMSO. Aliquots (20 μL) were removed at 0.5, 5, 10, 15, 20, and 30 minutes and quenched with 100 μL of cold stop solution (100% ACN, 100 nM alprazolam, caffeine, and tolbutamide as internal standards). Samples were centrifuged at 4,000 rpm and 4°C for 20 minutes, and a 40 μL aliquot of the supernatant was mixed with 160 μL of pure water for LC-MS/MS analysis. Each incubation was performed in duplicate. Peak areas were determined from the extracted ion chromatograms, and the percentage (%) of the parent remaining was calculated from the peak areas of the test compound/control. The slope value k was determined by linear regression of the natural logarithm of the percentage of the parent remaining versus the incubation time curve using Microsoft Excel. The in vitro half-life was calculated from -(natural logarithm (ln) of 2/k) and converted to in vitro intrinsic clearance using Equation 1. Equation 1 Human hepatocyte Clint assay

Human Hepatocytes CLint. Metabolism was initiated by adding compound to hepatocyte incubations to give a compound concentration of 1 μM with 1 X 10 ⁶ hepatocytes/ml. Samples incubated at 37°C were periodically pipetted into cold acetonitrile (5:1) containing internal standard over 120 min. Samples were then centrifuged and 40 μl of supernatant diluted with 160 μl of water (30 μl of supernatant diluted with 180 μl of water for human hepatocytes) and analyzed by LCMSMS. The natural logarithm of the % remaining parent at each time point was plotted versus time half-life and then versus _Clint . SALL-4 and AIOLOS luciferase degrader assays

Cell lines: HiBiT-IKZF3 MM.1S cells (obtained from Promega) were grown in RPMI-1640 (Gibco) supplemented with 10% FBS and GlutaMAX (Gibco). HiBiT-SALL4 SK-N-DZ cells (obtained from Promega) were grown in DMEM (high glucose) (Gibco) supplemented with 10% FBS, GlutaMAX (Gibco), sodium pyruvate (1 mM) (Gibco), and 1% non-essential amino acids (NEAA) (Sigma).

HiBiT assay: Compound ready assay plates were prepared using acoustic dispensing (Echo) to generate 12-point, half-log dose responses with a top concentration of 30 μM. Wells were backfilled with DMSO to 0.3% DMSO. DMSO and pomalidomide (30 μM) were used as point controls on the plate to determine the scale range. HiBiT-IKZF3 MM.1S cells and HiBiT-SALL4 SK-N-DZ cells were added to their respective media starting from frozen vials and dispensed into compound ready assay plates at 3000 (SALL4) or 20.000 (AIOLOS) cells/well using a multidrop combi. Plates were then spun at 300xg for 1 min and incubated for 6 h in a humidified incubator at 37°C, 5% CO2. HiBiT lysis assay reagent (Promega) was prepared according to the manufacturer's instructions, and 5 μl/well of lysis assay mix was added to each plate using a multidrop combi. The plates were spun at 300 g for 1 min, rotated at 300 rpm on an orbital shaker for 30 min, and luminescence was read on an Envision-1 plate reader according to the manufacturer's instructions.

Data analysis: Raw signals were analyzed using the "neutral control minus inhibitor" method in Genedata Screener, and dose-response curves were plotted using the "Smart Fit" compression method to calculate DC50 values. Compounds were considered active when ≥ 30% response was observed.

The cytotoxic potential of PROTACs was summarized in alternative cell screens performed in parallel to the degradation assays, allowing for a comprehensive analysis of whether the IC50 generated in the degradation assays represents true activity or whether it is indeterminate due to potential cytotoxicity associated with the PROTAC.

The SMARCA2 degradation of representative compounds of the present disclosure is provided in Table 1. [Table 1] Instance Number SMARCA2 DC ₅₀ （ µM ） SMARCA2 D _max ( % ) 1 0.064 57.0 2 0.035 86.6 3 0.022 73.5 4 0.094 72.3 5 0.004 86.8 6 0.014 87.1 7 0.008 81.2 8 0.038 69.5 9 0.067 68.1 10 0.078 62.3 11 0.005 88.9 12 0.006 88.4 13 0.002 92.2 14 0.003 86.3 15 0.007 83.0 16 0.003 82.2 17 0.063 79.9 18 0.002 92.4 19 0.004 88.0 20 0.038 73.9 twenty one 0.264 60.1 twenty two 0.016 80.0 twenty three 0.015 78.4 twenty four 0.129 71.6 25 0.095 75.7 26 0.103 68.1 27 0.064 79.4 28 0.042 78.8 29 0.010 78.4 30 0.032 69.8 31 0.023 73.7 32 0.078 55.5 33 0.009 82.7 34 0.027 80.5 35 0.130 66.5 36 0.069 78.9 37 0.011 70.8 38 1.063 65.0 39 0.006 93.1 40 0.175 77.1 41 0.007 83.8 42 0.002 79.7 43 0.030 68.5 44 0.007 90.5 45 0.018 76.7 46 0.042 78.8 47 0.018 77.0 48 0.009 89.3 49 0.016 94.4 50 0.064 76.8 51 0.014 82.7 52 0.014 82.0 53 0.026 75.4 54 0.006 83.1 55 0.030 66.2 56 0.120 78.9 57 0.101 79.5 58 0.007 91.5 59 0.044 84.0 60 0.022 87.9 61 0.004 89.9 62 0.004 91.0 63 0.008 91.1 64 0.017 82.4 65 0.073 87.9 66 0.049 80.3 67 0.023 72.3 68 0.023 71.5 69 0.031 84.4 70 0.029 70.7 71 0.002 91.8 72 0.006 85.6 73 0.054 61.4 74 0.004 92.4 75 0.026 87.6 76 0.028 94.1 77 0.013 81.6 78 0.048 86.8 79 0.023 80.8 80 0.115 81.2 81 0.026 84.1 82 0.008 86.6 83 0.014 84.4 84 0.022 80.8 85 0.006 87.6 86 0.080 70.2 87 0.028 87.9 88 0.027 75.4 89 0.023 79.0 90 0.020 74.0 91 0.034 73.6 92 0.029 61.9 93 0.008 83.7 94 0.134 79.8 95 0.079 76.5 96 0.202 74.2 97 0.014 90.7 98 0.037 62.7 99 0.046 90.3 100 0.016 85.2 101 0.035 82.7 102 0.029 80.5 103 0.017 85.5 104 0.023 83.2 105 0.013 85.2 106 0.016 87.5 107 0.022 86.3 108 0.065 76.8 109 0.044 82.6 110 0.052 79.1 111 0.073 81.5 112 0.027 87.1 113 0.005 91.0 114 0.008 84.1 115 0.022 82.0 116 0.037 82.3 117 0.049 81.9 118 0.046 83.7 119 0.087 80.0 120 0.090 79.4 121 0.010 88.5 122 0.046 87.1 123 0.004 92.5 124 0.013 89.3 125 0.024 85.9 126 0.102 72.6 127 0.062 67.0 128 0.005 93.4 129 0.006 90.0 130 0.047 82.8 131 0.052 76.6 132 0.006 89.3 133 0.062 78.5 134 0.054 81.1 135 0.219 78.3 136 0.188 87.6 137 0.077 83.6 138 0.134 84.4 139 0.104 81.5 140 0.243 73.2 141 0.015 86.1 142 0.071 78.3 143 0.033 86.3 144 0.075 75.4 145 0.003 90.7 146 > 0.319 48.6 147 > 0.319 42.9 148 0.012 84.2 149 0.004 88.0 150 0.014 87.6 151 0.044 70.5 152 0.013 76.7 153 > 0.319 31.6 154 > 0.319 46.4

