WRN inhibitors

Abstract

The present disclosure relates to compounds that can inhibit WRN. Also provided herein are methods of treating a disease associated with Werner Syndrome RecQ Like Helicase (WRN) activity, such as cancer, in a subject in need thereof, comprising administering to the subject a pharmaceutical composition as described herein.

Description

[0001] WRN INHIBITORS

[0002] BACKGROUND

[0003] Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, or WRN helicase, is an enzyme that in humans is encoded by the WRN gene, and is a member of the RecQ Helicase family (Monnat RJ (2010) Semin. Cancer Biol. 20 (5): 329- 39). Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division (DNA replication) and gene expression (transcription). In addition, WRN helicase has exonuclease capabilities allowing it to remove nucleotides at gaps formed by dsDNA breaks. Werner protein therefore plays a critical role in maintaining the structure and integrity of DNA.

[0004] Werner syndrome, a form of progeria, is a recessive disorder caused by mutations in the WRN gene (Oshima J (2000). BioEssays. 22 (10): 894-901 ). More than 20 mutations in the WRN gene are known to cause Werner syndrome, many of which result in a truncated WRN helicase. Evidence suggests that rather than being transported into the cell nucleus where it normally interacts with DNA, truncated WRN helicase is degraded by nonsense mediated decay leading to a loss of WRN helicase in the cell (Huang S, et al., Hum. Mutat. 27 (6): 558-67).

[0005] Without functional WRN helicase in the nucleus, cells cannot perform the tasks of DNA replication, repair, and transcription. Cells expressing reduced amounts of WRN helicase have elevated mutation frequencies compared to wildtype cells (Kamath-Loeb AS, et al., (2012) J. Biol. Chem. 287 (15): 12480-90). Increased mutation may give rise to cancer. Thus, patients with Werner syndrome demonstrate an increased incidence of cancers, including soft tissue sarcomas, osteosarcoma, thyroid cancer and melanoma (Goto M, et al., (1996). Cancer Epidemiol. Biomarkers Prev. 5 (4): 239-46).

[0006] To combat cancer, several therapies are available for cancer patients, including radiation, chemotherapy, and immunotherapy. While each of these can eliminate cancer cells, they can also cause damage to healthy, non-cancerous cells. In addition, several types of cancer can evade the effects of immunotherapies. Thus, there is a need for alternative treatment strategies.

[0007] Inducing synthetic lethality (SL) is one such strategy. SL arises when a combination of genetic deficiencies (e.g., gene mutations, silencing, or global genomic lesions) and / or molecular perturbations (e.g., gene expression knockout / knockdown and pharmacological inhibition / activation) affect separate genes within the same cell. While each individual genetic deficiency / perturbation does not affect cell viability, the simultaneous disruption of two or more genes causes cell death (Dobzhansky T, (2020). Genetics 31 : 269-290 and Huang et al, (2020) Nature Reviews Drug Discovery 19: 23-38). Therefore, if the right combination of genes is perturbed, healthy cells would not be affected by the same treatment that kills mutation-riddled cancer cells.

[0008] Thus, there is a need for cancer therapies that inhibit WRN and / or induce synthetic lethality.

[0009] SUMMARY

[0010] The present disclosure relates to compounds that inhibit WRN. As such, these compounds are useful in the treatment of a variety of diseases, such as, for example, cancer.

[0011] In an aspect, provided herein is a compound of Formula I: or a pharmaceutically acceptable salt thereof, where the variables are defined herein.

[0012] In another aspect, provided herein is a compound of Formula VII: or a pharmaceutically acceptable salt thereof, where the variables are defined herein.

[0013] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0014] In yet another aspect, provided herein is a method of inhibiting WRN activity, which comprises administering to an individual a compound described herein.

[0015] In still another aspect, provided herein is a method of treating a cancer associated with WRN activity, comprising administering to a patient a therapeutically effect amount of a compound described herein. The cancer may have a microsatellite instability (MSI)-positive phenotype or MSI-high (MSI-H) phenotype. Additionally, the cancer may have a mismatch repair defective gene or mismatch repair mutated gene. The cancer may be colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, or ovarian cancer. DETAILED DESCRIPTION

[0016] Provided here are compounds that inhibit WRN. As such, these compounds, as well as pharmaceutical compositions that comprise these compounds, are useful in the treatment of a variety of indications, including cancer.

[0017] I. Compounds and Compositions

[0018] In some embodiments, the present disclosure relates to compounds that can enhance WRN inhibition.

[0019] In one aspect, provided herein is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0020] R1is H, C1-C6 alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C aryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(Ce-Cwaryl), or C1-C4 alkylene(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-( Ce-Cwaryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-5 substituents selected from R5; each R3is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C aryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3- C cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(Ce-Cio aryl), and C1-C4 alkylene-(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R6; each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(0)-0H, C(0)-NH2, and C(0)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, N02, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(0)-0H, C(0)-NH2, and C(0)-Ci-C6alkyl; each R6, is independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(0)0H, C(0)NH2, and C(0)-Ci-C6alkyl; y is 0, 1 , 2, 3, 4, or 5; z is 0, 1 , or 2;

[0021] Ring A is absent or is selected from the group consisting of C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R7; each R7is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, =N-O-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-(Ce- Cio aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R8; each R8is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-OCi-Ce alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(0)-Ci-C6alkyl, C(0)-0Ci-C6alkyl and 5- membered heteroaryl; and

[0022] W is selected from -S- and -O-.

[0023] In one embodiment, the compound of Formula I is selected from Formulae lla-llc:

[0024] or a pharmaceutically acceptable salt thereof, wherein: each — represents a single bond or a double bond; and

[0025] X1, X2, X3, and X4are each independently selected from the group consisting of -O-, =N-, -NH-, NR7, =CH-, -CH2-, -CHR7-, =CR7-, and C(R7)2.

[0026] In a particular embodiment, the compound of Formula I is Formulae Ila- lie, or a pharmaceutically acceptable salt thereof, wherein

[0027] R1is Ci-C6alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, and C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2.6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-( Ce-C-ioaryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-5 substituents selected from R5; each R3is, independently for each occurrence, selected from the group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl, each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, C(0)-0H, C(0)-NH2, and C(0)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, ON, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(0)-0H, C(O)-NH2, and C(0)-Ci-C6alkyl; each R7is, independently for each occurrence, selected from the group consisting of H, OH, =0, =NH, halo, ON, N02, =N-0-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamine, C(0)-0H, C(0)-NH2, C(0)-Ci-C6 alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, -0-(Co-C6 alkylene)-(C3-Cio cycloalkyl), -0-(Co-C6 alkylene)-(3-10 membered heterocycloalkyl), -0-(Co-C6 alkylene)-(Ce- Cio aryl), and -0-(Co-C6 alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R8; each R8is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-0CI-C6 alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(0)-Ci-C6alkyl, C(0)-0Ci-C6alkyl and 5- membered heteroaryl; y is 0, 1 , 2, 3, 4, or 5; z is 0, 1 , or 2; and

[0028] W is selected from -S- and -O-.

[0029] In another embodiment, the compound of Formula I is selected from Formulae I lla- lllf:

[0030] or a pharmaceutically acceptable salt thereof, wherein:

[0031] X1and X4are each independently selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, =CR7-, and C(R7)2; and

[0032] X2and X3are each independently =CH-, -CH2-, -CHR7-, CR7, or C(R7)2.

[0033] In a particular embodiment, the compound of Formula I is Formulae Illa- lllf, or a pharmaceutically acceptable salt thereof, wherein

[0034] R1is C1-C6 alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, and C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2.6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-( Ce-C aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-5 substituents selected from R5; each R3is, independently for each occurrence, selected from the group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl, each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2.6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl; each R7is, independently for each occurrence, selected from the group consisting of H, OH, =0, =NH, halo, CN, NO2, =N-O-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6 alkylamine, C(O)-OH, C(0)-NH2, C(O)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, -0-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -0-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -0-(Co-Ce alkylene)-(Ce- Cio aryl), and -0-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R8; each R8is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-OCI-C6 alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-C6alkyl, C(O)-OCi-C6alkyl and 5- membered heteroaryl; y is 0, 1 , 2, 3, or 4; z is 0, 1 , or 2; and

[0035] W is selected from -S- and -O-.

[0036] In still another embodiment, the compound of Formula I is Formulae IVa- IVc: or a pharmaceutically acceptable salt thereof.

[0037] In a particular embodiment, the compound of Formula I is Formulae IVa- IVc, or a pharmaceutically acceptable salt thereof, wherein

[0038] R1is Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, and C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-( Ce-C aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-5 substituents selected from R5; each R3is, independently for each occurrence, selected from the group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl, each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl; each R7is, independently for each occurrence, selected from the group consisting of H, OH, =0, =NH, halo, CN, NO2, =N-0-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-(Ce- Cio aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R8; each R8is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-OCi-Ce alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-C6alkyl, C(O)-OCi-C6alkyl and 5- membered heteroaryl; y is 0, 1 , 2, 3, or 4; z is 0, 1 , or 2; and

[0039] W is selected from -S- and -O-.

[0040] In yet another embodiment, the compound of Formula I is of the Formulae Va-Vg:

[0041] or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, and X4are each independently =CH-, -CH2-, -CHR7-, CR7, or C(R7)2.

[0042] In a particular embodiment, the compound of Formula I is Formulae Va-Vg, or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, and C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -0-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -0-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -0-(Co-Ce alkylene)-( Ce-C aryl), and -0-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-5 substituents selected from R5; each R3is, independently for each occurrence, selected from the group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl, each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R7is, independently for each occurrence, selected from the group consisting of H, OH, =0, =NH, halo, CN, NO2, =N-O-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, -0-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -0-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -0-(Co-Ce alkylene)-(Ce- Cio aryl), and -0-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R8; and each R8is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-OCi-Ce alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-C6alkyl, C(O)-OCi-C6alkyl and 5- membered heteroaryl; y is 0, 1 , 2, 3, or 4; and z is 0, 1 , or 2.

[0043] In a particular embodiment, the compound of Formula I is of the Formulae Va’, Vb’, Vf, and Vg’ or a pharmaceutically acceptable salt thereof, wherein

[0044] or a pharmaceutically acceptable salt thereof,

[0045] R1is C1-C6 alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, and C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -0-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -0-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -0-(Co-Ce alkylene)-( Ce-C aryl), and -0-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-5 substituents selected from R5; each R3is, independently for each occurrence, selected from the group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl, each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl; each R7is, independently for each occurrence, selected from the group consisting of H, OH, =0, =NH, halo, CN, NO2, =N-0-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, -0-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -0-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -0-(Co-Ce alkylene)-(Ce- Cio aryl), and -0-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R8; and each R8is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-OCi-Ce alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-C6alkyl, C(O)-OCi-C6alkyl and 5- membered heteroaryl; y is 0, 1 , 2, 3, or 4; and z is 0, 1 , or 2.

[0046] In a particular embodiment, the compound of Formula I is Formulae IVa- IVc, or a pharmaceutically acceptable salt thereof, wherein

[0047] R1is Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, and C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-( Ce-C aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-5 substituents selected from R5; each R3is, independently for each occurrence, selected from the group consisting of halo, Ci-Ce alkyl, and Ci-Ce haloalkyl, each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl; each R7is, independently for each occurrence, H or Ci-Ce alkyl; and each R8is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-OCi-Ce alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(0)-Ci-C6alkyl, C(0)-0Ci-C6alkyl and 5- membered heteroaryl.

[0048] In another embodiment, R1is selected from the group consisting of Ci-Ce alkyl, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and Ce-Cioaryl, wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1-3 substituents selected from R4; and

[0049] R4is, independently for each occurrence, selected from OH, =0, =NH, halo, -CN, Ci- Ce alkyl, C2-6 alkynyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-Ce alkyl. In a further embodiment, R1is selected from linear Ci-Ce alkyl, branched Ci-Ce alkyl, alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and Ce-Cio aryl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with 1-2 substituents selected from R4; and

[0050] R4is, independently for each occurrence, selected from OH, =0, =NH, halo, and Ci- Ce alkyl.

[0051] In yet another embodiment, R1is selected from

[0052] In still another embodiment, each R2is, independently for each occurrence, selected from the group consisting of halo, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(Co-Ce alkylene)-

[0053] (C3-C10 cycloalkyl), and -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), and wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-4 substituents selected from R5; and

[0054] R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, -CN, Ci-C6alkyl, C2.6alkynyl, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl.

[0055] In a further embodiment, each R2is, independently for each occurrence, selected from the group consisting of halo, Ci-Ce alkyl, Ci-Ce alkoxy, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 substituents selected from R5'

[0056] In yet another embodiment, R3is, independently for each occurrence, selected from the group consisting of halo, -CN, -Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, and C3-C10 cycloalkyl. In a further embodiment, R3is, independently for each occurrence, selected from the group consisting of halo, -Ci-Ce alkyl, Ci-Ce alkoxy, and Ci-Ce alkylamine.

[0057] In another embodiment, X1is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

[0058] In still another embodiment, X2is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

[0059] In yet another embodiment, X3is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2. In another embodiment, X4is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

[0060] In still another embodiment, R7of NR7is, independently for each occurrence, selected from the group consisting of Ci-Ce alkyl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl, and wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 substituents selected from R8.

[0061] In yet another embodiment, R8is, independently for each occurrence, selected from the group consisting of halo, =0, =NH, OH, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, C(O)-OH, C(O)- NH2, and C(0)-Ci-C6alkyl.

[0062] In another embodiment, R7of -CHR7-, CR7, and C(R7)2is, independently for each occurrence, selected from the group consisting of =0, halo, CN, =N-O-(Ci-Ce alkyl), Ci-Ce alkyl, Ci-Ce alkoxy, C(0)-0H, C(0)-NH2, C(0)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(C3-Cio cycloalkyl), -W-(3-10 membered heterocycloalkyl), -W-(Ci-Ce alkylene)-(C3-Cio cycloalkyl), and -W-(Ci-Ce alkylene)-(3-10 membered heterocycloalkyl), and wherein the alkyl, cycloalkyl, and heterocycloalkyl, are optionally substituted with 1-3 substituents selected from R8.

[0063] In still another embodiment, each R8is, independently for each occurrence, selected from the group consisting of halo, OH, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C(O)-OH, C(O)-NH2, and C(O)-Ci-Ce alkyl.

[0064] In yet another embodiment, at least one R8is selected from the group consisting of C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl.

[0065] In another aspect, provided herein is a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein: each — individually represents a single bond or a double bond;

[0066] R1is H, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(C6-Cioaryl), or C1-C4 alkylene-(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-(Ce-Cio aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl, are optionally substituted with 1-5 substituents selected from R5;

[0067] A1and A2are each, independently for each occurrence, selected from the group consisting of NH, NR3, CH, CR3, CH2, and C(R3)2; each R3is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cioaryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3- C10 cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(Ce-Cio aryl), and C1-C4 alkylene(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents selected from R6; each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R6is independently, for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)OH, C(O)NH2, and C(O)-Ci-C6alkyl; y is 0, 1 , 2, 3, 4, or 5;

[0068] X1, X3, and X4are each independently selected from the group consisting of -O-, =N-, -NH-, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2;

[0069] X2is selected from the group consisting of absent, -O-, =N-, -NH-, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2; each R7is independently for each occurrence, selected from the group consisting of H, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, and 5-10 membered heteroaryl, wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R8; each R8is, independently for each occurrence, selected from the group consisting of H, OH, =0, =NH, =N-OCI-C6alkyl, halo, CN, NO2, =N-O-(CI-C6alkyl), Ci-C6alkyl, Ci-C6 alkoxy, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, C(O)-OCi-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, -W-(Co- Ce alkylene)-(C3-Cio cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W- (Co-Ce alkylene)-(Ce-Cio aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R10;

[0070] W is selected from -S- and -O-; each R9is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; and each R10is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl.

[0071] In one embodiment, the compound of Formula VI is a compound of Formula VI’: or a pharmaceutically acceptable salt thereof.

[0072] In another embodiment, R1is selected from Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and Ce-C aryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1-3 substituents selected from R4; and

[0073] R4is, independently for each occurrence, selected from OH, =0, =NH, halo, CN, Ci- Ce alkyl, C2-6 alkynyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl.

[0074] In still another embodiment, each R2is, independently for each occurrence, selected from the group consisting of halo, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), and -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-4 substituents selected from R5; and

[0075] R5is, independently for each occurrence, selected from OH, =0, =NH, halo, CN, Ci- Ce alkyl, C2.6 alkynyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl. In yet another embodiment, R3is, independently for each occurrence, selected from the group consisting of halo, CN, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, and C3-C10 cycloalkyl.

[0076] In another embodiment, X1is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

[0077] In still another embodiment, X2is selected from the group consisting of absent, =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

[0078] In yet another embodiment, X3is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

[0079] In another embodiment, X4is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

[0080] In still another embodiment, R7of NR7is, independently for each occurrence, selected from the group consisting of Ci-Ce alkyl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 substituents selected from R8.

[0081] In yet another embodiment, each R8is, independently for each occurrence, selected from the group consisting of halo, =0, =NH, OH, -CN, -Ci-Ce alkyl, -Ci-Ce alkoxy, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl.

[0082] In another embodiment, R7of -CHR7-, CR7, and C(R7)2 is, independently for each occurrence, selected from the group consisting of =0, halo, -CN, =N-O-(Ci-Ce alkyl), Ci-Ce alkyl, Ci-Ce alkoxy, C(0)-0H, C(O)-NH2, C(O)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(C3-Cio cycloalkyl), -W-(3-10 membered heterocycloalkyl), -W-(Ci-Ce alkylene)-(C3-Cio cycloalkyl), and -W-(Ci-Ce alkylene)-(3-10 membered heterocycloalkyl), wherein the alkyl, cycloalkyl, and heterocycloalkyl, are optionally substituted with 1-3 substituents selected from R8.

[0083] In still another embodiment, each R8is, independently for each occurrence, selected from the group consisting of halo, OH, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C(O)-OH, C(O)-NH2, and C(O)-Ci-Ce alkyl.

[0084] In yet another embodiment, at least one R8is selected from the group consisting of C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl.

[0085] In another aspect, the compound is selected from a compound in Table 1 , or a pharmaceutically acceptable salt thereof.

[0086] Table 1.

[0087]

[0088]

[0089]

[0090]

[0091] (“rac-” indicates racemic; “entant.” indicates enantiomers; “iso.” Indicates isomer)

[0092] In one aspect, provided herein is a compound of Formula VII: or a pharmaceutically acceptable salt thereof, wherein:

[0093] R1Aand R1Bare, independently for each occurrence, selected from the group consisting of H, halo, Ci-Ce alkyl, C2-C6 alkenyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C-io aryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(C6-Cioaryl), and C1-C4 alkylene(5-10 membered heteroaryl), wherein the alkyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R5, or wherein R1Aand R1Btogether with the atom to which they are attached form a double bond;

[0094] R2is selected from the group consisting of H, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -W-(Co-Ce alkylene)-(3- 10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-( Ce-Cio aryl), and -W-(Co-Ce alkylene)- (5-10 membered heteroaryl), and wherein the alkyl, alkylene, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R6; each R3is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3- C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C aryl, 5-10 membered heteroaryl, C(O)-OH, C(O)-NH2, C(O)-CI-C6alkyl, -W-(C0-C6alkylene)-(C3-Ci0cycloalkyl), -W-(C0-C6alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-( Ce-Cio aryl), and -W-(Co- Ce alkylene)-(5-10 membered heteroaryl), wherein the alkyl, alkynyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R7; y is 0, 1 , 2, 3, 4, or 5;

[0095] Ring A is absent or is selected from the group consisting of C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R9;

[0096] Ring B is selected from the group consisting of C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R4; each R4is, independently for each occurrence, selected from the group consisting of OH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(Ce-Cioaryl), and C1-C4 alkylene-(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R8; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C(0)-0H, C(O)-NH2, and C(0)-Ci-C6alkyl; each R6, is independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C(0)-0H, C(0)-NH2, and C(0)-Ci-C6alkyl; each R7, is independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C(0)-0H, C(0)-NH2, and C(0)-Ci-C6alkyl; each R8, is independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C(0)-0H, C(O)-NH2, and C(0)-Ci-C6alkyl; each R9is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, N02, =N-0-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamine, C(0)-0H, C(0)-NH2, C(0)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-(Ce- Cio aryl), and -W-(Co-Ce alkylene)-(5-10 membered heteroaryl), and wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R10; each R10is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-0Ci-Ce alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(0)-0H, C(0)-NH2, C(0)-Ci-C6alkyl, C(0)-0Ci-C6alkyl, and 5- membered heteroaryl; and

[0097] W is selected from -CH2-, -S- and -0-.

[0098] In one embodiment, if R1Aor R1Bis aryl, arylalkyl, aryloxy, heteroaryl, or heteroaryloxy then Ring A is present.

[0099] In another embodiment, the compound of Formula VII is selected from a compound of Formulae VI lla-VII If: or a pharmaceutically acceptable salt thereof, wherein X is, independently for each occurrence, halo or Ci-Ce alkyl.

[0100] In still another embodiment, the compound of Formula VII is selected from a compound of Formulae IXa-IXd: or a pharmaceutically acceptable salt thereof, wherein each — represents a single bond or a double bond;

[0101] Ring A is selected from the group consisting of C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R9;

[0102] A1, A2, A3, A4, and A5are each, independently for each occurrence, selected from the group consisting of -N=, =CH-, and =CR4-, provided that at least one of A1, A2, A3, A4, and A5is not -N=;

[0103] B, B1, B2, and B3are each, independently for each occurrence, selected from the group consisting of -O-, -S-, -NH-, -NR4-, -CHR4-, -CH2-, and -C(R4)2-; and

[0104] C1and C2are each, independently for each occurrence, selected from the group consisting of -O-, -S-, -NH-, -NR4-, -N=, -CHR4-, -CH2-, -C(R4)2-, =CH-, and =CR4-. In yet another embodiment, Ring A is selected from the group consisting of C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cwaryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R9. In a further embodiment, Ring A is selected from the group consisting of 3-10 membered heterocycloalkyl, Ce-C aryl, and 5-10 membered heteroaryl, wherein the heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from R9.

[0105] In another embodiment, Formula VII is selected from a compound of Formulae Xa-Xf:

[0106] or a pharmaceutically acceptable salt thereof, wherein: each — represents a single bond or a double bond;

[0107] X1, X2, X3, and X4are each independently, for each occurrence, selected from the group consisting of -O-, =N-, -NH-, NR9, =CH-, -CH2-, -CHR9-, =CR9-, and C(R9)2; A1, A3, and A5are each independently, for each occurrence, selected from the group consisting of =N-, =CH-, or =CR4-;

[0108] A2is selected from the group consisting of -NH-, -NR4-, -CHR4-, -CH2-, and -C(R4)2-

[0109] B3is selected from the group consisting of -O-, -S-, -NH-, -NR4-, -CHR4-, -CH2-, and - C(R4)2-; and C1and C2are each, independently for each occurrence, selected from the group consisting of -O-, -S-, -NH-, -NR4-, -N=, -CHR4-, -CH2-, -C(R4)2-, =CH-, and =CR4-.

[0110] In still another embodiment, the compound of Formula VII is selected from a compound of Formulae Xla-Xlg: or a pharmaceutically acceptable salt thereof, wherein:

[0111] X1and X4are each independently selected from the group consisting of =N-, -NH, NR9, =CH-, -CH2-, -CHR9-, CR9, and C(R9)2;

[0112] X2and X3are each independently =CH-, -CH2-, -CHR9-, CR9, or C(R9)2; and C2is -O-, -S-, -NH-, -NR4-, -CHR4-, -CH2-, and -C(R4)2-.

[0113] In yet another embodiment, the compound of Formula VII is a compound of Formula

[0114] XI la or Formula XI lb: or a pharmaceutically acceptable salt thereof,

[0115] X1is selected from the group consisting of -NH, NR9, -CH2-, -CHR9-, and C(R9)2; and X4is selected from the group consisting of =N-, =CH-, and CR9.

[0116] In another embodiment, the compound of Formula VII is a compound of Formulae Xllla- Xlllg:

[0117] (Xllld)

[0118] (Xlllc)

[0119] or a pharmaceutically acceptable salt thereof, wherein X1and X4are each independently selected from the group consisting of -CH2-, -CHR9-, and C(9)2.

[0120] In still another embodiment, R1Aand R1Bare, independently for each occurrence, selected from the group consisting of H, halo, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(Ce-Cio aryl), and C1-C4 alkylene(5-10 membered heteroaryl), wherein the alkyl, alkoxy, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from R5.

[0121] In yet another embodiment, R1Aand R1Btogether with the atom to which they are attached form a double bond.

[0122] In another embodiment, R2is selected from the group consisting of H, halo, CN, Ci- Ce alkyl, Ci-Ce alkoxy, and Ci-Ce alkylamine, and wherein the alkyl is optionally substituted with 1-3 substituents selected from R5; and

[0123] R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, Ci-C6alkyl, C2.6alkynyl, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl.

[0124] In still another embodiment, R3is, independently for each occurrence, selected from the group consisting of halo, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), and -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), and wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-4 substituents selected from R7; and

[0125] R7is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, Ci-C6alkyl, C2.6alkynyl, C(0)-0H, C(0)-NH2, and C(0)-Ci-C6alkyl.

[0126] In yet another embodiment, R3is, independently for each occurrence, selected from the group consisting of halo, CN, Ci-Ce alkyl, C2.6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, and C3-C10 cycloalkyl.

[0127] In another embodiment, R9of NR9is, independently for each occurrence, selected from the group consisting of Ci-Ce alkyl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl, and wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 substituents selected from R10.

[0128] In still another embodiment, each R10is, independently for each occurrence, selected from the group consisting of halo, =0, =NH, OH, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C(0)-0H, C(0)-NH2, and C(0)-Ci-C6alkyl.

[0129] In yet another embodiment, R9of -CHR9-, =CR9-, and C(R9)2is, independently for each occurrence, selected from the group consisting of =0, halo, CN, =N-0-(Ci-Ce alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamine, C(0)-0H, C(0)-NH2, C(0)-Ci-C6alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(C3-Cio cycloalkyl), -W-(3-10 membered heterocycloalkyl), -W-(Ci-Ce alkylene)-(C3-Cio cycloalkyl), and -W-(Ci-Ce alkylene)-(3-10 membered heterocycloalkyl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 substituents selected from R10.

[0130] In another embodiment, each R10is, independently for each occurrence, selected from the group consisting of halo, OH, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C(0)-0H, C(0)-NH2, and C(O)-Ci-Ce alkyl.

[0131] In still another embodiment, at least one R10is selected from the group consisting of C(0)-0H, C(0)-NH2, and C(0)-Ci-C6alkyl.

[0132] In another aspect, the compound is selected from a compound in Table 2, or a pharmaceutically acceptable salt thereof.

[0133]

[0134] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0135] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as 0- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a -methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1 ,2-diaminocyclohexane and the like.

[0136] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0137] In some embodiments, the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated.

[0138] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1 / - / - and 3 / - / -imidazole, 1 / - / -, 2H- and 4 / - / - 1 ,2,4- triazole, 1 / - / - and 2H- isoindole and 1 / - / - and 2 / - / -pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0139] Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971 ; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011 ). Isotopically labeled compounds can used in various studies such as NMR spectroscopy, metabolism experiments, and / or assays.

[0140] Substitution with heavier isotopes such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. (A. Kerekes et.al. J. Med. Chem. 2011 , 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312). Unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium). In embodiments, the compounds provided herein have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0141] II. Methods of Treatment

[0142] Compounds provided herein can inhibit the activity of the WRN protein. For example, compounds of the present disclosure can be used to inhibit activity of WRN in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibiting amount of one or more compounds of the present disclosure to the cell, individual, or patient.

[0143] As WRN inhibitors, the compounds provided herein are useful in the treatment of various diseases associated with abnormal expression or activity of WRN. Compounds which inhibit WRN will be useful in providing a means of preventing the growth or inducing apoptosis in tumors, or by inhibiting angiogenesis. It is therefore anticipated that compounds of the present disclosure will prove useful in treating or preventing proliferative disorders such as cancers.

[0144] In an aspect, disclosed herein are methods of treating or ameliorating a disease state or condition that is modulated through or causally related to the target protein, i.e., WRN.

[0145] In another aspect, provided herein are methods of treating a disease or disorder comprising administering to a subject an amount of a compound disclosed herein, or an amount of a pharmaceutical composition disclosed herein.

[0146] In an embodiment, the disease or disorder is a disease associated with Werner Syndrome RecQ Like Helicase (WRN) activity. In a further embodiment, the method comprises inhibiting WRN activity.

[0147] In another embodiment, the disease is cancer. In a further embodiment, the cancer has a microsatellite instability (MSI)-positive phenotype or MSI-high (MSI-H) phenotype. In another embodiment, the cancer has a mismatch repair defective gene or mismatch repair mutated gene. In still another embodiment the cancer is colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, or ovarian cancer.

[0148] In yet another embodiment, the cancer is an adrenocortical carcinoma, a bladder carcinoma, a breast carcinoma, a cervical squamous cell carcinoma, an endocervical adenocarcinoma, a cholangiocarcinoma, a chronic lymphocytic leukemia, a colorectal cancer, a colon adenocarcinoma, a cutaneous T-cell lymphoma, a lymphoid neoplasm diffuse large B-cell lymphoma, an esophageal carcinoma, a glioblastoma multiforme, a head and neck squamous cell carcinoma, a kidney chromophobe, a kidney renal papillary cell carcinoma, an acute myeloid leukemia, a lower-grade glioma, a liver hepatocellular carcinoma, a lung adenocarcinoma, a lung squamous cell carcinoma, a mesothelioma, a nasopharyngeal carcinoma, an ovarian cancer, an ovarian serous cystadenocarcinoma, a pancreatic adenocarcinoma, a pheochromocytoma, paraganglioma, a prostate adenocarcinoma, a rectal adenocarcinoma, a sarcoma, a skin cutaneous melanoma, a stomach adenocarcinoma, a testicular germ cell tumor, a thyroid carcinoma, a thymoma, an uterine corpus endometrial carcinoma, an uterine carcinosarcoma, an uveal melanoma, a pediatric acute myeloid leukemia, a pediatric neuroblastoma, or a pediatric high-risk Wilms tumor.

[0149] In a further embodiment, the cancer is an ovarian cancer, a uterine corpus endometrial carcinoma, a colorectal cancer, a colon adenocarcinoma, or a stomach adenocarcinoma.

[0150] III. Kits and devices

[0151] The disclosure provides a variety of kits and devices for conveniently and / or effectively carrying out methods of the present disclosure. Typically kits will comprise sufficient amounts and / or numbers of components to allow a user to perform multiple treatments of a subject(s) and / or to perform multiple experiments.

[0152] In one embodiment, the present disclosure provides kits for inhibiting cancer cell growth in vitro or in vivo, comprising a construct of the present disclosure or a combination of constructs of the present disclosure, optionally in combination with any other active agents.

[0153] The kit may further comprise packaging and instructions and / or a delivery agent to form a formulation composition. The delivery agent may comprise a saline, a buffered solution, or any delivery agent disclosed herein. The amount of each component may be varied to enable consistent, reproducible higher concentration saline or simple buffer formulations. The components may also be varied in order to increase the stability of the constructs in the buffer solution over a period of time and / or under a variety of conditions.

[0154] The present disclosure provides for devices which may incorporate constructs of the present disclosure. These devices contain in a stable formulation available to be immediately delivered to a subject in need thereof, such as a human patient. In some embodiments, the subject has cancer.

[0155] Non-limiting examples of the devices include a pump, a catheter, a needle, a transdermal patch, a pressurized olfactory delivery device, iontophoresis devices, multilayered microfluidic devices. The devices may be employed to deliver constructs of the present disclosure according to single, multi- or split-dosing regiments. The devices may be employed to deliver constructs of the present disclosure across biological tissue, intradermal, subcutaneously, or intramuscularly.

[0156] IV. Definitions

[0157] Listed below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0158] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0159] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0160] As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0161] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. The term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound. The terms “hal,” “halo,” or “halogen,” as used herein, refer to an atom selected from fluorine, chlorine, bromine, and iodine.

[0162] The term “alkyl,” as used herein, refers to saturated, straight-chain, or branched hydrocarbon radicals containing, in embodiments, from one to twenty, including from one to ten, or from one to six, carbon atoms. Branched means that one or more lower C1.6 alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. Examples of C1.6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of C1-20 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals. Examples of C1-20 alkyl radicals include but are not limited to hexadecamethyl, hexadecaethyl, hexadecopropyl, octadecamethyl, octadecaethyl, octadecapropyl and the like.

[0163] The terms “haloalkyl,” “haloalkenyl,” or “haloalkynyl,” as used herein refer to an alkyl, alkenyl or alkynyl, including straight-chain and branched, that is substituted with one or more halogens or halo groups. Examples of haloalkyl include but are not limited to CF3, CH2CF3, and CCI3.

[0164] The term “cycloalkyl,” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound. Included within the term “cycloalkyl” are C3-10 ring members C3-8 ring members, and C3-6 ring members. Also included within the term “cycloalkyl” are monocyclic C4, C5, Ce, and C7cycloalkyl groups. Cycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) or spirocyclic ring systems. Examples of C3-8 cycloalkyl (3- to 8-membered cycloalkyl) include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C3-12 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl and the like.

[0165] “Heterocyclyl” or “heterocycloalkyl,” as used herein, are cyclic systems containing carbon and at least one heteroatom selected from N, O, S, and P, wherein there is not delocalized TT electrons (aromaticity) shared among the ring carbon or heteroatoms, i.e., the cyclic ring system in non-aromatic. Included within the term “heterocycloalkyl” are 3-10 ring members, 4-7 ring members, 3-6 ring members, or 4-6 ring members. Also included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1 , 2, or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0166] As used herein, the term “aryl” means an aromatic carbocyclic system containing 1 , 2 or 3 rings, wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term “aryl” includes, but is not limited to, phenyl, naphthyl, indanyl, and 1 ,2,3,4-tetrahydronaphthalenyl. In some embodiments, aryl groups have 6 carbon atoms. In some embodiments, aryl groups have from six to ten carbon atoms. In some embodiments, aryl groups have from six to sixteen carbon atoms. In an embodiment, the aryl group has six to ten carbon atoms.

[0167] As used herein, the term “heteroaryl” means an aromatic carbocyclic system containing 1 , 2, 3, or 4 heteroatoms selected independently from N, O, and S and having 1 , 2, or 3 rings wherein such rings may be fused, wherein fused is defined above. The term “heteroaryl” includes, but is not limited to, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1 ,2-a]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, 5, 6,7,8- tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta-[c]pyridinyl, 1 ,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2, 4,5,6- tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1 ,2-b] pyrazolyl, 6,7-dihydro-5H- pyrrolo[1 ,2-b][ 1 ,2,4]triazolyl, 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[1 ,5-a]pyridinyl, 4, 5,6,7- tetrahydropyrazolo[1 ,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro- 2H-indazolyl. In embodiment, heteroaryl is 5-10 membered heteroaryl. In another embodiment, heteroaryl is 5-6 membered heteroaryl.

[0168] It is to be understood that if an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms (i.e., shown or described without denotation of a specific point of attachment), then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridinyl” means 2-, 3- or 4-pyridinyl, the term “thienyl” means 2- or 3-thienyl, and so forth.

[0169] The term “independently selected” is used herein to indicate that, for a variable which occurs in more than one location in a genus, the identity of the variable is determined separately in each instance. For example, if Rxappears as a substituent on two different atoms, the two instances of Rxmay be the same moiety, or different moieties. The same is true if a single atom is substituted with more than one instance of Rx. The identity of Rxin each instance is determined independently of the identity of the other(s).

[0170] It will be appreciated that the compounds, as described herein, may be substituted with one, two, three, four, five or more (up to the total possible number of substituents for the particular compound) independently selected substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas disclosed herein, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples of substituents on the moieties disclosed herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, non-aromatic heterocycle groups) include, but are not limited to, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroaryl, aryl, cycloalkyl, cycloalkenyl, non- aromatic heterocycle, hydroxyl, carbamoyl, oxo, amino, nitro, azido, -SH, and -CN.

[0171] As described herein, compounds of the disclosure may optionally be substituted with one or more substituents, such as those described generally above, or as exemplified by particular classes, subclasses, and species of the disclosure. Unless otherwise indicated, an optionally substituted group may have a substituent at any or each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent independently selected from a specified group, the substituent may be either the same or different at each substituted every position.

[0172] It is also to be understood that floating substituents on ring-containing scaffolds (e.g., cycloalkyl, heterocycloalkyl, aryl, and heteroaryl) are groups that can be designated to any substitutable position defined by the ring.

[0173] A “pharmaceutical composition” is a formulation containing one or more therapeutic agents (e.g., one or more compounds of the present disclosure) in a form suitable for administration to a subject. In embodiments, the pharmaceutical composition is in bulk form, e.g., for storage. Alternatively, the pharmaceutical composition is in unit dosage form. It can be advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active reagent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active agents and the particular therapeutic effect to be achieved, and the limitations in the art of compounding such an active agent for the treatment of individuals.

