WO2025045141A1

WO2025045141A1 - Kras inhibitors and uses thereof

Info

Publication number: WO2025045141A1
Application number: PCT/CN2024/115467
Authority: WO
Inventors: Zheng Wang; Ding Zhou; Ziqiang CHENG
Original assignee: Suzhou Zanrong Pharma Limited
Priority date: 2023-08-31
Filing date: 2024-08-29
Publication date: 2025-03-06

Abstract

Provided are novel compounds useful as inhibitors of KRAS, in particular KRAS G12D and/or other KRAS G12 mutants, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

Description

KRAS INHIBITORS AND USES THEREOF

TECHNICAL FIELD

The present disclosure generally relates to novel compounds useful as inhibitors of KRAS, in particular KRAS G12D and/or other KRAS G12 mutants, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

BACKGROUND OF THE INVENTION

RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30%of all human cancers. As the most frequently mutated RAS isoform, KRAS (Kirsten-rat sarcoma viral oncogene homolog) is intensively studied in the past years. KRAS and the highly related NRAS and HRAS GTPases hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP) . They control diverse cellular functions by cycling between an active, GTP-bound and an inactive, GDP-bound conformation (Hobbs, G.A., et al. J. Cell Sci. 129, 1287–1292. (2016) ) .

KRAS is a prominent oncogene that has been proven to drive tumorigenesis (G G Jinesh, et al. Oncogene volume 37, pages 839–846 (2018) ) . KRAS also modulates numerous genetic regulatory mechanisms and forms a large tumorigenesis network. KRAS gene encodes a 21 kDa protein, called KRAS, part of the RAS/MAPK pathway. The KRAS protein is a GTPase, which means it binds to guanine nucleotides GDP and guanosine-triphosphate (GTP) with high affinity and can hydrolyze GTP to GDP (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170 (1) : 17–33) . GDP/GTP cycling is tightly regulated by a diverse family of multi-domain proteins: guanine nucleotide exchange-factors (GEFs) and GTPase-activating proteins (GAPs) . GEFs stimulate the dissociation of GDP and subsequent association of GTP, activating RAS proteins, while GAPs act to accelerate intrinsic GTP hydrolysis, converting RAS to its inactive state (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170 (1) : 17–33) . The GTP bound form of KRAS is considered the active form, and downstream signaling effectors specifically bind to the GTP-bound form of KRAS. The KRAS protein is turned off (inactivated) when the protein is bound to GDP and does not relay signals to the cell's nucleus.

The cancer-promoting KRAS mutations most commonly occur at codon 12, 13, or 61 (Jozsef Timar, et al. Cancer and Metastasis Reviews volume 39, pages 1029–1038 (2020) ) . Among these mutation sites, G12 is the most frequently mutated residue (89%) and it most often mutates to aspartate (G12D, 36%) followed by valine (G12V, 23%) and cysteine (G12C, 14%) . G12 is located at the protein active site, which consists of a phosphate binding loop (P-loop, residues 10–17) and two switch regions (Switch-I (SI) , residues 25–40, and Switch-II (SII) , residues 60–74) (Prior, I. A., et al. Cancer Res 72, 2457–2467, (2012) ) . The residues in the active site bind to the phosphate groups of GTP and are responsible for the GTPase function of KRAS. The switch regions SI and SII are additionally responsible for controlling binding to effector and regulator proteins. Numerous studies have shown the heterogeneity of KRAS mutations in various aspects, including intrinsic GTPase activity and the affinity of effectors and metastatic sites (Ihle, N. T. et al. J. Natl Cancer Inst. 104, 228–239 (2012) ) . The mutation of glycine at position 12 to aspartate (G12D) in the P-loop leads to impair GTP hydrolysis and freeze KRAS in its active (GTP-bound) state, which causes uncontrollable cellular growth and evasion of apoptotic signals (Malumbres, M. &Barbacid, M. Nat Rev Cancer 3, 459–465, (2003) ) . The G12D mutation causes a shift in the population of local conformational states of KRAS, especially in Switch-II (SII) and α3-helix regions, in favor of a conformation that is associated with a catalytically impaired state through structural changes; it also causes SII motions to anti-correlate with other regions (Sezen Vatansever, et al. Sci Rep. 2019 Aug 13; 9 (1) : 11730) .

Apart from KRAS G12D mutation, other KRAS mutation, such as KRAS (G12C) , KRAS (G12V) , KRAS (G12A) , KRAS (G12S) or KRAS (G12R) , also influences the function of KRAS and the occurrence, development of tumors or resistance to target therapy. Other KRAS mutations or secondary mutations of KRAS that disrupt covalent or potentially noncovalent drug binding can be used to illustrate clinical resistance to KRAS‐mutant targeting therapy (Awad MM, et al. N Engl J Med. 2021; 384 (25) : 2382–93. ) . KRAS gene amplification and overexpression are also relevant for tumor progression (E Birkeland, et al. Br. J Cancer. 2012 Dec 4; 107 (12) : 1997-2004) . The publication also suggested wild type KRAS inhibition could also be a viable therapeutic strategy to treat KRAS wild type dependent cancer (Lisa Maria Mustachio, et al. Cancers (Basel) . 2021 Mar; 13 (6) : 1204. ) .

KRAS mutations (e.g. amino acids G12, G13, Q61, A146) are present in up to 25%of cancers, the oncogenic variants have different prevalence rates in different cancers including lung cancer, colorectal cancer and pancreatic cancer (Cox et al., Nat, Rev. Drug Discov., 2014, 13 (11) : 825-51) . In pancreatic ductal adenocarcinoma cases, the most common KRAS alteration is the G12D substitution. The G12D variant is also the focus of drug discovery efforts by Mirati, which plans to bring its lead compound, MRTX1133 to clinical trials. Based on epidemiology data reported in Globocan 2022 (accessed November 2019) and frequencies by mutation, KRAS G12D mutation is present in an estimated around 36%of Pancreatic cancer, in 4%colorectal cancer, in around 6%endometrial cancer and in around 4%NSCLC. This significant patient population with high unmet need. The discovery of inhibitors that target KRAS (G12D) while preserving the wild-type or other mutant KRAS, such as KRAS (G12V) or KRAS (G12S) is a breakthrough in the research field (Gongmin Zhu, et al. Mol Cancer. 2021 Nov 6; 20 (1) : 143) .

Therefore, there is still unmet need to develop new compounds efficacious in the treatment of cancers medicated by KRAS, especially for KRAS mutated in position 12, for example G12D, or 13 and/or in wild-type amplified KRAS mediated cancer.

SUMMARY OF THE INVENTION

Disclosed herein are novel compounds that are capable of inhibiting KRAS proteins. As a result, the compounds of the present disclosure are useful in the treatment of KRAS-associated diseases such as cancers.

In one aspect, the present disclosure provides a compound having Formula (I) , Formula (II) or Formula (III) :

or a pharmaceutically acceptable salt thereof,

wherein

Ring A is

X is -C (R^eR^f) -, -O-or -N (R^X) -;

R^X is hydrogen, deuterium, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more deuterium;

Ring E is

Z is -C (R^jR^k) -, -O-or -N (R^Z) -;

R^Z is hydrogen, deuterium, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more deuterium;

R¹ and R² are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;

R³ and R⁴ are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium; or

R³ and R⁴ together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;

R⁵ and R⁶ are each independently selected from hydrogen, deuterium, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;

R⁷ and R⁸ are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;

R⁹ and R¹⁰ are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;

each of R^a, R^b, R^c, R^d, R^e, and R^f is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium; or

two of R⁷, R⁸, R⁹, R¹⁰, R^a, R^b, R^c, R^d, R^e, R^f, and R^X together with the interval atoms formcycloalkyl or heterocyclyl, wherein each of cycloalkyl and heterocycle optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;

provided that when the compound has a Formula (I) , at least one of R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ is not hydrogen;

R¹¹ and R¹² are each independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;

R¹³ and R¹⁴ are each independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;

each of R^s, R^t, R^v, and R^u is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium;

each of R^j and R^k is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium; or

R^j and R^k together with the carbon atom to which they are attached form

provided that when the compound has a Formula (II) or Formula (III) , at least one of R⁵, R⁶, R¹¹, R¹², R¹³ and R¹⁴ is alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy substituted with one or more deuterium;

each R is independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl and alkynyl, wherein the alkyl, alkenyl, alkynyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;

each R’ is independently hydrogen or deuterium;

each R” is independently hydrogen, deuterium or halogen;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2 or 3; and

p is 0, 1, 2 or 3.

In another aspect, the present disclosure provides a compound having a formula selected from:

or a pharmaceutically acceptable salt thereof,

wherein

R⁵ is selected from alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl is optionally substituted with one or more deuterium;

Ring B is cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;

provided that at least one of R⁷ and R⁹ is not hydrogen; and

provided that R¹¹ is alkyl substituted with one or more deuterium.

In another aspect, the present disclosure provides a compound selected from any one as set forth in Table 1.

In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In a further aspect, the present disclosure provides a method for inhibiting wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and/or KRas Q61H activity in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.

In a further aspect, the present disclosure provides a method for treating a cancer associated with wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and/or KRas Q61H comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.

In a further aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising:

(a) acquiring the knowledge that the cancer is associated with wild type KRas, KRas G12D , KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and/or KRas Q61H; and

(b) administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure.

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

In another aspect, the present disclosure provides a compound of present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for use in the treatment of cancer.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present disclosure as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, the present disclosure controls. All references, patents, patent applications cited in the present disclosure are hereby incorporated by reference in their entireties.

It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination. It must be noted that, as used in the specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural forms of the same unless the context clearly dictates otherwise. Thus, for example, reference to “acompound” includes a plurality of compounds.

DEFINITIONS

Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2^nd Edition, University Science Books, Sausalito, 2006; Smith and March March’s Advanced Organic Chemistry, 6^th Edition, John Wiley &Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3^rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4^th Edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference.

At various places in the present disclosure, linking substituents are described. It is specifically intended that each linking substituent includes both the forward and backward forms of the linking substituent. For example, -NR (CR’ R” ) -includes both -NR (CR’ R” ) -and - (CR’ R” ) NR-. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

As used herein, a dash “-” at the front or end of a chemical group is used, a matter of convenience, to indicate a point of attachment for a substituent. For example, -OH is attached through the carbon atom; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. As used herein, a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

When any variable (e.g., Rⁱ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Rⁱ moieties, then the group may optionally be substituted with up to two Rⁱ moieties and Rⁱ at each occurrence is selected independently from the definition of Rⁱ. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

As used herein, the term “KRas G12A” refers to a mutant form of a mammalian Kras protein that contains an amino acid substitution of an alanine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human Kras is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp. Gly12Asp. As used herein, a “Kras G12A inhibitor” refers to compounds capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of Kras G12A. A “Kras G12A-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having a Kras G12A mutation. A non-limiting example of a Kras G12A-associated disease or disorder is a Kras G12A-associated cancer.

Similarly, the term “KRas G12C” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. The term “KRas G12D” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The term “KRas G12R” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an arginine for a glycine at amino acid position 12. The term “KRas G12S” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12. The term “KRas G12V” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a valine for a glycine at amino acid position 12. The term “KRas G13D” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 13. The term “KRas Q61H” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a histidine for a glutamine at amino acid position 61.

As used herein, the term “compounds provided herein” , or “compounds disclosed herein” or “compounds of the present disclosure” refers to the compounds of Formula (I) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , Formula (If) as well as the specific compounds disclosed herein.

As used herein, the term “C_i-j” indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i. For examples, C_1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms. In some embodiments, the term “C_1-12” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.

As used herein, the term “alkyl” , whether as part of another term or used independently, refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below. The term “C_i-j alkyl” refers to an alkyl having i to j carbon atoms. In some embodiments, alkyl groups contain 1 to 10 carbon atoms. In some embodiments, alkyl groups contain 1 to 9 carbon atoms. In some embodiments, alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of “C_1-10 alkyl” include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of “C_1-6 alkyl” are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.

As used herein, the term “alkenyl” , whether as part of another term or used independently, refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms. Examples of alkenyl group include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.

As used herein, the term “alkynyl” , whether as part of another term or used independently, refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms. Examples of alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

As used herein, the term “alkoxy” , whether as part of another term or used independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. The term “C_i-j alkoxy” means that the alkyl moiety of the alkoxy group has i to j carbon atoms. In some embodiments, alkoxy groups contain 1 to 10 carbon atoms. In some embodiments, alkoxy groups contain 1 to 9 carbon atoms. In some embodiments, alkoxy groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of “C_1-6 alkoxy” include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy) , t-butoxy, neopentoxy, n-hexoxy, and the like.

As used herein, the term “amino” refers to –NH₂ group. Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amino groups.

As used herein, the term “cyano” refers to –CN.

As used herein, the term “cycloalkyl” , whether as part of another term or used independently, refer to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms. In some embodiments, the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms. Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. In the case of polycyclic ring system, the cycloalkyl includes fused (for example, a cycloalkyl ring fused with another cycloalkyl ring) , spiro and bridged ring systems. Examples of monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyl group include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decanyl, bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, and the like.

As used herein, the term “halogen” refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .

As used herein, the term “haloalkyl” refers to an alkyl, as defined above, that is substituted by one or more halogens, as defined above. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.

As used herein, the term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxides) .

As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. The heterocyclyl group may be a monocyclic or polycyclic ring system. In the case of the polycyclic ring system, the heterocyclyl group may include fused, spiro, or bridged ring systems. For example, a polycyclic heterocyclyl may comprise a heterocyclyl ring fused to one or more additional rings such as cycloalkyl or heterocyclyl ring, or a cycloalkyl ring fused to one or more heterocyclyl ring. In some embodiments, the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen. The heterocyclyl radical may be carbon linked or nitrogen linked where such is possible. In some embodiments, the heterocycle is carbon linked. In some embodiments, the heterocycle is nitrogen linked. For example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) .

In some embodiments, the term “3-to 12-membered heterocyclyl” refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of heterocyclyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, dihydrofuryl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl.

As used herein, the term “hydroxyl” or “hydroxy” refers to –OH.

As used herein, the term “hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

As used herein, the term “nitro” refers to –NO₂.

As used herein, the term “partially unsaturated” refers to a radical that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

As used herein, the term “substituted” , whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted” , references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

COMPOUNDS

or a pharmaceutically acceptable salt thereof,

wherein

Ring A is

X is -C (R^eR^f) -, -O-or -N (R^X) -;

Ring E is

Z is -C (R^jR^k) -, -O-or -N (R^Z) -;

two of R⁷, R⁸, R⁹, R¹⁰, R^a, R^b, R^c, R^d, R^e, R^f, and R^X together with the interval atoms formcycloalkyl or heterocyclyl, wherein each of cycloalkyl and heterocyclyl optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;

R^j and R^k together with the carbon atom to which they are attached form

each R’ is independently hydrogen or deuterium;

each R” is independently hydrogen, deuterium or halogen;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2 or 3; and

p is 0, 1, 2 or 3.

In some embodiments of the compound of Formula (I) , Formula (II) or Formula (III) , both R¹ and R² are hydrogen.

In some embodiments of the compound of Formula (I) , Formula (II) or Formula (III) , one of R³ and R⁴ is hydrogen, and the other is alkyl optionally substituted with one or more deuterium. In certain embodiments, one of R³ and R⁴ is hydrogen, and the other is C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, one of R³ and R⁴ is hydrogen, and the other is methyl optionally substituted with one or more deuterium. In certain embodiments, one of R³ and R⁴ is hydrogen, and the other is -CH₃ or -CD₃.

