Modulators of alpha-1 antitrypsin

Abstract

Described herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof. The compounds can be capable of modulating alpha- 1 antitrypsin (AAT) activity, and useful for the treatment of alpha- 1 antitrypsin deficiency (AATD). The invention further features intermediates and processes for preparing compounds of the invention.

Description

[0001] MODULATORS OF ALPHA-1 ANTITRYPSIN

[0002] RELATED APPLICATION

[0003] This application claims benefit and priority of United States Provisional Patent Application serial no. 63 / 648,872 filed May 17, 2024, incorporated herein by reference in its entirety.

[0004] BACKGROUND

[0005] The disclosure provides compounds that are capable of modulating alpha-1 antitrypsin (AAT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) by administering one or more such compounds.

[0006] AATD is a genetic disorder characterized by low circulating levels of alpha-1 antitrypsin (AAT). AAT is produced primarily in the liver and secreted into the blood, although other cell types, including lung epithelial cells, monocytes, macrophages, and neutrophils, produce small amounts of the protein locally (see, e.g., Bergin, et al, Sci Tr and Med. 2014; 6(217):217; Geraghty, et al., Am J Respir Crit Care Med. 2014; 190(11): 1229- 42). AAT inhibits several serine proteinases secreted by polymorphonuclear neutrophils (PMNs; most notably neutrophil elastase, cathepsin G, and proteinase-3) and thus protects organs such as the lung from damage by these proteinases, especially during periods of infection and increased inflammation. (Loomba et al., Aliment Pharmacol Ther. 2024, 1-13). The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene that encodes the AAT protein. This mutation, known as the Z mutation, leads to misfolding of the translated protein, which polymerizes within hepatocytes and is not secreted into the bloodstream. Consequently, circulating AAT levels in individuals homozygous for the Z mutation (PiZZ) are markedly reduced; only approximately 15% of mutant Z-AAT protein folds correctly and is secreted by hepatocytes into the circulation. The accumulation of polymerized Z-AAT protein within hepatocytes causes cytotoxicity that can result in neonatal liver disease or progressive liver disease in adulthood that can lead to cirrhosis or liver cancer. The reduced levels of circulating, active AAT result in an imbalance between proteinase and antiprotease activity, which has its greatest impact in the lung. Consequently, lung tissue is damaged over time resulting in emphysema, which is one pathology occurring in the lungs of subjects with chronic obstructive pulmonary disease (COPD) that contributes to the poorly reversible airflow obstruction that is characteristic of COPD. Emphysema in PiZZ individuals typically manifests in middle age and usually results in a progressive decline in lung function, a decline in quality of life and shortened lifespan (mean 67 years of age) (Piitulainen, Eeva, and Hanan A. Tanash. COPD: Journal of Chronic Obstructive Pulmonary Disease 12. sup1 (2015): 36-41 ). PiZZ individuals account for the majority (-95%) of those with clinically relevant AATD-related lung disease. A milder form of AATD is associated with a mutation in alpha-1 antitrypsin known as the SZ mutation, which results in clinically significant lung disease but not liver disease (Fregonese, Laura, and Jan Stolk. Orphanet journal of rare diseases 3 (2008): 1-9). As with the ZZ mutation, the deficiency of circulating AAT in subjects with the SZ mutation results in unregulated protease activity that degrades lung tissue over time and can result in emphysema, particularly in smokers. The current standard of care for AAT deficient individuals who have or show signs of developing significant lung or liver disease is augmentation therapy (AAT replacement therapy). AAT augmentation therapy involves administration of a pooled, purified human plasma protein concentrate to augment the reduced circulating levels of AAT in subjects with severe AATD. Infusions of plasma protein have been shown in randomized placebo controlled clinical studies to slow the rate of emphysema progression on CT scans. However, AAT augmentation therapy does not halt lung disease progression and also does not restore the AAT acute phase response which occurs in response to various insults in normal, healthy (PIMM) subjects, including infection, smoking, stress and trauma. During the normal AAT acute phase response, plasma AAT levels increase 2-fold in response to an insult (such as a pulmonary exacerbation) leading to greater protection of the lung from the increased lung burden of P MN -de rived serine proteinases which is associated with increased neutrophilic lung inflammation which occurs during a pulmonary exacerbation. Similarly, although AAT replacement therapy shows promise in slowing the progression of emphysema in subjects with severe AATD, only 2% of the administered drug reaches the lungs. In addition, replacement AAT therapy requires weekly visits for treatment which is burdensome to patients. Thus, there is a continuing need for new and more effective treatments for AATD.

[0007] There is a continuing need for new and more effective treatments for AATD.

[0008] SUMMARY OF THE INVENTION

[0009] The invention features a having the structure of Formula (I):

[0010] Formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0011] R° is hydrogen, optionally substituted CB-C-IO aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocyclyl, optionally substituted C3-C12 cycloalkyl, optionally substituted CI-CB alkyl C3-C12 heterocyclyl, or -C(O)-RA;

[0012] RAis optionally substituted CB-C-IO aryl or optionally substituted C5-C12 heteroaryl;

[0013] R1and R2are each, independently, hydrogen or optionally substituted CI-CB alkyl, alkoxy, or R1and R2, together with the carbon atom to which they are attached, combine to form an oxo, an optionally substituted CS-CB cycloalkyl or an optionally substituted C3-C12 heterocyclyl;

[0014] R3is hydrogen, optionally substituted CB-C-IO aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocyclyl, or optionally substituted C3-C12 cycloalkyl;

[0015] R4and R5are each, independently, hydrogen or optionally substituted CI-CB alkyl, alkoxy, or R4and R5, together with the carbon atom to which they are attached, combine to form an oxo, an optionally substituted CS-CB cycloalkyl or an optionally substituted C3-C12 heterocyclyl; and

[0016] X is hydrogen, halo, or methyl. In certain embodiments, the is further described by Formula (Ila) or Formula (lib): or a phar described in Formula (I). In some embodiments, R° is CB-C-IO aryl substituted with a carboxyl group. In particular embodiments, X is fluorine. In some embodiments, R1and R2are each, independently, hydrogen or methyl. In other embodiments, R1and R2, together with the carbon atom to which they are attached, combine to form an oxo, an optionally substituted Cs-Ce cycloalkyl or an optionally substituted C3-C12 heterocyclyl. For example, R1and R2, together with the carbon atom to which they are attached, can combine to form a tetrahydropyran ring. In other embodiments, R1and R2, together with the carbon atom to which they are attached, combine to form an optionally substituted Cs-Ce cycloalkyl.

[0017] In particular embodiments, R3is optionally substituted CB-C-IO aryl or optionally substituted Cs- C12 heteroaryl. For example, R3can be a phenyl substituted with one or more halo groups. In particular embodiments, R4and R5are each, independently, hydrogen or methyl. In other embodiments, R4and R5, together with the carbon atom to which they are attached, combine to form an oxo, an optionally substituted Cs-Ce cycloalkyl or an optionally substituted C3-C12 heterocyclyl. For example, R4and R5, together with the carbon atom to which they are attached, can combine to form a tetrahydropyran ring. In other embodiments, R4and R5, together with the carbon atom to which they are attached, combine to form an optionally substituted Cs-Ce cycloalkyl.

[0018] In particular embodiments, the of formula (I) can be a selected from: p-{11 ,11 -dimethy l-12-oxo-4, 5, 10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 , 3(7), 5,8- tetraen-13-yl}benzoic acid; p-[10-(p-fluorophenyl)-11 , 11 -d Im ethy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid; p-[10-(p-fluorophenyl)-11 , 11-dimethyl-12-oxo-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid; p-[10-(p-fluorophenyl)-11 , 11-dimethyl-12-oxo-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid; p-[10-(p-fluorophenyl)-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 , 3(7), 5,8- tetraen-13-yl]benzoic acid; p-[10-(p-fluorophenyl)-12-oxo-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1,3(7),5,8-tetraen-13-yl]benzoic acid; p-[10'-( p-flu 0 ro phe ny I )-2 , 3, 5,6-tetrahydrospiro[pyran-4, 11'- [4,5, 10,13]tetraazatricyclo[7.4.0.03,7]-trideca[1,3(7),5,8]tetraen]-13'-yl]benzoic acid; p-[10'-(p-fluorophenyl)-12'-oxo-2,3,5,6-tetrahydrospiro[pyran-4,11'- [4,5, 10,13]tetraazatricyclo[7.4.0.03,7]-trideca[1,3(7),5,8]tetraen]-13'-yl]benzoic acid; p-[ 10-(3,4-d ifluoropheny I )-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10'-(p-fluorophenyl)spiro[cyclopentane-1 , 11'-

[0019] [4.5. 10.13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]benzoic acid p-[10-(p-fluorophenyl)-12, 12-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(3,4-difluorophenyl)-2-fluoro-11 ,11 -dimethyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[11 , 11 -dimethyl-10-(2-methyl-4-pyridyl)-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10'-(p-fluorophenyl)-4,5-dihydro-2H-spiro[furan-3, 11'-

[0020] [4.5. 10.13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]phenyl}methanol

[0021] 10'-(p-fluorophenyl)-13'-(p-tolyl)-4,5-dihydro-2H-spiro[furan-3,11'-

[0022] [4.5. 10.13]tetraazatricyclo[7.4.0.03,7]trideca[1 ,3(7),5,8]tetraene]

[0023] 10'-(p-fluorophenyl)-13'-(p-tolyl)spiro[cyclobutane-1 ,1 V-

[0024] [4.5. 10.13]tetraazatricyclo[7.4.0.03,7]trideca[1 ,3(7),5,8]tetraene] p-[10'-(p-fluorophenyl)-4,5-dihydro-2H-spiro[furan-3, 11'-

[0025] [4.5. 10.13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]benzoic acid p-[2-fluoro-10-(p-fluorophenyl)-11 ,11-dimethy 1-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0026] 10-(p-fluorophenyl)-11,11-dimethyl-13-[(tetrahydro-4H-pyran-4-yl)methyl]- 4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraene p-[(R)-10-(p-fluorophenyl)-11-(methoxymethyl)-11-methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid m-[10-(p-fluorophenyl)-11 ,11 -dimethyl-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(m-fluorophenyl)-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(3-fluoro-5-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(p-fluorophenyl)-11-isopropyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(p-fluorophenyl)-11-methyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1(9),2,5,7-tetraen-13-yl]benzoic acid p-[(R)-10-(p-fluorophenyl)-11 -(hydroxymethyl)-l 1-methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[(R)-10-(p-fluorophenyl)-11-methyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1,3(7),5,8-tetraen-13-yl]benzoic acid p-[(S)-10-(p-fluorophenyl)-11 -methy I-4, 5, 10, 13-tetraazatricyclo[7.4.0.03,7]trideca- 1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(3,4-difluoro-5-methoxyphenyl)-11 , 11 -d imethy I-4 , 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[ 10-(2 , 4-d iflu oro ph eny I )- 11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(4-fluoro-2-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[11 , 11 -diethyl-10-(p-fluorophenyl)-4, 5, 10, 13-tetraazatricyclo[7.4.0.03 7]trideca- 1,3(7),5,8-tetraen-13-yl]benzoic acid

[0027] (1 r,3r)-3-[10-(p-fluorophenyl)-11 , 11 -dimethyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]cyclobutanecarboxylic acid

[0028] (1s,3s)-3-[10-(p-fluorophenyl)-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]cyclobutanecarboxylic acid p-[10-(4-fluoro-3-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0029] [( 1 s, 3s)-3-[ 10-(p-fluorophenyl)-11 , 11 -d i methy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]cyclobutyl]methanol

[0030] [( 1 r, 3r)-3-[10-(p-fluorophenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]cyclobutyl]methanol p-[10-(p-fluorophenyl)-11 , 11 -d im ethy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzonitrile p-[10-(p-fluorophenyl)-11 , 11 -d im ethy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzamide

[0031] 4-[10-(p-fluorophenyl)-11 , 11 -d im ethy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]-2-anisic acid

[0032] 2-fluoro-4-[10-(p-fluorophenyl)-11 , 11-dimethy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0033] 5-{p-[ 10-(p-fluorophenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]phenyl}-2H-tetraazole m-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(p-fluorophenyl)-11-(methoxymethyl)-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[(R)-2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11-methyl- 4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[(R)-10-(p-fluorophenyl)-11 -(methoxymethyl)-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[(S )- 10-(p-fluorophenyl)-11-(methoxymethyl)-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-11,11 -dimethyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[(S)-10-(p-fluorophenyl)-11-(methoxymethyl)-11 -methyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[(R)-2-fluoro-10-(p-fluorophenyl)-11-(methoxymethyl)-11 -methyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[ 10-(4-fl uoro-3-toly I )-11 , 11 -d imethy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(4-fluoro-2-methoxyphenyl)-4, 5, 10, 13-tetraazatricyclo[7.4.0.03,7]trideca-

[0034] 1(9),2,5,7-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3-hydroxyphenyl)-11 , 11 -d imethy i-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(3-ethoxy-4-fluorophenyl)-2-fluoro-11 , 11 -d i methy i-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3-trifluoromethoxyphenyl)-11 , 11 -d imethy i-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(3-difluoromethoxy-4-fluorophenyl)-2-fluoro-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[(R)-10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11 -methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3-isopropoxyphenyl)-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(3-cyclobutoxy-4-fluorophenyl)-2-fluoro-11 ,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(3-chloro-4-fluorophenyl)-2-fluoro-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0035] 4-[10-(p-fluorophenyl)-11 , 11 -d im ethy i-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]-3-anisic acid p-[10-(p-fluorophenyl)-11-(2-methoxyethyl)-11 -methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0036] 4-[10-(p-fluorophenyl)-11 , 11 -d im ethy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]-2-hydroxybenzoic acid p-[(S)-10-(p-fluorophenyl)-11-(2-methoxyethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-{ 10-[3-( 1 , 1-difluoroethyl)-4-fluorophenyl]-2-fluoro-11, 11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl}benzoic acid p-[(R)-10-(p-fluorophenyl)-11-(2-methoxyethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-{2-fluoro-10-[4-fluoro-3-(2H3)methoxyphenyl]-11 , 11-dimethyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl}benzoic acid p-{2-fluoro-10-[4-fluoro-3-(trifluoromethyl)pheny l]-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl}benzoic acid p-[2-fluoro-10-(3-fluoro-4-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0037] 3-fluoro-4-[10-(p-fluorophenyl)-11 , 11-dimethy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid {m-[10-(p-fluorophenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]phenyl}acetic acid p-[(R)-10-(3,4-difluorophenyl)-2-fluoro-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3,5-dimethoxyphenyl)-11 , 11 -d i methy I-4, 5 , 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(4-chloro-3-fluorophenyl)-2-fluoro-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(3-cyano-4-fluorophenyl)-2-fluoro-11 , 11 -d imethy I-4 , 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-{2-fluoro-10-[4-fluoro-3-(methylamino)phenyl]-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl}benzoic acid p-[10-(4-chloro-3-methoxy phenyl)-2-fluoro-11 , 11 -d i methy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0038] (1 r,4r)-4-[10-(p-fluorophenyl)-11 , 11 -dimethyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]cyclohexanecarboxylic acid p-[(R)-10-(3,4-difluorophenyl)-11-(methoxymethyl)-11-methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-{10-[3-(difluoromethyl)-4-fluorophenyl]-2-fluoro-11 ,11 -dimethyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl}benzoic acid p-[ 10-(2H-1 ,3-benzodioxol-5-yl)-2-fluoro-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[ 10-(2H-1 ,3-benzodioxol-4-yl)-2-fluoro-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0039] 2-fluoro-4-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11 , 11 -d i methy I-4, 5 , 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0040] 5-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]-2-toluic acid p-[(R)-10-(3-chloro-4-fluorophenyl)-11 -(methoxymethyl)-l 1-methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid

[0041] 2-chloro-4-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11 , 11 -dimethyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid 2-chloro-4-[(R)-10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11-methyl- 4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid 2-cyano-4-[10-(p-fluorophenyl)-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[(S)-10-(p-fluorophenyl)-11-(methoxymethyl)-11-methyl-12-oxo-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid or a pharmaceutically acceptable salt thereof. In particular embodiments, the of formula (I) can be a selected from those in Table 1 :

[0042] Number Compound Number Compound Number Compound Number Compound Number Compound Number Compound Number Number Compound

[0043] 16

[0044]

[0045] The invention also features a pharmaceutical composition including a of the invention, and a pharmaceutically acceptable excipient.

[0046] The invention further features a method of treating alpha-1 antitrypsin deficiency in a subject in need thereof, the method including administering an effective amount of a of the invention, or a pharmaceutically acceptable salt thereof, to the subject. In particular embodiments, the subject has a Z mutation in alpha-1 antitrypsin. In some embodiments, the subject has an SZ mutation in alpha-1 antitrypsin. In other embodiments, the subject is homozygous for Z-mutations in alpha-1 antitrypsin.

[0047] The invention also features a method of modulating alpha-1 antitrypsin activity including contacting the alpha-1- antitrypsin with a of the invention, or a pharmaceutically acceptable salt thereof.

[0048] To facilitate the understanding of this invention, several terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the invention. Terms such as “a”, “an,” and “the” are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims.

[0049] It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0050] The term “about” refers to a relative term denoting an approximation of plus or minus 10% of the nominal value to which it refers, in one embodiment, to plus or minus 5%, in another embodiment, to plus or minus 2%. For the field of this disclosure, this level of approximation is appropriate unless the value is specifically stated to require a tighter range.

[0051] The term “AAT” as used herein means alpha-1 antitrypsin or a mutation thereof, including, but not limited to, the AAT gene mutations such as Z mutations. As used herein, “Z-AAT” means AAT mutants which have the Z mutation.

[0052] The term “AATD” as used herein means alpha-1 antitrypsin deficiency, which is a genetic disorder characterized by low circulating levels of AAT.

[0053] The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human.

[0054] As used herein, the term “pharmaceutically acceptable salt” means those salts of the compounds described that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting to the free base group with a suitable acid.

[0055] As used herein, the term “pharmaceutical composition” refers to an active compound, formulated together with one or more pharmaceutically acceptable excipients. In some embodiments, a of the invention is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In certain embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, or capsules; and intravenous injection.

[0056] As used herein, the term “effective amount” refers to an amount sufficient to ameliorate a symptom of disease, effect beneficial or desired results, such as clinical results, and, as such, a “therapeutically effective amount” depends upon the context in which it is being applied. For example, an effective amount can be an amount of a of the invention that ameliorates a symptom of AATD and / or reduces the rate of onset or incidence of AATD or a symptom of AATD, including, but not limited to, the following benefits: improved liver and / or spleen function, lessened jaundice, improved lung function, lessened lung diseases and / or pulmonary exacerbations (e.g., emphysema), lessened skin disease (e.g., necrotizing panniculitis), increased growth in children, improved appetite, and reduced fatigue.

[0057] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 6 carbon atoms (e.g., 1 to 2 carbon atoms, 3 to 4 carbon atoms, or 5 to 6 carbon atoms). The alkyl can be optionally substituted (i.e., one or more of the hydrogen atoms of the alkyl can be replaced) with a halo, hydroxyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, oxo, thiol, or carboxyl group.

[0058] The term “alkyl heterocyclyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group. The heterocyclyl and alkyl portions may be optionally substituted as the individual groups as described herein.

[0059] The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthy I, indanyl, and 1 H-indenyl. The aryl can be optionally substituted (i.e., one or more of the hydrogen atoms of the aryl can be replaced) with a Ci-Ce alkyl, halo, hydroxyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, oxo, thiol, or carboxyl group.

[0060] The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, and monovalent mono- or polycarbocyclic radical of 3 to 6 carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The cycloalkyl can be optionally substituted (i.e., one or more of the hydrogen atoms of the cycloalkyl can be replaced) with a Ci-Ce alkyl, halo, hydroxyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, oxo, thiol, or carboxyl group.

[0061] The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1 , 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl. The heteroaryl can be optionally substituted (i.e., one or more of the hydrogen atoms of the heteroaryl can be replaced) with a Ci-Ce alkyl, halo, hydroxyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, oxo, thiol, or carboxyl group.

[0062] The term “heterocyclyl,” as used herein, refers a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridging, and / or spirocyclic rings having 3 to 12 atoms having at least one non-aromatic ring containing 1 , 2, 3, or 4 ring atoms selected from N, O or S and no aromatic ring containing any N, O, or S atoms. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl. The heterocyclyl can be optionally substituted (i.e., one or more of the hydrogen atoms of the heterocyclyl can be replaced) with a Ci-Ce alkyl, halo, hydroxyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, oxo, thiol, or carboxyl group. The term “halo,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0063] The term “hydroxyl,” as used herein, represents an — OH group.

[0064] The term “nitro,” as used herein, represents an — NO2 group.

[0065] The term “oxo,” as used herein, represents an =0 group.

[0066] The term “thiol,” as used herein, represents an — SH group.

[0067] The term “carboxyl,” as used herein, represents an — C(O)-OR group, where R is H or Ci-Ce alkyl.

[0068] DETAILED DESCRIPTION OF THE INVENTION

[0069] The invention features compounds that promote the proper folding of Z-AAT in multiple cell line models, reducing intracellular Z-AAT protein polymerization, and increasing secretion of functionally active AAT. The compounds can also facilitate proper folding and secretion of functionally active AAT in transgenic mice engineered to express human Z-AAT. Thus, compounds of the invention have the potential to address both the I oss-of-fu notion and the gain-of-function aspects of the Z mutation. By restoring physiological levels of circulating AAT activity, the compounds can reduce the risk of lung disease. By preventing Z-polymer formation in the liver, the compounds may reduce the risk of developing progressive liver disease (fibrosis and cirrhosis).

[0070] Compounds

[0071] The compounds of the invention may be made according to standard chemical practices or as described in the Examples.

[0072] Formulation and Administration

[0073] Exemplary routes of administration of pharmaceutical compositions (or the compounds of the composition) include oral and intravenous routes of administration.

[0074] The pharmaceutical compositions of the invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. Pharmaceutical compositions for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or spray drying equipment.

[0075] The pharmaceutical compositions of the invention can be administered in a pharmaceutically acceptable intravenous formulation containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for intravenous administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions. For example, to prepare such a composition, the compounds of the invention may be dissolved or suspended in an intravenously acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water; water adjusted to a suitable pH by addition of an appropriate amount of acid, base, or a suitable buffer; 1 ,3-butanediol; Ringer’s solution; and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p- hydroxybenzoate. Conventional procedures and ingredients for the selection and preparation of suitable intravenous formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 23rdEd., Adejare, Ed., Academic Press (2020) and in The United States Pharmacopeia and National Formulary (USP-NF 2021 Issues 1-3), published in 2021.

[0076] For administration to human subjects, a daily dose of a of the invention may be, for example, in the range 0.001 mg / kg to 5 mg / kg depending, of course, on the mode of and frequency of administration and the age and condition of the subject, etc. An oral daily dose can be in the range of 0.1 mg to 200 mg (e.g. , 1 mg to 50 mg) may be used. For convenience, the compounds of the present invention can be administered in a unit dosage form. If desired, multiple doses per day of the unit dosage form can be used to increase the total daily dose. For administration to human subjects, an infusion daily dose a of the invention may be in the range 1 mg to 50 mg depending, of course, on the mode of and frequency of administration and the age and condition of the subject, etc. The total daily dose may be administered in single or divided doses and may, at the physician’s discretion, fall outside of the typical ranges given herein.

[0077] Therapy

[0078] The compounds of the invention can be useful for treating conditions caused by AATD. The pathophysiology of AATD varies by the organ affected. Abnormally folded AAT, especially Z-type (Z- AAT), aggregates and polymerizes within hepatocytes, resulting in liver disease, such as cirrhosis and, in some cases, hepatocellular carcinoma. Lung disease has been classically thought to be due to a loss-of-function mechanism: lower AAT levels lead to unchecked activity of neutrophil elastase and subsequent alveolar destruction. Less common manifestations of AAT deficiency include membranoproliferative glomerular nephritis, rheumatoid arthritis, vascular disease including bleeding disorders, panniculitis, uveitis, and vasculitis.

[0079] AATD leads to lung disease due to reduced inhibition of neutrophil elastase in the lung. AAT enters the lung interstitium and alveolar lining fluid via passive diffusion from plasma. Unchecked elastase activity in alveolae leads to destruction of the lung parenchyma. The primary manifestation of disease is emphysema with severe airflow obstruction. Subjects may also develop chronic bronchitis, bronchiectasis and asthma. Between 85 and 100% of subjects with the PiZZ genotype develop lung disease in their fourth or fifth decade. Other genotypes have a lower likelihood of developing lung disease and generally develop disease in their fifth decade or later. Smoking dramatically alters the phenotype in all AAT deficient subjects. Smokers are more likely to develop disease and to experience earlier onset (generally 20 years earlier) and more severe disease. Lung disease in AATD may additionally be due to monocyte and macrophage derived pathogenic Z-protein. Misfolded AAT in PiZZ or PiSZ mutants is expressed by macrophages and has been demonstrated to be pro- inflammatory. The more severe lung phenotype of PiZZ and PiSZ genotypes may be due to the secretion of an altered protein in lung tissue by macrophages and monocytes.

[0080] AATD leads to liver disease in up to 50% of AAT subjects and leads to severe liver disease in up to 30% of subjects. Liver disease may manifest as: (a) cirrhosis during that is self-limiting, (b) severe cirrhosis during childhood or adulthood that requires liver transplantation or leads to death and (c) hepatocellular carcinoma that is often deadly. The onset of liver disease is bi-modal, predominantly affecting children or adults. Childhood disease is self-limiting in many cases but may lead to end-stage, deadly cirrhosis. Up to 18% of subjects with the PiZZ genotype may develop clinically significant liver abnormalities during childhood. Approximately 2% of PiZZ subjects develop severe liver cirrhosis leading to death during childhood. Adult-onset liver disease may affect subjects with all genotypes but presents earlier in subjects with the PiZZ genotype. Approximately 2-10% of AAT deficient subjects develop adult-onset liver disease.

[0081] The development of liver disease in AATD may be fatal in a large proportion of subjects: in one study, 40% of adult-onset liver disease subjects survived less than 2 years.

