TW202509014A - Gsk3α inhibitors and methods of use thereof - Google Patents

Abstract

Disclosed are compounds and compositions which inhibit GSK3α, represented by the Formula (I’) or (X):

Description

GSK3α inhibitors and methods of use thereof

This application relates to GSK3α selective inhibitors and methods of use thereof, such as for enhancing anti-tumor immunity in an individual.

Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase encoded by two genes, GSK3α and GSK3β, first cloned by Woodgett JR [Woodgett JR, EMBO J 1990 ; 9(8):2431-8]. GSK3 kinase is a key regulator of the PI3K/mTOR/AKT downstream cell signaling pathway. GSK3 kinase phosphorylates a variety of substrates, including several transcription factors such as NFAT [Beals CR et al., Science 1997 ; 275(5308):1930-4], and c-Jun [Wei W et al., Cancer Cell 2005 ; 8(1):25-33]. In many cases, phosphorylation of substrates by GSK3 leads to subsequent ubiquitination by ubiquitin E3 ligases (e.g., FBXW7 or β-TrCP) followed by proteasomal degradation. Conversely, GSK3 inhibition can lead to stabilization and nuclear translocation of transcription factors, which in turn can activate multiple downstream pathways.

Given the important role of GSK3 in various cellular processes, targeting GSK3 with small molecule inhibitors may have therapeutic potential for different diseases, including (but not limited to) diabetes, cancer, viral infections, Alzheimer's disease and other CNS disorders. Several molecules have been tested in the clinic, including AZD1080 [Georgievska B et al., J Neurochem 2013 ; 125(3):446-56], LY2090314 [NCT01287520, NCT01214603] and others. However, dual inhibition of GSK3α and GSK3β results in activation of the Wnt/β-catenin pathway via stabilization of β-catenin, a potent oncogenic factor associated with hyperplasia in preclinical animal models [Hall AP et al., Toxicol Pathol 2015 ; 43(3):384-99].

Although the two isoforms, GSK3α and GSK3β, were initially thought to be functionally redundant, genetic studies have revealed functions that are unique to the homologs. Notably, while genetic knockout of GSK3β in mice is lethal [Hoeflich KP et al., Nature 2000 ; 406(6791):86-90], GSK3α knockout mice are viable [Zhou J et al., J Clin Invest 2013 ; 123(4):1821-32]. GSK3α knockout mice exhibit a mild aging phenotype that is associated with autophagy and mTOR pathway activation blockade, which can be reversed by treatment with the mTORC1 inhibitor everolimus (an immunosuppressive drug). Selective, acute inhibition of GSK3α or GSK3β in mouse embryonic stem cells (ESCs) also produces different morphological phenotypes and transcriptional patterns [Chen X et al., Dev Cell 2017 ; 43(5):563-576.e4]. In addition, Doble et al. reported that the absence of either GSK3α or GSK3β alone in mouse embryonic stem cells (ESCs) did not lead to accumulation of β-catenin, and that the absence of both homologs was required to stabilize β-catenin, which is consistent with the observations of dual GSK3 inhibitors [Doble BW et al., Dev Cell 2007 ; 12(6):957-71]. These lines of evidence suggest that selective inhibition of GSK3α by homologs may have different pharmacology and better safety/tolerability than dual GSK3 inhibition. There are early reports of such GSK3α selective compounds, however, the reported selectivity is limited, ranging from 3 to 40-fold [US20220112216A1; Wagner FF et al., Sci Transl Med 2018 ; 10(431):eaam8460; Amaral B et al., ACS Chem. Neurosci. 2023 ; 14(6):1080-94].

T cells are critical for immune surveillance and control of cancer progression. GSK3 inhibition is known to bypass the need for CD28-mediated T cell co-stimulation, leading to a surge and production of interleukins such as IL2 and IFNγ [Garcia CA et al., J Immunol 2008 ; 181(12):8363-71]. Dual GSK3 inhibitors have been identified in a phenotypic screening of a library of well-annotated kinase inhibitors for enhancers of antigen-specific T cell activation and tumor cell cytotoxicity. Inhibition of GSK3α but not GSK3β may generate anti-tumor immunity, and inhibition of GSK3α may be well tolerated. This hypothesis is supported by work from Pamela Ohashi's laboratory [Tran CW et al., J Immunol 2017 ; 199(12):4056-4065], which demonstrated that loss of GSK3α in CD4 T cells reduces levels of the negative T cell regulator Cbl-b after T cell stimulation. Other literature supporting selective targeting of GSK3α in immune and cancer cells comes from the work of Christopher E Rudd [Taylor A et al., Immunity 2016 ; 44(2):274-86] and the work of Alejandro Gutierrez [Hinze L et al., Cancer Cell 2019 ; 35(4):664-676.e7], which is through other proposed mechanisms.

This article describes the identification of selective inhibitors of GSK3α homologs and their use as single agents or in combination with anti-PD-1 or anti-PD-L1 in cancer immunotherapy. Without wishing to be bound by any theory, the mechanism is believed to be mediated through both T cells and other immune cell types (e.g., myeloid compartments) in the tumor microenvironment, although further investigation is ongoing. GSK3α selective inhibitors may be used as novel therapeutic approaches for the treatment of cancer and other diseases.

Provided herein are compounds and compositions that inhibit GSK3, more specifically GSK3α, thereby enhancing an individual's immune response. For example, the IC ₅₀ values for inhibition of GSK3α provided in Table 1 demonstrate that the compounds are potent inhibitors of GSK3α. The compounds provided herein are selective inhibitors of GSK3α. Also disclosed are methods of treating cancer using the compounds and compositions described herein.

In a first aspect, the present disclosure provides a compound of formula (I') or formula (X): (I') or (X), or a pharmaceutically acceptable salt thereof, wherein: is a single bond or a double bond; ^X1 is ^CR3 or N; ^X2 is selected from the group consisting of ^CR7 , N and ^NRd ; ^X3 is selected from the group consisting of ^CR12 , N and ^NRd ; ^X4 is selected from the group consisting of ^CR13 , N and ^NRd ; Z is O or S; ^R1 is selected from the group consisting of halogen, OH, CN, _C1 - _C4 alkyl and _C1 - _C4 alkoxy, wherein the _C1 - _C4 alkyl and the _C1 - _C4 alkoxy are each optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, OH and CN; ^R2 is selected from the group consisting of H, D, halogen, _C1 - _C4 alkyl and _C3 - _C10 cycloalkyl; R ³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , C ₃ -C ₁₀ cycloalkyl, 4- to 12-membered heterocyclic group, 4- to 12-membered aryl and 4- to 12-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₃ -C ₁₀ cycloalkyl and the 4- to 12-membered aryl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 residues each independently selected from the group consisting of O, S, N and NR ^d , and each of them is optionally substituted by 1 to 4 R ^c on the ring carbon; R ⁴ is selected from the group consisting of H, D, halogen, C ₁ -C ₄ alkyl and C ₃ -C ₁₀ cycloalkyl; R ⁵ is selected from the group consisting of halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted by 1 to 4 groups independently selected from the group consisting of halogen, OH and CN; R ⁶ is H or D; R ⁷ is selected from the group consisting of H, D, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C The present invention relates to a group consisting of a _C1 -C4 alkyl group, a C1-C4 alkoxy group, a C3-C10 cycloalkyl group and a 4-12 membered aryl group, wherein the _C1 - _C4 alkyl group, the _C1 - _C4 alkoxy group, the _C3 - _C10 cycloalkyl group and the 4-12 membered aryl group are each optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12 membered heterocyclic group and the 4-membered to 12 membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; R ⁸ is selected from the group consisting of H, D, halogen, _C1 - _C4 alkyl group and _C3 - _C10 cycloalkyl group; R ⁹ are each independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C ₁₀ cycloalkyl, 4- to 12-membered heterocyclic group, 4- to 12-membered aryl and 4- to 12-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₂ -C ₄ alkenyl, the C ₂ -C ₄ alkynyl, the C ₃ -C ₁₀ cycloalkyl and the 4- to 12-membered aryl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 R c each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; or R ⁷ and R ⁹ together with the carbon atom to which they are attached form Ring A, wherein Ring A is C ₃ -C ₁₀ cycloalkyl or a 4-membered to 12-membered heterocyclic group, wherein the C ₃ -C ₁₀ cycloalkyl is optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted by 1 to 4 R ^c on the ring carbon; or R ⁸ and R ⁹ together with the carbon atom to which they are attached form Ring B, wherein Ring B is C ₃ -C R ₈ and R 9 are taken together to form ═O; R 10 is selected from the group consisting of H, D, ^C ₁ -C ₄ alkyl, -(C(R a ) 2 ) n -OR b , -(C(R a ) 2 ) n -SO 2 R b , C 3 ^-C 10 cycloalkyl, 4 to 12 membered heterocyclic group, 4 to 12 membered aryl and 4 to 12 membered heteroaryl, wherein the C ₃ -C 10 cycloalkyl is optionally substituted with 1 to 4 R c, wherein the 4 to ¹² membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR d, and then optionally substituted with 1 to 4 R ^c on the ring carbon; or R ⁸ and R 9 are taken together to form ═O; R ¹⁰ is selected from the group consisting of H, D, C 1 -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ R ^b , C ₃ -C ₁₀ cycloalkyl, 4 to 12 membered heterocyclic group, 4 to 12 membered aryl and 4 to 12 membered heteroaryl, wherein the C _{The 1} - _C4 alkyl, the _C3 - _C10 cycloalkyl and the 4- to 12-membered aryl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 ring hetero atoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted with 1 to 4 R ^c on the ring carbon; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a 4- to 12-membered heterocyclic group having 1 to 4 ring hetero atoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted with 1 to 4 R ^c on the ring carbon; or R ⁷ and R ^{R 9} together with the carbon atom to which it is attached forms Ring A, and R ⁸ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are attached respectively form Ring C, wherein Ring A and Ring C are each optionally substituted on the ring carbon by 1 to 4 R ^c ; R ¹¹ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₁ -C ₄ halogenalkyl and C ₃ -C ₁₀ cycloalkyl; R ¹² is selected from the group consisting of H, D, halogenyl, C ₁ -C ₄ alkyl and C ₃ -C ₁₀ cycloalkyl; or R ¹¹ and R ^{R 12} together with the nitrogen atom and the carbon atom to which they are respectively attached form a ring D, wherein the ring D is selected from the group consisting of a 4-membered to 12-membered heterocyclic group and a 4-membered to 12-membered heteroaryl group, wherein the 4-membered to 12-membered heterocyclic group and the 4-membered to 12-membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; R ¹³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₁₀ cycloalkyl, a 4-membered to 12-membered heterocyclic group, a 4-membered to 12-membered aryl group and a 4-membered to 12-membered heteroaryl group, wherein the C ₁ -C The C 1 -C ₄ alkyl, the C ₁ -C ₄ alkoxy, the C ₃ -C ₁₀ cycloalkyl and the 4- to 12-membered aryl are each optionally substituted by 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted on the ring carbon by 1 to 4 R ^c ; R ¹⁴ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C _4- membered alkoxy groups are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH and CN; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-membered to 12-membered heterocyclic group, 4-membered to 12-membered aryl and 4-membered to 12-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₃ -C ₁₀ cycloalkyl and the 4-membered to 12-membered aryl are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH and CN, wherein the 4-membered to 12-membered heterocyclic group and the 4-membered to 12-membered heteroaryl have 1 to 4 groups each independently selected from O, S, N and NR ^d , and then optionally substituted on the ring carbon with 1 to 4 groups each independently selected from the group consisting of halogen, OH and CN; each R ^c is independently selected from the group consisting of H, D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, or two R ^c connected to the same atom form =0, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH and CN; each R ^d is independently selected from the group consisting of H, D, C _{1 -C 4} alkyl and C(O)C _1-4 alkyl; and m is 1, 2 or 3, and n is 0, 1, 2 or 3.

Another aspect of the present disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and a compound disclosed herein or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure is a method for treating a disease or condition responsive to inhibition of GSK3 (e.g., GSK3α), the method comprising administering to a subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound(s) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is cancer.

Another aspect of the present disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease or condition responsive to inhibition of GSK3 (e.g., GSK3α). In some embodiments, the disease or condition is cancer.

Another aspect of the present disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition responsive to inhibition of GSK3 (e.g., GSK3α). In some embodiments, the disease or condition is cancer.

Related applications

This application claims the benefit of U.S. Provisional Application No. 63/465,428 filed on May 10, 2023 and U.S. Provisional Application No. 63/530,858 filed on August 4, 2023, the entire teachings of which are incorporated herein by reference in their entirety.

The disclosed compounds are GSK3α inhibitors that can be used to treat diseases or conditions that are responsive to inhibition of GSK3α. Such diseases or conditions include cancer.

Example implementations include:

First embodiment: A compound represented by formula (I) or a pharmaceutically acceptable salt thereof (I), the variables in formula (I) are as described above for formula (I') in the first aspect.

Second embodiment: A compound represented by formula (II) or a pharmaceutically acceptable salt thereof (II), wherein the variables in formula (II) are defined as in the first embodiment.

Third embodiment: A compound represented by formula (IIa), formula (IIb) or formula (IIc) or a pharmaceutically acceptable salt thereof (IIa) (IIb) or (IIc), wherein the variables in formula (IIa), formula (IIb) and formula (IIc) are defined as in the first embodiment.

Fourth embodiment: A compound represented by Formula (I'), Formula (I), Formula (X), Formula (IIa), Formula (IIb) or Formula (IIc) or a pharmaceutically acceptable salt thereof, wherein Ring A is _C3 - _C6 cycloalkyl or 4-9 membered heterocyclic group, wherein the _C3 - _C6 cycloalkyl is optionally substituted by 1 to 2 ^Rc , wherein the 4-9 membered heterocyclic group has 1 to 2 ring heteroatoms independently selected from the group consisting of O, S and ^NRd , and then optionally substituted by 1 to 2 ^Rc on the ring carbon. The remaining variables in Formula (I'), Formula (I), Formula (X), Formula (IIa), Formula (IIb) or Formula (IIc) are as defined in the first embodiment. In some embodiments, the compound is represented by formula (IIc) or a pharmaceutically acceptable salt thereof.

Fifth embodiment: A compound represented by formula (I'), formula (I), formula (X), formula (IIa), formula (IIb) or formula (IIc) or a pharmaceutically acceptable salt thereof, wherein ring A is and the remaining variables in Formula (I'), Formula (I), Formula (X), Formula (IIa), Formula (IIb) and Formula (IIc) are as defined in the first or fourth embodiment. In some embodiments, the compound is represented by Formula (IIc) or a pharmaceutically acceptable salt thereof.

Sixth embodiment: A compound represented by formula (III) or a pharmaceutically acceptable salt thereof (III), wherein the variables in formula (III) are defined as in the first embodiment.

Seventh embodiment: A compound represented by formula (IIIa) or formula (IIIb) or a pharmaceutically acceptable salt thereof (IIIa) or (IIIb), wherein the variables in formula (IIIa) and formula (IIIb) are defined as in the first embodiment.

Eighth embodiment: A compound represented by formula (I'), formula (I), formula (X), formula (III), formula (IIIa) or formula (IIIb) or a pharmaceutically acceptable salt thereof, wherein ring B is _C3 - _C6 cycloalkyl or 4-6 membered heterocyclic group, wherein the _C3 - _C6 cycloalkyl is optionally substituted by 1 to 4 ^Rc , wherein the 4-6 membered heterocyclic group has 1 to 2 ring heteroatoms independently selected from the group consisting of O, S and ^NRd , and then optionally substituted by 1 to 2 ^Rc on the ring carbon. The remaining variables in formula (I'), formula (I), formula (X), formula (III), formula (IIIa) and formula (IIIb) are as defined in the first aspect or the first embodiment.

Ninth embodiment: A compound represented by formula (I'), formula (I), formula (X), formula (III), formula (IIIa) or formula (IIIb) or a pharmaceutically acceptable salt thereof, wherein ring B is cyclopropane, cyclobutane, cyclopentane or tetrahydropyran, each of which is optionally substituted by 1 to 2 ^Rc on the ring carbon. The remaining variables in formula (I'), formula (I), formula (X), formula (III), formula (IIIa) and formula (IIIb) are as defined in the first aspect or the first embodiment.

Tenth embodiment: A compound represented by formula (IV) or a pharmaceutically acceptable salt thereof (IV), wherein the variables in formula (IV) are defined as in the first embodiment.

Eleventh embodiment: A compound represented by formula (IVa), formula (IVb), formula (IVc) or formula (IVd) or a pharmaceutically acceptable salt thereof (IVa), (IVb), (IVc); or (IVd), wherein the variables in Formula (IVa), Formula (IVb), Formula (IVc) and Formula (IVd) are as defined in the first embodiment. In some embodiments, the compound is represented by Formula (IVc) or Formula (IVd) or a pharmaceutically acceptable salt thereof.

The twelfth embodiment: A compound represented by Formula (I'), Formula (I), Formula (X), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc) or Formula (IVd) or a pharmaceutically acceptable salt thereof, wherein Ring C is a 4- to 10-membered heterocyclic group having 1 to 3 heterocyclic atoms each independently selected from the group consisting of O, S and ^NRd , and then optionally substituted by 1 to 2 ^Rc on the ring carbon. The remaining variables in Formula (I'), Formula (I), Formula (X), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc) and Formula (IVd) are as defined in the first embodiment. In some embodiments, the compound is represented by Formula (IVc) or Formula (IVd) or a pharmaceutically acceptable salt thereof.

Thirteenth embodiment: A compound represented by formula (I'), formula (I), formula (X), formula (IV), formula (IVa), formula (IVb), formula (IVc) or formula (IVd) or a pharmaceutically acceptable salt thereof, wherein ring C is hexahydropyridine, 1,4-oxazacycloheptane, azacyclobutane, morpholine, pyrrolidine, hexahydropyrazine, hexahydropyrazine-2-one, octahydrocyclopenta[c]pyrrole or azacycloheptane, each of which is optionally substituted with 1 to 2 ^Rc on the ring carbon. The remaining variables in formula (I'), formula (I), formula (X), formula (IV), formula (IVa), formula (IVb), formula (IVc) and formula (IVd) are as defined in the first embodiment. In some embodiments, the compound is represented by Formula (IVc) or Formula (IVd) or a pharmaceutically acceptable salt thereof.

Fourteenth embodiment: A compound represented by formula (I'), formula (I), formula (X), formula (IV), formula (IVa), formula (IVb), formula (IVc) or formula (IVd) or a pharmaceutically acceptable salt thereof, wherein ring C is represented by the following: ; ; ; ; ; ; ; ; or , each of which is optionally substituted with 1 or 2 R ^c ; and each R ^c is independently a C ₁ -C ₃ alkyl group optionally substituted with a halogen or OH. Alternatively, R ^c is -CH ₃ or -CH ₂ OH. The remaining variables in Formula (I'), Formula (I), Formula (X), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc) and Formula (IVd) are as defined in the first embodiment. In some embodiments, the compound is represented by Formula (IVc) or Formula (IVd) or a pharmaceutically acceptable salt thereof.

Fifteenth Embodiment: A compound represented by formula (V) or a pharmaceutically acceptable salt thereof (V), wherein the variables in formula (V) are defined as in the first embodiment.

Sixteenth embodiment: A compound represented by formula (Va) or formula (Vb) or a pharmaceutically acceptable salt thereof (Va) or (Vb), wherein the variables in formula (Va) and formula (Vb) are defined as in the first embodiment.

Example 17: A compound represented by formula (VI) or a pharmaceutically acceptable salt thereof (VI), wherein the variables in formula (VI) are defined as in the first embodiment.

Eighteenth Embodiment: A compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein: ^X1 is ^CR3 or N; ^X2 is ^CR7 or N; ^X3 is ^CR12 or N; ^X4 is ^CR13 or N; Z is O or S; ^R1 is selected from the group consisting of halogen, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 alkoxy and _C1 - _C4 halogen; ^R2 is selected from the group consisting of H, D, _C1 - _C4 alkyl and _C3 - _C10 cycloalkyl; ^R3 is selected from the group consisting of H, D, halogen, CN, _C1 - _C4 alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , a C ₃ -C ₁₀ cycloalkyl group, a 4- to 12-membered heterocyclic group, a 4- to 12-membered aryl group, and a 4- to 12-membered heteroaryl group, wherein the C ₁ -C ₄ alkyl group, the C ₃ -C ₁₀ cycloalkyl group, and the 4- to 12-membered aryl group are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR ^d , and then each is optionally substituted with 1 to 4 R ^c on a ring carbon; R ⁴ is selected from the group consisting of H, D, a C ₁ -C ₄ alkyl group, and a C ₃ -C ₁₀ cycloalkyl group; R ^R5 is selected from the group consisting of halogen, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 alkoxy and _C1 - _C4 halogen; ^R6 is H or D; ^R7 is selected from the group consisting of H, D, halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, _C3 - _C10 cycloalkyl and 4-12 membered heterocyclic group, wherein the _C1 - _C4 alkyl, the _C1 - _C4 alkoxy and the _C3 - _C10 cycloalkyl are each optionally substituted with 1 to 4 ^Rc , wherein the 4-12 membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and ^NRd , and then each is optionally substituted with 1 to 4 ^Rc on the ring carbon; R ^{R 8} is selected from the group consisting of H, D, C ₁ -C ₄ alkyl and C ₃ -C ₁₀ cycloalkyl; R ⁹ is each independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C ₁₀ cycloalkyl, 4- to 12-membered heterocyclic group, 4- to 12-membered aryl and 4- to 12-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₂ -C ₄ alkenyl, the C ₂ -C ₄ alkynyl, the C ₃ -C ₁₀ cycloalkyl and the 4- to 12-membered aryl are each optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group and the 4-membered to 12-membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted on a ring carbon by 1 to 4 R ^c ; or R ⁷ and R ⁹ together with the carbon atom to which they are attached form a ring A, wherein ring A is a C ₃ -C ₁₀ cycloalkyl group or a 4-membered to 12-membered heterocyclic group, wherein the C ₃ -C ₁₀ cycloalkyl group is optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted on a ring carbon by 1 to 4 R ^c ; and/or R ^{R 8} and R ⁹ together with the carbon atom to which they are attached form Ring B, wherein Ring B is C ₃ -C ₁₀ cycloalkyl or a 4-membered to 12-membered heterocyclic group, wherein the C ₃ -C ₁₀ cycloalkyl is optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted on the ring carbon by 1 to 4 R ^c ; or R ⁸ and R ⁹ together form =0; R ¹⁰ is selected from H, D, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ R ^b , C ₃ -C The present invention relates to a group consisting of a C ₁ -C ₄ alkyl group, a C ₃ -C 10 cycloalkyl group and a 4 -12 membered heterocyclic group, a 4 -12 membered aryl group and a 4 -12 membered heteroaryl group, wherein the C 1 -C 4 alkyl group, the C ₃ -C ₁₀ cycloalkyl group and the 4 -12 membered aryl group are each optionally substituted by 1 to 4 R ^c , wherein the 4 -12 membered heterocyclic group and the 4 -12 membered heteroaryl group have 1 to 4 ring hetero atoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a ring having 1 to 4 atoms each independently selected from the group consisting of O, S and NR d. ^d, and optionally substituted by 1 to 4 R ^c on the ring carbon; R ¹¹ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl and C ₃ -C ₁₀ cycloalkyl; R 12 is selected from the group consisting of H, D, halogen ^, C 1 -C 4 alkyl and C ₃ -C ₁₀ cycloalkyl; R ¹³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, C _{1 -C 4} alkoxy, C ₃ -C ₁₀ cycloalkyl, 4 to ₁₂ membered heterocyclic group, 4 to 12 membered aryl and 4 to 12 membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkoxy, the C _{3 -C 10} cycloalkyl _-C10 cycloalkyl and the 4- to 12-membered aryl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR ^d , and then each is optionally substituted on the ring carbon with 1 to 4 R ^c ; R ¹⁴ is selected from the group consisting of H, D, and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH, and CN; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₃ -C ₁₀ cycloalkyl, 4- to 12-membered heterocyclic group, 4- to 12-membered aryl group, and 4- to 12-membered heteroaryl group, wherein the C ₁ -C ₄ alkyl, the C ₃ -C ₁₀ cycloalkyl, and the 4- to 12-membered aryl group are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH, and CN, wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR ^d , and are then optionally substituted on the ring carbon with 1 to 4 groups each independently selected from the group consisting of halogen, OH, and CN; each R ^{R c} is independently selected from the group consisting of H, D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, or two R ^c connected to the same atom form =0, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, OH and CN; each R ^d is independently selected from the group consisting of H, D, C _{1 -C 4} alkyl and C(O)C _1-4 alkyl; and n is 0, 1, 2 or 3.

Nineteenth embodiment: A compound represented by formula (VI) or a pharmaceutically acceptable salt thereof, wherein: ^X1 is ^CR3 or N; ^X2 is ^CR7 or N; ^X3 is ^CR12 or N; ^X4 is ^CR13 or N; Z is O; ^R1 is selected from the group consisting of halogen, OH, _C1 - _C4 alkyl, _C1 - _C4 alkoxy and _C1 - _C4 haloalkyl; ^R2 is selected from the group consisting of H, D and _C1 - _C4 alkyl;

^R3 is selected from the group consisting of H, D, halogen, CN, _C1 - _C4 alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , _C3 - _C8 cycloalkyl, 4- to 10-membered heterocyclic group, 4- to 10-membered aryl and 4- to 10-membered heteroaryl, wherein the _C1 - _C4 alkyl, the _C3 - _C8 cycloalkyl and the 4- to 10-membered aryl are each optionally substituted with 1 to 3 R ^c , wherein the 4- to 10-membered heterocyclic group and the 4- to 10-membered heteroaryl have 1 to 3 residues each independently selected from O, S, N and NR ^d , and each of them is optionally substituted by 1 to 3 R ^c on the ring carbon; R ⁴ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ⁵ is selected from the group consisting of halogen, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ halogen; R ⁶ is H or D; R ⁷ is selected from the group consisting of H, D, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic groups, wherein the C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkoxy and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R c on the ring carbon; ^c -substituted, wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then each is optionally substituted on the ring carbon by 1 to 3 R ^c ; R ⁸ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ⁹ is each independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl, the C ₂ -C ₄ alkenyl, the C ₂ -C ₄ alkynyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R c-substituted. ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then each is optionally substituted on the ring carbon by 1 to 3 R ^c ; or R ⁷ and R ⁹ together with the carbon atom to which they are attached form Ring A, wherein Ring A is C ₃ -C ₈ cycloalkyl or a 4- to 10-membered heterocyclic group, wherein the C ₃ -C ₈ cycloalkyl is optionally substituted by 1 to 3 R ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted on the ring carbon by 1 to 3 R ^c ; and/or R ⁸ and R ^{R 9} together with the carbon atom to which it is attached forms Ring B, wherein Ring B is C ₃ -C ₈ cycloalkyl or a 4-membered to 10-membered heterocyclic group, wherein the C ₃ -C ₈ cycloalkyl is optionally substituted by 1 to 3 R ^c , wherein the 4-membered to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted on the ring carbon by 1 to 3 R ^c ; or R ⁸ and R ⁹ together form ═O; R ¹⁰ is selected from H, D, C ₁ -C 4 alkyl, -(C(R a ) 2 ) n -OR b , -(C(R ^a ) 2 ) n -SO 2 R _b , C 3 -C ₈ cycloalkyl, -(C(R a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ R ^b , The group consisting of a C _{1 -C 4} alkyl group, a C ₃ -C 8 cycloalkyl group and a 4 -10 membered heterocyclic group, a 4 -10 membered aryl group and a 4 -10 membered heteroaryl group, wherein the C 1 -C ₄ alkyl group, the C ₃ -C ₈ cycloalkyl group and the 4 -10 membered aryl group are each optionally substituted by 1 to 3 R ^c , wherein the 4 -10 membered heterocyclic group and the 4 -10 membered heteroaryl group have 1 to 3 ring hetero atoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 3 R ^c on the ring carbon; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a ring having 1 to 3 atoms each independently selected from the group consisting of O, S and NR d. ^d , and optionally substituted by 1 to 3 R ^c on the ring carbon; R ¹¹ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R 12 is selected from the group consisting of H, D, halogen and C ₁ -C ₄ alkyl; R ¹³ is selected from ^the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted by 1 to 3 R ^c ; R ¹⁴ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl and C ₁ -C 4 alkoxy. wherein the C ₁ -C _{4 alkyl} group and the C ₁ -C ₄ alkoxy group are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, 4- to 10-membered heterocyclic group, 4- to 10-membered aryl and 4- to 10-membered heteroaryl, wherein the C ₁ -C ₄ alkyl group, the C ₃ -C 8 The 4- to 10-membered cycloalkyl and the _4- to 10-membered aryl are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN, wherein the 4- to 10-membered heterocyclic group and the 4- to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and are then optionally substituted on the ring carbon with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN; each R ^c is independently selected from the group consisting of H, D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, or two R ^c attached to the same atom form =0, wherein the C ₁ -C ₄ alkyl and the C ₁ -C 4 alkoxy are each independently selected from the group consisting of ₄ alkoxy groups are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN; each R ^d is independently selected from the group consisting of H, D, C _1- C ₄ alkyl and C(O)C _1-4 alkyl; and n is 0, 1, 2 or 3.

Example 20: A compound represented by formula (VIa), formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg) or formula (VIh) or a pharmaceutically acceptable salt thereof (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg) or (VIh), wherein the definitions of the variables in Formula (VIa), Formula (VIb), Formula (VIc), Formula (VId), Formula (VIe), Formula (VIf), Formula (VIg) and Formula (VIh) are as defined in the first, eighteenth or nineteenth embodiment.

Example 21: A compound represented by formula (VII) or a pharmaceutically acceptable salt thereof (VII), wherein the variables in formula (VII) are as defined in the first, eighteenth or nineteenth embodiment.

Example 22: A compound represented by formula (VIIa) or formula (VIIb) or a pharmaceutically acceptable salt thereof (VIIa) or (VIIb), wherein the variables in Formula (VIIa) and Formula (VIIb) are as defined in the first, eighteenth or nineteenth embodiment.

Embodiment 23: A compound represented by formula (I), formula (VIIa) or formula (VIIb) or a pharmaceutically acceptable salt thereof, wherein ^X1 is ^CR3 or N; ^X4 is selected from the group consisting of ^CR13 , N and ^NRd ; ^R1 is selected from the group consisting of halogen, _C1 - _C4 alkyl and _C1 - _C4 halogen alkyl; ^R2 is selected from the group consisting of H, D and _C1 - _C4 alkyl; ^R3 is selected from the group consisting of H, D, halogen, CN, _C1 - _C4 alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , _C3 -C The group consisting of _a C _{1 -C 4 alkyl group and a 4- to 10-membered heterocyclic group, wherein the C 1} -C ₄ alkyl group and the C ₃ -C ₁₀ cycloalkyl group are each optionally substituted by 1 to 3 R ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted by 1 to 3 R ^c on the ring carbon; R ⁴ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ⁵ is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl; R ⁶ is H or D; R ⁷ is selected from the group consisting of H, D, halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, C ₃ -C The present invention relates to a group consisting of a C ₁ -C ₄ alkyl group, a C 1 -C ₄ alkoxy group and a C 3 -C 6 cycloalkyl group, wherein the C ₁ -C ₄ alkyl group, the C ₁ -C ₄ alkoxy group and the C 3 -C 6 cycloalkyl group are each optionally substituted by 1 to 3 R ^c , wherein the 4 to 7 membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then each is optionally substituted on the ring carbon by 1 to 3 R ^c ; R ⁸ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ⁹ is each independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C The group consisting of C ₁ -C _{4 alkyl, C 2 -C 4} alkynyl and C 3 -C 8 cycloalkyl and ₄ -membered to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl, the C 2 -C 4 alkynyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R ^c , wherein the 4-membered to 10-membered heterocyclic group has 1 to 3 ring hetero atoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted on the ring carbon by 1 to 3 R ^c ; or R ⁸ and R ⁹ together with the carbon atom to which they are attached form Ring B, wherein Ring B is C ₃ -C ₈ cycloalkyl or 4-membered to 10-membered heterocyclic group, wherein the C ₃ -C ₈ cycloalkyl is optionally substituted by 1 to 3 R c ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted by 1 to 3 R ^c on the ring carbon; or R ⁸ and R ⁹ together form =0; R ¹⁰ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, -(C(R a ) 2 ) n -OR b , -(C(R ^a ) ₂ ) _n -SO 2 R b , C 3 -C 8 cycloalkyl and 4- to 10-membered heterocyclic group ^, wherein the _C 1 -C 4 alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted by _{1 to 3} R ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, ^S and _NR d, and is then optionally substituted by 1 to 3 R c on the ring carbon; or R ₈ and R ₉ together form =0; R 10 is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, -( ^C( R a ) 2 ) n -OR b , -(C(R a ) 2 ) n -SO 2 R b , C 3 -C 8 cycloalkyl and 4- to 10-membered heterocyclic group R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring ^C , wherein the ring C is a 4- to 10-membered heterocyclic ^group having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted by 1 to 3 R ^c on the ring carbon; R ¹¹ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ¹² is selected from the group consisting of H, D, halogen and C ₁ -C ₄ alkyl; R ¹³ is selected from the group consisting of H, D, halogen, CN and C ₁ -C ₄ alkyl; R ¹⁴ is selected from the group consisting of H, D and C ₁ -C each R ^a is independently selected from the group consisting of H, D and C _{1- C 4} alkyl; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN, wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then is optionally substituted on the ring atoms with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN; each R ^R is independently selected from the group consisting of D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, or two R ^a connected to the same atom form =0, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, OH and CN; each R ^d is independently selected from the group consisting of H, D, C _{1 -C 4} alkyl and C(O)C _1-4 alkyl; and n is 0, 1, 2 or 3.

Example 24: A compound represented by formula (VIIIa), formula (VIIIb), formula (VIIIc) or formula (VIIId) or a pharmaceutically acceptable salt thereof (VIIIa), (VIIIb), (VIIIc) or (VIIId), wherein the variables in Formula (VIIIa), Formula (VIIIb), Formula (VIIIc) and Formula (VIIId) are as defined in the first, eighteenth, nineteenth or twenty-third embodiment.

Embodiment 25: A compound represented by formula (VIIIe), formula (VIIIf), formula (VIIIg) or formula (VIIIh) or a pharmaceutically acceptable salt thereof (VIIIe), (VIIIf), (VIIIg) or (VIIIh), wherein the variables in Formula (VIIIe), Formula (VIIIf), Formula (VIIIg) and Formula (VIIIh) are as defined in the first, eighteenth, nineteenth or twenty-third embodiment.

Embodiment 26: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein ^R1 is halogen, -OH, C1- _C4 alkyl, or _{C1 -} C and the remaining variables are as defined in the first aspect or the first, _eighteenth , nineteenth or twenty-third embodiment.

Embodiment 27: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CH ₃ , -Cl, -OH or -OMe; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth or twenty-third embodiment.

Embodiment 28: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein ^R2 is H, D, halogen, or _C1 -C ₄ alkyl; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth or twenty-seventh embodiment.

Embodiment 29: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ² is H; and the remaining variables are defined as in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth or twenty-seventh embodiment.

Embodiment 30: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein ^R3 is selected from H, D, halogen, CN, _C1 -C the group _consisting of -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , C ₃ -C ₆ cycloalkyl, 4- to 7-membered heterocyclic group, phenyl and 4- to 6-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₃ -C ₆ cycloalkyl and the phenyl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 7-membered heterocyclic group and the 4- to 6-membered heteroaryl have 1 to 3 ring hetero atoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted with 1 to 3 R c on the ring carbon ^c is replaced; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth or twenty-ninth embodiment.

Embodiment 31: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and ( _X ), or a pharmaceutically acceptable salt thereof, wherein ^R3 is selected _{from -CH2CH3, -CH2OCH3 , -CF 3.} -OCH ₃ , H, -CN, -CHF ₂ , -CHFCH ₃ , -CHF-CH ₂ F, -CH(CH ₃ )OMe, -OCHF ₂ , Cl, -OCH ₂ CH ₃ , F, -CH ₃ , -O-cyclopropyl, -O-CH ₂ CH ₂ CH ₃ , -O-CF ₃ , -N(CH ₃ ) ₂ , -O-CH(CH ₃ ) ₂ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CH ₂ SO ₂ CH ₃ , -CF ₂ Me, -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₂ CH ₃ , -CH ₂ CF ₃ and -CH ₂ CO ₂ H, or represented by one of the following structures: ; and the remaining variables are defined as in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth or twenty-ninth embodiment.

Embodiment 32: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ³ is -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CF 2 ₃ or -OCH ₃ ; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth or twenty-ninth embodiment.

Embodiment 33: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein ^R4 is H, D, halogen, or _C1 -C and the remaining variables are as defined in the first aspect or the first, _eighteenth , nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first or thirty-second embodiment.

Embodiment 34: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is H; and the remaining variables are defined as in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first or thirty-second embodiment.

Embodiment 35: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein ^R5 is halogen, OH, _C1 - _C4 alkyl, _C1 -C and the remainder of _the variables are as _defined in the first aspect or the first, _eighteenth , nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third or thirty-fourth embodiment.

Embodiment 36: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is Me, Cl, -OH, -CHF ₂ or -OCH ₃ and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third or thirty-fourth embodiment.

Embodiment 37: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein ^R7 is H, D, halogen, _C1 - _C4 alkyl, _C1 -C wherein the C ₁ -C _{4 alkyl} group and the C ₁ -C ₄ alkoxy group are each optionally substituted with 1 to 3 R ^c , wherein the 4 to 7 membered heterocyclic group has 1 to 3 ring hetero atoms each independently selected from the group consisting of O, S and NR ^d , and then each is optionally substituted with 1 to 3 R ^c on the ring carbon; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth or thirty-sixth embodiment.

Embodiment 38: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh) and (X), or a pharmaceutically acceptable salt thereof, wherein ^R7 is H, morpholine-N-yl, _-CF3 , -F, -OCHF ₂ , -OCH ₂ CH ₃ or -OCH ₃ ; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth or thirty-sixth embodiment.

Embodiment 39: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H; and the remaining variables are defined as in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth or thirty-sixth embodiment.

Embodiment 40: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein ^R8 is H, D, halogen, or _C1 -C and the remainder of the variables are as defined in the first aspect or the first, _eighteenth , nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth or thirty-ninth embodiment.

Embodiment 41: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein ^R8 is H or _-CH3 and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth or thirty-ninth embodiment.

Embodiment 42: A compound represented by any one of Formula (I'), Formula (I), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VIa), Formula (VIb), Formula (VIc), Formula (VId), Formula (VIe), Formula (VIf), Formula (VIg), Formula (VIh), Formula (VII), Formula (VIIa), Formula (VIIb), Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), Formula (VIIId), Formula (VIIIe), Formula (VIIIf), Formula (VIIIg), Formula (VIIIh), Formula (VII), Formula (VIIa), Formula (VIIb), Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), Formula (VIIId), Formula (VIIIe), Formula (VIIIf), Formula (VIIIg), Formula (VIIIh), and Formula (X), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth or thirty-ninth embodiment.

Embodiment 43: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh) and (X), or a pharmaceutically acceptable salt thereof, wherein ^R9 is independently H, D, _C1 - _C4 alkyl, _C2 -C or _{C3 - C8} cycloalkyl, wherein the _C1 - _{C4 alkyl, the C2-C4 alkynyl and} the C3- _C8 cycloalkyl are each optionally substituted ^with ₁ to ₃ R ^c ; and the remainder of the variables are as defined in the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, _thirtieth , thirty ^- first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first or forty-second embodiment.

Embodiment 44: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ⁹ is H, Me, -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ CHF ₂ , cyclopropyl, -CH ₂ C≡CH, -CH ₂ CH ₂ OCH ₃ or -CHF ₂ ; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first or forty-second embodiment.

Embodiment 45: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ⁹ is H, Me, -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₃ or -CH ₂ OCH ₃ ; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first or forty-second embodiment.

Embodiment 46: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh) and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is H, D, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C( ^Ra ) ₂ ) _n -SO ₂ R ^b or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted with 1 to 3 R ^c ; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth or forty-fifth embodiment.

Embodiment 47: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ SO ₂ CH ₃ , -CD ₂ CD ₃ , -CH ₂ CH ₂ OH , -CH ₂ CH ₂ OCH ₃ , -CH(CH ₃ ) ₂ or -CD ₃ ; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth or forty-fifth embodiment.

Embodiment 48: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is H, -CH ₃ or -CH ₂ CH ₃ and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth or forty-fifth embodiment.

Embodiment 49: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is H, D, halogen, or C ₁ -C and the remainder of the variables are as defined in the first aspect or the first, _eighteenth , nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh or forty-eighth embodiment.

Embodiment 50: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is H; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh or forty-eighth embodiment.

Embodiment 51: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹² is H, D, halogen, or C ₁ -C and the remaining variables are as defined in the first aspect or the first, _eighteenth , nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth or the fiftieth embodiment.

Embodiment 52: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹² is selected from the group consisting of H, D or a halogen; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth or fiftieth embodiment.

Embodiment 53: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹² is H or F; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth or fiftieth embodiment.

Embodiment 54: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹² is H; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth or fiftieth embodiment.

Embodiment 55: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is H, D, halogen, or C ₁ -C and the remaining variables are as defined in the first aspect or the first, _eighteenth , nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third or fifty-fourth embodiment.

Embodiment 56: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is selected from the group consisting of H, D or a halogen; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third or fifty-fourth embodiment.

Embodiment 57: A compound represented by any one of Formula (I'), Formula (I), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VIa), Formula (VIb), Formula (VIc), Formula (VId), Formula (VIe), Formula (VIf), Formula (VIg), Formula (VIh), Formula (VII), Formula (VIIa), Formula (VIIb), Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), Formula (VIIId), Formula (VIIIe), Formula (VIIIf), Formula (VIIIg), Formula (VIIIh), Formula (VII), Formula (VIIa), Formula (VIIb), Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), Formula (VIIId), Formula (VIIIe), Formula (VIIIf), Formula (VIIIg), Formula (VIIIh), and Formula (X), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is H or F; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third or fifty-fourth embodiment.

Embodiment 58: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is H; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second or fifty-third embodiment.

Embodiment 59: A compound represented by any one of Formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va), (Vb), (VI), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), and (X), or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is H; and the remaining variables are as defined in the first aspect or the first, eighteenth, nineteenth, twenty-third, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty, forty-first, forty-second, forty-third, forty-fourth, forty-fifth, forty-sixth, forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third, fifty-fourth, fifty-fifth, fifty-sixth, fifty-seventh or fifty-eighth embodiment.

Sixtieth Embodiment: A compound represented by formula (IXa) or formula (IXb) or a pharmaceutically acceptable salt thereof (IXa), (IXb), wherein R ¹ is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ halogen; R ³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted with 1 to 3 R ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 groups each independently selected from O, S and NR ^d , and optionally substituted by 1 to 3 R ^c on the ring carbon; R ⁵ is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ halogenalkyl; R ⁸ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ⁹ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 each independently selected from O, S and NR ^d , and optionally substituted with 1 to 3 R ^c on the ring carbon; R ¹⁰ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₃ -C ₁₀ cycloalkyl and 4-membered to 12-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₁₀ cycloalkyl are each optionally substituted with 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and optionally substituted with 1 to 4 R ^c on the ring carbon; or R ⁹ and R ^{R 10} together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a 4- to 10-membered heterocyclic group having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted by 1 to 3 R ^c on the ring carbon; R ¹¹ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ¹³ is selected from the group consisting of H, D, halogen, CN and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D and C ₁ -C ₄ alkyl; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy; each R ^c is independently selected from the group consisting of D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C 4 alkoxy; -C ₄ alkoxy, or two ^Ras attached to the same atom form =0; and each ^Rd is independently selected from the group consisting of H, D and C ₁ -C ₄ alkyl; and n is 0, 1 or 2.

Sixty-first embodiment: A compound represented by formula (IXa) or formula (IXb) or a pharmaceutically acceptable salt thereof, wherein: ^R1 is a halogen group or a _C1 - _C3 alkyl group; ^R3 is a _C1 - _C3 alkyl group or -(C(R ^a ) ₂ ) _n -OR ^b , wherein n is 0, and R _b is a _C1 - _C3 alkyl group, wherein the _C1 - _C3 alkyl group is optionally substituted by 1 to 3 R ^c , wherein R ^c is independently a halogen group or a _C1 - _C3 alkoxy group; ^R5 is a halogen group or a _C1 - _C3 alkyl group; ^R8 is H; ^R9 is a _C1 - _C3 alkyl group or -(C(R ^a ) ₂ ) _n -OR ^b , wherein n is 0, and R _b is a _C1 - _C3 alkyl group, wherein the _C1 - _C3 alkyl group is optionally substituted by 1 to 3 R c ^c , wherein R ^c is independently halogen or C ₁ -C ₃ alkoxy; R ¹⁰ is H or C ₁ -C ₃ alkyl; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a 4- to 6-membered heterocyclic group; R ¹¹ is H; and R ¹³ is H.

Embodiment 62: A compound represented by formula (IXa) or formula (IXb) or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CH ₃ or -Cl; R ³ is -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CF ₃ or -OCH ₃ ; R ⁵ is -CH ₃ or -Cl; R ⁸ is H; R ⁹ is H, -CH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₃ or -CH ₂ OCH ₃ ; R ¹⁰ is H, -CH ₃ or -CH ₂ CH ₃ ; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is represented by the following: ; R ¹¹ is H; and R ¹³ is H.

The present disclosure also includes the compounds prepared in the Examples in neutral form and their pharmaceutically acceptable salts. Synthetic schemes used to prepare the disclosed compounds are illustrated in the Examples.

Another embodiment of the present disclosure is the compounds disclosed herein, including formula (I'), formula (I), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), formula (IVb), formula (IVc), formula (IVd), formula (V), formula (Va), formula (Vb), formula (VI), formula (VIa), formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf) , (VIg), (VIh), (VII), (VIIa), (VIIb), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (IXa), (IXb) and (X), or a compound as disclosed in the Examples, or a pharmaceutically acceptable salt of any of the foregoing, wherein one or more hydrogen atoms are replaced with deuterium. The deuterium enrichment at any site where hydrogen has been replaced with deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a molar percentage and is obtained by dividing the amount of compounds having deuterium enrichment at the enriched site by the amount of compounds having hydrogen or deuterium at the enriched site.

In some embodiments, the compound is selected from the following table, which shows the structures of the compounds described herein. Examples plan LCMS (MH ⁺ ) Structure 1 1 458 2 1 442 3 1 413 4 1 446 or 5 1 433 6 1 450 7 1 464 8 1 406 9 1 458 or 10 1 499 11 1 462 12 1 468 or 13 1 468 or 14 1 483 15 1 476 16 1 484 or 17 1 463 18 1 463 or 19 1 463 or 20 1 477 twenty one 1 489 twenty two 1 503 twenty three 1 518 twenty four 1 477 or 25 1 507 26 1 493 27 1 449 or 28 1 464 29 1 424 30 1 424 31 1 493 or 32 1 515 or 33 1 480 34 1 489 35 1 537 or 36 1 454 37 1 442 38 1 455 39 1 442 40 1 445 41 1 463 or 42 1 453 43 1 444 or 44 1 474 or 45 1 459 46 1 525 47 1 515 or 48 1 495 49 1 484 or 50 1 453 or 51 1 475 or 52 1 461 53 1 463 or 54 1 494 55 1 495 56 1 509 57 1 469 or 58 1 499 or 59 1 525 or 60 1 477 61 1 503 62 1 493 or 63 1 493 64 1 491 65 1 489 66 1 463 or 67 1 463 or 68 1 507 or 69 1 507 or 70 1 513 or 71 1 456 72 1 472 73 1 475 74 1 449 or 75 1 505 or 76 1 507 or 77 1 479 78 1 489 or or or 79 1 489 or or or 80 1 493 or 81 1 503 or or or 82 1 499 or 83 1 503 or or or 84 1 503 or or or 85 1 499 or 86 1 491 87 1 487 or or or 88 1 461 or 89 1 501 or 90 1 491 or or or 91 1 463 92 1 463 or or or 93 1 463 or or or 94 1 451 95 1 477 or 96 1 477 or or or 97 1 469 98 1 463 99 1 423 100 1 477 or 101 1 463 or or or 102 1 477 or or or 103 1 463 or or or 104 1 423 or 105 1 429 106 1 503 107 1 483 or or or 108 1 483 or or or 109 1 529 110 1 503 111 1 483 or 112 1 497 or or or 113 1 483 or 114 1 443 or or or 115 1 497 or or or 116 1 483 or 117 1 483 or 118 1 514 119 1 527 120 1 473 121 1 531 or 122 1 517 or 123 1 502 124 1 517 125 1 477 126 1 437 or 127 1 437 128 1 443 or 129 1 492 or 130 1 437 or 131 1 477 132 1 490 or 133 1 503 134 1 490 or 135 1 519 or 136 1 477 or 137 1 463 or 138 1 482 139 1 489 or 140 1 507 or 141 1 507 or 142 1 464 or 143 1 513 or 144 1 443 or 145 1 433 146 1 447 or 147 1 393 or 148 1 461 or 149 1 463 150 1 487 or 151 1 487 or 152 1 460 153 1 434 or 154 1 483 155 1 425 or 156 1 457 157 1 449 158 1 511 159 1 478 or 160 1 478 or 161 1 437 162 1 503 163 1 479 164 1 442 165 1 555 166 1 491 or 167 1 or 168 1 462 or 169 1 or 170 1 470 .TFA 171 1 472 172 1 490 or 173 1 441 174 1 437 or or or 175 1 437 or or or 176 1 451 177 1 467 or 178 1 477 179 1 475 180 1 458 181 1 461 182 1 505 183 1 489 184 1 465 or 185 1 465 or 186 1 483 187 1 505 or 188 1 505 or 189 1 473 or 190 1 473 or 191 1 474 or 192 1 501 193 1 and FGI 510 194 1 and FGI 501 195 1 and FGI 489 or 196 1 and FGI 517 197 1 463 or 198 1 and FGI 491 199 1 505 200 1 and FGI 500 201 1 and FGI 500 202 1 and FGI 515 203 1 and FGI 497 204 1 and remove protection 485 or 205 1 and FGI 449 206 1 and double deprotection 420 or 207 1 and FGI 477 208 1 505 or 209 1 and FGI 514 210 1 476 or 211 1 474 or 212 1 492 or 213 1 461 or 214 1 475 or 215 1 475 or 216 1 487 217 1 442 218 1 407 or 219 1 464 or 220 1 448 221 1 and FGI 434 222 1 506 or Definition

As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, and allergic reactions and commensurate with a reasonable benefit/risk ratio within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66: 1-19. The compounds of the present invention having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid). The compounds of the present teachings having an acidic group can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable alkali salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkali earth metal salts (such as magnesium salts and calcium salts).

The term "alkyl" used alone or as part of a larger moiety (such as "alkoxy", "hydroxyalkyl", and the like) means a saturated aliphatic straight or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl radical typically has 1 to 6 carbon atoms ( _C1 - _C6 alkyl), or 1 to 3 carbon atoms ( _C1 - _C3 alkyl). " _C1 - _C6 alkyl" means a radical having 1 to 6 carbon atoms in a straight or branched chain arrangement, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and the like.

"Alkoxy" means an alkyl group linked via an oxygen linking atom, represented by -O-alkyl, wherein alkyl is as defined above. For example, "C ₁ -C ₆ alkoxy" includes methoxy, ethoxy, propoxy, butoxy, pentyloxy, isopentyloxy, isopropoxy and hexyloxy.

"Alkynyl" refers to a branched or unbranched hydrocarbon moiety containing at least one triple bond. Unless otherwise specified, an alkynyl group contains 2 to 6 carbon atoms or 2 to 4 carbon atoms. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-methylpropynyl, 2-methylpropynyl, 3-methylpropynyl, and the like.

"Alkenyl" refers to a branched or unbranched hydrocarbon moiety containing at least one double bond. Unless otherwise specified, alkenyl groups contain 2 to 6 carbon atoms or 2 to 4 carbon atoms. Representative examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-methylpropenyl, and the like.

"Aryl" when used alone or as part of another moiety (such as aralkyl) refers to an aromatic hydrocarbon having 6 to 10 ring atoms, such as phenyl or naphthyl.

The term "halogen", "halogen" or "halogen" refers to fluorine (fluoro) (F), chlorine (chloro) (Cl), bromine (bromo) (Br) or iodine (iodo) (I).

"Cycloalkyl" means a saturated aliphatic cyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl has 3 to 8 ring carbon atoms ( _C3 - _C8 cycloalkyl) (i.e., 3, 4, 5, 6, 7, 8, 9 or 10), or has 3 to 6 ring carbon atoms ( _C3 - _C6 cycloalkyl) (i.e., 3, 4, 5 or 6), or has 3 to 5 carbon atoms ( _C3 - _C5 cycloalkyl) (i.e., ₃ , 4 or ₅ ). "C3- _C6 cycloalkyl" means a radical having 3 to 6 carbon atoms arranged in a single ring. _C3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The C ₃ -C ₅ cycloalkyl group includes cyclopropyl, cyclobutyl and cyclopentyl.

The term "heterocyclic group" refers to a monocyclic or bicyclic non-aromatic cyclic group, unless otherwise specified, containing 3 to 12 or 3 to 8 ring atoms selected from carbon atoms and 1 to 4 heteroatoms (i.e., "3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered"). Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO); oxygen; and sulfur, including sulfone and sulfone. Representative heterocyclics include hexahydropyridinyl, 1,4-oxazacycloheptanyl, azacyclobutanyl, morpholinyl, pyrrolidinyl, hexahydropyrazinyl, hexahydropyrazin-2-onyl, octahydrocyclopenta[c]pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, azacycloheptanyl, and the like. In some embodiments, the heterocyclic group is a saturated monocyclic ring. In some embodiments, the heterocyclic group is a saturated bicyclic ring.

"Heteroaryl" refers to an aromatic 4- to 12-membered monocyclic or bicyclic ring system having 1 to 4 heteroatoms independently selected from O, N, S and ^NRd , and wherein N may be oxidized (e.g., N(O)) or quaternary ammonium, and S may be optionally oxidized to sulfone and sulfone. Monocyclic heteroaryl groups have 5 or 6 ring atoms, i.e., 5- to 6-membered. Examples of 5- to 6-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl or thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyranyl, pyrazinyl, pyrimidinyl, triazinyl, tetrazinyl, and the like. Bicyclic heteroaryl groups have 8 to 10 ring atoms, i.e., are 8- to 10-membered. Examples of 8- to 10-membered bicyclic heteroaryl groups include, but are not limited to, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothiofuranyl, quinolinyl, isoquinolinyl, and the like.

The term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl group having at least one non-hydrogen substituent replacing a hydrogen substituent on the alkyl group. For purposes of illustration, a monofluoroalkyl group is an alkyl group substituted with one fluorine substituent, and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be recognized that if more than one substitution is present on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise specified).

If a group is described as "optionally substituted," the group may be (1) unsubstituted, or (2) substituted.

If a group is described as optionally substituted with up to a specified number of non-hydrogen substituents, then the group may be (1) unsubstituted; or (2) substituted with up to the specified number of non-hydrogen substituents or with up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl group optionally substituted with up to 3 non-hydrogen substituents, then any cycloalkyl group having fewer than 3 substitutable positions will optionally be substituted with up to as many non-hydrogen substituents as the cycloalkyl group has substitutable positions.

Compounds with one or more chiral centers may exist in various stereoisomeric forms, i.e., each chiral center may have the R or S configuration, or may be a mixture of the two. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all non-mirror and mirror isomers of a compound. Mirror isomers are stereoisomers that are mirror images of each other. Non-mirror isomers are stereoisomers with two or more chiral centers that are not identical and are not mirror images of each other.

When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by a chemical name (e.g., where the configuration is indicated by " R " or " S " in the chemical name) or a structure (e.g., where the configuration is indicated by a "wedge" key), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% (unless the structure or name is accompanied by the designation "racemic" or "racemate" as explained in the following two paragraphs). The "enrichment of the indicated configuration relative to the opposite configuration" is a molar percentage and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center by the total number of all compounds in the mixture having the same or opposite stereochemical configuration.

When the stereochemical configuration at a chiral center in a compound is depicted by either the chemical name (e.g., where configuration is indicated by " R " or " S " in the name) or the structure (e.g., where configuration is indicated by a "wedge" bond) and the structure is accompanied by the nomenclature "racemic" or "racemate" or is specified in the chemical name, a racemic mixture is expected.

When two or more stereoisomers are depicted by a chemical name or structure and the names or structures are linked by "or", one or the other of the two or more stereoisomers is intended, but not both.

When a disclosed compound having a chiral center is depicted by a structure without showing the configuration at the chiral center, the structure is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of the R and S configurations at the chiral center. When a disclosed compound having a chiral center is depicted by a chemical name without using " S " or " R " to indicate the configuration at the chiral center, the name is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of the R and S configurations at the chiral center.

A racemic mixture means a mixture of 50% of one mirror image isomer and 50% of its corresponding mirror image isomer. The present teachings encompass all mirror image pure mixtures, mirror image enriched mixtures, non-mirror image pure mixtures, non-mirror image enriched mixtures and racemic mixtures and non-mirror image mixtures of the compounds described herein.

Mirror isomers and non-mirror isomer mixtures can be separated into their component mirror isomers or stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex or crystallization of the compound in a chiral solvent. Mirror isomers and non-mirror isomers can also be obtained from non-mirror pure or mirror pure intermediates, reagents and catalysts by well-known asymmetric synthesis methods.

"Peak 1" or "first eluting isomer" in the experimental section refers to the desired reaction product compound obtained from chromatographic separation/purification, which elutes earlier than the second desired reaction product compound from the same previous reaction. The second desired product compound is referred to as "Peak 2" or "second eluting isomer".

When a compound is represented by a name or structure that designates a single mirror image isomer, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "mirrorically pure") unless otherwise indicated. Optical purity is the weight of the mixture of the named or depicted mirror image isomers divided by the total weight of the mixture of the two mirror image isomers.

When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a non-imaging isomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of encompassed stereoisomers is included unless otherwise indicated. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomeric purity is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

The number of carbon atoms in a group is designated herein by the prefix "C _x -C _xx ", where x and xx are integers. For example, "C ₁ -C ₃ alkyl" is an alkyl group having 1 to 3 carbon atoms.

The suffix "基" added to the end of a chemical name indicates that the named part is bonded to the molecule at one point, i.e., it is monovalent. The suffix "伸" added to the beginning of a chemical name indicates that the named part is bonded to the molecule at two points, i.e., it is divalent.

The compounds of the present disclosure are GSK3 inhibitors, more specifically GSK3α inhibitors. The term "inhibitor" is used to mean that the compound or a pharmaceutically acceptable salt thereof inhibits the activity of GSK3 (e.g., GSK3α). "Inhibition" herein means a reduction in the activity of the enzyme compared to the activity of the target enzyme in the absence of the inhibitor. In some alternatives, the term "inhibition" means a reduction in the activity of GSK3 (e.g., GSK3α) by at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, at least 80%, at least 90%, or at least 95%. In other alternatives, inhibition means a reduction in the activity of GSK3α by 5% to 25%, 25% to 50%, 50% to 70%, 75% to 100%. In some embodiments, inhibition means that the activity of GSK3 (eg, GSK3α) is reduced by about 95% to 100%, such as 95%, 96%, 97%, 98%, 99% or 100%. Such reduction can be measured using a variety of techniques known to those skilled in the art, including in vitro kinase assays.

The compounds of the present disclosure are selective GSK3α inhibitors. As used herein, "selective GSK3α inhibitor" refers to a compound or a pharmaceutically acceptable salt thereof that is capable of selectively inhibiting GSK3α kinase relative to other targets. More specifically, a selective GSK3α inhibitor is capable of selectively inhibiting GSK3α relative to another kinase. A selective GSK3α inhibitor is capable of selectively reducing target signaling activity relative to off-target signaling activity by directly or indirectly interacting with the target. The ability of a compound or a pharmaceutically acceptable salt thereof to selectively target GSK3α provides advantages in terms of improved efficacy, reduced off-target activity, and increased probability of clinical success compared to a non-selective compound or salt. The activity of a GSK3α inhibitor that selectively inhibits GSK3α relative to another kinase can be at least 2-fold (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selective; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200-fold). In some alternatives, a selective GSK3α inhibitor exhibits at least 15-fold selectivity relative to another kinase (e.g., GSK3β). In some alternatives, a selective GSK3α inhibitor has selectivity greater than GSK3β.

The present disclosure provides a method for modulating (e.g., inhibiting) the activity of GSK3 (more specifically GSK3α) in a patient in need thereof, the method comprising administering to the patient a compound provided herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the present disclosure or a pharmaceutically acceptable salt thereof can be used for therapeutic administration to enhance, stimulate and/or improve immunity in a patient in need thereof, such as a cancer patient or a patient suffering from a viral infection, diabetes, Alzheimer's disease and other CNS disorders.

In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used for therapeutic administration to enhance at least one of the activation, priming, migration, proliferation, survival and cytolytic activity of T cells relative to before administration. In certain aspects, the activation of T cells is characterized by an increase in the level of IL-2, IFN-γ or granzyme B production or surface markers of T cells relative to before administration of the compound or its pharmaceutically acceptable salt. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used for therapeutic administration to enhance the differentiation of T cells to a cytotoxic/exhaustion phenotype. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to modulate the phosphorylation level, stability and activity of immune pathway transcription factors such as NFAT and c-Jun. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to modulate the autophagy pathway in tumor cells and immune cells.

In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to reduce the recruitment, infiltration and differentiation of monocytes, tumor-associated macrophages and myeloid-derived suppressor cells. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to regulate regulatory T cells. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to enhance the cytotoxic function of NK cells. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to enhance the secretion of inflammatory cytokines by immune cell types other than T lymphocytes. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts indirectly inhibit the growth of cancer cells by regulating the tumor microenvironment. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to induce an immune response against a tumor or virus (i.e., a vaccine) to enhance or generate antiviral/anti-tumor immunity. In one case, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to enhance or strengthen the response to a vaccine (such as a cancer vaccine or a personalized cancer vaccine (PCV)) or CAR-T cell therapy.

Methods for treating diseases or conditions responsive to inhibition of GSK3 (e.g., GSK3α) activity may include administering to a patient in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. For example, the disease or condition is cancer. The term "cancer" encompasses all forms of cancer, including (but not limited to) all forms of carcinoma, melanoma, blastoma, sarcoma, lymphoma, leukemia. In some embodiments, cancer includes metastatic forms. In addition, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure or their pharmaceutically acceptable salts. For the uses described herein, any compound of the present disclosure or its pharmaceutically acceptable salt may be used alone or in combination with other therapeutic agents.

In some embodiments, a treatment produces a sustained response in a subject after the treatment has stopped. A "sustained response" refers to a persistent effect of reducing tumor growth after the treatment has stopped. For example, the tumor size can remain the same or smaller than it was at the beginning of the administration period. In some embodiments, a sustained response lasts at least as long as the duration of the treatment, at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the length of the treatment.

The treatment methods disclosed herein may produce a partial or complete response. As used herein, a "complete response" or "CR" means that all target lesions disappear; a "partial response" or "PR" means that the SLD of the target lesions decreases by at least 30% relative to the baseline sum of longest diameters (SLD); and "stable disease" or "SD" means that the target lesions have neither shrunk sufficiently to qualify as a PR nor increased sufficiently to qualify as a PD relative to the minimum SLD since the start of treatment. As used herein, "overall response rate" (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

The treatment methods disclosed herein can prolong progression-free survival and overall survival of individuals administered a selective GSK3α inhibitor. As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment that the disease being treated (e.g., cancer) does not get worse. Progression-free survival can include the amount of time a patient experiences a complete response or a partial response, as well as the amount of time a patient experiences stable disease.

As used herein, "overall survival" (OS) refers to the percentage of individuals in a group who are likely to survive after a specified duration.

Other cancers include, for example, sweat gland cancer, spinal tumors, breast cancer, and environmentally induced cancers, including those induced by asbestos. In some embodiments, cancers treatable using the compounds of the present disclosure or their pharmaceutically acceptable salts include, but are not limited to, advanced solid tumors with an inflammatory phenotype. In some embodiments, the inflamed solid tumor is a high tumor mutation burden (TMB-H) cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer (including urothelial carcinoma and Bacille Calmette-Guérin (BCG) unresponsive high-risk non-muscle invasive bladder cancer (NMIBC)), breast cancer (including triple-negative breast cancer), cervical cancer, colorectal cancer, endometrial cancer, squamous cell carcinoma of the skin, gastroesophageal cancer (including gastric cancer, gastroesophageal junction cancer and esophageal squamous cell carcinoma), hepatocellular carcinoma, leukemia (including acute myeloid leukemia (AML)), lung cancer (including malignant pleural mesothelioma, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), melanoma (including metastatic melanoma), lymphoma (including Hodgkin's lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL, including diffuse large B-cell lymphoma (DLBCL) and primary diaphragmatic large B-cell lymphoma), Merkel cell carcinoma, microsatellite instability-high (MSI-H) cancer, mismatch repair-deficient (dMMR) cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, squamous cell carcinoma of the head and neck (SCCHN), tumor mutation burden-high (TMB-H) cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of AML, bladder cancer, breast cancer, colorectal cancer, endometrial cancer, gastroesophageal cancer, hepatocellular carcinoma, melanoma, NHL, NSCLC, ovarian cancer, renal cell carcinoma, SCLC and SCCHN. In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, gastroesophageal cancer, hepatocellular carcinoma, malignant melanoma, NSCLC, renal cell carcinoma and SCCHN. In some embodiments, the cancer is selected from the group consisting of hepatocellular carcinoma, melanoma, NSCLC, SCLC and urothelial carcinoma. In some embodiments, the cancer is selected from the group consisting of melanoma, NSCLC and urothelial carcinoma.

In some embodiments, diseases and conditions treatable using the compounds of the present disclosure or pharmaceutically acceptable salts thereof include, but are not limited to, hematological cancers, sarcomas, respiratory cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include, for example, lymphomas and leukemias, such as acute lymphocytic leukemia (ALL), AML, acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (NHL) (including primary ventricular B-cell lymphoma (PMBCL), relapsed or refractory NHL), relapsed filtrate lymphoma (MLL), and leukemia. Follicular and primary CNS lymphomas, Hodgkin's lymphoma, myeloproliferative disorders (including primary myelofibrosis (PMF)), polycythemia vera (PV), essential thrombocythemia (ET), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

Exemplary sarcomas include, e.g., chondrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hamartoma, soft tissue sarcoma, and teratoma.

Exemplary respiratory tract cancers include, e.g., lung cancer, such as non-small cell lung cancer (NSCLC), small cell lung cancer, epidermoid carcinoma, bronchogenic carcinoma (including squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma), adenocarcinoma, alveolar (bronchial) carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, and pleuropulmonary blastoma.

Exemplary gastrointestinal cancers include, for example, esophageal cancer, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; gastric cancer, including carcinoma, lymphoma, and leiomyosarcoma; pancreatic cancer, including ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and vasoactive intestinal peptide tumor (vipoma); small intestinal cancer, including adenocarcinoma, lymphoma, carcinoid tumor, cardiomyopathy, and ulcerative colitis. Posey's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma and fibroma; colorectal cancer, including adenocarcinoma, tubular adenoma, villous adenoma, hamartoma and leiomyoma; colon cancer; and gallbladder cancer, including adenocarcinoma; as well as enteric and diffuse gastric adenocarcinoma, rectal cancer, common adenomatous polyposis cancer and hereditary non-polyposis colorectal cancer (CRC).

Exemplary genitourinary tract cancers include, for example, renal cancer, including adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma, urothelial carcinoma, juxtarenal glomerular cell tumor (nephrinoma), angiomyolipoma, renal oncocytoma, Bellinio duct carcinoma, carcinoma), renal clear cell sarcoma, and mesodermal nephroma; adrenal cancer; renal pelvic cancer; bladder cancer, including transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma; urethral cancer, including squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; prostate cancer, including adenocarcinoma, sarcoma, and carcinoma; testicular cancer, including seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma; penile cancer; and pancreatic cancer.

Exemplary liver cancers include, for example, hepatocellular carcinomas, including hepatocellular carcinoma, biliary carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, biliary carcinoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma, fibrosarcoma, malignant fibrohistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (including reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochronfroma (including osteochondrotic exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

Exemplary nervous system cancers include, for example, cranial cancers, including osteoma, hemangioma, granuloma, xanthomas, and osteitis deformans; meningeal cancers, including meningioma, meningiosarcoma, and neuroglioma; brain cancers, including astrocytoma, medulloblastoma, neuroglioma, ependymoma, embryonal neuroblastoma (pinealoma), neuroectodermal tumor, neuroglioblastoma, pleomorphic neuroglioma, oligodendritic neuroglioma, neurothectomy, retinoblastoma, congenital tumors, brain stem and hypothalamic neuroglioma; and spinal cord cancers, including neurofibroma, meningioma, neuroglioma and sarcoma; as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include, for example, uterine cancer, including endometrial cancer; cervical cancer, including cervical cancer, preneoplastic cervical dysplasia, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, glass cell carcinoma, and villous adenocarcinoma; ovarian cancer, including ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, endometrioid tumor, high-grade serous carcinoma (HGSC) or high-grade serous ovarian cancer (HGSOC)), granulosa-theca cell tumor, Sertoli-Leydig cell tumor (Sertoli-Leydig cell tumor), and ovarian cancer (ovarian cancer). tumor), malignant embryonal tumor, malignant teratoma, and ovarian adenoma containing testicular cells; vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; vaginal cancer, including clear cell carcinoma, squamous cell carcinoma, and botryoid sarcoma (embryonal rhabdomyosarcoma); labia cancer; and fallopian tube cancer.

Exemplary skin cancers include, for example, melanoma, sebaceous gland carcinoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell carcinoma, moles dysplastic nevi, lipoma, hemangioma, dermal fibroma, and keloid.

Examples of breast cancer include, e.g., ER+/HER2- breast cancer, triple-negative breast cancer (TNBC), invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Exemplary head and neck cancers include, e.g., neuroglioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer (including oropharyngeal cancer, laryngeal cancer), nasopharyngeal cancer, nasal and paranasal cancer, salivary gland cancer, oral cancer, eye cancer, acoustic neuroma, pituitary adenoma, hypopharyngeal cancer, and thyroid (medullary and papillary) and parathyroid cancer.

Other cancers include, for example, sweat gland cancer, spinal tumors, breast cancer and environmentally induced cancers, including those induced by asbestos.

In some cases, the disease or condition treatable using the compounds of the present disclosure or their pharmaceutically acceptable salts is a viral infection, such as infections caused by hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, and human immunodeficiency virus (HIV). Combination Therapy

The compounds of the present disclosure or their pharmaceutically acceptable salts can be administered as the sole pharmaceutical agent or in combination with one or more other anticancer agents for the treatment of cancer, wherein the combination does not cause unacceptable adverse effects. In some embodiments, the other anticancer agent is an immune-oncology agent, an anticancer agent that acts as an enzyme/protein/receptor inhibitor, radiation or chemotherapy.

The compounds of the present disclosure or their pharmaceutically acceptable salts can be co-formulated with tumor immunogens. Tumor immunogens include, for example, small molecule drugs, antibodies, or other biological agents or small molecules. Examples of biological tumor immunogens include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is a humanized or human antibody. In another aspect, the antibody is a bispecific antibody.

In one aspect, the tumor immunotherapy agent is (i) an agonist of stimulatory (including co-stimulatory) receptors or (ii) an antagonist of inhibitory (including co-inhibitory) signals on T cells, both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint regulators).

Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the family of TNF molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin alpha/TNP beta, TNFR2, TNF alpha, LTR, lymphotoxin alpha 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

In one embodiment, T cell responses can be stimulated by a combination of a compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more of the following: (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB, (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

In one aspect, the compounds of the present disclosure or their pharmaceutically acceptable salts may be administered in combination with at least one other immune checkpoint inhibitor. In other aspects, the compounds of the present disclosure or their pharmaceutically acceptable salts may be administered for the treatment of immune checkpoint inhibitor-resistant NSCLC, including situations where the individual is refractory or partially responsive to platinum and/or paclitaxel and/or docetaxel therapy. Depending on the circumstances, the compounds of the present disclosure or their pharmaceutically acceptable salts may be administered in combination with at least one other anticancer agent (such as paclitaxel, docetaxel, or platinum anticancer therapy). In some aspects, the compounds of the present disclosure or their pharmaceutically acceptable salts may be administered as a second or third line of treatment after platinum therapy. The compounds of the present disclosure or pharmaceutically acceptable salts thereof can be administered for the treatment of first-line NSCLC expressing high PD-L1 (tumor proportion score (TPS) ≥ 50%), wild-type EGFR or wild-type ALK.

Other agents that can be combined with the compounds of the present disclosure or their pharmaceutically acceptable salts for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds of the present disclosure can be combined with KIR antagonists (such as lirilumab).

Other agents for use in combination therapy include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies, including RG7155 or FPA-008.

In another embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof can be used together with one or more of the following: agonists that bind to positive co-stimulatory receptors, inhibitors that attenuate signal transduction through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome unique immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1/PD-1 interaction), depleting or inhibiting Treg (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing/preventing T cell anergy or exhaustion), and agents that trigger innate immune activation and/or inflammation at the tumor site.

In some embodiments, the tumor immunotherapy agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another embodiment, the tumor immunotherapy agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) or MEDI-0680 (AMP-514; WO2012/145493). Tumor immunotherapy agents may also include pidilizumab (CT-011), but its specificity for PD-1 binding is questioned. Another approach to targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224.

In another embodiment, the tumor immunotherapy agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874) and MSB0010718C (WO2013/79174).

In another aspect, the tumor immunotherapy agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10/19570, WO14/08218) or IMP-731 or IMP-321 (WO08/132601, WO09/44273).

In another embodiment, the tumor immunotherapy agent is a CD137 (4-1BB) agonist, such as an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12/32433).

In another aspect, the tumor immunotherapy agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WO11/028683).

In another embodiment, the tumor immunotherapy agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indoximod or NLG-919 (WO09/73620, WO09/1156652, WO111/56652, WO12/142237).

In another aspect, the tumor immunotherapy agent is an OX40 agonist, such as an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the tumor immunotherapy agent is an OX40L antagonist, such as an antagonist OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879).

In another embodiment, the tumor immunotherapy agent is a CD40 agonist, such as an agonist CD40 antibody. In another embodiment, the tumor immunotherapy agent is a CD40 antagonist, such as an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

In another aspect, the tumor immunotherapy agent is a CD27 agonist, such as an agonist CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

In another embodiment, the tumor immunotherapy agent is MGA271 (targeting B7H3) (WO1 1/109400).

The compounds of the present disclosure or their pharmaceutically acceptable salts can be used in combination with anticancer agents, which are enzyme/protein/receptor inhibitors that exhibit different preferences for the targets of their modulatory activity, to treat such diseases. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the likelihood of drug resistance in a cell population and/or reduce the toxicity of treatment.

The compounds of the present disclosure or their pharmaceutically acceptable salts can be used in combination with one or more other enzyme/protein/receptor inhibitors for the treatment of cancer. For example, the compounds of the present disclosure or their pharmaceutically acceptable salts can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βPv, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFotR, PDGFpR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4 , EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.

In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts can be combined with one or more of the following inhibitors for the treatment of cancer. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for the treatment of cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3 or FGFR4, such as fisogatinib, AZD4547, BAY 1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JJ-42756493, Debiol347, INCB54828, INCB62079 and INCB63904), JAK inhibitors (JAK1 and/or JAK2, such as ruxolitinib, baricitinib or itacitinib), (INCB39110)), IDO inhibitors (e.g., epacadostat and NLG919), LSD1 inhibitors (e.g., GSK2979552, INCB59872, and INCB60003), TDO inhibitors, PI3K-δ inhibitors (e.g., INCB50797 and INCB50465), PI3K-γ inhibitors (e.g., PI3K-γ selective inhibitors (eganelisib) or dual PI3K-δ/γ selective inhibitors (duvelisib), CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), angiogenesis inhibitors (e.g., Avastin) (bevacizumab), interleukin receptor inhibitors, bromodomain and extra terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329 and INCB57643), and adenosine receptor antagonists or combinations thereof. HDAC inhibitors (such as panobinostat and vorinostat) can be combined with the compounds of the present disclosure. c-Met inhibitors (such as onartumzumab, tivantnib and capmatinib) (INC-280) can be combined with the compounds of the present disclosure or their pharmaceutically acceptable salts. BTK inhibitors (such as ibrutinib) can be combined with the compounds of the present disclosure or their pharmaceutically acceptable salts. mTOR inhibitors (such as rapamycin, sirolimus, temsirolimus and everolimus) can be combined with the compounds of the present disclosure or their pharmaceutically acceptable salts. Raf inhibitors (such as vemurafenib and dabrafenib) can be combined with the compounds of the present disclosure or their pharmaceutically acceptable salts. MEK inhibitors (such as trametinib, selumetinib and GDC-0973) can be combined with the compounds of the present disclosure or their pharmaceutically acceptable salts. KIT inhibitors include avapritinib, imatinib, sunitinib, regorafenib, ripritinib (DCC2618), PLX9486, PLX3397, crenolanib, CDX-0158, CDX-0159. RET inhibitors, including pralsetinib, selperctinib, alectinib, levatinib, cabozantinib, BOS172738 (DS-5010), SL-1001, TPX-0046, sitravatinib (MGCD516), and RXDX-105. Hsp90 inhibitors (e.g., tanespimycin), cyclin-dependent kinase inhibitors (e.g., palbociclib), PARP inhibitors (e.g., olaparib), and Pim kinase inhibitors (LGH447, INCB053914, and SGI-1776), and KRAS inhibitors (e.g., sotorasib) may also be combined with the compounds of the present disclosure or their pharmaceutically acceptable salts.

The compounds of the present disclosure or their pharmaceutically acceptable salts can be used in combination with one or more agents for treating cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid or an immunomodulator. Examples of alkylating agents include bendamustine, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cytoxan, isocyclophosphamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphamide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX).

