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 USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Patent Application Serial No. 63 / 736,545, filed December 19, 2024, the entire contents of which are incorporated by reference herein.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. etal., 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 ability7to 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., JAMIA 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 (Lili, C. M. etal., 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 values were corrected for GBA or LRRK2mutations, 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. etal., Broc. Natl. Acad. Sci. U. S. A. 2017, Vol. 114, pp. 2389-2394). Impaired mitochondrial respiration w as 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 knockdown 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. el 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:(R3)qFormula Ior 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 IV:(R3)qFormula IVor 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 pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0011] 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.

[0012] 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

[0013] 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

[0014] In an aspect, provided herein is a compound of Formula I:(R3)qFormula 1or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, whereinZ1is Ci-6 alkyl or Ci-4 alkylene-aryl, substituted with one or two halogens, orRing A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl attached to X2or X3; Ring B is selected from 5- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N; X1is absent, CR5, or N;X2and X3are each independently CR5orN;X4and 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 CH, CH2, and N, wherein hydrogen of CH or CH2 is optionally substituted by R3;X7is selected from CH, CH2, and N. wherein hydrogen of CH or CH2 is optionally substituted by R3;X8is selected from C and N;R1is H or C1-4 alkyl;R2is H or C1-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with one, two, or three substituents independently selected from halogen, hydroxy, cyano, Ci-4 alkoxy, and C1-4 haloalkoxy; oroptionally R1and R2, together with the carbon atom to which R1and R2are attached, form a C3-4 spirocyclic ring;each R3is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring;R4is H or C1-6 alkyl;each R5is independently selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, oxo, and 5- to 6-membered heterocyclyl;q is an integer 0-4; andn 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, X7is N, X8is C, Ring B is phenyl, and Ring A is attached to X2, q is an integer 1-4; when X6is CH, X7is N or CH, X8is C, Ring B is phenyl, X1, X2, X4, and X5are CH, X3is C, and Ring A is N-bound 6-membered heterocyclyl, q is an integer 1-4; and when X6is CH, X7is N, X8is C, Ring B is phenyl, X1, X2, X4, and X5are CH, X3is C, and Ring A is triazole, q is an integer 1-4.

[0015] In some embodiments, provided herein is a compound of Formula II:Formula IIor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, whereinRing A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl attached to X2or X3; Ring B is selected from 5- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 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 CR3to which X2or X3is attached is absent;X6is absent or is selected from CH, CH2, and N, wherein hydrogen of CH or CH2 is optionally substituted by R3;X7is selected from CH, CH2, and N, wherein hydrogen of CH or CH2 is optionally substituted by R3;X8is selected from C and N;R1is H or C1-4 alkyl;R2is H or C1-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, C1-4 alkoxy, and C1-4 haloalkoxy; oroptionally R1and R2, together with the carbon atom to which R1and R2are attached, form a C3-4 spirocyclic ring;each R3is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring;R4is H or C1-6 alkyl;each R5is independently selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy:each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, oxo, and 5- to 6-membered heterocyclyl;q is an integer 1-4; andn 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, 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, q is an integer 1-4; when X6is CH, X7is N or CH, X8is C, Ring B is phenyl, X1, X2, X4, and X5are CH, X3is C, and Ring A is N-bound 6-membered heterocyclyl, q is an integer 1-4; and when X6is CH, X7is N, X8is C, Ring B is phenyl, X1, X2, X4, and X5are CH, X3is C, and Ring A is triazole, q is an integer 1-4.

[0016] 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, whereinRing A is 5- to 6-membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N;Ring B is selected from 5- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 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 CH, CH2, and N, wherein hydrogen of CH or CH2 is optionally substituted by R3;X7is selected from CH, CH2, and N, wherein hydrogen of CH or CH2 is optionally substituted by R3;X8is selected from C and N;R1is H or C1-4 alkyl;R2is H or C1-4 alkyl, wherein the Cwalkyl is optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, C1-4 alkoxy, and C1-4 haloalkoxy; oroptionally R1and R2, together with the carbon atom to which R1and R2are attached, form a C3-4 spirocyclic ring;each R3is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalky 1, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring;R4is H or C1-6 alkyl;each R5is independently selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, and 5- to 6-membered heterocyclyl;q is an integer 1-4; and26130n is an integer 0-5.

[0017] In some embodiments, provided herein is a compound of Formula II-B:Formula II-Bor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, whereinRing A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl attached to X2or X3; Ring B is selected from 5- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 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, R5of the CR5to which X2or XJis attached is absent;X6and X7are each independently selected from CH, CH2, and N, wherein hydrogen of CH or CH2 is optionally substituted by R3;X8is selected from C and N;R1is H or C1-4 alkyl;R2is C1-4 alkyl optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano. C1-4 alkoxy, and C1-4 haloalkoxy;each R3is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring;R4is H;26130each R5is independently selected from H, halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, and Ci-6 haloalkoxy;each R6is independently selected from halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C3-6 cycloalkyl, oxo, and 5- to 6-membered heterocyclyl;q is an integer 1-4; andn 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 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, q is an integer 1-4; when X6is CH, X7is N or CH, X8is C, Ring B is phenyl, X1, X2, X4, and X5are CH, X3is C, and Ring A is N-bound 6-membered heterocyclyl, q is an integer 1-4; and when X6is CH, X7is N, X8is C, Ring B is phenyl, X1, X2, X4, and X5are CH, X3is C, and Ring A is triazole, q is an integer 1-4.

[0018] In some embodiments, provided herein is a compound of Formula 11-C:Formula II-Cor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, whereinRing A is 5- to 6-membered heteroaryl containing 1-2 heteroatoms selected from O, S, andN;Ring B is selected from 5- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 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 CH, CH2, and N, wherein hydrogen of CH or CH2 is optionally substituted by R3;26130X8is selected from C and N;R1is H or Ci-4 alkyl;R2is Ci-4 alkyl optionally substituted with one, two, or three substituents selected from halogen, hydroxy, cyano, Ci-4 alkoxy, and Ci-4 haloalkoxy;each R3is independently selected from halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-C1-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1 -3 halogen, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring;R4is H;each R5is independently selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, oxo, and 5- to 6-membered heterocyclyl;q is an integer 1-4; andn is an integer 0-5.

[0019] In some embodiments, the compound is a compound of Formula II-D:Formula II-Dor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0020] In some embodiments, the compound is a compound of Formula II-E:26130Formula II-Eor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0021] In some embodiments, the compound is a compound of Formula II-F:Formula II-For a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0022] In some embodiments, the compound is a compound of Formula II-G:Formula II-Gor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the variables are as defined herein.

[0023] In some embodiments, X1, X3, X4, and X5are CR5or N and X2is C.

[0024] In some embodiments, X1, X2, X4, and X3are CR5or N and X3is C.

[0025] In some embodiments, X1, X2, X4, and X3are CR5.

[0026] In some embodiments, X1, X3, X4, and X5are CR5.

[0027] In some embodiments, one of X1, X2, X4, and X5is N.

[0028] In some embodiments, one of X1, X3, X4, and X5is N.

[0029] In some embodiments, the compound is a compound of Formula II-H:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0030] In some embodiments, the compound is a compound of Formula II-J:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0031] In some embodiments, the bicyclic ring containing X6. X7. X8. and Ring B is selected from:bicyclic ring is substituted with 1-4 R3.

[0032] In some embodiments, the bicyclic ring containing X6, X7, X8, and Ring B is selected from:bicyclic ring is substituted with 1-4 R3.

[0033] In some embodiments, the bicyclic ring containing X6. X7. X8. and Ring B is selected from:substituted with 1-4 R3.

[0034] In some embodiments, q is an integer 1-4. In some embodiments, q is an integer 1-3. In some embodiments, q is an integer 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments q is 4.

[0035] In some embodiments, R1is H or C1-2 alkyl. In some embodiments, R1is H or methyl. In some embodiments, R1is H. In some embodiments, R1is methyl.

[0036] In some embodiments, R2is H or C1-4alkyl optionally substituted with one or two halogen, hydroxy, or C1-2 alkoxy. In some embodiments, R2is Ci-4 alkyl optionally substituted with hydroxy. In some embodiments, R2is methyl or ethyl. In some embodiments, R2is H.

[0037] In other embodiments, R1and R2, together with the carbon atom to which R1and R2are attached, form a C3-4 spirocyclic ring. For example, R1and R2, together with the carbon atom towhich R1and R2are atached, form a C3 spirocyclic ring (a “spirocyclopropy 1” ring) or a C4 spirocyclic ring (a “spirocyclobutyl” ring).

[0038] In some embodiments, R4is H.

[0039] In some embodiments, Ring A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl attached to X2. In some embodiments, Ring A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl attached to X3. In some embodiments, Ring A is 5- to 6-membered heteroaryl. In some embodiments. Ring A is 5- to 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 pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, and oxazolyl. In some embodiments, Ring A is pyridyl, pyrazolyl, or imidazolyl. In some embodiments. Ring A is pyridyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is imidazolyl.

[0040] In some embodiments, each R3is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms. In some embodiments, R3is selected from halogen, C1-2 alkyl, C1-2 alkoxy, C1-2 haloalkyl, C1-2 haloalkoxy, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms. In some embodiments, R3is halogen, cyano, C1-2 alkyl, C1-2 haloalkyl, C1-2 haloalkoxy, C2-3 alkenyl, C2-3 haloalkenyl, C2-3 alkynyl, C2-3 haloalkynyl, C3-4 cycloalkyl, C3-4 halocycloalkyl, C3-4 cycloalkyloxy, C3-4 halocycloalkyloxy, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms. In some embodiments, 2 R3may be present on a single Ring B atom. In some embodiments, where when 2 R3alkyl are present on a single Ring B atom, the 2 R3may be joined, together with the atom to which they are atached, to form a C3-6 spirocyclic ring. In some embodiments, the 2 R3may be joined, together with the atom to which they are attached, to form a C3 spirocyclic ring. In some embodiments, the 2 R3may be joined, together with the atom to which they are atached, to form a C4 spirocyclic ring. In some embodiments, the 2 R’ may be joined, together with the atom to which they are atached, to form a C5 spirocyclic ring. In some embodiments, the 2 R3may be joined, together with the atom to which they are atached, to form a Ce spirocyclic ring.

[0041] In some embodiments, each R3is halogen, hydroxy, cyano, C1-6 alkyl. C1-6 alkoxy, di-C1-4 alkylamine, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkoxy, 5- to 6-membered26130heterocyclyl, which may be substituted by 1-3 halogen atoms, and C3-6 spirocyclic ring. In some embodiments, each R3is independently selected from Cl, F, CH3, CF3, CH2CH3, CH2CF3,form a C3 spirocyclic ring, or a C4 spirocyclic ring.

[0042] In some embodiments, each R5is independently selected from H, halogen, hydroxy, cyano, and C1-6alkyl. In some embodiments, each R5is independently selected from H, halogen, and C1-6 alkyl. In some embodiments, each R5is independently selected from H, halogen, and C1-2 alkyl. In some embodiments, R5is selected from H or F.

[0043] In some embodiments, n is an integer 0-5. 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 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0044] In some embodiments, each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and C3-6 cycloalkyl. In some embodiments, each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, and C3-6 cycloalkyl. In some embodiments, each R6is independently selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl. In some embodiments, R6is selected from F, Cl, hydroxy, cyano, methyl, ethyl, methoxy, and cyclopropyl. In still other embodiments, each R6is independently selected from F and CH3.

[0045] In some embodiments, provided herein is a compound of Formula IV:(R3)qFormula IV26130or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, whereinRing B is selected from 5- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N;X1is absent, CR5, or N;X2is CZ1, CR5, or N;X3is CZ1, CR5, or N;X4is CR5orN;X5is CR5orN;provided that 0, 1 or 2 of X1. X2. X3. X4. and X5are N, and one of X2and X3is CZ1; Z1is Ci-6 alkyl, or Ci-4 alkylene-aryl, where the Ci-6 alkyl, or Ci-4 alkylene-aryl is ( A\ _ (R6)nsubstituted with one or two halogens, orRing A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl;X6is absent or is selected from CH, CR3, CH2, CHR3, CR32, and N;X7is selected from CH, CR3, CH2. CHR3, CR32. and N;X8is selected from C and N;R1is H or C1-4 alkyl;R2is H or C1-4 alkyl, wherein the R2C1-4 alkyl is optionally substituted with one, two, or three substituents independently selected from halogen, hydroxy, cyano, C1-4 alkoxy, and Ci-4 haloalkoxy; oroptionally R1and R2, together with the carbon atom to which R1and R2are attached, form a C3-4 spirocyclic ring;each R3is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms, where when 2 R3alky l are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring;R4is H or C1-6 alkyl;26130each R5is independently selected from H, halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, and Ci-6 haloalkoxy;each R6is independently selected from halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C3-6 cycloalkyl, oxo, and 5- to 6-membered heterocyclyl;q is an integer 1-4; andn is an integer 0-5.

[0046] In some embodiments of Formula IV, the bicyclic ring containing X6, X7, X8, and Ring B is selected from:bicyclic ring is substituted with 1-4 R3.

[0047] In some embodiments of Formula IV, the bicyclic ring containing X6, X7, X8, and Ring B is selected from:26130wherein the bicyclic ring is substituted with 1-4 R3.

[0048] In some embodiments of Formula IV, the bicyclic ring containing X6, X7, X8, and Ring B is selected from:substituted with 1-4 R3.

[0049] In some embodiments of Formula IV, q is an integer 1-4. In some embodiments, q is an integer 1-3. In some embodiments, q is an integer 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments q is 4.

[0050] In some embodiments of Formula IV, R1is H or C1-2 alkyl. In some embodiments, R1is H or methyl. In some embodiments, R1is H. In some embodiments, R1is methyl.

[0051] In some embodiments of Formula IV, R2is H or C1-4 alkyl optionally substituted with one or two halogen, hydroxy, or C1-2 alkoxy. In some embodiments, R2is C1-4 alkyl optionally substituted with hydroxy. In some embodiments, R2is methyl or ethyl. In some embodiments, R2is H.

[0052] In other embodiments of Formula IV, R1and R2, together with the carbon atom to which R1and R2are attached, form a C3-4 spirocyclic ring. For example, R1and R2, together with the carbon atom to which R1and R2are attached, form a C3 spirocyclic ring.

[0053] In some embodiments of Formula IV, R4is H.

[0054] In some embodiments of Formula IV, Ring A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl attached to X2. In some embodiments, Ring A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl attached to X3. In some embodiments, Ring A is 5- to 6-membered heteroaryl. In some embodiments, Ring A is 5- to 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 pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, and oxazolyl. In some embodiments, Ring A is pyridyl, pyrazolyl, or imidazolyl. In some embodiments. Ring A is pyridyl. In some embodiments, Ring A is pyrazolyl. In some embodiments. Ring A is imidazolyl.26130

[0055] In some embodiments of Formula IV, each R3is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms. In some embodiments, R3is halogen, cyano, C1-2 alkyl, C1-2 alkyl substituted by 1-3 halogen, C1-2 alkoxy, C1-2 alkoxy substituted by 1- 3 halogen, C2-3 alkenyl, C2-3 alky nyl, C3-4 cycloalkyl, C3-4 cycloalkyl substituted by 1-3 halogen. C3-4 cycloalkoxy, and C3-4 cycloalkoxy substituted by 1-3 halogen. In some embodiments, 2 R3may be present on a single Ring B atom. In some embodiments, where when 2 R3alky 1 are present on a single Ring B atom, the 2 R3may be joined to form a C3-6 spirocyclic ring. In some embodiments, the 2 R3may be joined to form a C3 spirocyclic ring. In some embodiments, the 2 R3may be joined to form a C4 spirocyclic ring. In some embodiments, the 2 R3may be joined to form a C5spirocyclic ring. In some embodiments, the 2 R3may be joined to form a C6spirocyclic ring.

[0056] In some embodiments of Formula IV, each R3is halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, di-Ci-4 alkylamine, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkoxy, 5- to 6-membered heterocyclyl, which may be substituted by 1-3 halogen atoms, and C3-6 spirocyclic ring. In some embodiments, each R3is independently selected from Cl, F, CH3, CF3, CH2CH3,CCH2CF3, C≡CCH3, OCH3, OCHF2, OCF3,, or 2 R3are taken together with the atom to which they are attached, to form a C3 spirocyclic ring, or a C4 spirocyclic ring.

[0057] In some embodiments of Formula IV, each R5is independently selected from H, halogen, hydroxy, cyano, and C1-6 alky l. In some embodiments, each R5is independently selected from H, halogen, and C1-6 alkyl. In some embodiments, each R5is independently selected from H, halogen, and C1-2 alkyl. In some embodiments, each R5is independently selected from H or F.

[0058] In some embodiments of Formula IV, n is an integer 0-5. 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. In some embodiments, n is 4. In some embodiments, n is 5.26130

[0059] In some embodiments of Formula IV, each R6is independently selected from halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, and C3-6 cycloalkyl. In some embodiments, each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl C1-6 alkoxy, and C3-6 cycloalkyl. In some embodiments, each R6is independently selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl. In some embodiments, R6is selected from F, Cl, hydroxy, cyano, methyl, ethyl, methoxy, and cyclopropyl. In still other embodiments, each R6is independently selected from F and CH3.

[0060] In some embodiments, provided herein is a compound of Formula IV-A:Formula IV-Aor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, whereinRing A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl;Ring B is selected from 5- to 6-membered cycloalkyl;X1, X2, X4, and X5are CR5or N;provided that 0, 1 or 2 of X1, X2, X4, and X5are N;X6is absent or is selected from CH, CR3, CH2, CHR3, CR32, and N;X7is selected from CH, CR3, CH2, CHR3, CR32, and N;X8is selected from C and N;R1is H or C1-4 alkyl;R2is H or C1-4 alkyl, wherein the R2C1-4 alkyl is optionally substituted with one, two, or three substituents independently selected from halogen, hydroxy, cyano, C1-4 alkoxy, and C1-4 haloalkoxy; oreach R3is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-C1-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms, where when 2 R3alkyl are26130present on a single ring atom, the 2 R3may be joined to form a C3-6 spirocyclic ring;R4is H or C1-6 alkyl;each R5is independently selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, oxo. and 5- to 6-membered heterocyclyl;q is an integer 0-4; andn 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, X7is N, X8is C, Ring B is phenyl, and Ring A is attached to X2, q is an integer 1-4; when X6is CH, X7is N or CH, X8is C, Ring B is phenyl, X1, X2, X4, and X5are CH, X3is C, and Ring A is N-bound 6-membered heterocyclyl, q is an integer 1-4; and when X6is CH, X7is N, X8is C, Ring B is phenyl, X1, X2, X4, and X5are CH, X3is C, and Ring A is triazole, q is an integer 1-4.

[0061] In some embodiments, provided herein is a compound of Formula IV-B:Formula IV-Bor a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, whereinRing A is selected from 5-membered heteroaryl;Ring B is selected from 5- to 6-membered cycloalkyl;X7is selected from CH and N;R1is H or CH3;26130R2is H or CH3; oreach R3is independently selected from Cl, F, CH3, CF3, CH2CH3, CH2CF3, C≡CCH3,which they are attached, to form a C3 spirocyclic ring, or a C4 spirocyclic ring; R4is H or C1-6 alkyl;each R6is independently selected from halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl;q is an integer 1-4; andn is an integer 0-5.

[0062] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.261302613026130261302613026130261302613026130119120 Cli ^ z z ppz zyy r\ 1y y0 IZ I IZ IZyj \Z A> f.° T 'N" zz- ^..°121 o ^ o= U = HCIA rYJUYvy UnivJ o ^N_ o o Q122 It °zw. ZT zz 123' o o 124 9 = H nk Y Y x Y J^s. J 0 Jk cr N v >ZN~N 125126 2 i HJUL J A UY.^ZN~N 12712826130129130 H: Hcr A, N -fi o A Jk. Q c z _?z>s yQy * 131 H IZ IZHrc nrYt.N Y° rNriNo132o &4.. ZT ZI133 H H, A rYF AW r5 rN / o Wi '*jp Qix O134135136 N Hcr J n<x. XA N ^ o Ti Jk v > / N~N 137H Hn^rv o r kiA^KN__138° kJL^N N^26130261302613026130168 0C S ZX JJ'Y TYNY A— NHO Y=\ wJN 1 z 169I y f o o C p y yO wY wI^z 6zyZ IZ IZZ IZ IZ IZ1 Y Y Y Y Y......70 Y.o o o o o1 Y Y Y Y Y71 Y YY:zz-.ZI172 o 173 9? H[ i| 7 n p || c'-YYk. Y O YJY^N F N174175176177261302613026130261302613026130261302613026130acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof. In some embodiments, the compound is selected from26130pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof.Methods of Use

[0064] 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.

[0065] 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.

[0066] 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, Lcell disease, pseudo-Hurler poly dystrophy, 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,26130German / Serbian late infantile neuronal ceroid lipofuscinosis, congenital cathepsin D deficiency, Wolman disease, alpha-mannosidosis, beta-mannosidosis, aspartylglucosaminuria, and fucosidosis.

[0067] 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.

[0068] In some embodiments, the neurodegenerative disease is selected from 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.

[0069] In some embodiments, the neurodegenerative disease is selected from 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).

[0070] 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.

[0071] In some embodiments, the lysosomal storage disease is selected from sphingolipidoses, Farber disease. Krabbe disease, Galactosialidosis, Fabry’ disease, Schindler disease, betagalactosidase 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 poly dystrophy, 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 neuronal26130ceroid 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.

[0072] 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.

[0073] In some embodiments, the disease or disorder is selected from 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, Galactosiahdosis, 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 poly dystrophy, 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.

[0074] 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 sy nthase inhibitor. amicroRNA-17 inhibitor, a siRNA against p53, a KEAPl-Nrf2 activator, axanthine oxidase inhibitor, a PPARy agonist, an immunomodulator, a calcineurin inhibitor, a renin26130angiotensin 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 dipeptidy 1 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 famesoid x receptor agonist, a soluble guanylate cyclase stimulator, a thromboxane receptor antagonist, an erythropoietin receptor agonist, a cannabinoid receptor type 1 inverse agonist, aNADPH 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 APOL1 inhibitor, an Nrl2 activator / NF-kB inhibitor, a somatostatin receptor agonist, an AMP activated protein kinase stimulator, an arginine vasopressin receptor 2 antagonist, an antiamyloid 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 IKB inhibitor, a prostacyclin receptor agonist, a stimulator of hematopoiesis, an anticoagulant, a plateletinhibiting 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

[0075] 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.

[0076] The amount and concentration of compounds of Formula I, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof, in the pharmaceutical26130compositions, 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.

[0077] 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.

[0078] 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 or intrarectally, 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 injected26130using 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.

[0079] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com 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, com 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.

[0080] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coaling agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0081] 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, but l ated 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.

[0082] 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 upon the 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 active26130ingredient, e.g., from about 5 per cent to about 70 per cent, e.g., from about 10 per cent to about 30 per cent.

[0083] 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.

[0084] 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.

[0085] 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 a similar 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.

[0086] 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 or26130hydroxypropylmethyl 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.

[0087] 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 vary ing 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.

[0088] 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, benzy l alcohol, benzyl benzoate, propylene glycol, 1.3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0089] 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.

[0090] 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.26130

[0091] 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.

[0092] 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.

[0093] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure.

[0094] 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 intrastemal injection and infusion. In some embodiments, the compositions are administered by intravenous infusion or injection.

[0095] 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 intrastemal injection and infusion. Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise one or more compounds of the disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0096] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the disclosure include, but are not limited to, w ater, 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 ethyl26130oleate. 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.

[0097] 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.

[0098] 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.

[0099] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as poly lactide-poly glycolide. 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.

[0100] 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 composition containing, for example, 0.1 to 99.5% (e.g., 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0101] 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).

[0102] 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

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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%.

[0107] 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 itcan be expressed as the ratio LD50 / ED50. Compositions that exhibit large therapeutic indices are preferred.

[0108] 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.

[0109] 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 that 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.

[0110] The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0111] 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 times daily 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.

[0112] 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.Definitions

[0113] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0114] 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. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0115] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0116] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0117] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0118] As used herein, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.Chemical Definitions

[0119] 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.26130For example, the term “Ci-6 alkyl’" is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] An asterisk (*) or wavy line may be used in sub-formulas to indicate the bond that is connected to the core molecule as defined.

[0124] A dotted or dashed line may be used in formulas to indicate an optional double bond.

[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., =0), then 2 hydrogens on the atom are replaced. Ring double bonds, as used herein, 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, Ci-4 alkyl is intended to include Ci, C2, C3, and C4. C1-6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups and C1-8 alkyl is intended to include Ci, C2, C3, C4, C5, Ce, C7, and Cs. 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, C2-6 alkenyl is intended to include C2, C3, C4, C5, and Ce alkenyl groups and C2-8 alkenyl is intended to include C2, C3, C4,26130Cs, Ce, C7, and Cs alkenyl groups. Examples of C2-6 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4). pentenyl (Cs), pentadienyl (Cs), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), 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, C2-6 alkynyl is intended to include C2, C3, C4, Cs, and Ce alkynyl groups and C2-8 alkynyl is intended to include C2, C3, C4, Cs, Ce, C7, and Cs alkynyl 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 (Cs), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), 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, Cs, Ce. C7, and Cs cycloalkyl groups. Cycloalkyls may include multiple spiro- or fused or bridged rings. For example, cycloalkyl can include, but is not limited to, spiro propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, bicyclo butyl, pentyl, hexyl, heptyl, octy l, nonyl, or decyl groups, adamantyl groups, and norbomyl groups. The term “C3-8 spirocycle” or “C3-8 spirocyclic ring”, is intended to include, for example, two substituents attached to a single atom and joined to form a ring, which may be C3 spirocyclic ring (a spriocyclopropyl ring), C4 spirocyclic ring (a spriocyclobutyl ring), Cs spirocyclic ring (a26130spriocyclopentyl ring), Ce spirocyclic ring (a spriocyclohexyl ring), C7 spirocyclic ring (a spriocycloheptyl ring), or Cs spirocyclic ring (a spriocyclooctyl ring). 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- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro rings), or 11- to 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- to 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- to 10-membered heterocy clyl 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- to 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- to 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- to 8-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is26130independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 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 and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl 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-m aryl" refers to an aryl group having from n to m ring carbon atoms. In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci4 aryl”; e.g., anthracyl).26130“Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more cycloalkyl 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 and 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 that 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 heteroary ls 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, IH-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, thi enoimidazolyl, thiophenyl, triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl.26130

[0137] In some embodiments, a heteroaryl group is a 5- to 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- to 10-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 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- to 8-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 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- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 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 groups containing 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:26130wherein each Z is selected from carbonyl, N, NR*, O. and S; and R* is independently hydrogen, Ci-Cs alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl.

[0140] As used herein, "amine" or "amino" refers to unsubstituted -NH2 unless 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+1 wherein v = 1 to 3 and w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, tri chloromethyl, 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. C1-6 alkoxy, is intended to include Ci, C2, C3, C4, C5, and Ce alkoxy groups. Ci-s alkoxy, is intended to include Ci, C2, C3, C4, C5, Ce, C7, and Cs alkoxy 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] As used herein, the term "cycloalkyloxy" or ‘‘cycloalkoxy'’ is intended to include cycloalkyl groups as described above that are attached through an oxygen bridge. For example, the term " C3-8 cycloalkyloxy" is intended to include C3, C4, C5, Ce, C7, and Cs cycloalkyl groups that are attached through an oxygen bridge. For example, cycloalkyloxy can include, but is not limited to, spiro butyl, pentyl, hexyl, hepty l, octyl, nonyl, or decyl groups, bicyclo butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, adamantyl groups, and norbomyl groups that are attached through an oxygen bridge. Unless specified otherwise, cycloalkydoxy groups are26130optionally 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.

[0146] The term "hydroxyalkyl" means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxy alkyl groups include HO-CH2-. HO-CH2-CH2- and CH3-CH(OH)-.

[0147] 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.

[0148] As used herein, "oxo" is means a "=O" group.

[0149] As used herein, '‘nitro” refers to -NO2.

[0150] 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.

[0151] 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 X7forms a bond with the nitrogen adjacent to X6in Formula II.Other Definitions

[0152] 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.

[0153] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds or tautomers thereof, wherein the parent compound or a tautomer thereof, 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.26130Examples 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.

[0154] 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.

[0155] 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 moiety7by 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).26130

[0156] 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.

[0157] 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 anon-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0158] Disease, disorder, and condition are used interchangeably herein.

[0159] 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”).

[0160] 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.

[0161] 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.

[0162] In an alternate embodiment, the present disclosure contemplates administration of the compounds of the present disclosure or a pharmaceutically acceptable salt, solvate, hydrate,26130tautomer, 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 “prophy lactically 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.

[0163] The terms “activator” and “agonist” are used interchangeably to refer to an agent that increases or initiates a biological activity.

[0164] The term "hydrate" as used herein, refers to a compound formed by the union of water with the parent compound.

[0165] 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).

[0166] 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 are not 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.

[0167] 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); and26130Wilen, 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.

[0168] 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’7form 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.

[0169] 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 least about 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.

[0170] 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.

[0171] 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 have26130the 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.

[0172] All percentages and ratios used herein, unless otherwise indicated, are by weight.

[0173] 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.

[0174] " 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

[0175] 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.General.Intermediates A-E, Examples 1-241

[0176] All oxygen and / or moisture sensitive reactions were carried out under N2 atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N2 prior 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 on a Bruker (400 or 600 MHz 'l l). Agilent (400 MHz 'll) or Varian (400 MHz 'll) spectrometer. Proton and carbon chemical shifts are reported in ppm (5) 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 25 °C. 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:

[0177] Column: Shim-pack Scepter C18-120, 33*3.0mm, 3pm or YMC Triart C18, 50x4.6mm, 3pm; Mobile Phase: A: H2O(0.1%FA) B: CH3CN: Temperature: 35°C; Flow rate: 1.2mL / min;26130Run time: 0.1min@20%B,1.7min gradient (20-95% B), then 0.7min@95% B, then 0.4min@20% B; Injection volume: 5 pL; Detector: UV 220 / 254nm; Mass range: 100-1000; Scan:Positive / Negative.HPLC example conditions:

[0178] Column: YMC Triart Cl 8, 50x4.6mm, 3pm; Mobile phase: A:H2O / CH3CN / TFA=90 / l 0 / 0.1 B: H20 / 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°C;Detector: UV 220 / 254nm.Intermediates F-P, Examples 242-250

[0179] All oxygen and / or moisture sensitive reactions were carried out under N2atmosphere in glassware that was oven-dried overnight (100°C) 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 on a Varian (500 MHz 1H) spectrometer. Proton chemical shifts are reported in ppm (5) 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 300 K. Flash chromatography was accomplished using automated flash chromatography system, with a UV detector monitoring at 254 nm, 280 nm, and 200-300nm, with RediSep® Rf silica gel disposable flash columns (60 A porosity, 40-60 pm) or RediSep® Rf Gold® silica gel disposable flash columns (60 A porosity, 20-40 pm).

[0180] Analytical LC-MS was commonly performed on a Waters SQD single quadrupole mass spectrometer with electrospray ionization in positive ion detection mode (mass range set at 150-900 daltons, data collected in centroid mode and scan time set to 0.2 seconds) and a Waters Acquity UPLC system (binary solvent manager, sample manager, and TUV). The column used was a Waters Acquity BEH Cl 8 1 * 50 mm, 1.7 pm, heated to 50°C. The mobile phases used were water (with 0.1% TFA modifier) for Solvent A and 100% MeCN (with 0.1% TFA modifier) for Solvent B. A tw o-minute run w as established at a flow' rate of 0.3 mL / min with initial conditions of 95% Solvent A and ramping up to 99% Solvent B at 1.60 minutes and holding at 99% Solvent B for 0.40 minutes. The injection volume was 0.5 pL using partial loop needle overfill injection mode. The TUV monitored wavelength 215 or 254 nm with a sampling rate of 20 points / second, normal filter constant and absorbance data mode.

[0181] Preparative reverse-phase chromatography w as generally carried out on a Teledyne ISCO ACCQPrep HP 150 apparatus equipped with UV and ELSD detectors. The UV detector ty pically monitored wavelengths of 215, 254 nm and 200-300nm. The column was commonly26130one of the following: Waters XBridge Prep C18 OBD 5 pm 30 x 150 mm, Waters XBridge Prep C18 OBD 5 pm 30 x 250 mm. Waters XBridge Prep C18 OBD 5 pm 50 x 250 mm, Waters SunFire Prep C18 OBD 5 pm 30 x 150 mm, Waters SunFire Prep C18 OBD 10 pm 30 x 150 mm, Waters SunFire Prep C18 OBD 5 pm 50 x 250 mm, Waters SunFire Prep Cl 8 OBD 10 pm 50 x 250 mm, or Phenomenex Luna Prep C18 5 pm 50 x 250 mm. The mobile phases consisted of mixtures of MeCN (with 0.1% TFA modifier) and water (with 0.1% TFA modifier).

