BENZIMIDAZOLE DERIVATIVES AND THEIR USES

Abstract

The present provides a compound of formula (1) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the present, a method for manufacturing compounds of the present, and therapeutic uses thereof.

Description

BENZIMIDAZOLE DERIVATIVES AND THEIR USES The present invention refers, in general terms, to canonical transient receptor potential channel (TRPC) proteins and, more particularly, to inhibitors of the activity of transient receptor potential channel 6 (TRPC6) proteins, pharmaceutical compositions comprising said inhibitors and methods for using said inhibitors. BACKGROUND OF THE INVENTION The TRPC6 channel, a member of the transient receptor potential (TRP) family, which is a non-selective cation-permeable channel, is activated by diacylglycerol and the like produced by phospholipase C activation and produces physiological and pathophysiological effects. TRPC6 has effects, such as fibrosis and pathological cardiac hypertrophy, evolution of myocardial damage into muscular dystrophy, acute pulmonary vasoconstriction, pathological evolution of pulmonary hypertension induced by chronic hypoxia, allergic airway response, migration of cells, such as neutrophils, increased permeability of endothelial cells in inflammation, pathological crushing of podocytes and evolution of glomerular damage, and proliferation or infiltration of malignant tumors, and is diversely distributed in the brain, heart, lungs, kidneys, placenta, ovaries, spleen and the like ( See, for example, J. IF-2019-169515 62-APN-ANP#INP|I Page 1 of 557 Clin. Invest. 116:3114-3126, 2006; Dev. Cell. 23:705-715, 2012; Circ. Res. 114:823-832, 2014; Proc. Natl. Acd. Sci. USA 103:19093-19098, 2006; J. Cardiovasc. Pharmacol. 57:140-147, 2011; Hypertension 63:173-80, 2014; Clin. Exp. Allergy 38:1548-1558, 2008; Acta. Physiol. 195:3-11, 2009; J. Exp. Med. 209:1953-1968, 2011; Arterioscler. Thromb. Go away. Biol. 33:2121-2129, 2013; PLoS ONE 5: el2859, 2010; Expert Opinion. Ther. Targets. 14:513-27, 2010; and BMC Cancer 13:116, 2013). In familial focal segmental glomerulosclerosis (FSGS), gain-of-function mutants of TRPC6 have been identified, and in patients with spheroid-resistant nephrotic syndrome or idiopathic pulmonary arterial hypertension, a single nucleotide polymorphism has been identified in the promoter region that increases TRPC6 mRNA expression (see, for example, Pediatr Res. Nov 2013; 74(5):511-6 and Circulation. May 5, 2009; 119(17):2313-2322). Therefore, hyperfunction and increased expression of TRPC6 are considered to contribute to the pathological evolution of nephrotic syndrome, pulmonary hypertension and the like (see, for example, Science 308:1801-1804, 2005; Nat. Genet. 37: 739-744, 2005; PLoS One 4: e7771, 2009; :104, 2013; Pediatr. Res. 74:511-516, 2013. Likewise, it has been reported IF-2019-169515 62-APN-ANP#INIJ Page 2 of 557 increased expression of TRPC6 in minimal change nephrotic syndrome, membranous nephropathy, and diabetic nephropathy (see, for example, Circulation 119:2313-2322, 2009; J. Am. Soc. Nephrol. 18:29-36, 2007 ; and Nephrol. Dial. Transplant 27:921-929. New approaches are needed to modulate TRPC6 activity and more particularly, to inhibit TRPC6 activity in the prevention and / or treatment of nephrotic syndrome, minimal change disease, focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis , IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor and muscular dystrophy. There remains a need for agents that exploit different mechanisms of action and may have better outcomes in terms of symptom relief, patient safety and mortality, both in the short and long term. DIGEST OF THE INVENTION The present invention provides compounds that inhibit TRPC proteins and, more specifically, inhibit TRPC6 proteins. In one aspect, the present invention provides benzimidazole compounds that inhibit the activity IF-2019-169515 62-APN-ANP#INPJ Page 3 of 557 of TRPC6. Inhibition of TRPC6 activity may be particularly desirable in the treatment or prevention of a variety of diseases, including nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, diabetic nephropathy, heart failure, stroke, acute lung injury, acute respiratory distress (ARDS) and acute kidney failure. In one aspect, the invention provides substituted benzimidazole compounds that modulate TRPC6 activity. Preferably, the substituted benzimidazole compounds of the invention are TRPC6 inhibitors. The substituted benzimidazole compounds of the invention are compounds and salts according to formula (I): R6 Also provided is a pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or adjuvant and at least one compound of formula (I) or subformulas thereof. The pharmaceutical compositions provided by the invention are suitable for use in the treatment of diseases modulated by TRPC6 activity. In certain aspects, the IF-2019-169515 62-A PN-AN P# IN P4 Page 4 of 557 pharmaceutical compositions of the invention are suitable for use in the treatment of, for example, nephrotic syndrome, minimal change disease, focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure , chronic kidney failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, heart failure, stroke, malignant tumor or muscular dystrophy. Also provided is a packaged pharmaceutical composition comprising a pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or adjuvant and at least one compound of formula (I) or subformulas thereof, and instructions for using the composition to treat a patient suffering from of a disease mediated by TRPC6 activity or, more particularly, to treat a patient suffering from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure , chronic kidney failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, IF-2019-169515 62-A PN - AN P# IN ig Page 5 of 557 malignant tumor or muscular dystrophy. In certain cases, the patient suffers from nephrotic syndrome, membranous nephropathy and acute renal failure. Also provided is a method of treating or preventing a disease in a mammal, which comprises administering to a mammal in need thereof a therapeutically effective amount of at least one compound of formula (I) or subformulas thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or adjuvant and at least one compound of formula (I) or subformulas thereof. Also provided is a method for modulating the activity of TRPC6 in a mammal, which comprises administering to the mammal in need thereof a therapeutically effective amount of at least one compound of formula (I) or subformulas thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or adjuvant and at least one compound of formula (I) or subformulas thereof. Another aspect of the invention relates to a method of treating a TRPC6-mediated disease or disorder, which comprises administering a TRPC6 inhibitor of the invention to a patient requiring treatment. In certain embodiments, the TRPC6-mediated disease or disorder is selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, IF-2019-169515 62-APN-ANP#IN® Page 6 of 557 collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, accident cerebrovascular, malignant tumor or muscular dystrophy. In certain cases, the patient suffers from nephrotic syndrome, membranous nephropathy and acute renal failure. Also provided is the use of at least one compound of formula I or subformulas thereof in the production of a medicament for treating or preventing a disease mediated by TRPC6 activity. Other aspects and embodiments will be apparent to those skilled in the art from the detailed description below. DETAILED DESCRIPTION OF THE INVENTION The invention relates, generally, to compounds of formula I and salts and tautomers thereof that inhibit the activity of the TRPC protein and, more particularly, inhibit the activity of the TRPC6 protein. In particular, the invention relates to compounds that selectively inhibit the activity of TRPC6 protein. In a first embodiment, the invention provides a IF-2019-169515 62-APN-ANP#INPl Page 7 of 557 compound or pharmaceutically acceptable salt thereof according to formula I: (I) where: p is 0 or 1; when p is 0, then R1 is hydrogen, Ci-Ce alkyl, halogen or hydroxy; R2 is amino or aminoalkylCi-Co' R3 is hydrogen and R4 is hydrogen, alkylCi-Ce or phenyl; or when p is 0, then R1 and R3, taken in combination, form a fused Cs-Cg cycloalkyl ring or a fused 4- to 6-membered heterocycle ring with 1 or 2 ring heteroatoms independently selected from N, O or S, and the cycloalkyl o heterocycle is optionally substituted with amino; R2 is hydrogen, Ci-Ce alkyl or Ci-C4 aminoalkyl; and R4 is hydrogen; or when p is 1, then R1 is NHRla; Rla is hydrogen, Ci-C4 alkyl, Cs-C? cycloalkyl, hydroxyCi-C4 alkyl or 4- to 6-membered heterocycloalkyl with a ring heteroatom selected from N, O or S; R2 is hydrogen, Ci-C4 alkyl, hydroxyCi-C4 alkyl or C(O)NH2; R3 is hydrogen, halogen, Ci-C4 alkyl, Ci-C4 alkoxy or hydroxy; and R4 is hydrogen, Ci-C4 alkyl or halogen; either IF-2019-169515 62-A PN-AN P#IN IB Page 8 of 557 when p is 0 or 1, then CRW, in combination, forms a spirocyclic 4- to 6-membered heterocycloalkyl; R3 is hydrogen, halogen, Ci-C4 alkyl, Ci~C4 alkoxy or hydroxy; and R4 is hydrogen or halogen; or when p is 1, then R1 and R3, taken in combination, form a fused 4- to 6-membered heterocycle or a fused 3- to 7-membered carbocycle, and the heterocycle comprises a ring nitrogen atom and optionally, 0 or 1 heteroatoms. rings selected from N, O and S, and the carbocycle is replaced with amino; and R2 is hydrogen; and R4 is hydrogen, halogen or hydroxy; R5 represents 1 or 2 substituents independently selected from hydrogen, halogen, hydroxy, amino, Ci-Ce alkyl or Ci-Ce alkoxy; R6es -(CR7R8)-A; either R6 is a 4- to 7-membered lactam optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, CiC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, hydroxyalkylCi-Ce, alkoxyCi-CealkylCi-Cg, phenyl, 4 to 7 membered heterocycle with 1 ring atom selected from N, OoSyOol additional ring N atoms or 5 or 6 membered heteroaryl with one ring heteroatom selected from N, OoSyOol atoms additional ring nitrogen, where the group IF-2019-169515 62-APN-ANP#INF9 Page 9 of 557 heteroaryl, heterocycle or phenyl is optionally substituted with 0, 1 or 2 alkylCi~C6o halogen; either R6 is a partially unsaturated 9- or 10-membered bicyclic carbocycle, which is optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, Ci-Cg alkyl, C2C6 alkenyl, C2-C6 alkynyl, Ci-Cg haloalkyl, Ci-Ce alkoxy, Ci-haloalkoxy. C6, C(O)NH2y C (0) NHalkylCi-C6; Ά is a 5- or 6-membered heteroaryl comprising one ring heteroatom selected from N, 0 or S and 0, 1 or 2 additional ring nitrogen atoms, said heteroaryl being optionally substituted with 0, 1, 2, 3 or 4 groups independently selected from halogen, cyano, alkylCi-Ce, alkenylC2-C6, alkynylC2-C6, cycloalkylC3C6, haloalkylCi-C6, alkoxyCi-C6, haloalkoxyCi-C6, C(O)N(Ra)2, S (0)2alkyl0i-c6, 5- or 6-membered phenyl or heteroaryl with one ring heteroatom selected from N, 0 or S and 0, 1 or 2 additional ring nitrogen atoms, wherein the optional heteroaryl or phenyl substituent is further substituted with 0, 1 or 2 alkylCi- Cg; either A is phenyl substituted with 1, 2 or 3 substituents independently selected from halogen, alkylCi-Ce, alkenylC2-Ce, alkynylC2-Cs, haloalkylCi-Ce, cyanoalkylCi-Ce, alkoxyCi-Ce, haloalkoxyCi-Ce, cyanoalkoxyCi-Ce, S ( 0)qalkylCi-C6, S(O)2NH2, S (0)2NHalkylCi-C6, S (0)2N (alkylCi-C6) 2, C(O)NH2, IF-2019-169515 62-APN-ANP#INtQ Page 10 of 557 C(O)NHalkylCi-Ce, C(O)N(alkylCi-Cg)2, hydroxy, cyano 0 a 5 0 6 membered heteroaryl with one ring heteroatom selected from N, OoSyO, additional 1 0 2 ring nitrogen atoms, and is further substituted with 0, 1 or 2 alkylCi-Cg; either A is C(O)OR9o C(O)NR9R10; either A is a 9- or 10-membered aromatic or partially unsaturated bicycle optionally substituted with 0, 1 or 2 ring nitrogen atoms and 0 or 1 additional ring heteroatoms selected from N, O or S, and said bicycle is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halogen, cyano, alkylCi-Cg, alkenylCa-Ce, alkynylC2~ C6, haloalkylCi-C6, alkoxyCi-Ce, haloalkoxyCi-Cs, C(O)NH2, C(O)OH or C (O) NHalkylCi-Ce; at each occurrence, RA is independently selected from hydrogen or Ci-C4 alkyl; either N(Ra)2, in combination, forms a 4 to 7 membered azacycle optionally substituted with 0, 1 or 2 alkylCiC4; R7 is hydrogen, alkylCi-Ch or amino; R8 is hydrogen or Ci-C4 alkyl; either CR7R8, in combination, forms a 3- to 6-membered cycloalkandiyl group; R9 is hydrogen, alkylCi-Ce, cycloalkylCs-Ce, hydroxyalkylCi-Cg, alkoxyCi-CyalkylCi-Ce, haloalkylCiIF-2019-169515 62-A PN - AN P# INPÍ Page 11 of 557 Ce, cyanoalkylCi-Ce or -(CH2)rR9A, wherein r is 0 or 1 and R9A is phenyl, 4 to 7 membered heterocycle with a ring heteroatom selected from N, 0 or S, said ring sulfur can be optionally oxidized and 0 or 1 additional ring N atoms or 5- or 6-membered heteroaryl with one ring heteroatom selected from N, 0 or S and 0. 1 or 2 additional ring N atoms, said phenyl, heterocycle or heteroaryl being optionally substituted with 0. 1 or 2 halogen,Ci-C4alkyl or C(O)Ci-Co'alkyl R10is hydrogen, alkylCi-Cg, alkenylC2-Ce, alkynylC2-C6, haloalkylCi-Cg, cycloalkylCs-C? or 5- or 6-membered aromatic, saturated or partially unsaturated heterocycle with 1 or 2 ring heteroatoms independently selected from N, O and S, said sulfur is optionally oxidized and said heterocycle is optionally substituted with 1 or 2 substituents independently selected from Ci-Ce alkyl and halogen, said heterocycle has 1 or 2 ring heteroatoms selected from N, O or S, said sulfur can be optionally oxidized, and wherein each alkyl or cycloalkyl is optionally substituted with cyano, halogen, hydroxy, alkoxyCi-Ce, S(0 )qalkylCi-C6, 4 to 6 membered heterocycle with 1 or 2 ring heteroatoms selected from N, 0 or S or 5 or 6 membered heteroaryl with 1 ring heteroatom selected from N, O or S and 0, 1 or 2 atoms of additional ring nitrogen and where each heterocycle or heteroaryl is optionally substituted IF-2019-169515 62-APN-ANP#INH Page 12 of 557 with 0, 1 or 2 alkylCi-C4; either NR9R10, in combination, forms a saturated or partially unsaturated monocyclic or bicyclic 4- to 10-membered heterocycle with one or two ring nitrogen atoms and 0 or 1 additional ring heteroatoms selected from N, O or S, said ring sulfur can be optionally oxidized , said heterocycle is optionally substituted with 0, 1 or 2 substituents selected from halogen, oxo, hydroxy, cyano, alkylCi-Cg, cycloalkylCs-Cs, haloalkylCi-Cg, hydroxyalkylCi-Ce, cyanoalkylCi-Cg, alkoxyCi-Ce, haloalkoxyCi-Ce , alkoxyCi-C6alkylCi-C4, S (O)qalkylCi-C6, alkylCi-C6S (O) qalkylCi-C6C02H, C (O)alkylCi-C6, C(O)OCi-C6alkyl, C(0)C3-C6cycloalkyl, N(R15)C(0)Ci-C6alkyl or C(O)N(R15)2, phenyl, 4- to 6-membered heterocycle with 1 or 2 ring heteroatoms selected from N, 0, or S or a 5- or 6-membered heteroaryl members with 1 ring heteroatom selected from N, 0 or S and 0, 1 or 2 additional ring nitrogen atoms and where each heterocycle or heteroaryl is optionally substituted with 0, 1 or 2Ci-C4 alkyl; q is 0, 1 or 2; Z1es N or CR11; Z2es N or CR12; Z3es N or CR13; Z4es N or CR14; IF-2019-169515 62-A PN-AN P# INF3 Page 13 of 557 each of Z5and Z6is independently N or C; where 0, 1 or 2 of Z1, Z2, Z3, Z4, Z5 and Z6 are N; each of R11, R12, R13 and R14 is independently selected from the group consisting of hydrogen, halogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, Ci-Cg haloalkyl, Ci-Cg haloalkoxy, C3-C7 cycloalkyl, cyano, SchalkylCi-Cs, phenyl and aromatic, saturated or partially unsaturated 5- or 6-membered heterocycle with 1 or 2 ring heteroatoms independently selected from N, O and S, said heterocycle being optionally substituted with 1 or 2 substituents independently selected from alkylCi-Cg and halogen; and in each occurrence, R15 is selected from hydrogen or Ci-C4 alkyl, or N(R15)2 in combination forms a 4 to 7 membered azacycle optionally substituted with 0, 1 or 2 Ci-C4 alkyl; provided that the compounds of Formula I do not include 1—[7—fluoro-6—methoxy-1-[[2(trifluoromethyl)phenyl]methyl]-lH-benzimidazol-2-yl]-3piperidinamine. In a second embodiment of the invention, compounds and salts are provided according to formula I generally represented by the structure: IF-2019-169515 62-APN-ANP#INM Page 14 of 557 where: p is 0 or 1; when p is 0, then R1 is hydrogen, Ci-Ce alkyl, halogen or hydroxy; R2 is amino or aminoCi-C4alkyl; R3 is hydrogen and R4 is hydrogen, Ci-Cg alkyl or phenyl; or when p is 0, then R1 and R3, taken in combination, form a fused Ca-Cg cycloalkyl ring or a fused 4- to 6-membered heterocycle ring with 1 or 2 ring heteroatoms independently selected from N, O or S, and the cycloalkyl or heterocycle is optionally substituted with amino; R2 is hydrogen, Ci-Ce alkyl or Ci-C4 aminoalkyl; and R4 is hydrogen; or when p is 1, then R1 is NHRla; Rla is hydrogen, Ci-C4 alkyl, Cs-C? cycloalkyl, hydroxyCi-C4 alkyl or 4- to 6-membered heterocycloalkyl with a ring heteroatom selected from N, O or S; R2 is hydrogen, Ci-C4 alkyl, hydroxyCi-C4 alkyl or C(O)NH2; R3 is hydrogen, halogen, Ci-C4 alkyl, Ci-C4 alkoxy or hydroxy; and R4 is hydrogen, Ci-C4 alkyl or halogen; or when p is 0 or 1, then C(NHRla)R2, in combination, forms a 4- to 6-membered heterocycloalkyl IF-2019-169515 62-APN-ANP#INf$ Page 15 of 557 spirocyclic; R3 is hydrogen, halogen, Ci-C4 alkyl, Ci-C4 alkoxy, or hydroxy; and R4 is hydrogen or halogen; or when p is 1, then R1 and R3, taken in combination, form a fused 4- to 6-membered heterocycle or a fused 3- to 7-membered carbocycle, and the heterocycle comprises a ring nitrogen atom and optionally, 0 or 1 heteroatoms. rings selected from N, 0 and S, and the carbocycle is replaced with amino; and R2 is hydrogen; and R4 is hydrogen, halogen or hydroxy; R5 represents 1 or 2 substituents independently selected from hydrogen, halogen, hydroxy, amino, Ci-Cg alkyl or Ci-Ce alkoxy; R6es -(CR7R8)-A; either R6 is a 4 to 7 membered lactam optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, CiCe alkyl, C2~C6 alkenyl, C2-C6 alkynyl, haloCi-Cg alkoxy, Ci-Ce alkoxy, Ci-Cg haloalkoxy, hydroxyCi-Ce alkyl, alkoxyCiCsalkylCi-Cg, phenyl or 5- or 6-membered heteroaryl with a ring heteroatom selected from N, OoSyOol additional ring nitrogen atoms, wherein the heteroaryl or phenyl group is optionally substituted with 0, 2Ci-C6alkyl or halogen; either R6 is a partially unsaturated 9- or 10-membered bicyclic carbocycle, which is optionally substituted with 1 or 2 substituents independently IF-2019-169515 62-A PN - AN P# IN W Page 16 of 557 selected from halogen, cyano, alkylCi-C6, alkenylC2C6, alkynylC2-C6, haloalkylCi-C6, alkoxyCi-C6, haloalkoxyCi-Ce, C(O)NH2y C (O) NHalkylCi-Ce; A is a 5- or 6-membered heteroaryl comprising one ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, said heteroaryl being optionally substituted with 0, 1, 2, 3 or 4 groups independently selected from halogen, cyano, alkylCi-Ce, alkenylC2-Cs, alkynylC2-Cs, haloalkylCiCe, alkoxyCi-Cg, haloalkoxyCi-Ce, C(O)NH2, C (O) NHalkylCiCe, phenyl or 5- or 6-membered heteroaryl with a ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, wherein the optional heteroaryl or phenyl substituent is additionally substituted with 0, 1 or 2Ci-Ce alkyl; either A is phenyl substituted with 1, 2 or 3 substituents independently selected from halogen, alkylCi-Ce, alkenylC2-Ce, alkynylC2-Ce, haloalkylCi-Cg, cyanoalkylCi-Ce, alkoxyCi-Cg, haloalkoxyCi-Ce, cyanoalkoxyCi-Cg, S ( O)qalkylCi~C6, S(O)2NH2, S (O)2NHalkylCi-C6, S (O)2N (alkylCi-C6) 2, C(O)NH2, C(O)NHalkylCi-Cg, C(0)N(alkylCi-Ce)2, hydroxy, cyano or a 5- or 6-membered heteroaryl with one ring heteroatom selected from N, 0 or S and 0, 1 or 2 atoms of additional ring nitrogens, and said heteroaryl is further substituted with 0, 1 or 2Ci-Ce alkyl; either IF-2019-169515 62-APN-ANP#INf7 Page 17 of 557 A is C(O)OR9o C(O)NR9R10; either A is a 9- or 10-membered aromatic or partially unsaturated bicycle optionally substituted with 0.1 or 2 ring nitrogen atoms and 0 or 1 additional ring heteroatoms selected from N, O or S, and said bicycle is optionally substituted with 0.1 or 2 substituents independently selected from the group consisting of halogen, cyano, alkylCi-Cs, alkenylCsÜ6, alkynylC2-C6, haloalkylCi-Cg, alkoxyCi-Cg, haloalkoxyCi-C6, C(O)NH2, C(O)OH or C ( O) NHalkylCi-C6; R7 is hydrogen, Ci-C4 alkyl or amino; R8 is hydrogen or Ci-C4 alkyl; either CR7R8, in combination, forms a 3- to 6-membered cycloalkandiyl group; R9 is hydrogen, Ci-C6 alkyl, hydroxyCi-Ce alkyl, haloCi-Cs alkyl or cyanoCi-Ce alkyl; R10is hydrogen, alkylCi-Cg, alkenylC2_C6, alkynylC2-C6, haloalkylCi-Ce, cycloalkylCs-C? or 4 to 7 membered heterocycle with 1 or 2 ring heteroatoms selected from N, O or S, said sulfur can be optionally oxidized, and wherein each alkyl or cycloalkyl is optionally substituted with cyano, halogen, hydroxy, alkoxyCi-Cg, S (O)qalkylCi-C6, 4 to 6 membered heterocycle with 1 or 2 ring heteroatoms selected from N, 0 or S or 5 or 6 membered heteroaryl with 1 ring heteroatom selected from N, O or S IF-2019-169515 62-APN-ANP#INÍ8 Page 18 of 557 and 0, 1 or 2 additional ring nitrogen atoms; either NR9R10, in combination, forms a 4 to 9 membered monocyclic or bicyclic heterocycle with one ring nitrogen atom and 0 or 1 additional ring heteroatoms selected from N, 0 or S, said ring sulfur can be optionally oxidized, said heterocycle is optionally substituted with 0, 1 or 2 substituents selected from halogen, oxo, hydroxy, cyano, alkylCi-Cs, haloalkylCiCe, hydroxyalkylCi-Ce, alkoxyCi-Ce, S (O)qalkylCi-C6, CO2H, C(0)alkylCi-Cs or C (O)NH2; q is 0, 1 or 2; Z1es N oCR Z2es N oCR Z3es N oCR Z4is N or CR each of Z5and Z6is independently N or C; where 0, 1 or 2 of Z1, Z2, Z3, Z4, Z5 and Z6 are N; each of R11, R12, R13, and R14 is independently selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, C2_C6 alkenyl, C2~C6 alkynyl, C2-C6 alkoxy, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, C3-C7 cycloalkyl, cyano, S02Ci-alkyl. C6, phenyl and aromatic, saturated or partially unsaturated 5- or 6-membered heterocycle with 1 or 2 ring heteroatoms independently selected from N, O and S, said heterocycle being optionally substituted with 1 or 2 IF-2019-169515 62-A PN-AN P# ΙΝΪ9 Page 19 of 557 substituents independently selected from alkylCi-Ce and halogen; and provided that the compounds of Formula I do not include 1-[7-fluoro-6-methoxy-l-[[2(trifluoromethyl)phenyl]methyl]-lH-benzimidazol-2-yl]-3 piperidinamine. The condition is presented in the first embodiment to specifically exclude and describe the identified compound, which is indicated with the CAS number 101440724-9. In certain aspects of the first or second embodiment, compounds of Formula I include compounds of Formula la: R6 where the variables p, R1, R2, R3, R4, R\ R6, Z.1, Z2, Z3, Z4, Z5 and Z6 are as defined in the first or second embodiment. In a third embodiment, the invention provides compounds of the first or second embodiment in which p is 0; R1 is hydrogen, Ci-Ce alkyl, halogen or hydroxy; R2 is aminoalkylCi-Czi; and R3 and R4 are hydrogen. In a fourth embodiment, the invention provides compounds of the first or second embodiment in which p IF-2019-169515 62-A PN-AN P# IN2Q Page 20 of 557 is 0; R1 and R3, taken in combination, form a fused C3-C6 cycloalkyl ring or a fused 4- to 6-membered azacyclo ring, and said cycloalkyl or azacyclo is optionally substituted with amino; and R2 and R4 are hydrogen. . In a fifth embodiment, the invention provides compounds of the fourth embodiment in which R1 and R3 taken in combination form a fused pyrrolidine and R2 and R4 are hydrogen. In a sixth embodiment, the invention provides compounds of the first or second embodiment in which p is 1, R1 is NHRla; Rlais hydrogen, alkylCi-C4, cycloalkylCa-C? or 4- to 6-membered heterocycloalkyl with a ring heteroatom selected from N, 0 or S; R2 is hydrogen or Ci-Ci alkyl; R3 is hydrogen, halogen, Ci-C4 alkyl, Ci-C4 alkoxy, or hydroxy; and R4 is hydrogen, halogen or Ci-C4 alkyl. In a seventh embodiment, the invention provides compounds of the sixth embodiment in which R1 is NHRla; Rla is hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl; R2 is hydrogen or methyl; R3 is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy or hydroxy; and R4 is hydrogen, halogen, methyl or ethyl. In certain aspects of the seventh embodiment, compounds are provided in which Rla is hydrogen or methyl; R2 is hydrogen, R3 is hydrogen, fluorine, methyl or hydroxy; and R4 is hydrogen, halogen, methyl or ethyl. IF-2019-169515 62-APN-ANP#INÍl Page 21 of 557 In an eighth embodiment, the invention provides compounds of the sixth or seventh embodiment in which R1 is NH2; R2 is hydrogen; R3 is hydrogen, fluorine, methyl or hydroxy; and R4 is hydrogen, fluorine or methyl. In a ninth embodiment, the invention provides compounds of the first or second embodiment wherein p is 1; CRXR2, in combination, forms a spirocyclic 4- to 6-membered heterocycloalkyl; R3 is hydrogen, halogen, Ci-C4 alkyl, Ci-C4 alkoxy, or hydroxy; and R4 is hydrogen or halogen. In a tenth embodiment, the invention provides compounds of the first or second embodiment in which p is 1; R1 and R3 taken in combination form a fused 4- or 5-membered carbocycle substituted with amino, and R2 and R4 are hydrogen. In an eleventh embodiment, the invention provides compounds of any of the first to tenth embodiments wherein R5 represents 1 or 2 substituents independently selected from hydrogen, halogen, hydroxy, Ci-C4 alkyl. In a twelfth embodiment, the invention provides compounds of the eleventh embodiment in which R5 represents hydrogen. In a thirteenth embodiment, the invention provides compounds of any of the first to the twelfth embodiment in which R6 is -(CR7R8)-A. IF-2019-169515 62-A PN - AN P# INÍ2 Page 22 of 557 In a fourteenth embodiment, the invention provides compounds of the thirteenth embodiment in which R7 is hydrogen, methyl or ethyl; R8 is hydrogen; or CR7R8, in combination, forms a cyclopropandiyl group. In a fifteenth embodiment, the invention provides compounds of the thirteenth or fourteenth embodiment in which R7 is hydrogen or methyl; and R8 is hydrogen. In a sixteenth embodiment, the invention provides compounds of any of the thirteenth to fifteenth embodiments wherein A is a 5- or 6-membered heteroaryl comprising a ring heteroatom selected from N, O or S and 0, 1 or 2 nitrogen atoms. additional rings, said heteroaryl is optionally substituted with 0, 1 or 2 groups independently selected from halogen, cyano, alkylCi-Ce, alkenylC2-Cs, alkynylC2-C6, haloalkylCiCe, alkoxyCi-Ce, haloalkoxyCi-Ce, C(O)NH2, C(O) NHalkylCiCe, phenyl or 5- or 6-membered heteroaryl with one ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, wherein the optional heteroaryl or phenyl substituent is further substituted with 0 , 1 or 2 alkylCi-Ce· In a seventeenth embodiment, the invention provides compounds of the sixteenth embodiment wherein A is pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl or pyrazin-2yl, each of which is substituted with 1 to 3 groups independently selected from the group consisting of IF-2019-169515 62-APN-ANP#lNH Page 23 of 557 halogen, cyano, Ci-C4alkyl, haloCi-Céalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, C(O)NH2, C (O) NHalkylCi-C4, phenyl or 5-membered heteroaryl with a ring heteroatom selected from N, OoSyO, 1 or 2 additional ring nitrogen atoms, wherein the optional heteroaryl or phenyl substituent is additionally substituted with 0, 1 or 2 alkylCi-Cg. In an eighteenth embodiment, the invention provides compounds of any of the thirteenth to fifteenth embodiments wherein A is phenyl substituted with 1, 2 or 3 substituents independently selected from halogen, alkylCi-Cg, haloalkylCi-Cs, alkoxyCi-Cg, haloalkoxyCi- Cg, hydroxy, cyano or 5- or 6-membered heteroaryl with a ring heteroatom selected from N, OoSyO, 1 or 2 additional ring nitrogen atoms, and said heteroaryl is further substituted with 0, 1 or 2 alkylCi-Cg. In a nineteenth embodiment, the invention provides compounds of the eighteenth embodiment wherein A is phenyl substituted with a substituent selected from the group consisting of halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, Ci-haloalkoxy, hydroxy, cyano or heteroaryl 5-membered with a ring heteroatom selected from N, OoSyO, 1 or 2 additional ring nitrogen atoms, and wherein the phenyl group is optionally substituted with halogen, Ci-C4 alkyl, IF-2019-169515 62-A PN-AN P # INÍ4 Page 24 of 557 alkoxyCi-C4, haloalkylCi-C4 or haloalkoxyCi-C4. In a twentieth embodiment, the invention provides compounds of the eighteenth or nineteenth embodiment wherein A is phenyl substituted with 1 or 2 substituents independently selected from halogen, Ci-C3 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, Ci-haloalkoxy, hydroxy or cyano. In a twenty-first embodiment, the invention provides compounds of any of the thirteenth to fifteenth embodiments wherein A is C(O)NR9R10; R9 is hydrogen or Ci-C4 alkyl; R10 is Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C7 cycloalkyl or 4 to 7 membered heterocycle, and said heterocycle has 1 or 2 ring heteroatoms selected from N, O or S, said sulfur can be optionally oxidized, and wherein each alkyl or cycloalkyl is optionally substituted with cyano, halogen, hydroxy, alkoxyCi-Ce, S(O)qalkylCi-Ce; either NR9R10, in combination, forms a 4- to 9-membered monocyclic or bicyclic azacycle with one ring nitrogen atom and 0 or 1 additional ring heteroatoms selected from N, O or S, said ring sulfur may be optionally oxidized, said azacycle is optionally substituted with 0, 1 or 2 substituents selected from halogen, oxo, hydroxy, cyano, alkylCi-Cg, haloalkylCiCe, hydroxyalkylCi-Ce, alkoxyCi-Ce, S(O)2alkylCi-C6, CO2H, C(O)alkylCi-Ce or C (O)NH2. IF-2019-169515 62-APN-ANP#INÍS Page 25 of 557 In a twenty-second embodiment, the invention provides compounds of the twenty-first embodiment in which R9 is hydrogen, methyl or ethyl; and R10 is Ci-C4 alkyl or Ci-C4 haloalkyl, where each alkyl is optionally substituted with cyano, halogen, hydroxy, Ci-Cg alkoxy or S(O)qCi~C6 alkyl. In a twenty-third embodiment, the invention provides compounds of the twenty-first embodiment in which NR9R10, in combination, forms a 4- to 6-membered monocyclic azacycle or a 7- to 9-membered bicyclic azacycle, each of which with a nitrogen atom ring and 0 or 1 additional ring heteroatoms selected from N, O or S, said ring sulfur may be optionally oxidized, wherein each azacycle is optionally substituted with 0, 1 or 2 substituents selected from halogen, oxo, hydroxy, cyano, alkylCi- Cg, haloalkylCi-Ce, hydroxyalkylCi-Ce, alkoxyCi-Cg, S(O)2alkylCi-Cs, CO2H, C(O)alkylCi-Ce or C(O)NH2. In a twenty-fourth embodiment, the invention provides compounds of the twenty-third embodiment in which the 4- to 6-membered monocyclic azacycle is selected from group consisting of: ON F p 4 0 4 4 N N N N , “'A O Gl· O IF-2019-169515 62-A PN-AN P# IN26 Page 26 of 557 .