The SMARCA4 and PBRMI degradation of representative compounds of the present disclosure are provided in Table 2. [ Table 2] Instance Number SMARCA4 DC ₅₀ （ µM ） SMARCA4 D _max ( % ) PBRM1 DC ₅₀ （ µM ） PBRM1 _Dmax ( % ) 3 > 0.319 22.7 0.296 55.7 7 0.319 23.2 0.319 35.6 12 1.009 36.4 0.319 45.8 13 0.319 38.7 0.167 54.0 14 0.319 22.5 0.319 33.8 15 0.319 19.1 0.319 29.4 16 0.106 18.1 0.106 31.1 18 0.319 39.9 0.899 48.0 20 1.009 8.6 0.319 22.4 twenty one 31.67 0.3 3.33 13.6 twenty two 0.319 25.2 1.009 35.4 26 3.33 13.6 1.009 23.8 31 0.319 12.8 1.009 16.3 33 31.67 8.8 0.319 20.3 35 1.009 9.3 3.333 28.4 36 3.333 5.9 1.009 43.6 38 31.67 9.1 10.000 15.3 39 1.009 23.1 0.319 41.6 40 ＞ 3.333 23.3 ＞ 31.67 19.1 43 > 0.319 15.8 ＞ 1.009 35.5 44 ＞ 1.009 29.6 ＞ 1.009 37.6 45 > 0.319 9.1 ＞ 1.009 28.3 46 ＞ 1.009 21.5 ＞ 1.009 21.8 47 > 0.319 12.1 > 0.319 44.0 49 ＞ 1.009 38.1 0.186 74.0 51 > 0.319 18.0 ＞ 1.009 30.2 52 > 0.319 8.8 ＞ 1.009 21.2 53 ＞ 1.009 18.3 ＞ 1.009 38.8 54 > 0.319 19.2 > 0.106 30.5 55 ＞ 31.67 12.6 ＞ 1.009 26.2 56 > 0.319 16.7 2.08 55.6 62 > 0.319 40.6 > 0.319 45.1 64 ＞ 1.009 4.1 ＞ 1.009 25.1 65 ＞ 3.333 21.1 ＞ 3.333 33.3 66 ＞ 1.009 8.0 ＞ 31.67 54.2 67 ＞ 31.67 3.2 > 0.319 14.1 68 ＞ 31.67 1.8 ＞ 1.009 18.5 69 ＞ 1.009 12.8 ＞ 1.009 22.3 70 ＞ 1.009 17.0 ＞ 1.009 35.8 71 > 0.319 33.1 > 0.319 39.4 72 ＞ 0.016 26.1 > 0.106 35.3 73 > 0.319 9.1 ＞ 1.009 26.0 75 ＞ 1.009 30.2 > 0.319 40.0 77 > 0.319 5.6 ＞ 1.009 26.8 79 ＞ 31.67 5.8 ＞ 1.009 17.4 80 ＞ 31.67 5.1 ＞ 1.009 14.3 83 > 0.319 30.9 > 0.319 33.8 85 ＞ 1.009 20.5 > 0.319 41.3 87 ＞ 1.009 17.3 ＞ 1.009 32.3 91 > 0.319 18.9 ＞ 1.009 27.2 92 ＞ 31.67 1.6 ＞ 1.009 22.3 93 ＞ 31.67 11.7 > 0.319 23.5 94 ＞ 31.67 14.7 ＞ 31.67 10.3 97 ＞ 3.333 35.6 0.670 57.5 98 ＞ 10.0 10.9 ＞ 10.0 51.6 99 ＞ 3.333 31.2 ＞ 3.333 38.2 102 ＞ 1.009 28.2 2.09 54.2 103 ＞ 1.009 19.3 ＞ 3.333 38.4 104 ＞ 31.67 6.8 > 0.319 27.4 105 ＞ 31.67 14.3 ＞ 3.333 28.9 106 ＞ 1.009 24.5 > 0.319 26.3 110 ＞ 1.009 28.5 ＞ 1.009 44.5 111 ＞ 3.333 13.8 ＞ 1.009 35.5 114 ＞ 31.67 13.8 ＞ 1.009 19.3 115 ＞ 1.009 17.2 ＞ 1.009 26.6 116 ＞ 31.67 18.8 ＞ 1.009 29.3 117 ＞ 31.67 13.9 ＞ 1.009 23.7 118 ＞ 1.009 7.4 ＞ 1.009 14.6 119 ＞ 3.333 7.5 ＞ 1.009 23.1 120 ＞ 31.67 1.6 ＞ 3.333 15.1 121 ＞ 1.009 20.0 > 0.319 42.7 122 ＞ 31.67 15.2 ＞ 1.009 34.4 130 ＞ 31.67 9.5 ＞ 1.009 24.9 131 ＞ 31.67 7.3 ＞ 3.333 14.7 132 ＞ 1.009 32.2 0.026 68.5 133 > 0.319 21.1 0.201 62.0 134 ＞ 31.67 5.0 ＞ 1.009 16.9 135 ＞ 31.67 -0.4 ＞ 3.333 10.0 136 ＞ 1.009 20.0 ＞ 31.67 13.7 137 ＞ 31.67 7.9 ＞ 3.333 15.2 138 ＞ 31.67 8.7 ＞ 31.67 11.2 139 ＞ 10.0 12.8 0.985 63.9 140 ＞ 31.67 7.0 ＞ 10.0 43.0 142 ＞ 31.67 6.1 ＞ 3.333 17.8 143 ＞ 1.009 31.3 ＞ 3.333 23.8 144 ＞ 31.67 8.5 ＞ 3.333 19.8 148 ＞ 1.009 20.0 > 0.319 43.5 151 ＞ 31.67 6.1 > 0.319 31.4 152 ＞ 31.67 11.7 > 0.319 39.7

The in vitro intrinsic clearance of representative compounds of the present disclosure in human liver microsomes and hepatocytes is provided in Table 3. [Table 3] Instance Number In vitro human liver microsome intrinsic clearance (uL/min/mg) In vitro human hepatocyte intrinsic clearance (uL/min/mg) (uL/min/1 x 10 ⁶ cells) 1 10.7 - 2 61.6 - 3 ＜ 8.4 - 4 9.3 ＜ 1 5 13.8 3.2 6 17.2 5.7 7 ＜ 8.3 2.5 8 ＜ 3.0 3.0 9 ＜ 4.6 2.6 10 14.2 - 11 13.1 ＜ 1 12 ＜ 10.4 4.9 13 13.4 ＜ 2.0 14 10.5 4.6 15 11.1 1.7 16 14.3 4.1 17 16.6 5.0 18 18.8 5.1 19 17.0 - 20 ＜ 3.0 3.4 twenty one ＜ 3.0 - twenty two 11.6 3.6 twenty three 9.1 2.8 twenty four 11.8 - 25 ＜ 3.0 3.6 26 ＜ 3.0 - 27 12.8 - 28 20.8 - 29 10.8 2.5 30 47.3 10.3 31 ＜ 3.8 3.2 32 15.2 - 33 14.9 4.8 34 ＜ 3.0 2.9 35 ＜ 3.0 < 1.0 36 4.1 - 37 19.9 - 38 NV - 39 8.8 4.5 40 32.9 - 41 22.7 3.9 42 21.1 6.5 43 21.1 - 44 ＜ 3 6.7 45 6.1 - 46 66.8 14.3 47 73.8 10.7 48 59.5 12.2 49 36.2 6.9 50 29.2 - 51 23.9 9.7 52 14.5 10.1 53 15.7 - 54 12.1 7.3 55 ＜ 3 - 56 ＜ 3 3.8 57 ＜ 3 - 58 6.9 4.2 59 - 4.6 60 9.5 ＜ 1 61 10.8 - 62 7.7 3.0 63 15.2 2.4 64 14.9 3.6 65 10.7 8.8 66 ＜ 3 ＜ 1 67 ＜ 3 1.6 68 12.2 2.5 69 ＜ 3 1.3 70 ＜ 3 - 71 25.3 7.3 72 12.7 4.3 73 12.3 - 74 15.7 - 75 9.4 5.0 76 14.9 - 77 10.9 2.3 78 6.8 2.3 79 8.8 3.6 80 ＜ 3 2.3 81 ＜ 4.4 ＜ 1 82 - 4.6 83 8.2 ＜ 1 84 6.8 1.2 85 15.0 ＜ 1 86 10.2 ＜ 1 87 9.9 ＜ 1 88 15.6 - 89 17.3 - 90 15.8 4.3 91 ＜ 3 - 92 ＜ 3 - 93 ＜ 3 ＜1 94 - - 95 12.9 - 96 ＜ 3 6.6 97 19.0 16.3 98 - - 99 5.1 2.6 100 ＜ 3 - 101 23.9 - 102 ＜ 1 - 103 ＜ 3.3 ＜ 1 104 ＜ 2.9 ＜ 1 105 ＜ 5.7 ＜ 1 106 ＜ 3.8 1.5 107 11.3 - 108 6.5 - 109 ＜ 3 - 110 ＜ 3 - 111 18.6 - 112 10.2 ＜ 1 113 8.3 - 114 22.7 ＜ 1 115 ＜ 3.3 ＜ 1 116 ＜ 3 ＜ 1 117 4.4 ＜ 1 118 5.2 ＜ 1 119 ＜ 3 ＜ 1 120 ＜ 3 ＜ 1 121 ＜ 4.8 ＜ 1 122 3.5 ＜ 1 123 - - 124 25.8 7.0 125 43.2 - 126 150 - 127 115 - 128 18.1 - 129 7.4 - 130 ＜ 3 - 131 ＜ 3 - 132 39.4 - 133 70.9 - 134 ＜ 3 - 135 ＜ 3 - 136 ＜ 3 - 137 4.8 - 138 ＜ 3 - 139 8.4 - 140 ＜ 3 - 141 ＜ 3 - 142 4.5 - 143 4.4 - 144 ＜ 3 - 145 8.2 - 146 100.3 - 147 66.5 - 148 8.7 - 149 12.4 - 150 4.8 - 151 68.7 - 152 191.5 - 153 247.0 - 154 143.5 -

