Tmem175 agonists, compositions, and methods of use

Abstract

The present disclosure relates to compounds of the Formula I or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Also provided are compositions comprising said compounds and methods of use for treating certain diseases or disorders, including, for example, neurodegenerative diseases and lysosomal storage diseases.

Description

TMEM175 AGONISTS, COMPOSITIONS, AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 524,082, filed June 29, 2023, and 63 / 524,085, filed June 29, 2023, the contents of each of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0002] The present disclosure relates to compounds and compositions which activate TMEM175 and are useful for the treatment or prevention of a variety of diseases and disorders, such as neurodegenerative diseases and lysosomal storage diseases. BACKGROUND

[0003] Lysosome dysfunction is a key component in a variety of diseases and disorders such as neurodegenerative diseases and lysosomal storage diseases (e.g., Parkinson’s Disease (PD)) (Robak, L. A. et al., Brain J. Neurol.2017, Vol.140, pp.3191–3203; Nguyen, M. et al., Trends Neurosci.2019, Vol.42, pp.140–149). For example, mutations in the lysosomal TMEM175 gene are prevalent and significant risk factors for PD (Jinn, S. et al., Hum. Mol. Genet.2019, Vol.28, pp.3244-54; Krohn, L. et al., Ann. Neurol.2019, Vol.87, pp.139- 153). TMEM175 encodes a lysosomal potassium and proton ion channel with unique structure, biophysical properties and pharmacology (see, e.g., Cang, C., et al., Cell 2015, Vol. 162, pp.1101–1112). The 12-transmembrane span architecture and lack of canonical ion selectivity filter in this channel, as well as its higher permeability to cesium ions relative to potassium ions and its ability to permeate protons make TMEM175 distinct from any known ion channel (Brunner, J. D. et al., bioRxiv 2018).

[0004] The TMEM175 M393T allele is present in 14% of the general population and 25% of PD patients (Paul, K. C., et al., JAMA Neurol.2018, Vol.75, pp.360–366). This mutation significantly alters age-of-onset in PD with a risk factor of 1.2 years per allele and provides the second greatest genetic risk factor for age of onset in the idiopathic population following GBA (Lill, C. M. et al., Mov. Disord. Off. J. Mov. Disord. Soc.2015, Vol.30, pp.847–850; Iwaki, H. et al., Neurol. Genet.2019, Vol.5, e348). The M393T allele also showed a significant correlation with reduced glucocerebrosidase (GCase) activity in PD patients. M393T heterozygotes showed a 6.2% decrease in GCase activity compared to wild-type carriers, while homozygotes showed a 12.4% decrease (Krohn, L. et al.2019). These valueswere corrected for GBA or LRRK2 mutations, emphasizing the deleterious effect of the M393T allele on enzyme activity. Additional studies have identified the M393T mutation as a risk factor for certain diseases and disorders including REM sleep disorder (Krohn, L. et al., Nat. Commun.2022, Vol.13, 7496), dementia with Lewy Bodies (Guo, P. et al., BMC Med. 2022, Vol.20, 214), and amyotrophic lateral sclerosis (Wightman, D. P. et al., Neurobiol. Aging 2023, Vol.127, pp.99–112). Beyond M393T, 15 less common loss of function mutations in TMEM175 have also been associated with onset of Parkinson’s Disease, some of them highly penetrant (Palomba, N. P. et al., Mol. Neurobiol.2023, Vol.60, pp.2150– 2173). Functional data indicated that the majority of these loss of function mutations, including M393T, led to decreased ion current through the channel. Interestingly, a putative protective allele (Q65P) has also been identified (Jinn, S. et al.2019). Molecular dynamics simulations suggest that the Q65P mutation affects TMEM175 channel structure and conductance (Krohn, L. et al.2019).

[0005] Multiple studies have demonstrated that loss of TMEM175 via genetic knock-out in cell lines and animals led to lysosome dysfunction, including pH destabilization (via direct conduction of protons through the channel), reduced enzyme activity, and impaired autophagy (Cang, C. et al.2015; Jinn, S. et al., Proc. Natl. Acad. Sci. U. S. A.2017, Vol.114, pp.2389–2394). Impaired mitochondrial respiration was also observed. Introduction of the M393T mutation via CRISPR in SH-SY5Y cells led to an intermediate effect, indicating that this allele is a partial loss of function (Jinn, S. et al.2019). The M393T mutation did not alter lysosomal localization of TMEM175 (Krohn, L. et al.2019), suggesting the mutation disrupts protein function rather than assembly or trafficking. In iPSC-derived human neurons, TMEM175 knock-down led to increased phosphorylated alpha-synuclein (p-a-syn) accumulation following exposure to alpha-synuclein pre-formed fibrils (a-syn PFF) (Jinn, S. et al.2017). These results were confirmed in cultured rat primary neurons (Jinn, S. et al. 2019). TMEM175+ / -heterozygous neurons displayed an intermediate phenotype, reinforcing the gene dosing effect observed in human genetic studies. In normal neurons, overexpression of wild-type TMEM175 was able to reduce p-a-syn inclusions resulting from exposure to a- syn PFF, but overexpression of TMEM175-M393T was not (Jinn, S. et al.2019).

[0006] Accordingly, there is a need to develop novel compounds and compositions that activate TMEM175 and provide therapeutic benefit, especially in patients with an M393T or other loss of function mutation. The compounds and compositions disclosed herein are directed toward this need.SUMMARY

[0007] The present disclosure provides compounds of Formula I and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, and compositions comprising said compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, which activate TMEM175 and are useful for treatment of a variety of diseases and disorders such as diseases and disorders associated with lysosome dysfunction.

[0008] In an aspect, provided herein is a compound of Formula I:Formula I or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0009] In another aspect, provided herein is a compound of Formula II:Formula II or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0010] In another aspect, provided herein is a compound of Formula II-A:Formula II-Aor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0011] In another aspect, provided herein is a compound of Formula II-B:Formula II-B or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0012] In another aspect, provided herein is a compound of Formula II-C:Formula II-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0013] In another aspect, provided herein is a compound of Formula III:Formula III or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0014] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0015] In another aspect, the disclosure provides a method of treating a disease or disorder that can be treated by activating TMEM175, the method comprising administering to a patient in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.

[0016] Still other objects and advantages of the disclosure will become apparent to those of skill in the art from the disclosure herein, which is simply illustrative and not restrictive. Thus, other embodiments will be recognized by the skilled artisan without departing from the spirit and scope of the disclosure. DETAILED DESCRIPTION

[0017] As generally described herein, the present disclosure provides compounds of Formula I and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, compositions comprising said compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof, which activate TMEM175 and are useful for treatment of a variety of diseases and disorders such as diseases and disorders associated with lysosome dysfunction (e.g., neurodegenerative diseases and lysosomal storage diseases). Compounds

[0018] In an aspect, provided herein is a compound of Formula I:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Z1is C1-6alkyl or C1-4alkylene-aryl, substituted with one or two halogen, orRing A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X2or X3;Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1is absent, CR5or N; X2, X3, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X3, X4, and X5are N; and when X2or X3to which ring A is attached is CR5, R5of the CR5to which X2or X3is attached is absent; X6is absent or is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X7 is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl or H, wherein the C1-4alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; or R1and R2, together with the carbon atom to which R1and R2are attached, form C3-4cycloalkylene; R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H or C1-6alkyl; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; optionally, provided that: when X6is CH, X7is N or CH, X8is C, ring B is phenyl, and n is 0, q is an integer 1- 4; when X6is absent, X7is C(=O), X8is C, ring B is phenyl, and n is 0, q is an integer 1- 4;when X6is CH wherein the H of CH is optionally substituted by methyl, X7 is N, X8is C, ring B is phenyl, and ring A is attached to X2, ring B is substituted with 1-4 R3; when X6is CH, X7is N or CH, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not N-bound 6-membered heterocyclyl; and when X6is CH, X7is N, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not triazole.

[0019] In some embodiments, provided herein is a compound of Formula II:Formula II or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X2or X3; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1, X2, X3, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X3, X4, and X5are N; and when X2or X3to which ring A is attached is CR5, R5of the CR5to which X2or X3is attached is absent; X6is absent or is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X7is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl or H, wherein the C1-4alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; orR1and R2, together with the carbon atom to which R1and R2are attached, form C3-4cycloalkylene; R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H or C1-6alkyl; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that: when X6is CH, X7is N or CH, X8is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X6is absent, X7 is C(=O), X8is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X6is CH wherein the H of CH is optionally substituted by methyl, X7 is N, X8is C, ring B is phenyl, and ring A is attached to X2, ring B is substituted with 1- 4 R3; when X6is CH, X7is N or CH, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not N-bound 6-membered heterocyclyl; and when X6is CH, X7is N, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not triazole.

[0020] In some embodiments, provided herein is a compound of Formula II-A:Formula II-Aor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1, X2, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X4, and X5are N; X6is absent or is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X7is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl or H, wherein the C1-4alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; or R1and R2, together with the carbon atom to which R1and R2are attached, form C3-4cycloalkylene; R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H or C1-6alkyl; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6 cycloalkyl, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that q and n are not both 0.

[0021] In some embodiments, provided herein is a compound of Formula II-B:Formula II-B or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X2or X3; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1, X2, X3, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X3, X4, and X5are N; and when X2or X3to which ring A is attached is CR5, R5of the CR5to which X2or X3is attached is absent; X6and X7are each independently selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that:when X6is CH, X7 is N or CH, X8is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X6is CH wherein the H of CH is optionally substituted by methyl, X7 is N, X8is C, ring B is phenyl, and ring A is attached to X2, ring B is substituted with 1- 4 R3; when X6is CH, X7is N or CH, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not N-bound 6-membered heterocyclyl; and when X6is CH, X7is N, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not triazole.

[0022] In some embodiments, provided herein is a compound of Formula II-C:Formula II-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1, X2, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X4, and X5are N; X6and X7 are each independently selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy;R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that q and n are not both 0.

[0023] In some embodiments, the compound is a compound of Formula II-D:Formula II-D or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0024] In some embodiments, the compound is a compound of Formula II-E:Formula II-E or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0025] In some embodiments, the compound is a compound of Formula II-F:Formula II-F or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0026] In some embodiments, the compound is a compound of Formula II-G:Formula II-G or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0027] In some embodiments, X1, X3, X4, and X5are CR5or N and X2is C.

[0028] In some embodiments, X1, X2, X4, and X5are CR5or N and X3is C.

[0029] In some embodiments, X1, X2, X4, and X5are CR5.

[0030] In some embodiments, X1, X3, X4, and X5are CR5.

[0031] In some embodiments, one of X1, X2, X4, and X5is N.

[0032] In some embodiments, one of X1, X3, X4, and X5is N.

[0033] In some embodiments, the compound is a compound of Formula II-H:Formula II-H or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0034] In some embodiments, the compound is a compound of Formula II-J:Formula II-J or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0035] In some embodiments, the bicyclic ring containing X6, X7, X8, and ring B is selected from the group consisting of:wherein the bicyclic ring is substituted with 0-4 R3.

[0036] In some embodiments, the bicyclic ring containing X6, X7, X8, and ring B is selected from the group consisting of:wherein the bicyclic ring is substituted with 0-4 R3.

[0037] In some embodiments, the bicyclic ring containing X6, X7, X8, and ring B is selected from the group consisting of:wherein the bicyclic ring is substituted with 0-4 R3.

[0038] In some embodiments, q is an integer 0-3. In some embodiments, q is an integer 0-2. In some embodiments, q is 0. In some embodiments, q is an integer 1-3. In some embodiments, q is an integer 1-2. In some embodiments, q is 1. In some embodiments, q is 2.

[0039] In some embodiments, R1is H or C1-2alkyl. In some embodiments, R1is H or methyl. In some embodiments, R1is H. In some embodiments, R1is methyl.

[0040] In some embodiments, R2is H or C1-4alkyl optionally substituted with one or two halogen, hydroxy, or C1-2 alkoxy. In some embodiments, R2is C1-4alkyl optionally substituted with hydroxy. In some embodiments, R2is methyl or ethyl. In some embodiments, R2is H.

[0041] In other embodiments, R1and R2, together with the carbon atom to which R1and R2are attached, form C3-4cycloalkylene. For example, R1and R2, together with the carbon atom to which R1and R2are attached, form cyclopropylene.

[0042] In some embodiments, R4is H.

[0043] In some embodiments, ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X2. In some embodiments, ring A is 5-6 membered heteroaryl or 6- membered heterocyclyl attached to X3. In some embodiments, ring A is 5-6 membered heteroaryl. In some embodiments, ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N. In some embodiments, ring A is 6-membered heterocyclyl. In some embodiments, ring A is selected from the group consisting of pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, and oxazolyl. In some embodiments, ring A is pyridyl, pyrazolyl, or imidazolyl.

[0044] In some embodiments, R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, di-C1-4alkylamine, and 5-6 membered heterocyclyl. In some embodiments, R3is selected from the group consisting of halogen, hydroxy, C1-2 alkyl, C1-2 alkoxy, di-C1-4alkylamine, and 5-membered N-containing heterocyclyl. In some embodiments, R3is halogen or C1-2 alkyl. In some embodiments, R3is halogen. In some embodiments, R3is Cl or F.

[0045] In some embodiments, R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, and C1-6alkyl. In some embodiments, R5is selected from the group consisting of H, halogen, and C1-6alkyl. In some embodiments, R5is selected from the group consisting of H, halogen, and C1-2 alkyl. In some embodiments, R5is selected from the group consisting of H or F.

[0046] In some embodiments, n is an integer 0-4. In some embodiments, n is an integer 0-3. In some embodiments, n is 0. In some embodiments, n is an integer 1-4. In some embodiments, n is an integer 1-3. In some embodiments, n is an integer 1-2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0047] In some embodiments, R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, and C3-6cycloalkyl. In some embodiments, R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, and C3-6cycloalkyl. In some embodiments, R6is selected from the group consisting of halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl. In some embodiments, R6is selected from the group consisting of F, Cl, hydroxy, cyano, methyl, ethyl, methoxy, and cyclopropyl.

[0048] In some embodiments, provided herein is a compound of Formula III:Formula III or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R1is H or C1-4alkyl; R2is C1-4alkyl; X1is absent, CH, or N; X3is C or N; X2, X4, and X5are each independently CH or N; provided that not more than two of X1, X2, X3, X4, and X5are N; X6is absent or is selected from the group consisting of CH, CH2, and N; X7is selected from the group consisting of CH, CH2, and N; R3is halogen; R4is H or C1-6alkyl; and Z1is C1-6alkyl or C1-4alkylene-aryl substituted with one or two halogen.

[0049] In some embodiments, X1is absent. In other embodiments, X1is CH. In some embodiments, X1is N.

[0050] In some embodiments, X2, X4, and X5are each CH. In other embodiments, one of X2, X4, and X5is N.

[0051] In some embodiments, X3is C. In other embodiments, X3is N.

[0052] In some embodiments, X1is absent and one of X2, X3, X4, and X5is N. In some embodiments, X1is absent and two of X2, X3, X4, and X5are N.

[0053] In some embodiments, X1is CH and one of X2, X3, X4, and X5is N. In some embodiments, X1is N, X3is C, and X2, X4, and X5are CH.

[0054] In some embodiments, provided herein is a compound of Formula III-I:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0055] In some embodiments, provided herein is a compound of Formula III-II:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0056] In some embodiments, the compound is a compound of Formula III-A:Formula III-A or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0057] In some embodiments, the compound is a compound of Formula III-B:Formula III-B or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0058] In some embodiments, the compound is a compound of Formula III-C:Formula III-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0059] In some embodiments, the compound is a compound of Formula III-D:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0060] In some embodiments, the compound is a compound of Formula III-E:Formula III-E or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0061] In some embodiments, X6is absent. In other embodiments, X6is CH.

[0062] In some embodiments, X7 is CH. In other embodiments, X7 is CH2.

[0063] In some embodiments, X6is absent and X7is CH2. In some embodiments, X6is CH and X7 is CH.

[0064] In some embodiments, R1is H or C1-2alkyl. In some embodiments, R1is H or methyl. In some embodiments, R1is H. In some embodiments, R1is C1-4alkyl. In some embodiments, R1is C1-2alkyl. In some embodiments, R1is methyl.

[0065] In some embodiments, R2is C1-2 alkyl. In some embodiments, R2is methyl or ethyl.

[0066] In some embodiments, R4is H.

[0067] In some embodiments, R3is Cl or F. In some embodiments, R3is Cl.

[0068] In some embodiments, Z1is C1-6alkyl. In some embodiments, Z1is ethyl.

[0069] In some embodiments, Z1is C1-4alkylene-aryl optionally substituted with halogen. In some embodiments, Z1is benzyl optionally substituted with halogen. In some embodiments, Z1is benzyl substituted with F.

[0070] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds of the disclosureMethods of Use

[0071] Provided herein, in some embodiments, is a method of activating TMEM175 in a subject in need thereof, the method comprising administering to the subject a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.

[0072] Also provided herein, in some embodiments, is a method of treating a disease or disorder that can be treated by activation of TMEM175 in a subject in need thereof, the method comprising administering to the subject a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.

[0073] Diseases or disorders that can be treated by activation of TMEM175 include, but are not limited to, Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy, FTDP-17, Alzheimer’s Disease, Multi System Atrophy, Corticobasal Degeneration, Huntington’s Disease, Sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorder, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, Pompe disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, Saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, Sialidosis, I-cell disease, pseudo-Hurler polydystrophy, Glc-NAc-1- phosphotransferase deficiency, mucolipin 1 deficiency, Santavuori-Haltia disease, Jansky- Bielschowsky disease, Batten disease, Batten-Spielmeyer-Vogt disease, Kufs disease, Finnish variant neuronal ceroid lipofuscinosis, late infantile variant neuronal ceroid lipofuscinosis, type 7 neuronal ceroid lipofuscinosis, northern epilepsy neuronal ceroid lipofuscinosis, Turkish late infantile neuronal ceroid lipofuscinosis, German / Serbian late infantile neuronal ceroidlipofuscinosis, congenital cathepsin D deficiency, Wolman disease, alpha-mannosidosis, beta- mannosidosis, aspartylglucosaminuria, and fucosidosis.

[0074] In some embodiments, provided herein is a method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.

[0075] In some embodiments, the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy, FTDP-17, Alzheimer’s Disease, Multi System Atrophy, Corticobasal Degeneration, and Huntington’s Disease.

[0076] In some embodiments, the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, and Amyotrophic Lateral Sclerosis (ALS).

[0077] In some embodiments, provided herein is a method of treating a lysosomal storage disease in a subject in need thereof, the method comprising administering to the subject a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.

[0078] In some embodiments, the lysosomal storage disease is selected from the group consisting of sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorder, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay- Sachs disease, Gaucher disease, Pompe disease, lysosomal acid lipase deficiency, Niemann- Pick disease, metachromatic leukodystrophy, Saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, Sialidosis, I-cell disease, pseudo-Hurler polydystrophy, GlcNAc-1- phosphotransferase deficiency, mucolipin 1 deficiency, Santavuori-Haltia disease, Jansky- Bielschowsky disease, Batten disease, Batten-Spielmeyer-Vogt disease, Kufs disease, Finnish variant neuronal ceroid lipofuscinosis, late infantile variant neuronal ceroid lipofuscinosis, type7 neuronal ceroid lipofuscinosis, northern epilepsy neuronal ceroid lipofuscinosis, Turkish late infantile neuronal ceroid lipofuscinosis, German / Serbian late infantile neuronal ceroid lipofuscinosis, congenital cathepsin D deficiency, Wolman disease, alpha-mannosidosis, beta- mannosidosis, aspartylglucosaminuria, and fucosidosis.

[0079] In some embodiments, provided herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising: (a) detecting a disease or disorder associated with TMEM175; and (b) administering to the subject an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition described herein.

[0080] In some embodiments, the disease or disorder is selected from the group consisting of Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy, FTDP-17, Alzheimer’s Disease, Multi System Atrophy, Corticobasal Degeneration, Huntington’s Disease, sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorder, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, Pompe disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, Saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, Sialidosis, I-cell disease, pseudo-Hurler polydystrophy, GlcNAc-1- phosphotransferase deficiency, mucolipin 1 deficiency, Santavuori-Haltia disease, Jansky- Bielschowsky disease, Batten disease, Batten-Spielmeyer-Vogt disease, Kufs disease, Finnish variant neuronal ceroid lipofuscinosis, late infantile variant neuronal ceroid lipofuscinosis, type 7 neuronal ceroid lipofuscinosis, northern epilepsy neuronal ceroid lipofuscinosis, Turkish late infantile neuronal ceroid lipofuscinosis, German / Serbian late infantile neuronal ceroid lipofuscinosis, congenital cathepsin D deficiency, Wolman disease, alpha-mannosidosis, beta- mannosidosis, aspartylglucosaminuria, and fucosidosis.