[0182] Chiral chromatography was commonly performed by supercritical fluid chromatography using an appropriate column, for example: ChiralPak AD, ChiralPak AD-3, ChiralPak ADH, ChiralPak AS, ChiralPak AS-3, ChiralPak AS-H, ChiralPak IB-N, ChiralPak OD-H, ChiralPak OJ-3, ChiralPak OJ-H, Phenomenex-Cellulose-2, (S, S)Whelk-01, or similar. Mobile phases consisted of mixtures of CO2 or hexane with MeOH, EtOH. or IPA using 0.05-0.1% DEA or NH4OH modifier. Mobile phase gradients were optimized for the individual compounds.Pressure w as typically maintained at 100 bar, and flow rates ranged from 50-200 rnL / min. UV monitoring w as generally carried out at 220 or 205 nm.Generic Synthetic SchemesGeneric Scheme 1

[0183] Additional compounds with substituted fused saturated pyrimidinone ring systems may be synthesized using a sequence of reactions starting with an appropriately functionalized cyclic ketone. Acylation of the alpha-position may then be carried using an appropriate base and acylating reagent such as diethyl- or dimethyl-carbonate. The resulting beta ketoesters may then cyclized to the corresponding pyrimidinone using an appropriate reagent such as formamidine. Pyrimidinone N-alkylation using an appropriate base and alpha-halo / alpha-trifl ate containing amide or Mitsunobu reaction with an appropriate alpha-hydroxy amide may then yield the desired compounds.26130Generic Scheme 2

[0184] Compounds with substituted saturated pyridinone ring systems may also be synthesized using a sequence of reactions starting with an appropriately functionalized cyclic ketone. Tritiate formation may be carried out with an appropriate base and triflic anhydride or similar reagent. Alkyne couple using a Sonagashira or similar reaction may then yield an enyne which can be semi-reduced using a reaction system such as a quinoline-poisoned Lindlar catalyst and hydrogen to give the corresponding diene ester. Cyclization to the desired pyridinone may then be carried out through conversion to the corresponding isocyanate via a Curtius rearrangement using conditions such as a sequence of ester hydrolysis and reaction with diphenylphosphoryl azide. Pyridinone N-alkylation using an appropriate base and alpha-halo / alpha-triflate containing amide or Mitsunobu reaction with an appropriate alpha-hydroxy amide may then yield the desired compounds.Table 2. Abbreviations'H NMR proton nuclear magnetic resonanceIN 1 normalACN acetonitrileAcOH acetic acidAgF2silver(II) fluorideAr arylBINAP 2,2'-bis(diphenvlphosphino)-l,l'-binaphthvl Bn benzylBoc t-butoxv carbonylBpin boronic acid pinacol esterCU(OAC)2copper(II) acetateDCM dichloromethaneDEA diethyl amineDIAD Diisopropyl azodicarboxvlateDIEA or DIPEA N. JV-diisopropylethylamine26130DMA N. A-dimethyl acetamideDMAP 4-dimethylaminopyridineDME 1.2-dimethoxy ethaneDMF A A-dimethvI formamideDMF-DMA A. A-dimethyl formamide dimethyl acetal DMSO dimethylsulfoxideDPPA diphenvlphosphoryl azidedppf 1, 1’ -bis(dipheny lphosphino)ferrocene ELSD evaporative light scattering detector ESI electrospray ionizationEt2O diethyl etherEtOAc ethyl acetateEtOH ethanolFA formic acidH2hydrogen gasHATU <9-(7-azabenzotriazol- 1 -yl)-A, A A A tetramethvluronium hexafluorophosphate HPLC high performance liquid chromatography hr or h hourLCMS or LC-MS or LC / MS liquid chromatography mass spectrometry LDA lithium diisopropylamideMS Mass spectrometryM molarMe methylMeCN acetonitrileMeOH methanolmin minutemL millilitermm millimetermmol millimoleMTBE methyl tert-buty l etherNa2S2O3sodium thiosulfateNa2SO4sodium sulfateNaH sodium hydrideNaHCO₃ sodium bicarbonaten-BuLi / ?-butvl lithiumNCS N -chlorosuccinimideNH4CI ammonium chloridenm nanometerNMI 1 -methylimidazoleOTBDPS (tert-butyldiphenvlsilvl)oxy Pd(dppf)Cl21, 1 -bis(diphenylphosphino)ferrocene- palladium(II)dichloridePd(PPh3)4 tetrakisftriphenylphosphine)palladium(O) Pd / C palladium on carbonPd2(dba)3tris(dibenzylideneacetone)dipalladium PTSA p-toluenesulfonic acidrt room temperature26130s secondsatd, sat’d, or sat. saturatedSelectfluor 1 -(chloromethyl)-4-fluoro-l,4- diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborateSEM-C1 2-(trimethylsilyl)ethoxvmethyl chloride SFC supercritical fluid chromatography TBAF tetrabutylammonium fluorideTCFH N, N, N'. N'-tetramethylchloroformamidinium hexafluorophosphateTEA or EtsN tri ethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyTol tolueneTs p-toluenesulfonylTsOH p-toluenesulfonic acidUV ultravioletXPhos-Pd-G2 chloro(2-dicyclohexylphosphino-2',4',6'- triisopropy 1- 1, l'-bipheny 1) [2-(2'-amino- 1,1'- biphenyl)lpalladium(II)ZnBn zinc bromidepm micrometerpmol micromoleIntermediate A. Synthesis of 4-(l-methyl-lH-pyrazol-5-yl)anilinePd(dppf)CI2, K2CO3dioxane / H2O, 90°C

[0185] To a mixture of 4-bromoaniline (5.0 g, 29 mmol) and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (6.7 g, 32 mmol) in dioxane / EhO (80 mL / 20 mL) were added K2CO3 (12.1 g, 87.2 mmol) and Pd(dppf)Ch (1.1 g, 1.5 mmol). The mixture was stirred at 90°C under N2 overnight. 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-(l-methyl-lH-pyrazol-5-yl)aniline. LC / MS ESI (m / z): 174 (M+H)+.26130Intermediate B. Synthesis of 4-(3-fluoropyridin-2-yl)anilinePd(dppf)CI2, K2CO3dioxane / H2O, 90°Cintermediate B

[0186] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.73 g, 17.0 mmol) in dioxane (50 mL) and H2O (10 rnL) were added 2-bromo-3-fluoropyridine (3.00 g, 17.0 mmol). K2CO3 (7.07 g, 51.1 mmol) and Pd(dppf)Ch (1.3 g, 1.7 mmol). The resulting mixture was stirred at 90°C under N2 overnight. The mixture was concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-50% EtOAc in petroleum ether) to afford 4-(3-fluoropyridin-2-yl)aniline. LC / MS ESI (m / z): 189 (M+H).Intermediate C. Synthesis of 4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)anilineCH3I n-BuLi, l2NaH. THF -78°C, THF 1 2Pd(dppf)CI2, Na2CO3dioxane / H20, 100°Cintermediate CStep 1. 4-Fluoro-l-methyl-lH-pyrazole

[0187] To a solution of 4-fluoro-lH-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. 'l l NMR (400 MHz, CDCh) 67.30 (d, J= 4.1 Hz, 1H), 7.24 (d, J= 4.8 Hz, 1H), 3.83 (s, 3H).Step 2, 4-Fluoro-5-iodo-l -methyl- IH-pyrazole

[0188] To a solution of 4-fluoro-l-methyl-lH-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 for261301 h. Then a solution of I2 (13.5 g, 52.0 mmol) in THF (20 rnL) was added dropwise at -78°C. The reaction was allowed to warm up to rt and stirred for 2 h and was quenched with saturated Na2S20s (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-l-methyl-lH-pyrazole. LC / MS ESI (m / z): 227 (M+H)+. 'H NMR (400 MHz, CDCls) 67.36 (d, J = 4.9 Hz. 1H), 3.87 (s, 3H).Step 3. 4-(4-Fluoro-l-methyl-lH-pyrazol-5-yl)aniline

[0189] To a solution of 4-fluoro-5-iodo-l-methyl-lH-pyrazole (3.27 g, 14.5 mmol) in dioxane (50 mL) and water (5 mL) were added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.5 g, 16 mmol), NazCOs (4.6 g, 43 mmol) and Pd(dppf)Ch (530 mg, 0.72 mmol). The mixture was stirred at 100°C under N2 for 18 h. The mixture was concentrated in vacuo and purified by flash column chromatography (silica gel, 0-30% EtOAc in petroleum ether) to afford the title compound 4-(4-fluoro-l -methyl- lH-pyrazol-5-yl)aniline. LC / MS ESI (m / z): 192 (M+H)+.Intermediate D. Synthesis of 4-(4-fluoro-l-methyl-lH-pyrazol-3-yl)anilineintermediate D Step 1. 3-Bromo-4-fluoro-l-methyl-lH-pyrazole

[0190] To a solution of 3-bromo-l -methyl- IH-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-l -methyl- 1H-pyrazole. LC / MS ESI (m / z): 180, 182 (M+H)+.Step 2, 4-(4-Fluoro-l-methyl-lH-pyrazol-3-yl)aniline

[0191] To a solution of crude 3-bromo-4-fluoro-l-methyl-lH-pyrazole (1.2 g, 6.7 mmol) in dioxane (20 mL) and water (4 mL) were added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.5 g, 6.7 mmol), K2CO3 (2.3 g, 17 mmol), and Pd(dppf)C12 (490 mg, 0.67 mmol). The reaction was stirred at 90°C under N2 for 18 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography eluting with (petroleum ether / EtOAc = 3 / 1, v / v) to afford the title compound 4-(4-fluoro-l-methyl-lH-pyrazol-3-yl)aniline. LC / MS ESI (m / z): 19226130(M+H)+. NMR (400 MHz, DMSO-cL) 5 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-l-oxoisoquinolin-2(lH)-yl)propanoic acidMg(Of-Bu)2, f-BuOK THF, rt~55°C intermediate E Step 1. (E’)-5-Chloro-3-(2-ethoxyvinyl)picolinonitrile

[0192] To a solution of 3-bromo-5-chloropicolinonitrile (4.0 g, 18 mmol) in dioxane (40 mL) and H2O (8 mL) were added (7?)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.9 g, 20 mmol), Pd(dppf)Ch (1.0 g, 1.4 mmol), and K2CO3 (7.6 g, 55 mmol). The resulting mixture was stirred at 90°C under N2 overnight. After cooling down to rt, the reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (0~9% EtOAc in petroleum ether) to afford (E)-5-chloro-3-(2-ethoxyvinyl)picolinonitrile. LC / MS ESI (m / z): 209 (M+H)+.Step 2, (E)-5-Chloro-3-(2-ethoxyvinyl)picolinamide

[0193] To a solution of (E)-5-chloro-3-(2-ethoxyvinyl)picolinonitrile (3.3 g, 16 mmol) in acetone (50 mL) was added 3M Na2CO? (90 mL) followed by 30% H2O2 (90 mL) dropwise. The mixture was stirred at rt for 3 h and was then quenched with NajSCh (aq.). The mixture was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give (E)-5-chloro-3-(2-ethoxy vinyl)picolinamide, which was used directly in the next step. LC / MS ESI (m / z): 227 (M+H)+.Step 3. 3-Chloro-L7-naphthyridin-8(7H)-one

[0194] 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 NaHCOs (aq) and suspended in DCM. The product was collected by filtration and dried under vacuum to afford 3-chloro-L7-naphthyridin-8(7H)-one, which was used directly in the next step. LC / MS ESI (m / z): 181 (M+H)+.Step 4, (7?)-2-(3-Chloro-8-oxo-1.7-naphthyridin-7(8H)-yl)propanoic acid

[0195] 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 GS')-2-chloropropanoic acid (2.9 g, 27 mmol) to maintain the internal temperature at < 35°C. After26130aging 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-l,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 HC1 was added, and the resultant was filtered to remove unreacted starting material. The filtrate was concentrated and purified by reverse phase column chromatography (Cis column, 0-23% MeCN in water) to give (7?)-2-(3-chloro-8-oxo-l,7-naphthyridin-7(8H)-yl)propanoic acid. LC / MS ESI (m / z): 253 (M+H)+.Intermediate F. Synthesis of 2-Chloro-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)propenamideStep 1. 4-fluoro-5-iodo-l-methyl-lH-pyrazole

[0196] To a solution of 4-fluoro-l -methyl- IH-pyrazole (2.50 g, 25.0 mmol) in THF (50 mL) was added n-BuLi (2.5 M in THF. 13.0 mL. 32.5 mmol) at -78°C over 5 min. After the addition, the reaction mixture was stirred at -78°C for 30 min. Then iodine (8.24 g, 32.5 mmol) in 10 mL THF was added dropwise for 20 min. The reaction mixture was allowed to warm to rt and was quenched by sat'd Na2S20s (25 mL). The aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (50 mL), dried (NazSCL), and concentrated to afford the crude title compound 4-fluoro-5-iodo-l -methyl- IH-pyrazole.Step 2, 4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)aniline

[0197] A mixture of 4-fluoro-5-iodo-l-methyl-lH-pyrazole (5.64 g, 25.0 mmol), 4-aminobenzeneboronic acid hydrochloride (4.54 g, 26.2 mmol), potassium phosphate, tribasic (10.6 g, 49.9 mmol), XPhos-Pd-G2 (982 mg, 1.25 mmol), 1,4-dioxane (69.3 mL) and water (13.9 mL) was stirred vigorously at 80°C. After 20 h, the reaction mixture was concentrated and purified by silica gel chromatography to afford the title compound 4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)aniline.26130Step 3, 2-chloro-N-(4-(4-fluoro-l -methyl- lH-pyrazol-5-yl)phenyl)propanamide

[0198] To a mixture of 4-(l -methyl- lH-pyrazol-5-yl)aniline (1.2 g, 6.9 mmol), 2-chloropropionic acid (0.9 g, 0.7 mL, 8.3 mmol), HATU (2.9 g, 7.6 mmol) and DCM (69 mL) was added DIPEA (1.8 g, 2.4 mL, 13.9 mmol) dropwise at rt. The reaction mixture was stirred at rt for 1 h. Then, the reaction mixture was poured into sat’d NH4CI (50 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography to afford the title compound 2-chloro-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)propanamide. MS ESI (m / z): 282.2 (M+H)+.

[0199] The following intermediate w as prepared by the procedure analogous to the synthesis of Intermediate F.Intermediate Structure Name MS [M+l]GN2-chloro-A-(4-(l-0MS ESI (m / z):methyl- l / f-pyrazol-5- 2642 (M+H) yl)phenyl)propanamide+Intermediate H. Synthesis of 6,6-Dimethyl-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-oneStep 1. ethyl 4.4-dimethyl-2-oxocvclopentane-l -carboxylate

[0200] To a suspension of NaH (285 mg, 90% Wt, 10.7 mmol) in THF (15 mL) under inert atmosphere was added ethyl carbonate (948 mg, 0.972 mL, 8.02 mmol). Then the reaction mixture was warmed to 60°C and stirred vigorously for 10 min. After that, 3,3-dimethylcyclopentan-l-one (300 mg, 2.68 mmol) in 5 mL THF was added dropwise over 20 min. The reaction w as stirred for another 2 hr at 60°C after the completion of the addition. The reaction was cooled to 0°C by an ice- ater bath, and sat’d NH4CI (50 mL) was carefully added dropwise. The aqueous layer was extracted with Et20 (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried (Na2SO4). and concentrated. The residue was purified by silica gel chromatography to afford the title compound ethyl 4,4-dimethyl-2-oxocyclopentane-l-carboxylate.26130Step 2, 6.6-Dimethyl-3.5.6.7-tetrahydro-4H-cyclopenta[d1pyrimidin-4-one

[0201] Ethyl 4.4-dimethyl-2-oxocyclopentane-l -carboxylate (222 mg, 1.21 mmol) and formamidine hydrochloride (194 mg, 2.41 mmol) were dissolved in 8 mL MeOH. The reaction mixture was stirred at 65°C for 10 min. Sodium methoxide (782 mg, 25% Wt in MeOH, 3.62 mmol) was added dro wise over 5 min, and the reaction was stirred for another 18 hr. After that, the reaction was cooled to rt and concentrated. The residue was purified by silica gel chromatography to afford the title compound 6,6-dimethy 1-3.5, 6,7-tetrahy dro-4H-cyclopenta[d]pyrimidin-4-one. MS ESI (m / z): 1 5.2 (M+H)+.

[0202] The following intermediate was prepared by the procedure analogous to the synthesis of Intermediate H by using the corresponding ketones.Intermediate Structure Name MS [M+l]I7,7-dimethyl-5,6,7,8- MS ESI (m / z): tetrahydroquinazolin- 179.2 (M+H)+ 4(3H)-oneO J F3C. / N. 7 -(trifluoromethy 1)- 5, 6,7,8- MS ESI (m / z): tetrahy droquinazolin- 219.2 (M+H)+ O 4(3H)-oneK7-methyl-5.6.7.8- MS ESI (m / z): tetrahydroquinazolin- 165.1 (M+H)+ 4(3H)-oneOL 5',8'-dihydro-3'H- spiro[cyclopropane- MS ESI (m / z): l,7'-quinazolin]- 177.1 (M+H)+ 0 4'(6'H)-oneM 5',8'-dihydro-3'H- spirofcyclobutane- MS ESI (m / z): l,7'-quinazolin]- 191.2 (M+H)+o 4'(6'H)-oneIntermediate N. Synthesis of5,5-Difhioro-5,6,7,8-tetrahydroisoquinolin-l(2H)-oneAgF2MeCN, 25 °CF F Step 1. 5.5-difluoro-5.6.7.8-tetrahvdroisoquinoline

[0203] 5.6.7,8-Tetrahydroisoquinolin-5-one (100 mg, 0.679 mmol) was mixed with DeoxoFluor® (902 mg, 50% Wt in Toluene, 2.04 mmol). The reaction was stirred at 80 °C for 1 hr. The26130reaction was then cooled to rt and poured into sat'd aqueous NaHCCh (10 mL). The aqueous layer was extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography to afford the title compound 5,5-difluoro-5,6,7,8-tetrahydroisoquinoline.Step 2, 1.5.5-trifluoro-5.6.7.8-tetrahydroisoquinoline

[0204] To 5,5-difluoro-5,6,7,8-tetrahydroisoquinoline (30 mg, 0.18 mmol) was added MeCN (5 mL) followed by AgF2 (78 mg, 0.53 mmol). The reaction was stirred vigorously at 55 °C for 1 hr. Then the reaction mixture was filtered, and the filtrate was poured into 10% Na2S2Ch (10 mL), extracted with EtOAc (15 mL x 2). The combined organic layers were washed with 10% Na2S2Ch (10 mL), brine (10 mL), dried (Na2SO4), and concentrated. The crude was carried to Step 3.Step 3, 5.5-difluoro-5.6.7.8-tetrahvdroisoquinotin-l(2H)-one

[0205] To the crude from Step 2 was added 1,4-dioxane (2 mL) and aqueous IN NaOH (2 mL). The reaction was heated to 100 °C for 90 minutes in a microwave reactor. The reaction was cooled to rt and concentrated to dry. The residue was purified by silica gel chromatography to afford the title compound 5,5-difluoro-5,6,7,8-tetrahydroisoquinolin-l(2H)-one. MS ESI (m / z): 186.1 (M+H)+.Intermediate O. Synthesis of 6,6-Dimethyl-5,6,7,8-tetrahydroisoquinolin-l(2H)-oneMeOH, 25 °C Step 1. 5.5-dimethylcvclohex-l-en-l-yl trifluoromethanesulfonate

[0206] LDA (2.0 M in THF / n-heptane / ethylbenzene, 2.48 mL, 4.95 mmol) was added to anhydrous THF (30 mL) at -78°C. 3,3-dimethylcyclohexan-l-one (500 mg, 3.96 mmol) in 10 mL THF was added dropwise to the solution. The resulting solution was stirred at -78°C for 60 min. Then phenyl triflimide (2.12 g, 5.94 mmol) was added, and the reaction mixture was stirred for another 20 min at -78°C. The reaction was allowed to warm to rt and was stirred overnight. The reaction mixture was poured into sat’d NFUC1 (50 mL) and extracted with Et20 (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and concentrated. The26130residue was purified by silica gel chromatography to afford the title compound 5,5-dimethylcyclohex-l-en-l-yl trifluoromethanesulfonate.Step 2, methyl 3-(5,5-dimethylcvclohex-l-en-l-yl)propiolate

[0207] LDA (2.0 M in THF / n-heptane / ethylbenzene, 0.62 mL, 1.24 mmol) was added to anhydrous THF (10 mL) at -78°C. Methyl propiolate (97.7 mg, 101 pL, 1.16 mmol) in 2 mL THF was added dropwise to the solution. The resulting solution was stirred at -78°C for 15 min. After that, ZnBn (305 mg. 1.36 mmol) in 5 mL THF was added. The resulting mixture was warmed to 0°C. 5,5-dimethylcyclohex-l-en-l-yl trifluoromethanesulfonate (200 mg, 774 pmol) and Pd(PPh3)4 (44.7 mg, 38.7 pmol) in 2 mL THF was added. The reaction was allowed to warm to rt and was stirred overnight. The reaction mixture was poured into sat'd NH4CI (10 mL) and extracted with Et20 (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried (NazSCL), and concentrated. The residue was purified by silica gel chromatography to afford the title compound methyl 3-(5,5-dimethylcyclohex-l-en-l-yl)propiolate.Step 3, methyl (Z)-3-(5.5-dimethylcvclohex-l-en-l-yl)acrylate

[0208] Methyl 3-(5,5-dimethylcyclohex-l-en-l-yl)propiolate (100 mg, 520 pmol), Lindlar’s catalyst (11.1 mg), quinoline (134 mg, 123 pL, 1.04 mmol) and MeOH (5 mL) were mixed and stirred at rt for 10 min. Then the reaction vessel was evacuated and backfilled with H2 (1 atm) three times. The reaction was stirred vigorously under H2 (1 atm) at rt for 2 hr. Then the reaction mixture was carefully filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography to afford the title compound methyl (Z)-3-(5,5-dimethylcyclohex-l-en-l-yl)acrylate.Step 4, (Z)-3-(5,5-dimethylcvclohex-l-en-l-yl)acrylic acid

[0209] Methyl (Z)-3-(5,5-dimethylcyclohex-l-en-l-yl)acrylate (61.3 mg, 316 pmol) was mixed with lithium hydroxide hydrate (39.7 mg, 947 pmol), THF (3 mL), Water (1 mL) and MeOH (1 mL). The reaction mixture w as stirred vigorously at rt overnight. Then the pH of the reaction was adjusted to 1 by IN HO. The reaction mixture was poured into sat’d NH4CI (50 mL), extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and concentrated. The crude was carried to Step 5.Step 5, 6.6-dimethyl-5.6.7.8-tetrahydroisoquinolin-l(2H)-one

[0210] To the crude from Step 4 was added toluene (3 mL) followed by DPPA (95.5 mg, 347 pmol) and Et? N (63.9 mg, 88.0 pL, 631 pmol). The mixture w as stirred at rt for 6 hr and then warmed to 80°C for another 6 hr. After that, the reaction mixture was concentrated and purified by silica gel chromatography to afford the title compound 6,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-l(2H)-one. MS ESI (m / z): 178.2 (M+H)+.26130

[0211] The following intermediate was prepared by the procedure analogous to the synthesis of Intermediate O using the corresponding ketone.Intermediate Structure Name MS [M+l]P 7',8'-dihydro-277- ^0 spiro [cyclopropane- MS ESI (m / z):0- l,6'-isoquinolin]- 176.2 (M+H)+l'(577)-oneExample 1. Synthesis of (7?)-2-(6,7-difhioro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)propenamide (1)o

[0212] 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

[0213] 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 rt 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 FLO. The organic layer was washed with brine, dried, filtered, and evaporated to afford 4,5 -difl uoro-2 -methylbenzamide.Step 2, (E)-N-((Dimethylamino)methylene)-4.5-difluoro-2-methylbenzamide

[0214] 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 N2 for 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. LC / MS ESI (m / z): 22726130(M+H)+. NMR (400 MHz, DMSO-rfe) 5 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-l(2H)-one

[0215] 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 rnL, 1.0 M in THF). The resulting mixture was stirred at 65°C under N2 for 2 h. After being cooled down to rt, the mixture was partitioned between EtOAc and NH4CI (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% EtOAc in petroleum ether) to afford 6,7-difluoroisoquinolin-l(2H)-one.LC / MS ESI (m / z): 182 (M+H)+.Step 4, CR)-2-(6.7-Difluoro-l-oxoisoquinolin-2(lH)-yl)propanoic acid

[0216] 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 N2 for 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-l(2H)-one (170 mg, 0.94 mmol) was charged. The mixture stirred at rt for 2.5 h and then at 55°C 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 crude (A)-2-(6,7-difluoro-l-oxoisoquinolin-2(lH)-yl)propanoic acid. LC / MS ESI (m / z): 254 (M+H)+.Step 5, (7?)-2-(6.7-Difluoro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)propenamide

[0217] To a solution of (A)-2-(6.7-difluoro-l-oxoisoquinolin-2(lH)-yl)propanoic acid (40 mg, 0.16 mmol) in DMF (5 rnL) were added 4-(l-methyl-lH-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 NaHCOs (aq). The organic layer was separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried overNa2SO4. filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-80% EtOAc in petroleum ether) and prep-HPLC to afford (?)-2-(6,7-difluoro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)propanamide. LC / MS ESI (m / z): 409 (M+H)+.1H NMR (400 MHz, CDCh) 58.69 (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,261302H), 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= 1A Hz, 1H), 3.92 (s, 3H), 1.71 (d, J= 7.2 Hz, 3H).

[0218] The following compound was prepared by a procedure similar to that described for Example 1 using the corresponding aniline intermediate for the last step.Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 409 (M+H)+. 'H NMR (400 MHz, 2-(6,7-difluoro-l- DMSO-tfc) 6 10.54 (s, 1H), 8.10 (dd, J= 10.9, 8.3 Hz, oxoisoquinolin-2( 1H)- 1H), 7.83 (dd, J= 11.2, 7.7 Hz, 1H), 7.74-7.70 (m, 2H), 2 yl)- / V-(4-( 1 -methyl- 1H- 7.64 (d, J= 7.6 Hz, 1H), 7.50-7.47 (m, 2H), 7.44 (d, J = pyrazol-5- 1.8 Hz, 1H). 6.72 (d, J= 7.6 Hz, 1H). 6.36 (d, J= 1.8 yl)phenyl)propanamide Hz, 1H), 5.64 (q, J= 7.2 Hz, 1H), 3.84 (s, 3H), 1.69 (d,J = 7.3 Hz, 3H).Example 3. Synthesis of 2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l,4-dimethyl-lH-pyrazol-5-yl)phenyl)propanamide (3)

[0219] The aniline intermediate used in the second step was prepared by a procedure similar to that described for Intermediate A.Step 1. (7?)-2-(6-Chloro-l-oxoisoquinolin-2(lH)-yl)propanoic acid

[0220] 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-l(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 HC1 was added. The mixture was partitioned between EtOAc and H2O. The organic layer was separated and concentrated to dryness and was triturated from EtOAc / petr oleum ether to give crude ( / ?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)propanoic acid. LC / MS ESI (m / z): 252 (M+H)+. 'H NMR (400 MHz,26130DMSO- s) 5 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-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l,4-dimethyl-lH-pyrazol-5- yllphenyllpropenamide

[0221] To a solution of (7?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)propanoic acid (100 mg, 0.40 mmol) in DMF (5 mL) was added 4-(l,4-dimethyl-lH-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 it 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% EtOAc in petroleum ether) to give the crude product, which was further purified by prep-HPLC to afford 2-(6-chloro- 1 -oxoisoquinolin-2( 1 H)-yl)-N-(4-( 1,4-dimethyl- 1 H-pyrazol-5 -yl)phenyl)propanamide. LC / MS ESI (m / z): 421 (M+H)+. 'H NMR (400 MHz, DMSO-tL) 5 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).

[0222] The following compounds were prepared by a procedure similar to that described in Example 3 with the corresponding quinazolin-4(3H)-one / isoquinolin-l(2H)-one / phthalazin-l(2H)-one derivative as the starting material and analogous aniline intermediates for the second step.

[0223] 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.Ex. No. Name LCMS, ' H NMRLC / MS ESI (m / z): 388 (M+H)+. 'H NMR (400 MHz, (7?)-A-(4-( 1 -methyl- \H- DMSO-ofe) 5 10.42 (s. 1H), 8.44 (s. 1H), 8.04 (d, J= 8.1 pyrazol-3-yl)phenyl)-2- Hz, 1H), 7.71 (dd, J= 12.1, 5.4 Hz, 3H), 7.61 (d, J= 8.7 4 (7-methyl-4- Hz, 2H), 7.54 (s, 1H). 7.39 (d, J= 8.2 Hz, 1H). 6.62 (d, oxoquinazolin-3(477)- J= 2.2 Hz, 1H), 5.57 (q, J= 7.3 Hz, 1H), 3.86 (s, 3H), yl)propanamide2.48 (s, 3H), 1.76 (d, J= 1A Hz, 3H).LC / MS ESI (m / z): 388 (M+H)+. 'H NMR (400 MHz, (A)-A-(4-(l -methyl- 1 H- DMSO-ofe) 5 10.56 (d, J= 4.4 Hz, 1H), 8.45 (d, J= 6.1 pyrazol-5-yl)phenyl)-2- Hz, 1H), 8.09-8.00 (m, 1H), 7.72 (dd, J= 7.6, 5.7 Hz, 5 (7-methyl-4- 2H). 7.56-7.37 (m, 5H). 6.41-6.33 (m, 1H). 5.63-5.51 oxoquinazolin-3(477)- (m, 1H), 3.84 (d, J= 6.0 Hz, 3H), 3.34 (s, 3H), 1.78 (t, J yl)propanamide= 6.1 Hz, 3H).26130Ex. No. Name LCMS, NMRLC / MS ESI (m / z): 421 (M+H)+. 'H NMR (400 MHz, 2-(6-chloro-l- CD3OD) 5 8.28 (d, J= 8.7 Hz, 1H). 7.73-7.66 (m, 3H). oxoisoquinolin-2(l / Z)- 7.60 (d, J= 7.6 Hz, 1H), 7.49 (dd, J= 8.7, 2.0 Hz, 1H), 6 yl)-JV-(4-( 1,3-dimethyl- 7.44-7.36 (m, 2H), 6.72 (d, J= 7.6 Hz, 1H), 6.12 (s, 177-pyrazol-5- 1H), 5.75-5.62 (m, 1H), 3.76 (s, 3H), 2.23 (s, 3H), 1.76 yl)phenyl)propanamide(d, J = 7.3 Hz, 3H).LC / MS ESI (m / z): 374 (M+H)+. 'H NMR (400 MHz, (7?)-N-(4-(l -methyl-177- DMSO-<7e) 6 10.43 (s, 1H), 8.48 (s, 1H), 8.17 (dd, J = pyrazol-3-yl)phenyl)-2- 8.0, 1.3 Hz, 1H), 7.87 (ddd, J= 8.5, 7.3, 1.5 Hz, 1H), 7(4-oxoquinazolin-3(477)- 7.74 (d, J= 8.6 Hz, 3H), 7.70 (d, J= 2.2 Hz, 1H), 7.64- yl)propanamide 7.55 (m, 3H), 6.63 (d, J= 2.2 Hz, 1H), 5.59 (q, J= 7.4Hz, 1H), 3.86 (s, 3H), 1.79 (d, J= 7.4 Hz, 3H).( / ?)-2-(7-methoxy-4- LC / MS ESI (m / z): 404 (M+H)+. ’H NMR (400 MHz,CDCh) 5 8.47 (s, 1H), 8.27 (s, 1H), 8.21 (dd, J= 8.7, oxoquinazolin-3(477)- 2.4 Hz, 1H), 7.73 (d, J= 8.7 Hz, 2H), 7.55 (d, J= 8.7 8 y l)-JV-(4-( 1 -methyl- 177- Hz, 2H), 7.35 (d, J= 2.2 Hz, 1H), 7.13-7.07 (m, 2H), pyrazol-3- 6.49 (d, J = 2.3 Hz, 1H), 5.68 (q, J = 7.3 Hz, 1H), 3.93 yl)phenyl)propanamide(d, J= 1.2 Hz, 6H), 1.81 (d, J = 7.3 Hz, 3H).LC / MS ESI (m / z): 392 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-fluoro-l- DMSO-d>) 5 10.14 (s, 1H), 8.48 (s, 1H), 8.34 (dd, J = oxophthal azin-2( 177)- 8.8, 5.4 Hz, 1H), 7.83 (dd, J= 8.9, 2.5 Hz, 1H), 7.77- 9 y l)-JV-(4-( 1 -methyl- 177- 7.67 (m, 4H), 7.60 (d, J= 8.7 Hz, 2H), 6.62 (d, J= 2.2 pyrazol-3- Hz, 1H), 5.58 (q, J = 7.0 Hz, 1H), 3.86 (s, 3H). 1.65 (d, yl)phenyl)propanamide J = 7.1 Hz, 3H).LC / MS ESI (m / z): 391 (M+H)+. ’H NMR (400 MHz, (7?)-2-(6-fluoro-l- DMSO-cL) 5 10.38 (s, 1H), 8.28 (dd, J= 8.9, 5.9 Hz, oxoisoquinolin-2( 177)- 1H). 7.76-7.68 (m, 3H). 7.62 (dd. J = 8.2, 2.8 Hz, 3H).10 yl)-7V-(4-( 1 -methyl- 177- 7.52 (dd, J= 9.9, 2.5 Hz, 1H), 7.35 (td, J= 8.8, 2.6 Hz, pyrazol-3- 1H). 6.69 (d, J= 7.6 Hz, 1H). 6.62 (d, J= 2.2 Hz, 1H). yl)phenyl)propanamide 5.64 (q, J= 7.3 Hz, 1H), 3.86 (s, 3H), 1.67 (d, J= 7.3Hz, 3H).LC / MS ESI (m / z): 391 (M+H)+. 'HNMR (400 MHz, 2-(6-fluoro-l- CDCh) 5 8.87 (d, J= 4.2 Hz, 1H), 8.38 (dd, J= 8.8, 5.6 oxoisoquinolin-2( 177)- Hz, 1H), 7.60-7.49 (m, 2H), 7.41 (d, J= 1.9 Hz, 1H), 11 y l )- / V-(4-( 1 -methyl-177- 7.31-7.23 (m, 3H), 7.18-7.09 (m, 2H), 6.53 (d, J= 7.6 pyrazol-5- Hz, 1H), 6.17 (d, J= 1.9 Hz, 1H), 5.78 (q, J= 7.2 Hz, yl)phenyl)propanamide1H). 3.77 (s, 3H), 1.67 (d. J= 7.2 Hz. 3H).LC / MS ESI (m / z): 392 (M+H)+. *HNMR (400 MHz, (7?)-2-(6-fluoro-l- DMSO-tZs) 5 10.28 (s. 1H), 8.48 (s. 1H), 8.35 (dd, J = oxophthal azin-2( 177) - 8.8, 5.4 Hz, 1H), 7.83 (dd, J= 8.9, 2.5 Hz, 1H), 7.78- 12 yl)-jV-(4-(l-methyl-177- 7.69 (m. 3H), 7.48-7.43 (m. 3H), 6.35 (d. J= 1.8 Hz. pyrazol-5- 1H), 5.58 (q, J= 7.1 Hz, 1H), 3.83 (s, 3H), 1.65 (d, J = yl)phenyl)propanamide7.1 Hz, 3H).