The SALL4 and IKZF1 degradation activities of representative compounds of the present disclosure are provided in Table 4. [Table 4] Instance Number SALL4 degrader IC50 ( μM ) IKZF1 degrader, at 10 μM 1 ＞ 30.0 2 ＞ 30.0 without 3 ＞ 30.0 6 ＞ 30.0 without 7 ＞ 30.0 without 8 ＞ 30.0 9 ＞ 30.0 10 ＞ 30.0 11 ＞ 30.0 without 12 ＞ 30.0 without 14 ＞ 30.0 15 ＞ 30.0 16 ＞ 30.0 18 ＞ 30.0 20 ＞ 30.0 twenty three ＞ 30.0 25 ＞ 30.0 26 ＞ 30.0 27 ＞ 30.0 29 ＞ 30.0 31 ＞ 30.0 32 ＞ 30.0 85 > 30 -

The SALL4 and AIOLOS degradation activities of representative compounds of the present disclosure are provided in Table 5. [Table 5] Instance Number SALL4 degrader IC50 ( μM ) AIOLOS Degrader IC50 ( μM ) 1 ＞ 30.0 - 2 ＞ 30.0 - 3 ＞ 30.0 - 6 ＞ 30.0 - 7 ＞ 30.0 - 8 ＞ 30.0 - 9 ＞ 30.0 - 10 ＞ 30.0 - 11 ＞ 30.0 ＞ 21.2 12 ＞ 30.0 - 14 ＞ 30.0 - 15 ＞ 30.0 - 16 ＞ 30.0 - 18 ＞ 30.0 - 20 ＞ 30.0 - twenty three ＞ 30.0 - 25 ＞ 30.0 ＞ 30.0 26 ＞ 30.0 - 27 ＞ 30.0 - 29 ＞ 16.9 - 31 ＞ 30.0 - 32 ＞ 30.0 - 33 ＞ 30.0 ＞ 30.0 36 ＞ 30.0 - 47 ＞ 30.0 ＞ 30.0 62 ＞ 30.0 - 69 ＞ 30.0 ＞ 30.0 77 ＞ 30.0 ＞ 30.0 85 ＞ 30.0 - 87 ＞ 30.0 ＞ 30.0 93 ＞ 30.0 ＞ 30.0 94 ＞ 30.0 ＞ 30.0 99 ＞ 30.0 ＞ 30.0 103 ＞ 30.0 - 104 ＞ 30.0 4.6* 105 ＞ 30.0 10.6* 106 ＞ 30.0 ＞30.0 107 - ＞ 30.0 110 - ＞ 30.0 112 ＞ 30.0 ＞ 30.0 115 ＞ 30.0 ＞ 30.0 116 ＞ 30.0 ＞ 30.0 117 ＞ 30.0 ＞ 30.0 118 ＞ 10.0 ＞ 30.0 121 - ＞ 30.0 122 ＞ 30.0 29.5 129 - ＞ 30.0 130 - ＞ 30.0 132 ＞ 30.0 ＞ 30.0 137 - ＞ 30.0 140 - ＞ 30.0 141 - ＞ 30.0 142 - ＞ 30.0 143 - ＞ 30.0 * Partially exposed

Now that the compounds, compositions, and methods herein have been fully described, those skilled in the art will understand that they can be performed over a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof. All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. V. Presentation

The present disclosure also provides the following specific statements.

Description 1. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or

X ³ does not exist;

L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

G ² is (C ₁ -C ₆ )alkylene or a direct bond;

^G3 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )alkoxy; a cyano group; or a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or a cyano group;

G ⁴ is (C ₁ -C ₆ )alkylene or a direct bond;

W is -C≡C- or direct key;

^R7 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl;

R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which is optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; and

R ¹⁰ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C ₃ -C ₆ )cycloalkyl.

Statement 2. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I) where:

E series: , ,or ;

R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ;

The conditions are:

(i) When R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ² is: ;as well as

(ii) When R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ;

R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ;

X ¹ is CR ³ or N;

R ³ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

X ² is CR ⁴ or N;

R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl;

R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl;

R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl;

R ⁶ is hydrogen, (C ₁ -C ₆ ) alkyl, or cyano;

X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or

X ³ does not exist;

L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W;

^G1 is ( _C1 - _C6 )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano;

G ² is (C ₁ -C ₆ )alkylene or a direct bond;

^G3 is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )alkoxy; a cyano group; a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, or cyano; or a 5- to 10-membered heteroaryl group;

G ⁴ is (C ₁ -C ₆ )alkylene, (C ₃ -C ₆ )cycloalkylene, or a direct bond;

W is -C≡C- or direct key;

^R7 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl;

R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl;

R ⁹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which is optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; and

R ¹⁰ is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C ₃ -C ₆ )cycloalkyl.

Statement 3. The compound according to statement 1 or 2 or a pharmaceutically acceptable salt thereof, having formula (II): (II).

Statement 4. The compound according to statement 1 or 2 or a pharmaceutically acceptable salt thereof, having formula (III): (III).

Statement 5. A compound according to any one of Statements 1 to 4 or a pharmaceutically acceptable salt thereof, wherein E is E-1.

Statement 6. The compound according to Statement 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is hydrogen.

Statement 7. The compound according to Statement 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is (C ₁ -C ₆ ) alkyl, which is optionally substituted with one, two or three substituents independently selected from halogen or cyano.

Statement 8. The compound according to Statement 7 or a pharmaceutically acceptable salt thereof, wherein R ^5a is methyl.

Statement 9. The compound according to Statement 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is (C ₃ -C ₆ )cycloalkyl.

Statement 10. The compound according to Statement 9 or a pharmaceutically acceptable salt thereof, wherein R ^5a is cyclopropyl.

Statement 11. The compound according to Statement 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ )alkyl.

Statement 12. The compound according to Statement 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is cyano.

Statement 13. The compound according to Statement 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is aryl, which is optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ ) alkyl.

Statement 14. The compound according to Statement 5 or a pharmaceutically acceptable salt thereof, wherein R ^5a is a 5-membered or 6-membered heteroaryl group, which is optionally substituted by one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ ) alkyl.

Statement 15. A compound according to any one of Statements 1 to 4 or a pharmaceutically acceptable salt thereof, wherein E is E-2.

Statement 16. A compound according to any one of Statements 1-4 or a pharmaceutically acceptable salt thereof, wherein E is E-3.

Statement 17. A compound according to any one of Statements 1 to 16 or a pharmaceutically acceptable salt thereof, wherein:

R ¹ series: and

R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy.

Statement 18. The compound according to Statement 17 or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl.

Statement 19. The compound according to Statement 18 or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen, fluorine, or methyl.

Statement 20. The compound according to any one of Statements 17 to 19 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen.

Statement 21. A compound according to any one of statements 1 to 16 or a pharmaceutically acceptable salt thereof, wherein:

R ² series: and

^R1 is hydrogen, halogen, (C1-C6) alkyl, or (C1-C6) alkoxy.

Statement 22. The compound according to Statement 21 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl.

Statement 23. The compound according to Statement 22 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, fluorine, or methyl.

Statement 24. The compound according to any one of Statements 21 to 23 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is hydrogen.

Statement 25. The compound according to any one of Statements 1 to 24 or a pharmaceutically acceptable salt thereof, wherein X ¹ is CR ³ .

Statement 26. The compound according to Statement 25 or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

Statement 27. The compound according to Statement 25 or a pharmaceutically acceptable salt thereof, wherein R ³ is a halogen.

Statement 28. The compound according to Statement 25 or a pharmaceutically acceptable salt thereof, wherein R ³ is (C ₁ -C ₆ ) alkyl.

Statement 29. The compound according to any one of Statements 1 to 24 or a pharmaceutically acceptable salt thereof, wherein X ¹ is N.

Statement 30. The compound according to any one of Statements 1 to 29 or a pharmaceutically acceptable salt thereof, wherein X ² is CR ⁴ .

