EA043189B1 - BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS TRPC6 INHIBITORS - Google Patents

Description

The present invention relates generally to transient receptor potential cation channel (TRPC) proteins, and more particularly to inhibitors of transient receptor potential channel 6 (TRPC6) protein activity, to pharmaceutical compositions containing said inhibitors, and to methods of using such inhibitors.

Prerequisites for the creation of the invention

The TRPC6 channel, which is a member of the transient receptor potential (TRP) channel family and which is a non-selective cation permeable channel, is activated by diacylglycerol and the like produced by activating phospholipase C, and has physiological and pathophysiological effects. TRPC6 mediates effects such as pathological cardiac hypertrophy and fibrosis, progression of myocardial injury in muscular dystrophy, acute pulmonary vasoconstriction, pathological progression in chronic hypoxia-induced pulmonary hypertension, allergic airway reaction, migration of cells such as neutrophils, increased permeability of endothelial cells in inflammation, pathological flattening of podocytes and progression of glomerular damage, as well as the proliferation or infiltration of malignant tumors, and it is distributed in varying degrees in the brain, heart, lungs, kidneys, placenta, ovaries, spleen, and the like. (See, for example, J. 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. Vasc. Biol. 33:21212129, 2013; PLoS ONE 5: e12859, 2010; Expert. Opin. Ther Targets 14:513-27, 2010 and Navy Cancer 13:116, 2013). In hereditary focal segmental glomerulosclerosis (FSGS), gain-of-function TRPC6 mutant variants have been identified, and in patients with steroid-resistant nephrotic syndrome or idiopathic pulmonary arterial hypertension, a single nucleotide polymorphism in the promoter region has been identified that increases mRNA expression for TRPC6 (see, for example: Pediatr Res. 2013 Nov;74(5):511-6 and Circulation.2009 May 5;119(17):2313-2322). Thus, hyperfunction and increased expression of TRPC6 are believed to be responsible for the pathological progression 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; Clin. J. Am. Soc. Nephrol. 6:1139-1148 2011; Mol Biol Cell 22:1824-1835, 2011; BMC Nephrol 14:104, 2013; Pediatr Res 74:511516, 2013 and Nephrol Dial Transplant 28:1830-1838, 2013) . In addition, increased TRPC6 expression has been reported to be present 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, 2012).

New approaches are needed to modulate TRPC6 activity and, more specifically, inhibit TRPC6 activity in the prevention and/or treatment of nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal insufficiency, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, cancer and muscular dystrophy. There remains a need for agents that use different mechanisms of action and may have better outcomes in terms of symptom relief, patient safety and mortality, both short and long term.

Brief description 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 TRPC6 activity. Inhibition of TRPC6 activity may be particularly advantageous in the treatment or prevention of a number of diseases, including nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, diabetic nephropathy, heart failure, stroke, acute lung injury, acute respiratory failure syndrome (ARDS) and acute renal failure.

In one aspect, the present invention provides substituted benzimidazole compounds that modulate TRPC6 activity. Preferably, the substituted benzimidazole compounds of the present invention are TRPC6 inhibitors.

Substituted benzimidazole compounds of the present invention are compounds and salts according to formula (I)

- 1 043189

Also provided is a pharmaceutical composition containing a pharmaceutically acceptable excipient, carrier or excipient and at least one compound of formula (I) or subformulas thereof. The pharmaceutical compositions of the present invention are suitable for use in the treatment of a disease modulated by TRPC6 activity. In certain aspects, the pharmaceutical compositions of the present invention are suitable for use in the treatment of, for example, the treatment of nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, heart failure, stroke, malignant tumor or muscular dystrophy.

Also provided is a method for treating or preventing a disease in a mammal, the method comprising 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 containing a pharmaceutically acceptable excipient, carrier, or excipient, and at least one compound of formula (I) or subformulas thereof.

Also provided is a method for modulating TRPC6 activity in a mammal, the method comprising 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 containing a pharmaceutically acceptable excipient, carrier, or excipient and at least one compound of formula (I) or subformulas thereof. Another aspect of the present invention relates to a method for treating a TRPC6 mediated disease or disorder, the method comprising administering a TRPC6 inhibitor of the present invention to a patient in need of therapy. In some embodiments, the TRPC6-mediated disease or disorder is selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, cancer, or muscular dystrophy. In certain cases, the patient suffers from nephrotic syndrome, membranous nephropathy and acute renal failure.

Also contemplated is the use in the manufacture of a medicament for the treatment or prevention of a disease mediated by TRPC6 activity of at least one compound of formula I or subformulas thereof.

Other aspects and embodiments will be apparent to those skilled in the art from the following detailed description.

Detailed description of the invention

The present invention relates generally to compounds of formula I and their salts and tautomers, which inhibit the activity of the TRPC protein and, more specifically, inhibit the activity of the TRPC6 protein. In particular, the present invention relates to compounds that selectively inhibit the activity of the TRPC6 protein.

In a first embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to formula I

where p is 0 or 1;

if p is 0, then R ¹ is hydrogen, C1-C6 alkyl, halogen or hydroxy; R ² is amino or amino-C1-C4-alkyl; R ³ is hydrogen; and R ⁴ represents hydrogen, C1-C ₆ -alkyl or phenyl; or

- 2 043189 if p is 0, then R ¹ and R ³ taken in combination form a fused C3-C6 cycloalkyl ring or a fused 4-6 membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from N, O or S, wherein the cycloalkyl or heterocycle is optionally substituted with amino; R ² represents hydrogen, C1-C ₆ -alkyl or amino-C ₁ -C ₄ -alkyl; and R ⁴ is hydrogen; or if p is 1, then R ¹ is NHR ^1a ; R ^1a is hydrogen, C1C4 alkyl, C3-C7 cycloalkyl, hydroxy-C1-C4 alkyl or 4-6 membered heterocycloalkyl containing one ring heteroatom selected from N, O or S; R ² is hydrogen, C1-C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl or C(O)NH ₂ ; R ³ is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy or hydroxy; and R ⁴ is hydrogen, C1-C ₄ alkyl or halogen; or if p is 0 or 1, then C(NHR ^1a )R ² taken in combination forms a spirocyclic 4-6 membered heterocycloalkyl; R ³ represents hydrogen, halogen, C ₁ -C ₄ -alkyl, C1-C4 alkoxy or hydroxy; and R ⁴ is hydrogen or halogen; or if p is 1, then R ¹ and R ³ taken in combination form a fused 4-6 membered heterocycle or a fused 3-7 membered carbocycle, wherein the heterocycle contains a ring nitrogen and optionally 0 or 1;

an additional ring heteroatom selected from N, O, and S, wherein the carbocycle is substituted with amino; and R ² is hydrogen; and R ⁴ is hydrogen, halogen or hydroxy;

R ⁵ represents 1 or 2 substituents independently selected from hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -αlkoxy;

R ⁶ is -(CR ⁷ R ⁸ )-A;

A is a 5- or 6-membered heteroaryl, wherein the heteroaryl contains one ring heteroatom selected from N, O, or S and 0, 1, or 2 additional ring nitrogen atoms, the heteroaryl being optionally substituted with 0, 1, or 2 groups, independently selected from halogen, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ -cycloalkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ alkoxy, C(O)N(R ^a ) ₂ , S(O) ₂ C ₁ -C ₆ -alkyl, phenyl or 5- or 6-membered heteroaryl containing one ring heteroatom selected from N, O, or S, and 0, 1, or 2 additional ring nitrogens, wherein the optional heteroaryl or phenyl substituent is further substituted with 0, 1, or 2 C ₁ -C ₆ alkyl;

R ⁷ is hydrogen, C ₁ -C ₄ alkyl or amino;

R ⁸ is hydrogen or C ₁ -C ₄ alkyl; or

CR7R ⁸ taken in combination forms a 3-6 membered cycloalkanediyl group;

Z ¹ is N or CR ¹¹ ;

Z ² is CR ¹² ;

Z ³ is CR ¹³ ;

Z ⁴ is N or CR ¹⁴ , Z ⁵ and Z ⁶ are each independently C;

each of R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C1-C ₆ alkoxy , halogen-C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkoxy, C ₃ C ₇ -cycloalkyl, cyano, SO ₂ C ₁ -C ₆ -alkyl, phenyl and saturated, partially unsaturated or aromatic 5- or a 6-membered heterocycle containing 1 or 2 ring heteroatoms independently selected from N, O and S, wherein the heterocycle is optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ alkyl and halogen; with the proviso that the compounds of formula I do not include 1-[7-fluoro-6methoxy-1-[[2-(trifluoromethyl)phenyl]methyl]-1H-benzimidazol-2-yl]-3-piperidineamine.

In a second embodiment of the present invention, compounds and salts according to formula I are provided, which are generally represented by the structure

^R6

^R1 (I), where p is 0 or 1;

if p is 0, then R ¹ is hydrogen, C1-C6 alkyl, halogen or hydroxy; R ² is amino or amino C1- _C4 alkyl; R ³ is hydrogen; and R ⁴ is hydrogen, C ₁ -C ₆ alkyl or phenyl; or if p is 0, then R ¹ and R ³ taken in combination form a fused C3-C6 cycloalkyl ring or a fused 4-6 membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from N, O or S , wherein the cycloalkyl or heterocycle is optionally substituted with amino; R ² represents hydrogen, C1-C ₆ -alkyl or amino-C ₁ -C ₄ -alkyl; and ^R4

- 3 043189 is hydrogen; or if p is 1, then R ¹ is NHR ^1a ; R ^1a is hydrogen, C1C4 alkyl, C3-C7 cycloalkyl, hydroxy-C1-C4 alkyl or 4-6 membered heterocycloalkyl containing one ring heteroatom selected from N, O or S; R ² is hydrogen, C1-C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl or C(O)NH ₂ ; R ³ is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy or hydroxy; and R ⁴ is hydrogen, C1-C ₄ alkyl or halogen; or if p is 0 or 1, then C(NHR ^1a )R ² taken in combination forms a spirocyclic 4-6 membered heterocycloalkyl; R ³ is hydrogen, halo-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or hydroxy; and R ⁴ is hydrogen or halogen; or if p is 1, then R ¹ and R ³ taken in combination form a fused 4-6 membered heterocycle or a fused 3-7 membered carbocycle, wherein the heterocycle contains a ring nitrogen atom and optionally 0 or 1 additional ring heteroatom, selected from N, O and S, and wherein the carbocycle is substituted with amino; and R ² is hydrogen; and R ⁴ is hydrogen, halogen or hydroxy;

R ⁵ represents 1 or 2 substituents independently selected from hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy;

R ⁶ is -(CR ⁷ R ⁸ )-A; or

A is a 5- or 6-membered heteroaryl, wherein the heteroaryl contains one ring heteroatom selected from N, O, or S, and 0, 1, or 2 additional ring nitrogen atoms, wherein the heteroaryl is optionally substituted with 0, 1, 2 groups, independently selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₂ C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen-C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, halogen-C 1 - C ₆ -alkoxy, C(O)NH ₂ , C(O)NHC ₁ -C ₆ -alkyl, phenyl or 5- or 6-membered heteroaryl containing one ring heteroatom selected from N, O or S, and 0, 1 or 2 additional ring nitrogens, wherein the optional heteroaryl or phenyl substituent is further substituted with 0, 1 or 2 C ₁ -C ₆ alkyl; or

R ⁷ is hydrogen, C ₁ -C ₄ alkyl or amino;

R ⁸ is hydrogen or C ₁ -C ₄ alkyl; or

CR7R ⁸ taken in combination forms a 3-6 membered cycloalkanediyl group;

Z ¹ is N or CR ¹¹ ;

Z ² is CR ¹² ;

Z ³ is CR ¹³ ;

Z ⁴ is N or CR ¹⁴ , Z ⁵ and Z ⁶ are each independently C;

each of R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ - alkoxy, halogen-C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkoxy, C ₃ C ₇ -cycloalkyl, cyano, SO ₂ C ₁ -C ₆ -alkyl, phenyl and saturated, partially unsaturated or aromatic 5 - or a 6-membered heterocycle containing 1 or 2 ring heteroatoms independently selected from N, O and S, while the heterocycle is optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ -alkyl and halogen; and provided that the compounds of formula I do not include 1-[7-fluoro6-methoxy-1-[[2-(trifluoromethyl)phenyl]methyl]-1 H-benzimidazol-2-yl]-3-piperidinamine.

The condition is presented in the first embodiment to specifically exclude and relinquish rights thereto, an identified compound that is indexed as CAS No. 1014407-24-9.

In certain ^{aspects of the} first or ^second embodiment ^{, the} compounds ^{of formula I} include compounds of formula ^{Ia 5} and Z ⁶ are defined in the first or second embodiment.

In a third embodiment, the present invention provides compounds according to the first or second embodiments, wherein p is 0; R ¹ is hydrogen, C1-C6 alkyl, halo or hydroxy; R ² is amino-C1-C4-alkyl; and R ³ and R ⁴ are hydrogen.

In a fourth embodiment, the present invention provides compounds according to the first or second embodiments, wherein p is 0; R ¹ and R ³ taken in combination form a fused C ₃ -C ₆ cycloalkyl ring or a fused 4-6 membered azacyclic ring, wherein the cycloalkyl or azacycle is optionally substituted with amino; and R ² and R ⁴ are hydrogen.

In a fifth embodiment, the present invention provides compounds according to

- 4 043189 fourth embodiment, in which R ¹ and R ³ taken in combination form a fused pyrrolidine; and R ² and R ⁴ are hydrogen.

In a sixth embodiment, the present invention provides compounds according to the first or second embodiments, wherein p is 1, R ¹ is NHR ^1a ; R ^1a is hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl or 4-6 membered heterocycloalkyl containing one ring heteroatom selected from N, O or S; R ² is hydrogen or C1- _C4 alkyl; R ³ is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy or hydroxy; and R ⁴ is hydrogen, halo, or C1- _C4 alkyl.

In the seventh embodiment, the present invention provides compounds according to the sixth embodiment, wherein R ¹ is NHR ^1a ; R ^1a is hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl; R ² is hydrogen or methyl; R ³ is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy or hydroxy; and R ⁴ is hydrogen, halogen, methyl or ethyl. In certain aspects of the seventh embodiment, compounds are provided wherein R ^1a is hydrogen or methyl; R ² is hydrogen, R ³ is hydrogen, fluorine, methyl or hydroxy; and R ⁴ is hydrogen, halogen, methyl or ethyl.

In an eighth embodiment, the present invention provides compounds according to the sixth or seventh embodiments, wherein R ¹ is NH ₂ ; R ² is hydrogen; R ³ is hydrogen, fluorine, methyl or hydroxy; and R ⁴ is hydrogen, fluoro or methyl.

In a ninth embodiment, the present invention provides compounds according to the first or second embodiments, wherein p is 1; CR1R ² taken in combination form a spirocyclic 4-6 membered heterocycloalkyl; R ³ is hydrogen, halogen or C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy; and R ⁴ is hydrogen or halogen.

In a tenth embodiment, the present invention provides compounds according to the first or second embodiments, wherein p is 1; R ¹ and R ³ taken in combination form a fused 4- or 5-membered carbocycle substituted with amino; and R ² and R ⁴ are hydrogen.

In an eleventh embodiment, the present invention provides compounds according to any of the first to tenth embodiments wherein R ⁵ is 1 or 2 substituents independently selected from hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl.

In the twelfth embodiment, the present invention provides compounds according to the eleventh embodiment, wherein R ⁵ is hydrogen.

In a thirteenth embodiment, the present invention provides compounds according to any of the first to twelfth embodiments, wherein R ⁶ is -(CR ⁷ R ⁸ )-A.

In the fourteenth embodiment, the present invention provides compounds according to the thirteenth embodiment, wherein R ⁷ is hydrogen, methyl or ethyl; R ⁸ is hydrogen; or CR7R ⁸ taken in combination forms a cyclopropanediyl group.

In a fifteenth embodiment, the present invention provides compounds according to the thirteenth or fourteenth embodiments, wherein R ⁷ is hydrogen or methyl; and R ⁸ is hydrogen.

In a sixteenth embodiment, the present invention provides compounds according to any one of the thirteenth to fifteenth embodiments, wherein A is a 5- or 6-membered heteroaryl, wherein the heteroaryl contains one ring heteroatom selected from N, O, or S, and 0 , 1 or 2 additional ring nitrogens, wherein the heteroaryl is optionally substituted with 0, 1, or 2 groups independently selected from halogen, cyano, C1- _C6 alkyl, _{C2 - C6} alkenyl, _C2C6 alkynyl, halogen C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, halogen C ₁ -C ₆ alkoxy, C(O)NH ₂ , C(O)NHC ₁ -C ₆ alkyl, phenyl or 5- or A 6-membered heteroaryl containing one ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogens, wherein the optional heteroaryl or phenyl substituent is further substituted with 0, 1 or 2 C ₁ -C ₆ alkyl.

In a seventeenth embodiment, the present invention provides compounds according to a sixteenth embodiment, wherein A is pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, or pyrazin-2-yl, each of which is substituted with 1-3 groups independently selected from the group consisting of halo, cyano, C1- _C4 alkyl, halo-C1- _C4 alkyl, C1- _C4 alkoxy, halo- _C1 - _C4 alkoxy, C(O) NH ₂ , C(O)NHC ₁ -C ₄ -alkyl, phenyl or 5-membered heteroaryl containing one ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, where optional heteroaryl or the phenyl substituent is additionally substituted with 0, 1 or 2 C1C6 alkyls.

In an eighteenth embodiment, the present invention provides compounds wherein the 4-6 membered monocyclic azacycle is selected from the group consisting of

- 5 043189

In a nineteenth embodiment, the present invention provides compounds according to any of the first to twelfth embodiments, wherein R ⁶ is 2-oxopyrrolidin-3-yl or 2-oxopiperidin-3-yl, each of which is substituted on the nitrogen atom C1C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, halogen-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen-C ₁ -C ₆ alkoxy, hydroxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, phenyl or 5 - or 6-membered heteroaryl containing a ring heteroatom selected from N, O or S, and 0 or 1 additional atom nitrogen of the ring, where the heteroaryl or phenyl group is optionally substituted with 0, 1 or 2 C ₁ -C ₆ alkyls or halogens.

In the twentieth embodiment, the present invention provides compounds in which

R ⁶ is

where t is 1 or 2; And

R ¹⁹ is C1- _C6 alkyl, phenyl substituted with 0, 1 or 2 halogen atoms.

In the twenty-first embodiment, the present invention provides compounds with in which Z ¹ represents CR ¹¹ ;

Z ² is CR ¹² ;

Z ³ is CR ¹³ ;

Z ⁴ is N or CR ¹⁴ , each of Z ⁵ and Z ⁶ is C;

R ¹¹ represents hydrogen, halogen, cyano or C ₁ -C ₄ -alkyl;

each of R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, halo-C ₁ -C ₄ alkyl, C ₁ -C ₄ -alkoxy, halogen-C ₁ - C ₄ -alkoxy, C ₃ -C ₆ -cycloalkyl or 5-membered saturated, partially unsaturated or aromatic 5 - or 6-membered heterocycle containing 1 or 2 ring heteroatoms independently selected from N, O and S; And

R ¹⁴ is hydrogen, halogen, cyano or C ₁ -C ₄ alkyl.

In certain aspects of the twenty-second embodiment, compounds are provided in which R ¹¹ is hydrogen.

In certain other aspects of the twenty-second embodiment, compounds are provided wherein R ¹⁴ is hydrogen, fluorine, chlorine, methyl, or cyano. In certain aspects of the twenty-second embodiment, compounds are provided wherein R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, C ₁ -C ₄ alkyl, halo-C ₁ -C ₄ alkyl , C ₁ -C ₄ -alkoxy and halo-C ₁ -C ₄ -alkoxy.

In still other aspects of the twenty-second embodiment, compounds are provided wherein R ¹¹ is hydrogen; R ¹⁴ represents hydrogen, fluorine, chlorine, methyl or cyano; and each of R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy.

In the twenty-third embodiment, the present invention provides compounds according to the twenty-ninth embodiment, which include compounds of formula III

- 6 043189 where X ¹ represents CR ¹⁶ or N;

X ² is CR ¹⁷ or N;

X ³ is CR ¹⁸ or N;

where at least one of X ¹ , X ² and X ³ represents N;

Z ⁴ is N or CR ¹⁴ ;

R ¹ is NHR ^1a ;

R ^1a represents hydrogen or C ₁ -C ₄ -alkyl;

R ² represents hydrogen or C ₁ -C ₄ -alkyl;

R ³ is hydrogen or halogen;

R ⁴ is hydrogen or halogen;

R ⁷ is hydrogen, methyl or ethyl;

R ¹¹ represents hydrogen, halogen, cyano or C ₁ -C ₄ -alkyl;

each of R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, halo-C ₁ -C ₄ alkyl, C ₁ -C ₄ -alkoxy, or halo-C ₁ - C ₄ alkoxy;

R ¹⁴ represents hydrogen, halogen, cyano or C ₁ -C ₄ -alkyl;

R ¹⁵ is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen-C ₁ -C ₄ alkyl, halogen-C ₁ -C ₄ alkoxy, C(O) NH ₂ , C(O)NH(C ₁ -C ₄ -alkyl) or 5-membered heteroaryl containing one ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms;

R ¹⁶ is hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo-C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkoxy;

R ¹⁷ is hydrogen or halogen; And

R ¹⁸ is hydrogen, halogen, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halo-C ₁ -C ₄ -alkyl or halo-C ₁ -C ₄ -alkoxy, where at least one of R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ is not hydrogen.

In certain aspects of the twenty-third embodiment, compounds of formula (III) include compounds of formula (IIIa)

In certain other aspects of the twenty-third embodiment, compounds of formula (III) include compounds of formula (IIIb)

In certain other aspects of the twenty-third embodiment, compounds of formula (IIIb) include compounds of formula (IIIc)

In a twenty-fourth embodiment, the present invention provides compounds according to wherein R ² is hydrogen, R ⁷ is hydrogen or methyl; and Z ⁴ is CR ¹⁴ .

- 7 043189

In the twenty-fifth embodiment, the present invention provides compounds according to the first or second embodiments, wherein the compound is shown in Table. And lower.

Table A (S)-6-((2-(3-Aminopiperidin-1-yl)-6-chloro-1H-benzo[(1]imidazol-1 yl)methyl)nicotinonitrile;

(8)-6-((2-(3-aminopiperidin-1-yl)-5-chloro-1H-benzo[(1]imidazol-1yl)methyl)nicotinonitrile;

(8)-6-((2-(3-aminopiperidin-1-yl)-4-chloro-1H-benzo[(1]azol-1-yl imide)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-1H-benzo[<1]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-1H-benzo[(1]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[(1]imidazol-1yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-5-chloro-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile;

6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[(1]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3^48)-3-amino-4-fluoropiperidin-1-yl)-5-chloro-1H-benzo[<1]imidazol-1yl)methyl)nicotinonitrile;

(R)-6-((2-(3-amino-4,4-diφτoppipiperidin-1-yl)-4-chloro-1H-benzo[(1]imidazol-1 yl)methyl)nicotinonitrile;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1Hbenzo[d]imidazole-4-κapbonitril;

(R)-6-((2-(3-amino-4,4-diφτopπpiperidin-1-yl)-6-chloro-1H-benzo[(1]imidazol-1 yl)methyl)nicotinonitrile;

(R)-6-((2-(3-Amino-4,4-difluoropiper id in-1-yl)-5-chloro-1H-6eH3o[d]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-6-(τpiφtormethyl)-lHbenzo[d]imidazol-l-yl)methyl)niκotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-(τpiφtormethyl)-lHbenzo[d]imidazol-l-yl)methyl)niκotinonitrile;

6-((2-((38.48)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[(1]imidazol-1 yl)methyl)nicotinonitrile;

(8)-6-((2-(5-Amino-3,3-difluoropiperidin-1-yl)-1H-benzo^]imidazol-1-8043189yl)methyl)nicotinonitrile;

2-((3 R,4R)-3-amino-4-φτoppiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-6fluoro-1H-benzo[(1]imidazole -4-carbonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethoxy)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-(τpiφtormetoκci)-lHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτoppiperidin-l-yl)-6-φτop-5-(τpiφτopmethyl)-lHbenzo[d]imidazol-l-yl)methyl)niκotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-φτop-6-(τpiφτopmethyl)-lHbenzo[d]imidazol-l-yl)methyl)niκotinonitrile;

6-((2-((3 aS, 7 aR)-heκcahydro ro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)-1Hbenzo[d]imidazol-l-yl) methyl) nicotinonitrile;

6-((2-((3aS, 7a8)-hexahydro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile ;

6-((2-((3aS, 7a8)-hexahydro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)-1Hbenzo[0]imidazol-1-yl)methyl)nicotinonitrile ;

6-((2-((3 aS, 7 aR)-heκcahydro ro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)-1Hbenzo[d]imidazol-l-yl) methyl) nicotinonitrile;

(R)-6-((2-(l,6-diazapipo[3.5]nonan-6-yl)-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile;

(S)-6-((2-(l,6-diazapipo[3.5]nonan-6-yl)-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile;

(3R,4R)-l-(l-((5-chloropyridin-2-yl)methyl)-6-(methylsylphonyl)-lHbenzo[d]imidazol-2-yl)-4-φτoppiperidin-3-amine;

(3R,4R)-l-(l-((5-chloropyridin-2-yl)methyl)-5-(methylsylphonyl)-lHbenzo[4]imidazol-2-yl)-4-fluoropiperidin-3-amine;

2-((3 R,4R)-3-amino-4-φτoppiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6φτop-lH-benzo[d]imidazol-4 -κapbonitril;

(ЗR,4R)-l-(5,7-diφτop-l-((5-φtorpyridin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperide in-3-amine ;

(ЗR,4R)-l-(4,6-diφτop-l-((5-φtorpyridin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperide in-3-amine ;

(3R,4R)-l-(5,7-diφτop-l-((5-φtorpyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3-amine;

(3R,4R)-l-(4,6-diφτop-l-((5-φtorpyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3-amine;

2-((3 R,4 S)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1-((5-fluoropyrimide in-2yl)methyl)-lH-benzo[d] imidazole-4-κapbonitril;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-6-fluoro-1-((5-fluoropyrimidin-2-9 043189 yl)methyl)-1H-benzo[0 ]imidazole-4-carbonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

(3R,4S)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl) ^-z- fluoropiper idin-3-amine;

(3^48)-1-(1-((5-chloropyrimidin-2-yl)methyl)-5-fluoro-1H-benzo[b]imidazol-2-yl)fluoropiper idin-3-amine;

(R)-2-(3-amino-4,4-difluoropiperid in-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1H benzo[d]imidazol-6-κapbonitril;

(R)-2-(3-amino-4,4-difluoropiperid in-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1H benzo[(1]imidazole-5-carbonitrile ;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5,6-dichloro-lH-benzo[d]imidazolyl)methyl)nicotinonitrile;

τpet-butyl-((ЗR,4R)-1 -(1 -((5-cyanopyridin-2-yl)methyl)-5,6-dimethyl-1Нbenzo[b]imidazol-2-yl)-4-fluoropiperidine -3-yl)carbamate;

(S)-6-((2-(3-aminopiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

(S)-6-((2-(3-aminopiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4S)-3-amino-4-φτoppipiperidin-l-yl)-5-φτop-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-1H-benzo[b]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

(S)-2-(3-aminopiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1Hbenzo[d]imidazole-6-κapbonitril;

(S)-2-(3-aminopiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H6eH3o[d]imidazole-5-carbonitrile;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1Hbenzo[d]imidazole-6-κapbonitril;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H6eH3o[d]imidazole-5-carbonitrile;

(R)-2-(3-amino-4,4-difluoropiper id in-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1Hbenzo[d]imidazole-6-κapbonitril;

(R)-2-(3-amino-4,4-difluoropiperid in-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H6eH3o[d]imidazole-5-carbonitrile;

(8)-6-((2-(3-aminopiperidin-1-yl)-4,6-dichloro-1H-6eH3o[d]imidazol-1-10043189 yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4,6-dichloro-1H-6eH3o[d]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3^48)-3-amino-4-fluoropiperidin-1-yl)-4,6-dichloro-1H-benzo[c1]imide azol-1yl)methyl)nicotinonitrile;

(R)-6-((2-(3-amino-4,4-difluoropiper id in-1-yl)-4,6-dichloro-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

(S)-6-((2-(3-aminopiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile;

(8)-6-((2-(3-aminopiperidin-1-yl)-5,7-difluoro-1H-benzo^]imidazol-1yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5,7-diφτop-lH-benzo[d]imide azol-1yl)methyl)nicotinonitrile;

6-((2-((3^48)-3-amino-4-fluoropiperidin-1-yl)-4,6-difluoro-1H-benzo|^]imidazol-1yl)methyl)nicotinonitrile;

6-((2-((3^48)-3-amino-4-fluoropiperidin-1-yl)-5,7-difluoro-1H-benzo|^]imidazol-1yl)methyl)nicotinonitrile;

(R)-6-((2-(3-amino-4,4-difluoropiper id in-1-yl)-5,7-difluoro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

2-((3 R,4 S)-3-amino-4-fluoropiper idin-1-yl)-1-((5-cyanopyride in-2-yl)methyl)-1Hbenzo[d]imidazol-6 -κapbonitril;

2-((3 R,4 8)-3-amino-4-fluoropiper idin-1-yl)-1-((5-cyanopyrid in-2-yl)methyl)-1Hbenzo[d]imidazol-5 -κapbonitril;

(8)-6-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

(R)-6-((2-(3-amino-4,4-difluoropiper idin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile;

6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((1R, 5S)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1Hbenzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride;

6-((2-((1S,5R)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1Hbenzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3a^4^6a8)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1Hbenzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3aS, 4S, 6aI)-4-aminohexahydrocyclopenta[c]pyrrol-2( 1H)-yl)-1H- 11 043189 benzo[(1]imidazol-1 - yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3A,48,6a8)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1Hbenzo[(1]imidazol-1-yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3aS,4R,6aR)-4-aminohexcahydrocyclopenta[c]pyrpol-2(lH)-yl)-lHbenzo[(1]imidazol-1-yl)methyl)nicotinonitrile hydrochloride;

(R)-6-((2-(3-(aminomethyl)pyrrolidin-1-yl)-1H-benzo[(1]imidazol-1yl)methyl)nicotinonitrile hydrochloride;

(8)-6-((2-(3-(aminomethyl)pyrrolide in-1-yl)-1H-benzo[<1]imidazol-1yl)methyl)nicotinonitrile hydrochloride;

6-((2-((ZK,48)-3-amino-4-fluoropiperidin-1-yl)-5,6-dichloro-1H-benzo[(1]azol-1yl imide)methyl)nicotinonitrile hydrochloride;

6-((2-((ZK,48)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[(1]imidazol-1yl)methyl)nicotinonitrile hydrochloride;

(R)-6-((2-(3-Amino-4,4-difluoropiper id in-1-yl)-5,6-difluoro-1H-benzo[(1]imidazol-1yl)methyl)nicotinonitrile hydrochloride ;

(R)-1-(1-((5-chloropyridin-2-yl)methyl)-1 H-benzo[(1]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride;

(3R,4S)-l-(l-((5-chloropyridin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine hydrochloride;

(R)-6-((2-(3-amino-4,4-difluoropiperid in-1-yl)-4,6-difluoro-1H-benzo[4]imidazol-1yl)methyl)nicotinonitrile hydrochloride;

(R)-6-((2-(3-amino-4,4-difluoropiper idin-1-yl)-6-fluoro-1H-benzo[4]imidazol-1 yl)methyl)nicotinonitrile;

(R)-6-((2-(3-amino-4,4-difluoropiperid in-1-yl)-4-(trifluoromethyl)-1Hbenzo[4]imidazol-1-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-4-(τpφtormethyl)-lHbenzo[4]imidazol-1-yl)methyl)nicotinonitrile;

6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-4-(trifluoromethyl)-1Hbenzo[4]imidazol-1-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-6-chloro-3H-imidazo[4,5-b]pyridin3-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-6-chloro-lH-imidazo[4,5-b]pyridin1-yl)methyl)nicotinonitrile;

6-((2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-6-chloro-lH-imidazo[4,5-b]pyridin1-yl)methyl)-M-( tert-butyl)nicotinamide;

6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-1H-benzo[4]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3S,4S)-3-amino-4-hydroxypiperidin-1-yl)-1H-benzo[4]imidazol-1yl)methyl)nicotinonitrile;

6-((2-(2,6-diazaspiro[3.4]octan-6-yl)-1H-benzo[4]imidazol-1-12043189yl)methyl)nicotinonitrile;

6-((2-((4aK,7a8)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)- 1Hbenzo[(1]imidazol-1-yl)methyl)nicotinonitrile hydrochloride;

6-((2-((4aS,7aR)-heκcahydropirpolo[3,4-b][l,4]ocazin-6(2H)-yl)-lHbenzo[(1]imidazol-1-yl)methyl)nicotinonitrile hydrochloride;

6-((2-((4aK,7aK)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)-1Hbenzo[c!]imidazol-1-yl)methyl)nicotinonitrile ;

6-((2-((4a8,7a8)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)-1Hbenzo[(1]imidazol-1-yl)methyl)nicotinonitrile ;

(S)-3-amino-1-(1-((5-cyanopyridine in-2-yl)methyl)-1H-benzo[<1]imidazol-2yl)piperidine-3-carboxamide;

(R)-3-amino-1-(1-((5-cyanopyridine-2-yl)methyl)-1H-benzo[c1]imide azol-2yl)piperidine-3-carboxamide;

(8)-6-((2-(3-amino-3-(hydroxymethyl)piperidin-1-yl)-1H-benzo[c1]imidazol-1yl)methyl)nicotinonitrile;

(R)-6-((2-(3-amino-3-(hydroxymethyl)piperidin-1-yl)-1H-benzo[c1]imidazol-1yl)methyl)nicotinonitrile;

6-((2-((3R,4S)-3-amino-4-fluoro-1-piper id inyl)-6-(trifluoromethyl)-1Hbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3^48)-3-amino-4-fluoro-1-piperidinyl)-5-(trifluoromethyl)-1Hbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R)-3-amino-4,4-diφτop-l-piperidinyl)-6-(τpiφtormethyl)-lHbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R)-3-amino-4,4-diφτop-l-piperidinyl)-5-(τpiφtormethyl)-lHbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5-methyl-1H-benzimidazol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-6-methyl-1 H-benzimid azol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-6-chloro-5-methyl-lH-benzimidazol1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-5-chloro-6-methyl-lH-benzimidazol1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-6-φτop-5-methyl-lH-benzimidazol1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-5-φτop-6-methyl-lH-benzimidazol1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3S)-3-(methylamine o)-1-piperide inyl)-1 H-benzimid azol-1-yl)methyl)-3 pyridinecarbonitrile;

6-((2-((3R)-3 -(methylamino)-1-piper idinyl)-1 H-benzimidazol-1 -yl)methyl)-3 - 13 043189 pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-6-(difluoromethoxy)-1Hbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-5-(diφτopmetoκci)-lHbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-4-methoxy-1 H-benzimidazol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-4-methyl-1 H-benzimid azol-1 yl)methyl)-3-pyridinecarbonitrile;

5-((2-((3R,4S)-3-amino-4-φτop-l-piperidinyl)-6-(τpiφtormethyl)-lHbenzimidazol-1-yl)methyl)-2-pyrazinecarboxamide;

5-((2-((3R,4S)-3-amino-4-φτop-l-piperidinyl)-5-(τpiφtormethyl)-lHbenzimidazol-1-yl)methyl)-2-pyrazinecarboxamide;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-6-chloro-5-(τpφτopmetoκci)-lHbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-5-chloro-6-(τpiφτopmetoκci)-lHbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-6-chloro-5-(τpφτopmethyl)-lHbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-5-chloro-6-(τpiφτopmethyl)-lHbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((5R)-1,7-diazaspiro[4.5 ] decan-7-yl)-1 H-benzimidazol-1 -yl)methyl)-3 pyridinecarbonitrile, 6-((2-((5 S)-1,7-d iazaspiro[4.5]d ecan-7-yl)-1 H-benzimidazol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((6R)-1,8-diazaspiro[5.5]undecan-8-yl)-1 H-benzimidazol-1-yl)methyl)-3 pyridinecarbonitrile;

6-((2-((6S)-1,8-diazaspiro[5.5]undecan-8-yl)-1 H-benzimidazol-1-yl)methyl)-3 pyridinecarbonitrile;

6-((2-((4aR,8aR)-heκcahydro-2H-πirido[4,3-b][l,4]ocazin-6(5H)-yl)-lHbenzimidazol-1 -yl)methyl)-3 -pyridinecarbonitrile;

6-((2-((4a8,8a8)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)-yl)-1Hbenzimidazol-1-yl)methyl)-3 -pyridinecarbonitrile;

5-((2-((3R,4R)-3-amino-4-φτop-1-piperidinyl)-5,6-difluoro-1 H-benzimidazol-1 yl)methyl)-2-pyrazinecarboxamide;

5-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-6-(τpiφtormethyl)-lHbenzimidazol-1-yl)methyl)-2-pyrazinecarboxamide;

6-((2-((5R)-1,7-diazaspiro[4.5] decan-7-yl)-1 H-benzimidazol-1-yl)methyl)-3 pyridinecarbonitrile;

6-((2-((5 S)-1,7-d iazaspiro[4.5 ]d decan-7-yl)-1 H-benzimidazol-1-yl)methyl)-3 pyridinecarbonitrile;

- 14 043189

6-((2-((3R)-3-amino-4,4-difluoro-1-piperidinyl)-5-methoxy-1H-benz imidazol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R)-3-amino-4,4-difluoro-1-piperid inyl)-6-methoxy-1H-benz imidazol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3S)-3-(methylamino)-1-piperide inyl)-6-(trifluoromethyl)-1 H-benzimid azol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3S)-3-(methylamino)-1-piperide inyl)-5-(trifluoromethyl)-1 H-benzimid azol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3S)-3-amino-3-methyl-1-piperide inyl)-1 H-benzimid azol-1-yl)methyl)-3 pyridinecarbonitrile;

(8)-6-((2-(3-aminopiperidin-1-yl)-6-methoxy-1H-benzo[(1]azol-1-yl imide)methyl)nicotinonitrile yl-2,2,2-trifluoroacetate;

(8)-6-((2-(3-aminopiperidin-1-yl)-5-methoxy-1H-benzo[(1]imidazol-1 yl)methyl)nicotinonitrile yl-2,2,2-trifluoroacetate;

6-((2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-4-chloro-6-φτop-lHbenzo[(1]imidazol-1-yl)methyl)nicotinonitrile yl- 2,2,2-trifluoroacetate;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-methoκci-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-methoxy-1H-benzo[c1]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4S)-3-amino-4-fluoropiper idin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3^48)-3-amino-4-fluoropiperidin-1-yl)-5-methoxy-1H-benzo|^]imidazol-1yl)methyl)nicotinonitrile hydrochloride;

2-((3 R,4 S)-3-amino-4-fluoropiper idin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-6φτop-lH-benzo[d] imidazole-4-κapbonitril;

(R)-2-(3-amino-4,4-difluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-5φτop-lH-benzo[d]imidazol-7-κapbonitril ;

(R)-2-(3-amino-4,4-difluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6φτop-lH-benzo[d]imidazol-4-κapbonitril ;

6-((2-((3R,4R)-3-amino-4-hydroκc and π and pieridin-1 -yl)-6-chloro-1H-benzo[(1]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4S)-3-amino-4-hydroxypiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

(R)-4-((2-(3-amino-4,4-difluoropiperidin-1-yl)-1H-6eH3o[d]imidazol-1yl)methyl)benzonitrile;

4-((2-((3R, 4R)-3-amino-4-hydroxypiperide in-1-yl)-1Hbenzo[d]imidazol-l-yl)methyl)benzonitril dihydrochloride with 4-((2-( (38.48)-3-amino-4hydroκcypiperidin-l-yl)-lH-benzo[d]imidazol-l-yl)methyl)benzonitrile (1:1);

4-((2-((3R,4R)-3-amino-4-φτop-1-piperidinyl)-5,7-difluoro-1H-benz imidazol-1-15043189 yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-4,6-difluoro-1H-benz imidazol-1 yl)methyl)benzonitrile;

2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-1-(4-cyanobenzyl)-1H-benzimidazole-6carbonitrile;

2-((3 R,4R)-3-amino-4-φτop-1-piperidinyl)-1-(4-cyanobenzyl)-1H-benzimid azole-5 carbonitrile;

2-((3R)-3-amino-4,4-difluoro-1-piper idinyl)-1-(4-cyanobenzyl)-1H-benzimidazole6-carbonitrile;

2-((3 R)-3-amino-4,4-difluoro-1-piper idinyl)-1-(4-cyanobenzyl)-1H-benzimidazole5-carbonitrile;

(R)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[(1]imidazol-1-yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-methylpiperidin-1-yl)-1H-benzo[(1]imidazol-1 yl)methyl)benzonitrile;

4-((2-(3-(aminomethyl)-3-methylpyrrolidin-1-yl)-1H-benzo[(1]imidazol-1 yl)methyl)benzonitrile;

4-((2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)- 1H-benzo[(1]imidazol-1 yl)methyl)benzonitrile and 4-((2-( (3R,4S)-3-amino-4-phenylpyrrolide in-1-yl)-1H benzo[(1]imidazol-1-yl)methyl)benzonitrile;

(S)-4-((2-(3-aminopyrrolidin-1-yl)-1H-benzo[(1]imidazol-1 yl)methyl)benzonitrile;

(S)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[(1]imidazol-1-yl)methyl)benzonitrile;

4-((2-(6-Amino-2-azaspiro[4.4]nonan-2-yl)-1H-benzo[(1]imidazol-1yl)methyl)benzonitrile;

4-((2-(4-aminohexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)-1 H-benzo[(1] imidazol-1 yl)methyl)benzonitrile;

4-((2-((38.48)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[c1]imidazol-1 yl)methyl)benzonitrile;

4-((2-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[(1]imidazol-1yl)methyl)benzonitrile;

4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[(1]imidazol-1 yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[(1]imidazol-1 yl)methyl)benzonitrile;

(R)-4-((2-(3-(aminomethyl)-3-fluoropyrrolide in-1-yl)-1 H-benzo[(1]imidazol-1 yl)methyl)benzonitrile-2,2,2 -trifluoroacetate;

(8)-4-((2-(3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-1H-benzo[c1]imidazol-1 yl)methyl)benzonitryl-2,2,2-trifluoroacetate;

(R)-4-((2-(3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)- 1H-benzo[(1]imidazol-1 yl)methyl)benzonitryl-2,2,2-trifluoroacetate ;

- 16 043189 (8)-4-((2-(3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)- lH-6eH3o[d]imidazol-1 yl)methyl)benzonitryl-2,2,2 -trifluoroacetate;

(8)-4-((2-(3-(aminomethyl)pyrrolide in-1-yl)-1H-6eH3o[d]imidazol-1yl)methyl)benzonitrile;

molecular weight: 331.41;

(R)-4-((2-(3-(aminomethyl)pyrrolidin-1-yl)-1H-6eH3o[d]imidazol-1yl)methyl)benzonitrile;

molecular weight: 331.41;

4-((2-((3 S,4 S)-3 -amino-4-methylpiperide in-1 -yl)-1 H-6eH3o[d]imidazol-1 yl)methyl)benzonitrile yl-2,2, 2-trifluoroacetate;

4-((2-((3 S,4R)-3 -amino-4-methylpiperidin-1 -yl)- lH-benzo[d]imidazol-1 yl)methyl)benzonitryl yl-2,2,2-trifluoroacetate ;

4-((2-((3R,4S)-3-amino-4-methylpiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)methyl)benzonitryl-2,2,2-trifluoroacetate;

4-((2-(( 1 S,5R)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1Hbenzo[(1]imidazol-1-yl)methyl)benzonitrile;

4-((2-((1R, 5S)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1Hbenzo[(1]imidazol-1-yl)methyl)benzonitrile;

(R)-4-((2-(3-aminopiperidin-1-yl)-6-methoxy-1H-6eH3o[d]imidazol-1yl)methyl)benzonitrile;

(R)-4-((2-(3-aminopiperidin-1-yl)-5-methoxy-1H-6eH3o[d]imidazol-1yl)methyl)benzonitrile;

(2-((3R,4R)-3-amino-4-φτoppipiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[(1]imidazole-6-carbonitrile;

(3R,4R)-4-φτop-1-(1-((5-φτoppyrimidin-2-yl)methyl)-lH-benzo[d]imide azol-2yl)piper idine-3-amine;

(3R,4R)-4-φτop-l-(l-((5-φτoppyridin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)piper idin-3-amine;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-fluoropyridin-2-yl)methyl)-1Hbenzo[d]imidazol-6-κapbonitril;

2-((3R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-fluoropyridin-2-yl)methyl)-1Hbenzo[d]imidazol-5-κapbonitril;

(3R,4R)-l-(l-((5-bromopyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)-4fluoropiper idin-3-amine;

(3R,4R)-4-φτop-1 -(1-((5-(trifluoromethyl)pyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3-amine;

(3R,4R)-4-φτop-l-(l-((5-methoκcypyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)piper idin-3-amine;

(3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)-4fluoropiper idin-3-amine;

- 17 043189

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-fluoropyrimide in-2-yl)methyl)-1Hbenzo[d]imidazol-6-κapbonitril;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-fluoropyrimide in-2-yl)methyl)-1Hbenzo[d]imidazol-5-κapbonitril;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-cyanopyrimide in-2-yl)methyl)lH-benzo[d]imidazol-5-κapbonitril ;

2-((3R,4R)-3-amino-4-φτoppiperide in-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-5-κapbonitril;

2-((3R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-bromopyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-6-κapbonitril;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-bromopyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-5-κapbonitril;

5-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)methyl)pyrazine-2-carbonitrile;

2-((3 R,4 S)-3-amino-4-fluoropiper idin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-1Hbenzo[d]imidazol-6- κapbonitril;

2-((3 R,4 S)-3-amino-4-fluoropiper idin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-1Hbenzo[d]imidazol-5- κapbonitril;

(3R,4R)-3-amino-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1Hbenzo[c!]imidazol-2-yl)piperidin-4-ol;

(3R,4R)-3-amino-l-(l-((5-chloropyrimidin-2-yl)methyl)-5-φτop-lHbenzo[c!]imidazol-2-yl)piperidin-4-ol;

6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-hydroκc and π and pieridin-1 -yl)-5-fluoro-1H-benzo[c1]imidazol-1 yl)methyl)nicotinonitrile;

(S)-1-(1-((5-chloropyridin-2-yl)methyl)-lH-6eH3o[d]imidazol-2-yl)piperidin-3-amine;

(S)-5-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1 yl)methyl)picolinonitrile;

(3R,4R)-l-(l-((5-chloropyridin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine hydrochloride;

(R)-6-((2-(3-amino-4,4-difluoropiper id in-1-yl)-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-chloropyride in-2-yl)methyl)-1Hbenzo[c1]imidazole-6-carbonitrile hydrochloride ;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-chloropyride in-2-yl)methyl)-1Hbenzo[c1]imidazole-5-carbonitrile hydrochloride ;

(3R,4R)-l-(l-((R)-l-(5-chloropyridin-2-yl)ethyl)-lH-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine hydrochloride;

- 18 043189 (3R,4R)-1-(1 -((S)-1 -(5-chloro pyridin-2-yl)ethyl)- lH-benzo[d]imidazol-2-yl)-4fluoropiperidin- 3-amine hydrochloride;

(3R,4R)-1-(1 -((R)-1 -(5-chloropyridine in-2-yl)ethyl)-5,6-d iftoro-1 H-benzo[d]imidazol-2yl) -4-fluoropiperidine-3-amine hydrochloride;

(ЗR,4R)-l-(l-((S)-l-(5-chloropyridin-2-yl)ethyl)-5,6-diφΊΌp-lH-benzo[d]imide azol-2yl)-4- fluoropiperidine-3-amine hydrochloride;

(ЗR,4R)-l-(5-chloro-l-((R)-l-(5-chloropyridin-2-yl)ethyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperidin- 3-amine hydrochloride;

(3R,4R)-1 -(5-chloro-1 -((S)-1 -(5-chloropyridin-2-yl)ethyl)- lH-benzo[d]imidazol-2-yl)4-fluoropiperidin- 3-amine hydrochloride;

(3R,4R)-1 -(6-chloro-1 -((R)-1 -(5-chloropyridin-2-yl)ethyl)- lH-benzo[d]imidazol-2-yl)4-fluoropiperidin- 3-amine hydrochloride;

(3R,4R)-1 -(6-chloro-1 -((S)-1 -(5-chloropyridin-2-yl)ethyl)- lH-benzo[d]imidazol-2-yl)4-fluoropiperidin- 3-amine hydrochloride;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((R)-1-(5-cyanopyridin-2-yl)ethyl)lH-benzo[d ]imidazole-6-κapbonitril hydrochloride;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((R)-1-(5-cyanopyridin-2-yl)ethyl)lH-benzo[d ]imidazole-5-κapbonitril hydrochloride;

2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((S)-1-(5-cyanopyridine in-2-yl)ethyl)lH-benzo[d ]imidazole-6-κapbonitril hydrochloride;

2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((S)-1-(5-cyanopyridine in-2-yl)ethyl)1H-benzo|^ ]imidazole-5-carbonitrile hydrochloride;

(ЗR,4R)-l-(l-((5-chloropyridin-2-yl)methyl)-5,6-diφτop-lH-benzo[d]imidazol-2-yl)4-fluoropiperidin-3-amine hydrochloride ;

(3R,4R)-l-(5,6-diφτop-l-((5-φtorpyridin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperidin-3-amine hydrochloride ;

(R)-l-(l-((5-chloropyridin-2-yl)methyl)-5,7-diφτop-lH-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride;

(R)-l-(l-((5-chloropyridin-2-yl)methyl)-4,6-diφτop-lH-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride;

(R)-1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)- lH-benzo[d]imidazol-1-yl)-2,3 dihydro-1H-indene -5-carbonitrile hydrochloride;

(S)-1 -(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)- lH-benzo[d]imidazol-1 -yl)-2,3 dihydro-1H- indene-5-carbonitrile hydrochloride;

(R)-5-((2-(3-amino-4,4-diφτopπpiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1 yl)methyl)pyrazine-2-carbonitrile;

(R)-5-((2-(3-amino-4,4-diφτoppipiperidin-1-yl)-5-chloro-III-benzoimidazol-1-yl)methyl)pyrazine-2-carbonitrile;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1 yl)-M-isopropylacetamide;

- 19 043189

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1-(azetidine-1 -yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-Ni(2-cyanopropyl) -14-ethylacetamide;

-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1-methylpyrrolide in-2- He;

-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-phenylpiperide in-2- He;

-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1-(4-chlorophenyl) pyrrolidin-2-one;

2-((3 R,4R)-3-amino-4-φτoppiperidin-1-yl)-1-((5-methoxypyrimidin-2-yl)methyl)1H-benzo[b]imidazole-5-carbonitrile hydrochloride ;

2-((3 R,4R)-3-amino-4-φτoppiperid in-1-yl)-1-((5-methoxypyrimidin-2-yl)methyl)1H-benzo[b]imidazole-6-carbonitrile hydrochloride ;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((6-(trifluoromethyl)pyridin-3 yl)methyl)-1H-benzo[b] imidazole-6-carbonitrile hydrochloride;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((6-(trifluoromethyl)pyridin-3 yl)methyl)-1H-benzo[b] imidazole-5-carbonitrile hydrochloride;

(S)-3-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lHbenzo[(1]imidazol-1-yl)-1-methylpyrrolidine -2-he;

(R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-d iftoro-1H6eH3o[d]imidazol-1-yl)-1-methylpyrrolidine -2-he;

(S)-3-(2-((ЗR,4R)-3-amino-4-φτopπiperidin-l-yl)-5,6-diφτop-lHbenzo[d]imidazol-1-yl)-1 -(4 -chlorophenyl)pyrrolidin-2-one;

(R)-3 -(2-((3R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-d iftoro-1Hbenzo[b]imidazol-1 -yl)-1 -( 4-chlorophenyl)pyrrolidin-2-one;

2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-1-((5-cyano-2-pyrazinyl)methyl)-1H-benzimidazole-6-carbonitrile;

2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-1-((5-cyano-2-pyrazinyl)methyl)-1H-benzimidazole-5-carbonitrile;

5-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-4,6-difluoro-1H-benz imidazol-1 yl)methyl)-2-pyrazinecarbonitrile;

5-((2-((3R,4R)-3-amino-4-φτop-1-piperidinyl)-5,7-difluoro-1H-benz imidazol-1 yl)methyl)-2-pyrazinecarbonitrile;

(3 S)-1-(1-((5-fluoro-2-pyridinyl)methyl)-1 H-benzim idazol-2-yl)-M-methyl-3 piperidinamine;

(3 S)-1-(1-((5-chloro-2-pyridinyl)methyl)-1 H-benz and mide azol-2-yl)-N-methyl-3-piperidineamine;

6-((1 R)-1-(2-((3 S)-3-(methylamino)-1-piperide inyl)-1 H-benzimid azol-1-yl)ethyl)-3 pyridinecarbonitrile;

- 20 043189

6-((lS)-l-(2-((3S)-3-(methylamino)-1-piper idinyl)-1 H-benzimidazol-1-yl)ethyl)-3 pyridinecarbonitrile;

(3R,4R)-1-(1-((5-chloro-2-pyrimide inyl)methyl)-5,7-difluoro-1 H-benzimid azol-2-yl)-4fluoro-3-piperidineamine;

(3R,4R)-1-(1-((5-chloro-2-pyrimide inyl)methyl)-4,6-d iftor-1 H-benzimid azol-2-yl)-4fluoro-3-piperidineamine;

(3R,4R)-1-(5,6-difluoro-1-((1-methyl-1H-indazol-4-yl)methyl)-1H-benzimidazol-2yl)-4-fluoro-3-piperidineamine;

(3R,4R)-1-(5,6-difluoro-1-(5-quinolinylmethyl)-1 H-benzimid azol-2-yl)-4-fluoro-3-piperidineamine;

(3R,4R)-1-(5,6-difluoro-1-((1R)-1-(8-quinolinyl)ethyl)-1 H-benzimid azol-2-yl)-4fluoro-3-piperidinamine;

(3R,4R)-1-(5,6-difluoro-1-((1S)-1-(8-quinolinyl)ethyl)-1H-benzimidazol-2-yl)-4fluoro-3-piperidinamine;

(ЗR,4R)-l-(l-((3-(3-chloroφenyl)-l,2-oκcazol-5-yl)methyl)-5,6-diφτop-lHbenzimidazol-2-yl)-4-fluoro -3-piperidinamine;

(3R,4R)-1-(5,6-difluoro-1-((1-methyl-1H-indazol-7-yl)methyl)-1H-benzimidazol-2yl)-4-fluoro-3-piperidinamine;

(3R,4R)-l-(l-(2,6-dichlorobenzyl)-5,6-diφτop-lH-benzimidazol-2-yl)-4-φτop-3piperidinamine;

-(1-azetidinyl)-2-(2-((3S)-3-(methylamino)-1-piperide inyl)-1H-benzimidazol-1 yl)ethanone;

6-((lR)-l-(4,6-diφτop-2-((4aR,8aR)-heκcahydro-2H-pyrido[4,3-b][l,4]oκcasin-6(5H)yl) -1 H-benzimidazol-1 -yl)ethyl)-3-pyridinecarbonitrile;

6-((^)-1-(4,6-difluoro-2-((4a8,8a8)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)yl) -1 H-benzimidazol-1 -yl)ethyl)-3-pyridinecarbonitrile;

6-((18)-1-(4,6-difluoro-2-((4a8,8a8)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)yl) -1 H-benzimidazol-1 -yl)ethyl)-3-pyridinecarbonitrile;

6-((18)-1-(4,6-diφτop-2-((4aR,8aR)-heκcahydro-2H-pyrido[4,3-b][l,4]oκcasin-6(5H)yl) -1 H-benzimidazol-1 -yl)ethyl)-3-pyridinecarbonitrile;

6-((1 R)-1-(5,7-d iftoro-2-((4а^ 8aR)-heκcahydro-2H-pyrido[4,3 -b ] [ 1,4 ]oxazine-6(5Н) yl)-1H-benzimidazol-1-yl)ethyl)-3-pyridinecarbonitrile;

6-((^)-1-(5,7-difluoro-2-((4a8,8a8)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)yl) -1 H-benzimidazol-1 -yl)ethyl)-3-pyridinecarbonitrile;

6-((18)-1-(5,7-difluoro-2-((4a8,8a8)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)yl) -1 H-benzimidazol-1 -yl)ethyl)-3-pyridinecarbonitrile;

6-((18)-1-(5,7-diφτop-2-((4aR,8aR)-heκcahydro-2H-pyrido[4,3-b][l,4]oκcasin-6(5H)yl) -1 H-benzimidazol-1 -yl)ethyl)-3-pyridinecarbonitrile;

2-(2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benzimidazol-1-yl)N-methylacetamide;

- 21 043189

2-(2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1 H-benzimid azol-1 -yl)1 -(4-morpholinyl) ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1 H-benzimid azol-1 -yl)1 -(1-pyrrolide inyl )ethanone;

2-(2-((3 R, 4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1 H-benzimid azol-1 -yl) N, N-dimethylacetamide;

(2R)-2-(2-((3R,4R)-3-amino-4-fluoro-1-piperide inyl)-5,6-difluoro-1 H-benzimidazol1-yl)-I, N-dimethylpropanamide;

(2S)-2-(2-((3R,4R)-3-amino-4-φτop-1-piperidinyl)-5,6-difluoro-1H-benzimidazol-1 yl)-I, N-dimethylpropanamide;

2-(2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1 H-benzimid azol-1 -yl)1 -(1-piperide inyl )ethanone;

2-(2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benzimid azol-1-yl)N-ethylacetamide;

-((5-chloro-2-pyrimidinyl)methyl)-2-((3R,4R)-4-φτop-3 -(methylamino)-1 piperidinyl)-1H-benzimidazole-6-carbonitrile;

-((5-chloro-2-pyrimidinyl)methyl)-2-((3R,4R)-4-φτop-3 -(methylamino)-1 piperidinyl)-1H-benzimidazole-5-carbonitrile;

2-(2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-6-chl op-1 H-benzimid azol-1-yl)-1-(1 azetidinyl)ethanone ;

2-(2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-5-chloro-1 H-benzimid azol-1-yl)-1-(1-azetidinyl)ethanone;

2-((3 R,4 S)-3-amino-4-fluoro-1-piperide inyl)-1-(2-(1-azetide inyl)-2-oxoethyl)-1H-benzimidazole-6-carbonitrile;

2-((3 R,4 S)-3-amino-4-fluoro-1-piperide inyl)-1-(2-(1-azetide inyl)-2-oxoethyl)-1H-benzimidazole-5-carbonitrile;

(3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl)-4fluoropiper idin-3-amine;

(3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-5-φτop-lH-benzo[d]imidazol-2-yl)-4fluoropiper idin-3-amine;

(R)-6-((2-(3-aminopiperidin-1-yl)-1H-benzo[b]imidazol-1-yl)methyl)nicotinonitrile;

(R)-5-((2-(3-aminopiperidin-1-yl)-1H-benzo[b]imidazol-1 yl)methyl)picolinonitryl-2,2,2-trifluoroacetate;

(R)-l-(l-(isoquinolin-7-ylmethyl)-lH-benzo[d]imidazol-2-yl)piperidin-3-amine;

(R)-1-(1-((1-methyl-1H-indazol-7-yl)methyl)-1H-6eH3o[d]imidazol-2-yl)piperidine3-amine;

6-((R)-1-(2-((S)-3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)ethyl)nicotinonitrile hydrochloride;

6-((S)-1-(2-((S)-3-aminopiperidin-1-yl)-lH-benzo[d]imidazole-1-22 043189 yl)ethyl)nicotinonitrile hydrochloride;

6-((R)-1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)ethyl)nicotinonitrile hydrochloride;

6-((S)-1 -(2-((3 R,4R)-3-amino-4-fluoro piper idin-1 -yl)- lH-benzo[d]imidazol-1 yl)ethyl)nicotinonitrile hydrochloride ;

6-((R)-1-(2-((8)-3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)propyl)nicotinonitrile hydrochloride;

6-((S)-1-(2-((8)-3-aminopiperidin-1-yl)-1H-benzo[(1]imidazol-1 yl)propyl)nicotinonitrile hydrochloride;

(3R,4R)-l-(5,6-diφτop-l-((5-φtorpyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3-amine;

-(1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-diftor-1H-6eH3o[d]imidazol1-yl)ethyl)benzonitrile;

(3R,4R)-l-(5,6-diφτop-l-((5-φtorpyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3-amine;

(3R,4 S)-1 -(5,6-d iftor-1 -((5-fluoropyride in-2-yl)methyl)-1 H-6eH3o[d]azol-2-yl imide)4-fluoropiperide in-3-amine;

(3R,4 δ)-4-φτορ-1 -(1 -((5-fluoropyrimide in-2-yl)methyl)-6-(trifluoromethyl)-1Нbenzo[d]imidazol-2-yl)piperidin- 3-amine;

(3R,4 δ)-4-φτορ-1-(1 -((5-fluoropyrimide in-2-yl)methyl)-5 -(trifluoromethyl)-1Нbenzo[d]imidazol-2-yl)piperidin-3 -amine;

(R)-1 -(5,6-difluoro-1 -((5-fluoropyride in-2-yl)methyl)-1 H-6eH3o[d]imidazol-2-yl)-4,4d iftorpiper idin- 3-amine;

2-(2-((3 R,4 8)-3-amino-4-fluoropiperide in-1-yl)-6-(trifluoromethyl)-1H6eH3o[d]imidazol-1-yl)-1-( azetidin-1-yl)ethane-1-one;

2-(2-((3 R,4 S)-3-amino-4-fluoropiperide in-1-yl)-5-(trifluoromethyl)-1H6eH3o[d]imidazol-1-yl)-1-(azetidine -1 -yl)ethan-1 -one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(2.2 -dimethylpyrrolidin-1-yl)ethan-1-one;

6-((2-((3 R,4δ)-3-amino-4-hydroκc and piperidin-1-yl)-6-φτop-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4δ)-3-amino-4-hydroκc and piperidin-l-yl)-5-φτop-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile;

4-((R)-1-(2-((8)-3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)ethyl)benzonitrile hydrochloride;

4-((S)-1-(2-((8)-3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)ethyl)benzonitrile hydrochloride;

(8)-4-((2-(3-aminopiperidin-1-yl)-1 H-6eH3o[d]imidazol-1-yl)methyl)-3 fluorobenzonitrile hydrochloride;

(S)-l-(l-(4-chlorobenzyl)-lH-benzo[d]imidazol-2-yl)piperidin-3-amine

- 23 043189 hydrochloride;

4-((R)-1-(2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[c1]imidazol-1 yl)ethyl)benzonitrile hydrochloride;

4-((S)-1-(2-((3 R,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[c1]imidazol-1 yl)ethyl)benzonitrile hydrochloride;

4-((R)-1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[c1]imidazol-1 yl)ethyl)benzonitrile hydrochloride;

4-((S)-1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[c1]imidazol-1-yl)ethyl)benzonitrile hydrochloride;

(S)-4-((2-(3-aminopiperidin-1-yl)-1 H-benzo[<1]imidazol-1-yl)methyl)-3 chlorobenzonitrile hydrochloride;

(3R,4R)-1-(1 -((1R)-1 -(2,4-dichlorophenyl)ethyl)-5,6-difluoro-1 H-benzimid azol-2-yl)-4fluoro-3-piper idynamine;

(3R,4R)-1 -(1 -((1 S)-1 -(2,4-dichlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4fluoro-3-piperidineamine ;

(3R,4R)-1 -(1 -((1R)-1 -(2-chlorophenyl)ethyl)-5,6-difluoro-1 H-benzimid azol-2-yl)-4fluoro-3-piperidineamine ;

(3R,4R)-1-(1-((1S)-1-(2-chlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4fluoro-3-piper-idynamine;

(3R,4R)-1 -(1 -((1R)-1 -(3-chlorophenyl)ethyl)-5,6-difluoro-1 H-benzimid azol-2-yl)-4fluoro-3-piperidineamine ;

(3R,4R)-1-(1-((1S)-1-(3-chlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4fluoro-3-piper-idynamine;

(3R,4R)-l-(l-((lR)-l-(2,5-dichlorophenyl)ethyl)-5,6-diφτop-lH-benzimidazol-2-yl)-4fluoro-3-piperidineamine;

(3R,4R)-1 -(1 -((1 S)-1 -(2,5-dichlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4fluoro-3-piperidineamine ;

(3R,4R)-l-(l-((lR)-l-(2,4-difluorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4fluoro-3-piperidineamine;

(3R,4R)-1-(1-((1S)-1-(2,4-difluorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4fluoro-3-piperidineamine;

(3R,4R)-1-(1 -((1R)-1 -(3,4-dichlorophenyl)ethyl)-5,6-difluoro-1 H-benzimid azol-2-yl)-4fluoro-3-piper idynamine;

(3R,4R)-1 -(1 -((1S)-1 -(3,4-d chlorophenyl)ethyl)-5,6-difluoro-1 H-benzimidazol-2-yl)-4fluoro-3 - piper idynamine;

(3R,4R)-1 -(1 -((1R)-1 -(2,5-difluorophenyl)ethyl)-5,6-difluoro-1 H-benzimid azol-2-yl)-4fluoro-3-piper idynamine;

(3R,4R)-1 -(1 -((1 S)-1 -(2,5-difluorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4fluoro-3-piperidineamine ;

(3R,4R)-1 -(5,6-difluoro-1 -((1R)-1 -(4-(trifluoromethyl)phenyl)ethyl)-1 H-benzimidazole- 24 043189

2-yl)-4-fluoro-3-piperide inamine;

(3R,4R)-l-(5,6-diφτop-l-((lR)-l-(4-(τpiφτopmetoκci)φenyl)ethyl)-lHbenzimidazol-2-yl)-4-fluoro-3-piperidinamine;

(3R,4R)-l-(l-(5-chloro-2-(τpiφτopmetoκci)benzyl)-5,6-diφτop-lH-benzimid azol-2yl)-4-fluoro-3-piper idynamine;

(3R,4R)-1 -(5,6-difluoro-1 -(4-(1H-1,2,4-triazol-1 -yl)benzyl)- 1H-benzimidazol-2-yl)4-fluoro- 3-piper idynamine;

2-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benz imidazol-1 yl)methyl)-5-chlorobenzonitrile;

(3R,4R)-1-(1-(2,4-d-ichlorobenzyl)-5,6-difluoro-1 H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine;

4-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benz imidazol-1 yl)methyl)-3-(difluoromethoxy)benzonitrile ;

(3R,4R)-1-(1-(2,5-dichlorobenzyl)-5,6-difluoro-1 H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine;

(3R, 4R)-1-(1-(4-(1,1-difluoroethyl)benzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4fluoro-3-piperidinamine;

4-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benz imidazol-1 yl)methyl)-2-methylbenzonitrile;

4-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benz imidazol-1 yl)methyl)-2-chlorobenzonitrile;

2-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benz imidazol-1 yl)methyl)-4-chlorobenzonitrile;

(3R,4R)-l-(l-(2-(diφτopmetoκci)benzyl)-5,6-diφτop-lH-benzimidazol-2-yl)-4fluoro-3-piperidinamine;

(3R,4R)-1-(1-(3-chloro-4-fluorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine;

(3R,4R)-l-(l-(4-chloro-2-methoκcibenzyl)-5,6-diφτop-lH-benzimidazol-2-yl)-4-φτop3-piperidinamine;

(3R,4R)-l-(l-(2,4-diφτopbenzyl)-5,6-diφτop-lH-benzimidazol-2-yl)-4-φτop-3piperidinamine;

(3R,4R)-1-(5,6-difluoro-1-(2-(trifluoromethyl)benzyl)-1H-benzimidazol-2-yl)-4-fluoro3-piperidineamine;

2-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benz imidazol-1 yl)methyl)benzonitrile;

(3R,4R)-l-(l-(2-chlorobenzyl)-5,6-diφτop-lH-benzimidazol-2-yl)-4-φτop-3-piperidineamine;

(3R,4R)-1-(1-(2-chloro-4-fluorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidineamine;

(3R,4R)-1 -(5,6-difluoro-1 -(4-fluoro-2-(trifluoromethyl)benzyl)- 1H-benzimidazol-2-yl)- 25 043189

4-fluoro-3-piper idynamine;

(3R,4R)-l-(l-(3,4-diφτopbenzyl)-5,6-diφτop-lH-benzimidazol-2-yl)-4-φτop-3piperidinamine;

(3R,4R)-1-(1-(4-chloro-2-fluoro-benzyl)-5,6-d iffluoro-1 H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine;

(3R,4R)-1-(1-(3,4-d-ichlorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidineamine;

(3R,4R)-1-(1-(4-chloro-3-fluorobenzyl)-5,6-d iffluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidineamine;

(3R,4R)-1-(5,6-difluoro-1-(4-(trifluoromethyl)benzyl)-1H-benzimidazol-2-yl)-4-fluoro3-piperidineamine;

(3R,4R)-1-(5,6-difluoro-1-(4-(trifluoromethoxy)benzyl)-1H-benzimidazol-2-yl)-4fluoro-3-piperidinamine;

(3R,4R)-l-(l-(4-(diφτopmethyl)benzyl)-5,6-diφτop-lH-benzimidazol-2-yl)-4-φτop3-piperidineamine;

(3R,4R)-l-(5,6-diφτop-l-(3-(τpiφτopmetoκci)benzyl)-lH-benzimidazol-2-yl)-4fluoro-3-piperidinamine;

(3R,4R)-1-(5,6-difluoro-1-(3-(trifluoromethyl)benzyl)-1H-benzimidazol-2-yl)-4-fluoro3-piperidinamine;

-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1H-benz imidazol-1 yl)methyl)benzonitrile;

(3R,4R)-1-(1-(3-chlorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidineamine;

(S)-1-(1-(4-fluorobenzyl)-1 H-benzo[c1]imidazol-2-yl)piperidin-3-amine;

(S)-1-(1-(4-(1,2,4-oxadiazol-3-yl)benzyl)-1H-benzo[c1]imidazol-2-yl)piper idine-3 amine;

(R)-1-(1-(4-(methylsulfonyl)benzyl)-1H-benzo[c1]imidazol-2-yl)piper idin-3 amine;

(R)-1-(1-(4-(1H-1,2,4-triazol-1-yl)benzyl)-1H-benzo[c1]imidazol-2-yl)piperidine3-amine;

(R)-2-((2-(3-aminopiperidin-1-yl)-1H-benzo[c1]imidazol-1-yl)methyl)benzonitrile;

(R)-1-(1-(2,6-d-ichlorobenzyl)-1 H-benzo[<1]imidazol-2-yl)piperide in-3-amine;

(R)-1-(1-(2-chlorobenzyl)-1 H-benzo[<1]imide azol-2-yl)piperide in-3-amine;

(R)-1-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[<1]imidazol-2-yl)piper idin-3-amine;

(R)-1-(1-(4-(trifluoromethoxy)benzyl)-1H-benzo[c1]imidazol-2-yl)piper idin-3 amine;

(R)-1-(1-(4-chlorobenzyl)-1 H-benzo[c1]imide azol-2-yl)piperide in-3-amine;

(R)-1-(1-(3-chlorobenzyl)-1 H-benzo[c1]imide azol-2-yl)piperide in-3-amine;

(R)-1-(1-(4-(1,1-difluoroethyl)benzyl)-1H-benzo[<1]imide azol-2-yl)piperide in-3-amine;

(R)-2-(4-((2-(3-aminopiperidin-1-yl)-1 H-benzo[<1]imidazol-1-yl)methyl)phenyl)-2-26 043189 methylpropanenitrile;

(K)-1-(1-(4-(difluoromethyl)benzyl)-1H-benzo[<1]imidazol-2-yl)piperidine-3-amine;

(R)-4-((2-(3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)methyl)-Mmethylbenzamide;

(R)-4-((2-(3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)methyl)-3-fluorobenzonitrile;

(R)-2-(4-((2-(3-aminopiperidin-1-yl)-lH-6eH3o[d]imidazol-1-yl)methyl)phenoxy)acetonitrile;

(R)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[b]imidazol-1-yl)methyl)-H N-dimethylbenzenesulfonamide;

(R)-1-(1-(4-methylbenzyl)-1H-benzo[c1]imidazol-2-yl)piper idin-3-amine;

(R)-l-(l-(4-φτopbenzyl)-lH-benzo[d]imidazol-2-yl)piperidin-3-amine;

(R)-1-(1-((1-methyl-1H-indazol-7-yl)methyl)-1H-6eH3o[d]imidazol-2-yl)piperidine3-amine;

(R)-1-(1-(2,4-difluorobenzyl)-1 H-6eH3o[d]azol-2-yl imide)piperide in-3-amine;

(R)-1-(1-(3,4-difluorobenzyl)-1 H-6eH3o[d]azol-2-yl imide)piperide in-3-amine;

(R)-1-(1-(4-Chloro-3-fluorobenzyl)-1 H-6eH3o[d]imidazol-2-yl)piperidin-3-amine;

(R)-1-(1-((3-(3-chlorophenyl)isoxazol-5-yl)methyl)-1H-6eH3o[d]imidazol-2yl)piperidine-3-amine;

(R)-1-(1-(3-chloro-4-methoxybenzyl)-lH-benzo[d]imidazol-2-yl)πiπep idin-3-amine;

(R)-4-((2-(3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)methyl)-3 chlorobenzonitrile;

(R)-1-(1-(2,4-d-ichlorobenzyl)-1 H-6eH3o[d]imidazol-2-yl)piperide in-3-amine;

(R)-4-((2-(3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)methyl)-3-methoxybenzonitrile;

(R)-2-((2-(3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)methyl)-5chlorobenzonitrile;

4-((R)-1-(2-((R)-3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)ethyl)benzonitrile;

4-(1-(2-((8)-3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)ethyl)benzonitrile;

(R)-3-((2-(3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3R,4S)-3-amino-4-fluoropiper idin-1-yl)-6-chloro-1H-benzo[d]imidazol-1 yl)methyl)benzonitrile hydrochloride;

(8)-4-((2-(3-aminopiperidin-1-yl)-6-methoxy-1H-6eH3o[d]azol-1-yl)methyl)benzonitrile imide hydrochloride;

4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-methoxy-lH-benzo[d]imidazol-1-yl)methyl)benzonitrile;

(8)-4-((2-(3-aminopiperidin-1-yl)-5-methoxy-3H-imidazo[4,5-b]pyridin-3yl)methyl)benzonitrile hydrochloride;

(R)-4-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1-27043189 yl)methyl)benzonitrile;

(R)-4-((2-(3-amino-4,4-diφτoppipiperidin-1-yl)-6-methoxy-lH-benzo[d]imidazol-1 yl)methyl)benzonitrile;

(R)-4-((2-(3-amino-4,4-diφτopπpiperidin-1-yl)-4-chloro-1H-6eH3o[d]imidazol-1yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-1H-benzo[d]imidazol-1 yl)methyl)benzonitrile;

4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-1H-benzo[d]imidazol-1 yl)methyl)benzonitrile;

(R)-4-((2-(3-amino-4,4-diφτoppipiperidin-1-yl)-4-methoxy-lH-benzo[d]imidazol-1 yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-fluoropiperide in-1-yl)-1 H-imide azo[4,5-c]pyridin-1 yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-3H-imidazo[4,5-c]pyridin-3yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-6-ethoxy-1H-benzimid azol-1 yl)methyl)benzonitrile;

4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1 H-imidazo[4,5-b]pyridin-1 yl)methyl)benzonitrile;

4-((2-((3R)-3-amino-4,4-difluoro-1-piper id inyl)-6-fluoro-1H-benzimidazol-1 yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-lH-imidazo[4,5-b]pyridin-lyl)methyl)benzonitrile;

(8)-4-((2-(3-aminopiperidin-1-yl)-4-chloro-1H-benzo[b]azol-1-yl)methyl)benzonitrile imide 2,2,2-trifluoroacetate;

(8)-4-((2-(3-aminopiperidin-1-yl)-3H-imidazo[4,5-b]pyridin-3yl)methyl)benzonitrile hydrochloride;

4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[b]imidazol-1 yl)methyl)benzonitrile hydrochloride;

(8)-4-((2-(3-aminopiperidin-1-yl)-6-chloro-1H-benzo[b]imide azol-1yl)methyl)benzonitrile;

(8)-4-((2-(3-aminopiperidin-1-yl)-5-chloro-1H-benzo[b]imidazol-1yl)methyl)benzonitrile;

(R)-1-(2-((8)-3-aminopiperidin-1-yl)-1 H-benzo[(1]imidazol-1-yl)-2,3-dihydro-1Nindene-5-carbonitrile;

(S)-1-(2-((8)-3-aminopiperidin-1-yl)-1H-benzo[b]imidazol-1-yl)-2,3-dihydro-1Hindene-5-carbonitrile;

(3R,4R)-4-φτop-l-(l-((5-methoκcypyridin-2-yl)methyl)-lH-benzo[d]imidazol-2-28 043189 yl)piper idin-3-amine;

l-(2-(2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)azetidine-3 - carbonitrile;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1 -(3 -( tert-butoxy)azetide in-1-yl)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(3.3 -difluoroazetidin-1-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(3-isopropylazetidine -1 -yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 - yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1 -(6.6 -difluoro-2-azaspiro[3.3]heptan-2-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-1-(7-oxa -2-azaspiro[3.5]nonan-2-yl)ethanone;

(R)-6-((2-(4,4-diφtorop-3-(methylamino)piperidin-1-yl)-6-fluoro-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile;

(R)-6-((2-(4,4-diφτop-3-((2-hydroκciethyl)amino)piperidin-l-yl)-6-φτop-lHbenzo[d]imidazol-l-yl)methyl) nicotinonitril;

(S)-6-((2-(3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)methyl)nicotinic acid;

(S)-6-((2-(3-aminopiperidin-1-yl)-lH-benzo[d]imidazol-1-yl)methyl)nicotinamide;

6-((2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1 H-6eH3o[d]imidazol-1 yl)methyl)nicotinamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)acetic acid;

6-((R)-1 -(4,6-d iφτop-2-((ЗR,4R)-4-φτop-3 -(methylamino)piperide in-1-yl)-1Нbenzo[d]imidazol-l -yl)ethyl)nicotinonitrile;

6-((S)-1 -(4,6-diφτop-2-((ЗR,4R)-4-φτop-3 -(methylamino)piperidin-1-yl)-1Нbenzo[d]imidazol-l-yl )ethyl)nicotinonitrile;

6-((R)-1-(5,7-d and φτop-2-((ЗR,4R)-4-φτop-3 -(methylamino)piperide in-1-yl)-1Нbenzo[(1]imidazole- 1 -yl)ethyl)nicotinonitrile and

6-((S)-1 -(5,7-diφτop-2-((ЗR,4R)-4-φτop-3 -(methylamino)piperidin-1 -yl)-1Нbenzo[(1] imidazol-1 - yl)ethyl)nicotinonitrile.

In another aspect of the thirty-eighth embodiment, the present invention provides compounds according to the first embodiment, wherein the compound is shown in Table. A-1 below.