[0174] A compound of the present disclosure may be administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable excipient. The formulation may be adapted for administration by any of a variety of routes including oral, buccal, rectal, vaginal, intranasal, intraocular, transdermal, subcutaneous, intravenous, or intramuscular.

[0175] The term “pharmaceutical” or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient. As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0176] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17thEd., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1 ), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

[0177] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0178] Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0179] Some of the compounds of the present disclosure may exist in unsolvated as well as solvated forms such as, for example, hydrates.

[0180] “Pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes any excipient that is acceptable for veterinary use and / or human pharmaceutical use. A “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient.

[0181] The terms “treat,” “treating,” and “treatment,” etc., as used herein, refer to any action providing a benefit to a patient for which the present compounds may be administered, including the treatment of any disease state or condition that is modulated through the target protein to which the present compounds bind. Disease states or conditions, including cancer, inflammatory diseases / disorders, autoimmune diseases / disorders, neurological and neurodegenerative diseases, and / or cardiovascular diseases / disorders, which may be treated using compounds according to the present disclosure are set forth hereinabove. The term “disease state or condition” is used to describe any disease state or condition wherein protein dysregulation (i.e., the amount of protein expressed in a patient is elevated) occurs and where degradation of the protein in a subject or patient may provide beneficial therapy or relief of symptoms to a subject or patient in need thereof. In certain instances, the disease state or condition may be cured.

[0182] The term “prevent,” “preventing,” or “prevention” as used herein comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.

[0183] The term “administration” or the like as used herein refers to the providing a therapeutic agent to a subject. Multiple techniques of administering a therapeutic agent exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration. The term “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. Exemplary cancers that may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include adrenocortical carcinoma, a bladder carcinoma, a breast carcinoma, a cervical squamous cell carcinoma, an endocervical adenocarcinoma, a cholangiocarcinoma, a chronic lymphocytic leukemia, a colorectal cancer, a colon adenocarcinoma, a cutaneous T-cell lymphoma, a lymphoid neoplasm diffuse large B-cell lymphoma, an esophageal carcinoma, a glioblastoma multiforme, a head and neck squamous cell carcinoma, a kidney chromophobe, a kidney renal papillary cell carcinoma, an acute myeloid leukemia, a lower- grade glioma, a liver hepatocellular carcinoma, a lung adenocarcinoma, a lung squamous cell carcinoma, a mesothelioma, a nasopharyngeal carcinoma, an ovarian cancer, an ovarian serous cystadenocarcinoma, a pancreatic adenocarcinoma, a pheochromocytoma, paraganglioma, a prostate adenocarcinoma, a rectal adenocarcinoma, a sarcoma, a skin cutaneous melanoma, a stomach adenocarcinoma, a testicular germ cell tumor, a thyroid carcinoma, a thymoma, an uterine corpus endometrial carcinoma, an uterine carcinosarcoma, an uveal melanoma, a pediatric acute myeloid leukemia, a pediatric neuroblastoma, or a pediatric high-risk Wilms tumor.

[0184] The expressions “ambient temperature” and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20 °C to about 30 °C.

[0185] V. Equivalents and scope

[0186] While various disclosure embodiments have been particularly shown and described in the present disclosure, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the spirit and scope of the embodiments disclosed herein and set forth in the appended claims.

[0187] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present disclosure is not intended to be limited to the above description, but rather is as set forth in the appended claims. In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of a group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all group members are present in, employed in, or otherwise relevant to a given product or process.

[0188] It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the terms “consisting of’ and “or including” are thus also encompassed and disclosed.

[0189] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0190] In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiments of compositions disclosed herein can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

[0191] All cited sources, for example, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control.

[0192] Section and table headings are not intended to be limiting.

[0193] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. EXAMPLES

[0194] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art.

[0195] The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings of the present disclosure as set forth. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations, and / or methods of the disclosure may be made without departing from the spirit of the disclosure and the scope of the appended claims. Definitions of the variables in the structures in the schemes herein are commensurate with those of corresponding positions in the formulae presented herein. In the below examples, X is defined as halo.

[0196] General Synthetic Schemes.

[0197] Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below.

[0198] The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[0199] Preparation of compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6thEd. (Wiley, 2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 1997, 74(11 ), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0200] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0201] The Schemes below provide general guidance in connection with preparing the compounds of the present disclosure. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds provided herein.

[0202] Synthesis of Butynamides

[0203] Scheme 1. Scheme 3.

[0204] Example 1. Synthesis of Intermediates.

[0205] 2-chloro-5H,7H-furo[3,4-b]pyridine

[0206] Step 1 : 2-((prop-2-yn-1-yloxy)methyl)pyrimidine. To a solution of pyrimidin-2-ylmethanol (5.0 g, 45.4 mmol, 1 .0 equiv.) in THF (80 mL) was added NaH (2.72 g, 68.1 mmol, 1 .5 equiv., 60% purity) at 0 °C. After stirring at 0 °C for 0.5 h, to the above mixture was added propargyl bromide (4.70 mL, 54.5 mmol, 1 .2 equiv.). After stirring for 3 hours at 50 °C, the mixture was allowed to cool down to room temperature, diluted with water (80 mL) and extracted with ethyl acetate (80 mL x 4). The combined organic layers were washed with water (80 mL), brine (80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with MeOH in DCM (5 %), to afford 2- [(prop-2-yn-1-yloxy)methyl]pyrimidine as an oil.

[0207] LCMS (MS, ESI):149 [M+H]+.

[0208] Step 2: 5,7-dihydrofuro[3,4-b]pyridine. A solution of 2-[(prop-2-yn-1- yloxy)methyl]pyrimidine (6.2 g, 41.8 mmol, 1.0 equiv.) in toluene (70 mL) was stirred at 130 °C for 2 days. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate in petroleum ether (40 %), to afford 5,7-dihydrofuro[3,4-b]pyridine as a liquid.

[0209] LCMS (MS, ESI):122 [M+H]+.

[0210] Step 3: 5,7-dihydrofuro[3,4-b]pyridine 1 -oxide To a solution of 5,7-dihydrofuro[3,4- b]pyridine (4.01 g, 33.1 mmol, 1 equiv.) in DCM (60 mL) was added m-CPBA (8.55 g, 42.1 mmol, 1 .27 equiv., 85%) at room temperature. After stirring for 2 hours at room temperature, the resulting mixture was quenched with a saturated solution of sodium bicarbonate in water (15 mL) and extracted with MeOH / DCM (1 :10, 30 mL x 6). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product that was purified by silica gel column chromatography, eluting with MeOH in DCM (3.5 %), to afford 5,7-dihydrofuro[3,4-b]pyridine 1-oxide 5H,7H-furo[3,4-b]pyridin-1-ium-1-olate as a solid.

[0211] LCMS (MS, ESI):138 [M+H]+.

[0212] Step 4: 2-chloro-5,7-dihydrofuro[3,4-b]pyridine. A solution of 5,7-dihydrofuro[3,4- b]pyridine 1-oxide (5.07 g, 23.3 mmol, 1.0 equiv., 63% purity) in POCh (30 mL) was stirred at 100 °C for 3 hours. After cooling to room temperature, the residue was basified to pH 9 with NaOH (10% in water) at 0 °C and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate in petroleum ether (11 %) to give 2-chloro-5,7-dihydrofuro[3,4-b]pyridine 2-chloro-5H,7H-furo[3,4-b]pyridine as a solid.

[0213] LCMS (MS, ESI):156, 158 [M+H]+.1H NMR (400 MHz, Chloroform-d) 5 7.54 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1 H), 5.16 (s, 2H), 5.05 (s, 2H).

[0214] 3-iodo-1-methyl-1 ,4,5,6-tetrahydrocyclopenta[c]pyrazole

[0215] Step 1 : 3-iodo-1-methyl-1 ,4,5,6-tetrahydrocyclopenta[c]pyrazole To a solution of 3-iodo- 1 ,4,5,6-tetrahydrocyclopenta[c]pyrazole (500 mg, 2.14 mmol, 1.0 equiv.) in THF (4 mL) was added NaH (153 mg, 6.41 mmol, 3.0 equiv., 60% purity) at 0°C. After stirring for 30 minutes at 0°C, a solution of CH3I (242 mg, 1 .71 mmol, 0.8 equiv.) in THF (1 mL) was added. The resulting mixture was stirred for additional 3 hours at room temperature, quenched by water (30 mL) at 0°C and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (18% EA) to afford 3-iodo-1-methyl-1 , 4,5,6- tetrahydrocyclopenta[c]pyrazole 3-iodo-1-methyl-4H,5H,6H-cyclopenta[c]pyrazole as a solid.

[0216] LCMS (MS, ESI): 249 [M+H]+.1HNMR (400 MHz, Chloroform-d) 5 3.78 (s, 3H), 2.70 - 2.78 (m, 2H), 2.51 - 2.62 (m, 4H).

[0217] 5-chloro-1-methylimidazo[4,5-b]pyridine

[0218] Step 1 : 5-chloro-1-methylimidazo[4,5-b]pyridine To a solution of 5-chloro-3H- imidazo[4,5-b]pyridine (2.0 g, 13.0 mmol, 1.0 equiv.) in THF (20 mL) was added NaH (1.04 g, 26.0 mmol, 2.0 equiv., 60% purity) in portions at O °C. After stirring for 30 minutes at O °C under an atmosphere of nitrogen, Mel (2.0 mL, 32.2 mmol, 2.47 equiv.) was added to the reaction mixture. The resulting mixture was stirred for 2 hours at room temperature under an atmosphere of nitrogen. The reaction mixture was quenched with water (25 mL) at 0 °C and extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE in EA (100% EA) to afford 5-chloro-1-methylimidazo[4,5-b]pyridine as a solid.

[0219] LCMS (MS, ESI): 168, 170 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 8.50 (s, 1 H), 8.14 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H).

[0220] 1 -(5-chloro-1 H-pyrazolo[4,3-b]pyridin-1 -yl)-2-methylpropan-2-ol

[0221] Step 1 : 1-(5-chloro-1H-pyrazolo[4,3-b]pyridin-1-yl)-2-methylpropan-2-ol. To a solution of 5-chloro-1 / - / -pyrazolo[4,3-b] pyridine (2.00 g, 13.0 mmol, 1.0 equiv.) in DMF (40 mL) was added NaH (780 mg, 19.5 mmol, 1 .5 equiv, 60% purity) at 0 °C. After stirring for 30 min at RT, 1-chloro-2-methylpropan-2-ol (2.0 mL, 19.5 mmol, 1.5 equiv.) was added at 0 °C. The reaction mixture was stirred for 16 h at 100 °C, quenched with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (38%) to afford 1-(5-chloropyrazolo[4,3-b] pyridin-1-yl-2-methylpropan-2-ol as a solid.

[0222] LCMS (MS, ESI): 226, 228 [M+H]+.

[0223] Intermediate 156: 5-methyl-2,3-dihydrofuro[2,3-b]pyridin-6-amine

[0224] Step 1 : 5-iodo-2,3-dihydrofuro[2,3-b]pyridin-6-amine To a solution of 2 / - / ,3 / - / -furo[2,3- b]pyridin-6-amine (500 mg, 3.67 mmol, 1.0 equiv.) in ACN (10 mL) was added NIS (909 mg, 4.04 mmol, 1.10 equiv.) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (40% EA) to afford 5-iodo-2 / - / ,3 / - / -furo[2,3-b]pyridin-6-amine as a solid.

[0225] LCMS (MS, ESI): 263 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 7.65 (s, 1 H), 5.82 (s, 2H), 4.48 (t, J = 8.5 Hz, 2H), 3.04 (t, J = 8.5 Hz, 2H).

[0226] Step 2: 5-methyl-2,3-dihydrofuro[2,3-b]pyridin-6-amine To a stirred solution of 5-iodo- 2H,3 / - / -furo[2,3-b]pyridin-6-amine (1.1 g, 4.20 mmol, 1 .0 equiv.) in dioxane (10 mL) were added Pd(dppf)Ch (154 mg, 0.210 mmol, 0.05 equiv.) and dimethylzinc (8.4 mL, 8.40 mmol, 2.00 equiv., 1M in THF) dropwise at 0 °C under an atmosphere of nitrogen. The reaction mixture was stirred for 3 hours at 110 °C. After cooling to room temperature, the reaction mixture was quenched with water (50 mL). The resulting mixture was filtered, and the filter cake was washed with EA (2 x 10 mL). The filtrate was extracted with EA (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (42% EA) to give a product. The product was dissolved in EA (20 mL) and treated with 500 mg of SiliaMetS Thiol (Scavenger for removing Pd). The resulting mixture was stirred at room temperature for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure to afford 5- methyl-2H,3 / - / -furo[2,3-b]pyridin-6-amine as a solid.

[0227] LCMS (MS, ESI): 151 [M+H]+. 5-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine and 5-chloro-2- (tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[4,3-b]pyridine

[0228] Step 1 : 5-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-b]pyridine and 5-chloro- 2-(tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[4,3-b]pyridine. To a solution of 5-chloro-1 / - / - pyrazolo[4,3-b]pyridine (1.0 g, 6.51 mmol, 1.0 equiv.) in DMF (15 mL) were added CS2CO3 (6.5 g, 20.0 mmol, 3.06 equiv.) and oxan-4-yl methanesulfonate (1 .4 g, 7.77 mmol, 1.19 equiv.) at 0 °C. After stirring for 15 hours at room temperature under an atmosphere of nitrogen, the reaction mixture was quenched with water (50 mL) and extracted with EA (60 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (50% EA) to afford 5-chloro-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine as a solid and 5-chloro- 2-(oxan-4-yl)pyrazolo[4,3-b]pyridine. As a solid.

[0229] 5-chloro-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine: LCMS (MS, ESI): 238, 240 [M+H]+.1HNMR (400 MHz, DMSO-d6): 5 8.38 (dd, J = 8.9, 1.0 Hz, 1 H), 8.29 (s, 1H), 7.48 (d, J = 8.9 Hz, 1H), 4.90 - 5.00 (m, 1H), 3.95 - 4.05 (m, 2H), 3.51 - 3.58 (m, 2H), 2.07 - 2.17 (m, 2H), 1.89 - 1.95 (m, 2H).

[0230] 5-chloro-2-(oxan-4-yl)pyrazolo[4,3-b]pyridine: LCMS (MS, ESI): 238, 240 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.77 (s, 1 H), 8.20 (dd, J = 8.9, 0.9 Hz, 1 H), 7.31 (d, J = 9.0 Hz, 1 H), 4.77 - 4.85 (m, 1 H), 4.00 - 4.04 (m, 2H), 3.47 - 3.56 (m, 2H), 2.07 - 2.18 (m, 4H).

[0231] 2-bromo-3-methyl-5-(oxetan-2-ylmethoxy)pyridine

[0232] Step 1 : 2-bromo-3-methyl-5-(oxetan-2-ylmethoxy)pyridine. To a stirred mixture of 6- bromo-5-methylpyridin-3-ol (1.0 g, 5.31 mmol, 1.0 equiv.) and oxetan-2-ylmethanol (470 mg, 5.32 mmol, 1.0 equiv.) in THF (20 mL) was added PPha (2.1 g, 8.03 mmol, 1.51 equiv.) at 0 °C under an atmosphere of nitrogen. After stirring for 30 minutes at 0 °C, DIAD (1 .60 mL, 8.08 mmol, 1.52 equiv.) was added dropwise to the reaction mixture. After stirring for 4 hours at room temperature, the reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (25% EA) to afford 2-bromo-3-methyl-5-(oxetan-2-ylmethoxy)pyridine as an oil.

[0233] LCMS (MS, ESI): 258, 260 [M+H]+.

[0234] Intermediate 140: 1-(5-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol

[0235] Step 1 : 1-(5-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol. To a solution of 5-chloro-1 / - / -pyrazolo[4,3-b] pyridine (2.00 g, 13.0 mmol, 1.0 equiv.) in DMF (40 mL) was added NaH (780 mg, 19.5 mmol, 1 .5 equiv., 60% purity) at 0 °C. After stirring for 30 min at RT, 1-chloro-2-methylpropan-2-ol (2 mL, 19.5 mmol, 1 .5 equiv.) was added at 0 °C. The reaction mixture was stirred for 16 h at 100 °C. After cooling down to RT, the reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (38%) to afford 1-(5- chloropyrazolo[4,3-b] pyridin-2-yl-2-methylpropan-2-ol as a solid.

[0236] LCMS (MS, ESI): 226, 228 [M+H]+.

[0237] 5-chloro-1-(2-methoxy-2-methylpropyl)-1H-pyrazolo[4,3-b]pyridine

[0238] Step 1 : 5-chloro-2-(2-methoxy-2-methylpropyl)-2H-pyrazolo[4,3-b]pyridine. A solution of 1-(5-chloro-2 / - / -pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol (600 mg, 2.13 mmol, 1.0 equiv., 80% purity) (synthesized by the procedure of Intermediate 140 step 1) in DMF (10 mL) was added NaH (128 mg, 3.19 mmol, 1.5 equiv., 60% purity) at 0 °C. After stirred at room temperature for 20 min, to the reaction mixture was added CH3I (0.20 mL, 3.19 mmol, 1 .5 equiv.) at 0 °C. After stirring for 2 h at room temperature, the reaction was quenched with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (2 x 30 mL) and brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (13%) to afford 5-chloro-2-(2- methoxy-2-methylpropyl)pyrazolo[4,3-b]pyridine as a solid.

[0239] LCMS (MS, ESI): 240, 242 [M+H]+.

[0240] Intermediates 137a and 137b: 5-bromo-1-methylpyrazolo[3,4-c] pyridine and 5-bromo- 2-methyl-2H-pyrazolo[3,4-c] pyridine

[0241] 5-bromo-1-methylpyrazolo[3,4-c] pyridine (Intermediate 137a) and 5-bromo-2-methyl- 2 / - / -pyrazolo[3,4-c] pyridine (Intermediate 137b). To a solution of 5-bromo-1 / - / -pyrazolo[3,4-c] pyridine (2.00 g, 10.1 mmol, 1.0 equiv.) in THF (40 mL) was added KOH (1 .70 g, 30.3 mmol, 3.0 equiv.) at 0 °C. After stirring for 30 min at RT, Mel (0.94 mL, 15.2 mmol, 1.5 equiv.) was added at 0°C. The reaction mixture was stirred for 2 h at room temperature, quenched with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (29%) to afford 5-bromo-1-methylpyrazolo[3,4-c] pyridine (1.15 g, 50%) as a solid, and eluted with ethyl acetate in petroleum ether (44%) to afford 5-bromo-2-methyl-2 / - / -pyrazolo[3,4-c] pyridine as a solid.5-bromo-1- methylpyrazolo[3,4-c] pyridine: LCMS (MS, ESI): 212, 214 [M+H]+.1H-NMR (400 MHz, DMSO-ofe) 5 9.01 (s, 1 H), 8.16 (s, 1 H), 8.02 (s, 1H), 4.16 (s, 3H).

[0242] 5-bromo-2-methyl-2H-pyrazolo[3,4-c] pyridine: LCMS (MS, ESI): 212, 214 [M+H]+.1H-NMR (400 MHz, DMSO-d6) 5 8.89 (s, 1H), 8.48 (s, 1 H), 7.97 (s, 1 H), 4.27 (s, 3H).

[0243] 1-(2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1 -one

[0244] Step 1 : 1-(2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-1-one. To a stirred mixture of 2-chloro-5 / - / , GH, 7 / - / -pyrrolo[3,4-b]pyridine hydrochloride (900 mg, 4.71 mmol, 1.0 equiv.) in DCM (18 mL) were added DIEA (3.28 mL, 18.8 mmol, 4.0 equiv.) and AC2O (0.54 mL, 5.71 mmol, 1 .21 equiv.) dropwise at 0 °C under an atmosphere of nitrogen. Then to the above mixture was added DMAP (115 mg, 0.941 mmol, 0.20 equiv.) in portions at O °C. After stirring for 1 h, the reaction was quenched with water (20 mL) and extracted with DCM / MeOH (10:1) (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (3.3% MeOH) to afford 1-{2-chloro-5 / - / ,7 / - / -pyrrolo[3,4-b]pyridin-6-yl}ethanone as a solid.

[0245] LCMS (MS, ESI): 197, 199 [M+H]+.

[0246] 5-bromo-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b] pyridine and 5-bromo-2-(oxetan-3-yl)-2H- pyrazolo[4,3-b]pyridine

[0247] A mixture of 5-bromo-1 / - / -pyrazolo[4,3-b]pyridine (3.00 g, 15.2 mmol, 1.0 equiv.), oxetan-3-yl 4-methylbenzenesulfonate (6.92 g, 30.3 mmol, 2.0 equiv.) and CS2CO3 (14.8 g, 45.5 mmol, 3.0 equiv.) in DMF (20 mL) was stirred for 16 h at 60 °C. The cooled mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were washed with water (120 mL x 2) and brine (150 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 :3) to afford 5-bromo-1- (oxetan-3-yl)pyrazolo[4,3-b]pyridine as a solid and and 5-bromo-2-(oxetan-3-yl)-2 / - / - pyrazolo[4,3-b]pyridine pyridine as a solid.

[0248] LCMS (MS, ESI): 254, 256 [M+H]+.

[0249] Intermediate A: 4-bromo-2-cyclopropyl-5-methylaniline

[0250] Step 1 : 1 -cyclopropyl-4-methyl-2-nitrobenzene A mixture of 1-iodo-4-methyl-2- nitrobenzene (5.0 g, 19.0 mmol, 1.0 equiv.), cyclopropylboronic acid (3.27 g, 38.0 mmol, 2.0 equiv.), K3PO4 (8.07 g, 38.0 mmol, 2.0 equiv.), SPhos (1.56 g, 3.80 mmol, 0.2 equiv.) and Pd(0Ac)2 (0.43 g, 1.90 mmol, 0.1 equiv.) in toluene (37.5 mL) and H2O (7.5 mL) at 100°C was stirred for 4 hours at 100°C under an atmosphere of nitrogen. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 1-cyclopropyl-4- methyl-2-nitrobenzene as an oil.

[0251] 1H NMR (400 MHz, DMSO-d6) 5 7.67 (s, 1 H), 7.41 (dd, J = 8.0, 1.9 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1 H), 2.34 (s, 3H), 2.34 - 2.14 (m, 1 H), 0.99 - 0.93 (m, 2H), 0.71 - 0.67 (m, 2H). Step 2: 2-cyclopropyl-5-methylaniline A mixture of 1-cyclopropyl-4-methyl-2-nitrobenzene (10.5 g, 59.3 mmol, 1.0 equiv.), NH4CI (15.9 g, 296 mmol, 5.0 equiv.) and Fe (19.9 g, 356 mmol, 6.0 equiv.) in 1 ,4-dioxane (100 mL), H2O (60 mL) and EtOH (40 mL) was stirred for 2 hours at 100°C. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (9% EA) to afford 2-cyclopropyl-5-methylaniline as an oil.

[0252] LCMS (MS, ESI): 148 [M+H]+.

[0253] Step 3: 4-bromo-2-cyclopropyl-5-methylaniline (Intermediate A). To a stirring mixture of 2-cyclopropyl-5-methylaniline (2.0 g, 13.6 mmol, 1.0 equiv.) in CAN (40 mL) was added NBS (2.30 g, 12.9 mmol, 0.95 equiv.) in portions at 0°C. After stirring for 2 hours at room temperature, the reaction was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (9% EA) to afford 4- bromo-2-cyclopropyl-5-methylaniline as an oil.

[0254] LCMS (MS, ESI): 226, 228 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 6.86 (s, 1 H), 6.55 (s, 1 H), 5.06 (s, 2H), 2.14 (s, 3H), 1.62 - 1.58 (m, 1 H), 0.91 - 0.63 (m, 2H), 0.49 - 0.25 (m, 2H).

[0255] 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile

[0256] Step 1 : 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile. A solution of 5- chloro-1 / - / -pyrrolo[3,2-b]pyridine-3-carbonitrile (500 mg, 2.81 mmol, 1.0 equiv.) in THF (20 mL) was treated with NaH (81 mg, 3.38 mmol, 1 .2 equiv.) for 30 min at 0 °C followed by the addition of Mel (400 mg, 2.82 mmol, 1 .0 equiv.) dropwise at 0 °C. After stirring for 1 h at 20 °C, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (30 mL x 1) and brine (30 mL x 1 ), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :2) to afford to afford 5-chloro-1-methylpyrrolo[3,2-b]pyridine-3- carbonitrile as a solid.

[0257] LCMS (MS, ESI): 192, 194 [M+H]+.

[0258] Step 1 : 3-iodo-1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole. To a solution of pyrano[4,3-c]pyrazole (2.00 g, 16.1 mmol, 1.0 equiv.) in DMF (40 mL) was added NIS (4.00 g, 17.8 mmol, 1.1 equiv.) in portions at 0 °C. After stirring for 10 min at 0 °C, the reaction was stirred overnight at room temperature, quenched with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (240 mL x 3), brine (240 mL), dried over NazSC . After filtration, the filtrate was concentrated under reduced pressure to afford 3-iodo-1 / - / ,4 / - / ,6 / - / ,7 / - / -pyrano[4,3-c]pyrazole as a solid.

[0259] LCMS (MS, ESI): 251 [M+H]+.

[0260] Step 2: 3-iodo-1-methyl-1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole. To a solution of 3-iodo- 1 / - / ,4 / - / ,6 / - / ,7 / - / -pyrano[4,3-c]pyrazole (2.40 g, 9.60 mmol, 1.0 equiv.) in THF (40 mL) was added NaH (1.2 g, 30.0 mmol, 3.1 equiv., 60% purity) in portions at 0 °C. After stirring for 30 min at 0 °C, to the above reaction mixture was added dropwise CH3I (0.90 mL, 14.4 mmol, 1 .5 equiv.) at 0 °C. After stirring for 10 min at 0 °C, the reaction was stirred for 3 h at room temperature, quenched with water (50 mL) at 0 °C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (150 mL x 2), brine (150 mL), dried over NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash (Cis column, H2O / CAN, 27% CAN) to afford 3- iodo-1-methyl-4 / - / ,6 / - / ,7 / - / -pyrano[4,3-c]pyrazole as a solid.

[0261] LCMS (MS, ESI): 265 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 4.33 (t, J=1.2 Hz, 2H), 3.80-3.83 (m, 2H), 3.70 (s, 3H), 2.65-2.68 (m, 2H). 2-chloro-6,7-dihydro-9H-pyrido[2’,3’:4,5]imidazo[2,1-c][1,4]oxazine

[0262] Step 1 : (Z)- / V-(6-chloro-3-iodopyridin-2-yl)morpholin-3-imine To a solution of morpholin- 3-one (2.38 g, 23.6 mmol, 2.0 equiv.) in toluene (60 mL) was added POCI3 (1.1 mL, 11 .8 mmol, 1 .0 equiv.) at 0 °C. After stirring for 2 hours at 0 °C, to the above mixture was added 6-chloro-3-iodopyridin-2-amine (3.00 g, 11 .8 mmol, 1 .0 equiv.) at 0 °C. After stirring at 120 °C for 4 h, the reaction mixture was cooled to RT, quenched with aqueous saturated NaHCOs (60 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with water (60 mL), brine (60 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (11 %) to afford (3Z)-A / -(6-chloro-3-iodopyridin-2-yl) morpholin-3- imine as an oil.

[0263] LCMS (MS, ESI): 338, 340 [M+H]+.

[0264] Step 2: 2-chloro-6,7-dihydro-9H-pyrido[2’,3’:4,5]imidazo[2,1-c][1,4]oxazine. To a solution of (3Z)-A / -(6-chloro-3-iodopyridin-2-yl) morpholin-3-imine (2.00 g, 5.93 mmol, 1.0 equiv.), Cui (225 mg, 1.19 mmol, 0.2 equiv.), K3PO4 (1.26 g, 5.93 mmol, 1.0 equiv.) and DMEDA (156 mg, 1.78 mmol, 0.3 equiv.) in DMSO (60 mL) was degassed and backfilled with nitrogen for five times. After stirring at 120 °C for 4 h under an atmosphere of nitrogen, the reaction mixture was cooled to RT, diluted with water (120 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed with water (120 mL), saturated brine (120 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate in petroleum ether (97%) to afford the product. The product was dissolved in ethyl acetate (30 mL) and treated with 200 mg of SiliaMetS TAAcONa (Scavenger for removing Cu). After filtration, the filtrate was concentrated under reduced pressure to give 2-chloro-6,7-dihydro-9 / - / -pyrido [2’,3’:4,5] imidazo[2,1-c] [1 ,4] oxazine as a solid.

[0265] LCMS (MS, ESI): 210, 212 [M+H]+. (3S,4 / ?)-4-(5-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)tetrahydrofuran-3-ol

[0266] Step 1 : (3S,4 / ?)-4-(5-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)tetrahydrofuran-3-ol. To a mixture of 5-bromo-1 / - / -pyrazolo[4,3-b]pyridine (5.30 g, 26.8 mmol, 1 .0 equiv.), CS2CO3 (21.8 g, 66.9 mmol, 2.5 equiv.) in dry DMF (100 mL) was added 3,6-dioxabicyclo[3.1.0]hexane (3.46 g, 40.1 mmol, 1.5 equiv.). After stirring for 1 hour at 100 °C, the reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography, eluted with 38% EA in PE to afford (3S,4R)-4-(5-bromo- 1 / - / -pyrazolo[4,3-b]pyridin-1-yl)-tetrahydrofuran-3-ol as a solid.

[0267] (3S,4R)-4-(5-bromo-1 / - / -pyrazolo[4,3-b]pyridin-1-yl)-tetrahydrofuran-3-ol (trans isomer): LCMS (MS, ESI): 284, 286 [M+H]+.1H-NMR (400 MHz, DMSO-d6) 5 8.34 (s, 1 H), 8.25 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 5.64 (d, J = 4.2 Hz, 1 H), 5.17 - 5.24 (m, 1 H), 4.43 - 4.52 (m, 1 H), 4.29 (dd, J = 9.6, 6.9 Hz, 1 H), 4.01 - 4.11 (m, 2H), 3.68 (dd, J = 9.3, 3.4 Hz, 1 H).

[0268] Step 2: 5-bromo-1 -((3 / ?,4S)-4-methoxytetrahydrofuran-3-yl)-1 H-pyrazolo[4,3-b]pyridine.

[0269] To a mixture of NaH (190 mg, 4.75 mmol, 1.5 equiv., 60% purity) in dry THF (20 mL) was added a solution of (3S,4R)-4-(5-bromo-1 / - / -pyrazolo[4,3-b]pyridin-1-yl)-tetrahydrofuran-3-ol (900 mg, 3.17 mmol, 1 .0 equiv.) in dry THF (20 mL) at 0 °C under an atmosphere of nitrogen. After stirring for 0.5 h at 0 °C, a solution of Mel (899 mg, 6.33 mmol, 2.0 equiv.) in dry THF (3 mL) was added. The resulting mixture was stirred for 1 h at room temperature, quenched with water (30 mL) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL x 2), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 5-bromo-1-((3R,4S)-4-methoxy-tetrahydrofuran-3-yl)-1 / - / -pyrazolo[4,3- b]pyridine as a solid.

[0270] LCMS (MS, ESI): 298, 300 [M+H]+. 5-chloro-1-ethyl-1H-imidazo[4,5-b]pyridine

[0271] Step 1 : 5-chloro-1-ethyl-1H-imidazo[4,5-b]pyridine. To a stirred mixture of 5-chloro-3 / - / - imidazo[4,5-b]pyridine (3.0 g, 19.5 mmol, 1.0 equiv.) in THF (30 mL) was added NaH (1.56 g, 39.1 mmol, 2.0 equiv., 60% purity) in portions at 0 °C under an atmosphere of nitrogen. After stirring for 30 min at 0 °C, to the above mixture was added iodoethane (4.57 g, 29.3 mmol, 1 .5 equiv.) dropwise. The resulting mixture was stirred for additional 2 hours at RT, quenched with water (20 mL) and extracted with EA (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous NazSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (20% EA) to afford 5-chloro-1-ethylimidazo[4,5- b]pyridine as a solid.

[0272] LCMS (MS, ESI): 182, 184 [M+H]+.

[0273] 5-bromo-2-((3S,4 / ?)-4-methoxytetrahydrofuran-3-yl)-2H-pyrazolo[4,3-b]pyridine

[0274] Step 1 : (3 / ?,4S)-4-(5-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)tetrahydrofuran-3-ol. To a mixture of 5-bromo-1 / - / -pyrazolo[4,3-b]pyridine (5.30 g, 26.8 mmol, 1 .0 equiv.) and CS2CO3 (21.8 g, 66.9 mmol, 2.5 equiv.) in DMF (100 mL) was added 3,6-dioxabicyclo[3.1.0]hexane (3.46 g, 40.1 mmol, 1.5 equiv.) at 25 °C. After stirring for 1 h at 100 °C, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with water (200 mL x 2) and brine (200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2:1 ) to afford (3S,4R)-4-{5-bromopyrazolo[4,3-b]pyridin-1- yl}oxolan-3-ol as a solid.

[0275] LCMS (MS, ESI): 284, 286 [M+H]+.

[0276] Step 2: 5-bromo-2-((3S,4 / ?)-4-methoxytetrahydrofuran-3-yl)-2H-pyrazolo[4,3-b]pyridine. A solution of (3R,4S)-4-{5-bromopyrazolo[4,3-b]pyridin-2-yl}oxolan-3-ol (520 mg, 1.83 mmol, 1.0 equiv.) in THF (10 mL) was treated with NaH (110 mg, 2.75 mmol, 1.5 equiv., 60% purity) for 30 min at 0 °C, followed by the addition of Mel (520 mg, 3.66 mmol, 2.0 equiv.) dropwise at 0 °C. After stirred for 2 h at 20 °C, the reaction mixture was quenched with water (50 mL) at 0 °C and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water (50 mL x 2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 :3) to afford to afford 5-bromo-2-[(3S,4R)-4- methoxyoxolan-3-yl]pyrazolo[4,3-b]pyridine as a solid.

[0277] LCMS (MS, ESI): 298, 300 [M+H]+.1H NMR (400 MHz, Chloroform-d) 5 8.23 (s, 1 H), 7.91 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 5.08 - 5.11 (m, 1 H), 4.23 - 4.39 (m, 4H), 3.88 - 3.93 (m, 1 H), 3.44 (s, 3H).

[0278] 2-bromo-5-(((racemic trans)-4-methoxytetrahydrofuran-3-yl)oxy)-3-methylpyridine

[0279] Step 1 : (racemic trans)-4-((6-bromo-5-methylpyridin-3-yl)oxy)tetrahydrofuran-3-ol. To a solution of 6-bromo-5-methylpyridin-3-ol (1.00 g, 5.32 mmol, 1.0 equiv.) in DMF (10 mL) was added 3,6-dioxabicyclo[3.1 .0]hexane (550 mg, 6.38 mmol, 1.2 equiv.) and CS2CO3 (4.33 g, 13.3 mmol, 2.5 equiv.) at room temperature. After stirring for 2 hours at 120 °C, the reaction mixture was cooled to RT, diluted with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (80 mL x 3), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether = 1 :1 ) to give (racemic trans)-4-((6-bromo-5-methylpyridin-3- yl)oxy)tetrahydrofuran-3-ol as an oil.

[0280] LCMS (MS, ESI): 274, 276 [M+H]+.1H-NMR (400 MHz, chloroform-d): 5 7.94 (d, J = 3.0 Hz, 1H), 7.13 (d, J = 3.0 Hz, 1 H), 4.65 - 4.78 (m, 1 H), 4.38 - 4.48 (m, 1 H), 4.25 (dd, J = 10.4, 4.8 Hz, 1 H), 4.06 (dd, J = 10.0, 4.2 Hz, 1 H), 3.91 (dd, J = 10.4, 2.0 Hz, 1 H), 3.83 (dd, J = 10.0, 2.0 Hz, 1 H), 2.93 (s, 1 H), 2.35 (s, 3H).

[0281] Step 2: 2-bromo-5-(((racemic trans)-4-methoxytetrahydrofuran-3-yl)oxy)-3- methylpyridine. To a solution of (racemic trans)-4-((6-bromo-5-methylpyridin-3- yl)oxy)tetrahydrofuran-3-ol (750 mg, 2.45 mmol, 1 .0 equiv.) in DMF (8 mL) was added NaH (196 mg, 4.90 mmol, 2.0 equiv., 60% purity) at 0 °C. After stirring for 30 minutes at 0 °C, a solution of iodomethane (365 mg, 2.57 mmol, 1 .05 equiv.) in DMF (3 mL) was added. The mixture was warmed to room temperature and further stirred for 1 hour, quenched with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with water (50 mL x 5), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduce pressure to give 2-bromo-5-(((race)-4-methoxytetrahydrofuran-3- yl)oxy)-3-methylpyridine (700 mg, 98%) as light yellow oil.

[0282] GCMS (EI-MS, detector temp. 300 °C): 287, 289 [M]+.