Statement 31. The compound according to Statement 30 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

Statement 32. The compound according to Statement 30 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a halogen.

Statement 33. The compound according to Statement 30 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is (C ₁ -C ₆ ) alkyl.

Statement 34. The compound according to any one of Statements 1 to 29 or a pharmaceutically acceptable salt thereof, wherein X ² is N.

Statement 35. The compound according to Statement 5 or a pharmaceutically acceptable salt thereof, wherein E-1 is: , , , , , , , , , , , ,or .

Statement 36. The compound according to Statement 15 or a pharmaceutically acceptable salt thereof, wherein E-2 is: .

Statement 37. The compound according to Statement 16 or a pharmaceutically acceptable salt thereof, wherein E-3 is: .

Statement 38. The compound according to any one of Statements 1 to 37 or a pharmaceutically acceptable salt thereof, wherein G ¹ is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano.

Statement 39. The compound according to Statement 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

n is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to G ² .

Statement 40. The compound according to Statement 39 or a pharmaceutically acceptable salt thereof, wherein each R ¹² is independently fluoro, methyl, methoxy, cyano, or -CHF ₂ ; and n is 0, 1, or 2.

Statement 41. A compound according to Statement 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : , , ,or ;

And the key marked with "*" is attached to G ² .

Statement 42. A compound according to Statement 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Among them, X ⁴ is -O-;

each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; and

Keys marked with a "*" are attached to G ² .

Statement 43. The compound according to Statement 42 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : or and

Keys marked with a "*" are attached to G ² .

Statement 44. The compound according to Statement 38 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : and

Keys marked with a "*" are attached to G ² .

Statement 45. The compound according to any one of Statements 1 to 37 or a pharmaceutically acceptable salt thereof, wherein G ¹ is a 7- to 11-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano.

Statement 46. The compound according to Statement 45 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

Each R ¹³ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

o is 0, 1, 2, or 3;

p, q, r, and s are independently 1, 2, or 3; and

Keys marked with a "*" are attached to G ² .

Statement 47. The compound according to Statement 46 or a pharmaceutically acceptable salt thereof, wherein:

p and q are 1;

r is 1 or 2;

s is 1 or 2; and

R ¹³ is a halogen.

Statement 48. The compound according to Statement 46 or a pharmaceutically acceptable salt thereof, wherein R ¹³ is fluorine and o is 0, 1, or 2.

Statement 49. The compound according to Statement 46 or a pharmaceutically acceptable salt thereof, wherein ^G1 is: and

Keys marked with a "*" are attached to G ² .

Statement 50. The compound according to statement 45 or a pharmaceutically acceptable salt thereof, wherein:

G1 ^Series : ;

a is 0 or 1;

b is 0 or 1; and

Keys marked with a "*" are attached to G ² .

Statement 51. The compound according to Statement 50 or a pharmaceutically acceptable salt thereof, wherein ^G1 is: or and

Keys marked with a "*" are attached to G ² .

Statement 52. The compound according to any one of Statements 1 to 49 or a pharmaceutically acceptable salt thereof, wherein G ² is a direct bond.

Statement 53. The compound according to any one of Statements 1 to 49 or a pharmaceutically acceptable salt thereof, wherein G ² is (C ₁ -C ₆ )alkylene.

Statement 54. The compound according to Statement 53 or a pharmaceutically acceptable salt thereof, wherein G ² is -CH ₂ -.

Statement 55. The compound according to any one of Statements 1 to 54 or a pharmaceutically acceptable salt thereof, wherein G ³ is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano.

Statement 56. The compound according to Statement 55 or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: , , , ,or ;

Each R ¹⁴ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

t is 0, 1, 2, or 3; and

Keys marked with a "*" are attached to G ⁴ .

Statement 57. The compound according to Statement 56 or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is fluorine or methyl and t is 0 or 1.

Statement 58. The compound according to Statement 56 or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , ,or .

Statement 59. The compound according to any one of Statements 1 to 54 or a pharmaceutically acceptable salt thereof, wherein G ³ is a 7- to 11-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano.

Statement 60. The compound according to Statement 59 or a pharmaceutically acceptable salt thereof, wherein G ³ is: and

Keys marked with a "*" are attached to G ⁴ .

Statement 61. The compound according to Statement 59 or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: ;

Each R ¹⁵ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano;

u is 0, 1, 2, or 3;

v, w, x, and y are independently 1, 2, or 3; and

Keys marked with a "*" are attached to G ⁴ .

Statement 62. A compound according to Statement 61 or a pharmaceutically acceptable salt thereof, wherein v, w, x, and y are independently 1 or 2.

Statement 63. The compound according to Statement 59 or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: ;

^xa and ^ya are independently 1, 2, or 3; and

Keys marked with a "*" are attached to G ⁴ .

Statement 64. The compound according to Statement 59 or a pharmaceutically acceptable salt thereof, wherein G ³ is: , , , , , , , , , , , , , ,or and

Keys marked with a "*" are attached to G ⁴ .

Statement 65. The compound according to any one of Statements 1 to 64 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is (C ₁ -C ₆ )alkylene.

Statement 66. The compound according to Statement 65 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is -CH ₂ - or -CH ₂ CH ₂ -.

Statement 67. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 2 to 64, wherein G ⁴ is (C ₃ -C ₆ )cycloalkylene.

Statement 68. The compound according to Statement 67 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is: or .

Statement 69. The compound according to any one of Statements 1 to 64 or a pharmaceutically acceptable salt thereof, wherein G ⁴ is a direct bond.

Statement 70. The compound according to any one of Statements 1 to 37 or a pharmaceutically acceptable salt thereof, wherein L is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or and

The key marked with "*" is attached to E.

Statement 71. The compound according to any one of Statements 2 to 37 or a pharmaceutically acceptable salt thereof, wherein L is: , , and

The key marked with "*" is attached to E.

Statement 72. A compound according to any one of Statements 1-71 or a pharmaceutically acceptable salt thereof, wherein W is -C≡C-.

Statement 73. A compound according to any one of Statements 1-71 or a pharmaceutically acceptable salt thereof, wherein W is a direct bond.

Statement 74. The compound according to any one of Statements 1 to 73 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Statement 75. The compound according to Statement 74 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is halogen or (C ₁ -C ₆ ) alkyl.

Statement 76. The compound according to Statement 75 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is fluoro or methyl.

Statement 77. The compound according to any one of Statements 74 to 76 or a pharmaceutically acceptable salt thereof, wherein R ⁸ , R ⁹ , and R ¹⁰ are H.

Statement 78. The compound according to any one of Statements 1 to 76 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Statement 79. The compound according to Statement 78 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halogen or (C ₁ -C ₆ ) alkyl.

Statement 80. The compound according to Statement 79 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is fluorine or methyl.

Statement 81. The compound according to any one of Statements 78 to 80 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁹ , and R ¹⁰ are hydrogen.

Statement 82. The compound according to any one of Statements 1-76 or 67-69 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Statement 83. The compound according to Statement 82 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is a halogen.

Statement 84. The compound according to Statement 83 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is fluorine.

Statement 85. The compound according to any one of Statements 82 to 84 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , and R ¹⁰ are hydrogen.

Statement 86. The compound according to any one of Statements 1-76, 78-80, or 82-84, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens.

Statement 87. The compound according to Statement 86 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a halogen.

Statement 88. The compound according to Statement 87 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is fluorine.

Statement 89. The compound according to any one of Statements 86 to 88 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , and R ⁹ are hydrogen.

Statement 90. The compound according to any one of Statements 1-73 or a pharmaceutically acceptable salt thereof, wherein R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are H.

Statement 91. A compound according to any one of statements 1-2, 5-9, or 35 or a pharmaceutically acceptable salt thereof, having formula (IV): (IV) where:

Each R ¹² is independently hydrogen or fluorine;

n is 0, 1, or 2; and

R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are independently hydrogen, fluorine, or methyl.

Statement 92. The compound according to Statement 91 or a pharmaceutically acceptable salt thereof, wherein:

G ³ Series: , , , , , , ,or and

G ⁴ is a direct bond, -CH ₂ - or -CH ₂ CH ₂ -.

Statement 93. The compound according to Statement 91 or a pharmaceutically acceptable salt thereof, wherein G ³ is: or .