[0082] The following examples are meant to illustrate the invention. They are not meant to limit the invention in any way. The LC-MS methods described in the Examples can be any of methods A-D, described below.

[0083] Method A:

[0084] Instrumentation

[0085] LC: Waters Acquity H-Class

[0086] UV Detection: Waters Acquity PDA eA (195-360nm), 20 pts / sec

[0087] MS Detection: Waters Acquity QDa Performance, ESI (ES+ / ES-, 120-1200 amu) Mobile Phase

[0088] Eluent A: Milli-Q H2O + 10mM Ammonium Formate pH: 3.8 (Am.F.)

[0089] Eluent B: ACN

[0090] Column: Waters Acquity UPLC CSH C18, 1.7pm, 2.1 x 30mm at 40°C

[0091] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0092] Flow: 0.9 mL / min

[0093] Method B: Instrumentation LC: Waters Acquity H-Class

[0094] UV Detection: Waters Acquity PDA eA (195-360nm), 20 pts / sec MS Detection: Waters Acquity QDa Performance, ESI (ES+ / ES-, 120-1200 amu) Mobile Phase

[0095] Eluent A: Milli-Q H2O + 10mM Ammonium Bicarbonate pH: 10 (Am.B.)

[0096] Eluent B: ACN

[0097] Column: Waters Acquity UPLC CSH C18, 1.7pm, 2.1 x 30mm at 40°C

[0098] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1.8 minute

[0099] Flow: 0.9 mL / min

[0100] Method C: Instrumentation

[0101] LC: Waters Acquity H-Class

[0102] UV Detection: Waters Acquity PDA eA (195-360nm), 20 pts / sec

[0103] MS Detection: Waters Acquity QDa Performance, ESI (ES+ / ES-, 120-1200 amu) Mobile Phase

[0104] Eluent A: Milli-Q H2O + 10mM Ammonium Formate pH: 3.8 (Am.F.)

[0105] Eluent B: ACN

[0106] Column: Waters Acquity UPLC CSH C18, 1.7pm, 2.1 x 30mm at 40°C

[0107] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0108] Flow: 0.9 mL / min

[0109] Method D:

[0110] Instrumentation

[0111] LC: Waters Acquity H-Class

[0112] UV Detection: Waters Acquity PDA eA (195-360nm), 20 pts / sec

[0113] MS Detection: Waters Acquity QDa Performance, ESI (ES+ / ES-, 120-1200 amu) Mobile Phase

[0114] Eluent A: Milli-Q H2O + 10mM Ammonium Formate pH: 3.8 (Am.F.)

[0115] Eluent B: ACN

[0116] Column: Waters Acquity UPLC CSH C18, 1.7pm, 2.1 x 30mm at 40°C

[0117] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1.8 minute

[0118] Flow: 0.9 mL / min

[0119] EXAMPLES

[0120] Example 1 : 1 Synthesis

[0121] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)benzoic acid (1 ).

[0122] Synthesis of 5-bromo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazole: bromo-6-nitro-1 H-indazole (1.00 g, 4.13 mmol) in dichloromethane (15 mL), was added 3,4-dihydro- 2H-pyran (1.17 mL, 12.4 mmol), followed by p-toluenesulfonic acid monohydrate (79.8 mg, 0.41 mmol). The reaction mixture was stirred at room temperature for 1 h. Volatiles were removed under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (1-10% ethyl acetate in heptanes) to afford the titled (1.19 g, 87%) as a yellow solid. Product did not ionize in mass spectrometry, carried forward to the next step without further characterization.

[0123] Synthesis of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-amine: To a solution of 5- bromo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazole (757 mg, 2.32 mmol) in DMSO (10 mL), were added 2,2'-bipyridy I (18.5 mg, 0.116 mmol), followed by tetrahydroxydiboron (837 mg, 9.28 mmol). The reaction mixture was stirred at 35 °C for 1.5 h. Then was treated with sat. aq. NaHCOs (25 mL) and extracted with ethyl acetate (2x25 mL). Combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude residue, which was purified using normal phase flash chromatography on silica gel (1-50% of ethyl acetate in heptanes) to afford the title (600 mg, 85%) as a white solid. LS-MS (m / z): calc. 296.17, found 296.0 (M+H).

[0124] Synthesis of 6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[3,4- g]quinoxalin-7-one: To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine (600 mg, 2.03 mmol), 2-amino-2-methylpropanoic acid (421 mg, 4.05 mmol), DMEDA (134 pL, 1.22 mmol), and K3PO4 (439 mg, 2.03 mmol), was added DMSO (10 mL). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then CuCI (62 mg, 0.608 mmol) was added. The reaction mixture was heated to 140 °C for 5 h. After cooling down to room temperature, the resulting suspension was filtered through CELITE® pad and washed with EtOAc (50 mL). The filtrate was washed with water (25 mL), followed by brine (25 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude title compound. The yield considered quantitative and carried forward to the next step without further purification. LS-MS (m / z): calc. 300.36, found 301.2 (M+H).

[0125] Synthesis of ethyl 4-(6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a suspension of 6,6-dimethyl-1-(tetrahydro-2H-pyran-2- yl)-1 ,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one (680 mg, 2.26 mmol; from previous step) in degassed dioxane (10.6 mL), was added ethyl 4-bromobenzoate (1.13 mL, 6.79 mmol), followed by (1R,2R)-N1 ,N2-dimethylcyclohexane-1 ,2-diamine (Ligand; 304 pL, 1.81 mmol), and K2CO3 (626 mg, 4.53 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then Cui (173 mg, 0.906 mmol) was added. The reaction mixture was heated to 100 °C for 8 h, cooled down to room temperature, filtered through a pad of CELITE®, and washed with ethyl acetate (50 mL). The filtrate was washed with water (25 mL), followed by brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified using reverse phase flash chromatography on C18 (5-70% acetonitrile in 10 mM ammonium bicarbonate buffer pH=10) to afford the title (510 mg, 48%) as an off-white solid. LS-MS (m / z): calc. 448.52, found 449.3 (M+H).

[0126] Synthesis of ethyl 4-(5-(4-fluorophenyl)-6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-

[0127] 1.5.6.7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a mixture of ethyl 4-(6,6-dimethyl- 7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (485 mg, 1.08 mmol) in toluene (9.6 mL), was added NaOtBu (214 mg, 2.16 mmol), followed by 1- bromo-4-fluorobenzene (144 pL, 1.30 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then tBuXphos Pd G3 (44.3 mg, 0.054 mmol) was added. The reaction mixture was heated to 110 °C for 18 h, cooled down to room temperature, diluted with ethyl acetate (25 mL), filtered through CELITE® pad, and washed with ethyl acetate (25 mL). The filtrate was washed with water (25 mL), followed by brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified using reverse phase flash chromatography on C18 (5-100% acetonitrile in 10 mM ammonium bicarbonate buffer pH=10) to afford the title (95 mg, 16%) as an off-white solid. LS-MS (m / z): calc. 542.61 , found 543.2 (M+H).

[0128] Synthesis of 4-(5-(4-fluorophenyl)-6, 6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 , 5,6,7- tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid:

[0129] Step 1 : To a solution of ethyl 4-(5-(4-fluorophenyl)-6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-

[0130] 1.5.6.7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (50 mg, 0.092 mmol) in THF (0.5 mL) was added (CHs^S BHs (22.0 pL, 0.230 mmol). The reaction mixture was stirred at room temperature for 1 h, then at 80 °C for 1 h, and then at 90 °C for 1 h. The mixture was cooled down to room temperature and treated with sat. aq. NaHCOs, and extracted with ethyl acetate (2x20 mL). Combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude yellow residue was carried forward to the next step without further purification. LC-MS (m / z): calc. 528.63, found 529.3 (M+H).

[0131] Step 2: To a solution of above crude (25 mg, 0.047 mmol) in 2 ml_ of solvent mixture THF / MeOH / water (2:1 :1 ), was added 4M aq. NaOH (0.355 mL, 1.42 mmol). The reaction mixture was stirred at 40 °C for 1 h. After removing all volatiles, the pH of the solution was adjusted to 3 with 1 M aq. HCI and then extracted with EtOAc (2x15 mL). Combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the titled as a yellow solid. The yield considered quantitative, and the was carried forward to the next step without purification. LC-MS (m / z): calc. 500.57, found 501.3 (M+H).

[0132] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoic acid (1 ): To a solution of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro- 2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (23 mg, 0.046 mmol) in 1.25 mL of solvent mixture EtOAc / MeOH / water (2:2:1) was added p-toluenesulfonic acid monohydrate (17.7 mg, 0.092 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled down, diluted with water (25 mL), and extracted into ethyl acetate (2x20 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified using reverse phase flash chromatography on C18 (5-50% acetonitrile in aq. 10 mM ammonium bicarbonate buffer pH=10) to afford the title (1; 6.40 mg, 33%) as a yellow solid. LC-MS (m / z): calc. 416.46, found 417.2 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.21 (br s, 1 H), 7.91 (d, J = 8.6, 2H), 7.55 (d, J = 0.9, 1 H), 7.43 (d, J = 8.6, 2H), 7.36 - 7.26 (m, 4H), 6.99 (s, 1H), 6.05 (s, 1 H), 3.73 (s, 2H), 1.09 (s, 6H).

[0133] Example 2: 2 Synthesis

[0134] Synthesis of 4-(6,6-dimethyl-7-oxo-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid

[0135] Compound 2

[0136] Synthesis of 4-(6,6-dimethyl-7-oxo-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid: To a solution of ethyl 4-(6,6-dimethyl-7-oxo-1-(tetrahydro- 2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (45 mg, 0.100 mmol) in 5 ml of solvent mixture of THF / MeOH / water (2: 1:1 ), was added 4M aq. NaOH (125 L, 0.502 mmol). The reaction mixture was stirred at room temperature for 1 h. After removing volatiles under reduced pressure, the pH of the solution was adjusted to ~3 with 1 M aq. HCI and extracted with EtOAc (15 mL X 2). Combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title as an off-white solid. The yield considered quantitative, and the was carried forward to the next step without purification. LC-MS (m / z): calc. 420.18, found 421.3 (M+H).

[0137] Synthesis of 4-(6,6-dimethyl-7-oxo-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8- yljbenzoic acid (2): To a solution of 4-(6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 , 5,6,7- tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (36 mg, 0.085 mmol) in 2.25 ml of solvent mixture EtOAc / MeOH / water (2:2:1) was added p-toluenesulfonic acid monohydrate (33.1 mg, 0.171 mmol). The reaction mixture was stirred at 70 °C for 2h. The reaction mixture was cooled down to room temperature, diluted with water (25 mL), and extracted into ethyl acetate (25 mL, 15 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was lyophilized in acetonitrile and water mixture to afford the titled (2; 24.80 mg, 93%) as a brown solid. LC-MS (m / z): calc. 336.351, found 337.1 (M+H).1H NMR (400 MHz, DMSO) 5 = 12.36 (s, 1 H), 8.11 - 8.07 (m, 2H), 7.79 (d, J = 0.9, 1H), 7.34 - 7.28 (m, 2H), 7.06 (s, 1 H), 6.15 (s, 1H), 6.09 (s, 1 H), 1.34 (s, 6H); exchangeable acid proton is not visible.

[0138] Example 3: 3 Synthesis

[0139] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-7-oxo-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g']quinoxalin-

[0140] 8-yl)benzoic acid (3).

[0141] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-7-oxo-1-(tetrahydro-2 / - / -pyran-2-yl)-1 , 5,6,7- tetrahydro-8 / - / -pyrazolo[3,4-g']quinoxalin-8-yl)benzoic acid: To a solution of ethyl 4-(5-(4-fluoropheny I)- 6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)benzoate (30 mg, 0.055 mmol) in 2.5 ml_ of solvent mixture THF:MeOH:water (2:1 :1 ), was added 4M aq. NaOH (415 pL, 1.66 mmol). The reaction mixture was stirred at 40 °C for 1 h. After removing all volatiles under reduced pressure, the pH of the solution was adjusted to ~3 with 1 M aq. HCI and extracted with EtOAc (15 mL X 2). Combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the titled as a yellow solid. The yield considered quantitative, and the was carried forward to the next step without purification. LC-MS (m / z): calc. 514.2, found 515.2 (M+H).

[0142] Synthesis 4-(5-(4-fluorophenyl)-6,6-dimethyl-7-oxo-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4- g]quinoxalin-8-yl)benzoic acid (3): To a solution of 4-(5-(4-fluorophenyl)-6,6-dimethyl-7-oxo-1- (tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (15 mg, 0.029 mmol) in 0.75 ml of solvent mixture EtOAc: MeOH:water (2:2:1 ) was added p-toluenesulfonic acid monohydrate (11.3 mg, 0.058 mmol). The reaction mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled down to room temperature, diluted with water (25 ml_), and extracted into ethyl acetate (25 ml_, 15 ml_). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified over reverse phase flash chromatography on C18 (5-50% acetonitrile in aq. 10 mM ammonium bicarbonate buffer pH=10) to afford the title (3; 5.06 mg, 40%) as a white solid. LC-MS (m / z): calc. 430.439, found 431.2 (M+H).1H NMR (400 MHz, DMSO) 5 12.44 (s, 1 H), 8.14 (d, J = 8.1 , 2H), 7.74 (s, 1 H), 7.51 - 7.42 (m, 4H), 7.38 - 7.32 (m, 2H), 6.43 (s, 1 H), 6.29 (s, 1 H), 1.32 (s, 6H); acid proton is not visible. Example 4: 4 Synthesis

[0143] Synthesis of p-[10-(p-fluorophenyl)-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13- yl]benzoic acid (4).

[0144] Compound 4

[0145] Synthesis of / V-(4-fluorophenyl)-6-nitro-1-(tetrahydro-2 / - / -pyran-2-yl)-1 / - / -indazol-5-amine: To a mixture of 5-bromo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazole (1.40 g, 4.08 mmol), Pd(OAc)2 (189 mg, 0.816 mmol), BINAP (777 mg, 1.22 mmol), and CS2CO3 (2.71g, 8.16 mmol), 4-fluoroaniline (468 L, 4.89 mmol) was added toluene (16.8 ml_). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes. The reaction mixture was heated to 100 °C, stirring continued for 2 h, cooled down to room temperature, the resulting suspension was filtered through CELITE® using EtOAc (100 mL). The filtrate was concentrated under reduced pressure to afford a crude residue, which was purified using normal phase flash chromatography on silica gel (1-10% of ethyl acetate in heptanes) to afford the title (1.40 g, 96%) as a red solid. LC-MS (m / z): calc. 356.13, found 356.2 (M+H).

[0146] Synthesis of / V5-(4-fluorophenyl)-1-(tetrahydro-2 / - / -pyran-2-yl)-1 / - / -indazole-5,6-diamine: To a mixture of / V-(4-fluorophenyl)-6-nitro-1-(tetrahydro-2 / - / -pyran-2-yl)-1 / - / -indazol-5-amine (600 mg, 1.60 mmol) in 37.5 ml of solvent mixture EtOAc:MeOH (1 :4) was added 10% wt / wt of Pd / C (89.9 mg). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 5 h. The reaction mixture was then diluted with ethyl acetate (25 mL) and MeOH (25 mL), filtered through CELITE®. The filtrate was concentrated under reduced pressure to afford the title (480 mg, 92%) as an off-white solid. LC-MS (m / z): calc. 326.15, found 327.2 (M+H).

[0147] Synthesis of 5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,8-tetrahydro-7H- pyrazolo[3,4-g]quinoxalin-7-one:

[0148] Step 1 : A solution of / V5-(4-fluorophenyl)-1-(tetrahydro-2 / - / -pyran-2-yl)-1 / - / -indazole-5,6-diamine (310 mg, 0.950 mmol), EtsN (147 pL, 1.04 mmol) in tetrahydrofuran (7.5 mL) was cooled down to 0 °C, and bromoacetyl chloride (83.3 pL, 0.950 mmol) was added slowly. The reaction mixture was allowed to warm up to room temperature, stirring continued for 20 min, diluted with water (25 mL), and extracted into ethyl acetate (25 mL, 15 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford an off-white solid. The crude residue was carried forward to the next step without further purification.

[0149] Step 2: To a solution of above crude (410 mg, 0.917 mmol) in 7.50 ml of solvent mixture THF:DMF (2:1 ), was added K2CO3 (139 mg, 1.01 mmol). The reaction mixture was heated to 60 °C and stirring continued for 4 h. Cooled down to room temperature, diluted with water (25 mL), and extracted into EtOAc (25 mL x 3). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly purified using normal phase flash chromatography on silica gel (1-20% ethyl acetate in heptanes) to afford the title (224 mg, 49%) as an off-white solid. LC-MS (m / z): calc. 366.15, found 367.2 (M+H).

[0150] Synthesis of ethyl 4-(5-(4-fluorophenyl)-7-oxo-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro- 8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a suspension of 5-(4-fluorophenyl)-1-(tetrahydro-2H- pyran-2-yl)-1 ,5,6,8-tetrahydro-7 / - / -pyrazolo[3,4-g]quinoxalin-7-one (180 mg, 0.368 mmol) in dioxane (2.91 mL), was added ethyl 4-bromobenzoate (184 pL, 1.11 mmol)), followed by (1R,2R)-N1 ,N2- dimethylcyclohexane-1,2-diamine (Ligand, 12.4 pL, 0.074 mmol), and K2CO3 (107 mg, 0.774 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then Cui (14.1 mg, 0.074 mmol) was added. The reaction mixture was heated to 100 °C, stirring continued for 18 h, cooled down to room temperature, diluted with ethyl acetate (10 mL), filtered through a pad of CELITE®, and washed with ethyl acetate (—50 mL). The filtrate was washed with water (25 mL), followed by brine (25 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified using reverse phase flash chromatography on C18 (5-70% acetonitrile in 10 mM aq. ammonium bicarbonate pH=10) to afford the title (116 mg, 61%) as a white solid. LC-MS (m / z): calc. 514.20, found 515.2 (M+H).

[0151] Synthesis of 4-(5-(4-fluorophenyl)-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid:

[0152] Step 1 : To a solution of ethyl 4-(5-(4-fluorophenyl)-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 , 5,6,7- tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (35 mg, 0.068 mmol) in tetrahydrofuran (400 pL), was added (CHs^S BHs (16.1 pL, 0.170 mmol). The reaction mixture was stirred at room temperature for 1 h, then at 80 °C for 5 h. The mixture was cooled down to room temperature and treated with satd. aq. solution of NaHCOs (25 mL) and extracted with ethyl acetate (25 mL, 15 mL). Combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a yellow solid. The crude residue was carried forward to the next step without further purification.

[0153] Step 2: To a solution of above crude (35 mg, 0.069 mmol) in 5.0 ml_ of solvent mixture THF:MeOH:water (2:1 :1 ), was added 4M aq. NaOH (524 pL, 2.10 mmol). The reaction mixture was stirred at 50 °C for 1 h. After removing all volatiles, the pH of the solution was adjusted to ~3 with 1 M aq. HCI and extracted with EtOAc (15 mL X 2). Combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title as a yellow solid. The yield considered quantitative, and the was carried forward to the next step without purification. LC-MS (m / z): calc. 472.19, found 473.3 (M+H).

[0154] Synthesis of p-[10-(p-fluoropheny l)-4, 5, 10, 13-tetraazatricyclo[7.4.0.03,7]trideca-1 , 3(7), 5,8- tetraen-13-yl]benzoic acid (4): To a solution of 4-(5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (40 mg, 0.085 mmol) in 2.0 ml of solvent mixture EtOAc:MeOH:water (2:2:1 ) was added p-toluenesulfonic acid monohydrate (32.7 mg, 0.169 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled down to room temperature, diluted with water (25 mL), and extracted into ethyl acetate (25 mL, 15 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified using reverse phase flash chromatography on C18 (5-50% acetonitrile in aq. 10 mM ammonium bicarbonate buffer pH=10) to afford the title (4; 6.53 mg, 33%) as a yellow solid. LC-MS (m / z): calc. 388.402, found 389.1 (M+H).1H NMR (400 MHz, DMSO- D6) 5 12.44 (s, 1H), 7.90 (d, J=8.4, 2H), 7.74 (d, J=0.8, 1 H), 7.38 (d, J=8.4, 2H), 7.30 - 7.24 (m, 2H), 7.24 - 7.17 (m, 2H), 7.08 (s, 1H), 6.96 (s, 1 H), 3.91 - 3.84 (m, 2H), 3.77 - 3.71 (m, 2H); acid proton was not visible. Example 5: 5 and 6 Synthesis

[0155] Synthesis of 4-(5-(4-fluorophenyl)-6-oxo-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (5) and 4-(5-(4-fluorophenyl)-7-oxo-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (6).

[0156] Compound 5 Compound 6

[0157] Synthesis of 4-((5-(2-chloro-N-(4-fluorophenyl)acetamido)-1-(tetrahydro-2H-pyran-2-yl)-1 H- indazol-6-yl)amino)benzoic acid and 4-(2-chloro-N-(5-((4-fluorophenyl)amino)-1-(tetrahydro-2H-pyran- 2-yl)-1 H-indazol-6-yl)acetamido)benzoic acid: To a solution of 4-((5-((4-fluorophenyl)amino)-1- (tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-yl)amino)benzoic acid (68.0 mg, 152 pmol) in tetrahydrofuran (2.00 ml_) at 0 °C, was added sodium hydride 60% in dispersion in mineral oil (30.5 mg, 762 pmol) and stirring continued for 10 min. A solution of chloroacetyl chloride (14.7 pL, 183 pmol) in tetrahydrofuran (2.00 ml_) was added slowly, and then the reaction mixture was allowed to warm to room temperature, stirring continued for 3 h. Additional quantity of chloroacetyl chloride (36.7 pL, 457 pmol) was added, and continued the stirring at room temperature for additional 17 h (until complete conversion by LC-MS). The reaction mixture was quenched with saturated aq. ammonium chloride solution (10 ml_) and extracted with ethyl acetate (2x25 ml_). The combined organics were dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a mixture of 4-((5-(2- chloro-N-(4-fluorophenyl)acetamido)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)amino)benzoic acid and 4-(2-chloro-N-(5-((4-fluorophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6- yl)acetamido)benzoic acid (73 mg, 92%). LC-MS (m / z): calc. 522.15, found 523.2 (M+H). The mixture was carried forward to the next step without purification / separation. Synthesis of 4-(5-(4-fluorophenyl)-6-oxo-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)benzoic acid (5) and 4-(5-(4-fluorophenyl)-7-oxo-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)benzoic acid (6): To a solution of 4-((5-(2-chloro-N-(4-fluorophenyl)acetamido)-1-(tetrahydro-2H- pyran-2-yl)-1 H-indazol-6-yl)amino)benzoic acid and 4-(2-chloro-N-(5-((4-fluorophenyl)amino)-1- (tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-yl)acetamido)benzoic acid mixture in ethyl acetate / methanol / water mixture (1 : 1 :0.5 ml_), was added p-toluenesulfonic acid monohydrate (172 mg, 889 pmol). The reaction mixture was heated to 70 °C, stirring continued for 1 h, showing complete conversion to THP deprotected intermediate by LC-MS. The reaction mixture was basified to pH ~ 9 using 1 M aq. KOH solution (~3 mL) and heated to 70 °C, stirring continued for 1 h, showing complete cyclization by LC-MS. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by reverse phase column chromatography on C18 column (5-100% acetonitrile in 10 mM aq. ammonium bicarbonate buffer pH=10) to obtain the title compounds. 5: 8 mg, 14% yield, white solid. LC-MS (m / z): calc. 402.385, found 403.2 (M+H).1H NMR (400 MHz, CD3OD) 5 8.07 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 0.8 Hz, 1 H), 7.45 - 7.37 (m, 4H), 7.32 (t, J = 8.7 Hz, 2H), 7.18 (s, 1H), 6.79 (s, 1 H), 4.49 (s, 2H). 6: 1.20 mg, 2.1% yield, white solid. LC-MS (m / z): calc. 402.385, found 403.2 (M+H).1H NMR (400 MHz, DMSO) 5 12.56 (s, 1H), 8.14 (d, J=8.4, 2H), 7.85 (s, 1 H), 7.52 (d, J=8.2, 2H), 7.38 - 7.32 (m, 2H), 7.31 - 7.25 (m, 2H), 7.09 (s, 1 H), 6.39 (s, 1 H), 4.38 (s, 2H). Acid proton is not visible.

[0158] Example 6: 7 Synthesis

[0159] Synthesis of p-[10'-(p-fluorophenyl)-2,3,5,6-tetrahydrospiro[pyran-4,11'- [4,5,10,13]tetraazatricyclo[7.4.0.03,7]trideca[1,3(7),5,8]tetraen]-13'-yl]benzoic acid (7).

[0160] This was prepared using the methods described in Example 1 but using 4-aminotetrahydro-

[0161] 2H-pyran-4-carboxylic acid to produce 7 (shown below). Compound 7

[0162] LC-MS (m / z): calc. 458.493, found 459.2 (M+H).1H NMR (400 MHz, DMSO) 5 12.26 (s, 1 H), 7.90 (d,

[0163] J=8.8, 2H), 7.59 - 7.57 (m, 1 H), 7.50 (d, J=8.8, 2H), 7.38 - 7.32 (m, 2H), 7.31 - 7.26 (m, 2H), 7.02 (s, 1 H), 6.11 (s, 1H), 4.02 (s, 2H), 3.65 - 3.55 (m, 2H), 3.40 - 3.34 (m, 2H), 1.62 - 1.55 (m, 4H). Acid proton is not visible. Example 7: 8 Synthesis

[0164] Synthesis of p-[10'-(p-fluorophenyl)-12'-oxo-2,3,5,6-tetrahydrospiro[pyran-4, 11'- [4,5,10,13]tetraazatricyclo[7.4.0.03,7]trideca[1,3(7),5,8]tetraen]-13'-yl]benzoic acid (8).