[0081] In some embodiments, the methods further comprise administering to the subject a second therapeutic agent. In some embodiments, the second therapeutic agent is an mTOR inhibitor, a V2 receptor antagonist, a tyrosine kinase inhibitor, a glucosylceramide synthaseinhibitor, a microRNA-17 inhibitor, a siRNA against p53, a KEAP1-Nrf2 activator, a xanthine oxidase inhibitor, a PPARγ agonist, an immunomodulator, a calcineurin inhibitor, a renin angiotensin aldosterone system inhibitor, an antiproliferative agent, an alkylating agent, a corticosteroid, an angiotensin converting enzyme inhibitor, an adrenocorticotropic hormone stimulant, an angiotensin receptor blocker, a sodium glucose transport protein 2 inhibitor, a dual sodium-glucose transport protein 1 / 2 inhibitor, a nuclear Factor- 1 (erythroid-derived 2)- like 2 agonist, a chemokine receptor 2 inhibitor, a chemokine receptor 5 inhibitor, an endothelin 1 receptor antagonist, a beta blocker, a mineralocorticoid receptor antagonist, a loop or thiazide diuretic, a calcium channel blocker, a statin, a short- intermediate or long-acting insulin, a dipeptidyl peptidase 4 inhibitor, a glucagon-like peptide 1 receptor agonist, a sulfonylurea, an apoptosis signal-regulating kinase- 1, a chymase inhibitor, a selective glycation inhibitor, a renin inhibitor, an interleukin-33 inhibitor, a farnesoid X receptor agonist, a soluble guanylate cyclase stimulator, a thromboxane receptor antagonist, an erythropoietin receptor agonist, a cannabinoid receptor type 1 inverse agonist, a NADPH oxidase inhibitor, an anti-vascular endothelial growth factor B, an anti-fibrotic agent, a neprilysin inhibitor, a dual CD80 / CD86 inhibitor, a CD40 antagonist, a cellular cholesterol and lipid blocker, a PDGFR antagonist, a Slit guidance ligand 2, an APOLl inhibitor, an Nrl2 activator / NF-kB inhibitor, a somatostatin receptor agonist, an AMP activated protein kinase stimulator, an arginine vasopressin receptor 2 antagonist, an anti-amyloid beta antibody, an anti-Tau antibody, an anti-synuclein antibody, a dopamine precursor, a dopamine agonist, a MAO-B inhibitor, an anticholinergic, an enhancer of beta-glucocerebrosidase activity, an acetylcholinesterase inhibitor, an NMDA receptor antagonist, a COX inhibitor, a prostanoid, an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, a soluble guanylate cyclase stimulator, a rho-kinase inhibitor, an epoprostenol derivative, a serotonin blocker, an endothelin receptor antagonist, a PDE inhibitor, a soluble guanylate cyclase inhibitor, an inhaled nitric oxide and nitric oxide- donating agents, an ΙκΒ inhibitor, a prostacyclin receptor agonist, a stimulator of hematopoiesis, an anticoagulant, a platelet-inhibiting agent, dietary and nutritional supplement, an immunosuppressant, an anti-hypertensive agent, a lipid / cholesterol-lowering agent, or a treatment for hyperphosphatemia or hyperparathyroidism. Pharmaceutical Compositions and Routes of Administration

[0082] The present disclosure also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

[0083] The amount and concentration of compounds of Formula I, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof, in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in the pharmaceutical compositions, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0084] While it is possible for a compound disclosed herein to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the compound is combined with one or more pharmaceutically acceptable diluents, excipients, or carriers. The compounds according to the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine. In some embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting. Regardless of the route of administration selected, the compounds of the present disclosure, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art.

[0085] Thus, another aspect of the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof, formulated together with one or more pharmaceutically acceptable carriers. As described in detail below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally orintrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally; or (10) intrathecally. Additionally, compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Patent No.3,773,919; and U.S. Patent No.3,270,960.

[0086] Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0087] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0088] Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0089] Formulations of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending uponthe host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, e.g., from about 5 per cent to about 70 per cent, e.g., from about 10 per cent to about 30 per cent.

[0090] In some embodiments, methods of preparing these formulations or compositions include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0091] Formulations of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. A compound of the present disclosure may also be administered as a bolus, electuary or paste.

[0092] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0093] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0094] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0095] Liquid dosage forms for oral administration of the compounds of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0096] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0097] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0098] Formulations of the pharmaceutical compositions of the disclosure for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0099] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the heart, lung, bladder, urethra, ureter, rectum, or intestine. Furthermore, compositions can be formulated for delivery via a dialysis port.

[0100] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure.

[0101] Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion. In some embodiments, the compositions are administered by intravenous infusion or injection.

[0102] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise one or more compounds of the disclosure in combinationwith one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0103] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the disclosure include, but are not limited to, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0104] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0105] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0106] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0107] When the compounds of the present disclosure are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (e.g., 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0108] The addition of the active compound of the disclosure to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977).

[0109] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site. Dosages

[0110] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0111] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0112] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0113] The amount of compound that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1% to 99% of compound, e.g., from about 5% to about 70%, e.g., from 10% to about 30%.

[0114] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit large therapeutic indices are preferred.

[0115] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0116] The therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the EC50(i.e., the concentration of the therapeutic which achieves a half- maximal effect) as determined in cell culture. Levels in plasma may be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay.

[0117] The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0118] With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment or make other alteration to treatment regimen. The dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to the drugs. The desired dose can be administered at one time or divided into subdoses, e.g., 2-4 subdoses and administered over a period of time, e.g., at appropriate intervals through the day or other appropriate schedule. Such sub-doses can be administered as unit dosage forms. In some embodiments, administration is chronic, e.g., one or more doses daily over a period of weeks or months. Examples of dosing schedules are administration daily, twice daily, three timesdaily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more.

[0119] The present disclosure contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present disclosure contemplates administration via any of the foregoing routes of administration. One of skill in the art can select the appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated. Chemical Definitions

[0120] At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0121] For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R.

[0122] It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0123] In case a compound of the present disclosure is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.

[0124] An asterisk or wavy line may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

[0125] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom, usually a carbon, oxygen, or nitrogen atom, is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto or oxo (i.e. , =O), then 2 hydrogens on the atom are replaced. Ring double bonds, as usedherein, are double bonds that are formed between two adjacent ring atoms (e.g. , C=C, C=N, N=N, etc.).

[0126] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C1-4alkyl is intended to include C1, C2, C3, and C4. C1-6alkyl is intended to include C1C2, C3, C4, C5, and C6alkyl groups and C1-8alkyl is intended to include C1, C2, C3, C4, C5,C6, C7, and C8. Some examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n- hexyl, n-heptyl, and n-octyl.

[0127] As used herein, "alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more carbon-carbon double bonds and optionally one or more carbon–carbon triple bonds that can occur in any stable point along the chain. In some embodiments, alkenyl does not contain any triple bonds. For example, C2-6alkenyl is intended to include C2, C3, C4, C5, and C6alkenyl groups and C2-8 alkenyl is intended to include C2, C3, C4, C5, C6, C7, and C8alkenyl groups. Examples of C2–6alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1–butenyl (C4), 2–butenyl (C4), butadienyl ( C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0128] As used herein, "alkynyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more carbon-carbon triple bonds and optionally one or more carbon–carbon double bonds that can occur in any stable point along the chain. In some embodiments, alkynyl does not contain any double bonds. The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). For example, C2-6alkynyl is intended to include C2, C3, C4, C5, and C6alkynyl groups and C2-8 alkynyl is intended to include C2, C3, C4, C5, C6, C7, and C8alkynyl groups. The one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–6 alkynyl groups include, without limitation, ethynyl (C2), 1– propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl ( C7), octynyl (C8), and the like.

[0129] As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. A non-limiting example of such an alkylene moiety that is a diradical is -CH2CH2-, i.e., a C2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule. The alkylene, alkenylene, and alkynylene diradicals are also known as "alkylenyl," “alkenylenyl,” and“alkynylenyl” radicals, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.

[0130] As used herein, "cycloalkyl" is intended to include saturated or unsaturated nonaromatic ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and includes cyclic, bicyclic, tricyclic, spiro, fused, or bridged cyclic hydrocarbon groups. For example, the term "C3-8 cycloalkyl" is intended to include C3, C4, C5, C6, C7, and C8cycloalkyl groups. Cycloalkyls may include multiple spiro- or fused or bridged rings. For example, cycloalkyl can include, but is not limited to, spiro butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, bicyclo butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, adamantyl groups, and norbornyl groups. Unless specified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In some embodiments, the cycloalkyl group is unsubstituted.

[0131] As used herein, the term "heterocycloalkyl," “heterocyclyl,” or “heterocyclic” refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, Se, B, Si, or P), unless specified otherwise. A heterocyclyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocyclyl is a monocyclic 4-6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocyclyl is a monocyclic or bicyclic 4-10 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, oxiranyl,azetidinyl, oxetanyl, thietanyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl and the like.

[0132] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0133] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0134] As used herein, "aryl" includes groups with aromaticity, including "conjugated," or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Aryl may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-maryl" refers to an aryl group having from n to m ring carbon atoms. In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1– naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

[0135] As used herein, the terms "aromatic heterocycle," "aromatic heterocyclic," or "heteroaryl" ring are intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or polycyclic aromatic ring which contains carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic aromatic heterocyclic or heterocycle or heteroaryl rings, only one of the two rings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or R wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O)P, wherein p = 1 or 2). In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. In other embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 2. In other embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 3.

[0136] Examples of aromatic heterocycles, aromatic heterocyclics, or heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzooxadiazoly, carbazolyl, 4aH- carbazolyl, carbolinyl, cinnolinyl, furazanyl, imidazolyl, imidazolonyl, lH-indazolyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylbenztriazolyl, methylfuranyl, methylimidazolyl, methylthiazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl.

[0137] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0138] Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groupscontaining three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6– bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0139] Examples of representative heteroaryls include the following:wherein each Z is selected from carbonyl, N, NR*, O, and S; and R* is independently hydrogen, C1-C8alkyl, C3-C10carbocyclyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5- 10 membered heteroaryl.

[0140] As used herein, "amine" or "amino" refers to unsubstituted -NH2unless otherwise specified.

[0141] As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo substituents.

[0142] As used herein, "haloalkyl" is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms,substituted with one or more halogen (for example -CvFwH2v.w+1wherein v = 1 to 3 and w = 1 to (2v+l)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichlorom ethyl, pentafluoroethyl, and pentachloroethyl.

[0143] As used herein, "alkoxyl" or "alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-6alkoxy, is intended to include C1, C2, C3, C4, C5, and C6alkoxy groups. C1-8alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, and C8alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, s-pentoxy, n-heptoxy, and n- octoxy.

[0144] The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0145] The term "hydroxyalkyl" means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2- and CH3-CH(OH)-.

[0146] The term "cyano" as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N.

[0147] As used herein, "oxo" is means a "=O" group.

[0148] As used herein, “nitro” refers to -NO2.

[0149] As used herein, "unsaturated" refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds.

[0150] When a ring atom such as X1, or X6is absent, the remaining ring atoms form a ring. For example, if X6is absent from Formula II, then X7 forms a bond with the nitrogen adjacent to X6in Formula II. Other Definitions

[0151] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds or salts, solvates, hydrates, tautomers, and stereoisomers thereof, materials, compositions, 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.

[0152] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds or tautomers thereof, wherein the parent compound or a tautomerthereof, is modified by making of the acid or base salts thereof of the parent compound or a tautomer thereof. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art.

[0153] 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 include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, or a tautomer thereof, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxy ethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic.

[0154] The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound or a tautomer thereof that contains a basic or acidic moiety by conventional chemical methods. Generally, such pharmaceutically acceptable salts can be prepared by reacting the free acid or base forms of these compounds or tautomers thereof 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, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p.1445 (1990).

[0155] As used herein, "stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction, and formulation into an efficacious therapeutic agent.

[0156] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0157] Disease, disorder, and condition are used interchangeably herein.

[0158] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (also “therapeutic treatment”).

[0159] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0160] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, e.g., by activating TMEM175, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0161] In an alternate embodiment, the present disclosure contemplates administration of the compounds of the present disclosure or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition. As used herein, “prophylactic treatment” contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition. As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0162] The terms “activator” and “agonist” are used interchangeably to refer to an agent that increases or initiates a biological activity.

[0163] The term "hydrate" as used herein, refers to a compound formed by the union of water with the parent compound.

[0164] The term "solvate" as used herein, refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of the solute).

[0165] The term “tautomer” as used herein, refers to constitutional isomers of the disclosed compounds that readily convert by tautomerization or tautomerism. The interconversion commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. Exemplary tautomeric pairs include, but arenot limited to, ketone and enol, enamine and imine, nitroso and oxime, amide and imidic acid, lactam and lactim (an amide and imidic tautomerism in heterocyclic rings), and open-chain and cyclic forms of an acetal or hemiacetal.

[0166] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0167] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In some embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0168] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound. In some embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at leastabout 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. In some embodiments, the enantiomerically pure S– compound in such compositions can, for example, comprise, at least about 95% by weight S– compound and at most about 5% by weight R–compound, by total weight of the compound. In some embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0169] Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; F may be in any isotopic form, including18F and19F; and the like.

[0170] In the specification, the singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification will control.

[0171] All percentages and ratios used herein, unless otherwise indicated, are by weight.

[0172] As used herein, the articles "a" and "an" refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.

[0173] "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. EXAMPLES

[0174] Examples are provided below to facilitate a more complete understanding of the disclosure. The following examples illustrate exemplary modes of making and practicing the disclosure. However, the scope of the disclosure is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results.

[0175] General. All oxygen and / or moisture sensitive reactions were carried out under N2atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N2prior to use. All reagents and solvents were purchased from commercial vendors and used as received or synthesized according to the footnoted references. NMR spectra were recorded ona Bruker (400 or 600 MHz1H), Agilent (400 MHz1H) or Varian (400 MHz1H) spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br = broad, s = singlet, t = triplet, q = quartet, m = multiplet; coupling constant(s) in Hz). Unless otherwise indicated NMR data were collected at 25oC. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMnO4) stain followed by heating. Flash chromatography was performed using 100-200 mesh silica gel. High performance liquid chromatography (HPLC) and Liquid Chromatography / Mass Spectrometry (LCMS) were performed on Agilent or Shimadzu system. LCMS example conditions:

[0176] Column: Shim-pack Scepter C18-120, 33*3.0mm, 3um or YMC Triart C18, 50x4.6mm, 3um; Mobile Phase: A: H2O(0.1%FA) B: CH3CN: Temperature: 35°C; Flow rate: 1.2mL / min; Run time: 0.1min@20%B,1.7min gradient (20-95% B), then 0.7min@95% B, then 0.4min@20% B; Injection volume: 5 uL; Detector: UV 220 / 254nm; Mass range: 100-1000; Scan: Postive / Negative. HPLC example conditions:

[0177] Column: YMC Triart C18, 50x4.6mm, 3um; Mobile phase: A: H2O / CH3CN / TFA=90 / 10 / 0.1 B: H2O / CH3CN / TFA=10 / 90 / 0.1; Flow rate: 2.5mL / min; Run time: 0.4 min@ 20% B, 3.4min gradient (20-95% B), then 0.8min@95%B; Temperature: 40 ℃; Detector: UV 220 / 254nm. Table 2. AbbreviationsIntermediate A. Synthesis of 4-(1-methyl-1H-pyrazol-5-yl)aniline

[0178] To a mixture of 4-bromoaniline (5.0 g, 29 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.7 g, 32 mmol) in dioxane / H2O (80 mL / 20 mL) were added K2CO3(12.1 g, 87.2 mmol) and Pd(dppf)Cl2(1.1 g, 1.5 mmol). The mixture was stirred at 90°C under N2overnight. The volatile solvents were evaporated. The residue was extracted with EtOAc twice. The organic layer was concentrated and chromatographed on silica gel (25~35% EtOAc in petroleum ether) to give 4-(1-methyl-1H-pyrazol-5-yl)aniline (3.8 g, 76%) as a white solid. LC / MS ESI (m / z): 174 (M+H)+. Intermediate B. Synthesis of 4-(3-fluoropyridin-2-yl)aniline

[0179] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.73 g, 17.0 mmol) in dioxane (50 mL) and H2O (10 mL) were added 2-bromo-3-fluoropyridine (3.00 g, 17.0 mmol), K2CO3(7.07 g, 51.1 mmol) and Pd(dppf)Cl2(1.3 g, 1.7 mmol). The resulting mixture was stirred at 90℃ under N2overnight. The mixture was concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford 4-(3-fluoropyridin-2-yl)aniline (3.1 g, 96%) as a yellow solid. LC / MS ESI (m / z): 189 (M+H)+. Intermediate C. Synthesis of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)anilineStep 1.4-Fluoro-1-methyl-1H-pyrazole

[0180] To a solution of 4-fluoro-1H-pyrazole (5.0 g, 58 mmol) in THF (100 mL) was added NaH (4.7 g, 60% in mineral oil, 120 mmol) at 0°C. The mixture was stirred at 0°C for 30 min. Then CH3I (9.9 g, 70 mmol) was added. The mixture was stirred at rt overnight and carefully poured into water. Then it was extracted with DCM twice, washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the crude title compound 4-fluoro-1-methyl-1H- pyrazole (4.0 g, 68%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 4.1 Hz, 1H), 7.24 (d, J = 4.8 Hz, 1H), 3.83 (s, 3H). Step 2.4-Fluoro-5-iodo-1-methyl-1H-pyrazole

[0181] To a solution of 4-fluoro-1-methyl-1H-pyrazole (4.0 g, 40 mmol) in THF (40 mL) was added 1.6 M n-BuLi (33 mL, 52 mmol) at -78°C dropwise. The mixture was stirred at -78°C for 1 h. Then a solution of I2 (13.5 g, 52.0 mmol) in THF (20 mL) was added dropwise at - 78°C. The reaction was allowed to warm up to room temperature and stirred for 2 h and was quenched with saturated Na2S2O3(10 mL). The mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4,and purified by flash column chromatography (silica gel, 0~20% EtOAc in petroleum ether) to afford the title compound 4-fluoro-5-iodo-1-methyl-1H-pyrazole (3.3 g, 36%) as a yellow solid. LC / MS ESI (m / z): 227 (M+H)+.1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 4.9 Hz, 1H), 3.87 (s, 3H). Step 3.4-(4-Fluoro-1-methyl-1H-pyrazol-5-yl)aniline

[0182] To a solution of 4-fluoro-5-iodo-1-methyl-1H-pyrazole (3.27 g, 14.5 mmol) in dioxane (50 mL) and water (5 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (3.5 g, 16 mmol), Na2CO3(4.6 g, 43 mmol) and Pd(dppf)Cl2(530 mg, 0.72 mmol). The mixture was stirred at 100°C under N2for 18 h. The mixture was concentrated in vacuoand purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford the title compound 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)aniline (2.2 g, 79%) as a black solid. LC / MS ESI (m / z): 192 (M+H)+. Intermediate D. Synthesis of 4-(4-fluoro-1-methyl-1H-pyrazol-3-yl)anilineStep 1.3-Bromo-4-fluoro-1-methyl-1H-pyrazole

[0183] To a solution of 3-bromo-1-methyl-1H-pyrazole (2.0 g, 12 mmol) in MeCN (30 mL) was added Selectfluor (6.6 g, 19 mmol). The mixture was stirred at 80°C for 18 h. Then it was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo to afford the crude title compound 3-bromo-4-fluoro-1-methyl-1H- pyrazole (1.2 g, 54%) as a black solid. LC / MS ESI (m / z): 180, 182 (M+H)+. Step 2.4-(4-Fluoro-1-methyl-1H-pyrazol-3-yl)aniline

[0184] To a solution of crude 3-bromo-4-fluoro-1-methyl-1H-pyrazole (1.2 g, 6.7 mmol) in dioxane (20 mL) and water (4 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (1.5 g, 6.7 mmol), K2CO3(2.3 g, 17 mmol) and Pd(dppf)Cl2(490 mg, 0.67 mmol). The reaction was stirred at 90°C under N2for 18 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography eluting with (petroleum ether / ethyl acetate = 3 / 1, v / v) to afford the title compound 4-(4-fluoro-1-methyl-1H-pyrazol-3-yl)aniline (200 mg, 15%) as a black solid. LC / MS ESI (m / z): 192 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 4.6 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 6.61 (d, J = 8.5 Hz, 2H), 5.23 (s, 2H), 3.76 (s, 3H). Intermediate E. Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid

[0185] To a three-necked round bottom flask were charged Mg(Ot-Bu)2 (9.5 g, 56 mmol) and THF (50 mL). The mixture was degassed and backfilled with N2. Then (S)-2-chloropropanoic acid (3.9 g, 36 mmol) was added dropwise over 20 min to maintain the internal temperature <35°C. After aging for 10 min, t-BuOK (1.0 M in THF, 31 mL) was added dropwise. After aging for another 20 min, 6-chloroisoquinolin-1(2H)-one (5.0 g, 28 mmol) was added and additional THF (5 mL) was added to rinse the side of the flask. Then the mixture was stirred at rt for 2 h and then at 55°C (internal temperature) overnight.23 mL of 6 M HCl was added. The mixture was partitioned between EtOAc and H2O. The organic layer was separated and concentrated to dryness and was triturated from EtOAc / petroleum ether to give crude (R)-2-(6-chloro-1- oxoisoquinolin-2(1H)-yl)propanoic acid (5.9 g, ~75% purity, mixed with 25% starting material) as an off-white solid. LC / MS ESI (m / z): 252 (M+H)+.1H NMR (400 MHz, DMSO- d6) δ 12.98 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.58 – 7.51 (m, 2H), 6.66 (d, J = 7.5 Hz, 1H), 5.29 (q, J = 7.3 Hz, 1H), 1.59 (d, J = 7.3 Hz, 3H). Intermediate F. Synthesis of (R)-2-(3-chloro-8-oxo-1,7-naphthyridin-7(8H)-yl)propanoicStep 1. (E)-5-Chloro-3-(2-ethoxyvinyl)picolinonitrile

[0186] To a solution of 3-bromo-5-chloropicolinonitrile (4.0 g, 18 mmol) in dioxane (40 mL) and H2O (8 mL) were added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.9 g, 20 mmol), Pd(dppf)Cl2(1.0 g, 1.4 mmol) and K2CO3(7.6 g, 55 mmol). The resulting mixture was stirred at 90℃ under N2overnight. After cooling down to room temperature, the reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (0~9% ethyl acetate in petroleum ether) to afford (E)-5-chloro-3-(2- ethoxyvinyl)picolinonitrile (3.3 g, 86%) as a white solid. LC / MS ESI (m / z): 209 (M+H)+. Step 2. (E)-5-Chloro-3-(2-ethoxyvinyl)picolinamide

[0187] To a solution of (E)-5-chloro-3-(2-ethoxyvinyl)picolinonitrile (3.3 g, 16 mmol) in acetone (50 mL) was added 3 M Na2CO3(90 mL) followed by 30% H2O2(90 mL) dropwise. The mixture was stirred at room temperature for 3 h and was then quenched with Na2SO3(aq.). The mixture was extracted with DCM twice. The combined organic layers were washed withbrine, dried over Na2SO4, filtered and concentrated to give (E)-5-chloro-3-(2- ethoxyvinyl)picolinamide (3.5 g) which was used directly in the next step. LC / MS ESI (m / z): 227 (M+H)+. Step 3.3-Chloro-1,7-naphthyridin-8(7H)-one

[0188] To a solution of (E)-5-chloro-3-(2-ethoxyvinyl)picolinamide (3.0 g, 13 mmol) in toluene (10 mL) was added TsOH (86 mg, 0.5 mmol). The mixture was stirred at 100°C for 16 h. The solvent was evaporated. The residue was basified with NaHCO3(aq) and suspended in DCM. The solid was collected by filtration and dried under vacuum to afford 3-chloro-1,7- naphthyridin-8(7H)-one (1.7 g) which was used directly in the next step. LC / MS ESI (m / z): 181 (M+H)+. Step 4. (R)-2-(3-Chloro-8-oxo-1,7-naphthyridin-7(8H)-yl)propanoic acid

[0189] To a 3-necked round bottom flask was charged Mg(Ot-Bu)2(6.2 g, 37 mmol). After purging with N2, anhydrous THF (60 mL) was added followed by drop-wise addition of (S)-2- chloropropanoic acid (2.9 g, 27 mmol) to maintain the internal temperature at ≤35°C. After aging for 10 min, KOt-Bu (19 mL, 19 mmol, 1.0 M in THF) was added and additional THF (5 mL) was charged to rinse the side of the flask. After the resulting mixture was aged at rt for another 15 min, 3-chloro-1,7-naphthyridin-8(7H)-one (3.3 g, 18.3 mmol) was added and additional THF (5 mL) was added to rinse the side of the flask. Then the mixture was stirred at rt for 2.5 h and then at 55°C (internal temperature) overnight. 20 mL of 6 M HCl was added and the resultant was filtered to remove unreacted starting material. The filtrate was concentrated and purified by reverse phase column chromatography (C18 column, 0~23% MeCN in water) to give (R)-2-(3-chloro-8-oxo-1,7-naphthyridin-7(8H)-yl)propanoic acid (700 mg, 15%) as an off-white solid. LC / MS ESI (m / z): 253 (M+H)+. Example 1. Synthesis of (R)-2-(6,7-difluoro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-methyl- 1H-pyrazol-3-yl)phenyl)propenamide (1)

[0190] The aniline intermediate used in the last step was prepared by a procedure similar to that described for Intermediate A. Step 1.4,5-Difluoro-2-methylbenzamide

[0191] To a solution of 4,5-difluoro-2-methylbenzoic acid (1.0 g, 5.8 mmol) in 10 mL of DCM were added oxalyl chloride (1.5 mL, 17 mmol) and DMF (2 drops using a syringe) at 0°C. The mixture was stirred at room temperature for 2 h. It was then concentrated to dryness and taken up in DCM (10 mL) and added to ammonium hydroxide (3 mL) at 0°C. The mixture was stirred for 30 min and then partitioned between DCM and H2O. The organic layer was washed with brine, dried, filtered and evaporated to afford 4,5-difluoro-2-methylbenzamide (800 mg, 80%) as a solid. Step 2. (E)-N-((Dimethylamino)methylene)-4,5-difluoro-2-methylbenzamide

[0192] A mixture of 4,5-difluoro-2-methylbenzamide (700 mg, 4.09 mmol) and DMF-DMA (585 mg, 4.91 mmol) in THF (10 mL) was stirred at refluxing temperature under N2for 3 h. The solvents were evaporated to give the crude product, which was triturated from hexanes to give (E)-N-((dimethylamino)methylene)-4,5-difluoro-2-methylbenzamide (790 mg, 85%) as a white solid. LC / MS ESI (m / z): 227 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.97 (dd, J = 12.0, 8.9 Hz, 1H), 7.33 (dd, J = 11.9, 8.0 Hz, 1H), 3.20 (s, 3H), 3.10 (s, 3H), 2.53 (s, 3H). Step 3.6,7-Difluoroisoquinolin-1(2H)-one

[0193] To a solution of (E)-N-((dimethylamino)methylene)-4,5-difluoro-2-methylbenzamide (740 mg, 3.27 mmol) in THF (5 mL) was added t-BuOK (4.2 mL, 1.0 M in THF). The resultingmixture was stirred at 65℃ under N2for 2 h. After being cooled down to room temperature, the mixture was partitioned between EtOAc and NH4Cl (aq). The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford 6,7- difluoroisoquinolin-1(2H)-one (170 mg, 28%) as a yellow solid. LC / MS ESI (m / z): 182 (M+H)+. Step 4. (R)-2-(6,7-Difluoro-1-oxoisoquinolin-2(1H)-yl)propanoic acid

[0194] To a suspension of Mg(Ot-Bu)2 (320 mg, 1.88 mmol) in dry THF (5 mL) was added (S)-2-chloropropanoic acid (150 mg, 1.39 mmol) dropwise. After being stirred at rt under N2for 30 min, t-BuOK (1.4 mL, 1.0 M in THF) was added. After stirring at rt for another 30 min, 6,7-difluoroisoquinolin-1(2H)-one (170 mg, 0.94 mmol) was charged. The mixture stirred at rt for 2.5 h and then at 55℃ for 12 h. Then it was cooled to rt and quenched with concentrated HCl. The mixture was partitioned between EtOAc and H2O. The organic layer was separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was triturated in EtOAc and petroleum ether to give 80 mg of crude (R)-2-(6,7-difluoro-1-oxoisoquinolin-2(1H)-yl)propanoic acid as a light yellow solid. LC / MS ESI (m / z): 254 (M+H)+. Step 5. (R)-2-(6,7-Difluoro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol-3-yl) phenyl)propenamide

[0195] To a solution of (R)-2-(6,7-difluoro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (40 mg, 0.16 mmol) in DMF (5 mL) were added 4-(1-methyl-1H-pyrazol-3-yl)aniline (30 mg, 0.18 mmol), HATU (70 mg, 0.18 mmol) and DIEA (0.08 mL, 0.48 mmol). After being stirred at rt for 1 h, the reaction was partitioned between EtOAc and NaHCO3 (aq). The organic layer was separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) and prep- HPLC to afford (R)-2-(6,7-difluoro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol- 3-yl)phenyl)propanamide (31 mg, 48%) as an off-white solid. LC / MS ESI (m / z): 409 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 22.5 Hz, 1H), 8.24 – 8.12 (m, 1H), 7.75 – 7.67 (m, 2H), 7.58 – 7.48 (m, 2H), 7.38 – 7.32 (m, 2H), 7.32 – 7.26 (m, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 5.83 (q, J = 7.1 Hz, 1H), 3.92 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H).

[0196] The following compound was prepared by a procedure similar to that described for Example 1 using the corresponding aniline intermediate for the last step.Example 3. Synthesis of 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1,4-dimethyl-1H- pyrazol-5-yl)phenyl)propanamide (3)

[0197] The aniline intermediate used in the second step was prepared by a procedure similar to that described for Intermediate A. Step 1. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid

[0198] To a three-necked round bottom flask were charged Mg(Ot-Bu)2(9.5 g, 56 mmol) and THF (50 mL). The mixture was degassed and backfilled with N2. Then (S)-2-chloropropanoic acid (3.9 g, 36 mmol) was added dropwise over 20 min to maintain the internal temperature < 35°C. After aging for 10 min, t-BuOK (1.0 M in THF, 31 mL) was added dropwise. After aging for another 20 min, 6-chloroisoquinolin-1(2H)-one (5.0 g, 28 mmol) was added and additional THF (5 mL) was added to rinse the side of the flask. Then the mixture was stirred at rt for 2 h and then at 55°C (internal temperature) overnight.23 mL of 6 M HCl was added. The mixture was partitioned between EtOAc and H2O. The organic layer was separated and concentrated to dryness and was triturated from EtOAc / petroleum ether to give crude (R)-2-(6-chloro-1- oxoisoquinolin-2(1H)-yl)propanoic acid (5.9 g, ~75% purity, mixed with 25% SM) as an off- white solid. LC / MS ESI (m / z): 252 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.58 – 7.51 (m, 2H), 6.66 (d, J = 7.5 Hz, 1H), 5.29 (q, J = 7.3 Hz, 1H), 1.59 (d, J = 7.3 Hz, 3H).Step 2.2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)phenyl) propenamide

[0199] To a solution of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (100 mg, 0.40 mmol) in DMF (5 mL) was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)aniline (120 mg, 0.60 mmol), HATU (290 mg, 0.70 mmol) and DIPEA (0.20 mL, 1.8 mmol). After being stirred at rt overnight, the reaction was quenched with water. The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~90% ethyl acetate in petroleum ether) to give the crude product, which was further purified by prep- HPLC to afford 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1,4-dimethyl-1H-pyrazol-5- yl)phenyl)propanamide (54 mg, 32%, racemized under these conditions) as a white solid. LC / MS ESI (m / z): 421 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.53 (dd, J = 8.6, 2.1 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.30 (s, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.64 (q, J = 7.3 Hz, 1H), 3.68 (s, 3H), 1.94 (s, 3H), 1.69 (d, J = 7.3 Hz, 3H).

[0200] The following compounds were prepared by a procedure similar to that described in Example 3 with the corresponding quinazolin-4(3H)-one / isoquinolin-1(2H)-one / phthalazin- 1(2H)-one derivative as the starting material and analogous aniline intermediates for the second step.

[0201] For the following examples, the aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate A using the corresponding aryl halide and aryl-Bpin.

[0202] For the following examples, the aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate B using the corresponding aryl halide and aminophenyl-Bpin.Examples 18 and 19. Synthesis of (R)-2-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)-N-(4-(1- methyl-1H-pyrazol-5-yl)phenyl)propanamide (18) and (R)-2-(5,6-difluoro-1- oxophthalazin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propanamide (19)Step 1.4,5-Difluoro-2-formylbenzoic acid and 3,4-difluoro-2-formylbenzoic acid

[0203] At -78℃, to a solution of 2-bromo-4,5-difluorobenzoic acid (2.0 g, 8.4 mmol) in THF (20 mL) was added n-BuLi (8.4 mL, 2.5 M in THF). The mixture was stirred at -78℃ for 30 min. Then DMF (6 mL, 74.5 mmol) was added. After being stirred at rt for 1 h, the reaction was quenched with saturated NH4Cl (aq) and adjusted to pH 1-3. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford a crude mixture of 4,5-difluoro- 2-formylbenzoic acid and 3,4-difluoro-2-formylbenzoic acid (940 mg, 60%) as a yellow oil. LC / MS ESI (m / z): 185 (M-H)-. Step 2.6,7-Difluorophthalazin-1(2H)-one and 5,6-difluorophthalazin-1(2H)-one

[0204] To a solution of crude mixture of 4,5-difluoro-2-formylbenzoic acid and 3,4-difluoro-2-formylbenzoic acid (400 mg, 2.1 mmol) in ethanol (15 mL) were added N2H4-H2O (540 mg, 8.6 mmol) and 3 M HCl (0.1 mL). The resulting mixture was stirred at 80℃ for 2 h. After being cooled down to room temperature, the reaction mixture was quenched with water and extracted with DCM twice. The organic layers were dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) to afford a crude mixture of 6,7-difluorophthalazin-1(2H)-one and 5,6- difluorophthalazin-1(2H)-one (180 mg, 46%) as a yellow solid. LC / MS ESI (m / z): 183 (M+H)+. Step 3. (R)-2-(6,7-Difluoro-1-oxophthalazin-2(1H)-yl)propanoic acid and (R)-2-(5,6- difluoro-1-oxophthalazin-2(1H)-yl)propanoic acid

[0205] At 0℃, to a suspension of Mg(Ot-Bu)2(340 mg, 2.0 mmol) in THF (20 mL) was added (S)-2-chloropropanoic acid (160 mg, 1.5 mmol) dropwise. The mixture was stirred at 0℃ for 10 min. Then t-BuOK (1.5 mL, 1.0 M in THF) was added to the reaction. After being stirred at 0°C for 20 min, a crude mixture of 6,7-difluorophthalazin-1(2H)-one and 5,6- difluorophthalazin-1(2H)-one (180 mg, 1.0 mmol) was added. The resulting mixture was stirred at rt for 2 h and then at 60℃ overnight. After being cooled down to room temperature, the reaction was quenched with 3 M HCl and adjusted to pH 1-3. The aqueous was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford a crude mixture of (R)-2-(6,7-difluoro-1- oxophthalazin-2(1H)-yl)propanoic acid and (R)-2-(5,6-difluoro-1-oxophthalazin-2(1H)- yl)propanoic acid (140 mg, 55%) as a colorless oil. LC / MS ESI (m / z): 255 (M+H)+. Step 4. (R)-2-(6,7-Difluoro-1-oxophthalazin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol-5- yl)phenyl)propanamide and (R)-2-(5,6-difluoro-1-oxophthalazin-2(1H)-yl)-N-(4-(1-methyl- 1H-pyrazol-5-yl)phenyl)propenamide

[0206] To a mixture of (R)-2-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)propanoic acid and (R)-2-(5,6-difluoro-1-oxophthalazin-2(1H)-yl)propanoic acid (140 mg, 0.6 mmol) in DMF (10 mL) were added 4-(1-methyl-1H-pyrazol-5-yl)aniline (95 mg, 0.6 mmol), HATU (250 mg, 0.7 mmol) and DIEA (0.3 mL, 1.9 mmol). After being stirred at rt overnight, the reaction was partitioned between EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) followed by prep-HPLC to afford the following compounds.

[0207] Example 18. (R)-2-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)-N-(4-(1-methyl-1H- pyrazol-5-yl)phenyl)propanamide (8.7 mg, 3.8%), white solid. LC / MS ESI (m / z): 410 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.48 (s, 1H), 8.26 – 8.18 (m, 1H), 8.17 – 8.07 (m, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.51 – 7.37 (m, 3H), 6.35 (d, J = 1.9 Hz, 1H), 5.57 (q, J = 7.0 Hz, 1H), 3.83 (s, 3H), 1.66 (d, J = 7.1 Hz, 3H).

[0208] Example 19. (R)-2-(5,6-difluoro-1-oxophthalazin-2(1H)-yl)-N-(4-(1-methyl-1H- pyrazol-5-yl)phenyl)propanamide (91.1 mg, 40.2%), white solid. LC / MS ESI (m / z): 410 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.67 (s, 1H), 8.20 – 8.13 (m, 1H), 8.02 – 7.93 (m, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.49 – 7.41 (m, 3H), 6.35 (d, J = 1.9 Hz, 1H), 5.59 (q, J = 7.0 Hz, 1H), 3.83 (s, 3H), 1.66 (d, J = 7.1 Hz, 3H).

[0209] The following compound was prepared by a procedure similar to that described for Example 19 using the corresponding aniline intermediate for the last step.Example 21. Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(4- methyloxazol-2-yl)phenyl)propanamide (21)Step 1.2-Bromo-4-methyloxazole

[0210] To a solution of 4-methyloxazole (200 mg, 2.4 mmol) in THF (6 mL) were added n- BuLi (1.9 mL, 1.6 M in THF) slowly at -65°C. The mixture was stirred for 30 min. Then 1,2- dibromo-1,1,2,2-tetrafluoroethane (660 mg, 2.3 mmol) was added. The mixture was slowly warmed to rt overnight and quenched with H2O. Then it was extracted with DCM twice. The organic layer was dried over Na2SO4and evaporated at 0°C to afford 2-bromo-4-methyloxazole (190 mg, 50%) as a brown oil. Step 2.4-(4-Methyloxazol-2-yl)aniline

[0211] To a solution of 2-bromo-4-methyloxazole (190 mg, 1.1 mmol) in dioxane / H2O (5 mL / 1 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (270 mg, 1.2 mmol), Pd(dppf)Cl2(80 mg, 0.1 mmol) and K2CO3(460 mg, 3.3 mmol). The mixture was sealed and stirred at 90°C under N2overnight. The volatile solvents were evaporated. The residue was extracted with EtOAc twice. The organic layer was concentrated and chromatographed on silica gel (20~35% EtOAc in petroleum ether) to give 4-(4-methyloxazol- 2-yl)aniline (200 mg, 95%) as a brown solid. LC / MS ESI (m / z): 175 (M+H)+.1H NMR (400 MHz, CDCl3) δ 7.84 – 7.79 (m, 2H), 7.33 (dd, J = 2.4, 1.2 Hz, 1H), 6.72 – 6.68 (m, 2H), 3.91 (br, 2H), 2.21 (d, J = 1.3 Hz, 3H). Step 3. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(4-methyloxazol-2-yl)phenyl) propenamide

[0212] At 0℃, to a solution of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (140 mg, 0.54 mmol) and 4-(4-methyloxazol-2-yl)aniline (78 mg, 0.45 mmol) in pyridine (3 mL) was added POCl3(100 mg, 0.68 mmol) dropwise. After being stirred at 0℃ for 1 h, the reaction was quenched with ice water and extracted with DCM twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to give the crude product, which was further purified by prep-HPLC to afford (R)-2-(6-chloro-1-oxoisoquinolin- 2(1H)-yl)-N-(4-(4-methyloxazol-2-yl)phenyl)propanamide (23 mg, 12%) as a white solid. LC / MS ESI m / z: 408 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.92 – 7.81 (m, 4H), 7.77 – 7.72 (m, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.53 (dd, J = 8.6, 2.1 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.63 (q, J = 7.2 Hz, 1H), 2.14 (d, J = 1.1 Hz, 3H), 1.68 (d, J = 7.3 Hz, 3H). Example 22. Synthesis of (R)-2-(3-chloro-8-oxo-1,7-naphthyridin-7(8H)-yl)-N-(4-(3- fluoropyridin-2-yl)phenyl)propanamide (22)O H Step 1. tert-Butyl (R)-(1-((4-(3-fluoropyridin-2-yl)phenyl)amino)-1-oxopropan-2-yl) carbamate