[0224] 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.26130Ex. No. Name LCMS, NMRLC / MS ESI (m / z): 422 (M+H)+. 'H NMR (400 MHz, 2-(6-chloro-l- CDCh) 3 8.86 (d, J= 3.6 Hz, 1H), 8.48 (dt. J= 4.5, 1.6 oxoisoquinolin-2( 177)- Hz, 1H), 8.35 (dd, J= 8.7, 2.1 Hz, 1H), 7.95 (dd, J = 13 yl)- / V-(4-(3- 8.7, 1.5 Hz, 2H), 7.66 (d, J= 8.7 Hz, 2H), 7.52 (d, J = fluoropyridin-2- 1.9 Hz, 1H), 7.48-7.42 (m, 2H), 7.36 (d, J= 7.6 Hz, 1H), yl)phenyl)propanamide 7.22 (ddd, J= 8.3, 4.5, 3.8 Hz, 1H), 6.56 (d, J= 7.6 Hz,1H), 5.86 (q,.7= 7.2 Hz, 1H), 1.73 (d,.7= 7.2 Hz, 3H). LC / MS ESI (m / z): 406 (M+H)+. 'H NMR (400 MHz, 2-(6-fluoro-l- DMSO-cL) 6 10.56 (s, 1H), 8.52 (dd, J= 2.9, 1.7 Hz, oxoisoquinolin-2(177)- 1H), 8.29 (dd, J= 8.9, 5.9 Hz, 1H), 7.99-7.86 (m, 2H), 14yl)-7V-(4-(3- 7.85-7.71 (m, 3H), 7.64 (d, J= 7.6 Hz, 1H), 7.57-7.47 fluoropyridin-2- (m, 1H), 7.47-7.39 (m, 1H), 7.39-7.28 (m, 1H), 6.71 (d, yl)phenyl)propanamide.7= 7.6 Hz, 1H), 5.66 (q,.7= 7.2 Hz, 1H), 1.69 (d, J =7.3 Hz, 3H).LC / MS ESI (m / z): 389 (M+H)+. 'H NMR (400 MHz, 7V-(4-(3 -fluoropyridin-2- DMSO-tfc) 6 10.57 (s, 1H), 9.12 (d, J= 0.7 Hz, 1H), yl)phenyl)-2-(l-oxo-2,6- 8.67 (d, J= 5.3 Hz, 1H), 8.59-8.44 (m, 1H), 8.04 (d, J = 15naphthyridin-2( 177)- 5.3 Hz, 1H), 7.97-7.86 (m, 2H), 7.84-7.71 (m, 4H), 7.51- yl)propanamide 7.38 (m, 1H), 6.85 (d. J = 7.5 Hz. 1H), 5.68 (q. J = 7.3Hz, 1H), 1.72 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 407 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chl oro-1 - DMSO-d>) 6 10.50 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), oxoisoquinolin-2( 177)- 7.83 (d, J = 2.1 Hz, 1H), 7.73-7.67 (m, 2H), 7.65-7.60 16 yl)-7V-(4-(l -methyl- 177- (m, 3H), 7.53 (dd, J= 8.6, 2.1 Hz, 1H), 7.21 (d, J= l.l imidazol-2- Hz, 1H), 6.94 (d, J= 1.1 Hz, 1H), 6.70 (d, J= 7.6 Hz, yl)phenyl)propanamide 1H), 5.63 (q, J= 7.3 Hz, 1H), 3.72 (s, 3H), 1.68 (d, J =7.3 Hz, 3H).LC / MS ESI (m / z): 418 (M+H)+. *HNMR (400 MHz, 2-(6-chloro-l- CDCh) 6 8.86 (d, J= 8.9 Hz. 1H), 8.52 (d, J= 4.2 Hz, oxoisoquinolin-2( 177)- 1H), 8.35 (dt, J= 8.8, 4.4 Hz, 1H), 7.66-7.57 (m, 3H), 17 yl)-7V-(4-(3- 7.53-7.42 (m, 4H), 7.37 (d, J= 7.6 Hz, 1H), 7.18 (dd, J methylpyridin-2- = 7.7, 4.8 Hz, 1H), 6.56 (d, J= 7.6 Hz, 1H), 5.86 (q, J = yl)phenyl)propanamide7.1 Hz, 1H). 2.33 (s, 3H). 1.73 (d, J= 7.2 Hz, 3H).Examples 18 and 19. Synthesis of (7?)-2-(6,7-difluoro-l-oxophthalazin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide (18) and (7?)-2-(5,6-difluoro-l-oxophthalazin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide (19)26130n-BuLi, DMF N2H4-H2O EtonMg(Ot-Bu)2, f-BuOK, THFHATU, DIEA, DMFStep 1. 4.5-Difluoro-2-formylbenzoic acid and 3.4-difluoro-2-formylbenzoic acid

[0225] At -78°C, 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°C 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 NH4CI (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 NazSCL, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, EtOAc in petroleum ether) to afford a crude mixture of 4,5-difluoro-2-formylbenzoic acid and 3, 4-difluoro-2 -formylbenzoic acid. LC / MS ESI (m / z): 185 (M-H)'.Step 2, 6.7-Difluorophthalazin-l(2H)-one and 5.6-difluorophthalazin-l(2H)-one

[0226] 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 HC1 (0.1 mL). The resulting mixture was stirred at 80°C for 2 h. After being cooled dow n to rt, the reaction mixture was quenched with water and extracted with DCM twice. The organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, 0-80% EtOAc in petroleum ether) to afford a crude mixture of 6,7-difluorophthalazin-l(2H)-one and 5,6-difluorophthalazin-l(2H)-one. LC / MS ESI (m / z): 183 (M+H)+.Step 3, (7?)-2-(6.7-Difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid and ( )-2-(5.6-difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid

[0227] At 0°C, to a suspension of Mg(Ot-Bu)2 (340 mg, 2.0 mmol) in THF (20 mL) was added (lS')-2-chloropropanoic acid (160 mg, 1.5 mmol) dropwise. The mixture was stirred at 0°C for 1026130min. 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-l(2H)-one (180 mg, 1.0 mmol) was added. The resulting mixture was stirred at rt for 2 h and then at 60°C overnight. After being cooled down to rt, the reaction was quenched with 3 M HC1 and adjusted to pH 1-3. The aqueous w as 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% EtOAc in petroleum ether) to afford a crude mixture of (7?)-2-(6,7-difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid and (7?)-2-(5,6-difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid. LC / MS ESI (m / z): 255 (M+H)+.Step 4, (7?)-2-(6.7-Difluoro-l-oxophthalazin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)propanamide and (7?)-2-(5,6-difluoro-l-oxophthalazin-2( lH)-yl)-N-(4-(l- methyl-lH-pyrazol-5-yl)phenyl)propenamide

[0228] To a mixture of (7?)-2-(6,7-difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid and (R)-2-(5,6-difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid (140 mg, 0.6 mmol) in DMF (10 mL) were added 4-(l-methyl-lH-pyrazol-5-yl)aniline (95 mg, 0.6 mmol), HATU (250 mg, 0.7 mmol), and D1EA (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 w ere w ashed with brine, dried over NazSCL, filtered, and concentrated. The residue w as purified by flash column chromatography (silica gel, 0-50% EtOAc in petroleum ether) followed by prep-HPLC to afford the following compounds.

[0229] Example 18. ( )-2-(6,7-difluoro-l-oxophthalazin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide. LC / MS ESI (m / z): 410 (M+H)+. 'H NMR (400 MHz, DMSO-<fe) 5 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).

[0230] Example 19. (7?)-2-(5,6-difluoro-l-oxophthalazin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide. LC / MS ESI (m / z): 410 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 5 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,,7= 7.1 Hz, 3H).

[0231] The following compound w as prepared by a procedure similar to that described for Example 19 using the corresponding aniline intermediate for the last step.26130Ex. No. Name LCMS, NMR(7?)-2-(5,6-di fluoro- 1 - LC / MS EST (m / z): 410 (M+H)+. 'H NMR (400 MHz, oxophthal azin-2( 177)- DMSO-rfc) 5 10.17 (s. 1H), 8.66 (s, 1H), 8.22-8.07 (m, 20 yl)-7V-(4-(l-methyl-177- 1H), 8.05-7.90 (m, 1H), 7.79-7.65 (m, 3H), 7.60 (d, J = pyrazol-3- 8.6 Hz, 2H), 6.62 (d, J= 2.1 Hz, 1H), 5.59 (q, J= 7.0yl)phenyl)propanamide Hz, 1H), 3.86 (s, 3H), 1.66 (d, J= 7.1 Hz, 3H).Example 21. Synthesis of (7?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(4-methyloxazol- 2-yl)phenyl)propanamide (21)n-BuLi, THF Pd(dppf)CI2, K2CO3-65°C~rt dioxane / H2O, 90°CStep 1. 2-Bromo-4-methyloxazole

[0232] 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-l,l,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 Na2SOr and evaporated at 0°C to afford 2-bromo-4-methyloxazole.Step 2, 4-(4-Methyloxazol-2-yl)aniline

[0233] 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-l,3,2-dioxaborolan-2-yl)aniline (270 mg, 1.2 mmol), Pd(dppf)Ch (80 mg, 0.1 mmol) and K2CO3 (460 mg, 3.3 mmol). The mixture was sealed and stirred at 90°C under N2 overnight. 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. LC / MS ESI (m / z): 175 (M+H)+. NMR (400 MHz, CDCh) 5 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).26130Step 3, (7?)-2-(6-Chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(4-methyloxazol-2- yl)phenyl)propenamide

[0234] At 0°C, to a solution of (?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-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 POCh (100 mg, 0.68 mmol) dropwise. After being stirred at 0°C for 1 h, the reaction was quenched with ice water and extracted with DCM twice. The combined organic layers were dried overNa2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50% EtOAc in petroleum ether) to give the crude product, which was further purified by prep-HPLC to afford (?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(4-methyloxazol-2-yl)phenyl)propanamide. LC / MS ESI m / z: 408 (M+H)+.JH NMR (400 MHz, DMSO-O 5 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 (?)-2-(3-chloro-8-oxo-l,7-naphthyridin-7(8H)-yl)-N-(4-(3-fluoropyridin-2-yl)phenyl)propanamide (22)26130Step 1. tert-Butyl (A)-(l-((4-(3-fluoropyridin-2-yl)phenyl)amino)-l-oxopropan-2- vDcarbamate

[0235] 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%, EtOAc in petroleum ether) to afford tert-buty l (A)-(l-((4-(3-fluoropyridin-2-yl)phenyl)amino)-l-oxopropan-2-yl)carbamate. LC / MS ESI (m / z): 360 (M+H)+.Step 2, (A)-2-Amino-N-(4-(3-fluoropyridin-2-yl)phenyl)propenamide

[0236] To a solution of tert-butyl (R)-(l-((4-(3-fluoropyridin-2-yl)phenyl)amino)-l-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 h, the mixture was concentrated by rotary evaporation to give 3.6 g of the crude product, which was used directly in the next step. LC / MS ESI (m / z): 260 (M+H)+.Step 3, tert-Butyl 3-bromo-5-chloropicolinate

[0237] 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% EtOAc in petroleum ether) to afford tert-butyl 3-bromo-5-chloropicolinate. LC / MS ESI (m / z): 292, 294 (M+H)+.Step 4, tert-Butyl ( / / )-5-chloro-3-(2-ethoxyvinyl (picolinate

[0238] 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-L3.2-dioxaborolane (190 mg, 0.94 mmol) in dioxane (10 mL) and H2O (1 mL) were added Pd(dppf)C12 (57 mg, 0.08 mmol) and K2CO3 (325 mg, 2.35 mmol). The resulting mixture was stirred at 90°C under N2 overnight. The solvents were removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-25% EtOAc in petroleum ether) to afford tert-butyl ( / / )-5-chloro-3-(2-ethoxyvinyl)picolinate. LC / MS ESI (m / z): 284 (M+H)+.Step 5. 3-Chloro-8H-pyrano[3.4-b]pyridin-8-one

[0239] 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%26130EtOAc in petroleum ether) to afford 3-chloro-8H-pyrano[3,4-b]pyridin-8-one. LC / MS ESI (m / z): 182 (M+H)+.Step 6, (7?)-2-(3-Chloro-8-oxo-L7-naphthyridin-7(8H)-yl)-N-(4-(3-fluoropyridin-2- yl)phenyl)propenamide

[0240] A mixture of 3-chloro-8H-pyrano[3,4-b]pyridin-8-one (120 mg, 0.66 mmol), (7?)-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, 0-1 % MeOH in DCM) and prep-HPLC to afford (?)-2-(3-chloro-8-oxo-l,7-naphthyridin-7(8H)-yl)-N-(4-(3-fluoropyridin-2-yl)phenyl)propanamide. LC / MS ESI (m / z): 423 (M+H)+. 'H NMR (400 MHz, CDCh) 59.56 (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 (7?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fhioro-l-methyl-lH-pyrazol-5-yl)phenyl)propanamide (23)Step 1. (7?)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid

[0241] At 0°C, 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°C 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°C overnight. After being cooled down to rt, the reaction was quenched with 3M HC1 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. LC / MS ESI (m / z): 253 (M+H)+.26130Step 2, (7?)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-l -methyl-lH-pyrazol- 5-yl)phenyl)propenamide

[0242] At 0°C, to a solution of 4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)aniline (98 mg, 0.5 mmol) in ACN (15 mL) were added (7?)-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°C 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% EtOAc in petroleum ether) to give the crude product, which was further purified by prep-HPLC and separated by chiral SFC to afford (?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)propanamide. LC / MS ESI (m / z): 426 (M+H)+. 'H NMR (400 MHz, DMSO-Je) 5 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). Optical purity -100%. Preparative separation method: Instrument: Shimadzu prep solution SFC; Column: ChiralPak AS, 250x20 mm I. D., 5 pm; Mobile phase: A for CO2 and B for MeOH; Gradient: B 30%; Flow rate: 40mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm; Cycle-time: 7 min; Elution time: 2 h.

[0243] 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-l(2H)-one / isoquinolin-l(2H)-one / 5.6.7.8-tetrahydroquinazolin-4(3H)-one / 5,6,7,8-tetrahydroisoquinolin-l(2H)-one derivative as the starting material and analogous aniline intermediates for the second step.

[0244] 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 and halide and aryl-Bpin.Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 380 (M+H)+. 'H NMR (400 MHz, (7?)- / V-(4-(l-methyl-177- DMSO-cfc) 8 10.57 (s, 1H), 8.53 (s, 1H), 7.71 (d, J= 8.7 pyrazol-5-yl)phenyl)-2- Hz, 2H), 7.64 (d, J= 5.8 Hz, 1H), 7.52-7.47 (m, 2H), 24 (4-oxothieno[2,3- 7.45 (d, J= 1.9 Hz, 1H), 7.42 (d, J= 5.8 Hz, 1H), 6.37 <7]pyrimidin-3(477)- (d. J = 1.9 Hz. 1H), 5.62 (q. J = 7.4 Hz. 1H), 3.84 (s, yl)propanamide3H), 1.79 (d, J= 7.4 Hz, 3H).26130Ex. No. Name LCMS, NMRLC / MS ESI (m / z): 380 (M+H)+. 'H NMR (400 MHz, (A)-N-(4-(l -methyl- 17 / - DMSO-rfc) 5 10.58 (s. 1H), 8.55 (s, 1H), 8.24 (d, J= 5.3 pyrazol-5-yl)phenyl)-2- Hz, 1H), 7.72 (d, J= 8.7 Hz, 2H), 7.50 (d, J= 8.7 Hz, 25 (4-oxothieno[3,2- 2H), 7.47-7.42 (m, 2H), 6.37 (d, J= 1.8 Hz, 1H), 5.64 < / ]pyrimidin-3(4 / 7)- (q, J= 7.3 Hz, 1H), 3.84 (s, 3H), 1.80 (d, J= 7.4 Hz, yl)propanamide3H).LC / MS ESI (m / z): 408 (M+H)+. 'H NMR (400 MHz, ( / ?)-2-(7 -chloro-4- DMSO-rfe) 6 10.55 (s, 1H), 8.54 (s, 1H), 8.16 (d, J= 8.6 oxoquinazolin-3(4 / / )- Hz, 1H), 7.81 (d, J= 2.0 Hz, 1H), 7.71 (d, J= 8.7 Hz, 26 y l)- / V-(4-( 1 -methyl- 1 / / - 2H), 7.61 (dd, J= 8.6, 2.1 Hz, 1H), 7.49 (d, J= 8.7 Hz, pyrazol-5- 2H), 7.44 (d, J= 1.9 Hz, 1H), 6.36 (d, J= 1.9 Hz, 1H), yl)phenyl)propanamide 5.56 (q, J= 7.3 Hz, 1H), 3.83 (s, 3H), 1.78 (d, J= 7.4 Hz, 3H).LC / MS ESI (m / z): 408 (M+H)+. 'l l NMR (400 MHz, (S)-2-(7-chloro-4- DMSO-rfe) 5 10.55 (s, 1H), 8.54 (s, 1H), 8.16 (d, J= 8.6 oxoquinazolin-3(47 / )- Hz, 1H), 7.81 (d, J= 2.0 Hz, 1H), 7.71 (d, J= 8.7 Hz, 27 yl)- / V-(4-(l-methyl-l / / - 2H), 7.61 (dd, J= 8.6, 2.1 Hz, 1H), 7.49 (d, J= 8.7 Hz, pyrazol-5- 2H), 7.44 (d, J= 1.9 Hz, 1H), 6.36 (d, J= 1.9 Hz, 1H), yl)phenyl)propanamide 5.56 (q, J = 7.4 Hz, 1H), 3.83 (s, 3H), 1.79 (d, J = 7.4Hz, 3H). Separated by chiral SFC, optical purity7-100%.

[0245] 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 and aminophenyl-Bpin.Ex. No. Name LCMS, 'H NMRLC / MS ESI (m / z): 441 (M+H)+. *HNMR (400 MHz, (7?)-2-(7-chloro-4- CDCh) 5 8.74 (s, 1H), 8.58-8.48 (m, 2H), 8.24 (s, 1H), oxoquinazolin-3(4 / / )- 8.15 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.62- 28 y l)- / V-(3 -fluoro-4-(4- 7.55 (m, 1H), 7.43 (dd, J = 8.6. 2.0 Hz. 1H), 7.27-7.21 fluoropyridin-3- (m, 2H), 7.09 (dd, J= 9.3, 5.7 Hz, 1H), 5.61 (q,.7= 7.2 yl)phenyl)propanamideHz, 1H). 1.78 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 421 (M+H)+ 1HNMR (400 MHz, (7?)-jV-(3-fluoro-4-(3- DMSO-t / e) 6 10.70 (s. 1H). 8.54 (s. 1H), 8.50 (d. J = 3.8 methylpyridin-2- Hz, 1H), 8.23 (dd, J= 8.9, 6.3 Hz, 1H), 7.77 (d, J= 7.5 29 yl)phenyl)-2-(7-fluoro- Hz, 1H), 7.68 (dd. J= 12.5. 1.6 Hz. 1H), 7.54 (dd, J = 4-oxoquinazolin-3(47 / )- 10.0, 2.5 Hz, 1H), 7.47-7.35 (m, 4H), 5.55 (q, J= 7.4 yl)propanamideHz, 1H), 2.17 (s, 3H). 1.80 (d, J = 7.4 Hz, 3H).LC / MS ESI (m / z): 403 (M+H)+. *HNMR (400 MHz, (7?)-2-(7-fluoro-4- DMSO-c / ,) 5 10.52 (s. 1H), 8.54 (s. 1H), 8.47 (dd, J = oxoquinazolin-3(4 / / )- 4.6, 1.1 Hz, 1H), 8.23 (dd, J= 8.9, 6.3 Hz, 1H), 7.73 (d, 30 yl)-N-(4-(3- J= 7.4 Hz, 1H). 7.69 (d, J= 8.6 Hz, 2H). 7.54 (dd. J = methylpyridin-2- 9.3, 2.1 Hz, 3H), 7.44 (td, J= 8.7, 2.5 Hz, 1H), 7.29 (dd, yl)phenyl)propanamide J= 7.6, 4.8 Hz, 1H), 5.59 (q, J= 7.4 Hz, 1H), 2.34 (s,3H), 1.80 (d, J = 7.4 Hz, 3H).26130Ex. No. Name LCMS, ’H NMR(7?)-N-(3-fluoro-4-(3 - LC / MS EST (m / z): 425 (M+H)+. 'H NMR (400 MHz, fluoropyridin-2- DMSO-tfc) 5 10.74 (s, 1H), 8.58-8.51 (m. 2H), 8.23 (dd, 31 yl)phenyl)-2-(7-fluoro- J= 8.9, 6.2 Hz, 1H), 7.89-7.80 (m, 1H), 7.70 (dd, J =4-oxoquinazolin-3(477)- 12.7, 1.8 Hz, 1H), 7.62-7.51 (m, 3H), 7.50-7.42 (m, 2H), yl)propanamide 5.55 (q, J= 7.3 Hz, 1H), 1.79 (d, J= 7.4 Hz, 3H).LC / MS ESI (m / z): 423 (M+H)+. 'HNMR (400 MHz, (2?)-JV-(4-(3- CDCls) 5 8.51 (dd, J= 4.6, 1.3 Hz, 1H), 8.46 (s, 1H), chloropyridin-2- 8.25 (dd, J= 9.7, 5.2 Hz, 2H), 7.73 (dd, J= 8.0, 1.2 Hz, 32 y l)pheny l)-2-(7-fluoro- 1H), 7.65 (d, J= 8.7 Hz, 2H), 7.57 (d, J= 8.7 Hz, 2H),4-oxoquinazolin-3(4 / / )- 7.33 (dd, J= 9.4, 2.4 Hz, 1H), 7.20 (d, J= 2.5 Hz, yl)propanamide 0.2H), 7.19-7.13 (m, 1.8H), 5.63 (q, J= 7.3 Hz, 1H),1.77 (d,.7= 7.3 Hz, 3H).LC / MS ESI m / z: 392 (M+H)+. H NMR (400 MHz, JV-(4-(3 -fluoropyridin-2- CDCh) 59.45 (s, 1H), 8.41 (dt, J=4.5, 1.5 Hz, 1H), yl)phenyl)-2-(l -oxo- 7.87 (dd, J= 8.7, 1.4 Hz, 2H), 7.63-7.55 (m, 2H), 7.42- 33 5, 6,7,8- 7.33 (m, 1H), 7.22-7.19 (m, 1H), 7.18-7.12 (m, 1H), tetrahydroisoquinolin- 6.03 (d, J = 7.2 Hz, 1H), 5.72 (q, J = 7.2 Hz, 1H), 2.56- 2(lE / )-yl)propanamide2.42 (m, 4H), 1.75-1.64 (m, 4H), 1.59 (d, 3H).LC / MS ESI (m / z): 439 (M+H)+. 'H NMR (400 MHz, (7?)-2-(7 -chloro-4- CDCh) 5 8.54 (s, 1H), 8.50 (dd, J= 4.6, 1.4 Hz, 1H), oxoquinazolin-3(4 / / )- 8.26 (s, 1H), 8.13 (d, J= 8.6 Hz, 1H), 7.72 (dd, J= 8.1, 34 yl)- / V-(4-(3- 1.3 Hz, 1H), 7.67 (d..7- 2,0 Hz. 1H), 7.65 (d, J = 8.7 chloropyridin-2- Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.40 (dd. J = 8.6, 2.0 yl)phenyl)propanamide Hz, 1H), 7.14 (dd, J = 8.1, 4.7 Hz, 1H), 5.64 (q, J= 7.3Hz, 1H). 1.76 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 437 (M+H)+. ’HNMR (400 MHz, (7?)-2-(7-chloro-4- DMSO-<7e) 6 10.70 (s. 1H), 8.55 (s. 1H), 8.46 (d. J = 5.0 oxoquinazolin-3(4L / )- Hz, 1H), 8.35 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.83 (d, 35 y l)-N-(3 -fluoro-4-(4- J= 2.0 Hz, 1H). 7.70 (dd. J= 12.4. 1.9 Hz. TH), 7.62 methylpyridin-3- (dd, J = 8.6, 2.1 Hz, 1H), 7.45 (dd, J = 8.4, 1.9 Hz, 1H), yl)phenyl)propanamide 7.36 (dd, J= 10.8, 6.1 Hz, 2H). 5.55 (q, J= 7.3 Hz, 1H).2.17 (s, 3H), 1.80 (d, J= 7.4 Hz, 3H).LC / MS ESI (m / z): 441 (M+H)+. 'H NMR (400 MHz, (A)-2-(7 -chloro-4- CD3OD) 5 8.53 (d, J= 2.2 Hz, 1H), 8.49 (s, 1H), 8.45 oxoquinazolin-3(4 / 7)- (d. J= 5.0 Hz. 1H), 8.22 (d. J= 8.6 Hz. 1H), 7.77-7.70 36 yl)-7V-(3-fluoro-4-(3- (m, 2H), 7.56 (dd, J= 8.6, 2.0 Hz, 1H), 7.54-7.50 (m, fluoropyridin-4- 1H). 7.47 (dd. J = 4.0, 1.0 Hz, 2H). 5.63 (q, J= 7.4 Hz, yl)phenyl)propanamide1H), 1.86 (d, J = 7.4 Hz, 3H).LC / MS ESI (m / z): 437 (M+H) '. 'H NMR (400 MHz, (7?)-2-(7 -chloro-4- CDsOD) 5 8.50 (s, 1H), 8.46 (s, 1H), 8.40 (d, J = 5.1 Hz, oxoquinazolin-3(477)- 1H). 8.22 (d, J= 8.6 Hz, 1H). 7.74 (d, J= 1.9 Hz, 1H).37 yl)-JV-(3-fluoro-4-(3- 7.70 (dd, J= 12.2, 1.9 Hz, 1H), 7.56 (dd, J= 8.6, 2.0 methylpyridin-4- Hz, 1H), 7.44 (dd. J= 8.4, 1.9 Hz, 1H). 7.27 (dd. J = yl)phenyl)propanamide 10.6, 6.0 Hz, 2H), 5.63 (q, J = 7.3 Hz, 1 H), 2.22 (s, 3H),1.86 (d, J = 7.4 Hz, 3H).26130Ex. No. Name LCMS, NMRLC / MS EST (m / z): 420 (M+H)+. 'H NMR (400 MHz, (A)-2-(7-chloro-4- CDCh) 5 8.84 (s, 1H), 8.76 (d, J= 2.2 Hz, 1H), 8.55 (d, oxopyrido[3,2- J= 3.8 Hz, 1H), 8.42 (s, 1H), 8.09 (d, J= 2.2 Hz, 1H), d]pyrimidin-3(4 / 7)-yl)- 38 7.76 (d, J= 7.2 Hz, TH), 7.63 (d, J= 8.7 Hz, 2H), 7.487V-(4-(3-methylpyridin- (d, J= 8.6 Hz, 2H), 7.33 (dd, J= 7.7, 5.1 Hz, 1H), 5.81 2- (q, J= 7.2 Hz, TH), 2.37 (s, 3H), 1.86 (d, J = 7.2 Hz, yl)phenyl)propanamide3H).(R)-2-(7-chloro-4- LC / MS ESI (m / z): 440 (M+H)+. 1H NMR (400 MHz, oxopyrido[3,2- DMSO-d6) 5 10.59 (s, 1H), 8.86 (d, J = 2.2 Hz, 1H), d]pyrimidin-3(4H)-yl)- 8.65-8.55 (m, 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.03 (d, J = 232N-(4-(3-chloropyridin- 8.1 Hz, 1H), 7.75-7.65 (m, 4H), 7.42 (dd, J = 8.1, 4.6 2- Hz, 1H), 5.62 (q, J = 7.1 Hz, 1H), 1.81 (d, J = 7.4 Hz,yl)phenyl)propanamide 3H).

[0246] In the following examples, the aniline intermediate used in step 2 was prepared by a procedure similar to that described for intermediate C.Ex. No. Name LCMS, ’H NMR(7?)-2-(7-chloro-4- LC / MS ESI (m / z): 444 (M+H)+. 'l l NMR (400 MHz, oxoquinazolin-3(477)- DMSO-tfe) 5 10.78 (s, 1H), 8.55 (s, 1H), 8.16 (d, J= 8.6 yl)-JV-(3-fluoro-4-(4- 39 Hz, 1H), 7.83 (d, J= 2.0 Hz, 1H), 7.79-7.74 (m, 1H), fluoro- 1 -methy 1- 177- 7.65-7.57 (m, 2H), 7.54-7.48 (m, 2H), 5.53 (q, J= 7.3 pyrazol-5- Hz, 1H), 3.69 (s, 3H), 1.79 (d, J= 7.4 Hz, 3H). yl)phenyl)propanamide( / ?)-#- / 4-(4-ll uoro- 1 - LC / MS ESI (m / z): 396 (M+H)+. 'H NMR (400 MHz, methyl- 177-pyrazol-5- DMSO-ch) 5 10.60 (s, 1H), 8.34 (s, 1H), 7.78-7.74 (m, vl)phenyl)-2-(4-oxo- 2H). 7.57 (d, J= 4.6 Hz, 1H). 7.49 (d, J= 8.5 Hz, 2H).405, 6,7,8-' 5.47 (q, J= 7.4 Hz, 1H), 3.78 (s, 3H), 2.60-2.53 (m, tetrahydroquinazolin- 2H). 2.36 (t, J = 5.7 Hz, 2H), 1.76-1.70 (m. 5H), 1.69- 3(47 / )-yl)propanamide 1.61 (m, 2H).(7?)- / V-(4-(4-fluoro-l- LC / MS ESI (m / z): 406 (M+H)+. 'H NMR (400 MHz, methyl- 177-py razol-5- CD3OD) 3 8.45 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.79- 41 y l)pheny l)-2 -( 7 -methyl- 7.74 (m, 2H), 7.54 (s, 1H), 7.47-7.39 (m, 4H), 5.66 (q, J 4-oxoquinazolin-3(477)- = 7.4 Hz, 1H), 3.79 (s, 3H), 2.52 (s, 3H), 1.85 (d, J= 7.4 yl)propanamide Hz, 3H). Separated by chiral SFC, optical purity -100%.LC / MS ESI (m / z): 410 (M+H)+. 'H NMR (400 MHz, (7?)-N-(4-(4-fluoro-l- CDCh) 8 8.69 (s, 1H), 8.27 (s, 1H). 8.24 (dd. J= 8.9, methyl- 17f-pyrazol-5- 6.0 Hz, 1H), 7.59-7.54 (m, 2H), 7.34 (dd, J= 9.4, 2.5 42 yl)phenyl)-2-(7-fluoro- Hz, 1H), 7.30 (d, 4.5 Hz, 1H), 7.27 (d, J = 8.5 Hz,4-oxoquinazolin-3(477)- 2H), 7.21-7.15 (m, 1H), 5.66 (q, J= 7.3 Hz, 1H), 3.70 yl)propanamide (s, 3H), 1.79 (d, J= 7.3 Hz, 3H). Separated by chiral SFC, optical puritv -100%.LC / MS ESI (m / z): 426 (M+H)+. *HNMR (400 MHz, (7?)-2-(6-chl oro-1 - CD3OD) 3 8.40 (s, 1H), 8.33 (d, J= 8.6 Hz, 1H), 7.99 oxophthalazin-2( 177)- (d, J= 2.0 Hz. 1H), 7.85 (dd, J= 8.6, 2.0 Hz, 1H), 7.75 43 y 1 )-N-(4-(4- fl uoro- 1 - (d, J= 8.7 Hz, 2H), 7.43 (dd, J= 6.4, 2.0 Hz, 3H), 5.66 methyl- 177-py razol-5- (q, J= 7.1 Hz. 1H), 3.80 (s, 3H), 1.79 (d, J= 7.1 Hz, yl)phenyl)propanamide3H). Separated by chiral SFC, optical puritv -100%.26130Ex. No. Name LCMS, NMRLC / MS ESI (m / z): 392 (M+H)+. 'H NMR (400 MHz, DMSO-tfc) 5 10.59 (s, 1H), 8.49 (s, 1H), 8.17 (dd, J = ( / ?)- / V-(4-(4- fluoro- 1 - 8.0, 1.2 Hz, 1H), 7.88 (ddd, J= 8.4, 7.2, 1.5 Hz, 1H), methyl- 177-pv razol-5- 7.79-7.75 (m, 2H), 7.74 (d, J= 7.7 Hz, 1H), 7.59 (dd, J 44 yl)phenyl)-2-(4- = 8.0, 1.0 Hz, 1H), 7.57 (d,.7= 4.6 Hz, 1H), 7.49 (d, J = oxoquinazolin-3(477)- 8.5 Hz, 2H), 5.59 (q, J= 7.4 Hz, 1H), 3.78 (s, 3H), 1.79 yl)propanamide(d, J= 7.4 Hz, 3H). Separated by chiral SFC, optical purity -100%.LC / MS ESI (m / z): 405 (M+H)+. 'H NMR (400 MHz, (A)-jV-(4-(4-fluoro- 1 - DMSO-tfe) 6 10.56 (s, 1H), 8.12 (d, J= 8.2 Hz, 1H), methyl- 177- py razol-5- 7.80-7.76 (m, 2H), 7.57-7.46 (m, 5H), 7.34 (dd, J= 8.3, 45 yl)phenyl)-2-(6-methyl- 0.9 Hz, 1H), 6.63 (d, J= 7.6 Hz, 1H), 5.66 (q, J= 7.3 1 -oxoisoquinolin-2(177)- Hz, 1H), 3.78 (s, 3H), 2.45 (s, 3H), 1.68 (d, J= 7.3 Hz, yl)propanamide3H). Separated by chiral SFC, optical purity -100%.223 (R)-2-(7-chloro-4- LC / MS ESI (m / z): 427 (M+H)+. 1H NMR (400 MHz, oxopyrido[3,2- DMSO-d6) 5 10.61 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), d]pyrimidin-3(4H)-yl)- 8.62 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 8.7 N-(4-(4-fluoro-l- Hz, 2H), 7.56 (d, J = 4.6 Hz, 1H), 7.49 (d, J = 8.5 Hz, methyl-lH-pyrazol-5- 2H). 5.60 (q, J = 7.4 Hz, 1H). 3.78 (s. 3H). 1.80 (d. J =yl)phenyl)propanamide 7.4 Hz, 3H).