λλλ / v In a twenty-fifth embodiment, the invention provides compounds of the twenty-third embodiment in which the 7- to 9-membered bicyclic azacycle is selected from the group consisting of: In a twenty-sixth embodiment, the invention provides compounds of any of the first to the twelfth embodiment wherein R6 is a 2-oxo-prolidin-3-yl or 2-oxopiperidin-3-yl, each of which is substituted on nitrogen with Ci-Ce alkyl, Cz-Ce alkenyl, C2_C6 alkynyl, haloCi-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, hydroxyCi-Ce alkyl, Ci-Ce alkoxy-Cgalkyl, phenyl or 5- or 6-membered heteroaryl with a ring heteroatom selected from N, OoSyOol additional ring nitrogen atoms, wherein the heteroaryl or phenyl group is optionally substituted with 0, 1 or 2Ci-Ce alkyl or halogen. In a twenty-seventh embodiment, the invention provides compounds of the twenty-sixth embodiment in which R6es IF-2019-169515 62-A PN-AN P# IN>7 Page 27 of 557 where t is 1 or 2; and R19 is Ci-Ce alkyl, phenyl substituted with 0, 1 or 2 halogens. In a twenty-eighth embodiment, the invention provides compounds of any of the first to the twenty-seventh embodiment in which Z1 is CR11; Z2 is CR12; Z3 is CR13; Z4es N or CR14, each of Z5and Z6es C; R11 is hydrogen, halogen, cyano or Ci-C4 alkyl; each R12 and R13 is independently selected from the group consisting of hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, Ci-C4 haloalkoxy, Cs-Ce cycloalkyl or aromatic, partially unsaturated or 5-saturated 5- or 6-membered heterocycle members with 1 or 2 ring heteroatoms independently selected from N, O and S; and R14 is hydrogen, halogen, cyano or Ci-C4 alkyl. In certain aspects of the twenty-eighth embodiment, compounds are provided in which R11 is hydrogen. In certain other aspects of the twenty-eighth embodiment, compounds are provided in which R14 is hydrogen, fluorine, chlorine, methyl or cyano. In certain aspects of the twenty-eighth modality, IF-2019-169515 62-A PN - AN P# IN29 Page 28 of 557 compounds in which each of R12 and R13 is independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy and Ci-C4 haloalkoxy. In still other aspects of the twenty-eighth embodiment, compounds are provided in which R11 is hydrogen; R14 is hydrogen, fluorine, chlorine, methyl or cyano; and each of R12 and R13 is independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy. In a twenty-ninth embodiment, the invention provides compounds of the first or second embodiment that include compounds of formula II: where: R1 is NHRla; Rlais hydrogen, alkylCi-C4, cycloalkylCs-C? or 6-membered heterocycloalkyl with a ring heteroatom selected from N, O or S; R2 is hydrogen or Ci-C4 alkyl; IF-2019-169515 62-A PN - AN P# I N$ Page 29 of 557 R3 is hydrogen, halogen, Ci-C4 alkyl, Ci-C4 alkoxy or hydroxy; R4 is hydrogen or halogen, R7 is hydrogen, methyl or ethyl; A is C(O)NR9R10; either A is a 5- or 6-membered heteroaryl comprising one ring heteroatom selected from N, 0 or S and 0, 1 or 2 additional ring nitrogen atoms, said heteroaryl being optionally substituted with 0, 1 or 2 groups independently selected from halogen, cyano, alkylCi-Ce, alkenylCs-Ce, alkynylC2-Ce, haloalkylCiC6, alkoxyCi-Cg, haloalkoxyCi-Cg, C(O)NH2, C (O) NHalkylCiCe, phenyl or 5- or 6-membered heteroaryl with a ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, wherein the optional heteroaryl or phenyl substituent is additionally substituted with 0, 1 or 2Ci-Ce alkyl; either A is phenyl substituted with a substituent selected from the group consisting of halogen, CiC4alkyl, haloCi-C4alkyl, Ci-C4alkoxy, haloCi-C4alkoxy, hydroxy, cyano or 5-membered heteroaryl with a ring heteroatom selected from N, OoSyO, 1 or 2 additional ring nitrogen atoms, and wherein the phenyl group is optionally substituted with halogen, Ci-C4 alkyl, Ci-C4 alkoxy, haloCi-C4 alkyl or haloCi-C4 alkoxy; R9 is hydrogen or Ci-C4 alkyl; IF-2019-169515 62-APN-ANP#INÍ0 Page 30 of 557 Is R10 alkylCi-C4, haloalkylCi-C4, cycloalkylCs-C? or 4 to 7 membered heterocycle, and said heterocycle has 1 or 2 ring heteroatoms selected from N, O or S, said sulfur can be optionally oxidized, and wherein each alkyl or cycloalkyl is optionally substituted with cyano, halogen, hydroxy, alkoxyCi -Cg, S (O)qalkylCi-C6; either NR9R10, in combination, forms a 4 to 9 membered monocyclic or bicyclic azacycle with one ring nitrogen atom and 0 or 1 additional ring heteroatoms selected from N, 0 or S, said ring sulfur can be optionally oxidized, said azacycle is optionally substituted with 0, 1 or 2 substituents selected from halogen, oxo, hydroxy, cyano, alkylCi-Ce, haloalkylCiCe, hydroxyalkylCi-Cg, alkoxyCi-Ce, S (O)2alkylCi-C6, CO2H, C (O)alkylCi-Ce or C (O)NH2; Z4es CR14o N; R11 is hydrogen, halogen, cyano or Ci-C4 alkyl; each R12 and R13 is independently selected from the group consisting of hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, Ci-C4 haloalkoxy, Cs-Cs cycloalkyl or aromatic, partially unsaturated or saturated 5- or 6-membered heterocycle members with 1 or 2 ring heteroatoms independently selected from N, O and S; and R14 is hydrogen, halogen, cyano or Ci-C4 alkyl. In certain aspects of the twenty-ninth IF-2019-169515 62-A PN-AN P# IN34 Page 31 of 557 embodiment, compounds of Formula (II) include compounds of Formula (lia): In a thirtieth embodiment, the invention provides compounds of the twenty-ninth embodiment that include compounds of formula III: R1J / ,X1 M R11 d12 1 / A X ΑγΧ R13 ^Z4 N R1 where: X1 is CR16 or N; 10 X2 is CR17 or N; X3 is CR18 or N; Z4 is N or CR14; R1 is NHRla; Rla is hydrogen or Ci-C-j alkyl; 15 R2 is hydrogen or Ci-C4 alkyl; R3 is hydrogen or halogen, R4 is hydrogen or halogen, R7 is hydrogen, methyl or ethyl; / r4 ^R3 R2 (III) IF-2019-169515 62-A PN-AN P# INJ2 Page 32 of 557 R11 is hydrogen, halogen, cyano or Ci~C4 alkyl; each of R12 and R13 is independently selected from the group consisting of hydrogen, halogen, cyano, Ci-C4 alkyl, hydroxyCi-C4 alkyl, Ci-C4 alkoxy or haloCi-C4 alkoxy; R14 is hydrogen, halogen, cyano or Ci-C4 alkyl; R15 is hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 alkoxy, haloCi-C4 alkyl, haloCi-C4 alkoxy, C(O)NH2, C (O) NH (Ci-C4 alkyl) or 5-membered heteroaryl with a ring heteroatom selected from N, OoSyO, 1 or 2 additional ring nitrogen atoms; R16 is hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 alkoxy, haloCi-C4 alkyl or haloCi-C4 alkoxy; R17 is hydrogen or halogen; and R18 is hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 alkoxy, haloCi-C4 alkyl or haloCi-C4 alkyl, where at least one of R15, R16, R17 or R18 is not hydrogen. In certain aspects of the thirtieth embodiment, compounds of Formula (III) include compounds of Formula (Illa): R1(Illa) . IF-2019-169515 62-A PN-AN P# IN$6 Page 33 of 557 In certain other aspects of the thirtieth embodiment, compounds of Formula (III) include compounds of Formula (Illb): In certain other aspects of the thirtieth embodiment, compounds of Formula (Illb) include compounds of Formula (lile): In a thirty-first embodiment, the invention provides compounds of the twenty-ninth or thirtieth embodiment in which R2 is hydrogen, R7 is hydrogen or methyl; and Z4es CR14. In a thirty-second embodiment, the invention provides compounds of the twenty-ninth embodiment which include compounds of formula (IV): IF-2019-169515 62-A PN - AN P# I NM Page 34 of 557 where: Rla is hydrogen or Ci-C4 alkyl; R3 is hydrogen or halogen, R4 is hydrogen or halogen, R7 is hydrogen, methyl or ethyl; R11 is hydrogen, halogen, cyano or Ci-C4 alkyl; each of R12 and R13 is independently selected from the group consisting of hydrogen, halogen, cyano, Ci-C4 alkyl, hydroxyCi-C4 alkyl, Ci-C4 alkoxy, or haloCi-C4 alkoxy; R14 is hydrogen, halogen, cyano or Ci-C4 alkyl; and R15 is hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 alkoxy, Ci-C4 haloakyl, Ci-C4 haloalkoxy, C(O)NH2 or 15 C (O) NH (Ci-C4 alkyl). In certain aspects of the thirty-second embodiment, compounds of Formula (IV) include compounds of Formula (IVa): IF-2019-169515 62-APN-ANP#IN33 Page 35 of 557 In a thirty-third embodiment, the invention provides compounds of the twenty-ninth embodiment that include compounds of formula (V): where: Rla is hydrogen or Ci-C4 alkyl; R3 is hydrogen or halogen, R4 is hydrogen or halogen, R7 is hydrogen, methyl or ethyl; R11 is hydrogen, halogen, cyano or Ci-C4 alkyl; each of R12 and R13 is independently selected from the group consisting of hydrogen, halogen, cyano, Ci-C4 alkyl, hydroxyCi-C4 alkyl, Ci-C4 alkoxy or haloCi-C4 alkoxy; IF-2019-169515 62-APN-ANP#INJ8 Page 36 of 557 R14 is hydrogen, halogen, cyano or Ci-C4 alkyl; and R15 is hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 alkoxy, Ci-C4 halokyl, Ci-C4 haloalkoxy, C(O)NH2 or C (0) NH (Ci-C4 alkyl). In certain aspects of the thirty-third embodiment, compounds of Formula (V) include compounds of Formula (Va): In a thirty-fourth embodiment, the invention provides compounds of the twenty-ninth embodiment that include compounds of formula (VI): where: Rla is hydrogen or Ci-C4 alkyl; R3 is hydrogen or halogen, IF-2019-169515 62-APN-ANP#INJ7 Page 37 of 557 R4 is hydrogen or halogen, R7 is hydrogen, methyl or ethyl; R11 is hydrogen, halogen, cyano or Ci-Cé alkyl; each of R12 and R13 is independently selected from the group consisting of hydrogen, halogen, cyano, Ci-C4 alkyl, hydroxyCi-C4 alkyl, Ci-C4 alkoxy or haloCi-C4 alkoxy; R14 is hydrogen, halogen, cyano or Ci-C4 alkyl; R15 is hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 alkoxy, Ci-C4 haloalkyl, Ci-C4 haloalkoxy, C(O)NH2, C (0) NH (Ci-C4 alkyl) or 5-membered heteroaryl with a ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms; R16 is hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 alkoxy, haloCi-C4 alkyl or haloCi-C4 alkoxy; R17 is hydrogen or halogen; and R18 is hydrogen, halogen, cyano, Ci-C4 alkyl, Ci-C4 alkoxy, haloCi-C4 alkyl or haloCi-C4 alkyl, where at least one of R15, R16, R17 or R18 is not hydrogen. In certain aspects of the thirty-fourth embodiment, compounds of Formula (VI) include compounds of Formula (Via): IF-2019-169515 62-A PN - AN P# IN38 Page 38 of 557 In a thirty-fifth embodiment, the invention provides compounds of the twenty-ninth embodiment that include compounds of formula (VII): where: Rla is hydrogen or Ci-C4 alkyl; R3 is hydrogen or halogen, R4 is hydrogen or halogen, R7 is hydrogen, methyl or ethyl; R9 is hydrogen, methyl or ethyl; R10 is Ci-C4 alkyl or haloCi-C4 alkyl, wherein each alkyl is optionally substituted with cyano, halogen, hydroxy, Ci-Ce alkoxy or S(O)qCi-Ce alkyl; either NR9R10, in combination, forms a monocyclic azacycle IF-2019-169515 62-A PN-AN P# INK) Page 39 of 557 4 to 6 membered or a 7 to 9 membered bicyclic azacycle, each with one ring nitrogen atom and 0 or 1 additional ring heteroatoms selected from N, 0 or S, said ring sulfur can be oxidized optionally, wherein each azacycle is optionally substituted with 0, 1 or 2 substituents selected from halogen, oxo, hydroxy, cyano, alkylCi-Ce, haloalkylCiCe, hydroxyalkylCi-Cg, alkoxyCi-Ce, S(O)2alkylCi-C6, CO2H, C(O)alkylCi-C6o C(O)NH2; R11 is hydrogen, halogen, cyano or Ci-Cé alkyl; each of R12 and R13 is independently selected from the group consisting of hydrogen, halogen, cyano, Ci-C4 alkyl, hydroxyCi-C4 alkyl, Ci-C4 alkoxy or haloCi-C4 alkoxy; and R14 is hydrogen, halogen, cyano or Ci-C4 alkyl. In certain aspects of the thirty-fifth embodiment, compounds of Formula (VII) include compounds of Formula (Vila): In a thirty-sixth embodiment, the invention provides compounds of any of the twenty-ninth to the IF-2019-169515 62-A PN-AN P# IN4Q Page 40 of 557 thirty-fifth mode in which R11 is hydrogen. In a thirty-seventh embodiment, the invention provides compounds of any of the thirty-first to the thirty-fifth embodiments in which Rla is hydrogen or methyl; R3 is hydrogen or fluorine; and R4 is hydrogen or fluorine. In a forty-first embodiment, the invention provides compounds of the first or second embodiment, wherein the compound is indicated in Table A below: TABLE A (S)-6-((2-(3-aminopiperidin -l-yl)-6-chloro-lHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-l-yl)-5-chloro-lHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-l-yl)-4-chloro-lHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-4chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6- ((2- ((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; IF-2019-169515 62-A PN-AN P# ΙΝΦ1 Page 41 of 557 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-5chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-4chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5cyanopyridin-2-yl)methyl)-ΙΗ-benzo[ d]imidazole-4carbonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-5chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethyl)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile; 6-((2-((3S,4S)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S)-6-((2-(5-amino-3,3-difluoropiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5cyanopyridin-2-yl)methyl)-6-fluoro-lH-benzo[d]imidazol-4carbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethoxy)-IH-benzo[d]imidazole-1IF-2019-169515 62-APN-ANP# IN$2 Page 42 of 557 il)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethoxy)-IH-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-5-(trifluoromethyl)-IH-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-β-(trifluoromethyl)-IH-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3aS,7aR)-hexahydro-lH-pyrrolo[2,3-c]pyridin6(2H)-yl)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3aS,7aS)-hexahydro-lH-pyrrolo[2,3-c]pyridin6(2H)-yl)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3aS,7aS)-hexahydro-lH-pyrrolo[2,3-c]pyridin6(2H)-yl)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3aS,7aR)-hexahydro-lH-pyrrolo[2,3-c]pyridin6(2H)-yl)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)—6—((2-(1,6-diazaspiro[3.5]nonan-6-yl)-IHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S) — 6—((2-(1,6-diazaspiro[3.5]nonan-6-yl)-IHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (3R,4R)-l-(l-((5-chloropyridin-2-yl)methyl)-6(methylsulfonyl)-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine; (3R,4R)-1-(1-((5-chloropyridin-2-yl)methyl)-5IF-2019-169515 62-A PN-AN P# INft Page 43 of 557 (methylsulfonyl)-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-IH-benzo[d]imidazole-carbonitrile; (3R,4R)-1-(5,7-difluoro-1-((5-fluoropyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyridin-210yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; (3R,4R)-1-(5,7-difluoro-l-((5-fluoropyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; (3R,4R)-1-(4,β-difluoro-1-((5-fluoropyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6-fluoro-l((5-fluoropyrimidin-2-yl)methyl)-IH-benzo[d]imidazole-420 carbonitrile ; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6-fluoro-l((5-fluoropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-4carbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1H25 benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (3R,43)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoroIF-2019-169515 62-APN-ANP#INW Page 44 of 557 IH-benzo[d]imidazole-2-yl)-4-fluoropiperidin-3-amine; (3R,4S)-l-(l-((5-chloropyrimidin-2-yl)methyl)-5-fluoroIH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (R)-2-(3-amino-4,4-difluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazole-6carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazole-5carbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6dichloro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; ((3R,4R)-1-(1-((5-cyanopyridin-2-yl)methyl)-5,6dimethyl-lH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3yl)carbamate tert-butyl; (S)-6-((2-(3-aminopiperidin-l-yl)-6fluoro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile hydrochloride; (S)-6-((2-(3-aminopiperidin-l-yl)-5fluoro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-6-fluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-5-fluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-5-fluoro-lH-benzo[d]imidazole-1IF-2019-169515 62-APN-ANP#IN43 hydrochloride Page 45 of 557 il)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-5-fluoro-lH-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; (S)-2-(3-aminopiperidin-l-yl)-1-((5-cyanopyridin-2yl)methyl)-ΙΗ-benzo[d]imidazole-6-carbonitrile; (S)-2-(3-aminopiperidin-l-yl)-1-((5-cyanopyridin-2yl)methyl)-ΙΗ-benzo[d]imidazole-5-carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((510 cyanopyridin-2-yl)methyl)-ΙΗ-benzo[d]imidazol-6carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5cyanopyridin-2-yl)methyl)-IH-benzo[d]imidazole-5carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-l-yl)-1-((5cyanopyridin-2-yl)methyl)-IH-benzo[d]imidazole-6carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-l-yl)-1-((5cyanopyridin-2-yl)methyl)-IH-benzo[d]imidazole-520 carbonitrile; (S)-6-((2-(3-aminopiperidin-l-yl)-4,6-dichloro-lHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4,6dichloro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-4,6dichloro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; IF-2019-169515 62-A PN-AN P# IN48 Page 46 of 557 (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-4,6dichloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-l-yl)-4,6-difIuoro-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-l-yl)-5,7-difIuoro-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4,6difluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,7difluoro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-4,6difluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-5,7difluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-5,7difluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1-((5cyanopyridin-2-yl)methyl)-IH-benzo[d]imidazole-6carbonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1-((5cyanopyridin-2-yl)methyl)-IH-benzo[d]imidazole-5carbonitrile; (S)-6-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4difluoropiperidin-l-yl)-5-fluoro-lH-benzo[d]imidazole-1IF-2019-16951562-A PN-A N P# hydrochloride I.W. Page 47 of 557 il)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((IR, 5S)-1-(aminomethyl)-3azabicyclo[3.1.0]hexan-3-yl)-IH-benzo[d]imidazol-lyl ) methyl ) nicotinonitrile hydrochloride; 6-((2-((IS,5R)-1-(aminomethyl)-3azabicyclo[3.1.0]hexan-3-yl)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 6-((2-((3aR,4R,6aS)-4aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-IHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3aS,4S,6aR)-4aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-IHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3aR,4S,6aS)-4aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-IHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3aS,4R,6aR)-4aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-IHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-(aminomethyl)pyrrolidin-1yl)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile hydrochloride; (S)-6-((2-(3-(aminomethyl)pyrrolidin-1IF-2019-16951562-A PN-A N P# IN49) hydrochloride Page 48 of 557 il)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-5,6-dichloro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-5,6-difluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-1-(1-((5-chloropyridin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)-4,4-difluoropiperidin-3-amine hydrochloride; (3R,4S)-1-(1-((5-chloropyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine hydrochloride; (R)-6-((2-(3-amino-4,4difluoropiperidin-l-yl)-4,6-difluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-4(trifluoromethyl)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4(trifluoromethyl)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-4IF-2019-169515 62-A PN - AN P# IW9 Page 49 of 557 (trifluoromethyl)-IH-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6chloro-lH-imidazo[4,5-b]pyridin-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6chloro-lH-imidazo[4,5-b]pyridin-l-yl)methyl)-N-( tert-butyl)nicotinamide; 6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3S,4S)-3-amino-4-hydroxypiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-(2,β-diazaspiro[3.4]octan-6-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((4aR,7aS)-hexahydropyrrolo[3,4b][1,4]oxazin-β(2H)-yl)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 6-((2-((4aS,7aR)-hexahydropyrrolo[3,4b][1,4]oxazin-β(2H)-yl)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 6-((2-((4aR,7aR)-hexahydropyrrolo[3, 4-b][1,4]oxazin6(2H)-yl)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((4aS,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin6(2H)-yl)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S)-3-amino-l-(1-((5-cyanopyridin-2-yl)methyl)-1HIF-2019-169515 62-A PN-AN P# I NOT Page 50 of 557 benzo[d]imidazole-2-yl)piperidine-3-carboxamide; (R)-3-amino-l-(1-((5-cyanopyridin-2-yl)methyl)-1Hbenzo[d]imidazol-2-yl)piperidine-3-carboxamide; (3)-6-((2-(3-amino-3-(hydroxymethyl)piperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-3-(hydroxymethyl)piperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoro-l-piperidinyl)-6(trifluoromethyl)-lH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4S)-3-amino-4-fluoro-l-piperidinyl)-5(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-6(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-5(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5methyl-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6methyl-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6chloro-5-methyl-lH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; IF-2019-16951562-APN-ANP#WI Page 51 of 557 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5chloro-6-methyl-lH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6fluoro-5-methyl-lH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5fluoro-6-methyl-lH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3S)-3-(methylamino)-1-piperidinyl)-1Hbenzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R)-3-(methylamino)-1-piperidinyl)-1Hbenzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6(difluoromethoxy)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5(difluoromethoxy)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4methoxy-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4methyl-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 5-((2-((3R,4S)-3-amino-4-fluoro-l-piperidinyl)-6(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-2pyrazinecarboxamide; IF-2019-16951562-A PN-A N P# IN$2 Page 52 of 557 5-((2-((3R,4S)-3-amino-4-fluoro-l-piperidinyl)-5(trifluoromethyl)-lH-benzimidazol-l-yl)methyl)-2pyrazinecarboxamide; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6chloro-5-(trifluoromethoxy)-lH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5chloro-6-(trifluoromethoxy)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6chloro-5-(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5chloro-6-(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((5R)-1,7-diazaspiro[4.5]decan-7-yl)-1Hbenzimidazol-l-yl)methyl)-3-pyridinecarbonitrile, 6-( (2((5S)-1 ,7-diazaspiro[4.5]decan-7-yl)-IH-benzimidazol-lyl)methyl)-3-pyridinecarbonitrile; 6-((2-((6R)-1,8-diazaspiro[5.5]undecan-8-yl)-1Hbenzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-( (2-((6S) —1,8-diazaspiro[5.5]undecan-8-yl)-1Hbenzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((4aR,8aR)-hexahydro-2H-pyrido[4,3b][1,4]oxazin-6(5H)-yl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile ; IF-2019-169515 62-APN-ANP#IN53 Page 53 of 557 6-((2-((4aS,8aS)-hexahydro-2H-pyrido[4,3b][1,4]oxazin-6(5H)-yl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile ; 5-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)methyl)-2-pyrazinecarboxamide; 5-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-2pyrazinecarboxamide; 6-((2-((5R)-1,7-diazaspiro[4.5]decan-7-yl)-1Hbenzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((5S) —1,7-diazaspiro[4.5]decan-7-yl)-1Hbenzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-5methoxy-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-6methoxy-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3S)-3-(methylamino)-1-piperidinyl)-6(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3S)-3-(methylamino)-1-piperidinyl)-5(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3S)-3-amino-3-methyl-l-piperidinyl)-1Hbenzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; (S)-6-((2-(3-aminopiperidin1-yl)-6-methoxy-lH-benzo[d]imidazol-1IF-2019-169515 62-A PN-AN P 2,2,2-trifluoroacetate #IN34 Page 54 of 557 il)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin1-yl)-5-methoxy-lH-benzo[d]imidazol-1yl)methyl)nicotinonitrile 2,2,2-trifluoroacetate; 6-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-4-chloro-6-fluoro-lH-benzo[d]imidazol1-yl) 2,2,2-trifluoroacetate methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-5-methoxy-lH-benzo[ d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-6-methoxy-lH-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-6-methoxy-lH-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-5-methoxy-lH-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-lH-benzo[d]imidazole-4carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-5-fluoro-lH-benzo[d]imidazol-7carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-l-yl)-1-((5IF-2019-169515 62-A PN-AN P# IN$*J Page 55 of 557 chloropyrimidin-2-yl) met11)-6-fluoro-IH-benzo[d]imidazole-4carbonitrile; 6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-hydroxypiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-4-((2-(3-amino-4,4-difluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)benzonitrile; compound of 4-((2-((3R,4R)-3-amino-4hydroxypiperidin-l-yl)-IH-benzo[d]imidazol-lyl ) methyl ) benzonitrile with 4-((2-(( 3S,4S)3-amino-4-hydroxypiperidin-l-yl)-IH-benzo[d]imidazol-1iyl)methyl)benzonitrile (1:1); 4-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,7difluoro-lH-benzimidazol-l-yl)methyl) benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4,6dif luoro-IH-benzimidazol-l-yl).methyl) benzonitrile; 2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-1-(4cyanobenzyl)-lH-benzimidazole-6-carbonitrile; 2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-1-(4cyanobenzyl)-lH-benzimidazole-5-carbonitrile; 2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-1-(4cyanobenzyl)-lH-benzimidazole-6-carbonitrile; 2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-1-(4cyanobenzyl)-lH-benzimidazole-5-carbonitrile; (R)-4-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazolIF-2019-169515 62-A PN-AN P# INJQ Page 56 of 557 1-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-methylpiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-(3-(aminomethyl)-3-methylpyrrolidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3S,4R)-3-amino-4-phenylpyrrolidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl) benzonitrile and 4-((2-((3R, 4S)3-amino-4-phenylpyrrolidin-l-yl)-IH-benzo[d]imidazol-lyl)methyl)benzonitrile; (S)-4-((2-(3-aminopyrrolidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)benzonitrile; (S)-4-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)benzonitrile; 4-((2-(6-amino-2-azaspiro[4.4]nonan-2-yl)-IHbenzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-(4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)IH-benzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3S,4S)-3-amino-4-fluoropiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3S, 4R)-3-amino-4-fluoropiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)benzonitrile; (R)-4-((2-(3-(aminomethyl)-3IF-2019-16951562-A PN-A N P# INJ7) 2,2,2-trifluoroacetate Page 57 of 557 fluoropyrrolidin-l-yl)-IH-benzo[d]imidazol-lyl )methyl )benzonitrile; (S)-4-((2-(3-(aminomethyl)-3fluoropyrrolidin-l-yl)-IH-benzo[d]imidazol-lyl)methyl)benzonitrile 2,2,2-trifluoroacetate; (R)-4-((2-(3-(aminomethyl)-3hydroxypyrrolidin-l-yl)-IH-benzo[d]imidazol-1yl)methyl)benzonitrile 2,2,2-trifluoroacetate; (S)-4-((2-(3-(aminomethyl)-3hydroxypyrrolidin-l-yl)-IH-benzo[d]imidazol-1yl)methyl)benzonitrile 2,2,2-trifluoroacetate; (S) —4 — ((2-(3-(aminomethyl)pyrrolidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)benzonitrile; Molecular weight: 331.41; (R)-4-((2-(3-(aminomethyl)pyrrolidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)benzonitrile; Molecular weight: 331.41; 4-((2-((3S,4S)-3-amino-4methylpiperidin-l-yl)-IH-benzo[d]imidazol-lyl)methyl)benzonitrile 2,2,2-trifluoroacetate; 4-((2-((3S,4R)-3-amino-4methylpiperidin-l-yl)-IH-benzo[d]imidazol-lyl)methyl)benzonitrile 2,2,2-trifluoroacetate; 4-((2-((3R,4S)-3-amino-4methylpiperidin-l-yl)-IH-benzo[d]imidazol-lyl)methyl)benzonitrile 2,2,2-trifluoroacetate; IF-2019-169515 62-A PN-AN P# INJJJ Page 58 of 557 4-((2-((IS,5R)-1-(aminomethyl)-3azabicyclo[3.1.0]hexan-3-yl)-IH-benzo[d]imidazol-1yl)methyl)benzonitrile; 4-((2-((IR,5S)-1-(aminomethyl)-3azabicyclo[3.1.0]hexan-3-yl)-IH-benzo[d]imidazol-1yl)methyl)benzonitrile; (R)-4-((2-(3-aminopiperidin-l-yl)-6-methoxy-lHbenzo[d]imidazol-l-yl)methyl)benzonitrile; (R)-4-((2-(3-aminopiperidin-l-yl)-5-methoxy-lHbenzo[d]imidazol-l-yl)methyl)benzonitrile; (2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile; (3R,4R)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)piperidin-3-amine; (3R,4R)-4-fluoro-l-(1-((5-fluoropyridin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)piperidin-3-amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5fluoropyridin-2-yl)methyl)-IH-benzo[d]imidazole-6carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5fluoropyridin-2-yl)methyl)-IH-benzo[d]imidazole-5carbonitrile; (3R,4R)-1-(1-((5-bromopyrimidin-2-yl)methyl)-IHbenzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (3R,4R)-4-fluoro-l-(1-((5-(trifluoromethyl)pyrimidin-2IF-2019-169515 62-APN-ANP#INJ3 Page 59 of 557 il)methyl)-IH-benzo[d]imidazol-2-yl)piperidin-3-amine; (3R,4R)-4-fluoro-1-(1-((5-methoxypyrimidin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)piperidin-3-amine; (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5fluoropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5fluoropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-5carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5cyanopyrimidin-2-yl)methyl)-IH-benzo[d]imidazole-5carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-5carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5bromopyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5bromopyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-5carbonitrile; 5-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)pyrazine-2-carbonitrile; 2-((3R,4 S)-3-amino-4-fluoropiperidin-l-yl)-1-((5IF-2019-169515 62-A PN-AN P# IN®] Page 60 of 557 chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazole-6carbonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-5carbonitrile; (3R,4R)-3-amino-l-(1-((5-chloropyrimidin-2-yl)methyl)-6fluoro-lH-benzo[d]imidazol-2-yl)piperidin-4-ol; (3R,4R)-3-amino-l-(1-((5-chloropyrimidin-2-yl)methyl)-5fluoro-lH-benzo[d]imidazol-2-yl)piperidin-4-ol; 6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S)-1-(1-((5-chloropyridin-2-yl)methyl)-IHbenzo[d]imidazol-2-yl)piperidin-3-amine; (S)-5-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)picolinonitrile; (3R,4R)-1-(1-((5-chloropyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine hydrochloride; (R)-6-((2-(3-amino-4,4difluoropiperidin-l-yl)-IH-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-lyl)-1-((5-chloropyridin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile hydrochloride; IF-2019-169515 62-APN-ANP# WI Page 61 of 557 2-((3R,4R)-3-amino-4-fluoropiperidin-lyl)-1- ((5-chloropyridin-2-yl)methyl)-IH-benzo[d]imidazole-5carbonitrile hydrochloride ; (3R,4R)-1-(1-((R)-1-(5-chloropyridin-2yl)ethyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine hydrochloride; (3R,4R)-1-(1-((S)-1-(5-chloropyridin-2yl)ethyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine hydrochloride; (3R,4R)-1-(1-((R)-1-(5-chloropyridin-2yl)ethyl)-5,6-difluoro-lH-benzo[d]imidazol-2-yl)-4fluoropiperidin hydrochloride -3-amine; (3R,4R)-l-(l-((S)-l-(5-chloropyridin-2yl)ethyl)-5,6-difluoro-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin hydrochloride -3-amine; (3R,4R)-1-(5-chloro-l-((R)-1-(5chloropyridin-2-yl)ethyl)-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3 hydrochloride -amine; (3R,4R)-1-(5-chloro-l-((S)-1-(5chloropyridin-2-yl)ethyl)-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3 hydrochloride -amine; (3R,4R)-1-(6-chloro-l-((R)-1-(5chloropyridin-2-yl)ethyl)-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3 hydrochloride -amine; (3R,4R)-1-(6-chloro-l-((S)-1-(5chloropyridin-2-yl)ethyl)-IH-benzo[d]imidazol-2-yl)-4IF hydrochloride -169515 62-A PN - AN P# I N©í Page 62 of 557 fluoropiperidin-3-amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-lyl)-1-((R)-1-(5-cyanopyridin-2-yl)ethyl)-IHbenzo[d]imidazole-6 hydrochloride -carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-lyl)-1-((R)-1-(5-cyanopyridin-2-yl)ethyl)-IHbenzo[d]imidazole-5 hydrochloride -carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-lyl)-1-((S)-1-(5-cyanopyridin-2-yl)ethyl)-IHbenzo[d]imidazole-6 hydrochloride -carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-lyl)-1-((S)-1-(5-cyanopyridin-2-yl)ethyl)-IHbenzo[d]imidazole-5 hydrochloride -carbonitrile; (3R,4R)-1-(1-((5-chloropyridin-2yl)methyl)-5,6-difluoro-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine hydrochloride; (3R,4R)-1-(5,6-difluoro-l-((5fluoropyridin-2-yl)methyl)-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine hydrochloride; (R)-1-(1-((5-chloropyridin-2-yl)methyl) 5,7-difluoro-IH-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride; (R)-1-(1-((5-chloropyridin-2-yl)methyl)4,6-difluoro-IH-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride; (R)-l-(2-((3R,4R)-3-amino-4) hydrochlorideIF-2019-169515 62-A PN-AN P# INJ3 Page 63 of 557 fluoropiperidin-l-yl)-IH-benzo[d]imidazol-l-yl)-2,3dihydro-lH-indene-5-carbonitrile; (S)-1-(2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-IH-benzo[d]imidazol-l-yl)-2,3dihydro-IH-indene hydrochloride 5-carbonitrile; (R)-5-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6chloro-IH-benzo[d]imidazol-l-yl)methyl)pyrazine-2carbonitrile; (R)-5-((2-(3-amino-4,4-difluoropiperidin-l-yl)-5chloro-lH-benzo[d]imidazol-l-yl)methyl)pyrazine-2carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-isopropylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(azetidin-1yl)ethanone ; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2-cyanopropyl)- Nethylacetamide; 3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-l-methylpyrrolidin-2-one; 3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-l-phenylpiperidin-2-one; 3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4chlorophenyl)pyrrolidin-2 -ona; IF-2019-169515 62-A PN-AN P# IW4 Page 64 of 557 2-((3R,4R)-3-amino-4-fluoropiperidin-1yl)-1-((5-methoxypyrimidin-2-yl)methyl)-IH-benzo[d]imidazol5-carbonitrile hydrochloride ; 2-((3R,4R)-3-amino-4-fluoropiperidin-1yl)-1-((5-methoxypyrimidin-2-yl)methyl)-IH-benzo[d]imidazol6-carbonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1yl)-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1Hbenzo[d]imidazol-6-carbonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1yl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1Hbenzo[d]imidazol-5-carbonitrile