[0213] To a solution of 4-(3-fluoropyridin-2-yl)aniline (2.0 g, 11 mmol) in DMF (20 mL) was added (tert-butoxycarbonyl)-D-alanine (2.41 g, 12.8 mmol), HATU (4.85 g, 12.8 mmol) and DIEA (5.3 mL, 32 mmol). After being stirred at rt overnight, the reaction was partitioned between EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-(1-((4-(3-fluoropyridin- 2-yl)phenyl)amino)-1-oxopropan-2-yl)carbamate (3.7 g, 96%) as a yellow oil. LC / MS ESI (m / z): 360 (M+H)+. Step 2. (R)-2-Amino-N-(4-(3-fluoropyridin-2-yl)phenyl)propenamide

[0214] To a solution of tert-butyl (R)-(1-((4-(3-fluoropyridin-2-yl)phenyl)amino)-1- oxopropan-2-yl)carbamate (3.7 g, 10 mmol) in DCM (30 mL) was added TFA (15 mL). After being stirred at rt for 2 hrs, the mixture was concentrated by rotary evaporation to give 3.6 g of the crude product as a yellow solid, which was used directly in the next step. LC / MS ESI (m / z): 260 (M+H)+. Step 3. tert-Butyl 3-bromo-5-chloropicolinate

[0215] To a solution of 3-bromo-5-chloropicolinic acid (500 mg, 2.13 mmol) and Boc2O(1.28 g, 6.34 mmol) in THF (20 mL) was added DMAP (387 mg, 3.17 mmol). The resulting mixture was heated to 60°C overnight. The solvents were evaporated. The residue was purified by flash column chromatography (silica gel, 0~10% ethyl acetate in petroleum ether) to afford tert-butyl 3-bromo-5-chloropicolinate (230 mg, 37%) as an oil. LC / MS ESI (m / z): 292, 294 (M+H)+. Step 4. tert-Butyl (E)-5-chloro-3-(2-ethoxyvinyl)picolinate

[0216] To a solution of tert-butyl 3-bromo-5-chloropicolinate (230 mg, 0.79 mmol) and (E)- 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (190 mg, 0.94 mmol) in dioxane (10 mL) and H2O (1 mL) were added Pd(dppf)Cl2(57 mg, 0.08 mmol) and K2CO3(325 mg, 2.35 mmol). The resulting mixture was stirred at 90°C under N2overnight. The solvents were removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0~25% ethyl acetate in petroleum ether) to afford tert-butyl (E)-5-chloro-3-(2- ethoxyvinyl)picolinate (180 mg, 80%) as an oil. LC / MS ESI (m / z): 284 (M+H)+. Step 5.3-Chloro-8H-pyrano[3,4-b]pyridin-8-one

[0217] A solution of tert-butyl (E)-5-chloro-3-(2-ethoxyvinyl)picolinate (180 mg, 0.63 mmol) in TFA (5.0 mL, 65 mmol) was stirred at 100°C for 3 h. The solvents were removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0~10% ethyl acetate in petroleum ether) to afford 3-chloro-8H-pyrano[3,4-b]pyridin-8-one (100 mg, 86%) as a white solid. LC / MS ESI (m / z): 182 (M+H)+. Step 6. (R)-2-(3-Chloro-8-oxo-1,7-naphthyridin-7(8H)-yl)-N-(4-(3-fluoropyridin-2-yl) phenyl)propenamide

[0218] A mixture of 3-chloro-8H-pyrano[3,4-b]pyridin-8-one (120 mg, 0.66 mmol), (R)-2- amino-N-(4-(3-fluoropyridin-2-yl)phenyl)propanamide (342 mg, 1.32 mmol) and DIPEA (255 mg, 1.98 mmol) in MeOH (5 mL) was stirred at 70°C overnight. The solvents were evaporated. The residue was purified by flash column chromatography (silica gel, 0~10% MeOH in DCM) and prep-HPLC to afford (R)-2-(3-chloro-8-oxo-1,7-naphthyridin-7(8H)-yl)-N-(4-(3- fluoropyridin-2-yl)phenyl)propanamide (8.0 mg, 2.8%) as a white solid. LC / MS ESI (m / z): 423 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.49 (d, J = 10.0 Hz, 1H), 8.44 – 8.36 (m, 1H), 7.90 – 7.83 (m, 2H), 7.78 – 7.69 (m, 2H), 7.65 (d, J = 5.6 Hz, 1H), 7.41 – 7.34 (m, 2H), 7.17 – 7.12 (m, 1H), 6.38 (d, J = 7.6 Hz, 1H), 5.94 (q, J = 7.0 Hz, 1H), 1.65 (d, J = 7.0 Hz, 3H). Example 23. Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1- methyl-1H-pyrazol-5-yl)phenyl)propanamide (23)Step 1. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid

[0219] At 0℃, to a solution of Mg(Ot-Bu)2 (9.4 g, 55 mmol) in THF (50 mL) was added (S)- 2-chloropropanoic acid (3.6 g, 33 mmol) dropwise. The resulting mixture was stirred at 0℃ for 10 min. Then t-BuOK (31 mL, 1.0 M in THF) was added to the reaction. After being stirred at 0°C for 20 min, 7-chloroquinazolin-4(3H)-one (5.0 g, 28 mmol) was added. The resulting mixture was stirred at 60℃ overnight. After being cooled down to room temperature, the reaction was quenched with 3 M HCl and adjusted to pH 1~3. The mixture was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was triturated from EtOAc / petroleum ether to afford (R)-2-(7-chloro-4- oxoquinazolin-3(4H)-yl)propanoic acid (5.8 g, 83%) as an off-white solid. LC / MS ESI (m / z): 253 (M+H)+. Step 2. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)propenamide

[0220] At 0°C, to a solution of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)aniline (98 mg, 0.5 mmol) in ACN (15 mL) were added (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid (130 mg, 0.5 mmol), NMI (88 mg, 1.1 mmol) and TCFH (160 mg, 0.6 mmol). After being stirred at 0℃ for 30 min. the reaction was partitioned between EtOAc and ice water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to give the crude product, which was further purified by prep-HPLC and separated by chiral SFC to afford (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)propanamide (74 mg, 34%) as a white solid. LC / MS ESI (m / z): 426 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.54 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.61 (dd, J = 8.6, 2.1 Hz, 1H), 7.56 (d, J = 4.6 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 5.56 (q, J = 7.4 Hz, 1H), 3.77 (s, 3H), 1.79 (d, J = 7.4 Hz, 3H). Opticalpurity ~100%. Preparative separation method: Instrument: Shimadzu prep solution SFC; Column: ChiralPak AS, 250×20 mm I.D., 5 µm; Mobile phase: A for CO2and B for MeOH; Gradient: B 30%; Flow rate: 40mL / min; Back pressure: 100 bar; Column temperature: 35℃; Wavelength: 220 nm; Cycle-time: 7 min; Elution time: 2 h.

[0221] The following compounds were prepared by a procedure similar to that described for Example 23 with the corresponding thieno[3,2-d]pyrimidin-4(3H)-one / thieno[2,3- d]pyrimidin-4(3H)-one / quinazolin-4(3H)-one / phthalazin-1(2H)-one / isoquinolin-1(2H)- one / 5,6,7,8-tetrahydroquinazolin-4(3H)-one / 5,6,7,8-tetrahydroisoquinolin-1(2H)-one derivative as the starting material and analogous aniline intermediates for the second step.

[0222] The following examples were prepared using the aniline intermediate (step 2) prepared by a procedure similar to that described for Intermediate A using the corresponding aryl halide and aryl-Bpin.

[0223] In the following examples, the aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate B using the corresponding aryl halide andaminophenyl-Bpin.

[0224] In the following examples, the aniline intermediate used in step 2 was prepared by a procedure similar to that described for intermediate C.

[0225] In the following examples, the aniline intermediate used in step 2 was prepared by the procedure described for Intermediate D.Example 48. Synthesis of (R)-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-(1-oxo-6- (pyrrolidin-1-yl)isoquinolin-2(1H)-yl)propanamide (48)Step 1.6-(Pyrrolidin-1-yl)isoquinolin-1(2H)-one

[0226] A solution of 6-fluoroisoquinolin-1(2H)-one (100 mg, 0.6 mmol) in tetrahydropyrrole (6 mL) was stirred at 100°C overnight. The mixture was concentrated to dryness to give 6- (pyrrolidin-1-yl)isoquinolin-1(2H)-one (100 mg, 76%) as a yellow solid, which was used directly. LC / MS ESI (m / z): 215 (M+H)+. Step 2. (R)-2-(1-Oxo-6-(pyrrolidin-1-yl)isoquinolin-2(1H)-yl)propanoic acid

[0227] To a suspension of Mg(Ot-Bu)2 (110 mg, 0.6 mmol) in THF (5 mL) under N2was added (S)-2-chloropropanoic acid (76 mg, 0.7 mmol) dropwise at 0°C. After 10 min, t-BuOK (0.6 mL, 1.0 M in THF, 0.6 mmol) was added. After another 20 min, 6-(pyrrolidin-1- yl)isoquinolin-1(2H)-one (100 mg, 0.5 mmol) was added. The solution was stirred at rt for 2 h and then at 55°C overnight. After being cooled to rt, the mixture was adjusted to pH 2-3 withHCl (6 M) and was extracted with DCM twice. The combined organic layers were chromatographed on silica gel (0~10% MeOH in DCM) to afford (R)-2-(1-oxo-6-(pyrrolidin- 1-yl)isoquinolin-2(1H)-yl)propanoic acid (74 mg, 55%) as a white solid. LC / MS ESI (m / z): 287 (M+H)+. Step 3. (R)-N-(4-(1-Methyl-1H-pyrazol-5-yl)phenyl)-2-(1-oxo-6-(pyrrolidin-1-yl)isoquinolin -2(1H)-yl)propenamide

[0228] To a solution of (R)-2-(1-oxo-6-(pyrrolidin-1-yl)isoquinolin-2(1H)-yl)propanoic acid (50 mg, 0.2 mmol) in pyridine (5 mL) were added 4-(1-methyl-1H-pyrazol-5-yl)aniline (36 mg, 0.2 mmol) and POCl3(27 mg, 0.2 mmol) at 0°C. The mixture was stirred at 0°C for 40 min under N2and quenched with H2O. The mixture was extracted with DCM twice and concentrated. The residue was chromatographed on silica gel (0~10% MeOH in DCM) to give the crude product, which was further purified by prep-HPLC to afford (R)-N-(4-(1-methyl-1H- pyrazol-5-yl)phenyl)-2-(1-oxo-6-(pyrrolidin-1-yl)isoquinolin-2(1H)-yl)propanamide (8.4 mg, 11%) as a white solid. LC / MS ESI (m / z): 442 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.10 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.49 – 7.35 (m, 4H), 6.83 (dd, J = 9.1, 2.3 Hz, 1H), 6.56 (dd, J = 20.2, 4.9 Hz, 2H), 6.33 (d, J = 1.9 Hz, 1H), 5.68 (q, J = 7.2 Hz, 1H), 3.84 (s, 3H), 3.40 (t, J = 6.5 Hz, 4H), 2.11 – 2.03 (m, 4H), 1.71 (d, J = 7.3 Hz, 3H). Example 49. Synthesis of 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(3-fluoropyridin-2-Step 1. Ethyl 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)acetate

[0229] To a solution of 6-chloroisoquinolin-1(2H)-one (250 mg, 1.39 mmol) in DMF (5 mL) were added Cs2CO3(680 mg, 2.09 mmol) and ethyl 2-bromoacetate (349 mg, 2.09 mmol). The mixture was stirred at 50°C under N2for 3 h. Then it was diluted with EtOAc and washed withwater and brine. The organic layer was concentrated and purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to give 300 mg of ethyl 2- (6-chloro-1-oxoisoquinolin-2(1H)-yl)acetate as a brown solid. LC / MS ESI (m / z): 266 (M+H)+. Step 2.2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)acetic acid

[0230] To a suspension of ethyl 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)acetate (100 mg, 0.38 mmol) in ethanol (3 mL) was added LiOH (aq) (0.8 mL, 1 M). The mixture was stirred at rt for 3 h and concentrated.6 N HCl was added to adjust the pH to ~2. Then the mixture was extracted with EtOAc and concentrated to dryness to give 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)acetic acid (90 mg, 0.38 mmol). LC / MS ESI (m / z): 238 (M+H)+. Step 3.2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(3-fluoropyridin-2-yl)phenyl) acetamide

[0231] To a solution of 2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)acetic acid (90 mg, 0.38 mmol) and 4-(3-fluoropyridin-2-yl)aniline (86 mg, 0.45 mmol) and NMI (65 mg, 0.8 mmol) in ACN (3 mL) was added TCFH (117 mg, 0.42 mmol) at 0°C. The reaction was stirred at 0°C under N2overnight. The mixture was partitioned between EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was triturated in petroleum ether / EtOAc and dried under vacuum to afford 2-(6-chloro-1-oxoisoquinolin- 2(1H)-yl)-N-(4-(3-fluoropyridin-2-yl)phenyl)acetamide (8.2 mg, 5.3%) as a white solid. LC / MS ESI (m / z): 408 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.59 – 8.45 (m, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.86 – 7.77 (m, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.55 (t, J = 8.2 Hz, 2H), 7.47 – 7.38 (m, 1H), 6.66 (d, J = 7.3 Hz, 1H), 4.86 (s, 2H). Example 50. Synthesis of (R)-2-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)-N-(4-(1-methyl- 1H-pyrazol-3-yl)phenyl)propanamide (51)Step 1. Methyl 4,5-difluoro-2-vinylbenzoate

[0232] To a solution of methyl 2-bromo-4,5-difluorobenzoate (1.0 g, 4.0 mmol) in THF (17 mL) and water (3 mL) were added potassium trifluoro(vinyl)borate (590 mg, 4.4 mmol), Cs2CO3(3.9 g, 12 mmol) and Pd(PPh3)2Cl2(280 mg, 0.40 mmol). The mixture was stirred at 80°C under N2for 18 h and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10% EtOAc in petroleum ether) to afford the title compound methyl 4,5-difluoro-2-vinylbenzoate (590 mg, 75%) as a yellow solid.NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 10.9, 8.2 Hz, 1H), 7.45 (ddd, J = 17.4, 11.0, 1.2 Hz, 1H), 7.36 (dd, J = 11.4, 7.7 Hz, 1H), 5.60 (d, J = 17.4 Hz, 1H), 5.40 (d, J = 11.0 Hz, 1H), 3.90 (s, 3H). Step 2. Methyl 4,5-difluoro-2-formylbenzoate

[0233] To a solution of methyl 4,5-difluoro-2-vinylbenzoate (590 mg, 3.0 mmol) in THF (5 mL) and water (5 mL) were added K2OsO4(100 mg, 0.3 mmol) and NaIO4(1.9 g, 9.0 mmol). The reaction was stirred at rt for 2 h. Then it was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~25% DCM in petroleum ether) to afford the title compound methyl 4,5-difluoro-2-formylbenzoate (450 mg, 76%) as a white solid. Step 3.6,7-Difluorophthalazin-1(2H)-one

[0234] To a solution of methyl 4,5-difluoro-2-formylbenzoate (450 mg, 2.3 mmol) in EtOH (5 mL) was added N2H4-H2O (280 mg, 5.6 mmol). The mixture was stirred at 80°C for 1 h.The solid was filtered off. The filtrate was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to afford the title compound 6,7-difluorophthalazin-1(2H)-one (110 mg, 27%) as a white solid. LC / MS ESI (m / z): 183 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.34 (s, 1H), 8.17 (dd, J = 10.3, 7.9 Hz, 1H), 8.10 (dd, J = 10.5, 7.6 Hz, 1H). Step 4. (R)-2-(6,7-Difluoro-1-oxophthalazin-2(1H)-yl)propanoic acid

[0235] To a suspension of Mg(Ot-Bu)2(210 mg, 1.2 mmol) in THF (2 mL) was added (S)-2- chloropropanoic acid (98 mg, 0.9 mmol) at 0°C. After aging for 10 min, 1.0 M t-BuOK (0.6 mL, 0.6 mmol) was added. After being stirred for 20 min, 6,7-difluorophthalazin-1(2H)-one (110 mg, 0.6 mmol) was added. The resulting mixture was stirred at rt for 2.5 h and then at 55°C for 18 h. The reaction was concentrated in vacuo. The residue was adjusted to pH 2~3 with 2 M HCl and diluted with EtOAc. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~10% MeOH in DCM) to afford the crude title compound (R)-2-(6,7-difluoro-1- oxophthalazin-2(1H)-yl)propanoic acid (90 mg, 58%) as a yellow oil. LC / MS ESI (m / z): 255 (M+H)+. Step 5. (R)-2-(6,7-Difluoro-1-oxophthalazin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol-3-yl) phenyl)propenamide

[0236] To a solution of (R)-2-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)propanoic acid (50 mg, 0.20 mmol) in MeCN (2 mL) were added 4-(1-methyl-1H-pyrazol-3-yl)aniline (34 mg, 0.20 mmol), NMI (34 mg, 0.42 mmol) and TCFH (60 mg, 0.22 mmol) at 0°C. The mixture was stirred at 0°C for 1 h and diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (R)-2-(6,7-difluoro-1-oxophthalazin-2(1H)-yl)-N-(4-(1-methyl-1H- pyrazol-3-yl)phenyl)propanamide (18 mg, 22%) as a white solid. LC / MS ESI (m / z): 409 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.30 – 8.23 (m, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.59 – 7.53 (m, 3H), 7.38 (d, J = 2.2 Hz, 1H), 6.51 (d, J = 2.3 Hz, 1H), 5.84 (q, J = 7.0 Hz, 1H), 3.96 (s, 3H), 1.80 (d, J = 7.0 Hz, 3H). Example 51. Synthesis of (R)-N-(4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(6- fluoro-1-oxoisoquinolin-2(1H)-yl)propanamide (51)

[0237] The aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate B. Step 1. (R)-2-(6-Fluoro-1-oxoisoquinolin-2(1H)-yl)propanoic acid

[0238] At 0℃, to a suspension of Mg(Ot-Bu)2(1.5 g, 8.6 mmol) in THF (20 mL) under N2was added (S)-2-chloropropanoic acid (610 mg, 5.6 mmol) dropwise. The resulting mixture was stirred at 0℃ for 10 min. Then t-BuOK (5.2 mL, 1.0 M in THF) was added. After being stirred at 0°C for 20 min, 6-fluoroisoquinolin-1(2H)-one (700 mg, 4.3 mmol) was added. And the resulting mixture was stirred at 60℃ overnight. After being cooled down to room temperature, the reaction was quenched with 3 M HCl and adjusted to pH 1-3. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4and concentrated. The residue was triturated with petroleum ether to afford (R)-2-(6-fluoro-1- oxoisoquinolin-2(1H)-yl)propanoic acid (820 mg, 71%) as a white solid. LC / MS ESI (m / z): 236 (M+H)+. Step 2. (R)-N-(4-(4-Cyano-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(6-fluoro-1-oxoisoquinolin- 2(1H)-yl)propanamide

[0239] At -20℃, to a solution of (R)-2-(6-fluoro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (150 mg, 0.6 mmol) in DCM (5 mL) were added 5-(4-aminophenyl)-1-methyl-1H-pyrazole-4- carbonitrile (110 mg, 0.6 mmol), pyridine (0.3 mL). Then POCl3(110 mg, 0.7 mmol) was added dropwise. After being stirred at -20℃ for 40 min, the reaction was quenched with ice water. The aqueous layer was extracted with DCM twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to give the crude product, which was further purified by prep-HPLC to afford (R)-N-(4-(4-cyano-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(6-fluoro-1-oxoisoquinolin-2(1H)-yl)propanamide (85 mg, 32%) as a white solid. LC / MS ESI m / z: 416 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.35 – 8.22 (m, 1H), 8.12 (s, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.53 (dd, J = 9.9, 2.5 Hz, 1H), 7.35 (td, J = 8.8, 2.6 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.64 (q, J = 7.3 Hz, 1H), 3.84 (s, 3H), 1.69 (d, J = 7.3 Hz, 3H).

[0240] The following compounds were prepared by a procedure similar to that described for Example 51 with the corresponding isoquinolin-1(2H)-one derivative as the starting material and analogous aniline intermediates for the second step. For the following compounds, the aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate A using the corresponding aryl halide and aryl-Bpin.

[0241] For the following examples, the aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate B using the corresponding aryl halide and aminophenyl-Bpin.