[0247] In the following examples, the aniline intermediate used in step 2 was prepared by the procedure described for Intermediate D.Ex. No. Name LCMS, ' H NMRLC / MS ESI (m / z): 426 (M+H)+. 'H NMR (400 MHz, (7?)-2-(7-chloro-4- DMSO-rie) 5 10.49 (s. 1H), 8.54 (s, 1H), 8.16 (d, J= 8.6 oxoquinazolin-3(477)- Hz, 1H), 7.93 (d, J= 4.6 Hz, 1H), 7.81 (d, J= 2.0 Hz, 46 y l)- / V-(4-(4-fluoro- 1 - 1H). 7.71-7.65 (m, 4H). 7.61 (dd, J= 8.6, 2.1 Hz, 1H), methyl- 177-py razol-3- 5.57 (q, J= 7.3 Hz, 1H), 3.81 (s, 3H), 1.78 (d, J= 7.4 yl)phenyl)propanamideHz, 3H).(7?)-2-(6-chloro-l- LC / MS ESI (m / z): 426 (M+H)+. 'H NMR (400 MHz, oxophthal azin-2( 177) - CD3OD) 5 8.39 (s, 1H), 8.33 (d, J= 8.6 Hz, 1H), 7.98 47 y l)-JV-(4-(4-fluoro- 1 - (d, J= 1.8 Hz, 1H), 7.84 (dd, J= 8.6, 1.9 Hz, 1H), 7.71 methyl- 177-py razol-3- (d. J= 8.6 Hz. 2H), 7.64-7.59 (m. 3H), 5.64 (q. J= 7.1yl)phenyl)propanamide Hz, 1H), 3.84 (s, 3H), 1.78 (d, J= 7.1 Hz, 3H).26130Example 48. Synthesis of (?)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)-2-(l-oxo-6- (pyrrolidin-l-yl)isoquinolin-2(lH)-yl)propanamide (48)Step 1. 6-(Pyrrolidin-l-yl)isoquinolin-l(2H)-one

[0248] A solution of 6-fluoroisoquinolin-l(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-l-yl)isoquinolin-l(2H)-one, which was used directly. LC / MS ESI (m / z): 215 (M+H)+.Step 2, (7?)-2-(l-Oxo-6-(pyrrolidin-l-yl)isoquinolin-2(lH)-yl)propanoic acid

[0249] To a suspension of Mg(Ot-Bu)2 (110 mg, 0.6 mmol) in THF (5 mL) under N2 was 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-l-yl)isoquinolin-l(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 with HC1 (6 M) and was extracted with DCM twice. The combined organic layers were chromatographed on silica gel (0-10% MeOH in DCM) to afford (7?)-2-(l-oxo-6-(pyrrolidin-l-yl)isoquinolin-2(lH)-yl)propanoic acid. LC / MS ESI (m / z): 287 (M+H).Step 3, (7?)-N-(4-(l-Methyl-lH-pyrazol-5-yl)phenyl)-2-(l-oxo-6-(pyrrolidin-l-yl)isoquinolin-2(lH)-yl)propenamide

[0250] To a solution of ( )-2-(l-oxo-6-(pyrrolidin-l-yl)isoquinolin-2(lH)-yl)propanoic acid (50 mg, 0.2 mmol) in pyridine (5 mL) were added 4-( 1 -methyl- lH-pyrazol-5-yl)aniline (36 mg, 0.2 mmol) and POCI3 (27 mg, 0.2 mmol) at 0°C. The mixture was stirred at 0°C for 40 min under N2 and 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 (7?)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)-2-(l-oxo-6-(pyrrolidin-l-yl)isoquinolin-2(lH)-yl)propanamide. LC / MS ESI (m / z): 442 (M+H)+.26130JHNMR(400 MHz, CD3OD) 5 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-l-oxoisoquinolin-2(lH)-yl)-N-(4-(3-fhioropyridin-2-yl)phenyl)acetamide (49)Step 1. Ethyl 2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)acetate

[0251] To a solution of 6-chloroisoquinolin-l(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 N2 for 3 h. Then it was diluted with EtOAc and washed with water and brine. The organic layer was concentrated and purified by flash column chromatography (silica gel, 0-50% EtOAc in petroleum ether) to give 300 mg of ethyl 2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)acetate. LC / MS ESI (m / z): 266 (M+H)+.Step 2, 2-(6-Chloro-l-oxoisoquinolin-2(lH)-yl)acetic acid

[0252] To a suspension of ethyl 2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)acetate (100 mg. 0.38 mmol) in ethanol (3 mL) was added Li OH (aq) (0.8 mL, 1 M). The mixture was stirred at rt for 3 h and concentrated. 6N HC1 was added to adjust the pH to -2. Then the mixture was extracted with EtOAc and concentrated to dryness to give 2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)acetic acid (90 mg, 0.38 mmol). LC / MS ESI (m / z): 238 (M+H)+.Step 3, 2-(6-Chloro-l-oxoisoquinolin-2( lH)-yl)-N-(4-(3-fluoropyridin-2- yl)phenyl)acetamide

[0253] To a solution of 2-(6-chloro-l-oxoisoquinolin-2(lH)-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 N2 overnight. The mixture was partitioned between EtOAc and water. The organic layer was26130separated. 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-l-oxoisoquinolin-2(lH)-yl)-N-(4-(3-fluoropyridin-2-yl)phenyl)acetamide. LC / MS ESI (m / z): 408 (M+H)+.NMR (400 MHz, DMSO-d6) 5 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 (!?)-2-(6,7-difluoro-l-oxophthaIazin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)propanamide (51)F K2OSO4, NalO4Pd(PPh3)2CI2, Cs2CO3THF / H2ON2H4-H2O EtOH Mg(Ot-Bu)2, f-BuOK,THF, O to 55°CTCFH NMI. ACNStep 1. Methyl 4.5-difluoro-2-vinylbenzoate

[0254] 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)2Ch (280 mg, 0.40 mmol). The mixture was stirred at 80°C under N2 for 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-vmylbenzoate.JH NMR (400 MHz, CDCh) 57.75 (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

[0255] 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).26130The 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.Step 3, 6.7-Difluorophthalazin-l(2H)-one

[0256] 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-l(2H)-one. LC / MS ESI (m / z): 183 (M+H)+.rH NMR (400 MHz, DMSO-iL) 6 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, (7?)-2-(6.7-Difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid

[0257] 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-l(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 HC1 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 (7?)-2-(6,7-difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid. LC / MS ESI (m / z): 255 (M+H).Step 5, (7?)-2-(6.7-Difluoro-l-oxophthalazin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-3- yl)phenyl)propenamide

[0258] To a solution of (J?)-2-(6,7-difluoro-l-oxophthalazin-2(lH)-yl)propanoic acid (50 mg, 0.20 mmol) in MeCN (2 mL) were added 4-(l-methyl-lH-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 (7?)-2-(6,7-difluoro-l-oxophthalazin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)propanamide. LC / MS ESI (m / z): 409 (M+H)+.1H NMR (400 MHz, CDCh) 58.38 (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).26130Example 51. Synthesis of (7?)-N-(4-(4-cyano-l-methyl-lH-pyrazol-5-yl)phenyl)-2-(6-fhioro-l-oxoisoquinolin-2( lH)-yl)propanamide (51)

[0259] The aniline intermediate used in step 2 was prepared by a procedure similar to that described for Intermediate B.Step 1. (7?)-2-(6-Fluoro-l-oxoisoquinolin-2(lH)-yl)propanoic acid

[0260] At 0°C, to a suspension of Mg(Ot-Bu)2 (1.5 g, 8.6 mmol) in THF (20 mL) under N2 was added (S)-2-chloropropanoic acid (610 mg, 5.6 mmol) dropwise. The resulting mixture was stirred at 0°C 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-l(2H)-one (700 mg, 4.3 mmol) was added. And the resulting mixture was stirred at 60°C overnight. After being cooled down to rt, the reaction was quenched with 3 M HC1 and adjusted to pH 1-3. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4 and concentrated. The residue was triturated with petroleum ether to afford (?)-2-(6-fluoro-l-oxoisoquinolin-2(lH)-yl)propanoic acid. LC / MS ESI (m / z): 236 (M+H)+.Step 2, CR)-N-(4-(4-Cyano-l-methyl-lH-pyrazol-5-yl)phenyl)-2-(6-fluoro-l- oxoisoquinolin-2(lH)-yl)propan amide

[0261] At -20°C, to a solution of (7?)-2-(6-fluoro-l-oxoisoquinolin-2(lH)-yl)propanoic acid (150 mg, 0.6 mmol) in DCM (5 mL) were added 5-(4-aminophenyl)-l-methyl-lH-pyrazole-4-carbonitrile (110 mg, 0.6 mmol), pyridine (0.3 mL). Then POCh (110 mg, 0.7 mmol) was added dropwise. After being stirred at -20°C 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 w as purified by flash column chromatography (silica gel, 0-50% EtOAc in petroleum ether) to give the crude product, which was further purified by prep-HPLC to afford (R)-N-(4-(4-cyano-l-methyl-lH-pyrazol-5-yl)phenyl)-2-(6-fluoro-l-oxoisoquinolin-2(lH)-yl)propanamide. LC / MS ESI m / z: 416 (M+H)+. 'H NMR (400 MHz, DMSO-tL) 5 10.65 (s, 1H), 8.35 - 8.22 (m, 1H), 8.12 (s, 1H), 7.83 (d, J= 8.6 Hz, 2H), 7.63- Ill -26130(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..7= 7.6 Hz. 1H), 5.64 (q. J= 7.3 Hz. 1H), 3.84 (s, 3H), 1.69 (d, J= 7.3 Hz, 3H).

[0262] The following compounds were prepared by a procedure similar to that described for Example 51 with the corresponding isoquinolin- l(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.Ex. No. Name LCMS, 'H NMRLC / MS ESI (m / z): 407 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chl oro-1 - CDCh) 58.85 (d, J= 23.9 Hz, 1H), 8.38 (d, J= 8.6 Hz, oxoisoquinolin-2( 177)- 1H), 7.74 (s, 1H), 7.57-7.46 (m, 4H), 7.38 (dd,.7 = 16.5.52 y 1 )- / V-(3 -( 1 -methy 1- 177- 7.7 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 7.5 pyrazol-5- Hz, 1H), 6.32 (s, 1H), 5.85 (q, J= 7.0 Hz, 1H), 3.91 (s, yl)phenyl)propanamide3H), 1.75 (d, J= 7.1 Hz, 3H).LC / MS ESI (m / z): 407 (M+H)+. 'H NMR (400 MHz, DMSO-O 5 10.37 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), (7?)-2-(6-chloro- 1 - 8.07 (d,.7= 1.6 Hz, 1H), 7.83 (d,.7= 2.1 Hz, 1H), 7.71 oxoisoquinolin-2(177)- (d,.7= 2.2 Hz, 1H), 7.63 (d,.7= 7.6 Hz, 1H), 7.52 (dd,.7 53 y l)-7V-(3 -( 1 -methyl- 177- = 8.7, 2.1 Hz, 2H), 7.45 (d,.7= 7.8 Hz, 1H), 7.31 (t, J= pyrazol-3- 7.9 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.60 (d, J= 2.2 yl)phenyl)propanamideHz, 1H), 5.63 (q, J= 7.3 Hz, 1H), 3.86 (s, 3H), 1.67 (d,.7= 7.3 Hz, 3H).LC / MS ESI (m / z): 425 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chloro-l- DMSO-O 5 10.72 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), oxoisoquinolin-2(177)- 7.84 (d..7= 2.1 Hz, 1H), 7.76-7.70 (m, 1H), 7.63 (d, J = 54 y 1)-7V- (3 -fluoro-4-( 1 - 7.6 Hz, 1H), 7.53 (dd, J= 8.6, 2.1 Hz, 1H), 7.49 (d, J = methyl- 177-pyrazol-5- 1.9 Hz, 1H), 7.47-7.41 (m, 2H), 6.71 (d, J = 7.6 Hz, yl)phenyl)propanamide 1H), 6.35 (d, J = 1.7 Hz, 1H), 5.60 (q, J= 7.3 Hz, 1H),3.71 (d,.7= 0.8 Hz, 3H), 1.68 (d,.7= 7.3 Hz, 3H).LC / MS ESI (m / z): 409 (M+H)+. 'H NMR (400 MHz, DMSO-cL) 5 10.73 (s, 1H), 8.28 (dd. J= 8.9, 5.9 Hz, (7?)-2-(6-fluoro-l- 1H), 7.77-7.72 (m, 1H), 7.63 (d, J= 7.6 Hz, 1H), 7.54 oxoisoquinolin-2( 177)- (dd,.7= 9.9, 2.5 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 55 y l)- / V-(3 -fluoro-4-( 1 - 7.48-7.42 (m, 2H), 7.36 (td, J= 8.8, 2.6 Hz, 1H), 6.72 methyl- 177-py razol-5- (d,.7= 7.6 Hz, 1H), 6.36 (d, J= 1.7 Hz, 1H), 5.61 (q, J yl)phenyl)propanamide= 7.3 Hz, 1H), 3.72 (d, J= 0.9 Hz, 3H), 1.69 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 421 (M+H)+. 'H NMR (400 MHz, DMSO-O 5 10.53 (s, 1H), 8.22 (d, J= 8.6 Hz, 1H), (7?)-2-(6-chloro-l- 7.84 (d, J = 2.0 Hz, 1H). 7.74 (d. J = 8.6 Hz, 2H). 7.65 oxoisoquinolin-2( 177)- (d,.7= 7.6 Hz, 1H), 7.53 (dd, J= 8.6, 2.1 Hz, 1H), 7.35 56 yl)- / V-(4-(l,4-dimethyl- (d, J= 8.6 Hz, 2H), 7.30 (s, 1H). 6.70 (d, J= 7.6 Hz, 177-pyrazol-5- 1H), 5.64 (q, J= 7.3 Hz, 1H), 3.68 (s, 3H), 1.94 (s, 3H), yl)phenyl)propanamide1.69 (d, J= 7.3 Hz, 3H). Separated by chiral SFC.Enantiomeric ratio 99: 1.26130Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 421 (M+H)+. ‘H NMR (400 MHz, DMSO-O 5 10.52 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), (5)-2-(6-chloro-l- 7.84 (d, J= 2.0 Hz, 1H), 7.74 (d, J= 8.6 Hz, 2H), 7.65 oxoisoquinolin-2( 17 / )- (d, J= 7.6 Hz, 1H), 7.57-7.50 (m, 1H), 7.35 (d, J= 8.6 57 yl)- / V-(4-(l,4-dimethyl- Hz, 2H), 7.30 (s, 1H), 6.70 (d, J= 7.6 Hz, 1H), 5.64 (q, l / / -pyrazol-5- J= 7.2 Hz, 1H), 3.68 (s, 3H), 1.94 (s, 3H), 1.68 (d, J = yl)phenyl)propanamide7.3 Hz, 3H). separated by chiral SFC: Enantiomeric ratio 95:5.LC / MS ESI (m / z): 387 (M+H)+. 'H NMR (400 MHz, ( / ?)- / V-(4-( 1,4-dimethyl- DMSO-O 5 10.52 (s, 1H), 8.23 (d, J= 8.1 Hz, 1H),7.76-7.67 (m, 4H), 7.58-7.49 (m, 2H), 7.38-7.33 (m, 58 17 / -pyrazol-5-yl)phenyl)- 2-(l -oxoisoquinolin- 2H), 7.30 (s, 1H), 6.71 (d, J= 7.6 Hz, 1H), 5.66 (q, J= 2(17f)-yl)propanamide 7.3 Hz, 1H), 3.68 (s, 3H), 1.94 (s, 3H), 1.68 (d, J= 7.3Hz, 3H).LC / MS ESI (m / z): 373 (M+H)+. 'H NMR (400 MHz, DMSO-O 5 10.51 (s, 1H), 8.27-8.20 (m, 1H), 7.73 (7?)- / V-(4-(l-methyl-17Z- (ddd, J = 6.8, 4.6, 1.5 Hz, 3H), 7.69 (t, J = 4.0 Hz, 1 H), pyrazol-5-yl)phenyl)-2- 59 7.56 (d, J= 7.6 Hz, 1H), 7.54-7.46 (m, 3H), 7.44 (d, J =( 1 -oxoisoquin olin-2( 17 / )- 1.9 Hz. 1H), 6.71 (d. J = 7.5 Hz. 1H), 6.36 (d. J= 1.9 yl)propanamideHz, 1H), 5.67 (q, J= 7.3 Hz, 1H), 3.83 (s, 3H), 1.68 (d,.7= 7.3 Hz. 3H).LC / MS ESI (m / z): 405 (M+H)+.1H NMR (400 MHz, ( / ?)- / V-(4-( 1,4-dimethyl- DMSO-r / s) 5 10.54 (s, 1H), 8.29 (dd, J= 8.9, 5.9 Hz, 177-pyrazol-5-yl)phenyl)- 1H), 7.76-7.72 (m, 2H), 7.63 (d, J= 7.6 Hz, 1H), 7.53 60 2-(6-fluoro-l- (dd, J= 9.8, 2.5 Hz, 1H), 7.38-7.33 (m, 3H), 7.31 (s, oxoisoquinolin-2( 177)- 1H), 6.71 (d, J= 7.6 Hz, 1H), 5.63 (q, J= 7.2 Hz, 1H), yl)propanamide3.68 (s. 3H), 1.94 (s. 3H), 1.69 (d, J = 7.3 Hz. 3H). LC / MS ESI (m / z): 422 (M+H)+.1H NMR (400 MHz, (7?)-2-(6-chloro-l- DMSO-ds) 5 10.70 (s, 1H), 8.90 (d, J= 2.2 Hz, 1H), oxoisoquinolin-2(177)- 8.21 (d, J= 8.6 Hz, 1H), 8.16 (dd, J = 8.6, 2.6 Hz, 1H), 61 yl)- / V-(6-( 1,4-dimethy 1- 7.84 (d,.7= 2.1 Hz, 1H), 7.64 (d. J= 7.6 Hz, 1H), 7.53177-pyrazol-5-yl)pyridin- (dd, J= 8.6, 2.0 Hz, 2H), 7.31 (s, 1H), 6.71 (d, J= 7.6 3-yl)propanamide Hz. 1H), 5.63 (q. J= 7.3 Hz. 1H), 3.85 (s, 3H), 2.05 (s,3H), 1.69 (d, J= 7.3 Hz, 3H).LC / MS ESI m / z: 407 (M+H)+. 'H NMR (400 MHz. CDCl3) 59.09 (S, 1H), 8.21 (d, J= 8.7 Hz, 1H), 7.57 (d, (7?)-2-(6-chloro-l- J= 8.6 Hz. 2H), 7.42 (dt, J= 10.6. 5.3 Hz. 2H), 7.34 oxoisoquinolin-2(17 / )- (dd, J= 8.7, 2.0 Hz, 1H), 7.27 (dd, J= 15.1, 8.1 Hz, 62 yl)-jV-(4-(l-methyl-177- 3H), 6.50 (d, J = 7.6 Hz, 1H), 6.17 (d, J = 1.9 Hz, 1H), pyrazol-5- 5.81 (q,.7= 7.1 Hz, 1H), 3.77 (s, 3H), 1.66 (d, J= 7.1 yl)phenyl)propanamideHz. 3H). Separated by chiral SFC, optical purity-100%.26130Ex. No. Name LCMS, ’H NMRLC / MS ESI m / z: 407 (M+H)+.1H NMR (400 MHz, CDCh) 59.17 (s. 1H), 8.19 (d. J= 8.7 Hz. 1H), 7.61- (5)-2-(6-chloro-l- 7.54 (m, 2H), 7.43 (dd, J= 8.7, 1.9 Hz, 2H), 7.33 (dd, J oxoisoquinolin-2( 177)- = 8.7, 2.0 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.27-7.22 63 y l)-JV-(4-( 1 -methy 1- 177- (m, 2H), 6.50 (d, J= 7.6 Hz, 1H), 6.18 (dd, J= 5.6, 1.9 pyrazol-5- Hz, 1H), 5.82 (q, 7= 7.1 Hz, 1H), 3.77 (s, 3H), 1.66 (d, yl)phenyl)propanamide7= 7.1 Hz, 3H). Separated by chiral SFC; Enantiomeric ratio 99:1.LC / MS ESI m / z: 391 (M+H)+. 'H NMR (400 MHz, (7?)-JV-(4-( 1,4-dimethyl- CDCh) 59.46 (d, 7= 9.3 Hz, 1H), 7.58 (d, 7= 8.6 Hz, 177-pyrazol-5-yl)phenyl)- 2H), 7.28 (s, 1H), 7.21-7.20 (m, 0.5H), 7.19-7.14 (m, 64 2-(l-oxo-5, 6,7,8- 2.5H), 6.04 (d, 7= 7.2 Hz, 1H), 5.69 (q, 7= 7.1 Hz, tetrahydroisoquinolin- 1H), 3.65 (s, 3H), 2.59-2.44 (m, 4H), 1.90 (s, 3H), 2(177)-yl)propanamide1.75-1.64 (m, 4H), 1.61 (d, 7= 7.2 Hz, 3H).LC / MS ESI m / z: 421 (M+H)+. 'H NMR (400 MHz, DMSO-O 5 10.61 (s, 1H), 8.23 (d, 7= 8.7 Hz, 1H), (7?)-2-(6-chloro-l- 7.84 (d, 7= 2.1 Hz, 1H), 7.73 (d, 7= 8.7 Hz, 2H), 7.67 oxoisoquinolin-2( 177)- (d, 7= 7.6 Hz, 1H), 7.54 (dd, 7= 8.7, 2.1 Hz, 1H), 7.49 65 yl)- / V-(4-( 1 -methyl- 177- (d, J = 8.7 Hz, 2H), 7.44 (d, J = 1.9 Hz, 1H), 6.71 (d, 7 pyrazol-5- = 7.6 Hz, 1H), 6.36 (d, 7= 1.9 Hz, 1H), 5.64 (dd, 7 = yl)phenyl)butan amide10.1, 5.8 Hz. 1H), 3.84 (s, 3H), 2.21 (dt.7= 13.8. 6.9 Hz, 1H), 2.10-2.02 (m, 1H), 0.89 (t, 7= 7.3 Hz, 3H). LC / MS ESI (m / z): 421 (M+H)+. 'H NMR (400 MHz. (7?)-2-(6-chl oro-1 - CDCh) 58.63 (s, 1H), 8.39-8.32 (m, 1H), 7.73-7.69 oxoisoquinolin-2( 177)- (m. 2H), 7.57-7.52 (m. 3H), 7.47-7.42 (m. 1H), 7.39- 66 yl)- / V-(4-( 1 -methyl- 177- 7.34 (m, 2H), 6.54 (d, 7= 7.6 Hz, 1H), 6.48 (d, 7= 2.3 pyrazol-3- Hz. 1H), 5.58 (t, 7= 7.8 Hz, 1H), 3.93 (s, 3H), 2.36 (dq. yl)phenyl)butanamide 7= 15.0, 7.4 Hz, 1H), 2.00 (dt, 7 = 16.7, 7.4 Hz, 1H),1.01 (t.7= 7.4 Hz. 3H).LC / MS ESI (m / z): 407 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chloro- 1 - CDCh) 58.85 (d, 7= 23.9 Hz. 1H), 8.38 (d.7= 8.6 Hz. oxoisoquinolin-2( 177)- 1H), 7.74 (s, 1H), 7.57-7.46 (m, 4H), 7.38 (dd, 7= 16.5, 52 yl)-jV-(3-(l-methyl-177- 7.7 Hz. 2H), 7.16 (d.7= 7.6 Hz. 1H), 6.59 (d, 7= 7.5 pyrazol-5- Hz, 1H), 6.32 (s, 1H), 5.85 (q, 7= 7.0 Hz, 1H), 3.91 (s, yl)phenyl)propanamide3H), 1.75 (d, 7= 7.1 Hz, 3H).