Table A-1

2-((2-((3R,4R)-3-Amino-4-fluoropiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1 yl)methyl)pyrimidine-5-carbonitrile;

2-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1 yl)methyl)pyrimidine-5-carbonitrile;

- 29 043189 (3R, 4R)-4-φτop-1 -(6-φτορ-1 -((5-methox ipyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3- amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1H-benzo[(1]imidazol-1-yl)M-methyl-M-( 2,2,2-trifluoroethyl)acetamide;

(3R, 4R)-4-φτop-1-(5-fluoro-1-((5-methox ipyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-2-yl)piperidin-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-cyano-6-fluoro-1Нbenzo[d]imidazol-l-yl)-N-methyl-N -(2,2,2-τpiφtoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1 yl)-N, N-dimethylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-methoxy-lH-benzo[d]imidazol-1 yl)-M-methyl-M-(2 ,2,2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-methoxy-1H-benzo[d]imidazol-1 yl)^, N-dimethylacetamide;

6-((2-((3R,4R)-3-amino-4-methoxypiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτoppiperidin-l-yl)-6-φτop-4-methoκci-lHbenzo[d]imidazol-l-yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-5-(τpφτopmethyl)-3H-imidazo[4,5b]pyridin-3-yl)methyl)nicotinonitrile;

(3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl)-4methoxypiperidin-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-bromo-lH-benzo[d]imidazol-1-yl)1-(azetidin-1-yl )ethane-1-one;

(3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl)-4methoxypiperidin-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-lH-benzo[d]imidazol-1-yl)M-methyl-M-(2 ,2,2-trifluoroethyl)acetamide;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-5-(τpφτopmethyl)-lH-imidazo[4,5b]pyridin-1-yl)methyl)nicotinonitrile;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethyl)- 1H6eH3o[d]imidazol-1-yl)-1-morpholinoethan-1-one ;

2-(2-((3 R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-φτop-lH-benzo[d]imidazol-l-yl)N-methyl-H-(2 ,2,2-trifluoroethyl)acetamide;

2-(2-((3^48)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1-yl)N, N-dimethylacetamide;

2-(2-((3 R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-N-benzoIimidazol-1-yl)^methyl-M-(2,2,2- trifluoroethyl)acetamide;

6-((2-((3R,4S)-3-amino-4-methoxypiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile;

- 30 043189

2-(2-((3 R,4 S)-3-amino-4-fluoropiperide in-1-yl)-6-(trifluoromethyl)-1Hbenzo[(1] imidazol-1-yl)-1 - morpholinoethane-1-one;

(R)-2-(2-(3-amino-4,4-difluoropiper idin-1-yl)-6-fluoro-1 H-6eH3o[d]imidazol-1-yl)^methyl-M-(2 ,2,2-trifluoroethyl)acetamide;

2-(2-((3 R,4 S)-3-amino-4-fluoropiperide in-1-yl)-6-fluoro-1 H-6eH3o[d]imidazol-1-yl)M-methyl-M -(2,2,2-trifluoroethyl)acetamide;

(3R,4S)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl)-4methoxypiperide in-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-6-(trifluoromethoxy)-1Hbenzo[d]imidazol-l-yl)-N,N-dimethylacetamide;

2-(6-φτop-2-((ЗR,4R)-4-φτop-3 -(methylamino)piperidin-1-yl)- 1Нbenzo[d]imidazol-l-yl)-N-methyl-N-( 2,2,2-τpiφtoroethyl)acetamide;

2-(2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-bromo-lH-benzo[d]imidazol-l-yl)1-(azetidin-1-yl) ethane-1 -one;

2-(2-((3 R,4 S)-3-amino-4-fluoropiperide in-1-yl)-5-chloro-1 H-6eH3o[d]imidazol-1-yl)N, N-dimethylacetamide ;

2-(6-fluoro-2-( 1,7-d iazaspiro[4.5] decan-7-yl)-1 H-6eH3o[d] imidazol-1 -yl)-M-methyl^(2,2, 2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-5-(trifluoromethyl)-1H6eH3o[d]imidazol-1-yl)-1-morpholinoethane-1 - He;

2-(2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-5-(trifluoromethoxy)-1Hbenzo[d]imidazol-l-yl)-N,N-dimethylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-5-(trifluoromethoxy)-1H6eH3o[d]imidazol-1-yl)-1-morpholinoethane-1 - He;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-5-φτop-7-metoκci-lHbenzo[d]imidazol-1-yl)methyl)nicotinonitrile;

(3R,4S)-l-(l-((5-chloropyrimidin-2-yl)methyl)-5-φτop-lH-benzo[d]imidazol-2-yl)-4methoxypiperide in-3-amine;

2-(2-((3 R,4 S)-3-amino-4-fluoropiperide in-1-yl)-5-(trifluoromethyl)-1Н6eH3o[d]imidazol-1-yl)-1-morpholinoethane-1 -He;

2-(5-φτop-2-((ЗR,4R)-4-φτop-3 -(methylamino)piperidin-1-yl)-1Нbenzo[d]imidazol-l-yl)-N-methyl-N-( 2,2,2-τpiφtoroethyl)acetamide;

2-(2-(3-amino-4-methylpyrrolidin-1-yl)-6-fluoro-1 H-6eH3o[d]imidazole-1-ππ)-N methyl-M-(2,2,2-trifluoroethyl )acetamide;

2-(2-((3 R,4R)-3-amino-4-hydroκcipiperide in-1-yl)-6-φτop-lH-benzo[d]imidazol-1 yl)-N-methyl-N-( 2,2,2-τpiφtoroethyl)acetamide;

(R)-2-(2-(3-amino-4,4-difluoropiper idin-1-yl)-5-fluoro-lH-benzo[d]imidazol-1-yl)M-methyl-M-(2 ,2,2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-methoκcipiperide in-1-yl)-5-fluoro-1H-benzo[b]imidazol-1 yl)-N-methyl-N-( 2,2,2-τpiφtoroethyl)acetamide;

- 31 043189

2-(2-((3 R)-3-amino-4-hydroxypiperidin-1-yl)-5-fluoro-1 H-benzo[c1]imidazol-1-yl)^methyl^-(2,2, 2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-methoxypiperidin-1-yl)-6-fluoro-1H-benzo[c1]imidazol-1 yl)-X-methyl-X-(2 ,2,2-trifluoroethyl)acetamide;

2-(2-(3-(aminomethyl)-3-fluoropyrrolide in-1-yl)-6-fluoro-1H-benzo[c1]imidazol-1-yl)^methyl^-(2,2,2-trifluoroethyl )acetamide;

2-(2-(3-(aminomethyl)-3-fluoropyrrolide in-1-yl)-5-fluoro-1H-benzo[c1]imidazol-1-yl)M-methyl-M-(2,2,2 -trifluoroethyl)acetamide;

2-(6-φτop-2-((4aR,8aR)-heκcahydro-2H-pyrido[4,3-b][l,4]oκcasin-6(5H)-yl)-lHbenzo[c1]imidazole-1 -yl)-M-methyl-M-(2,2,2-trifluoroethyl)acetamide;

(8)-2-(2-(3-aminopyrrolidin-1-yl)-6-fluoro-1H-benzo[(1]imidazol-1-yl)-M-methyl-M(2,2,2-trifluoroethyl )acetamide;

(R)-2-(2-(3-aminopyrrolidin-1-yl)-6-fluoro-1H-benzo[c1]imidazol-1-yl)-M-methyl-M(2,2,2-trifluoroethyl) acetamide;

(S)-2-(2-(3-(aminomethyl)pyrrolidin-1-yl)-6-fluoro-1H-benzo[c1]imidazol-1-yl)-Mmethyl-M-(2,2,2- trifluoroethyl)acetamide;

2-(6-φτop-2-((4aR,8aR)-heκcahydro-2H-pyrido[4,3-b][l,4]oκcasin-6(5H)-yl)-lHbenzo[c1]imidazole-1 -yl)-M-methyl-M-(2,2,2-trifluoroethyl)acetamide;

2-(5-fluoro-2-((4a8,8a8)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)-yl)-1Hbenzo[c1]imidazol-1 -yl)-M-methyl-M-(2,2,2-trifluoroethyl)acetamide;

(3R,4R)-3-amino-l-(l-((5-chloropyrimidin-2-yl)methyl)-5-φτop-lHbenzo[c!]imidazol-2-yl)piperidin-4-ol;

2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[c1]imidazol-1-yl)1-morpholinoethanone;

(3R,4R)-3-amino-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1Hbenzo[c!]imidazol-2-yl)piperidin-4-ol;

(2-((3R,4R)-3-amino-4-φτoppipiperidin-1-yl)-5-chloro-1H-benzo[c1]imidazol-1-yl)-1 morpholinoethanone;

(ЗR,4R)-l-(l-((R)-l-(5-chloropyrimidin-2-yl)ethyl)-5,6-diφτop-lHbenzo[c!]imidazol-2-yl)-4- fluoropiperidine-3-amine;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-6-(τpφτopmethyl)-lH-imidazo[4,5b]pyridin-1-yl)methyl)nicotinonitrile;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[c1]imidazol-1 yl)^-methyl^-(2 ,2,2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[c1]imidazol-1 yl)^-methyl^-(thiazole -2-yl)acetamide;

2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[c1]imidazol-1-yl)N,N-dimethylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1-(azetidin-1- yl) ethane-1-one;

- 32 043189

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(3-( trifluoromethyl)piper idin-1-yl)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(6.7 -dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethan-1-one;

2-(2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-chloro-lH-benzo[d]imidazol-l-yl)N, N-dimethylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-1-(2-methylmorpholino )ethane-1-one;

(ЗR,4R)-l-(l-((R)-l-(5-chloropyrimidin-2-yl)ethyl)-5,6-diφτop-lHbenzo[c!]imidazol-2-yl)-4- fluoropiperidine-3-amine;

2-(2-((ЗR,4R)-3-amino-4-φτoppiperidin-l-yl)-5-φτop-7-methoksi-lHbenzo[d]imidazol-l-yl)-N-methyl-N- (2,2,2-τpiφtoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(azocan-1 -yl)ethane-1-one;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1H-benzo[c1]imidazol-1 yl)-1 -(4-( pyrazin-2-yl)piperazin-1-yl)ethan-1-one;

methyl-1-(2-(2-((ЗR,4R)-3-amino-4-φτopππep idin-1-yl)-5,6-d iftoro-1Нbenzo[c!]imidazol-1-yl)acetyl )piperidine-4-carboxylate;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-1-(2-ethylmorpholino )ethane-1-one;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5 -fluoro-1 H-6eH3o[d]imidazol-1 -yl)1 -(azetidin-1 - yl) ethane-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-(1,1 -dioxido-2,3-dihydrothiophen-3-yl)-M-phenylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(4-methylpiperidine -1 -yl)ethan-1 -one;

(3R,4R)-4-φτop-1 -(6-fluoro-1 -((4-methox and pyridin-2-yl)methyl)- 1Hbenzo[c!]imidazol-2-yl)piperidin-3-amine ;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-1-(2-ethylmorpholino )ethane-1-one;

6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-6-(τpφτopmethyl)-3H-imidazo[4,5b]pyridin-3-yl)methyl)nicotinonitrile;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-1 H-6eH3o[d]imidazol-1-yl)-1(azetidin-1-yl)ethan- 1 -one;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol 1-yl)acetyl)piperidin-2 -carboxamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-I-( 1.1 o-tetrahydrothiophen-3-yl)-N-(thiophen-2-ylmethyl)acetamide-dioxide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-1-(octahydroisoquinoline-2 (1H)-yl)ethan-1-one;

- 33 043189 (3 R,4R)-4-φτop-1 -(5-fluoro-1 -((4-methoxypyridin-2-yl)methyl)- 1Hbenzo[4]imidazol-2-yl)piperidin-3 -amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-( 1.1 o-tetrahydrothiophen-3-yl)-M-methylacetamide dioxide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-T4-cyclopropyl-T4- (1,1-Otetrahydrothiophen-3-yl)acetamide dioxide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-( 1.1 o-tetrahydrothiophen-3-yl)-M-ethylacetamide dioxide;

4-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)piperazin-2- He;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1 -(4-( pyrrolidine-1-carbonyl)piperide in-1-yl)ethan-1-one;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1 -yl)acetyl)piper idin-3 -carboxamide;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1H-benzo[4]imidazol-1 yl)-1 -(4-( cyclopropanecarbonyl)piperazin-1-yl)ethan-1-one;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)piperidin-4- carboxamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-(2-cyanopropane -2-yl)-M-methylacetamide;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)-M-methylpiperidine -4-carboxamide;

N-(1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1Hbenzo[4]imidazol-1-yl)acetyl)piperide in-3-yl)acetamide;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1 -(4-( piperidine-1-carbonyl)piperide in-1-yl)ethan-1-one;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1H-benzo[4]imidazol-1 yl)-1 -(4-( azepan-1-carbonyl)piperide in-1-yl)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-( 1.1 o-tetrahydrothiophen-3-yl)-M-(2-methoxyethyl)acetamide dioxide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1-(4-( 3-methylpiperidin-1-carbonyl)piperidin-1-yl)ethan-1-one;

-(4-acetylpiperazin-1-yl)-2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6d iftor-1H-benzo[b]imidazole -1 -yl)ethan-1 -one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-( 1.1 o-tetrahydrothiophen-3-yl)-M-((tetrahydrofuran-2-yl)methyl)acetamide dioxide;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)-M-isopropyl -M-methylpiperidine-4-carboxamide;

2-(2-((3 R,4R)-3-amino-4-methoxypiperidin-1-yl)-6-fluoro-1H-benzo[b]imidazol-1 yl)-T4-methyl-L1-(2 ,2,2-trifluoroethyl)acetamide;

- 34 043189

2-(2-((ЗR,4R)-3-amino-4-φτoppiperidin-l-yl)-5-φτop-7-methoksi-lHbenzo[b]imidazol-1-yl)-M-methyl-M- (2,2,2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-4-methoxy-1Нbenzo[(1]imidazol-1-yl)-1-morpholinoethane- 1 -one;

2-(2-((3 R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-φτop-7-methoksi-lH6eH3o[d] imidazol-1 -yl)-1-morpholinoethane-1 -He;

(R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H6eH3o[d]imidazol-1-yl)-1-cyclopropylpyrrolidin- 2-he;

(S)-3-(2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5,6-diφτop-lH6eH3o[d]imidazol-1-yl)-1-(tetrahydro -2H-pyran-4-yl) pyrrolide in-2-one;

(S)-3-(2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5,6-diφτop-lH6eH3o[d]imidazol-1-yl)-1-cyclopropylpyrrolidin- 2-he;

(R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H6eH3o[d]imidazol-1-yl)-1-(tetrahydro -2H-pyran-4-yl) pyrrolide in-2-one;

(ЗR,4R)-l-(5,6-diφτop-l-((5-methylthiazol-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperide in-3-amine ;

(3R,4R)-1 -(4,6-difluoro-1 -((5-methyl-1,3,4-thiadiazol-2-yl)methyl)- 1Нbenzo[b]imidazol-2-yl)-4 -fluoropiperidine-3-amine;

(3R,4R)-1 -(5,6-difluoro-1 -((5-methyl-1,3,4-thiadiazol-2-yl)methyl)- 1Нbenzo[b]imidazol-2-yl)-4 -fluoropiperidine-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethyl)-1Нbenzo[d]imidazol-l-yl)-N-methyl-N-( 2,2,2-τpiφtoroethyl)acetamide;

(ЗR,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-imidazo[4,5-b]pyridin-2yl)-4-fluoropiperide in-3 - amine;

(3R,4R)-1 -(4,6-difluoro-1 -((5-(methylsulfonyl)pyridin-2-yl)methyl)- 1Hbenzo[b]imidazol-2-yl)-4-fluoropiperidin-3- amine;

(3R,4R)-1-(1 -((5 -(difluoromethyl)-1,3,4-thiad iazol-2-yl)methyl)-4,6-difluoro-1Hbenzo[b]imidazol-2-yl )-4-fluoropiperidine-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 - yl)-4,6-difluoro-1H-benzo[b]imidazol-1 yl)-H-methyl-H- (2,2,2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[b]imidazol-1-yl)H-methyl-H-(2 ,2,2-trifluoroethyl)acetamide;

(3R,4R)-1-(1 -((5 -(difluoromethyl)-1,3,4-thiad iazol-2-yl)methyl)-5,6-difluoro-1Hbenzo[b]imidazol-2-yl )-4-fluoropiperidine-3-amine;

(ЗR,4R)-4-φτop-1 -(6-fluoro-1 -((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1Нbenzo[b]imidazol-2-yl) piperidine-3-amine;

(ЗR,4R)-l-(5,6-diφτop-l-((5-(methylcylφonyl)pyridin-2-yl)methyl)-lHbenzo[b]imidazol-2-yl)-4-fluoropiperidin-3- amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethyl)-1Hbenzo[b]imidazol-1-yl)-T4, N-dimethylacetamide;

- 35 043189 (ЗR,4R)-l-(5,6-diφτop-l-((5-methylisoκcasol-3-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3 -amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1 yl)-N, N-dimethylacetamide;

2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1H-6eH3o[d]imidazol-1-yl)N,N-dimethylacetamide;

(3R,4R)-l-(5,6-diφτop-l-((5-methyloκcazol-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperidin-3-amine;

(ЗR,4R)-l-(5,6-diφτop-l-((4-methylthiazol-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperide in-3-amine ;

(ЗR,4R)-4-φτop-1 -(6-fluoro-1 -((3 -(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)- 1Нbenzo[d]imidazol-2 -yl) π-piperidine-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-chloro-lH-benzo[d]imidazol-1-yl)X-methyl-M-(2 ,2,2-trifluoroethyl)acetamide;

(3R,4R)-1 -(5,6-difluoro-1 -((5-methyl-1,3,4-oxadiazol-2-yl)methyl)- 1Hbenzo[d]imidazol-2-yl)-4 -φτoppiperidine-3-amine;

(3R,4R)-1 -(5,6-difluoro-1 -((5-methyl-1,2,4-oxadiazol-3 -yl)methyl)- 1Hbenzo[d]imidazol-2-yl)-4 -φτoppiperidine-3-amine;

(3R,4R)-1 -(1 -((5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)methyl)-6-fluoro-1Hbenzo[d]imidazol-2-yl)-4 -φτoppiperidine-3-amine;

(3R,4R)-4-φτop-1 -(6-fluoro-1 -((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1 H-imide azo[4,5 b ] pyr id in-2-yl)piper idin-3-amine;

(ЗR,4R)-l-(l-((4,5-dimethylokkazol-2-yl)methyl)-5,6-diφτop-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3 - amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-1H-6eH3o[d]imidazol-1-yl)N,N-dimethylacetamide;

(3R,4R)-1 -(1 -((5-ethyl-1,2,4-oxadiazol-3 -yl)methyl)-5,6-difluoro-1Hbenzo[d]imidazol-2-yl)-4 -φτoppiperidine-3-amine;

(3R,4R)-1 -(1 -((5-cyclopropyl-1,2,4-oxadiazol-3 -yl)methyl)-5,6-difluoro-1Hbenzo[d]imidazol-2-yl)-4 -φτoppiperidine-3-amine;

(3R,4R)-l-(5,6-diφτop-l-((3-methylisoκcazol-5-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-(trifluoromethyl)-1Нbenzo[d]imidazol-l-yl)-N-methyl-N-( 2,2,2-τpiφtoroethyl)acetamide;

(3R,4R)-1 -(1 -((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-5,6-difluoro-1Нbenzo[d]imidazol-2-yl)-4 -φτoppiperidine-3-amine;

(ЗR,4R)-4-φτop-1 -(5-fluoro-1 -((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1Нbenzo|4]imidazol-2-yl) piperidine-3-amine;

(3R,4R)-l-(3-((5-chloropyrimidin-2-yl)methyl)-6-φτop-3H-imidazo[4,5-b]pyridin-2yl)-4-fluoropiperide in-3 - amine;

- 36 043189 (3 R,4R)-4-φτop-1 -(5-fluoro-1 -((3 -(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)- 1Hbenzo[d ]imidazol-2-yl)piperidin-3-amine;

(ЗR,4R)-4-φτop-1 -(6-fluoro-1 -((4-methyl-2-phenylthiazol-5-yl)methyl)- 1Нbenzo[d]imidazol-2-yl)piperidin-3- amine;

(3R,4R)-1-(1 -((4,5-dimethyl-4H-1,2,4-triazol-3 -yl)methyl)-5,6-d iftor-1Hbenzo[(1]imidazol- 2-yl)-4-fluoropiperidin-3-amine;

(3R,4R)-1 -(1 -((5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)methyl)-5-fluoro- 1Hbenzo[(1]imidazol-2-yl)- 4-fluoropiperidine-3-amine;

(R)-4,4-diφτop-1 -(6-fluoro-1 -((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1Hbenzo[(1]imidazol-2-yl )piperidine-3-amine;

(ЗR,4R)-l-(l-((2,4-dimethylthiazol-5-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl)4-fluoropiperide in-3-amine ;

(3R,4R)-4-φτop-l-(6-φτop-3-((5-methyl-l,3,4-thiadiazol-2-yl)methyl)-3H-imidazo[4,5b] pyride in-2-yl)piper idin-3-amine;

2-(2-((3 R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5,7-diφτop-lH-benzo[d]imidazol-lyl)-N-methyl-N-( 2,2,2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-(trifluoromethyl)-1Hbenzo[d]imidazol-l-yl)-N,N-dimethylacetamide;

(ЗR,4R)-4-φτop-1 -(5-fluoro-1 -((4-methyl-2-phenylthiazol-5-yl)methyl)-1Нbenzo[d]imidazol-2-yl)piperidin-3- amine;

2-(2-((3 R,4R)-3-amino-4-φτoppiperidin-l-yl)-5,7-diφτop-lH-benzo[d]imidazol-lyl)-N, N-dimethylacetamide;

(ЗR,4R)-l-(5,7-diφτop-l-((5-(methylcylφonyl)pyridin-2-yl)methyl)-lHbenzo[d]imidazol-2-yl)-4-φtorpipiperidin-3- amine;

(ЗR,4R)-l-(l-((2,4-dimethylthiazol-5-yl)methyl)-5-φτop-lH-benzo[d]imidazol-2-yl)4-fluoropiperide in-3-amine ;

(R)-4,4-diφτop-1 -(5-fluoro-1 -((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1Hbenzo[d]imidazol-2-yl) piperidine-3-amine;

(ЗR,4R)-l-(l-((5-(diφτopmethyl)-l,3,4-thiadiazol-2-yl)methyl)-5,7-diφτop-lHbenzo[d]imidazol-2-yl) -4-φτoppiperidine-3-amine;

(ЗR,4R)-l-(5,7-diφτop-l-((5-methyl-l,3,4-thiadiazol-2-yl)methyl)-lHbenzo[d]imidazol-2-yl)-4 -φτoppiperidine-3-amine;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(2-methylazetide in-1-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-(2,2 -difluoroethyl)-M-methylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-cyclopropyl-M- methylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-N-((R) -1-cyanoethyl)-M-methylacetamide;

- 37 043189

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-N-methyl-N- ((R)-1-(pyridin-2-yl)ethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-N-ethyl-N- methyl acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-(2-fluoroethyl )-M-methylacetamide;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1 -((1R, 5 S)-3-azabicyclo[3.1.0]hexan-3-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-methyl-M- (1-(pyridin-2-yl)ethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(2-azabicyclo [3.1.0] hexan-2-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-K-((8) -1-cyanoethyl)^-methylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-methyl-M- (tetrahydrofuran-3-yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-(1-cyanopropane -2-yl)-M-methylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-methyl-M- (1-(pyridin-4-yl)ethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-M-methyl^-( 1,1,1-trifluoropropan-2-yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-M-(cyanomethyl)- M-methylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-methyl-M- propylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-cyclopropyl-M- (2-hydroxyethyl)acetamide;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)-3-fluoropyrrolidine -3 - carbonitrile;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(2-oxa -5-azabicyclo[2.2.1]heptan-5-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(hexahydropyrano[4 ,3-b] [ 1,4]oxazin-4(7H)-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-M-(2-cyanopropyl )-M-methylacetamide;

-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-methyl-M-( 3,3,3-trifluoropropyl)acetamide;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1 -((1R, 5 S)-6,6-d iftoro-3-azabicyclo[3.1.0]hexan-3-yl)ethanone;

- 38 043189

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-1 -(4-( pyrimide in-2-yl)piperazin-1-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-1-(2-isopropylazetidine -1 -yl)ethanone;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1 -(3 -( difluoromethoxy)pyrrolidin-1-yl)ethanone;

4-(2-(2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol 1-yl)acetyl)morpholin-2 -carbonitrile;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(3-hydroxypiperidine -1 -yl)ethanone;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol 1-yl)acetyl)-4- methylpiperidine-4-carbonitrile;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(3.4 -dihydro-1,8-naphthyridin-1(2H)-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-H-cyclopropyl-H- (2,2-difluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-1-(5H-pyrrolo [3,4-b]pyridin-6(7H)-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-H-methyl-N- ((tetrahydrofuran-3-yl)methyl)acetamide;

-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-Н-(2,2- difluoroethyl)-N-methylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)^-methyl-K-( 2,2,2-trifluoroethyl)acetamide;

(R)-1 -(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1Hbenzo[d]imidazol-l-yl)acetyl) pyrpolidine-2-κapbonitril;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[4]imidazol-1 yl)-N-((lr, 4R)-4-hydroxycyclohexyl)-N-methylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro- lH-benzo[d]imidazol-1 yl)-H-methyl-M- ((8)-1-(pyridin-2-yl)ethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(octahydro-1 H-pyrano[4,3-b]pyridin-1-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)-1-(4-hydroxypiperide in-1-yl)ethanone;

- (3 - (1 Η-1,2,4-triazol-1 -yl) azetide in-1 -yl) -2- (2- ((ЗR,4R) -3 -amino-4φτopπ and pieridin-l-yl) -5,6-diφτop-lH-benzo[d]imidazol-l-yl)ethanone;

7-(2-(2-((3 R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol 1-yl)acetyl)hexahydroimidazo[ 1.5-a] pyrazin-3(2H)-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-lH-benzo[d]imidazol-1 yl)^-(2-cyanoethyl) ^-((tetrahydrofuran-3-yl)methyl)acetamide;

- 39 043189

4-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)-M-methylmorpholine -2-carboxamide;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1 -(3 -( (methylsulfonyl)methyl)pyrrolidin-1-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1-(5.6 -dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[c1]imidazol-1 yl)-1-(2-( methoxymethyl)morpholino)ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1-(3-hydroxy -3-methylpyrrolidin-1-yl)ethanone;

2-(2-((3 R,4R)-3 -amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-1 -(4-( methylsulfonyl)piperazin-1-yl)ethanone;

N-((l -acetylpyrrolidin-3 -yl)methyl)-2-(2-((ЗR,4R)-3-amino-4-fluoropiperidin-1 yl)-5,6-d iftoro-1 H-benzo [b] imidazole-1-ππ)-N-ethylacetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-T4-( 1.1 otetrahydro-2H-thiopyran-4-yl)-T4-methylacetamide dioxide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-((1, 1-dioxidotetrahydrothiophen-3-yl)methyl)-M-methylacetamide;

2-(1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1Hbenzo[(1]imidazol-1-yl)acetyl) piperidin-4-yl)-2-methylpropanenitrile;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)-M-methylpiper idine-3-carboxamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-(2-hydroxyethyl )-M-(pyridin-3-ylmethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[b]imidazol-1 yl)-M-(2-cyanoethyl )-M-(tetrahydro-2H-pyran-4-yl)acetamide;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1 -yl)acetyl)-Н N- dimethylpiperidine-3-carboxamide;

l-(2-(2-((ЗR,4R)-3-amino-4-φτopπpiperidin-l-yl)-5,6-diφτop-lH-benzo[d]imidazol1-yl)acetyl)-4-( methoxymethyl)piperidine-4-carbonitrile;

7-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-d iftor-1 H-benzo[b]imidazol1-yl)acetyl)tetrahydro- 1 H-oxazolo[3,4-a] pyrazin-3(5H)-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[b]imidazol-1-yl)PM-(thiazol-2- yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[b]imidazol-1-yl)M-(2.2, 2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-lH-benzo[d]imidazol-1-yl)M-cyclopropyl-M-(2 ,2,2-trifluoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[b]imidazol-1-yl)M-(2-methoxyethyl) -M-methylacetamide;

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2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)N-methyl-K-( (8)-tetrahydrofuran-3-yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)T4-methyl-M- (^)-tetrahydrofuran-3-yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)N-((S) -1 -(pyridin-2-yl)ethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)M-((8)- tetrahydrofuran-3-yl)-M-(2,2,2-trifluoroethyl)acetamide;

2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1H-benzo[(1]imidazol-1-yl)N-cyclobutyl acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)N-((S) -1-cyanopropan-2-yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)N-((R) -1-cyanopropan-2-yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)X-ethyl-T4- (2-methoxyethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)N-((R) -tetrahydropoφyran-3-yl)-N-(2,2,2-τpiφtoroethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)N-(3.3 ,3-trifluoropropyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)N-((R) -1 -(pyridin-2-yl)ethyl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)M-((8) -tetrahydrofuran-3-yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[(1]imidazol-1-yl)N-((R) -tetrahydropoφyran-3-yl)acetamide;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1-(2-methylazetidine- 1 -yl)ethan-1 -one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[<1]imidazol-1-yl)1-((8) -3-methylmorpholino)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1 -((R)- 2-methylpyrpolidin-1-yl)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1 -((R)- 3-(methoxymethyl)morpholino)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1 -((R)- 3-methylmorpholino)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1H-benzo[c1]imidazol-1-yl)1 -((8)-2 -methylpyrrolidin-1-yl)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1-(3.5 - dimethylmorpholino)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1-(3-ethylmorpholino) ethane-1 -one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1-((8)- 3-cyclopropylmorpholino)ethan-1-one;

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1 -((R)- 3 -(hydroxymethyl)morpholino)ethan-1 -one and

2-(2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1 H-benzo[c1]imidazol-1-yl)1 -(3,3 - dimethylmorpholino)ethan-1-one.

In the twenty-sixth embodiment, the present invention provides compounds according to the first or second embodiments, wherein the compound is shown in Table. In below.

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Table B

6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1Hbenzo[(1]imidazole-4-carbonitrile ;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-5-(τpiφtormethyl)-lHbenzo[d]imidazol-l-yl)methyl)niκotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethoxy)-1Hbenzo[d]imidazol-l-yl)methyl)nicotinonitrile;

2-((3 R,4R)-3-amino-4-φτoppiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6φτop-lH-benzo[d]imidazol-4 -κapbonitril;

(ЗR,4R)-l-(4,6-diφτop-l-((5-φtorpyridin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperide in-3-amine ;

(3R,4R)-l-(4,6-diφτop-l-((5-φtorpyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3-amine;

2-((3 R,4R)-3-amino-4-fluoropiperide in-1-yl)-6-fluoro-1-((5-fluoropyrimidin-2yl)methyl)-lH-benzo[d]imidazole-4 -κapbonitril;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4S)-3-amino-4-φτoppipiperidin-l-yl)-5-φτop-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-4,6-diφτop-lH-benzo[d]imidazol-lyl)methyl)nicotinonitrile;

(R)-6-((2-(3-amino-4,4-difluoropiper id in-1-yl)-4,6-difluoro-1H-6eH3o[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

(R)-6-((2-(3-amino-4,4-difluoropiper idin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

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6-((2-((3R,4R)-3-amino-4-φτopπpiperidin-l-yl)-6-chloro-lH-imidazo[4,5-b]pyridin1-yl)methyl)nicotinonitrile;

6-((2-((3R)-3-amino-4,4-difluoro-1-piper id inyl)-6-(trifluoromethyl)-1Hbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-φτop-l-piperidinyl)-5-(diφτopmetoκci)-lHbenzimidazol-1-yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-4-methoxy-1H-benz imidazol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R)-3-amino-4,4-difluoro-1-piperid inyl)-6-methoxy-1H-benz imidazol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-methoxy-1H-benzo[b]imidazol-1-yl)methyl)nicotinonitrile hydrochloride;

2-((3 R,4 S)-3-amino-4-fluoropiper idin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-6fluoro-1H-benzo[b] imidazole-4-carbonitrile;

(R)-2-(3-amino-4,4-difluoropiperid in-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6fluoro-1H-benzo[b]imidazol-4 -carbonitrile;

4-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-4,6-difluoro-1H-benz imidazol-1 yl)methyl)benzonitrile;

4-((2-((38.48)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[b]imidazol-1 yl)methyl)benzonitrile;

4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[b]imidazol-1 yl)methyl)benzonitrile;

(R)-4-((2-(3-aminopiperidin-1-yl)-6-methoxy-1 H-benzo[b]imidazol-1 yl)methyl)benzonitrile;

(2-((3R,4R)-3-amino-4-φτoppipiperidin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-1Hbenzo[d]imidazol-6-κapbonitril;

(3R,4R)-4-φτop-l-(l-((5-φτoppyrimidin-2-yl)methyl)-lH-benzo[d]imide azol-2yl)piper idin-3-amine;

2-((3R,4R)-3-amino-4-φτoppiperide in-1-yl)-1-((5-fluoropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-6-κapbonitril;

2-((3 R,4 S)-3-amino-4-fluoropiper idin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-1Hbenzo[d]imidazol-6- κapbonitril;

(3R,4R)-3-amino-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lHbenzo[d]imidazol-2-yl)piperidin-4-ol;

(R)-l-(l-((5-chloropyridin-2-yl)methyl)-4,6-diφτop-lH-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride;

(3R,4R)-l-(l-((5-chloro-2-pyrimidinyl)methyl)-4,6-diφτop-lH-benzimidazol-2-yl)-4fluoro-3-piperidineamine;

2-(2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-5,6-difluoro-1 H-benzimid azol-1 -yl)1 -(1-piperide inyl )ethanone;

2-(2-((3 R,4R)-3-amino-4-fluoro-1-piper idinyl)-6-chloro-1 H-benzimidazol-1-yl)-1-(1-azetidinyl)ethanone;

(3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl)-4fluoropiper idin-3-amine;

(3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-5-φτop-lH-benzo[d]imidazol-2-yl)-4fluoropiper idin-3-amine;

(3R,4R)-l-(5,6-diφτop-l-((5-φtorpyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3-amine;

(3^48)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)-6-(trifluoromethyl)-1Hbenzo[b]imidazol-2-yl)piperidin-3-amine

4-((2-((3R,4R)-3-amino-4-φτoppipiperidin-l-yl)-6-chloro-lH-benzo[d]imidazol-lyl)methyl)benzonitrile hydrochloride.

In the fortieth embodiment, the present invention provides compounds according to the first or second embodiments, wherein the compound is shown in Table. From below.

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Table C

6-((2-((3R,4S)-3-amino-4-fluoropiper idin-1-yl)-6-chloro-1H-benzo[b]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethoxy)-1Hbenzo[b]imidazol-1-yl)methyl)nicotinonitrile;

2-((3 R,4R)-3-amino-4-φτoppiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6fluoro-1Н-benzo[b]imidazol-4 -carbonitrile;

(ЗR,4R)-l-(4,6-diφτop-l-((5-φtorpyridin-2-yl)methyl)-lH-benzo[d]imidazol-2-yl)4-fluoropiperide in-3-amine ;

(3R,4R)-l-(4,6-diφτop-l-((5-φtorpyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperidin-3-amine;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-lH-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile;

(R)-6-((2-(3-amino-4,4-difluoropiper id in-1-yl)-4,6-difluoro-1H-6eH3o[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride;

(R)-6-((2-(3-amino-4,4-difluoropiper idin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-4-methoxy-1 H-benzimidazol-1 yl)methyl)-3-pyridinecarbonitrile;

6-((2-((3R)-3-amino-4,4-difluoro-1-piperid inyl)-6-methoxy-1 H-benzimidazol-1 yl)methyl)-3-pyridinecarbonitrile;

2-((3 R,4 S)-3-amino-4-fluoropiper idin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-6fluoro-1H-benzo[b] imidazole-4-carbonitrile;

(R)-2-(3-amino-4,4-difluoropiper idin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6fluoro-1H-benzo[b]imidazol-4- carbonitrile;

(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-1Hbenzo[b]imidazole-6-carbonitrile;

(3R,4R)-4-φτop-1-(1-((5-φτoppyrimidin-2-yl)methyl)-lH-benzo[d]imide azol-2yl)piper idine-3-amine;

2-((3 R,4 S)-3-amino-4-fluoropiper idin-1-yl)-1-((5-chloropyrimide in-2-yl)methyl)-1Hbenzo[d]imidazol-6- κapbonitril;

(R)-l-(l-((5-chloropyridin-2-yl)methyl)-4,6-diφτop-lH-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride;

(3R,4R)-1-(1-((5-chloro-2-pyrimide inyl)methyl)-4,6-d iftor-1 H-benzimid azol-2-yl)-4fluoro-3-piperidinamine and ( 3R,4R)-l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl)-4fluoropiper idin-3-amine.

In the twenty-seventh embodiment, the present invention provides compounds according to the first or second embodiments, wherein the compound is shown in Table. D below.

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Table D

6-((2-((3R,4S)-3-amino-4-fluoropiper idin-1-yl)-6-chloro-1H-benzo[b]imidazol-1 yl)methyl)nicotinonitrile;

2-((3 R,4R)-3-amino-4-φτoppiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6fluoro-1Н-benzo[b]imidazol-4 -carbonitrile;

(3R,4R)-l-(4,6-diφτop-l-((5-φtorpyrimidin-2-yl)methyl)-lH-benzo[d]imidazol-2yl)-4-fluoropiperide in-3-amine;

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[b]imidazol-1 yl)methyl)nicotinonitrile;

(R)-6-((2-(3-Amino-4,4-difluoropiper id in-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride ;

(R)-6-((2-(3-amino-4,4-difluoropiper idin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile;

6-((2-((3R,4R)-3-amino-4-fluoro-1-piper idinyl)-4-methoxy-1H-benz imidazol-1 yl)methyl)-3-pyridinecarbonitrile;

(2-((3R,4R)-3-amino-4-φτoppipiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-6-κapbonitril;

(3R,4R)-4-φτop-l-(l-((5-φτoppyrimidin-2-yl)methyl)-lH-benzo[d]imide azol-2yl)piperidine-3-amine and (3R,4R) -l-(l-((5-chloropyrimidin-2-yl)methyl)-6-φτop-lH-benzo[d]imidazol-2-yl)-4fluoropiper idin-3-amine.

In a further embodiment, each of the compounds disclosed herein is in the form of a pharmaceutically acceptable salt.

In a twenty-eighth embodiment, the present invention provides 6-((2((3 R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1 H-benzo[d]imidazol-1- yl)methyl)nicotinonitrile. In certain aspects of the twenty-eighth embodiment, the present invention provides a pharmaceutically acceptable salt of 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1Hbenzo[d]imidazol- 1 -yl)methyl)nicotinonitrile.

In a twenty-ninth embodiment, the present invention provides 2-((3R,4R)-3amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1 H -benzo[d]imidazole-4carbonitrile. In certain aspects of the twenty-ninth embodiment, the present invention provides a pharmaceutically acceptable salt of 2-((3R,4R)-3-αmino-4-fluoropiperidin-1-yl)-1((5-chloropyrimidin-2-yl)methyl)- 6-fluoro-1H-benzo[d]imidazole-4-carbonitrile.

In a thirtieth embodiment, the present invention provides (3R,4R)-1-(4,6difluoro-1-((5-fluoro-pyrimidin-2-yl)methyl)-1 H-benzo[d]imidazol-2-yl)- 4-fluoropiperidine-3-amine. In certain aspects of the thirtieth embodiment, the present invention provides a pharmaceutically acceptable salt of (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-2 -yl)-4-fluoropiperidin-3-amine.

In the thirty-first embodiment, the present invention provides 6-((2-((3R,4R)3-amino-4-fluoropiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile . In certain aspects of the thirty-first embodiment, the present invention provides a pharmaceutically acceptable salt of 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1yl) methyl) nicotinonitrile.

In a thirty-second embodiment, the present invention provides (R)-6-((2-(3amino-4,4-difluoropiperidin-1-yl)-4,6-difluoro-1H-benzo[b]imidazol-1- yl)methyl)nicotinonitrile. In certain aspects of the thirty-second embodiment, the present invention provides a pharmaceutically acceptable salt of (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-fluoro-1Hbenzo[d]imidazol- 1-yl)methyl)nicotinonitrile. A particularly preferred aspect of the thirty-second embodiment is the hydrochloride salt, e.g. 1-yl)methyl)nicotinonitrile hydrochloride.

In a thirty-third embodiment, the present invention provides (R)-6-((2-(3amino-4,4-difluoropiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl) methyl)nicotinonitrile. In certain aspects of the thirty-third embodiment, the present invention provides a pharmaceutically acceptable salt of (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-ul)-6-fluoro-1Hbenzo[d]imidazole- 1 -yl)methyl)nicotinonitrile.

In a thirty-fourth embodiment, the present invention provides 6-((2((3 R,4R)-3-amino-4-fluoro-1-piperidinyl)-4-methoxy-1 H-benzimidazol-1-yl)methyl) -3pyridinecarbonitrile. In certain aspects of the thirty-fourth embodiment, the present invention provides a pharmaceutically acceptable salt of 6-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-4-methoxy-1H-benzimidazol-1-yl) methyl)-3-pyridinecarbonitrile.

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In a thirty-fifth embodiment, the present invention provides (2-((3R,4R)-3amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1H-benzo[d ]imidazole-6-carbonitrile In certain aspects of a thirty-fifth embodiment, the present invention provides a pharmaceutically acceptable salt of (2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5chloropyrimidine- 2-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile.

In a thirty-sixth embodiment, the present invention provides (3R,4R)-4fluoro-1-(1-((5-fluoro-pyrimidin-2-yl)methyl)-1 H-benzo[d]imidazol-2-yl)piperidin- 3-amine. In certain aspects of the thirty-sixth embodiment, the present invention provides a pharmaceutically acceptable salt of (3R,4R)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazol-2- yl) piperidine-3-amine.

In a thirty-seventh embodiment, the present invention provides (3R,4R)-1-(1((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1 H-benzo[d]imidazol-2-yl)- 4-fluoropiperidine-3-amine. In certain aspects of the thirty-seventh embodiment, the present invention provides a pharmaceutically acceptable salt of (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1Hbenzo[d]imidazol-2- yl)-4-fluoropiperidin-3-amine.

In a further aspect of each of the embodiments, the compounds and pharmaceutically acceptable salts provided therein may be used in the preparation of a medicament for use in the treatment of a disease mediated by TRPC6 activity. In certain aspects, the compounds provided in the embodiments, or a pharmaceutically acceptable salt thereof, can be used in the manufacture of a medicament for the treatment of a disease or disorder selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA - nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory failure syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. In still other aspects, the compounds of any of the embodiments, or a pharmaceutically acceptable salt thereof, may be used in the preparation of a medicament for the treatment of nephrotic syndrome, membranous nephropathy, and acute renal failure.

In a thirty-eighth embodiment, a method is provided for treating a disease or disorder in a patient in need of therapy, the method comprising the step of administering a pharmaceutically acceptable composition comprising a compound according to any of the forty-second to fifty-first embodiments, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, syndrome acute respiratory failure (ARDS), heart failure, stroke, cancer, or muscular dystrophy. In certain aspects of the thirty-eighth embodiment, the disease or disorder is selected from nephrotic syndrome, membranous nephropathy, and acute renal failure.

In a further embodiment, the present invention provides methods for preparing a compound of formula IIIb or subformulas thereof

The method includes the following stages of synthesis.

(a) alkylation of a halogenated benzimidazole characterized by the formula

- 46 043189 using an electrophilic fragment characterized by the formula

under basic conditions to obtain a compound, which is an alkylated halogenated benzimidazole, characterized by the formula

where X represents chlorine, bromine or iodine, and Q represents chlorine, bromine, iodine, C ₁ -C ₆ alkylsulfonate or optionally substituted phenylsulfonate;

(b) coupling the alkylated halogenated benzimidazole formed in step (a) with a protected piperidine having the formula

where PG is an amide protecting group resistant to nucleophilic aromatic substitution (such as an alkoxycarbonyl protecting group) under conditions allowing nucleophilic aromatic substitution to give an alkylated 2-(piperidin-1-yl)benzimidazole compound having the formula

(c) removing PG from the alkylated 2-(piperidin-1 yl)benzimidazole compound formed in step (b) to form a compound of formula (IIIb) where the variables are X ¹ , X ² , X ³ , Z ⁴ , R ^1a , R ² , R ³ , R ⁴ , R ⁷ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ have the definitions given in the thirtieth embodiment.

In preferred aspects of the synthesis process, the basic conditions in step (a) involve contacting the halogenated benzimidazole with the electrophilic moiety in the presence of a carbonate base such as potassium carbonate or more preferably cesium carbonate.

In a further embodiment, the present invention provides methods for preparing compounds of formula IIIb or subformulas thereof

- 47 043189

The method includes the following stages of synthesis:

(a) a combination of a halogenated benzimidazole characterized by the formula

with protected piperidine, which is characterized by the formula

under conditions that provide nucleophilic aromatic substitution, with the formation of a compound representing 2-(piperidin-1-yl)benzimidazole, characterized by the formula

where X represents chlorine, bromine or iodine, and PG represents an amide protecting group resistant to nucleophilic aromatic substitution, such as an alkoxycarbonyl protecting group;

(b) alkylating the 2-(piperidin-1-yl)benzimidazole compound formed in step (a) with an electrophilic moiety having the structure

under basic conditions to obtain a compound, which is an alkylated 2(piperidin-1-yl)benzimidazole, characterized by the formula

where Q represents chlorine, bromine, iodine, C1-C ₆ -alkylsulfonate or optionally substituted phenylsulfonate;

(c) removing PG from the alkylated 2-(piperidin-1yl)benzimidazole compound formed in step (b) to form a compound of formula (IIIb) where the variables X ¹ , X ² , X ³ , Z ⁴ , R ^1a , R ² , R ³ , R ⁴ , R ⁷ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ have the definitions given in the thirtieth embodiment.

In a further embodiment, the present invention provides methods for preparing compounds of formula IIIb or subformulas thereof

- 48 043189

The method includes the following stages of synthesis:

(a) a combination of a brominated isothiocyanate compound having the formula

with a protected piperidine compound having the formula

Under conditions that ensure the formation of thiourea, with the formation of a compound that is an N,N'-disubstituted thiourea, characterized by the formula

where PG is an amide protecting group such as an alkoxycarbonyl protecting group;

(b) condensing the N,N'-didisplaced thiourea compound formed in step (a) with an amine compound having the formula

under conditions suitable for the formation of guanidine, to obtain a compound representing N,N',N-trisubstituted guanidine, characterized by the formula

- 49 043189

(c) intramolecular cyclization of the N,N',N''-trisubstituted guanidine compound formed in step (b) in the presence of a transition metal catalyst to form an alkylated 2-(piperidin-1-yl ) benzimidazole, characterized by the formula

(d) removing PG from the alkylated 2-(piperidin-1 yl)benzimidazole compound formed in step (c) to give a compound of formula (IIIb) where the variables

X ¹ , X ² , X ³ , Z ⁴ , R ^1a , R ² , R ³ , R ⁴ , R ⁷ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ have the definitions given in the thirtieth embodiment.

In a further embodiment, the present invention provides methods for preparing compounds of formula IIId or subformulas thereof

The method involves the following steps in the synthesis:

with a primary amine characterized by the formula

- 50 043189 under conditions suitable for nucleophilic aromatic substitution, to obtain a secondary amine, while the amine is characterized by the formula

b) the formation of a compound, which is an alkylated-2-chlorobenzimidazole, characterized by the formula

by reducing the nitro substituent in the secondary amine compounds formed in step (a) to form in situ a dianiline compound, cyclizing said dianiline with a carbonyl source, and chlorinating (with a chlorine source such as P (O)C1 ₃ ) to form a compound that is an alkylated-2-chlorobenzimidazole;

c) coupling the alkylated 2-chlorobenzimidazole compound formed in step (b) with a protected piperidine having the formula

under conditions suitable for nucleophilic aromatic substitution to form an alkylated 2-(piperidin-1-yl)benzimidazole compound having the formula

(d) removing PG from the alkylated 2-(piperidin-1yl)benzimidazole compound formed in step (c) to form a compound of formula (IIId) where the variables X ¹ , X ² , X ³ , R ^1a , R ² , R ³ , R ⁴ , R ⁷ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ have the definitions given in the thirtieth embodiment.

In a further embodiment, the present invention provides methods for preparing compounds of formula VII or subformulas thereof

- 51 043189

comprising: (a) a combination of a halogenated benzimidazole characterized by the formula

with protected piperidine, characterized by the formula

under conditions that provide nucleophilic aromatic substitution, with the formation of a compound representing 2-(piperidin-1-yl)benzimidazole, characterized by the formula

where X represents chlorine, bromine or iodine, and PG represents an amide protecting group resistant to nucleophilic aromatic substitution, such as an alkoxycarbonyl protecting group;

(b) alkylating the 2-(piperidin-1-yl)benzimidazole compound formed in step (a) with a halo ester

where Y corresponds to X and represents chlorine, bromine or iodine, and R represents C1-C6 alkyl, to form a compound that is a substituted 1-acetyl-2-(piperidin-1yl)benzimidazole, characterized by the formula

(c) saponifying the substituted 1-acetyl-2-(piperidin-1yl)benzimidazole compound formed in step (b) to give the free acid followed by amination with the amine HNR ⁹ R ¹⁰ under conditions to form an amide communication, to obtain a compound representing 1-[(2-piperidin-1-yl)benzimidazole)]acetamide;

(d) removing PG from the 1-[(2-piperidin-1yl)benzimidazole)]acetamide compound formed in step (c) to form a compound of formula (VII) where the variables X ¹ , X ² , X ³ , Z ⁴ , R ^1a , R ² , R ³ , R ⁴ , R ⁷ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ are defined in three

- 52 043189 twenty-fourth embodiment.

In another embodiment, pharmaceutical compositions are provided that contain one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound according to any of Formula I or subformulas thereof. In some aspects, the composition is in a form selected from the group consisting of an injectable fluid, an aerosol, a tablet, a pill, a capsule, a syrup, a cream, a gel, and a transdermal patch.

In another embodiment, combinations, in particular pharmaceutical compositions, are provided that contain a therapeutically effective amount of a compound according to any of Formula I or subformulas thereof.

In another embodiment, methods are provided for modulating TRPC protein activity in a subject, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula I or subformulas thereof. In preferred aspects of the embodiment, methods are provided for inhibiting TRPC6 activity in a subject, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula I or subformulas thereof. In certain aspects of the embodiment, methods are provided for inhibiting TRPC6 activity in a subject, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula I or subformulas thereof.

In other embodiments, methods are provided for treating a disorder or disease in a subject mediated by TRPC protein activity, in particular, methods are provided for treating a disease or disorder mediated by TRPC6 protein activity. The methods involve administering to a subject a therapeutically effective amount of a compound of Formula I or subformulas thereof.

In another embodiment, methods are provided for treating or preventing a disease or disorder, wherein the disease or disorder is selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory failure syndrome (ARDS), heart failure, stroke, malignancy, or muscular dystrophy, the method comprising the step of administering to a subject in need of therapy a therapeutically effective amount compounds or salts of formula I or its subformulas. In certain aspects of this embodiment, the method comprises treating a disease or disorder selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy , sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, cancer, or muscular dystrophy. In some cases, methods of treatment and/or methods of prevention are suitable for the treatment and/or prevention of nephrotic syndrome, membranous nephropathy and acute renal failure.

In another aspect, the present invention provides for the use of compounds of Formula I or subformulas thereof for use in the manufacture of a medicament or for use in the manufacture of a medicament for the treatment of a disorder or disease in a subject mediated by TRPC protein activity. In certain other aspects, the present invention contemplates the use of a compound of formula I or subformulas thereof in the treatment of nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic kidney failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, cancer, or muscular dystrophy. In certain instances, the present invention contemplates the use of compounds of formula I, or subformulas thereof, for use in the manufacture of a medicament or for use in the manufacture of a medicament for the treatment of a disease or disorder in a subject selected from nephrotic syndrome, membranous nephropathy, and acute renal failure.

For purposes of interpretation of this specification, the following definitions will be used and, if necessary, terms used in the singular will also include the plural and vice versa.

As used herein, the term alkyl means a fully saturated branched or unbranched hydrocarbon moiety containing not more than 20 carbon atoms. Unless otherwise specified, alkyl means hydrocarbon moieties containing 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. Illustrative examples of alkyl include, without limitation, methyl, ethyl, n-propyl, isopropyl,

- 53 043189 n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl , n-nonyl, n-decyl, and the like.

As used herein, the term alkylene means a divalent alkyl group, as defined herein above, containing from 1 to 20 carbon atoms. Unless otherwise specified, alkylene means moieties containing 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. Illustrative examples of alkylene include, without limitation, methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, t-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2, 3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, ndecylene, and the like.

As used herein, the term haloalkyl means alkyl, as defined herein, which is substituted with one or more halogen groups, as defined herein. Haloalkyl may be monohaloalkyl, dihaloalkyl, or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl may contain one iodine, bromine, chlorine or fluorine atom in the alkyl group. Dihaloalkyl and polyhaloalkyl groups may contain two or more of the same halogen atoms, or a combination of different halogen groups in the alkyl. As a rule, polyhaloalkyl contains no more than 12, or 10, or 8, or 6, or 4, or 3, or 2 halogen groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhaloalkyl means alkyl in which all hydrogen atoms are replaced by halogen atoms.

As used herein, the term hydroxyalkyl means alkyl, as defined herein, which is substituted with one or more hydroxy groups. The term hydroxycycloalkylalkyl means an alkyl group that is substituted with a cycloalkyl group as defined herein and is further substituted with hydroxy. The hydroxy group may be present on an alkyl group, a cycloalkyl group, or on each of the alkyl and cycloalkyl groups.

The term aryl means an aromatic hydrocarbon group containing 6-20 carbon atoms in the annular portion. As a rule, aryl is a monocyclic, bicyclic or tricyclic aryl containing 6-20 carbon atoms. Moreover, the term aryl as used herein means an aromatic substituent, which may be a single aromatic ring or multiple aromatic rings that are fused to each other. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted with 1-4 substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(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 heterocycle, heterocyclyl, heterocycloalkyl, or heterocyclo means a saturated or unsaturated non-aromatic ring or ring system, for example, which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one heteroatom selected from O, S and N, where N and S may also optionally be oxidized to various oxidation states. The heterocyclic group may be attached at a heteroatom or carbon atom. Heterocyclyl may include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran, dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithian, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3 -dioxane, 1,3-dithian, oxatian, thiomorpholine, azetidine, thiazolidine, morpholine, and the like.

As used herein, the term azacycle means a heterocycle which contains at least one ring nitrogen atom, and which may optionally contain 0, 1, or 2 additional ring heteroatoms selected from N, O, or S.

As used herein, the term cycloalkyl means saturated or partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms. For the avoidance of ambiguity, cycloalkyl is intended not to include aromatic groups such as naphthylene or phenyl. Unless otherwise indicated, cycloalkyl means cyclic hydrocarbon groups containing from 3 to 9 ring carbon atoms or from 3 to 7 ring carbon atoms, each of which may be optionally substituted with one, or two, or three or more substituents, independently selected from the group consisting of alkyl, halogen, 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. Illustrative monocyclic hydrocarbon groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, and the like. Illustrative bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,

- 54 043189 bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1 ]heptyl, bicyclo[2.2.2]octyl, etc. Illustrative tricyclic hydrocarbon groups include adamantyl and the like. The term hydroxycycloalkyl specifically means a cycloalkyl group substituted with one or more hydroxy groups.

As used herein, the term alkoxy means alkyl-O-, where alkyl is defined herein above. Illustrative examples of alkoxy include, without limitation, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy, and the like. Typically, alkoxy groups contain about 1-7, more preferably about 1-4 carbon atoms.

As used herein, the term cycloalkoxy means cycloalkyl-O- and cycloalkylalkyl-O, where cycloalkyl and alkyl are defined herein above. Illustrative examples of cycloalkoxy include, without limitation, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, 1-methylcyclopropyloxy, cyclopropylmethoxy, 1-methylcyclobutyloxy, and the like. Typically, cycloalkoxy groups contain about 3-7, more preferably about 3-6 carbon atoms.

Divalent substituents are represented by the suffix diyl. Thus, a divalent alkyl linker is called an alkanediyl group, and a divalent cycloalkane group is called a cycloalkanediyl (eg, cyclopropanediyl).

As used herein, the term heteroaryl means a 5-14 membered monocyclic or bicyclic or tricyclic aromatic ring system containing 1-8 heteroatoms selected from N, O and S. In certain preferred aspects, heteroaryl is a 5-10 membered ring system (for example, 5-7-membered monocycle or 8-10-membered bicycle) or 5-7-membered ring system. Illustrative monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 51,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl and 2-, 4- and 5-pyrimidinyl . Illustrative bicyclic heteroaryl groups include 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1 -, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7- or 8-benzimidazolyl and 1-, 2-, 3 -, 4-, 5-, 6-, 7- or 8-indolyl.

The term heteroaryl also means a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.

The terms bicycle and bicyclyl mean a ring system containing two fused rings, each of the rings of which may be carbocyclic or heterocyclic, and each of the rings may be saturated, unsaturated or aromatic.

As used herein, the term halogen or halo means fluorine, chlorine, bromine and iodine.

As used herein, the term optionally substituted, unless otherwise indicated, means a group that is unsubstituted or substituted with one or more, typically 1, 2, 3 or 4, suitable substituents other than hydrogen. Unless the identity of an optional substituent is clearly defined in the context of an optionally substituted group, then each optional substituent is independently selected from the group consisting of alkyl, hydroxy, halo, oxo, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, CO ₂ H, heterocycloalkyloxy (which is heterocyclic group linked via an oxygen bridge), -CO ₂ alkyl, mercapto, nitro, cyano, sulfamoyl, sulfonamide, aryl, -OC(O)alkyl, -OC(O)aryl, aryl-S-, aryloxy; alkylthio, formyl (i.e. HC(O)-), -C(O)NH ₂ , 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 a group is indicated as being optionally substituted, the present invention includes embodiments in which the group is unsubstituted as well as embodiments in which the group is substituted.

As used herein, the term isomers refers to various compounds that have the same molecular formula but differ in the arrangement and configuration of atoms. Also used herein, the term optical isomer or stereoisomer means any of the various stereoisomeric configurations that may exist for a given compound of the present invention and includes geometric isomers. It is known that a substituent can be attached at a chiral center on a carbon atom. Therefore, the present invention includes the 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 term is used to refer to a racemic mixture where appropriate. Application rel. indicates that the diastereomeric orientation is known, but the absolute stereochemistry is unknown. Where absolute stereochemistry has not been determined, optical rotation and/or chiral chromatochemical conditions

- 55 043189 graphs 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 given according to the Cahn-Ingold-Prelog R-S system. In the case where the compound is a pure enantiomer, the stereochemistry at each chiral carbon atom may be indicated as either R or S. Separated compounds whose absolute configuration is unknown may be denoted (+) or (-), depending on the direction (right or left-handed) in which they rotate plane polarized light at the sodium D line wavelength or retention time in chiral chromatographic separation. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus provide enantiomers, diastereomers, and other stereoisomeric forms, which may be defined relative to absolute stereochemistry as (R)- or (S)- or by sign (+) or (-). The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. Optically active (R)- and (S)-isomers can be obtained using chiral synthons or chiral reagents or separated using conventional techniques. If the compound contains a double bond, then the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, then the cycloalkyl substituent may be in the cis or trans configuration.

It is clear that for any compound presented in this document, including any compound of formula (I), or any variant of its implementation, or any compound from the table. A, B, or C, or a salt of any of the above, the compound may exist in any stereochemical form, such as a single enantiomer, diastereomer, or tautomer, or a mixture of one or more enantiomers, diastereomers, and tautomers in any ratio.

As used herein, the terms salt or salts mean an acid addition salt or a base addition salt of a compound of the present invention. Salts include, in particular, pharmaceutically acceptable salts. The term pharmaceutically acceptable salts means salts which retain the biological efficacy and properties of the compounds of the present invention and which are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acidic and/or basic salts due to the presence of amino groups and/or carboxyl groups or groups like them.

Pharmaceutically acceptable acid addition salts can be formed using inorganic acids and organic acids.

Inorganic acids with which salts can be formed include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids with which salts can be prepared 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.

Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

Inorganic bases with which salts can be prepared include, for example, ammonium salts and metals from Groups I-XII of the Periodic Table of the Elements. In certain embodiments, salts are prepared using sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper. In certain other embodiments, the salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

Organic bases with which salts can be prepared 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, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

In another aspect, the present invention provides compounds disclosed herein in the form of a salt, which is acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, Chlortieophyllonate, citrate, etandisulfonat, fumarat, glintate, gluconate, glucuronate, glutamate, glutarate, glycolyate, hypopurates, hydroodidide/iodide, lactate, lactobionate, lairal sulfate, malat, maleat, Medonate, Mandalat, masculite, mascalam, mandalate, mascalam, mandalate, mascalam, mandalate, mascalam, mandalate, mascalam, mandalate, mascalam, mascaralate, mascalam, mandalate, mascalam, mascara. methyl sulfate, mucat, naftoate, napsilate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrophosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenate, trifluoroacetate, or xinafoate. In yet another aspect, the present invention provides the compounds disclosed herein in the form of an acid addition salt formed using

- 56 043189 by ionization of N-N-alkyl sulfonic acid, benzene sulfonic acid or mono-, di- or tri-C 1 -C ₄ alkyl-substituted benzene sulfonic acid.

Any formula given herein is also intended to represent the unlabeled forms as well as the isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted using the formulas given herein, except that one or more atoms are replaced by an atom characterized by a selected atomic mass or mass number. Examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁴ I, ¹²⁵ I, respectively. The present invention provides isotopically labeled compounds as defined herein, for example, compounds in which radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C are present. Such isotopically labeled compounds are useful in metabolic studies (using ¹⁴ C), reaction kinetics studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including analyzes of drug or substrate tissue distribution, or in radiotherapy patients. In particular, a ¹⁸ F compound or a labeled compound may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention and their salts can generally be prepared by following the procedures disclosed in the Schemes or in the examples and preparations described below by replacing a non-isotopically labeled reagent with a readily available isotopically labeled reagent.

In addition, substitution with heavier isotopes, in particular deuterium (i.e. ² H or D), may provide certain therapeutic advantages resulting from higher resistance to metabolic inactivation, such as increased in vivo half-life, or reduced requirements to dose, or an improvement in the therapeutic index. It is clear that deuterium in this context is considered as a substituent of the compounds of formula (I). The concentration of such a heavier isotope, in particular deuterium, can be determined by the isotopic enrichment factor. The term isotopic enrichment factor as used herein means the ratio between the abundance of an isotope and the abundance of said isotope in nature. When a substituent in a compound of the present invention is designated deuterium, that compound has at least 50% deuterium inclusion for each designated deuterium atom, 60% deuterium inclusion, at least 75% deuterium inclusion, at least 90% deuterium inclusion, at least at least 95% deuterium inclusion, at least 99% deuterium inclusion, or at least 99.5% deuterium inclusion.

The compounds of the present invention may, by nature or design, form solvates with solvents (including water). Therefore, the present invention is intended to cover both solvated and unsolvated forms. The term solvate means a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Such solvent molecules are solvent molecules that are commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term hydrate means a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates in accordance with the present invention include solvates, where the solvent of crystallization can be isotopically substituted, for example, D ₂ O, d ₆ acetone, d ₆ -DMSO.

The term “therapeutically effective amount of a compound of the present invention” means an amount of a compound of the present invention that elicits a biological or medical response in a subject, such as reducing the activity or inhibition of an enzyme or protein, or reducing the intensity of symptoms, alleviating conditions, slowing or delaying the progression of a disease, or preventing diseases, etc. In one non-limiting embodiment, the term therapeutically effective amount means an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition or disorder or disease or biological process , (i) mediated by TRPC6 activity or (ii) associated with TRPC6 activity; or (2) inhibition of TRPC6 activity. In another non-limiting embodiment, the term therapeutically effective amount means an amount of a compound of the present invention which, when administered to a cell or tissue or non-cellular biological material or medium, is effective to at least partially inhibit TRPC6 activity.

As used herein, the term subject means an animal. Typically, the animal is a mammal. Subject also means, for example, primates (eg, 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 embodiments, the subjects

- 57 043189 volume is a person.

As used herein, the term inhibit, inhibiting, or effecting inhibition means the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant reduction in the original activity of a biological activity or process.

As used herein, the term treat, treat, or treat any disease or disorder, in one embodiment, means ameliorating the disease or disorder (i.e., slowing down, or stopping, or reducing the progression of the disease or at least one of its clinical symptoms) . In another embodiment, the term treat, treat, or treat means attenuating or reducing the intensity of at least one physical parameter, including parameters that may not be discernible to the patient. In another embodiment, the term treat, treat, or treat means to modulate a disease or disorder, either physically (eg, stabilizing a discernible symptom) or physiologically (eg, stabilizing a physical parameter), or both.

As used herein, the term prevent, effecting the prevention or prevention of any disease or disorder in one embodiment means delaying or preventing the onset of the disease or disorder (i.e., slowing or preventing the onset of the disease or disorder in a patient susceptible to the development of the disease or disorder) .

As used herein, a subject is in need of treatment if such subject would benefit from such treatment from a biological, medical, or quality of life standpoint.

As used herein, the term in the singular, plural and similar terms used in the context of the present invention (especially in the context of the claims) should be construed to encompass both the singular and the plural, unless otherwise specified herein or expressly does not contradict the context.

Any asymmetric atom (eg, carbon or the like) in the compound(s) of the present invention may be present in racemic or enantiomerically enriched, eg (R)-, (S) or (R,S)-configuration. In certain embodiments, each asymmetric atom is characterized by 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 at least 95% enantiomeric excess or at least 99% enantiomeric excess in the (R)- or ^-configuration. Substituents on atoms with unsaturated bonds may, if possible, be present in the cis-(Z)- or trans-(E) form.

Accordingly, the compound of the present invention as used herein may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, e.g., substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes). ), racemates or mixtures thereof.

Any mixtures of isomers obtained may be separated, on the basis of the physicochemical differences of the components, into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and/or fractional crystallization.

Any resulting racemates of end products or intermediates may be resolved into optical antipodes by known methods, for example by separating their diastereomeric salts prepared using an optically active acid or base and isolating the optically active acidic or basic compound. In particular, the main moiety can thus be used to separate the compounds of the present invention into their optical antipodes, for example by fractional crystallization of a salt formed using an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di- O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated using chiral chromatography, such as high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) using a chiral adsorbent.

Mixtures of isomers obtained in accordance with the present invention may be separated by a method known to those skilled in the art into individual isomers; diastereoisomers can be separated, for example, by separation between polyphasic solvent mixtures, recrystallization and/or chromatographic separation, for example on silica gel, or by means of, for example, medium pressure liquid chromatography on a reverse phase column, and racemates can be separated, for example , by formation of salts using optically pure salt-forming reagents and separation of the mixture of diastereoisomers thus obtained, for example, by fractional crystallization, or by chromatography on optically active

- 58 043189 column materials.

Within the scope of this text, only an easily removable group that is not a component of the particular desired end product of the compounds of the present invention is referred to as a protecting group, unless the context indicates otherwise. The protection of functional groups with such protecting groups, the protecting groups themselves and their cleavage reactions 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/I, 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 (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A feature of protecting groups is that they can be easily removed (i.e. without causing unwanted side reactions), for example, by solvolysis, reduction, photolysis or, alternatively, in physiological conditions (for example, by enzymatic digestion).

Intermediates and end products may be processed and/or purified according to standard methods, for example using chromatographic methods, partitioning methods, (re)crystallization, and the like.

All methods described herein can be performed in any convenient order, unless otherwise specified in this document or otherwise clearly contradicts the context. The use of any and all examples or illustrative language (eg, such as) provided herein is intended solely to better explain the present invention and does not limit the scope of the present invention, unless otherwise stated.

Any of the process steps disclosed herein may be carried out under reaction conditions that are known to those skilled in the art, including under the conditions specified specifically, in the absence or, in the usual manner, in the presence of solvents or diluents, including e.g. solvents or diluents which are inert with respect to the reactants used and dissolve them, in the absence or presence of catalysts, condensing or neutralizing agents, e.g. ion exchangers, such as cation exchangers, e.g. in the H ⁺ form, depending on the nature of the reaction and/or reactants at low, normal or elevated temperature, for example, in the temperature range from about -100°C to about 250°C, including, for example, from about -80°C to about 250°C, for example, at -80 to -60°C, at room temperature, at -20 to 40°C or at reflux temperature, at atmospheric pressure or in a closed vessel, where appropriate, under pressure and/or inert atmosphere , for example, in an argon or nitrogen atmosphere.

Solvents from which those suitable for any particular reaction may be selected include those solvents specified specifically or, for example, water, esters such as lower alkyl lower alkanoates, such as ethyl acetate, ethers such as aliphatic ethers such as diethyl ether or cyclic ethers such as tetrahydrofuran or dioxane, liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol or 1- or 2-propanol, nitriles such as acetonitrile, halogenated hydrocarbons such as such as methylene chloride or chloroform, acid amides such as dimethylformamide or dimethylacetamide, bases such as heterocyclic nitrogen bases such as pyridine or N-methylpyrrolidin-2one, carboxylic acid anhydrides such as lower alkanoic acid anhydrides such as acetic anhydride, cyclic, linear or branched hydrocarbons such as cyclohexane, hexane or isopentane, methylcyclohexane, or mixtures of such solvents, for example aqueous solutions, unless otherwise indicated in the description of the methods. Such solvent mixtures can also be used in processing, for example by chromatography or separation.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In an additional embodiment, the composition contains at least two pharmaceutically acceptable carriers, such as the carriers described herein. For the purposes of the present invention, unless otherwise indicated, solvates and hydrates are generally considered in the context of compositions. Preferably, the pharmaceutically acceptable carriers are sterile. The pharmaceutical composition may be formulated for specific routes of administration such as oral administration, parenteral administration and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention may be formulated in solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, without limitation, solutions, suspensions, or emulsions). Pharmaceutical compositions may be subjected to conventional pharmaceutical procedures such as sterilization

- 59 043189 and/or may contain conventional inert diluents, lubricants or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

As used herein, the term pharmaceutically acceptable carrier includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterials, antifungals), isotonic agents, absorption delay agents, salts, preservatives, drugs, drug stabilizers, binders, fillers, disintegrants, lubricants, sweeteners, flavoring agents, colorants, and the like. and combinations thereof, which would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). 3a except where any conventional carrier is incompatible with the active ingredient, it is intended to be used in therapeutic or pharmaceutical compositions.

Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient together with one or more of a) diluents, eg 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; in the case of tablets also c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if required, d) disintegrants, for example starches, agar, alginic acid or its sodium salt or effervescent mixtures; and (e) absorbents, colorants, flavors and sweeteners. Tablets may be either film-coated or enteric-coated according to methods known in the art. Suitable compositions for oral administration contain an effective amount of a compound of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or tinctures. Compositions intended for oral administration are prepared in accordance with any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives, in order to providing pharmaceutically superior and palatable formulations. The tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such fillers are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrators, for example corn starch or alginic acid; binders, for example starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained release over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral administration may be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily vehicle, for example , peanut butter, liquid paraffin or olive oil. Some injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are predominantly prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution activators, salts for adjusting osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75% or about 1-50% of the active ingredient. Suitable compositions for transdermal use include an effective amount of a compound of the present invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable, pharmacologically acceptable solvents designed to facilitate passage through the host's skin. For example, transdermal devices are in the form of a dressing containing a support member, a reservoir containing a compound, optionally with carriers, optionally a rate-controlling barrier, for delivering the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and means for attaching the device to the skin. Suitable compositions for topical application, for example to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels, or spray formulations, for example, for delivery by aerosol or the like. Such topical delivery systems will be particularly suitable for application to the skin, for example

- 60 043189 for the treatment of skin cancer, for example for prophylactic use in sunscreens, lotions, sprays and the like. Thus, they are particularly suitable for use in topical, including cosmetic, formulations well known in the art. Such systems may contain solubilizers, stabilizers, tonicity enhancers, buffers and preservatives. As used herein, topical application may also refer to inhalation or intranasal application. They can be conveniently delivered in dry powder form (either singly, as a mixture, e.g. dry mix with lactose, or as a particle of mixed components, e.g. with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, dispenser , atomizer or nebulizer with or without suitable propellant.

The present invention further provides anhydrous pharmaceutical compositions and dosage forms containing the compounds of the present invention as active ingredients, since water may promote degradation of some compounds.

The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture ingredients and low moisture or low humidity conditions. The anhydrous pharmaceutical composition may be prepared and stored in such a manner as to retain its anhydrous nature. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in suitable pharmaceutical kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, single dose containers (eg, vials), blister packs, and blister packs.

The present invention further provides pharmaceutical compositions and dosage forms that contain one or more agents that reduce the rate at which the compound of the present invention will degrade as an active ingredient. Such agents referred to herein as stabilizers include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or saline buffers, and the like.

Options for preventive and therapeutic use.

The compounds disclosed herein in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g., properties of modulating the TRPC protein and, more specifically, inhibiting the activity of the TRPC6 protein, e.g., as indicated in the in vitro and in vivo tests presented in the following sections, and are therefore intended for therapy.

The present invention provides methods for treating a disease or disorder associated with TRPC6 protein activity by administering to a subject in need thereof an effective amount of a compound disclosed herein. In certain aspects, a disease or disorder suitable for therapy by administering a compound of the present invention includes, without limitation, nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic kidney failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, cancer, 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 for treating or preventing kidney disease by administering to a subject in need thereof an effective amount of a compound disclosed herein. In certain embodiments, patients who are currently asymptomatic but at risk of developing kidney disease are eligible for administration of a compound of the present invention. Methods for treating or preventing kidney disease include, without limitation, methods for treating or preventing nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, and diabetic nephropathy.

The pharmaceutical composition or combination of the present invention may be a unit dose of active ingredients of about 1-1000 mg of active ingredient(s) for a subject weighing 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. A therapeutically effective dose of a compound, pharmaceutical composition, or combinations thereof will depend on the type of subject, body weight, age, and individual condition, disorder or disease being treated, or severity thereof. A physician, clinician or veterinarian of ordinary skill 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 properties of the above dose are demonstrated in in vitro and in vivo tests using pre

- 61 043189 proprietary mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues and preparations thereof. The compounds of the present invention can be administered in vitro in the form of solutions, eg aqueous solutions, and in vivo equally enterally, parenterally, preferably intravenously, eg as a suspension or in aqueous solution. The dose for in vitro use may be in the range of molar concentrations from about 10 ^-3 to 10 ^-9 . A therapeutically effective amount for in vivo use, depending on the route of administration, may be in the range of about 0.1-500 mg/kg or about 1-100 mg/kg.

The activity of a compound of the present invention can be assessed using in vitro and in vivo methods, such as those described in the examples below.

The compound of the present invention can be administered either simultaneously with one or more other therapeutic agents, or before or after them. The compound of the present invention can be administered alone, by the same or different route of administration, or together in the same pharmaceutical composition as other agents.

In one embodiment, the present invention provides a product containing a compound disclosed herein and at least one other therapeutic agent, in the form of 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 TRPC protein activity. In preferred aspects, the therapy is the treatment of nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute disease lungs, acute respiratory distress syndrome (ARDS), heart failure, stroke, cancer, or muscular dystrophy.

Products presented as a combination preparation include a composition containing a compound disclosed herein and other therapeutic agent(s) together in the same pharmaceutical composition, or a compound disclosed herein, and other therapeutic agent(s) in a separate form, for example in the form of a kit.

In one embodiment, the present invention provides a pharmaceutical composition containing the compound disclosed in this document, and other(s) therapeutic(s) agent(s). Optionally, the pharmaceutical composition may contain a pharmaceutically acceptable carrier as described above.

In one embodiment, the present invention provides a kit containing two or more separate pharmaceutical compositions, at least one of which contains the compound disclosed in this document. In one embodiment, the kit contains means for storing said compositions separately, such as a container, a split vial, or a split foil pouch. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules, and the like.

The kit of the present invention can be used to administer various dosage forms, such as oral and parenteral, to administer separate compositions at different intervals between doses, or to adjust the doses of individual compositions relative to each other. To facilitate adherence to a treatment regimen, the kit of the present invention typically contains instructions for administration.

In combination therapy variations of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, a compound of the present invention and another therapeutic agent may be combined in a combination therapy agent: (i) prior to providing the combination product to clinicians (eg, in the case of a kit containing a compound of the present invention and another therapeutic agent); (ii) by physicians themselves (or under the guidance of a physician) shortly before administration; (iii) in the patients themselves, for example, during the sequential administration of a compound of the present invention and another therapeutic agent.

Accordingly, the present invention contemplates the use of a compound disclosed herein for the treatment of a disease or condition mediated by TRPC protein activity, wherein the drug is formulated to be administered with another therapeutic agent. The present invention also contemplates the use of another therapeutic agent for the treatment of a disease or condition mediated by TRPC protein activity, wherein the drug is administered with a compound disclosed herein. In another aspect, the present invention provides the use of a compound disclosed herein for the treatment of a disease or disorder selected from nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal insufficiency, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute

- 62 043189 lung disease, acute respiratory failure syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy, where the medicinal product is received for administration with another therapeutic agent. The present invention also contemplates 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, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal insufficiency, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, cancer, or muscular dystrophy, wherein the drug is administered with a compound disclosed herein.

The present invention also provides a compound disclosed herein for use in a method of treating a disease or condition mediated by TRPC protein activity, wherein the compound is prepared for administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by TRPC protein activity, wherein the other therapeutic agent is formulated to be administered with a compound disclosed herein. The present invention also provides a compound disclosed herein for use in a method of treating a disease or condition mediated by TRPC protein activity, wherein the compound is administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by TRPC protein activity, wherein the other therapeutic agent is administered with a compound disclosed herein.

The present invention also contemplates the use of a compound disclosed herein for the treatment of a disease or condition mediated by TRPC protein activity where the patient has previously (eg, within 24 hours) been treated with another therapeutic agent. The present invention also contemplates the use of another therapeutic agent for the treatment of a disease or condition mediated by TRPC protein activity where the patient has previously (eg, within 24 hours) received treatment with a compound disclosed herein.

The pharmaceutical compositions may be administered alone or in combination with other active ingredients known to be beneficial in the treatment of kidney disease, or more particularly in the treatment of FSGS, nephrotic syndrome, minimal change disease, or diabetic kidney disease. The combination therapy regimen may be additive, or it may provide synergistic results (eg, improved renal function that is greater than expected from the combined use of the two agents). In some embodiments, the present invention provides a combination therapy for the prevention and/or treatment of kidney disease, or more specifically FSGS, nephrotic syndrome, or minimal change diseases, with a compound of the present invention and a second therapeutic agent selected from the group consisting of ACE/ ARBs (such as captopril, lisinopril, or losartan), a steroid therapeutic agent (such as prednisone), immunomodulators (such as mycophenolate mofetil, tacrolimus, or cyclosporine A), adrenocorticotropic hormone analogs (such as Aktar gel), 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) , an anti-hyperlipidemia agent (such as rosuvastatin), an anemia therapeutic agent (darbepoetin alfa), or an anti-hyperuricemia agent (febuxostat).

In one embodiment, the present invention provides a method for inhibiting TRPC protein activity, or more preferably, inhibiting TRPC6 protein activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as defined in formula (I). The present invention further provides methods for inhibiting TRPC protein activity, or more preferably, inhibiting TRPC6 protein activity in a subject by administering a compound disclosed herein, wherein the method comprises administering to the subject a therapeutically effective amount of a compound disclosed herein.

In one embodiment, the present invention provides a compound disclosed herein for use as a drug.

In one embodiment, the present invention provides for the use of a compound disclosed herein for the treatment of a disorder or disease in a subject characterized by TRPC protein activity or, more preferably, TRPC6 protein activity. In particular, the present invention contemplates the use of a compound disclosed herein for the treatment of a disorder or disease mediated by TRPC protein activity, or more preferably TRPC6 protein activity, e.g., nephrotic syndrome, minimal change disease, focal segmental segmental disease. glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor or muscular dystrophy. In certain preferred aspects, the present invention provides for the use of a compound disclosed herein for the treatment of a disorder or disease mediated by TRPC6 protein activity selected from nephrotic syndrome, membranous nephropathy, and acute renal failure.

In one embodiment, the present invention provides for the use of a compound disclosed herein in the manufacture of a medicament for the treatment of a disorder or disease in a subject characterized by TRPC protein activity or, more preferably, TRPC6 protein activity. More specifically, in the manufacture of a medicament for the treatment of a disease or disorder in a subject characterized by TRPC protein activity, or more preferably TRPC6 protein activity, e.g., nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignancy, or muscular dystrophy. In certain preferred aspects, the present invention contemplates the use of a compound disclosed herein in the manufacture of a medicament for the treatment of nephrotic syndrome, membranous nephropathy and acute renal failure.

In one embodiment, the present invention provides for the use of a compound disclosed herein for the treatment of a disorder or disease in a subject characterized by TRPC protein activity or, more preferably, TRPC6 protein activity. More specifically, the present invention provides for the use of the compounds provided herein in the treatment of a disease or disorder characterized by TRPC protein activity, or more preferably TRPC6 protein activity, e.g., nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, glomerulopathy, membranous nephropathy, membranous proliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignancy, 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 compounds of the present invention for the treatment or prevention of nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS) , heart failure, stroke, cancer, or muscular dystrophy. In certain embodiments, patients who are currently asymptomatic but at risk of developing symptomatic nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung disease, acute respiratory failure syndrome ( ARDS), heart failure, stroke, cancer, or muscular dystrophy are suitable for administering a compound of the present invention. Use in the treatment or prevention of nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignancy, or muscular dystrophy includes without limitation, 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, acute lung disease, acute respiratory distress syndrome (ARDS), heart failure , stroke, cancer, or muscular dystrophy.

The present invention further includes any variant of the methods of the present invention in which an intermediate product obtained in any of its steps is used as a starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under reaction conditions, or in which the reaction components are used in the form of their salts or optically pure materials.

- 64 043189

The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperature values are in degrees Celsius (°C). Unless otherwise indicated, all evaporation operations are carried out under reduced pressure, typically from about 15 to 100 mmHg. Art. (=20-133 mbar). The structure of end products, intermediates and starting materials is confirmed using standard analytical methods, eg microanalysis and spectroscopic characterization, eg MS, IR, NMR. The abbreviations used are the abbreviations commonly used in the art.

The present invention also relates to those forms of the process in which the compound obtained as an intermediate in any step of the process is used as the starting material and the remaining steps 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 protected form or in salt form, or the compound obtained by the method of the present invention is prepared under the conditions of the method and further processed in situ.

All starting materials, building blocks, reagents, acids, bases, dehydrators, solvents, and catalysts used to synthesize the compounds of the present invention are either commercially available or can be obtained using organic synthetic methods known to a person skilled in the art.

experimental part

Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. All parts are by weight and temperatures are in degrees Celsius unless otherwise noted. All reactions under the influence of microwave radiation were carried out using a Smith synthesizer from Biotage. Mass spectral data were determined using an electrospray ionization technique. All examples were purified to >95% purity as determined by high performance liquid chromatography. Unless otherwise indicated, the 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.

Compound names, i.e. IUPAC names for the compounds described in this application were obtained using ChemDraw compound naming software.

The following abbreviations are used.

CDI - 1,1'-carbonyldiimidazole;

DCM - dichloromethane;

DMSO - dimethyl sulfoxide;

DMF - N,N-dimethylformamide;

THF - tetrahydrofuran;

Et ₂ O - diethyl ether;

EtOAc - ethyl acetate;

EtOH - ethyl alcohol;

Ms - mesylate;

MeCN - acetonitrile;

MeOH - methyl alcohol;

SFC - supercritical fluid chromatography;

TFA - trifluoroacetic acid;

tap - 2,2,6,6-tetramethylpiperidine;

h - hour;

min - minute;

k.t. - room temperature (22-25°C);

ml - milliliters;

µl - microliters;

g - grams;

mcg - micrograms;

mg - milligrams;

µmol - micromoles.

General method of obtaining

The compounds described herein were prepared using procedures known to those skilled in the art, through the reaction sequences depicted in Schemes 16, as well as by other methods. In addition, in the following schemes, where specific acids, bases, reagents, binders, solvents, etc. are mentioned, it should be understood that other suitable acids, bases, reagents, binders, solvents, etc. can be used, and they are included in the scope of the present invention.

The synthesis of selected compounds of the present invention was carried out as described in Scheme 1. Coupling reaction with CDI of the desired bis-aniline provided the corresponding benzimi

- 65 043189 dazolone. Refluxing the POC13 provided chlorobenzimidazole. These intermediates can be alkylated with various electrophiles, then subjected to SnAr conditions to give Boc-protected secondary intermediates. The action of various acids ensured the removal of the protective Boc group to obtain the final products.

Scheme 1

^R4

An alternative approach to the preparation of benzimidazole intermediates, which was used in the present invention for the synthesis of additional compounds, is shown in Scheme 2. The coupling reaction with the CDI of the desired bis-aniline provided the corresponding benzimidazolone. Refluxing the POCl3 provided chlorobenzimidazole. These intermediates were heated with base and nucleophile to give SnAr products. Alkylation with various electrophiles followed by acid deprotection of the Boc group provided the final compounds.

Scheme 2

or h-butanol

In addition, examples in the present invention can be synthesized using the methods shown in schemes 3-6.

Scheme 3

The formation of isothiocyanate was carried out using various reagents. The addition of secondary amines followed by condensation with primary amines provided the corresponding substituted guanidine.

Intramolecular cyclizations were carried out using a copper catalyst. The final acidic removal of the Boc protecting group provided the desired compounds.

NHBoc

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Scheme 4

Exposure of substituted piperidines to cyanogen bromide provided the corresponding piperidine-1-carbonitriles. They were subjected to nucleophilic attack with various aniline nucleophiles, which were then captured with benzyl electrophiles. The corresponding guanidine was subjected to an intramolecular cross-coupling reaction in the presence of palladium and copper catalysts. The final removal of the Boc protecting group under acidic conditions provided the desired compounds.

Scheme 5

The benzimidazoles were alkylated with various electrophiles and a base. These intermediates were treated with Zn(tmp)2, a copper catalyst and benzoylhydroxylamines to give aminated products. Final exposure to acidic Boc deprotection provided the desired products.

Scheme 6

SnAr transformations were carried out on substituted fluoronitrobenzenes using primary benzylamines and a base. The appropriate nitrogen-containing intermediates were reduced with iron or zinc, then subjected to coupling reactions with CDI and POCl ₃ chlorination reactions. These intermediates were re-exposed to SnAr conditions, then the Boc-protecting group was removed under acidic conditions to give the final compounds.

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Scheme 7

General synthesis of alkyl intermediates

^R4

NC

Intermediate 1

intermediate connection

F Intermediate 2

1: 6-((2-chloro-5,7-difluoro-1H-benzo[b]imidazol-1 yl)methyl)nicotinonitrile and intermediate 2: 6-((2-chloro-4,6-difluoro-1H -benzo[b]imidazol1 -yl)methyl)nicotinonitrile

hh ₂

NHCDI

THF

Step 1. 4,6-Difluoro-1H-benzo[b]imidazol-2(3H)-one.

3,5-Difluorobenzene-1,2-diamine (210.0 g, 1.457 mol, 1.0 eq.) and CDI (236.0 g, 1.457 mol, 1.0 eq.) were dissolved in anhydrous THF (2, 5 L, 11.9 ml/g) and stirred for 12 hours at room temperature. LCMS indicated completion of the reaction. The reaction mixture was diluted with water (6.0 L) and extracted with ethyl acetate (2x6.0 L). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 4,6-difluoro-1Hbenzo[d]imidazol-2(3H)-one as a black solid which was used for the next step without further purification. Ή NMR (400 MHz, DMSO-d ₆ ): 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, positive, ion) mass/charge: 171.0 [M+1]

POCI ₃

Step 2 2-Chloro-4,6-difluoro-1H-benzo[c1]imidazole.

4,6-Difluoro-1H-benzo[b]imidazol-2(3H)-one (180.0 g, 1.058 mol, 1.0 eq.) was suspended in POCl ₃ (2.0 L) and heated with stirring at 110°C for 2 h, after which LCMS showed the completion of the reaction. Excess POCl ₃ was removed by vacuum distillation and the remaining residue was diluted with acetonitrile (1.0 L) and sat. aq. sodium bicarbonate solution (1.0 L), then extracted with ethyl acetate (2x4.0 L). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-4,6-difluoro-1Hbenzo[c1]imidazole as a brown solid which was used for the next reaction without further purification. Ή NMR (400 MHz, DMSO-d ₆ ): 13.40 (bs, 1H), 7.31-7.03 (m, 2H). MS (ESI, posit, ion) mass/charge: 189.0 [M+1].

Vg

Pd(PPh ₃ ) ₄ , Zn(CN) ₂ » ^NC

OH DMF100C

He

Step 3: 6-(Hydroxymethyl)nicotinonitrile.

(5-Bromopyridin-2-yl)methanol (75.0 g, 399.0 mmol, 1.0 eq.), zinc cyanide (141.0 g, 1.197 mol, 3.0 eq.) and tetrakis(triphenylphosphine) palladium(0) (46.1 g, 39.9 mmol, 0.1 equiv.) was dissolved in Ν,Νdimethylformamide (750.0 ml, 10.0 ml/g) and degassed with nitrogen for 30 min. The reaction mixture was heated at 110°C for 2 hours LCMS showed the formation of the product. After completion of the reaction, the mixture was allowed to cool to room temperature, diluted with water (700 ml) and extracted with ethyl acetate (3x700 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 using a Biotage Isolera One column preloaded with silica gel eluting with a gradient of 40% ethyl acetate in hexane to give 6-(hydroxymethyl)nicotinonitrile as a white solid. Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (dt, J=l.8, 0.8 Hz, 1H), 8.32-8.28 (m, 1H), 7.66 (dt , J=8.3, 0.9Hz, 1H), 5.68 (td, J=5.9, 0.8Hz, 1H), 4.64 (d, J=5.8Hz, 2H) . MS (ESI, posit, ion) mass/charge: 135.0 [M+1].

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1 ^NC - MsCI, DIPEA 'η Ϊ

DCM**

X=CI

X=OMs

Step 4: 6-(Chloromethyl)nicotinonitrile and (5-cyanopyridin-2-yl)methylmethanesulfonate.

6-(Hydroxymethyl)nicotinonitrile (25.0 g, 186.0 mmol, 1.0 eq.) was dissolved in dichloromethane (360.0 ml, 14.4 ml/g) and cooled to 0°C. N,N-diisopropylethylamine (48.8 mL, 280.0 mmol, 1.5 eq.) was added followed by methanesulfonyl chloride (16.0 g, 205.0 mmol, 1.1 eq.) dropwise over 15 min. . The reaction mixture was allowed to warm to room temperature and stirred for 45 min. LCMS showed product formation. The reaction mixture was diluted with water (500 ml) and extracted with DCM (2x250 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude material which was adsorbed onto a silica gel plug (230-400 mesh) and purified by chromatography through a Biotage Isolera One column pre-packed with silica gel, eluting with a gradient of 15 % ethyl acetate in hexane to give 6-(chloromethyl)nicotinonitrile(VI) as a yellowish solid. ¹ H NMR (400 MHz, DMSO-d6) 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). Additional gradient elution of the column with 50% ethyl acetate in hexane provided 5-cyanopyridin-2yl)methyl methanesulfonate as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) 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, positive ion) mass/charge: 213.2 [M+1]. Both compounds were suitable electrophiles for alkylation (step 5).

Step 5. 6-((2-Chloro-4,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile and 6-((2-chloro5,7-difluoro-1H-benzo[d ]imidazol-1-yl)methyl)nicotinonitrile.

2-Chloro-4,6-difluoro-1H-benzo[d]imidazole (50.0 g, 265.0 mmol, 1.0 eq) and 6(chloromethyl)nicotinonitrile (40.5 g, 265.0 mmol , 1.0 eq.) was dissolved in acetonitrile (500.0 ml, 10.0 ml/g) at room temperature. Cesium carbonate (138.0 g, 427.0 mmol, 1.6 eq.) 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 (2x200 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was adsorbed onto a silica gel plug (60-120 mesh) and purified by column chromatography eluting with a gradient of 25% ethyl acetate in hexane to give 6-((2-chloro-4,6-difluoro-Nibenzo[d]imidazole-1 -yl)methyl)nicotinonitrile and 6-((2-chloro-5,7-difluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile as a mixture of isomers (light yellow solid). In some cases, a mixture of isomers was transferred without separation, while in others the isomers were separated at this stage.

Step 6. Separation of 6-((2-chloro-5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-nicotinonitrile (intermediate 1) and 6-((2-chloro-4,6 -difluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile (intermediate 2)

Dissolve 1.0 g sample in 20 ml methanol, column: Lux C4 (250x50 mm, 5 μm), mobile phase: 70:30 (A:B), A: liquid CO ₂ , B: methanol, flow rate: 120 ml/ min, wavelength: 220 nm, sample loading: 100 mg/injection, inlet pressure: 200-210 bar, cycle time: 3.5, analysis time: 10. In total (51.0 g of mixture of isomers) were separated using SFC to give 6-((2-chloro-5,7-difluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile (intermediate 1, peak 1) and 6-((2-chloro-4,6 -difluoro-Nibenzo[d]imidazol-1-yl)methyl)nicotinonitrile (intermediate 2, peak 2) as yellow solids. Peak 1: 1H NMR (400 MHz, DMSO-d6): 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). MS (ESI, positive ion) mass/charge: 304.0 [M+1]. Peak 2: 1H NMR (400 MHz, DMSO-d ₆ ): 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, 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, positive ion) mass/charge: 304.0 [M+1].

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The following intermediates were synthesized using the same sequence as used in the synthesis of intermediates 1 and 2 and in general scheme 7 above.