The compounds of the present disclosure or their pharmaceutically acceptable salts may be administered in combination with one or more anticancer drugs (e.g., chemotherapeutic agents). Example chemotherapeutic agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, de), bleomycin, bortezombi, bortezomib, brivanib, buparlisib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carmustine, cediranib, cetuximab, chlorambucil, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, actinomycin D dactinomycin, dalteparin sodium, dasatinib, actinomycin D, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate acetate), ibritumomab tiuxetan, idarubicin, idelalisib, isocyclophosphamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, purine, methotrexate, methoxsalen, mithramycin, mitromycin C mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium disodium), pentostatin, pilaralisib, pipobroman, plicamycin, cisplatin, carboplatin, oxaliplatin, ponatinib, prednisone, procarbazine, quinacrine, rasburicase, regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib, streptozotocin, sunitinib, sunitinib maleate, tamoxifen, Tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

Other anticancer agents include antibody therapies, such as trastuzumab (Herceptin).

The compounds of the present disclosure or their pharmaceutically acceptable salts can be administered as the sole pharmaceutical agent or in combination with one or more antiviral agents for the treatment of chronic viral infections, wherein the combination does not cause unacceptable adverse effects. Chronic viral infections include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). Parasitic infections (e.g., malaria) can also be treated by the above method, wherein compounds known to treat parasitic diseases are added instead of antiviral agents as appropriate.

Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure or their pharmaceutically acceptable salts may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.

Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emitricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and designated as β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (l-(ethoxy-methyl)-5-(l-methylethyl)-6-(phenylmethyl)-(2,4(lH,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Item No. 11607.

When more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (e.g., for two or more agents). For example, when administered with an additional anticancer agent or antiviral agent, the disclosed compounds or pharmaceutically acceptable salts thereof may be administered simultaneously in the same pharmaceutical formulation or simultaneously in separate pharmaceutical formulations. Alternatively, when administered with an additional anticancer agent or antiviral agent, the disclosed compounds or pharmaceutically acceptable salts thereof may be administered at different times, depending on the dosing requirements of the additional anticancer agent or antiviral agent.

Disclosed are pharmaceutical compositions comprising one or more compounds provided herein (e.g., Formula (I'), Formula (I), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IV), Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VIa), Formula (VIb), Formula (VIc), Formula (VId), Formula (VIe), Formula (VIf), Formula (VIg) , a compound of any one of Formula (VIh), Formula (VII), Formula (VIIa), Formula (VIIb), Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), Formula (VIIId), Formula (VIIIe), Formula (VIIIf), Formula (VIIIg), Formula (VIIIh), Formula (IXa), Formula (IXb) and Formula (X), or a compound as disclosed in the Examples) or a pharmaceutically acceptable salt thereof, and generally at least one additional substance (such as a formulator), known therapeutic agents other than those of the present disclosure, and combinations thereof. In some embodiments, the disclosed compounds or their pharmaceutically acceptable salts may be used in combination with other agents known to have beneficial activity against the diseases or conditions listed above. For example, the disclosed compounds or their pharmaceutically acceptable salts can be administered alone or in combination with one or more anticancer agents or antiviral agents and their pharmaceutically acceptable salts.

As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable the composition to be delivered to the desired site of biological action. Such methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used for the agents and methods described herein are described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

An "individual" is a mammal, preferably a human, requiring medical treatment, but may also be an animal requiring veterinary treatment, such as companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cattle, sheep, pigs, horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

The precise amount of compound or pharmaceutically acceptable salt thereof that provides an "effective amount" of the compound to be administered to a subject will depend on the mode of administration, the type and severity of the disease or disorder, and the characteristics of the subject, such as general health, age, sex, weight, and tolerance to drugs. Depending on these and other factors, one skilled in the art will be able to determine the appropriate dosage. When administered in combination with other therapeutic agents, for example, when administered in combination with anticancer agents or antiviral agents, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Appropriate dosages of approved therapeutic agents are known and can be adjusted by those skilled in the art according to the individual condition, the type of disease being treated, and the amount of the compound of the present disclosure or its pharmaceutically acceptable salt used, for example, as reported in the literature and recommended in the Physician's Desk Reference (57th edition, 2003).

The term "effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical results, such as inhibiting, suppressing or reducing symptoms of the disorder being treated in the subject as compared to a control.

The specific mode of administration and dosage regimen will be selected by the attending clinician taking into account the specific circumstances of the case (e.g., the individual, the disease, the disease state involved, the specific treatment, and whether the treatment is preventive). Treatment may involve daily or multiple daily or less than daily (e.g., weekly or monthly, etc.) administration over a period of several days to several months or even years.

The pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. In one embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

"Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the formulation of the active agent and/or its administration to a subject and/or absorption by a subject and that can be included in the composition of the present disclosure without producing significant adverse toxic effects to the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavor enhancers, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, linear starch or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine and coloring agents, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants and/or aromatic substances, and the like) that do not deleteriously react with the compounds provided herein or interfere with their activity. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds. General Synthetic Methods and Intermediates

The compounds of the present disclosure (including salts and N-oxides thereof) can be prepared using organic synthesis techniques known to those skilled in the art and/or by reference to the schemes and synthetic examples shown below. The schemes below are synthetic schemes intended to provide general guidance for preparing the compounds of the present disclosure. Those skilled in the art will understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present disclosure.

The reactions used to prepare the compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, one skilled in the art can select a suitable solvent for a specific reaction step.

The preparation of compounds of the present disclosure may 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 Wuts and Greene, Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.

The reaction may be monitored according to any suitable method known in the art. For example, product formation may be monitored by spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1H or 13C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS) or by analytic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Scheme 1 LG is a deradical, usually OMe

In Scheme 1, compounds of formula (I) can be prepared from compounds of formula (ii) and formula (iii) using an amide coupling reaction, typically in the presence of _Me3Al , in an aprotic solvent such as toluene at elevated temperature. Protecting groups such as tBoc can be removed in situ or as a separate step using a suitable acid such as TFA or HCl.

Compounds of formula (I) can be further reacted to provide alternative compounds of formula (I). For example, when ^X1 = ^CR3 , where ^R3 = halogen, one or more functional group interconversions known to those skilled in the art can be performed to provide alternative compounds where ^R3 is defined as in formula (I).

Those skilled in the art will appreciate that it may be necessary to employ an appropriate protecting group strategy for the preparation of compounds of formula (I). Typical protecting groups may include 4-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, carbamate or phthalimide, preferably Boc or phthalimide, for protecting primary or secondary aliphatic amines.

Additionally, it will be further understood that it may be necessary and/or desirable to perform the transformations in an order different from that depicted in the schemes, or to modify one or more of the transformations, in order to provide the desired compounds of the present invention.

In particular, typical functional group interconversions (FGI) include, in the case of ^X1 = ^CR3 , where ^CR3 = CHal, conversion to other compounds of formula (I), where ^X1 = ^CR3 , where ^R3 is defined in formula (I); a) palladium-catalyzed cross coupling with heterocyclic boronic acids or boronic acid salts; b) conversion of CHal to boronic acid followed by palladium-catalyzed cross coupling; c) reaction of CHal with an appropriate alcohol to give the corresponding ether; d) conversion of CHal to an alternative compound where ^R3 is described in formula (I). Scheme 2

_LG1 is a detached group, usually Cl. OR' is an alkyloxy group, usually OMe.

PG is an amine protecting group, usually 4-methoxybenzyl, 2,4-dimethoxybenzyl and Boc

In Scheme 2, compounds of formula (ii) can be prepared generally from compounds of formula (iv), formula (v), formula (vi), formula (vii), formula (viii) and formula (ix) using the steps outlined.

Compounds of formula (v) can be prepared by hydrolyzing compounds of formula (iv) in AcOH at elevated temperature.

Compounds of formula (vii) may be prepared by reacting compounds of formula (v) with a suitable amine of formula (vi) (PG) ₂ NH in the presence of an organic base such as DIPEA in an aprotic solvent such as DMSO at elevated temperature.

Compounds of formula (ix) can be prepared by reacting compounds of formula (vii) and formula (viii) in the presence of a base such as _K2CO3 or _DIPEA in DMF or DMSO at elevated temperature.

Compounds of formula (ii) can be prepared by deprotecting compounds of formula (ix) in excess TFA at elevated temperature.

Compounds of formula (ii) and/or formula (ix) can be further reacted to provide alternative compounds of formula (I). For example, when X ¹ = CR ³ , where R ³ = halogen, one or more functional groups can be interconverted to obtain alternative compounds where R ³ is as defined in formula (I).

It will be appreciated that it may be necessary and/or desirable to perform the transformations in an order different from that depicted in the schemes, or to modify one or more of the transformations, in order to provide the desired compounds of the invention.

Compounds containing one or more stereocenters may be separated into their individual stereoisomers by typical methods such as chiral SFC or chiral HPLC techniques as indicated in the Intermediates and Examples below.

The following examples are intended to be illustrative and not limiting in any way. Example Abbreviation 9-BBN 9-boronabicyclo[3.3.1]nonane Å Angstrom Ac ₂ O Acetic anhydride AcOH Acetic acid ATP Adenosine-5'-triphosphate BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl BID BID BIW BIC Boc tert-butyloxycarbonyl (Boc) ₂ O Di-tert-butyl dicarbonate BOP (1H-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate C Celsius CSA Camphorsulfonic acid DAST Diethylaminosulfur trifluoride DCE Dichloroethane DCM Dichloromethane DEAD Diethyl azodicarboxylate DIPA N,N-diisopropylamine DIPEA N,N-diisopropylethylamine DME Dimethoxyethane DMF Dimethylformamide DMAP 4-Dimethylaminopyridine DMSO Dimethylsulfoxide DPPA Diphenylphosphatidyl azide DTT Dithiothreitol EDC-HCl (3-Dimethylaminopropyl)-ethyl-carbodiimide hydrochloride EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDTA Ethylenediaminetetraacetic acid EtOAc Ethyl acetate EtMgBr Ethylmagnesium bromide EtOH Ethanol h hours HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide HEPES N-2-Hydroxyethylhexahydropyrazine-N'-2-ethanesulfonic acid Hex Hexane HOBt 1-Hydroxybenzotriazole HP-β-CD 2-Hydroxypropyl-β-cyclodextrin HPLC HPLC IC50 50% inhibition concentration IPA or i-PrOH Isopropyl alcohol Ir[dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ [4,4'- bis (1,1-dimethylethyl)-2,2'-bipyridyl- N 1, N 1'] bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl- N ]phenyl-C]iridium(III) hexafluorophosphate ip intraperitoneal iv intravenous KHMDS Potassium hexamethyldisilazane amide or potassium bis(trimethylsilyl)amide KOAc Potassium acetate LCMS Liquid chromatography-mass spectrometry LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide m/z Mass-to-charge ratio min MTBE methyl tert-butyl ether MeCN acetonitrile MeOH methanol MPLC medium pressure liquid chromatography NaOAc sodium acetate NaO ^t Bu sodium tert-butoxide n-BuLi n-butyl lithium NMO N-methylmorpholine N-oxide NMP N-methyl-2-pyrrolidone PBS phosphate buffered saline PdCl ₂ (PPh ₃ ) ₂ -bis(triphenylphosphine)palladium(II) chloride Pd ₂ (dba) _3- tris(diphenylmethylacetone)palladium(0) Pd(dppf)Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc) ₂ -palladium(II) acetate Pd(PPh ₃ ) _4Tetrakis (triphenylphosphine)palladium(0) PE Petroleum ether PPh _{3Triphenylphosphine} PPTS Pyridinium p-toluenesulfonate prep-HPLC Preparative high performance liquid chromatography prep-TLC Preparative thin layer chromatography rt Room temperature sat. aq. Saturated aqueous solution SFC Supercritical fluid chromatography t-BuOH tert-Butanol TBAB Tetrabutylammonium bromide TBAF Tetrabutylammonium fluoride TBHP tert-Butyl hydroperoxide TFA Trifluoroacetic acid TEA Triethylamine THF Tetrahydrofuran Ti(O ⁱ Pr) _4Titanium (IV) isopropoxide or titanium(IV) tetraisopropoxide TMSN _{3Trimethylsilyl} nitride

HPLC Code and Method .

Organic gradient 0-100%, optimized for each sample.

HPLC-1 (Phenomenex Luna C18 75 × 30 mm, 3 μm; MeCN/H ₂ O (0.2% HCO ₂ H)); HPLC-2 (Phenomenex Luna C18; 150 × 30 mm, 5 μm; MeCN/H ₂ O (0.2% HCO ₂ H); HPLC-3 (Phenomenex Luna C18; 200 × 40 mm, 10 μm; MeCN/H ₂ O (0.2% HCO ₂ H); HPLC-4 (Phenomenex Luna C18; 100 × 30 mm, 5 μm; MeCN/H ₂ O (0.2% HCO ₂ H); HPLC-5 (Phenomenex Luna C18; 100 × 25 mm, 4 μm; MeCN/H ₂ O (0.2% HCO ₂ H); HPLC-6 (Phenomenex Luna C18; 100 × 40 mm, 3 μm; MeCN/H ₂ O (0.2% HCO ₂ H); HPLC-7 (Phenomenex Luna C18; 80 × 30 mm, 3 μm; MeCN/H ₂ O (0.2% HCO ₂ H)); HPLC-10 (Gilson C18 150 × ₂₀ μm; MeCN/ _{H 2} O ( _0.1 % TFA)) _; Xbridge OBD 150 × 40 mm, 10 μm; MeCN/H ₂ O (NH ₄ HCO ₃ ); HPLC-12 (Waters XBridge C18 150 × 19 mm, 3 μm; MeCN/H ₂ O (0.1% TFA ₎ ; HPLC-13 (Waters ₂ H); HPLC-14 (Phenomenex Synergi Polar-RP, 100 × 25 mm, 4 μm; MeCN/H ₂ O (0.2% HCO ₂ H); HPLC-15 (Phenomenex Luna C18, 75 × 30 mm, 3 μm; MeCN/H ₂ O (NH ₄ HCO ₃ ); HPLC-16 (Phenomenex Gemini NX) C18, 75 × 30 mm, 3 μm; MeCN/H ₂ O (0.05% NH ₄ OH + 10 mM NH ₄ HCO ₃ ); HPLC-17 (Xtimate C18 250 × 80 mm, 10 μm; MeCN/H ₂ O (0.05% NH ₄ OH + 10 mM NH ₄ HCO ₃ ); HPLC-18 (YMC-Triart Prep _{HPLC - 19 ​ ​ ​ ​ 3} )); HPLC-20 ((Phenomenex luna C18, 250 × 70 mm, 15 μm); 1%-13% MeCN/H ₂ O (+ HCl); HPLC-21 (Phenomenex Titank C18 Bulk 250 × 70 mm, 10 μm; MeCN/H ₂ O (0.05% NH ₄ OH + 10 mM NH ₄ HCO ₃ )); HPLC-22 (Phenomenex Luna C18, 250 × 70 mm, 15 μm); MeCN/H ₂ O (0.2% HCO ₂ H)); HPLC-23 (Kromasil C18, 250 × 50 mm, 10 μm); MeCN/H ₂ O (0.05% NH ₄ OH + 10 mM NH ₄ HCO ₃ )); HPLC-24 (Phenomenex Luna C18 75 × 30 mm, 3 μm _; MeCN/(H ₂ O(+TFA)) _; HPLC-25 ₍ Waters _{( Welch ​ ​ ​ ​} NH ₄ HCO ₃ )). Intermediate A1. (S)-3-(1-amino-2-methoxyethyl)aniline. Step 1. Synthesis of 2-amino-2-(3-nitrophenyl)acetic acid

To a solution of 2-amino-2-phenyl-acetic acid (20 g, 132 mmol) in H ₂ SO ₄ (60 mL) at 0° C. was added a mixture of HNO ₃ (24.9 mL) in H ₂ SO ₄ (24 mL), and the mixture was stirred at 0° C. for 3 h. The reaction was quenched by adding to ice-cold H ₂ O (300 mL), and the solid was collected by filtration. The solid was triturated with H ₂ O (200 mL) at 25° C. and stirred for 20 min. The solid was then collected by filtration to give the title compound (25 g, 96%) as a light yellow solid. LCMS m/z = 197 [M+H] ⁺ . Step 2. Synthesis of 2-((tert-butoxycarbonyl)amino)-2-(3-nitrophenyl)acetic acid

To a solution of 2-amino-2-(3-nitrophenyl)acetic acid (25 g, 127 mmol) and (Boc) ₂ O (27.8 g, 127 mmol) in THF (50 mL) and H ₂ O (50 mL) was added Na ₂ CO ₃ (27 g, 255 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was triturated with HCl (20 mL) at 25 °C to pH = 2 and stirred for 20 min. The solid was collected by filtration to give the title compound as a yellow solid (22 g, 58%), which was used without further purification. Step 3. Synthesis of tert-butyl (2-hydroxy-1-(3-nitrophenyl)ethyl)carbamate

To a solution of 2-(tert-butoxycarbonylamino)-2-(3-nitrophenyl)acetic acid (10.5 g, 35.4 mmol) in THF (50 mL) was added BH ₃ .THF (1 M, 70.9 mL) at 0° C., and the mixture was stirred at 0° C. for 2 h. The reaction was quenched by adding MeOH (200 mL) at 0° C., and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (3.8 g, 38%) as a yellow oil. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ: 8.28-8.23 (m, 1H), 8.16 (dd, 1H), 7.76 (d, 1H), 7.65-7.55 (m, 1H), 4.77 (s, 1H), 3.82-3.65 (m, 3H), 1.45 (s, 9H). Step 4. Synthesis of 2-amino-2-(3-nitrophenyl)ethan-1-ol

A solution of tert-butyl (2-hydroxy-1-(3-nitrophenyl)ethyl)carbamate (3.8 g, 13.5 mmol) in HCl/EtOAc (40 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Xtimate C18, 250×80 mm, 10 μm; 1%-25% MeCN/H ₂ O (0.05% NH ₄ OH + 10 mM NH ₄ HCO ₃ )) to give the title compound as a white solid (1.83 g, 74%). LCMS m/z = 183 [M+H] ⁺ . Step 5. Synthesis of 2-methoxy-1-(3-nitrophenyl)ethan-1-amine

To a solution of 2-amino-2-(3-nitrophenyl)ethanol (1 g, 5.49 mmol) in THF (10 mL) was added NaH (329 mg, 8.23 mmol) at 0 °C for 5 min, and MeI (779 mg, 5.49 mmol) was added, and the mixture was stirred at 70 °C for 1 h. The reaction mixture was quenched by adding saturated aqueous NH ₄ Cl solution (15 mL) at 0 °C. The pH was adjusted to pH = 10 with saturated aqueous Na ₂ CO ₃ solution, and then extracted with EtOAc (3× 20 mL). The combined organics were dried ( _Na2SO4 ), evaporated to dryness in vacuo, and the residue purified by MPLC ( _SiO2 , 0-16% MeOH/EtOAc) _to give the title compound as a white solid (450 mg, 41.8%). LCMS m/z = 197 [M+H] ⁺ . Step 6. Synthesis of (S)-3-(1-amino-2-methoxyethyl)aniline

To a solution of 2-methoxy-1-(3-nitrophenyl)ethan-1-amine (450 mg, 2.29 mmol) in MeOH (5 mL) was added Pd/C (450 mg, 2.29 mmol, 10% purity), and the mixture was stirred under _H2 at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-(1-amino-2-methoxyethyl)aniline (340 mg, 89%) as a white solid.

The residue was purified by prep-HPLC (Xtimate C18, 250 × 80 mm, 10 μm; 15%-45% MeCN/H ₂ O (NH ₄ OH+NH ₄ HCO ₃ )) followed by SFC (REGIS (s,s) WHELK-O1, 250 × 50 mm, 10 μm); 50% IPA (+0.1% NH 4 OH) in CO ₂ ) to give: Peak 1, Intermediate A1 , (S)-3-(1-amino-2-methoxyethyl)aniline (130 mg, 38%) as a white solid. LCMS m/z = 167 [M+H] ⁺ . Intermediate A2. (R)-tert-butyl(1-(3-aminophenyl)ethyl)(methyl)carbamate Step 1. Synthesis of tert-butyl (R)-(1-(3-aminophenyl)ethyl)carbamate

Na ₂ CO ₃ (6.23 g, 58.7 mmol) was added to a solution of (R)-3-(1-aminoethyl)aniline (4 g, 29.4 mmol) and di-tert-butyl dicarbonate (6.41 g, 29.4 mmol) in THF (30 mL) and H ₂ O (10 mL), and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H ₂ O (20 mL) and extracted with EtOAc (3×20 mL). The combined organics were evaporated to dryness under reduced pressure and the residue was purified by MPLC (SiO ₂ , 1%-5% EtOAc/PE) to give the title compound as a yellow oil (5.05 g, 73%). Step 2. Synthesis of (R)-3-(1-(methylamino)ethyl)aniline

To a solution of tert-butyl (R)-(1-(3-aminophenyl)ethyl)carbamate (5.05 g, 21.4 mmol) in THF (100 mL) was added _LiAlH4 (4.06 g, 107 mmol) at 0° _C , and the mixture was stirred at 50°C under N2 for 3 h. The reaction mixture was quenched by adding _Na2SO4.10H2O ( ₅ g) at ₀ °C, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (3.4 g, crude). LCMS m/z = 151 [M+H] ⁺ . Intermediate A3. tert-butyl (R)-(1-(3-aminophenyl)ethyl)(methyl)carbamate.

To a solution of (R)-3-(1-(methylamino)ethyl)aniline (3.40 g, 22.6 mmol) in THF (30 mL) was added (Boc) ₂ O (2.96 g, 13.6 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 1%-5% EtOAc/PE) to give the title compound as a yellow solid (3.5 g, 62%). Intermediates A4 and A5. tert-butyl (R)-2-(5-aminopyridin-3-yl)hexahydropyridine-1-carboxylate and tert-butyl (S)-2-(5-aminopyridin-3-yl)hexahydropyridine-1-carboxylate. Step 1. Synthesis of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine - 1(2H) -carboxylate .

KHMDS (1 M, 502 mL) in THF (250 mL) was added to a solution of tert-butyl 2-oxohexahydridine-1-carboxylate (100 g, 502 mmol) in THF (500 mL) at -78°C, and the mixture was stirred at -78°C for 1 h, then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (197 g, 552 mmol) was added to the mixture, and the resulting mixture was stirred at -78°C for 1 h. The reaction mixture was slowly poured into H ₂ O (1000 mL) under nitrogen at 0°C-10°C, and extracted with EtOAc (3×1000 mL). The combined organics were washed with brine (2 x 1000 mL), dried ( _Na2SO4 ) and concentrated _to give the title compound as a yellow oil (220 g, crude) which was used without additional purification. ^1H NMR (400 MHz, _CDCl3 ): 5.14 (t, 1H), 3.47-3.42 (m, 2H), 2.11 (dt, 2H), 1.89 (s, 1H), 1.34 (s, 9H), 1.13-1.09 (m, 1H). Step 2. Synthesis of tert-butyl 5'-amino-5,6-dihydro-[2,3'- bipyridine ]-1(4H)-carboxylate .

To a mixture of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (63.41 g, 191 mmol) and (5-amino-3-pyridinyl)boronic acid (33 g, 239 mmol) in dioxane (300 mL) and H ₂ O (100 mL) was added K ₂ CO ₃ (126.64 g, 916 mmol) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (5.86 g, 7.18 mmol) at 25° C. and the mixture was stirred under N ₂ at 100° C. for 1 h. The reaction mixture was partitioned between EtOAc (1000 mL) and H ₂ O (1000 mL), and the aqueous phase was extracted with EtOAc (3×1000 mL). The combined organics were dried ( _Na2SO4 ) and evaporated _to dryness in vacuo. The residue was purified by column chromatography ( _SiO2 , 33%-100% EtOAc/PE) to give the title compound as a yellow solid (60 g, 91%). LCMS m/z = 276 [M+H] ⁺ . Step 3. Synthesis of (R)-tert-butyl 2-(5-aminopyridin - 3- yl)hexahydropyridine - 1 -carboxylate and (S)-tert-butyl 2-(5-aminopyridin - 3- yl) hexahydropyridine -1- carboxylate .

To a mixture of tert-butyl 5'-amino-5,6-dihydro-[2,3'-bipyridine]-1(4H)-carboxylate (15 g, 54.5 mmol) in EtOAc (150 mL) was added Pd/C (15 g, 10% purity) at 25 °C, and the reaction mixture was stirred under _H2 at 50 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 2-(5-amino-3-pyridyl)hexahydropyridine-1-carboxylate (15 g, crude) as a white solid.

The racemate was separated by SFC (Chiralcel C2-3, 100 × 4.6 mm, 3 μm; EtOH (0.1% IPAm) in CO ₂ ) to give: Peak 1. Intermediate A4 , (R)-2-(5-aminopyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (23 g, 60%). Peak 2. Intermediate A5 , (S)-2-(5-aminopyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (23 g, 60%). Intermediate A6. ((5-aminopyridin-3-yl)methyl)(methyl)carbamic acid tert-butyl ester. Step 1. Synthesis of 1-(5- bromopyridin -3- yl)-N-methylmethanamine .

A mixture of 5-bromopyridine-3-carbaldehyde (5 g, 26.88 mmol) in methylamine (27.83 g, 269 mmol, 30% purity) was stirred at 25 °C under _N2 for 12 h, and _NaBH4 (2.03 g, 53.8 mmol) was added at 0 °C. The resulting mixture was stirred at 25 °C under _N2 for 2 h. The reaction mixture was quenched by the addition of saturated 0.5 M HCl (10 mL) at 0 °C and extracted with EtOAc (3 x ₁₀ mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as a yellow oil (5.30 g). LCMS m/z = 201 [M+H] ⁺ . Step 2. Synthesis of tert-butyl ((5- bromopyridin -3- yl)methyl)(methyl)carbamate .

To a solution of 1-(5-bromopyridin-3-yl)-N-methylmethanamine (5.20 g, 25.9 mmol) and (Boc) ₂ O (5.64 g, 25.9 mmol) in THF (52 mL) and H ₂ O (13 mL) was added Na ₂ CO ₃ (5.48 g, 51.7 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction was diluted with H ₂ O (80 mL) and extracted with EtOAc (3× 50 mL). The combined organics were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 50% EtOAc/PE) to give the title compound (4.50 g, 57.8%) as a yellow oil. LCMS m/z = 301 [M+H] ⁺ . Step 3. Synthesis of tert-butyl ((5-((diphenylmethylene)amino) pyridin -3- yl)methyl)(methyl)carbamate .

To a solution of tert-butyl ((5-bromopyridin-3-yl)methyl)(methyl)carbamate (4.40 g, 14.61 mmol) and diphenylformaniline (2.91 g, 16.07 mmol) in dioxane (70 mL) were added _Pd2 (dba) ₃ (1.34 g, 1.46 mmol), Xantphos (1.69 g, 2.92 mmol) and _Cs2CO3 (14.28 g, 43.83 mmol), and the mixture was stirred under _N2 at 100 °C for 3 h _. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 50% EtOAc/PE) to give the title compound as a yellow oil (3.50 g, 60%). LCMS m/z = 402 [M+H] ⁺ . Step 4. Synthesis of tert-butyl ((5-aminopyridin - 3- yl)methyl)(methyl)carbamate .

To a solution of tert-butyl ((5-((diphenylmethylene)amino)pyridin-3-yl)methyl)(methyl)carbamate (3.40 g, 8.47 mmol) in MeOH (40 mL) were added _NH2OH.HCl (1.18 g, 16.94 mmol) and NaOAc (1.39 g, 16.94 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure _to give a residue that was purified by MPLC ( _SiO2 , EtOAc) to give the title compound as a yellow oil (2.00 g, 99.5%). LCMS m/z = 238 [M+H] ⁺ . Intermediate A7. (R)-tert-butyl(1-(5-aminopyridin-3-yl)butyl)carbamate. Step 1. Synthesis of (E)-N-((5- bromopyridin -3- yl)methylene)-2-methylpropane-2-sulfenamide .

To a solution of 5-bromonicotinaldehyde (5 g, 26.88 mmol) and 2-methylpropane-2-sulfenamide (3.58 g, 29.57 mmol) in THF (60 mL) was added Ti(OEt) ₄ (7.97 g, 34.95 mmol) and the mixture was stirred at 40 °C for 12 h. The reaction mixture was added to H ₂ O (50 mL) and then the solids were removed by filtration and the filter cake was washed with EtOAc (3× 20 mL). The aqueous phase was extracted with additional EtOAc (3× 50 mL) and the combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was purified by MPLC (SiO ₂ , 1%-50% EtOAc/PE) to give the title compound (6 g, 77%) as a white solid. LCMS m/z = 291 [M+H] ⁺ . Step 2. Synthesis of N-(1-(5- bromopyridin -3- yl)butyl)-2-methylpropane-2-sulfenamide .

To a solution of (E)-N-((5-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfenamide (Step 1, 3.90 g, 13.49 mmol) in THF (20 mL) was added propylmagnesium chloride (2 M, 10.11 mL) at -78 °C, and the mixture was stirred at 0 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc) to give the title compound (5.10 g, crude) as a yellow solid. LCMS m/z = 335 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (5-(1-((tert-butylsulfinyl)amino)butyl) pyridin -3- yl)carbamate .

To a solution of tert-butyl carbamate (3.51 g, 30 mmol) and N-(1-(5-bromopyridin-3-yl)butyl)-2-methylpropane-2-sulfenamide (5.00 g, 15 mmol) in dioxane (30 mL) were added _{Cs2CO3 (} 7.33 g, 22.5 mmol) and _Pd2 (dba) ₃ (1.37 g, 1.50 mmol), XPhos (715 mg, 1.50 mmol), and the mixture was stirred under _N2 at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (3.00 g, 54%) as a white solid. LCMS m/z = 370 [M+H] ⁺ . Step 4. Synthesis of 5-(1-aminobutyl) pyridin -3- amine .

A solution of tert-butyl (5-(1-((tert-butylsulfinyl)amino)butyl)pyridin-3-yl)carbamate (3.00 g, 8.12 mmol) in HCl/EtOAc (1 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under _N2 to give the title compound as a yellow solid (2.60 g, crude). LCMS m/z = 166 [M+H] ⁺ . Step 5. Synthesis of tert-butyl (R)-(1-(5-aminopyridin - 3- yl)butyl)carbamate .

To a solution of 5-(1-aminobutyl)pyridin-3-amine (1.10 g, 6.66 mmol) in dioxane (10 mL) and H ₂ O (5 mL) were added NaHCO ₃ (559 mg, 6.66 mmol) and (Boc) ₂ O (581 mg, 2.66 mmol), and the mixture was stirred at 25° C. for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give tert-butyl (1-(5-aminopyridin-3-yl)butyl)carbamate, which was further separated by SFC (DAICEL CHIRALPAK AD, 250 × 30 mm, 10 μm); 30% EtOH (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 2. Intermediate A7 . (R)-tert-butyl (1-(5-aminopyridin-3-yl)butyl)carbamate (white solid, 210 mg, 11.9%). LCMS m/z = 266 [M+H] ⁺ . Intermediate A8. (S)-tert-butyl(1-(5-aminopyridin-3-yl)propyl)carbamate or (R)-tert-butyl(1-(5-aminopyridin-3-yl)propyl)carbamate.

The title compound was prepared using a 5-step procedure similar to that described for intermediate A7 . Chiral SFC (DAICEL CHIRALPAK AD, 250 × 30 mm, 10 μm); 33% EtOH (+ 0.1% NH ₄ OH in CO ₂ )) gave: Peak 2, intermediate A8 . (S)-tert-butyl(1-(5-aminopyridin-3-yl)propyl)carbamate or (R)-tert-butyl(1-(5-aminopyridin-3-yl)propyl)carbamate (yellow solid: 1.1 g, 15%); LCMS m/z = 252 [M+H] ⁺ . Intermediate A9. (S)-tert-butyl((5-aminopyridin-3-yl)(cyclopropyl)methyl)carbamate or (R)-tert-butyl((5-aminopyridin-3-yl)(cyclopropyl)methyl)carbamate.

The title compound was prepared using a 5-step procedure similar to that described for intermediate A7 .

Chiral SFC (DAICEL CHIRALPAK AD, 250 × 50 mm, 10 μm); 30% EtOH (+ 0.1% NH ₄ OH in CO ₂ )) gave: Peak 1, intermediate A9 . (S)-tert-butyl((5-aminopyridin-3-yl)(cyclopropyl)methyl)carbamate or (R)-tert-butyl((5-aminopyridin-3-yl)(cyclopropyl)methyl)carbamate (yellow oil: 630 mg, 13%); LCMS m/z = 252 [M+H] ⁺ . Intermediates A10 and A11. tert-butyl (R)-(1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate and tert-butyl (S)-(1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate. Step 1. Synthesis of tert-butyl (5-(2-ethoxyacetyl) pyridin -3- yl)carbamate .

n-BuLi (2.5 M in hexanes, 14.65 mL) was added dropwise to a solution of tert-butyl N-(5-bromo-3-pyridinyl)carbamate (5.00 g, 18.3 mmol) in THF (150 mL) at -60 °C. The mixture was stirred at -60 °C for 30 min under _N2 , and ethyl 2-ethoxyacetate (2.90 g, 22 mmol) was added, and the mixture was stirred at 25 °C under _N2 for 2 h. The reaction mixture was quenched by the addition of saturated aqueous _NH4Cl solution (20 mL) at 0 °C, and then diluted with _H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge Prep OBD C18, 150 × 40 mm, 10 μm; 15%-45% MeCN/H ₂ O (NH ₄ OH + NH ₄ HCO ₃ )) to give the title compound as a yellow oil (1.40 g, 27%). LCMS m/z = 281 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (E)-(5-(2-ethoxy-1-(hydroxyimino)ethyl) pyridin -3- yl)carbamate .

To a mixture of tert-butyl (5-(2-ethoxyacetyl)pyridin-3-yl)carbamate (1.28 g, 4.57 mmol) in EtOH (20 mL) was added NH ₂ OH.HCl (381 mg, 5.48 mmol) and NaOAc (749 mg, 9.13 mmol), and the mixture was stirred at 75 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH ₄ Cl (20 mL) at 0 °C, diluted with H ₂ O (20 mL) and extracted with EtOAc (3× 20 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound (1.30 g, 96%). LCMS m/z = 291 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (5-(1-amino-2-ethoxyethyl) pyridin -3- yl)carbamate .

A mixture of (E)-tert-butyl(5-(2-ethoxy-1-(hydroxyimino)ethyl)pyridin-3-yl)carbamate (1.05 g, 3.56 mmol), Pd/C (600 mg, 3.56 mmol, 10% purity), NH ₄ OH (1 mL) and IPA (10 mL) was degassed and purged with H ₂ (50 psi) for 3 h, and then the mixture was stirred under H ₂ (50 psi) at 50 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (960 mg, 96%) as a white solid. LCMS m/z = 282 [M+H] ⁺ . Step 4. Synthesis of 5-(1-amino-2-ethoxyethyl) pyridin -3- amine hydrochloride .

A mixture of tert-butyl (5-(1-amino-2-ethoxyethyl)pyridin-3-yl)carbamate (800 mg, 2.84 mmol) in EtOAc (6 mL) and HCl/EtOAc (3 mL) was stirred at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (400 mg, 77%). LCMS m/z = 182 [M+H] ⁺ . Step 5. Synthesis of tert-butyl (R)-(1-(5-aminopyridin - 3- yl)-2-ethoxyethyl)carbamate and (S)-tert-butyl (1-(5-aminopyridin - 3- yl)-2-ethoxyethyl)carbamate .

A mixture of 5-(1-amino-2-ethoxyethyl)pyridin-3-amine hydrochloride (400 mg, 1.84 mmol), Boc ₂ O (160 mg, 0.735 mmol), NaHCO ₃ (309 mg, 3.67 mmol) in THF (15 mL) and H ₂ O (5 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H ₂ O (10 mL) and extracted with EtOAc (3×10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure _to give tert-butyl (1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate, which was separated by chiral SFC (DAICEL CHIRALPAK IC, 250×30 mm, 10 μm); 28% EtOH (0.1% _NH4OH ) in _CO2 ) to give: Peak 1, intermediate A10 . (R)-tert-butyl (1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate or (S)-tert-butyl (1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate. Peak 2, intermediate A11 , (R)-(1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamic acid tert-butyl ester or (S)-(1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamic acid tert-butyl ester. LCMS m/z = 282 [M+H] ⁺ . Intermediate A12. 5-((ethylamino)methyl)pyridin-3-amine. Step 1. Synthesis of N-ethyl-5-nitronicotinamide .

To a solution of 5-nitronicotinic acid (5 g, 29.7 mmol) in pyridine (10 mL) were added ethylamine hydrochloride (12.13 g, 148.7 mmol) and EDCI (8.55 g, 44.61 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (3.5 g, 60%) as a white solid. LCMS m/z = 196 [M+H] ⁺ . Step 2. Synthesis of 5-amino-N-ethylnicotinamide .

To a mixture of N-ethyl-5-nitronicotinamide (3.4 g, 17.42 mmol) in MeOH (5 mL) was slowly added Pd/C (4 g, 25.62 mmol, 10% purity), and the mixture was stirred under _H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (2.8 g, 97%). LCMS m/z = 166 [M+H] ⁺ . Step 3. Synthesis of 5-((ethylamino)methyl) pyridin -3- amine .

To a solution of N-ethyl-5-nitronicotinamide (1.5 g, 9.08 mmol) was added BH ₃ .THF (1 M, 45.4 mL) under N ₂ at 0 °C, and the mixture was stirred at 50 °C for ₂ h under N 2. The reaction mixture was quenched with 0.1 M HCl (50 mL) at 0 °C, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Xbridge Prep OBD C18, 150 × 40 mm, 10 μm; 1%-5% MeCN/H 2 O (NH ₄ OH+NH ₄ HCO ₃ )) to give the title compound (550 mg, 40%) as a yellow oil. LCMS m/z = 152 [M+H] ⁺ . Intermediate A13. (S)-tert-butyl 2-(5-aminopyridin-3-yl)pyrrolidine-1-carboxylate. Step 1. Synthesis of 2-(5- aminopyridin - 3- yl )-1H -pyrrole -1- carboxylic acid tert-butyl ester .

A mixture of 5-bromopyridin-3-amine (1.50 g, 8.67 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-1-carboxylate (2.80 g, 9.54 mmol), Pd(dppf)Cl ₂ (634 mg, 0.87 mmol) and K ₃ PO ₄ (3.68 g, 17.3 mmol) in H ₂ O (15 mL) and THF (40 mL) was stirred at 80 °C under N ₂ for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (2 g, 89%) as a yellow solid. LCMS m/z = 260 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (S)-2-(5-aminopyridin - 3- yl) pyrrolidine -1- carboxylate

To a solution of tert-butyl 2-(5-aminopyridin-3-yl)-1H-pyrrole-1-carboxylate (Step 1, 1 g, 3.86 mmol) in EtOH (20 mL) was added Pd/C (1.00 g, 10% purity) at 25 °C. The mixture was stirred under _H2 (15 psi) at 60 °C for 25 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue to afford tert-butyl 2-(5-aminopyridin-3-yl)pyrrolidine-1-carboxylate (700 mg, 69%) as a yellow solid. The solid was further purified by prep-SFC (DAICEL CHIRALPAK IG, 250 × 30 mm, 10 μm); 33% IPA (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 2 Intermediate A13 : (S)-2-(5-aminopyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (yellow solid, 330 mg, 47%). LCMS m/z = 264 [M+H] ⁺ . Intermediates A14 and A15 . (S)-5-(1-(methylamino)ethyl)pyridin-3-amine and (R)-5-(1-(methylamino)ethyl)pyridin-3-amine. Step 1. Synthesis of (Z)-N-(1-(5- bromopyridin -3- yl)ethylidene)-2-methylpropane-2-sulfenamide

To a mixture of 1-(5-bromo-3-pyridyl)ethanone (25 g, 125 mmol) in THF (300 mL) were added 2-methylpropane-2-sulfenamide (15.91 g, 131 mmol) and Ti(OEt) ₄ (37.06 g, 162 mmol), and the mixture was stirred at 45 °C for 12 h. The reaction mixture was diluted with H ₂ O (300 mL), filtered and extracted with EtOAc (4× 200 mL). The combined organics were concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-25% EtOAc/PE) to give the title compound (33 g, 87%) as a yellow oil. LCMS m/z = 303 [M+H] ⁺ . Step 2. Synthesis of N-(1-(5- bromopyridin -3- yl)ethyl)-2-methylpropane-2-sulfenamide

NaBH ₄ (5.75 g, 152 mmol) was added to a solution of (Z)-N-(1-(5-bromopyridin-3-yl)ethylidene)-2-methylpropane-2-sulfenamide (Step 1, 30 g, 99 mmol) in MeOH (200 mL) at 0° C. and the mixture was stirred at 20° C. for 1 h. The reaction mixture was quenched by the addition of aqueous NH ₄ Cl (200 ml) at 0° C. and aqueous Na 2 CO 3 was added until pH=10. The mixture was extracted with EtOAc (4×100 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The reaction was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (22 g, 73%) as a white solid. LCMS m/z = 307 [M+H] ⁺ . Step 3. Synthesis of N-(1-(5- bromopyridin -3- yl)ethyl)-N,2-dimethylpropane-2-sulfenamide.

NaH (1.18 g, 29.5 mmol, 60% purity) was added to a solution of iodomethane (4.65 g, 32.8 mmol) in DMF (40 mL) under _N2 at -5 °C, and the mixture was stirred for 20 min at -5 °C. N-(1-(5-bromopyridin-3-yl)ethyl)-2-methylpropane-2-sulfenamide (step 2, 5 g, 16.4 mmol) was added thereto, and the mixture was stirred for 20 min at -5 °C. The reaction was quenched by adding _NH4Cl (100 mL) at 0 °C, and the mixture was extracted with EtOAc (4 x 200 mL). The combined organics were evaporated to dryness and the residue was purified by prep-HPLC (Phenomenex C18 250 x 70 mm, 10 μm; 30%-55% MeCN/ _H2O ( _NH4OH + _NH4HCO3 )) _to give the title compound as a brown oil (6.3 g, crude). Step 4. Synthesis of tert-butyl (5-(1-((tert-butylsulfinyl)(methyl)amino)ethyl) pyridin -3- yl)carbamate.

A mixture _of N-(1-(5-bromopyridin-3-yl)ethyl)-N,2-dimethylpropane-2-sulfenamide (step 3, 5.2 g, 16.3 mmol), tert-butyl carbamate (3.82 g, 32.6 mmol), _Cs2CO3 (7.96 g, 24.4 mmol), XPhos (776 mg, 1.63 mmol) and _Pd2 (dba) ₃ (1.49 g, 1.63 mmol) in dioxane (40 mL) was degassed and purged with _N2 (×3), and the mixture was stirred under _N2 at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound as a yellow oil (4.5 g, 77%). LCMS m/z = 356 [M+H] ⁺ . Step 5. Synthesis of (S)-5-(1-(methylamino)ethyl) pyridin -3- amine and (R)-5-(1-(methylamino)ethyl) pyridin -3- amine.

To a solution of tert-butyl (5-(1-((tert-butylsulfinyl)(methyl)amino)ethyl)pyridin-3-yl)carbamate (Step 5, 3 g, 8.44 mmol) in EtOAc (10 mL) was added HCl/EtOAc (20 mL), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give 5-(1-(methylamino)ethyl)pyridin-3-amine (600 mg, 25%) as a white solid, which was separated by prep-SFC (DAICEL CHIRALPAK IG, 250 × 30 mm, 10 μm); 30% heptane/EtOH (0.1% NH4OH) in _CO2 to give: Peak 1 Intermediate A14 (S)-5-(1-(methylamino)ethyl)pyridin-3-amine or (R)-5-(1-(methylamino)ethyl)pyridin-3-amine (brown oil, 240 mg, 18%); LCMS m/z = 152 [M+H] ⁺ . Peak 2 Intermediate A15 (S)-5-(1-(methylamino)ethyl)pyridin-3-amine or (R)-5-(1-(methylamino)ethyl)pyridin-3-amine (brown oil, 240 mg, 18%); LCMS m/z = 152 [M+H] ⁺ . Intermediates A16 and A17 . 3-butyl (S)-(1-(5-aminopyridin-3-yl)ethyl)carbamate and 3-butyl (R)-(1-(5-aminopyridin-3-yl)ethyl)carbamate. Step 1. Synthesis of 1-(5- bromopyridin -3- yl)ethan-1-amine .

A mixture of N-(1-(5-bromopyridin-3-yl)ethyl)-2-methylpropane-2-sulfenamide (Intermediate A14 Step 2, 14 g, 45.87 mmol) in EtOAc (1 mL) and HCl/EtOAc (2 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under _N2 to give the title compound as a yellow oil (9 g, 97%). LCMS m/z = 201 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (1-(5- bromopyridin -3- yl)ethyl)carbamate .

To a mixture of 1-(5-bromopyridin-3-yl)ethan-1-amine (Step 1, 8.5 g, 42.3 mmol) in dioxane (80 mL) and H ₂ O (15 mL) was added Boc ₂ O (10.15 g, 46.50 mmol) and NaHCO ₃ (7.10 g, 84.6 mmol), and the mixture was stirred at 25 °C for 1 h. The solids were removed by filtration, and the filtrate was extracted with EtOAc (3×150 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (8.6 g, 67%). LCMS m/z = 301 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (1-(5-((diphenylmethylene)amino) pyridin -3- yl)ethyl)carbamate .

To a mixture of tert-butyl (1-(5-bromopyridin-3-yl)ethyl)carbamate (Step 2, 8.5 g, 28.22 mmol) and diphenylformaniline (5.63 g, 31.04 mmol) in dioxane (2 mL) were added _Pd2 (dba) ₃ (1.29 g, 1.41 mmol) and Xantphos (1.63 g, 2.82 mmol) _{and Cs2CO3} (18.39 g, 56.44 mmol), and the mixture was stirred under _N2 at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (11 g, 97%). LCMS m/z = 402 [M+H] ⁺ . Step 4. Synthesis of tert-butyl (S)-(1-(5-aminopyridin - 3- yl)ethyl)carbamate and (R)-(1-(5- aminopyridin -3- yl)ethyl)carbamate .

To a mixture of tert-butyl (1-(5-((diphenylmethylene)amino)pyridin-3-yl)ethyl)carbamate (Step 3, 10 g, 24.9 mmol) in MeOH (100 mL) was added _NH2OH.HCl (2.60 g, 37.4 mmol) and NaOAc (3.06 g, 37.4 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% MeOH/DCM) followed by chiral SFC (DAICEL CHIRALPAK IC, 250 × 30 mm, 10 μm); 40% EtOH (0.1% NH ₄ OH) in CO ₂ to give: Peak 1, intermediate A16 . (S)-tert-butyl(1-(5-aminopyridin-3-yl)ethyl)carbamate or (R)-tert-butyl(1-(5-aminopyridin-3-yl)ethyl)carbamate (yellow oil, 1.9 g, 39%); LCMS m/z = 238 [M+H] ⁺ . Peak 2, intermediate A17 . (S)-tert-butyl(1-(5-aminopyridin-3-yl)ethyl)carbamate or (R)-tert-butyl(1-(5-aminopyridin-3-yl)ethyl)carbamate (yellow oil, 1.8 g, 38%); LCMS m/z = 238 [M+H] ⁺ . Intermediate A18. 5-(3-aminophenyl)hexahydropyrazin-2-one. Step 1. Synthesis of 5-(3- aminophenyl ) pyrazin -2(1H) -one .

To a solution of (3-aminophenyl)boronic acid (1 g, 7.30 mmol, 1 eq) and 5-bromopyrazin-2(1H)-one (1.28 g, 7.30 mmol) in _H2O (5 mL) and EtOH ( ₂₀ mL) were added _K3PO4 (3.10 g, 14.6 mmol) and cataCXiumA PdG2 (488 mg, 0.73 mmol), and the mixture was stirred under _N2 at 80 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Xbridge BEH C18 250 × 50 mm, 10 μm; 1%-35% MeCN/H ₂ O (NH ₄ OH + NH ₄ HCO ₃ )) to give the title compound (1.18 g, 86%) as a yellow solid. LCMS m/z = 188 [M+H] ⁺ . Step 2. Synthesis of 5-(3-aminophenyl)hexahydropyrazin - 2- one .

To a solution of 5-(3-aminophenyl)pyrazin-2(1H)-one (Step 1, 1 g, 5.34 mmol) in EtOAc (20 mL) was added Pd/C (1 g, 5.34 mmol, 10% purity), and the mixture was stirred under _H2 at 50 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (268 mg, 26%). LCMS m/z = 192 [M+H] ⁺ . Intermediate A19. tert-butyl (1-(5-aminopyridin-3-yl)-3-methoxypropyl)carbamate. Step 1. Synthesis of tert-butyl (5-(methoxy(methyl)aminoformyl) pyridin -3- yl)carbamate .

DIPEA (2.17 g, 16.8 mmol) and HATU (4.79 g, 12.6 mmol) were added to a mixture of 5-((tert-butoxycarbonyl)amino)nicotinic acid (2 g, 8.39 mmol) and N-methoxymethylamine hydrochloride (1.23 g, 12.59 mmol) in DMSO (10 mL), and the mixture was stirred at 25 °C for 2 h. The mixture was diluted with _H2O (50 mL) and extracted with EtOAc (4 x 100 mL). The combined organics were evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound (2 g, 84%) as a white oil. LCMS m/z = 282 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (5-acryloylpyridin - 3- yl)carbamate .

To a mixture of tert-butyl (5-(methoxy(methyl)aminoformyl)pyridin-3-yl)carbamate (step 1, 500 mg, 1.78 mmol) in THF (6 mL) was added (vinyl)magnesium bromide (1 M in THF, 6.22 mL) at 0 °C, and the mixture was stirred at 0 °C for another 1 min. The mixture was stirred at 25 °C under _N2 for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (5 mL) at 0 °C and extracted with EtOAc (3 x 10 mL). The combined organics were dried _{( Na2SO4} ) and concentrated under reduced pressure to give the title compound as a yellow solid (700 mg, 79%). Step 3. Synthesis of tert-butyl (5-(3-methoxypropanoyl) pyridin -3- yl)carbamate .

NaOMe (152 mg, 2.82 mmol) was added to a solution of tert-butyl (5-acryloylpyridin-3-yl)carbamate (Step 2, 350 mg, 1.41 mmol) in MeOH (6 mL), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) to give the title compound as a yellow oil (200 mg, 25%). LCMS m/z = 281 [M+H] ⁺ . Step 4. Synthesis of tert-butyl (Z)-(5-(1-(hydroxyimino)-3-methoxypropyl) pyridin -3- yl)carbamate .

TEA (361 mg, 3.57 mmol) and _NH2OH.HCl (186 mg, 2.68 mmol) were added to a solution of tert-butyl (5-(3-methoxypropanoyl)pyridin-3-yl)carbamate (Step 3, 250 mg, 0.89 mmol) in EtOH (5 mL), and the mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) to give the title compound (170 mg, 64%) as a yellow oil. LCMS m/z = 296 [M+H] ⁺ . Step 5. Synthesis of tert-butyl (5-(1-amino-3-methoxypropyl) pyridin -3- yl)carbamate .

To a mixture of tert-butyl (Z)-(5-(1-(hydroxyimino)-3-methoxypropyl)pyridin-3-yl)carbamate (Step 4, 160 mg, 0.542 mmol) in EtOH (6 mL) was added Ni (160 mg, 2.73 mmol), and the mixture was stirred under _H2 at 50 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (150 mg, 98%). LCMS m/z = 282 [M+H] ⁺ . Step 6. Synthesis of 5-(1-amino-3-methoxypropyl) pyridin -3- amine .

A solution of tert-butyl (5-(1-amino-3-methoxypropyl)pyridin-3-yl)carbamate (Step 5, 150 mg, 0.533 mmol) in HCl/MeOH (2 mL) and MeOH (0.5 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated under _N2 flow to give the title compound as a yellow oil (90 mg, 93%). LCMS m/z = 182 [M+H] ⁺ . Step 7. Synthesis of tert-butyl (1-(5-aminopyridin - 3- yl)-3-methoxypropyl)carbamate .

Boc ₂ O (57.8 mg, 0.265 mmol) and NaHCO ₃ (74.2 mg, 0.883 mmol) were added to a solution of 5-(1-amino-3-methoxypropyl)pyridin-3-amine (Step 6, 80 mg, 0.441 mmol) in dioxane (3 mL) and H ₂ O (1 mL), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-16 (3%-35% MeCN) to give the title compound (100 mg, 80%) as a yellow oil. LCMS m/z = 282 [M+H] ⁺ . Intermediate A20. (R)-2-(3-aminophenyl)pyridine-1-carboxylic acid tert-butyl ester or (S)-2-(3-aminophenyl)pyridine-1-carboxylic acid tert-butyl ester. Step 1. Synthesis of tert-butyl 6-(3-aminophenyl)-3,4-dihydropyridine - 1(2H)-carboxylate

To a solution of 3-bromoaniline (556 mg, 3.23 mmol) and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (1 g, 3.23 mmol) in _H2O (5 mL) and dioxane (20 mL) were added _K3PO4 (1.37 g, 6.47 mmol) and _XPHOS -PD-G2 (254 mg, 0.323 μmol), and the mixture was stirred under _N2 at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 1%-25% EtOAc/PE) to give the title compound (350 mg, 39%) as a white solid. LCMS m/z = 275 [M+H] ⁺ . Step 2. Synthesis of (R)-tert - butyl 2-(3-aminophenyl) pyridinehexahydrogenate or (S)-tert- butyl 2-(3-aminophenyl) pyridinehexahydrogenate .

To a solution of tert-butyl 6-(3-aminophenyl)-3,4-dihydropyridine-1(2H)-carboxylate (Step 1, 330 mg, 1.20 mmol) in MeOH (10 mL) was added Pd/C (330 mg, 1.20 mmol, 10% purity) and the mixture was stirred under _H2 (50 psi) at 50 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-17 (15%-45% MeCN), followed by chiral SFC (REGIS (s,s) WHELK-O1, 250 × 50 mm, 10 μm); 50% IPA (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 2, intermediate A20 . (R)-2-(3-aminophenyl)pyridinehexahydrocarboxylic acid tert-butyl ester or (S)-2-(3-aminophenyl)pyridinehexahydrocarboxylic acid tert-butyl ester (yellow oil, 120 mg, 37%); LCMS m/z = 277 [M+H] ⁺ . Intermediate A21. (R)-2-(5-amino-2-fluoropyridin-3-yl)pyridinehexahydrocarboxylic acid tert-butyl ester or (S)-2-(5-amino-2-fluoropyridin-3-yl)pyridinehexahydrocarboxylic acid tert-butyl ester.

The title compound was prepared from 5-bromo-6-fluoropyridin-3-amine and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate using a 2-step procedure analogous to that described for intermediate A20. Prep-SFC (Diacel Chiralpak IC, 250 × 30 mm, 10 μm; 55% MeOH (0.1% NH ₄ OH) in CO ₂ ).

Peak 1, intermediate A21 . (R)-2-(5-amino-2-fluoropyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester or (S)-2-(5-amino-2-fluoropyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (white solid, 200 mg, 42%). LCMS m/z = 296 [M+H] ⁺ . Intermediate A22. (R)-(1-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamic acid tert-butyl ester or (S)-(1-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamic acid tert-butyl ester. Step 1. Synthesis of 2- amino -2-(5 - bromopyridin -3- yl ) acetonitrile .

The reaction was carried out three times.

Ti( ^OiPr ) ₄ (31.17 g, 110 mmol) and _NH3 (5 M, 235 mL) were added to a solution of 5-bromonicotinaldehyde (17 g, 91.39 mmol) in MeOH (100 mL), and the mixture was stirred at 25°C for 1 h, and a solution of trimethylsilanecarbonitrile (10.88 g, 110 mmol) in MeOH (30 mL) was added. The resulting mixture was stirred at 25°C for 12 h, and poured into ice-water (250 mL) with stirring. The mixture was filtered, and the filtrate was extracted with EtOAc (3× 250 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid. Three batches were combined to give ( _28.6 g, 49%). LCMS m/z = 212 [M+H] ⁺ . Step 2. Synthesis of methyl 2-(5- bromopyridin - 3- yl )-2-(( tert-butoxycarbonyl ) amino ) acetate .

A solution of 2-amino-2-(5-bromopyridin-3-yl)acetonitrile (Step 1, 11.64 g, 54.9 mmol) in HCl/MeOH (50 mL) was stirred at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 2-amino-2-(5-bromopyridin-3-yl)acetate hydrochloride (80.8 g, crude) as a yellow solid which was used without further purification. To a solution of methyl 2-amino-2-(5-bromopyridin-3-yl)acetate hydrochloride (80.8 g, 287 mmol) and Boc ₂ O (62.6 g, 287 mmol) in THF (450 mL) and H ₂ O (150 mL) was added NaHCO ₃ (48.22 g, 574 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H ₂ O (200 mL) and extracted with EtOAc (3×200 mL). The combined extracts were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) _to give the title compound as a yellow oil (48 g, 48%). LCMS m/z = 345 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (1-(5- bromopyridin -3- yl)-2-hydroxyethyl)carbamate .

LiCl (1.72 g, 40.7 mmol) was added to a mixture of NaBH ₄ (1.54 g, 40.7 mmol) in EtOH (50 mL), and the mixture was stirred at 0° C. for 10 min. To this was added a solution of methyl 2-(5-bromopyridin-3-yl)-2-((tert-butoxycarbonyl)amino)acetate (Step 2, 5.40 g, 15.64 mmol) in THF (50 mL) dropwise at 0° C. over 20 min, and the mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched by adding H ₂ O (20 mL) at 0° C., and extracted with EtOAc (3×20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) _to give the title compound as a yellow oil (3.50 g, 70%). LCMS m/z = 317 [M+H] ⁺ . Step 4. Synthesis of tert-butyl (1-(5- bromopyridin- 3- yl)-2-methoxyethyl)carbamate .

To a solution of tert-butyl (1-(5-bromopyridin-3-yl)-2-hydroxyethyl)carbamate (Step 3, 1.60 g, 5.04 mmol) in THF (15 mL) was added MeI (573 mg, 4.04 mmol) at 0°C, and the mixture was stirred at 25°C for 15 min. NaH (403.5 mg, 10.09 mmol, 60% purity) was added thereto at 0°C, and stirred at 25°C for 2 h. The mixture was quenched by adding H ₂ O (10 mL) at 0°C, and extracted with EtOAc (3×10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (1%-50% EtOAc/PE) _to give the title compound as a yellow oil (1.40 g, 42%). LCMS m/z = 331 [M+H] ⁺ . Step 5. Synthesis of tert-butyl (1-(5-((tert-butoxycarbonyl)amino) pyridin -3- yl)-2-methoxyethyl)carbamate .

To a solution of tert-butyl (1-(5-bromopyridin-3-yl)-2-methoxyethyl)carbamate (Step 4, 335 mg, 1.01 mmol) and tert-butyl carbamate (178 mg, 1.52 mmol) in dioxane (5 _mL ) were added _Cs2CO3 (494 mg, 1.52 mmol), XPhos (48.22 mg, 0.101 mmol) and _Pd2 (dba) ₃ (92.6 mg, 0.101 mmol), and the mixture was stirred under _N2 at 100 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (1%-50% EtOAc/PE) to give the title compound as a yellow oil (1.10 g, 99%). LCMS m/z = 368 [M+H] ⁺ . Step 6. Synthesis of 5-(1-amino-2-methoxyethyl) pyridin -3- amine hydrochloride .

A solution of tert-butyl (1-(5-((tert-butoxycarbonyl)amino)pyridin-3-yl)-2-methoxyethyl)carbamate (Step 5, 1.05 g, 2.86 mmol) in HCl/EtOAc (10 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give the title compound as a yellow oil (500 mg, 86%). LCMS m/z = 168 [M+H] ⁺ . Step 7. Synthesis of tert-butyl (R)-(1-(5-aminopyridin - 3- yl)-2-methoxyethyl)carbamate or (S)-tert-butyl (1-(5-aminopyridin - 3- yl)-2-methoxyethyl)carbamate .

To a solution of 5-(1-amino-2-methoxyethyl)pyridin-3-amine hydrochloride (450 mg, 2.21 mmol) and (Boc) ₂ O (241.1 mg, 1.10 mmol) in H ₂ O (3 mL) and THF (15 mL) was added NaHCO ₃ (371 mg, 4.42 mmol), and the mixture was stirred at 25 °C for 1 h. The mixture was quenched with H ₂ O (10 mL) at 0 °C, and extracted with EtOAc (3×10 mL). The combined extracts were evaporated to dryness and the residue was purified by column chromatography on silica gel (1%-33% EtOAc/PE) followed by chiral SFC (Diacel Chiralpak IC, 250×30 mm, 10 μm; 10%-50% EtOH (+ 0.1% NH ₄ OH) in CO ₂ ) to give: Peak 1, intermediate A22 ; (R)-tert-butyl(1-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamate or (S)-tert-butyl(1-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamate. LCMS m/z = 268 [M+H] ⁺ . Intermediate A23. (R)-tert-butyl(1-(5-aminopyridin-3-yl)-2-methoxyethyl)(methyl)carbamate or (S)-tert-butyl(1-(5-aminopyridin-3-yl)-2-methoxyethyl)(methyl)carbamate. Step 1. Synthesis of tert-butyl (1-(5- bromopyridin -3- yl)-2-methoxyethyl)(methyl)carbamate .

To a solution of tert-butyl (1-(5-bromopyridin-3-yl)-2-hydroxyethyl)carbamate (Intermediate A22 Step 3, 5 g, 15.76 mmol) in THF (30 mL) was added NaH (2.52 g, 63 mmol, 60% purity) at 0 °C for 10 min followed by MeI (17.9 g, 126 mmol) and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl solution (20 ml) at 0 °C. The mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (3× 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-25% EtOAc/PE) _to give the title compound as a yellow oil (3 g, 55%). LCMS m/z = 347 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (1-(5-((diphenylmethylene)amino) pyridin -3- yl)-2-methoxyethyl)(methyl)carbamate .

To a solution of tert-butyl (1-(5-bromopyridin-3-yl)-2-methoxyethyl)(methyl)carbamate (Step 1, 2.98 g, 8.63 mmol) and diphenylformimine (1.88 g, 10.4 mmol) in dioxane (30 mL) were added _{Cs2CO3 (} 5.62 g, 17.3 mmol), Xantphos (999 mg, 1.73 mmol) and Pd(dba) ₂ (248 mg, 0.43 mmol), and the mixture was stirred at 100 °C under _N2 for 2 h. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by MPLC ( _SiO2 , 0-25% EtOAc/PE) _to give the title compound as a yellow oil (2.40 g, 62%). LCMS m/z = 446 [M+H] ⁺ . Step 3. (R)-tert-butyl(1-(5-aminopyridin - 3 -yl)-2-methoxyethyl)(methyl)carbamate and (S)-tert-butyl(1-(5-aminopyridin - 3- yl)-2-methoxyethyl)(methyl)carbamate .

To a solution of tert-butyl (1-(5-((diphenylmethylene)amino)pyridin-3-yl)-2-methoxyethyl)(methyl)carbamate (Step 2, 2.30 g, 5.16 mmol) in MeOH (25 mL) was added _NH2OH.HCl (430 mg, 6.19 mmol) and NaOAc (508 mg, 6.19 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure, and the residue was extracted with EtOAc (3 x 30 mL). The combined organics were dried ( _Na2SO4 ), concentrated under reduced pressure, and _the residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) followed by prep-SFC (Phenomenex-Cellulose-2, 250×30 mm, 10 μm); 45% MeOH (0.1% _NH4OH ) to give: Peak 1, intermediate A23 . (R)-tert-butyl(1-(5-aminopyridin-3-yl)-2-methoxyethyl)(methyl)carbamate or (S)-tert-butyl(1-(5-aminopyridin-3-yl)-2-methoxyethyl)(methyl)carbamate (yellow oil, 575 mg, 40%). LCMS m/z = 282 [M+H] ⁺ . Intermediate A24. tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate. Step 1. Synthesis of N-ethyl-5-nitronicotinamide .

To a mixture of 5-nitronicotinic acid (7 g, 41.6 mmol) and ethylamine hydrochloride (17 g, 208 mmol) in pyridine (60 mL) was added EDCI (12 g, 62.5 mmol) in one portion, and the mixture was stirred at 25° C. for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the reactant was purified by column chromatography (SiO ₂ , 50% PE/EtOAc) to give the title compound (6.11 g, 75%) as a yellow solid. LCMS m/z = 196 [M+H] ⁺ . Step 2. Synthesis of 5-amino-N-ethylnicotinamide .

To a solution of N-ethyl-5-nitronicotinamide (6 g, 30.74 mmol) in MeOH (100 mL) was slowly added Pd/C (6 g, 25.62 mmol, 10% purity), and the mixture was stirred under _H2 (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (5 g, 98%). LCMS m/z = 166 [M+H] ⁺ . Step 3. Synthesis of 5-((ethylamino)methyl) pyridin -3- amine .

To 5-amino-N-ethylnicotinamide (4.5 g, 27.24 mmol, 1 eq) was added BH ₃ .THF (1 M, 136.2 mL) in one portion at 0 °C under N ₂ , and the mixture was stirred at 60 °C for 12 h. The reaction mixture was quenched with 0.1 N HCl (50 mL) at 0 °C, and stirred at 80 °C for 1 h. The pH was adjusted to pH 6-7 by adding 1 N NH ₄ OH to pH 6-7, and the solid was removed by filtration. The filtrate was evaporated to dryness to give the title compound as a yellow oil (5.1 g, crude). LCMS m/z = 152 [M+H] ⁺ . Step 4. Synthesis of tert-butyl ((5-aminopyridin - 3- yl)methyl)(ethyl)carbamate .

To a mixture of 5-((ethylamino)methyl)pyridin-3-amine (5 g, 33 mmol) and di-tert-butyl dicarbonate in THF (15 mL) and H ₂ O (5 mL) was added NaHCO ₃ (5.56 g, 66.1 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (3× 20 mL). The combined organics were dried (Na ₂ SO ₄ ), evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 50% PE/EtOAc) to give the title compound as a yellow oil (3 g, 36%). LCMS m/z = 252 [M+H] ⁺ . Intermediate A25. 5-((isopropylamino)methyl)pyridin-3-amine. Step 1. Synthesis of N-isopropyl-5-nitronicotinamide .

To a mixture of 5-nitronicotinic acid (2 g, 11.9 mmol) and propan-2-amine (4.92 g, 83.3 mmol) in DMF (15 mL) was added HATU (6.79 g, 17.6 mmol) and DIPEA (2.31 g, 17.6 mmol) at 0°C, and the mixture was stirred at 0°C for 10 min and at 25°C for 30 min. The solid was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound (1.8 g, 72%) as a yellow solid. LCMS m/z = 210 [M+H] ⁺ . Step 2. Synthesis of 5-amino-N-isopropylnicotinamide .

To a solution of N-isopropyl-5-nitronicotinamide (Step 1, 1.5 g, 7.17 mmol) in MeOH (15 mL) was added Pd/C (1 g, 10% purity), and the mixture was stirred under H2 at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (1 g, 78%). LCMS m/z = 180 [M+H] ⁺ . Step 3. Synthesis of 5-((isopropylamino)methyl) pyridin -3- amine .

To a solution of 5-amino-N-isopropylnicotinamide (Step 2, 800 mg, 4.46 mmol) was added BH ₃ .THF (1 M, 22.32 mL) under N ₂ at 0 ° _C , and the mixture was stirred at 60 °C for 2 h under N 2. The reaction mixture was quenched with 0.1 M HCl (50 mL) at 0 °C, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC-11 (1%-10% MeCN) to give the title compound (100 mg, 13%) as a yellow oil. LCMS m/z = 166 [M+H] ⁺ . Intermediate A26. (R)-5-(2-amino-1-methoxypropan-2-yl)pyridin-3-amine or (S)-5-(2-amino-1-methoxypropan-2-yl)pyridin-3-amine. Step 1. Synthesis of 2 - amino -2-(5 -bromopyridin - 3- yl ) propionitrile .

To a solution of 1-(5-bromopyridin-3-yl)ethan-1-one (10 g, 50 mmol) in MeOH (20 mL) were added titanium tetraisopropoxide (17.05 g, 60 mmol) and NH ₃ (5 M, 140 mL), and stirred at 25° C. for 1 h. Then a solution of trimethylsilanecarbonitrile (5.95 g, 60 mmol) in MeOH (20 mL) was added thereto, and the mixture was stirred at 25° C. for 12 h. The reaction mixture was poured into ice-water (50 mL), and the resulting mixture was filtered through celite. The filtrate was extracted with EtOAc (3× 50 mL), and the combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15%-50% EtOAc/PE) to give the title compound as a yellow solid (4.40 g, 39%). LCMS m/z = 228 [M+H] ⁺ . Step 2. Synthesis of methyl 2-amino-2-(5- bromopyridin -3- yl)propanoate .

A mixture of 2-amino-2-(5-bromopyridin-3-yl)propanenitrile (Step 1, 4.40 g, 19.5 mmol) in HCl/MeOH (50 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a brown oil (5.50 g, crude, HCl). LCMS m/z = 259 [M+H] ⁺ . Step 3. Synthesis of 2-amino-2-(5- bromopyridin- 3- yl)propan-1-ol .

To a solution of _NaBH4 (759 mg, 20 mmol) in EtOH (50 mL) was added LiCl (851 mg, 20 mmol) and the mixture was stirred at 0 °C for 10 min. A solution of methyl 2-amino-2-(5-bromopyridin-3-yl)propanoate (Step 2, 2.00 g, 7.72 mmol) in THF (50 mL) was added dropwise at 0 °C over 20 min and the mixture was warmed to 25 °C for 2 h. The reaction mixture was quenched by the addition of _H2O (50 mL) at 0 °C and extracted with EtOAc (3 x 50 _mL ). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20% MeOH/EtOAc) to give the title compound as a yellow oil (1.50 g, 84%). LCMS m/z = 231 [M+H] ⁺ . Step 4. Synthesis of 2-(5- bromopyridin- 3- yl)-1-methoxypropan-2-amine .

NaH (929 mg, 23.2 mmol, 60% purity) was added to a solution of 2-amino-2-(5-bromopyridin-3-yl)propan-1-ol (Part 3, 1.79 g, 7.75 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 25° C. for 15 min, and MeI (880 mg, 6.20 mmol) was added at 0° C. The mixture was stirred at 25° C. for 2 h, quenched by addition of saturated aqueous NH ₄ Cl solution (10 mL) at 0° C., and extracted with EtOAc (3×10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (100% EtOAc) _to give the title compound as a yellow oil (970 mg, 51%). LCMS m/z = 245 [M+H] ⁺ . Step 5. Synthesis of tert-butyl (5-(2-amino-1-methoxypropan-2-yl) pyridin- 3- yl)carbamate .

To a solution of 2-(5-bromopyridin-3-yl)-1-methoxypropan-2-amine (step 4, 940 mg, 3.83 mmol) and tert-butyl carbamate (674 mg, 5.75 mmol) in dioxane (10 mL ₎ were added _Cs2CO3 (1.87 g, 5.75 mmol) and _Pd2 (dba) ₃ (351 mg, 0.38 mmol) and XPhos (183 mg, 0.38 mmol), and the mixture was stirred under _N2 at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (100% EtOAc) to give the title compound as a yellow oil (900 mg, 83%). LCMS m/z = 282 [M+H] ⁺ . Step 6. Synthesis of (R)-5-(2-amino-1-methoxypropan-2-yl) pyridin -3- amine and (S)-5-(2-amino-1-methoxypropan-2-yl) pyridin -3- amine .

A solution of tert-butyl (5-(2-amino-1-methoxypropan-2-yl)pyridin-3-yl)carbamate (Step 5, 880 mg, 3.13 mmol) in HCl/MeOH (5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the pH of the residue was adjusted to pH = 8, and purified by prep-SFC (DAICEL CHIRALPAK IC, 250 × 30 mm, 10 μm; 50% IPA (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 1, intermediate A26 . (R)-5-(2-amino-1-methoxypropan-2-yl)pyridin-3-amine or (S)-5-(2-amino-1-methoxypropan-2-yl)pyridin-3-amine (200 mg, 35%); LCMS m/z = 182 [M+H] ⁺ . Intermediate A27. (R)-3-(5-aminopyridin-3-yl)-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester or (S)-3-(5-aminopyridin-3-yl)-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester. Step 1. Synthesis of tert-butyl 3-oxo-1,4-oxazolidinone-heptane-4-carboxylate .

To a solution of 1,4-oxazacycloheptan-3-one (1.94 g, 16.9 mmol) and (Boc) _2O (11 g, 50.6 mmol) in DCM (30 mL) was added DMAP (206 mg, 1.69 mmol) and TEA (2.56 g, 25.3 mmol), and the mixture was stirred at 40 °C under _N2 for 12 h. The reaction mixture was diluted with _H2O (60 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2 x 30 mL), dried _{( Na2SO4} ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 0-25% EtOAc/PE) to give the title compound as a brown oil (2.52 g, 69%). LCMS m/z = 216 [M+H] ⁺ . Step 2. Synthesis of tert-butyl 3-((diphenoxyphosphoryl)oxy)-6,7-dihydro-1,4-oxazacycloheptatriene-4(5H)-carboxylate .

To a solution of tert-butyl 3-oxo-1,4-oxazolidinone-heptane-4-carboxylate (Step 1, 1.5 g, 6.97 mmol) in THF (25 mL) was added KHMDS (1 M, 10.45 mL) for 1.5 h at -78 °C and diphenyl chlorophosphate (2.81 g, 10.45 mmol). The mixture was stirred at 0 °C under _N2 for 1 h. The reaction mixture was diluted with _H2O (80 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (2 x 30 mL), dried _{( Na2SO4} ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 0-25% EtOAc/PE) to give the title compound as a yellow oil (1.46 g, 46%). LCMS m/z = 448 [M+H] ⁺ . Step 3. Synthesis of tert-butyl 3-(5-aminopyridin - 3- yl)-6,7-dihydro-1,4-oxazacycloheptatriene-4(5H)-carboxylate .

To a solution of tert-butyl 3-((diphenoxyphosphoryl)oxy)-6,7-dihydro-1,4-oxazanizocycloheptatriene-4(5H)-carboxylate (Step 2, 1.32 g, 2.94 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyridin-3-amine (970 mg, 4.41 mmol) in DME (15 mL) was added Pd(PPh ₃ ) ₄ (170 mg, 0.147 mmol) and Na ₂ CO ₃ (2M, 2.94 mL), and the mixture was stirred under N ₂ at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 0-50% EtOA/PE) to give the title compound (340 mg, 40%) as a brown solid. LCMS m/z = 292 [M+H] ⁺ . Step 4. Synthesis of (R)-3-(5-aminopyridin - 3- yl)-1,4-oxazolidinone-4-carboxylic acid tert-butyl ester or (S)-3-(5-aminopyridin - 3- yl)-1,4-oxazolidinone-4-carboxylic acid tert-butyl ester .

A mixture of tert-butyl 3-(5-aminopyridin-3-yl)-6,7-dihydro-1,4-oxazacycloheptane-4(5H)-carboxylate (Step 3, 320 mg, 1.10 mmol) and Pd/C (400 mg, 10% purity) in MeOH (5 mL) was stirred under _H2 (50 psi) at 50 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 3-(5-aminopyridin-3-yl)-1,4-oxazacycloheptane-4-carboxylate (190 mg) as a white solid. Chiral SFC (DAICEL CHIRALPAK AD, 250 × 30 mm, 10 μm); 20% MeOH (0.1% NH ₄ OH) in CO ₂ ) was used to separate 3-(5-aminopyridin-3-yl)-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester to give: Peak 1 , intermediate A27 . (R)-3-(5-aminopyridin-3-yl)-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester or (S)-3-(5-aminopyridin-3-yl)-1,4-oxazacycloheptane-4-carboxylic acid tert-butyl ester (brown oil, 92 mg, 28%); LCMS m/z = 294 [M+H] ⁺ . Intermediate A28. 5-(5-aminopyridin-3-yl)-1,4-oxazolidinone-4-carboxylic acid tert-butyl ester.

The title compound was prepared from 1,4-oxazacycloheptane-5-one using a 4-step procedure similar to that described for intermediate A27 without chiral SFC purification. LCMS m/z = 294 [M+H] ⁺ . Intermediates A29 and A30. (R)-tert-butyl 2-(5-aminopyridin-3-yl)azacycloheptane-1-carboxylate and (S)-tert-butyl 2-(5-aminopyridin-3-yl)azacycloheptane-1-carboxylate.

The title compound was prepared from azacycloheptane-2-one using a 4-step procedure similar to that described for intermediate A27. Chiral SFC (REGIS (s, s) WHELK-O1, 250 × 50 mm, 10 μm); 40% EtOH (0.1% NH4OH) in _CO2 ) afforded: Peak 1 , intermediate A29 . (R)-tert-butyl 2-(5-aminopyridin-3-yl)azacycloheptane-1-carboxylate or (S)-tert-butyl 2-(5-aminopyridin-3-yl)azacycloheptane-1-carboxylate (white solid, 1.35 g, 42%); LCMS m/z = 292 [M+H] ⁺ . Peak 2 , intermediate A30 . (R)-2-(5-aminopyridin-3-yl)azocycloheptane-1-carboxylic acid tert-butyl ester or (S)-2-(5-aminopyridin-3-yl)azocycloheptane-1-carboxylic acid tert-butyl ester (white solid, 1.5 g, 46%); LCMS m/z = 292 [M+H] ⁺ . Intermediates A31, A32, A33 and A34. tert-butyl (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylate and tert-butyl (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylate and tert-butyl (2R,6S)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylate and tert-butyl (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylate. Step 1. Synthesis of tert-butyl 2-methyl-6-oxohexahydropyridine - 1- carboxylate .