[0263] 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.26130Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 404 (M+H)+. ‘H NMR (400 MHz, DMSO-O 5 10.48 (s, 1H), 8.65 (dt, J= 4.7. 1.4 Hz, 1H), 8.39 (t, J= 1.8 Hz, 1H), 8.21 (d,.7= 8.6 Hz, 1H), (A)-2-(6-chloro-l- 7.88 (dd, J= 6.2, 1.5 Hz, 2H), 7.84 (d, J= 2.1 Hz, 1H), oxoisoquinolin-2(177)- 67 7.78-7.74 (m, 1H), 7.70-7.66 (m, 1H), 7.64 (d, J= 7.6 yl)- / V-(3-(pyridin-2- Hz, 1H), 7.53 (dd, J= 8.6, 2.1 Hz, 1H), 7.43 (t, J= 7.9 yl)phenyl)propanamideHz, 1H), 7.36 (ddd, J= 6.1, 4.8, 2.5 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.65 (q, J= 7.3 Hz, 1H), 1.69 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 434 (M+H)+.1H NMR (400 MHz, (A)-2-(6-chloro-l- DMSO-Js) 8 10.40 (s, 1H), 8.22 (d, J= 8.6 Hz, 1H), oxoisoquinolin-2(l / Z)- 7.84 (d, J= 2.1 Hz, 1H), 7.76-7.66 (m, 3H), 7.64 (d, J = 68 yl)- / V-(4-(l-methyl-2- 7.6 Hz, 1H), 7.60 (dd, J= 7.0, 1.9 Hz, 3H), 7.53 (dd, J oxo- 1,2-dihy dropy ridin- = 8.6, 2.1 Hz, 1H), 6.70 (d, J= 7.6 Hz, 1H), 6.31 (t, J= 3-yl)phenyl)propanamide 6.9 Hz, 1H), 5.65 (q, J= 7.3 Hz, 1H), 3.50 (s, 3H), 1.68(d, J = 7.3 Hz, 3H).LC / MS ESI (m / z): 405 (M+H)+. 'H NMR (400 MHz, DMSO-O 8 10.57 (s, 1H), 9.22 (d, J= 1.5 Hz, 1H), (A)-2-(6-chloro-l- 8.68 (dd. J = 2.5. 1.6 Hz. 1H), 8.56 (d. J = 2.5 Hz. 1H), oxoisoquinolin-2(177)- 8.21 (d, J= 8.6 Hz, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.84 69yl)- / V-(4-(pyrazin-2- (d, J = 2.1 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.65 (d, J yl)phenyl)propanamide = 7.6 Hz, 1H), 7.53 (dd, J = 8.6, 2.1 Hz, 1H), 6.71 (d, J = 7.6 Hz. 1H), 5.65 (q. J= 7.3 Hz. 1H), 1.69 (d. J = 7.3 Hz, 3H).LC / MS ESI (m / z): 432 (M+H)+. 'H NMR (400 MHz. (A)-2-(6-chloro- 1 - DMSO-O 8 10.65 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), oxoisoquinolin-2(l / / )- 8.12 (s. 1H), 7.89-7.79 (m. 3H), 7.65 (d. J= 7.6 Hz. 70 yl)- / V-(4-(4-cyano-l- 1H), 7.58 (d, J= 8.7 Hz, 2H), 7.53 (dd, J= 8.6, 2.1 Hz, methyl-1 H-pyrazol-5- 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.63 (q, J= 7.3 Hz, 1H), yl)phenyl)propanamide3.84 (s, 3H), 1.69 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 389 (M+H). 'H NMR (400 MHz, (A)- / V-(4-(3- DMSO-O 8 10.57 (s, 1H), 8.95 (dd, J= 4.5, 1.8 Hz, fluoropyridin-2- 1H), 8.57-8.50 (m, 2H), 7.92 (dd, J= 8.7, 1.4 Hz, 2H), 71 yl)phenyl)-2-(5-oxo- 1,6- 7.86-7.74 (m, 4H), 7.53 (dd, J= 8.1, 4.5 Hz, 1H), 7.46- naphthyridin-6 / 5 / / )- 7.42 (m, 1H), 6.79 (d, J= 7.8 Hz, 1H), 5.67 (q, J= 7.3 yl)propanamideHz, 1H), 1.72 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 429 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chloro- 1 - DMSO-O 8 10.62 (s, 1H), 8.91 (dd, J= 4.8, 1.7 Hz, oxoisoquinolin-2( 17 / )- 1H), 8.41 (dd, J = 1.9, 1.7 Hz, 1H), 8.23 (d, J= 8.6 Hz, 72 yl)- / V-(4-(3- 1H), 7.89-7.78 (m, 5H), 7.66 (d, J= 7.6 Hz, 1H), 7.58 cyanopyridin-2- (dd, J = 7.9, 4.8 Hz, 1H), 7.54 (dd. J = 8.6, 2.1 Hz, 1H). yl)phenyl)propanamide 6.71 (d, J= 7.6 Hz, 1H), 5.66 (q, J= 7.3 Hz, 1H), 1.70(d, J= 7.3 Hz, 3H).26130Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 413 (M+H)+. ‘H NMR (400 MHz, DMSO-O 5 10.62 (s, 1H), 8.91 (dd, J= 4.8, 1.7 Hz, (7?)-N-(4-(3- 1H), 8.41 (dd, J= 7.9, 1.7 Hz, 1H), 8.29 (dd, J= 8.9, cyanopyridin-2- 5.9 Hz, 1H), 7.89-7.78 (m, 4H), 7.65 (d, J= 7.6 Hz, 73 y l)pheny l)-2-(6-fluoro- 1 - 1H), 7.57 (dd, J= 7.9, 4.8 Hz, 1H), 7.53 (dd, J= 9.9, oxoisoquinolin-2( 17 / )- 2.5 Hz, 1H), 7.36 (td, J= 8.8, 2.6 Hz, 1H), 6.71 (d, J = yl)propanamide7.6 Hz, 1H), 5.66 (q, J = 7.3 Hz, 1H), 1.70 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 418 (M+H)+. 'H NMR (400 MHz, DMSO-O 5 10.48 (s, 1H), 8.40 (d, J= 5.0 Hz, 1H), ( / ?)-2-(6-chloro-l- 8.35 (s, 1H), 8.22 (d, J= 8.7 Hz, 1H), 7.84 (d, J= 2.1 oxoisoquinolin-2( 17 / )- Hz, 1H), 7.71 (d, J= 8.6 Hz, 2H), 7.65 (d, J= 7.6 Hz, 74 yl)- / V-(4-(4- 1H), 7.53 (dd, J= 8.6, 2.1 Hz, 1H), 7.36 (d, J= 8.6 Hz, methylpyridin-3- 2H), 7.31 (d, J= 5.0 Hz, 1H), 6.70 (d, J= 7.6 Hz, 1H), yl)phenyl)propanamide5.65 (q, J= 1.3 Hz, 1H), 2.26 (s, 3H), 1.69 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 418 (M+H)+. 'H NMR (400 MHz, ( / ?)-2-(6-chl oro-1 - CDCh) 58.79 (s, 1H), 8.49-8.41 (m, 2H), 8.39 (d, J = oxoisoquinolin-2( 17 / )- 8.8 Hz. 1H), 7.61 (d, J = 8.6 Hz. 2H), 7.54 (d. J = 2.0 75 yl)- / V-(4-(3- Hz, 1H), 7.48 (dd, 7 = 8.8, 2.0 Hz, 1H), 7.35 (d, J= 7.6 methylpyridin-4- Hz. 1H), 7.28 (s. 1H), 7.25-7.23 (m. 1H), 7.10 (d. J = yl)phenyl)propanamide 4.8 Hz, 1H), 6.57 (d, 7= 7.8 Hz, 1H), 5.83 (q, J = 7.6Hz. 1H), 2.25 (s. 3H), 1.74 (d, J = 7.2 Hz, 3H).LC / MS ESI (m / z): 418 (M+H)+.JH NMR (400 MHz, ( / ?)-2-(6-chloro- 1 - CD3OD) 5 8.39 (dd, J = 5.0, 1.7 Hz. 1H), 8.29 (d.7 = oxoisoquinolin-2(l / / )- 8.7 Hz, 1H), 7.70 (t, 7= 5.1 Hz, 3H), 7.66 (dd, 7 = 7.8, 76 yl)- / V-(4-(2- 1.6 Hz. 1H), 7.61 (d..7= 7.6 Hz. 1H), 7.50 (dd, J= 8.7, methylpyridin-3- 2.0 Hz, 1H), 7.32 (dt, J= 8.4, 2.1 Hz, 3H), 6.73 (d, J = yl)phenyl)propanamide 7.6 Hz. 1H), 5.71 (q.7= 7.3 Hz. 1H), 2.47 (s, 3H), 1.77(d, J = 7.3 Hz, 3H).LC / MS ESI (m / z): 421 (M+H). 'H NMR(400 MHz, ( / ?)-2-(6-chl oro-1 - CD3OD) 5 8.29 (d, J= 8.7 Hz, 1H), 7.70 (d, J= 1.9 Hz, oxoisoquinolin-2( 17 / )- 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H), 77 yl)- / V-(4-(l,4-dimethyl- 7.56 (d, J= 8.7 Hz, 2H), 7.50 (dd, J= 8.7, 2.0 Hz, 1H), l / / -pyrazol-3- 7.40 (s. 1H), 6.72 (d. J= 7.6 Hz. 1H), 5.71 (q. J= 7.3 yl)phenyl)propanamide Hz, 1H), 3.85 (s, 3H), 2.17 (s, 3H), 1.76 (d, J= 7.3 Hz,3H).LC / MS ESI (m / z): 419 (M+H)+. 'H NMR (400 MHz, (Z?)-2-(6-chloro-l- CD3OD) 5 8.99 (s, 1H), 8.66 (s, 1H), 8.28 (d, J= 8.7 oxoisoquinolin-2(lH)- Hz, 1H), 7.77 (d, J= 8.6 Hz, 2H), 7.70 (d, J= 1.5 Hz, 78 yl)- / V-(4-(5- 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H), methylpyrimidin-4- 7.49 (dd, 7= 8.6, 1.8 Hz, 1H), 6.72 (d, 7= 7.6 Hz, 1H), yl)phenyl)propanamide 5.78-5.64 (m, 1H), 2.40 (s. 3H), 1.77 (d, J = 7.3 Hz.3H).26130Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 419 (M+H)+. ’H NMR (400 MHz, (A)-2-(6-chloro- 1 - DMSO-O 5 10.54 (s, 1H), 8.55-8.52 (m, 1H), 8.49 (d, oxoisoquinolin-2( 177)-.7= 2.5 Hz, 1H), 8.22 (d,.7= 8.6 Hz, 1H), 7.84 (d, J = 79 yl)- / V-(4-(3- 2.1 Hz, 1H), 7.76-7.72 (m, 2H), 7.67-7.60 (m, 3H), methylpyrazin-2- 7.53 (dd, J = 8.6, 2.1 Hz, 1H), 6.71 (d, J= 7.6 Hz, 1H), yl)phenyl)propanamide 5.65 (q, J= 7.3 Hz, 1H), 2.58 (s, 3H), 1.69 (d, J= 7.3Hz, 3H).LC / MS ESI (m / z): 403 (M+H)+.1H NMR (400 MHz, (7?)-2-(6-fluoro-l- DMSO-O 5 10.54 (s, 1H), 8.56-8.51 (m, 1H), 8.49 (d, oxoisoquinolin-2(177)- J= 2.5 Hz, 1H), 8.28 (dd, J = 8.9, 5.9 Hz, 1H), 7.76- 80yl)-7V-(4-(3- 7.72 (m, 2H), 7.65-7.60 (m, 3H), 7.53 (dd, J= 9.9, 2.5 methylpyrazin-2- Hz, 1H), 7.35 (td, J= 8.8, 2.6 Hz, 1H), 6.71 (d, J= 7.6 yl)phenyl)propanamide Hz, 1H), 5.65 (q, J= 7.3 Hz, 1H), 2.57 (s, 3H), 1.69 (d,J= 7.3 Hz, 3H).LC / MS ESI (m / z): 388 (M+H)+. 'H NMR (400 MHz, (7?)- / V-(4-(3- DMSO-O 5 10.55 (s, 1H), 8.55-8.46 (m, 1H), 8.23 (d, fluoropyridin-2-.7= 8.0 Hz, 1H), 7.92 (dd, J= 8.7, 1.4 Hz, 2H), 7.83- 81 yl)phenyl)-2-(l- 7.71 (m, 4H), 7.69 (d, J = 7.0 Hz, 1H), 7.57 (d, J= 7.6 oxoisoquinolin-2( 177)- Hz. 1H), 7.52 (ddd, J= 8.2, 6.9, 1.5 Hz. 1H), 7.46-7.41 yl)propanamide (m, 1H), 6.71 (d, J= 7.6 Hz, 1H), 5.68 (q, J= 13 Hz,1H), 1.69 (d. J = 7.3 Hz. 3H).LC / MS ESI (m / z): 389 (M+H)+.1H NMR (400 MHz,(A)-N-(4-(3- CDC13) 59.58 (S. 1H). 8.93 (s. 1H), 8.72 (d. J = 5.5 Hz. fluoropyridin-2- 1H), 8.47 (dt, J= 4.5, 1.5 Hz, 1H), 7.95 (dd, J= 8.7, 82 yl)phenyl)-2-( l-oxo-2,7- 1.4 Hz. 2H), 7.69-7.65 (m. 2H), 7.57 (d. J= 7.6 Hz.naphthyridin-2( 177) - 1H), 7.45 (ddd, J= 11.2, 8.3, 1.3 Hz, 1H), 7.36 (d, J = yl)propanamide 5.5 Hz. 1H), 7.25-7.20 (m. 1H), 6.60 (d. J = 7.6 Hz.1H), 5.90 (q, J= 7.1 Hz, 1H), 1.75 (s, 3H).LC / MS ESI (m / z): 389 (M+H)+. 'H NMR (400 MHz, (7?)-N-(4-(3- CDCh) 59.06 (d, J= 16.2 Hz, 1H), 8.90 (d, J= 3.6 Hz, fluoropyridin-2- 1H), 8.48 (dd,.7= 3.0, 1.5 Hz, 1H), 7.94 (d, J= 7.5 Hz, 83 yl)phenyl)-2-(8-oxo-l,7- 2H), 7.89 (d, J= 7.5 Hz, 1H), 7.72-7.67 (m, 2H), 7.61- naphthyridin-7(877)- 7.54 (m, 1H), 7.47-7.42 (m, 2H), 7.24-7.20 (m, 1H), yl)propanamide 6.60 (dd, <7= 7.4, 5.2 Hz, 1H), 6.02-5.95 (m, 1H), 1.75(d, J = 7.1 Hz, 3H).LC / MS ESI (m / z): 424 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-fluoro-l- CD3OD) 5 8.47 (dt, J= 4.7, 1.3 Hz, 1H), 8.37 (dd, J = oxoisoquinolin-2(177)- 8.9, 5.7 Hz, 1H), 7.75-7.68 (m, 2H), 7.59 (d, J= 7.6 84 yl)-JV-(3-fluoro-4-(3- Hz. 1H), 7.54-7.48 (m. 2H), 7.45 (dd, J= 8.5, 2.0 Hz, fluoropyridin-2- 1H), 7.36 (dd, J= 9.5, 2.5 Hz, 1H), 7.28 (Id, J= 8.8, yl)phenyl)propanamide 2.5 Hz, 1H), 6.75 (d, J= 7.6 Hz, 1H), 5.69 (q, J= 7.3Hz, 1H), 1.77 (d, J= 7.3 Hz, 3H).LC / MS ESI (m / z): 419 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chloro-l- CD3OD) 5 8.98 (d, J= 5.2 Hz, 1H), 8.29 (d, J= 8.7 Hz, oxoisoquinolin-2( 177)- 1H), 7.78 (d, J= 8.7 Hz, 2H), 7.71 (d, J= 2.0 Hz, 1H), 85 yl)- / V-(4-(4- 7.65 (d, J= 5.2 Hz, 1H), 7.61 (d, J= 7.6 Hz, 1H), 7.55 methylpyridazin-3- (d,.7= 8.7 Hz, 2H), 7.50 (dd, J= 8.7, 2.0 Hz, 1H), 6.73 yl)phenyl)propanamide (d, J= 7.6 Hz, 1H), 5.72 (q, J= 7.3 Hz, 1H), 2.39 (s,3H), 1.78 (d, J= 7.3 Hz, 3H).26130

[0264] For the following molecules, the aniline intermediate used in step 2 was prepared by the procedure described for Intermediate C.Ex. No. Name LCMS, 'H NMRLC / MS ESI (m / z): 425 (M+H)+.1H NMR (400 MHz, (7?)-2-(6-chloro-l- CDCh) 59.01 (s, 1H), 8.34 (d, J= 8.7 Hz, 1H), 7.67 (d, oxoisoquinolin-2(l / Z)- J= 8.7 Hz, 2H), 7.53 (d, J= 2.0 Hz, 1H), 7.45 (dd, J = 86 y l)- / V-(4-(4-fluoro- 1 - 8.7, 2.0 Hz, 1H), 7.38-7.32 (m, 4H), 6.57 (d, J= 7.6 methyl- 177-py razol-5- Hz, 1H), 5.85 (q, J = 7.2 Hz, 1H), 3.78 (s, 3H), 1.73 (d, yl)phenyl)propanamide J= 7.2 Hz, 3H). Separated by chiral SFC, optical purity -100%.LC / MS ESI (m / z): 425 (M+H)+.1H NMR (400 MHz, (5)-2-(6-chloro-l- CDCh) 58.95 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 7.68- oxoisoquinolin-2( 177)- 7.64 (m, 2H), 7.53 (d, J= 2.0 Hz, 1H), 7.46 (dd, J = 87 yl)-JV-(4-(4-fluoro-l- 8.7, 2.0 Hz, 1H), 7.38-7.33 (m, 4H), 6.57 (d, J= 7.6 methyl- 177-pyrazol-5- Hz, 1H), 5.84 (q, J= 7.2 Hz, 1H), 3.78 (s, 3H), 1.73 (d, yl)phenyl)propanamide J= 7.2 Hz, 3H). Separated by chiral SFC, Enantiomeric ratio 98:2.LC / MS ESI (m / z): 409 (M+H)+.1H NMR (400 MHz, (A)-jV-(4-(4-fluoro-l - CDCh) 58.98 (s. 1H). 8.45 (dd, J = 8.9. 5.7 Hz. 1H), methyl- 177-py razol-5- 7.68-7.64 (m, 2H), 7.37 (d, J = 4.5 Hz, 1H), 7.34 (d, J = 88 y l)pheny l)-2-(6-fluoro- 1 - 8.2 Hz. 3H), 7.25-7.20 (m. 1H), 7.18 (dd, J = 9.1, 2.4 oxoisoquinolin-2(177)- Hz, 1H), 6.60 (d, J= 7.6 Hz, 1H), 5.85 (q, J= 7.2 Hz, yl)propanamide 1H), 3.78 (s, 3H), 1.74 (d, J= 7.2 Hz, 3H). Separated bv chiral SFC, optical purity7-100%.LC / MS ESI (m / z): 391 (M+H)+. 'H NMR (400 MHz, DMSO-O 5 10.56 (s, 1H), 8.23 (d, J= 8.1 Hz, 1H), (7?)-jV-(4-(4-fluoro-l - 7.81-7.76 (m, 2H). 7.75-7.71 (m, 1H). 7.69 (d, J= 7.0 methyl- 177-py razol-5- Hz, 1H), 7.58-7.54 (m, 2H), 7.52 (ddd, J= 8.2, 6.9, 1.5 89 yl)phenyl)-2-(l- Hz. 1H), 7.47 (d. J= 8.5 Hz. 2H), 6.71 (d. J= 7.5 Hz. oxoisoquinolin-2(177)- 1H), 5.66 (q, J= 7.3 Hz, 1H), 3.77 (s, 3H), 1.68 (d, J = yl)propanamide7.3 Hz. 3H). Separated by chiral SFC, optical purity -100%.LC / MS ESI (m / z): 427 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-fluoro-l- DMSO-ds) 5 10.77 (s, 1H), 8.28 (dd, J= 8.9, 5.9 Hz, oxoisoquinolin-2( 177)- 1H), 7.78 (d, J= 13.0 Hz, 1H). 7.61 (dd. J= 11.7, 6.1 yl)-7V-(3-fluoro-4-(4- 90 Hz, 2H), 7.55-7.45 (m, 3H), 7.36 (td, J= 8.8, 2.6 Hz, fluoro-1 -methyl-177- 1H), 6.71 (d, J= 7.6 Hz, 1H), 5.60 (q, J= 7.3 Hz, 1H), pyrazol-5- 3.68 (s, 3H), 1.68 (d, J= 7.3 Hz, 3H). Separated by yl)phenyl)propanamidechiral SFC. optical pun tv -100%LC / MS ESI (m / z): 427 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chloro- 1 -oxo- DMSO-O 5 10.26 (s, 1H), 7.89 (d, J= 8.3 Hz, 1H), 3,4-dihydroisoquinolin- 7.82-7.77 (m, 2H), 7.56 (d, J= 4.6 Hz, 1H), 7.49-7.41 91 2(177)-yl)-jV-(4-(4-fluoro- (m, 4H), 5.31 (q, J = 1.2 Hz, 1H), 3.77 (s, 3H), 3.69- 1 -methyl- 1 / / -pyrazol-5- 3.58 (m, 2H), 3.10-2.96 (m, 2H), 1.45 (d, J= 7.2 Hz, yl)phenyl)propanamide3H).26130Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 394 (M+H)+. ‘H NMR (400 MHz, DMSO4) 510.62 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), (7?)-2-(6-chloro- 1 - 8.18 (s, 1H), 7.94 (d, J= 8.8 Hz, 2H), 7.84 (d, J =2.0 oxoisoquinolin-2( 1H)- 92 Hz, 1H), 7.77 (d, J= 8.8 Hz, 2H), 7.64 (d, J= 7.6 Hz, yl)- / V-(4-(oxazol-2- 1H), 7.53 (dd, J= 8.6, 2.1 Hz, 1H), 7.35 (s, 1H), 6.71 yl)phenyl)propanamide(d, J= 7.6Hz, 1H), 5.64 (q, J= 7.3 Hz, 1H), 1.69 (d, J= 7.3 Hz, 3H).Example 93. Synthesis of (7?)-2-(6-(dimethylamino)-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide (93)Step 1. 6-Bromo-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-l(2H)-one

[0265] To a solution of 6-bromoisoquinolin-l(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-C1 (1.1 g, 6.7 mmol) at 0°C. Then the mixture was stirred at rt under N2 overnight and quenched with H2O. The mixture was extracted with EtOAc twice. The organic layer was dried over Na2SOr and chromatographed on silica gel (10-11% EtOAc in petroleum ether) to give 6-bromo-2-((2-(trimethylsilyl)ethoxy)methyl) isoquinolin- l(2H)-one. LC / MS ESI (m / z): 354, 356 (M+H)+.Step 2, 6-(Dimethylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-l(2H)-one

[0266] A mixture of 6-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-l(2H)-one (870 mg, 2.5 mmol), dimethylamine (1.4 mL, 2.0 M, 2.7 mmol), Pd2(dba)s (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 N2 overnight. 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-l(2H)-one. LC / MS ESI (m / z): 319 (M+H)+.26130Step 3, 6-(Dimethylamino)isoquinolin-l(2H)-one

[0267] To a solution of 6-(dimethylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)isoquinolin-l(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-l(2H)-one. LC / MS ESI (m / z): 189 (M+H)+.Step 4. (7?)-2-(6-(Dimethylamino)-l-oxoisoquinolin-2(lH)-yl)propanoic acid

[0268] 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-l(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 HC1 (6 M) and extracted with DCM twice. The combined organic layers were chromatographed on silica gel (0-10% MeOH in DCM) to afford (J?)-2-(6-(dimethylamino)-l-oxoisoquinolin-2(lH)-yljpropanoic acid. LC / MS ESI (m / z): 261 (M+Hft.Step 5. (7?)-2-(6-(Dimethylamino)-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide

[0269] At -10°C, to a solution of (J?)-2-(6-(dimethylamino)-l-oxoisoquinolin-2(lH)-yljpropanoic acid (200 mg, 0.8 mmol) and 4-(l-methyl-lH-pyrazol-5-yl)aniline (170 mg, 1.0 mmol) in pyridine / DCM (2 mL / 5 mL) under N2 were added POCh (180 mg, 1.2 mmol) dropwise. Then the mixture w as 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 (?)-2-(6-(dimethylamino)-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide. LC / MS ESI (m / z): 416 (M+H)+.1HNMR (400 MHz, DMSO-d6) 510.47 (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, 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,.7 =7.3 Hz, 3H).Example 94. Synthesis of (?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-ethyl-lH-pyrazol-5-yl)phenyl)propanamide (94)26130n-BuLi, I2THF, -78°C Pd(dppf)CI2, Na2CO3,dioxane, H2O, 100°C

[0270] The acid intermediate used in step 3 was prepared by the procedure described for Intermediate E.Step 1. l-Ethyl-5-iodo-lH-pyrazole

[0271] At -78°C, to a solution of 1-ethyl-lH-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°C for 1 h, the reaction quenched with NH4CI (aq) and Na2S20s (aq). The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over NazSCh, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-20% EtOAc in petroleum ether) to afford l-ethyl-5-iodo-lH-pyrazole.NMR (400 MHz, CDCh) 57.43 (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-(l -Ethyl- lH-pyrazol-5-yl)aniline

[0272] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (400 mg, 1.8 mmol) and l-ethyl-5-iodo-lH-pyrazole (810 mg, 3.7 mmol) in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (130 mg, 0.18 mmol) and Na2CO3 (580 mg, 5.5 mmol). The resulting mixture was heated to 100°C under N2 overnight and concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-40% EtOAc in petroleum ether) to afford 4-(l-ethyl-lH-pyrazol-5-yl)aniline. LC / MS ESI (m / z): 188 (M+H)+.Step 3, (7?)-2-(6-Chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-ethyl-lH-pyrazol-5-yllphenyllpropanamide

[0273] At -20°C, to a solution of (?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)propanoic acid (100 mg, 0.40 mmol) and 4-(l-ethyl-lH-pyrazol-5-yl)aniline (100 mg, 0.40 mmol) in DCM (5 mL) were added pyridine (5 mL) followed by POCh (61 mg, 0.40 mmol) dropwise. The resulting mixture was stirred at -20°C for 0.5 h and quenched with water. The mixture was extracted with DCM twice. The combined organic layers were washed with brine, dried overNa2SO4, filtered,26130and concentrated. The residue was purified by flash column chromatography (silica gel, 0-80% EtOAc in petroleum ether) and prep-HPLC, to afford (7?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-ethyl-lH-pyrazol-5-yl)phenyl)propanamide. LC / MS ESI (m / z): 421 (M+H)+. 'H NMR (400 MHz, DMSO-tL) 5 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, 1.8 Hz, 1H), 5.64 (q, J - 13 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 (?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(pyrimidin-2-yl)phenyl)propanamide (95)H2, Pd / C Pd(dppf)CI2, K2CO3MeOHdioxane, H2O, 80°CStep 1. 2-(4-Nitrophenyl)pyrimidine

[0274] 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)Ch (100 mg, 0.14 mmol). The resulting mixture was stirred at 80°C under N2 overnight. After being cooled down to rt, the reaction was concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, EtOAc in petroleum ether) to afford 2-(4-nitrophenyl)pyrimidine.Step 2, 4-(Pyrimidin-2-yl)aniline

[0275] 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 diatomaceous earth (CELITE®). The filtrate was concentrated to dryness to give 270 mg of the crude product. LC / MS ESI (m / z): 172 (M+H)+.Step 3, (7?)-2-(6-Chloro-l-oxoisoquinolin-2( lH)-yl)-N-(4-(pyrimidin-2- yl)phenyl)propanamide

[0276] To a solution of 4-(pyrimidin-2-yl)aniline (270 mg, 1.58 mmol) and (7?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)propanoic acid (610 mg, 2.43 mmol) in DCM (10 mL) were added26130pyridine (3 mL) and POCh (0.18 mL, 2.02 mmol) dropwise. After being stirred at -20°C 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 DCM) followed by prep-HPLC to afford (7?)-2-(6-chloro- l-oxoisoquinolin-2( I H)-yl)-N-(4-(pyrimidin-2-yl)phenyl)propanamide. LC / MS ESI (m / z): 405 (M+H)+.NMR (400 MHz, DMSO-cL) 5 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,.7 = 2.0 Hz, 1H), 7.75 (d,.7 = 8.8 Hz, 2H), 7.64 (d,.7= 7.6 Hz, 1H), 7.53 (dd,.7= 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).

[0277] The following compounds were prepared by a procedure similar to that described for Example 95 starting from the corresponding chloropyrimidine.Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 419 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chloro-l - CDCls) 5 8.82 (d, J = 27.4 Hz, 1H), 8.52 (d, J = 5.0 Hz, oxoisoquinolin-2( 177)- 1H). 8.34-8.24 (m, 3H). 7.62-7.55 (m, 2H). 7.45 (dd. J = 96 yl)- / V-(4-(4- 5.2, 2.0 Hz, 1H), 7.40-7.35 (m, 1H), 7.29 (d, J = 7.6 Hz, methylpyrimidin-2- 1H). 6.93 (d, J = 5.0 Hz, 1H). 6.49 (d,.7= 7.6 Hz, 1H). yl)phenyl)propanamide 5.79 (q,.7= 7.1 Hz, 1H), 2.49 (s, 3H), 1.65 (d, J = 1.2 Hz, 3H).LC / MS ESI (m / z): 405 (M+H)+. 'H NMR (400 MHz, DMSO-rie) 5 10.63 (s. 1H), 9.19 (s, 1H), 8.81 (d, J= 5.5 (7?)-2-(6-chl oro-1 - Hz, 1H), 8.21 (d,.7= 8.8 Hz, 3H), 8.04 (dd, J = 5.5, 1.2 oxoisoquinolin-2( 177)- 97 Hz, 1H), 7.86-7.82 (m, 1H), 7.79 (d, J= 8.8 Hz, 2H), yl)-N-(4-(pyrimidin-4- 7.65 (d, J = 7.6 Hz, 1H), 7.53 (dd, J= 8.6, 2.0 Hz, 1H), yl)phenyl)propanamide6.71 (d, J= 7.6 Hz, 1H), 5.64 (q, J= 7.3 Hz, 1H), 1.69(d, J = 7.3 Hz, 3H).Example 98. Synthesis of (?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-ethyl-lH-pyrazol-3-yl)phenyl)propanamide (98)K2CO3, DMF, 60°C Pd(dppf)CI2, K2CO3dioxane / H2O, 100°C26130Step 1. 3 -Bromo- 1 -ethyl- IH-pyrazole, 5-bromo-l -ethyl- IH-pyrazole

[0278] To a solution of 3-bromo-lH-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°C overnight. After being cooled down to rt, 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% EtOAc in petroleum ether) to afford 600 mg of 3 -bromo- 1-ethyl-lH-pyrazole and 5-bromo-l -ethyl-lH-pyrazole mixture. LC / MS EST (m / z): 175, 177 (M+H)+.Step 2, 4-(l-Ethyl-lIT-pyrazol-3-yl)aniline

[0279] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (630 mg, 2.87 mmol) and 500 mg mixture of 3-bromo-l -ethyl- IH-pyrazole and 5-bromo-l-ethyl-lH-pyrazole in dioxane (20 mL) and H2O (6 mL) were added Pd(dppf)C12 (210 mg, 0.29 mmol) and K2CO3 (1.19 g, 8.63 mmol). The resulting mixture was heated to 100°C under N2 overnight. The solvents were removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0-40% EtOAc in petroleum ether) and prep-HPLC to afford 4-( 1-ethyl-lH-pyrazol-3-yl)aniline. LC / MS ESI (m / z): 188 (M+H)+. 'H NMR (400 MHz, DMSO- e) 57.65 (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, CR)-2-(6-Chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-ethyl-lH-pyrazol-3- yl)phenyl)propanamide

[0280] At -10°C, to a solution of (R)-2-(6-chl oro-1 -oxoisoquinolin-2(lH)-yl)propanoic acid (100 mg, 0.40 mmol) and 4-(l-ethyl-lH-pyrazol-3-yl)aniline (74 mg, 0.40 mmol) in DCM (2 mL) were added pyridine (2 mL) and POCh (92 mg, 0.60 mmol) dropwise. The resulting mixture was stirred at -10°C for 0.5 h and quenched with water. The mixture was extracted with DCM twice. The combined organic layers w ere washed with brine, dried overNa2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-80% EtOAc in petroleum ether) and prep-HPLC to afford (R)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l -ethyl- lH-pyrazol-3-yl)phenyl)propanamide. LC / MS ESI (m / z): 421 (M+H)+. 'H NMR (400 MHz, DMSO-t / e) 5 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).26130Example 99. Synthesis of (?)-N-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)phenyl)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide (99)

[0281] The acid intermediate used in step 3 was prepared by a procedure similar to that described for Intermediate E.Step 1. 4-Chloro-l-methyl-5-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-lEI-pyrazole

[0282] To a solution of l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-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 rt, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted wi th 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% EtOAc in petroleum ether) to afford 4-chloro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole. LC / MS ESI (m / z): 243 (M+H)+.Step 2, 4-(4-Chloro-l-methyl-lH-pyrazol-5-yl)aniline

[0283] To a solution of 4-chloro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (500 mg, 2.1 mmol) and 4-bromoaniline (390 mg, 2.3 mmol) in dioxane / FLO (15 mL / 3 mL) were added K2CO3 (860 mg, 6.3 mmol) and Pd(dppf)C12 (75 mg, 0.1 mmol). The mixture was stirred at 90°C under N2 overnight. The solvents were removed by rotary evaporation. The residue was chromatographed on silica gel (20-40% EtOAc in petroleum ether) to give 4-(4-chloro- 1 -methyl- lH-pyrazol-5-yl)aniline. LC / MS ESI (m / z): 208 (M+H)+.Step 3, (A)-N-(4-(4-Chloro-l-methyl-lH-pyrazol-5-yl)phenyl)-2-(7-fluoro-4- oxoquinazolin-3(4H)-yl)propanamide

[0284] To a solution of 4-(4-chloro-l-methyl-lH-pyrazol-5-yl)aniline (42 mg, 0.2 mmol) in MeCN (5 ml) were added (A)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanoic acid (40 mg, 0.2 mmol). 1-methyl-lH-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 FEO. The mixture was extracted26130with DCM twice. The organic layer was dried over Na2SO4 and chromatographed on silica gel (60-75% EtOAc in petroleum ether) to give the crude product, which was further purified by prep-HPLC to afford (7?)-N-(4-(4-chloro-l-methyl-lH-pyrazol-5-yl)phenyl)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide. LC / MS ESI (m / z): 426 (M+H)+.JH NMR (400 MHz, DMSO-tL) 5 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).

[0285] 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.Ex. No. Name LCMS, ' H NMR(7?)-JV-(4-(4-chloro- 1 - LC / MS ESI (m / z): 442 (M+H).'H NMR (400 MHz, methyl- 17 / -py razol-5- DMSO-cL) 5 10.62 (s, 1H), 8.55 (s. 1H), 8.16 (d, J= 8.6 100 yl)phenyl)-2-(7 -chloro- Hz, 1H), 7.81 (d, J= 6.4 Hz, 1H), 7.79-7.74 (m, 2H),4-oxoquinazolin-3(47 / )- 7.67-7.56 (m, 2H), 7.49-7.43 (m, 2H), 5.57 (q, J= 7.3yl)propanamide Hz, 1H), 3.76 (s, 3H), 1.80 (d, J = 7.4 Hz, 3H).Example 101. Synthesis of (7?)-2-(7-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-N-(4-(l-methyl- lH-pyrazol-5-yl)phenyl)propanamide (101)o SnCI2CH(OEt)3EtOH 150“C Mg(Of-Bu)2, f-BuOK,THF, 55°CStep 1. 3-Amino-5-chloropicolinamide

[0286] To a solution of 5-chloro-3-nitropicolinonitrile (1.0 g, 5.5 mmol) in EtOH (20 mL) was added SnCh (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 diatomaceous earth (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. LC / MS ESI (m / z): 172 (M+H)+.26130Step 2, 7-Chloropyrido[3.2-d1pyrimidin-4(3H)-one

[0287] A solution of 3-amino-5-chloropicolinamide (800 mg, 4.7 mmol) in CH(OEt)s (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 product was collected by fdtration and dried under high vacuum to afford the crude title compound 7-chloropyrido[3,2-d]pyrimidin-4(3H)-one. LC / MS ESI (m / z): 182 (M+H)+.Step 3, (7?)-2-(7-Chloro-4-oxopyrido[3.2-d1pyrimidin-3(4H)-yl)propanoic acid

[0288] 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, IM 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 2M HC1 and concentrated. The residue was purified by prep-HPLC to afford the title compound (J?)-2-(7-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)propanoic acid. LC / MS ESI (m / z): 254 (M+H)+.Step 4, CR)-2-(7-Chloro-4-oxopyrido[3.2-d1pyrimidin-3(4H)-yl)-N-(4-(l-methyl-lH- pyrazol-5-yl)phenyl)propanamide

[0289] To a solution of (7?)-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-(l -methyl- lH-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 (7?)-2-(7-chloro-4-oxopyrido[3,2-d]pyrimidin-3(4H)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide. LC / MS ESI (m / z): 409 (M+H)+. *H NMR (400 MHz, CDCh) 58.83 (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 ( / ?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fhioro-4-(4-methyloxazol-5-yl)phenyl)propanamide ( 102)26130

[0290] 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

[0291] 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 l-((l-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 and chromatographed on silica gel (10-17% EtOAc in petroleum ether) to give 5-(2-fluoro-4-nitrophenyl)-4-methyloxazole.Step 2, 3-Fluoro-4-(4-methyloxazol-5-yl)aniline

[0292] 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 NH4CI (150 mg, 2.7 mmol). The resulting mixture was stirred at 90°C for 2 h and filtered through a diatomaceous earth (CELITE®) pad. The filtrate was concentrated to give crude 3-fluoro-4-(4-methyloxazol-5-yl)amline. LC / MS ESI (m / z): 193 (M+H)+.Step 3, (7?)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(4-methyloxazol-5-yl)phenyl)propanamide

[0293] To a solution of 3-fluoro-4-(4-methyloxazol-5-yl)aniline (90 mg, 0.5 mmol) in MeCN (5 mL) were added (J?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid (100 mg, 0.4 mmol), 1-methyl-lH-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 wi th 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 (7?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(3-fluoro-4-(4-methyloxazol-5-yl)phenyl)-propanamide. LC / MS ESI (m / z): 427 (M+H)+. 'H NMR (400 MHz. DMSO-tL) 5 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), 7.7226130(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= 1A Hz, 3H).Example 103. Synthesis of (7?)-2-(5-Fluoro-l-oxoisoindolin-2-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide (103)Mg(0t-Bu)2,KOt-Bu, THF35 °C Step 1. (7?)-2-(5-Fluoro-l-oxoisoindolin-2-yl)propanoic acid

[0294] To a mixture of Mg(Ot-Bu)2 (560 mg, 3.3 mmol) in anhydrous THF (8 mL) was added portion-wise (5)-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 the resulting mixture was stirred at rt for another 15 min. 5-Fluoroisoindolin-l-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 0°C, and water (20 mL) was 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 HC1 and extracted with EtOAc (3 x 25 mL), the combined organic layers washed with brine (25 mL), dried over Na2SO4, fdtered, and concentrated to obtain (A)-2-(5-fluoro-l-oxoisoindolin-2-yl)propanoic acid. LC / MS ESI (m / z): 223.9 (M+H)+.Step 2, (7?)-2-(5-Fluoro-l-oxoisoindolin-2-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propenamide

[0295] To a stirred solution of (7?)-2-(5-fluoro-l-oxoisoindolin-2-yl)propanoic acid (75 mg, 0.33 mmol), 4-(l -methyl- lH-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 rt. After the completion of the reaction, water was added and the reaction mixture was extracted into EtOAc (2 x 10 mL), combined organic layer washed with saturated sodium bicarbonate solution (5 mL) and with brine (5 mL), dried over sodium sulfate, fdtered, concentrated, and subjected to flash chromatography (60% EtOAc / hexane) to obtain the (R)-2-(5-fluoro-l-oxoisoindolin-2-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propenamide. LC / MS ESI (m / z): 378.7 (M+H)+. *HNMR (CD3OD, 600 MHz) 87.82 - 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).