[0283] 5-bromo-1,2-dimethyl-1,2-dihydro-3H-pyrazolo[4,3-b]pyridin-3-one

[0284] 5-bromo-1,2-dimethyl-1,2-dihydro-3H-pyrazolo[4,3-b]pyridin-3-one. A mixture of methyl

[0285] 6-bromo-3-fluoropyridine-2-carboxylate (950 mg, 4.06 mmol, 1.0 equiv.), 1 ,2- dimethylhydrazine dihydrochloride (1.10 g, 8.27 mmol, 2.0 equiv.) and K2CO3 (2.30 g, 16.6 mmol, 4.1 equiv.) in EtOH (20 mL) was stirred overnight at 80 °C. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 9). The combined organic layers were washed with water (200 mL x 3), brine (200 mL), dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-bromo-1 ,2-dimethylpyrazolo[4,3-b]pyridin-3-one as a solid.

[0286] LCMS (MS, ESI): 242, 244 [M+H]+.

[0287] 2-chloro-7-methyl-6,7-dihydro-1,7-naphthyridin-8(5H)-one

[0288] Step 1 : methyl 6-chloro-3-(cyanomethyl)picolinate. To a stirred solution of methyl 3- (bromomethyl)-6-chloropyridine-2-carboxylate (3.0 g, 11.3 mmol, 1.0 equiv.) in CAN (70 mL) were added K2CO3 (3.92 g, 28.4 mmol, 2.50 equiv.) and TMSCN (3.55 mL, 28.4 mmol, 2.5 equiv.) at - 30 °C. After stirring for 16 hours at room temperature under an atmosphere of nitrogen, the resulting mixture was quenched with water (70 mL:) and extracted with DCM (5 x 350 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (30% EA) to afford methyl 6-chloro-3-(cyanomethyl)pyridine-2-carboxylate as a solid.

[0289] LCMS (MS, ESI): 211 , 213 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.11 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1 H), 4.30 (s, 2H), 3.91 (s, 3H).

[0290] Step 2: 2-chloro-6,7-dihydro-1,7-naphthyridin-8(5H)-one. To a stirred solution of methyl 6-chloro-3-(cyanomethyl)picolinate (2.0 g, 9.50 mmol, 1.0 equiv.) in MeOH (100 mL) was added Raney Ni (163 mg, 1.90 mmol, 0.20 equiv.). After stirring for 16 hours at room temperature under an atmosphere of hydrogen, the reaction mixture was diluted with MeOH (50 mL) and filtered through a pad of Celite. The filter cake was washed with MeOH (2 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DOM (5% MeOH) to afford 2-chloro- 6,7-dihydro-5 / - / -1 ,7-naphthyridin-8-one as a solid.

[0291] LCMS (MS, ESI): 183, 185 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.27 (s, 1 H), 7.86 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 3.37 - 3.84 (m, 2H), 2.96 (t, J = 6.6 Hz, 2H).

[0292] Step 3: 2-chloro-7-methyl-6,7-dihydro-1,7-naphthyridin-8(5H)-one. To a stirred solution of 2-chloro-6,7-dihydro-5 / - / -1 ,7-naphthyridin-8-one (600 mg, 3.29 mmol, 1.0 equiv.) in DMF (10 mL) was added CS2CO3 (2.14 g, 6.57 mmol, 2.0 equiv.) at 0 °C. Then a solution of CH3I (0.20 mL, 3.29 mmol, 1 .0 equiv.) in DMF (3 mL) was added dropwise to the reaction mixture at 0 °C. After stirring for 2 hours at room temperature under an atmosphere of nitrogen, the reaction mixture was purified by silica gel column chromatography, eluted with MeOH in DCM (6% MeOH) to afford 2-chloro-7-methyl-5,6-dihydro-1 ,7-naphthyridin-8-one as a solid.

[0293] LCMS (MS, ESI): 197, 199 [M+H]+.

[0294] 6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0295] Step 1 : 6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine To a solution of 6-chloro-1 / - / - pyrazolo[3,4-b]pyridine (2.00 g, 13.0 mmol, 1 .0 equiv.) in THF (20 mL) was added NaH (0.78 g, 19.5 mmol, 1.5 equiv., 60% purity) at 0 °C. The mixture was stirred for 0.5 h at 0 °C, followed by the addition of Mel (3.70 g, 26.0 mmol, 2.0 equiv.) in THF (20 mL). After stirring for 1 h at room temperature, the final mixture was quenched with water (30 mL) at 0 °C and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, eluent: 18% EA in petroleum ether) to afford 6-chloro-1-methyl-1 / - / -pyrazolo[3,4- b]pyridine as a solid.

[0296] LCMS (MS, ESI): 168, 170 [M+H]+.1H-NMR (400 MHz, DMSO-d6): 5 8.49 (s, 1 H), 8.28 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 4.20 (s, 3H).

[0297] 1-(3-iodo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one.

[0298] Step 1 : tert-butyl 3-iodo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate and tert-butyl 3-iodo-2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carboxylate. To a solution of tert-butyl 3-iodo-1 ,4,6,7-tetrahydro-5 / - / - pyrazolo[4,3-c]pyridine-5-carboxylate (2.00 g, 5.73 mmol, 1 .0 equiv.) in THF (14 mL) was added NaH (270 mg, 11 .5 mmol, 2.0 equiv., 60% purity) in batches at 0 °C. The mixture was stirred for 30 minutes, followed by the addition of CH3I (810 mg, 5.73 mmol, 1.0 equiv.) at 0 °C. After stirring for 1 hour at room temperature, the reaction mixture was quenched with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The organic layer was washed with water (50 mL x 2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether = 2:5) to give tert-butyl 3-iodo-1- methyl-1 ,4,6,7-tetrahydro-5 / - / -pyrazolo[4,3-c]pyridine-5-carboxylate as a solid and tert-butyl 3-iodo-2-methyl-2,4,6,7-tetrahydro-5 / - / -pyrazolo[4,3-c]pyridine-5-carboxylate as a solid, tert-butyl 3-iodo-1 -methyl- 1 ,4,6, 7-tetrahydro-5 / - / -pyrazolo[4,3-c]pyridine-5- carboxylate: LCMS (MS, ESI): 364 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 4.10 (s, 2H), 3.69 (s, 3H), 3.58 (t, J = 6.0 Hz, 2H), 2.64 (t, J = 5.6 Hz, 2H), 1 .41 (s, 9H). tert-butyl 3-iodo-2-methyl-2,4,6,7-tetrahydro-5 / - / -pyrazolo[4,3-c]pyridine-5-carboxylate: LCMS (MS, ESI): 364 [M+H]+.1H NMR (400 MHz, DMSO-rt6) 5 4.15 (s, 2H), 3.77 (s, 3H), 3.58 (t, J = 5.8 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 1 .41 (s, 9H).

[0299] Step 2: 3-iodo-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine 2,2,2- trifluoroacetate. To a solution of tert-butyl 3-iodo-1-methyl-1 ,4,6,7-tetrahydro-5 / - / - pyrazolo[4,3-c]pyridine-5-carboxylate (500 mg, 1.38 mmol, 1.0 equiv.) in DCM (4 mL) was added TFA (2 mL) dropwise at room temperature. After stirred for 16 hours at room temperature, the mixture was evaporated to dryness to give 3-iodo-1 -methyl-4, 5,6,7- tetrahydro-1 / - / -pyrazolo[4,3-c]pyridine (1 .00 g, TFA salt) as a crude product, which was used for the next step directly.

[0300] LCMS (MS, ESI): 264 [M+H]+.

[0301] Step 3: 1-(3-iodo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1- one. To a solution of 3-iodo-1 -methyl-4, 5,6, 7-tetrahydro-1 / - / -pyrazolo[4,3-c]pyridine (1.00 g, crude) in dry DCM (8 mL) was added dry TEA (697 mg, 6.89 mmol) dropwise at 0 °C. The mixture was stirred for 15 minutes at 0 °C, followed by the addition of acetyl chloride (130 mg, 1 .65 mmol). After stirring for 1 hour at room temperature, the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure to give 1-(3-iodo-1- methyl-1 ,4,6,7-tetrahydro-5 / - / -pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one as a solid.

[0302] LCMS (MS, ESI): 306 [M+H]+.

[0303] 2-chloro-6-ethyl-3-fluoro-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0304] Step 1 : 5-fluoro-2-(methoxycarbonyl)-3-methylpyridine 1 -oxide To a solution of methyl 5-fluoro-3-methylpyridine-2-carboxylate (4.66 g, 27.5 mmol, 1.0 equiv.) in DCM (138 mL) was added m-CPBA (11 .9 g, 55.0 mmol, 2.0 equiv., 80% purity) at 0 °C under an atmosphere of nitrogen. After stirring for 16 h at 45 °C, the reaction mixture was cooled to RT and filtered through a Buchner funnel (a short pad of Celite and silica gel). The filter cake was washed with DCM (100 mL x 3). The filtrate was washed with aqueous saturated NaHCOa (300 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (46%) to afford 5-fluoro-2-(methoxycarbonyl)-3-methylpyridin-1-ium-1-olate as a solid.

[0305] LCMS (MS, ESI): 186 [M+H]+. Step 2: Methyl 6-chloro-5-fluoro-3-methylpicolinate. To a solution of 5-fluoro-2- (methoxycarbonyl)-3-methylpyridin-1-ium-1-olate (4.80 g, 25.9 mmol, 1.0 equiv.) in toluene (150 mL) was added POCh (12 mL, 130 mmol, 5.0 equiv.). After stirring at 90 °C for 3 h, the reaction mixture was cooled to RT, quenched with aqueous saturated NaHCOa (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (11%) to afford methyl 6-chloro-5-fluoro-3-methylpyridine-2-carboxylate as a solid.

[0306] LCMS (MS, ESI): 204, 206 [M+H]+.

[0307] Step 3: Methyl 6-chloro-3-(dibromomethyl)-5-fluoropicolinate. To a solution of methyl 6- chloro-5-fluoro-3-methylpyridine-2-carboxylate (4.20 g, 20.6 mmol, 1.0 equiv.) in CCI4 (103 mL) was added NBS (7.34 g, 41 .3 mmol, 2.0 equiv.) and AIBN (677 mg, 4.13 mmol, 0.2 equiv.). After stirring at 80 °C for 5 h, the reaction was quenched with water (200 mL) and extracted with methanol in dichloromethane (200 mL x 3). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 6-chloro-3- (dibromomethyl)-5-fluoropyridine-2-carboxylate as an oil.

[0308] LCMS (MS, ESI): 360, 362, 363.90 [M+H]+.

[0309] Step 4: Methyl 3-(bromomethyl)-6-chloro-5-fluoropicolinate. To a solution of methyl 6- chloro-3-(dibromomethyl)-5-fluoropyridine-2-carboxylate (7.00 g, 19.4 mmol, 1.0 equiv.) in CAN (190 mL) were added diethyl phosphonate (2.50 mL, 19.4 mmol, 1.0 equiv.) and DIEA (6.75 mL, 38.7 mmol, 2.0 equiv.) at 0 °C. After stirring at 0 °C for 1 h, the reaction was quenched with water (400 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with water (1 L) and brine (1 L), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (9.4%) to afford methyl 3-(bromomethyl)-6-chloro-5- fluoropyridine-2-carboxylate as an oil.

[0310] LCMS (MS, ESI): 282, 284 [M+H]+.

[0311] Step 5: 2-chloro-6-ethyl-3-fluoro-5,6-dihydro-7H-pyrrolo[3,4-b]pyriclin-7-one. To a solution of methyl 3-(bromomethyl)-6-chloro-5-fluoropyridine-2-carboxylate (1.00 g, 3.54 mmol, 1.0 equiv.) in EtOH (20 mL) and TEA (1.97 mL, 14.2 mmol, 4.0 equiv.) was added ethanamine hydrochloride (577 mg, 7.08 mmol, 2.0 equiv.). After stirring at 80 °C for 3 h, the reaction mixture was cooled to RT and quenched with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (62%) to afford 2-chloro-6-ethyl-3-fluoro-5 / - / -pyrrolo[3,4-b] pyridin-7-one as a solid.

[0312] LCMS (MS, ESI): 215, 217 [M+H]+.

[0313] 5-bromo-1-methyl-2-(tetrahydrofuran-3-yl)-1 H-imidazo[4,5-b]pyridine

[0314] Step 1 : / V-(3-amino-6-bromopyridin-2-yl)tetrahydrofuran-3-carboxamide To a solution of 6-bromopyridine-2,3-diamine (1.40 g, 7.45 mmol, 1.0 equiv.) in DCM (15 mL) were added TEA (2.2 mL, 15.8 mmol, 2.1 equiv.) and oxolane-3-carbonyl chloride (0.79 mL, 7.45 mmol, 1 .0 equiv.) dropwise at 0 °C. After stirring for 3 hours at room temperature under an atmosphere of nitrogen, the resulting mixture was quenched with water (100 mL) and extracted with DCM (4 x 250 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (100 mL) to afford N- 3- amino-6-bromopyridin-2-yl)oxolane-3-carboxamide as a solid.

[0315] LCMS (MS, ESI): 286, 288 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 9.41 (s, 1 H), 7.58 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.36 (s, 2H), 3.91 - 3.95 (m, 1 H), 3.66 - 3.79 (m, 3H), 3.24 - 3.28 (m, 1 H), 2.01 - 2.13 (m, 2H).

[0316] Step 2: 5-bromo-2-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyridine. To a solution of N- (3-amino-6-bromopyridin-2-yl)oxolane-3-carboxamide (2.0 g, 6.99 mmol, 1.0 equiv.) in DMF (30 mL) was added CsF (10.1 g, 66.4 mmol, 9.5 equiv.) at room temperature. The resulting mixture was stirred for 16 hours at 130 °C under an atmosphere of nitrogen. After cooling to room temperature, the resulting mixture was quenched with water (100 mL) and extracted with EA (4 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 5-bromo-2-(oxolan-3-yl)-1 / - / -imidazo[4,5-b]pyridine as a solid.

[0317] LCMS (MS, ESI): 268, 270 [M+H]+.

[0318] Step 3: 5-bromo-1-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyridine. To a solution of 5-bromo-2-(oxolan-3-yl)-1 / - / -imidazo[4,5-b]pyridine (1.20 g, 4.48 mmol, 1.0 equiv.) in DMF (16 mL) were added CS2CO3 (2.95 g, 9.05 mmol, 2.0 equiv.) and Mel (0.28 mL, 4.48 mmol, 1 .0 equiv.) at 0 °C under an atmosphere of nitrogen. After stirring at room temperature for 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with EA (4 x 150 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE cann EA (28% EA)) to afford 5-bromo-1-methyl-2-(oxolan-3-yl)imidazo[4,5-b]pyridine as a solid and 5-bromo-3-methyl-2-(oxolan-3-yl)imidazo[4,5-b]pyridine as a solid.

[0319] 5-bromo-1-methyl-2-(oxolan-3-yl)imidazo[4,5-b]pyridine (03-734-3): LCMS (MS, ESI): 282, 284 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.98 (d, J = 8.3 Hz, 1 H), 7.43 (d, J = 8.3 Hz, 1H), 4.13 - 4.17 (m, 1H), 3.84 - 3.96 (m, 4H), 3.83 (s, 3H), 2.23 - 2.41 (m, 2H).

[0320] 6-chloro-2,5-dimethylpyrazolo[3,4-b]pyridine

[0321] Step 1 : 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine. To a solution of 5-bromo-1 / - / - pyrazolo[3,4-b]pyridine (4.0 g, 20.2 mmol, 1.0 equiv.) in THF (100 mL) was added KOH (3.40 g, 60.6 mmol, 3.0 equiv.). After stirring at 0 °C for 1 hour, to the above mixture was added Mel (1.89 mL, 30.3 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred for 5 hours at room temperature, quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate in petroleum ether (75%) to afford 5-bromo-2-methylpyrazolo[3,4-b] pyridine as a solid.

[0322] LCMS (MS, ESI): 212, 214 [M+H]+.

[0323] Step 2: 2,5-dimethyl-2H-pyrazolo[3,4-b]pyridine. A mixture of 5-bromo-2- methylpyrazolo[3,4-b]pyridine (3.2 g, 15.1 mmol, 1.0 equiv.), trimethyl-1 ,3,5,2,4,6- trioxatriborinane (6.47 mL, 22.6 mmol, 1.5 equiv., 3.5 M in THF), Pd(dppf)Ch (1.10 g, 1.51 mmol, 0.1 equiv.) and CS2CO3 (12.3 g, 37.7 mmol, 2.5 equiv.) in dioxane (100 mL) and water (25 mL) was degassed and backfilled with nitrogen for five times. After stirring for 2 hours at 90 °C, the mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filter cake was washed with ethyl acetate (50 mL x 3). The filtrate was washed with water (60 mL), brine (60 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate in petroleum ether (100%) to afford the product. The product was dissolved in EA (30 mL) and treated with 2.6 g of SiliaMetS Thiol (Scavenger for removing Pd). After filtration, the filtrate was concentrated under reduced pressure to give 2,5-dimethylpyrazolo[3,4-b]pyridine as a solid.

[0324] LCMS (MS, ESI): 148 [M+H]+.

[0325] Step 3: 2,5-dimethyl-2H-pyrazolo[3,4-b]pyridine 7-oxide. A mixture of 2,5- dimethylpyrazolo[3,4-b]pyridine (1.24 g, 8.43 mmol, 1.0 equiv.) and mCPBA (3.42 g, 16.9 mmol, 2.0 equiv., 85% purity) in DCM (12 mL) was stirred for 16 h at 45°C. The reaction mixture was cooled to 0°C and filtered through a Buchner funnel. The filter cake was washed with dichloromethane (20 mL x 3). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with methanol in dichloromethane (3%) to afford 2,5-dimethyl-2 / - / - pyrazolo[3,4-b]pyridine 7-oxide as a solid.

[0326] LCMS (MS, ESI): 164 [M+H]+.

[0327] Step 4: 6-chloro-2,5-dimethyl-2H-pyrazolo[3,4-b]pyridine. To a solution of 2,5- dimethylpyrazolo[3,4-b]pyridin-7-ium-7-olate (580 mg, 3.55 mmol, 1.0 equiv.) in toluene (16 mL) was added POCh (1 .66 mL, 17.8 mmol, 5.0 equiv.) dropwise. After stirring for 3 h at 90 °C, the reaction mixture was cooled to room temperature, basified to pH=10 with a saturated solution of NaHCOa in water and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water (60 mL), brine (60 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (59%) to afford 6-chloro-2,5-dimethylpyrazolo[3,4- b]pyridine as a solid.

[0328] LCMS (MS, ESI): 182, 184 [M+H]+.

[0329] 2-bromo-7,8-dihydro-6H,10H-pyrazolo[T,2’:1,2]pyrazolo[4,3-b]pyridin-10-one

[0330] Step 1 : 2-bromo-7,8-dihydro-6H,10H-pyrazolo[r,2’:1,2]pyrazolo[4,3-b]pyridin-10-one.

[0331] A mixture of methyl 6-bromo-3-fluoropyridine-2-carboxylate (1.00 g, 4.27 mmol, 1.0 equiv.), pyrazolidine dihydrochloride (1 .24 g, 8.55 mmol, 2.0 equiv.) and TEA (3.00 mL, 21 .6 mmol, 5.0 equiv.) in EtOH (20 mL) was stirred overnight at 80 °C. After removing the solvent under reduced product, the residue was diluted with water (30 mL) and extracted with (DCM / MeOH 10:1) (30 mL x 7). The combined organic layers were washed with water (200 mL x 2), brine (200 mL), dried over NazSC and concentrated under reduced pressure to afford 10-bromo- 2,6,9-triazatricyclo[6.4.0.0A{2,6}]dodeca-1 (12),8,10-trien-7-one as a solid.

[0332] LCMS (MS, ESI): 254, 256 [M+H]+.

[0333] (E)-2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one O-methyl oxime

[0334] Step 1 : (E)-2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one O-methyl oxime. A mixture of 2-chloro-5 / - / ,6 / - / -cyclopenta[b]pyridin-7-one (500 mg, 2.98 mmol, 1.0 equiv.) and O-methylhydroxylamine hydrochloride (500 mg, 5.99 mmol, 2.0 equiv.) in MeOH (10 mL) was stirred for 3 hours at 65 °C under an atmosphere of nitrogen. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE in EA (45% EA) to afford (7E)-2-chloro-A / -methoxy-5 / - / ,6 / - / -cyclopenta[b]pyridin-7-imine as a solid.

[0335] LCMS (MS, ESI): 197, 199 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 7.88 (d, J = 8.2, 1.0 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1 H), 3.96 (s, 3H), 2.96 - 2.99 (m, 2H), 2.83 - 2.89 (m, 2H).

[0336] 2-chloro-3,6-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0337] Step 1 : 5-bromo-2-(methoxycarbonyl)-3-methylpyridine 1 -oxide To a solution of methyl 5-bromo-3-methylpyridine-2-carboxylate (5.00 g, 21.7 mmol, 1.0 equiv.) in DCM (100 mL) was added m-CPBA (9.38 g, 43.5 mmol, 2.0 equiv, 80% purity) at 0 °C under an atmosphere of nitrogen. After stirring for 16 h at 45 °C, the reaction mixture was cooled to RT, it was quenched with water (200 mL) and extracted with dichloromethane (200 mL x 3). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (46%) to afford 5-bromo-2- (methoxycarbonyl)-3-methylpyridin-1-ium-1-olate as an oil.

[0338] LCMS (MS, ESI): 246, 248 [M+H]+.

[0339] Step 2: Methyl 5-bromo-6-chloro-3-methylpicolinate. To a solution of 5-bromo-2- (methoxycarbonyl)-3-methylpyridin-1-ium-1-olate (2.16 g, 8.78 mmol, 1.0 equiv.) in toluene (44 mL) was added POCh (4 mL, 43.9 mmol, 5.0 equiv.). After stirring at 110 °C for 3 h, the reaction mixture was cooled to RT. The mixture was quenched with water (80 mL), basified to pH 8 with NaOH (20% in water), and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (80 mL), brine (80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (33%) to afford methyl 5- bromo-6-chloro-3-methylpyridine-2-carboxylate as a solid.

[0340] LCMS (MS, ESI): 264, 266 [M+H]+.

[0341] Step 3: Methyl 5-bromo-6-chloro-3-(dibromomethyl)picolinate. To a solution of methyl 5- bromo-6-chloro-3-methylpyridine-2-carboxylate (1.66 g, 6.28 mmol, 1.0 equiv.) in CCI4 (35 mL) was added NBS (2.23 g, 12.6 mmol, 2.0 equiv.) and AIBN (210 mg, 1 .26 mmol, 0.2 equiv.). After stirring at 80 °C for 5 h, the reaction was quenched with water (70 mL) and extracted with dichloromethane (70 mL x 3). The combined organic layers were washed with water (70 mL) and brine (70 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 5-bromo-6-chloro-3- (dibromomethyl) pyridine-2-carboxylate as a solid.

[0342] LCMS (MS, ESI): 420, 422, 424 [M+H]+.

[0343] Step 4: Methyl 5-bromo-3-(bromomethyl)-6-chloropicolinate. To a solution of methyl 5- bromo-6-chloro-3-(dibromomethyl) pyridine-2-carboxylate (2.67 g, 6.32 mmol, 1.0 equiv.) in CAN (40 mL) were added DIEA (2.2 mL, 12.6 mmol, 2.0 equiv.) and diethyl phosphonate (0.81 mL, 6.32 mmol, 1 .0 equiv.) at 0 °C. After stirring at 0 °C for 2 h, the reaction was quenched with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (8%) to afford methyl 5-bromo- 3-(bromomethyl)-6-chloropyridine-2-carboxylate as an oil.

[0344] Step 5: 2-chloro-3,6-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one. To a solution of methyl 5-bromo-3-(bromomethyl)-6-chloropyridine-2-carboxylate (1.63 g, 4.75 mmol, 1.0 equiv.) in EtOH (47 mL) and TEA (2.64 mL, 19.0 mmol, 4.0 equiv.) was added methylamine hydrochloride (641 mg, 9.49 mmol, 2.0 equiv.). After stirring at 80 °C for 3 h, the reaction mixture was cooled to RT, quenched with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (80 mL), brine (80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (83%) to afford 3-bromo-2- chloro-6-methyl-5 / - / -pyrrolo[3,4-b] pyridin-7-one as a solid.

[0345] LCMS (MS, ESI): 261 , 263 [M+H]+.

[0346] 5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridine-3-carbonitrile

[0347] Step 1 : 5-chloro-3-iodo-1-methyl-1H-pyrazolo[4,3-b]pyridine. To a solution of 5-chloro-3- iodo-1 / - / -pyrazolo[4,3-b]pyridine (1 .3 g, 4.65 mmol, 1 .0 equiv.) and CS2CO3 (3.04 g, 9.33 mmol, 2.01 equiv.) in DMF (15 mL) was added Mel (0.44 mL, 7.07 mmol, 1 .52 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (lOnmol / LNH^COa), Mobile Phase B: CAN; Flow rate: 60 mL / min; Gradient: 25% B to 55 % B in 10 min; Wave Length: 254nm / 220nm; RT1 (min): 8.5) to afford 5-chloro-3-iodo- 1-methyl-1 / - / -pyrazolo[4,3-b]pyridine as a solid and 5-chloro-3-iodo-2-methyl-2 / - / - pyrazolo[4,3-b]pyridine as a solid.

[0348] 5-chloro-3-iodo-1-methyl-1 / - / -pyrazolo[4,3-b]pyridine: LCMS (MS, ESI): 294, 296 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.27 - 8.30 (m, 1 H), 7.55 - 7.58 (m, 1 H), 4.12 (s, 3H).

[0349] 5-chloro-3-iodo-2-methyl-2 / - / -pyrazolo[4,3-b]pyridine: LCMS (MS, ESI): 294, 296 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.15 - 8.19 (m, 1 H), 7.32 - 7.36 (m, 1 H), 4.24 (s, 3H).

[0350] Step 2: 5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridine-3-carbonitrile. To a solution of 5- chloro-3-iodo-1-methyl-1 / - / -pyrazolo[4,3-b]pyridine (400 mg, 1.36 mmol, 1.0 equiv.) in DMF (6 mL) was added CuCN (321 mg, 3.58 mmol, 2.63 equiv.) in portions at room temperature under an atmosphere of nitrogen. The resulting mixture was stirred for additional 16 h at 130 °C. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with EA / PE (30% EA) to the product. The product was dissolved in ethyl acetate (15 mL) and treated with 800 mg of SiliaMetS TAAcONa (Scavenger for removing Cu). After filtration, the filtrate was concentrated under reduced pressure to afford 5-chloro-1-methylpyrazolo[4,3-b]pyridine-3-carbonitrile as a solid.

[0351] LCMS (MS, ESI): 193, 195 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 8.52 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1 H), 4.24 (s, 3H).

[0352] 5-chloro-1-(1-methoxypropan-2-yl) pyrazolo[4,3-b] pyridine (03-535-2) and 5-chloro-2- (1 -methoxy propan-2 -yl) pyrazolo[4,3-b] pyridine

[0353] Step 1 : 1-methoxypropan-2-yl 4-methylbenzenesulfonate. To a mixture of NaH (490 mg, 12.2 mmol, 1.1 equiv., 60% purity) in THF (20 mL) was added methoxyisopropanol (1.0 g, 11.1 mmol, 1.0 equiv.) at 0 °C. After stirring for 1 hour at RT, TsCI (2.33 g, 12.2 mmol, 1.1 equiv.) was added at RT. The reaction mixture was stirred for 16 hours at RT, quenched with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (11 %) to afford 1-methoxypropan-2-yl 4- methylbenzenesulfonate as an oil.

[0354] LCMS (MS, ESI): 245 [M+H]+.

[0355] Step 2: 5-chloro-1-(1-methoxypropan-2-yl)-1H-pyrazolo[4,3-b]pyridine and 5-chloro-2- (1 -methoxypropan-2-yl)-2H-pyrazolo[4,3-b]pyridine. To a solution of 5-chloro-1 / - / - pyrazolo[4,3-b] pyridine (940 mg, 6.12 mmol, 1.0 equiv.) in DMF (19 mL) was added NaH (370 mg, 9.18 mmol, 1 .5 equiv., 60% purity) at 0 °C. After stirring for 30 min at RT, 1- methoxypropan-2-yl 4-methylbenzenesulfonate (1.79 g, 7.35 mmol, 1.2 equiv.) was added at 0 °C. The reaction mixture was stirred for 1 h at 60 °C, quenched with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (13%) to afford 5-chloro-1-(1-methoxypropan-2-yl) pyrazolo[4,3-b] pyridine as an oil, and eluted with ethyl acetate in petroleum ether (19%) to afford 5-chloro-2-(1- methoxypropan-2-yl) pyrazolo[4,3-b] pyridine as a solid.

[0356] 5-chloro-1-(1-methoxypropan-2-yl) pyrazolo[4,3-b] pyridine: LCMS (MS, ESI): 226, 228 [M+H]+.1HNMR (400 MHz, DMSO-d6) 5 8.32 (d, J =8.8 Hz, 1 H), 8.29 (s, 1H), 7.45 (d, J =8.8 Hz, 1 H), 5.07 - 5.12 (m, 1H), 3.61 - 3.72 (m, 2H), 3.12 (s, 3H), 1.46 (d, J =6.8 Hz, 3H).

[0357] 5-chloro-2-(1-methoxypropan-2-yl) pyrazolo[4,3-b] pyridine: LCMS (MS, ESI): 226, 228 [M+H]+.1H-NMR (400 MHz, DMSO-d6) 5 8.70 (s, 1H), 8.19 (d, J =8.8 Hz, 1 H), 7.30 (d, J =8.8 Hz, 1 H), 4.91 - 4.96 (m, 1H), 3.67 - 3.83 (m, 2H), 3.19 (s, 3H), 1.51 (d, J =6.8 Hz, 3H).

[0358] 5-chloro-1-(2-methoxypropyl)-1H-pyrazolo[4,3-b]pyridine (03-536-1) and 5-chloro-2-(2- methoxypropyl)-2H-pyrazolo[4,3-b]pyridine

[0359] Step 1 : 5-chloro-1-(2-methoxypropyl)-1H-pyrazolo[4,3-b]pyridine and 5-chloro-2-(2- met h oxy propy I )-2H-pyrazolo [4, 3-b] pyridine. To a solution of 2-methoxypropanol (0.94 mL, 9.77 mmol, 1.5 equiv.), 5-chloro-1 / - / -pyrazolo[4,3-b]pyridine (1.0 g, 6.51 mmol, 1.0 equiv.) and PPha (2.56 g, 9.77 mmol, 1 .5 equiv.) in THF (20 mL) was added DEAD (1 .53 mL, 9.77 mmol, 1.5 equiv.) at 0 °C. After stirring at 0°C for 1 h under an atmosphere of nitrogen, the reaction solution was quenched with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (20%) to give 5- chloro-2-(2-methoxypropyl)pyrazolo[4,3-b]pyridine as a solid, and ethyl acetate in petroleum ether (21%) to give 5-chloro-1-(2-methoxypropyl)pyrazolo[4,3-b]pyridine as a semi-solid. 5-chloro-2-(2-methoxypropyl)pyrazolo[4,3-b]pyridine: LCMS (MS, ESI): 226 , 228 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.27 (s, 1 H), 8.25 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H), 3.72 - 3.79 (m, 1 H), 3.10 (s, 3H), 1.08 (d, J = 6.0 Hz, 3H).

[0360] 5-chloro-1-(2-methoxypropyl)pyrazolo[4,3-b]pyridine: LCMS (MS, ESI): 226, 228 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.61 (s, 1 H), 8.18 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 4.42 - 4.58 (m, 2H), 3.84 - 3.91 (m 1 H), 3.17 (s, 3H), 1.09 - 1.11 (m, 3H). 5-bromo-1,6-dimethyl-1H-pyrazolo[4,3-b]pyridine and 5-bromo-2,6-dimethyl-2H- pyrazolo[4,3-b]pyridine

[0361] Step 1 : 2,5-dimethylpyridin-3-amine. To a stirred solution of 5-bromo-2-methylpyridin-3- amine (500 mg, 2.67 mmol, 1.0 equiv.) and trimethyl-1 ,3,5,2,4,6-trioxatriborinane (1.01 g, 8.02 mmol, 3.0 equiv.) were added K2CO3 (1 .29 g, 9.36 mmol, 3.5 equiv.) and Pd(dppf)Cl2 CH2Cl2 (1.09 g, 1.34 mmol, 0.5 equiv.) at room temperature under an atmosphere of nitrogen. The resulting mixture was stirred for 2 h at 110 °C. After cooling to room temperature, the reaction was diluted with EA (25 mL). The resulting mixture was filtered through a pad of Celite. The filter cake was washed with EA (3 x 20 mL). The filtrate was concentrated under reduced pressure to the crude product. The crude product was purified by silica gel column chromatography, eluted with EA / PE (45% EA) to afford 2,5- dimethylpyridin-3-amine as a solid.

[0362] LCMS (MS, ESI): 123 [M+H]+.

[0363] Step 2: 6-bromo-2,5-dimethylpyridin-3-amine To a solution of 2,5-dimethylpyridin-3- amine (9.8 g, 80.2 mmol, 1 .0 equiv.) in DMF (100 mL) was added NBS (12.1 g, 68.2 mmol, 0.85 equiv.) in portions at 0°C under an atmosphere of nitrogen. After stirring for 1 h at RT, the reaction mixture was quenched with water (300 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with EA / PE (25% EA) to afford 6-bromo-2,5-dimethylpyridin-3-amine as a solid.

[0364] LCMS (MS, ESI): 201 , 203 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 6.87 (s, 1 H), 5.15 (s, 2H), 2.19 (s, 3H), 2.15 (s, 3H).

[0365] Step 3: 1-(5-bromo-6-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one. To a stirred solution of 6-bromo-2,5-dimethylpyridin-3-amine (1.2 g, 5.97 mmol, 1.0 equiv.) in CHCI3 (10 mL) were added KOAc (703 mg, 7.16 mmol, 1.20 equiv.) and AC2O (2.26 mL, 23.9 mmol, 4.0 equiv.) in sequence at room temperature under an atmosphere of nitrogen. After stirring for 2 h at 55 °C, to the above mixture were added 3-methylbutyl nitrite (1.76 mL, 13.1 mmol, 2.2 equiv.) dropwise and 18-Crown-6 (158 mg, 0.598 mmol, 0.10 equiv.) at O °C. The resulting mixture was stirred for additional 16 h at 70 °C under an atmosphere of nitrogen. After cooling to room temperature, the reaction mixture was quenched with a saturated solution of sodium bicarbonate in water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with EA / PE (12%EA) to afford 5-bromo-6-methyl-1 / - / -pyrazolo[4,3-b]pyridine as a solid.

[0366] LCMS (MS, ESI): 254, 256 [M+H]+.1H NMR (400 MHz, Chloroform-d): 5 8.58 (s, 1 H), 8.26 (s, 1 H), 2.81 (s, 3H), 2.60 (s, 3H).

[0367] Step 4: 5-bromo-6-methyl-1H-pyrazolo[4,3-b]pyridine. A solution of 1-{5-bromo-6- methylpyrazolo[4,3-b]pyridin-1-yl}ethanone (6.0 g, 23.6 mmol, 1.0 equiv.) and KOH (3.31 g, 59.0 mmol, 2.50 equiv.) in MeOH (30 mL) / H2O (30 mL) was stirred for 2 h at room temperature. The reaction solution was quenched with water (60 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 5-bromo-6-methyl-1 / - / -pyrazolo[4,3-b]pyridine.

[0368] LCMS (MS, ESI): 212, 214 [M+H]+.

[0369] Step 5: 5-bromo-1 ,6-dimethyl-1 H-pyrazolo[4,3-b]pyridine and 5-bromo-2,6-dimethyl- 2H-pyrazolo[4,3-b]pyridine. A stirred solution of 5-bromo-6-methyl-1 / - / -pyrazolo[4,3- b]pyridine (3.0 g, 14.1 mmol, 1 .0 equiv.) in THF (30 mL) was added NaH (1.7 g, 42.5 mmol, 3.00 equiv., 60% purity) in portions at 0 °C under an atmosphere of nitrogen. After stirring for 30 mins at 0 °C, to the above mixture was added Mel (1 .77 mL, 28.4 mmol, 2.01 equiv.) dropwise. The resulting mixture was stirred for 10 mins at 0 °C and for 2 h at room temperature. The reaction mixture was quenched with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with EA in PE (43% EA) to afford 5-bromo-1 ,6-dimethylpyrazolo[4,3-b]pyridine as a solid and 5-bromo-2,6- dimethylpyrazolo[4,3-b]pyridine as a solid.

[0370] LCMS (MS, ESI): 226, 228 [M+H]+.1H NMR (400 MHz, Chloroform-d) 5 8.09 (s, 1 H), 7.59 (s, 1 H), 4.06 (s, 3H), 2.55 (s, 3H).