hydrochloride; (S)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-l-methylpyrrolidin- 2-one; (R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-l-methylpyrrolidin- 2-one; (S)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4chlorophenyl )pyrrolidin-2-one; (R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4chlorophenyl )pyrrolidin-2-one; 2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-1-((5cyano-2-pyrazinyl)methyl)-lH-benzimidazole-6-carbonitrile; 2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-1-((5cyano-2-pyrazinyl)methyl)-lH-benzimidazole-5-carbonitrile; IF-2019-169515 62-APN-ANP#INÍ3 Page 65 of 557 5-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4,6difluoro-lH-benzimidazol-l-yl)methyl)-2pyrazinecarbonitrile; 5-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,7difluoro-lH-benzimidazol-l-yl)methyl)-2pyrazinecarbonitrile; (3S)-1-(1-((5-fluoro-2-pyridinyl)methyl)-1Hbenzimidazol-2-yl)-N-methyl-3-piperidinamine; (3S)-1-(1-((5-chloro-2-pyridinyl)methyl)-1Hbenzimidazol-2-yl)-N-methyl-3-piperidinamine; 6-((1R)-1-(2-((3S)-3-(methylamino)-1-piperidinyl)-1Hbenzimidazol-l-yl)ethyl)-3-pyridinecarbonitrile; 6-((IS)-1-(2-((3S)-3-(methylamino)-1-piperidinyl)-1Hbenzimidazol-l-yl)ethyl)-3-pyridinecarbonitrile; (3R,4R)-l-(l-((5-chloro-2-pyrimidinyl)methyl)-5,7difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((5-chloro-2-pyrimidinyl)methyl)-4,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-((l-methyl-lH-indazol-4yl)methyl)-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,β-difluoro-1-(5-quinolinylmethyl)-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-((1R)-1-(8-quinolinyl)ethyl)lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-((IS)-1-(8-quinolinyl)ethyl)lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; IF-2019-16951562-APN-ANP#IN®8 Page 66 of 557 (3R,4R)-1-(1-((3-(3-chlorophenyl)-1,2-oxazol-5yl)methyl)-5,6-difluoro-lH-benzimidazol-2-yl) -4-fluoro-3piperidinamine; (3R,4R)-1-(5,6-difluoro-1-((l-methyl-lH-indazol-75yl)methyl)-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(2,6-dichlorobenzyl)-5,6-difIuoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; 1-(1-azetidinyl)-2-(2-((3S)-3-(methylamino)-1piperidinyl)-lH-benzimidazol-l-yl)ethanone; 6-((1R)-1-(4,β-difluoro-2-((4aR,8aR)-hexahydro-2Hpyrido[4,3-b][1,4]oxazin-6(5H)-yl)- IH-benzimidazol-lyl)ethyl)-3-pyridinecarbonitrile; 6-((1R)-1-(4,6-difluoro-2-((4aS,8aS)-hexahydro-2Hpyrido[4,3-b][1,4]oxazin-6(5H)-yl)- lH-benzimidazol-115 yl)ethyl)-3-pyridinecarbonitrile; 6-((IS)-1-(4,6-difluoro-2-((4aS,8aS)-hexahydro-2Hpyrido[4,3—b][1,4]oxazin-6(5H)-yl)- IH-benzimidazol-lyl)ethyl)-3-pyridinecarbonitrile; 6-((IS)-1-(4,6-difluoro-2-((4aR,8aR)-hexahydro-2H20 pyrido[4,3-b] [1,4]oxazin-6 (5H)-yl) -IH-benzimidazol-lyl)ethyl)-3-pyridinecarbonitrile; 6-((1R)-1-(5,7-difluoro-2-((4aR,8aR)-hexahydro-2Hpyrido[4,3-b][1,4]oxazin-6(5H)-yl)- IH-benzimidazol-lyl)ethyl)-3-pyridinecarbonitrile; 6-((1R)-1-(5,7-difluoro-2-((4aS,8aS)-hexahydro-2Hpyrido[4,3-b][1,4]oxazin-6(5H)-yl)- IH-benzimidazole-lIF-2019-1695 1562-APN-ANP#IW Page 67 of 557 il)ethyl)-3-pyridinecarbonitrile; 6- ((IS)-1-(5,7-difluoro-2-((4aS,8aS)-hexahydro-2Hpyrido[4,3-b][1,4]oxazin-6(5H)-yl)- IH-benzimidazol-lyl)ethyl)-3-pyridinecarbonitrile; 6-((IS)-1-(5,7-difluoro-2-((4aR,8aR)-hexahydro-2Hpyrido[4,3-b][1,4]oxazin-β(5H)-yl)- IH-benzimidazol-lyl)ethyl)-3-pyridinecarbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)-N-methylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)-1-(4-morpholinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)-1-(1-pyrrolidinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)-N,N-dimethylacetamide; (2R)-2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl) 5,6-difluoro-lH-benzimidazol-l-yl)-N,N-dimethylpropanamide; (2S)-2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)5,6-difluoro-lH-benzimidazol-l-yl)-N,N-dimethylpropanamide; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)-1-(1-piperidinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)-N-ethylacetamide; 1-((5-chloro-2-pyrimidinyl)methyl)-2-((3R,4R)-4-fluoro3-(methylamino)-1-piperidinyl)-lH-benzimidazole-6carbonitrile; IF-2019-169515 62-A PN-AN P# IN0S Page 68 of 557 1-((5-chloro-2-pyrimidinyl)methyl)-2-((3R,4R)-4-fluoro3-(methylamino)-1-piperidinyl)-lH-benzimidazole-5carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6-chloroIH-benzimidazol-l-yl)-1-(1-azetidinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5-chloroIH-benzimidazol-l-yl)-1-(1-azetidinyl)ethanone; 2-((3R,4S)-3-amino-4-fluoro-l-piperidinyl)-1-(2-(1azetidinyl)-2-oxoethyl)-lH-benzimidazole-6-carbonitrile; 2-((3R,4S)-3-amino-4-fluoro-l-piperidinyl)-1-(2-(1azetidinyl)-2-oxoethyl)-lH-benzimidazole-5-carbonitrile; (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoroIH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-5-fluoroIH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (R)-6-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)nicotinonitrile; (R)-5-((2-(3-aminopiperidinl-yl)-IH-benzo[d]imidazol-l-yl)methyl)picolinonitrile 2,2,2-trifluoroacetate; (R)-1-(1-(isoquinolin-7-ylmethyl)-IH-benzo[d]imidazol2 —yl)piperidin-3-amine; (R)-1-(1-((l-methyl-lH-indazol-7-yl)methyl)-IHbenzo[d]imidazol-2-yl)piperidin-3-amine; 6-((R)-1-(2-((S)-3-aminopiperidin-lyl)-IH-benzo[d]imidazol-l-yl)ethyl)nicotinonitrile hydrochloride; 6-((S)-1-(2-((S)-3-aminopiperidin-lIF-2019-16951562-APN-ANP#IN$9) hydrochloride Page 69 of 557 il)-IH-benzo[d]imidazol-l-yl)ethyl)nicotinonitrile; 6-((R)-1-(2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-IH-benzo[d]imidazol-lyl)ethyl)nicotinonitrile hydrochloride; 6-((S)-1-(2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-IH-benzo[d]imidazol-lyl)ethyl)nicotinonitrile hydrochloride; 6-((R)-1-(2-((S)-3-aminopiperidin-lyl)-IH-benzo[d]imidazol-l-yl)propyl)nicotinonitrile hydrochloride; 6-((S)-1-(2-((S)-3-aminopiperidin-lyl)-lH-benzo[d]imidazol-l-yl)propyl)nicotinonitrile hydrochloride; (3R,4R)-1-(5,6-difluoro-1-((5-fluoropyrimidin-2yl)methyl)-lH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; 3-(1-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)ethyl)benzonitrile; (3R,4R)-1-(5,6-difluoro-1-((5-fluoropyrimidin-2yl)methyl)-lH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; (3R,4S)-1-(5,6-difluoro-1-((5-fluoropyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; (3R,4S)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl) 6-(trifluoromethyl)-IH-benzo[d]imidazol-2-yl)piperidin-3amine; (3R,4S)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl) IF-2019-169515 62-A PN-AN P# IN® Page 70 of 557 5-(trifluoromethyl)-IH-benzo[d]imidazol-2-yl)piperidin-3amine; (R)-1-(5,6-difluoro-1-((5-fluoropyridin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)-4,4-difluoropiperidin-3-amine; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-1-(azetidin-1yl) ethan-l-one; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-1-(azetidin-1yl) ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-1-(2,2dimethylpyrrolidin-l -yl)ethan-l-one; 6-((2-((3R,4S)-3-amino-4-hydroxypiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-hydroxypiperidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 4-((R)-1-(2-((S)-3-aminopiperidin-lyl)-IH-benzo[d]imidazol-l-yl)ethyl)benzonitrile hydrochloride; 4-((S)-1-(2-((S)-3-aminopiperidin-lyl)-IH-benzo[d]imidazol-l-yl)ethyl)benzonitrile hydrochloride; (S)-4-((2-(3-aminopiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)-3-fluorobenzonitrile hydrochloride; (S)-1-(1-(4-chlorobenzyl)-IHbenzo[d]imidazol-2-yl)piperidin-3-amine hydrochloride; 4-((R)-l-(2-((3R,4S)-3-amino-4IF-2019-169515 62-A PN-AN P# INTI) hydrochloride Page 71 of 557 fluoropiperidin-l-yl)-IH-benzo[d]imidazol-1yl)ethyl)benzonitrile; 4-((S)-1-(2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-IH-benzo[d]imidazol-1yl)ethyl)benzonitrile hydrochloride; 4-((R)-1-(2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-IH-benzo[d]imidazol-1yl)ethyl)benzonitrile hydrochloride; 4-((S)-1-(2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-IH-benzo[d]imidazol-1yl)ethyl)benzonitrile hydrochloride; (S)-4-((2-(3-aminopiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)-3-chlorobenzonitrile hydrochloride; (3R,4R)-1-(1-((1R)-1-(2,4-dichlorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((IS)-1-(2,4-dichlorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((1R)-1-(2-chlorophenyl)ethyl)-5,6-difluorolH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((IS)-1-(2-chlorophenyl)ethyl)-5,6-difluorolH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((1R)-1-(3-chlorophenyl)ethyl)-5,6-difluorolH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((1S)-1-(3-chlorophenyl)ethyl)-5,6-difluorolH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((1R)-1-(2,5-dichlorophenyl)ethyl)-5,6IF-2019-16951562-A PN-A N P# INH Page 72 of 557 difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((IS)-1-(2,5-dichlorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((1R)-1-(2,4-difluorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)—1—(1—((IS)—1—(2,4-difluorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-l-(l-((lR)-l-(3,4-dichlorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((IS)-1-(3,4-dichlorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((1R)-1-(2,5-difluorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-l-(l-((IS)-1-(2,5-difluorophenyl)ethyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-l-((1R)-1-(4(trifluoromethyl)phenyl)ethyl)-lH-benzimidazol-2-yl)-4-fluoro3-piperidinamine; (3R,4R)-1-(5,6-difluoro-l-((1R)-1-(4(trifluoromethoxy)phenyl)ethyl)-lH-benzimidazol-2-yl)-4-. fluoro-3-piperidinamine; (3R,4R)-1-(1-(5-chloro-2-(trifluoromethoxy)benzyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-l-(4-(1H-1,2,4-triazol-1yl)benzyl)-lH-benzimidazol-2-yl)-4-fluoro-3 -piperidinamine; 2-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6IF-2019-169515 62-A PN-AN P# INJ3 Page 73 of 557 difluoro-lH-benzimidazol-l-yl)methyl)-5-chlorobenzonitrile; (3R,4R)-1-(1-(2,4-dichlorobenzyl)-5,6-difIuoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; 4-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)methyl)-3(difluoromethoxy)benzonitrile; (3R,4R)-1-(1-(2,5-dichlorobenzyl)-5,6-difIuoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(4-(1,1-difluoroethyl)benzyl)-5,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; 4-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)methyl)-2-methylbenzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)methyl)-2-chlorobenzonitrile; 2-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)methyl)-4-chlorobenzonitrile; (3R,4R)-1-(1-(2-(difluoromethoxy)benzyl)-5,6-difluorolH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(3-chloro-4-fluorobenzyl)-5,6-difIuoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(4-chloro-2-methoxybenzyl)-5,6-difIuoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(2,4-difluorobenzyl)-5,6-difIuoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(2-(trifluoromethyl)benzyl)lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; IF-2019-169515 62-A PN-AN P# IN74 Page 74 of 557 2-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)methyl)benzonitrile; (3R,4R)-1-(1-(2-chlorobenzyl)-5,6-difluoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(2-chloro-4-fluorobenzyl)-5,6-difluoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(4-fluoro-2(trifluoromethyl)benzyl)-lH-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-(3,4-difluorobenzyl)-5,6-difluoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(4-chloro-2-fluorobenzyl)-5,β-difluoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(3,4-dichlorobenzyl)-5,6-difluoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(4-chloro-3-fluorobenzyl)-5,6-difluoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(4-(trifluoromethyl)benzyl)lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(4-(trifluoromethoxy)benzyl)lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-l-(l-(4-(difluoromethyl)benzyl)-5,6-difluorolH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(3-(trifluoromethoxy)benzyl)lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(3-(trifluoromethyl)benzyl)IF-2019-169515 62-A PN-AN P# INjg Page 75 of 557 lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; 3-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)methyl)benzonitrile; (3R,4R)-1-(1-(3-chlorobenzyl)-5,6-difIuoro-1Hbenzimidazol-2-yl)-4-fluoro-3-piperidinamine; (S)-1-(1-(4-fluorobenzyl)-IH-benzo[d]imidazol-2yl)piperidin-3-amine; (S)—1—(1— (4—(1,2,4-oxadiazol-3-yl)benzyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)—1—(1—(4—(methylsulfonyl)benzyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-(1H-1,2,4-triazol-1-yl)benzyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)-2-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)benzonitrile; (R)-1-(1-(2,β-dichlorobenzyl)-IH-benzo[d]imidazol-2yl)piperidin-3-amine; (R)-1-(1-(2-chlorobenzyl)-IH-benzo[d]imidazol-2yl)piperidin-3-amine; (R)-1-(1-(4-(trifluoromethyl)benzyl)-IHbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)-l-(l-(4-(trifluoromethoxy)benzyl)-IHbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-chlorobenzyl)-IH-benzo[d]imidazol-2yl)piperidine-3-amine; (R)-1-(1-(3-chlorobenzyl)-IH-benzo[d]imidazole-2IF-2019-169515 62-A PN-AN P# INK Page 76 of 557 il)piperidin-3-amine; (R)-1-(1-(4-(1,1-difluoroethyl)benzyl)-IHbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)-2-(4-((2-(3-aminopiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)phenyl)-2-methylpropanenitrile; (R)-1-(1-(4-(difluoromethyl)benzyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)-4-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)-N-methylbenzamide; (R)-4-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)-3-fluorobenzonitrile; (R)-2-(4-((2-(3-aminopiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)methyl)phenoxy)acetonitrile; (R)-4-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)-N,N-dimethylbenzenesulfonamide; (R)-1-(1-(4-methylbenzyl)-IH-benzo[d]imidazol-2yl)piperidin-3-amine; (R)-1-(1-(4-fluorobenzyl)-IH-benzo[d]imidazol-2yl)piperidine-3-amine; (R)-1-(1-((l-methyl-lH-indazol-7-yl)methyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(2,4-difluorobenzyl)-IH-benzo[d]imidazol-2yl)piperidin-3-amine; (R)-1-(1-(3,4-difluorobenzyl)-IH-benzo[d]imidazol-2yl)piperidin-3-amine; (R)-1-(1-(4-chloro-3-fluorobenzyl)-IH-benzo[d]imidazolIF-2019-16951562-A PN-A N P# INffl Page 77 of 557 2-yl)piperidin-3-amine; (R)-1-(1-((3-(3-chlorophenyl)isoxazol-5-yl)methyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(3-chloro-4-methoxybenzyl)-IH-benzo[d]imidazol2-yl)piperidin-3-amine; (R)-4-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)-3-chlorobenzonitrile; (R)-1-(1-(2,4-dichlorobenzyl)-IH-benzo[d]imidazol-2yl)piperidin-3-amine; (R)-4-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)-3-methoxybenzonitrile; (R)-2-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)-5-chlorobenzonitrile; 4-((R)-1-(2-((R)-3-aminopiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)ethyl)benzonitrile; 4-(1-(2-((S)-3-aminopiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)ethyl)benzonitrile; (R)-3-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)benzonitrile; 4-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-6-chloro-lH-benzo[d]imidazol-lyl)methyl)benzonitrile hydrochloride; (S)-4-((2-(3-aminopiperidin-l-yl)-6methoxy-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile hydrochloride; 4-((2-((3R,4 S)-3-amino-4-fluoropiperidin-l-yl)-6methoxy-IH-benzo[d]imidazol-l-yl)methyl)benzonitrile; IF-2019-169515 62-A PN-AN P# IN^J Page 78 of 557 (S)-4-((2-(3-aminopiperidin-l-yl)-5methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl) benzonitrile hydrochloride; (R)-4-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile; (R)-4-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6methoxy-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile; (R)-4-((2-(3-amino-4,4-difluoropiperidin-l-yl)-4chloro-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4chloro-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-4chloro-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile; (R)-4-((2-(3-amino-4,4-difluoropiperidin-l-yl)-4methoxy-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4methoxy-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Himidazo[4,5-c]pyridin-l-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-3Himidazo[4,5-c]pyridin-3-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6ethoxy-lH-benzimidazol-l-yl)methyl)benzonitrile; 4-((2-((3R,' 4S) -3-amino-4-fluoropiperidin-l-yl) -1Himidazo[4,5-b]pyridin-l-yl)methyl)benzonitrile; 4-((2-((3R)-3-amino-4,4-difluoro-1-piperidinyl)-6fluoro-lH-benzimidazol-l-yl)methyl)benzonitrile; IF-2019-169515 62-A PN-AN P# INT9 Page 79 of 557 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Himidazo[4,5-b]pyridin-l-yl)methyl)benzonitrile; (S)-4-((2-(3-aminopiperidin1-yl)-4-chloro-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile 2,2,2-trifluoroacetate; (S)-4-((2-(3-aminopiperidin-l-yl)-3Himidazo[4,5-b]pyridin-3-yl)methyl)benzonitrile hydrochloride; 4-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-6-chloro-lH-benzo[d]imidazol-lyl)methyl)benzonitrile hydrochloride; (S)-4-((2-(3-aminopiperidin-l-yl)-6-chloro-lHbenzo[d]imidazol-l-yl)methyl)benzonitrile; (S)-4-((2-(3-aminopiperidin-l-yl)-5-chloro-lHbenzo[d]imidazol-l-yl)methyl)benzonitrile; (R)-1-(2-((S)-3-aminopiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)-2,3-dihydro-lH-indene-5carbonitrile; (S)-1-(2-((S)-3-aminopiperidin-l-yl)-IHbenzo[d]imidazol-l-yl)-2,3-dihydro-lH-indene-5carbonitrile; (3R, 4R)-4-fluoro-l-(1-((5-methoxypyridin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)piperidin-3-amine; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)azetidine-3carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3-(tertIF- 2019-169515 62-A PN-AN P# IW Page 80 of 557 butoxy)azetidin-l-yl)ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3,3-difluoroazetidin1 -yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3-isopropylazetidin1—yl )ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(6,6-difluoro -2azaspiro[3.3]heptan-2-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(7-oxa-2azaspiro [3.5]nonan-2-yl)ethanone; (R)-6-((2-(4,4-difluoro-3-(methylamino)piperidin-l-yl) 6-fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(4,4-difluoro-3-((2hydroxyethyl)amino)piperidin-l-yl)-6-fIuoro-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinic acid; (S)-6-((2-(3-aminopiperidin-l-yl)-IH-benzo[d]imidazoll-yl)methyl)nicotinamide; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)5,6-difluoro-lH-benzo[d]imidazol-l-yl)acetic acid; IF-2019-169515 62-A PN-AN P# IW1 Page 81 of 557 6-((R)-1-(4,β-difluoro-2-((3R,4R)-4-fluoro-3(methylamino)piperidin-1-yl)-IH-benzo[d]imidazol-lyl) ethyl)nicotinonitrile; 6-((S)-1-(4,6-difluoro-2-((3R,4R)-4-fluoro-3(methylamino)piperidin-1-yl)-IH-benzo[d]imidazol-lyl) ethyl)nicotinonitrile; 6-((R)—1—(5,7-difluoro-2-((3R,4R)-4-fluoro-3(methylamino)piperidin-l-yl)-IH-benzo[d]imidazol-lyl) ethyl) nicotinonitrile and 6-((S)-1-(5,7-difluoro-2-((3R,4R)-4-fluoro-3(methylamino)piperidin-l-yl)-IH-benzo[d]imidazol-lyl) ethyl) nicotinonitrile. In other aspects of the thirty-eighth embodiment, the invention provides compounds of the first embodiment, in which the compound is indicated in Table A-l below: TABLE A-l 2-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl)pyrimidine-5carbonitrile; 2-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)methyl)pyrimidine-5carbonitrile; (3R,4R)-4-fluoro-1-(6-fluoro-1-((5-methoxypyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)piperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6IF-2019-16951562-APN-ANP#IN»2 Page 82 of 557 fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl)acetamide; (3R,4R)-4-fluoro-l-(5-fluoro-l-((5-methoxypyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)piperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4-cyano6-fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N- (2,2,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6methoxy-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5methoxy-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5methoxy-IH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; 6-((2-((3R,4R)-3-amino-4-methoxypiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-4-methoxy-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3yl)methyl)nicotinonitrile; (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoroIH-benzo[d]imidazol-2-yl)-4-methoxypiperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6-bromoIH-benzo[d]imidazol-l-yl)-1-(azetidin-l-yl)ethan -canvas; IF-2019-169515 62-A PN-AN P# IN$3 Page 83 of 557 (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoroIH-benzo[d]imidazol-2-yl)-4-methoxypiperidin-3-amine ; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-IH-imidazo[4,5-b]pyridin-1yl)methyl)nicotinonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-1-morpholinoethan1-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2—trifluoroethyl)acetamide; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6-chloroIH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; 6- ((2-((3R,4S)-3-amino-4-methoxypiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-1-morpholinoethan1-one; (R)-2-(2-(3-amino-4,4-difluoropiperidin-l-yl)-6fluoro-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2IF-2019-169515 62-A PN - AN P# I N&4 Page 84 of 557 trifluoroethyl)acetamide; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; (3R,4S)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoroIH-benzo[d]imidazol-2-yl)-4-methoxypiperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethoxy)-IH-benzo[d]imidazol-l-yl)-N,Ndimethylacetamide; 2-(6-fluoro-2-((3R,4R)-4-fluoro-3(methylamino)piperidin-l-yl)-IH-benzo[d]imidazol-l-yl)-Nmethyl-N-(2 ,2,2-trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5-bromoIH-benzo[d]imidazol-l-yl)-1-(azetidin-l-yl)ethan -canvas; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-5-chloroΙΗ-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; 2-(6-fluoro-2-(1,7-diazaspiro[4.5]decan-7-yl)-IHbenzo[d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl)acetamide ; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-1-morpholinoethan1-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethoxy)-IH-benzo[d]imidazol-l-yl)-N,Ndimethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5IF-2019-169515 62-A PN-AN P# INQ3 Page 85 of 557 (trifluoromethoxy)-IH-benzo[d]imidazol-l-yl)-1morpholinoethane-l-one; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-7-methoxy-lH-benzo[d]imidazol-lyl)methyl) nicotinonitrile; (3R,4S)-1-(1-((5-chloropyrimidin-2-yl)methyl)-5-fluoroIH-benzo[d]imidazol-2-yl)-4-methoxypiperidin-3-amine; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-1-morpholinoethan1-one; 2-(5-fluoro-2-((3R,4R)-4-fluoro-3(methylamino)piperidin-l-yl)-IH-benzo[d]imidazol-l-yl)-Nmethyl-N-(2 ,2,2-trifluoroethyl)acetamide; 2-(2-(3-amino-4-methylpyrrolidin-l-yl)-6-fIuoro-1Hbenzo[ d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-hydroxypiperidin-l-yl)-6fluoro-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; (R)-2-(2-(3-amino-4,4-difluoropiperidin-l-yl)-5fluoro-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-methoxypiperidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; 2- (2- (.(3R) -3-amino-4-hydroxypiperidin-l-yl) -5-fluoroIF-2019-169515 62-APN-ANP#INJS Page 86 of 557 IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-methoxypiperidin-l-yl)-6fluoro-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; 2-(2-(3-(aminomethyl)-3-fluoropyrrolidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl)acetamide ; 2-(2-(3-(aminomethyl)-3-fluoropyrrolidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl)acetamide ; 2-(6-fluor0-2-((4aR,8aR)-hexahydro-2H-pyrido[4,3— b][1,4]oxazin-6(5H)-yl)-IH-benzo[d]imidazole -l-yl)-N-methylN-(2,2,2-trifluoroethyl)acetamide; (S)-2-(2-(3-aminopyrrolidin-l-yl)-6-fIuoro-1Hbenzo[d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl)acetamide; (R)-2-(2-(3-aminopyrrolidin-l-yl)-6-fIuoro-1Hbenzo[d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl)acetamide; (S)-2-(2-(3-(aminomethyl)pyrrolidin-l-yl)-6-fIuoro-1Hbenzo[d]imidazol-l-yl)-N-methyl-N-(2,2,2trifluoroethyl) acetamide; 2-(6-fluoro-2-((4aR,8aR)-hexahydro-2H-pyrido[4,3b][1,4]oxazin-6(5H)-yl)-IH-benzo[d]imidazole-l -yl)-N-methylN-(2,2,2-trifluoroethyl)acetamide; IF-2019-169515 62-A PN-AN P# IW Page 87 of 557 2-(5-fluoro-2-((4aS,8aS)-hexahydro-2H-pyrido[4,3b][1,4]oxazin-6(5H)-yl)-IH-benzo[d]imidazole-l -yl)-N-methylN-(2,2,2-trifluoroethyl)acetamide; (3R,4R)-3-amino-l-(1-((5-chloropyrimidin-2-yl)methyl)-5fluoro-lH-benzo[d]imidazol-2-yl)piperidin-4-ol; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6-chloroIH-benzo[d]imidazol-l-yl)-1-morpholinoethanone; (3R,4R)-3-amino-l-(1-((5-chloropyrimidin-2-yl)methyl)-6fluoro-lH-benzo[d]imidazol-2-yl)piperidin-4-ol; -(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5-chloroΙΗ-benzo[d]imidazol-l-yl)-1-morpholinoethanone; (3R,4R)-1-(1-((R)-1-(5-chloropyrimidin-2-yl)ethyl)-5,6difluoro-lH-benzo[d]imidazol-2-yl)-4-fluoropiperidin -3amine; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethyl)-lH-imidazo[4,5-b]pyridin-lyl)methyl) nicotinonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2 ,2,2—trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(thiazol -2yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6-chlorolH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6IF-2019-169515 62-A PN-AN P# INJRJ Page 88 of 557 fluoro-lH-benzo[d]imidazol-l-yl)-1-(azetidin-l-yl)ethan-lone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3(trifluoromethyl)piperidin -l-yl)ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(6,7-dihydrothiene [3,2c]pyridin-5(4H)-yl)ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5-chloroIH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(2methylmorpholino)ethan-l -ona; (3R,4R)-1-(1-((R)-1-(5-chloropyrimidin-2-yl)ethyl)-5,6difluoro-lH-benzo[d]imidazol-2-yl)-4-fluoropiperidin -3amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-7-methoxy-lH-benzo[d]imidazol-l-yl)-N-methyl-N- (2,2,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(azocan-l-yl )etan-canvas; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-1-(4-(pyrazin- 2yl)piperazin-l-yl)ethan-l-one; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6IF-2019-16951562-APN-ANP#IN89 Page 89 of 557 methyl difluoro-IH-benzo[d]imidazol-l-yl)acetyl)piperidine-4carboxylate; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(2-ethylmorpholino)ethanl -one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)-1-(azetidin-l-yl)ethan -canvas; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-N-(1,l-dioxide -2,3dihydrothiophen-3-yl)-N-phenylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4-methylpiperidin-lyl )ethan-l-one; (3R,4R)-4-fluoro-l-(6-fluoro-l-((4-methoxypyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)piperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(2-ethylmorpholino)ethanl -one; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3yl)methyl)nicotinonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)-1-(azetidin-l-yl)ethan-l-one ; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)acetyl)piperidine-2IF- 2019-16951562-A PN-A N P# INJU Page 90 of 557 carboxamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(1,1dioxidotetrahydrothiophen-3 -yl)-N-(thiophen-2ylmethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(octahydroisoquinolin2(1H)- il)ethan-l-one; (3R,4R)-4-fluoro-l-(5-fluoro-l-((4-methoxypyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)piperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(1,1dioxidotetrahydrothiophen-3 -yl)-N-methylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-cyclopropyl-N-(1 ,1dioxidotetrahydrothiophen-3-yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-N-(1,1dioxidotetrahydrothiophen-3 -yl)-N-ethylacetamide; 4-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)piperazin-2- ona; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4-(pyrrolidine- 1carbonyl)piperidin-l-yl)ethan-l-one; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)acetyl)piperidine-3IF- 2019-169515 62-A PN-AN P# I N?1 Page 91 of 557 carboxamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4(cyclopropanecarbonyl) piperazin -1-yl)ethan-l-one; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)acetyl)piperidine-4carboxamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2-cyanopropan-2 -yl) N-methylacetamide; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)-Nmethylpiperidine-4 -carboxamide; N-(1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl) 5,6-difluoro-IH-benzo[d]imidazol-l-yl)acetyl) piperidin-3yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4-(piperidine- 1carbonyl)piperidin-l-yl)ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4-(azepane- 1carbonyl)piperidin-l-yl)ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(1,1dioxidotetrahydrothiophen-3 -yl)-N-(2-methoxyethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6IF-2019-16951562-APN-ANP#IN$2 Page 92 of 557 difluoro-lH-benzo[d]imidazol-l-yl)-1-(4-(3-methylpiperidine1-carbonyl)piperidin-l-yl)ethan-l-one; 1-(4-acetylpiperazin-l-yl)-2-(2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-5,6-difluoro-lH-benzo[d]imidazole-lyl ) ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(1,1dioxidotetrahydrothiophen-3 -yl)-N-((tetrahydrofuran-2yl)methyl)acetamide; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)-N-isopropyl -Nmethylpiperidine-4-carboxamide; 2-(2-((3R,4R)-3-amino-4-methoxypiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-7-methoxy-lH-benzo[d]imidazol-l-yl)-N-methyl-N- (2,2,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-4-methoxy-lH-benzo[d]imidazol-l-yl)-1-morpholinoethan1-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-7-methoxy-lH-benzo[d]imidazol-l-yl)-1-morpholinoethan1-one; (R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-cyclopropylpyrrolidinIF- 2019-16951562-APN-ANP#IN$3 Page 93 of 557 2-one; (S)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(tetrahydro -2H-pyran4-yl)pyrrolidin-2-one; (S)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-cyclopropylpyrrolidin2- ona; (R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(tetrahydro -2H-pyran10 4-yl)pyrrolidin-2-one; (3R,4R)-1-(5,6-difluoro-1-((5-methylthiazol-2-yl)methyl)IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; i (3R,4R)-1-(4,6-difluoro-1-((5-methyl-l,3,4-thiadiazol2-yl)methyl)-IH-benzo[d]imidazol-2-yl)- 4-fluoropiperidin-315 amine; (3R,4R)-1-(5,β-difluoro-l-((5-methyl-l,3,4-thiadiazol-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4 -fluoropiperidin-3amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-620 (trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-N-methyl-N(2 ,2,2-trifluoroethyl)acetamide; (3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-fluorolH-imidazo[4,5-b]pyridin-2-yl)-4-fluoropiperidin-3-amine ; (3R,4R)-1-(4,β-difluoro-1-((5-(methylsulfonyl)pyridin25 2-yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine ; IF-2019-16951562-A PN-A N P# IN$>4 Page 94 of 557 (3R,4R)-1-(1-((5-(difluoromethyl)-1,3,4-thiadiazol-2yl)methyl)-4,6-difluoro-lH-benzo[d]imidazole- 2-yl)-4fluoropiperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(2 ,2,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6-chloroIH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; (3R,4R)-1-(1-((5-(difluoromethyl)-1,3,4-thiadiazol-2yl)methyl)-5,6-difluoro-lH-benzo[d]imidazol-2-yl) -4fluoropiperidin-3-amine; (3R,4R)-4-fluoro-1-(6-fluoro-1-((5-methyl-l,3,4thiadiazol-2-yl)methyl)-IH-benzo[d]imidazol-2-yl) piperidin-3amine; (3R,4R)-1-(5,6-difluoro-1-((5-(methylsulfonyl)pyridin2-yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-N,Ndimethylacetamide; (3R,4R)-1-(5,6-difluoro-1-((5-methylisoxazol-3yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4,6difluoro-IH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; IF-2019-16951562-A PN-A N P# IN$3 Page 95 of 557 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; (3R,4R)-1-(5,6-difluoro-1-((5-methyloxazol-2-yl)methyl)IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (3R,4R)-1-(5,6-difluoro-1-((4-methylthiazol-2-yl)methyl)IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (3R,4R)-4-fluoro-1-(6-fluoro-1-((3-(trifluoromethyl) 1,2,4-oxadiazol-5-yl)methyl)-IH-benzo[d]imidazol-2yl )piperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5-chloroIH-benzo[d]imidazol-l-yl)-N-methyl-N-(2,2 ,2trifluoroethyl)acetamide; (3R,4R)-1-(5,6-difluoro-1-((5-methyl-l,3,4-oxadiazol-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4 -fluoropiperidin-3amine; (3R,4R)-1-(5,6-difluoro-1-((5-methyl-l,2,4-oxadiazol-3yl)methyl)-IH-benzo[d]imidazol-2-yl)-4 -fluoropiperidin-3amine; (3R,4R)-1-(1-((5-(difluoromethyl)-1,3,4-thiadiazol-2yl)methyl)-6-fluoro-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin -3-amine; (3R,4R)-4-fluoro-1-(6-fluoro-1-((5-methyl-l,3,4thiadiazol-2-yl)methyl)-IH-imidazo[4,5-b]pyridin- 2yl)piperidin-3-amine; (3R,4R)-1-(1-((4,5-dimethyloxazol-2-yl)methyl)-5,6difluoro-lH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3IF-2019 -16951562-APN-ANP#IN<RJ Page 96 of 557 amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; (3R,4R)-1-(1-((5-ethyl-l,2,4-oxadiazol-3-yl)methyl)-5,6difluoro-lH-benzo[d]imidazol-2-yl)-4 -fluoropiperidin-3amine; (3R,4R)-l-(l-((5-cyclopropyl-l,2,4-oxadiazol-3yl)methyl)-5,6-difluoro-lH-benzo[d]imidazol-2-yl)-4fluoropiperidin -3-amine; (3R,4R)-1-(5,6-difluoro-1-((3-methylisoxazol-5yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-N-methyl-N(2 ,2,2-trifluoroethyl)acetamide; (3R,4R)-1-(1-((5-cyclopropyl-l,3,4-oxadiazol-2yl)methyl)-5,β-difluoro-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin -3-amine; (3R,4R)-4-fluoro-l-(5-fluoro-1-((5-methyl-l,3,4thiadiazol-2-yl)methyl)-IH-benzo[d]imidazol-2-yl) piperidin-3amine; (3R,4R)-1-(3-((5-chloropyrimidin-2-yl)methyl)-6-fluoro3H-imidazo[4,5-b]pyridin-2-yl)-4-fluoropiperidin-3-amine ; (3R,4R)-4-fluoro-l-(5-fluoro-l-((3-(trifluoromethyl)1,2,4-oxadiazol-5-yl)methyl)-IH-benzo[d]imidazol-2yl )piperidin-3-amine; IF-2019-16951562-A PN-A N P# IW Page 97 of 557 (3R,4R)-4-fluoro-l-(6-fluoro-1-((4-methyl-2phenylthiazol-5-yl)methyl)-IH-benzo[d]imidazol-2-yl) piperidin3-amine; (3R,4R)-l-(l-((4,5-dimethyl-4H-l,2,4-triazol-3yl)methyl)-5,6-difluoro-lH-benzo[d]imidazole-2- il)-4fluoropiperidin-3-amine; (3R,4R)-1-(1-((5-(difluoromethyl)-1,3,4-thiadiazol-2yl)methyl)-5-fluoro-IH-benzo[d]imidazol-2-yl)-4fluoropiperidin -3-amine; (R)-4,4-difluoro-1-(6-fluoro-1-((5-methyl-l,3,4thiadiazol-2-yl)methyl)-IH-benzo[d]imidazol-2-yl) piperidin-3amine; (3R,4R)-l-(l-((2,4-dimethylthiazol-5-yl)methyl)-6-fluoroIH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (3R,4R)-4-fluoro-1-(6-fluoro-3-((5-methyl-l,3,4thiadiazol-2-yl)methyl)-3H-imidazo[4,5-b]pyridin- 2yl)piperidin-3-amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,7difluoro-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2 ,2,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-IH-benzo[d]imidazol-l-yl)-N,Ndimethylacetamide; (3R,4R)-4-fluoro-l-(5-fluoro-l-((4-methyl-2phenylthiazol-5-yl)methyl)-IH-benzo[d]imidazol-2-yl)piperidin3-amine; IF-2019-16951562-A PN-A N P# IN$3 Page 98 of 557 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,7difluoro-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide; (3R,4R)-1-(5,7-difluoro-1-((5-(methylsulfonyl)pyridin2-yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-35 amine ; (3R,4R)-l-(l-((2,4-dimethylthiazol-5-yl)methyl)-5-fluoroIH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (R)-4,4-difluoro-1-(5-fluoro-1-((5-methyl-l,3,4thiadiazol-2-yl)methyl)-IH-benzo[d]imidazol-2-yl) piperidine-310 amine; (3R,4R)-1-(1-((5-(difluoromethyl)-1,3,4-thiadiazol-2yl)methyl)-5,7-difluoro-IH-benzo[d]imidazol-2-yl) -4fluoropiperidin-3-amine; (3R,4R)-1-(5,7-difluoro-l-((5-methyl-l,3,4-thiadiazol-215yl)methyl)-IH-benzo[d]imidazol-2-yl)- 4-fluoropiperidin-3amine; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(2-methylazetidin-lyl )ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2,2-difluoroethyl )-Nmethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-cyclopropyl-N25 methylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6IF-2019-16951562-APN-ANP#IN$9 Page 99 of 557 difluoro-lH-benzo[d]imidazol-l-yl)-N-((R)-1-cyanoethyl)-Nmethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(( R)-1(pyridin-2-yl)ethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-ethyl-N-methylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2-fluoroethyl)- Nmethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-1-((IR,5S) -3azabicyclo[3.1.0]hexan-3-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(1 -(pyridin-2yl)ethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(2azabicyclo[3.1.0 ]hexan-2-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-((S)-1 -cyanoethyl)-Nmethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N(tetrahydrofuran- 3-yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6IF-2019-169515 62-A PN-AN P# INtJU Page 100 of 557 difluoro-lH-benzo[d]imidazol-l-yl)-N-(l-cyanopropan-2-yl) N-methylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(1 -(pyridin-4yl)ethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(1 ,1,1trifluoropropan-2-yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(cyanomethyl)-Nmethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5, 6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-Npropylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-cyclopropyl-N-(2hydroxyethyl )acetamide; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)-3fluoropyrrolidine-3 -carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(2-oxa-5azabicyclo [2.2.1]heptan-5-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(hexahydropyran[4,3b ][1,4]oxazin-4(7H)-yl)ethanone; IF-2019-169515 62-A PN-AN P# I?KP|I Page 101 of 557 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2-cyanopropyl)- Nmethylacetamide; -(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-(3, 3,3trifluoropropyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-((IR,5S) -6,6-difluoro3-azabicyclo[3.1.0]hexan-3-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4-(pyrimidin- 2yl)piperazin-l-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(2-isopropylazetidin1-yl )ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3(difluoromethoxy)pyrrolidine -l-yl)ethanone; 4-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)morpholine-2carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3-hydroxypiperidin-lyl )ethanone; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)-4IF-2019 -169515 62-A PN-AN P# Page 102 of 557 methylpiperidine-4-carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3,4-dihydro -l,8naphthyridin-1(2H)-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5, 6difluoro-lH-benzo[d]imidazol-l-yl)-N-cyclopropyl-N-(2 ,2difluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5, 6difluoro-IH-benzo[d]imidazol-l-yl)-1-(5H-pyrrolo[3 ,4 — b]pyridin-6(7H)-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N((tetrahydrofuran -3-yl)methyl)acetamide; -(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2,2-difluoroethyl) -Nmethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-N-methyl-N-(2 ,2,2trifluoroethyl)acetamide; (R)-1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl) 5,6-difluoro-lH-benzo[d]imidazol-l-yl)acetyl )pyrrolidine-2carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-((Ir,4R) -4hydroxycyclohexyl)-N-methylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6IF-2019-169515 62-A PN - AN P# I MB· Page 103 of 557 difluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-((S)-1(pyridin-2-yl)ethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(octahydro-lHpyran[4 ,3-b]pyridin-l-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4-hydroxypiperidin-lyl )ethanone; 1- (3-(1H-1,2,4-triazol-l-yl)azetidin-l-yl)-2 - (2((3R,4R)-3-amino-4-fluoropiperidin-l-yl) -5,6-difIuoro-1Hbenzo[d]imidazol-l-yl)ethanone; 7-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)hexahydroimidazo[1, 5-a]pyrazin-3(2H)-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2-cyanoethyl)- N((tetrahydrofuran-3-yl)methyl)acetamide; 4- (2- (2-( (3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)-N-methylmorpholine2 -carboxamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3((methylsulfonyl) methyl)pyrrolidin-l-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-1-(5,6-dihydro - [1,2,4]tr iazolo[1,5-a]pyrazin-7(8H)-yl)ethanone; IF-2019-169515 62-APN-ANP# WI Page 104 of 557 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(2(methoxymethyl)morpholino )ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(3-hydroxy-3methylpyrrolidin -l-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-1-(4(methylsulfonyl)piperazin -1-yl)ethanone; N-((l-acetylpyrrolidin-3-yl)methyl)-2-(2-((3R,4R)-3amino-4-fluoropiperidin-l-yl)-5,6-difIuoro-1Hbenzo[d]imidazole- l-yl)-N-ethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5, 6difluoro-IH-benzo[d]imidazol-l-yl)-N-(1,1dioxidotetrahydro-2H -thiopyran-4-yl)-N-methylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)-N-((1,1dioxidotetrahydrothiophen- 3-yl)methyl)-N-methylacetamide; 2-(1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)5,6-difluoro-IH-benzo[d]imidazol-l-yl)acetyl) piperidin-4yl)-2-methylpropanenitrile; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)-Nmethylpiperidine-3 -carboxamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2-hydroxyethyl)- NIF-2019-169515 62-A PN - AN P# I Page 105 of 557 (pyridin-3-ylmethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)-N-(2-cyanoethyl)- N(tetrahydro-2H-pyran-4-yl)acetamide; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-IH-benzo[d]imidazol-l-yl)acetyl)-N,Ndimethylpiperidine -3-carboxamide; 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)-4(methoxymethyl )piperidine-4-carbonitrile; 7-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5,6difluoro-lH-benzo[d]imidazol-l-yl)acetyl)tetrahydro-lHoxazole[ 3,4-a]pyrazin-3(5H)-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-(thiazol-2-yl)acetamide ; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-IH-benzo[d]imidazol-l-yl)-N-(2,2,2trifluoroethyl)acetamide ; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-cyclopropyl-N-(2,2 ,2trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-(2-methoxyethyl)-Nmethylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-((S) IF-2019-169515 62-A PN - AN P# I Page 106 of 557 tetrahydrofuran-3-yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-methyl-N-((R) tetrahydrofuran-3-yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-((S)-1-( pyridin-2yl)ethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-((S)-tetrahydrofuran-3yl )-N-(2,2,2-trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-cyclobutylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-((S)-l-cyanopropan -2yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-((R)-l-cyanopropan -2yl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-ethyl-N-(2methoxyethyl)acetamide ; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-((R)-tetrahydrofuran-3yl )-N-(2,2,2-trifluoroethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-(3,3,3IF-2019 -16951562-APN-ANP#Df^I Page 107 of 557 trifluoropropyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-((R)-1-( pyridin-2yl)ethyl)acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-((S)-tetrahydrofuran-3yl )acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-N-((R)-tetrahydrofuran-3yl )acetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-(2-methylazetidin-lyl)ethan -canvas; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-((S)-3methylmorpholino)ethan -canvas; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-((R)-2-methylpyrrolidin1 -yl)ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-((R)-3(methoxymethyl )morpholino)ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-((R)-3methylmorpholino)ethan -canvas; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6IF-2019-169515 62-A PN-AN P# ITO Page 108 of 557 fluoro-lH-benzo[d]imidazol-l-yl)-1-((S)-2-methylpyrrolidin1-yl)ethan-l-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-(3,5dimethylmorpholino)ethan-l -ona; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-(3-ethylmorpholino)ethan-lone ; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-((S)-3cyclopropylmorpholino)ethan -canvas; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-((R)-3(hydroxymethyl ) morpholino)ethan-l-one and 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)-1-(3,3dimethylmorpholino)ethan-l -ona. In a thirty-ninth embodiment, the invention provides compounds of the first or second embodiment, wherein the compound is indicated in Table B below: TABLE B 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5cyanopyridin-2-yl)methyl)-IH-benzo[d]imidazole-4IF-2019-169515 62- APN-ANP#IW Page 109 of 557 carbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-5(trifluoromethyl)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethoxy)-IH-benzo[d]imidazol-lyl ) methyl ) nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-lH-benzo[d]imidazol-4carbonitrile; (3R,4R)-l-(4,6-difluoro-1-((5-fluoropyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6-fluoro-l((5-fluoropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-4carbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-5-fluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-5-fluoro-lH-benzo[d]imidazole-1IF-2019-169515 62-APN-ANP#IWJ hydrochloride Page 110 of 557 il)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4,6difluoro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4difluoropiperidin-l-yl)-4,β-difluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6fluoro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6chloro-lH-imidazo[4,5-b]pyridin-l-yl)methyl)nicotinonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-6(trifluoromethyl)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5(difluoromethoxy)-IH-benzimidazol-l-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4methoxy-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-6methoxy-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R,4S)-3-amino-4fluoropiperidin-l-yl)-6-methoxy-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-lH-benzo[d]imidazole-4carbonitrile; IF-2019-169515 62-A PN - AN P# IMRI Page 111 of 557 (R)-2-(3-amino-4,4-difluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-IH-benzo[d]imidazole -4carbonitrile; 4-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4,6difluoro-IH-benzimidazol-l-yl)methyl) benzonitrile; 4-((2-((3S,4S)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)benzonitrile; (R)-4-((2-(3-aminopiperidin-l-yl)-6-methoxy-lHbenzo[d]imidazol-l-yl)methyl)benzonitrile; (2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile; (3R,4R)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)piperidin-3-amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5fluoropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile; (3R,4R)-3-amino-1-(1-((5-chloropyrimidin-2-yl)methyl)-6fluoro-lH-benzo[d]imidazol-2-yl)piperidin-4-ol; (R)-1-(1-((5-chloropyridin-2-yl)methyl)- hydrochloride 4,6- difluoro-IH-benzo[d]imidazol-2-yl)-4,4- IF-2019-169515 62-APN-ANP#IW Page 112 of 557 difluoropiperidin-3-amine; (3R,4R)-l-(l-((5-chloro-2-pyrimidinyl)methyl)-4,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-5,6difluoro-lH-benzimidazol-l-yl)-1-(1-piperidinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-6-chlorolH-benzimidazol-1-yl)-1-(1-azetidinyl)ethanone; (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoroIH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-5-fluoroΙΗ-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (3R,4R)-1-(5,6-difluoro-1-((5-fluoropyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; (3R, 4S)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)6-(trifluoromethyl)-IH-benzo[d]imidazol-2-yl)piperidin-3amine and hydrochloride of 4-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-6-chloro-lH-benzo[d]imidazol-lyl)methyl)benzonitrile. In a fortieth embodiment, the invention provides compounds of the first or second embodiment, wherein the compound is indicated in Table C below: TABLE C 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6IF-2019-169515 62-A PN-AN P# IN13 Page 113 of 557 chloro-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-6(trifluoromethoxy)-IH-benzo[d]imidazol-lyl)methyl)nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-lH-benzo[d]imidazol-4carbonitrile; (3R,4R)-l-(4,6-difluoro-1-((5-fluoropyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-5-fluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-4,6difluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4difluoropiperidin-l-yl)-4,6-difluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4IF-2019-169515 62-APN-ANP#IWl Page 114 of 557 methoxy-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-l-piperidinyl)-6methoxy-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-IH-benzo[d]imidazole-4carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-IH-benzo[d]imidazol-4carbonitrile; (2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile; (3R,4R)-4-fluoro-l-(1-((5-fluoropyrimidin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)piperidin-3-amine; 2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d]imidazol-6carbonitrile; (R)-1-(1-((5-chloropyridin-2-yl)methyl) 4,6-difluoro-lH-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride; (3R,4R)-1-(1-((5-chloro-2-pyrimidinyl)methyl)-4,6difluoro-lH-benzimidazol-2-yl)-4-fluoro-3-piperidinamine and (3R,4R) -1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluorolH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine. In a forty-first embodiment, the invention provides compounds of the first or second embodiment, in which IF-2019-169515 62-A PN-AN P# ITO Page 115 of 557 that the compound is indicated in Table D below: TABLE D 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-lH-benzo[d]imidazol-4carbonitrile; (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4difluoropiperidin-l-yl)-4,β-difluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4methoxy-lH-benzimidazol-l-yl)methyl)-3-pyridinecarbonitrile; (2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-ΙΗ-benzo[d]imidazol-6carbonitrile; (3R,4R)-4-fluoro-l-(1-((5-fluoropyrimidin-2-yl)methyl)ΙΗ-benzo[d]imidazol-2-yl)piperidin-3-amine and (3R,4R) -1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoroIF-2019-169515 62-APN-ANP#Iim Page 116 of 557 IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine. In a further embodiment, each of the compounds described herein is provided in the form of a pharmaceutically acceptable salt. In a forty-second embodiment, the invention provides 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6chloro-lH-benzo[d]imidazol-l-yl)methyl )nicotinonitrile. In certain aspects of the forty-second embodiment, the invention provides a pharmaceutically acceptable salt of 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-l-yl)-6-chloro-lHbenzo[d ]imidazol-l-yl)methyl)nicotinonitrile. In a forty-third embodiment, the invention provides 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-6-fluoro-lH- benzo[d]imidazole-4carbonitrile. In certain aspects of the forty-third embodiment, the invention provides a pharmaceutically acceptable salt of 2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-1-((5-chloropyrimidin-2-yl)methyl )-6fluoro-lH-benzo[d]imidazole-4-carbonitrile. In a forty-fourth embodiment, the invention provides (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyrimidin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)- 4-fluoropiperidin-3amine. In certain aspects of the forty-fourth embodiment, the invention provides a pharmaceutically acceptable salt of (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyrimidin2-yl)methyl)-IH-benzo[d ]imidazole-2-yl)-4-fluoropiperidin-3IF-2019-169515 62-APN-ANP# W Page 117 of 557 amine. In a forty-fifth embodiment, the invention provides 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile. In certain aspects of the forty-fifth embodiment, the invention provides a pharmaceutically acceptable salt of 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1Hbenzo[d]imidazole-l -yl)methyl)nicotinonitrile. In a forty-sixth embodiment, the invention provides (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-4,6difluoro-lH-benzo[d]imidazol-l-yl )methyl)nicotinonitrile. In certain aspects of the forty-sixth embodiment, the invention provides a pharmaceutically acceptable salt of (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6-fIuoro-1Hbenzo[d ]imidazol-l-yl)methyl)nicotinonitrile. The hydrochloride salt is a particularly preferred aspect of the forty-sixth embodiment, for example, (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6-fIuoro-hydrochloride 1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile. In a forty-seventh embodiment, the invention provides (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6fluoro-lH-benzo[d]imidazol-l-yl)methyl )nicotinonitrile. In certain aspects of the forty-seventh embodiment, the invention provides a pharmaceutically acceptable salt of (R)-6-((2-(3-amino-4,4-difluoropiperidin-l-yl)-6-fIuoro-1Hbenzo[d ]imidazol-l-yl)methyl)nicotinonitrile. IF-2019-169515 62-A PN - AN P# I^|gl Page 118 of 557 In a forty-eighth embodiment, the invention provides 6-((2-((3R,4R)-3-amino-4-fluoro-l-piperidinyl)-4methoxy-lH-benzimidazol-l-yl)methyl)-3- pyridinecarbonitrile. In certain aspects of the forty-eighth embodiment, the invention provides a pharmaceutically acceptable salt of 6-((2-((3R,4R)-3-amino-4-fluoro-lpiperidinyl)-4-methoxy-lH-benzimidazol-l -yl)methyl)-3pyridinecarbonitrile. In a forty-ninth embodiment, the invention provides 2-((3R,4R)-3-amino-4-fluoropiperidin-l-yl)-1-((5chloropyrimidin-2-yl)methyl)-IH-benzo[d] imidazole-6carbonitrile. In certain aspects of the forty-ninth embodiment, the invention provides a pharmaceutically acceptable salt of 2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-1-((5-chloropyrimidin-2-yl)methyl )-1Hbenzo[d]imidazole-6-carbonitrile. In a fiftieth embodiment, the invention provides (3R,4R)-4-fluoro-l-(1-((5-fluoropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3- amine. In certain aspects of the fiftieth embodiment, the invention provides a pharmaceutically acceptable salt of (3R,4R)-4-fluoro-1(1-((5-fluoropyrimidin-2-yl)methyl)-IH-benzo[d]imidazole -2yl)piperidin-3-amine. In a fifty-first embodiment, the invention provides (3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6fluoro-lH-benzo[d]imidazol-2-yl)-4- fluoropiperidin-3-amine. IF-2019-169515 62-A PN - AN P# I TO Page 119 of 557 In certain aspects of the fifty-first, the invention provides a pharmaceutically acceptable salt of (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fIuoro-1Hbenzo[d]imidazol- 2-yl)-4-fluoropiperidin-3-amine. In a further aspect of each of the forty-second to the fifty-first embodiments, each of the compounds and pharmaceutically acceptable salts provided therein can be used in the preparation of a medicament for use in the treatment of a disease mediated by activity of TRPC6. In certain aspects, the compounds provided in the forty-second to the fifty-first embodiment, or pharmaceutically acceptable salts thereof, can be used in the production of a medicament for the treatment of a disease or disorder selected from nephrotic syndrome, minimal change disease , focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure , stroke, malignant tumor or muscular dystrophy. In still other aspects, the compounds of the forty-second to fifty-first embodiments, or salts pharmaceutically IF-2019-169515 62-APN-ANP#IT|®J Page 120 of 557 acceptable of these, they can be used in the preparation of a medicine for the treatment of nephrotic syndrome, membranous nephropathy and acute renal failure. In a fifty-second embodiment, a method is provided for treating a disease or disorder in a patient in need of treatment, said method comprising the step of administering a pharmaceutically acceptable composition comprising a compound of any of the forty-second to the fifty-first embodiment, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure , diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. In certain aspects of the fifty-first modality of the disease or disorder is selected from nephrotic syndrome, membranous nephropathy and acute renal failure. In a further embodiment, the invention provides methods for producing a compound of formula Illb or IF-2019-169515 62-A PN-AN P# Page 121 of 557 subformulas of this. The method comprises the synthesis steps of (a) alkylation of a formula: halogenated benzimidazole with electrophilic remainder with the formula: Benzimidazole compound is basic to provide a halogenated alkylated compound with the formula: IF-2019-169515 62-APN-ANP#!® Page 122 of 557 wherein (b) coupling the alkylated halogenated benzimidazole generated in step (a) with a protected piperidine with the formula: R1aPGwhere PG is an amide protecting group stable in nucleophilic aromatic substitution (such as an alkoxycarbonyl protecting group) under conditions conducive to nucleophilic aromatic substitution to generate an alkylated 2-(piperidin-l-yl)benzimidazole compound with the formula: (c) removal of PG from the alkylated 2-(piperidin-1-yl)benzimidazole compound formed in step (b) to generate the compound of Formula (Illb), where the variables X1, X2, X3, Z4, Rla, R2, R3, R4, R7, R11, R12, R13y IF-2019-169515 62-APN-ANP#W23 Page 123 of 557 R15 are defined as in the thirtieth modality. In preferred aspects of the synthesis method, the basic conditions of step (a) of the halogenated benzimidazole comprise contacting the electrophilic moiety in the presence of a carbonate base, such as potassium carbonate or more preferably, cesium carbonate. In a further embodiment, the invention provides methods for producing compounds of formula Illb subformulas of this. The method comprises the coupling synthesis steps of a halogenated benzimidazole with the formula: R1 R x with a piperidine protected with R4 R3 R2the formula: R1aTG under conditions conducive to nucleophilic aromatic substitution to generate a 2-(piperidin-l-yl)benzimidazole compound with the formula: IF-2019-169515 62-A PN-AN P# IN24 Page 124 of 557 wherein 2- (piperidin-1with a residue a under basic conditions to provide alkylated 2(piperidin-l-yl)benzimidazole compound with the formula: wherein Q is chloro, bromo, iodine, alkylCiCgsulfonate or optionally substituted phenylsulfonate; (c) removal of PG from the alkylated 2-(piperidin-l-yl) benzimidazole compound generated in step (b) to generate the compound of Formula (Illb), wherein the IF-2019-169515 62-APN-ANP#W23 Page 125 of 557 variables X1, In a further embodiment, the invention provides methods for producing compounds of formula Illb or subformulae thereof. illb). The method comprises the synthesis steps of (a) coupling of a brominated isothiocyanate compound R11with the formula r13with a protected piperidine compound with the formula: R1atg under conditions conducive to the formation of thiourea to generate an N,N'-disubstituted thiourea compound with the IF-2019-169515 62-APN-ANP# M Page 126 of 557 formula pg wherein PG is an amide protecting group such as an alkoxycarbonyl protecting group; (b) condensation of the N,N'5 disubstituted thiourea compound generated in step (a) with a compound R1? / x1 V / x2-^\ \__-R7amine with the formulaH2N. under conditions suitable for guanidine formation to provide an N,Ν',N-trisubstituted guanidine compound with the formula: (c) intramolecular cyclization of guanidine compound N, Ν', N-trisubstituted generated in step (b) in IF-2019-169515 62-A PN-AN P# IW Page 127 of 557 presence of a transition metal catalyst to form a compound of 2-(piperidin-l-yl)alkylated benzimidazole with the formula: (d) removal of PG from the alkylated 2-(piperidin-15-yl)benzimidazole compound generated in step (c) to provide a compound of Formula (Illb), where the variables X1, X2, X3, Z4, Rla, R2 , R3, R4, R7, R11, R12, R13 and R15 are defined as in the thirtieth embodiment. In a further embodiment, the invention provides methods for producing compounds of formula Illd or subformulas thereof. The method includes the synthesis stages of a) coupling of an optionally substituted ortho-fluoronitrobenzene compound with the IF-2019-169515 62-A PN-AN P# ΙΝΓ8 Page 128 of 557 formula: with a primary amine with the formula:H2Nunder conditions suitable for nucleophilic aromatic substitution to provide a secondary amine with the formula: b) generation of an alkylated 2-chlorobenzimidazole compound with the formula: by reducing the nitro substituent on the secondary amine compounds generated in step (a) to form a IF-2019-169515 62-APN-ANP#IN29 Page 129 of 557 dianiline compound in situ, cyclizing said dianiline with a carbonyl source and cloning (with a chlorine source such as, for example, P(O)C13) to generate the 2-chlorobenzimidazolalkylated compound; c) coupling of the alkylated 2-chlorobenzimidazole compound generated in step (b) with a piperidine / N\ protected with the formula: R1apg under conditions suitable for nucleophilic aromatic substitution to generate a 2-(piperidin-l-yl)benzimidazole compound d) removal of the PG from the alkylated 2-(piperidin-lyl) benzimidazole compound generated in step (c) to generate the compound of Formula (Illd), where the variables X1, X2, X3, Rla, R2, R3, R4 , R7, R11, R12, R13, R14y R15 are defined as in the thirtieth modality. In a further embodiment, the invention provides methods for producing compounds of formula VII or subformulas thereof. IF-2019-169515 62-A PN-AN P# IPRJU Page 130 of 557 of Halogenated benzimidazole coupling with the formula: a with a piperidine protected with the formula R4 R3 R2 R1apg under conditions conducive to nucleophilic aromatic substitution to generate a 2-(piperidin-l-yl)benzimidazole compound with the formula / N\ R1aTG wherein (b) alkylation of the alkylated 2-(piperidin-lyl)benzimidazole compound generated in step (a) with a IF-2019-169515 62-APN-ANP# W|I Page 131 of 557 haloester where Y is (c) saponification of the l-acetyl-2-(piperidinl-yl)benzimidazole compound generated in step (b) to provide a free acid followed by amination with amine, HNR9R10, under conditions conducive to the formation of amide bonds to provide a 1-[(2-piperidin-lyl)benzimidazole)]acetamide compound; (d) removal of PG from the compound 1-[(2-piperidin-lyl)benzimidazole)]acetamide generated in step (c) to generate the compound of Formula (VII), where the variables X1, X2, X3, Z4 , Rla, R2, R3, R4, R7, R11, R12, R13 and R15 are defined as in the thirty-fourth embodiment. In another embodiment, pharmaceutical compositions are provided comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of any of formula I or a subformula thereof. In some aspects, the composition is formulated in a form selected from the group IF-2019-169515 62-A PN-AN P# Page 132 of 557 which consists of an injectable fluid, a spray, a tablet, a pill, a capsule, a syrup, a cream, a gel and a transdermal patch. In another embodiment, combinations are provided, in particular pharmaceutical combinations, comprising a therapeutically effective amount of the compound of any of formula I or a subformula thereof. In another embodiment, methods are provided for modulating TRPC protein activity in a subject, which comprise administering to the subject a therapeutically effective amount of formula I or a subformula thereof. In preferred aspects of the embodiment, methods are provided for inhibiting TRPC6 activity in a subject, which comprise administering to the subject a therapeutically effective amount of a compound of formula I or a subformula thereof. In certain aspects of the embodiment, a method of inhibiting TRPC6 activity in a subject is provided, which comprises administering to the subject a therapeutically effective amount of a compound of formula I or a subformula thereof. In still other embodiments, methods are provided for treating a disorder or disease in a subject mediated by TRPC protein activity and, in particular, methods are provided for treating a disease or disorder mediated by TRPC6 protein activity. The methods comprise administering to the subject a therapeutically effective amount IF-2019-169515 62-APN-ANP#IW Page 133 of 557 of the compound of Formula I or a subformula thereof. In another embodiment, methods are provided for treating or preventing a disease or disorder selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure. , diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy, and said method comprises the step of administering to a subject in need of therapy an amount therapeutically effective of a compound or salt of formula I or a subformula thereof. In certain aspects, the method comprises treating a disease or disorder selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. In certain cases, IF-2019-169515 62-A PN-AN P# Ιί)φ|Ι Page 134 of 557 treatment methods and / or prevention methods are suitable for the treatment or prevention of nephrotic syndrome, membranous nephropathy and acute renal failure. In another aspect, the invention provides for the use of compounds of Formula I or subformulas thereof in the preparation of a medicament or in the production of a medicament for the treatment of a disease or disorder mediated by TRPC protein activity in a subject. In certain other aspects, the invention provides for the use of a compound according to formula I or a subformula thereof in the treatment of nephrotic syndrome, minimal change disease, focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. In certain cases, the invention provides for the use of compounds of Formula I or subformulas thereof in the preparation of a medicament or in the production of a medicament or the treatment of a disease or disorder in a subject that is selected from nephrotic syndrome, nephropathy membranous and renal failure IF-2019-169515 62-APN-ANP#IW5 Page 135 of 557 acute. For the purposes of interpreting this specification, the following definitions will apply and when necessary, terms used in the singular will also include the plural and vice versa. As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety of up to 20 carbon atoms. Unless otherwise stated, "alkyl" refers to hydrocarbon moieties with 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms or 1 to 4 carbon atoms. carbon. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tere-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl , 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, noctyl, n-nonyl, n-decyl and the like. As used herein, the term "alkylene" refers to a divalent alkyl group as defined hereinabove with 1 to 20 carbon atoms. Unless otherwise stated, "alkylene" refers to moieties with 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms or 1 to 4 carbon atoms. . Representative examples of alkylene include, but are not limited to IF-2019-169515 62-ΑΡΝ-ΑΝΡ#ΠΟ5 Page 136 of 557 exhaustive, methylene, ethylene, n-propylene, isopropylene, nbutylene, sec-butylene, isobutylene, tert-butylene, npentylene, isopentylene, neopentylene, n-hexylene, 3methylhexylene, 2,2-dimethylpentylene, 2,3- dimethylpentylene, n-heptylene, n-octylene, n-nonylene, n-decylene and the like. As used herein, the term "haloalkyl" refers to an alkyl as defined herein, which is replaced with one or more halo groups defined herein. The haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl, which includes perhaloalkyl. A monohaloalkyl may have an iodine, bromine, chlorine or fluorine in the alkyl group. Dihaloalkyl and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups on the alkyl. Usually, polyhaloalkyl contains up to 12, 10, 8, 6, 4, 3 or 2 halo groups. Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refers to an alkyl in which all hydrogen atoms are replaced with halogen atoms. As used herein, the term IF-2019-16951562-APN-ANP#lNBT Page 137 of 557 "hydroxyalkyl" refers to an alkyl as defined herein, which is substituted with one or more hydroxy groups. The term "hydroxycycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group, as defined herein, and additionally substituted with a hydroxy group. The hydroxy group can be found in the alkyl group, the cycloalkyl group, or in each of the alkyl and cycloalkyl groups. The term "aryl" refers to an aromatic hydrocarbon group with 6-20 carbon atoms in the ring part. Usually, the aryl is a monocyclic, bicyclic or tricyclic aryl with 6-20 carbon atoms. Likewise, the term "aryl", as used herein, refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which can be optionally substituted with 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkylene (O) -O-, aryl -O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-nitro, cyano, carboxy, alkyl-O-C(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl and heterocyclyl. As used herein, the terms IF-2019-169515 62-APN-ANP#ITW8 Page 138 of 557 "heterocycle", "heterocyclyl" "heteroskyalkyl" "heterocycle" refer to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring system, bicyclic 7, 8, 9, 10, 11 or 12 membered, or 10, 11, 12, 13, 14 or 15 membered tricyclic, and contains at least one heteroatom selected from O, S and N, where N and S can also be optionally oxidize in various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom. Heterocyclyl may include fused or bridged rings, as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran, dihydrofuran, 1,4-dioxane, morpholino, 1,4-dithiano, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1, 3-dioxane, 1,3dithiane, oxathane, thiomorpholine, azetidine, thiazolidine, morpholine and the like. As used herein, the term "azacycle" refers to a heterocycle comprising at least one ring nitrogen atom and which may optionally comprise 0, 1 or 2 additional ring heteroatoms selected from N, O or S. As used herein, the term "cycloalkyl" refers to saturated monocyclic, bicyclic or tricyclic hydrocarbon groups or IF-2019-169515 62-A PN-AN P# M Page 139 of 557 partially unsaturated with 3-12 carbon atoms. For the avoidance of doubt, "cycloalkyl" is not intended to include aromatic groups such as naphthylene or phenyl. Unless otherwise indicated, "cycloalkyl" refers to cyclic hydrocarbon groups with 3 to 9 ring carbon atoms or 3 to 7 ring carbon atoms, each of which may optionally be substituted with one, two or more ring carbon atoms. , three or more substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy, alkoxy, alkyl-C(O)-, acylamino, carbamoyl, alkyl-NH-, (alkyl)2N-, thiol, alkyl-S -, nitro, cyano, carboxy, alkyl-O-C(O)-, sulfonyl, sulfonamido, sulfamoyl and heterocyclyl. Examples of monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl, and the like. Examples of bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6dimethylbicyclo[3.1.1]heptyl, 2,6,6trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like. Examples of tricyclic hydrocarbon groups include adamantyl and the like. "Hydroxycycloalkyl" specifically refers to a cycloalkyl group substituted with one or more hydroxy groups. As used herein, the term “alkoxy” IF-2019-169515 62-A PN-AN P# IW0 Page 140 of 557 refers to alkyl-O-, where alkyl was defined hereinabove. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, 5-hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Usually, alkoxy groups have about 1-7 carbons, more preferably, about 1-4 carbons. As used herein, the term "cycloalkoxy" refers to cycloalkyl-O- and cycloalkyl-alkyl-O, where cycloalkyl and alkyl are as defined hereinabove. Representative examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, 1-methylcyclopropyloxy, cyclopropylmethoxy, 115-methylcyclobutyloxy and the like. Usually, cycloalkoxy groups have about 3-7 carbon atoms, more preferably, about 3-6 carbon atoms. Divalent substituents are represented with a "diyl" suffix. Therefore, a divalent alkyl linker is referred to as an alkanbyyl group and a cycloalkane group is referred to as a cycloalkanbyyl (e.g., cyclopropanbyyl). As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic or tricyclic aromatic ring system with 1 to 8 heteroatoms selected from N, O and S. In beterminabos IF-2019-169515 62-APN-ANP#WI Page 141 of 557 preferred aspects, the heteroaryl is a 5-10 membered ring system (for example, 5-7 membered unicycle or 8-10 membered bicyclic) or a 5-7 membered ring system. Examples of monocyclic heteroaryl groups include 2-thienyl or 3-thienyl, 2-furyl or 3-furyl, 2-pyrrolyl or 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl, 2thiazolyl, 4-thiazolyl or 5-thiazolyl, 3-isothiazolyl, 4isothiazolyl or 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl or 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl, 3-1,2, 4-triazolyl or 5-1,2,4-triazolyl, 4-1,2,3-triazolyl or 5-1,2,3-triazolyl, tetrazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, 3- pyridazinyl or 4-pyridazinyl, 3-pyrazinyl, 4-pyrazinyl or 5-pyrazinyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl. Examples of bicyclic heteroaryl groups include 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6isoquinolinyl, 7-isoquinolinyl or 8-isoquinolinyl, 2quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7- quinolinyl or 8-quinolinyl, 1isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl or 8isoquinolinyl, 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl or 8- benzimidazolyl and 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, IF-2019-169515 62-A PN-AN P# ΙΝΨ2 Page 142 of 557 7-indolyl or 8-indolyl. The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, in which the radical or point of attachment is located on the heteroaromatic ring. The terms "bicycle" and "bicyclyl" refer to a ring system with two fused rings, each of which can be carbocyclic or heterocyclic and each of which can be saturated, unsaturated, or aromatic. As used herein, the terms "halogen" or "halo" refer to fluorine, chlorine, bromine and iodine. As used herein, unless otherwise indicated, "optionally substituted" refers to a group unsubstituted or substituted with one or more, usually 1, 2, 3 or 4, suitable non-hydrogen substituents. If the identity of the "optional substituent" is not clearly defined in the context of the optionally substituted group, then each substituent is independently selected from the group consisting of: alkyl, hydroxy, halogen, oxo, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, CO2H, heterocycloalkyloxy (indicating a heterocyclic group linked through an oxygen bridge), -C02alkyl, IF-2019-16951562-A PN-AN P# IW Page 143 of 557 mercapto, nitro, cyano, sulfamoyl, sulfonamide, aryl, OC(O)alkyl, -0C(0)aryl, aryl-S-, aryloxy; alkylthio, formyl (i.e. HC(0)-), -C(O)NH2, aralkyl (alkyl substituted with aryl), aryl and aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O) NH-, alkylamino, dialkylamino or halogen. It is understood that when it is indicated that a group is optionally substituted, the description includes both modalities in which the group is not substituted and modalities in which the group is substituted. As used herein, the term "isomer" refers to different compounds that have the same molecular formula, but different arrangement and configuration of atoms. Also as used herein, "an optical isomer" or "a stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention and include geometric isomers. It is understood that a substituent can be attached to a chiral center of a carbon atom. Accordingly, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic mixture." The expression is used to designate a racemic mixture when appropriate. The use of "reí" indicates that IF-2019-169515 62-APN-ANP#IWI Page 144 of 557 the diasteromeric orientation is known, but the absolute stereochemistry is not known. In cases where absolute stereochemistry has not been determined, chiral chromatography and / or optical rotation conditions will indicate which isomer is present. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) in the that rotate the plane of polarized light to the wavelength of the sodium D line or the retention time in chiral chromatography separation. Some of the compounds described herein contain one or more asymmetric centers and therefore can generate enantiomers, diastereomers and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S), or with the signs (+) or (-). The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R) and (S) isomers can be prepared with synthons IF-2019-169515 62-A PN-AN P# Page 145 of 557 chiral or chiral reagents, or can be resolved by conventional techniques. If the compound contains a double bond, the substituent may be in E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. It is understood that, for any compound provided herein, including any compound of formula (I), or any embodiment thereof, or any compound of Table A, B or C, or a salt of any of the above, The compound may exist in any stereochemical form, such as simple enantiomers, diastereomers or tautomers or as a mixture of one or more enantiomers, diastereomers and tautomers in any ratio. As used herein, the terms "salt" or "salts" refer to an acid addition or base addition salt of a compound of the invention. Salts include, in particular, "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the properties and biological efficacy of the compounds of this invention and that are usually not biologically or otherwise undesirable. In many cases, the compounds of the present invention have the ability to form acidic and / or basic salts by virtue of the IF-2019-169515 62-A PN-AN P# IW Page 146 of 557 presence of amino and / or carboxyl groups or groups similar to these. It is possible to prepare pharmaceutically acceptable acid addition salts from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like. It is possible to prepare pharmaceutically acceptable base addition salts from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper. In certain other embodiments, the salts are IF-2019-169515 62-APN-ANP#IW Page 147 of 557 select from ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Certain organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. In another aspect, the present invention provides compounds described herein in the form of acetate salt, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophilonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, iodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsilate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate triphenatate, trifluoroacetate or xinafoate. In IF-2019-169515 62-APN-ANP#IW Page 148 of 557 In yet another aspect, the present invention provides compounds as described herein in the form of addition salt of Ci-C4 alkylSuf onic acid, benzenesulfonic acid or mono-, di- or tri-substituted Ci-C4 alkyl benzenesulfonic acid. It is also intended that any formulas included herein represent unlabeled forms of the compounds, as well as isotopically labeled forms. Isotopically labeled compounds have structures illustrated by the formulas included herein, except for the replacement of one or more atoms by an atom with a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, HQ, ng, 14C, 15N, 18F, 31P, 32P, 35S, 36C1,124I,125I, respectively. The invention includes various isotopically labeled compounds as defined herein, for example, those in which radioactive isotopes, such as 3H, 13C and 14C, are present. Such isotopically labeled compounds are useful in metabolic studies (con14C), reaction kinetics studies (e.g., con2H or3H), imaging or detection techniques, such as positron emission tomography (PET) or single-photon emission computed tomography. (SPECT), which includes IF-2019-169515 62-APN-ANP#IW Page 149 of 557 distribution of substrate or drug in tissues, or in the radioactive treatment of patients. In particular, a compound labeled o18F may be desirable for PET or SPECT studies. In general, the isotopically labeled compounds of the present invention and salts thereof can be prepared by the procedures described in the schemes or in the examples, and the preparations described below, by replacing an available isotopically labeled reagent with a reagent not isotopically labeled. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may imply certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, or a improvement of the therapeutic index. It is understood that, in this context, deuterium is considered a substituent of a compound of formula (I). The concentration of said heavier isotope, specifically deuterium, can be defined according to the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent on a compound of this invention is indicated to be deuterium, said compound has at least 50% deuterium incorporation in each IF-2019-169515 62-APN-ANP#IW Page 150 of 557 designated deuterium atom % of deuterium incorporation, at least 75% deuterium incorporation, at least 90% deuterium incorporation, at least 95% deuterium incorporation, at least 99% deuterium incorporation or at least 99.5% deuterium incorporation deuterium. The compounds of the present invention can form solvates with solvents (including water) inherently or by design. Accordingly, the invention is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly known in the pharmaceutical art, which are known to be harmless to a receptor, for example, water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, dg-acetone, dg-DMSO. The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will produce the biological or medical response of a subject, per IF-2019-169515 62-A PN-AN P #IWI Page 151 of 557 example, reduction or inhibition of an enzyme or protein activity, or will improve symptoms, alleviate conditions, slow or delay the progression of the disease, or prevent a disease, etc. In a non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) alleviate, inhibit, prevent and / or improve the less partially a condition, disorder, disease or biological process (i) mediated by TRPC6 activity or (ii) associated with TRPC6 activity, or (2) inhibit TRPC6 activity. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, a tissue, a non-cellular biological material or a medium, is effective to inhibit at least partially the activity of TRPC6. As used herein, the term "subject" refers to an animal. Usually, the animal is a mammal. A subject also refers to, for example, primates (e.g. humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In still other modalities, the subject is a human being. IF-2019-169515 62-A PN-AN P# 1?^ Page 152 of 557 As used herein, "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, disorder or disease, or a significant reduction in the baseline activity of a process. or biological activity. As used herein, "treat", "to treat" or "treatment" of any disease or disorder refers, in one embodiment, to improving the disease or disorder (i.e., slowing, stopping or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "to treat" or "treatment" refers to alleviating or improving at least one physical parameter, including those that are imperceptible to the patient. In yet another embodiment, "treat", "to treat" or "treatment" refers to the modulation of the disease or disorder either physically (for example, stabilization of a perceptible symptom), physiologically (for example, stabilization of a parameter physical) or both. As used herein, "prevent", "preventing" or "prevention" of any disease or disorder refers, in one embodiment, to delaying or avoiding the onset of the disease or disorder (i.e., slowing or preventing the appearance of the disease or disorder in a patient susceptible to the development of IF-2019-16951562-APN-ANP#ITO Page 153 of 557 disease or disorder). As used herein, a subject "needs" a treatment if such treatment would benefit said subject biologically, medically, or in terms of quality of life. As used herein, the terms "a", "an", "the", "the" and similar terms used in the context of the present invention (especially in the context of the claims) will be understood to encompass both the singular as well as the plural unless otherwise indicated herein or the context clearly contradicts it. Any asymmetric atom (e.g., carbon or the like) of the compounds of the present invention may be present in racemic or enantiomerically enriched form, e.g., the (R), (S) or (R,S) configurations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess in the (R) or (S) configuration. Substituents on atoms with unsaturated bonds may, if possible, be present in cis (Z) or trans (E) form. IF-2019-169515 62-APN-ANP#EW Page 154 of 557 Accordingly, as used herein, a compound of the present invention may be found in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as geometric isomers (cis or trans). substantially pure, diastereomers, optical isomers, racemates or mixtures thereof. Any resulting mixtures of isomers can be separated based on physicochemical differences of the constituents into substantially pure optical or geometric isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization. It is possible to resolve any racemates resulting from final products or intermediates into the optical isomers by known methods, for example, by separating the diasteomeric salts thereof, obtained with an optically active acid or base and releasing the optically active acid or basic compound. In particular, it is possible to employ such a basic moiety to resolve the compounds of the present invention into their optical isomers, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'p-toluoyltartaric acid, mandelic acid, malic acid or acid IF-2019-169515 62-A PN-AN P# IW5 Page 155 of 557 camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high performance chromatography (HPLC) or supercritical fluid chromatography (SFC) with a chiral adsorbent. The mixtures of isomers that can be obtained according to the invention can be separated in a manner known to those skilled in the art into the individual isomers; it is possible to separate diastereomers, for example, by splitting into polyphase solvent mixtures, recrystallization and / or chromatographic separation, for example, on silica qel or, for example, medium pressure liquid chromatography on a reverse phase column, and it is possible separating racemates, for example, by forming salts with optically pure salt-forming reagents and separating the mixture of diastereomers that can be obtained in this way, for example, by fractional crystallization or by chromatography on optically active column materials . Within the scope of this text, only an easily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated "protecting group", unless the context indicates otherwise. The protection of functional groups by said protecting groups, the protecting groups themselves and their IF-2019-169515 62-A PN-AN P# INOT reactions Page 156 of 557 cleavage are described, for example, in standard reference works, such as J. F. W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, third edition, Wiley, New York 1999, in The Peptides; volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in Methoden der organischen Chemie (Methods of organic chemistry), Houben Weyl, 4th edition, volume 15 / 1, Georg Thieme Verlag , Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, Aminosauren, Peptide, Proteine ​​{Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharide and Derivate {Carbohydrate chemistry: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be easily removed (i.e. without the occurrence of unwanted side reactions), for example by solvolysis, reduction, photolysis or, alternatively , under physiological conditions (for example, by enzymatic cleavage). The intermediates and final products can be processed and / or purified according to standard methods, for example, by chromatographic methods, distribution methods, crystallization, recrystallization and the like. All methods described herein can be IF-2019-16951562-A PN-A N P# IW7 Page 157 of 557 carried out in any proper order, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or illustrative expressions (e.g., "such as") provided herein is intended merely to better illustrate the invention, and is not intended to limit the scope of the invention. another way is claimed. Any of the process steps described herein can be carried out under reaction conditions known to those skilled in the art, including those specifically mentioned in the absence or, usually, in the presence of solvents or diluents, including, for example, solvents or diluents that are not inert with respect to the reagents used and that dissolve them, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example, ion exchangers, such as cation exchangers, for example, in the H+ form , according to the nature of the reaction and / or the reactants at reduced, normal or elevated temperature, for example, in a temperature range of about 100 ° C to about 250 ° C, which includes, for example , from about -80 °C to about 250 °C, for example, from -80 to -60 °C, at room temperature, from -20 to 40 °C or at reflux temperature, at atmospheric pressure or in a closed container , under pressure when appropriate, IF-2019-169515 62-APN-ANP#IW8 Page 158 of 557 and / or in an inert atmosphere, for example, in an argon or nitrogen atmosphere. Solvents from which it is possible to select such suitable solvents for a particular reaction include those specifically mentioned or, for example, water, esters, such as lower alkyl lower alkanoates, for example, ethyl acetate, ethers, such as aliphatic ethers, for example , diethyl ether or cyclic ethers, for example, tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1-propanol or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such such as methylene chloride or chloroform, acidic amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for example, pyridine or N-methylpyrrolidin-2one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example for example, acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methylcyclohexane or mixtures of these solvents, for example, aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures can also be used for processing, for example, by chromatography or partition. In another aspect, the present invention provides a IF-2019-169515 62-APN-ANP#M9 Page 159 of 557 pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For the purposes of the present invention, unless otherwise indicated, solvates and hydrates are generally considered compositions. Preferably, the pharmaceutically acceptable carriers are sterile. The pharmaceutical composition may be formulated for particular routes of administration, such as oral administration, parenteral administration and rectal administration, etc. Furthermore, the pharmaceutical compositions of the present invention can be produced in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders or suppositories) or in a liquid form (including, but not limited to, not limited to, solutions, suspensions or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations, such as sterilization, and / or may contain inert diluents, lubricating agents or conventional buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. As used herein, the expression IF-2019-16951562-A PN-A N P# IWO Page 160 of 557 "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption retarding agents, salts , preservatives, drugs, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, dyes and the like, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18.aed. , Mack Printing Company, 1990, pp. 1289-1329). Except to the extent that any conventional agent is incompatible with the active ingredient, its use in pharmaceutical or therapeutic compositions is contemplated. Usually, pharmaceutical compositions are gelatin tablets or capsules comprising the active ingredient together with one or more of: a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, d) disintegrants, for example, starches, agar, IF-2019-169515 62-APN-ANP#IWI Page 161 of 557 alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners. The tablets may be film coated or enteric coated according to methods known in the art. Compositions suitable for oral administration include an effective amount of a compound of the invention in the form of tablets, wafers, aqueous or oil suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions for oral use are prepared according to any method known in the art for producing pharmaceutical compositions and said compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents to provide oral preparations. pleasant flavor and pharmaceutically elegant. The tablets may contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients that are suitable for the production of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, disintegrating and granulating agents, for example, corn starch or alginic acid, binding agents, for example , starch, gelatin, or acacia and lubricating agents, for example, magnesium stearate, stearic acid or IF-2019-169515 62-APN-ANP#IW Page 162 of 557 talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. For example, a delayed action material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient It is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Certain injectable compositions are aqueous isotonic solutions or suspensions and suppositories are prepared from fatty suspensions or emulsions. Said compositions may be sterilized and / or may contain adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may also contain other substances with therapeutic value. Such compositions are prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75% or contain about 1-50% of the active ingredient. The IF-2019-169515 62-APN-ANP#HW3 Page 163 of 557 compositions suitable for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal administration include absorbable pharmacologically acceptable solvents to promote passage through the patient's skin. For example, transdermal devices form a bandage comprising a support member, a reservoir containing the compound optionally with carriers; optionally, a rate-controlled barrier for delivering the compound to the skin of the host at a controlled, predetermined rate over an extended period of time, and means for securing the device to the skin. Compositions suitable for topical application, for example, to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or aerosol formulations, for example, for administration by aerosol or the like. Such topical delivery systems will be particularly suitable for dermal application, for example, for the treatment of skin cancer, for example, for prophylactic use in sunscreens, lotions, sprays and the like. Therefore, they are particularly suitable for use in topical formulations, including cosmetics, known in the art. These may contain solubilizers, stabilizers, moisture-enhancing agents. IF-2019-169515 62-APN-ANP#FWI Page 164 of 557 tone, buffers and preservatives. As used herein, a topical application may also refer to an inhalation or an intranasal application. They can be conveniently administered in the form of a dry powder (either alone, as a mixture, for example, a dry mixture of lactose, or a mixed component particle, for example, with phospholipids) from an aerosol presentation. or dry powder inhaler in a pressurized container, pump, aerosol, atomizer or nebulizer, with or without use of a suitable propellant. The present invention also provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds. The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared by using anhydrous or low moisture containing ingredients and low humidity conditions. An anhydrous pharmaceutical composition can be prepared and stored so that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable containers include, but are not limited to, sealed foils, IF-2019-169515 62-APN-ANP#IW Page 165 of 557 plastics, unit dose containers (e.g. vials), blisters and protective packaging. Furthermore, the invention provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate with which the compound of the present invention as an active ingredient will decompose. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. Prophylactic and therapeutic uses The compounds described herein in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, for example, TRPC protein modulation properties and, more particularly, inhibition of TRPC6 protein activity, for example, such as indicated by in vitro and in vivo assays as set out in the following sections and are therefore indicated for therapy. The present invention provides methods of treating a disease or disorder that is associated with the activity of the TRPC6 protein by administering to a subject in need thereof an effective amount of a compound described herein. In certain aspects, the disease or disorder suitable for therapy by administration of the compound of the invention includes, IF-2019-169515 62-APN-ANP#IW Page 166 of 557 non-exhaustive, nephrotic syndrome, minimal change disease, focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. In certain cases, the patient suffers from nephrotic syndrome, membranous nephropathy and acute renal failure. In a specific embodiment, the present invention provides a method of treating or preventing kidney disease by administering to a subject in need thereof an effective amount of a compound described herein. In certain embodiments, patients who are currently asymptomatic but are at risk of developing kidney disease are suitable for administration of a compound of the invention. Methods of treatment or prevention of kidney diseases include, but are not limited to, methods of treatment or prevention of nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, and diabetic nephropathy. The combination or pharmaceutical composition of the IF-2019-169515 62-APN-ANP#! W Page 167 of 557 The present invention may be a unit dosage of about 1-1000 mg of active ingredients for a subject of about 50-70 kg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredients. The therapeutically effective dosage of a compound, pharmaceutical composition or combinations thereof depends on the subject's species, body weight, age and the individual condition, disorder or disease or severity of what is being treated. A physician, doctor or veterinarian skilled in the art can easily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progression of the disorder or disease. The dosage properties mentioned above can be demonstrated in in vitro and in vivo assays through the beneficial use of mammals, for example, mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, for example, aqueous solutions, and in vivo, either enterally, parenterally, beneficially intravenously, for example, as a suspension or in solution watery In vitro dosage can vary between concentrations of around 10"3 and 10-9molar. A therapeutically effective amount in vivo may vary depending on IF-2019-16951562-APN-ANP#IW Page 168 of 557 the route of administration, between about 0.1-500 mg / kg, or between about 1-100 mg / kg. The activity of a compound according to the present invention can be evaluated by in vitro and in vivo methods, such as those described in the examples below. The compound of the present invention can be administered simultaneously with, before or after, one or more therapeutic agents. The compound of the present invention can be administered separately, by the same or a different route of administration, or together in the same pharmaceutical composition as the other agents. In one embodiment, the invention provides a product comprising a compound described herein and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by the activity of the TRPC protein. In preferred aspects, the therapy is a treatment for nephrotic syndrome, minimal change disease, focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, difficulty syndrome IF-2019-169515 62-A PN-AN P# IW9 Page 169 of 557 acute respiratory syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. Products provided as a combination preparation include a composition comprising the compound described herein and the other therapeutic agents together in the same pharmaceutical composition, or the compound described herein and the other therapeutic agents in a separate form, e.g. , in the form of a kit. In one embodiment, the invention provides a pharmaceutical composition comprising a compound as described herein and other therapeutic agents. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above. In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound described herein. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, a bottle with divisions, or a foil package with divisions. An example of this kit is a blister pack, such as is typically used to wrap 25 tablets, capsules and the like. The kit of the invention can be used to IF-2019-16951562-A PN-A N P# INFO Page 170 of 557 administer different dosage forms, for example, oral and parenteral, to administer the individual compositions at different dosage intervals or to titrate the individual compositions to each other. The kit of the invention typically comprises administration directions to assist with compliance. In combination therapies of the invention, the same manufacturer or different manufacturers can produce and / or formulate the compound of the invention and the other therapeutic agent. Likewise, the compound of the invention and the other therapeutic agent can be brought together in a combination therapy: (i) before presentation of the combined product to physicians (for example, in the case of a kit comprising the compound of the invention and the other therapeutic agent 15); (ii) by the physicians themselves (or with the guidance of the physician) shortly before administration; (iii) in the patients themselves, for example, during sequential administration of the compound of the invention and the other therapeutic agent. Accordingly, the invention provides the use of a compound, as described herein, to treat a disease or condition mediated by the activity of the TRPC protein, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent to treat a disease or condition mediated by IF-2019-169515 62-A PN-AN P# INP1 Page 171 of 557 TRPC protein activity, wherein the medicament is administered with a compound as described herein. In another aspect, the invention provides the use of a compound as described herein for the treatment of a disease or disorder selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis , IgA nephropathy, acute kidney failure, chronic kidney failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy, where the drug is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for the treatment of a disease or disorder selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic kidney failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or IF-2019-16951562-A PN-A N P# INP2 Page 172 of 557 muscular dystrophy, wherein the medicament is administered with a compound as described herein. The invention also provides a compound as described herein for use in a method of treating a disease or condition mediated by the activity of the TRPC protein, wherein the compound is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the activity of the TRPC protein, wherein the other therapeutic agent is prepared for administration with a compound as described herein. The invention also provides a compound as described herein for use in a method of treating a disease or condition mediated by the activity of the TRPC protein, wherein the compound is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the activity of the TRPC protein, wherein the other therapeutic agent is administered with a compound as described herein. The invention also provides the use of a compound as described herein to treat a disease or condition mediated by the activity of the TRPC protein, wherein the patient received treatment IF-2019-169515 62-A PN-AN P# IW3 Page 173 of 557 prior (for example, within a 24-hour period) with another therapeutic agent. The invention also provides the use of another therapeutic agent to treat a disease or condition mediated by the activity of the TRPC protein, wherein the patient was previously treated (e.g., within a 24 hour period) with a compound as described at the moment. The pharmaceutical compositions may be administered alone or in combination with other molecules known to have a beneficial effect in the treatment of kidney diseases or, more specifically, in the treatment of FSGS, nephrotic syndrome, minimal change diseases or diabetic kidney disease. A combination therapy regimen may be additive or may produce synergistic results (e.g., improvement in renal function that is greater than expected from combined use of the two agents). In some embodiments, the present invention provides a combination therapy to prevent and / or treat kidney diseases or, more specifically, FSGS, nephrotic syndrome or minimal change diseases with a compound of the invention and a second therapeutic agent selected from the group consisting of ACE / ARB (such as captopril, llisinopril, or losartan), steroid therapy (such as prednisone), immunomodulators (such as mycophenolate mofetil, tacrolimus, or cyclosporine A), hormone analogs IF-2019-169515 62-A PN-AN P# FW Page 174 of 557 adrenocorticotropic (such as acthar gel), anti-CD20 antibodies (such as rituximab), calcium channel blockers (such as amlodipine), diuretics (such as hydrochlorothiazide), antiplatelet agents (such as dipyridamole), anticoagulants ( such as heparin), DPP-4 inhibitors (such as sitagliptin), SGLT2 inhibitors (such as dapagliflozin), antihyperlipidemia (such as rosuvastatin), anemia therapy (darbepoetin alfa) or antihyperuricemia (febxostat). In one embodiment, the invention provides a method for inhibiting the activity of a TRPC protein or, more preferably, for inhibiting the activity of the TRPC6 protein, in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound. according to the definition of formula (I). The invention also provides methods for inhibiting the activity of a TRPC protein or, more preferably, for inhibiting the activity of the TRPC6 protein, in a subject, by administering a compound as described herein, wherein the method It comprises administering to the subject a therapeutically effective amount of the compound as described herein. In one embodiment, the invention provides a compound as described herein for use as a medicament. In one embodiment, the invention provides the use of a IF-2019-169515 62-A PN - AN P# INP5 Page 175 of 557 compound as described herein for treating a disorder or disease in a subject that is characterized by the activity of a TRPC protein or, more preferably, the activity of the TRPC6 protein. In particular, the invention provides the use of a compound as described herein for the treatment of a disorder or disease mediated by the activity of the TRPC protein or, more preferably, the activity of the TRPC6 protein, for example, syndrome nephrotic, minimal change disease, focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. In certain preferred aspects, the invention provides the use of a compound as described herein for the treatment of a disorder or disease mediated by the activity of the TRPC6 protein selected from nephrotic syndrome, membranous nephropathy and acute renal failure. In one embodiment, the invention provides for the use of a compound as described herein in the manufacture of a medicament to treat a disorder or disorder. Page 176 of 557 disease in a subject that is characterized by the activity of a TRPC protein or, more preferably, the activity of the TRPC6 protein. More specifically, in the preparation of a medicament for the treatment of a disease or disorder in a subject that is characterized by the activity of a TRPC protein or, more preferably, the activity of the TRPC6 protein, for example, nephrotic syndrome, disease minimal change, focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS) , heart failure, stroke, malignant tumor or muscular dystrophy. In certain preferred aspects, the invention provides the use of a compound as described herein in the preparation of a medicament for the treatment of nephrotic syndrome, membranous nephropathy and acute renal failure. In one embodiment, the invention provides the use of a compound as described herein to treat a disorder or disease in a subject that is characterized by the activity of a TRPC protein or, more preferably, the activity of the TRPC6 protein. . More IF-2019-16951562-A PN-A N P# Page 177 of 557 Specifically, the invention provides uses of the compounds provided herein in the treatment of a disease or disorder that is characterized by the activity of a TRPC protein or, more preferably, the activity of the TRPC6 protein, e.g. , nephrotic syndrome, minimal change disease, focal and segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute pulmonary disorder, distress syndrome acute respiratory syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. In certain embodiments, the uses of the compounds provided herein are for the treatment of a disease or disorder selected from nephrotic syndrome, membranous nephropathy and acute renal failure. In a specific embodiment, the present invention provides the use of the compounds of the invention to treat or prevent nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute pulmonary disorder, distress syndrome acute respiratory syndrome (ARDS), heart failure, stroke, malignant tumor or dystrophy IF-2019-169515 62-A PN-AN P# IN79 Page 178 of 557 muscular. In certain embodiments, patients who are currently asymptomatic but are at risk of developing symptomatic nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute pulmonary disorder, distress syndrome acute respiratory syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy, are suitable for administration of a compound of the invention. Use in the treatment or prevention of nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute pulmonary disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy includes, but is not limited to, uses in the treatment or prevention of one or more symptoms or aspects of nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, disorder acute pulmonary disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. The invention also includes any variant of IF-2019-169515 62-A PN-AN P# IW9 Page 179 of 557 present processes, in which an intermediate product that can be obtained anywhere is used as a starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure materials. The examples below are intended to illustrate the invention and should not be construed as limitations thereof. Temperatures are expressed in degrees Celsius (°C). Unless otherwise indicated, all evaporations are carried out under reduced pressure, usually between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of the final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. The abbreviations used are those conventional in the art. The invention also comprises those forms of the process in which a compound that can be obtained as an intermediate at any stage of the process is used as a starting material and the remaining stages of the process are carried out; or in which the starting material is formed under the reaction conditions; or is used in the form of a derivative, for example, in a protected form or in the form IF-2019-169515 62-APN-ANP#IWÍ Page 180 of 557 of a salt; or a compound obtainable by the process according to the invention is produced under process conditions and is further processed in situ. All starting materials, basic components, reagents, acids, bases, dehydrating agents, solvents and catalysts used in the synthesis of the compounds of the present invention are commercially available or can be produced by synthesis methods known to the person skilled in the art. technique. Experimental practice Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in degrees Celsius unless otherwise indicated. All microwave-assisted reactions were carried out with a Smith Synthesizer from Biotage. Mass spectral data were determined using the electrospray ionization technique. All examples were purified to >95% purity, as determined by high-performance liquid chromatography. Unless otherwise stated, reactions were carried out at room temperature. Commercially available materials were purchased from Sigma Aldrich, HDH Pharma, Pharmablock, Alfa Aesar, Enovation Chemicals and Combi-Blocks. IF-2019-169515 62-APN-ANP#IWI Page 181 of 557 Compound names, i.e., IUPAC names, for the compounds described in the present application were generated with ChemDraw compound naming software. The following abbreviations are used: CDI - 1,1'-carbonyldiimidazole DCM - dichloromethane DMSO - dimethyl sulfoxide DMF - Ν,Ν-dimethylformamide THF - tetrahydrofuran Et2O - diethyl ether EtOAc - ethyl acetate EtOH - ethyl alcohol Ms - mesylate MeCN - acetonitrile MeOH - methyl alcohol SFC - supercritical fluid chromatography TFA - trifluoroacetic acid tmp - 2,2,6,6-tetramethylpiperidine h - hour min - minutes rt - room temperature (22-25 °C) mL milliliters pL microliters g grams pg micrograms IF-2019-16951562-A PN-A N P# IW Page 182 of 557 mg milligrams pmoL micromolars General preparation method The compounds described herein are prepared by techniques known to those skilled in the art through the reaction sequences described in Schemes 1-6, as well as by other methods. Furthermore, in the following schemes, where acids, bases, reagents, coupling agents, specific solvents, etc. are mentioned, it is understood that it is possible to use other acids, bases, reagents, coupling agents, solvents, etc. and that they are included in the scope of the present invention. Syntheses of selected compounds of the present invention were prepared as described in Scheme 1. CDI coupling of the desired bisanline provided the corresponding benzimidazolone. Refluxing POCI3 provided the chlorobenzimidazole. These intermediates could be alkylated with a variety of electrophiles and then subjected to SnAr conditions to provide the penultimate Boc-protected intermediates. Exposure to a variety of acids caused deprotection of Boc to provide the final products. Scheme 1 IF-2019-16951562-A PN-A N P# ΙΓΟ Page 183 of 557 9? ΤΓ-Αο HOI An alternative approach to benzimidazole intermediates that was used to synthesize additional compounds in the present invention is shown in Scheme 2. Coupling with GDI of the desired bisanline provided the corresponding benzimidazolone. Refluxing POCI3 provided the chlorobenzimidazole. These intermediates were heated with base and nucleophiles to provide the SnAr products. Alkylation with a variety of electrophiles followed by acidic Boc deprotection provided the final compounds. Scheme 2 Additionally, the examples herein IF-2019-169515 62-APN-ANP#EW Page 184 of 557 invention could be synthesized by the methods illustrated in Schemes 3-6. Scheme 3 Isothiocyanate formation was achieved by using a variety of reagents. Addition of secondary amines followed by condensation with primary amines provided the corresponding substituted guanidine. Intramolecular cyclizations were achieved with copper catalysis. Final acidic Boc deprotection provided the desired compounds. Scheme 4 Subjecting substituted piperidines to cyanogen bromide provided the corresponding piperidine-l-carbonitriles. These were susceptible to nucleophilic attack by various anlyline nucleophiles, which were then trapped with benzyl electrophiles. The corresponding guanidine was subjected to intramolecular cross-coupling in copper and palladium catalysis. The IF-2019-169515 62-APN-ANP#IN85 Page 185 of 557 final boc deprotection under acidic conditions provided the desired compounds. Scheme 5 Benzimidazoles were alkylated with a variety of electrophiles and base. These intermediates were subjected to Zn(tmp)2, copper catalysis, and benzoylhydroxylamines to provide the amino products. Final subjection to acidic Boc deprotection conditions provided the desired products. Scheme 6 SnAr transformations were achieved into fluoronitrobenzenes substituted with primary benzylamines and base. The corresponding nitro intermediates are IF-2019-169515 62-APN-ANP#IW Page 186 of 557 were reduced with iron or zinc, then subjected to couplings with CDI and chlorination reactions with POCI3. These intermediates were again subjected to conditions of SnAr, then Boc was deprotected under acidic conditions to provide the final compounds. 1JF&. NH.Cto Zn. AeOH 2;. was 3) POCI.r, ——;------> Scheme 7. General synthesis of alkylated intermediates R4 Intermediate 1: 6-((2-chloro-5,7-difIuoro-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile and Intermediate 2: 6-((2-chloro-4,6-difluoro-lH-benzo[d]imidazol-lyl )methyl) nicotinonitrile IF-2019-169515 62-APN-ANP#IW Page 187 of 557 CDI THF Step 1. 4,6-difluoro-lH-benzo[d]imidazole-2(3H)-one 3,5-Difluorobenzene-1,2-diamine (210.0 g, 1.457 mol, 1.0 equiv.) and CDI (236.0 g, 1.457 mol, 1.0 equiv.) were dissolved in anhydrous THE (2 .5 L, 11.9 mL / g) and stirred for 12 hours at room temperature. LCMS indicated that the reaction was complete. The reaction mixture was diluted with water (6.0 L) and extracted with ethyl acetate (2 x 6.0 L). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide crude 4,6-difluoro-1H-benzo[d]imidazole-2(3H)-one as a black solid which was used. in the next step without further purification. 1H NMR (400 MHz, DMSO-ds): δ 11.20 (s, 1H), 11.05 (s, 1H), 6.85 (td, J = 10.7, 2.2 Hz, 1H), 6.69 (dd, J = 8.6, 2.2 Hz, 1H). MS (ESI, pos. ion) m / z: 171.0 [M+l] Step 2. 2-chloro-4,6-difluoro-lH-benzo[d]imidazole 4,6-Difluoro-lH-benzo[d]imidazole-2(3H)one (180.0 g, 1.058 mol, 1.0 equiv.) was suspended in POCI3 (2.0 L) and IF-2019-169515 62-A PN-AN P# I Page 188 of 557 heated with stirring at 110 °C for 2 hours, at which time LCMS indicated that the reaction was complete. Excess POCI3 was removed by vacuum distillation and the remaining residue was diluted with acetonitrile (1.0 L) and saturated aqueous sodium bicarbonate solution (1.0 L), and then extracted with ethyl acetate (2 x 4 .0L). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 2-chloro-4,6difluoro-lH-benzo[d]imidazole as a brown solid which was used in the following reaction without further purification. .4Η NMR (400 MHz, DMSO-cfo): 13.40 (bs, 1H), 7.31 - 7.03 (m, 2H). MS (ESI, pos. ion) m / z: 189.0 [M+l]. Pd(PPh3)4, Zn(CN)2 DMF 100C Step 3. 6-(hydroxymethyl)nicotinonitrile (5-bromopyridin-2-yl)methanol (75.0 g, 399.0 mmol, 1.0 equiv.), zinc cyanide (141.0 g, 1.197 mol, 3.0 equiv.) and tetrakis were dissolved (triphenylphosphine)palladium(0) (46.1 g, 39.9 mmol, 0.1 equiv.) in N, N-dimethylphonmamide (750.0 mL, 10.0 mL / g) and degassed with nitrogen for 30 minutes. The reaction mixture was heated at 110 °C for 2 hours. LCMS indicated the formation of the product. After completing the reaction, the mixture was allowed to cool to room temperature and diluted with water. IF-2019-169515 62-APN-ANP#IW5 Page 189 of 557 (700 mL) and extracted with ethyl acetate (3 x 700 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel (230-400 mesh) and purified through a Biotage Isolera-one preloaded silica gel column, eluting with a gradient of 40% ethyl acetate in hexanes to provide 6-(hydroxymethyl)nicotinonitrile as a white solid. .28 (m, 1H), 7.66 (dt, J = 8.3, 0.9 Hz, 1H), 5.68 (td, J = 5.9, 0.8 Hz, 1H), 4, 64 (d, J 5.8 Hz, 2H). MS (ESI, pos. ion) m / z: 135.0 [M+l] X = IQ X = OMs Step 4. 6-(chloromethyl)nicotinonitrile and (5-cyanopyridin-2-yl)methyl methanesulfonate 6-(Hydroxymethyl)nicotinonitrile (25.0 g, 186.0 mmol, 1.0 equiv.) was dissolved in dichloromethane (360.0 mL, 14.4 mL / g) and cooled to 0 °C. N,Ndiisopropylethylamine (48.8 mL, 280.0 mmol, 1.5 equiv.) was added, followed by dropwise addition of methanesulfonyl chloride (16.0 g, 205.0 mmol, 1.1 equiv. ) in 15 minutes. The reaction mixture was allowed to warm until IF-2019-169515 62-A PN-AN P# Iff Page 190 of 557 room temperature and stirred for 45 minutes. LCMS indicated the formation of the product. The reaction mixture was diluted with water (500 mL) and extracted with DCM (2 x 250 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material which was adsorbed onto a plug of silica gel (230-400 mesh) and purified by column chromatography. of Biotage Isolera-one preloaded silica gel, eluted with a gradient of 15% ethyl acetate in hexanes to provide 6-(chloromethyl)nicotinonitrile (VI) as a yellowish solid.XH NMR (400 MHz, DMSO-dg ) δ 9.03 (dd, J = 2.2, 1.0 Hz, 1H) , 8.38 (dd, J = 8.1, 2.2 Hz, 1H) , 7.77 (dd, J = 8.1, 0.9 Hz, 1H), 4.88 (s, 2H). Further elution of the column with a gradient of 50% ethyl acetate in hexanes gave 5cyanopyridin-2-yl)methyl methanesulfonate as a brown solid.ΤΗ NMR (400 MHz, DMSO-d6) δ 9.06 (dt, J = 2.1, 1.0 Hz, 1H), 8.41 (dt, J = 8.2, 1.7 Hz, 1H), 7.73 (dd, J = 8.2, 1.0 Hz) , 1H), 5.42 (d, J = 1.1 Hz, 2H), 3.34 (s, 3H). MS (ESI, pos. ion) m / z: 213.2 [M+l]. Both compounds were alkylation-competent electrophiles (step 5). IF-2019-169515 62-APN-ANP# WI Page 191 of 557 Step 5. 6-((2-chloro-4,6-difluoro-lH-benzo[d]imidazoll-yl)methyl)nicotinonitrile and 6-((2-chloro-5,7-difluoro-1Hbenzo[d]imidazole -l-yl)methyl)nicotinonitrile 2-Chloro-4,6-difIuoro-1Hbenzo[d]imidazole (50.0 g, 265.0 mmol, 1.0 equiv.) and 6(chloromethyl)nicotinonitrile (40.5 g, 265.0 mmol) were dissolved , 1.0 equiv.) in acetonitrile (500.0 mL, 10.0 mL / g) at room temperature. Cesium carbonate (138.0 g, 427.0 mmol, 1.6 equiv.) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel (60-120 mesh) and purified by column chromatography, eluting with a gradient of 25% ethyl acetate in hexanes to provide 6-((2chloro-4, 6-difluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile and 6-((2-chloro-5,7-difluoro-lHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile as a mixture of isomers (light yellow solid). In some cases, the IF-2019-16951562-APN-ANP#IW Page 192 of 557 mixing of isomers was carried out without separation and in other cases, the isomers were separated at this stage. Step 6. Separation of 6-((2-chloro-5,7-difIuoro-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile (Intermediate 1) and 6- ((2-chloro-4,6-difluoro -lH-benzo[d]imidazole-lyl)methyl)nicotinonitrile (Intermediate 2) SFC separation:....................» A 1.0 g sample was dissolved in 20 mL of methanol, Lux C4 column (250 χ 50 mm, 5pm), mobile phase: 70:30 (A:B), A: liquid CO2, B: Methanol, speed of flow: 120 mL / min, wavelength: 220 nm, sample loading: 100 mg / injection, inlet pressure: 200-210 bar, cycle time: 3.5, run time: 10. In total, ( 51.0 g of isomer mixture) was separated by SFC to obtain 6((2-chloro-5,7-difluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile (Intermediate 1, peak 1) and 6 -((2chloro-4,6-difluoro-lH-benzo[d]imidazol-lyl ) methyl ) nicotinonitrile (Intermediate 2, peak 2) as yellow solids. Peak 1:1H NMR (400 MHz, DMSO-ds) : δ 8.90 (d, J = 2.0 Hz, 1H), 8.37 (dd, J = 8.2, 2.1 Hz, 1H) , 7.70 (d, J = 8.2 Hz, 1H), 7.42 (dd, J = 9.0, 2.2 Hz, 1H) , IF-2019-169515 62-A PN-AN P# l?)^ Page 193 of 557 7.22 (ddd, J = 11.9, 10.3, 2.2 Hz, 1H), 5.79 (s, 2H). MS (ESI, pos. ion) m / z: 304.0 [M+l]. Peak 2:XH NMR (400 MHz, DMSO-d6) : δ 8.91 (t, J = 3.0 Hz, 1H), 8.37 (ddd, J = 8.2, 4.4, 2.1 Hz, 1H), 7.67 (dd, J = 8.4, 4.2 Hz, 1H), 7.49 (dt, 5 J = 8.7, 3.0 Hz, 1H), 7.20 ( tdd, J = 10.7, 4.5, 2.1 Hz, 1H), 5.79 (d, J = 3.8 Hz, 2H). MS (ESI, pos. ion) m / z: 304.0 [M+l]. The following intermediates were synthesized using a sequence analogous to that used to synthesize the 10 Intermediates 1 and 2 and General Scheme 7 above: Table 1. Rented intermediates Int. Structure Compound name 1H NMR MS MH+ Separation conditions 1 z 6-((2-chloro- 5,7-difluoro- 1H- benzo[d]imidazo 1-1- 11)methyl)nicoti nonitrile m NMR (400 MHz , DMSOd6) : δ 8.90 (d, J = 2.0 Hz, 1H) , 8.37 (dd, J = 8.2, 2.1 Hz, 1H) , 7.70 (d, J = 8 .2 Hz, 1H), 7.42 (dd, J = 9.0, 2.2 Hz, 1H), 7.22 (ddd, J = 11.9, 10.3, 2.2 Hz, 1H) , 5.79 (s, 2H) 304.0 Column Lux C4, MeOH 30%, peak 1 2 NC n Ρχ^^Ν 1 JL Gci F 6- ( (2-chloro- 4,6-difluoro- 1H- benzo [d]imidazo 1-1-yljmethyl)nicoti nonitrile 4.4, 2.1 Hz, 1H), 7, 67 (dd, J = 8.4, 4.2 Hz, 1H), 7.49 (dt, J = 8.7, 3.0 Hz, 1H) ), 7.20 (tdd, 0 = 10.7, 4.5, 2.1 Hz, 304.0 Column Lux C4, MeOH 30%, peak 2 IF-2019-169515 62-APN-ANP# Wi Page 194 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 1H), 5.79 (d, J = 3.8 Hz, 2H) 3 NC or Il JL / >~ci 6-((2,6- dichloro-lHbenzo [d]imidazo 1-1-yl)methyl)nicoti nonitrile m NMR (400 MHz, DMSOde) : δ 8.90 (dd, J = 2.1, 0.9 Hz, 1H) , 8.36 (dd, J = 8.2, 2.2 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.29 (dd, J = 8.6, 2.1 Hz, 1H), 5.79 (s, 2H) 303.0 YMC Amyose SA, Methanol THE (70:30) 40%; peak 1 4 NC V Il Jl J~CI 6-((2,5dichloro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 1H NMR (400 MHz, DMSOd6) : δ 8.90 (d, J = 2.1 Hz, 1H), 8.35 (dd, J = 8.2, 2.1 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.66 - 7 .55 (m, 2H), 7.33 (dd, J = 8.7, 2.1 Hz, 1H), 5.79 (s, 2H) 303.0 YMC Amyose SA, Methanol THE (70:30) 40%; peak 2 5 NC o ü JL / >~CI 6-((2-chloro-6- fIuoro-1Hbenzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 1H NMR (400 MHz, DMSOd6) : δ 8, 93 - 8.86 (m, 1H), 8.34 (dd, J = 8.2, 2.1 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.54 (dd, J = 9.2, 2.6 Hz, 1H), 7.17 - 7.06 (m, 1H), 5.75 (s, 2H) 287.0 YMC Amyose SA, Methanol THE (70:30) 40 %; peak 1 6 NC o N-\ δ 8.90 (d, J = 2.3 Hz, 1H), 8.34 (dt, J = 8.0, 2.3 Hz, 1H), 7.59 (tq, J = 7.5, 2 .2 Hz, 2H), 7.48 (dq, J = 287.0 YMC Amyose SA, Methanol THE (70:30) 40%; pica IF-2019-169515 62-A PN - AN P# IW Page 195 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 9.5, 2.4 Hz, 1H), 7.24 - 7.05 (m, 1H), 5.77 (s, 2H) 2 7 NC A n [I A / >”CI 6-((2-chloro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 1H NMR (400 MHz, DMSOd6) : δ 8.92 (d, J = 2.1 Hz, 1H), 8.34 (dd, J = 8.1, 2.1 Hz, 1H), 7.67 - 7.54 (m, 3H), 7.30 - 7.245 (m, 2H), 5 .76 (s, 2H) 269.2 -- 8 NC o N-\ í X ^ci cf3 6-((2-chloro-4- (trifluoromethyl)-IH- benzo[d]imidazo 1-1-yl) methyl)nicoti nonitrile — 337.2 — 9' NC or nA Tl T >~CI 'n^n 6-((2,6dichloro-lHimidazo[4,5b]pyridin-1yl)methyl)nicoti nonitrile -- 304.0 Separation into final product 10 NC 0, β JL / >“c' CN 2-chloro-l-((5cyanopyridin-2ylmethyl)-IHbenzo [d]imidazo 1-4carbonitrile -- 294.0 -- 11 NC u Fx^^ n Ü 1 J~CI \^^·Ν CN 2-chloro-l- ((5cyanopyridin-2yl)methyl)-6fluoro-lHbenzo[d]imidazc 312.2 — IF-2019-169515 62-APN-ANP#IlW Page 196 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 1-4- carbonitrile 12a NC u T JL '>~ci 6- ( (2-chloro-6(trifluoromethox i)-1H- benzo[d]imidazo 1-1 - yl)methyl)nicoti nonitrile -- 353.2 Separation into final product 13a Cl O MeC^S N 1 JL / >~ci 2-chloro-l-((5chloropyridin-2yljmethyl)-6(methylsulfonyl) -1H- benzo[ d]imidazo 1 -- 357.8 Separation into final product 14 S^J^° or 2-chloro-l-((5chloropyrimidin2-yl)methyl)-6fIuoro-1Hbenzo[d]imidazo 1-4carbonitrile — 323.8 — 15a R. O N-\ and JL / )-01 F 2-chloro-4,6difluoro-1-((5fluoropyridin2-yl)methyl)-1Hbenzo[d]imidazo 1 — 298.0 Separation into final product 16a R / N IJ N--\ y JL ^~c< F 2-chloro-4,6- difluoro-1-((5fluoropyrimidin -2-yl)methyl)- 1H- benzo[d]imidazo — 299.0 Separation into product final IF-2019-169515 62-APN-ANP#IW Page 197 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 1 17a ci f N 'ν-Λ y JL / >“ci 2-chloro-l-((5chloropyrimidin- 2-yl)methyl)-6- fluoro-IH- benzo [d]imidazo 1 -- 297.0 Separation into final product 18 R / N u f'Vx^<n y JL ^)-01 CN 2-chloro-6- fluoro-1-((5- fluoropyrimidin -2- il)methyl) - 1H- benzo[d]imidazo 1-4- carbonitrile -- 306.2 -- 19' z or hi xz ? 6- ((2-chloro-6- (trifluoromethyl)-IH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile -- 337.0 Separation into final product 20' Q 6-( (2.5 - dichloro-6- methyl-lH- benzo[d]imidazo 1-1- yl(methyl)nicoti nonitrile -- 317.0 Separation into final product 21' NC / N HF2C0\<^^N / T JL / >~ CI Χίί^Ν 6-((2-chloro-6- (difluoromethoxy )-IH- benzo[d]imidazo 1-1-yl)methyl)nicoti — 335.0 Separation into final product IF-2019-169515 62-APN-ANP#! W8 Page 198 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions nonitrile 22 NC / N Ο Λ / )“CI OMe 6-((2-chloro-4methoxy-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile - - 299.2 Separation in final product 23 NC ! N β JL / >~ci Me 6-((2-chloro-4- methyl-lH- benzo[d]imidazo 1-1- yljmethyl)nicoti nonitrile — 283.2 — 24a NC / N U T / )-01 6- ((2-chloro-6- methoxy-lHbenzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile — 299.2 Separation into final product 25a NC / N F'VZ<5^N I Σ ')“C| f3c^^n 6-((2-chloro-6- fluoro-5(trifluoromethyl)-IH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile -- 355.0 Separation in final product 26 a NC / N vj? I JL ^~a f3cx^íí^n 6-((2,6- dichloro-5(trifluoromethyl )-IH- benzo [d] imidazo 1-1- yljmethyl)nicoti nonitrile — 371.0 Separation into final product IF-2019-169515 62-A PN - AN P# IW Page 199 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 27 ' NC Γ N JL A F3ccr^^^ 6-((2,6- dichloro-5- (trifluoromethox i)-IH- benzo[d]imidazo 1-1 - 11)methyl)nicoti nonitrile — 387.0 Separation into final product 28 NC or N\ I A ACI C|N 6-((2,5,6trichloro-lHbenzo[d]imidazo 1-1-yljmethyl)nicoti nonitrile — 337 ,0 -- 29 NC Q Il JL / >~ciF-^Xi^N 6- ( (2-chloro- 5,6-difluoro- 1H- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile - - 305.1 — 30 ci o nA 6 A ^~a 2-chloro-l-((5chloropyridin-2yl)methyl)-IHbenzo [d]imidazo 1 — 278.2 -- 31a NC o n-A U A AC| 'N F 6-((2-chloro- 4,6-difluoro- 1H- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile — 305.2 Separation into final product IF-2019-169515 62-A PN-AN P# I WO Page 200 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 32 NC or Ti t / )-° N Cl 6-((2,4- dichloro-6- fluoro-lHbenzo[d]imidazo 1-1- yl)methyl) nicoti nonitrile -- 321.0 -- 33a NC q Il J -^Cl 2-chloro-l-((5cyanopyridin-211)methyl)-IHbenzo [d] imidazo 1-6carbonitrile -- 294.0 Separation into final product 34 ' NC ,V F\X^5r-'N T I / >”CI 6-((2-chloro-6fluoro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile — 287.0 Separation into final product 35 2 2 Φ <0 Ujs' o 6-((2-chloro- 5,6-dimethyl-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile -- 297.0 — 36 NC o n-\ u JL i~Ci Cl 6-( (2,4,6- trichloro-lHbenzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile -- 336.8 — 37' z o ^'X ^z z 6-((2 ,6- dichloro-lHbenzo[d]imidazo 1-1- — 304.0 Separation into final product IF-2019-169515 62-APN-ANP#IWI Page 201 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions yl)methyl)nicoti nonitrile 38 o Z 6-((2,4dichloro-lHbenzo[d)imidazo 1-1- yljmethyl)nicoti nonitrile — 304.2 — 39a z υ ^“Z sz 0 z 2-chloro-l-((5cyanopyridin-2yljmethyl)-1Hbenzo[d]imidazo 1-6carbonitrile -- 294.2 Separation into final product 40a 2 0 N o z 6-((2-chloro-6 - methyl-lH- benzo[d]imidazo 1-1- yljmethyl)nicoti nonitrile — 283.2 Separation into final product 41a z y o z 6-((2-chloro-5- fluoro-6-methyl- 1H- benzo[d] imidazo 1-1-yl)methyl)nicoti nonitrile -- 301.2 Separation into final product 42 a —N V-CN / A j N ΐ X , / ~a 5-((2-chloro-6- (trifluoromethyl 1 -1H- benzo[d]imidazo 1-1- yl)methyl)pyrazi n-2- carbonitrile — 338.2 Separation into final product IF-2019-169515 62-A PN-AN P# I®J2 Page 202 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 43 z ^z^z LL U. 5- ((2-chloro- 5,6- difluoro- 1H- benzo[d]imidazo 1-1- yl)methyl) pyrazi n-2- carbonitrile -- 306.2 — 44 a NC A ü 1 / )“CI 4-((2-chloro-lHbenzo[d]imidazo 1-1- yl)methyl)benzon ytrile -- 268.2 — 45 ' NC θ F-^ / ^r-N 1 JL / >~ci F 4- ( (2-chloro- 4,6-difluoro- 1H- benzo[d]imidazo 1-1- yl)methyl)benzon ytrile - - 304.2 Separation in final product 46 · φσ5 or 2-chloro-l-(4- cyanobenzyl)- 1H- benzo[d]imidazo 1-6- carbonitrile -- 293.2 Separation in final product 47 a NC / N , H T JZ Cl 2- ((2-chloro-6fluoro-lHbenzo[d]imidazo 1-1-yl)methyl)pyrimi din-5- carbonitrile — 288.2 Separation into final product IF-2019-16951562-ΑΡΝ-ΑΝΡ#Π2ΚΒ Page 203 of 557 Int. Structure Compound name 1H FMN MS MH+ Separation conditions 48 a MeO / N, [Í JJ ^”ci 2-chloro-6fluoro-1-(tome toxypyrimidin -2-yl)methyl) - IH- benzo[d]imidazo 1 -- 293.2 Separation in final product 49 a Month N^X / CF3Oí\ T JT c| 2-(2-chloro-6- fIuoro-1Hbenzo[d]imidazo 1-1-yl)-Nmethyl-N-(2,2,2-trifluoroethyl)a cetamide — 324.2 Separation into final product 50 ' Month N —\ V cf3os5\ 11JC ci 2-(2-chloro-6methoxy-lHbenzo[d]imidazo 1-1-yl)-Nmethyl-N-(2,2,2trifluoroethyl)a cetamide -- 336.0 Separation into final product 51 a 2 ® O 01 / Z^ / ^Z Y 2-(2-chloro-6methoxy-lHbenzo[d]imidazo l-l-yl)-N,Ndimethylacetamid a -- 268.2 Separation into final product 52 Month N--\ 7 CF3 P ° ) FxYzZ^r*N y I / >~CI N CN 2- (2-chloro-4cyano-6-fluoro1H- benzo[d]imidazo 1-1-yl)-N- methyl-N-( 2,2,2trifluoroethyl)a cetamide -- 349.2 IF-2019-169515 62-APN-ANP# IW4 Page 204 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 53 a Mex N—\ / cf3 y JL / )-01 OMe 2-(2-chloro-6fluoro-4methoxy-lHbenzo[d]imidazo 1-1-yl)- N- methyl-N- (2,2,2trifluoroethyl)a cetamide -- 354.2 Separation into final product 54 a NC υ F3CX^N^N I cl 6-((2-chloro-5(trifluoromethyl) -3H- imidazo [4,5- b]pyridin-3yl)methyl)nicoti nonitrile -- 338.2 Separation into final product 55 a O ° β ¿5 1- (azetidin-1yl)-2-(6-bromo- 2-chloro- lHbenzo[d]imidazo 1-1-yl)ethanone — 329.2 Separation into final product 56 at 1 ^z° or 2-(2-chloro-6(trifluoromethyl)-lH- benzo[d]imidazo 1-1- 11)-1- morpholinoetanon a — 348.2 Separation in final product 57 ' O Mi; Z. Z^ / ^Z T s o φ 2-(2,6-dichloro- 1H- benzo[d]imidazo l-l-yl)-N,N- dimethlacetamide — 273.0 Separation into final product IF-2019-169515 62-A PN-AN P# Page 205 of 557 Int. Structure Compound name 1H NMR MS MH+ Separation conditions 58 a O o 0 o ZVZ-^ 1 s o ° 2-(2-chloro-6(trifluoromethox i)-1H- benzo[d]imidazo 1-1-yl) -N,N- dimethylacetamid a — 322.2 Separation into final product 59 ' 1 ^ / ° or 2- (2-chloro-6(trifluoromethox i)-lH- benzo[d]imidazo 1-1-yl)-1 - morpholinoethane a -- 264.2 Separation in final product [a] Mixture of isomers formed through nonselective benzylation that separated into the final product or penultimate intermediate. Scheme 8. Advancement of rented intermediates to final products iPrsE IN, OMSO □ ,Ί-bulanol TiFA or HCI ----► IF-2019-169515 62-APN-ANP#I®lfó Page 206 of 557 Example 38: 6-((2-((3R,4R)-3-amino-4-fluoropiperidinyl-yl)-IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile DMSO 130°C Step 1. ((3R,4R)-1-(1-((5-cyanopyridin-2-yl)methyl)IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-yl)carbamate tere-butyl 1,1'-dimethyltriethylamine (1.300 ml, 7.44 mmol), terebutyl ((3R, 4R)-4-fluoropiperidin-3-yl)carbamate (0.975 g, 4.47 mmol), 6-(( 2-chloro-lHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile (Intermediate 7, 1 g, 3.72 mmol) and dimethyl sulfoxide (7.44 ml) in a flask and heated to 130 °C for 36 hours . The mixture was cooled, poured into water and then extracted with EtOAc (3X). The organic elements were combined, dried over Na2SO4, filtered and concentrated. The crude material was loaded onto an 80 g RediSep ISCO cartridge, eluting with 10-50% EtOAc in heptanes to provide ((3R,4R)-1-(1-((5-cyanopyridin-2-yl) tere-butyl methyl)-1Hbenzo[d]imidazol-2-yl)-4-fluoropiperidin-3-yl)carbamate as a light orange foam. MS (ESI, pos. ion) m / z: 451.2 [M+l] Note: n-butanol is a competent substitute for DMSO. IF-2019-169515 62-A PN-AN P# Page 207 of 557 It was necessary to heat the difInorated piperidines until 150°C. Boc deprotection procedure with TFA (Procedure B) NC NC DCM NH2 HN-Boc Step 2. 