[0296] The following compounds were prepared by procedures analogous to the synthesis of Example 103 using corresponding anilines and acids.Ex. No. Name LCMS, ' H NMR(R)-2-(5 -fluoro- 1 - LC / MS ESI (m / z): 378.7 (M+H)+. 'HNMR (CD3OD, oxoisoindolin-2-yl)-jV- 600 MHz) 57.82-7.80 (m, 1H), 7.71 (d, 2H), 7.60-7.57 104 (4-(l-methyl-122- (m, 3H), 7.39 (d, 1H), 7.27 (m, 1H), 6.57 (d, 1H), 5.09 pyrazol-3- (q, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 3.91 (s, 3H), 1.66 (d, yl)phenyl)propanamide 3H).(A)-2-(5-chloro-l- LC / MS ESI (m / z): 395.7 (M+H)+ 1H NMR (DMSO-ofe, oxoisoindolin-2-yl)-2V- 600 MHz) 310.27 (s, 1H), 7.78 (s, 1H), 7.71-7.67 (m, 105 (4-( 1 -methyl- 122- 4H). 7.62 (d, 2H). 7.58 (d, 1H), 6.63 (d, 1H), 5.00 (q, pyrazol-5- 1H), 4.75 (q, 2H), 3.86 (s, 3H), 1.54 (d, 3H). yl)phenyl)propanamide( / ? )-2 -(5 -chloro- 1 - LC / MS ESI (m / z): 381.5 (M+H)+ 1H NMR (DMSO-c / c. oxoisoindolin-2-yl)-jV- 600 MHz) 310.50 (s, 1H), 8.18 (s, 1H), 7.94 (d, 2H), 106(4-(oxazol-2- 7.78-7.76 (m, 3H), 7.73 (d, 1H), 7.58 (d, 1H), 7.35 (s, vl)phenvl)propanamide 1H), 5.00 (q, 1H), 4.74 (q, 2H), 1.57 (d, 3H). (2?)-2-(5 -chloro- 1 - LC / MS ESI (m / z): 381.5 (M+H)+ 1H NMR (DMSO-rfe, oxoisoindolin-2-yl)-jV- 600 MHz) 5 10.39 (s, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 107(4-(oxazol-5- 7.70-7.65 (m, 5H), 7.58 (d, 1H), 7.55 (s, 1H):4.99 (q, yl)phenyl)propanamide 1H), 4.72 (q, 2H), 1.55 (d, 3H).(R)-2-(5 -chloro- 1 - LC / MS ESI (m / z): 394.9(M+H)+.1H NMR (DMSO-Je, oxoisoindolin-2-yl)-jV- 600 MHz) 310.25 (s, 1H), 7.76 (s, 1H), 7.71-7.67 (m, 108 (4-(l-methyl-127- 4H), 7.59 (d, 2H), 7.55 (d, 1H), 6.61 (d, 1H), 5.00 (q, pyrazol-3- 1H), 4.73 (q, 2H), 3.84 (s. 3H), 1.54 (d. 3H). yl)phenyl)propanamide(2?)-2-(5-chloro-l- LC / MS ESI (m / z): 408.8 (M+H)+ 1H NMR (CDCh, 600 oxoisoindolin-2-yl)-2V- MHz) 58.83 (s, 1H), 7.75 (d, 1H), 7.71 (d, 2H), 7.58 (d, 109 (4-( 1 -methyl- 122- 2H), 7.47-7.43 (m, 2H). 7.34 (d, 1H), 6.47 (d, 1H), 4.90 pyrazol-3- (t, 1H), 4.67 (d, 1H), 4.45 (d, 1H), 3.92 (s, 3H), 2.21 (m, vl)phenvl)butan amide 1H). 1.92 (m, 1H), 0.99 (t, 3H).(2?)-2-(6-chloro- 1 -oxo- LC / MS ESI (m / z): 409.0 (M+H)+ 1H NMR (DMSO-Je, 3,4-dihydroisoquinolin- 600 MHz) 5 10.05 (s. 1H), 7.88 (d. 1H), 7.71-7.67 (m, 110 2(127)-yl)-7V-(4-(l- 3H), 7.62 (d, 2H), 7.43 (s, 1H), 7.41 (d, 1H), 6.60 (d, methyl- 122-py razol-5- 1H), 5.29 (q, 1H), 3.84 (s. 3H), 3.67-3.56 (m. 2H), 3.05- yl)phenyl)propanamide 2.96 (m, 2H), 1.43 (d, 3H).(2?)-2-(6-Fluoro-l-oxo- LC / MS ESI (m / z): 392.5. 'H NMR (CDCh, 600 MHz) 5 3,4-dihydroisoquinolin- 8.56 (broad s, 1H), 8.11 (m, 1H), 7.76 (d, 2H), 7.60 (d, 111 2(127)-yl)-7V-(4-(l- 2H). 7.38 (s, 1H). 7.04 (t. 1H), 6.91 (m, 1H). 6.51 (s.methyl- 122-py razol-5- 1H), 5.52 (t, 1H), 3.96 (s, 3H), 3.65-3.59 (m, 2H), 3.00 vl)phenvl)propanamide (d. 2H), 1.53 (d. 3H).(2?)-2-(6-Fluoro- 1-oxo- LC / MS ESI (m / z): 407.9.JH NMR (CDCh, 600 MHz) 5 3,4-dihydroisoquinolin- 8.75 (broad s, 1H), 8.51 (s, 1H), 8.11 (s, 1H). 7.99 (d, 112 2(127)-yl)-7V-(4-(3- 2H), 7.71 (d, 2H), 7.48 (t, 1H), 7.25 (m, 1H), 7.04 (t, fluoropyridin-2- 1H). 6.91 (d, 1H). 5.55 (t. 1H), 3.66-3.60 (m. 2H), 3.01yl)phenyl)propanamide (d, 2H), 1.54 (d, 3H).Ex. No. Name LCMS, NMR(7?)-2-(6-Fluoro-l -oxo- LC / MS ESI (m / z): 403.9. ’H NMR (CDCk, 600 MHz) 5 3,4-dihydroisoquinolin- 8.88 (s, 1H), 8.51 (d, 1H). 8.06 (m, 1H), 7.69 (d, 2H), 113 2(122)-yl)- / V-(4-(3- 7.58 (d, 1H), 7.51 (d, 2H), 7.17 (m, 1H), 7.00 (m, 1H), methylpyridin-2- 6.88 (dd, 1H), 5.56 (t, 1H), 3.65-3.60 (m, 2H), 3.05-2.95 yl)phenyl)propanamide (m, 2H), 2.36 (s, 3H), 1.52 (d, 3H).(2?)-2-(5-Chloro-l,3- LC / MS ESI (m / z): 422.9. 'H NMR (CDCh, 600 MHz) 5 dioxoisoindolin-2-yl)- / V- 8.37 (broad s, 1H), 7.81-7.83 (m. 2H), 7.76-7.73 (m. 114 (4-(l-methyl-122- 3H), 7.51 (d, 2H), 7.38 (d, 1H), 6.51 (d, 1H), 4.87 (dd, pyrazol-3- 1H). 3.96 (s, 3H), 2.41-2.33 (m, 2H), 1.01 (t, 3H). yl)phenyl)butanamide(2?)-2-(5 -Chloro- 1- LC / MS ESI (m / z): 407.3.^ NMR (CDsOD, 600 MHz) oxoisoindolin-2-yl)-2V- 6 8.80 (d, 2H), 6 8.36 (d, 2H), 7.78-7.68 (m, 4H). 7.54 115(4-(pyrimidin-2- (d, 1H), 7.32 (t, 1H), 4.99 (q, 1H), 4.94 (d, 1H), 4.65 (d, yl)phenyl)butanamide 1H), 2.20-2.01 (m, 2H), 1.04 (t, 3H).(2?)-2-(5-fluoro-l- LC / MS ESI (m / z): 378.7 (M+H)+. 'H NMR (CD3OD, oxoisoindolin-2-yl)-2V- 600 MHz) 57.82-7.80 (m, 1H), 7.71 (d, 2H), 7.60-7.57 104 (4-( 1 -methyl- 122- (m, 3H), 7.39 (d, 1H), 7.27 (m, 1H), 6.57 (d, 1H), 5.09 pyrazol-3- (q, 1H), 4.85 (d, 1H), 4.67 (d, 1H), 3.91 (s, 3H), 1.66 (d, yl)phenyl)propanamide 3H).(R)-2-(5 -chloro- 1 - LC / MS ESI (m / z): 395.7 (M+H)+ 1H NMR (DMSO-tfc, oxoisoindolin-2-yl)- / V- 600 MHz) 310.27 (s, 1H), 7.78 (s, 1H), 7.71-7.67 (m, 105 (4-(l-methyl-122- 4H), 7.62 (d, 2H), 7.58 (d, 1H), 6.63 (d, 1H), 5.00 (q, pyrazol-5- 1H). 4.75 (q, 2H), 3.86 (s. 3H), 1.54 (d. 3H). yl)phenyl)propanamide(2?)-2-(5-chloro-l- LC / MS ESI (m / z): 381.5 (M+H)+ 1H NMR (DMSO-rfe, oxois oindolin-2-y 1)-2V- 600 MHz) 310.50 (s, 1H), 8.18 (s, 1H), 7.94 (d, 2H), 106(4-(oxazol-2- 7.78-7.76 (m, 3H), 7.73 (d, 1H), 7.58 (d, 1H), 7.35 (s, yl)phenyl)propanamide 1H), 5.00 (q, 1H), 4.74 (q, 2H), 1.57 (d, 3H). (2?)-2-(5-chloro-l- LC / MS ESI (m / z): 381.5 (M+H)+ 1H NMR (DMSO-de, oxois oindolin-2-y 1)-2V- 600 MHz) 5 10.39 (s, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 107(4-(oxazol-5- 7.70-7.65 (m, 5H), 7.58 (d, 1H), 7.55 (s, 1H), 4.99 (q, yl)phenyl)propanamide 1H), 4.72 (q, 2H), 1.55 (d, 3H).(2?)-2-(5-chloro-l- LC / MS ESI (m / z): 394.9(M+H)+.1HNMR (DMSO-Je, oxoisoindolin-2-yl)-2V- 600 MHz) 310.25 (s, 1H), 7.76 (s, 1H), 7.71-7.67 (m, 108 (4-( 1 -methyl- 122- 4H). 7.59 (d, 2H), 7.55 (d, 1H), 6.61 (d, 1H), 5.00 (q, pyrazol-3- 1H), 4.73 (q, 2H), 3.84 (s, 3H), 1.54 (d, 3H). vl)phenvl)propanamide(R)-2-(5 -chloro- 1 - LC / MS ESI (m / z): 408.8 (M+H)+ 1H NMR (CDCh, 600 oxoisoindolin-2-yl)- / V- MHz) 58.83 (s, 1H), 7.75 (d, 1H), 7.71 (d, 2H), 7.58 (d, 109 (4-( 1 -methyl- 122- 2H), 7.47-7.43 (m, 2H). 7.34 (d, 1H), 6.47 (d, 1H), 4.90 pyrazol-3- (t, 1H), 4.67 (d, 1H), 4.45 (d, 1H), 3.92 (s, 3H), 2.21 (m. yl)phenyl)butanamide 1H), 1.92 (m, 1H), 0.99 (t, 3H).(2?)-2-(6-chloro- 1 -oxo- LC / MS ESI (m / z): 409.0 (M+H)+ 1H NMR (DMSO-t / e, 3,4-dihydroisoquinolin- 600 MHz) 5 10.05 (s, 1H), 7.88 (d, 1H), 7.71-7.67 (m, 110 2(127)-yl)-7V-(4-(l- 3H). 7.62 (d, 2H). 7.43 (s. 1H). 7.41 (d. 1H), 6.60 (d.methyl- 122-py razol-5- 1H), 5.29 (q, 1H), 3.84 (s, 3H), 3.67-3.56 (m, 2H), 3.05-vl)phenvl)propanamide 2.96 (m. 2H), 1.43 (d. 3H).Ex. No. Name LCMS, NMR(7?)-2-(6-Fluoro-l -oxo- LC / MS ESI (m / z): 392.5. ’H NMR (CDCk, 600 MHz) 5 3,4-dihydroisoquinolin- 8.56 (broad s, 1H), 8.11 (m, 1H), 7.76 (d, 2H), 7.60 (d, Ill 2(177)-yl)-7V-(4-(l- 2H), 7.38 (s, 1H), 7.04 (t, 1H), 6.91 (m, 1H), 6.51 (s, methyl-l / f-pyrazol-5- 1H), 5.52 (t, 1H), 3.96 (s, 3H), 3.65-3.59 (m, 2H), 3.00yl)phenyl)propanamide (d, 2H), 1.53 (d, 3H).Example 116. (7?)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-4-hydroxy-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)butanamide (116)Step 1. ( / ?)-teil-Butyl (4-((tert-buNldiphenylsilyl)oxy)-l-((4-(l -methyl- lH-pyrazol-3- yl)phenyl)amino)-l-oxobutan-2-yl)carbamate

[0297] To a stirred solution of (R)-2-((tert-butoxycarbonyl)amino)-4-((tert-butyldiphenylsilyl)oxy)butanoic acid (500 mg, 1.09 mmol) and 4-(l -methyl- lH-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 0°C. After the completion of the reaction, water (25 mL) was added, and the reaction mixture was extracted into EtOAc (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 flash chromatography (60% EtOAc / hexane) to obtain the ( )-tert-butyl (4-((tert-butyldiphenylsilyl)oxy)-l-((4-(l-methyl-lH-pyrazol-3-yl)phenyl)amino)-l-oxobutan-2-yl)carbamate. LC / MS ESI (m / z): 612.8 (M+H)+.26130Step 2, (7?)-2-Amino-4-((tert-butyrldiphenylsilyl)oxy)-N-(4-(l-methyl-lH-pyrazol-3- yllphenyllbutanamide

[0298] To a stirred solution of (R)-2-amino-4-((tert-butyldiphenylsilyl)oxy)-N-(4-( 1 -methyl-lH-pyrazol-3yl)phenyl)butanamide (500 mg, 0.81 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.37 mL, 4.9 mmol) at 0°C and then stirred at rt. After the completion of the reaction, it was concentrated to obtain the crude compound. The reaction mixture was basified with sat. NaHCCh solution to pH 7.0-8.0. The aqueous layer was extracted with CH2CI2 (2 x 50 mL), the combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated to obtain (7?)-2-amino-4-((tert-butyldiphenylsilyl)oxy)-N-(4-(l -methyl- 1H-pyrazol-3-yl)phenyl)butanamide.Step 3, CR)-4-((tert-Butyldiphenylsilyl)oxy)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4- (l-methyl-lH-pyrazol-3-yl)phenyl)butanamide

[0299] To a stirred solution of (7?)-2-amino-4-((tert-butyldiphenylsilyl)oxy)-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)butanamide (300 mg, 0.58 mmol)) in 1,4-dioxane (80 mL) was added (Ej-methyl 4-chloro-2-(((dimethylamino)methylene)amino)benzoate (140 mg, 0.58 mmol) and p-toluenesulfonic acid (11 mg, 0.05 mmol) at rt, and the resultant reaction mixture was stirred at 100°C for 4 h. After the completion of reaction, it was cooled to rt, treated with EtsN (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 (7?)-4-((tert-butyldiphenylsilyl)oxy)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(l -methyl- lH-pyrazol-3-yl)phenyl)butanamide. LCMS ESI (m / z): 676.0 (M+H)+.Step 4, (J?)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-4-hvdroxy-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)butanamide

[0300] To a stirred solution of (R)-4-((tert-butyldiphenylsilyl)oxy)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(l-methyl-lH-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 rt, and the resultant reaction mixture was stirred for Ih. 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 (7?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-4-hydroxy-N-(4-(l-methyl-lH-pyrazol-3 yl)phenyl)butanamide. LC / MS ESI (m / z): 437.7 (M+H)+. 'H NMR (600 MHz, CD3OD) 58.55 (s, IH), 8.24 (d. IH), 7.77 - 7.72 (m, 3H), 7.64 (d, 2H), 7.58 (d, 2H), 6.60 (s, IH), 5.80 (s, IH), 3.93 (s, 3H), 3.74 (d, IH), 3.64 (s, IH), 2.55 (d, IH), 2.41 (d, IH).26130

[0301] The following compounds were prepared by procedures analogous to the synthesis of Example 116.Ex. No. Name LCMS,1H NMR(A)-2-(7-Chloro-4- LC / MS ESI (m / z): 423.9 (M+H)+. 'H NMR (600 MHz, oxoquinaz.olin-3(4 / 7)- Acetone-^) 89.78 (s, 1H), 8.58 (s, 1H), 8.20 (d, 1H), 117 yl)-3-hydroxy-A-(4-(l- 7.76 (d, 2H), 7.70 (s, 1H), 7.67 (d, 2H), 7.58 (s, 1H), methyl- lEf-pyrazol-5- 7.54 (d, 1H), 6.58 (d, 1H), 5.57 (t, 1H), 4.42 (m, 1H), yl)phenyl)propanamide 4.36 (m, 1H), 3.89 (s, 3H).(A)-2-(7-Chloro-4- oxoquinazolin-3(477)- LC / MS ESI (m / z): 438.8.JH NMR (600 MHz, CD3OD) yl)-A-(4-(3- 8 8.66 (s, 1H), 8.46 (s, 1H), 8.25 (d, 1H), 7.90 (d, 2H), 118fluoropyridin-2- 7.77-7.75 (m, 3H), 7.69 (t, 1H), 7.57 (d, 1H), 7.42 (s, yl)phenyl)-3- 1H), 5.75 (s, 1H), 4.38-4.26 (m, 2H).hy droxy propanamide(A)-2-(7-chloro-4- LC / MS ESI (m / z): 437.7 (M+H)+. 'H NMR (600 MHz, oxoquinazolin-3(477)- CDCh) 89.54 (s, 1H), 8.48 (s, 1H), 8.02 (d, 1H), 7.69- yl)-A-(4-(l,4-dimethyl- 119 7.65 (m. 3H), 7.36 (d, 1H), 7.33 (s, 1H), 7.25 (d, 2H),17f-pyrazol-5- 5.74 (s, 1H), 4.34-4.28 (m, 2H), 3.70 (s, 3H), 1.94 (s, yl)phenyl)-3- 3H).hydroxypropanamideLC / MS ESI (m / z): 451.8 (M+H)+. 'H NMR (600 MHz, (A)-2-(7-Chloro-4- CDCh) 8 8.45 (s, 1H), 7.92 (d, 1H), 7.80 (d, 2H), 7.68 120 oxoquinazolin-3(477)- (d, 2H). 7.39 (s, 1H), 6.88 (d. 1H), 6.68 (s, 1H), 6.53 (s, yl)-4-methoxy-A-(4-(l - 1H), 5.81 (s, 1H), 5.76 (s, 1H), 4.20 (m, 1H), 4.09 (d, methyl- l / f-pyrazol-3- 1H). 3.97 (s, 3H), 3.03 (s. 3H), 2.36 (d. IH), 2.14 (d. yl)phenyl)butanamidew _ _Example 62-1. (7?)-2-(6-Chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l-methyI-lH-pyrazol-5-yl)phenyl)propanamide (62-1)0C'Y\> H Cl OH POCI3, Pyridine Mg(OtBu)2, KO'Bu DCM, 0 °C to rtTHF, 35 °C, 48 h 2 h Step 1. (7?)-2-(6-Chloro-l-oxoisoquinolin-2(lH)-yl)propanoic acid

[0302] To a mixture of Mg(Ot-Bu)2 (28.4 g, 167 mmol) in anhydrous THF (100 mL) was added dropwise fS')-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-l(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 0°C 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 HC1 to adjust to pH 2.0-2.5 and extracted with EtOAc (100 mL x 2).26130The combined organic layers were washed with brine, dried over Na2SO4, fdtered, and concentrated to obtain (?)-2-(6-chloro- l-oxoisoquinolin-2(l H)-yl)propanoic acid.Step 2, (7?)-2-(6-Chloro-l-oxoisoauinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)propenamide

[0303] To a mixture of (J?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)propanoic acid (11.0 g, 43.7 mmol) and 4-(l -methyl- lH-pyrazol-5-yl)aniline (7.50 g, 43.7 mmol) and pyridine (13.8 mL, 175 mmol) in DCM (110 mL) was added POCh (4.80 mL, 52.4 mmol) at 0°C. The reaction mixture was stirred for 12 h at rt. After the completion of the reaction, water (100 mL) was added, and the reaction mixture was extracted into EtOAc (3 x 100 mL), washed with sat. bicarbonate solution (2 x 100 mL), and brine (2 x 100 mL), dried over Na2SO4, fdtered, concentrated, and purified by flash chromatography (75% EtOAc / hexane). The product 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 (7?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(1 -methyl- lH-pyrazol-5-yl) phenyl)propanamide. LC / MS ESI (m / z): 406.8 (M+H)+. 'H NMR (DMSO-de, 400 MHz) 5 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).

[0304] The following compounds were prepared by procedures analogous to the synthesis of Example 62-1.Ex. No. Name LCMS, ' H NMR(7?)-2-(6-Chloro-l- LC / MS ESI (m / z): 406.8.JH NMR (DMSO-de, 600 oxoisoquinolin-2( 17 / )- MHz) 8 10.36 (s, 1H), 8.20 (d, 1H). 7.81 (s, 1H). 7.71- 121 yl)-JV-(4-( 1 -methyl- 17 / - 7.67 (m, 3H), 7.62-7.59 (m, 3H), 7.51 (d, 1H), 6.68 (d, pyrazol-3- 1H). 6.60 (s, 1H), 5.63 (q. 1H), 3.84 (s. 3H), 1.65 (d. yl)phenyl)propanamide 3H).(7?)-2-(6-Chloro-l- LC / MS ESI (m / z): 407.8. 'H NMR (DMSO-de. 600 oxophthalazin-2(177)- MHz) 5 10.14 (s, 1H), 8.46 (s, 1H), 8.25 (d, 1H), 8.1 l(s, 122 yl)-JV-(4-( 1 -methyl- 177- 1H), 7.91 (dd, 1H), 7.69-7.68 (m, 3H), 7.58 (d, 2H), pyrazol-3- 6.60 (d, 1H), 5.57 (q, 1H), 3.84 (s, 3H), 1.63 (d, 3H). vl)phenvl)propanamide(7?)-2-(7 -chloro-4- LC / MS ESI (m / z): 441.0 (M+H)+. 'H NMR (DMSO-de, oxoquinazolin-3(4 / / )- 400 MHz) 5 10.76 (s, 1H), 8.55 (s, 2H), 8.16 (d, 1H), 123 yl)- / V-(3-fluoro-4-(3- 7.87-7.82 (m, 2H), 7.70 (dd, 1H), 7.63-7.52 (m, 3H), fluoropyridin-2- 7.49-7.41 (m, 1H), 5.55 (q, 1H), 1.79 (d, 3H). yl)phenyl)propanamide(7?)-2-(7-chloro-4- LC / MS ESI (m / z): 426.3 (M+H)1. 'H NMR (DMSO-de, oxoquinazolin-3(477)- 400 MHz) 5 10.73 (s, 1H), 8.53 (s, 1H), 8.15 (d, 1H), 124 y l)-N-(3 -fluoro-4-( 1 - 7.81 (s, 2H), 7.72 (d, 1H). 7.61 (d, 1H). 7.49-7.47 (m, methyl- 177-pyrazol-5- 1H), 7.44 (s, 2H), 6.35 (s, 1H), 3.71 (s, 3H), 1.78 (d,vl)phenvl)propanamide 3H).26130Ex. No. Name LCMS, NMR(7?)-N-(3-fluoro-4-(l - LC / MS ESI (m / z): 410.1 (M+H). 'H NMR (DMSO-cL. methyl- 177-pyrazol-5- 400 MHz) 5 10.75 (s, 1H), 8.53 (s, 1H), 8.24-8.20 (m, 125 yl)phenyl)-2-(7-fluoro- 1H). 7.72 (d, 1H). 7.55-7.42 (m, 5H). 6.36 (s. 1H), 5.53 4-oxoquinazolin-3(477)- (q, 1H), 3.71 (s, 3H), 1.78 (d,3H). yl)propanamide(A)-2-(7 -chloro-4- LC / MS ESI (m / z): 422.3 (M+H)+. ’HNMR (DMSO-Je, oxoquinazolin-31477)- 400 MHz) 5 10.56 (s, 1H), 8.54 (s, 1H), 8.15 (d, 1H), 126 y l)- / V-(4-( 1 -ethyl- 1 / 7- 7.82 (d, 1H), 7.71 (d, 2H), 7.61 (dd, 1H), 7.47 (d. 1H), pyrazol- 7.42 (d, 2H), 6.31 (d, 1H), 5.56 (q, 1H), 4.10 (q, 2H), 5yl)phenyl)propanamide 1.78 (d, 3H), 1.28 (t, 3H).(R)-N-(4-( 1 -ethyl- 177- LC / MS ESI (m / z): 406.2 (M+H)+. ’H NMR (DMSO-A pyrazol-5-yl)phenyl)-2- 400 MHz) 5 10.57 (s, 1H), 8.54 (s, 1H), 8.24-8.20 (m, 127 (7-fluoro-4- 1H), 7.71 (d, 2H), 7.54 (dd, 1H), 7.47-7.42 (m, 4H), oxoquinazolin-3(477)- 6.31 (d, 1H), 5.57 (q, 1H), 4.11 (q, 2H), 1.78 (d, 3H), yl)propanamide 1.28 (t, 3H).(7?)-2-(7 -chloro-4- LC / MS ESI (m / z): 422.2 (M+H)+. ’H NMR (DMSO-Je, oxoquinazolin-3(477)- 400 MHz) 5 10.42 (s, 1H), 8.53 (s, 1H), 8.15 (d, 1H), 128 yl)-7V-(4-(l -ethyl- 177- 7.81 (d, 1H), 7.74-7.72 (m, 3H), 7.60 (d, 3H), 6.62 (d, pyrazol-3- 1H), 5.55 (q, 1H), 4.14 (q, 2H), 1.77 (d, 3H), 1.39 (t, yl)phenyl)propanamide 3H).(A)-^-(4-(3- LC / MS ESI (m / z): 414.1 (M+H)+. ’H NMR (DMSO-de, cyanopyridin-2- 400 MHz) 5 10.65 (s, 1H), 8.91 (dd, 1H), 8.55 (s, 1H), 129 y l)pheny l)-2-(7-fluoro- 8.40 (dd, 1H), 8.24-8.21 (m, 1H), 7.87 (d, 2H), 7.78 (d,4-oxoquinazolin-3(477)- 2H), 7.59-7.53 (m, 2H), 7.46-7.41 (m, 1H), 5.58 (q, 1H), vl)propanamide 1.80 (d, 3H).(7?)-2-(7 -chloro-4- LC / MS ESI (m / z): 430.2 (M+H)+. ’H NMR (DMSO-Je, oxoquinazohn-3(477)- 400 MHz) 5 10.64 (s, 1H), 8.90 (s, 1H), 8.79 (d, 1H), 130 yl)- / V-(4-(4- 8.55 (s, 1H), 8.16 (d, 1H), 7.96 (d, 1H), 7.82-7.77 (m, cy anopyri din-3 - 3H). 7.66-7.60 (m, 3H). 5.58 (q, 1H), 1.80 (d, 3H). yl)phenyl)propanamide(7?)-2-(7-chloro-4- LC / MS ESI (m / z): 423.1 (M+H)+. 'HNMR (DMSO-cL. oxoquinazolin-3(477)- 400 MHz) 5 10.57 (s, 1H), 8.73 (d, 1H), 8.59-8.54 (m, 131 yl)-JV-(4-(4- 2H), 8.16 (d, 1H), 7.82 (d, 1H), 7.74 (d, 2H), 7.62-7.58 fluoropyridin-3- (m, 3H), 7.45-7.41 (m, 1H), 5.57 (q, 1H), 1.79 (d, 3H). vl)phenvl)propanamide(7?)-2-(7-fluoro-4- LC / MS ESI (m / z): 406.1 (M+H)+. 'HNMR (DMSO-A oxoquinazolin-3(477)- 400 MHz) 5 10.65 (s, 1H), 8.55 (s, 1H), 8.25-8.21 (m, 132 yl)-JV-(4-( 1 -methyl- 177- 1H), 7.71 (d, 2H), 7.55-7.44 (m, 5H), 6.36 (s, 1H), 5.56- pyrazol-5- 5.52 (m. 1H), 3.83 (s. 3H), 2.32-2.21 (m. 2H), 0.94-0.84 yl)phenyl)butanamide (m, 3H).LC / MS ESI (m / z): 417.6 (M+H)+. ’H NMR (DMSO-A (7?)-2-(7-fluoro-4- 400 MHz) 5 10.97 (s, 1H), 8.73 (d, 1H), 8.56 (s, 1H), oxoquinazolin-3(477)- 8.48 (d, 1H), 8.25-8.22 (m, 1H), 7.92-7.85 (m, 3H), 7.67 133 yl)-7V-(4-(3- (d, 2H), 7.55 (dd, 1H), 7.48 -7.43 (m, 1H), 5.59-5.55 methylpyridin-2- (m, 1H). 2.43 (s, 3H). 2.36-2.25 (m, 1H). 2.24-2.21 (m, yl)phenyl)butanamide1H), 0.93 (t, 3H).26130Ex. No. Name LCMS, NMR(7?)-2-(7 -chi oro-4- LC / MS ESI (m / z): 437.1 (M+H)+. 'H NMR (DMSO-Je, oxoquinazolin-3(477)- 400 MHz) 5 10.59 (s, 1H), 8.54 (s, 1H), 8.15 (d, 1H), 134 yl)-jV-(4-(3-fluoro-6- 7.90 (d, 2H), 7.81 (s, 1H), 7.72 (d, 2H), 7.69-7.64 (m, methylpyridin-2- 1H), 7.60 (d, 1H), 7.26 (d, 1H), 5.58 (q, 1H), 2.50 (s, yl)phenyl)propanamide 3H), 1.79 (d, 3H).(A)-2-(7 -chloro-4- LC / MS ESI (m / z): 420.2 (M+H)+. 'H NMR (DMSO-cL. oxoquinazolin-3(47 / )- 400 MHz) 5 10.58 (s, 1H), 9.04 (d, 1H), 8.55 (s, 1H), 135 yl)-N-(4-(4- 8.16 (d, 1H), 7.82 (d, 1H), 7.74 (d, 2H), 7.62-7.59 (m, methylpyridazin-3- 4H). 4.62-4.59 (m, 1H). 2.33 (s, 3H), 1.80 (d. 3H). yl)phenyl)propanamide(7?)-2-(7-chloro-4- LC / MS ESI (m / z): 422.2 (M+H)+ 1H NMR (DMSO-A oxoquinazolin-3(477)- 400 MHz) 310.64 (s, 1H), 8.56 (s, 1H), 8.17 (d, 1H), 136 yl)- / V-(4-(l-methyl-17 / - 7.82 (d, 1H), 7.71 (d, 2H), 7.61 (dd, 1H), 7.49 (d, 2H), pyrazol-5- 7.44 (d, 1H), 6.36 (d, 1H), 5.55-5.51 (m, 1H), 3.83 (s, yl)phenyl)butan amide 3H), 2.29-2.20 (m, 2H), 0.92 (t, 3H).( / ?)-2-(7 -chloro-4- LC / MS ESI (m / z): 422.2 (M+H)+ 1H NMR (DMSO-cL. oxoquinazolin-3(42 / )- 400 MHz) 310.53 (s, 1H), 8.55 (s, 1H), 8.16 (d, 1H), 137 y l)-N-(4-( 1 -methyl- 177- 7.82 (d, 1H), 7.74-7.69 (m, 3H), 7.62 (d, 3H), 6.62 (d, pyrazol-3- 1H), 5.55-5.51 (m, 1H), 3.85 (s, 3H), 2.32-2.18 (m, 2H), yl)phenyl)butanamide 0.91 (m, 3H)(7?)-jV-(4-(4-cy ano- 1 - LC / MS ESI (m / z): 417.3 (M+H)+. 'H NMR (DMSO-de, methyl- 177-py razol-5- 400 MHz) 5 10.67 (s, 1H), 8.53 (s, 1H), 8.24-8.20 (m, 138 y l)pheny l)-2-(7-fluoro- 1H), 8.12 (s, 1H), 7.81 (d, 2H), 7.59 (d, 2H), 7.53 (dd,4-oxoquinazolin-3(477)- 1H), 7.46-7.41 (m, 1H), 5.56 (q, 1H), 3.83 (s. 3H), 1.79 vl)propanamide (d, 3H).(7?)-2-(7 -chloro-4- LC / MS ESI (m / z): 433.2 (M+H)+. 'HNMR (DMSO-CL. oxoquinazolin-3(477)- 400 MHz) 5 10.51 (s, 1H), 8.55 (s, 1H), 8.16 (d, 1H), 139 yl)-N-(4-(3,6- 7.81 (d, 1H), 7.67 (d, 2H), 7.61 (dd, 1H), 7.56 (d, 1H), dimethylpyridin-2- 7.49 (d, 2H), 7.11 (d, 1H), 5.58 (q, 1H), 2.44 (s, 3H), yl)phenyl)propanamide 2.27 (s, 3H), 1.79 (d, 3H).(7?)-2-(7-chloro-4- LC / MS ESI (m / z): 433.6 (M+H)+. 'H NMR (DMSO-de, oxoquinazolin-3(477)- 400 MHz) 5 10.52 (s, 1H), 8.55 (s, 1H), 8.27 (d, 1H), 140yl)-JV-(4-(2,4- 8.16 (d, 1H), 7.81 (s, 1H). 7.69 (d, 2H). 7.61 (d, 1H).dimethylpyridin-3- 7.17-7.15 (m, 3H), 5.57 (q, 1H), 2.16 (s, 3H), 1.99 (s, vl)phenvl)propanamide 3H). 1.79 (d, 3H).(7?)-N-(4-(l,4-dimethyl- LC / MS ESI (m / z): 406.3 (M+H)+. 'HNMR (DMSO-cL.177-imidazol-5- 400 MHz) 5 10.55 (s, 1H), 8.53 (s, 1H), 8.24-8.20 (m, 141 yl)phenyl)-2-(7-fluoro- 1H), 7.72 (d, 2H), 7.53 (dd, 1H), 7.46-7.42 (m, 1H),4-oxoquinazolin-3(477)- 7.36 (d, 2H), 7.30 (s, 1H). 5.56 (q, 1H). 3.68 (s, 3H). yl)propanamide 1.94 (s, 3H), 1.78 (d, 3H).(A)-N-(4-(3- LC / MS ESI (m / z): 389.3 (M+H)+. 'HNMR (DMSO-cL. methylpyridin-2- 400 MHz) 5 10.52 (s, 1H), 8.46 (d, 1H), 8.33 (s, 1H), vl)phenvl)-2-(4-oxo- 142 7.70-7.66 (m, 3H), 7.52 (d, 2H), 7.28-7.25 (m, 1H), 5.475, 6, 7, 8- (q, 1H), 2.56 (s, 2H), 2.36-2.33 (m, 5H), 1.72-1.65 (m, tetrahydroquinazolin- 7H).3 (477)-y l)propanamide26130Ex. No. Name LCMS, NMR(7?)-2-(7 -chi oro-4- LC / MS ESI (m / z): 433.2 (M+H). 'H NMR (DMSO-A oxoquinazolin-3(4 / / )- 400 MHz) 510.57 (s, 1H), 8.56 (d, 2H), 8.15 (d, 1H), 143 yl)-jV-(4-(4-cyano-l - 7.83-7.80 (m, 3H), 7.73-7.70 (m, 2 H), 7.60 (dd, 1H), methyl- l / / -pyrazol-3- 5.56 (q, 1H), 3.92 (s, 3H), 1.78 (d, 3H). yl)phenyl)propanamide(A)-2-(7 -chloro-4- LC / MS ESI (m / z): 444.2 (M+H)+. ’H NMR (DMSO-Je, oxoquinazohn-31477)- 400 MHz) 510.63 (s, 1H), 8.54 (s, 1H), 8.26 (d, 1H), 144 yl)-7V-(4-(3-cyano-6- 8.16 (d, 1 H), 7.85-7.81 (m, 3H), 7.77-7.75 (m, 2H), methylpyridin-2- 7.60 (dd, 1H), 7.43 (d, 1H), 5.58 (q, 1H), 2.60 (s, 3H), yl)phenyl)propanamide 1.79 (d, 3H).(7?)-2-(7-chloro-4- LC / MS ESI (m / z): 435.2 (M+H)+. 'H NMR (DMSO-A oxoquinazolin-3(4 / / )- 400 MHz) 510.51 (s, 1H), 8.54 (s, 1H), 8.22 (d, 1H), 145 yl)- / V-(4-(3- 8.16 (d, 1H), 7.89 (d, 2H), 7.82 (d, 1H), 7.65 (d, 2H), methoxypyridin-2- 7.60 (dd, 1H), 7.53 (d, 1H), 7.34-7.31 (m, 1H), 5.58 (q, yl)phenyl)propanamide 1H), 3.85 (s, 3H), 1.79 (d, 3H).(7?)-2-(7 -chloro-4- LC / MS ESI (m / z): 408.2 (M+H)+. 'HNMR (DMSO-Je, oxoquinazolin-3(42 / )- 400 MHz) 510.51 (s, 1H), 8.54 (s, 1H), 8.15 (d, 1H), 146 y l)-N-(4-( 1 -methyl- 17 / - 7.82 (d, 1H), 7.69 (d, 1H), 7.70-7.66 (m, 2H), 7.60 (dd, imidazol-5- 1H), 7.45 (d, 2H), 7.02 (s, 1H), 5.56 (q, 1H), 3.66 (s, yl)phenyl)propanamide 3H), 1.78 (d, 3H).(A)-2-(7-chloro-4- LC / MS ESI (m / z): 433.5 (M+H)+. 'H NMR (DMSO-de, oxoquinazolin-3(477)- 400 MHz) 510.62 (s, 1H), 8.57 (s, 1H), 8.46 (d, 1H), 147yl)-7V-(4-(3- 8.17 (d, 1H), 7.82 (d, 1H), 7.69 (d, 3H), 7.61 (dd, 1H), methylpyridin-2- 7.53 (d, 2H), 7.28-7.25 (m, 1H), 5.57-5.53 (m, 1H), 2.33 vl)phenvl)butan amide (s, 3H), 2.30-2.20 (bm, 2H), 0.92 (t, 3H).(7?)-2-(7-fluoro-4- LC / MS ESI (m / z): 392.3 (M+H)+. 'HNMR (DMSO-rfe, oxoquinazolin-3(4 / 7)- 400 MHz) 510.52 (s, 1H), 8.53 (d, 1H), 8.24-8.20 (m, 148 y l)- / V-(4-( 1 -methyl- 1 / 7- 1H), 7.68-7.66 (m, 3H), 7.54 (dd, 1H), 7.46-7.41 (m, imidazol-5- 3H), 7.00 (s, 1H), 5.56 (q, 1H), 3.65 (s, 3H), 1.78 (d, yl)phenyl)propanamide 3H).(2?)-JV-(4-(3- LC / MS ESI (m / z): 379.2 (M+H)+. 'HNMR (DMSO-Je, fluoropyridin-2- 400 MHz) 510.58 (s, 1H), 8.52-8.51 (m, 1H), 8.42 (s, yl)phenyl)-2-(4-oxo- 149 1H), 7.92 (d, 2H), 7.83-7.78 (m, 1H), 7.73 (d, 2H), 7.46- 4,5,6,7-tetrahydro-3Z7- 7.42 (m, 1H), 5.53 (q, 1H), 2.80 (t, 2H), 2.66 (t, 2H), cyclopenta[d]pyrimidin- 2.04-1.97 (m, 2H), 1.72 (d, 3H).3-yl)propanamide(A)-2-(7-chloro-8- LC / MS ESI (m / z): 426.2 (M+H)+. 'H NMR (DMSO-c / . fluoro-4-oxoquinazolin- 400 MHz) 510.56 (s, 1H), 8.61 (s, 1H), 7.97 (d, 1H), 150 3(4 / 7)-yl)-7V-(4-(l- 7.74-7.69 (m, 3H), 7.49 (d, 2H), 7.44 (d, 1H), 6.36 (d, methyl- 1 / 7-py razol-5- 1H), 5.56 (q, 1H), 3.83 (s, 3H),1.79 (d, 3H). vl)phenvl)propanamide(7?)-2-(7 -chloro-4- LC / MS ESI (m / z): 436.2 (M+H)+. 'H NMR (DMSO-c / . oxoquinazolin-3(4 / 7)- 400 MHz) 510.55 (s, 1H), 8.53 (s, 1H), 8.15 (d, 1H), 151 yl)- / V-(4-(l-isopropyl- 7.81 (d, 1H), 7.71 (d, 2H), 7.60 (dd, 1H), 7.49 (d, 1H), l / f-pyrazol-5- 7.37 (d, 2H), 6.25 (d, 1H), 5.56 (q, 1H), 4.52-4.47 (m,yl)phenyl)propanamide 1H), 1.78 (d, 3H), 1.34 (d, 6H).26130Ex. No. Name LCMS, NMR(7?)-2-(7-chloro-4- LC / MS ESI (m / z): 434.2 (M+H)+. 'H NMR (DMSO-Je, oxoquinazolin-3(4E / )- 400 MHz) 5 10.54 (s, 1H), 8.54 (s, 1H), 8.15 (d, 1H), 152 yl)- / V-(4-(l -cyclopropyl- 7.81 (d, 1H), 7.71 (d, 2H), 7.60 (d, 3H), 7.40 (d, 1H),17f-pyrazol-5- 6.37 (d, 1H), 5.56 (q, 1H), 3.72-3.69 (m, 1H), 1.79 (d, yl)phenyl)propanamide 3H), 0.92 (d, 4H).(A)-2-(7 -chloro-4- LC / MS ESI (m / z): 450.3 (M+H)+. 'HNMR (DMSO-Je, oxoquinazolin-3(47 / )- 400 MHz) 5 10.57 (s, 1H), 8.54 (s, 1H), 8.15 (d, 1H), 153 yl)-7V-(4-(4-isopropyl- 1 - 7.82 (d, 1H), 7.72 (d, 2H), 7.61 (dd, 1H), 7.38-7.32 (m, methyl- lLf-pyrazol-5- 3H), 5.56 (q, 1H), 3.61 (s, 3H), 2.70-2.50 (m, 1H), 1.78 yl)phenyl)propanamide (d, 3H), 1.27 (d, 6H).(7?)-2-(7-chloro-4- LC / MS ESI (m / z): 438.5 (M+H)+. 'H NMR (DMSO-A o\oquinazolin-3(4 / 7)- 400 MHz) 5 10.52 (s, 1H), 8.53 (s, 1H), 8.15 (d, 1H), 154 yl)-jV-(4-(4-methoxy-l - 7.81 (d, 1H), 7.69 (d, 2H), 7.60 (dd, 1H), 7.42 (d, 2H), methyl- 1 / / -py razol-5- 7.38 (s, 1H), 5.56 (q, 1H), 3.73 (s, 3H), 3.68 (s, 3H), yl)phenyl)propanamide 1.78 (d, 3H).1,4-dimethy 1- LC / MS ESI (m / z): 378.3 (M+H)+. 'H NMR (DMSO-Je, 127-pyrazol-5- 400 MHz) 5 10.56 (s, 1H), 8.42 (s, 1H), 7.72 (d, 2H), yl)phenyl)-2-(4-oxo- 155 7.35 (d, 2H), 7.30 (s, 1H), 5.51 (q, 1H), 3.68 (s, 3H),4.5.6.7-tetrahydro-3 / 7- 2.80 (t, 2H). 2.68 (t, 2H), 2.04-1.96 (m. 2H), 1.94-1.90 cyclopenta[d]pyrimidin- (m, 3H), 1.71 (d, 3H).3-yl)propanamideExample 26-1. Synthesis of ( / ?)-2-(7-chloro-4-oxoqiiinazolin-3(4H)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide (26-1)B(OHh2. TFA, DCMStep 1. 4-(l-Methyl-lH-pyrazol-5-yl)aniline