Statement 94. The compound according to Statement 1 or a pharmaceutically acceptable salt thereof, selected from any one or more of the following compounds: 1-[1-[1-[[7-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-7-azaspiro[3.5]non-2-yl]methyl]-4-piperidinyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]prop-2-ynyl]-7-azaspiro[3.5]non-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]non-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-4-piperidinyl]indol-4-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[2-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-4-piperidinyl]-1-methyl-indol-6-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]methyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[(2S)-4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]oxathiapiperidin-2-yl]methyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[2-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]ethyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-(1-(3-((1-(3-(3-(3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4-fluorophenyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undec-9-yl)-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-(5-(7-((1-(5-(-3-(3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione; (3-(1-(7-((1-(5-(3-(3-amino-6-(2-hydroxyphenyl)tetrahydropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-dioxotetrahydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate; and 1-(1-(2-((1-(5-(-3-(3-amino-6-(2-hydroxyphenyl)oxathia-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. The compound according to statement 85, which is selected from any one or more of the following compounds: 1-[1-[1-[[7-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-7-azaspiro[3.5]non-2-yl]methyl]-4-piperidinyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-(1-(3-((1-(3-(3-(3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-4-fluorophenyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undec-9-yl)-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; (3-(1-(7-((1-(5-(3-(3-amino-6-(2-hydroxyphenyl)tetrahydropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)-3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-dioxotetrahydropyrimidin-1(2H)-yl)methyl dihydrogen phosphate; 1-(1-(2-((1-(5-(-3-(3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-[2-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-4-piperidinyl]-1-methyl-indol-6-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]non-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]methyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[(2S)-4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)oxathiapiperidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]oxathiapiperidin-2-yl]methyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; and 1-(5-(7-((1-(5-(-3-(3-amino-6-(2-hydroxyphenyl) pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione; or a pharmaceutically acceptable salt thereof. Statement 96. The compound or pharmaceutically acceptable salt thereof according to statement 2 is selected from any one or more of the following compounds: 1-[1-[(6r,9r)-4-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-1-oxa-4-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(1r,3r)-3-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[(2S)-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5r,8r)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[(2R)-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,8-dihydro-5H-imidazo[1,2-a]pyridine-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[(2S)-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[7-[[rel-(3aR,5r*,6aS)-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[7-[[rel-(3aR,5r*,6aS)-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[6-Fluoro-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[6-Fluoro-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-cyclopropyl-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-cyclopropyl-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile; 1-[3-methyl-1-[3-[[rel-(4R*)-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile; 1-[3-methyl-1-[3-[[rel-(4R*)-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5s,8s)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5s,8s)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[rel-(3S*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-Methyl-1-[rel-(3R*)-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione (Isomer 1) 1-[1-[(5s,8s)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5r,8r)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[rel-(3S*)-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[rel-(3R*)-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5r,8r)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]spiro[5.5]undecane-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5s,8s)-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(3s,6s)-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(3r,6r)-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(1s,3s)-3-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]cyclobutyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3-b]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-1-piperidinyl]benzonitrile; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[2-[3-cyclopropyl-5-(2,4-dioxohexahydroxypyrimidin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]-7-azaspiro[3.5]nonan-7-yl]methyl]-1-piperidinyl]benzonitrile; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[(1R,5S,6s)-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hex-6-yl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[(1R,5S,6s)-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hex-6-yl]methyl]-7-azaspiro[3.5]non-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(1s,3s)-3-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[(2R)-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-2-chloro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; and 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; or a pharmaceutically acceptable salt thereof.

Statement 97. The compound according to Statement 94 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Statement 98. The compound according to Statement 94 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Statement 99. The compound according to Statement 94 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Statement 100. The compound according to Statement 96 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Statement 101. The compound according to Statement 96 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Statement 102. The compound according to Statement 96 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Statement 103. The compound according to Statement 96 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Statement 104. The compound according to Statement 96 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

Statement 105. A pharmaceutical composition comprising a compound according to any one of Statements 1-104 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable formulation.

Statement 106. A method for degrading SMARCA2 protein in humans, the method comprising administering an effective amount of a compound according to any one of Statements 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to Statement 105 to a human in need thereof.

Statement 107. A method for reducing the level of SMARCA2 activity in a human, the method comprising administering an effective amount of a compound according to any one of Statements 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to Statement 105 to a human in need thereof.

Statement 108. A method for treating human cancer, comprising administering an effective amount of a compound according to any one of Statements 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to Statement 105 to a person in need thereof.

Statement 109. The method according to statement 108, wherein the cancer is a SMARCA2-sensitive cancer.

Statement 110. The method according to statement 108, wherein the cancer is a SMARCA2 mutant cancer.

Statement 111. The method according to any one of statements 108-110, wherein the cancer is a solid tumor.

Statement 112. The method according to any one of statements 108-110, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

Statement 113. A compound according to any one of Statements 1 to 104 or a pharmaceutically acceptable salt thereof, or a composition according to Statement 105, for use in degrading SMARCA2 protein in humans.

Statement 114. A compound according to any one of Statements 1-104 or a pharmaceutically acceptable salt thereof, or a composition according to Statement 105, for use in reducing the activity level of SMARCA2 in humans.

Statement 115. A compound according to any one of Statements 1 to 104 or a pharmaceutically acceptable salt thereof, or a composition according to Statement 105, for use in treating human cancer.

Statement 116. The compound for use according to Statement 115, wherein the cancer is a SMARCA2-sensitive cancer.

Statement 117. The compound for use according to Statement 115, wherein the cancer is a SMARCA2 mutation cancer.

Statement 118. The compound for use according to any one of Statements 115-117, wherein the cancer is a solid tumor.

Statement 119. The compound for use according to any one of Statements 115-117, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

Statement 120. Use of the compound according to any one of Statements 1-104 or a pharmaceutically acceptable salt thereof, or the composition according to Statement 105, in the manufacture of a medicament for degrading SMARCA2 protein in humans.

Statement 121. Use of the compound according to any one of Statements 1-104 or a pharmaceutically acceptable salt thereof, or the composition according to Statement 105, in the manufacture of a medicament for reducing the activity level of SMARCA2 in humans.

Statement 122. Use of a compound according to any one of Statements 1 to 104 or a pharmaceutically acceptable salt thereof, or a composition according to Statement 105, in the manufacture of a medicament for treating human cancer.

Statement 123. A compound or a pharmaceutically acceptable salt thereof for use according to statement 122, wherein the cancer is a SMARCA2-sensitive cancer.

Statement 124. A compound or a pharmaceutically acceptable salt thereof for use according to statement 122, wherein the cancer is a SMARCA2 mutation cancer.

Statement 125. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Statements 122-124, wherein the cancer is a solid tumor.

Statement 126. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Statements 122-124, wherein the cancer is lung cancer, liver cancer, colorectal cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.

without

without

without

Claims (124)