Table 1

Alkylated intermediates

No. prom, conn. Structure Name connections 1HNMR MS MH+ Separation conditions 1 6-((2-chloro-5,7difluoro-1Hbenzo[d]imidaz ol-1yl)methyl)nicot inonitrile ^X H NMR (400 MHz, DMSO-d6): 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, 304.0 Column Lux C4, 30% MeOH, peak 1 J=9.0, 2.2Hz, 1H), 7.22(ddd, J=ll.9, 10.3,2.2Hz, 1H), 5.79(s, 2H) 2 NC7 6-((2-chloro-4,6difluoro-1Hbenzo[d]imidaz ol-1yl)methyl)nicot inonitrile ^X H 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, J=8.7, 3.0 Hz, 1H), 7.20 (tdd, J =10.7, 4.5.2.1Hz, 1H), 5.79 (d, J=3.8Hz, 2H) 304.0 Column Lux C4, 30% MeOH, peak 2 3 7a ABOUT 6-((2,6-dichl op1Hbenzo[d]imidaz ol-1yl)methyl)nicot inonitrile ^X H NMR (400 MHz, DMSO-d ₆ ): 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), 7.687.60 (m, 2H), 7.29 (dd, J=8.6, 2.1 Hz, 1H), 5 .79(s, 2H) 303.0 YMC Amyose SA, methanolTHF (70:30) 40%; peak 1 4 And O 6-((2,5-dichloro1Нbenzo[d]imidaz ol-1yl)methyl)nicot inonitrile 1HNMR (400 MHz, DMSO-d6): 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, 2.1Hz, 1H), 5.79 (s, 2H) 303.0 YMC Amyose SA, methanolTHF (70:30) 40%; peak 2

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5 ll 6-((2-Chloro-6fluoro-1Hbenzo[d]imidaz ol-1yl)methyl)nicot inonitrile 1HNMR (400 MHz, DMSO-d6): δ 8.938.86 (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- THF (70:30) 40%; peak 1 6 NC C 6-((2-chloro-5fluoro-1Hbenzo[b]imidaz ol-1yl)methyl)nicot inonitrile 1HNMR (400 MHz, DMSO-d6): 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=9.5, 2.4 Hz, 1H), 7.24-7.05 (m, 1H), 5.77(s, 2H) 287.0 YMC Amyose SA, methanolTHF (70:30) 40%; peak 2 7 NC C ί XX ^C| 6-((2-chloro-1Hbenzo[b]imidaz ol-1yl)methyl)nicot inonitrile 1HNMR (400 MHz, DMSO-d6): 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 f JT ^ci 6-((2-chloro-4(trifluoromethyl) -1Hbenzo[(1]imidaz ol-1yl)methyl)nicot inonitrile - 337.2 - ^9a NC 3 TT />-« ^ _n ^ n 6-((2,6-dichl op1Nimidazo[4,5b]pyridine-1- - 304.0 Divided upon receipt of the final

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yl)methyl)nicotine inonitrile product 10 NC c Cea ^ci CN 2-chloro-1-((5 cyanopyridin2-yl)methyl)1Hbenzo[c!]imidazol-4carbonitrile - 294.0 - And LL. 2-chloro-1-((5 cyanopyridin2-yl)methyl)-6fluoro-1Hbenzo[c!]imidaz ol-4carbonitrile - 312.2 - 12 ^a ABOUT 6-((2-chloro-6(trifluoromethoxy)-1Hbenzo[c!]imidazol-1yl)methyl)nicot inonitrile - 353.2 Separated upon receipt of the final product 13 ^a oh oh 2-chloro-1-((5 chloropyridin2-yl)methyl)-6(methyl sulfone yl)-1Hbenzo[<1]imidazol - 357.8 Separated upon receipt of the final product 14 3 T T / W ^{s |} CN 2-chloro-1-((5 chloropyrimidi n-2-yl)methyl)6-fluoro-1Hbenzo[<1]imidase - 323.8 -

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ol-4carbonitrile ^15a ABOUT 2-chl op-4,6difluoro-l-((5fluoropyridin2-yl)methyl)- 1Hbenzo[s!]imidase ol - 298.0 Separated upon receipt of the final product ^16a bTT^ ^ci 2-chloro-4,6difluoro-1-((5fluoropyrimidi n-2-yl)methyl)1Hbenzo[c!]imidazol - 299.0 Separated upon receipt of the final product ^17a C T»· 2-chloro-1-((5 chloropyrimidi n-2-yl)methyl)6-fluoro-1Hbenzo[c!]imidazol - 297.0 Separated upon receipt of the final product 18 /7 2-chloro-6-fluoro1-((5fluoropyrimidi n-2-yl)methyl)1Hbenzo[c!]imidaz ol-4carbonitrile - 306.2 - ^19a 6-((2-chloro-6(trifluoromethyl) -1Hbenzo[c!]imidazol-1- - 337.0 Separated upon receipt of the final product

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yl)methyl)nicotine inonitrile ^20a NC 6-((2,5-dichloro6-methyl-1Hbenzo[(1]imidazol-1yl)methyl)nicot inonitrile - 317.0 Separated upon receipt of the final product ^21a ifi about £ 6-((2-chloro-6(difluoromethox u)-1Hbenzo[<1]imidaz ol-1yl)methyl)nicot inonitrile - 335.0 Separated upon receipt of the final product 22 NC C ome 6-((2-chloro-4methoxy-1Hbenzo[(1]imidaz ol-1yl)methyl)nicot inonitrile - 299.2 Separated upon receipt of the final product 23 NC 4prl Me 6-((2-Chloro-4methyl-1Hbenzo[(1]imidazol-1yl)methyl)nicot inonitrile - 283.2 - ^24a NC C ¥T ^ ^ci 6-((2-Chloro-6methoxy-1Hbenzo[(1]imidaz ol-1yl)methyl)nicot inonitrile - 299.2 Separated upon receipt of the final product

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^25a NC 3 1 X '3 ^ci 6-((2-chloro-6fluoro-5(trifluoromethyl) -1Hbenzo[<1]imidazol-1yl)methyl)nicot inonitrile - 355.0 Separated upon receipt of the final product ^26a 'o-TA Q 6-((2,6-dichl op5(trifluoromethyl) -1Hbenzo[(1]imidaz ol-1yl)methyl)nicot inonitrile - 371.0 Separated upon receipt of the final product ^27a NC C i X ')~ ^ci P ₃ Κ:Ά4 6-((2,6-dichl op5(trifluoromethoxy)-1Hbenzo[(1]imidazol-1yl)methyl)nicot inonitrile - 387.0 Separated upon receipt of the final product 28 NC 3 ^C Χ/Χ.Ί jf X ^ci 6-((2,5,6trichloro-1Hbenzo[0]imidaz ol-1yl)methyl)nicot inonitrile - 337.0 - 29 Ai LL LL 6-((2-chloro-5,6difluoro-1Hbenzo[(1]imidazol-1yl)methyl)nicot - 305.1 -

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inonitrile thirty ( T 2-chloro-1 -((5chloropyridin2-yl)methyl)1Hbenzo[c!]imidazol - 278.2 - ^31a NC 'p>- 6-((2-chloro-4,6difluoro-1Hbenzo[<1]imidaz ol-1yl)methyl)nicot inonitrile - 305.2 Separated upon receipt of the final product 32 Ω 6-((2,4-dichloro6-fluoro-1Hbenzo[(1]imidaz ol-1yl)methyl)nicot inonitrile - 321.0 - ^33a Q 2-chloro-1-((5 cyanopyridin2-yl)methyl)1Hbenzo[c1]imidazol-6carbonitrile - 294.0 Separated upon receipt of the final product ^34a NC.7XXr 6-((2-chloro-6fluoro-1Hbenzo[c1]imidaz ol-1yl)methyl)nicot inonitrile - 287.0 Separated upon receipt of the final product

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35 NC C 6-((2-chloro-5,6dimethyl-1Hbenzo[<1]imidazol-1yl)methyl)nicot inonitrile - 297.0 - 36 NC C Cl 6-((2,4,6trichloro-1Hbenzo[<1]imidaz ol-1yl)methyl)nicot inonitrile - 336.8 - ^37a 6-((2,6-dichl o1Hbenzo[(1]imidaz ol-1yl)methyl)nicot inonitrile - 304.0 Separated upon receipt of the final product 38 cm ? ^>r 6-((2,4-dichloro1Hbenzo[(1]imidaz ol-1yl)methyl)nicot inonitrile - 304.2 - ^39a 1 ^JZCl 2-chloro-1-((5 cyanopyridin2-yl)methyl)1Hbenzo[c1]imidazol-6carbonitrile - 294.2 Separated upon receipt of the final product ^40a /^Χ-'θΝ ‘Ό> 6-((2-chloro-6methyl-1Нbenzo[с1]imidazol-1- - 283.2 Divided upon receipt of the final

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yl)methyl)nicotine inonitrile product ^41a / ^cS= \^CN M j _r XXr ^j 6-((2-chloro-5fluoro-6-methyl1Hbenzo[(1]imidazol-1yl)methyl)nicot inonitrile - 301.2 Separated upon receipt of the final product ^42a 'W- 5-((2-chloro-6(trifluoromethyl) -1Hbenzo[(1]imidaz ol-1yl)methyl)pyraz in-2carbonitrile - 338.2 Separated upon receipt of the final product 43 jf ?T ^~ ^a 5-((2-chloro-5,6difluoro-1Hbenzo[(1]imidaz ol-1yl)methyl)pyraz in-2carbonitrile - 306.2 - 44a NC ί L ^Cl 4-((2-Chloro-1Нbenzo[(1]imidazol-1yl)methyl)benzonitrile - 268.2 - ^45a 0 4-((2-chloro-4,6difluoro-1Hbenzo[(1]imidazol-1yl)methyl)benzonitrile - 304.2 Separated upon receipt of the final product

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^46a NC 2-chloro-1-(4cyanobenzyl)- 1Hbenzo[c!]imidase ol-6carbonitrile - 293.2 Separated upon receipt of the final product 47a NC I JI % ¹ 2-((2-chloro-6fluoro-1Hbenzo[c!]imidaz ol-1yl)methyl)pyrimidine-5carbonitrile - 288.2 Separated upon receipt of the final product ^48a MeO 2-chloro-6-fluoro1-((5methoxypyrimidin-2yl)methyl)-1Hbenzo[c!]imidazol - 293.2 Separated upon receipt of the final product 49a Me Ό> 2-(2-Chloro-6fluoro-1Hbenzo[c!]imidaz ol-1-yl)-Mmethyl-M-(2,2,2trifluoroethyl)acetamide - 324.2 Separated upon receipt of the final product ^{50a M} \-V, °S ''“Ό> 2-(2-Chloro-6methoxy-1Hbenzo[c!]imidaz ol-1-yl)-Mmethyl-M-(2,2,2trifluoroethyl)acetamide - 336.0 Separated upon receipt of the final product

- 79 043189

^51a Me 2-(2-Chloro-6methoxy-1Hbenzo[<1]imidazol-1-yl)-H N-dimethylacetamide - 268.2 Separated upon receipt of the final product 52 - lXb ^ci CM 2-(2-chloro-4cyano-6-fluoro1Hbenzo[<1]imidazol-1-yl)-Mmethyl-N-(2,2,2trifluoroethyl)acetamide - 349.2 -- ^53a Me 'n-x ome 2-(2-Chloro-6fluoro-4methoxy-1Hbenzo[<1]imidazol-1-yl)-Xmethyl-Ni-(2,2,2trifluoroethyl)acetamide - 354.2 Separated upon receipt of the final product ^54a NC 7 IXb" 6-((2-chloro-5(trifluoromethyl)-3nimidazo[4,5b]pyridin-3 yl)methyl)nicot inonitrile - 338.2 Separated upon receipt of the final product ^55a from 1-(azetidin-1yl)-2-(6-bromo2-chloro-1Hbenzo[(1]imidazol-1-yl)ethanone - 329.2 Separated upon receipt of the final product

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56 ^a _0 ώ 2-(2-chloro-6(trifluoromethyl)-1Hbenzo[<1]imidazol-1-yl)-1morpholinoethane - 348.2 Separated upon receipt of the final product 57 ^a Me 's-me _o °z 2-(2,6-dichloro1Hbenzo[<1]imidaz ol-1-yl)-BT, Νdimethylacetamide - 273.0 Separated upon receipt of the final product 58 ^a me Y-Me 3 Ύ T / 3 ^C1 2-(2-chloro-6(trifluoromethoxy c)-1Hbenzo[(1]imidazol-1-yl)-I, Νdimethylacetam id - 322.2 Separated upon receipt of the final product 59 ^a 0 C T T ^S1 2-(2-chloro-6(trifluoromethoxy)-1Hbenzo[<1]imidazol-1-yl)-1morpholinoethane He - 264.2 Separated upon receipt of the final product

[a] A mixture of isomers formed by non-selective benzylation, which are separated to obtain the final product or secondary intermediate.

Scheme 8

Converting alkylated intermediates to final products

38:

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1 H-benzo[d]imidazol-1 Example yl)methyl)nicotinonitrile

Step 1. tert-Butyl((3R,4R)-1-(1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4- 81 043189 fluoropiperidin- 3-yl)carbamate.

1,1'-Dimethyltriethylamine (1.300 ml, 7.44 mmol), tert-butyl ((3R,4R)-4-fluoropiperidin-3yl) carbamate (0.975 g, 4.47 mmol), 6-((2-chloro -N-benzo^]imidazol-1-yl)methyl)nicotinonitrile (intermediate 7, 1 g, 3.72 mmol) and dimethyl sulfoxide (7.44 ml) were combined in a flask and heated to 130°C for 36 h. The mixture was cooled, poured into water, then extracted with EtOAc (3X). The organics were combined, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was loaded onto an 80 g RediSep ISCO cartridge eluting with 10-50% EtOAc in heptanes to give t-butyl((3R,4R)-1-(1-((5-cyanopyridin-2-yl)methyl)- 1Hbenzo[d]imidazol-2-yl)-4-fluoropiperidin-3-yl)carbamate as a light orange foam. MS (ESI, positive ion) mass/charge: 451.2 [M+1].

Note: n-butanol is a suitable substituent for DMSO. Difluorinated piperidines require heating up to 150°C.

Boc Deprotection Procedure with TFA (Procedure B)

Step 2 6-((2-((3R,4R)-3-Amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile (Example 43).

tert-Butyl ((3R,4R)-1-(1-((5-cyanopyridin-2-yl)methyl)-N-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-yl)carbamate (1 .31 g, 2.91 mmol, 1 eq.) was dissolved in DCM (10 ml) and slowly dropped into a flask with chilled (0°C) TFA (~10 ml). After 1 h, the removal of the protecting group was completed. The mixture was poured onto an SCX column (pre-wetted with MeOH), washed with MeOH, then eluted with methanolic ammonia. The methanolic ammonia was concentrated and the light orange oil was redissolved in MeCN/water, frozen and lyophilized to give 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), 3.92-4.06 (m, 1H), 3.61-3.79 (m, 2H), 3.20-3.32 (m, 2H), 2.24-2.41 (m, 1H), 1.92-2.14 ( m, 1H). (ESI, positive ion) mass/charge: 351.2 [M+1].

NC

Example 45 6-((2-((3 R,4R)-3-amino-4-fluoropiperidin-1-yl)-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride

Intermediate 6 nhboc

Step 1. (S)-tert-Butyl(1-(1-((5-cyanopyridin-2-yl)methyl)-5-fluoro-1 H-benzo[d]imidazol-2yl)piperidin-3-yl) carbamate.

To a suspension of 6-((2-chloro-6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile (150 mg, 0.523 mmol) and Hunig's base (137 µl, 0.785 mmol) in 1-butanol (2093 μl) (S)-tert-butylpiperidin-3-ylcarbamate (115 mg, 0.576 mmol) was added. The reaction mixture 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 heptane to give the title compound as an off-white solid. (ESI, positive ion) mass/charge: 451.2 [M+1].

Deprotection of the Boc group with HCl (Procedure A)

hh ₂

- 82 043189 (S)-6-((2-(3-aminopiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride (Example 51).

Stage 2. ^)-tert-Butyl ( 1- (1 - ((5-cyanopyridin-2-yl) methyl) -5 -fluoro-1 H-benzo [d]imidazol-2yl) piperidin-3-yl) carbamate (77 mg) was dissolved in dioxane (2 ml) and 4N was added. HCl in dioxane (585 µl, 2.340 mmol). The reaction mixture was stirred at ambient temperature. After 16 hours, LC/MS analysis indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give the title compound as an off-white solid. ¹ H NMR (400 MHz, d ₆ 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, positive ion) mass/charge: 351.0 [M+1].

Note: The HCl salt was sometimes converted to the free base form using aqueous workup or using ion exchange chromatography. The release of salt or free base is indicated in the table.

The following compounds were obtained in a manner analogous to that described above.

hh ₂

Example 8: 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile.

6-((2-((3R,4 S)-3-Amino-4-fluoropiperidin-1-yl)-6-chloro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile was synthesized on a scale of 1 mmol following a procedure similar to the sequence outlined above using Boc deprotection with TFA (procedure B). This was separated to give an intermediate containing Boc: Chiralcel OD-H, 25% IPA, peak 1. 1H NMR (500 MHz, MeOD) δ 8.86 (d, J=1.30 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=1.95, 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, positive ion) mass/charge: 387.2 [M+1].

Example 93: (R)-6-((2-(3-Amino-4,4-difluoropiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile.

(R)-6-((2-(3-Amino-4,4-difluoropiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile was synthesized in scale 1, 9 mmol following a procedure similar to the sequence outlined above, using Boc deprotection with TFA (procedure B). This was separated to give the chlorobenzimidazole intermediate (YMC Amyose SA, methanol-THF (70:30) 40%; peak 1). 1H NMR (500 MHz, MeOD) δ 8.84 (d, J=1.82 Hz, 1H), 8.15 (dd, J=2.08, 8.30 Hz, 1H), 7.40-7 .52 (m, 2H), 6.91-7.00 (m, 2H), 5.47-5.62 (m, 2H), 3.34-3.54 (m, 2H), 3.08 -3.28 (m, 3H), 2.21-2.36 (m, 1H), 2.00-2.21 (m, 1H). (ESI, positive ion) mass/charge: 351.0 [M+1].

Examples in the table. 2 was synthesized using a sequence similar to that used in the synthesis of examples 38, 45, 8 and 88 and in general scheme 8 above.

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Table 2 Compounds prepared according to Scheme 8. Boc deprotection procedure: procedure A=HC1, procedure B=TFA

Note. No. Alkylated Intermediate Amine Procedure for removing the Boc protection group Structure Connection name MSMH+ 1 37 n IN A^ (S)-6-((2-(3aminopiperidin1-yl)-6-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 367.0 2 37 ^NHBoc T IN Wu Ai ω (S)-6-((2-(3aminopiperidin1-yl)-5-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 367.0 3 38 ^NHBoc V IN NC h Cl A< ₂ (S)-6-((2-(3aminopiperidin1-yl)-4-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 367.0 4 38 F JL_,NHBoc T IN NC c an > Cl ν ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-4-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 385.0 5 38 Η IN NC c SsAE Cl ^NH 2 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-4-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 385.0 6 37 F JL _t ,NHBoc H IN NC c NI1 ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 385.0

- 84 043189

7 37 F JL_,NHBoc ί V NC c ..OO NI1 ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 385.0 8 37 F JL..NHBoc T V NC c 'X' o 1ch ₂ 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 385.0 9 37 F JL_,NHBoc T V L ,.WITH ^M ΤΊ 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 385.0 10 38 .NHBoc T V NC c OH>: Cl ^NH 2 (R)-6-((2-(3amino-4,4difluoropiperidin1-yl)-4-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 403.0 eleven 10 F JL_,NHBoc T V NC ί )~ ^F N \—( CN ^NN 2 2-((3R,4R)-3amipo-4fluoropiperidin-1 yl)-1-((5cyanopyridin-2yl)methyl)-1 Hbenzo[<1]imidazole4-carbonitrile 376.0

- 85 043189

12 37 _t NHBqc τ V NC c nh ₂ (R)-6-((2-(3amino-4,4difluoropiperidin1 -yl)-6-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 403.0 13 37 ^NHBoc τ V NC c ,G> -o: hn ₂ (R)-6-((2-(3amino-4,4difluoropiperidin1-yl)-5-chloro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 403.0 14 19 F JL ,ΝΗΒοο τ V NC L I >- ^f 'nh ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethyl)1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 419.0 15 19 F JL ,NHBoc τ V NC c jQ>O- ^f X--< 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethyl)1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 419.0 16 7 F Jk^NHBac V NC C GAQ..... nh ₂ 6-((2-((3S,4S)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazole1- 351.2

- 86 043189

yl)methyl)nicotine onitrile 17 7 - ^HBos V V NC h .. CO-0 nn ₂ (8)-6-((2-(5-amino- 3,3difluoropiperidin1-yl)-1Hbenzo[c!]imidazol- 1yl)methyl)nicotine onitrile 369.2 18 eleven F JL _t ,NHBoc H V NC .4 IT \--( cn 'nh ₂ 2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1-((5cyanopyridin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazole4-carbonitrile 394.4 19 12 F JL _t ,NHBoc T V NC 4 1 T z>-\ \ί<^ Ν X--< nh ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethoxy)1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 435.4 20 12 F JL _t ,NHBoc T V C Nl l ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethoxy)1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 435.4

- 87 043189

21 25 F JL_,NHBoc H V NC c. 'O mn ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-5(trifluoromethyl)1Hbenzo[c!]imidazol1yl)methyl)nicotine onitrile 437.0 22 25 F JL _t ,NHBoc H V NC c ^yuo b1H ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-6(trifluoromethyl)1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 437.0 23 7 H V 3 n 6-((2-((3aS,7aR)hexahydro-ΙΗpyrrolo[2,3c]pyridin-6(2H)yl)-1Hbenzo[c!]imidazol1yl)methyl)nicotine onitrile 359.2 24 7 c9'“ V V ^N C h CO-Oj N 6-((2-((3aS,7aS)hexahydro-ΙΗpyrrolo[2,3c]pyridin-6(2H)yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 359.2

- 88 043189

25 7 At V NC c /—\ JT \ \---( 1 g 6-((2-((3aS,7aS)hexahydro-ΙΗpyrrolo[2,3c]pyridin-6(2H)yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 359.2 26 7 Ί V c 6-((2-((3aS,7aR)hexahydro-ΙΗpyrrolo[2,3c]pyridin-6(2H)yl)-1Hbenzo[(1]imidazol1yl)methyl)nicotine onitrile 359.2 27 7 H V “CSH1 HN J (R)-6-((2-(l,6diazaspiro[3.5]no nan-6-yl)-1Hbenzo[c!]imidazol1yl)methyl)nicotine onitrile 359.2 28 7 Sr H V NC HN^J (S)-6-((2-(1,6diazaspiro[3.5]no nan-6-yl)-1H6enzo[c1]imidazol1yl)methyl)nicotine onitrile 359.2 29 13 F JL_,NHBoc T V Cl c ^Me °2 ^S x^i^N /__h T T 'ΝΙ1 ₂ (3R,4R)-1-(1-((5chloropyridin-2yl)methyl)-6(methylsulfonyl)-1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 amine 438.0

- 89 043189

thirty 13 F JL.NHBoc T V /—\ Jl X /~ ^P nh ₂ (3R,4R)-1-(1-((5chloropyridin-2yl)methyl)-5(methylsulfonyl)-1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 amine 438.0 31 14 F JL,NHBoc T V Cl G 1 T w N X--/ I _N M 2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazole4-carbonigril 404.0 32 15 F JL,NHBoc T V d'/X ll (3R,4R)-l-(5,7difluoro-1-((5fluoropyridin-2yl)methyl)-1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 - amine 380.0 33 15 F JL,NHBoc T V 4 /--\ T />~\ >-F X---( F N' (3R,4R)-1-(4,6difluoro-1-((5fluoropyridin-2yl)methyl)-1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 amine 380.0 34 16 F JL_,NHBoc T V Ji T/W / ^-F nh ₂ (3R,4R)-l-(5,7difluoro-1-((5fluoropyrimidin-2yl)methyl)-1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 - amine 381.2

- 90 043189

35 16 F JL_,NHBoc ί V δ' LL (3R,4R)-1-(4,6difluoro-1-((5fluoropyrimidin-2yl)methyl)-1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 amine 381.2 36 18 F V 0-5LL 2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1-((5fluoropyrimidin-2yl)methyl)-1 Hbenzo[<1]imidazole4-carbonigril 338.0 37 18 F JL_,NHBoc T V F N-\ ^F W An 2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1-((5fluoropyrimidin-2yl)methyl)-1 Hbenzo[<1]imidazole4-carbonigril 338.0 38 7 F JL_,NHBoc H V NC C ί )- ^F N \--( nu ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 351.2 39 17 F JL _iV NHBoc T V 0' -LL (3R,4S)-l-(l-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 amine 379.2

- 91 043189

40 17 F JL_,NHBoc T IN ^C| \ c /¾. '1 /—\ XX^O- ^f f^X^^n \—/ nh ₂ (3R,4S)-l-(l-((5chloropyrimidin-2yl)methyl)-5-fluoro1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 amine 379.2 41 39 ^NHBoc T IN ^Cl \ c • "ng NI1 ₂ (C)-2-(3-amino4,4difluoropiperidin1-yl)-1-((5-chloropyrimidin-2yl)methyl)-1 Hbenzo[c!]imidazole6-carbonigril 404.2 42 39 .NHBoc V V ^C| \ c LH}< nii ₂ W)-2-(3-amino4,4difluoropiperidin1-yl)-1-((5-chloropyrimidin-2yl)methyl)-1 Hbenzo[c!]imidazole5-carbonigril 404.2 43 28 F J^NHBoc Sr H V NC C For: - nh ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-dichloro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 419.0 44 35 F , _v NHBoc Sr H V NC C »x> nh ₂ tert6yrHn((3R,4R)-l(1-((5cyanopyridin-2yl)methyl)-5,6dimethyl-1Hbenzo[<1]imidazol2-yl)-4fluoropiperidin-3 - 379.2

- 92 043189

silt) carbamate 45 34 ^JMHBoc H A NC Wo nh ₂ (S)-6-((2-(3aminopiperidin1-yl)-6-fluoro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 351.0 46 34 H A NC C nh ₂ (S)-6-((2-(3aminopiperidin1-yl)-5-fluoro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 351.0 47 34 F A.NHBot H A O'ay 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 369.0 48 34 Fl.NHBoc A NC C nh ₂ 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5-fluoro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 369.0 49 34 F L^neos H A NC C _f £XH> ^f NH ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-1Hbenzo[<1]imidazol1yl)methyl)nicotine 369.0

- 93 043189

onitrile hydrochloride 50 5 F AschNVos Η A NC Λ T XX ^F N \—( b|H ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 369.0 51 33 ^.NHBoc IN NC c Wo nh ₂ (S)-2-(3aminopiperidin1 -yl)-1-((5 cyanopyridin-2yl)methyl)-1 Hbenzo[c!]imidazole6-carbonitrile 358.0 52 33 ^.NHBoe th IN NC c %n ₂ (S)-2-(3aminopiperidin1 -yl)-1-((5 cyanopyridin-2yl)methyl)-1 Hbenzo[c!]imidazole5-carbonitrile 358.0 53 33 F A-mneos AG H IN NC C ΧίΗ>· NHz 2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1-((5cyanopyridin-2yl)methyl)-1 Hbenzo[c!]imidazole6-carbonitrile 376.0 54 33 F LschNVos H V NC B "XChlo-" blH ₂ 2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1-((5cyanopyridin-2yl)methyl)-1 Hbenzo[c!]imidazole5-carbonitrile 376.0

- 94 043189

55 33 .„NHSot Y V NC C Χίο νη ₂ (K)-2-(3-amino4,4difluoropiperidin1 -yl)-1-((5 cyanopyridin-2 yl)methyl)-1 Hbenzo[<1] imidazo l6-carbonigril 394.0 56 33 ,,ΝΗβος Y V NC c _nc jCXX>ϊιη ₂ (R)-2-(3-aMHHO- 4,4difluoropiperidin1-yl)-1-((5cyanopyridin-2yl)methyl)-1Hbenzo[<1]imidazole5-carbonigril 394.0 57 36 ^.NHBoc H V NC u i ”nh ₂ (S)-6-((2-(3aminopiperidin1-yl)-4,6-dichloro1Hbenzo[b]imidazol1yl)methyl)nicotine onitrile 401.0 58 36 F J^-NHBoc H V NC C a>c- a nh ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-4,6-dichloro1Hbenzo[b]imidazol1yl)methyl)nicotine onitrile 419.0 59 36 F A.NHBoc H V NC L 050 (tl nh ₂ 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-4,6-dichloro1Hbenzo[b]imidazol1yl)methyl)nicotine onitrile 419.0

- 95 043189

60 36 Η V NC l ^Sk -X ^ / - h F XXHN (tl NH ₂ (R)-6-((2-(3amino-4,4difluoropiperidin1 -yl)-4,6-dichloro- 1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 437.0 61 31 ,NHBoc V NC ΝΗ ₂ (S)-6-((2-(3aminopiperidin1-yl)-4,6-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 369.0 62 31 -JMHBoc H V NC A , OM ; hh ₂ (S)-6-((2-(3aminopiperidin1-yl)-5,7-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 369.0 63 31 F A^NHBoe rr H V NC C NH ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-4,6-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 387.0 64 31 F LlynVos H V NC B ,CH? ilH ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,7-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine 387.0

- 96 043189

onitrile 65 31 F Jo ^NHBoc V NC c ^F O:H>' ί νη ₂ 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-4,6-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 387.0 66 31 F A.NHBot H V N.C. O. α>ο ΝΗ ₂ 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5,7-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 387.0 67 31 H V NC ft ,Δλοί %n ₂ (R)-6-((2-(3amino-4,4difluoropiperidin1-yl)-5,7-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 405.0 68 33 F A^NHBoc T V - UK)' nh ₂ 2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-1-((5cyanopyridin-2yl)methyl)-1Hbenzo[<1]imidazole6-carbonitrile 376.0 69 33 F J.NHBot H V ^NC ^J jQXJ _nc a^ ⁿ 2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-1-((5cyanopyridin-2yl)methyl)-1Н- 376.0

- 97 043189

benzo[<1]imidazole5-carbonitrile 70 7 ^JMHBoc H A r/c" (S)-6-((2-(3aminopiperidin1-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 333.0 71 34 H A 4 _F .cac < nh ₂ (R)-6-((2-(3amino-4,4difluoropiperidin1-yl)-5-fluoro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 387.0 72 29 F L^neos H IN NC. 7 Χΰ-ζ>IH ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 387.0 73 7 F A.NHBot th A NC t 'nh ₂ 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 351.0 74 7 hn0> N _g G1 A nc^^ HCI H _: N ^Z 6-((2-((lR,5S)-l(aminomethyl)-3 azabicyclo[3.1.0]g exan-3-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine 345.2

- 98 043189

onitrile hydrochloride 75 7 ^Η Ό> Η ₂ Ν A NC CO^ ¹ HCl H _Z N 6-((2-((1S,5R)-1(aminomethyl)-3 azabicyclo[3.1.0]g exan-3-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 345.2 76 7 hh ₂ A NC ί X > ⁿ uT>'<r^N''A nh ₂ HCl 6-((2((3aR,4R,6aS)-4aminohexahydrocyclopenta[c]pyrro l-2(1H)-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 359.0 77 7 ^hn C:O Nh ₂ A NC ( T /M O Nh ₂ HCl ^z 6-((2((3aS,4S,6aR)-4aminohexahydrocyclopenta[c]pyrro l-2(1H)-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 359.0 78 7 ⁿ OO nh ₂ A NC q _ CtHP Nh ₂ 6-((2((3aR,4S,6aS)-4aminohexahydrocyclopenta[c]pyrro l-2(1H)-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 359.2

- 99 043189

79 7 ^hn CQ nh ₂ A NC Q . iXXQ nh ₂ 6-((2((3aS,4R,6aR)-4aminohexahydrocyclopenta[c]pyrro l-2(1H)-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 359.2 80 7 A NC C.. CXHX... (R)-6-((2-(3(aminomethyl)pyrr olidin-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 333.2 81 7 A NC at.. (S)-6-((2-(3(aminomethyl)pyrr olidin-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 333.2 82 28 F JL.NHBoc H IN NC C Nt l ₂ 1ICI 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5,6-dichloro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 419.2 83 29 F JL..NHBoc H IN NC C 1mh ₂ I ICI 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro1Hbenzo[<1]imidazole- 387.2

- 100 043189

1yl)methyl)nicotine onitrile hydrochloride 84 29 DShVos V V NC c :η>ο< nh ₂ hci (R)-6-((2-(3amino-4,4difluoropiperidin1-yl)-5,6-difluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 405.2 85 thirty DShVos Sr Η V Cl C α+Q' 'NHjHCI (R)-l-(l-((5chloropyridin-2yl)methyl)-1 Hbenzo[c!]imidazol2-yl)-4,4difluoropiperidin3-amine hydrochloride 378.2 86 thirty F JL..NHBoc H V Cl C a + o- _g NH ₂ HCI (3R,4S)-l-(l-((5chloropyridin-2yl)methyl)-1Hbenzo[c!]imidazol2-yl)-4fluoropiperidin-3 amine hydrochloride 360.2 87 31 δ ^Η “ H V NC C'XXHN ] 'NHj.HCI (R)-6-((2-(3amino-4,4difluoropiperidin1 -yl)-4,6-difluoro- 1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 405.2

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88 5 δ * ^B Η V NC. h COO νη ₂ (R)-6-((2-(3amino-4,4difluoropiperidin1-yl)-6-fluoro-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 387.2 89 8 δ” ^Β “Η A 1ι 1 ι Cd 3 HH* (R)-6-((2-(3amino-4,4difluoropiperidin1-yl)-4(trifluoromethyl)1Hbenzo[<1]imidazol- 1yl)methyl)nicotine onitrile 437.2 90 8 6Η A NC h CH? GF ₃ ^ ^H g 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-4(trifluoromethyl)1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 419.2 91 8 F ..NHBoc A NC h CcCO cf ₃ '^n _g 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-4(trifluoromethyl)1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 419.2

- 102 043189

92 9 ό..... ^.. Η A A 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-chloro-3Nimidazo[4,5b]pyridin-3yl)methyl)nicotine onitrile 386.2 93 9 ό..... ^.. Η A ' _Ama 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-chloro-1Nimidazo[4,5b]pyridin-1yl)methyl)nicotine onitrile 386.0 94 9 F .Φ ,ΝΗΒ<Χ A ^b L- o ⁿ b °w nn ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-chloro-1Nimidazo[4,5b]pyridin-1yl)methyl)-H-(tert-butyl)nicotines D 460.2 95 7 HE LzChNSun th A ^Ν h OAO™ ΪΝΗ _Ζ 6-((2-((3R,4R)-3amino-4hydroxypiperidi n-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 349.2 96 7 he A/ZhVos A A a "d _; - 6-((2-((3S,4S)-3amino-4hydroxypiperidi n-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 349.2

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97 7 Mr. NBoc A NC Q ^X-bn 6-((2-(2,6diazaspiro[3.4]oxtan-6-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 345.2 98 7 s/ \sun A NC HCI aκο Η 6-((2-((4aR,7aS)hexahydropyrrole o[3,4b][1,4]oxazin6(2H)-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 361.2 99 7 C> \|Sun V A NC C NS, 6-((2-((4aS,7aR)hexahydropyrrole o[3,4b][1,4]oxazin6(2H)-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 361.2 100 7 () \lBoc V A NC ABOUT α> "ς> 6-((2-((4aR,7aR)hexahydropyrrole o[3,4b][1,4]oxazin6(2H)-yl)-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 361.2 101 7 ζ) \lBoc and Η A NC C 6-((2-((4aS,7aS)hexahydropyrrole o[3,4b][1,4]oxazin6(2H)-yl)-1Hbenzo[<1]imidazole- 361.2

- 104 043189

1yl)methyl)nicotine onitrile 102 7 0 I F - NC C it ^N Vh ^Cnh ₂ h ₂ n (8)-3-Amino-1-(1((5-cyanopyridin2-yl)methyl)-1Hbenzo[<1]imidazol2-yl)piperidine-3carboxamide 376.2 103 7 c* ^h ~ X G ] I z o t k> (I)-3-amino-1-(1((5-cyanopyridin2-yl)methyl)-1Hbenzo[b]imidazol2-yl)piperidine-3carboxamide 376.2 104 7 To A mid X Z (8)-6-((2-(3-amino3(hydroxymethyl)p-iperidin-1-yl)1Hbenzo[b]imidazol1yl)methyl)nicotine onitrile 363.2 105 7 V A NC h χί^^Ν y—\ C1Ζ W ^k N —£-nh ₂ ho ^z (R)-6-((2-(3amino-3(hydroxymethyl)p-iperidin-1-yl)1Hbenzo[b]imidazol1yl)methyl)nicotine onitrile 363.2 106 19 F _tl NHBoc H IN λ 6-((2-((3R,4S)-3amino-4-fluoro-1piperidinyl)-6(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 419.2

- 105 043189

107 19 F .NHBoc H V G/ 6-((2-((3R,4S)-3amino-4-fluoro-1piperidinyl)-5(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 419.2 108 19 F ^NHBoc sr and V 6-((2-((3R)-3amino-4,4-difluoro1-piperidinyl)-6(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 437.2 109 19 F Jr.NHBoc Sr I V 6-((2-((3R)-3amino-4,4-difluoro1-piperidiiyl)-5(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 437.2 BY 40 F JL ,NHBoc H V G 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5methyl-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitr silt 365.2 111 40 F JL ,,NHBoc H V 'WQ- 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-6methyl-1Hbenzimidazol-1yl)methyl)-3pyridinecarbonitr silt 365.2

- 106 043189

112 20 F JL ₀ NHBdc H IN ^NC ^\ ZONE Eun ₂ 6-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-6chloro-5-methyl-1Hbenzimidazol-1yl)methyl)-3pyridipcarbopytr silt 399.1 113 20 F JL ₀ NHBdc tl V NC H XO O- NH, 6-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5chloro-6-methyl-1Hbenzimidazol-1yl)methyl)-3pyridinecarbonitr silt 399.1 114 41 F JL ,NHBoc H V NC L XXX and 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-6fluoro-5-methyl-1Hbenzimidazol-1yl)methyl)-3pyridinecarbonitr silt 383.1 115 41 F JL ,NHBoc H V NC h-X-A /—\ I Ty 3 ^F f 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5fluoro-6-methyl-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitr silt 383.1 116 7 1^.NBoc H V NC Chz OhE ΝΗ / 6-((2-((3 S)-3(methylamino)-1 piperidinyl)-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitryl 347.2

- 107 043189

117 7 1 _l ,NBoc τ V NG Q Ah / 6-((2-((3R)-3(methylamino)-1 piperidinyl)-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitr silt 347.2 118 21 F JL ,NHBoc V NC h ххк >'νη _ξ 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-6(difluoromethoxy)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 417.2 119 21 F JL _f ,NHBoc V NC. c IX + ^Ν X ^F F ₂ HCO- - ^:; N '—' KH, 6-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5(difluoromethoxy)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 417.2 120 22 F JL _f ,NHBoc V NC A C0-E-OMe YN ₃ 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-4methoxy-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitr silt 381.2 121 23 F JL _f ,NHBoc H V NC q QH > 1 M 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-4methyl-1Hbenzimidazol-1yl)methyl)-3pyridinecarbonitr silt 365.2

- 108 043189

122a 42 F A _y NHBoc V V LL. oj c‘ qo 5-((2-((3R,4S)-3amino-4-fluoro-1 piperidinyl)-6(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-2pyrazinecarboxam ID 438.2 123a 42 F A "NHBoc S" ³ H V n^s c 5-((2-((3R,4S)-3amino-4-fluoro-1 piperidinyl)-5(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-2pyrazinecarboxam ID 438.2 124 27 F JL ₀ NHBdc ^FT H V NC 7 FlH;, 6-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-6chloro-5(trifluoromethoxy)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 469.2 125 27 F JL ₀ NHBdc ^FT H V nc'^jn ^f :xxh> 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5chloro-6(trifluoromethoxy)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 469.2 126 26 F JL ₀ NHBdc ^FT H V NC IXX ^F F ₃ r '^N 4 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-6chloro-5(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr 453.2

- 109 043189

silt 127 26 F JL ,ΝΗΒοο τ IN NC ech. 6-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5chloro-6(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonitr silt 453.2 128 7 ^hnX ) BacN V NC 6-((2-((5R)-l,7diazaspiro[4.5]decan-7-yl)-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitryl, 6-((2-((5S)-l,7diazaspiro [4.5]decan-7-yl)-1Hbenzimidazol-1yl)methyl)-3pyridinecarbonitr silt 373.2 129 7 ΗΝ ^Λ Χ XX-NBoc O V NC H CQHl _n „ O 6-((2-((6R)-l,8diazaspiro[5.5]un decan-8-yl)-1Hbenzimidazol-1yl)methyl)-3pyridinecarbonitr silt 387.2 130 7 Hf/ ) ν^-ΝΒοα V NC h Ν-^Λνη 6-((2-((6S)-l,8diazaspiro[5.5]un decan-8-yl)-1Hbenzimidazol-1yl)methyl)-3pyridinecarbonitr silt 387.2 131 7 UN )-0 M) BocN^ V OlSH ΗΝ—/ 6-((2-((4aR,8aR)hexahydro-2Hpyrido[4,3b][1,4]oxazin6(5H)-yl)-1H- 375.2

- 110 043189

benzimidazol-1yl)methyl)-3pyridinecarbonitryl 132 7 UJ IN NC 3 _p Qz-Qa HNO 6-((2-((4aS,8aS)hexahydro-2Hpyrido[4,3b][1,4]oxazin6(5H)-yl)-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitr silt 375.2 133a 43 F JL ,NHBoc IN HjNOC :x?z<> NH _Z 5-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,6difluoro-1Hbenzimidazol-1yl)methyl)-2pyrazinecarboxam ID 406.2 134a 42 F JL ,NHBoc IN H,NOC V= ^N c 'SeNCH ΪΝΗ ₂ 5-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-6(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-2pyrazinecarboxam ID 438.2 135 7 BocN^ IN NC ί 6-((2-((5R)-l,7diazaspiro[4.5]decan-7-yl)-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitryl 373.2 136 7 ΗΝ^Λ vZsZ V C0 cP 6-((2-((5S)-l,7diazaspiro[4.5]decan-7-yl)-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitr 373.2

- 111 043189

IL 137 24 J<\nHBoc τ IN XXSSf ΜβΟ '- ^{ί Ν λ} —< HHj 6-((2-((3R)-3amino-4,4-difluoro1-piperidinyl)-5methoxy-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonitr silt 399.2 138 24 F Jr ₄ NHBoc ^N^ H V NC NH, 6-((2-((3R)-3amino-4,4-difluoro1-piperidinyl)-6methoxy-1Hbenzimidazol-1 yl)methyl)-3pyridinecarbonigryl 399.2 139 19 jJlBoc T V ^ys ts ^FlC So HN- 6-((2-((3 S)-3(methylamino)-1 piperidinyl)-6(trifluoromethyl)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonyl silt 415.2 140 19 _^_..MVss Sr H V NC HN- 6-((2-((3 S)-3(methylamino)-1 piperidinyl)-5(grifluoromethyl)1 H-benzimidazol1-yl)methyl)-3pyridinecarbonyl silt 415.2 141 7 ^LnHBoc H V NC 4 x^^N /—\ GC nz NH ₂ 6-((2-((3S)-3amino-3-methyl-1piperide inyl)-1Hbenzimidazol-1yl)methyl)-3pyridinecarbonitryl 347.2

- 112 043189

142 24 Ό YNVos V nc Λ nA. ho^cf _'s 'Oyo A, (S)-6-((2-(3aminopiperidin1-yl)-6-methoxy1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile-2,2,2trifluoroacetate 363.2 143 24 Ό jnSun V ^N V\ ⁰ HO^CFz 'nh ₂ (S)-6-((2-(3aminopiperidin1-yl)-5-methoxy1Hbenzo[<1]imidazol1yl)methyl)nicotine oni1ryl-2,2,2trifluoroacetate 363.2 144 32 F KlHBoc V NC C j^ _r 'oao Cl 'nh ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-4-chloro-6-fluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile-2,2,2trifluoroacetate 403.0 145 24 HN^^F hHBoc A NC ^G A ... {Xaj -- ₀ -A<A o_/ 'nh ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-methoxy-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 381.0 146 24 hn^f KlHBoc A NC 0 .. Oo nh ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-methoxy-1Hbenzo[<1]imidazole- 381.0

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1yl)methyl)nicotine onitrile hydrochloride 147 24 NHBcc A NC X NA H-CI •ΌΧΟ-ΪΙΗ ₂ 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6-methoxy-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 381.0 148 24 ⁿ O ^x ΝΗΒϋύ A NC <uh.. XG Ό' NH, 6-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5-methoxy-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile hydrochloride 381.0 149 14 Η IN Ck u _F n XXH> ^F CN 2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-1-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazole4-carbonitrile 404.0 150 14 ιFΗ A IN Cl Q NC Y i XX ^f 'nh ₂ (R)-2-(3-aMHHO4,4difluoropiperidin1-yl)-1-((5chloropyrimidin-2yl)methyl)-5-fluoro1Hbenzo[<1]imidazole7-carbonitrile 422.0

- 114 043189

151 14 δ'ΎΥ Η IN CI Q% CN (C)-2-(3-Amino4,4difluoropiperidin1-yl)-1-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazole4-carbonchryl 422.0 152 3 Oh JL .NhBoc V V NC c ^α Ό:λΟ "Kn ₂ 6-((2-((3R,4R)-3amino-4- hydroxypiperidi n-1-yl)-6-chloro-1Hbenzo[<1]imidazol- 1- yl)methyl)nicotine onitrile 383.2 153 3 Oh ^^.NhBoc V O'.X 6-((2-((3R,4S)-3amino-4- hydroxypiperidi n-1-yl)-6-chloro-1Hbenzo[<1]imidazol- 1- yl)methyl)nicotine onitrile 383.2 154 44 b ⁹ H V NC c ί T x ⁴ -( ^F hlH ₂ (R)-4-((2-(3amino-4,4difluoropiperidin1-yl)-1Hbenzo[c!]imidazol1yl)methyl)benzonitrile 368.2 155 44 OH [A^NHBoc 11 racemic A “q ... +, ... Sy-O” Sy-Q '№ _g νη ₂ 4((2-((3R,4R)-3amino-4hydroxypiperidi n-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile dihydrochloride 346.2

- 115 043189

compounds with 4((2-((3S,4S)-3amino-4hydroxypiperidi n-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile (1:1) 156 45 JL ^NHEoc V V (VA 4-((2-((3R,4R)-3amino-4-fluoro-1-piperidinyl)-5,7difluoro-Hbenzimidazol-1yl)methyl)benzonitrile 386.2 157 45 F JL _f ,NHBoc H V L' ό LL. 4-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-4,6difluoro-Hbenzimidazol-1 yl)methyl)benzonitrile 386.2 158 46 F 1. ^NHBoc H V NC ABOUT I X Ό n NHj 2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-1 (4-cyanobenzyl)1 H-benzimidazole6-carbonitrile 375.2 159 46 F JL ₀ NHBdc ^FT H V NC 3 _nc XXfO ^f NHj 2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-1 (4-cyanobenzyl)1 H-benzimidazole5-carbonitrile 375.2 160 46 FL.^HBoc n V NC a, W! fti Hj 2-((3R)-3-aMHHO4,4-difluoro-1piperidinyl)-1(4-cyanobenzyl)1 H-benzimidazole- 6-carbonitrile 393.3

- 116 043189

161 46 bZ .DNSun th V NC 7 .. O' X NH ₂ 2-((3V)-3-amino4,4-difluoro-1piperidinyl)-1(4-cyanobenzyl)1 H-benzimidazole5-carbonitrile 393.3 162 44 H A T and (R)-4-((2-(3aminopiperidin1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 332.2 163 44 Me H A F if 4-((2-((3R,4R)-3amino-4- methylpiperidin1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 346.0 164 c 44 Me LLLNVos Η A NC B ^nh ₂ 4-((2-(3(aminomethyl)-3 methylpyrrolidin1-yl)-1Hbenzo[b]imidazol1yl)methyl)benzonitrile 346.2 165 44 Racemic X) HN J 'nhboc A NC C GE ( IHj ⁴ ---'>. _NH2 NC 7 o ί Τ^ΓΙ 4-((2-((3S,4R)-3amino-4phenylpyrrolidin -1-yl)-1Hbenzo[b]imidazol1yl)methyl)benzonitrile and 4-((2((3R,4S)-3-aMHHO4phenylpyrrolidine -1 -yl)-1Hbenzo[<1]imidazole- 394.2

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1yl)methyl)benzotril 166 44 NHBdc Q H A NC q αλο..... (8)-4-((2-(3aminopyrrolidin -1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 318.2 167 44 ^.NHBoc A NC q OX} 'nh ₇ (8)-4-((2-(3aminopiperidin1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 332.2 168 44 Boc H A NC q GX\X/ 4-((2-(6-Amino-2azaspiro[4.4]nona n-2-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 32.0 169 44 /X^NHBoc Q H A NC q ί XX / X^^-N MH ₂ 4-((2-(4aminohexahydrocyclopenta[c]pyrro l-2(1H)-yl)-1Hbenzo[c!]imidazol1yl)methyl)benzonitrile 358.2 170 44 F H A χέ 4-((2-((3S,4S)-3amipo-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 350.2

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171 44 ά..... Η A NC 3.\ _nr 4-((2-((3S,4R)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 350.2 172 44 σ'....... Η A A .0 I : L 4-((2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 350.2 173 44 ά..... Η A NC c y --- y ( X ^F Ά+: x-f Kn _g 4-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 350.2 174 44 F NHBoc X Η IN NC but^; CccQ H,N ^Z (R)-4-((2-(3(aminomethyl)-3 fluoropyrrolidin1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzo 1ryl-2,2,2trifluoroacetate 350.0 175 44 F NHftac: X Η IN NC Ηθ+^ /ХА (Χ+Α ¹ h ₂ n ^z (S)-4-((2-(3(aminomethyl)-3 fluoropyrrolidin1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzo 1ryl-2,2,2trifluoroacetate 350.0

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176 44 HO NHfta:: 3 Η V NC C-L: ndg (R)-4-((2-(3(aminomethyl)-3 hydroxypyrrolide in-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile tril-2,2,2trifluoroacetate 348.2 177 44 HO NHftot: 3 Η V NC C L; Ax ¹ ' ¹ (xna' (S)-4-((2-(3(aminomethyl)-3 hydroxypyrrolide in-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzoni tril-2,2,2trifluoroacetate 348.2 178 44 NHBoc 3 Η A 43 a <S Z \ / (S)-4-((2-(3(aminomethyl)pyrr olidin-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile, molecular weight: 331.41 332.2 179 44 MNEkes: σ' Η A NC h ₂ n ^x (R)-4-((2-(3(aminomethyl)pyrr olidin-1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile, molecular weight: 331.41 332.2 180 44 Me J. ^NIIBoc: V IN NC Ts-th θ-Ν ^/ ^ ^Ν θ ^{> Μβ} 'νη ₂ 4-((2-((3S,4S)-3amino-4methylpiperidin1-yl)-1Hbenzo[<1]imidazole1- 346.2

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yl)methyl)benzoni tril-2,2,2trifluoroacetate 181 44 Me 0'......... Η V NC _Ζ Χ, N f \ Η £ N Y- Me λ---( 'nh ₂ 4-((2-((3S,4R)-3amino-4methylpiperidin1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzoni tril-2,2,2trifluoroacetate 346.2 182 44 Me H V NC Ts-v xxn /—\ TsG“Vm. NHj 4-((2-((3R,4S)-3amino-4methylpiperidin1-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzoni tril-2,2,2trifluoroacetate 346.2 183 44 NHBoc r H A NC7. ax x nh ₂ 4-((2-((1S,5R)-1(aminomethyl)-3 azabicyclo[3.1.0]g exan-3-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 344.2 184 44 NHBoc r H A NC C ax '-^NJ ί ₂ 4-((2-((lR,5S)-l(aminomethyl)-3 azabicyclo[3.1.0]g exan-3-yl)-1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 344.2 185 44 x^NHBoc rr H A NC 7 ^MC °xX4^N y-h (R)-4-((2-(3aminopiperidin1 -yl)-6-methoxy1Hbenzo[c!]imidazole- 362.2

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1yl)methyl)benzotril 186 44 A NC at XX nh ₂ (R)-4-((2-(3aminopiperidin1-yl)-5-methoxy1Hbenzo[<1]imidazol1yl)methyl)benzonitrile 362.2 442 47 F J, ₍₁ NHBoc V IN NC /X \ A ΌΧ4 nh ₂ 2-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol1yl)methyl)pyrimide in-5-carbonitrile 370.2 443 47 F J, ₍₁ NHBoc V IN NC C nh ₂ 2-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-1Hbenzo[<1]imidazol1yl)methyl)pyrimide in-5-carbonitrile 370.2 444 48 JL ₍₁ NHBoc T IN MeO n nA ^f x^^n /—\ OACC nh ₂ (3R,4R)-4^to _P -1(6-fluoro-1-((5methoxypyrimidi n-2-yl)methyl)-1Hbenzo[<1]imidazol2-yl)piperidine-3amine 375.4 445 49 F J. _(k NHBoc T V Me 1 XX ^f Ά 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol1 -yl)-N-methyl-N(2,2,2trifluoroethyl)aceta 406.2

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MFA 446 48 ό'”“ Η V MeO c / o ^Ν /-Ch _F O>O m (3R,4R)A^ _TO pl(5-φτορ-1-((5methoxypyrimidi n-2-yl)methyl)-1Ηbenzo[<1]imidazol2-yl)piperidine-3amine 375.2 447 52 ό" Η V _measure o=H ΪΤη N \---( CN *N ^H 2 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-4-cyano-6fluoro-1Hbenzo[<1]imidazol1 -yl)-N-methyl-N(2,2,21fluoroethyl)aceta MFA 431.2 448 51 JL ₍₁ NHBoc τ V _Me'N -M _C 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-methoxy-1Hbenzo[<1]imidazol1-yl)-N,Ndimethylacetamide 350.2 449 50 ό'”“ Η V of \___/ *»0 οΞ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-methoxy-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,2trifluoroethyl)aceta MFA 418.0 450 51 F JL..NHBoc τ V Me °3 „ΧΧλ<> 'ΝΗ; 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-methoxy-1Нbenzo[<1]imidazol1-yl)-N, Ndimethylacetamide 350.2

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451 5 OM„ _N φΎτ IN NC l 10 ^ 3-0 ". m 6-((2-((3R,4R)-3amino-4- methoxypiperidi n-1-yl)-6-fluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 381.2 452 53 Ng/ νη 7\ V b ХсНХ ОMe ^ ⁿ 2 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-4methoxy-1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 399.2 453 54 Hr/ ^F NH 4 7\ V NC ABOUT Xtg-O 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethyl)3H-imidazo[4,5b]pyridin-3yl)methyl)nicotine onitrile 420.2 454 17 φΎχ V th ,ν about CD (3R,4R)-1-(1-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazol2-yl)-4methoxypiperidium n-3-amine 391.2 455 55 Hr/ ^F ^n 4 7\ V ^ΒΓ ΌΧΟ 1jh _z 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-bromo-1Hbenzo[<1]imidazol1-yl)-1-(azetidin1-yl)ethan-1-one 412.0

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456 17 φΆ IN Sd XX^O-° ^me A _g (3R,4R)-1-(1-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazol2-yl)-4methoxypiperidium n-3-amine 391.2 457 49 ΝΗ 4 7\ V C _F °7 yn ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,21fluoroethyl)aceta MFA 406.2 458 54 X V Ό-C-' ABOUT' " NC 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethyl)1H-imidazo[4,5b]pyridin-1yl)methyl)nicotine onitrile 420.2 459 56 HN^->F A 4 7\ V S A ^and F~ \n ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethyl)1Нbenzo[<1]imidazol1-yl)-1morpholinoethan-1 one 430.2 460 49 hnQ^f A A Ά V with X _f £xH> ^f Нн _? 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-1Hbenzo[<1]imidazol1 -yl)-N-methyl-N- 406.2

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(2,2,2trifluoroethyl)acetate MFA 461 57 \HBoc V x ^α Ό>ΌΚιη ₂ 2-(2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6-chloro-1Hbenzo[<1]imidazole1-ηπ)-Ν,Νdimethylacetamide 354.2 462 49 ^Hf Q''F \HBr. _; : V C _F X CHO' nh- 2-(2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,21fluoroethyl)aceta MFA 406.2 463 17 HC1? ^Me n Q'TY V NC N 1—ι 1 X /'° ^Me NHj 6-((2-((3R,4S)-3amino-4- methoxypiperidi n-1-yl)-6-fluoro1Hbenzo[<1]imidazol1yl)methyl)nicotine onitrile 381.2 464 56 hnQ- ^f \IIBol V ABOUT 'TSHE* AND 2-(2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethyl)1Нbenzo[<1]imidazol1-yl)-1morpholinoethan-1 one 430.2

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465 49 ht/ NH °+ V s °h XcH> NH ₂ (K)-2-(2-(3-Amino4,4difluoropiperidin1-yl)-6-fluoro-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,21fluoroethyl)aceta MFA 424.2 466 49 hQ $JHBdc V from _F °h HcJun 2-(2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,2trifluoroethyl)aceta MFA 406.2 467 17 HCI or^H H V CI _F δ ΌλΟ · ^όμ · bn ₂ (3R,4S)-l-(l-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazol2-yl)-4methoxypiperidium n-3-amine 391.2 468 58 HN^^F \h 4 V ^F %iH>'N# 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethoxy)1Hbenzo[<1]imidazole1-ηπ)-Ν,Νdimethylacetamide 404.2 469 49 z V C _F °h w> bin f 2-(6-fluoro-2((3R,4R)-4-φτop-3(methylamino)piperidin-1-yl)-1Hbenzo[c!]imidazol1-yl)-N-methyl-N (2,2 ,2- 420.2

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trifluoroethyl)acetate MFA 470 55 HN^^F NH 4 -χ V cX, book ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-bromo-1Hbenzo[<1]imidazol1-yl)-1-(azetidin1-yl)ethan-1-one 410.0 471 57 ⁿ O\nSun V ri -S f Ύ >n ;-f _C |XXn X Tsn _g 2-(2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5-chloro-1Нbenzo[<1]imidazol1-yl)-N, Ndimethylacetamide 354.2 472 49 Dp ^ο= 0 V x zj J 2-(6-fluoro-2-(1,7diazaspiro[4.5]decan-7-yl)-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,21fluoroethyl)aceta MFA 428.2 473 56 ^h <> ^f NHBcc V 0 °Λ DSHD nh. 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethyl)1Нbenzo[<1]imidazol1-yl)-1morpholinoethan-1 one 430.2 474 58 HN^y-F nH 7 V °7 _Ρι00 £Χλ€7 Mn _g 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethoxy)1Hbenzo[(1]imidazole1-ηπ)-Ν,Ν- 404.2

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dimethylacetamide 475 59 Hl /^ ΪΙΗ A IN About 0 'nh ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethoxy)1Нbenzo[<1]imidazol1-yl)-1morpholinoethan-1 one 446.2 476 53 Hl / ^-*F NH4A IN NC ^ MeO ) ί X Η F'+r^N Μ 'νη ₂ 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-7methoxy-ΙΗbenzo[<1]imidazol1yl)methyl)nicotine onitrile 399.2 477 17 HCl? ^Me H V Cl _f I00 ⁿ 0 ^o “ 'NHj (3R,4S)-l-(l-((5chloropyrimidin-2yl)methyl)-5-fluoro1Hbenzo[<1]imidazol2-yl)-4methoxypiperidium n-3-amine 391.2 478 56 NIIBoc V U.11 o*o 2-(2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethyl)1Нbenzo[<1]imidazol1-yl)-1morpholinoethan-1 one 430.2

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479 49 6'0 g V G N* NH / 2-(5-fluoro-2((3R,4R)-4-fluoro-3(methylamino)piperidin-1-yl)-1Hbenzo[<1]imidazol1-yl)-N-methyl-N (2,2 ,21fluoroethyl)acetate MFA 420.2 480 49 ⁰ Ά V ABOUT,. L 2-(2-(3-amino-4methylpyrrolidin1-yl)-6-fluoro-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,2trifluoroethyl)aceta MFA 388.2 481 49 Οθ* ^{0Η HN} ^O^NHBcc V oA IX Ά h ° ⁿ '-G^N { nh. 2-(2-((3R,4R)-3amino-4- hydroxypiperidi n-1-yl)-6-fluoro1Hbenzo[<1]imidazol1-yl)-N-methyl-N (2,2,2trifluoroethyl)aceta MFA 404.2 482 49 HN^y^F ΝΗ h “Λ V G N 6 DN> NH ₂ (R)-2-(2-(3-aMHHO4,4difluoropiperidin1-yl)-5-fluoro-1Hbenzo[c!]imidazole1 -ηπ)-N-methyl-N(2,2,2trifluoroethyl)aceta MFA 424.2 483 49 g V With 6 //—lO-OMe ΝΗ; 2-(2-((3R,4R)-3amino-4methoxypiperidi n-1-yl)-5-fluoro1Hbenzo[<1]imidazol- 418.2

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1 -ηπ) -Ν -methyl-N (2,2,2trifluoroethyl)acetate MFA 484 49 HN3-0H nh v\ V CF ₃ C _F h Ό» ΜΗ, 2-(2-((3R)-3amino-4- hydroxypiperidi n-1-yl)-5-fluoro1Hbenzo[<1]imidazole1 -ηπ)-N-methyl-N (2,2,2trifluoroethyl)aceta MFA 404.2 485 49 Chlf ¹ o V CFj V ^f WN /— _v [1 IA ^N ^OMe Άv ⁴ —/ NH ₂ 2-(2-((3R,4R)-3amino-4- methoxypiperidi n-1-yl)-6-fluoro1Hbenzo[<1]imidazol1-yl)-N-methyl-N (2,2,2trifluoroethyl)aceta MFA 418.2 486 49 NHBoc V c _F 4 F XX Choa 2-(2-(3(aminomethyl)-3 fluoropyrrolidin1-yl)-6-fluoro-1Hbenzo[<1]imidazole1 -ηπ)-Ν -methyl-N - (2,2,2trifluoroethyl)acetate MFA 406.2 487 49 HtA'y ^F NHBk V CR V “4 F dkch 2-(2-(3(aminomethyl)-3 fluoropyrrolidin1-yl)-5-fluoro-1Hbenzo[<1]imidazole1 -ηπ)-Ν -methyl-N - (2,2,2trifluoroethyl)acetate MFA 406.2

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488 49 ™Qy BocN- ⁷ V _F 'XXLOY HN— 2-(6-fluoro-2((4aR,8aR)hexahydro-2Нpyrido[4,3- b][1,4]oxazine- 6(5H)-yl)-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,21rifluoroethyl)aceta MFA 430.2 489 49 V (S)-2-(2-(3aminopyrrolidin-1-yl)-6-fluoro-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,2trifluoroethyl)aceta MFA 374.2 490 49 V oX pF ^f WN (R)-2-(2-(3aminopyrrolidin-1-yl)-6-fluoro-1Hbenzo[<1]imidazol1-yl)-N-methyl-N(2,2,2trifluoroethyl)aceta MFA 374.2 491 49 NHBcc hnX^ V /—\ o X g l ^L ° 0 LL (S)-2-(2-(3(aminomethyl)pyrr olidin-1 -yl)-6fluoro-1Hbenzo[<1]imidazole1 -ηπ)-N-methyl-N(2,2,2trifluoroethyl)aceta MFA 388.2 492 49 Qy BocN^ V XcNH HN—/ 2-(6-fluoro-2((4aR,8aR)hexahydro-2Hpyrido[4,3b][1,4]oxazin6(5H)-yl)-1H- 430.2

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benzo[<1]imidazole1 -ηπ)-Ν -methyl-N (2,2,2trifluoroethyl)aceta MFA 493 49 BocN^ V J CF ₃ X _v -N /—\ rOAQj HN—' 2-(5-fluoro-2((4aS,8aS)hexahydro-2Hpyrido[4,3b][1,4]oxazin6(5H)-yl)-1Hbenzo[<1]imidazol1-yl)-N-methyl-N (2,2,2trifluoroethyl)acetate MFA 430.2

[a] nitrile hydrolysis occurring during SnAr, [b] Ritter reactivity observed during Boc deprotection, [c] undefined stereochemistry refers to mixtures of enantiomers or diastereomers.

Table 3

Characterization data for compounds prepared according to Scheme 8.

The Separation Step column indicates after which process step the regioisomers formed due to the asymmetric substitution of the benzimidazole at R ¹ in Scheme 8 were separated during the preparation of the final compound shown in Table (I=after the preparation of the alkylated intermediate 1-59 (where at least one R ¹ is not hydrogen); B=before deprotection of the Bos group or F=final compound)

At m. No. Frequency, solvent W NMR data (δppm) Separation stage Conditions SFC for isomer separation 1 400MHz d ₄ -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), 7.12-7.16 (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) IN Chiralpak AD-H, 20% MeOH, peak 1 2 500MHz d ₄ -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- IN Chiralpak AD-H, 20%

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7.10 (m, 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), 1.922.01 (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) MeOH peak 2 3 500MHz d ₄ -MeOH 8.75-8.80 (m, 1H), 8.06 (d, J=8.30 Hz, 1H), 7.23-7.31 (m, 1H), 7.11 (d, J= 7.27 Hz, 1H), 6.94-7.05 (m, 2H), 5.44 (s, 2H), 3.48 (br d, 1=10.12 Hz, 1H), 3.24 -3.30(m, 1H), 3.233.28(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), 1.51-1.65 (m, 1H), 1.19-1.35 (m, 1H) - - 4 500MHz d ₄ -MeOH 8.83 (s, 1H), 8.11-8.16 (m, 1H), 7.39 (d, J=8.30 Hz, 1H), 7.18 (d, J=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, 1=12.46 Hz, 1H), 3.14-3.22 (m, 1H), 3.09 (dq, J=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 d ₄ -MeOH 8.83 (s, 1H), 8.10-8.15 (m, 1H), 7.37 (d, J=8.04 Hz, 1H), 7.17 (d, J=7.01 Hz , 1H), 7.01-7.09 (m, 2H), 5.52 (s, 2H), 3.43 (dd, J=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, J=4.93, 9.80 , 14.34 Hz, 1H), 1.88-2.04 (m, 1H) - - 6 500MHz d ₄ -MeOH 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=1.95, 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) IN Chiralcel OD-H, 25% IP A peak 1

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7 500MHz d ₄ -MeOH 8.86 (d, J=l.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) IN Chiralcel OD-H, 25% IP A, peak 2 8 500MHz d ₄ -MeOH 8.86 (d, J=l.82 Hz, 1H), 8.14-8.19 (m, 1H), 7.47 (d, 1=8.56 Hz, 1H), 7.43 (d , J=8.04Hz, 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), 2.08-2.20 (m, 1H), 1.88-2, 03(m, 1H) IN Chiralcel OD-H, 25% IP A peak 1 9 500MHz d ₄ -MeOH 8.86 (d, J=l.30 Hz, 1H), 8.14-8.19 (m, 1H), 7.49 (s, 1H), 7.41 (d, J=8.04 Hz , 1H), 7.12 (s, 2H), 5.53 (s, 2H), 3.37-3.49 (m, 2H), 3.28 (dd, 1=3.37, 8.04 Hz, 2H), 3.03-3.21 (m, 2H), 2.09-2.18 (m, 1H), 1.89-2.05 (m, 1H) V Chiralcel OD-H, 25% IP A, peak 2 10 500MHz d ₄ -MeOH 8.84 (s, 1H), 8.16 (d, J=8.04 Hz, 1H), 7.427.47 (m, 1H), 7.19-7.23 (m, 1H), 7.05 -7.12 (m, 2H), 5.58 (s, 2H), 3.59 (br d, J=11.42 Hz, 1H), 3.45-3.53 (m, 1H), 3 .37 (ddd, J=3.l 1, 9.54, 12.78 Hz, 1H), 3.16-3.30 (m, 2H), 2.30 (tdd, 1=4.70, 9 .67, 14.66 Hz, 1H), 2.06-2.22 (m, 1H) - - AND 500MHz d ₄ -MeOH 8.80-8.84 (m, 1H), 8.14-8.19 (m, 1H), 7.457.51 (m, 2H), 7.41 (d, J=8.04 Hz, 1H) , 7.17 (t, J=7.91 Hz, 1H), 5.54-5.60 (m, 2H), 4.354.53 (m, 1H), 3.70-3.76 (m, 1H ), 3.50-3.64 (m, 1H), 3.19-3.26 (m, 1H), 3.14 (dq, J=4.15, 8.82 Hz, 1H), 2, 98-3.08 (m, 1H), 2.11-2.23 (m, 1H), 1.80-1.95 (m, 1H) - -

-135043189

12 500MHz d ₄ -MeOH 8.85(d, 1=1.56Hz, 1H), 8.15-8.20(m, 1H), 7.48(d, 1=8.56Hz, 2H), 7.23(d, J=1.56 Hz, 1H), 7.19 (dd, J=1.82, 8.56 Hz, 1H), 5.56 (s, 2H), 3.53 (br d, 1=12, 20 Hz, 1H), 3.40-3.48 (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, 25% MeOH, peak 1 13 500MHz d ₄ -MeOH 8.85(d, 3=1.04Hz, 1H), 8.15-8.19(m, 1H), 7.50(s, 1H), 7.46(d, J=8.04Hz, 1H), 7.077.15 (m, 2H), 5.54-5.59 (m, 2H), 3.56 (br d, 1=12.20 Hz, 1H), 3.40-3.50 ( m, 1H), 3.343.39 (m, 1H), 3.13-3.29 (m, 2H), 2.24-2.39 (m, 1H), 2.06-2.22 (m, 1H) F Chiralcel OD-H, 25% MeOH, peak 2 14 500MHz d ₄ -MeOH 8.85 (d, 3=1.82Hz, 1H), 8.15-8.20 (m, 1H), 7.64 (d, 1=8.30Hz, 1H), 7.44-7, 54 (m, 3H), 5.59-5.64 (m, 2H), 4.36-4.54 (m, 1H), 3.603.71 (m, 1H), 3.48-3.56 ( m, 1H), 3.14-3.22 (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) IN Chiralcel OD-H 15% IP A peak 1 15 500MHz d ₄ -MeOH 8.82-8.87(m, 1H), 8.15-8.21(m, 1H), 7.78(s, 1H), 7.48(d, 1=8.30Hz, 1H) , 7.41 (d, 1=8.56 Hz, 1H), 7.31 (d, J=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, 1=8.82, 12.46 Hz, 1H), 2.13-2.27 (m, 1H), 1.83-1.97 (m, 1H) IN Chiralcel OD-H 15% IP A, peak 2 16 500MHz d ₄ -MeOH 8.86(d, 3=1.30Hz, 1H), 8.11-8.18(m, 1H), 7.53(d, 1=7.79Hz, 1H), 7.37(d, J=8.04 Hz, 1H), 7.18-7.25 (m, 1H), 7.11-7.17 (m, 2H), 5.51-5.57 (m, 2H), 4 .37-4.53(m, 1H), 3.573.65(m, 1H), 3.40-3.54(m, 1H), 3.09-3.21(m, 2H), 2.99 (dd, J=8.95, 12.33 Hz, 1H), 2.19 (tt, 1=4.28, 13.62 Hz, 1H), 1.81-1.98 (m, 1H) -- -

- 136 043189

17 500MHz d ₄ -MeOH 8.90 (d, 1=1.30 Hz, 1H), 8.08-8.16 (m, 1H), 7.33-7.38 (m, 1H), 7.25 (d, J= 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, 1=13.23 Hz, 1H), 3.04-3.16 (m, 1H), 2.832.94 (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, 1=7.28, 15.02 Hz, 1H) - - 18 500MHz d ₄ -MeOH 8.83 (dd, 1=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, 1=3.11 Hz, 2H), 3.04-3.26 (m, 3H), 2.99 (br d, 1=8.04 Hz, 2H), 2.11-2.26 (m, 1H), 1.84-2.01 (m, 2H) - - 19 500MHz d ₄ -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, 1=12.46 Hz , 1H), 3.45-3.56 (m, 1H), 3.11-3.22 (m, 2H), 3.01 (dd, 1=9.21, 12.33 Hz, 1H), 2.12-2.25 (m, 1H), 1.83-1.97 (m, 1H) IN Chiralpak AD-H, 15% MeOH, peak 1 20 500MHz d ₄ -MeOH 8.85(d, 1=1.30Hz, 1H), 8.11-8.21(m, 1H), 7.45(d, 1=8.30Hz, 1H), 7.40(s , 1H), 7.177.24 (m, 1H), 7.01-7.08 (m, 1H), 5.51-5.60 (m, 2H), 4.37-4.54 (m, 1H ), 3.61-3.68 (m, 1H), 3.45-3.57 (m, 1H), 3.05-3.23 (m, 2H), 3.00 (dd, 1=9 .08, 12.46 Hz, 1H), 2.13-2.27 (m, 1H), 1.90 (ddd, 1=3.63, 9.60, 13.23 Hz, 1H) IN Chiralpak AD-H, 15% MeOH, peak 2 21 500MHz d ₄ -MeOH 8.84 (d, 1=2.08 Hz, 1H), 8.16-8.22 (m, 1H), 7.46-7.54 (m, 2H), 7.35 (d, 1= 11.16 Hz, 1H), 5.57-5.61(m, 2H), 4.36-4.53(m, 1H), 3.64-3.72(m, 1H), 3.49 -3.59 (m, 1H), 3.153.24 (m, 1H), 3.07-3.15 (m, 1H), 3.02 (dd, 1=8.95, 12.59 Hz, 1H ), 2.18 (br dd, 1=4.80, 9.21Hz, 1H), 1.82-1.92(m, 1H) V Phenomenex Lux Cellulose-2, 15% MeOH, peak 1

- 137043189

22 500MHz d ₄ -MeOH 8.83(d, 1=1.30Hz, 1H), 8.16-8.21(m, 1H), 7.73(d, 1=6.23Hz, 1H), 7.52(d, J=8.30Hz, 1H), 7.21(d, 1=10.38Hz, 1H), 5.58(s, 2H), 4.34-4.53( _m , 1H), 3.63( br dd, J=l.56, 12.46 Hz, 1H), 3.49 (br s, 1H), 3.05-3.22 (m, 2H), 2.99 (dd, J=8, 82, 12.46 Hz, 1H), 2.11-2.26 (m, 1H), 1.89 (ddd, J=3.63, 9.67, 13.43 Hz, 1H) IN Phenomenex Lux Cellulose-2, 15% MeOH, peak 2 23 500MHz d ₄ -MeOH 8.85 (s, 1H), 8.06-8.13 (m, 1H), 7.51 (d, 1=7.79 Hz, 1H), 7.29 (d, J=8.30 Hz , 1H), 7.05-7.22 (m, 3H), 5.49 (s, 2H), 3.30-3.36 (m, 2H), 3.10-3.23 (m, 3H ), 2.94-3.09 (m, 1H), 2.38 (qd, J=6.47, 12.52 Hz, 1H), 1.882.03 (m, 2H), 1.66-1, 88(m, 2H) IN Chiralpak AD-H, 30% IP A peak 1 24 500MHz d ₄ -MeOH 8.85 (s, 1H), 8.18-8.23 (m, 1H), 7.50-7.59 (m, 2H), 7.27-7.33 (m, 1H), 7. 21-7.26 (m, 2H), 5.61 (s, 2H), 4.00 (br dd, J=2.47, 12.85 Hz, 1H), 3.80-3.91 (m , 1H), 3.37-3.56 (m, 4H), 3.25 (br d, 1=2.34 Hz, 3H), 2.13-2.28 (m, 3H), 1.88 -2.07(m, 3H), 1.69-1.83(m, 1H) V Chiralpak AD-H, 30% IP A, peak 2 25 500MHz d ₄ -MeOH 8.85 (s, 1H), 8.06-8.13 (m, 1H), 7.51 (d, 1=7.79 Hz, 1H), 7.29 (d, J=8.30 Hz , 1H), 7.05-7.22 (m, 3H), 5.49 (s, 2H), 3.30-3.36 (m, 2H), 3.10-3.23 (m, 3H ), 2.94-3.09 (m, 1H), 2.38 (qd, J=6.47, 12.52 Hz, 1H), 1.882.03 (m, 2H), 1.66-1, 88(m, 2H) V Chiralpak AD-H, 30% IP A, peak 3 26 500MHz d ₄ -MeOH 8.85 (s, 1H), 8.18-8.23 (m, 1H), 7.50-7.59 (m, 2H), 7.27-7.33 (m, 1H), 7. 21-7.26 (m, 2H), 5.61 (s, 2H), 4.00 (br dd, J=2.47, 12.85 Hz, 1H), 3.80-3.91 (m , 1H), 3.37-3.56 (m, 4H), 3.25 (br d, 1=2.34 Hz, 3H), 2.13-2.28 (m, 3H), 1.88 -2.07(m, 3H), 1.69-1.83(m, 1H) V Chiralpak AD-H, 30% IP A, peak 4

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27 400ΜΓ c d ₄ -MeOH 8.83 (dd, J=0.62, 2.07 Hz, 1H), 8.08 (dd, 1=2.07, 8.09 Hz, 1H), 7.49-7.54 (m, 1H), 7.32 (d, 1=8.29 Hz, 1H), 7.07-7.19 (m, 3H), 5.45-5.52 (m, 2H), 3.38-3 .45 (m, 2H), 2.993.17 (m, 2H), 1.94-2.14 (m, 2H), 1.57-1.86 (m, 4H) IN Chiralpak IC, 40% MeOH, peak 1 400MHz d ₄ -MeOH 8.83 (dd, J=0.83, 2.07 Hz, 1H), 8.06-8.11 (m, 1H), 7.49-7.55 (m, 1H), 7.32 ( d, J=8.29 Chiralpak IC, 28 Hz, 1H), 7.05-7.19 (m, 3H), 5.47-5.52 (m, 2H), 3.37-3.46 (m, 2H), 3.01-3, 18 (m, 2H), IN 40% MeOH peak 2 1.96-2.18 (m, 2H), 1.56-1.84 (m, 4H) 8.49 (d, 1=2.34 Hz, 1H), 7.83-7.87 (m, 1H), 29 500MHz d ₄ -MeOH 7.75-7.79 (m, 2H), 7.66 (d, J=8.30 Hz, 1H), 7.36 (d, 1=8.56 Hz, 1H), 5.52 (s , 2H), 4.424.59 (m, 1H), 3.77 (dtd, J=l.69, 4.27, 12.62 Hz, 1H), 3.56-3.67 (m, 1H), 3.18-3.26 (m, V Chiralcel OD-H, 25% MeOH, peak 1 2H), 3.09 (s, 3H), 3.02-3.08 (m, 1H), 2.15- 2.26(m, 1H), 1.84-1.96(m, 1H) 8.48 (d, 1=2.34 Hz, 1H), 8.04-8.08 (m, 1H), 7.83-7.88 (m, 1H), 7.69 (dd, 1=1.82, 8.56 Hz, 1H), 7.37 (dd, J=4.02, 8.43 Hz, 2H), Chiralcel an 500MHz 5.48-5.53(m, 2H), 4.47-4.65(m, 1H), 3.79 D OD-H, 25% _d4 -MeOH (dtd, J=l.69, 4.27, 12.62 Hz, 1H), 3.58-3.67 MeOH peak (m, 1H), 3.33-3.38 (m, 1H), 3.17-3.25 (m, 1H), 3.07-3.14 (m, 4H), 2.18-2 .29 (m, 1H), 1 1.87-2.03(m, 1H) 8.77-8.82(m, 2H), 7.35-7.43(m, 1H), 7.28- 7.32(m, 1H), 5.54(s, 2H), 4.38-4.60(m, 31 400MHz d ₄ -MeOH 1H), 3.76 (dtd, 1=1.97, 4.31, 12.62 Hz, 1H), 3.56-3.68 (m, 1H), 3.16-3.26 (m, 2H), 2.973.10 (m, 1H), 2.12-2.26 (m, 1H), 1.79-1.98 - - (m, 1H) 400MHz d ₄ -MeOH 8.37 (d, 1=2.90 Hz, 1H), 7.57-7.64 (m, 1H), Regis 32 7.33 (dd, J=4.35, 8.71 Hz, 1H), 7.05 (dd, 1=2.07, 8.91 Hz, 1H), 6.73 (ddd, 1=2, 18, V Whilk-O, 20% MeOH,

- 139 043189

33 400MHz d ₄ -MeOH 9.85, 11.61 Hz, 1H), 5.49 (s, 2H), 4.39-4.60 (m, 1H), 3.70 (dtd, J=l.76, 4.28, 12.49Hz, 1H), 3.49-3.61(m, 1H), 3.11-3.31(m, 2H), 3.04(dd, J=9.12, 12.44Hz , 1H), 2.13-2.28 (m, 1H), 1.83-2.04 (m, 1H) 8.41 (d, J=2.90 Hz, 1H), 7.57-7.64 (m, 1H), 7.35 (dd, J=4.15, 8.71 Hz, 1H), 6 .71-6.85(m, 2H), 5.41(s, 2H), 4.32-4.54(m, 1H), 3.61 (dtd, J=l.66, 4.17, 12.39 Hz, 1H), 3.43- IN peak 2 Regis Whilk-O 20% MeOH 3.53 (m, 1H), 3.06-3.20 (m, 2H), 2.97 (dd, J=8.60, 12.34 Hz, 1H), 2.11-2.25 ( m, 1H), peak 1 1.80-1.97(m, 1H) 8.66-8.74(m, 2H), 6.86-6.92(m, 1H), 6.72- 6.82 (m, 1H), 5.51 (s, 2H), 4.36-4.59 (m, Regis 34 400MHz 1H), 3.64 (dtd, J=1.87, 4.28, 12.39 Hz, 1H), D whelk-o, _d4 -MeOH 3.47-3.57(m, 1H), 3.09-3.22(m, 2H), 2.99 15% MeOH (dd, J=8.91, 12.44 Hz, 1H), 2.07-2.26 (m, peak 2 1H), 1.75-1.99 (m, 1H) 8.67-8.72(m, 2H), 7.03-7.08(m, 1H), 6.68- 6.77 (m, 1H), 5.62 (d, J=0.83 Hz, 2H), 4.44- Regis Whilk-O 15% MeOH 35 400MHz d ₄ -MeOH 4.65 (m, 1H), 3.69 (dtd, J=l.76, 4.35, 12.54 Hz, 1H), 3.44-3.58 (m, 1H), 3.24- 3.32 (m, 1H), 3.12-3.19 (m, 1H), 3.05 (dd, J=9.43, IN 12.54 Hz, 1H), 2.17-2.27 (m, 1H), 1.84-2.01 (m, 1H) 8.73 (s, 2H), 7.39-7.44 (m, 1H), 7.35 (dd, 36 500MHz d ₄ -MeOH J=2.34, 9.34 Hz, 1H), 5.57 (d, J=4.15 Hz, 2H), 5.00-5.16 (m, 1H), 3.72-3.85 (m, 2H), 3.46-3.54 (m, 2H), 3.35-3.44 (m, 1H), 1.98- - - 2.19(m, 2H) 8.72 (s, 2H), 7.37-7.41 (m, 1H), 7.31 (dd, 500MHz d ₄ -MeOH J=2.47, 9.47Hz, 1H), 5.55(s, 2H), 4.41- 37 4.60 (m, 1H), 3.78 (dtd, J=l.82, 4.25, 12.78 Hz, 1H), 3.56-3.70 (m, 1H), 3.16- 3.29 (m, 2H), 3.07 (dd, J=9.34, 12.72 Hz, 1H), 2.14- — —

- 140 043189

2.24 (m, 1H), 1.83-1.96 (m, 1H) 8.81-8.92(m, 1H), 8.23(dd, J=8.30, 2.08Hz, 1H), 7.49-7.66(m, 2H), 7, 17-7.39 (m, 38 500MHz d ₄ -MeOH 3H), 5.64 (s, 2H), 4.69-4.86 (m, 1H), 3.924.06 (m, 1H), 3.61-3.79 (m, 2H), 3.20 -3.32(m, 2H), 2.24-2.41(m, 1H), 1.92-2.14(m, - - 1H) 8.74-8.81(m, 2H), 7.39-7.51(m, 1H), 7.00 39 500MHz d ₄ -MeOH (dd, J=8.95, 2.47 Hz, 1 H), 6.94 (ddd, 1=9.86, 8.82, 2.60 Hz, 1 H), 5.51 (s, 2 H), 4.98 (dt, J=5.26, 2.43 Hz, 1 H), 3.48 (dd, J=11.94, 3.89 Hz, 1 H), 3.19-3 .41 (m, 5H), IN Chiralpak IC, 20% IP A, peak 1 1.92-2.21(m, 2H) 500MHz d ₄ -MeOH 8.78(s, 2H), 7.04-7.25(m, 2H), 6.80-6.96 Chiralpak IC, 40 (m, 1 H), 5.45-5.61 (m, 2 H), 3.42-3.58 (m, 1 H), 3.17-3.40 (m, 5 H), 1 .88-2.23(m, 2H) IN 20% IP A peak 2 8.81 (s, 2H), 7.67-7.71 (m, 1H), 7.61 (d, Chiralpak OJ, 15% MeOH peak 9 41 500MHz d ₄ -MeOH 1=8.30Hz, 1H), 7.49-7.53(m, 1H), 5.61(s, 2H), 3.69-3.77(m, 1H), 3.58-3, 66 (m, 1H), 3.43-3.53 (m, 1H), 3.36-3.43 (m, 1H), 3.23- V 3.30 (m, 1H), 2.14-2.41 (m, 2H) 8.79 (s, 2H), 7.80-7.86 (m, 1H), 7.42-7.48 Chiralpak OJ, 15% MeOH, peak 1 42 500MHz d ₄ -MeOH (m, 1H), 7.37 (d, J=8.30 Hz, 1H), 5.61 (s, 2H), 3.66-3.74 (m, 1H), 3.55-3, 63 (m, 1H), 3.34-3.53 (m, 3H), 3.22-3.30 (m, 1H), 2.29- V 2.41 (m, 1H), 2.07-2.27 (m, 1H) 8.93 (d, 7=1.35 Hz, 1H), 8.32 (dd, 7=2.18, 8.19Hz, 1H), 7.67(s, 1H), 7.54(s, 1H), 43 400MHz d ₆ -DMSO 7.52-7.56(m, 1H), 7.49(d, 7=7.92Hz, 1H), 5.56(s, 2H), 4.22-4.48(m, 1H) , 3.36-3.45(m, 2H), 2.97-3.09(m, 1H), 2.72-2.94(m, 2H), 1.97-2.11(m, 1H), 1.61-1.77 (m, 1H) - - 44 400MHz 8.96 (s, 1H), 8.27 (dd, 7=2.18, 8.19 Hz, 1H), - -

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_d6 -DMSO 7.27 (d, 7=7.98 Hz, 1H), 7.23 (s, 1H), 6.92 (s, 1H), 5.44 (s, 2H), 4.21-4.48 (m, 1H), 3.35 (br s, 3H), 2.86-3.03 (m, 2H), 2.74 (dd, 7=8.60, 12.44 Hz, 1H), 2 .24 (s, 3H), 2.20 (s, 3H), 1.93-2.12 (m, 1H), 1.87 (br s, 1H), 1.64-1.82 (m, 1H) 45 400MHz d ₆ -DMSO 8.92-8.95 (m, 1H), 8.36-8.50 (m, 3H), 7.76 (d, 7=8.09 Hz, 1H), 7.53-7.60 ( m, 1H), 7.357.43 (m, 1H), 7.18 (t, 7=9.23 Hz, 1H), 5.655.84 (m, 2H), 3.86 (br d, 7=10, 47 Hz, 1H), 3.26-3.52 (m, 3H), 3.15 (br t, 7=9.90 Hz, 1H), 1.82-2.01 (m, 2H), 1 .40-1.69 (m, 2H) IN Chiralcel OD-H, 15% IP A, peak 1 46 400MHz d ₆ -DMSO 8.94 (s, 1H), 8.48 (br s, 2H), 8.40 (dd, 7=2.18, 8.19 Hz, 1H), 7.77 (d, 7=8.19 Hz, 1H), 7.40 (dd, 7=2.85, 8.66 Hz, 2H), 7.14 (dt, 7=2.38, 9.33 Hz, 1H), 5.65-5 .84 (m, 2H), 3.89 (br d, 7=10.57 Hz, 1H), 3.28-3.52 (m, 3H), 3.18 (br t, 7=9.80 Hz, 1H), 1.942.02 (m, 1H), 1.81-1.93 (m, 1H), 1.47-1.72 (m, 2H) IN Chiralcel OD-H, 15% IP A, peak 2 47 400MHz d ₆ -DMSO 8.93 (s, 1H), 8.71 (br s, 2H), 8.38 (dd, 7=1.75, 8.24 Hz, 1H), 7.73 (d, 7=8.17 Hz, 1H), 7.57 (dd, 7=4.54, 8.69 Hz, 1H), 7.36 (br d, 7=8.30 Hz, 1H), 7.16 (t, 7= 8.68 Hz, 1H), 5.65-5.82 (m, 2H), 5.06-5.24 (m, 1H), 3.79 (br d, 7=12.07 Hz, 1H) , 3.62-3.74 (m, 1H), 3.36-3.52 (m, 3H), 3.24-3.33 (m, 1H), 2.09-2.20 (m, 1H), 1.88-2.09 (m, 1H) V Chiralcel OD-H, 15% IP A, peak 1 48 400MHz d ₆ -DMSO 8.94 (s, 1H), 8.66 (br s, 3H), 8.37 (dd, 7=1.82, 8.17 Hz, 1H), 7.67 (d, 7=8.17 Hz, 1H), 7.37 (dd, 7=2.14, 9.02 Hz, 1H), 7.31 (br dd, 7=4.41, 8.69 Hz, 1H), 7.07 ( t, 7=8.71 Hz, 1H), 5.60-5.78 (m, 2H), 5.05-5.24 (m, 1H), 3.62-3.78 (m, 2H) , 3.36-3.51 (m, 2H), 3.22-3.31 (m, 1H), 2.09-2.18 (m, 1H), 1.93- V Chiralcel OD-H, 15% IP A, peak 2

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49 400MHz d ₆ -DMSO 2.07 (m, 1H) 8.90-8.96 (m, 1H), 8.87 (br s, 2H), 8.40 (dd, 7=1.95, 8.17 Hz, 1H) , 7.76 (d, 7=8.30 Hz, 1H), 7.58 (dd, 7=4.54, 8.69 Hz, 1H), 7.39 (br d, 7=7.40 Hz , 1H), 7.18 (t, 7=8.78 Hz, 1H), 5.68-5.84 (m, 2H), 4.86-5.05 (m, 1H), 4.04 ( br d, 7=12.46 Hz, 1H), 3.59-3.73 (m, 1H), 3.33-3.53 (m, 2H), 3.22 (brt, 7=11.42 Hz, 1H), 2.22-2.32(m, 1H), 1.75-1.92(m, 1H) 8.94 (s, 1H), 8.90 (br s, 2H), 8.39 (dd, 7=1.62, 8.24 Hz, 1H), 7.76 (d, 7=8.17 Hz, 1H), 7.35-7.45 (m, 2H), 7.13 (t, 7=8.77 Hz, IN Chiralcel OD-H, 15% IP A, peak 1 Chiralcel 400MHz 1H), 5.68-5.84 (m, 2H), 4.87-5.07 (m, 1H), D OD-H 15% _d6 -DMSO 4.07 (br d, 7=12.72 Hz, 1H), 3.60-3.73 (m, IP A, 1H), 3.36-3.53 (m, 2H), 3.25 (brt, 7=11.55 Hz, 1H), 2.23-2.32 (m, 1H), 1.78-1 .91 (m, peak 2 1H) 8.94 (d, 7=1.45 Hz, 1H), 8.32 (dd, 7=2.18, 51 400MHz d ₆ -DMSO 8.19 Hz, 1H), 7.72 (d, 7=0.93 Hz, 1H), 7.45- 7.55 (m, 3H), 5.56 (s, 2H), 3.48 (br d, 7=11.71 Hz, 1H), 3.34-3.42 (m, 1H), 2.842, 95 (m, 1H), 2.61-2.78 (m, 2H), 1.74-1.83 (m, 1H), 1.59-1.72 (m, 1H), 1.40- 1.58(m, V Chiralpak AD-H, 20% methanol, peak 1 1H), 1.03-1.29 (m, 1H) 8.93(d, 7=1.35Hz, 1H), 8.32(dd, 7=2.18, 8.19Hz, 1H), 7.89(d, 7=1.14Hz, 1H ), 7.477.54 (m, 1H), 7.42 (d, 7=1.45 Hz, 1H), 7.32 Chiralpak 52 400MHz d ₆ -DMSO (d, 7=8.29 Hz, 1H), 5.57 (s, 2H), 3.38-3.50 (m, 1H), 3.29-3.37 (m, 1H), 2, 87 (brs, 1H), V AD-H, 20% methanol, 2.78 (br s, 1H), 2.66 (br dd, 7=9.07, 11.87 Hz, 1H), 1.74-1.85 (m, 1H), 1.62-1, 74 (m, 1H), 1.43-1.57 (m, 1H), 1.11-1.31 (m, 1H) peak 2 SQ 400MHz 8.93 (dd, 7=0.73, 2.07 Hz, 1H), 8.33 (dd, η Chiralpak _d6 -DMSO 7=2.07, 8.19 Hz, 1H), 7.74 (d, 7=0.93 Hz, AD-H, 25%