[0242] For the following molecules, the aniline intermediate used in step 2 was prepared by the procedure described for intermediate C.Example 93. Synthesis of (R)-2-(6-(dimethylamino)-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1- methyl-1H-pyrazol-5-yl)phenyl)propanamide (93)Step 1.6-Bromo-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-1(2H)-one

[0243] To a solution of 6-bromoisoquinolin-1(2H)-one (1.0 g, 4.5 mmol) in THF (15 mL) were added t-BuOK (13 mL, 1.0 M in THF) and SEM-Cl (1.1 g, 6.7 mmol) at 0°C. Then the mixture was stirred at rt under N2overnight and quenched with H2O. The mixture was extracted with EtOAc twice. The organic layer was dried over Na2SO4and chromatographed on silica gel (10~11% EtOAc in petroleum ether) to give 6-bromo-2-((2- (trimethylsilyl)ethoxy)methyl)isoquinolin-1(2H)-one (830 mg, 53%) as a white solid. LC / MS ESI (m / z): 354, 356 (M+H)+. Step 2.6-(Dimethylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-1(2H)-one

[0244] A mixture of 6-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-1(2H)-one (870 mg, 2.5 mmol), dimethylamine (1.4 mL, 2.0 M, 2.7 mmol), Pd2(dba)3 (230 mg, 0.2 mmol), BINAP (310 mg, 0.5 mmol) and t-BuONa (710 mg, 7.4 mmol) in toluene (8 mL) was stirred at 110°C under N2overnight. The solvents were evaporated. The residue was chromatographed on silica gel (10~11% EtOAc in petroleum ether) to give 6-(dimethylamino)-2-((2- (trimethylsilyl)ethoxy)methyl)isoquinolin-1(2H)-one (750 mg, 96%) as a yellow oil. LC / MS ESI (m / z): 319 (M+H)+. Step 3.6-(Dimethylamino)isoquinolin-1(2H)-one

[0245] To a solution of 6-(dimethylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin- 1(2H)-one (750 mg, 2.3 mmol) in THF (3 mL) was added TBAF (7.0 mL, 1.0 M in THF, 7.0 mmol). Then the mixture was stirred at 60°C overnight, cooled to rt and quenched with H2O.The mixture was extracted with EtOAc twice. The organic layer was concentrated and chromatographed on silica gel (70~100% EtOAc in petroleum ether) to give 6- (dimethylamino)isoquinolin-1(2H)-one (270 mg, 61%) as a yellow solid. LC / MS ESI (m / z): 189 (M+H)+. Step 4. (R)-2-(6-(Dimethylamino)-1-oxoisoquinolin-2(1H)-yl)propanoic acid

[0246] To a suspension of Mg(Ot-Bu)2(490 mg, 2.9 mmol) in THF (10 mL) was added (S)- 2-chloropropanoic acid (230 mg, 2.1 mmol) at 0°C under N2. After aging for 10 min, t-BuOK (1.5 mL, 1.0 M in THF) was added. After aging for another 20 min, 6- (dimethylamino)isoquinolin-1(2H)-one (270 mg, 1.4 mmol) was added. Then the mixture was stirred at rt for 2 h and then at 55°C overnight. After cooling to rt, the mixture was adjusted to pH 2-3 with HCl (6 M) and extracted with DCM twice. The combined organic layers were chromatographed on silica gel (0~10% MeOH in DCM) to afford (R)-2-(6-(dimethylamino)- 1-oxoisoquinolin-2(1H)-yl)propanoic acid (320 mg, 86%) as a white solid. LC / MS ESI (m / z): 261 (M+H)+. Step 5. (R)-2-(6-(Dimethylamino)-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol- 5-yl)phenyl)propanamide

[0247] At -10°C, to a solution of (R)-2-(6-(dimethylamino)-1-oxoisoquinolin-2(1H)- yl)propanoic acid (200 mg, 0.8 mmol) and 4-(1-methyl-1H-pyrazol-5-yl)aniline (170 mg, 1.0 mmol) in pyridine / DCM (2 mL / 5 mL) under N2were added POCl3(180 mg, 1.2 mmol) dropwise. Then the mixture was stirred at -10°C for 30 min and quenched with H2O. The mixture was extracted with DCM twice. The organic layer was concentrated and chromatographed on silica gel (0~10% MeOH in DCM) to give the crude product, which was further purified by prep-HPLC to afford (R)-2-(6-(dimethylamino)-1-oxoisoquinolin-2(1H)- yl)-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propanamide (59 mg, 18%) as a white solid. LC / MS ESI (m / z): 416 (M+H)+.1HNMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.76 – 7.70 (m, 2H), 7.50 – 7.45 (m, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 6.95 (dd, J = 9.1, 2.6 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 1.9 Hz, 1H), 5.62 (q, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.04 (s, 6H), 1.62 (d, J = 7.3 Hz, 3H). Example 94. Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-ethyl-1H- pyrazol-5-yl)phenyl)propanamide (94)

[0248] The acid intermediate used in step 3 was prepared by the procedure described for intermediate E. Step 1.1-Ethyl-5-iodo-1H-pyrazole

[0249] At -78℃, to a solution of 1-ethyl-1H-pyrazole (1.0 g, 10 mmol) in THF (20 mL) were slowed added n-BuLi (12 mL, 1.6 M in hexanes) followed by a solution of I2 (3.96 g, 15.6 mmol) in THF (10 mL). After being stirred at -78℃ for 1 h, the reaction quenched with NH4Cl (aq) and Na2S2O3 (aq). The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20% ethyl acetate in petroleum ether) to afford 1-ethyl-5-iodo-1H-pyrazole (1.5 g, 65%) as a solid.1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 1.8 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). Step 2.4-(1-Ethyl-1H-pyrazol-5-yl)aniline

[0250] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (400 mg, 1.8 mmol) and 1-ethyl-5-iodo-1H-pyrazole (810 mg, 3.7 mmol) in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)CI3(130 mg, 0.18 mmol) and Na2CO3(580 mg, 5.5 mmol). The resulting mixture was heated to 100oC under N2overnight and concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford 4-(1-ethyl-1H-pyrazol-5-yl)aniline (230 mg, 67%). LC / MS ESI (m / z): 188 (M+H)+. Step 3. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl) propanamide

[0251] At -20℃, to a solution of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (100 mg, 0.40 mmol) and 4-(1-ethyl-1H-pyrazol-5-yl)aniline (100 mg, 0.40 mmol) in DCM (5 mL) were added pyridine (5 mL) followed by POCl3(61 mg, 0.40 mmol) dropwise. The resulting mixture was stirred at -20℃ for 0.5 h and quenched with water. The mixture was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) and prep-HPLC, to afford (R)-2-(6-chloro- 1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)propanamide (11 mg, 5.0%) as a white solid. LC / MS ESI (m / z): 421 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.53 (dd, J = 8.6, 2.1 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.44 – 7.38 (m, 2H), 6.71 (d, J = 7.6 Hz, 1H), 6.31 (d, J = 1.8 Hz, 1H), 5.64 (q, J = 7.3 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 1.69 (d, J = 7.3 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). Example 95. Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(pyrimidin-2- yl)phenyl)propanamide (95)Step 1.2-(4-Nitrophenyl)pyrimidine

[0252] To a solution of (4-nitrophenyl)boronic acid (400 mg, 2.39 mmol) in dioxane (5 mL) and H2O (1 mL) were added 2-chloropyrimidine (300 mg, 2.63 mmol), K2CO3(1.08 g, 7.83 mmol) and Pd(dppf)Cl2(100 mg, 0.14 mmol). The resulting mixture was stirred at 80℃ under N2overnight. After being cooled down to room temperature, the reaction was concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 2-(4-nitrophenyl)pyrimidine (350 mg, 73%) as a yellow solid.Step 2.4-(Pyrimidin-2-yl)aniline

[0253] To a solution of 2-(4-nitrophenyl)pyrimidine (350 mg, 1.74 mmol) in MeOH (10 mL) was added 10% Pd / C (80 mg). After being stirred at rt under H2 for 1 h, the reaction was filtered through Celite. The filtrate was concentrated to dryness to give 270 mg of the crude product as a yellow oil. LC / MS ESI (m / z): 172 (M+H)+. Step 3. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(pyrimidin-2-yl)phenyl) propanamide

[0254] To a solution of 4-(pyrimidin-2-yl)aniline (270 mg, 1.58 mmol) and (R)-2-(6-chloro- 1-oxoisoquinolin-2(1H)-yl)propanoic acid (610 mg, 2.43 mmol) in DCM (10 mL) were added pyridine (3 mL) and POCl3(0.18 mL, 2.02 mmol) dropwise. After being stirred at -20℃ for 1 h, the reaction was quenched with H2O. The mixture was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10% MeOH in dichloromethane) followed by prep-HPLC to afford (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)- yl)-N-(4-(pyrimidin-2-yl)phenyl)propanamide (30 mg, 4.7%) as a white solid. LC / MS ESI (m / z): 405 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.86 (d, J = 4.8 Hz, 2H), 8.35 (d, J = 8.8 Hz, 2H), 8.21 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.53 (dd, J = 8.6, 2.1 Hz, 1H), 7.39 (t, J = 4.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.65 (q, J = 7.2 Hz, 1H), 1.69 (d, J = 7.3 Hz, 3H).

[0255] The following compounds were prepared by a procedure similar to that described for Example 95 starting from the corresponding chloropyrimidine.Example 98. Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-ethyl-1H- pyrazol-3-yl)phenyl)propanamide (98)Step 1.3-Bromo-1-ethyl-1H-pyrazole, 5-bromo-1-ethyl-1H-pyrazole

[0256] To a solution of 3-bromo-1H-pyrazole (1.5 g, 10 mmol) in DMF (15 mL) were added K2CO3(4.3 mg, 31 mmol) and CH3CH2I (3.2 g, 21 mmol). The resulting mixture was heated to 60℃ overnight. After being cooled down to room temperature, the reaction was quenched with water. The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15% ethyl acetate in petroleum ether) to afford 600 mg of 3-bromo-1-ethyl-1H-pyrazole and 5-bromo-1-ethyl-1H-pyrazole mixture. LC / MS ESI (m / z): 175, 177 (M+H)+. Step 2.4-(1-Ethyl-1H-pyrazol-3-yl)aniline

[0257] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (630 mg, 2.87 mmol) and 500 mg mixture of 3-bromo-1-ethyl-1H-pyrazole and 5-bromo-1-ethyl-1H- pyrazole in dioxane (20 mL) and H2O (6 mL) were added Pd(dppf)Cl2(210 mg, 0.29 mmol) and K2CO3(1.19 g, 8.63 mmol). The resulting mixture was heated to 100℃ under N2overnight. The solvents were removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) and prep-HPLC to afford 4-(1-ethyl-1H-pyrazol-3-yl)aniline (180 mg). LC / MS ESI (m / z): 188 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 2.2 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 6.57 (d, J = 8.5 Hz, 2H), 6.43 (d, J = 2.2 Hz, 1H), 5.24 (br, 2H), 4.10 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.3 Hz, 3H). Step 3. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-ethyl-1H-pyrazol-3-yl)phenyl) propanamide

[0258] At -10℃, to a solution of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (100 mg, 0.40 mmol) and 4-(1-ethyl-1H-pyrazol-3-yl)aniline (74 mg, 0.40 mmol) in DCM (2 mL) were added pyridine (2 mL) and POCl3(92 mg, 0.60 mmol) dropwise. The resulting mixture was stirred at -10℃ for 0.5 h and quenched with water. The mixture was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) and prep-HPLC to afford (R)-2-(6-chloro-1- oxoisoquinolin-2(1H)-yl)-N-(4-(1-ethyl-1H-pyrazol-3-yl)phenyl)propanamide (11.2 mg, 7%) as a white solid. LC / MS ESI (m / z): 421 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.76 – 7.71 (m, 3H), 7.63 (t, J = 8.2 Hz, 3H), 7.53 (dd, J = 8.6, 2.1 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 5.65 (q, J = 7.3 Hz, 1H), 4.15 (q, J = 7.3 Hz, 2H), 1.68 (d, J = 7.3 Hz, 3H), 1.40 (t, J = 7.3 Hz, 3H). Example 99. Synthesis of (R)-N-(4-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(7- f

[0259] The acid intermediate used in step 3 was prepared by a procedure similar to that described for intermediate E. Step 1.4-Chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0260] To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (1.0 g, 4.8 mmol) in DMF (10 mL) was added NCS (705 mg, 5.28 mmol). The resulting mixture was heated at 70°C for 3 h. After being cooled down to room temperature, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20% ethyl acetate in petroleum ether) to afford 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 85%) as a solid. LC / MS ESI (m / z): 243 (M+H)+. Step 2.4-(4-Chloro-1-methyl-1H-pyrazol-5-yl)aniline

[0261] To a solution of 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (500 mg, 2.1 mmol) and 4-bromoaniline (390 mg, 2.3 mmol) in dioxane / H2O (15 mL / 3 mL) were added K2CO3(860 mg, 6.3 mmol) and Pd(dppf)Cl2(75 mg, 0.1 mmol). The mixture was stirred at 90°C under N2overnight. The solvents were removed by rotary evaporation. The residue was chromatographed on silica gel (20~40% ethyl acetate in petroleum ether) to give 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)aniline (80 mg, 18%) as a yellow oil. LC / MS ESI (m / z): 208 (M+H)+. Step 3. (R)-N-(4-(4-Chloro-1-methyl-1H-pyrazol-5-yl)phenyl)-2-(7-fluoro-4-oxoquinazolin- 3(4H)-yl)propanamide

[0262] To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)aniline (42 mg, 0.2 mmol) in MeCN (5 ml) were added (R)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanoic acid (40 mg, 0.2 mmol), 1-methyl-1H-imidazole (29 mg, 0.4 mmol) and TCFH (52 mg, 0.2 mmol) at 0°C. Then the mixture was stirred at 0°C for 40 min and quenched with H2O. The mixture was extracted with DCM twice. The organic layer was dried over Na2SO4and chromatographed on silica gel (60~75% ethyl acetate in petroleum ether) to give the crude product, which was further purified by prep-HPLC to afford (R)-N-(4-(4-chloro-1-methyl-1H-pyrazol-5- yl)phenyl)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide (10 mg, 14%) as a white solid. LC / MS ESI (m / z): 426 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.54 (s, 1H), 8.23 (dd, J = 8.9, 6.3 Hz, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.64 (s, 1H), 7.54 (dd, J = 10.0, 2.5 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.44 (dd, J = 8.8, 2.6 Hz, 1H), 5.57 (q, J = 7.4 Hz, 1H), 3.76 (s, 3H), 1.79 (d, J = 7.4 Hz, 3H).

[0263] The following compound was prepared by a synthetic procedure similar to that described for Example 99, using (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid as the acid intermediate for the last step.Example 101. Synthesis of (R)-2-(7-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-N-(4- (1-methyl-1H-pyrazol-5-yl)phenyl)propanamide (101)Step 1.3-Amino-5-chloropicolinamide

[0264] To a solution of 5-chloro-3-nitropicolinonitrile (1.0 g, 5.5 mmol) in EtOH (20 mL) was added SnCl2(3.1 g, 16 mmol) at 0°C. The reaction was stirred at rt for 2 h. The reaction was quenched with KF (aq). The precipitate was filtered off through a Celite pad. The filtrate was partitioned between EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo to afford the crude title compound 3-amino-5-chloropicolinamide (800 mg, 85%) as a yellow solid. LC / MS ESI (m / z): 172 (M+H)+. Step 2.7-Chloropyrido[3,2-d]pyrimidin-4(3H)-one

[0265] A solution of 3-amino-5-chloropicolinamide (800 mg, 4.7 mmol) in CH(OEt)3(10 mL) was heated to 150°C and stirred for 2 h. Then it was cooled to rt and suspended in EtOAc and water. The solid was collected by filtration and dried under high vacuum to afford the crude title compound 7-chloropyrido[3,2-d]pyrimidin-4(3H)-one (740 mg, 87%) as a yellow solid. LC / MS ESI (m / z): 182 (M+H)+. Step 3. (R)-2-(7-Chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)propanoic acid

[0266] To a solution of Mg(Ot-Bu)2(1.4 g, 8.2 mmol) in THF (20 mL) was added (S)-2- chloropropanoic acid (660 mg, 6.1 mmol) at 0°C. After aged for 10 min, 1M t-BuOK (4.3 mL, 4.3 mmol) was added and stirred for 20 min. Then 7-chloropyrido[3,2-d]pyrimidin-4(3H)-one (740 mg, 4.1 mmol) was added. The resulting mixture was stirred at rt for 2.5 h and then heated to 55°C and stirred for 18 h. The reaction was concentrated in vacuo. The residue was adjusted to pH 2~3 with 2 M HCl and concentrated. The residue was purified by prep-HPLC to afford the title compound (R)-2-(7-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)propanoic acid(250 mg, 24%) as a white solid. LC / MS ESI (m / z): 254 (M+H)+. Step 4. (R)-2-(7-Chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-N-(4-(1-methyl-1H-pyrazol- 5-yl)phenyl)propanamide

[0267] To a solution of (R)-2-(7-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)propanoic acid (50 mg, 0.20 mmol) in ACN (2 mL) were added 4-(1-methyl-1H-pyrazol-5-yl)aniline (34 mg, 0.20 mmol), NMI (34 mg, 0.42 mmol) and TCFH (61 mg, 0.22 mmol) at 0°C. The mixture was stirred at 0°C for 1 h. The reaction was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified by prep- HPLC to afford the title compound (R)-2-(7-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-N- (4-(1-methyl-1H-pyrazol-5-yl)phenyl)propanamide (63 mg, 78%) as a white solid. LC / MS ESI (m / z): 409 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.42 (s, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 6.30 (d, J = 1.9 Hz, 1H), 5.85 (q, J = 7.2 Hz, 1H), 3.90 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H). Example 102. Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(4- methyloxazol-5-yl)phenyl)propanamide (102)

[0268] The acid intermediate used in the last step was prepared by a procedure similar to that described for intermediate E. Step 1.5-(2-Fluoro-4-nitrophenyl)-4-methyloxazole

[0269] To a solution of 2-fluoro-4-nitrobenzaldehyde (100 mg, 0.6 mmol) in MeOH (5 mL) were added K2CO3(250 mg, 1.8 mmol) and 1-((1-isocyanoethyl)sulfonyl)-4-methylbenzene (120 mg, 0.6 mmol). The mixture was stirred at 75°C for 1.5 h, cooled to rt and quenched with H2O. The mixture was extracted with EtOAc twice. The organic layer was concentrated andchromatographed on silica gel (10~17% EtOAc in petroleum ether) to give 5-(2-fluoro-4- nitrophenyl)-4-methyloxazole (110 mg, 91%) as a white solid. Step 2.3-Fluoro-4-(4-methyloxazol-5-yl)aniline

[0270] To a solution of 5-(2-fluoro-4-nitrophenyl)-4-methyloxazole (70 mg, 0.3 mmol) in MeOH were added iron powder (190 mg, 3.4 mmol) and NH4Cl (150 mg, 2.7 mmol). The resulting mixture was stirred at 90°C for 2 h and filtered through a Celite pad. The filtrate was concentrated to give crude 3-fluoro-4-(4-methyloxazol-5-yl)aniline (63 mg, 96%) as a solid. LC / MS ESI (m / z): 193 (M+H)+. Step 3. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(4-methyloxazol-5-yl) phenyl)propanamide

[0271] To a solution of 3-fluoro-4-(4-methyloxazol-5-yl)aniline (90 mg, 0.5 mmol) in MeCN (5 mL) were added (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid (100 mg, 0.4 mmol), 1-methyl-1H-imidazole (68 mg, 0.8 mmol) and TCFH (120 mg, 0.4 mmol) at 0°C. Then the mixture was stirred at 0°C for 40 min and quenched with H2O. The mixture was extracted with DCM twice. The organic layer was concentrated and chromatographed on silica gel (70~85% EtOAc in petroleum ether) to give the crude product, which was further purified by prep-HPLC to afford (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(4- methyloxazol-5-yl)phenyl)-propanamide (52 mg, 31%) as a white solid. LC / MS ESI (m / z): 427 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 13.1, 1.9 Hz, 1H), 7.62 (dd, J = 8.6, 2.1 Hz, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.48 – 7.43 (m, 1H), 5.53 (q, J = 7.4 Hz, 1H), 2.19 (d, J = 1.9 Hz, 3H), 1.78 (d, J = 7.4 Hz, 3H). Example 103. Synthesis of (R)-2-(5-Fluoro-1-oxoisoindolin-2-yl)-N-(4-(1-methyl-1H- pyrazol-5-yl)phenyl)propanamide (103)Step 1. (R)-2-(5-Fluoro-1-oxoisoindolin-2-yl)propanoic acid

[0272] To a mixture of Mg(Ot-Bu)2(560 mg, 3.3 mmol) in anhydrous THF (8 mL) was added portion-wise (S)-2-chloropropionic acid (270 mg, 2.4 mmol) to maintain the internal temperature at 30 to 35 °C. After 10 min, KOt-Bu (1.18 g, 10.5 mmol) was added, and theresulting mixture was stirred at rt for another 15 min.5-Fluoroisoindolin-1-one (250 mg, 1.6 mmol) and additional THF (1 mL) was then added, and the reaction mixture stirred at 35 °C for 36 h. After the completion of reaction, it was cooled to 0oC and water (20 mL) added. The reaction mixture was extracted with MTBE (30 mL) to remove the unreacted starting material. The aqueous layer was adjusted to pH 2.0-2.5 with 3M HCl and extracted with EtOAc (3 X 25 mL), the combined organic layers washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated to obtain (R)-2-(5-fluoro-1-oxoisoindolin-2-yl)propanoic acid (270 mg, 72%) as an off-white solid. LC / MS ESI (m / z): 223.9 (M+H)+. Step 2. (R)-2-(5-Fluoro-1-oxoisoindolin-2-yl)-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl) propenamide

[0273] To a stirred solution of (R)-2-(5-fluoro-1-oxoisoindolin-2-yl)propanoic acid (75 mg, 0.33 mmol), 4-(1-methyl-1H-pyrazol-5-yl)aniline (57 mg, 0.33 mmol) and HATU (190 mg, 0.49 mmol) in DMF (1.0 mL) was treated with DIPEA (0.12 mL, 0.66 mmol) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. After the completion of the reaction, water was added and the reaction mixture was extracted into ethyl acetate (2 X 10 mL), combined organic layer washed with saturated sodium bicarbonate solution (5 mL) and with brine (5 mL), dried over sodium sulfate, filtered, concentrated, and subjected to flash chromatography (60% EtOAc / hexane) to obtain the (R)-2-(5-fluoro-1-oxoisoindolin-2-yl)-N- (4-(1-methyl-1H-pyrazol-5-yl)phenyl)propenamide (95 mg, 75%) as a white solid. LC / MS ESI (m / z): 378.7 (M+H)+.1H NMR (CD3OD, 600 MHz) δ 7.82 – 7.80 (m, 1H), 7.71 (d, 2H), 7.61 – 7.57 (m, 3H), 7.39 (d, 1H), 7.26 (t, 1H), 6.57 (s, 1H), 5.09 (q, 1H), 4.83 (d, 1H), 4.67 (d, 1H), 3.91 (s, 3H), 1.66 (d, 3H).