[0371] LCMS (MS, ESI): 226, 228 [M+H]+.1H NMR (400 MHz, Chloroform-d) 5 8.06 (s, 1 H), 7.83 (s, 1 H), 4.23 (s, 3H), 2.51 (s, 3H). 2-chloro-5,6-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0372] Step 1 : methyl 3-ethylpicolinate. To a mixture of methyl 3-bromopicolinate (10.0 g, 46.3 mmol, 1.0 equiv.) and Pd(PPh3)4 (2.67 g, 2.31 mmol, 0.05 equiv.) in 1 ,4-dioxane (50 mL) was added ZnEt2 (46.3 mL, 1M in hexane, 46.3 mmol, 1.0 equiv.) dropwise at room temperature under an atmosphere of nitrogen. After stirring for 2 hours at 60 °C, the reaction mixture was cooled to RT, quenched with water (150 mL) and stirred for 30 minutes. After filtration, the filtrate was extracted with DCM (200 mL x 3). The combined organic layers were washed with water (100 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give methyl 3- ethylpicolinate as an oil.

[0373] LCMS (MS, ESI): 166 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.52 - 8.54 (m, 1H), 7.63 - 7.66 (m, 1 H), 7.35 - 7.38 (m, 1 H), 3.97 (s, 3H), 2.95 (q, J = 7.5 Hz, 2H), 1 .25 (t, J = 7.5 Hz, 3H).

[0374] Step 2: 3-ethyl-2-(methoxycarbonyl)pyridine 1 -oxide To a solution of methyl 3- ethylpicolinate (5.50 g, 22.0 mmol, 1.0 equiv., 66% purity) in DCM (20 mL) was added m- CPBA (5.68 g, 33.0 mmol, 1 .5 equiv.) at 0 °C. After stirring for 4 hours at room temperature, the reaction mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with saturated sodium carbonate solution (50 mL x 5), water (30 mL x 3), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with methanol / dichloromethane, 1 :19) to afford 3-ethyl-2- (methoxycarbonyl)pyridine 1 -oxide as an oil.

[0375] LCMS (MS, ESI): 182 [M+H]+.

[0376] Step 3: Methyl 6-chloro-3-ethylpicolinate and methyl 4-chloro-3-ethylpicolinate. To a solution of 3-ethyl-2-(methoxycarbonyl)pyridine 1-oxide (1.40 g, 6.18 mmol, 1.0 equiv., 81 % purity) in DCE (20 mL) was added POCI3 (3.79 g, 24.7 mmol, 4.0 equiv.) at room temperature. After stirring for 12 hours at 80 °C, the reaction mixture was cooled to RT, quenched with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with water (30 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether, 1 :7) to give methyl 6-chloro-3-ethylpicolinate as an oil and methyl 4-chloro-3-ethylpicolinate as an oil.

[0377] Methyl 6-chloro-3-ethylpicolinate: LCMS (MS, ESI): 200, 202 [M+H]+.1H NMR (400 MHz, CDCI3) 5 7.63 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1 H), 3.99 (s, 3H), 2.93 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H). methyl 4-chloro-3-ethylpicolinate: LCMS (MS, ESI): 200, 202 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.43 (d, J = 5.1 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1 H), 4.01 (s, 3H), 3.02 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H).

[0378] Step 4: methyl 3-(1-bromoethyl)-6-chloropicolinate. To a solution of methyl 6-chloro-3- ethylpicolinate (700 mg, 3.51 mmol, 1.0 equiv.) in CCI4 (10 mL) were added NBS (940 mg, 5.26 mmol, 1.5 equiv.) and AIBN (120 mg, 0.701 mmol, 0.2 equiv.) at room temperature. After stirring for 3 hours at 80 °C, the cooled mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether, 1 :1) to give methyl 3-(1-bromoethyl)-6-chloropicolinate as a solid.

[0379] LCMS (MS, ESI): 278, 280 [M+H]+.

[0380] Step 5: 2-chloro-5,6-dimethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one. To a solution of methyl 3-(1-bromoethyl)-6-chloropicolinate (720 mg, 2.59 mmol, 1.0 equiv.) and TEA (2.62 g, 25.9 mmol, 10.0 equiv.) in EtOH (6 mL) was added methylamine hydrochloride (870 mg, 12.9 mmol, 5.0 equiv.) at room temperature. After stirring for 3 hours at 80 °C, the cooled mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether, 1 :1) to afford 2-chloro- 5,6-dimethyl-5,6-dihydro-7 / - / -pyrrolo[3,4-b]pyridin-7-one as an oil.

[0381] LCMS (MS, ESI): 197, 199 [M+H]+.1H NMR (400 MHz, CDCI3) 5 7.77 (d, J = 8.0 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 4.49 (q, J = 6.8 Hz, 1H), 3.19 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H).

[0382] 3-ethyl-5-methylpyridin-2 -amine

[0383] Step 1 : 5-methyl-3-vinylpyridin-2-amine. A mixture of 3-bromo-5-methylpyridin-2-amine (1 .00 g, 5.35 mmol, 1.0 equiv.), potassium ethenyltrifluoroboranuide (1 .43 g, 10.7 mmol, 2.0 equiv.), Pd(Oac)2 (120 mg, 0.535 mmol, 0.1 equiv.), S-Phos (440 mg, 1.07 mmol, 0.2 equiv.) and K3PO4 (2.27 g, 10.7 mmol, 2.0 equiv.) in dioxane (80 mL) and water (16 mL) was stirred for 4 h at 100 °C under an atmosphere of nitrogen. After cooling to room temperature, the resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated NH4CI aqueous (150 mL x 2), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE / EA, 10% EA) to afford 3-ethenyl-5-methylpyridin-2-amine as an oil.

[0384] LCMS (MS, ESI): 135 [M+H]+.

[0385] Step 2: 3-ethyl-5-methylpyridin-2-amine To a solution of 3-ethenyl-5-methylpyridin-2- amine (500 mg, 3.73 mmol, 1 .0 equiv.) in MeOH (3 mL) was added Pd / C (793 mg, 0.745 mmol, 0.2 equiv., 10% purity). After stirring for 2 h at room temperature under an atmosphere of hydrogen (1 atm), the solid was filtered off. The filtrate was concentrated under reduced pressure to afford 3-ethyl-5-methylpyridin-2-amine as a solid.

[0386] LCMS (MS, ESI): 137 [M+H]+.

[0387] 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-amine

[0388] Step 1 : benzyl (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)carbamate. To a solution of 4 / - / ,5 / - / ,6 / - / ,7 / - / -pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (2.0 g, 12.0 mmol, 1.0 equiv.) in toluene (30 mL) were added TEA (1.67 mL, 12.0 mmol, 1.0 equiv.) and DPPA (2.60 mL, 12.0 mmol, 1.0 equiv.). After stirring at room temperature for 2 h under an atmosphere of nitrogen, to the above mixture was added benzyl alcohol (1.25 mL, 12.0 mmol, 1.0 equiv.). The resulting mixture was stirred at 100 °C for 1 h. After cooling to RT, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol in dichloromethane (3%) to give benzyl A / -{4 / - / ,5 / - / ,6 / - / ,7 / - / -pyrazolo[1 ,5-a]pyridin-2-yl}carbamate as a solid.

[0389] LCMS (MS, ESI): 272 [M+H]+.

[0390] Step 2: 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-amine. A mixture of benzyl N- (4H,5H,6H,7H-pyrazolo[1 ,5-a]pyridin-2-ylcarbamate (800 mg, 2.95 mmol, 1.0 equiv.) and Pd / C (784 mg, 0.737 mmol, 0.25 equiv., 10% purity) in MeOH (15 mL) was stirred at room temperature for 2 h under an atmosphere of hydrogen (3 atm). The mixture was filtered through Celite. The filter cake was washed with MeOH (15 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (5%) to afford 4 / - / ,5 / - / ,6 / - / ,7 / - / -pyrazolo[1 ,5- a]pyridin-2-amine as an oil.

[0391] LCMS (MS, ESI): 138 [M+H]+. [1 ,3]dioxolo[4,5-b]pyridin-5-amine

[0392] Step 1 : [1,3]dioxolo[4,5-b]pyridine. To a solution of 2,3-dihydroxypyridine (6.00 g, 54.0 mmol, 1 .0 equiv.) in DMF (60 mL) was added K2CO3 (11 .2 g, 81.0 mmol, 1 .5 equiv.) and dibromomethane (14.1 g, 81.0 mmol, 1.5 equiv.). After stirring at 100 °C for 16 h, the reaction was quenched with water (120 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed with a solution of sodium thiosulfate (120 mL, 10% in water) and brine (120 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 2H- [1 ,3] dioxolo[4,5-b] pyridine as an oil.

[0393] LCMS (MS, ESI): 124 [M+H]+.

[0394] Step 2: 5-nitro-[1 ,3]dioxolo[4,5-b]pyridine To a solution of 2H- [1 ,3] dioxolo[4,5-b] pyridine (1.98 g, 16.2 mmol, 1.0 equiv.) in H2SO4 (10 mL) was added HNO3 (5 mL, 85% purity) at 0 °C, After stirring at RT for 2 h, the mixture was quenched with water (40 mL), basified to pH 8 with NaOH (20% in water), and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate in petroleum ether (38%) to afford 5-nitro-2H- [1 ,3] dioxolo[4,5-b] pyridine as a solid.

[0395] LCMS (MS, ESI): 169 [M+H]+.

[0396] Step 3: [1,3]dioxolo[4,5-b]pyridin-5-amine. To a solution of 5-nitro-2H- [1 ,3] dioxolo[4,5-b] pyridine (700 mg, 4.16 mmol, 1 .0 equiv.) in DMF (14 mL) was added B2(OH)4 (1.12 g, 12.5 mmol, 3.0 equiv.) and 4,4’-bipyridine (7 mg, 0.042 mmol, 0.01 equiv.). After stirring for 5 min at 0 °C, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (41 %) to afford 2H- [1 ,3] dioxolo[4,5-b] pyridin-5-amine as a solid.

[0397] LCMS (MS, ESI): 139 [M+H]+. 4-methyl-2,3-dihydrofuro[2,3-b]pyridin-6-amine

[0398] Step 1 : 4,6-dichloro-2-(pent-3-yn-1-yloxy)pyrimidine. To a stirred solution of NaH (1.09 g, 27.3 mmol, 1.0 equiv., 60% purity) in THF (500 mL) was added a solution of 3-pentyn-1-ol (2.3 g, 27.3 mmol, 1 .0 equiv.) in THF (10 mL) dropwise at 0°C under an atmosphere of nitrogen. After stirring for 1 h at 0 °C, a solution of 4,6-dichloro-2-methanesulfonylpyrimidine (8.07 g, 35.5 mmol, 1.3 equiv.) in THF (50 mL) was added dropwise. The resulting mixture was stirred for 16 h at room temperature, quenched with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with a saturated solution of NaHCOa in water (2 x 30 mL) and brine (2 x 30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (20% EA) to afford 4,6-dichloro-2- (pent-3-yn-1-yloxy)pyrimidine as a solid.

[0399] LCMS (MS, ESI): 231 , 233 [M+H]+.

[0400] Step 2: 6-chloro-4-methyl-2,3-dihydrofuro[2,3-b]pyridine. A solution of 4,6-dichloro-2- (pent-3-yn-1-yloxy)pyrimidine (1.0 g, 4.33 mmol, 1.0 equiv.) in nitrobenzene (10 mL) was stirred for 8 h at 250 °C under N2 atmosphere. After cooling to RT, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (15% EA) to afford 6-chloro-4-methyl-2 / - / ,3 / - / -furo[2,3- b]pyridine as an oil.

[0401] LCMS (MS, ESI): 170, 172 [M+H]+.

[0402] Step 3: N-(2,4-dimethoxybenzyl)-4-methyl-2,3-dihydrofuro[2,3-b]pyridin-6-amine. To a stirred mixture of 6-chloro-4-methyl-2 / - / ,3 / - / -furo[2,3-b]pyridine (220 mg, 1.30 mmol, 1.0 equiv.) and 1-(2,4-dimethoxyphenyl)methanamine (325 mg, 1.95 mmol, 1.5 equiv.) in 1 ,4- dioxane (6 mL) were added Pd2(dba)3 (75 mg, 0.130 mmol, 0.1 equiv.), DavePhos (102 mg, 0.259 mmol, 0.2 equiv.) and CS2CO3 (1.27 g, 3.89 mmol, 3.0 equiv.) in portions at room temperature under an atmosphere of nitrogen. After stirring for 2 h at 80 °C, the mixture was allowed to cool down to RT, quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.

[0403] The residue was purified by silica gel column chromatography, eluted with EA / PE (36% EA) to afford the product. The product was dissolved in EA (30 mL) and treated with 440 mg of SiliaMetS Thiol (Scavenger for removing Pd). After filtration, the filtrate was concentrated under reduced pressure to afford A / -[(2,4-dimethoxyphenyl)methyl]-4-methyl-2 / - / ,3 / - / -furo[2,3- b]pyridin-6-amine as a solid.

[0404] LCMS (MS, ESI): 301 [M+H]+.

[0405] Step 4: 4-methyl-2,3-dihydrofuro[2,3-b]pyridin-6-amine A solution of A / -[(2,4- dimethoxyphenyl)methyl]-4-methyl-2 / - / ,3 / - / -furo[2,3-b]pyridin-6-amine (700 mg, 2.33 mmol, 1 .0 equiv.) in TFA (1 mL) / DCM (3 mL) was stirred for 1 h at room temperature. The reaction was quenched with a saturated solution of NaHCOa in water (20 mL) at 0 °C and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to give 4-methyl-2 / - / ,3 / - / -furo[2,3-b]pyridin-6-amine as a solid.

[0406] LCMS (MS, ESI): 151 [M+H]+.

[0407] 5-bromo-1 ,2-dimethylimidazo[4,5-b]pyridine and 5-bromo-2,3-dimethylimidazo[4,5- bjpyridine

[0408] A solution of 5-bromo-2-methyl-3 / - / -imidazo[4,5-b]pyridine (2.50 g, 11.8 mmol, 1.0 equiv.) in THF (60 mL) was added NaH (1.41 g, 35.4 mmol, 3.0 equiv., 60% purity) in portions at 0 °C. After stirring for 30 min at 0 °C, to the reaction mixture was added dropwise Mel (1 .10 mL, 17.7 mmol, 1 .5 equiv.) at 0 °C. After stirring for 10 min at 0 °C, the reaction mixture was stirred for 2 h at room temperature, quenched with water (60 mL) at 0 °C and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with water (180 mL x 2), brine (180 mL), dried over Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash (Cis column, H2O / CAN, 34% CAN) to afford 5-bromo-1 ,2-dimethylimidazo[4,5-b]pyridine as a solid and 5-bromo-2,3-dimethylimidazo[4,5-b]pyridine as a solid.

[0409] 5-bromo-1 ,2-dimethylimidazo[4,5-b]pyridine: LCMS (MS, ESI): 226, 228 [M+H]+.1HNMR (400 MHz, DMSO-d6): 5 7.92-7.94 (m, 1H), 7.38 (d, J = 8.3Hz, 1H), 3.76 (s, 3H), 2.57 (s, 3H).

[0410] 5-bromo-2,3-dimethylimidazo[4,5-b]pyridine: LCMS (MS, ESI): 226, 228 [M+H]+.1HNMR (400 MHz, DMSO-d6): 5 7.87 - 7.89 (m, 1 H), 7.36 - 7.38 (m, 1 H), 3.71 (s, 3H), 2.56 (s, 3H). 2-chloro-6-(2-methoxyethoxy)-3-methylpyridine and 6-chloro-2-(2-methoxyethoxy)-3- methylpyridine

[0411] Step 1 : 2-chloro-6-(2-methoxyethoxy)-3-methylpyridine and 6-chloro-2-(2- methoxyethoxy)-3-methylpyridine. To a stirred solution of 2-methoxyethanol (7.1 mL, 93.1 mmol, 5.03 equiv.) in THF (30 mL) was added NaH (2.96 g, 74.1 mmol, 4.0 equiv., 60% purity) at 0°C under an atmosphere of nitrogen. After stirring for 30 min at 0 °C, to the above mixture was added 2,6-dichloro-3-methylpyridine (3.0 g, 18.5 mmol, 1.0 equiv.) at 0 °C. The resulting mixture was stirred for additional 6 h at 60 °C. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column chromatography, eluted with EA / PE (28% EA) to afford 2-chloro-6-(2-methoxyethoxy)-3-methylpyridine as an oil and 6-chloro-2- (2-methoxyethoxy)-3-methylpyridine as an oil.

[0412] 2-chloro-6-(2-methoxyethoxy)-3-methylpyridine: LCMS (MS, ESI): 202, 204 [M+H]+.1HNMR (400 MHz, Chloroform-d) 5 7.43 (d, J = 8.0 Hz, 1 H), 6.68 (d, J = 8.0 Hz, 1H), 4.45 - 4.47 (m, 2H), 3.73 - 3.76 (m, 2H), 3.45 (s, 3H), 2.29 (s, 3H).

[0413] 6-chloro-2-(2-methoxyethoxy)-3-methylpyridine: LCMS (MS, ESI): 202, 204 [M+H]+.1HNMR (400 MHz, Chloroform-d) 5 7.30 - 7.35 (m, 1H), 6.81 (d, J = 8.0 Hz, 1 H), 4.48 - 4.51 (m, 2H), 3.75 - 3.78 (m, 2H), 3.45 (s, 3H), 2.18 (s, 3H).

[0414] 2-bromo-3-methyl-5-(2H-oxet-3-yloxy)pyridine

[0415] Step 1 : 2-bromo-3-methyl-5-(2H-oxet-3-yloxy)pyridine. To a stirred mixture of 6-bromo-5- methylpyridin-3-ol (500 mg, 2.66 mmol, 1 equiv.) and oxetan-3-yl 4-methylbenzenesulfonate (730 mg, 3.19 mmol, 1 .20 equiv.) in DMF (10 mL) was added CS2CO3 (2.2 g, 6.70 mmol, 2.52 equiv.) at room temperature. The resulting mixture was stirred for 15 hours at 60 °C. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) at room temperature and extracted with EA (20 mL x 2). The combined organic layers were washed with water (20 mL) and brine (50 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (25% EA) to afford 2-bromo-3-methyl-5-(2 / - / - oxet-3-yloxy)pyridine as a solid.

[0416] LCMS (MS, ESI): 244, 246 [M+H]+.

[0417] 3-iodo-1-methylindazole-5-carbonitrile and 3-iodo-2-methylindazole-5-carbonitrile

[0418] Step 1 : 3-iodo-1 H-indazole-5-carbonitrile. To a stirred solution of 1 H-indazole-5- carbonitrile (500 mg, 3.49 mmol, 1 .0 equiv.) in DMF (10 mL) were added I2 (1 .77 g, 6.99 mmol, 2.0 equiv.) and KOH (734 mg, 13.1 mmol, 3.75 equiv.) at room temperature. After stirring for 3 h at room temperature, the reaction mixture was quenched with a saturated solution of sodium bisulfite in water (20 mL). The precipitated solids were collected by filtration and washed with water (3 x 20 mL) to give a crude product that was dried under vacuum to give 3-iodo-1 / - / -indazole-5-carbonitrile as a solid.

[0419] LCMS (MS, ESI): 270 [M+H]+

[0420] Step 2: 3-iodo-1-methyl-1 H-indazole-5-carbonitrile and 3-iodo-2-methyl-2H-indazole-5- carbonitrile. To a stirred solution of 3-iodo-1 / - / -indazole-5-carbonitrile (500 mg, 1.86 mmol, 1 .0 equiv.) and CS2CO3 (787 mg, 2.42 mmol, 1.3 equiv.) in CAN (5 mL) were added Mel (0.35 mL, 5.57 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred for 1 .5 h at 80°C. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (30%EA) to afford 3-iodo-1-methylindazole-5- carbonitrile as a solid and 3-iodo-2-methylindazole-5-carbonitrile as a solid.

[0421] 3-iodo-1-methylindazole-5-carbonitrile: LCMS (MS, ESI): 284 [M+H]+ 1H NMR (400 MHz, DMSO-de) 5 8.05 (d, J = 1.3 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.80 (dd, J = 8.8, 1 .5 Hz, 1H), 4.12 (s, 3H).

[0422] 3-iodo-2-methylindazole-5-carbonitrile: LCMS (MS, ESI): 284 [M+H]+ 1H NMR (400 MHz, DMSO-de) 5 8.09 (s, 1 H), 7.77 (d, J = 8.9 Hz, 1 H), 7.52 (dd, J = 8.9, 1 .6 Hz, 1 H), 4.24 (s, 3H).

[0423] 3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine Step 1 : 3-iodo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine. To a solution of 6,7- dihydro-5 / - / -cyclopenta[b]pyridin-2-amine (500 mg, 3.73 mmol, 1.0 equiv.) in CAN (10 mL) was added NIS (922 mg, 4.10 mmol, 1.1 equiv.) in portions at O °C. After stirring for 16 hours at room temperature, the reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (2% MeOH) to afford 3-iodo- 6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-amine as a solid.

[0424] 1H NMR (400 MHz, DMSO-d6) 5 7.73 (s, 1 H), 5.78 (s, 2H), 2.66 - 2.73 (m, 4H), 1.94 - 2.01 (m, 2H).

[0425] Step 2: 3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine. To a mixture of 3-iodo- 6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-amine (550 mg, 2.12 mmol, 1.0 equiv.) and Pd(dppf)Ch (77 mg, 0.105 mmol, 0.05 equiv.) in dioxane (8 mL) was added ZnMe2 (4.40 mL, 4.40 mmol, 2.08 equiv., 1 M in THF) dropwise at 0 °C under an atmosphere of nitrogen. The reaction mixture was stirred for 3 hours at 110 °C. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH, 20:1) to afford 3-methyl-6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-amine as a solid.

[0426] 1H NMR (400 MHz, DMSO-d6) 5 7.08 (s, 1 H), 5.37 (s, 2H), 2.61- 2.70 (m, 4H), 1.99 (s, 3H), 1.91 - 1.97 (m, 2H).

[0427] 3-aminobenzo[c / ]isothiazole-5- carbonitrile

[0428] Step 1 : 5-iodobenzo[d]isothiazol-3-amine To a stirred solution of 2-fluoro-5- iodobenzonitrile (500 mg, 2.02 mmol, 1.0 equiv.) in DMSO (50 mL) was added sodium sulfide (1.58 g, 20.2 mmol, 1 .0 equiv.). After stirring for 16 hours at 70 °C, the reaction mixture was cooled to 0 °C. Then aqueous NH3 (50 mL, 30% in water) and NaCIO (50 mL, 8% in water) were added dropwise to the reaction mixture. After stirring for 5 hours at room temperature, the resulting mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography with the following conditions: (Cis column; 40-60A; mobile phase, CAN in Water, 5% to 50% gradient in 20 min; detector, UV 254 nm) to afford 5-iodo-1 ,2-benzothiazol-3-amine as a solid. LCMS (MS, ESI): 277 [M+H]+.

[0429] Step 2: 3-aminobenzo[c / ]isothiazole-5-carbonitrile To a mixture of 5-iodo-1 ,2- benzothiazol-3-amine (1.5 g, 4.18 mmol, 1.0 equiv., 77% purity) and Zn(CN)2 (300 mg, 2.56 mmol, 0.61 equiv.) in DMF (15 mL) was added Pd(PPh3)4 (230 mg, 0.199 mmol, 0.05 equiv.). The resulting mixture was stirred for 2 hours at 110 °C under an atmosphere of nitrogen. After cooling to room temperature, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (30% EA) to afford the product. The product was dissolved in EA (20 mL) and treated with 500 mg of SiliaMetS Thiol (Scavenger for removing Pd). The resulting mixture was stirred at room temperature for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure to afforded 3-amino-1 ,2-benzothiazole-5- carbonitrile as a solid.

[0430] LCMS (MS, ESI): 176 [M+H]+.

[0431] 5-methoxy-2,3-dihydrofuro[2,3-b]pyridin-6-amine

[0432] Step 1 : 5-methoxy-2,3-dihydrofuro[2,3-b]pyridin-6-amine To a mixture of 5-iodo-2,3- dihydrofuro[2,3-b]pyridin-6-amine (300 mg, 1.15 mmol, 1.0 equiv.) (Synthesized by the procedure of Intermediate 156 at step 1 (03-594-1)) and 1 ,10-phenanthroline (41 mg, 0.228 mmol, 0.20 equiv.) in MeOH (2 mL) and NMP (2 mL) were added Cul (24 mg, 0.126 mmol, 0.11 equiv.) and CS2CO3 (750 mg, 2.30 mmol, 2.01 equiv.). The resulting mixture was stirred for 16 hours at 100 °C under an atmosphere of nitrogen. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (MeOH / DCM, 1 :50) to afford a crude product. The crude product was purified by prep-HPLC with the following conditions (Column: Welch Ultimate XB-C18 50*250, 10 pm; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: CAN; Flow rate: 60 mL / min; Gradient: 1 % B to 30 % B in 30 min; Wave Length: 254 nm / 220 nm; RT1 (min): 22). Concentration under reduced pressure afforded 5-methoxy-2,3-dihydrofuro[2,3-b]pyridin-6- amine as a solid.

[0433] LCMS (MS, ESI): 167 [M+H]+. 2-chloro-6,7,8,9-tetrahydroimidazo[1 ,2-a:4,5-b’]dipyridine

[0434] Step 1 : (Z)- / V-(6-chloro-3-iodopyridin-2-yl)piperidin-2-imine To a stirred solution of 2- piperidinone (3.9 g, 39.3 mmol, 2.0 equiv.) in toluene (300 mL) was added POCI3 (1 .83 mL, 19.6 mmol, 1.0 equiv.) dropwise at 0 °C under an atmosphere of nitrogen. After stirring for additional 2 h at 0 °C, 6-chloro-3-iodopyridin-2-amine (5.0 g, 19.6 mmol, 1.0 equiv.) was added in portions. The resulting mixture was stirred for 4 h at 120 °C. After cooling down to room temperature, the supernatant was removed. The resulting residue was dissolved in DCM / MeOH (10:1 , 80 mL) and was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluted with methanol in dichloromethane (6%) to afford 6-chloro-3-iodo-A / -[(2Z)-piperidin-2-ylidene]pyridin-2-amine as a solid.

[0435] LCMS (MS, ESI): 336, 338 [M+H]+.

[0436] Step 2: 2-chloro-6,7,8,9-tetrahydroimidazo[1 ,2-a:4,5-b’]dipyridine. To a stirred solution of 6-chloro-3-iodo-A / -[(2Z)-piperidin-2-ylidene]pyridin-2-amine (5.5 g, 16.39 mmol, 1.0 equiv.) in DMSO (50 mL) were added K3PO4 (3.48 g, 16.4 mmol, 1 .0 equiv.), Cui (625 mg, 3.28 mmol, 0.2 equiv.) and DMEDA (0.55 mL, 5.08 mmol, 0.3 equiv.) in sequence. After stirring for 4 h at 120°C under an atmosphere of nitrogen, the mixture was allowed to cool down to room temperature, quenched with water (3 x 30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure to the crude product. The crude product was purified by silica gel column chromatography, eluted with methanol in dichloromethane (3%) to afford the product. The product was dissolved in ethyl acetate (50 mL) and treated with 2.0 g of SiliaMetS TAAcONa (Scavenger for removing Cu). After filtration, the filtrate was concentrated under reduced pressure to afford 5-chloro-1 ,6,8-triazatricyclo[7.4.0.0A{2,7}]trideca-2,4,6,8-tetraene as a solid.

[0437] LCMS (MS, ESI): 208, 210 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 7.98 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1 H), 4.14 (t, J = 8.0 Hz, 2H), 3.01 (t, J = 8.0 Hz, 2H), 2.00 - 2.09 (m, 2H), 1.90 - 1.99 (m, 2H).

[0438] 4-bromo-2-(2-methoxyethoxy)-5-methylaniline Step 1 : 1-bromo-5-(2-methoxyethoxy)-2-methyl-4-nitrobenzene. To a solution of 1- bromo-5-fluoro-2-methyl-4-nitrobenzene (2.00 g, 8.55 mmol, 1.0 equiv.) in DMF (20 mL) were added 2-methoxyethanol (980 mg, 12.8 mmol, 1.5 equiv.) and CS2CO3 (5.57 g, 17.1 mmol, 2.0 equiv.). After stirring at 100 °C for 2 h, the reaction was quenched with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with a solution of sodium thiosulfate (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (30%) to afford 1-bromo-5-(2- methoxyethoxy)-2-methyl-4-nitrobenzene as a semi-solid.

[0439] LCMS (MS, ESI): 290, 292 [M+H]+.

[0440] Step 2: 4-bromo-2-(2-methoxyethoxy)-5-methylaniline. A mixture of 1-bromo-5-(2- methoxyethoxy)-2-methyl-4-nitrobenzene (2.00 g, 6.89 mmol, 1.0 equiv.), NH4CI (1.84 g, 34.5 mmol, 5.0 equiv.) and iron powder (1.92 g, 34.5 mmol, 5.0 equiv.) in H2O (5 mL) and EtOH (15 mL) was stirred for 3 hours at 65°C. After cooling to room temperature, the reaction was quenched with water (40 mL) and extracted with EA (40 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (40%) to afford 4-bromo-2-(2-methoxyethoxy)-5-methylaniline as a solid.

[0441] LCMS (MS, ESI): 260, 262 [M+H]+.

[0442] 1-bromo-5-cyclopropoxy-4-iodo-2-methyl benzene

[0443] Step 1 : 1-cyclopropoxy-4-methyl-2-nitrobenzene. To a mixture of 1-fluoro-4-methyl-2- nitrobenzene (10.0 g, 64.5 mmol, 1.0 equiv.) and cyclopropanol (5.00 g, 86.1 mmol, 1.3 equiv.) in DMF (100 mL) was added tBuONa (18.0 g, 194 mmol, 3.0 equiv.) in portions. After stirring for 3 h at room temperature, the reaction was quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with water (600 mL x 3) and brine (600 mL), dried over Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 20% EA) to afford 1-cyclopropoxy-4-methyl-2-nitrobenzene as an oil.

[0444] 1H NMR (400 MHz, DMSO-d6) 5 7.68 (s, 1 H), 7.50 - 7.52 (m, 2H), 4.01 - 4.06 (m, 1 H), 2.31 (s, 3H), 0.81 - 0.85 (m, 2H), 0.68 - 0.72 (m, 2H).

[0445] Step 2: 2-cyclopropoxy-5-methylaniline. To a solution of 1-cyclopropoxy-4-methyl-2- nitrobenzene (14.4 g, 74.5 mmol, 1.0 equiv. 85%) in DMF (220 mL) was added 4,4’- bipyridine (1 .28 g, 8.20 mmol, 0.1 equiv.) and B2(OH)4 (20.2 g, 225 mmol, 3.0 equiv.) at 0 °C. After stirring for 30 mins at room temperature, the reaction was quenched with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with water (900 mL x 3) and brine (900 mL), dried over Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 2% EA) to afford 2-cyclopropoxy-5-methylaniline as an oil.

[0446] LCMS (MS, ESI): 164 [M+H]+.

[0447] Step 3: 4-bromo-2-cyclopropoxy-5-methylaniline. To a mixture of 2-cyclopropoxy-5- methylaniline (3.80 g, 18.4 mmol, 1 .0 equiv., 79%) in CAN (100 mL) was added NBS (2.95 g, 16.6 mmol, 0.9 equiv.) in portions at 0 °C. After stirring for 10 min at 0 °C, the reaction mixture was stirred for 2 h at room temperature. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (PE / EA, 1 % EA) to afford 2-cyclopropoxy-4-iodo-5-methylaniline as an oil.

[0448] LCMS (MS, ESI): 242, 244 [M+H]+.

[0449] Step 4: 1-bromo-5-cyclopropoxy-4-iodo-2-methylbenzene. A mixture of 4-bromo-2- cyclopropoxy-5-methylaniline (600 mg, 2.03 mmol, 1.0 equiv., 89%) and tBuNC>2 (0.44 mL, 3.67 mmol, 1.8 equiv.) in CH2I2 (6 mL) was stirred for 30 min at 80 °C under an atmosphere of nitrogen. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (60 mL), dried over Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA, 1 % EA) to afford 1-bromo-5-cyclopropoxy-4-iodo-2-methylbenzene as an oil.

[0450] GCMS (MS, El): 352, 354 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.75 (s, 1 H), 7.41 (s, 1H), 3.95 - 4.01 (m, 1H), 2.25 (s, 3H), 0.80 - 0.87 (m, 2H), 0.66 - 0.69 (m, 2H).

[0451] 2-chloro-7-methyl-5H,6H-cyclopenta[b]pyridin-7-ol Step 1 : 2-chloro-7-methyl-5H,6H-cyclopenta[b]pyridin-7-ol. To a solution of 2-chloro- 4a / - / ,5 / - / ,6 / - / ,7a / - / -cyclopenta[b]pyridin-7-one (500 mg, 2.95 mmol, 1.0 equiv.) in THF (15 mL) was added methylmagnesium bromide (2.4 mL, 7.2 mmol, 2.5 equiv., 3M in EtzO) dropwise at 0°C under nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (50% EA) to afford 2-chloro-7-methyl- 5 / - / ,6 / - / -cyclopenta[b]pyridin-7-ol as a solid.

[0452] LCMS (MS, ESI): 184, 186 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.72 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1 H), 5.23 (brs, 1H), 2.86 - 2.94 (m, 1 H), 2.68 - 2.76 (m, 1H), 2.04 - 2.12 (m, 2H), 1.42 (s, 3H).

[0453] 5-bromo-1-methylpyrazolo[4,3-b]pyridine and 5-bromo-2-methylpyrazolo[4,3- bjpyridine

[0454] To a solution of 5-bromo-1 H-pyrazolo[4,3-b]pyridine (3.0 g, 15.2 mmol, 1.0 equiv.) in THF (60 mL) was added KOH (3.0 g, 53.5 mmol, 3.53 equiv.) at 0 °C. After stirring for 30 minutes at 0 °C, Mel (1.54 mL, 24.7 mmol, 1 .63 equiv.) was added dropwise to the reaction mixture. After stirring for 1 hour at room temperature, the reaction mixture was quenched with water (80 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with water (80 mL) and brine (80 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (20% EA) to afford 5-bromo-1- methylpyrazolo[4,3-b]pyridine as a solid and 5-bromo-2-methylpyrazolo[4,3-b]pyridine as a solid.

[0455] 5-bromo-1-methylpyrazolo[4,3-b]pyridine:1H NMR (400 MHz, DMSO-de) 5 8.26 (s, 1 H), 8.18 (d, J = 8.9 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 1H), 4.10 (s, 3H).

[0456] 5-bromo-2-methylpyrazolo[4,3-b]pyridine:1H NMR (400 MHz, DMSO-de) 6 8.65 (s, 1 H), 8.07 (d, J = 8.9 Hz, 1 H), 7.40 (d, J = 9.0 Hz, 1H), 4.21 (s, 3H).

[0457] 5-methoxypent-2-ynoic acid Step 1 : 5-methoxypent-2-ynoic acid. To a stirred solution of 4-methoxybut-1-yne (200 mg, 2.38 mmol, 1.0 equiv.) in diethyl ether (10 mL) was added n-BuLi (1.05 mL, 2.62 mmol, 1.1 equiv., 2.5M in n-hexane) dropwise at -78 °C under an atmosphere of nitrogen. After stirring for 1 hour at -78 °C under an atmosphere of nitrogen, excess dry ice was added to the reaction mixture. The resulting mixture was warmed to room temperature over 1 hour and stirred at room temperature for 10 minutes. Then the reaction mixture was quenched with water (10 mL) at -10 °C. The resulting mixture was acidified to pH 4 with saturated citric acid aqueous solution and extracted with EA (4 x 50 mL). The combined organic layers were dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography, eluted with MeOH in DCM (1 % MeOH) to afford 5-methoxypent-2-ynoic acid as an oil.

[0458] 1H NMR (400 MHz, DMSO-d6) 5 13.39 (s, 1 H), 3.46 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.62 (t, J = 6.3 Hz, 2H). but-2-ynoyl-d3chloride

[0459] Step 1 : tert-butyl but-2-ynoate-d3. To a solution of tert-butyl prop-2-ynoate (10.0 g, 79.3 mmol, 1 .0 equiv.) in THF (200 mL) was added n-BuLi (38.0 mL, 95.0 mmol, 1.20 equiv., 2.5M in hexane) dropwise at -78 °C under an atmosphere of nitrogen. After stirring for 30 minutes at the same temperature, a solution of CD3I (17.2 g, 119 mmol, 1.5 equiv.) in THF (20 mL) was added. The resulting mixture was gradually warmed to -10 °C in 2 h. The reaction solution was quenched by the addition of a saturated solution of NH4CI in water (100 mL) at -10 °C and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (200 mL x 1 ), dried over anhydrous NazSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1 :10) to afford tert-butyl but-2-ynoate-rt3 as an oil.