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54 400MHz 1H), 7.48-7.58 (m, 3H), 5.61 (s, 2H), 4.254.48 (m, 1H), 3.38-3.57 (m, 2H), 3.03 -3.16(m, 1H), 2.80-2.92(m, 2H), 1.97-2.13(m, 1H), 1.61-1.80(m, 3H) 8.92 (s, 1H), 8.33 (dd, 7=2.12, 8.14 Hz, 1H), 7.91 (d, 7=1.14 Hz, 1H), 7.54 (d , 7=8.29 Hz, 1H), 7.45 (dd, 7=1.50, 8.24 Hz, 1H), 7.33 (d, 7=8.29 Hz, 1H), 5.61 (s, 2H), 4.25-4.48 (m, IN methanol peak 1 Chiralpak AD-H, 25% _d6 -DMSO 1H), 3.36-3.52 (m, 3H), 3.07 (br s, 1H), 2.79-2.95 (m, 2H), 1.96-2.18 (m, 1H ), 1.65- methanol peak 2 1.80(m, 2H) 8.88(d, 7=1.35Hz, 1H), 8.00(dd, 7=2.13, 8.14Hz, 1H), 7.64(d, 7=8.19Hz, 1H ), 7.45- Chiralpak s s 400MHz 7.54 (m, 1H), 7.28 (d, 7=1.04 Hz, 1H), 7.21- D AD-H, 20% J J CDC1 ₃ 7.26 (m, 1H), 5.36-5.47 (m, 2H), 3.43-3.63 r> IP A, (m, 3H), 3.14-3.33 (m, 2H), 2.27-2.40 (m, peak 1 1H), 2.10-2.24 (m, 1H), 1.75 (br s, 2H) 8.89 (d, 7=1.35 Hz, 1H), 7.99 (dd, 7=2.07, 56 400MHz CDC1 ₃ 8.09 Hz, 1H), 7.92 (d, 7=0.93 Hz, 1H), 7.42 (dd, 7=1.45, 8.29 Hz, 1H), 7.20 (d, 7=8.19Hz, 1H), 7.06(d, 7=8.19Hz, 1H), 5.40-5.54(m, 2H), 3.40-3.62(m, 3H ), 3.17-3.35 (m, 2H), 2.29-2.42 (m, 1H), 2.01-2.26 (m, 1H), V Chiralpak AD-H, 20% IP A, peak 2 1.95 (brs, 2H) 8.93 (s, 1H), 8.31 (brd, 7=8.19 Hz, 1H), 7.48 (d, 7=8.19 Hz, 1H), 7.35 (s, 1H), 7.24 (s, 1H), 5.53 (s, 2H), 3.39 (br d, 7=11.09 Hz, 57 400MHz d ₆ -DMSO 2H), 3.29 (br d, 7=12.44 Hz, 2H), 2.84 (br t, 7=10.37 Hz, 1H), 2.57-2.78 (m, 2H), 1.77 - - (br dd, 7=3.89, 8.55 Hz, 1H), 1.65 (br dd, 7=4.20, 9.38 Hz, 1H), 1.40-1.61 (m, 1H ), 1.05-1.21(m, 1H) 58 400MHz d ₆ -DMSO 8.93 (s, 1H), 8.32 (d, 7=8.19 Hz, 1H), 7.52 (d, 7=8.19 Hz, 1H), 7.36 (s, 1H), 7.26 (s, 1H), 5.58 (s, 2H), 4.24-4.47 (m, 1H), 3.34- - -

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3.52 (br, 3H), 2.98-3.10 (m, 1H), 2.78-2.95 (m, 2H), 2.05 (br t, 7=12.70 Hz, 1H ), 1.841.99 (m, 1H), 1.64-1.83 (m, 1H) 8.93 (s, 1H), 8.32 (d, 7=8.29 Hz, 1H), 7.52 (d, 7=8.09 Hz, 1H), 7.35 (s, 1H), 7.26 (s, 59 400MHz d ₆ -DMSO 1H), 5.57 (s, 2H), 4.64-4.86 (m, 2H), 3.173.38 (m, 2H), 3.05-3.17 (m, 1H), 2.93 -3.02(m, 1H), 2.82-2.93(m, 1H), 1.92-2.04(m, - - 1H), 1.79(brs, 1H) 8.89-8.96 (m, 1H), 8.33 (d, 7=7.79 Hz, 1H), 7.56 (d, 7=8.29 Hz, 1H), 7.32-7.40 (m, 1H), 60 400MHz d ₆ -DMSO 7.28 (s, 1H), 5.54-5.66 (m, 2H), 3.34-3.46 (m, 2H), 3.15-3.26 (m, 1H), 2, 96-3.14 (m, 2H), 2.16-2.31 (m, 1H), 1.87-2.08 (m, 2H), - - 1.78-1.87(m, 1H) 8.94 (s, 1H), 8.31 (dd, 7=2.07, 8.19 Hz, 1H), 7.44 (d, 7=8.29 Hz, 1H), 7.02 (d, 7=8.78 Hz, Regis 400MHz d ₆ -DMSO 1H), 6.95 (t, 7=10.39 Hz, 1H), 5.50 (s, 2H), whelk-0s, 61 3.33 (br d, 7=11.82 Hz, 2H), 3.23 (br d, 7=12.23 Hz, 2H), 2.66-2.87 (m, 2H), 2.54 - IN s, 30% methanol, 2.63 (m, 1H), 1.73-1.90 (m, 1H), 1.60-1.72 (m, 1H), 1.41-1.58 (m, 1H), 1, 16 (brs, 1H) 8.93 (s, 1H), 8.31 (dd, 7=1.97, 8.19 Hz, 1H), peak 2 7.48 (d, 7=8.29 Hz, 1H), 7.14 (dd, 7=1.92, Regis 62 400MHz d ₆ -DMSO 9.28 Hz, 1H), 6.85 (t, 7=10.74 Hz, 1H), 5.50 (s, 2H), 3.34-3.44 (m, 4H), 2.73- 2.91 (m, 2H), 2.63 (dd, 7=9.07, 11.87 Hz, 1H), 1.74- IN Whelk-0 s, s, 30% methanol, 1.86 (m, 1H), 1.62-1.74 (m, 1H), 1.43-1.60 peak 1 (m, 1H), 1.11-1.28 (m, 1H) 8.93 (s, 1H), 8.32 (dd, 7=2.02, 8.24Hz, 1H), 7.50 (d, 7=8.19 Hz, 1H), 7.03 (d, 7=8.98 Hz, Chiral cel OJ- 63 400MHz 1H), 6.98 (t, 7=10.69 Hz, 1H), 5.55 (s, 2H), D H, 15% _d6 -DMSO 4.33-4.59 (m, 1H), 3.69-4.05 (m, 2H), 3.31- methanol, 3.50 (m, 2H), 2.96-3.09 (m, 2H), 2.83 (dd, 7=9.02, 12.54 Hz, 1H), 2.02-2.12 ( m, 1H), peak 2

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1.67-1.79(m, 1H) 64 400MHz d ₆ -DMSO 8.92 (s, 1H), 8.32 (dd, 7=1.76, 8.19 Hz, 1H), 7.52 (d, 7=8.29 Hz, 1H), 7.16 (dd , 7=1.92, 9.28 Hz, 1H), 6.87 (t, 7=10.73 Hz, 1H), 5.55 (s, 2H), 4.26-4.49 (m, 1H), 3.36-3.45 (m, 2H), 3.02-3.10 (m, 1H), 2.88-2.99 (m, 1H), 2.82 (dd, 7= 8.60, 12.44 Hz, 1H), 1.92-2.15 (m, 1H), 1.66-1.86 (m, 3H) IN Chiralcel O.J. H, 15% methanol, peak 1 65 400MHz d ₆ -DMSO 8.94 (s, 1H), 8.31 (dd, 7=1.97, 8.19 Hz, 1H), 7.48 (d, 7=8.19 Hz, 1H), 7.02 (d , 7=8.08 Hz, 1H), 6.96 (t, 7=10.40 Hz, 1H), 5.49-5.58 (m, 2H), 4.63-4.83 (m, 1H), 3.04-3.26 (m, 3H), 2.84-2.97 (m, 2H), 1.75-2.01 (m, 2H), 1.65 (br s, 2H ) IN Phenomenex Lux Cellulose-2, 20% methanol, peak 2 66 400MHz d ₆ -DMSO 8.92 (s, 1H), 8.31 (dd, 7=1.87, 8.19 Hz, 1H), 7.51 (d, 7=8.19 Hz, 1H), 7.16 (dd , 7=1.92, 9.28 Hz, 1H), 6.86 (t, 7=10.73 Hz, 1H), 5.49-5.59 (m, 2H), 4.81 (br s , 1H), 3.103.29 (m, 3H), 2.90-3.02 (m, 2H), 1.81-2.03 (m, 2H), 1.63 (br s, 2H) IN Phenomenex Lux Cellulose-2, 20% methanol, peak 1 67 400MHz d ₆ -DMSO 8.92 (s, 1H), 8.32 (dd, 7=1.97, 8.19 Hz, 1H), 7.55 (d, 7=8.19 Hz, 1H), 7.19 (dd , 7=1.81, 9.28 Hz, 1H), 6.89 (t, 7=10.66 Hz, 1H), 5.59 (s, 2H), 3.33-3.56 (m, 2H), 3.10-3.26(m, 2H), 2.98-3.10(m, 1H), 2.21-2.32(m, 1H), 2.00-2.14( m, 1H), 1.78 (brs, 2H) V Phenomenex Lux Cellulose-2, 20% methanol, peak 1 68 400MHz d ₆ -DMSO 8.93 (s, 1H), 8.33 (dd, 7=2.18, 8.19 Hz, 1H), 7.74 (d, 7=1.04 Hz, 1H), 7.48-7 .58 (m, 3H), 5.61 (s, 2H), 4.25-4.47 (m, 1H), 3.38-3.57 (m, 2H), 3.04-3.17 (m, 1H), 2.80-2.92 (m, 2H), 1.99-2.12 (m, 1H), 1.60-1.79 (m, 3H) V Chiralpak AD-H, 25% methanol, peak 1 69 400MHz d ₆ -DMSO 8.92 (s, 1H), 8.33 (dd, 7=2.18, 8.19 Hz, 1H), 7.91 (d, 7=1.14 Hz, 1H), 7.54 (d , 7=8.19 Hz, 1H), 7.45 (dd, 7=1.45, 8.29 Hz, 1H), 7.33 (d, 7=8.29 Hz, 1H), 5.62 (s, 2H), 4.27-4.48 (m, V Chiralpak AD-H, 25% methanol, peak 2

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70 71 72 73 400MHz d ₆ -DMSO 400MHz d ₆ -DMSO 400MHz d ₆ -DMSO 400MHz d ₆ -DMSO 1H), 3.36-3.56 (m, 2H), 3.01-3.14 (m, 1H), 2.79-2.96 (m, 2H), 1.96-2.22 ( m, 2H), 1.811.96 (m, 1H), 1.66-1.81 (m, 1H) 8.96(d, 7=1.45Hz, 1H), 8.28(dd, 7=2.18, 8.19Hz, 1H), 7.43(d, 7=7.67Hz, 1H ), 7.32 (d, 7=8.29 Hz, 1H), 6.98-7.13 (m, 3H), 5.47 (s, 2H), 3.35 (br dd, 7=3 .42, 11.71 Hz, 2H), 3.14-3.30 (m, 1H), 2.67-2.89 (m, 2H), 2.58 (dd, 7=9.02, 11 .71 Hz, 1H), 1.73-1.87 (m, 1H), 1.60-1.72 (m, 1H), 1.42-1.60 (m, 2H), 1.08- 1.22(m, 1H) 9.06 (br s, 3H), 8.88-9.00 (m, 1H), 8.37 (dd, 7=2.18, 8.19 Hz, 1H), 7.67 (d, 7 =8.19Hz, 1H), 7.38(dd, 7=2.44, 9.17Hz, 1H), 7.27(dd, 7=4.56, 8.81Hz, 1H), 7 .05 (t, 7=9.27 Hz, 1H), 5.61-5.87 (m, 2H), 3.96-4.12 (m, 1H), 3.90 (br d, 7= 12.85 Hz, 1H), 3.42-3.54 (m, 2H), 3.23-3.34 (m, 1H), 2.45-2.60 (m, 1H), 2.20 -2.37(m, 1H) 8.94 (d, 7=1.45 Hz, 1H), 8.31 (dd, 7=2.18, 8.19 Hz, 1H), 7.50 (t, 7=9.11 Hz, 1H ), 7.45 (d, 7=8.50 Hz, 1H), 7.36 (dd, 7=7.36, 10.78 Hz, 1H), 5.52 (s, 2H), 4.23 -4.46 (m, 1H), 3.22-3.45 (m, 3H), 2.81-3.05 (m, 2H), 2.76 (dd, 7=8.60, 12, 44 Hz, 1H), 1.87-2.12 (m, 1H), 1.63-1.87 (m, 3H) 8.96 (dd, 7=0.73, 2.07 Hz, 1H), 8.29 (dd, 7=2.18, 8.19 Hz, 1H), 7.45 (d, 7=7, 54 Hz, 1H), 7.37 (d, 7=8.29 Hz, 1H), 7.00-7.13 (m, 3H), 5.51 (s, 2H), 4.63-4, 84 (m, 1H), 3.063.26 (m, 3H), 2.88-3.00 (m, 2H), 1.79-2.03 (m, 2H), 1.59 (br s, 2H ) IN Chiralcel OD-H, 15% IP A, peak 2 74 400MHz d ₆ -DMSO 8.90 (d, 7=1.45 Hz, 1H), 8.37-8.43 (m, 1H), 8.34 (br s, 2H), 7.85 (d, 7=8.19 Hz, 1H), 7.46-7.54 (m, 2H), 7.22-7.34 (m, 2H ), 5.93 IN Chiralpak AD-H, 30% isopropane

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(s, 2H), 3.83-4.11 (m, 4H), 3.60-3.75 (m, 1H), 2.95-3.15 (m, 2H), 1.91 (td , 7=4.13, 8.22Hz, 1H), 1.03 (dd, 7=5.29, 7.77Hz, 1H), 0.52 (t, 7=4.87Hz, 1H) l, peak 1 75 400MHz d ₆ -DMSO 8.90 (d, 7=1.97 Hz, 1H), 8.39 (s, 1H), 8.34 (br s, 3H), 7.86 (d, 7=8.29 Hz, 1H) , 7.477.53 (m, 2H), 7.22-7.34 (m, 2H), 5.93 (s, 2H), 4.04-4.13 (m, 1H), 3.83-4 .02 (m, 3H), 3.63-3.73 (m, 1H), 2.95-3.20 (m, 2H), 1.91 (td, 7=4.09, 8.19 Hz , 1H), 0.98-1.07 (m, 1H), 0.52 (t, 7=4.87 Hz, 1H) IN Chiralpak AD-H, 30% isopropanol, peak 2 76 400MHz d ₆ -DMSO 8.89-8.97 (m, 1H), 8.50 (br s, 2H), 8.41 (dd, 7=2.13, 8.24 Hz, 1H), 7.91 (d, 7 =8.29Hz, 1H), 7.49(d, 7=8.71Hz, 2H), 7.23-7.34(m, 2H), 5.88-6.16(m, 2H) , 4.21 (br dd, 7=6.22, 10.88 Hz, 1H), 3.87 (br dd, 7=7.26, 10.26 Hz, 1H), 3.42-3.77 (m, 3H), 2.97-3.16 (m, 1H), 2.82-2.94 (m, 1H), 1.71-2.04 (m, 3H), 1.42-1 .64 (m, 1H) IN Phenomenex Lux Cellulose-2, 25% isopropanol with 0.2% DEA, peak 1 77 400MHz d ₆ -DMSO 8.92 (d, 7=1.45 Hz, 1H), 8.47 (br d, 7=1.35 Hz, 3H), 8.41 (dd, 7=2.07, 8.19 Hz, 1H), 7.89 (br d, 7=8.09 Hz, 1H), 7.49 (d, 7=8.09 Hz, 2H), 7.23-7.34 (m, 2H), 5 .86-6.14 (m, 2H), 4.10-4.29 (m, 1H), 3.75-4.02 (m, 1H), 3.54-3.73 (m, 3H) , 2.97-3.07 (m, 1H), 2.82.92 (m, 1H), 1.74-1.99 (m, 3H), 1.41-1.65 (m, 1H) V Phenomenex Lux Cellulose-2, 25% isopropanol with 0.2% DEA, peak 4 78 400MHz d ₄ methanol 8.82 (s, 1H), 8.20-8.29 (m, 1H), 7.79 (d, 7=8.19 Hz, 1H), 7.28-7.50 (m, 4H) , 5.90 (s, 2H), 3.92-4.12 (m, 3H), 3.69-3.76 (m, 1H), 3.55-3.63 (m, 1H), 3 .02-3.17 (m, 1H), 2.892.96 (m, 2H), 2.28-2.38 (m, 1H), 2.18 (dtd, 7=5.34, 7.78, 13.31Hz, 1H), 1.73-1.85(m, 1H), 1.60-1.72(m, 1H) V Phenomenex Lux Cellulose-2, 25% isopropanol with 0.2% DEA, peak 2

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79 400MHz d ₄ methanol 8.82 (d, 3=1.45 Hz, 1H), 8.26 (dd, 3=2.07, 8.19 Hz, 1H), 7.78 (d, 3=8.09 Hz, 1H ), 7.297.50 (m, 4H), 5.85-5.93 (m, 2H), 4.05-4.12 (m, 1H), 3.91-4.01 (m, 2H), 3.55-3.77 (m, 2H), 3.01-3.18 (m, 1H), 2.92 (ddt, 3=4.28, 4.51, 8.41 Hz, 1H), 2.28-2.37 (m, 1H), 2.132.23 (m, 1H), 1.74-1.85 (m, 1H), 1.58-1.71 (m, 1H), 1, 43(s, 1H) IN Phenomenex Lux Cellulose-2, 25% isopropanol with 0.2% DEA, peak 3 80 400MHz d ₆ -DMSO 8.91 (d, 3=1.45 Hz, 1H), 8.40 (dd, 3=2.18, 8.19Hz, 1H), 8.28(brs, 3H), 7.82(d, 3=8.09Hz, 1H), 7.48(dd, 3=3.21, 7.77Hz , 2H), 7.28-7.33 (m, 1H), 7.25 (d, 3=7.37 Hz, 1H), 5.94 (d, 3=3.73 Hz, 2H), 3 .87-3.94 (m, 1H), 3.64-3.86 (m, 3H), 2.88 (br t, 3=6.27 Hz, 2H), 2.61-2.70 (m, 1H), 2.16 (br d, 3=6.22 Hz, 1H), 1.82-1.91 (m, 1H) IN Chiralpak IC, 40% isopropanol with 0.2% DEA, peak 1 81 400MHz d ₆ -DMSO 8.91 (d, 3=1.45 Hz, 1H), 8.36-8.43 (m, 1H), 8.33 (br s, 2H), 7.82 (d, 3=8.19 Hz, 1H), 7.49 (dd, 3=3.84, 7.67 Hz, 2H), 7.21-7.36 (m, 2H), 5.89-5.97 (m, 2H) , 3.65-3.93(m, 5H), 3.47-3.51(m, 1H), 2.79-2.96(m, 2H), 2.61-2.72(m, 1H), 2.12-2.21(m, 1H), 1.821.92(m, 1H) V Chiralpak IC, 40% isopropanol with 0.2% DEA, peak 2 82 500MHz DMSO-d ₆ 8.92 (s, 1H), 8.54 (br s, 2H), 8.33 (br d, 3=7.79 Hz, 1H), 7.72 (s, 1H), 7.57 (br s, 2H), 5.62 (q, 3=17.82 Hz, 2H), 5.01-5.20 (m, 1H), 3.59-3.63 (m, 1H), 3.20 -3.31 (m, 2H), 3.08 (br t, 3=10.96 Hz, 1H), 2.08 (br s, 1H), 1.86-2.03 (m, 1H) V - 83 400MHz DMSO-d ₆ 8.93 (s, 1H), 8.40 (br s, 2H), 8.33 (dd, 3=1.66, 8.09 Hz, 1H), 7.48-7.57 (m, 2H ), 7.38 (dd, 3=7.46, 10.26 Hz, 1H), 5.50-5.63 (m, 2H), 5.00-5.20 (m, 1H), 3, 50 (br s, 1H), 3.24-3.33 (m, 1H), 3.15-3.23 (m, 1H), 3.023.14 (m, 1H), 1.87-2.12 (m, 2H) V -

- 149043189

84 400ΜΓ c DMSO-d ₆ 500 MHz, 8.90-8.97 (m, 1H), 8.86 (br s, 2H), 8.34 (br d, 7=8.29 Hz, 1H), 7.53-7.63 (m, 2H), 7.40 (dd, 7=7.31, 10.52 Hz, 1H), 5.54-5.73 (m, 2H), 3.92-4.21 (m, 2H), 3 .65-3.78 (m, 2H), 3.33 (br d, 7=7.05 Hz, 1H), 3.09-3.21 (m, 1H), 2.15-2.32 ( m, 1H) 8.86-8.99 (m, 2H), 8.56 (d, 7=2.21 Hz, 1H), 7.99 (br d, 7=8.04 Hz, 1H), 7.47- 7.59 (m, 2H), 7.25 (brs, 2H), 7.15-7.23 (m, 1H), IN - 85 DMSO- _d6 5.50-5.67 (m, 2H), 4.06-4.14 (m, 1H), 3.78- IN — 3.95 (m, 3H), 3.25-3.39 (m, 1H), 2.25-2.35 (m, 1H) 8.55 (d, 7=2.21 Hz, 1H), 8.47 (br s, 2H), 7.96 (dd, 7=2.34, 8.43 Hz, 1H), 7.50 ( d, 86 500 MHz, DMSO- _d6 7=7.78 Hz, 1H), 7.40(br d, 7=7.40 Hz, 1H), 7.09-7.22(m, 3H), 5.43-5.58(m, 2H), 5.045.22 (m, 1H), 3.72-3.84 (m, 2H), 3.62-3.69 (m, 2H), 3.36-3.43 (m, 2H) , 3.19-3.28 (m, V - 1H), 2.04-2.16 (m, 1H) 8.93 (d, 7=1.95 Hz, 1H), 8.81 (br s, 2H), 8.34 (dd, 7=2.08, 8.17 Hz, 1H), 7.59 ( d, 7=8.17 Hz, 1H), 6.98-7.06 (m, 2H), 5.56- 87 500 MHz, DMSO- _d6 5.75 (m, 2H), 4.00 (dt, 7=3.63, 5.51 Hz, 1H), 3.73 (br d, 7=12.33 Hz, 1H), 3.38 ( br d, 7=12.33 Hz, 1H), 3.27-3.34 (m, 1H), 3.103.19 (m, 1H), 2.37-2.44 (m, 1H), 2, 16-2.33 V - (m, 1H) 8.84 (d, 7=1.82 Hz, 1H), 8.15 (dd, 7=2.08, YMC 500MHz d ₄ -MeOH 8.30 Hz, 1H), 7.40-7.52 (m, 2H), 6.91-7.00 amyose SA, 88 (m, 2H), 5.47-5.62 (m, 2H), 3.34-3.54 (m, 2H), 3.08-3.28 (m, 3H), 2.21-2 .36 (m, 1H), I methanol- THF (70:30) 2.00-2.21(m, 1H) 40%; peak 1 500MHz d ₆ -DMSO 8.94 (d, 7=1.56 Hz, 1H), 8.33 (dd, 7=1.95, 89 8.17 Hz, 1H), 7.57 (d, 7=8.56 Hz, 1H), 7.43 (t, 7=7.27 Hz, 2H), 7.18 (t, 7=7, 91Hz, 1H), -

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5.58-5.69 (m, 2H), 3.34-3.28 (m, 3H), 3.023.13 (m, 2H), 2.18-2.33 (m, 1H), 1, 97-2.13(m, 1H) 90 600MHz d ₆ -DMSO 8.95(d, 7=1.56Hz, 1H), 8.34(dd, 7=2.02, 8.25Hz, 1H), 7.54(d, 7=8.10Hz, 1H ), 7.44 (d, 7=8.10 Hz, 1H), 7.41 (d, 7=7.79 Hz, 1H), 7.16 (t, 7=7.94 Hz, 1H), 5.54-5.67 (m, 2H), 4.26-4.45 (m, 1H), 3.38-3.50 (m, 2H), 3.013.10 (m, 1H), 2, 79-2.92(m, 2H), 2.00-2.13(m, 1H), 1.66-1.80(m, 1H) - - 91 600MHz d ₆ -DMSO 8.95(d, 7=1.25Hz, 1H), 8.33(dd, 7=2.02, 8.25Hz, 1H), 7.53(d, 7=8.41Hz, 1H ), 7.43 (d, 7=8.10 Hz, 1H), 7.40 (d, 7=7.79 Hz, 1H), 7.16 (t, 7=7.79 Hz, 1H), 5.54-5.66 (m, 2H), 4.66-4.84 (m, 1H), 3.30 (br d, 7=3.74 Hz, 1H), 3.25 (td, 7 =4.05, 12.77 Hz, 1H), 3.083.16 (m, 1H), 2.97-3.05 (m, 1H), 2.83-2.95 (m, 1H), 1, 95-2.02(m, 1H), 1.78-1.94(m, 1H) -- - 92 500MHz d ₄ -MeOH 8.79(d, 7=1.30Hz, 1H), 8.15(dd, 7=2.08, 8.04Hz, 1H), 8.05(d, 7=1.82Hz, 1H ), 7.77 (d, 7=2.08 Hz, 1H), 7.54 (d, 7=8.04 Hz, 1H), 5.52-5.64 (m, 2H), 4.30 -4.48(m, 1H), 3.683.75(m, 1H), 3.58-3.67(m, 1H), 3.14-3.23(m, 1H), 2.94-3 .06 (m, 2H), 2.08-2.19 (m, 1H), 1.75-1.87 (m, 1H) V Separated by flash chromatography 93 500MHz d ₄ -MeOH 8.83(d, 7=1.30Hz, 1H), 8.17-8.22(m, 2H), 7.66(d, 7=2.34Hz, 1H), 7.54(d , 7=8.30Hz, 1H), 5.54(s, 2H), 4.32-4.50(m, 1H), 3.643.75(m, 1H), 3.52-3.64( m, 1H), 3.15-3.27 (m, 1H), 3.02-3.10 (m, 1H), 2.99 (dd, 7=8.56, 12.20 Hz, 1H) , 2.06-2.23(m, 1H), 1.78-1.92(m, 1H) V Separated by flash chromatography

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94 500MHz d ₄ -MeOH 8.80 (d, 7=1.82 Hz, 1H), 8.19 (d, 7=2.34 Hz, 1H), 8.12 (dd, 7=2.34, 8.04 Hz, 1H ), 7.62 (d, 7=2.08 Hz, 1H), 7.41 (d, 7=8.04 Hz, 1H), 5.49 (s, 2H), 4.34-4.50 (m, 1H), 3.70-3.77 (m, 1H), 3.58-3.66 (m, 1H), 3.21 (ddd, 7=2.47, 10.19, 13, 04Hz, 1H), 3.06-3.15(m, 1H), 2.99-3.05(m, 1H), 2.10-2.20(m, 1H), 1.82-1 .92 (m, 1H), 1.43 (s, 9H) IN Separated by flash chromatography 95 500MHz d ₄ -MeOH 8.86(d, 7=1.30Hz, 1H), 8.13(dd, 7=2.08, 8.30Hz, 1H), 7.51(d, 7=7.79Hz, 1H ), 7.31 (d, 7=8.30 Hz, 1H), 7.16-7.22 (m, 1H), 7.097.16 (m, 2H), 5.51 (s, 2H), 3 .57-3.63 (m, 1H), 3.37-3.51 (m, 2H), 3.01-3.10 (m, 1H), 2.76-2.92 (m, 2H) , 1.95-2.03(m, 1H), 1.571.72(m, 1H) - - 96 500MHz d ₄ -MeOH 8.85(d, 7=1.56Hz, 1H), 8.13(dd, 7=2.08, 8.30Hz, 1H), 7.51(d, 7=8.04Hz, 1H ), 7.31 (d, 7=8.56 Hz, 1H), 7.16-7.21 (m, 1H), 7.097.15 (m, 2H), 5.51 (s, 2H), 3 .56-3.64 (m, 1H), 3.37-3.51 (m, 2H), 3.06 (dt, 7=2.60, 12.07 Hz, 1H), 2.78-2 .92 (m, 2H), 1.99 (br dd, 7=2.85, 13.23 Hz, 1H), 1.60-1.71 (m, 1H) -- - 97 500MHz d ₄ -MeOH 8.86 (s, 1H), 8.08 (dd, 7=2.08, 8.30 Hz, 1H), 7.37 (d, 7=7.79 Hz, 1H), 7.23 (d , 7=8.04 Hz, 1H), 7.07-7.13 (m, 2H), 7.01 (t, 7=7.53 Hz, 1H), 5.55 (s, 2H), 3 .68 (s, 2H), 3.49-3.61 (m, 6H), 2.15 (t, 7=6.88 Hz, 2H) - - 98 500MHz d ₄ -MeOH 8.83(d, 7=1.30Hz, 1H), 8.26(dd, 7=2.08, 8.04Hz, 1H), 7.80(d, 7=8.30Hz, 1H ), 7.51 (d, 7=8.04 Hz, 1H), 7.33-7.47 (m, 3H), 5.95 (d, 7=19.72 Hz, 1H), 5.80 (br d, 7=18.68 Hz, 1H), 4.17-4.37 (m, 3H), 3.97-4.10 (m, 2H), 3.80 (br t, 7=8 .95 Hz, 1H), 3.68-3.76 (m, 1H), 3.55 (dd, 7=1.95, 13.36 Hz, 1H), 3.32- V Chiralcel OD-H, 25% MeOH, peak 1

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3.46(m, 2H) 99 500MHz d ₄ -MeOH 8.83 (s, 1H), 8.27 (dd, 7=1.82, 8.30 Hz, 1H), 7.80 (d, 7=8.56 Hz, 1H), 7.51 (d , 7=8.04 Hz, 1H), 7.38-7.47 (m, 2H), 7.35 (br d, 7=8.04 Hz, 1H), 5.94 (d, 7=18 .68 Hz, 1H), 5.80 (br d, 7=18.68 Hz, 1H), 4.18-4.36 (m, 3H), 3.95-4.06 (m, 2H), 3.80 (br t, 7=8.30 Hz, 1H), 3.67-3.76 (m, 1H), 3.50-3.59 (m, 1H), 3.33-3.47 (m, 2H) IN Chiralcel OD-H, 25% MeOH, peak 2 100 500MHz d ₄ -MeOH 8.87(d, 7=1.30Hz, 1H), 8.11(dd, 7=2.08, 8.04Hz, 1H), 7.38(d, 7=7.79Hz, 1H ), 7.28 (d, 7=8.30 Hz, 1H), 7.07-7.16 (m, 2H), 6.997.06 (m, 1H), 5.63 (d, 7=18, 42 Hz, 1H), 5.48 (d, 7=18.42 Hz, 1H), 3.93 (dd, 7=2.72, 11.81 Hz, 1H), 3.64-3.75 ( m, 3H), 3.48-3.63 (m, 2H), 3.43 (dd, 7=8.95, 10.77 Hz, 1H), 2.84-3.00 (m, 3H) IN Chiralcel OD-H, 20% MeOH, peak 1 101 500MHz d ₄ -MeOH 8.87(d, 7=1.56Hz, 1H), 8.11(dd, 7=2.08, 8.30Hz, 1H), 7.38(d, 7=8.04Hz, 1H ), 7.28 (d, 7=8.30 Hz, 1H), 7.07-7.16 (m, 2H), 6.997.06 (m, 1H), 5.63 (d, 7=18, 42 Hz, 1H), 5.48 (d, 7=18.68 Hz, 1H), 3.93 (dd, 7=2.60, 11.94 Hz, 1H), 3.64-3.74 ( m, 3H), 3.47-3.62 (m, 2H), 3.43 (dd, 7=8.95, 10.77 Hz, 1H), 2.85-2.99 (m, 3H) V Chiralcel OD-H, 20% MeOH, peak 2 102 500MHz d ₄ -MeOH 8.79-8.88 (m, 1H), 8.12 (dd, 7=2.21, 8.17 Hz, 1H), 7.50 (d, 7=7.79 Hz, 1H), 7 .38 (d, 7=8.30 Hz, 1H), 7.06-7.21 (m, 3H), 5.48- 5.65 (m, 2H), 3.46 (d, 7=11.94 Hz, 1H), 3.35-3.42(m, 1H), 3.17-3.23(m, 1H), 3.033.12(m, 1H), 2.12(ddd, 7=4.41, 11.35 , 13.30Hz, 1H), 1.89-2.01(m, 1H), 1.70-1.80(m, 1H), 1.59-1.68(m, 1H) F Chiralpak AD-H, 60% MeOHc 0.2% DEA, peak 1

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103 500MHz d ₄ -MeOH 8.85(d, 7=1.56Hz, 1H), 8.13(dd, 7=2.08, 8.30Hz, 1H), 7.51(d, 7=7.79Hz, 1H ), 7.39 (d, 7=8.04 Hz, 1H), 7.08-7.22 (m, 3H), 5.515.66 (m, 2H), 3.47 (d, 7=12, 20 Hz, 1H), 3.37-3.43 (m, 1H), 3.21 (br d, 7=12.20 Hz, 1H), 3.04-3.11 (m, 1H), 2 .07-2.18 (m, 1H), 1.90-2.01 (m, 1H), 1.72-1.81 (m, 1H), 1.581.70 (m, 1H) F Chiralpak AD-H, 60% MeOHc 0.2% DEA, peak 2 104 500MHz d ₄ -MeOH 8.86(d, 7=1.56Hz, 1H), 8.12(dd, 7=2.08, 8.30Hz, 1H), 7.51(d, 7=7.78Hz, 1H ), 7.32 (d, 7=8.30 Hz, 1H), 7.06-7.23 (m, 3H), 5.485.62 (m, 2H), 3.54 (d, 7=10, 90 Hz, 1H), 3.37 (d, 7=10.90 Hz, 1H), 3.24-3.28 (m, 1H), 3.08-3.22 (m, 2H), 3, 04 (br d, 7=11.94 Hz, 1H), 1.79-1.90 (m, 1H), 1.66-1.77 (m, 1H), 1.61 (ddd, 7=4 .28, 9.02, 13.43 Hz, 1H), 1.44-1.54 (w ₅ 1H) IN Chiralcel OD-H, 25% iPrOH with 0.2% DEA, peak 1 105 500MHz d ₄ -MeOH 8.86(d, 7=1.30Hz, 1H), 8.12(dd, 7=2.08, 8.04Hz, 1H), 7.51(d, 7=7.78Hz, 1H ), 7.33 (d, 7=8.04 Hz, 1H), 7.07-7.22 (m, 3H), 5.515.62 (m, 2H), 3.54 (d, 7=11, 16 Hz, 1H), 3.37 (d, 7=11.16 Hz, 1H), 3.24-3.28 (m, 1H), 3.09-3.22 (m, 2H), 3, 01-3.08(m, 1H), 1.79-1.90(m, 1H), 1.67-1.77(m, 1H), 1.62(ddd, 7=4.41, 9 .02, 13.56 Hz, 1H), 1.46-1.56 (m, 1H) IN Chiralcel OD-H, 25% iPrOH with 0.2% DEA, peak 2 106 600MHz DMSO-d ₆ 8.94 (d, 7=1.48 Hz, 1H), 8.33 (dd, 7=2.10, 8.17 Hz, 1H), 7.58-7.63 (m, 2H), 7 .51 (d, 7=8.25 Hz, 1H), 7.42 (d, 7=8.21 Hz, 1H), 5.61-5.68 (m, 2H), 4.75-4, 83 (m, 1H), 4.684.73 (m, 1H), 3.28-3.32 (m, 3H), 3.24 (td, 7=4.03, 12.81 Hz, 1H), 3 .05-3.19 (m, 2H), 2.86-3.04 (m, 3H), 2.57-2.65 (m, 1H), 2.332.48 (m, 1H), 1.92 -2.01(m, 1H), 1.77-1.91(m, 1H) IN SFC: Chiralcel OD-H, 15% methanol

- 154043189

107 600MHz DMSO-d ₆ 9.00 (d, 7=1.32 Hz, 1H), 8.39 (dd, 7=2.10, 8.25 Hz, 1H), 7.84 (s, 1H), 7.58 (d , 7=8.17 Hz, 1H), 7.37-7.45 (m, 2H), 5.63-5.72 (m, 2H), 4.83-4.90 (m, 1H), 4.76-4.81 (m, 1H), 3.33-3.37 (m, 2H), 3.30 (td, 7=3.99, 12.65 Hz, 1H), 3.13- 3.25 (m, 2H), 2.95-3.11 (m, 2H), 2.01-2.09 (m, 1H), 1.87-2.00 (m, 1H) IN SFC: Chiralcel OD-H, 15% methanol 108 600MHz DMSO-d ₆ 8.94 (d, 7=1.40 Hz, 1H), 8.34 (dd, 7=2.14, 8.21 Hz, 1H), 7.62 (s, 1H), 7.63 (d , 7=6.89 Hz, 1H), 7.56 (d, 7=8.17 Hz, 1H), 7.44 (d, 7=8.47 Hz, 1H), 5.65-5.73 (m, 2H), 3.183.26 (m, 1H), 2.98-3.12 (m, 2H), 2.17-2.29 (m, 1H), 1.89-2.07 (m , 1H), 1.79 (brs, 2H) IN SFC: Chiralcel OD-H, 15% methanol 109 600MHz DMSO-d ₆ 8.94 (dd, 7=0.66, 2.06 Hz, 1H), 8.34 (dd, 7=2.14, 8.21 Hz, 1H), 7.80 (s, 1H), 7 .56 (d, 7=8.17Hz, 1H), 7.38 (dd, 7=1.21, 8.45Hz, 1H), 7.33 (d, 7=8.41Hz, 1H) , 5.58-5.69 (m, 2H), 3.37-3.44 (m, 1H), 3.20-3.30 (m, 1H), 3.07-3.18 (m, 1H), 2.99-3.06 (m, 1H), 2.212.31 (m, 1H), 1.96-2.11 (m, 2H), 1.92 (br s, 1H) V SFC: Chiralcel OD-H, 15% methanol 110 600MHz DMSO-d ₆ 8.94 (d, 7=1.48 Hz, 1H), 8.49 (br s, 3H), 8.36 (dd, 7=2.06, 8.21 Hz, 1H), 7.55 ( br d, 7=8.10 Hz, 1H), 7.33 (s, 1H), 7.10 (d, 7=8.25 Hz, 1H), 6.99 (br d, 7=8.17 Hz, 1H), 5.55-5.63 (m, 2H), 4.69-4.81 (m, 1H), 4.244.38 (m, 1H), 3.81 (br d, 7=12 .38 Hz, 1H), 3.61 (br s, 1H), 3.54 (br d, 7=12.69 Hz, 1H), 3.10-3.21 (m, 2H), 2.51 -2.54(m, 9H), 2.37(s, 3H), 2.21(brt, 7=9.81Hz, 1H), 1.821.90(m, 1H) V SFC: Phenomenex Lux Cellulose-2, 25% methanol 111 600MHz DMSO-d ₆ 8.40 (br s, 1H), 8.27 (dd, 7=2.06, 8.21 Hz, 1H), 7.47 (br d, 7=8.17 Hz, 1H), 6.94 -6.98 (m, 1H), 5.44-5.54 (m, 1H), 4.76 (dt, 7=4.94, 9.17 Hz, 1H), 3.90-4.72 (m, 3H), V SFC: Phenomenex Lux Cellulose-2,

-155043189

3.69 (br d, 7=12.61 Hz, 1H), 3.52 (br s, 1H), 3.42 (br d, 7=12.38 Hz, 1H), 2.98-3, 12 (m, 1H), 2.42-2.52 (m, 5H), 2.23 (s, 2H), 2.11 (brt, 7=9.81 Hz, 1H), 1.72-1 .81 (m, 1H) 25% methanol 112 600MHz DMSO-d ₆ 8.95 (dd, 7=0.70, 2.02 Hz, 1H), 8.31 (dd, 7=2.14, 8.21 Hz, 1H), 7.41 (s, 1H), 7 .41 (d, 7=6.67 Hz, 1H), 7.29 (s, 1H), 5.43-5.54 (m, 2H), 4.34-4.43 (m, 1H), 4.26-4.34(m, 1H), 3.25-3.38(m, 11H), 2.96-3.05(m, 1H), 2.85-2.91(m, 1H ), 2.76 (dd, 7=8.60, 12.50 Hz, 1H), 2.34 (s, 3H), 1.94-2.08 (m, 2H), 1.65-1, 83 (m, 1H) IN SFC: Phenomenex Lux Cellulose-2, 20% methanol FROM 600MHz DMSO-d ₆ 8.96 (s, 1H), 8.31 (dd, 7=2.14, 8.21 Hz, 1H), 7.38-7.53 (m, 2H), 7.15 (s, 1H) , 5.38-5.53(m, 2H), 4.25-4.43(m, 1H), 3.38-3.40(m, 1H), 3.29-3.34(m, 1H), 2.97-3.05 (m, 1H), 2.84-2.92 (m, 1H), 2.76 (dd, 7=8.56, 12.53 Hz, 1H), 2 .30 (s, 3H), 1.98-2.09 (m, 1H), 1.63-1.80 (m, 3H) IN SFC: Phenomenex Lux Cellulose-2, 20% methanol 114 600MHz DMSO-d ₆ 8.95 (s, 1H), 8.30 (dd, 7=2.14, 8.21 Hz, 1H), 7.37 (d, 7=8.33 Hz, 1H), 7.31 (d , 7=6.93Hz, 1H), 7.03(d, 7=9.89Hz, 1H), 5.44-5.52(m, 2H), 4.35-4.41(m, 1H), 4.26-4.34 (m, 1H), 3.19-3.33 (m, 1H), 2.93-3.02 (m, 1H), 2.782.93 (m, 1H) , 2.74 (dd, 7=8.64, 12.46 Hz, 1H), 2.25 (d, 7=1.48 Hz, 3H), 2.10-2.23 (m, 1H), 1.95-2.09(m, 2H), 1.66-1.83(m, 1H) V SFC: Phenomenex Lux Cellulose-2, 20% methanol 115 600MHz DMSO-d ₆ 8.92-8.98(m, 1H), 8.30(d, 7=7.92Hz, 1H), 7.31-7.44(m, 2H), 7.22(d, 7= 10.43 Hz, 1H), 7.03 (d, 7=7.01 Hz, 1H), 5.36-5.51 (m, 2H), 4.35-4.41 (m, 1H), 4.26-4.34 (m, 1H), 3.26-3.44 (m, 1H), 2.85-3.02 (m, 1H), 2.692.81 (m, 2H), 2, 23-2.27(m, 1H), 2.21(d, 7=1.56Hz, 3H), 1.92-2.08(m, 1H), 1.601.92(m, 1H) V SFC: Phenomenex Lux Cellulose-2, 20% methanol

- 156 043189

116 600MHz DMSO-d ₆ 8.98 (d, 7=1.63 Hz, 1H), 8.31 (dd, 7=2.14, 8.21 Hz, 1H), 7.44 (d, 7=7.63 Hz, 1H ), 7.38 (d, 7=8.25 Hz, 1H), 7.07-7.15 (m, 2H), 6.947.04 (m, 1H), 5.44-5.50 (m, 2H), 3.38-3.48(m, 1H), 3.23-3.32(m, 1H), 2.82-2.91(m, 1H), 2.52-2.62( m, 1H), 2.43-2.49 (m, 1H), 2.11 (s, 3H), 1.80-1.88 (m, 1H), 1.68 (td, 7=3, 67, 13.14 Hz, 1H), 1.50-1.61(m, 1H), 1.11-1.23(m, 1H) 8.96 (s, 1H), 8.34 (dd, 7=2.14, 8.21 Hz, 1H), 7.52 (d, 7=7.98 Hz, 2H), 7.27 (s , 1H), 7.157.20 (m, 1H), 7.12 (d, 7=7.93 Hz, 1H), 7.10 IN - 600MHz DMSO-d ₆ (s, 1H), 5.62 (d, 7=17.75 Hz, 1H), 5.55 (d, 117 7=17.75 Hz, 1H), 3.68 (br d, 7=11.83 Hz, 1H), 3.34 (br s, 1H), 3.19-3.28 (m, 2H), 3.01 — — (br t, 7=9.42 Hz, 1H), 2.51-2.61 (m, 3H), 1.98-2.06 (m, 1H), 1.83 (dt, 7=2, 88, 6.50 Hz, 1H), 1.53-1.67 (m, 2H) 8.94 (s, 1H), 8.33 (dd, 7=2.14, 8.21 Hz, 1H), 7.47 (dd, 7=2.18, 8.33 Hz, 2H), 7 .05-7.09 (m, 2H), 6.95 (d, 7=8.98 Hz, 1H), 5.51-5.58 SFCs: 118 600MHz (m, 2H), 4.47-4.56 (dt, 7=4.59, 8.68 Hz, R Chiralcel DMSO- _d6 1H), 3.43-3.57(m, 1H), 3.37-3.43(m, 1H), OD-H 15% 3.10-3.23(m, 1H), 2.96-3.03(m, 1H), 2.87 methanol (dd, 7=9.26, 12.61 Hz, 1H), 2.05-2.12 (m, 1H), 1.70-1.79 (m, 1H) 8.95 (s, 1H), 8.32 (dd, 7=2.14, 8.21 Hz, 1H), 7.45 (d, 7=8.33 Hz, 1H), 7.22-7.30 (m, 1H), 7.10-7.18 (m, 1H), 6.87 (dd, 7=2.34, 8.56 SFCs: 1 1 Q 600MHz Hz, 1H), 5.50-5.57 (m, 2H), 4.43 (dt, D Chiralcel DMSO- _d6 7=4.59, 8.25 Hz, 1H), 3.40-3.49 (m, 1H), OD-H, 15% 3.37-3.40 (m, 1H), 2.91-3.07 (m, 1H), 2.81 (dd, 7=8.80, 12.53 Hz, 1H), 2.57- 2.65 (m, 1H), 2.01-2.11 (m, 1H), 1.68-1.78 (m, 1H) methanol

- 157 043189

120 600MHz DMSO-d ₆ 8.95(d, 7=1.95Hz, 1H), 8.29(dd, 7=2.10, 8.25Hz, 1H), 7.33(d, 7=8.25Hz, 1H ), 6.96 (t, 7=8.02 Hz, 1H), 6.73 (d, 7=8.02 Hz, 1H), 6.67 (d, 7=8.08 Hz, 1H), 5.44-5.53 (m, 2H), 4.28-4.34 (m, 1H), 3.89 (s, 3H), 3.24-3.42 (m, 1H), 2, 85-3.01 (m, 2H), 2.75 (dd, 7=8.64, 12.46 Hz, 1H), 1.98-2.16 (m, 1H), 1.95 (br s , 1H), 1.69-1.86 (m, 1H) - - 121 600MHz DMSO-d ₆ 8.94 (s, 1H), 8.30 (dd, 7=1.95, 8.17 Hz, 1H), 7.43 (d, 7=8.25 Hz, 1H), 6.91-7 .03 (m, 3H), 5.48-5.57 (m, 2H), 4.86-4.78(m, 1H), 3.643.78 (m, 1H), 3.48-3.63 (m, 1H), 3.06-3.17 (m, 1H), 2.99 (br t, 7=11.44 Hz, 1H), 2.462.49 (m, 1H), 2.14-2 .23 (m, 1H), 1.82-1.91 (m, 1H) - - 122 600MHz DMSO-d ₆ 9.03 (d, 7=1.40 Hz, 1H), 8.71-8.78 (m, 1H), 8.28 (br s, 1H), 7.86 (br s, 1H), 7 .67 (s, 1H), 7.60 (d, 7=8.33 Hz, 1H), 7.42 (d, 7=8.47 Hz, 1H), 5.64-5.77 (m, 2H), 4.75-71(m, 1H), 3.30-3.31(m, 2H), 3.07-3.17(m, 1H), 2.863.02(m, 1H), 2 .28-2.45(m, 1H), 1.93-2.12(m, 1H), 1.78-1.93(m, 1H) IN SFC: Chiralpak AD-H, 25% methanol 123 600MHz DMSO-d ₆ 9.03 (d, 7=1.32 Hz, 1H), 8.75 (d, 7=1.32 Hz, 1H), 8.27 (s, 1H), 7.86 (br s, 1H) , 7.77 (s, 1H), 7.34-7.41 (m, 2H), 5.68 (d, 7=1.79 Hz, 2H), 4.77-4.72 (m, 1H ), 3.22-3.32 (m, 1H), 3.09-3.20 (m, 1H), 2.89-3.04 (m, 2H), 1.952.05 (m, 1H), 1.80-1.94 (m, 1H), 1.76 (brs, 1H) IN SFC: Chiralpak AD-H, 25% methanol 124 600MHz DMSO-d ₆ 8.92(s, 1H), 8.33(dd, 7=2.14, 8.21Hz, 1H), 7.70(s, 1H), 7.52(d, 7=8.47Hz , 1H), 7.49 (s, 1H), 5.60 (s, 2H), 4.35-4.35 (m, 1H), 3.38-3.51 (m, 1H), 2, 98-3.08 (m, 1H), 2.82.90 (m, 1H), 2.78 (dd, 7=8.64, 12.53 Hz, 1H), 2.00-2.09 (m, 1H), 1.77(brs, 1H), V SFC: Chiralpak AD-H, 25% methanol

-158043189

1.63-1.74 (m, 1H) 125 600MHz DMSO-d ₆ 8.94 (s, 1H), 8.33 (dd, 7=2.14, 8.21 Hz, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.55 (d, 7=8.35Hz, 1H), 5.54-5.63(m, 2H), 4.39-4.27(m, 1H), 3.37-3.46(m, 2H ), 2.98-3.09 (m, 1H), 2.82-2.91 (m, 1H), 2.78 (dd, 7=8.60, 12.57 Hz, 1H), 1, 98-2.09(m, 1H), 1.63-1.80(m, 1H) IN SFC: Chiralpak AD-H, 25% methanol 126 600MHz DMSO-d ₆ 8.93 (s, 1H), 8.34 (dd, 7=2.14, 8.21 Hz, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.55 (d, 7=8.25Hz, 1H), 5.63-5.71(m, 2H), 4.37-4.28(m, 1H), 3.36-3.51(m, 2H ), 3.04-3.11 (m, 1H), 2.79-2.88 (m, 2H), 2.00-2.08 (m, 1H), 1.621.78 (m, 1H) IN SFCs: Chiralcel O.J. H, 10% methanol 127 600MHz DMSO-d ₆ SNMR (600 MHz, DMSO-d ₆ ) δ 8.93 (d, 7=1.40 Hz, 1H), 8.34 (dd, 7=2.10, 8.17 Hz, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.57 (d, 7=8.17 Hz, 1H), 5.60-5.67 (m, 2H), 4.374.42-4, 29 (m, 1H), 3.36-3.45 (m, 1H), 3.143.29 (m, 1H), 3.00-3.09 (m, 1H), 2.77-2.89 ( m, 2H), 1.95-2.08 (m, 1H), 1.64-1.81 (m, 1H) V SFCs: Chiralcel O.J. H, 10% methanol 128 600MHz DMSO-d ₆ 8.90-8.99 (m, 1H), 8.26-8.35 (m, 1H), 7.527.44 (d, 7=7.66 Hz, 1H), 7.33 (d, 7= 8.30 Hz, 1H), 7.23-7.29(m, 1H), 7.00-7.19(m, 1H), 6.99-7.19(m, 1H), 5.76 -5.42 (m, 2H), 2.983.15 (m, 2H), 2.72-2.91 (m, 2H), 2.69-2.65 (s, 1H), 2.22-2 .39 (m, 1H), 1.71 (br d, 7=6.36 Hz, 1H), 1.69 (br d, 7=5.19 Hz, 1H), 1.42-1.62 ( m, 6H), 1.38(s, 1H). - - 129 600MHz DMSO-d ₆ 8.97 (s, 1H), 8.30 (dd, 7=2.14, 8.21 Hz, 1H), 7.45 (d, 7=7.79 Hz, 1H), 7.33 (d, 7=8.17 Hz, 1H), 7.18 (d, 7=7.79 Hz, 1H), 7. 00-7.14(m, V SFC: Phenomenex Lux

- 159043189

2H), 5.47-5.60 (m, 2H), 3.12-3.27 (m, 1H), 3.06 (br d, 7=11.99 Hz, 1H), 2.88- 3.01 (m, 2H), 2.56-2.64 (m, 1H), 2.51-2.56 (m, 1H), 1.64-1.73 (m, 2H), 1, 46-1.59(m, 1H), 1.211.41(m, 7H) Cellulose-2, 30% methanol 130 600MHz DMSO-d ₆ 8.97(d, 7=1.71Hz, 1H), 8.30(dd, 7=2.14, 8.21Hz, 1H), 7.45(d, 7=7.55Hz, 1H ), 7.33 (d, 7=8.17 Hz, 1H), 7.18 (d, 7=7.86 Hz, 1H), 7.02-7.12 (m, 2H), 5.47 -5.58 (m, 2H), 3.123.26 (m, 1H), 3.06 (br d, 7=12.07 Hz, 1H), 2.87-3.01 (m, 2H), 2 .56-2.63 (m, 1H), 2.52.55 (m, 1H), 1.63-1.73 (m, 2H), 1.46-1.58 (m, 1H), 1.21 -1.41(m, 7H) IN SFC: Phenomenex Lux Cellulose-2, 30% methanol 131 600MHz DMSO-d ₆ 8.96 (s, 1H), 8.29 (dd, 7=2.14, 8.21 Hz, 1H), 7.44 (d, 7=7.71 Hz, 1H), 7.35 (d , 7=8.25 Hz, 1H), 7.06-7.12 (m, 2H), 6.93-7.04 (m, 1H), 5.41-5.51 (m, 2H), 4.10 (br s, 1H), 3.75 (td, 7=2.88, 10.98 Hz, 1H), 3.69 (q, 7=3.58 Hz, 1H), 3.37- 3.49 (m, 1H), 3.01-3.21 (m, 2H), 2.80-2.94 (m, 2H), 2.43-2.49 (m, 1H), 1, 81 (br s, 1H), 1.67-1.79 (m, 1H) IN SFC: Phenomenex Lux Cellulose-2, 30% methanol 132 600MHz DMSO-d ₆ 8.96 (s, 1H), 8.29 (dd, 7=2.14, 8.21 Hz, 1H), 7.45 (d, 7=7.97 Hz, 1H), 7.37 (d , 7=8.25 Hz, 1H), 7.07-7.13 (m, 2H), 6.98-7.06 (m, 1H), 5.44-5.52 (m, 2H), 4.11 (br s, 1H), 3.80 (td, 7=2.86, 11.25 Hz, 1H), 3.74 (br d, 7=3.11 Hz, 1H), 3.44 -3.54 (m, 1H), 3.14-3.21 (m, 2H), 2.94-3.12 (m, 2H), 2.51-2.62 (m, 1H), 1 .83 (br s, 1H), 1.69-1.80 (m, 1H) V SFC: Phenomenex Lux Cellulose-2, 30% methanol 133 600MHz DMSO-d ₆ 9.04 (s, 1H), 8.70 (s, 1H), 7.85 (m, 1H), 7.52 (dd, 7=7.47, 10.98 Hz, 1H), 7.50 (br dd, 7=7.32, 10.35 Hz, 1H), 7.10-7.25(m, 1H), 5.57(s, 2H), 4.45-4.60(m, 1H), 3.623.70 (m, 1H), 3.36-3.46 (m, 1H), 2.97 (brt, 7=11.21 Hz, 1H), 2.75 (br dd, 7= 10.12 - -

- 160043189

12.30 Hz, 1H), 2.33-2.46 (m, 1H), 2.10-2.20 (m, 1H), 1.78-1.86 (m, 1H) 134 600MHz DMSO-d ₆ 9.03 (d, 7=1.37 Hz, 1H), 8.74-8.75 (dd, 7=1.37, 5.87 Hz, 1H), 8.25 (br d, 7=3 .97 Hz, 1H), 7.83 (br s, 1H), 7.5-7.68 (s, 1H), 7.60 (d, 7=8.32 Hz, 1H), 7.36- 7.44 (m, 2H), 5.72 (s, 1H), 5.68 (s, 1H), 4.36-4.45 (m, 1H), 3.38-3.54 (m, 2H), 3.02-3.13 (m, 1H), 2.802.95 (m, 2H), 1.99-2.16 (m, 1H), 1.67-1.78 (m, 1H) -- - 135 600MHz DMSO-d ₆ 8.98(d, 7=1.56Hz, 1H), 8.30(dd, 7=2.14, 8.21Hz, 1H), 7.44(d, 7=7.79Hz, 1H ), 7.33 (d, 7=8.25 Hz, 1H), 7.15 (d, 7=7.86 Hz, 1H), 7.10 (t, 7=7.76 Hz, 1H), 7.03 (t, 7=7.58 Hz, 1H), 5.54-5.60 (m, 1H), 5.44-5.52 (m, 1H), 3.15-3.27 ( m, 1H), 3.04-3.13 (m, 2H), 2.752.89 (m, 3H), 2.56-2.64 (m, 1H), 1.65-1.76 (m, 1H), 1.54-1.63 (m, 2H), 1.42-1.52 (m, 4H), 1.27-1.41 (m, 1H) V SFC: Phenomenex Lux Cellulose-2, 40% methanol 136 600MHz DMSO-d ₆ 8.98 (dd, 7=0.74, 2.06 Hz, 1H), 8.30 (dd, 7=2.14, 8.21 Hz, 1H), 7.44 (d, 7=7, 55Hz, 1H), 7.33(d, 7=8.33Hz, 1H), 7.15(d, 7=7.86Hz, 1H), 7.10(dt, 7=1.17, 7.59Hz, 1H), 7.00-7.06(m, 1H), 5.57(d, 7=17.91Hz, 1H), 5.48(d, 7=17.91Hz, 1H), 3.153.27 (m, 1H), 3.02-3.14 (m, 2H), 2.75-2.90 (m, 3H), 2.56-2.64 (m, 1H) , 1.65-1.76 (m, 1H), 1.54-1.63 (m, 2H), 1.42-1.52 (m, 4H), 1.27-1.40 (m, 1H) V SFC: Phenomenex Lux Cellulose-2, 40% methanol 137 600MHz DMSO-d ₆ 8.96(d, 7=1.48Hz, 1H), 8.29(dd, 7=2.14, 8.21Hz, 1H), 7.38(d, 7=8.17Hz, 1H ), 7.05 (s, 1H), 7.01 (d, 7=8.55 Hz, 1H), 6.67 (dd, 7=2.41, 8.72 Hz, 1H), 5.46 -5.55 (m, 2H), 3.73 (s, 1H), 3.08-3.24 (m, 2H), 2.97 (br dd, V SFCs: Chiralcel O.J. H, 15% methanol

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7=9.03, 11.29 Hz, 1H), 2.52-2.57 (m, 1H), 2.19-2.28 (m, 1H), 1.93-2.09 (m, 1H), 1.83(brs, 1H) 138 600MHz DMSO-d ₆ 8.96(d, 7=1.63Hz, 1H), 8.29(dd, 7=2.10, 8.17Hz, 1H), 7.39(d, 7=8.10Hz, 1H ), 7.36 (d, 7=8.52 Hz, 1H), 6.78 (s, 1H), 6.74 (d, 7=8.78 Hz, 1H), 5.53 (s, 2H ), 3.66-3.69 (m, 1H), 3.05-3.17 (m, 2H), 2.90-2.96 (m, 1H), 2.17-2.26 (m , 1H), 1.97-2.07 (m, 1H), 1.75 (br s, 1H) IN SFCs: Chiralcel O.J. H, 15% methanol 139 600MHz DMSO-d ₆ 8.95(d, 7=1.95Hz, 1H), 8.30-8.35(m, 1H), 7.60(s, 1H), 7.59(d, 7=10.87Hz , 1H), 7.50 (d, 7=8.17 Hz, 1H), 7.42 (dd, 7=1.32, 8.33 Hz, 1H), 5.56-5.63 (m, 2H), 3.49 (br dd, 7=3.23, 12.03 Hz, 2H), 2.87-2.94 (m, 1H), 2.57-2.69 (m, 1H), 2.42-2.48 (m, 1H), 2.11 (s, 3H), 1.81-1.87 (m, 1H), 1.64-1.71 (m, 1H), 1, 48-1.56(m, 1H), 1.15-1.28(m, 1H) IN SFC: Chiralcel OD-H, 15% methanol with 0.2% DEA 140 600MHz DMSO-d ₆ 8.95(d, 7=1.63Hz, 1H), 8.33(dd, 7=2.10, 8.25Hz, 1H), 7.75(s, 1H), 7.50(d , 7=8.25 Hz, 1H), 7.29-7.40 (m, 2H), 5.51-5.60 (m, 2H), 3.48 (br dd, 7=3.23, 12.03 Hz, 2H), 2.86-2.95 (m, 1H), 2.62 (dd, 7=9.03, 12.07 Hz, 1H), 2.43-2.48 (m , 1H), 2.09-2.13 (m, 3H), 1.81-1.88 (m, 1H), 1.69 (td, 7=3.79, 13.29 Hz, 1H), 1.51-1.59 (m, 1H), 1.16-1.28 (m, 1H) V SFC: Chiralcel OD-H, 15% methanol with 0.2% DEA 141 600MHz DMSO-d ₆ 8.97 (s, 1H), 8.28 (dd, 7=2.02, 8.17 Hz, 1H), 7.43 (d, 7=7.79 Hz, 1H), 7.32 (d , 7=8.25 Hz, 1H), 7.16 (d, 7=7.79 Hz, 1H), 7.09 (t, 7=7.24 Hz, 1H), 7.02 (t, 7 =7.28 Hz, 1H), 5.47-5.57 (m, 2H), 3.08-3.25 (m, 2H), 2.96 (br t, 7=8.95 Hz, 1H ), 2.77-2.89 (m, 2H), 1.73 (tdd, 7=4.41, 8.78, 13.23 Hz, 1H), 1.55 (td, 7=3.37 , 6.50 Hz, 2H), 1.29-1.48 (m, - -

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2H), 0.93(s, 1H) 142 500MHz DMSO-d ₆ 8.95 (s, 1H), 8.36 (br d, 7=8.19 Hz, 1H), 8.10 (br s, 3H), 7.56 (d, 7=8.19 Hz, 1H ), 7.15 (d, 7=8.81 Hz, 1H), 7.07 (s, 1H), 6.81 (br d, 7=8.91 Hz, 1H), 5.52-5, 65 (m, 2H), 3.77 (s, 3H), 3.58-3.75 (m, 1H), 3.34 (br d, 7=13.27 Hz, 2H), 3.21 ( br dd, 7=8.71, 12.13 Hz, 1H), 3.07 (br t, 7=9.23 Hz, 1H), 1.96 (br s, 1H), 1.83 (br s , 1H), 1.58 (brs, 2H) IN SFC: Chiralpak IC, 40% isopropane JI 143 500MHz DMSO-d ₆ 8.95 (s, 1H), 8.35 (d, 7=8.09 Hz, 1H), 8.02 (br s, 3H), 7.52 (d, 7=8.29 Hz, 1H) , 7.42 (d, 7=8.50 Hz, 1H), 6.83-6.89 (m, 2H), 5.515.66 (m, 2H), 3.48-3.67 (m, 1H), 3.34 (br s, 1H), 3.26 (br d, 7=13.48 Hz, 1H), 3.15 (br dd, 7=8 .34, 12.39 Hz, 1H), 2.94-3.07 (m, 1H), 1.94 (br s, 1H), 1.81 (br s, 1H), 1.56 (br s , 2H) IN SFC: Chiralpak IC, 40% isopropane JI 144 500MHz DMSO-d ₆ 8.91 (d, 7=1.45 Hz, 1H), 8.41 (brs, 3H), 8.33 (dd, 7=2.07, 8.19 Hz, 1H), 7.55 (d, 7=8.29 Hz, 1H), 7.15-7.21 (m, 2H), 5 .40- 5.64(2, 2H), 4.72-4.84(dt, 7=5.03, 9.36Hz, 1H), 3.69-3.78(m, 1H), 3.51( br s, 1H), 3.43 (br d, 7=12.54 Hz, 1H), 2.94-3.12 (m, 2H), 2.12-2.22 (m, 1H), 1 .73-1.88 (m, 1H) - - 145 500MHz DMSO-d ₆ 8.94 (d, 7=1.55 Hz, 1H), 8.75 (br s, 3H), 8.37 (dd, 7=2.07, 8.19 Hz, 1H), 7.66 ( br d, 7=7.15 Hz, 1H), 7.21 (br d, 7=8.71 Hz, 1H), 7.08 (d, 7=2.28 Hz, 1H), 6.84 ( br d, 7=8.40 Hz, 1H), 5.60-5.76 (m, 2H), 4.86-4.98 (m, 1H), 3.95 (br d, 7=6, 95 Hz, 1H), 3.59-3.79 (m, 1H), 3.28-3.52 (m, 1H), 3.00-3.27 (m, 2H), 2.19-2 .31 (m, 1H), 1.79-1.91 (m, 1H) V SFC: Chiralpak AD-H, 20% methanol

-163043189

146 500MHz DMSO-d ₆ 8.94 (d, 7=1.45 Hz, 1H), 8.74 (br s, 3H), 8.35 (dd, 7=2.07, 8.19 Hz, 1H), 7.60 ( br d, 7=7.98 Hz, 1H), 7.40-7.47 (m, 7=8.71 Hz, 1H), 6.93 (br s, 1H), 6.81-6.90 (m, 7=8.60 Hz, 1H), 5.59-5.76 (m, 2H), 4.81-5.01 (m, 1H), 3.86 (br d, 7=11, 30 Hz, 1H), 3.59-3.79 (m, 1H), 3.33-3.55 (m, 1H), 3.05-3.32 (m, 2H), 2.17-2 .33 (m, 1H), 1.70-1.88 (m, 1H) IN SFC: Chiralpak AD-H, 20% methanol 147 500MHz CDC1 ₃ 8.87 (s, 2H), 8.05 (d, 7=8.19 Hz, 2H), 7.65 (d, 7=8.19 Hz, 2H), 5.84 (q, 7=6 .57 Hz, 2H), 3.08 (s, 6H), 1.78 (d, 7=6.63 Hz, 6H), 1.62 (br s, 3H), 1.44 (br s, 2H ) IN SFC: Chiralcel OD-H, 20% methanol 148 500MHz DMSO-d ₆ 8.97 (s, 1H), 8.59 (br s, 3H), 8.33 (dd, 7=1.95, 8.17 Hz, 1H), 7.48 (br d, 7=7, 91 Hz, 1H), 7.30-7.44 (m, 1H), 7.04-7.11 (m, 2H), 6.73 (d, 7=9.04 Hz, 1H), 5, 50-5.63 (m, 2H), 5.10-5.20 (br s, 1H), 3.70-3.80 (m, 1H), 3.44-3.65 (m, 2H) , 3.10-3.29(m, 2H), 1.932.16(m, 2H). V SFC: Chiralcel OD-H, 20% methanol 149 500MHz DMSO-d ₆ 8.92 (s, 2H), 7.59 (d, 7=8.89 Hz, 1H), 7.52 (d, 7=9.41 Hz, 1H), 5.60 (d, 7=2 .02 Hz, 2H), 4.73-4.84 (m, 1H), 3.37-3.49 (m, 1H), 3.113.17 (m, 1H), 2.97-3.08 ( m, 2H), 2.51-2.55(m, 1H), 1.93-2.03(m, 1H), 1.78-1.91(m, 1H). - - 150 500MHz DMSO-d ₆ 8.91 (s, 2H), 7.55-7.63 (m, 2H), 5.59-5.69 (m, 2H), 3.87-4.10 (m, 1H), 3.47 (br d, 7=13.23 Hz, 1H), 3.32-3.42 (m, 1H), 3.12-3.20 (m, 2H), 2.36 (br d, 7=1.69 Hz, 1H), 2.26 (br s, 1H). V 0.1% NH4OH in ACN and water as mobile phase 151 500MHz DMSO-d ₆ 8.89 (s, 2H), 7.52-7.64 (m, 2H), 5.55-5.74 (m, 2H), 3.83-3.95 (m, 1H), 3. 32-3.50 (m, 2H), 3.10-3.22 (m, 2H), 2.36-2.44 (m, 1H), 2.11-2.33 (m, 1H) V 0.1% NH4OH in ACN and water as

- 164 043189

152 500MHz MeOD 8.82-8.86 (m, 1H), 8.11-8.20 (m, 1H), 7.377.46 (m, 2H), 7.21 (d, J=l.82 Hz, 1H) , 7.16 (dd, J=l.82, 8.30 Hz, 1H), 5.49 (s, 2H), 3.58-3.63 (m, 1H), 3.42-3.53 (m, 2H), 3.05 (dt, J=2.34, 12.07 Hz, 1H), 2.80-2.91 (m, 2H), 1.95-2.02 (m, 1H ), 1.59-1.70 (m, 1H) 8.84 (br s, 1H), 8.07-8.20 (m, 1H), 7.37- I mobile phase YMC Amyose SA, methanol- THF (70:30) 40%; peak 1 YMC 500MHz MeOD 7.50 (m, 2H), 7.06-7.27 (m, 2H), 5.52 (br s, amyose SA, 153 2H), 3.93 (br s, 1H), 3.34-3.43 (m, 2H), 3.01-3.16 (m, 2H), 1.85 (br d, J=3, 37 Hz I methanol- THF (70:30) 2H) 40%; peak 1 7.77-7.83 (m, 3=7.98 Hz, 2H), 7.48 (d, 3=7.67 Hz, 1H), 7.29-7.36 (m, 3=7, 98 Hz 154 400MHz d ₆ -DMSO 2H), 7.03-7.19 (m, 3H), 5.47 (s, 2H), 3.353.41 (m, 1H), 3.26-3.30 (m, 1H), 3.11 -3.24 (m, 2H), 2.94-3.05 (m, 1H), 2.19-2.34 (m, 1H), 2.01-2.16 (m, 1H), 1 .76 (brs, 2H) 8.54 (br d, 3=3.01 Hz, 2H), 7.86 (d, 3=8.29 Hz, 2H), 7.60 (d, 3=7.52 Hz, 1H), 7 .44-7.53 — — 155 400MHz d ₆ -DMSO (m, 3=8.19 Hz, 2H), 7.23-7.39 (m, 3H), 5.66 (br d, 3=9.95 Hz, 2H), 4.04 (br d, 3=9.95Hz, 1H), 3.72-3.80(m, 1H), 3.57-3.64(m, 1H), 3.31-3.53(m, 2H), 3 .01-3.29 (m, 2H), 1.96- - - 2.08 (m, 1H), 1.47-1.64 (m, 1H) 7.79-7.84 (m, 3=8.41 Hz, 2H), 7.26-7.32 (m, 156 600MHz DMSO-d ₆ 3=8.41Hz, 2H), 7.18(dd, 3=2.18, 9.26Hz, 1H), 6.91(t, 3=10.35Hz, 1H), 5.43( s, 2H), 4.39-4.38 (m, 1H), 3.39-3.51 (m, 1H), 3.363.14-3.28 (m, 1H), 3.04-3, 13 (m, 1H), 2.923.03 (m, 1H), 2.84 (dd, 3=8.60, 12.65 Hz, 1H), 1.94-2.13 (m, 1H), 1 .74-1.91 (m, 1H) V SFC: Chiralcel OD-H, 15% methanol

- 165 043189

157 600MHz DMSO-d ₆ δ 7.79-7.84 (m, 2H), 7.28-7.33 (m, 7=8.49 Hz, 2H), 7.08 (dd, 7=2.22, 8.84 Hz , 1H), 6.99 (dt, 7=2.18, 10.59 Hz, 1H), 5.41-5.48 (m, 2H), 4.28-4.36 (m, 1H), 3.37-3.43 (br, 1H), 2.99-3.06 (m, 1H), 2.93 (tdd, 7=4.16, 7.88, 14.31 Hz, 1H), 2.79 (dd, 7=8.60, 12.50 Hz, 1H), 2.01-2.13 (m, 1H), 1.66-1.80 (br, 1H) IN SFCs: Chiralcel O.J. N, 15% methanol 158 600MHz DMSO-d ₆ 7.81-7.84 (t, 7=8.25 Hz, 2H), 7.78 (s, 1H), 7.43-7.58 (t, 2H), 7.28-7.33 ( t, 2H), 5.51 (s, 2H), 4.39-4.36 (t, 1H), 3.49-3.54 (t, 1H), 3.40-3.48 (t, 1H), 3.03-3.17 (t, 1H), 2.73-2.94 (t, 1H), 1.93-2.11 (t, 1H), 1.82 (br s, 1H ), 1.63-1.79 (t, 1H), IN SFC: Chiralpak AD-H, 25% methanol 159 600MHz DMSO-d ₆ 7.94 (s, 1H), 7.78-7.84 (t, 7=8.25 Hz, 2H), 7.47 (dd, 7=1.01, 8.25 Hz, 1H), 7 .36 (d, 7=8.33 Hz, 1H), 7.26-7.32 (t, 7=8.17 Hz, 2H), 5.47-5.56 (t, 2H), 4, 42-4.34 (dt, 7=4.32, 8.19 Hz, 1H), 3.44-3.52 (t, 1H), 3.38-3.43 (t, 1H), 3, 15-3.28 (t, 1H), 3.043.14 (t, 1H), 2.80-2.97 (t, 2H), 2.03-2.12 (t, 1H), 1.70- 1.88 (t, 1H) V SFC: Chiralpak AD-H, 25% methanol 160 600MHz DMSO-d ₆ 7.76-7.85 (t, 3H), 7.46-7.65 (t, 2H), 7.297.38 (t, 2H), 5.54 (s, 2H), 3.85-4, 05 (t, 1H), 3.35-3.46 (t, 1H), 3.21-3.35 (t, 1H), 3.03-3.20 (t, 1H), 2.54- 2.79 (t, 1H), 2.182.32 (t, 1H), 1.98-2.14 (t, 1H), V SFC: Chiralpak AD-H, 25% methanol 161 600MHz DMSO-d ₆ 7.96 (d, 7=1.17 Hz, 1H), 7.81 (d, 7=8.43 Hz, 2H), 7.48 (dd, 7=1.49, 8.24 Hz, 1H ), 7.297.38 (t, 3H), 5.48-5.57 (t, 2H), 3.34-3.47 (t, 1H), 3.20-3.30 (t, 1H), 3.10-3.19 (t, 1H), 2.96-3.09 (t, 1H), 2.17-2.32 (t, 1H), 1.99-2.15 (t, 1H ), 1.79 (br d, 7=19.33 Hz, 1H) V SFC: Chiralpak AD-H, 25% methanol

- 166 043189

162 400MHz d ₆ -DMSO 7.80 (d, 7=8.29 Hz, 2H), 7.43 (d, 7=7.46 Hz, 1H), 7.30 (d, 7=8.29 Hz, 2H), 7. 15 (d, 7=7.88 Hz, 1H), 6.98-7.11 (m, 2H), 5.39 (s, 2H), 3.57 (s, 1H), 3.38 (br dd, 7=3.42, 11.82 Hz, 1H), 3.20-3.28 (m, 1H), 2.78-2.91 (m, 2H), 2.63 (dd, 7= 9.12, 11.82 Hz, 1H), 2.082.28 (m, 1H), 1.78-1.87 (m, 1H), 1.65-1.75 (m, 1H), 1.49 -1.63(m, 1H) - - 163 500MHz d ₆ -DMSO 7.81 (d, 7=8.30 Hz, 2H), 7.45 (d, 7=7.53 Hz, 1H), 7.32 (d, 7=8.30 Hz, 2H), 7. 07-7.18 (m, 2H), 6.98-7.07 (m, 1H), 5.47 (s, 2H), 3.383.48 (m, 1H), 3.05-3.17 ( m, 2H), 2.79-2.93(m, 1H), 1.83(brs, 1H), 1.60-1.74(m, 1H), 1.41-1.54(m , 1H), 0.94 (d, 7=6.75 Hz, 3H) - - 164 600MHz d ₆ -DMSO 7.81 (d, 7=8.10 Hz, 2H), 7.29 (d, 7=7.78 Hz, 1H), 7.25 (d, 7=8.10 Hz, 2H), 7. 14 (d, 7=7.79 Hz, 1H), 7.03 (t, 7=7.63 Hz, 1H), 6.93 (t, 7=7.63 Hz, 1H), 5.51 ( s, 2H), 3.513.59 (m, 2H), 3.42 (d, 7=9.65 Hz, 1H), 3.18 (s, 1H), 3.14 (d, 7=9.65 Hz, 1H), 2.43 (d, 7=4.36 Hz, 1H), 1.77-1.85 (m, 1H), 1.491.56 (m, 1H), 0.96 (s, 3H ) - - 165 600MHz d ₆ -DMSO 7.82 (d, 7=8.10 Hz, 2H), 7.21-7.37 (m, 8H), 7.17 (d, 7=7.79 Hz, 1H), 7.04-7 .08 (m, 1H), 6.95 (t, 7=7.47 Hz, 1H), 5.49-5.58 (m, 2H), 3.94 (dd, 7=7.79, 9 .65 Hz, 1H), 3.73 (dd, 7=6.85, 9.34 Hz, 1H), 3.66 (t, 7=9.19 Hz, 1H), 3.42 (q, 7 =7.16Hz, 1H), 3.18(d, 7=4.67Hz, 1H), 3.06(q, 7=7.79Hz, 1H), 1.72(brs, 2H) -- - 166 600MHz d ₆ -DMSO 7.82 (d, 7=8.10 Hz, 2H), 7.25-7.32 (m, 3H), 7.11 (d, 7=8.10 Hz, 1H), 7.03 (t , 7=7.47 Hz, 1H), 6.92 (t, 7=7.63 Hz, 1H), 5.50 (s, 2H), 3.57-3.66 (m, 2H), 3 .44-3.51 (m, 2H), 3.14 (dd, 7=4.83, 9.50 Hz, 1H), 1.95 (qd, 7=6.40, - -

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12.26 Hz, 1H), 1.61 (qd, 7=6.34, 12.42 Hz, 1H) 167 400MHz d ₆ -DMSO 7.80 (d, 7=8.29 Hz, 2H), 7.43 (d, 7=7.46 Hz, 1H), 7.30 (d, 7=8.29 Hz, 2H), 7. 15 (d, 7=7.88 Hz, 1H), 6.98-7.11 (m, 2H), 5.39 (s, 2H), 3.57 (s, 1H), 3.38 (br dd, 7=3.42, 11.82 Hz, 1H), 3.20-3.28 (m, 1H), 2.78-2.91 (m, 2H), 2.63 (dd, 7= 9.12, 11.82 Hz, 1H), 2.082.28 (m, 1H), 1.78-1.87 (m, 1H), 1.65-1.75 (m, 1H), 1.49 -1.63(m, 1H) -- - 168 500MHz d ₆ -DMSO Mixture of diastereomers: 7.80 (br d, J=7.79 Hz, 2H), 7.27 (br dd, J=7.91, 17.52 Hz, 3H), 7.13 (br d, J= 8.04 Hz, 1H), 7.02 (br t, J=8.04Hz, 1H), 6.93(br d, J=7.53Hz, 1H), 5.45-5.57(m, 2H), 3.56-3.79(m, 1H), 3.093.19 (m, 2H), 1.92-2.05 (m, 1H), 1.71-1.90 (m, 2H), 1.15-1.66 (m, 7H) - - 169 600MHz DMSO-d ₆ Mixture of diastereomers: 1.20-1.38 (m, 2 H), 1.56-1.71 (m, 2 H), 1.88-2.07 (m, 1 H), 2.07-2 .24 (m, 1 H), 2.52-2.59 (m, 1 H), 2.62-2.72 (m, 1 H), 2.87 (q, J=5.45 Hz, 1 H), 3.06 (br d, J=10.12 Hz, 1 H), 3.12-3.21 (m, 4H), 3.23-3.31 (m, 2 H), 3 .31-3.42 (m, 3 H), 3.43-3.56 (m, 1 H), 3.61 (dd, J=10.35, 4.59 Hz, 1 H), 5, 47-5.55 (m, 2 H), 6.92-7.01 (m, 1 H), 7.06 (t, J=7.47 Hz, 1 H), 7.11-7.19 (m, 1 H), 7.22-7.31 (m, 2 H), 7.37 (d, J=7.79Hz, 1H), 7.80(d, J=7.75Hz, 2H) -- - 170 400MHz MeOD 8.45 (br s, 3H), 7.83 (d, 7=8.29 Hz, 2H), 7.49-7.58 (m, 1H), 7.36 (d, 7=8.09 Hz, 2H), 7.07-7.25(m, 3H), 5.49(s, 2H), 4.71-4.91(m, 1H), 3.75-3.84(m, 1H), 3.61-3.73(m, 1H), 3.36-3.48(m, 1H), 2.95-3.22(m, 2H), 2.13-2.25( m, 1H), 1.72-1.95 (m, 1H) - -

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400ΜΓ c 8.34 (br d, 4=1.04 Hz, 3H), 7.82 (d, 7=8.29 Hz, 2H), 7.46-7.56 (m, 1H), 7.34 ( d,7=8.29 Hz, 2H), 7.07-7.24 (m, ZN), 5.48 (s, 2H), 171 MeOD 5.03-5.21(m, 1H), 3.76-3.87(m, 1H), 3.523.61(m, 1H), 3.31-3.42(m, 1H), 3, 07-3.28 (m, 2H), 1.89-2.16 (m, 2H) 8.37 (br s, 3H), 7.83 (d, 7=8.29 Hz, 2H), 7.48-7.56 (m, 1H), 7.35 (d, 7=8.29 Hz, 2H), 172 400MHz MeOD 7.08-7.23(m, 3H), 5.48(s, 2H), 5.01-5.22(m, 1H), 3.74-3.91(m, 1H), 3, 57 (br dd, 7=4.04, 12.75 Hz, 1H), 3.40 (br d, 7=11.20 Hz, 1H), 3.08-3.27 (m, 2H), 1 .92-2.18 (m, - - 2H) 7.75-7.84 (m, 2H), 7.39-7.49 (m, 1H), 7.31 (d, 7=8.50 Hz, 2H), 7.15-7.21 ( m, 1H), 7.11 173 400MHz MeOD (dt, 7=1.35, 7.52Hz, 1H), 7.02-7.07(m, 1H), 5.44(s, 2H), 4.26-4.48(m, 1H ), 3.333.44 (m, 2H), 2.90-3.09 (m, 2H), 2.80 (dd, 7=8.71, 12.44 Hz, 1H), 2.00-2, 16 (m, 1H), - - 1.70-1.87 (m, 2H) 7.75-7.83(m, 2H), 7.52-7.58(m, 1H), 7.33- Phenomenex 174 400MHz MeOD 7.47 (m, 5H), 5.68-5.89 (m, 2H), 4.00-4.23 (m, 4H), 3.42-3.65 (m, 2H), 2, 48-2.64(m, 1H), 2.24-2.47(m, 1H) IN Cellulose-2, 25% MeOH, peak 1 7.76-7.82(m, 2H), 7.52-7.57(m, 1H), 7.32- Phenomenex Lux Cellulose-2, 25% MeOH, peak 2 175 400MHz MeOD 7.46 (m, 5H), 5.68-5.88 (m, 2H), 4.01-4.17 (m, 4H), 3.44-3.65 (m, 2H), 2, 50-2.63(m, 1H), 2.26-2.47(m, 1H) IN 7.75-7.82(m, 2H), 7.50-7.55(m, 1H), 7.39- Chiralpak 400MHz MeOD 7.46 (m, 3H), 7.33-7.37 (m, 2H), 5.65-5.86 AD-H, 30% 176 (m, 2H), 4.08 (dt, 4=7.05, 9.74 Hz, 1H), 3.91-4.01 (m, 2H), 3.78 (dd, 4=1.14 , 10.26 V MeOHc 0.2% DEA Hz, 1H), 3.22 (d, 4=2.28 Hz, 2H), 2.08-2.28 peak 1

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(m, 2H) 177 400MHz MeOD 7.74-7.83 (m, 2H), 7.50-7.55 (m, 1H), 7.387.48 (m, 3H), 7.31-7.38 (m, 2H), 5, 66-5.86 (m, 2H), 4.08 (dt, 7=6.95, 9.80 Hz, 1H), 3.89-4.01 (m, 2H), 3.79 (dd, 7=1.14, 10.26Hz, 1H), 3.23(d, 7=2.70Hz, 2H), 2.11-2.33(m, 2H) IN Chiralpak AD-H, 30% MeOHc 0.2% DEA, peak 2 178 400MHz MeOD 7.66-7.74 (m, 2H), 7.36-7.44 (m, 1H), 7.29 (d, J=8.71 Hz, 2H), 7.00-7.16 ( m, 3H), 5.485.55 (m, 2H), 3.68 (dd, J=7.15, 9.64Hz, 1H), 3.59 (dd, J=6.12, 7.98Hz , 2H), 2.70 (d, J=7.26 Hz, 2H), 2.31-2.43 (m, 1H), 2.12 (dd, J=6.01, 12.23 Hz, 1H), 1.70 (dd, J=8.29, 12.44 Hz, 1H), 1.25-1.34 (m, 1H) - - 179 400MHz MeOD 7.70 (d, 7=8.50 Hz, 2H), 7.36-7.43 (m, 1H), 7.29 (d, 7=8.71 Hz, 2H), 6.99-7 .17 (m, 3H), 5.46-5.59 (m, 2H), 3.68 (dd, 7=7.26, 9.54 Hz, 1H), 3.54-3.64 (m , 2H), 2.69 (d, 7=7.26 Hz, 2H), 2.31-2.43 (m, 1H), 2.12 (d, 7=6.01 Hz, 1H), 1 .61-1.78 (m, 1H) - - 180 400MHz d ₆ -DMSO 8.39 (br s, 3H), 7.87 (d, J=8.29 Hz, 2H), 7.53-7.62 (m, 1H), 7.50 (d, J=8.29 Hz, 2H), 7.27-7.36(m, 1H), 7.22-7.26(m, 2H), 5.535.75(m, 2H), 3.86-4.00(m, 1H), 3.41-3.65 (m, 3H), 3.28-3.36 (m, 1H), 3.00-3.17 (m, 2H), 1.89-2.09 ( m, 2H), 1.51 (br dd, J=3.01, 12.96Hz, 1H), 1.00 (d, J=6.63Hz, 3H) - - 181 400MHz d ₆ -DMSO 8.12-8.25(m, 3H), 7.83(d, J=8.29Hz, 2H), 7.48-7.56(m, 1H), 7.35-7.40( m, 2H), 7.107.26 (m, 3H), 5.49 (br d, J=l.66 Hz, 2H), 3.74-3.87 (m, 1H), 3.39 (br d , J=12.65 Hz, 1H), 2.92-3.13 (m, 3H), 1.64-1.82 (m, 2H), 1.32-1.47 (m, 1H), 1.04 (d, J=6.22Hz, 3H) - -