[0165] This was prepared using the methods described in Example 1 , but using 4-aminotetrahydro-

[0166] 2H-pyran-4-carboxylic acid to produce 8 (shown below). Compound 8

[0167] LC-MS (m / z): calc. 472.476, found 473.2 (M+H).1H NMR (400 MHz, DMSO) 5 12.59 (s, 1 H), 8.23 -

[0168] 8.02 (m, 2H), 7.85 (s, 1H), 7.56 - 7.47 (m, 2H), 7.45 - 7.40 (m, 2H), 7.30 - 7.22 (m, 3H), 6.33 (s, 1 H), 3.87 - 3.78 (m, 2H), 3.69 - 3.59 (m, 2H), 1.91 - 1.82 (m, 2H), 1.68 - 1.59 (m, 2H). Acid proton is not visible.

[0169] Example 8: 9 Synthesis

[0170] Synthesis of (R)-2-chloro-4-(5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-1,5,6,7- tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (9).

[0171] Synthesis of (6S)-6-(hydroxymethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,8-tetrahydro- 7H-pyrazolo[3,4-g] quinoxalin-7-one: To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1 H- indazol-6-amine (2.5 g, 8.44 mmol), (S)-2-amino-3-hydroxy-2-methylpropanoic acid (2.0 g, 16.88 mmol), DMEDA (594.9 mg, 6.75 mmol) and K3PO4 (3.5 g, 16.88 mmol) was added DMSO (10 ml_). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then CuBr (482 mg, 3.38 mmol) was added. The reaction mixture was heated to 140 °C for 4 h. After completion of the reaction, the reaction mixture cooled down to room temperature, the resulting suspension was filtered through CELITE® pad and washed with ethyl acetate (50 ml_). The filtrate was diluted with water (100 ml_) and extracted with ethyl acetate (3x50 ml_), dichloromethane (50 ml_). The organic layer was washed with brine (100 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to a crude residue, which was purified using normal phase flash chromatography on silica gel (60-120% of ethyl acetate in heptane’s) to afford the title (1.3 g, 49%) as a pale-brown solid. LC-MS (m / z): calc. 316.15, found 317.17 (M+H).

[0172] Synthesis of ((6S)-6-methyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-5,6,7,8-tetrahydro-1 H- pyrazolo[3,4-g] quinoxalin-6-yl) methyl methane sulfonate: To a solution of (6S)-6-(hydroxymethyl)-6- methyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,8-tetrahydro-7H-pyrazolo[3,4-g] quinoxalin-7-one (1.3 g, 4.10 mmol) in dichloromethane (20 mL) was added pyridine (1.65 mL, 20.54 mmol). The reaction mixture was cooled to 0 °C, followed by the addition of methane sulfonyl chloride (0.48 mL, 6.16 mmol) and was stirred at RT for 5 h. After completion of the reaction, the reaction mixture was diluted with water (80 mL), extracted with dichloromethane (3x75 mL) followed by brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude (1.6 g). LC-MS (m / z): calc. 394.13, found 395.13 (M+H).

[0173] Synthesis of (1aS)-1a-methyl-5-(tetrahydro-2H-pyran-2-yl)-1 ,1a,3,5-tetrahydro-2H-azirino[1 ,2- a] pyrazolo[3,4-g] quinoxalin-2-one: To a solution of ((6S)-6-methyl-7-oxo-1-(tetrahydro-2H-pyran-2- yl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-g] quinoxalin-6-yl) methyl methane sulfonate (1.6 g, 4.05 mmol) in methanol (10 mL) was added DIPEA (3.5 mL, 20.28 mmol). The reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction (by TLC), volatiles were removed under reduced pressure to afford the crude material, diluted with water (50 mL), extracted with dichloromethane (2x50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to provide the crude material (1.2 g). LC-MS (m / z): calc. 298.14, found 299.40 (M+H).

[0174] Synthesis of (6S)-6-(methoxymethyl)-6-methyl-1 -(tetrahydro-2H-pyran-2-yl)-1, 5,6,8- tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one: To a solution of (1aS)-1a-methyl-5-(tetrahydro-2H- pyran-2-yl)-1 ,1a,3,5-tetrahydro-2H-azirino[1 ,2-a] pyrazolo[3,4-g] quinoxalin-2-one (1.22 g, 4.08 mmol) in methanol (25 mL) was added p-toluene sulphonic acid (77.78 mg, 0.40 mmol). The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, volatiles were removed under reduced pressure to afford the crude material, diluted with water (50 mL), extracted with dichloromethane (2x50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to provide the crude material which was directly purified by normal phase flash chromatography on silica gel (40-50% ethyl acetate in hexanes) to afford the titled (0.52 g; 38%) as a brown solid. LS-MS (m / z): calc. 330.17, found 331.38 (M+H).

[0175] Synthesis of tert-butyl 2-chloro-4-((6S)-6-(methoxymethyl)-6-methyl-7-oxo-1-(tetrahydro-2H- pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a suspension of (6S)- 6-(methoxymethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[3,4- g]quinoxalin-7-one (0.3 g, 0.91 mmol) in dioxane (20 mL), was added tert-butyl 4-bromo-2- chlorobenzoate (0.794 g, 2.72 mmol), followed by (1R,2R)-N1 ,N2-dimethylcyclohexane-1,2-diamine (0.103 g, 0.73 mmol), and K2CO3 (0.251 g, 1.82 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then Cui (0.069 g, 0.36 mmol) was added. The reaction mass was heated to 100 °C for 16 h. After completion of the reaction, the reaction mixture was cooled down to room temperature, filtered through a pad of CELITE® and washed with ethyl acetate (75 mL). Volatiles were concentrated under reduced pressure to provide the crude material which was directly purified by normal phase flash chromatography on silica gel (30-35 % ethyl acetate in hexanes) to afford the titled (0.3 g; 61%) as a pale-brown solid. LS-MS (m / z): calc. 540.21 , found 541.23 (M+H).

[0176] Synthesis of tert-butyl 2-chloro-4-((6S)-5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6- methyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)benzoate: To a suspension of tert-butyl 2-chloro-4-((6S)-6-(methoxymethyl)-6-methyl-7-oxo-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (175 mg, 0.32 mmol) in toluene (5 mL), was added NaOtBu (93.25 mg, 0.97 mmol), followed by 4-bromo-1- fluoro-2-methoxybenzene (198 mg, 0.97 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then chloro[(tri-tertbutylphosphine)-2-(2-aminobiphenyl)] palladium (II) (82.87 mg, 0.16 mmol) was added. The reaction mass was heated to 900C for 3 h. After completion of the reaction, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate (20 mL), filtered through CELITE® pad, and washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified using normal phase flash chromatography on silica gel (30-35 % ethyl acetate in hexanes) to afford the titled (0.1 g) as palebrown solid. LS-MS (m / z): calc. 664.24, found 665.34 (M+H).

[0177] Synthesis of tert-butyl 2-chloro-4-((6R)-5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6- methyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a solution of tert-butyl 2-chloro-4-((6S)-5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-7- oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (190 mg, 0.28 mmol) in THF (10 mL) was added (CH3)2S BH3(0.71 mL, 1.43 mmol)( 2 M in THF). The reaction mixture was gradually heated to 70 °C for 5 h. After completion of the reaction (by TLC), the reaction mass was cooled down to room temperature and slowly quenched with methanol (5 mL) at 0 °C and stirred at same temperature for 20 min. Volatiles were removed under reduced pressure to provide the crude material (180 mg) as a pale-yellow solid which was taken as such for the next step without any purification. LC-MS (m / z): calc. 650.26, found 651.05 (M+H).

[0178] Synthesis of (R)-2-chloro-4-(5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl- 1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (9): To a stirred solution of tert-butyl 2-chloro-4-((6R)-5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (190 mg, 0.29 mmol) in dichloromethane (10 mL) was added TFA (0.67 mL, 8.75 mmol) at 0 °C . The reaction mixture gradually heated to 40 °C and stirred at the same temperature for 16 h. After completion of the reaction, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate (20 mL), filtered through CELITE® pad, and washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC, Column: YMC ACTUS TRIART PHENYL C8 (100*20mm), 3 urn, Mobile Phase A: 0.1% Formic Acid in water Mobile Phase B: 100% Acetonitrile; Flow Rate: 10 mL / min to afford the title 9 (30 mg, 20%) as a paleyellow solid. LC-MS (m / z): calc. 510.14, found 511.29 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.87 (br. s, 1H), 12.32 (br. s, 1H), 7.84 (d, J = 8.8 Hz, 1 H), 7.63 (s, 1H), 7.41 - 7.31 (m, 3H), 7.11 (s, 1 H), 7.03 (dd, J = 2.4, 8.0 Hz, 1 H), 6.85 - 6.81 (m, 1 H), 6.18 (s, 1 H), 4.06 - 4.03 (m, 1 H), 3.83 (s, 3H), 3.58 - 3.55 (m, 1 H), 3.28 - 3.26 (m, 2H), 2.98 (s, 3H), 1.05 (s, 3H).

[0179] Example 9: 10 Synthesis

[0180] Synthesis of 4-(9-fluoro-5-(4-fluoro-3-isopropoxyphenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (10) bromo-6-nitro-1 H-indazole (3.00 g, 12.39 mmol) in dichloromethane (35 ml_), was added 3,4-dihydro- 2H-pyran (3.12 g, 37.18 mmol), followed by p-toluene sulfonic acid monohydrate (236 mg, 1.24 mmol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, volatiles were removed under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (1-10% ethyl acetate in hexanes) to afford the titled (2.5 g, 61.8%) as brown gummy mass. Product did not ionize in mass spectrometry, carried forward to the next step without further characterization.

[0181] Synthesis of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-amine: To a solution of 5- bromo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazole (500 mg, 1.53 mmol) in EtOH (10 ml_) and water (2 ml_), were added ammonium chloride (410 mg, 7.66 mmol) and iron powder (421.5 mg, 7.66 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite bed. The celite bed was washed with dichloromethane (20 ml_) and the filtrate was concentrated to get the crude material. The crude material was diluted with water (50 ml_) and extracted with ethyl acetate (2x25 ml_). Volatiles were removed under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (10-30% ethyl acetate in hexanes) to afford the titled (257 mg, 56%) as brown solid. LC-MS (m / z): calc. 295.15, found 296.2 (M+H).

[0182] Synthesis of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-amine: To a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-amine (5 g, 16.88 mmol) in THF (30 ml_) and ACN (30 ml_), were added Sodium bicarbonate (4.25 g, 50.64 mmol) and SELECTFLUR™ (6.57 g, 18.57 mmol) at RT. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with water (100 ml_) and extracted with ethyl acetate (3x100 ml_). Volatiles were removed under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (10-15 % ethyl acetate in hexanes) to afford the titled (3 g, 56%) as brown gummy material. LC-MS (m / z): calc. 313.02, found 314.03 (M+H).

[0183] Synthesis of 9-fluoro-6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,8-tetrahydro-7H- pyrazolo[3,4-g] quinoxalin-7-one: To a mixture of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1 H- indazol-6-amine (3 g, 9.54 mmol), 2-amino-2-methylpropanoic acid (1.96 g, 19.09 mmol), DMEDA (0.822 mL, 7.63 mmol), and K3PO4 (4.05 g, 19.09 mmol), was added DMSO (35 mL). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then CuBr (411 mg, 2.86 mmol) was added. The reaction mixture was heated to 140 °C for 5 h. After completion of the reaction, the reaction mixture was cooled down to room temperature, the resulting suspension was filtered through CELITE® pad and washed with ethyl acetate (75 mL). The filtrate was washed with water (30 mL), followed by brine (30 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude which was directly purified by normal phase flash chromatography on silica gel (20-30 % ethyl acetate in hexanes) to afford the titled (1.3 g, 42%) as brown solid. LC-MS (m / z): calc. 318.15, found 319.18 (M+H).

[0184] Synthesis of tert-butyl 4-(9-fluoro-6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 , 5,6,7- tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a suspension of 9-fluoro-6,6-dimethyl-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one (1.3 g, 4.08 mmol) in degassed dioxane (15 mL), was added tert-butyl 4-iodobenzoate (2.48 g, 8.16 mmol), followed by (1R,2R)-N1 ,N2-dimethylcyclohexane-1 ,2-diamine (0.58 g, 4.08 mmol), and K2CO3 (1.12 g, 8.16 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then Cui (0.38 g, 2.04 mmol) was added. The reaction mixture was heated to 90 °C for 15 h. After completion of the reaction, cooled down to room temperature, filtered through a pad of CELITE®, and washed with ethyl acetate (75 mL). The filtrate was washed with water (30 mL), followed by brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by normal phase flash chromatography on silica gel (20-50 % ethyl acetate in hexanes) to afford the titled (1.4 g, 70%) as brown solid LC-MS (m / z): calc. 494.23, found 495.28 (M+H).

[0185] Synthesis of tert-butyl 4-(9-fluoro-5-(4-fluoro-3-isopropoxyphenyl)-6,6-dimethyl-7-oxo-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a mixture of tert-butyl 4-(9-fluoro-6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (350 mg, 0.688 mmol) in toluene (5 mL), was added NaOtBu (132.26 mg, 1.37 mmol), followed by 4-bromo-1-fluoro-2-isopropoxybenzene (481.19 mg, 2.06 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then chloro[(tri- tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(ll) (176.3 mg, 0.344 mmol) was added. The reaction mixture was heated to 90 °C for 2 h. After completion of the reaction, cooled down to room temperature, diluted with ethyl acetate (20 mL), filtered through CELITE® pad, and washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified using normal phase flash chromatography on silica gel (10-15 % ethyl acetate in hexanes) to afford the titled (0.3 g, 65%) as pale brown solid LC-MS (m / z): calc. 646.30, found 647.38 (M+H) Synthesis of tert-butyl 4-(9-fluoro-5-(4-fluoro-3-isopropoxyphenyl)-6,6-dimethyl-1-(tetrahydro- 2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a solution of tertbutyl 4-(9-fluoro-5-(4-fluoro-3-isopropoxyphenyl)-6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)- 1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (300 mg, 0.474 mmol) in THF (10 mL) was added (CHs^S BHs (2 M in THF) (2.37 mL, 4.74 mmol). The reaction mixture gradually heated to 80 °C for 4 h. After completion of the reaction (by TLC), the reaction mass was cooled down to room temperature and slowly quenched with methanol (5 mL) at 0 °C and stirred at same temperature for 30 min. The reaction mass was concentrated to dryness under reduced pressure. The crude residue was re-dissolved in methanol (2 mL) and THF (1 mL) and was added 4 M sodium hydroxide (3.5 mL, 14.22 mmol). The reaction mass was heated to 40 °C for 1 h. The reaction mixture was concentrated to dryness under reduced pressure, diluted with water. Dilute HCI (10 ml) was added to adjust the pH to acidic and extracted with ethyl acetate (3x50 mL). Volatiles were evaporated under reduced pressure to afford the crude titled product (250 mg) as a brown gum. The crude yellow residue was carried forward to the next step without further purification LC-MS (m / z): calc. 632.32, found 633.40 (M+H).

[0186] Synthesis of 4-(9-fluoro-5-(4-fluoro-3-isopropoxyphenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (10): To a solution of tert-butyl 4-(9-fluoro-5-(4-fluoro-3- isopropoxyphenyl)-6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoate (280 mg, 0.443 mmol) in methylene chloride (15 mL) was added TFA (1.5 g, 13.27 mmol) and stirred at 40 °C for 16 h. After completion of the reaction (by TLC), volatiles were removed by concentrating under reduced pressure. Diluted the crude material obtained with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate solution (2x30 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep- HPLC, Column: X-Bridge C8 (250*19mm), 5 urn, Mobile Phase A: 0.1% Formic Acid in water Mobile Phase B: 100% Acetonitrile, to afford the title 10 (28 mg, 12.85%) as an off white solid.1H NMR (400 MHz, DMSO-d6) 5 12.98 (br. s, 1H), 12.49 - 12.45 (m, 1 H), 7.84 (d, J = 9.0 Hz, 2H), 7.78 (d, J = 3.0 Hz, 1H), 7.38 - 7.30 (m, 1 H), 7.18 - 7.09 (m, 2H), 7.02 (dd, J = 2.1, 7.9 Hz, 1 H), 6.84 - 6.76 (m, 1H), 6.02 (s, 1H), 4.68 - 4.56 (m, 1H), 3.95 (s, 2H), 1.26 (d, J = 6.0 Hz, 6H), 1.04 (s, 6H). LC-MS (m / z): calc. 492.20, found 493.38 (M+H).

[0187] Example 10: 11 Synthesis

[0188] Synthesis of 4-(5-(benzo[d][1 ,3] dioxol-5-yl)-9-fluoro-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoic acid (11 ).

[0189] This was prepared using the methods described in Example 9 but using 5- bromobenzo[d][1 ,3]dioxole to produce 11 (shown below). Compound 11

[0190] LC-MS (m / z): calc. 460.15, found 461.28 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.03 - 12.85 (m, 1 H), 12.57 - 12.31 (m, 1H), 7.91 - 7.68 (m, 3H), 7.10 (d, J = 7.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 1 H), 6.81 (d, J = 2.0 Hz, 1 H), 6.70 (dd, J = 2.0, 8.3 Hz, 1 H), 6.11 (s, 2H), 6.03 (s, 1 H), 3.91 (s, 2H), 1.03 (s, 6H).

[0191] Example 11 : 12 Synthesis

[0192] Synthesis of 4-(5-(3-(difluoromethyl)-4-fluorophenyl)-9-fluoro-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (12).

[0193] This was prepared using the methods described in Example 9 but using 4-bromo-2- (difluoromethyl)-l-fluorobenzene to produce 12 (shown below). Compound 12

[0194] LC-MS (m / z): calc. 484.15, found 485.28 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.04 - 12.48 (br. s, 2H), 7.84 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 3.5 Hz, 1 H), 7.58 - 7.47 (m, 3H), 7.37 - 7.03 (m, 3H), 5.97 (s, 1 H), 3.97 (s, 2H), 1.03 (s, 6H).

[0195] Example 12: 13 Synthesis

[0196] Synthesis of 4-(9-fluoro-5-(4-fluoro-3-(methylamino) phenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (13).

[0197] This was prepared using the methods described in Example 9 but using 5-bromo-2-fluoro-N- methylaniline to produce 13 (shown below). Compound 13

[0198] LC-MS (m / z): calc. 463.18, found 464.24 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.95 (br. s, 1 H), 7.82 (d, J = 9.2 Hz, 2H), 7.76 (br. s, 1 H), 7.15 - 7.10 (m, 3H), 6.45 - 6.37 (m, 2H), 6.03 (s, 1H), 5.68 - 5.67 (m, 1 H), 3.92 (s, 2H), 2.67 - 2.65 (m, 3H), 1 .05 (s, 6H). One exchangeable proton is not visible.

[0199] Example 13: 14 Synthesis

[0200] Synthesis of 4-(5-(3-cyano-4-fluorophenyl)-9-fluoro-6,6-dimethyl-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (14).

[0201] This was prepared using the methods described in Example 9 but using 2-fluoro-5- iodobenzonitrile to produce 14 (shown below). Compound 14

[0202] LC-MS (m / z): calc. 459.15, found 460.21 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.05 (br. s, 1 H), 12.51 (br. s, 1H), 7.93 (dd, J = 2.4, 5.9 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 2.3 Hz, 1 H), 7.73 - 7.62 (m, 2H), 7.15 (dd, J = 2.1 , 8.9 Hz, 2H), 6.03 (s, 1H), 3.95 (s, 2H), 1.03 (s, 6H).

[0203] Example 14: 15 Synthesis

[0204] Synthesis of 4-(5-(4-chloro-3-fluorophenyl)-9-fluoro-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-y I) benzoic acid (15).

[0205] This was prepared using the methods described in Example 9 but using 1-chloro-2-fluoro-4- iodobenzene to produce 15 (shown below).

[0206] Compound 15

[0207] LC-MS (m / z): calc. 468.12, found 469.23 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.05 (br. s, 1 H), 12.46 (br. s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 3.3 Hz, 1 H), 7.73 (t, J = 8.6 Hz, 1H), 7.41 (dd, J = 2.4, 10.4 Hz, 1 H), 7.15 (dd, J = 2.1 , 8.9 Hz, 3H), 6.09 (s, 1 H), 3.95 (s, 2H), 1.05 (s, 6H).

[0208] Example 15: 16 Synthesis

[0209] Synthesis of p-[(S)-10-(p-fluorophenyl)-11-(methoxymethyl)-11-methyl-12-oxo-4,5,10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (16).

[0210] This was prepared starting with (6S)-6-(methoxymethyl)-6-methyl-1-(tetrahydro-2H-pyran-2- yl)-1 ,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one (prepared as described in Example 8) and then following Example 8, using tert-butyl 4-iodobenzoate and 1-bromo-4-fluorobenzene, to produce 16 (shown below). pound 16

[0211] LC-MS (m / z): calc.460.465, found 461.35 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.38 - 13.22 (m, 1 H), 12.45 - 12.35 (m, 1H), 8.20 - 8.14 (m, 2H), 7.71 (d, J = 0.8 Hz, 1 H), 7.52 - 7.45 (m, 4H), 7.41 - 7.34 (m, 2H), 6.33 (s, 1H), 6.24 (s, 1 H), 3.65 (d, J = 10.0 Hz, 1H), 3.40 (s, 1 H), 3.17 (s, 3H), 1.29 (s, 3H).

[0212] Example 16: 17 Synthesis

[0213] Synthesis of p-[10-(3,4-difluoropheny l)-11 , 11-dimethyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid (17).

[0214] This was prepared as described in Example 1 , using 1 ,2-difluoro-4-iodobenzene, to produce

[0215] 17 (shown below).

[0216] LC-MS (m / z): calc.434.446, found 435.2 (M+H).1H NMR (500 MHz, DMSO) 5 12.21 (s, 1 H), 7.94 (d, J = 8.4, 2H), 7.61 - 7.53 (m, 2H), 7.44 - 7.36 (m, 3H), 7.16 - 7.11 (m, 1 H), 6.96 (s, 1 H), 6.15 (s, 1 H), 3.72 (s, 2H), 1.13 (s, 6H).

[0217] Example 17: 18 Synthesis

[0218] Synthesis of (R)-4-(5-(3,4-difluorophenyl)-9-fluoro-6-(methoxymethyl)-6-methyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (18).

[0219] This was prepared using the methods described in Example 9 (preparation of 5-bromo-7- fluoro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-amine) and then following Example 8, using 1 ,2- difluoro-4-iodobenzene, to produce 18 (shown below).

[0220] LC-MS (m / z): calc. 482.16, found 483.15 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.03 (br. s, 1 H), 8.42 (br. s, 1H), 7.87 - 7.73 (m, 3H), 7.62 - 7.54 (m, 1 H), 7.47 - 7.37 (m, 1 H), 7.18 - 7.00 (m, 3H), 6.04 (s, 1 H), 4.27 (d, J = 13.5 Hz, 1H), 3.59 (d, J = 13.5 Hz, 1 H), 3.18 (d, J = 9.0 Hz, 1 H), 3.10 (d, J = 9.3 Hz, 1H), 2.72 (s, 3H), 0.99 (s, 3H).

[0221] Example 18: 19 Synthesis

[0222] Synthesis of 2-(3-(5-(4-fl uoropheny I )-6, 6-d imethy 1-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8- yl) phenyl) acetic acid (19).

[0223] This was prepared using the methods described in Example 1 but using methyl 2-(3- bromophenyl) acetate to produce 19 (shown below).

[0224]

[0225] LC-MS (m / z): calc. 430.16, found 431.21 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.06 (s, 1 H), 7.50 (d, J = 0.8 Hz, 1H), 7.42 - 7.26 (m, 7H), 7.12 - 7.05 (m, 1H), 6.58 (s, 1H), 6.00 (s, 1H), 3.60 (d, J = 4.5 Hz, 4H), 1.16 (s, 6H). One exchangeable proton is not visible.

[0226] Example 19: 20 Synthesis

[0227] Synthesis of p-[2-fluoro-10-(3-fluoro-4-methoxyphenyl)-11 ,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (20).

[0228] This was prepared using the methods described in Example 9 but using 2-fluoro-4-iodo-1- methoxybenzene to produce 20 (shown below).

[0229] LC-MS (m / z): calc. 464.47, found 465.27 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.99 - 12.49 (m, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 3.3 Hz, 1 H), 7.32 - 7.25 (m, 1H), 7.19 - 7.10 (m, 3H), 7.07 - 7.01 (m, 1 H), 6.00 (s, 1H), 3.93 (s, 2H), 3.91 (s, 3H), 1.03 (s, 6H).

[0230] Example 20: 21 Synthesis

[0231] Synthesis of (R)-4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid, stereocenter arbitrary assigned (21 ).

[0232] Racemic 4-(5-(3,4-difluorophenyl)-9-fluoro-6,6-dimethyl-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g'] quinoxalin-8-yl) benzoic acid (24, Example 23) (40 mg) was separated by chiral SFC (Column: CHIRALCEL OD-H, MeOH, CO2 / Co-solvent = 65:35) to afford two enantiomers. Peak l : arbitrary assigned as (S)-4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid, 8 mg, off-white solid, 99.61% ee; and Peak 2: arbitrary assigned as (R)-4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid, 3 mg, off-white solid, 99.01% ee.

[0233] Peak 2 (21 ): LC-MS (m / z): calc. 460.19, found 461.41 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.70 - 12.52 (m, 1H), 12.21 (br. s, 1 H), 7.94 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 0.8 Hz, 1 H), 7.44 (d, J = 8.8 Hz, 2H), 7.37 - 7.25 (m, 4H), 6.99 (s, 1H), 6.12 (s, 1H), 3.82 (d, J = 12.3 Hz, 1 H), 3.68 (d, J = 12.3 Hz, 1 H), 3.28 - 3.21 (m, 2H), 3.04 (s, 3H), 1.92 - 1.83 (m, 1 H), 1.75 - 1.66 (m, 1 H), 1.08 (s, 3H).

[0234] Example 21 : 22 Synthesis

[0235] Synthesis of (S)-4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-1,5,6,7-tetrahydro-8 / - / - pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid, stereocenter arbitrary assigned (22).

[0236] This was prepared from racemic 24 (Example 23), following the method described in Example 20.