[0460] 1H NMR (400 MHz, Chloroform-d) 5 1.51 (s, 9H).

[0461] Step 2: but-2-ynoic-d3 acid. To a stirred solution of tert-butyl but-2-ynoate-d3 (1.88 g, 13.1 mmol, 1.0 equiv.) in DCM (25 mL) was added TFA (10 mL) dropwise at O °C. After stirring for 2 h at room temperature, the resulting mixture was concentrated under reduced pressure to give but-2-ynoic-d3 acid as a solid.1H NMR (400 MHz, Chloroform-d) 5 10.32 (br s, 1H).

[0462] Step 3: but-2-ynoyl-d3 chloride. To a stirred solution of but-2-ynoic-d3 acid (500 mg, 5.741 mmol, 1 .0 equiv.) in DCM (5 mL) were added (COCI)2 (0.54 mL, 6.315 mmol, 1.1 equiv.) and DMF (2 drops) dropwise at 0 °C under an atmosphere of nitrogen. The resulting mixture was stirred for 1 h at 0°C to give a solution of but-2-ynoyl-d3 chloride (about 1 M in DCM) in DCM. The resulting mixture was used in the next step directly without further purification.

[0463] 3-(tetrahydrofuran-3-yl)propiolic acid p

[0464] Step 1 : 3-(tetrahydrofuran-3-yl)propiolic acid. To a stirred solution of 3-ethynyloxolane (200 mg, 2.08 mmol, 1 .0 equiv.) in diethyl ether (15 mL) was added nBuLi (0.92 mL, 2.29 mmol, 1.1 equiv., 2.5M in THF) dropwise at -78 °C under an atmosphere of nitrogen. After stirring for 1 hour at -78 °C, excess dry ice was added to the reaction mixture. The resulting mixture was warmed to room temperature over 1 hour and stirred at room temperature for 10 minutes. The reaction mixture was quenched with saturated citric acid aqueous solution (15 mL) at 0 °C and extracted with EA (4 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product that was purified by silica gel column chromatography, eluted with MeOH in DCM (2% MeOH) to afford 3-(oxolan-3-yl) prop-2-ynoic acid as a solid.

[0465] 1 H NMR (400 MHz, DMSO-d6) 5 13.51 (s, 1H), 3.88 - 3.92 (m, 1H), 3.77 - 3.83 (m, 1 H), 3.69 - 3.74 (m, 1 H), 3.57 - 3.60 (m, 1 H), 3.20 - 3.27 (m, 1H), 2.18 - 2.27 (m, 1 H), 1.86 - 1.94 (m, 1 H).

[0466] 6-bromo-2-(methoxymethyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridine and 6-bromo-3- (methoxymethyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridine. Step 1 : 1-methoxy-3-(trityloxy)propan-2-ol. To a stirred solution of glycerin methyl ether (10.0 g, 94.2 mmol, 1 .0 equiv.) in THF (200 mL) were added TEA (39.0 mL, 283 mmol, 3.0 equiv.) and DMAP (2.3 g, 18.9 mmol, 0.2 equiv.) at 0 °C. After stirring for 30 minutes at 0 °C, triphenylmethyl chloride (26.0 g, 94.2 mmol, 1.0 equiv.) was added to the reaction mixture at 0 °C. The resulting mixture was stirred for 3 hours at 65 °C. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (30% EA) to afford 1-methoxy-3-(triphenylmethoxy)propan-2-ol as an oil.

[0467] 1H NMR (400 MHz, DMSO-d6) 5 7.24 - 7.48 (m, 15H), 4.92 (d, J = 5.4 Hz, 1H), 3.76 - 3.80 (m, 1 H), 3.30 - 3.34 (m, 2H), 3.22 (s, 3H), 2.94 (d, J = 5.6 Hz, 2H).

[0468] Step 2: 1-methoxy-3-(trityloxy)propan-2-yl 4-methylbenzenesulfonate To a stirred solution of 1-methoxy-3-(triphenylmethoxy)propan-2-ol (20.0 g, 57.4 mmol, 1.0 equiv.) in DCM (500 mL) was added TEA (16.0 mL, 115 mmol, 2.01 equiv.) at 0 °C. After stirring for 30 minutes at 0 °C, TsCI (13.0 g, 68.9 mmol, 1.2 equiv.) was added to the reaction mixture. After stirring for 3 hours at room temperature, the resulting mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (50% EA) to afford 1-methoxy-3- (triphenylmethoxy)propan-2-yl 4-methylbenzenesulfonate as an oil.

[0469] 1H NMR (400 MHz, DMSO-d6) 5 7.79 (d, J = 7.9 Hz, 2H), 7.42 - 7.44 (m, 2H), 7.22 - 7.38 (m, 15H), 4.71 (t, J = 4.8 Hz, 1 H), 3.40 - 3.53 (m, 2H), 2.96 - 3.14 (m, 5H), 2.35 - 2.43 (m, 3H).

[0470] Step 3: 6-bromo-2-chloro-3-((1-methoxy-3-(trityloxy)propan-2-yl)oxy)pyridine and 6- bromo-2-chloro-3-(3-methoxy-2-(trityloxy)propoxy)pyridine. To a stirred mixture of 6- bromo-2-chloropyridin-3-ol (280 mg, 1.33 mmol, 0.67 equiv.) and 1-methoxy-3- (triphenylmethoxy)propan-2-yl 4-methylbenzenesulfonate (1.5 g, 2.984 mmol, 1.5 equiv.) in DMF (30 mL) was added CS2CO3 (1 .3 g, 3.98 mmol, 2.00 equiv.) at room temperature. After stirring for 16 hours at 80 °C, the reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (30% EA) to afford a mixture of 6-bromo-2-chloro-3-((1-methoxy-3-(trityloxy)propan-2-yl)oxy)pyridine and 6- bromo-2-chloro-3-(3-methoxy-2-(trityloxy)propoxy)pyridine as an oil.1H NMR (400 MHz, DMSO-d6) 5 7.73 - 7.80 (m, 1 H), 7.55 - 7.68 (m, 1 H), 7.20 - 7.46 (m, 15H), 4.71 - 4.94 (m, 1 H), 3.58 - 3.68 (m, 1H), 3.41 - 3.53 (m, 1H), 3.13 - 3.25 (m, 3H), 3.04 - 3.12 (m, 2H).

[0471] Step 4: 2-((6-bromo-2-chloropyridin-3-yl)oxy)-3-methoxypropan-1-ol and 1-((6-bromo- 2-chloropyridin-3-yl)oxy)-3-methoxypropan-2-ol. To a stirred mixture (2.0 g, 3.71 mmol, 1.0 equiv.) of 6-bromo-2-chloro-3-((1-methoxy-3-(trityloxy)propan-2-yl)oxy)pyridine and 6- bromo-2-chloro-3-(3-methoxy-2-(trityloxy)propoxy)pyridine in DCM (40 mL) was added TFA (20 mL, 269 mmol, 72.6 equiv.) at room temperature. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: (C18 column; Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 50 mL / min; Gradient: 5% B to 100% B in 30 min, 15% B; Wave Length: 254 nm) to afford a mixture of 2-((6-bromo-2- chloropyridin-3-yl)oxy)-3-methoxypropan-1-ol and 1-((6-bromo-2-chloropyridin-3-yl)oxy)-3- methoxypropan-2-ol as an oil.

[0472] 1H NMR (400 MHz, DMSO-d6) 5 7.69 - 7.80 (m, 1 H), 7.61 (s, 2H), 3.92 - 3.99 (m, 1 H), 3.53 - 3.65 (m, 2H), 3.38 - 3.48 (m, 2H), 3.28 (s, 3H).

[0473] Step 5: 6-bromo-2-(methoxymethyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridine and 6- bromo-3-(methoxymethyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridine. To a stirred mixture (200 mg, 0.674 mmol, 1 .0 equiv.) of 2-((6-bromo-2-chloropyridin-3-yl)oxy)-3-methoxypropan- 1 -ol and 1-((6-bromo-2-chloropyridin-3-yl)oxy)-3-methoxypropan-2-ol in DMF (4 mL) was added NaH (85 mg, 2.02 mmol, 3.0 equiv., 60% purity) at 0 °C. After stirring for 3 hours at 90 °C under an atmosphere of nitrogen, the reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with EA (10 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: (C18 column; Mobile Phase A: Water, Mobile Phase B: CAN; Flow rate: 50 mL / min; Gradient: 5% B to 100% B in 30 min, 40% B; Wave Length: 254 nm) to afford a mixture of 6-bromo-2- (methoxymethyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridine and 6-bromo-3-(methoxymethyl)- 2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridine as an oil.

[0474] LCMS (MS, ESI): 260, 262 [M+H]+.

[0475] 2-bromo-3-methyl-5-((tetrahydrofuran-3-yl)oxy)pyridine Step 1 : 2-bromo-3-methyl-5-((tetrahydrofuran-3-yl)oxy)pyridine. To a mixture of 6- bromo-5-methylpyridin-3-ol (500 mg, 2.66 mmol, 1.0 equiv.) and CS2CO3 (1.73 g, 5.318 mmol, 2.0 equiv.) in DMF (10 mL) was added oxolan-3-yl 4-methylbenzenesulfonate (774 mg, 3.19 mmol, 1 .2 equiv.). After stirring for 2 hours at 60 °C, the mixture was allowed to cool down to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (19%) to afford 2- bromo-3-methyl-5-(oxolan-3-yloxy) pyridine as a an oil.

[0476] LCMS (MS, ESI): 258, 260 [M+H]+.

[0477] (5aS,8aS)-2-bromo-5a,6,8,8a-tetrahydrofuro[3’,4’:5,6][1 ,4]dioxino[2,3-b]pyridine

[0478] Step 1 : (5aS,8aS)-2-bromo-5a,6,8,8a-tetrahydrofuro[3’,4’:5,6][1,4]dioxino[2,3- b]pyridine. A mixture of 2,6-dibromopyridin-3-ol (2.00 g, 7.91 mmol, 1.0 equiv.), (1 R,5S)- 3,6-dioxabicyclo [3.1.0] hexane (1.70 g, 19.78 mmol, 2.5 equiv.), benzyltriethylammonium chloride (TEBAC; 360 mg, 1.58 mmol, 0.2 equiv.) and CS2CO3 (7.73 g, 23.7 mmol, 3.0 equiv.) in DMF (40 mL) was degassed and backfilled with nitrogen for five times. After stirring at 120 °C for 16 h under an atmosphere of nitrogen, the reaction mixture was cooled to RT, quenched with ice water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with water (80 mL), brine (80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (15%) to afford (5aS,8aS)-2- bromo-5a,6,8,8a-tetrahydrofuro [3’,4’:5,6] [1 ,4] dioxino[2,3-b] pyridine as a solid.

[0479] LCMS (MS, ESI): 258, 260 [M+H]+.

[0480] 3-(2-methyltetrahydro-2H-pyran-4-yl)propiolic acid

[0481] Step 1 : (E)-4-(methoxymethylene)-2-methyltetrahydro-2H-pyran. To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (18.0 g, 52.6 mmol, 1.5 equiv.) in THF (80 mL) was added NaHMDS (26.3 mL, 52.6 mmol, 1 .5 equiv., 2M in THF) at -10°C under an atmosphere of nitrogen. After stirring for 1 hours at same temperature, 2-methyloxan-4-one (4.0 g, 35.0 mmol, 1 .0 equiv.) in THF (10 mL) was added dropwise to the above reaction mixture. The resulting mixture was stirred 15 hours at RT and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (10% EA) to afford (4E)-4-(methoxymethylidene)-2-methyloxane as an oil.

[0482] 1H NMR (400 MHz, Chloroform-d) 5 5.84 - 5.86 (m, 1H), 4.01 - 4.04 (m, 1 H), 3.57 (d, J = 0.8 Hz, 3H), 3.33 - 3.40 (m, 2H), 2.65 - 2.71 (m, 0.5H), 2.55 - 2.61 (m, 0.5H), 2.16 - 2.24 (m, 0.5H), 1.94 - 2.02 (m, 1 H), 1.83 - 1.91 (m, 1 H), 1 .62 - 1 .69 (m, 0.5H), 1.21 (dd, J = 8.2, 6.1 Hz, 3H).

[0483] Step 2: 2-methyltetrahydro-2H-pyran-4-carbaldehyde. A solution of (4E)-4- (methoxymethylidene)-2-methyloxane (2 g, 7.03 mmol, 1.0 equiv.) in 1 ,4-dioxane (10 mL) was added HCI (gas) (10 mL, 4M in 1 ,4-dioxane). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (10% EA) to afford 2- methyloxane-4-carbaldehyde as an oil.

[0484] 1H NMR (400 MHz, Chloroform-d) 5 9.62 (d, J = 1.3 Hz, 1 H), 3.41 - 3.55 (m, 3H), 2.47 - 2.58 (m, 1 H), 1.78 - 1.95 (m, 3H), 1.54 - 1.63 (m, 1 H), 1.25 (d, J = 6.1 Hz, 3H). Step 3: 4-ethynyl-2-methyltetrahydro-2H-pyran. To a stirred solution of 2-methyloxane-4- carbaldehyde (900 mg, 7.02 mmol, 1.0 equiv.) and K2CO3 (1.94 g, 14.0 mmol, 2.0 equiv.) in MeOH (10 mL) was added seyferth-gilbert homologation reagent (1.6 mL, 10.5 mmol, 1.5 equiv.) at 0°C under an atmosphere of nitrogen. The resulting mixture was stirred for 15 hours at RT, quenched with water (30 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (12% EA) to afford 4-ethynyl-2- methyloxane as an oil.1H NMR (400 MHz, Chloroform-d) 5 3.95 - 4.02 (m, 1H), 3.33 - 3.45 (m, 2H), 2.45 - 2.55 (m, 1 H), 2.08 (d, J = 2.4 Hz, 1 H), 1.86 - 1.96 (m, 1H), 1.78 - 1.85 (m, 1 H), 1.63 - 1.71(m, 2H), 1.20 (d, J = 6.2 Hz, 3H).

[0485] Step 4: 3-(2-methyltetrahydro-2H-pyran-4-yl)propiolic acid. To a solution of 4-ethynyl-2- methyloxane (300 mg, 2.42 mmol, 1.0 equiv.) in Et2<D (15 mL) was added n-BuLi (1.06 mL, 2.66 mmol, 1.1 equiv., 2.5M in THF) at -78°C under an atmosphere of nitrogen. After stirring for 30 minutes at -78 °C, excess solid carbon dioxide (dry ice) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hours. The reaction mixture was quenched with hydrochloric acid (10 mL, 1M in water) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure to afford 3-(2-methyloxan-4-yl)prop-2-ynoic acid as a solid.

[0486] 1H NMR (400 MHz, DMSO-d6) 5 13.18 (br s, 1 H), 3.79 - 3.87 (m, 1H), 3.28 - 3.40 (m, 2H), 2.72 - 2.82 (m, 1 H), 1 .82 - 1 .89 (m, 1 H), 1 .73 - 1.80 (m, 1 H), 1 .39 - 1 .55 (m, 2H), 1.08 (d, J = 6.1 Hz, 3H).

[0487] 3-(8-oxabicyclo[3.2.1]octan-3-yl)propiolic acid

[0488] Step 1 : 3-(methoxymethylene)-8-oxabicyclo[3.2.1 ]octane. To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (12.2 g, 35.7 mmol, 1.5 equiv.) in THF (20 mL) was added NaHMDS (17.8 mL, 35.7 mmol, 1 .5 equiv., 2M in THF) at -10 °C under an atmosphere of nitrogen. After stirring for 1 hours at the same temperature, a solution of 8- oxabicyclo[3.2.1]octan-3-one (3.0 g, 23.8 mmol, 1.0 equiv.) dissolved in THF (10 mL) was added dropwise to above reaction mixture, and stirred for 16 h at room temperature. The resulting mixture was purified by silica gel column chromatography, eluted with EA / PE (12% EA) to afford 3-(methoxymethylidene)-8-oxabicyclo[3.2.1]octane as an oil.

[0489] 1H NMR (400 MHz, Chloroform-d) 5 5.85-5.89 (m, 1 H), 4.40-4.46 (m, 2H), 3.56 (d, J = 1.4 Hz, 3H), 2.39 - 2.47 (m, 2H), 2.11 - 2.19 (m, 1 H), 1.82 - 1.92 (m, 2H), 1.74 (d, J = 13.7 Hz, 1 H), 1.58-1.70 (m, 2H).

[0490] Step 2: 8-oxabicyclo[3.2.1]octane-3-carbaldehyde To a stirred solution of 3- (methoxymethylidene)-8-oxabicyclo[3.2.1]octane (2.5 g, 16.212 mmol, 1.0 equiv.) in 1 ,4- dioxane (12 mL) was added HCI (gas) in 1 ,4-dioxane (12 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (15% EA) to afford 8-oxabicyclo[3.2.1]octane-3- carbaldehyde as an oil.

[0491] 1H NMR (400 MHz, DMSO-rt6) 5 9.51 (d, J = 1.2 Hz, 1 H), 4.33 - 4.39 (m, 2H), 2.70 - 2.80 (m, 1 H), 1.80 - 1.89 (m, 2H), 1.71 - 1.78 (m, 2H), 1.57 - 1.65 (m, 4H).

[0492] Step 3: 3-ethynyl-8-oxabicyclo[3.2.1]octane To a stirred solution of 8- oxabicyclo[3.2.1]octane-3-carbaldehyde (2.0 g, 14.27 mmol, 1.0 equiv.) and K2CO3 (3.94 g, 28.5 mmol, 2.0 equiv.) in MeOH (20 mL) was added seyferth-gilbert homologation reagent (4.11 g, 21 .4 mmol, 1 .5 equiv.) at 0 °C under an atmosphere of nitrogen. After stirring overnight at room temperature, the reaction solution was quenched by water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (7% EA) to afford 3-ethynyl-8-oxabicyclo[3.2.1]octane as a solid.

[0493] 1H NMR (400 MHz, Chloroform-rt) 5 4.33 - 4.42 (m, 2H), 2.67 - 2.79 (m, 1 H), 2.04 (d, J = 2.3 Hz, 1 H), 1.92 - 2.02 (m, 2H), 1.82 - 1 .91 (m, 2H), 1 .67 - 1 .76 (m, 4H).

[0494] Step 4: tert-butyl 3-(8-oxabicyclo[3.2.1]octan-3-yl)propiolate. To a stirred solution of 3- ethynyl-8-oxabicyclo[3.2.1]octane (500 mg, 3.67 mmol, 1.0 equiv.) in THF (10 mL) was added n-BuLi (1 .54 mL, 3.86 mmol, 1 .05 equiv., 2.5M in THF) at -78 °C under an atmosphere of nitrogen. After stirring for 15 minutes at the same temperature, to the above mixture was added BOC2O (0.82 mL, 3.86 mmol, 1 .05 equiv.) dropwise at -78 °C. The resulting mixture was allowed to warm to RT and stirred for 4 h, quenched by a saturated solution of NH4CI in water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (5% EA) to afford tert-butyl 3-{8- oxabicyclo[3.2.1]octan-3-yl}prop-2-ynoate as an oil.

[0495] 1H NMR (400 MHz, Chloroform-rt) 5 4.37 - 4.40 (m, 2H), 2.81 - 2.90 (m, 1 H), 1.95 - 2.03 (m, 2H), 1.87 - 1.92 (m, 2H), 1.66 - 1.76 (m, 4H), 1.50 (s, 9H).

[0496] Step 5: 3-(8-oxabicyclo[3.2.1]octan-3-yl)propiolic acid. To a stirred solution of tert-butyl 3-{8-oxabicyclo[3.2.1]octan-3-yl}prop-2-ynoate (600 mg, 2.54 mmol, 1.0 equiv.) in DCM (6 mL) was added TFA (3.0 mL, 40.4 mmol, 15.9 equiv.) dropwise at 0 °C. The resulting mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure to afford 3-{8-oxabicyclo[3.2.1]octan-3-yl}prop-2-ynoic acid as an oil.1H NMR (400 MHz, DMSO-d6) 5 4.22 - 4.34 (m, 2H), 2.94 - 3.06 (m, 1 H), 1 .87 -

[0497] 1.59 (m, 8H).

[0498] 3-(tetrahydro-2H-pyran-4-yl)propiolic acid

[0499] Step 1 : 3-(tetrahydro-2H-pyran-4-yl)propiolic acid. To a stirred solution of 4-ethynyloxane (200 mg, 1 .82 mmol, 1 .0 equiv.) in diethyl ether (8 mL) was added n-BuLi (0.80 mL, 2.00 mmol, 1.1 equiv. 2.5M in hexane) dropwise at -78 °C under an atmosphere of nitrogen. After stirring for 1 hour at -78 °C, excess dry ice was added to the reaction mixture. The resulting mixture was warmed to room temperature in 1 hour and stirred at room temperature for 10 minutes, was quenched with saturated citric acid aqueous solution (15 mL) at 0 °C and extracted with EA (4 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluted with MeOH / DCM (2% MeOH) to afford 3-(oxan-4-yl) prop-2- ynoic acid as a solid.

[0500] 1H NMR (400 MHz, DMSO-d6) 5 13.44 (br s, 1 H), 3.72 - 3.77 (m, 2H), 3.37 - 3.43 (m, 2H), 2.81 - 2.88 (m, 1 H), 1.75 - 1.81 (m, 2H), 1.50 - 1.59 (m, 2H).

[0501] 2-chloro-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0502] Step 1 : methyl 2-(aminomethyl)-6-chloro-5-methylnicotinate. To a mixture of methyl 6- chloro-2-cyano-5-methylpyridine-3-carboxylate (2.0 g, 9.50 mmol, 1.0 equiv.) in EtOH (60 mL) and CHCh (20 mL) was added PtO2(367 mg, 1.62 mmol, 0.2 equiv.) at room temperature. After stirring for 24 hours under an atmosphere of hydrogen (1 atm) at room temperature, the reaction mixture was filtered through a pad of Celite. The filter cake was washed with EtOH (3 x 5 mL). The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography, eluted with MeOH in DOM (2% MeOH) to afford methyl 2-(aminomethyl)-6-chloro-5- methylnicotinate as a solid.

[0503] LCMS (MS, ESI):215, 217 [M+H]+. Step 2: 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. To a solution of methyl 2-(aminomethyl)-6-chloro-5-methylpyridine-3-carboxylate (1.4 g, 6.52 mmol, 1.0 equiv.) in MeOH (14 mL) was added TEA (1.81 mL, 13.0 mmol, 2.0 equiv.) at room temperature. After stirring for 16 hours at room temperature under an atmosphere of nitrogen, the reaction mixture was quenched with water (80 mL) and extracted with EA (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (100% EA) to afford 2-chloro-3-methyl-6 / - / ,7 / - / -pyrrolo[3,4-b]pyridin-5-one as a solid.

[0504] LCMS (MS, ESI):183, 185 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 5 8.76 (s, 1 H), 7.44 (s, 1H), 4.35 (s, 2H), 2.60 (s, 3H).

[0505] Step 3: 2-chloro-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. To a mixture of 2-chloro-3-methyl-6,7-dihydro-5 / - / -pyrrolo[3,4-b]pyridin-5-one (1.1 g, 6.02 mmol, 1.0 equiv.) and CS2CO3 (3.93 g, 12.0 mmol, 2.0 equiv.) in DMF (11 mL) was added CH3I (0.38 mL, 6.02 mmol, 1 .0 equiv.) dropwise at 0 °C. After stirring for 1 hour at room temperature under an atmosphere of nitrogen, the reaction mixture was purified by reversed-phase flash chromatography, eluted with CAN in H2O (20% CAN) to afford 2-chloro-3,6-dimethyl-7 / - / - pyrrolo[3,4-b]pyridin-5-one as a solid.

[0506] LCMS (MS, ESI): 197, 199 [M+H]+.

[0507] 4-bromo-2-cyclobutyl-5-methylaniline

[0508] Step 1 : 2-cyclobutyl-5-methylaniline. To a solution of cyclobutylmagnesium bromide (16.0 mL, 16.0 mmol, 1 .0 equiv., 1 M in THF) was added a solution of ZnCh (22.9 mL, 16.0 mmol, 1 .0 equiv., 0.7M in THF) at 0 °C under an atmosphere of nitrogen. After stirring for 0.5 h at the same temperature, the resulting solution was added to a mixture of 2-bromo-5- methylaniline (3.0 g, 16.1 mmol, 1.0 equiv.) and Pd(P(tBu)3)2 (7.42 g, 14.5 mmol, 0.9 equiv.) in THF (30 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 50°C, quenched with a saturated solution of NH4CI in water (50 mL) and extracted with EA (3x100 mL), The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluting with EA in PE (9% EA) to give 2-cyclobutyl-5- methylaniline as an oil.

[0509] LCMS (MS, ESI): 162 [M+H]+. Step 2: 4-bromo-2-cyclobutyl-5-methylaniline. A solution of 2-cyclobutyl-5-methylaniline (1 .2 g, 7.44 mmol, 1 .0 equiv.) in DM F (10 mL) was added NBS (1 .19 g, 6.70 mmol, 0.9 equiv.) at 0 °C. The resulting mixture was stirred for 3 hours at room temperature, quenched with water (50 mL) and extracted with EA (3x60 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (30% EA) to afford 4-bromo-2-cyclobutyl-5-methylaniline as an oil.

[0510] LCMS (MS, ESI): 240, 242 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.04 (s, 1 H), 6.54 (s, 1 H), 4.81 (s, 2H), 3.36-3.41 (m, 1 H), 2.27-2.34 (m, 2H), 2.16 (s, 3H), 1.87-1.96 (m, 3H), 1.73-1.78 (m, 1 H).

[0511] 4-bromo-2-cyclopropyl-5-ethylaniline

[0512] Step 1 : 1-bromo-4-ethyl-2-nitrobenzene. To a stirred solution of 1-bromo-4-ethylbenzene (3.0 g, 16.2 mmol, 1 .0 equiv.) in H2SO4 (15 mL) was added HNO3 (1.0 mL) dropwise over 5 minutes at 0 °C. After stirring for 30 minutes at room temperature, the reaction mixture was quenched with water (80 mL) at 0 °C and extracted with EA (100 mL x 2). The combined organic layers were washed with saturated sodium carbonate aqueous solution (100 mL x 2), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (20% EA) to afford 1-bromo-4-ethyl-2-nitrobenzene as an oil.

[0513] 1H NMR (400 MHz, Chloroform-d) 5 7.69 (d, J = 2.1 Hz, 1 H), 7.64 (d, J = 8.2 Hz, 1 H), 7.27 - 7.30 (m, 1 H), 2.72 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H).

[0514] Step 2: 1 -cyclopropyl-4-ethyl-2-nitrobenzene To a mixture of 1-bromo-4-ethyl-2- nitrobenzene (1.0 g, 4.35 mmol, 1.0 equiv.) and cyclopropylboronic acid (560 mg, 6.52 mmol, 1.50 equiv.) in toluene (15 mL) and H2O (1.5 mL) were added Pd(Oac)2 (100 mg, 0.445 mmol, 0.10 equiv.), Sphos (180 mg, 0.438 mmol, 0.10 equiv.) and K3PO4 (2.78 g, 13.1 mmol, 3.01 equiv.) at room temperature. After stirring for 4 hours at 100 °C under an atmosphere of nitrogen, the reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (20% EA) to give the product. The product was dissolved in ethyl acetate (30 mL) and treated with 3 g of SiliaMetS Thiol (Scavenger for removing Pd). After filtration, the filtrate was concentrated under reduced pressure to afford 1-cyclopropyl-4-ethyl-2-nitrobenzene as an oil.

[0515] 1H NMR (400 MHz, DMSO-d6) 5 7.68 (s, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1H), 2.65 (q, J = 7.6 Hz, 2H), 2.14 - 2.21 (m, 1 H), 1.18 (t, J = 7.5 Hz, 3H), 0.93 - 0.99 (m, 2H), 0.67 - 0.75 (m, 2H).

[0516] Step 3: 2-cyclopropyl-5-ethylaniline. To a stirred mixture of 1-cyclopropyl-4-ethyl-2- nitrobenzene (260 mg, 1.36 mmol, 1.0 equiv.) and B2(OH)4 (400 mg, 4.46 mmol, 3.28 equiv.) in DMF (5 mL) was added 4-(pyridin-4-yl)pyridine (22 mg, 0.141 mmol, 0.10 equiv.) in portions at 0 °C. After stirring for 5 minutes at room temperature, the reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (35% EA) to afford 2- cyclopropyl-5-ethylaniline as an oil.

[0517] LCMS (MS, ESI): 162 [M+H]+.

[0518] Step 4: 4-bromo-2-cyclopropyl-5-ethylaniline To a stirred solution of 2-cyclopropyl-5- ethylaniline (280 mg, 1.74 mmol, 1 .0 equiv.) in CAN (5.6 mL) was added NBS (155 mg, 0.871 mmol, 0.50 equiv.) at 0 °C. After stirring for 2 hours at room temperature, the reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (30% EA) to afford 4-bromo-2-cyclopropyl-5-ethylaniline as an oil.

[0519] LCMS (MS, ESI): 240, 242 [M+H]+.

[0520] 4-bromo-2-isopropyl-5-methylaniline

[0521] Step 1 : 4-methyl-2-nitro-1-(prop-1-en-2-yl)benzene. To a mixture of 1-bromo-4-methyl-2- nitrobenzene (5.0 g, 23.1 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1 ,3,2- dioxaborolane (5.0 g, 29.8 mmol, 1 .29 equiv.) and Pd(dppf)Ch (1.0 g, 1.23 mmol, 0.053 equiv.) in dioxane (76 mL) was added a solution of NaHCOa (3.0 g, 35.7 mmol, 1 .54 equiv.) in H2O (24 mL) at room temperature. The resulting mixture was stirred for 4 hours at 95 °C under an atmosphere of nitrogen. After cooling to room temperature, the reaction mixture was quenched with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (20% EA) to afford the product. The product was dissolved in EA (30 mL) and treated with 3 g of SiliaMetS Thiol (Scavenger for removing Pd). After filtration, the filtrate was concentrated under reduced pressure to afford 4-methyl-2-nitro-1-(prop-1-en-2-yl)benzene as an oil.

[0522] LCMS (MS, ESI): 178 [M+H]+.

[0523] Step 2: 2-isopropyl-5-methylaniline. To a stirred mixture of 4-methyl-2-nitro-1-(prop-1-en- 2-yl)benzene (1.5 g, 8.47 mmol, 1.0 equiv.) and Pd / C (750 mg, 0.705 mmol, 0.083 equiv., 10% purity) in MeOH (30 mL) was added TEA (2.4 mL, 17.3 mmol, 2.04 equiv.) at room temperature. After stirring for 16 hours at room temperature under an atmosphere of hydrogen (1 atm.), the resulting mixture was filtered through a pad of Celite. The filter cake was washed with MeOH (3 x 60 mL). The filtrate was concentrated under reduced pressure to afford the product. The product was dissolved in EA (30 mL) and treated with 2 g of SiliaMetS Thiol (Scavenger for removing Pd). The resulting mixture was stirred at room temperature for 30 minutes. After filtration, the filtrate was concentrated under reduced pressure to afford 2-isopropyl-5-methylaniline as an oil.

[0524] 1H NMR (400 MHz, DMSO-d6) 5 6.86 (d, J = 7.7 Hz, 1 H), 6.42 (s,1H), 6.34 (dd, J = 7.7, 1.8 Hz, 1 H), 4.70 (s, 2H), 2.86 - 2.96 (m, 1 H), 2.12 (s, 3H), 1.11 (d, J = 6.8 Hz, 6H). Step 3: 4-bromo-2-isopropyl-5-methylaniline To a solution of 2-isopropyl-5-methylaniline (650 mg, 4.36 mmol, 1 .0 equiv.) in DMF (8 mL) was added a solution of NBS (465 mg, 2.61 mmol, 0.60 equiv.) in DMF (5 mL) dropwise at 0 °C. After stirring for 2 hours at 0 °C, the resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (20 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (10% EA) to afford 4-bromo-2-isopropyl-5-methylaniline as an oil.

[0525] LCMS (MS, ESI): 228, 230 [M+H]+. 5-chloro-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-b]pyridine and 5-chloro-2- (tetrahydrofuran-3-yl)-2H-pyrazolo[4,3-b]pyridine

[0526] Step 1 : 5-chloro-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-b]pyridine and 5-chloro-2- (tetrahydrofuran-3-yl)-2H-pyrazolo[4,3-b]pyridine. To a solution of 5-chloro-1 / - / - pyrazolo[4,3-b]pyridine (2.0 g, 13.0 mmol, 1.0 equiv.) in DMF (20 mL) was added NaH (1.04 g, 26.0 mmol, 2.0 equiv., 60% purity) at 0°C. After stirring at 0°C for 30 min, to the reaction mixture was added oxolan-3-yl methanesulfonate (2.82 mL, 19.5 mmol, 1.5 equiv.) at 0 °C. After stirring at 65 °C for 2 h, the reaction mixture was quenched with H2O (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (32%) to give 5-chloro-1-(oxolan-3-yl)pyrazolo[4,3-b]pyridine as a solid and eluted with ethyl acetate in petroleum ether (40%) to give 5-chloro-2-(oxolan-3-yl)pyrazolo[4,3-b]pyridine as a solid.

[0527] 5-chloro-1-(oxolan-3-yl)pyrazolo[4,3-b]pyridine: LCMS (MS, ESI): 224, 226 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.27 - 8.34 (m, 2H), 7.50 (d, J = 9.2 Hz, 1H), 5.52 - 5.56 (m, 1 H), 4.04-4.14 (m, 2H), 3.85 - 3.94 (m, 2H), 2.42 - 2.48 (m, 1 H), 2.25 - 2.36 (m, 1 H).

[0528] 5-chloro-2-(oxolan-3-yl)pyrazolo[4,3-b]pyridine: LCMS (MS, ESI): 224, 226 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.72 (s, 1 H), 8.19 (d, J = 9.6 Hz, 1 H), 7.30 (d, J = 9.2 Hz, 1 H), 5.38 - 5.43 (m, 1 H), 4.02-4.12 (m, 3H), 3.85 - 3.91 (m, 1H), 2.51 - 2.57 (m, 1 H), 2.39 - 2.48 (m, 1 H).

[0529] 2-chloro-6-(tetrahydrofuran-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0530] 2-chloro-6-(tetrahydrofuran-3-yl)-5,6-dihydro-7 / - / -pyrrolo[3,4-b]pyridin-7-one. To a solution of methyl 3-(bromomethyl)-6-chloropyridine-2-carboxylate (1.0 g, 3.78 mmol, 1.0 equiv.) (synthesized by the procedure of Compound 186a at step 1) in EtOH (37 mL) was added oxolan-3-amine (1.30 mL, 15.1 mmol, 4.0 equiv.) and TEA (1.05 mL, 7.56 mmol, 2.0 equiv.). After stirring for 3 hours at 80 °C, the mixture was allowed to cool down to room temperature and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (100%) to afford 2-chloro-6-(oxolan-3-yl)-5 / - / -pyrrolo[3,4-b]pyridin-7-one as a solid.

[0531] LCMS (MS, ESI): 239, 241 [M+H]+.

[0532] 3-iodo-1-methyl-1 / - / -indazole-5-carbonitrile and 3-iodo-2-methyl-2 / - / -indazole-5- carbonitrile

[0533] Step 1 : 3-iodo-1 H-indazole-5-carbonitrile. To a stirred solution of 1 / - / -indazole-5- carbonitrile (500 mg, 3.49 mmol, 1 .0 equiv.) in DMF (10 mL) were added I2 (1 .77 g, 6.99 mmol, 2.0 equiv.) and KOH (734 mg, 13.1 mmol, 3.75 equiv.) at room temperature. After stirring for 3 h at room temperature, the reaction mixture was quenched with a saturated solution of sodium bisulfite in water (20 mL). The precipitated solids were collected by filtration and washed with water (3 x 20 mL) to give a crude product that was dried under vacuum to give 3-iodo-1 / - / -indazole-5-carbonitrile as a solid.

[0534] LCMS (MS, ESI): 270 [M+H]+

[0535] Step 2: 3-iodo-1-methyl-1 H-indazole-5-carbonitrile and 3-iodo-2-methyl-2H-indazole-5- carbonitrile. To a stirred solution of 3-iodo-1 H-indazole-5-carbonitrile (500 mg, 1.86 mmol, 1 .0 equiv.) and CS2CO3 (787 mg, 2.42 mmol, 1.3 equiv.) in CAN (5 mL) were added Mel (0.35 mL, 5.57 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred for 1 .5 h at 80°C. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (30%EA) to afford 3-iodo-1-methylindazole-5- carbonitrile (200 mg, 38%) as a solid and 3-iodo-2-methylindazole-5-carbonitrile as a solid.

[0536] 3-iodo-1-methylindazole-5-carbonitrile: LCMS (MS, ESI): 284 [M+H]+ 1H NMR (400 MHz, DMSO-de) 5 8.05 (d, J = 1.3 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.80 (dd, J = 8.8, 1 .5 Hz, 1H), 4.12 (s, 3H).