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182 400MHz d ₆ -DMSO 8.12 (br d, 1=1.24 Hz, 3H), 7.83 (d, J=8.50 Hz, 2H), 7.48-7.58 (m, 1H), 7.31- 7.40 (m, 2H), 7.17-7.25 (m, 2H), 7.07-7.17 (m, 1H), 5.47 (d, 1=1.66 Hz, 2H) , 3.79 (br d, J=9.74 Hz, 1H), 3.38 (br d, 1=12.85 Hz, 1H), 2.893.18 (m, 3H), 1.58-1, 85 (m, 2H), 1.40 (br d, 1=11.40 Hz, 1H), 1.04 (d, 1=6.22 Hz, 3H) - - 183 400MHz MeOD 7.66-7.75 (m, 2H), 7.39-7.47 (m, 1H), 7.27 (d, 1=8.50 Hz, 2H), 7.03-7.20 ( m, 3H), 5.445.51 (m, 2H), 3.76 (d, 1=9.33 Hz, 1H), 3.523.69 (m, 3H), 2.90-3.00 (m, 1H ), 2.80 (d, 1=13.48 Hz, 1H), 1.49-1.58 (m, 1H), 0.840.95 (m, 1H), 0.69-0.79 (m, 1H), 0.53 (t, 1=4.56 Hz, 1H) F Chiralpak AD-H, 20% MeOHc 0.2% DEA, peak 1 184 400MHz MeOD 7.65-7.75 (m, 2H), 7.37-7.45 (m, 1H), 7.27 (d, 1=8.29 Hz, 2H), 7.00-7.19 ( m, 3H), 5.48 (s, 2H), 3.76 (d, 1=9.33 Hz, 1H), 3.51-3.67 (m, 3H), 2.94 (br d, 1=13.48Hz, 1H), 2.81(s, 1H), 1.53(td, 1=3.81, 7.93Hz, 1H), 0.74(dd, 1=5.18 , 7.88 Hz, 1H), 0.52 (t, 1=4.35 Hz, 1H) F Chiralpak AD-H, 20% MeOHc 0.2% DEA, peak 2 185 400MHz MeOD 7.70 (d, 1=8.50 Hz, 2H), 7.38-7.44 (m, 1H), 7.31 (d, 1=8.29 Hz, 2H), 6.82 (dd , 1=2.28, 8.71 Hz, 1H), 6.71 (d, 1=2.28 Hz, 1H), 5.40 (s, 2H), 3.38-3.46 (m, 1H), 3.21 (td, 1=4.17, 11.97 Hz, 1H), 2.88-2.99 (m, 2H), 2.79 (dd, 1=8.91, 11, 61 Hz, 1H), 1.90-2.01(m, 1H), 1.76-1.87(m, 1H), 1.60-1.73(m, 1H), 1.281.40(m , 1H) F Chiralpak IC, 45% IPA with 0.2% DEA, peak 1 186 400MHz MeOD 7.69 (d, 1=8.29 Hz, 2H), 7.27-7.34 (m, 2H), 7.07 (d, 1=2.49 Hz, 1H), 7.00 (d , 1=8.71Hz, 1H), 6.75(dd, 1=2.49, 8.71Hz, 1H), 5.37(s, 2H), 3.42-3.50(m, 1H), 3.26 (br d, 1=12.23 Hz, 1H), 2.89-3.02 (m, 2H), 2.81 (dd, 1=8.91, 11.61 Hz, 1H), 1.93-2.01 (m, 1H), F Chiralpak IC, 45% IPA with 0.2% DEA, peak 2

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1.76-1.86 (m, 1H), 1.59-1.75 (m, 1H), 1.28- 1.41(m, 1H) 442 500MHz d ₄ -MeOH 9.05-9.18 (m, 2H), 7.39-7.56 (m, 1H), 6.867.12 (m, 2H), 5.51-5.68 (m, 2H), 4, 40-4.67(m, 1H), 3.60-3.71(m, 1H), 3.46-3.56(m, 1H), 3.28(dd, 1=4.25, 8 .40 Hz, 1H), 3.073.16 (m, 1H), 3.02 (dd, J=9.43, 12.34 Hz, 1H), 2.17-2.28 (m, 1H), 1 .83-1.98 (m, 1H) IN Chiralpak OD-H 15% IP A peak 1 443 500MHz d ₄ -MeOH 9.06-9.17 (m, 2H), 7.12-7.23 (m, 2H), 6.846.93 (m, 1H), 5.57-5.67 (m, 2H), 4, 36-4.57 (m, 1H), 3.58-3.69 (m, 1H), 3.48-3.55 (m, 1H), 3.09-3.19 (m, 2H), 2.98 (dd, J=8.82, 12.46 Hz, 1H), 2.18-2.27 (m, 1H), 1.81-1.96 (m, 1H) IN Chiralpak OD-H 15% IP A, peak 2 444 500MHz d ₄ -MeOH 8.47 (s, 2H), 7.39-7.51 (m, 1H), 7.00 (dd, 1=2.34, 8.82 Hz, 1H), 6.95 (ddd, J= 2.47, 8.76, 9.80 Hz, 1H), 5.36-5.51 (m, 2H), 4.604.80 (m, 1H), 3.89-3.99 (m, 3H) , 3.77-3.89 (m, 1H), 3.61-3.71 (m, 1H), 3.57 (br dd, 1=4.28, 8.95 Hz, 1H), 3, 07-3.20(m, 2H), 2.20-2.36(m, 1H), 1.91-2.06(m, 1H) V Chiralpak OD-H, 15% MeOH, peak 1 445 500MHz d ₄ -MeOH 7.37-7.42(m, 1H), 6.71-6.87(m, 2H), 5.065.16(m, 2H), 4.47-4.61(m, 1H), 4, 14-4.29 (m, 2H), 3.77-3.85 (m, 3H), 3.48-3.55 (m, 1H), 3.02-3.09 (m, 1H), 2.94-3.00 (m, 1H), 2.17-2.25 (m, 1H), 1.91-2.01 (m, 1H) V Chiralpak IC, 20% MeOH, peak 1 446 500MHz d ₄ -MeOH 8.39-8.49 (m, 2H), 7.10-7.24 (m, 2H), 6.776.93 (m, 1H), 5.34-5.49 (m, 2H), 4, 35-4.57 (m, 1H), 3.70 (dtd, J=l.82, 4.17, 12.42 Hz, 1H), 3.51-3.60 (m, 1H), 3, 13-3.23 (m, 2H), 3.01 (dd, J=8.82, 12.46 Hz, 1H), 2.14-2.28 (m, 1H), 1.78-1, 99(m, 1H) V Chiralpak OD-H, 15% MeOH, peak 2 447 500MHz d ₄ -MeOH 7.26-7.43 (m, 2H), 5.07-5.23 (m, 2H), 4.424.59 (m, 1H), 4.12-4.24 (m, 1H), 3, 61-3.70 - -

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(m, 1H), 3.44-3.56 (m, 1H), 3.19-3.27 (m, 1H), 2.99-3.11 (m, 1H), 2.12-2 .27 (m, 1H), 1.86-1.99 (m, 1H) 448 500MHz d ₄ -MeOH 7.37-7.40(m, 1H), 6.79-6.87(m, 2H), 5.03(s, 2H), 4.47-4.57(m, 1H), 4, 38-4.61(m, 2H), 3.83(s, 3H), 3.47-3.57(m, 2H), 3.23(s, 3H), 3.05-3.11( m, 1H), 3.03 (s, 3H), 2.96 (br dd, J=8.95, 12.07 Hz, 1H), 2.152.28 (m, 2H), 1.87-2, 08(m, 3H IN Chiralpak OD-H, 15% MeOH, peak 1 449 500MHz d ₄ -MeOH 7.37-7.42(m, 1H), 6.71-6.87(m, 2H), 5.065.16(m, 2H), 4.47-4.61(m, 1H), 4, 14-4.29 (m, 2H), 3.77-3.85 (m, 3H), 3.48-3.55 (m, 1H), 3.02-3.09 (m, 1H), 2.94-3.00 (m, 1H), 2.17-2.25 (m, 1H), 1.91-2.01 (m, 1H) IN Chiralpak IC, 15% MeOH, peak 2 450 500MHz d ₄ -MeOH 7.11 (d, J=8.82 Hz, 1H), 7.05 (d, J=2.34 Hz, 1H), 6.80-6.85 (m, 1H), 5.01 (s , 2H), 4.444.58 (m, 1H), 3.82 (s, 3H), 3.53-3.60 (m, 1H), 3.41-3.47 (m, 2H), 3, 21 (s, 3H), 3.073.14 (m, 1H), 3.02 (s, 3H), 2.93-2.99 (m, 1H), 2.18-2.28 (m, 1H) , 1.91-2.03 (m, 1H) V Chiralpak OD-H, 15% MeOH, peak 2 451 600MHz DMSOd ₆ 8.95 (d, 7=1.48 Hz, 1H), 8.30 (dd, 7=2.10, 8.25 Hz, 1H), 7.41 (td, 7=4.55, 8.80 Hz, 2H), 7.09 (dd, 7=2.41, 9.19 Hz, 1H), 6, 92 (t, 7=9.42 Hz, 1H), 5.49 (s, 2H), 3.40 (br s, 1H), 3.24-3.36 (m, 3H), 3.17 ( s, 1H), 2.862.98 (m, 2H), 2.60-2.75 (m, 2H), 1.89-2.04 (m, 1H), 1.26-1.43 (m, 1H) - - 452 600MHz DMSOd ₆ 8.94 (d, 7=1.40 Hz, 1H), 8.29 (dd, 7=2.14, 8.21 Hz, 1H), 7.37 (d, 7=8.17 Hz, 1H ), 6.69 (dd, 7=2.26, 8.88 Hz, 1H), 6.59 (dd, 7=2.22, 12.18 Hz, 1H), 5.48 (s, 2H) , 4.25-4.38(m, 1H), 3.89(s, 3H), 3.22-3.29(m, 1H), 2.842.98(m, 2H), 2.62-2 .76 (m, 1H), 1.99-2.07 (m, 1H), 1.79 (br s, 1H), 1.64-1.76 (m, 1H) - -

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8.90 (s, 1H), 8.34 (dd, 7=2.14, 8.21 Hz, 1H), 7.90 (d, 7=8.10 Hz, 1H), 7.64 (d, 7=8.35 Hz, 600MHz Chiralpak 1H), 7.61 (d, 7=8.06 Hz, 1H), 5.64 (s, 2H), 453 DMSO- IN AD-H, 25% 4.30-4.44(m, 1H), 3.59-3.68(m, 2H), 3.13- de IP A peak 1 3.28 (m, 1H), 2.77-2.90 (m, 2H), 1.99-2.08 (m, 1H), 1.57-1.70 (m, 1H) 8.91 (s, 2H), 7.40 (dd, 7=4.90, 8.64Hz, 1H), 7.11 (dd, 7=2.49, 9.26Hz, 1H), 6 .91 (ddd, 600MHz Chiralpak 7=2.57, 8.68, 10.08 Hz, 1H), 5.45-5.52 (m, 454 DMSO- IN AD-H, 25% 2H), 3.27-3.29 (m, 3H), 2.86-2.97 (m, 2H), de 2.61-2.71 (m, 2H), 1.96-2.05 (m, 1H), 1.58 IP A peak 1 (br s, 2H), 1.31-1.48 (m, 1H) 7.47(d, 7=1.82Hz, 1H), 7.35(d, 7=8.30Hz, 1H), 7.22(dd, 7=1.75, 8.37Hz, 1H ), 4.75(s, 500MHz 2H), 4.24-4.31 (m, 2H), 3.95 (t, 7=7.66 Hz, 455 DMSO- 2H), 3.33-3.38 (m, 1H), 2.97-3.06 (m, 2H), - - _d6 2.80 (dd, 7=8.30, 12.59 Hz, 1H), 2.36 (s, 1H), 2.29 (quin, 7=7.62 Hz, 2H), 2.08-2 .17 (m, 1H), 1.74-1.94 (m, 1H) 8.91 (s, 2H), 7.22 (dd, 7=2.41, 9.81 Hz, 1H), 7.14 (dd, 7=4.79, 8.68 Hz, 1H), 6.85 (ddd, 600MHz 7=2.49, 8.70, 9.91 Hz, 1H), 5.49 (d, 7=2.10 456 DMSO- Hz, 2H), 3.36-3.43 (m, 2H), 3.28-3.30 (m, - - _d6 3H), 2.90-2.99 (m, 1H), 2.66-2.72 (m, 2H), 1.98-2.06 (m, 1H), 1.62 (br s, 1H ), 1.331.42(m, 1H) 7.38-7.43 (m, 1H), 7.12 (dd, 7=2.49, 9.26 Hz, 1H), 6.90-6.96 (m, 1H), 5.07- 5.16(m, 600MHz Chiralpak 2H), 4.23-4.50 (m, 1H), 4.23 (q, 7=9.45 Hz, 457 DMSO- V AD-H, 25% 1H), 3.21-3.29 (m, 3H), 2.93-3.01 (m, 3H), de 2.72-2.81 (m, 1H), 1.96-2.12 (m, 1H), 1.72- IP A peak 1 1.90(m, 3H) 600MHz 8.93 (dd, 7=0.66, 2.06 Hz, 1H), 8.34 (dd, Chiralpak 458 DMSO- 7=2.14, 8.21 Hz, 1H), 7.72 (d, 7=8.10 Hz, V AD-H, 25% _d6 1H), 7.61 (d, 7=8.56 Hz, 1H), 7.49 (d, IP A peak 1

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7=8.10Hz, 1H), 5.66(d, 7=1.71Hz, 2H), 4.32-4.43(m, 1H), 3.50-3.64(m, 2H ), 3.153.28 (m, 1H), 2.85-2.94 (m, 2H), 2.04-2.12 (m, 1H), 1.66-1.77 (m, 1H) 459 600MHz DMSO d ₆ 7.66 (s, 1H), 7.57 (d, 7=8.25 Hz, 1H), 7.41 (dd, 7=1.25, 8.33 Hz, 1H), 5.11-5 .21 (m, 2H), 4.38-4.49 (m, 1H), 3.64-3.72 (m, 2H), 3.61 (td, 7=4.74, 9.75 Hz, 4H), 3.44- 3.53(m, 2H), 3.34-3.41 (m, 1H), 3.17 (d, 7=4.90 Hz, 1H), 3.09 (ddd, 7=2.84, 9.48, 12, 59 Hz, 1H), 2.95-3.05 (m, 1H), 2.86 (dd, 7=8.06, 12.65 Hz, 1H), 2.09-2.19 (m, 1H ), 1.75-1.93 (m, 1H) IN Chiralpak AD-H, 25% IP A, peak 1 460 600MHz DMSOd ₆ 7.23 (d, 7=9.81 Hz, 1H), 7.16-7.20 (m, 1H), 6.92 (t, 7=8.84 Hz, 1H), 5.08-5 .17 (m, 2H), 4.32-4.51 (m, 1H), 4.23 (q, 7=9.55 Hz, 2H), 3.34-3.39 (m, 1H), 3.25-3.30 (m, 4H), 2.933.05 (m, 2H), 2.74-2.85 (m, 1H), 2.03-2.13 (m, 1H), 1, 71-1.89(m, 1H) IN Chiralpak AD-H, 25% IP A, peak 2 461 600MHz DMSO d ₆ 7.39 (d, 7=8.41 Hz, 1H), 7.33 (d, 7=2.02 Hz, 1H), 7.09 (dd, 7=2.10, 8.41 Hz, 1H ), 4.945.05 (m, 2H), 4.70-4.84 (m, 1H), 3.14-3.28 (m, 2H), 3.10-3.13 (m, 6H), 2.91-3.06 (m, 2H), 2.89 (s, 1H), 1.87-2.05 (m, 1H), 1.68 (br s, 1H) V Chiralpak AD-H, 25% IP A, peak 1 462 600MHz DMSOd ₆ 8.42 (br s, 2H), 7.44-7.48 (m, 1H), 7.20 (dd, 7=2.37, 9.23 Hz, 1H), 6.99 (t, 7 =9.27 Hz, 1H), 5.10-5.21 (m, 2H), 5.04-5.10 (m, 1H), 4.36-4.55 (m, 1H), 4, 23 (q, 7=9.52 Hz, 2H), 3.78 (br s, 1H), 3.48 (br dd, 7=4.01, 12.42 Hz, 1H), 3.26-3 .34 (m, 1H), 3.02-3.17 (m, 2H), 2.99 (s, 1H), 2.51-2.65 (m, 1H), 1.952.12 (m, 2H ) V Chiralpak AD-H, 25% IP A peak 1

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463 600MHz DMSO d ₆ 8.95 (d, 7=1.32 Hz, 1H), 8.30 (dd, 7=2.10, 8.17 Hz, 1H), 7.38-7.45 (m, 2H), 7 .07 (dd, 7=2.49, 9.19Hz, 1H), 6.92 (ddd, 7=2.57, 8.66, 10.10Hz, 1H), 5.47-5.57 (m, 2H), 3.24-3.31 (m, 3H), 3.13-3.23 (m, 2H), 2.993.10 (m, 2H), 2.89-2.98 (m , 2H), 1.75-1.89 (m, 1H), 1.53-1.67 (m, 1H). - - 464 600MHz DMSOd ₆ 8.44 (br s, 2H), 7.74 (s, 1H), 7.62 (d, 7=8.33 Hz, 1H), 7.46 (d, 7=8.21 Hz, 1H) , 5.14-5.24 (m, 2H), 4.88 (dt, 7=4.87, 9.32 Hz, 1H), 4.69-4.83 (m, 1H), 4.42 -4.55 (m, 1H), 3.733.83 (m, 1H), 3.69 (br d, 7=4.36 Hz, 3H), 3.57-3.65 (m, 4H), 3 .37-3.56 (m, 3H), 2.993.17 (m, 2H), 2.24 (br t, 7=9.46 Hz, 1H), 1.83-1.92 (m, 1H) IN Chiralpak AD-H, 25% IP A peak 1 465 600MHz DMSOd ₆ 8.73 (br s, 2H), 7.46-7.50 (m, 1H), 7.217.23 (m, 1H), 6.98-7.02 (m, 1H), 5.17-5 .22 (m, 1H), 4.36-4.53 (m, 1H), 4.13-4.32 (m, 2H), 3.95-4.13 (m, 2H), 3.64 (br d, 7=12.53 Hz, 1H), 3.25-3.34 (m, 3H), 3.09-3.15 (m, 1H), 2.52-2.65 (m, 3H) V Chiralpak AD-H, 25% IP A, peak 1 466 600MHz DMSOd ₆ 8.38 (br s, 2H), 7.23-7.30 (m, 1H), 6.99 (t, 7=9.27 Hz, 1H), 5.05-5.21 (m, 2H ), 4.49 (q, 7=8.93 Hz, 1H), 4.23 (q, 7=9.52 Hz, 2H), 3.79 (br s, 1H), 3.44-3, 66 (m, 1H), 3.303.37 (m, 1H), 3.28 (s, 2H), 3.06-3.18 (m, 1H), 2.52-2.55 (m, 3H) , 1.93-2.11 (m, 1H) V Chiralpak AD-H, 25% IP A, peak 1 467 600MHz DMSOd ₆ 8.91 (s, 2H), 7.40 (dd, 7=4.87, 8.68Hz, 1H), 7.07 (dd, 7=2.53, 9.30Hz, 1H), 6 .91 (ddd, 7=2.53, 8.62, 10.10 Hz, 1H), 5.46-5.57 (m, 2H), 3.25-3.31 (m, 3H), 3 .12-3.22 (m, 1H), 2.90-3.08 (m, 4H), 1.84 (dtd, 7=3.58, 7.67, 13.31 Hz, 1H), 1 .49-1.64 (m, 1H), 1.40 (br s, 1H) V Chiralpak AD-H, 25% IP A, peak 1

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468 600MHz DMSO d ₆ 7.47(d, 7=8.56Hz, 1H), 7.31(s, 1H), 7.06(dd, 7=1.21, 8.60Hz, 1H), 4.97-5 .07 (m, 2H), 4.34-4.45 ( _m , 1H), 3.32 (s, 1H), 3.12 (s, 3H), 2.95-3.09 (m, 2H ), 2.89 (s, 3H), 2.762.85 (m, 1H), 2.06-2.15 (m, 1H), 1.72-1.89 (m, 2H) IN SFC: Chiralpak AD-H analytical column, 15% methanol with 0.2% DEA 469 600MHz DMSOd ₆ 9.07 (br s, 2H), 7.44-7.48 (m, 1H), 7.21 (dd, 7=2.57, 9.26 Hz, 1H), 6.96-7.03 (m, 1H), 5.06-5.19 (m, 2H), 4.92-5.03 (m, 1H), 4.23 (q, 7=9.58 Hz, 2H), 3, 56-3.86 (m, 2H), 3.46 (br s, 1H), 3.29 (s, 3H), 3.11 (br dd, 7=9.89, 12.61 Hz, 1H) , 2.92-3.04 (m, 1H), 2.68 (br s, 3H), 2.16-2.25 (m, 1H), 1.82-1.95 (m, 1H) -- - 470 600MHz DMSOd ₆ 7.58 (d, 7=1.82 Hz, 1H), 7.17-7.24 (m, 2H), 4.70-4.77 (m, 2H), 4.46-4.35 ( m, 1H), 4.214.29 (m, 2H), 3.94 (t, 7=7.72 Hz, 2H), 3.333.41 (m, 2H), 2.97-3.08 (m, 2H ), 2.82 (dd, 7=8.30, 12.59 Hz, 1H), 2.28 (quin, 7=7.72 Hz, 2H), 2.14 (ddd, 7=4.61, 8.66, 17.09Hz, 1H), 1.73-1.88(m, 1H) V SFC: Chiralpak IC, 45% methanol, peak 2 471 600MHz DMSOd ₆ 7.44 (d, 7=2.02 Hz, 1H), 7.19 (d, 7=8.49 Hz, 1H), 7.07 (dd, 7=2.02, 8.41 Hz, 1H ), 4.935.04 (m, 2H), 4.79-4.84 (m, 1H), 4.70-4.76 (m, 1H), 3.10-3.23 (m, 6H), 2.94-3.10 (m, 2H), 2.88 (s, 2H), 1.86-2.05 (m, 1H), 1.75 (br s, 1H) V SFC: Chiralpak IC, 30% methanol, peak 2 472 600MHz DMSOd ₆ 7.21(d, 7=9.28Hz, 1H), 6.96-7.03(m, 2H), 5.09-5.17(m, 2H), 4.17-4.40( m, 1H), 3.393.56 (m, 1H), 3.13-3.25 (m, 2H), 3.00 (s, 1H), 2.89 (br t, 7=10.63 Hz, 1H), 2.52-2.55 (m, 2H), 2.35-2.46 (m, 2H), 1.92-2.00 (m, 2H), 1.73-1.86 ( m, 1H), 1.19-1.29 (m, 1H), - -

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473 600MHz DMSO d ₆ 7.74 (s, 1H), 7.37-7.46 (m, 2H), 5.08-5.18 (m, 2H), 4.36-4.50 (m, 1H), 3, 56-3.72 (m, 6H), 3.42-3.54 (m, 2H), 3.35-3.41 (m, 2H), 2.98-3.11 (m, 2H), 2.85 (dd, 4=8.17, 12.61 Hz, 1H), 2.03-2.19 (m, 1H), 1.75-1.91 (m, 1H) IN SFC: IC, 15% methanol, peak 2 474 600MHz DMSOd ₆ 7.39 (s, 1H), 7.26 (d, 4=8.56 Hz, 1H), 7.05 (d, 4=8.79 Hz, 1H), 4.98-5.11 (m , 2H), 3.353.41 (m, 1H), 3.11-3.17 (m, 3H), 2.96-3.10 (m, 2H), 2.89 (s, 3H), 2, 77-2.86 (m, 1H), 2.07-2.17 (m, 1H), 1.73-1.90 (m, 3H) IN SFC: Chiralpak AD-H analytical column, 15% methanol with 0.2% DEA, peak 2 475 600MHz DMSOd ₆ 7.40 (s, 1H), 7.29 (d, 4=8.64 Hz, 1H), 7.06 (d, 4=8.63 Hz, 1H), 4.98-5.12 (m , 2H), 4.374.48 (m, 1H), 3.56-3.71 (m, 5H), 3.41-3.54 (m, 2H), 3.37-3.41 (m, 1H ), 3.12-3.26 (m, 2H), 2.93-3.09 (m, 2H), 2.79-2.90 (m, 1H), 2.05-2.22 (m , 1H), 1.75-1.87 (m, 1H) V Chiralcel OD-H column, peak 2 476 600MHz DMSOd ₆ 8.90 (s, 1H), 8.27 (dd, 4=2.10, 8.25 Hz, 1H), 7.30 (d, 4=8.33 Hz, 1H), 6.87 (dd , 4=2.18, 9.34 Hz, 1H), 6.57 (dd, 4=2.18, 11.91 Hz, 1H), 5.48-5.56 (m, 2H), 4, 37 4.45(m, 1H), 3.55(s, 3H), 3.38-3.48(m, 2H), 3.17(s, 1H), 2.96-3.06(m , 2H), 2.81 (dd, 4=8.91, 12.57 Hz, 1H), 2.01-2.11 (m, 1H), 1.68-1.80 (m, 1H) V SFC: Chiralpak AD-H, 25% methanol peak 1 477 600MHz DMSOd ₆ 8.91 (s, 2H), 7.22 (dd, 4=2.49, 9.81 Hz, 1H), 7.10 (dd, 4=4.75, 8.72 Hz, 1H), 6 .84 (ddd, 4=2.49, 8.70, 9.91 Hz, 1H), 5.46-5.58 (m, 2H), 3.26-3.31 (m, 3H), 2 .98-3.24 (m, 4H), 2.93 (td, 4=3.28, 6.75 Hz, 1H), 1.86 (dtd, 4=3.54, 7.61, 13, 38Hz, 1H), 1.58-1.66(m, 1H), 1.40(brs, 1H) V SFC: Phenomenex Lux Cellulose-2, 15% methanol, peak 2

-178043189

478 600MHz DMSO d ₆ 8.47 (br s, 2H), 7.78 (s, 1H), 7.44-7.50 (m, 2H), 5.09-5.23 (m, 2H), 4.80-4 .88 (m, 1H), 3.72-3.84 (m, 1H), 3.69 (br d, 3=4.52 Hz, 3H), 3.57-3.66 (m, 4H) , 3.38-3.53 (m, 2H), 3.13 (brdd, 3=10.32, 12.57 Hz, 1H), 3.05 (br t, 3=11.60 Hz, 1H) , 2.24 (br t, 3=9.54 Hz, 1H), 1.85-1.93 (m, 1H), 1.15-1.27 (m, 1H) IN SFC: Chiralpak IC, 15% methanol, peak 2 479 600MHz DMSOd ₆ 7.26-7.29(m, 1H), 7.25(t, 3=6.83Hz, 1H), 6.99(t, 3=9.32Hz, 1H), 5.05-5 .21 (m, 2H), 4.87-5.01 (m, 1H), 4.23 (q, 3=9.55 Hz, 2H), 3.69-3.79 (m, 1H), 3.58 (dt, 3=4.36, 8.99 Hz, 1H), 3.27-3.30 (m, 3H), 3.06-3.14 (m, 1H), 2.97- 3.03 (m, 2H), 2.65 (s, 3H), 2.16- 2.25(m, 1H), 1.81-1.95(m, 1H) IN FC using it (column 2x Chiralpak IC 2x25 cm, 5 µm), peak 2 480 600MHz DMSOd ₆ 8.23-8.31 (br s, 1H), 6.90-7.33 (m, 3H), 5.13-5.26 (m, 2H), 4.11-4.29 (m, 1H), 3.823.91(m, 1H), 3.63(brd, 3=9.19Hz, 1H), 3.45-3.59(m, 1H), 3.36(td, 3=8 .29, 16.43 Hz, 1H), 3.28 (s, 3H), 3.10-3.23 (m, 1H), 2.52-2.55 (m, 1H), 2.34- 2.47 (m, 1H), 0.971.19 (m, 3H) - - 481 600MHz DMSOd ₆ 7.28-7.59 (m, 1H), 7.05-7.16 (m, 1H), 6.756.95 (m, 1H), 4.77-4.93 (m, 1H), 4, 08-4.53 (m, 1H), 4.02-4.32 (m, 1H), 3.32-3.32 (m, 2H), 3.21-3.30 (m, 1H), 2.76-2.93 (m, 1H), 2.53-2.70 (m, 1H), 1.68-1.86 (m, 1H), 1.451.63 (m, 1H), 1, 02-1.18 (m, 1H), -0.05-0.15 (m, 1H) - - 482 600MHz DMSOd ₆ 8.70 (br s, 2H), 7.26-7.32 (m, 1H), 7.02 (ddd, 3=2.53, 8.86, 9.79 Hz, 1H), 5.15 -5.24 (m, 1H), 4.12-4.30 (m, 2H), 4.03-4.12 (m, 1H), 3.68 (br d, 3=11.91 Hz, 5H), 3.26-3.40 (m, 3H), 3.11-3.18 (m, 1H), 2.65 (br s, 1H), V SFC with Chiralcel OD-H, 10% methanol, peak 2

- 179043189

2.58-2.63 (m, 1H), 2.52-2.56 (m, 4H) 483 600MHz DMSO d ₆ 8.70 (br s, 2H), 7.26-7.32 (m, 2H), 7.02 (ddd, 7=2.53, 8.86, 9.79 Hz, 1H), 5.15 -5.24 (m, 2H), 4.12-4.30 (m, 2H), 4.03-4.12 (m, 2H), 3.68 (br d, 7=11.91 Hz, 2H), 3.26-3.40(m, 4H), 3.11-3.18(m, 1H), 2.65(brs, 1H), 2.58-2.63(m, 1H ). IN SFC: Chiralpak IC, 25% isopropane L, peak 2 484 600MHz DMSOd ₆ 8.14 (br s, 2H), 7.22-7.27 (m, 2H), 7.117.19 (m, 1H), 5.03-5.15 (m, 2H), 4.23 (dq , 7=3.35, 9.37 Hz, 1H), 3.58-3.69 (m, 2H), 3.27 (s, 3H), 3.15-3.25 (m, 2H), 2.96-3.03(m, 2H), 2.85-2.93(m, 1H), 1.79-2.00(m, 1H), 1.55-1.61(m, 1H ) IN SFC: Chiralpak IC, 25% isopropanol, peak 1 485 600MHz DMSOd ₆ 8.14 (br s, 2H), 7.23-7.28 (m, 2H), 6.98 (t, 7=9.21 Hz, 1H), 5.03-5.18 (m, 2H ), 4.23 (q, 7=9.47 Hz, 2H), 3.63-3.82 (m, 1H), 3.47 (br s, 1H), 3.29-3.42 (m , 1H), 3.28 (s, 2H), 2.97-3.11 (m, 2H), 2.87-2.96 (m, 1H), 2.5-2.55 (m, 4H), 2, 14-2.31(m, 1H), 1.38-1.50(m, 1H) V SFC using Chiralpak IC 2x25 cm, 5 microns, mobile phase: 25% isopropanol, peak 2 486 600MHz DMSOd ₆ 8.23 (br s, 2H), 7.15-7.28 (m, 1H), 6.987.14 (m, 2H), 6.78-6.91 (m, 1H), 5.09-5 .28 (m, 1H), 4.16-4.29 (m, 1H), 3.50-3.89 (m, 3H), 3.40-3.49 (m, 1H), 3.26 -3.30(m, 2H), 2.54(s, 2H), 2.15-2.33(m, 1H) V SFC: analytical column Chiralpak AD-H, 25% isopropanol, peak 1

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487 600MHz DMSOd ₆ 8.23 (br s, 2H), 7.14-7.28 (m, 1H), 7.12 (br s, 1H), 6.99-7.10 (m, 1H), 5.16- 5.29 (m, 1H), 4.16-4.29 (m, 1H), 3.64-3.83 (m, 2H), 3.41 (br s, 2H), 3.37-3 .39 (m, 1H), 3.263.29 (m, 2H), 2.52-2.55 (m, 2H), 2.15-2.33 (m, 1H) IN SFC: analytical column Chiralpak AD-H, 25% isopropano L, peak 2 488 600MHz DMSOd ₆ 7.36-7.43 (m, 1H), 7.09 (dd, 7=2.49, 9.34 Hz, 1H), 6.87-6.96 (m, 1H), 5.03- 5.09 (m, 2H), 4.17-4.28 (m, 2H), 3.73-3.79 (m, 1H), 3.71 (br d, 7=3.11 Hz, 1H), 3.40-3.49 (m, 2H), 3.23-3.29(m, 1H), 2.89-3.08(m, 6H), 2.512.57(m, 1H), 1.72-1.82(m, 1H) IN SFC using two columns Regis Whelk-0 s, s 2x25 cm, 5 micron, peak 2 489 600MHz DMSOd ₆ 7.16-7.21 (m, 1H), 7.05 (dd, 7=2.49, 9.42 Hz, 1H), 6.78-6.84 (m, 1H), 5.07- 5.19 (m, 2H), 4.20-4.46(m, 2H), 3.52-3.65(m, 2H), 3.403.51(m, 2H), 3.26(s, 3H), 3.07-3, 14 (m, 1H), 1.87-2.00 (m, 1H), 1.62 (qd, 7=6.18, 12.45 Hz, 1H) - - 490 600MHz DMSOd ₆ 7.16-7.21 (m, 1H), 7.05 (dd, 7=2.49, 9.42 Hz, 1H), 6.78-6.84 (m, 1H), 5.07- 5.19 (m, 2H), 4.16-4.31 (m, 2H), 3.92 (br s, 1H), 3.77 (br s, 1H), 3.44-3.58 (m, 3H), 3.25- 3.29 (m, 1H), 2.99 (s, 1H), 2.52-2.55 (m, 1H), 2.28 (qd, 7=7.20, 13.97 Hz, 1H) , 2.00 (br d, 7=4.83 Hz, 1H) - - 491 600MHz DMSOd ₆ 7.17-7.23 (m, 1H), 7.08 (dd, 7=2.49, 9.42 Hz, 1H), 6.79-6.89 (m, 1H), 5.07- 5.21(m, 2H), 4.16-4.41(m, 2H), 3.39-3.58(m, 2H), - -

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3.14-3.27 (m, 2H), 2.94-3.03 (m, 1H), 2.68 (br d, 7=6.93 Hz, 2H), 2.52-2.57 (m, 1H), 2.27-2.34 (m, 1H), 1.95-2.04 (m, 1H), 1.65 (qd, 7=8.03, 12.28 Hz, 1H ) 492 600MHz DMSOd ₆ 1.79 (br dd, 7=8.64, 3.11 Hz, 1H) 1.84 (br s, 1H) 2.88-2.97 (m, 2H) 2.97-3.13 (m , 4H) 3.17 (s, 1H), 3.24-3.28 (m, 3H) 3.38-3.53 (m, 2H) 3.68-3.80 (m, 2H) 4, 17-4.28 (m, 2H) 4.48 (q, 7=8.93 Hz, 1H) 5.00 (s, 1H) 5.07 (s, 1H) 6.87-6.94 (m , 1H) 7.15 (dd, 7=8.68, 4.79 Hz, 1H) 7.18-7.25 (m, 1H) - - 493 600MHz DMSOd ₆ 1.65-1.82 (m, 2H) 1.84 (br s, 1H) 2.52-2.56 (m, 1H) 2.90-2.96 (m, 2H) 2.98-3 .13 (m, 5H) 3.17 (s, 1H) 3.24-3.28 (m, 3H) 3.383.53 (m, 3H) 3.69-3.79 (m, 2H) 4.09 (br s, 1H) 4.16-4.29 (m, 2H) 4.48 (q, 7=9.16 Hz, 1H) 5.00 (s, 1H) 5.07 (s, 2H) 6 .88-6.94 (m, 1H) 7.13-7.25 (m, 2H) - -

Scheme 9

or "-butanol

NHBOC

Intermediate 60: tert-Butyl ((3K,4K)-1-(6-cyano-1H-benzo[c1]imidazol-2-yl)-4fluoropiperidin-3-yl)carbamate.

Step 1. 2-Oxo-2,3-dihydro-1H-benzo[c1]imidazole-5-carbonitrile.

To a solution of 1,2-diamino-4-cyanobenzene (1.00 ml, 7.51 mmol) in tetrahydrofuran (5 ml) was added 1, Γ-carbonyldiimidazole (1.22 g, 7.51 mmol). The reaction mixture was stirred at ambient temperature for one hour, concentrated, then triturated with water. The brown precipitate was collected by vacuum filtration to give 2-oxo-2,3-dihydro-1H-benzo[b]imidazole-5carbonitrile as a brown powder. MS (ESI, posit, ion) mass/charge: 160.2 [M+1].

Step 2 2-Chloro-1H-benzo[c1]imidazole-6-carbonitrile.

Phosphorus(at ) oxychloride (1.398 ml, 14.95 mmol). The reaction mixture was stirred at 110°C for 16 h, then cooled to room temperature. This was diluted with acetonitrile and then slowly added to a cold beaker with rapid stirring containing saturated aqueous sodium bicarbonate (50 ml). The mixture was extracted with ethyl acetate; this was dried over anhydrous magnesium sulfate, filtered and concentrated to give 2-chloro-1H-benzo[b]imidazole-6-carbonitrile as a tan powder. (ESI, put, ion) mass/charge: 178.2 [M+1].

Step 3: tert-Butyl ((3K,4O1 -(6-cyano-1H-benzo[0]imidazol-2-yl)-4-fluoropiperidin-3yl)carbamate (Intermediate 60).

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Ν,Ν-diisopropylethylamine (3.93 ml, 22.52 mmol), 2-chloro-III-benzoimidazole-6-carbonitrile (2 g, 11.26 mmol), tert-butyl ((3R,4R)-4- fluoro-niperidin-3-yl)carbamate (2.95 g, 13.51 mmol) and 1-butanol (25 ml) were combined in a flask and heated to 130°C for 48 h. The mixture was concentrated, then loaded onto a 125 g RediSep cartridge ISCO eluting with 0-4% MeOH in DCM to give the title compound as a light brown foam. (ESI, positive ion) mass/charge: 360.2 [M+1].

The following intermediates were synthesized using the same sequence as described for Intermediate 60 and General Scheme 9 above.

Table 4

Intermediates for SnAr prepared according to Scheme 9

No. prom. conn. Structure Connection name MSMH+ 60 ^nc ^^n T T X %% x-( FlHBoc tert-butyl ((3K,4K)-1 -(6-cyano-1Hbenzo[(1]imidazol-2-yl)-4fluoropiperide in-3-yl)carbamate 360.2 61 aw KlMeBoc (8)-tert-butyl(1-(1Hbenzo[d]imidazol-2-yl)piperide in-3yl)(methyl)carbamate 331.3 62 with Η ^F qww^N /—\ 1 X/>-\ X x—< J NHBoc tert-butyl ((3K,4R)-1 -(4,6-difluorolH-benzo[d]imidazol-2-yl)-4fluoropiperide in-3-yl)carbamate 371.2 63 p H VAa tert-Butyl-6-(4,6-difluoro-1Hbenzo[d]imidazol-2-yl)hexahydro2H-pyrido[4,3-b][1,4]oxazine-4(3H)carboxylate 396.2 64 N—Me ^Boez tert-butyl ((3K,4R)-1 -(6-cyano-1Hbenzo[d]imidazol-2-yl)-4fluoropiperidin-3yl)(methyl)carbamate 374.2 65 'NHBOC tert-butyl ((ZK,4K) -4-fluoro-1 - (6-fluoro-lH-benzo [d] imidazol-2yl) piperide in-3 -yl) carbamate 353.2 66 c H W 'NHBoc (K)-tert-butyl ( 1 - (6-chloro-1Hbenzo[d]imidazol-2-yl) -4,4 difluoropiperide in-3 -yl) carbamate 387.2 67 H kyu- HN-Boc tert-butyl ((3K,4R)-1 -(1Hbenzo[d]imidazol-2-yl)-4fluoropiperide in-3-yl)carbamate 335.0 68 TXA” X ^f HN-Boc tert-butyl ((ZK,4K)-1-(5,6-difluorolH-benzo[d]imidazol-2-yl)-4fluoropiperide in-3-yl)carbamate 371.2 69 IX ^z ^XX ^r AW'N X—( HN-Boc tert-butyl ((3K,4R)-1 -(6-chloro-1Hbenzo[d]imidazol-2-yl)-4fluoropiperide in-3-yl)carbamate 369.2 70 ^F VlQ' jl HN—Bqc (K)-tert-butyl (1-(4,6-difluoro-1Hbenzo[d]imidazol-2-yl)-4,4difluoropiperide in-3-yl)carbamate 389.2

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71 Η ί JI ^ ^Ν \ / NHBoc (8)-tert-butyl(1-(1Hbenzo[(1]imidazol-2-yl)piperide in-3yl)carbamate 317.2 72 0>Q NHBoc (I)-tert-butyl ( 1 - (1H6eH3o[d] imidazol-2-yl) piperide in-3 yl) carbamate 317.2 73 X NHBoc (I)-tert-butyl ( 1 - (1Hbenzo[d]imidazol-2-yl) -4,4 difluoropiperide in-3 -yl) carbamate 353.2 74 i Тър(y UX-n'-f 'NHBoc tert-butyl ((3K,4 S)-1 -(6-cyano-1Hbenzo[d]imidazol-2-yl)-4fluoropiperide in-3-yl)carbamate 360.2 75 P H W>· NHBoc tert-butyl ((3K,4R)-1 -(6-fluoro-1Hbenzo[b]imidazol-2-yl)-4hydroxypiperide in-3-yl)carbamate 351.2 76 'AUr'·' ΓΛ IX Ж ?- ^,F NHBoc tert-butyl ((3K,4 S)-1 -(5,6-difluoro-1Hbenzo[b]imidazol-2-yl)-4fluoropiperide in-3-yl)carbamate 371.0 77 with r H 'NHBoc tert-butyl ((3K,48)-4-fluoro-1-(6(trifluoromethyl)-1Hbenzo[b]imidazol-2-yl)piperide in-3yl)carbamate 403.2 78 ё LL l_L (I) -tert-butyl ( 1 - (5,6-difluoro-1H- benzoIimidazol-2-yl)-4,4- difluoropiperide in-3-yl)carbamate 389.2 79 (W NHBoc tert-butyl ((ZK,48) -1- (1Н- benzo[b]imidazol-2-yl)-4fluoropiperide in-3-yl)carbamate 335.2 80 kzJI GA XXX>° ^H HN—Sun tert-butyl ((3R,48)-1 -(6-fluoro-1Hbenzo[b]imidazol-2-yl)-4hydroxypiperide in-3-yl)carbamate 351.2 81 ΓΆ I x Sr ^N —( HN-Boc tert-butyl ((3K,4K)-4-fluoro-1-(6(trifluoromethyl)-1H-imidazo[4,5b]pyride in-2-yl)piperidin-3yl)carbamate 404.2 82 ^Loh'n - ^{b ° c} tert-butyl ((ZK,4K) -4-fluoro-1 - (6-fluoro4-methoxy-1 H-benzo[b] imidazol-2yl) piperide in-3 -yl) carbamate 383.2 83 ^F XcR> HN-Boc tert-butyl ((3K,4K)-4-fluoro-1-(6(trifluoromethyl)-1Hbenzo[d]imidazol-2-yl)piperide in-3yl)carbamate 403.2 84 J „ Ύ Th H ^{f 4} n^n U HN-Boc tert-butyl((3K,4K)-4-fluoro-1-(6-fluoro1H-imidazo[4,5-b]pyridin-2yl)piperide in-3-yl)carbamate 354.2 85 HN-Boc (I)-tert-butyl (4,4-difluoro-1 - (6-fluoro-lH-benzo [d] imidazol-2yl) piperide in-3 -yl) carbamate 371.2

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R ¹

Scheme 10 Conversion of SnAr intermediates to R ⁴ end products

^R3

R ² yn ₂

Example 187 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-6-carbonitrile

Step 1. tert-Butyl((3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-cyano-1 H-benzo[d]imidazol-2yl)-4-fluoropiperidine -3-yl)carbamate.

Cesium carbonate (0.707 mg, 2.170 mmol), tert-butyl ((3R,4R)-1-(6-cyano-1H-benzo[d]imidazol-2-yl)4-fluoropiperidin-3-yl)carbamate (390 mg, 1.085 mmol), (5-chloropyrimidin-2-yl)methylmethanesulfonate (290 mg, 1.302 mmol) and acetonitrile (10 ml) were combined in a vial and stirred overnight. The mixture was poured into water and extracted with DCM (3X). The organics were combined, dried over Na ₂ SO ₄ , filtered and concentrated. The brown solid was dissolved in DCM, loaded onto a 20 g silica plug and washed with EtOAc (˜4 column volumes). The EtOAc was concentrated to give tert-butyl((3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6cyano-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidine -3-yl)carbamate and tert-butyl ((3R,4R)-1-( 1 -((5chloropyrimidin-2-yl)methyl)-5-cyano-1H-benzo[d]imidazol-2-yl)- 4-fluoropiperidin-3-yl)carbamate as a mixture of isomers. The isomers were separated using chiral SFC (Chiralcel AD, 25% IPA, peak 1). (ESI, positive ion) mass/charge: 486.2 [M+1].

Deprotection of the Boc group using TFA (Procedure B)

Stage 2. 2-((3R,4R)-3-amino-4-fluoropiperidin-1 -yl)-1 -((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-6-carbonitrile ( example 187).

tert-Butyl((3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-cyano-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-yl )carbamate (150 mg, 0.309 mmol) was loaded into a vial. DCM (5 ml) was added followed by TFA (2 ml). After 1 hour, the mixture was poured onto an SCX column previously wetted with methanol, washed with methanol, then eluted with methanolic ammonia. The residue was redissolved in MeCN/H ₂ O, frozen and lyophilized to give the title compound as a white solid. 1H NMR (500 MHz, MeOD) δ 8.80 (s, 2H), 7.65-7.69 (m, 1H), 7.547.61 (m, 1H), 7.49 (d, J=8, 30 Hz, 1H), 5.57 (s, 2H), 4.42-4.60 (m, 1H), 3.72-3.80 (m, 1H), 3.64 (br d, J= 13.23 Hz, 1H), 3.15-3.27 (m, 2H), 3.06 (dd, J=9.21, 12.59 Hz, 1H), 2.13-2.27 (m , 1H), 1.80-1.99 (m, 1H). (ESI, positive ion) mass/charge: 386.2 [M+1].

Note: In some cases, the free base was redissolved in DCM and HCl was added to precipitate the HCl salt. This is noted in the table as deprotection with TFA and not as an HCl product.

Alternative Boc deprotection with HCl (Procedure A) Step 2 methyl)-1H-benzo[d]imidazole-6carbonitrile hydrochloride (Example 242)

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tert-Butyl((3R,4R)-1-(6-cyano-1-((5-methoxypyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-yl )carbamate (69 mg) was dissolved in dioxane (2 ml) and 4N was added. HCl in dioxane (500 µl). The reaction mixture was stirred at ambient temperature overnight then concentrated in vacuo to give the title compound as a white solid. ¹ H NMR (500 MHz, MeOD) δ 8.52 (s, 2H), 7.94 (s, 1H), 7.66-7.74 (m, 2H), 5.54-5.67 (m , 2H), 4.77-4.93 (m, 1H), 4.21-4.30 (m, 1H), 4.01 (br d, J=12.98 Hz, 1H), 3.96 (s, 3H), 3.71-3.78 (m, 1H), 3.43-3.50 (m, 2H), 2.322.46 (m, 1H), 1.98-2.14 (m , 1H). (ESI, positive ion) mass/charge: 382.2 [M+1].

Note: The HCl salt was sometimes converted to the free base using aqueous workup or using ion exchange chromatography. The release of salt or free base is indicated in the table.

The following compounds were prepared in a manner similar to those described in Schemes 9 and 10.

Example 188: (3R,4R)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2yl)piperidine-3-amine.

(3 R,4R)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine was synthesized on a scale 0.3 mmol according to the sequence similar to that described above. Removal of the Boc protecting group was carried out using the TFA procedure. ¹ H NMR (500 MHz, MeOD) δ 8.68-8.74 (s, 2H), 7.47-7.52 (m, 1H), 7.14-7.20 (m, 2H), 7 .08-7.13 (m, 1H), 5.53 (s, 2H), 4.34-4.52 (m, 1H), 3.64 (dtd, J=1.95, 4.14, 12.36Hz, 1H), 3.48-3.57(m, 1H), 3.04-3.21(m, 2H), 2.98(dd, J=8.82, 12.20Hz , 1H), 2.12-2.25(m, 1H), 1.82-1.92(m, 1H). (ESI, positive ion) mass/charge: 345.2 [M+1].

The following examples were synthesized using the same sequence as described for examples 239-240 and in general schemes 9-10 above.

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Table 5

Compounds obtained according to schemes 9-10

Note. No. Intermediate conn. SnAr electrophile Procedure for removing the protective group Structure Connection name MSMH+ 187 60 CI ό LAMB V a ^NC 4Z^n XXNL nh ₂ (2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5chloropyrimidin-2yl)methyl)-1Hbenzo[<1]imidazole-6carbonitrile 386.0 188 67 ό ^C1 V F / K! 0 T h X \--{ yn ₂ (3R,4R)-4^Top-l-(l((5-fluoropyrimidin2-yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3 amine 345.2 189 67 G ^C1 V h n G />-\ )- ^F ML X—/ nh ₂ (3R,4R)-4^Top-l-(l((5-fluoropyridin-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3 - amine 344.2 190 60 V l'a A 2-((3R,4R)-3-aMinio4-fluoropiperidin-1 yl)-1-((5fluoropyridin-2yl)methyl)-1Нbenzo[<1]imidazole-6carbonitrile 369.0

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191 60 V h χχ,ν /—\ ί a ^f nh ₂ 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5fluoropyridin-2yl)methyl)-1Hbenzo[c!]imidazole-5carbonigril 369.2 192 67 A ^N .N AI V Br 0 TA M'S X-( \h ₂ (3R,4R)-1-(1-((5bromopyrimidin-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidine-Zamine 405.0 193 67 A N V F- ₍ C C /4v- ^r /-\ ί X /Ah A ^f X--< blH ₂ (3R,4R)-4^to _P -1-(1((5(1rifluoromethyl)pyrimidin-2-yl)methyl)1Hbenzo[<1]imidazol-2yl)piperidine-3-amine 395.2 194 67 OMe ό ^Cl V MeO s x^s^-N /\ ί X a ^f nh ₂ (3R,4R)-4^to _P -1-(1((5methoxypyrimidin2-yl)methyl)-1Hbenzo[c!]imidazol-2yl)piperidine-3 amine 357.2 195 67 Clό X)Ms V ^c 4_ C /XJJ /-ch ί Xn A ^F \4xi X—/ Xih ₂ (3R,4R)-1-(1-((5chloropyrimidin-2yl)methyl)-1 Hbenzo[b]imidazol-2yl)-4fluoropiperidin-3 amine 361.8 196 60 A V c anch NH _Z 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5fluoropyrimidin-2yl)methyl)-1 Hbenzo[b]imidazol-6- 370.0

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carbonitrile 197 60 F IN F jAX nh ₂ 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5fluoropyrimidin-2yl)methyl)-1Hbenzo[c!]imidazole-5carbonitrile 370.0 198 60 Clό OMs IN C1 i X^ )- ^f _nc X^n W nh _z 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5cyanopyrimidin-2yl)methyl)-1Hbenzo[c!]imidazole-5carbonitrile 386.0 199 73 CN '.•q Ϊ Yr IN NC coxx nh ₂ 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5chloropyrimidin-2yl)methyl)-1Hbenzo[c!]imidazole-5carbonitrile 370.0 200 60 Br Λ N^N ^Cl IN Br NH _Z 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5bromopyrimidin-2yl)methyl)-1Hbenzo[c!]imidazole-6carbonitrile 432.0 201 60 A ^Ν γ ^Ν Xi IN Br /X 7 f X />-\ )- ^F nc-X^n M NH _z 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5bromopyrimidin-2yl)methyl)-1Hbenzo[c!]imidazole-5carbonitrile 432.0 202 67 W z—f IN NC [j X ⁿ . )— ^F 4^'N \ { Nl l ₂ 5-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[c!]imidazol-1 yl)methyl)pyrazin-2- 352.2

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carbonitrile 203 74 Clό %Ms IN c ..... ayu- nh ₂ 2-((3R,4S)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5chloropyrimidin-2yl)methyl)-1Нbenzo[<1]imidazole-6carbonitrile 386.2 204 74 Clό ^OMs B Cl JUL>-O- ^F ιΑΆν / nh ₂ 2-((3R,4S)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5chloropyrimidin-2yl)methyl)-1Нbenzo[<1]imidazole-5carbonitrile 386.2 205 75 Clό SDMs V Cl , A IX-HZA nh ₂ (3R,4R)-3-amino-1 (1-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazol-2yl)piperidin-4-ol 377.0 206 75 Clό \»ls V Cl [l 1 \*0H \--/ nh ₂ (3R,4R)-3-amino-1 (1-((5chloropyrimidin-2yl)methyl)-5-fluoro1Hbenzo[<1]imidazol-2yl)piperidin-4-ol 377.0 207 75 Clό 4)Ms V NC ft 11 1 U-on nh ₂ 6-((2-((3R,4R)-3amino-4- hydroxypiperidin1-yl)-6-fluoro-1Hbenzo[<1]imidazol-1 yl)methyl)nicotinone itrile 367.2 208 75 Cl A N OMs V FA ft T 6-((2-((3R,4R)-3amino-4hydroxypiperidine- 1-yl)-5-fluoro-1Hbenzo[c!]imidazol-1 yl)methyl)nicotinone 367.2

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itril 209 71 Cl 9 Br< IN Cl 7 SY-E NH ₂ (S)-l-(l-((5chloropyridin-2yl)methyl)-1Hbenzo[4]imidazol-2yl) piperidine-3 amine 342.0 210 71 CN X (id Br' IN NC G+O NH ₂ (S)-5-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)picolinone itrile 333.2 211 67 a Ф Br^ A C ^K 'GH> nh ₂ (3R,4R)-1-(1-((5chloropyridin-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidine-Zamine hydrochloride 360.0 212 73 CN JbG A NC c? . I»» nh ₂ (R)-6 -((2-(3-amino4,4difluoropiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)nicotinone itryl hydrochloride 369.0 213 60 Cl i' ^x Br B ^a c\ 4 I Ϊ/Η G NG 1ICI 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5chloropyridin-2yl)methyl)-1Hbenzo[c!]imidazole-6carbonitrile hydrochloride 385.0 214 60 Cl B ^{a C} k 7 NC 1X >- ^f XX'N \-( Ϊιη ₂ HCl 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5chloropyridin-2yl)methyl)-1Нbenzo[c!]imidazole-5carbonitrile 385.0

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hydrochloride 215 67 Cl$ B ^a OcrQ~ ^F nh ₂ hci (3R,4R)-1-(1-((R)-1(5-chloropyridin-2yl)ethyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine hydrochloride 374.2 216 67 Cl B ^{a c} \ A QrO- ^F nh ₂ hci (3R,4R)-1-(1-((S)-1(5-chloropyridin-2yl)ethyl)-1Hbenzo[(1]imidazol-2yl)-4fluoropiperidine-Zamine hydrochloride 374.2 217 68 Cl ό r^OMs B ^a Cl /Y F? NH ₂ HCI (3R,4R)-1-(1-((R)-1(5-chloropyridin-2yl)ethyl)-5,6-difluoro1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3amine hydrochloride 410.2 218 68 Cl J r^OMs B ^{a c} \ 4 ''GH ¹ /-\ .ΧΧχΟ~ ^: nh ₂ hci (3R,4R)-1-(1-((S)-1(5-chloropyridin-2yl)ethyl)-5,6-difluoro1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3amine hydrochloride 410.2 219 69 oh mr— s in B ^{a Cl} \ r ,XIX nh ₂ i ια (3R,4R)-1-(5-xhop-1((R)-l-(5chloropyridin-2yl)ethyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3amine hydrochloride 408.0

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220 69 ACA O Z—J A B ^a 4 XX /AA ^G CiA^-NX—( nh ₂ hci (3R,4R)-l-(5-xnop-l((S)-l-(5chloropyridin-2yl)ethyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine hydrochloride 408.0 221 69 Cl $ B ^a Cl nh ₂ hci (3R,4R)-1-(6-xhop-1((R)-l-(5chloropyridin-2yl)ethyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine hydrochloride 408.0 222 a 69 Cl $ B ^{a c} c C ^CI '^4^N ¥ TA ^f Aji^N \--/ *nh ₂ hci (3R,4R)-1-(6-xhop-1((S)-l-(5chloropyridin-2yl)ethyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3 amine hydrochloride 408.0 223 60 cn B ^a NC i—\ TIA A ^r 'nh ₂ iici 2-((3R,4R)-3-aMHHO4-fluoropiperidine-1 Hn)-l-((R)-l-(5cyanopyridin-2 yl)ethyl)-1Hbenzo[c!]imidazole-6carbonigril hydrochloride 390.2 224 60 m ^S ^O^\ B ^a NC 4 . O>Q 'NHjHCI 2-((3R,4R)-3-aMHHO4-fluoropiperidine-1 Hn)-l-((R)-l-(5cyanopyridin-2 yl)ethyl)-1Hbenzo[c!]imidazole-5carbonigryl hydrochloride 390.2

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225 60 in x z In ^a NC /-X IX I\ I nh ₂ on 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((8)-1-(5cyanopyridin-2 yl)ethyl)-1H- benzo[<1]imidazole-6carbonigryl hydrochloride 390.2 226 60 tn x l - ^ζ ο In ^a NC y. "a> x Kn ₂ on 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((8)-1-(5cyanopyridin-2 yl)ethyl)-1H- benzo[c!]imidazole-5carbonigryl hydrochloride 390.2 227 68 CI ΐ' Br In ^a a 7' NH ₂ HCI (3R,4R)-1-(1-((5chloropyridin-2yl)methyl)-5,6difluoro-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine hydrochloride 396.2 228 68 /Γ\ ? LL—# 4-- In ^a H.xx?o nu ₂ on (3R,4R)-l-(5,6difluoro-1 -((5fluoropyridin-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3 amine hydrochloride 380.2 229 70 03 z— ^z In ^a CI in .unu flour (R)-l-(l-((5chloropyridin-2yl)methyl)-5,7difluoro-1Hbenzo[<1]imidazol-2yl)-4,4difluoropiperidin-3 amine hydrochloride 414.2

- 194 043189

230 70 Clό xr B ^a fa A (R)-l-(l-((5chloropyridin-2yl)methyl)-4,6difluoro-ΙΗbenzo[<1]imidazol-2yl)-4,4difluoropiperidin-3 amine hydrochloride 414.2 231 67 NC Οη With/ A NC % «ox? hh ₂ (R)-l-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)-2,3-dihydro-1Nindene-5carbonigryl hydrochloride 376.2 232 67 NC X A NC 'vXi ^HCI ακ> Nh ₂ (S)-l-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)-2,3-dihydro-1Nindene-5carbonigryl hydrochloride 376.2 233 66 CN N% Y X1 A NC ^α ΌΧΟ 1h to _g (R)-5 -((2-(3-amino4,4difluoropiperidin-1 yl)-6-chloro-1Hbenzo[<1]imidazol-1 yl)methyl)pyrazine-2carbonigryl 404.0 234 66 CN kC y XI A NC XXX (C)-5-((2-(3-amino4,4difluoropiperidin-1 yl)-5-chloro-1Hbenzo[b]imidazol-1 yl)methyl)pyrazine-2carbonigril 404.0

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235 68 n nA ACl V hnA Ah Hy-oh 'hH ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazole-1 ηπ)-Νisopropyl acetamide 370.2 236 68 P A Cl V ρ ΑΗΡ ΪΝΗ ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(azetidin-1 yl)ethanone 368.2 237 68 NC /L-X p Gl V NC^__ /Α—χ Λ ΑλΟ- ΝΗ ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-N-(2cyanopropyl)-Nethyl acetamide 423.2 238 68 \IM At V _F Η NDP Νη ₂ 3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1methylpyrrolidin-2 - He 368.2 239 68 G P V O Ν-\ _O JP ΧΧο-> ΪΜΗ ₂ 3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Нbenzo[<1]imidazol-1 yl)-1phenylpiperidin-2one 444.2

- 196 043189

240 68 Cl J V Ci Y “P KN _g 3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(4chlorophenyl)pyrroli din-2-one 464.2 241 60 MeO Q Cl A MeO HCI nh ₂ 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5methoxypyrimidin2-yl)methyl)-1Hbenzo[c!]imidazole-5carbonigryl hydrochloride 382.2 242 60 MeO C Cl A MeO HCI nh ₂ 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((5methoxypyrimidin2-yl)methyl)-1Hbenzo[<1]imidazole-6carbonigryl hydrochloride 382.2 243 60 C Cl A ^F V HCI nh ₂ 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((6(1fluoromethyl)pyridin-3-yl)methyl)-1Hbenzo[<1]imidazole-6carbonigryl hydrochloride 419.2 244 60 F ₃ C X \u003d N C Cl A ^F V hci nh ₂ 2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-1-((6(1fluoromethyl)pyridin-3-yl)methyl)-1Hbenzo[c!]imidazole-5carbonigryl hydrochloride 419.2

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245 68 \ ots j Br IN \ ОА J Χάθ νη ₂ (S)-3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1methylpyrrolidin-2 - He 368.2 246 68 Br V \ ΟΑ J XcH> ΝΗ ₂ (R)-3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1methylpyrrolidin-2 - He 368.2 247 68 Cl 0 oC J Br V Cl ή X£k>'nh ₂ (S)-3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-1-(4chlorophenyl)pyrrolydin-2 -He 464.2 248 68 Cl V ^6f U_LL (R)-3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-1-(4chlorophenyl)pyrrolidin-2 -He 464.2 249 60 NC Br V NC O Nh ₂ 2-((3R,4R)-3-aMHHO4-fluoro-1piperidinyl)-1 -((5cyano-2pyrazinyl)methyl)1 H-benzimidazole-6carbonigryl 377.2

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250 60 NC An A Br IN δ 2-((3R,4R)-3-aMHHO4-fluoro-1piperidinyl)-1-((5cyano-2pyrazinyl)methyl)1Н-benzimidazole-5carbonigryl 377.2 251 62 NC 4 Cl V NC ,, A ^F OX> fl Hn ₂ 5-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-4,6difluoro-1Hbenzimidazol-1 yl)methyl)-2pyrazinecarbonitrile 388.2 252 62 ^NC >N o nA cr V NC B ί T a A pASl A Eun _g 5-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,7difluoro-Hbenzimidazol-1 yl)methyl)-2pyrazinecarbonitrile 388.2 253 61 HCJ c Br V οχ (38)-1-(1-((5-Fluoro-2pyridinyl)methyl)1 H-benzimidazol-2yl)-N-methyl-3piperidinamine 340.2 254 61 ^Cl \cBr V L co ΝΗ / (38)-1-(1-((5-chloro-2pyridinyl)methyl)1 H-benzimidazol-2yl)-N-methyl-3piperidinamine 356.2 255 61 NC 4 V NC % sho ΪΝΗ / 6-((lR)-1-(2-((38)-3(methylamino)-1 piperidinyl)-1Hbenzimidazol-1yl)ethyl)-3pyridinecarbonitrile 361.2

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256 61 MSO V oto Ън / 6-((lS)-l-(2-((3S)-3(methylamino)-1 piperidinyl)-1Hbenzimidazol-1 yl)ethyl)-3pyridinecarbonitrile l 361.2 257 62 ^c x^ OMs V ^C b a nh ₂ (3R,4R)-1-(1-((5chloro-2pyrimidinyl)methyl)-5,7-difluoro-1Hbenzimidazol-2-yl)- 4-fluoro-3piperidinamine 397.2 258 62 OMs V <x g _F η / NH ₂ (3R,4R)-l-(l-((5chloro-2pyrimidinyl)methyl)-4,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 397.2 259 68 ^BrNCO / V .7 , ΧΧ O- nh ₂ (3R,4R)-l-(5,6difluoro-1-((1-methyl1H-indazol-4yl)methyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 415.2 260 68 ca /=\ ABOUT V I IM and V-i NH; (3R,4R)-l-(5,6difluoro-1-(5quinolinylmethyl)1 H-benzimidazol-2yl)-4-fluoro-3piperidinamine 412.2 261 68 6V V :x> ^j, NH ₂ (3R,4R)-l-(5,6difluoro-1 -((1R)-1 -(8quinolinyl)ethyl)1 H-benzimidazol-2yl)-4-fluoro-3piperidinamine 426.2

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262 68 IN XX _n %vJ/~ ^{f F} \n _g (3R,4R)-l-(5,6difluoro-1 -((1S)-1 -(8quinolinyl)ethyl)1 H-benzimidazol-2yl)-4-fluoro-3piperidinamine 426.2 263 68 Cl V Khts KhCh<>nn- (3R,4R)-l-(l-((3-(3chlorophenyl)-1,2oxazol-5-yl)methyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 462.2 264 68 G & \=/co V /^N 'ΝΗ _Ζ (3R,4R)-l-(5,6difluoro-1-((1-methyl1H-indazol-7yl)methyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 415.2 265 68 R Cl V ¢/ UD (3R,4R)-l-(l-(2,6dichlorobenzyl)-5,6difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 429.0 266 61 ₀ No. 5 cr V No. O νη / 1 -(1-azetidinyl)-2(2-((3S)-3(methylamino)-1 piperidinyl)-1Hbenzimidazol-1yl)ethanone 328.2 267 63 CN i ¹ MsO''- V Ν 1 X y ^N , Xh 6-(( 1R)-1-(4,6difluoro-2((4aR,8aR)hexahydro-2Нpyrido[4,3- b][1,4]oxazin6(5H)-yl)-1Hbenzimidazol-1 yl)ethyl)-3pyridiumcarboxytri 425.2

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L 268 63 CNz MsCT'- IN .and 6-(( 1R)-1-(4,6difluoro-2-((4a8,8a8)hexahydro-2Hpyrido[4,3- b][1,4]oxazine- 6(5Н)-yl)-1Нbenzimidazol-1yl)ethyl)-3pyridinecarbonitrile 425.2 269 63 CN? MSO'- V N h F 45 6-((18)-1-(4,6difluoro-2-((4a8,8a8)hexahydro-2Hpyrido[4,3- b][1,4]oxazine- 6(5Н)-yl)-1Нbenzimidazol-1yl)ethyl)-3pyridinecarbonitrile 425.2 270 63 CN MSO' '- V Nr.. 6-((18)-1-(4,6difluoro-2((4aR,8aR)hexahydro-2Hpyrido[4,3b][1,4]oxazin6(5H)-yl)-1Hbenzimidazol-1yl)ethyl)-3pyridinecarbonitr l 425.2 271 63 CN z MsCU'- V N _Ρ 5όΧ<4, ^F X 6-((lR)-l-(5,7difluoro-2((4aR,8aR)hexahydro-2Hpyrido[4,3b][1,4]oxazin6(5H)-yl)-1Hbenzimidazol-1 yl)ethyl)- 3pyridinecarbonitrile 425.2

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l 272 63 CN ¢MsC'- V N ftft cha 6-((lR)-l-(5,7difluoro-2-((4a8,8a8)hexahydro-2Hpyrido[4,3b][1,4]oxazin6(5H)-yl)-1Hbenzimidazol-1 yl)ethyl) -3pyridinecarbonitrile l 425.2 273 63 CN $ V ,0¾ U_ 6-((18)-1-(5,7difluoro-2-((4a8.8a8)hexahydro-2Hpyrido[4.3b][1.4]oxazin6(5H)-yl)-1Hbenzimidazol-1yl)ethyl)- 3pyridinecarbonitrile l 425.2 274 63 CN MsO' '- V N in _r D>O \ ^F nA 6-((18)-1-(5,7difluoro-2((4aR,8aR)hexahydro-2Hpyrido[4,3b][1,4]oxazin6(5H)-yl)-1Hbenzimidazol-1yl)ethyl)-3pyridinecarbonitrile l 425.2 275 68 H V \n %'nh ₂ 2-(2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5,6difluoro-1Hbenzimidazol-1-yl)N-methyl acetamide 342.2

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276 68 0 Cl IN ^0 o xXXgXX-f ρΑΑί \-/ 'ΝΗ ₂ 2-(2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,6difluoro-1Hbenzimidazol-1 -yl)1-(4morpholinyl)ethanone 398.2 277 68 C-+ V C Х'чХ 1 X Gn >-F f'G N \_/ 'nh ₂ 2-(2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,6difluoro-1Hbenzimidazol-1 -yl)1-(1pyrrolidinyl)ethano n 382.2 278 68 yy Cl V _F °”S W7 blH ₂ 2-(2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,6difluoro-1Hbenzimidazol-1-yl)N, Ndimethylacetamide 356.2 279 68 SG < V X °X— IXX χ _f KXn vV 'nh ₂ (2R)-2-(2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,6difluoro-1Hbenzimidazol-1 -yl)N,Ndimethylpropanamide 370.2 280 68 Cl-X- V , Λ..... ^Γ ν χΝ /-\ fXxxO ^f 'nh2 (2S)-2-(2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,6difluoro-1Hbenzimidazol-1 -yl)N,Ndimethylpropanamide 370.2 281 68 Q V XrH > hH ₂ 2-(2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,6difluoro-1Hbenzimidazol-1 -yl)1-(1- 396.2

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piperidinyl)ethanone 282 68 at Br' IN HN-B _F :ххн> nh ₂ 2-(2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5,6difluoro-1Hbenzimidazol-1-yl)N-ethylacetamide 356.2 283 64 Clό V Cl c HN- 1-((5-chloro-2pyrimidinyl)methyl)-2-((ЗR,4R)-4-φτop3-(methylamino)-1piperidinyl)-1Нbenzimidazole-6carbonitrile 400.0 284 64 tn 9 W' ?— "ζ V CI P _NC -CcH> HN— 1-((5-Chloro-2pyrimidinyl)methyl)-2-((3R,4R)-4-φτop3-(methylamino)-1piperidinyl)-1Hbenzimidazole-5carbonigryl 400.0 285 69 Λ V R and 2-(2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-6chloro-1Hbenzimidazol-1 -yl)1-(1azetidinyl)ethanone 366.2 286 69 <> V d °b Tnh ₂ 2-(2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5chloro-1Hbenzimidazol-1 -yl)1-(1azetidinyl)ethanone 366.2 287 74 _ΒΑ V c ^gk Su <- NHj 2-((3R,4S)-3-aMHHO- 4-fluoro-1piperidinyl)-1 -(2(1-azetidinyl)-2 oxoethyl)- 1Hbenzimidazole-6carbonitrile 357.2

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288 74 A) Br V A 'mn ₂ 2-((3R,4S)-3-aMHHO4-fluoro-1piperidinyl)-1-(2(1-azetidinyl)-2oxoethyl)-1Hbenzimidazole-5carbonigryl 357.2 289 65 ClΔ MSCT V ci ъ YN _g (3R,4R)-1-(1-((5chloropyrimidin-2yl)methyl)-6-fluoro- 1H- benzo[b]imidazol-2yl)-4fluoropiperidin-3- amine 379.0 290 65 Clό MsO^ V Ck ijH ₂ (3R,4R)-1-(1-((5chloropyrimidin-2yl)methyl)-5-fluoro1Hbenzo[b]imidazol-2yl)-4fluoropiperidin-3- amine 379.0 291 71 y—ώ 0 z A ъ №\ ) NH _Z JSC (R)-6-((2-(3amino piperidin-1 yl)-1Hbenzo[b]imidazol-1 yl)methyl)nicotinone igril 333.2 292 72 N _; Ύ1 N - Br A ^NC _V N h .. CXcO Ό nh ₂ (R)-5-((2-(3aminopiperidin-1 yl)-1Hbenzo[b]imidazol-1 yl)methyl)picolinon igryl-2,2,2trifluoroacetate 333.0 293 72 OX ^Br A (R)-l-(l(isoquinolin-7 ylmethyl)-1Hbenzo[b]imidazol-2yl) piperidine-3 amine 358.2

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294 72 N A /^:N γ~ Cc7Q nh. (R)-1-(1-((1-methyl1H-indazol-7yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 361.2 295 71 γζϊ OMs A NC A LXXO n-ci 'nh ₂ 6-((R)-l-(2-((S)-3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)nicotinoni trila hydrochloride 347.2 296 71 χτ OMs A NC Ύ CX3 iM Hi 6-((S)-l-(2-((S)-3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)nicotinoni trila hydrochloride 347.2 297 67 γ N' OMs IN NC Λ 7 H-CI n -,., ox> nh ₂ 6-((R)-l-(2-((3R,4R)3-amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)nicotinoni trila hydrochloride 365.0 298 67 γ N' OMs IN NC C..... ^h - ^ci CXO 'MH ₂ 6-((S)-l-(2-((3R,4R)3-amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)nicotinoni trila hydrochloride 365.0 299 71 γ,,ΧΝ /γΧχ OMs IN NC Q, ^H -d exo NH, 6-((R)-l-(2-((S)-3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)propyl)nicotino nitrile hydrochloride 361.2

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300 71 OMs IN NC a,, ) H-CI ayu '\n ₂ 6-((S)-l-(2-((S)-3aminopiperidin-1 yl)-1Hbenzo[c!]imidazol-1 yl)propyl)nicotino nitrile hydrochloride 361.2 301 68 Xr ^ci HCI IN R (3R,4R)-l-(5,6difluoro-1-((5fluoropyrimidin-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3amine 381.2 302 68 a ⁿ cr IN CN /X XA 'ΝΗ, 3-(l-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)ethyl)benzonitrile 400.2 303 68 Ck nA _n Y HCI F IN . h ANH K1N ₂ (3R,4R)-l-(5,6difluoro-1 -((5fluoropyrimidin-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3amine 381.0 304 76 5 IN F C/ ^N IX NE - ^f _F MN '--( nh ₂ (3R,4S)-l-(5,6difluoro-1 -((5fluoropyridin-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3- amine 380.2 305 77 Cl nA _n Y HCI F IN F An ^F 'APQ-NH ₂ (3R,4S)-4^Top-l-(l((5-fluoropyrimidin2-yl)methyl)-6(trifluoromethyl)-1Hbenzo[c!]imidazol-2- 413.2

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yl) piperidine-3 amine 306 77 ^C, 1 N^N Y HCl F V h _FiC jO>Q' ^f Nh ₂ (3R,4S)A^to _P -1-(1((5-fluoropyrimidin2-yl)methyl)-5(trifluoromethyl)-1Hbenzo[<1]imidazol-2yl)piperidin-3-amine 413.2 307 78 ΞΓ Oh Oh V ,0 Χακχ KlH ₂ (R)-1-(5,6-difluoro-1((5-fluoropyridin-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)-4,4difluoropiperidin-3- amine 398.0 308 77 Scr V Νη ₂ 2-(2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethyl)-1Нbenzo[<1]imidazol-1 yl)-1-(azetidin-1 yl)ethan-1-one 400.2 309 77 o Xcr V _F1C XXH> νη ₂ 2-(2-((3R,4S)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethyl)-1Нbenzo[<1]imidazol-1 yl)-1-(azetidin-1 yl)ethan-1-one 400.2 310 68 V -β U.LL 2-(2-((3R,4R)-3amipo-4fluoropiperidin-1 yl)-5,6-difluoro-1Нbenzo[<1]imidazol-1 yl)-1-(2,2dimethylpyrrolidin -1-yl)ethan- 1-he 410.2

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311 80 j1 CD "Ar IN about about 6-((2-((3R,4S)-3amino-4- hydroxypiperidin1-yl)-6-fluoro-1Hbenzo[<1]imidazol-1 yl)methyl)nicotinon igril 367.2 312 80 CN r Br V NG c Kn ₂ 6-((2-((3R,4S)-3amino-4hydroxypiperidin1-yl)-5-fluoro-1Hbenzo[<1]imidazol-1 yl)methyl)nicotinone igril 367.2 313 71 CN A NC B- JSC ^,ια b|H ₂ 4-((R)-l-(2-((S)-3aminopiperidin-1 yl)-1Hbenzo[(1]imidazol-1 yl)ethyl)benzoni!ril a hydrochloride 346.2 314 71 CN$BO'- A NC in OAO ^on 'nHz 4-((S)-l-(2-((S)-3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)benzonigril a hydrochloride 346.2 315 71 ON 4Br A NC JSC "ing _g (S)-4-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)-3fluorobenzonigril hydrochloride 350.0 316 71 Cl9BA A CI at SAO ^{ns |} NHz (S)-l-(l-(4chlorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine hydrochloride 341.0 317 79 CN $ V g A NS o / CHA \ ίX y ^{, F} Άι \—ζ । ici' NHz 4-((R)-l-(2-((3R,4S)3-amino-4fluoropiperidin-1 yl)-1H- 364.0

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benzo[<1]imidazol-1 yl)ethyl)benzonitrile a hydrochloride 318 79 CN $ ΒγΆ A NC ay ·. ying _g 4-((S)-l-(2-((3R,4S)3-amino-4fluoropiperidin-1 yl)-1Hbenzo[(1]imidazol-1 yl)ethyl)benzonigril a hydrochloride 364.0 319 67 CN B ΒγΆ A NC O, ί X Ά A •Λ-n A on νη ₂ 4-((R)-l-(2-((3R,4R)3-amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)benzonigril a hydrochloride 364.2 320 67 CNθ A NC B OHR _u NH ₂ 4-((S)-l-(2-((3R,4R)3-amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)benzonigril a hydrochloride 364.2 321 71 CN ό, ow A NC su sao NH _? (8)-4-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)-3chlorobenzenigril hydrochloride 366.0 322 68 kdu ^6g IN Cl cr ΎΑ λν Af = Ο 4ιη ₂ (3R,4R)-1-(1-((1R)-1(2,4dichlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 453.2

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323 68 XjC.Br IN CI _r (3R,4R)-1-(1-((1S)-1(2,4dichlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 453.2 324 68 th V , G χ" o- NH, (3R,4R)-1-(1-((1R)-1(2-chlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 409.2 325 68 l CD V HFO 'NH; (3R,4R)-1-(1-((1S)-1(2-chlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 409.2 326 68 _C |jOy ^Br V W>'nh ₂ (3R,4R)-1-(1-((1R)-1(3-chlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 409.2 327 68 _c! jOy^ V '1-0 w> νη ₂ (3R,4R)-1-(1-((1S)-1(3-chlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 409.2 328 68 AND V OVci F? 'ΝΗ _Ζ (3R,4R)-1-(1-((1R)-1(2,5dichlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 443.0 329 68 xg" V OO-ci ^c1 Hell XCco 'NH _Z (3R,4R)-1-(1-((1S)-1(2,5dichlorophenyl)ethyl)5,6-difluoro-1H- 443.0

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benzimidazol-2-yl)4-fluoro-3piperidinamine 330 68 γχ V y------S 1 G /M f _Γ νΎ ^λ ' f (3R,4R)-1-(1-((1R)-1(2,4difluorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 411.2 331 68 V , h XY-S- bn _g (3R,4R)-1-(1-((1S)-1(2,4difluorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 411.2 332 68 _C1 XXy V ^C| \ ^c, 40 XX 'NH; (3R,4R)-1-(1-((1R)-1(3,4dichlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 443.0 333 68 ^C| \X V CI 'ХХлSU' and (3R,4R)-1-(1-((1S)-1(3,4dichlorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 443.0 334 68 _fox V f _G »H>'X|H ₂ (3R,4R)-1-(1-((1R)-1(2,5difluorophenyl)ethyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 411.2 335 68 ,χχ V _F <_0'nh2 (3R,4R)-1-(1-((1S)-1- (2.5- difluorophenyl)ethyl)- 5,6-difluoro-1H- 411.2

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benzimidazol-2-yl)4-fluoro-3piperidinamine 336b 68 V FF ^F'NH ₂ (3R,4R)-l-(5,6difluoro-1-((1R)-l-(4(1rifluoromethyl)phenyl l)ethyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 443.2 337b 68 φ O F G V Xcma nor _g (3R,4R)-1-(5,6difluoro-1 -((1R)-1 -(4(1fluoromethoxy)phenyl)ethyl)-1Hbenzimidazol-2-yl)- 4-fluoro-3piperidinamine 459.2 338 68 S _l NA or V u YU - (3R,4R)-l-(l-(5chloro-2(1rifluoromethoxy)benzyl)-5,6-difluoro1 H-benzimidazol-2yl)-4-fluoro-3piperidinamine 479.2 339 68 And V N^N XiH> a ₂ (3R,4R)-l-(5,6- difluoro-1-(4-(1H1,2,4-1riazol-1yl)benzyl)-1Hbenzimidazol-2-yl)- 4-fluoro-3piperidinamine 428.2 340 68 Z V ci O'™ ddl<>'nh ₂ 2-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5,6difluoro-1Hbenzimidazol-1yl)methyl)-5chlorobenzonitrile 420.2 341 68 CI th. bJ V 'L w- Nl l _? (3R,4R)-1 -(1-(2,4dichlorobenzyl)-5,6difluoro-Hbenzimidazol-2-yl)- 429.2

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4-fluoro-3piperidinamine 342 68 CN qAochf ₂ in V NC Y^yOSNG _g IX VN /“F Ϊιη _ζ 4-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5,6difluoro-ΙΗbenzimidazol-1 yl)methyl)-3(difluoromethoxy)benzonitrile 452.2 343 68 ώ ο—ts V ci c—χχ Eun _g (3R,4R)-l-(l-(2,5dichlorobenzyl)-5,6difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 429.0 344 68 ^gu_^ W V XeH> ΝΗ, (3R,4R)-l-(l-(4-(l,ldifluoroethyl)benzyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 425.2 345 68 N •4 hg V N . uh, shu NH _? 4-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5,6difluoro-1Hbenzimidazol-1yl)methyl)-2methylbenzonitrile 400.2 346 68 __ X V Ch^X IX /X Η F-XY-N νγ NH _Z 4-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5,6difluoro-1Hbenzimidazol-1yl)methyl)-2chlorobenzonitrile 420.2 347 68 „.Ο/ V ^c| XX^ W> NFL 2-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5,6difluoro-1Hbenzimidazol-1yl)methyl)-4- 420.2

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chlorobenzonitrile 348 68 U_lil V UN ₂ (3R,4R)-1-(1-(2(difluoromethoxy)benzyl)-5,6-difluoro-1Hbenzimidazol-2-yl)- 4-fluoro-3- piperidinamine 427.2 349 68 Cl V about οι xzh AND (3R,4R)-l-(l-(3chloro-4-fluorobenzyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 413.0 350 68 V Cha ΧΆ Μ f (3R,4R)-1-(1-(4chloro-2methoxybenzyl)-5,6difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 425.2 351 68 XG V F Ck ^F XXHA F (3R,4R)-l-(l-(2,4difluorobenzyl)-5,6difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 397.2 352 68 a- V xS<> w (3R,4R)-l-(5,6difluoro-1-(2(trifluoromethyl)benzyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 429.2 353 68 OS V oa and 2-((2-((3R,4R)-3amino-4-fluoro-1 piperidinyl)-5,6difluoro-1Hbenzimidazol-1 yl)methyl)benzonitr silt 386.2

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354 68 Rco V C ^C| AND? bn ₂ (3R,4R)-1-( 1-(2- chlorobenzyl)-5,6- difluoro-1Hbenzimidazol-2-yl)- 4-fluoro-3- piperidinamine 395.0 355 68 TsTsvg V F G%-C1 m fXXxm^ b1H ₂ (3R,4R)-1-(1-(2chloro-4-fluorobenzyl)5,6-difluoro-1Hbenzimidazol-2-yl)- 4-fluoro-3- piperidinamine 413.0 356 68 -& V χΜ Tso HM 'nh ₂ (3R,4R)-l-(5,6difluoro-1-(4-φτορ-2(trifluoromethyl)benzyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 447.2 357 68 to. V X 'un _g (3R,4R)-1-(1-(3,4difluorobenzyl)-5,6difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 397.2 358 68 hCCv ^g V to .'+ ^F Xr^,N >— _h IX M >F f-KKn X NH _; (3R,4R)-l-(l-(4chloro-2-fluorobenzyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 413.0 359 68 :a..· V •to 3,ΧΧ/Ό-' (3R,4R)-1-(1-(3,4- dichlorobenzyl)-5,6difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 429.0 360 68 Xb V to mk> (3R,4R)-l-(l-(4chloro-3-fluorobenzyl)5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3- 413.2

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piperidinamine 361 68 - Chg V l LI? Fn _g (3R,4R)-l-(5,6difluoro-1-(4(1fluoromethyl)benzyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 429.2 362 68 /—ώά ll Lu V dho-ilH ₂ (3R,4R)-l-(5,6difluoro-1-(4(trifluoromethoxy)benzyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 445.2 363 68 ^4Br V XO-O- νη ₂ (3R,4R)-1-(1-(4(difluoromethyl)benzyl)-5,6-difluoro-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 411.2 364 68 0 Or V Yol i τι A (3R,4R)-l-(5,6difluoro-1-(3(1fluoromethoxy)benzyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 445.2 365 68 Kommersant Br V (VA LL. AND- (3R,4R)-l-(5,6difluoro-1-(3(trifluoromethyl)benzyl)-1Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 429.2 366 68 W V N L whether? in ₂ 3-((2-((3R,4R)-3amino-4-fluoro-1piperidinyl)-5,6difluoro-ΙΗbenzimidazol-1yl)methyl)benzoyl silt 386.2

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367 68 Cl Λ V C.I. in ,:000NH ₂ (3R,4R)-l-(l-(3chlorobenzyl)-5,6difluoro-Hbenzimidazol-2-yl)4-fluoro-3piperidinamine 395.2 368 71 V u ayu nh ₂ (S)-l-(l-(4fluorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 325.3 369 71 Ζ ζ---1 W 7 V OOO nh ₂ (S)-1-(1-(4-(1,2,4oxadiazol-3yl)benzyl)-1Hbenzo[c!]imidazol-2yl)piperidine-3 amine 375.2 370 72 SO ₂ Me $ B A V MeO ₂ S at ayu (R)-l-(l-(4(methylsulfonyl)benzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 385.2 371 72 CD 'MA-A V L NN y /Ά /—\ COQ NH _? (R)-l-(l-(4-(lH1,2,4-1riazol-1yl)benzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3 - amine 374.0 372 72 At A a and (R)-2-((2-(3aminopiperidin-1 yl)-1Hbenzo[c!]imidazol-1 yl)methyl)benzonitr silt 332.2 373 72 A XV ^e1 cg / "A (R)-l-(l-(2,6dichlorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 376.2

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374 72 U· A CcpQnh, (R)-l-(l-(2chlorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 341.2 375 72 ί ³ SC A F ₃ C 4 QA (R)-l-(l-(4(trifluoromethyl)benzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 375.2 376 72 OCF, X A F ₄ CO 4 nh ₂ (R)-l-(l-(4(trifluoromethoxy)benzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 391.0 377 72 Ci ί ³ SK A ^Cl \ C (R)-l-(l-(4chlorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 341.2 378 72 ? A Cl A O> ⁿ Q NH, (R)-l-(l-(3chlorobenzyl)-1Hbenzo[c!]imidazol-2yl) piperidine-3 amine 341.2 379 72 X SC A OPQ Nl 1; (R)-l-(l-(4-(l,ldifluoroethyl)benzyl)1Hbenzo[<1]imidazol-2yl)piperidine-3amine 371.2 380 72 fM ⁿ ί ϋΚ A Me Ms .Me ^NC Ή (R)-2-(4-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)phenyl)-2methylpropanenitrile 374.2

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381 72 SC A I A LL (R)-l-(l-(4(difluoromethyl)benzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 357.0 382 72 Me or L 0 9 A ⁴ Qa>q. (R)-4-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1] imidazol-1 yl)methyl)-Mmethylbenzamide 364.2 383 72 CN h s K A NC al NH ₂ (R)-4-((2-(3aminopiperidin-1 yl)-1Hbenzo[b]imidazol-1 yl)methyl)-3fluorobenzonigril 350.2 384 72 O-^CN sK A (R)-2-(4-((2-(3aminopiperidin-1 yl)-1Hbenzo[b]imidazol-1 yl)methyl)phenoxy)a cetonitrile 362.2 385 72 SO ₂ NMe ₂ δ A Me ₂ NO ₂ S 4 (R)-4-((2-(3aminopiperidin-1 yl)-1Hbenzo[b]imidazol-1 yl)methyl)-N, Ndimethylbenzenesulfonamide 414.2 386 72 Me A Me 4 caq \n ₂ (R)-l-(l-(4methylbenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 321.2 387 72 A '4 OQ \h ₂ (R)-l-(l-(4fluorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 324.4