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-lyl) -IH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile (Example 43) Tere-butyl ((3R,4R)-1-(1-((5-cyanopyridin-2yl)methyl)-IH-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3yl)carbamate was dissolved 1.31 g, 2.91 mmol, 1 equiv.) in DCM (10 mL) and allowed to drip slowly into a chilled (0 °C) TEA flask (~10 mL). After 1 hour, deprotection was completed. The mixture was poured onto an SCX column (pre-wetted with MeOH), rinsed with MeOH, and then eluted with methanolic ammonia. The methanolic ammonia was concentrated, and the light orange oil was redissolved in MeCN / water, frozen, and lyophilized to provide the title compound as a light yellow solid.1H NMR (500 MHz, MeOD) δ 8.81- 8.92 (m, 1H), 8.23 ​​(dd, J=8.30, 2.08 Hz, 1H), 7.49-7.66 (m, 2H), 7.17-7, 39 (m, 3H), 5.64 (s, 2H), 4.69-4.86 (m, 1H), 3.92IF-2019-169515 62-APN-ANP#I^®§ Page 208 of 557 4.06 (m, 1H), 3.61-3.79 (m, 2H), 3.20-3.32 (m, 2H), 2.242.41 (m, 1H), 1.92-2, 14 (m, 1H). (ESI, pos. ion) m / z: 351.2 [M+l]. Example 45: 6-((2-((3R,4R)-3-amino-4fluoropiperidin-l-yl)-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride Intermediate 6 ---► DMSO 130CC Step 1. (1-(1-((5-cyanopyridin-2-yl)methyl)-5-fluoro10 lH-benzo[d]imidazol-2-yl)piperidin-3-yl)carbamate of (S)tert- butyl (S)-tert-butyl piperidin-3-ylcarbamate (115 mg, 0.576 mmol) was added to a suspension of 6-((2-chloro-6fluoro-IH-benzo[d]imidazol-l-yl)methyl) nicotinonitrile (150 mg, 0.523 mmol) and Hunig base (137 μΐ, 0.785 mmol) in 1butanol (2093 μΐ). The reaction was stirred at 130 °C overnight. After 24 hours, the reaction mixture was concentrated and purified by column chromatography, eluting with 20-100% ethyl acetate in heptanes. IF-2019-169515 62-A PN-AN P# IW Page 209 of 557 to provide the title compound as an off-white solid. (ESI, pos. ion) m / z: 451.2 [M+l] Deprotection of Boc with HC1 (Procedure A) HC1 in dioxane (S)-6-((2-(3-aminopiperidin-l-yl)-5fluoro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile hydrochloride (Example 51) Step 2. (l-(l-((5-cyanopyridin-2yl)methyl)-5-fluoro-lH-benzo[d]imidazol-2-yl)piperidin-3yl)carbamate of (S)-tere- was dissolved. butyl (77 mg) in dioxane (2 mL), and 4 N HC1 in dioxane (585 pL, 2,340 mmol) was added. The reaction mixture was stirred at room temperature. After 16 hours, LC / MS analysis showed that the reaction was complete. The reaction mixture was concentrated in vacuo to give the title compound as an off-white solid. 1H NMR (400 MHz, dg-DMSO) δ 8.94 (s, 1H), 8.48 (br s, 2H), 8 .40 (dd, J=2.18, 8.19 Hz, 1H) , 7.77 (d, J=8.19 Hz, 1H) , 7.40 (dd, J=2.85, 8.66 Hz, 2H), 7.14 (dt, <J=2.38, 9.33 Hz, 1H), 5.65-5.84 (m, 2H), 3.89 (br d, J=10, 57 Hz, 1H), 3.28-3.52 (m, 3H), 3.18 (br t, J=9.80 Hz, 1H), 1. 94-2.02 (m, 1H), 1 .81-1.93 (m, 1H), 1.47-1.72 (m, 2H). (ESI, pos. ion) m / z: 351.0 [M+l]. IF-2019-169515 62-APN-ANP#E2F® Page 210 of 557 Note: HC1 salt was occasionally converted to a free base form with aqueous processing or ion exchange chromatography. The isolation of the salt or free base is specified in the table. The following compounds were produced in a manner analogous to that described above: Example 8: 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-lyl) -6-chloro-lH-benzo[d]imidazol-l-yl)methyl)nicotinonitrile 6-((2-((3R,4S)-3-amino-4-fluoropiperidinyl-yl)-6-chloro-lH-benzo[d]imidazol-lyl )methyl) nicotinonitrile was synthesized on a scale of 1 mmol followed of a procedure analogous to the sequence described above with the deprotection of Boc from TFA (procedure B). Boc separated in the middle: Chiralcel OD-H, IPA 25%, peak 1.XH NMR (500 MHz, MeOD) δ 8.86 (d, J=l,30 Hz, 1H), 8.14-8.20 (m, 1H), 7.47 (d, J=8.56 Hz, 1H), 7.44 (d, J=8.30 Hz, 1H), 7.23 (d, J=2.08 Hz, 1H), 7.19 (dd, J=l.95, 8.43 Hz, 1H) , 5.53 (s, 2H) , 4.33-4.50 (m, 1H) , 3.53-3.61 ( m, 1H), 3.43-3.50 (m, 1H), 3.02-3.20 (m, 2H), 2.95 (dd, J=8.69, 12.33 Hz, 1H) , 2.12-2.24 (m, 1H) , 1.82-1.94 (m, 1H). (ESI, pos. ion) m / z: 387.2 [M+l]. IF-2019-169515 62-APN-ANP#E5Pf Page 211 of 557 Example 93: (R)-6-((2-(3-amino-4,4-difluoropiperidinyl-yl)-6-fluoro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile (R)-6-((2-(3-amino-4, 4-difluoropiperidinyl-yl)-6-fluoro-lH-benzo[d]imidazol-lyl )methyl) nicotinonitrile was synthesized on a scale of 1.9 mmol, followed by a procedure analogous to the sequence described above with deprotection of Boc from TFA (method B). The intermediate chlorobenzimidazole (YMC Amyose SA, Methanol THF (70:30) 40%; peak 1) was separated. 8.15 (dd, J=2.08, 8.30 Hz, 1H), 7.40-7.52 (m, 2H) ,6,917.00 (m, 2H), 5.47-5.62 ( m, 2H), 3.34-3.54 (m, 2H), 3.083.28 (m, 3H), 2.21-2.36 (m, 1H), 2.00-2.21 (m, 1H).(ESI, pos. ion) m / z: 351.0 [M+l]. The examples in Table 2 were synthesized by a sequence analogous to that used to synthesize Examples 38, 45, 8 and 88 and Scheme 8 above: Table 2. Compounds made according to Scheme 8 Boc deprotection procedure: A = IF-2019-16951562-A PN-A N P# Page 212 of 557 HC1 procedure, B = TFA procedure Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 1 37 ^^.<NHBoc H B NC o / \---< nh2 ¢5)-6-((2-(3- aminopiperidin1-yl)-6-chloro1H- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 367.0 2 37 ^^..NHBoc H B NC or n^A. XX'+O nh2 ¢5)-6-((2-(3- aminopiperidin- 1-yl)-5-chloro- 1H- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 367.0 3 38 ^^.NHBoc H B nc O N-\ Q>O Cl 'NH2 (S)-6-((2-(3aminopiperidin1-yl)-4-chloro1H- benzo[d]imidazo 1-1- yl)methyl) nicoti nonitrile 367, 0 4 38 F Jx <NHBoc H B NC O n-A rx^r'N / —\ y JL / ~F \^-N 5-( Cl ''NH2 6-((2-((3R,4R )- 3-amino-4- fluoropiperidin -1-yl)-4-chloro- 1H- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 385.0 IF-2019-16951562-A PN-A N P# Page 213 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 5 38 F Js. ..NHBoc H B NC o n-A O>o-F Cl ”'NH2 6-((2-((3R,48)- 3-amino-4fluoropiperidin -1-yl)-4-chloro- 1H- benzo[d]imidazo 1 -1- iDmethyl) nicoti nonitrile 385.0 6 37 F J^-NHBoc H B NC ft, CI-χ^Ν Tl Γ / >-N >-F >----( nh2 6- ( (2-((3R .4R)- 3-amino-4- fluoropiperidin -1-yl)-6-chloro- 1H- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 385.0 7 37 F JL .NHBoc H B NC ft , ^S^N / -\ j T Z>-N >-F nh2 6-((2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5-chloro- 1H- benzo [d]imidazo 1-1- yl)methyl)nicoti nonitrile 385.0 8 37 F tlNHBoc H B NC ft / f nh2 6-(¢2-((3R,4S)- 3-amino-4- fluoropiperidin -1- il)-6-chloro- 1H- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 385.0 IF-2019-16951562-APN-ANP#IW Page 214 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 9 37 F Jx-NHBoc H B NC n n-A jO><> nh2 6-((2-((3R,4S)- 3-amino-4- fluoropiperidin -1-yl )-5-chloro1H- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 385.0 10 38 F. F .NHBoc H B NC o N-\ <YNV Ή / y I / >-n xl \- --( r Cl 'NH2 (R)-6-((2-(3- amino-4,4- difluoropiperid in-l-yl)-4- chloro-lH- benzo[d]imidazo 1-1- il )methyl)nicoti nonitrile 403.0 11 10 F ,4NHBoc H B NG o n-\ N / —\ y T n / f L^'-n \--f CN NH2 2- ( (3R,4R)-3amino- 4fluoropiperidin -l-yl)-l-((5cyanopyridin-2yljmethyl)-IHbenzo [d]imidazo 1-4carbonitrile 376, 0 12 37 F. F ..NHBoc H B NC o nA Ύ T / >~N. XF nh2 (R )-6-(¢2-(3- amino-4,4- difluoropiperid in-l-yl)-6- chloro-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 403.0 IF-2019-169515 62-APN-ANP#Mf$ Page 215 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 13 37 F. F 34 tNHB0C H B NC q li 1 )-5chloro-lH- benzo[d]imidazo 1-1- yl )methyl)nicoti nonitrile 403.0 14 19 F ..NHBoc H B NC Q F3CX,X^N Ti T z>-n >-f >-- --( nh2 6- ( (2-((3R,4R)- 3-amino-4- fluoropiperidin -l-yl)-6- (trifluoromethyl )-lH- benzo[d]imidazo 1-1- yl )methyl )nicoti nonitrile 419.0 15 19 F ...NHBoc ^NF H B NC A n / —\ í J / >“Nx / “F f3cx^a'n '— nh2 6-((2-((3R,4R )- 3-amino-4- fluoropiperidin -l-yl)-5- (trifluoromethyl )-lH- benzo[d]imidazo 1-1- yl)methyl) nicoti nonitrile 419.0 16 7 F ^Á^NHBOC H B NC O N^X. ex x~NC~^,F nh2 6-((2-({3S, 4S) - 3-amino-4- fluoropiperidin -1-yl)-1H- benzo[d]imidazo 1-1- il) methyl) nicoti nonitrile 351.2 IF-2019-169515 62-ΑΡΊ N-ANP#I@Í9 Page 216 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 17 7 .NHBoc F”l I H B NC o nA f OO nh2 (3)-6-((2-(5- amino-3,3- difluoropiperid in-l-yl )-1Hbenzo[d]imicazo 1-1-yl)methyl)nicoti nonitrile 369.2 18 11 F J. ...NHBoc H B NC or n-A / ----. Tl T / >-N >-F '---( CN ''NH2 2-((3R,4R)-3- amino-4- fluoropiperidin -l-yl)-l-((5- cyanopyridin-2- il)methyl)-6- fIuoro-1H- benzo[d]imidazo 1-4- carbonitrile 394.4 19 12 F J^-NHBoc H B NC 4 # N-\ F3C0^^^N / V y T / ~F \ ίί^·Ν ' ( nh2 6-((2-((3R,4R)3-amino-4- fluoropiperidin -1-11)-6- (trifluoromethox i)-lH- benzo[d]imidazo 1-1- il)methyl)nicoti nonitrile 435.4 20 12 F JL ,NHBoc H B NC A ix^NT-'N / —\ fi JL / >-N\ / F f3c<t — N '— nh2 6-((2- ((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5- (trifluoromethox i)-IH- benzo [d]imidazo 1-1- yl)methyl)nicoti 435.4 IF-2019-16951562-APN-ANP#IW Page 217 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH 1 nonitrile 21 25 F J. .NHBoc H B NC A I JL / >“Nv z~F F3CxA^A'N X nh2 6-( (2-((3R,4R) - 3-amino-4fluoropiperidin -1-yl)-6- fluoro-5- (trifluoromethyl ) -1H- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 437.0 22 25 F ..NHBoc H B NC n nA F3CyVN Ii JL / F nh2 6- ( (2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5- fluoro-6- (trifluoromethyl ) -IH- benzo[d] imidazo 1-1-yl)methyl)nicoti nonitrile 437.0 23 7 H B NC or n-A. O>Cb hr H 6-((2- ( (3aS,7aR)hexahydro-lHpyrrolo[2,3c]pyridin- 6(2H)-yl)-IH- benzo[d]imidazo 1-1- yl)methyl) nicoti nonitrile 359.2 IF-2019-169515 62-A PN-AN P# I^fg Page 218 of 557 Ex. No. Inter middle lease side Amina Proce dim. despr otec tion Boc Structure Compound name MS MH+ 24 7 UsyN-BOC H B NC o Η 1 / >-n )...... N '---< \ H 6-((2- ((3aS, 7aS) hexahydro-lHpyrrolo[2,3c]pyridin- 6(2H)-yl)-IHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 359.2 25 7 ^AyN'BOC ^ff H B NC or [ 1 1 / >-N \^--N '--< \ ir H 6-((2- ((3aS,7aS)hexahydro-lHpyrrolo[2,3c]pyridin- 6(2H)-yl)-1Hbenzo[ d]imidazo 1-1- yl)methyl)nicoti nonitrile 359.2 26 7 JsyN-B0C ^FT H B NC o n-N fi Γ Z>-N >- \^~n >—ς J H 6-((2- ( (3aS,7aR)hexahydro-lHpyrrolo[2,3c]pyridin- 6(2H)-yl)-IHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 359.2 27 7 | pNBoc H B NC or Ν-Λ. 0>O HÑ-J (R)-6-((2-(1,6diazaspiro[3.5 ]nonan-6-yl)IH- benzo[d]imidazo 1-1-yl)methyl)nicoti 359.2 IF-2019-16951562-APN-ANP#IÍ® S Page 219 of 557 Ex. No. Inter middle rent side Amina Proce dim. depr otection Boc Structure Compound name MS MH + nonitrile 28 7 | p-NBoc H B Γ rz I J 1 Ά8 ¢3)-6-((2-(1,6- diazaspiro[3.5 ]nonan-6-yl) - 1H- benzo[d]imidazo 1-1- yl)methyl) nicoti nonitrile 359.2 29 13 F Js. .NHBoc H B Cl o Ύ )-4- fluoropiperidin -3-amine 438.0 30 13 F Js^^NHBoc H B Cl o N-*\ fi JL z>“\ / F MeO2S'^s<i^N '—. )-1-(1- ¢(5- chloropyridin-2-yl)methyl)-5(methylsulfonyl)-1H- benzo[d]imidazo l-2-yl)-4-fluoropiperidin-3-amine 438.0 31 14 F Js-NHSoc H B ci ! N N- ¡J n-A / ---V Tl Γ / >-N >-F \--( CN 'NH2 2-((3R,4R)-3- amino-4fluoropiperidin -1-11)-1-( (5chloropyrimidin2-yl)methyl)-6fluoro-lHbenzo[d]imidazo 404.0 IF-2019-16951562-APN-ANP#I®J Page 220 of 557 Ex. No. Inter middle rent side Amina Proce dim. of despr otection Boc Structure Compound name MS MH+ 1-4- carbonitrile 32 15 F JL .NHBoc H B F. O F\ ? fi JL / “F nh2 (3R,4R)-l-(5,7difluoro-1-((5fluoropyridin2-yl)methyl)-1Hbenzo[d]imidazo l-2-yl)-4fluoropiperidin -3-amine 380.0 33 15 F JL .NHBoc H B F. O F'V^><N / —\ y JL / “F ¿ nh2 (3R,4R)-1-(4,6difluoro-1-((5fluoropyridin2-yl)methyl) -1Hbenzo[d]imidazo l-2-yl)-4fluoropiperidin -3-amine 380.0 34 16 F JL ,,NHBoc H B F. / N F \ fi JL / “F nh2 (3R,4R)-1-(5 , Ίdifluoro-1-((5fluoropyrimidin -2-yl)methyl)1H- benzo[d]imidazo 1-2-yl)-4fluoropiperidin -3-amine 381.2 35 16 F Js. ..NHBoc H B ó1 z^ / 'z^z JLZ2 (3R,4R)-1-(4,6difluoro-1-((5fluoropyrimidin -2-yl)methyl)1H- benzo[d]imidazo l-2-yl )-4- fluoropiperidin 381.2 IF-20 19-169515 62-APN-ANP#HS2>I Page 221 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ -3-amine 36 18 F ^X<-NHBoc H B F. ¡ N IJ N-\ FYXK>- CN ”'NH2 2- ( (3R,4S)-3- amino-4- fluoropiperidin -1-yl)-6- fluoro-1-((5- fluoropyrimidin -2-yl)methyl)- 1H- benzo[d]imidazo 1-4- carbonitrile 338.0 37 18 F,, NHBoc ^FT H B F. / N » 11 n-A f'yX5s^n / —\ y jz / ~f >---( CN *NH2 2-((3R,4R)-3- amino-4- fluoropiperidin -1 -yl)-6- fluoro-1-((5- fluoropyrimidin -2-yl)methyl) - 1H- benzo[d]imidazo 1-4- carbonitrile 338.0 38 7 F Js ,.ΝΗΒοο XFT H B NC or n-A. n / —\ y J / >-\ / -f nh2 6-((2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-1H- benzo[d]imidazo 1 -1-yl)methyl)nicoti nonitrile 351.2 39 17 F Js..NHBoc H B Cl ¡ N Λ nh2 (3 R, 4 S) — 1 — (1— ( (5-chloropyrimidin- 2-yl)methyl )-6fluoro-lHbenzo[d]imidazo 379.2 IF-2019-1695 1562-APN-ANP#ΙΓ222 Page 222 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 1-2-yl)-4- fluoropiperidin -3-amine 40 17 F ..NHBoc H B Cl / N XA pXZ'N '- nh2 (3 R, 4 S) — 1 — (1 — ( (5-chloropyrimidin2-yl)methyl)-5fluoro-lHbenzo[d]imidazo 1-2-yl)-4- fluoropiperidin -3-amine 379.2 41 39 F. F 54. ,,NHBoc H B Cl / N 6carbonitrile 404.2 42 39 F. F 54 ...NHBoc H B Cl / N \---( nh2 (R)-2-(3-amino4,4- difluoropiperid in-l-yl)-l-((5chloropyrimidin2 -yl)methyl)-1Hbenzo[d]imidazo 1-5- carbonitrile 404.2 43 28 F X.NHBOC H B NC A :x» c~ NHj 6-((2-((3R,4R)3-amino- 4- fluoropiperidin -1-yl)-5,6dichloro-lH- benzo[d]imidazo !-l- 419.0 IF-2019-169515 62-A PN-AN P# ΙΓ22Ϊ Page 223 of 557 Ex. No. Inter middle rent side Amina Proce dim. of despr otection Boc Structure Compound name MS MH+ il)methyl)nicoti nonitrile 44 35 F A..,NHBoc H B NC n n-A / —\ j J Z^N )-F \—ζ nh2 ((3R,4R)- tert-butyl 1-(1((5-cyanopyridin-2yl)methyl)-5, 6dimethyl-lHbenzo[d]imidazo 1-2-ID-4fluoropiperidin-3-yl)carbamate 379.2 45 34 ^\.NHBoc H A NC Λ HCI N-\ FO>O nh2 hydrochloride of (5)-6-((2-(3- aminopiperidin- 1-yl)-6-fluoro- 1H- benzo[d]imidazo 1-1-yl) methyl)nicoti nonitrile 351.0 46 34 / x^NHBoc H A NC N ,cco nh2 hydrochloride of (5)-6-((2-(3aminopiperidin1-yl)-5-fluoro1H- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 351.0 47 34 F A^NHBoc H A NC , V ο>ο· nh2 6-((2-((3R,4S) - 3-amino-4- fluoropiperidin -1-yl) hydrochloride -6fluoro-lH- benzo[d]imidazo 369.0 IF-2019-169515 62-A PN-AN P# Μ Page 224 of 557 Ex. No. Intermediate rental side Amine Process dim. Boc desprotect ion Structure Compound name MS MH+ 1-1-yl)methyl)nicoti nonitrile 48 34 F .NHBoc H A NC A nh2 6-((2-((3R,4S)- 3-amino-4fluoropiperidin hydrochloride -1-yl)-5- fluoro-lH- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 369.0 49 34 F A-^NHBoc Η A NC ti j X άν A nh2 hydrochloride of 6- ((2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5- fluoro-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 369.0 50 5 F A .»NHBoc ''Ίψ H A NC A tXH> nh2 hydrochloride of 6-((2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5- fluoro-lH- benzo[d ]imidazo 1-1-yl)methyl)nicoti nonitrile 369.0 IF-2019-169515 62-A PN-AN P# I®23 Page 225 of 557 Ex. N. 0 Inter medium rented side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ 51 33 / x-NHBoc H B NC nh2 (3)-2-(3aminopiperidinl-yl)-I-(iS- ci anopy r idin — 2 — yljmethyl)-IHbenzo [d ]imidazo 1-6carbonitrile 358.0 52 33 / \.sNHBoc H B NC nh2 (3)-2-(3- aminopiperidin1-11)-1-((5-cyanopyridin-2yljmethyl)-1Hbenzo[d]imidazo 1-5carbonitrile 358.0 53 33 F A.NHBOC H B NC 6 'OK- NH2 2- ( (3R,4R)-3amino-4fluoropiperidin -l-yl)-l-((5cyanopyridin-2yljmethyl)-1Hbenzo[d]imidazo 1- 6carbonitrile 376.0 54 33 F Λ-NHBoc ^l\F H B NC „£Χλν1>nh2 2- ( (3R,4R)-3amino-4fluoropiperidin -1-11)-1-((5cyanopyridin-2yljmethyl)-1Hbenzo[d ]imidazo 1-5carbonitrile 376.0 IF-2019-169515 62-A PN-AN P# 1826 Page 226 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 55 33 E F >1XNHBoc H B NC nh2 (R)-2-(3-amino- 4, 4- difluoropiperid in-l-yl)-1-((5- cyanopyridin- 2yl)methyl)-1Hbenzo[d]imidazo 1-6carbonitrile 394.0 56 33 E F 34 ,'NHBoc H B NC jama nh2 (R)-2-(3-amino- 4,4- difluoropiperid in-l-yl)- 1-{(5cyanopyridin-2yljmethyl)-1Hbenzo[d]imidazo 1-5- carbonitrile 394.0 57 36 / ^.NHBoc H B NC. N ci nh2 ¢3)-6-((2-(3aminopiperidinl-yl)-4,6dichloro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 401.0 58 36 F A ...NHBoc H B NC A M><> Cl NH2 6- ( (2-((3R,4R)- 3-amino-4fluoropiperidin -l-yl)-4,6dichloro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 419 ,0 IF-2019-169515 62-A PN-AN P# ΙΪ2Ρ7 Page 227 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 59 36 F ,0NHBoc H B NC u>Q* Cl Nh2 6-((2-((3R,4S)3-amino-4- fluoropiperidin -1-yl)-4 ,6dichloro-lHbenzo[d]imidazo 1-1- yl )methyl)nicoti nonitrile 419.0 60 36 E F 34 ,xNHBoc H B NC a ^l\rx^>r--N / --\ F VftO; Cl nh3 (R)-6-(¢2-(3- amino-4,4- difluoropiperid in-l-yl)-4,6dichloro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 437, 0 61 31 / ^.NHBoc H B NC C< 'pJ-O F NH2 (5)-6-((2-(3aminopiperidin1-yl)-4,6- difluoro-lH- benzo[d]imidazo 1-1- il)methyl)nicoti nonitrile 369.0 62 31 ^NHBoc ^hT H B NC ft nh2 (S)-6- ( (2-(3aminopiperidinl-yl)-5,7difluoro-lHbenzo[d]imidazo 1-1-yl) methyl)nicoti nonitrile 369.0 IF-2019-169515 62-APN-ANP#IW Page 228 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 63 31 F Λ,.ΝΗΒοε H B NC n n-A F 'NH2 6-((2-((3R,4R)- 3-amino-4fluoropiperidin -1-yl)-4 ,6- dif 1uoro-lHbenzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 387.0 64 31 F A-NHBoc H B NC » ήχ> nh2 6-((2-((3R,4R)- 3 -amino-4fluoropiperidin -l-yl)-5,7difluoro-lHbenzo[d]imidazo 1-1-yl)methyl)nicotí nonitrile 387.0 65 31 F óNHBoc n^ H B NC fXXaOf ¿ nh2 6-((2— ( (3R,4S)3-amino-4- fluoropiperidin -1-yl)-4,6- difluoro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 387.0 66 31 F A^NHBoc H B nc M ,«-O · nh2 6-((2-((3R,4S)- 3-amino-4fluoropiperidin -1-yl)-5,7difluoro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 387.0 IF-2019-169515 62-A PN-AN P# TO Page 229 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 67 31 F F 3< ,,NHBoc H B NC R .0 > or: nh2 (R)-6-((2-(3- amino-4, 4difluoropiperid in-l- il)-5,7difluoro-lHbenzo[d]imidazo 1-1- yl )methyl)nicoti nonitrile 405.0 68 33 F ^A^NHBoc H B NC N yji “χχλο·* nh2 2-((3R,4S)- 3amino-4fluoropiperidin -l-yl)-l-((5cyanopyridin-2yljmethyl)-1Hbenzo[d]imidazo 1-6carbonitrile 376.0 69 33 F >x.NHBoc H B NC 7 JXHR- nh2 2- ( (3R,4S) -3amino-4fluoropiperidin -l-yl)-l-((5cyanopyridin-2yljmethyl)-1Hbenzo[d]imidazo 1-5carbonitrile 376, 0 70 7 ..NHBoc H A NC a>o nh2 ¢3)-6-((2 -(3- aminopiperidin- 1-yl)-1H- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 333.0 IF-2019-169515 62-A PN - AN P# IKRJ Page 230 of 557 Ex · No. Intermediate rented side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 71 34 F, F 36 ,xNHBoc H A NC N f£x?Q: nh2 hydrochloride of (R)-6-(¢2-(3- amino-4 r4- difluoropiperid in-l-yl)-5fluoro-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 387.0 72 29 F Á.,,NHBoc H B NC N nh2 6-((2-((3R ,4R)- 3-amino-4- fluoropiperidin -l-yl)-5,6- difluoro-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 387.0 73 7 F 0NHBoc H A NC N VA nh2 6-((2-((3R,4S)- 3-amino-4- fluoropiperidin -1-yl)-1H- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 351.0 74 7 hn^£> h2nZ A NC 7 QN^<> 7 HCl H2N 6-((2- ( (1R,5S)- 1-(aminomethyl)- 3-azabicyclo[3.1. 0]hexan-3-yl) hydrochloride) - 1H- benzo[d]imidazo 1-1- yl)methyl)nicoti 345.2 IF-2019-169515 62-APN-ANP# WI Page 231 of 557 Ex. No. Inter medium rented .1 ado Amine Process dim. despr otection Boc Structure Compound name MS MH+ nonitrile 75 7 hnq> h2n A NC Q / VN ,—,. HCl H2N hydrochloride of 6-((2-((1S,5R)- 1-(aminomethyl)- 3- azabicyclo[3.1. 0]hexan-3-yl) - 1H- benzo[d]imidazo 1-1-yl )methyl)nicoti nonitrile 345.2 76 7 hnCiQ> nh2 A NCS / N ( T / HOT > nh2 HCl 6-((2- ((3aR,4R,6aS)- 4- aminohexahydroc iclopenta[c]pyrrol) hydrochloride -2(1H)-yl)- IH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 359.0 77 7 hn\ o nh2 A NC N O \^^N nh2 HCI hydrochloride of 6-(( 2- ((3aS,4S,6aR)- 4- aminohexahydroc iclopenta[c]pyr rol-2(1H)-yl) - 1H- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 359.0 IF-2019-169515 62-A PN - AN P# IKJ2 Page 232 of 557 Ex. No. Intermediate rental side Amine Process dim. desprotection Boc Structure Compound name MS MH+ 78 7 nh2 A NC N N. U '-'N HCI CXOO nh2 hydrochloride of 6-((2- ( (3aR,4S,6aS) - 4- aminohexahydroc iclopenta[c ]pir rol-2(1H)-yl) - IH- benzo [d]imidazo 1-1-yljmethyl)nicoti nonitrile 359.2 79 7 h€Q nh2 A NC X; <q nh2 clorhidrato de 6-((2- ((3as, 4r,6ar)- 4- aminohexahidroc iclopenta[cj pir rol-2(1h)-il) ih- benzo [d]imidazo 1-1- il)metil)nicoti nonitrilo 359,2 80 7 ην^'ί a nc u; hc! 0><XNH2 hydrochloride of <R)-6-((2-(3- (aminomethyl)pyrrolidin-l-yl) - IH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 333.2 IF-2019-169515 62-A PN-AN P# 1^3 Page 233 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otec tion Boc Structure Compound name MS MH+ 81 7 hn] A NC 0; „c, (S)-6-ΐ(2-(3- (aminomethyl)pyrrolidin-l-yl)-1H- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile hydrochloride 333.2 82 28 F ,tNHBoc ^FF H B NC o CIYYV / ,F Ci^^N W nh2.hci hydrochloride of 6-((2-((3R,4S)- 3-amino-4fluoropiperidin -1-yl)-5,6- dichloro-lHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 419.2 83 29 F J^.NHBoc ^FF H B MC A »Η> nh2.hci 6-((2-((3R,4S) hydrochloride )- 3-amino-4fluoropiperidin -1-yl)-5,6- difluoro-lH- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 387.2 84 29 E F t.NHBoc ^FF H B NC . 3 w-o< nh2hci hydrochloride of (R)-6-((2-(3amino-4,4- difluoropiperid in-l-yl)-5,6difluoro-lHbenzo[d]imidazo 1-1- 405.2 IF-2019-169515 62-A PN-AN P# 104 Page 234 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ il)methyl)nicoti nonitrile 85 30 F. F .NHBoc H B Cl\ 7 OH>: nh2.hci hydrochloride of (R)-l-(l-((5chloropyridin-2yl )methyl)-1Hbenzo[d]imidazo l-2-yl)-4,4difluoropiperid in-3-amine 378.2 86 30 F ..NHBoc H B c'\ 3 Cellonh2.hci hydrochloride of (3R,4S) -1-(1- ((5-chloropyridin-2-yl)methyl)-1Hbenzo[d]imidazo 1-2-yl)-4fluoropiperidin -3-amine 360.2 87 31 F. F ..NHBOC H B NC or N-*\ FW\_ u JL / O 4,6- difluoro-lH- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 405.2 88 5 E F 54^NHBoc H B NC N O / oCK nh2 (R)-6-((2-(3 - amino-4,4- difluoropiperid in-l-yl)-6fluoro-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti 387.2 IF-2019-169515 62-AP1 N-ANP#IKJ3 Page 235 of 557 Ex. N. 0 Middle rented side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ nonitrile 89 8 F F trifluoromethyl )-IH- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 437.2 90 8 F Λ. .%NHBoc H A NC N CF3 NH2 6-((2-((3R,4R)- 3-amino-4- fluoropiperidin -l-yl)-4- (trifluoromethyl )-IH- benzo[d]imidazo 1-1 - yl)methyl)nicoti nonitrile 419.2 91 8 F A^NHBoc ^N^ H A NC N Qn^Of ^ψ^Ν \—< CF3NH2 6-((2-((3R,4S)- 3-amino-4 - fluoropiperidin -l-ylJ-4- (trifluoromethyl )-IH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 419.2 92 9 F J. .,'NHBoc ^N^ H A NC, A / N N' J JL >-N' / ~F x—< nh2 6-((2-((3R,4R)3-amino-4- fluoropiperidin -1-yl)-6-chloro3H-imidazo[4,5b] pyridin-3- 386.2 IF-2019-169515 62-A PN-AN P# ISJ6 Page 236 of 557 Ex. No. Intermediate rental side Amine Process dim. of despr otection Boc Structure Compound name MS MH+ il)methyl)nicoti nonitrile 93 9 F A^NHBoc H A NC M X 6-chloro- lH-imidazo[4,5b]pyridin-1yl)methyl)nicoti nonitrile 386.0 94 9 F X^NHBoc H Ab 0 N-\ H >N V-X "WO nh2 6- ( (2-((3R ,4R)3-amino-4fluoropiperidin -1-yl)-6-chloroIH-imidazo[4,5b]pyridin-1-yl)methyl)-N(tert-butyl)nicotinam ida 460.2 95 7 OH Λ %. xNHBoc H A NC A / —\ l[ ON z-°H a^^n \— / nh2 6-{¢2-((3R,4R)3-amino-4- hydroxypiperidi n-l-yl)-IHbenzo [d] imidazo 1-1-yl)methyl)nicoti nonitrile 349.2 96 7 OH A^NHBoc Η A NC °; r^í\r-N / —\ 1 L >OH x—ζ nh2 6-((2-((3S .4Ξ)- 3-amino-4hydroxypiperidi n-l-yl)-IHbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 349.2 IF-2019-16951562-A PN-A N P# Μ Page 237 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 97 7 i—NBoc hr H A NC N L £ MX 6-((2-(2,6diazaspiro[3.4 ]octan-6-yl)- 1H- benzo[d]imidazo 1 -1-yl)methyl)nicoti nonitrile 345.2 98 7 0 NBoc 0 H A NC N HCI CI >-nO H 6-((2- ( (4aR,7aS)hexahydropyrrole o[3,4- b] hydrochloride) 1,4]oxazin- 6 (2H)-yl)-1Hbenzo[d]imidazo 1-1- yl)methyl·)nicoti nonitrile 361.2 99 7 O XNBoc 0 H A NC N VA HCI avco H hydrochloride of 6-( (2- ((4aS,7aR)hexahydropyrrole o[3,4- b][1,4]oxazin- 6(2H)-yl)-1Hbenzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 361, 2 100 7 0 - benzo[d]imidazo 361.2 IF-2019-169515 62-A PN-AN P# IT2B8 Page 238 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 1-1-yl)methyl)nicoti nonitrile 101 7 O NBoc $ H A NC N ¿HO H 6-((2- ( (4aS,7aS)hexahydropyrrole o[3,4 - b] [1,4]oxazin- 6(2H)-yl)-IHbenzo [d]imidazo 1-1-yl)methyl)nicoti nonitrile 361.2 102 7 ' 0 <>Λνη2 L J NH2 N H — NC N / —\ CX x-O ^^N '—(·ιΝΗ2 >=° h2n (S)-3-amino-l(1-((5- cyanopyridin-2yl)methyl)-IHbenzo[d]imidazo 1-2-yl) piperidine3-carboxamide 376.2 103 7 0 P^nh2 L J NH2 N H — NC N Cl N '—\"NH2 >=° h2n (R)-3-amino-l(1-((5cyanopyridin-2yl)methyl)- 1Hbenzo[d]imidazo 1-2-yl)piperidine3-carboxamide 376.2 104 7 ^OH χΧ-NHBoc H A NC N e x zX\ / '—GnH2 HO7 ¢5)-6-((2-(3- amino- 3- (hydroxymethyl)p iperidin-l-yl) - 1H- benzo[d]imidazo 1-1-yl)methyl)nicoti 363.2 IF-2019-16951562-A PN-A N P# F2&$ Page 239 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ nonitrile 105 7 ^-OH r^V-NHBoc H A NC N C 3- (hydroxymethyl) p iperidin-l-yl) - 1H- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 363.2 106 19 F Jx ..NHBoc H B u. 6- ( (2-((3R,4S) 3-amino-4fluoro-l- piperidinyl) -6(trifluoromethyl )-lH- benzimidazol-1yl)methyl) -3pyridinecarbonityl 419.2 107 19 F A. ,,ΝΗΒοο Η B J A -° 6-((2-((3R,4S)- 3-amino-4- fluoro-1- piperidinyl)-5(trifluoromethyl )-lH- benzimidazol-1yl)methyl)-3pyridinecarbonityl 419.2 108 19 F J<, .NHBOC H B Ό* -1piperidinyl)-6(trifluoromethyl)-lH-benzimidazole-1- 437.2 IF-2019-169515 62-A PN-AN P# 11340 Page 240 of 557 Ex. No. Intermediate rental side Amine Process dim. of despr otection Boc Structure Compound name MS MH+ iljmethyl)-3- pyridinecarbonitril 109 19 F J< ,tNHBoc H B Ó 6-((2-((3R)-3- amino-4,4difluoro-1- piperidinyl)- 5(trifluoromethyl )—lH — benzimidazol-1yl)methyl)-3pyridinecarbonityl 437.2 110 40 F JL .NHBoc H B N . 5 .,XXA-Q- NHj 6-((2-((3R,4R)3-amino-4fluoro-1- piperidinyl)-5methyl-lH- benzimidazol-1yljmethyl)-3pyridinecarbonityl 365.2 111 40 F Jx- NHBoc H B N s A XXAQ- NHj 6-((2-((3R,4R)3-amino-4fluoro-1piperidinyl)-6methyl-lH- benzimidazol-1yl)methyl)-3pyridinecarbonityl 365.2 112 20 F J^.NHBoc H B NC V nh2 6-(¢2-((3R,4R)- 3-amino-4- fluoro-1- piperidinyl)-6chloro-5-methyl- 1H- 399.1 IF-2019-16951562-API N- ANP#IWH Page 241 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH-i- benzimidazol-1yljmethyl)-3- pyridinecarbonityl 113 20 F J. ..NHBoc H B NC clXcH> nh2 6-((2-((3R,4R)- 3 -amino-4- fluoro-1- piperidinyl)-5- chloro-6-methyl- 1H- benzimidazol-1- yl)methyl)-3- pyridinecarbonityl 399.1 114 41 F ..NHBoc ^N^ H B NC . 3 nh2 6-((2-((3R,4R)3-amino-4- fluoro-1- piperidinyl)-6fluoro-5-methyl1H- benzimidazol-1yl)methyl)-3pyridinecarbonityl 383.1 115 41 F Js. ..NHBoc ^N^ H B NC A nh2 6-((2-((3R,4R)- 3-amino-4- fluoro-1- piperidinyl)-5fluoro-6-methyl1H- benzimidazol-1yl)methyl)-3pyridinecarbonit rile 383.1 IF-2019-16951562-ΑΡΝ-ΑΝΡ#Ι®42 Page 242 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 116 7 1 ,.NBoc H B NC N oto NH / 6-((2-((3S)-3(methylamino)-1piperidinyl) 1H-benzimidazol-1yljmethyl)-3pyridinecarbonit ryl 347.2 117 7 / ^1XNBoc H B NC N xa-n χ—ς NH / 6-((2-((3R)-3(methylamino)-1piperidinyl) 1H- benzimidazol-1yl)methyl)-3pyridinecarbonityl 347, 2 118 21 F ..NHBoc H B NC N FlHCOlXK> nh2 6-( (2-((3R,4R)- 3-amino-4- fluoro-1- piperidinyl)-6(difluoromethoxy )-lH- benzimidazol-1yljmethyl) -3pyridinecarbonit ryl 417.2 119 21 F J. ..NHBoc H B NC. Γχνθ-F F2HCCrx-''X^N s—( nh2 6-((2-((3R,4R).- 3-amino-4 - fluoro-1-piperidinyl)-5(difluoromethoxy)-1H-benzimidazol-1yl)methyl)-3pyridinecarbonityl 417.2 IF-2019-169515 62-A PN-AN P# MÍJ Page 243 of 557 Ex. N. 0 Inter medium rented side Amina Proce dim. despr otection Boo Structure Compound name MS MH+ 120 22 F JL .NHBoc H B NC N \_J / Qc^nQ-f OMe NH2 6-((2-((3R,4R)3-amino-4fluoro-1- piperidinyl)-4methoxy-lHbenzimidazol-1yl)methyl)-3pyridinecarbonityl )-4methyl-lH- benzimidazol-1yl)methyl)-3pyridinecarbonit ryl 365, 2 122 42 F A^.'NHBoc H B H2NOC TW nh2 5-((2-((3R,4S)- 3-amino-4- fluoro- 1- piperidinyl)-6(trifluoromethyl )-1H- benzimidazol-1yl)methyl)-2pyrazinecarboxa mide 438.2 123 42 F N\.