LDA (2 M, 33.1 mL) was added to a solution of 6-methylhexahydropyridin-2-one (6.8 g, 60.1 mmol) in THF (60 mL) at -78 °C for 30 min. To this was added (Boc) ₂ O (14.43 g, 66.1 mmol), and the mixture was stirred under N ₂ at -78 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH ₄ Cl solution (100 mL) at 0 °C, and extracted with EtOAc (3×100 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound (12 g, 93%) as a yellow oil. Step 2. Synthesis of tert-butyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine - 1(2H) -carboxylate .

LDA (2 M, 35.17 mL) was added to a solution of tert-butyl 2-methyl-6-oxopyridine-1-carboxylate (Step 1, 10 g, 46.9 mmol) in THF (50 mL) at -78 °C under _N2 , and the mixture was stirred at -78 °C for 0.5 h. A solution of N-(5-chloro-2-pyridinyl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (20.25 g, 51.6 mmol) in THF was added dropwise thereto, and the mixture was stirred at 25 °C under _N2 for 2 h. The reaction mixture was quenched by the addition of saturated aqueous _NH4Cl solution (100 mL) at 0 °C, and then extracted with EtOAc (3 x 100 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography ( _SiO2 , 0-5% EtOAc/PE) _to give the title compound as a yellow oil (11 g, 68%). Step 3. Synthesis of tert-butyl 5'-amino-6-methyl-5,6-dihydro-[2,3'- bipyridine ]-1(4H) -carboxylate .

To a mixture of tert-butyl 2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (Step 2, 10.5 g, 30.41 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (7.03 g, 31.93 mmol) in dioxane (100 mL) and _H2O (10 mL) were added Pd( _PPh3 ) ₄ (1.05 g, 0.912 mmol) and _{Cs2CO3 (} 19.81 g, 60.81 mmol), and the mixture was stirred under _N2 at 110 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 10%-100% EtOAc/PE) to give the title compound (5.5 g, 62%) as a yellow oil. LCMS m/z = 290 [M+H] ⁺ . Step 4. Synthesis of (2S,6R)-2-(5-aminopyridin - 3- yl)-6-methylhexahydropyridine -1- carboxylic acid tert-butyl ester, (2S,6S)-2-(5-aminopyridin - 3- yl)-6-methylhexahydropyridine- 1 - carboxylic acid tert-butyl ester, (2R,6S)-2-(5-aminopyridin - 3- yl)-6-methylhexahydropyridine - 1- carboxylic acid tert-butyl ester and (2R,6R)-2-(5-aminopyridin - 3 - yl)-6-methylhexahydropyridine -1- carboxylic acid tert-butyl ester .

To a solution of tert-butyl 5'-amino-6-methyl-5,6-dihydro-[2,3'-bipyridine]-1(4H)-carboxylate (Step 3, 2 g, 6.91 mmol) in MeOH (40 mL) was added Pd/C (2 g, 6.91 mmol, 10% purity), and the mixture was stirred under _H2 at 50 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylate (1.3 g, 64%) as a white solid, which was purified by chiral SFC (REGIS(S, S) WHELK-O1, 250 × 25 mm, 10 μm); 30% IPA (0.1% NH4OH) in _CO2 ) to give: Peak 1, intermediate A31 . (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester (white solid, 580 mg). LCMS m/z = 292 [M+H] ⁺ . Peak 2, intermediate A32 . (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester (white solid, 280 mg). LCMS m/z = 292 [M+H] ⁺ . Peak 3, intermediate A33 . (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester (yellow oil, 600 mg). LCMS m/z = 292 [M+H] ⁺ . Peak 4, intermediate A34 . (2S,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2S,6S)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2R,6S)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester or (2R,6R)-2-(5-aminopyridin-3-yl)-6-methylhexahydropyridine-1-carboxylic acid tert-butyl ester (yellow oil, 300 mg). LCMS m/z = 292 [M+H] ⁺ . Intermediates A35, A36, A37 and A38 . tert-butyl (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylate and tert-butyl (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylate and tert-butyl (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylate and tert-butyl (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylate. Step 1. Synthesis of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)-1H -pyrrole .

A mixture of 2-methylpyrrole (8.00 g, 98.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (12.52 g, 49.3 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.06 g, 3.94 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (1.31 g, 1.97 mmol) in hexane (80 mL) was degassed and purged with _N2 (×3) and stirred under _N2 at 30 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-10% EtOAc/PE) to give the title compound (8.1 g, 40%) as a yellow solid. LCMS m/z = 208 [M+H] ⁺ . Step 2. Synthesis of 3-(5- methyl -1H -pyrrol -2- yl )-5- nitropyridine .

To a solution of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (Part 1, 8.08 g, 39 mmol) in dioxane (40 mL) and H ₂ O (4 mL) were added 3-bromo-5-nitro-pyridine (5.50 g, 27.1 mmol), K ₂ CO ₃ (7.49 g, 54.2 mmol) and Pd(PPh ₃ ) ₄ (3.13 g, 2.71 mmol), and the mixture was stirred at 110° C. for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was diluted with H ₂ O (50 mL) and extracted with EtOAc (3× 40 mL). The combined organics were washed with brine (2 x 30 mL), dried _{( Na2SO4} ) and concentrated under reduced pressure. The residue was purified by column chromatography ( _SiO2 , 0-50% EtOAc/PE/EtOAc) to give the title compound as a yellow solid (8.40 g). LCMS m/z = 204 [M+H] ⁺ . Step 3. Synthesis of tert-butyl 2 - methyl -5-(5- nitropyridin - 3- yl )-1H -pyrrole - 1-carboxylate .

To a solution of 3-(5-methyl-1H-pyrrol-2-yl)-5-nitropyridine (Part 2, 8.2 g, 40.4 mmol) in DCM (50 mL) was added DMAP (245 mg, 2.02 mmol) and di-tert-butyl dicarbonate (9.26 g, 42.42 mmol), and the mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with _H2O (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2 x 30 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-20% EtOAc/PE) to give the title compound (7.50 g, 61%) as a yellow solid. LCMS m/z = 304 [M+H] ⁺ . Step 4. Synthesis of (2R,5R)-2-(5-aminopyridin - 3- yl)-5- methylpyrrolidine -1- carboxylic acid tert-butyl ester and (2S,5S)-2-( 5 -aminopyridin-3-yl)-5-methylpyrrolidine- 1 - carboxylic acid tert - butyl ester and (2S,5R)-2-(5-aminopyridin - 3- yl)-5-methylpyrrolidine - 1- carboxylic acid tert-butyl ester .

To a solution of tert-butyl 2-methyl-5-(5-nitropyridin-3-yl)-1H-pyrrole-1-carboxylate (Step 3, 7 g, 23.1 mmol) in EtOH (100 mL) was added Pd/C (7 g, 10% purity), and the mixture was stirred under _H2 at 60 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylate (6 g) as a white solid, which was purified by chiral SFC (REGIS(S, S) WHELK-O1, 250 × 25 mm, 10 μm); 30% IPA (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 1, intermediate A35 . (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (white solid, 1.35 g). LCMS m/z = 278 [M+H] ⁺ . Peak 2, intermediate A36 . (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (white solid, 1.5 g). LCMS m/z = 278 [M+H] ⁺ . Peak 3, intermediate A37 . (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (white solid, 1.5 g). LCMS m/z = 278 [M+H] ⁺ . Peak 4, intermediate A38 . (2R,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2S,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2R,5S)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester or (2S,5R)-2-(5-aminopyridin-3-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (white solid, 1.35 g). LCMS m/z = 278 [M+H] ⁺ . Intermediate A39. 5-(1-aminocyclopentyl)pyridine-3-amine. Step 1. Synthesis of methyl 2-(5- bromopyridin- 3- yl)acetate .

To a solution of 2-(5-bromopyridin-3-yl)acetic acid (5 g, 23.14 mmol) in MeOH (40 mL) was added SOCl ₂ (4 mL), and the mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H ₂ O (10 mL) and extracted with EtOAc (3× 10 mL). The combined organics were concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 1%-5% EtOAc/PE) to give the title compound (5.26 g, 98%) as a white oil. LCMS m/z = 230 [M+H] ⁺ . Step 2. Synthesis of methyl 1-(5- bromopyridin -3- yl)cyclopentane-1-carboxylate .

To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (Step 1, 1.5 g, 6.52 mmol) and 1,4-diiodobutane (2.02 g, 6.52 mmol) in THF (5 mL) was added LiHMDS (1 M, 8.15 mL) at 0 °C, and the mixture was stirred under _N2 at 25 °C for 2 h. To this was added LiHMDS (1 M, 8.15 mL) at 0 °C, and the mixture was stirred under _N2 at 25 °C for 2 h. The reaction mixture was quenched by adding saturated aqueous _NH4Cl solution (2 mL) at 0 °C and diluted with _H2O (2 mL), and extracted with EtOAc (3 x 2 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by MPLC ( _SiO2 , 1%-5% EtOAc/PE) _to give the title compound as a brown oil (1.32 g, 71%). LCMS m/z = 284 [M+H] ⁺ . Step 3. Synthesis of 1-(5- bromopyridin -3- yl)cyclopentane-1-carboxylic acid .

To a solution of methyl 1-(5-bromopyridin-3-yl)cyclopentane-1-carboxylate (Step 2, 1.32 g, 4.65 mmol) in THF (10 mL) and H ₂ O (5 mL) was added LiOH (222 mg, 9.29 mmol) and the mixture was stirred at 40 °C for 4 h. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to pH 4-5 with 1 M HCl, diluted with H ₂ O (20 mL) and extracted with EtOAc (3× 20 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound as a red solid (1.09 g, 87%). LCMS m/z = 270 [M+H] ⁺ . Step 4. Synthesis of 1-(5- bromopyridin -3- yl)-N-hydroxycyclopentane-1-carboxamide .

To a solution of 1-(5-bromopyridin-3-yl)cyclopentane-1-carboxylic acid (Step 3, 1.36 g, 5.03 mmol) and hydroxylamine hydrochloride (420 mg, 6.04 mmol) and DIPEA (1.95 g, 15.1 mmol) in DMF (1 mL) was added BOP reagent (3.34 g, 7.55 mmol), and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched by addition of _H2O (3 mL) at 0 °C and extracted with EtOAc (3 x 5 mL). The combined organics were dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and the residue was purified by prep-HPLC-15 (5%-35% MeCN) to give the title compound as a white solid (216 mg, 15%). LCMS m/z = 285 [M+H] ⁺ . Step 5. Synthesis of 1-(5-bromopyridin - 3- yl)cyclopentan-1-amine .

To a solution of 1-(5-bromopyridin-3-yl)-N-hydroxycyclopentane-1-carboxamide (Step 4, 195 mg, 0.684 mmol) in DMSO (3 mL) was added K ₂ CO ₃ (472 mg, 3.42 mmol), and the mixture was stirred at 80 °C for 12 h. The reaction mixture was extracted with H ₂ O (10 mL) and EtOAc (3×10 mL). The combined organics were concentrated under reduced pressure, and the residue was purified by prep-TLC (SiO ₂ , 10% MeOH/EtOAc) to give the title compound (113 mg, 68%) as a yellow oil. LCMS m/z = 241 [M+H] ⁺ . Step 6. Synthesis of tert-butyl (5-(1-aminocyclopentyl) pyridin -3- yl)carbamate .

To a solution of 1-(5-bromopyridin-3-yl)cyclopentan-1-amine (step 5, 100 mg, 0.415 mmol) and tert-butyl carbamate (72.9 mg, 0.622 mmol) in dioxane (5 mL) was added _Pd2 (dba) ₃ (38 mg, 0.415 mmol), XPhos (19.77 mg, 0.415 mmol) and _Cs2CO3 (203 _mg , 0.622 mmol), and the mixture was stirred at 100 °C under _N2 for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, and the residue was purified by prep-TLC (EtOAc) to give the title compound (105 mg, 91%) as a yellow solid. LCMS m/z = 278 [M+H] ⁺ . Step 7. Synthesis of 5-(1-aminocyclopentyl) pyridin -3- amine .

To a solution of tert-butyl (5-(1-aminocyclopentyl)pyridin-3-yl)carbamate (Part 6, 105 mg, 0.378 mmol) in HCl/EtOAc (2 mL) was added and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was adjusted to pH 8-9 with DIPEA and purified by prep-HPLC-13 (1%-15% MeCN) to give the title compound as a white solid (43 mg, 64%). LCMS m/z = 178 [M+H] ⁺ . Intermediate A40. tert-butyl (1-(5-aminopyridin-3-yl)cyclopropyl)carbamate. Steps 1 to 3. Synthesis of 1-(5-bromopyridin - 3- yl)cyclopropane-1-carboxylic acid .

The title compound was prepared using a 3-step procedure analogous to that described for 1-(5-bromopyridin-3-yl)cyclopentane-1-carboxylic acid (Intermediate A39 steps 1 to 3). LCMS: m/z = 242 [M+H] ⁺ . Step 4. Synthesis of tert-butyl (1-(5- bromopyridin -3- yl)cyclopropyl)carbamate .

To a solution of 1-(5-bromopyridin-3-yl)cyclopropane-1-carboxylic acid (Step 3, 600 mg, 2.48 mmol) in t-BuOH (24 mL) was added DPPA (1.02 g, 3.72 mmol), 4 Å molecular sieve (600 mg) and triethylamine (376 mg, 3.72 mmol). The reaction mixture was stirred at 25 °C for 1 h and at 100 °C for 3 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried ( _Na2SO4 ), concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-25% EtOAc/PE) _to give the title compound as an off-white solid (730 mg, 94%). LCMS: m/z = 313 [M+H] ⁺ . Step 5. Synthesis of tert-butyl (1-(5-((diphenylmethylene)amino) pyridin -3- yl)cyclopropyl)carbamate .

A mixture of tert-butyl (1-(5-bromopyridin-3-yl)cyclopropyl)carbamate (Step 4, 365 mg, 2.01 mmol), diphenylformimine (600 mg, 1.92 mmol), cesium carbonate (1.87 g, 5.75 mmol), XantPhos (222 mg, 0.38 mmol) and _Pd2 (dba) ₃ (175 mg, 0.19 mmol) in dioxane (15 mL) was degassed and purged with _N2 (3x), and stirred under _N2 at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-25% EtOAc/PE) to give the title compound (590 mg, 74%) as a yellow oil. LCMS: m/z = 414 [M+H] ⁺ . Step 6. Synthesis of tert-butyl (1-(5-aminopyridin - 3- yl)cyclopropyl)carbamate .

To a solution of tert-butyl (1-(5-((diphenylmethylene)amino)pyridin-3-yl)cyclopropyl)carbamate (Step 5, 590 mg, 1.43 mmol) in MeOH (20 mL) was added hydroxylamine hydrochloride (3.80 g, 54.7 mmol) and sodium acetate (5.80 g, 70.7 mmol), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution (100 mL), concentrated under reduced pressure to remove MeOH, _and the residue was extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc/PE) to give the title compound as an off-white solid (330 mg, 93%). LCMS: m/z = 198 [M+H] ⁺ . Intermediate A41. 3-((ethylamino)methyl)aniline. Step 1. Synthesis of N-(3-nitrobenzyl)ethylamine .

To a solution of 3-nitrobenzaldehyde (3 g, 19.85 mmol) in EtOH (40 mL) was added ethylamine (984 mg, 21.84 mmol) dropwise, and the mixture was stirred at 25 °C under _N2 for 5 h. _NaBH4 (1.55 g, 41 mmol) was added at 0 °C, and the resulting mixture was stirred at 25 °C under _N2 for 2 h. The reaction mixture was quenched by the addition of saturated aqueous _NH4Cl solution (30 mL) at ₀ °C, and extracted with DCM (3 x 30 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as a brown oil (2.4 g, 67%). LCMS m/z = 181 [M+H] ⁺ . Step 2. Synthesis of 3-((ethylamino)methyl)aniline .

To a solution of N-(3-nitrobenzyl)ethylamine (2.4 g, 13.32 mmol) in MeOH (30 mL) was added Pd/C (3 g, 10% purity), and the mixture was stirred under _H2 (15 psi) at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-18 (5%-35% MeCN) to give the title compound (1.08 g, 54%) as a brown oil. LCMS m/z = 151 [M+H] ⁺ . Intermediate A42. 5,6-Dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidino]-4-amine. Step 1. Synthesis of 3,5-dibromo-4-(but-3-en-1-yl) pyridine

To a solution of 3,5-dibromo-4-methyl-pyridine (25 g, 99.63 mmol) in THF (200 mL) was added LDA (2 M, 64.76 mL) at -78 °C under _N2 , and after 45 min, 3-bromoprop-1-ene (18.08 g, 149 mmol) in THF (30 mL) was added, and the mixture was stirred at -78 °C under _N2 for 2 h. The reaction mixture was quenched by addition of saturated aqueous _NH4Cl solution (200 mL) at 0 °C, and extracted with EtOAc (3 x 100 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 1%-10% EtOAc/PE) to give the title compound as a brown oil (27.8 g, 96%). LCMS m/z = 292 [M+H] ⁺ . Step 2. Synthesis of 4-bromo-7-methylene-6,7-dihydro-5H-cyclopenta[c] pyridine

To a solution of 3,5-dibromo-4-(but-3-en-1-yl)pyridine (Step 1, 26.8 g, 92.1 mmol) in MeCN (200 mL) was added TEA (18.64 g, 184 mmol), Pd(OAc) ₂ (1.03 g, 4.61 mmol) and _PPh3 (2.42 g, 9.21 mmol), and the mixture was stirred at 80 °C under _N2 for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 1%-16% EtOAc/PE) to give the title compound (12.5 g, 65%) as a white solid. LCMS m/z = 210 [M+H] ⁺ . Step 3. Synthesis of ethyl 3-(7-azido-4-bromo-6,7-dihydro-5H-cyclopenta[c] pyridin -7- yl)propanoate

To a solution of 4-bromo-7-methylene-6,7-dihydro-5H-cyclopenta[c]pyridine (3.1 g, 14.76 mmol) and ethyl 2-diazoacetate (3.37 g, 29.51 mmol) in i-PrOH (50 mL) was added diacetyl iron (257 mg, 1.48 mmol), TEA (2.99 g, 29.51 mmol), TMSN ₃ (3.40 g, 29.51 mmol) and TBHP (5.5 M, 8.05 mL), and the mixture was stirred at 50 °C under N ₂ for 2 h. The reaction mixture was quenched by the addition of saturated aqueous Na ₂ SO ₃ solution (50 mL) at 0 °C, and then extracted with EtOAc (3× 80 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound as a brown oil (1.98 g, 39%). LCMS m/z = 339 [M+H] ⁺ . Step 4. Synthesis of 4-bromo-5,6-dihydrospiro[cyclopenta[c] pyridine -7,2′ - pyrrolidino ]-5′- one

To a solution of ethyl 3-(7-azido-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propanoate (Step 3, 1.52 g, 4.48 mmol) in THF (20 mL), i-PrOH (4 mL), AcOH (4 mL) was added Zn (2.91 g, 44.5 mmol) and the mixture was stirred at 40 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was diluted with _H2O (70 mL), extracted with EtOAc (40 mL), dried ( _Na2SO4 ) and concentrated under _reduced pressure. The residue was purified by MPLC (SiO ₂ , 1%-100% EtOAc/PE) to give the title compound (573 mg, 48%) as a white solid. LCMS m/z = 267 [M+H] ⁺ . Step 5. Synthesis of tert-butyl (5'-oxo-5,6-dihydrospiro[cyclopenta[c] pyridine -7,2' - pyrrolidino ]-4- yl)carbamate

A mixture of 4-bromo-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidino]-5'-one (step 4, 553 mg, 2.07 mmol), tert-butyl carbamate (970 mg, 8.28 mmol), _Pd2 (dba) ₃ (190 mg, 0.207 mmol), XPhos (98.7 mg, 0.207 mmol) and _Cs2CO3 (1.01 g, 3.11 mmol) in dioxane (10 mL) was added and the _mixture was stirred under _N2 at 100 °C for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 1%-100% EtOAc/PE) to give the title compound (360 mg, 57%) as a brown solid. LCMS m/z = 304 [M+H] ⁺ . Step 6. Synthesis of 4-amino-5,6-dihydrospiro[cyclopenta[c] pyridine -7,2' - pyrrolidino ]-5'- one

A mixture of tert-butyl (5'-oxo-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidino]-4-yl)carbamate (116 mg, 0.382 mmol) in HCl/EtOAc (2 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (112 mg) as a white solid. LCMS m/z = 204 [M+H] ⁺ . Step 7. Synthesis of 5,6-dihydrospiro[cyclopenta[c] pyridine -7,2' - pyrrolidino ]-4- amine

To a solution of 4-amino-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidino]-5'-one (Step 6, 137 mg, 0.674 mmol) in THF (2 mL) was added borane dimethyl sulfide complex (10 M, 0.674 mL) at 0 °C, and the mixture was stirred at 60 °C under _N2 for 2 h. The reaction mixture was quenched by the addition of 1 M HCl (2 mL) at 0 °C, and then concentrated under reduced pressure. The residue was purified by prep-HPLC-16 (1%-30% MeCN) to give the title compound (45 mg, 35%) as a yellow oil. LCMS m/z = 190 [M+H] ⁺ . Intermediate A43. (R)-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine or (S)-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine. Step 1. Synthesis of 4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c] pyridine -7- ol .

To a mixture of 4-bromo-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (100 mg, 0.472 mmol) in THF (2.5 mL) was added MeMgBr (3 M, 471 μL) in THF at _-78 °C, and the mixture was stirred at 25 °C for 18 h under N2, and then at 80 °C for 1 h under _N2 . The reaction mixture was quenched by the addition of saturated aqueous _NH4Cl solution (10 mL) at 0 °C, and then extracted with EtOAc (3 x 15 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure _to give a residue that was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a white solid (400 mg, 53%). LCMS m/z = 228 [M+H] ⁺ . Step 2. Synthesis of 7-azido-4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c] pyridine .

To a solution of 4-bromo- ₇ -methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Step 1, 120 mg, 0.526 mmol) in DCM (2 mL) was added TMSN ₃ (182 mg, 1.58 mmol) under N2. Indium tribromide (373 mg, 1.05 mmol) was added, and the mixture was stirred at 0 °C and at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound (250 mg, 62%) as a yellow oil. LCMS m/z = 253 [M+H] ⁺ Step 3. Synthesis of 4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c] pyridin -7- amine .

Zn (310 mg, 4.74 mmol) was added to a solution of 7-azido-4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine (Part 2, 200 mg, 0.79 mmol) in _THF (4 mL), IPA (1 mL) and AcOH (1 mL) under N2, and the mixture was stirred at 20 °C for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-15 (5%-45% MeCN) to give the title compound (150 mg, 83%) as a yellow solid. LCMS m/z = 227 [M+H] ⁺ Step 4. Synthesis of tert-butyl (7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[c] pyridin -4- yl)carbamate .

To a mixture of 4-bromo-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (step 3, 100 mg, 0.44 mmol) and tert-butyl carbamate (103 mg, 0.88 mmol) in dioxane (4 mL) was added _Pd2 (dba) ₃ (40.3 mg, 0.044 mmol) and XPhos (21 mg, _0.044 mmol) and _Cs2CO3 (287 mg, 0.88 mmol), and the mixture was stirred at 100 °C under _N2 for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (100 mg, 86%) as a yellow oil. LCMS m/z = 264 [M+H] ⁺ Step 5. Synthesis of (R)-7-methyl-6,7-dihydro-5H-cyclopenta[c] pyridine -4,7- diamine and (S)-7-methyl-6,7-dihydro-5H-cyclopenta[c] pyridine -4,7- diamine .

A mixture of tert-butyl (7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)carbamate (Step 4) in EtOAc (1 mL) and HCl/EtOAc (1 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under _N2 , and the residue was purified by prep-HPLC (Phenomenex Luna C18 200 × 40 mm, 10 μm; 1%-15% MeCN/ _H2O ( _HCO2H )), followed by prep-SFC (Diacel Chiralpak AD, 250 × 30 mm, 10 μm; 25% MeOH (+ 0.1% _NH4OH ) in _CO2 ) to give: Peak 2, intermediate A43 . (R)-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine or (S)-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4,7-diamine (yellow oil, 30 mg, 50%); LCMS m/z = 164 [M+H] ⁺ intermediates A44 and A45. (S)-tert-butyl(1-(5-aminopyridin-3-yl)-3,3-difluoropropyl)carbamate and (R)-tert-butyl(1-(5-aminopyridin-3-yl)-3,3-difluoropropyl)carbamate. Step 1. Synthesis of methyl 2-(5- bromopyridin- 3- yl)acetate

A mixture of 2-(5-bromo-3-pyridinyl)acetonitrile (10 g, 50.75 mmol) in HCl/MeOH (30 mL) was stirred at 25 °C for 12 h. The mixture was treated with saturated aqueous Na ₂ CO ₃ solution until pH = 8, diluted with H ₂ O (50 mL), and extracted with EtOAc (3× 50 mL). The combined organics were washed with brine (3× 50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound as a yellow oil (11.63 g, 99%). LCMS m/z = 230 [M+H] ⁺ Step 2. Synthesis of methyl 2-(5- bromopyridin -3- yl)-4,4-difluorobutanoate

To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (Part 1, 11.0 g, 47.8 mmol) in THF (250 mL) was added LDA (2 M, 35.86 mL) at -78 °C over 30 min. To this was added a solution of 2,2-difluoroethyl trifluoromethanesulfonate (15.36 g, 71.72 mmol) in THF (20 mL), and the mixture was stirred under _N2 at 25 °C for 1 h. The reaction mixture was quenched by adding _H2O (50 mL) at 0 °C and extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ), concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-25% EtOAc/PE) _to give the title compound as a yellow oil (10.6 g, 75%). LCMS m/z = 294 [M+H] ⁺ Step 3. Synthesis of 2-(5- bromopyridin -3- yl)-4,4-difluorobutyric acid

To a solution of methyl 2-(5-bromopyridin-3-yl)-4,4-difluorobutanoate (Step 2, 10.60 g, 36.04 mmol) in THF (20 mL) and H ₂ O (5 mL) was added LiOH (2.59 g, 108 mmol) and the mixture was stirred at 25 °C for 1 h. The mixture was acidified to pH 2 with 1 M HCl and extracted with EtOAc (3× 50 mL). The combined organics were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound as a yellow solid (8.08 g, 80%). LCMS m/z = 280 [M+H] ⁺ Step 4. Synthesis of 2-(5- bromopyridin- 3- yl)-4,4-difluoro-N-hydroxybutyramide

To a solution of 2-(5-bromopyridin-3-yl)-4,4-difluorobutanoic acid (Step 3, 8.08 g, 28.9 mmol) and hydroxylamine hydrochloride (2.41 g, 34.62 mmol) in DMF (20 mL) were added DIPEA (11.2 g, 86.6 mmol) and BOP (16.59 g, 37.5 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with _H2O (100 mL) and extracted with EtOAc (3 x 100 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) to give the title compound (7.60 g, crude) as a yellow oil. LCMS m/z = 295 [M+H] ⁺ Step 5. Synthesis of 1-(5- bromopyridin -3- yl)-3,3-difluoropropan-1-amine

_K2CO3 (7.10 g, 51.38 mmol) was added to a solution _of 2-(5-bromopyridin-3-yl)-4,4-difluoro-N-hydroxybutyramide (Part 4, 7.58 g, 25.69 mmol) in DMSO (50 mL), and the mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with _H2O (100 mL) and extracted with EtOAc (3 x 100 mL), dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as _a yellow oil (4.00 g, crude). LCMS m/z = 251 [M+H] ⁺ Step 6. Synthesis of tert-butyl (1-(5- bromopyridin -3- yl)-3,3-difluoropropyl)carbamate

To a solution of 1-(5-bromopyridin-3-yl)-3,3-difluoropropan-1-amine (Step 5, 4 g, 15.9 mmol) in dioxane (20 mL) and H ₂ O (4 mL) were added NaHCO ₃ (2.68 g, 31.9 mmol) and Boc 2 O (3.48 g, 15.9 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with H ₂ O (50 mL), and extracted with EtOAc (3×50 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-25% EtOAc/PE) _to give the title compound as a white solid (3.70 g, 66%). LCMS m/z = 351 [M+H] ⁺ Step 7. Synthesis of tert-butyl (1-(5-((diphenylmethylene)amino) pyridin -3- yl)-3,3-difluoropropyl)carbamate

To a solution of tert-butyl (1-(5-bromopyridin-3-yl)-3,3-difluoropropyl)carbamate (Step 6, 3.70 g, 10.54 mmol) and diphenylformaniline (2.10 g, 11.59 mmol, 1.94 mL, 1.10 _eq ) in dioxane (30 mL) were added _Cs2CO3 (10.3 g, 31.61 mmol), Xantphos (1.22 g, 2.11 mmol) and _Pd2 (dba) ₃ (965 mg, 1.05 mmol), and the mixture was stirred under _N2 at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with _H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-25% EtOAc/PE) _to give the title compound as a yellow oil (3.45 g, 72%). LCMS m/z = 452 [M+H] ⁺ Step 8. Synthesis of (S)-(1-(5-aminopyridin - 3- yl)-3,3-difluoropropyl)carbamic acid tert-butyl ester and (R)-(1-(5-aminopyridin - 3- yl)-3,3-difluoropropyl)carbamic acid tert-butyl ester

To a solution of tert-butyl (1-(5-((diphenylmethylene)amino)pyridin-3-yl)-3,3-difluoropropyl)carbamate (Step 7, 3.45 g, 7.64 mmol) in MeOH (30 mL) was added _NH2OH.HCl (1.06 g, 15.28 mmol) and NaOAc (1.25 g, 15.28 mmol) and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with _H2O (100 mL) and extracted with EtOAc (3 x 100 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) followed by chiral SFC (DAICEL CHIRALPAK AD, 250 × 50 mm, 10 μm); 25% EtOH (+ 0.1% NH ₄ OH) in CO ₂ ) to give: Peak 1, intermediate A44 . (S)-(1-(5-aminopyridin-3-yl)-3,3-difluoropropyl)carbamic acid tert-butyl ester or (R)-(1-(5-aminopyridin-3-yl)-3,3-difluoropropyl)carbamic acid tert-butyl ester (yellow solid, 800 mg, 36%); LCMS m/z = 288 [M+H] ⁺ Peak 2, intermediate A45 . (S)-tert-butyl(1-(5-aminopyridin-3-yl)-3,3-difluoropropyl)carbamate or (R)-tert-butyl(1-(5-aminopyridin-3-yl)-3,3-difluoropropyl)carbamate (yellow solid, 880 mg, 40%); LCMS m/z = 288 [M+H] ⁺ intermediate A46. (1S,3aR,6aS)-2-(tert-Butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid.

A mixture of (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester hydrochloride (4.60 g, 20.94 mmol) and LiOH.H ₂ O (5.27 g, 126 mmol) in MeOH (20 mL), THF (20 mL) and H ₂ O (20 mL) was stirred at 25° C. for 12 h. (Boc) ₂ O (9.14 g, 41.87 mmol) was added, and the mixture was stirred at 25° C. for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was treated with EtOAc (30 mL) and stirred at 20° C. for 0.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (4.20 g, 78%). LCMS m/z = 256 [M+H] ⁺ . Intermediate A47. 5-((3aS,6aR)-Octahydrocyclopenta[c]pyrrol-1-yl)pyridin-3-amine. Step 1. Synthesis of tert-butyl (5- iodopyridin -3- yl)carbamate .

A mixture of tert-butyl N-(5-bromopyridin-3-yl)carbamate (5 g, 18.31 mmol), CuI (349 mg, 1.83 mmol), NaI (5.49 g, 36.6 mmol) and N',N'-dimethylethane-1,2-diamine (2.42 g, 27.5 mmol) in dioxane (30 mL) was stirred at 110 °C for 24 h under N _2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE/) to give the title compound (4 g, 68%) as a white solid. LCMS m/z = 321 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (3aS,6aR)-1-(5-((tert-butoxycarbonyl)amino) pyridin -3- yl)hexahydrocyclopenta[c] pyrrole -2(1H) -carboxylate .

To a solution of tert-butyl (5-iodopyridin-3-yl)carbamate (Step 1, 163 mg, 0.51 mmol) and (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (Intermediate 46, 100 mg, 0.392 mmol) in DMF (3 mL) was added (Ir[dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ (4.39 mg, 3.92 μmol), dichloronickel;1,2-dimethoxyethane (8.61 mg, 39.2 μmol), Cs ₂ CO ₃ (383 mg, 1.18 mmol) and 4-tert-butyl-2-(4-tert-butyl-2-pyridinyl)pyridine (15.8 mg, 59 μmol), and the mixture was stirred at 25° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-11 (40%-75% MeCN) to give the title compound (150 mg, 47%) as a yellow oil. LCMS m/z = 402 [M+H] ⁺ . Step 3. Synthesis of 5-((3aS,6aR)-octahydrocyclopenta[c] pyrrol -1- yl) pyridin -3- amine .

tert-Butyl (3aS,6aR)-1-(5-((tert-butoxycarbonyl)amino)pyridin-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Step 2, 150 mg, 0.372 mmol) in HCl/EtOAc (1 mL) and EtOAc (0.5 mL) was stirred at 25 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (10 mL) and treated with _NH4OH (0.5 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC-15 (1%-30% MeCN) to give the title compound (50 mg, 66%) as a white solid. LCMS m/z = 204 [M+H] ⁺ . Intermediate A48. (R)-2-(1-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-1,3-dione or (S)-2-(1-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-1,3-dione. Step 1. Synthesis of 1-(5- bromopyridin -3- yl)-2,2-difluoroethan-1-ol .

To a solution of 5-bromopyridine-3-carbaldehyde (5 g, 26.88 mmol) and difluoromethyl(trimethyl)silane (5.01 g, 40.32 mmol) in DMF (50 mL) was added CsF (817 mg, 5.38 mmol) and the mixture was stirred under _N2 at 25 °C for 12 h. TBAF (1 M, 40.32 mL) was added and the mixture was stirred under _N2 at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with H2O (70 mL) and extracted with EtOAc (3 x 50 mL ₎ . The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 50% PE/EtOAc) to give the title compound as a yellow oil (1.3 g, 20% yield). LCMS m/z = 238 [M+H] ⁺ . Step 2. Synthesis of 2-(1-(5- bromopyridin - 3- yl )-2,2 -difluoroethyl ) isoindoline - 1,3- dione .

To a solution of 1-(5-bromopyridin-3-yl)-2,2-difluoroethan-1-ol (Step 1, 1.2 g, 5.04 mmol) and isoindoline-1,3-dione (816 mg, 5.55 mmol) in THF (30 mL) were added PPh ₃ (1.45 g, 5.55 mmol) and DEAD (1.05 g, 6.05 mmol), and the mixture was stirred under N ₂ at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 50% PE/EtOAc) to give the title compound (950 mg, 51%) as a yellow oil. LCMS m/z = 367 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (5-(1-(1,3- dioxoisoindolin - 2- yl )-2,2 -difluoroethyl ) pyridin -3- yl ) carbamate .

To a mixture of 2-(1-(5-bromopyridin-3-yl)-2,2-difluoroethyl)isoindoline-1,3-dione (step 2, 900 mg, 2.45 mmol) and tert-butyl carbamate (431 mg, 3.68 mmol) in dioxane (15 mL) were added XPhos (117 mg, 0.245 mmol), Cs ₂ CO ₃ (1.20 g, 3.68 mmol) and Pd ₂ (dba) ₃ (224 mg, 0.245 mmol), and the mixture was stirred at 100 °C under N ₂ for 2 h. The mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was purified by MPLC (SiO ₂ , 0-33% EtOAc/PE) to give the title compound (500 mg, 50%) as a yellow solid. LCMS m/z = 404 [M+H] ⁺ . Step 4. Synthesis of (R)-2-(1-(5- aminopyridin - 3- yl )-2,2 -difluoroethyl ) isoindoline -1,3- dione or (S)-2-(1-(5- aminopyridin - 3- yl )-2,2 -difluoroethyl ) isoindoline - 1,3- dione .

tert-Butyl (5-(1-(1,3-dioxoisoindolin-2-yl)-2,2-difluoroethyl)pyridin-3-yl)carbamate (Step 3, 470 mg, 1.17 mmol) was dissolved in HCl/EtOAc (5 mL) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc and the pH was adjusted to pH = 9-10 with _NH4OH . The reaction mixture was extracted with EtOAc (3 x 30 mL) and the combined organics were dried and concentrated under reduced pressure. The residue was separated by SFC (DAICEL CHIRALCEL OJ, 250 × 30 mm, 10 μm); 26% MeOH (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 1, intermediate A48 . (R)-2-(1-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoleline-1,3-dione or (S)-2-(1-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoleline-1,3-dione (yellow oil, 150 mg, 42%); LCMS m/z = 304 [M+H] ⁺ . Intermediate A49. 2-(((5-aminopyridin-3-yl)methyl)amino)ethan-1-ol. Step 1. Synthesis of N-((5- bromopyridin -3- yl)methyl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-amine .

To a solution of 5-bromopyridine-3-carbaldehyde (5 g, 26.9 mmol) in EtOH (20 mL) was added 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine (5.18 g, 29.6 mmol) at 25°C, and the mixture was stirred under _N2 at 25°C for 12 h. _NaBH4 (2.03 g, 53.8 mmol) was added thereto at 0°C, and the resulting mixture was stirred under N2 at 25°C for 2 h. The reaction mixture was quenched by adding saturated _NH4Cl (25 mL) at 0°C, and extracted with EtOAc (3 x 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure _to give the title compound as a yellow solid (8.7 g, 93%). LCMS m/z = 347 [M+H] ⁺ . Step 2. Synthesis of tert-butyl ((5- bromopyridin -3- yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate .

To a mixture of N-((5-bromopyridin-3-yl)methyl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-amine (Step 1, 8.5 g, 24.6 mmol), Na ₂ CO ₃ (5.22 g, 49.2 mmol) in THF (30 mL) and H ₂ O (10 mL) was added di-tert-butyl dicarbonate (5.37 g, 24.6 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered. The filtrate was diluted with H ₂ O (30 mL) and extracted with EtOAc (3× 30 mL). The combined organics were washed with brine (2× 20 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (9.5 g, 86%) as a yellow solid. LCMS m/z = 447 [M+H] ⁺ . Step 3. Synthesis of tert-butyl ((5-((tert-butoxycarbonyl)amino) pyridin -3- yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate .

A mixture of ((5-bromopyridin-3-yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)-carbamic acid tert-butyl ester (Step 2, 9.3 g, 20.88 mmol), tert-butyl carbamate (4.89 g, 41.75 mmol), _Pd2 (dba) ₃ (1.91 g, 2.09 mmol), _XPhos (995.24 mg, 2.09 mmol) and _Cs2CO3 (10.20 g, 31.32 mmol) in dioxane (80 mL) was degassed and purged with _N2 (3x), and the mixture was stirred under _N2 at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was diluted with _H2O (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (2 x 30 mL), dried _{( Na2SO4} ) and concentrated under reduced pressure. The residue was purified by column chromatography ( _SiO2 , 0-100% EtOAc/PE) to give the title compound as a yellow solid (9.5 g, 94%). LCMS m/z = 482 [M+H] ⁺ . Step 4. Synthesis of 2-(((5-aminopyridin - 3- yl)methyl)amino)ethan-1-ol .

A solution of tert-butyl ((5-((tert-butoxycarbonyl)amino)pyridin-3-yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (Step 3, 1.5 g, 3.11 mmol) in HCl/EtOAc (20 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under _N2 , and the residue was diluted with EtOAc (30 mL), and the pH was adjusted to pH ≥7 with _NH4OH at 0 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-11 (1%-15% MeCN) to give the title compound (150 mg, 28%) as a yellow solid. LCMS m/z = 168 [M+H] ⁺ . Intermediate A50. tert-butyl ((5-aminopyridin-3-yl)methyl)carbamate.

To a solution of 5-aminonicotinolinecarbonitrile (500 mg, 4.20 mmol) in EtOH (15 mL) was added NiCl ₂ (544 mg, 4.20 mmol) and NaBH ₄ (635 mg, 16.8 mmol) at 0°C, and the mixture was stirred at 25°C for 8 h. Di-tert-butyl dicarbonate (1.37 g, 6.30 mmol) was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was quenched by the addition of saturated aqueous NH ₄ Cl at 0°C, and then extracted with EtOAc (3× 30 mL). The combined organics were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (550 mg, 58%) as a yellow solid. LCMS m/z = 224 [M+H] ⁺ . Intermediate A51. tert-butyl (1-(5-aminopyridin-3-yl)cyclobutyl)carbamate. Step 1. Synthesis of 1-(5- bromopyridin- 3- yl)cyclobutane-1-carboxylic acid .

To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (500 mg, 2.17 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (57.5 mg, 0.217 mmol) in DMF (6 mL) was added NaH (261 mg, 6.52 mmol, 60% purity) at 0°C, and the mixture was stirred at 0°C for 0.5 h. 1,3-Dibromopropane (483 mg, 2.39 mmol) in DMF (1 mL) was added thereto, and the mixture was stirred at 25°C for 5 h. The reaction mixture was quenched by adding water (30 mL), and extracted with ethyl acetate (3×30 mL) and the combined organics were discarded. The aqueous phase was acidified to pH = 2-3 by adding 6 M HCl and extracted with EtOAc (3× 60 mL). The combined organics were washed with brine (2× 30 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound (540 mg, crude) as a light yellow oil. LCMS m/z = 256 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (1-(5- bromopyridin -3- yl)cyclobutyl)carbamate .

To a mixture of 1-(5-bromopyridin-3-yl)cyclobutane-1-carboxylic acid (Part 1, 500 mg, 1.95 mmol) in t-BuOH (15 mL) was added DPPA (806 mg, 2.93 mmol), TEA (296 mg, 2.93 mmol) and 4 Å molecular sieves (500 mg), and the mixture was stirred at 25 °C for 1 h and then at 100 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound as a white solid (200 mg, 31%). LCMS m/z = 327 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (1-(5-((diphenylmethylene)amino) pyridin -3- yl)cyclobutyl)carbamate .

The title compound (120 mg, 92%) was prepared as a yellow oil from tert-butyl (1-(5-bromopyridin-3-yl)cyclobutyl)carbamate (step 2) using a method analogous to that described for intermediate A16, step 3. LCMS m/z = 428 [M+H] ⁺ . Step 4. Synthesis of tert-butyl (1-(5-aminopyridin - 3- yl)cyclobutyl)carbamate .

The title compound was prepared from tert-butyl (1-(5-((diphenylmethylene)amino)pyridin-3-yl)cyclobutyl)carbamate (step 3) using a method analogous to that described for intermediate A16, step 4. LCMS m/z = 264 [M+H] ⁺ . Intermediate A52. 5-(2-aminopropan-2-yl)pyridin-3-amine. Step 1. Synthesis of tert-butyl (tert-butoxycarbonyl)(5- cyanopyridin -3- yl)carbamate .

To a mixture of 5-aminopyridine-3-carbonitrile (5 g, 42 mmol) in DCM (50 mL) were added DMAP (2.56 g, 21 mmol) and TEA (6.37 g, 63 mmol, 8.76 mL) and Boc ₂ O (13.74 g, 63 mmol), and the mixture was stirred at 25 °C for 12 h. The mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (3× 40 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound (9.2 g, 68%) as a yellow oil. LCMS m/z = 264 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (5-(2-aminopropan-2-yl) pyridin- 3- yl)carbamate .

tert-Butyl (tert-butoxycarbonyl)(5-cyanopyridin-3-yl)carbamate (Step 1, 2 g, 6.26 mmol) in THF (25 mL) was stirred with methylmagnesium bromide (3 M, 16.70 mL) at 0 °C for 30 min. To this was added Ti(O ⁱ Pr) ₄ (1.78 g, 6.26 mmol) at 0 °C, and the mixture was stirred at 70 °C under N ₂ for 2 h. The mixture was quenched with H ₂ O (30 mL), and the mixture was filtered and the filter cake was washed with EtOAc (3× 40 mL). The aqueous was extracted with EtOAc (3× 30 mL), and the combined organics were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by prep-HPLC-11 (5%-45% MeCN) to give the title compound (500 mg, 31%) as a yellow oil. LCMS m/z = 252 [M+H] ⁺ . Step 3. Synthesis of 5-(2-aminopropan-2-yl) pyridin -3- amine .

A solution of tert-butyl (5-(2-aminopropan-2-yl)pyridin-3-yl)carbamate (Step 2, 400 mg, 1.59 mmol) in EtOAc (1 mL) and HCl/EtOAc (5 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under _N2 , and the pH of the residue was adjusted to pH 6-7 with 1 M _NH4OH . The residue was purified by prep-HPLC-11 (1%-20% MeCN) to give the title compound (70 mg, 29%) as a yellow oil. LCMS m/z = 152 [M+H] ⁺ . Intermediate A53. tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl- _d5 )carbamate. Step 1. Synthesis of tert-butyl ((5- bromopyridin -3- yl)methyl)carbamate .

To a mixture of (5-bromo-3-pyridyl)methanamine (4.9 g, 26.20 mmol) in THF (40 mL) and H ₂ O (4 mL) were added NaHCO ₃ (4.40 g, 52.4 mmol) and di-tert-butyl dicarbonate (6.29 g, 28.8 mmol), and the mixture was stirred at 20 °C for 0.5 h. The reaction mixture was partitioned between EtOAc (20 mL) and H ₂ O (15 mL), and the aqueous phase was extracted with EtOAc (3× 20 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (6.5 g, 86%) as a white solid. LCMS m/z = 289 [M+H] ⁺ . Step 2. Synthesis of tert-butyl ((5- bromopyridin -3- yl)methyl)(ethyl-d ₅ )carbamate .

To a solution of tert-butyl ((5-bromopyridin-3-yl)methyl)carbamate (Step 1, 450 mg, 1.57 mmol) in DMF (3 mL) was added NaH (125 mg, 3.13 mmol, 60% purity) at 0°C, and the mixture was stirred at 0°C for 0.5 h. To this was added a solution of 1-iodoethane-1,1,2,2,2- _d5 (378 mg, 2.35 mmol) in DMF (0.5 mL), and the mixture was stirred at 0°C for 0.5 h. NaCl (saturated aqueous solution, 5 mL) was added, and the reaction mixture was partitioned between EtOAc (10 mL) and _H2O (5 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 0-25% EtOAc/PE) _to give the title compound as a white oil (480 mg, 95%). LCMS m/z = 322 [M+H] ⁺ . Step 3. Synthesis of tert-butyl ((5-((diphenylmethylene)amino) pyridin -3- yl)methyl)(ethyl- _d5 )carbamate .

The title compound (480 mg, 87%) was prepared as a yellow oil from tert-butyl ((5-bromopyridin-3-yl)methyl)(ethyl-d ₅ )carbamate (step 2) using a method analogous to that described for intermediate A16 (step 3). LCMS m/z = 421 [M+H] ⁺ . Step 4. Synthesis of tert-butyl ((5-aminopyridin - 3- yl)methyl)(ethyl-d ₅ )carbamate .

The title compound was prepared from tert-butyl (1-(5-((diphenylmethylene)amino)pyridin-3-yl)cyclobutyl)carbamate (step 3) using a method analogous to that described for intermediate A16. LCMS m/z = 257 [M+H] ⁺ . Intermediate A54. (S)-5-(1-((methyl-d ₃ )amino)ethyl)pyridin-3-amine or (R)-5-(1-((methyl-d ₃ )amino)ethyl)pyridin-3-amine.

The title compound was prepared from 1-(5-bromopyridin-3-yl)ethan-1-one using a 5-step procedure analogous to that described for intermediates A14 and A15. Chiral SFC (DAICEL CHIRALPAK IG, 250 × 30 mm, 10 μm); 30% heptane/EtOH (+ 0.1% NH ₄ OH) in CO ₂ ) afforded: Peak 1, intermediate A54 : (S)-5-(1-((methyl-d ₃ )amino)ethyl)pyridin-3-amine or (R)-5-(1-((methyl-d ₃ )amino)ethyl)pyridin-3-amine (yellow solid, 600 mg, 40%). LCMS m/z = 155 [M+H] ⁺ . Intermediate A55. 5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-amine. Step 1. Synthesis of (Z)-N-(dihydro-2H- pyran - 3(4H) -ylidene)-2-methylpropane-2-sulfenamide .

Ti(OEt) ₄ (29.62 g, 130 mmol) was added to a mixture of tetrahydropyran-3-one (10 g, 100 mmol) and 2-methylpropane-2-sulfenamide (12.11 g, 100 mmol) in THF (100 mL), and the mixture was stirred at 25° C. for 12 h. The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ solution (100 mL) and H ₂ O (100 mL) at 0° C. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1%-50% EtOAc/PE) to give the title compound (4 g, 20%) as a yellow solid. LCMS m/z = 204 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (5-(3-((tert-butylsulfinyl)amino)tetrahydro-2H- pyran - 3- yl) pyridin -3- yl)carbamate .

n-BuLi (2.5 M, 9.15 mL) was added to a solution of tert-butyl N-(5-bromo-3-pyridinyl)carbamate (2.5 g, 9.15 mmol) in THF (60 mL) at -78 °C, and the mixture was stirred under _N2 at -78 °C for 0.5 h. To the mixture was added a solution of (Z)-N-(dihydro-2H-pyran-3(4H)-ylidene)-2-methylpropane-2-sulfenamide (Step 1, 4.65 g, 22.9 mmol) in THF (40 mL) and stirred under _N2 at -78 °C for 0.5 h. The reaction mixture was added to saturated aqueous _NH4Cl solution (100 mL) at 0 °C, and extracted with EtOAc (3 x 100 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by MPLC ( _SiO2 , 0-100% EtOAc/PE) to give the title compound as a yellow solid (1.5 g, crude). _LCMS m/z = 398 [M+H] ⁺ . Step 3. Synthesis of 5-(3-aminotetrahydro-2H- pyran - 3- yl) pyridin -3- amine .

A solution of tert-butyl (5-(3-((tert-butylsulfinyl)amino)tetrahydro-2H-pyran-3-yl)pyridin-3-yl)carbamate (Step 2, 1.4 g, 3.52 mmol) in HCl/EtOAc (15 mL) was stirred at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC-18 (1%-25% MeCN) to give the title compound (50 mg, 7%) as a yellow solid. LCMS m/z = 194 [M+H] ⁺ . Intermediate A56. tert-butyl ((5-aminopyridin-3-yl)methyl)(methyl)carbamate. Step 1. Synthesis of 1-(5- bromopyridin -3- yl)-N-methylmethanamine .

The title compound was prepared from 5-bromonicotinaldehyde using a method analogous to that described for intermediate A41 (step 1). LCMS m/z = 201 [M+H] ⁺ . Step 2. Synthesis of tert-butyl ((5- bromopyridin -3- yl)methyl)(methyl)carbamate .

To a solution of 1-(5-bromopyridin-3-yl)-N-methylmethanamine (Step 1, 5.20 g, 25.9 mmol) and (Boc)2O (5.64 g, 25.9 mmol) in THF (52 mL) and _H2O (13 _mL ) was added _Na2CO3 (5.48 g, 51.7 mmol) and the mixture was stirred at 25 °C for 2 h. The reaction was diluted with _H2O (80 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 50% EtOAc/PE) _to give the title compound as a yellow oil (4.5 g, 58%). LCMS m/z = 301 [M+H] ⁺ . Step 3. Synthesis of tert-butyl ((5-((diphenylmethylene)amino) pyridin -3- yl)methyl)(methyl)carbamate .

To a solution of tert-butyl ((5-bromopyridin-3-yl)methyl)(methyl)carbamate (Step 2, 4.40 g, 14.61 mmol) and diphenylformaniline (2.91 g, 16.07 mmol) in dioxane (70 mL) were added _Pd2 (dba) ₃ (1.34 g, 1.46 mmol), Xantphos (1.69 g, 2.92 _mmol ) and _Cs2CO3 (14.28 g, 43.83 mmol), and the mixture was stirred under _N2 at 100 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 50% EtOAc/PE) to give the title compound as a yellow oil (3.50 g, 59%). LCMS m/z = 402 [M+H] ⁺ . Step 4. Synthesis of tert-butyl ((5-aminopyridin - 3- yl)methyl)(methyl)carbamate .

To a solution of tert-butyl ((5-((diphenylmethylene)amino)pyridin-3-yl)methyl)(methyl)carbamate (Step 3, 3.40 g, 8.47 mmol) in MeOH (40 mL) were added _NH2OH.HCl (1.18 g, 16.94 mmol) and NaOAc (1.39 g, 16.94 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , EtOAc) _to give the title compound as a yellow oil (2.00 g, 99%). LCMS m/z = 402 [M+H] ⁺ . Intermediates A57A and A57B. (S)-tert-butyl(1-(5-aminopyridin-3-yl)but-3-yn-1-yl)carbamate and (R)-tert-butyl(1-(5-aminopyridin-3-yl)but-3-yn-1-yl)carbamate. Step 1. Synthesis of N-(1-(5- bromopyridin -3- yl)-4-(trimethylsilyl)but-3-yn-1-yl)-2-methylpropane-2-sulfenamide .

Indigane (397 mg, 3.46 mmol) and 3-bromoprop-1-ynyl(trimethyl)silane (1.65 g, 8.64 mmol) were added to a solution of (E)-N-((5-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfenamide (Intermediate A7, Step 1, 500 mg, 1.73 mmol) in THF (16 mL), and the mixture was stirred at 60 °C for 7 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-19 (45%-75% MeCN) to give the title compound (930 mg, 33%) as a brown solid. LCMS m/z = 403 [M+H] ⁺ . Step 2. Synthesis of N-(1-(5-((diphenylmethylene)amino) pyridin -3- yl)-4-(trimethylsilyl)but-3-yn-1-yl)-2-methylpropane-2-sulfenamide .

A mixture of N-(1-(5-bromopyridin-3-yl)-4-(trimethylsilyl)but-3-yn-1-yl)-2-methylpropane-2-sulfenamide (step 1, 880 mg, 2.19 mmol), _{diphenylformimine} (795 mg, 4.38 mmol), _Cs2CO3 (1.43 g, 4.38 mmol), Xantphos (507 mg, 0.88 mmol) and Xantphos Pd G4 (422 mg, 0.44 mmol) in dioxane (10 mL) was degassed and purged with _N2 (×3), and the mixture was stirred under _N2 at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-25% EtOAc/PE) to give the title compound (1.5 g, crude) as a yellow oil. LCMS m/z = 502 [M+H] ⁺ . Step 3. Synthesis of N-(1-(5-aminopyridin - 3- yl)-4-(trimethylsilyl)but-3-yn-1-yl)-2-methylpropane-2-sulfenamide .

To a solution of N-(1-(5-((diphenylmethylene)amino)pyridin-3-yl)-4-(trimethylsilyl)but-3-yn-1-yl)-2-methylpropane-2-sulfenamide (Step 2, 1.3 g, 2.59 mmol) in MeOH (10 mL) was added _NH2OH.HCl (270 mg, 3.89 mmol) and NaOAc (319 mg, 3.89 mmol), and the mixture was stirred at 25 °C for 1 h. The residue was diluted with _H2O (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2 x 30 mL), dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as _a white solid (1.1 g, crude). LCMS m/z = 338 [M+H] ⁺ . Step 4. Synthesis of 5-(1-amino-4-(trimethylsilyl)but-3-yn-1-yl) pyridin -3- amine .

A mixture of N-(1-(5-aminopyridin-3-yl)-4-(trimethylsilyl)but-3-yn-1-yl)-2-methylpropane-2-sulfenamide (Step 3, 1 g, 2.96 mmol) in HCl/EtOAc (7 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (650 mg, 94%). LCMS m/z = 234 [M+H] ⁺ . Step 5. Synthesis of 5-(1-aminobut-3-yn-1-yl) pyridin -3- amine .

To a solution of 5-(1-amino-4-(trimethylsilyl)but-3-yn-1-yl)pyridin-3-amine (600 mg, 2.57 mmol) in MeOH (2 mL) was added K ₂ CO ₃ (1.07 g, 7.71 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (500 mg, crude). LCMS m/z = 162 [M+H] ⁺ . Step 6. Synthesis of tert-butyl (S)-(1-(5-aminopyridin - 3- yl)but-3-yn-1-yl)carbamate and (R)-tert-butyl (1-(5-aminopyridin - 3- yl)but-3-yn-1-yl)carbamate .

_Na2CO3 (657 mg, 6.20 mmol) was added to a solution _of 5-(1-aminobut-3-yn-1-yl)pyridin-3-amine (Step 5, 500 mg, 3.10 mmol) and (Boc) ₂ (677 mg, 3.1 mmol) in _H2O (3 mL) and MeOH (10 mL), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) followed by chiral SFC (DAICEL CHIRALPAK AD, 250 × 30 mm, 10 μm); 30% EtOH (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 1, intermediate A57A : (S)-(1-(5-aminopyridin-3-yl)but-3-yn-1-yl)carbamic acid tert-butyl ester or (R)-(1-(5-aminopyridin-3-yl)but-3-yn-1-yl)carbamic acid tert-butyl ester (yellow solid, 70 mg, 8.6%). LCMS m/z = 262 [M+H] ⁺ . Peak 2, intermediate A57B : (S)-(1-(5-aminopyridin-3-yl)but-3-yn-1-yl)carbamic acid tert-butyl ester or (R)-(1-(5-aminopyridin-3-yl)but-3-yn-1-yl)carbamic acid tert-butyl ester (yellow solid, 90 mg, 11%). LCMS m/z = 262 [M+H] ⁺ . Intermediate A58. (1S,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-1-amine or (1R,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-1-amine. Step 1. Synthesis of 3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid .

To a mixture of 3-aminocyclohexanecarboxylic acid (10 g, 69.8 mmol) and NaOH (4.19 g, 105 mmol) in dioxane (80 mL) and H ₂ O (30 mL) was added di-tert-butyl dicarbonate (22.86 g, 105 mmol) at 0° C., and the mixture was stirred at 20° C. for 12 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (100 mL) and H ₂ O (100 mL). The aqueous phase was washed with EtOAc (3× 100 mL). The pH of the aqueous phase was adjusted to pH 5 with 1 M HCl. The solid was collected by filtration to give the title compound (14 g, 82%) as a white solid. LCMS m/z = 243 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (3-((2,4-dimethoxybenzyl)aminoformyl)cyclohexyl)carbamate .

To a mixture of 3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (Step 1, 10 g, 41.10 mmol) and (2,4-dimethoxyphenyl)methanamine (7.56 g, 45.21 mmol) in DMF (50 mL) was added DIPEA (10.62 g, 82.20 mmol) and HATU (23.44 g, 61.65 mmol), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and _H2O (15 mL), and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 0-100% EtOAc/PE) _to give the title compound as a white solid (13 g, crude). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.07 (d, 1H), 6.38-6.33 (m, 2H), 5.87 (br s, 1H), 4.26 (d, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 2.06-2.00 (m, 2H), 1.86 (br d, 1H), 1.77-1.69 (m, 2H), 1.35 (s, 9H), 1.32-1.24 (m, 2H), 1.04-0.95 (m, 1H). Step 3. Synthesis of 3-amino-N-(2,4-dimethoxybenzyl)cyclohexane-1-carboxamide .

A solution of tert-butyl (3-((2,4-dimethoxybenzyl)aminocarbonyl)cyclohexyl)carbamate (Step 2, 13 g, 33.1 mmol) in HCl/EtOAc (100 mL) was stirred at 25 °C for 1 h. The mixture was washed with saturated _{aqueous Na2CO3} solution (5 ml) until pH = 9 and concentrated under reduced pressure. The residue was diluted with _H2O (20 mL) and extracted with DCM (3 x 20 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a white solid (7.5 g, 77%). LCMS m/z = 294 [M+H] ⁺ . Step 4. Synthesis of (1S,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-1-amine or (1R,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-1-amine .

_BH3- DMS (10 M, 23.26 mL) was added to a solution of 3-amino-N-(2,4-dimethoxybenzyl)cyclohexane-1-carboxamide (Step 3, 6.8 g, 23.26 mmol) in THF (10 mL) at 0 °C, and the mixture was stirred at 60 °C under _N2 for 2 h. The reaction mixture was quenched by the addition of _H2O (5 mL) at 0 °C and concentrated under reduced pressure. The residue was purified by prep-HPLC-20 (1%-13% MeCN) and prep-SFC (ChiralPak IH, 250 × 30 mm, 10 μm; 25% EtOH (+ 0.1% IPAm) in CO2) to give: Peak 1, intermediate A58 : (1S,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-1-amine or (1R,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-1-amine (yellow oil, 1 g, 15%). LCMS m/z = 280 [M+H] ⁺ . Intermediate A59. 5-aminopyridazine-3-carboxamide. Step 1. Synthesis of tert-butyl (6-chloropyridazine - 4- yl)carbamate .

To a solution of 6-chloropyridazin-4-amine (5 g, 38.6 mmol) in DCM (50 mL) were added (Boc) _2O (29.5 g, 135 mmol), DMAP (7.07 g, 57.9 mmol) and TEA (13.7 g, 135 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with _H2O (80 mL) and extracted with DCM (3 x 80 mL). The combined organics were dried _{( Na2SO4} ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 50% PE:EtOAc) to give the title compound as a yellow solid (6.40 g, crude). LCMS m/z = 230 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (6-cyanopyridazin - 4- yl)carbamate .

To a solution of tert-butyl (6-chloropyridazin-4-yl)carbamate (Step 1, 6.30 g, 27.4 mmol) in DMF (70 mL) was added BrettPhos Pd G3 (2.49 g, 2.74 mmol), Zn(CN) ₂ (16.11 g, 137 mmol) and BRETTPHOS (1.47 g, 2.74 mmol), and the mixture was stirred at 80 °C under N ₂ for 2 h. The mixture was diluted with H ₂ O (80 mL) and extracted with EtOAc (3 x 80 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 50% EtOAc/PE) to give the title compound (4.00 g, crude) as a yellow oil. LCMS m/z = 221 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (6-aminoformylpyridazin- 4 - yl)carbamate .

To a solution of tert-butyl (6-cyanopyridazin-4-yl)carbamate (Part 2, 4 g, 18.2 mmol) in DMSO (40 mL) was added K ₂ CO ₃ (5.02 g, 36.3 mmol), and the mixture was stirred at 20 °C for 30 min. To this was added H ₂ O ₂ (20.6 g, 182 mmol), and stirred at 20 °C for 2 h. KOH (2.04 g, 36.3 mmol) was added, and the resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous Na ₂ SO ₃ solution (5 mL) at 0 °C, diluted with H ₂ O (50 mL), and extracted with EtOAc (3×50 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 50% EtOAc/PE) _to give the title compound as a white solid (350 mg, 8%). LCMS m/z = 239 [M+H] ⁺ . Step 4. Synthesis of 5-aminopyridazine - 3- carboxamide .

A solution of tert-butyl (6-aminoformylpyridazin-4-yl)carbamate (330 mg, 1.39 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (160 mg, crude). LCMS m/z = 139 [M+H] ⁺ . Intermediate A60. tert-butyl (S)-(1-(5-aminopyridin-3-yl)propyl)carbamate and tert-butyl (R)-(1-(5-aminopyridin-3-yl)propyl)carbamate. Step 1. Synthesis of 1-(5- bromopyridin -3- yl)propan-1-amine hydrochloride .

To a solution of (E)-N-(( ₅ -bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfenamide (Intermediate A7, step 1, 116 g, 401 mmol) in THF (1.2 L) was added EtMgBr (3 M, 140 mL) at -78 °C under N2, and the mixture was stirred at 0 °C for 2 h under _N2 . The reaction mixture was quenched by the addition of saturated aqueous _NH4Cl solution (1 L) at 0 °C, diluted with water (1 L), and extracted with EtOAc (4 x 1 L). The combined organics were dried ( _Na2SO4 ) and concentrated _to give N-(1-(5-bromopyridin-3-yl)propyl)-2-methylpropane-2-sulfenamide (500 g, crude) as a yellow solid. The solid was dissolved in EtOAc/HCl (1.2 L) and stirred at 25 °C for 12 h. The reaction mixture was evaporated to dryness to give the title compound as a yellow solid (560 g). LCMS m/z = 215 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (1-(5- bromopyridin -3- yl)propyl)carbamate .

To a mixture of 1-(5-bromopyridin-3-yl)propan-1-amine hydrochloride (Step 1, 560 g, 2.60 mol) and (Boc) _2O (625 g, 2.86 mol) in THF (1.2 L) and _H2O (0.3 L) was added NaOH (1 M, 1 L) and the mixture was stirred at 25 °C for 3 h. The reaction mixture was partitioned between EtOAc (1 L) and _H2O (1 L). The aqueous phase was extracted with EtOAc (3 x 1 L). _The combined organics were dried ( _Na2SO4 ) and evaporated to dryness. The residue was purified by column chromatography on silica gel (25%-33% EtOAc/PE) to give the title compound as a yellow solid (151 g, 18%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.60 (s, 1H), 8.49 (br s, 1H), 7.76 (s, 1H), 4.89 (d, 1H), 4.58 (br s, 1H), 1.87-1.75 (m, 2H), 1.45 (br s, 9H), 0.96 (t, 3H). Step 3. Synthesis of tert-butyl (1-(5-((diphenylmethylene)amino) pyridin -3- yl)propyl)carbamate .

To a mixture of tert-butyl (1-(5-bromopyridin-3-yl)propyl)carbamate (Step 2, 130 g, 412 mmol) and diphenylformaniline (82.22 g, 454 mmol) in dioxane (1500 mL) were added _Pd2 (dba) ₃ (37.77 g, 41.24 mmol), Xantphos (47.73 g, 82.5 mmol) _{and Cs2CO3} (268.76 g, 825 mmol), and the mixture was stirred under _N2 at 100 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (15%-33% EtOAc/PE) to give the title compound as a brown oil (150 g, 87%). LCMS m/z = 416 [M+H] ⁺ . Step 4. Synthesis of (S)-tert-butyl(1-(5-aminopyridin - 3 -yl)propyl)carbamate and (R)-tert-butyl(1-(5- aminopyridin -3- yl)propyl)carbamate .

To a mixture of tert-butyl (1-(5-((diphenylmethylene)amino)pyridin-3-yl)propyl)carbamate (Step 3, 68 g, 164 mmol) in MeOH (800 mL) was added _NH2OH.HCl (22.74 g, 327 mmol) and NaOAc (33.56 g, 409 mmol), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was partitioned between EtOAc (1000 mL) and _H2O (800 mL), and the aqueous phase was extracted with EtOAc (3 x 1000 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the _residue was purified by MPLC ( _SiO2 , 0-100% EtOAc/PE), followed by chiral SFC (DAICEL CHIRALPAK AD, 250×30 mm, 10 μm); 35% EtOH (0.1% NH4OH) in _CO2 ) to give: Peak 2, intermediate A60 , (S)-tert-butyl(1-(5-aminopyridin-3-yl)propyl)carbamate or (R)-tert-butyl(1-(5-aminopyridin-3-yl)propyl)carbamate as a white solid (22 g, 53%). LCMS m/z = 252 [M+H] ⁺ . Intermediate A61. (S)-tert-butyl 2-(3-aminophenyl)pyrrolidine-1-carboxylate. Step 1. Synthesis of tert-butyl 2-(3-nitrophenyl)-1H -pyrrole -1- carboxylate .

To a solution of 1-bromo-3-nitrobenzene (4.4 g, 21.8 mmol) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-1-carboxylate (6.39 g, 21.8 mmol) in DME (15 mL)/H ₂ O (4 mL) were added Pd(PPh ₃ ) ₄ (2.52 g, 2.18 mmol) and Na ₂ CO ₃ (4.62 g, 43.6 mmol), and the mixture was stirred under N ₂ at 90 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO ₂ , 0-16% EtOAc/PE) to give the title compound as a yellow oil (5.8 g, 92%). Step 2. Synthesis of (S)-2-(3-aminophenyl) pyrrolidine -1- carboxylic acid tert-butyl ester and (R)-2-(3-aminophenyl) pyrrolidine - 1- carboxylic acid tert-butyl ester .

To a mixture of tert-butyl 2-(3-nitrophenyl)-1H-pyrrole-1-carboxylate (5.8 g, 20.12 mmol) in MeOH (50 mL) was slowly added Pd/C (4.7 g, 10% purity) and the mixture was stirred under H ₂ (50 psi) at 60 °C for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by chiral SFC (Lux Cellulose-2, 250 × 30 mm; 10 μm; 25% EtOH (+0.1% NH ₄ OH) in CO ₂ ) to give: Peak 1, Intermediate A61 : (S)-2-(3-aminophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester or (R)-2-(3-aminophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (1.3 g, 24%). LCMS m/z = 163 [M-Boc+H] ⁺ . Intermediate A62. tert-butyl (1-(5-aminopyridin-3-yl)cyclopropyl)carbamate. Step 1. Synthesis of 1-(5- bromopyridin- 3- yl)cyclopropane-1-carboxylic acid .

The title compound was prepared from 2-(5-bromopyridin-3-yl)acetic acid using a 3-step procedure analogous to that described for intermediate A39, steps 1 to 3. LCMS m/z = 242 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (1-(5- bromopyridin -3- yl)cyclopropyl)carbamate .

To a solution of 1-(5-bromopyridin-3-yl)cyclopropane-1-carboxylic acid (Step 1, 600 mg, 2.48 mmol) in t-BuOH (24 mL) were added DPPA (1.02 g, 3.72 mmol), 4 Å molecular sieve (600 mg) and triethylamine (376 mg, 3.72 mmol), and the mixture was stirred at 25 °C for 1 h and at 100 °C for 3 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-25% EtOAc/PE) _to give the title compound as an off-white solid (730 mg, 94%). LCMS m/z = 313 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (1-(5-((diphenylmethylene)amino) pyridin -3- yl)cyclopropyl)carbamate .

A mixture of tert-butyl (1-(5-bromopyridin-3-yl)cyclopropyl)carbamate (Step 2, 365 mg, 2.01 mmol), diphenylformimine (600 mg, 1.92 mmol), _Cs2CO3 (1.87 g, 5.75 mmol), _XantPhos (222 mg, 383 μmol) and _Pd2 (dba) ₃ (175 mg, 192 μmol) in dioxane (15 mL) was degassed and purged with nitrogen (3x), and the mixture was stirred under _N2 at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography column (0-25% EtOAc/PE) to give the title compound (590 mg, 74%) as a yellow oil. LCMS m/z = 414 [M+H] ⁺ . Step 4. Synthesis of tert-butyl (1-(5-aminopyridin - 3- yl)cyclopropyl)carbamate .

To a solution of tert-butyl (1-(5-((diphenylmethylene)amino)pyridin-3-yl)cyclopropyl)carbamate (Step 3, 590 mg, 1.43 mmol) in MeOH (20 mL) were added hydroxylamine hydrochloride (3.80 g, 54.7 mmol) and sodium acetate (5.80 g, 70.7 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was added to saturated aqueous sodium bicarbonate solution (100 mL) and concentrated under reduced pressure to remove MeOH, and the residue was extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ), concentrated under reduced pressure, and the residue was purified by _silica gel chromatography column (0-100% EtOAc/PE) to give the title compound as an off-white solid (330 mg, 93%). LCMS m/z = 250 [M+H] ⁺ . Intermediate A63. tert-butyl (4-(5-aminopyridin-3-yl)tetrahydro-2H-pyran-4-yl)carbamate.

The title compound was prepared by a 4-step procedure analogous to that described for intermediate A62. LCMS m/z = 294 [M+H] ⁺ . Intermediate A64. tert-butyl (2-amino-6-methoxyphenethyl)(methyl)carbamate. Step 1. Synthesis of 2-(bromomethyl)-1-methoxy-3-nitrobenzene .

To a solution of 1-methoxy-2-methyl-3-nitrobenzene (3 g, 17.95 mmol) in tetrachloromethane (60 mL) were added N-bromosuccinimide (3.51 g, 19.74 mmol) and benzoyl peroxide (435 mg, 1.79 mmol), and the mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-20% EtOAc/PE) _to give the title compound (4.3 g, 97%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): 7.55 (d, 1H), 7.43 (t, 1H), 7.16 (d, 1H), 4.84 (s, 2H), 3.99 (s, 3H). Step 2. Synthesis of 2-(2-methoxy-6-nitrophenyl) acetonitrile .

To a solution of 2-(bromomethyl)-1-methoxy-3-nitrobenzene (Step 1, 4.3 g, 17.48 mmol) in acetonitrile (60 mL) was added lithium hydroxide monohydrate (880 mg, 20.97 mmol) followed by trimethylsilyl cyanide (2.60 g, 26.21 mmol) at 0 °C and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 60 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% EtOAc/PE) to give the title compound as a yellow solid (3.1 g, 92%). Step 3. Synthesis of tert-butyl (2-methoxy-6-nitrophenethyl)carbamate .

To a solution of 2-(2-methoxy-6-nitrophenyl)acetonitrile (Step 2, 1.5 g, 7.81 mmol) in THF (80 mL) was added borane-THF complex (1 M, 23.42 mL) at 25 °C under _N2 , and the mixture was heated at 60 °C for 16 h. The reaction mixture was quenched by adding MeOH (5 mL) and stirred for 0.5 h. HCl (1 M, 10 mL) was added thereto, and the mixture was heated to 60 °C and stirred for 0.5 h. The mixture was diluted with _H2O (100 mL) and extracted with EtOAc (3× 80 mL). The combined organics were discarded. The aqueous phase was basified to pH = 8~9 by adding saturated aqueous sodium bicarbonate solution and used directly. Di-tert-butyl dicarbonate (1.90 g, 8.71 mmol) was added and the mixture was stirred at 25°C for 1 h. The reaction mixture was extracted with EtOAc (3 x 60 mL) and the combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-16% EtOAc/PE) _to give the title compound (1.5 g, 66%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): 7.39 (d, 1H), 7.32 (t, 1H), 7.08 (d, 1H), 4.79 (s, 1H), 3.92 (s, 3H), 3.44 (t, 2H), 3.01 (t, 2H), 1.41 (s, 9H). Step 4. Synthesis of tert-butyl (2-methoxy-6-nitrophenylethyl)(methyl)carbamate .

To a solution of tert-butyl (2-methoxy-6-nitrophenethyl)carbamate (step 3, 500 mg, 1.69 mmol) in THF (20 mL) was added NaH (135 mg, 3.37 mmol, 60% purity) at 25 °C, and the mixture was stirred at 25 °C for 0.5 h and MeI (479 mg, 3.37 mmol) was added. The resulting mixture was stirred at 40 °C for 15.5 h. Additional NaH (135 mg, 3.37 mmol, 60% purity) was added to the reaction mixture at 25 °C, and then heated to 40 °C and stirred for another 15.5 h. The reaction mixture was quenched with H ₂ O (30 mL) and extracted with EtOAc (3× 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by chromatography ( _SiO2 , 0-70% MeCN/ _H2O (0.1% HCl)) _to give the title compound as a yellow oil (210 mg, 40%). ^1H NMR (400 MHz, _CDCl3 ): 7.40 (d, 1H), 7.32 (t, 1H), 7.06 (d, 1H), 3.90 (s, 3H), 3.49 (t, 2H), 3.03 (t, 2H), 2.90 (s, 3H), 1.39 (s, 9H). Step 5. Synthesis of tert-butyl (2-amino-6-methoxyphenethyl)(methyl)carbamate .

To a solution of tert-butyl (2-methoxy-6-nitrophenethyl)(methyl)carbamate (Step 4, 210 mg, 0.677 mmol) in EtOH (9 mL) and H ₂ O (3 mL) were added iron (189 mg, 3.38 mmol) and ammonium chloride (189 mg, 3.38 mmol) and the mixture was stirred at 70 °C for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was diluted with H ₂ O (20 mL) and extracted with EtOAc (3× 20 mL). The combined organics were washed with brine (60 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 33%-50% EtOAc/PE) to give the title compound (170 mg, 75%) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ): 6.86 (t, 1H), 6.29 (d, 1H), 6.20 (d, 1H), 5.32-4.59 (m, 2H), 3.67 (s, 3H), 3.25-3.08 (m, 2H), 2.83-2.73 (m, 3H), 2.70-2.59 (m, 2H), 1.42-1.29 (m, 9H). Intermediate A65. 2-(3-aminophenyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester. Step 1. Synthesis of 2-methyl 5-(3-nitrophenyl)-1H -pyrrole -1,2- dicarboxylate 1-(tert-butyl) ester

A solution of (1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (1.004 g, 3.96 mmol), 1-bromo-3-nitrobenzene (667 mg, 3.30 mmol), _PdCl2 (dppf)-DCM adduct (139 mg, 0.165 mmol), and tBuXPhos (107 mg, 0.248 mmol) in dioxane (18 mL) and saturated _{aqueous Na2CO3} solution (4.5 mL) was purged with _N2 for 10 min and heated to 80 °C for 3 h. The reaction was cooled, filtered through celite and washed with 75 mL of EtOAc. The filtrate was concentrated by rotary evaporation and the residue was purified by flash chromatography (SiO ₂ , 0-70% EtOAc/Hex) to give the title compound as a yellow oil (336 mg, 28%). LCMS m/z = 369 [M+Na] ⁺ . Step 2. 1-(tert-butyl)-2-methyl 5-(3-aminophenyl) pyrrolidine -1,2- dicarboxylate .

To a solution of 1-(tert-butyl)-2-methyl 5-(3-nitrophenyl)-1H-pyrrole-1,2-dicarboxylate (Step 1, 719 mg, 2.07 mmol) in MeOH (10 mL) was added Pt/C (5 wt %, 661 mg, 0.17 mmol). The flask was bubbled with _H2 for 10 min and then stirred under a balloon of _H2 at room temperature for 19 h. The reaction mixture was then filtered through Celite and washed with EtOAc (30 mL) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-70% EtOAc/Hex) to provide the title compound as a viscous yellow oil which partially solidified under vacuum (504 mg, 76%). LCMS m/z = 343 [M+Na] ⁺ . Step 3. 2-(3-aminophenyl)-5-(hydroxymethyl) pyrrolidine -1- carboxylic acid tert-butyl ester .