In some embodiments of the compound of Formula (I) , Formula (II) or Formula (III) , R³ and R⁴ taken together with the carbon atom to which they are both attached form cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. In some embodiments, R³ and R⁴ taken together with the carbon atom to which they are both attached form C_3-6 cycloalkyl, C_3-5 cycloalkyl, or C_3-4 cycloalkyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. In certain embodiments, R³ and R⁴ taken together with the carbon atom to which they are both attached form cyclopropyl optionally substituted with one or more deuterium.

In some embodiments of the compound of Formula (I) , Formula (II) or Formula (III) , one of R⁵ and R⁶ is alkyl optionally substituted with one or more deuterium, and the other is hydrogen. In certain embodiments, one of R⁵ and R⁶ is C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium, and the other is hydrogen. In certain embodiments, one of R⁵ and R⁶ is -CH₃ or -CD₃, and the other is hydrogen.

In some embodiments of the compound of Formula (I) , R⁷, R⁸, R⁹ and R¹⁰ are hydrogen.

In some embodiments of the compound of Formula (I) , one of R⁵ and R⁶ is alkyl optionally substituted with one or more deuterium, the other is hydrogen, and R⁷, R⁸, R⁹ and R¹⁰ are hydrogen. In certain embodiments, one of R⁵ and R⁶ is C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium, the other is hydrogen, and R⁷, R⁸, R⁹ and R¹⁰ are hydrogen.

In some embodiments of the compound of Formula (I) , Formula (II) or Formula (III) , both R⁵ and R⁶ are hydrogen.

In some embodiments of the compound of Formula (I) , one of R⁷ and R⁸ is alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R⁷ and R⁸ is C_1-6 alkyl, C_1-6 alkoxy, - (C_1-6 alkyl) - (C_1-6 alkoxy) , C_1-6 hydroxyalkyl or C_1-6 haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R⁷ and R⁸ is -CH₃, -CD₃, -CH₂-OCH₃, -CH₂-OCD₃, -CH₂-OH, -CH₂F, -CHF₂ or -CF₃, and the other is hydrogen or deuterium.

In some embodiments of the compound of Formula (I) , both R⁵ and R⁶ are hydrogen, one of R⁷ and R⁸ is alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R⁷ and R⁸ is C_1-6 alkyl, C_1-6 alkoxy, - (C_1-6 alkyl) - (C_1-6 alkoxy) , C_1-6 hydroxyalkyl or C_1-6 haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R⁷ and R⁸ is -CH₃, -CD₃, -CH₂-OCH₃, -CH₂-OCD₃, -CH₂-OH, -CH₂F, -CHF₂ or -CF₃, and the other is hydrogen or deuterium.

In some embodiments of the compound of Formula (I) , one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen, C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen, methyl or CD₃.

In some embodiments of the compound of Formula (I) , both R⁵ and R⁶ are hydrogen, one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen, C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen, methyl or CD₃.

In some embodiments of the compound of Formula (I) , R⁷ and R⁹ together with the interval atoms form a heterocyclyl, or R⁷ and R^a together with the interval atoms form a heterocyclyl. In certain embodiments, Ring A is

In some embodiments of the compound of Formula (I) , X is -C (R^eR^f) -, one of R^e and R^f is hydrogen, and the other is halogen. In certain embodiments, one of R^e and R^f is hydrogen, and the other is -F. In certain embodiments, both of R^e and R^f are hydrogen.

In some embodiments of the compound of Formula (I) , both R⁵ and R⁶ are hydrogen, R⁷ and R⁹ together with the interval atoms form a heterocyclyl, or R⁷ and R^a together with the interval atoms form a heterocyclyl. In certain embodiments, both R⁵ and R⁶ are hydrogen, and Ring A is

In some embodiments of the compound of Formula (I) , X is -C (R^eR^f) -, and R^a and R^e together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl. In certain embodiments, X is -C (R^eR^f) -, and R^a and R^e together with the carbon atoms to which they are attached form a C_3-6 cycloalkyl or 3-to 6-membered heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.

In some embodiments of the compound of Formula (I) , n is 0.

In some embodiments of the compound of Formula (I) , when n is 0, Ring A is

In some embodiments of the compound of Formula (I) , both R⁵ and R⁶ are hydrogen, Ring A iswherein one of R⁷ and R⁸ is alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R⁷ and R⁸ is alkyl (e.g., C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl) , and the other is hydrogen or deuterium. In certain embodiments, one of R⁷ and R⁸ is -CH₃ or -CD₃, and the other is hydrogen or deuterium. In some embodiments, one of R⁹ and R¹⁰ is hydrogen or deuterium, and the other is hydrogen or alkyl (e.g., C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl) optionally substituted with one or more deuterium. In certain embodiments, both R⁹ and R¹⁰ are hydrogen.

In some embodiments of the compound of Formula (I) , X is -C (R^eR^f) -, and R^e and R^f together with the carbon atom to which they are attached formIn some embodiments, each R” is independently selected from hydrogen or halogen. In some embodiments, one R” is halogen, the other is hydrogen. In some embodiments, both R” are halogen, such as fluoro.

In some embodiments of the compound of Formula (I) , both R⁵ and R⁶ are hydrogen.

In some embodiments of the compound of Formula (I) , one of R⁷ and R⁸ is alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R⁷ and R⁸ is C_1-6 alkyl, C_1-6 alkoxy, - (C_1-6 alkyl) - (C_1-6 alkoxy) or C_1-6 haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R⁷ and R⁸ is -CH₃, -CD₃, -CH₂-OCH₃, -CH₂-OCD₃, -CH₂F, -CHF₂ or -CF₃, and the other is hydrogen or deuterium.

In some embodiments of the compound of Formula (I) , one of R⁷ and R⁸ is alkyl optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R⁷ and R⁸ is C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each substituted with one or more deuterium, and the other is hydrogen.

In some embodiments of the compound of Formula (I) , one of R⁷ and R⁸ is -CH₃ or -CD₃, and the other is hydrogen or deuterium.

In some embodiments of the compound of Formula (I) , one of R⁹ and R¹⁰ is hydrogen or deuterium, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen, C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen, methyl or CD₃. In certain embodiments, both R⁹ and R¹⁰ are hydrogen.

In some embodiments of the compound of Formula (II) or Formula (III) , one of R¹¹ and R¹² is alkyl substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R¹¹ and R¹² is C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1- ₂ alkyl, each substituted with one or more deuterium, and the other is hydrogen. In certain embodiments, one of R¹¹ and R¹² is -CD₃, and the other is hydrogen.

In some embodiments of the compound of Formula (II) or Formula (III) , both R⁵ and R⁶ are hydrogen, one of R¹¹ and R¹² is alkyl substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R¹¹ and R¹² is C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each substituted with one or more deuterium, and the other is hydrogen. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R¹¹ and R¹² is -CD₃, and the other is hydrogen.

In some embodiments of the compound of Formula (II) or Formula (III) , one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen, C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen, methyl or CD₃. In certain embodiments, both of R¹³ and R¹⁴ are hydrogen.

In some embodiments of the compound of Formula (II) or Formula (III) , both R⁵ and R⁶ are hydrogen, one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen, C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1- ₃ alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen, methyl or CD₃. In certain embodiments, both R⁵ and R⁶ are hydrogen, and both of R¹³ and R¹⁴ are hydrogen.

In some embodiments of the compound of Formula (II) or Formula (III) , one of R^u and R^v is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, one of R^u and R^v is hydrogen, and the other is hydrogen, C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, one of R^u and R^v is hydrogen, and the other is hydrogen, methyl or CD₃.

In some embodiments of the compound of Formula (II) or Formula (III) , both R⁵ and R⁶ are hydrogen, one of R^u and R^v is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R^u and R^v is hydrogen, and the other is hydrogen, C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, both R⁵ and R⁶ are hydrogen, one of R^u and R^v is hydrogen, and the other is hydrogen, methyl or CD₃.

In some embodiments of the compound of Formula (II) or Formula (III) , Z is -C (R^jR^k) -, one of R^j and R^k is hydrogen, and the other is halogen. In certain embodiments, one of R^j and R^k is hydrogen, and the other is -F.

In some embodiments of the compound of Formula (II) or Formula (III) , Z is -C (R^jR^k) -, and R^j and R^k together with the carbon atom to which they are attached formIn some embodiments, one R” is halogen, the other is hydrogen. In some embodiments, both R” are halogen, such as fluoro.

In some embodiments of the compound of Formula (II) or Formula (III) , both R⁵ and R⁶ are hydrogen.

In some embodiments of the compound of Formula (II) or Formula (III) , one of R¹¹ and R¹² is alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R¹¹ and R¹² is C_1-6 alkyl, C_1-6 alkoxy, - (C_1-6 alkyl) - (C_1-6 alkoxy) or C_1-6 haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R¹¹ and R¹² is -CH₃, -CD₃, -CH₂-OCH₃, -CH₂-OCD₃, -CH₂F, -CHF₂ or -CF₃, and the other is hydrogen or deuterium.

In some embodiments of the compound of Formula (II) or Formula (III) , one of R¹¹ and R¹² is alkyl optionally substituted with one or more deuterium, and the other is hydrogen or deuterium. In certain embodiments, one of R¹¹ and R¹² is C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each substituted with one or more deuterium, and the other is hydrogen.

In some embodiments of the compound of Formula (II) or Formula (III) , one of R¹¹ and R¹² is -CH₃ or -CD₃, and the other is hydrogen or deuterium.

In some embodiments of the compound of Formula (II) or Formula (III) , one of R¹³ and R¹⁴ is hydrogen or deuterium, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen, C_1-6 alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl or C_1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen, methyl or CD₃. In certain embodiments, both of R¹³ and R¹⁴ are hydrogen.

In some embodiments of the compound of Formula (II) or Formula (III) , Z is -O-.

In a further aspect, the present disclosure provides a compound having a formula selected from:

or a pharmaceutically acceptable salt thereof,

wherein

provided that at least one of R⁷ and R⁹ is not hydrogen; and

provided that R¹¹ is alkyl substituted with one or more deuterium.

In some embodiments of the compound of Formula (I) , Formula (II) , Formula (III) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , Formula (If) , Formula (IIa) or Formula (IIb) , m is 1, 2, 3 or 4. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4.

In some embodiments of the compound of Formula (I) , Formula (II) , Formula (III) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , Formula (If) , Formula (IIa) or Formula (IIb) , each R is independently selected from cyano, halogen, hydroxyl, amino, haloalkyl, alkyl or alkynyl, wherein the alkyl or alkynyl are optionally substituted with one or more deuterium. In some embodiments, each R is independently selected from cyano, halogen, hydroxyl, amino, C_1-6 haloalkyl, C_1-5 haloalkyl, C_1-4 haloalkyl, C_1-3 haloalkyl, C_1-2 haloalkyl, C_1- ₆ alkyl, C_1-5 alkyl, C_1-4 alkyl, C_1-3 alkyl, C_1-2 alkyl, C_2-6 alkynyl, C_2-5 alkynyl, C_2-4 alkynyl, or C_2-3 alkynyl, wherein the alkyl or alkynyl are optionally substituted with one or more deuterium. In certain embodiments, each R is independently selected from fluoro, chloro, -NH₂, -CF₃, hydroxyl, ethyl or ethynyl, wherein the ethyl or ethynyl are optionally substituted with one or more deuterium.

In some embodiments of the compound of Formula (I) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , or Formula (If) , is selected from the group consisting of:

In some embodiments of the compound of Formula (II) or Formula (IIa) , is selected from the group consisting of

In some embodiments of the compound of Formula (III) or Formula (IIIa) , is selected from the group consisting of:

In some embodiments of the compound of Formula (I) , Formula (II) , Formula (III) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , Formula (If) , Formula (IIa) or Formula (IIb) , each R’ is independently hydrogen or deuterium.

In some embodiments of the compound of Formula (I) , Formula (II) , Formula (III) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , Formula (If) , Formula (IIa) or Formula (IIb) , each R’ is hydrogen.

In some embodiments of the compound of Formula (I) , Formula (II) , Formula (III) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , Formula (If) , Formula (IIa) or Formula (IIb) , each R’ is deuterium.

In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, exemplary compounds of the present disclosure are as set forth in Table 1 below:

Table 1. Exemplary compounds of the present disclosure

Compounds provided herein are described with reference to both generic formulae and specific compounds. In addition, the compounds of the present disclosure may exist in a number of different forms or derivatives, including but not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites) , and their pharmaceutically acceptable salts, all within the scope of the present disclosure.

As used herein, the term “prodrugs” refers to compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems” , Vol. 14 of the A. C. S. Symposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety.

As used herein, the term “soft drug” refers to compounds that exert a pharmacological effect but break down to inactive metabolites degradants so that the activity is of limited time. See, for example, “Soft drugs: Principles and methods for the design of safe drugs” , Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449-469, 1984, which is hereby incorporated by reference in its entirety.

As used herein, the term “metabolite” , e.g., active metabolite overlaps with prodrug as described above. Thus, such metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodrug. Of these, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compound is generally inactive or of lower activity than the metabolic product. For active metabolites, the parent compound may be either an active compound or may be an inactive prodrug.

Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem 40: 2011-2016; Shan et al., J Pharm Sci 86: 756-757; Bagshawe, 1995, DrugDev Res 34: 220-230; Wermuth, supra.

As used herein, the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.

As used herein, the term “pharmaceutically acceptable salt” , unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remington’s Pharmaceutical Sciences, 19^thed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

It is also to be understood that the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.

As used herein, the term “solvate” or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H₂O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

As used herein, the terms “crystal form” , “crystalline form” , “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to ¹H, ²H, ³H, ¹¹C, ¹²C, ¹³C, ¹⁴C, ¹⁴N, ¹⁵N, ¹⁶O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³²S, ³³S, ³⁴S, ³⁶S, ¹⁷F, ¹⁸F, ¹⁹F, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁴I, ¹²⁷I and ¹³¹I. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, carbon includes ¹²C and ¹³C. Isotopically-enriched compounds of Formula (I) , (II) , (III) , (Ia) , (Ib) , (Ic) , (Id) , (Ie) , (If) , (IIa) or (IIIa) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

In some embodiments, the present disclosure includes compounds of Formula (I) , (II) , (III) , (Ia) , (Ib) , (Ic) , (Id) , (Ie) , (If) , (IIa) or (IIIa) wherein one or more hydrogens attached to a carbon atom is/are replaced by deuterium. Such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

Those of skill in the art will appreciate that compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. By way of examples, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system. Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

SYNTHESIS OF COMPOUNDS

The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

Reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials (reactants) , intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by one skilled in the art.

Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley &Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G. M. Wuts, Greene's Protective Groups in Organic Synthesis, 5^th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. ¹H or ¹³C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) . Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) , 874-883, which is incorporated herein by reference in its entirety) , and normal phase silica chromatography.

USE OF COMPOUNDS

In an aspect, the present disclosure provides compounds capable of inhibiting KRAS protein. In some embodiments, the KRAS protein is selected from wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H protein. In certain embodiments, the KRAS protein is KRas G12D protein.

As used herein, the term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving beneficial or desired clinical results. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it. Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. The term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.

As used herein, the term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

The term “treatment” is used synonymously with “therapy” . Similarly, the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.

In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure for use in therapy, for example, for use in therapy associated with KRAS protein. In some embodiments, the therapy is associated with wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H protein. In certain embodiments, the therapy is associated with KRAS G12D protein.

In a further aspect, the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer.

In some embodiments, the cancer is mediated by KRAS protein. In some embodiments, the cancer is mediated by wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H protein. In certain embodiments, the cancer is mediated by KRAS G12D protein.