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388 72 CC ⁿ J Me A Σ f L J ? J (R)-1-(1-((1-methyl1H-indazol-7yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 361.2 389 72 ί· A F yy OY ⁿ Q\h ₇ (R)-1-(1-(2,4difluorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 343.2 390 72 A 4 0>Q nh ₇ (R)-1-(1-(3,4difluorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 343.2 391 72 Cl A +8 (R)-l-(l-(4-xnop-3fluorobenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 359.2 392 72 V° SG from g A (R)-1-(1-((3-(3chlorophenyl)isoxazol-5-yl)methyl)- 1Hbenzo[<1]imidazol-2yl)piperidine-3amine 408.2 393 72 Omi? I.C.K. A MeC^^F 8 exp \1H ₂ (R)-1-(1-(3-xnop-4methoxybenzyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 371.2 394 72 CN.1 A NC tq OQ \n ₇ (R)-4-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)-3chlorobenzonitrile 366.2

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395 72 Cl 0. A ci r (R)-1-(1-(2,4dichlorobenzyl)-1Hbenzo[b]imidazol-2yl)piperidine-3 amine 376.2 396 72 c A NC Y^y-Ome A CQ-Q NH _? (R)-4-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)-3methoxybenzonigril 362.2 397 72 Cl X A Cl/Gc-QNH _? (R)-2-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)-5chlorobenzonitrile 366.2 398 72 CN$MsO Me A NC O ^yix CcoQ nh ₂ 4-((R)-l-(2-((R)-3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)benzonigril 347.2 399 71 Φ'= ^/ 2 A NC mind CcxQ 'NH _a 4-(l-(2-((S)-3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)ethyl)benzonigril 346.2 400 72 o g A CN A 0>Q nh ₂ (R)-3-((2-(3aminopiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)methyl)benzonitr silt 332.2 494 Clό Sils IN Cl X nh ₂ (3R,4R)-3-amino-1 (1-((5chloropyrimidin-2yl)methyl)-5-fluoro1Hbenzo[<1]imidazol-2yl)piperidin-4-ol 377.2

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495 o ^a ^ο V 0 A ^α Ό><> νη ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-chloro-1Hbenzo[<1]imidazol-1 yl)-1morpholinoethanone 396.2 496 75 Clό AMs V Ό>ο" (3R,4R)-3-amino-1 (1-((5chloropyrimidin-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazol-2yl)piperidin-4-ol 377.2 497 69 0 L^O V 0 3 _α ΧΧλ<> Мн, -(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-chloro-1Hbenzo[<1]imidazol-1 yl)-1morpholinoethanone 396.2 498 68 i>o V “I Ya .-ΌΌ /—, T Hn wf ^a An ή book ₂ (3R,4R)-1-(1-((R)-1(5-chloropyrimidin2-yl)ethyl)-5,6difluoro-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 411.0 499 81 /“Oh ^- V N.C.7 I X F N S^N Η Ή 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethyl)-1Nimidazo[4,5b]pyridin-1yl)methyl)nicotinone igril 420.2

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500 68 4 V f,f Ή _F °4 NH _Z 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazole-1 - yl)-M-methyl-M(2,2,2trifluoroethyl)acetam id 424.2 501 68 X N ^==0 Cl V at? ΧΪη> NH _S 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-M-methyl-M(thiazol-2yl)acetamide 425.2 502 69 1 °y ^N . Br V ^C| x>x'\n _r 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-chloro-1Нbenzo[<1]imidazol-1 yl)-N, Ndimethylacetamide 354.2 503 65 Cl V 4 _F °4 ZONE> Ή 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol-1 yl)-1-(azetidin-1 yl)ethan-1-one 350.2 504 68 X ο^Λ Cl V .y Hsn> NH> 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(3(trifluoromethyl)piperidin-1-yl )ethane-1 - He 464.2

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505 68 L A Cl V χίΧ νη ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(6,7dihydrothieno[3,2c]pyridine- 5(4Н)yl)ethan-1-one 450.2 506 69 1 °γ ^N -. Br V Ν' _α ΌΧθ 'νη ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-chloro-1Нbenzo[<1]imidazol-1 yl)-N, Ndimethylacetamide 354.2 507 68 Ό l Cl V 3 ύ' 'Ά 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Нbenzo[<1]imidazol-1 yl)-1-(2methylmorpholino)eth an-1-one 412.2 508 68 ω V Ck I :»n>'νη ₂ (3R,4R)-1-(1-((R)-1(5-chloropyrimidin2-yl)ethyl)-5,6difluoro-Nibenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 411.0 509 82 οΧ CI V MeO X ' bn _g 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-7methoxy-1Hbenzo[<1]imidazole-1 ππ)-N-methyl-N(2,2,2trifluoroethyl)acetam id 436.2

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510 68 0 a V 0 .4 I T W νη ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Нbenzo[<1]imidazol-1 yl)-1-(azocan-1yl)ethan-1-one 424.2 511 68 uch ¹ C? Ao CI V Np ^N ,-N O _F X TONE w 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(4-(pyrazin-2yl)piperazin-1 yl) ethane-1-one 475.2 512 68 ΐ Aό ci V in _F °a \-%,Ν /—χ I zlM A ^F νΗ ₂ methyl 1-(2-(2((3R,4R)-3-aMHHO-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)acetyl)piperidium n-4-carboxylate 454.2 513 68 A 'Ν Cl V U o zVLaaa T V o 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(2ethylmorpholino)ethan-1-one 426.2 514 65 Cl V 0 h .HAASA mn _g 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-1Hbenzo[<1]imidazol-1 yl)-1-(azetidin-1 yl)ethan-1-one 350.2

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515 68 With V ::CAO 1JH ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-N-(1,1-dioxido2,3-dihydrothiophene- 3-yl)-S- phenylacetamide 520.2 516 68 ό 00 Ci V 6 ΧίΟ NHj 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(4methylpiperidin-1 yl)ethan-1-one 410.2 517 65 h. V LO Me0--\d T T o? A yn ₂ (3R,4R)-4^Top-l-(6fluoro-1-((4methoxypyridin-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)piperidine-3 - amine 375.2 518 68 Chek A Cl V l YXan A X---/ nh ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(2ethylmorpholino)ethan-1-one 426.2 519 81 CD AZA V Ahn> NH, X NC 6-((2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethyl)-3Nimidazo[4,5b]pyridin-3yl)methyl)nicotinone itrile 420.2

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520 65 <1 IN Oh oh \FT 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-1Hbenzo[<1]imidazol-1 yl)-1-(azetidin-1 yl)ethan-1-one 332.2 521 68 \ K/P Am ι ⁰ ί ° Cl V _F A: mon> Nh ₂ 1 -(2-(2-((3R,4R)-3 amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)acetyl)piperidium n-2-carboxamide 439.2 522 68 Λ* h° Cl V А νΆ, ₀ ХАО \n ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro- 1Hbenzo[<1]imidazol-1 yl)-N-(1,1dioxidotetrahydro thiophen-3-yl)- M(thiophen-2ylmethyl)acetamide 542.2 523 68 Λ Cl V A4O ^f mn ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1(octahydroisoquinol in-2( 1 H)-yl) ethane-1 - He 450.2 524 65 ^VeO v'4 h OMs V MeoX^D^ _f jQH> w (3B,4B)-4-fluoro-1-(5fluoro-1-((4methoxypyridin-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3-amine 375.2

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525 68 pF N At V x _f x ano \n ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-N-(1,1dioxidotetrahydro thiophen-3-yl)- Mmethyl acetamide 460.2 526 68 o C' V _o ^y Aho-bn ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazole-1 ππ)-N-cyclopropyl - N-(l,ldioxidotetrahydro thiophen-3yl)acetamide 486.2 527 68 p4 h V _F X * XAO ^H _g 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-N-(1,1dioxytetrahydro thiophei-3-yl)^ethyl acetamide 474.2 528 68 A° A V x ° _F % NH ₂ 4-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)acetyl)piperazine H-2-0H 411.2 529 68 o o 0 V Q 0 \n ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(4(pyrrolidin-1- 493.2

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carbonyl)piperidine -1-yl)ethan-1-one 530 68 0 ^Λνη ₂ A V O G ΝΗ _Ξ 1 -(2-(2-((3R,4R)-3 amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)acetyl)piperidium n-3-carboxamide 439.2 531 68 0 g Cl V V 0 _F АЖИ> \n ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(4(cyclopropanecarbonyl)piperazin-1 yl) ethane-1-he 465.2 532 68 oZh o δ' V ^N 0O _F X Hyogo \n ₂ 1 -(2-(2-((3R,4R)-3 amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)acetyl)piperidium n-4-carboxamide 439.2 533 68 n δ V \ L^ ⁿ νΆΓ _F g ChFOhm 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-M-(2cyanopropan-2-yl)N-methyl acetamide 409.2 534 68 000 Cl V / hn _l ',ac^ \n ₂ 1 -(2-(2-((3R,4R)-3 amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)acetyl)-Mmethylpiperidine-4carboxamide 453.2

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535 68 cP cAr Cl IN A _F L Acre \n _g N-(l-(2-(2-((3R,4R)3-amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)acetyl)piperidium n-3- yl)acetamide 453.2 536 68 I X IN Q th Gr L ARP 'nh ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(4-(piperidine1carbonyl)piperidin-1-yl )ethane-1-one 507.2 537 68 JO b P Cl V _F L Μα-ν T G H \ w _f aPn A hH _; 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(4-(azepane-1 carbonyl)piperidine -1-yl)ethan-1-one 521.2 538 68 , A V ο ^Ζ _π A / AO mal» _F L ⁰ Αλπ Yn _g 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-K1-(1,1dioxidotetrahydro thiophen-3-yl)- K1-(2methoxyethyl)acetamide 504.2 539 68 W ABOUT V Ύ/ν NG l ACR 'nh ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Нbenzo[(1]imidazol-1 yl)-1-(4-(3methylpiperidine-1 carbonyl)piperidine 521.2

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-1-yl)ethan-1-one 540 68 0 g V y °, -Ν O 1mn ₂ 1-(4acetylpiperazin-1 mi)-2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)ethan-1-one 439.2 541 68 0 01 V and _F X ⁰ w> Yn ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-N-(1,1dioxytetrahydro thiophen-3-yl)-M((tetrahydrofuran2yl)methyl)acetamide 530.2 542 68 ί s V ιΉ _F Υ _F XiH>'nh ₂ 1-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)acetyl)Isopropyl-Nmethylpiperidine-4carboxamide 495.2 543 68 4, ϋ V y. ⁰ X Nh ₂ 2-(2-((3R,4R)-3amino-4- methoxypiperidin1-yl)-6-fluoro-1Hbenzo[(1]imidazol-1 yl)N-methyl-N(2,2,2trifluoroethyl)acetamide 418.2

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544 82 Cl IN ⁿ ^cf ₃ MeO Xy Ankh NH; 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-7methoxy-1Hbenzo[c!]imidazol-1 yl)-N-methyl-N(2,2,2trifluoroethyl)acetam id 436.2 545 82 About 0 IN 0 _F %OMe 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-4methoxy-1Hbenzo[c!]imidazol-1 yl)-1morpholinoethan-1-one 410.2 546 82 ABOUT X/° IN O oD _f J0C0Q- ^f nh ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-7methoxy-1Hbenzo[c!]imidazol-1 yl)-1morpholinoethan-1-one 410.2 547 68 O A J °=<p XXxCj- ^f pX/X X- NH _? (R)-3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-1cyclopropylpyrrole idin-2-one 394.2 548 68 0 N->_ °=o Br A Q N ^ °=K1 JO0O (S)-3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-1-(tetrahydro2H-pyran-4yl) pyrrolidin-2-one 438.2

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549 68 3 y A oC J ITX NH _? (S)-3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1cyclopropylpyrrole idin-2-one 394.2 550 68 h o=^l Br A Q N-_ O=4j XXxO ^F \n ₂ (R)-3-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(tetrahydro2H-pyran-4yl) pyrrolidin-2-one 438.2 551 68 Me XI IN tx (3R,4R)-l-(5,6difluoro-1 -((5methylthiazol-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3 amine 382.2 552 62 Me xn X XI IN MeN A "W-F NH ₂ (3R,4R)-1-(4,6difluoro-1 -((5-methyl1,3,4-thiadiazole-2- yl)methyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 383.2 553 68 Me xn S^N XI V N Me y XXXO- ^f _f AAn x—< nh ₂ (3R,4R)-l-(5,6difluoro-1-((5-methyl1,3,4-thiadiazol-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3amine 383.2

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554 83 F ₃ C^ mFJ Al IN 0D-O γΑ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6- (trifluoromethyl)-1Hbenzo[<1]imidazole-1 ηπ)-N-methyl-N(2,2,2trifluoroethyl)acetam id 456.2 555 84 Cl A OMs B δ* lN Ll_ (3R,4R)-1-(1-((5chloropyrimidin-2yl)methyl)-6-fluoro1H-imidazo[4,5b]pyridin-2-yl)-4fluoropiperidin-3 - amine 380.0 556 62 M 0 Me _l s \u003d o AW XI V δ* Nya (3R,4R)-1-(4,6difluoro-1-((5(methylsulfonyl)pyridin-2-yl)methyl)1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 - amine 440.2 557 62 F ^F \ T Al V δ' ^£ Aya LL. (3R,4R)-l-(l-((5(difluoromethyl)-1,3,4thiadiazol-2yl)methyl)-4,6difluoro-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 419.2 558 62 X Me'Y Al V u. o ^P \IHZh /—\ Ύ T X^^N X-< (1 nh ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-4,6-difluoro-1Hbenzo[<1]imidazole-1 ηπ)-N-methyl-N(2,2,2- 424.2

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trifluoroethyl)acetamide 559 69 F ₃ C^ Me ^N y° XI V Q. C “Ό:Η> toX \-( NH _; 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-chloro-1Hbenzo[4]imidazole-1 ηπ)-N-methyl-N(2,2,2trifluoroethyl)acetam VD 422.2 560 68 F ^F \ X Ml V X hy LL LL (3R,4R)-l-(l-((5(difluoromethyl)-1,3,4thiadiazol-2yl)methyl)-5,6difluoro- 1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 - amine 419.0 561 65 Me Ή XI V N Me ^ N th ΌΧΧ 'NHj (3R,4R)-4^Top-l-(6fluoro-1 -((5-methyl1,3,4-thiadiazol-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3 amine 365.2 562 68 me. /I M-o 7 XI V Mcg\ c XtoO 'nh ₂ (3R,4R)-l-(5,6difluoro-1-((5(methylsulfonyl)pyridin-2-yl)methyl)1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 - amine 440.2 563 83 Me Me^y ⁰ XI V Me N-me /—\ XX zmCJJ-f Nj^N '-< 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6(trifluoromethyl)-1Hbenzo[<1]imidazole-1 - 388.2

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yl)-N, Ndimethylacetamide 564 68 Me IN Cl V 0' Huh LL|_L (3R,4R)-l-(5,6difluoro-1-((5methylisoxazol-3yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3 amine 366.2 565 62 Me mau ⁰ XI V Me Y-Me 0=4 y X W '----< [1 nh ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-4,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-N, Ndimethylacetamide 356.2 566 65 Me XI V Me >^Me 1 X f ^n ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-N, Ndimethylacetamide 338.2 567 68 -.z I f^° 2 V a hy LL LL (3R,4R)-l-(5,6difluoro-1 -((5methyloxazol-2 yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3amine 366.2 568 68 Me A XI V a hy LL LL (3R,4R)-l-(5,6difluoro-1-((4methylthiazol-2yl)methyl)-1Hbenzo[c!]imidazol-2yl)-4fluoropiperidin-3 - amine 382.0

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569 65 “P F V N F ₂ C-^4 ^h O _F A HZH? 'ΝΗ _; (3R,4R)-4-fluoro-1-(6fluoro-1-((3(trifluoromethyl)1,2,4-oxadiazol-5yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3-amine 403.2 570 69 F ₃ C^ MA ^N y ^G XI V With". °γ lx> νη ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-chloro-1Hbenzo[<1]imidazol-1 yl)-H-methyl-N(2,2,21fluoroethyl)acetamide 422.2 571 68 Me CAN XI V Me—A Ή A I T -ΆΑ \—f ή (3R,4R)-l-(5,6difluoro-1-((5-methyl1,3,4-oxadiazol-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3amine 367.2 572 68 Me y°. N ,N XI V 0' G Y U_U- (3R,4R)-l-(5,6difluoro-1-((5-methyl1,2,4-oxadiazol-Zyl)methyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 367.2 573 65 F ^F \ /=N T XI V F \ ιχ /—S' N ΌΡΟ nh ₂ (3R,4R)-l-(l-((5(difluoromethyl)-1,3,4thiadiazol-2yl)methyl)-6-fluoro1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 401.2

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574 84 Me Ή X XI V hr Me —N g nh ₂ (3R,4R)-4-fluoro-1-(6fluoro-1-((5-methyl1,3,4-thiadiazol-2 yl)methyl)-1Nimidazo[4,5b]pyridin-2yl)piperidine-3 amine 366.2 575 68 Me^__^Me °γ ^N XI V 0 X >9 (3R,4R)-l-(l-((4,5dimethyloxazol-2yl)methyl)-5,6difluoro-Nibenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 380.2 576 65 Me MeJ XI V X and 1.9' X 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5-fluoro-1Hbenzo[<1]imidazole-1 ηπ)-N, Νdimethylacetamide 338.2 577 68 Et NyN XI V 0' w / \ (3R,4R)-l-(l-((5ethyl-1,2,4oxadiazol-3yl)methyl)-5,6difluoro-Nibenzo[<1]imidazol-2yl)-4fluoropiperidine-3 - amine 381.2 578 68 Si N N XI V ν-Α ΑΖ^Ο^ 'nh ₂ (3R,4R)-l-(l-((5cyclopropyl-1,2,4oxadiazol-3yl)methyl)-5,6difluoro-Nibenzo[<1]imidazol-2yl)-4fluoropiperidin-3 - amine 393.2

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579 68 Me i XI V p 9 (3R,4R)-l-(5,6difluoro-1-((3methylisoxazol-5 yl)methyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidine-Zamine 366.2 580 83 F ₃ C^ Me- ^N y ° XI V Ο - Χ _F yC£H> ³ \n _r 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethyl)-1Hbenzo[<1]imidazole-1 - ηπ)-N-methyl-N(2,2,2trifluoroethyl)acetamide 456.2 581 68 OyN XI V R (3R,4R)-1-(1-((5cyclopropyl-1,3,4oxadiazol-2yl)methyl)-5,6difluoro-Nibenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 393.2 582 65 Me A T XI V X l l (3B,4B)-4-fluoro-1-(5fluoro-1 -((5-methyl1,3,4-thiadiazol-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3 - amine 365.2 583 84 <l ^o— \ —/ V CI /n % l N-\ /L'' /-\ _f XXbO NH _? (3R,4R)-1 -(3-((5chloropyrimidin-2yl)methyl)-6-fluoro3H-imidazo[4,5b]pyridin-2-yl)-4fluoropiperidin-3amine 380.2

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584 65 F ₃ C ^Ν γ° Χι V N X Хх χΌ“ ^ρ nh ₂ (3R,4R)-4-fluoro-1-(5fluoro-1-((3(trifluoromethyl)1,2,4-oxadiazol-5yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3-amine 403.0 585 65 I. ^S 's^'Me V O>O nh _: (3K,4K)-4-fluoro-1-(6fluoro-1 -((4-methyl-2phenylthiazol-5yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3amine 440.2 586 68 Me hch V N. Me-^Z> N \4 Me' / _P XXnO 'NH _Z (3R,4R)-l-(l-((4,5dimethyl-4H-1,2,4triazol-3yl)methyl)-5,6difluoro-Nibenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 380.2 587 65 F ^F \ X=N SyN Xl V F A 'ΝΗ _? (3R,4R)-l-(l-((5(difluoromethyl)-1,3,4thiadiazol-2yl)methyl)-5-fluoro1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3- amine 401.2 588 85 Me T XI V Me-γ ^Ν 'Ν , Ά WX nh ₂ (R)-4,4-diφτop-1 -(6fluoro-1 -((5-methyl1,3,4-thiadiazol-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3 amine 383.2

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589 65 Me t* V U l V S ,4 T| (3R,4R)-l-(l-((2,4dimethylthiazol-5yl)methyl)-6-fluoro1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 378.2 590 84 Me > ^N . Y XI V N H Χχνχ rJJ λ-( NH _? (3R,4R)A^to _P - 1-(6fluoro-3 -((5-methyl1,3,4-thiadiazol-2yl)methyl)-3Nimidazo[4,5b]pyridin-2yl)piperidine-3 amine 366.2 591 62 ^F ' ^c > M.- ^N y° >31 V at . W Λ and- Σ^/^Ζ ^Ζ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,7-difluoro-1Hbenzo[<1]imidazol-1 yl)N-methyl-N(2,2,21fluoroethyl)acetam id 424.2 592 83 Me Ms ^N y° Xl V Me N-Me jj Tf φ—N /— ^F f ₃ c-^4^n ' NH _? 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5(trifluoromethyl)-1Нbenzo[<1]imidazol-1 yl)-N, Ndimethylacetamide 388.2 593 65 4.X?' V Οχγ i T/XH _F Y<ji^N \--( nh ₂ (3R,4R)-4^Top-l-(5fluoro-1 -((4-methyl-2phenylthiazol-5yl)methyl)-1Hbenzo[c!]imidazol-2yl) piperidine-3 amine 440.2

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594 62 Me Me ^K y ° Αι V Me \-Me F ⁰ ^ Gm ^ O- ^f nh ₂ 2-(2-((3R,4R)-3amino-4fluoropiperidin-1 yl)-5,7-difluoro-1Hbenzo[<1]imidazole-1 ηπ)-Ν, Νdimethylacetamide 356.2 595 62 o /—< o 0X1 AA / / \ / About X V eV A (3R,4R)-l-(5,7difluoro-1 -((5(methylsulfonyl)pyridin-2 -yl)methyl)1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3- amine 440.2 596 65 Me ^E yAle Al V ,, L ⁶ A _f A¥A \-< nh ₂ (3R,4R)-l-(l-((2,4dimethylthiazol-5yl)methyl)-5-fluoro1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 378.2 597 85 Me Η X X! V X (R)-4,4-diφτop-1 -(5fluoro-1 -((5-methyl1,3,4-thiadiazol-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)piperidine-3 amine 383.2 598 62 F F-\ An X ^C1 V AX X “Π (3R,4R)-14H(5(difluoromethyl)-1,3,4thiadiazol-2yl)methyl)-5,7difluoro-Nibenzo[<1]imidazol-2yl)-4fluoropiperidin-3amine 419.2 599 62 Me Ή X ^C1 V N me N ln> (3R,4R)-l-(5,7difluoro-1-((5-methyl1,3,4-thiadiazol-2yl)methyl)-1Hbenzo[<1]imidazol-2yl)-4fluoropiperidin-3 amine 383.2

[a] Boc was removed using TFA. The free base was redissolved in DCM and HCl was added to precipitate the HCl salt. [b] Indefinite stereochemistry refers to a mixture of enantiomers or diastereomers.

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Table 6

Characterization data for compounds prepared according to Schemes 9-10 The Separation step column indicates after which process step the regioisomers formed due to the asymmetric substitution of benzimidazole at R ¹ in Scheme 10 were separated during the preparation of the final compound shown in the table (1 = after preparation of the intermediate the Na-alkyl-2-piperidinyl-benzimidazole compound in the first step of Scheme 10 (wherein at least one R ¹ is not hydrogen); B=before removal of the Boc-protecting group or T=final compound).

Note. Frequency, W NMR data (δ ppm) Stage SFC Terms No. dissolve spruce divided nya For separation of isomers 187 500MHz d ₄ -MeOH 8.80 (s, 2H), 7.65-7.69 (m, 1H), 7.547.61 (m, 1H), 7.49 (d, J=8.30 Hz, 1H), 5.57 (s, 2H), 4.42-4.60 (m, 1H), 3.723.80 (m, 1H), 3.64 (br d, 1=13.23 Hz, 1H), 3.15-3 .27 (m, 2H), 3.06 (dd, J=9.21, 12.59 Hz, 1H), 2.13-2.27 (m, 1H), 1.80-1.99 (m , 1H) IN Chiralpak ADH, 25% IP A, peak 1 188 500MHz d ₄ -MeOH 8.68-8.74 (s, 2H), 7.47-7.52 (m, 1H), 7.14-7.20 (m, 2H), 7.08-7.13 (m, 1H ), 5.53 (s, 2H), 4.34-4.52 (m, 1H), 3.64 (dtd, 1=1.95, 4.14, 12.36 Hz, 1H), 3, 48-3.57 (m, 1H), 3.04-3.21 (m, 2H), 2.98 (dd, J=8.82, 12.20 Hz, 1H), 2.122.25 (m, 1H), 1.82-1.92 (m, 1H) - - 189 400MHz d ₄ -MeOH 8.40 (d, 1=2.90 Hz, 1H), 7.47-7.58 (m, 2H), 7.21 (dd, 1=4.35, 8.71 Hz, 1H), 7 .13-7.17 (m, 1H), 7.06-7.13 (m, 2H), 4.32-4.55 (m, 1H), 3.62 (dtd, J=l.66, 4.17, 12.39 Hz, 1H), 3.41-3.52(m, 1H), 3.04-3.18(m, 2H), 2.92-3.01(m, 1H) , 2.07-2.22(m, 1H), 1.80-1.97(m, 1H) - - 190 400MHz d ₄ -MeOH 8.40 (d, J=2.90 Hz, 1H), 7.61 (dt, 1=2.90, 8.50 Hz, 1H), 7.52-7.56 (m, 2H), 7 .42-7.46(m, 1H), 7.40(dd, 1=4.35, 8.71Hz, 1H), 5.46(s, 2H), 4.32-4.54(m , 1H), 3.67-3.75 (m, 1H), 3.55-3.65 (m, 1H), 3.21 (ddd, J=2.90, 10.21, 12.80 Hz , 1H), 3.06-3.14 (m, 1H), 2.98-3.05 (m, 1H), 2.10-2.25 (m, 1H), 1.89 (ddd, J =3.52, 9.69, 13.53 Hz, 1H) IN Chiralpak AD- H, 20% MeOH, peak 1

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191 400MHz d ₄ -MeOH 8.39 (d, J=2.90 Hz, 1H), 7.75-7.78 (m, 1H), 7.61 (dt, J=2.90, 8.50 Hz, 1H), 7 .35-7.42(m, 2H), 7.27(d, J=8.29Hz, 1H), 5.45-5.50(m, 2H), 4.32-4.54(m , 1H), 3.68 (did, J=l.66, 4.02, 12.28 Hz, 1H), 3.51-3.63 (m, 1H), 3.15-3.25 (m , 1H), 3.10 (ddd, J=3.94, 7.72, 9.48 Hz, 1H), 2.96-3.06 (m, 1H), 2.13-2.27 (m , 1H), 1.81-1.97 (m, 1H) IN Chiralpak AD- H, 20% MeOH, peak 2 192 500MHz d ₄ -MeOH 8.98 (s, 2H), 7.42-7.47 (m, 1H), 7.077.15 (m, 2H), 7.01-7.06 (m, 1H), 5.49 (s, 2H), 4.33-4.51 (m, 1H), 3.37-3.50 (m, 2H), 2.99-3.07 (m, 2H), 2.82 (br dd, J =8.95, 12.07 Hz, 1H), 2.00-2.16 (m, 1H), 1.65-1.79 (m, 1H) - - 193 400MHz CDC1 ₃ 8.97 (s, 2H), 7.60-7.67 (m, 1H), 7.167.23 (m, 1H), 7.03-7.15 (m, 2H), 5.455.56 (m, 2H), 4.29-4.56(m, 1H), 3.643.76(m, 1H), 3.51-3.63(m, 1H), 3.143.33(m, 2H), 3.03 (dd, J=8.60, 12.54Hz, 1H), 2.08-2.24(m, 1H), 1.83-2.03(m, 1H) - - 194 400MHz CDC1 ₃ 8.36-8.39 (m, 2H), 7.60 (d, J=8.50 Hz, 1H), 7.14-7.20 (m, 2H), 7.06-7.14 ( m, 1H), 5.36 (d, J=2.07 Hz, 2H), 4.344.56 (m, 1H), 3.90 (s, 3H), 3.63-3.78 (m, 2H ), 3.14-3.31 (m, 2H), 3.04 (dd, J=8.40, 12.54 Hz, 1H), 2.11-2.25 (m, 1H), 1, 90-2.05(m, 1H) - - 195 400MHz d ₄ -MeOH 8.76 (s, 2H), 7.44-7.54 (m, 1H), 7.067.19 (m, 3H), 5.50 (br s, 2H), 4.324.53 (m, 1H), 3.62 (br d, 1=12.23 Hz, 1H), 3.51 (br d, J=12.02 Hz, 1H), 3.02-3.21 (m, 2H), 2.89 -3.01(m, 1H), 2.12-2.26(m, 1H), 1.81-1.98(m, 1H) - -

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196 500MHz d ₄ -MeOH 8.70-8.75 (m, 2H), 7.65-7.69 (m, 1H), 7.58 (d, 1=8.30 Hz, 1H), 7.45-7.52 ( m, 1H), 5.58 (s, 2H), 4.43-4.65 (m, 1H), 3.76-3.83 (m, 1H), 3.67 (br d, J=12 .98 Hz, 1H), 3.16-3.32 (m, 2H), 3.09 (dd, 1=9.34, 12.46 Hz, 1H), 2.15-2.29 (m, 1H), 1.86-1.99 (m, 1H) 8.72 (s, 2H), 7.77-7.82 (m, 1H), 7.417.45 (m, 1H), 7.32-7.38 (m, 1H), 5.59 IN Chiralpak AD- H, 20% MeOH, peak 1 197 500MHz d ₄ -MeOH (s, 2H), 4.33-4.51 (m, 1H), 3.65-3.71 (m, 1H), 3.53-3.63 (m, 1H), 3.16-3 .24 (m, 1H), 3.05-3.14 (m, 1H), 2.96-3.04 (m, 1H), 2.14-2.28 (m, 1H), 1.89 (ddd, J=3.63, 9.67, 13.43Hz, 1H) 8.70-8.89(m, 1H), 7.72-7.98(m, 1H), IN Chiralpak AD- H, 20% MeOH, peak 2 198 400MHz d ₄ -MeOH 7.17-7.54(m, 2H), 5.31-5.67(m, 2H), 4.39-4.66(m, 1H), 3.57-3.82(m, 2H ), 3.01-3.25 (m, 3H), 2.15-2.35 (m, 1H), 1.93 (td, J=l.22, 9.80 Hz, 1H) 8.90 (d, 1=1.45 Hz, 1H), 8.75-8.78 (m, V Chiralpak ADH 25% IPA Peak 2 199 400MHz d ₄ -MeOH 1H), 7.48-7.56 (m, 1H), 7.08-7.23 (m, 4H), 5.66 (s, 2H), 3.39-3.59 (m, 3H) , 3.13-3.30 (m, 2H), 2.25-2.40 (m, 1H), 2.04-2.25 (m, 1H) 8.88 (s, 2H), 7.63-7.68 (m, 1H), 7.537.59 (m, 1H), 7.45-7.50 (m, 1H), 5.53 - - 200 400MHz d ₄ -MeOH (s, 2H), 4.36-4.58 (m, 1H), 3.72 (br dd, 1=1.45, 12.65 Hz, 1H), 3.58-3.66 (m, 1H), 3.10-3.26(m, 2H), 2.99-3.07(m, 1H), 2.13-2.27(m, 1H), 1.82-1.95( m, 1H) V Chiralpak ADH 25% IPA Peak 1 201 400MHz d ₄ -MeOH 8.86-8.90 (m, 2H), 7.80-7.84 (m, 1H), 7.45 (dd, J=l.24, 8.29 Hz, 1H), 7.347.39 ( m, 1H), 5.56 (s, 2H), 4.33-4.53 (m, 1H), 3.62-3.70 (m, 1H), 3.53-3.60 V Chiralpak ADH 25% IPA Peak 1

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400MHz (m, 1H), 3.14-3.23 (m, 1H), 3.02-3.13 (m, 1H), 2.94-3.02 (m, 1H), 2.18-2 .26 (m, 1H), 1.80-1.96 (m, 1H) 9.11 (s, 1H), 8.92 (s, 1H), 8.30-8.39 (m, 3H), 7.47-7.53 (m, 1H), 7.23 (d, J=7.88 Hz, 1H), 7.14-7.19 (m, 1H), 202 CDC1 ₃ 7.11(d, 1=7.26Hz, 1H), 5.68(s, 2H), 4.81-4.92(m, 1H), 3.59-3.74(m, 2H) , 3.45-3.55(m, 1H), 3.03-3.16(m, 2H), 2.14-2.24(m, 1H), 1.80-1.93(m, 1H) 8.79(s, 2H), 7.75-7.89(m, 1H), 7.45 203 500MHz d ₄ -MeOH (dd, J=8.30, 1.30 Hz, 1 H), 7.36 (d, 1=8.04 Hz, 1 H), 5.55-5.60 (m, 2 H), 3 .44-3.54( _m , 2H), 3.35-3.42(m, 2H), 3.06-3.25(m, 3H), 1.89-2.18(m , 2H) 8.80 (s, 2 H), 7.65-7.69 (m, 1 H), 7.56- IN Chiralpak OJ, 15% MeOH, peak 1 500MHz d ₄ -MeOH 7.61(m, 1H), 7.51(dd, J=8.30, 1.56 Chiralpak OJ, 204 Hz, 1 H), 5.57 (s, 2 H), 3.37-3.57 (m, 3 H), 3.06-3.26 (m, 3 H), 2.09-2, 18(m, 1H), 1.90-2.08(m, 2H) 8.78 (s, 2H), 7.39-7.48 (m, 1H), 6.99 (dd, J=2.47, 8.95 Hz, 1H), 6.90-6.95 V 15% MeOH peak 2 500MHz d ₄ -MeOH (m, 1H), 5.48 (s, 2H), 3.64 (dd, Chiralpak AD- 205 J=l.82, 7.79Hz, 1H), 3.42-3.53(m, 2H), 3.05(dt, J=2.60, 12.07Hz, 1H), 2.83 -2.90 (m, 2H), 2.01 (qd, J=3.62, 13.01 Hz, 1H), 1.62-1.71 (m, 1H) 8.75-8.79 ( m, 2H), 7.12-7.22 (m, 2H), 6.82-6.93 (m, 1H), 5.49 (s, 2H), 3.65- V H25% MeOH peak 2 500MHz d ₄ -MeOH 3.72 (m, 1H), 3.53-3.62 (m, 1H), 3.44- Chiralpak AD- 206 3.52 (m, 1H), 3.08 (dt, J=2.60, 12.20 Hz, 1H), 2.86-2.97 (m, 2H), 2.02 (qd, J= 3.61, 13.04Hz, 1H), 1.62-1.75(m, 1H) V H25% MeOH peak 1

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207 500MHz d ₄ -MeOH 8.82-8.85 (m, 1H), 8.09-8.15 (m, 1H), 7.36 (d, J=8.04 Hz, 1H), 7.18 (dd, J= 2.34, 9.34 Hz, 1H), 7.09 (dd, J=4.54, 8.69 Hz, 1H), 6.87 (dt, J=2.47, 9.28 Hz, 1H ), 5.46-5.51 (m, 2H), 3.583.66 (m, 1H), 3.46-3.54 (m, 1H), 3.383.44 (m, 1H), 3.02- 3.14 (m, 1H), 2.732.90 (m, 2H), 1.93-2.04 (m, 1H), 1.581.72 (m, 1H) IN Chiralpak ADH, 25% IP A, peak 1 208 500MHz d ₄ -MeOH 8.84 (d, J=l.30 Hz, 1H), 8.09-8.18 (m, 1H), 7.41-7.47 (m, 1H), 7.37 (d, J= 8.30Hz, 1H), 6.90-7.00(m, 2H), 5.48(s, 2H), 3.50-3.59(m, 1H), 3.363.47(m, 2H ), 3.04 (dt, J=2.60, 11.94 Hz, 1H), 2.72-2.87 (m, 2H), 1.91-2.04 (m, 1H), 1, 56-1.69(m, 1H) IN Chiralpak ADH, 25% IP A, peak 2 209 400MHz d ₆ -DMSO 8.56 (d, 7=2.1 Hz, 1H), 7.93 (dd, 7=2.5, 8.4 Hz, 1H), 7.52-7.31 (m, 2H), 7 .25 (d, 7=8.4 Hz, 1H), 7.14-7.01 (m, 2H), 5.47-5.34 (m, 2H), 3.55 (br dd, 7=3.2, 12.2 Hz, 1H), 3.27-3.18 (m, 2H), 3.17-2.90 (m, 2H), 2.01-1.89 (m, 1H), 1.79 (br dd, 7=3.4, 9.9 Hz, 1H), 1.64-1.45 (m, 2H) - - 210 400MHz d ₆ -DMSO 8.72 (d, 7=1.66 Hz, 1H), 8.31 (br s, 2H), 8.02 (d, 7=8.09 Hz, 1H), 7.837.89 (m, 1H) , 7.57 (d, 7=7.77 Hz, 1H), 7.27 (m, 3H), 5.54-5.61 (m, 2H), 3.70 (br dd, 7=2, 80, 12.44 Hz, 1H), 3.48 (br s, 1H), 3.27-3.44 (m, 2H), 3.07-3.16 (m, 1H), 1.96- 2.10 (m, 1H), 1.83-1.94 (m, 1H), 1.59-1.73 (m, 2H) - - 211 400MHz d ₆ -DMSO 8.92 (br s, 3H), 8.55 (d, 7=2.18 Hz, 1H), 8.03 (dd, 7=2.49, 8.40 Hz, 1H), 7.67 ( d, 7=8.40 Hz, 1H), 7.60 (d, - -

- 249 043189

7=7.77 Hz, 1H), 7.28-7.44 (m, 3H), 5.64-5.78 (m, 2H), 4.88-5.10 (m, 1H), 4 .18 (br d, 7=12.65 Hz, 1H), 3.77 (br d, 7=13.58 Hz, 1H), 3.54-3.63 (m, 1H), 3.43- 3.53(m, 1H), 3.21-3.42(m, 1H), 2.26-2.37(m, 1H), 1.82-1.94(m, 1H) 212 400MHz d ₆ -DMSO 9.12 (br s, 3H), 8.94 (s, 1H), 8.40 (d, 7=8.19 Hz, 1H), 7.77 (d, 7=8.19 Hz, 1H) , 7.61 (d, 7=7.88 Hz, 1H), 7.257.39 (m, 3H), 5.72-5.93 (m, 2H), 4.03 (br d, 7=12, 75 Hz, 2H), 3.57-3.70 (m, 2H), 3.42 (br t, 7=10.78 Hz, 1H), 2.532.62 (m, 1H), 2.23-2 .38 (m, 1H) - - 213 500MHz DMSO-J ₆ 8.57 (br s, 2H), 8.50-8.55 (m, 1H), 7.94-8.00 (m, 2H), 7.43-7.51 (m, 2H), 7 .35 (d, 7=8.30Hz, 1H), 5.54 (d, 7=7.66Hz, 2H), 4.81 (dt, 7=4.87, 9.11Hz, 1H) , 3.83-3.92 (m, 1H), 3.50-3.58 (m, 2H), 3.16 (br dd, 7=10.19, 12.65 Hz, 1H), 3, 06 (br t, 7=11.74 Hz, 1H), 2.20 (br t, 7=9.54 Hz, 1H), 1.76-1.88 (m, 1H) IN Chiralpak ADH, 25% IP A, peak 2 214 500MHz DMSO-J ₆ 8.66 (br s, 2H), 8.54 (d, 7=2.21 Hz, 1H), 7.98 (dd, 7=2.34, 8.43 Hz, 1H), 7.78 ( s, 1H), 7.57-7.63 (m, 7=8.30 Hz, 1H), 7.51-7.57 (m, 7=8.30 Hz, 1H), 7.46 (d , 7=8.43 Hz, 1H), 5.49-5.62 (m, 2H), 4.79-4.99 (m, 1H), 3.95 (br d, 7=12.98 Hz , 1H), 3.71-3.84 (m, 2H), 3.20 (br t, 7=11.48 Hz, 1H), 3.07 (br t, 7=11.81 Hz, 1H) , 2.21 (br t, 7=9.67 Hz, 1H), 1.80 (br t, 7=9.93 Hz, 1H) IN Chiralpak ADH, 25% IP A, peak 2 215 500MHz DMSO-7 ₆ 8.59 (br d, 7=2.47 Hz, 3H), 7.86-7.91 (m, 1H), 7.45 (d, 7=7.91 Hz, 1H), 7.33 V Chiralpak IC, 20% methanol,

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(s, 1H), 7.27-7.32 (m, 1H), 7.02-7.09 (m, 1H), 6.92-6.97 (m, 2H), 5.86 (q , 7=6.96 Hz, 1H), 4.76-4.99 (m, 1H), 3.65-3.76 (m, 2H), 3.37 (br s, 1H), 3.14 -3.22 (m, 1H), 3.07 (br t, 7=11.16 Hz, 1H), 2.19-2.27 (m, 1H), 1.89-1.98 (m, 1H), 1.86 (d, 7=7.14 Hz, 3H) peak 1 216 500MHz DMSO-7 ₆ 8.63 (d, 7=1.95 Hz, 1H), 7.89 (br dd, 7=1.88, 8.50 Hz, 1H), 7.47 (d, 7=7.92 Hz, 1H), 7.28 (d, 7=8.43 Hz, 1H), 7.07 (t, 7=6.55 Hz, 1H), 6.94-7.00 (m, 2H), 5, 87 (q, 7=7.01 Hz, 1H), 4.71-4.90 (m, 1H), 3.66-3.77 (m, 1H), 3.58-3.64 (m, 1H), 3.40-3.48 (m, 1H), 3.02-3.18 (m, 2H), 2.20-2.28 (m, 1H), 1.96-2.02 ( m, 1H), 1.92 (d, 7=7.14 Hz, 3H) IN Chiralpak IC, 20% methanol, peak 2 217 500MHz DMSO-7 ₆ 8.56 (d, 7=2.34 Hz, 1H), 8.53 (br s, 2H), 7.90 (dd, 7=2.47, 8.43 Hz, 1H), 7.50 ( dd, 7=7.59, 10.96 Hz, 1H), 7.39 (d, 7=8.43 Hz, 1H), 7.13 (dd, 7=7.33, 10.83 Hz, 1H ), 5.83 (q, 7=7.09 Hz, 1H), 4.75-4.93 (m, 1H), 3.65 (br dd, 7=4.48, 9.15 Hz, 2H ), 3.29 (br d, 7=11.94 Hz, 1H), 3.07-3.18 (m, 1H), 3.02 (br t, 7=11.03 Hz, 1H), 2 .16-2.24 (m, 1H), 1.85-1.92 (m, 1H), 1.83 (d, 7=7.14 Hz, 3H) IN Chiralcel OZ- H, 15% methanol, peak 1 218 500MHz DMSO-A 8.65 (br s, 2H), 8.62 (d, 7=2.34 Hz, 1H), 7.94 (dd, 7=2.47, 8.56 Hz, 1H), 7.55 ( dd, 7=7.66, 11.03 Hz, 1H), 7.39 (d, 7=8.56 Hz, 1H), 7.15-7.21 (m, 1H), 5.87 (q , 7=7.09 Hz, 1H), 4.80-4.97(m, 1H), 3.62-3.79(m, 2H), 3.16(dd, 7=10.12, 11 .94 Hz, 1H), 3.03 (br t, 7=11.55 Hz, 1H), 2.25 (br t, 7=9.41 V Chiralcel OZH, 15% methanol, peak 2

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Hz, 1H), 1.94-2.03 (m, 1H), 1.91 (d, 7=7.27 Hz, ZN) 219 500MHz DMSO-p 8.58 (br s, 1H), 8.58 (br s, 2H), 7.91 (dd, 7=2.47, 8.56 Hz, 1H), 7.44 (d, 7=8, 36 Hz, 1H), 7.39 (d, 7=8.39 Hz, 1H), 7.02-7.09 (t, 2H), 5.84 (q, 7=7.09 Hz, 1H) , 4.73-4.97 (t, 1H), 3.68 (br dd, 7=4.09, 10.70 Hz, 2H), 3.32 (br d, 7=11.42 Hz, 1H ), 3.10-3.21 (t, 1H), 3.05 (br t, 7=11.03 Hz, 1H), 2.16-2.27 (t, 1H), 1.86-1 .93 (t, 1H), 1.83 (d, 7=7.14 Hz, ZN) IN Regis Whilk0 s, s, 20% methanol, peak 1 220 500MHz DMSO-L 8.64 (d, 7=2.46 Hz, 1H), 8.56 (br s, 2H), 7.95 (dd, 7=2.47, 8.56 Hz, 1H), 7.46- 7.51 (t, 7=8.43 Hz, 1H), 7.357.43 (t, 7=8.56 Hz, 1H), 7.05-7.16 (t, 2H), 5.87 (q , 7=7.14 Hz, 1H), 4.78-4.99 (t, 1H), 3.75 (br d, 7=12.20 Hz, 2H), 3.37-3.50 (t , 1H), 3.13-3.21 (t, 1H), 3.07 (br t, 7=11.55 Hz, 1H), 2.25 (br t, 7=9.34 Hz, 1H) , 1.95-2.04 (t, 1H), 1.92 (d, 7=7.14 Hz, ZN) IN Regis Whilk0 s, s, 20% methanol, peak 2 221 500MHz DMSO-L 8.62 (br s, 1H), 8.60 (br s, 2H), 7.95 (dd, 7=2.47, 8.43 Hz, 1H), 7.54 (d, 7=1, 56 Hz, 1H), 7.40 (d, 7=8.56 Hz, 1H), 6.97-7.05 (t, 2H), 5.88 (q, 7=7.01 Hz, 1H) , 4.77-5.04 (t, 1H), 3.76 (br s, 3H), 3.57 (s, 1H), 3.44 (br d, 7=12.07 Hz, 1H), 3.18-3.32 (t, 1H), 3.13 (brt, 7=11.16 Hz, 1H), 2.232.32 (t, 1H), 1.92-2.01 (t, 1H) , 1.89 (d, 7=7.01 Hz, ZN) V Regis Whilk0 s, s, 20% methanol, peak 3 222 500MHz DMSO-L 8.62 (br d, 7=2.34 Hz, 3H), 7.92 (dd, 7=2.47, 8.56 Hz, 1H), 7.54 (s, 1H), 7.35 ( d, 7=8.56 Hz, 1H), 6.99-7.05 (t, V Regis Whelk0 s, s, 20% methanol, peak

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2H), 5.87 (q, 7=7.01 Hz, 1H), 4.805.01 (m, 1H), 3.78 (br dd, 7=5.00, 11.87 Hz, 2H), 3 .44-3.53 (m, 1H), 3.20 (dd, 7=10.38, 12.07 Hz, 1H), 3.10 (br t, 7=11.48 Hz, 1H), 2 .27 (br t, 7=9.41 Hz, 1H), 1.95-2.04 (m, 1H), 1.92 (d, 7=7.14 Hz, 3H) 4 223 500MHz DMSO-J ₆ 9.00 (s, 1H), 8.63 (br s, 3H), 8.38 (dd, 7=1.69, 8.30 Hz, 1H), 7.58-7.70 (m, 3H ), 7.52 (d, 7=8.30 Hz, 1H), 6.00 (q, 7=7.01 Hz, 1H), 4.81-5.00 (m, 1H), 3.74 -3.83 (m, 1H), 3.65-3.74 (m, 1H), 3.42 (br d, 7=11.68 Hz, 1H), 3.24 (br dd, 7=9 .80, 12.39 Hz, 1H), 3.13 (br t, 7=11.16 Hz, 1H), 2.23-2.32 (m, 1H), 1.94 (br d, 7= 7.14Hz, 4H) IN Phenomenex Lux Cellulose2 20% Isopropanol Peak 1 224 500MHz DMSO-J ₆ 9.00 (s, 1H), 8.69-8.73 (m, 2H), 8.36 (dd, 7=1.88, 8.24Hz, 1H), 8.00 (s, 1H) , 7.66 (d, 7=8.30 Hz, 1H), 7.41 (d, 7=8.43 Hz, 1H), 7.17 (d, 7=8.43 Hz, 1H), 6 .04 (q, 7=6.96 Hz, 1H), 4.865.04 (m, 1H), 3.77 (br d, 7=12.72 Hz, 1H), 3.65-3.73 (m , 1H), 3.42 (br d, 7=11.94 Hz, 1H), 3.26 (br dd, 7=9.60, 12.59 Hz, 1H), 3.12 (br t, 7 =11.09 Hz, 1H), 2.25-2.34 (m, 1H), 1.90-1.99 (m, 4H) IN Phenomenex Lux Cellulose- 2, 20% isopropanol, peak 2 225 500MHz DMSO-tZg 8.98-9.02 (m, 1H), 8.62 (br d, 7=3.24Hz, 2H), 8.36 (dd, 7=1.88, 8.24Hz, 1H), 7.63 (dd, 7=3.18, 8.24 Hz, 2H), 7.59 (s, 1H), 7.52 (d, 7=8.17 Hz, 1H), 5.96 (q , 7=6.96 Hz, 1H), 4.79-4.98 (m, 1H), 3.74-3.86 (m, 1H), 3.68-3.72 (m, 1H), 3.46 (br d, 7=11.94 Hz, 1H), 3.14-3.26 (m, 1H), 3.09 (br t, 7=12.00 V Phenomenex Lux Cellulose- 2, 20% isopropanol, peak 3

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Hz, 1H), 2.19-2.30 (m, 1H), 1.97 (br d, 7=7.27 Hz, 4H) 226 500MHz DMSO-7 ₆ 8.92-8.96 (m, 1H), 8.58 (br s, 3H), 8.28 (dd, 7=1.95, 8.30 Hz, 1H), 7.94 (s, 1H ), 7.53 (d, 7=8.30 Hz, 1H), 7.34 (dd, 7=1.30, 8.43 Hz, 1H), 7.23 (s, 1H), 7.07 -7.16 (m, 2H), 7.03 (s, 1H), 5.94 (q, 7=6.92 Hz, 1H), 4.72-4.93 (m, 1H), 3, 68-3.79 (m, 1H), 3.58-3.68 (m, 1H), 3.40 (br d, 7=12.85 Hz, 1H), 3.15 (br t, 7= 11.35 Hz, 1H), 3.04 (br t, 7=11.74 Hz, 1H), 2.20 (br t, 7=9.54 Hz, 1H), 1.95 (m, 1H) , 1.91 (d, 7=7.01 Hz, 3H) IN Phenomenex Lux Cellulose- 2, 20% isopropanol, peak 4 227 500MHz DMSO-7 ₆ 8.54 (br d, 7=2.21 Hz, 1H), 8.52 (br s, 2H), 7.96 (dd, 7=2.47, 8.43 Hz, 1H), 7.54 (dd, 7=7.53, 10.90 Hz, 1H), 7.337.44 (m, 2H), 5.37-5.52 (m, 2H), 4.734.92 (m, 1H), 3, 75-3.83 (m, 1H), 3.513.62 (m, 1H), 3.45 (br d, 7=12.20 Hz, 1H), 3.12 (br dd, 7=10.64, 12.33Hz, 1H), 3.01(brt, 7=11.61Hz, 1H), 2.142.23(m, 1H), 1.76-1.90(m, 1H) IN - 228 500MHz DMSO-7 ₆ 8.52 (br s, 2H), 8.49 (d, 7=2.85 Hz, 1H), 7.76 (dt, 7=2.98, 8.69 Hz, 1H), 7.53 ( dd, 7=7.40, 11.03 Hz, 1H), 7.44 (t, 7=6.74 Hz, 1H), 7.37 (t, 7=8.28 Hz, 1H), 5, 38-5.51 (m, 2H), 4.73-4.95 (m, 1H), 3.75-3.83 (m, 1H), 3.47 (br d, 7=12.98 Hz , 1H), 3.12 (dd, 7=10.19, 12.52 Hz, 1H), 3.01 (br t, 7=11.42 Hz, 1H), 2.15-2.23 (m , 1H), 1.77-1.87 (m, 1H) IN - 229 400MHz DMSO-7 ₆ 8.80 (br s, 2H), 8.52 (d, 7=2.38 Hz, 1H), 7.96 (dd, 7=2.44, 8.45 Hz, 1H), V Regis Whilk0 s, s, 15%

-254043189

7.39 (d, 4=8.40 Hz, 1H), 7.21 (dd, 4=2.13, 9.17 Hz, 1H), 6.95 (t, 4=10.40 Hz, 1H ), 5.45-5.58 (m, 2H), 3.76 (br d, 4=12.02 Hz, 1H), 3.31-3.47 (m, 2H), 3.17-3 .26 (m, 1H), 2.33 (m, 3H) methanol, peak 1 230 500MHz DMSO-4 ₆ 8.87 (br s, 2H), 8.55 (s, 1H), 7.97 (br d, 4=8.17 Hz, 1H), 7.46 (br d, 4=8.30 Hz, 1H), 6.95-7.04 (m, 2H), 5.41-5.63 (m, 2H), 3.95-4.06 (m, 1H), 3.77 (br d, 4 =12.20Hz, 1H), 3.30-3.45(m, 2H), 3.18(br t, 4=10.19Hz, 1H), 2.19-2.35(m, 1H ) IN Regis Whilk0 s, s, 15% methanol, peak 2 231 500MHz d ₄ -MeOH 7.86 (s, 1H), 7.65 (d, 4=8.04 Hz, 1H), 7.55 (d, 4=7.79 Hz, 1H), 7.42 (t, 4=7 .66 Hz, 1H), 7.16-7.26 (m, 2H), 6.64 (br dd, 4=1.82, 9.08 Hz, 1H), 6.27 (br t, 4= 8.69 Hz, 1H), 4.89-5.03(m, 1H), 4.13-4.24(m, 1H), 3.92-4.01(m, 1H), 3.79 -3.90(m, 1H), 3.50-3.64(m, 2H), 3.39-3.48(m, 1H), 3.24-3.30(m, 1H), 2 .97-3.08 (m, 1H), 2.70 (qd, 4=9.45, 13.43 Hz, 1H), 2.52 (dt, 4=4.67, 7.79 Hz, 1H ), 2.17-2.34 (m, 1H) IN Phenomenex Lux Cellulose2, 30% MeOH, peak 1 232 500MHz d ₄ -MeOH 7.86 (s, 1H), 7.64 (d, 4=8.04 Hz, 1H), 7.54 (d, 4=7.78 Hz, 1H), 7.40 (t, 4=7 .79 Hz, 1H), 7.14-7.22 (m, 2H), 6.65 (br d, 4=7.53 Hz, 1H), 6.27 (br t, 4=9.08 Hz , 1H), 4.88-5.00 (m, 1H), 4.08-4.16 (m, 1H), 3.86-3.99 (m, 2H), 3.39-3.58 (m, 3H), 3.24-3.30 (m, 1H), 3.01-3.11 (m, 1H), 2.62-2.77 (m, 1H), 2.44-2 .56 (m, 1H), 2.10-2.27 (m, 1H) V Phenomenex Lux Cellulose2, 30% MeOH, peak 2 233 500MHz d ₄ -MeOH 8.90 (d, 4=1.30 Hz, 1H), 8.82 (d, 4=1.30 Hz, 1H), 7.46 (d, 4=8.56 Hz, V Chiralpak IC, 15% MeOH,

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1H), 7.28 (d, 7=2.08 Hz, 1H), 7.18 (dd, 7=1.95, 8.43 Hz, 1H), 5.65 (s, 2H), 3, 38-3.51 (m, 2H), 3.28 (br d, 7=3.37 Hz, 1H), 3.16-3.25 (m, 1H), 3.08-3.15 (m , 1H), 2.23-2.36 (m, 1H), 2.07-2.22 (m, 1H) peak 1 234 500MHz d ₄ -MeOH 8.91 (d, 7=1.30 Hz, 1H), 8.82 (d, 7=1.04 Hz, 1H), 7.50 (d, 7=1.82 Hz, 1H), 7. 15-7.19 (m, 1H), 7.09-7.15 (m, 1H), 5.67 (s, 2H), 3.42-3.55 (m, 2H), 3.33- 3.38 (m, 1H), 3.20-3.28 (m, 1H), 3.13-3.20 (m, 1H), 2.25-2.38 (m, 1H), 2, 09-2.23(m, 1H) IN Chiralpak IC, 15% MeOH, peak 2 235 600MHz d ₆ -DMSO 8.30 (br d, 7=7.79 Hz, 1H), 7.46 (dd, 7=7.47, 11.21 Hz, 1H), 7.36 (dd, 7=7.32, 10 .74 Hz, 1H), 4.64 (s, 2H), 4.30-4.46 (m, 1H), 3.84-3.93 (m, 1H), 3.37-3.43 ( m, 1H), 2.93-3.05 (m, 2H), 2.79 (dd, 7=8.72, 12.46 Hz, 1H), 2.062.17 (m, 1H), 1.75 -1.85 (m, 1H), 1.10 (dd, 7=1.87, 6.54Hz, 6H) - - 236 600MHz d ₆ -DMSO 7.46 (dd, 7=7.47, 11.21 Hz, 1H), 7.38 (dd, 7=7.32, 10.74 Hz, 1H), 4.73 (s, 2H), 4 .33-4.47 (m, 1H), 4.27 (dt, 7=4.67, 7.63 Hz, 2H), 3.89-3.99 (m, 2H), 3.34-3 .40 (m, 2H), 2.95-3.06 (m, 2H), 2.80 (dd, 7=8.25, 12.61 Hz, 1H), 2.26-2.34 (m , 2H), 2.06-2.18 (m, 1H), 1.75-1.85 (m, 1H) - - 237 600MHz d ₆ -DMSO 7.44-7.52(m, 1H), 7.28-7.38(m, 1H), 5.02-5.12(m, 2H), 4.32-4.47(m, 1H ), 3.55-3.86 (m, 2H), 3.18-3.55 (m, 5H), 2.93-3.07 (m, 2H), 2.74-2.84 (m , 1H), 2.03-2.17 (m, 1H), 1.71-1.84 (m, 1H), 1.01-1.36 (m, 6H) (mixture 2 - -

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diastereomers/rotamers) 238 600MHz d ₆ -DMSO 7.53 (dd, 7=7.47, 11.21 Hz, 1H), 7.097.20 (m, 1H), 5.28 (t, 7=9.96 Hz, 1H), 4.30-4 .48 (m, 1H), 3.56-3.64 (m, 1H), 3.42-3.50 (m, 1H), 3.30-3.42 (m, 2H), 2.97 -3.09 (m, 2H), 2.88 (s, 3H), 2.762.85 (m, 1H), 2.54-2.59 (m, 1H), 2.272.37 (m, 1H), 2.07-2.19(m, 1H), 1.761.93(m, 1H) - - 239 600MHz d ₆ -DMSO 7.45-7.54( _m , 2H), 7.39-7.44(m, 2H), 7.35-7.38(m, 2H), 7.27(dt, 7=0.93, 7 .32Hz, 1H), 5.21-5.32(m, 1H), 4.324.50(m, 1H), 4.08-4.20(m, 1H), 3.613.68(m, 1H) , 3.29-3.39(m, 2H), 2.973.11(m, 2H), 2.73-2.90(m, 1H), 2.512.63(m, 1H), 2.07-2 .32 (m, 4H), 1.821.92 (m, 1H) -- - 240 600MHz d ₆ -DMSO 7.76-7.81(m, 2H), 7.53-7.58(m, 1H), 7.48-7.53(m, 2H), 7.34-7.41(m, 1H ), 5.59 (dd, 7=9.65, 11.21 Hz, 1H), 4.344.49 (m, 1H), 4.06 (br t, 7=9.19 Hz, 1H), 3, 92-4.00 (m, 1H), 3.34-3.43 (m, 2H), 3.01-3.09 (m, 2H), 2.82 (ddd, 7=8.88, 12 .69, 14.87 Hz, 1H), 2.642.72 (m, 1H), 2.54-2.61 (m, 1H), 2.102.20 (m, 1H), 1.80-1.90 ( m, 1H) -- - 241 500MHz d ₄ -MeOH 8.51 (s, 2H), 7.95 (d, 7=0.78 Hz, 1H), 7.65-7.70 (m, 1H), 7.59-7.64 (m, 1H) , 5.57-5.68 (m, 2H), 4.77-4.95 (m, 1H), 4.23-4.32 (m, 1H), 3.98-4.06 (m, 1H), 3.95 (s, 3H), 3.71-3.80 (m, 1H), 3.423.53 (m, 2H), 2.34-2.44 (m, 1H), 2.012.15 (m, 1H) V Chiralcel O.J. H, 15% MeOH, peak 2 242 500MHz d ₄ -MeOH 8.52 (s, 2H), 7.94 (s, 1H), 7.66-7.74 (m, 2H), 5.54-5.67 (m, 2H), 4.77-4, 93 V Chiralcel O.J. H, 15%

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(m, 1H), 4.21-4.30 (m, 1H), 4.01 (br d, 7=12.98 Hz, 1H), 3.96 (s, 3H), 3.713.78 (m , 1H), 3.43-3.50 (m, 2H), 2.322.46 (m, 1H), 1.98-2.14 (m, 1H) MeOH peak 1 243 600MHz d ₆ -DMSO 8.82 (br d, 7=3.89 Hz, 3H), 8.73 (s, 1H), 7.94 (d, 7=1.04 Hz, 1H), 7.867.90 (m, 1H) , 7.80-7.85(m, 1H), 7.647.68(m, 1H), 7.56-7.63(m, 1H), 5.585.72(m, 2H), 4.87-5 .04 (m, 1H), 3.944.03 (m, 1H), 3.57-3.64 (m, 2H), 3.31 (dd, 7=10.12, 12.98 Hz, 1H), 3.16 (br t, 7=11.42 Hz, 1H), 2.20-2.32 (m, 1H), 1.79-1.96 (m, 1H) IN Chiralpak ADH, 20% MeOH, peak 1 244 600MHz d ₆ -DMSO 8.73 (br d, 7=4.15 Hz, ZN), 8.71 (d, 7=1.56 Hz, 1H), 8.01 (d, 7=1.30 Hz, 1H), 7 .83-7.91 (m, 1H), 7.79 (dd, 7=1.43, 8.17 Hz, 1H), 7.51-7.60 (m, 1H), 7.37-7 .51 (m, 1H), 5.55-5.73 (m, 2H), 4.81-5.03 (m, 1H), 3.85-3.96 (m, 1H), 3.58 -3.66 (m, 1H), 3.49-3.54 (m, 1H), 3.25 (dd, 7=9.86, 12.98 Hz, 1H), 3.11 (br t, 7=11.42Hz, 1H), 2.20-2.31(m, 1H), 1.82-1.95(m, 1H) IN Chiralpak AD- H, 20% MeOH, peak 2 245 500MHz d ₄ -MeOH 7.36(dd, J=7,T1, 10.64Hz, 1H), 7.06(dd, 7=7.01, 10.12Hz, 1H), 5.39(t, 7=9, 99 Hz, 1H), 4.34-4.52 (m, 1H), 3.67-3.74 (m, 1H), 3.57-3.65 (m, 1H), 3.48 (br dd, 7=3.76, 7.14 Hz, 2H), 3.08-3.20 (m, 2H), 3.01 (s, 3H), 2.95 (dd, 7=8.95, 12.33 Hz, 1H), 2.64-2.74 (m, 1H), 2.46 (qd, 7=9.81, 12.88 Hz, 1H), 2.18-2.29 (m , 1H), 1.92-2.03 (m, 1H) F Chiralpak IC, 25% MeOH with 0.2% DEA, peak 1 246 500MHz d ₄ -MeOH 7.36 (dd, 7=7.27, 10.64 Hz, 1H), 7.06 (dd, 7=7.01, 10.12 Hz, 1H), 5.39 (t, F Chiralpak IC, 25% MeOH

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7=9.99 Hz, 1H), 4.36-4.52(m, 1H), 3.67-3.74(m, 1H), 3.58-3.65(m, 1H), 3 .52-3.58 (m, 1H), 3.38-3.46 (m, 1H), 3.11-3.20 (m, 2H), 3.01 (s, 3H), 2.93 (dd, 7=8.56, 12.46 Hz, 1H), 2.61-2.71 (m, 1H), 2.45 (qd, 7=9.74, 13.07 Hz, 1H), 2.18-2.29 (m, 1H), 1.92-2.04 (m, 1H) with 0.2% DEA, peak 2 247 500MHz d ₄ -MeOH 7.78 (d, 7=9.08 Hz, 2H), 7.46 (d, 7=9.08 Hz, 2H), 7.40 (dd, 7=7.27, 10.64 Hz, 1H ), 7.21 (br dd, 7=6.88, 10.25 Hz, 1H), 5.63 (dd, 7=9.47, 11.03 Hz, 1H), 4.37-4.55 (m, 1H), 4.06-4.20 (m, 2H), 3.55-3.63 (m, 1H), 3.41-3.49 (m, 1H), 3.14-3 .23 (m, 2H), 2.96 (dd, 7=8.82, 12.20 Hz, 1H), 2.75-2.84 (m, 1H), 2.58-2.73 (m , 1H), 2.19-2.33 (m, 1H), 1.92-2.06 (m, 1H) F Chiralcel ODH, 30% MeOH with 0.2% DEA, peak 1 248 500MHz d ₄ -MeOH 7.77 (d, 7=8.82 Hz, 2H), 7.43-7.49 (m, 2H), 7.40 (dd, 7=7.27, 10.64 Hz, 1H), 7 .17-7.24 (m, 1H), 5.59-5.67 (m, 1H), 4.37-4.54 (m, 1H), 4.06-4.20 (m, 2H) , 3.48-3.56 (m, 2H), 3.12-3.21 (m, 2H), 2.95-3.07 (m, 1H), 2.78-2.87 (m, 1H), 2.62-2.72 (m, 1H), 2.20-2.31 (m, 1H), 1.94-2.06 (m, 1H) F Chiralcel ODH, 30% MeOH with 0.2% DEA, peak 2 249 DMSO- _d6 9.09 (d, 7=1.48 Hz, 1H), 8.96 (d, 7=1.40 Hz, 1H), 7.78 (d, 7=1.48 Hz, 1H), 7. 56 (d, 7=8.29 Hz, 1H), 7.50 (d, 7=8.50 Hz, 1H), 5.66-5.76 (m, 2H), 4.39-4.37 (m, 1H), 3.39-3.49 (m, 2H), 3.06-3.17 (m, 1H), 2.80-2.95 (m, 2H), 2.00-2 .14 (m, 2H), 1.67-1.83 (m, 1H) IN SFCs: Chiralpak ADH, 30% methanol 250 DMSO- _d6 9.08 (d, 7=1.40 Hz, 1H), 8.97 (d, 7=1.40 Hz, 1H), 7.93 (d, 7=1.48 Hz, IN SFCs: Chiralpak AD-

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1H), 7.46 (d, 7=8.36 Hz, 1H), 7.39 (d, 7=8.21 Hz, 1H), 5.67-5.76 (m, 2H), 4, 38-4.34 (m, 1H), 3.37-3.46 (m, 2H), 3.02-3.12 (m, 1H), 2.79-2.98 (m, 2H), 2.00-2.16(m, 1H), 1.68-1.79(m, 1H) Η, 25% methanol 251 DMSO- _d6 9.10 (d, 7=1.40 Hz, 1H), 8.97 (d, 7=1.32 Hz, 1H), 7.17 (dd, 7=2.18, 9.26 Hz, 1H ), 6.89 (t, 7=10.46 Hz, 1H), 5.63-5.70 (m, 2H), 4.26-4.31 (m, 1H), 3.37-3, 51 (m, 2H), 3.03-3.12 (m, 1H), 2.92-3.01 (m, 1H), 2.79-2.91 (m, 1H), 1.99- 2.17 (m, 1H), 1.70-1.84 (m, 1H) IN SFCs: Chiralpak ADH, 30% methanol 252 DMSO- _d6 9.02-9.15 (m, 1H), 8.93-8.98 (m, 1H), 7.17 (d, 7=8.96 Hz, 1H), 6.82-6.94 ( m, 1H), 5.61-5.70 (m, 2H), 4.34 (dt, 7=4.28, 8.25 Hz, 1H), 3.37-3.44 (m, 1H) , 3.03-3.10 (m, 1H), 2.87-2.886 (m, 2H), 2.32-2.47 (m, 1H), 2.02-2.18 (m, 1H) , 1.69-1.83 (m, 1H) IN SFCs: Chiralpak ADH, 25% methanol 253 DMSO- _d6 10.99-11.51(m, 1H), 8.46-8.48(m, 1H), 7.65-7.72(m, 1H), 7.51-7.57(m, 1H ), 7.13-7.20 (m, 2H), 6.84-6.95 (m, 2H), 4.09-4.26 (m, 1H), 3.88-4.08 (m , 1H), 3.74-3.82 (m, 2H), 2.80-3.00 (m, 2H), 2.58-2.67 (m, 1H), 2.20-2.26 (m, 3H), 1.93-2.00 (m, 1H), 1.74-1.84 (m, 1H), 1.47-1.55 (m, 2H) - - 254 DMSO- _d6 8.48-8.64 (s, 1H), 7.83-7.99 (m, 1H), 7.43-7.58 (m, 1H), 7.26 (d, 7=8.30 Hz, 1H), 7.01-7.20 (m, 2H), 6.89 (br dd, 7=3.05, 5.51 Hz, 2H), 4.55 (s, 1H), 4, 01 (br d, 7=12.20 Hz, 1H), 3.74-3.83 (m, 1H), 3.55-3.69 (m, 1H), 2.82-3.04 (m , 2H), 2.58-2.66 (m, 1H), 2.35-2.47 (m, 1H), 2.25 (s, 2H), 1.95 (br s, 1H), -- --

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1.80 (br dd, 7=3.18, 6.16 Hz, 1H), 1.44-1.63 (m, 1H), 255 DMSO- _d6 9.04 (d, 7=2.02 Hz, 1H), 8.30 (d, 7=8.16 Hz, 1H), 7.40-7.47 (m, 2H), 7.05 (t , 7=7.59 Hz, 1H), 6.92-7.00 (m, 2H), 5.81-5.87 (m, 1H), 3.37-3.48 (m, 1H), 2.85-2.94 (m, 2H), 2.52-2.69 (m, 3H), 2.37-2.47 (m, 1H), 2.15 (s, 3H), 1, 85-1.95 (m, 2H), 1.71-1.82 (m, 1H), 1.59-1.69 (m, 1H), 1.14-1.26 (m, 1H) IN SFC: Chiralpak IC, 25% methanol 256 DMSO- _d6 9.04 (d, 7=1.48 Hz, 1H), 8.29 (d, 7=8.18 Hz, 1H), 7.45 (d, 7=8.80 Hz, 1H), 7. 41 (d, 7=8.07 Hz, 1H), 7.05 (ddd, 7=1.87, 6.46, 8.02 Hz, 1H), 6.907.00 (m, 2H), 5.80 -5.88 (m, 1H), 3.38-3.50 (m, 2H), 3.21-3.28 (m, 1H), 2.82-2.94 (m, 1H), 2 .67 (dd, 7=9.07, 11.64 Hz, 1H), 2.51-2.62 (m, 2H), 2.25 (s, 2H), 2.15 (s, 1H), 1.91 (d, 7=7.16 Hz, 4H), 1.62-1.80 (m, 2H), 1.18-1.28 (m, 1H) IN SFC: Chiralpak IC, 25% methanol 257 DMSO- _d6 8.92 (s, 2H), 7.15 (dd, 7=2.18, 9.34 Hz, 1H), 6.86 (t, 7=10.48 Hz, 1H), 5.51-5 .60 (m, 2H), 4.298-4.44 (m, 1H), 3.34-3.42 (m, 2H), 3.02-3.10 (m, 1H), 2.88-2 .97 (m, 1H), 2.81 (dd, 7=8.45, 12.57 Hz, 1H), 2.04-2.12 (m, 1H), 1.66-1.82 (m , 1H) IN SFC/MS with MeOH as co-solvent in isocratic mode at 10%, column: 4- ethylpyridine, 21.2x 150 mm 258 DMSO- _d6 8.92 (s, 2H), 7.06 (dd, 7=2.26, 8.88 Hz, 1H), 6.95 (dt, 7=2.18, 10.63 Hz, 1H), 5 .50-5.57 (m, 2H), 4.26-4.43 (m, V SFC/MS with MeOHv quality

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1H), 3.25-3.42 (m, 1H), 2.93-3.09 (m, 2H), 2.86 (br s, 1H), 2.76 (br dd, 7=8, 60, 12.34 Hz, 1H), 2.00-2.09 (m, 1H), 1.62-1.73 (m, 1H) cosolvent i in isocratic mode at 10%, column: 4- ethylpyridine, 21.2x150 mm 259 DMSO- _d6 7.85(d, 7=0.78Hz, 1H), 7.57(d, 7=8.49Hz, 1H), 7.50(dd, 7=7.43, 11.17Hz, 1H ), 7.33 (dd, 7=7.08, 8.41 Hz, 1H), 7.25 (dd, 7=7.32, 10.67 Hz, 1H), 6.77 (d, 7= 6.70 Hz, 1H), 5.595.66 (m, 2H), 4.27-4.41 (m, 1H), 4.03 (s, 3H), 3.42-3.59 (m, 1H ), 2.99-3.12 (m, 1H), 2.89-2.98 (m, 1H), 2.83 (dd, 7=8.68, 12.57 Hz, 1H), 2, 29-2.47(m, 1H), 1.94-2.11(m, 1H), 1.67-1.77(m, 1H) - - 260 DMSO- _d6 8.97 (dd, 7=1.56, 4.20 Hz, 1H), 8.61 (d, 7=8.02 Hz, 1H), 7.97 (d, 7=8.49 Hz, 1H ), 7.67 (t, 7=7.95 Hz, 1H), 7.617.65 (m, 1H), 7.53 (dd, 7=7.47, 11.13 Hz, 1H), 7.25 (dd, 7=7.32, 10.67 Hz, 1H), 7.00 (d, 7=7.19 Hz, 1H), 5.795.86 (m, 2H), 4.27-4.40 ( m, 1H), 3.37-3.52 (m, 2H), 3.01-3.10 (m, 1H), 2.89-2.99 (m, 1H), 2.83 (dd, 7=8.49, 12.53Hz, 1H), 2.02(dddd, 7=4.28, 8.60, 12.62, 16.77Hz, 1H), 1.67-1.83( m, 1H) - - 261 DMSO- _d6 8.91 (dd, 7=1.71, 4.13 Hz, 1H), 8.40 (dd, 7=1.48, 8.25 Hz, 1H), 7.98 (d, 7=8, 10 Hz, 1H), 7.87 (d, 7=7.16 Hz, 1H), 7.65 (t, 7=7.71 Hz, 1H), 7.57 (dd, V SFC: Chiralpak IC column, 20% methanol

-262043189

7=4.17, 8.21Hz, 1H), 7.37-7.52(m, 2H), 6.75(q, 7=7.19Hz, 1H), 4.334.41(m, 1H ), 3.35-3.46 (m, 2H), 2.963.09 (m, 2H), 2.72 (dd, 7=8.76, 12.34 Hz, 1H), 2.52-2, 56 (m, 1H), 1.97-2.10 (m, 4H), 1.63-1.79 (m, 1H) 262 DMSO- _d6 8.91 (dd, 7=1.71, 4.13 Hz, 1H), 8.39 (dd, 7=1.56, 8.25 Hz, 1H), 7.98 (d, 7=8, 02 Hz, 1H), 7.86 (d, 7=7.16 Hz, 1H), 7.65 (t, 7=7.71 Hz, 1H), 7.56 (dd, 7=4.13, 8.25 Hz, 1H), 7.46 (dd, 7=7.63, 11.13 Hz, 1H), 7.39 (dd, 7=7.36, 11.25 Hz, 1H), 6, 73 (q, 7=7.14 Hz, 1H), 4.28-4.36 (m, 1H), 3.36-3.46 (m, 1H), 3.14-3.28 (m, 2H), 2.83-2.97(m, 2H), 2.52-2.55(m, 1H), 2.38(brs, 1H), 1.91-2.05(m, 4H ), 1.68-1.85 (m, 1H) IN SFC: Chiralpak IC column, 20% methanol 263 DMSO- _d6 7.92 (t, 7=1.71 Hz, 1H), 7.84 (td, 7=1.31, 7.65 Hz, 1H), 7.51-7.59 (m, 4H), 7 .14 (s, 1H), 5.57 (s, 2H), 4.294.50 (m, 1H), 3.36-3.49 (m, 3H), 2.993.13 (m, 1H), 2, 87 (dd, 7=8.37, 12.57Hz, 1H), 2.04-2.20(m, 1H), 1.77-1.92(m, 1H) - - 264 DMSO- _d6 8.06 (s, 1H), 7.68 (d, 7=8.02 Hz, 1H), 7.54 (t, 7=9.20 Hz, 1H), 7.18 (dd, 7=7 .59, 10.47 Hz, 1H), 6.99 (t, 7=7.59 Hz, 1H), 6.48 (d, 7=7.30 Hz, 1H), 5.98 (d, 7 =17.36Hz, 1H), 5.91(d, 7=17.36Hz, 1H), 4.36-4.45(m, 1H), 4.31-4.35(m, 3H) , 3.40-3.57 (m, 2H), 3.08-3.13 (m, 1H), 2.90-2.97 (m, 1H), 2.86 (dd, 7=8, 14, 12.57 Hz, 1H), 2.54-2.66(m, 1H), 1.99-2.07(m, 1H), 1.67-1.83(m, -- -

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1H) 265 DMSO- _d6 7.47-7.56 (m, 3H), 7.42 (dd, 7=7.67, 8.52 Hz, 1H), 6.75 (dd, 7=7.24, 10.82 Hz, 1H), 5.50-5.56 (m, 2H), 4.29-4.47 (m, 1H), 3.40-3.51 (m, 1H), 3.35-3.40 ( m, 1H), 3.01-3.14 (m, 1H), 2.91-3.01 (m, 1H), 2.82 (dd, 7=8.76, 12.42 Hz, 1H) , 2.08-2.17 (m, 1H), 1.72-1.84 (m, 1H) - - 266 DMSO- _d6 7.37-7.41(m, 1H), 7.18(d, 7=7.38Hz, 1H), 7.07(t, 7=6.39Hz, 2H), 4.624.71(m , 2H), 4.25 (t, 7=7.63 Hz, 2H), 3.89-3.97 (m, 2H), 3.40-3.48(m, 1H), 3.23-3.29(m, 1H), 2.83-2.91(m, 1H), 2.52-2.65(m, 1H ), 2.25-2.32 (m, 1H), 1.83-1.93 (m, 1H), 1.71-1.79 (m, 1H), 1.60-1.69 (m , 1H), 1.21-1.33 (m, 1H) - - 267 DMSO- _d6 9.53 (br s, 1H), 8.97 (d, 7=1.63 Hz, 1H), 8.33 (d, 7=8.66 Hz, 1H), 7.55 (d, 7= 8.47 Hz, 1H), 7.23 (dd, 7=2.22, 9.07 Hz, 1H), 6.88 (t, 7=10.52 Hz, 1H), 5.82-5, 96 (m, 1H), 4.02 (br dd, 7=3.93, 7.90 Hz, 2H), 3.61-3.79 (m, 1H), 3.57 (br s, 1H), 3.50 (br dd, 7=4.09, 12.42 Hz, 1H), 3.28 (br s , 1H), 3.13-3.26 (m, 1H), 3.09 (br d, 7=12.77 Hz, 1H), 2.51-2.66 (m, 2H), 1.97 (br s, 2H), 1.84-1.93 (m, 3H) V SFC: Chiralpak IC, 15% methanol (primary treatment). Chiralpak ADH, 10% methanol (secondary treatment of fraction A) - 268 DMSO- _d6 9.46 (br s, 1H), 8.93-9.04 (m, 1H), 8.33 (d, 7=8.76 Hz, 1H), 7.55 (d, 7=8.51 Hz, 1H), 7.23 (dd, 7=2.18, 9.03 Hz, 1H), 6.89 (t, 7=10.51 Hz, 1H), 5.85-5.96 (m , 1H), 3.92-4.07 (m, 2H), V SFC: Chiralpak IC, 15% methanol (primary treatment).