_LiBH4 (160 mg, 7.8 mmol) was added to 1-(tert-butyl)-2-methyl 5-(3-aminophenyl)pyrrolidine-1,2-dicarboxylate (Step 2, 417 mg, 1.3 mmol) in MeOH (13 mL) and stirred at room temperature for 15 min and then at 50 °C for 3 days. Additional _LiBH4 (166 mg, 7.8 mmol) was added and heating at 50 °C was continued for 19 h. The reaction mixture was poured into aqueous ammonium chloride and extracted with EtOAc (3 x 30 mL). The combined organics were washed twice with water, brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-100% EtOAc/Hex) to give the title compound (112 mg, 29%) as a white solid. LCMS m/z = 315 [M+Na] ⁺ . ¹ H-NMR analysis showed a single non-imaging isomer, but the identity could not be determined due to peak broadening. The trans isomer is most likely based on literature precedent for the synthetic route used (see: Kaiser and Muchowski, J. Org. Chem, 1984, 49 (22), 4203-4209). Intermediate A66. tert-butyl ((5-aminopyridin-3-yl)methyl)(2-(methylsulfonyl)ethyl)carbamate. Step 1. Synthesis of tert-butyl ((5- bromopyridin -3- yl)methyl)(2-(methylsulfonyl)ethyl)carbamate .

To a suspension of 5-bromonicotinaldehyde (563 mg, 3.0 mmol) and 2-(methylsulfonyl)ethan-1-amine hydrochloride (492 mg, 3.0 mmol) in DCE (10 mL) was added DIPEA (0.630 mL, 3.6 mmol) and NaBH(OAc) ₃ (899 mg, 4.2 mmol) in sequence, and the resulting mixture was stirred at room temperature for 7 h. The reaction was poured into saturated aqueous sodium bicarbonate solution and extracted with EtOAc (3× 30 mL). The combined organics were washed with brine, dried ( _MgSO4 ) and concentrated by rotary evaporation to give N-((5-bromopyridin-3-yl)methyl)-2-(methylsulfonyl)ethan-1-amine. The crude amine was dissolved in THF (12 mL) and _Boc2O (722 mg, 3.15 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction was poured into aqueous sodium bicarbonate and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-100% EtOAc/hex) to give the title compound (423 mg, 36% yield, 2 steps) as a clear yellow oil. LCMS m/z = 393 [M+H] ⁺ . Step 2. Synthesis of tert-butyl ((5-aminopyridin - 3- yl)methyl)(2-(methylsulfonyl)ethyl)carbamate .

To a suspension of tert-butyl ((5-bromopyridin-3-yl)methyl)(2-(methylsulfonyl)ethyl)carbamate (Part 1, 414 mg, 1.05 mmol) and cuprous oxide (68 mg, 0.42 mmol) in NMP (4 mL) was added aqueous ammonium hydroxide (28%-30%, 1.5 mL, 10.5 mmol). The flask was sealed and heated to 100 °C for 21 h. The reaction was cooled to room temperature, poured into water and extracted with EtOAc (4 x 10 mL). The combined organics were washed with water (x2), brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 12 g silica, 0-100% EtOAc/hex followed by 10% MeOH/DCM) to give the title compound (234 mg, 67%) as a highly viscous, clear yellow oil. 1H-NMR analysis showed a mixture of rotanoisomers in a ratio of approximately 40:60. LCMS m/z = 330 [M+H] ⁺ . Intermediate A67. (R)-3-Fluoro-5-(1-(methylamino)ethyl)aniline. Step 1. Synthesis of (S,E)-N-(3-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfenamide.

To a solution of (S)-2-methylpropane-2-sulfenamide (4.41 g, 37.5 mmol) and 3-bromo-5-fluorobenzaldehyde (2.538 g, 12.5 mmol) in DCM (25 mL) was added PPTS (315 mg, 1.25 mmol) and MgSO ₄ (7.31 g, 67.5 mmol) in sequence at room temperature, and the reaction mixture was stirred at room temperature for 17 h. The reaction was filtered through a 1-inch silica gel and celite pad, washed with 100 mL DCM and 20 mL 10% MeOH/DCM. The combined organics were evaporated to dryness and the residue was purified by flash chromatography (ISCO, 80 g silica, 0-70% EtOAc/hex) to give the title compound (3.094 g, 81%) as a white solid. LCMS m/z = 306 [M+H] ⁺ . Step 2. Synthesis of (S)-N-((R)-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide .

To a dry flask under _N2 atmosphere was added a solution of (S,E)-N-(3-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfenamide (Step 1, 1.256 g, 4.0 mmol) in anhydrous DCM (25 mL). The solution was cooled to -78 °C and MeMgBr solution (3 M in Et2O, 3.00 mL, 9.0 mmol) was added dropwise over 4 min and the reaction was placed in a cooling bath to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL), diluted with DCM (100 mL) and poured into water (100 mL). The aqueous phase was extracted with DCM (2 x 50 mL). The combined organics were washed with brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 40 g silica, 0-100% EtOAc/hex) to provide the title compound (1.003 g, 77%) as a clear, colorless oil. LCMS m/z = 322 [M+H] ⁺ . Step 3. Synthesis of (R)-1-(3-bromo-5-fluorophenyl)ethan-1-amine hydrochloride .

4 M HCl in dioxane (1.55 mL, 6.2 mmol) was added to a solution of (S)-N-((R)-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide (Step 2, 1.003 g, 3.11 mmol) in MeOH (6.5 mL) at room temperature, and the reaction was stirred at room temperature for 45 min. The mixture was concentrated under reduced pressure until the material just completely dissolved, and then poured into _Et2O (100 mL). A white precipitate (ppt) precipitated, and the mixture was allowed to stand for 15 min. The precipitate was collected by filtration, washed with 100 mL of diethyl ether and dried to provide the title compound as a white solid (701 mg, 88%). LCMS m/z = 218 [M+H] ⁺ . Step 4. Synthesis of tert-butyl (R)-(1-(3-bromo-5-fluorophenyl)ethyl)carbamate .

To a suspension of (R)-1-(3-bromo-5-fluorophenyl)ethan-1-amine hydrochloride (Step 3, 688 mg, 2.70 mmol) in DCM (20 mL) was added TEA (0.60 mL, 4.32 mmol). The reaction mixture was stirred at room temperature for 30 min, and _Boc2O (568 mg, 2.65 mmol) was added in one portion and the reaction was stirred at room temperature for 3 h. The reaction was then diluted with DCM (75 mL) and washed successively with dilute aqueous HCl, saturated aqueous sodium bicarbonate, water, and brine. The organics were dried ( _MgSO4 ) and concentrated by rotary evaporation. Flash chromatography (ISCO, 12 g silica, 0-80% EtOAc/hexanes) provided the title compound as a white solid (731 mg, 85%). LCMS m/z = 340 [M+Na] ⁺ . Step 5. Synthesis of tert-butyl (R)-(1-(3-amino-5-fluorophenyl)ethyl)carbamate .

To a suspension of (R)-tert-butyl(1-(3-bromo-5-fluorophenyl)ethyl)carbamate (Step 4, 162 mg, 0.51 mmol), _{Cs2CO3 (} 240 mg, 0.71 mmol), _Pd2 (dba) ₃ (34.5 mg, 0.026 mmol) and BINAP (32.2 mg, 0.51 mmol) in anhydrous toluene (2 mL) was added benzophenone imine (0.110 mL, 0.61 mmol), and the mixture was purged with nitrogen for 10 min, and then heated to 80 °C for 15 h. The reaction was cooled to room temperature, and filtered through celite and washed with EtOAc. Flash chromatography (ISCO, 12 g silica, 0-50% EtOAc/Hex) afforded the intermediate (R)-tert-butyl(1-(3-((diphenylmethylene)amino)-5-fluorophenyl)ethyl)carbamate (130 mg) enriched to about 90% purity. A solution of (R)-tert-butyl(1-(3-((diphenylmethylene)amino)-5-fluorophenyl)ethyl)carbamate (130 mg, 0.31 mmol) in MeOH (5 mL) was cooled on ice, and hydroxylamine hydrochloride (64.8 mg, 0.93 mmol) and sodium acetate (126 mg, 1.55 mmol) were added sequentially. The reaction was removed from the ice and stirred at room temperature for 4 h. The reaction was poured into aqueous ammonium chloride and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 4 g silica, 0-100% EtOAc/hex) to give the title compound as a clear yellow oil (72.1 mg, 55% yield, 2 steps). LCMS m/z = 255 [M+H] ⁺ . Step 6. Synthesis of (R)-3-fluoro-5-(1-(methylamino)ethyl)aniline .

A solution of (R)-tert-butyl(1-(3-amino-5-fluorophenyl)ethyl)carbamate (Step 5, 69.1 mg, 0.27 mmol) in anhydrous THF (5 mL) was cooled on ice. _LiAlH4 (54 mg, 1.35 mmol) was added in portions. The reaction was removed from the ice bath and heated to 65 °C for 4 h. The reaction was cooled to room temperature, diluted with EtOAc (5 mL) and carefully quenched with water (200 μL). 1 M aqueous NaOH (1 mL) was added and the mixture was stirred at room temperature for 5 min. Excess _MgSO4 was added and the mixture was filtered through a 1 inch pad of _MgSO4 , washing with EtOAc (50 mL). The filtrate was concentrated to provide the title compound (40.3 mg, 89%) as a clear yellow oil. ¹ H NMR (500 MHz, CDCl ₃ ): 6.47-6.37 (m, 2H), 6.26 (dt, 1H), 3.93-3.59 (m, 2H), 3.53 (q, 1H), 2.31 (s, 3H), 1.32 (d, 3H). Intermediate A68. 3-(5-aminopyridin-3-yl)morpholine-4-carboxylic acid tert-butyl ester. Step 1. Synthesis of 3-(5- bromopyridin -3- yl) morpholine

To a solution of 2-((tributyltinyl)methoxy)ethan-1-amine (1092 mg, 3.00 mmol) in DCM (15 mL) was added 5-bromonicotinaldehyde (558 mg, 3.0 mmol) and 4 Å molecular sieve (350 mg) at ambient temperature under an inert atmosphere. The reaction mixture was stirred for 2 h and filtered through a pad of celite, rinsing with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure to give 1-(5-bromopyridin-3-yl)-N-(2-((tributyltinyl)methoxy)ethyl)methanimine.

Separately, anhydrous copper(II) trifluoromethanesulfonate (1085 mg, 3.0 mmol) was added to a solution of 2,6-lutidine (0.35 mL) in 1,1,1,3,3,3-hexafluoropropan-2-ol (12 mL) and stirred at room temperature for 1 h. A solution of 1-(5-bromopyridin-3-yl)-N-(2-((tributyltinyl)methoxy)ethyl)methanimine in anhydrous DCM (48 mL) was added in one portion and the resulting mixture was stirred at room temperature for 36 h. The reaction was quenched with a mixture of NaHCO ₃ (24 mL) and 10% aqueous NH ₄ OH (12 mL) and stirred vigorously for 15 min. The layers were then separated and the aqueous layer was extracted with DCM (3× 10 mL). The combined organics were then washed with water (3 x 10 mL), brine (5 mL), dried ( _Na2SO4 ) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-15% MeOH (containing 5% _NH4OH ) in DCM) to provide the title compound as a yellow solid (351 mg, 48%). _LCMS m/z = 244 [M+H] ⁺ . Step 2. Synthesis of tert-butyl 3-(5- bromopyridin -3- yl) morpholine -4- carboxylate

To a solution of 3-(5-bromopyridin-3-yl)morpholine (Step 1, 350 mg, 1.44 mmol) in DCM (2.9 mL) was added (Boc) _2O (368 μl, 1.58 mmol), DMAP (8.8 mg, 0.066 mmol) and TEA (301 μl, 2.16 mmol) and the mixture was stirred at ambient temperature for 4 h. The mixture was poured into water (10 mL) and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organics were washed with saturated aqueous _NH4Cl solution (10 mL), brine (10 _mL ), dried ( _Na2SO4 ) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 24 g silica, 10%-50% EtOAc/Hex) to give the title compound (481 mg, 97%) as a white solid. LCMS m/z = 344 [M+H] ⁺ . Step 3. Synthesis of tert-butyl 3-(5-aminopyridin - 3- yl) morpholine -4- carboxylate .

To a suspension of tert-butyl 3-(5-bromopyridin-3-yl)morpholine-4-carboxylate (Step 2, 480 mg, 1.399 mmol), Cs ₂ CO ₃ (683 mg, 2.098 mmol), Pd ₂ (dba) ₃ (64 mg, 0.070 mmol) and BINAP (87 mg, 0.140 mmol) in anhydrous toluene (5.6 mL) was added benzophenone imine (290 μL, 1.68 mmol). The mixture was bubbled with N ₂ for 10 min and then heated to 80 °C for 15 h. The reaction was cooled to room temperature and filtered through celite and washed with EtOAc. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-40% EtOAc/Hex) to provide tert-butyl 3-(5-((diphenylmethylene)amino)pyridin-3-yl)morpholine-4-carboxylate (236 mg, 49%) as a light yellow solid. A solution of tert-butyl 3-(5-((diphenylmethylene)amino)pyridin-3-yl)morpholine-4-carboxylate (184 mg, 0.415 mmol) in MeOH (6.9 mL) was cooled to 0 °C, and hydroxylamine hydrochloride (86 mg, 1.245 mmol) and sodium acetate (170 mg, 2.0 mmol) were added sequentially. The reaction was removed from ice and stirred at room temperature for 2 h. The reaction mixture was poured into aqueous NH ₄ Cl and extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-15% MeOH (containing 5% NH ₄ OH) in DCM) to provide the title compound (90 mg, 78%) as a light beige solid. LCMS m/z = 280 [M+H] ⁺ . Intermediate A69. rel-(2S,5S)-2-(3-aminophenyl)-5-methylpyrrolidine-carboxylic acid tert-butyl ester. Step 1. Synthesis of 1-(3-nitrophenyl)pentane-1,4-dione .

A solution of acetylpropionic acid (1.749 g, 15.0 mmol), H ₂ O (0.70 mL, 37.5 mmol) and pivalic anhydride (4.6 mL, 22.5 mmol) in THF (40 mL) was added to Pd(OAc) ₂ (109 mg, 0.45 mmol), tris(4-methoxyphenyl)phosphine (377 mg, 1.05 mmol), (3-nitrophenyl)boronic acid (3.061 g, 18.0 mmol) in THF (50 mL). The flask was vigorously purged with N ₂ for 10 min, sealed and heated to 60 °C for 42 h. The mixture was filtered through celite and washed with EtOAc (100 mL). The filtrate was evaporated to remove THF, diluted with EtOAc (150 mL), washed with saturated aqueous NaHCO3 (3x), brine, dried ( _MgSO4 ) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, silica, 0-10% MeOH/DCM) to give a residue that was dissolved in EtOAc (50 mL) and washed with (3x, 1 M NaOH), _H2O (2x), brine, dried ( _MgSO4 ) and concentrated by rotary evaporation to provide the title compound as a yellow solid (473 mg, 14%). LCMS m/z = 222 [M+H] ⁺ . Step 2. Synthesis of 2-methyl-5-(3-nitrophenyl)-1H -pyrrole .

_MgSO4 (511 mg, 4.25 mmol, 2.1 equiv) was added to a solution of 1-(3-nitrophenyl)pentane-1,4-dione (Step 1, 461 mg, 2.05 mmol) and ammonium acetate (483 mg, 6.15 mmol) in MeOH (40 mL). Glacial acetic acid (0.12 mL, 2.05 mmol) was added with stirring at room temperature and the mixture was stirred at room temperature for 4 days. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in EtOAc (50 mL), washed with water (2x), saturated aqueous sodium bicarbonate solution, brine, dried ( _MgSO4 ) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO 24 g silica, 0-10% MeOH/DCM) to give the title compound as a reddish orange solid (298 mg, 72%). LCMS m/z = 203 [M+H] ⁺ . Step 3. Synthesis of tert-butyl 2-methyl-5-(3-nitrophenyl)-1H -pyrrole - 1-carboxylate .

To a solution of 2-methyl-5-(3-nitrophenyl)-1H-pyrrole (Step 2, 376 mg, 1.85 mmol) in MeCN (8 mL) was added DMAP (46.4 mg, 0.36 mmol) and _Boc2O (786 mg, 3.60 mmol) and the mixture was heated to 80 °C for 22 h. The mixture was poured into dilute aqueous HCl and extracted with EtOAc (3 x 50 mL). The combined organics were washed with saturated aqueous _NaHCO3 , water (2 x), brine, dried ( _MgSO4 ) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-75% EtOAc/hex) to provide the title compound as a reddish orange solid (434 mg, 80%). LCMS m/z = 303 [M+H] ⁺ . Step 4. Synthesis of tert-butyl rel-(2S,5S)-2-(3-aminophenyl)-5-methylpyrrolidine - 1- carboxylate .

To a solution of tert-butyl 2-methyl-5-(3-nitrophenyl)-1H-pyrrole-1-carboxylate (Step 3, 458 mg, 1.50 mmol) in MeOH (15 mL) was added Pt/C (5 wt %, 616 mg, 0.15 mmol), and the reaction flask was bubbled with _H for 10 min and stirred under a balloon of _H at room temperature overnight. The reaction was filtered through Celite and washed with MeOH. The combined organics were evaporated to dryness and the residue was purified using 2 cycles of flash chromatography (ISCO, 24 g silica, 0-80% EtOAc/hex; followed by ISCO, 12 g silica, 20%-90% EtOAc/hex) to give the title compound as a highly viscous colorless oil (293 mg, 70%). LCMS m/z = 277 [M+H] ⁺ . Intermediate A70. tert-butyl (1-(3-aminophenyl)cyclobutyl)carbamate. Step 1. Synthesis of tert-butyl (1-(3-((diphenylmethylene)amino)phenyl)cyclobutyl)carbamate .

To a solution of tert-butyl (1-(3-bromophenyl)cyclobutyl)carbamate (500 mg, 1.53 mmol) and diphenylformaniline (306 mg, 1.69 mmol) in dioxane (10 mL) were added _Pd2 (dba) ₃ (140 mg, 0.153 mmol, 0.1 eq), Xantphos (177 mg, 0.306 mmol) and _Cs2CO3 (1.50 g, 4.60 mmol), and the mixture was stirred under _N2 at 100 °C for 3 _h . The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 20% EtOAc/PE) to give the title compound (700 mg, crude) as a green oil. LCMS m/z = 427 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (1-(3-aminophenyl)cyclobutyl)carbamate .

To a solution of tert-butyl (1-(3-((diphenylmethylene)amino)phenyl)cyclobutyl)carbamate (Step 1, 650 mg, 1.52 mmol) in MeOH (10 mL) were added hydroxylamine hydrochloride (2.54 g, 36.6 mmol) and NaOAc (5.63 g, 68.6 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was added to saturated aqueous _NaHCO3 solution (10 mL), and concentrated under reduced pressure to remove the solvent. The residue was extracted with EtOAc (3 x 50 mL) and the combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure and the residue was purified by MPLC ( _SiO2 , 50% EtOAc/PE) _to give the title compound as a yellow solid (330 mg, 82%). LCMS m/z = 207 [M+H] ⁺ . Intermediate A71. 2-(((5-aminopyridin-3-yl)methyl)amino)ethan-1-ol. Step 1. Synthesis of N-((5- bromopyridin -3- yl)methyl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-amine .

To a solution of 5-bromopyridine-3-carbaldehyde (5 g, 26.9 mmol) in EtOH (20 mL) was added 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine (5.18 g, 29.6 mmol) at 25°C, and the mixture was stirred under _N2 at 25°C for 12 h. _NaBH4 (2.03 g, 53.8 mmol) was added thereto at 0°C, and the resulting mixture was stirred under _N2 at 25°C for 2 h. The reaction mixture was quenched by adding saturated _NH4Cl (25 mL) at 0°C, and extracted with EtOAc (3 x 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure _to give the title compound as a yellow solid (8.7 g, 94%). LCMS m/z = 347 [M+H] ⁺ . Step 2. Synthesis of tert-butyl ((5- bromopyridin -3- yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate .

(Boc) _2O (5.37 g, 24.61 mmol) was added to a mixture of N-((5-bromopyridin-3-yl)methyl)-2-((tert-butyldimethylsilyl)oxy)ethan-1-amine (Step 1, 8.5 g, 24.6 mmol), _{Na2CO3 (} 5.22 g, 49.2 mmol) in THF (30 mL) and _H2O (10 mL), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was diluted with _H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with 40 mL of brine (2× 20 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound as a yellow solid (9.5 g, 86%). LCMS m/z = 447 [M+H] ⁺ . Step 3. Synthesis of tert-butyl ((5-((tert-butoxycarbonyl)amino) pyridin -3- yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate .

A mixture of tert-butyl ((5-bromopyridin-3-yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (Step 2, 9.3 g, 20.9 mmol), (Boc) _2O (4.89 g, 41.8 mmol), _Pd2 (dba) ₃ (1.91 g, 2.09 mmol), XPhos (995 mg, 2.09 mmol) and _Cs2CO3 (10.20 g, 31.32 mmol) in _dioxane (80 mL) was degassed and purged with _N2 (3x), and stirred at 100 °C under N2 for 2 h. The reaction mixture was filtered, and the filtrate was diluted with _H2O (60 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (2 x 30 mL), dried _{( Na2SO4} ), concentrated under reduced pressure, and the residue was purified by column chromatography ( _SiO2 , 0-100% EtOAc/PE) to give the title compound as a yellow solid (9.5 g, 94%). LCMS m/z = 482 [M+H] ⁺ . Step 4. Synthesis of 2-(((5-aminopyridin - 3- yl)methyl)amino)ethan-1-ol .

A mixture of tert-butyl ((5-((tert-butoxycarbonyl)amino)pyridin-3-yl)methyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (Step 3, 1.5 g, 3.11 mmol) in HCl/EtOAc (20 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under _N2 , and the residue was diluted with EtOAc (30 mL), and the pH was adjusted to pH >7 with _NH4OH at 0 °C. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC-11 (1%-15% MeCN) to give the title compound (150 mg, 29%) as a yellow solid. LCMS m/z = 168 [M+H] ⁺ . Intermediate A72. rel-(2S,5S)-tert-butyl 2-(3-aminophenyl)-5-methylpyrrolidine-1-carboxylate. Step 1. Synthesis of 1-(3-nitrophenyl)pentane-1,4-dione .

To a mixture of Pd(OAc) ₂ (109 mg, 0.45 mmol), tris(4-methoxyphenyl)phosphine (377 mg, 1.05 mmol) and (3-nitrophenyl)boronic acid (3.061 g, 18.0 mmol) in THF (50 mL) was added a solution of acetylpropionic acid (1.749 g, 15.0 mmol), water (0.70 mL, 37.5 mmol, 2.5 equiv) and pivalic anhydride (4.6 mL, 22.5 mmol) in THF (40 mL), and the mixture was vigorously purged with _N2 for 10 min, and then sealed and heated to 60 °C for 42 h. The mixture was filtered through celite, washed with EtOAc (100 mL). The filtrate was concentrated by rotary evaporation, diluted with EtOAc (150 mL) and washed with saturated aqueous sodium bicarbonate (3×), brine, dried (MgSO ₄ ) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 80 silica, 0-10% MeOH/DCM) to give a mixture of the title compound and pivalic acid. The combined fractions were dissolved in EtOAc (50 mL) and washed three times with 1 M aqueous sodium hydroxide, twice with water and once with brine, dried over MgSO ₄ , filtered and concentrated by rotary evaporation to provide the title compound as a yellow solid (473 mg, 14%). LCMS m/z = 221 [M+H] ⁺ . Step 2. Synthesis of 2-methyl-5-(3-nitrophenyl)-1H -pyrrole .

MgSO ₄ (511 mg, 4.25 mmol) was added to a solution of 1-(3-nitrophenyl)pentane-1,4-dione (Step 1, 461 mg, 2.05 mmol) and ammonium acetate (483 mg, 6.15 mmol) in MeOH (40 mL), and glacial acetic acid (0.12 mL, 2.05 mmol) was added while stirring at room temperature, and the mixture was stirred at room temperature for 4 days. The reaction mixture was evaporated to dryness, and the residue was dissolved in EtOAc (50 mL), washed with H ₂ O (×2), saturated aqueous sodium bicarbonate solution, brine, dried (MgSO ₄ ), evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO 24 g silica, 0-0% MeOH/DCM) to provide the title compound as a red-orange solid (298 mg, 72%). LCMS m/z = 203 [M+H] ⁺ . Step 3. 2-Methyl-5-(3-nitrophenyl)-1H -pyrrole -1- carboxylic acid tert-butyl ester .

To a solution of 2-methyl-5-(3-nitrophenyl)-1H-pyrrole (Step 2, 376 mg, 1.85 mmol) in MeCN (8.0 mL) was added DMAP (46.4 mg, 0.36 mmol) and _Boc2O (786 mg, 3.60 mmol) and the reaction mixture was heated to 80 °C for 22 h. The reaction mixture was poured into dilute aqueous HCl and extracted with EtOAc (3 x 50 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, _H2O (2 x), brine, dried ( _MgSO4 ) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-75% EtOAc/hex) to give the title compound (434 mg, 80%) as a reddish orange solid. LCMS m/z = 303 [M+H] ⁺ . Step 4. rel-(2S,5S)-2-(3-aminophenyl)-5-methylpyrrolidine - 1- carboxylic acid tert-butyl ester

To a solution of tert-butyl 2-methyl-5-(3-nitrophenyl)-1H-pyrrole-1-carboxylate (Step 4, 458 mg, 1.50 mmol) in MeOH (15 mL) was added Pt/C (5 wt %, 616 mg, 0.15 mmol), and the reaction flask was purged with _H2 for 10 min and then stirred under a balloon of _H2 at room temperature overnight. The reaction mixture was filtered through Celite, washed with MeOH and the filtrate was evaporated to dryness. The residue was purified by two cycles of flash chromatography (ISCO, 24 g silica, 0-80% EtOAc/hex followed by ISCO, 12 g silica, 20%-90% EtOAc/hex) to afford the title compound (293 mg, 70%) as a clear, colorless, highly viscous oil. The relative stereochemistry could not be confirmed by NMR analysis due to signal broadening; however, it was assumed to be cis- based on literature precedent. LCMS m/z = 277 [M+H] ⁺ . Intermediate A73. 5-(((2-methoxyethyl)amino)methyl)pyridin-3-amine

The title compound was prepared using a 4-step procedure analogous to that described for intermediate A71. LCMS m/z = 182 [M+H] ⁺ . Intermediate A74. (R)-2-(5-aminopyridin-3-yl)-5-oxohexahydropyrazine-1-carboxylic acid tert-butyl ester or (S)-2-(5-aminopyridin-3-yl)-5-oxohexahydropyrazine-1-carboxylic acid tert-butyl ester. Step 1. Synthesis of 5-(5- aminopyridin - 3- yl ) pyrazin -2(1H) -one .

To a solution of (5-amino-3-pyridyl)boronic acid (78.83 mg, 0.57 mmmol) and 5-bromopyrazin-2-ol (50 mg, 0.285 mmol) in H ₂ O (0.5 mL) and EtOH (2 mL) were added K ₃ PO ₄ (121.31 mg, 0.57 mmol) and cataCXium® A Pd G2 (19.11 mg, 0.028 mmol), and the mixture was stirred at 80 °C under N ₂ for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.1 g, 39%) as a white solid. LCMS m/z = 189 [M+H] ⁺ . Step 2. Synthesis of 5-(5- aminopyridin - 3- yl ) hexahydropyrazin - 2- one .

To a solution of 5-(5-amino-3-pyridinyl)-1H-pyrazin-2-one (Step ₂ , 1.9 g, 10.10 mmol) in MeOH (10 mL) and DMF (30 mL) was added Pd/C (1.9 g, 10.10 mmol, 10% purity) under N2, and the suspension was degassed under vacuum and purged with _H2 several times. The mixture was stirred under _H2 (50 psi) at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (3 g, crude). LCMS m/z = 193 [M+H] ⁺ . Step 3. Synthesis of (R)-2-(5- aminopyridin - 3- yl )-5 -oxohexahydropyrazine - 1- carboxylic acid tert-butyl ester or (S)-2-(5- aminopyridin - 3- yl )-5 -oxohexahydropyrazine - 1- carboxylic acid tert-butyl ester .

A solution of 5-(5-amino-3-pyridinyl)hexahydropyrazin-2-one (Step 2, 2 g, 10.40 mmol) and (Boc) _2O (2.27 g, 10.40 mmol) in MeOH (10 mL) was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-(5-amino-3-pyridinyl)hexahydropyrazin-2-one as a yellow solid. The residue was separated by SFC (DAICEL CHIRALPAK IG, 250 × 30 mm, 10 μm); 50% MeOH (0.1% NH4OH) in CO2) to give: Peak 1, intermediate A74. (R)-2-(5-aminopyridin-3-yl)-5-oxohexahydropyrazine-1-carboxylic acid tert-butyl ester or (S)-2-(5-aminopyridin-3-yl)-5-oxohexahydropyrazine-1-carboxylic acid tert-butyl ester (white solid; 75 mg, 2.5%). LCMS m/z = 293 [M+H] ⁺ . Intermediate A75. Synthesis of (S)-tert-butyl 2-(3-amino-2-morpholinylphenyl)pyrrolidine-1-carboxylate and (R)-tert-butyl 2-(3-amino-2-morpholinylphenyl)pyrrolidine-1-carboxylate. Step 1. Synthesis of 4-(2-bromo-6-nitrophenyl) morpholine .

To a solution of 1-bromo-2-fluoro-3-nitro-benzene (2 g, 9.09 mmol) and morpholine (792 mg, 9.09 mmol) in DMSO (5 mL) was added DIPEA (3.52 g, 27.3 mmol) at 25° C., and the reaction mixture was stirred at 100° C. for 16 h. Water (5 ml) was added and the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (2.5 g, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.79 (d, 1H), 7.57 (d, 1H), 7.10 (t, 1H), 3.90-3.77 (m, 4H), 3.21-3.07 (m, 4H). Step 2. Synthesis of tert-butyl 2-(2- oxolinyl - 3- nitrophenyl)-1H -pyrrole -1- carboxylate .

To a solution of 4-(2-bromo-6-nitro-phenyl)pyrrolidine (Step 11, 2.40 g, 8.36 mmol) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-1-carboxylate (5.88 g, 20.1 mmol) in DME (35 mL) and H ₂ O (7 mL) were added Na ₂ CO ₃ (1.77 g, 16.7 mmol) and Pd(PPh ₃ ) ₄ (1.45 g, 0.418 mmol) at 25° C. and the reaction mixture was stirred at 90° C. for 2 h under N _2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by MPLC (SiO ₂ , 10% EtOAc/PE) to give the title compound (2.5 g, 80%) as a yellow solid. LCMS m/z = 374 [M+H] ⁺ . Step 3. Synthesis of tert -butyl 2-(3-amino-2- morpholinylphenyl ) pyrrolidine -1- carboxylate .

Pd/C (1.50 g, 10% pure) was added to a mixture of tert-butyl 2-(2-morpholinyl-3-nitrophenyl)-1H-pyrrole-1-carboxylate (2.5 g, 6.70 mmol) in THF (20 mL) at 25° C., and the resulting mixture was stirred under H ₂ (15 psi) at 50° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-17 (25%-60% MeCN). The residue was further separated by SFC (Chiralpak IC, 250 × 30 mm, 10 μm; 40% IPA (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 2, intermediate A75 , (S)-2-(3-amino-2-morpholinylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester or (R)-2-(3-amino-2-morpholinylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 9%) as a white solid. LCMS m/z = 348 [M+H] ⁺ . Intermediates A76 and A77. (S)-tert-butyl 2-(3-amino-2-morpholinylphenyl)pyrrolidine-1-carboxylate or (R)-tert-butyl 2-(3-amino-2-morpholinylphenyl)pyrrolidine-1-carboxylate. Step 1. Synthesis of tert-butyl 2-(2-fluoro-3-nitrophenyl)-1H-pyrrole-1-carboxylate.

The title compound (2.5 g, 90%) was prepared as a yellow oil from 1-bromo-2-fluoro-3-nitro-benzene and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatolan-2-yl)pyrrole-1-carboxylate using a method analogous to that described for intermediate A75, step 2). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.07-7.96 (m, 1H), 7.69-7.62 (m, 1H), 7.55-7.47 (m, 1H), 7.35-7.30 (m, 1H), 6.36-6.29 (m, 2H), 1.44 (s, 9H). Step 2. Synthesis of (S)-2-(3-amino-2- oxolinylphenyl ) pyrrolidine - 1- carboxylic acid tert-butyl ester or (R)-2-(3-amino-2-oxolinylphenyl ) pyrrolidine - 1 - carboxylic acid tert-butyl ester .

The title compound was prepared from tert-butyl 2-(2-fluoro-3-nitrophenyl)-1H-pyrrole-1-carboxylate (Step 1) using a method analogous to that described for A75, Step 3. Chiral SFC (DAICEL CHIRALCEL OJ, 250 × 30 mm, 10 μm); 25% IPA (0.1% NH ₄ OH) in CO ₂ ).

Peak 1, intermediate A76, (S)-2-(3-amino-2-morpholinylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester or (R)-2-(3-amino-2-morpholinylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (white solid: 20 mg, 11%). LCMS m/z = 225 [M-56+H] ⁺ .

Peak 2, intermediate A77, (R)-2-(3-amino-2-oxolinylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester or (S)-2-(3-amino-2-oxolinylphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (white solid: 20 mg, 11%). LCMS m/z = 225 [M-56+H] ⁺ . Intermediate A78. (3-amino-2-(trifluoromethyl)benzyl)carbamic acid tert-butyl ester Step 1. Synthesis of 3-bromo-2-(trifluoromethyl)benzamide

To a solution of 3-bromo-2-(trifluoromethyl)benzoic acid (2.5 g, 9.29 mmol) in DMF (15 mL) was added NH ₄ Cl (2.49 g, 46.5 mmol), HATU (5.30 g, 13.9 mmol) and DIPEA (7.21 g, 55.8 mmol), and the mixture was stirred at 25 °C for 2 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (3× 30 mL). The combined organics were dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and the residue was purified by prep-HPLC-21 (15%-45% MeCN) to give the title compound (3.50 g, 70%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₅ ) δ: 8.01 (s, 1H), 7.92 (d, 1H), 7.67 (s, 1H), 7.60 (t, 1H), 7.46 (d, 1H). Step 2. Synthesis of (3-bromo-2-(trifluoromethyl)phenyl)methanamine

To a mixture of 3-bromo-2-(trifluoromethyl)benzamide (Step 1, 1.50 g, 5.60 mmol) in THF (25 mL) was added BH ₃ .THF (1 M, 84 mL) at 0° C., and the mixture was stirred under N ₂ at 50° C. for 17 h. The reaction mixture was quenched by adding MeOH (20 mL) at 0° C., and the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC-22 (5%-35% MeCN) to give the title compound (950 mg, 33%) as a white solid. LCMS m/z = 254 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (3-bromo-2-(trifluoromethyl)benzyl)carbamate

To a solution of (3-bromo-2-(trifluoromethyl)phenyl)methanamine (Step 2, 830 mg, 3.27 mmol), (Boc) _2O (1.07 g, 4.90 mmol) in _H2O (2 mL) and THF (10 mL) was added _Na2CO3 (693 mg, 6.53 mmol), and the mixture was stirred at 25 °C for 1 h. _The mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (25% EtOAc/PE) to give the title compound (460 mg, 40%) as a yellow oil. LCMS m/z = 298 [M-56+H] ⁺ . Step 4. Synthesis of tert-butyl (3-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)benzyl)carbamate

To a solution of tert-butyl (3-bromo-2-(trifluoromethyl)benzyl)carbamate (step 3, 410 mg, 1.16 mmol) and tert-butyl carbamate (203 mg, 1.74 mmol) in dioxane (10 mL) were added Cs ₂ CO ₃ (566 mg), Xphos (55.2 mg, 0.116 mmol) and Pd ₂ (dba) ₃ (106 mg, 0.116 mmol), and the mixture was stirred at 100 °C under N ₂ for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by prep-TLC (20% EtOAc/PE) to give the title compound (370 mg, 82%) as a yellow oil. LCMS m/z = 235 [M-156+H] ⁺ . Step 5. Synthesis of 3-(aminomethyl)-2-(trifluoromethyl)aniline

A solution of tert-butyl (3-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)benzyl)carbamate (Step 4, 360 mg, 0.922 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (110 mg, 63%). LCMS m/z = 191 [M+H] ⁺ . Step 6. Synthesis of tert-butyl (3-amino-2-(trifluoromethyl)benzyl)carbamate

To a solution of 3-(aminomethyl)-2-(trifluoromethyl)aniline (Step 5, 80 mg, 0.42 mmol) and (Boc) _2O (73.5 mg, 0.337 mmol) in _H2O (0.60 mL) and THF (3 mL) was added _Na2CO3 (89.2 _mg , 0.841 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-11 (20%-55% MeCN) to give the title compound (40 mg, 33%) as a yellow oil. LCMS m/z = 235 [M-56+H] ⁺ . Intermediate A79 . (R)-2-(5-aminopyridazin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester or (S)-2-(5-aminopyridazin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester.

The title compound was prepared from 6-chloropyridazin-4-amine and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate using a 2-step procedure analogous to that described for intermediate A20. Chiral SFC (Phenomenex Cellulose-2, 250 × 30 mm, 10 μm; 40% MeOH (0.1% NH ₄ OH) in CO ₂ .

Peak 1, intermediate A79 . (R)-2-(5-aminopyridazine-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester or (S)-2-(5-aminopyridazine-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (white solid, 50 mg, 29%). LCMS m/z = 279 [M+H] ⁺ . Intermediate A80 . (R)-6-(1-aminoethyl)pyrazine-2-amine or (S)-6-(1-aminoethyl)pyrazine-2-amine. Step 1. Synthesis of tert-butyl (6 - bromopyrazin -2- yl ) carbamate .

To a solution of 6-bromopyrazin-2-amine (13 g, 74.7 mmol) in DCM (100 mL) was added DMAP (9.13 g, 74.7 mmol), TEA (11.34 g, 112 mmol) and Boc ₂ O (16.3 g, 74.7 mmol) at 0° C., and the mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by MPLC (SiO ₂ , 0-33% EtOAc/PE) to give the title compound (15.31 g, 75%) as a yellow solid. LCMS m/z = 274 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (6-( prop -1- en -2- yl ) pyrazin -2- yl ) carbamate .

To a solution of tert-butyl (6-bromopyrazin-2-yl)carbamate (Step 1, 15.2 g, 55.5 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (18.64 _g , 111 mmol) in dioxane (100 mL) and _H2O (5 mL) were added _K2CO3 (15.33 g, 111 mmol) and Pd(dppf) _Cl2 (1.22 g, 1.66 mmol), and the mixture was stirred under _N2 at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 1%-5% EtOAc/PE) to give the title compound (12.1 g, 93%) as a yellow solid. LCMS m/z = 236 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (6- acetylpyrazin - 2- yl ) carbamate .

Ozone was bubbled through a solution of tert-butyl (6-(prop-1-en-2-yl)pyrazin-2-yl)carbamate (Step 2, 11 g, 46.8 mmol) in DCM (100 mL) at -78 °C until it turned light blue (1 h, 15 psi). The reaction was quenched with _Me2S (30.8 g, 496 mmol ₎ at 25 °C and the resulting mixture was stirred at 25 °C for 1 h. The mixture was diluted with _H2O (100 mL) and extracted with DCM (3 x 80 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 1%-17% EtOAc/PE) to give the title compound as a brown solid (3.13 g, 28%). LCMS m/z = 238 [M+H] ⁺ . Step 4. Synthesis of tert-butyl (Z)-(6-(1-((tert-butylsulfinyl)imino)ethyl) pyrazin -2- yl)carbamate .

To a solution of 2-methylpropane-2-sulfenamide (1.15 g, 9.48 mmol, 1.5 eq) and tert-butyl (6-acetylpyrazin-2-yl)carbamate (Step 3, 1.5 g, 6.32 mmol) in THF (20 mL) was added Ti(OEt) ₄ (2.88 g, 12.6 mmol), and the mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with H ₂ O (20 mL), and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was diluted with _H2O (20 mL) and extracted with EtOAc (3 x 30 mL), dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as a brown oil ( _1.6 g, 74%). LCMS m/z = 341 [M+H] ⁺ . Step 5. Synthesis of tert-butyl (6-(1-((tert-butylsulfinyl)amino)ethyl) pyrazin -2- yl)carbamate .

To a solution of tert-butyl (Z)-(6-(1-((tert-butylsulfinyl)imino)ethyl)pyrazin-2-yl)carbamate (Step 4, 1.6 g, 4.70 mmol) in MeOH (20 mL) was added _NaBH4 (440 mg, 11.6 mmol) at 0°C, and the mixture was stirred at 25°C for 1 h. The reaction mixture was quenched by addition of 0.5 M HCl (10 mL) at 0°C, and extracted with EtOAc (3 x 30 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 1%-50% EtOAc/PE) _to give the title compound as a brown solid (1.04 g, 65% yield). LCMS m/z = 343 [M+H] ⁺ . Step 6. Synthesis of (R)-6-(1-aminoethyl) pyrazin -2- amine or (S)-6-(1-aminoethyl) pyrazin -2- amine .

A solution of tert-butyl (6-(1-((tert-butylsulfinyl)amino)ethyl)pyrazin-2-yl)carbamate (Step 5, 1.04 g, 3.04 mmol) in HCl/MeOH (15 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-11 (1%-5% MeCN), followed by chiral SFC (DAICEL CHIRALPAK IC, 250 × 30 mm, 10 μm); 45% IPA (0.1% NH ₄ OH) in CO 2 to give: Peak 1 , intermediate A80. (R)-6-(1-aminoethyl)pyrazin-2-amine or (S)-6-(1-aminoethyl)pyrazin-2-amine (brown solid; 97 mg, 23%). LCMS m/z = 139 [M+H] ⁺ . Intermediate A81 . 2-(3-amino-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester. Step 1. Synthesis of tert-butyl 2-(2-methoxy-3-nitrophenyl)-1H -pyrrole -1- carboxylate.

To a mixture of 1-bromo-2-methoxy-3-nitrobenzene (463 mg, 2.00 mmol), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (633 mg, 3.00 mmol), tBuXPhos ₍ 63.7 mg, 0.15 mmol) and PdCl2(PPh3) ₂ (70.2 mg, 0.10 mmol) in dioxane (16 mL) and saturated aqueous sodium carbonate solution (4 mL) was bubbled with nitrogen for 10 min and then heated to 80 °C overnight. The reaction mixture was filtered through celite, washed with 75 mL EtOAc and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 40 g silica, 0-70% EtOAc/hex) to give the title compound (633 mg, 85% yield) as a clear yellow oil. LCMS m/z = 341 [M+Na] ⁺ . Step 2. Synthesis of tert-butyl 2-(3-amino-2-methoxyphenyl) pyrrolidine -1- carboxylate .

To a mixture of tert-butyl 2-(2-methoxy-3-nitrophenyl)-1H-pyrrole-1-carboxylate (Step 1, 626 mg, 2.0 mmol) and Pt/C (5 wt %, 680 mg, 0.20 mmol, 10 mol %) in methanol (20 mL) was bubbled with hydrogen for 5 min and then stirred under a hydrogen balloon atmosphere at room temperature for 3 days. The reaction mixture was filtered through celite, washed with methanol and evaporated to dryness. The residue was purified by flash chromatography (ISCO 24 g silica, 0-5% MeOH/DCM) followed by (ISCO 24 g silica, 0-60% EtOAc/hex) to give the title compound as a white solid (356 mg, 58%). LCMS m/z = 293 [M+H] ⁺ . Intermediate A82 . Synthesis of (3-amino-2-methoxyphenyl)methanol.

A dry flask containing _LiAlH4 (484 mg, 12.5 mmol) was evacuated and backfilled with nitrogen three times, and anhydrous THF (20 mL) was added and the mixture was cooled on ice. A suspension of 3-amino-2-methoxybenzoic acid (830 mg, 5.0 mmol) in anhydrous THF (30 mL) was added dropwise over 15 min with stirring, and the reaction was allowed to warm to room temperature and heated to 60 °C for 3 h. The reaction was allowed to cool to room temperature and quenched carefully by adding water dropwise. The mixture was diluted with EtOAc (10 mL), saturated aqueous NH4Cl solution (1 mL) was added and stirred at room temperature for 1.5 h. The mixture was poured into _aqueous NaHCO3 solution and extracted with EtOAc (4× 50 mL). The combined organics were washed with water (x2), brine, dried (MgSO4), and evaporated to dryness by rotary evaporation. The residue was purified by flash chromatography (ISCO 40 g silica, 0-20% MeOH/DCM) to give the title compound as a waxy amber solid (466 mg, 60%). LCMS m/z = 154 [M+H] ⁺ . Intermediate A83 . 3-(Aminomethyl)-2-ethoxyaniline. Step 1. Synthesis of 2-ethoxy-3-nitrobenzoic acid .

A solution of methyl 2-fluoro-3-nitrobenzoate (997 mg, 5.0 mmol) in DMF (12 mL) was purged with _N2 and cooled on ice, to which was added sodium ethanolate solution (2.00 mL, 21 w/w% in ethanol, 5.25 mmol), and the reaction was stirred at 0°C for 30 min and then at room temperature overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3× 30 mL). The combined organics were washed with water (×2), brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (ISCO, 24 g silica, 0050% EtOAc/hex), and the residue (1.025 g) was dissolved in MeOH (3 mL) and water (5 mL). NaOH (12.5 mmol, 497 mg) was added thereto, and the mixture was heated to 60° C. overnight. The reaction mixture was acidified to pH 1 with aqueous HCl, and the resulting precipitate was collected by suction filtration. The solid was washed with water to give the title compound as a yellow solid (424 mg, 40% yield, 2 steps). LCMS m/z = 212 [M+H] ⁺ . Step 2. Synthesis of 2-ethoxy-3-nitrobenzamide .

To a solution of 2-ethoxy-3-nitrobenzoic acid (Step 1, 424 mg, 2.0 mmol) in MeCN (13.5 mL) was added DIPEA (1.40 mL, 8.0 mmol), HOBT hydrate (459 mg, 3.0 mmol) and EDC-HCl (576 mg, 3.0 mmol) in sequence, and the mixture was stirred at room temperature for 10 min, followed by the addition of ammonium carbonate (1.17 g, 18.0 mmol), and then stirred at room temperature for 3 days. The reactant was concentrated by rotary evaporation, and water (30 mL) was added to the residue. The resulting slurry was stirred at room temperature for 1 h and collected by suction filtration and washed with water (50 mL) to provide the title compound as a white solid (214 mg, 51%). LCMS m/z = 211 [M+H] ⁺ . Step 3. Synthesis of (2-ethoxy-3-nitrophenyl)methanamine .

A solution of 2-ethoxy-3-nitrobenzamide (Step 2, 211 mg, 1.0 mmol) in anhydrous THF (7 mL) was added dropwise to an ice-cold _BH3 -THF solution (2.30 mL, 1 M in THF, 2.30 mmol), and the reaction was heated to 67 °C overnight. The reaction was cooled to room temperature, quenched with 6 M aqueous HCl (2 mL) and stirred for 1 h. The volatiles were removed by rotary evaporation, and the crude residue was neutralized to pH > 10 with saturated aqueous _NaHCO3 , 1 M aqueous NaOH, and extracted with EtOAc (4 x 25 mL). The combined organics were washed with water, brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by chromatography (ISCO, 4 g silica, 0-10% MeOH/DCM) to provide the title compound as a yellow solid (39 mg, 20%). LCMS m/z = 197 [M+H] ⁺ . Step 4. Synthesis of 3-(aminomethyl)-2-ethoxyaniline .

To a mixture of (2-ethoxy-3-nitrophenyl)methanamine (step 3, 39.7 mg, 0.20 mmol) and Pd/C (19.1 mg, 10 wt %, 0.020 mmol) in MeOH (1.5 mL) was bubbled with _H for 10 min and stirred under _H balloon atmosphere at room temperature for 3 h. The reaction was filtered through celite, washed with MeOH and concentrated to provide the title compound as a yellow film (29.7 mg, 89%) which was used without purification. LCMS m/z = 167 [M+H] ⁺ . Intermediate A84 . tert-butyl (3-amino-2-(difluoromethoxy)benzyl)carbamate. Step 1. Synthesis of 2-(difluoromethoxy)-3-nitrobenzamide .

Part A: To an ice-cold solution of methyl 2-hydroxy-3-nitrobenzoate (587 mg, 3.0 mmol) in MeCN (20 mL) and diethyl (bromodifluoromethyl)phosphonate (0.85 mL, 4.80 mmol) were added KOH (1.643 g, 30.0 mmol) and water (2.0 mL) dropwise over 2 min, and the reaction was stirred at 0 °C for 10 min, and then at room temperature overnight. The reaction was poured into water and extracted with EtOAc (3 x 50 mL), and the organic component was discarded. The aqueous phase was adjusted to pH <3 with aqueous HCl and extracted with EtOAc (3 x 50 mL). The combined organics were washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to give a yellow solid (561 mg).

Part B: To a solution of 2-(difluoromethoxy)-3-nitrobenzoic acid (Part A, 561 mg, 2.4 mmol, about 35% of the mixture) in MeCN (16 mL) was added DIPEA (1.60 mL, 9.60 mmol), HOBT hydrate (549 mg, 3.60 mmol) and EDC-HCl (686 mg, 3.60 mmol) in sequence and stirred at room temperature for 10 min, and ammonium carbonate (1.40 g) was added and the resulting mixture was stirred at room temperature for 3 days. The volatiles were removed by rotary evaporation, and the residue was poured into water and extracted with EtOAc (3×25 mL). The combined organics were washed with 1 M aqueous HCl (×3), saturated aqueous NaHCO ₃ , water, brine, dried over MgSO ₄ and evaporated to dryness. The residue was purified by chromatography (ISCO 24 g silica, 0-10% MeOH/DCM) to give the title compound as a yellow solid (135 mg, 19% yield, 2 steps). LCMS m/z = 233 [M+H] ⁺ . Step 2. Synthesis of (2-(difluoromethoxy)-3-nitrophenyl)methanamine .

The reaction was run under nitrogen atmosphere. BH3-THF (2.40 mL, 1 M in THF, 2.40 mmol, 2.3 equiv) was cooled on ice. A solution of 2-(difluoromethoxy)-3-nitrobenzamide BJG-01-154 (239 mg, 1.02 mmol, 1.0 equiv) in anhydrous THF (7 mL) was added dropwise over 5 min. The reaction was heated to 67 °C overnight. The reaction was cooled to room temperature, quenched with 6 M aqueous HCl (3 mL), and stirred for 1 h. Volatiles were removed by rotary evaporation. The crude residue was neutralized to pH >10 with 1 M aqueous NaOH and then extracted with EtOAc (4×30 mL). The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated by rotary evaporation. Flash chromatography (ISCO, 12 g silica, 0 to 10% MeOH/DCM, 10 min gradient) afforded the title compound (65.6 mg, 29% yield) as a yellow-orange solid. LCMS m/z = 219 [M+H] ⁺ . Step 3. Synthesis of tert-butyl (3-amino-2-(difluoromethoxy)benzyl)carbamate .

To a solution of (2-(difluoromethoxy)-3-nitrophenyl)methanamine (Step 2, 65.6 mg, 0.30 mmol) in DCM (2 mL) was added _Boc2O (73.5 mg, 0.30 mmol) followed by _Et3N (46 μL, 0.33 mmol) and the reaction was stirred at room temperature for 4 h. The reaction was diluted with DCM (20 mL), washed with 1 M aqueous HCl, saturated aqueous NaHCO3, brine, dried (MgSO4) and concentrated under reduced pressure. To the residue and Pd/C (31.7 mg, 10 wt %, 0.030 mmol) in MeOH (3 mL) was bubbled with hydrogen for 10 min and then stirred under a balloon of _H2 at room temperature overnight. The reaction mixture was filtered through celite and washed with methanol. The filtrate was evaporated to dryness and the residue was purified by chromatography (ISCO, 4 g silica, 0-100% EtOAc/Hex) to give the title compound (54.6 mg, 63%, 2 steps) as a clear colorless oil. LCMS m/z = 311 [M+Na] ⁺ . Intermediate A85 . 2-(3-amino-5-fluorophenyl)hexahydropyridine-1-carboxylic acid tert-butyl ester. Step 1. Synthesis of tert-butyl 6-(3-fluoro-5-nitrophenyl)-3,4-dihydropyridine - 1(2H)-carboxylate .

To a mixture of 1-bromo-3-fluoro-5-nitrobenzene (219 mg, 1.00 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (413 mg, 1.30 mmol), tBuXPhos (33.1 mg, 0.075 mmol), PdCl2( _PPh3 ) _{2 (} 35.6 mg, 0.050 mmol) in dioxane (4 mL) and saturated aqueous sodium carbonate solution (1 mL) was bubbled with _N2 for 10 min and heated to 80 °C overnight. The reaction was filtered through celite, washed with EtOAc and concentrated under reduced pressure. The residue was purified by chromatography (ISCO 12 g silica, 0-80% EtOAc/Hex) to give the title compound (83.1 mg, 26%) as a clear yellow oil. LCMS m/z = 345 [M+Na] ⁺ . Step 2. Synthesis of tert-butyl 2-(3-amino-5-fluorophenyl)hexahydropyridine - 1- carboxylate .

To a mixture of tert-butyl 6-(3-nitrophenyl)-3,4-dihydropyridine-1(2H)-carboxylate (Step 1, 78.4 mg, 0.24 mmol) and Pd/C (27.5 mg, 10 wt %, 0.024 mmol) in MeOH (5 mL) was added H ₂ using 4 fill/vacuum cycles. The flask was pressurized to 40 psi H ₂ , sealed and heated to 60 °C overnight. The reaction was filtered through celite, washed with MeOH and the filtrate was concentrated to provide the title compound as a yellow oil (66.5 mg, 93%). The material was used in the next step without purification. LCMS m/z = 317 [M+Na] ⁺ . Intermediate A85. (S)-tert-butyl 2-(3-amino-2-fluorophenyl)pyrrolidine-1-carboxylate or (R)-tert-butyl 2-(3-amino-2-fluorophenyl)pyrrolidine-1-carboxylate.

Pd/C (200 mg, 10% purity) was added to tert-butyl 2-(2-fluoro-3-nitrophenyl)-1H-pyrrole-1-carboxylate (Intermediate A76 and A77, step 1, 200 mg, 0.653 mmol) in MeOH (2 mL), and the mixture was stirred under _H2 (50 psi) at 60 °C for 20 h. The reaction mixture was filtered and the filtrate was evaporated to dryness, and the residue was purified by prep-TLC (50% EtOAc/PE/) and by SFC (DAICEL CHIRALCEL OJ, 250 × 30 mm, 10 μm); 25% IPA (0.1% NH4OH) in _CO2 ) to give: Peak 1, intermediate A85. (S)-2-(3-amino-2-fluorophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester or (R)-2-(3-amino-2-fluorophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (white solid, 20 mg, 11%). LCMS m/z = 225 [M-56+1] ⁺ . Intermediate B1. 4-(Bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-chloro-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4,6-dichloropyrimidine-5-carboxylate (670 g, 3.10 mol, 95.7% purity) and AcOH (2.51 kg, 41.8 mol) was stirred at 120 °C for 24 h under _N2 . The reaction mixture was concentrated under reduced pressure, and the residue was triturated with EtOAc (500 mL) at 25 °C for 16 h. The solid was collected by filtration to give the title compound as a brown solid (1.50 kg, crude), which was used without further purification. ¹ H NMR (400 MHz, DMSO- _d6 ) δ: 8.31 (s, 1H), 3.81 (s, 3H). Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A 5 L three-necked flask was charged with DMSO (2.50 L). Methyl 4-chloro-6-oxo-1,6-dihydropyrimidine-5-carboxylate (300 g, 1.22 mol, 76.5% purity), bis(4-methoxybenzyl)amine (313 g, 1.22 mol), DIPEA (315 g, 2.43 mol) were added thereto in sequence at 20°C-25°C, and the resulting mixture was stirred at 75°C-80°C for 5 h. The reaction mixture was cooled to 20°C-25°C, poured into water (8 L), and extracted with DCM (2×5 L). The combined organics were washed with brine (3 x 1.5 L) and separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was triturated with MTBE (1 L) at 15-20° C. for 1 h and the solid was collected by filtration and the filter cake dried under vacuum to give the title compound as a yellow solid (421 g, 80.4%). LCMS m/z = 410 [M+H] ⁺ . Intermediate B2. Synthesis of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

To a solution of methyl 4-chloro-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, Step 1, 1 g, 5.30 mmol) and bis(2,4-dimethoxybenzyl)amine (3.37 g, 10.6 mmol) in DMSO (8 mL) was added DIPEA (2.74 g, 21.2 mmol), and the mixture was stirred at 100 °C for 12 h. Water (10 mL) was added, and the mixture was extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography ( _SiO2 , 0-100% EtOAc/PE) _to give the title compound as a yellow oil (2.4 g, 96%). LCMS m/z = 470 [M+H] ⁺ . Intermediate B3. Methyl 4-amino-1-((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-1-(2-bromo-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

K ₂ CO ₃ (6.75 g, 48.9 mmol) was added to a mixture of 1-bromo-2-fluoro-3-nitro-benzene (6.45 g, 29.3 mmol) and methyl 4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B2, 11.47 g, 24.4 mmol) in DMF (80 mL), and the mixture was stirred at 80° C. for 1 h. The solid was removed by filtration, and H ₂ O (100 mL) was added to the filtrate. The resulting solid was collected by filtration to give the title compound (14.5 g, 89%) as a yellow solid. LCMS m/z = 669 [M+H] ⁺ . Step 2. Synthesis of 1-(2-amino-6-bromophenyl)-4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester

Fe (12.1 g, 216 mmol) and NH ₄ Cl (11.6 g, 216 mmol) were added to a mixture of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-1-(2-bromo-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (14.5 g, 21.7 mmol) in THF (100 mL), H ₂ O (20 mL) and EtOH (30 mL), and the mixture was stirred at 80° C. for 1 h. The solid was removed by filtration, and H ₂ O (100 mL) was added to the filtrate. The resulting solid was collected to give the title compound (13 g, 94%) as a yellow solid. LCMS m/z = 607 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-1-(2-bromo-6-chlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a mixture of methyl 1-(2-amino-6-bromophenyl)-4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (5 g, 7.82 mmol, 1 eq), CuCl (1.55 g, 15.6 mmol), CuCl ₂ (2.10 g, 15.6 mmol) in CH ₃ CN (40 mL) was added isoamyl nitrite (2.75 g, 23.46 mmol, 3.16 mL) in CH ₃ CN (2 ml), and then the mixture was stirred under N 2 at 20 °C for 1 h. The reaction mixture was evaporated under a stream of N _2. The residue was diluted with H ₂ O (50 mL) and extracted with EtOAc (4× 50 mL). The combined organics were dried ( _Na2SO4 ) and evaporated to dryness in _vacuo , and the residue was purified by column chromatography ( _SiO2 , 0-100% EtOAc/PE) to give the title compound as a yellow oil (13 g, crude). LCMS m/z = 660 [M+H] ⁺ . Step 4. Synthesis of methyl 4-amino-1-(2-bromo-6-chlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A mixture of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-1-(2-bromo-6-chlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (11.5 g, 17.5 mmol) in TFA (5 mL) and DCM (10 mL) was stirred at 20 °C for 1 h. The reaction mixture was evaporated to dryness under a stream of N _2. The residue was diluted with H ₂ O (50 mL), and saturated aqueous Na ₂ CO ₃ was added until pH=8, and the mixture was extracted with EtOAc (4× 50 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (3.8 g, 61%) as a yellow solid. LCMS m/z = 360 [M+H] ⁺ . Step 5. Synthesis of methyl 4-amino-1-(2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of 4-amino-1-(2-bromo-6-chloro-phenyl)-6-oxo-pyrimidine-5-carboxylic acid methyl ester (2.02 g, 5.63 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (2.12 g, 8.45 mmol, 2.36 mL, 50% purity), Pd(dppf) _Cl2 (412.2 mg, 0.563 mmol) and _K2CO3 (1.56 g, 11.3 mmol) in _dioxane (20 mL) was degassed with _N2 (3x) and stirred under _N2 at 100 °C for 1.5 h. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-66% EtOAc/PE) to give (rac)-4-amino-1-(2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. The racemate was separated by chiral SFC (Diacel Chiralpak IG, 250 × 30 mm, 10 μm; 35% (0.1% NH ₄ OH/IPA) in CO ₂ ) to give: Peak 1, Intermediate B3 : 4-amino-1-((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (yellow solid, 400 mg, 17.3%). LCMS m/z = 294 [M+H] ⁺ . Intermediate B4. 4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-bromo-6-chloro-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

DIPEA (10.1 g, 78.2 mmol) was added to a solution of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 6.4 g, 15.63 mmol) and 1-bromo-3-chloro-2-fluoro-5-nitro-benzene (3.98 g, 15.63 mmol) in DMSO (50 mL), and the mixture was stirred at 100 °C for 8 h. The reaction mixture was treated with _H2O (30 mL), filtered and the filter cake was dried under reduced pressure to give the title compound as a brown solid (10.2 g, crude). LCMS m/z = 645 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-methyl-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (4.06 g, 16.15 mmol, 4.52 mL, 50% purity), methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-bromo-6-chloro-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (8 g, 12.42 mmol) in dioxane (100 mL) was added Pd(dppf) _Cl2 (455 mg, 0.621 mmol) and _K2CO3 (3.43 g, 24.9 mmol), and the mixture was stirred under _N2 at 100 ° _C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 0-50% THF/PE) to give the title compound (8.26 g, crude) as a brown solid. LCMS m/z = 579 [M+H] ⁺ . Step 3. Synthesis of methyl 1-(4-amino-2-chloro-6-methylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-methyl-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (8.2 g, 14.2 mmol), NH ₄ Cl (7.58 g, 142 mmol), Fe (7.91 g, 142 mmol) in THF (40 mL), EtOH (40 mL) and H ₂ O (10 mL) was stirred at 80° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was diluted with H ₂ O (80 mL) and extracted with EtOAc (3× 60 mL). The combined organics were dried ( _Na2SO4 ) and evaporated to dryness under reduced pressure _to give the title compound as a brown solid (7.05 g, 90%). LCMS m/z = 549 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of methyl 1-(4-amino-2-chloro-6-methylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (7 g, 12.8 mmol) in MeCN (150 mL) were added TBAB (24.66 g, 76.50 mmol), CuBr (2.19 g, 15.3 mmol), ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid (8.89 g, 38.3 mmol) and _NaNO2 (2.64 g, 38.3 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H ₂ O (100 mL) and extracted with EtOAc (3× 60 mL). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) to give the title compound as a yellow solid (5 g, 64%). LCMS m/z = 614 [M+H] ⁺ . Step 5. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (2 g, 3.26 mmol) in MeOH (6 mL) and toluene (6 mL) were added _Pd2 (dba) ₃ (149.4 mg, 0.163 mmol), t- _BuXphos (138.6 mg, 0.326 mmol) and _K3PO4 (1.04 g, 4.89 mmol), and the mixture was stirred under _N2 at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (870 mg, 1.54 mmol, 47%) as a brown solid. LCMS m/z = 564 [M+H] ⁺ . Step 6. Synthesis of methyl (S)-4-amino-1-(2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (870 mg, 1.54 mmol) in TFA (8 mL) was stirred at 80 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was adjusted to pH 7-8 with NaHCO3. The mixture was diluted with _H2O (20 mL) and extracted with EtOAc (3×10 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) followed by chiral SFC (DAICEL CHIRALPAK AD, 250 × 30 mm, 10 μm); 27% (0.1% NH ₄ OH/IPA) in CO ₂ ) to give: Peak 1, intermediate B4. (S)-4-amino-1-(2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (white solid, 187 mg, 37%). LCMS m/z = 324 [M+H] ⁺ . Intermediate B5. (S)-4-amino-1-(2-chloro-4-ethoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester.

The title compound was prepared using a method similar to that described for Intermediate B4. Chiral SFC (DAICEL CHIRALPAK IC, 250 × 30 mm, 10 μm); 45% (0.1% NH ₄ OH/IPA) in CO ₂ ) gave: Peak 1, Intermediate B5 . (S)-4-amino-1-(2-chloro-4-ethoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (white oil, 730 mg, 46%). LCMS m/z = 338 [M+H] ⁺ . Intermediate B6. 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

DIPEA (1.58 g, 12.21 mmol) was added to a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 2.5 g, 6.11 mmol) and 1,3-dichloro-2-fluoro-5-nitro-benzene (5.13 g, 24.42 mmol) in DMSO (15 mL), and the mixture was stirred at 100 °C for 5 h. The reaction mixture was partitioned between EtOAc (30 mL) and _H2O (20 mL), and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organics were dried ( _Na2SO4 ) and evaporated _to dryness in vacuo. The residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) to give the title compound as a yellow solid (4 g, crude). LCMS m/z = 599 [M+H] ⁺ . Step 2. Synthesis of methyl 1-(4-amino-2,6-dichlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

Pd/C (0.2 g, 10% pure) was added to a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 4 g, 6.67 mmol) in MeOH (5 mL) and EtOAc (5 mL), and the mixture was stirred under _H2 (15 psi) at 15 °C for 1 h. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo to give the title compound as a yellow solid (2.2 g) which was used without further purification. Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

A mixture of methyl 1-(4-amino-2,6-dichlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 2, 3.5 g, 6.15 mmol), CuBr (1.06 g, 7.38 mmol), TBAB (11.89 g, 36.9 mmol), (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid (3.69 g, 18.44 mmol) and _NaNO2 (1.27 g, 18.44 mmol) in MeCN (40 mL) was stirred at 15 °C for 12 h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (30 mL) and H ₂ O (20 mL). The aqueous phase was further extracted with EtOAc (3× 30 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO ₂ , 0-50% EtoAc/PE) to give the title compound as a yellow solid (1.5 g, 38.5%). LCMS m/z = 634 [M+H] ⁺ . Step 4. Synthesis of methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

Methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 3, 1.5 g, 2.37 mmol) in TFA (2 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (20 mL) and saturated _{aqueous Na2CO3} solution (15 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL) and _the combined organics were dried ( _Na2SO4 ) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (800 mg, crude) as a yellow solid. LCMS m/z = 394 [M+H] ⁺ . Intermediate B7. Methyl 4-amino-1-(2,6-dichloro-4-propoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-propoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 3, 500 mg, 0.789 mmol) in toluene (1 mL) and 1-propanol (1 mL) were added t-BuXphos (33.5 mg, 0,079 mmol) and _Pd2 (dba) ₃ (72.3 mg, 0.079 mmol), _{K3PO4 (} 251 mg, 1.18 mmol), and the mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-25% EtOAc/PE) to give the title compound (300 mg, 62%) as a brown oil. LCMS m/z = 612 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-propoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-propoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 270 mg, 0.441 mmol) in TFA (4 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under _N2 and the residue was diluted with _H2O (20 mL), and saturated _{aqueous Na2CO3} was added until pH = 8, and the mixture was extracted with EtOAc (3 x 20 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-33% EtOAc/PE) to give the title compound as a white solid (110 mg, 67%). LCMS m/z = 372 [M+H] ⁺ . Intermediate B8. Methyl 4-amino-1-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 1-(4-amino-2,6-dichlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, step 2; 500 mg, 0.88 mmol) in MeOH (5 mL) was added AcOH (52.73 mg, 0.88 mmol) to pH = 5, and then HCHO (356 mg, 4.39 mmol), and the mixture was stirred at 25 °C for 1 h. NaBH ₃ CN (82.8 mg, 1.32 mmol) was added thereto, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (5 mL), and extracted with EtOAc (3× 4 mL). The combined organics were washed with brine (2 x 3 mL), dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as a white solid (500 mg). LCMS m/z = 597 [M+H] ₊ ^. Step 2. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 450 mg, 0.75 mmol) in TFA (5 mL) was stirred at 80 °C for 1 h. The reaction mixture was quenched by the addition of saturated aqueous _Na2CO3 solution ₍ 3 mL) at 0 °C and extracted with EtOAc (3 x 4 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by prep-TLC to give the title compound (50 mg, 18%) as _a white solid. LCMS m/z = 357 [M+H] ⁺ . Intermediate B9. Synthesis of methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

To methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 150 mg, 0.382 mmol) in MeOH (10 mL) and THF (1 mL) was added Pd/C (0.2 g, 10% purity), and the mixture was stirred under _H2 (15 psi) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (50% EtOAc/PE) to give the title compound (70 mg, 58.4%) as a yellow solid. LCMS m/z = 314 [M+H] ⁺ . Intermediate B10. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

A mixture of methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5- _carboxylate (Intermediate B6, 500 mg, 1.27 mmol), _Cs2CO3 (829 mg, 2.54 mmol) and RockPhos Pd G3 (107 mg, 0.127 mmol) in dioxane (5 mL) and MeOH (0.20 mL) was stirred at 80 °C under _N2 for 2 h. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by prep-HPLC (Xbridge Prep OBD C18, 150 × 40 mm, 10 μm; 20%-50% MeCN/H ₂ O (10 mM NH ₄ HCO ₃ )) to give the title compound as a white solid (150 mg, 34%). LCMS m/z = 344 [M+H] ⁺ . Intermediate B11. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

The title compound (140 mg, 30%) was prepared as a white solid from methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6) and cyclopropanol using a method similar to that described for Intermediate B10. LCMS m/z = 370 [M+H] ⁺ . Intermediate B12. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

To a solution of methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 500 mg, 1.27 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (319 mg, 1.27 mmol, 355.69 uL, 50% purity) in dioxane (10 mL) were added Pd(dppf) _Cl2 (93 mg, 0.127 mmol) and _K2CO3 (352 mg, 2.54 mmol), and the _mixture was stirred under _N2 at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (15%-50% MeCN/H ₂ O (0.05% NH ₄ OH + 10 mM NH ₄ HCO ₃ )) to give the title compound as a white solid (190 mg, 45%). LCMS m/z = 328 [M+H] ⁺ . Intermediate B13. Methyl 4-amino-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-cyanophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

The title compound (10 g, 72%) was prepared as a yellow solid from methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1) and 3,5-dichloro-4-fluoro-benzonitrile using a method similar to that described for Intermediate B6, Step 1. LCMS m/z = 579 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-cyanophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (5 g, 8.63 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (2.17 g, 8.63 mmol, 2.41 mL, 50% purity) in dioxane (20 mL) were added XPHOS-PD-G2 (679 mg, 0.863 mmol) and K ₃ PO ₄ (3.66 g, 17.3 mmol), and the mixture was stirred at 80 °C for 3 h under N ₂ . The solid was removed by filtration and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Phenomenex Luna C18, 250 × 70 mm, 15 μm; 60%-85% MeCN/(H ₂ O + 0.2% HCO ₂ H)) to give methyl 4-(bis(2,4-dimethoxybenzyl)amino)-1-(2-chloro-4-cyano-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (110 mg, 0.204 mmol, 2.4%) as a white solid. The racemate was separated by chiral SFC (DAICEL CHIRALPAK AD, 250 × 30 mm, 10 μm; 35% (0.1% NH4OH/IPA) in _CO2 ) to give: Peak 1, intermediate B13: 4-(bis(4-methoxybenzyl)amino)-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (white solid, 320 mg). LCMS m/z = 559 [M+H] ⁺ . Step 3. Synthesis of 4-amino-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (step 2, peak 1, 320 mg, 0.572 mmol) in TFA (2 mL) was stirred at 80 °C for 15 min. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was purified by prep-TLC (EtOAc) to give the title compound (120 mg, 66%) as a light yellow solid. LCMS m/z = 319 [M+H] ⁺ . Intermediate B14. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-cyanophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-cyanophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B13, Step 1; 3.00 g, 5.18 mmol) in TFA (20 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with _H2O (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (2 x 15 mL), dried ( _Na2SO4 ) and _evaporated to dryness in vacuo. The residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (1.7 g, 97%) as a white solid. LCMS m/z = 339 [M+H] ⁺ . Intermediate B15. Methyl 4-amino-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 1-(4-amino-2,6-dichlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, Step 2; 500 mg, 0.878 mmol), CuCl (174 mg, 1.76 mmol), _CuCl2 (354 mg, 2.63 mmol) in MeCN (9 mL) was added isoamyl nitrite (308 mg, 2.63 mmol) in MeCN (0.9 mL), and the mixture was stirred under _N2 at 25 °C for 1 h. The reaction mixture was quenched by addition of _H2O (30 mL) at 0 °C and extracted with MeCN (3 x 30 mL). The combined organics were dried ( _Na2SO4 ) and evaporated to dryness in vacuo to give the title compound as a brown oil (400 mg, crude). LCMS m/z = 589 [M+H] ⁺ . Step 2. Synthesis of methyl ₄ -amino-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxylate (350 mg, 0.594 mmol) in TFA (8 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to pH 6-7 with 1 M Na ₂ CO _3. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (150 mg, 72%) as a yellow solid. LCMS m/z = 352 [M+H] ⁺ . Intermediate B16. 4-amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of 1,3-dichloro-5-(difluoromethyl)-2-fluorobenzene .

To a solution of 3,5-dichloro-4-fluoro-benzaldehyde (5 g, 25.9 mmol) in DCM (50 mL) was added DAST (20.88 g, 130 mmol) at -78 °C. The mixture was stirred at 25 °C for 3 h under _N2 . The reaction mixture was quenched by the addition of saturated aqueous _NaHCO3 solution (30 mL) at 0 °C _and extracted with DCM (3 x 20 mL). The combined organics were dried ( _Na2SO4 ) and evaporated to dryness in vacuo. The residue was purified by column chromatography ( _SiO2 , 20:1 PE/EtOAc) to give the title compound (5.3 g, 95%) as a light yellow oil which was used without further purification. Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of 1,3-dichloro-5-(difluoromethyl)-2-fluorobenzene (2.7 g, 12.6 mmol) and methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine- ₅ -carboxylate (Intermediate B1, 2.86 g, 6.98 mmol) in DMF (20 mL) was added _K2CO3 (1.93 g, 13.95 mmol), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound as a light yellow solid (2.24 g, 53%). LCMS m/z = 604 [M+H] ⁺ . Step 3. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (2.24 g, 3.71 mmol) in TFA (10 mL) was stirred at 80°C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, 0-50% EtOAc/PE) to give the title compound (1.35 g, 100%) as a light yellow solid. LCMS m/z = 364 [M+H] ⁺ . Intermediate B17. Synthesis of methyl 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

To a mixture of methyl 4-amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B16, 500 mg, 1.37 mmol) in dioxane (9 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (1.03 g, 4.12 mmol, 1.15 mL, 50% purity) and Xphos-Pd-G2 (108 mg, 0.137 mmol) and K ₃ PO ₄ (583 mg, 2.75 mmol), degassed and purged with N ₂ (×3), and the mixture was stirred under N ₂ at 80 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (800 mg, 90%). LCMS m/z = 324 [M+H] ⁺ . Intermediate B18. Methyl 4-amino-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 1, 6.00 g, 10.01 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (5.03 g, 20.02 mmol) in dioxane (100 mL) were added K ₃ PO ₄ (4.25 g, 20.02 mmol) and Xphos-Pd-G2 (472.54 mg, 0.60 mmol), and the mixture was stirred under N 2 at 80 °C for 12 h. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 25%-50% EtOAc/PE) to give the title compound (5.00 g, 89%) as a yellow solid. LCMS m/z = 559 [M+H] ⁺ . Step 2. Synthesis of methyl 1-(4-amino-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 5.00 g, 8.95 mmol) in THF (50 mL) and MeOH (50 mL) was added Pd/C (6.00 g, 10% purity), and the mixture was stirred under _H2 (15 psi) at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-23 (50%-70% MeCN) to give the title compound (4.50 g, crude) as a yellow solid. LCMS m/z = 529 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 1-(4-amino-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 1.92 g, 3.63 mmol, 1.00 eq), CuBr (625 mg, 4.36 mmol), CSA (2.53 g, 10.9 mmol) and TBAB (7.03 g, 21.8 mmol) in MeCN (30 mL) was added _NaNO2 (752 mg, 10.9 mmol) and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (1.70 g, 79%) as a white solid. LCMS m/z = 592 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 3, 1.12 g, 1.89 mmol), _Pd2 (dba) ₃ (173 mg, 0.19 mmol), t-BuXphos (80.3 mg, 0.19 mmol) and _{K3PO4 (} 602 mg, 2.84 mmol) in toluene (8 mL) and MeOH (8 mL) was stirred at 80 °C under _N2 for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a brown oil (800 mg, 77%). LCMS m/z = 544 [M+H] ⁺ . Step 5. Synthesis of methyl 4-amino-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 4, 1.20 g, 2.21 mmol) in TFA (20 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the pH was adjusted _to pH 6-7 with 1 M _Na2CO3 , and the residue was purified by column chromatography (0-50% EtOAc/PE) to give the title compound (560 mg, 83%) as a light yellow solid. LCMS m/z = 304 [M+H] ⁺ . Intermediate B19. 4-amino-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(hydroxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of tributyltinylmethanol (1.67 g, 5.21 mmol), methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 3; 1.10 g, 1.74 mmol) in dioxane (10 mL) was added Pd(PPh ₃ ) ₄ (100 mg, 0.087 mmol), and the mixture was stirred at 100 °C under N ₂ for 3 h. The residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (2.60 g, 85%) as a yellow solid. LCMS m/z = 584 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(hydroxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (2.15 g, 3.68 mmol) in THF (25 mL) were added NaOH (220 mg, 5.52 mmol) and dimethyl sulfate (4.07 g, 32.27 mmol), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with _H2O (50 mL) and extracted with EtOAc (3 x 25 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by prep-HPLC-11 (35%-70% MeCN) to give the title compound (180 mg, 0.300 mmol, 8.2%) as a white oil. LCMS m/z = 598 [M+H] ⁺ . Step 3. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (180 mg, 0.300 mol) in TFA (2 mL) was stirred at 80 °C for 0.5 h. The residue was purified by prep-TLC (50% EtOAc/PE) to give the title compound (60 mg, 0.168 mmol, 55.7%) as a brown solid. LCMS m/z = 358 [M+H] ⁺ . Intermediate B20. Synthesis of tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate.