[0237] Peak 1 (22): LC-MS (m / z): calc. 460.19, found 461.28 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.21 (br. s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.58 (s, 1 H), 7.44 (d, J = 8.8 Hz, 2H), 7.37 - 7.27 (m, 4H), 6.99 (s, 1 H), 6.11 (s, 1H), 3.82 (d, J = 12.4 Hz, 1 H), 3.68 (d, J = 12.0 Hz, 1 H), 3.28 - 3.21 (m, 2H), 3.04 (s, 3H), 1.92 - 1.85 (m, 1 H), 1.73 - 1.66 (m, 1H), 1.08 (s, 3H). One exchangeable proton is not visible.

[0238] Example 22: 23 Synthesis

[0239] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] q u inoxal i n-8-y I)- 2-hydroxybenzoic acid (23).

[0240] This was prepared using the methods described in Example 1 but using methyl 4-bromo-2- (methoxymethoxy)benzoate to produce 23 (shown below).

[0241]

[0242] F Compound 23

[0243] LC-MS (m / z): calc. 432.17, found 433.39 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.59 - 11.59 (m, 2H), 7.72 (d, J = 8.8 Hz, 1 H), 7.60 (d, J = 0.8 Hz, 1 H), 7.39 - 7.26 (m, 4H), 7.14 (s, 1 H), 6.94 (dd, J = 2.0, 8.8 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1 H), 6.09 (s, 1 H), 3.76 (s, 2H), 2.07 (s, 1H), 1.09 (s, 6H).

[0244] Example 23: 24 Synthesis

[0245] Synthesis of 4-(5-(3,4-difluorophenyl)-9-fluoro-6,6-dimethyl-1,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g'] Synthesis of ethyl 2-((diphenylmethylene)amino)-4-methoxybutanoate: To a solution of ethyl

[0246] 2-((diphenylmethylene)amino) acetate (10 g, 37.408 mmol) in tetrahydrofuran (75 mL) was added 2M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (37.41 mL, 74.817 mmol) at -78 °C and reaction mixture was stirred at the same temperature for 1 h. This was followed by the addition of 1-bromo-2- methoxyethane (7.799 g, 56.11 mmol) at -78 °C and reaction mixture was stirred at the same temperature for another 2 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3x150 mL). Volatiles were removed under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (5-7% ethyl acetate in hexanes) to afford the titled (5.5 g) as a yellow oil.

[0247] Synthesis of ethyl 2-((diphenylmethylene)amino)-4-methoxy-2-methylbutanoate: To a stirred and degassed mixture of ethyl 2-((diphenylmethylene)amino)-4-methoxybutanoate (3.0 g, 9.22 mmol) in tetrahydrofuran (30 mL) was added 2M sodium bis(trimethy lsilyl)amide in tetrahydrofuran (13.83 mL, 27.66 mmol) at -78 °C and reaction mixture was stirred at the same temperature for 1 h. This was followed by the addition of 1-bromo-2-methoxyethane (0.856 mL, 13.83 mmol) at -78 °C and reaction mixture was stirred at the room temperature for 1 h. Diluted the reaction mass with ice-water (50 mL) and extracted with ethyl acetate (2x90 mL). Volatiles were removed under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (18-20% ethyl acetate in hexanes) to afford the titled (1.5 g, 47.9%) as a yellow oil. LC-MS (m / z): calc. 339.18, found 340.25 (M+H).

[0248] Synthesis of 2-amino-4-methoxy-2-methylbutanoic acid: To a stirred mixture of ethyl 2- ((diphenylmethylene)amino)-4-methoxy-2-methylbutanoate (4.1 g, 12.08 mmol) in 1,4-dioxane (5 mL) was added 4N HCI in water (5 mL) at RT. Reaction mixture was stirred at 100 °C for 16 h. Diluted the reaction mass with ice-water (100 mL) and extracted with dichloromethane (2x100 mL). Volatiles were removed under reduced pressure, and the crude residue was co-d istilled with toluene to afford the racemic titled (2.1 g) as a brown gum. LC-MS (m / z): calc. 147.09, found 148.20 (M+H).

[0249] Synthesis of 6-(2-methoxyethyl)-6-methyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,8-tetrahydro-7H- pyrazolo[3,4-g]quinoxalin-7-one: To a stirred mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1 H- indazol-6-amine (0.8 g, 2.70 mmol), 2-amino-4-methoxy-2-methylbutanoic acid (1.98 g, 13.51 mmol) in dimethyl sulfoxide (10 mL) was added potassium phosphate (0.573 g, 2.70 mmol) at RT and reaction mixture was degassed with argon for 2 minutes, followed by the addition of DMEDA (0.142 g, 1.62 mmol) and copper(l) chloride (80 mg, 0.81 mmol) at RT. The resulting mixture was stirred at 150 °C for 4 h. Cooled the reaction mass to RT and filtered through celite bed using ethyl acetate (90 mL). The filtrate was concentrated under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (30-33% ethyl acetate in hexanes) to afford the titled (0.350 g) as a brown solid. LC-MS (m / z): calc. 344.18, found 345.40 (M+H).

[0250] Synthesis of tert-butyl 4-(6-(2-methoxyethyl)-6-methyl-7-oxo-1-(tetrahydro-2 / - / -pyran-2-yl)- 1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a solution of 6-(2-methoxyethyl)-6- methyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,8-tetrahydro-7 / - / -pyrazolo[3,4-g]quinoxalin-7-one (350 mg, 1.01 mmol) and tert-butyl 4-iodobenzoate (927 mg, 3.05 mmol) in 1 ,4 dioxane (10 mL) was added potassium carbonate (280 mg, 2.03 mmol) at RT and reaction mixture was degassed with argon for 2 minutes, followed by the addition of copper iodide (96.6 mg, 0.51 mmol) and N,N- Dimethylcyclohexylamine Dimethyl cyclohexylamine (64.7 mg, 0.51 mmol) at RT. The resulting mixture was stirred at. 100 °C for 16 h. Cooled the reaction mass to RT and filtered through celite bed. The filtrate was concentrated under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (20% ethyl acetate in hexanes) to afford the titled (0.340 g) as a brown solid. LC-MS (m / z): calc. 520.27, found 521.25 (M+H).

[0251] Synthesis of tert-butyl 4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-7-oxo-1-(tetrahydro- 2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoate : A mixture of tert-butyl 4-(6-(2-methoxyethyl)-6-methyl-7-oxo-1-(tetrahydro-2 / - / -pyran-2-yl)-1,5,6,7-tetrahydro-8 / - / - pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (0.340 g, 0.65 mmol), 1-bromo-4-fluorobenzene (0.171 g, 0.98 mmol) and sodium tert-butoxide (0.188 g, 1.96 mmol) in toluene (6 mL) at RT was degassed with argon for 5 minutes, followed by the addition of Bis(tri-tert-butyl phosphine)palladium(O) (334 mg, 0.65 mmol) at RT. The resulting mixture was stirred at 100 °C for 3 h. Cooled the reaction mass to RT and filtered through celite bed. The filtrate was concentrated under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (15% ethyl acetate in hexanes) to afford the titled (210 mg, 52%) as a brown solid. LC-MS (m / z): calc. 614.29, found 615.37 (M+H).

[0252] Synthesis of tert-butyl 4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-1-(tetrahydro-2 / - / - pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a solution of tert-butyl 4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-7-oxo-1 -(tetrahydro-2H-pyran-2-yl)-1 , 5,6,7- tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (200 mg, 0.32 mmol) in tetrahydrofuran (10 mL) was added 2.0M borane dimethylsulfide (1.62 mL, 3.25 mmol) at RT. The resulting mixture was stirred at RT for 1 h and 70 °C for 2 h. Cooled the reaction mass to 0 °C, added MeOH dropwise and stirred for 15 min. Volatiles were removed under reduced pressure to afford the titled (200 mg) as white gum. LC-MS (m / z): calc. 600.31, found 601.39 (M+H).

[0253] Synthesis of 4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-1-(tetrahydro-2 / - / -pyran-2-yl)- 1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid: To a solution of tert-butyl 4-(5-(4- fluorophenyl)-6-(2-methoxyethyl)-6-methyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / - pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (200 mg, 0.33 mmol) in THF (2 mL), MeOH (1 mL) and water (2 mL) was added lithium hydroxide (79.736 mg, 3.33 mmol) at RT. The reaction mixture was stirred at 60 °C for 16 h. Cooled to RT and reaction mixture was acidified to pH-2 using 4N HCI and extracted with DCM (2x30 mL). The organic layer was washed with water (100 mL), brine (100 mL). Volatiles were removed under reduced pressure to afford the titled (190 mg) as brown gum. LC-MS (m / z): calc. 544.25, found 545.25 (M+H).

[0254] Synthesis of 4-(5-(4-fluorophenyl)-6-(2-methoxyethyl)-6-methyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (24): To a stirred mixture of 4-(5-(4-fluorophenyl)-6-(2- methoxyethyl)-6-methyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin- 8-yl)benzoic acid (0.190 g, 0.35 mmol) in ethyl acetate (2 mL), water (1 mL) and methanol (2 mL) was added p-toluenesulfonic acid monohydrate (6.6 mg, 0.03 mmol) at room temperature and the reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with ice-water (5 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-HPLC, Column: X-Bridge C18 (150*19mm), 5um; Mobile Phase A: 0.1% Formic Acid in water Mobile Phase B: 100% Acetonitrile, Flow Rate:

[0255] 12 mL / min, to afford the racemic titled 24 (40 mg, 25%) as a white solid. LC-MS (m / z): calc. 460.19, found 461.40 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.20 (br. s, 1 H), 7.95 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 0.8 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.38 - 7.24 (m, 4H), 6.95 (s, 1 H), 6.11 (s, 1 H), 3.81 (d, J = 12.3 Hz, 1 H), 3.67 (d, J = 12.3 Hz, 1 H), 3.25 - 3.19 (m, 2H), 3.05 (s, 3H), 1.93 - 1.80 (m, 1H), 1.74 - 1 .67 (m, 1 H), 1 .08 (s, 3H). One exchangeable proton is not visible. Example 24: 25 Synthesis

[0256] Synthesis of 4-(5-(3-(difluoromethoxy)-4-fluorophenyl)-9-fluoro-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-y I) benzoic acid (25).

[0257] This was prepared using the methods described in Example 9 but using 4-bromo-2-(difluoro methoxy )-1-fluorobenzene to produce 25 (shown below).

[0258] N Compound 25

[0259] LC-MS (m / z): calc. 500.14, found 501.4 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.03 (br s, 1 H), 12.50 (br s, 1 H), 7.87 - 7.82 (m, 2H), 7.78 (d, J = 3.3 Hz, 1 H), 7.58 - 7.53 (m, 1 H), 7.50 - 7.10 (m, 5H), 6.03 (s, 1 H), 3.95 (s, 2H), 1.04 (s, 6H).

[0260] Example 25: 26 Synthesis

[0261] Synthesis of 4-(9-fluoro-5-(4-fluoro-3-hydroxyphenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g] quinoxalin-8-yl) benzoic acid (26).

[0262] This was prepared using the methods described in Example 9 but using 4-bromo-1-fluoro-2- methoxybenzene to produce 26 (shown below).

[0263] Compound 26

[0264] LC-MS (m / z): calc. 450.15, found 451.27 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.97 - 12.48 (m, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 3.3 Hz, 1H), 7.34 (dd, J = 8.5, 11.5 Hz, 1 H), 7.14 (dd, J = 2.1 , 8.9 Hz, 2H), 6.99 (dd, J = 2.4, 7.9 Hz, 1 H), 6.84 - 6.78 (m, 1 H), 6.01 (s, 1 H), 4.08 (q, J = 7.0 Hz, 2H), 3.94 (s, 2H), 1.32 (t, J = 6.9 Hz, 3H), 1.05 (s, 6H).

[0265] Example 26: 27 Synthesis Synthesis of 4-(5-(4-fluoro-2-methoxyphenyl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (27).

[0266] This was prepared using the methods described in Example 4 but using 4-fluoro-1-iodo-2- methoxybenzene to produce 27 (shown below).

[0267] LC-MS (m / z): calc. 418.16, found 419.33 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.02 (br. s, 1 H), 12.10 (br. s, 1H), 7.92 (s, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.66 - 7.62 (m, 1H), 7.58 - 7.51 (m, 2H), 7.39 - 7.27 (m, 4H), 6.69 (s, 1H), 6.04 (s, 1 H), 3.67 (s, 2H), 1.15 (s, 6H).

[0268] Example 27: 28 Synthesis

[0269] Synthesis of (S)-4-(5-(4-fluorophenyl)-6-(methoxymethyl)-6-methyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-y I) benzoic acid (28).

[0270] This was prepared using the methods described in Example 8 but using (R)-2-amino-3- hydroxy-2-methylpropanoic acid to produce 28 (shown below).

[0271] LC-MS (m / z): calc. 445.19, found 447.36 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.23 (br. s, 1 H), 7.92 (d, J = 8.5 Hz, 2H), 7.58 (s, 1 H), 7.45 - 7.27 (m, 6H), 7.00 (s, 1 H), 6.09 (s, 1 H), 4.00 (d, J = 12.3 Hz, 1H), 3.55 (d, J = 12.3 Hz, 1H), 3.34 (d, J = 9.3 Hz, 1H), 3.24 (d, J = 9.0 Hz, 1 H), 2.97 (s, 3H), 1.03 (s, 3H). One exchangeable proton is not visible.

[0272] Example 28: 29 Synthesis

[0273] Synthesis of 4-(5-(4-fluorophenyl)-6-(methoxymethyl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin- 8-yl) benzoic acid (29). This was prepared using the methods described in Example 1 and 8 but using O-methyl serine to produce 29 (shown below).

[0274] LC-MS (m / z): calc. 432.16, found 433.33 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.73 - 12.31 (m, 2H), 7.96 - 7.91 (m, 2H), 7.68 (d, J = 0.8 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.29 - 7.20 (m, 2H), 7.05 (s, 1H), 6.74 (s, 1 H), 4.07 - 3.96 (m, 2H), 3.65 (dd, J = 3.4, 12.1 Hz, 1 H), 3.42 - 3.38 (m, 1 H), 3.29 - 3.25 (m, 1 H), 3.06 (s, 3H).

[0275] Example 29: 30 Synthesis

[0276] Synthesis of (R)-4-(5-(4-fluorophenyl)-6-(methoxymethyl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-y I) benzoic acid, stereocenter arbitrary assigned (30).

[0277] Compound 29 Compound 30 Compound 31 racemate stereocenter arbitrary assigned stereocenter arbitrary assigned

[0278] Racemic 4-(5-(4-fluorophenyl)-6-(methoxymethyl)-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl) benzoic acid (29, Example 28) (60 mg) was separated by chiral SFC (Column: CHIRALCEL OD-H, MeOH, CO2 / Co-solvent = 60:40) to afford two enantiomers. Peak 1: arbitrary assigned as (R)-4-(5- (4-fluorophenyl)-6-(methoxymethyl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid, 21.6 mg, pale brown solid, 97.73% ee; and Peak 2: arbitrary assigned as (S)-4-(5-(4- fluorophenyl)-6-(methoxymethyl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] q ui noxali n-8-y I) benzoic acid, 17.4 mg, pale brown solid, 96.94% ee.

[0279] Peak 1 (30): LC-MS (m / z): calc. 432.16, found 433.37 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.33 (br. s, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.67 (s, 1 H), 7.42 - 7.32 (m, 4H), 7.29 - 7.18 (m, 2H), 7.02 (s, 1H), 6.74 (s, 1 H), 4.09 - 3.94 (m, 2H), 3.65 (dd, J = 3.4, 12.1 Hz, 1 H), 3.40 (dd, J = 5.3, 9.5 Hz, 1H), 3.29 - 3.27 (m, 1 H), 3.07 (s, 3H). Example 30: 31 Synthesis

[0280] Synthesis of (S)-4-(5-(4-fluorophenyl)-6-(methoxymethyl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g] quinoxalin-8-yl) benzoic acid, stereocenter arbitrary assigned (31).

[0281] This was prepared from racemic 29 (Example 28), following the method described in Example

[0282] Compound 31 stereocenter arbitrary assigned

[0283] Peak 2 (31 ): LC-MS (m / z): calc. 432.16, found 433.33 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.33 (br. s, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.67 (s, 1 H), 7.43 - 7.32 (m, 4H), 7.29 - 7.21 (m, 2H), 7.02 (s, 1H), 6.74 (s, 1 H), 4.08 - 3.93 (m, 2H), 3.65 (dd, J = 3.5, 12.3 Hz, 1 H), 3.40 (dd, J = 5.3, 9.5 Hz, 1H), 3.27 -

[0284] 3.20 (m, 1 H), 3.07 (s, 3H).

[0285] Example 31 : 32 Synthesis

[0286] Synthesis of 8-(4-(2H-tetrazol-5-y I) phenyl)-5-(4-fluorophenyl)-6,6-dimethyl-5,6,7,8-tetrahydro-1 / - / - pyrazolo[3,4-g] quinoxaline (32).

[0287]

[0288] Synthesis of 6,6-dimethyl-1-(tetrahydro-2 / - / -pyran-2-yl)-8-(4-(2-trityl-2 / - / -tetrazol-5-yl)phenyl)- 5,6,7,8-tetrahydro-1 / - / -pyrazolo[3,4-g]quinoxaline: To a stirred mixture of 6,6-dimethyl-1-(tetrahydro- 2H-pyran-2-yl)-5,6,7,8-tetrahydro-1 H-pyrazolo[3,4-g]quinoxaline (0.290 g, 1.01 mmol) [prepared as described in Example 33], 5-(4-bromophenyl)-2-trityl-2H-tetrazole (1.42 g, 3.04 mmol) and sodium tert-butoxide (291.94 mg, 3.04 mmol) in toluene (5 ml_) was degassed with argon for 10 minutes, followed by the addition of bis(tri-tert-buty I phosphine)palladium(O) (0.103 g, 0.20 mmol) at room temperature and the reaction mixture was stirred at 90 °C for 1 h. After completion of the reaction, the reaction mixture was filtered through CELITE® pad and washed with ethyl acetate (50 ml_). The filtrate was concentrated under reduced pressure. The residue was purified using normal phase flash chromatography on silica gel (30% ethyl acetate in heptanes) to afford the title (190 mg, 27%) as a pale-yellow solid. LC-MS (m / z): calc. 672.33, found 673.45 (M+H).

[0289] Synthesis of 5-(4-fluorophenyl)-6,6-dimethyl-1 -(tetrahydro-2 / - / -pyran-2-yl)-8-(4-(2-trityl-2H- tetrazol-5-yl)phenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-g7quinoxaline: A stirred mixture of 6,6- dimethyl-1-(tetrahydro-2H-pyran-2-yl)-8-(4-(2-trityl-2H-tetrazol-5-yl)phenyl)-5,6,7,8-tetrahydro-1 H- pyrazolo[3,4-g]quinoxaline (0.190 g, 0.28 mmol), 1-fluoro-4-iodobenzene (0.188 g, 0.85 mmol, 3.0 eq.) and sodium tert-butoxide (81.41 mg, 0.85 mmol) in toluene (5 ml_) was degassed with argon for 10 minutes, followed by the addition of bis(tri-tert-butyl phosphine)palladium(O) (28.86 mg, 0.06 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After completion of the reaction, the reaction mixture was filtered through CELITE® pad and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified using normal phase flash chromatography on silica gel (30% ethyl acetate in heptane’s) to afford the title (60 mg, 27%) as a yellow gum. LC-MS (m / z): calc. 766.35, found 767.41 (M+H). Synthesis of 8-(4-(2H-tetrazol-5-yl) phenyl)-5-(4-fluorophenyl)-6,6-dimethyl-5,6,7,8-tetrahydro- 1 / - / -pyrazolo[3,4-g] quinoxaline (32): To a stirred mixture of 5-(4-fluorophenyl)-6,6-dimethyl-1- (tetrahydro-2H-pyran-2-yl)-8-(4-(2-trity l-2H-tetrazol-5-yl) phenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-g] quinoxaline (40 mg, 0.05 mmol) in ethyl acetate (2 ml_), methanol (1 ml_) and water (1 ml_) were added p-toluene sulfonic acid monohydrate (39.68 mg, 0.21 mmol) at room temperature and was stirred at 70 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with water (3 ml_) and extracted with 10% methanol / dichloromethane (3x5 ml_). The organic layer was washed with brine (3 ml_), dried over anhydrous IXfeSC , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC, Column: X-Bridge C8 (250*19mm), 5 urn, Mobile Phase A: 0.1% Formic Acid in water, Mobile Phase B: 100% Acetonitrile, to afford the title 32 (3.3 mg, 14%) as an off- white solid. LC-MS (m / z): calc. 440.19, found 441.40 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.20 (s, 1 H), 8.05 (d, J = 8.8 Hz, 2H), 7.61 - 7.57 (m, 3H), 7.38 - 7.29 (m, 4H), 6.99 (s, 1H), 6.08 (s, 1H), 3.76 (s, 2H), 1.14 (s, 6H). One exchangeable proton is not visible.

[0290] Example 32: 33 Synthesis

[0291] Synthesis of 4-(5-(4-fluoropheny l)-7, 7-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)benzoic acid (

[0292] Synthesis of 6-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazole: To a solution of 6- bromo-5-nitro-1 H-indazole (2.00 g, 7.93 mmol) in dichloromethane (26.4 ml_) was added 3,4-dihydro- 2H-pyran (2.24 ml_, 23.8 mmol), followed by p-toluenesulfonic acid monohydrate (153 mg, 793 pmol), and the resulting reaction mixture was stirred at room temperature for 1 h, and a sample was injected on LC-MS (showed complete conversion). The reaction mixture was absorbed on silica gel and purified over normal phase flash chromatography on silica column (0-50% EtOAc in hexanes), to afford the titled (1.71 g, 66%) as a yellow powder.1H NMR (400 MHz, CDCIs) 5 8.35 (s, 1 H), 8.14 (d, J = 0.8 Hz, 1H), 8.01 - 7.99 (m, 1H), 5.73 (dd, J = 8.9, 2.6 Hz, 1 H), 4.04 - 3.97 (m, 1H), 3.82 - 3.73 (m, 1 H), 2.54 - 2.41 (m, 1H), 2.20 - 2.07 (m, 2H), 1.85 - 1.66 (m, 3H).

[0293] Synthesis of 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-5-amine: A 100 mL round bottom flask equipped with a Teflon-coated stir bar and rubber septum was charged with 6-bromo-5- nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.00 g, 3.07 mmol), followed by DMSO (10.2 mL), 2,2'-bipyridyl (24.4 mg, 153 pmol), and tetrahydroxydiboron (1.13 g, 12.3 mmol). The mixture was heated to 35 °C, stirring continued for 1 h, and a sample was injected on LC-MS (showed complete conversion). The reaction mixture was cooled down to room temperature, diluted with EtOAc (25 mL), washed with satd. aq. NaHCOs, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the titled (908 mg, 73%) as a pale tan solid. MS (m / z): 296.0 = M+H. The was carried forward to the next step without further purification.

[0294] Synthesis of 7,7-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,7,8-tetrahydro-6H-pyrazolo[3,4- g]quinoxalin-6-one: A 45 mL sealed tube equipped with a T eflon-coated stir bar and rubber septum was charged with 6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (1540 mg, 5.20 mmol), followed by a-aminoisobutyric acid (1.08 g, 10.4 mmol), N,N-dimethylethylenediamine (459 pL, 4.16 mmol), potassium phosphate tribasic (1.13 g, 5.20 mmol), and DMSO (26 mL). The resulting reaction mixture was degassed under nitrogen for 5 min, and then copper (I) chloride (212 mg, 2.08 mmol) was added. After degassing for 3 more minutes, the reaction mixture was heated at 140 °C, stirring continued for 8h, and a sample was injected on LCMS (showed complete conversion). The reaction mixture was diluted with EtOAc (25 mL), filtered through a pad of CELITE®, and washed with EtOAc (25 mL). The filtrate was washed with 10% aq. NH4OH, followed by brine, and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the titled (750 mg, 33%) as a pale blue solid. MS (m / z): 301.2 = M+H. The was carried forward to the next step without further purification and characterization.

[0295] Synthesis of 5-(4-fluorophenyl)-7,7-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,7,8-tetrahydro- 6H-pyrazolo[3,4-g]quinoxalin-6-one: A 48 mL sealed tube equipped with a Teflon-coated stir bar and rubber septum was charged with 7,7-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,7,8-tetrahydro-6H- pyrazolo[3,4-g]quinoxalin-6-one (750 mg, 2.50 mmol), followed by potassium carbonate (690 mg, 4.99 mmol), 4-fluoroiodobenzene (441 pL, 3.75 mmol), (1 R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine (335 pL, 2.00 mmol), and dioxane (16.7 mL). The reaction mixture was degassed by bubbling with nitrogen gas for 5 min. Then copper(l) iodide (191 mg, 999 pmol) was added. After degassing for 3 more minutes, the reaction mixture was heated at 100 °C, stirring continued for 8 h, and a sample was injected on LC-MS (complete conversion). The reaction mixture was transferred into a 250 mL flask (rinsing with EtOAc), water (50 mL) was added, and extracted with EtOAc (3 X 25 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and filtrate absorbed on silica gel, and purified over normal phase flash chromatography on silica gel (0-100% EtOAc in hexanes) to afford the titled (275 mg, 25%) as a brown powder. MS (m / z): 395.3 = M+H.

[0296] Synthesis of tert-butyl 4-(5-(4-fluorophenyl)-6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)- 1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: A 25 mL sealed tube was charged with 5-(4-fluorophenyl)-7,7-dimethyl-1 -(tetrahydro-2H-py ran-2-y l)-1 ,5,7, 8-tetrahydro-6H-pyrazolo[3,4- g]quinoxalin-6-one (275 mg, 697 pmol), followed by tert-butyl 4-bromobenzoate (554 mg, 2.09 mmol), sodium tert-butoxide (207 mg, 2.09 mmol), and toluene (6.97 mL). The reaction mixture was degassed by bubbling with nitrogen gas for 5 min, and then bis(tri-t-butylphosphine) palladium (0) (364 mg, 697 mol) was added. The tube was sealed, placed in a pre-heated oil bath (95 °C), stirring continued for 2 h, and a sample was injected on LC-MS (showed complete conversion). The reaction mixture was quenched with water (25 mL), extracted with EtOAc (3 X 15 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified over reverse phase flash chromatography on C18 column (5-100% ACN in 10 mM AmB mobile phase) to afford the titled (340 mg, 79%) as an off-white solid. MS (m / z): 571.3 = M+H.