[0274] The following compounds were prepared by procedures analogous to the synthesis of Example 103 using corresponding anilines and acids.Example 116. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-4-hydroxy-N-(4-(1-methyl-1H- pyrazol-3-yl)phenyl)butanamide (116)Step 1. (R)-tert-Butyl (4-((tert-butyldiphenylsilyl)oxy)-1-((4-(1-methyl-1H-pyrazol-3-yl) phenyl)amino)-1-oxobutan-2-yl)carbamate

[0275] To a stirred solution of (R)-2-((tert-butoxycarbonyl)amino)-4-((tert- butyldiphenylsilyl)oxy)butanoic acid (500 mg, 1.09 mmol) and 4-(1-methyl-1H-pyrazol-5- yl)aniline (189 mg, 1.09 mmol) and HATU (294 mg, 1.63 mmol) in DMF (5.0 mL) was added DIPEA (0.38 mL, 2.2 mmol) at 0oC. After the completion of the reaction, water (25 mL) was added and the reaction mixture was extracted into ethyl acetate (3 X 25 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (10 mL) and with brine (2 X 25 mL), dried over sodium sulfate, filtered, concentrated, and subjected to flashchromatography (60% EtOAc / hexane) to obtain the (R)-tert-butyl (4-((tert- butyldiphenylsilyl)oxy)-1-((4-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-1-oxobutan-2- yl)carbamate (510 mg, 76%) as a white solid. LC / MS ESI (m / z): 612.8 (M+H)+. Step 2. (R)-2-Amino-4-((tert-butyldiphenylsilyl)oxy)-N-(4-(1-methyl-1H-pyrazol-3-yl) phenyl)butanamide

[0276] To a stirred solution of (R)-2-amino-4-((tert-butyldiphenylsilyl)oxy)-N-(4-(1- methyl-1H-pyrazol-3yl)phenyl)butanamide (500 mg, 0.81 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.37 mL, 4.9 mmol) at 0oC and then stirred at room temperature. After the completion of the reaction, it was concentrated to obtain the crude compound. The reaction mixture was basified with sat. NaHCO3solution to pH 7.0-8.0. The aqueous layer was extracted with CH2Cl2(2 X 50 mL), the combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated to obtain (R)-2-amino-4-((tert- butyldiphenylsilyl)oxy)-N-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)butanamide (359 mg, 86%). Step 3. (R)-4-((tert-Butyldiphenylsilyl)oxy)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1- methyl-1H-pyrazol-3-yl)phenyl)butanamide

[0277] To a stirred solution of (R)-2-amino-4-((tert-butyldiphenylsilyl)oxy)-N-(4-(1-methyl- 1H-pyrazol-3-yl)phenyl)butanamide (300 mg, 0.58 mmol) ) in 1,4-dioxane (80 mL) was added (E)-methyl 4-chloro-2-(((dimethylamino)methylene)amino)benzoate (140 mg, 0.58 mmol) and p-toluenesulfonic acid (11 mg, 0.05 mmol) at room temperature and the resultant reaction mixture was stirred at 100 °C for 4 h. After the completion of reaction, it was cooled to room temperature, treated with Et3N (0.2 mL) and the reaction mixture evaporated to obtain the crude compound. It was purified by silica gel flash chromatography (70% EtOAc / hexane) to obtain the (R)-4-((tert-butyldiphenylsilyl)oxy)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1- methyl-1H-pyrazol-3-yl)phenyl)butanamide (230 mg, 58%) as a white solid. LCMS ESI (m / z): 676.0 (M+H)+. Step 4. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-4-hydroxy-N-(4-(1-methyl-1H-pyrazol- 3-yl)phenyl)butanamide

[0278] To a stirred solution of (R)-4-((tert-butyldiphenylsilyl)oxy)-2-(7-chloro-4- oxoquinazolin-3(4H)-yl)-N-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)butanamide (200 mg, 0.45 mmol) in THF (3 mL) was added TBAF solution (1.0 M in THF, 0.9 ml, 0.9 mmol) at room temperature and the resultant reaction mixture was stirred for 1h. After completion of the reaction, it was diluted with water (10 mL) and EtOAc (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 X 25 mL). The combined organic layer was washed with brine (2 X 25 mL), dried over sodium sulfate, filtered,concentrated, and subjected to flash chromatography (90% EtOAc / hexane) to obtain (R)-2- (7-chloro-4-oxoquinazolin-3(4H)-yl)-4-hydroxy-N-(4-(1-methyl-1H-pyrazol-3 yl)phenyl)butanamide (100 mg, 81%) as a white solid. LC / MS ESI (m / z): 437.7 (M+H)+.1H NMR (600 MHz, CD3OD) δ 8.55 (s, 1H), 8.24 (d, 1H), 7.77 – 7.72 (m, 3H), 7.64 (d, 2H), 7.58 (d, 2H), 6.60 (s, 1H), 5.80 (s, 1H), 3.93 (s, 3H), 3.74 (d, 1H), 3.64 (s, 1H), 2.55 (d, 1H), 2.41 (d, 1H).

[0279] The following compounds were prepared by procedures analogous to the synthesis of Example 116.Example 62-1. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol-5- yStep 1. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid

[0280] To a mixture of Mg(Ot-Bu)2(28.4 g, 167 mmol) in anhydrous THF (100 mL) was added dropwise (S)-2-chloropropionic acid (13.5 g, 125 mmol) to maintain the internal temperature at ≤35 °C. After stirring for 10 min, KOtBu (9.8 g, 87 mmol) was added followed by 6-chloroisoquinolin-1(2H)-one (15.0 g, 83.5 mmol) and additional THF (50 mL). The reaction mixture was allowed to stir at 35 °C for 36 h. After the completion of reaction, it was cooled to 0oC and quenched with water (20 mL). To the above reaction mixture was added EtOAc (100 mL) and the organic layer was separated to remove the unreacted starting material. The aqueous layer was treated with 3M HCl to adjust to pH 2.0-2.5 and extracted with EtOAc (100 mL X 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)- yl)propanoic acid (18.0 g, 85%) as a white solid. Step-2. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol-5-yl) phenyl)propenamide

[0281] To a mixture of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (11.0 g, 43.7 mmol) and 4-(1-methyl-1H-pyrazol-5-yl)aniline (7.50 g, 43.7 mmol) and pyridine (13.8 mL, 175 mmol) in DCM (110 mL) was added POCl3(4.80 mL, 52.4 mmol) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. After the completion of the reaction, water (100 mL) was added and the reaction mixture was extracted into ethyl acetate (3 X 100 mL), washed with sat. bicarbonate solution (2 X 100 mL), and brine (2 X 100 mL), dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (75% EtOAc / hexane) to obtain a white solid. The solid was diluted with methanol (60 vol). The resulting mixture was heated at 70 °C for 45 min. After cooling to rt, the solution was filtered, and filtrate was concentrated to afford (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)- N-(4-(1-methyl-1H-pyrazol-5-yl) phenyl)propanamide (5.2 g, 30%) as a pale yellow solid. LC / MS ESI (m / z): 406.8 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 10.53 (s, 1H), 8.21 (d, 1H), 7.84 (d, 1H), 7.72 (d, 2H), 7.64 (d, 1H), 7.53 (dd, 1H), 7.48 (d, 2H), 7.44 (d, 1H), 6.70 (d, 1H), 6.36 (d, 1H), 5.63 (q, 1H), 3.83 (s, 3H), 1.68 (d, 3H).

[0282] The following compounds were prepared by procedures analogous to the synthesis of Example 62-1.Example 26-1. Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1-methyl- 1H-pyrazol-5-yl)phenyl)propanamide (26-1)Step 1.4-(1-Methyl-1H-pyrazol-5-yl)aniline

[0283] To a mixture of 5-bromo-1-methyl-1H-pyrazole (20.0 g, 124 mmol) in dioxane (200 mL) and water (20 mL) was added (4-aminophenyl) boronic acid hydrochloride (28.0 g, 161 mmol) and potassium carbonate (42.9 g, 311 mmol) at room temperature. The mixture was degassed before addition of Pd(dppf)Cl2^CH2Cl2(4.54 g, 6.21 mmol) and heated at 100 °C for 16 h. After the completion of reaction, the reaction mixture was cooled to room temperature, filtered and washed with EtOAc (3 X 300 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (35% EtOAc / hexane) to obtain 4-(1- methyl-1H-pyrazol-5-yl)aniline (15 g, 70%) as a brown solid. Step 2. (R)-tert-Butyl (1-((4-(1-methyl-1H-pyrazol-5-yl)phenyl)amino)-1-oxopropan-2-yl) carbamate

[0284] A mixture of 4-(1-methyl-1H-pyrazol-5-yl)aniline (8.0 g, 46 mmol), (R)-2-((tert- butoxycarbonyl)amino)propanoic acid (8.74 g, 46.2 mmol) and HATU (21.1 g, 55.3 mmol) in DMF (80 mL) was cooled to 0-5 °C. DIPEA (20.2 mL, 115 mmol) was added to the reaction mixture and stirred overnight at rt. After the completion of the reaction, water (250 mL) was added and the reaction mixture was extracted into ethyl acetate (3 X 150 mL), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to obtain (R)-tert-butyl (1-((4- (1-methyl-1H-pyrazol-5-yl)phenyl)amino)-1-oxopropan-2-yl)carbamate (13 g, 81%). The crude material was used in the next step without further purification. Step 3. (R)-2-Amino-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propenamide

[0285] To a stirred solution of (R)-tert-butyl (1-((4-(1-methyl-1H-pyrazol-5- yl)phenyl)amino)-1-oxopropan-2-yl)carbamate (13.0 g, 37.8 mmol) in CH2Cl2(65 mL) was added TFA (14.5 mL, 189 mmol) at 0 °C . The reaction mixture was stirred for 6 h at rt. After the completion of the reaction, the reaction mixture was concentrated, diluted with water (200 mL), extracted with CH2Cl2(2 X 50 mL). The organic layer was separated to remove the unreacted starting material. The aqueous layer was basified with sat. NaHCO3solution to pH 7.0 – 8.0 and extracted with 10% MeOH / DCM (2 X 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to obtain (R)-2-amino-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propanamide (8.0 g, 86%). Step 4. (E)-Methyl 4-chloro-2-(((dimethylamino)methylene)amino)benzoate

[0286] A solution of methyl 2-amino-4-chlorobenzoate (7.00 g, 32.4 mmol) in N,N- dimethylformamide dimethyl acetal (3.08 mL, 38.9 mmol) was heated at 90 °C for 16 h. After the completion of the reaction, the reaction mixture was concentrated to obtain (E)-methyl 4-chloro-2-(((dimethylamino)methylene)amino)benzoate (8.0 g, 87%) as a brown liquid. The crude material was used in the next step without further purification. Step 5. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl) propenamide

[0287] A solution of (R)-2-amino-N-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propanamide (8.0 g, 33 mmol), (E)-methyl 4-chloro-2-(((dimethylamino)methylene)amino)benzoate (7.93 g, 32.8 mmol) and p-toluenesulfonic acid (0.62 g, 3.27 mmol) in dioxane (80 mL) was stirred at 100 °C for 3 h. After the completion of reaction, the reaction mixture was cooled to room temperature and water (250 mL) was added to precipitate the crude product as brown solid. The crude material was purified by silica gel flash chromatography (90% EtOAc / hexane) to obtain a white solid. The isolated material was diluted with methanol (60 vol) and heated at 70 °C for 1 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated to afford (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1-methyl-1H- pyrazol-5-yl)phenyl)propanamide (6.5 g, 55%) as a white solid. LC / MS ESI (m / z): 408.2 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 10.56 (s, 1H), 8.54 (s, 1H), 8.15 (d, 1H), 7.82 (d, 1H), 7.71 (d, 2H), 7.61 (dd, 1H), 7.49 (d, 2H), 7.44 (d, 1H), 6.36 (d, 1H), 5.56 (q, 1H), 3.83 (s, 3H), 1.78 (d, 3H).

[0288] The following compounds were prepared by procedures similar to the synthesis of Example 26-1 using the corresponding aryl halides and aniline / amines.Example 166. Synthesis of (R)-2-(5-chloro-1-oxoisoindolin-2-yl)-N-(4-(3-methylpyridin-2- yl) phenyl)propanamide (166)Step 1.4-(3-Methylpyridin-2-yl)aniline

[0289] To a mixture of 2-bromo-3-methylpyridine (700 mg, 4.06 mmol) in dioxane (7 mL) and water (0.7 mL) was added (4-aminophenyl) boronic acid hydrochloride (917 mg, 5.29 mmol) and potassium carbonate (1.40 g, 10.2 mmol). The resulting reaction mixture was degassed with argon gas for 20 min. After addition of Pd(dppf)Cl2·CH2Cl2(148 mg, 0.20 mmol), the reaction mixture was allowed to stir at 100 °C for 16 h. After the completion of reaction, the reaction mixture was cooled to room temperature, filtered through celite pad and washed with EtOAc (3 X 70 mL). The filtrate was washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (35% EtOAc / hexane) to obtain the 4-(3-methylpyridin-2-yl)aniline (400 mg, 54%) as a brown solid. Step 2. (R)-tert-Butyl (1-((4-(3-methylpyridin-2-yl) phenyl) amino)-1-oxopropan-2-yl) carbamate

[0290] A mixture of 4-(3-methylpyridin-2-yl)aniline (100 mg, 0.54 mmol), (R)-2-((tert- butoxycarbonyl) amino)propanoic acid (103 mg, 0.54 mmol) and HATU (248 mg, 0.65 mmol) in DMF (1 mL) was cooled to 0 – 5 °C. The reaction mixture was treated with DIPEA (0.23 mL, 1.4 mmol) and stirred overnight at room temperature under nitrogen atmosphere. After the completion of the reaction, water (25 mL) was added and the reaction mixture was extracted into ethyl acetate (3 X 20 mL). The combined organic layers were washed with brine (2 X 10 mL), dried over sodium sulfate, filtered and concentrated to obtain (R)-tert-butyl (1-((4-(3-methylpyridin-2-yl)phenyl)amino)-1-oxopropan-2-yl)carbamate (100 mg, 52%) as a brown gum. Step 3. (R)-2-Amino-N-(4-(3-methylpyridin-2-yl)phenyl)propenamide

[0291] A mixture of (R)-tert-butyl (1-((4-(3-methylpyridin-2-yl)phenyl)amino)-1- oxopropan-2-yl)carbamate (100 mg, 0.28 mmol) in DCM (0.5 mL) was cooled to 0 – 5 °C and treated with trifluoroacetic acid (0.3 mL) dropwise. After stirring for 4 h at room temperature under nitrogen atmosphere, the reaction mixture was concentrated, diluted with water (20 mL) and extracted with EtOAc (2 X 10 mL) to remove the unreacted starting material. The aqueous phase was basified with sat. NaHCO3 solution to pH 7 – 8 and extracted with 10% MeOH / DCM (2 X 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain (R)-2-amino-N-(4-(3- methylpyridin-2-yl) phenyl)propanamide (70 mg) as a pale yellow gum. Step 4. (R)-2-(5-Chloro-1-oxoisoindolin-2-yl)-N-(4-(3-methylpyridin-2-yl) phenyl) propenamide

[0292] A mixture of (R)-2-amino-N-(4-(3-methylpyridin-2-yl) phenyl)propanamide (70 mg, 0.27 mmol), methyl 2-(bromomethyl)-4-chlorobenzoate (72 mg, 0.27 mmol) and triethyl amine (0.09 mL, 0.68 mmol) in methanol (1 mL) was allowed to stir at 60 °C for 5 h. After the completion of reaction, it was cooled to room temperature. The resultant mixture was concentrated and purified by flash chromatography (50% EtOAc / hexane) to obtain (R)-2-(5- chloro-1-oxoisoindolin-2-yl)-N-(4-(3-methylpyridin-2-yl) phenyl)propanamide (11 mg, 10%) as an off-white solid. LC / MS ESI (m / z): 406.0 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 10.34 (s, 1H), 8.45 (d, 1H), 7.77 (s, 1H), 7.73 – 7.67 (m, 4H), 7.58 – 7.56 (m, 1H), 7.51 (d, 2H), 7.27 – 7.24 (m, 1H), 5.05 – 5.00 (m, 1H), 4.80 – 4.62 (m, 2H), 2.32 (s, 3H), 1.57 (d, 3H).

[0293] The following compounds were prepared by a procedure analogous to the synthesis of Example 166 using the corresponding aryl halides.Example 169. Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1,4-dimethyl- 1H-pyrazol-5-yl) phenyl)propanamide (169)Step 1. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid

[0294] To a mixture of Mg(Ot-Bu)2 (18.8 g, 111 mmol) in anhydrous THF (70 mL) was added drop-wise (S)-2-chloropropionic acid (7.1 mL, 83 mmol) to maintain the internal temperature at ≤35 °C. After 10 min, KOt-Bu (6.5 g, 58 mmol) was added followed by 7- chloroquinazolin-4(3H)-one (10 g, 55 mmol) and additional THF (30 mL). The reaction mixture was allowed to stir at 35 °C for 36 h. After the completion of reaction, the mixture was cooled to 0oC, quenched into water (20 mL) and extracted with MTBE (3 X 10 mL) to remove unreacted starting material. The aqueous layer was acidified with 3M HCl to pH 2.0- 2.5 and extracted with EtOAc (2 X 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain (R)-2-(7-chloro-4- oxoquinazolin-3(4H)-yl)propanoic acid (6.0 g, 43%) as an off-white solid. Step 2. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1,4-dimethyl-1H-pyrazol-5-yl) phenyl)propenamide

[0295] A mixture of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid (200 mg, 1.06 mmol), 4-(1,4-dimethyl-1H-pyrazol-5-yl)aniline (274 mg, 1.06 mmol) and HATU (487 mg, 1.28 mmol) in DMF (2.0 mL) was cooled to 0-5° C. The reaction mixture was treated with DIPEA (0.46 mL, 2.7 mmol) and stirred overnight at room temperature under nitrogen atmosphere. After the completion of the reaction, water (10 mL) was added and the mixture was extracted into ethyl acetate (5 X 10 mL). The combined organic layers were washed with brine (5 X 5 mL), dried over sodium sulfate, filtered, concentrated, and subjected to flash chromatography (80% EtOAc / hexane) to obtain the (R)-2-(7-chloro-4-oxoquinazolin-3(4H)- yl)-N-(4-(1,4-dimethyl-1H-pyrazol-5-yl)phenyl)propanamide (120 mg, 26%) as a brown solid. LC / MS ESI (m / z): 421.8 (M+H)+.1H NMR (DMSO-d6, 400 MHz) δ 10.55 (s, 1H),8.54 (s, 1H), 8.16 (d, 1H), 7.81 (s, 1H), 7.73 (d, 2H), 7.61 (d, 1H), 7.36 (d, 2H), 7.30 (s, 1H), 5.60 –5.54 (m, 1H), 3.68 (s, 3H), 1.99 (s, 3H), 1.79 (d, 3H).