PHARMACEUTICAL COMPOSITIONS

In a further aspect, there is provided pharmaceutical compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.

As used herein, the term “pharmaceutical composition” refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject.

As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient. The term “pharmaceutically acceptable excipient” also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .

The particular excipient used will depend upon the means and purpose for which the compounds of the present disclosure is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.

In some embodiments, suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes) ; and/or non-ionic surfactants such as TWEEN^TM, PLURONICS^TM or polyethylene glycol (PEG) .

In some embodiments, suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) . The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) . A “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

The pharmaceutical compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.

A variety of routes are contemplated for the pharmaceutical compositions provided herein, and accordingly the pharmaceutical composition provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable as liquid dosage forms, and a powder suitable for reconstitution with an appropriate solution as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage form. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.

The quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved. As used herein, the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for oral administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) . The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for injection administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for inhalation administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.

Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21^st Edition, LWW (2005) , which are incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form. The amount of the compounds provided herein in the single dosage form will vary depending on the subject treated and particular mode of administration.

In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.001-1000 mg/kg body weight/day, for example, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body weight/day, 1-50 mg/kg body weight/day, 1-45 mg/kg body weight/day, 1-40 mg/kg body weight/day, 1-35 mg/kg body weight/day, 1-30 mg/kg body weight/day, 1-25 mg/kg body weight/day of the compounds provided herein, or a pharmaceutically acceptable salt thereof, can be administered. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosage regimes, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Accordingly, the pharmaceutical formulations of the present disclosure may also be formulated for controlled release or for slow release.

In a further aspect, there is also provided veterinary compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

The pharmaceutical compositions or veterinary compositions may be packaged in a variety of ways depending upon the method used for administering the drug. For example, an article for distribution can include a container having deposited therein the compositions in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

In a further aspect, there is also provided pharmaceutical compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient.

In some embodiments, the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.

METHOD OF TREATMENT OF DISEASE

In a further aspect, the present disclosure provides a method for treating cancer, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein to a subject in need thereof.

In some embodiments, the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for the treatment of a cancer associated with wild type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound provided herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof.

In some embodiments, the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein can be used to treat:

(i) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

(ii) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

(iii) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ;

(iv) Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ;

(v) Liver: hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

(vi) Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

(vii) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ;

(viii) Gynecological: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ;

(ix) Hematologic: blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ;

(x) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and

(xi) Adrenal glands: neuroblastoma.

In certain embodiments, the cancer that can be treated with the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

The concentration and route of administration to the subject will vary depending on the cancer to be treated. In certain embodiments, the administering is conducted via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.

The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

In some embodiments, the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts can be administered simultaneously, separately or sequentially with one or more additional therapeutic agents. In certain embodiments, the additional therapeutic agent is selected from an anti-PD-1 antagonist, an MEK inhibitor, a SHP2 inhibitor, a platinum agent or pemetrexed. In certain embodiments, the anti-PD-1 antagonist is selected from nivolumab, pembrolizumab, or AMB 404. In certain embodiments, the MEK inhibitor is trametinib. In certain embodiments, the SHP2 inhibitor is RMC-4630.

In another aspect, the present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising:

(a) acquiring the knowledge that the cancer is associated with wild type KRas or KRas G12D , KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H; and

(b) administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides a method for inhibiting wild type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H activity in a subject in need thereof, comprising administering the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.

EXAMPLES

For the purpose of illustration, the following examples are included. However, it is to be understood that these examples do not limit the present disclosure and are only meant to suggest a method of practicing the present disclosure.

Example A Synthesis of Compounds

Intermediate 1

tTert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylthio) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (Intermediate 1)

Step 1. tert-butyl (1S, 2S, 5R) -2- ( (S) -1- ( (7-chloro-8-fluoro-2- (methylthio) -4-oxo-3, 4-dihydropyrido [4, 3-d] pyrimidin-5-yl) oxy) ethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a flask containing tert-butyl (1S, 2S, 5R) -2- ( (S) -1-hydroxyethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.92 g, 3.57 mmol) in THF (20 mL) was added NaH (42.84 g, 10.71 mmol) followed by the addition of 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol (1.0 g, 3.57 mmol) at 0℃. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH₄Cl solution. The aqueous layer was extracted with EA (3×10 mL) . The combined organic layers were dried by Na₂SO₄, filtered and concentrated. The crude material was purified by prep-TLC eluting with DCM: MeOH=10: 1 to provide the title compound (1.6 g, 89.4%) as a white solid. LCMS: MS (ESI) m/z: 500 [M+H] ⁺

Step 2: tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylthio) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of tert-butyl (1R, 2S, 5S) -2- ( (S) -1- ( (7-chloro-8-fluoro-4-hydroxy-2-(methylthio) pyrido [4, 3-d] pyrimidin-5-yl) oxy) ethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.6 g, 3.29 mmol) in ACN (40 mL) were added PyBOP (3.43 g, 6.59 mmol) , TEA (1.37 mL, 9.88 mmol) , and the reaction was stirred at 80℃ for 1 hour. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the Intermediate 1 (1.2 g, 75.6%) . LCMS: (M+H) ⁺=482

Example 1

(5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (R) -2-methyl-3- ( (R) -3-methylmorpholino) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (Compound 1)

Step 1. (R) -2-methyl-3- ( (R) -3-methylmorpholino) propan-1-ol

To a solution of (S) -3-bromo-2-methylpropan-1-ol (300 mg, 1.9 mmol) in MeCN (6 mL) were added (R) -3-methylmorpholine (195 mg, 1.9 mmol) , K₂CO₃ (813 mg, 5.9 mmol) and KI (390 mg, 2.3 mmol) . The reaction mixture was stirred at 70℃ overnight. Then the mixture was concentrated under vacuum to obtain a residue, which was diluted with H₂O (5 ml) and extracted with EtOAc (10 ml x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated, the residue was purified by flash column chromatography (silica gel, 0 -10%MeOH in DCM) to givetitle product (118 mg, 35%yield) as a light yellow oil.

LC-MS (ESI) (m/z) : 174 [M+H] ⁺.

Step 2. tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylsulfonyl) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

At 0℃, to a solution of tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylthio) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (100 mg, 2.1 mmol) in DCM (5 mL) was added m-CPBA (71 mg, 4.1 mmol ) in portions. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by aq. NaHCO₃ (1 mL) , H₂O (5 mL) and extracted with DCM (5 mL x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated to dryness to give the title product (105 mg, 98%yield) as a yellow oil.

LC-MS (ESI) (m/z) : 514 [M+H] ⁺

Step 3. tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (R) -2-methyl-3- ( (R) -3-methylmorpholino) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a mixture of (R) -2-methyl-3- ( (R) -3-methylmorpholino) propan-1-ol (64 mg, 0.37 mmol) andMS (110 mg) in toluene (3 mL) was added t-BuONa (178 mg, 1.85 mmol) at 0℃, the resulting mixture was stirred at room temperature for 30 min before tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylsulfonyl) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (105 mg, 0.20 mmol) was added. After addition, the reaction was stirred at room temperature overnight. After removal of solvents, the residue was purified by silica gel column chromatography (EtOAc) to give the title compound (56mg, 43.1%yield) .

LC-MS (ESI) m/z: 607 [M+H] ⁺.

Step 4. tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8-( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (R) -2-methyl-3- ( (R) -3-methylmorpholino) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (R) -2-methyl-3- ( (R) -3-methylmorpholino) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (56 mg, 0.09 mmol) in THF (5 mL) and H₂O (1 mL) were added ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (63 mg, 0.14 mmol) , X-Phos Pd G₂ (7 mg, 0.009 mmol) , and K₃PO₄ (59 mg, 0.28 mmol) under N₂, and the reaction was stirred at 60℃ for 2 hours. After being cooled down to room temperature, the reaction was diluted with ice-water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 0 -10%MeOH in DCM) to give the title compound (45 mg, 54.2%yield) .

LC-MS (ESI) m/z: 897 [M+H] ⁺.

Step 5. (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (R) -2-methyl-3- ( (R) -3-methylmorpholino) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene

At 0℃, to a solution of tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8-( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (R) -2-methyl-3- ( (R) -3-methylmorpholino) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (45 mg, 0.05 mmol) and HMDS (20 mg, 0.12 mmol) in DCM (5 mL) was added TMSOTf (14 mg, 0.06 mmol) , the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with aq. Na₂CO₃ at 0℃ and then extracted with DCM twice. The combined organic layers were washed with water and brine, dried and concentrated to give the title product (38 mg, 95%yield) .

LC-MS ESI (m/z) : 797 [M+H] ⁺.

Step 6. (5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (R) -2-methyl-3- ( (R) -3-methylmorpholino) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene

To a solution of (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (R) -2-methyl-3- ( (R) -3-methylmorpholino) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (38 mg, 0.05 mmol) in DMF (5 mL) was added CsF (290 mg, 1.91 mmol) . The resulting mixture was stirred at 40℃ for 1 hour. The reaction was purified by prep-HPLC (chromatographic column: YMC-Actus Triart C18 150*20mm; mobile phase A: 0.1%NH₃ in water, mobile phase B: MeCN; gradient: 45%B to 95%B in 18 min; flow rate of 25 ml/min; Wave length : 220nm/254nm; Target Retention time: 10.5MIN (90%MECN) ) to provide the Compound 1 (8.5 mg, 30.5%yield) .

LC-MS (ESI) m/z: 641 [M+H] ⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.08 (t, J = 7.5 Hz, 2H) , 7.70 –7.52 (m, 2H) , 7.43 (q, J = 8.8 Hz, 1H) , 5.43 (d, J = 13.2 Hz, 1H) , 4.57 (dd, J = 15.4, 7.6 Hz, 2H) , 4.29 (dd, 1H) , 4.12 (d, J = 9.1 Hz, 1H) , 3.76 (dd, 2H) , 3.69 –3.55 (m, 3H) , 3.46 (d, J = 11.0 Hz, 1H) , 3.24 –3.09 (m, 2H) , 3.02 –2.82 (m, 2H) , 2.49 –2.35 (m, 1H) , 2.34 –2.21 (m, 2H) , 2.18 –2.02 (m, 2H) , 1.94 –1.76 (m, 3H) , 1.58 (t, J = 6.8 Hz, 3H) , 1.09 (dd, J = 6.7, 2.0 Hz, 3H) , 0.97 (d, J = 6.0 Hz, 3H) .

Example 26

(8S, 8aS, 9S, 12R) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-8-methyl-2- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene (Compound 26)

Step1: methyl (S) -1- (3-methylmorpholine-4-carbonyl) cyclopropane-1-carboxylate

To a mixture of 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (1 g, 6.9 mmol) in DCM (10 mL) was added DMF (0.15 mL, 0.93 mmol) . The mixture was cooled to 0℃ and then oxalyl chloride (0.89 mL, 10.4 mmol) was added drop-wisely at 0℃. The reaction mixture was stirred at room temperature for 1 hour. Then the mixture was concentrated under vacuum to obtain a residue. A solution of the residue dissolved in DCM (5 ml) was added dropwise to a solution of (S) -3-methylmorpholine (0.8 mL, 9.7 mmol) and TEA (2.9 mL, 20.8 mmol) in DCM (10 mL) at 0℃ under N₂. The mixture was stirred at room temperature for 1 hour. Then the mixture was quenched with H₂O (5 ml) , extracted with DCM (5 ml x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash chromatography (silica gel, 0 -30%EtOAc in PE) to give the title product (720 mg, 48%yield) as a yellow oil. MS (ESI) (m/z) : 228 [M+H] +.

Step 2: (S) - (1- ( (3-methylmorpholino) methyl) cyclopropyl) methanol

To a solution of methyl (S) -1- (3-methylmorpholine-4-carbonyl) cyclopropane-1-carboxylate (600 mg, 2.6 mmol) in THF (5 mL) was added LiAlH₄ (5.3 mL, 5.3 mmol, 1 M in THF) drop-wisely at 0℃ under N₂. The mixture was stirred at room temperature for 1 hour. Then the mixture was quenched by H₂O (0.1 ml) , aq. NaOH (0.1 ml, 15%wt) and H₂O (0.5 ml) . The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 ～ 10%MeOH in DCM) to give the title product (360 mg, 74%yield) as a yellow oil. LC-MS (ESI) (m/z) : 186 [M+H] ⁺.

Step 3: tert-butyl (8S, 8aS, 9S, 12R) -5-chloro-4-fluoro-8-methyl-2- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (100 mg, 1.9 mmol) and (S) - (1- ( (3-methylmorpholino) methyl) cyclopropyl) methanol (73 mg, 3.9 mmol) in toluene (5 ml ) was addedMS and stirred at room temperature for 30 mins. Then sodium 2-methylpropan-2-olate (98 mg, 9.5 mmol) was added to the reaction mixture at 0℃ and stirred at room temperature for 1 h. The mixture was diluted with water (10 ml) and extracted with EtOAc (10 ml x 3) . The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30%EtOAc in PE) to give the title product (80 mg, 67%yield) as a yellow oil. MS (ESI) (m/z) : 619 [M+H] ⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.14 –8.02 (m, 2H) , 7.68 –7.53 (m, 2H) , 7.49 –7.36 (m, 1H) , 4.94 (s, 2H) , 4.66 –4.52 (m, 1H) , 4.51 –4.40 (m, 1H) , 4.14-4.10 (m, 1H) , 3.75-3.72 (m, 1H) , 3.70 –3.57 (m, 2H) , 3.49 –3.41 (m, 1H) , 3.26-3.23 (m, 1H) , 3.21 –3.06 (m, 4H) , 3.03 –2.90 (m, 2H) , 2.83-2.81 (m, 1H) , 2.64 –2.42 (m, 2H) , 2.12 –1.99 (m, 1H) , 1.98 –1.89 (m, 2H) , 1.89 –1.77 (m, 2H) , 1.61-1.58 (m, 1H) .

Step 4. tert-butyl (5S, 5aS, 6S, 9R) -2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) - 5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of tert-butyl (8S, 8aS, 9S, 12R) -5-chloro-4-fluoro-8-methyl-2- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (60 mg, 1.0 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL) were added X-Phos Pd G₂ (19.1 mg, 0.25 mmol) , tripotassium phosphate (61.2 mg, 3.0 mmol) and ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (52.6 mg, 1.2 mmol) . The mixture was stirred at 60℃ for 1 hour. Then the mixture was quenched with H₂O (2 ml) and extracted with DCM (2 ml x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash chromatography (silica gel, 0 -10%MeOH in DCM) to give the title product (50 mg, 56.7%yield ) as a yellow oil. LC-MS (ESI) (m/z) : 909 [M+H] ⁺.

Step 5. (8S, 8aS, 9S, 12R) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-methyl-2- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene

To a solution of tert-butyl (8S, 8aS, 9S, 12R) -4-fluoro-5- (7-fluoro-8-( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-methyl-2- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (50 mg, 0.06 mmol) in DCM (2 mL) were add HMDS (0.2 mL) and TMSOTf (0.2 mL) at 0℃. The mixture was stirred at room temperature for 1 hour. Then the mixture was quenched with H₂O (2 mL) and extracted with DCM (2 mL x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated without further purification to give the title product (50 mg crude) as a yellow solid. MS (ESI) (m/z) : 809 [M+H] ⁺.