[0537] 3-iodo-2-methylindazole-5-carbonitrile: LCMS (MS, ESI): 284 [M+H]+ 1H NMR (400 MHz, DMSO-ofe) 5 8.09 (s, 1 H), 7.77 (d, J = 8.9 Hz, 1 H), 7.52 (dd, J = 8.9, 1 .6 Hz, 1 H), 4.24 (s, 3H).

[0538] Step 1 : N-(4-bromo-2-cyclopropyl-5-methylphenyl)-5-methylpyridin-2-amine. To a stirred mixture of 4-bromo-2-cyclopropyl-5-methylaniline (1.0 g, 4.42 mmol, 1 equiv.) (synthesized by the procedure of Intermediate A and 2-bromo-5-methylpyridine (910 mg, 5.31 mmol, 1.2 equiv.) in toluene (10 mL) were added BINAP (0.55 g, 0.88 mmol, 0.2 equiv.), Pd(Oac)2 (0.10 g, 0.44 mmol, 0.1 equiv.) and LiHMDS (1.48 g, 8.84 mmol, 2.0 equiv., 1 M in THF) in sequence at room temperature under an atmosphere of nitrogen. After stirring for 4 hours at 80°C, the reaction was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (18% EA) to afford N-(4-bromo-2-cyclopropyl-5-methylphenyl)pyridin-2-amine as a solid.

[0539] LCMS (MS, ESI): 317, 319 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.97 (s, 1 H), 7.93 (d, J = 2.4 Hz, 1H), 7.69 (s, 1 H), 7.38 (dd, J = 8.4, 2.5 Hz, 1 H), 7.06 (s, 1 H), 6.78 (d, J = 8.4 Hz, 1H), 2.21 (s, 3H), 2.16 (s, 3H), 1.96 - 1.89 (m, 1 H), 0.91 - 0.86 (m, 2H), 0.59 - 0.55 (m, 2H).

[0540] Step 2: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-(5-methylpyridin-2-yl)but-2- ynamide. To a stirred solution of A / -(4-bromo-2-cyclopropyl-5-methylphenyl)-5-methylpyridin- 2-amine (200 mg, 0.630 mmol, 1.0 equiv.) in THF (4 mL, 49.4 mmol, 78.3 equiv.) was added NaH (76 mg, 1.89 mmol, 3.0 equiv., 60% purity) dropwise at 0°C under N2 atmosphere. The resulting mixture was stirred for 0.5 h at 0°C under N2 atmosphere. Then to the above mixture was added but-2-ynoyl chloride (80 mL, 0.945mmol, 1 .5 equiv.) dropwise at 0°C.

[0541] The resulting mixture was stirred for additional 1.5 h at 0°C. The reaction was quenched with solid sodium sulfate at 0°C. The resulting mixture was diluted with EA. The resulting mixture was filtered, the filter cake was washed with EA (3x10 mL). The filtrate was concentrated under reduced pressure to give residue. The crude product was purified by Prep-HPLC with the following conditions (Column: XselectCSH Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: CAN; Flow rate: 60 mL / min mL / min; Gradient: 51 % B to 81 % B in 8 min; Wave Length: 254nm / 220nm nm; RT1 (min): 7.18). Lyophilization afforded A / -(4-bromo-2-cyclopropyl-5-methylphenyl)-A / -(5-methylpyridin-2- yl)but-2-ynamide as a solid. LCMS (MS, ESI): 383, 385 [M+H]+.1H NMR (300 MHz, DMSO-d6): 58.18 (s, 1H), 7.73-7.57 (m, 2H), 7.28 (s, 1H), 7.16 (s, 1H), 2.29 (s, 3H), 2.27 (s, 3H), 1.87- 1.76 (m, 4H), 0.95-0.81 (m, 1H), 0.75-0.57 (m, 3H).

[0542] The following compounds were prepared in a manner analogous to the procedures described above for A / -(4-bromo-2-cyclopropyl-5-methylphenyl)-A / -(5-methylpyridin-2-yl)but- 2-ynamide (Compound 203a):

[0543] • Compound 167a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-[1-(2- methoxyethyl)pyrazolo[4,3-b]pyridin-5-yl]pent-2-ynamide as a solid.

[0544] LCMS (MS, ESI): 481 , 483 [M+H]+.1H NMR (400 MHz, DMSO-d6) 58.24 (d, J = 8.8 Hz, 1H), 8.12-8.22 (m, 1H), 7.63-7.92 (m, 1H), 7.39 (s, 1H), 7.19(s, 1H), 4.60 (t, J=4.8 Hz, 2H), 3.74 (t, J= 4.8 Hz, 2H), 3.17 (s, 3H), 2.32 (s, 3H), 2.16 (q, J= 7.6 Hz, 2H), 1.83- 1.96 (m, 1H), 0.83- 1.02 (m, 1H), 0.78 (t, J= 7.6 Hz, 3H), 0.51 -0.71 (m, 3H).

[0545] • Compound 159a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-(2,3-dihydro-

[0546] [1 ,4]dioxino[2,3-b]pyridin-6-yl)pent-2-ynamide as a solid.

[0547] LCMS (MS, ESI): 441, 443 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 57.31 (d, J = 8.4 Hz, 1H), 7.26 (d, J= 8.4 Hz, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 4.31-4.36 (m, 2H), 4.19- 4.23 (m, 2H), 2.30 (s, 3H), 2.14 (q, J = 7.2 Hz, 2H), 1.78 - 1.96 (m, 1 H), 0.74 - 1.00 (m, 5H), 0.52-0.70 (m, 2H).

[0548] • Compound 134a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-{2H,3H-furo[2,3- b]pyridin-6-yl}pent-2-ynamide as a solid.

[0549] LCMS (MS, ESI): 425, 427 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 57.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.20 (d, J= 6.7 Hz, 2H), 7.14 (s, 1H), 4.53 (t, J= 8.6 Hz, 2H), 3.16-3.21 (m, 2H), 2.30 (s, 3H), 2.14 (q, J= 7.4 Hz, 2H), 1.80 - 1.87 (m, 1H), 0.80 - 0.85 (m, 5H), 0.60 -0.62 (m, 2H).

[0550] • Compound 126a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-(5-methyl- 2H,3H-furo[2,3-b]pyridin-6-ylpent-2-ynamide as a solid.

[0551] LCMS (MS, ESI): 439, 441 [M+H]+.

[0552] 1H NMR (400 MHz, DMSO-d6): 51H NMR (400 MHz, DMSO-d6) 57.56 (s, 1H), 7.00 -7.15 (m, 2H), 4.52 (t, J= 8.6 Hz, 2H), 3.19 (t, J= 8.5 Hz, 2H), 2.19-2.33 (m, 6H), 2.00- 2.14 (m, 3H), 0.84- 1.02 (m, 5H), 0.55-0.70 (m, 2H).

[0553] • Compound 79a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-[(7E)-7- (methoxyimino)-5H,6H-cyclopenta[b]pyridin-2-yl]but-2-ynamide as a solid.

[0554] LCMS (MS, ESI): 452, 454 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 57.83 (d, J = 8.3, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.17(s, 1H), 3.90 (s, 3H), 2.89-2.95 (m, 2H), 2.74 - 2.84 (m, 2H), 2.31 (s, 3H), 1.82 - 1.93 (m, 1 H), 1.80 (s, 3H), 0.74 - 0.87 (m, 2H), 0.63 -0.64 (m, 2H). • Compound 71a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-{3,6-dimethyl-7- oxo-5H-pyrrolo[3,4-b] pyridin-2-yl} but-2-ynamide as a solid.

[0555] LCMS (MS, ESI): 452, 454 [M+H]+. VT NMR (400 MHz, DMSO-d6) 5 7.98 (s, 1 H), 7.15 (s, 2H), 4.43 (s, 2H), 3.07 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 2.12 (s, 1H), 1.78 (s, 3H), 0.67 - 0.74 (m, 2H), 0.84 - 0.94 (m, 2H).

[0556] • Compound 52a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-(3,6-dimethyl-7- oxo-5H-pyrrolo[3,4-b] pyridin-2-ylpent-2-ynamide as a solid.

[0557] LCMS (MS, ESI): 466, 468 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.98 (s, 1H), 7.18 (s, 1 H), 7.15 (s, 1 H), 4.43 (s, 2H), 3.07 (s, 3H), 2.44 (s, 3H), 2.27 (s, 3H), 2.11 - 2.17 (m, 3H), 0.86 - 0.95 (m, 2H), 7.35 (t, J = 7.6 Hz, 3H), 0.70 - 0.71 (m, 2H).

[0558] • Compound 50a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-{3-cyano-1- methylpyrazolo[4,3-b]pyridin-5-yl}but-2-ynamide as a solid.

[0559] LCMS (MS, ESI): 448, 450 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 8.47 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1 H), 7.41 (s, 1 H), 7.24 (s, 1 H), 4.23 (s, 3H), 2.32 (s, 3H), 1.86 - 1 .91 (m, 1 H), 1 .85 (s, 3H), 0.45 - 1 .00 (m, 4H).

[0560] • Compound 40a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-(3-cyano-1- methylpyrazolo[4,3-b]pyridin-5-ylpent-2-ynamide as a solid.

[0561] LCMS (MS, ESI): 462, 464 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.39 (d, J = 9.2 Hz, 1 H), 7.88 (d, J = 9.2 Hz, 1 H), 7.37 (s, 1H), 7.22 (s, 1 H), 4.20 (s, 3H), 2.33 (s, 3H), 2.12 - 2.21 (m, 2H), 1.81 - 1.90 (m, 1 H), 0.74 - 0.88 (m, 5H), 0.56 - 0.66 (m, 2H).

[0562] • Compound 103a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-{7-hydroxy-7- methyl-5H,6H-cyclopenta[b]pyridin-2-yl}pent-2-ynamide as a solid.

[0563] LCMS (MS, ESI): 453, 455 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.66 (d, J = 8.4 Hz, 1 H), 7.40 - 7.44 (m, 1 H), 7.30 (s, 1 H), 7.14 (s, 1 H), 4.65 (s, 1 H), 2.85 - 2.91 (m, 1 H), 2.65 - 2.71 (m, 1 H) 2.30 (s, 3H), 2.03 - 2.15 (m, 4H), 1.90 - 2.00 (m, 1 H), 1.33 (s, 3H), 0.75 - 0.90 (m, 5H), 0.55 - 0.71 (m, 2H).

[0564] A / -(4-bromo-2-cyclopropyl-5-methylphenyl)-A / -{7-hydroxy-7-methyl-5 / - / ,6 / - / - cyclopenta[b]pyridin-2-yl}pent-2-ynamide (Compound 103a) (45 mg, 0.099 mmol, 1.0 equiv.) was separated by prep-chiral-HPLC with the following conditions (Column: CHIRALPAKIC3; Mobile Phase A: Hex: (IPA: DCM=1 : 1 )=70: 30; Flow rate: 1 mL / min; Gradient: isocratic). Lyophilization afforded ('R)-A / -(4-bromo-2-cyclopropyl-5-methylphenyl)-A / -(7-hydroxy-7- methyl-6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-yl)pent-2-ynamide (first fraction, stereochemistry not determined) and (S)-A / -(4-bromo-2-cyclopropyl-5-methylphenyl)-A / -(7- hydroxy-7-methyl-6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-yl)pent-2-ynamide (second fraction, stereochemistry not determined) as solids. • Compound 65a: (7?j-N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-(7-hydroxy-7- methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)pent-2-ynamide (first fraction, stereochemistry not determined): LCMS (MS, ESI): 453, 455 [M+H]+.1H NMR (400 MHz, DMSO-de) 57.71 (d, J= 8.0 Hz, 1H), 7.23-7.55 (m, 2H), 7.16 (s, 1H), 4.97 (br s, 1H), 2.83-2.97 (m, 1H), 2.63-2.76 (m, 1H), 2.30 (s, 3H), 2.11 -2.22 (m, 2H), 1.88-2.10 (m, 3H), 1.32 (s, 3H), 0.73-0.94 (m, 5H), 0.56-0.72 (m, 2H).

[0565] • Compound 64a: (S)-N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-(7-hydroxy-7- methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)pent-2-ynamide (second fraction, stereochemistry not determined): LCMS (MS, ESI): 453, 455 [M+H]+.1H NMR (400 MHz, DMSO-d6) 57.71 (d, J = 8.0 Hz, 1 H), 7.26 - 7.59 (m, 2H), 7.16 (s, 1H), 4.97 (brs, 1H), 2.84-2.98 (m, 1H), 2.63-2.77 (m, 1H), 2.30 (s, 3H), 2.10- 2.21 (m, 2H), 1.86-2.10 (m, 3H), 1.32 (s, 3H), 0.73- 1.02 (m, 5H), 0.53-0.71 (m, 2H).

[0566] • Compound 160a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-[2- (methoxymethyl)-2H,3H-[1 ,4]dioxino[2,3-b]pyridin-6-yl]but-2-ynamide as a solid. HNMR indicated that it contained 22% of A / -(4-bromo-2-cyclopropyl-5-methylphenyl)- A / -(3-(methoxymethyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-6-yl)but-2-ynamide. LCMS (MS, ESI): 471 , 473 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 57.34 - 7.38

[0567] (m, 1H), 7.22-7.27 (m, 1H), 7.15 (s, 1H), 4.44-4.49 (m, 0.78H), 4.38-4.42 (0.22H), 4.29 -4.37 (m, 1H), 4.29-4.30 (m, 1H), 4.11 -4.15 (m, 0.22H), 3.97-4.01 (m, 0.78H), 3.54- 3.62 (m, 2H), 3.31 (s, 0.73H), 3.30 (s, 2.27H), 2.29 - 2.32 (m, 3H), 1.82 - 1.88 (m, 1 H), 1.79 (s, 3H), 0.79 - 0.85 (m, 2H), 0.59 - 0.64 (m, 2H).

[0568] • Compound 109a. N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-((5aS,8aS)- 5a,6,8,8a-tetrahydrofuro [3’,4’:5,6] [1,4] dioxino[2,3-b] pyridin-2-yl) pent-2 - ynamide as a solid.

[0569] LCMS (MS, ESI): 483, 485 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 57.49 (d, J = 8.4 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.24 (s, 1H), 7.16(s, 1 H), 4.50 - 4.55 (m, 1H), 4.40- 4.46 (m, 1H), 4.14-4.19 (m, 2H), 3.68-3.75 (m, 2H), 2.31 (s, 3H), 2.11 -2.15 (m, 2H), 1.81 -1.84 (m, 1 H), 0.81 - 0.85 (m, 5H), 0.60 - 0.62 (m, 2H).

[0570] • Compound 99a. N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-{3,6-dimethyl-5- oxo-7H-pyrrolo[3,4-b]pyridin-2-yl}pent-2-ynamide as a solid.

[0571] LCMS (MS, ESI): 466, 468 [M+H]+.1H NMR (400 MHz, DMSO-d6) 57.73 (s, 1 H), 7.34 (s, 1H), 7.21 (s, 1H), 4.31 (s, 2H), 3.01 (s, 3H), 2.63 (s, 3H), 2.31 (s, 3H), 2.18 (q, J = 7.5 Hz, 2H), 1.72- 1.75 (m, 1 H), 0.83 - 0.95 (m, 1 H), 0.78 (t, J = 7.4 Hz, 3H), 0.50 - 0.71 (m, 3H). Example 3. Synthesis of Compound 108a: N-(2-cvclopropyl-4-iodo-5-methylphenyl)-N-(2-

[0572] Step 1 : / V-(3-amino-6-bromopyridin-2-yl)-2-methoxyacetamide. To a solution of 6- bromopyridine-2,3-diamine (2.00 g, 10.6 mmol, 1.0 equiv.) in DCM (53 mL) was added TEA (2.96 mL, 21 .3 mmol, 2.0 equiv.) and methoxyacetyl chloride (0.9 mL, 10.6 mmol, 1 .0 equiv.) at 0 °C. After stirring at RT for 1 h, the reaction was quenched with water (100 mL) and extracted with methanol in dichloromethane (10%, 100 mL x 3). The combined organic layers were washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (49%) to afford the product. After filtration, the filtrate was concentrated under reduced pressure to afford A / -(3-amino-6-bromopyridin-2-yl)-2- methoxyacetamide as a solid.

[0573] LCMS (MS, ESI): 260, 262 [M+H]+.

[0574] Step 2: 5-bromo-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine. To a solution of N- 3- amino-6-bromopyridin-2-yl)-2-methoxyacetamide (1 .65 g, 6.34 mmol, 1.0 equiv.) in DMF (63 mL) was added CsF (9.15 g, 60.3 mmol, 9.5 equiv.). After stirring at 130 °C for 16 h, the reaction mixture was cooled to RT, quenched with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with water (120 mL) and brine (120 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (49%) to afford 5-bromo-2-(methoxymethyl)-1 / - / -imidazo[4,5-b] pyridine as a solid.

[0575] LCMS (MS, ESI): 242, 244 [M+H]+.

[0576] Step 3: tert-butyl 5-bromo-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-1- carboxylate. To a solution of 5-bromo-2-(methoxymethyl)-1 / - / -imidazo[4,5-b] pyridine (450 mg, 1 .86 mmol, 1 .0 equiv.) in DCM (18 mL) was added DEA (720 mg, 5.58 mmol, 3.0 equiv.), BOC2O (608 mg, 2.79 mmol, 1.5 equiv.) and DMAP (23 mg, 0.186 mmol, 0.1 equiv.) at 0 °C. After stirring at RT for 1 h, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL), brine (60 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (21%) to afford tert-butyl 5-bromo-2-(methoxymethyl) imidazo[4,5-b] pyridine-1- carboxylate as a solid.

[0577] LCMS (MS, ESI): 342, 344 [M+H]+.

[0578] Step 4: tert-butyl 5-((2-cyclopropyl-4-iodo-5-methylphenyl)amino)-2-(methoxymethyl)- 1 H-imidazo[4,5-b]pyridine-1 -carboxylate. A mixture of tert-butyl 5-bromo-2- (methoxymethyl) imidazo[4,5-b] pyridine-1-carboxylate (390 mg, 1.14 mmol, 1.0 equiv.), 2- cyclopropyl-4-iodo-5-methylaniline (342 mg, 1.25 mmol, 1.1 equiv.), Pd2(dba)3 (104 mg, 0.114 mmol, 0.1 equiv.), DTBPF (108 mg, 0.228 mmol, 0.2 equiv.) and CS2CO3 (928 mg, 2.85 mmol, 2.5 equiv.) in dioxane (11 mL) was degassed and backfilled with nitrogen for five times. After stirring at 70 °C for 2 h under an atmosphere of nitrogen, the reaction mixture was cooled to RT and filtered through a pad of Celite. The filter cake was washed with EA (11 mL x 3). The filtrate was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (41%) to afford the product. The product was dissolved in ethyl acetate (30 mL) and treated with 500 mg of SiliaMetS Thiol (Scavenger for removing Pd). After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 5-[(2-cyclopropyl-4-iodo-5-methylphenyl) amino]-2- (methoxymethyl) imidazo[4,5-b] pyridine-1-carboxylate as a solid.

[0579] LCMS (MS, ESI): 535 [M+H]+.

[0580] Step 5: tert-butyl 5-(N-(2-cyclopropyl-4-iodo-5-methylphenyl)but-2-ynamido)-2- (methoxymethyl)-1H-imidazo[4,5-b]pyridine-1 -carboxylate. To a solution of tert-butyl 5- [(2-cyclopropyl-4-iodo-5-methylphenyl) amino]-2-(methoxymethyl) imidazo[4,5-b] pyridine-1 - carboxylate (100 mg, 0.187 mmol, 1.0 equiv.) in THF (0.6 mL) was added LiHMDS (0.56 mL, 0.560 mmol, 3.0 equiv., 1 M in THF) at -70 °C under an atmosphere of nitrogen. After stirring for 30 min at -70 °C, to the above mixture was added but-2-ynoyl chloride (17 mg, 0.561 mmol, 3.0 equiv.) dropwise. The resulting mixture was stirred for additional 1 h at -70 °C, quenched with aqueous saturated NH4CI (1 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic layers were washed with water (2 mL), brine (2 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (35%) to afford tert-butyl 5-[W- (2-cyclopropyl-4-iodo-5-methylphenyl) but-2-ynamido]-2-(methoxymethyl) imidazo[4,5-b] pyridine-1 -carboxylate (100 mg, 89%) as a solid.

[0581] LCMS (MS, ESI): 601 [M+H]+.

[0582] Step 6: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(2-(methoxymethyl)-1 H- imidazo[4,5-b]pyridin-5-yl)but-2-ynamide. To a solution of tert-butyl 5-[A / -(2-cyclopropyl-4- iodo-5-methylphenyl) but-2-ynamido]-2-(methoxymethyl) imidazo[4,5-b] pyridine-1 - carboxylate (100 mg, 0.167 mmol, 1 .0 equiv.) in DCM (2 mL) was added TFA (0.4 mL) at 0 °C. The resulting mixture was stirred for 1 .5 h at room temperature, quenched with saturated sodium bicarbonate aqueous solution (4 mL) and extracted with ethyl acetate (4 mL x 3). The combined organic layers were washed with water (4 mL), brine (4 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC with the following conditions (Column: XselectCSH Prep OBD C-is Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CAN; Flow rate: 60 mL / min; Gradient: 40% B to 55% B in 8 min; Wave Length: 254nm / 220nm; RT1 (min): 7.27). Lyophilization afforded to afford A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -[2-(methoxymethyl)-1 / - / -imidazo[4,5-b] pyridin-5-yl] but-2-ynamide as a solid.

[0583] LCMS (MS, ESI): 501 [M+H]+.1H VT-NMR (400 MHz, DMSO-rt6) 5 12.71 (br s, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 (s, 1 H), 7.25 (s, 1 H), 4.59 (s, 2H), 3.37 (s, 3H), 2.33 (s, 3H), 1.87 - 1 .94 (m, 1 H), 1.77 (s, 3H), 0.78 - 0.83 (m, 2H), 0.56 - 0.60 (m, 2H).

[0584] The following compounds were prepared in a manner analogous to the procedures described above for A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -(2-(methoxymethyl)-1 / - / - imidazo[4,5-b]pyridin-5-yl)but-2-ynamide (Compound 108a):

[0585] • Compound 47a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[2-(oxetan-2-yl)-1H- imidazo[4,5-b]pyridin-5-yl]but-2-ynamide as a solid.

[0586] LCMS (MS, ESI): 513 [M+H]+.1H NMR (400 MHz, DMSO-rt6) 5 13.42 (br s, 1H), 8.06 (s, 1 H), 7.53 - 7.72 (m, 1 H), 7.40 (s, 1 H), 7.29 (s, 1 H), 5.68 - 5.95 (s, 1 H), 4.70 (t, J = 7.6 Hz, 2H), 2.88 - 3.10 (m, 2H), 2.32 (s, 3H), 1.81 - 1.94 (m, 4H), 0.82 - 0.97 (m, 1H), 0.55 - 0.74 (m, 3H).

[0587] • Compound 46a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[2-(oxolan-2-yl)-1H- imidazo[4,5-b]pyridin-5-yl]but-2-ynamide as a solid.

[0588] LCMS (MS, ESI): 527 [M+H]+.1H VT-NMR (400 MHz, DMSO-rt6) 5 12.69 (br s, 1 H), 7.93 (d, J = 8.5 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 (s, 1 H), 7.25 (s, 1 H), 5.05 (t, J = 6.8 Hz, 1H), 3.94 - 3.99 (m, 1H), 3.84 (q, J = 7.2 Hz, 1 H), 2.23 - 2.33 (m, 4H), 2.14 - 2.23 (m, 1 H), 1 .84 - 2.03 (m, 3H), 1 .78 (s, 3H), 0.77 - 0.84 (m, 2H), 0.57 - 0.63 (m, 2H).

[0589] Step 1 : / V-(2,5-dimethyl-4-((trimethylsilyl)ethynyl)phenyl)-2,3-dihydro-[1 ,4]dioxino[2,3- b]pyridin-6-amine. To a mixture of A / -(4-iodo-2,5-dimethylphenyl)-2 / - / ,3 / - / -[1 ,4]dioxino[2,3- b]pyridin-6-amine (180 mg, 0.471 mmol, 1.0 equiv.), Pd(PPh3)2Cl2 (34 mg, 0.047 mmol, 0.1 equiv.), Cui (18 mg, 0.094 mmol, 0.2 equiv.) in dioxane (4 mL) was added trimethylsilylacetylene (70 mg, 0.706 mmol, 1.5 equiv.) and TEA (0.20 mL, 1.41 mmol, 3.0 equiv.). The reaction mixture was degassed and backfilled with nitrogen for five times. After stirring at 110 °C for 2 h under an atmosphere of nitrogen, the reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filter cake was washed with EA (20 mL x 3). The filtrate was washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (16 %) to afford the product. The product was dissolved in ethyl acetate (30 mL) and treated with 320 mg of SiliaMetS Thiol (Scavenger for removing Pd). After filtration, the filtrate was concentrated under reduced pressure A / -(2,5-dimethyl-4-[2-(trimethylsilyl)ethynyl]phenyl-2 / - / ,3 / - / -[1 ,4]dioxino[2,3- b]pyridin-6-amine as a solid.

[0590] LCMS (MS, ESI): 353 [M+H]+.

[0591] Step 2: N-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-N-(2,5-dimethyl-4- ((trimethylsilyl)ethynyl)phenyl)but-2-ynamide. To a solution of A / -(4-iodo-2,5- dimethylphenyl)-2 / - / ,3 / - / -[1 ,4]dioxino[2,3-b]pyridin-6-amine (130 mg, 0.340 mmol, 1.0 equiv.) in THF (3 mL) was added LiHMDS (0.74 mL, 0.738 mmol, 2.0 equiv., 1 M in THF) at - 78 °C under an atmosphere of nitrogen. After stirring for 30 min at -70 °C, to the above mixture was added but-2-ynoyl chloride (114 mg, 1.11 mmol, 3.0 equiv.) dropwise. The resulting mixture was stirred for additional 2 h at -70 °C, quenched with aqueous saturated NH4CI (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash column chromatography, eluted with ethyl acetate in petroleum ether (23%) to afford A / -(2,5-dimethyl-4-[2-(trimethylsilyl)ethynyl]phenyl- A / -(2 / - / ,3 / - / -[1 ,4]dioxino[2,3-b]pyridin-6-ylbut-2-ynamide as an oil.

[0592] LCMS (MS, ESI): 419 [M+H]+.

[0593] Step 3: N-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-N-(4-ethynyl-2,5- dimethylphenyl)but-2-ynamide. To a solution of A / -(2,5-dimethyl-4-[2- (trimethylsilyl)ethynyl]phenyl-A / -(2 / - / ,3 / - / -[1 ,4]dioxino[2,3-b]pyridin-6-ylbut-2-ynamide (150 mg, 0.358 mmol, 1 equiv.) in THF (5 mL) was added TBAF (0.54 mL, 0.540 mmol, 1.5 equiv., 1 M in THF) at 0°C. After stirring at 0 °C for 10 min, the reaction was quenched with water (10 mL) at 0 °C and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purification by prep-HPLC with following conditions (Column: XselectCSH Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CAN; Flow rate: 60 mL / min; Gradient: 39% B to 69% B in 8 min; Wave Length: 254nm / 220nm; RT1 (min): 7.15). Lyophilization gave N- ,4]dioxino[2,3-b]pyridin-6-yl-A / -(4-ethynyl-2,5-dimethylphenyl)but-2-ynamide.

[0594] LCMS (MS, ESI): 347 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.37 - 7.43 (m, 2H), 7.22 - 7.32 (m, 1 H), 7.10 - 7.20 (m, 1 H), 4.42 (s, 1 H), 4.32 - 4.38 (m, 2H), 4.20 - 4.27 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.82 (s, 3H).

[0595] The following compounds were prepared in a manner analogous to the procedures described above for A / -(2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-6-yl)-A / -(4-ethynyl-2,5- dimethylphenyl)but-2-ynamide (Compound 200a):

[0596] • Compound 190a: N-(2-cyclopropyl-4-ethynyl-5-methylphenyl)-N-{1- methylpyrazolo[4,3-b]pyridin-5-yl}but-2-ynamide as a solid.

[0597] LCMS (MS, ESI): 369 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.09 (d, J = 9.0, 1 H), 8.02 (s, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 7.17 (s, 1 H), 6.97 (s, 1H), 4.15 (s, 1 H), 3.99 (s, 3H), 2.27 (s, 3H), 1 .75 - 1.80 (m, 1 H), 1 .70 (s, 3H), 0.60 - 0.80 (m, 2H), 0.50 - 0.51 (m, 2H).

[0598] • Compound 122a: N-(5-cyclopropyl-4-ethynyl-2-methylphenyl)-N-{2H,3H-[1,4] dioxino [2,3-5] pyridin-6-yl}but-2-ynamide as a solid.

[0599] LCMS (MS, ESI): 373 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.31 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1 H), 7.14 (s, 1 H), 7.02 (s, 1 H), 4.33 - 4.34 (m, 2H), 4.20 - 4.21 (m, 2H), 4.14 - 4.15 (m, 1 H), 2.33 (s, 3H), 1.80 - 1.87 (m, 1 H), 1.77 (s, 3H), 0.77 - 0.81 (m, 2H), 0.59 - 0.60 (m, 2H). • Compound 66a: N-(2-cyclopropyl-4-ethynyl-5-methylphenyl)-N-{6-methyl-7-oxo- 5H-pyrrolo[3,4-b]pyridin-2-yl}but-2-ynamide as a solid.

[0600] LCMS (MS, ESI): 384 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 5 8.06 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2, 1H), 7.23 (s, 1 H), 7.07 (s, 1 H), 4.44 (s, 2H), 4.17 (s, 1H), 3.08 (s, 3H), 2.35 (s, 3H), 1 .78 - 1.81 (m, 4H), 0.76 - 0.78 (m, 2H), 0.58 - 0.59 (m, 2H).

[0601] Example 5. Synthesis of Compound 202a: N-(4-bromo-2,5-dimethylphenyl)-N-(6, 7-dihydro- 5H-cyclopentafb]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propiolamide.

[0602] N-(4-bromo-2,5-dimethylphenyl)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3- (tetrahydro-2H-pyran-4-yl)propiolamide. To a solution of DCC (120 mg, 0.568 mmol, 2.5 equiv.) in DCM (2 mL) was added 3-(oxan-4-yl) prop-2-ynoic acid (70 mg, 0.454 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C under nitrogen atmosphere followed by the addition of A / -(4-bromo-2,5-dimethylphenyl)-5 / - / ,6 / - / ,7 / - / - cyclopenta[b]pyridin-2-amine (72 mg, 0.227 mmol, 1.0 equiv.) at 0°C. After stirring for additional 1.5 hours at 0 °C and 24 hours at room temperature, the reaction mixture was quenched by the addition of water (10 mL) at 0 °C and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions (Column: XselectCSH Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (H2O), Mobile Phase B: CAN; Flow rate: 60 mL / min mL / min; Gradient: isocratic Wave Length: 254 nm / 220 nm). Lyophilization afforded A / -(4-bromo-2,5-dimethylphenyl)-A / -{5 / - / ,6 / - / ,7 / - / -cyclopenta[b]pyridin-2-yl}-3-(oxan-4- yl) prop-2-ynamide as a solid.

[0603] LCMS (MS, ESI): 453, 455 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.70 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.33 - 7.50 (m, 2H), 3.32 - 3.35 (m, 4H), 2.74 - 2.89 (m, 5H), 2.30 (s, 3H), 2.19 (s, 3H), 2.01 - 2.05 (m, 2H), 1.55-1.57 (m, 2H), 1.19-1.24 (m, 2H).

[0604] Step 1 : 2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. To a solution of 2- chloro-6,7-dihydro-5 / - / -pyrrolo[3,4-b]pyridin-5-one (300 mg, 1.64 mmol, 1.0 equiv.) in DMF (6 mL) were added CS2CO3 (1.07 g, 3.28 mmol, 2.0 equiv.) and iodomethane (280 mg, 1.97 mmol, 1 .20 equiv.) in sequence. After stirring for 2 hours at room temperature under an atmosphere of nitrogen, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with water (15 mL x 1 ) and brine (15 mL x 1), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (ethyl acetate) to afford 2-chloro-6-methyl-7 / - / -pyrrolo[3,4-b]pyridin-5-one as an oil.

[0605] LCMS (MS, ESI): 183, 185 [M+H]+.

[0606] Step 2: 2-((4-bromo-2,5-dimethylphenyl)amino)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one. To a mixture of 2-chloro-6-methyl-7 / - / -pyrrolo[3,4-b]pyridin-5-one (150 mg, 0.821 mmol, 1.0 equiv.) and 4-bromo-2,5-dimethylaniline (197 mg, 0.985 mmol, 1.2 equiv.) in DMF (3 mL) were added Pd(OAc)2 (55 mg, 0.246 mmol, 0.3 equiv.) , Xantphos (143 mg, 0.247 mmol, 0.3 equiv.) and CS2CO3 (188 mg, 2.46 mmol, 3.0 equiv.) at room temperature under an atmosphere of nitrogen. After stirring for 2 hours at 65 °C, the mixture was allowed to cool down to room temperature, quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with water (10 mL x 1 ) and brine (10 mL x 1), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (C 18 column; 40-60A; mobile phase, CAN in Water, acetonitrile / water, 5%-100% in 30 minutes, 40%) to afford the product. The product was dissolved in EA (30 mL) and treated with 500 mg of SiliaMetS Thiol (Scavenger for removing Pd). After filtration, the filtrate was concentrated under reduced pressure to afford 2-[(4-bromo-2,5- dimethylphenyl)amino]-6-methyl-7 / - / -pyrrolo[3,4-b]pyridin-5-one (88 mg, 28%) as a solid.

[0607] LCMS (MS, ESI): 346, 348 [M+H]+.

[0608] Step 3: N-(4-bromo-2,5-dimethylphenyl)-N-(6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-2-yl)but-2-ynamide. To a mixture of 2-[(4-bromo-2,5-dimethylphenyl)amino]-6- methyl-7H-pyrrolo[3,4-b]pyridin-5-one (50 mg, 0.144 mmol, 1.0 equiv.) in THF (1 mL) was added NaH (23 mg, 0.575 mmol, 3.98 equiv., 60% purity) in portions at 0 °C. After stirring at 0 °C for 30 minutes, but-2-ynoyl chloride (16 pL, 0.176 mmol, 1.22 equiv.) was added dropwise. The resulting mixture was stirred for 2 hours at room temperature, quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (10 mL x 1 ) and brine (10 mL x 1), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions (Column: XselectCSH Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CAN; Flow rate: 60 mL / min; Gradient: 41 % B to 56% B in 8 min; Wave Length: 254nm / 220nm;

[0609] RT1 (min): 6.87). Lyophilization afforded A / -(4-bromo-2,5-dimethylphenyl)-A / -{6-methyl-5-oxo- 7 / - / -pyrrolo[3,4-b]pyridin-2-yl}but-2-ynamide as a solid.

[0610] LCMS (MS, ESI): 412, 414 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 8.15 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1 H), 7.61 (s, 1 H), 7.32 (s, 1H), 4.40 (s, 2H), 3.04 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H), 1.84 (s, 3H).

[0611] The following compound was prepared in a manner analogous to the procedures described above for A / -(4-bromo-2,5-dimethylphenyl)-A / -{6-methyl-5-oxo-7 / - / -pyrrolo[3,4- b]pyridin-2-yl}but-2-ynamide (Compound 201a):

[0612] • Compound 189a: N-(4-bromo-2,5-dimethylphenyl)-N-(5,7-dihydrofuro[3,4- b]pyridin-2-yl)but-2-ynamide as a solid.

[0613] LCMS (MS, ESI): 385, 387 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.85 (d, J = 8.0 Hz, 1H), 7.54 - 7.66 (m, 2H), 7.27 (s, 1 H), 5.06 (s, 2H), 4.82 (s, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 1.84 (s, 3H).

[0614] Step 1 : / V-(2-cyclopropyl-4-iodo-5-methylphenyl)-3,5-dimethylpyridin-2-amine A mixture of 2-cyclopropyl-4-iodo-5-methylaniline (300 mg, 1.10 mmol, 1.0 equiv.) and 2- bromo-3,5-dimethylpyridine (185 mg, 0.994 mmol, 0.91 equiv.) in KHMDS (1.8 mL, 1.800 mmol, 1 .60 equiv., 1M in THF) was stirred for 2 hours at 60 °C under an atmosphere of nitrogen. After cooling to room temperature, the resulting mixture was filtered through a pad of Celite. The filter cake was washed with THF (2 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA, 3:1 ) to afford N-(2- cyclopropyl-4-iodo-5-methylphenyl)-3,5-dimethylpyridin-2-amine as an oil.

[0615] LCMS (MS, ESI): 379 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.99 (s, 1H), 7.85 (s, 1 H), 7.39 (s, 1 H), 7.32 (s, 1 H), 7.18 (s, 1 H), 2.30 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 1.81 - 1 .88 (m, 1 H), 0.83 - 0.90 (m, 2H), 0.55 - 0.59 (m, 2H).