- 264 043189

3.83 (br s, 2H), 3.55-3.79 (m, 1H), 3.50 (br dd, 7=4.13, 12.46 Hz, 1H), 3.25-3, 33 (m, 1H), 3.13-3.25 (m, 1H), 3.09 (br d, 7=12.53 Hz, 1H), 2.51-2.56 (m, 2H), 1.96 (br s, 2H), 1.83-1.92 (m, 3H) Chiralpak AD- H, 10% methanol (secondary treatment of fraction A) 269 DMSO- _d6 9.44 (br s, 1H), 8.94-8.99 (m, 1H), 8.30-8.35 (m, 1H), 7.49-7.56 (m, 1H), 7 .23 (dd, 7=2.26, 9.03 Hz, 1H), 6.89 (t, 7=10.49 Hz, 1H), 5.86-5.94 (m, 1H), 3, 95-4.09 (m, 2H), 3.71-3.80 (m, 2H), 3.57-3.69 (m, 1H), 3.50 (br dd, 7=4.09, 12.26 Hz, 1H), 3.12-3.26 (m, 2H), 3.09 (br d, 7=12.77 Hz, 1H), 2.51-2.62 (m, 2H) , 1.91-1.97 (m, 1H), 1.85-1.91 (m, 3H) IN SFC: Chiralpak IC, 15% methanol (primary treatment). Lux-Cellulose 2, 15% methanol (secondary treatment of fraction B), - 270 DMSO- _d6 9.45 (br s, 1H), 8.97 (d, 7=1.48 Hz, 1H), 8.29-8.36 (m, 1H), 7.48-7.56 (m, 1H ), 7.23 (dd, 7=2.18, 9.03 Hz, 1H), 6.89 (t, 7=10.48 Hz, 1H), 5.85-5.94 (m, 1H) , 3.97-4.07 (m, 2H), 3.71-3.80 (m, 2H), 3.57-3.69 (m, 1H), 3.29 (br s, 1H), 3.12-3.26 (m, 1H), 3.09 (br d, 7=12.53 Hz, 1H), 2.52-2.55 (m, 2H), 1.96-2.06 (m, 1H), 1.94 (br s, 1H), 1.83-1.91 (m, 3H) IN SFC: Chiralpak IC, 15% methanol (primary treatment). Lux-Cellulose 2, 15% methanol (secondary fraction B treatment) 271 DMSO- _d6 9.32 (br s, 1H), 8.86 (br s, 1H), 8.328.37 (m, 1H), 7.55-7.59 (m, 1H), 6.99 (dt, 7= 2.06, 10.53 Hz, 1H), 6.79 (dd, 7=1.99, 8.99 Hz, 1H), 5.92 (q, 7=7.16 Hz, 1H), 3, 95-4.10 (m, 2H), 3.81 (br d, 7=9.50 Hz, 1H), 3.70-3.78 (m, 1H), .61-3.69 (m, 1H), 3.39-3.48 (m, 2H), V SFC: Chiralpak IC, 15% methanol (primary treatment). Chiralcel OZH, 25%

-265 043189

3.07-3.17 (m, 1H), 2.52-2.55 (m, 2H), 1.87-1.99 (m, 5H) methanol (secondary treatment of fraction C), - 272 DMSO- _d6 9.33 (br s, 1H), 8.88 (br s, 1H), 8.35 (br d, 7=8.17 Hz, 1H), 7.57 (d, 7=8.25 Hz, 1H), 6.97-7.10 (m, 1H), 6.79 (br d, 7=8.88 Hz, 1H), 5.89-5.98 (m, 1H), 3.99- 4.07 (m, 2H), 3.78-3.84 (m, 1H), 3.70-3.78 (m, 1H), 3.64 (br t, 7=11.29 Hz, 1H ), 3.41-3.53 (m, 1H), 3.24 (br s, 1H), 3.07-3.17 (m, 1H), 2.54 (s, 2H), 1.86 -1.99(m, 5H) IN SFC: Chiralpak IC, 15% methanol (primary treatment). fraction C). Regis Whelk0 s, s, 20% methanol (secondary treatment of C1-C3 peaks) 273 DMSO- _d6 9.33 (br s, 1H), 8.90 (br d, 7=18.92 Hz, 1H), 8.32-8.37 (m, 1H), 7.57 (dd, 7=6, 89, 7.67 Hz, 1H), 6.99 (t, 7=10.22 Hz, 1H), 6.79 (br d, 7=8.95 Hz, 1H), 5.87-5.94 (m, 1H), 3.97-4.09 (m, 2H), 3.81 (br d, 7=8.95 Hz, 1H), 3.70-3.78 (m, 1H), 3 .61-3.69 (m, 1H), 3.57-3.69 (m, 1H), 3.29 (br s, 1H), 3.15 (br d, 7=14.09 Hz, 1H ), 2.52-2.56 (m, 2H), 2.00 (br d, 7=5.99 Hz, 1H), 1.92 (d, 7=7.16 Hz, 4H) IN SFC: Chiralpak IC, 15% methanol (primary treatment). Regis Whelk0 s, s, 30% methanol (secondary fraction D) 274 DMSO- _d6 9.33 (br s, 1H), 8.80-8.96 (m, 1H), 8.32-8.37 (m, 1H), 7.57 (t, 7=7.49 Hz, 1H ), 6.99 (dt, 7=2.02, 10.51 Hz, 1H), 6.79 (br d, 7=9.03 Hz, 1H), 5.87-5.94 (m, 1H ), 3.96-4.08 (m, 2H), 3.80 (br s, 1H), 3.70-3.78 (m, 1H), 3.55-3.69 (m, 1H) , 3.40-3.53 (m, 1H), 3.15 (br d, 7=14.17 Hz, 1H), 3.10 (br d, 7=13.39 V SFC: Chiralpak IC, 15% methanol (primary treatment). Regis Whilk0 s, s, 30% methanol

-266043189

275 DMSO- _d6 Hz, 1H), 2.51-2.55 (m, 2H), 1.92 (d, 4=7.16 Hz, 5H) 8.27 (br d, 4=7.21 Hz, 1H), 7.47 (dd, 4=7.47, 11.21 Hz, 1H), 7.34 (dd, 4=7.32, 10 .67 Hz, 1H), 4.62-4.69 (m, 2H), 4.32-4.44 (m, 2H), 3.33-3.50 (m, 1H), 3.17 ( br s, 1H), 2.96-3.11 (m, 2H), 2.77-2.85 (m, 1H), 2.66 (d, 4=4.59 Hz, ZN), 2, 07-2.15(m, 1H), 1.75-1.83(m, 1H) - (secondary treatment of fraction D) DMSO- _d6 7.46 (t, 4=9.25 Hz, 1H), 7.40 (t, 4=8.98 Hz, 1H), 4.98-5.07 (m, 2H), 4.35-4.47 ( _m , 1H), 3.63-3.73(m, 2H), 3.56-3.62(m, 4H), 3.38-3.54(m, 2H), 276 3.22-3.37 (m, 2H), 3.17 (br s, 1H), 2.94-3.10 (m, 1H), 2.80 (dd, 4=8.14, 12, 57 Hz, 1H), 2.06-2.17 (m, 1H), 1.75-1.84 (m, 1H) 7.46 (dd, 4=7.47, 11.13 Hz, 1H), 7.38 (dd, 4=7.32, 10.74 Hz, 1H), 4.84-4.94 (m, 2H), 4.35-4.44 (m, 1H), 3.51-3.66 (m, 2H), 3.23-3.41 (m, 2H), 2.94-3.11 277 DMSO- _d6 (m, 4H), 2.80 (dd, 4=8.21, 12.57 Hz, 2H), 2.29-2.47 (m, 1H), 2.02-2.18 (m, 2H ), 1.96 (quin, 4=6.83 Hz, 1H), 1.751.86 (m, 1H) 7.46 (dd, 4=7.47, 11.21 Hz, 1H), 7.37 (dd, 4=7.36, 10.78 Hz, 1H), 4.93-5.02 (m, 2H), 4.32-4.44 (m, 1H), 3.24-3.42 278 DMSO- _d6 (m, 1H), 3.17 (br s, 1H), 3.11 (s, 6H), 2.94-3.06 (m, 1H), 2.88 (s, 1H), 2.79 (dd, 4=8.21, 12.65Hz, 1H), 2.05-2.16(m, 1H), 1.74-1.84(m, 1H) 279 DMSO- _d6 7.53 (dd, 4=7.55, 11.13 Hz, 1H), 7.39 V SFCs:

- 267 043189

(dd, 7=7.43, 11.09 Hz, 1H), 5.51 (q, 7=6.98 Hz, 1H), 4.39-4.47 (dt, 7=4.13, 7 .94 Hz, 1H), 3.07-3.26 (m, 3H), 2.722.81 (m, 7H), 2.52-2.56 (m, 1H), 2.102.28 (m, 1H) , 1.71-1.86 (m, 1H), 1.61 (d, 7=7.01 Hz, 3H) analytic column Chiralpak IC, 15% methanol with 0.2% DEA 280 DMSO- _d6 7.53 (dd, 7=7.55, 11.13 Hz, 1H), 7.39 (dd, 7=7.43, 11.09 Hz, 1H), 5.51 (q, 7=6, 98Hz, 1H), 4.39-4.47(dt, 7=4.13, 7.94Hz, 1H), 3.07-3.26(m, 3H), 2.722.81(m, 7H ), 2.52-2.56 (m, 1H), 2.102.28 (m, 1H), 1.71-1.86 (m, 1H), 1.61 (d, 7=7.01 Hz, 3H) IN SFC: Chiralpak IC analytical column, 15% methanol with 0.2% DEA 281 DMSO- _d6 7.46 (dd, 7=7.47, 11.21 Hz, 1H), 7.37 (dd, 7=7.36, 10.78 Hz, 1H), 4.99 (d, 7=2, 34 Hz, 2H), 4.31-4.39 (m, 1H), 3.40-3.54 (m, 3H), 3.19-3.29 (m, 1H), 2.93-3 .04 (m, 2H), 2.78 (dd, 7=8.25, 12.53 Hz, 1H), 2.06-2.16 (m, 1H), 1.71-1.83 (m , 3H), 1.54-1.66 (m, 4H), 1.40-1.53 (m, 2H) - - 282 DMSO- _d6 8.31-8.41 (m, 1H), 7.47 (dd, 7=7.47, 11.21 Hz, 1H), 7.35 (dd, 7=7.28, 10.70 Hz, 1H), 4.61-4.68 (m, 2H), 4.32-4.47 (m, 1H), 3.35-3.45 (m, 1H), 3.11-3.28 ( m, 2H), 2.95-3.08 (m, 2H), 2.80 (dd, 7=8.68, 12.65 Hz, 1H), 2.03-2.18 (m, 1H) , 1.99 (br s, 1H), 1.56-1.91 (m, 1H), 1.06 (t, 7=7.24 Hz, 3H) - - 283 DMSO- _d6 8.94 (s, 2H), 7.80 (d, 7=1.09 Hz, 1H), 7.55 (d, 7=8.39 Hz, 1H), 7.50 (d, 7=8 .39 Hz, 1H), 5.54-5.62(m, 2H), 4.44-4.57( _m , 1H), 3.45-3.56(m, 2H), 3.07-3, 13 (m, 1H), 2.81 (dd, 7=8.56, 12.92 Hz, 1H), 2.52- V SFC: analytical column Chiralpak ADH, 30% methanol

- 268 043189

2.64 (m, 1H), 2.17 (s, 3H), 1.95-2.10 (m, 1H), 1.70-1.82 (m, 1H) 284 DMSO- _d6 8.94 (s, 2H), 7.91 (d, 7=1.01 Hz, 1H), 7.46 (dd, 7=1.56, 8.25 Hz, 1H), 7.39 (d , 7=8.25Hz, 1H), 5.60(s, 2H), 4.424.57(m, 1H), 3.47-3.54(m, 1H), 3.373.46(m, 1H) , 3.04-3.11 (m, 1H), 2.79 (dd, 7=8.52, 12.81 Hz, 1H), 2.52-2.65 (m, 1H), 2.18 (s, 3H), 1.95-2.11 (m, 1H), 1.71-1.84 (m, 1H) IN SFC: analytical column Chiralpak ADH, 30% methanol 285 DMSO- _d6 7.42 (d, 7=8.49 Hz, 1H), 7.38 (d, 7=2.02 Hz, 1H), 7.12-7.15 (m, 1H), 4.73-4 .80 (m, 2H), 4.57-4.69 (m, 1H), 3.95 (t, 7=7.71 Hz, 2H), 3.51-3.56 (m, 1H), 3.31-3.44 (m, 2H), 3.28 (br s, 1H), 3.17 (s, 1H), 2.99-3.10 (m, 1H), 2.95 (br dd, 7=9.34, 12.61 Hz, 1H), 2.25-2.32(m, 2H), 2.06-2.23(m, 1H), 1.72-1.89( m, 1H) IN SFC: Chiralpak IC analytical column, 45% methanol 286 DMSO- _d6 7.47 (d, 7=1.95 Hz, 1H), 7.25 (d, 7=8.49 Hz, 1H), 7.13 (dd, 7=1.95, 8.49 Hz, 1H ), 4.72-4.79 (m, 2H), 4.58-4.70 (dt, 7=4.59, 8.68 Hz, 1H), 4.23-4.29 (m, 1H ), 3.94 (t, 7=7.71 Hz, 1H), 3.513.59 (m, 1H), 3.31-3.47 (m, 2H), 3.28 (br s, 1H), 3.17 (s, 1H), 3.01-3.12 (m, 1H), 2.96 (br dd, 7=9.23, 12.65 Hz, 2H), 2.13-2.31 (m, 1H), 1.79-1.89 (m, 1H) V SFC: Chiralpak IC analytical column, 45% methanol 287 DMSO- _d6 7.77 (d, 7=1.01 Hz, 1H), 7.46-7.54 (m, 2H), 4.74-4.86 (m, 3H), 4.25-4.36 ( m, 2H), 3.96 (t, 7=7.71 Hz, 2H), 3.123.29 (m, 3H), 3.01-3.09 (m, 2H), 2.30 (quin, 7 = 7.69 Hz, 2H), 2.01-2.08 (m, 1H), 1.80-1.99 (m, 1H) V SFC: Chiralpak IC analytical column, 35% methanol

- 269 043189

288 DMSO- _d6 7.86-7.92(m, 1H), 7.46-7.52(m, 1H), 7.33-7.42(m, 1H), 4.74-4.86(m, 3H ), 4.25-4.36 (m, 2H), 3.96 (t, 7=7.71 Hz, 2H), 3.12-3.29 (m, 3H), 3.01-3, 09 (m, 2H), 2.30 (quin, 7=7.69 Hz, 2H), 2.012.08 (m, 1H), 1.80-1.99 (m, 1H) IN SFC: Chiralpak IC analytical column, 35% methanol 289 DMSO- _d6 8.92 (s, 2H), 7.42 (dd, 7=4.87, 8.68Hz, 1H), 7.11 (dd, 7=2.49, 9.26Hz, 1H), 6 .92 (ddd, 7=2.57, 8.68, 10.08 Hz, 1H), 5.47-5.56 (m, 2H), 4.26-4.42 (m, 1H), 3 .35-3.49 (m, 2H), 2.93-3.03 (m, 1H), 2.82-2.92 (m, 1H), 2.74 (dd, 7=8.60, 12.42Hz, 1H), 1.97-2.12(m, 1H), 1.64-1.82(m, 1H) IN SFC: Chiralcel OD-H, 15% isopropanol 290 DMSO- _d6 8.92 (s, 2H), 7.24 (dd, 7=2.45, 9.77Hz, 1H), 7.14 (dd, 7=4.75, 8.72Hz, 1H), 6 .87 (ddd, 7=2.49, 8.70, 9.91 Hz, 1H), 5.51 (d, 7=2.10 Hz, 2H), 4.274.34 (m, 1H), 3, 35-3.44 (m, 2H), 2.983.06 (m, 1H), 2.83-2.93 (m, 1H), 2.78 (dd, 7=8.60, 12.57 Hz, 1H), 1.99-2.09(m, 1H), 1.64-1.79(m, 1H) V SFC: Chiralcel OD-H, 15% isopropanol 291 500MHz DMSO-d ₆ 8.96 (s, 1H), 8.28 (br dd, 7=1.95, 8.17 Hz, 1H), 7.36-7.50 (m, 1H), 7.32 (br d, 7=8.04Hz, 1H), 7.05-7.20(m, 2H), 6.98-7.05(m, 1H), 5.47(s, 2H), 3.3(m , 1H), 2.83 (br t, 7=10.06 Hz, 2H), 2.74 (br s, 1H), 2.60-2.67 (m, 1H), 1.79 (br d , 7=8.30Hz, 1H), 1.66(brs, 1H), 1.51(brd, 7=10.77Hz, 1H), 1.15(brd, 7=10.64Hz, 1H) -- -- 292 500MHz DMSO-d ₆ 8.67 (d, 7=1.66 Hz, 1H), 8.02 (br d, 7=7.98 Hz, 3H), 7.77 (dd, 7=1.97, 8.09 Hz, 1H), 7.52 (d, 7=7.77 Hz, 1H), 7.13-7.28 (m, 3H), 5.54 (s, 2H), - -

- 270 043189

3.57-3.65 (m, 1H), 3.45 (br s, 1H), 3.30 (br d, 7=12.75 Hz, 1H), 3.18 (dd, 7=8, 50, 12.44 Hz, 1H), 2.98-3.07 (m, 1H), 1.99 (br d, 7=9.02 Hz, 1H), 1.83 (br s, 1H), 1.54-1.70 (m, 2H) 293 500MHz DMSO-d ₆ 9.23 (s, 1H), 8.48 (br d, 7=5.71 Hz, 1H), 7.95 (br d, 7=8.17 Hz, 1H), 7.88 (s, 1H ), 7.79 (br d, 7=5.58 Hz, 1H), 7.57 (br d, 7=8.43 Hz, 1H), 7.44 (br d, 7=7.66 Hz, 1H), 7.17 (br d, 7=7.91 Hz, 1H), 7.08 (br t, 7=7.46 Hz, 1H), 6.977.04 (m, 1H), 5.49 ( s, 2H), 2.78-2.95 (m, 2H), 2.53-2.72 (m, 2H), 1.82 (br d, 7=10.25 Hz, 2H), 1, 68 (br s, 1H), 1.61 (br s, 1H), 1.18 (br d, 7=9.73 Hz, 1H) - -- 294 500MHz DMSO-d ₆ 8.05 (s, 1H), 7.67 (br d, 7=7.92 Hz, 1H), 7.46 (br d, J=7.l% Hz, 1H), 7.08 (br t , 7=6.75 Hz, 1H), 6.92-7.03 (m, 3H), 6.59 (br d, 7=6.88 Hz, 1H), 5.835.96 (m, 2H), 4.32 (s, 3H), 3.37-3.59 (m, 1H), 2.86-2.99 (m, 1H), 2.82 (br s, 1H), 2.53-2 .76 (m, 1H), 1.78 (br s, 2H), 1.65 (br s, 1H), 1.58 (br s, 1H), 1.19 (brd, 7=9.99 Hz , 1H) - - 295 500MHz DMSO-d ₆ 9.03 (s, 1H), 8.29 (br d, 7=6.74 Hz, 1H), 7.36-7.51 (m, 2H), 6.99-7.12 (m, 1H ), 6.94 (d, 7=3.94 Hz, 2H), 5.825.99 (m, 1H), 4.03 (q, 7=7.15 Hz, 1H), 3.39 (br d, 7=10.78Hz, 1H), 3.17(br d, 7=12.65Hz, 1H), 2.81-3.05(m, 2H), 1.75-1.95(m, 4H), 1.54-1.70 (m, 1H), 1.31-1.47 (m, 1H), 1.17 (t, 7=7.10 Hz, 1H) V SFC: Chiralpak IC, 20% methanol with 0.2% DEA 296 500MHz DMSO-d ₆ 9.04 (d, 7=1.55 Hz, 1H), 8.24-8.31 (m, 1H), 7.36-7.48 (m, 2H), 7.01-7.09 ( m, V SFCs: Chiralpak IC,

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1H), 6.89-6.99 (m, 2H), 5.83-5.96 (m, 1H), 3.35-3.53 (m, 2H), 3.21 (br d, 3 =12.13 Hz, 1H), 3.12 (br s, 1H), 2.773.02 (m, 2H), 1.75-1.95 (m, 1H), 1.67 (br d, 3= 9.23 Hz, 1H), 1.29-1.46 (m, 1H). 20% methanol with 0.2% DEA 297 500MHz DMSO-d ₆ 9.03 (d, 3=1.55 Hz, 1H), 8.80 (br s, 3H), 8.36 (dd, 3=2.07, 8.29 Hz, 1H), 7.66 ( br d, 3=8.29 Hz, 1H), 7.56 (d, 3=7.98 Hz, 1H), 7.39 (br s, 1H), 7.007.15 (m, 2H), 6, 04 (q, 3=6.77 Hz, 1H), 4.92-5.05 (m, 1H), 3.84 (br d, 3=12.75 Hz, 1H), 3.75 (br s , 1H), 3.62-3.71 (m, 1H), 3.32-3.54 (m, 1H), 3.06-3.30 (m, 1H), 2.77-3.05 (m, 1H), 2.53-2.75 (m, 1H), 2.27-2.47 (m, 1H), 1.91-2.02 (m, 4H). IN SFC: Chiralpak IC, 20% methanol with 0.2% DEA 298 500MHz DMSO-d ₆ 9.02 (d, 3=1.45 Hz, 1H), 8.80 (br s, 3H), 8.35 (dd, 3=2.18, 8.29 Hz, 1H), 7.63 ( d, 3=7.56Hz, 1H), 7.58(d, 3=7.48Hz, 1H), 7.20-7.29(m, 1H), 7.03-7.15(m , 2H), 6.01 (q, 3=6.91 Hz, 1H), 4.90-5.02 (m, 1H), 3.91 (s, 1H), 3.87 (br s, 1H ), 3.65-3.81 (m, 1H), 3.59-3.64 (m, 1H), 3.26 (br t, 3=11.25 Hz, 1H), 2.32 (br d, 3=3.84Hz, 1H), 2.01 (d, 3=7.05Hz, 4H) IN SFC: Chiralpak IC, 20% methanol with 0.2% DEA 299 500MHz DMSO-d ₆ 9.07 (d, 3=1.55 Hz, 1H), 8.36-8.52 (m, 4H), 7.84 (d, 3=8.19 Hz, 1H), 7.63 (d , 3=7.98 Hz, 1H), 7.28-7.39 (m, 1H), 7.21 (br d, 3=3.63 Hz, 2H), 5.90 (br dd, 3= 4.77, 10.47Hz, 1H), 4.02 (br d, 3=14.10 Hz, 1H), 3.89 (br s, 1H), 3.59-3.81 (m, 1H), 3.33-3.54 (m, 2H), 3.10-3.32 (m, 2H), 2.56 (br V SFC: Chiralpak IC, 25% methanol with 0.2% DEA

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dd, 7=7.20, 13.73 Hz, 1H), 2.31 (qd, 7=7.03, 10.63 Hz, 1H), 2.08 (br s, 1H), 1.96- 2.05 (m, 1H), 1.74 (br d, 7=8.60 Hz, 1H), 1.60 (br d, 7=4.35 Hz, 1H), 0.59 (brt, 7 =7.15Hz, 3H) 300 500MHz DMSO-d ₆ 9.06 (d, 7=1.56 Hz, 1H), 8.51 (br s, 3H), 8.38-8.48 (m, 1H), 7.79 (br d, 7=8, 40 Hz, 1H), 7.61 (d, 7=8.09 Hz, 1H), 7.26-7.34 (m, 1H), 7.13-7.22 (m, 2H), 5, 71 (br dd, 7=5.65, 9.80 Hz, 1H), 3.67-3.78 (m, 1H), 3.42-3.50 (m, 1H), 3.16 (s , 1H), 3.10 (br s, 1H), 2.55-2.69 (m, 1H), 2.26-2.45 (m, 2H), 1.98-2.12 (m, 1H), 1.86 (br s, 2H), 1.65 (br s, 1H), 1.10-1.31 (m, 1H), 0.64-0.71 (m, 3H). IN SFC. Chiralpak IC, 25% methanol with 0.2% DEA 301 500MHz DMSO-d ₆ 8.87 (s, 2H), 8.40 (br s, 2H), 7.53 (dd, 7=7.43, 11.02 Hz, 1H), 7.39 (t, 7=8.98 Hz, 1H), 5.50-5.60 (m, 2H), 4.72-4.84 (m, 1H), 3.62-3.75 (m, 1H), 3.42-3, 59 (m, 1H), 3.17-3.29 (m, 1H), 2.95-3.08 (m, 2H), 2.13-2.20 (m, 1H), 1.73- 1.82(m, 1H) - - 302 500MHz DMSO-d ₆ 7.85(s, 1H), 7.77(d, 7=7.71Hz, 1H), 7.49-7.56(m, 2H), 7.44(d, 7=8.32Hz , 1H), 7.20 (t, 7=8.97 Hz, 1H), 5.83 (q, 7=7.08 Hz, 1H), 4.36-4.46 (m, 1H), 4 .03-4.16 (m, 1H), 3.35-3.39 (m, 1H), 3.14-3.19 (m, 1H), 2.99-3.13 (m, 1H) , 2.78-2.92 (m, 1H), 2.08-2.20 (m, 1H), 1.76-1.94 (m, 4H) - - 303 500MHz DMSO-d ₆ 8.88 (s, 2H), 7.50 (dd, 7=7.43, 11.09 Hz, 1H), 7.38 (t, 7=8.94 Hz, 1H), 5.495.58 (m , 2H), 4.45-4.54 (dt, 7=4.55, 8.66 Hz, 1H), 3.43-3.61 (m, 1H), 3.38- - -

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3.42 (m, 1H), 3.05-3.24 (m, 1H), 2.953.03 (m, 1H), 2.86 (dd, 7=9.19, 12.61 Hz, 1H) , 1.98-2.11 (m, 1H), 1.66-1.76 (m, 1H) 304 500MHz DMSO-d ₆ 8.50 (d, 7=2.88 Hz, 1H), 7.73 (dt, 7=2.96, 8.72 Hz, 1H), 7.48 (dd, 7=7.47, 11, 21 Hz, 1H), 7.30-7.38 (m, 2H), 5.36-5.43 (m, 2H), 4.65-4.82 (m, 1H), 6 3.16- 3.29 (m, 2H), 3.04-3.14 (m, 1H), 2.88-3.00 (m, 2H), 1.94-2.01 (m, 1H), 1, 80-1.92 (m, 1H). - - 305 500MHz DMSO-d ₆ 8.88(s, 2H), 7.65(s, 1H), 7.58(d, 7=8.43Hz, 1H), 7.41(dd, 7=1.25, 8.33Hz , 1H), 5.59-5.67 (m, 2H), 4.66-4.73 (m, 1H), 3.24-3.30 (m, 2H), 3.07-3.18 (m, 1H), 2.83-2.99 (m, 2H), 1.92-2.00 (m, 1H), 1.75-1.90 (m, 1H). IN SFCs: Chiralpak ADH, 25% methanol 306 500MHz DMSO-d ₆ 8.88 (s, 2H), 7.75 (s, 1H), 7.36 (s, 2H), 5.55-5.64 (m, 2H), 4.70-4.76-4, 81 (m, 1H), 3.24-3.31 (m, 2H), 3.08-3.18 (m, 1H), 2.86-3.00 (m, 2H), 1.93- 2.03(m, 1H), 1.76-1.92(m, 1H). IN SFCs: Chiralpak ADH, 25% methanol 307 500MHz DMSO-d ₆ 8.46-8.51 (m, 1H), 7.74 (t, 7=8.73 Hz, 1H), 7.51 (t, 7=9.21 Hz, 1H), 7.41 (d , 7=8.81 Hz, 1H), 7.34 (t, 7=9.19 Hz, 1H), 5.40-5.47 (m, 2H), 3.50 (br d, 7=12 .46Hz, 1H), 3.15-3.23(m, 1H), 3.10(td, 7=4.45, 16.87Hz, 1H), 2.973.02(m, 1H), 2 .52-2.59(m, 1H), 2.182.29(m, 1H), 1.98-2.11(m, 1H). -- - 308 500MHz DMSO-d ₆ 7.63 (s, 1H), 7.56 (d, 7=8.25 Hz, 1H), 7.41 (dd, 7=1.28, 8.29 Hz, 1H), 4.764.89 (m , 3H), 4.26-4.33 (m, 2H), 3.96 (t, 7=7.75 Hz, 2H), 3.15-3.29 (m, 2H), 2.97- 3.13 (m, 2H), 2.30 (td, 7=7.66, V SFC: Chiralpak IC, 15% methanol

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15.43 Hz, 2H), 1.90-2.09 (m, 1H) 309 500MHz DMSO-d ₆ 7.73 (s, 1H), 7.41 (s, 2H), 4.75-4.88 (m, 3H), 4.24-4.34 (m, 2H), 3.95 (t, 7=7.71Hz, 2H), 3.14-3.28(m, 3H), 2.98-3.12(m, 2H), 2.29(td, 7=7.69, 15, 45Hz, 2H), 1.91-2.09(m, 2H) IN SFC: Chiralpak IC, 15% methanol 310 500MHz DMSO-d ₆ 7.45 (dd, 7=7.47, 11.13 Hz, 1H), 7.37 (dd, 7=7.32, 10.74 Hz, 1H), 4.77-4.86 (m, 2H), 4.32-4.46(m, 1H), 3.59-3.67(m, 2H), 2.94-3.12(m, 2H), 2.78(dd, 7= 8.29, 12.57 Hz, 1H), 2.00-2.13(m, 1H), 1.84-1.94(m, 3H), 1.71-1.84(m, 4H) , 1.35 (d, 7=2.96 Hz, 6H). - - 311 500MHz MeOD 8.86 (s, 1H), 8.14-8.20 (m, 1H), 7.48 (br dd, J=5.06, 8.69 Hz, 1H), 7.43 (br d, J=8.30 Hz, 1H), 6.93-7.01 (m, 2H), 5.46-5.58 (m, 2H), 3.94-4.01 (m, 1H), 3 .34-3.48 (m, 3H), 3.20-3.26 (m, 1H), 3.09 (br dd, J=5.32, 12.07 Hz, 1H), 1.87 ( q, J=5.71Hz, 2H) IN Cel2, 20% MeOH, 0.2% DEA Peak 1 312 500MHz MeOD 8.86 (s, 1H), 8.16 (br dd, J=l.95, 8.17 Hz, 1H), 7.42 (br d, J=8.56 Hz, 1H), 7.21 (br dd, J=2.34, 9.34 Hz, 1H), 7.11 (br dd, J=4.54, 8.69 Hz, 1H), 6.86-6.94 (m, 1H ), 5.48-5.58 (m, 2H), 3.95-4.06 (m, 1H), 3.35-3.52 (m, 3H), 3.11-3.20 (m , 1H), 1.81-1.92 (m, 2H) V Cel2, 20% MeOH, 0.2% DEA Peak 2 313 400MHz d ₆ -DMSO 8.45 (br s, 2H), 7.89 (d, 7=8.40 Hz, 2H), 7.55-7.64 (m, 3H), 7.31 (t, 7=7.62 Hz, 1H), 7.18 (t, 7=7.62 Hz, 1H), 7.08 (d, 7=8.19 Hz, 1H), 5.98 (q, 7=6.98 Hz, 1H), 3.64-3.74 (m, 2H), 3.44-3.51 (m, 1H), 3.31-3.38 (m, 1H), 3.11-3.20 ( m, 1H), 1.96-2.05 (m, 2H), 1.93 (d, 7=7.05 Hz, 3H), 1.64-1.79 (m, V Chiralpak IC, 30% IP A, peak 1

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2H) 314 400MHz d ₆ -DMSO 8.40 (br s, 3H), 7.85 (d, 7=8.50 Hz, 2H), 7.55-7.61 (m, 1H), 7.52 (d, 7=8.29Hz, 2H), 7.25(br t, 7=7.62Hz, 1H), 7.04-7.15(m, 2H), 5.89(q, 7=7.05Hz, 1H), 3.72-3.78(m, 2H), 3.31-3.38(m, 2H), 3.13-3.22(m, 1H), 2 .02-2.08 (m, 1H), 2.00 (d, 7=7.05 Hz, 3H), 1.89-1.97 (m, 1H), 1.62-1.79 (m , 2H) IN Chiralpak IC, 30% IP A, peak 2 315 400MHz d ₆ -DMSO 8.43 (br s, 3H), 7.97 (dd, 7=1.14, 10.06 Hz, 1H), 7.70 (d, 7=7.59 Hz, 1H), 7.58 ( d, 7=7.88 Hz, 1H), 7.397.48 (m, 1H), 7.23-7.38 (m, 3H), 5.525.65 (m, 2H), 3.79 (br d, 7=10.16 Hz, 1H), 3.34-3.51 (m, 3H), 3.11-3.22 (m, 1H), 1.95-2.04 (m, 1H), 1 .83-1.95 (m, 1H), 1.58-1.75 (m, 2H) - - 316 400MHz d ₆ -DMSO 8.55 (br s, 3H), 7.60 (d, 7=7.77 Hz, 1H), 7.45 (d, 7=7.92 Hz, 2H), 7.277.39 (m, 5H) , 5.47-5.62 (m, 2H), 3.92 (br d, 7=10.37 Hz, 1H), 3.64-3.74 (m, 1H), 3.41-3, 53 (m, 2H), 3.18-3.29 (m, 1H), 1.96-2.05 (m, 1H), 1.86-1.96 (m, 1H), 1.57- 1.76(m, 2H) - - 317 400MHz d ₆ -DMSO 8.67 (br s, 3H), 7.87 (d, 7=8.40 Hz, 2H), 7.51-7.62 (m, 3H), 7.26 (t, 7=7.00 Hz, 1H), 7.04-7.17 (m, 2H), 5.94-6.01 (m, 1H), 5.10-5.30 (m, 1H), 3.84-3, 97 (m, 1H), 3.57-3.68 (m, 2H), 3.23-3.37 (m, 2H), 2.18-2.29 (m, 1H), 2.07- 2.18 (m, 1H), 1.95 (d, 7=7.05 Hz, 3H) V Chiralpak IC, 25% IP A, peak 1 318 400MHz d ₆ -DMSO 8.85 (br s, 3H), 7.85 (d, 7=8.40 Hz, 2H), 7.52-7.63 (m, 3H), 7.22-7.35 (m, V Chiralpak IC, 25% IP A,

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1H), 7.06-7.18 (m, 2H), 5.94 (q, 4=7.05 Hz, 1H), 5.13-5.34 (m, 1H), 3.83-4 .00 (m, 1H), 3.72-3.80 (m, 1H), 3.51-3.61 (m, 1H), 3.40 (br s, 2H), 2.24 (br d , 4=2.38 Hz, 2H), 1.99-2.05 (m, 3H) peak 2 319 400MHz d ₆ -DMSO 8.83 (br s, 3H), 7.87 (d, 4=8.40 Hz, 2H), 7.53-7.62 (m, 3H), 7.28 (t, 4=7.06 Hz, 1H), 7.14 (t, 4=7.77 Hz, 1H), 7.05 (d, 4=8.09 Hz, 1H), 5.98 (q, 4=6.88 Hz, 1H), 4.89-5.11 (m, 1H), 3.87 (br d, 4=12.75 Hz, 1H), 3.78 (br d, 4=6.84 Hz, 1H), 3.42-3.61(m, 2H), 3.18-3.29(m, 1H), 2.29-2.38(m, 1H), 1.98-2.07(m, 1H ), 1.95 (d, 4=6.95 Hz, ZN) IN Chiralpak IC, 25% IP A, peak 1 320 400MHz d ₆ -DMSO 8.86 (br s, 3H), 7.85 (d, 4=8.40 Hz, 2H), 7.50-7.61 (m, 3H), 7.25 (t, 4=7.52 Hz, 1H), 7.04-7.15 (m, 2H), 5.94 (q, 4=6.81 Hz, 1H), 4.87-5.09 (m, 1H), 3.91 (br d, 4=12.75 Hz, 1H), 3.79 (br s, 1H), 3.47-3.55 (m, 1H), 3.353.44 (m, 1H), 3.22- 3.31 (m, 1H), 2.272.38 (m, 1H), 2.02-2.08 (m, 1H), 1.99 (d, 4=7.15 Hz, ZN) IN Chiralpak IC, 25% IP A, peak 2 321 400MHz d ₆ -DMSO 8.48 (br s, 3H), 8.21 (d, 4=1.45 Hz, 1H), 7.84 (dd, 4=1.45, 8.09 Hz, 1H), 7.61 ( d, 4=7.98 Hz, 1H), 7.31-7.45(m, 2H), 7.19-7.29(m, 2H), 5.45-5.60(m, 2H) , 3.73-3.82 (m, 1H), 3.42-3.54 (m, 2H), 3.34 (br d, 4=13.06 Hz, 1H), 3.17 (br t , 4=9.43 Hz, 1H), 1.95-2.06 (m, 1H), 1.83-1.94 (m, 1H), 1.59-1.78 (m, 2H) - - 322 600MHz 7.91 (d, 4=8.49 Hz, 2H), 7.48-7.56 (m, V SFC: Chiralcel

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DMSO- _d6 2H), 7.19 (dd, 7=7.32, 10.90 Hz, 1H), 5.88 (q, 7=7.06 Hz, 1H), 4.32-4.48 (m, 1H ), 3.35-3.41 (m, 1H), 3.24-3.28 (m, 1H), 3.17-3.22 (m, 3H), 2.99-3.09 (m , 1H), 2.87 (dd, 7=8.52, 12.50 Hz, 1H), 2.51-2.57 (m, 1H), 2.08-2.19 (m, 1H), 1.98 (br d, 7=7.08 Hz, 1H), 1.74-1.90 (m, 1H) OJ-H, 15% methanol 323 600MHz DMSO-d ₆ 7.90 (d, 7=7.91 Hz, 2H), 7.47-7.56 (m, 2H), 7.20 (dd, 7=7.28, 10.86 Hz, 1H), 5 .88 (q, 7=7.06 Hz, 1H), 4.32-4.41 (m, 1H), 3.36-3.43 (m, 1H), 3.16-3.27 (m , 1H), 2.99-3.13 (m, 1H), 2.80 (dd, 7=8.56, 12.46 Hz, 1H), 2.51-2.62 (m, 1H), 2.08-2.26 (m, 1H), 1.93 (d, 7=7.16 Hz, 3H), 1.79-1.91 (m, 1H) IN SFC: Chiralcel OJ-H, 15% methanol 324 600MHz DMSO-d ₆ 7.74 (d, 7=7.73 Hz, 1H), 7.42-7.52 (m, 3H), 7.33-7.41 (m, 2H), 5.87 (q, 7= 7.14 Hz, 1H), 4.31-4.42(m, 1H), 3.20-3.27(m, 1H), 3.17(s, 1H), 2.913.00(m, 2H ), 2.78 (dd, 7=8.88, 12.30 Hz, 1H), 1.99-2.14 (m, 1H), 1.94 (d, 7=7.24 Hz, 4H) , 1.69-1.87 (m, 1H) IN SFCs: Chiralpak ADH, 10% methanol 325 600MHz DMSO-d ₆ 7.72 (d, 7=8.01 Hz, 1H), 7.51 (dd, 7=7.67, 11.09 Hz, 1H), 7.41-7.46 (m, 2H), 7 .32-7.40 (m, 2H), 5.87 (q, 7=7.11 Hz, 1H), 4.31-4.41 (m, 1H), 3.25-3.40 (m , 1H), 3.17 (s, 1H), 3.11 (br d, 7=12.61 Hz, 1H), 2.92-3.07 (m, 1H), 2.74 (dd, 7 =8.99, 12.34Hz, 1H), 2.01-2.17(m, 1H), 1.94(d, 7=7.16Hz, 4H), 1.71-1.89( m, 1H) V SFCs: Chiralpak ADH, 10% methanol 326 600MHz DMSO-d ₆ 7.52 (dd, 7=7.63, 11.06 Hz, 1H), 7.33- 7.39 (m, 3H), 7.19 (dd, 7=7.28, 10.94 Hz, 1H), 7.08-7.15 (m, 1H), 5.74-5.82 V SFCs: Chiralpak AD- H, 10%

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327 600MHz DMSO-d ₆ (m, 1H), 4.34-4.45(m, 1H), 3.35-3.42(m, 1H), 2.97-3.08(m, 2H), 2.86(dd , 7=8.68, 12.42 Hz, 1H), 2.05-2.20 (m, 1H), 1.78-1.96 (m, 5H) 7.52 (dd, 7=7.59, 11.09 Hz, 1H), 7.347.38 (m, 3H), 7.19 (dd, 7=7.32, 10.90 Hz, 1H), 7 .08-7.16(m, 1H), 5.73-5.82(m, 1H), 4.35-4.45(m, 1H), 3.34-3.43(m, 2H) , 3.21-3.28 (m, 1H), 3.00-3.10 (m, 1H), 2.81 (dd, 7=8.52, 12.42 Hz, 1H), 2.07 -2.21(m, 1H), 1.78-1.96(m, 5H) 7.77 (s, 1H), 7.41-7.54 (m, 4H), 5.83 IN methanol SFCs: Chiralpak ADH, 10% methanol (q, 7=7.14 Hz, 1H), 4.28-4.40 (m, 1H), SFC: column 328 600MHz 3.10 (br d, 7=12.38 Hz, 1H), 2.90-3.04 D Chiralcel OD- DMSO- _d6 (m, 2H), 2.72 (dd, 7=8.87, 12.30 Hz, H, 10% 1H), 2.00-2.16 (m, 1H), 1.95 (d, isopropanol 7=7.16 Hz, ZN), 1.68-1.87 (m, 2H) 7.79 (s, 1H), 7.42-7.54 (m, 4H), 5.84 (q, 7=7.14Hz, 1H), 4.27-4.41(m, 1H), SFC: column 600MHz 3.16-3.27(m, 1H), 2.87-3.00(m, 2H), D Chiralcel OD- DMSO- _d6 2.78 (dd, 7=9.03, 12.38 Hz, 1H), 2.00- H, 10% 2.13 (m, 1H), 1.95 (d, 7=7.16 Hz, ZN), isopropanol 1.69-1.86 (m, 2H) 7.75-7.80 (m, 1H), 7.48 (dd, 7=7.63, 11.06 Hz, 1H), 7.26 (dd, 7=7.28, 11.02 Hz, 1H), 7.14-7.20 (m, 2H), 5.89 (q, SFC: 15 600MHz 7=6.95Hz, 1H), 4.40-4.47(m, 1H), D Chiralpak AD- DMSO- _d6 4.33-4.39(m, 1H), 3.27-3.30(m, 2H), H, 15% 2.94-3.01 (m, 2H), 2.86 (dd, 7=8.95, 12.46 Hz, 1H), 2.02-2.14 (m, 1H), 1.85- 2.00(m, 5H) isopropanol 331 600MHz DMSO-d ₆ 7.74-7.82 (m, 1H), 7.48 (dd, 7=7.67, 11.09 Hz, 1H), 7.26 (dd, 7=7.32, 11.05 Hz, 1H), 7.14-7.20 (m, 2H), 5.88 (q, IN SFC: 15 Chiralpak AD- H, 15%

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7=7.11 Hz, 1H), 4.34-4.48(m, 1H), 3.28-3.39(m, 1H), 3.23(br dd, 7=5.41, 7 .43 Hz, 2H), 3.03-3.13 (m, 1H), 2.78 (dd, 7=8.37, 12.42 Hz, 1H), 2.07-2.22 (m, 1H), 1.94 (d, 7=7.16 Hz, 3H), 1.64-1.86 (m, 1H) isopropanol 332 600MHz DMSO-d ₆ 7.57 (s, 1H), 7.59 (d, 7=11.19 Hz, 1H), 7.52 (dd, 7=7.59, 11.09 Hz, 1H), 7.26 (dd , 7=7.28, 10.94 Hz, 1H), 7.10 (d, 7=8.54 Hz, 1H), 5.77 (q, 7=7.16 Hz, 1H), 4.32 -4.45 (m, 1H), 3.24-3.38 (m, 1H), 2.96-3.09 (m, 2H), 2.85 (dd, 7=8.56, 12, 46Hz, 1H), 2.05-2.21(m, 1H), 1.77-1.94(m, 5H) IN SFC: Chiralpak ADH 25 cm column, 20% isopropanol 333 600MHz DMSO-d ₆ 7.51-7.61(m, 3H), 7.26(t, 7=9.06Hz, 1H), 7.10(d, 7=8.29Hz, 1H), 5.745.81(m , 1H), 4.31-4.45 (m, 1H), 3.213.28 (m, 1H), 2.98-3.12 (m, 2H), 2.80 (dd, 7=8.49 , 12.46 Hz, 1H), 2.09-2.20 (m, 1H), 1.78-1.93 (m, 5H) IN SFC: Chiralpak ADH 25 cm column, 20% isopropanol 334 600MHz DMSO-d ₆ 7.62 (ddd, 7=3.15, 5.99, 9.15 Hz, 1H), 7.48 (dd, 7=7.59, 11.09 Hz, 1H), 7.35 (dd, 7=7.32, 11.05Hz, 1H), 7.13-7.25(m, 2H), 5.91(q, 7=7.14Hz, 1H), 4.32-4.44 (m, 1H), 3.25-3.29 (m, 1H), 2.92-3.03 (m, 2H), 2.87 (dd, 7=8.84, 12.26 Hz, 1H ), 1.99-2.14 (m, 1H), 1.86-1.96 (m, 5H), 1.83 (br s, 1H) IN SFC: Chiralpak AD- H, 15% isopropanol 335 600MHz DMSO-d ₆ 7.72 (d, 7=8.17 Hz, 2H), 7.53 (dd, 7=7.55, 10.90 Hz, 1H), 7.45 (br d, 7=7.08 Hz, 2H), 7.17 (t, 7=8.84 Hz, 1H), 5.87 (q, 7=6.95 Hz, 1H), 4.314.40 (m, 1H), 3.35-3, 41 (m, 2H), 3.213.26 (m, 1H), 3.17 (s, 1H), 2.97-3.10 (m, 2H), 2.77-2.94 (m, 1H) , 2.02-2.18 V SFC: Chiralpak AD- N, 15% isopropanol

- 280 043189

(m, 1H), 1.93 (d, 7=7.16 Hz, 3H), 1.72-1.90 (m, 3H) 336 600MHz DMSO-d ₆ 7.72 (d, 7=8.17 Hz, 2H), 7.53 (dd, 7=7.55, 10.90 Hz, 1H), 7.45 (br d, 7=7.08 Hz, 2H), 7.17 (t, 7=8.84 Hz, 1H), 5.87 (q, 7=6.95 Hz, 1H), 4.314.45 (m, 1H), 3.21-3, 26 (m, 1H), 3.17 (s, 1H), 2.97-3.10 (m, 1H), 2.77-2.94 (m, 1H), 2.02-2.18 ( m, 1H), 1.93 (d, 7=7.16 Hz, 3H), 1.72-1.90 (m, 2H) IN SFC: Regis Whelk-O s, s, 15% methanol 337 600MHz DMSO-d ₆ 7.51 (dd, 7=7.59, 10.78 Hz, 1H), 7.327.39 (m, 4H), 7.15 (dd, 7=7.32, 10.90 Hz, 1H), 5 .81 (q, 7=7.08 Hz, 1H), 4.34.4.45 ( _m , 1H), 3.22-3.39 (m, 1H), 2.96-3.12 (m, 2H ), 2.77-2.94 (m, 1H), 2.07-2.19 (m, 1H), 1.78-1.93 (m, 5H) IN SFC: Regis Whelk-O s, s, 15% methanol 338 600MHz DMSO-d ₆ 8.87 (s, 2H), 7.48 (dd, 7=7.47, 11.13 Hz, 1H), 7.37 (dd, 7=7.32, 10.74 Hz, 1H), 5 .39-5.55 (m, 2H), 4.68-4.77 (m, 1H), 3.14-3.28 (m, 1H), 3.01-3.11 (m, 1H) , 2.83-2.94 (m, 2H), 1.88-2.01 (m, 1H), 1.69-1.87 (m, 1H), 1.63 (br s, 1H) V - 339 600MHz DMSO-d ₆ 8.50 (d, 7=2.88 Hz, 1H), 7.73 (dt, 7=2.96, 8.72 Hz, 1H), 7.48 (dd, 7=7.47, 11, 21 Hz, 1H), 7.30-7.38 (m, 2H), 5.36-5.43 (m, 2H), 4.75-4.82 (m, 1H), 4.65-4 .74 (m, 1H), 3.16-3.29 (m, 1H), 3.04-3.14 (m, 1H), 2.88-3.00 (m, 2H), 1.94 -2.01(m, 1H), 1.80-1.92(m, 1H), 1.59(brs, 1H) V - 340 600MHz DMSO-d ₆ 8.12 (d, 7=2.26 Hz, 1H), 7.71 (dd, 7=2.26, 8.49 Hz, 1H), 7.54 (dd, 7=7.47, 11, 06Hz, 1H), 7.36(t, 7=8.91Hz, 1H), 6.97(d, 7=8.56Hz, 1H), V -

- 281 043189

5.45-5.54 (m, 3H), 4.36-4.43 (m, 1H), 4.28-4.35 (m, 1H), 3.27-3.35 (m, 1H ), 3.17 (s, 1H), 2.99-3.07 (m, 1H), 2.862.98 (m, 1H), 2.76 (dd, 7=8.68, 12.57 Hz, 1H), 2.01-2.17(m, 1H), 1.66-1.82(m, 1H) 341 600MHz DMSO-d ₆ 8.12 (d, 7=2.26 Hz, 1H), 7.71 (dd, 7=2.26, 8.49 Hz, 1H), 7.54 (dd, 7=7.47, 11, 06Hz, 1H), 7.36(t, 7=8.91Hz, 1H), 6.97(d, 7=8.56Hz, 1H), 5.45-5.54(m, 2H) , 4.28-4.43(m, 1H), 3.27-3.35(m, 1H), 3.17(s, 1H), 2.993.07(m, 1H), 2.86-2 .98 (m, 1H), 2.76 (dd, 7=8.68, 12.57 Hz, 1H), 2.01-2.17 (m, 1H), 1.66-1.82 (m , 1H) IN -- 342 600MHz DMSO-d ₆ 7.80 (s, 1H), 7.65 (dd, 7=1.44, 7.98 Hz, 1H), 7.49-7.57 (m, 1H), 7.38 (s, 1H) , 7.32 (dd, 7=7.24, 10.67 Hz, 1H), 6.97 (d, 7=8.02 Hz, 1H), 5.33-5.40 (m, 2H), 4.29-4.42 (m, 1H), 3.36-3.45(m, 1H), 3.16-3.28(m, 1H), 2.98-3.05(m, 1H), 2.86-2.95(m, 1H ), 2.76 (dd, 7=8.72, 12.61 Hz, 1H), 1.982.10 (m, 1H), 1.65-1.79 (m, 1H) IN -- 343 600MHz DMSO-d ₆ 7.51-7.59 (m, 2H), 7.44 (dd, 7=2.57, 8.56 Hz, 1H), 7.37 (dd, 7=7.28, 10.70 Hz, 1H), 6.89 (d, 7=2.49 Hz, 1H), 5.31-5.38 (m, 2H), 4.29-4.41 (m, 1H), 3.35-3 .46 (m, 1H), 3.25-3.29 (m, 1H), 2.99-3.05 (m, 1H), 2.85-2.96 (m, 1H), 2.77 (dd, 7=8.64, 12.53Hz, 1H), 1.912.09(m, 1H), 1.65-1.76(m, 1H) V - 344 600MHz DMSO-d ₆ 7.48-7.56 (m, 3H), 7.39 (dd, 7=7.32, 10.67 Hz, 1H), 7.24 (d, 7=8.25 Hz, 2H), 5 .33-5.42(m, 2H), 4.31-4.43(m, V -

- 282 043189

1H), 3.43 (ddd, 7=3.39, 7.07, 8.86 Hz, 1H), 3.36-3.39 (m, 1H), 3.17 (d, 7=4, 75 Hz, 1H), 2.92-3.08 (m, 1H), 2.81 (dd, 7=8.56, 12.61 Hz, 1H), 1.982.11 (m, 1H), 1, 93 (t, 7=18.84 Hz, 3H), 1.63-1.87 (m, 1H) 345 600MHz DMSO-d ₆ 7.74 (s, 1H), 7.52-7.60 (m, 2H), 7.22 (dd, 7=7.36, 10.63 Hz, 1H), 6.68 (d, 7= 8.02 Hz, 1H), 5.31-5.40(m, 2H), 4.09-4.41(m, 1H), 3.36-3.45(m, 1H), 3.15-3.24(m, 1H), 3.00-3.07(m, 1H), 2.87-2.98(m, 1H ), 2.78 (dd, 7=8.33, 12.61 Hz, 1H), 2.342.39 (m, 3H), 1.98-2.10 (m, 1H), 1.611.79 (m, 1H) IN -- 346 600MHz DMSO-d ₆ 8.16 (d, 7=1.63 Hz, 1H), 7.75 (dd, 7=1.60, 8.06 Hz, 1H), 7.55 (dd, 7=7.43, 11, 09 Hz, 1H), 7.37 (dd, 7=7.32, 10.67 Hz, 1H), 6.89 (d, 7=8.10 Hz, 1H), 5.38-5.46 ( m, 2H), 4.29-4.40(m, 1H), 3.26(brs, 2H), 2.98-3.06(m, 1H), 2.83-2.97(m , 1H), 2.75 (dd, 7=8.60, 12.57 Hz, 1H), 1.98-2.16 (m, 1H), 1.62-1.79 (m, 1H) IN -- 347 600MHz DMSO-d ₆ 8.12 (d, 7=2.26 Hz, 1H), 7.71 (dd, 7=2.26, 8.49 Hz, 1H), 7.54 (dd, 7=7.44, 11, 09 Hz, 1H), 7.36 (dd, 7=7.28, 10.70 Hz, 1H), 6.97 (d, 7=8.56 Hz, 1H), 5.46-5.53 ( m, 2H), 4.24-4.43 (m, 1H), 3.09-3.24 (m, 2H), 2.99-3.06 (m, 1H), 2.83-2, 98 (m, 1H), 2.76 (dd, 7=8.60, 12.57 Hz, 1H), 2.02-2.10 (m, 1H), 1.67-1.86 (m, 1H) IN - 348 600MHz DMSO-d ₆ 7.51 (dd, 7=7.47, 11.21 Hz, 1H), 7.35- 7.42 (m, 1H), 7.15-7.28 (m, 4H), 6.86 V -

- 283 043189

(d, 3=7.65Hz, 1H), 5.30(s, 2H), 4.194.43(m, 1H), 3.37-3.49(m, 2H), 2.983.09(m, 1H), 2.89-2.97 (m, 1H), 2.78 (dd, 3=8.80, 12.61 Hz, 1H), 1.95-2.09 (m, 1H), 1 .65-1.83 (m, 1H) 349 600MHz DMSO-d ₆ 7.44-7.52 (m, 3H), 7.36 (t, 3=8.95 Hz, 1H), 7.09 (ddd, 3=2.18, 4.63, 8.52 Hz, 1H), 5.28-5.35(m, 2H), 4.27-4.47(m, 1H), 3.38-3.47(m, 1H), 3.09-3.23( m, 1H), 2.93-3.07 (m, 2H), 2.80 (dd, 3=8.60, 12.57 Hz, 1H), 2.00-2.14 (m, 1H) , 1.69-1.88 (m, 1H) IN - 350 600MHz DMSO-d ₆ 7.49 (dd, 3=7.43, 11.17 Hz, 1H), 7.25 (dd, 3=7.32, 10.67 Hz, 1H), 7.14 (d, 3=1, 95Hz, 1H), 6.93(dd, 3=1.95, 8.17Hz, 1H), 6.71(d, 3=8.17Hz, 1H), 5.18(s, 2H) , 4.24-4.43(m, 1H), 3.84(s, 3H), 3.36-3.48(m, 1H), 3.11-3.28(m, 1H), 2 .97-3.06 (m, 1H), 2.89-2.97 (m, 1H), 2.77 (dd, 3=8.80, 12.61 Hz, 1H), 1.96-2 .09 (m, 1H), 1.64-1.82 (m, 1H) IN -- 351 600MHz DMSO-d ₆ 7.50 (dd, 3=7.47, 11.13 Hz, 1H), 7.39 (dd, 3=7.24, 10.74 Hz, 1H), 7.29 (t, 3=9, 79 Hz, 1H), 7.00-7.08 (m, 2H), 5.34 (s, 2H), 4.29-4.45 (m, 1H), 3.373.50 (m, 2H), 2.99-3.07 (m, 1H), 2.902.98 (m, 1H), 2.78 (dd, 3=8.64, 12.53 Hz, 1H), 2.04-2.12 ( m, 1H), 1.69-1.87 (m, 1H) V - 352 600MHz DMSO-d ₆ 7.84 (d, 3=7.55 Hz, 1H), 7.51-7.61 (m, 3H), 7.30 (t, 3=8.69 Hz, 1H), 6.75 (d , 3=7.71Hz, 1H), 5.45(s, 2H), 4.224.39(m, 1H), 3.34-3.42(m, 1H), 3.223.28(m, 1H) , 2.95-3.09 (m, 1H), 2.832.92 (m, 1H), 2.62-2.78 (m, 1H), 1.89- V -

- 284 043189

2.03(m, 1H), 1.58-1.74(m, 1H) 353 600MHz DMSO-d ₆ 7.91 (dd, 7=1.01, 7.71 Hz, 1H), 7.64 (dt, 7=1.21, 7.73 Hz, 1H), 7.49-7.56 (m, 2H), 7.33 (dd, 7=7.28, 10.70 Hz, 1H), 6.98 (d, 7=7.86 Hz, 1H), 5.495.55 (m, 2H), 4, 26-4.42(m, 1H), 3.363.46(m, 1H), 3.09-3.26(m, 1H), 2.993.07(m, 1H), 2.86-2.96( m, 1H), 2.77 (dd, 7=8.68, 12.57 Hz, 1H), 1.92-2.09 (m, 1H), 1.64-1.82 (m, 1H) IN - 354 600MHz DMSO-d ₆ 7.54 (s, 1H), 7.51-7.53 (m, 1H), 7.35 (dt, 7=1.56, 7.67 Hz, 1H), 7.23-7.31 ( m, 2H), 6.78-6.82 (m, 1H), 5.32-5.40 (m, 2H), 4.24-4.44 (m, 1H), 3.36-3, 51 (m, 1H), 2.99-3.14 (m, 1H), 2.87-2.96 (m, 1H), 2.77 (dd, 7=8.60, 12.57 Hz, 1H), 2.00-2.07 (m, 1H), 1.85-1.98 (m, 1H), 1.65-1.78 (m, 1H) B - 355 600MHz DMSO-d ₆ 7.50-7.57 (m, 2H), 7.29 (t, 7=9.13 Hz, 1H), 7.17 (dt, 7=2.65, 8.49 Hz, 1H), 6 .86-6.90(m, 1H), 5.29-5.36(m, 2H), 4.19-4.46(m, 1H), 3.35-3.48(m, 1H), 3.26-3.29(m, 1H), 2.99-3.14(m, 1H), 2.87-2.95(m, 1H ), 2.77 (dd, 7=8.72, 12.61 Hz, 1H), 2.012.09 (m, 1H), 1.63-1.79 (m, 1H) V - 356 600MHz DMSO-d ₆ 7.76 (dd, 7=2.65, 9.03 Hz, 1H), 7.57 (dd, 7=7.47, 11.13 Hz, 1H), 7.46 (dt, 7=2, 65, 8.45 Hz, 1H), 7.33 (dd, 7=7.28, 10.63 Hz, 1H), 6.81 (dd, 7=5.29, 8.64 Hz, 1H), 5.38-5.45(m, 2H), 4.25-4.41(m, 1H), 3.34-3.49(m, 1H), 3.23-3.29(m, 1H ), 2.95-3.01 (m, 1H), 2.83-2.91 (m, 1H), 2.74 (dd, 7=8.91, 12.57 Hz, 1H), 1, 97-2.04 (m, V --

- 285 043189

357 600MHz DMSO-d ₆ 1H), 1.62-1.80 (m, 1H) 7.36-7.52(m, 3H), 7.29(t, 4=9.45Hz, 1H), 6.92-6.98(m, 1H), 5.27-5.34( m, 2H), 4.26-4.48 (m, 1H), 3.38-3.49 (m, 1H), 3.36-3.38 (m, 1H), 2.93-3, 07 (m, 2H), 2.81 (dd, 4=8.60, 12.57 Hz, 1H), 2.05-2.13 (m, 1H), 1.71-1.89 (m, 1H) 7.46-7.54 (m, 2H), 7.39 (dd, 4=7.32, 10.67 Hz, 1H), 7.24 (dd, 4=1.87, 8.33 Hz, 1H), 6.96 (t, 4=8.29 Hz, 1H), 5.35 IN - 358 600MHz DMSO-d ₆ (s, 2H), 4.27-4.44 (m, 1H), 3.36-3.49 (m, 2H), 3.00-3.17 (m, 1H), 2.89-2 .98 (m, 1H), 2.78 (dd, 4=8.68, 12.57 Hz, 1H), 2.02-2.13 (m, 1H), 1.67-1.84 (m , 1H) 7.58 (d, 4=8.33 Hz, 1H), 7.44-7.53 (m, 3H), 7.04 (dd, 4=2.02, 8.33 Hz, 1H), IN 359 600MHz DMSO-d ₆ 5.30-5.36(m, 2H), 4.30-4.46(m, 1H), 3.38-3.51(m, 2H), 2.93-3.07(m, 2H ), 2.80 (dd, 4=8.64, 12.61 Hz, 1H), 2.052.13 (m, 1H), 1.68-1.86 (m, 1H) Ή NMR (600 MHz, DMSO -d ₆ ) δ 7.55 (t, 4=8.15 Hz, 1H), 7.51 (t, 4=9.00 Hz, 1H), 7.43 (t, 4=8.77 Hz, 1H), 7.26 (dd, V 360 600MHz DMSO-d ₆ 4=1.87, 10.20 Hz, 1H), 6.94 (dd, 4=1.44, 8.29 Hz, 1H), 5.30-5.37 (m, 2H), 4.32 -4.46(m, 1H), 3.38-3.52(m, 2H), 3.00-3.08(m, 1H), 2.92-3.00(m, 1H), 2 .80 (dd, 4=8.60, 12.57 Hz, 1H), 1.96-2.13 (m, 1H), 1.69-1.87 (m, 1H) V - 7.68-7.74 (m, 4=8.17 Hz, 2H), 7.52 361 600MHz DMSO-d ₆ (dd, 4=7.43, 11.17 Hz, 1H), 7.41 (dd, 4=7.32, 10.67 Hz, 1H), 7.31-7.36 (m, 4=8 .02 Hz, 2H), 5.40-5.47 (m, 2H), 4.31-4.45 (m, 1H), 3.39-3.53 (m, 2H), V -

- 286 043189

3.00-3.07 (m, 1H), 2.91-2.99 (m, 1H), 2.80 (dd, ./=8.60, 12.57 Hz, 1H), 2.032.11 (m, 1H), 1.66-1.83 (m, 1H) 362 600MHz DMSO-d ₆ 7.50 (dd, 7=7.43, 11.17 Hz, 1H), 7.43 (dd, 7=7.32, 10.74 Hz, 1H), 7.34 (d, 7=8, 17 Hz, 2H), 7.27 (d, 7=8.06 Hz, 2H), 5.32-5.40 (m, 2H), 4.23-4.50 (m, 1H), 3, 39-3.46 (m, 1H), 3.36 (br s, 1H), 2.99-3.11 (m, 1H), 2.91-2.99 (m, 1H), 2.80 (dd, 7=8.68, 12.57Hz, 1H), 1.99-2.12(m, 1H), 1.65-1.81(m, 1H) IN - 363 600MHz DMSO-d ₆ 7.48-7.58 (m, 3H), 7.38 (dd, 7=7.32, 10.67 Hz, 1H), 7.27 (d, 7=8.10 Hz, 2H), 7 .00 (t, 7=55.86 Hz, 1H), 5.355.43 (m, 2H), 4.20-4.48 (m, 1H), 3.42 (ddd, 7=3.39, 7 .08, 8.91 Hz, 1H), 3.363.38 (m, 1H), 2.99-3.08 (m, 1H), 2.912.99 (m, 1H), 2.80 (dd, 7= 8.60, 12.57 Hz, 1H), 1.98-2.11(m, 1H), 1.65-1.82(m, 1H) IN -- 364 600MHz DMSO-d ₆ 7.43-7.52 (m, 3H), 7.27 (br d, 7=8.17 Hz, 1H), 7.19 (s, 1H), 7.11 (d, 7=7.79 Hz, 1H), 5.35-5.43(m, 2H), 4.31-4.42(m, 1H), 3.39-3.47(m, 1H), 3.36-3 .38 (m, 1H), 2.98-3.07 (m, 1H), 2.94 (tdd, 7=4.20, 7.94, 14.40 Hz, 1H), 2.80 (dd , 7=8.68, 12.57 Hz, 1H), 1.69-1.86 (m, 1H) V -- 365 600MHz DMSO-d ₆ Ή NMR (600 MHz, DMSO-d ₆ ) δ 7.65 (d, 7=8.23 Hz, 1H), 7.62 (s, 1H), 7.467.57 (m, 3H), 7.34 ( d, 7=7.71Hz, 1H), 5.39-5.47(m, 2H), 4.20-4.48(m, 1H), 3.39-3.47(m, 1H) , 3.35-3.38 (m, 1H), 2.91-3.06 (m, 2H), 2.80 (dd, 7=8.68, 12.57 Hz, 1H), 1.98 -2.11(m, 1H), V -

- 287 043189

366 600MHz DMSO-d ₆ 1.69-1.85 (m, Η) 7.76(d, 7=7.71Hz, 1H), 7.70(s, 1H), 7.48-7.57(m, 2H), 7.44(t, 7=8.87Hz , 1H), 7.40 (d, 7=8.08 Hz, 1H), 5.345.42 (m, 2H), 4.27-4.50 (m, 1H), 3.383.48 (m, 1H) , 3.15-3.26 (m, 1H), 3.003.13 (m, 1H), 2.91-3.00 (m, 1H), 2.80 (dd, 7=8.60, 12, 57 Hz, 1H), 1.99-2.16(m, 1H), 1.72-1.87(m, 1H) 7.50 (dd, 7=7.43, 11.17 Hz, 1H), 7.43 (dd, 7=7.32, 10.74 Hz, 1H), 7.35 (s, 1H), 7 .35 (d, 7=5.66 Hz, 1H), 7.27 (s, IN - 367 600MHz DMSO-d ₆ 1H), 7.01-7.06(m, 1H), 5.30-5.37(m, 2H), 4.26-4.51(m, 1H), 3.39-3.49( m, 1H), 3.36-3.38 (m, 1H), 2.92-3.07 (m, 2H), 2.80 (dd, 7=8.64, 12.53 Hz, 1H) , 1.96-2.14 (m, 1H), 1.72-1.84 (m, 1H) 7.47-7.53 (m, 1H), 7.09-7.23 (m, 5H ), 7.00-7.08 (m, 2H), 5.30 (s, 2H), 3.48- IN 368 400MHz d ₄ -MeOH 600MHz D ₆ -DMSO 3.55 (m, 1H), 3.24-3.30 (m, 1H), 2.923.06 (m, 2H), 2.86 (dd, J=8.81, 11.71 Hz, 1H) , 1.92-2.04 (m, 1H), 1.82 (td, J=4.07, 13.42 Hz, 1H), 1.64-1.76 (m, 1H), 1.30 -1.45(m, 1H) 7.98-8.03 (m, 2H), 7.44 (d, J=7.79 Hz, 1H), 7.34 (d, J=8.41 Hz, 2H), 7.167.18 (m , 1H), 7.07-7.11 (m, 1H), 6.99- - - 369 7.04 (m, 1H), 5.39 (s, 2H), 2.81-2.95 (m, 2H), 2.69 (br d, J=2.49 Hz, 1H), 1, 81-1.88 (m, 1H), 1.68-1.77 (m, 1H), 1.54-1.65 (m, 1H), 1.16-1.28 (m, 1H) 7.89 (br d, 7=8.04 Hz, 2H), 7.44 (br d, 370 500MHz d6-DMSO 7=7.53 Hz, 1H), 7.39 (br d, 7=8.04 Hz, 2H), 7.15 (br d, 7=7.79 Hz, 1H), 7.09 (br t , 7=7.14 Hz, 1H), 6.99-7.05 (m, - -

- 288 043189

1H), 5.41 (s, 2H), 3.40 (br d, 7=10.38 Hz, 1H), 3.25-3.30 (m, 1H), 2.83-2.92 ( m, 2H), 2.63-2.71 (m, 1H), 1.82 (br dd, 7=3.37, 8.04 Hz, 1H), 1.71 (br dd, 7=4, 54, 8.69 Hz, 1H), 1.52-1.65 (m, 1H), 1.15-1.27 (m, 1H) 371 500MHz d6-DMSO 9.23 (s, 1H), 8.21 (s, 1H), 7.81 (br d, 7=8.56 Hz, 2H), 7.43 (br d, 7=7.27 Hz, 1H ), 7.33 (br d, 7=8.56 Hz, 2H), 7.19 (br d, 7=7.53 Hz, 1H), 6.99-7.12 (m, 2H), 5 .35 (s, 2H), 3.43 (br d, 7=9.86 Hz, 1H), 2.83-2.95 (m, 2H), 2.61-2.71 (m, 1H) , 1.81-1.91 (m, 1H), 1.72 (br dd, 7=3.63, 9.08 Hz, 1H), 1.56-1.65 (m, 1H), 1, 15-1.30(m, 1H) -- -- 372 500MHz d6-DMSO 7.90 (br d, 7=7.01 Hz, 1H), 7.62 (br t, 7=7.27 Hz, 1H), 7.42-7.53 (m, 2H), 7.10 (br dd, 7=4.80, 7.14 Hz, 2H), 7.00-7.06 (m, 1H), 6.97 (br d, 7=7.78 Hz, 1H), 5, 48 (s, 2H), 3.30-3.43 (m, 2H), 2.76-2.91 (m, 3H), 2.61 (br dd, 7=9.08, 11.68 Hz , 1H), 1.77-1.87 (m, 1H), 1.65-1.74 (m, 1H), 1.52-1.62 (m, 1H) -- -- 373 500MHz d6-DMSO 7.48 (br d, 7=8.04 Hz, 2H), 7.38 (br d, 7=8.04 Hz, 2H), 6.98 (br t, 7=7.27 Hz, 1H) , 6.86 (br t, 7=7.40 Hz, 1H), 6.75 (br d, 7=8.04 Hz, 1H), 5.44-5.54 (m, 2H), 3, 41 (br d, 7=8.82 Hz, 2H), 2.802.94 (m, 2H), 2.61-2.69 (m, 1H), 1.86 (br dd, 7=3.76, 8.43 Hz, 1H), 1.741.81 (m, 1H), 1.58-1.70 (m, 1H), 1.ΜΙ.30 (m, 1H) - - 374 500MHz d6-DMSO 7.52 (br d, 7=7.01 Hz, 1H), 7.45 (br d, 7=7.79 Hz, 1H), 7.32 (br t, 7=7.01 Hz, - -

- 289 043189

1H), 7.22-7.28 (m, 1H), 6.96-7.13 (m, 3H), 6.79 (br d, 7=6.75 Hz, 1H), 5.32 ( s, 2H), 2.75-2.90 (m, 3H), 2.61 (br dd, 7=9.08, 11.68 Hz, 1H), 1.77-1.87 (m, 1H ), 1.67 (br dd, 7=3.76, 9.21 Hz, 1H), 1.47-1.61 (m, 1H), 1.10-1.26 (m, 1H) 375 500MHz d6-DMSO 7.70 (br d, 7=7.79 Hz, 2H), 7.43 (br d, 7=7.79 Hz, 1H), 7.34 (br d, 7=8.04 Hz, 2H) , 7.14 (br d, 7=7.79 Hz, 1H), 7.08 (br t, 7=7.14 Hz, 1H), 6.99-7.05 (m, 1H), 5, 39 (s, 2H), 3.39 (br d, 7=9.60 Hz, 2H), 2.78-2.91 (m, 3H), 2.63 (br dd, 7=9.34, 11.68 Hz, 1H), 1.81 (br dd, 7=3.89, 8.04 Hz, 1H), 1.66-1.76 (m, 1H), 1.52-1.64 ( m, 1H), 1.12-1.26 (m, 1H) - -- 376 500MHz d6-DMSO 7.40-7.47 (m, 1H), 7.23-7.37 (m, 4H), 7.17 (br d, J=8.04 Hz, 1H), 6.96-7.12 (m, 2H), 5.25-5.41 (m, 2H), 3.39 (br d, J=10.90 Hz, 2H), 2.77-2.89 (m, 2H), 2 .62 (br dd, J=9.21, 11.81 Hz, 1H), 1.78-1.88 (m, 1H), 1.54-1.75 (m, 2H), 1.12- 1.23(m, 1H) - - 377 500MHz d6-DMSO 7.34-7.46(m, 3H), 7.12-7.21(m, 3H), 6.96-7.11(m, 2H), 5.23-5.31(m, 2H), 3.35-3.42(m, 2H), 2.78-2.90(m, 3H), 2.57-2.68(m, 1H), 1.79-1.88(m, 1H ), 1.66-1.77 (m, 1H), 1.53-1.64 (m, 1H), 1.11-1.24 (m, 1H) - - 378 500MHz d6-DMSO 7.43 (br d, J=7.79 Hz, 1H), 7.30-7.37 (m, 2H), 7.25 (s, 1H), 7.19 (br d, J=7, 79 Hz, 1H), 6.99-7.12 (m, 3H), 5.24-5.36 (m, 2H), 3.39 (br d, J=10.12 Hz, 2H), 2 .78-2.92 (m, 2H), 2.62 (br - -

-290043189

dd, J=9.08, 11.68 Hz, 1H), 1.79-1.89 (m, 1H), 1.70 (br d, J=3.63 Hz, 1H), 1.53- 1.66 (m, 1H), 1.18 (br d, J=10.38 Hz, 1H) 379 500MHz d6-DMSO 7.52 (br d, J=8.30 Hz, 1H), 7.47-7.59 (m, 1H), 7.42 (br d, J=7.79 Hz, 1H), 7.25 (br d, J=7.78 Hz, 2H), 6.95-7.18 (m, 3H), 5.25-5.40 (m, 2H), 3.40 (br d, J=ll .68 Hz, 2H), 2.79-2.90 (m, 2H), 2.64 (br dd, J=9.21, 11.55 Hz, 1H), 1.92 (br t, J= 18.81 Hz, ZN), 1.82 (br dd, J=3.37, 9.08 Hz, 1H), 1.71 (br dd, J=4.02, 9.21 Hz, 1H), 1.60 (br s, 1H), 1.09-1.24 (m, 1H) - -- 380 500MHz d6-DMSO 7.39-7.49 (m, 3H), 7.22 (br d, J=8.30 Hz, 2H), 7.15 (br d, J=7.79 Hz, 1H), 6.97 -7.10 (m, 2H), 5.23-5.34 (m, 2H), 3.41 (br d, J=11.68 Hz, 2H), 2.78-2.91 (m, 2H), 2.59-2.69(m, 1H), 1.79-1.86(m, 1H), 1.68-1.76(m, 1H), 1.59-1.68( m, 6H), 1.12-1.24 (m, 1H) - - 381 500MHz d6-DMSO 7.53 (br d, J=7.78 Hz, 2H), 7.43 (br d, J=7.53 Hz, 1H), 7.27 (br d, J=7.79 Hz, 2H) , 6.96-7.16 (m, 4H), 5.28-5.39 (m, 2H), 3.40 (br d, J=9.86 Hz, 2H), 2.762.91 (m, 3H), 2.59-2.68 (m, 1H), 1.83 (br dd, 1=3.76, 8.17 Hz, 1H), 1.70 (br dd, J=4.41, 9.34Hz, 1H), 1.51-1.62(m, 1H), 1.11-1.25(m, 1H) - - 382 500MHz d6-DMSO 8.37 (br d, J=4.41 Hz, 1H), 7.76 (br d, J=8.30 Hz, 2H), 7.39-7.47 (m, 1H), 7.21 (br d, 1=8.04 Hz, 2H), 6.97-7.17 (m, 3H), 5.33 (s, 2H), 3.40 (br d, J=9.08 Hz, 2H), 2.78-2.91 (m, 2H), 2.63 (br dd, J=9.47, 11.29 Hz, 1H), - -

-291 043189

1.53-1.92 (m, 3H), 1.09-1.24 (m, 1H) 7.86-7.94(m, 1H), 7.57-7.66(m, 1H), 7.36-7.50(m, 1H), 6.93-7.23(m, 5H), 383 500MHz d6-DMSO 5.41 (s, 2H), 2.72-2.93 (m, 3H), 2.572.66 (m, 1H), 1.81 (br dd, J=3.l 1, 4.93 Hz, 1H), 1.65-1.74 (m, 1H), 1.51-1.63 (m, 1H), 1.10-1.26 (m, 1H) 7.41 (br d, J=7.53 Hz, 1H), 7.13-7.20 (m, 3H), 6.96-7.08 (m, 4H), 5.20-5.27 (m, 2H), 5.11 (s, 2H), 3.41 (br d, 384 500MHz d6-DMSO J=12.20 Hz, 2H), 2.81-2.89 (m, 2H), 2.63 (br dd, J=9.08, 11.68 Hz, 1H), 1.79-1, 88 (m, 1H), 1.72 (br dd, 1=3.89, 8.56 Hz, 1H), 1.61 (br dd, J=3.89, 10.90 Hz, 1H), 1 .18 (br d, J=10.38 Hz, 1H) 7.71 (br d, J=8.30 Hz, 2H), 7.44 (br d, J=7.78 Hz, 1H), 7.38 (br d, J=8.04 Hz, 2H) , 7.18 (br d, 1=7.79 Hz, 1H), 6.99- — — 385 500MHz d6-DMSO 7.12 (m, 2H), 5.36-5.45 (m, 2H), 3.37 (br d, J=11.68 Hz, 2H), 2.71-2.89 (m, 2H ), 1.76-1.84 (m, 1H), 1.65-1.73 (m, 1H), 1.48-1.61 (m, 2H), 1.11-1.22 (m , 1H) 7.41 (br d, J=7.79 Hz, 1H), 6.96-7.16 (m, 5H), 7.16 (br s, 1H), 5.15-5.29 (m, 386 500MHz d6-DMSO 2H), 3.40 (br d, J=ll.42 Hz, 2H), 2.79-2.89 (m, 2H), 2.58-2.67 (m, 1H), 2.24 ( s, 3H), 1.79-1.87 (m, 1H), 1.69 (br d, J=3.63 Hz, 1H), 1.54-1.65 (m, 1H), 1, 13-1.22(m, 1H) - - 7.41 (br d, J=7.53 Hz, 1H), 7.11-7.27 387 500MHz d6-DMSO (m, 5H), 6.97-7.09 (m, 2H), 5.21-5.35 (m, 2H), 3.39 (br d, J=11.94 Hz, 2H), 2 .79-2.89 (m, 2H), 2.62 (br dd, J=9.21, - -

- 292 043189

11.55 Hz, 1H), 1.78-1.88 (m, 1H), 1.71 (br dd, J=3.63, 8.56 Hz, 1H), 1.54-1.65 (m, 1H), 1.08-1.25 (m, 1H) 388 500MHz d6-DMSO 8.05 (s, 1H), 7.64-7.71 (m, 1H), 7.46 (br d, 1=7.79 Hz, 1H), 7.02-7.12 (m, 1H ), 6.90-7.02 (m, 3H), 6.56-6.64 (m, 1H), 5.90 (br d, J=5.97 Hz, 2H), 4.32 (s , 3H), 3.40 (br d, J=10.90 Hz, 2H), 2.89-2.96 (m, 1H), 2.78-2.86 (m, 1H), 2.70 (br dd, J=8.69, 11.81 Hz, 1H), 1.74-1.82 (m, 1H), 1.64-1.70 (m, 1H), 1.50-1, 60 (m, 1H), 1.11-1.26 (m, 1H) - -- 389 500MHz d6-DMSO 7.40-7.45 (m, 1H), 7.24-7.32 (m, 1H), 7.16 (br d, J=7.79 Hz, 1H), 6.96-7.11 (m, 3H), 5.26-5.33 (m, 1H), 3.37 (br d, J=l.56 Hz, 2H), 2.77-2.91 (m, 2H), 2 .58-2.65 (m, 1H), 1.80-1.87 (m, 1H), 1.67-1.76 (m, 1H), 1.52-1.64 (m, 1H) , 1.09-1.24 (m, 1H) - - 390 500MHz d6-DMSO 7.33-7.45 (m, 2H), 7.16-7.30 (m, 2H), 7.00-7.11 (m, 2H), 6.95 (br s, 1H), 5 .22-5.33 (m, 2H), 3.39 (br d, J=11.16 Hz, 2H), 2.85 (br d, J=9.60 Hz, 2H), 2.63 ( br dd, J=9.34, 11.68 Hz, 1H), 1.78-1.88 (m, 1H), 1.71 (br d, J=3.63 Hz, 1H), 1.59 (br dd, J=2.47, 10.51 Hz, 1H), 1.12-1.24 (m, 1H) - - 391 500MHz d6-DMSO 7.53 (br t, J=7.91 Hz, 1H), 7.43 (br d, J=7.53 Hz, 1H), 7.23 (br d, J=8.82 Hz, 1H) , 7.18 (br d, J=7.78 Hz, 1H), 6.997.12 (m, 2H), 6.94 (br d, J=7.78 Hz, 1H), 5.25-5, 34 (m, 2H), 3.38 (br d, J=ll, 42 Hz, 2H), 2.80-2.91 (m, 2H), 2.63 (br dd, J=9.34, 11.68 Hz, 1H), 1.78-1.88 (m, 1H), 1.67-1.77 (m, 1H), - -

-293 043189

1.60 (br s, 1H), 1.12-1.24 (m, 1H) 392 500MHz d6-DMSO 7.92 (s, 1H), 7.84 (br d, J=7.53 Hz, 1H), 7.49-7.59 (m, 2H), 7.44 (br d, J=7, 01 Hz, 1H), 7.35 (br d, J=7.01 Hz, 1H), 7.04-7.16 (m, 3H), 5.47-5.57 (m, 2H), 3 .38-3.46 (m, 2H), 2.85-2.96 (m, 2H), 2.69 (br dd, J=9.08, 11.42 Hz, 1H), 1.81- 1.90 (m, 1H), 1.77 (br dd, J=4.15, 8.82 Hz, 1H), 1.61-1.70 (m, 1H), 1.18-1.29 (m, 1H) - -- 393 500MHz d6-DMSO 7.41 (br d, J=7.53 Hz, 1H), 7.29 (s, 1H), 7.20 (br d, J=7.53 Hz, 1H), 6.997.12 (m, 4H ), 5.17-5.25 (m, 2H), 3.80 (s, 3H), 3.40 (br d, J=9.86 Hz, 2H), 2.79-2.91 (m , 2H), 2.62 (br dd, J=9.34, 11.68 Hz, 1H), 1.84 (br dd, J=4.02, 8.17 Hz, 1H), 1.72 ( br d, J=3.37 Hz, 1H), 1.53-1.66 (m, 2H), 1.10-1.25 (m, 1H) - -- 394 500MHz d6-DMSO 8.15 (br d, J=1.30 Hz, 1H), 7.75 (br dd, J=1.17, 7.91 Hz, 1H), 7.46 (br d, J=8.04 Hz, 1H), 7.00-7.14 (m, 3H), 6.88 (br d, J=8.04 Hz, 1H), 5.33-5.44 (m, 2H), 3, 15-3.24 (m, 2H), 2.74-2.89 (m, 2H), 2.60 (br dd, J=9.34, 11.42 Hz, 1H), 1.77-1 .85 (m, 1H), 1.63-1.73 (m, 1H), 1.46-1.57 (m, 1H), 1.09-1.25 (m, 1H) - -- 395 500MHz d6-DMSO 7.66-7.74(m, 1H), 7.42-7.48(m, 1H), 7.31-7.38(m, 1H), 7.00-7.16(m, 3H ), 6.79 (br d, J=8.30 Hz, 1H), 5.30 (s, 2H), 3.14-3.27 (m, 2H), 2.73-2.91 (m , 2H), 2.60 (br dd, J=9.21, 11.81 Hz, 1H), 1.77-1.86 (m, 1H), 1.67-1.74 (m, 1H) , 1.50-1.61 (m, 1H), 1.09-1.20 (m, - -

-294043189

1H) 396 500MHz d6-DMSO 7.54-7.58 (m, 1H), 7.44 (br d, 1=7.27 Hz, 1H), 7.33 (br d, J=8.04 Hz, 1H), 6.98 -7.14(m, 3H), 6.71-6.77(m, 1H), 5.20-5.27(m, 1H), 5.18-5.28(m, 1H), 3 .10-3.23 (m, 2H), 2.75-2.88 (m, 2H), 2.58-2.64 (m, 1H), 1.79-1.84 (m, 1H) , 1.64-1.71 (m, 1H), 1.51-1.58 (m, 1H), 1.16 (br dd, J=8.04, 10.90 Hz, 1H) - - 397 500MHz d6-DMSO 8.11 (br d, J=2.08 Hz, 1H), 7.67-7.74 (m, 1H), 7.46 (br d, J=8.30 Hz, 1H), 7.07 -7.15 (m, 2H), 7.04 (br d, J=7.53 Hz, 1H), 6.95 (br d, J=8.56 Hz, 1H), 5.46 (s, 2H), 3.17-3.26 (m, 2H), 2.782.88 (m, 2H), 2.57-2.65 (m, 1H), 1.771.86 (m, 1H), 1.66 -1.75(m, 1H), 1.531.62(m, 1H), 1.14-1.22(m, 1H) - -- 398 400MHz MeOD 7.69-7.76 (m, 2H), 7.50-7.56 (m, 1H), 7.46 (d, J=8.09 Hz, 2H), 7.11-7.19 ( m, 1H), 6.95-7.07 (m, 2H), 5.91 (q, J=7.12 Hz, 1H), 3.43 (dd, J=3.73, 11.61 Hz , 1H), 3.27-3.31 (m, 1H), 2.95-3.08 (m, 2H), 2.87 (dd, J=8.91, 11.61 Hz, 1H), 1.96-2.00 (m, 2H), 1.95-2.01 (m, 1H), 1.86-1.94 (m, 1H), 1.69-1.83 (m, 1H ), 1.33-1.47 (m, 1H) - -- 399 400MHz MeOD Mixture of diastereomers: 7.70-7.78 (m, 2H), 7.52 (d, J=7.88 Hz, 1H), 7.45 (dd, J=6.32, 7.98 Hz, 2H ), 7.15 (dt, J=l.24, 7.57 Hz, 1H), 6.94-7.07 (m, 2H), 5.86-5.98 (m, 1H), 3, 40-3.54 (m, 1H), 3.36 (s, 2H), 2.97-3.09 (m, 2H), 2.86 (ddd, J=8.91, 11.51, 16 .27 Hz, 1H), 2.00 (dd, J=7.36, 8.19 Hz, ZN), 1.68-1.92 (m, 2H), 1.32-1.45 (m, 1H - -

-295 043189

400 400MHz d ₆ -DMSO 8.03 (br s, 3H), 7.79 (d, J=7.67 Hz, 1H), 7.72 (s, 1H), 7.55-7.62 (m, 1H), 7. 47.7.54 ( _m , 2H), 7.11-7.25 (m, 3H), 5.44 (s, 2H), 3.66 (br dd, J=3.01, 12.54 Hz, 1H ), 3.47 (br d, J=2.90 Hz, 1H), 3.25-3.34 (m, 1H), 3.21 (dd, 1=8.50, 12.23 Hz, 1H ), 2.98-3.09 (m, 1H), 1.95-2.03 (m, 1H), 1.79-1.90 (m, 1H), 1.53-1.71 (m , 2H) -- -- 8.77 (s, 2H), 7.39-7.45 (m, 1H), 6.98 494 500MHz d ₄ -MeOH (dd, J=2.34, 8.82 Hz, 1H), 6.85-6.93 (m, 1H), 5.50 (s, 2H), 3.90 (td, J=3.60 , 7.07 Hz, 1H), 3.31-3.44 (m, 3H), 3.223.29 (m, 1H), 3.06-3.15 (m, 1H), 3.03 (td, 1=3.50, 7.01Hz, 1H), 1.77-1.93(m, 2H) 7.42-7.47 (m, 1H), 7.31 (d, J=1.82 Hz, 1H), 7.18 (dd, J=1.95, 8.43 Hz, 1H), 5 .08 (s, 2H), 4.38-4.55 (m, 1H), 3.75- V Chiralpak ID, 25% IP A with 0.2% DEA, peak 1 500MHz d ₄ -MeOH 3.81 (m, 2H), 3.71-3.75 (m, 2H), 3.67- Chiralpak IC, 495 3.70 (m, 2H), 3.59-3.65 (m, 2H), 3.53 (br d, 1=12.46 Hz, 1H), 3.38 (s, 1H), 3, 16-3.22 (m, 1H), 3.07-3.15 (m, 1H), 2.97 (dd, J=8.56, 12.46 Hz, 1H), 2.182.29 (m, 1H), 1.89-2.01 (m, 1H) V 35% MeOH peak 1 496 500MHz d ₄ -MeOH 8.77 (s, 2H), 7.15-7.19 (m, 1H), 7.107.14 (m, 1H), 6.83-6.90 (m, 1H), 5.50 (s, 2H), 3.90 (td, 1=3.44, 7.14 Hz, 1H), 3.24-3.45 (m, 4H), 3.11-3.18 (m, 1H), 2 .99-3.05(m, 1H), 1.79-1.95(m, 2H) V Chiralpak ID, 25% IP A c 0.2% DEA Peak 2 497 500MHz d ₄ -MeOH 7.45-7.50 (m, 1H), 7.20-7.24 (m, 1H), 7.13-7.20 (m, 1H), 5.08 (s, 2H), 4.414, 58 (m, 1H), 3.75-3.81 (m, 2H), 3.70 (td, J=4.57, 16.28 Hz, 4H), 3.60-3.66 V Chiralpak IC, 35% MeOH, peak 2

- 296 043189

(m, 2H), 3.56 (dtd, J=l.95, 4.23, 12.42 Hz, 1H), 3.41-3.48 (m, 1H), 3.18-3.26 (m, 1H), 3.10-3.16 (m, 1H), 2.99 (dd, 1=8.69, 12.59 Hz, 1H), 2.18-2.30 (m, 1H ), 1.89-2.02 (m, 1H) 498 600MHz DMSO - d ₆ 8.97 (s, 2H), 7.50 (dd, 3=7.59, 11.09 Hz, 1H), 7.13 (dd, 3=7.36, 10.94 Hz, 1H), 5 .93 (q, 3=7.19 Hz, 1H), 4.364.57 (m, 1H), 3.38-3.56 (m, 1H), 3.22 (br d, 3=7.24 Hz , 1H), 2.94-3.00 (m, 1H), 2.88 (dd, 3=8.76, 12.34 Hz, 1H), 2.37-2.47 (m, 1H), 2.07-2.14 (m, 1H), 1.88 (d, 3=7.16 Hz, 4H) IN Chiralpak ADH, 25% IP A, peak 1 499 600MHz DMSO - d ₆ 8.92-8.95 (m, 1H), 8.53-8.56 (m, 1H), 8.35 (dd, 3=2.10, 8.17 Hz, 1H), 8.01 ( d, 3=2.10 Hz, 1H), 7.60 (d, 3=8.17 Hz, 1H), 5.69 (s, 2H), 4.33-4.44 (m, 1H), 3.51-3.70(m, 1H), 3.14-3.19(m, 1H), 2.81-2.91(m, 1H), 2.51-2.55(m, 1H ), 2.37-2.47(m, 1H), 2.02-2.09(m, 1H), 1.62-1.76(m, 1H). IN Chiralpak ADH, 25% IP A, peak 1 500 600MHz DMSO - d ₆ 7.45-7.54(m, 1H), 7.26-7.42(m, 1H), 5.01-5.18(m, 2H), 4.35-4.54(m, 2H ), 4.22 (q, 3=9.60 Hz, 2H), 3.32-3.41 (m, 1H), 3.20-3.26 (m, 1H), 2.94-3, 07 (m, 3H), 2.81 (dd, 3=8.17, 12.59 Hz, 1H), 2.65-2.74 (m, 1H), 2.02-2.19 (m, 1H), 1.77 (brd, 3=9.86Hz, 1H) - - 501 600MHz DMSO - d ₆ 7.57-7.62 (m, 2H), 7.51 (dd, 3=7.40, 11.13 Hz, 1H), 7.32 (d, 3=3.50 Hz, 1H), 5 .37-5.43 (m, 2H), 4.36-4.48 (m, 1H), 3.83 (s, 3H), 3.51 (br d, 3=13.00 Hz, 1H) , 3.13-3.23(m, 2H), 2.99-3.10(m, 1H), 2.79-2.84(m, 1H), 2.07-2.14(m, 1H), 1.75-1.84 (m, 1H) - -

-297043189

502 600MHz DMSO - d ₆ 8.43 (br s, 2H), 7.44 (d, 7=8.51 Hz, 1H), 7.41 (s, 1H), 7.14 (dd, 7=2.06, 8.45 Hz, 2H), 4.98-5.07 (m, 2H), 4.734.92 (m, 1H), 3.65-3.72 (m, 2H), 3.34 (br s, 1H), 2.77-3.13(m, 6H), 2.512.55(m, 2H), 2.16-2.24(m, 1H), 1.811.90(m, 1H) IN Chiralpak ADH, 25% IP A, peak 1 503 600MHz DMSO - d ₆ ¹ 7.41 (dd, 7=4.87, 8.68 Hz, 1H), 7.15 (dd, 7=2.49, 9.19 Hz, 1H), 6.94 (ddd, 7=2 .53, 8.64, 10.08 Hz, 1H), 4.67-4.80 (m, 2H), 4.50-4.65 (m, 1H), 4.22-4.33 (m , 2H), 3.94 (t, 7=7.71 Hz, 2H), 3.393.57 (m, 1H), 3.23-3.39 (m, 1H), 2.963.10 (m, 1H) , 2.88 (dd, 7=8.99, 12.57 Hz, 1H), 2.52-2.55 (m, 1H), 2.29 (quin, 7=7.69 Hz, 2H), 2.11-2.20(m, 1H), 1.80-1.88(m, 1H) IN Chiralpak ADH, 25% IP A, peak 1 504 600MHz DMSO - d ₆ 7.35-7.48(m, 2H), 4.99-5.12(m, 2H), 4.40-4.47(m, 1H), 4.30-4.39(m, 1H ), 3.90 (br d, 7=13.23 Hz, 1H), 3.15-3.30 (m, 4H), 2.94-3.04 (m, 2H), 2.90 (br t, 7=11.64 Hz, 1H), 2.69-2.84 (m, 2H), 2.04-2.16 (m, 1H), 1.91-2.03 (m, 1H) , 1.71-1.89(m, 1H), 1.54-1.67(m, 2H) - - 505 600MHz DMSO - d ₆ 7.40-7.52 (m, 3H), 6.92 (dd, 7=5.14, 10.98 Hz, 1H), 5.14-5.18 (m, 1H), 5.08- 5.12 (m, 1H), 4.75 (s, 1H), 4.57 (s, 1H), 3.78-3.89 (m, 2H), 3.20-3.29 (m, 2H), 2.93-3.03(m, 2H), 2.75-2.83(m, 2H), 2.37-2.46(m, 1H), 1.92-2.11( m, 2H), 1.70-1.79 (m, 1H) - - 506 600MHz DMSO - d ₆ 7.45(d, 7=1.87Hz, 1H), 7.20(d, 7=8.49Hz, 1H), 7.08(dd, 7=2.02, 8.49Hz, 1H ), 4.94-5.04 (m, 2H), 4.33-4.48 (m, 1H), 3.28-3.38 (m, 1H), 2.96-3.13 V Chiralpak ADH, 25% IP A, peak 2