Step 6. (8S, 8aS, 9S, 12R) -5- (8-ethynyl-7-fluoronaphthalen-1-yl) -4-fluoro-8-methyl-2- ( (1-( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene

To a solution of (8S, 8aS, 9S, 12R) -4-fluoro-5- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -8-methyl-2- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene (50 mg, 0.06 mmol) in DMF (1 mL) was added CsF (188 mg, 1.1 mmol) and stirred at room temperature for 1 hour. Then the mixture was filtered and purified by pre-HPLC to give the Compound 26 (16.9 mg, 41%yield) .

LC-MS (ESI) (m/z) : 653 [M+H] ⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.12-8.04 (m, 2H) , 7.67-7.53 (m, 2H) , 7.42 (m, 1H) , 5.38 (m, 1H) , 4.75 (m, 1H) , 4.53 (m, 1H) , 4.10-3.99 (m, 2H) , 3.77-3.46 (m, 6H) , 3.41 (dd, J =12.8, 7.6 Hz, 1H) , 3.21-3.12 (m, 2H) , 3.07 (dd, J = 12.0, 2.7 Hz, 1H) , 2.37 (dd, J = 8.8, 6.1 Hz, 1H) , 2.22 (t, J = 10.7 Hz, 1H) , 2.16 –2.07 (m, 1H) , 1.84 (m, 3H) , 1.65 (d, J = 12.8 Hz, 1H) , 1.57 (dd, J = 8.0, 6.5 Hz, 3H) , 0.93 (d, J = 6.2 Hz, 3H) , 0.77-0.70 (m, 1H) , 0.67-0.55 (m, 2H) , 0.41 (s, 1H) .

Example 27 and Example 28

(5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (R) -3-(methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (Compound 27) and (5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (Compound 28)

Step 1.2- (2-chloroethoxy) acetaldehyde

To a solution of (COCl) ₂ (18.34 g, 144.509 mmol) in anhydrous CH₂Cl₂ (150 mL) was added DMSO (18.82 g, 240.848 mmol) at -78℃ under N₂. After being stirred for 30 min, a solution of 2- (2-chloroethoxy) ethan-1-ol (15.0 g, 120.4 mmol) in anhydrous CH₂Cl₂ (150 mL) was added dropwise. The mixture was stirred at -78℃ for 30 min～45 min and then Et₃N (83.7 mL, 602.1mmol) was added dropwise. After being stirred at -78℃ for 30 min, the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was acidified with 2N aqueous HCl solution to pH=5～6 and then extracted with CH₂Cl₂. The combined organic layers were dried over anhydrous MgSO₄, filtered to afford crude product as a colorless solution in DCM (200 mL) which was used for the next step directly without further purification.

Step 2. (R) -N- (2- (2-chloroethoxy) ethylidene) -2-methylpropane-2-sulfinamide

Anhydrous copper sulfate (38.58 g, 241.730 mmol) was suspended in a solution of (R) -2-methylpropane-2-sulfinamide (10.37 g, 85.581 mmol) and 2- (2-chloroethoxy) acetaldehyde (9.2 g, 75.071 mmol) in dichloromethane (100 mL) . The mixture was stirred at room temperature for 16 hours, filtered through a pad of Celite. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel to give the title product (4.85 g, 28.6%) as colorless oil.

LC/MS (ESI) (m/z) : 226 [M+H] ⁺.

Step 3. (R) -N- (1- (2-chloroethoxy) propan-2-yl-3, 3, 3-d3) -2-methylpropane-2-sulfinamide

Deuterated methyl magnesium iodide (66.5 mL, 66.45 mmol, 1M in Et₂O) was added under N₂ to a stirred solution of (R) -N- (2- (2-chloroethoxy) ethylidene) -2-methylpropane-2-sulfinamide (10 g, 44.3 mmol) in anhydrous toluene (150 mL) at -78℃. The reaction mixture was stirred at -78℃ for 1～2 h. TLC and LCMS showed the reaction was over, the reaction was quenched by sat. NH₄Cl (aq. ) at -78℃. Then the mixture was extracted twice with EtOAc (100 mL) . The combined organic phase was washed with a sat. NaCl (aq. ) , dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by flash chromatography (silica, hexane/EtOAc, gradient: 0%to 75%EtOAc) to afford the title product (8.0 g, 73.8%) as a yellow oil.

LC/MS (ESI) (m/z) : 245 [M+H] ⁺.

Step 4.4- ( (R) -tert-butylsulfinyl) -3- (methyl-d3) morpholine

60 %w/w NaH in mineral oil (1.44 g, 35.9 mmol, 60%in oil) was added to the solution of (R) -N- (1- (2-chloroethoxy) propan-2-yl-3, 3, 3-d3) -2-methylpropane-2-sulfinamide (2.93 g, 12.0 mmol) and 18-crown-6 (1.58 g, 5.99mmol) in anhydrous THF (50 mL) at 0℃ under N₂. The mixture was stirred at room temperature for 2 hours. TLC and LCMS showed the reaction was completed, the mixture was quenched with ice water and extracted with Et₂O. The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. Purification of the residue by column chromatography to afford the title product (1.8 g, 72.3%) as a white solid.

LC/MS (ESI) (m/z) : 209 [M+H] ⁺.

Step 5.3- (methyl-d3) morpholine

To a solution of 4- ( (R) -tert-butylsulfinyl) -3- (methyl-d3) morpholine (200 mg, 0.96 mmol) in DCM (1 mL) were added HCl/dioxane (5 mL, 4 mol/L) , and the reaction was stirred at room temperature for 1 hour. Then reaction was concentrated to afford the title product (100 mg) as a yellow solid which was used for next step directly.

LC/MS (ESI) (m/z) : 105 [M+H] ⁺.

Step 6. methyl 1- (3- (methyl-d3) morpholine-4-carbonyl) cyclopropane-1-carboxylate

Cyclopropane-1, 1-dicarboxylate methyl ester (200 mg, 1.4 mmol) was dissolved in dichloromethane (10 mL) , cooled to 0℃. N, N-dimethylformamide (1 drop) and oxalyl chloride (0.22 g, 1.8 mmol) were added. After stirring the reaction at room temperature for 1 hour, the reaction solution was concentrated to dryness. The residue was diluted with dichloromethane (10 mL) , and the resulting solution was added dropwise to a solution of 3- (methyl-d3) morpholine (100 mg, 1 mmol) and Et₃N (200 mg, 2 mmol) at 0℃. The reaction mixture was stirred at room temperature for 16 hours and concentrated to afford a reside. The residue was purified by silica gel column chromatography to afford the title product (150 mg, 67.9%) .

LC/MS (ESI) (m/z) : 231 [M+H] ⁺.

Step 7. (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methanol

The solution of Methyl 1- (3- (methyl-d3) morpholine-4-carbonyl) cyclopropane-1-carboxylate (150 mg, 9.8 mmol ) in 20 mL THF was cooled to 0℃. Lithium aluminum hydride THF solution (20 mL, 1 M) was slowly added under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 3 hours. Sodium sulfate decahydrate (500 mg) was added to the reaction mixture in portions at 0℃ to give a white suspension. Ethyl acetate (25 mL) was added, and the suspension was stirred for about 18 hours at room temperature. The resulting suspension was filtered and washed with diethyl ether. The combined filtrates were concentrated to obtain crude product (120 mg) which was used for the next step directly without further purification.

LC/MS (ESI) (m/z) : 189 [M+H] ⁺.

Step 8. tert-butyl (8S, 8aS, 9S, 12R) -5-chloro-4-fluoro-8-methyl-2- ( (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methanol (165 mg, 0.58 mmol) in toluene (5 mL) were added sodium tert-butoxide (375 mg, 3.9 mmol) andMolecular Sieves (100 mg) . The mixture was stirred at room temperature for 20min, then the solution of tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylsulfonyl) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (200 mg, 0.39 mmol) in toluene (5mL) was added in dropwise, and stirred at room temperature for 2 hours under N₂. The mixture was filtered, and the filtrate was concentrated. The residue was loaded on a silica gel plate. The plate was eluted with EA: PE=1: 1 to afford tert-butyl the title product (120 mg, 50%yield) as a white solid.

MS (ESI) m/z: 622 [M+H] ⁺.

Step 9. tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8-( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of tert-butyl (8S, 8aS, 9S, 12R) -5-chloro-4-fluoro-8-methyl-2- ( (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (120 mg, 0.19 mmol) and ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl)ethynyl) triisopropylsilane (175 mg, 0.38 mmol) in THF (2 mL) and water (0.4 mL) was added K₃PO₄ (121 mg, 0.57 mmol) , followed by cataCXium (R) A Pd G₃ (29 mg, 0.04 mmol) . The mixture was refluxed at 80℃ for 1.5 hours under N₂ atmosphere. The reaction mixture was concentrated in vacuum. The crude product was chromatographed on silica gel (DCM /MeOH 10/1) to give the title product (100 mg , 56.8%yield) as a white solid.

MS (ESI) m/z: 912 [M+H] ⁺.

Step 10. (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (100 mg, 0.11 mmol) in DCM (3 mL) was added HMDS (0.2 mL) and TMSOTf (0.1 mL) at 0℃ and the reaction was stirred at room temperature for 1 hour. The reaction was added sat. NaHCO₃, extracted with DCM, dried and concentrated in vacuo to afford the title product (80 mg, 90%yield) without further purification.

LC/MS ESI (m/z) : 812 [M+H] ⁺

Step 11. (5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene

To a flask containing (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (80 mg, 0.1 mmol) was added N,N-dimethylmethanamide (3 mL) followed by the addition of CsF (608 mg, 4 mmol) . The mixture was stirred at 40℃ for 2 hours under N₂. The mixture was filtered and the filtrate was purified by prep-HPLC (chromatographic column: YMC-Actus Triart , 50*250 mm, 7 um; mobile phase A: 0.1%NH₃ in water, mobile phase B: CH₃CN; gradient: 35%B to 95%B in 30 min; flow rate of 25 mL/min; ultraviolet wavelength: 220/254 nm) to provide crude product (60 mg, 95%yield) as a white solid.

LC/MS (ESI) m/z: 656 [M+H] ⁺.

The crude product (60 mg) was further purified by chiral preparation (Preparative separation method: Instrument: Shimadzu LC-20AT; Coumn: CHIRALCEL OD-H (ODH0CE-KJ063) , 0.46 cm I. D. × 25 cm L; Mobile Phase A: MeCN, Mobile Phase B: MEOH+0.1%MEA) ; Flow rate: 1.0 mL/min; Gradient: isocratic 30%B; Column Temperature (℃) : 35; Wave Length: 214 nm) to get Compound 28 (19 mg, retention time: 5.01 min) and Compound 27 (22 mg, retention time: 5.93 min) respectively.

Compound 27:

¹H NMR (400 MHz, CD₃OD) δ 8.16 –8.01 (m, 2H) , 7.68 –7.53 (m, 2H) , 7.45 (m, 1H) , 5.50 (d, J = 12.3 Hz, 1H) , 4.73 –4.53 (m, 3H) , 4.21 (t, J = 16.5 Hz, 2H) , 3.99 (d, J = 43.1 Hz, 2H) , 3.82 (s, 1H) , 3.78 –3.43 (m, 4H) , 3.17 –2.99 (m, 2H) , 2.27 –2.18 (m, 1H) , 2.14 –1.89 (m, 4H) , 1.60 (t, J = 6.8 Hz, 3H) , 1.30 (t, J = 7.3 Hz, 3H) , 0.77 (d, J = 42.3 Hz, 3H) , 0.53 (s, 1H) .

LC/MS (ESI) m/z: 656 [M+H] ⁺.

Compound 28:

¹H NMR (400 MHz, CD₃OD) δ 8.13 –8.06 (m, 2H) , 7.66 –7.64 (m, 1H) , 7.59 (m, 7.3 Hz, 1H) , 7.44 (m, 1H) , 5.48 (d, J = 13.6 Hz, 1H) , 4.74 –4.55 (m, 3H) , 4.23 (d, J = 8.5 Hz, 1H) , 4.21 –4.10 (m, 1H) , 4.04 (s, 1H) , 3.93 (s, 1H) , 3.76 (m, 4H) , 3.46 (d, J = 11.7 Hz, 1H) , 3.04 (m, 2H) , 2.25 (s, 1H) , 2.12 –1.84 (m, 4H) , 1.63 –1.57 (m, 3H) , 1.30 (t, J = 7.3 Hz, 3H) , 0.78 (d, J = 45.9 Hz, 3H) , 0.53 (s, 1H) .

LC/MS (ESI) m/z: 656 [M+H] ⁺.

Example 30

5-ethyl-6-fluoro-4- ( (5S, 5aS, 6S, 9R) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalen-2-yl) naphthalen-2-ol (Compound 30)

Step1: tert-butyl (5S, 5aS, 6S, 9R) -2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of tert-butyl (8S, 8aS, 9S, 12R) -5-chloro-4-fluoro-8-methyl-2- ( (1- (morpholinomethyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (65 mg, 1.05 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL) were added X-Phos Pd G2 (20.1 mg, 0.25 mmol) , tripotassium phosphate (66.8 mg, 3.15 mmol) and 2- (8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (45.4 mg, 1.26 mmol) . The mixture was stirred at 60℃ for 1 h. Then the mixture was quenched with H₂O (5 ml) and extracted with DCM (5 ml x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash chromatography (silica gel, 0 -10%MeOH in DCM) to give tert-butyl (5S, 5aS, 6S, 9R) -2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (50 mg, 58.3%yield ) as a yellow oil. MS (ESI) (m/z) : 817 [M+H] ⁺.

Step 2: 5-ethyl-6-fluoro-4- ( (5S, 5aS, 6S, 9R) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalen-2-yl) naphthalen-2-ol

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -2- (8-ethyl-7-fluoro-3-(methoxymethoxy) naphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (50 mg, 0.06 mmol) in dry DCM (2 mL) was added TFA (1 mL) and stirred at room temperature for 1 hour. Then the mixture was quenched with H₂O (2 mL) and extracted with DCM (2 mL x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered and purified by pre-HPLC to give the Compound 30 (3.5 mg, 8.5%yield) .

LC/MS (ESI) m/z: 673 [M+H] ⁺.

¹H NMR (400 MHz, CD₃OD) δ 7.69 –7.62 (m, 1H) , 7.28 (t, J = 2.7 Hz, 1H) , 7.23 (dd, J = 13.2, 5.3 Hz, 1H) , 7.03 (dd, J = 52.9, 2.6 Hz, 1H) , 4.71 –4.63 (m, 2H) , 4.21 (dd, J = 19.9, 9.7 Hz, 2H) , 4.00 (s, 1H) , 3.87 (dd, J = 10.8, 5.9 Hz, 2H) , 3.82 –3.77 (m, 1H) , 3.70 (dd, J =20.8, 11.1 Hz, 3H) , 3.23 –3.18 (m, 2H) , 2.45 (s, 2H) , 2.24 –2.15 (m, 2H) , 1.98 (dd, J = 26.7, 7.2 Hz, 3H) , 1.58 (d, J = 6.3 Hz, 3H) , 1.31 (d, J = 17.9 Hz, 4H) , 1.03 (d, J = 5.5 Hz, 3H) , 0.98 –0.88 (m, 2H) , 0.80 (d, J = 7.3 Hz, 2H) , 0.70 (s, 2H) .

Example 38

(5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (Compound 38)

Step 1. methyl (S) -1- (2-methylpiperidine-1-carbonyl) cyclopropane-1-carboxylate.

To a solution of 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (280 mg, 1.9 mmol) in DCM (5 mL) was added oxalyl dichloride (493 mg, 3.9 mmol) and catalytic amount of DMF at 0℃. The mixture was stirred at 25℃ for 1 hour. The reaction was concentrated. The solution of the residue dissolved in DCM (5 mL) was added dropwise to a solution of (S) -2-methylpiperidine (289 mg, 2.9 mmol) and Et₃N (589 mg, 5.8 mmol) in DCM (5 mL) at 0℃. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with DCM (5 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluted with PE/EtOAc (9: 1～4: 1) to give the title product (350 mg, 80%yield) as a yellow oil.