[0305] To a mixture of 5-bromo-l -methyl-lH-pyrazole (20.0 g, 124 mmol) in dioxane (200 mL) and water (20 mL) was added (4-aminophenyl) boronic acid hydrochloride (28.0 g, 16126130mmol) and potassium carbonate (42.9 g, 311 mmol) at rt. The mixture was degassed before addition of Pd(dppf)C12'CH2C12 (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 rt, 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-(l-methyl-lH-pyrazol-5-yl)aniline.Step 2, (R)-tert-Butyl (l-((4-(l-methyl-lH-pyrazol-5-yl)phenyl)amino)-l-oxopropan-2- yllcarbamate

[0306] A mixture of 4-(l-methyl-lH-pyrazol-5-yl)aniline (8.0 g, 46 mmol), (?)-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 EtOAc (3 * 150 mL), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to obtain (A)-tert-butyl (l-((4-(l-methyl-lH-pyrazol-5-yl)phenyl)amino)-l-oxopropan-2-yl)carbamate. The crude material was used in the next step without further purification.Step 3. (7?)-2-Amino-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propenamide

[0307] To a stirred solution of (7?)-tert-butyl (l-((4-(l-methyl-lH-pyrazol-5-yl)phenyl)amino)- 1-oxopropan-2-yl)carbamate (13.0 g, 37.8 mmol) in CH2CI2 (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), and extracted with CH2CI2 (2 x 50 mL). The organic layer was separated to remove the unreacted starting material. The aqueous layer was basified with sat. NaHCCL solution 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 (7?)-2-amino-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide.Step 4, (D-Methyl 4-chloro-2-(((dimethylamino)methylene)amino)benzoate

[0308] 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 (A)-methyl 4-chloro- 2-(((dimethylamino)methylene)amino)benzoate. The crude material was used in the next step without further purification.26130Step 5, (7?)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)propenamide

[0309] A solution of (7?)-2-amino-N-(4-(l-methyl-lH-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 rnL) was stirred at 100°C for 3 h. After the completion of reaction, the reaction mixture w as cooled to rt, and w ater (250 mL) was added to precipitate the crude product. The crude material was purified by silica gel flash chromatography (90% EtOAc / hexane). The isolated material was diluted with methanol (60 vol) and heated at 70°C for 1 h. The reaction mixture w as cooled to rt and filtered. The filtrate was concentrated to afford (R)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)propanamide. LC / MS ESI (m / z): 408.2 (M+H)+. 'H NMR (DMSO-tie, 400 MHz) 5 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).

[0310] The following compounds were prepared by procedures similar to the synthesis of Example 26-1 using the corresponding aryl halides and aniline / amines.Ex. No. Name LCMS, ‘H NMR(7?)-2-(7-Chloro-4- LC / MS ESI (m / z): 407.6. ‘H NMR (DMSO-dfc, 600 oxoquinazolin-3(4 / 7)- MHz) 5 10.43 (s, 1H), 8.52 (s, 1H), 8.13 (d, 1H), 7.80 156 yl)-A-(4-(l -methyl- 177- (d, 1H), 7.72-7.68 (m, 3H), 7.60-7.58 (m, 3H), 6.61 (d, pyrazol-3- 1H). 5.58 (q, 1H), 3.84 (s. 3H), 1.76 (d. 3H). yl)phenyl)propanamide(7?)-2-(7-Chloro-4- LC / MS ESI (m / z): 436.8. ‘H NMR (CDCh, 600 MHz) d oxoquinazolin-3(477)- 9.56 (broad s, 1H), 8.62 (m, 1H), 8.39 (s, 1H), 8.18 (d, 157 yl)- / V-(3-fluoro-4-(3- 1H), 7.73 (s, 1H), 7.62 (d, 1H), 7.45-7.44 (m, 2H), 7.25- methylpyridin-2- 7.27 (m, 2H), 7.18 (s, 1H), 5.76 (d, 1H), 2.20 (s, 3H), vl)phenvl)propanamide 1.80 (d, 3H).(7?)-A-(4-(l-methyl-177- LC / MS ESI (m / z): 378.2 (M+H)+; ’HNMR (DMSO-cL. pyrazol-5-yl)phenyl)-2- 400 MHz) 5 10.56 (s, 1H), 8.33 (s, 1H), 7.70 (d, 2H), 158 (4-oxo-5, 6,7,8- 7.50-7.44 (m, 3H), 6.36 (s, 1H), 5.45 (q, 1H), 3.83 (s, tetrahydroquinazolin- 3H). 2.55-2.50 (m, 2H). 2.35 (bs. 2H), 1.71-1.67 (m. 3 (477)-y l)propanamide 7H).(7?)-A-(4-(3- LC / MS ESI (m / z): 393.3 (M+H)+; ‘HNMR (DMSO- fluoropyridin-2- <7<5,400 MHz) 5 10.59 (s, 1H), 8.52 (d, 1H), 8.33 (s, 1H), vl)phenvl)-2-(4-oxo- 159 7.92 (d, 2H), 7.83-7.78 (m, 1H), 7.73 (d, 2H), 7.46-7.425, 6, 7, 8-’(m, 1H), 5.47 (q, 1H), 2.56 (bs, 2H), 2.35 (s, 2H), 1.72- tetrahydroquinazolin- 1.67 (m, 7H).3(477)-yl)propanamide26130Ex. No. Name LCMS, ’H NMR( / ?)-7V-(4-( 1,4-dimethyl- l / f-pyrazol-5- LC / MS ESI (m / z): 392.6 (M+H)+; 'HNMR (CD3OD, yl)phenyl)-2-(4-oxo- 400 MHz) 58.36 (s, 1H), 7.73 (d, 2H), 7.34-7.32 (m, 1605, 6,7,8- 3H), 5.53 (q, 1H), 3.66 (s, 3H), 2.67-2.64 (m, 2H), 2.50- tetrahydroquinazolin- 2.47(m, 2H), 1.99 (s, 3H), 1.83-1.79 (m, 7H). 3(477)-yl)propanamide(7?)-2-(6,7 -difluoro-4- LC / MS ESI (m / z): 424.7 (M+H)+; ’HNMR (DMSO-tfc, oxoquinazolin-3(477)- 400 MHz) 5 10.56 (s, 1H), 8.54 (s, 1H), 8.10-8.06 (m, 161 yl)- / V-(4-(l,4-dimethyl- 1H), 7.87-7.82 (m, 1H), 7.72 (d, 2H), 7.36 (d, 2H), 7.30 l / / -pyrazol-5- (s, 1H), 5.56 (q, 1H), 3.68 (s, 3H), 1.94 (s, 3H), 1.79 (d, yl)phenyl)propanamide 3H).LC / MS ESI (m / z): 447.4 (M+H)+; ’HNMR (DMSO-ck (7?)-2-(7-chloro-4- 400 MHz) 5 10.63 (s, 1H), 8.58 (s, 1H), 8.46 (d, 1H), oxoquinazolin-3(427)- 8.17 (d, 1H), 7.82 (d, 1H), 7.70-7.68 (m, 3H), 7.61 (dd, 162 yl)-JV-(4-(3- 1H), 7.53 (d, 2H), 7.28-7.25 (m, 1H), 5.68-5.64 (d, 1H), methylpyridin-2- 2.33 (s, 3H), 2.24-2.20 (m, 2H), 1.32-1.23 (m, 2H), yl)phenyl)pentanamide0.95-0.85 (m, 3H).(7?)-2-(8-fluoro-4- LC / MS ESI (m / z): 392.3 (M+H)+; ’HNMR (DMSO-cL. oxoquinazolin-3(4 / 7)- 400 MHz) 5 10.56 (s, 1H), 8.53 (s, 1H), 8.24-8.20 (m, 163 y l)- / V-(4-( 1 -methyl- 177- 1H), 7.71 (d, 2H), 7.54 (dd, 1H), 7.49 (d, 2H), 7.46-7.41 pyrazol-5- (m, 2H), 6.36 (d, 1H), 5.56 (d, 1H), 3.83 (s, 3H), 1.78 (d, yl)phenyl)propanamide 3H).(A)-2-(8-chloro-4- LC / MS ESI (m / z): 408.2 (M+H)+; ’H NMR (DMSO-ds, oxoquinazolin-3(477)- 400 MHz) 5 10.54 (s, 1H), 8.61 (s, 1H), 8.12 (dd. 1H), 164 yl)-JV-(4-(l-methyl-177- 8.02 (dd, 1H). 7.71 (d, 2H). 7.56-7.52 (m, 1H). 7.49 (d, pyrazol-5- 2H), 7.44 (d, 1H), 6.36 (d, 1H), 5.55 (q, 1H), 3.83 (s, vl)phenvl)propanamide 3H). 1.79 (d, 3H).(7?)-2-(7,8-difluoro-4- LC / MS ESI (m / z): 410.2 (M+H)+; ’HNMR (DMSO-A oxoquinazolin-3(4 / / )- 400 MHz) 5 10.54 (s, 1H), 8.60 (s, 1H), 8.03-7.99 (m, 165 y l)- / V-(4-( 1 -methyl- 177- 1H), 7.70 (d, 2H), 7.69-7.60 (m, 1H), 7.49 (d, 2H), 6.36 pyrazol-5- (d, 1H), 5.56 (q, 1H), 6.70 (d. 1H), 3.83 (s. 3H), 1.79 (d, yl)phenyl)propanamide 3H).224 (R)-2-(7-chloro-4- LC / MS ESI (m / z): 426 (M+H)+. 1H NMR (600 MHz.oxoquinazolin-3(4H)- CDC13) 59.03 (br. s, 1H), 8.35 (s, 1H), 8.23 (d, 1H), yl)-N-(3-fluoro-4-(l- 7.78 (s, 1H), 7.65 (d, 1H). 7.54-7.50 (m, 2H). 7.25-7.24 methyl-lH-pyrazol-3- (m, 2H), 6.28 (s, 1H), 5.72 (q, 1H), 3.77 (s, 3H), 1.88 (d,vl)phenvl)propanamide 3H).Example 166. Synthesis of (l?)-2-(5-chloro-l-oxoisoindolin-2-yl)-N-(4-(3-methylpyridin-2-yl) phenyl)propanamide (166)26130Step 1. 4-(3-Methylpyridin-2-yl)anihne

[0311] 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)C12 CH2CI2 (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 rt, filtered through diatomaceous earth (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.Step 2, (7?)-tert-Butyl (l-((4-(3-methylpyridin-2-yl) phenyl) amino)-! -oxopropan-2-yl)carbamate

[0312] 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 rt under N2 atmosphere. After the completion of the reaction, water (25 mL) was added, and the reaction mixture was extracted into EtOAc (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 ( / )-tert-butyl (l-((4-(3-methylpyridin-2-yl)phenyl)amino)-l-oxopropan-2-yl)carbamate.Step 3, ( / ?)-2-Arnino-N-(4-(3-methylpyridin-2-yl)phenyl)propenamide

[0313] A mixture of (A)-tert-butyl (l-((4-(3-methylpyridin-2-yl)phenyl)amino)-l-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 rt under N2 atmosphere, the reaction mixture was concentrated, diluted with water (20 mL), and extracted wi th EtOAc (2 x 10 mL) to remove the unreacted starting material. The aqueous phase was basified with sat.26130NaHCCh 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 Na2SOr, filtered, and concentrated to obtain (J?)-2-amino-N-(4-(3-methylpyridin-2-yl) phenyl)propanamide.Step 4, (7?)-2-(5-Chloro-l-oxoisoindolin-2-yl)-N-(4-(3-methylpyridin-2-yl) phenyl)propenamide

[0314] A mixture of (A)-2-amino-N-(4-(3-methylpyri din-2 -yl) phenyl)propanamide (70 mg, 0.27 mmol), methyl 2-(bromomethyl)-4-chlorobenzoate (72 mg, 0.27 mmol) and tri ethyl 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 rt. The resultant mixture was concentrated and purified by flash chromatography (50% EtOAc / hexane) to obtain (7?)-2-(5-chloro- l-oxoisoindolin-2-yl)-N-(4-(3-methylpyridin-2-yl) phenyl)propanamide. LC / MS ESI (m / z): 406.0 (M+H)+. 'H NMR (DMSO-tid, 400 MHz) 5 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).

[0315] The following compounds were prepared by a procedure analogous to the synthesis of Example 166 using the corresponding aryl halides.Ex. No. Name LCMS,1H NMR(A)-2-(6-chloro-l- LC / MS ESI (m / z): 395.1 (M+H)+; *HNMR (DMSO-cL. oxoisoindolin-2-yl)-A- 400 MHz) 5 10.27 (s, 1H), 7.72-7.69 (m, 6H), 7.61 (d, 167 (4-( 1 -methyl- \H- 2H), 6.62 (d, 1H), 5.01-4.98 (m, 1H), 4.78-4.60 (m, 2H), pyrazol-3- 3.85 (s, 3H), 1.56 (d, 3H).yl)phenyl)propanamide(7?)-2-(6-chloro-l- LC / MS ESI (m / z): 395.0 (M+H)+; 'H NMR (DMSO-cL. oxoisomdolm-2-yl)- / V- 400 MHz) 5 10.41 (s, 1H), 7.73-7.69 (m, 5H), 7.48 (d, 168 (4-( 1 -methyl- 177- 2H). 7.44 (d, 1H). 6.36 (d, 1H). 5.03-5.01 (m, 1H). 4.78- pyrazol-5- 4.61 (m, 2H), 3.83 (s, 3H), 1.57 (d, 3H).yl)phenyl)propanamideExample 169. Synthesis of (l?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(l,4-dimethyl-lH-pyrazol-5-yl) phenyl)propanamide (169)Step 1. (7?)-2-(7-Chloro-4-oxociuinazolin-3(4H)-yl)propanoic acid

[0316] 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-261304(3H)-one (10 g, 55 mmol) and additional THF (30 rnL). The reaction mixture was allowed to stir at 35°C for 36 h. After the completion of reaction, the mixture was cooled to 0°C, 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 HC1 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 (7?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid.Step 2, (7?)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(1.4-dimethyl-lH-pyrazol-5-yl) phenyDpropenamide

[0317] A mixture of (7?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)propanoic acid (200 mg, 1.06 mmol), 4-(l,4-dimethyl-lH-pyrazol-5-yl)aniline (274 mg, 1.06 mmol) andHATU (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 rt under N2 atmosphere. After the completion of the reaction, water (10 mL) was added, and the mixture was extracted into EtOAc (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 ( )-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(l,4-dimethyl-lH-pyrazol-5-yl)phenyl)propanamide. LC / MS ESI (m / z): 421.8 (M+H)+. ’H XMR (DMSO-tfc, 400 MHz) 5 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).

[0318] The following compounds were prepared using a procedure similar to the synthesis of Example 169 using the corresponding aryl halides.Ex. No. Name LCMS,1H NMRLC / MS ESI (m / z): 423.3 (M+H)+. 'H NMR (J?)-2-(7-chloro-4- (DMSO-cL. 400 Mhz) 5 10.59 (s, 1H), 8.54-8.51 oxoquinazolin-3(4 / / )-yl)-2V-(4- 170 (m, 2 H), 8.16 (d. 1 H). 7.92 (d, 2H), 7.83-7.81 (3 -fluoropy ridin-2- (m, 2H), 7.74 (d, 2H), 7.61 (dd, 1H), 7.46-7.42 yl)phenyl)propanamide(m, 1H), 5.59-5.57 (m, 1H). 1.79 (d, 3H).LC / MS ESI (m / z): 392.2 (M+H)+. ’H NMR (7?)-2-(7-fluoro-4- (DMSO-rfc. 400 MHz) 5 10.42 (s, 1H). 8.52 (s, oxoquinazolin-3(477)-yl)- / V-(4- 171 1H), 8.22 (t, 1 H), 7.74-7.69 (m, 3H), 7.61-7.59 (l-methyl-17f-pyrazol-3- (m, 2H), 7.53 (d, 1H), 7.43 (t, 1H), 6.62 (s. yl)phenyl)propanamide1H), 5.58-5.56 (m, 1H), 3.85 (s, 3H), 1.77 (d, 3H). LC / MS ESI (m / z): 408.0 (M+H)+. 'H NMR (J?)-2-(7-chloro-4- (DMSO-A 400 MHz) 5 10.27 (s, 1H), 8.48 (s, oxoquinazolin-3(4 / 7)-yl)- / V-(4- 172 1H), 8.27 (d, 1H). 8.13 (d, 1H). 7.92 (dd. 1H), (l-methyl-lH-pyrazol-5- 7.69 (d, 2H), 7.47 -7.43 (m, 3H), 6.35 (d, 1H), yljphenyl) propanamide5.60 -5.55 (m, 1H). 3.83 (s, 3H), 1.65 (d, 3H).26130Ex. No. Name LCMS, NMRLC / MS ESI (m / z): 410.1 (M+H)+.1HNMR (7?)-2-(6,7-difluoro-4- (DMSO-rfe, 400 MHz) 5 10.44 (s, IH). 8.53 (s, oxoquinazolin-3(4EZ)-yl)-jV-(4- 173 IH), 8.08 (t, IH), 7.87-7.82 (m, IH), 7.72 (t, 3H),(1 -methyl- IH -pyrazol-3- 7.61 -7.59 (m, 2H), 6.63 (s, IH), 5.57-5.55 (m, yl)phenyl)propanamideIH), 3.86 (s, 3H), 1.78 (d, 3H).LC / MS ESI (m / z): 422.0 (M+H)+. ’H NMR (7?)-2-(7-chloro-4- (DMSO-A 400 MHz) 8 10.55 (s, IH), 8.54 (s, oxoquinazolin-3(4J7)-yl)- / V-(4- 174 IH), 8.15 (d, IH), 7.81 (s, IH), 7.69 (d, 2H), 7.61( 1,3 -dimethyl- 1 H-py razol-5- (d, IH), 7.45 (d, 2 H), 6.13 (s, IH), 5.58- 5.53 (m, yl)phenyl)propanamideIH), 3.73 (s, 3H), 2.14 (s, 3H), 1.78 (d, 3H). LC / MS ESI (m / z): 419.2 (M+H)+. ’H NMR (7?)-2-(7-chloro-4- (DMSO-dc, 400 MHz) 8 10.52 (s, IH). 8.55 (s, oxoquinazolin-3(4 / 7)-yl)- / V-(4- IH), 8.46 (d, IH), 8.16 (d, IH), 7.82 (d, IH), 7.70- 175(3-methylpyridin-2- 7.67 (m, 3H), 7.61 (dd, 1 H), 7.54-7.52 (m, 2H), yl)phenyl)propanamide 7.28-7.25 (m, IH), 5.60-5.55 (m, IH), 2.33 (s,3H), 1.79 (d, 3H).LC / MS ESI (m / z): 419.9 (M+H)+? H NMR (7?)-2-(7-chloro-4- (DMSO-A 400 MHz) 8 10.61 (s, IH), 9.05 (s, oxoquinazolin-3(4 / 7)-yl)- / V-(4- 176 IH), 8.39 (s, IH), 8.54 (s, IH), 8.15 (d, IH), 7.82(5-methyl- (d, IH), 7.75 -7.69 (m, 4H), 7.61 (dd, IH), 5.60 - pyrimidinyphenyl)propanamide5.54 (m, IH), 2.37 (s, 3H), 1.79 (d, 3H).LC / MS ESI (m / z): 392.1 (M+H)+. *HNMR (7?)-2-(7-fluoro-4- (DMSO-tL. 400 MHz) 8 10.56 (s, IH), 8.53 (s, oxoquinazolin-3(4J7)-yl)- / V-(4- 177 IH), 8.24-8.20 (m, IH), 7.72-7.65 (m, 2H), 7.55- (1-methyl-lH -pyrazol-5- 7.42 (m, 5H). 6.36 (s. IH), 5.59-5.54 (m. IH), yl)phenyl)propanamide3.83 (s, 3H), 1.78 (d, 3H).LC / MS ESI (m / z): 420.0 (M+H)+. 'H NMR (7?)-2-(7-chloro-4- (DMSO-A 400 MHz) 810.61 (s, IH), 8.70 (d, oxoquinazolin-3(4 / 7)-yl)- / V-(4- 178 IH), 8.54 (s, IH), 8.35 (d, 2 H), 8.15 (d, IH), 7.82(4-methylpyrimidin-2- (d, IH), 7.51 (d, 2 H), 7.61 (dd, IH), 7.27 (d, yl)phenyl)propanamide1H),5.57 (q, 1 H). 2.52 (s, 3H). 1.79 (d, 3H). LC / MS ESI (m / z): 408.1 (M+H)+. *HNMR (7?)-2-(7-chloro-4- (DMSO-cL. 400 MHz) 8 10.54 (s, IH). 8.54 (s, oxoquinazolin-3(4J7)-yl)- / V-(4- 179 IH), 8.15 (d, 1 H), 7.81 (d, 1 H), 7.70-7.59 (m, (l-methyl-17f -imidazol-2- 5H), 7.22 (s, 1 H), 6.95 (s, 1 H), 5.56 (q, 1H),3.72 yl)phenyl)propanamide(s, 3 H), 1.78 (d, 3H).LC / MS ESI (m / z): 409.0 (M+H)+. 'H NMR (7?)-2-(7-chloro-4- (DMSO-A 400 MHz) 810.62 (s, IH), 8.53 (s, oxoquinazolin-3(4 / 7)-yl)- / V-(4- 180 IH), 8.15 (d, 1 H), 7.91-7.81 (m. 4H), 7.73 (d.(4-methyloxazol-2- 2H), 7.60 (dd, IH), 5.55 (q, 1 H), 2.14 (s, 3H), yl)phenyl)propanamide1.78 (d. 3H).LC / MS ESI (m / z): 410.0 (M+H)+. *HNMR (7?)-2-(6,7-difluoro-4- (DMSO-rfe. 400 MHz) 8 10.56 (s, IH). 8.54 (s, oxoqumazolin-3(47 / )-yl)- / V-(4- 181 IH), 8.08 (t, IH), 7.86-7.82 (m, IH), 7.71-7.64 (l-methyl-17f -pyrazol-5- (m, 2H), 7.50-7.44 (m, 3H), 6.36 (s, 1 H), 5.57- yl)phenyl)propanamide5.55 (m, IH), 3.83 (s, 3H), 1.78 (d, 3H).26130Ex. No. Name LCMS, NMRLC / MS ESI (m / z): 410.0 (M+H)+. ’H NMR (J?)-2-(5-chloro- 1 - (DMSO-i / e, 400 MHz) 8 10.43 (s, 1H). 8.52-8.51 oxoisoindolin-2-yl)-jV-(4-(3- (m, 1H), 7.92-7.90 (m, 2H), 7.83-7.71 (m, 5H), 182fluoropyridin-2- 7.57 (dd, 1H), 7.46-7.41 (m, 1H). 5.03 (q, yl)phenyl)propanamide 1H), 4.79-4.75 (m, 1H), 4.66-4.62 (m, 1H), 1.57 (d, 3H).LC / MS ESI (m / z): 430.3 (M+H)+. ’H NMR (J?)-2-(7-chloro-4- (DMSO-i / e, 400 MHz) 8 10.63 (s, 1H), 8.90 (dd, oxoquinazolin-3(477)-yl)-A-(4- 183 1H), 8.55 (s, 1H), 8.40 (dd, 1H), 8.16 (d, 1H), (3-cyanopyridin-2- 7.87 (d, 2H), 7.81 (d, 1H), 7.77 (d, 2H), 7.62-7.55 yl)phenyl)propanamide(m, 2H), 5.58(q, 1H), 1.80 (d, 3H).LC / MS ESI (m / z): 407.1 (M+H)+. *HNMR (J?)-2-(7-fluoro-4- (DMSO-A 400 MHz) 8 10.59 (s, 1H), 8.54-8.51 oxoquinazolin-3(477)-yl)-Ar-(4- 184 (m, 2H), 8.24-8.20 (m, 1H), 7.92 (d, 2H), 7.83- (3-fluoropyridin-2- 7.80 (m, 1H), 7.75 (d, 2H), 7.54 (dd, 1H),7.46- yl)phenyl)propanamide7.41 (m, 2H), 5.58 (q. 1H), 1.79 (d, 3H).LC / MS ESI (m / z): 409.3 (M+H)+. 'H NMR (7?)-2-(5-chloro- 1 - (DMSO-A 400 MHz) 8 10.39 (s, 1H), 7.77 (s, oxoisoindolin-2-yl)- / V-(4-( 1,4- 1H), 7.74-7.71 (m, 3H), 7.56 (dd, 1H), 7.34 (d, 185dimethyl- 17 / -pyrazol-5- 2H), 7.30 (s, 1H), 5.02 (q, 1H), 4.79-4.74 (m, 1H), yl)phenyl)propanamide 4.66-4.61 (m, 1H), 3.67 (s, 3H), 1.94 (s, 3H), 1.56(d, 3H).LC / MS ESI (m / z): 424.2 (M+H)+. 'H NMR (J?)-2-(7-chloro-4- (DMSO-A 400 MHz) 810.70 (s, 1H), 9.08 (d, oxoquinazolin-3(4 / / )-yl)-jV-(4- 186 1H), 8.92 (d, 1H). 8.54 (s, 1H). 8.16-8.09 (m, 3H).(5-fluoropyrimidin-4- 7.82-7.80 (m, 3H), 7.60 (dd, 1H), 5.58-5.54 (m, yl)phenyl)propanamide1H), 1.79 (d, 3H).LC / MS ESI (m / z): 389.3 (M+H)+. ’H NMR ( / ?)-Af-(4-(3-lluoropyridm-2- (DMSO-rfc, 400 MHz) 8 10.59 (s, 1H), 8.52 (d, 187 yl)phenyl)-2-(4-oxoquinazolin- 1H), 8.49 (s, 1H), 8.16 (d, 1H), 7.92 (d, 2 H),3 (4 / 7)-y 1 Ipropanami de 7.89-7.78 (m, 2H), 7.76-7.72 (m. 3H), 7.57 (t,lH).7.46-7.42 (m, 1H), 5.56 (q, 1H), 1.79 (d, 3H).Example 198. Synthesis of ( / ?)-2-(7-chloio-4-oxoquinazolin-3(4H)-yl)-N-(4-(3-hydroxypyridin-2-yl) phenyl)piopanamide (198)