A compound having formula (A) or a pharmaceutically acceptable salt thereof: (A), where: E is: , ,or ; R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; Provided that: (i) when R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy, then R ² is: ; and (ii) when R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ; R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ; X ¹ is CR ³ or N; R ³ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl; X ² is CR ⁴ or N; R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl; R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl; R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl; R ⁶ is hydrogen, (C ₁ -C ₆ )alkyl, or cyano; X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or X ³ is absent; L is G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W; G ¹ is (C ₁ -C ₆ )alkylene; (C ₃ -C ₆ )cycloalkylene; -O-CH ₂ -CH ₂ -; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano or hydroxy; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or cyano; G ² is (C ₁ -C ₆ )alkylene, -C(=O)-, 4- to 6-membered heterocycloalkylene optionally substituted by one, two or three fluorine groups, or a direct bond; G ³ is -C(=O)-; -C(=O)-CH ₂ CH ₂ -; (C ₁ -C ₆ )alkylene; tetrahydronaphthyl; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or cyano; 7- to 11-membered heterocycloalkylene-C(═O)-; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or cyano; G ⁴ is (C ₁ -C ₆ )alkylene; (C ₃ -C ₆ )cycloalkylene; 4- to 6-membered heterocycloalkylene; or a direct bond; W is -C≡C- or a direct bond; ^R7 is hydrogen; halogen; ( _C1 - _C6 ) alkyl, which may be substituted by one, two or three halogens; cyano; or ( _C3 - _C6 ) cycloalkyl; ^R8 is hydrogen; halogen; ( _C1 - _C6 ) alkyl, which may be substituted by one, two or three halogens; cyano; or ( _C3 - _C6 ) cycloalkyl; ^R9 is hydrogen; halogen; ( _C1 - _C6 ) alkyl, which may be substituted by one, two or three halogens; cyano; or ( _C3 - _C6 ) cycloalkyl; ^R10 is hydrogen; halogen; ( _C1 - _C6) )alkyl, which is optionally substituted by one, two or three halogens; cyano; or (C ₃ -C ₆ )cycloalkyl; ^Ra is hydrogen or a halogen; ^Rb is hydrogen or a halogen; and ^Rc is hydrogen or a methyl group. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I), where: E is: , ,or ; R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; Provided that: (i) when R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy, then R ² is: ; and (ii) when R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ; R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ; X ¹ is CR ³ or N; R ³ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl; X ² is CR ⁴ or N; R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl; R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl; R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl; R ⁶ is hydrogen, (C ₁ -C ₆ )alkyl, or cyano; X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or X ³ is absent; L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W; G ¹ is (C ₁ -C ₆ )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C 1 -C ₆ )alkoxy, or cyano; G ² is (C ₁ -C ₆ )alkylene or a direct bond; G ³ is 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C _{1 -C 6} )alkoxy, or cyano; or a 7- to 11-membered heterocycloalkyl group, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; G ⁴ is (C ₁ -C ₆ )alkylene or a direct bond; W is -C≡C- or a direct bond; R ⁷ is hydrogen, a halogen, a (C ₁ -C ₆ )alkyl group which is optionally substituted by one, two or three halogens, a cyano group, or a (C ₃ -C ₆ )cycloalkyl group; R ⁸ is hydrogen, a halogen, a (C ₁ -C ₆ )alkyl group which is optionally substituted by one, two or three halogens, a cyano group, or a (C ₃ -C ₆ )cycloalkyl group; R ^R9 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl; and ^R10 is hydrogen, halogen, ( _C1 - _C6 )alkyl which may be substituted by one, two or three halogens, cyano, or ( _C3 - _C6 )cycloalkyl. A compound having formula (I) or a pharmaceutically acceptable salt thereof: (I), where: E is: , ,or ; R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; Provided that: (i) when R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy, then R ² is: ; and (ii) when R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ; R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ; X ¹ is CR ³ or N; R ³ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl; X ² is CR ⁴ or N; R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl; R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl; R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl; R ⁶ is hydrogen, (C ₁ -C ₆ )alkyl, or cyano; X ³ is -CH ₂ CH ₂ - or -CH ₂ -O-CH ₂ -; or X ³ is absent; L is -G ¹ -G ² -G ³ -G ⁴ -, wherein G ¹ is attached to W; G ¹ is (C ₁ -C ₆ )alkylene; 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; or 7- to 11-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C 1 -C ₆ )alkoxy, or cyano; G ² is (C ₁ -C ₆ )alkylene or a direct bond; G ³ is 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C _{1 -C 6} )alkoxy, or cyano; )alkoxy, or cyano; 7- to 11-membered heterocycloalkyl, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; or 5- to 10-membered heteroaryl; G ⁴ is (C ₁ -C ₆ )alkylene, (C ₃ -C ₆ )cycloalkylene, or a direct bond; W is -C≡C- or a direct bond; R ⁷ is hydrogen, halogen, (C ₁ -C ₆ )alkyl optionally substituted by one, two or three halogens, cyano, or (C ₃ -C ₆ )cycloalkyl; R ⁸ is hydrogen, halogen, (C 1 -C _{6 )} alkyl optionally substituted by one, two or three halogens R ⁹ is hydrogen, halogen, (C 1 -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C _{3 -C 6} )cycloalkyl; and ^{R 10} _is hydrogen, halogen, (C ₁ -C ₆ )alkyl which may be substituted by one, two or three halogens, cyano or (C _{3 -C 6 )} cycloalkyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 2 or 3 has the formula (II): (II). The compound or a pharmaceutically acceptable salt thereof as described in claim 2 or 3 has the formula (III): (III). The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ^5a is hydrogen. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ^5a is (C ₁ -C ₆ ) alkyl, which is optionally substituted with one, two or three substituents independently selected from halogen or cyano. The compound or a pharmaceutically acceptable salt thereof as described in claim 7, wherein R ^5a is methyl. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ^5a is (C ₃ -C ₆ )cycloalkyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 9, wherein R ^5a is cyclopropyl. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ^5a is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, cyano or (C ₁ -C ₆ )alkyl. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ^5a is cyano. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein: R ¹ is: ; and R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ² is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ² is hydrogen, fluorine, or methyl. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein R ¹¹ is hydrogen. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein: R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy; and R ² is: . The compound or a pharmaceutically acceptable salt thereof as described in claim 17, wherein R ¹ is hydrogen, halogen, or (C ₁ -C ₆ ) alkyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 18, wherein R ¹ is hydrogen, fluorine, or methyl. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 17 to 19, wherein R ¹¹ is hydrogen. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein X ¹ is CR ³ . The compound or a pharmaceutically acceptable salt thereof as described in claim 21, wherein R ³ is hydrogen. The compound or a pharmaceutically acceptable salt thereof as described in claim 21, wherein R ³ is a halogen. The compound or a pharmaceutically acceptable salt thereof as described in claim 21, wherein R ³ is (C ₁ -C ₆ ) alkyl. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein ^X1 is N. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein X ² is CR ⁴ . The compound or a pharmaceutically acceptable salt thereof as described in claim 26, wherein R ⁴ is hydrogen. The compound or a pharmaceutically acceptable salt thereof as described in claim 26, wherein R ⁴ is a halogen. The compound or a pharmaceutically acceptable salt thereof as described in claim 26, wherein R ⁴ is (C ₁ -C ₆ ) alkyl. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein ^X2 is N. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein E is: , , , , , , , , , , , , ,or . The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein E is: or . The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein E is: . The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33, wherein ^G1 is ( _C3 - _C6 ) cycloalkylene; or 4- to 6-membered heterocycloalkylene, which is optionally substituted by one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, cyano, or hydroxyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 34, wherein: ^G1 is: ; each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, or hydroxy; n is 0, 1, 2, or 3; and the bond marked with "*" is attached to G ² . The compound or pharmaceutically acceptable salt thereof as claimed in claim 35, wherein each R ¹² is independently fluoro, methyl, methoxy, cyano, or -CHF ₂ ; and n is 0, 1, or 2. The compound or a pharmaceutically acceptable salt thereof as described in claim 35, wherein: ^G1 is: , , , ,or And the key marked with "*" is attached to G ² . The compound or a pharmaceutically acceptable salt thereof as described in claim 34, wherein: ^G1 is: ; wherein X ⁴ is -O-; each R ¹² is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; and the bond marked with "*" is attached to G ² . The compound or a pharmaceutically acceptable salt thereof as described in claim 38, wherein: ^G1 is: or ; and the key marked with "*" is attached to G ² . The compound or a pharmaceutically acceptable salt thereof as described in claim 34, wherein: ^G1 is: ; and the key marked with "*" is attached to G ² . The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein G ¹ is a cyclohexylene group. The compound or a pharmaceutically acceptable salt thereof as described in claim 41, wherein: ^G1 is: or ; and the key marked with "*" is attached to G ² . The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33, wherein ^G1 is a 7- to 11-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, ( _C1 - _C6 ) alkyl, ( _C1 - _C6 ) alkoxy, or cyano. The compound or a pharmaceutically acceptable salt thereof as described in claim 43, wherein: ^G1 is: ; each R ¹³ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; o is 0, 1, 2, or 3; p, q, r, and s are independently 1 or 2; the bond marked with "*" is attached to G ² . A compound or a pharmaceutically acceptable salt thereof as described in claim 44, wherein: p and q are 1; r is 1 or 2; s is 1 or 2; and R ¹³ is a halogen. The compound or pharmaceutically acceptable salt thereof as described in claim 45, wherein R ¹³ is fluorine and o is 0, 1, or 2. The compound or a pharmaceutically acceptable salt thereof as described in claim 44, wherein ^G1 is: ; and the key marked with "*" is attached to G ² . The compound or a pharmaceutically acceptable salt thereof as described in claim 43, wherein: ^G1 is: ; a is 0 or 1; b is 0 or 1; and the key marked with "*" is attached to G ² . The compound or a pharmaceutically acceptable salt thereof as described in claim 48, wherein ^G1 is: , , ,or ; and the key marked with "*" is attached to G ² . The compound or a pharmaceutically acceptable salt thereof as described in claim 43, wherein ^G1 is: or ; and the key marked with "*" is attached to G ² . The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 50, wherein ^G2 is a direct bond. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 or 6-50, wherein ^G2 is C(=O). The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 50, wherein G ² is (C ₁ -C ₆ ) alkylene. The compound or a pharmaceutically acceptable salt thereof as described in claim 53, wherein G ² is -CH ₂ -. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 54, wherein G ³ is a 4- to 6-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano. The compound or a pharmaceutically acceptable salt thereof as described in claim 55, wherein: ^G3 is: , , , ,or ; each R ¹⁴ is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; t is 0, 1, 2, or 3; and the bond marked with "*" is attached to G ⁴ . The compound or a pharmaceutically acceptable salt thereof as described in claim 56, wherein R ¹⁴ is fluorine or methyl and t is 0 or 1. The compound or a pharmaceutically acceptable salt thereof as described in claim 56, wherein ^G3 is: , , ,or ; and the key marked with "*" is attached to G ⁴ . The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 54, wherein G ³ is a 7- to 11-membered heterocycloalkyl group, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano. The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein ^G3 is or ; and the key marked with "*" is attached to G ⁴ . The compound or a pharmaceutically acceptable salt thereof as described in claim 59, wherein ^G3 is: ; and the key marked with "*" is attached to G ⁴ . The compound or a pharmaceutically acceptable salt thereof as described in claim 59, wherein ^G3 is: or ; and the key marked with "*" is attached to G ⁴ . The compound or a pharmaceutically acceptable salt thereof as described in claim 59, wherein: ^G3 is: ; each R ¹⁵ is independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; u is 0, 1, 2, or 3; v, w, x, and y are independently 1, 2, or 3; and the bond marked with "*" is attached to G ⁴ . The compound or a pharmaceutically acceptable salt thereof as described in claim 63, wherein v, w, x, and y are independently 1 or 2. The compound or a pharmaceutically acceptable salt thereof as described in claim 63, wherein R ¹⁵ is fluorine. The compound or a pharmaceutically acceptable salt thereof as described in claim 59, wherein: ^G3 is: ; x ^a and ^ya are independently 1 or 2; and the keys marked with "*" are attached to G ⁴ . The compound or a pharmaceutically acceptable salt thereof as described in claim 59, wherein ^G3 is: , , , , , , , , , , , , , , , , , ,or ; and the key marked with "*" is attached to G ⁴ . The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein ^G3 is ; and the key marked with "*" is attached to G ⁴ . The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 68, wherein G ⁴ is (C ₁ -C ₆ ) alkylene. The compound or a pharmaceutically acceptable salt thereof as described in claim 69, wherein G ⁴ is -CH ₂ - or -CH ₂ CH ₂ -. The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein G ⁴ is (C ₃ -C ₆ )cycloalkylene. The compound or a pharmaceutically acceptable salt thereof as described in claim 71, wherein ^G4 is: or ; and the key marked with "*" is attached to E. The compound or a pharmaceutically acceptable salt thereof as described in claim 71, wherein ^G4 is: or ; and the key marked with "*" is attached to G ⁴ . The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 68, wherein ^G4 is a direct bond. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33, wherein L is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; and the key marked with "*" is attached to E. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 33, wherein L is: , , , ,or ; and the key marked with "*" is attached to E. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-76, wherein W is -C≡C-. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-76, wherein W is a direct bond. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 78, wherein R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are H. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 78, wherein R ⁷ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens. The compound or a pharmaceutically acceptable salt thereof as described in claim 80, wherein R ⁷ is halogen or (C ₁ -C ₆ ) alkyl. The compound or pharmaceutically acceptable salt thereof as described in claim 81, wherein ^R7 is fluorine or methyl. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 80 to 82, wherein R ⁸ , R ⁹ , and R ¹⁰ are hydrogen. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 78, wherein R ⁸ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens. The compound or a pharmaceutically acceptable salt thereof as described in claim 84, wherein R ⁸ is halogen or (C ₁ -C ₆ ) alkyl. The compound or pharmaceutically acceptable salt thereof as described in claim 85, wherein R ⁸ is fluorine or methyl. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 84 to 86, wherein R ⁷ , R ⁹ , and R ¹⁰ are hydrogen. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 78, wherein R ⁹ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens. The compound or pharmaceutically acceptable salt thereof as described in claim 88, wherein R ⁹ is a halogen. The compound or pharmaceutically acceptable salt thereof as described in claim 89, wherein R ⁹ is fluorine. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 88 to 90, wherein R ⁷ , R ⁸ , and R ¹⁰ are hydrogen. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 78, wherein R ¹⁰ is halogen, (C ₁ -C ₆ )alkyl, cyano, or (C ₃ -C ₆ )cycloalkyl, wherein the (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three halogens. The compound or a pharmaceutically acceptable salt thereof as described in claim 92, wherein R ¹⁰ is a halogen. The compound or a pharmaceutically acceptable salt thereof as described in claim 93, wherein R ¹⁰ is fluorine. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 92 to 94, wherein R ⁷ , R ⁹ , and R ⁹ are hydrogen. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 78, wherein R ¹⁰ is cyano. The compound or a pharmaceutically acceptable salt thereof as described in claim 96, wherein R ¹⁰ is cyano; and R ⁷ , R ⁸ , and R ⁹ are hydrogen. A compound having formula (V) or a pharmaceutically acceptable salt thereof, (V), wherein: each R ¹² is fluorine or hydroxyl; n is 0, 1, 2, or 3; E is: , ,or ; R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; R ² is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or ; Provided that: (i) when R ¹ is hydrogen, halogen, (C ₁ -C ₆ ) alkyl, or (C ₁ -C ₆ ) alkoxy, then R ² is: ; and (ii) when R ² is hydrogen, halogen, (C ₁ -C ₆ )alkyl, or (C ₁ -C ₆ )alkoxy, then R ¹ is: ; R ¹¹ is hydrogen or -(C ₁ -C ₆ )alkyl-OP(=O)-(OH) ₂ ; X ¹ is CR ³ or N; R ³ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl; X ² is CR ⁴ or N; R ⁴ is hydrogen, halogen, or (C ₁ -C ₆ )alkyl; R ^5a is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein (C ₁ -C ₆ )alkyl is optionally substituted with one, two or three substituents independently selected from halogen or cyano; and the 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, cyano, or (C ₁ -C ₆ )alkyl; R ^5b is hydrogen, (C ₁ -C ₆ )alkyl, or (C ₃ -C ₆ )cycloalkyl; R ⁶ is hydrogen, (C ₁ -C ₆ )alkyl, or cyano; X ³ is -CH ₂ CH ₂ - or is absent; G ³ is tetrahydronaphthyl; 4- to 6-membered heterocycloalkyl, which is optionally substituted with one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano substituents; 7- to 11-membered heterocycloalkyl-C(=O)-; or 7- to 11-membered heterocycloalkyl, which is optionally substituted by one, two or three substituents independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or cyano; G ⁴ is absent or is cyclobutyl; R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are independently hydrogen, fluorine, methyl, or cyano; ^Ra is hydrogen, chlorine, methyl, or fluorine; R ^b is hydrogen, chlorine, methyl, or fluorine; and R ^c is hydrogen or methyl. The compound or a pharmaceutically acceptable salt thereof as described in claim 98, wherein: ^G3 is: , , , , , , ,or . The compound or a pharmaceutically acceptable salt thereof as described in claim 98, wherein ^G3 is: , , ,or . The compound or a pharmaceutically acceptable salt thereof as described in claim 98, wherein ^G3 is: , , , , , , , , , , , , , , , , , , ,or . The compound or pharmaceutically acceptable salt thereof as described in claim 1, selected from any one or more of the following compounds: 1-[1-[1-[[7-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-7-azaspiro[3.5]non-2-yl]methyl]-4-piperidinyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]prop-2-ynyl]-7-azaspiro[3.5]non-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]non-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-4-piperidinyl]indol-4-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2 ,4-dione 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl) pyrrolidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[2-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-4-piperidinyl]-1-methyl-indol-6-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)piperidin-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]methyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[(2 S )-4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]thiophen-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[2-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]ethyl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-4-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[5-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione; [3-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]-2,6-dioxo-hexahydropyrimidin-1-yl]methyl dihydrogen phosphate; 1-[1-[2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2-azaspiro[3.5]nonan-7-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(6 r ,9 r )-4-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-1-oxa-4-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(1 r ,3 r )-3-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[(2S)-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]phthalimide-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[(2 S )-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,8-dihydro- 5H -imidazo[1,2- a ]pyridine-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[[(2 R )-4-[[7-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-7-azaspiro[3.5]non-2-yl]methyl]phthalimide-2-yl]methyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[7-[[ rel -(3 aR ,5 r *,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3 a ,4,5,6,6 a -hexahydro-1 H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not confirmed]; 1-[3-methyl-1-[7-[[(3 aR ,5 s ,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a , 4,5,6,6a -hexahydro- 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[7-[[( 3aR , 5r , 6aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a , 4,5,6,6a -hexahydro- 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[7-[[ rel- ( 3aR , 5r *, 6aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3a,4,5,6,6a-hexahydro- 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not confirmed]; 1-[3-methyl-1-[7-[[(3 aR ,5 s ,6 aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -3,3a , 4,5,6,6a -hexahydro- 1H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[7-[[( 3aR , 5r , 6aS )-2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3 a ,4,5,6,6 a -hexahydro-1 H -cyclopenta[ c ]pyrrol-5-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[6-fluoro-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not confirmed]; 1-[6-fluoro-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[6-fluoro-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[6-fluoro-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not confirmed]; 1-[6-fluoro-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[6-fluoro-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-cyclopropyl-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not