LCMS (ESI) (m/z) : 226 [M+H] ⁺.

Step 2. (S) - (1- ( (2-methylpiperidin-1-yl) methyl) cyclopropyl) methanol.

To a solution of methyl (S) -1- (2-methylpiperidine-1-carbonyl) cyclopropane-1-carboxylate (350 mg, 1.55 mmol) in THF (10 mL) was added LiAlH₄ (118 mg, 3.1 mmol) at 0℃ under N₂. The mixture was stirred at 0℃ for 1 hour. The reaction mixture was quenched with aq. NaOH (15%wt) (0.6 mL) at 0℃. After stirring at 0℃ for 15 mins, the mixture was filtered through a celite pad, and the filtrate was concentrated to give the title product (250 mg, 87%yield) as a yellow oil.

LCMS (ESI) (m/z) : 184 [M+H] ⁺.

Step 3. tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate.

To a solution of (S) - (1- ( (2-methylpiperidin-1-yl) methyl) cyclopropyl) methanol (78 mg, 0.4 mmol) in toluene (5 mL) was added sodium tert-butoxide (617 mg, 6.4 mmol) and molecular sieves (600 mg) , the reaction was stirred at room temperature for 10 mins. Then a solution of tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylsulfonyl) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (110 mg, 0.2 mmol) in toluene (0.5 mL) was added and the mixture was stirred at room temperature for 20 mins. The reaction was filtered immediately and the filtrate was concentrated. The residue was purified by prep-HPLC (DCM/MeOH =15: 1) to give the title product (70 mg, 53%yield) as a yellow oil.

LCMS (ESI) (m/z) : 617 [M+H] ⁺.

Step 4. tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate.

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (70 mg, 0.14 mmol) in THF/water (5 mL/1 mL) were added ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (92 mg, 0.21 mmol) , X-Phos Pd G₂ (24 mg, 0.03 mmol) and K₃PO₄ (86 mg, 0.41 mmol) . The mixture was stirred at 60℃ for 2 hours under N₂. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x3) . The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by prep-TLC (DCM/MeOH = 15: 1) to give the title product (60 mg, 49%yield) as a yellow solid.

LCMS (ESI) (m/z) : 907 [M+H] ⁺.

Step 5. (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) - 5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene.

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (60 mg, 0.07 mmol) in DCM (2 mL) was added HMDS (0.2 mL) and TMSOTF (0.1 mL) at 0℃ under N₂, the mixture was stirred at 0℃ for 30 mins. The mixture poured into sat. NaHCO₃ (10 mL) and extracted with DCM (5 mL x3) . The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated to give the title product (50 mg, 94%yield) as a yellow solid.

LCMS (ESI) (m/z) : 807 [M+H] ⁺

Step 6. (5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene.

To a solution of (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (40 mg, 0.05 mmol) in DMF (1.5 mL) was added caesium fluoride (301 mg, 1.98 mmol) and the mixture was stirred at room temperature for 30 mins. The mixture was purified by prep-HPLC (chromatographic column: YMC-Actus Triart C18 150*20mm; mobile phase A: 0.1%NH₃ in water, mobile phase B: MeCN; gradient: 20%B to 95%B in 18 min; flow rate of 25 ml/min; Wave length : 220nm/254nm; Target Retention time: 9MIN (75%MECN) ) to give the Compound 38 (5.5 mg, 17%yield) .

LC/MS (ESI) (m/z) : 651 [M+H] ⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.08 (m, 2H) , 7.69 –7.53 (m, 2H) , 7.42 (m, 1H) , 5.43 –5.34 (m, 1H) , 4.71 –4.63 (m, 2H) , 4.53 (m, 2H) , 4.16 –4.05 (m, 2H) , 3.77 –3.46 (m, 3H) , 3.22 –3.08 (m, 2H) , 2.31 (s, 1H) , 2.15 (m, 7.3 Hz, 2H) , 1.91 –1.74 (m, 4H) , 1.57 (m, 8H) , 1.05 (d, J = 6.0 Hz, 3H) , 0.67 (m, 2H) , 0.51 (d, J = 56.0 Hz, 2H) .

Example 86

(5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-12- ( (1- ( ( (R) -3-fluoropyrrolidin-1-yl) methyl) cyclopropyl) methoxy) -5-methyl-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (Compound 86)

Step 1. (S) -2-methyl-3-morpholinopropan-1-ol

To a mixture of (R) -3-bromo-2-methylpropan-1-ol (1 g, 6.5 mmol) in MeCN (10 mL) was added K₂CO₃ (2.72 g, 19.7 mmol) , KI (1.3 g, 7.9 mmol) and morpholine (0.68 g, 7.9 mmol) . The reaction mixture was stirred at 80℃ overnight. Then the mixture was filtered. The filtrate was concentrated and purified by flash chromatography (silica gel, EtOAc: PE = 1: 1) to give the title product (840 mg, 80 %yield) as a colorless oil. LC-MS (ESI) (m/z) : 160 [M+H] ⁺.

Step 2. tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (S) -2-methyl-3-morpholinopropoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a three-necked flask addedmolecular sieve and sodium (S) - (1- ( (3-methylmorpholino) methyl) cyclopropyl) methanol (121 mg, 4 mmol) , the mixture was heated to keep dry and added (S) -2-methyl-3-morpholinopropan-1-ol (80 mg, 10 mmol) in dry toluene (5 mL) at 0℃. After stirred at 0℃ for 20 minutes, and dropwise tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylsulfonyl) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (100 mg, 2.0 mmol) in dry toluene (5 mL) . The resulting mixture was stirred at room temperature for 30 minutes. LCMS showed the reaction was complete. The mixture was quenched with H₂O (5 mL) and extracted with DCM (5 mL x 3) . The organic layer was dried over Na₂SO₄, filtered and concentrated under vacuum. The resulting crude material was purified by flash chromatography (silica gel, DCM: MeOH =20: 1) to afford the desired product (70 mg, 60.8 %yield) as a yellow oil.

LC-MS (ESI) (m/z) : 593 [M+H] ⁺.

Step 3. tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (S) -2-methyl-3-morpholinopropoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (S) -2-methyl-3-morpholinopropoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (70 mg, 1.2 mmol) in tetrahydrofuran (4 mL) and water (0.8 mL) were added X-Phos Pd G₂ (16.7 mg, 0.3 mmol) , tripotassium phosphate (53.6 mg, 3.6 mmol) and ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)naphthalen-1-yl) ethynyl) triisopropylsilane (46 mg, 2.4 mmol) . The mixture was stirred at 60℃ for 1 hour. Then the mixture was quenched with H₂O (4 mL) and extracted with DCM (4 mL x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash chromatography (silica gel, DCM: MeOH =20: 1) to give the title product (60 mg, 57.6%yield ) as a yellow oil.

LC-MS (ESI) (m/z) : 883 [M+H] ⁺.

Step 4. (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (S) -2-methyl-3-morpholinopropoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (S) -2-methyl-3-morpholinopropoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (60 mg, 0.068 mmol) in DCM (2 mL) were add HMDS (0.2 mL) and TMSOTf (0.1 mL) at 0℃. The mixture was stirred at room temperature for 1 hour. Then the mixture was quenched with H₂O (2 ml) and extracted with DCM (2 ml x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated without further purification to give the title product (60 mg crude) as a yellow solid.

LC-MS (ESI) (m/z) : 783 [M+H] ⁺.

Step 5. (5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (S) -2-methyl-3-morpholinopropoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene

To a solution of (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (S) -2-methyl-3-morpholinopropoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (60 mg, 0.076 mmol) in DMF (1 mL) was added CsF (282 mg, 27.6 mmol) and stirred at room temperature for 1 hour. Then the mixture was filtered and purified by pre-HPLC to give the Compound 86 (21.4 mg, 44.6%yield) .

LC-MS (ESI) (m/z) : 627 [M+H] ⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.08 (q, J = 6.5 Hz, 2H) , 7.66 –7.53 (m, 2H) , 7.43 (q, J = 8.9 Hz, 1H) , 5.39 (d, J = 13.5 Hz, 1H) , 4.55 (dd, J = 12.6, 8.0 Hz, 2H) , 4.29 (dd, J = 18.9, 8.3 Hz, 1H) , 4.09 (d, J = 9.1 Hz, 1H) , 3.64 (d, J = 26.3 Hz, 6H) , 3.48 (s, 1H) , 3.17 (d, J = 11.2 Hz, 1H) , 2.47 (d, J = 16.1 Hz, 5H) , 2.27 (d, J = 8.0 Hz, 2H) , 2.08 (s, 1H) , 1.82 (d, J = 20.5 Hz, 3H) , 1.58 (t, J = 7.1 Hz, 3H) , 1.09 (dd, J = 6.1, 3.4 Hz, 3H) .

Example 87

(5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (R) -2-methyl-3- (piperidin-1-yl) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (Compound 87)

Step 1. (R) -2-methyl-3- (piperidin-1-yl) propan-1-ol

To a mixture of (S) -3-bromo-2-methylpropan-1-ol (300 mg, 1.9 mmol) in MeCN (6 mL) were added piperidine (217 mg, 2.6 mmol) , K₂CO₃ (813 mg, 5.9 mmol) and NaI (353 mg, 2.4 mmol) . The reaction mixture was stirred at 70℃ overnight. Then the mixture was concentrated under vacuum to obtain a residue, which was diluted with H₂O (5 mL) , extracted with EtOAc (10 mL x 3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash column chromatography (silica gel, 0 -10%MeOH in DCM) to give the title product (243 mg, 79%yield) as a light yellow oil.

LC-MS (ESI) (m/z) : 158 [M+H] ⁺.

Step 2. tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (R) -2-methyl-3- (piperidin-1-yl) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a mixture of (R) -2-methyl-3- (piperidin-1-yl) propan-1-ol (46 mg, 0.3 mmol) and MS (80 mg) in toluene (3 mL) was added t-BuONa (141 mg, 1.47 mmol) at 0℃, the resulting mixture was stirred at room temperature for 30 min before tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylsulfonyl) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (100 mg, 0.19 mmol) was added. The reaction was stirred at room temperature overnight. After removal of solvents, the residue was purified by silica gel column chromatography (EtOAc) to give the title compound (52 mg, 30.1%yield) .

LC-MS (ESI) m/z: 591 [M+H] ⁺.

Step 3. tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (R) -2-methyl-3- (piperidin-1-yl) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (R) -2-methyl-3- (piperidin-1-yl) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (52 mg, 0.09 mmol) in THF (5 mL) and H₂O (1 mL) were added ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)naphthalen-1-yl) ethynyl) triisopropylsilane (42 mg, 0.09 mmol) , X-Phos Pd G₂ (7 mg, 0.009 mmol) , and K₃PO₄ (54 mg, 0.25 mmol) under N₂, and the reaction was stirred at 60℃ for 2 hours. The reaction was diluted with ice-water and then extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH=20: 1) to give the title compound (40 mg, 66.7%yield) .

LC-MS (ESI) m/z: 881 [M+H] ⁺.

Step 4. (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (R) -2-methyl-3- (piperidin-1-yl) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene

To a solution of tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (R) -2-methyl-3- (piperidin-1-yl) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate (40 mg, 0.04 mmol) and HMDS (20 mg, 0.12 mmol) in DCM (5 mL) was added TMSOTf (14 mg, 0.06 mmol) at 0℃, the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with aq. Na₂CO₃ at 0℃ and then extracted with DCM twice. The combined organic layers were washed with water and brine, dried and concentrated to give the title product (35 mg, 98%yield) .

LC-MS ESI (m/z) : 781 [M+H] ⁺.

Step 5. (5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (R) -2-methyl-3- (piperidin-1-yl) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene

To a solution of (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (R) -2-methyl-3- (piperidin-1-yl) propoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene (35 mg, 0.04 mmol) in DMF (5 mL) was added CsF (234 mg, 1.54 mmol) . The mixture was stirred at 40℃ for 1 hour. The reaction was purified by prep-HPLC (chromatographic column: YMC-Actus Triart C18 150*20mm; mobile phase A: 0.1%NH₃ in water, mobile phase B: MeCN; gradient: 35%B to 95%B in 18 min; flow rate of 25 ml/min; Wave length : 220nm/254nm; Target Retention time: 13MIN (85%MECN) ) to provide the Compound 87 (6.2 mg, 31%yield) .

LC-MS (ESI) m/z: 625 [M+H] ⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.14 –8.03 (m, 2H) , 7.74 –7.51 (m, 2H) , 7.43 (q, J =9.0 Hz, 1H) , 5.44 –5.35 (m, 1H) , 4.57 –4.45 (m, 2H) , 4.26 (s, 1H) , 4.08 (d, J = 8.6 Hz, 1H) , 3.78 –3.47 (m, 3H) , 3.21 –3.13 (m, 1H) , 2.43 (d, J = 83.2 Hz, 7H) , 2.07 (s, 1H) , 1.90 –1.75 (m, 3H) , 1.67 –1.55 (m, 7H) , 1.48 (s, 2H) , 1.14 –1.07 (m, 3H) .

The following compounds were prepared according to the above-described methods using different starting materials.

Example 2

¹H NMR (400 MHz, CD₃OD) δ 8.08 (q, J = 6.2 Hz, 2H) , 7.69 –7.53 (m, 2H) , 7.43 (q, J = 9.0 Hz, 1H) , 5.40 (d, J = 13.4 Hz, 1H) , 4.58 –4.53 (m, 1H) , 4.46 –4.38 (m, 1H) , 4.35 –4.26 (m, 1H) , 4.14 –4.08 (m, 1H) , 3.78 –3.47 (m, 1H) , 3.77 –3.70 (m, 2H) , 3.70–3.59 (m, 3H) , 3.26 –3.13 (m, 2H) , 2.87 –2.78 (m, 1H) , 2.73 –2.63 (m, 1H) , 2.48 –2.37 (m, 1H) , 2.34 –2.15 (m, 3H) , 2.13 –2.04 (m, 1H) , 1.93 –1.76 (m, 3H) , 1.58 (t, J = 6.9 Hz, 3H) , 1.10 (dd, J = 6.6, 1.9 Hz, 3H) , 1.00 (d, J = 6.3 Hz, 3H) .

Example 13

¹H NMR: (400 MHz, CD₃OD) δ 8.15 –8.03 (m, 2H) , 7.69 –7.52 (m, 2H) , 7.49 –7.36 (m, 1H) , 5.45 –5.34 (m, 1H) , 4.60 –4.47 (m, 2H) , 4.40 –4.25 (m, 1H) , 4.09 (d, J = 8.6 Hz, 1H) , 3.82 –3.40 (m, 7H) , 3.26 –3.00 (m, 3H) , 2.49 –2.29 (m, 2H) , 2.24 –2.03 (m, 2H) , 2.01 –1.93 (m, 2H) , 1.91 –1.72 (m, 5H) , 1.58 (t, J = 6.9 Hz, 3H) , 1.10 (dd, J = 6.7, 2.4 Hz, 3H) .