To a mixture of 4-amino-1-(4-bromo-2, 6-dichloro-phenyl)-6-oxo-pyrimidine-5-carboxylic acid methyl ester (Intermediate B6, 500 mg, 1.27 mmol) and tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate (Intermediate A24, 479.6 mg, 1.91 mmol) in toluene (9 mL) was added _AlMe3 (2 M in toluene, 1.91 mL) at 0°C. The mixture was stirred under _N2 atmosphere at 100°C for 0.5 h. The reaction mixture was quenched by the addition of 1 M aqueous NaOH solution (50 mL) at 0°C and extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure _to give a residue that was purified by column chromatography ( _SiO2 , 0-100% EtOAc/PE) to give the title compound as a yellow solid (2 g, 64%). LCMS m/z = 613 [M+H] ⁺ . Intermediate B21. Synthesis of 4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl)pyridin-3-yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorobenzoic acid.

To a solution of tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (310 mg, 0.506 mmol) and oxalic acid (319 mg, 3.54 mmol) in DMF (2 mL) were added Pd(OAc) ₂ (11.37 mg, 0.051 mmol), Xantphos (29.29 mg, 0.051 mol), _Ac2O (155 mg, 1.52 mmol) and DIPEA (196 mg, 1.52 mmol), and the mixture was stirred under _N2 at 100 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-24 to give the title compound (120 mg, 41%) as a white solid. LCMS m/z = 577 [M+H] ⁺ . Intermediate B22. Methyl 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(hydroxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 750 mg, 1.27 mmol) and tributyltinylmethanol (1.22 g, 3.80 mmol) in dioxane (7 mL) was added Pd(PPh ₃ ) ₄ (146 mg, 0.127 mmol). The mixture was stirred at 100 °C under N ₂ for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (1.30 g, 2.39 mmol, 94%) as a yellow oil. LCMS m/z = 544 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(hydroxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (200 mg, 0.368 mmol) in THF (5 mL) were added NaOH (22.1 mg, 0.552 mmol) and dimethyl sulfate (381 mg, 3.02 mmol), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with _H2O (35 mL) and extracted with EtOAc (3 x ₃₅ mL). The combined extracts were dried ( _Na2SO4 ) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound as a yellow oil (300 mg, 24%). LCMS m/z = 558 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (200 mg, 0.359 mmol) in TFA (5 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to pH 6-7 with 1 M NH ₄ OH. The residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (110 mg, 97%) as a white solid. LCMS m/z = 318 [M+H] ⁺ . Intermediate B23. 4-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 5 g, 12.21 mmol) and 1,3-dichloro-2-fluoro-5-(trifluoromethyl)benzene (3.19 g, 13.43 mmol) and K ₂ CO ₃ (3.38 g, 24.42 mmol) in DMF (15 mL) was stirred at 80 °C for 3 h. The reaction mixture was filtered, and H ₂ O was added to the filtrate. The resulting solid was then collected by filtration to give the title compound as a yellow solid (7.50 g, crude), which was used without further purification. LCMS m/z = 623 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (7.50 g, 12.05 mmol) in TFA (20 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to pH 6-7 with 1 M NH ₄ OH and extracted with EtOAc. The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (3.5 g, 76%) as a white solid. LCMS m/z = 382 [M+H] ⁺ . Intermediate B24. Methyl 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A suspension of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate _B1 , 1.605 g, 4.0 mmol), _K2CO3 (1.129 g, 8.0 mmol, 2.0 equiv) and 1,3-dichloro-2-fluoro-5-(trifluoromethyl)benzene (0.650 mL, 4.20 mmol) in DMA (8 mL) was heated to 80 °C for 22 h. The reaction was cooled, diluted with EtOAc (75 mL) and washed three times with water. The aqueous phase was back extracted with EtOAc (20 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 40 g silica, 0-100% EtOAc/hex) afforded the title compound as a light yellow foam (1.690 g, 68%). LCMS m/z = 622 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

To a suspension of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 1.681 g, 2.70 mmol), K ₃ PO ₄ (1.72 g, 8.10 mmol) and Xphos Pd G3 (240 mg, 0.270 mmol) in dioxane (9 mL) was added trimethylcyclotriboroxane solution (50 wt% in THF, 1.80 mL, 6.75 mmol). The solution was purged with N ₂ for 8 min and then heated to 80 °C for 16 h. The reaction was then cooled, filtered through celite, and washed with EtOAc. Flash chromatography (ISCO 40 g silica, 0-100% EtOAc/hex) afforded a light yellow solid. The intermediate methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate was dissolved in TFA (8 mL) and heated to 80 °C for 2 h. The reaction was poured into saturated aqueous _NaHCO3 and extracted with EtOAc (3 x 40 mL). The combined organics were washed with water, brine, dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 24 g silica, 0-100% EtOAc/hex) afforded the title compound as a pink solid (779 mg, 85% yield, 2 steps). LCMS m/z = 342 [M+H] ⁺ . Intermediate B25. Methyl 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

_K3PO4 (4.60 g, 21.69 mmol) and XPHOS-PD-G2 (512 mg, 0.651 mmol) were added to a _mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 1, 6.5 g, 10.84 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (5.45 g, 21.69 mmol) in dioxane (100 mL), and the mixture was stirred under _N2 at 80 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE) to give the title compound as a yellow solid (5 g, crude). LCMS m/z = 559 [M+H] ⁺ . Step 2. Synthesis of methyl 1-(4-amino-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (4.7 g, 8.41 mmol) in THF (30 mL) and MeOH (30 mL) was added Pd/C (0.5 g, 8.41 mmol, 10% purity), and the mixture was stirred under H ₂ (15 psi) at 20 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (4.5 g, crude). LCMS m/z = 529 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

_NaNO2 (1.64 g, 23.84 mmol) was added to a mixture of methyl 1-(4-amino-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 4.2 g, 7.95 mmol), CuBr (1.37 g, 9.53 mmol), TBAB (15.37 g, 47.67 mmol) and CSA (5.54 g, 23.84 mmol) in MeCN (60 mL), and the mixture was stirred at 20 °C for 3 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (20 mL) and _H2O (15 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL) and the combined organics were dried ( _Na2SO4 ) and evaporated to dryness in vacuo. The residue was purified by MPLC ( _SiO2 , 0-50% EtOAc/PE) to give _the title compound (3.6 g, 76.5%) as a yellow oil. LCMS m/z = 592 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-hydroxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl ₎ -6-oxo-1,6-dihydropyrimidine-5-carboxylate (B18, step 3, 710 mg, 1.20 mmol) in dioxane (7.5 mL) and _H2O (2.5 mL) were added _K3PO4 (382 mg, 1.80 mmol), t-BuXphos (50.9 mg, 0.120 mmol) and _Pd2 (dba) ₃ (110 mg, 0.120 mmol), and the mixture was stirred under _N2 at 80 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO ₂ , 0-33% EtOAc/PE) to give the title compound (1.6 g, 84%) as a brown oil. LCMS m/z = 530 [M+H] ⁺ . Step 5. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-hydroxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1 g, 1.89 mmol) and iodoethane (353.4 mg, 2.27 mmol) in DMF (5 mL) was added K ₂ CO ₃ (522 mg, 3.78 mmol), and the mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (3×10 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound as a brown oil (1 g, crude). LCMS m/z = 558 [M+H] ⁺ . Step 6. Synthesis of methyl 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1 g, 1.79 mmol) in TFA (1 mL) was stirred at 80 °C for 1 h. The reaction mixture was evaporated under _N2 flow and the residue was diluted with saturated aqueous _NaHCO3 solution (3 ml), extracted with EtOAc (3× 3 ml) and evaporated to dryness in vacuo. The residue was purified by column chromatography ( _SiO2 , 0-50% EtOAc/PE) to give the title compound (340 mg, 56%) as a light yellow solid. LCMS m/z = 318 [M+H] ⁺ . Intermediate B26. 4-amino-1-(2,6-dimethyl-4-propoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester.

The title compound was prepared as a white solid from methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18, step 3) using a 3-step procedure analogous to that described for Intermediate B25 (steps 4, 5 and 6). LCMS m/z = 332 [M+H] ⁺ . Intermediate B27. Methyl 4-amino-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18, step 3; 1.12 g, 1.89 mmol), _Pd2 (dba) ₃ (173 mg, 0.189 mmol), t-BuXphos (80.3 mg, 0.189 mmol) and _K3PO4 (602 mg, 2.84 mmol) _in toluene (8 mL) and MeOH (8 mL) was stirred at 80 °C for 2 h under _N2 . The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound (800 mg, 1.47 mmol, 77%) as a brown oil. LCMS m/z = 544 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 1.20 g, 2.21 mmol) was dissolved in TFA (20 mL), and the mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to pH 6-7 with 1 M _Na2CO3 . The residue was purified by column chromatography (0-50% EtOAc/PE) to give the _title compound (560 mg, 83%) as a light yellow solid. LCMS m/z = 304 [M+H] ⁺ . Intermediate B28. 4-amino-1-(2,6-dichloro-4-(ethoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(ethoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(hydroxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.20 g, 2.05 mmol) in DCM (6 mL) was added DIPEA (796 mg, 6.16 mmol) to pH 10 followed by triethyloxonium tetrafluoroborate (1.56 g, 8.21 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h, quenched by addition of saturated aqueous Na ₂ CO ₃ solution (10 mL) at 0 °C, and extracted with DCM (3×10 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO ₂ , 0-25% EtOAc/PE) to give the title compound (430 mg, 34%) as a yellow solid. LCMS m/z = 588 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-(ethoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(ethoxymethyl)phenyl) _-6 -oxo-1,6-dihydropyrimidine-5-carboxylate (400 mg, 0.653 mmol) in TFA (5 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the pH of the residue was adjusted to pH 8-9 with _Na2CO3 , diluted with _H2O (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2 x 30 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (210 mg, 86%) as a white solid. Intermediate B29. 4-amino-1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester Step 1. Synthesis of methyl 1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-4-((4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(hydroxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (B22, step 1, 1.00 g, 1.84 mmol) in DCM (5 mL) was added DIPEA (476 mg, 3.68 mmol) and triethyloxonium tetrafluoroborate (1.40 g, 7.36 mmol) at 0°C, and the mixture was stirred at 25°C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous _NaHCO3 solution (20 mL) at 0°C, and extracted with DCM (3 x 20 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give a residue which was purified by prep-HPLC-25 (30%-60% MeCN) to give the title compound as a white solid (170 mg, 20.5%). LCMS m/z = 452 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

Methyl 1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-4-((4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 170 mg, 0.377 mol) was dissolved in TFA (2 mL) and the mixture was stirred at 80 °C for 1 h. The reaction mixture was quenched by the addition of saturated _{aqueous Na2CO3} solution (20 mL) and extracted with EtOAc (3 x 40 mL). _The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 50% EtOAc/PE) to give the title compound (100 mg, 0.302 mmol, 80%) as a white solid. LCMS m/z = 332 [M+H] ⁺ . Intermediate B30. Methyl 4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6 Step 3, 3.00 g, 4.74 mmol) in dioxane (30 mL) and H ₂ O (10 mL) were added K ₃ PO ₄ (1.51 g, 7.11 mmol), t-Bu Xphos (201 mg, 0.474 mmol) and Pd ₂ (dba) ₃ (434 mg, 0.474 mmol), and the mixture was stirred at 80 °C under N ₂ for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (4 g) as a yellow solid. LCMS m/z = 570 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.96 g, 3.44 mmol) and iodoethane (804 mg, 5.15 mmol) in DMF (15 mL) was added K ₂ CO ₃ (950 mg, 6.87 mmol), and the mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with H ₂ O (5.00 mL) at 0 °C and extracted with EtOAc (3×10 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (1.70 g, 83%) as a yellow solid. LCMS m/z = 598 [M+H] ⁺ . Step 3. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (3.30 g, 5.51 mmol) in TFA (30 mL) was stirred at 80 °C for 1 hour. The reaction mixture was added to saturated aqueous NaHCO ₃ solution (10 ml) and concentrated under reduced pressure and extracted with EtOAc (3×10 ml). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (1.10 g, 56% yield) as a white solid. LCMS m/z = 358 [M+H] ⁺ . Intermediate B31. Methyl 4-amino-1-(2,6-dichloro-4-isopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

The title compound was prepared as a brown solid from methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, Step 3) using a 3-step method analogous to that described for Intermediate B30. LCMS m/z = 372 [M+H] ⁺ . Intermediate B32. Methyl 4-amino-1-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of 1-(4-allyl-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 500 mg, 0.844 mmol) in dioxane (6 mL) were added Pd(PPh ₃ ) ₄ (97.5 mg, 0.084 mol) and allyl(tributyl)tinane (1.08 g, 3.25 mmol), and the mixture was stirred at 80 °C under N ₂ for 12 h. The reaction mixture was quenched by the addition of 4 M KF (10 mL) at 0 °C, and the mixture was extracted with EtOAc (4×10 mL). The combined organics were concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 1%-50% EtOAc/PE) to give the title compound (953 mg, crude) as a yellow solid. LCMS m/z = 554 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(2,3-dihydroxypropyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of methyl 1-(4-allyl-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (903 mg, 1.63 mmol) in acetone (8 mL) and H ₂ O (1.20 mL) were added K ₂ OsO ₄ .2H ₂ O (60.1 mg, 0.163 mmol) and NMO (287 mg, 2.45 mmol), and the mixture was stirred at 25 °C under N ₂ for 2 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was purified by prep-HPLC (C18, 250 × 50 mm, 10 μm; 30%-70% MeCN/H ₂ O (NH ₄ HCO ₃ )) to give the title compound (810 mg, 84.5%) as a gray solid. LCMS m/z = 588 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-(2-oxoethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(2,3-dihydroxypropyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (790 mg, 1.34 mmol) in MeOH (14 mL) was added NaIO ₄ (575 mg, 2.69 mmol) and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (3×10 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO ₂ , 1%-50% EtOAc/PE) to give the title compound (810 mg, 84.5%) as a white solid. LCMS m/z = 556 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-(2-oxoethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step ₃ , 580 mg, 1.04 mmol) in DCM (10 mL) was added DAST (1.68 g, 10.44 mmol) at -78 °C under _N2 , and the mixture was stirred at -78 °C under N2 for 0.5 h, and then at 25 °C under _N2 for 1 h. The reaction mixture was quenched by the addition of saturated aqueous _NaHCO3 solution (20 mL) at 0 °C, and extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and evaporated to dryness, and the residue was purified by MPLC ( _SiO2 , 1%-50% EtOAc/PE) _to give the title compound as a white solid (450 mg, 74.6%). LCMS m/z = 578 [M+H] ⁺ . Step 5. Synthesis of methyl 4-amino-1-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (440 mg, 0.762 mmol) in TFA (3 mL) was stirred at 80 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to pH 8-9 with NaHCO _3. The mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (3× 15 mL). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 1%-50% EtOAc/PE) to give the title compound (190 mg, 74%) as a white solid. LCMS m/z = 338 [M+H] ⁺ . Intermediate B33. Methyl 4-amino-1-(4-(2-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(2-hydroxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-(2-oxoethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B32 Step 3, 650 mg, 1.17 mmol) in MeOH (5 mL) was added _NaBH4 (46.5 mg, 1.23 mmol), and the mixture was stirred at 25 °C for 10 min. The reaction mixture was quenched by the addition of aqueous HCl (1 M, 2 mL) at 0 °C and extracted with EtOAc (3 x 20 mL). The combined organics were dried ( _Na2SO4 ), concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) to give the title compound as a _light yellow oil (440 mg, 67%). LCMS m/z = 558 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(2-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(2-hydroxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 440 mg, 0.789 mmol) in DCM (4 mL) was added DAST (636 mg, 3.95 mmol) at -78 °C for 0.5 h, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO ₃ solution (5 mL) at 0 °C and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and the residue was purified by prep-TLC (EtOAc) to give the title compound as a pale yellow oil (310 mg, 70%). LCMS m/z = 560 [M+H] ⁺ . Step 3. Synthesis of methyl 4-amino-1-(4-(2-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(2-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 310 mg, 0.554 mmol) in TFA (1 mL) was stirred at 80 °C for 1 h. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ solution (5 mL) at 0 °C and then extracted with EtOAc (3×10 mL). The combined organics were dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and the residue was purified by prep-TLC (EtOAc) to give the title compound (150 mg, 84%) as a light yellow oil. LCMS m/z = 320 [M+H] ⁺ . Intermediate B34. Synthesis of methyl 4-amino-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 3.40 g, 5.74 mmol) in TFA (40 mL) was stirred at 80 °C for 0.5 h. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM (40 mL) and _Na2CO3 (15 mL). The aqueous phase was extracted with DCM (3 x 40 mL) and _the combined organics were dried ( _Na2SO4 ) and evaporated _to dryness in vacuo. The residue was purified by MPLC (SiO ₂ , 0-5% EtOAc/PE) to give the title compound as a yellow solid (2 g, crude). ¹ H NMR (400 MHz, CDCl ₃ ): 8.90 (s, 1H), 7.59 (s, 1H), 7.25 (s, 2H), 3.80 (s, 3H), 2.05 (s, 6H). Intermediate B35. Synthesis of methyl 4-amino-1-mesityl-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

To a mixture of methyl 4-amino-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B34, 300 mg, 0.852 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (1.07 g, 4.26 mmol) in dioxane (5 mL) were added Xphos-Pd-G2 (67.02 mg, 0.085 μmol) and K ₃ PO ₄ (271 mg, 1.28 mmol), and the mixture was stirred under N ₂ at 80 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ ; 1%-50% EtOAc/PE) to give the title compound (350 mg, 71.5%) as a white solid. LCMS m/z = 288 [M+H] ⁺ . Intermediate B36. Synthesis of tert-butyl ((5-(4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(methyl)carbamate.

To a mixture of methyl 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B17, 50 mg, 0.155 mmol) and tert-butyl ((5-aminopyridin-3-yl)methyl)(methyl)carbamate (55.1 mg, 0.232 mmol) in toluene (4 mL) was added _AlMe3 (2 M, 0.232 mL) at 0 °C and the mixture was stirred at 0 °C for another 5 min. The mixture was stirred at 100 °C under _N2 for 1 h. The reaction mixture was quenched with _H2O (1 mL) and TFA (1 mL) at 0 °C and concentrated under reduced pressure to give the title compound (80 mg, 98%) as a white solid. LCMS m/z = 529 [M+H] ⁺ . Intermediate B37. 4-amino-1-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of 2-chloro-6-nitro-4-(trifluoromethoxy)aniline

To a solution of 2-nitro-4-(trifluoromethoxy)aniline (8.4 g, 37.82 mmol) in AcOH (15 mL) was added sulfonyl chloride (7.66 g, 56.73 mmol, 5.67 mL) at 0°C. The mixture was stirred at 25°C for 12 h and then evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO ₂ , 25%-100% EtOAc/PE) to give the title compound as a yellow solid (7.4 g, 76%). ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.05-8.01 (m, 1 H), 7.97 (d, 1 H), 7.51 (br s, 2 H). Step 2. Synthesis of 1,2-dichloro-3-nitro-5-(trifluoromethoxy)benzene

To a mixture of 2-chloro-6-nitro-4-(trifluoromethoxy)aniline (5 g, 19.49 mmol) in MeCN (30 mL) was added CuCl ₂ (3.14 g, 23.4 mmol) followed by tert-butyl nitrite (3.01 g, 29.23 mmol) at 25° C., and the mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-TLC (1:10 EtOAc/PE) to give the title compound (4.1 g, 76%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.36-8.32 (m, 1 H), 8.30-8.27 (m, 1 H). Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-nitro-4-(trifluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 5 g, 12.21 mmol) and 1,2-dichloro-3-nitro-5-(trifluoromethoxy)benzene (Step 2, 3.71 g, 13.43 mmol) in DMF (15 mL) was added K ₂ CO ₃ (3.38 g, 24.42 mmol), and the mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-26 (50%-80% MeCN) to give the title compound (1.9 g, 24%) as a white solid. LCMS m/z = 649 [M+H] ⁺ . Step 4. Synthesis of methyl 1-(2-amino-6-chloro-4-(trifluoromethoxy)phenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-nitro-4-(trifluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 3, 1.6 g, 2.47 mmol) in _H2O (10 mL) and EtOH (30 mL) were added Fe (1.38 g, 24.7 mmol) and _NH4Cl (1.32 g, 24.7 mmol), and the mixture was stirred at 80 °C for 6 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (850 mg, 55%) as a yellow solid. LCMS m/z = 619 [M+H] ⁺ . Step 5. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

Isoamyl nitrite (454 mg, 3.88 mmol) in MeCN (3 mL) was added dropwise to a mixture of methyl 1-(2-amino-6-chloro-4-(trifluoromethoxy)phenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (800 mg, 1.29 mmol), CuCl (256 mg, 2.58 mmol) and _CuCl2 (521 mg, 3.88 mmol) in MeCN (10 mL), and the mixture was stirred under _N2 at 25 °C for 1 h. The residue was diluted with _H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as a white solid (800 mg, 97% yield). LCMS m/z = 639 [M+H] ⁺ . Step 6. Synthesis of methyl ₄ -amino-1-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (600 mg, 0.94 mmol) in TFA (3 mL) was stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the pH of the residue was adjusted to pH 6-7 with 1 M Na ₂ CO ₃ (10 ml), and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (330 mg, 88%) as a yellow solid. LCMS m/z = 398 [M+H] ⁺ . Intermediate B38. Synthesis of methyl 4-amino-1-(2,6-dimethyl-4-(trifluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A mixture of methyl 4-amino-1-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B37, 180 mg, 0.452 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (568 mg, 2.26 mmol), XPHOS-PD-G2 (35.6 mg, 0.045 mmol), K ₃ PO ₄ (192 mg, 0.904 mmol) in dioxane (6 mL) was degassed and purged with N ₂ (3×), and the mixture was stirred under N ₂ at 80 °C for 6 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (50% EtOAc/PE) to give the title compound (130 mg, 80%) as a yellow solid. LCMS m/z = 358 [M+H] ⁺ . Intermediate B39. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

The title compound was prepared from methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1) and 1,2-dichloro-5-fluoro-3-nitrobenzene using a method analogous to that described in steps 3 to 6 of Intermediate B37. LCMS m/z = 332 [M+H] ⁺ . Intermediates B40 and B41. (S)-4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester and (R)-4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-vinylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 3 g, 5.06 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- _{dioxaborolane cyclopentane (1.17 g, 7.60 mmol), K2CO3 (} 1.40 g, 10.13 mmol), Pd(dppf) _Cl2 (370.5 mg, 0.51 mmol) in dioxane (30 mL) and _H2O (2 mL) was degassed and purged with _N2 (×3), and the mixture was stirred under _N2 at 100 °C for 1 h. The solid was removed by filtration and the filtrate was evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO ₂ , 0-50 EtOAc/PE) to give the title compound (2.6 g, 95%) as a yellow solid. LCMS m/z = 540 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1,2-dihydroxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-vinylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (2.57 g, 4.76 mmol), 4-methylporoline 4- _oxide ( _{837 mg, 7.14 mmol) and K2OsO4.2H2O (} 175 mg, 0.476 mmol) in acetone (30 mL) and _H2O (4 mL) was degassed and purged with _N2 (×3), and the mixture was stirred under _N2 at 25°C for 2 h. The reaction mixture was partitioned between DCM (30 mL) and _H2O (30 mL), and the aqueous phase was extracted with DCM (3×30 mL). The combined organics were dried ( _Na2SO4 ) and evaporated _to dryness in vacuo. The residue was purified by column chromatography ( _SiO2 , 0-100% EtOAc/PE) to give the title compound as a yellow solid (1.15 g, 42%). LCMS m/z = 574 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

DAST (843 mg, 5.23 mmol) was added to a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1,2-dihydroxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (300 mg, 0.523 mmol) in DCM (20 mL), and the mixture was stirred at -78 °C for 0.5 h, and then at 25 °C for 1 h under _N2 . The reaction mixture was quenched by the addition of saturated aqueous _NaHCO3 solution (20 mL) at 0 °C, and extracted with DCM (3 x 20 mL). The combined organics were dried ( _Na2SO4 ) and evaporated to dryness in vacuo _to give the title compound as a yellow solid (800 mg, 88%). LCMS m/z = 578 [M+H] ⁺ . Step 4. Synthesis of (S)-methyl 4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate and (R)-methyl 4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (700 mg, 1.21 mmol) in TFA (20 mL) was stirred at 80 °C for 1 h under _N2 . The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in THF (20 ml) and the pH was adjusted to pH 9-11 with _NH4OH at 0 °C. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give methyl 4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Chiral SFC (DAICEL CHIRALCEL OJ (250 × 30 mm, 10 μm); 13% (0.1% NH 4 OH/IPA) in CO ₂ ) was used to separate: Intermediate B40 , Peak 1; (S)-4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester or (R)-4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (yellow solid, 100 mg). LCMS m/z = 338 [M+H] ⁺ . Intermediate B41 , peak 2; (S)-4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester or (R)-4-amino-1-(4-(1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (yellow solid, 110 mg). LCMS m/z = 338 [M+H] ⁺ . Intermediates B42 and B43 . (S)-4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester and (R)-4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester.

The title compound was prepared from methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, step 3) using a 4-step procedure analogous to that described for intermediates B40 and B41. Chiral SFC (DAICEL CHIRALCEL OJ (250 × 30 mm, 10 μm); 30% (0.1% NH ₄ OH/IPA) in CO ₂ ) gave: intermediate B42 , peak 1; (S)-methyl 4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate or (R)-methyl 4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (white solid, 250 mg, 25.6%). LCMS m/z = 378 [M+H] ⁺ . Intermediate B43 , peak 2; (S)-4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester or (R)-4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (white solid, 300 mg, 30.7%). LCMS m/z = 378 [M+H] ⁺ . Intermediate B44. 4-amino-1-(2-chloro-4-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Part 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-fluoro-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a solution of 1-chloro-2,5-difluoro-3-nitrobenzene (539 mg, 2.75 mmol) in anhydrous MeCN (8 mL) was added methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 1.03 g, 2.50 mmol) and _K2CO3 (701 mg, 5.00 mmol) and the mixture was heated to 80 °C for ₂ h. The reaction was cooled, poured into _H2O (100 mL) and extracted with EtOAc (4 x 30 mL). The combined organics were washed twice with water, brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 40 g silica, 0-10% MeOH/DCM) to give the title compound as a yellow foam (1.29 g, 89%). LCMS m/z = 583 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-bromo-6-chloro-4-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

A suspension of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-fluoro-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 1.25 g, 2.15 mmol) and iron powder (811 mg, 12.90 mmol) in MeOH (22 mL)/glacial acetic acid (2 mL) was heated to 50 °C for 4 h. The reaction was cooled and residual iron was removed with a magnet. The mixture was poured into _H2O (200 mL) and stirred at room temperature for 15 min to produce a precipitate. The precipitate was collected by filtration, washed with H ₂ O (200 mL) and dried to provide a beige powder, which was dissolved in MeCN (25 mL). A 48% aqueous HBr solution (0.61 mL, 5.38 mmol) was added thereto, and the mixture was cooled on ice, followed by addition of tert-butyl nitrite (0.31 mL, 5.16 mmol), and the mixture was stirred at 0° C. for 45 min, and then CuBr (383 mg, 2.58 mmol) was added at 0° C., and the reaction mixture was placed in an ice bath to gradually warm to room temperature. Another portion of tBuONO (0.30 mL, 2.58 mmol) was added, and stirring was continued for 1.5 h. The mixture was filtered, washed with EtOAc and MeOH. The combined organics were evaporated to dryness and the residue was dissolved in EtOAc (75 mL) and dilute aqueous HCl (150 mL). The aqueous component was extracted with EtOAc (2×50 mL). The combined organics were washed with saturated aqueous NaHCO ₃ , water, brine, dried (MgSO ₄ ) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO 40 g silica, 0-100% EtOAc/hex) to give the title compound (748 mg, 56% yield, 2 steps) as a light yellow foam. LCMS m/z = 616 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a suspension of methyl 4-(bis(4-methoxybenzyl)amino)-1- ₍ 2-bromo-6-chloro-4-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 505 mg, 0.81 mmol), _K2CO3 (224 mg, 1.62 mmol) and Pd(dppf) _Cl2 DCM adduct (40.2 mg, 0.041 mmol) in dioxane (3 mL) was added trimethylcyclotriboroxane solution (50 wt% in THF, 0.30 mL, 1.05 mmol). The mixture was purged with _N2 for 10 min and heated to 100 °C for 90 min. The reaction was cooled, filtered through celite and washed with EtOAc. The combined organics were evaporated to dryness and the residue was purified by flash chromatography (ISCO 40 g silica, 0-70% EtOAc/hex) to give an off-white foam. The foam was dissolved in TFA (3.5 mL) and heated to 80 °C for 1 h. The reaction was then cooled, poured into saturated aqueous NaHCO ₃ and extracted with EtOAc (3× 25 mL). The combined organics were washed with water, brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO 12 g silica, 10%-80% EtOAc/hex) to give the title compound as an off-white solid (155 mg, 61% yield, 2 steps). LCMS m/z = 312 [M+H] ⁺ . Intermediate B45 . Methyl 4-amino-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.39 g, 2.44 mmol) and sodium 2-chloro-2,2-difluoroacetate (743 mg, 4.87 mmol) in DMF (15 mL) was added K ₂ CO ₃ (370 mg, 2.68 mmol) and the mixture was stirred at 60 °C under N ₂ for 6 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (3× 20 mL). The combined organics were washed with brine (2× 20 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness under reduced pressure. The residue was purified by MPLC (SiO ₂ , 1%-50% EtOAc/PE) to give the title compound (657 mg, 43.5%) as a brown solid. LCMS m/z = 620 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (657 mg, 1.06 mmol) in TFA (5 mL) was stirred at 80 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the pH of the residue was adjusted to pH 7-8 with NaHCO _3. The mixture was diluted with H ₂ O (15 mL) and extracted with EtOAc (3× 8 mL). The combined extracts were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by MPLC (SiO ₂ , 1%-33% EtOAc/PE) to give the title compound as a brown solid (381 mg, 94.7%). Intermediate B46. (S)-4-amino-1-(2-chloro-4-(difluoromethyl)-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2-chloro-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of 5-bromo-1-chloro-2-fluoro-3-nitrobenzene (5 g, 19.65 mmol) and methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 8.05 g, 19.65 mmol) in DMSO (15 mL) was added DIPEA (5.08 g, 39.3 mmol) and the mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a brown oil (12.5 g, 98%). LCMS m/z = 645 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-(hydroxymethyl)-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2-chloro-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 12.5 g, 19.4 mmol) and tributyltinylmethanol (12.47 g, 38.8 mmol) in dioxane (30 mL) was added Pd(PPh ₃ ) ₄ (1.12 g, 0.97 mmol), and the mixture was stirred at 100 °C for 2 h under N _2. The reaction mixture was quenched by the addition of saturated aqueous KF solution (20 mL) at 0 °C, and then extracted with EtOAc (3×20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) _to give the title compound as a brown solid (5.2 g, 45%). LCMS m/z = 595 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-formyl-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-(hydroxymethyl)-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 5.2 g, 8.74 mmol) in DCM (2 mL) was added Dess-Martin periodinane (5.56 g, 13.11 mmol) at 0 °C and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO ₃ solution (20 mL) at 0 °C and extracted with EtOAc (3×20 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid (3.6 g, 69%). LCMS m/z = 593 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-(difluoromethyl)-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-formyl-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (3.6 g, 6.07 mmol) in DCM (3 mL) was added DAST (4.89 g, 30.36 mmol) at -78 °C, and the mixture was stirred at 25 °C under _N2 for 3 h. The reaction mixture was quenched by the addition of saturated aqueous _NaHCO3 solution (15 mL) at 0 °C, and extracted with DCM (3 x 15 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) _to give the title compound as a yellow solid (2.64 g, 71%). LCMS m/z = 615 [M+H] ⁺ . Step 5. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(difluoromethyl)-2-methyl-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-(difluoromethyl)-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 4, 2.6 g, 4.23 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (2.12 g, 8.46 mmol) in dioxane (15 mL) was added XPHOS-PD-G2 (333 mg, 0.423 mmol) and K ₃ PO ₄ (1.79 g, 8.46 mmol), and the mixture was stirred at 80 °C under N ₂ for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with _H2O (15 mL) and extracted with EtOAc (3 x 15 mL), dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a white solid (2.2 g, 87%). LCMS m/z = 595 [M ₊ H] ⁺ . Step 6. Synthesis of methyl 1-(2-amino-4-(difluoromethyl)-6-methylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(difluoromethyl)-2-methyl-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 5, 2.1 g, 3.53 mmol) in MeOH (15 mL) was added Pd/C (2 g, 3.53 mmol, 10% purity), and the mixture was stirred under _H2 (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (1.36 g, 68%). LCMS m/z = 564 [M+H] ⁺ . Step 7. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-(difluoromethyl)-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 1-(2-amino-4-(difluoromethyl)-6-methylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 6, 1.36 g, 2.41 mmol) in MeCN (10 mL) were added CuCl (477 mg, 4.82 mmol), _CuCl2 (972 mg, 7.23 mmol) and isoamyl nitrite (847 mg, 7.23 mmol), and the mixture was stirred under _N2 at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a light yellow solid (1 g, 71%). LCMS m/z = 584 [M+H] ⁺ . Step 8. Synthesis of methyl (S)-4-amino-1-(2-chloro-4-(difluoromethyl)-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-(difluoromethyl)-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 7, 1 g, 1.71 mmol) in TFA (5 mL) was stirred at 80 °C for 1 h. The reaction mixture was quenched by the addition of saturated aqueous _NaHCO3 solution (10 mL) at 0 °C and extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to afford racemic methyl 4-amino-1-(2-chloro _- 4-(difluoromethyl)-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate as a yellow solid (170 mg, 29%). The racemate was separated by SFC (DAICEL CHIRALPAK AS; 250 × 30 mm, 10 μm); 23% MeOH (0.1% NH ₄ OH)) to give: Peak 1, intermediate B46 . (S)-4-amino-1-(2-chloro-4-(difluoromethyl)-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (white solid, 407 mg, 23%). LCMS m/z = 344 [M+H] ⁺ . Intermediate B47. Synthesis of 4-amino-1-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-nitro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

K ₂ CO ₃ (5.67 g, 41.1 mmol) was added to a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 8.41 g, 20.53 mmol) and 1-chloro-2-fluoro-3-nitro-5-(trifluoromethyl)benzene (5 g, 20.53 mmol, 3.11 mL) in DMF (50 mL), and the mixture was stirred at 80 °C for 1 h. The mixture was diluted with H ₂ O (200 mL), filtered and extracted with EtOAc (3× 200 mL) to give the title compound (12.8 g, 98%) as a yellow solid. LCMS m/z = 633 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-methyl-6-nitro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-nitro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 7 g, 11.1 mmol) in dioxane (30 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborahexane (8.33 g, 33.2 mmol), XPHOS-PD-G2 (870 mg, 1.11 mmol) and _K3PO4 (4.69 g, 22.1 mmol), and _the mixture was degassed and purged with _N2 (3x) and stirred at 80 °C under _N2 for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound as a yellow oil (5 g 73%). LCMS m/z = 613 [M+H] ⁺ . Step 3. Synthesis of methyl 1-(2-amino-6-methyl-4-(trifluoromethyl)phenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

Fe (7.29 g, 130 mmol) and _NH4Cl (6.99 g, 130 mmol) were added to a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-methyl-6-nitro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 8 g, 13.1 mmol) in THF (30 mL), EtOH (30 mL) and _H2O (10 mL), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was evaporated to dryness, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow solid (4.5 g, 59%). LCMS m/z = 583 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 1-(2-amino-6-methyl-4-(trifluoromethyl)phenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 3, 4.3 g, 7.38 mmol) in MeCN (40 mL) was added CuCl (1.46 g, 14.8 mmol), _CuCl2 (2.98 g, 22.1 mmol) and isoamyl nitrite (2.59 g, 22.1 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with _H2O (20 mL) and extracted with EtOAc (4 x 20 mL). The combined extracts were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a yellow oil (3.5 g, 78%). LCMS m/z = 602 [M+H] ⁺ . Step 5. Synthesis of methyl 4-amino-1-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 4, 1.5 g, 2.49 mmol) in TFA (2 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) followed by chiral SFC (DAICEL CHIRALCEL OD, 250 × 30 mm, 10 μm; 15% IPA (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 2, Intermediate B47 . 4-Amino-1-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (white solid, 400 mg, 40%). LCMS m/z = 362 [M+H] ⁺ . Intermediate B48. Synthesis of methyl 4-amino-1-((S)-2-chloro-6-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of 1-(difluoromethyl)-2-fluoro-3-nitrobenzene .

To a mixture of 2-fluoro-3-nitrobenzaldehyde (5 g, 29.6 mmol) in DCM (50 mL) at -78 °C under _N2 was added DAST (14.30 g, 88.7 mmol) and the mixture was stirred at -78 °C for 0.5 h followed by 0.5 h at 20 °C under _N2 . The reaction mixture was partitioned between DCM (50 mL) and saturated aqueous _NaHCO3 solution (50 mL). The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by MPLC ( _SiO2 , 0-16% EtOAc/PE) to give the title compound (5 g, 88%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.24 (t, 1H), 7.97 (br t, 1H), 7.49 (t, 1H), 7.15-6.88 (m, 1H). Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-(difluoromethyl)-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 3.32 g, 8.11 mmol) and 1-(difluoromethyl)-2-fluoro-3-nitrobenzene (Step 1, 3.1 g, 16.2 mmol) in DMSO (40 mL) was added DIPEA (2.10 g, 16.2 mmol), and the mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-33% EtOAc/PE) to give the title compound (4.7 g, 99%) as a white solid. LCMS m/z = 581 [M+H] ⁺ . Step 3. Synthesis of methyl 1-(2-amino-6-(difluoromethyl)phenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-(difluoromethyl)-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 4.7 g, 8.10 mmol) in MeOH (2 mL) and THF (2 mL) was added Pd/C (50 mg, 8.10 mmol, 10% purity), and the mixture was stirred under _H2 (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (4.8 g, crude). LCMS m/z = 551 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 1-(2-amino-6-(difluoromethyl)phenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 3, 4.8 g, 8.72 mmol) in MeCN (30 mL) was added CuCl (1.73 g, 17.44 mmol), _CuCl2 (3.52 g, 26.2 mmol) and a solution of isoamyl nitrite (3.06 g, 26.2 mmol) in MeCN (5 mL), and the mixture was stirred under _N2 at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with _H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) _to give the title compound as a yellow solid (3.13 g, 63%). LCMS m/z = 570 [M+H] ⁺ . Step 5. Synthesis of methyl 4-amino-1-((S)-2-chloro-6-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 4, 3.13 g, 5.49 mmol) in TFA (30 mL) was stirred at 80 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-100% EtOAc/PE) to give racemic methyl 4-amino-1-(2-chloro-6-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.76 g, 97%) as a yellow solid. The racemic material was separated by chiral SFC (DAICEL CHIRALPAK AD, 250 × 30 mm, 10 μm); 30% IPA (0.1% NH ₄ OH)) to give: Intermediate B48 , peak 1; 4-amino-1-((S)-2-chloro-6-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (white solid, 445 mg, 44%). LCMS m/z = 330 [M+H] ⁺ . Intermediate B49. 4-amino-1-(2,6-dichloro-4-(2-methoxyethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of 1-chloro-2-fluoro-3-nitro-5-vinylbenzene .

To a mixture of 5-bromo-1-chloro-2-fluoro-3-nitrobenzene (8 g, 31.4 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.26 g, 47.2 mmol) in dioxane (80 mL) and _H2O (10 mL) were added _{K2CO3 (} 8.69 g, 62.8 mmol) and Pd(dppf) _Cl2 (2.30 g, 3.14 mmol), and the mixture was stirred under _N2 at 100 °C for 2 h. The solid was removed by filtration and the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 0-16% EtOAc/PE) to give the title compound (4.2 g, 66%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.87 (dd, 1H), 7.64 (dd, 1H), 6.57 (dd, 1H), 5.75 (d, 1H), 5.41 (d, 1H). Step 2. Synthesis of 2-(3-chloro-4-fluoro-5-nitrophenyl)ethan-1-ol .

To a mixture of 1-chloro-2-fluoro-3-nitro-5-vinylbenzene (Step 2, 2.1 g, 10.42 mmol) in THF (20 mL) was added 9-BBN (0.5 M, 62.5 mL) at 0°C, and the mixture was stirred at 20°C for 12 h under _N2 . The pH of the reaction mixture was adjusted to pH 10 by adding _NaOH (1 M, 36.46 mL, 3.5 eq) at 0°C. _H2O2 (10.87 g, 0.096 mmol, 9.21 mL, 30% purity) was added thereto under _N2 , and the resulting mixture was stirred at 20°C for 2 h under N2. The mixture was added to a saturated aqueous _Na2SO3 solution ( ₅₀ mL) at 0°C, and extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 0-50% EtOAc/PE) _to give the title compound as a yellow oil (700 mg, 30%). ^1H NMR (400 MHz, _CDCl3 ) δ: 7.77 (dd, 1H,), 7.54 (dd, 1H), 3.85 (t, 2H), 2.83 (t, 2H). Step 3. Synthesis of 1-chloro-2-fluoro-5-(2-methoxyethyl)-3-nitrobenzene .

To a mixture of 2-(3-chloro-4-fluoro-5-nitrophenyl)ethan-1-ol (1.3 g, 5.92 mmol) in CHCl ₃ (15 mL) was added trimethyloxonium tetrafluoroborate (3.5 g, 23.7 mmol) and stirred at 40 °C for 1 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO ₃ solution (15 mL), and the aqueous phase was extracted with EtOAc (3× 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure _to give a residue which was purified by MPLC ( _SiO2 , 0-33% EtOAc/PE) to give the title compound as a yellow oil (700 mg, 50%). ^1H NMR (400 MHz, CDCl3) δ: 7.86 (dd, 1H), 7.63 (td, 1H), 3.65 (t, 2H), 3.38 (s, 3H), 2.95-2.87 (m, 2H). Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-(2-methoxyethyl)-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 1 g, 2.44 mmol) and 1-chloro-2-fluoro-5-(2-methoxyethyl)-3-nitrobenzene (Step 3, 570 mg, 2.44 mmol) in DMF (6 mL) was added K ₂ CO ₃ (675 mg, 4.88 mmol) and the mixture was stirred at 80 °C for 1 h. The mixture was filtered and the filtrate was evaporated to dryness in vacuo and the residue was partitioned between EtOAc (20 mL) and H ₂ O (15 mL) and the aqueous was extracted with EtOAc (3× 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 0-66% EtOAc/PE) to give the title compound (1.1 g, 1.77 mmol, 72.29% yield) as _a yellow oil. LCMS m/z = 623 [M+H] ⁺ . Step 5. Synthesis of methyl 1-(2-amino-6-chloro-4-(2-methoxyethyl)phenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

Fe (968 mg, 17.3 mmol) and NH ₄ Cl (927 mg, 17.3 mmol) were added to a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-(2-methoxyethyl)-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 4, 1.08 g, 1.73 mmol) in THF (8 mL), EtOH (8 mL) and H ₂ O (3 mL) and stirred at 70° C. for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was treated with DCM (10 mL), filtered and concentrated under reduced pressure to give the title compound as a yellow oil (1.0 g, crude). LCMS m/z = 593 [M+H] ⁺ . Step 6. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(2-methoxyethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 1-(2-amino-6-chloro-4-(2-methoxyethyl)phenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 5, 950 mg, 1.60 mmol) in MeCN (15 mL) was added CuCl ₂ (646 mg, 4.81 mmol), CuCl (317 mg, 3.20 mmol). A solution of isoamyl nitrite (563 mg, 4.81 mmol) in MeCN (2 mL) was added dropwise thereto, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was partitioned between EtOAc (20 mL) and H ₂ O (15 mL), and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 0-100% EtOAc/PE) _to give the title compound as a yellow oil (700 mg, 71%). LCMS m/z = 612 [M+H] ⁺ . Step 7. Synthesis of methyl 4-amino-1-(2,6-dichloro-4-(2-methoxyethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dichloro-4-(2-methoxyethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (680 mg, 1.11 mmol) in TFA (5 mL) was stirred at 80 °C for 0.5 h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO ₃ solution (15 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL) and the combined organics were dried ( _Na2SO4 ), concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 0-100% EtOAc/PE) to give _the title compound as a brown solid (350 mg, 84%). LCMS m/z = 372 [M+H] ⁺ . Intermediate B50. Methyl 4-amino-1-(4-fluoro-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-fluoro-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of 1-chloro-2,5-difluoro-3-nitrobenzene (1.156 g, 6.0 mmol) in anhydrous MeCN (20 mL) was added methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1, 2.71 g, 6.6 mmol) and K ₂ CO ₃ (1.70 g, 12.0 mmol) and the reaction was heated to 80 °C overnight. The reaction was poured into 200 mL of water and extracted with EtOAc (4× 75 mL). The combined organics were washed twice with water, brine, dried (MgSO ₄ ) and concentrated by rotary evaporation. Flash chromatography (ISCO 40 g silica, 0-80% EtOAc/hex) afforded the title compound as a yellow foam (3.286 g, 94%). LCMS m/z = 583 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-bromo-6-chloro-4-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A suspension of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-4-fluoro-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 3.286 g, 5.65 mmol) and iron powder (2.02 g, 33.9 mmol) in MeOH (33 mL)/glacial acetic acid (6 mL) was heated to 50 °C overnight. The reaction was then cooled and residual iron was removed with a magnet. The mixture was poured into 250 mL of water and stirred at room temperature for 15 minutes to produce a precipitate. The precipitate was collected by filtration, washed with 150 mL of water and dried to provide a yellow powder that was used without purification. LCMS m/z = 575 [M+Na] ⁺ .

A solution of crude methyl 1-(2-amino-6-chloro-4-fluorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (5.65 mmol) in MeCN (55 mL) and 48% aqueous HBr (1.60 mL, 14.1 mmol) was cooled on ice. Sodium nitrite (494 mg, 6.78 mmol) was added and the mixture was stirred at 0 °C for 75 min, followed by CuBr (979 mg, 6.78 mmol) at 0 °C. The reaction mixture was stirred for 3 h and gradually warmed to room temperature in an ice bath. The mixture was filtered to remove copper salts and washed with EtOAc and MeOH. The combined organics were concentrated by rotary evaporation. The crude residue was dissolved in EtOAc (150 mL) and dilute aqueous HCl (200 mL). The aqueous phase was extracted with EtOAc (2× 50 mL). The combined organics were washed with saturated aqueous NaHCO ₃ , water, brine, dried (MgSO ₄ ) and evaporated to dryness. The residue was purified by flash chromatography (ISCO 40 g silica, 0-100% EtOAc/hex) to give the title compound as a light yellow foam (1.641 g, 47% yield, 2 steps). The material was used in the next step without further purification. LCMS m/z = 616 [M+H] ⁺ . Step 3. Synthesis of methyl 4-amino-1-(4-fluoro-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a suspension of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-bromo-6-chloro-4-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 1.64 g, 2.65 mmol), K ₃ PO ₄ (1.703 g, 7.95 mmol) and Xphos Pd G3 (223 mg, 0.265 mmol) in dioxane (10 mL) was added trimethylcyclotriboroxane solution (50 wt% in THF, 1.90 mL, 6.63 mmol), and the mixture was purged with N ₂ for 10 min and heated to 80 °C for 16 h. The reaction was filtered through celite and washed with EtOAc. The combined organics were evaporated to dryness and the residue was purified by flash chromatography (ISCO 40 g silica, 0-100% EtOAc/hex) to give a viscous amber oil. The oil was dissolved in TFA (6 mL) and heated to 80 °C for 1 h, cooled, poured into saturated aqueous NaHCO3 solution, and extracted with EtOAc (3 x 30 mL). The combined organics were washed with water, brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 24 g silica, 0-10% MeOH/DCM) to give the title compound as a light yellow powder (767 mg, 79% yield, 2 steps). LCMS m/z = 292 [M+H] ⁺ . Intermediate B51. Methyl 4-amino-1-(4-(1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1-ethoxyvinyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 3.5 g, 5.91 mmol), tributyl(1-ethoxyvinyl)tinane (3.20 g, 8.86 mmol), Pd(PPh ₃ ) ₄ (683 mg, 0.591 mmol) in dioxane (15 mL) was degassed and purged with N ₂ (3×), and the mixture was stirred at 80 °C under N ₂ for 12 h. The reaction mixture was quenched by the addition of saturated aqueous KF solution (30 mL) at 0 °C and extracted with EtOAc (3× 20 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as a brown oil (3 g, crude). LCMS m/z = 584 [M+H] ⁺ . Step 2. Synthesis of methyl 1-( ₄ -acetyl-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1-ethoxyvinyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 3 g, 5.14 mmol) in THF (10 mL) was added aqueous citric acid (2 M, 50 mL), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with _H2O (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2 x 30 mL), dried _{( Na2SO4} ) and concentrated under reduced pressure, and the residue was purified by column chromatography ( _SiO2 , 0-66% EtOAc/PE) to give the title compound as a yellow solid (10.2 g, crude). LCMS m/z = 556 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1-hydroxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 1-(4-acetyl-2,6-dimethylphenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 10 g, 9.00 mmol) in MeOH (100 mL) was added NaBH ₄ (2.04 g, 54 mmol, 6 eq) at 0° C. and the mixture was stirred at 0° C. for 20 min. The reaction mixture was quenched by the addition of 1 M HCl (10 ml) at 0° C., basified with aqueous Na ₂ CO ₃ solution, and extracted with EtOAc (4×50 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by prep-HPLC-27 (50%-80% MeCN) to give the title compound (1 g, 20%) as a white solid. LCMS m/z = 558 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1-hydroxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 3, 300 mg, 0.538 mmol) in THF (6 mL) were added NaOH (32.3 mg, 0.81 mmol) and dimethyl sulfate (679 mg, 5.38 mmol) and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by prep-HPLC-11 (35%-65% MeCN) to give the title compound (150 mg, 49%) as a white solid. LCMS m/z = 572 [M+H] ⁺ . Step 5. Synthesis of methyl 4-amino-1-(4-(1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 4, 140 mg, 0.245 mmol) in TFA (2.5 mL) was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in THF and the pH was adjusted to pH 9-11 with aqueous NaHCO ₃ solution and concentrated under reduced pressure. The residue was purified by prep-HPLC-11 (10%-40% MeCN) to give the title compound (60 mg, 74%) as a white solid. LCMS m/z = 332 [M+H] ⁺ . Intermediate B52. 4-amino-1-(3,5-dichloropyridin-4-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-1-(3,5-dichloropyridin - 4- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B2, 2 g, 4.26 mmol) and 3,5-dichloro-4-fluoropyridine (1.06 g, 6.39 mmol) in DMF (10 mL) was added K ₂ CO ₃ (1.18 g, 8.52 mmol), and the mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H ₂ O (50 mL) and extracted with EtOAc (3×40 mL). The combined organics were washed with brine (2 x 30 mL), dried _{( Na2SO4} ) and concentrated under reduced pressure. The residue was purified by MPLC ( _SiO2 , 1%-100% EtOAc/PE) to give the title compound as a white solid (2.3 g, 87%). LCMS m/z = 615 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(3,5-dichloropyridin - 4- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(2,4-dimethoxybenzyl)amino)-1-(3,5-dichloropyridin-4-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 2.3 g, 3.74 mmol) in TFA (3 mL) and DCM (20 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with _H2O (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2 x 30 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 1%-50% EtOAc/PE) to give the title compound (942 mg, 80% yield) as a white solid. LCMS m/z = 315 [M+H] ⁺ . Intermediate B53. Methyl 4-amino-1-(2,6-dimethyl-4-((methylsulfonyl)methyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(hydroxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B18 Step 3, 2.00 g, 3.38 mmol) in dioxane (100 mL) were added cataCXium® A Pd G2 (226 mg, 0.338 mmol) and tributyltinylmethanol (4.34 g, 13.5 mmol) at 0 °C and the reaction mixture was stirred under _N2 at 110 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/PE) to give the title compound (1.80 g, 98%) as a black solid. LCMS m/z = 544 [M+H] ⁺ . Step 2. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-(((methylsulfonyl)oxy)methyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 4-(bis(4-methoxybenzyl)amino)-1-(4-(hydroxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 500 mg, 0.92 mmol) in DCM (10 mL) was added TEA (186 mg, 1.84 mmol) and MsCl (220 mg, 1.92 mmol) at 0° C., and the reaction mixture was stirred at 25° C. for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution (2 mL) and H ₂ O (8 mL), and extracted with DCM (3×10 mL). The combined organics were washed with brine (10 mL) and dried ( _Na2SO4 ) and concentrated _to give the title compound as a yellow oil (570 mg, crude) which was used without further purification. Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-((methylsulfonyl)methyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-(((methylsulfonyl)oxy)methyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 2, 200 mg, 0.322 mmol) in DMF (1 mL) was added sodium methanesulfinate (131 mg, 1.29 mmol) and the mixture was stirred at 100 °C for 1.5 h. The reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as a white solid (190 mg, crude). _LCMS m/z = 606 [M+H] ⁺ . Step 4. Synthesis of methyl 4-amino-1-(2,6-dimethyl-4-((methylsulfonyl)methyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A solution of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2,6-dimethyl-4-((methylsulfonyl)methyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (180 mg, 0.297 mmol) in TFA (2 mL) was stirred at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was extracted with DCM (3×10 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was purified by prep-TLC (10% EtOAc/MeOH) to give the title compound (90 mg, 83%) as a yellow oil. LCMS m/z = 366 [M+H] ⁺ . Intermediate B54. (R)-4-amino-1-(4-(1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester or (S)-4-amino-1-(4-(1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester. Step 1. Synthesis of methyl 4-amino-1-(4-(1-ethoxyvinyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-amino-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B34, 3 g, 8.52 mmol), tributyl(1-ethoxyvinyl)tinane (4.61 g, 12.8 mmol), Pd(PPh ₃ ) ₄ (984 mg, 0.85 mmol) in dioxane (80 mL) was degassed and purged with N ₂ (×3), and the mixture was stirred at 80° C. for 12 h under N _2. The reaction mixture was quenched by the addition of saturated aqueous KF solution (30 mL) at 0° C., and then extracted with EtOAc (3×20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure, and the residue was purified by column chromatography ( _SiO2 , 0-50% EtOAc/PE) to give the title compound as a yellow solid (2 g, 68%). LCMS m/z = 344 [M+H] ⁺ . Step 2. Synthesis of methyl 1-(4-acetyl-2,6-dimethylphenyl)-4-amino-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

A mixture of methyl 4-amino-1-(4-(1-ethoxyvinyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 2 g, 5.82 mmol), citric acid (2 M, 75 mL) in THF (15 mL) was degassed and the mixture was stirred at 25 °C for 40 min. The reaction mixture was concentrated under reduced pressure and the residue was diluted with _H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as _a white solid (3.60 g, 98%). LCMS m/z = 316 [M+H] ⁺ . Step 3. Synthesis of methyl 4-amino-1-(4-(1-hydroxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a mixture of methyl 1-(4-acetyl-2,6-dimethylphenyl)-4-amino-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B54, step 2, 1.50 g, 4.76 mmol) in MeOH (40 mL) was added NaBH ₄ (360 mg, 9.51 mmol) at 0° C., and the mixture was then stirred at 0° C. for 2 min. The reaction was quenched with aqueous Na ₂ CO ₃ (10 mL) until pH=10, and the mixture was extracted with EtOAc (4×10 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by prep-HPLC (C18; 250 × 50 mm, 10 μm); 10%-35% MeCN/H ₂ O (NH ₄ HCO ₃ )) to give the title compound (1.00 g, 33%) as a white solid. LCMS m/z = 318 [M+H] ⁺ . Step 4. Synthesis of (R)-4-amino-1-(4-(1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester or (S)-4-amino-1-(4-(1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester

To a solution of methyl 4-amino-1-(4-(1-hydroxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step ₃ , 410 mg, 1.29 mmol) in DCM (8 mL) was added DAST (479 mg, 2.97 mmol) under N2 at -78 °C, and the mixture was stirred at -78 °C for 3 h and at 25 °C for 9 h. The reaction mixture was quenched by the addition of saturated NaHCO3 ( ₃₀ mL) at 0 °C, and extracted with EtOAc (3 x 30 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was separated by SFC (DAICEL CHIRALCEL OJ, 250 × 30 mm, 10 μm); 20% IPA (0.1% _NH4OH )) _to give: Peak 2, Intermediate B54 : (R)-4-amino-1-(4-(1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester or (S)-4-amino-1-(4-(1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (white solid, 190 mg, 46%); LCMS m/z = 320 [M+H] ⁺ . Intermediate B55. Synthesis of methyl 4-amino-1-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

A solution of methyl 1-(4-acetyl-2,6-dimethylphenyl)-4-amino-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B54, Step 2; 120 mg, 0.38 mmol) in DAST (4 mL) was stirred at 45 °C for 12 h under _N2 . The reaction mixture was quenched by the addition of saturated aqueous _NH4Cl solution (15 mL) at 0 °C and then extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (10 mL), dried ( _Na2SO4 ) and _concentrated under reduced pressure. The residue was purified by TLC (100% EtOAc1) to give the title compound (80 mg, 62%) as a yellow solid. LCMS m/z = 338 [M+H] ⁺ . Intermediate B56. Methyl 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-thionyl-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(tert-butoxycarbonyl)amino)-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

To a suspension of methyl 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B24, 607 mg, 1.76 mmol) in THF (9 mL) was added DMAP (21.4 mg, 0.176 mmol), triethylamine (0.50 mL, 3.52 mmol) and _Boc2O (1.085 g, 5.28 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 5 h. The reaction was diluted with EtOAc (50 mL) and washed with water, saturated aqueous _NaHCO3 solution, brine, dried ( _MgSO4 ) and concentrated by rotary evaporation. Flash chromatography (ISCO 24 g silica, 0-80% EtOAc/Hex) afforded the title compound as a yellow solid (755 mg, 79%). LCMS m/z = 542 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-thionyl-1,6-dihydropyrimidine-5-carboxylate .

A suspension of methyl 4-(bis(tert-butoxycarbonyl)amino)-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 412 mg, 0.76 mmol) and Lawesson's reagent (308 mg, 0.76 mmol) in anhydrous toluene (3 mL) was heated to 110 °C for 24 h. The reaction was cooled, diluted with EtOAc (40 mL) and washed with dilute aqueous HCl, water, and brine. The organics were dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 24 g silica, 0-65% EtOAc/hex) to give a mixture of Boc protected intermediates as a yellow foam (366 mg). The yellow foam (366 mg) was dissolved in DCM (4 mL) and TFA (1 mL) and stirred at room temperature for 2 h. The reaction was poured into saturated aqueous _NaHCO3 and extracted with DCM (3 x 15 mL). The combined organics were washed with water and brine, dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 24 g silica, 0-100% EtOAc/hex) afforded the title compound as a yellow solid (63.5 mg, 23% yield, 2 steps). LCMS m/z = 358 [M+H] ⁺ . Intermediate B57. Methyl 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-thionyl-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(tert-butoxycarbonyl)amino)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To a solution of methyl 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B22, 53.6 mg, 0.170 mmol) in THF (2 mL) was added DMAP (3.1 mg, 0.017 mmol), triethylamine (48 μL, 0.340 mmol) and Boc ₂ O (113 mg, 0.510 mmol) sequentially at room temperature, and the reaction was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, and the residue was purified by flash chromatography (ISCO, 4 g silica, 0-100% EtOAc/Hex) to provide the title compound (77.8 mg, 88%) as a white solid. LCMS m/z = 518 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-thionyl-1,6-dihydropyrimidine-5-carboxylate .

A suspension of methyl 4-(bis(tert-butoxycarbonyl)amino)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 77.8 mg, 0.150 mmol) and Lawson's reagent (61.7 mg, 0.150 mmol) in anhydrous toluene (0.75 mL) was heated to 110 °C for 19 h. The reaction was cooled, diluted with EtOAc (30 mL), washed with dilute aqueous HCl, water, and brine (2x). The combined organics were dried ( _MgSO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO 4 g silica, 0-75% EtOAc/hex) to provide a yellow oil. The yellow oil was dissolved in DCM (2 mL) and TFA (0.5 mL) and stirred at room temperature for 2 h. The reaction was poured into saturated aqueous _NaHCO3 solution and extracted with DCM (3×10 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated by rotary evaporation. Flash chromatography (ISCO 4 g silica, 0-100% EtOAc/hex) gave the title compound as a yellow solid (13.3 mg, 26% yield, 2 steps). LCMS m/z = 334 [M+H] ⁺ . Intermediate B58. Synthesis of methyl 4-amino-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate.

The title compound was prepared from methyl 4-amino-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B34) using a method analogous to that described for Intermediate B35. LCMS m/z = 288 [M+H] ⁺ . Intermediate B59. Methyl 4-amino-1-(2-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

To methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate BP1491664_A1 (intermediate B1, 400 mg, 0.977 mmol) and (2-methoxyphenyl)boronic acid (445 mg, 2.93 mmol) in DMF (4.00 mL) were added pyridine (232 mg, 2.93 mmol) and Cu(OAc) ₂ (266 mg, 1.47 mmol), and the mixture was stirred under _O2 (15 psi) at 100 °C for 12 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC (SiO ₂ , 0-50% EtOAc/PE/EtOAc) to give the title compound as a yellow solid (230 mg, crude). LCMS m/z = 516 [M+H] ⁺ . Step 2. Synthesis of methyl 4-amino-1-(2-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

Methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Step 1, 230 mg, 0.446 mmol) in TFA (3 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (3 mL) and saturated aqueous Na ₂ CO ₃ solution (5 mL) at 0 °C. The aqueous solution was extracted with EtOAc (3× 5 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by prep-TLC (100% EtOAc) to give the title compound (110 mg, 89%) as an off-white solid. LCMS m/z = 276 [M+H] ⁺ . Intermediate B60. Methyl 4-amino-1-(2-chloro-6-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate. Step 1. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

The title compound (2.3 g, 83%) was prepared as a yellow oil from methyl 4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B1) and 1-chloro-2-fluoro-3-nitro-benzene using a method analogous to that described for Intermediate B4, Step 1. LCMS m/z = 565 [M+H] ⁺ . Step 2. Synthesis of methyl 1-(2-amino-6-chlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

The title compound (2.03 g, 93%) was prepared as a yellow oil from methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (step 1) using a method analogous to that described for intermediate B3, step 2. LCMS m/z = 535 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-bromo-6-chlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

The title compound (700 mg, 31%) was prepared as a yellow solid from methyl 1-(2-amino-6-chlorophenyl)-4-(bis(4-methoxybenzyl)amino)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (step 2) using a method analogous to that described for intermediate B4, step 4. LCMS m/z = 600 [M+H] ⁺ . Step 4. Synthesis of methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

The title compound (170 mg, 53%) was prepared as a yellow oil from methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-bromo-6-chlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (step 3) using a method analogous to that described for intermediate B25, step 4. LCMS m/z = 536 [M+H] ⁺ . Step 5. Synthesis of methyl 4-amino-1-(2-chloro-6-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate .

The title compound (40 mg, 43%) was prepared as an oil from methyl 4-(bis(4-methoxybenzyl)amino)-1-(2-chloro-6-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (step 4) using a method analogous to that described for intermediate B7, step 2. LCMS m/z = 296 [M+H] ⁺ . Example 1. Synthesis of (S)-4-amino-N-(3-(1-amino-2-methoxyethyl)phenyl)-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

AlMe ₃ (2 M in toluene, 69.5 μL) was added to a mixture of methyl 4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B4, 15 mg, 0.046 mmol) and (S)-3-(1-amino-2-methoxyethyl)aniline (Intermediate A1, 10.78 mg, 0.065 mmol) in toluene (3 mL) at 0°C, and the mixture was stirred at 0°C for 5 min. The mixture was stirred at 100°C under N ₂ for 1 h. The reaction mixture was treated with H ₂ O (0.2 mL) and TFA (0.2 mL) at 0°C and concentrated under reduced pressure. The residue was purified by prep-HPLC-2 (10%-45% MeCN) to give the title compound (9.4 mg, 44%) as a white solid. LCMS m/z = 458 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.80 (s, 1H), 10.07 (d, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.57 (d, 1H), 7.32-7.29 (m, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.85 (d, 1H), 5.95 (d, 1H), 4.20 (dd, 1H), 3.87 (s, 3H), 3.55 (dd, 1H), 3.45 (d, 1H), 3.40 (s, 3H), 2.23 (s, 3H). Example 2. Synthesis of (R)-4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-(3-(1-(methylamino)ethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

_AlMe3 ( ₂ M in toluene, 46.3 μL) was added to a solution of 4-amino-1-((S)-2-chloro-4-methoxy-6-methyl-phenyl)-6-oxo-pyrimidine-5-carboxylic acid methyl ester (Intermediate B4, 10 mg, 0.031 mmol) and (R)-3-(1-(methylamino)ethyl)aniline (Intermediate A2, 6.96 mg, 0.0463 mmol) in toluene (1 mL) and THF (0.5 mL) under _N2 at 0°C, and the mixture was stirred at 40°C under N2 for 1 h. The reaction mixture was quenched with 10% NaOH solution (5 mL) at 0°C, and extracted with EtOAc (3 x 3 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by prep-HPLC-1 (5%-45% MeCN) to give the title compound (8.1 mg, 53%) as a yellow oil. LCMS m/z = 442 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.96 (s, 1H), 9.67 (d, 1H), 8.55 (d, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 7.63-7.63 (m, 1H), 7.65 (d, 1H), 7.48 (s, 1H), 7.30 (t, 1H), 7.09-7.04 (m, 2H), 3.86 (s, 3H), 3.74-3.65 (m, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 2.10 (s, 1H), 1.29 (d, 3H). Examples 3 to 32 .

The title compound was prepared using a method similar to that described for Example 1 Instance Number Name, Reactants, HPLC, Data 3 (R)-4-amino-1-((S)-2-chloro-6-methylphenyl)-N-(3-(1-(methylamino)ethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B3, Intermediate A2 HPLC-1 (10%-44% MeCN); pale yellow solid (4.4 mg, 10%); LCMS m/z = 413 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.91 (s, 1H), 9.68 (d, 1H), 8.58 (d, 1H), 8.33-8.31 (m, 2H), 7.65 (d, 1H), 7.58-7.56 (m, 1H), 7.52-7.50 (m, 1H), 7.47-7.45 (m, 2H), 7.29 (t, 1H), 7.06 (d, 1H), 3.70 (d, 1H), 2.19 (d, 6H, J), 1.29 (d, 3H). 4 (R)-4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-(5-(1-((methyl-d3)amino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-(5-(1-((methyl-d3)amino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B4, Intermediate A54 HPLC-1 (1%-40% MeCN); white solid (29.9 mg, 49%); LCMS m/z = 446 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.98 (s, 1H), 9.98 (br d, 1H), 8.68 (d, 1H), 8.31-8.37 (m, 2H), 7.76 (s, 1H), 6.99 (d, 1H), 6.85 (d, 1H), 6.06 (br d, 1H), 3.94 (q, 1H), 3.87 (s, 3H), 2.23 (s, 3H), 1.58 (d, 3H). 5 4-Amino-1-(2,6-dichlorophenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B9, Intermediate A12 HPLC-1 (3%-35% MeCN); white solid (2.5 mg, 9%); LCMS m/z = 433 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.78 (s, 1H), 10.00 (s, 1H), 8.61 (d, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 7.74-7.72 (m, 1H), 7.56-7.54 (m, 2H), 7.47-7.43 (m, 1H), 6.06 (s, 1H), 4.00 (s, 2H), 2.87 (q, 2H), 1.26 (t, 3H). 6 (R)-4-amino-1-(2,6-dichlorophenyl)-N-(3-fluoro-5-(1-(methylamino)ethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate intermediate B9, intermediate A67 HPLC-10 (20%-50% MeCN); white solid (19.4 mg, 23%); LCMS m/z = 450 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 12.02 (s, 1H), 9.53 (d, 1H), 8.86 (s, 1H), 8.74 (d, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 7.82 (dt, 1H), 7.71-7.68 (m, 2H), 7.57 (t, 1H), 7.25 (s, 1H), 6.97 (d, 1H), 4.20 (q, 1H), 2.36 (t, 3H), 1.43 (d, 3H). 7 (S)-4-amino-N-(3-(1-amino-2-methoxyethyl)phenyl)-1-((S)-2-chloro-6-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B48, Intermediate A1 HPLC-1 (1%-45% MeCN); white solid (3.4 mg, 14%); LCMS m/z = 464 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.57 (s, 1H), 10.12 (d, 1H), 7.84-7.69 (m, 3H), 7.69-7.57 (m, 2H), 7.53 (d, 1H), 7.34-7.29 (m, 1H), 7.14 (d, 1H), 6.86-6.45 (m, 1H), 6.10 (d, 1H), 4.22 (dd, 1H), 3.60-3.54 (m, 1H), 3.53-3.45 (m, 1H), 3.39 (s, 3H). 8 (R)-4-amino-N-(3-(1-aminoethyl)phenyl)-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide intermediate B13, intermediate A: (R)-3-(1-aminoethyl)aniline HPLC-2 (8%-40%); pale yellow solid (3.8 mg, 9%); LCMS m/z = 406 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.78 (s, 1H), 9.71 (d, 1H), 8.68 (d, 1H), 8.38-8.34 (m, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.69-7.65 (m, 1H), 7.50 (s, 1H), 7.29 (t, 1H), 7.11 (d, 1H), 4.11 (q, 1H), 2.24 (s, 3H), 1.33 (d, 3H). 9 (R)-4-amino-1-(2,6-dichloro-4-cyanophenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-cyanophenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B14, Intermediate A14 HPLC-2 (20%-60% MeCN); off-white solid (19.4 mg, 58%); LCMS m/z = 458 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.75 (s, 3H) 2.55 (s, 3H) 4.18-4.25 (m, 1H) 6.23-6.28 (m, 1H) 7.73 (s, 1H) 7.88 (s, 2H) 8.37 (s, 1H) 8.57 (s, 1H) 8.64 (d, 1H) 10.07 (d, 1H) 11.70 (s, 1H). 10 4-Amino-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B45, Intermediate A12 HPLC-2 (3%-33% MeCN); colorless oil (6.8 mg, 20%); LCMS m/z = 499 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.76 (s, 1H), 9.65 (s, 1H), 8.79 (d, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.73 (s, 2H), 7.50 (t, 1H), 3.75 (s, 2H), 2.58-2.56 (m, 2H), 1.04 (t, 3H). 11 4-Amino-1-((S)-2-chloro-4-(difluoromethyl)-6-methylphenyl)-N-(3-((ethylamino)methyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B46, Intermediate A41 HPLC-1 (20%-50% MeCN); white solid (20.9 mg, 47%); LCMS m/z = 462 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )：11.66 (s, 1H), 10.05 (br d, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 7.39 (br d, 1H), 7.30-7.27 (m, 1H), 7.12 (br d, 1H), 6.80-6.51 (m, 1H), 6.07 (br d, 1H), 3.91 (s, 2H), 2.84 (q, 2H), 2.31 (s, 3H), 1.19 (t, 3H). 12 (R)-4-amino-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide intermediate B15, intermediate A14 HPLC-2 (5%-35% MeCN); white solid (12 mg, 28%); LCMS m/z = 468 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.63 (s, 1H), 9.99-9.98 (m, 1H), 8.60 (br d, 1H), 8.20 (s, 1H), 8.12 (br s, 1H), 7.63 (s, 1H), 7.50 (s, 2H), 6.13 (br s, 1H), 3.73 (br d, 1H), 2.27 (s, 3H), 1.39 (br d, 3H). 13 (S)-4-amino-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide intermediate B15, intermediate A15 HPLC-1 (10-30); white solid (9.3 mg, 15%); LCMS m/z = 468 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.43-1.47 (m, 1H) 1.51 (d, 3H) 2.21 (d, 1H) 2.28 (s, 1H) 2.35-2.43 (m, 3H) 2.44-2.48 (m, 1H) 2.78-3.23 (m, 6H) 3.82-3.91 (m, 1H) 6.16-6.39 (m, 1H) 7.13-7.17 (m, 1H) 7.25-7.28 (m, 1H) 7.34-7.41 (m, 1H) 7.47-7.53 (m, 1H) 7.58-7.63 (m, 1H) 7.71-7.78 (m, 1H) 8.24-8.36 (m, 2H) 8.67-8.72 (m, 1H) 9.98-10.14 (m, 1H) 11.74 (s, 1H) 11.85 (d, 1H) 11.96-12.01 (m, 1H). 14 4-Amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A12 HPLC-2 (3%-33% MeCN); orange solid (8.1 mg, 24%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.73 (s, 1H), 9.67 (s, 1H), 8.83 (d, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.04 (s, 3H), 7.16 (t, 1H), 3.75 (s, 2H), 2.58-2.56 (m, 2H), 1.04 (t, 3H). 15 4-Amino-N-(5-(2-aminopropan-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A52 HPLC-1 (1%-40% MeCN); yellow solid (25.2 mg, 90%); LCMS m/z = 476 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.78 (s, 1H), 9.95 (s, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 7.73 (s, 1H), 7.52 (s, 2H), 6.57 (d, 1H), 4.51 (s, 2H), 3.48 (s, 3H), 1.66 (s, 6H). 16 (R)-4-amino-1-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-N-(5-(1-((methyl-d3)amino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-N-(5-(1-((methyl-d3)amino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B47, Intermediate A54 HPLC-1 (1%-40% MeCN); white solid (34.6 mg, 64%); LCMS m/z = 484 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.84 (s, 1H), 10.06 (d, 1H), 8.66 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 7.76 (d, 2H), 7.63 (s, 1H), 6.31 (d, 1H), 4.03 (q, 1H), 2.37 (s, 3H), 1.64 (d, 3H). 17 4-Amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A12 HPLC-2 (3%-35% MeCN); white solid (2.1 mg, 5%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )：11.74 (s, 1H), 9.92 (d, 1H), 8.58 (d), 8.31 (s, 1H), 8.26 (s, 1H), 7.66-7.65 (m, 1H), 6.99-6.98 (m, 2H), 5.94 (s, 1H), 3.87 (s, 2H), 3.80 (s, 3H), 2.72 (q, 2H), 1.18 (t, 3H). 18 (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide intermediate B10, intermediate A14 HPLC-11 (20%-50% MeCN); white solid (8.8 mg, 31%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.79 (s, 1H), 10.06 (d, 1H), 8.69 (d, 1H), 8.25 (d, 1H), 8.11 (t, 1H), 7.74 (s, 1H), 7.07 (s, 2H), 6.22 (d, 1H), 3.88 (s, 3H), 3.69 (q, 1H), 2.31 (s, 3H), 1.38 (d, 3H). 19 (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide intermediate B10, intermediate A15 HPLC-2 (5%-40% MeCN); white solid (21.2 mg, 56%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.90 (s, 1H), 10.00 (d, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 8.38 (d, 1H), 8.33 (d, 1H), 7.75 (s, 1H), 7.09 (s, 2H), 6.15 (d, 1H), 4.00 (q, 1H), 3.90 (s, 3H), 2.41 (s, 3H), 1.61 (d, 3H). 20 4-Amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((isopropylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A25 HPLC-2 (5%-35% MeCN); white solid (38.8 mg, 50%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )：11.83 (s, 1H), 10.00 (br d, 1H), 8.63 (d, 1H), 8.34 (s, 2H), 7.74 (s, 1H), 7.08 (s, 2H), 6.11 (br d, 1H), 3.93 (s, 2H), 3.90 (s, 3H), 3.02 (td, 1H), 1.22 (d, 6H). twenty one 4-Amino-N-(5-(1-aminocyclopentyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A39 HPLC-3 (15%-40% MeCN); yellow solid (7.2 mg, 18%); LCMS m/z = 489 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ )：11.78 (s, 1H), 10.08 (d, 1H), 8.79-8.71 (m, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 7.76 (s, 1H), 7.10 (s, 2H), 6.08 (d, 1H), 3.91 (s, 3H), 2.09-1.91 (m, 8H). twenty two 4-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A12 HPLC-1 (5%-45% MeCN); white solid (75 mg, 80%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.67 (s, 1H), 10.09 (s, 1H), 8.61 (s, 1H), 8.45-8.34 (m, 3H), 7.85 (s, 2H), 7.74 (s, 1H), 6.21 (d, 1H), 3.97 (s, 2H), 2.84 (q, 2H), 1.22 (t, 3H). twenty three 4-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-(((2-hydroxyethyl)amino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A71 HPLC-1 (1%-40% MeCN); white solid (35.3 mg, 39%); LCMS m/z = 518 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.69 (s, 1H) 10.02 (br d, 1H) 8.57 (br s, 1H) 8.44 (br s, 1H) 8.35 (br s, 1H) 7.83 (s, 2H) 7.72 (s, 1H) 6.38 (br d, 1H) 4.07 (br s, 2H) 3.79 (br s, 2H) 2.99 (br s, 2H). twenty four (R)-4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide intermediate B30, intermediate A15 HPLC-1 (5%-40% MeCN); white solid (22.7 mg, 38%) LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.84 (s, 1H), 10.02 (d, 1H,), 8.67 (d, 1H), 8.27 (dd, 2H), 7.73 (s, 1H), 7.05 (s, 2H), 6.18 (d, 1H), 4.09 (q, 2H), 3.85 (q, 1H), 2.36 (s, 3H), 1.51-1.43 (m, 6H). 25 4-Amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(((2-methoxyethyl)amino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A73 HPLC-3 (5%-45% MeCN); white solid (13.1 mg, 31%); LCMS m/z = 507 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.48 (t, 3H), 2.82 (t, 2H), 3.37 (s, 3H), 3.53 (t, 2H), 3.85 (s, 2H), 4.10 (q, 2H), 6.02 (s, 1H), 7.06 (s, 2H), 7.74 (s, 1H), 8.16 (s, 1H), 8.30 (d, 1H), 8.69 (d, 1H), 10.05 (d, 1H), 11.79 (s, 1H). 26 4-Amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(((2-hydroxyethyl)amino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A71 HPLC-1 (10%-40% MeCN); white solid (28.3 mg, 46%); LCMS m/z = 493 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.87 (s, 1H), 9.93 (d, 1H), 8.59 (d, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.74 (s, 1H), 7.05 (s, 2H), 6.21 (d, 1H) 4.00 - 4.17 (m, 4H) 3.78 (s, 2H) 2.99 (s, 2H) 1.47 (t, 3H). 27 (R)-4-amino-N-(7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(7-amino-7-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A43 HPLC-1 (1%-35% MeCN); white solid (10.8 mg, 38%); LCMS m/z = 449 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.78 (s, 1H), 9.93 (br d, 1H), 9.26 (s, 1H), 8.39 (s, 1H), 7.72 (s, 1H), 7.21 (s, 2H), 6.02 (br d, 1H), 4.47 (s, 2H), 3.47 (s, 3H), 3.10-2.97 (m, 1H), 2.93-2.78 (m, 1H), 2.19 (d, 8H), 1.55 (s, 3H). 28 5-(4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridazine-3-carboxamide intermediate B30, intermediate A59 HPLC-1 (20%-50% MeCN); yellow solid (2.9 mg, 4.8%); LCMS m/z = 464 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.26 (s, 1H), 9.90 (d, 1H), 9.43 (d, 1H), 8.73 (d, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.06 (s, 2H), 6.21-6.13 (m, 1H), 5.71 (d, 1H), 4.10 (q, 2H), 1.47 (t, 3H). 29 5-(4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridazine-3-carboxamide Intermediate B25, Intermediate A59 HPLC-3 (15%-45% MeCN); white solid (5.4 mg, 9%); LCMS m/z = 424 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 1.32-1.36 (m, 3H), 2.04 (s, 6H), 4.06 (q, 2H), 6.81 (s, 2H), 7.87 (s, 1H), 8.24 (s, 1H), 8.49 (s, 1H), 8.66-8.76 (m, 2H), 9.31 (d, 1H), 9.39 (d, 1H), 12.51 (s, 1H). 30 5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridazine-3-carboxamide Intermediate B22, Intermediate A59 HPLC-3 (20%-45% MeCN); white solid (10.4 mg, 23%); LCMS m/z = 424 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 2.09 (s, 6H), 3.33 (s, 3H), 4.42 (s, 2H), 7.20 (s, 2H), 7.87 (s, 1H), 8.27 (s, 1H), 8.49 (s, 1H), 8.72 (d, 1H), 8.74 (d, 1H), 9.31 (d, 1H), 9.41 (d, 1H), 12.47 (s, 1H). 31 (R)-4-amino-N-(5-(2-amino-1-methoxypropan-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(2-amino-1-methoxypropan-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide intermediate B10, intermediate A26 HPLC-1 (1%-40% MeCN); white solid (51.9 mg, 64%); LCMS m/z = 493 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.83 (s, 1H), 9.93 (d, 1H), 8.70 (d, 1H), 8.47-8.43 (m, 1H), 8.30 (s, 1H), 7.74-7.71 (m, 1H), 7.06 (s, 2H), 6.24 (d, 1H), 3.87 (s, 3H), 3.61 (s, 1H), 3.55-3.52 (m, 1H), 3.35 (s, 3H), 1.59 (s, 3H). 32 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((1R,3aS,6aR)-octahydrocyclopenta[c]pyrrol-1-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((1S,3aR,6aS)-octahydrocyclopenta[c]pyrrol-1-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A47 HPLC-1 (1%-50% MeCN); white solid (33.3 mg, 71%); LCMS m/z = 515 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.87 (s, 1H), 9.63 (d, 1H), 8.75-8.69 (m, 2H), 8.41 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.38 (s, 2H), 3.90 (s, 3H), 3.62 (d, 2H), 3.37-3.31 (m, 1H), 2.77-2.64 (m, 2H), 2.39 (q, 1H), 1.69-1.48 (m, 6H). Example 33. Synthesis of 4-amino-1-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-N-(3-((R)-1-(methylamino)ethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

_AlMe3 (2 M in toluene, 104 μL) was added to a solution of methyl 4-amino-1-((S)-2-chloro-6-methyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B47, 25 mg, 0.069 mmol) and (R)-3-(1-(methylamino)ethyl)aniline (Intermediate A2, 20.77 mg, 0.138 mmol) in toluene (2 mL) at 0°C, and the mixture was stirred under _N2 at 40°C for 0.5 h. The reaction mixture was quenched by the addition of 0.2 M saturated NaOH (5 mL) at 0°C, and extracted with EtOAc (3 x 5 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by prep-HPLC-1 (10%-50% MeCN) to give the title compound (3.2 mg, 9.7%) as a white solid. LCMS m/z = 480 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.59 (s, 1H), 10.06 (d, 1H), 8.55 (s, 1H), 7.65-7.62(m, 3H), 7.52 (s, 1H), 7.45 (d, 1H), 7.26 (t, 1H), 7.12 (d, 1H), 5.98 (d, 1H), 3.83 (q, 1H), 2.27 (d, 6H), 1.50 (d, 3H). Example 34. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (S)-2-(5-(4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)hexahydropyridine - 1- carboxylic acid tert-butyl ester .