>NHBoc H B H2 NOC f>Q' nh2 5- ( (2-((3R,4S )3-amino-4fluoro-1- piperidinyl)-5(trifluoromethyl)-lH-benzimidazol-1-yl)methyl)-2pyrazinecarboxa 438.2 IF-2019-169515 62-A PN - AN P# I Page 244 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ measure 124 27 F JL .NHBoc H B NC N ciXYa<>f f3cox<^n M nh2 6-((2-((3R,4R)3-amino-4- fluoro -1- piperidinyl)-6chloro-5- (trifluoromethox i)-lH- benzimidazol-1yl)methyl)-3pyridinecarbonityl 469.2 125 27 F -A. .NHBoc H B NC N nh2 6-((2-((3R,4R)3-amino-4fluoro-1- piperidinyl)-5chloro-6- (trifluoromethox i)-lH- benzimidazol-1yljmethyl)-3pyridinecarbonityl 469.2 126 26 F Js..NHBoc H B NC N VJ7 NH2 6-((2-((3R,4R)3-amino-4fluoro-1- piperidinyl)-6chloro-5- (trifluoromethyl)-1H- benzimidazol-1yl) methyl)-3pyridinecarbonit ryl 453.2 IF-2019-169515 62-A PN - AN P# Page 245 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 127 26 F ,NHBoc H B NC *< Xuc» nh2 6-((2-((3R,4R)- 3-amino-4- fluoro-1- piperidinyl)-5chloro -6- (trifluoromethyl )-1H- benzimidazol-1yljmethyl)-3- pyridinecarbonityl 453.2 128 7 HIM) BocN^y B NC Q, OXQ 6-((2-((5R)- 1, 7- diazaspiro[ 4.5 ]decan-7-yl)- 1H-benzimidazol-1yljmethyl)-3pyridinecarbonityl, 6-((2- ¢(53)-1,7- diazaspiro[4.5 ]decan-7-yl)- 1H-benzimidazol-1yljmethyl )-3pyridinecarbonityl 373.2 129 7 HN / / -NBoc B NC O n-A CXN^ON„ or 6-((2-((6R)1,8- diazaspiro[5.5 ]undecan-8-yl)1H- benzimidazole -1yl)methyl)-3pyridinecarbonityl 387.2 IF-2019-16951562-AP] M-ANP#I54Q Page 246 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 130 7 HN / A-NBoc B NC o n-A L JT / Vyf,,NH 6-((2-((63)- 1,8- diazaspiro[5.5 ]undecan- 8-yl) 1H- benzimidazol-1yl)methyl)-3pyridinecarbonityl 387.2 131 7 HN )— 0 M} BocN—' B NC nA ΟΑνΗ HN-X 6-((2- ((4aR,8aR)- hexahydro -2H- pyrido[4,3— b][1,4]oxazin- 6(5H)-yl)-1H- benzimidazol-1yl)methyl)-3pyridinecarbonityl 375.2 132 7 HN^ O BocN— B NC o nA [CV / >-N / \·Ό \An \ HN-^ 6-((2- ((4aS,8aS) - hexahydro-2H- pyrido[4,3- b] [1,4]oxazin- 6 (5H)-yl)-1H- benzimidazol-1yl)methyl)-3pyridinecarbonityl 375.2 133 43 F J. ..NHBoc ^FT H B H2NOC >> N nh2 5-((2-((3R,4R)- 3-amino-4- fluoro-1- piperidinyl)- 5,6-difluoro- 1H- benzimidazol-1-yljmethyl)-2- 406.2 IF-2019-1695 1562-APN-ANP#IW Page 247 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ pyrazinecarboxa mida 134 42 F ..NHBoc H B H2NOC \=χΝ F,CU?QF nh2 5-((2-((3R,4R)3-amino-4fluoro-l- piperidinyl) -6(trifluoromethyl )-lH- benzimidazol-1yljmethyl)-2- pyrazinecarboxamide 438.2 135 7 HNO BocN^ B NC u CPQ 6-{{2-((5R)- 1 / 7- diazaspiro[4.5 ] decan-7-yl) 1H- benzimidazol-1yl)methyl)-3pyridinecarbonityl 373.2 136 7 «O bX) B NC n N-\ V_Z HNU 6-((2-((55)- 1, 7- diazaspiro [4.5 ]decan-7-yl) - 1H- benzimidazol-1- yl)methyl)-3pyridinecarbonityl 373.2 137 24 3<FnhBoc H B NC N „.0XX>-€X nh2 6-( (2-(( 3R)-3- amino-4,4- difluoro-1piperidinyl)-5- methoxy-1H-benzimidazol-1yl)methyl)-3- 399.2 IF-2019-169515 62-A PN-AN P# Page 248 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ pyridinecarbonityl 138 24 F J<\nhboc H B NC N V-A "xXcx nh2 6- ( (2-((3R)-3amino-4,4difluoro-1piperidinyl)-6methoxy-lHbenzimidazol- 1yljmethyl)-3pyridinecarbonityl 399.2 139 19 / xaNBoc H B NC 3pyridinecarbonityl 415.2 140 19 1 _ / \aÑBoc H B NCX N HN- 6-((2-((3S)-3(methylamino)-1piperidinyl)-5(trifluoromethyl)-1H- benzimidazol-1yl)methyl)- 3pyridinecarbonityl 415.2 141 7 / \LnHBoc H B NC N / %_N / —\ í )-3pyridinecarbonityl 347.2 IF-2019-16951562-AP1 N-ANP#TO Page 249 of 557 Ex. No. Intermediate rental side Amine Process dim. of despr otection Boc Structure Compound name MS MH+ 142 24 Ηθ ÑHBoc B NC „οΧ, nh2 2,2,2- trifluoroacetate of (S)-6-((2(3- aminopiperidin1-yl)-6-methoxy1Hbenzo [d]imidazo 1-1yl)methyl)nicoti nonitrile 363.2 143 24 H G / l ÑHBoc B NV\ 0 ζ J hcAcf Ν\ HU Uf-3 xOX-Q nh2 2,2,2- trifluoroacetate of (S) -6-((2(3- aminopiperidin- 1-yl)-5-methoxy- 1H- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 363.2 144 32 HN^~~F NHBoc B NC . Cl >NH2 2,2,2- trifluoroacetate or 6-((2- ((3R,4R)-3- amino-4- fluoropiperidin -1-yl)-4-chloro- 6-fluoro-lH- benzo[ d]imidazo 1-1-yl)methyl)nicoti nonitrile 403.0 IF-2019-169515 62-A PN - AN P# I MU Page 250 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 145 24 HN^ NHBoc A NC u ) H-CI nh2 hydrochloride of 6-( (2-((3R,4R)- 3-amino-4fluoropiperidin -1-11)- 5- methoxy-lH- benzo[d]imidazo 1-1- yl )methyl)nicoti nonitrile 381.0 146 24 HN^ J^F NHBoc A NC n ΝΛ H-CI 11 Λ An AF '—( nh2 hydrochloride of 6 -((2-((3R,4R)- 3-amino-4fluoropiperidin -1-yl)-6- methoxy-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 381.0 147 24 HN ^ F NHBoc A NC n N'N h-ci Ύ 30 A-n / F nh2 6-( (2-((3R,4S)- 3-amino-4- fluoropiperidin -1-yl)-6- methoxy-hydrochloride lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 381.0 148 24 hnJJ.f NHBoc A NC nA h-ci 'ϋΠΜ}·ρ nh2 6-((2-((3R, 4S)- 3-amino-4- fluoropiperidin -l-yl)-5- methoxy-lH- benzo[d]imidazo 381.0 IF-2019-169515 62-A PN-AN P# I Page 251 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 1-1- yl)methyl)nicoti nonitrile 149 14 ? H M 0 1 H B Cl Q N-\ ΪΪΗ )F CN *NH2 2- ( (3R,4S)-3amino-4fluoropiperidin -1-11)-1-((5chloropyrimidin2-yl)methyl)-6fluoro-lHbenzo[d] imidazo 1-4carbonitrile 404.0 150 14 M ° 1 H B Cl Q N-\ NC. / XX 14 AFVr u 0 1 H B Cl )methyl)-6fluoro-lHbenzo[d]imidazo 1-4carbonitrile 422.0 IF-2019-16951562-APN-ANP#I@92 Page 252 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 152 3 OH A. ..NHBoc H B NC 0 CIWN ,γ-α y Γ n >—oh nh2 6-( (2-((3R,4R)3-amino- 4hydroxypiperidi n-l-yl)-6chloro-lH- benzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 383.2 153 3 OH J<.NHBoc H B NC Q Cl V'VXii i / >—n / -oh '---( nh2 6-((2-((3R,4S)- 3-amino-4hydroxypiperidi n-l-yl)-6- chloro-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 383.2 154 44 F F 34 -1-yl)methyl)benzon ytrile 368.2 155 44 OH JL ..NHBOC H racemic A NC. NC '—A HCI '-'X HCI CVOoh CVQ'oh NH, NHj compound of 4((2-(( 3R,4R)-3- amino-4- hydroxypiperidi n-l-yl)-1Hbenzo[d]imidazo 1-1-yl)methyl)benzon ytrile with 4-((2- 346.2 dihydrochloride IF-2019-169515 62-ΑΡΝ-ΑΝΡ#Ι®53 Page 253 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ ((3S,4S)-3-amino-4hydroxypiperidi n-l-yl)-1Hbenzo[d]imidazo 1-1- iyl)methyl)benzonitrile (1:1) 156 45 F J. ..NHBoc H B NC nh2 4- ( (2-((3R,4R)- 3-amino-4- fluoro-lpiperidinyl ) - 5,7-difluoro- 1H- benzimidazol-1yl)methyl)benzon ytrile 386 ,2 157 45 F .'NHBoc H B NC Λ •COO- F NH2 4- ( (2-((3R,4R)- 3-amino-4- fluoro-1- piperidinyl) - 4,6-difluoro- 1H- benzimidazol-1-yl)methyl)benzon ytrile 386.2 158 46 F . 'NHBoc ^N^ H B NC 7 -O5-Q- nh2 2- ( (3R,4R)-3- amino-4-fluorol-piperidinyl ) 1-(4cyanobenzyl) 1H- benzimidazole-6carbonitrile 375.2 IF-2019-169515 62-A PN-AN P# IH54 Page 254 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 159 46 F ,tNHBoc ^ff H B NC B Ν0£ΧΗ>ρ nh2 2-((3R,4R)-3- amino-4-fluorol-piperidinyl ) 1-(4cyanobenzyl )1H- benzimidazole-5carbonitrile 375.2 160 46 E F 3< xNHBoc ^FF H B NC O'H>: nh2 2-((3R)-3- amino-4,4- difluoro-l- piperidinyl )-1- ( 4- cyanobenzyl) - 1H- benzimidazol-6- carbonitrile 393.3 161 46 F, F 34 ,'NHBoc ^FF H B NC K ,.ÍX«3-Í nh2 2- ( (3R)-3- amino-4, 4- difluoro-l-piperidinyl ) — 1— (4- cyanobenzyl) - 1H- benzimidazole-5- carbonitrile 393.3 162 44 ✓x^NHBoc ^FF H A NC or N ¿ NH2 (R)-4-((2 -(3- aminopiperidin- 1-yl)-IH- benzo[d]imidazo 1-1-yl)methyl)benzon ytrile 332.2 IF-2019-169515 62-A PN-AN P# 1^53 Page 255 of 557 Ex. N. 0 Inter medium rented side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ 163 44 Me NHBoc H A NC θ ft I N Me nh2 4-( (2-((3R,4R)- 3-amino-4- me tilpiperidin- 1-yl)-1H - benzo[d]imidazo 1-1- yl)methyl)benzon ytrile 346.0 164 44 Me / \ NHBoc H A NC 0 I O\LMe ^nh2 4-((2-(3- (aminomethyl)-3methylpyrrolidin -1- il)-IH- benzo [d]imidazo 1-1- il)methyl)benzon ytrile 346.2 165 44 Racemic >o HN J ''NHBoc A NC Q / o / ΐχ^ N ft ΊΓ O\ J \^N V ^'--Nh2 NC Ό / o Λύ'^ ft T O\1 *NH2 4-((2-((3S,4R)- 3-amino-4- phenylpyrrolidin -1-yl)-1H- benzo[d] imidazo 1-1- yl)methyl)benzon ytrile and 4-((2- ((3R,4S)-3- amino-4- phenylpyrrolidin -1-yl)-IH- benzo[d]imidazo 1-1- yl )methyl)benzon ytrile 394.2 IF-2019-169515 62-A PN-AN P# IW3 Page 256 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 166 44 NHBoc H A NC H JL / >"N\ J (S)-4-((2-(3- aminopyrrolidin -1-yl)-1Hbenzo[d]imidazo 1 -1- yl) methyl) benzon ytrile 318.2 167 44 z\ ..NHBoc H A NC Q (ΧΗ3 nh2 (3)-4-((2-(3- aminopiperidin- 1-yl)-1H- benzo[d ]imidazo 1-1-yl)methyl)benzon ytrile 332.2 168 44 Boc HN^ / K H A NC Q Z^S^N nh2 h r -X \íZ^N \ 4-((2-(6-amino2- azaspiro[ 4.4]n onan-2-yl)-1Hbenzo[d]imidazo 1-1yl)methyl)benzon ytrile 32.0 169 44 / K^NHBoc Q H A NC O 0 JL 1 / nh2 4-((2-(4- aminohexahydroc iclopenta[c]pyr rol-2(1H)-yl)- 1H- benzo[d]imidazo 1-1- yl)methyl)benzon ytrile 358.2 170 44 F ✓k / NHBoc ^N^ H A NC θ CcXQ· * nh2 4-((2-((3S,4S)- 3-amino-4- fluoropiperidin -1-yl)-1H- benzo[d]imidazo 1-1- 350.2 IF-20 19-16951562-APN -ANP#IW Page 257 of 557 Ex. N. 0 Middle rented side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ il)methyl)benzon ytrile 171 44 F J^^NHBOC H A NC o OoQ-f nh2 4-( (2-((3S,4R)- 3-amino-4- fluoropiperidin -1-yl)-1H- benzo[d]imidazo 1-1- yl)methyl)benzon ytrile 350.2 172 44 F JL ..NHBoc ^hF H A NC Q o>o nh2 4-((2-(( 3R,4S)- 3-amino-4- fluoropiperidin -1-yl)-IH- benzo[d]imidazo 1-1-yl)methyl)benzon ytrile 350.2 173 44 F ..NHBoc H A NC o / —X . 0 A \ / ~F N '---' NH2 4-((2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-1H- benzo[d]imidazo 1-1- yl )methyl)benzon ytrile 350.2 174 44 F NHBoc H B NC \___ 0 < / JLx f \-=Z HO q< — \ If 2 F C>CL· h2nx 2,2,2- trifluoroacetate or (R)- 4-((2- (3- (aminomethyl)-3fluoropyrrolidi n-l-yl)-IHbenzo[d]imidazo 1-1-yl)methyl)benzon ytrile 350.0 IF-2019-169515 62-APN-ANP#ES$8 Page 258 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otec tion Boc Structure Compound name MS MH+ 175 44 F NHBoc H B NC N—x o \__-7 HO N< '-Ά. If > F fi JL ÍLf ''b η2νζ 2,2,2- trifluoroacetate of (S)-4-((2(3- (aminomethyl)-3fluoropyrrolidi n-l-yl)-IHbenzo [d]imidazo 1-1- il)methyl)benzon ytrile 350, 0 176 44 HO NHBoc H B NC dl JLf \^< ho γζ \ If / F 0 \1-oh h2nx 2,2,2- trifluoroacetate of (R)-4-((2 (3- (aminomethyl)-3hydroxypyrrolid in-l-yl)-1Hbenzo[d]imidazo 1-1- yl)methyl)benzon ytrile 348.2 177 44 HO NHBoc d7 H B NC XN ϊ f NssZ HO If / F rzz5% 5r-N D \ 1—OH h2nz 2,2,2- trifluoroacetate of (S)-4-((2- (3- (aminomethyl)-3hydroxypyrrolid in-l-yl)-1Hbenzo[d]imidazo 1-1 -yl)methyl)benzon ytrile 348.2 IF-2019-169515 62-A PN-AN P# Ig59 Page 259 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 178 44 NHBOC & H A NC y JL J H2N (S)-4-((2-(3- (aminomethyl)pyrrolidin-l-yl)- 1H- benzo[d ]imidazo 1-1- yl)methyl)benzon ytrile Molecular weight: 331.41 332.2 179 44 NHBoc ..... / H A NC and JL J \^^N h2nz (R)-4-((2- (3- (aminomethyl)pyrrolidin-l-yl)- 1H- benzo[d]imidazo 1-1- yl)methyl)benzon ytrile Molecular weight: 331.41 332.2 180 44 Me A. ..NHBoc ^N ^ H B NC A í F \s=< HO >< \ 1 F OL z)- / -\Me nh2 2,2,2- trifluoroacetate of 4-((2- ( (3S,4S)-3- amino -4- methylIpiperidin- 1-yl)-1H- benzo[d]imidazo 1-1- yl)methyl)benzon ytrile 346.2 181 44 Me JL ..NHBoc H B NC A Ju HO η< \ 1 F / F H T N > —Me \--( nh2 2,2,2- trifluoroacetate or 4-((2- ( (3S,4R)-3- amino-4- methylpiperidin- 346.2 IF-20 19-169515 62-APN- ANP#IS$0 Page 260 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 1-yl)-1H- benzo[d]imidazo 1-1- yl)methyl)benzon ytrile 182 44 Me NHBoc H B NC Q 4>-Ν^Λ···· Μβ nh2 2,2,2- trifluoroacetate or 4-((2- ((3R,4S)-3- amino-4- methylpiperidin- 1-yl)-1H- benzo[d]imidazo 1-1-yl) methyl)benzon ytrile 346.2 183 44 NHBoc 3- azabicyclo[3.1. 0]hexan-3-yl)- 1H- benzo[d]imidazo 1-1- yl)methyl)benzon ytrile 344.2 184 44 NHBoc G H A NC Ό 7 H 0 Σ / )" \ J > nh2 4-((2-((IR,5S)- 1-(aminomethyl)- 3- azabicyclo[3.1. 0]hexan-3-yl)- 1H- benzo[d]imidazo 1-1- yl)methyl )benzon ytril 344.2 IF-2019-169515 62-APN-ANP# Wi Page 261 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boo Structure Compound name MS MH+ 185 44 ^ / X^^NHBoc H A NC XXanQ nh2 (R)-4-((2-(3- aminopiperidin1-yl)-6-methoxy1H- benzo[d]imidazo 1-1- yl)methyl)benzon ytrile 362.2 186 44 ✓^.NHBoc ^NF H A NC o XX't-O MeO^^'N '—\ nh2 (R)-4-((2-(3 - aminopiperidin- 1-yl)-5-methoxy- 1H- benzo[d]imidazo 1-1-yl)methyl)benzon ytrile 362.2 442 47 F .A. .NHBoc ^hF H B NC / N » IJ N—\ A / X^N / \ I jl / f \-5^·Ν x ( nh2 2- ( (2-((3R,4R)- 3-amino- 4- fluoropiperidin -1-yl)-6- fIuoro-1H- benzo[d]imidazo 1-1- yl)methyl)pyrimi din-5- carbonitrile 370.2 443 47 F Js.NHBoc H B NC / N » IJ N ^K / X^N / -\ fi JI / >-\ >"F nh2 2- ( (2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5- fluoro-lH - benzo[d]imidazo 1-1-yl)methyl)pyrimi din-5-carbonitrile 370.2 IF-2019-16951562-APN-ANP#I®2 Page 262 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boo Structure Compound name MS MH+ 444 48 F .JXIHBoc H B MeO / N 'nA, fVz^n y JL / -F nh2 (3R,4R)-4- fluoro-1-(6- fluoro-1- ((5- methoxypyrimidin -2-yl)methyl)- IH- benzo [d]imidazo 1-2- yl) piperidin-3- amine 375, 4 445 49 F J. ..NHBoc XhF H B Mex N—X / cf3 o=K F'v<x55^n / —X y JL )"F nh2 2-(2-((3R,4R)- 3-amino-4fluoropiperidin -1-yl)-6fluoro-lHbenzo[d]imidazo 1 -1-yl)-N- methyl-N-(2,2,2trifluoroethyl)a cetamide 406.2 446 48 F ..NHBOC s'n'z / H B MeO / N fj N-~\ Í JL / ~F nh2 (3R,4R)-4- fluoro-1-(5- fluoro-1-((5- methoxypyrimidin -2-yl)methyl)- IH- benzo[d]imidazo 1-2- yl)piperidin-3- amine 375.2 447 52 F Js.NHBoc ^FT H B # Ο Ξ / \ \\ Φ .A ' 2-(2-((3R,4R)3-amino-4- fluoropiperidin -1-yl)-4- cyano6-fluoro-lHbenzo[d]imidazo 1-1-yl)-N- 431.2 IF-2019-169515 62-A PN-AN P# IW3 Page 263 of 557 Ex. N. 0 Middle rented side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ methyl-N-(2,2,2trifluoroethyl)a cetamide 448 51 F JL .NHBOC H B Me N'MeO==^\ T T z~f nh2 2-(2-( (3R,4R)3-amino-4fluoropiperidin -1-01)-6methoxo-lHbenzo[d]imidazo l-l-ol)-N,Ndimethylacetamid at 350.2 449 50 F Λ. ,tNHBoc H B Φ o H 1 J Zx Ζ·^ / *ζ / ?? 2-(2-((3R,4R)3-amino-4fluoropiperidin -1-yl)-5methoxy-lHbenzo[d]imidazo 1-1-yl)-N-methyl-N-(2,2,2trifluoroethyl)a cetamide 418.0 450 51 F J. .NHBoc H B Ó* Φ T s 1 z^ / ^z z ΦΖ \ / ' ° Q o Φ 5 2-(2-((3R,4R)- 3-amino-4fluoropiperidin - 1-01)-5methoxo-lHbenzo[d]imidazo l-l-ol)-N,Ndimethylacetamid a 350.2 451 5 o'— IZ Φ '____, s / \ o—Í zi B NC N vA / —\ l| I j>—N ft-OMe x—< nh2 6-((2-((3R,4R)- 3-amino-4- methoxypiperidin -1-yl)-6- fluoro-lH- 1 benzo[d]imidazo 381.2 IF-2019-169515 62-A PN-AN P# IM4 Page 264 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ 1-1- yl)methyl)nicoti nonitrile 452 53 NH °A 0 A B NC tx^nq~f OMe NH2 6-( (2-((3R,4R)- 3 -amino-4fluoropiperidin -l-yl)-6fluoro-4methoxy-lHbenzo[d]imidazo 1-1- yl)methyl)nicoti nonitrile 399.2 453 54 HN^ F NH °=K 0 A B NC GN v><> NH2 6- ( (2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5- (trifluoromethyl ) -3H- imidazo[4,5- b]pyridin-3- yl)methyl) nicoti nonitrile 420.2 454 17 Λ·'Ύ°α M ° 1 H B CL N N-\ TAHA0' nh2 (3R,4R)-1-(1((5chloropyrimidin2-yl)methyl)-6fluoro-lHbenzo[d] imidazo 1-2-yl)-4-methoxypiperidin-3-amine 391.2 IF-2019-169515 62-A PN-AN P# IW3 Page 265 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ 455 55 F NH °=< 0 70 B B °3 W nh2 2- (2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)- 6-bromo- 1H- benzo[d]imidazo 1-1-yl)-1- (azetidin-1- yl)ethan-l-one 412.0 456 17 A >° iz 4) '_____. s / \ OH zi B cix N N \ nh2 (3R,4R)-1-(1- ¢(5- chloropyrimidin- 2-yl)methyl)-6fluoro-lH- benzo[d]imidazo l-2-yl)- 4- methoxypiperidin -3-amine 391.2 457 49 hn\ NH 0=( 0 ti B cf3 N 0=S AH? nh2 2- (2-((3R,4R)- 3-amino-4fluoropiperidin -1-yl )-6- fluoro-lH- benzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2trifluoroethyl)a cetamide 406.2 458 54 hn^~^Hf NH 0 ti B M ) NH2 ti NC 6-((2-((3R,4R)- 3-amino-4- fluoropiperidin -1-11)-5- (trifluoromethyl )-lH- imidazo[4,5- bj pyridin-1- yl) methyl)nicoti 420.2 IF-2019-16951562-A PN-A N P# IWJ Page 266 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ nonitrile 459 56 I B O 0=S FfÜH> nh2 2-(2-((3R,4R)- 3-amino-4fluoropiperidin -1-yl)-6- (trifluoromethyl )- lH- benzo[d]imidazo 1-1-iD-l- morpholinoethane- 1-one 430.2 460 49 HN^ NH M 0 ~i\ B cf3 N 0=S f-OXnQ~f nh2 2- (2- ((3R,4R)- 3-amino-4fluoropiperidin -1-yl)-5- fluoro-lHbenzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2trifluoroethyl)a cetamide 406 ,2 461 57 hnQf NHBoc B \ N Q^S "ΌΧΙ' nh2 2-(2-((3R,4S)- 3-amino-4fluoropiperidin -1-yl)-6-clcro- 1H- benzo[d]imidazo 1 -1-yl)-N,Ndimethylacetamid a 354.2 462 49 F NHBoc B cf3 N XXO- nh2 2-(2-((3R,4S)- 3-amino-4fluoropiperidin -1-yl)-6fluoro-lHbenzo[ d]imidazo 1-1-yl)-N- 406.2 IF-20 19-16951562-APN-ANP#H2CT Page 267 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ methyl-N-(2,2,2trifluoroethyl) a cetamide 463 17 HCI OMeH Q'Tr H B NC XX¿-nQ-°m. ñh2 6-((2-((3R,4S)- 3-amino-4methoxypiperidin -1-yl)-6- fluoro-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 381.2 464 56 ηγ / ^ -'F NHBoc B c N-^ °χ nh2 2-(2-((3R,48)- 3-amino-4fluoropiperidin -1-11)-6- (trifluoromethyl )-lH- benzo[d ]imidazo 1-1-yl)-1- morpholinoethane- 1-one 430.2 465 49 hnQ4 NH B cf3 Ν' o=S nh2 (R)-2-(2-(3- amino-4,4- difluoropiperid in-l-yl)-6- fIuoro-1H- benzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2- trifluoroethyl)a cetamide 424.2 IF-2019-169515 62-A PN-AN P# IW8 Page 268 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ 466 49 hnQf NHBoc B cf3 Ν' OXQ·' nh2 2-(2-((3R, 4S)- 3-amino-4fluoropiperidin -1-yl)-6fluoro-lHbenzo[ d]imidazo 1-1-yl)-N- methyl-N-¢2,2,2trifluoroethyl) to cetamide 406.2 467 17 HCl 9m'h QTX H B N A ¡J N\ OZQ0· nh2 (3R,4S)-1- (1((5chloropyrimidin2-yl)methyl)-6fluoro-lHbenzo[d]imidazo 1-2-11)-4methoxypiperidin -3-amine 391, 2 468 58 hn3-f NH 0=K B \ N Γ,"ΌΧ> NH2 2- (2-((3R,4R)- 3-amino-4fluoropiperidin -l-ylJ-6- (trifluoromethox i)-IH- benzo[d]imidazo 1-1-yl)-N,Ndimethylacetamid a 404.2 469 49 Hr / F N— °=K 0 V\ B cf3 N ° =\ f—\ y i / ~f NH / 2- (6-fluoro-2- ( (3R,4R)-4- fluoro-3- ( methylamino)pip eridin-l-yl) - 1H- benzo[d]imidazo 1-1-iD-N- 420.2 IF-2019-169515 62-A PN-AN P# TO Page 269 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ methyl-N-(2,2,2trifluoroethyl)a cetamide 470 55 Hl / NH 0 X B NH2 2-(2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5-bromo1H- benzo[d]imidazo 1-1-yl)-1(azetidin-1-yl) etan-l-one 410.0 471 57 HNQf NHBoc B \ N αΧΧλΟ,ρ nh2 2-(2-((3R,4S) - 3-amino-4fluoropiperidin -1-yl)-5-chloro- 1H- benzo[ d]imidazo 1-1-yl)-N,Ndimethylacetamid a 354.2 472 49 °X B X )- 1H- benzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2— trifluoroethyl)a cetamide 428.2 473 56 Hl· / F NHBoc B o 0==\ FiCjOXQf nh2 2-(2-((3R,4R)- 3-amino-4- fluoropiperidin -1-yl)-5- (trifluoromethyl )-1h- 430.2 IF-2019-169515 62-A PN-AN P# IKTO Page 270 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ benzo[d]imidazo 1-1-yl)-1- morpholinoethane- 1-one 474 58 h / F NH 0=( B \ Ν' °=s NH2 2- ( 2-((3R,4R)- 3-amino-4fluoropiperidin -1-yl)-5- (trifluoromethox i)-1H- benzo[d]imidazo 1-1-yl)-N,Ndimethylacetamid a 404.2 475 59 HN\ F NH 0 -yl)-1- morpholinoethane- 1-one 446.2 476 53 HN\ / ^F NH °=< B NC, or MeO / nh2 6-((2-((3R,4R)- 3-amino- 4fluoropiperidin -1-yl)-5fluoro-7methoxy-lH- benzo[d]imidazo 1-1-yl)methyl)nicoti nonitrile 399.2 IF-2019-169515 62-APN-ANP#IEPI Page 271 of 557 Ex. No. Intermediate rental side Amine Process dim. despr otection Boc Structure Compound name MS MH+ 477 17 HCI 9MeH QXY H B Cl Nρ£ΧλΟ°"· nh2 (3R,4S)-1-(1- ( (5-chloropyrimidin2-yl)methyl)-5fluoro-lHbenzo [d]imidazo 1-2-yl)-4methoxypiperidin -3-amine 391.2 478 56 HN^X F NHBoc B c hr °=s FjCXX^Q-f nh2 2- (2- ( (3R,4S) - 3-amino -4- fluoropiperidin -1-yl)-5- (trifluoromethyl )-lH- benzo[d]imidazo 1-1-yl)-1- morpholinoethane- 1-one 430.2 479 49 Hl / F N— M 0 X B cf3 N 0=S NH / 2- (5-fluoro-2- ((3R,4R)-4- fluoro-3- (methylamino)pip eridin-l-yl) - IH- benzo[d]imidazo 1-1- yl)-N- methyl-N-(2,2,2trifluoroethyl) a cetamide 420.2 480 49 B \ ,n^Vf °X F F < X N\X 2- (2-(3-amino- 4- methylpyrrolidin -1 -yl)-6fluoro-lH- benzo[d]imidazo 1-1-yl)-N- 388.2 IF-2019-16951562-A PN-A N P# F2P2 Page 272 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ methyl-N-(2,2,2- trifluoroethyl)a cetamide 481 49 HNx^XNHBoc B \ N-\ oA CF= F'V / XrN / —\ || I N V-OH —( nh2 2-(2-((3R,4R)3-amino-4hydroxypiperidi n-l-yl)-6fIuoro-1Hbenzo[d]imidazo 1-1-yl)-N- methyl-N-(2 ,2,2trifluoroethyl)a cetamide 404.2 482 49 / —\ F HN V-F NH 0=( 0 B cf3 N nh2 (R)-2-(2-(3- amino-4,4- difluoropiperid in-l- il)-5fluoro-lHbenzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2trifluoroethyl) a cetamide 424.2 483 49 'NH °A B Γ Ν'- f£W°" nh2 2- (2-((3R,4R)- 3-amino-4- methoxypiperidin -1-11)-5- fluoro-lHbenzo[d]imidazo 1-1-yl)-N- methyl-N-(2 ,2,2trifluoroethyl) to cetamide 418.2 IF-2019-169515 62-A PN-AN P# I®73 Page 273 of 557 Ex. N. 0 Middle rented side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ 484 49 Hl· / OH NH 0=( B cf3 N 0= / nh2 2-(2-((3R)-3amino-4- hydroxypiperidi n-l-yl)-5fluoro- lHbenzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2trifluoroethyl) a cetamide 404.2 485 49 Hf / ^^OMe NH 0 (C00H)2 B Γ 0==S FXXZ "Q" · nh2 2-(2- ( (3R,4R)- 3-amino-4- methoxypiperidin -1-yl)-6- fIuoro-1Hbenzo[d]imidazo 1-1-yl)-N- methyl- N-¢2,2,2trifluoroethyl) a cetamide 418.2 486 49 HN^x / ' NHBoc B CN I z aminomethyl)-3fluoropyrrolidi n-l-yl)-6fluoro-lHbenzo[d]imidazo 1-1-yl)-Nmethyl-N-(2,2,2trifluoroethyl)a cetamide 406.2 487 49 ην-λ / NHBoc B cf3 0 = \ / F II .1 / >—N I NH2 2-(2-(3- (aminomethyl)-3fluoropyrrolidi n-l-yl)-5fluoro-lHbenzo[d]imidazo 1-1-yl)-N- 406.2 IF-2019-169515 62-A PN-AN P# 1874 Page 274 of 557 Ex. No. Inter middle rent side Amina Proce dim. depr otection Boc Structure Compound name MS MH+ methyl-N-(2,2,2trifluoroethyl)a cetamide 488 49 Qj BocN-7 B oJ^'CF3FOA€>°) HN^ 2- (6-fluoro-2( (4aR,8aR) hexahydro-2Hpyrido[4,3b] [1,4]oxazin- 6 (5H)-yl)-1Hbenzo[d]imidazo 1-1-yl)-Nmethyl-N-(2,2, 2trifluoroethyl )a cetamide 430.2 489 49 0 Ά B \ F F fVJVnQ ^'nh. (S)-2-(2-(3aminopyrrolidin -1-yl)-6fluoro-lH- benzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2trifluoroethyl)a cetamide 374, 2 490 49 ΛΑτθ 0 Ά B \ ,N\rF °A f f ΧΑΑΝΗ2 (R)-2- (2-(3aminopyrrolidin -1-yl)-6fluoro-lHbenzo[d]imidazo 1-1-yl)-N- methyl -N-(2,2,2trifluoroethyl)a cetamide 374.2 IF-2019-169515 62-A PN - AN P# IW3 Page 275 of 557 Ex. No. Inter middle rent side Amina Proce dim. despr otection Boc Structure Compound name MS MH+ 491 49 NHBoc B oX CF3 Ύ -lHbenzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2trifluoroethyl)a cetamide 388.2 492 49 BocN-^ B \ _ CF3 HN^ 2- (6-fluoro-2 - ((4aR,8aR)- hexahydro-2H- pyrido[4,3- b][1,4]oxazin- 6(5H)-yl)-1Hbenzo[d]imidazo 1-1-yl)-N- methyl -N-(2,2,2trifluoroethyl) a cetamide 430, 2 493 49 BocN-7 B 1 X1 co II C-Λ z ° 0 2-(5-fluoro-2- ((4aS,8aS) - hexahydro-2H - pyrido[4,3- b][1,4]oxazin- 6(5H)-yl)-1Hbenzo[d]imidazo 1-1-yl)-N- methyl-N-(2,2,2trifluoroethyl)a cetamide 430.2 [a] Nitrile hydrolysis that occurred during SnAr. [b] Ritter reactivity observed during Boc deprotection. [c] Unspecified stereochemistry meaning mixtures of enantiomers or diastereomers. IF-2019-169515 62-APN-ANP#! W Page 276 of 557 Table 3. Characterization data for compounds prepared according to Scheme 8. The “Separation step” column indicates after which process step the formed regioisomers 5 were separated due to the asymmetric benzimidazole substitution in R1 in Scheme 8 during the preparation of the final tabulated compound (I = after the preparation of the alkylated intermediate 1 -59 (where at least one R1 is not hydrogen); B = before boc deprotection or F = final compound) E j . Fre. No., Solvent Data ΤΗ NMR (δ ppm) Separation step Separation conditions isomer SFC 1 400MHz cU-MeOH 8.85 (dd, J=0.83, 2.07 Hz, 1H), 8.12 -8.16 (m, 1H), 7.44 (d, J=8.50 Hz, 1H), 7.37 (dd, J=0.62, 8.29 Hz, 1H), 7.20 ( d, J=l.66 Hz, 1H), 7.127.16 (m, 1H), 5.48 (s, 2H), 3.50 (br s, 1H), 2.97-3.03 (m, 1H), 2.89-2.96 (m, 1H), 2.78-2.86 (m, 1H), 1.92-2.01 (m, 1H), 1.81 (dt, J= 3.94, 8.71 Hz, 1H), 1.57-1.72 (m, 1H), 1.31-1.42 (m, 1H) B Chiralpak AD-H, MeOH 20%, Peak 1 2 500MHz d^-MeOH 8.81-8.86 (m, 1H), 8.11-8.17 (m, 1H), 7, 44-7, 48 (m, 1H), 7.36 (d, J=8.04 Hz, 1H), 7.06-7.10 (in, 2H), 5.49 (s, 2H), 3.52 (br dd, J=l.69, 11.81 Hz, 1H), 2.97-3.06 (m, 1H), 2.90-2.96 (m, 1H), 2.80-2.88 (m, 1H), 1.92-2.01 ( m, 1H), 1.82 (br dd, J=4.28, 9.47 Hz, 1H), 1.58-1.71 (m, 1H), 1.29-1.41 (m, 1H ) B Chiralpak AD-H, MeOH 20%, Peak 2 IF-2019-169515 62-A PN-AN P# Page 277 of 557 E j . No. Free., Solvent 30 Hz, 1H), 7.23-7.31 (m, 1H), 7.11 (d, 3=7.27 Hz, 1H), 6, 94-7.05 (m, 2H), 5, 44 (s, 2H), 3.48 (br d, 3=10.12 Hz, 1H), 3.24-3.30 (m, 1H), 3.23-3.28 (m, 1H), 2, 94-3.04 (m, 1H), 2.77-2.90 (m, 2H), 1.83-1.96 (m, 1H), 1.71-1.81 (m, 1H ), 1.511.65 (m, 1H), 1.19-1.35 (m, 1H) — — 4 500MHz cU-MeOH 8.83 (s, 1H), 8.11-8.16 (m, 1H ), 7.39 (d, 3=8.30 Hz, 1H), 7.18 (d, 3=7.01 Hz, 1H), 7.02-7.11 (m, 2H), 5.53 (s, 2H), 4, 33-4.52 (m, 1H), 3.59-3.66 (m, 1H), 3.50 (br d, 3=12.46 Hz, 1H), 3 .14-3.22 (m, 1H), 3.09 (dq, 3=4.02, 8.69 Hz, 1H), 2.95-3.05 (m, 1H), 2.07-2 .22 (m, 1H), 1.76-1.94 (m, 1H) — — 5 500MHz cU-MeOH 8.83 (s, 1H), 8.10-8.15 (m, 1H) , 7 .37 (d, 3=8.04 Hz, 1H), 7.17 (d, 3=7.01 Hz, 1H), 7.01-7.09 (m, 2H), 5.52 (s, 2H), 3.43 (dd, 3=4.15, 12.20 Hz, 1H), 3.20-3.35 (m, 2H), 3.18-3.35 (m, 1H), 3 .04-3.17 (m, 1H), 2.10 (ddd, 3=4.93, 9.80, 14.34 Hz, 1H), 1.88-2.04 (m, 1H) — — 6 500MHz d4-MeOH 8.86 (d, 3=1.30 Hz, 1H), 8.14-8.20 (m, 1H), 7.47 (d, 3=8.56 Hz, 1H), 7.44 (d, 3=8.30 Hz, 1H), 7.23 (d, 3=2.08 Hz, 1H), 7.19 (dd, 3=1.95, 8.43 Hz, 1H ), 5.53 (s, 2H), 4.334.50 (m, 1H), 3.53-3.61 (m, 1H), 3.43-3.50 (m, 1H), 3.02- 3.20 (m, 2H), 2.95 (dd, 3=8.69, 12.33 Hz, 1H), 2.12-2.24 (m, 1H), 1.82-1.94 ( m, 1H) B Chiralcel OD-H, IPA 25%, peak 1 IF-2019-169515 62-A PN - AN P# I MU Page 278 of 557 Ex. No. Free., Solvent Data 1H NMR (δ ppm) Separation step Separation conditions isomer SFC 7 500MHz di-MeOH 8.86 (d, J=1,30 Hz, 1H), 8.13-8.20 (m, 1H), 7.49 (s, 1H), 7.42 (d, J=8.30 Hz, 1H), 7.12 (s, 2H), 5.54 (s, 2H), 4 .43 (s, 1H), 3.57-3.63 (m, 1H), 3.45-3.55 (m, 1H), 3.12- 3.20 (m, 1H), 3.03 -3.12 (m, 1H), 2.97 (dd, J=8.82, 12.46 Hz, 1H), 2.12-2.24 (m, 1H), 1.80-1.96 (m, 1H) B Chiralcel OD-H, IPA 25%, peak 2 8 500MHz d4-MeOH 8.86 (d, 0=1.82 Hz, 1H), 8.14-8.19 (m, 1H) , 7.47 (d, J=8.56 Hz, 1H), 7.43 (d, 0=8.04 Hz, 1H), 7.22 (s, 1H), 7.13-7.20 ( m, 1H), 5.53 (s, 2H), 4.75-4.81 (m, 1H), 3.37-3.43 (m, 1H), 3.01-3.29 (m, 4H), 2,082.20 (m, 1H), 1.88-2.03 (m, 1H) B Chiralcel OD-H, IPA 25%, peak 1 9 500MHz d4-MeOH 8.86 (d, 0=1 .30 Hz, 1H), 8.14-8.19 (m, 1H), 7.49 (s, 1H), 7.41 (d, 0=8.04 Hz, 1H), 7.12 (s , 2H), 5.53 (s, 2H), 3.37-3.49 (m, 2H), 3.28 (dd, 0-3.37, 8.04 Hz, 2H), 3.03- 3.21 (m, 2H), 2.09-2.18 (m, 1H), 1.89-2.05 (m, 1H) B Chiralcel OD-H, IPA 25%, peak 2 10 500MHz d4- MeOH 8.84 (s, 1H), 8.16 (d, 0=8.04 Hz, 1H), 7.42-7.47 (m, 1H), 7.19-7.23 (m, 1H ), 7.05-7.12 (m, 2H), 5.58 (s, 2H), 3.59 (br d, 0=11.42 Hz, 1H), 3.45-3.53 (m , 1H), 3.37 (ddd, 0=3.11, 9.54, 12.78 Hz, 1H), 3.163.30 (m, 2H), 2.30 (tdd, 0=4.70, 9 .67, 14.66 Hz, 1H), 2.06-2.22 (m, 1H) — — 11 500MHz d4-MeOH 8.80-8.84 (m, 1H), 8.14-8.19 (m, 1H), 7.45-7.51 (m, 2H), 7.41 (d, 0=8.04 Hz, 1H), 7.17 (t, 0=7.91 Hz, 1H) , 5.54-5.60 (m, 2H), 4.35-4.53 (m, 1H), 3.70-3.76 (m, 1H), 3.503.64 (m, 1H), 3 .19-3.26 (m, 1H), 3.14 (dq, 0=4.15, 8.82 Hz, 1H), 2.98-3.08 (m, 1H), 2.11-2 .23 (m, 1H), 1.80-1.95 (m, 1H) — _ IF-2019-169515 62-A PN-AN P# 11279 Page 279 of 557 E j . No. Free., Solvent (m, 1H), 7.48 (d, 0=8.56 Hz, 2H), 7.23 (d, 0=1.56 Hz, 1H), 7.19 (dd, J=l.82, 8.56 Hz, 1H), 5.56 (s, 2H), 3.53 (br d, 0=12.20 Hz, 1H), 3.403.48 (m, 1H), 3.28-3.32 (m, 1H), 3.12-3.27 (m, 2H), 2.23-2.37 (m, 1H), 2.06-2.21 (m, 1H) F Chiralcel OD-H, MeOH 25%, peak 1 13 500MHz d4-MeOH 8.85 (d, 0=1.04 Hz, 1H), 8.15-8.19 (m, 1H), 7.50 (s, 1H), 7 .46 (d, 0=8.04 Hz, 1H), 7.07-7.15 (m, 2H), 5.54-5.59 (τη, 2H), 3.56 (br d, 0= 12.20 Hz, 1H), 3.40-3.50 (m, 1H), 3.34-3.39 (m, 1H), 3.13-3.29 (m, 2H), 2.24 -2.39 (m, 1H), 2.06-2.22 (m, 1H) F Chiralcel OD-H, MeOH 25%, peak 2 14 500MHz d4-MeOH 8.85 (d, 0=1.82 Hz, 1H), 8.15-8.20 (m, 1H), 7.64 (d, 0=8.30 Hz, 1H), 7.44-7.54 (m, 3H), 5.59 -5.64 (m, 2H), 4.36-4.54 (m, 1H), 3.60-3.71 (m, 1H), 3.48-3.56 (m, 1H), 3.143 .22 (m, 1H), 3.06-3.13 (m, 1H), 2.95-3.03 (m, 1H), 2.12-2.23 (m, 1H), 1.81 -1.97 (m, 1H) B Chiralcel OD-H, IPA 15%, peak 1 15 500MHz d4-MeOH 8.82-8.87 (m, 1H), 8.15-8.21 (m, 1H) ), 7.78 (s, 1H), 7.48 (d, 0=8.30 Hz, 1H), 7.41 (d, 0=8.56 Hz, 1H), 7.31 (d, 0 =8.30 Hz, 1H), 5.55-5.64 (m, 2H), 4.35-4.54 (m, 1H), 3.603.69 (m, 1H), 3.50-3, 59 (m, 1H), 3.15-3.22 (m, 1H), 3.06-3.15 (m, 1H), 3.01 (dd, 0=8.82, 12.46 Hz, 1H), 2.13-2.27 (m, 1H), 1.83-1.97 (m, 1H) B Chiralcel OD-H, IPA 15%, peak 2 IF-2019-169515 62-A PN-AN P# I WO Page 280 of 557 E j . No. Free., Solvent NMR data (δ ppm) Separation step Separation conditions isomer SFC 16 500MHz d4-MeOH 8.86 (d, 0=1.30 Hz, 1H), 8.11-8.18 ( m, 1H), 7.53 (d, J=7.79 Hz, 1H), 7.37 (d, 0=8.04 Hz, 1H)., 7.18-7.25 (m, 1H) , 7.11-7.17 (m, 2H), 5.515.57 (m, 2H), 4.37-4.53 (m, 1H), 3.57-3.65 (m, 1H) , 3 .40-3.54 (m, 1H), 3.09-3.21 (m, 2H), 2.99 (dd, 0=8.95, 12.33 Hz, 1H), 2.19 (tt , 0=4.28, 13.62 Hz, 1H) , 1.81-1.98 (m, 1H) — — 17 500MHz d4-MeOH 8.90 (d, 0=1.30 Hz, 1H), 8.08-8.16 (m, 1H), 7.33-7.38 (m, 1H), 7.25 (d, 0=8.04 Hz, 1H), 7.06-7.11 ( m, 2H), 6.96-7.02 (m, 1H), 5.45 (s, 2H), 4.14-4.23 (m, 1H), 3.26 (br d, 0=13 .23 Hz, 1H), 3.04-3.16 (m, 1H), 2.83-2.94 (m, 1H), 2.49-2.60 (m, 2H), 2.43- 2.46 (m, 1H), 1.99-2.13 (m, 1H), 1.48-1.57 (m, 1H), 1.38 (qd, 0=7.28, 15.02 Hz, 1H) — — 18 500MHz d4-MeOH 8.83 (dd, 0=1.56, 16.35 Hz, 1H), 8.18-8.25 (m, 1H), 7.50-7, 61 (m, 1H), 7.27-7.37 (m, 2H), 5.56 (d, 0=3.11 Hz, 2H), 3.04-3.26 (m, 3H), 2 .99 (br d, 0=8.04 Hz, 2H), 2.11- 2.26 (m, 1H), 1.84-2.01 (m, 2H) — — 19 500MHz d4-MeOH 8, 84 (s, 1H), 8.13-8.21 (m, 1H), 7.52-7.58 (m, 1H), 7.43-7.50 (m, 1H), 7.06- 7.18 (m, 2H), 5.50-5.61 (m, 2H), 4.39-4.58 (m, 1H), 3.64 (br d, 0=12.46 Hz, 1H) ), 3.45-3.56 (m, 1H), 3.11-3.22 (m, 2H), 3.01 (dd, 0=9.21, 12.33 Hz, 1H), 2.122, 25 (m, 1H), 1.83-1.97 (m, 1H) B Chiralpak AD-H, MeOH 15%, peak 1 IF-2019-169515 62-APN-ANP# WI Page 281 of 557 Ex. No. Free., Solvent iH NMR data (δ ppm) Separation step Separation conditions isomer SFC 20 500MHz d4-MeOH 8.85 (d, 0=1.30 Hz, 1H), 8.11-8.21 ...

Claims

1 A compound, characterized in that it is of formula I: (I) wherein: p is 0 or 1; when p is 0, then R1 is hydrogen, C1-6 alkyl, halogen or hydroxy; R2 is amino or C1-4 aminoalkyl; R3 is hydrogen; and R4 is hydrogen, C1-6 alkyl or phenyl; or when p is 0, then R1 and R3, taken in combination, form a fused C3-6 cycloalkyl ring or a fused 4- to 6-membered heterocycle ring with 1 or 2 ring heteroatoms independently selected from N, O or S, the cycloalkyl or heterocycle being optionally substituted with amino; R2 is hydrogen, C1-6 alkyl or C1-4 aminoalkyl; and R4 is hydrogen; or when p is 1, then R1 is NHR 1a; R 1a is hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C1-4 hydroxyalkyl or 4- to 6-membered heterocycloalkyl with a ring heteroatom selected from N, O or S; R 2 is hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl or C(O)NH2; R 3 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or hydroxy;and R4 is hydrogen, C1-4 alkyl, or halogen; or when p is 0 or 1, then C(NHR 1a)R2, taken in combination, forms a spirocyclic 4- to 6-membered heterocycloalkyl; R3 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, or hydroxy; and R4 is hydrogen or halogen; or when p is 1, then R1 and R3, taken in combination, form a fused 4- to 6-membered heterocycle or a fused 3- to 7-membered carbocycle, the heterocycle comprising a ring nitrogen atom and optionally 0 or 1 additional ring heteroatoms selected from N, O, and S, and the carbocycle being substituted with amino; and R2 is hydrogen; and R4 is hydrogen, halogen, or hydroxy; R 5 represents 1 or 2 independently selected substituents of hydrogen, halogen, hydroxy, amino, C1-6 alkyl or C1-6 alkoxy. R 6 is -(CR 7 R 8 )-A;A is a 5- or 6-membered heteroaryl, said heteroaryl comprising a ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, said heteroaryl being optionally substituted with 0, 1, 2, 3 or 4 groups independently selected from halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C(O)NH2, C(O)NHC1-6 alkyl, phenyl or 5- or 6-membered heteroaryl with a ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, wherein the optional heteroaryl or phenyl substituent is further substituted with 0, 1 or 2 C1-6 alkyl; or R 7 is hydrogen, C1-4 alkyl or amino; R 8 is hydrogen or C1-4 alkyl;or CR 7 R 8 , in combination, forms a 3- to 6-membered cycloalkandiyl group R 9 is hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 cyanoalkyl or a 4- to 7-membered heterocycle, the heterocycle having 1 or 2 ring heteroatoms selected from N, O or S, the sulfur of which may be optionally oxidized; R 10 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl or C3-7 cycloalkyl wherein each alkyl or cycloalkyl is optionally substituted with cyano, halogen, hydroxy, C1-6 alkoxy, S(O)q C1-6 alkyl, 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms selected from N, O or S or 5- or 6-membered heteroaryl having 1 ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms;or NR9R10, in combination, forms a 4- to 9-membered monocyclic or bicyclic heterocycle with a ring nitrogen atom and 0 or 1 additional ring heteroatoms selected from N, O, or S, said ring sulfur being optionally oxidized, said heterocycle being optionally substituted with 0, 1, or 2 substituents selected from halogen, oxo, hydroxy, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, S(O)qC1-6 alkyl, CO2H, C(O)C1-6 alkyl, or C(O)NH2; q is 0, 1, or 2; Z1 is N or CR11; Z2 is N or CR12; Z3 is N or CR13; Z4 is N or CR14; each Z 5 and Z 6 is independently N or C; where 0, 1 or 2 of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 are N;Each R11, R12, R13 and R14 is independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C3-7 cycloalkyl, cyano, SO2C1-6 alkyl, phenyl and aromatic 5 or 6-membered heterocycle, saturated or partially unsaturated with 1 or 2 ring heteroatoms independently selected from N, O and S, said heterocycle being optionally substituted with 1 or 2 substituents independently selected from C1-6 alkyl and halogen; or a pharmaceutically acceptable salt thereof; and provided that the compounds of Formula I do not include 1-[7-fluoro-6-methoxy-1-[[2-(trifluoromethyl)phenyl]methyl]-1H-benzimidazol-2-yl]-3-piperidinamine. 14 Claims follow;