Example 25

¹H NMR: (400 MHz, CD₃OD) δ 8.07 (dd, J = 9.0, 6.4 Hz, 2H) , 7.65 –7.53 (m, 2H) , 7.42 (q, J = 9.1 Hz, 1H) , 5.39 (dd, J = 13.3, 2.8 Hz, 1H) , 4.73 –4.68 (m, 1H) , 4.56 –4.50 (m, 1H) , 4.10 (s, 1H) , 4.07 (s, 1H) , 3.78 –3.73 (m, 1H) , 3.70 (s, 1H) , 3.63 (d, J = 10.6 Hz, 1H) , 3.59 (s, 2H) , 3.46 (d, J = 16.2 Hz, 1H) , 3.38 (d, J = 12.9 Hz, 1H) , 3.21 –3.13 (m, 2H) , 3.07 (d, J = 11.5 Hz, 1H) , 2.37 (s, 1H) , 2.22 (s, 1H) , 2.07 (s, 1H) , 1.88 –1.75 (m, 3H) , 1.68 (d, J = 14.2 Hz, 1H) , 1.60 –1.55 (m, 3H) , 0.94 (dd, J = 6.2, 2.1 Hz, 3H) , 0.73 (d, J = 9.7 Hz, 1H) , 0.66 –0.55 (m, 2H) , 0.41 (s, 1H) .

Example 29

¹H NMR: (400 MHz, CD₃OD) δ 7.64 (dd, J = 9.2, 5.6 Hz, 1H) , 7.27 (t, J = 2.6 Hz, 1H) , 7.25 –7.18 (m, 1H) , 7.03 (dd, J = 53.2, 2.5 Hz, 1H) , 5.44 –5.34 (m, 1H) , 4.77 –4.70 (m, 1H) , 4.58 –4.52 (m, 1H) , 4.14 –4.04 (m, 2H) , 3.73 (d, J = 16.8 Hz, 2H) , 3.61 (t, J = 12.9 Hz, 3H) , 3.38 (d, J = 12.6 Hz, 1H) , 3.24 –3.14 (m, 2H) , 3.08 (d, J = 11.8 Hz, 1H) , 2.53 –2.35 (m, 2H) , 2.32 –2.00 (m, 3H) , 1.90 –1.75 (m, 3H) , 1.68 (d, J = 12.9 Hz, 1H) , 1.56 (d, J = 6.3 Hz, 3H) , 0.93 (dd, J = 14.8, 6.7 Hz, 4H) , 0.77 (dd, J = 15.0, 7.6 Hz, 3H) , 0.67 –0.55 (m, 2H) , 0.45 –0.38 (m, 1H) .

Example 33

¹H NMR: (400 MHz, MeOD) δ 8.24 –7.90 (m, 2H) , 7.78 –7.51 (m, 2H) , 7.48 –7.36 (m, 1H) , 5.36 (d, 1H) , 4.59 –4.43 (m, 2H) , 4.46 –4.28 (m, 3H) , 4.08 (d, J = 8.8 Hz, 1H) , 3.96 (d, J = 7.7 Hz, 1H) , 3.78 –3.48 (m, 5H) , 3.22 –3.13 (m, 1H) , 2.94 (d, J = 10.1 Hz, 1H) , 2.84 –2.72 (m, 1H) , 2.65 (d, J = 12.9 Hz, 2H) , 2.26 –1.93 (m, 2H) , 1.82 –1.65 (m, 3H) , 1.60 –1.52 (m, 3H) , 0.68 (d, 2H) , 0.54 (d, J = 22.5 Hz, 2H) .

Example 37

¹H NMR: (400 MHz, CD₃OD) δ 8.21 –7.99 (m, 2H) , 7.74 –7.50 (m, 2H) , 7.42 (m, 1H) , 5.51 –5.26 (m, 1H) , 4.82 –4.38 (m, 4H) , 4.31 –4.01 (m, 2H) , 3.81 –3.40 (m, 3H) , 3.22 –3.05 (m, 2H) , 2.26 –1.94 (m, 2H) , 1.89 –1.59 (m, 7H) , 1.57 (t, J = 6.8 Hz, 3H) , 1.45 –1.25 (m, 3H) , 1.21 –0.99 (m, 3H) , 0.84 –0.40 (m, 4H) .

Example 85

¹H NMR: (400 MHz, CD₃OD) δ 8.17 –7.99 (m, 2H) , 7.70 –7.50 (m, 2H) , 7.43 (q, J =9.0 Hz, 1H) , 5.44 –5.30 (m, 1H) , 4.62 –4.45 (m, 3H) , 4.25 (m, 1H) , 4.08 (d, J = 8.7 Hz, 1H) , 3.82 –3.43 (m, 7H) , 3.22 –3.10 (m, 1H) , 2.60 –2.36 (m, 5H) , 2.33 –2.22 (m, 2H) , 2.11 –2.00 (m, 1H) , 1.93 –1.73 (m, 3H) , 1.63 –1.52 (m, 3H) , 1.09 (dd, J = 6.3, 2.8 Hz, 3H) .

Example 90

¹H NMR: (400 MHz, CD₃OD) δ 7.67 (m, 1H) , 7.33 (m, 2H) , 7.15 –6.98 (m, 2H) , 5.39 (m, 1H) , 4.70 (d, J = 10.8 Hz, 1H) , 4.50 (m, 1H) , 4.07 (d, J = 10.1 Hz, 2H) , 3.71 (d, J = 9.5 Hz, 2H) , 3.65 –3.57 (m, 3H) , 3.38 –2.95 (m, 2H) , 3.22 –3.15 (m, 2H) , 3.07 (d, J = 12.1 Hz, 1H) , 2.36 (s, 1H) , 2.23 (s, 1H) , 2.06 (s, 1H) , 1.82 (m, 3H) , 1.68 (d, J = 13.9 Hz, 1H) , 1.57 (t, J = 6.6 Hz, 3H) , 0.74 (s, 1H) , 0.60 (m, 2H) , 0.41 (s, 1H) .

Example 92

¹H NMR: (400 MHz, CD₃OD) δ 7.64 (m, 1H) , 7.29 –7.18 (m, 2H) , 7.04 (m, 1H) , 5.38 (m, 1H) , 4.78 –4.53 (m, 3H) , 4.14 –4.04 (m, 2H) , 3.76 –3.68 (m, 2H) , 3.65 –3.56 (m, 3H) , 3.38 (d, J = 12.8 Hz, 1H) , 3.22 –3.12 (m, 2H) , 3.07 (m, 1H) , 2.53 –2.45 (m, 1H) , 2.35 (dd, J = 8.8, 3.2 Hz, 1H) , 2.23 (m, 1H) , 2.09 –2.02 (m, 1H) , 1.82 –1.75 (m, 2H) , 1.67 (d, J = 12.8 Hz, 1H) , 1.56 (dd, J = 6.4, 1.9 Hz, 3H) , 0.98 –0.76 (m, 5H) , 0.67 –0.56 (m, 2H) , 0.45 –0.38 (m, 1H) .

Example 97a

¹H NMR: (400 MHz, CD₃OD) δ 8.16 –8.01 (m, 2H) , 7.70 –7.52 (m, 2H) , 7.42 (q, J =9.0 Hz, 1H) , 5.48 –5.32 (m, 1H) , 4.67 (t, J = 10.6 Hz, 1H) , 4.60 –4.35 (m, 2H) , 4.19 –4.02 (m, 2H) , 3.78 –3.43 (m, 3H) , 3.41 –3.33 (m, 1H) , 3.24 –3.11 (m, 1H) , 2.30 (s, 1H) , 2.13 –1.64 (m, 9H) , 1.57 (t, J = 6.9 Hz, 3H) , 1.45 –1.22 (m, 2H) , 1.08 (d, J = 10.7 Hz, 3H) , 0.81 –0.41 (m, 4H) .

Example 97b

¹H NMR: (400 MHz, CD₃OD) δ 8.14 –8.02 (m, 2H) , 7.69 –7.51 (m, 2H) , 7.42 (q, J =9.2 Hz, 1H) , 5.50 –5.27 (m, 1H) , 4.76 –4.43 (m, 3H) , 4.23 –4.03 (m, 2H) , 3.84 –3.41 (m, 3H) , 3.27 –2.95 (m, 3H) , 2.54 (d, J = 94.8 Hz, 2H) , 2.14 –1.99 (m, 1H) , 1.96 –1.68 (m, 7H) , 1.57 (t, J = 7.0 Hz, 4H) , 1.04 (s, 3H) , 0.81 –0.36 (m, 4H) .

Example 102a

¹H NMR (400 MHz, CD₃OD) δ 8.12 –8.04 (m, 2H) , 7.68 –7.53 (m, 2H) , 7.42 (q, J =9.1 Hz, 1H) , 5.44 –5.34 (m, 1H) , 4.77 –4.37 (m, 3H) , 4.13 –3.99 (m, 2H) , 3.79 –3.33 (m, 5H) , 3.23 –3.11 (m, 1H) , 2.30 –2.22 (m, 1H) , 2.12 –1.64 (m, 9H) , 1.61 –1.54 (m, 3H) , 1.45 –1.28 (m, 1H) , 0.78 –0.70 (m, 1H) , 0.69 –0.61 (m, 1H) , 0.60 –0.53 (m, 1H) , 0.47 –0.38 (m, 1H) .

Example 102b

¹H NMR (400 MHz, CD₃OD) δ 8.12 –8.03 (m, 2H) , 7.68 –7.53 (m, 2H) , 7.42 (m, 1H) , 5.44 –5.34 (m, 1H) , 4.67 (m, 1H) , 4.58 –4.36 (m, 2H) , 4.08 (m, 2H) , 3.77-3.44 (m, 1H) , 3.68 (d, J = 5.6 Hz, 1H) , 3.59 (d, J = 4.8 Hz, 1H) , 3.40 –3.33 (m, 1H) , 3.18 (dd, J = 12.9, 8.9 Hz, 1H) , 2.26 (d, J = 10.2 Hz, 1H) , 2.11 –2.02 (m, 2H) , 1.98 –1.62 (m, 7H) , 1.61 –1.53 (m, 3H) , 1.45 –1.31 (m, 1H) , 0.78 –0.70 (m, 1H) , 0.68 –0.60 (m, 1H) , 0.60 –0.53 (m, 1H) , 0.47 –0.39 (m, 1H) .

Example 103a

¹H NMR (400 MHz, CD₃OD) δ7.74 –7.66 (m, 1H) , 7.21 (m, 1H) , 7.17 –7.04 (m, 2H) , 5.37 (m, 1H) , 4.83 –4.67 (m, 1H) , 4.64 –4.56 (m, 1H) , 4.54 –4.44 (m, 1H) , 4.15 (m, 1H) , 4.09 –4.02 (m, 1H) , 3.67 (d, J = 5.7 Hz, 1H) , 3.58 (m, 1H) , 3.64 –3.22 (m, 1H) , 3.16 (m, 1H) , 3.08 –2.97 (m, 1H) , 2.63 (d, J = 8.1 Hz, 1H) , 2.47 –2.36 (m, 1H) , 2.10 –2.03 (m, 1H) , 1.93 –1.70 (m, 7H) , 1.63 –1.43 (m, 4H) , 0.77 –0.69 (m, 1H) , 0.69 –0.61 (m, 1H) , 0.60 –0.53 (m, 1H) , 0.48 –0.40 (m, 1H) .

Example 103b

¹H NMR (400 MHz, CD₃OD) δ7.70 (m, 1H) , 7.21 (m, 1H) , 7.17 –7.04 (m, 2H) , 5.38 (m, 1H) , 4.66 (m, 6.6 Hz, 1H) , 4.58 –4.36 (m, 2H) , 4.08 (m, 2H) , 3.68 (d, J = 5.7 Hz, 1H) , 3.65 –3.32 (m, 3H) , 3.17 (m, 1H) , 2.26 (d, J = 10.1 Hz, 1H) , 2.10 –1.61 (m, 10H) , 1.56 (m, 3H) , 1.44 –1.32 (m, 1H) , 0.77 –0.70 (m, 1H) , 0.68 –0.60 (m, 1H) , 0.60 –0.52 (m, 1H) , 0.47 –0.38 (m, 1H) .

Example 116a

¹H NMR (400 MHz, CD₃OD) δ 8.11 –8.04 (m, 2H) , 7.67 –7.53 (m, 2H) , 7.42 (dd, J = 18.5, 9.2 Hz, 1H) , 5.42 –5.35 (m, 1H) , 4.79 (d, J = 10.8 Hz, 1H) , 4.57 –4.48 (m, 1H) , 4.08 (d, J = 8.7 Hz, 1H) , 3.98 (dd, J = 10.8, 6.0 Hz, 1H) , 3.77 –3.42 (m, 6H) , 3.23 –3.10 (m, 6H) , 2.22 –2.14 (m, 1H) , 2.10 –2.02 (m, 1H) , 1.91 –1.72 (m, 4H) , 1.60 –1.54 (m, 3H) , 1.41 (dd, J = 12.8, 4.6 Hz, 1H) , 1.11 (d, J = 6.3 Hz, 3H) , 0.91 (dd, J = 6.2, 2.8 Hz, 3H) , 0.80 –0.72 (m, 1H) , 0.66 –0.57 (m, 2H) , 0.43 –0.35 (m, 1H) .

Example 116b

¹H NMR (400 MHz, CD₃OD) δ 8.08 (q, J = 6.2 Hz, 2H) , 7.67 –7.62 (m, 1H) , 7.62 –7.53 (m, 1H) , 7.42 (q, J = 9.0 Hz, 1H) , 5.40 –5.34 (m, 1H) , 4.56 –4.48 (m, 2H) , 4.30 (dd, J =10.7, 3.9 Hz, 1H) , 4.08 (d, J = 8.8 Hz, 1H) , 3.79 –3.45 (m, 6H) , 3.17 (dd, J = 12.8, 9.4 Hz, 1H) , 2.84 (dd, J = 6.0, 3.0 Hz, 1H) , 2.74 –2.57 (m, 2H) , 2.36 –2.28 (m, 2H) , 2.12 –2.02 (m, 1H) , 1.91 –1.74 (m, 3H) , 1.57 (dd, J = 8.0, 6.6 Hz, 3H) , 1.12 (d, J = 6.2 Hz, 3H) , 1.00 (d, J =6.6 Hz, 3H) , 0.73 –0.62 (m, 2H) , 0.51 –0.44 (m, 2H) .

Example 117a

¹H NMR (400 MHz, CD₃OD) δ 8.13 -8.04 (m, 2H) , 7.67 -7.52 (m, 2H) , 7.42 (q, J =9.1 Hz, 1H) , 5.43 -5.35 (m, 1H) , 4.76 -4.61 (m, 1H) , 4.56 -4.49 (m, 1H) , 4.08 (d, J = 8.1 Hz, 2H) , 3.77 –3.42 (m, 5H) , 3.14 (m, 1H) , 2.14 -1.98 (m 2H) , 1.88 -1.53 (m, 11H) , 1.35 -1.32 (m, 1H) , 1.08 (s. 3H) , 1.01 -0.93 (m, 1H) , 0.90 -0.85 (m, 3H) , 0.82 -0.39 (m, 4H) .

Example 117b

¹H NMR (400 MHz, CD₃OD) δ 8.13 -8.02 (m, 2H) , 7.68 -7.52 (m, 2H) , 7.42 (q, J=8.9Hz, 1H) , 5.41 -5.34 (m, 1H) , 4.56 -4.32 (m, 3H) , 4.08 (d, J=8.6Hz, 1H) , 3.78 -3.40 (m, 4H) , 3.26 -3.12 (m, 2H) , 2.65 -2.51 (m, 2H) , 2.40 -2.26 (m, 1H) , 2.09 -2.04 (m, 1H) , 189 -1.65 (m, 5H) , 1.60 -1.55 (m, 3H) , 1.53 -1.42 (m, 2H) , 1.34 (dd, J=3.7, 2.2Hz, 1H) , 1.06 -0.95 (m, 3H) , 0.91 (dd, J=6.4, 2.6Hz, 3H) , 0.75 -0.64 (m, 2H) , 0.59 -0.41 (m, 2H) .