To a mixture of methyl 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B10, 30 mg, 0.087 mmol) and tert-butyl (S)-2-(5-aminopyridin-3-yl)hexahydropyridine-1-carboxylate (Intermediate A5, 48.4 mg, 0.174 mmol) in toluene (2 mL) was added _AlMe3 (2 M in toluene, 130 μL), and the mixture was stirred at 0 °C for 5 min, and then at 100 °C for 0.5 h under _N2 . The reaction mixture was quenched by the addition of 1 N aqueous NaOH (4 mL) at 0 °C, and extracted with EtOAc (4 x 5 mL). The combined organics were washed with brine (5 mL), dried ( _Na2SO4 ) and evaporated to dryness in vacuo _to give the title compound as a black oil (40 mg, crude) which was used without further purification. LCMS m/z = 589 [M+H] ⁺ . Step 2. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(5-(hexahydropyridin - 2- yl) pyridin -3- yl)-1,6-dihydropyrimidine-5-carboxamide .

(S)-tert-butyl 2-(5-(4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)hexahydropyridine-1-carboxylate (Step 1, 40 mg, 0.068 mmol) was dissolved in DCM (1 mL) and TFA (1 mL), and the mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-1 (1%-50% MeCN) to give the title compound (16.5 mg, 45%) as a white solid. LCMS m/z = 489 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.78 (s, 1H), 10.03 (br d, 1H), 8.67 (d, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.07 (s, 2H), 6.00 (br d, 1H), 3.88 (s, 3H), 3.76-3.69 (m, 1H), 3.19 (br d, 1H), 2.87-2.70 (m, 2H), 1.95-1.82 (m, 2H), 1.73-1.62 (m, 3H), 1.57-1.46 (m, 1H). Example 35. Synthesis of (R)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (R)-(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)propyl)carbamic acid tert-butyl ester or (S)-(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)propyl)carbamic acid tert-butyl ester

To a solution of methyl 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B22, 30 mg, 0.095 mmol) and tert-butyl (S)-(1-(5-aminopyridin-3-yl)propyl)carbamate or (R)-tert-butyl (1-(5-aminopyridin-3-yl)propyl)carbamate (Intermediate A8, 47.52 mg, 0.189 mmol) in toluene (4 mL) was added _AlMe3 (2 M, 141 μL) at 0 °C and the mixture was stirred at 40 °C for 1 h under _N2 . The reaction mixture was quenched by adding H ₂ O (0.20 mL) and TFA (0.20 mL) at 0° C., and then concentrated under reduced pressure to give the title compound (40.00 mg, crude) as a yellow oil. LCMS m/z = 537 [M+H] ⁺ . Step 2. Synthesis of (R)-4-amino-N-(5-(1-aminopropyl) pyridin -3- yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminopropyl) pyridin -3 -yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

A solution of (R)-tert-butyl(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)propyl)carbamate or (S)-tert-butyl(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)propyl)carbamate (Step 1, 40 mg, 0.075 mmol) in TFA (0.50 mL) and DCM (1.50 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under N ₂ , and the residue was purified by prep-HPLC-1 (20%-50% MeCN) to give the title compound (10 mg, 27%) as a white solid. LCMS m/z = 537 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 0.85 (t, 3 H) 1.74-1.89 (m, 2 H) 2.18 (d, 6 H) 3.45 (s, 3 H) 3.93 (t, 1 H) 4.46 (s, 2 H) 6.04-6.15 (m, 1 H) 7.21 (s, 2 H) 7.73 (s, 1 H) 8.23 (d, 2 H) 8.59 (s, 1 H) 9.84 (d, 1 H) 12.02 (s, 1 H). Examples 36 to 173

The title compound was prepared from the appropriate amine and ester using a 2-step procedure similar to that described for Example 35. Instance Number Structure, Reactants, HPLC, Data 36 (S)-4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-N-(3-(pyrrolidin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide intermediate B4, intermediate A61 HPLC-2 (5%-35% MeCN); light yellow solid (25.8 mg, 57%); LCMS m/z = 454 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.80 (s, 1H), 10.00 (d, 1H), 7.78-7.69 (m, 2H), 7.46 (d, 1H), 7.27-7.23 (m, 1H), 7.15 (d, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 6.02 (d, 1H), 4.37 (t, 1H), 3.85 (s, 3H), 3.36-3.04 (m, 2H), 2.35-2.25 (m, 1H), 2.21 (s, 3H), 2.15-1.91 (m, 3H). 37 (S)-4-amino-1-(2-chloro-4-fluoro-6-methylphenyl)-6-oxo-N-(3-(pyrrolidin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide intermediate B44, intermediate A61 HPLC-1 (10%-50% MeCN); orange solid (8.6 mg, 42%); LCMS m/z = 442 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.69 (s, 1H), 10.14 (br.s, 1H), 7.73 (s, 1H), 7.67-7.53 (m, 2H), 7.24 (dd, 1H), 7.17 (d, 1H), 7.09 (dd, 1H), 5.96 (br.s, 1H), 4.40-4.00 (m, 1H), 3.30-3.17 (m, 1H), 3.15-2.97 (m, 1H), 2.29 (s, 3H), 2.25-2.20 (m, 1H), 2.00-1.88 (m, 2H), 1.82-1.73 (m, 1H), 1.38-1.18 (m, 1H). 38 4-amino-N-(3-(1-aminocyclobutyl)phenyl)-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B4, Intermediate A70 HPLC-1 (20%-60% MeCN); white solid (28.2 mg, 44%); LCMS m/z = 455 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.76 (s, 1H), 9.91 (d, 1H), 7.71 (s, 1H), 7.63 (br s, 1H), 7.43 (d, 1H), 7.27 (s, 1H), 7.12 (d, 1H), 6.96 (s, 1H), 6.82 (br s, 1H), 6.09 (s, 1H), 3.84 (s, 3H), 2.53 (s, 2H), 2.41 (br dd, 2H), 2.21 (s, 3H), 2.12 (d, 1H), 1.83-1.68 (m, 1H). 39 (S)-4-amino-1-(2-chloro-4-fluoro-6-methylphenyl)-6-oxo-N-(3-(pyrrolidin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide intermediate B44, intermediate A61 HPLC-1 (10%-45% MeCN); light yellow solid (21 mg, 52%); LCMS m/z = 442 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.59 (s, 1H), 10.03 (br d, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.47 (d, 1H), 7.13 (dd, 1H), 7.04 (br d, 1H), 6.98 (dd, 1H), 5.95 (s, 1H), 4.11 (br t, 1H), 3.16-3.09 (m, 1H), 3.02-2.93 (m, 1H), 2.18 (s, 3H), 2.16-2.09 (m, 1H), 1.94-1.64 (m, 3H). 40 (S)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B9, Intermediate A13 HPLC-1 (10%-44% MeCN); white solid (85.1 mg, 94%); LCMS m/z = 445 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.77 (s, 1H), 9.95 (br s, 1H), 8.58 (s, 1H), 8.51-8.50 (m, 1H), 8.42 (s, 1H), 8.37-8.29 (m, 1H), 8.33 (s, 1H), 7.79-7.70 (m, 1H), 7.61-7.52 (m, 2H), 7.50-7.43 (m, 1H), 7.51-7.43 (m, 1H), 6.61-6.19 (m, 1H), 4.49 (t, 1H), 3.42-3.19 (m, 2H), 2.37 (d, 1H), 2.25-2.00 (m, 3H). 41 (S)-4-amino-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-N-(3-(hexahydropyridin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-N-(3-(hexahydropyridin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B13, Intermediate A20 HPLC-2 (3%-33% MeCN); white solid (4.6 mg, 25%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.55 (s, 1H), 10.13 (d, 1H), 7.75 (d, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.48 (d, 1H), 7.24 (s, 1H), 7.22-7.18 (m, 1H), 6.15 (d, 1H), 3.73 (dd, 1H), 3.12 (d, 1H), 2.74 (dt, 1H,), 2.32 (s, 3H), 1.93-1.82 (m, 3H), 1.74-1.63 (m, 2H), 1.50 (dd, 1H). 42 (S)-4-amino-N-(3-(1-amino-2-methoxyethyl)phenyl)-1-((S)-2-chloro-4-cyano-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B13, Intermediate A1 HPLC-1 (5%-40% MeCN); white solid (3.9 mg, 18%); LCMS m/z = 453 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.54 (s, 1H), 10.09 (br d, 1H), 7.75 (s, 1H), 7.70-7.67 (m, 2H), 7.62 (s, 1H), 7.45 (d, 1H), 7.30-7.27 (m, 1H), 7.13 (d, 1H), 6.26 (d, 1H), 4.22 (d, 1H), 3.56-3.49 (m, 2H), 3.37 (s, 3H), 2.32 (s, 3H), 1.21 (d, 1H). 43 (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyanophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyanophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B14, Intermediate A16 HPLC-2 (5%-35% MeCN); white solid (11.3 mg, 69%); LCMS m/z = 444 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.65 (s, 1H), 9.71 (br d, 1H), 8.86 (br d, 1H), 8.72 (d, 1H), 8.54-8.40 (m, 3H), 8.28 (d, 1H), 8.00 (t, 1H), 4.06 (q, 1H), 1.29 (d, 3H). 44 (S)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyanophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyanophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B14, Intermediate A22 HPLC-1 (10%-45% MeCN); white solid (6.4 mg, 46%); LCMS m/z = 474 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOH-d ₃ ): 8.85-8.82 (m, 1H), 8.33 (d, 1H), 8.28 (d, 1H), 8.16 (s, 1H), 8.15 (d, 2H), 4.52 (br dd, 1H), 3.76-3.71 (m, 2H), 3.45 (s, 3H). 45 (S)-4-amino-1-(2,6-dichloro-4-methylphenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B12, Intermediate A13 HPLC-2 (5%-35% MeCN); white solid (19.4 mg, 86%); LCMS m/z = 459 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.78 (s, 1H ), 10.01 (d, 1H), 8.65 (d, 1H), 8.34 (d, 1H), 8.23-8.27 (m, 1H ), 7.72 (s, 1H ), 7.35 (s, 2H ), 6.16 (d, 1H), 4.31 (t, 1H), 3.20-3.31 (m, 1H), 3.09-3.18 (m, 1H), 2.43 (s, 3H), 2.24-2.33 (m, 1H), 2.00-2.08 (m, 1H), 1.86-1.98 (m, 2H). 46 (S)-4-amino-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B45, Intermediate A5 HPLC-1 (30%-80% MeCN); white solid (18.1 mg, 56%); LCMS m/z = 525 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.90 (s, 1H), 9.82 (d, 1H), 8.69 (s, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 7.71 (s, 1H), 7.34 (s, 2H), 6.81-6.43 (m, 1H), 6.20 (d, 1H), 4.13 (d, 1H), 3.36 (d, 1H), 3.02-2.93 (m, 1H), 2.13 (q, 1H), 2.06-1.90 (m, 3H), 1.87-1.78 (m, 1H), 1.68-1.57 (m, 1H). 47 (R)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B45, Intermediate A22 HPLC-2 (5%-35% MeCN); white solid (10.7 mg, 58%); LCMS m/z = 515 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.76 (s, 1H), 9.66 (br d, 1H), 8.80-8.73 (m, 2H), 8.44 (s, 1H), 8.27 (br s, 1H), 8.00 (br s, 1H), 7.72 (s, 2H), 7.67-7.30 (m, 1H), 4.10 (br s, 1H), 3.41 (br s, 2H), 3.25 (s, 3H). 48 (S)-4-amino-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B15, Intermediate A5 HPLC-1 (5%-40% MeCN); white solid (43.9 mg, 95%); LCMS m/z = 495 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.70 (s, 1H), 10.01 (d, 1H), 8.58 (s, 1H), 8.38 (d, 3H), 7.71 (s, 1H), 7.58 (s, 2H), 6.34 (s, 1H), 3.91-3.82 (m, 1H), 3.22 (d, 1H), 2.88-2.77 (m, 1H), 2.01-1.85 (m, 3H), 1.81-1.69 (m, 2H), 1.63-1.49 (m, 1H). 49 (R)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B15, Intermediate A22 HPLC-4 (1%-40% MeCN); yellow solid (9.2 mg, 26%); LCMS m/z = 484 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.67 (s, 1H), 10.07 (s, 1H), 8.69 (d, 1H), 8.30-8.36 (m, 1H), 8.20 (s, 1H), 7.71 (s, 1H), 7.57 (s, 2H), 6.14 (d, 1H), 4.24 (dd, 1H), 3.48-3.57 (m, 1H), 3.40-3.45 (m, 1H), 3.38-3.40 (m, 3H). 50 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-6-oxo-1-(2,4,6-trichlorophenyl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B15, Intermediate A16 HPLC-1 (1%-40% MeCN); yellow oil (16.4 mg, 50%); LCMS m/z = 453 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.61 (s, 1H), 9.97 (d, 1H), 8.57 (d, 1H), 8.24 (d, 1H), 8.10-8.17 (m, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.08 (d, 1H), 4.14 (q, 1H), 1.38 (d, 3H). 51 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B11, Intermediate A16 HPLC-1 (10%-40% MeCN); yellow solid (18.1 mg, 40%); LCMS m/z = 475 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 0.82-0.86 (m, 2 H), 0.88 (d, 2H), 1.52 (d, 3H), 3.79 (tt, 1H), 4.27 (dd, 1H), 6.12-6.37 (m, 1H), 7.21 (s, 2H), 7.72 (s, 1H), 8.29 (s, 2H), 8.56 (s, 1H), 9.89 (d, 1H), 11.81 (s, 1H). 52 4-amino-N-(5-(aminomethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B11, Intermediate A50 HPLC-3 (15%-45% MeCN); white solid (7 mg, 17%); LCMS m/z = 461 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.84-11.72 (m, 1H), 9.96-9.78 (m, 1H), 8.56-8.44 (m, 1H), 8.32-8.20 (m, 2H), 7.72 (s, 1H), 7.16 (s, 2H), 6.52-6.16 (m, 1H), 4.16-3.84 (m, 2H), 3.76 (d,1H), 0.92-0.86 (m, 2H), 0.84 (s, 2H). 53 (R)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B18, Intermediate A29 HPLC-4 (1%-35% MeCN); white solid (12.8 mg, 42%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.06 (s, 1H), 9.91 (s, 1H), 8.62 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 6.75 (s, 2H), 6.01 (s, 1H), 3.95-4.01 (m, 1H), 3.83 (s, 3H), 3.15 (d, 1H), 2.90-2.98 (m, 1H), 2.15 (s, 6H), 2.01 (s, 2H), 1.89 (s, 2H), 1.78 (s, 2H), 1.61-1.71 (m, 2H). 54 (S)-4-amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-N-(3-(pyrrolidin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide intermediate B16, intermediate A61 HPLC-1 (10%-50% MeCN); white solid (3.4 mg, 16%); LCMS m/z = 494 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.56 (s, 1H), 10.15 (d, 1H), 7.81-7.69 (m, 4H), 7.52 (d, 1H), 7.32 (s, 1H), 7.19 (br d, 1H), 6.93-6.50 (m, 1H), 6.10 (d, 1H), 4.40 (d, 1H), 3.43-3.09 (m, 2H), 2.39-2.22 (m, 1H), 2.20-1.88 (m, 3H). 55 (S)-4-amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A13 HPLC-1 (10%-50% MeCN); white solid (3.4 mg, 20%); LCMS m/z = 495 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.75 (s, 1H), 9.67 (d, 1H), 8.83 (d, 1H), 8.76 (d, 1H), 8.49 (s, 1H), 8.31 (d, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 8.03 (s, 2H), 7.36-6.96 (m, 1H), 4.28 (t, 1H), 3.21-3.00 (m, 2H), 2.27-2.20 (m, 1H), 1.93-1.81 (m, 2H), 1.77-1.66 (m, 1H). 56 (S)-4-amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A5 HPLC-1 (1%-50% MeCN); white solid (21.2 mg, 84%); LCMS m/z = 509 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.66 (s, 1H), 10.07 (d, 1H), 8.61 (d, 1H), 8.40-8.32 (m, 3H), 7.71 (d, 3H), 6.84-6.54 (m, 1H), 6.20 (d, 1H), 3.80 (dd, 1H), 3.17 (d, 1H), 2.79 (td, 1H), 2.07-1.61 (m, 6H), 1.60-1.46 (m, 1H). 57 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A17 HPLC-1 (3%-33% MeCN); white solid (12.4 mg, 68%); LCMS m/z = 469 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.74 (s, 1 H) 9.68 (br d, 1H) 8.83 (br d, 1H) 8.75 (d, 1H) 8.49 (s, 1 H) 8.27-8.34 (m, 1 H) 6.96-7.37 (m, 1 H) 4.11 (q, 1H) 1.31 (d, 3H). 58 (R)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A22 HPLC-2 (1%-35% MeCN); yellow solid (9.2 mg, 50%); LCMS m/z = 499 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOH-d ₄ ): 8.83 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.86 (s, 2H), 7.06-6.77 (m, 1H), 4.39 (t, 1H), 3.71-3.62 (m, 2H), 3.42 (s, 3H). 59 (R)-N-(5-(1,4-oxazoloheptan-3-yl)pyridin-3-yl)-4-amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazoloheptan-3-yl)pyridin-3-yl)-4-amino-1-(2,6-dichloro-4-(difluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B16, Intermediate A27 HPLC-3 (1%-40% MeCN); white solid (25.1 mg, 91%); LCMS m/z = 525 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.60 (s, 1H), 9.96 (s, 1H), 8.60 (s, 1H), 8.29-8.14 (m, 2H), 7.68-7.60 (m, 3H), 6.61 (t, 1H), 6.21 (s, 1H), 4.02 (d, 1H), 3.88 (d, 2H), 3.76-3.76 (m, 1H), 3.78 (d, 1H), 3.63 (d, 1H), 3.16 (d, 1H), 3.05-2.92 (m, 1H), 2.13-1.87 (m, 2H). 60 4-amino-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A24 HPLC-1 (15%-45% MeCN); yellow solid (14.7 mg, 44%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 10.05-9.94 (m, 1H), 8.58 (d, 1H), 8.20 (d, 1H), 8.06 (d, 1H), 7.64 (s, 1H), 7.44 (s, 2H), 5.97 (d, 1H), 4.43 (s, 2H), 3.73 (s, 2H), 3.40 (s, 3H), 2.60 (d, 2H), 1.05 (t, 3H). 61 (S)-4-amino-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A5 HPLC-1 (10%-40% MeCN); yellow solid (4.2 mg, 30%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.87 (s, 1H), 9.88 (d, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.71 (s, 1H), 7.51 (s, 2H), 6.09 (d, 1H), 4.51 (s, 2H), 4.09-4.02 (m, 1H), 3.48 (s, 3H), 3.30-3.21 (m, 1H), 2.96-2.86 (m, 1H), 2.15-2.08 (m, 1H), 2.07-1.97 (m, 4H), 1.69-1.55 (m, 1H). 62 (R)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A22 HPLC-1 (10%-40% MeCN); white solid (18.3 mg, 50%); LCMS m/z = 493 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.80 (s, 1H), 9.83 (d, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.73 (s, 1H), 7.50 (s, 2H), 6.40 (d, 1H), 4.50 (s, 2H), 4.41 (s, 1H), 3.73 (t, 1H), 3.65-3.60 (m, 1H), 3.46 (s, 3H), 3.39 (s, 3H). 63 4-amino-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(5-(((2-hydroxyethyl)amino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A71 HPLC-1 (1%-30% MeCN); yellow solid (16.3 mg, 72%); LCMS m/z = 493 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.79 (s, 1H), 9.94 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 7.49 (s, 2H), 6.47 (s, 1H), 4.49 (s, 2H), 4.02 (s, 2H), 3.76 (s, 2H), 3.46 (s, 3H), 2.94 (s, 2H). 64 4-amino-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(5-((isopropylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A25 HPLC-1 (1%-40% MeCN); white solid (28.3 mg, 67%); LCMS m/z = 491 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.66 (s, 1H), 9.95 (d, 1H), 8.55 (d, 1H), 8.21 (d, 2H), 7.64 (s, 1H), 7.44 (s, 2H), 6.03 (d, 1H), 4.43 (s, 2H), 3.79 (s, 2H), 3.40 (s, 3H), 2.88 (td, 1H), 1.08 (d, 6H). 65 4-amino-N-(5-(1-aminocyclobutyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A51 HPLC-1 (15%-45% MeCN); yellow gum (11.2 mg, 30%); LCMS m/z = 489 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.93 (s, 1H), 9.64 (s, 1H), 8.93 (s, 1H), 8.85 (d, 1H), 8.47 (d, 2H), 8.12 (d, 1H), 7.71 (s, 2H), 4.55 (s, 2H), 3.39 (s, 3H), 2.66-2.59 (m, 2H), 2.48-2.42 (m, 2H), 2.18-2.09 (m, 1H), 1.87-1.77 (m, 1H). 66 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A17 HPLC-1 (1%-40% MeCN); yellow solid (11.4 mg, 30%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.67 (s, 1H), 9.94 (d, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7.44 (s, 2H), 6.02 (d, 1H ), 4.43 (s, 2H), 4.15 (d, 1H), 3.40 (s, 3H), 1.43-1.38 (m, 3H). 67 (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A16 HPLC-1 (1%-40% MeCN); yellow solid (11.4 mg, 31%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.77 (s, 1H), 9.87 (d, 1H), 8.64-8.43 (m, 1H), 8.40-8.16 (m, 2H), 7.72 (s, 1H), 7.51 (s, 2H), 7.28 (s, 3H), 6.39-6.24 (m, 1H), 4.51 (s, 2H), 4.43-4.27 (m, 1H), 3.48 (s, 3H), 1.56 (s, 3H). 68 (S)-4-amino-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A23 HPLC-1 (15%-55% MeCN); white solid (16.5 mg, 36%); LCMS m/z = 507 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.82 (s, 1H), 10.02 (d, 1H), 8.69 (s, 1H), 8.41 (s, H), 8.33 - 8.38 (m, 1H), 7.72 (s, 1H), 7.52 (s, 2H), 6.11 (d, 1H), 4.51 (s, 2H), 3.98-4.16 (m, 1H), 3.70-3.79 (m, 2H), 3.62-3.70 (m, 1H), 3.48 (s, 3H), 3.39 (s, 3H), 2.49 (s, 3H). 69 (R)-4-amino-N-(5-(1-amino-2-ethoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-ethoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A10 HPLC-1 (20%-60% MeCN); white solid (15.3 mg, 40%); LCMS m/z = 507 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.80 (s, 1H), 9.94 (d, 1H), 8.62 (d, 1H), 8.36 (d, 2H), 7.73 (s, 1H), 7.53 (s, 2H), 6.25 (d, 1H), 4.52 (s, 2H), 4.34 (dd, 1H), 3.68-3.60 (m, 2H), 3.57 (ddd, 2H), 3.49 (s, 3H), 1.21 (t, 3H). 70 (R)-4-amino-N-(5-(1-amino-3,3-difluoropropyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-3,3-difluoropropyl)pyridin-3-yl)-1-(2,6-dichloro-4-(methoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B19, Intermediate A44 HPLC-1 (5%-35% MeCN); white solid (24.7 mg, 53%); LCMS m/z = 513 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.83 (s, 1H), 10.04 (d, 1H), 8.68 (d, 1H), 8.31 (d, 1H), 8.24 (s, 1H), 7.74 (s, 1H), 7.54 (s, 2H), 6.18 (d, 1H), 5.93 (tt, 1H), 4.52 (s, 2H), 4.26 (dd, 1H), 3.49 (s, 3H), 2.27-2.18 (m, 2H). 71 (R)-4-amino-1-((S)-2-chloro-4-ethoxy-6-methylphenyl)-N-(3-(1-(methylamino)ethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B5, Intermediate A2 HPLC-1 (1%-40% MeCN); white solid (50.2 mg, 70%); LCMS m/z = 456 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.83 (s, 1H), 10.04 (d, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.53 (d, 1H), 7.31 (t, 1H), 7.11 (d, 1H), 6.95 (d, 1H), 6.81 (d, 1H), 6.04 (d, 1H), 4.06 (q, 2H), 3.82 (q, 1H), 2.34 (s, 3H), 2.20 (s, 3H), 1.50 (d, 3H), 1.44 (t, 3H). 72 (S)-4-amino-N-(3-(1-amino-2-methoxyethyl)phenyl)-1-((S)-2-chloro-4-ethoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B5, Intermediate A1 HPLC-1 (5%-40% MeCN); pale yellow solid (7.9 mg, 11%); LCMS m/z = 472 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.79 (s, 1H), 10.01 (d, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.52 (d, 1H), 7.30 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 6.81 (d, 1H), 5.97 (d, 1H), 4.19 (dd, 1H), 4.06 (q, 2H), 3.56-3.51 (m, 1H), 3.48-3.43 (m, 1H), 3.38 (s, 3H), 2.20 (s, 3H), 1.45 (t, 3H). 73 (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A13 HPLC-1 (10%-50% MeCN); white solid (3.6 mg, 13%); LCMS m/z = 475 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.90 (s, 1H), 9.63 (d, 1H), 8.79 (d, 1H), 8.76 (d, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.40 (s, 1H), 7.42-7.37 (m, 1H), 4.32 (t, 1H), 3.91 (s, 3H), 3.22-2.99 (m, 2H), 2.32-2.17 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.66 (m, 2H). 74 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A17 HPLC-1 (5%-35% MeCN); yellow oil (14.1 mg, 57%); LCMS m/z = 449 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.83 (s, 1H), 9.59 (s, 1H), 8.72 (d, 2H), 8.38 (s, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.35 (s, 2H), 4.09 (d, 1H), 3.86 (s, 3H), 1.29 (d, 3H). 75 (R)-N-(5-(1,4-oxazoloheptan-3-yl)pyridin-3-yl)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazoloheptan-3-yl)pyridin-3-yl)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A27 HPLC-1 (5%-40% MeCN); white solid (11.8 mg, 28%); LCMS m/z = 505 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.71 (s, 1H), 9.95 (br d, 1H), 8.65 (d, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.66 (s, 1H), 6.99 (s, 2H), 5.97 (br d, 1H), 3.95-3.84 (m, 3H), 3.80 (s, 3H), 3.80-3.73 (m, 1H), 3.45 (dd, 1H), 3.14 (dt, 1H), 2.94 (ddd, 1H), 1.92-1.89 (m, 2H). 76 (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(6-fluoro-5-(hexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(6-fluoro-5-(hexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A21 HPLC-2 (5%-40% MeCN); white solid (30 mg, 65%); LCMS m/z = 507 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.75 (s, 1H), 9.97 (br d, 1H), 8.42 (dd, 1H), 8.30-8.27 (m, 1H), 7.72 (s, 1H), 7.06 (s, 2H), 6.14 (br d, 1H), 4.02-3.95 (m, 1H), 3.88 (s, 3H), 3.27 (br d, 1H), 2.83 (td, 1H), 1.91 (br d, 2H, J = 10.4 Hz), 1.70-1.50 (m, 4H). 77 (S)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A22 HPLC-1 (1%-40% MeCN); yellow solid (57.7 mg, 79%); LCMS m/z = 479 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.83 (s, 1H), 9.63 (d, 1H), 8.74 (d, 1H), 8.72 (d, 1H), 8.40 (s, 1H), 8.26 (d, 1H), 8.00 (d, 1H), 7.37 (s, 2H), 4.08 (t, 1H), 3.89 (s, 3H), 3.38 (d, 2H), 3.24 (s, 3H). 78 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A35 HPLC-1 (15%-55% MeCN); white solid (50.5 mg, 93%); LCMS m/z = 489 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.80 (s, 1H), 9.99 (d, 1H), 8.64 (d, 1H), 8.39-8.25 (m, 2H), 7.74 (s, 1H), 7.08 (s, 2H), 6.15 (d, 1H), 4.40 (t, 1H), 3.89 (s, 3H), 3.61-3.46 (m, 1H), 2.37-2.25 (m, 1H), 2.20-2.09 (m, 1H), 2.09-1.96 (m, 1H), 1.82-1.61 (m, 1H), 1.29 (d, 3H). 79 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A38 HPLC-3 (30%-65% MeCN); yellow solid (8.8 mg, 17%); LCMS m/z = 489 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.11 (s, 1H), 9.81 (d, 1H), 8.80-9.05 (m, 1H), 8.40-8.63 (m, 2H), 7.73 (s, 1H), 6.98-7.10 (m, 2H), 6.15 (d, 1H), 4.80-4.99 (m, 1H), 3.85-4.00 (m, 4H), 2.39-2.52 (m, 2H), 2.27-2.38 (m, 1H), 1.76-1.96 (m, 1H), 1.44 (d, 3H). 80 (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A23 HPLC1-1 (05%-36% MeCN); white solid (45.5 mg, 71%); LCMS m/z = 493 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.79 (s, 1H), 10.06 (br d, 1H), 8.74 (d, 1H), 8.29 (d, 1H), 8.14 (t, 1H), 7.74 (s, 1H), 7.07 (s, 2H), 6.11 (d, 1H), 3.88 (s, 3H), 3.80 (dd, 1H), 3.49-3.42 (m, 2H), 3.37 (s, 3H), 2.31 (s, 3H). 81 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A33 HPLC-1 (1%-40% MeCN); white solid (33 mg, 98%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.79 (s, 1H), 9.99 (d, 1H), 8.57 (d, 1H), 8.41-8.39 (m, 1H), 8.36 (d, 1H), 7.72 (s, 1H), 7.06 (s, 2H), 6.12 (d, 1H), 4.18 (dd, 1H), 3.88 (s, 3H), 3.42-3.38 (m, 1H), 1.97-1.88 (m, 3H), 1.80-1.67 (m, 2H), 1.51-1.47 (m, 1H), 1.27 (d, 3H). 82 (R)-4-amino-N-(5-(1-amino-3,3-difluoropropyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-3,3-difluoropropyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A44 HPLC-1 (1%-40% MeCN); white solid (22.1 mg, 39%); LCMS m/z = 499 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.86 (s, 1H), 9.98 (d, 1H), 8.65 (s, 1H), 8.32-8.21 (m, 2H), 7.74 (d, 1H), 7.07 (d, 2H), 6.14 (d, 1H), 6.08-5.74 (m, 1H), 4.26 (t, 1H), 3.88 (d, 3H), 2.36-2.24 (m, 2H). 83 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A32 HPLC-1 (5%-35% MeCN); white solid (18.6 mg, 39%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.05 (d, 3H), 1.21-1.29 (m, 1H), 1.47-1.63 (m, 2H), 1.67 (d, 1H), 1.79 (d, 1H), 1.87-1.93 (m, 1H), 2.83-2.90 (m, 1H) 3.73-3.79 (m, 1H), 3.88 (s, 3H), 6.06 (s, 1H), 7.07 (s, 2H), 7.73 (s, 1H), 8.17 (s, 1H), 8.34 (s, 1H), 8.72 (d, 1H), 10.04 (d, 1H), 11.76 (s, 1H). 84 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A31 HPLC-1 (1%-40% MeCN); white solid (20.6 mg, 50%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.79 (s, 1H), 10.01 (d, 1H), 8.58 (d, 1H), 8.39 (d, 2H), 7.72 (s, 1H), 7.06 (s, 2H), 6.10 (d, 1H), 4.17 (dd, 1H), 3.88 (s, 3H), 3.45-3.33 (m, 1H), 2.03-1.87 (m, 3H), 1.81-1.66 (m, 2H), 1.55-1.44 (m, 1H), 1.27 (d, 3H). 85 (R)-4-amino-N-(5-(1-amino-3,3-difluoropropyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-3,3-difluoropropyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A44 HPLC-1 (10%-40% MeCN); white solid (8.7 mg, 23%); LCMS m/z = 499 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.86 (s, 1H), 10.01 (d, 1H), 8.67 (d, 1H), 8.30 (d, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.07 (s, 2H), 6.06-6.03(m, 1H), 5.94-5.75 (m, 1H), 4.24 (dd, 1H), 3.88 (s, 3H), 2.29-2.16 (m, 2H). 86 4-amino-1-(2,6-dichloro-4-propoxyphenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B7, Intermediate A24 HPLC-3 (5%-35% MeCN); white solid (23.7 mg, 48%); LCMS m/z = 491 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.73 (s, 1H), 9.93 (br.d, 1H), 8.56 (d, 1H), 8.21 (s, 1H), 8.15 (br.s, 1H), 7.65 (s, 1H), 6.98 (s, 2H), 6.07 (br.d, 1H), 3.89 (t, 2H), 3.77 (s, 2H), 2.64 (q, 2H), 1.77 (sxt, 2H), 1.08 (br.t, 3H), 0.98 (t, 3H). 87 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2R,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B24, Intermediate A37 HPLC-1 (1%-40% MeCN); yellow solid (21.9 mg, 65%); LCMS m/z = 487 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.82 (s, 1H), 10.03 (d, 1H), 8.69 (d, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.71 (s, 1H), 7.51 (s, 2H), 6.10 (d, 1H), 4.44 (t, 1H), 3.55-3.50 (m, 1H), 2.37-2.33 (m, 1H), 2.26 (s, 6H), 2.20-2.09 (m, 1H), 1.85-1.78 (m, 1H), 1.52-1.45 (m, 1H), 1.24 (d, 3H). 88 (R)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B24, Intermediate A8 HPLC-1 (5%-35% MeCN); white solid (22.5 mg, 34%); LCMS m/z = 461 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.90 (s, 1H), 10.00 (d, 1H), 8.66 (d, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.74 (s, 1H), 7.54 (s, 2H), 6.26 (d, 1H), 3.94 (t, 1H), 2.29 (d, 6H), 1.85-1.75 (m, 2H), 0.90 (t, 3H). 89 (R)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B24, Intermediate A29 HPLC-1 (10%-50% MeCN); brown oil (32.2 mg, 63%); LCMS m/z = 501 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.89 (s, 1H), 10.01 (d, 1H), 8.63 (d, 1H), 8.41-8.27 (m, 2H), 7.74 (s, 1H), 7.55 (s, 2H), 6.14 (d, 1H), 4.12-3.96 (m, 1H), 3.21-3.09 (m, 1H), 3.05-2.89 (m, 1H), 2.29 (s, 6H), 2.11-2.01 (m, 2H), 1.98-1.88 (m, 2H), 1.86-1.75 (m, 2H), 1.75-1.59 (m, 2H). 90 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2R,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2S,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2R,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-((2S,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B24, Intermediate A31 HPLC-1 (10%-40% MeCN); pink solid (38.3 mg, 91%); LCMS m/z = 491 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.28 (d, 3H), 1.42-1.57 (m, 1H), 1.66-1.84 (m, 2H), 1.84-2.00 (m, 3H), 2.27 (s, 6H), 3.41 (d, 1H), 4.18 (t, 1H), 6.03 (d, 1H), 7.52 (s, 2H), 7.72 (s, 1H), 8.26-8.47 (m, 2H), 8.63 (s, 1H), 9.99 (d, 1H), 11.85 (s, 1H). 91 (R)-4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B25, Intermediate A4 HPLC-4 (1%-40% MeCN); white solid (72 mg, 66%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.07 (s, 1H), 9.85 (d, 1H), 8.57 (d, 1H), 8.35 (d, 2H), 7.74 (s, 1H), 6.72 (s, 2H), 6.32 (d, 1H), 4.04 (q, 2H), 3.81 (dd, 1H), 3.18 (d, 1H), 2.82-2.74 (m, 1H), 2.12 (s, 6H), 1.92 (d, 1H), 1.89-1.81 (m, 2H), 1.74-1.66 (m, 2H), 1.57-1.48 (m, 1H), 1.42 (t, 3H). 92 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B25, Intermediate A37 HPLC-1 (1%-40% MeCN); white solid (23 mg, 35%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.07 (s, 1H), 9.87 (d, 1H), 8.62 (s, 1H), 8.30 (d, 2H), 7.75 (s, 1H), 6.73 (s, 2H), 6.01 (d, 1H), 4.59 (t, 1H), 4.05 (q, 3H), 3.69 (d, 1H), 2.42-2.33 (m, 1H), 2.30-2.19 (m, 1H), 2.13 (d, 6H), 2.08-1.98 (m, 1H), 1.72-1.59 (m, 1H), 1.43 (t, 3H), 1.30 (d, 3H). 93 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B25, Intermediate A38 HPLC-1 (1%-40% MeCN); white solid (29.6 mg, 90%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.30 (d, 3 H), 1.47 (t, 3 H), 1.53-1.67 (m, 1 H), 1.88-2.02 (m, 1 H), 2.17 (s, 6 H), 2.21 (d, 1 H), 2.32-2.45 (m, 1 H), 3.59-3.69 (m, 1 H), 4.09 (q, 2 H), 4.53 (t, 1 H), 6.02 (d, 1 H), 6.77 (s, 2 H), 7.78 (s, 1 H), 8.23 (s, 1 H), 8.31-8.38 (m, 1 H), 8.70 (s, 1 H), 9.94 (d, 1 H), 12.07 (s, 1 H). 94 (R)-4-amino-N-(5-(1-aminobutyl)pyridin-3-yl)-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B25, Intermediate A7 HPLC-1 (20%-60% MeCN); white solid (19.8 mg, 30%); LCMS m/z = 451 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.07 (s, 1H), 9.76 (s, 1H), 8.53 (s, 1H), 8.31-8.21 (m, 2H), 7.74 (s, 1H), 6.73 (s, 2H), 6.20 (d, 1H), 4.05 (q, 3H), 2.13 (d, 6H), 1.89-1.72 (m, 2H), 1.43 (t, 3H), 1.31-1.14 (m, 2H), 0.87 (t, 3H). 95 (R)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B25, Intermediate A29 HPLC-1 (20%-60% MeCN); white solid (19 mg, 38%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.97 (s, 1 H), 9.83 (d, 1H), 8.52 (s, 1 H), 8.12-8.30 (m, 2 H), 7.67 (s, 1 H), 6.66 (s, 2 H), 5.83 (d, 1H), 3.96-4.07 (m, 2 H), 3.91-3.95 (m, 1 H), 2.98-3.14 (m, 1 H), 2.82-2.93 (m, 1 H), 2.06 (s, 6 H), 1.90-2.02 (m, 2 H), 1.78-1.90 (m, 2 H), 1.53-1.75 (m, 4 H), 1.36 (t, 3H). 96 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2R,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-ethoxy-2,6-dimethylphenyl)-N-(5-((2S,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B25, Intermediate A31 HPLC-1 (10%-40% MeCN); white solid (51 mg, 85%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.96 (s, 1H), 9.83 (d, 1H), 8.52 (d, 1H), 8.29 (d, 2H), 7.67 (s, 1H), 6.65 (s, 2H), 5.90 (d, 1H), 4.08 (dd, 1H), 3.98 (q, 2H), 3.38-3.22 (m, 1H), 2.05 (s, 6H), 1.92-1.77 (m, 3H), 1.72-1.56 (m, 2H), 1.41 (d, 1H), 1.36 (t, 3H), 1.18 (d, 3H). 97 (R)-4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A4 HPLC-1 (15%-45% MeCN); white solid (33.6 mg, 81%); LCMS m/z = 469 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.90 (s, 1H), 9.89 (d, 1H), 8.63-8.41 (m, 2H), 8.28 (d, 1H), 7.73 (s, 1H), 7.40 (s, 2H), 6.84-6.49 (m, 1H), 6.09 (d, 1H), 3.92 (dd, 1H), 3.21 (d, 1H), 2.86 (dt, 1H), 2.25 (d, 6H), 2.04-1.89 (m, 3H), 1.88-1.69 (m, 2H), 1.65-1.48 (m, 1H). 98 (R)-4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A4 HPLC-1 (15%-55% MeCN); white solid (21.8 mg, 81%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.02 (s, 1 H) 9.88 (s, 1 H) 8.48 (s, 1 H) 7.72 (s, 1 H) 7.21 (s, 2 H) 6.03 (s, 1 H) 4.46 (s, 2 H) 3.83-3.96 (m, 1 H) 3.45 (s, 3 H) 3.16 (d, 1 H) 2.73-2.87 (m, 1 H) 2.18 (d, 6 H) 1.88-2.02 (m, 3 H) 1.68-1.85 (m, 2 H) 1.49-1.60 (m, 1 H). 99 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((methylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A6 HPLC-1 (5%-35% MeCN); white solid (34.6 mg, 64%); LCMS m/z = 423 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.07 (s, 1H), 9.82 (br s, 1H), 8.55 (br s, 1H), 8.46 (br s, 1H), 8.31 (br s, 1H), 7.71 (s, 1H), 7.19 (s, 2H), 6.49 (br s, 1H), 4.44 (s, 2H), 3.98 (br s, 2H), 3.43 (s, 3H), 2.50 (br s, 3H), 2.15 (s, 6H). 100 (R)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A30 HPLC-1 (1%-40% MeCN); white solid (20.5 mg, 55%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.92 (s, 1H), 9.85 (d, 1H), 8.53 (d, 1H), 8.22 (d, 2H), 7.65 (s, 1H), 7.13 (s, 2H), 5.88 (d, 1H), 4.39 (s, 2H), 3.89 (t, 1H), 3.37 (s, 3H), 3.03-3.01 (m, 1H), 2.87-2.82 (m, 1H), 2.10 (s, 6H), 1.95-1.91 (m, 2H), 1.84-1.79 (m, 2H), 1.71-1.50 (m, 4H). 101 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A38 HPLC-1 (10%-40% MeCN); white solid (31.7 mg, 77%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.31 (d, 3H), 1.63-1.79 (m, 1H), 2.02-2.15 (m, 1H), 2.19 (d, 6H), 2.24-2.34 (m, 1H), 2.35-2.46 (m, 1H), 3.46 (s, 3H), 3.67-3.82 (m, 1H), 4.48 (s, 2H), 4.64 (dd, 1H), 6.02 (d, 1H), 7.22 (s, 2H), 7.73 (s, 1H), 8.23-8.41 (m, 2H), 8.63 (d, 1H), 9.89 (d, 1H), 12.03 (s, 1H). 102 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A34 HPLC-3 (1%-40% MeCN); white solid (33.9 mg, 61%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.27 (d, 3H), 1.49 (d, 1H), 1.67-1.80 (m, 2H), 1.88-2.07 (m, 3H), 2.17 (s, 6H), 3.45 (s, 3H), 4.18 (d, 1H), 4.46 (s, 2H), 6.11 (d, 1H), 7.20 (s, 2H), 7.72 (s, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.91 (d, 1H) 12.00 (s, 1H). 103 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2R,5R)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-((2S,5S)-5-methylpyrrolidin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A37 HPLC-1 (1%-40% MeCN); yellow solid (57.9 mg, 85%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.30 (d, 3H), 1.64-1.78 (m, 1H), 2.07-2.15 (m, 1H), 2.17 (d, 6H), 2.24-2.33 (m, 1H), 2.34-2.44 (m, 1H), 3.45 (s, 3H), 3.72-3.82 (m, 1H), 4.46 (s, 2H), 4.64 (d, 1H), 6.09 (d, 1H), 7.20 (s, 2H), 7.71 (s, 1H), 8.29 (d, 1H), 8.35 (s, 1H), 8.60 (d, 1H), 9.86 (d, 1H), 12.01 (s, 1H). 104 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-ethoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B25, Intermediate A16 HPLC-1 (5%-35% MeCN); white solid (10.2 mg, 25%); LCMS m/z = 423 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.99 (s, 1H), 9.74 (s, 1H), 8.51 (s, 1H), 8.20 (s, 2H), 7.67 (s, 1H), 6.65 (s, 2H), 6.08 (d, 1H), 4.15 (d, 1H), 3.97 (q, 2H), 2.05(d, 6H), 1.41-1.33(m, 6H). 105 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((methylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A56 HPLC-1 (10%-40% MeCN); white solid (60.9 mg, 92%); LCMS m/z = 429 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.99 (s, 1H), 9.93 (d, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.41 (s, 2H), 6.67 (t, 1H), 6.08 (d, 1H), 4.01 (s, 2H), 2.56 (s, 3H), 2.25 (s, 6H). 106 (R)-4-amino-N-(5-(1-aminobutyl)pyridin-3-yl)-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A7 HPLC-1 (1%-40% MeCN); white solid (28.2 mg, 41%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.94 (s, 1H), 9.82 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 8.25 (s, 1H), 7.71 (s, 1H), 7.38 (s, 2H), 6.84-6.47 (m, 1H), 6.42 (s, 1H), 4.14-4.02 (m, 1H), 2.23 (d, 6H, J = 8.4 Hz), 1.94-1.74 (m, 2H), 1.26 (br s, 2H), 0.86 (t, 3H). 107 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2R,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2S,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2R,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2S,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A31 HPLC-1 (5%-45% MeCN); white solid (44.6 mg, 98%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.93 (s, 1H), 10.00 (d, 1H), 8.65 (d, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.75 (s, 1H), 7.42 (s, 2H), 6.68 (t, 1H ), 6.23 (d, 1H), 4.18 (t, 1H), 3.40 (d, 1H), 2.27 (s, 6H), 2.27-1.91 (m, 3H), 1.74-1.71 (m, 2H), 1.51-1.47 (m, 1H), 1.29 (d, 3H). 108 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2R,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2S,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2R,6R)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-N-(5-((2S,6S)-6-methylhexahydropyridin-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A33 HPLC-1 (5%-35% MeCN); white solid (20.9 mg, 92%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.93 (s, 1H), 10.09-9.90 (m, 1H), 8.64 (d, 1H), 8.43 (d, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.42 (s, 2H), 6.91-6.46 (m, 1H), 6.11 (d, 1H), 4.24-4.13 (m, 1H), 3.42 (d, 1H), 2.26 (s, 6H), 1.95 (d, 3H), 1.84-1.67 (m, 2H), 1.57-1.44 (m, 1H), 1.30 (d, 3H). 109 (S)-4-amino-1-(2,6-dichloro-4-(trifluoromethoxy)phenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide intermediate B37, intermediate A13 HPLC-2 (10%-40% MeCN); yellow solid (10.1 mg, 60%); LCMS m/z = 529 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.64 (s, 1H), 10.10 (s, 1H), 8.69 (d, 1H), 8.35 (d, 1H), 8.20 (t, 1H), 7.73 (s, 1H), 7.46 (d, 2H), 6.12 (d, 1H), 4.28 (t, 1H), 3.25-3.23 (m, 1H), 3.15-3.09 (m, 1H), 2.06-1.94 (m, 2H), 1.92-1.89 (m, 1H), 1.86-1.76 (m, 1H). 110 (R)-4-amino-1-(2,6-dimethyl-4-(trifluoromethoxy)phenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B38, Intermediate A4 HPLC-1 (1%-40% MeCN); white solid (21.2 mg, 66%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.26 (s, 1 H), 1.48-1.58 (m, 1 H), 1.70-1.79 (m, 2 H), 1.85-1.96 (m, 2 H), 2.21 (d, 6 H), 2.81 (dd, 1 H), 3.20 (br.d, 1 H), 3.78 (dd, 1 H), 5.97 (br.d, 1 H), 7.10 (s, 2 H), 7.72 (s, 1 H), 8.29-8.35 (m, 2 H), 8.63 (d, 1 H), 9.97 (d, 1 H), 11.83-11.93 (m, 1 H). 111 4-Amino-1-(4-((R)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B40, Intermediate A4 HPLC-3 (10%-40% MeCN); white solid (22.8 mg, 50%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.47-1.64 (m, 1H), 1.77 (q, 2H), 1.87-2.02 (m, 3H), 2.23 (d, 6H), 2.71-2.92 (m, 1H), 3.19 (d, 1H), 3.71-3.96 (m, 1H), 4.49-4.88 (m, 2H), 5.58-5.87 (m, 1H), 5.99 (d, 1H), 7.26 (s, 2H), 7.73 (s, 1H), 8.29-8.38 (m, 1H), 8.41 (s, 1H), 8.58 (d, 1H), 9.95 (br d, 1H), 11.92 (s, 1H). 112 4-amino-N-(5-((R)-azacycloheptan-2-yl)pyridin-3-yl)-1-(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((R)-azacycloheptan-2-yl)pyridin-3-yl)-1-(4-((R)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(5-((S)-Azacycloheptane-2-yl)pyridin-3-yl)-1-(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-Azacycloheptane-2-yl)pyridin-3-yl)-1-(4-((R)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B40, Intermediate A29 HPLC-1 (10%-50% MeCN); white solid (28.9 mg, 44%); LCMS m/z = 497 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.57-1.82 (m, 4H), 1.88 (d, 2H), 2.01 (br d, 2H), 2.21 (s, 6H), 2.85-3.21 (m, 2H), 3.98 (s, 1H), 4.48-4.82 (m, 2H), 5.61-5.79 (m, 1H), 6.19 (d, 1H), 7.24 (s, 2H), 7.71 (s, 1H), 8.26-8.35 (m, 2H), 8.60 (s, 1H), 9.94 (br s, 1H), 11.92 (br s, 1H). 113 4-Amino-1-(4-((R)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B41, Intermediate A4 White solid (42 mg, 84%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.94 (s, 1H), 9.93 (d, 1H), 8.59 (s, 1H), 8.37 (d, 2H), 7.73 (s, 1H), 7.25 (s, 2H), 6.20 (d, 1H), 5.82-5.61 (m, 1H), 4.77-4.63 (m, 2H), 3.84 (dd, 1H), 3.19 (d, 1H), 2.81 (t, 1H), 2.22 (d, 6H), 2.00-1.84 (m, 3H), 1.79-1.68 (m, 2H), 1.62-1.48 (m, 1H). 114 4-amino-N-(5-((R)-1-aminoethyl)pyridin-3-yl)-1-(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((R)-1-aminoethyl)pyridin-3-yl)-1-(4-((R)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(5-((S)-1-aminoethyl)pyridin-3-yl)-1-(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-1-aminoethyl)pyridin-3-yl)-1-(4-((R)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B41, Intermediate A16 HPLC-3 (5%-30% MeCN); white solid (11.1 mg, 31%); LCMS m/z = 443 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.98 (s, 1H), 9.91 (s, 1H), 8.60 (s, 1H), 8.33 (br s, 3H), 7.74 (s, 1H), 7.26 (s, 2H), 6.25 (s, 1H), 5.88-5.61 (m, 1H), 4.82-4.74 (m, 1H), 4.73-4.68 (m, 1H), 4.67-4.63 (m, 1H), 4.61-4.57 (m, 1H), 4.30 (d, 1H), 2.23 (d, 6H), 1.53 (d, 3H). 115 4-amino-N-(5-((R)-azacycloheptan-2-yl)pyridin-3-yl)-1-(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((R)-azacycloheptan-2-yl)pyridin-3-yl)-1-(4-((R)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -(5-((S)-Azacycloheptane-2-yl)pyridin-3-yl)-1-(4-((S)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-Azacycloheptane-2-yl)pyridin-3-yl)-1-(4-((R)-1,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B41, Intermediate A29 HPLC-1 (20%-50% MeCN); white solid (22.1 mg, 41%); LCMS m/z = 497 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.92 (s, 1H), 9.98 (d, 1H), 8.65 (d, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.73 (s, 1H), 7.29 (s, 2H), 6.04 (d, 1H), 5.87-5.59 (m, 1H), 4.81-4.52 (m, 2H), 3.98 (dd, 1H), 3.15 (td, 1H), 3.04 - 2.85 (m, 1H), 2.23 (s, 6H), 2.11-1.55 (m, 8H). 116 (R)-4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-N-(5-((methylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-N-(5-((methylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B42, Intermediate A56 HPLC-1 1%-50% MeCN; white solid 40.8 mg, 88%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.72 (s, 1H), 9.98 (d, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 7.71 (s, 1H), 7.56 (s, 2H), 6.38-6.38 (m, 1H), 5.82-5.61 (m, 1H), 4.83-4.55 (m, 2H), 3.96 (s, 2H), 2.52 (s, 3H). 117 (R)-4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-N-(5-((methylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-(1,2-difluoroethyl)phenyl)-N-(5-((methylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B43, Intermediate A56 HPLC-1 (5%-35% MeCN); white solid (27.8 mg, 61%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.72 (s, 1H), 10.05 (br d, 1H), 8.62 (d, 1H), 8.34 (br d, 2H), 7.73 (s, 1H), 7.58 (s, 2H), 6.16 (br d, 1H), 5.84-5.63 (m, 1H), 4.85-4.71 (m, 1H), 4.71-4.58 (m, 1H), 3.91 (s, 2H), 2.51 (s, 3H). 118 (S)-4-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A13 HPLC-1 (1%-50% MeCN); white solid (22.1 mg, 50%); LCMS m/z = 514 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 1.53-1.66 (m, 1H), 1.74-1.88 (m, 2H), 2.13-2.24 (m, 1H), 2.94-3.00 (m, 1H), 3.03-3.08 (m, 1H), 4.17 (br.t, 2H), 8.04 (t, 1H), 8.24 (s, 1H), 8.26 (br. s, 1H), 8.28 (d, 1H), 8.32 (s, 2H), 8.48 (s, 1H), 8.70 (d, 1H), 8.85 (br.d, 1H), 9.50-9.85 (m, 1H), 11.55-11.93 (m, 1H). 119 (S)-4-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A5 HPLC-1 (1%-50% MeCN); white solid (14 mg, 31%); LCMS m/z = 527 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 1.37-1.50 (m, 3 H), 1.60 (d, 1H), 1.70-1.85 (m, 2 H), 2.64-2.75 (m, 1 H), 3.09 (d, 1H), 3.68 (d, 1H), 8.08 (t, 1H), 8.27 (d, 1H), 8.24 (d, 1H), 8.33 (s, 2H), 8.48 (s, 1H), 8.67 (d, 1H), 8.86 (d, 1H), 9.69 (d, 1H), 11.71 (s, 1H). 120 4-amino-N-(5-(aminomethyl)pyridin-3-yl)-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A50 HPLC-1 (1%-30% MeCN); white solid (10.8 mg, 15%); LCMS m/z = 473 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.65 (s, 1H), 10.11 (d, 1H), 8.62 (d, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.85 (s, 2H), 7.74 (s, 1H), 6.19 (d, 1H), 3.95 (s, 2H). 121 (R)-4-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A23 HPLC-1 (25%-55% MeCN); white solid (36.3 mg, 56%); LCMS m/z = 531 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 2.62 (s, 3H), 3.39 (s, 3H), 3.76 (dd, 1H), 3.96 (br dd, 1H), 4.28 (br dd, 1H), 6.26 (br d, 1H), 7.72 (s, 1H), 7.82 (s, 2H), 8.41 (br s, 1H) 8.60 (s, 1H), 8.67 (br s, 1H), 10.03 (br d, 1H), 11.76 (s, 1H). 122 (R)-4-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B23, Intermediate A22 HPLC-3 (5%-35% MeCN); white solid (24.4 mg, 53%); LCMS m/z = 517 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.64 (s, 1 H), 10.13 (br s, 1H), 8.71 (d, 1H), 8.35 (s, 1H), 8.22 (br s, 1H), 7.84 (s, 2H), 7.73 (s, 1H), 6.24 (br d, 1H), 4.26 (br d, 1H), 3.51-3.60 (m, 1H), 3.45-3.45 (m, 1H), 3.45 (br d, 1H), 3.41 (s, 3H). 123 (S)-4-amino-1-(2,6-dichloro-4-(dimethylamino)phenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B8, Intermediate A5 HPLC-1 (1%-70% MeCN); yellow solid (23.4 mg, 85%); LCMS m/z = 502 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.90 (s, 1H), 9.96 (br d, 1H), 8.59 (s, 1H), 8.39 (br d, 2H), 7.75 (s, 1H), 6.72 (s, 2H), 6.12 (br s, 1H), 3.85-3.80 (m, 1H), 3.14 (br d, 1H), 3.03 (s, 6H), 2.78 (dt, 1H), 1.98-1.92 (m, 1H), 1.89 (br t, 2H), 1.76 (br d, 1H), 1.74-1.63 (m, 2H), 1.55-1.48 (m, 1H). 124 (S)-4-amino-1-(2,6-dichloro-4-isopropoxyphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B31, Intermediate A5 HPLC-2 (5%-40% MeCN); white solid (34.1 mg, 75%); LCMS m/z = 517 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.91 (s, 1H), 9.63 (d, 1H), 8.78-8.72 (m, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.36 (s, 2H), 4.84 (td, 1H), 3.83 (d, 1H), 3.16 (d, 1H), 2.79 (t, 1H), 1.88-1.76 (m, 2H), 1.65 (s, 1H), 1.51 (d, 3H), 1.32 (d, 6H). 125 (R)-4-amino-1-(2,6-dimethyl-4-propoxyphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B26, Intermediate A4 HPLC-1 (5%-40% MeCN); yellow solid (26 mg, 57%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.06 (s, 1H), 9.94 (br.d, 1H), 8.68 (d, 1H), 8.36 (d, 1H), 8.24 (t, 1H), 7.77 (s, 1H), 6.76 (s, 2H), 5.95 (br.d, 1H), 3.96 (t, 2H), 3.72 (dd, 1H), 3.21 (br.d, 1H), 2.80 (td, 1H), 2.15 (s, 6H), 1.93 (br.d, 1H), 1.87-1.83 (m, 2H), 1.67 (br.d, 2H), 1.60-1.47 (m, 1H), 1.07 (t, 3H). 126 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dimethyl-4-propoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dimethyl-4-propoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B26, Intermediate A16 HPLC-1 (5%-35% MeCN); white solid (18.5 mg, 76%); LCMS m/z = 437 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 0.97 (t, 3H), 1.39 (d, 3H), 1.64-1.82 (m, 2 H), 2.05 (d, 6H), 3.86 (t, 2H), 4.14 (d, 1H), 5.86-6.17 (m, 1H), 6.66 (s, 2H), 7.67 (s, 1H), 8.20 (d, 2H), 8.53 (s, 1H), 9.79 (d, 1H), 12.00 (s, 1H). 127 4-amino-1-(2,6-dimethyl-4-propoxyphenyl)-N-(5-((methylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B26, Intermediate A56 HPLC-1 (1%-40% MeCN); white solid (39 mg, 62%); LCMS m/z = 437 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.11 (s, 1H), 9.88 (br.d, 1H), 8.58 (s, 1H), 8.39 (br.s, 1H), 8.31 (s, 1H), 7.75 (s, 1H), 6.73 (s, 2H), 6.12 (br.d, 1H), 3.97-3.87 (m, 4H), 2.48 (s, 3H), 2.13 (s, 6H), 1.86-1.76 (m, 2H), 1.05 (br.t, 3H). 128 (R)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(4-(difluoromethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B17, Intermediate A17 HPLC-1 (1%-30% MeCN); white solid (23.7 mg, 47%); LCMS m/z = 443 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 0.66-0.86 (m, 3H), 1.64-1.93 (m, 2H), 2.14 (d, 6H), 3.91 (s, 1H), 6.35 (s, 1H), 6.57 (t, 1H), 7.30 (s, 2H), 7.63 (s, 1H), 8.17 (s, 1H), 8.24 (s, 1H), 8.45 (s, 1H), 9.76 (d, 1H), 11.85 (s, 1H). 129 (R)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(2,6-dichloro-4-(ethoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(2,6-dichloro-4-(ethoxymethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B28, Intermediate A8 HPLC-1 (1%-40% MeCN); white solid (11.3 mg, 30%); LCMS m/z = 492 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 0.83 (t, 3H), 1.29 (t, 3H), 1.76-1.92 (m, 2H), 3.61 (q, 2H), 3.94 (t, 1H), 4.53 (s, 2H), 6.49 (s, 1H), 7.51 (s, 2H), 7.70 (s, 1H), 8.26 (d, 2H), 8.57 (d, 1H), 9.95 (d, 1H), 11.76 (s, 1H). 130 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B29, Intermediate A16 HPLC-1 (10%-30% MeCN); white solid (17.2 mg, 47%); LCMS m/z = 437 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.94 (s, 1H), 9.73 (d, 1H), 8.49 (s, 1H), 8.50-8.14 (m, 2H), 7.63 (s, 1H), 7.13 (s, 2H), 6.11 (d, 1H), 4.42 (s, 3H), 4.42-4.16 (m, 1H), 3.52 (q, 2H), 2.09 (d, 6H), 1.43 (s, 3H), 1.20 (t, 3H). 131 (R)-4-amino-1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B29, Intermediate A4 HPLC-3 (1%-30% MeCN); white solid (50.9 mg, 80%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.28 (t, 3H), 1.46-1.59 (m, 1H), 1.63-1.80 (m, 2H), 1.83-1.98 (m, 3H), 2.17 (s, 6H), 2.77 (td, 1H), 3.14 (d, 1H), 3.60 (q, 2H), 3.76-3.86 (m, 1H), 4.50 (s, 2H), 6.21 (d, 1H), 7.21 (s, 2 H), 7.71 (s, 1H), 8.32-8.40 (m, 2H), 8.58 (d, 1H), 9.90 (d, 1H), 12.02 (s, 1H). 132 (R)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-(ethoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B29, Intermediate A30 HPLC-1 (15%-45% MeCN); white solid (10.7 mg, 39%); LCMS m/z = 490 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.93 (s, 1H), 9.84 (d, 1H), 8.53 (d, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.64 (s, 1H), 7.14 (s, 2H), 5.98 (d, 1H), 4.43 (s, 2H), 3.91 (t, 1H), 3.52 (q, 2H), 3.14-2.96 (m, 1H), 2.92-2.79 (m, 1H), 2.10 (s, 6H), 1.99-1.90 (m, 2H), 1.88-1.76 (m, 2H), 1.75-1.47 (m, 4H), 1.21 (t, 3H). 133 (S)-4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A5 HPLC-1 (5%-45% MeCN); white solid (10.9 mg, 30%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.80 (s, 1H), 10.00 (d, 1H), 8.63 (s, 1H), 8.37 (br.s, 1H), 8.31 (s,1H), 7.72 (s, 1H), 7.04 (s, 2H), 6.15 (d, 1H), 4.09 (q, 2H), 3.79-3.74 (m, 1H), 3.19 (d, 2H), 2.83-2.75 (m, 1H), 2.03-1.87 (m, 2H), 1.87-1.82 (m, 1H), 1.80-1.75 (m, 1H), 1.73-1.68 (m, 2H), 1.46 (t, 3H). 134 (R)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A22 HPLC-1 (15%-45% MeCN); white solid (10.7 mg, 39%); LCMS m/z = 490 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.80 (s, 1H), 10.00 (d, 1H), 8.63 (s, 1H), 8.37 (br.s, 1H), 8.31 (s,1H), 7.72 (s, 1H), 7.04 (s, 2H), 6.15 (d, 1H), 4.09 (q, 2H), 3.79-3.74 (m, 1H), 3.19 (d, 2H), 2.83-2.75 (m, 1H), 2.03-1.87 (m, 2H), 1.87-1.82 (m, 1H), 1.80-1.75 (m, 1H), 1.73-1.68 (m, 2H), 1.46 (t, 3H). 135 (R)-N-(5-(1,4-oxazoloheptan-3-yl)pyridin-3-yl)-4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazoloheptan-3-yl)pyridin-3-yl)-4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A27 HPLC-1 (1%-40% MeCN); white solid (20.3 mg, 44%); LCMS m/z = 519 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.81 (s, 1H), 10.00 (d, 1H), 8.70 (d, 1H), 8.31 (d, 1H), 8.21 (s, 1H), 7.73 (s, 1H), 7.05 (s, 2H), 6.12 (d, 1H), 4.12-4.03 (m, 3H), 4.01-3.91 (m, 2H), 3.89-3.81 (m, 1H), 3.62 (dd, 1H), 3.22 (td, 1H), 3.04 (ddd, 1H), 2.12-1.94 (m, 2H), 1.46 (t, 3H). 136 (R)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A8 HPLC-3 (15%-35% MeCN); white solid (33.7 mg, 92%); LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.78 (s, 1H), 9.86 (d, 1H), 8.51 (s, 1H), 8.28-8.17 (m, 2H), 7.68 (s, 1H), 7.00 (s, 2H), 6.46 (d, 1H), 4.04 (q, 2H), 3.99-3.91 (m, 1H), 1.96-1.68 (m, 2H), 1.42 (t, 3H, J = 6.8 Hz), 0.80 (t, 3H). 137 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A16 HPLC-1 (10%-50% MeCN); white solid (21.9 mg, 65%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.87 (s, 1H), 9.63 (s, 1H), 8.77 (s, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.36 (s, 2H), 4.21 - 4.15 (m, 3H), 1.38-1.33 (m, 6H). 138 4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(((ethyl-d5)amino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A53 HPLC-1 (1%-40% MeCN); white solid (32.1 mg, 88%); LCMS m/z = 482 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.84 (s, 1H), 10.00 (br d, 1H), 8.60 (d, 1H), 8.43 (br s, 1H), 8.34 (s, 1H), 7.74 (s, 1H), 7.06 (s, 2H), 6.07 (d, 1H), 4.10 (q, 2H), 3.96 (s, 2H), 1.48 (t, 3H). 139 (R)-4-amino-N-(5-(amino(cyclopropyl)methyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(amino(cyclopropyl)methyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A9 HPLC-1 (15%-45% MeCN); yellow solid (36.4 mg, 50%); LCMS m/z = 489 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.81 (s, 1H), 9.82 (br s, 1H), 8.51 (s, 1H), 8.39 (br s, 1H), 8.31 (br s, 1H), 7.71 (s, 1H), 7.02 (s, 2H), 6.53 (br s, 1H), 4.07 (q, 2H), 3.41 (br d, 1H), 1.45 (t, 3H), 1.30 (br d, 1H), 0.68 (br s, 1H), 0.57-0.48 (m, 2H), 0.27 (br d, 1H). 140 (R)-4-amino-N-(5-(1-amino-2-ethoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-ethoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A10 HPLC-1 (10%-40% MeCN); white solid (32.4 mg, 97%); LCMS m/z = 507 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.84 (s, 1H), 9.95 (d, 1H), 8.66 (d, 1H), 8.34 (d, 2H), 7.74 (s, 1H), 7.06 (s, 2H), 6.17 (s, 1H), 4.32 (dd, 1H), 4.10 (q, 2H), 3.63-3.66 (m, 1H), 3.56 (dd, 3H), 1.48 (t, 3H), 1.21 (t, 3H). 141 (R)-4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(2-methoxy-1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A23 HPLC-1 (25%-65% MeCN); white solid (29.6 mg, 59%); LCMS m/z = 507 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.28 (s, 1H), 10.13 (d, 1H), 8.92-9.16 (m, 1H), 8.86 (s, 1H), 8.52-8.79 (m, 1H), 7.96 (s, 1H), 7.50 (s, 2H), 6.36-6.46 (m, 1H), 4.54 (s, 1H), 4.31 (q, 2H), 4.12-4.22 (m, 1H), 3.98-4.06 (m, 1H), 3.61 (s, 3H), 2.86 (s, 3H), 1.69 (t, 1H). 142 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A17 HPLC-1 (10%-40% MeCN); white solid (32.2 mg, 68%); LCMS m/z = 464 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.81 (s, 1H), 9.96 (br s, 1H), 8.62 (s, 1H), 8.32-8.26 (m, 2H), 7.74 (s, 1H), 7.06 (s, 2H), 6.23-6.15 (m, 1H), 4.27-4.12 (m, 1H), 4.10 (q, 2H), 3.62 -3.44 (m, 3H), 1.50-1.46 (m, 6H). 143 (R)-4-amino-N-(5-(1-amino-3,3-difluoropropyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-3,3-difluoropropyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A45 HPLC-1 (10%-40% MeCN); white solid (42.1 mg, 77%); LCMS m/z = 513 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.86 (s, 1H), 10.02 (d, 1H), 8.70 (d, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.75 (s, 1H), 7.07 (s, 2H), 6.09-5.76 (m, 2H), 4.25 (dd, 1H), 4.11 (q, 2H), 2.31-2.17 (m, 2H), 1.48 (t, 3H). 144 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B32, Intermediate A16 HPLC-1 (10%-40% MeCN); white solid (22.2 mg, 81%); LCMS m/z = 443 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.90 (s, 1H), 9.84 (d, 1H), 8.54 (s, 1H), 8.29-8.06 (m, 2H), 7.66 (s, 1H), 7.06 (s, 2H), 6.08-5.71 (m, 2H), 4.14 (s, 1H), 3.83-3.74 (m, 2H), 3.07 (td, 2H), 2.10 (d, 6H), 1.38 (s, 3H). 145 (R)-4-amino-1-mesityl-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B35, Intermediate A4 HPLC-3 (15%-40% MeCN); white solid (23.9 mg, 47%); LCMS m/z = 433 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.06 (s, 1H), 9.89 (br.d, 1H), 8.59 (br.s, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 7.07 (s, 2H), 5.98 (d, 1H), 3.96 (d, 1H), 3.16 (d, 1H), 2.93-2.77 (m, 1H), 2.38 (s, 3H), 2.17 (d, 6H), 2.09-1.92 (m, 3H), 1.91-1.71 (m, 2H), 1.68-1.49 (m, 1H). 146 (R)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-mesityl-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-mesityl-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B35, Intermediate A29 HPLC-1 (25%-65% MeCN); white solid (31.3 mg, 63%); LCMS m/z = 447 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.06 (s, 1H), 9.73 (br.d, 1H), 8.47 (br.s, 1H), 8.43 (s, 1H), 8.24 (br.s, 1H), 7.66 (s, 1H), 6.96 (s, 2H), 5.95 (br.d, 1H), 4.08 (br.d, 1H), 3.10-2.89 (m, 2H), 2.28 (s, 3H), 2.25-2.15 (m,1H), 2.05 (d, 6H), 1.98-1.83 (m, 3H), 1.79-1.50 (m, 4H). 147 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-mesityl-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-mesityl-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B35, Intermediate A16 HPLC-1 (1%-35% MeCN); white solid (37.9 mg, 70%); LCMS m/z = 393 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.99 (s, 1H), 9.73 (d, 1H), 8.46 (d, 1H), 8.46-8.20 (m, 3H), 7.65 (s, 1H), 6.95 (s, 2H), 6.43-6.41 (m, 1H), 6.31-6.26 (m, 1H), 6.39-6.17 (m, 1H), 4.19 (d, 1H), 2.26 (s, 3H), 2.04 (d, 6H,), 1.43 (d, 3H). 148 (R)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(azacycloheptane-2-yl)pyridin-3-yl)-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B58, Intermediate A29 HPLC-1 (15%-45% MeCN); pink solid (38.3 mg, 100%); LCMS m/z = 461 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.19 (t, 3H) 1.50-1.63 (m, 2H) 1.64-1.74 (m, 2H) 1.75-1.88 (m, 2H) 1.89-1.98 (m, 2H) 2.07 (s, 6H) 2.57 (q, 2H) 2.77-2.92 (m, 1H) 3.03 (d, 1H) 3.89 (t, 1H) 5.98 (d, 1H) 6.98 (s, 2H) 7.19 (s, 1H) 7.67 (s, 1H) 8.16-8.27 (m, 1H) 8.19-8.27 (m, 1H) 8.53 (d, 1H) 9.84 (d, 1H) 11.96 (s, 1H). 149 (S)-4-amino-1-(2,6-dichloro-4-fluorophenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide intermediate B39, intermediate A13 HPLC-2 (5%-35% MeCN); white solid (19.9 mg, 54%); LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.73 (s, 1H), 9.92 (br d, 1H), 8.62 (d, 1H), 8.41 (s, 2H), 7.70 (s, 1H), 7.31 (d, 2H), 6.25 (br d, 1H), 4.64-4.52 (m, 1H), 3.51-3.25 (m, 2H), 2.41 (dt, 1H), 2.28-2.17 (m, 2H), 2.16-2.02 (m, 1H). 150 (R)-4-amino-N-(5-(1-aminobut-3-yn-1-yl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminobut-3-yn-1-yl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A57B HPLC-1 (10%-50% MeCN); white solid (11.8 mg, 27%); LCMS m/z = 487 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.86 (s, 1H), 10.04 (d, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.77 (s, 1H), 7.08 (s, 2H), 6.18-6.09 (m, 1H), 4.26 (t, 1H), 4.12 (q, 2H), 2.69-2.53 (m, 2H), 2.10 (s, 1H), 1.50 (t, 3H). 151 (R)-4-amino-N-(5-(1-aminobut-3-yn-1-yl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminobut-3-yn-1-yl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A57A HPLC-1 (1%-40% MeCN); white solid (21.8 mg, 35%); LCMS m/z = 487 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.84 (s, 1H), 10.06 (d, 1H), 8.72 (d, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.76 (s, 1H), 7.07 (s, 2H), 6.11 (d, 1H), 4.23 (t, 1H), 4.11 (q, 2H), 2.66-2.52 (m, 2H), 2.08 (s, 1H), 1.49 (t, 3H). 152 (R)-4-amino-1-(3,5-dichloropyridin-4-yl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B52, Intermediate A4 HPLC-2 (5%-35% MeCN); white solid (46.6 mg, 43%); LCMS m/z = 460 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.60 (s, 1H), 9.71 (d, 1H), 8.98 (s, 2H), 8.88 (d, 1H), 8.63 (d, 1H), 8.47 (s, 1H), 8.24 (d, 1H), 8.05 (s, 1H), 3.60-3.52 (m, 1H), 3.02 (d, 1H), 2.68-2.58 (m, 1H), 1.78 (d, 1H), 1.69 (d, 1H), 1.55 (d, 1H), 1.49-1.35 (m, 2H), 1.34-1.22 (m, 1H). 153 (R)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(3,5-dichloropyridin-4-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminopropyl)pyridin-3-yl)-1-(3,5-dichloropyridin-4-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B52, Intermediate A60 HPLC-15 (20%-40% MeCN); white solid (12.5 mg, 30%); LCMS m/z = 434 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.59 (s, 1H), 9.72 (br d, 1H), 8.99 (s, 2H), 8.88 (br d, 1H), 8.71 (d, 1H), 8.48 (s, 1H), 8.23 (d, 1H), 7.95 (t, 1H), 3.72 (t, 1H), 1.94 (br s, 2H), 1.65-1.50 (m, 2H), 0.78 (t, 3H). 154 4-amino-1-(2,6-dichloro-4-(2-methoxyethyl)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B49, Intermediate A24 HPLC-1 (1%-40% MeCN); white solid (28.3 mg, 76%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.71 (s, 1H), 9.91 (br d, 1H), 8.50 (d, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.63 (s, 1H), 7.34 (s, 2H), 5.98 (br d, 1H), 3.89 (s, 2H), 3.58 (t, 2H), 3.30 (s, 3H), 2.84 (t, 2H), 2.79-2.70 (m, 2H), 1.12 (t, 3H). 155 (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-(2-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-(2-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B33, Intermediate A16 HPLC-7 (1%-25% MeCN); white solid (18.5 mg, 40%); LCMS m/z = 425 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.04-12.00 (m, 1H), 9.83 (br s, 1H), 8.56 (br s, 1H), 8.36-8.31 (m, 2H), 7.76 (d, 1H), 7.31 (d, 1H), 7.31-7.30 (m, 1H), 6.36 (br d, 1H), 6.09-5.73(m, 2H), 4.77-4.63 (m, 2H), 4.36-4.24 (m, 1H), 3.08-3.29 (m, 2H), 2.18 (d, 6H), 1.54-1.49 (m, 3H). 156 4-amino-1-(4-(2,2-difluoroethyl)-2,6-dimethylphenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B32, Intermediate A24 HPLC-1 (20%-60% MeCN); yellow solid (18.9 mg, 69%); LCMS m/z = 457 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.99 (s, 1H), 9.91 (d, 1H), 8.57 (d, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.73 (s, 1H), 7.13 (s, 2H), 6.13-5.82 (m, 2H), 3.95 (s, 2H), 3.15 (dt, 2H), 2.84 (q, 2H), 2.17 (s, 6H), 1.18 (t, 3H). 157 4-amino-N-(5-(1-aminocyclobutyl)pyridin-3-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A51 HPLC-7 (1%-40% MeCN); white solid (23.6 mg, 57%); LCMS m/z = 449 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.92 (s, 1H), 9.89 (d, 1H), 8.65 (d, 1H), 8.34 (s, 1H), 8.05 (br s, 1H), 7.66 (s, 1H), 7.14 (s, 2H), 5.88 (d, 1H), 4.39 (s, 2H), 3.37 (s, 3H), 2.53-2.45 (m, 2H), 2.20-2.14 (m, 2H), 2.11 (s, 6H), 2.06-1.98 (m, 1H), 1.78-1.67 (m, 1H). 158 (R)-4-amino-1-(2,6-dimethyl-4-((methylsulfonyl)methyl)phenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B53, Intermediate A4 HPLC-1 (15%-40% MeCN); white solid (12 mg, 14%); LCMS m/z = 511 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.95 (s, 1H), 9.61 (d, 1H), 8.57-8.50 (m, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.64 (s, 1H), 7.23 (s, 2H), 5.90 (d, 1H), 4.24-4.16 (m, 2H), 4.05-3.94 (m, 1H), 3.26 (d, 1H), 2.94-2.87 (m, 1H), 2.84 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 2.05-1.85 (m, 4H), 1.81-1.67 (m, 1H), 1.62-1.44 (m, 1H). 159 (R)-4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(5-oxohexahydropyrazin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(5-oxohexahydropyrazin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A74 HPLC-1 (1%-25% MeCN); white solid (14.2 mg, 52%); LCMS m/z = 478 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.05 (s, 1H), 9.84 (br d, 1H), 8.59 (s, 1H), 8.29 (br d, 2H), 7.66 (s, 1H), 7.14 (s, 2H), 6.10 (br d, 2H), 4.39 (s, 2H), 4.06 (br t, 1H), 3.67 (br d, 2H), 3.37-3.39 (m, 5H), 2.10 (s, 6H). 160 (R)-4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(5-oxohexahydropyrazin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(5-oxohexahydropyrazin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B22, Intermediate A74 HPLC-1 (1%-30% MeCN); white solid (16.1 mg, 59%); LCMS m/z = 478 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.04 (s, 1H), 9.84 (br d, 1H), 8.58 (d, 1H), 8.32-8.25 (m, 2H), 7.66 (s, 1H), 7.14 (s, 2H), 6.09 (br s, 2H), 4.39 (s, 2H), 4.06 (t, 1H), 3.75-3.61 (m, 2H), 3.42-3.34 (m, 5H), 2.10 (s, 6H). 161 (R)-4-amino-1-(4-fluoro-2,6-dimethylphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate intermediate B50, intermediate A4 HPLC-12 (10%-40% MeCN); white solid (16.1 mg, 59%); LCMS m/z = 437 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 12.23 (s, 1H), 9.50 (d, 1H), 9.01-8.85 (m, 2H), 8.75-8.64 (m, 1H), 8.61 (d, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.16 (d, 2H), 4.31 (t, 1H), 3.37 (d, 1H), 3.05 (q, 1H), 2.09 (s, 6H), 1.96 (d, 1H), 1.92-1.78 (m, 3H), 1.74-1.56 (m, 2H). 162 (R)-4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-6-thionyl-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate intermediate B56, intermediate A4 HPLC-12 (10%-40% MeCN); white solid (18.9 mg, 34%); LCMS m/z = 503 [M+H] ⁺ ; ¹ H NMR (500 MHz, CDCl ₃ ): 14.48 (s, 1H), 10.46 (s, 1H), 10.02 (s, 1H), 9.62 (s, 2H), 8.85 (s, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 7.79 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 6.56 (s, 1H), 4.28 (d, 1H), 3.51 (d, 1H), 3.23 - 2.99 (m, 1H), 2.26 (s, 3H), 2.14 (s, 3H), 2.13-1.83 (m, 5H), 1.67 (q, 1H). 163 (R)-4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-6-thionyl-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate intermediate B57, intermediate A4 HPLC-12 (10%-40% MeCN); white solid (10.8 mg, 38%); LCMS m/z = 479 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 12.81 (s, 1H), 8.86 (d, 1H), 8.80 (s, 1H), 8.73 (q, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.11 (s, 2H), 5.68 (s, 2H), 4.35 (s, 2H), 4.27 (t, 1H), 3.27 (s, 3H), 3.02 (t, 1H), 1.99 (s, 6H), 1.93-1.73 (m, 4H), 1.69-1.52 (m, 2H). 164 4-amino-1-((S)-2-chloro-6-methylphenyl)-N-(3-methoxy-2-(2-(methylamino)ethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B3, Intermediate A64 HPLC-14 (33%-53% MeCN); yellow solid (31.4 mg, 57%); LCMS m/z = 442 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOH-d ₄ ): 11.69 (s, 1H), 8.08 (s, 1H), 7.57 (d, 1H), 7.54-7.48 (m, 1H), 7.46 (t, 1H), 7.43-7.38 (m, 1H), 7.29 (t, 1H), 6.87 (d, 1H), 3.88 (s, 3H), 3.16-3.10 (m, 2H), 3.08-3.00 (m, 2H), 2.61 (s, 3H), 2.26 (s, 3H). 165 4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, Intermediate A66 HPLC-12 (10%-40% MeCN); white solid (41 mg, 51%); LCMS m/z = 555 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 12.01 (s, 1H), 9.57 (d, 1H), 9.08 (s, 2H), 8.86 (d, 1H), 8.79 (d, 1H), 8.43 (s, 1H), 8.38 (d, 1H), 8.29 (t, 1H), 7.35 (s, 2H), 4.26 (s, 2H), 4.18 (q, 2H), 3.53 (dd, 2H), 3.42 (s, 2H), 3.13 (s, 3H), 1.36 (t, 3H). 166 (S)-4-amino-1-(2-methoxyphenyl)-N-(2-oxolinyl-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2-methoxyphenyl)-N-(2-oxolinyl-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide intermediate B59, intermediate A75 HPLC-16 (15%-45% MeCN); yellow solid (14.4 mg, 16%); LCMS m/z = 491 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.21 (s, 1H), 10.03 (d, 1H), 8.15 (dd, 1H), 7.83 (s, 1H), 7.50-7.48 (m, 1H), 7.30 (dd, 1H), 7.23-7.20 (m, 2H), 7.10-7.08 (m, 2H), 5.76 (d, 1H), 4.51 (t, 1H), 3.95-3.92 (m, 2H), 3.87 (s, 3H), 3.70 (dd, 2H), 3.27-3.25 (m, 3H), 3.01-2.96 (m, 1H), 2.93 (d, 2H), 2.26-2.20 (m, 1H), 1.90-1.88 (m, 2H), 1.68-1.65 (m, 1H). 167 (S)-4-amino-1-(2,6-dichlorophenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2,6-dichlorophenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B9, Intermediate A76 HPLC-1 (5%-35% MeCN); yellow solid (7.1 mg, 31%); LCMS m/z = 462 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.83 (s, 1H), 10.08 (s, 1H), 8.30 (t, 1H), 7.73 (s, 1H), 7.55 (d, 2H), 7.46-7.42 (m, 1H), 7.16-7.09 (m, 2H), 6.03 (s, 1H), 4.52-4.50 (m, 1H), 3.22-3.14 (m, 2H), 2.27 (s, 1H), 1.96-1.80 (m, 3H). 168 (S)-4-amino-1-(2,6-dichlorophenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2,6-dichlorophenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B9, Intermediate A77 HPLC-16 (30%-60% MeCN); yellow solid (3.4 mg, 16%); LCMS m/z = 462 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.70 (s, 1H), 10.00 (s, 1H), 8.18 (t, 1H), 7.64 (s, 1H), 7.45 (d, 2H), 7.37-7.33 (m, 1H), 7.09-6.99 (m, 2H), 5.90 (s, 1H), 4.38-4.34 (m, 1H), 3.12-2.96 (m, 2H), 2.19-2.11 (m, 1H), 1.86-1.79 (m, 3H). 169 (R)-4-amino-1-(2,6-dichlorophenyl)-N-(2-methoxy-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichlorophenyl)-N-(2-methoxy-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B9, Intermediate A81 Chiral SFC (Rilas Technologies, Regis Whelk O-1 (S,S) 250 × 21 mm, 30% EtOH + 0.25% diethylamine in CO ₂ (Medium) HPLC-1 (1%-50% MeCN); white solid (15 mg); LCMS m/z = 474 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 11.92 (s, 1H), 9.74 (d, 1H), 8.60 (d, 1H), 8.40 (s, 1H), 8.22 (dd, 1H), 7.77 (d, 2H), 7.64 (dd, 1H), 7.19 (dd, 1H), 7.05 (t, 1H), 4.27 (t, 1H), 3.63 (s, 3H), 3.07-2.97 (m, 1H), 2.87 (q, 1H), 2.11 (dq, 1H), 1.85 - 1.66 (m, 2H), 1.47-1.36 (m, 1H). 170 4-amino-N-(3-(aminomethyl)-2-(difluoromethoxy)phenyl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate intermediate B9, intermediate A84 HPLC-12 (10%-50% MeCN); white solid (3.4 mg, 5%); LCMS m/z = 470 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 11.95 (s, 1H), 9.62 (d, 1H), 8.71 (d, 1H), 8.42 (s, 1H), 8.37 (d, 1H), 8.16 (s, 3H), 7.77 (d, 2H), 7.64 (t, 1H), 7.41 (t, 1H), 7.28 (d, 1H), 7.01 (t, 1H), 4.05 (q, 2H). 171 4-amino-N-(3-(aminomethyl)-2-(trifluoromethyl)phenyl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B9, Intermediate A78 HPLC-1 (10%-40% MeCN); white solid (6.6 mg, 36%); LCMS m/z = 472 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.61 (br d, 1H), 9.62 (br s, 1H), 8.67 (br s, 1H), 8.53-8.31 (m, 1H), 7.75 (d, 2H), 7.74-7.67 (m, 1H), 7.65-7.60 (m, 1H), 7.55 (d, 1H), 3.90 (d, 2H). 172 (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(6-(hexahydropyridin-2-yl)pyridazin-4-yl)-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-N-(6-(hexahydropyridin-2-yl)pyridazin-4-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, Intermediate A79 HPLC-2 (5%-35% MeCN); brown solid (13.7 mg, 51%); LCMS m/z = 490 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.07 (s, 1H), 9.89 (d, 1H), 9.17 (d, 1H), 8.10 (d, 1H), 7.75 (s, 1H), 7.07 (s, 2H), 6.28 (d, 1H), 4.14-4.07 (m, 1H), 3.89 (s, 3H), 3.31 (d, 1H), 2.96-2.87 (m, 1H), 2.03 (d, 1H), 1.94 (s, 1H), 1.72 (s, 1H), 1.66 (d, 1H), 1.63-1.55 (m, 2H). 173 (S)-4-amino-1-(2-chloro-6-hydroxyphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B60, Intermediate A5 HPLC-1 (1%-40% MeCN); yellow oil (8.7 mg, 45%); LCMS m/z = 441 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.09-12.04 (m, 1H), 9.53 (br d, 1H), 8.72-8.68 (m, 1H), 8.54 (br d, 1H), 8.28-8.26 (m, 2H), 8.12 (s, 1H), 7.37-7.31 (m, 1H), 7.08-7.01 (m, 2H), 3.80 (br d, 2H), 3.13 (br d, 1H), 2.80-2.72 (m, 1H), 1.84-1.74 (m, 2H), 1.62 (br s, 1H), 1.49 (br d, 3H). Examples 174 and 175.4-amino-N-(5-((R)-1-aminoethyl)pyridin-3-yl)-1-(4-((R)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-1-aminoethyl)pyridin-3-yl)-1-(4-((R)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -Synthesis of amino-N-(5-((R)-1-aminoethyl)pyridin-3-yl)-1-(4-((S)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-1-aminoethyl)pyridin-3-yl)-1-(4-((S)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1.AlMe was added to a mixture of 4-amino-1-(4-(1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (intermediate B51, 50 mg, 0.151 mmol) and (S)-(1-(5-aminopyridin-3-yl)ethyl)carbamic acid tert-butyl ester or (R)-(1-(5-aminopyridin-3-yl)ethyl)carbamic acid tert-butyl ester (intermediate A16, 53.7 mg, 0.226 mmol) in toluene (3 mL) at 0°C.₃(2 M in toluene, 0.226 mL), and the mixture was heated under N ₂Stir at 40 °C for 1 h. Dilute the reaction mixture with 1 M NaOH (20 mL) and extract with EtOAc (3× 20 mL). Wash the combined organics with brine (2× 10 mL), dry (Na ₂SO ₄) and concentrated under reduced pressure to obtain a residue. By prep-TLC (50% EtOAc/PE), followed by prep-SFC (DAICEL CHIRALPAK IE, 250 × 30 mm, 10 μm); 40% [heptane-(4:1 IPA:MeCN)] in CO ₂The residue was purified by HPLC to obtain peak 1 (10 mg, 12%) as a white solid and peak 2 (10 mg, 12%) as a white solid, which were independently subjected to the next step. Step 2a. 4-amino-N-(5-((R)-1-aminoethyl) Pyridine Pyridine -3- 1-(4-((R)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-1-aminoethyl) Pyridine Pyridine -3- 1-(4-((R)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((R)-1-aminoethyl) Pyridine Pyridine -3- 1-(4-((S)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-1-aminoethyl) Pyridine Pyridine -3- Synthesis of 1-(4-((S)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