[0297] Synthesis of 4-(5-(4-fluorophenyl)-6, 6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 , 5,6,7- tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid. Step 1 : A 15-20 ml_ microwave vial equipped with a Teflon-coated stir bar and rubber septum was charged with tert-butyl 4-(5-(4- fluorophenyl)-6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoate (340 mg, 596 pmol), followed by THF (2.98 mL), and borane dimethylsulfide complex (141 L, 1 .49 mmol). The vial was sealed and placed in a pre-heated oil bath (85 °C), stirring continued for 1 h, and a sample was injected on LC-MS (complete conversion). The reaction mixture was cooled down to room temperature, carefully quenched with satd. aq. NaHCOs (10 mL) and extracted with EtOAc (3 X 10 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a yellow solid, which was used in the next step as is. MS (m / z): 569.3 = M+BH2. Step 2: A 100 mL round bottom flask containing above Step 1 crude (202 mg, 355 mol) was charged with a Teflon-coated stir bar, followed by THF: MeOH:H2O (2: 1:1 ) (3.5 mL), and 4 M aq. sodium hydroxide (1.92 mL, 7.70 mmol). The reaction mixture was stirred at 60 °C, for 4 h, and a sample was injected on LC-MS (showed complete conversion). The reaction mixture was cooled down to room temperature, pH neutralized with 1 M aq. HCI, and extracted into EtOAc (3 X 10 mL), combined organics dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the titled (178 mg, quant, yield) as a tan powder. MS (m / z): 501.3 = M+H.

[0298] Synthesis of 4-(5-(4-fluoropheny l)-7, 7-d i methy 1-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoic acid (33): A 100 mL round bottom flask containing 4-(5-(4-fluorophenyl)-6,6- dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (178 mg, 355 mol) was dissolved in MeOH: EtOAc: Water (2:1 :1) (1.42 mL), and was added p- toluenesulfonic acid monohydrate (138 mg, 710 pmol). The reaction mixture was heated to 70 °C stirring continued for 1 h, and a sample was injected on LC-MS (complete conversion). Volatiles removed under reduced pressure, and the crude residue was purified over reverse phase flash chromatography on C18 column (5-100% ACN in 10 mM AmB mobile phase) to afford the titled 33 (125 mg, 84%) as an off-white powder. LC-MS (m / z): calc.416.456, found 417.29 (M+H).1H NMR (400 MHz, DMSO-D6) 5 12.01 (br s, 1 H), 8.10 (d, J = 8.2 Hz, 2H), 7.57 (s, 1 H), 7.43 - 7.33 (m, 4H), 7.27 - 7.20 (m, 2H), 6.80 (s, 1H), 5.81 (s, 1 H), 3.60 (s, 2H), 1.18 (s, 6H). Acid proton is not visible. Example 33: 34 Synthesis

[0299] Synthesis of (1s,3s)-3-(5-(4-fluorophenyl)-6,6-dimethyl-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-y I) cyclobutane-1 -carboxylic acid, stereocenters arbitrary assigned (34).

[0300] Synthesis of 6,6-dimethyl-1-(tetrahydro-2 / - / -pyran-2-yl)-5,6,7,8-tetrahydro-1 / - / -pyrazolo[3,4- g]quinoxaline: To a stirred mixture of 6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,8-tetrahydro-7H- pyrazolo[3,4-g]quinoxalin-7-one (2.7 g, 9.0 mmol) in tetrahydrofuran (35 ml_) was added borane dimethyl sulfide, 2.0M in THF (13.5 ml_, 27 mmol) at 0 °C and the reaction mixture was stirred at 60 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with methanol, stirred for 5 minutes and concentrated under reduced pressure. The residue was purified using normal phase flash chromatography on silica gel (30% ethyl acetate in heptanes) to afford the title (1.9 mg, 74%) as an off-white solid. LC-MS (m / z): calc. 286.18, found 287.26 (M+H).

[0301] Synthesis of methyl 3-(6,6-dimethyl-1 -(tetrahydro-2H-pyran-2-y l)-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)cyclobutane-1-carboxylate: A stirred mixture of 6,6-dimethyl-1- (tetrahydro-2H-pyran-2-yl)-5,6,7,8-tetrahydro-1 H-pyrazolo[3,4-g]quinoxaline (0.400 g, 1.40 mmol) and methyl 3-oxocyclobutane-1 -carboxylate (0.357 g, 2.79 mmol) in dichloroethane (15 ml_) was degassed with argon for 5 minutes, followed by the addition of sodium triacetoxyborohydride (0.592 g, 2.79 mmol) at RT and the reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified using normal phase flash chromatography on silica gel (30% ethyl acetate in heptanes) to afford the title (0.220 g, 39%) as a pale-yellow gum. LC-MS (m / z): calc. 398.23, found 399.44 (M+H).

[0302] Synthesis of methyl 3-(5-(4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7- tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)cyclobutane-1 -carboxylate: The stirred mixture of methyl 3-(6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)cyclobutane-1 -carboxylate (0.220 g, 0.55 mmol), 1-bromo-4-fluorobenzene (0.289 g, 1.66 mmol) and sodium tert-butoxide (0.159 g, 1.66 mmol) in toluene (6 mL) was degassed with argon for 5 minutes, followed by the addition of bis(tri-tert-butyl phosphine)palladium(O) (0.282 g, 0.55 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was filtered through CELITE® pad and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified using normal phase flash chromatography on silica gel (20% ethyl acetate in heptanes) to afford the title (0.091 g, 33%) as a pale-yellow gum. LC-MS (m / z): calc. 492.25, found 493.41 (M+H).

[0303] Synthesis of 3-(5-(4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7- tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)cyclobutane-1 -carboxylic acid: To a stirred mixture of methyl 3-(5-(4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)cyclobutane-1-carboxylate (0.09 g, 0.18 mmol) in methanol (4 mL), tetrahydrofuran (4 mL) was added 4N NaOH (0.6 mL) at room temperature and the reaction mixture was stirred at 40 °C for 1 h. After completion of the reaction, the reaction mixture was acidified with dil. HCI up to pH ~ 2 and extracted with ethyl acetate twice. The combined organic layer was washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford the title (0.065 g, 74%) as a brown gum. LC-MS (m / z): calc. 478.24, found 479.44 (M+H).

[0304] Synthesis of 3-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)cyclobutane-1-carboxylic acid: To a stirred mixture of 3-(5-(4-fluorophenyl)-6,6- dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)cyclobutane-1 -carboxylic acid (0.065 g, 0.14 mmol) in methanol (3 mL), ethyl acetate (3 mL) and water (1.5 mL) was added p-toluene sulfonic acid monohydrate (51.67 mg, 0.27 mmol) at room temperature and the reaction mixture was stirred at 70 °C for 2 h. After completion of the reaction (by TLC), the reaction mixture was diluted with water and extracted with dichloromethane twice. The combined organic layer was washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford the title 3-(5-(4-fluorophenyl)-6,6-dimethyl-1, 5,6,7- tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) cyclobutane-1 -carboxylic acid (0.045 g, 84%; a mixture of diastereoisomers) as a brown solid. LC-MS (m / z) calc. 394.18, found 395.32 (M+H).

[0305] Synthesis of (1s,3s)-3-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-y I) cyclobutane-1 -carboxylic acid (34): Mixture of diastereoisomers 3-(5-(4-fluoropheny I)- 6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) cyclobutane-1 -carboxylic acid (45 mg) was purified by prep-HPLC: X-Bridge C18 column, 19X150mm, 5pm, Mobile Phase A: 0.1% TFA in Water; B: Acetonitrile, to afford 34 (6 mg, off-white solid; stereocenters arbitrary assigned as 1s, 3s) and 35 (6 mg, off-white solid; stereocenters arbitrary assigned as 1 r,3r). 34. LC-MS (m / z): calc. 394.18, found 395.29 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.18 (br. s, 2H), 7.45 (s, 1H), 7.34 - 7.27 (m, 2H), 7.24 - 7.19 (m, 2H), 6.51 (s, 1H), 5.85 (s, 1 H), 4.03 - 3.93 (m, 1 H), 3.05 (s, 2H), 2.94 - 2.83 (m, 1 H), 2.64 - 2.56 (m, 2H), 2.27 - 2.18 (m, 2H), 1.13 (s, 6H).

[0306] Example 34: 35 Synthesis Synthesis of (1r,3r)-3-(5-(4-fluorophenyl)-6,6-dimethyl-1,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g'] quinoxalin-8-yl) cyclobutane-1 -carboxylic acid, stereocenters arbitrary assigned (35), was performed as described in Example 33.

[0307] 35. LC-MS (m / z): calc. 394.18, found 395.37 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.13 (br. s, 1 H), 7.45 (s, 1H), 7.35 - 7.28 (m, 2H), 7.25 - 7.18 (m, 2H), 6.44 (s, 1H), 5.85 (s, 1 H), 4.21 - 4.12 (m, 1 H), 3.06 (s, 2H), 2.93 - 2.84 (m, 1 H), 2.60 - 2.54 (m, 2H), 2.40 - 2.30 (m, 2H), 1.14 (s, 6H). One exchangeable proton is not visible.

[0308] Example 35: 36 Synthesis

[0309] Synthesis of ((1s,3s)-3-(5-(4-fluorophenyl)-6,6-dimethyl-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]

[0310] Synthesis of ( 3-( 5-(4-fl uoropheny I )-6, 6-d imethy I- 1 -(tetrahyd ro-2H-py ran-2-y I )-1 , 5, 6, 7- tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)cyclobutyl)methanol: To a stirred mixture of methyl 3-(5- (4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)cyclobutane-1-carboxylate (0.130 g, 0.26 mmol) [prepared as described in Example 33] in tetrahydrofuran (10 ml_) was added lithium aluminum hydride (0.4 ml_, 0.79 mmol, 2.0 M in THF) at -70 °C and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride solution at 0 °C, stirred for 10 minutes and extracted with dichloromethane twice. The combined organic layer was washed with water, brine, dried over anhydrous IXfeSC , filtered and concentrated under reduced pressure to afford the title (0.09 g, 73%) as an off-white solid. LC-MS (m / z): calc. 464.26, found 465.36 (M+H).

[0311] Synthesis of (3-(5-(4-fluorophenyl)-6,6-dimethyl-1,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4- g]quinoxalin-8-yl)cyclobutyl)methanol: A stirred mixture of (3-(5-(4-fluorophenyl)-6,6-dimethyl-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)cyclobutyl)methanol (0.09 g, 0.19 mmol) in methanol (3 ml_), ethyl acetate (3 ml_) and water (1.5 ml_) was added p-toluene sulfonic acid monohydrate (73.699 mg, 0.39 mmol) at room temperature and the reaction mixture was stirred at 70 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane twice. The combined organic layer was washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford the title (0.065 g, 88%) as a brown solid. LC-MS (m / z): calc. 380.20, found 381.31 (M+H).

[0312] Synthesis of ((1s,3s)-3-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-y I) cyclobutyl) methanol (36): Diastereoisomeric mixture of (3-(5-(4-fluoropheny l)-6,6- dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) cyclobutyl) methanol (65 mg) was purified by prep-HPLC: X-Bridge C18 column, 19X150mm, 5pm, Mobile Phase A: 0.1% TFA in Water; B: Acetonitrile, to afford to afford the title 36 (13 mg, off-white solid; stereocenters arbitrary assigned) and 37 (8 mg, off-white solid; stereocenters arbitrary assigned).

[0313] 36. LC-MS (m / z): calc. 380.20, found 381.17 (M+H).1H NMR (400 MHz, DMSO-de) 5 = 12.13 (br. s, 1H), 7.44 (s, 1 H), 7.34 - 7.28 (m, 2H), 7.26 - 7.16 (m, 2H), 6.50 (s, 1H), 5.84 (s, 1 H), 4.53 (t, J = 5.3 Hz, 1 H), 3.90 - 3.81 (m, 1H), 3.41 (t, J = 5.4 Hz, 2H), 3.04 (s, 2H), 2.44 - 2.34 (m, 2H), 2.25 - 2.16 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.13 (s, 6H).

[0314] Example 36: 37 Synthesis

[0315] Synthesis of ((1 r, 3 r)-3-(5-(4-fluoro pheny l)-6, 6-d imethy I- 1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) cyclobutyl) methanol, stereocenters arbitrary assigned (37), was synthesized as described in Example 35.

[0316] 37. LC-MS (m / z): calc. 380.20, found 381.17 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.13 (br. s, 1 H), 7.45 (s, 1H), 7.35 - 7.29 (m, 2H), 7.25 - 7.20 (m, 2H), 6.42 (s, 1H), 5.84 (s, 1 H), 4.70 (t, J = 5.0 Hz, 1H), 4.11 - 4.02 (m, 1 H), 3.59 (t, J = 5.6 Hz, 2H), 3.05 (s, 2H), 2.34 - 2.15 (m, 5H), 1.15 (s, 6H).

[0317] Example 37: 38 Synthesis

[0318] Synthesis of (R)-4-(5-(4-fluorophenyl)-6-methyl-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid, stereocenter arbitrary assigned (38).

[0319] The racemic mixture of 4-(5-(4-fluorophenyl)-6-methyl-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (50 mg) [from Example 39] was separated by chiral SFC: CHIRALPAK AD-H column, 4.6*150mm, 5pm, CO2 I 0.5% FA in methanol = 70:30, to afford two enantiomers. Peak 1 (38): arbitrary assigned as (R), 3.6 mg, pale green solid, ee 96.81%. Peak 2 (39): arbitrary assigned as (S), 7.8 mg, pale green solid, ee 88.27%.

[0320] 38. LC-MS (m / z): calc. 402.15, found 403.27 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.24 (br. s, 1 H), 7.93 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.33 - 7.21 (m, 4H), 6.98 (s, 1 H), 6.65 (s, 1 H), 4.01 - 3.99 (m, 1 H), 3.85 - 3.78 (m, 1 H), 3.74 - 3.68 (m, 1H), 1.08 (d, J = 6.5 Hz, 3H). One exchangeable proton is not visible.

[0321] Example 38: 39 Synthesis

[0322] Synthesis of (S)-4-(5-(4-fluorophenyl)-6-methyl-1,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-y I) benzoic acid, stereocenter arbitrary assigned (39) performed as described in Example 37.

[0323] 39. LC-MS (m / z): calc. 402.15, found 403.30 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.28 (br. s, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.64 (s, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.33 - 7.20 (m, 4H), 6.96 (s, 1 H), 6.65 (s, 1 H), 4.04 - 3.97 (m, 1 H), 3.83 - 3.80 (m, 1 H), 3.74 - 3.68 (m, 1 H), 1.09 (d, J = 6.3 Hz, 3H).

[0324] Example 39: 40 Synthesis

[0325] Synthesis of 4-(5-(4-fluorophenyl)-6-methyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] q ui noxal in-8-y I) benzoic acid (40).

[0326] This was prepared using the methods described in Example 1 but using DL-alanine to produce racemic 40 (shown below).

[0327] LC-MS (m / z): calc. 402.16, found 403.27 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.71 - 12.25 (m, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 0.8 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 2H), 7.34 - 7.22 (m, 4H), 7.03 (s, 1 H), 6.65 (s, 1H), 4.04 - 3.95 (m, 1 H), 3.84 - 3.79 (m, 1 H), 3.76 - 3.69 (m, 1H), 1.07 (d, J = 6.5 Hz, 3H).

[0328] Example 40: 41 Synthesis

[0329] Synthesis of (R)-4-(5-(4-fluorophenyl)-6-(methoxymethyl)-6-methyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (41 ).

[0330] This was synthesized according to procedure described in Example 8, using (S)-2-amino-3- hydroxy-2-methylpropanoic acid to produce 41 (shown below).

[0331] LC-MS (m / z): calc. 446.482, found 447.4 (M+H).1H NMR (500 MHz, DMSO-d6) 5 12.23 (br s, 1 H), 7.94 - 7.89 (m, 2H), 7.59 (d, J = 1.0 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.36 - 7.29 (m, 4H), 7.03 (s, 1 H), 6.10 (s, 1 H), 4.02 (d, J = 12.3 Hz, 1 H), 3.56 (d, J = 12.3 Hz, 1H), 3.33 (d, J = 9.2 Hz, 1 H), 3.23 (d, J = 9.2 Hz, 1 H), 2.96 (s, 3H), 1.02 (s, 3H). One exchangeable proton is not visible.

[0332] Example 41 : 42 Synthesis

[0333] Synthesis of 4-(5-(4-fluorophenyl)-6-isopropyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] q u i noxal in-8-y I ) benzoic acid (42).

[0334] Synthesis of 6-isopropyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,8-tetrahydro-7H-pyrazolo[3,4- g]quinoxalin-7-one: A stirred mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-amine (3.0 g, 10.13 mmol), DL-Valine (2.37 g, 20.26 mmol), potassium phosphate (2.15 g, 10.13 mmol), N,N'- Dimethyl ethylenediamine (0.893 g, 10.13 mmol) in dimethyl sulfoxide (5 mL) was degassed with argon for 10 minutes, followed by the addition of copper monochloride (0.501 g, 5.06 mmol) at room temperature. The reaction mixture was stirred at 140 °C for 16 h. After completion of the reaction (by TLC), diluted the reaction mixture with water (40 mL) and extracted with ethyl acetate (2*30 mL). The combined organic layers were concentrated under reduced pressure to afford the crude which was directly purified by normal phase flash chromatography on silica gel (30-40 % ethyl acetate in hexanes) to afford the titled as yellow solid (0.9 g, 43%). LC-MS (m / z): calc. 314.17, found 315.27 (M+H).

[0335] Synthesis of ethyl 4-(6-isopropyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,7-dihydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoate: A stirred mixture of 6-isopropyl-1-(tetrahydro-2H-pyran-2- yl)-1 ,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one (0.900 g, 2.87 mmol), (R,R)-(-)-N,N - dimethyl-1 ,2-cyclohexanediamine (0.326 g, 2.29 mmol), potassium carbonate (0.791 g, 5.72 mmol) and ethyl 4-iodobenzoate (2.37 g, 8.59 mmol) in 1 ,4-dioxane (10 mL) was degassed with argon for 10 minutes, followed by the addition of copper iodide (0.218 g, 1.14 mmol,) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, diluted the reaction mass with water (75 mL) and extracted with ethyl acetate (2x35 mL). The combined organic layers were concentrated under reduced pressure to afford the crude which was directly purified by normal phase flash chromatography on silica gel (15-20 % ethyl acetate in hexanes) to afford the titled as an off white solid (0.8 g, 61%). LC-MS (m / z): calc. 460.21 , found 461.42 (M+H).

[0336] Synthesis of ethyl 4-(6-isopropyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoate: To a stirred solution of ethyl 4-(6-isopropyl-7-oxo-1- (tetrahydro-2H-pyran-2-yl)-1 ,7-dihydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoate (0.800 g, 1.74 mmol) in methanol (20 mL) was added w / w 10 % Pd / C (400 mg) at room temperature. The reaction mixture was stirred under 70 PSI of H2 for 16 h. After completion of the reaction, filtered the reaction mixture through CELITEObed and washed with methanol (25 mL). The filtrate was concentrated under reduced pressure to afford the titled (0.750 g, 93%) as an off-white solid. LC-MS (m / z): calc. 462.23, found 463.38 (M+H).

[0337] Synthesis of ethyl 4-(6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoate: To a stirred mixture of ethyl 4-(6-isopropyl-7-oxo-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoate (0.500 g, 1.08 mmol) in tetrahydrofuran (5 mL) was added borane dimethyl sulfide (2.16 mL, 4.33 mmol) at 0 °C and the reaction mixture was stirred at 70 °C for 3 h. After completion of the reaction, the reaction mass was cooled to 0 °C and quenched with methanol (5 mL). Volatiles were concentrated under reduced pressure which was directly purified by normal phase flash chromatography on silica gel (20 % ethyl acetate in hexanes) to provide the titled as yellow oil solid (0.2 g; 41%). LC-MS (m / z): calc. 448.25, found 449.34 (M+H).

[0338] Synthesis of ethyl 4-(5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1 , 5,6,7- tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: A stirred mixture of ethyl 4-(6-isopropyl-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoate (0.200 g, 0.45 mmol), 1-bromo-4-fluorobenzene (0.234 g, 1.34 mmol) and sodium tert-butoxide (0.128 g, 1.34 mmol) in toluene (3 mL) was degassed with argon for 5 minutes, followed by the addition of bis(tri- tert-butyl phosphine)palladium(O) (0.683 g, 1.34 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After completion of the reaction, filtered the reaction mixture through celite bed and washed with dichloromethane, The filtrate was concentrated under reduced pressure to afford the crude which was directly purified by normal phase flash chromatography on silica gel (15- 20 % ethyl acetate in hexanes) to provide the titled as an off white solid (0.08 g, 31%). LC-MS (m / z): calc. 542.27, found 543.44 (M+H).

[0339] Synthesis of 4-(5-(4-fluorophenyl)-6-isopropyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro- 8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid: To a stirred mixture of ethyl 4-(5-(4-fluorophenyl)-6- isopropyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (0.08 g, 0.14 mmol) in methanol (1.5 mL), tetrahydrofuran (1.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (29.40 mg, 0.70 mmol) at room temperature. The reaction mass was stirred at 70 °C for 6 h. After completion of the reaction (by TLC), cooled the reaction mass and was acidified with dil. HCI up to pH ~ 2, extracted with ethyl acetate (2*15 mL). Volatiles were concentrated under reduced pressure to afford the titled (0.060 g) as an off-white solid. LC-MS (m / z): calc. 514.27, found 515.37 (M+H).

[0340] Synthesis of 4-(5-(4-fluorophenyl)-6-isopropyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoic acid (42): To a stirred mixture of 4-(5-(4-fluorophenyl)-6-isopropyl-1- (tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (0.060 g, 0.10 mmol) in methanol (1.5 mL), ethyl acetate (1.5 mL) and water (0.5 mL) was added p-toluene sulfonic acid monohydrate (39.99 mg, 0.21 mmol). The reaction mass was stirred at 70 °C for 2 h. After completion of the reaction, volatiles were concentrated under reduced pressure. The residue was purified by prep- HPLC, Column:-X-Bridge C8 (250*19mm), 5 urn, Mobile Phase A: 0.1% Formic Acid in water Mobile Phase B: 100% Acetonitrile, to afford the titled 42 (0.014 g; 31%) as an off-white solid. LC-MS (m / z): calc. 430.27, found 431.30 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.76 - 12.69 (br. s, 1H), 12.35 (br. s, 1H), 7.97 - 7.91 (m, 2H), 7.75 - 7.70 (m, 1 H), 7.45 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 6.8 Hz, 4H), 7.05 (s, 1 H), 7.01 (s, 1 H), 3.86 - 3.76 (m, 1 H), 3.61 - 3.51 (m, 2H), 1.80 - 1.67 (m, 1 H), 1.05 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H).

[0341] Example 42: 43 Synthesis

[0342] Synthesis of 10'-(p-fluorophenyl)-13'-(p-tolyl)spiro[cyclobutane-1 , 1 T- [4,5,10,13]tetraazatricyclo[7.4.0.03,7]trideca[1,3(7),5,8]tetraene] (43).

[0343] This was prepared following the methods described in Example 1 but using 1- aminocyclobutane-1 -carboxylic acid to produce 43 (shown below).

[0344] LC-MS (m / z): calc. 398.485, found 399.35 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.04 (s, 1H), 7.51 (s, 1 H), 7.36 (t, J = 8.8 Hz, 2H), 7.33 - 7.24 (m, 6H), 6.44 (s, 1H), 6.12 (s, 1 H), 3.75 (s, 2H), 2.35 (s, 3H), 2.17 - 2.05 (m, 2H), 1.89 (t, J = 9.2 Hz, 2H), 1.72 - 1.58 (m, 1 H), 1.53 - 1.40 (m, 1 H).

[0345] Example 43: 44 Synthesis

[0346] Synthesis of p-[11 , 11-dimethyl-10-(2-methyl-4-pyridyl)-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-

[0347] 1 ,3(7),5,8-tetraen-13-yl]benzoic acid (44).

[0348] This was prepared following the methods described in Example 1 but using 4-bromo-2- methylpyridine to produce 44 (shown below).

[0349] Compound 44

[0350] LC-MS (m / z): calc. 413.481 , found 414.2 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.27 (bs, 1 H), 8.50 (d, J = 5.3 Hz, 1H), 7.95 - 7.92 (m, 2H), 7.63 (d, J = 1.0 Hz, 1 H), 7.47 - 7.43 (m, 2H), 7.14 (d, J = 2.0 Hz, 1 H), 7.06 (dd, J = 5.3, 1.8 Hz, 1 H), 7.01 (s, 1 H), 6.36 (s, 1H), 3.72 (s, 2H), 2.49 (s, 3H), 1.17 (s, 6H). Acid proton is not visible. Example 44: 45 Synthesis

[0351] Synthesis of 2-cyano-4-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (45).

[0352] This was prepared using the methods described in Example 1 but using methyl 4-bromo-2- cyanobenzoate to produce 45 (shown below).

[0353] Compound 45

[0354] LC-MS (m / z): calc. 441.46, found 442.36 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 12.30 (s, 1 H), 11.17 - 11.05 (m, 1 H), 7.78 - 7.68 (m, 3H), 7.62 (s, 1 H), 7.39 - 7.25 (m, 4H), 7.12 (s, 1 H), 6.13 (s, 1 H), 3.85 (s, 2H), 1.10 (s, 6H).

[0355] Example 45: 46 Synthesis

[0356] Synthesis of p-[10-(3,4-difluorophenyl)-2-fluoro-11,11-dimethyl-4, 5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (46).

[0357] This was prepared following the methods described in Example 9 but using 1 ,2-difluoro-4- iodobenzene to produce 46 (shown below).

[0358] Compound 46

[0359] LC-MS (m / z): calc. 452.436, found 453.2 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.02 (br. s, 1 H), 12.45 (br. s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 3.3 Hz, 1 H), 7.63 - 7.51 (m, 1 H), 7.45 - 7.40 (m, 1 H), 7.14 (dd, J = 2.1, 8.6 Hz, 3H), 6.03 (s, 1H), 3.94 (s, 2H), 1.04 (s, 6H).