[0616] Step 2: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(3,5-dimethylpyridin-2-yl)but-2- ynamide. A solution of A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-3,5-dimethylpyridin-2-amine (100 mg, 0.264 mmol, 1 .0 equiv.) in THF (2 mL) was treated with NaH (30 mg, 0.75 mmol, 2.84 equiv., 60% purity) for 30 minutes at 0°C under an atmosphere of nitrogen followed by the addition of but-2-ynoyl chloride (0.06 mL, 0.528 mmol, 2 equiv.) dropwise at 0°C. After stirring for additional 2 hours at room temperature, the reaction mixture was quenched with Na2SO4' 10 H2O at 0°C. The solid was filtered off. The filter cake was washed by EA (50 mL). The combined filtrate was concentrated under reduced pressure to give a crude product.

[0617] The crude product was purified by prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: CAN; Flow rate: 60 mL / min; Gradient: 61% B to 91 % B in 10 min; Wave Length: 254nm I 220nm; RT1 (min): 8.18). Lyophilization afforded A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / - (3,5-dimethylpyridin-2-yl) but-2-ynamide as a solid.

[0618] LCMS (MS, ESI): 445 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.03 - 8.18 (m, 1 H), 7.58 - 7.64 (m, 1 H), 7.31 -7.37 (m, 1 H), 7.13 - 7.15 (m, 0.5H), 6.93 (s, 0.5H), 2.22 - 2.33 (m, 9H), 1 .95 - 2.04 (m, 1 H), 1 .79 - 1 .83 (m, 3H), 0.85 - 1.05 (m, 2H), 0.55 - 0.83 (m, 2H).

[0619] The following compounds were prepared in a manner analogous to the procedures described above for A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -(3,5-dimethylpyridin-2-yl)but- 2-ynamide (Compound 199a):

[0620] • Compound 193a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(3-methoxy-5- methylpyridin-2-yl)but-2-ynamide as a solid.

[0621] LCMS (MS, ESI): 461 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.83 (s, 1H), 7.41 (s, 1 H), 7.29 (s, 1 H), 7.13 (s, 1 H), 3.86 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.12 - 2.24 (m, 1 H), 1 .76 (s, 3H), 0.81 - 0.88 (m, 2H), 0.59 - 0.64 (m, 2H).

[0622] • Compound 187a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{7-fluoro-2H,3H- [1 ,4]dioxino[2,3-b]pyridin-6-yl}but-2-ynamide as a solid.

[0623] LCMS (MS, ESI): 493 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 5 7.42 (d, J = 9.4 Hz, 1H), 7.37 (s, 1H), 7.15 (s, 1 H), 4.25 - 4.37 (m, 4H), 2.32 (s, 3H), 1.94 - 2.00 (m, 1 H), 1 .81 (s, 3H), 0.82 - 0.86 (m, 2H), 0.60 - 0.63 (m, 2H).19F NMR (400 MHz, DMSO-d6): - 128.38, -130.93. • Compound 180a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{1,2- dimethylimidazo[4,5-b]pyridin-5-yl}but-2-ynamide as a solid.

[0624] LCMS (MS, ESI): 485 [M+H]+. 1 H VT_NMR (400 MHz, DMSO-d6): 57.91 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.24 (s, 1H), 3.74 (s, 3H), 2.53 (s, 3H), 2.33 (s, 3H), 1.90 - 1.97 (m, 1 H), 1.75 (s, 3H), 0.78 - 0.84 (m, 2H), 0.57 - 0.61 (m, 2H).

[0625] • Compound 173a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[6-(2- methoxyethoxy)-3-methylpyridin-2-yl]but-2-ynamide as a solid.

[0626] LCMS (MS, ESI): 505 [M+H]+.1H NMR (400 MHz, DMSO-d6) 57.64 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.11 (s, 1H), 6.69 (d, J =8.4 Hz, 1H), 4.20 (t, J = 4.8 Hz, 2H), 3.48 (t, J = 5.1 Hz, 2H), 3.20 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H), 2.06-2.17 (m, 1H), 1.76-1.81 (m, 3H), 0.80 - 1.0 (m, 2H), 0.60 - 0.75 (m, 2H).

[0627] • Compound 155a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[3-methyl-5- (oxetan-3-yloxy)pyridin-2-yl]but-2-ynamide as a solid.

[0628] LCMS (MS, ESI): 503 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 57.73 - 7.94 (m, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 6.96-7.15 (m, 1H), 5.30-5.36 (m, 1H), 4.91 (t, J= 6.6 Hz, 2H), 4.53-4.56 (m, 2H), 2.21 -2.38 (m, 6H), 1.98-2.12 (m, 1H), 1.78 (s, 3H), 0.77-0.98 (m, 2H), 0.58-0.70 (m, 2H).

[0629] • Compound 151a: N-(5-cyano-1-methylindazol-3-yl)-N-(2-cyclopropyl-4-iodo-5- methylphenyl)but-2-ynamide as a solid.

[0630] LCMS (MS, ESI): 495 [M+H]+.1H NMR (400 MHz, DMSO-d6) 58.26 (s, 1H), 7.68 - 7.80 (m, 2H), 7.34 - 7.48 (m, 2H), 3.99 (s, 3H), 2.34 (s, 3H), 1.92 - 2.06 (m, 1 H), 1.76 (s, 3H), 0.73 - 0.95 (m, 2H), 0.54 - 0.70 (m, 2H).

[0631] • Compound 177a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(3,5- dimethylpyridin-2-yl)-5-methoxypent-2-ynamide as a solid.

[0632] LCMS (MS, ESI): 489 [M+H]+. 1H VT-NMR (400 MHz, DMSO-d6) 58.07 (s, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.10 (s, 1H), 3.14-3.15 (m, 2H), 3.13 (s, 3H), 2.38 (t, J= 6.4 Hz, 2H), 2.29-2.30 (m, 6H), 2.26 (s, 3H), 2.00-2.10 (m, 1H), 0.74-0.98 (m, 2H), 0.66-0.67 (m, 2H).

[0633] • Compound 149a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(3-methoxy-5- methylpyridin-2-yl)pent-2-ynamide as a solid.

[0634] LCMS (MS, ESI): 475 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 57.83 (s, 1H), 7.41 (s, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 3.86 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 2.16 - 2.24 (m, 1H), 2.12 (q, J = 7.5 Hz, 2H), 0.81 -0.85 (m, 5H), 0.57-0.61 (m, 2H).

[0635] • Compound 148a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(3-methoxy-5- methylpyridin-2-yl)-3-(oxan-4-yl)prop-2-ynamide as a solid. LCMS (MS, ESI): 531 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.84 (s, 1 H), 7.42 (s, 1H), 7.30 (s, 1 H), 7.20 (s, 1 H), 3.86 (s, 3H), 3.30 - 3.44 (m, 4H), 2.66 - 2.71 (m, 1 H), 2.29 - 2.31 (m, 6H), 2.15 - 2.25 (m, 1 H), 1.50 - 1.55 (m, 2H), 1.16 - 1.26 (m, 2H), 0.75 - 0.94 (m, 2H), 0.61 - 0.62 (m, 2H).

[0636] Step 1 : N-(4-bromo-2-cyclopropyl-5-methylphenyl)-1 -methyl-1 ,4,5,6- tetrahydrocyclopenta[c]pyrazol-3-amine. To a stirred mixture of 3-iodo-1-methyl- 4 / - / ,5 / - / ,6 / - / -cyclopenta[c]pyrazole (140 mg, 0.564 mmol, 1.0 equiv.) and 4-bromo-2- cyclopropyl-5-methylaniline (191 mg, 0.846 mmol, 1.5 equiv.) (synthesized by the procedure of Intermediate A in toluene (3 mL) were added t-BuONa (162 mg, 1 .69 mmol, 3.0 equiv.), Pd2(dba)3 (22 mg, 0.024 mmol, 0.3 equiv.) and Xantphos (97 mg, 0.169 mmol, 0.3 equiv.). After stirring for 0.5 hours at 80°C under an atmosphere of nitrogen, the reaction mixture was cooled to RT, quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (15% EA) to give the product. The product was dissolved in EA (30 mL) and treated with 300 mg of SiliaMetS Thiol (Scavenger For removing Pd). After filtration, the filtrate was concentrated under reduced pressure to give A / -(4-bromo-2-cyclopropyl-5-methylphenyl)-1-methyl-4 / - / ,5 / - / ,6 / - / - cyclopenta[c]pyrazol-3-amine as a solid.

[0637] LCMS (MS, ESI): 346, 348 [M+H]+.

[0638] Step 2: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-1 -methyl-1 ,4,5,6- tetrahydrocyclopenta[c]pyrazol-3-amine. To a stirred mixture of A / -(4-bromo-2- cyclopropyl-5-methylphenyl)-1-methyl-4 / - / ,5 / - / ,6 / - / -cyclopenta[c]pyrazol-3-amine (100 mg, 0.289 mmol, 1.0 equiv.) and (1 S,2S)-A / 1, A^-dimethylcyclohexane-1 ,2-diamine (12 mg, 0.087 mmol, 0.3 equiv.) in n-BuOH (2 mL) were added Cui (27 mg, 0.144 mmol, 0.5 equiv.) and Nal (173 mg, 1.16 mmol, 4.0 equiv.). After stirring for 15 hours at 130 °C under an atmosphere of nitrogen, the reaction mixture was cooled to RT, quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (15% EA) to give the product. The product was dissolved in EA (30 mL) and treated with 300 mg of SiliaMetS TAAcONa (Scavenger for removing Cu). After filtration, the filtrate was concentrated under reduced pressure to give A / -(2-cyclopropyl-4-iodo-5- methylphenyl)-1-methyl-4 / - / ,5 / - / ,6 / - / -cyclopenta[c]pyrazol-3-amine as a solid.

[0639] LCMS (MS, ESI): 394 [M+H]+.

[0640] Step 3: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(1 -methyl-1, 4,5,6- tetrahydrocyclopenta[c]pyrazol-3-yl)but-2-ynamide To a solution of A / -(2-cyclopropyl-4- iodo-5-methylphenyl)-1-methyl-4 / - / ,5 / - / ,6 / - / -cyclopenta[c]pyrazol-3-amine (30 mg, 0.076 mmol, 1 .0 equiv.) in THF (1 mL) was added LiHMDS (1 M in THF, 0.23 mL, 0.230 mmol, 3.0 equiv.) at -60°C under an atmosphere of nitrogen. After stirring for 30 minutes at same temperature, but-2-ynoyl chloride (20 pL, 0.228 mmol, 3.0 equiv.) was added dropwise to the above reaction mixture. The resulting solution was stirred for 2 h at -60 °C and was applied to prep- TLC (PE:EA, 3:1 ) to afford the crude product. The crude product was purified by prep-HPLC with the following conditions (Column: Xselect CSH Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CAN; Flow rate: 60 mL / min; Gradient: 57% B to 66% B in 8 min; Wave Length: 254nm / 220nm; RT1 (min): 7.05). Lyophilization gave A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -{1-methyl-4 / - / ,5 / - / ,6 / - / - cyclopenta[c]pyrazol-3-yl}but-2-ynamide as a solid.

[0641] LCMS (MS, ESI): 460 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 5 7.35 (s, 1H), 7.12 (s, 1 H), 3.55 (s, 3H), 2.65 (t, J = 7.2 Hz, 2H), 2.52 - 2.56 (m, 2H), 2.38 - 2.46 (m, 2H), 2.32 (s, 3H), 1.77 - 1.84 (m, 4H), 0.79 - 0.87 (m, 2H), 0.56 - 0.63 (m, 2H).

[0642] The following compounds were prepared in a manner analogous to the procedures described above for A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -{1-methyl-4 / - / ,5 / - / ,6 / - / - cyclopenta[c]pyrazol-3-yl}but-2-ynamide (Compound 198a):

[0643] • Compound 196a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[2-(2- methoxyethyl)pyrazolo[4,3-b]pyridin-5-yl]pent-2-ynamide as a solid.

[0644] LCMS (MS, ESI): 529 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.53 (s, 1H), 8.14 (d, J = 9.2Hz, 1H), 7.47 - 7.74 (m, 1 H), 7.41 (s, 1 H), 7.31 (s, 1 H), 4.57 (t, J = 4.8Hz, 2H), 3.81 (t, J = 5.2Hz, 2H), 3.20 (s, 3H), 2.33 (s, 3H), 2.13 - 2.19 (m, 2H), 1.73 - 1.87 (m, 1H), 0.81 - 0.98 (m, 1 H), 0.77 (t, J = 7.2Hz, 3H), 0.40 - 0.71 (m, 3H).

[0645] • Compound 181a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(1- methylimidazo[4,5-b]pyridin-5-ylbut-2-ynamide as a solid. LCMS (MS, ESI): 471 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 5 8.35 (s, 1H), 8.05 (d, J = 8.6 Hz, 1 H), 7.62 (d, J = 8.6 Hz, 1H), 7.39 (s, 1 H), 7.26 (s, 1 H), 3.86 (s, 3H), 2.33 (s, 3H), 1.88 - 1.92 (m, 1 H), 1 .77 (s, 3H), 0.73 - 0.86 (m, 2H), 0.59 - 0.60 (m, 2 H).

[0646] • Compound 161a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[1-(2-hydroxy-2- methylpropyl) pyrazolo[4,3-b] pyridin-5-yl] but-2-ynamide as a solid.

[0647] LCMS (MS, ESI): 529 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.17 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H), 7.64 (d, J = 9.2 Hz, 1 H), 7.41 (s, 1 H), 7.27 (s, 1 H), 4.38 (s, 1 H), 4.32 (s, 2H), 2.34 (s, 3H), 1.85 - 1.93 (m, 1 H), 1.77 (s, 3H), 1.13 (s, 6H), 0.78 - 0.80 (m, 2H), 0.57 - 0.59 (m, 2H).

[0648] • Compound 154a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[2-(oxan-4- yl)pyrazolo[4,3-b]pyridin-5-yl]pent-2-ynamide as a solid.

[0649] LCMS (MS, ESI): 555 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 5 8.52 (s, 1H), 8.06 (dd, J = 9.2, 0.9 Hz, 1 H), 7.58 (d, J = 9.2 Hz, 1 H), 7.38 (s, 1 H), 7.24 (s, 1 H), 4.65 - 4.73 (m, 1 H), 3.94 - 3.97 (m, 2H), 3.46 - 3.54 (m, 2H), 2.31 (s, 3H), 2.09 - 2.15 (m, 2H), 2.05 - 2.08 (m, 4H), 1 .76 - 1.83 (m, 1 H), 0.74 - 0.78 (m, 5H), 0.54 - 0.60 (m, 2H).

[0650] • Compound 153a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[1-(oxolan-3- yl)pyrazolo[4,3-b]pyridin-5-yl]pent-2-ynamide as a solid.

[0651] LCMS (MS, ESI): 541 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.30 (d, J = 8.8 Hz, 1 H), 8.21 (s, 1 H), 7.65 - 7.93 (m, 1 H), 7.42 (s, 1 H), 7.34 (s, 1 H), 5.43 - 5.60 (m, 1 H), 4.00 - 4.13 (m, 2H), 3.80 - 3.99 (m, 2H), 2.40 - 2.50 (m, 1 H), 2.26 - 2.39 (m, 4H), 2.16 (q, J = 7.2 Hz, 2H), 1.75 - 1.92 (m, 1 H), 0.83 - 1 .00 (m, 1 H), 0.78 (t, J = 8.0 Hz, 3H), 0.50 - 0.70 (m, 3H).

[0652] • Compound 143a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[3-methyl-5- (oxetan-2-ylmethoxy)pyridin-2-yl]but-2-ynamide as a solid.

[0653] LCMS (MS, ESI): 517 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 5 7.85 - 8.00 (m, 1 H), 7.22 - 7.38 (m, 2H), 6.92 - 7.08 (s, 1 H), 4.86 - 4.95 (m, 1 H), 4.35 - 4.47 (m, 2H), 4.09 -4.17 (m, 2H), 2.56 - 2.66 (m, 1 H), 2.44 - 2.49 (m, 1 H), 2.23 (s, 3H), 2.20 (s, 3H), 1.93 - 2.04 (m, 1 H), 1 .69 (s, 3H), 0.72 - 0.85 (m, 2H), 0.51 - 0.63 (m, 2H).

[0654] • Compound 142a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[1-(oxan-4- yl)pyrazolo[4,3-b]pyridin-5-yl]pent-2-ynamide as a solid.

[0655] LCMS (MS, ESI): 555 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.28 (d, J = 9.1 Hz, 1H), 8.14 (s, 1H), 7.74 (d, J = 9.0 Hz, 1 H), 7.41 (s, 1 H), 7.30 (s, 1 H), 4.85 - 4.92 (m, 1 H), 3.99 - 4.03 (m, 2H), 3.53 - 3.59 (m, 2H), 2.34 (s, 3H), 2.08 - 2.18 (m, 4H), 1.82 - 1.94 (m, 3H), 0.78 - 0.80(m, 5H), 0.57 - 0.59 (m, 2H).

[0656] • Compound 140a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[2-(2-hydroxy-2- methylpropyl) pyrazolo[4,3-b] pyridin-5-yl] but-2-ynamide as a solid. LCMS (MS, ESI): 529 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.37 (s, 1 H), 8.08 (d, J = 9.2 Hz, 1 H), 7.53 (d, J = 9.2 Hz, 1H), 7.41 (s, 1 H), 7.26 (s, 1 H), 4.53 (s, 1 H), 4.33 (s, 2H), 2.34 (s, 3H), 1.83 - 1.87 (m, 1 H), 1.78 (s, 3H), 1.12 (s, 6H), 0.76 - 0.81 (m, 2H), 0.57 - 0.59 (m, 2H).

[0657] • Compound 139a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[1-(2-methoxy-2- methylpropyl) pyrazolo[4,3-b] pyridin-5-yl] but-2-ynamide as a solid.

[0658] LCMS (MS, ESI): 543 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.14 (d, J = 9.2 Hz, 1H), 8.11 (s, 1H), 7.66 (d, J = 9.2 Hz, 1 H), 7.41 (s, 1 H), 7.29 (s, 1 H), 4.41 (s, 2H), 3.14 (s, 3H), 2.35 (s, 3H), 1.87 - 1.91 (m, 1 H), 1.77 (s, 3H), 1.12 (s, 6H), 0.78 - 0.80 (m, 2H), 0.57 - 0.59 (m, 2H).

[0659] • Compound 138a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[2-(2-methoxy-2- methylpropyl)pyrazolo[4,3-b]pyridin-5-yl]but-2-ynamide as a solid.

[0660] LCMS (MS, ESI): 543 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.33 (s, 1 H), 8.09 (d, J = 9.2 Hz, 1 H), 7.54 (d, J = 9.2 Hz, 1 H), 7.42 (s, 1 H), 7.26 (s, 1 H), 4.42 (s, 2H), 3.20 (s, 3H), 2.34 (s, 3H), 1.80 - 1.89 (m, 1 H) 1.78 (s, 3H), 1.13 (s, 6H), 0.68 - 0.90 (m, 2H), 0.41 - 0.67 (m, 2H).

[0661] • Compound 137a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(1- methylpyrazolo[3,4-c] pyridin-5-ylbut-2-ynamide as a solid.

[0662] LCMS (MS, ESI): 471 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.92 (s, 1 H), 8.15 (s, 1 H), 7.95 (s, 1 H), 7.37 (s, 1 H), 7.27 (s, 1 H), 4.13 (s, 3H), 2.32 (s, 3H), 1.95 - 1.99 (m, 1 H), 1.75 (s, 3H), 0.82 - 0.85 (m,2H), 0.59 - 0.61 (m, 2H).

[0663] • Compound 136a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(2-methyl-2H- pyrazolo[3,4-c]pyridin-5-yl)but-2-ynamide as a solid.

[0664] LCMS (MS, ESI): 471 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.94 (s, 1 H), 8.43 (s, 1 H), 7.85 (s, 1 H), 7.36 (s, 1 H), 7.26 (s, 1 H), 4.24 (s, 3H), 2.32 (s, 3H), 1 .95 - 2.02 (m, 1 H), 1.74 (s, 3H), 0.81 - 0.85 (m, 2H), 0.58 - 0.61 (m, 2H).

[0665] • Compound 135a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{1,2- dimethylimidazo[4,5-b]pyridin-5-yl}pent-2-ynamide as a solid.

[0666] LCMS (MS, ESI): 499 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 5 7.86 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1 H), 7.31 (s, 1 H), 7.20 (s, 1 H), 3.67 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H), 2.05 (q, J = 7.4 Hz, 2H), 1.81 - 1.88 (m, 1 H), 0.71 - 0.82 (m, 5H), 0.51 - 0.53 (m, 2H).

[0667] • Compound 133a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(1- methylimidazo[4,5-b]pyridin-5-ylpent-2-ynamide as a solid. LCMS (MS, ESI): 485 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.35 (s, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 7.63 (d, J = 8.5 Hz, 1H), 7.40 (s, 1 H), 7.29 (s, 1 H), 3.86 (s, 3H), 2.34 (s, 3H), 2.12 (q, J = 7.4 Hz, 2H), 1.86 - 1 .93 (m, 1 H), 0.77 - 8.32 (m, 5H), 0.58 - 0.60 (m, 2H).

[0668] • Compound 131a: N-{6-acetyl-5H,7H-pyrrolo[3,4-b]pyridin-2-yl}-N-(2- cyclopropyl-4-iodo-5-methylphenyl)but-2-ynamide as a solid.

[0669] LCMS (MS, ESI): 500 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 7.80 - 7.84 (m, 1 H), 7.55 - 7.63 (m, 1 H), 7.39 - 7.42 (m, 1 H), 7.23 (s, 1 H), 4.67 - 4.86 (m, 2H), 4.44 - 4.64 (m, 2H), 2.33 (s, 3H), 2.01 - 2.04 (m, 3H), 1 .76 - 1 .82 (m, 4H), 0.74 - 0.82 (m, 2H), 0.55 - 0.62 (m, 2H).

[0670] • Compound 130a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[1-(oxetan-3- yl)pyrazolo[4,3-b]pyridin-5-yl]pent-2-ynamide as a solid.

[0671] LCMS (MS, ESI): 527 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.27 (s, 1 H), 8.21 (d, J = 9.2 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 1H), 7.42 (s, 1 H), 7.30 (s, 1 H), 5.94 - 6.04 (m, 1 H), 5.02 (d, J = 6.8 Hz, 4H), 2.34 (s, 3H), 2.14 (q, J = 7.4 Hz, 2H), 1.76 - 1.88 (m, 1 H), 0.74 - 0.81 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H), 0.51 - 0.66 (m, 2H).

[0672] • Compound 129a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[2-(oxetan-3- yl)pyrazolo[4,3-b]pyridin-5-yl]pent-2-ynamide as a solid.

[0673] LCMS (MS, ESI): 527 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.64 (s, 1 H), 8.15 - 8.18 (m, 1 H), 7.65 (d, J = 9.2 Hz, 1 H), 7.42 (s, 1 H), 7.29 (s, 1 H), 5.80 - 5.86 (m, 1 H), 5.00 - 5.04 (m, 4H), 2.34 (s, 3H), 2.17 (q, J = 7.4 Hz, 2H), 1.75 - 1.89 (m, 1 H), 0.80 (t, J = 7.4 Hz, 3H), 0.70 - 0.81 (m, 2H), 0.49 - 0.62 (m, 2H).

[0674] • Compound 128a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-2-yl)pent-2-ynamide as a solid.

[0675] LCMS (MS, ESI): 460 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.37 (s, 1 H), 7.17 (s, 1 H), 6.24 (s, 1 H), 3.94 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 8.0 Hz, 2H), 2.41 - 2.44 (m, 2H), 2.33 (s, 3H), 2.08 - 2.17 (m, 2H), 1.78 - 1.88 (m, 1 H), 0.76 - 0.91 (m, 5H), 0.54 - 0.68 (m, 2H).

[0676] • Compound 125a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[1-(2-hydroxy-2- methylpropyl) pyrazolo[4,3-b] pyridin-5-yl] pent-2-ynamide as a solid.

[0677] LCMS (MS, ESI): 543 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.18 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.68 (d, J = 8.8 Hz, 1 H), 7.41 (s, 1 H), 7.29 (s, 1 H), 4.38 (s, 1 H), 4.32 (s, 2H), 2.35 (s, 3H), 2.09 - 2.15 (m, 2H), 1.85 - 1.92 (m, 1 H), 1.12 (s, 6H), 0.77 - 0.81 (m, 5H), 0.57 - 0.59 (m, 2H).

[0678] • Compound 119a: N-(3-cyano-1-methylpyrrolo[3,2-b]pyridin-5-yl-N-(2- cyclopropyl-4-iodo-5-methylphenyl)but-2-ynamide as a solid. LCMS (MS, ESI): 495 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.39 (s, 1 H), 8.11 (d, J = 8.7 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1H), 7.40 (s, 1 H), 7.28 (s, 1 H), 3.89 (s, 3H), 2.32 (s, 3H), 1.93 - 1 .99 (m, 1 H), 1 .79 (s, 3H), 0.80 - 0.88 (m, 2H), 0.59 - 0.66 (m, 2H).

[0679] • Compound 114a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-{1-methyl- 4H,5H,6H-cyclopenta[c]pyrazol-3-yl}but-2-ynamide as a solid.

[0680] LCMS (MS, ESI): 412, 414 [M+H]+.1HNMR (400 MHz, DMSO-d6) 5 7.16 (s, 1 H), 7.11 (s, 1 H), 3.56 (s, 3H), 2.61 - 2.71 (m, 2H), 2.50 - 2.59 (m, 2H), 2.39 - 2.47 (m, 2H), 2.30 (s, 3H), 1.67 - 1 .91 (s, 4H), 0.75 - 0.93 (m, 2H), 0.54 - 0.69 (m, 2H).

[0681] • Compound 110a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{1-methyl- 4H,6H,7H-pyrano[4,3-c]pyrazol-3-yl}but-2-ynamide as a solid.

[0682] LCMS (MS, ESI): 476 [M+H]+.1H VT_NMR (400 MHz, DMSO-d6) 5 7.36 (s, 1H), 7.16 (s, 1 H), 4.47 (s, 2H), 3.83 (t, J = 5.7 Hz, 2H), 3.57 (s, 3H), 2.68 (t, J = 5.7 Hz, 2H), 2.33 (s, 3H), 1.73 - 1.88 (m, 4H), 0.73 - 0.94 (m, 2H), 0.61 (s, 2H).

[0683] • Compound 106a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(6,7-dihydro-9H- pyrido [2',3':4,5] imidazo[2,1 -c] [1,4] oxazin-2-yl) but-2-ynamide as a solid.

[0684] LCMS (MS, ESI): 513 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.97 - 7.99 (m, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.39 (s, 1 H) ,7.24 (s, 1 H), 4.94 (s, 2H), 4.21 - 4.23 (m, 2H), 4.14 - 4.17 (m, 2H), 2.33 (s, 3H), 1.88 - 1.93 (m, 1 H). 1.77 (s, 3H), 0.77 - 0.84 (m, 2H), 0.59 - 0.61 (m, 2H).

[0685] • Compound 102a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(1-((3 / ?,4S)-4- methoxy-tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pent-2-ynamide as a solid.

[0686] LCMS (MS, ESI): 571 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.30 (d, J = 9.2 Hz, 1H), 8.20 (s, 1H), 7.77 (d, J = 9.2 Hz, 1 H), 7.42 (s, 1 H), 7.30 (s, 1 H), 5.33 - 5.35 (m, 1 H), 4.26 - 4.29 (m, 2H), 4.13 (dd, J = 9.8, 5.3 Hz, 1 H), 3.99 (dd, J = 9.5, 4.7 Hz, 1 H), 3.83 (dd, J = 9.9, 3.1 Hz, 1 H), 3.28 (s, 3H), 2.34 (s, 3H), 2.14 (q, J = 7.4 Hz, 2H), 1.81 - 1.90 (m, 1 H), 0.76 - 0.81 (m, 5H), 0.56 - 0.61 (m, 2H).

[0687] • Compound 98a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{1- ethylimidazo[4,5-b]pyridin-5-yl}pent-2-ynamide as a solid.

[0688] LCMS (MS, ESI): 499 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.50 (s, 1H), 8.19 (d, J = 12 Hz, 1H), 7.59 - 7.77 (m, 1 H), 7.28 - 7.44 (m, 2H), 4.28 - 4.33 (m, 2H), 2.30 - 2.36 (m, 3H), 2.12 - 2.17 (m, 2H), 1.86 - 1.95 (m, 1 H), 1.42 (t, J = 4.0 Hz, 3H), 0.83 - 0.97 (m, 2H), 0.76 (t, J = 8.0 Hz, 3H), 0.57 - 0.66 (m, 2H).

[0689] • Compound 92a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{2-[(3S,4 / ?)-4- methoxyoxolan-3-yl]pyrazolo[4,3-b]pyridin-5-yl}pent-2-ynamide as a solid. LCMS (MS, ESI): 571 [M+H]+.1H NMR (400 MHz, Chloroform-d) 5 8.17 (s, 1H), 8.05 (d, J = 9.2 Hz, 1 H), 7.61 - 7.74 (m, 1 H), 7.45 (s, 1 H), 7.22 (s, 1 H), 5.03 - 5.10 (m, 1 H), 4.18 - 4.35 (m, 4H), 3.88 (dd, J = 9.8, 3.0 Hz, 1 H), 3.43 (s, 3H), 2.40 (s, 3H), 2.14 (q, J = 7.5 Hz, 2H), 1.75 - 1 .82 (m, 1 H), 0.82 - 0.95 (m, 4H), 0.45 - 0.75 (m, 3H).

[0690] • Compound 91a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(5-(((3S,4S)-4- methoxytetrahydrofuran-3-yl)oxy)-3-methylpyridin-2-yl)but-2-ynamide as a solid.

[0691] LCMS (MS, ESI): 547 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.94 - 8.07 (m, 1 H), 7.31 - 7.49 (m, 2H), 6.99 - 7.16 (m, 1 H), 4.94 - 4.99 (m, 1 H), 3.92 - 4.03 (m, 3H), 3.70 - 3.75 (m, 2H), 3.32 (s, 3H), 2.25 - 2.37 (m, 6H), 1 .98 - 2.16 (m, 1 H), 1.80 (s, 3H), 0.60 - 1 .06 (m, 4H).

[0692] • Compound 89a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{1,2-dimethyl-3- oxopyrazolo[4,3-b]pyridin-5-yl}but-2-ynamide as a solid.

[0693] LCMS (MS, ESI): 501 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 8.11 (d, J = 8.9Hz, 1 H), 7.89 (d, J =8.9 Hz, 1 H), 7.41 (s, 1 H), 7.31 (s, 1 H), 3.37 - 3.38 (m, 6H), 2.33 (s, 3H), 1.82 (s, 4H), 0.62 - 0.86 (m, 4H).

[0694] • Compound 86a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(1-methyl-1H- pyrazolo[3,4-b]pyridin-6-yl)but-2-ynamide as a solid.

[0695] LCMS (MS, ESI): 471 [M+H]+.1HNMR (400 MHz, DMSO-d6) 5 8.28 (d, J = 8.4 Hz, 1 H), 8.14 (s, 1 H), 7.44 (s, 1 H), 7.38 - 7.42 (m, 1 H), 7.32 (s, 1 H), 3.90 (s, 3H), 2.33 (s, 3H), 1 .87 - 1.92 (m, 1 H), 1 .85 (s, 3H), 0.54 - 0.97 (m, 4H).

[0696] • Compound 85a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(7,8-dihydro-6H- pyrrolo[1 ',2':1,2]imidazo[4,5-b]pyridin-2-yl)but-2-ynamide as a solid.

[0697] LCMS (MS, ESI): 497 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.90 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1 H), 7.38 (s, 1 H), 7.25 (s, 1 H), 4.16 (t, J = 7.2 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2H), 2.54 - 2.67 (m, 2H), 2.32 (s, 3H), 1 .86 - 1.98 (m, 1 H), 1 .77 (s, 3H), 0.72 - 0.98 (m, 2H), 0.53 - 0.69 (m, 2H).

[0698] • Compound 84a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(7-methyl-8-oxo- 5,6-dihydro-1 ,7-naphthyridin-2-yl)but-2-ynamide as a solid.

[0699] LCMS (MS, ESI): 500 [M+H]+. 1 H VT-NMR (400 MHz, DMSO-d6) 5 8.20 (s, 0.13 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 1H), 7.42 (s, 1 H), 7.24 (s, 1 H), 3.54 (t, J = 6.7 Hz, 2H), 3.10 - 3.00 (m, 2H), 2.99 (s, 3H), 2.33 (s, 3H), 1.82 - 1.93 (m, 1 H), 1.79 (s, 3H), 0.70 - 0.85 (m, 2H), 0.61 - 0.62 (m, 2H).

[0700] • Compound 82a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(2-methyl-2H- pyrazolo[3,4-b]pyridin-6-yl)but-2-ynamide as a solid. LCMS (MS, ESI): 471 [M+H]+.1H-NMR (400 MHz, DMSO-d6) 5 8.39 (s, 1 H), 8.24 (d, J = 8.8 Hz, 1 H), 7.42 - 7.53 (m, 2H), 7.29 (s, 1 H), 4.13 (s, 3H), 2.34 (s, 3H), 1.83 (s, 3H), 1 .76 - 7.82 (m, 1 H), 0.79-0.93 (m, 1 H), 0.46 - 0.77 (m, 3H).

[0701] • Compound 81a: N-(5-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)- / V-(2-cyclopropyl-4-iodo-5-methylphenyl)but-2-ynamide as a solid.

[0702] LCMS (MS, ESI): 517 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6): 5 7.36 (s, 1H), 7.19 (s, 1 H), 4.37 (s, 2H), 3.70 (s, 2H), 3.44 - 3.68 (m, 3H), 2.57 - 2.85 (m, 2H), 2.15 - 2.41 (m, 3H), 2.06 (s, 3H), 1 .57 - 1 .89 (m, 4H), 0.70 - 1.04 (m, 2H), 0.42 - 0.70 (m, 2H).

[0703] • Compound 80a: N-(6-acetyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridin-3-yl)-A / -(2-cyclopropyl-4-iodo-5-methylphenyl)but-2-ynamide as a solid.

[0704] LCMS (MS, ESI): 517 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.34 (s, 1 H), 7.13 (s, 1 H), 4.57 (s, 2H), 3.58 - 3.66 (m, 5H), 2.49 - 2.62 (m, 1 H), 2.39 - 2.46 (m, 1 H), 2.32 (s, 3H), 2.09 (s, 3H), 1 .88 - 1 .96 (m, 1 H), 1 .79 (s, 3H), 0.78 - 1 .92 (m, 2H), 0.56 - 0.67 (m, 2H).

[0705] • Compound 74a: N-(4-bromo-2-cyclopropyl-5-methylphenyl)-N-(3-cyano-1- methyl-1 H-pyrrolo[3,2-b]pyridin-5-yl)but-2-ynamide as a solid.

[0706] LCMS (MS, ESI): 447, 449 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 9.2 Hz, 1H), 7.31 (s, 1 H), 7.17 (s, 1 H), 3.89 (s, 3H), 2.30 (s, 3H), 1 .94 - 2.07 (m, 1 H), 1 .79 (s, 3H), 0.78 - 0.94 (m, 2H), 0.58 - 0.72 (m, 2H).

[0707] • Compound 69a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(7-methyl-8-oxo- 5,6,7,8-tetrahydro-1 ,7-naphthyridin-2-yl)pent-2-ynamide as a solid.

[0708] LCMS (MS, ESI): 514 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) 5) 7.84 (d, J = 8.0 Hz, 1 H), 7.76 - 7.81 (m, 1 H), 7.44 (s, 1 H), 7.29 (s, 1 H), 3.54 (t, J = 6.6 Hz, 2H), 2.99 - 3.03 (m, 5H), 2.32 (s, 3H), 2.17 (q, J = 7.4 Hz, 2H), 1.83 - 1.90 (m, 1 H), 0.60 - 0.88 (m, 7H).

[0709] • Compound 67a: N-[3-cyano-1-(2-methoxyethyl)pyrrolo[3,2-b]pyridin-5-yl]-N-(2- cyclopropyl-4-iodo-5-methylphenyl)but-2-ynamide as a solid.

[0710] LCMS (MS, ESI): 539 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.52 (s, 1H), 8.23 (d, J = 8.8 Hz, 1 H), 7.50 - 7.63 (s, 1 H), 7.40 (s, 1 H), 7.26 - 7.33 (s, 1 H), 4.46 (t, J = 5.0 Hz, 2H), 3.68 (t, J = 5.0 Hz, 2H), 3.20 (s, 3H), 2.31 (s, 3H), 1.97 - 2.05 (m, 1 H), 1 .82 (s, 3H), 0.72 - 1.06 (m, 2H), 0.52 - 0.71 (m, 2H).