[0319] A mixture (7?)-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 IM boron tribromide in DCM (0.45 mL, 045 mmol) and stirred overnight at rt under N2. After the reaction was complete, it was cooled to 0°C, quenched into sat. NaHCCh (25 mL) and extracted into 10% MeOH / DCM (3 x 30 mL). The organic layers were dried over NazSCL, filtered, concentrated,26130and subjected to flash chromatography (2% MeOH / DCM) to obtain (7?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(3-hydroxypyridin-2-yl)phenyl)propanamide. LC / MS ESI (m / z): 421.3 (M+H)+. 'H NMR (DMSO-cL. 400 MHz) 5 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 (7?)-2-(7-chloro-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazoI-3-yl) phenyljpropanamide (199)Step 1. CM-2-Chloro-N-(4-(l-methyl-lH-pyrazol-3-yl) phenyl)propenamide

[0320] A mixture of 4-(l-methyl-lH-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 rt under N2. After the completion of the reaction, water (25 mL) was added, and the reaction mixture was extracted into EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated to obtain the (S)-2-chloro-N-(4-(l-methyl-lH-pyrazol-3-yl) phenyljpropenamide, which was used directly in the next step.Step 2. (7?)-2-(7-Chloro-l-oxo-3.4-dihvdroisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH- pyrazol-3-yl) phenvDpropenamide

[0321] A mixture of (S)-2-chloro-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)propanamide (150 mg, 0.56 mmol). 6-chloro-3.4-dihydroisoquinolin-l(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 N2. 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 (7?)-2-(7-chloro-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)-N-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)propanamide. LC / MS ESI (m / z): 409.1 (M+H)+. *HNMR (DMSO-cL. 400 MHz) 5 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).26130Example 22-1. Alternative synthesis of ( / ?)-2-(3-chloro-8-oxo-l,7-naphthyridin-7(8H)-yl)-N-(4-(3-fluoropyridin-2-yl)phenyl)propanamide (22)

[0322] To a mixture of 4-(3-fluoropyridin-2-yl)aniline (75 mg, 0.4 mmol) and (7?)-2-(3-chloro-8-oxo-l,7-naphthyridin-7(8H)-yl)propanoic acid (100 mg, 0.4 mmol) in DCM (20 mL) at -20°C were added pyridine (0.2 mL, 2.4 mmol) and POCh (370 mg, 2.4 mmol) dropwise. After being stirred at -20°C for 1 h, the reaction was quenched with 2 N HC1 (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 (7?)-2-(3-chloro-8-oxo-l,7-naphthyridin-7(8H)-yl)-N-(4-(3-fluoropyridin-2-yl)phenyl)propanamide. LC / MS ESI (m / z): 423 (M+H)+.!H NMR (400 MHz, DMSO-cfc) 5 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).

[0323] The following compounds were prepared by a procedure similar to the synthesis of Example 22-1 using the corresponding acids and anilines.Ex. No. Name LCMS, ' H NMRLC / MS ESI (m / z): 424 (M+H)+. 'H NMR (400 MHz, (7?)-2-(7-chloro-4- DMSO-<7g) 5 10.61 (s. 1H), 8.86 (d. J= 2.2 Hz. 1H), oxopyrido[3,2- 8.63 (s, 1H), 8.56-8.48 (m, 1H), 8.37 (d, J= 2.3 Hz, 200 d]pyrimidin-3(477)-yl)- 1H). 7.96-7.90 (m, 2H). 7.81 (ddd, J= 11.9, 8.3, 1.2 Hz, JV-(4-(3 -fluoropyridin-2- 1H), 7.75 (d, J= 8.8 Hz, 2H), 7.48-7.41 (m, 1H), 5.62 yl)phenyl)propanamide(q. J = 7.3 Hz. 1H), 1.81 (d. J = 7.4 Hz. 3H).LC / MS ESI (m / z): 443 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chloro-l- DMSO-i*) 5 10.77 (s. 1H), 8.22 (d. J= 8.6 Hz. 1H), oxoisoquinolin-2(177)- 7.85 (d, J= 2.0 Hz, 1H), 7.78 (d, J= 12.9 Hz, 1H), 7.64 yl)- / V-(3-fluoro-4-(4- 201 (d. J = 7.6 Hz. 1H), 7.60 (d. J = 4.5 Hz. 1H), 7.54 (dd, J fluoro- 1 -methyl- 1H- = 8.6, 2.0 Hz, 1H), 7.52-7.47 (m, 2H), 6.72 (d, J= 7.6 pyrazol-5- Hz, 1H), 5.60 (q, J= 7.2 Hz, 1H), 3.69 (s, 3H), 1.69 (d, yl)phenyl)propanamide.7= 7.3 Hz, 3H).LC / MS ESI (m / z): 425 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chl oro-1 - DMSO-cfc) 8 10.44 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), oxoisoquinolin-2( 177)- 7.92 (d, J= 4.6 Hz, 1H), 7.83 (d, J= 2.0 Hz, 1H), 7.71- 202 yl)-JV-(4-(4-fluoro-l- 7.61 (m, 5H), 7.53 (dd, J= 8.6, 2.1 Hz, 1H), 6.69 (d, J= methyl- 177-pyrazol-3- 7.6 Hz, 1H). 5.64 (q, J= 7.3 Hz, 1H). 3.81 (s, 3H), 1.67 yl)phenyl)propanamide(d, J = 7.3 Hz, 3H).26130Ex. No. Name LCMS, NMR225 (7?)-2-(3-chloro-8-oxo- LC / MS ESI (m / z): 426 (M+H)+. 'H NMR (400 MHz,1, 7-naphthy ri din-7 (8 / / )- DMSO-C / G) 5 10.59 (s. 1H), 8.78 (d, J= 2.2 Hz, 1H), y l)-jV-(4-(4-fluoro- 1 - 8.38 (d, J= 2.4 Hz, 1H), 7.79-7.73 (m, 3H), 7.56 (d, J = methyl- 177-py razol-5- 4.5 Hz, 1H), 7.49-7.46 (m, 2H). 6.69 (d, J= 7.6 Hz, 1H), yl)phenyl)propanamide 5.67 (q, J= 7.3 Hz, 1H), 3.77 (s, 3H), 1.69 (d, J= 7.3 Hz, 3H).226 (7?)-2-(3-chloro-8-oxo- LC / MS ESI (m / z): 444 (M+H)+. 'H NMR (400 MHz,1, 7-naphthy ri din-7 (877)- DMSO-rie) 6 10.79 (s, 1H), 8.79 (d, J= 2.3 Hz, 1H), y l)-7V-(3 -fluoro-4-(4- 8.39 (d, J= 2.3 Hz, 1H), 7.80-7.72 (m, 2H), 7.60 (d, J = fluoro- 1 -methyl- 177- 4.5 Hz, 1H), 7.54-7.46 (m, 2H). 6.70 (d, J= 7.6 Hz, 1H), pyrazol-5- 5.64 (q, J= 7.1 Hz, 1H), 3.69 (s, 3H), 1.70 (d, J= 7.3 yl)phenyl)propanamide Hz, 3H).227 (7?)-2-(3-chloro-8-oxo- LC / MS ESI (m / z): 408 (M+H)+. ’H NMR (400 MHz,1, 7 -naphthy ri din-7 (877)- DMSO-c / c) 6 10.54 (s, 1H), 8.78 (d, J= 2.4 Hz, 1H), yl)- / V-(4-(l-methyl-177- 8.37 (d, J = 2.4 Hz, 1H), 7.75-7.69 (m, 3H), 7.50-7.46 pyrazol-5- (m, 2H), 7.43 (d, J = 1.9 Hz, 1H), 6.68 (d, J= 7.6 Hz, yl)phenyl)propanamide 1H), 6.36 (d, J= 1.9 Hz, 1H), 5.67 (q, J= 7.2 Hz, 1H),3.83 (s, 3H), 1.69 (d, J= 7.3 Hz, 3H).228 (7?)-2-(3-chloro-8-oxo- LC / MS ESI (m / z): 426 (M+H)+. 'H NMR (400 MHz,1, 7-naphthy ri din-7 (8H)- CD3OD) 6 8.74 (d, J= 2.3 Hz, 1H), 8.23 (d, J= 2.3 Hz, y l)-7V-(3 -fluoro-4-( 1 - 1H), 7.77-7.68 (m, 2H), 7.51 (d, J= 2.0 Hz, 1H), 7.43 methyl- 177-py razol-5- (dd, J = 8.5, 2.0 Hz, 1H), 7.36 (t, 8.2 Hz, 1H), 6.74 yl)phenyl)propanamide (d, J = 7.6 Hz. 1H), 6.35 (d. J = 1.9 Hz. 1H), 5.74 (q, J =7.3 Hz, 1H), 3.75 (d,.7= 1.2 Hz, 3H), 1.78 (d, J= 7.3 Hz, 3H).229 (7?)-2-(3-chloro-8-oxo- LC / MS ESI (m / z): 426 (M+H)+. *HNMR (400 MHz,1, 7 -naphthy ri din-7 ( 877)- DMSO-rie) 6 10.46 (s. 1H), 8.78 (d. J = 2.4 Hz. 1H), yl)- / V-(4-(4-fluoro-l- 8.37 (d, J= 2.4 Hz, 1H), 7.92 (d, J= 4.6 Hz, 1H), 7.74 methyl- 177-py razol-3- (d. J= 7.6 Hz. 1H). 7.71-7.64 (m. 4H). 6.68 (d. J= 7.6 yl)phenyl)propanamide Hz, 1H), 5.67 (q, J= 7.2 Hz, 1H), 3.81 (s, 3H), 1.68 (d,J = 7.3 Hz, 3H).230 (7?)-2-(3-chloro-8-oxo- LC / MS ESI (m / z): 444 (M+H)+. 'HNMR (400 MHz,1,7-naphthyridin-7(877)- DMSO-rie) 5 10.66 (s. 1H), 8.78 (d. J= 2.3 Hz. 1H), yl)- / V-(3-fluoro-4-(4- 8.38 (d, J= 2.3 Hz, 1H), 7.94 (d, J= 4.7 Hz, 1H), 7.73 fluoro- 1 -methyl- 177- (d..7= 7.6 Hz. 1H), 7.68 (dd, J= 12.9, 1.9 Hz, 1H), 7.56 pyrazol-3- (t, J= 8.4 Hz, 1H), 7.41 (dd,.7= 8.5, 1.9 Hz, 1H), 6.69 yl)phenyl)propanamide (d..7= 7.6 Hz. 1H), 5.64 (q. J= 7.2 Hz. 1H), 3.83 (s.3H), 1.69 (d, J = 7.3 Hz, 3H).231 (7?)-2-(3-chloro-8-oxo- LC / MS ESI (m / z): 441 (M+H) '. 'H NMR (400 MHz,1, 7 -naphthy ri din-7 (877)- DMSO-cfc) 5 10.75 (s, 1H), 8.78 (d, J= 2.3 Hz, 1H), yl)-N-(3-fluoro-4-(3- 8.63-8.48 (m, 1H), 8.38 (d, J= 2.4 Hz, 1H), 7.89-7.79 fluoropyridin-2- (m, 1H), 7.77-7.68 (m, 2H), 7.60-7.47 (m, 3H), 6.70 (d, yl)phenyl)propanamide J= 7.6 Hz, 1H). 5.65 (q, J= 7.2 Hz, 1H). 1.70 (d, J =7.3 Hz, 3H).26130Ex. No. Name LCMS, NMR235 (J?)-jV-(4-(4-fluoro-l - LC / MS ESI (m / z): 41 1 (M+H)+. 'H NMR (400 MHz, methyl- 177-py razol-5- DMSO-C / G) 5 10.26 (s. 1H), 7.96 (dd, J= 8.3, 6.0 Hz, yl)phenyl)-2-(6-fluoro- 1H), 7.80 (d, J= 8.7 Hz, 2H), 7.56 (d, J= 4.5 Hz, 1H), 1 -oxo-3, 4- 7.47 (d, J= 8.5 Hz, 2H), 7.24-7.14 (m, 2H), 5.31 (q, J = dihydroisoquinolin- 7.2 Hz, 1H), 3.78 (s, 3H), 3.69-3.58 (m, 2H), 3.20-3.00 2( 1 / / )-v l)propanamide (m, 2H), 1.46 (d, J= 7.2 Hz, 3H).236 (7?)-2-(6-fluoro- 1 -oxo- LC / MS ESI (m / z): 429 (M+H)+. 'H NMR (400 MHz,3,4-dihydroisoquinolin- DMSO-tie) 6 10.47 (s, 1H), 7.98-7.93 (m, 1H), 7.82 (dd, 2(17 / )-yl)- / V-(3-fluoro-4- J= 12.6, 1.8 Hz, 1H), 7.63-7.45 (m, 3H), 7.23-7.16 (m, (4-fluoro-l -methyl- \ / f- 2H), 5.29 (q, J= 7.2 Hz, 1H), 3.69 (s. 3H), 3.63 (t, J= pyrazol-5- 6.5 Hz, 2H), 3.10-2.98 (m, 2H), 1.46 (d, J= 7.2 Hz, 3H). yl)phenyl)propanamide238 (R)-jV-(4-(4-fluoro- 1 - LC / MS ESI (m / z): 410 (M+H)+. ’H NMR (400 MHz, methyl- 177-py razol-5- DMSO-c / c) 6 10.59 (s, 1H), 8.78 (d, J= 2.8 Hz, 1H), y l)pheny l)-2 - ( 3 -fluoro- 8.08 (dd, J= 9.3, 2.8 Hz, 1H), 7.77 (d, J= 8.7 Hz, 2H), 8-oxo- 1,7 -naphthyridin- 7.73 (d, J= 7.5 Hz, 1H), 7.56 (d, J= 4.5 Hz, 1H), 7.48 7(8#)-yl)propanamide (d, J= 8.5 Hz, 2H), 6.70 (d, J= 7.6 Hz, 1H), 5.67 (q, J =7.2 Hz, 1H), 3.77 (s, 3H), 1.69 (d, J= 13 Hz, 3H). 239 (A)-jV-(3-fluoro-4-(4- LC / MS ESI (m / z): 428 (M+H)+. 'H NMR (400 MHz, fluoro- 1 -methyl- 1H- DMSO-d>) 5 10.79 (s, 1H), 8.78 (d, J= 2.7 Hz, 1H), pyrazol-5-yl)phenyl)-2- 8.08 (dd, J= 9.3, 2.8 Hz, 1H), 7.78 (d, J= 12.7 Hz, 1H), (3-fluoro-8-oxo-l,7- 7.73 (d, 7.6 Hz, 1H), 7.59 (d, J= 4.5 Hz, 1H), 7.50 naphthyridin-7(87 / )- (d, J = 4.3 Hz. 2H), 6.71 (d. J = 7.6 Hz. 1H), 5.63 (q. J =yl)propanamide 7.2 Hz, 1H), 3.68 (s, 3H), 1.69 (d, J= 13 Hz, 3H).Example 203. Synthesis of l-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)cyclopropane-l-carboxamide (203)Step 1. tert-Butyl (l-((4-(4-fluoro-l-methyl-lH-pyrazol-5- yl)phenyl)carbamoyl)cvclooropyl)carbamate

[0324] To a solution of 4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)aniline (200 mg, 1.05 mmol) and l-((tert-butoxycarbonyl)amino)cyclopropane-l -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 resulting26130mixture was stirred at rt for 1 h and quenched with water. The mixture was extracted with EtOAc, washed with NaHCCh (aq), dried over Na2SO4, and purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to afford tert-butyl (l-((4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)carbamoyl)cyclopropyl)carbamate. LC / MS ESI (m / z): 375 (M+H)+.Step 2, l-Amino-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)cvclopropane-l- carboxamide

[0325] To a solution of tert-butyl (l-((4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)carbamoyl)cyclopropyl)carbamate (350 mg, 0.94 mmol) in DCM (10 mL) was added HC1 in dioxane (3.0 mL, 4.0 M). The mixture was stirred at rt for 2 h and then concentrated to dryness to afford l-amino-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)cyclopropane-l-carboxamide, which was used in the next step directly. LC / MS ESI (m / z): 275 (M+H)+.Step 3, l-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5- yDphenvDcvclopropane- 1 -carboxamide

[0326] To a solution of l-amino-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)cyclopropane-l -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 100°C for 2 h. The solvents were removed by rotary evaporation. The residue was purified by silica gel column chromatography (0-70% EtOAc in petroleum ether) and prep-HPLC to afford l-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)cyclopropane-l-carboxamide. LC / MS ESI (m / z): 438 (M+H)+. 'H NMR (400 MHz, DMSO-cL) 59.70 (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).

[0327] The following compound was prepared by a procedure similar to the synthesis of Example 203 using the corresponding aniline.Ex. No. Name LCMS, ' H NMRl-(7-chloro-4- LC / MS ESI (m / z): 453 (M+H)+. ’H NMR (400 MHz, oxoquinazolin-3(477)- y l)- / V-(3 -fluoro-4-(3- DMSO-J6) 59.81 (s, 1H), 8.57-8.52 (m, 1H), 8.50 (s, 204 1H). 8.16 (d, J= 8.5 Hz, 1H). 7.90-7.78 (m, 2H). 7.66 fluoropyridin-2- (dd,.7= 13.0, 1.6 Hz, 1H), 7.62 (dd, J = 8.5, 2.1 Hz, yl)phenyl)cyclopropane- 1H). 7.57-7.49 (m, 3H). 1.86 (s, 2H). 1.52 (s. 2H).1 -carboxamide26130Example 205. Synthesis of ( / ?)-2-(7-chloio-4-oxoqiiinazolin-3(4II)-yl)-N-(4-(4-fkioio-l-methyl- lH-pyrazol-5-yl)phenyl)-N-methylpropanamide (205)Step 1. tert-Butyl (4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)carbamate

[0328] A mixture of 4-(4-fluoro-l -methyl -lH-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- lH-pyrazol-5-yl)pheny l)carbamate.Step 2, tert-Butyl (4-(4-fluoro-l -methyl- lH-pyrazol-5-yl)phenyl)(methyl)carbamate

[0329] To a solution of tert-butyl (4-(4-fluoro-l-methyl-lH-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-l-methyl-lH-pyrazol-5-yl)phenyl)(methyl)carbamate (100 mg, 92%). LC / MS ESI (m / z): 306 (M+H)+.Step 3, 4-(4-Fluoro-l-methyl-lH-pyrazol-5-yl)-N-methylaniline

[0330] To a solution of tert-butyl (4-(4-fluoro- 1 -methyl -lH-pyrazol-5-yl)phenyl)(methyl)carbamate (100 mg, 0.33 mmol) in DCM (2 mL) was added HC1 in dioxane (2.0 mL, 4.0 M). The mixture was stirred at rt overnight and concentrated to afford 4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)-N-methylaniline. LC / MS ESI (m / z): 206 (M+H)+.Step 4, (7?)-2-(7-Chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-l -methyl- IH-pyrazol-5-yl)phenyl)-N-methylpropanamide

[0331] To a solution of 4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)-N-methylaniline (60 mg, 0.29 mmol) and (7?)-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 with26130EtOAc. The combined organic layers were washed with NaHCCh (aq), dried over Na2SC>4, filtered, and concentrated. The crude product was purified by prep-HPLC to give (7?)-2-(7-chloro-4-oxoquinazolin-3(4H)-yl)-N-(4-(4-fluoro-l-methyl-lH-pyrazol-5-yl)phenyl)-N-methylpropanamide. LC / MS ESI (m / z): 440 (M+H)+. 'H NMR (400 MHz, CD3OD) 58.24 (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, 14.3, 7.2 Hz, 1H). 3.84 (s, 3H), 3.33 (s. 3H), 1.59 (d. J = 7.0 Hz. 3H).

[0332] The following compound was prepared by a procedure similar to the synthesis of Example 205 using the corresponding aniline.Ex. No. Name LCMS, ’H NMR(A)-2-(7-chloro-4- LC / MS ESI (m / z): 455 (M+H)+. 'H NMR (400 MHz, oxoquinazolin-3(4H)- DMSO-cL) 8 8.60 (m, 1H), 8.40 (s, 1H), 8.12 (d, J= 8.5 yl)-N-(3-fluoro-4-(3- 206 Hz, 1H), 7.91 (m, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.70 (t, fluoropyridin-2- J= 8.1 Hz, 1H), 7.64-7.48 (m, 4H), 5.50 (br s, 1H), 3.27 yl)phenyl)-N- (s, 3H), 1.56 (d, J= 5.1 Hz, 3H).methylpropanamideExample 207. Synthesis of (7?)-2-(6-chloro-l-oxoisoquinoIin-2(lH)-yI)-N-(6-(4-fluoro-l-methyl- lH-pyrazol-5-yl)pyridin-3-yl)propanamide (207)CH3I NaH, THF n-BuLi, THF, -78”C Pd(dppf)CI2, K2CO:THF / H2O, 80°CStep 1. 4-Fluoro-l -methyl- IH-pyrazole

[0333] To a solution of 4-fluoro-lH-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 overNa2S04, and concentrated in vacuo to afford the crude title compound 4-fluoro-l -methyl- IH-pyrazole. 'H NMR (400 MHz, CDCk) 87.30 (d, J= 4.1 Hz, 1H), 7.24 (d, J= 4.8 Hz, 1H), 3.83 (s, 3H).Step 2, 4-Fluoro-l-methyl-5-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-lH-pyrazole

[0334] To a solution of 4-fluoro-l-methyl-lH-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-261304,4,5,5-tetramethyl-l,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-l-methyl-lH-pyrazol-5-yl)pyridin-3-amine

[0335] To a solution of 4-fluoro-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (400 mg, 1.8 mmol) in THF (10 mL) and water (1 mL) were added 6-bromopy ri din-3 -amine (310 mg, 1.8 mmol), K2CO3 (610 mg, 4.4 mmol) and Pd(dppf)C12 (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-l-methyl-lH-pyrazol-5-yl)pyridin-3-amine. LC / MS ESI (m / z): 193 (M+H)+.Step 4, (7?)-2-(6-Chloro-l-oxoisoauinolin-2(lH)-yl)-N-(6-(4-fluoro-l-methyl-lH-pyrazol- 5-yl)pyridin-3-yl)propan amide

[0336] To a solution of 6-(4-fluoro-l-methyl-lH-pyrazol-5-yl)pyridin-3-amine (140 mg, 0.73 mmol) and (7?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)propanoic acid (180 mg, 0.73 mmol) in DCM (2 mL) at -20°C was added pyridine (1 mL) followed by POCI3 (220 mg, 1.5 mmol) dropwise. The reaction was stirred at -20°C for 1 h and partitioned between with DCM and water. The organic layer was washed wi th brine and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (7?)-2-(6-chloro-l-oxoisoquinolin-2(IH)-yl)-N-(6-(4-fluoro-l-methyl-lH-pyrazol-5-yl)pyridin-3-yl)propanamide. LC / MS ESI (m / z): 426 (M+H)+.XH NMR (400 MHz, CDCh) 59.13 (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,.7= 7.1 Hz, 1H), 4.11 (s, 3H), 1.75 (d, J= 7.2 Hz, 3H).

[0337] The following compounds were prepared by procedures similar to the synthesis of Example 207 using 4-methoxy-lH-pyrazole and the corresponding bromoanilines.Ex. No. Name LCMS, ’H NMRLC / MS ESI (m / z): 437 (M+H)+. 'H NMR (400 MHz, (7?)-2-(6-chloro-l- DMSO-tfc) 6 10.50 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), oxoisoquinolin-2(17 / )- 7.84 (s, 1H), 7.71 (d, J= 8.1 Hz, 2H), 7.64 (d, J= 7.5 233 yl)- / V-(4-(4-methoxy- 1 - Hz, 1H), 7.53 (d, J= 8.3 Hz, 1H), 7.47-7.34 (m, 3H), methyl- 177-pyrazol-5- 6.70 (d, J= 7.3 Hz, 1H), 5.70-5.60 (m, 1H), 3.74 (s, yl)phenyl)propanamide3H), 3.69 (s, 3H), 1.68 (d, J= 6.9 Hz, 3H).26130Ex. No. Name LCMS, NMRLC / MS ESI (m / z): 455 (M+H)+. 'H NMR (400 MHz, (A)-2-(6-chloro- 1 - DMSO-tfc) 5 10.71 (s, 1H), 8.22 (d, J= 8.6 Hz, 1H), oxoisoquinolin-2(177)- 7.85 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 12.5, 1.9 Hz, 1H), yl)-JV-(3-fluoro-4-(4- 234 7.64 (d, J= 7.6 Hz, 1H), 7.54 (dd, J= 8.6, 2.1 Hz, 1H), methoxy- 1 -methyl- \H- 7.46-7.35 (m, 3H), 6.71 (d, J= 7.6 Hz, 1H), 5.65-5.57 pyrazol-5- (m, 1H), 3.67 (s, 3H), 3.61 (s, 3H), 1.69 (d, J ="1.3 Hz, yl)phenyl)propanamide3H).Example 208. Synthesis of (7?)-2-(6-chloro-l-oxoisoquinolin-2(lH)-yl)-N-(4-(l- (difluoromethyl)- lH-pyrazol-5-yl)phenyl)propanamide (208)KF, ACN, rt Pd(dppf)CI2, K2C03, dioxane, H2O, 90°CStep 1. l-(Difluoromethyl)-5-iodo-lH-py...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula IV:(R3)qFormula IVor a pharmaceutically acceptable salt thereof, whereinRing B is selected from 5- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl, wherein the heteroaryl and heterocyclyl contains one or two heteroatoms selected from S and N;X1is absent, CR5, or N;X2is CZ1, CR5, or N;X3is CZ1, CR5, or N;X4is CR5orN;X5is CR5orN;provided that 0, 1 or 2 of X1, X2, X3, X4, and X5are N, and one of X2and X3is CZ1; Z1is Ci-6 alky l, or Ci-4 alkyl ene-aryl, where the Ci-6 alky I, or Ci-4 alkylene-aryl is( Aw 27^(R6)nsubstituted with one or two halogens, orRing A is 5- to 6-membered heteroaryl or 6-membered heterocyclyl;X6is absent or is selected from CH, CR3, CH2, CHR3, CR32, and N;X7is selected from CH, CR3, CH2, CHR3, CR32, and N;X8is selected from C and N;R1is H or C1-4 alkyl;R2is H or C1-4 alkyl, wherein the R2Ci-4 alkyl is optionally substituted with one, two, or three substituents independently selected from halogen, hydroxy, cyano, C1-4 alkoxy, and C1-4 haloalkoxy; oroptionally R1and R2. together with the carbon atom to which R1and R2are attached, form a C3-4 spirocyclic ring;each R3is independently selected from halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring;R4is H or C1-6 alkyl;each R5is independently selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, oxo, and 5- to 6-membered heterocyclyl;q is an integer 1-4; andn is an integer 0-5.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein bicyclic ring containing X6, X7, X8, and Ring B is selected from:bicyclic ring is substituted with 1-4 R3.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the bicyclic ring containing X6, X7, X8, and Ring B is selected from:bicyclic ring is substituted with 1-4 R3.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the bicyclic ring containing X6, X7, X8, and Ring B is selected from:substituted with 1-4 R3.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is an integer 1 or 2.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is H or C1-2 alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1is H.

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1is methyl.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2is H or Ci-4 alkyl optionally substituted with one or two substituents selected from halogen, hydroxy, or C1-2 alkoxy.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R2is H.

11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R2is methyl or ethyl.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein q is 4.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1and R2, together with the carbon atom to which R1and R2are attached, form a C3-4 spirocyclic ring.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4is H.

15. The compound of any one of claims 1 to 14. or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, pyrazolyl, imidazolyl, and oxazolyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl, pyrazolyl, or imidazolyl.

17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl.

18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl.

19. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Ring A is imidazolyl.2613020. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from halogen, hydroxy, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, oxo, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from halogen, C1-2 alky l, C1-2 alkoxy, C1-2 haloalky l, C1-2 haloalkoxy, C2-6 alkenyl. C2-6 haloalkenyl. C2-6 alkynyl. C2-6 haloalkynyl. C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 cycloalkyloxy, C3-6 halocycloalkyloxy, di-Ci-4alkylamine, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by71-3 halogen atoms, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring.

22. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from C1-2 alkyl, C1-2 haloalkyl, C1-2 haloalkoxy, C2-3 alkenyl, C2-3 haloalkenyl, C2-3 alkynyl, C2-3 haloalkynyl, C3-4 cycloalkyl, C3-4 halocycloalkyl, C3-4 cycloalkyloxy. C3-4 halocycloalkyloxy, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms, where when 2 R3alkyl are present on a single ring atom, the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring.

23. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from C1-2 alkyl, C1-2 haloalkyl, C1-2 haloalkoxy, C2-3 alkenyl, C2-3 haloalkenyl, C2-3 alkynyl, C2-3 haloalkynyl, C3-4 cycloalkyl, C3-4 halocycloalkyl, C3-4 cycloalkyloxy, C3-4 halocycloalkyloxy, and 5- to 6-membered heterocyclyl that is unsubstituted or substituted by 1-3 halogen atoms.

24. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein 2 R3alky l are present on a single Ring B atom, and the 2 R3may be joined, together with the atom to which they are attached, to form a C3-6 spirocyclic ring.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein 2 R3are joined, together with the atom to which they are attached, to form spirocyclopropyl ring.

26. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein 2 R3are joined, together with the atom to which they are attached, to form a spirocyclobutyl ring.

27. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from Cl, F, CH₃, CF₃, CH2CH3, CH2CF3, C=CCH3, OCH3, OCHF2,or 2 R3are taken together with the atom to which they are attached, to form a spirocyclopropyl ring, or a spirocyclobutyl ring.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from H, halogen, hydroxy, cyano, and C1-6 alkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from H, halogen, and C1-2 alky l.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from H or F.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein n is an integer 0-3.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein each R6is independently selected from halogen, hydroxy, cyano, C1-6 alky l, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and C3-6 cycloalkyl.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, each R6is independently selected from halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy, and C3-6 cycloalkyl.

34. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein each R6is independently selected from halogen, hydroxy, cyano. C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein each R6is independently selected from F, Cl, hydroxy, cyano, methyl, ethyl, methoxy, and cyclopropyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein each R6is independently selected from F and CH3.

37. The compound of claim 1, wherein the compound is26130acceptable salt thereof.

38. The compound of claim 1, wherein the compound is26130or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

40. 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 to 38, or a pharmaceutically acceptable salt thereof, or a composition of claim 39.

41. 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 to 38, or a pharmaceutically acceptable salt thereof, or a composition of claim 39.

42. The method of claim 41, wherein the neurodegenerative disease is selected from 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.

43. The method of claim 42, wherein the neurodegenerative disease is selected from 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).

44. 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 to 38, or a pharmaceutically acceptable salt thereof, or a composition of claim 39.

45. The method of claim 44, wherein the lysosomal storage disease is selected from 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,26130Pompe 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-Hurl er poly dystrophy, 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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