[0360] Example 46: 47 Synthesis

[0361] Synthesis of (R)-4-(5-(3-chloro-4-fluorophenyl)-6-(methoxymethyl)-6-methyl-1,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-y I) benzoic acid (47). This was prepared following the methods described in Example 8 but using 2-chloro-1-fluoro-

[0362] 4-iodobenzene to produce 47 (shown below).

[0363] LC-MS (m / z): calc. 480.14, found 481.23 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 12.60 - 12.27 (m, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.62 - 7.52 (m, 3H), 7.42 (d, J = 8.8 Hz, 2H), 7.33 - 7.29 (m, 1 H), 7.04 (s, 1 H), 6.17 (s, 1 H), 4.00 (d, J = 8.4 Hz, 1H), 3.58 - 3.55 (m, 1H), 3.27 - 3.25 (m, 2H), 2.97 (s, 3H), 1.03 (s, 3H).

[0364] Example 47: 48 Synthesis

[0365] Synthesis of 4-(9-fluoro-5-(4-fluoro-3-methoxyphenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl)-2-methylbenzoic acid (48).

[0366] This was prepared following the methods described in Example 9 but using tert-butyl 4- bromo-2-methylbenzoate and 1-fluoro-4-iodo-2-methoxybenzene to produce 48 (shown below).

[0367] LC-MS (m / z): calc. 478.18, found 479.42 (M+H). 1 H NMR (400 MHz, DMSO-d6) 5 = 13.05 - 12.95 (m, 1 H), 12.52 - 12.40 (m, 1H), 7.81 - 7.76 (m, 2H), 7.37 - 7.32 (m, 1H), 7.02 - 6.93 (m, 3H), 6.84 - 6.80 (m, 1 H), 6.00 (s, 1 H), 3.92 (s, 2H), 3.82 (s, 3H), 2.53 (s, 3H), 1.06 (s, 6H).

[0368] Example 48: 49 Synthesis

[0369] Synthesis of 2-fluoro-4-(9-fluoro-5-(4-fluoro-3-methoxyphenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8 / - / - pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (49). This was prepared following the methods described in Example 9 but using tert-butyl 4- bromo-2-fluorobenzoate and 1-fluoro-4-iodo-2-methoxybenzene to produce 49 (shown below).

[0370] LC-MS (m / z): calc. 482.16, found 483.39 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.05 - 12.74 (m, 2H), 7.85 - 7.74 (m, 2H), 7.37 - 7.32 (m, 1H), 7.03 - 6.92 (m, 3H), 6.84 - 6.80 (m, 1 H), 6.02 (s, 1 H), 3.99 (s, 2H), 3.81 (s, 3H), 1.07 (s, 6H).

[0371] Example 49: 50 Synthesis

[0372] Synthesis of 4-(5-(benzo[d][1,3] dioxol-4-yl)-9-fluoro-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g] quinoxalin-8-yl)benzoic acid (50).

[0373] This was prepared following the methods described in Example 9 but using 4- bromobenzo[d][1 ,3]dioxole to produce 50 (shown below).

[0374] LC-MS (m / z): calc. 460.15, found 461.28 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.05 - 12.95 (m, 1 H), 12.52 - 12.40 (m, 1H), 7.87 - 7.77 (m, 3H), 7.16 - 7.08 (m, 2H), 7.03 - 6.94 (m, 2H), 6.75 (dd, J = 1.5, 7.8 Hz, 1H), 6.12 (s, 1 H), 5.96 (d, J = 8.5 Hz, 2H), 3.93 (s, 2H), 1.09 - 1.04 (m, 6H).

[0375] Example 50: 51 Synthesis

[0376] Synthesis of ((R)-4-(5-(3,4-difluorophenyl)-6-(methoxymethyl)-6-methyl-1,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (51).

[0377] This was prepared using the methods described in Example 8 but using 1 ,2-difluoro-4- iodobenzene to produce 51 (shown below).

[0378] LC-MS (m / z): calc. 464.17, found 465.38 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 12.42 - 11.78 (m, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.62 - 7.53 (m, 2H), 7.47 - 7.35 (m, 3H), 7.18 - 7.12 (m, 1 H), 7.02 (s, 1 H), 6.18 (s, 1H), 3.99 (d, J = 12.3 Hz, 1 H), 3.55 (d, J = 12.3 Hz, 1 H), 3.28 - 3.23 (m, 2H), 2.97 (s, 3H), 1.04 (s, 3H).

[0379] Example 51 : 52 Synthesis

[0380] Synthesis of p-[2-fluoro-10-(p-fluorophenyl)-11 , 11 -dimethy l-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (52).

[0381] This was prepared following the methods described in Example 9 but using 1-bromo-4- fluorobenzene to produce 52 (shown below).

[0382] LC-MS (m / z): calc.434.446, found 435.1 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.99 (s, 1 H), 7.88 - 7.81 (m, 2H), 7.78 - 7.73 (m, 1H), 7.39 - 7.32 (m, 2H), 7.32 - 7.26 (m, 2H), 7.16 - 7.09 (m, 2H), 5.95 (s, 1 H), 3.95 (s, 2H), 1.02 (s, 6H).

[0383] Example 52: 53 Synthesis

[0384] Synthesis of 4-(5-(4-chloro-3-methoxyphenyl)-9-fluoro-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g] quinoxalin-8-y I) benzoic acid (53).

[0385] This was prepared following the methods described in Example 9 but using 1-chloro-4-iodo-2- methoxybenzene to produce 53 (shown below). Compound 53

[0386] LC-MS (m / z): calc. 480.15, found 481.37 (M+H). 1 H NMR (400 MHz, DMSO-d6) 5 13.00 (br. s, 1 H), 12.51 (br. s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.77 (br. s, 1 H), 7.56 (d, J = 8.3 Hz, 1H), 7.17 - 7.11 (m, 2H), 6.99 (d, J = 2.3 Hz, 1 H), 6.85 (dd, J = 2.3, 8.3 Hz, 1H), 6.05 (s, 1 H), 3.95 (s, 2H), 3.84 (s, 3H), 1.06 (s, 6H).

[0387] Example 53: 54 Synthesis

[0388] Synthesis of p-[10'-(p-fluorophenyl)-4,5-dihydro-2H-spiro[furan-3,11'- [4,5,10,13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]benzoic acid (54).

[0389] This was prepared following the methods described in Example 1 but using 3-aminooxolane- 3-carboxylic acid to produce 54 (shown below). Compound 54

[0390] LC-MS (m / z): calc. 444.466, found 445.5 (M+H).1H NMR (500 MHz, DMSO) 5 12.09 (br s, 1 H), 7.54 (s, 1 H), 7.44 - 7.38 (m, 4H), 7.37 - 7.31 (m, 4H), 6.56 (s, 1 H), 6.16 (s, 1H), 3.76 - 3.66 (m, 5H), 3.62 - 3.54 (m, 1 H), 2.04 - 1.96 (m, 1 H), 1.93 - 1.85 (m, 1 H). One exchangeable proton is not visible.

[0391] Example 54: 55 Synthesis

[0392] Synthesis of p-[2-fluoro-10-(4-fluoro-3,5-dimethoxyphenyl)-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid (55).

[0393] This was prepared using the methods described in Example 9 but using 5-bromo-2-fluoro-1 ,3- dimethoxybenzene to produce 55 (shown below).

[0394] F Compound 55

[0395] LC-MS (m / z): calc. 494.18, found 495.2 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.04 - 12.36 (m, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 3.3 Hz, 1 H), 7.15 (dd, J = 2.3, 9.0 Hz, 2H), 6.63 (d, J = 7.0 Hz, 2H), 6.07 (s, 1 H), 3.94 (s, 2H), 3.80 (s, 6H), 1.08 (s, 6H).

[0396] Example 55: 56 Synthesis

[0397] Synthesis of 3-fluoro-4-[ 10-(p-fluoropheny l)-11 , 11 -d imethyl-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (56).

[0398] Synthesis of methyl 3-fluoro-4-((5-nitro-1-(tetrahydro-2 / - / -pyran-2-yl)-1 / - / -indazol-6-yl) amino) benzoate: To a solution of 6-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.0 g, 3.07 mmol) in toluene (10 ml_) were added methyl 4-amino-3-fluorobenzoate (0.622 g, 3.68 mmol) and cesium carbonate (1.99 g, 6.13 mmol) at room temperature. The reaction mixture was degassed with argon for 5 minutes, followed by the addition of Xantphos (0.887 g, 1.53 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.280 g, 0.31 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through CELITE® pad and washed with ethyl acetate (50 ml_). Volatiles were removed under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (2-15% ethyl acetate in hexanes) to afford the titled (0.6 g) as a brown solid. LC-MS (m / z): calc. 414.13, found 415.16 (M+H). Synthesis of methyl 4-((5-amino-1-(tetrahydro-2 / - / -pyran-2-yl)-1 / - / -indazol-6-yl) amino)-3- fluorobenzoate: To a stirred mixture of methyl 3-fluoro-4-((5-nitro-1-(tetrahydro-2 / - / -pyran-2-yl)-1H- indazol-6-y I) amino) benzoate (0.6 g, 1.45 mmol) in ethanol (10 mL) were added iron powder (0.404 g, 7.24 mmol) and ammonium chloride (0.387 g, 7.24 mmol) in water (50 mL) at room temperature and stirred at 70 °C for 5 h. The reaction mass was filtered through CELITE® pad. The filtrate was diluted with water (25 mL) and extracted with dichloromethane (3x30 mL). Volatiles were removed under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (20% ethyl acetate in hexanes) to afford the titled (0.5 g) as an off-white solid. LC-MS (m / z): calc. 384.16, found 383.16 (M-H).

[0399] Synthesis of methyl 4-(6,6-dimethyl-7-oxo-1-(tetrahydro-2 / - / -pyran-2-yl)-1,5,6,7-tetrahydro-8 / - / - pyrazolo[3,4-g]quinoxalin-8-yl)-3-fluorobenzoate: To a stirred mixture of methyl 4-((5-amino-1- (tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-yl)amino)-3-fluorobenzoate (0.5 g, 1.3 mmol), 1 , 1 , 1 -trichloro- 2-methylpropan-2-ol (0.461 g, 2.6 mmol) in dichloromethane (10 mL) were added sodium hydroxide (0.260 g, 6.5 mmol) and benzyl triethylammonium chloride (59.25 mg, 0.26 mmol) at 0 °C. The reaction mass was stirred at room temperature for 16 h. Diluted the reaction mass with water (10 mL) and extracted with dichloromethane (3x20 mL). The layers were separated, and volatiles were concentrated under reduced pressure. The crude residue was directly purified by normal phase flash chromatography on silica gel (30% ethyl acetate in hexanes) to afford the titled (0.2 g) as a brown solid. LC-MS (m / z): calc. 452.19, found 453.33 (M+H).

[0400] Synthesis of methyl 3-fluoro-4-(5-(4-fluorophenyl)-6,6-dimethyl-7-oxo-1-(tetrahydro-2 / - / -pyran- 2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: A mixture of methyl 4-(6,6- dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)-3- fluorobenzoate (200 mg, 0.44 mmol) and 1-fluoro-4-iodobenzene (196.249 mg, 0.88 mmol) in toluene (5 mL) at RT was degassed with argon for 5 minutes, followed by the addition sodium tert-butoxide (84.95 mg, 0.88 mmol) and bis(tri-tert-buty I phosphine)palladium(O) (225.8 mg, 0.44 mmol) at RT. The resulting mixture was stirred at 100 °C for 3 h. Cooled the reaction mixture and filtered through celite pad. The filtrate was concentrated under reduced pressure, and the crude residue was directly purified by normal phase flash chromatography on silica gel (30% ethyl acetate in hexanes) to afford the titled (0.120 g) as a brown solid. LC-MS (m / z): calc. 546.21 , found 547.26 (M+H).

[0401] Synthesis of methyl 3-fluoro-4-(5-(4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)- 1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a solution of methyl 3-fluoro-4-(5- (4-fluorophenyl)-6,6-dimethyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoate (0.120 g, 0.22 mmol) in tetrahydrofuran (3 mL) was added 2.0 M borane dimethylsulfide (0.33 mL, 0.66 mmol) at RT. The resulting mixture was stirred at 65 °C for 2 h. The reaction mixture was cooled to 0 °C, added MeOH (5 mL) dropwise and stirred for 5 min at 0 °C. Volatiles were removed under reduced pressure to afford the titled (0.120 g) as an off-white solid. LC- MS (m / z): calc. 532.23, found 533.28 (M+H).

[0402] Synthesis of 3-fluoro-4-( 5-(4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 , 5,6,7- tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid: To a solution of methyl 3-fluoro-4-(5-(4- fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoate (0.170 g, 0.32 mmol) in THF (2 ml_), MeOH (1 ml_) and water (2 ml_) was added lithium hydroxide monohydrate (0.134 g, 3.19 mmol) at RT. The reaction mixture was stirred at 60 °C for 16 h. Cooled the reaction mass to RT and was acidified to pH-2 using citric acid solution and extracted with ethyl acetate (3x10 ml_). The organic layer was washed with water (10 ml_), brine (10 ml_). Volatiles were removed under reduced pressure to afford the titled (0.170 g) as a green solid. LC-MS (m / z): calc. 518.21 , found 519.26 (M+H).

[0403] Synthesis of 3-fluoro-4-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzoic acid (56): To a stirred mixture of 3-fluoro-4-(5-(4-fluorophenyl)-6,6-dimethyl- 1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (0.170 g, 0.33 mmol) in ethyl acetate (3 ml_), water (1 ml_) and methanol (1 ml_) was added p-toluene sulfonic acid monohydrate (125 mg, 0.66 mmol) at room temperature and was stirred at 60 °C for 1 h. The reaction mass was diluted with ice-water (10 ml_) and extracted with ethyl acetate (3x20 ml_). The combined organic layer was washed with water (10 ml_), brine (10 ml_), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by prep- HPLC, Column AVANTOR® ACE® C18 (150*21.2mm), 5um; Mobile Phase A: 0.1% Formic Acid in water; Mobile Phase B: 100% Acetonitrile, to afford the titled 56 (10 mg, 7%) as a pale-yellow solid. LC-MS (m / z): calc. 434.16, found 435.12 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.08 (br. s, 1 H), 8.20 (s, 1 H), 7.86 (dd, J = 1.8, 8.3 Hz, 1 H), 7.78 (dd, J = 1.8, 12.0 Hz, 1 H), 7.58 (t, J = 8.1 Hz, 1 H), 7.54 (d, J = 1.0 Hz, 1 H), 7.39 - 7.28 (m, 4H), 6.39 (s, 1 H), 6.03 (s, 1H), 3.66 (s, 2H), 1.17 (s, 6H).

[0404] Example 56: 57 Synthesis

[0405] Synthesis of p-{2-fluoro-10-[4-fluoro-3-(trifluoromethyl)phenyl]-11 , 11 -d imethy I-4, 5 , 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl}benzoic acid (57).

[0406] This was prepared using the methods described in Example 9 but using 4-bromo-1-fluoro-2- (trifluoromethyl) benzene to produce 57 (shown below).

[0407] LC-MS (m / z): calc. 502.44, found 503.45 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 13.12 - 12.38 (m, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 3.5 Hz, 1 H), 7.70 - 7.61 (m, 3H), 7.17 (dd, J = 2.4, 8.9 Hz, 2H), 6.00 (s, 1H), 3.97 (s, 2H), 1.04 (s, 6H).

[0408] Example 57: 58 Synthesis Synthesis of p-{2-fluoro-10-[4-fluoro-3-(2H3)methoxyphenyl]-11 ,11-dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl}benzoic acid (58).

[0409] This was prepared using the methods described in Example 9 but using 4-bromo-1-fluoro-2- (methoxy-c / 3) benzene to produce 58 (shown below).

[0410] LC-MS (m / z): calc. 467.18, found 468.23 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 12.98 - 12.41 (m, 2H), 7.84 (d, J = 9.0 Hz, 2H), 7.79 - 7.75 (m, 1H), 7.35 (dd, J = 8.5, 11.3 Hz, 1 H), 7.14 (dd, J = 2.1 , 8.9 Hz, 2H), 7.00 (dd, J = 2.5, 8.0 Hz, 1 H), 6.86 - 6.76 (m, 1 H), 6.01 (s, 1H), 3.95 (s, 2H), 1.05 (s, 6H).

[0411] Example 58: 59 Synthesis

[0412] Synthesis of p-{10-[3-( 1 , 1-difluoroethyl)-4-fluorophenyl]-2-fluoro-11 , 11 -d i methy I-4, 5 , 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl}benzoic acid (59).

[0413] This was prepared using the methods described in Example 9 but using 4-bromo-2-(1 ,1- difluoroethyl)-1-fluorobenzene to produce 59 (shown below).

[0414] LC-MS (m / z): calc. 498.18, found 499.23 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 13.03 (br. s, 1 H), 12.43 (br. s, 1H), 7.87 - 7.75 (m, 3H), 7.55 - 7.44 (m, 2H), 7.41 - 7.35 (m, 1H), 7.15 (dd, J = 2.0, 8.8 Hz, 2H), 5.98 (s, 1 H), 3.97 (s, 2H), 2.05 (t, J = 19.3 Hz, 3H), 1.03 (s, 6H).

[0415] Example 59: 60 Synthesis

[0416] Synthesis of p-[10'-(p-fluorophenyl)spiro[cyclopentane-1 ,11'-

[0417] [4,5,10,13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]benzoic acid (60).

[0418] This was prepared following the procedure described in Example 1 , using 1-aminocyclopentane-1- carboxylic acid. LC-MS (m / z): calc. 442.494, found 443.4 (M+H).1H NMR (500 MHz, DMSO-D6) 5 12.23 (br s, 1 H), 7.94 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 0.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.36 - 7.29 (m, 4H), 7.01 (s, 1H), 6.14 (s, 1 H), 3.72 (s, 2H), 1.70 - 1.62 (m, 2H), 1.62 - 1.56 (m, 2H), 1.48 - 1.39 (m, 4H). One exchangeable proton is not visible.

[0419] Example 60: 61 Synthesis

[0420] Synthesis of 4-[10-(p-fluorophenyl)-11 ,11-di methy l~4,5, 10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7), 5, 8-tetraen-13-yl]-3-anisic acid (61).

[0421] This was prepared using the methods described in Example 55 but using methyl 4-amino-3- methoxybenzoate to produce 61 (shown below).

[0422] F Compound 61

[0423] LC-MS (m / z): calc. 446.15, found 447.27 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.98 (br. s, 1 H), 11.98 (br. s, 1H), 7.69 - 7.65 (m, 2H), 7.53 - 7.46 (m, 2H), 7.39 - 7.26 (m, 4H), 6.16 (s, 1 H), 5.99 (s, 1 H), 3.85 (s, 3H), 3.64 - 3.50 (m, 2H), 1.17 (s, 6H). LC-MS (M+H): 403.27.

[0424] Example 61 : 62 Synthesis

[0425] Synthesis of p-[10-(3-chloro-4-fluorophenyl)-2-fluoro-11 ,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (62).

[0426] This was prepared using the methods described in Example 9 but using 2-chloro-1-fluoro-4- lodobenzene to produce 62 (shown below). Compound 62

[0427] LC-MS (m / z): calc. 468.18, found 469.23 (M+H). 1 H NMR (400 MHz, DMSO-d6) 5= 13.03 (br. s, 1 H), 12.51 (s, 1H), 7.79 (dd, J = 3.20, Hz, 3H), 7.57-7.53 (m, 2H), 7.32-7.29 (m, 1 H), 7.15 (dd, J = 2.00, 8.80 Hz, 2H), 6.02 (s, 1 H), 3.95 (s, 2H), 1.04 (s, 6H).

[0428] Example 62: 63 Synthesis

[0429] Synthesis of p-[10-(3-cyclobutoxy-4-fluorophenyl)-2-fluoro-11 ,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (63).

[0430] This was prepared using the methods described in Example 9 but using 4-bromo-2- cyclobutoxy-1-fluorobenzene to produce 63 (shown below).

[0431] Compound 63

[0432] LC-MS (m / z): calc. 504.19, found 505.3 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 13.03 - 12.94 (m, 1 H), 12.56 - 12.37 (m, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 1.8 Hz, 1 H), 7.34 (dd, J = 8.4, 11.4 Hz, 1H), 7.14 (d, J = 7.3 Hz, 2H), 6.86 - 6.77 (m, 2H), 6.01 (s, 1H), 4.79 - 4.70 (m, 1H), 3.94 (s, 2H), 2.40 - 2.30 (m, 2H), 2.11 - 1.98 (m, 2H), 1.81 - 1.68 (m, 1H), 1.64 - 1.55 (m, 1 H), 1.03 (s, 6H).

[0433] Example 63: 64 Synthesis

[0434] Synthesis of 2-chloro-4-(9-fluoro-5-(4-fluoro-3-methoxyphenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8 / - / - pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (64).

[0435] This was prepared using the methods described in Example 9 but using 4-bromo-2- chlorobenzoate and 1-fluoro-4-iodo-2-methoxybenzene to produce 64 (shown below). Compound 64

[0436] LC-MS (m / z): calc. 498.13, found 499.24 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.05 (br. s, 1 H), 7.79 - 7.77 (m, 2H), 7.37 - 7.32 (m, 1 H), 7.15 - 7.01 (m, 3H), 6.85 - 6.81 (m, 1 H), 6.02 (s, 1H), 3.95 (s, 2H), 3.82 (s, 3H), 1 .07 (s, 6H). One exchangeable proton is not visible.

[0437] Example 64: 65 Synthesis

[0438] Synthesis of (R)-4-(5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (65). Synthesis of tert-butyl 4-((6S)-6-(methoxymethyl)-6-methyl-7-oxo-1-(tetrahydro-2H-pyran-2- yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a suspension of (6S)-6- (methoxymethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,8-tetrahydro-7H-pyrazolo[3,4- g]quinoxalin-7-one (0.5 g, 1.51 mmol) in dioxane (10 ml_), was added tert-butyl 4-iodobenzoate (0.92 g, 3.02 mmol), followed by (1R,2R)-N1,N2-dimethylcyclohexane-1 ,2-diamine (0.17 g, 1.21 mmol), and K2CO3 (0.418 g, 3.02 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then Cui (0.15 g, 0.605 mmol) was added. The reaction mixture was heated to 90 °C for 15 h. After completion of the reaction, the reaction mixture was cooled down to room temperature, filtered through a pad of CELITE® and washed with ethyl acetate (75 mL). Volatiles were concentrated under reduced pressure to provide the crude material which was directly purified by normal phase flash chromatography on silica gel (30-40% ethyl acetate in hexanes) to afford the titled (0.54 g; 70%) as a yellow solid. LS-MS (m / z): calc. 506.25, found 507.33 (M+H).

[0439] Synthesis of tert-butyl 4-((6S)-5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-7- oxo-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a suspension of tert-butyl 4-((6S)-6-(methoxymethyl)-6-methyl-7-oxo-1-(tetrahydro-2H-pyran-2-yl)- 1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (540 mg, 1.06 mmol) in toluene (5 mL), was added NaOtBu (307.36 mg, 3.19 mmol), followed by 1-fluoro-4-iodo-2-methoxybenzene (656 mg, 3.18 mmol). The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes, and then bis (tri-tert-buty I phosphine) palladium (146.1 mg, 0.28 mmol) was added. The reaction mixture was heated to 900C for 2 h. After completion of the reaction, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate (20 mL), filtered through CELITE® pad, and washed with ethyl acetate (25 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified using normal phase flash chromatography on silica gel (10-15 % ethyl acetate in hexanes) to afford the titled (0.3 g; 44%) as a pale-yellow solid. LS-MS (m / z): calc. 630.29, found 631.35 (M+H).

[0440] Synthesis of tert-butyl 4-((6R)-5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate: To a solution of tert-butyl 4-((6S)-5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-7-oxo-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (300 mg, 0.476 mmol) in THF (8 mL) was added (CHs^S BHs, 2 M in THF (1.4 mL, 2.85 mmol). The reaction mixture gradually heated to 80 °C for 4 h. After completion of the reaction, the mixture was cooled down to room temperature and slowly quenched with methanol (5 mL) at 0 °C and stirred at the same temperature for 30 min. Volatiles were removed under reduced pressure to provide the crude material (280 mg) which was taken as such for the next step without any purification. LC-MS (m / z): calc. 616.31 , found 617.63 (M+H).

[0441] Synthesis of (R)-4-(5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-1 ,5,6,7- tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid (65): To a stirred solution of tert-butyl 4- ((6R)-5-(4-fluoro-3-methoxyphenyl)-6-(methoxymethyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzoate (280 mg, 0.454 mmol) in dichloromethane (5 mL) was added TFA (1 mL, 13.5 mmol) at 0 °C . The reaction mixture gradually heated to 40 °C and stirred at the same temperature for 16 h. After completion of the reaction, volatiles were removed under reduced pressure, diluted the crude material with ethyl acetate, washed with sodium bicarbonate (2x25 mL), dried over anhydrous sodium sulphate, filtered and concentrated to get the crude. The residue was purified by prep- HPLC, Column:-X-Bridge C8 (250*19mm), 5 urn, Mobile Phase A: 0.1% Formic Acid in water Mobile Phase B: 100% Acetonitrile, to afford the title 65 (40 mg, 18.85%) as a yellow solid. LC-MS (m / z): calc. 476.19, found 477.28 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.70 - 12.13 (m, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.61 (s, 1 H), 7.42 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 8.6, 11.4 Hz, 1H), 7.06 - 7.01 (m, 2H), 6.88 - 6.76 (m, 1 H), 6.16 (s, 1H), 4.03 (d, J = 12.3 Hz, 1H), 3.83 (s, 3H), 3.56 (d, J = 12.3 Hz, 1 H), 3.30 - 3.24 (m, 2H), 2.96 (s, 3H), 1.05 (s, 3H).

[0442] Example 65: 66 Synthesis

[0443] Synthesis of p-[2-fluoro-10-(4-fluoro-3-trifluoromethoxyphenyl)-11 ,11-dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (66).