[0711] • Compound 59a: N-(6-cyclopropyl-4-iodo-3-methylcyclohexa-2,4-dien-1-yl)-N-(6- ethyl-3-fluoro-7-oxo-5H-pyrrolo[3,4-b] pyridin-2-ylpent-2-ynamide as a solid.

[0712] LCMS (MS, ESI): 532 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.10 (d, J = 9.2 Hz, 1H), 7.43 (s, 1H), 7.26 (s, 1 H), 4.49 (s, 2H), 3.55 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 2.14 - 2.20 (m, 2H), 1.94 - 2.01 (m, 1 H), 1.18 (t, J = 7.2 Hz, 3H), 0.82 - 0.86 (m, 5H), 0.61 - 0.62(m, 2H).19F NMR (400 MHz, DMSO) 5 -117.22, -120.16.

[0713] • Compound 58a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[1-methyl-2- (oxolan-3-yl)imidazo[4,5-b]pyridin-5-yl]but-2-ynamide as a solid.

[0714] LCMS (MS, ESI): 541 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.96 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1 H), 7.39 (s, 1 H), 7.23 (s, 1 H), 4.10 - 4.12 (m, 1 H), 3.90 - 3.92 (m, 2H), 3.83 - 3.85 (m, 1 H), 3.79 (s, 3H), 2.22 - 2.33 (m, 6H), 1 .85 - 1 .94 (m, 1 H), 1 .76 (s, 3H), 0.75 - 0.84 (m, 2H), 0.59 - 0.60 (m, 2H).

[0715] • Compound 56a: N-(3-cyano-1-ethyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-(2- cyclopropyl-4-iodo-5-methylphenyl)but-2-ynamide as a solid and N-(4-bromo-2- cyclopropyl-5-methylphenyl)-N-(3-cyano-1-ethyl-1H-pyrrolo[3,2-b]pyridin-5- yl)but-2-ynamide (0.6 mg, 13%) as a solid. A / -(3-cyano-1-ethyl-1 / - / -pyrrolo[3,2-b]pyridin-5-yl)-A / -(2-cyclopropyl-4-iodo-5- methylphenyl)but-2-ynamide: LCMS (MS, ESI): 509 [M+H]+.1H VT-NMR (400 MHz, DMSO- de) 5 8.48 (s, 1 H), 8.16 (d, J = 8.8 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.40 (s, 1 H), 7.28 (s, 1 H), 4.30 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1 .93 - 2.04 (m, 1 H), 1 .79 (s, 3H), 1 .42 (t, J = 7.0 Hz, 3H), 0.78 - 0.89 (m, 2H), 0.55 - 0.70 (m, 2H).

[0716] A / -(4-bromo-2-cyclopropyl-5-methylphenyl)-A / -(3-cyano-1-ethyl-1 / - / -pyrrolo[3,2- b]pyridin-5-yl)but-2-ynamide: LCMS (MS, ESI): 461 , 463 [M+H]+.1H VT-NMR (400 MHz, DMSO-ofe) 6 8.48 (s, 1 H), 8.16 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.32 (s, 1 H), 7.17 (s, 1 H), 4.30 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 1.95 - 2.10 (m, 1 H), 1.79 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 0.82 - 0.88 (m, 2H), 0.63 - 0.68 (m, 2H).

[0717] • Compound 55a: N-{3-cyano-1-isopropylpyrrolo[3,2-b]pyridin-5-yl}-N-(2- cyclopropyl-4-iodo-5-methylphenyl)but-2-ynamide as a solid.

[0718] LCMS (MS, ESI): 523 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 8.63 (s, 1 H), 8.23 (d, J = 9.2 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1H), 7.40 (s, 1 H), 7.29 (s, 1 H), 4.82 - 4.89 (m, 1 H), 2.32 (s, 3H), 1 .94 - 2.02 (m, 1 H), 1 .80 (s, 3H), 1 .50 (d, J = 6.8 Hz, 6H), 0.75 - 0.95 (m, 2H), 0.59- 0.72 (s, 2H).

[0719] • Compound 48a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(2,5-dimethyl-2H- pyrazolo[3,4-b]pyridin-6-yl)but-2-ynamide as a solid.

[0720] LCMS (MS, ESI): 485 [M+H]+.1H VT -NMR (400 MHz, DMSO-d6) 5 8.25 (s, 1H), 8.07 (s, 1 H), 7.39 (s, 1 H), 7.11 (s, 1 H), 4.13 (s, 3H), 2.40 (s, 3H), 2.29 (s, 3H), 2.10 - 2.17 (m, 1 H), 1.77 (s, 3H), 0.83 - 0.94 (m, 2H), 0.65 - 0.74 (m, 2H).

[0721] • Compound 45a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{7-oxo-2,6,9- triazatricyclo[6.4.0.0A{2,6}]dodeca-1(12),8,10-trien-10-yl}but-2-ynamide as a solid. LCMS (MS, ESI): 513 [M+H]+.1H VT_NMR (400 MHz, DMSO-d6) 57.88 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.41 (s, 1H), 7.26 (s, 1H), 3.81 - 3.85 (m, 2H), 3.67 (t, J = 6.8 Hz, 2H), 2.55 - 2.61 (m, 2H), 2.34 (s, 3H), 1.81 -1.88 (m, 1 H), 1.78 (s, 3H), 0.77 - 0.82 (m, 2H), 0.57-0.61 (m, 2H).

[0722] • Compound 72a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-{1- ethylimidazo[4,5-b]pyridin-5-yl}but-2-ynamide as a solid.

[0723] LCMS (MS, ESI): 485 [M+H]+.1H NMR (400 MHz, DMSO-d6) 58.51 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.55 - 7.68 (m, 1H), 7.40 (s, 1H), 7.27 - 7.33 (m, 1H), 4.28 - 4.33 (m, 2H), 2.32 (s, 3H), 1.88- 1.97 (m, 1 H), 1.81 (s, 3H), 1.42 (t, J = 8.0 Hz, 3H), 0.68 - 0.98 (m, 2H), 0.58 - 0.66 (m,2H).

[0724] • Compound 204a: N-{5H,6H,7H-cyclopenta[b]pyridin-2-yl}-N-(2-cyclopropyl-4- iodo-5-methylphenyl)-3-(oxolan-3-yl)prop-2-ynamide as a solid.

[0725] LCMS (MS, ESI): 513 [M+H]+. 1H VT-NMR (400 MHz, DMSO-d6) 57.63 (d, J= 8.1 Hz, 1H), 7.39- 7.42 (m, 2H), 7.23 (s, 1H), 3.71 (t, J = 7.6 Hz, 1H), 3.59-3.61 (m, 1H), 3.48- 3.53 (m, 1H), 3.16 - 3.20 (m, 1H), 2.98 - 3.02 (m, 1H), 2.87 (t, J = 7.4 Hz, 2H), 2.79 (t, J = 7.7 Hz, 2H), 2.33 (s, 3H), 1.96 - 2.17 (m, 3H), 1.80- 1.87 (m, 1H), 1.43- 1.50 (m, 1H), 0.78- 0.83 (m, 2H), 0.57-0.61 (m, 2H).

[0726] / V-{5H,6H,7H-cyclopenta[b]pyridin-2-yl}- / \ / -(2-cyclopropyl-4-iodo-5-methylphenyl)-3- (oxolan-3-yl)prop-2-ynamide (Compound 204a) (50 mg, 0.097 mmol, 1.0 equiv.) was separated by prep-chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 pm; Mobile Phase A: Hex — (HPLC grade), Mobile Phase B: IPA: DCM=1: 1 (HPLC grade); Flow rate: 20 mL / min; Gradient: isocratic 40% B; Wave Length: 254 / 220 nm; RT1 (min): 7.80; RT2 (min): 9.21; Sample Solvent: EtOH (HPLC grade); Injection Volume: 0.5 mL; Number Of Runs: 5). Lyophilization afforded N-{5H,GH H- cyclopenta[b]pyridin-2-yl}-A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-3-[(2R)-oxolan-2-yl]prop- 2-ynamide (7.5 mg, 15%) as a solid and / V-{5H,6H,7H-cyclopenta[b]pyridin-2-yl}- / \ / -(2- cyclopropyl-4-iodo-5-methylphenyl)-3-[(2S)-oxolan-2-yl]prop-2-ynamide as a solid.

[0727] A / -{5 / - / ,6 / - / ,7 / - / -cyclopenta[b]pyridin-2-yl}-A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-3- [(2R)-oxolan-2-yl]prop-2-ynamide (Compound 170a): LCMS (MS, ESI): 513 [M+H]+.1H VT- NMR (400 MHz, DMSO-ofe) 57.63 (d, J = 8.0 Hz, 1 H), 7.39 - 7.42 (m, 2H), 7.24 (s, 1 H), 3.71 (t, J=7.7Hz, 1H), 3.57-3.63 (m, 1H), 3.49 (q, J=7.5Hz, 1H), 3.15- 3.18 (m, 1H), 2.96- 3.00 (m, 1 H), 2.87 (t, J = 7.5 Hz, 2H), 2.79 (t, J = 7.7 Hz, 2H), 2.33 (s, 3H), 1.94 - 2.06 (m, 3H), 1.79- 1.86 (m, 1H), 1.41 - 1.47 (m, 1H), 0.76-0.81 (m, 2H), 0.58-0.59 (m, 2H).

[0728] A / -{5 / - / ,6 / - / ,7 / - / -cyclopenta[b]pyridin-2-yl}-A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-3- [(2S)-oxolan-2-yl]prop-2-ynamide (Compound 169a): LCMS (MS, ESI): 513 [M+H]+. 1H_VT- NMR (400 MHz, DMSO-d6) 57.64 (t, J= 7.4 Hz, 1H), 7.39 - 7.44 (m, 2H), 7.23 - 7.25 (m, 1H), 3.70- 3.72 (m, 1H), 3.61 -3.64 (m, 1H), 3.50 - 3.53 (m, 1H), 3.15-3.20 (m, 1H), 2.98- 3.02 (m, 1 H), 2.88 (q, J = 7.2 Hz, 2H), 2.80 (q, J = 7.4 Hz, 2H), 2.33 - 2.35 (m, 3H), 1.94 - 2.08 (m, 3H), 1.79 - 1.87 (m, 1 H), 1.47 - 1.49 (m, 1 H), 0.76 - 0.86 (m, 2H), 0.60 - 0.61 (m, 2H).

[0729] • Compound 141a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[3-methyl-5- (oxolan-3-yloxy)pyridin-2-yl]but-2-ynamide as a solid.

[0730] LCMS (MS, ESI): 517 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 7.94 (s, 1 H), 7.32 - 7.34 (m, 2H), 7.09 (s, 1 H), 5.04 - 5.10 (m, 1 H), 3.57 - 3.91 (m, 4H), 2.18 - 2.36 (m, 7H), 2.07 (s, 1 H), 1.92 - 2.01 (m, 1 H), 1.78 (s, 3H), 0.81 - 0.94 (m, 2H), 0.60 - 0.70 (m, 2H).

[0731] A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -[3-methyl-5-(oxolan-3-yloxy)pyridin-2- yl]but-2-ynamide (Compound 141a) (45 mg, 0.087 mmol, 1.0 equiv.) was separated by prep- CHIRAL HPLC with the following conditions (Column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 pm; Mobile Phase A: Hex (0.1 % FA), Mobile Phase B: EtOH: DCM=1 : 1 ; Flow rate: 30 mL / min; Gradient: isocratic 40; Wave Length: 254 / 220nm; RT1(min): 9.07; RT2(min): 10.3; Sample Solvent: EtOH; Injection Volume: 0.5 mL. Concentration and lyophilization afforded A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -(3-methyl-5-[(3R)-oxolan-3-yloxy]pyridin-2-ylbut- 2-ynamide as a solid, and A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -(3-methyl-5-[(3S)- oxolan-3-yloxy]pyridin-2-ylbut-2-ynamide as a solid.

[0732] A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -(3-methyl-5-[(3R)-oxolan-3-yloxy]pyridin- 2-ylbut-2-ynamide (Compound 88a): LCMS (MS, ESI): 517 [M+H]+.1H VT-NMR (400 MHz, DMSO-ofe) 5 7.94 (s, 1 H), 7.32 - 7.34 (m, 2H), 7.09 (s, 1 H), 5.04 - 5.11 (m, 1 H), 3.82 - 3.91 (m, 2H), 3.72 - 3.79 (m, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 2.19 - 2.26 (m, 1 H), 2.03 - 2.12 (m, 1 H), 1.93 - 2.00 (m, 1 H), 1 .78 (s, 3H), 0.82 - 0.93 (m, 2H), 0.62 - 0.69 (m, 2H).

[0733] A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -(3-methyl-5-[(3S)-oxolan-3-yloxy]pyridin- 2-ylbut-2-ynamide (Compound 87a): LCMS (MS, ESI): 517 [M+H]+.1H VT-NMR (400 MHz, DMSO-ofe) 5 7.94 (s, 1 H), 7.32 - 7.34 (m, 2H), 7.09 (s, 1 H), 5.05 - 5.09 (m, 1 H), 3.81 - 3.92 (m, 2H), 3.72 - 3.79 (m, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 2.19 - 2.26 (m, 1 H), 2.04 - 2.11 (m, 1 H), 1.93 - 2.00 (m, 1 H), 1 .78 (s, 3H), 0.82 - 0.91 (m, 2H), 0.63 - 0.69 (m, 2H).

[0734] A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -{1 ,2-dimethyl-3-oxopyrazolo[4,3-b]pyridin- 5-yl}-3-(oxolan-3-yl)prop-2-ynamide (20 mg, 0.036 mmol, 1.0 equiv.) was purified by prep- CHIRAL_HPLC with the following conditions (Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 pm; Mobile Phase A: Hex, Mobile Phase B: EtOH: DCM=1 : 1 ; Flow rate: 30 mL / min; Gradient: isocratic 30; Wave Length: 254 / 220 nm; RT1 (min): 12.2; RT2(min): 14.2; Sample Solvent: EtOH; Injection Volume: 1.0 mL. Lyophilization afforded / \ / -(2-cyclopropyl-4-iodo-5- methylphenyl)- / \ / -{1 ,2-dimethyl-3-oxopyrazolo[4,3-b]pyridin-5-yl}-3-[(3R)-oxolan-3-yl]prop-2- ynamide (first fraction, stereochemistry stereochemistry not determined) as a solid and N- (2-cyclopropyl-4-iodo-5-methylphenyl)- / \ / -{1 ,2-dimethyl-3-oxopyrazolo[4,3-b] pyridin-5-yl}-3- [(3S)-oxolan-3-yl] prop-2-ynamide (second fraction, stereochemistry stereochemistry not determined) as a solid.

[0735] A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -{1 ,2-dimethyl-3-oxopyrazolo[4,3-b]pyridin- 5-yl}-3-[(3R)-oxolan-3-yl]prop-2-ynamide (Compound 33a) (first fraction, stereochemistry not determined): LCMS (MS, ESI): 557 [M+H]+.1H VT_NMR (400 MHz, DMSO-d6) 5 8.03 (d, J = 8.9 Hz, 1 H), 7.88 (d, J = 8.9 Hz, 1 H), 7.42 (s, 1H), 7.30 (s, 1 H), 3.67 - 3.71 (m, 1 H), 3.57 - 3.63 (m, 1 H), 3.44 - 3.50 (m, 1 H), 3.35 (s, 3H), 3.34 (s, 3H), 3.15 - 3.18 (m, 1 H), 2.98 - 3.03 (m, 1 H), 2.35 (s, 3H), 1 .95 - 2.03 (m, 1 H), 1 .76 - 1 .83 (m, 1 H), 1 .41 - 1 .49 (m, 1 H), 0.74 - 0.81 (m, 2H), 0.56 - 0.58 (m, 2H).

[0736] A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -{1 ,2-dimethyl-3-oxopyrazolo[4,3-b] pyridin-5-yl}-3-[(3S)-oxolan-3-yl] prop-2-ynamide (Compound 32a) (second fraction, stereochemistry not determined): LCMS (MS, ESI): 557 [M+H]+.1H VT_NMR (400 MHz, DMSO-ofe) 5 8.02 - 8.05 (m, 1 H), 7.89 (d, J = 8.9 Hz, 1 H), 7.42 (s, 1 H), 7.31 (s, 1 H), 3.67 - 3.71 (m, 1 H), 3.58 - 3.63 (m, 1 H), 3.44 - 3.50 (m, 1 H), 3.35 (s, 3H), 3.34 (s, 3H), 3.15 - 3.18 (m, 1 H), 2.97 - 3.03 (m, 1 H), 2.35 (s, 3H), 1.95 - 2.03 (m, 1H), 1.77 - 1.84 (m, 1 H), 1.41 - 1 .49 (m, 1 H), 0.74 - 0.82 (m, 2H), 0.56 - 0.58 (m, 2H).

[0737] • Compound 68a. N-{6-ethyl-7-oxo-5H-pyrrolo[3,4-b]pyridin-2-yl}-N-(4-iodo-2- isopropyl-5-methylphenyl)but-2-ynamide as a solid.

[0738] LCMS (MS, ESI): 502 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.14 (d, J = 8.3 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.84 (s, 1 H), 7.24 (s, 1 H), 4.48 (s, 2H), 3.53 (q, J = 7.2 Hz, 2H), 2.93 - 3.00 (m, 1 H), 2.31 (s, 3H), 1.83 (s, 3H), 1.13 - 1.20 (m, 6H), 1.08 (d, J = 6.8 Hz, 3H).

[0739] Compound 152a. N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-[2-(oxolan-3- yl)pyrazolo[4,3-b]pyridin-5-yl]pent-2-ynamide as a solid.

[0740] LCMS (MS, ESI): 541 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 8.62 (s, 1 H), 8.16 (d, J = 9.2 Hz, 1 H), 7.55 - 7.75 (m, 1 H), 7.42 (s, 1 H), 7.31 (s, 1 H), 5.29 - 5.39 (m, 1 H), 3.97 - 4.12 (m, 3H), 3.81 - 3.92 (m, 1 H), 2.38 - 2.49 (m, 2H), 2.36 (s, 3H), 2.17 (q, J = 7.6 Hz, 2H), 1.71 - 1.87 (m, 1 H), 0.83 - 0.98 (m, 1 H), 0.78 (t, J = 7.2 Hz, 3H), 0.50-0.70 (m, 3H).

[0741] • Compound 113a. N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(2-[(3R)-oxolan-3- yl]pyrazolo[4,3-b]pyridin-5-ylpent-2-ynamide as a solid and Compound 112a; N- (2-cyclopropyl-4-iodo-5-methylphenyl)-N-(2-[(3S)-oxolan-3-yl]pyrazolo[4,3- b]pyridin-5-ylpent-2-ynamide as a solid.

[0742] A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -(2-[(3R)-oxolan-3-yl]pyrazolo[4,3- b]pyridin-5-ylpent-2-ynamide: LCMS (MS, ESI): 541 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 8.62 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.55 - 7.80 (m, 1 H), 7.42 (s, 1 H), 7.31 (s, 1 H), 5.21 - 5.43 (m, 1 H), 3.94 - 4.16 (m, 3H), 3.79 - 3.92 (m, 1 H), 2.38 - 2.49 (m, 2H), 2.33 (s, 3H), 2.17 (q, J = 7.6 Hz, 2H), 1.71 - 1.87 (m, 1 H), 0.83 - 0.98 (m, 1H), 0.78 (t, J = 7.2 Hz, 3H), 0.50 - 0.70 (m, 3H).

[0743] N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(2-[(3S)-oxolan-3-yl]pyrazolo[4,3- b]pyridin-5-ylpent-2-ynamide: LCMS (MS, ESI): 541 [M+H]+.1H NMR (400 MHz, DMSO-d6): 5 8.62 (s, 1H), 8.16 (d, J = 9.2 Hz, 1 H), 7.55 - 7.75 (m, 1H), 7.42 (s, 1 H), 7.31 (s, 1 H), 5.28 - 5.39 (m, 1 H), 3.96 - 4.17 (m, 3H), 3.75 - 3.95 (m, 1 H), 2.38 - 2.50 (m, 2H), 2.33 (s, 3H), 2.17 (q, J = 7.6 Hz, 2H), 1 .70 - 1.89 (m, 1 H), 0.82 - 0.97 (m, 1 H), 0.78 (t, J = 8.0 Hz, 3H), 0.49 - 0.71 (m, 3H).

[0744] Example 9: Synthesis of Compound 116a: N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-

[0745] Stepl . 3-chloro- / V-(2-cyclopropyl-4-iodo-5-methylphenyl)isonicotinimidamide. To a solution of 3-chloropyridine-4-carbonitrile (1.0 g, 7.22 mmol, 1.0 equiv.) in DMSO (10 mL) was added NaH (600 mg, 15.0 mmol, 2.1 equiv., 60% purity) at 0 °C. After stirring for 30 minutes at 0 °C under an atmosphere of nitrogen, a solution of 2-cyclopropyl-4-iodo-5- methylaniline (1 .99 g, 7.29 mmol, 1 .01 equiv.) in DMSO (5 mL) was added to the reaction mixture. After stirring for 2 hours at room temperature, the resulting mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (50% EA) to afford 3-chloro-A / -(2-cyclopropyl- 4-iodo-5-methylphenyl)pyridine-4-carboximidamide as a solid.

[0746] LCMS (MS, ESI): 412, 414 [M+H]+.

[0747] Step 2. / V-(2-cyclopropyl-4-iodo-5-methylphenyl)isothiazolo[5,4-c]pyridin-3-amine. To a mixture of 3-chloro-A / -(2-cyclopropyl-4-iodo-5-methylphenyl)pyridine-4-carboximidamide (600 mg, 1 .46 mmol, 1 .0 equiv.) in DMSO (4 mL) and toluene (8 mL) were added sulfur (1.87 g, 7.30 mmol, 5.01 equiv.) and K3PO4 (620 mg, 2.92 mmol, 2.0 equiv.). The resulting mixture was stirred for 16 hours at 135 °C. After cooling to room temperature, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous NazSO^ After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (70% EA) to afford N-(2- cyclopropyl-4-iodo-5-methylphenyl)-[1 ,2]thiazolo[5,4-c]pyridin-3-amine as a solid.

[0748] LCMS (MS, ESI): 408 [M+H]+.

[0749] Step 3. N-(2-cyclopropyl-4-iodo-5-methylphenyl)-N-(isothiazolo[5,4-c]pyridin-3-yl)but- 2-ynamide. To a stirred solution of A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-

[0750] [1 ,2]thiazolo[5,4-c]pyridin-3-amine (200 mg, 0.491 mmol, 1.0 equiv.) in THF (2 mL) was added NaH (60 mg, 1 .500 mmol, 3.05 equiv., 60% purity) at 0 °C. After stirring for 30 minutes at 0 °C under an atmosphere of nitrogen, but-2-ynoyl chloride (90 pL, 0.533 mmol, 2.1 equiv.) was added dropwise to the reaction mixture. After stirring for 2 hours at 0 °C, the resulting mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NazSC . After filtration, the filtrate was concentrated under reduced pressure.

[0751] The residue was purified by reversed phase flash chromatography (Cis column), eluted with ACN in H2O (60% ACN) to give a crude product. The crude product was purified by prep- HPLC with the following conditions (Column: Xselect CSH Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 58% B to 68% B in 8 min; Wave Length: 254 nm / 220 nm; RT1 (min): 7.03).

[0752] Lyophilization afforded A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-A / -{[1 ,2]thiazolo[5,4- c]pyridin-3-yl}but-2-ynamide as a solid.

[0753] LCMS (MS, ESI): 474 [M+H]+.1H VT-NMR (400 MHz, DMSO-d6) 5 9.53 (s, 1 H), 8.60 (d, J = 5.7 Hz, 1 H), 7.90 (d, J = 5.7 Hz, 1H), 7.44 (s, 1 H), 7.37 (s, 1 H), 2.34 (s, 3H), 1.88 - 1 .92 (m, 1 H), 1 .78 (s, 3H), 0.70 - 0.72 (m, 2H), 0.56 - 0.57 (m, 2H).

[0754] Step 1. 5-cyclopropyl-4-((3,5-dimethylpyridin-2-yl)amino)-2-methylbenzonitrile To a solution of A / -(2-cyclopropyl-4-iodo-5-methylphenyl)-3,5-dimethylpyridin-2-amine (260 mg, 0.687 mmol, 1.0 equiv.) (Synthesized by the procedure of Example 7 at step 1 ) in DMF (2 mL) were added Zn(CN)2 (81 mg, 0.687 mmol, 1.0 equiv.) and Pd(PPh3)4 (40 mg, 0.034 mmol, 0.05 equiv.). The suspension was degassed under vacuum and purged with nitrogen three times. After stirring at 110 °C for 2 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The solids were filtered out. The filtrate was washed with water (50 mL x 3), brine (50 mL x 3), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (85%) to give the product. The product was dissolved in EA (10 mL) and treated with 200 mg of SiliaMetS thiol (Scavenger for removing Pd). After filtration, the filtrate was concentrated under reduced pressure to give 5-cyclopropyl-4-[(3,5-dimethylpyridin-2-yl)amino]-2- methylbenzonitrile as a solid.

[0755] LCMS (MS, ESI): 278 [M+H]+.

[0756] Step 2. N-(4-cyano-2...

Claims

CLAIMS1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is H, C1-C6 alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-C aryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(Ce-Cwaryl), or C1-C4 alkylene(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3- 10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-( Ce-Cwaryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-5 substituents selected from R5; each R3is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cwaryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3- C cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(Ce-Cio aryl), and C1-C4 alkylene-(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R6; each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl;each R6, is independently for each occurrence, selected from the group consisting of halo, CN, NO2, C1-C6 alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)OH, C(O)NH2, and C(O)-Ci-C6alkyl; y is 0, 1 , 2, 3, 4, or 5; z is 0, 1 , or 2;Ring A is absent or is selected from the group consisting of C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R7; each R7is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, =N-O-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-(Ce- Cio aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), and wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1- 5 substituents selected from R8; each R8is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, =N-OCi-Ce alkyl, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-C6alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-C6alkyl, C(O)-OCi-C6alkyl and 5- membered heteroaryl; andW is selected from -S- and -O-.

2. The compound of claim 1 , wherein the compound of Formula I is selected from Formulae lla-llc:or a pharmaceutically acceptable salt thereof, wherein: each — represents a single bond or a double bond; andX1, X2, X3, and X4are each independently selected from the group consisting of -O-, =N-, -NH-, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

3. The compound of claim 1 or 2, wherein the compound of Formula I is selected fromFormulae llla-lllf:or a pharmaceutically acceptable salt thereof, wherein:X1and X4are each independently selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2;X2and X3are each independently =CH-, -CH2-, -CHR7-, CR7, or C(R7)2.

4. The compound of any one of claims 1-3, wherein the compound of Formula I is Formulae IVa-IVc:or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-3, wherein the compound of Formula I is of theFormulae Va-Vg:and (Vg) or a pharmaceutically acceptable salt thereof, whereinX1, X2, X3, and X4are each independently =CH-, -CH2-, -CHR7-, CR7, or C(R7)2.

6. The compound of any one of claims 1-5, wherein R1is selected from the group consisting of Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and Ce-C aryl,wherein the alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1-3 substituents selected from R4; andR4is, independently for each occurrence, selected from OH, =0, =NH, halo, -CN, Ci- C6alkyl, C2.6 alkynyl, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl.

7. The compound of any one of claims 1-6, wherein each R2is, independently for each occurrence, selected from the group consisting of halo, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), and -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), and wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-4 substituents selected from R5; andR5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, -CN, Ci-C6alkyl, C2.6alkynyl, C(0)-0H, C(O)-NH2, and C(0)-Ci-C6alkyl.

8. The compound of any one of claims 1-7, wherein R3is, independently for each occurrence, selected from the group consisting of halo, -CN, -Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, and C3-C10 cycloalkyl.

9. The compound of any one of claims 2-8, wherein X1is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

10. The compound of any one of claims 2-8, wherein X2is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.11 . The compound of any one of claims 2-8, wherein X3is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

12. The compound of claim 2, wherein X4is selected from the group consisting of =N-, - NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

13. The compound of any one of claims 1-12, wherein R7of NR7is, independently for each occurrence, selected from the group consisting of Ci-Ce alkyl, C3-C10 cycloalkyl, and 3- 10 membered heterocycloalkyl, and wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 substituents selected from R8.

14. The compound of claim 13, wherein each R8is, independently for each occurrence, selected from the group consisting of halo, =0, =NH, OH, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl.

15. The compound of any one of claims 1-14, wherein R7of -CHR7-, CR7, and C(R7)2is, independently for each occurrence, selected from the group consisting of =0, halo, CN, =N- 0-(Ci-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, C(0)-0H, C(O)-NH2, C(0)-Ci-C6alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(C3-Cio cycloalkyl), -W-(3-10 membered heterocycloalkyl), -W-(Ci-Ce alkylene)-(C3-Cio cycloalkyl), and -W-(Ci-Ce alkylene)-(3-10 membered heterocycloalkyl), and wherein the alkyl, cycloalkyl, and heterocycloalkyl, are optionally substituted with 1-3 substituents selected from R8.

16. The compound of claim 15, wherein each R8is, independently for each occurrence, selected from the group consisting of halo, OH, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C(0)-0H, C(O)-NH2, and C(0)-Ci-C6alkyl.

17. The compound of claim 14 or 16, wherein at least one R8is selected from the group consisting of C(0)-0H, C(O)-NH2, and C(0)-Ci-Ce alkyl.

18. A compound of Formula VI:or a pharmaceutically acceptable salt thereof, wherein: each — individually represents a single bond or a double bond;R1is H, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cioaryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3-Cio cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(C6-Cioaryl), or C1-C4 alkylene-(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R4; each R2is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2.6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, -W-(Co-Ce alkylene)- (C3-C10 cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W-(Co-Ce alkylene)-(C6-Cio aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), wherein the alkyl, alkoxy, alkylamine, cycloalkyl, and heterocycloalkyl, are optionally substituted with 1-5 substituents selected from R5;A1and A2are each, independently for each occurrence, selected from the group consisting of NH, NR3, CH, CR3, CH2, and C(R3)2; each R3is, independently for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, C2.6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cioaryl, 5-10 membered heteroaryl, C1-C4 alkylene-(C3- C10 cycloalkyl), C1-C4 alkylene-(3-10 membered heterocycloalkyl), C1-C4 alkylene-(Ce-Cio aryl), and C1-C4 alkylene(5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with 1-5 substituents selected from R6; each R4is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R5is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, C2.6 alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl; each R6is independently, for each occurrence, selected from the group consisting of halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)OH, C(O)NH2, and C(O)-Ci-C6alkyl; y is 0, 1 , 2, 3, 4, or 5;X1, X3, and X4are each independently selected from the group consisting of -O-, =N-, -NH-, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2;X2is selected from the group consisting of absent, -O-, =N-, -NH-, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2; each R7is independently for each occurrence, selected from the group consisting of H, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, and 5-10 membered heteroaryl, wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R8; each R8is, independently for each occurrence, selected from the group consisting of H, OH, =0, =NH, =N-OCI-C6alkyl, halo, CN, NO2, =N-O-(CI-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, C(O)-Ci-Ce alkyl, C(O)-OCi-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, Ce-Cio aryl, 5-10 membered heteroaryl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), -W- (Co-Ce alkylene)-(C6-Cio aryl), and -W-(Co-Ce alkylene)-( 5-10 membered heteroaryl), wherein the alkyl, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with 1-5 substituents selected from R10;W is selected from -S- and -O-; each R9is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl; and each R10is, independently for each occurrence, selected from the group consisting of OH, =0, =NH, halo, CN, NO2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkylamine, C(0)-0H, C(O)-NH2, and C(0)-Ci-C6alkyl.

19. The compound of claim 18, wherein the compound of Formula VI is a compound of Formula VI’:or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18, wherein R1is selected from Ci-Ce alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and Ce-C aryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, and aryl are optionally substituted with 1-3 substituents selected from R4; andR4is, independently for each occurrence, selected from OH, =0, =NH, halo, CN, Ci- Ce alkyl, C2.6 alkynyl, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl.

20. The compound of claim 18 or 19, wherein each R2is, independently for each occurrence, selected from the group consisting of halo, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(Co-Ce alkylene)-(C3-Cio cycloalkyl), and -W-(Co-Ce alkylene)-(3-10 membered heterocycloalkyl), wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-4 substituents selected from R5; andR5is, independently for each occurrence, selected from OH, =0, =NH, halo, CN, Ci- C6alkyl, C2.6 alkynyl, C(O)-OH, C(O)-NH2, and C(0)-Ci-C6alkyl.21 . The compound of any one of claims 18-20, wherein R3is, independently for each occurrence, selected from the group consisting of halo, CN, Ci-Ce alkyl, C2-6 alkynyl, Ci-Ce alkoxy, Ci-Ce alkylamine, and C3-C10 cycloalkyl.

22. The compound of any one of claims 18-21 , wherein X1is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

23. The compound of any one of claims 18-22, wherein X2is selected from the group consisting of absent, =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

24. The compound of any one of claims 18-23, wherein X3is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

25. The compound of any one of claims 18-24, wherein X4is selected from the group consisting of =N-, -NH, NR7, =CH-, -CH2-, -CHR7-, CR7, and C(R7)2.

26. The compound of any one of claims 18-25, wherein R7of NR7is, independently for each occurrence, selected from the group consisting of Ci-Ce alkyl, C3-C10 cycloalkyl, and 3- 10 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1-3 substituents selected from R8.

27. The compound of any one of claims 18-26, wherein each R8is, independently for each occurrence, selected from the group consisting of halo, =0, =NH, OH, -CN, -Ci-Ce alkyl, -Ci-C6alkoxy, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl.

28. The compound of any one of claims 18-27, wherein R7of -CHR7-, CR7, and C(R7)2 is, independently for each occurrence, selected from the group consisting of =0, halo, -CN, =N- 0-(Ci-C6alkyl), Ci-C6alkyl, Ci-C6alkoxy, C(O)-OH, C(O)-NH2, C(0)-Ci-C6alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -W-(C3-Cio cycloalkyl), -W-(3-10 membered heterocycloalkyl), -W-(Ci-Ce alkylene)-(C3-Cio cycloalkyl), and -W-(Ci-Ce alkylene)-(3-10 membered heterocycloalkyl), wherein the alkyl, cycloalkyl, and heterocycloalkyl, are optionally substituted with 1-3 substituents selected from R8.

29. The compound of any one of claims 18-28, wherein each R8is, independently for each occurrence, selected from the group consisting of halo, OH, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C(O)-OH, C(O)-NH2, and C(O)-Ci-C6alkyl.

30. The compound of claim 27 or 29, wherein at least one R8is selected from the group consisting of C(O)-OH, C(O)-NH2, and C(O)-Ci-Ce alkyl.31 . The compound of any one of claims 1-30, wherein the compound is selected from a compound in Table 1 , or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound of any one of claims 1-31 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

33. A method of treating a disease, wherein the disease is associated with Werner Syndrome RecQ Like Helicase (WRN) activity, comprising administering to a patient a therapeutically effect amount of a compound of any one of claims 1-31 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32.

34. The method of claim 33, wherein the method comprises inhibiting WRN activity.

35. The method of claim 33 or 34, wherein the disease is cancer.

36. The method of claim 35, wherein the cancer has a microsatellite instability (MSApositive phenotype or MSI-high (MSI-H) phenotype.

36. The method of claim 35 or 36, wherein the cancer has a mismatch repair defective gene or mismatch repair mutated gene.

37. The method of claim 35 or 36, wherein the cancer colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney, or ovarian cancer.

38. The method of claim 35 or 36, where the cancer is an adrenocortical carcinoma, a bladder carcinoma, a breast carcinoma, a cervical squamous cell carcinoma, an endocervical adenocarcinoma, a cholangiocarcinoma, a chronic lymphocytic leukemia, a colorectal cancer, a colon adenocarcinoma, a cutaneous T-cell lymphoma, a lymphoid neoplasm diffuse large B-cell lymphoma, an esophageal carcinoma, a glioblastomamultiforme, a head and neck squamous cell carcinoma, a kidney chromophobe, a kidney renal papillary cell carcinoma, an acute myeloid leukemia, a lower-grade glioma, a liver hepatocellular carcinoma, a lung adenocarcinoma, a lung squamous cell carcinoma, a mesothelioma, a nasopharyngeal carcinoma, an ovarian cancer, an ovarian serous cystadenocarcinoma, a pancreatic adenocarcinoma, a pheochromocytoma, paraganglioma, a prostate adenocarcinoma, a rectal adenocarcinoma, a sarcoma, a skin cutaneous melanoma, a stomach adenocarcinoma, a testicular germ cell tumor, a thyroid carcinoma, a thymoma, an uterine corpus endometrial carcinoma, an uterine carcinosarcoma, an uveal melanoma, a pediatric acute myeloid leukemia, a pediatric neuroblastoma, or a pediatric high-risk Wilms tumor.

39. The method of claim 38, wherein the cancer is an ovarian cancer, a uterine corpus endometrial carcinoma, a colorectal cancer, a colon adenocarcinoma, or a stomach adenocarcinoma.

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