Peak 1 compound (Fraction 1 Peak 1, 10 mg, 18.64 μmol) was stirred in DCM (2 mL) and TFA (2 mL) at 25 °C for 0.5 h, and the reaction mixture was concentrated under _N2 and reduced pressure. The residue was purified by prep-HPLC-1 (1%-50% MeCN) to give Example 174. White solid (4.2 mg, 46%). LCMS m/z = 437 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.46 (d, 3H), 1.53 (br d, 3H), 2.19 (d, 6H), 3.31 (s, 3H), 4.31 (q, 2H), 6.26 (br d, 1H), 7.18 (br d, 2H), 7.75 (s, 1H), 8.33 (br d, 3H), 8.58 (s, 1H), 9.85 (br s, 1H), 12.03 (s, 1H). Step 2b. 4-amino-N-(5-((R)-1-aminoethyl) pyridin -3- yl)-1-(4-((R)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-1-aminoethyl) pyridin -3- yl)-1-(4-((R)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or -Synthesis of amino-N-(5-((R)-1-aminoethyl) pyridin -3- yl)-1-(4-((S)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-(5-((S)-1-aminoethyl) pyridin -3- yl)-1-(4-((S)-1-methoxyethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Peak 2 compound (fraction 1, peak 2) was deprotected in a manner similar to that described for peak 1 to afford Example 175. White solid (4.2 mg, 46%). LCMS m/z = 437 [M+H] ⁺ ;] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.37 (d, 3 H) 1.46 (br d, 3 H) 2.10 (d, 6 H) 3.21 (s, 3 H) 4.13-4.33 (m, 2 H) 6.19 (br s, 1 H) 7.08 (s, 2 H) 7.65 (s, 1 H) 8.26 (br d, 2 H) 8.47 (s, 1 H) 9.74 (br s, 1 H) 11.93 (s, 1 H). Example 176. Synthesis of (R)-4-amino-N-(5-(1-aminobutyl)pyridin-3-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of tert-butyl (R)-(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)butyl)carbamate .

_AlMe3 (2 M, 142 μL) was added dropwise to a solution of methyl 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B22, 30 mg, 0.095 mmol) and tert-butyl (R)-(1-(5-aminopyridin-3-yl)butyl)carbamate (Intermediate A7, 37.6 mg, 0.142 mmol) in toluene (2 mL) at 0°C, and the mixture was stirred under _N2 at 40°C for 1 h. The reaction mixture was quenched with 1 N aqueous NaOH (2 mL) at 0°C and extracted with EtOAc (4 x 5 mL). The combined organics were washed with brine (5 mL) and dried ( _Na2SO4 ) and evaporated to dryness _to give the title compound as a yellow oil (50 mg, crude). LCMS m/z = 551 [M+H] ⁺ ; Step 2. Synthesis of (R)-4-amino-N-(5-(1-aminobutyl) pyridin -3- yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

(R)-tert-butyl(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)butyl)carbamate (Part 1, 50 mg, 0.091 mmol) was dissolved in DCM (1 mL) and TFA (1 mL), and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-8 (20%-55% MeCN) to give the title compound (12.3 mg, 27%) as a light yellow solid. LCMS m/z = 451 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 0.91 (t, 3H) 1.19-1.39 (m, 2H) 1.67 (d, 2H) 2.18 (s, 6 H) 3.45 (s, 3H) 3.94 (t, 1H) 4.46 (s, 2 H) 6.07 (br d, 1H) 7.21 (s, 2H) 7.73 (s, 1H) 8.12 (s, 1H) 8.26 (s, 1H) 8.67 (d, 1H) 9.97 (d, 1H) 12.01 (s, 1H). Example 177. Synthesis of (S)-4-amino-N-(5-(1-amino-2-ethoxyethyl)pyridin-3-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(1-amino-2-ethoxyethyl)pyridin-3-yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (S)-t-butyl(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)-2-ethoxyethyl)carbamate or (R)-t-butyl(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)-2-ethoxyethyl)carbamate .

To a solution of methyl 4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (intermediate B22, 50 mg, 0.158 mmol) and tert-butyl (S)-(1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate or (R)-tert-butyl (1-(5-aminopyridin-3-yl)-2-ethoxyethyl)carbamate (intermediate A11, 66.5 mg, 0.236 mmol) in toluene (3 mL) was added _AlMe3 (2 M in toluene, 394 μL) at 0 °C and the mixture was stirred at 60 °C for 1 h under _N2 . The reaction mixture was quenched by adding H ₂ O (0.5 mL) and TFA (0.5 mL) at 0° C., filtered and concentrated under reduced pressure to give the title compound (75 mg, 0.132 mmol, 84%) as a white solid. LCMS m/z = 451 [M+H] ⁺ . Step 2. Synthesis of (S)-4-amino-N-(5-(1-amino-2-ethoxyethyl) pyridin -3 -yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(1-amino-2-ethoxyethyl) pyridin -3 -yl)-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

A mixture of (S)-tert-butyl(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-ethoxyethyl)carbamate or (R)-tert-butyl(1-(5-(4-amino-1-(4-(methoxymethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-ethoxyethyl)carbamate (Step 1, 70 mg, 0.124 mmol) in DCM (1 mL) and TFA (2 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under N ₂ , and the residue was purified by prep-HPLC-9 (10%-45% MeCN) to give the title compound (9.90 mg, 16%) as a brown solid. LCMS m/z = 467 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.95 (s, 1H) 9.84 (d, 1H) 8.62 (d, 1H) 8.25 (s, 1H) 8.17 (s, 1H) 7.66 (s, 1H) 7.13 (s, 2H) 5.94 (d, 1H) 4.39 (s, 2 H) 4.18 (dd, 1H) 3.40-3.55 (m, 4 H) 3.37 (s, 3H) 2.10 (s, 6H) 1.13 (t, 3H). Example 178. Synthesis of 4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

_AlMe3 (2 M in toluene, 209 μL) was added to a mixture of methyl 4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B30, 50 mg, 0.140 mmol) and 5-((ethylamino)methyl)pyridin-3-amine (Intermediate A12, 31.7 mg, 0.209 mmol) in toluene (2 mL), and the mixture was stirred at 0 °C for 5 min, and then at 100 °C for 0.5 h under _N2 . The reaction mixture was quenched by the addition of 1 N aqueous NaOH (2 mL) at 0 °C, and extracted with EtOAc (4 x 5 mL). The combined organics were washed with saturated aqueous NaCl (5 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by prep-HPLC-8 (5%-40% MeCN) to give the title compound (45.2 mg, 61%,) as a white solid. LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.84 (s, 1H), 9.96 (d, 1H), 8.58 (d, 1H), 8.47-8.41 (m, 2H), 8.32 (s, 1H), 7.72 (s, 1H), 7.04 (s, 2H), 6.20 (d, 1H), 4.08 (q, 2H), 3.97 (s, 2H), 2.83 (q, 2H), 1.46 (t, 3H), 1.26-1.15 (m, 3H). Example 179. Synthesis of 4-amino-N-(5-(1-aminocyclobutyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of tert-butyl (1-(5-(4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)cyclobutyl)carbamate .

AlMe ₃ ( ₂ M, 262 uL) was added to a solution of methyl 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B10, 60.0 mg, 0.174 mmol) and tert-butyl (1-(5-aminopyridin-3-yl)cyclobutyl)carbamate (Intermediate A51, 51.0 mg, 0.192 mmol) in toluene (15 mL) under N 2 at 0 °C, and the mixture was heated at 80 °C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3× 30 mL). The combined organics were dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO ₂ , 50% EtOAc/PE) to give the title compound as a yellow solid (30 mg, 30%). LCMS m/z = 575 [M+H] ⁺ . Step 2. Synthesis of 4-amino-N-(5-(1-aminocyclobutyl) pyridin -3- yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

A mixture of tert-butyl (1-(5-(4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)cyclobutyl)carbamate (30.0 mg, 52.1 μmol) in hydrochloric acid/dioxane (4 M, 6 mL) was stirred at 25 °C for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-1 (12%-42% MeCN) to give the title compound (8.20 mg, 30% yield) as a white solid. LCMS m/z = 475 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOH-d ₄ ): 8.81-8.77 (m, 1H), 8.53 (s, 1H), 8.40-8.35 (m, 1H), 8.22 (t, 1H), 8.08 (s, 1H), 7.23 (s, 2H), 3.90 (s, 3H), 2.73-2.62 (m, 2H), 2.46-2.38 (m, 2H), 2.23-2.12 (m, 1H), 1.96-1.82 (m, 1H). Example 180. Synthesis of 4-amino-1-(2,6-dichlorophenyl)-N-(3-((2R,5R)-5-methylpyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichlorophenyl)-N-(3-((2S,5S)-5-methylpyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

A dry flask containing methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 50.3 mg, 0.160 mmol) and tert-butyl rel-(2S,5S)-2-(3-aminophenyl)-5-methylpyrrolidine-1-carboxylate (Intermediate A72, 64.1 mg, 0.192 mmol) was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) was added and the solution was cooled to 0 °C and trimethylaluminum solution (2.0 M in toluene, 0.240 mL, 0.480 mmol) was added. The flask was removed from the ice bath and the reaction was stirred at room temperature for 10 min and then heated to 100 °C for 1 h. The reaction was cooled to room temperature, quenched with methanol (2 mL) and TFA (0.2 mL), poured into water (30 mL) and extracted with DCM (4 x 10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, water and brine, dried (MgSO ₄ ) and evaporated to dryness in vacuo. The residue was dissolved in DCM (2 mL) and TFA (1 mL) and the solution was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness and the residue was purified by prep-HPLC-10 (10%-60%) followed by chiral SFC (Regis Whelk O-1 (S,S) 4.6 × 100 mm, 3 μm; 45% EtOH + 0.25% diethylamine in CO ₂ ) to give: Peak 1, Example 180. 4-Amino-1-(2,6-dichlorophenyl)-N-(3-((2R,5R)-5-methylpyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichlorophenyl)-N-(3-((2S,5S)-5-methylpyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (white powder, 17.9 mg). LCMS m/z = 458 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 11.90 (s, 1H), 9.68 (d, 1H), 9.43 (s, 1H), 8.73 (d, 1H), 8.46 (s, 1H), 8.43-8.28 (m, 1H), 7.84 (dd, 1H), 7.77 (d, 2H), 7.71-7.58 (m, 2H), 7.40 (t, 1H), 7.15 (d, 1H), 4.68-4.55 (m, 1H), 3.81-3.65 (m, 1H), 2.40 (ddt, 1H), 2.25 (dq, 1H), 2.13 (dtd, 1H), 1.72 (dq, 1H), 1.34 (d, 3H). Examples 181 to 186

The title compound was prepared using a 2-step procedure analogous to that described for Example 179 from the appropriate ester and the appropriate amine. Instance Number Name, Structure, Starting Material (SM), Data 181 4-amino-N-(5-(1-aminocyclopropyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, intermediate A40 HPLC-1 (10%-40% MeCN); white solid (9.7 mg, 24%); LCMS m/z = 461 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOH-d ₄ ): 8.70 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 8.06-8.03 (m, 1H), 7.22 (s, 2H), 3.90 (s, 3H), 1.18-1.13 (m, 2H), 1.11-1.05 (m, 2H). 182 4-amino-N-(5-(4-aminotetrahydro-2H-pyran-4-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B10, intermediate A63 HPLC-2 (9%-39% MeCN); white solid (10.1 mg, 48%); LCMS m/z = 505 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.82 (s, 1H), 9.79-9.49 (m, 1H), 8.77 (s, 1H), 8.74-8.66 (m, 1H), 8.45 (s, 1H), 8.40 (d, 1H), 8.04 (d, 1H), 7.37 (d, 2H), 3.89 (s, 3H), 3.87-3.81 (m, 2H), 3.62 (d, 2H), 2.00-1.92 (m, d, 2H). 183 4-amino-N-(5-(1-aminocyclobutyl)pyridin-3-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Intermediate B30, intermediate A51 HPLC-5 (30%-50% MeCN); white solid (20 mg, 80%); LCMS m/z = 489 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOH-d ₄ ): 12.16 (s, 1H), 8.93 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 7.22 (s, 2H), 4.18-4.11 (m, 2H), 2.91-2.79 (m, 2H), 2.70-2.60 (m, 2H), 2.34-2.20 (m, 1H), 2.13-1.90 (m, 1H), 1.47-1.40 (t, 3H). 184 4-amino-1-(4-((R)-1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-((S)-1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide or Intermediate B54, intermediate A4 HPLC-13 (35%-60% MeCN); yellow solid (20.4 mg, 58%); LCMS m/z = 465 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.96 (s, 1H), 10.11-9.89 (m, 1H), 8.70 (d, 1H), 8.34 (d, 1H), 8.19 (s, 1H), 7.74 (s, 1H), 7.25 (s, 1H), 7.21 (s, 1H), 5.97 (d, 1H), 5.77-5.51 (m, 1H), 3.73-3.65 (m, 1H), 3.21 (d, 1H), 2.27-2.17 (m, 6H), 1.92 (d, 2H), 1.87-1.78 (m, 2H), 1.71 (d, 2H), 1.65 (d, 1H), 1.63-1.47 (m, 3H). 185 4-amino-1-(4-((R)-1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(4-((S)-1-fluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-((R)-hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide or Intermediate B54, intermediate A4 HPLC-13 (30%-60% MeCN); gray solid (9.6 mg, 27%); LCMS m/z = 465 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.87 (s, 1H), 9.92 (d, 1H), 8.62 (d, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 7.65 (s, 1H), 7.16 (s, 1H), 7.12 (s, 1H), 5.93 (d, 1H), 5.65-5.46 (m, 1H), 3.59-3.54 (m, 1H), 3.12 (d, 1H), 2.75-2.67 (m, 1H), 2.12 (d, 6H), 1.71 (s, 2H), 1.62 (d, 2H), 1.56 (d, 2H), 1.49-1.40 (m, 3H). 186 (R)-4-amino-1-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide Intermediate B55, Intermediate A4 HPLC-13 (25%-65% MeCN); gray solid (47.7 mg, 93%); LCMS m/z = 483 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.93 (s, 1H), 10.04 (d, 1H), 8.70 (d, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 7.74 (s, 1H), 7.40 (s, 2H), 6.25 (d, 1H), 3.67 (d, 1H), 3.23 (d, 1H), 2.81 (t, 1H), 2.25 (s, 6H), 1.97 (t, 6H), 1.82 (d, 1H), 1.73-1.65 (m, 1H), 1.61-1.49 (m, 3H). Examples 187 and 188. Synthesis of (R)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide and (S)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

To a mixture of 4-amino-1-(2,6 _- dichloro-4-methoxy-phenyl)-6-oxo-pyrimidine-5-carboxylic acid methyl ester (Intermediate B10, 60 mg, 0.174 mmol) and _5- (3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-amine (Intermediate A55, 40.4 mg, 0.209 mmol) in toluene (2 mL) was added AlMe 3 (2 M, 0.26 mL) under N ₂ at 0° C., and the mixture was stirred at 100° C. under N 2 for 0.5 h. The reaction mixture was quenched by H ₂ O (0.2 mL) and TFA (0.2 mL), and the mixture was purified by prep-HPLC-1 (5%-40% MeCN). The residue was further separated by SFC (DAICEL CHIRALCEL OX, 250 × 30 mm, 10 μm); 55% EtOH (+0.1% NH4OH)) to obtain: Peak 1, Example 187. (R)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. White solid (20.1 mg, 21%). LCMS m/z = 505 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.70 (s, 1H), 9.98 (d, 1H), 8.70 (d, 1H), 8.48 (d, 1H), 8.23 (t, 1H), 7.66 (s, 1H), 6.99 (s, 2H), 5.96 (d, 1H), 3.86-3.80 (m, 4H), 3.67 (d, 1H), 3.53-3.46 (m, 2H), 2.06 (d, 1H), 1.91-1.82 (m, 1H), 1.74-1.71 (m, 1H), 1.54-1.47 (m, 1H). Peak 2, Example 188. (R)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(3-aminotetrahydro-2H-pyran-3-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. White solid (14.5 mg, 44%). LCMS m/z = 505 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.81 (s, 1H), 10.09 (d, 1H), 8.81 (d, 1H), 8.58 (d, 1H), 8.33 (t, 1H), 7.77 (s, 1H), 7.10 (s, 2H), 6.05 (d, 1H), 3.96-3.91 (m, 4H), 3.77 (d, 1H), 3.63-3.59 (m, 2H), 2.17-2.12 (m, 1H), 2.03 (s, 1H), 1.85-1.81 (m, 1H), 1.64-1.58 (m, 1H). Examples 189 and 190. Synthesis of (R)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-N-(3-(5-oxohexahydropyrazin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide and (S)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-N-(3-(5-oxohexahydropyrazin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide

The title compound was prepared from methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B9) and 5-(3-aminophenyl)hexahydropyrazin-2-one (Intermediate A18) using a method similar to that described for Examples 179 and 180. SFC (DAICEL CHIRALPAK IH-3, 50 × 4.6 mm, 3 μm); MeOH (+0.1% isopropylamine)) gave: Peak 1, Example 189. (R)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-N-(3-(5-oxo-hexahydropyrazin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-N-(3-(5-oxo-hexahydropyrazin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide. Yellow solid (59.5 mg, 74%). LCMS m/z = 473 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.78 (s, 1H), 9.74 (br d, 1H), 8.74-8.71 (m, 1H), 8.46 (s, 1H), 7.82-7.77 (m, 3H), 7.65-7.60 (m, 3H), 7.29 (t, 1H), 7.13 (br d, 1H), 3.90-3.88 (m, 1H), 3.36 (s, 3H), 3.31-3.27 (m, 2H), 3.13-3.08 (m, 1H), 2.96 (br s, 1H). Peak 2, Example 190. (R)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-N-(3-(5-oxohexahydropyrazin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-N-(3-(5-oxohexahydropyrazin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide. White solid (42.8 mg, 53%). LCMS m/z = 473 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.76 (s, 1H), 9.72 (br d, 1H), 8.69 (br d, 1H), 8.43 (s, 1H), 7.78-7.74 (m, 3H), 7.66-7.57 (m, 3H), 7.27 (t, 1H), 7.10 (d, 1H), 3.88 (dd, 1H), 3.31-3.24 (m, 3H), 3.12-3.06 (m, 1H). Example 191. Synthesis of 4-amino-1-(2,6-dichlorophenyl)-N-(3-((2R,5R)-5-(hydroxymethyl)pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichlorophenyl)-N-(3-((2S,5S)-5-(hydroxymethyl)pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

Methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 51 mg, 0.160 mmol) and tert-butyl 2-(3-aminophenyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylate (Intermediate A65, 55.8 mg, 0.192 mmol) were evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) was added and the solution was cooled to 0 °C. AlMe ₃ solution (2.0 M in toluene, 0.24 mL) was added and the reaction was stirred at room temperature for 10 min and then at 100 °C for 1 h. The reaction was cooled to room temperature and quenched with methanol (2 mL) and TFA (0.2 mL), poured into 30 mL of water, and extracted with DCM (4 x 10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, water, brine, dried (MgSO ₄ ), and evaporated to dryness. The residue was dissolved in DCM (2 mL) and TFA (1 mL), and the solution was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by prep-HPLC-10 (10%-60% MeCN) followed by chiral SFC (Rilas Technologies, Regis Whelk O-1 (S,S) 21 × 250 mm, 45% EtOH + 0.25% diethylamine in CO2) to give: Peak 1, Example 191. 4-amino-1-(2,6-dichlorophenyl)-N-(3-((2R,5R)-5-(hydroxymethyl)pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-(2,6-dichlorophenyl)-N-(3-((2S,5S)-5-(hydroxymethyl)pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. White solid (16.6 mg), LCMS m/z = 474 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 11.67 (s, 1H), 9.73 (d, 1H), 8.64 (d, 1H), 8.42 (s, 1H), 7.76 (d, 2H), 7.64 (t, 1H), 7.56 (d, 1H), 7.46 (s, 1H), 7.21 (t, 1H), 7.06 (d, 1H), 4.45 (s, 1H), 4.06 (t, 1H), 3.40-3.34 (m, 1H), 3.23-3.14 (m, 1H), 2.57 (q, 1H), 2.04 (dtd, 1H), 1.78 (dq, 1H), 1.58-1.37 (m, 2H), 1.03 (dt, 1H). Example 192. Synthesis of 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidino]-4-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

To a solution of 4-amino-1-(2,6-dichloro-4-methoxy-phenyl)-6-oxo-pyrimidine-5-carboxylic acid methyl ester (Intermediate B10, 30 mg, 0.087 mmol) and 5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-pyrrolidin]-4-amine (Intermediate A42, 26.4 mg, 0.139 mmol) in THF (1.5 mL) was added LiHMDS (1 M, 0.262 mL) at 0° C., and the mixture was stirred under N ₂ at 20° C. for 12 h. The reaction mixture was quenched by adding H ₂ O (1 mL) at 0° C., and concentrated under reduced pressure. The residue was purified by prep-HPLC-1 (5%-40% MeCN) to give the title compound (2.3 mg, 4.8%) as a pale yellow solid. LCMS m/z = 501 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.56 (s, 1H), 10.05 (d, 1H), 9.27 (s, 1H), 8.38 (s, 1H), 7.71 (s, 1H), 7.06 (s, 2H), 5.96 (d, 1H), 3.88 (s, 3H), 3.31-3.21 (m, 1H), 3.20-3.12 (m, 1H), 3.11-3.00 (m, 1H), 2.93-2.80 (m, 1H), 2.30-2.21 (m, 2H), 2.19-2.05 (m, 3H), 2.05-1.99 (m, 2H). Example 193. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-N-(3-(pyrrolidin-2-yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of tert-butyl (S)-2-(3-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl) pyrrolidine -1- carboxylate .

To a solution of 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-pyrimidine-5-carboxylic acid methyl ester (Intermediate B6, 400 mg, 1.02 mmol) and (S)-2-(3-aminophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate A61, 320 mg, 1.22 mmol) in toluene (8 mL) was added AlMe ₃ (2 M in toluene, 1.53 mL) at 0° C. and the mixture was stirred at 100° C. under N ₂ for 1 h. The reaction mixture was quenched by addition of saturated aqueous NaOH solution (5 mL) at 0° C. and extracted with EtOAc (3×7 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , 1%-50% EtOAc/PE) to give the title compound (180 mg, 28%) as a white solid. LCMS m/z = 622 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (S)-2-(3-(4-amino-1-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl) pyrrolidine -1- carboxylate

To a solution of tert-butyl (S)-2-(3-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-1-carboxylate (Step 1, 150 mg, 0.241 mmol) in dioxane (3 mL) and _H2O (1 mL) were added _Pd2 (dba) ₃ (22 mg, 0.024 mmol), t-BuXphos (20.4 mg, 0.048 mmol) and KOH (27 mg, 0.481 mmol), and the mixture was stirred under _N2 at 100 °C for 1 h. The reaction mixture was concentrated under _N2 , and the residue was purified by prep-HPLC-16 (35%-65% MeCN) to give (R)-tert-butyl 2-(3-(4-amino-1-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-1-carboxylate or (S)-tert-butyl 2-(3-(4-amino-1-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-1-carboxylate (20 mg, 15%) as a white solid. LCMS m/z = 560 [M+H] ⁺ . Step 3. Synthesis of (S)-2-(3-(4-amino-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl) pyrrolidine -1- carboxylic acid tert-butyl ester

To a solution of (S)-tert-butyl 2-(3-(4-amino-1-(2,6-dichloro-4-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-1-carboxylate (Step 2, 15 mg, 0.027 mmol) and sodium 2-chloro-2,2-difluoroacetate (8.16 mg, 0.054 mmol) in DMF (0.5 mL) was added K ₂ CO ₃ (4.07 mg, 0.029 mmol), and the mixture was stirred at 60 °C for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H ₂ O (1 mL) and extracted with EtOAc (3× 2 mL). The combined organic layers were washed with brine (2 x 1 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound as a white solid (15 mg, 92%). LCMS m/z = 610 [M+H] ⁺ . Step 4. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-N-(3-( pyrrolidin -2- yl)phenyl)-1,6-dihydropyrimidine-5-carboxamide .

A solution of (S)-tert-butyl 2-(3-(4-amino-1-(2,6-dichloro-4-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)phenyl)pyrrolidine-1-carboxylate (Step 3, 15 mg, 0.025 mmol) in DCM (0.9 mL) and TFA (0.3 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-2 (20%-55% MeCN) to give the title compound (3 mg, 22%) as a white solid. LCMS m/z = 510 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.57 (s, 1H), 10.07 (br s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.46 (br d, 1H), 7.35 (s, 2H), 7.29 (br s, 1H), 7.16 (br d, 1H), 6.79-6.42 (m, 1H), 6.10 (br d, 1H), 4.42 (br d, 1H), 3.25 (br d, 2H), 2.32 (br d, 1H), 2.18-2.06 (m, 2H), 2.06-2.00 (m, 1H). Example 194. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-N-(5-(pyrrolidin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (S)-tert-butyl 2-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl) pyrrolidine -1- carboxylate .

To a solution of (S)-tert-butyl 2-(5-aminopyridin-3-yl)pyrrolidine-1-carboxylate (Intermediate A13, 402 mg, 1.53 mmol) and methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 400 mg, 1.02 mmol) in toluene (5 mL) was added _AlMe3 (2 M, 1.53 mL) at 0°C, and the mixture was stirred at 100°C under _N2 for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaOH solution (4 mL) at 0°C, and extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by MPLC ( _SiO2 , 1%-100% EtOAc/PE) _to give the title compound as a white solid (350 mg, 55%). LCMS m/z = 625 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (S)-2-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl) pyrrolidine -1- carboxylate .

To a mixture of (S)-tert-butyl 2-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyrrolidine-1-carboxylate (Step 1, 15 mg, 0.024 mmol) and cyclopropanol (6.98 mg, 0.120 mmol) in toluene (2 mL) were added RockPhos Pd G3 (2.01 mg, 2.40 μmol) and _Cs2CO3 (11.74 mg, 36 μmol), and the mixture was stirred _{under N2} at 110 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue to afford the title compound as a yellow oil (25 mg, crude). LCMS m/z = 601 [M+H] ⁺ . Step 3. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-N-(5-( pyrrolidin -2- yl) pyridin -3- yl)-1,6-dihydropyrimidine-5-carboxamide .

A mixture of (S)-tert-butyl 2-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyrrolidine-1-carboxylate (Step 2, 25 mg, 0.042 mmol) in DCM (0.9 mL) and TFA (0.3 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under _N2 , and the residue was purified by prep-HPLC-6 (5%-40% MeCN) to give the title compound (10.6 mg, 46%) as a brown oil. LCMS m/z = 501 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.85 (s, 1H), 9.60 (d, 1H), 8.75 (d, 2H), 8.41 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.44 (s, 2H), 4.25 (d, 1H), 4.06 (td, 1H), 3.58 (t, 1H), 3.17-3.09 (m, 1H), 3.04 (s, 1H), 2.22 (d, 1H), 1.94-1.80 (m, 2H), 1.76-1.63 (m, 1H), 0.92-0.79 (m, 2H), 0.78-0.61 (m, 2H). Example 195. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (S)-4-amino-1-(4-bromo-2,6-dichlorophenyl)-N-(5-(1-(methylamino)ethyl) pyridin -3 -yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(4-bromo-2,6-dichlorophenyl)-N-(5-(1-(methylamino)ethyl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

To a mixture of 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-pyrimidine-5-carboxylic acid methyl ester (Intermediate B6, 190 mg, 0.483 mmol) and (S)-5-(1-(methylamino)ethyl)pyridin-3-amine or (R)-5-(1-(methylamino)ethyl)pyridin-3-amine (Intermediate A14, 110 mg, 0.725 mmol) in toluene (13 mL) was added _AlMe3 (2 M, 0.725 mL) at 0°C, and the mixture was stirred under _N2 at 60°C for 0.2 h. The reaction mixture was diluted with _H2O (5 mL) and TFA (5 mL) at 0°C, and the mixture was concentrated under reduced pressure to give the title compound (350 mg, crude) as a yellow solid. LCMS m/z = 513 [M+H] ⁺ . Step 2. Synthesis of (S)-(1-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)ethyl)(methyl)carbamic acid tert-butyl ester or (R)-(1-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)ethyl)(methyl)carbamic acid tert-butyl ester

To a solution of (S)-4-amino-1-(4-bromo-2,6-dichlorophenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(4-bromo-2,6-dichlorophenyl)-N-(5-(1-(methylamino)ethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Step 1, 350 mg, 0.683 mmol) in THF (15 mL) and H ₂ O (5 mL) were added NaHCO ₃ (115 mg, 1.37 mmol) and di-tert-butyl dicarbonate (149 mg, 0.683 mmol), and the mixture was stirred at 25 °C for 1 h. h. The reaction mixture was added to H ₂ O (50 mL) at 0° C. and extracted with EtOAc (3× 20 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/PE) to give the title compound (370 mg, 88%) as a yellow solid. LCMS m/z = 613 [M+H] ⁺ . Step 3. Synthesis of (S)-(1-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)ethyl)(methyl)carbamic acid tert-butyl ester or (R)-(1-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)ethyl)(methyl)carbamic acid tert-butyl ester

To a solution of (S)-tert-butyl(1-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate or (R)-tert-butyl(1-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate (Step 2, 55 mg, 0.090 mol) in toluene (5 mL) were added RockPhos Pd G3 (7.53 mg, 8.98 μmol) and Cs ₂ CO ₃ (43.9 mg, 0.135 mmol) and cyclopropanol (26 mg, 30 mL). 0.449 mmol) and the mixture was stirred at 110 °C under N2 for 1.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with _H2O (30 mL) and extracted with EtOAc (3× 20 mL), dried ( _Na2SO4 ) and concentrated under reduced pressure. The residue was purified by prep-TLC (50% EtOAc/PE) to give the title compound (80 mg, 75%) as _a yellow solid. LCMS m/z = 589 [M+H] ⁺ . Step 4. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-N-(5-(1-(methylamino)ethyl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-N-(5-(1-(methylamino)ethyl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

A mixture of (S)-tert-butyl(1-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate or (R)-tert-butyl(1-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)(methyl)carbamate (Step 3, 70 mg, 0.1189 mmol) in HCl/EtOAc (5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under N ₂ , and the residue was purified by prep-HPLC-3 (5%-40% MeCN) to give the title compound as a light yellow solid (13.9 mg, 21%). LCMS m/z = 489 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.86 (s, 1 H), 10.00 (d, 1H), 8.66 (s, 1 H), 8.32 (d, 2H), 7.73 (s, 1 H), 7.21 (s, 2 H), 6.19 (d, 1H) 3.93 (d, 1H), 3.75-3.84 (m, 1 H), 2.38 (s, 3 H), 1.56 (d, 3H) 0.78-0.94 (m, 4 H). Example 196. Synthesis of (S)-methyl 4-(4-amino-6-oxo-5-((5-(hexahydropyridin-2-yl)pyridin-3-yl)aminocarbonyl)pyrimidin-1(6H)-yl)-3,5-dichlorobenzoate. Step 1. Synthesis of (S)-tert-butyl 2-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl) hexahydropyridine -1- carboxylate .

To a solution of 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-pyrimidine-5-carboxylic acid methyl ester (100 mg, 0.254 mmol) and (S)-tert-butyl 2-(5-aminopyridin-3-yl)hexahydropyridine-1-carboxylate (Intermediate A5, 70.6 mg, 0.254 mmol) in toluene (3 mL) was added _AlMe3 (2 M, 0.382 mL in toluene) at 0°C, and the mixture was stirred at 100°C under _N2 for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaOH (1 M, 5 mL) at 0°C, and then extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure, and the residue was purified by prep-TLC (50% EtOAc/PE) _to give the title compound as a white solid (118 mg, 72%). LCMS m/z = 639 [M+H] ⁺ . Step 2. Synthesis of (S)-4-(4-amino-5-((5-(1-(tert-butoxycarbonyl)hexahydropyridin - 2- yl) pyridin -3- yl)carbamoyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorobenzoic acid

To a solution of oxalic acid (116.5 mg, 1.29 mmol) in DMF (2 mL) was added tert-butyl (S)-2-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)hexahydropyridine-1-carboxylate (Step 1, 118 mg, 0.185 mmol), Pd(OAc) ₂ (4.15 mg, 0.018 mmol), _Ac2O (56.6 mg, 0.555 mmol), DIPEA (71.7 mg, 0.555 mmol) and Xantphos (10.7 mg, 0.018 mmol), and the mixture was stirred under _N2 at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H ₂ O (5 mL) and extracted with EtOAc (3× 5 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by prep-TLC (10:1 EtOAc/MeOH) to give the title compound (70 mg, 63%) as a brown oil. LCMS m/z = 603 [M+H] ⁺ . Step 3. Synthesis of (S)-methyl 4-(4-amino-6-oxo-5-((5-(hexahydropyridin - 2- yl) pyridin -3- yl)aminocarbonyl)pyrimidin-1(6H)-yl)-3,5-dichlorobenzoate

To a solution of (S)-4-(4-amino-5-((5-(1-(tert-butoxycarbonyl)hexahydropyridin-2-yl)pyridin-3-yl)carbamoyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorobenzoic acid (Step 2, 70 mg, 0.116 mmol) in MeOH (1 mL) was added _SOCl2 (55.2 mg, 0.464 mmol) at 0°C, and the mixture was stirred under _N2 at 80°C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-1 (3%-35% MeCN) to give the title compound (20 mg, 30%) as a white solid. LCMS m/z = 517 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.66 (s, 1H), 10.04 (d, 1H), 8.61 (d, 1H), 8.36 (s, 1H), 8.33-8.34 (m, 1H), 8.19 (s, 2H), 7.71 (s, 1H), 6.18 (d, 1H), 4.00 (s, 3H), 3.81 (m, 1H), 3.21 (d, 1H), 1.77-2.00 (m, 4H), 1.68-1.74 (m, 2H), 1.51-1.61 (m, 1H). Example 197. Synthesis of (R)-4-amino-N-(5-(1-amino-3-methoxypropyl)pyridin-3-yl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-3-methoxypropyl)pyridin-3-yl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of tert-butyl (1-(5-(4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)-3-methoxypropyl)carbamate .

To a mixture of methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 20 mg, 0.064 mmol) and tert-butyl (1-(5-aminopyridin-3-yl)-3-methoxypropyl)carbamate (Intermediate A19, 19.7 mg, 0.070 mmol) in toluene (3 mL) was added AlMe3 (2 M in toluene, 96 μL) at 0°C, and the mixture was stirred at 0°C for 5 min. The mixture was stirred at 40°C under _N2 for 60 min. The reaction mixture was diluted with _H2O (0.2 mL) and TFA (0.2 mL) at 0°C, and the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC-2 (30%-60% MeCN) to give the title compound (30 mg, 83%) as a white solid. LCMS m/z = 563 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (S)-(1-(5-(4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin - 3- yl)-3-methoxypropyl)carbamate or (R)-(1-(5-(4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)-3-methoxypropyl)carbamate .

Purification of tert-butyl (1-(5-(4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin- _{3-yl)-3-methoxypropyl)carbamate (Step 1, 118.7 mg, 211 mmol) was performed by SFC separation (REGIS(S, S)WHELK-O1, 250 × 25} mm, 10 μm); 45% EtOH (0.1% NH 4 OH) in CO 2 ) to give: Peak 2. (S)-tert-butyl(1-(5-(4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate or (R)-tert-butyl(1-(5-(4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate (yellow oil, 20 mg, 16%). Step 3. Synthesis of (R)-4-amino-N-(5-(1-amino-3-methoxypropyl) pyridin -3- yl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-3-methoxypropyl) pyridin -3 -yl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

A mixture of (S)-tert-butyl(1-(5-(4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate or (R)-tert-butyl(1-(5-(4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-3-methoxypropyl)carbamate (fraction 2, peak 2, 10 mg, 0.018 mmol) in DCM (1.5 mL) and TFA (0.5 mL) was stirred under _N2 at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-2 (5%-35% MeCN) to give the title compound (1.3 mg, 14%) as a white solid. LCMS m/z = 463 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.74-11.85 (m, 1H), 9.61-9.69 (m, 1H), 8.73-8.80 (m, 2H), 8.46 (s, 1H), 8.19-8.35 (m, 2H), 7.98-8.03 (m, 1H), 7.74-7.80 (m, 2H), 7.61-7.68 (m, 1H), 3.93-4.03 (m, 1H), 3.21-3.26 (m, 2H), 3.19 (s, 3H), 1.74-1.92 (m, 2H). Example 198. Synthesis of methyl 4-(4-amino-5-((5-((ethylamino)methyl)pyridin-3-yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorobenzoate. Step 1. Synthesis of tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)methyl)(ethyl)carbamate .

AlMe3 (2 M in toluene, 1.91 mL) was added to a mixture of methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 500 mg, 1.27 mmol) and tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate (Intermediate A24, 480 mg, 1.91 mmol) in toluene (9 mL) at 0°C, and the mixture was stirred under _N2 at 100°C for 0.5 h. The reaction mixture was quenched by the addition of 1 M aqueous NaOH (50 mL) at 0°C, and then extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ), concentrated under reduced pressure, and the residue was purified by column chromatography ( _SiO2 , 0-100% EtOAc/PE) _to give the title compound as a yellow solid (2 g, 64%). LCMS m/z = 613 [M+H] ⁺ . Step 2. Synthesis of 4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl) pyridin -3- yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorobenzoic acid .

To a solution of tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Step 1, 310 mg, 0.506 mmol) and oxalic acid (319 mg, 3.54 mmol) in DMF (2 mL) was added Pd(OAc) ₂ (11.4 mg, 0.051 mmol), Xantphos (29.3 mg, 0.051 mmol), _Ac2O (155 mg, 1.52 mmol) and DIPEA (196 mg, 1.52 mmol), and the mixture was stirred under _N2 at 100 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-1 (30%-60% MeCN) to give the title compound (120 mg, 41%) as a white solid. LCMS m/z = 577 [M+H] ⁺ . Step 3. Synthesis of methyl 4-(4-amino-5-((5-((ethylamino)methyl) pyridin -3- yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorobenzoate

To a solution of 4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl)pyridin-3-yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorobenzoic acid (Part 2, 60 mg, 0.104 mmol) in MeOH (1 mL) was added thionyl chloride (49.5 mg, 0.416 mmol) at 0 °C, and the mixture was stirred under _N2 at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-1 (3%-35% MeCN) to give the title compound (22.6 mg, 44%) as a white solid. LCMS m/z = 491 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.59 (s, 1H), 9.97 (d, 1H), 8.53 (d, 1H), 8.32-8.18 (m, 2H), 8.11 (s, 2H), 7.63 (s, 1H), 6.19 (d, 1H), 3.92 (s, 3H), 3.83 (s, 2H), 2.70 (q, 2H), 1.10 (t, 3H). Example 199. Synthesis of ethyl 4-(4-amino-5-((5-((ethylamino)methyl)pyridin-3-yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorobenzoate.

The title compound was prepared as a white solid from methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6) using a 3 -step procedure analogous to that described for Example 198. LCMS m/z = 505 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.70 (s, 1H), 10.08 (d, 1H), 8.65 (s, 1H), 8.32 (d, 2H), 8.22 (s, 2H), 7.74 (s, 1H), 6.22 (s, 1H), 4.48 (q, 2H), 3.92 (s, 2H), 2.78 (q, 2H), 1.47 (t, 3H), 1.20 (t, 3H). Example 200. Synthesis of 4-amino-1-(2,6-dichloro-4-(oxazol-5-yl)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)methyl)(ethyl)carbamate .

AlMe3 (2 M in toluene, 1.91 mL) was added to a mixture of methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6, 500 mg, 1.27 mmol) and tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate (Intermediate A24, 480 mg, 1.91 mmol) in toluene (9 mL) at 0°C, and the mixture was stirred under _N2 at 100°C for 0.5 h. The reaction mixture was quenched by the addition of 1 M aqueous NaOH (50 mL) at 0°C, and then extracted with EtOAc (3 x 50 mL). The combined organics were dried ( _Na2SO4 ), concentrated under reduced pressure, and the residue was purified by column chromatography ( _SiO2 , 0-100% EtOAc/PE) _to give the title compound as a yellow solid (2 g, 64%). LCMS m/z = 613 [M+H] ⁺ . Step 2. Synthesis of tert-butyl ((5-(4-amino-1-(2,6-dichloro-4-(oxazol-5-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)methyl)(ethyl)carbamate .

tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (part 1, 90 mg, 0.147 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (57.33 mg, 0.294 mmol), K ₃ PO ₄ (62.4 mg, 0.294 mmol), [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (23.13 mg, 0.029 mmol) in dioxane (4 mL) and H 2 O 4 . ₂ O (0.4 mL) was degassed and purged with N ₂ (×3), and the mixture was stirred under N ₂ at 110 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (80 mg, 90%) as a white solid. LCMS m/z = 600 [M+H] ⁺ . Step 3. Synthesis of 4-amino-1-(2,6-dichloro-4-(oxazol-5-yl)phenyl)-N-(5-((ethylamino)methyl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

To a mixture of tert-butyl ((5-(4-amino-1-(2,6-dichloro-4-(oxazol-5-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Part 2, 60 mg, 0.100 mmol) in DCM (2 mL) and TFA (1 mL) was added, and the mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC-1 (20%-50% MeCN) to give the title compound (8.2 mg, 16%) as a yellow oil. LCMS m/z = 500 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 1.05 (t, 3H) 2.57 (d, 2H) 3.74 (d, 2H) 8.05 (s, 1H), 8.08 (s, 1H), 8.15 (s, 2H), 8.25 (s, 1H), 8.50 (s, 1H), 8.65 (s, 1H), 8.70 (br s, 1H), 8.85 (d, 1H), 9.69 (d, 1H), 11.78 (s, 1H). Example 201. Synthesis of 4-amino-1-(2,6-dichloro-4-(oxazol-2-yl)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)methyl)(ethyl)carbamate .

The title compound was prepared from methyl 4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B6) and tert-butyl ((5-aminopyridin-3-yl)methyl)(ethyl)carbamate (Intermediate A24) using a method similar to that described for Example 190, Step 1. Step 2. Synthesis of tert-butyl ((5-(4-amino-1-(2,6-dichloro-4-(oxazol-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)methyl)(ethyl)carbamate

To a solution of tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Step 1, 50 mg, 0.082 mmol) in dioxane (1.5 mL) were added cataCXium® A Pd G2 (10.92 mg, 0.016 mmol) and 2-(tributyltinyl)oxazole (117 mg, 0.327 mmol), and the mixture was stirred at 80 °C under _N2 for 1 h. The reaction mixture was diluted with _H2O (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were washed with brine (2 x 1 mL), dried _{( Na2SO4} ) and concentrated under reduced pressure. The residue was purified by prep-HPLC-8 (30%-65% MeCN) to give the title compound as a yellow solid (20 mg, 41%). LCMS m/z = 600 [M+H] ⁺ . Step 3. Synthesis of 4-amino-1-(2,6-dichloro-4-(oxazol-2-yl)phenyl)-N-(5-((ethylamino)methyl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

The title compound was prepared from tert-butyl ((5-(4-amino-1-(2,6-dichloro-4-(oxazol-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (step 2) using a method similar to that described for Example 200, step 3. prep-HPLC-1 (1%-30% MeCN) gave the title compound as a white solid (5.1 mg, 14%). LCMS m/z = 500 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.69 (s, 1H), 10.07-10.15 (m, 1H), 8.68 (d, 1H), 8.30 (s, 1H), 8.24 (s, 2H), 8.15 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.36 (s, 1H), 6.06 (br dd, 1H), 3.83 (s, 2H), 2.70 (q, 2H), 1.15 (t, 3H). Example 202. Synthesis of 4-amino-1-(2,6-dichloro-4-(2,2,2-trifluoroethyl)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl) pyridin -3- yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorophenyl)boronic acid .

To a solution of tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Example 190, Step 1; 315 mg, 0.514 mmol) in dioxane (5.5 mL) were added Pd(dppf)Cl ₂ .DCM (42 mg, 0.051 mmol) and KOAc (101 mg, 1.03 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxaborolane) (653 mg, 2.57 mmol), and the mixture was stirred at N 2 4 ℃ for 1 h. ₂ and stirred at 80° C. for 15 h. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by prep-HPLC-8 (15%-45% MeCN) to give the title compound (1.3 g, 73%) as a white solid. LCMS m/z = 577 [M+H] ⁺ . Step 2. Synthesis of tert-butyl ((5-(4-amino-1-(2,6-dichloro-4-(2,2,2-trifluoroethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)methyl)(ethyl)carbamate .

A mixture of (4-(4-amino-5-((5-(((tert-butoxycarbonyl)(ethyl)amino)methyl)pyridin-3-yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dichlorophenyl)boronic acid (Part 1, 15 mg, 0.026 mmol), 1,1,1-trifluoro-2-iodoethane (109 mg, 0.520 mmol), _Pd2 (dba) ₃ (2.38 mg, 2.60 μmol), Xantphos (1.50 _mg , 2.60 μmol) and _Cs2CO3 (33.9 mg, 0.104 mmol) in dioxane (2 mL) and _H2O (0.1 mL) was degassed and purged with _N2 (3×) and the mixture was stirred under N2. ₂ and stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (45 mg, 93%) as a white solid without further purification. LCMS m/z = 615 [M+H] ⁺ . Step 3. Synthesis of 4-amino-1-(2,6-dichloro-4-(2,2,2-trifluoroethyl)phenyl)-N-(5-((ethylamino)methyl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

The title compound (5.1 mg, 13%) was prepared as a white solid from tert-butyl ((5-(4-amino-1-(2,6-dichloro-4-(2,2,2-trifluoroethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Step 2, 45 mg, 0.073 mmol) using a method analogous to that described for Example 200, Step 3. LCMS m/z = 515 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.15-1.21 (m, 3H), 2.91 (q, 2H), 3.37 (q, 2H), 4.00 (s, 2H), 6.09 (d, 1H), 7.42 (s, 2H), 7.64 (s, 1H), 8.29 (s, 1H), 8.48 (d, 2H), 9.84 (d, 2H), 11.71 (s,1H). Example 203. Synthesis of 4-amino-1-(2,6-dichloro-4-(2,2-difluoroethyl)phenyl)-N-(5-((ethylamino)methyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

The title compound was prepared as a white solid from tert-butyl ((5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)methyl)(ethyl)carbamate (Example 190, Step 1) and 1,1-difluoro-2-iodoethane using a 3-step method similar to that described for Example 202. LCMS m/z = 497 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 1.14-1.24 (m, 1H), 1.19 (d, 2H), 2.04 (d, 1H), 2.75 (d, 2H), 3.17-3.31 (m, 2H), 3.88 (s, 2H), 5.86-6.25 (m, 1H), 6.07-6.15 (m, 1H), 7.48 (s, 2H), 7.74 (d, 1H), 8.16-8.37 (m, 1H), 8.25 (s, 1H), 8.33 (s, 1H), 8.66 (s, 1H), 10.06 (d, 1H), 11.73 (s, 1H). Example 204. Synthesis of (R)-4-amino-N-(5-(1-amino-2,2-difluoroethyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2,2-difluoroethyl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(1-(1,3-dioxoisoindolin - 2 -yl)-2,2-difluoroethyl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(1-(1,3- dioxoisoindolin- 2 -yl)-2,2-difluoroethyl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

The title compound (50 mg, 56%) was prepared as a white solid from methyl 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B10) and (R)-2-(1-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-1,3-dione or (S)-2-(1-(5-aminopyridin-3-yl)-2,2-difluoroethyl)isoindoline-1,3-dione (Intermediate A48) using a method similar to that described for Example 2. LCMS m/z = 615 [M+H] ⁺ . Step 2. Synthesis of (R)-4-amino-N-(5-(1-amino-2,2-difluoroethyl) pyridin -3- yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2,2-difluoroethyl) pyridin -3- yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

To a solution of (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(1-(1,3-dioxoisoindolin-2-yl)-2,2-difluoroethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(1-(1,3-dioxoisoindolin-2-yl)-2,2-difluoroethyl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Step 1, 40 mg, 0.065 mmol) in EtOH (2 mL) was added hydrazine hydrate (15.31 mg, 0.260 mmol), and the mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was diluted with H ₂ O (3 mL) and extracted with EtOAc (3× 3 mL). The combined organics were washed with brine (2× 2 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure, and the residue was purified by prep-HPLC-3 (1%-35% MeCN) to give the title compound (17.9 mg, 51%) as a brown solid. LCMS m/z = 485 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ): 11.86 (s, 1H), 10.01 (br d, 1H), 8.75 (d, 1H), 8.34 (d, 1H), 8.27 (t, 1H), 7.74 (s, 1H), 7.07 (s, 2H), 6.03 (br d, 1H), 5.95-5.65 (m, 1H), 4.24 (ddd, 1H), 3.88 (s, 3H). Example 205. Synthesis of (R)-4-amino-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (R)-2-(5-(4-amino-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)hexahydropyridine - 1- carboxylic acid tert-butyl ester .

The title compound was prepared from methyl 4-amino-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B34) and tert-butyl (R)-2-(5-aminopyridin-3-yl)hexahydropyridine-1-carboxylate (Intermediate A4) using a method similar to that described for Example 2. LCMS m/z = 599 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (R)-2-(5-(4-amino-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)hexahydropyridine - 1- carboxylate .

To a mixture of (R)-tert-butyl 2-(5-(4-amino-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyridinehexahydrocarboxylate (Step 1, 250 mg, 0.418 mmol) in toluene (2 mL) and MeOH (2 mL) were added K ₃ PO ₄ (133 mg, 0.628 mmol), t-Bu Xphos (17.77 mg, 0.042 mmol) and Pd ₂ (dba) ₃ (38.31 mg, 0.042 mmol), and the mixture was stirred under N ₂ at 80 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give the title compound as a brown oil (500 mg). LCMS m/z = 594 [M+H] ⁺ . Step 3. Synthesis of (R)-4-amino-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-N-(5-(hexahydropyridin - 2- yl) pyridin -3 -yl)-1,6-dihydropyrimidine-5-carboxamide .

To a mixture of (R)-tert-butyl 2-(5-(4-amino-1-(4-methoxy-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyridine-1-carboxylate (Step 2, 500 mg, 0.911 mmol) in DCM (4 mL) was added TFA (1.5 mL), and the mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-3 (5%-45% MeCN) to give the title compound (40.3 mg, 10%) as a pale yellow solid. LCMS m/z = 449 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.09 (s, 1H), 9.93 (br d, 1H), 8.64 (s, 1H), 8.39 (s, 2H), 7.79 (s, 1H), 6.78 (s, 2H), 6.03 (br d, 1H), 3.87 (s, 3H), 3.83 (br d, 1H), 3.22 (br d, 1H), 2.86-2.79 (m, 1H), 2.18 (s, 6H), 1.99-1.85 (m, 3H), 1.73 (br d, 2H), 1.62-1.54 (m, 1H). Example 206. Synthesis of 4-amino-N-((1R,3S)-3-(aminomethyl)cyclohexyl)-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-((1S,3R)-3-(aminomethyl)cyclohexyl)-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of 4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-((1R,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-((1S,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

To a solution of (1S,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan-1-amine or (1R,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexan- ₁ -amine (intermediate A58, 130.28 mg, 0.468 mmol) and methyl 4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (intermediate B4, 101 mg, 0.312 mmol) in toluene (2 mL) was added _AlMe3 (2 M in toluene, 0.47 mL) under N2 at 0 °C and the mixture was stirred at 100 °C for 1 h under _N2 . The reaction mixture was quenched by adding saturated aqueous NaOH (2 mL) at 0°C and evaporated to dryness. The residue was purified by prep-TLC (10/1 EtOAc/MeOH) to give the title compound (70 mg, crude) as a light yellow oil. LCMS m/z = 571 [M+H] ⁺ . Step 2. Synthesis of tert-butyl (((1S,3R)-3-(4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)cyclohexyl)methyl)(2,4-dimethoxybenzyl)carbamate or tert-butyl (((1R,3S)-3-(4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)cyclohexyl)methyl)(2,4-dimethoxybenzyl)carbamate .

To a solution of 4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-((1R,3S)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-N-((1S,3R)-3-(((2,4-dimethoxybenzyl)amino)methyl)cyclohexyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Step 1, 60 mg, 0.105 mmol) in MeOH (2 mL) was added di-tert-butyl dicarbonate (68.9 mg, 0.316 mmol), and the mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-TLC (50% PE/EtOAc) to give the title compound (80 mg, crude) as a light yellow oil. LCMS m/z = 671 [M+H] ⁺ . Step 3. Synthesis of 4-amino-N-((1R,3S)-3-(aminomethyl)cyclohexyl)-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or 4-amino-N-((1S,3R)-3-(aminomethyl)cyclohexyl)-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

A solution of tert-butyl (((1S,3R)-3-(4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)cyclohexyl)methyl)(2,4-dimethoxybenzyl)carbamate or tert-butyl (((1R,3S)-3-(4-amino-1-((S)-2-chloro-4-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)cyclohexyl)methyl)(2,4-dimethoxybenzyl)carbamate (Step 2, 70 mg, 0.104 mmol) in TFA (2 mL) was stirred at 80 °C for 1 h. The reaction mixture was concentrated under N ₂ , and the residue was purified by prep-HPLC-1 (1%-50% MeCN) to give the title compound (15.8 mg, 36%) as a white solid. LCMS m/z = 420 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 0.87 (q, 2H), 1.10-1.22 (m, 1 H), 1.39 (q, 1 H), 1.82 (br d, 3H), 1.98 (br d, 1H), 2.18 (s, 4H), 2.71 (br d, 2H), 3.83 (s, 4H), 6.17 (br d, 1H), 6.79 (d, 1H), 6.93 (d, 1H), 7.66 (s, 1H), 8.49 (br s, 1H), 9.59 (d, 1H), 9.99 (br d, 1H). Example 207. Synthesis of (R)-2-(4-(4-amino-6-oxo-5-((5-(hexahydropyridin-2-yl)pyridin-3-yl)aminocarbonyl)pyrimidin-1(6H)-yl)-3,5-dimethylphenyl)acetic acid. Step 1. Synthesis of (R)-2-(5-(1-(4-allyl-2,6-dimethylphenyl)-4-amino-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl) hexahydropyridine -1- carboxylic acid tert-butyl ester .

To a solution of (R)-tert-butyl _2- (5-(4-amino-1-(4-bromo-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyridinehexahydrocarboxylate (Example 205, Step 1, 820 mg, 1.37 mmol) in DMF (5 mL) under N2 were added Pd( _PPh3 ) ₄ (159 mg, 0.137 mmol) and allyltributyltinane (500 mg, 1.51 mmol), and the mixture was stirred at 90 °C under _N2 for 3 h. The reaction mixture was quenched by the addition of saturated aqueous KF solution (30 mL) at 0 °C, and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by MPLC (SiO ₂ , EtOAc) to give the title compound (720 mg, 94%) as a yellow oil. LCMS m/z = 559 [M+H] ⁺ Step 2. Synthesis of (R)-tert-butyl 2-(5-(4-amino-1-(4-(2-methoxy-2-oxoethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl) hexahydropyridine -1- carboxylate .

Ozone (15 psi) was bubbled through a solution of (R)-tert-butyl 2-(5-(1-(4-allyl-2,6-dimethylphenyl)-4-amino-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)hexahydropyridine-1-carboxylate (Step 1, 280 mg, 0.501 mmol) in DCM (10 mL) and NaOH (2.5 M, 2.65 mL) in MeOH at -78 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (296 mg, crude) as a white solid. LCMS m/z = 591 [M+H] ⁺ Step 3. Synthesis of (R)-2-(4-(4-amino-5-((5-(1-(tert-butoxycarbonyl)hexahydropyridin - 2 - yl) pyridin -3- yl)aminocarbonyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dimethylphenyl)acetic acid .

To a solution of (R)-tert-butyl 2-(5-(4-amino-1-(4-(2-methoxy-2-oxoethyl)-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)hexahydropyridine-1-carboxylate (Step 2, 296 mg, 0.501 mol) in MeOH (3 mL) and _H2O (1 mL) was added NaOH (60 mg, 1.50 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC-13 (25%-45% MeCN) to give the title compound (68 mg, 23%) as a white solid. LCMS m/z = 577 [M+H] ⁺ Step 4. Synthesis of (R)-methyl 2-(4-(4-amino-6-oxo-5-((5-(hexahydropyridin - 2- yl) pyridin -3- yl)aminocarbonyl)pyrimidin-1(6H)-yl)-3,5-dimethylphenyl)acetate .

A solution of (R)-2-(4-(4-amino-5-((5-(1-(tert-butoxycarbonyl)hexahydropyridin-2-yl)pyridin-3-yl)carbamoyl)-6-oxopyrimidin-1(6H)-yl)-3,5-dimethylphenyl)acetic acid (Step 3, 68 mg, 0.118 mol) in HCl/EtOAc (1 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-1 (5%-35% MeCN) to give the title compound (37 mg, 63 %) as a yellow gum. LCMS m/z = 491 [M+H] ⁺ Step 5. Synthesis of (R)-2-(4-(4-amino-6-oxo-5-((5-(hexahydropyridin - 2- yl) pyridin -3- yl)aminocarbonyl)pyrimidin-1(6H)-yl)-3,5-dimethylphenyl)acetic acid .

To a solution of (R)-methyl 2-(4-(4-amino-6-oxo-5-((5-(hexahydropyridin-2-yl)pyridin-3-yl)aminocarbonyl)pyrimidin-1(6H)-yl)-3,5-dimethylphenyl)acetate (Step 4, 32 mg, 0.065 mmol) in MeOH (1 mL) and _H2O (0.3 mL) was added NaOH (7.83 mg, 0.20 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to pH 2-3 with 1 M HCl. The residue was purified by prep-HPLC-1 (5%-40% MeCN) to give the title compound (9.1 mg, 26%) as a white solid. LCMS m/z = 477 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₃ ): 12.14 (s, 1H), 9.52 (d, 1H), 8.68 (d, 1H), 8.51 (d, 1H), 8.25 (d, 2H), 8.09 (s, 1H), 7.13 (s, 2H), 3.70 (d, 1H), 3.54 (s, 2H), 3.09 (d, 1H), 2.69 (d, 1H), 2.06 (s, 6H), 1.84-1.70 (m, 2H), 1.60 (d, 1H), 1.45 (s, 3H). Example 208. Synthesis of (R)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-methoxyethyl)pyridin-3-yl)-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (R)-t-butyl(1-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)-2-methoxyethyl)carbamate or (S)-t-butyl(1-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)-2-methoxyethyl)carbamate .

To a solution of 4-amino-1-[2,6-dichloro-4-(cyclopropoxy)phenyl]-6-oxo-pyrimidine-5-carboxylic acid methyl ester (intermediate B11, 30 mg, 81 μmol) and tert-butyl (R)-(1-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamate or (S)-tert-butyl (1-(5-aminopyridin-3-yl)-2-methoxyethyl)carbamate (intermediate A22, 32.5 mg, 0.122 mmol) in toluene (1.5 mL) and THF (0.5 mL) was added _AlMe3 (2 M in toluene, 0.122 mL) at 0 °C and the mixture was stirred under _N2 at 60 °C for 1 h. The reaction mixture was quenched by adding TFA (0.2 mL) at 0°C, and the mixture was concentrated under reduced pressure to give the title compound (40 mg, 81%) as a brown oil. LCMS m/z = 605 [M+H] ⁺ . Step 2. Synthesis of (R)-4-amino-N-(5-(1-amino-2-methoxyethyl) pyridin -3- yl)-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-amino-2-methoxyethyl) pyridin -3- yl)-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

To a solution of (R)-tert-butyl(1-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-methoxyethyl)carbamate or (S)-tert-butyl(1-(5-(4-amino-1-(2,6-dichloro-4-cyclopropoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)-2-methoxyethyl)carbamate (step 1, 40 mg, 66 μmol) in DCM (1 mL) was added TFA (1 mL) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC-1 (3%-35% MeCN) to give the title compound (9.9 mg, 27%) as a pale yellow solid. LCMS m/z = 505 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.78 (s, 1H), 10.12-9.95 (m, 1H), 8.70 (s, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 7.73 (s, 1H), 7.22 (s, 2H), 6.08 (s, 1H), 4.28-4.17 (m, 1H), 3.79 (s, 1H), 3.52 (dd, 1H), 3.39 (s, 3H), 0.86 (d, 5H). Example 209. Synthesis of (S)-4-amino-1-(4-(azacyclobutan-1-yl)-2,6-dichlorophenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide.

To a solution of (S)-tert-butyl 2-(5-(4-amino-1-(4-bromo-2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)pyridine-1-carboxylate (Example 196, Step 1; 40 mg, 0.063 mmol) in dioxane (3 mL) were added _Pd2 (dba) ₃ (5.74 mg, 0.0063 mmol), Xantphos (3.63 mg, 0.0063 mmol) and ^NaOtBu (12 mg, 0.125 mmol), and the mixture was stirred at 100 °C under _N2 for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (100% EtOAc) to give a white solid, which was dissolved in TFA (1 mL) and DCM (1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under _N2 , and the residue was purified by prep-HPLC-1 (15%-45% MeCN) to give the title compound (6.8 mg, 20%) as a light yellow solid. LCMS m/z = 514 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.89 (s, 1H), 9.98 (d, 1H), 8.62 (d, 1H), 8.33 (s, 2H), 7.74 (s, 1H), 6.43 (s, 2H), 5.99 (d, 1H), 3.98 (t, 4H), 3.76 (dd, 1H), 3.18 (d, 2H), 2.82-2.75 (m, 1H), 2.49-2.41 (m, 2H), 1.94-1.85 (m, 2H), 1.73-1.68 (m, 3H), 1.53-1.48 (m, 1H). Example 210. Synthesis of (R)-N-(5-(1,4-oxazoloheptan-3-yl)pyridin-3-yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazoloheptan-3-yl)pyridin-3-yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of 3-(5- bromopyridin -3- yl)-1,4-oxazolidinone

To a solution of 3-((tributyltinyl)methoxy)propan-1-amine (1135 mg, 3.00 mmol) in DCM (15 mL) was added 5-bromonicotinaldehyde (558 mg, 3.0 mmol) and 4 Å molecular sieve (350 mg) at ambient temperature under an inert atmosphere. The reaction mixture was stirred for 2 h and filtered through a pad of celite, rinsing with DCM (50 mL). The filtrate was concentrated under reduced pressure to give 1-(5-bromopyridin-3-yl)-N-(3-((tributyltinyl)methoxy)propyl)methanimine. Separately, anhydrous copper(II) trifluoromethanesulfonate (1085 mg, 3.0 mmol) was added to a solution of 2,6-lutidine (0.35 mL) in 1,1,1,3,3,3-hexafluoropropan-2-ol (12 mL) in a dry Schlenk flask and stirred at room temperature for 1 h, during which time a homogeneous suspension was formed. A solution of 1-(5-bromopyridin-3-yl)-N-(3-((tributyltinyl)methoxy)propyl)methanimine in DCM (48 mL) was added in one portion and the resulting mixture was stirred at room temperature for 36 h. The reaction was quenched with a mixture of NaHCO ₃ (24 mL) and 10% aqueous NH ₄ OH (12 mL) and stirred vigorously for 15 min. The layers were separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organics were washed with water (3 x 10 mL), brine (5 mL), dried ( _Na2SO4 ) and evaporated to dryness in vacuo. Flash chromatography (ISCO, 24 g silica, 0-15% MeOH/DCM) afforded the title compound as an orange oil ( ₃₃₇ mg, 44%). LCMS m/z = 257 [M+H] ⁺ . Step 2. Synthesis of tert-butyl 3-(5-bromopyridin - 3- yl)-1,4-oxazolidinonecycloheptane-4-carboxylate .