[0296] The following compounds were prepared using a procedure similar to the synthesis of Example 169 using the corresponding aryl halides.Example 198. Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(3- hydroxypyridin-2-yl) phenyl)propanamide (198)

[0297] A mixture (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(3-methoxypyridin-2-yl) phenyl)propanamide (100 mg, 0.22 mmol) in DCM (2 mL) at 0 – 5 °C was treated with 1M boron tribromide in dichloromethane (0.45 mL, 045 mmol) and stirred overnight at room temperature under nitrogen. After the reaction was complete, it was cooled to 0oC, quenched into sat. NaHCO3(25 mL) and extracted into 10% MeOH / DCM (3 X 30 mL). The organic layers were dried over Na2SO4, filtered, concentrated, and subjected to flash chromatography (2% MeOH / DCM) to obtain (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(3- hydroxypyridin-2-yl)phenyl)propanamide (24 mg, 25%) as a pale brown solid. LC / MS ESI (m / z): 421.3 (M+H)+.1H NMR (DMSO-d6 , 400 MHz) δ 10.49 (s, 1H), 10.13 (s, 1H), 8.54 (s, 1H), 8.17 – 8.11 (m, 2H), 8.02 (d, 2H), 7.82 (d, 1H), 7.64 – 7.59 (m, 3H), 7.30 (dd, 1H), 7.17 – 7.14 (m, 1H), 5.58 (q, 1H), 1.78 (d, 3H). Example 199. Synthesis of (R)-2-(7-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-(4- (1-methyl-1H-pyrazol-3-yl) phenyl)propanamide (199)Step 1. (S)-2-Chloro-N-(4-(1-methyl-1H-pyrazol-3-yl) phenyl)propenamide

[0298] A mixture of 4-(1-methyl-1H-pyrazol-3-yl)aniline (500mg, 2.89 mmol), (S)-2- chloropropanoic acid (314 mg, 2.89 mmol) and HATU (1.30 g, 3.46 mmol) in DMF (5 mL) at 0-5° C was treated with DIPEA (1.20 mL, 7.22 mmol) and stirred overnight at room temperature under nitrogen. After the completion of the reaction, water (25 mL) was added and the reaction mixture was extracted into ethyl acetate (3 X 20 mL). The combined organic layers were washed with brine (2 X 10 mL), dried over Na2SO4, filtered, and concentrated toobtain the (S)-2-chloro-N-(4-(1-methyl-1H-pyrazol-3-yl) phenyl)propanamide (200 mg, 26%) as a brown gum which was used directly in the next step. Step 2. (R)-2-(7-Chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-(4-(1-methyl-1H- pyrazol-3-yl) phenyl)propenamide

[0299] A mixture of (S)-2-chloro-N-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)propanamide (150 mg, 0.56 mmol), 6-chloro-3,4-dihydroisoquinolin-1(2H)-one (207 mg, 1.13 mmol) and cesium carbonate (371 mg, 1.13 mmol) in toluene (2 mL) was heated for 16 h at 100°C under nitrogen. After the completion of the reaction, the reaction mixture was concentrated, diluted with water (20 mL) and extracted with EtOAc (2 X 15 mL). The combined organic layers were washed with brine, filtered, dried over Na2SO4, concentrated and purified by silica gel chromatography (25-30% EtOAc / hexanes) to obtain (R)-2-(7-chloro-1-oxo-3,4- dihydroisoquinolin-2(1H)-yl)-N-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)propanamide (16 mg, 6.0%) as a brown solid. LC / MS ESI (m / z): 409.1 (M+H)+.1H NMR (DMSO-d6 , 400 MHz) δ 10.04 (s, 1H), 7.74 – 7.66 (m, 4H), 7.63 – 7.61 (m, 2H), 7.44 – 7.22 (m, 2H), 6.61 (d, 1H), 5.28 – 5.26 (m, 1H), 3.85 (s, 3H), 3.53 – 3.49 (m, 2H), 2.72 (t, 2H), 1.52 (d, 3H). Example 22-1. Alternative synthesis of (R)-2-(3-chloro-8-oxo-1,7-naphthyridin-7(8H)-yl)- N-(4-(3-fluoropyridin-2-yl)phenyl)propanamide (22)

[0300] To a mixture of 4-(3-fluoropyridin-2-yl)aniline (75 mg, 0.4 mmol) and (R)-2-(3- chloro-8-oxo-1,7-naphthyridin-7(8H)-yl)propanoic acid (100 mg, 0.4 mmol) in DCM (20 mL) at -20℃ were added pyridine (0.2 mL, 2.4 mmol) and POCl3(370 mg, 2.4 mmol) dropwise. After being stirred at -20℃ for 1 h, the reaction was quenched with 2 N HCl (aq) and extracted with DCM twice. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to afford (R)-2-(3-chloro-8-oxo-1,7- naphthyridin-7(8H)-yl)-N-(4-(3-fluoropyridin-2-yl)phenyl)propanamide (60 mg, 36%) as a white solid. LC / MS ESI (m / z): 423 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.55 – 8.48 (m, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.7, 1.4 Hz, 2H), 7.80 (ddd, J = 11.9, 8.3, 1.3 Hz, 1H), 7.77 – 7.71 (m, 3H), 7.47 – 7.39 (m, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.69 (q, J = 7.3 Hz, 1H), 1.70 (d, J = 7.3 Hz, 3H).

[0301] The following compounds were prepared by a procedure similar to the synthesis of Example 22-1 using the corresponding acids and anilines.Example 203. Synthesis of 1-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1- methyl-1H-pyrazol-5-yl)phenyl)cyclopropane-1-carboxamide (203)Step 1. tert-Butyl (1-((4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)carbamoyl)cyclopropyl) carbamate

[0302] To a solution of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)aniline (200 mg, 1.05 mmol) and 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (231 mg, 1.15 mmol) in MeCN (5 mL) were added NMI (170 mg, 2.1 mmol) and TCFH (323 mg, 1.15 mmol). The resulting mixture was stirred at rt for 1 h and quenched with water. The mixture was extracted with EtOAc, washed with NaHCO3(aq), dried over Na2SO4and purified by silica gel column chromatography (0~50% ethyl acetate in petroleum ether) to afford tert-butyl (1-((4-(4-fluoro- 1-methyl-1H-pyrazol-5-yl)phenyl)carbamoyl)cyclopropyl)carbamate (350 mg, 89%). LC / MS ESI (m / z): 375 (M+H)+. Step 2.1-Amino-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)cyclopropane-1- carboxamide

[0303] To a solution of tert-butyl (1-((4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)carbamoyl)cyclopropyl)carbamate (350 mg, 0.94 mmol) in DCM (10 mL) was added HCl in dioxane (3.0 mL, 4.0 M). The mixture was stirred at room temperature for 2 h and then concentrated to dryness to afford 1-amino-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)cyclopropane-1-carboxamide which was used in the next step directly. LC / MS ESI (m / z): 275 (M+H)+. Step 3.1-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5-yl) phenyl)cyclopropane-1-carboxamide

[0304] To a solution of 1-amino-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)cyclopropane-1-carboxamide (150 mg, 0.55 mmol) and methyl (E)-4-chloro-2- (((dimethylamino)methylene)amino)benzoate (260 mg, 1.1 mmol) in toluene (10 mL) was added TEA (278 mg, 2.75 mmol). After 5 min, AcOH (330 mg, 5.5 mmol) was added and the mixture was heated to 100oC for 2 h. The solvents were removed by rotary evaporation. The residue was purified by silica gel column chromatography (0~70% ethyl acetate in petroleum ether) and prep-HPLC to afford 1-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1- methyl-1H-pyrazol-5-yl)phenyl)cyclopropane-1-carboxamide (17 mg, 7.0%) as a white solid. LC / MS ESI (m / z): 438 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.49 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.74 – 7.68 (m, 2H), 7.62 (dd, J = 8.5, 2.1 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.48 – 7.43 (m, 2H), 3.77 (s, 3H), 1.90 – 1.79 (m, 2H), 1.59 – 1.42 (m, 2H).

[0305] The following compound was prepared by a procedure similar to the synthesis of Example 203 using the corresponding aniline.Example 205. Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1- methyl-1H-pyrazol-5-yl)phenyl)-N-methylpropanamide (205)Step 1. tert-Butyl (4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)carbamate

[0306] A mixture of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)aniline (100 mg, 0.52 mmol) and Boc2O (170 mg, 0.78 mmol) in dioxane (5 mL) was stirred at 100°C for 5 h. The solvent was evaporated. The residue was purified by flash column chromatography to afford tert-butyl (4- (4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)carbamate (100 mg, 68%). Step 2. tert-Butyl (4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)(methyl)carbamate

[0307] To a solution of tert-butyl (4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)carbamate (100 mg, 0.35 mmol) in THF (2 mL) was added NaH (42 mg, 60% in mineral oil, 1.1 mmol) at 0°C. The mixture was stirred at 0°C for 20 min. CH3I (100 mg, 0.7 mmol) in THF (2 mL) was added and the mixture was then stirred at rt for 2 h. The reaction was quenched with water (2.5 mL) and extracted with DCM (3 mL X 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford tert-butyl (4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)(methyl)carbamate (100 mg, 92%). LC / MS ESI (m / z): 306 (M+H)+. Step 3.4-(4-Fluoro-1-methyl-1H-pyrazol-5-yl)-N-methylaniline

[0308] To a solution of tert-butyl (4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)(methyl)carbamate (100 mg, 0.33 mmol) in DCM (2 mL) was added HCl in dioxane (2.0 mL, 4.0 M). The mixture was stirred at rt overnight and concentrated to afford 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-N-methylaniline (60 mg, 89%). LC / MS ESI (m / z): 206 (M+H)+. Step 4. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)-N-methylpropanamide

[0309] To a solution of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-N-methylaniline (60 mg, 0.29 mmol) and (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid (96 mg, 0.38 mmol) in ACN (3 mL) at 0°C were added NMI (50 mg, 0.61 mmol) and TCFH (89 mg, 0.32 mmol).After stirring at 0°C for 2 h, the reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with NaHCO3(aq), dried over Na2SO4, filtered and concentrated. The crude product was purified by prep-HPLC to give (R)-2-(7- chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)-N- methylpropanamide (23 mg, 18%) as a white solid. LC / MS ESI (m / z): 440 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.60 – 7.51 (m, 5H), 7.47 (d, J = 4.4 Hz, 1H), 5.53 (dd, J = 14.3, 7.2 Hz, 1H), 3.84 (s, 3H), 3.33 (s, 3H), 1.59 (d, J = 7.0 Hz, 3H).

[0310] The following compound was prepared by a procedure similar to the synthesis of Example 205 using the corresponding aniline.Example 207. Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(6-(4-fluoro-1- methyl-1H-pyrazol-5-yl)pyridin-3-yl)propanamide (207)Step 1.4-Fluoro-1-methyl-1H-pyrazole

[0311] To a solution of 4-fluoro-1H-pyrazole (5.0 g, 58 mmol) in THF (100 mL) was added NaH (4.7 g, 60% in mineral oil, 120 mmol) at 0°C. After 30 min, CH3I (9.9 g, 70 mmol) was added. After stirring at rt overnight, the reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuo to afford the crude title compound 4-fluoro-1-methyl-1H-pyrazole (4.0 g, 68%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 4.1 Hz, 1H), 7.24 (d, J =4.8 Hz, 1H), 3.83 (s, 3H). Step 2.4-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0312] To a solution of 4-fluoro-1-methyl-1H-pyrazole (300 mg, 3.0 mmol) in THF (10 mL) was added 1.6 M n-BuLi (2.1 mL, 3.3 mmol) at -78°C and stirred for 30 min.2-Isopropoxy- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (670 mg, 3.6 mmol) was then added. The reaction was gradually warmed to rt and stirred for 2 h. The resulting mixture was quenched with MeOH (0.5 mL) and used directly in the next step. LC / MS ESI (m / z): 227 (M+H)+. Step 3.6-(4-Fluoro-1-methyl-1H-pyrazol-5-yl)pyridin-3-amine

[0313] To a solution of 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (400 mg, 1.8 mmol) in THF (10 mL) and water (1 mL) were added 6- bromopyridin-3-amine (310 mg, 1.8 mmol), K2CO3(610 mg, 4.4 mmol) and Pd(dppf)Cl2(130 mg, 0.18 mmol). After stirring at 80°C for 18 h, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (0~50% EtOAc in petroleum ether) to afford the title compound 6-(4-fluoro-1-methyl-1H-pyrazol-5-yl)pyridin-3-amine (140 mg, 41%) as a yellow solid. LC / MS ESI (m / z): 193 (M+H)+. Step 4. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(6-(4-fluoro-1-methyl-1H-pyrazol-5- yl)pyridin-3-yl)propanamide

[0314] To a solution of 6-(4-fluoro-1-methyl-1H-pyrazol-5-yl)pyridin-3-amine (140 mg, 0.73 mmol) and (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (180 mg, 0.73 mmol) in DCM (2 mL) at -20℃ was added pyridine (1 mL) followed by POCl3(220 mg, 1.5 mmol) dropwise. The reaction was stirred at -20℃ for 1 h and partitioned between with DCM and water. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (R)-2-(6-chloro-1-oxoisoquinolin- 2(1H)-yl)-N-(6-(4-fluoro-1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)propanamide (52 mg, 17%) as a yellow solid. LC / MS ESI (m / z): 426 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.13 (d, J = 13.3 Hz, 1H), 8.75 (d, J = 2.6 Hz, 1H), 8.38 (dd, J = 8.7, 5.3 Hz, 1H), 8.13 (dd, J = 8.7, 2.6 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.48 (dt, J = 8.7, 2.4 Hz, 1H), 7.35 (t, J = 5.8 Hz, 2H), 6.60 (d, J = 7.6 Hz, 1H), 5.83 (q, J = 7.1 Hz, 1H), 4.11 (s, 3H), 1.75 (d, J = 7.2 Hz, 3H).

[0315] The following compounds were prepared by procedures similar to the synthesis of Example 207 using 4-methoxy-1H-pyrazole and the corresponding bromoanilines.Example 208. Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1- (difluoromethyl)-1H-pyrazol-5-yl)phenyl)propanamide (208)Step 1.1-(Difluoromethyl)-5-iodo-1H-pyrazole and 1-(difluoromethyl)-3-iodo-1H-pyrazole

[0316] To a solution of 3-iodo-1H-pyrazole (1.9 g, 9.8 mmol) in ACN (30 mL) were added diethyl (bromodifluoromethyl)phosphonate (5.23 g, 19.6 mmol) and potassium fluoride (2.28 g, 39.2 mmol). After stirring at rt overnight, the reaction was filtered and the filtrate was concentrated to afford the crude mixture of 1-(difluoromethyl)-5-iodo-1H-pyrazole and 1- (difluoromethyl)-3-iodo-1H-pyrazole (2 g) as a yellow oil. Step 2.4-(1-(Difluoromethyl)-1H-pyrazol-5-yl)aniline

[0317] To a solution of crude 1-(difluoromethyl)-5-iodo-1H-pyrazole and 1- (difluoromethyl)-3-iodo-1H-pyrazole (2.0 g, 8.2 mmol) in dioxane (50 mL) and H2O (10 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.8 g, 8.2 mmol), K2CO3(3.4 g, 25 mmol) and Pd(dppf)Cl2(600 mg, 0.8 mmol). The resulting mixture was stirred at 90℃ under N2overnight. After cooling to room temperature, the reaction was concentrated invacuo. The residue was purified by flash column chromatography (silica gel, 0~20% ethyl acetate in petroleum ether) and prep-HPLC to afford 4-(1-(difluoromethyl)-1H-pyrazol-5- yl)aniline (240 mg, 14%) as a yellow oil. LC / MS ESI (m / z): 210 (M+H)+. Step 3. (R)-2-(6-Chloro-1-oxoisoquinolin-2(1H)-yl)-N-(4-(1-(difluoromethyl)-1H-pyrazol-5- yl)phenyl)propanamide

[0318] To a solution of 4-(1-(difluoromethyl)-1H-pyrazol-5-yl)aniline (160 mg, 0.8 mmol) and (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (200 mg, 0.8 mmol) in DCM (15 mL) were added pyridine (0.2 mL, 2.4 mmol) and POCl3(160 mg, 1.3 mmol) dropwise. After stirring at -20℃ for 40 min, the reaction mixture was quenched with ice water and extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (0~50% ethyl acetate in petroleum ether) and prep-HPLC to afford (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)- yl)-N-(4-(1-(difluoromethyl)-1H-pyrazol-5-yl)phenyl)propanamide (34 mg, 9.6%) as a white solid. LC / MS ESI (m / z): 443 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.84 (dd, J = 6.6, 1.8 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.72 – 7.49 (m, 3H), 7.46 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 5.63 (q, J = 7.2 Hz, 1H), 1.69 (d, J = 7.3 Hz, 3H). Intermediate AA. Synthesis of (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acidIntermediate AA

[0319] To a three-necked round bottom flask were charged Mg(Ot-Bu)2 (9.5 g, 56 mmol) and THF (50 mL). The mixture was degassed and backfilled with N2. Then (S)-2-chloropropanoic acid (3.9 g, 36 mmol) was added dropwise over 20 min to maintain the internal temperature < 35°C. After aging for 10 min, t-BuOK (1.0 M in THF, 31 mL) was added dropwise. After aging for another 20 min, 6-chloroisoquinolin-1(2H)-one (5.0 g, 28 mmol) was added and additional THF (5 mL) was added to rinse the side of the flask. Then the mixture was stirred at rt for 2 h and then at 55°C (internal temperature) overnight.23 mL of 6 M HCl was added. The mixture was partitioned between EtOAc and H2O. The organic layer was separated and concentrated to dryness and was triturated from EtOAc / petroleum ether to give crude (R)-2-(6-chloro-1- oxoisoquinolin-2(1H)-yl)propanoic acid (5.9 g, ~75% purity, mixed with 25% starting material) as an off-white solid. LC / MS ESI (m / z): 252 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.58 – 7.51 (m, 2H), 6.66 (d, J = 7.5 Hz, 1H), 5.29 (q, J = 7.3 Hz, 1H), 1.59 (d, J = 7.3 Hz, 3H).

[0320] The method can be used to prepare a variety of related chiral carboxylic acids by using quinazolin-4(3H)-one, phthalazin-1(2H)-one, isoquinolin-1(2H)-one, 5,6,7,8- tetrahydroquinazolin-4(3H)-one, 5,6,7,8-tetrahydroisoquinolin-1(2H)-one and isoindolin-1- one derivatives as the starting materials. Example 215. General amide coupling procedure using POCl3Intermediate AA Compound BB

[0321] A mixture of aryl amine (0.45 mmol) and (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)- yl)propanoic acid (Intermediate AA) (110 mg, 0.45 mmol) and pyridine (0.14 mL, 1.8 mmol) in DCM (1 mL) at 0 – 5 °C was treated with POCl3(0.10 mL, 0.54 mmol) and stirred overnight at room temperature under nitrogen. After the completion of the reaction, water (20 mL) was added and the mixture was extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with sat. NaHCO3 (3 X 10 mL) and brine (2 X 10 mL), dried over sodium sulfate, filtered, concentrated and purified by flash chromatography to obtain the corresponding Compound BB.

[0322] The following compounds were prepared by procedures analogous to the synthesis of Compound BB using the corresponding aryl amines.Example 222. General amide coupling procedure using HATUIntermediate CC Compound DD

[0323] To a stirred solution of isoindolin-1-one derivative (Intermediate CC, prepared by following a similar procedure used for the synthesis of Intermediate AA) (0.33 mmol), aryl amine (0.33 mmol) and HATU (190 mg, 0.49 mmol) in DMF (1.0 mL) was treated with DIPEA (0.12 mL, 0.66 mmol) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. After the completion of the reaction, water was added and the reaction mixture was extracted into ethyl acetate (2 X 10 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (5 mL) and with brine (5 mL), dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography to obtain the corresponding Compound DD.