Example 118

¹H NMR (400 MHz, Methanol-d₄) δ 8.08 (q, J = 6.6 Hz, 2H) , 7.68 –7.52 (m, 2H) , 7.42 (q, J = 9.2 Hz, 1H) , 5.39 (d, J = 13.4 Hz, 1H) , 4.69 –4.51 (m, 2H) , 4.22 –4.12 (m, 1H) , 4.09 (d, J = 8.7 Hz, 1H) , 3.80 –3.55 (m, 7H) , 3.55 –3.42 (m, 3H) , 3.19 (t, J = 12.3 Hz, 1H) , 3.05 (d, J = 12.0 Hz, 1H) , 2.37 (d, J = 34.5 Hz, 2H) , 2.11 –1.97 (m, 2H) , 1.93 –1.76 (m, 3H) , 1.57 (t, J = 7.1 Hz, 3H) , 0.71 (s, 1H) , 0.65 (dd, J = 9.5, 4.6 Hz, 1H) , 0.57 (d, J = 4.0 Hz, 1H) , 0.44 (d, J = 3.9 Hz, 1H) .

Example 119a

¹H NMR (400 MHz, CD₃OD) δ 8.08 (q, J = 6.2 Hz, 2H) , 7.68 –7.51 (m, 2H) , 7.42 (q, J = 9.0 Hz, 1H) , 5.43 –5.34 (m, 1H) , 4.71 –4.52 (m, 3H) , 4.18 –4.03 (m, 2H) , 3.78 –3.39 (m, 4H) , 3.21 –2.95 (m, 3H) , 2.67 (s, 1H) , 2.43 (s, 1H) , 2.10 (t, J = 9.9 Hz, 1H) , 1.92 –1.71 (m, 7H) , 1.56 (d, J = 6.6 Hz, 3H) , 1.02 (dd, J = 23.5, 6.8 Hz, 3H) , 0.80 –0.41 (m, 4H) .

Example 119b

¹H NMR (400 MHz, CD₃OD) δ 8.09 (q, J = 6.2 Hz, 2H) , 7.66 –7.53 (m, 2H) , 7.43 (q, J = 9.1 Hz, 1H) , 5.43 –5.35 (m, 1H) , 4.56 (d, J = 14.9 Hz, 3H) , 4.12 (d, J = 8.8 Hz, 2H) , 3.77 –3.47 (m, 4H) , 3.20 (d, J = 10.2 Hz, 1H) , 2.21 –1.97 (m, 7H) , 1.94 –1.68 (m, 5H) , 1.60 –1.56 (m, 3H) , 1.23 –1.11 (m, 3H) , 0.85 –0.47 (m, 4H) .

Example 120

¹H NMR (400 MHz, CD₃OD) δ 7.75-7.67 (m, 1H) , 7.26-7.03 (m, 3H) , 5.41-5.34 (m, 1H) , 4.53-4.40 (m, 2H) , 4.36 (d, J = 10.9 Hz, 1H) , 4.07 (d, J = 8.7 Hz, 1H) , 3.72-3.62 (m, 6H) , 3.59 (s, 1H) , 3.21-3.12 (m, 1H) , 2.54-2.37 (m, 6H) , 2.07 (s, 1H) , 1.93-1.76 (m, 3H) , 1.59-1.54 (m, 3H) , 0.71 (s, 2H) , 0.50 (s, 2H) .

Example 121

¹H NMR (400 MHz, CD₃OD) δ 7.67 (t, J = 7.5 Hz, 1H) , 7.42 –7.34 (m, 1H) , 7.29 (dd, J = 16.4, 8.1 Hz, 1H) , 7.13 (d, J = 2.3 Hz, 1H) , 7.05 (dd, J = 38.1, 2.4 Hz, 1H) , 5.36 (dd, J =8.8, 4.7 Hz, 1H) , 4.47 (m, 2H) , 4.36 (dd, J = 10.9, 2.7 Hz, 1H) , 4.07 (d, J = 8.7 Hz, 1H) , 3.71 –3.58 (m, 6H) , 3.17 (dd, J = 13.0, 7.7 Hz, 1H) , 2.49 (d, J = 12.9 Hz, 4H) , 2.45 –2.38 (m, 2H) , 2.19 –2.01 (m, 2H) , 1.89 –1.73 (m, 3H) , 1.56 (t, J = 7.0 Hz, 3H) , 0.70 (s, 2H) , 0.50 (s, 2H) .

Example 122

¹H NMR (400 MHz, CD₃OD) δ 7.84 –7.75 (m, 1H) , 7.26 (dt, J = 13.6, 6.0 Hz, 2H) , 7.15 (dd, J = 40.9, 2.5 Hz, 1H) , 5.41 –5.34 (m, 1H) , 4.52 (dt, J = 8.8, 6.3 Hz, 1H) , 4.45 (dd, J = 10.9, 6.7 Hz, 1H) , 4.36 (dd, J = 10.9, 2.8 Hz, 1H) , 4.07 (d, J = 8.8 Hz, 1H) , 3.65 (d, J = 4.6 Hz, 3H) , 3.59 (s, 1H) , 3.50 –3.32 (m, 1H) , 3.17 (dd, J = 13.2, 7.7 Hz, 1H) , 2.50 (s, 3H) , 2.41 (dd, J = 18.3, 7.7 Hz, 2H) , 2.07 (s, 1H) , 1.90 –1.74 (m, 3H) , 1.57 (t, J = 6.9 Hz, 3H) , 1.28 (s, 3H) , 0.71 (d, J = 6.4 Hz, 2H) , 0.49 (d, J = 4.8 Hz, 2H) .

Example 123

¹H NMR (400 MHz, CD₃OD) δ 7.70 –7.59 (m, 1H) , 7.29 –7.17 (m, 2H) , 7.03 (dd, J = 52.0, 2.6 Hz, 1H) , 5.42 (d, J = 13.2 Hz, 1H) , 4.59 (s, 2H) , 4.44 (q, J = 10.2, 9.6 Hz, 2H) , 4.17 –4.10 (m, 1H) , 3.82 (s, 1H) , 3.78 –3.69 (m, 2H) , 3.67 (t, J = 4.4 Hz, 4H) , 3.25 (d, J = 13.7 Hz, 1H) , 2.62 –2.49 (m, 6H) , 2.21 –2.11 (m, 2H) , 1.90 –1.82 (m, 2H) , 1.57 (d, J = 6.3 Hz, 3H) , 0.98 –0.78 (m, 3H) , 0.74 (d, J = 5.1 Hz, 2H) , 0.54 (s, 2H) .

Example 128

¹H NMR (400 MHz, CD₃OD) δ6.34 (s, 1H) , 5.36 (m, 1H) , 4.70 (d, J = 10.6 Hz, 1H) , 4.55 –4.49 (m, 1H) , 4.11 –4.06 (m, 2H) , 3.75 –3.60 (m, 5H) , 3.49 –3.37 (m, 1H) , 3.21 –3.07 (m,4H) , 2.53 (d, J = 2.0 Hz, 3H) , 2.39 (s, 1H) , 2.26 (s, 1H) , 2.06 (s, 1H) , 1.78 (d, J = 6.9 Hz, 3H) , 1.57 (d, J = 6.4 Hz, 3H) , 0.74 (d, J = 8.9 Hz, 1H) , 0.67 –0.58 (m, 2H) , 0.43 (s, 1H) .

Example 162

¹H NMR (400 MHz, CD₃OD) δ 7.77 –7.67 (m, 1H) , 7.27 –7.03 (m, 3H) , 5.43 –5.31 (m, 1H) , 4.82 –4.68 (m, 1H) , 4.54 –4.45 (m, 1H) , 4.13 –3.98 (m, 2H) , 3.77 –3.67 (m, 2H) , 3.64 –3.57 (m, 3H) , 3.43 –3.40 (m, 1H) , 3.24 –3.00 (m, 4H) , 2.38 –2.30 (m, 1H) , 2.28 –2.17 (m, 1H) , 2.16 –2.06 (m, 1H) , 1.93 –1.74 (m, 3H) , 1.70 –1.59 (m, 1H) , 0.79 –0.69 (m, 1H) , 0.69 –0.53 (m, 2H) , 0.46 –0.35 (m, 1H) .

Example 163

¹H NMR (400 MHz, CD₃OD) δ 8.12 –8.04 (m, 2H) , 7.68 –7.53 (m, 2H) , 7.42 (m, 1H) , 5.44 –5.34 (m, 1H) , 4.77 –4.37 (m, 3H) , 4.13 –3.99 (m, 2H) , 3.79 –3.33 (m, 5H) , 3.23 –3.11 (m, 1H) , 2.30 –2.22 (m, 1H) , 2.12 –1.64 (m, 9H) , 1.61 –1.54 (m, 3H) , 1.45 –1.28 (m, 1H) , 0.78 –0.70 (m, 1H) , 0.69 –0.61 (m, 1H) , 0.60 –0.53 (m, 1H) , 0.47 –0.38 (m, 1H) .

Example 164

¹H NMR (400 MHz, CD₃OD) δ7.74 –7.67 (m, 1H) , 7.22 (m, 1H) , 7.17 –7.04 (m, 2H) , 5.43 –5.32 (m, 1H) , 4.76 –4.62 (m, 1H) , 4.59 –4.37 (m, 2H) , 4.13 –3.99 (m, 2H) , 3.70 (s, 1H) , 3.64 –3.35 (m, 3H) , 3.23 –3.11 (m, 1H) , 2.29 (d, J = 9.6 Hz, 1H) , 2.15 –1.63 (m, 9H) , 1.60 –1.54 (m, 3H) , 1.45 –1.27 (m, 2H) , 0.78 –0.71 (m, 1H) , 0.69 –0.61 (m, 1H) , 0.61 –0.54 (m, 1H) , 0.47 –0.39 (m, 1H) .

Example B Biology Assay

The following assays were used to measure the effects of the compounds of the present disclosure.

Phospho-ERK 1/2 assay:

Allowed PNAC-1 cell growth in a T75 flask in DMEM and 10%1 fetal calf serum (FCS; ) , using standard tissue culture procedures until ～80%confluency is achieved. Day 1, seed 6000 cells/well in 384 well plate and incubated at 37℃, 5%CO2. Added diluted compound by Echo 550, final DMSO is 0.5%, incubate cells at 37℃, 5%CO2 for 3 hours. Then, removed medium and fixed cells with 3.7%formaldehyde in PBS (PFA) by Apricot. Washed with PBS once. Permeabilized cells with cold 100%methanol and repeated wash once with PBS. Added Li-Cor blocking buffer to each well and incubated 1.5 hours at RT. Removed blocking buffer and added primary antibody mixture (rabbit anti pERK, mouse anti GAPDH) . Incubated at 4℃ overnight. Day 2, washed with PBST (Tween-20 in PBS) with total 3 times and then added secondary antibody mixture (goat anti rabbit 800CW (1: 800 dilution in the combined solution) and goat anti mouse 680RD (1: 800 dilution in the combined solution) ) , incubated for 60 minutes at RT away from light. Repeated washing with PBST 3 times. After final wash, centrifuged plate up-side-down at 1000 rpm to remove wash solution completely from wells. Before plate scanning, cleaned the bottom plate surface and theImager scanning bed (if applicable) with moist, lint-free tissue to avoid any obstructions during scanning. Scanned plate with detection in both 700 and 800 nm channel.

The Phospho-ERK 1/2 assay results for some exemplary compounds of the present disclosure are shown in Table 2 below.

Table 2.

KRAS (G12D) : SOS1 Nucleotide Exchange Binding Assay

Thawed GDP loaded KRAS (G12D) on ice and diluted GDP loaded KRAS (G12D) to 500 nM in RBD-RAS binding buffer. Prepared the master mixture (6 μl) : 96 wells × (1 μl diluted GDP loaded KRAS (G12D) , 500 nM + 5 μl RBD-RAS binding buffer) . Added 6 μl of master mix to each well. Prepared serial dilutions of the test compound in DMSO at 200X testing concentration. Then diluted the compound 20-fold in deionized water to prepare the 10X intermediate solution. For positive and negative controls, used 5%DMSO in water as a 10X intermediate so that all wells contained the same amount of DMSO. Added 1 μl of 10X intermediate solution of the test compound to the testing wells. Added 1 μl 5%DMSO to the positive and negative control wells. Briefly centrifuged the plate and incubate for 30 minutes at room temperature. Thaw GTP (10 mM) and SOS1 on ice. Diluted SOS1 in RBD-RAS binding buffer at 5 μM. Combined GTP (10 mM) and diluted SOS1 (5 μM) at 1: 1 ratio. Initiated the exchange reaction by adding 2 μl of GTP/SOS1 mixture to the testing and the positive control wells. Thawed RBD-cRAF and dilute RBD-cRAF in RBD-RAS binding buffer at 25 nM. After the 30-minute incubation with SOS1/GTP (RBD-RAS buffer for the negative control) , added 1 μl of diluted RBD-cRAF (25 nM) to all wells. Briefly centrifuged the plate and incubated at room temperature for 30 minutes. Diluted 3X Immuno Buffer in deionized water to prepare 1X Immuno buffer. Added one volume of 3X Immuno Buffer to two volumes of deionized water. Diluted Glutathione Acceptor beads (PerkinElmer #AL109C) and Nickel chelate Donor beads (PerkinElmer #AS101D) at 1: 500 and 1: 250 respectively in 1x Immuno buffer. Added 20 μl of acceptor/donor beads mixture per well is needed. Therefore added 16 μl of Glutathione Acceptor beads and 32 μl of Nickel Donor beads to 8 mL of 1X Immuno buffer) . Incubated 30 min at room temperature. Read Alpha-counts using a compatible plate reader.

KRAS G12D 2DProliferation Assay:

AsPC-1 (ATCC CRL-1682) and LS513 (ATCC CRL-2134) cells were purchased from ATCC, GP2D (Cobioer CBP60010) , AGS (Cobioer CBP60476) , SW1990 (Cobioer CBP60691) cells were purchased from Cobioer biosciences CO., LTD, MKN-1 (JCRB, JCRB0252) cells was purchased from JCRB cell bank. Each cell was cultured in medium supplemented with 10%fetal bovine serum (FBS) , according to the protocol recommended by the manufacture. Cells were seeded 800 cells/well in 384-well plates (Corning) and incubated at 37℃, 5%CO₂ for 18 hours. Serially diluted compound was added to the cells, and plates were incubated at 37℃, 5%CO₂ for 72 hours. Cell viability was measured using aLuminescent Cell Viability Assay kit (Promega) according to the manufacturer’s protocol.

KRAS G12D 3DProliferation Assay

Panc-1 (ATCC CRL-1469) , HPAC (ATCC CRL-2119) , Panc0403 (ATCC CRL-2555) and AsPC-1 (ATCC CRL-1682) cells were purchased from ATCC, GP2D (Cobioer CBP60010) , AGS (Cobioer CBP60476) , SW1990 (Cobioer CBP60691) cells were purchased from Cobioer biosciences CO., LTD, MKN-1 (JCRB, JCRB0252) cells was purchased from JCRB cell bank. Each cell was cultured in medium supplemented with 10%fetal bovine serum (FBS) , according to the protocol recommended by the manufacture. Serially diluted compound was added to 384-well Ultra-Low Attachment Surface round bottom plate (Corning) . 400 cells/well were seeded in plate and incubated at 37℃, 5%CO₂ for 7days. Cell viability was measured using a3D Cell Viability Assay kit (Promega) according to the manufacturer’s protocol, as shown in Table 3.