confirmed]; 1-[3-cyclopropyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-cyclopropyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-cyclopropyl-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not confirmed]; 1-[3-cyclopropyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-cyclopropyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[3-[[ rel -(4 R* )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not confirmed]; 1-[3-methyl-1-[3-[[(4 R )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[3-[[(4 S )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-4-fluoro-1-piperidinyl]benzonitrile; 1-[3-methyl-1-[3-[[ rel -(4 R* )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not confirmed]; 1-[3-methyl-1-[3-[[(4 R )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[3-[[(4 S )-1-[5-[3-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3,3-difluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[ rel -(3 S* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not confirmed]; 1-[3-methyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[ rel -(3 R* )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not confirmed]; 1-[3-methyl-1-[(3 S )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[(3 R )-8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-8-azaspiro[4.5]dec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[ rel -(3 S* )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 1) [*absolute configuration not confirmed]; 1-[3-methyl-1-[(3 S )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[(3 R )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[ rel -(3 R* )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione (isomer 2) [*absolute configuration not confirmed]; 1-[3-methyl-1-[(3 S )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[(3 R )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1-oxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 r ,8 r )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]spiro[5.5]undecane-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(3 s ,6 s )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(3 r ,6 r )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxazolidin-9-azaspiro[5.5]undecane-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[4-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]piperidin-1-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[9-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-ethyl-pyrrolo[2,3- b ]pyridin-1-yl]-3-azaspiro[5.5]undec-3-yl]methyl]-1-piperidinyl]benzonitrile; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[2-[3-cyclopropyl-5-(2,4-dioxohexahydroxypyrimidin-1-yl)pyrrolo[2,3- b ]pyridin-1-yl]-7-azaspiro[3.5]nonan-7-yl]methyl]-1-piperidinyl]benzonitrile; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[(1 R ,5 S ,6 s )-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[(1 R ,5 S ,6 s )-3-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(1 s ,3 s )-3-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[(2 R )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]thiazol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-6-fluoro-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-2-chloro-phenyl]-4-piperidinyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[8-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undecane-9-yl]pyrrolo[1,2- a ]pyrimidin-3-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(2 S )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(2 R )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(2 S )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(2 R )-6-[[4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidin-1-yl]methyl]tetrahydronaphthalen-2-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[(1 s ,4 s )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]cyclohexyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[(1 r ,4 r )-4-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]cyclohexyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(3 r ,6 r )-9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-11,11-difluoro-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(1 r ,4 r )-4-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclohexyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(1 s ,4 s )-4-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclohexyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(1 r ,3 r )-3-[8-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-fluoro-4-piperidinyl]methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]cyclobutyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]piperidine-4-carbonyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[3-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-ethyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 4-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4-[[3-[3-cyclopropyl-5-(2,4 1-[1-[3-[[1-[5-[3-[3-amino-6-(5-fluoro- 2 -hydroxy-phenyl)pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-4-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-3-azaspiro[5.5]undec-9-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[7-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(3 S )-1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]pyrrolidin-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(3 R )-1-[[1-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-4-fluoro-4-piperidinyl]methyl]pyrrolidin-3-yl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3-azabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-ethyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[7-[[ rac- (2 S ,3 aR ,6 aR )-5-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-2,3,3 a ,4,6,6 a -hexahydrofuro[2,3- c ]pyrrol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[3-methyl-1-[7-[[ rac -(2 S ,3 aR ,6 aR )-5-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl] -2,3,3a , 4,6,6a -hexahydrofuro[2,3- c ]pyrrol-2-yl]methyl]-7-azaspiro[3.5]nonan-2-yl]pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(3-chloro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxy-3-methyl-phenyl) pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undecane-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl) pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl) pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[(3 S )-4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]-3-methyl-piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[(3 S )-4-[3-amino-6-(2-hydroxyphenyl)thiazol-4-yl]-3-methyl-piperidin-1-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[3-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]methyl]-3-azaspiro[5.5]undec-9-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3-fluoro-2-hydroxy-phenyl) pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl) pyrimidine-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[(5 s ,8 s )-2-[[1-[5-[3-[3-amino-6-(3,5-difluoro-2-hydroxy-phenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-6,10-dioxa-2-azaspiro[4.5]dec-8-yl]indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-6-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[2-[4-[2-[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]phenoxy]ethyl]piperimide-1-yl]ethyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[2-[4-[2-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenoxy]ethyl]piperimide-1-yl]ethyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]indol-4-yl]hexahydropyrimidine-2,4-dione; 1-[1-[9-[[1-[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]-4-hydroxy-4-piperidinyl]methyl]-1,5-dioxa-9-azaspiro[5.5]undec-3-yl]-3-cyclopropyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; 1-[1-[1-[4-[[5-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazobicyclo[3.2.1]octan-8-yl]-2-fluoro-phenyl]methyl]piperidin-1-carbonyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; -[1-[1-[4-[[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimide-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]methyl]piperidin-1-carbonyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2,4-dione; -[1-[1-[3-[4-[[5-[3-[3-amino-6-(2-hydroxyphenyl) pyrimidine-4-yl]-3,8-diazobicyclo[3.2.1]oct-8-yl]-2-fluoro-phenyl]methyl]piperidin-1-yl]-3-oxo-propyl]-4-piperidinyl]-3-methyl-pyrrolo[ 2,3- ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; or 1-[1-[1-[3-[4-[[3-[3-[3-amino-6-(2-hydroxyphenyl)phthalimidine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl]methyl]piperidin-1-yl]-3-oxo-propyl]-4-piperidinyl]-3-methyl-pyrrolo[2,3- b ]pyridin-5-yl]hexahydropyrimidine-2,4-dione; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 102 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable formulation. A method for degrading SMARCA2 protein in humans, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 102, or a composition as described in claim 103, to a human in need thereof. A method for reducing the level of SMARCA2 activity in a human, comprising administering to a human in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 102, or a composition as described in claim 103. A method for treating human cancer, comprising administering to a person in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-102, or a composition as described in claim 103. The method of claim 106, wherein the cancer is a SMARCA2-sensitive cancer. The method of claim 106, wherein the cancer is a SMARCA2 mutant cancer. The method of any of claims 106-108, wherein the cancer is a solid tumor. The method of any one of claims 106-108, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer, or ovarian cancer. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 102, or the composition as described in claim 103, is used for degrading SMARCA2 protein in humans. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 102, or the composition as described in claim 103, for use in reducing the activity level of SMARCA2 in humans. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 102, or a composition as described in claim 103, for use in treating human cancer. The compound for use as claimed in claim 113, wherein the cancer is a SMARCA2-sensitive cancer. The compound for use as claimed in claim 113, wherein the cancer is a SMARCA2 mutation cancer. A compound for use as claimed in any one of claims 113 to 115, wherein the cancer is a solid tumor. A compound for use as described in any one of claims 113 to 115, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer. Use of the compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 102, or the composition as described in claim 103, in the manufacture of a medicament for degrading SMARCA2 protein in humans. Use of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 102, or a composition as described in claim 103, in the manufacture of a medicament for reducing the activity level of SMARCA2 in humans. Use of a compound as described in any one of claims 1 to 102 or a pharmaceutically acceptable salt thereof, or a composition as described in claim 103, in the manufacture of a medicament for treating human cancer. A compound or a pharmaceutically acceptable salt thereof for use as described in claim 120, wherein the cancer is a SMARCA2-sensitive cancer. A compound or a pharmaceutically acceptable salt thereof for use as described in claim 120, wherein the cancer is a SMARCA2 mutation cancer. A compound or a pharmaceutically acceptable salt thereof for use as described in any one of claims 120-122, wherein the cancer is a solid tumor. A compound or a pharmaceutically acceptable salt thereof for use as described in any one of claims 120-122, wherein the cancer is lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer or ovarian cancer.