To a solution of 3-(5-bromopyridin-3-yl)-1,4-oxazolidinone (Step 1, 337 mg, 1.311 mmol) in DCM (2.6 mL) was added (Boc) _2O (335 μl, 1.44 mmol), DMAP (8.0 mg, 0.066 mmol) and TEA (274 μl, 1.96 mmol) and the reaction was stirred at room temperature for 16 h. The mixture was poured into water (10 mL) and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organics were washed with _NH4OH (10 mL) and brine ( ₁₀ mL), dried ( _Na2SO4 ) and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 24 g silica, 10%-60% EtOAc/Hex) to give the title compound as an off-white solid (249 mg, 53%). LCMS m/z = 395 [M+K] ⁺ . Step 3. Synthesis of tert-butyl 3-(5-aminopyridin - 3- yl)-1,4-oxazolidinone-heptane-4-carboxylate .

To a suspension of tert-butyl 3-(5-bromopyridin-3-yl)-1,4-oxazolidinone-4-carboxylate (Step 2, 248 mg, 0.694 mmol), Cs ₂ CO ₃ (339 mg, 1.041 mmol), Pd ₂ (dba) ₃ (31.8 mg, 0.035 mmol) and BINAP (43.2 mg, 0.069 mmol) in anhydrous toluene (2.75 mL) was added benzophenone imine (144 μL, 0.83 mmol), and the mixture was bubbled with N ₂ for 10 min, and then heated to 80 °C for 15 h. The reaction was filtered through celite, washed with EtOAc, and the filtrate was evaporated to dryness. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-60% EtOAc/Hex) to give tert-butyl 3-(5-((diphenylmethylene)amino)pyridin-3-yl)-1,4-oxazanazocycloheptane-4-carboxylate intermediate (322 mg, 91% yield) as a viscous yellow oil, which was dissolved in MeOH (10.5 mL) and cooled to 0 °C. Hydroxylamine hydrochloride (132 mg, 1.90 mmol) and NaOAc (260 mg, 3.17 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into aqueous _NH4Cl solution and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine, dried ( _Na2SO4 ) and concentrated by rotary evaporation. The residue was purified by flash chromatography (ISCO, 24 g silica, 0-15% MeOH (containing 10% _NH4OH )/DCM) to give _the title compound as a white solid (162 mg, 87%). LCMS m/z = 294 [M+H] ⁺ ; Step 4. Synthesis of (R)-N-(5-(1,4-oxazoloheptan-3-yl) pyridin -3- yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazoloheptan-3-yl) pyridin -3- yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5- carboxamide .

Methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 55 mg, 0.175 mmol) and tert-butyl 3-(5-aminopyridin-3-yl)-1,4-oxazolidinylcycloheptane-4-carboxylate MEN-005-082 (Step 3, 61.6 mg, 0.210 mmol) were added to a dry flask and evacuated and backfilled with _N2 (×3). Anhydrous toluene (3.5 mL) was added and the solution was cooled to 0 °C, and _AlMe3 solution (2 M in toluene, 263 μL, 0.525 mmol) was added dropwise. The reaction was stirred at ambient temperature for 10 min and at 100 °C for 1.5 h. The reaction mixture was quenched with MeOH (2 mL), TFA (0.2 mL), poured into water (15 mL), and extracted with DCM (4× 10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, water, brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was dissolved in DCM (1.7 mL) and TFA (43.8 μL, 0.191 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h and heated to 40 °C for 16 h. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by flash chromatography (ISCO, 12 g silica, 0-15% MeOH (containing 10% NH ₄ OH)/DCM) followed by chiral SFC (Regis Whelk O-1 (S,S) 21×250 mm, 45% EtOH + 0.25% diethylamine in CO ₂ ) to provide

Peak 1, Example 210. (R)-N-(3-(1,4-oxazoloheptan-3-yl)phenyl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazoloheptan-5-yl)pyridin-3-yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (white solid, 21 mg, 25%); LCMS m/z = 476 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 11.84 (s, 1H), 9.71 (s, 1H), 8.91-8.70 (m, 2H), 8.52 (s, 1H), 8.32 (d, 1H), 8.05 (d, 1H), 7.83 (d, 2H), 7.71 (t, 1H), 4.03-3.81 (m, 3H), 3.76 (dt, 1H), 3.47-3.42 (m, 1H), 3.11 (d, 1H), 2.88 (dt, 1H), 1.91 (t, 2H). Example 211. Synthesis of (R)-N-(3-(1,4-oxazoloheptan-3-yl)phenyl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(3-(1,4-oxazoloheptan-3-yl)phenyl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of 3-(3-nitrophenyl)-1,4-oxazolidinone .

Using a procedure similar to that described for Example 210, Step 1, the title compound was prepared as a white solid (152 mg, 45%). LCMS m/z = 223 [M+H] ⁺ . Step 2. Synthesis of tert-butyl 3-(3-nitrophenyl)-1,4-oxazanilideheptane-4-carboxylate .

The title compound (125 mg, 57%) was prepared as a light yellow oil using a procedure similar to that described for Example 210, Step 2. LCMS m/z = 345 [M+Na] ⁺ . Step 3. Synthesis of tert-butyl 3-(3-aminophenyl)-1,4-oxazanilidenecycloheptane-4-carboxylate .

To a mixture of tert-butyl 3-(3-nitrophenyl)-1,4-oxazolidinone-heptane-4-carboxylate (Step 2, 125 mg, 0.400 mmol) in THF (3 mL) and water (1.75 mL) were added Fe (112 mg, 2.00 mmol) and ammonium chloride (107 mg, 2.00 mmol), and the mixture was heated to 60 °C and stirred overnight. The reaction was cooled and filtered through celite, washing with EtOAc. The filtrate was washed with aqueous NaHCO ₃ solution (10 mL) and brine (10 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo to give the title compound as a yellow solid (103 mg, 88%). LCMS m/z = 315 [M+Na] ⁺ . Step 4. Synthesis of (R)-N-(3-(1,4-oxazoloheptan-3-yl)phenyl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(3-(1,4-oxazoloheptan-3-yl)phenyl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Using a procedure similar to that described for Example 210, Step 4, the title compound was prepared as a white solid (11.1 mg, 12%). Chiral SFC (Regis Whelk O-1 (S,S) 21 × 250 mm, 35% EtOH + 0.25% diethylamine in CO ₂ ) provided: Peak 1, Example 211. (R)-N-(3-(1,4-oxazoloheptan-3-yl)phenyl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(3-(1,4-oxazoloheptan-3-yl)phenyl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (white solid, 11.1 mg, 12%); LCMS m/z = 474 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 11.74 (s, 1H), 9.74 (s, 1H), 8.67 (s, 1H), 8.44 (d, 1H), 7.79 (d, 2H), 7.69-7.59 (m, 2H), 7.49 (d, 1H), 7.26 (t, 1H), 7.05 (d, 1H), 3.90-3.76 (m, 3H), 3.70 (dt, 1H), 3.06 (s, 1H), 2.81 (dt, 1H), 1.86 (q, 2H), 1.06 (d, 2H). Example 212. Synthesis of (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(oxolin-3-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(oxolin-3-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

Methyl 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B10, 60 mg, 0.175 mmol) and tert-butyl 3-(5-aminopyridin-3-yl)morpholine-4-carboxylate (Intermediate A68, 58.4 mg, 0.210 mmol) were added to a dry flask and evacuated and backfilled with _N2 (3x). Anhydrous toluene (3.5 mL) was added, and the solution was cooled to 0 °C and _AlMe3 (2 M in toluene; 262 μL, 0.525 mmol) was added dropwise. The reaction was removed from the ice bath and stirred at room temperature for 10 min, and then at 100 °C for 1.5 h. The reaction was cooled to room temperature and quenched with MeOH (2 mL) and TFA (0.2 mL), poured into water (15 mL) and extracted with DCM (4×10 mL). The combined organics were washed with saturated aqueous NaHCO ₃ solution, water, brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was dissolved in EtOAc (2.5 mL) and HCl (4 M in dioxane, 218 μL, 0.872 mmol) was added dropwise. The mixture was stirred at room temperature for 18 h and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO, 12 g silica, 0-10% MeOH (containing 10% NH ₄ OH) in DCM) followed by chiral SFC (ChiralPak AD-H 21×250 mm, 40% MeOH + 0.25% diethylamine in CO ₂ ) to give: Peak 1, Example 212 . (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(oxolin-3-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(oxolin-3-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (white solid, 21.9 mg, 26%); LCMS m/z = 492 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 11.79 (s, 1H), 10.03 (s, 1H), 8.74 (d, 1H), 8.33 (d, 1H), 8.19 (s, 1H), 7.73 (s, 1H), 7.06 (s, 2H), 5.98 (s, 1H), 3.97 (dd, 1H), 3.91-3.79 (m, 5H), 3.66 (t, 1H), 3.41 (t, 1H), 3.20-3.06 (m, 1H), 3.01 (d, 1H). Example 213. Synthesis of (S)-4-amino-N-(5-(azacyclobutan-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(azacyclobutan-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of tert-butyl 2-(5-aminopyridin - 3- yl)azinecyclobutane-1-carboxylate .

A suspension of 5-bromopyridin-3-amine (77.1 mg, 0.45 mmol), 1-(tert-butoxycarbonyl)azinecyclobutane-2-carboxylic acid (214 mg, 0.90 mmol), Cs ₂ CO ₃ (448 mg, 1.35 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl (18.4 mg, 0.068 mmol), NiCl ₂ DME adduct (10.1 mg, 0.045 mmol) and [Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)]PF ₆ (5.0 mg, 0.0045 mmol) in anhydrous DMF (15 mL) was purged with N ₂ for 20 min and then heated in a Penn PhD M2 photoreactor using 450 nM blue LED light at room temperature for 72 h. The reaction was filtered through celite and washed with EtOAc (50 mL). The filtrate was washed with water (3×) and brine, and evaporated to dryness. The residue was purified by flash chromatography (ISCO, 12 g silica, 0-10% MeOH/DCM) to provide the title compound (44.3 mg, 39%) as a yellow-orange oil, which was used in step 2 without further purification. Step 2. Synthesis of (S)-4-amino-N-(5-(azacyclobutan-2-yl) pyridin -3- yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(azacyclobutan-2-yl) pyridin -3- yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

A dry vial containing methyl 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B10, 41.4 mg, 0.120 mmol) and tert-butyl 2-(5-aminopyridin-3-yl)azinecyclobutane- ₁ -carboxylate (Step 1, 43.4 mg, 0.168 mmol) was evacuated and backfilled with _N2 (3x). Anhydrous toluene (1.5 mL) was added, and the mixture was cooled on ice. To this solution was added AlMe3 solution (2.0 M in toluene, 0.180 mL) dropwise. The reaction was stirred on ice for 5 min, at room temperature for 5 min, and then at 100 °C for 1 h. The reaction was cooled, diluted with DCM (5 mL) and quenched with MeOH (1 mL) and TFA (0.2 mL). The mixture was poured into water and extracted with DCM (4×10 mL). The combined organics were washed with saturated aqueous NaHCO3, saturated aqueous Rochelle salt, brine, dried (MgSO4) and concentrated by rotary evaporation. The residue was purified by prep-HPLC-1 (1%-50% MeCN) followed by chiral SFC (REGIS(S,S)WHELK-O1 250×25 mm, 10 μm; 50% MeOH (+0.1% _NH4OH ) in _CO2 ) to give: Peak 1, Example 213 ; (S)-4-amino-N-(5-(azacyclobutan-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(azacyclobutan-2-yl)pyridin-3-yl)-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (4.7 mg, 27%) as a white solid. LCMS m/z = 461 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.82 (s, 1H), 10.02 (d, 1H), 8.66 (s, 1H), 8.29 (s, 2H), 7.73 (s, 1H), 7.07 (s, 2H), 6.07 (d, 1H), 5.09 (t, 1H), 3.88 (s, 3H), 3.87-3.81 (m, 1H), 3.50 (td, 1H), 2.69-2.58 (m, 1H), 2.47 (dd, 1H). Example 214. Synthesis of 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,4R)-4-methylazolobutyl-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide formate or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,4S)-4-methylazolobutyl-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide formate. Step 1. Synthesis of 2-(5-aminopyridin - 3- yl)-4-methylazinecyclobutane-1-carboxylic acid tert-butyl ester trifluoroacetate .

The title compound (91 mg, 60%) was prepared as a yellow oil as a mixture of non-mirror isomers from 1-(tert-butoxycarbonyl)-4-methylazinecyclobutane-2-carboxylic acid using a procedure similar to that described for Example 213, Step 1. prep-HPLC-12 (10%-40% MeCN). LCMS m/z = 264 [M+H] ⁺ . Step 2. Synthesis of 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2S,4R)-4-methylazolobutyl-2-yl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide formate or 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-((2R,4S)-4-methylazolobutyl-2-yl) pyridin -3- yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide formate .

A suspension of tert-butyl 2-(5-aminopyridin-3-yl)-4-methylazinecyclobutane-1-carboxylate trifluoroacetate (88 mg, 0.240 mmol) and K ₂ CO ₃ (202 mg, excess) in MeCN (3 mL) was stirred at room temperature for 20 min. The mixture was filtered, washed with MeCN and the filtrate was evaporated to dryness. A mixture of the residue and methyl 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B10, 60 mg, 0.171 mmol) was evacuated and backfilled with N ₂ (3×). Anhydrous toluene (2.1 mL) was added and the mixture was cooled on ice. To this was added dropwise AlMe ₃ solution (2.0 M in toluene, 0.514 mmol) and the reaction was stirred on ice for 5 min, at room temperature for 5 min and at 100 °C for 1 h. The reaction was cooled, diluted with DCM (5 mL) and quenched with MeOH (1.0 mL) and TFA (0.1 mL). The mixture was poured into water and extracted with DCM (4× 15 mL). The combined organics were washed with saturated aqueous NaHCO ₃ solution, saturated aqueous Rochelle salt solution, brine, dried (MgSO ₄ ) and evaporated to dryness. The residue was dissolved in DCM (3 mL) and TFA (0.6 mL) and stirred at room temperature for 2 h and evaporated to dryness in vacuo. The residue was purified by reverse phase HPLC-12 (10%-50% MeCN) to give 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(5-(4-methylazinocyclobutan-2-yl)pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate (74.1 mg TFA salt) as a light yellow solid as a 1:1 non-mirror isomer mixture. The TFA salt was dissolved in MeCN (4 mL) and saturated aqueous NaHCO ₃ solution (0.5 mL), and the mixture was stirred at room temperature for 40 min. The solid was removed by filtration, and the filtrate was evaporated to dryness. The residue was separated by chiral SFC to give the title compound (4 mg, 43%) as a light yellow solid. LCMS m/z = 475 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.89 (s, 1H), 9.73-9.63 (m, 1H), 8.82-8.73 (m, 1H), 8.68 (d, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 7.43 (s, 2H), 4.94 (t, 1H), 3.94 (s, 3H), 3.84-3.72 (m, 1H), 2.32-2.26 (m, 2H), 1.44-1.37 (m, 3H). Example 215. Synthesis of (R)-N-(5-(1,4-oxazoloheptan-5-yl)pyridin-3-yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazoloheptan-5-yl)pyridin-3-yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

Methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 55 mg, 0.175 mmol) and tert-butyl 5-(5-aminopyridin-3-yl)-1,4-oxazolidinone-4-carboxylate (Intermediate A28, 61.6 mg, 0.21 mmol) were added to a dry flask and evacuated and backfilled with _N2 (3x). Anhydrous toluene (3.5 mL) was added and the solution was cooled to 0 °C before _AlMe3 solution (2 M in toluene, 263 μL, 0.525 mmol) was added dropwise. The reaction was removed from the ice bath and stirred at ambient temperature for 10 min and at 100 °C for 1.5 h. The reaction was cooled to room temperature and quenched with MeOH (2 mL) and TFA (0.2 mL), poured into H ₂ O (15 mL) and extracted with DCM (4×10 mL). The combined organics were washed with saturated aqueous NaHCO ₃ , water, brine, dried (Na ₂ SO ₄ ) and evaporated to dryness. The residue was dissolved in DCM (1.7 mL) and TFA (13.49 μl, 0.175 mmol) was added dropwise. The mixture was stirred at room temperature for 18 h and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ISCO, 12 g silica, 0-15% MeOH (+10% NH ₄ OH)/DCM) to give an off-white solid (32 mg, 38%). The racemate was separated by chiral SFC (REGIS (S,S) WHELK-O1, 250 × 25 mm, 10 μm); 50% MeOH (0.1% NH ₄ OH) in CO ₂ ) to give: Peak 1, Example 215 . (R)-N-(5-(1,4-oxazacycloheptan-5-yl)pyridin-3-yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-N-(5-(1,4-oxazacycloheptan-5-yl)pyridin-3-yl)-4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (off-white solid, 9.9 mg, 30%). LCMS m/z = 475 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.66 (s, 1H), 9.98 (br d, 1H), 8.61 (br s, 1H), 8.27 (br s, 1H), 8.11 (s, 1H), 7.66 (s, 1H), 7.49-7.47 (m, 2H), 7.41-7.39 (m, 1H), 5.99 (br d, 1H), 3.97 (br t, 1H), 3.90-3.70 (m, 4H), 3.11-3.06 (m, 1H), 3.01-2.95 (m, 1H), 2.07-2.04 (m, 2H). Example 216. Synthesis of (R)-4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-N-(5-(hexahydropyridin-2-yl)pyridin-3-yl)-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (R)-2-(5-(4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl) hexahydropyridine -1- carboxylic acid tert-butyl ester .

To _a mixture of methyl 4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B24, 1.1 g 3.22 mmol) and tert-butyl (R)-2-(5-amino-3-pyridinyl)hexahydropyridine-1-carboxylate (Intermediate A4, 983 mg, 3.55 mmol) in toluene (20 mL) was added _AlMe3 (2 M in toluene, 4.83 mL) under N2 at 0°C. The reaction mixture was stirred at 100°C under _N2 for 1 h. The reaction mixture was quenched with 2 M NaOH (50 ml) and extracted with EtOAc (3 x 60 mL). The combined organics were dried ( _Na2SO4 ) and evaporated _to dryness in vacuo. The residue was purified by column chromatography on silica gel (0-50% EtOAc/PE) to give the title compound as a brown solid (1 g, 53%). LCMS m/z = 587 [M+H] ⁺ . Step 2. Synthesis of (R)-4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-N-(5-(hexahydropyridin - 2- yl) pyridin- 3- yl)-1,6-dihydropyrimidine-5-carboxamide.

A mixture of (R)-tert-butyl 2-(5-(4-amino-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)hexahydropyridine-1-carboxylate (Step 1, 800 mg, 1.36 mmol) in HCl/EtOAc (2 mL) and EtOAc (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was evaporated to dryness in vacuo, and the pH of the residue was adjusted to pH 9-10 with 0.25 M aqueous Na ₂ CO ₃ solution. The solid was collected to give the title compound (560 mg, 84%) as a white solid. LCMS m/z = 487 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.77 (s, 1 H), 9.95 (d, 1H), 8.60 (d, 1H), 8.23 (d, 1H), 8.08 (t, 1H), 7.63 (s, 1 H), 7.44 (s, 2 H), 6.12 (d, 1H), 3.52-3.61 (m, 1 H), 3.13 (d, 1H), 2.64-2.76 (m, 1 H), 2.18 (s, 6 H), 1.72-1.86 (m, 2 H), 1.55-1.61 (m, 1 H), 1.45-1.51 (m, 1 H), 1.36-1.45 (m, 2 H). Example 217. Synthesis of (S)-4-amino-1-((S)-2-chloro-6-methylphenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-((S)-2-chloro-6-methylphenyl)-N-(2-fluoro-3-(pyrrolidin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (S)-2-(3-(4-amino-1-((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-2-fluorophenyl) pyrrolidine -1- carboxylic acid tert-butyl ester or (R)-2-(3-(4-amino-1-((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-2-fluorophenyl) pyrrolidine -1 -carboxylic acid tert-butyl ester .

To a mixture of methyl 4-amino- ₁ -((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B3, 100 mg, 0.340 mmol) and tert-butyl (S)-2-(3-amino-2-fluorophenyl)pyrrolidine-1-carboxylate or tert-butyl (R)-2-(3-amino-2-fluorophenyl)pyrrolidine-1-carboxylate (Intermediate A85, 124 mg, 0.443 mmol) in toluene (1.5 mL) was added _AlMe3 (2 M, 0.51 mL) in toluene under _N2 at 0°C and the mixture was stirred at 100°C under N2 for 0.5 h. The reaction mixture was quenched by adding into water (10 mL). The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM (20 mL) and 1 M aqueous NaOH (15 mL) and the aqueous phase was extracted with DCM (3 x 20 mL). The combined organics were dried _{( Na2SO4} ) and concentrated under reduced pressure and the residue was purified by prep-TLC ( _SiO2 , 50% EtOAc/PE). The residue was further purified by chiral SFC (Diacel Chiralpak AD, 30 × 250 mm, 10 μm; 33% IPA (0.1% NH ₄ OH) in CO 2 ) to give: Peak 1, (S)-2-(3-(4-amino-1-((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-2-fluorophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester or (R)-2-(3-(4-amino-1-((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-2-fluorophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 22%). LCMS m/z = 564 [M+Na] ⁺ . Step 2. Synthesis of (S)-4- amino-1-((S)-2-chloro-6-methylphenyl)-N-(2-fluoro-3-( pyrrolidin -2- yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-1-((S)-2-chloro-6-methylphenyl)-N-(2-fluoro-3-( pyrrolidin -2- yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

(S)-tert-butyl 2-(3-(4-amino-1-((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-2-fluorophenyl)pyrrolidine-1-carboxylate or (R)-tert-butyl 2-(3-(4-amino-1-((S)-2-chloro-6-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-2-fluorophenyl)pyrrolidine-1-carboxylate (Step 1, 40 mg, 0.074 mmol) in HCl/EtOAc (2 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under N ₂ flow, and the residue was purified by prep-HPLC-3 (10%-50% MeCN) to give the title compound (10.1 mg, 31%) as a yellow solid. LCMS m/z = 442 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.10 (d, 1H), 9.61 (d, 1H), 8.62 (d, 1H), 8.32 (s, 1H), 8.27-8.24 (m, 1H), 7.58-7.56 (m, 1H), 7.52-7.45 (m, 2H), 7.25-7.22 (m, 1H), 7.14-7.10 (m, 1H), 4.34 (br t, 1H), 3.04-2.91 (m, 2H), 2.21-2.15 (m, 4H), 1.79-1.74 (m, 2H), 1.56-1.49 (m, 1H). Example 218. Synthesis of (R)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(5-(1-aminoethyl)pyridin-3-yl)-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of (R)-t-butyl(1-(5-(4-amino-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)ethyl)carbamate or (S)-t-butyl(1-(5-(4-amino-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido) pyridin -3- yl)ethyl)carbamate .

To a mixture of methyl 4-amino-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (intermediate B58, 30 mg, 0.100 mmol) and tert-butyl (S)-(1-(5-aminopyridin-3-yl)ethyl)carbamate or (R)-tert-butyl (1-(5-aminopyridin-3-yl)ethyl)carbamate BP1491256_A6 (intermediate A16, 30.71 mg, 0.129 mmol) in toluene (3 mL) was added _AlMe3 (2 M in toluene, 0.149.33 mL) at 0°C and the mixture was stirred under _N2 at 0°C for 5 min and at 40°C for 40 min. To the reaction mixture was added NaOH (2 M, 3 mL) at 0°C and then extracted with EtOAc (3 x 10 mL). The combined organics were dried ( _Na2SO4 ) and concentrated under reduced pressure to give the title compound as _a yellow solid (40 mg, 79%). LCMS m/z = 507 [M+H] ⁺ . Step 2. Synthesis of (S)-4-amino-N-(5-(1-aminoethyl) pyridin -3- yl)-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (R)-4-amino-N-(5-(1-aminoethyl) pyridin -3 -yl)-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide .

To a solution of (S)-tert-butyl(1-(5-(4-amino-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)carbamate or (R)-tert-butyl(1-(5-(4-amino-1-(4-ethyl-2,6-dimethylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)ethyl)carbamate (step 1, 35 mg, 0.069 mmol) in DCM (2 mL) was added TFA (2 mL) and the mixture was stirred at 25 °C for 20 min. The reaction mixture was concentrated under N ₂ , and the residue was purified by prep-HPLC-1 (10%-45% MeCN) to give the title compound (21.5 mg, 76%) as a white solid. LCMS m/z = 407 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 11.99 (s, 1H), 9.75 (d, 1H), 8.49 (d, 1H), 8.23 (d, 2H), 7.66 (s, 1H), 6.97 (s, 2H), 6.13 (d, 1H), 4.19 (d, 1H), 2.57 (q, 2H), 2.06 (d, 6H), 1.43 (d, 3H), 1.19 (t, 3H). Example 219. Synthesis of (R)-4-amino-N-(6-(1-aminoethyl)pyrazin-2-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-N-(6-(1-aminoethyl)pyrazin-2-yl)-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or

The title compound (16.3 mg, 23%) was prepared as a yellow solid from methyl 4-amino-1-(2,6-dichloro-4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B30) and 6-(1-aminoethyl)pyrazin-2-amine (Intermediate A80) using a method similar to that described for Example 2. HPLC-1 (10%-40% MeCN). LCMS m/z = 464 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ): 12.11 (s, 1 H) 9.97 (s, 1 H) 9.51 (s, 1 H) 8.27 (s, 1 H) 7.75 (s, 1 H) 7.04 (s, 2 H) 6.06 (s, 1 H) 4.22 (m, 1 H) 4.09 (m, 2 H) 1.44-1.49 (m, 6 H). Example 220. Synthesis of 4-amino-N-(3-(aminomethyl)-2-ethoxyphenyl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

The title compound (16.3 mg, 23%) was prepared as a yellow solid from methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B9) and 3-(aminomethyl)-2-ethoxyaniline (Intermediate A83) using a method similar to that described for Example 2. HPLC-12 (10%-50% MeCN); LCMS m/z = 448 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 12.03 (s, 1H), 9.68 (d, 1H), 8.67 (d, 1H), 8.43 (s, 1H), 8.35 (dd, 1H), 8.08 (s, 3H), 7.77 (d, 2H), 7.64 (t, 1H), 7.24-7.13 (m, 2H), 4.03 (s, 2H), 3.81 (q, 2H), 1.26 (t, 3H). Example 221. Synthesis of 4-amino-N-(3-(aminomethyl)-2-methoxyphenyl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate. Step 1. Synthesis of (3-amino-2-methoxyphenyl)methanol .

Anhydrous THF (20 mL) was added to LiAlH ₄ (484 mg, 12.5 mmol) under N ₂ , and the mixture was cooled on ice. A suspension of 3-amino-2-methoxybenzoic acid (830 mg, 5.0 mmol) in anhydrous THF (30 mL) was added dropwise over 15 min, and the reaction mixture was warmed to room temperature and heated to 60 °C for 3 h. The reaction was carefully quenched by dropwise addition of water. The mixture was diluted with EtOAc (10 mL) and saturated aqueous NH ₄ Cl solution (1 mL), and stirred at room temperature for 1.5 h. The mixture was poured into aqueous NaHCO ₃ solution, and extracted with EtOAc (4× 50 mL). The combined organics were washed with water (2x), brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (ISCO 40 g silica, 0-20% MeOH/DCM) to give the title compound as a waxy solid (466 mg, 60%). LCMS m/z = 154 [M+H] ⁺ . Step 2. Synthesis of 4-amino-1-(2,6-dichlorophenyl)-N-(3-(hydroxymethyl)-2-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate

Trimethylaluminum solution (2.0 M in toluene, 0.450 mmol) was added dropwise to an ice-cold mixture of methyl 4-amino-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B9, 49.1 mg, 0.150 mmol) and (3-amino-2-methoxyphenyl)methanol (Part 1, 34.5 mg, 0.225 mmol) in anhydrous toluene (3 mL). The reaction mixture was stirred at room temperature for 10 min and then heated to 100 °C for 75 min. The cooled reaction mixture was diluted with DCM (5 mL) and quenched with MeOH (2 mL) and TFA (0.2 mL). The mixture was poured into water and extracted with DCM (4 x 10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, water, brine, dried (MgSO ₄ ) and evaporated to dryness. The residue was purified by prep-HPLC-12 (10%-60% MeCN) to give the title compound as a white powder (26.5 mg, 32%). LCMS m/z = 435 [M+H] ⁺ . Step 3. Synthesis of 4-amino-N-(3-(aminomethyl)-2-methoxyphenyl)-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate .

A solution of 4-amino-1-(2,6-dichlorophenyl)-N-(3-(hydroxymethyl)-2-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide trifluoroacetate (Step 2, 24.4 mg, 0.044 mmol), DIPEA (11.5 μL, 0.066 mmol), CBr ₄ (24.1 mg, 0.072 mmol) and PPh ₃ (19.0 mg, 0.072 mmol) in DMF (0.8 mL) and DMSO (0.2 mL) was stirred at room temperature for 45 min. NaN ₃ (5.7 mg, 0.088 mmol) was added thereto, and the mixture was heated to 60 °C for 3 h. The reaction was diluted with EtOAc (20 mL) and washed with water (3x), brine, dried (MgSO4) and concentrated by rotary evaporation.

To the residue dissolved in THF (0.80 mL) were added PPh ₃ (28.1 mg, 0.107 mmol) and water (20.0 μL, 1.10 mmol), and stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by prep-HPLC-12 (10%-50% MeCN) to give the title compound (0.7 mg, 2%) as a colorless film. LCMS m/z = 434 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.05 (s, 1H), 9.70 (d, 1H), 8.70 (d, 1H), 8.48-8.37 (m, 2H), 8.09 (s, 3H), 7.78 (d, 2H), 7.65 (t, 1H), 7.20 (t, 1H), 7.15 (d, 1H), 4.05 (q, 2H), 3.70 (s, 3H). Example 222. Synthesis of (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(hexahydropyridin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(hexahydropyridin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide. Step 1. Synthesis of tert-butyl 2-(3-(4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-5-fluorophenyl) hexahydropyridine -1- carboxylate .

Trimethylaluminum solution (2.0 M in toluene, 0.110 mL, 0.214 mmol) was added dropwise to an ice-cold solution of methyl 4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (Intermediate B10, 24.5 mg, 0.071 mmol) and tert-butyl 2-(3-amino-5-fluorophenyl)pyridine-1-carboxylate (Intermediate A85, 33 mg, 0.107 mmol) in anhydrous toluene (1.4 mL). The reaction was stirred at room temperature for 10 min and then heated to 100 °C for 1 h. The reaction mixture was cooled, diluted with DCM (5 mL) and quenched with MeOH (2 mL) and TFA (0.2 mL). The mixture was poured into water and extracted with DCM (4 x 10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, water, brine, dried (MgSO ₄ ) and evaporated to dryness to give the title compound. LCMS m/z = 628 [M+Na] ⁺ . Step 2. (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(hexahydropyridin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(hexahydropyridin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide.

2-(3-(4-amino-1-(2,6-dichloro-4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamido)-5-fluorophenyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (Step 1) was dissolved in DCM (2 mL) and TFA (0.5 mL) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation and the residue was purified by prep-HPLC-12 (10%-50% MeCN), followed by chiral SFC (Rilas Technologies, Regis Whelk O-1 (S,S) 21 × 250 mm, 30% EtOH + 0.25% diethylamine in CO ₂ ), 70 mL/min) to give: Peak 1, Example 222. (R)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(hexahydropyridin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide or (S)-4-amino-1-(2,6-dichloro-4-methoxyphenyl)-N-(3-fluoro-5-(hexahydropyridin-2-yl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (white solid, 6.3 mg). LCMS m/z = 506 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ): 12.16 (s, 1H), 9.57 (s, 1H), 8.90 (s, 1H), 8.77 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.85 (d, 1H), 7.37 (s, 2H), 7.35 (s, 1H), 7.02 (d, 1H), 4.26 - 4.17 (m, 1H), 3.89 (s, 3H), 3.07-2.95 (m, 1H), 1.97-1.52 (m, 6H). Biological Example 1. In vitro enzyme activity analysis

Full-length human GSK3α or GSK3β expressed as N-terminal GST fusion proteins in a bacillivirus host was purchased from Carna Biosciences (Japan). The kinase was pre-incubated with ATP (adenosine-5'-triphosphate) for 45 min and then incubated with the test compounds for another 45 min in assay buffer containing 100 mM HEPES (N-2-hydroxyethylhexahydropyrazine-N'-2-ethanesulfonic acid) (pH 7.5), 10 mM MgCl ₂ , 1.0 mM DTT and 0.015% Briji-35. Serial dilutions of the compounds were prepared in DMSO (dimethyl sulfoxide) and transferred to 384-well plates (Greiner BioOne) by Mosquito (SPT Labtech). The final reaction mixture containing 0.2 nM GSK3α or GSK3β kinase, 1.0 mM ATP (ATP Km measured was 10-15 uM) and 1.0 μM peptide substrate (5-FAM-KRREILSRRPpSYR-COOH (SEQ ID NO: 1), ProfilerPro Peptide 15, Perkin Elmer) was initiated by adding substrate peptide and incubated at 25°C for 120 minutes. The reaction was terminated by adding excess EDTA. The substrate was separated from the product and the fluorescence intensity of the substrate and product peaks was determined by Labchip EZ Reader II (Caliper Life Sciences, Hopkinton, MA). The percentage of inhibition was plotted against compound concentration to generate a 10-point dose response curve of 3-fold serial dilutions starting from 10 μM. IC50 values were determined by 4-parameter logistic curve fitting. Biological Example 2. In vitro cell activity analysis

Cellular target engagement or cell binding of test compounds was measured in the NanoBRET ^™ assay, which is based on the binding competition between test compounds and a bioluminescent tracer in human embryonic kidney cells (HEK-293 cell line). In this assay, HEK293 cells stably expressing Nanoluc-GSK3A or Nanoluc-GSK3B were maintained in culture medium and seeded overnight in 384-well white plates containing 100 ng/ml doxycycline (Sigma) at a density of 5×10 ³ cells/well using a multi-drop dispenser. Compounds were first diluted in DMSO to generate a 9-point serial dilution and then diluted to 10× final concentration in Opti-MEM ^™ (Gibco). After overnight incubation, the cell culture medium was aspirated from the seeded cells using an automated microplate washer, followed by the addition of 27 μL of pre-warmed Opti-MEM ^™ containing a kinase tracer (K-8) and 3 μL of Opti-MEM ^™ diluted DMSO or compound to each well. The plate was protected from light, mixed on an orbital shaker at room temperature for 3 min, and incubated in a humidified incubator at 37°C, 5% CO ₂ for 2 hours. After acclimation at room temperature for 15 min, 15 μL of 3× Complete NanoBRET ^™ Nano-Glo Substrate/Inhibitor (Promega) was added to each well. The plate was mixed on an orbital shaker at room temperature for 3 min, and incubated for an additional 30 min. Donor emission at 460 nm and acceptor emission at 647 nm were measured in an EnVision multilabel plate reader (Perkin Elmer).

The bioassay data for the exemplary compounds are provided in Table 1 below. Examples GSK3α (nM) GSK3β (nM) NanoBRET GSK3α IC50 (nM) NanoBRET GSK3β IC50 (nM) 1 3.6 167.9 3.6 243 2 7 399.4 4.9 328.9 3 6.6 344.4 5 395.2 4 3.7 186.8 1.4 109.3 5 8.3 378.1 6.2 382.7 6 7.2 292.4 6.5 352 7 7.5 336.8 7.1 480.3 8 4.8 204.3 3.3 169.1 9 9.5 661.3 7.4 429.9 10 8.8 395 6.9 370.5 11 14.4 647.6 4.1 252.2 12 3.8 199.2 2.4 140.8 13 17.7 1006.8 9.8 502.6 14 6.4 318.4 4 230.7 15 4.5 208 2.2 118.6 16 4.1 254.7 1.9 132.3 17 7.8 339.6 3.8 270.6 18 11.9 621.5 7.1 428.9 19 3.2 231.7 3.5 179.8 20 14 685.1 7.2 396.5 twenty one 3.2 216.6 2.6 145.2 twenty two 8.4 389.3 5.6 334.1 twenty three 5 342.7 4.3 239.3 twenty four 4.1 297.8 2.8 146.9 25 13.9 691.8 7.5 714.9 26 5.5 327.2 4.4 268.7 27 2.4 54.2 1.7 42.5 28 9.6 320.4 9 698.8 29 92.2 3799.7 79.2 25000 30 63.9 1949 72.2 15760.8 31 6.9 404.8 5 417.8 32 6.3 269 2.6 157.8 33 6.4 343.1 8.3 460.7 34 6.5 344.4 3.7 268.1 35 14.7 693.4 6.2 411.6 36 7.3 301.9 4.4 289.8 37 8.4 388 7.6 431.4 38 4.6 282.3 3.6 229.9 39 2.6 106.9 2.1 128.6 40 10.1 418 5.8 430.5 41 12.1 604.8 5.9 385.9 42 4.8 297.5 2.9 257.1 43 4.9 283 5.4 284.7 44 4.7 381.8 7.6 518 45 8.5 384.4 6.6 364.7 46 10.5 489.3 7.3 395 47 3.2 227.3 2.9 173.9 48 5.2 343.4 4.7 297.9 49 2.5 160.6 2.8 144.5 50 16.5 708.3 7.4 438.9 51 2.8 141.9 2.2 123.5 52 4.4 208.8 2.5 131.5 53 12.9 625.3 6.8 356.2 54 5.4 345.2 5.4 340.3 55 9.1 430.1 6.5 483.3 56 5.7 323.4 4.8 272.8 57 7.9 382.2 5.4 276.8 58 2.1 152.5 2.8 146.6 59 3.1 224.3 2.5 187 60 6.5 333.8 3 199.5 61 6.4 465.5 3.7 284.4 62 2 123 2.4 155.4 63 4.5 209.4 4.4 234 64 11.7 621.3 6.5 489.4 65 5.1 302 3.1 217 66 6 348.8 2.9 206 67 2.1 105.1 1.4 73.4 68 2.6 167.3 1.9 219.6 69 12.5 536 7 513.3 70 2.9 145.3 2.4 201.4 71 6.3 383.4 4.8 353 72 7.5 468.3 5.1 378.6 73 6.7 318 5.8 374 74 9.6 464.8 6.6 363.4 75 2.4 106.1 3.6 186.2 76 16 854 9.4 591.4 77 2.2 152.1 3.5 195.9 78 11.4 958.4 7.7 703.4 79 4.3 316.9 2.4 169.8 80 2.5 269.9 2.9 270.7 81 5.9 313.7 2.3 116.6 82 4.5 247.6 4 269.3 83 7 490.1 4.1 336.3 84 3.8 253.8 2.5 179.3 85 9.4 551 4.2 373.8 86 6.6 413.7 4.2 320.9 87 17.9 1127.3 7.6 542.8 88 15.4 1015.7 8.1 453.6 89 10.2 668.9 6.4 484.6 90 15.6 1065.2 6.5 700.1 91 6 299.1 3.7 200.7 92 16.4 1027 6.8 584 93 31.7 1949.2 9.3 914.4 94 7.6 598.4 6.6 383.5 95 9.8 464.6 4.3 289.6 96 16.4 705.8 6.7 640.2 97 3.6 229.7 1.8 120.8 98 4.6 253.5 2.5 133.5 99 20.5 1023.6 7.4 565.2 100 8.2 347.8 3.9 293.1 101 19.6 941.3 7.8 799.7 102 16.5 683.8 5 584 103 13.2 581 6.6 532.5 104 16.2 746.2 7.9 520.9 105 19.3 1126.7 7.2 576.6 106 4.5 278.9 2.8 195.5 107 10 671.4 3.9 434.5 108 24.6 998.1 8.7 688.4 109 15.6 802.9 8.4 567 110 9.9 567.8 3.7 334.9 111 3 163.3 2 139.9 112 10.5 493.5 5.1 348.5 113 3 132.9 1.7 107 114 12.1 506.7 4.4 251.9 115 7.6 362.2 4.7 280.7 116 2.9 125.1 1.8 101.4 117 2.2 104.1 1.4 81.1 118 11.2 449.8 9.4 566.3 119 8.1 414.1 8.1 502.1 120 9.4 442.2 4.4 274.3 121 3.8 306.5 3.4 395.4 122 5.3 327 5 313.8 123 4.8 266.2 3.3 202.6 124 7 393.4 7.8 404.3 125 4.9 296.5 2.7 162.6 126 14.7 701.8 7.9 505.9 127 18.6 767.4 9.6 649.6 128 19 1175.6 7.7 545.9 129 2.1 104.8 1.2 81.7 130 13.5 591 5.3 461.4 131 4.9 201.7 2.3 159 132 5.5 228 2 180.7 133 9.7 508.2 6.1 349.5 134 3.4 212.1 3.2 204 135 3.2 184.2 4.5 264.3 136 2.9 205.7 1.8 118.1 137 1.9 129.4 1.7 87.1 138 6.4 321.7 2.9 211.7 139 10.9 559.7 5.1 281.2 140 24.2 1235.7 9.2 615.8 141 4.1 232 2.9 317.7 142 9.8 420.6 4.7 349.8 143 4.9 207.2 4.1 280.1 144 11 472.4 5 375.4 145 3 129.3 1 96.2 146 7.7 355.3 3.7 339.8 147 8.8 392 3.8 354 148 7.2 316.5 4.3 349 149 13.4 552.5 8.6 518.6 150 1.1 44.2 1 49.5 151 14.9 500.9 7.1 405.8 152 2.7 119.8 2.4 173.6 153 7.8 345.8 6.4 490.9 154 7 245.5 3.2 258.9 155 9.9 373.5 3.7 278.8 156 34.9 1252.1 8.1 956.6 157 32.5 1315.6 11.3 1155 158 9.3 355.1 37.3 531.9 159 90.6 2082.4 76.9 5788.8 160 161.4 2316.7 196.9 11315.6 161 7.2 378.8 3 287.3 162 5.6 218.3 5.4 300.5 163 5.6 250 2.8 205 164 29.4 1849.6 9.7 1165.9 165 10.8 434.3 9.3 1119.1 166 285.1 9383.3 176.6 16079.1 167 45.4 1814.1 27.2 1864 168 49.3 1526.6 27.1 1469.9 169 4.2 105.2 2 103.4 170 21.8 520 16.4 525.6 171 44.8 1278.1 30.1 851.3 172 6.3 259.9 3.5 98.8 173 1883.3 10000 1510.8 25000 174 28 705.1 8.7 559.8 175 32.6 803.3 8.1 580.7 176 5.1 272.3 2.6 190 177 4 199.7 2.8 283 178 7.2 335.2 4.8 259.7 179 3.7 256.8 3.3 178.6 180 6.4 297.5 4.7 321.6 181 7.9 535.6 7 490.7 182 17.4 914.6 8.2 643.1 183 7.9 576 5 299.9 184 3.9 175.3 2.1 166.7 185 3.5 147.8 1.6 128 186 4.4 169.2 2.1 151.9 187 8.4 356.6 5.6 421.1 188 10.4 460.4 3.9 345.1 189 133 2164.3 69.4 4579.9 190 37.6 971.5 26.7 3300.4 191 5.7 229.5 4.7 304.3 192 1.8 14.7 1.4 18.8 193 9.2 480.6 6.8 487.1 194 6.2 302.2 5.1 329.8 195 11 632.1 5.4 462.5 196 6.6 399.7 4.2 242.2 197 15 849.5 7.2 402.6 198 5.6 331.5 3.7 208.8 199 3.3 202.7 2.4 118 200 14.4 813.5 7.6 451.1 201 13.7 607.8 7.4 430.2 202 8.7 431.6 5.9 385.4 203 8 318.1 3.7 293.2 204 13.5 706.3 8.8 781.9 205 5 238 3.7 204.5 206 9.4 259.8 3.1 139.1 207 5.3 233.8 965.5 25000 208 2.4 203 2.4 166.2 209 5.2 383 5.9 300.4 210 3.9 204.5 4 227.7 211 15.9 887.5 8.6 797.4 212 4.7 272.2 7.6 519.8 213 33.2 1759.9 7.8 992.2 214 17.3 930 8.9 640 215 7.2 500.3 8.5 689.9 216 5.6 292.6 3.4 172.8 217 7.8 305 8 424.3 218 10.8 420.6 5.6 401.3 219 5.4 270.6 3.8 187.4 220 11.7 307.8 8.1 258.6 221 15.6 399.9 7.3 235.5 222 2.1 99.2 4.6 147.6 Biological Example 3. Efficacy in the MC38 syngeneic colorectal cancer model

Murine MC38 colorectal carcinoma cells were cultured in DMEM supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin at 37°C and 5% CO ₂ atmosphere. Cells with viability > 90% were harvested and counted for subcutaneous inoculation. Female C57BL/6 mice (Beijing Vital River Laboratory Animal Technology Co) aged 8-9 weeks with a body weight of approximately 18-22 g were acclimated for 1 week and then inoculated subcutaneously into the right flank with 100 μL of MC38 cell suspension (1×10 ⁶ cells) in PBS. Body weight and tumor volume of individual mice were used as randomization parameters to assign animals to treatment groups. Treatment was initiated when tumor size reached an average of 90 mm ³ (range 80-100 mm ³ ). Compounds were prepared freshly daily in vehicle (20% (w/w) HP-β-CD in 50 mM citrate buffer (pH 3)) and administered via orogastric gavage. Anti-PD-L1 injections were administered twice weekly with an initial intravenous loading dose of 5 mg/kg followed by an intraperitoneal maintenance dose of 2.5 mg/kg BIW. Animals were monitored daily for clinical symptoms and adverse effects were detected. The volume of implanted MC38 tumors was measured twice a week using a caliper. Tumor and body weight measurements were recorded for analysis. Figure 1 shows the tumor volume in the MC38 mouse colorectal cancer model treated with anti-PD-L1 antibody, compound 178, or a combination of anti-PD-L1 antibody and compound 178.

Figure 1 shows the tumor volume in the MC38 mouse colorectal cancer model treated with anti-PD-L1 antibody, compound 178, or the combination of anti-PD-L1 antibody and compound 178.

Claims (31)

A compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, wherein is a single bond or a double bond; ^X1 is ^CR3 or N; ^X2 is selected from the group consisting of ^CR7 , N and ^NRd ; ^X3 is selected from the group consisting of ^CR12 , N and ^NRd ; ^X4 is selected from the group consisting of ^CR13 , N and ^NRd ; Z is O or S; ^R1 is selected from the group consisting of halogen, OH, CN, _C1 - _C4 alkyl and _C1 - _C4 alkoxy, wherein the _C1 - _C4 alkyl and the _C1 - _C4 alkoxy are each optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, OH and CN; ^R2 is selected from the group consisting of H, D, halogen, _C1 - _C4 alkyl and _C3 - _C10 cycloalkyl; R ³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , C ₃ -C ₁₀ cycloalkyl, 4- to 12-membered heterocyclic group, 4- to 12-membered aryl and 4- to 12-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₃ -C ₁₀ cycloalkyl and the 4- to 12-membered aryl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 residues each independently selected from the group consisting of O, S, N and NR ^d , and each of them is optionally substituted by 1 to 4 R ^c on the ring carbon; R ⁴ is selected from the group consisting of H, D, halogen, C ₁ -C ₄ alkyl and C ₃ -C ₁₀ cycloalkyl; R ⁵ is selected from the group consisting of halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted by 1 to 4 groups independently selected from the group consisting of halogen, OH and CN; R ⁶ is H or D; R ⁷ is selected from the group consisting of H, D, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C The present invention relates to a group consisting of a _C1 -C4 alkyl group, a C1-C4 alkoxy group, a C3-C10 cycloalkyl group and a 4-12 membered aryl group, wherein the _C1 - _C4 alkyl group, the _C1 - _C4 alkoxy group, the _C3 - _C10 cycloalkyl group and the 4-12 membered aryl group are each optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12 membered heterocyclic group and the 4-membered to 12 membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; R ⁸ is selected from the group consisting of H, D, halogen, _C1 - _C4 alkyl group and _C3 - _C10 cycloalkyl group; R ⁹ are each independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C ₁₀ cycloalkyl, 4- to 12-membered heterocyclic group, 4- to 12-membered aryl and 4- to 12-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₂ -C ₄ alkenyl, the C ₂ -C ₄ alkynyl, the C ₃ -C ₁₀ cycloalkyl and the 4- to 12-membered aryl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 R c each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; or R ⁷ and R ⁹ together with the carbon atom to which they are attached form Ring A, wherein Ring A is C ₃ -C ₁₀ cycloalkyl or a 4-membered to 12-membered heterocyclic group, wherein the C ₃ -C ₁₀ cycloalkyl is optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted by 1 to 4 R ^c on the ring carbon; or R ⁸ and R ⁹ together with the carbon atom to which they are attached form Ring B, wherein Ring B is C ₃ -C R ₈ and R 9 are taken together to form ═O; R 10 is selected from the group consisting of H, D, ^C ₁ -C ₄ alkyl, -(C(R a ) 2 ) n -OR b , -(C(R a ) 2 ) n -SO 2 R b , C 3 ^-C 10 cycloalkyl, 4 to 12 membered heterocyclic group, 4 to 12 membered aryl and 4 to 12 membered heteroaryl, wherein the C ₃ -C 10 cycloalkyl is optionally substituted with 1 to 4 R c, wherein the 4 to ¹² membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR d, and then optionally substituted with 1 to 4 R ^c on the ring carbon; or R ⁸ and R 9 are taken together to form ═O; R ¹⁰ is selected from the group consisting of H, D, C 1 -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ R ^b , C ₃ -C ₁₀ cycloalkyl, 4 to 12 membered heterocyclic group, 4 to 12 membered aryl and 4 to 12 membered heteroaryl, wherein the C _{The 1} - _C4 alkyl, the _C3 - _C10 cycloalkyl and the 4- to 12-membered aryl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 ring hetero atoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted with 1 to 4 R ^c on the ring carbon; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a 4- to 12-membered heterocyclic group having 1 to 4 ring hetero atoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted with 1 to 4 R ^c on the ring carbon; or R ⁷ and R ^{R 9} together with the carbon atom to which it is attached forms Ring A, and R ⁸ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are attached respectively form Ring C, wherein Ring A and Ring C are each optionally substituted on the ring carbon by 1 to 4 R ^c ; R ¹¹ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₁ -C ₄ halogenalkyl and C ₃ -C ₁₀ cycloalkyl; R ¹² is selected from the group consisting of H, D, halogenyl, C ₁ -C ₄ alkyl and C ₃ -C ₁₀ cycloalkyl; or R ¹¹ and R ^{R 12} together with the nitrogen atom and the carbon atom to which they are respectively attached form a ring D, wherein the ring D is selected from the group consisting of a 4-membered to 12-membered heterocyclic group and a 4-membered to 12-membered heteroaryl group, wherein the 4-membered to 12-membered heterocyclic group and the 4-membered to 12-membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; R ¹³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₁₀ cycloalkyl, a 4-membered to 12-membered heterocyclic group, a 4-membered to 12-membered aryl group and a 4-membered to 12-membered heteroaryl group, wherein the C ₁ -C The C 1 -C ₄ alkyl, the C ₁ -C ₄ alkoxy, the C ₃ -C ₁₀ cycloalkyl and the 4- to 12-membered aryl are each optionally substituted by 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted on the ring carbon by 1 to 4 R ^c ; R ¹⁴ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C _4- membered alkoxy groups are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH and CN; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-membered to 12-membered heterocyclic group, 4-membered to 12-membered aryl and 4-membered to 12-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₃ -C ₁₀ cycloalkyl and the 4-membered to 12-membered aryl are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH and CN, wherein the 4-membered to 12-membered heterocyclic group and the 4-membered to 12-membered heteroaryl have 1 to 4 groups each independently selected from O, S, N and NR ^d , and then optionally substituted on the ring carbon with 1 to 4 groups each independently selected from the group consisting of halogen, OH and CN; each R ^c is independently selected from the group consisting of H, D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, or two R ^c connected to the same atom form =0, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH and CN; each R ^d is independently selected from the group consisting of H, D, C _{1 -C 4} alkyl and C(O)C _1-4 alkyl; and n is 0, 1, 2 or 3. The compound of claim 1, wherein the compound is a compound of formula (II), formula (IIa), formula (IIb), formula (III), formula (IIIa), formula (IIIb), formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va) or formula (Vb): (II) (IIa), (IIb), (III) (IIIa) (IIIb), (IV) (IVa), (IVb), (V) (Va) or (Vb), or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound is a compound of formula (IVc) or formula (IVd): (IVc); or (IVd), or a pharmaceutically acceptable salt thereof, wherein ring C is a 4- to 10-membered heterocyclic group having 1 to 3 ring hetero atoms each independently selected from the group consisting of O, S and NR ^d , and optionally substituted by 1 to 2 R ^c on the ring carbon. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein (i) ring C is hexahydropyridine, 1,4-oxazacycloheptane, azacyclobutane, morpholine, pyrrolidine, hexahydropyrazine, hexahydropyrazine-2-one, octahydrocyclopenta[c]pyrrole or azacycloheptane, each of which is optionally substituted with 1 to 2 R ^c on the ring carbon; or (ii) ring C is represented by: ; ; ; ; ; ; ; ; or , each of which is optionally substituted with 1 or 2 R ^c ; and each R ^c is independently C ₁ -C ₃ alkyl which is optionally substituted with halogen or OH. The compound of claim 1, wherein the compound is a compound of formula (VI): (VI), or a pharmaceutically acceptable salt thereof. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein ^X1 is ^CR3 or N; ^X2 is ^CR7 or N; ^X3 is ^CR12 or N; ^X4 is ^CR13 or N; Z is O or S; ^R1 is selected from the group consisting of halogen, OH, CN, _C1 - _C4 alkyl, _C1 - _C4 alkoxy and _C1 - _C4 halogen; ^R2 is selected from the group consisting of H, D, C1- _C4 alkyl and _C3 - _C10 cycloalkyl; ^R3 is selected from the group consisting of H, D, halogen, CN, _C1 - _C4 alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) _{2 ) n} -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , a group consisting _{of C3-C10 cycloalkyl} , a 4-membered to 12-membered heterocyclic group, a 4-membered to 12-membered aryl and a 4-membered to 12-membered heteroaryl group, wherein the _C1 - _C4 alkyl, the _C3 - _C10 cycloalkyl and the 4-membered to 12-membered aryl group are each optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group and the 4-membered to 12-membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; R ⁴ is selected from the group consisting of H, D, _C1 - _C4 alkyl and _C3 - _C10 cycloalkyl; R ⁵ is selected from the group consisting of halogen, OH, CN, C ^R6 is H or D; ^R7 is selected from the group consisting of H, D, halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, _C3 - _{C10 cycloalkyl} and _4- to 12-membered heterocyclic group, wherein the _C1 - _C4 alkyl, the C1- _C4 alkoxy and the C3 _{-C10 cycloalkyl} are each optionally substituted with ₁ to ₄ Rc, wherein the 4- to ₁₂ -membered heterocyclic group has ₁ to ₄ ring heteroatoms each independently selected from the group consisting of O, S and ^NRd , and then each is optionally substituted with 1 to 4 ^Rc on the ring carbon; ^R8 is selected from the group consisting of H, D, C1-C4 alkyl, C1- ^C4 alkoxy, C3- _C10 cycloalkyl and 4- to 12-membered heterocyclic group. R ⁹ is each independently selected from the group consisting of H, D, C ₁ -C 4 alkyl, C 2 -C ₄ alkenyl, C _{2 -C 4} alkynyl, -(C(R ^a ) _{2 ) n} -OR ^b , C _{3 -C 10} cycloalkyl, ₄ -membered to 12-membered heterocyclic group, 4-membered to 12-membered aryl and 4-membered to 12-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C _{2 -C 4} alkenyl, the C ₂ -C ₄ alkynyl, the C ₃ -C ₁₀ cycloalkyl and the 4-membered to 12-membered aryl are each optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group and the 4-membered to 12-membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted on a ring carbon by 1 to 4 R ^c ; or R ⁷ and R ⁹ together with the carbon atom to which they are attached form a ring A, wherein ring A is a C ₃ -C ₁₀ cycloalkyl group or a 4-membered to 12-membered heterocyclic group, wherein the C ₃ -C ₁₀ cycloalkyl group is optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted on a ring carbon by 1 to 4 R ^c ; and/or R ^{R 8} and R ⁹ together with the carbon atom to which they are attached form Ring B, wherein Ring B is C ₃ -C ₁₀ cycloalkyl or a 4-membered to 12-membered heterocyclic group, wherein the C ₃ -C ₁₀ cycloalkyl is optionally substituted by 1 to 4 R ^c , wherein the 4-membered to 12-membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted on the ring carbon by 1 to 4 R ^c ; or R ⁸ and R ⁹ together form =0; R ¹⁰ is selected from H, D, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ R ^b , C ₃ -C The present invention relates to a group consisting of a C ₁ -C ₄ alkyl group, a C ₃ -C 10 cycloalkyl group and a 4 -12 membered heterocyclic group, a 4 -12 membered aryl group and a 4 -12 membered heteroaryl group, wherein the C 1 -C 4 alkyl group, the C ₃ -C ₁₀ cycloalkyl group and the 4 -12 membered aryl group are each optionally substituted by 1 to 4 R ^c , wherein the 4 -12 membered heterocyclic group and the 4 -12 membered heteroaryl group have 1 to 4 ring hetero atoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 4 R ^c on the ring carbon; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a ring having 1 to 4 atoms each independently selected from the group consisting of O, S and NR d. ^d, and optionally substituted by 1 to 4 R ^c on the ring carbon; R ¹¹ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl and C ₃ -C ₁₀ cycloalkyl; R 12 is selected from the group consisting of H, D, halogen ^, C 1 -C 4 alkyl and C ₃ -C ₁₀ cycloalkyl; R ¹³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, C _{1 -C 4} alkoxy, C ₃ -C ₁₀ cycloalkyl, 4 to ₁₂ membered heterocyclic group, 4 to 12 membered aryl and 4 to 12 membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkoxy, the C _{3 -C 10} cycloalkyl _-C10 cycloalkyl and the 4- to 12-membered aryl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR ^d , and then each is optionally substituted on the ring carbon with 1 to 4 R ^c ; R ¹⁴ is selected from the group consisting of H, D, and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH, and CN; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₃ -C ₁₀ cycloalkyl, 4- to 12-membered heterocyclic group, 4- to 12-membered aryl group, and 4- to 12-membered heteroaryl group, wherein the C ₁ -C ₄ alkyl, the C ₃ -C ₁₀ cycloalkyl, and the 4- to 12-membered aryl group are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halogen, OH, and CN, wherein the 4- to 12-membered heterocyclic group and the 4- to 12-membered heteroaryl group have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR ^d , and are then optionally substituted on the ring carbon with 1 to 4 groups each independently selected from the group consisting of halogen, OH, and CN; each R ^{R c} is independently selected from the group consisting of H, D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, or two R ^c connected to the same atom form =0, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, OH and CN; each R ^d is independently selected from the group consisting of H, D, C _{1 -C 4} alkyl and C(O)C _1-4 alkyl; and n is 0, 1, 2 or 3. The compound of claim 5 or 6 or a pharmaceutically acceptable salt thereof, wherein ^X1 is ^CR3 or N; ^X2 is ^CR7 or N; ^X3 is ^CR12 or N; ^X4 is ^CR13 or N; Z is O; ^R1 is selected from the group consisting of halogen, OH, _C1 - _C4 alkyl, _C1 - _C4 alkoxy and _C1 - _C4 halogen; ^R2 is selected from the group consisting of H, D and _C1 - _C4 alkyl; ^R3 is selected from the group consisting of H, D, halogen, CN, _C1 - _C4 alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , _C3 -C The present invention relates to a group consisting of a C ₁ -C 4 alkyl group, a C 3 -C _{8 cycloalkyl group and a 4 -10 membered heterocyclic group, a 4 -10 membered aryl group and a 4 -10 membered heteroaryl group, wherein the C 1 -C 4 alkyl} group, the C ₃ -C ₈ cycloalkyl group and the 4 -10 membered aryl group are each optionally substituted by 1 to 3 R ^c , wherein the 4 -10 membered heterocyclic group and the 4 -10 membered heteroaryl group have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then each is optionally substituted by 1 to 3 R ^c on the ring carbon; R ⁴ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl group; R ⁵ is selected from the group consisting of halogen, OH, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group and C ₁ -C R ⁶ is H or D; R ⁷ is selected from the group consisting of H, D, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₈ cycloalkyl and 4-membered to _10- membered heterocyclic group, wherein the C ₁ -C ₄ alkyl, the C ₁ -C ₄ alkoxy and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R ^c , wherein the 4-membered to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then each is optionally substituted by 1 to 3 R ^c on the ring carbon; R ⁸ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ⁹ is each independently selected from the group consisting of H, D, C ₁ -C The present invention is a group consisting of C ₁ -C ₄ alkyl, C ₂ -C 4 alkenyl, C ₂ -C ₄ alkynyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl, the C ₂ -C ₄ alkenyl, the C ₂ -C ₄ alkynyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then each is optionally substituted on the ring carbon by 1 to 3 R ^c ; or R ⁷ and R ⁹ together with the carbon atom to which they are attached form Ring A, wherein Ring A is C ₃ -C wherein the C ₃ -C ₈ cycloalkyl group is optionally substituted with 1 to 3 R ^c , wherein the 4 to 10 membered heterocyclic group has 1 to 3 ring hetero atoms each independently selected from the group consisting of O, S and NR ^d , and then is optionally substituted on the ring carbon by 1 to 3 R c; and/or R ₈ and R 9 together with the carbon atom to which they are attached form Ring B, wherein Ring B is C 3 -C 8 cycloalkyl group or a 4 to 10 membered heterocyclic group, wherein the C 3 -C ⁸ cycloalkyl group is optionally substituted with 1 to 3 R ^{c, wherein the 4 to 10 membered heterocyclic group has 1 to 3 ring hetero atoms each independently selected from the group consisting of O, S and NR d, and then is optionally substituted on the ring carbon by 1 to 3 R c} ; and/or R ⁸ and R 9 together with the carbon atom to which they are attached form Ring B, wherein Ring B is C ₃ -C ₈ cycloalkyl group or a 4 to 10 membered heterocyclic group, wherein the C ₃ -C ₈ cycloalkyl group is optionally substituted with 1 to 3 R ^c , wherein the 4 to 10 membered heterocyclic group has 1 to 3 ring hetero atoms each independently selected from the group consisting of O, S and NR d ^d , and optionally substituted by 1 to 3 R ^c on the ring carbon; or R ⁸ and R ⁹ together form =0; R ¹⁰ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, -(C(R a ) 2 ) ⁿ -OR b , -(C(R ^a ) ₂ ) _n -SO _{2 R b , C 3 -C 8 cycloalkyl, 4- to 10-membered heterocyclic group, 4- to 10-membered aryl and 4- to 10-membered heteroaryl, wherein the C 1 -C 4 alkyl, the C 3 -C 8 cycloalkyl and the 4- to 10-membered aryl are each optionally substituted by 1 to 3 R c on the ring carbon; or R 8} ^and _{R 9 together} ^form ₌ 0; R 10 is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, -(C(R a _{) 2 )} n -OR b , -(C(R a ) 2 ) n -SO 2 R b , ^c , wherein the 4- to 10-membered heterocyclic group and the 4- to 10-membered heteroaryl group have 1 to 3 cyclic heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and are then optionally substituted on the ring carbon by 1 to 3 R ^c ; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a 4- to 10-membered heterocyclic group having 1 to 3 cyclic heteroatoms each independently selected from the group consisting of O, S and NR ^d , and are then optionally substituted on the ring carbon by 1 to 3 R ^c ; R ¹¹ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ¹² is selected from the group consisting of H, D, halogen and C ₁ -C ₄ alkyl; R ^{R 13} is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 3 R ^c ; R ¹⁴ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, OH and CN; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C 3 -C 4 alkyl, C ₃ -C The group consisting of a C _{1 -C 4} alkyl group, a C ₃ -C 8 cycloalkyl group and a 4 -10 membered heterocyclic group, a 4 -10 membered aryl group and a 4 -10 membered heteroaryl group, wherein the C 1 -C ₄ alkyl group, the C ₃ -C ₈ cycloalkyl group and the 4 -10 membered aryl group are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of a halogen group, OH and CN, wherein the 4 -10 membered heterocyclic group and the 4 -10 membered heteroaryl group have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and then are optionally substituted on the ring carbon with 1 to 3 groups each independently selected from the group consisting of a halogen group, OH and CN; each R ^c is independently selected from H, D, a halogen group, OH, CN, C ₁ -C 4 alkyl group, The invention relates to a group consisting of a C 1 -C ₄ alkyl group and a C ₁ -C ₄ alkoxy group, or two R ^c connected to the same atom form =0, wherein the C ₁ -C ₄ alkyl group and the C ₁ -C ₄ alkoxy group are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of a halogen group, OH and CN; each R ^d is independently selected from the group consisting of H, D, C _{1 -C 4} alkyl group and C(O)C _1-4 alkyl group; and n is 0, 1, 2 or 3. The compound of claim 1 or 5, wherein the compound is a compound of formula (VIa), formula (VIb), formula (VIc), formula (VId), formula (VIe), formula (VIf), formula (VIg) or formula (VIh): (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg) or (VIh), or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound is a compound of formula (VII), formula (VIIa) or formula (VIIb): (VII) (VIIa) or (VIIb), or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 9 or a pharmaceutically acceptable salt thereof, wherein X ¹ is CR ³ or N; X ⁴ is selected from the group consisting of CR ¹³ , N and NR ^d ; R ¹ is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ halogenalkyl; R ² is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic groups, wherein the C _{The C1} - _C4 alkyl group and the C3 _{- C10} cycloalkyl group are each optionally substituted by 1 to 3 ^Rc , wherein the 4-membered to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and ^NRd , and is then optionally substituted on the ring carbon by 1 to ^{3 Rc} ; R4 is selected from the group consisting of H, D and _C1 - _C4 alkyl; ^R5 is selected from the group consisting of halogen, _C1 - _C4 alkyl and _C1 - _C4 halogenalkyl; ^R6 is H or D; ^R7 is selected from the group consisting of H, D, halogen, _C1 - _C4 alkyl and _C1 - _C4 alkoxy, C3 _{- C6} cycloalkyl and 4-membered to 7-membered heterocyclic group, wherein the _C1 -C the C 1 -C ₄ alkyl, the C ₁ -C ₄ alkoxy and the C ₃ -C ₆ cycloalkyl are each optionally substituted by 1 to 3 R ^c , wherein the 4-membered to 7-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then each is optionally substituted on the ring carbon by 1 to 3 R ^c ; R ⁸ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ⁹ is each independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C ₈ cycloalkyl and 4-membered to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl, the C ₂ -C ₄ alkynyl and the C ₃ -C R _and R are each optionally substituted with 1 to 3 R ^c , wherein the 4-membered to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted with 1 to 3 R ^c on the ring carbon; or R ⁸ and R ⁹ together with the carbon atom to which they are attached form a ring B, wherein the ring B is a C ₃ -C ₈ cycloalkyl or a 4-membered to 10-membered heterocyclic group, wherein the C ₃ -C ₈ cycloalkyl is optionally substituted with 1 to 3 R ^c , wherein the 4-membered to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted with 1 to 3 R ^c on the ring carbon; or R ^{R 8} and R ⁹ together form =0; R ¹⁰ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ R ^b , C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted with 1 to 3 R ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted with 1 to 3 R ^c on the ring carbon; or R ⁹ and R ^{R 10} together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a 4- to 10-membered heterocyclic group having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted by 1 to 3 R ^c on the ring carbon; R ¹¹ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ¹² is selected from the group consisting of H, D, halogen and C ₁ -C ₄ alkyl; R ¹³ is selected from the group consisting of H, D, halogen, CN and C ₁ -C ₄ alkyl; R ¹⁴ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D and C _{1 -C 4} alkyl; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN, wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then optionally substituted on the ring atoms with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN; each R ^c is independently selected from the group consisting of D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, or two R cs attached to the same atom ^a forms =0, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halogen, OH and CN; each R ^d is independently selected from the group consisting of H, D, C _{1 -C 4} alkyl and C(O)C _1-4 alkyl; and n is 0, 1, 2 or 3. The compound of claim 1 or 9, wherein the compound is a compound of formula (VIIIe), formula (VIIIf), formula (VIIIg) or formula (VIIIh): (VIIIe), (VIIIf), (VIIIg) or (VIIIh), or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein: (i) R ¹ is halogen, -OH, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; or (ii) R ¹ is -CH ₃ , -Cl, -OH or -OMe. The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein: (i) R ² is H, D, halogen or C ₁ -C ₄ alkyl; or (ii) R ² is H. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein: (i) R ³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , C ₃ -C ₆ cycloalkyl, 4- to 7-membered heterocyclic group, phenyl and 4- to 6-membered heteroaryl, wherein the C ₁ -C ₄ alkyl, the C ₃ -C ₆ cycloalkyl and the phenyl are each optionally substituted by 1 to 4 R ^c , wherein the 4- to 7-membered heterocyclic group and the 4- to 6-membered heteroaryl group have 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ^d , and are then each optionally substituted on a ring carbon by 1 to 3 R ^c ; (ii) R ³ is selected from -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CF ₃ , -OCH ₃ , H, -CN, -CHF 2 , -CHFCH ₃ , -CHF-CH _{2 F} , -CH(CH ₃ )OMe, -OCHF ₂ , Cl, -OCH ₂ CH ₃ , F, -CH ₃ , -O-cyclopropyl, -O-CH ₂ CH ₂ CH ₃ , -O-CF ₃ , -N(CH ₃ ) ₂ , -O-CH(CH _{3 )} ) ₂ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CH ₂ SO ₂ CH ₃ , -CF ₂ Me, -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₂ CH ₃ , -CH ₂ CF ₃ and -CH ₂ CO ₂ H, or is represented by one of the following structures: ; or (iii) R ³ is -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CF ₃ or -OCH ₃ . The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein: (i) R ⁴ is H, D, halogen or C ₁ -C ₄ alkyl; (ii) R ⁴ is H. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein: (i) R ⁵ is halogen, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ halogenalkyl or C ₁ -C ₄ alkoxy; or (ii) R ⁵ is Me, Cl, -OH, -CHF ₂ or -OCH ₃ . The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein: (i) R ⁷ is H, D, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or a 4- to 7-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₁ -C ₄ alkoxy are each optionally substituted by 1 to 3 R ^c , wherein the 4- to 7-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and then each is optionally substituted by 1 to 3 R ^c on the ring carbon; (ii) R ⁷ is H, morpholin-N-yl, -CF ₃ , -F, -OCHF ₂ , -OCH ₂ CH ₃ or -OCH ₃ ; or (iii) R ⁷ is H. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein: (i) R ⁸ is H, D, halogen or C ₁ -C ₄ alkyl; (ii) R ⁸ is H or -CH ₃ ; or (ii) R ⁸ is H. The compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein: (i) R ⁹ is each independently H, D, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, -(C(R ^a ) ₂ ) _n -OR ^b or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₄ alkyl, the C ₂ -C ₄ alkynyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R ^c ; (ii) R ⁹ is each independently H, Me, -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ CHF ₂ , cyclopropyl, -CH ₂ C≡CH, -CH ₂ CH ₂ OCH ₃ or -CHF ₂ ; or (iii) each R ⁹ is independently H, Me, -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₃ or -CH ₂ OCH ₃ . The compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein: (i) R ¹⁰ is H, D, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ R ^b or C ₃ -C ₈ cycloalkyl, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted with 1 to 3 R ^c ; (ii) R ¹⁰ is H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ SO ₂ CH ₃ , -CD ₂ CD ₃ , -CH ₂ CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH(CH ₃ ) ₂ or -CD ₃ ; or (iii) R ¹⁰ is H, -CH ₃ or -CH ₂ CH ₃ . The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein: (i) R ¹¹ is H, D, halogen or C ₁ -C ₄ alkyl; or (ii) R ¹¹ is H. The compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: (i) R ¹² is H, D, halogen or C ₁ -C ₄ alkyl; (ii) R ¹² is H, D or halogen; (iii) R ¹² is H or F; or (iv) R ¹² is H. The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein: (i) R ¹³ is H, D, halogen or C ₁ -C ₄ alkyl; (ii) R ¹³ is H, D or halogen; (iii) R ¹³ is H or F; or (iv) R ¹³ is H. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is H. The compound of claim 1, wherein the compound is a compound of formula (IXa) or formula (IXb): (IXa), (IXb), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ halogen; R ³ is selected from the group consisting of H, D, halogen, CN, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , -(C(R ^a ) ₂ ) _n -C(O)OR ^b , -(C(R ^a ) ₂ ) _n -SO ₂ -R ^b , -N(R ^a ) ₂ , C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic groups, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R ^c -substituted, wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted on the ring carbon by 1 to 3 R ^c ; R ⁵ is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ halogenalkyl; R ⁸ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ⁹ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, -(C(R ^a ) ₂ ) _n -OR ^b , C ₃ -C ₈ cycloalkyl and 4- to 10-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₈ cycloalkyl are each optionally substituted by 1 to 3 R c-substituted. ^c , wherein the 4- to 10-membered heterocyclic group has 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted on the ring carbon with 1 to 3 R ^c ; R ¹⁰ is selected from the group consisting of H, D, C ₁ -C ₄ alkyl, C ₃ -C ₁₀ cycloalkyl and 4- to 12-membered heterocyclic group, wherein the C ₁ -C ₄ alkyl and the C ₃ -C ₁₀ cycloalkyl are each optionally substituted with 1 to 4 R ^c , wherein the 4- to 12-membered heterocyclic group has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted on the ring carbon with 1 to 4 R ^c ; or R ⁹ and R ^{R 10} together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a 4- to 10-membered heterocyclic group having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S and NR ^d , and is then optionally substituted by 1 to 3 R ^c on the ring carbon; R ¹¹ is selected from the group consisting of H, D and C ₁ -C ₄ alkyl; R ¹³ is selected from the group consisting of H, D, halogen, CN and C ₁ -C ₄ alkyl; each ^Ra is independently selected from the group consisting of H, D and C ₁ -C ₄ alkyl; each R ^b is independently selected from the group consisting of H, D, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy; each R ^c is independently selected from the group consisting of D, halogen, OH, CN, C ₁ -C ₄ alkyl and C ₁ -C 4 alkoxy; -C ₄ alkoxy, or two ^Ras attached to the same atom form =0; and each ^Rd is independently selected from the group consisting of H, D and C ₁ -C ₄ alkyl; and n is 0, 1 or 2. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R ¹ is a halogen group or a C ₁ -C ₃ alkyl group; R ³ is a C ₁ -C ₃ alkyl group or -(C(R ^a ) ₂ ) _n -OR ^b , wherein n is 0, and R _b is a C ₁ -C ₃ alkyl group, wherein the C ₁ -C ₃ alkyl group is optionally substituted by 1 to 3 R ^c , wherein R ^c is independently a halogen group or a C ₁ -C ₃ alkoxy group; R ⁵ is a halogen group or a C ₁ -C ₃ alkyl group; R ⁸ is H; R ⁹ is a C ₁ -C ₃ alkyl group or -(C(R ^a ) ₂ ) _n -OR ^b , wherein n is 0, and R _b is a C ₁ -C ₃ alkyl group, wherein the C ₁ -C ₃ alkyl group is optionally substituted by 1 to 3 R ^c , wherein R ^c is independently a halogen group or a C _{1 -C 3} alkoxy group; -C ₃ alkoxy; R ¹⁰ is H or C ₁ -C ₃ alkyl; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is a 4- to 6-membered heterocyclic group; R ¹¹ is H; and R ¹³ is H. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CH ₃ or -Cl; R ³ is -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CF ₃ or -OCH ₃ ; R ⁵ is -CH ₃ or -Cl; R ⁸ is H; R ⁹ is H, -CH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₃ or -CH ₂ OCH ₃ ; R ¹⁰ is H, -CH ₃ or -CH ₂ CH ₃ ; or R ⁹ and R ¹⁰ together with the carbon atom and the nitrogen atom to which they are respectively attached form a ring C, wherein the ring C is represented by the following: ; R ¹¹ is H; and R ¹³ is H. A pharmaceutical composition comprising: i) a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable carrier, excipient or diluent. A method for treating a subject suffering from a disease or condition responsive to inhibition of glycogen synthase kinase 3 (GSK3) activity, the method comprising administering to the subject an effective amount of a compound of claim 1 to 27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 28. The method of claim 29, wherein the disease or disorder is diabetes, cancer, viral infection, or a CNS disorder. The method of claim 29, wherein the disease or condition is cancer.