Table 3

Other compounds of the present disclosure show IC₅₀ value of 0.5 to 5000 nM. Some compounds of the present disclosure show IC₅₀ value of 1-4000 nM. Some compounds of the present disclosure show IC₅₀ value of 1-3000 nM. Some compounds of the present disclosure show IC₅₀ value of 1-2000 nM. Some compounds of the present disclosure show IC₅₀ value of 1-1000 nM. Some compounds of the present disclosure show IC₅₀ value of 1-500 nM.

DMPK assay

Caco-2 cell monolayers permeability

10 μM input concentration and pH 6.5/7.4 (apical/basolateral) , in the presence of efflux inhibitors, Zosuquidar, Benzbromarone and KO-143. Incubations were performed at 37℃ with shaking at 480 rpm on a rotary shaker over the course of 120 minutes, and samples were collected at 45 and 120 minutes to assess recovery. All incubations were performed in singlet. Lucifer yellow was used as a marker to confirm the integrity of the cell monolayers following 120 min of incubation. UPLC-MS/MS was used to quantify compound concentrations in the incubation medium of donor and receiver compartments. The concentration data was used to calculate the apparent permeability after 120 min of incubation. Results are shown in Table 4.

Table 4

MDCK-MDR1 Pgp assessment

Efflux transport mediated by P-glycoprotein (Pgp) was assessed by MDCK-MDR1 cells. The final concentrations of test compounds and control compound were at 1 μM. The multi-well insert plate was incubated at 37 ℃ for 2 hours. In order to reliably measure passive permeability coefficients, Pexact was reported, which automatically corrects for loss of compound. Results are shown in Table 5.

Table 5

In vivo mouse PK

Single dose following IV bolus (1 mg/kg, 0.2 mg/mL in 1%DMSO, 99%SBE-β-CD (10%w/v) in water) and oral gavage (10 mg/kg ～ 60 mg/kg) administration of test compounds in Balb/c Mice female. The blood samples were collected at 2min, 5min, 10min, 30min, 1hr, 2hr, 4hr, 8hr and 24hr (additional 32hr and 48hr for MRTX1133) after IV bolus, at 15min, 30min, 1hr, 1.5hr, 2hr, 3hr, 4hr, 8hr and 24hr (additional 32hr and 48hr for MRTX1133) after PO administration. The plasma concentrations of compounds were determined with UPLC-MS/MS. Results are shown in Table 6.

Table 6

In vivo rat PK

Single dose following IV infusion (1 mg/kg, 0.25 mg/mL) and oral gavage (5 mg/kg ～60 mg/kg) administration of test compounds in SD Rats male. The blood samples were collected at 10min, 30min, 1hr, 1.25hr, 1.5hr, 2hr, 4hr, 8hr and 24hr after IV infusion, at 15min, 30min, 1hr, 1.5hr, 2hr, 3hr, 4hr, 8hr and 24hr after PO administration. The plasma concentrations of compounds were determined with UPLC-MS/MS. Results are shown in Table 7.

Table 7

Anti-tumor activity in human tumor xenografts

Mice were maintained under pathogen-free conditions, and food and water were provided ad libitum. 6–8-week old, female, BALB/c nude mice (Anikeeper, Beijing, China) were injected subcutaneously with HPAC (ATCC, CRL-2119) cells in 100 μl of PBS in the right hind flank with 5.0 x 10⁶ cells. 6–8-week old, female, CB17 SCID (Vital river, Beijing, China) were injected subcutaneously with Panc-1 (ECACC, 87092802) cells in 100 μl of PBS in the right hind flank with 1.0 x 10⁷ cells. 6–8-week old, female, CB17 SCID (Vital river, Beijing, China) were injected subcutaneously with SW1990 (ATCC , CRL-2172) cells in 200 μl of PBS and Matrigel matrix (1: 1) in the right hind flank with 5.0 x 10⁶ cells. Mouse health was monitored daily, and caliper measurements began when tumors were palpable. Tumor volume measurements were determined utilizing the formula 0.5 x L x W² in which L refers to length and W refers to width of each tumor. When tumors reached an average tumor volume of 100～200 mm³, mice were randomized into treatment groups. Mice were treated by oral gavage with either vehicle consisting of 10%Solutol+90%Water or test compounds in vehicle at 20-120 mg/kg BID. Animals were monitored daily, tumors were measured 2 or 3 times per week, and body weights were measured 2 or 3times per week. Data are expressed as mean ±SEM. Statistical analysis of difference in tumor volume and tumor weight among the groups were conducted on the data obtained at the best therapeutic time point. A one-way ANOVA was performed to compare tumor volume and tumor weight among groups, and when a significant F-statistics (aratio of treatment variance to the error variance) was obtained, comparisons between groups were carried out with Games-Howell test, otherwise Dunnet (2-sided) was applied. The significance between two groups was analyzed by T-Test. All data was analyzed using SPSS 17.0 (IBM; Armonk, New York) . p < 0.05 was considered to be statistically difference, p < 0.01 was considered to be statistically significant difference. Results are shown in Table 8 and Table 9.

TGI (%) = (1- (T_n-T₀) / (C_n-C₀) ) *100%

Tn: average tumor volume of the treatment group on Day n;

T₀: average tumor volume of the treatment group on Day 0;

Cn: average tumor volume of the vehicle control group on Day n;

C₀: average tumor volume of the vehicle control group on Day 0.

Table 8. Panc-1 pancreatic xenograft model

Table 9. SW1990 pancreatic xenograft model

The in vivo pharmacology was conducted to evaluate the efficacy of test compounds post oral administration in the human pancreatic cancer cell Panc-1 and/or SW1990 and/or HPAC subcutaneous xenograft models. Test compounds significantly inhibited tumor growth in all models. The tumor-bearing mice were well-tolerated at all testing doses of test compounds.

hERG Inhibition Study

Inhibition of hERG channel was conducted in HEK 293 cell line stably expressing hERG channel by manual patch clamp.

hERG inhibition study was carried out with the compounds of the present disclosure.

In Vitro Hep Clint Assay

Test compounds at a concentration of 1 μM were incubated with cryopreserved hepatocytes for various time points, up to 120 minutes. The depletion of the test compounds was quantified using LC-MS/MS. The metabolic stability of the test compounds in hepatocytes was assessed by calculating intrinsic clearance (Clint) and half-life (T1/2) values. Positive controls were included in each assay run to validate the performance of the test system.

The foregoing description is considered as illustrative only of the principles of the present disclosure. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow.

Claims

A compound having Formula (I) , Formula (II) or Formula (III) :

or a pharmaceutically acceptable salt thereof,

wherein

Ring A is

X is -C (R^eR^f) -, -O-or -N (R^X) -;

R^X is hydrogen, deuterium, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more deuterium;

Ring E is

Z is -C (R^jR^k) -, -O-or -N (R^Z) -;

R^Z is hydrogen, deuterium, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more deuterium;

R¹ and R² are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;

R³ and R⁴ are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium; or

R³ and R⁴ together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;

R⁵ and R⁶ are each independently selected from hydrogen, deuterium, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;

R⁷ and R⁸ are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;

R⁹ and R¹⁰ are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;

each of R^a, R^b, R^c, R^d, R^e, and R^f is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium; or

two of R⁷, R⁸, R⁹, R¹⁰, R^a, R^b, R^c, R^d, R^e, R^f, and R^X together with the interval atoms formcycloalkyl or heterocyclyl, wherein each of cycloalkyl and heterocyclyl optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;

provided that when the compound has a Formula (I) , at least one of R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ is not hydrogen;

R¹¹ and R¹² are each independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;

R¹³ and R¹⁴ are each independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;

each of R^s, R^t, R^v, and R^u is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium;

each of R^j and R^k is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium; or

R^j and R^k together with the carbon atom to which they are attached form

provided that when the compound has a Formula (II) or Formula (III) , at least one of R⁵, R⁶, R¹¹, R¹², R¹³ and R¹⁴ is alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy substituted with one or more deuterium;

each R is independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl and alkynyl, wherein the alkyl, alkenyl, alkynyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;

each R’ is independently hydrogen or deuterium;

each R” is independently hydrogen, deuterium or halogen;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2 or 3; and

p is 0, 1, 2 or 3.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein both R¹ and R² are hydrogen.
The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein one of R³ and R⁴ is hydrogen, and the other is alkyl optionally substituted with one or more deuterium.
The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein one of R³ and R⁴ is hydrogen, and the other is methyl optionally substituted with one or more deuterium.
The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ taken together with the carbon atom to which they are both attached form cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.
The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ taken together with the carbon atom to which they are both attached form cyclopropyl optionally substituted with one or more deuterium.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein one of R⁵ and R⁶ is alkyl optionally substituted with one or more deuterium, and the other is hydrogen.
The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein one of R⁵ and R⁶ is -CH₃ or -CD₃, and the other is hydrogen.
The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (I) , and R⁷, R⁸, R⁹ and R¹⁰ are hydrogen.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein both R⁵ and R⁶ are hydrogen.
The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (I) , and one of R⁷ and R⁸ is alkyl, alkoxy, - alkyl-alkoxy, hydroxyalkyl or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein one of R⁷ and R⁸ is -CH₃, -CD₃, -CH₂-OCH₃, -CH₂-OCD₃, -CH₂-OH, -CH₂F, -CHF₂ or -CF₃, and the other is hydrogen or deuterium.
The compound of any one of claims 11-12, or a pharmaceutically acceptable salt thereof, wherein one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein one of R⁹ and R¹⁰ is hydrogen, and the other is hydrogen, methyl or CD₃.
The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (I) , and R⁷ and R⁹ together with the interval atoms form a heterocyclyl, or R⁷ and R^a together with the interval atoms form a heterocyclyl.
The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Ring A is
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (I) , X is -C (R^eR^f) -, one of R^e and R^f is hydrogen, and the other is halogen.
The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein one of R^e and R^f is hydrogen, and the other is -F.
The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein both of R^e and R^f are hydrogen.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (I) , and X is -C (R^eR^f) -, and R^a and R^e together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.
The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein n is 0.
The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein Ring A is
The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein both R⁵ and R⁶ are hydrogen.
The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein one of R⁷ and R⁸ is alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein one of R⁷ and R⁸ is alkyl optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein one of R⁷ and R⁸ is -CH₃ or -CD₃, and the other is hydrogen or deuterium.
The compound of any one of claims 22-26, or a pharmaceutically acceptable salt thereof, wherein one of R⁹ and R¹⁰ is hydrogen or deuterium, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein both R⁹ and R¹⁰ are hydrogen.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (I) , and X is -C (R^eR^f) -, and R^e and R^f together with the carbon atom to which they are attached form
The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein both R⁵ and R⁶ are hydrogen.
The compound of claim 29 or 30, or a pharmaceutically acceptable salt thereof, wherein one of R⁷ and R⁸ is alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein one of R⁷ and R⁸ is alkyl optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein one of R⁷ and R⁸ is -CH₃ or -CD₃, and the other is hydrogen or deuterium.
The compound of any one of claims 29-33, or a pharmaceutically acceptable salt thereof, wherein one of R⁹ and R¹⁰ is hydrogen or deuterium, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein both R⁹ and R¹⁰ are hydrogen.
The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (II) or Formula (III) , one of R¹¹ and R¹² is alkyl substituted with one or more deuterium, and the other is hydrogen or deuterium.
The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein one of R¹¹ and R¹² is -CD₃, and the other is hydrogen or deuterium.
The compound of claim 36 or claim 37, or a pharmaceutically acceptable salt thereof, wherein one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein one of R¹³ and R¹⁴ is hydrogen, and the other is hydrogen, methyl or CD₃.
The compound of claim 36 or 37, or a pharmaceutically acceptable salt thereof, wherein both of R¹³ and R¹⁴ are hydrogen.
The compound of claim 36 or claim 37, or a pharmaceutically acceptable salt thereof, wherein one of R^u and R^v is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein one of R^u and R^v is hydrogen, and the other is hydrogen, methyl or CD₃.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (II) or Formula (III) , Z is -C (R^jR^k) -, and one of R^j and R^k is hydrogen, and the other is halogen.
The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein one of R^j and R^k is hydrogen, and the other is -F.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (II) or Formula (III) , Z is -C (R^jR^k) -, and R^j and R^k together with the carbon atom to which they are attached form
The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein both R⁵ and R⁶ are hydrogen.
The compound of claim 45 or 46, or a pharmaceutically acceptable salt thereof, wherein one of R¹¹ and R¹² is alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein one of R¹¹ and R¹² is alkyl optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein one of R¹¹ and R¹² is -CH₃ or -CD₃, and the other is hydrogen or deuterium.
The compound of any one of claims 45-49, or a pharmaceutically acceptable salt thereof, wherein one of R¹³ and R¹⁴ is hydrogen or deuterium, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein both R¹³ and R¹⁴ are hydrogen.
The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (II) or Formula (III) , and Z is -O-.
The compound of claim 1, having a formula selected from:

or a pharmaceutically acceptable salt thereof,

wherein

R⁵ is selected from alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl is optionally substituted with one or more deuterium;

Ring B is cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;

provided that at least one of R⁷ and R⁹ is not hydrogen; and

provided that R¹¹ is alkyl substituted with one or more deuterium.
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3 or 4.
The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from cyano, halogen, hydroxyl, amino, haloalkyl, alkyl or alkynyl, wherein the alkyl or alkynyl are optionally substituted with one or more deuterium.
The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from fluoro, chloro, hydroxyl, -NH₂, -CF₃, ethyl or ethynyl, wherein the ethyl or ethynyl are optionally substituted with one or more deuterium.
The compound of any one of claims 1-28 and 53-56, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (I) , andis selected from the group consisting of:
The compound of any one of claims 1-8 and 36-56, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (II) , and is selected from the group consisting of
The compound of any one of claims 1-8 and 36-56, or a pharmaceutically acceptable salt thereof, wherein the compound has a Formula (III) , andis selected from the group consisting of:
The compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R’ is hydrogen.
The compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein each R’ is deuterium.
A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A method for inhibiting wild type KRas, Kras G12D, Kras G12C, Kras G12V, Kras G13D, Kras G12R, Kras G12S, Kras G12A, and/or Kras Q61H activity in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 63 to the subject.
A method for treating a cancer associated with wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and/or KRas Q61H comprising administering an effective amount of a compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 63 to a subject in need thereof.
The method of claim 65, wherein the cancer is selected from the group consisting of:

(i) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

(ii) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

(iii) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ;

(iv) Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ;

(v) Liver: hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

(vi) Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

(vii) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ;

(viii) Gynecological: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ;

(ix) Hematologic: blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ;

(x) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and

(xi) Adrenal glands: neuroblastoma.
The method of claim 65, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
A method for treating cancer in a subject in need thereof, the method comprising (a) acquiring the knowledge that the cancer is associated with wild type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H; and (b) administering to the subject an effective amount of a compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 63.
The method of any one of claims 64-68, wherein the administering is conducted via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.
The method of any one of claims 64-68, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents.
The method of claim 70, wherein the one or more additional therapeutic agents are selected from an anti-PD-1 or PD-L1 antagonist, an MEK inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, ERK inhibitor, a SHP2 inhibitor, a platinum agent, a SMARCA2 inhibitor or pemetrexed.
Use of the compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 63 in the manufacture of a medicament for treating cancer.
A compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 63, for use in the treatment of cancer.