[0444] This was prepared using the methods described in Example 9 but using 4-bromo-1-fluoro-2- (trifluoromethoxy) benzene to produce 66 (shown below). p Compound 66

[0445] LC-MS (m / z): calc. 518.13, found 519.25 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 13.05 (br. s, 1 H), 12.39 (br. s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 3.0 Hz, 1 H), 7.69 - 7.64 (m, 1 H), 7.55 - 7.49 (m, 1 H), 7.41 - 7.37 (m, 1 H), 7.15 (dd, J = 1.9, 8.9 Hz, 2H), 6.03 (s, 1 H), 3.96 (s, 2H), 1.03 (s, 6H).

[0446] Example 66: 67 Synthesis

[0447] Synthesis of p-[10-(3-ethoxy-4-fluorophenyl)-2-fluoro-11 ,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid (67).

[0448] This was prepared using the methods described in Example 9 but using 4-bromo-2-ethoxy-1- fluorobenzene to produce 67 (shown below). Compound 67

[0449] LC-MS (m / z): calc. 478.18, found 479.29 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 12.97 - 12.48 (m, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 3.3 Hz, 1H), 7.34 (dd, J = 8.5, 11.5 Hz, 1 H), 7.14 (dd, J = 2.1 , 8.9 Hz, 2H), 6.99 (dd, J = 2.4, 7.9 Hz, 1 H), 6.84 - 6.78 (m, 1 H), 6.01 (s, 1 H), 4.08 (q, J = 7.0 Hz,

[0450] 2H), 3.94 (s, 2H), 1.32 (t, J = 6.9 Hz, 3H), 1.05 (s, 6H). Example 67: 68 Synthesis

[0451] Synthesis of p-[ 10-(4-f I uo ro-3-toly I )- 11 ,11 -dimethy I-4, 5, 10, 13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid (68).

[0452] This was prepared following the methods described in Example 1 but using 4-bromo-1-fluoro- 2-methylbenzene to produce 68 (shown below).

[0453] LC-MS (m / z): calc. 430.18, found 431.56 (M+H). 1 H NMR (400 MHz, DMSO-d6) 5 = 12.20 (br. s, 1 H), 7.93 (d, J = 8.80 Hz, 2H), 7.58 (d, J = 0.40 Hz, 1 H), 7.44 (d, J = 8.40 Hz, 2H), 7.28 (t, J = 8.8 Hz, 1H), 7.19 (dd, J = 6.8, 2.2 Hz, 1 H), 7.12-7.09 (m, 1 H), 7.00 (s, 1 H), 6.08 (s, 1 H), 3.73 (s, 2H), 2.28 (s, 3H), 1.11 (s, 6H). One exchangeable proton is not visible.

[0454] Example 68: 69 Synthesis

[0455] Synthesis of p-[(R)-2-fluoro-10-(p-fluorophenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (69).

[0456] This was prepared starting from 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6- amine (described in Example 9) and using (S)-2-amino-3-hydroxy-2-methylpropanoic acid, following Example 8, to produce 69 (shown below).

[0457] LC-MS (m / z): calc. 464.16, found 465.42 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.03 (br. s, 1H), 12.47 (br. s, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.77 (d, J = 3.3 Hz, 1 H), 7.39 - 7.28 (m, 4H), 7.11 (d, J = 7.0 Hz, 2H), 5.96 (s, 1H), 4.30 (d, J = 13.3 Hz, 1H), 3.62 (d, J = 13.5 Hz, 1 H), 3.16 (d, J = 9.2 Hz, 1 H), 3.09 (d, J = 9.2 Hz, 1H), 2.72 (s, 3H), 0.97 (s, 3H). Example 69: 70 Synthesis

[0458] Synthesis of p-[10-(2,2-difluoro-2H-1 ,3-benzodioxol-5-y l)-11 , 11 -dimethyl-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (70).

[0459] This was prepared following the methods described in Example 1 but using 5-bromo-2,2- difluorobenzo[d][1 ,3]dioxole to produce 70 (shown below).

[0460] H

[0461] N

[0462] N. ompound 70

[0463] LC-MS (m / z): calc. 478.14, found 479.4 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.69 - 12.15 (m, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 0.8 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 2.0 Hz, 1 H), 7.10 (dd, J = 2.0, 8.5 Hz, 1H), 7.03 (s, 1 H), 6.16 (s, 1 H), 3.75 (s, 2H), 1.12 (s, 6H).

[0464] Example 70: 71 Synthesis

[0465] Synthesis of p-[(R)-2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (71 ).

[0466] This was prepared starting with 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-amine (described in Example 9) and (S)-2-amino-3-hydroxy-2-methylpropanoic acid, following Example 8 to produce 71 (shown below).

[0467] Compound 71

[0468] LC-MS (m / z): calc. 494.17, found 495.41 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.01 (br. s, 1 H), 12.52 (br. s, 1H), 7.88 - 7.75 (m, 3H), 7.34 (dd, J = 8.5, 11.3 Hz, 1H), 7.15 - 7.00 (m, 3H), 6.85 - 6.80 (m, 1 H), 6.02 (s, 1 H), 4.29 (d, J = 13.5 Hz, 1H), 3.82 (s, 3H), 3.62 (d, J = 13.3 Hz, 1 H), 3.21 (d, J = 9.5 Hz, 1H), 3.10 (d, J = 9.0 Hz, 1 H), 2.74 (s, 3H), 1.00 (s, 3H).

[0469] Example 71 : 72 Synthesis

[0470] Synthesis of m-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid (72).

[0471] This was prepared using the methods described in Example 9 but using methyl 3-bromobenzoate and 4-bromo-1-fluoro-2-methoxybenzene to produce 72 (shown below).

[0472] LC-MS (m / z): calc. 464.16, found 465.34 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 12.91 (br. s, 1 H), 7.76 (s, 1 H), 7.59 (s, 1H), 7.47 - 7.45 (m, 1 H), 7.38 - 7.32 (m, 3H), 7.02 (dd, J = 2.0, 8.0 Hz, 1H), 6.86 - 6.82 (m, 1 H), 6.00 (s, 1 H), 3.88 (s, 2H), 3.82 (s, 3H), 1.05 (s, 6H).

[0473] Example 72: 73 Synthesis

[0474] Synthesis of racemic p-[10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (73).

[0475] This was prepared using the methods described in Example 8 but using racemic 2-amino-3- hydroxy-2-methylpropanoic acid to produce 73 (shown below).

[0476] LC-MS (m / z): calc. 476.19, found 477.38 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.23 (br. s, 1 H), 7.92 (d, J = 8.5 Hz, 2H), 7.58 (s, 1 H), 7.45 - 7.27 (m, 6H), 7.00 (s, 1 H), 6.09 (s, 1 H), 4.00 (d, J = 12.3 Hz, 1H), 3.55 (d, J = 12.3 Hz, 1H), 3.34 (d, J = 9.3 Hz, 1H), 3.24 (d, J = 9.0 Hz, 1 H), 2.97 (s, 3H), 1.03 (s, 3H). One exchangeable proton not observed in NMR. Example 73: 74 Synthesis

[0477] Synthesis of 2-fluoro-4-[10-(p-fluorophenyl)-11 , 11 -dimethy 1-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (74).

[0478] This was prepared following Example 1 using methyl 4-bromo-2-fluorobenzoate to produce 74 (shown below).

[0479] LC-MS (m / z): calc. 434.15, found 441.4 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 12.88 - 12.66 (m, 1 H), 12.31 (br. s, 1 H), 7.81 (t, J = 8.8 Hz, 1 H), 7.61 (s, 1H), 7.40 - 7.20 (m, 5H), 7.18 (s, 2H), 6.11 (s, 1 H), 3.79 (s, 2H), 1.09 (s, 6H).

[0480] Example 74: 75 Synthesis

[0481] Synthesis of 4-[10-(p-fluorophenyl)-11 ,11-di methy l~4,5, 10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7), 5, 8-tetraen-13-yl]-2-anisic acid (75).

[0482] This was prepared following Example 1 using methyl 4-bromo-2-methoxybenzoate to produce 75 (shown below).

[0483] LC-MS (m / z): calc. 446.17, found 447.39 (M+H).1H NMR (400 MHz, DMSO-d6) 5 = 12.20 (s, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.57 (s, 1 H), 7.37 - 7.28 (m, 4H), 7.05 - 6.99 (m, 3H), 6.07 (s, 1 H), 3.83 (s, 3H), 3.76 (s, 2H), 1.12 (s, 6H).

[0484] Example 75: 76 Synthesis Synthesis of p-[10-(p-fluorophenyl)-11 , 11 -d i methy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzamide (76).

[0485] Compound 76

[0486] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 , 5,6,7- tetrahydro-8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzamide: To a stirred mixture of 4-(5-(4-fluorophenyl)- 6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8- yl)benzonitrile [Prepared in Example 76] (90 mg, 0.19 mmol) in dimethyl sulfoxide (5 ml_) were added potassium carbonate (51.65 mg, 0.37 mmol) and hydrogen peroxide (12.71 mg, 0.37 mmol) at room temperature and was stirred at 60 °C for 2 h. After completion of the reaction, the reaction mixture was filtered through CELITE® pad and washed with ethyl acetate (20 ml_). The filtrate was washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford the title (50 mg, 53%) as a yellow solid. LC-MS (m / z): calc. 499.24, found 500.43 (M+H).

[0487] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzamide (76): To a stirred mixture of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzamide (0.050 g, 0.10 mmol) in ethyl acetate (1 ml_), methanol (0.5 ml_) and water (0.5 ml_) was added p-toluene sulfonic acid monohydrate (38 mg, 0.20 mmol) at room temperature and the reaction mixture was stirred at 70 °C for 2 h. After completion of the reaction (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC Column: X-Bridge C18 (250*19mm), 5 urn; Mobile Phase A: 10mM Ammonium Bicarbonate in Water. Mobile Phase B: 100% Acetonitrile, to afford the title 76 (2.1 mg, 5%) as a yellow solid. LC-MS (m / z): calc. 415.18, found 416.35 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.17 (s, 1 H), 7.96 - 7.84 (m, 3H), 7.55 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.39 - 7.26 (m, 4H), 7.23 (br. s, 1 H), 6.91 (s, 1 H), 6.06 (s, 1H), 3.71 (s, 2H), 1.12 (s, 6H).

[0488] Example 76: 77 Synthesis

[0489] Synthesis of p-[10-(p-fluorophenyl)-11 , 11 -d i methy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzonitrile (77).

[0490] Synthesis of 4-(6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4- g]quinoxalin-8-yl)benzonitrile: A stirred mixture of 6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-5,6,7,8- tetrahydro-1 H-pyrazolo[3,4-g]quinoxaline (400 mg, 1.40 mmol), 4-bromobenzonitrile (762.7 mg, 4.19 mmol) and sodium tert-butoxide (402.68 mg, 4.19 mmol) in toluene (15 mL) was degassed with argon for 10 minutes, followed by the addition of bis(tri-tert-butyl phosphine)palladium(O) (142.76 mg, 0.28 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After completion of the reaction, the reaction mixture was filtered through CELITE® pad and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified using normal phase flash chromatography on silica gel (10-12% of ethyl acetate in heptanes) to afford the title (130 mg, 24%) as brown gum. LC-MS (m / z): calc. 387.21, found 388.18 (M+H).

[0491] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H- pyrazolo[3,4-g]quinoxalin-8-yl)benzonitrile: A stirred mixture of 4-(6,6-dimethyl-1-(tetrahydro-2H- pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g]quinoxalin-8-yl)benzonitrile (110 mg, 0.28 mmol), 1- bromo-4-fluorobenzene (149.03 mg, 0.85 mmol) and sodium tert-butoxide (81.84 mg, 0.85 mmol) in toluene (3 mL) was degassed with argon for 10 minutes, followed by the addition of bis(tri-tert-buty I phosphine)palladium(O) (145.08 mg, 0.28 mmol) at room temperature and the reaction mixture was stirred at 100 °C for 1 h. After completion of the reaction, the reaction mixture was filtered through CELITE® pad and washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified using normal phase flash chromatography on silica gel (40% of ethyl acetate in heptanes) to afford the title (30 mg, 22%) as a yellow solid. LC-MS (m / z): calc. 481 .23, found 482.16 (M+H).

[0492] Synthesis of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-y I) benzonitrile (77): To a stirred mixture of 4-(5-(4-fluorophenyl)-6,6-dimethyl-1- (tetrahydro-2H-pyran-2-yl)-1 ,5,6,7-tetrahydro-8H-pyrazolo[3,4-g] quinoxalin-8-yl) benzonitrile (35 mg, 0.07 mmol) in ethyl acetate (2 mL), methanol (1 mL) and water (1 mL) was added p-toluene sulfonic acid monohydrate (27.65 mg, 0.14 mmol) at room temperature and the reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC using Column: X-Bridge C18 (250*19mm), 5 urn; Mobile Phase A: 0.1% formic acid in Water. Mobile Phase B: 100% Acetonitrile, to afford the title 77 (2 mg, 7%) as an off-white solid. LC-MS (m / z): calc. 397.17, found 398.36 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.29 (br. s, 1 H), 7.75 (d, J = 8.8 Hz, 2H), 7.61 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.39 - 7.25 (m, 4H), 7.12 (s, 1H), 6.11 (s, 1 H), 3.79 (s, 2H), 1.09 (s, 6H). Example 77: 78 Synthesis

[0493] Synthesis of p-[10-(4-fluoro-2-methoxyphenyl)-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid (78).

[0494] This compound was prepared using the methods described in Example 1 using 1-bromo-4- fluoro-2-methoxybenzene to produce 78 (shown below).

[0495] 00-0006602

[0496] LC-MS (m / z): calc. 446.17, found 447.4 (M+H).1H NMR (400 MHz, DMS0-d6) 5 12.17 (br. s, 1 H), 7.92 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 0.8 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 2H), 7.24 (dd, J = 6.8, 8.5 Hz, 1 H), 7.11 (dd, J = 2.9, 11.1 Hz, 1H), 6.99 (s, 1 H), 6.91 - 6.84 (m, 1H), 6.00 (s, 1 H), 3.78 - 3.62 (m, 5H), 1.16 (s, 3H), 1.01 (s, 3H). One exchangeable proton is not visible.

[0497] Example 78: Compound 79 Synthesis

[0498] Synthesis of p-[10-(4-fluoro-3-methoxyphenyl)-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (79).

[0499] This compound was prepared using the methods described in Example 1 using 1-fluoro-4- iodo-2-methoxybenzene to produce 79 (shown below).

[0500] 00-0006624

[0501] LC-MS (m / z): calc. 446.17, found 447.39 (M+H).1H NMR (400 MHz, DMS0-d6) 5 12.31 (br. s, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 0.8 Hz, 1 H), 7.46 (d, J = 8.8 Hz, 2H), 7.35 (dd, J = 8.5, 11.3 Hz, 1 H), 7.05 - 6.98 (m, 2H), 6.85 - 6.80 (m, 1H), 6.14 (s, 1 H), 3.83 (s, 3H), 3.75 (s, 2H), 1.14 (s, 6H).

[0502] Example 79: 80 Synthesis Synthesis of p-[11 , 11 -diethyl-10-(p-fluorophenyl)-4, 5, 10,13-tetraazatricyclo[7.4.0.03,7]trideca-

[0503] Synthesis of 6,6-diethyl-1-(tetrahydro-2H-pyran-2-yl)-5,6,7,8-tetrahydro-1 H-pyrazolo[3,4-g] quinoxaline: To a stirred mixture of 6,6-diethyl-1-(tetrahydro-2H-pyran-2-yl)-1 ,5,6,8-tetrahydro-7H- pyrazolo[3,4-g] quinoxalin-7-one (1.0 g, 3.05 mmol, 1.0 equiv.) [Prepared as in Example 1, using 2- amino-2-ethylbutanoic acid] in tetrahydrofuran (12 ml_) was added borane dimethyl sulfide (4.57 ml_, 9.15 mmol) (2 M in THF) at room temperature and the reaction mixture was stirred at 60 °C for 2 h. The reaction mass was cooled to 0 °C and quenched with methanol (5 ml_). After completion of the reaction, volatiles were concentrated under reduced pressure which was directly purified by normal phase flash chromatography on silica gel (10-15 % ethyl acetate in hexanes) to provide the titled compound as pale green oil (0.6 g; 62%). LC-MS (m / z): calc. 314.32, found 315.40 (M+H).

[0504] Synthesis of 4-(6,6-diethyl-1-(tetrahydro-2 / - / -pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-y I) benzoate: To a stirred mixture of 6,6-diethyl-1-(tetrahydro-2H-pyran-2-yl)-5,6,7,8- tetrahydro-1 H-pyrazolo[3,4-g] quinoxaline (200 mg, 0.64 mmol) and tert-butyl 4-iodobenzoate (580.33 mg, 1.91 mmol) in toluene (5 ml_) was added sodium tert-butoxide (183.37 mg, 1.91 mmol) at room temperature. The suspension was degassed with argon for 5 minutes, followed by the addition of bis (tri-tert-buty I phosphine) palladium(O) (65.013 mg, 0.13 mmol) at room temperature and the reaction mixture was stirred at 90 °C for 2 h. After completion of the reaction, filtered the reaction mass and volatiles were concentrated under reduced pressure to provide the crude which was directly purified by normal phase flash chromatography on silica gel (10-15 % ethyl acetate in hexanes) to provide the titled compound as brown oil (0.10 g; 33%). LC-MS (m / z): calc. 490.23, found 491.50 (M+H).

[0505] Synthesis of tert-butyl 4-(6,6-diethyl-5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1 , 5,6,7- tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-yl) benzoate: To a stirred mixture of 4-(6,6-diethyl-1- (tetrahydro-2H-py ran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-yl) benzoate (170 mg, 0.34 mmol) and 1-bromo-4-fluorobenzene (181.90 mg, 1.04 mmol) in toluene (5 mL) was added sodium tert-butoxide (99.89 mg, 1.04 mmol) at room temperature. Reaction mixture was degassed with argon for 5 minutes, followed by the addition of bis (tri-tert-butyl phosphine) palladium (0) (177 mg, 0.35 mmol) at room temperature and was stirred at 90 °C for 1 h. After completion of the reaction, filtered the reaction mass through CELITEOpad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to provide the crude which was directly purified by normal phase flash chromatography on silica gel (10-15 % ethyl acetate in hexanes) to provide the titled compound as brown oil (0.10 g; 49%). LC-MS (m / z): calc. 584.20, found 585.48 (M+H).

[0506] Synthesis of 4-(6,6-diethyl-5-(4-fluorophenyl)-1 -(tetrahydro-2 / - / -pyran-2-yl)-1 , 5,6,7-tetrahydro- 8 / - / -pyrazolo[3,4-g]quinoxalin-8-yl)benzoic acid: To a stirred mixture of 4-(6,6-diethyl-1-(tetrahydro-2H- pyran-2-yl)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-y I) benzoate (80 mg, 0.14 mmol) in tetrahydrofuran (4 mL), methanol (1 mL) and water (1 mL) was added NaOH (164.17 mg, 4.104 mmol) at room temperature and the reaction mixture was stirred at 60 °C for 12 h. After completion of the reaction, the reaction mixture was acidified with dil. HCI up to pH ~ 2 and extracted with ethyl acetate twice. The combined organic layer was washed with water, brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford the title compound (0.05 g, 69 %) as yellow gum. LC-MS (m / z): calc. 528.25, found 529.41 (M+H).

[0507] Synthesis of 4-(6, 6-diethy l-5-(4-fl uoro pheny l)-1 ,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-y I) benzoic acid (Compound 80): To a stirred mixture of 4-(6,6-diethyl-5-(4- fluorophenyl)-1-(tetrahydro-2 / - / -pyran-2-yl)-1,5,6,7-tetrahydro-8 / - / -pyrazolo[3,4-g] quinoxalin-8-yl) benzoic acid (0.070 g, 0.13 mmol) in ethyl acetate (2 mL), methanol (2 mL) and water (1 mL) was added p-toluene sulfonic acid monohydrate (75.566 mg, 0.40 mmol) at room temperature and the reaction mixture was stirred at 60 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with (20 mL) and extracted with dichloromethane (3x20 mL). The combined organic layer was washed with water (10 mL)., brine (10 mL)., dried over anhydrous IXfeSCU, filtered and concentrated under reduced pressure. The crude was purified by prep. HPLC using, Mobile Phase A: 0.1% Formic Acid in water Mobile Phase B:

[0508] 100% Acetonitrile to afford the title Compound 80 (8 mg, 13%) as a pale-yellow solid. LC-MS (m / z): calc. 444.20, found 445.41 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.18 (br. s, 1 H), 7.94 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 0.8 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 2H), 7.33 - 7.28 (m, 4H), 6.91 (s, 1 H), 6.19 (s, 1 H), 3.71 (s, 2H), 1.61 - 1.42 (m, 4H), 0.75 (t, J = 7.4 Hz, 6H). One exchangeable proton is not visible. Example 80: 81 Synthesis

[0509] Synthesis of p-[10-(2,4-difluoropheny l)-11 , 11-dimethyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid (81 ).

[0510] This compound was prepared using the methods described in Example 1 using 1-bromo-2,4- difluorobenzene to produce 81 (shown below).

[0511] LC-MS (m / z): calc. 434.15, found 435.33 (M+H).1H NMR (400 MHz, DMSO-d6) 5 12.23 (br. s, 1 H), 7.94 (d, J = 8.8 Hz, 2H), 7.59 (s, 1 H), 7.51 - 7.38 (m, 4H), 7.26 - 7.22 (m, 1 H), 6.97 (s, 1H), 6.11 (s, 1 H), 3.73 (s, 2H), 1.20 (s, 3H), 1.07 (s, 3H).

[0512] Example 81 : 82 Synthesis

[0513] Synthesis of p-[10-(3,4-difluoro-5-methoxyphenyl)-11, 11-dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (82).

[0514] This compound was prepared using the methods described in Example 1 using 5-bromo-1 ,2- difluoro-3-methoxybenzene to produce 82 (shown below).

[0515] LC-MS (m / z): calc. 464.16, found 465.37 (M+H). 1 H NMR (400 MHz, DMSO-d6) 5 = 12.22 (br. s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 0.8 Hz, 1 H), 7.48 - 7.42 (m, 2H), 7.02 (s, 1H), 6.98 - 6.92 (m, 1 H), 6.89 - 6.88 (m, 1 H), 6.22 (s, 1 H), 3.87 (s, 3H), 3.73 (s, 2H), 1.15 (s, 6H). One exchangeable proton is not visible.

[0516] Example 82: 83 Synthesis

[0517] Synthesis of p-[10-(3-fluoro-5-methoxyphenyl)-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (83).

[0518] This compound was prepared using the methods described in Example 1 using 1-bromo-2,4- difluorobenzene to produce 83 (shown below). Compound 83

[0519] LC-MS (m / z): calc. 446.17, found 447.32 (M+H).1H NMR (400 MHz, DMSO-de) 5 12.32 - 12.14 (m, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 1.0 Hz, 1 H), 7.45 (d, J = 8.8 Hz, 2H), 7.00 (s, 1 H), 6.90 (td, J = 2.4, 10.9 Hz, 1H), 6.71 - 6.64 (m, 2H), 6.21 (s, 1H), 3.80 (s, 3H), 3.72 (s, 2H), 1.15 (s, 6H).

[0520] Example 83: 84 Synthesis

[0521] Synthesis of p-[2-fluoro-10-(m-fluorophenyl)-ll,ll-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-l(9),2,5,7-tetraen-13-yl]benzoic acid (84).

[0522] This compound was prepared using the methods described in Example 9 using 1-bromo-3- fluorobenzene to produce 84 (shown below).

[0523] LC-MS (m / z): calc. 434.16, found 435.4 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.01 (bs, 1 H), 7.86 - 7.81 (m, 2H), 7.78 (d, J = 3.2 Hz, 1H), 7.57 (dd, J = 15.4, 7.5 Hz, 1H), 7.28 (td, J = 8.6, 2.1 Hz, 1 H), 7.17 - 7.08 (m, 4H), 6.01 (s, 1H), 3.95 (s, 2H), 1.04 (s, 6H). One exchangeable proton is not visible.

[0524] Example 84: 85 Synthesis

[0525] Synthesis of p-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11 ,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (85).

[0526] This compound was prepared using the methods described in Example 9 using 4-bromo-1- fluoro-2-methoxybenzene to produce 85 (shown below).

[0527] LC-MS (m / z): calc. 464.17, found 465.37 (M+H).1H NMR (400 MHz, DMSO-de) 5 13.23 - 12.31 (m, 2H), 7.84 (d, J = 9.0 Hz, 2H), 7.77 (d, J = 3.5 Hz, 1 H), 7.35 (dd, J = 8.6, 11.4 Hz, 1 H), 7.15 (dd, J = 2.4, 8.9 Hz, 2H), 7.01 (dd, J = 2.4, 8.1 Hz, 1 H), 6.87 - 6.76 (m, 1 H), 6.01 (s, 1 H), 3.95 (s, 2H), 3.82 (s, 3H), 1.05 (s, 6H). One exchangeable proton is not visible.

[0528] Example 85: 86 Synthesis

[0529] Synthesis of m-[10-(p-fluorophenyl)-11 ,11-dimethyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid (86).

[0530] This compound was prepared using the methods described in Example 1 using methyl 3- bromobenzoate to produce 86 (shown below).

[0531] O

[0532] F Compound 86

[0533] LC-MS (m / z): calc. 416.16, found 417.35 (M+H).1H NMR (400 MHz, DMSO-d6) 5 13.02 (br. s, 1 H), 12.10 (br. s, 1H), 7.92 (s, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.66 - 7.62 (m, 1H), 7.58 - 7.51 (m, 2H), 7.39 - 7.27 (m, 4H), 6.69 (s, 1H), 6.04 (s, 1 H), 3.67 (s, 2H), 1.15 (s, 6H).

[0534] Example 86: 87 Synthesis

[0535] Synthesis of p-[(R)-10-(p-fluorophenyl)-11 -(hydroxy methyl)- 11 -methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (87).

[0536] This compound was prepared following the procedures described in Examples 8 and 40.