[0324] The following compound was prepared by a procedure analogous to the synthesis of Compound DD using the corresponding acid and aryl amine.Example 225. Synthesis of (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(5- methyloxazol-4-yl)phenyl)propanamideStep 1.2-Bromo-1-(4-bromo-2-fluorophenyl)propan-1-one

[0325] To a solution of 1-(4-bromo-2-fluorophenyl)propan-1-one (1.1 g, 4.8 mmol) in DCM (20 mL) at 0°C was added Br2 (910 mg, 5.7 mmol). The reaction was stirred at room temperature for 2h. The resultant mixture was poured into Na2S2O3(aq) and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude title compound (1.3 g) as an oil which was used directly. Step 2.4-(4-Bromo-2-fluorophenyl)-5-methyloxazole

[0326] A solution of 2-bromo-1-(4-bromo-2-fluorophenyl)propan-1-one (1.3 g, crude material from last step) in formamide (20 mL) was stirred at 110°C under N2atmosphere overnight. The resultant mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~70% ethyl acetate in petroleum ether) to afford 4- (4-bromo-2-fluorophenyl)-5-methyloxazole (890 mg, 83%) as a solid. LC / MS ESI (m / z): 256, 258 (M+H)+. Step 3.3-Fluoro-4-(5-methyloxazol-4-yl)aniline

[0327] To a solution of 4-(4-bromo-2-fluorophenyl)-5-methyloxazole (890 mg, 3.5 mmol) in toluene (15 mL) was added diphenylmethanimine (1.3 g, 7.0 mmol), Pd2(dba)3(640 mg, 0.69 mmol), BINAP (870 mg, 1.4 mmol) and Cs2CO3(3.4 g, 10 mmol). The resulting mixture was stirred at 110°C under N2overnight. The reaction was quenched with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by prep-HPLC afforded 3-fluoro-4-(5- methyloxazol-4-yl)aniline (300 mg, 45%) as a solid. LC / MS ESI (m / z): 193 (M+H)+. Step 4. (R)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(5-methyloxazol-4-yl) phenyl)propanamide

[0328] To a solution of 3-fluoro-4-(5-methyloxazol-4-yl)aniline (60 mg, 0.31 mmol) and (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid (160 mg, 0.63 mmol) in DCM (20 mL) at -20°C was added pyridine (150 mg, 1.9 mmol) and POCl3(190 mg, 1.3 mmol). After stirring at -20°C for 10 min, the reaction was quenched with H2O and extracted twice with DCM (30 mL). The combined organic layers were concentrated and purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) and prep-HPLC to afford (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(5-methyloxazol-4- yl)phenyl)propanamide (90 mg, 67%) as a solid. LC / MS ESI (m / z): 427 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.26 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 12.2, 1.9 Hz, 1H), 7.47 (t, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.6, 2.0 Hz, 1H), 7.12 (dd, J = 8.4, 1.9 Hz, 1H), 5.60 (q, J = 7.3 Hz, 1H), 2.30 (d, J = 2.9 Hz, 3H), 1.77 (d, J = 7.3 Hz, 3H). Example 240. Synthesis of (R)-N-(4-ethylphenyl)-2-(6-fluoro-1-oxoisoquinolin-2(1H)- yl)propenamideStep 1. (R)-2-(6-Fluoro-1-oxoisoquinolin-2(1H)-yl)propanoic acid

[0329] To a mixture of Mg(Ot-Bu)2 (630 mg, 3.7 mmol) in anhydrous THF (3.0 mL) was added (S)-2-chloropropanoic acid (0.23 mL, 2.8 mmol) dropwise to maintain the internal temperature ≤ 35 °C. After aging for 10 min, KOt-Bu (220 mg, 1.9 mmol) was added and the resulting mixture was aged at room temperature for 15 min.6-Fluoroisoquinolin-1(2H)-one (300 mg, 1.8 mmol) was added with the aid of THF (3 mL). The reaction mixture wasallowed to stir at 35 °C for 48 h. The reaction mixture was cooled to 0 °C, poured into water (20 mL) and washed with ethyl acetate (3 × 10 mL). The aqueous phase was acidified to pH 2.0 – 2.5 with 2M HCl and extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to obtain (R)-2- (6-fluoro-1-oxoisoquinolin-2(1H)-yl)propanoic acid (120 mg, 27%) as a solid. Step 2. (R)-N-(4-Ethylphenyl)-2-(6-fluoro-1-oxoisoquinolin-2(1H)-yl)propanamide

[0330] A mixture of 4-ethylaniline (62 mg, 0.51 mmol) and (R)-2-(6-fluoro-1- oxoisoquinolin-2(1H)-yl)propanoic acid (120 mg, 0.51 mmol) and TCFH (170 mg, 0.61 mmol) in acetonitrile (0.62 mL) was cooled to 0 – 5° C. The reaction mixture was treated with NMI (0.1 mL, 1.3 mmol) and stirred at room temperature under nitrogen atmosphere overnight. Water (10 mL) was added and the resultant mixture was extracted with ethyl acetate (5 × 10 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (silica gel, 80% ethyl acetate in hexane) to obtain the (R)-N-(4-ethylphenyl)-2-(6-fluoro-1- oxoisoquinolin-2(1H)-yl)propanamide as a solid. LC / MS ESI (m / z): 339 (M+H)+.1H NMR (DMSO-d6, 400 MHz): δ 10.24 (s, 1H), 8.29 – 8.25 (m, 1H), 7.60 (d, 1H), 7.52 – 7.48 (m, 3H), 7.36 – 7.31 (m, 1H), 7.13 (d, 2H), 6.68 (d, 1H), 5.62 (q, 1H), 2.57 – 2.50 (m, 2H), 1.64 (d, 3H), 1.14 (t, 3H).

[0331] The following compound was prepared by a procedure analogous to the synthesis of compound 240 using (R)-2-(6-chloro-1-oxoisoquinolin-2(1H)-yl)propanoic acid and 2- ethylpyrimidin-5-amine.Patch-clamp Electrophysiology-based TMEM175 Assay Cell Culture and Harvesting

[0332] HEK-293 Trex cells were stably transfected with a construct consisting of the human coding sequence for TMEM175 cloned into the tet-inducible plasmid pCDNA5 T / O and serially passaged. Cells are treated with doxycycline to induce expression of TMEM175 18-24 hours prior to testing. On the day of the experiment, growth media is removed, thecells are washed with phosphate-buffered saline (PBS) and lifted using TrypLE. CHO-SFM- II media is used to terminate digestion and cells are collected and pelletized by centrifugation before resuspension in Ringer’s solution (supplemented with doxycycline) at a density >800,000 cells per mL of solution. SyncroPatch Experiment

[0333] Compounds are dissolved to a concentration of 10 mM in DMSO, further dilution to 1000-fold the final tested concentration is done using DMSO. The compounds are mixed 1:313 – 1:1000 with the cell suspension and allowed to incubate approximately 30 minutes. The cell suspension is then delivered to the patch-clamp interface (SyncroPatch 384, Nanion Technologies Gmbh). Positive and negative controls are included on each plate. Compounds are typically tested in fivefold half log serial dilutions with n = 16. Following a current-clamp protocol to assess the effects of TMEM175 activation on cellular membrane potential, the amplifier is switched to voltage-clamp mode to directly record TMEM175 currents. Briefly, the cells are held at a membrane potential of -80 mV. Following a short pulse to -100 mV, the membrane potential is ramped to 0 mV and stepped to potentials intermediate between 0 mV and -80 mV. Currents are measured against positive control and negative control (DMSO) at 0 mV. Analysis and Statistics

[0334] Membrane potential and TMEM175 current data is exported as an ASCII .txt file and imported into Microsoft Excel for analysis. Following QC to remove aberrant wells, EC50values were calculated via non-linear regression using GraphPad Prism Software (GraphPad Software). Compound potency is determined by fitting either current-clamp or voltage-clamp data with bottom set by negative control wells and the top set to the maximum value experimentally determined by the curve-fitting program; Hill slope is not constrained.

[0335] The EC50determined for each compound using the assay is summarized in Table 3 below. The compound numbers correspond to those shown in Table 3. in the table, “A” indicates an EC50of less than 100 nM, “B” indicates an EC50range from 100 nM to 320 nM; “C” indicates an EC50range from greater than 320 nM to 1000 nM, and “D” indicates an EC50 greater than 1000 nM.Table 3. Efficacy of exemplary compounds of the disclosureEQUIVALENTS

[0336] It will be recognized that one or more features of any embodiments disclosed herein may be combined and / or rearranged within the scope of the disclosure to produce further embodiments that are also within the scope of the disclosure.

[0337] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosuredescribed herein. Such equivalents are intended to be within the scope of the present disclosure.

[0338] Although the disclosure has been described and illustrated in the foregoing illustrative embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the disclosure can be made without departing from the spirit and scope of the disclosure, which is limited only by the claims that follow. Features of the disclosed embodiments can be combined and / or rearranged in various ways within the scope and spirit of the disclosure to produce further embodiments that are also within the scope of the disclosure. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically in this disclosure. Such equivalents are intended to be encompassed in the scope of the following claims.

[0339] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the disclosure described and claimed herein.

Claims

CLAIMS 1. A compound of Formula I:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Z1is C1-6alkyl or C1-4alkylene-aryl, substituted with one or two halogen, or; Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X2or X3; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1is absent, CR5or N; X2, X3, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X3, X4, and X5are N; and when X2or X3to which ring A is attached is CR5, R5of the CR5to which X2or X3is attached is absent; X6is absent or is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X7 is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl or H, wherein the C1-4alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; or R1and R2, together with the carbon atom to which R1and R2are attached, form C3-4cycloalkylene;R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H or C1-6alkyl; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that when Z1isand when X6is CH, X7is N or CH, X8is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X6is absent, X7is C(=O), X8is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X6is CH wherein the H of CH is optionally substituted by methyl, X7is N, X8is C, ring B is phenyl, and ring A is attached to X2, ring B is substituted with 1- 4 R3; when X6is CH, X7 is N or CH, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not N-bound 6-membered heterocyclyl; and when X6is CH, X7 is N, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not triazole.

2. A compound of Formula II:Formula IIor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X2or X3; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1, X2, X3, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X3, X4, and X5are N; and when X2or X3to which ring A is attached is CR5, R5of the CR5to which X2or X3is attached is absent; X6is absent or is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X7 is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl or H, wherein the C1-4alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; or R1and R2, together with the carbon atom to which R1and R2are attached, form C3-4cycloalkylene; R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H or C1-6alkyl; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that: when X6is CH, X7is N or CH, X8is C, ring B is phenyl, and n is 0, q is an integer 1-4;when X6is absent, X7 is C(=O), X8is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X6is CH wherein the H of CH is optionally substituted by methyl, X7 is N, X8is C, ring B is phenyl, and ring A is attached to X2, ring B is substituted with 1- 4 R3; when X6is CH, X7is N or CH, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not N-bound 6-membered heterocyclyl; and when X6is CH, X7is N, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not triazole.

3. A compound of Formula II-A:Formula II-A or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1, X2, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X4, and X5are N; X6is absent or is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X7 is selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl;R2is C1-4alkyl or H, wherein the C1-4alkyl is optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; or R1and R2, together with the carbon atom to which R1and R2are attached, form C3-4cycloalkylene; R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H or C1-6alkyl; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6 cycloalkyl, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that q and n are not both 0.Formula II-B or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl or 6-membered heterocyclyl attached to X2or X3; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1, X2, X3, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X3, X4, and X5are N; andwhen X2or X3to which ring A is attached is CR5, the R5of CR5to which X2or X3is attached is absent; X6and X7 are each independently selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6 cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that: when X6is CH, X7 is N or CH, X8is C, ring B is phenyl, and n is 0, q is an integer 1-4; when X6is CH wherein the H of CH is optionally substituted by methyl, X7 is N, X8is C, ring B is phenyl, and ring A is attached to X2, ring B is substituted with 1- 4 R3; when X6is CH, X7is N or CH, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not N-bound 6-membered heterocyclyl; and when X6is CH, X7is N, X8is C, ring B is phenyl, q is 0, X1, X2, X4, and X5are CH, and X3is C, ring A is not triazole.

5. A compound of Formula II-C:Formula II-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N; Ring B is selected from the group consisting of 5-6 membered carbocyclyl, phenyl, 5- 6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1, X2, X4, and X5are each independently CR5or N; provided that not more than two of X1, X2, X4, and X5are N; X6and X7are each independently selected from the group consisting of CH, CH2, and N, wherein the hydrogen of CH or CH2is optionally substituted by R3; X8is selected from the group consisting of C and N; R1is H or C1-4alkyl; R2is C1-4alkyl optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, cyano, C1-4alkoxy, and C1-4haloalkoxy; R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, oxo, di-C1-4alkylamine, and 5-6 membered heterocyclyl; R4is H; R5is each independently selected from the group consisting of H, halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy; R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6 cycloalkyl, oxo, and 5-6 membered heterocyclyl; q is an integer 0-4; and n is an integer 0-5; provided that q and n are not both 0.

6. The compound of any one of claims 1, 2 and 4, wherein X1, X3, X4, and X5are CR5or N and X2is C.

7. The compound of any one of claims 1, 2 and 4, wherein X1, X2, X4, and X5are CR5or N and X3is C.

8. The compound of any one of claims 1-5 and 7, wherein X1, X2, X4, and X5are CR5.

9. The compound of any one of claims 1-5and 7, wherein one of X1, X2, X4, and X5is N.

10. The compound of any one of claims 1-5, wherein the compound is a compound of Formula II-H:Formula II-H or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

11. The compound of any one of claims 1-5, wherein the compound is a compound of Formula II-J:Formula II-J or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

12. The compound of any one of claims 1-11, wherein the bicyclic ring containing X6, X7, X8, and ring B is selected from the group consisting of:wherein the bicyclic ring is substituted with 0-4 R3.

13. The compound of any one of claims 1-12, wherein the bicyclic ring containing X6, X7, X8, and ring B is selected from the group consisting of:wherein the bicyclic ring is substituted with 0-4 R3.

14. The compound of any one of claims 1-13, wherein the bicyclic ring containing X6, X7, X8, and ring B is selected from the group consisting of:wherein the bicyclic ring is substituted with 0-4 R3.

15. The compound of any one of claims 1-14, wherein q is an integer 0-2.

16. The compound of any one of claims 1-15, wherein q is 0.

17. The compound of any one of claims 1-15, wherein q is 1.

18. The compound of any one of claims 1-15, wherein q is 2.

19. The compound of any one of claims 1-18, wherein R1is H or C1-2 alkyl.

20. The compound of any one of claims 1-19, wherein R1is H or methyl.

21. The compound of any one of claims 1-20, wherein R1is H.

22. The compound of any one of claims 1-20, wherein R1is methyl.

23. The compound of any one of claims 1-3 and 6-22, wherein R2is H or C1-4alkyl optionally substituted with one or two halogen, hydroxy, or C1-2 alkoxy.

24. The compound of any one of claims 1-23, wherein R2is C1-4alkyl optionally substituted with hydroxy.

25. The compound of any one of claims 1-24, wherein R2is methyl or ethyl.

26. The compound of any one of claims 1-3, and 6-23, wherein R2is H.

27. The compound of any one of claims 1-3, and 6-18, wherein R1and R2, together with the carbon atom to which R1and R2are attached, form C3-4cycloalkylene.

28. The compound of any one of claims 1-3, 6-18 and 27, wherein R1and R2, together with the carbon atom to which R1and R2are attached, form cyclopropylene.

29. The compound of any one of claims 1-28, wherein R4is H.

30. The compound of any one of claims 1-29, wherein ring A is selected from the group consisting of pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, and oxazolyl.

31. The compound of any one of claims 1-30, wherein ring A is pyridyl, pyrazolyl, or imidazolyl.

32. The compound of any one of claims 1-31, wherein R3is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, di-C1-4alkylamine, and 5-6 membered heterocyclyl.

33. The compound of any one of claims 1-32, wherein R3is selected from the group consisting of halogen, hydroxy, C1-2alkyl, C1-2alkoxy, di-C1-4alkylamine, and 5- membered N-containing heterocyclyl.

34. The compound of any one of claims 1-33, wherein R3is halogen.

35. The compound of any one of claims 1-34, wherein R3is Cl or F.

36. The compound of any one of claims 1-35, wherein R5is selected from the group consisting of H, halogen, and C1-6alkyl.

37. The compound of any one of claims 1-36, wherein R5is selected from the group consisting of H, halogen, and C1-2alkyl.

38. The compound of any one of claims 1-37, wherein R5is selected from the group consisting of H or F.

39. The compound of any one of claims 1-38, wherein n is an integer 0-3.

40. The compound of any one of claims 1-39, wherein n is 0.

41. The compound of any one of claims 1-39, wherein n is 1.

42. The compound of any one of claims 1-39, wherein n is 2.

43. The compound of any one of claims 1-39, wherein n is 3.

44. The compound of any one of claims 1-43, wherein R6is selected from the group consisting of halogen, hydroxy, cyano, C1-6alkyl, C1-6alkoxy, and C3-6 cycloalkyl.

45. The compound of any one of claims 1-44, wherein R6is selected from the group consisting of halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.

46. The compound of any one of claims 1-45, wherein R6is selected from the group consisting of F, Cl, hydroxy, cyano, methyl, ethyl, methoxy, and cyclopropyl.

47. A compound of Formula III:Formula III or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R1is H or C1-4alkyl; R2is C1-4alkyl; X1is absent, CH, or N; X3is C or N; X2, X4, and X5are each independently CH or N;provided that not more than two of X1, X2, X3, X4, and X5are N; X6is absent or is selected from the group consisting of CH, CH2, and N; X7 is selected from the group consisting of CH, CH2, and N; R3is halogen; R4is H or C1-6alkyl; and Z1is C1-6alkyl or C1-4alkylene-aryl substituted with one or two halogen.

48. The compound of claim 47, wherein the compound is a compound of Formula III-A:Formula III-A or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

49. The compound of claim 47, wherein the compound is a compound of Formula III-B:Formula III-B or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

50. The compound of claim 47, wherein the compound is a compound of Formula III-C:Formula III-C or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

51. The compound of claim 47, wherein the compound is a compound of Formula III-D:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

52. The compound of claim 47, wherein the compound is a compound of Formula III-E:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

53. The compound of any one of claims 47-52, wherein X6is absent.

54. The compound of any one of claims 47-52, wherein X6is CH.

55. The compound of any one of claims 47-54, wherein X7is CH.

56. The compound of any one of claims 47-54, wherein X7is CH2.

57. The compound of any one of claims 47-56, wherein R1is H or C1-2alkyl.

58. The compound of any one of claims 47-57, wherein R1is H or methyl.

59. The compound of any one of claims 47-58, wherein R1is H.

60. The compound of any one of claims 47-58, wherein R1is methyl.

61. The compound of any one of claims 47-60, wherein R2is methyl or ethyl. 62 The compound of any one of claims 47-61, wherein R4is H.

63. The compound of any one of claims 47-62, wherein R3is Cl or F.

64. The compound of any one of claims 47-63, wherein R3is Cl.

65. The compound of any one of claims 47-64, wherein Z1is C1-6alkyl.

66. The compound of any one of claims 47-65, wherein Z1is ethyl.

67. The compound of any one of claims 47-64, wherein Z1is C1-4alkylene-aryl optionally substituted with halogen.

68. The compound of any one of claims 47-64 and 67, wherein Z1is benzyl optionally substituted with halogen.

69. The compound of any one of claims 47-64, 67 and 68, wherein Z1is benzyl substituted with F.

70. The compound of claim 1, wherein the compound is selected from a compound listed in Table 1, or a pharmaceutically acceptable salt thereof.

71. A pharmaceutical composition comprising a compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

72. A method of activating TMEM175 in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition of claim 71.

73. A method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition of claim 71.

74. The method of claim 73, wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, Amyotrophic Lateral Sclerosis (ALS), Progressive Supranuclear Palsy, FTDP-17, Alzheimer’s Disease, Multi System Atrophy, Corticobasal Degeneration, and Huntington’s Disease.

75. The method of claim 73 or 74, wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease in TMEM175 mutation carriers, Idiopathic Parkinson’s Disease, GBA Parkinson’s Disease, LRRK2 Parkinson’s Disease, REM Sleep Behavior Disorder (RBD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Pick’s Disease, and Amyotrophic Lateral Sclerosis (ALS).

76. A method of treating a lysosomal storage disease in a subject in need thereof, the method comprising administering to the subject a compound of any one of claims 1-70, ora pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a composition of claim 71.

77. The method of claim 76, wherein the lysosomal storage disease is selected from the group consisting of Sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorder, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, Pompe disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, Saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, Sialidosis, I-cell disease, pseudo-Hurler polydystrophy, GlcNAc-1-phosphotransferase deficiency, mucolipin 1 deficiency, Santavuori-Haltia disease, Jansky-Bielschowsky disease, Batten disease, Batten-Spielmeyer-Vogt disease, Kufs disease, Finnish variant neuronal ceroid lipofuscinosis, late infantile variant neuronal ceroid lipofuscinosis, type 7 neuronal ceroid lipofuscinosis, northern epilepsy neuronal ceroid lipofuscinosis, Turkish late infantile neuronal ceroid lipofuscinosis, German / Serbian late infantile neuronal ceroid lipofuscinosis, congenital cathepsin D deficiency, Wolman disease, alpha-mannosidosis, beta-mannosidosis, aspartylglucosaminuria, and fucosidosis.

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