[0537] Compound 41 Compound 87

[0538] Synthesis of p-[(R)-10-(p-fluorophenyl)-11 -(hydroxy methyl)- 11 -methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid (Compound 87): p-[(R)-10-(p- Fluorophenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7- tetraen-13-yl]benzoic acid (Compound 41 ) (52.0 mg, 119 mol) was dissolved in THF (1 ml_) and BBrs 1 M solution in DCM (5.94 mmol, 5.94 ml_) was added at -78 °C. The reaction mixture was then stirred to reach RT for 3 h, where LCMS indicated full conversion of starting material into corresponding bromo-intermediate. LCMS (m / z): 497 (M+H). Sodium hydroxide, 4 M solution in water (11.9 mmol, 2.97 mL) was added to reaction and the final mixture was stirred at 45 °C for 2 h. 1 M HCI was added to bring pH to ~ 1-3. The mixture was extracted with EtOAc. The combined organic layers were dried over IXteSCU, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (5-60% ACN in AmB buffer) to afford the titled Compound 87 (2.98 mg, 5.5 %) as a white solid. LC-MS (m / z): calc.432.455, found 433.1 (M+H).1H NMR. (500 MHz, DMSO-d6) 5 12.10 (s, 1 H), 7.96 - 7.90 (m, 2H), 7.52 (s, 1 H), 7.36 - 7.27 (m, 6H), 6.77 (s, 1 H), 6.02 (s, 1 H), 4.86 - 4.81 (m, 1 H), 3.88 - 3.84 (m, 1 H), 3.56 - 3.53 (m, 1 H), 3.53 - 3.48 (m, 2H), 1.03 (s, 3H).

[0539] Example 87: 88 Synthesis

[0540] Synthesis of 10-(p-fluorophenyl)-11 ,11-dimethyl-13-[(tetrahydro-4H-pyran-4-yl)methyl]- 4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraene (88).

[0541] This compound was prepared following the procedures described in Examples 1, including the alkylation step with 4-(iodomethyl)oxane as shown below.

[0542]

[0543] LC-MS (m / z): calc.394.494, found 395.1 (M+H).1H NMR. (400 MHz, DMSO-d6) 5 = 12.06 (s, 1H), 7.44 (s, 1H), 7.34-7.26 (m, 2H), 7.24- 7.18 (m, 2H), 6.50 (s, 1H), 5.89 (s, 1H), 3.95- 3.85 (m, 2H), 3.36-3.27 (m, 4H, buried underwater peak), 3.26-3.20(m, 2H), 2.18-2.08(m, 1H), 1.73-1.66 (m, 2H), 1.40- 1.28 (m, 2H), 1.10 (s, 6H).

[0544] Example 88: 89 Synthesis

[0545] Synthesis of 10'-(p-fluoropheny l)-13'-( p-tolyl)~4, 5-dihydro-2H-spiro[furan-3, 11'- [4,5,10,13]tetraazatricyclo[7.4.0.03,7]trideca[1,3(7),5,8]tetraene] (89).

[0546] This was prepared following the methods described in Example 1 using 3-aminooxolane-3- carboxylic acid to produce 89 along with Compound 54 (Example 53) and Compound 90 (Example 89). Prep-HPLC purification (55-75% MeOH / 10 mM ammonium formate aq. buffer) provided the titled Compound 89 (30.2 mg, 19%) as an off-white solid.

[0547] Compound 89. LC-MS (m / z): calc.414.484, found 415.5 (M+H).1H NMR (500 MHz, DMSO) 512.06 (brs, 1H), 7.53 (d, J = 0.9 Hz, 1H), 7.36- 7.32 (m, 4H), 7.32-7.29 (m, 4H), 6.44 (s, 1H), 6.15 (s, 1H), 3.77- 3.63 (m, 5H), 3.63- 3.56 (m, 1H), 2.36 (s, 3H), 2.03- 1.97 (m, 1H), 1.92- 1.86 (m, 1H).

[0548] Example 89: 90 Synthesis Synthesis of {p-[10'-(p-fluorophenyl)-4,5-dihydro-2H-spiro[furan-3,1T- [4,5,10,13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]phenyl}methanol (90).

[0549] This was prepared following the methods described in Example 1 using 3-aminooxolane-3- carboxylic acid to produce 90 along with Compound 54 (Example 53) and Compound 89 (Example 88). Prep-HPLC purification (55-75% MeOH / 10 mM ammonium formate aq. buffer) provided the titled Compound 90 (5.52 mg, 3.4%) as a grey solid.

[0550] Compound 90. LC-MS (m / z): calc.430.483, found 431.4 (M+H).1H NMR (500 MHz, DMSO) 512.11 (brs, 1H), 7.54 (s, 1H), 7.46-7.41 (m, 2H), 7.38-7.32 (m, 6H), 6.55- 6.48 (m, 1H), 6.22- 6.12 (m, 1H), 5.25 (brs, 1H), 4.58- 4.50 (m, 2H), 3.78- 3.66 (m, 5H), 3.61 -3.56(m, 1H), 2.04- 1.96 (m, 1H), 1.93- 1.84 (m, 1H).

[0551] Example 90: 91 Synthesis

[0552] Synthesis of ( 1 r,4r)-4-[10-(p-fluorophenyl)-11,11 -dimethyl-4, 5, 10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1,3(7),5,8-tetraen-13-yl]cyclohexanecarboxylic acid (91).

[0553] This was prepared using the methods described in Example 55 using methyl 4-aminocyclohexane-1- carboxylate to produce 91 (shown below).

[0554] LC-MS (m / z): calc.422.15, found 423.27 (M+H). 1H NMR (400 MHz, DMSO-d6) 512.11 - 12.00 (m, 2H), 7.43 (s, 1H), 7.33 - 7.27 (m, 2H), 7.24 - 7.16 (m, 2H), 6.62 (s, 1H), 5.87 (s, 1H), 3.73 (br. s, 1H), 3.12 (s, 2H), 2.24-2.21 (m, 1H), 2.10-2.02 (m, 2H), 1.91 - 1.81 (m, 2H), 1.66- 1.52 (m, 4H), 1.09 (s,

[0555] 6H). Example 91 : Biological Validation of Activity in Cell-Based Z-A1AT Secretion Assay

[0556] Patients harboring the E342K mutation in a homozygous genotype, express Z-A1 AT have reduced A1 AT secretion relative to people without this mutation and reduced A1 AT protease inhibition function.

[0557] A1AT is primarily secreted as monomers by hepatocytes. To determine the level of secreted Z-A1AT, and effects of compounds on this endpoint, a commercially available A1 AT-specific ELISA kit was used to quantify the amount of Z-A1AT in supernatant obtained from a human hepatoma cell line HepG2, engineered to express the E342K-A1 AT from the endogenous locus of both alleles.

[0558] Materials and Instruments

[0559] Human alpha-1 antitrypsin ELISA kit, Abeam ab108799

[0560] CELLTITER-GLO® 2.0 Assay, Promega G9242

[0561] TRYPLE™ Express, Gibco 12604-013

[0562] EMEM culture media, ATCC 30-2003

[0563] HI-FBS, Gibco 12484-028

[0564] DPBS (1X), Gibco 14190-144

[0565] 96 well white opaque bottom plate for cell culture, Brandplate 781965

[0566] 96 well clear found bottom plate, Sarstedt 82.1582001

[0567] Plate reader: Perkin Elmer ENVISION™ 2105

[0568] To prepare the cells for the experiment the complete medium (EMEM + 10% FBS) was prewarmed at 37 °C. From the T175 flask in which the cells were grown, the culture media was removed and discarded. The cell layer was then rinsed with 10 mL of DPBS and 5 mL of TRYPLE™ Express was added to the flask. The cells were observed under an inverted microscope until the cell layer was dispersed. Once cells had detached from the flask, 5 mL of EMEM + 10% FBS medium was added, and the cell suspension was mixed by gently pipetting up and down. The contents of the flask were transferred to a 15 mL centrifuge tube and an aliquot taken for cell counting purposes. The 15 mL tube was then centrifuged at 300 x g for 5 minutes. The cells were counted with the COUNTESS™ 3 Automated Cell Counter. Following centrifugation, the supernatant was aspirated, and cells were resuspended in complete medium to achieve a 200,000 cells / mL dilution. Cells were seeded at 20,000 cells / well in a 96-well, opaque-bottom plate in a 100 pL volume.

[0569] A D300e Digital Dispenser (Tecan) was used to add compound to cells across a concentration range spanning 0-30 pM of compound, in a 8-point, 3-fold dilution format, in duplicate. DMSO was used as the vehicle control and the volume of DMSO was normalized across all treatment wells. Following the addition of compounds the plate was incubated overnight at 37°C.

[0570] Following compound incubation, the plate was centrifuged at 300 x g for 5 minutes and 50pL of supernatant from each well was transferred to a 96-well, V-bottom, polystyrene plate and stored at 4°C until running of the ELISA assay. The original plate containing the treated cells was equilibrated to room temperature for the CELLTITER-GLO® assay. Reagents for the CELLTITER-GLO® 2.0 assay were thawed and equilibrated to room temperature. To the 50 pL of media remaining in the wells of the plate containing cells, 50 pL of CELLTITER-GLO® 2.0 (ready-use reagent) was added. The plate was incubated at room temperature for 10 minutes, sealed with a plate sealer and then luminescence was read with 0.01 second integration on an ENVISION™ plate reader (PerkinElmer).

[0571] The ELISA assay was carried out essentially as described in the kit manual according to manufacturer instructions (ab108799). All reagents were equilibrated to room temperature. Then 1X Diluent N was made from 10X diluent N, 1 :10 in water, IX wash buffer from 20X wash buffer, 1 :20 in water, 1X biotinylated A1 AT detector Ab (freshly diluted just before use) from 50X stock, 1:50 in 1X diluent N to make enough for 55 pL / well, and 1X Streptavidin Peroxidase Ab (freshly diluted just before use) from 100X stock, 1 :100 in 1X Diluent N to make enough for 55 pL / well. All supernatant samples were diluted 1:100 in 1X Diluent N (2 pL samples + 198 pL 1X Diluent N) in a 96-well, roundbottom polypropylene plate. To the assay strip wells, 50 pL of appropriately diluted sample or standard per well was added and the plates were sealed with the provided seal. The standard was reconstituted with Diluent N and allowed to rehydrate for 10 min. A serial 1:2 dilution series of standard in Diluent N over 5 points was used in the assay, spanning 1.56-25 ng / mL of A1 AT. Three wells with Diluent N served as background controls. The plate was then incubated at room temperature for 2 hours on a shaker. The plate was then washed 5x with 200 pL / well with 1X wash buffer. After the last wash, all liquid was removed and 50 pL of 1X biotinylated A1 AT detection Ab was added to all wells. The plate was incubated for 1 hour at room temperature and following the incubation washed 5x with 200 pL / well with 1X wash buffer as described above. Then 50 pL of 1X Streptavidin Peroxidase Ab was added to all wells and the plate was incubated for 30 minutes at room temperature. The plate was then washed 5x with 200 pL / well of 1X wash buffer as described above. Then 50 pL of Chromogen Substrate was added to each well and the plate incubated at room temperature for 30 minutes or until blue color developed in positive wells. At this point, 50 pL of Stop Solution was added to each well and absorbance was measured at 450 nm on the ENVISION™ plate reader.

[0572] Assay Protocol

[0573] Day 1 Protocol

[0574] • Seed 20,000 HepG2-E342K cells per well in a 96 well plate (white with opaque bottom)

[0575] • T reat cells with compound(s)

[0576] • Incubate plates at 37 °C for 24h Day 2 Protocol

[0577] • Collect supernatant and run ELISA according to manufacturer protocol (Abeam, ab108799) read signal on ENVISION™ plate reader

[0578] • Perform CELLTITER-GLO® on plate to assess cell viability according to manufacturer protocol and read signal on ENVISION™ plate reader

[0579] Analysis

[0580] To determine A1AT concentration in samples, background is subtracted, and signal is corrected for viable cell number. Signal is then converted to A1 AT ng / mL using the A1 AT standard curve (provided in ELISA kit). Cut-off for significance is defined as baseline + 3x standard deviations. ECso values were determined using GraphPad Prism.

[0581] • Wash plate in PBS + 0.1% TWEENO20, protected from light

[0582] • Remove wash, dry plate and scan on Odyssey Imager with detection in both 700 nm and 800 nm channels

[0583] Results for compounds of the invention are provided in Table 1. EC50, potency, categories are defined as: “+++” means <1.5 pM; “++” means between 1.5 pM and 3 pM; and “+” means greater than 3.0 pM.

[0584] Table 1 : Potency in Cell-Based Z-A1AT Secretion Assay (EC50 data for Compounds)

[0585] Other Embodiments

[0586] Various modifications and variations of the described compositions, methods, and uses of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

[0587] Other embodiments are in the claims.

Claims

1. What is claimed is:CLAIMS1 . A compound having the structure of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein:R° is hydrogen, optionally substituted CB-C-IO aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocyclyl, optionally substituted C3-C12 cycloalkyl, optionally substituted CI-CB alkyl C3-C12 heterocyclyl, or -C(O)-RA;RAis optionally substituted CB-C-IO aryl or optionally substituted C5-C12 heteroaryl;R1and R2are each, independently, hydrogen or optionally substituted CI-CB alkyl, alkoxy, or R1and R2, together with the carbon atom to which they are attached, combine to form an oxo, an optionally substituted CS-CB cycloalkyl or an optionally substituted C3-C12 heterocyclyl;R3is hydrogen, optionally substituted CB-C-IO aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocyclyl, or optionally substituted C3-C12 cycloalkyl;R4and R5are each, independently, hydrogen or optionally substituted CI-CB alkyl, alkoxy, or R4and R5, together with the carbon atom to which they are attached, combine to form an oxo, an optionally substituted CS-CB cycloalkyl or an optionally substituted C3-C12 heterocyclyl; andX is hydrogen, halo, or methyl.

2. The compound of claim 1, the compound having the structure of Formula (Ila) or Formula (Hb):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R° is CB-C-IO aryl substituted with a carboxyl group.

4. The compound of any one of claims 1-3, wherein X is fluorine.

5. The compound of any one of claims 1-4, wherein R1and R2are each independently hydrogen or methyl.

6. The compound of any one of claims 1-4, wherein R1and R2, together with the carbon atom to which they are attached, combine to form an oxo, an optionally substituted Cs-Ce cycloalkyl, or an optionally substituted C3-C12 heterocyclyl.

7. The compound of claim 6, wherein R1and R2, together with the carbon atom to which they are attached, combine to form a tetrahydropyran ring.

8. The compound of claim 6, wherein R1and R2, together with the carbon atom to which they are attached, combine to form an optionally substituted Cs-Ce cycloalkyl.

9. The compound of any one of claims 1-8, wherein R3is optionally substituted CB-C-IO aryl or optionally substituted C5-C12 heteroaryl.

10. The compound of claim 9, wherein R3is a phenyl substituted with one or more halo groups.

11. The compound of any one of claims 1-10, wherein R4and R5are each independently hydrogen or methyl.

12. The compound of any one of claims 1-10, wherein R4and R5, together with the carbon atom to which they are attached, combine to form an oxo, an optionally substituted Cs-Ce cycloalkyl or an optionally substituted C3-C12 heterocyclyl.

13. The compound of claim 12, wherein R4and R5, together with the carbon atom to which they are attached, combine to form a tetrahydropyran ring.

14. The compound of claim 12, wherein R4and R5, together with the carbon atom to which they are attached, combine to form an optionally substituted Cs-Ce cycloalkyl.

15. The compound of any one of claims 1-14, wherein the is selected from: p-{11 ,11 -dimethy 1-12-oxo-4,5,10, 13-tetraazatricyclo[7.4.0.03,7]trideca-1 , 3(7), 5,8- tetraen-13-yl}benzoic acid; p-[10-(p-fluorophenyl)-11,11 -dimethyl-4,5, 10, 13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid; p-[10-(p-fluoropheny l)-11 , 11 -d imethy 1-12-oxo-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid; p-[10-(p-fluoropheny l)-11 , 11 -d imethy 1-12-oxo-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid; p-[10-(p-fluorophenyl)-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8- tetraen-13-yl]benzoic acid;p-[10-(p-fluorophenyl)-12-oxo-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid; p-[10'-(p-fluorophenyl)-2,3,5,6-tetrahydrospiro[pyran-4,1 T-[4,5,10,13]tetraazatricyclo[7.4.0.03,7]-trideca[1 ,3(7),5,8]tetraen]-13'-yl]benzoic acid; p-[10'-(p-fluorophenyl)-12'-oxo-2,3,5,6-tetrahydrospiro[pyran-4, 11'-[4.5.10.13]tetraazatricyclo[7.4.0.03,7]-trideca[1 ,3(7),5,8]tetraen]-13'-yl]benzoic acid; p-[ 10-( 3 , 4-d iflu oro phenyl)- 11 , 11 -d i methy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10'-(p-fluorophenyl)spiro[cyclopentane-1 ,11'-[4.5.10.13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]benzoic acid p-[10-(p-fluorophenyl)-12, 12-dimethyl-4,5, 10, 13-tetraazatricyclo[7.4.0.03 7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(3,4-difluorophenyl)-2-fluoro-11 , 11 -di methy i-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[11 , 11 -dimethyl-10-(2-methyl-4-pyridyl)-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid{p-[ 10'-(p-fluorophenyl)-4, 5-dihydro-2H-spiro[furan-3, 11 '-[4.5.10.13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]phenyl}methanol10'-(p-fluorophenyl)-13'-(p-tolyl)-4,5-dihydro-2H-spiro[furan-3,1 T-[4.5.10.13]tetraazatricyclo[7.4.0.03,7]trideca[1 ,3(7),5,8]tetraene]10'-(p-fluorophenyl)-13'-(p-tolyl)spiro[cyclobutane-1 ,11'-[4.5.10.13]tetraazatricyclo[7.4.0.03,7]trideca[1 ,3(7),5,8]tetraene] p-[10'-(p-fluorophenyl)-4,5-dihydro-2H-spiro[furan-3, 11 '-[4.5.10.13]tetraazatricyclo[7.4.0.03,7]trideca[1(9),2,5,7]tetraen]-13'-yl]benzoic acid p-[2-fluoro-10-(p-fluorophenyl)-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid 10-(p-fluorophenyl)-11,11-dimethyl-13-[(tetrahydro-4H-pyran-4-yl)methyl]- 4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraene p-[(R)-10-(p-fluorophenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid m-[10-(p-fluorophenyl)-11 ,11 -dimethyl-4,5, 10, 13-tetraazatricyclo[7.4.0.03 7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11, 11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(m-fluorophenyl)-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(3-fluoro-5-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(p-fluorophenyl)-11-isopropyl-4,5,10,13-tetraazatricyclo[7.4.0.03 7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acidp-[10-(p-fluoropheny l)-11-methyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 (9),2,5,7-tetraen-13-yl]benzoic acid p-[(R)-10-(p-fluorophenyl)-11-(hydroxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[(R)-10-(p-fluorophenyl)-11-methyl-4,5, 10,13-tetraazatricyclo[7.4.0.03,7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[(S)-10-(p-fluorophenyl)-11-methyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 (9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(3,4-difluoro-5-methoxyphenyl)-11 , 11 -d i methy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[ 10-(2 , 4-d iflu oro phenyl)- 11 , 11 -d i methy i-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(4-fluoro-2-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[11 , 11 -diethyl-10-(p-fluorophenyl)-4,5, 10,13-tetraazatricyclo[7.4.0.03 7]trideca- 1 ,3(7),5,8-tetraen-13-yl]benzoic acid( 1 r, 3r)-3-[ 10-(p-fluoropheny l)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]cyclobutanecarboxylic acid( 1s,3s)-3-[10-(p-fluorophenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]cyclobutanecarboxylic acid p-[10-(4-fluoro-3-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid[(1s,3s)-3-[10-(p-fluorophenyl)-11,11-dimethyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]cyclobutyl]methanol[(1 r, 3r)-3-[ 10-(p-fluorophenyl)-11 , 11 -d imethy I-4 , 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]cyclobutyl]methanol p-[10-(p-fluorophenyl)-11,11 -dimethyl-4,5, 10, 13-tetraazatricyclo[7.4.0.03 7]trideca- 1 , 3(7), 5, 8-tetraen-13-y l]benzonitrile p-[10-(p-fluorophenyl)-11,11 -dimethyl-4,5, 10, 13-tetraazatricyclo[7.4.0.03,7]trideca-1 (9),2,5,7-tetraen-13-yl]benzamide4-[10-(p-fluorophenyl)-11,11 -dimethyl-4,5, 10, 13-tetraazatricyclo[7.4.0.03 7]trideca- 1 , 3(7), 5, 8-tetraen-13-y l]-2-anisic acid2-fluoro-4-[10-(p-fluorophenyl)-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid5-{p-[ 10-(p-fluorophenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]phenyl}-2H-tetraazole m-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11,11 -dimethyl-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acidp-[10-(p-fluoropheny l)-11 -(methoxymethyl)-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[(R)-2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[(R)-10-(p-fluorophenyl)-11-(methoxymethyl)-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[(S)-10-(p-fluorophenyl)-11 -(methoxymethyl)-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[ 10-(2,2-difluoro-2H-1 ,3-benzodioxol-5-yl)-11,11 -dimethyl-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[(S)-10-(p-fluorophenyl)-11 -(methoxymethyl)-l 1 -methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[(R)-2-fluoro-10-(p-fluorophenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(4-fluoro-3-tolyl)-11 ,11 -dimethyl-4, 5, 10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(4-fluoro-2-methoxyphenyl)-4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 (9),2,5,7-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3-hydroxyphenyl)-11 ,11 -dimethyl-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(3-ethoxy-4-fluorophenyl)-2-fluoro-11 ,11 -dimethyl-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3-trifluoromethoxyphenyl)-11 ,11 -dimethyl-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(3-difluoromethoxy-4-fluorophenyl)-2-fluoro-11,11 -dimethyl-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[(R)-10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3-isopropoxyphenyl)-11 ,11 -dimethyl-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(3-cyclobutoxy-4-fluorophenyl)-2-fluoro-11 , 11 -d i methy I-4, 5 , 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[10-(3-chloro-4-fluorophenyl)-2-fluoro-11 ,11 -dimethyl-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid4-[10-(p-fluorophenyl)-11,11 -dimethyl-4, 5, 10, 13-tetraazatricyclo[7.4.0.03,7]trideca- 1 , 3(7), 5, 8-tetraen-13-y l]-3-anisic acid p-[10-(p-fluorophenyl)-11-(2-methoxyethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid4-[10-(p-fluorophenyl)-11,11 -dimethyl-4, 5, 10, 13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]-2-hydroxybenzoic acidp-[(S)-10-(p-fluorophenyl)-11-(2-methoxyethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-{10-[3-( 1 , 1 -difluoroethyl)-4-fluorophenyl]-2-fluoro-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl}benzoic acid p-[(R)-10-(p-fluorophenyl)-11-(2-methoxyethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-{2-fluoro-10-[4-fluoro-3-(2H3)methoxypheny l]-11 , 11 -d i methy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl}benzoic acid p-{2-fluoro-10-[4-fluoro-3-(trifluoromethyl)phenyl]-11,11 -dimethyl-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl}benzoic acid p-[2-fluoro-10-(3-fluoro-4-methoxyphenyl)-11, 11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid3-fluoro-4-[10-(p-fluorophenyl)-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid{m-[10-(p-fluorophenyl)-11 ,11 -dimethyl-4,5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]phenyl}acetic acid p-[(R)-10-(3,4-difluorophenyl)-2-fluoro-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[2-fluoro-10-(4-fluoro-3,5-dimethoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(4-chloro-3-fluorophenyl)-2-fluoro-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl]benzoic acid p-[10-(3-cyano-4-fluorophenyl)-2-fluoro-11 , 11 -d i methy I-4, 5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-{2-fluoro-10-[4-fluoro-3-(methylamino)phenyl]-11 ,11 -dimethyl-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1(9),2,5,7-tetraen-13-yl}benzoic acid p-[10-(4-chloro-3-methoxyphenyl)-2-fluoro-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid( 1 r, 4r)-4-[ 10-(p-fluoropheny l)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]cyclohexanecarboxylic acid p-[(R)-10-(3 , 4-d ifl uorophen y I )-11-(methoxymethyl)-11-methyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-{10-[3-(difluoromethyl)-4-fluorophenyl]-2-fluoro-11,11 -dimethyl-4, 5, 10, 13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl}benzoic acid p-[ 10-(2H-1 ,3-benzodioxol-5-yl)-2-fluoro-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[ 10-(2H-1 ,3-benzodioxol-4-yl)-2-fluoro-11,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid2-fluoro-4-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid5-[2-f I uo ro-10-(4-fluoro-3-methoxyphenyl)-11, 11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]-2-toluic acid p-[(R)-10-(3-chloro-4-fluorophenyl)-11-(methoxymethyl)-11-methyl-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid2-chloro-4-[2-fluoro-10-(4-fluoro-3-methoxyphenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid2-chloro-4-[(R)-10-(4-fluoro-3-methoxyphenyl)-11-(methoxymethyl)-11 -methyl- 4,5,10,13-tetraazatricyclo[7.4.0.03,7]trideca-1 ,3(7),5,8-tetraen-13-yl]benzoic acid 2-cyano-4-[10-(p-fluorophenyl)-11 ,11 -dimethyl-4,5, 10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid p-[(S)-10-(p-fluorophenyl)-11-(methoxymethyl)-11-methyl-12-oxo-4,5,10,13- tetraazatricyclo[7.4.0.03,7]trideca-1,3(7),5,8-tetraen-13-yl]benzoic acid16. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a of any one of claims 1-16, and a pharmaceutically acceptable excipient.

18. A method of treating alpha-1 antitrypsin deficiency in a subject in need thereof, the method comprising administering an effective amount of the compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, to the subject.

19. The method according to claim 18, wherein the subject has a Z mutation in alpha-1 antitrypsin.

20. The method according to claim 18, wherein the subject has an SZ mutation in alpha-1 antitrypsin.

21. The method according to claim 18, wherein the subject is homozygous for Z-mutations in alpha-1 antitrypsin.

22. A method of modulating alpha-1 antitrypsin activity comprising contacting the alpha-1 - antitrypsin with the compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof.

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