-298 043189

(m, 6H), 2.88 (s, 3H), 2.76-2.85 (m, 1H), 1.99-2.16 (m, 1H), 1.74-1.87 (m , 1H) 507 600MHz DMSO - d ₆ 7.46 (dd, 7=7.43, 11.17 Hz, 1H), 7.39 (t, 7=8.84 Hz, 1H), 5.06-5.19 (m, 1H), 4 .93 (br t, 7=18.33 Hz, 1H), 4.06-4.13 (m, 1H), 3.80-3.93 (m, 2H), 3.49-3.60 ( m, 1H), 3.36-3.48 (m, 1H), 3.28-3.30 (m, 1H), 3.20-3.28 (m, 2H), 3.17 (d, 7=5.06Hz, 1H), 2.88-3.05(m, 2H), 2.73-2.83(m, 1H), 2.42-2.48(m, 1H), 2 .00-2.16 (m, 1H), 1.92 (br s, 1H), 1.73-1.89 (m, 1H), 1.06-1.18 (m, 3H) - - 508 600MHz DMSO - d ₆ 8.97 (s, 2H), 7.50 (dd, 7=7.59, 11.09 Hz, 1H), 7.13 (dd, 7=7.36, 10.94 Hz, 1H), 5 .93 (q, 7=7.19 Hz, 1H), 4.364.57 (m, 1H), 3.38-3.56 (m, 1H), 3.22 (br d, 7=7.24 Hz , 1H), 2.94-3.00 (m, 1H), 2.88 (dd, 7=8.76, 12.34 Hz, 1H), 2.37-2.47 (m, 1H), 2.07-2.14 (m, 1H), 1.88 (d, 7=7.16 Hz, 4H) V Chiralpak ADH, 25% IP A, peak 2 509 600MHz DMSO - d ₆ 6.73 (dd, 7=2.26, 8.95 Hz, 1H), 6.566.64 (m, 1H), 5.03-5.12 (m, 2H), 4.294.49 (m, 1H) , 4.22 (q, 7=9.58 Hz, 2H), 3.89 (s, 3H), 3.26 (s, 3H), 3.18 (br d, 7=12.53 Hz, 1H ), 2.89-3.00 (m, 3H), 2.68-2.77 (m, 1H), 2.07 (ddd, 7=4.01, 8.91, 13.08 Hz, 1H ), 1.70-1.86 (m, 1H) V SFC: Whilk01, 25% methanol, peak 2 510 600MHz DMSO - d ₆ 7.47 (dd, 7=7.47, 11.13 Hz, 1H), 7.35 (dd, 7=7.36, 10.70 Hz, 1H), 4.99 (s, 2H), 4 .33-4.445 (m, 1H), 3.49-3.57 (m, 2H), 3.38-3.45 (m, 1H), 3.25-3.30 (m, 1H), 2 .91-3.04 (m, 2H), 2.78 (dd, 7=8.64, 12.53 Hz, 1H), 2.06-2.14 (m, - -

-299043189

1H), 1.71-1.87 (m, 5H), 1.57-1.66 (m, 4H), 1.43-1.57 (m, 4H) 511 600MHz DMSO - d ₆ 8.39 (d, 4=1.32 Hz, 1H), 8.13 (dd, 4=1.52, 2.61 Hz, 1H), 7.89 (d, 4=2.57 Hz, 1H ), 7.46 (t, 4=9.08 Hz, 1H), 7.42 (t, 4=8.88 Hz, 1H), 5.04-5.14 (m, 2H), 4.34.4 .35( _m , 1H), 3.67-3.79(m, 4H), 3.58-3.66(m, 4H), 3.23-3.28(m, 1H), 2.96 -3.05(m, 2H), 2.80(dd, 4=8.06, 12.57Hz, 1H), 2.07-2.15(m, 1H), 1.74-1.92 (m, 2H) - -- 512 600MHz DMSO - d ₆ 7.46 (t, 4=9.16 Hz, 1H), 7.39 (t, 4=9.02 Hz, 1H), 4.95-5.07 (m, 2H), 4.36-4 .44 (m, 1H), 4.18 (br t, 4=11.64 Hz, 1H), 3.83-3.97 (m, 1H), 3.63 (s, 2H), 3.13 -3.26 (m, 3H), 2.93-3.05 (m, 2H), 2.73-2.89 (m, 2H), 2.68 (tt, 4=3.97, 10, 94 Hz, 1H), 2.51-2.56 (m, 1H), 2.09 (br d, 4=13.16 Hz, 1H), 1.89-1.98 (m, 1H), 1 .74-1.89 (m, 2H), 1.60-1.70 (m, 1H), 1.40-1.50 (m, 1H) - -- 513 600MHz DMSO - d ₆ 7.46 (dd, 4=7.43, 11.02 Hz, 1H), 7.39 (dd, 4=7.55, 10.35 Hz, 1H), 5.07-5.18 (m, 1H), 4.93 (dd, 4=14.95, 17.28 Hz, 1H), 4.33-4.48 (m, 1H), 4.09-4.16 (br d, 4=13 .00 Hz, 1H), 3.82-3.93 (m, 2H), 3.53 (dt, 4=2.37, 11.46 Hz, 1H), 3.19-3.30 (m, 2H), 2.90-3.05(m, 2H), 2.69-2.84(m, 2H), 2.44-2.48(m, 1H), 2.06-2.16( m, 1H), 1.72-1.90 (m, 2H), 1.39-1.52 (m, 2H), 0.85-0.97 (m, 3H) - -- 514 600MHz DMSO - d ₆ 7.20-7.26 (m, 2H), 6.95 (ddd, 4=2.49, 8.74, 9.87 Hz, 1H), 4.71-4.77 (m, 2H), 4.63-4.55 (m, 1H), 4.23-4.29 (m, 2H), 3.94 (t, 4=7.71 Hz, 2H), 3.45-3.63 ( m, V SFC: Chiralpak IC, 40% methanol, peak 2

-300043189

1H), 3.39-3.45(m, 1H), 3.14-3.35(m, 1H), 2.98-3.12(m, 1H), 2.93(dd, 7= 9.19, 12.69 Hz, 1H), 2.28 (quin, 7=7.69 Hz, 2H), 2.08-2.23 (m, 1H), 1.79-1.89 (m , 1H) 515 600MHz DMSO - d ₆ 7.69 (d, 7=8.32 Hz, 2H), 7.48-7.65 (m, 7H), 5.67-5.99 (m, 1H), 5.17-5.57 ( m, 1H), 4.36-4.51 (m, 2H), 3.86 (br s, 1H), 3.49 (br d, 7=11.99 Hz, 1H), 3.38-3 .44 (m, 1H), 2.90-3.03 (m, 2H), 2.67-2.84 (m, 1H), 2.12 (br s, 1H), 1.68-1, 84(m, 1H) - - 516 600MHz DMSO - d ₆ 7.46 (dd, 7=7.47, 11.13 Hz, 1H), 7.37 (dd, 7=7.32, 10.74 Hz, 1H), 4.94-5.04 (m, 2H), 4.28 (br d, 7=12.85 Hz, 1H), 3.93 (br d, 7=13.23 Hz, 1H), 3.21-3.29 (m, 2H), 3.09 (br t, 7=11.91 Hz, 1H), 2.93-3.03 (m, 2H), 2.78 (dt, 7=8.41, 12.53 Hz, 1H), 2.59-2.65 (m, 1H), 2.07-2.14 (m, 1H), 1.67-1.82 (m, 4H), 1.63 (br d, 7=10, 98Hz, 2H), 1.10-1.18(m, 1H), 0.90-1.00(m, 3H) -- -- 517 600MHz DMSO - d ₆ 8.47 (d, 7=5.76 Hz, 1H), 7.41 (dd, 7=4.87, 8.68 Hz, 1H), 7.13 (dd, 7=2.49, 9, 26Hz, 1H), 6.91(ddd, 7=2.57, 8.68, 10.08Hz, 1H), 6.85(d, 7=5.84Hz, 1H), 5.36( s, 2H), 4.274.43 (m, 1H), 3.74 (s, 3H), 3.37-3.48 (m, 2H), 2.98-3.06 (m, 1H), 2 .91 (tdd, 7=4.17, 7.93, 14.39Hz, 1H), 2.80 (dd, 7=8.64, 12.46Hz, 1H), 1.93-2.09 (m, 1H), 1.65-1.79 (m, 1H) V SFC: Chiralpak OD analytical column, 15% isopropanol, peak 1 518 600MHz DMSO - d ₆ 7.46 (t, 7=8.90 Hz, 1H), 7.40 (t, 7=9.01 Hz, 1H), 5.13 (dd, 7=12.96, 17.56 Hz, 1H ), 4.93 (br t, 7=16.66 Hz, - -

- 301 043189

1H), 4.32-4.49 (m, 1H), 4.02-4.21 (m, 1H), 3.82-3.93 (m, 2H), 3.36-3.43 ( m, 1H), 3.19-3.28 (m, 3H), 2.90-3.06 (m, 3H), 2.72-2.83 (m, 2H), 2.00-2, 15 (m, 1H), 1.79 (br s, 1H), 1.39-1.54 (m, 1H), 0.86-0.97 (m, 3H) 519 600MHz DMSO - d ₆ 8.81-9.03(m, 1H), 8.27-8.41(m, 2H), 7.63-7.75(m, 1H), 7.38-7.55(m, 1H ), 5.85-5.99 (m, 2H), 4.19-4.51 (m, 3H), 2.83-2.95 (m, 1H), 2.63-2.78 (m , 1H), 1.94-2.14 (m, 1H), 1.69-1.86 (m, 1H), 1.41-1.58 (m, 1H) IN SFC: analytical column Regis Whelk0, 35% isopropanol, peak 2 520 600MHz DMSO - d ₆ 8.63 (br s, 2H), 7.22-7.35 (m, 2H), 7.11-7.22 (m, 2H), 4.74-4.85 (m, 2H), 4 .28 (t, 7=7.63 Hz, 1H), 3.94 (br t, 7=7.71 Hz, 1H), 3.43-3.78 (m, 6H), 3.04-3 .20 (m, 1H), 2.38-2.59 (m, 3H), 2.21-2.32 (m, 1H), 1.81-1.98 (m, 1H) - - 521 600MHz DMSO - d ₆ 7.34-7.51 (m, 4H), 7.24 (br s, 1H), 4.91-5.16 (m, 3H), 4.66 (br dd, 7=2.65, 17 .20 Hz, 1H), 4.32-4.48 (m, 1H), 3.84-3.90 (m, 1H), 3.17 (d, 7=4.13 Hz, 1H), 2 .93-3.05 (m, 2H), 2.61-2.74 (m, 1H), 2.07-2.22 (m, 1H), 1.74-1.89 (m, 2H) , 1.64 (br d, 7=12.77 Hz, 2H), 1.42-1.57 (m, 2H), 1.26-1.38 (m, 2H) - - 522 600MHz DMSO - d ₆ 7.48 (dd, 7=7.51, 10.78 Hz, 1H), 7.337.43 (m, 1H), 7.04 (d, 7=2.73 Hz, 2H), 7.04 (m , 1H), 5.20-5.38 (m, 1H), 4.905.05 (m, 2H), 4.75-4.87 (m, 1H), 4.68 (dd, 7=6.85 , 15.88 Hz, 1H), 3.67 (dt, 7=8.25, 13.04 Hz, 1H), 3.38-3.52 (m, 1H), 3.26 (br d, 7 \u003d 5.22 Hz, 1H), 3.09- - -

- 302 043189

3.23 (m, 3H), 2.88-3.05 (m, 1H), 2.792.86 (m, 1H), 2.57-2.70 (m, 1H), 2.512.57 (m, 1H), 2.31-2.47(m, 2H), 1.952.11(m, 1H), 1.71-1.87(m, 1H). 523 600MHz DMSO - d ₆ 7.44-7.63(m, 1H), 7.32-7.40(m, 1H), 4.96-5.13(m, 2H), 4.24-4.50(m, 1H ), 3.41 (br s, 1H), 3.21 (br s, 1H), 2.963.03 (m, 2H), 2.33-2.46 (m, 2H), 2.172.32 (m, 1H), 2.10 (br d, 7=10.20 Hz, 1H), 1.88 (br d, 7=6.85 Hz, 1H), 1.77 (br d, 7=8.49 Hz , 1H), 1.67 (br d, 7=9.81 Hz, 1H), 1.62 (br s, 1H), 1.56 (br s, 2H), 1.43-1.53 (m , 1H), 1.301.42 (m, 3H), 1.21-1.30 (m, 2H), 1.071.21 (m, 2H), 0.90-1.06 (m, 1H). - - 524 600MHz DMSO - d ₆ 8.47 (d, 7=5.84 Hz, 1H), 7.23 (d, 7=9.56 Hz, 1H), 7.18-7.21 (m, 1H), 6.83-6 .89 (m, 2H), 5.32-5.40 (m, 2H), 4.37-4.44 ( _m , 1H), 4.28-4.35 (m, 1H), 3.75 (s , 3H), 3.45-3.54 (m, 2H), 3.033.10 (m, 1H), 2.83 (dd, 7=8.68, 12.50 Hz, 1H), 2.03- 2.10(m, 1H), 1.65-1.80(m, 1H) V SFC: analytical column Chiralpak OD, 15% isopropanol, peak 2 525 600MHz DMSO - d ₆ 7.36-7.49(m, 2H), 5.09-5.19(m, 2H), 4.93-5.05(m, 2H), 4.36-4.44(m, 1H ), 3.61 (td, 7=8.79, 13.18 Hz, 1H), 3.373.49 (m, 1H), 3.24-3.30 (m, 1H), 3.103.24 (m, 3H), 3.07 (s, 3H), 2.93-3.05 (m, 3H), 2.74-2.83 (m, 3H), 2.18-2.34 (m, 1H) , 2.05-2.15 (m, 1H), 1.73-1.91 (m, 1H) - - 526 600MHz DMSO - d ₆ 7.45-7.58(m, 2H), 5.02-5.14(m, 2H), 4.40-4.49(m, 1H), 4.33-4.40(m, 1H ), 3.36-3.51 (m, 1H), 3.22-3.29 (m, 3H), 3.17 (s, 1H), 2.93-3.12 (m, 4H), 2.77 - -

-303 043189

(ddd, 7=4.17, 8.31, 12.59 Hz, 1H), 2.34-2.47 (m, 2H), 2.08-2.17 (m, 1H), 1.74 -1.92 (m, 1H), 1.06 (br d, 7=8.33 Hz, 2H), 0.94-1.03 (m, 2H) 527 600MHz DMSO - d ₆ 7.36-7.51(m, 2H), 4.95-5.24(m, 2H), 4.71-4.86(m, 1H), 4.45-4.54(m, 1H ), 4.32-4.38 (m, 1H), 3.45-3.55 (m, 1H), 3.35-3.44 (m, 2H), 3.24-3.31 (m , 2H), 3.09-3.22 (m, 2H), 2.92-3.04 (m, 2H), 2.73-2.81 (m, 1H), 2.23-2.39 (m, 2H), 2.04-2.15 (m, 1H), 1.65-1.92 (m, 3H), 1.25 (t, 7=7.05 Hz, 2H), 1, 05 (brt, 7=6.77Hz, 1H) - - 528 600MHz DMSO - d ₆ 7.46-7.54 (m, 2H), 5.00-5.15 (m, 2H), 4.68-4.86 (m, 1H), 4.23 (s, 1H), 3.914, 00 (m, 1H), 3.75 (br t, 7=5.29 Hz, 1H), 3.57-3.68 (m, 3H), 3.20-3.26 (m, 2H), 2.95-3.06(m, 2H), 2.51-2.65(m, 1H), 2.15-2.22(m, 1H), 1.82-1.92(m, 1H ) - - 529 600MHz DMSO - d ₆ 7.46 (dd, 7=7.51, 11.09 Hz, 1H), 7.38 (dd, 7=7.32, 10.74 Hz, 1H), 4.95-5.08 (m, 2H), 4.28-4.38 (m, 1H), 3.99 (br d, 7=13.31 Hz, 1H), 3.46-3.55 (m, 2H), 3.24- 3.30 (m, 4H), 3.11-3.23 (m, 1H), 2.93-3.10 (m, 2H), 2.68-2.82 (m, 3H), 2, 11 (ddd, 7=4.48, 8.31, 12.59 Hz, 1H), 1.89 (quin, 7=6.79 Hz, 2H), 1.681.82 (m, 5H), 1.64 (dt, 7=3.43, 12.26 Hz, 1H), 1.35-1.45 (m, 1H) - - 530 600MHz DMSO - d ₆ 7.40-7.48(m, 1H), 7.31-7.40(m, 1H), 4.94-5.09(m, 2H), 3.73-3.91(m, 2H ), 3.42-3.57 (m, 1H), 3.08-3.22 (m, 3H), 2.97-3.05 (m, 3H), 2.79 (tt, 7=8 .44, 12.15 Hz, 2H), 2.33-2.48 (m, 1H), - -

- 304 043189

2.01-2.16(m, 1H), 1.86-1.98(m, 1H), 1.68-1.84(m, 2H), 1.58-1.66(m, 1H ) 531 600MHz DMSO - d ₆ 7.46 (t, /=9.14 Hz, 1H), 7.41 (t, /=8.98 Hz, 1H), 5.00-5.12 (m, 2H), 4.35-4 .46 (m. 1H), 3.82 (br s, 1H), 3.49-3.82 (m, 7H), 3.23-3.30 (m, 1H), 2.94-3, 11 (m, 2H), 2.79 (dd, /=8.06, 12.57 Hz, 1H), 2.06-2.17 (m, 1H), 2.00 (br s, 1H), 1.73-1.92 (m, 2H), 0.71-0.80 (m, 4H) - - 532 600MHz DMSO - d ₆ 7.46 (dd, /=7.47, 11.13 Hz, 1H), 7.37 (dd, /=7.40, 10.74 Hz, 1H), 7.30 (br d, /=5 .37 Hz, 1H), 6.82 (br s, 1H), 4.955.06 (m, 2H), 4.31-4.45 (m, 1H), 4.224.30 (m, 1H), 3, 97 (br d, /=13.16 Hz, 1H), 3.10-3.22 (m, 2H), 2.91-3.09 (m, 3H), 2.66-2.82 (m , 2H), 2.35-2.47 (m, 1H), 2.00-2.16 (m, 1H), 1.77-1.85 (m, 2H), 1.71-1.77 (m, 1H), 1.56-1.68 (m, 1H), 1.36-1.44 (m, 1H) -- -- 533 600MHz DMSO - d ₆ 7.36 (t, /=9.19 Hz, 1H), 6.93 (s, 1H), 6.89 (s, 1H), 6.80 (dt, /=7.32, 10.20 Hz , 1H), 4.27-4.45 (m, 1H), 3.63-3.75 (m, 2H), 3.59 (br d, /=11.83 Hz, 1H), 3.11 -3.25 (m, 1H), 2.98-2.74-2.92 (m, 3H), 1.90-2.05 (m,lH), 1.58-1.72 (m, 2H), 1.44 (d, /=7.08 Hz, 3H), 1.36 (d, /=7.24 Hz, 3H) -- -- 534 600MHz DMSO - d ₆ 7.77 (br dd, /=4.44, 7.32 Hz, 1H), 7.46 (dd, /=7.43, 11.09 Hz, 1H), 7.37 (dd, /=7 .36, 10.70 Hz, 1H), 4.94-5.07 (m, 2H), 4.32-4.44 (m, 1H), 4.24-4.31 (m, 1H), 3.98 (br d, /=13.23 Hz, 1H), 3.26 (br s, 1H), 3.09-3.21 (m, 1H), 2.923.07 (m, 2H), 2 .66-2.81 (m, 2H), 2.58 - -

- 305 043189

(d, 7=4.59 Hz, 3H), 2.32-2.47 (m, 2H), 2.10 (br dd, 7=3.54, 13.20 Hz, 1H), 1.57 -1.86(m, 4H), 1.33-1.46(m, 1H) 535 600MHz DMSO - d ₆ 7.32-7.49(m, 2H), 4.89-5.05(m, 2H), 4.34-4.45(m, 1H), 3.69-3.85(m, 2H), 3.16-3.27(m, 1H), 2.95-3.12(m, 4H ), 2.72-2.88 (m, 1H), 1.98-2.16 (m, 2H), 1.86 (br d, 7=1.71 Hz, 4H), 1.70-1 .84 (m, 3H), 1.40-1.59 (m, 2H) - - 536 600MHz DMSO - d ₆ 7.46 (dd, 7=7.47, 11.13 Hz, 1H), 7.38 (dd, 7=7.36, 10.70 Hz, 1H), 4.95-5.08 (m, 2H), 4.35-4.44 (m, 3H), 3.98 (br d, 7=13.31 Hz, 1H), 3.49 (br s, 2H), 3.383.45 (m, 3H ), 3.16-3.28 (m, 2H), 2.913.04 (m, 3H), 2.71-2.83 (m, 2H), 1.972.15 (m, 1H), 1.73- 1.91 (m, 1H), 1.571.70 (m, 4H), 1.51 (br s, 2H), 1.361.46 (m, 3H) - - 537 600MHz DMSO - d ₆ 7.46 (dd, 7=7.43, 11.09 Hz, 1H), 7.38 (dd, 7=7.40, 10.74 Hz, 1H), 4.95-5.08 (m, 2H), 4.28-4.39 (m, 1H), 3.99 (br d, 7=13.39 Hz, 1H), 3.52 (br t, 7=5.99 Hz, 2H), 3.37-3.44(m, 2H), 3.25-3.30(m, 1H), 3.13-3.25(m, 2H), 2.94-3.05(m, 2H ), 2.85-2.93 (m, 1H), 2.70-2.85 (m, 2H), 2.11 (ddd, 7=4.44, 8.19, 12.51 Hz, 1H ), 1.74-1.84 (m, 2H), 1.63-1.72 (m, 5H), 1.58 (quin, 7=5.90 Hz, 2H), 1.40-1, 53(m, 5H) - -- 538 600MHz DMSO - d ₆ 7.47 (dd, 7=7.43, 11.17 Hz, 1H), 7.31 (dd, 7=7.28, 10.70 Hz, 1H), 5.03 (brs, 2H), 4.31-4.46(m, 2H), 3.55-3.71(m, 4H), 3.34-3.42(m, 4H), 3.21-3.28(m, 3H ), 3.04-3.20 (m, 2H), 2.92-3.03 (m, 2H), 2.69-2.81 (m, 1H), 2.26-2.40 (m , - -

-306043189

2H), 1.99-2.14 (m, 1H), 1.70-1.86 (m, 1H) 539 600MHz DMSO - d ₆ 7.46 (dd, 7=7.47, 11.13 Hz, 1H), 7.38 (dd, 7=7.40, 10.74 Hz, 1H), 5.01 (dq, 7=9, 61, 17.43 Hz, 2H), 4.43 (td, 7=4.02, 7.61 Hz, 1H), 4.31-4.38 (m, 1H), 4.29 (br s, 1H), 3.98 (br d, 7=13.23 Hz, 1H), 3.83-3.92 (m, 1H), 3.15-3.29 (m, 2H), 2.92- 3.04 (m, 4H), 2.73-2.81 (m, 2H), 2.51-2.62 (m, 1H), 2.06-2.15 (m, 1H), 1, 71-1.88 (m, 4H), 1.59-1.71 (m, 4H), 1.39 (brs, 2H), 1.09-1.17 (m, 1H), 0.90 (br d, 7=6.38 Hz, 2H), 0.85 (br d, 7=6.46 Hz, 2H) - - 540 600MHz DMSO - d ₆ 7.46 (t, 7=9.12 Hz, 1H), 7.40 (t, 7=9.00 Hz, 1H), 5.00-5.11 (m, 2H), 4.33-4 .44 (m, 1H), 3.51-3.63 (m, 5H), 3.43-3.49 (m, 3H), 3.23-3.30 (m, 1H), 2.94 -3.06 (m, 2H), 2.79 (dd, 7=8.06, 12.57 Hz, 1H), 2.02-2.17 (m, 4H), 1.75-1.93 (m, 2H) - - 541 600MHz DMSO - d ₆ 7.47 (t, 7=9.15 Hz, 1H), 7.30-7.41 (m, 1H), 4.99-5.17 (m, 2H), 4.30-4.44 ( m, 1H), 4.06-4.15 (m, 1H), 3.85-3.93 (m, 1H), 3.71-3.79 (m, 1H), 3.45-3, 64 (m, 2H), 3.35-3.42(m, 1H), 3.17 (d, 7=4.98 Hz, 1H), 3.05-3.13 (m, 1H), 2 .93-3.04 (m, 2H), 2.69-2.80 (m, 1H), 2.30-2.47 (m, 2H), 2.02-2.13 (m, 2H) , 1.91-1.96(m, 1H), 1.74-1.90(m, 4H), 1.46-1.54(m, 1H) - -- 542 600MHz DMSO - d ₆ 7.46 (dd, 7=7.47, 11.13 Hz, 1H), 7.38 (dd, 7=7.32, 10.74 Hz, 1H), 4.95-5.07 (m, 2H), 4.67 (spt, 7=6.76 Hz, 1H), 4.29-4.37 (m, 1H), 4.25 (td, 7=3.24, - -

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6.52 Hz, 1H), 3.99 (br d, 7=13.47 Hz, 1H), 3.17-3.35 (m, 1H), 2.92-3.05 (m, 3H) , 2.86 (s, 2H), 2.69-2.83 (m, 2H), 2.66 (s, 1H), 2.06-2.16 (m, 1H), 1.741.91 (m , 3H), 1.59-1.70 (m, 3H), 1.351.47 (m, 1H), 1.16 (dd, 7=2.57, 6.31 Hz, ZN), 1.02 ( dd, 7=3.58, 6.62 Hz, ZN) 543 600MHz DMSO - d ₆ 7.47-7.55(m, 1H), 7.26-7.33(m, 1H), 5.06-5.14(m, 2H), 4.38-4.56(m, 2H ), 4.11-4.27 (m, 1H), 3.36-3.46 (m, 1H), 3.11-3.28 (m, 3H), 2.93-3.09 (m , 2H), 2.79 (br s, 1H), 1.99-2.16 (m, 2H), 1.74 (br t, 7=9.42 Hz, 1H), 0.98 (d, 7=6.54 Hz, ZN), 0.83 (dd, 7=2.34, 6.62 Hz, ZN) - - 544 600MHz DMSO - d ₆ 6.80-6.88(m, 1H), 6.56-6.63(m, 1H), 5.03-5.14(m, 2H), 4.38-4.53(m, 1H ), 4.30-4.37 (m, 1H), 4.23 (q, 7=9.52 Hz, 2H), 3.73-3.77 (m, 3H), 3.24 (s, 3H), 2.92-3.04 (m, 3H), 2.72-2.82 (m, 1H), 2.03-2.13 (m, 1H), 1.73-1.90 ( m, 1H) V SFC: Chiralpak IC, 20% methanol, peak 1 545 600MHz DMSO - d ₆ 6.83 (dd, 7=2.18, 9.42 Hz, 1H), 6.61 (dd, 7=2.18, 11.99 Hz, 1H), 4.96-5.07 (m, 2H), 4.34-4.44(m, 1H), 3.80(s, 3H), 3.63-3.70(m, 2H), 3.59(br d, 7=4.83 Hz, 4H), 3.40-3.52 (m, 3H), 3.22-3.28 (m, 1H), 2.94-3.11 (m, 2H), 2.77 (dd, 7=8.49, 12.53Hz, 1H), 2.022.19(m, 1H), 1.75-1.84(m, 1H) V SFC: Chiralpak IC, 35% methanol, peak 1 546 600MHz DMSO - d ₆ 6.74 (dd, 7=2.26, 8.95 Hz, 1H), 6.57 (dd, 7=2.22, 12.18 Hz, 1H), 4.94-5.02 (m, 2H), 4.35-4.43 (m, 1H), 3.89 (s, 3H), 3.61-3.70 (m, 2H), 3.59 (br s, 3H), 3, 36-3.53 (m, 3H), 3.16-3.28 (m, V SFC: Chiralpak IC, 35% methanol, peak 2

- 308 043189

2H), 2.92-3.02 (m, 2H), 2.74 (dd, 7=8.17, 12.46 Hz, 1H), 1.98-2.14 (br, 1H), 1 .74-1.86 (m, 1H) 547 500 MHz, METHANOL -d4 7.35 (dd, 7=7.53, 10.64 Hz, 1H), 7.01 (dd, 7=6.88, 10.25 Hz, 1H), 5.38 (t, 7=10, 12 Hz, 1H), 4.34-4.52 (m, 1H), 3.59-3.69 (m, 1H), 3.55 (dt, 7=7.40, 9.67 Hz, 1H ), 3.41-3.51 (t, 2H), 3.053.22 (t, 2H), 2.94 (dd, 7=8.82, 12.46 Hz, 1H), 2.79-2, 87 (t, 1H), 2.61-2.70 (t, 1H), 2.37-2.48 (t, 1H), 2.18-2.30 (t, 1H), 1.91- 2.03 (t, 1H), 0.80-0.94 (t, 4H) IN SC: Regis Whelk-O, 30% IP A, peak 1 548 500 MHz, CHLOROPHO PM-d 7.39 (dd, 7=7.27, 10.64 Hz, 1H), 6.69 (dd, 7=7.01, 9.86 Hz, 1H), 5.21 (t, 7=9, 99 Hz, 1H), 4.27-4.46 (t, 2H), 4.04-4.16 (t, 2H), 3.48-3.70 (t, 6H), 3.14-3 .24 (t, 1H), 2.96-3.11 (t, 2H), 2.53-2.63 (t, 1H), 2.41 (qd, 7=9.54, 13.43 Hz , 1Н), 2.18-2.26 (t, 1Н), 1.92-2.08 (t, 2Н), 1.69-1.91 (t, ZN) IN SC: Chiralpak IC, 20% methanol, peak 1 549 500 MHz, METHANOL -d4 7.36 (dd, 7=7.27, 10.64 Hz, 1H), 7.02 (dd, 7=7.01, 10.38 Hz, 1H), 5.39 (t, 7=10, 12 Hz, 1H), 4.35-4.53 (t, 1H), 3.64 (dt, 7=1.04, 9.73 Hz, 1H), 3.503.60 (t, 2H), 3, 41 (br dd, 7=5.19, 7.27 Hz, 1H), 3.11-3.21 (t, 2H), 2.93 (dd, 7=8.56, 12.46 Hz, 1H ), 2.79-2.87 (t, 1H), 2.57-2.67 (t, 1H), 2.42 (qd, 7=9.87, 12.94 Hz, 1H), 2.172.30 ( t, 1H), 1.94-2.04 (t, 1H), 0.780.94 (t, 4H) IN SC: Regis Whelk-O, 30% IP A, peak 2 550 500 MHz, CHLOROPHO PM-d 7.39 (dd, 7=7.40, 10.51 Hz, 1H), 6.69 (dd, 7=6.75, 9.86 Hz, 1H), 5.19 (t, 7=9, 86 Hz, 1H), 4.35-4.47 (t, 2H), V SC: Chiralpak IC, 20% methanol, peak

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4.02-4.19 (m, 2H), 3.40-3.71 (m, 6H), 3.16-3.38 (m, 2H), 2.89 (dd, 7=8.69 , 12.59 Hz, 1H), 2.58 (dddd, 7=1.30, 7.72, 9.34, 13.30 Hz, 1H), 2.40 (qd, 7=9.68, 13.27 Hz, 1H) , 2.16-2.32 (m, 1H), 1.90-2.04 (m, 2H), 1.72-1.90 (w, 3H) 2 551 600 MHz, DMSO- _d6 7.46-7.56 (m, 2H), 7.38-7.45 (m, 1H), 5.56 (s, 2H), 4.32-4.50 (m, 1H), 3.373, 51 (m, 2H), 3.04-3.12 (m, 1H), 2.943.04 (m, 1H), 2.80-2.90 (m, 1H), 2.072.17 (m, 1H) , 1.73-1.85 (m, 1H) - - 552 500 MHz, METHANOL -d ₄ 7.06-7.14 (m, 1H), 6.80-6.91 (m, 1H), 5.76 (s, 2H), 4.54-4.72 (m, 1H), 3.663, 79 (m, 1H), 3.52-3.61 (m, 1H), 3.413.52 (m, 1H), 3.32 (t, 7=1.62 Hz, ZN), 3.15-3 .24 (m, 1H), 3.07-3.15 (m, 1H), 2.22-2.34 (m, 1H), 1.93-2.09 (m, 1H) IN Regis Whelk0 s, s, 25% MeOH, peak 2 553 600 MHz, DMSO- _d6 7.46-7.63(m, 2H), 5.68-5.79(m, 2H), 4.32-4.52(m, 1H), 3.37-3.47(m, 2H ), 2.98-3.11 (m, 2H), 2.79-2.88 (t, 1H), 2.62-2.69 (t, ZN), 2.07-2.17 (t , 1H), 1.75-1.85 (t, 1H) - - 554 500 MHz, METHANOL -d ₄ 7.54-7.67 (t, 2H), 7.43-7.53 (t, 1H), 5.21 (s, 2H), 4.10-4.57 (t, 3H), 3.523, 62 (t, 1H), 3.39-3.47 (t, 1H), 3.35 (s, 3H), 3.13 (t, 2H), 2.92-3.06 (t, 1H) , 2.12-2.28 (t, 1H), 1.86-2.03 (t, 1H) F Chiralpak ADH, 15% MeOH/DEA, peak 1 555 500 MHz, METHANOL -d ₄ 8.81 (s, 2H), 8.16 (t, 7=2.34 Hz, 1H), 7.58 (dd, 7=2.59, 8.43 Hz, 1H), 5.54 (s , 2H), 4.36-4.56 (t, 1H), 3.68-3.79 (t, 1H), 3.58-3.68 (t, 1H), 3.10-3.25 (t, 2H), 2.96-3.10 (t, 1H), 2.10-2.27 (t, 1H), 1.81-1.97 (t, 1H) F Chiralpak IC, 40% MeOH with 0.2% DEA, peak 2

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556 600 MHz, DMSO- _d6 8.98 (d, 7=1.79 Hz, 1H), 8.29-8.34 (br, 1H), 7.53 (d, 7=8.25 Hz, 1H), 7.017.06 (m , 1H), 6.97 (td, 7=10.59, 2.18 Hz, 1H), 5.57 (s, 2 H), 4.32-4.40 (m, 1 H), 3, 36-3.51 (m, 2H), 3.31 (s, 3H), 2.98-3.09 (m, 1H), 2.86-2.95 (m, 1H), 2.80 ( dd, 7=12.46, 8.49 Hz, 1H), 2.012.09 (m, 1H), 1.68-1.76 (m, 1H) IN Lux Cellulose2, 30% MeOH, peak 2 557 500 MHz, METHANOL -d ₄ 7.21-7.40 (m, 1H), 7.07-7.17 (m, 1H), 6.81-6.93 (m, 1H), 5.83-5.96 (m, 2H ), 4.63-4.80 (m, 1H), 3.73-3.86 (m, 1H), 3.54-3.72 (m, 2H), 3.12-3.25 (m , 2H), 2.24-2.36 (m, 1H), 1.98-2.10 (m, 1H) IN Regis WhelkO s, s, 10% MeOH, peak 2 558 500 MHz, METHANOL -d ₄ 7.00-7.08 (m, 1H), 6.74-6.84 (m, 1H), 5.19 (s, 2H), 4.38-4.56 (m, 1H), 4.064, 28 (m, 3H), 3.48-3.58 (m, 1H), 3.383.46 (m, 1H), 3.33 (s, 3H), 3.14-3.20 (m, 1H) , 2.88-3.02 (m, 1H), 2.14-2.27 (m, 1H), 1.88-2.00 (m, 1H) F Regis Whelk0 s, s, 15% MeOH, peak 1 559 500 MHz, METHANOL -d ₄ 7.39-7.50 (m, 1H), 7.22-7.34 (m, 1H), 7.09-7.23 (m, 1H), 5.10 (s, 2H), 4.114, 53 (t, 3H), 3.44-3.55 (t, 1H), 3.343.41 (t, 1H), 3.34 (s, 3H), 3.05-3.16 (t, 2H) , 2.87-2.98 (t, 1H), 2.12-2.25 (t, 1H), 1.82-2.00 (t, 1H) F Chiralpak ADH, 25% MeOH/DEA, peak 1 560 600 MHz, DMSO- _d6 7.42-7.68 (t, 3N), 5.84-5.98 (t, 2N), 4.30-4.51 (t, 1N), 3.34-3.49 (t, 2N ), 3.04-3.13 (t, 1H), 2.93-3.02 (t, 1H), 2.79-2.90 (t, 1H), 2.08-2.18 (t , 1H), 1.73-1.86 (t, 1H) - - 561 500 MHz, METHANOL -d ₄ 7.43.7.54( _t , 1H), 7.16-7.27(t, 1H), 6.94-7.04(t, 1H), 5.75(s, 2H), 4.544.74( t, 1H), 3.66-3.75 (t, 1H), 3.513.59 (t, 1H), 3.43-3.49 (t, 1H), 3.283.36 (t, 3N), 3 .06-3.24 (t, 2H), 2.22- IN Chiralpak AZH, 30% MeOH peak 2

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2.39 (m, 1H), 1.96-2.14 (m, 1H) 562 600 MHz, DMSO- _d6 8.92-9.00(m, 1H), 8.26-8.35(m, 1H), 7.44-7.57( _m , 2H), 7.32-7.42(m, 1H ), 5.55 (s, 2H), 4.29-4.48 (m, 1H), 3.383.47 (m, 2H), 3.31 (s, 3H), 2.99-3.09 ( m, 1H), 2.89-2.98 (m, 1H), 2.75-2.84 (m, 1H), 2.00-2.11 (m, 1H), 1.65-1, 78(m, 1H) - - 563 600 MHz, DMSO- _d6 7.64 (s, 1H), 7.56 (d, 3=8.33 Hz, 1H), 7.40 (dd, 3=8.33, 1.25 Hz, 1H), 5.065.15 (m , 2H), 4.38-4.46 (m, 1H), 3.393.41 (m, 2H), 3.07-3.15 (m, 4H), 2.99 (m, 1H), 2, 90 (s, 3H), 2.84 (dd, 3=12.69, 8.17 Hz, 1H), 2.01-2.17 (m, 1H), 1.74-1.85 (m, 1H) IN Chiralpak IC, 15% MeOH, peak 1 564 600 MHz, DMSO- _d6 7.47-7.52(m, 1H), 7.42-7.46(m, 1H), 6.07-6.14(m, 1H), 5.34(s, 2H), 4.314, 55 (m, 1H), 3.40-3.51 (m, 2H), 2.983.12 (m, 2H), 2.79-2.89 (m, 1H), 2.36 (s, 3H) , 2.07-2.18 (m, 1H), 1.75-1.85 (m, 1H) - - 565 600 MHz, DMSO- _d6 7.02-7.09(m, 1H), 6.90-6.98(m, 1H), 4.94-5.05(m, 2H), 4.31-4.49(m, 1H ), 3.32 (s, 2H), 3.12 (s, 3H), 2.93-3.07 (m, 2H), 2.88 (s, 3H), 2.75-2.82 ( m, 1H), 2.04-2.18 (m, 1H), 1.77-1.83 (m, 1H) IN Phenomenex CEL 2, 25% MeOH peak 1 566 600 MHz, DMSO- _d6 7.35-7.44( _m , 1H), 7.07-7.13(m, 1H), 6.84-6.95(m, 1H), 4.90-5.04(m, 2H), 4.31-4.49( _m , 1H), 3.24-3.25(m, 2H), 3.12(s, 3H), 2.93-3.03(m, 2H), 2, 89 (s, 3H), 2.72-2.81 (m, 1H), 2.03-2.17 (m, 1H), 1.73-1.86 (m, 1H) V Phenomenex CEL 2, 25% MeOH peak 1 567 600 MHz, DMSO- _d6 7.49-7.54( _m , 1H), 7.40-7.46(m, 1H), 6.77-6.87(m, 1H), 5.40(s, 2H), 4, thirty- - -

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4.48 (m, 1H), 3.37-3.50 (m, 2H), 3.033.13 (m, 1H), 2.91-3.00 (t, 1H), 2.80- 2.88 (t, 1H), 2.26 (d, 7=1.09 Hz, ZN), 2.06-2.15 (t, 1H), 1.72-1.81 (t, 1H) 568 600 MHz, DMSO- _d6 7.47-7.57 (t, 2H), 7.18-7.28 (t, 1H), 5.59 (s, 2H), 4.31-4.48 (t, 1H), 3.383, 51 (t, 2H), 3.03-3.12 (t, 1H), 2.923.01 (t, 1H), 2.79-2.88 (t, 1H), 2.32 (s, 3H) , 2.04-2.17 (t, 1H), 1.73-1.81 (t, 1H) - - 569 600 MHz, DMSO- _d6 7.45-7.53 (t, 1H), 7.35-7.42 (t, 1H), 6.96-7.06 (t, 1H), 5.89 (s, 2H), 4.284, 47 (t, 1H), 3.32 (t, 2H), 2.97-3.06 (t, 1H), 2.87-2.95 (t, 1H), 2.73-2.82 ( t, 1H), 2.04-2.14 (t, 1H), 1.67-1.77 (t, 1H) IN Chiralcel OD- H, 15% isopropanol, peak 1 570 500 MHz, METHANOL -d ₄ 7.42-7.52 (t, 1H), 7.09-7.21 (t, 2H), 5.11 (s, 2H), 4.09-4.53 (t, 3H), 3.463, 56 (t, 1H), 3.35-3.45 (t, 1H), 3.34 (s, 3H), 3.05-3.15 (t, 2H), 2.87-2.98 ( t, 1H), 2.13-2.26 (t, 1H), 1.85-1.97 (t, 1H) F Chiralpak ADH, 25% MeOH/DEA, peak 2 571 600 MHz, DMSO- _d6 7.48-7.57 (t, 2H), 5.59 (s, 2H), 4.324.50 (t, 1H), 3.39-3.46 (t, 2H), 3.023.10 (t, 1H), 2.94-3.02 (t, 1H), 2.762.88 (t, 1H), 2.47 (s, 3H), 2.06-2.17 (t, 1H), 1.73 -1.82 (t, 1H) - - 572 600 MHz, DMSO- _d6 7.48-7.56 (t, 1H), 7.39-7.47 (t, 1H), 5.44 (s, 2H), 4.31-4.50 (t, 1H), 3.353, 48 (t, 2H), 3.02-3.13 (t, 1H), 2.913.01 (t, 1H), 2.78-2.89 (t, 1H), 2.57 (s, 3H) , 2.06-2.16 (t, 1H), 1.72-1.80 (t, 1H) - - 573 500 MHz, METHANOL 7.47-7.56 (t, 1H), 7.10-7.37 (t, 2H), 6.99-7.07 (t, 1H), 5.90 (s, 2H), 4.65- IN Chiralcel ΟΠ- Η, 15%

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-d ₄ 4.84 (m, 1H), 3.75-3.84 (m, 1H), 3.53- 3.70 (m, 2H), 3.13-3.23 (m, 2H), 2.26- 2.37 (m, 1H), 2.00-2.11 (m, 1H) isopropanol, peak 1 574 500 MHz, METHANOL -d ₄ 8.18-8.24(m, 1H), 7.68-7.75(m, 1H), 5.73-5.82(m, 2H), 4.54-4.74(m, 1H ), 3.77-3.88 (m, 1H), 3.41-3.77 (m, 2H), 3.32 (td, 7=1.62, 3.24 Hz, 1H), 3.063, 22 (m, 1H), 2.68-2.79 (m, 3H), 2.21 (s, 1H), 1.90-2.05 (m, 1H) IN Chiralpak IC, 35% MeOH, peak 1 575 600 MHz, DMSO- _d6 7.47-7.55(m, 1H), 7.36-7.46(m, 1H), 5.35(s, 2H), 4.32-4.48(m, 1H), 3.393, 49 (m, 2H), 3.03-3.12 (m, 1H), 2.933.02 (m, 1H), 2.79-2.89 (m, 1H), 2.18 (s, 3H) , 2.05-2.14 (m, 1H), 1.97 (s, 3H), 1.70-1.82 (m, 1H) - - 576 600 MHz, DMSO- _d6 7.20-7.24(m, 1H), 7.12-7.19(m, 1H), 6.86-6.95(m, 1H), 4.91-5.05(m, 2H ), 4.31-4.48 (m, 1H), 3.33-3.39 (m, 2H), 3.12 (s, 3H), 2.93-3.06 (m, 2H), 2.89 (s, 3H), 2.74-2.82 (m, 1H), 2.05-2.15 (m, 1H), 1.74-1.82 (m, 1H) IN Chiralpak IC, 15% MeOH, peak 2 577 600 MHz, DMSO- _d6 7.42-7.54(m, 2H), 5.45(s, 2H), 4.294.49(m, 1H), 3.37-3.50(m, 2H), 3.033.13(m, 1H), 2.92 (m, 3H), 2.77-2.87 (m, 1H), 2.06-2.17 (m, 1H), 1.71-1.80 (m, 1H) , 1.24 (t, 7=7.55 Hz, 3H) - - 578 600 MHz, DMSO- _d6 7.43-7.56(m, 2H), 5.37-5.45(m, 2H), 4.31-4.49(m, 1H), 3.36-3.47(m, 2H ), 3.03-3.11 (m, 1H), 2.90-2.99 (m, 1H), 2.75-2.86 (m, 1H), 2.29-2.37 (m , 1H), 2.05-2.17 (m, 1H), 1.69-1.82 (m, 1H), 1.20-1.27 (m, 3H), 1.03-1.10 (m, 3H) - - 579 600 MHz, DMSO- _d6 7.45-7.58 (m, 2H), 6.28-6.36 (m, 1H), 5.45 (s, 2H), 4.32-4.51 (m, 1H), 3.393, 47 (m, 1H), 3.35-3.39 (m, 1H), 3.04- - -

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3.13 (m, 1H), 2.94-3.03 (m, 1H), 2.792.89 (m, 1H), 2.19 (s, 3H), 2.08-2.16 (m, 1H), 1.78-1.84 (m, 1H) 580 500 MHz, METHANOL -d ₄ 7.70-7.83 (m, 1H), 7.42-7.53 (m, 1H), 7.27-7.41 (m, 1H), 5.21 (s, 2H), 4.134, 56 (m, 3H), 3.51-3.62 (m, 1H), 3.403.48 (m, 1H), 3.37 (s, 3H), 3.12 (s, 2H), 2.93 -3.05(m, 1H), 2.14-2.30(m, 1H), 1.88-2.03(m, 1H) F Chiralpak ADH, 15% MeOH/DEA, peak 2 581 600 MHz, DMSO- _d6 7.47-7.61(m, 2H), 5.48-5.60(m, 2H), 4.30-4.49(m, 1H), 3.37-3.46(m, 2H ), 2.99-3.08 (m, 1H), 2.90-2.98 (m, 1H), 2.78-2.86 (m, 1H), 2.18-2.25 (m , 1H), 2.06-2.16 (m, 1H), 1.72-1.81 (m, 1H), 1.08-1.15 (m, 2H), 0.91-0.99 (m, 2H) - - 582 500 MHz, METHANOL -d ₄ 7.33-7.40(m, 1H), 7.16-7.25(m, 1H), 6.92-7.01(m, 1H), 5.70-5.80(m, 2H ), 4.48-4.68 (m, 1H), 3.65-3.75 (m, 1H), 3.50-3.59 (m, 1H), 3.36 (s, 3H), 3.303.34 (m, 1H), 3.14-3.25 (m, 1H), 3.023.12 (m, 1H), 2.22-2.34 (m, 1H), 1.932.07 (m, 1H) IN Chiralpak AZ- H, 30% MeOH, peak 1 583 500 MHz, METHANOL -d ₄ 8.70-8.80 (m, 2H), 7.94-8.04 (m, 1H), 7.56-7.66 (m, 1H), 5.62 (s, 2H), 4.394, 61 (m, 1H), 3.63-3.87 (m, 2H), 3.133.25 (m, 2H), 2.95-3.09 (m, 1H), 2.122.26 (m, 1H) , 1.74-1.92 (m, 1H) F Chiralpak IC, 40% MeOH with 0.2% DEA, peak 2 584 600 MHz, DMSO- _d6 7.37-7.45(m, 1H), 7.26-7.35(m, 1H), 6.95-7.06(m, 1H), 5.89(s, 2H), 4.304, 49 (m, 1H), 3.32-3.44 (m, 2H), 3.003.11 (m, 1H), 2.86-2.97 (m, 1H), 2.752.84 (m, 1H) , 2.06-2.17(m, 1H), 1.671.77(m, 1H) IN Chiralcel OD- H, 15% isopropanol, peak 2 585 600 MHz, DMSO- _d6 7.77-7.84 (m, 2H), 7.39-7.47 (m, 4H), 7.30 (dd, 7=9.23, 2.45Hz, 1H), 6.95 IN Chiralcel O.J. H, 30%

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(ddd, 7=10.02, 8.66, 2.57 Hz, 1H), 5.48-5.55(m, 2H), 4.34-4.48(m, 1H), 3.37 -3.51 (m, 2H), 3.03-3.12 (m, 2H), 2.84 (dd, 7=12.42, 8.91 Hz, 1H), 2.52 (s, 3H ), 2.12-2.21 (m, 1H), 1.79-1.97 (m, 1H) MeOH peak 1 586 600 MHz, DMSO- _d6 7.46-7.55 (m, 1H), 7.26-7.35 (m, 1H), 5.45 (s, 2H), 4.30-4.49 (m, 1H), 3, 39 (s, 5H), 2.96-3.11 (m, 2H), 2.78-2.88 (m, 1H), 2.26-2.32 (m, 3H), 2.06- 2.18 (m, 1H), 1.77-1.86 (m, 1H) - - 587 500 MHz, METHANOL -d ₄ 7.35-7.42(m, 1H), 7.23(s, 2H), 6.957.03(m, 1H), 5.90(s, 2H), 4.50-4.70(m, 1H), 3.67-3.77(m, 1H), 3.54-3.63(m, 1H), 3.37-3.49(m, 1H), 3.15-3.25( m, 1H), 3.02-3.13 (m, 1H), 2.21-2.33 (m, 1H), 1.94-2.08 (m, 1H) IN Chiralcel ΟΠ- Η, 15% isopropanol, peak 2 588 500 MHz, METHANOL -d ₄ 7.43-7.52 (m, 1H), 7.17-7.25 (m, 1H), 6.95-7.04 (m, 1H), 5.77 (d, 7=1.95 Hz, 2H), 3.50-3.61 (m, 1H), 3.40-3.49 (br, 1H), 3.29-3.35 (m, 2H), 3.14-3, 25 (t, 1H), 2.73 (s, 3H), 2.29-2.45 (t, 1H), 2.14-2.30 (t, 1H) IN Chiralcel ΟΠ- Η, 10% isopropanol, peak 1 589 600 MHz, DMSO- _d6 7.37-7.44 ( _t , 1H), 7.19-7.27 (t, 1H), 6.89-6.97 (t, 1H), 5.34-5.44 (t, 2H ), 4.30-4.49 (t, 1H), 3.37-3.47 (t, 2H), 2.97-3.11 (t, 2H), 2.75-2.85 (t , 1H), 2.46-2.48 (t, 3H), 2.39 (s, 3H), 2.09-2.19 (t, 1H), 1.81-1.91 (t, 1H ) IN Chiralcel O.J. H, 10% isopropanol, peak 1 590 500 MHz, METHANOL -d ₄ 7.86-7.98 (t, 1H), 7.34-7.49 (t, 1H), 6.05 (s, 2H), 4.65-4.85 (t, 2H), 4.484, 63 (t, 1H), 3.13-3.48 (t, ZN), 2.75 (s, ZN), 2.25-2.38 (t, 1H), 1.77-1.94 ( t, 1H) V Chiralpak IC, 35% MeOH, peak 2 591 500 MHz 6.87-6.95 (t, 1H), 6.74-6.86 (t, 1H), F Regis Whilk-

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METHANOL -d ₄ 5.07-5.21 (m, 2H), 4.12-4.56 (m, 3H), 3.45-3.59 (m, 1H), 3.36 (s, 3H), 2.893, 23 (m, 4H), 2.11-2.28 (m, 1H), 1.841.99 (m, 1H) 0s, s, 15% MeOH peak 2 592 600 MHz, DMSO- _d6 7.73 (s, 1H), 7.39 (s, 2H), 5.03-5.12 (m, 2H), 4.37-4.46 (m, 1H), 3.36-3, 44 (m, 2H), 3.14 (s, 3H), 2.96-3.12 (m, 2H), 2.89 (s, 3H), 2.84 (dd, 7=12.57, 8.29Hz, 1H), 2.08-2.17(m, 1H), 1.811.92(m, 1H) IN Chiralpak IC, 15% MeOH, peak 2 593 600 MHz, DMSO- _d6 7.76-7.83 (m, 2H), 7.39-7.46 (m, 3H), 7.36 (dd, 7=8.76, 4.71 Hz, 1H), 7.25 ( dd, 7=9.73, 2.49Hz, 1H), 6.95 (ddd, 7=9.85, 8.80, 2.53Hz, 1H), 5.52 (s, 2H), 4.35-4.49 (m, 1H), 3.39-3.54 (m, 2H), 3.03-3.15 (m, 2H), 2.87 (dd , 7=12.42, 8.91Hz, 1H), 2.47(s, 3H), 2.12-2.22(m, 1H), 1.78-1.94(m, 1H) IN Chiralcel O.J. H, 30% MeOH, peak 2 594 600 MHz, DMSO- _d6 7.09-7.17(m, 1H), 6.86-6.96(m, 1H), 4.96-5.09(m, 2H), 4.32-4.50(m, 1H ), 3.22-3.43 (m, 2H), 3.10 (s, 3H), 2.963.07 (m, 2H), 2.89 (s, 3H), 2.77-2.85 ( m, 1H), 2.07-2.18 (m, 1H), 1.74-1.87 (m, 1H) V Phenomenex CEL 2, 25% MeOH peak 2 595 600 MHz, DMSO- _d6 8.97(d, 7=1.79Hz, 1H), 8.32(dd, 7=8.25, 2.34Hz, 1H), 7.55(d, 7=8.33Hz, 1H ), 7.17 (dd, 7=9.26, 2.18 Hz, 1H), 6.88 (t, 7=10.33 Hz, 1H), 5.545.61 (m, 2H), 4.31 -4.45(m, 1H), 3.393.45(m, 2H), 3.04-3.14(m, 1H), 2.923.03(m, 1H), 2.85(dd, 7=12 .61, 8.49 Hz, 1H), 2.03-2.20 (m, 1H), 1.73-1.82 (m, 1H) V Lux Cellulose2, 30% MeOH, peak 1 596 600 MHz, DMSO- _d6 7.28-7.34(m, 1H), 7.20-7.26(m, 1H), 6.90-6.98 (m, 1H), 5.40 (s, 2H), 4.33- V Chiralcel O.J. H, 10%

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4.49 (m, 1H), 3.40-3.53 (m, 2H), 3.013.14 (m, 2H), 2.80-2.89 (m, 1H), 2.452.48 (m, 3H), 2.39 (s, 3H), 2.10-2.21 (m, 1H), 1.80-1.89 (m, 1H) isopropanol, peak 2 597 500 MHz, METHANOL -d ₄ 7.33-7.40(m, 1H), 7.16-7.26(m, 1H), 6.93-7.04(m, 1H), 5.77(d, 7=1.56 Hz, 2H), 3.54-3.63(m, 1H), 3.44-3.52(m, 1H), 3.37-3.43(m, 1H), 3.32(s, 1H), 3.18-3.27(m, 1H), 2.68-2.77(m, 3H), 2.31-2.44(m, 1H), 2.14-2.30( m, 1H) IN Chiralcel OD- N, 10% isopropanol, peak 2 598 500 MHz, METHANOL -d ₄ 7.24 (t, 7=55 Hz, 1H), 7.08-7.16 (m, 1H), 6.83-6.92 (m, 1H), 5.94 (s, 2H), 4 .70-4.86 (m, 1H), 3.85-3.93 (m, 1H), 3.73-3.83 (m, 1H), 3.64-3.72 (m, 1H) , 3.24 (dd, 7=10.45, 12.65 Hz, 2H), 2.25-2.38 (m, 1H), 2.08 (br dd, 7=1.36, 2.92 Hz, 1H) IN Regis WhelkO s, s, 10% MeOH, peak 1 599 500 MHz, METHANOL -d ₄ 7.04-7.11(m, 1H), 6.80-6.92(m, 1H), 5.79(s, 2H), 4.58-4.79(m, 1H), 3.743, 84 (m, 1H), 3.52-3.68 (m, 2H), 3.123.27 (m, 2H), 2.74 (s, 3H), 2.24-2.36 (m, 1H) , 1.99-2.10 (m, 1H) V Regis WhelkO s, s, 25% MeOH, peak 1

Scheme 11

Selective preparation of chlorobenzimidazoles

Intermediate 86: 4-((2,6-dichloro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile

Step 1 4-(((5-Chloro-2-nitrophenyl)amino)methyl)benzonitrile.

To a stirred solution of 4-chloro-2-fluoro-1-nitrobenzene (8.0 g, 45.6 mmol, 1 eq) in ethanol (104.0 ml) and water (80.0 ml) was added )benzonitrile hydrochloride (8.45 g, 50.1 mmol, 1.1 eq.) followed by the addition of potassium carbonate (11.34 g, 82.0 mmol, 1.8 eq.). The reaction mixture was heated to 85°C for 10 h, then stirred for 8 h at ambient temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 ml) and the solids were filtered. The resulting solid was dried under high vacuum to give 4-(((5-chloro-2-nitrophenyl)amino)methyl)benzonitrile (9 g, 68.6% yield) as a yellow solid. ^: H NMR (400 MHz, DMSO-d ₆ ): δ 8.85 (t, J=6.3 Hz, 1H), 8.08-8.13 (m, 1H), 7.86-7.79 (m, 2H), 7.56 (d, J=8.0 Hz, 2H), 6.90 (t, J=2.4 Hz, 1H), 6.77-6.66 (m, 1H) , 4.76 (d, J=6.3 Hz, 2H).

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Step 2 4-(((2-Amino-5-chlorophenyl)amino)methyl)benzonitrile To a stirred solution of 4(((5-chloro-2-nitrophenyl)amino)methyl)benzonitrile (9.0 g, 31.3 mmol, 1.0 eq.) in a mixture of tetrahydrofuran (90.0 ml), methanol (90.0 ml) and water (60.0 ml) was added iron powder (7.51 g, 135.0 mmol, 4.3 eq.) followed by the addition of ammonium chloride (7.53 g, 141.0 mmol, 4.5 eq.). The resulting reaction mixture was heated to 60° C. for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad and washed with ethyl acetate (100 ml). The filtrate was diluted with water (100 ml) and the layers were separated, the aqueous layer was washed with ethyl acetate (2x200 ml). The combined organic layers were washed with water (2x200 ml), brine (2x200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-(((2-amino-5-chlorophenyl)amino)methyl)benzonitrile (7 .5 g, 93% yield as a light yellow solid which was pure enough to be used in the next step. 1 H NMR (400 MHz, DMSO-d6): δ 7.81 (dd, J=8.3, 2.3 Hz, 2H), 7.65-7.45 (m, 2H), 6.53 (dd , J=8.2, 2.2Hz, 1H), 6.40 (dt, J=8.1, 2.4Hz, 1H), 6.19 (d, J=2.4Hz, 1H) , 5.58 (t, J=7.2 Hz, 1H), 4.75 (s, 2H), 4.54-4.28 (m, 2H).

NC

Step 3 4-((6-Chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile.

To a stirred solution of 4-(((2-amino-5-chlorophenyl)amino)methyl)benzonitrile (7.5 g, 29.1 mmol, 1.0 eq.) in 1,4-dioxane (120.0 mL) DIPEA (7.62 ml, 43.7 mmol, 1.5 eq.) and CDI (11.80 g, 72.8 mmol, 2.5 eq.) were added in portions. The resulting reaction mixture was heated to 100° C. for 1 h. After completion of the reaction (controlled by TLC), the reaction mixture was cooled to ambient temperature and slowly quenched with ice water (100 ml). The reaction mixture was extracted with ethyl acetate (2x150 ml). The combined organic layers were washed with water (2x150 ml) and brine (2x100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-((6-chloro-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1yl)methyl)benzonitrile (6 g, 72.7% yield) as a light brown solid which was sufficiently pure to be used in the next step as such. 1H NMR (400 MHz, DMSOd6): δ 11.21 (s, 1H), 7.86-7.79 (m, 2H), 7.54-7.40 (m, 2H), 7.23 (d , J=1.7 Hz, 1H), 7.06-6.97 (m, 2H), 5.12 (s, 2H). MS: (ESI negative ion) mass/charge: 282 [M-1].

Step 4 4-((2,6-dichloro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile.

A stirred solution of 4-((6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1yl)methyl)benzonitrile (6.0 g, 21.15 mmol, 1.0 eq.) in POCl ₃ (60.0 ml) was heated to 110°C for 5 hours After completion of the reaction (controlled by TLC), the reaction mixture was concentrated under high vacuum pressure. The resulting residue was diluted with DCM and slowly neutralized with 10% aqueous sodium bicarbonate at 0°C. The layers were separated and the aqueous layer was extracted with DCM (2x150 ml). The combined organic layers were washed with water (200 ml), brine (200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified on 230-400 mesh silica gel using petroleum ether and ethyl acetate as eluent (15-20%) to give 4-((2,6dichloro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile (2.5 g, 39.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ): δ 7.91-7.79 (m, 3H), 7.68 (d, J=8.7 Hz, 1H), 7.39-7.28 ( m, 3H), 5.67(s, 2H). MS: (ESI positive ion) mass/charge: 302.0 [M+1].

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Table 7

Intermediates prepared using the sequence in Scheme 11

No. prom, conn. Structure Name connections NMR MS MH+ 86 Oh 4-((2,6-dichloro-1 Hbenzo[c1]imidazole- 1yl)methyl)benzonitrile Ή NMR (400 MHz, DMSO-d ₆ ): δ 7.91-7.79 (m, 3H), 7.68 (d, J=8.7 Hz, 1H), 7.39-7.28 ( m, 3H), 5.67 (s, 2H) 302.0 87 NC c I X a 4-((2-chloro-6ethoxy-ΙΗbenzo[d]imidazole- 1yl)methyl)benzonitrile Ή NMR (400 MHz, DMSO-d ₆ ): δ 7.84 (dq, J=8.5, 1.9 Hz, 2H), 7.52 (dd, J=8.8, 1.2 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.22 (d, J=2.3 Hz, 1H), 6.88 (dt, J=8.8, 1.8 Hz, 1H), 5.62 (s, 2H), 4.02 (q, J=7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, ZN) 312.0 88 ^NC c ( X A ¹ 4-((2-chloro-1H- imidazo[4,5- b]pyridin-1yl)methyl)benzonitrile Ή NMR (400 MHz, DMSO-d ₆ ): δ 11.74 (s, 1H), 7.93 (d, J=5.l Hz, 1H), 7.82 (d, J=7.9 Hz , 2H), 7.49 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.5 Hz, 1H), 6.99 (dd, J=7.7, 5, 1Hz, 1H), 5.14(s, 2H) 251.2

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89 NC L Ύ T />s Χί^Ν 4-((2-chloro-6-fluoro1Ηbenzo[d]imidazol- 1yl)methyl)benzonitrile Ή NMR (400 MHz, DMS0-d ₆ ): δ 7.87-7.81 (m, 2H), 7.71-7.59 (m, 2H), 7.39-7.33 (m, 2H ), 7.15 (ddd, J=10.0, 8.9, 2.5 Hz, 1H), 5.64 (s, 2H) 286.0 90 NS h o 4-((2-chloro-1Ηimidazo[4,5c]pyridin-1yl)methyl)benzonitrile - 269.2 91 NC h ν-^γ-ν II ΙΉ Χί^Ν 4-((2-chloro-3Nimidazo[4,5c]pyridin-3yl)methyl)benzonitrile - 269.2 92 NC h h 4-((2,4-dichloro-1Hbenzo[<1]imidazole- 1yl)methyl)benzonitrile Ή NMR (400 MHz, DMS0-d ₆ ): δ 7.87-7.80 (m, 2H), 7.65-7.58 (m, 1H), 7.42-7.27 (m, 4H ), 5.70 (d, J=2.8 Hz, 2H) 302.1 93 NC 3 y Τ A ¹ Αί^Ν 4-((2-chloro-3Nimidazo[4,5b]pyridin-3yl)methyl)benzonitrile ^X H NMR (400 MHz, DMS0-d ₆ ): δ 8.41 (dd, J=4.7, 2.0 Hz, 1H), 8.13 (dt, J=8.l, 1.7 Hz , 1H), 7.83 (dd, J=8.3, 2.3 Hz, 2H), 7.46-7.34 (m, 3H), 5.64 (d, J=2.2 Hz, 2H) 269.0 94 α /Άί ίτ A Χ^Ν 4-((2,7-dichloro-1 Hbenzo[c1]imidazole- 1yl)methyl)benzonitrile 1H NMR (400 MHz, DMS0-d6): δ 7.84 (d, J=8.l Hz, 2H), 7.69 (dd, J=7.8, 1.1 Hz, 1H), 7, 36 (dd, J=7.9, 1.2 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.25 (d, J=8.1 Hz, 2H), 302.1

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5.89 (s, 2H) 95 NC c 4-((2-Chloro-6methoxy-1Hbenzo[d]imidazol1yl)methyl)benzonitrile - 298.2 96 NC c MeO N n ΧΧ-Ν 4-((2-Chloro-5-methoxy-3nimidazo[4,5b]pyridin-3yl)methyl)benzonitrile - 299.2 97 yr Q 4-((2-Chloro-4methoxy-1Hbenzo[d]imidazol1yl)methyl)benzonitrile Ή NMR (400 MHz, DMSO-d ₆ ): δ 7.87-7.80 (m, 2H), 7.36-7.27 (m, 2H), 7.26-7.14 (m, 2H ), 6.81 (dd, J=7.7, 1.3 Hz, 1H), 5.62 (s, 2H), 3.93 (s, 3H) 298.2 98 NC 5 ί T /> -C1 4-((2,5-dichloro- 1Hbenzo[c1]imidazole- 1yl)methyl)benzonitrile ... 302.2

Scheme 12 Conversion of benzylated intermediates to NC end products

^R3

^R2

R-E A, Ά' p

Intermediates 86-98 iPr ₂ EtN, DMSO or w-butanol

Step 1 4-((2,6-dichloro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile.

To a suspension of 4-((2,6-dichloro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile (50 mg, 0.165 mmol, 1 eq) and tert-butyl((3R,4R)-4 -fluoropiperidin-3-yl)carbamate (72.2 mg, 0.331 mmol, 2 eq.) in 1-butanol (662 μl, 0.25 M) DIEA (43.4 μl, 0.248 mmol, 1 .5 equiv.). The vial was heated to 130°C for 12 hours. The reaction mixture was cooled to room temperature, concentrated and loaded onto a 12 g RediSep ISCO cartridge eluting with 20-80% ethyl acetate in heptane to give t-butyl((3R,4R)- 1-(6-Chloro-1-(4-cyanobenzyl)-1Hbenzo[d]imidazol-2-yl)-4-fluoropiperidin-3-yl)carbamate (40 mg, 49.9% yield) as white solid . MS (ESI positive ion) mass/charge: 484.0 (M+H).

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Step 2 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile.

To a solution of tert-butyl ((3R,4R)-1-(6-chloro-1-(4-cyanobenzyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-yl)carbamate (40 mg , 0.083 mmol, 1 eq.) in 1,4-dioxane (1 ml) was added 4N. HCl in dioxane (0.517 ml, 2.066 mmol, 25 eq.). The reaction mixture was stirred at ambient temperature for 6 hours after which the reaction mixture was concentrated to give 4-((2-((3R,4R)-3amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo [d]imidazol-1-yl)methyl)benzonitrile hydrochloride as a white solid. 1 H NMR (400 MHz, DMSO-d ₆ ) 8.78 (br s, 2H), 7.87-7.80 (m, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.49-7.35(m, 3H), 7.31-7.21(m, 1H), 5.65-5.49(m, 2H), 5.05-4.91(m, 1H ), 3.95 (br d, J=12.3 Hz, 1H), 3.79-3.61 (m, 1H), 3.52-3.44 (m, 1H), 3.35-3 .22 (m, 1H), 3.12 (br t, J=11.5 Hz, 1H), 2.32-2.15 (m, 1H), 1.99-1.79 (m, 1H) . MS (ESI positive ion) mass/charge: 384.0 (M+H).

Table 8

Examples obtained in a manner similar to Schemes 11-12

Note. No. Benzimidazole Intermediate Amine Structure Connection name MS MN+ noe compound 401 86 6 ⁱⁿ "n" F BUT AyNHj Chg hch sg 4-((2-((3R,4S)-3amino-4fluoropiperidin-1-yl)6-chloro-1Hbenzo[<1]imidazol-1yl)methyl)benzonitrile a hydrochloride 384.0 402 95 .4 „NHBoc ' Oh ...... well (S)-4-((2-(3aminopiperidin-1 yl)-6-methoxy-1Hbenzo[<1]imidazol-1yl)methyl)benzonitrile a hydrochloride 362.0 403 95 n O'MeO ⁷ 4-((2-((3R,4S)-3amino-4fluoropiperidin-1-yl)6-methoxy-1Hbenzo[(1]imidazol-1yl)methyl)benzonitrile 380.0 404 95 „NHBoc fl Learn no I 1 MeO ⁷ (S)-4-((2-(3aminopiperidin-1 yl)-5-methoxy-3nimidazo[4,5b]pyridin-3yl)methyl)benzonitrile a hydrochloride 363.0 405 86 ZhinV" n sg (R)-4-((2-(3-amino-4,4difluoropiperidin-1 yl)-6-chloro-1Hbenzo[<1]imidazol-1yl)methyl)benzonitrile 402.0

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406 95 at Η & PH \ . (R)-4-((2-(3-amino-4,4difluoropiperidin-1 yl)-6-methoxy-1Hbenzo[<1]imidazol-1 yl)methyl)benzonitrile 398.0 407 92 F ΛήΗΒοο Η G& (R)-4-((2-(3-amino-4,4difluoropiperidin-1 yl)-4-chloro-1Hbenzo[<1]imidazol-1 yl)methyl)benzonitrile 402.0 408 92 F Ll Η 0"' MX 4-((2-((3 R,4R)-3amino-4fluoropiperidin-1 -yl)4-chloro-1Hbenzo[<1]imidazol-1 yl)methyl)benzonitrile 384.0 409 92 F J. „NHBoc τ er 4-((2-((3R,4S)-3amino-4fluoropiperidin-1-yl)4-chloro-1Hbenzo[<1]imidazol-1 yl)methyl)benzonitrile 384.0 410 97 / .„NHBoc Chg Η FF 0 ^Λ (R)-4-((2-(3-amino-4,4difluoropiperidin-1 yl)-4-methoxy-1Hbenzo[<1]imidazol-1 yl)methyl)benzonitrile 398.0 411 97 F T.NHBOC H 0' <8- 4-((2-((3R,4R)-3amino-4fluoropiperidin-1-yl)4-methoxy-1Hbenzo[<1]imidazol-1 yl)methyl)benzonitrile 380.2

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412 90 F JL ₀ NHBoc n NC 4 a: o- n.h. 4-((2-((3 R,4R)-3amino-4fluoropiperidin-1-yl)1H-imidazo[4,5c]pyridin-1yl)methyl)benzonitrile 351.2 413 91 F ^NHBoc T NC 4 aco NH ₂ 4-((2-((3R,4R)-3amino-4fluoropiperidin-1-yl)3H-imidazo[4,5c]pyridin-3yl)methyl)benzonitrile 351.2 414 87 F JL ₄ NHBoc n 4-((2-((3 R,4R)-3amino-4-fluoro-1piperidinyl)-6ethoxy-1H- benzimidazol-1yl)methyl)benzonitrile 394.2 415 88 F ίΓ at nh ₂ 4-((2-((3R,4S)-3amino-4fluoropiperidin-1-yl)1H-imidazo[4,5b]pyridin-1yl)methyl)benzonitrile 351.2 416 89 F ..NHBoc Sr H 4 4-((2-((3R)-3-amino4, 4-difluoro-1piperidinyl)-6-fluoro1 H-benzimidazol-1 yl)methyl)benzonitrile 386.2 417 88 F JL _it NHBoc V NC q ayu W ₂ 4-((2-((3R,4R)-3- amino-4fluoropiperidin-1-yl)1H-imidazo[4,5b]pyridine-1- 351.2

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yl)methyl)benzonitrile 418 92 ex H NC About A HO^^CF cao Ji * (S)-4-((2-(3aminopiperidin-1 yl)-4-chloro-1Hbenzo[(1]imidazol-1yl)methyl)benzonitrile -2,2,2-trifluoroacetate 366.0 419 93 Λ ^NHBoc τ NC About NC. Γ ^Ν Χ GA CtuQ 'NF (S)-4-((2-(3aminopiperidin-1 yl)-3H-imidazo[4,5b]pyridin-3yl)methyl)benzonitrile a hydrochloride 333.2 420 86 F JL.NHBoc T NC 3 TDAO HCI 4-((2-((3R,4R)-3amino-4fluoropiperidin-1-yl)6-chloro-1Hbenzo[c!]imidazol-1yl)methyl)benzonitrile a hydrochloride 384.2 421 86 ex H NC 3.. OcaO 'nh ₂ (S)-4-((2-(3aminopiperidin-1 yl)-6-chloro-1Hbenzo[c1]imidazol-1yl)methyl)benzonitrile 366.2 422 98 ^.NHBoc n NC X 'nh ₂ (S)-4-((2-(3aminopiperidin-1 yl)-5-chloro-1Hbenzo[c1]imidazol-1yl)methyl)benzonitrile 366.2

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Table 9

Characterization data for compounds prepared according to Schemes 11-12

Note. No. Frequency, Solvent W NMR data (δppm) 401 400MHz d ₆ -DMSO 8.57 (br s, 2H), 7.81-7.86 (m, 1H), 7.83 (d, 7=7.30 Hz, 1H), 7.507.55 (m, 1H), 7. 40-7.43 (m, 1H), 7.34-7.39 (m, 2H), 7.23 (dd, 7=1.92, 8.34 Hz, 1H), 5.49-5, 60 (m, 2H), 5.22-5.04 (m, 1H), 3.613.69 (m, 4H), 3.34-3.44 (m, 1H), 3.22-3.31 ( m, 1H), 3.08-3.22 (m, 1H), 2.05-2.16 (m, 1H), 1.93-2.05 (m, 1H) 402 400MHz d ₆ -DMSO 8.45 (br s, 3H), 7.87 (d, 7=8.29 Hz, 2H), 7.49 (t, 7=8.91 Hz, 3H), 6.95-7.02 ( m, 2H), 5.56-5.72 (m, 2H), 3.72 (s, 3H), 3.37 (br d, 7=7.67 Hz, 4H), 3.12 (br t , 7=10.05 Hz, 1H), 1.97 (br d, 7=8.40 Hz, 1H), 1.88 (br dd, 7=3.63, 9.64 Hz, 1H), 1 .62-1.70 (m, 1H), 1.56 (br dd, 7=4.09, 9.38 Hz, 1H) 403 400MHz d ₆ -DMSO 7.80 (d, 7=8.29 Hz, 2H), 7.27-7.37 (m, 3H), 6.81 (d, 7=2.38 Hz, 1H), 6.73 (dd , 7=2.44, 8.66 Hz, 1H), 5.40 (s, 2H), 4.66-4.87 (m, 1H), 3.68 (s, 3H), 3.14- 3.21 (m, 2H), 3.00-3.10 (m, 3H), 2.90-2.99 (m, 2H), 1.81-2.05 (m, 2H) 404 400MHz d ₆ -DMSO 8.40 (br s, 3H), 7.79-7.89 (m, 3H), 7.52 (d, 7=7.98 Hz, 2H), 6.75 (d, 7=8.60 Hz, 1H), 5.45-5.59 (m, 2H), 3.79 (s, 3H), 3.64-3.76 (m, 1H), 3.48 (br dd, 7=4 .25, 11.30 Hz, 2H), 3.21-3.31 (m, 1H), 3.00 (br t, 7=10.21 Hz, 1H), 1.93-2.02 (m , 1H), 1.80-1.93 (m, 1H), 1.46-1.69 (m, 2H) 405 400MHz d ₆ -DMSO 7.82 (d, 7=7.88 Hz, 2H), 7.47 (d, 7=8.40 Hz, 1H), 7.29-7.35 (m, 3H), 7.14 (d , 7=8.50 Hz, 1H), 5.49 (s, 2H), 3.26-3.40 (m, 2H), 3.08-3.24 (m, 2H), 2.93- 3.05 (m, 1H), 2.18-2.32 (m, 1H), 1.902.15 (m, 1H), 1.77 (br s, 2H) 406 400MHz d ₆ -DMSO 7.80 (d, 7=7.67 Hz, 2H), 7.28-7.39 (m, 3H), 6.82 (s, 1H), 6.74 (br d, 7=8.71 Hz, 1H), 5.44 (s, 2H), 3.68 (s, 3H), 3.19-3.29 (m, 2H), 3.08-3.18 (m, 2H), 2 .86-3.01 (m, 1H), 2.17-2.31 (m, 1H), 1.922.14 (m, 1H), 1.76 (br s, 2H) 407 400MHz d ₆ -DMSO 7.78-7.83 (m, 7=8.29 Hz, 2H), 7.31-7.36 (m, 7=8.40 Hz, 2H), 7.16 (dd, 7=0, 83, 13.06 Hz, 1H), 7.18 (br dd, 7=0.83, 12.85 Hz, 1H), 7.02-7.09 (m, 1H), 5.50 (s, 2H), 3.34-3.46(m, 2H), 3.00-3.26(m, 3H), 2.21-2.35(m, 1H), 1.98-2.16( m, 1H), 1.78 (brs, 2H) 408 400MHz d ₆ -DMSO 7.78-7.83 (m, 7=8.29 Hz, 2H), 7.28-7.34 (m, 7=8.29 Hz, 2H), 7.17 (t, 7=6, 59 Hz, 2H), 6.99-7.08(m, 1H), 5.46(s, 2H), 4.39-4.51(m, 1H), 4.29-4.36(m , 1H), 4.25-4.54 (m, 1H), 3.34-3.53 (m, 3H),

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3.02-3.10 (m, 1H), 2.91-3.02 (m, 1H), 2.80-2.90 (m, 1H), 2.02- 2.16(m, 2H), 1.76-1.85(m, 1H) 409 400MHz d ₆ -DMSO 7.77-7.83 (m, 7=8.40 Hz, 2H), 7.26-7.36 (m, 7=8.40 Hz, 2H), 7.16 (t, 7=8, 41 Hz, 2H), 7.00-7.07(m, 1H), 5.46(s, 2H), 4.80-4.88(m, 1H), 4.69-4.75(m , 1H), 4.68-4.89 (m, 1H), 3.26-3.41 (m, 3H), 3.10-3.25 (m, 2H), 2.95-3.07 (m, 2H), 1.84-2.12 (m, 2H) 410 400MHz d ₆ -DMSO 7.77-7.82 (m, 7=8.40 Hz, 2H), 7.27-7.33 (m, 7=8.29 Hz, 2H), 7.00 (t, 7=8, 03 Hz, 1H), 6.78 (d, 7=7.57 Hz, 1H), 6.69 (d, 7=7.77 Hz, 1H), 5.44 (s, 2H), 3.89 (s, 3H), 3.38-3.59 (m, 3H), 3.31-3.21 (m, 2H), 3.02-3.20 (m, 2H), 2.08-2 .36 (m, 2H) 411 400MHz d ₆ -DMSO 7.75-7.83 (m, 2H), 7.22-7.33 (m, 7=8.40 Hz, 2H), 6.97 (t, 7=7.85 Hz, 1H), 6 .78 (d, 7=7.46 Hz, 1H), 6.67 (d, 7=7.98 Hz, 1H), 5.40 (s, 2H), 4.24-4.47 (m, 1H), 3.89 (s, 3H), 3.11-3.41 (m, 4H), 2.88-3.08 (m, 2H), 2.77 (dd, 7=8.71, 12.44Hz, 1H), 1.92-2.15(m, 1H), 1.611.87(m, 2H) 412 500MHz d ₄ -MeOH 8.69 (s, 1H), 8.20 (d, 7=5.45 Hz, 1H), 7.72 (d, 7=8.30 Hz, 2H), 7.33 (d, 7=8 .04Hz, 2H), 7.24(d, 7=5.71Hz, 1H), 5.51(s, 2H), 4.34-4.55( _m , 1H), 3.61-3.69 (m, 1H), 3.47-3.54 (m, 1H), 3.073.22 (m, 2H), 3.01 (br dd, 7=9.08, 12.46 Hz, 1H), 2 .05-2.28 (m, 1H), 1.80-1.95 (m, 1H) 413 500MHz d ₄ -MeOH 8.34 (d, 7=0.78 Hz, 1H), 8.26 (d, 7=5.45 Hz, 1H), 7.74 (d, 7=8.56 Hz, 2H), 7. 50 (dd, 7=0.91, 5.58 Hz, 1H), 7.36 (d, 7=8.56 Hz, 2H), 5.53 (s, 2H), 4.33-4.50 (m, 1H), 3.66-3.75 (m, 1H), 3.54-3.64 (m, 1H), 3.17-3.26 (m, 1H), 2.99-3 .12 (m, 2H), 2.11-2.22 (m, 1H), 1.80-1.94 (m, 1H) 414 600MHz DMSO-d ₆ 7.81(d, 7=8.33Hz, 2H), 7.28-7.34(m, 3H), 6.81(d, 7=2.34Hz, 1H), 6.71(d , 7=8.92 Hz, 1H), 5.35-5.43 (m, 2H), 4.25-4.43 (m, 1H), 3.89-3.95 (m, 2H), 3.29-3.32(m, 1H), 3.21-3.29(m, 1H), 2.90-3.00(m, 2H), 2.74(dd, 7=8.68 , 12.42 Hz, 1H), 1.97-2.10 (m, 1H), 1.71-1.89 (m, 2H), 1.23-1.29 (m, 3H) 415 600MHz DMSO-d ₆ 8.07 (dd, 7=1.40, 4.90 Hz, 1H), 7.77-7.83 (m, 3H), 7.38 (d, 7=8.49 Hz, 2H), 7 .17 (dd, 7=4.90, 7.86 Hz, 1H), 5.46 (s, 2H), 4.76-4.83 (m, 0.5H), 4.68-4.73 (m, 0.5H), 3.21-3.29 (m, 2H), 3.08-3.20 (m, 1H), 2.89-3.02 (m, 2H), 1.80 -2.00(m, 2H)

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416 600MHz DMSO-d ₆ 7.78-7.83 (m, /=8.43 Hz, 2H), 7.46 (dd, /=4.93, 8.69 Hz, 1H), 7.30-7.35 (m, /=8.30 Hz, 2H), 7.14 (dd, /=2.47, 9.21 Hz, 1H), 6.96 (ddd, /=2.53, 8.69, 10.06 Hz , 1H), 5.46 (s, 2H), 3.28 (br d, /=6.36 Hz, 1H), 3.10-3.21 (t, 2H), 2.93-3.01 (t, 1H), 2.19-2.35 (t, 1H), 1.91-2.13 (t, 1H), 1.80 (br s, 2H) 417 500MHz d ₄ -MeOH 8.25 (d, J=4.93 Hz, 1H), 7.74 (d, J=8.04 Hz, 2H), 7.54 (d, J=7.79 Hz, 1H), 7. 36 (d, J=8.30 Hz, 2H), 7.13 (dd, J=5.06, 7.91 Hz, 1H), 5.50 (s, 2H), 4.36-4.54 (m, 1H), 3.69-3.78 (m, 1H), 3.51-3.64 (m, 1H), 3.18-3.26 (m, 1H), 3.09-3 .17 (m, 1H), 3.05 (dd, J=9.08, 12.72 Hz, 1H), 2.12-2.23 (m, 1H), 1.81-1.96 (m , 1H 418 400MHz d ₆ -DMSO 8.02 (br s, 3H), 7.82 (d, /=7.98 Hz, 2H), 7.31 (d, /=7.98 Hz, 2H), 7.20 (d, /= 7.77 Hz, 1H), 7.15 (d, J=7.98 Hz, 1H), 7.00-7.10 (m, 1H), 5.38-5.55 (m, 2H), 3.64 (br d, /=12.02 Hz, 1H), 3.07-3.27 (m, 2H), 2.85-2.97 (m, 1H), 1.98 (br d, /=9.23 Hz, 1H), 1.75-1.87 (m, 1H), 1.49-1.67 (m, 2H) 419 400MHz d ₆ -DMSO 8.39 (br s, 3H), 8.20 (d, /=4.98 Hz, 1H), 7.90 (d, /=7.87 Hz, 1H), 7.84 (d, /= 7.89 Hz, 2H), 7.47 (d, /=7.91 Hz, 2H), 7.31 (dd, /=4.99, 7.85 Hz, 1H), 5.48-5, 68 (m, 2H), 3.84 (br d, /=11.72 Hz, 1H), 3.28-3.42 (m, 2H), 3.01-3.10 (m, 1H), 1.93-2.06(m, 1H), 1.78-1.90(m, 1H), 1.48-1.72(m, 2H) 420 400MHz d ₆ -DMSO 8.78 (br s, 2H), 7.87-7.80 (m, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.497.35 (m, 3H), 7. 31-7.21 (m, 1H), 5.65-5.49 (m, 2H), 5.05-4.91 (m, 1H), 3.95 (br d, J=12.3 Hz , 1H), 3.79-3.61 (m, 1H), 3.52 - 3.44 (m, 1H), 3.35-3.22 (m, 1H), 3.12 (br t, J=11.5 Hz, 1H), 2.32-2.15 (m, 1H), 1.99-1.79 (m, 1H) 421 400MHz d ₆ -DMSO 7.82 (d, J=8.09 Hz, 2H), 7.46 (d, J=8.50 Hz, 1H), 7.25-7.35 (m, 3H), 7.13 (dd , J=l.66, 8.29 Hz, 1H), 5.39-5.51 (m, 2H), 4.04-4.14 (m, 1H), 3.48-3.57 (m , 1H), 3.20-3.26 (m, 1H), 2.81-3.02 (m, 2H), 1.86-1.98 (m, 1H), 1.69-1.83 (m, 1H), 1.37-1.62 (m, 2H) 422 400MHz d ₆ -DMSO 8.34 (br d, J=1.04 Hz, 3H), 7.82 (d, J=8.29 Hz, 2H), 7.51 (d, J=7.88 Hz, 1H), 7 .34 (d, J=8.29 Hz, 2H), 7.05-7.23 (m, 3H), 5.445.52 (m, 2H), 5.06 (br d, J=2.90 Hz , 1H), 3.78-3.88 (m, 1H), 3.733.92 (m, 1H), 3.52-3.61 (m, 1H), 3.33-3.43 (m, 1H ), 3.12-3.26 (m, 2H), 1.96-2.16 (m, 2H)

Scheme 13

Mesylate transfer chemistry

R

VlH ₂

Example 425: (3K,4K)-4-fluoro-1-(1-((5-methoxypyridin-2-yl)methyl)-1 H-benzo[b]imidazol-2yl)piperidine-3-amine

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NHBoc NHBoc

Step 1. tert-Butyl((3K,4K)-4-fluoro-1-(1-(methylsulfonyl)-1H-benzo[b]imidazol-2-yl)piperidin3-yl)carbamate.

tert-Butyl ((3K,4K)-1-(1H-benzo[b]imidazol-2-yl)-4-fluoropiperidin-3-yl)carbamate (Intermediate 54, 156 mg, 0.467 mmol) was dissolved in DCM ( 2.3 ml). The mixture was treated with methanesulfonyl chloride (100 μl, 0.700 mmol, 2 eq.) and anhydrous triethylamine (197 μl, 1.400 mmol). The resulting yellow solution was allowed to stir overnight. The reaction mixture was quenched with NH ₄ C1 (aq), diluted with DCM, extracted into DCM, dried over MgSO ₄ , filtered, concentrated to give the crude oil. The oil was purified by column chromatography (25 g SiO ₂ , 0-45% ethyl acetate in heptane) to give tert-butyl((3R,4K)-4fluoro-1-(1-(methylsulfonyl)-1H-benzo[b]imidazole -2-yl)piperidin-3-yl)carbamate as a colorless solid. (ESI, put, ion) mass/charge: 413.2 [M+1].

Meo

'NHBoc

Stage 2. tert-Butyl ((ZK,4K) -4-fluoro-1- (1- ((5-methoxypyridin-2-yl) methyl) -1H-benzo[b] imidazol-2yl) piperidin-3 -yl ) carbamate.

The vial was loaded with (S)-l-(l-(methylsulfonyl)-1H-benzo[b]imidazol-2-yl)piperidin-3-amine (150 mg, 0.38 mmol), 1-hydroxy-2.3 -dihydro- 1H-indene-5-carbonitrile (67 mg, 1.1 eq.) and Cs ₂ CO ₃ (150 mg, 1.2 eq.). The vial was fitted with a stirrer, capped and MeCN (1.3 ml) was added. The mixture was placed in a heating block set at 90° C. for 18 hours. The reaction mixture was diluted with EIO Ac and NH ₄ C1( _BOAH ) and the mixture was extracted into EIO Ac. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated to give the crude reaction product. The crude material was purified by column chromatography (4 g SiO ₂ , 0-30% EIU Ac in heptane) to give tert-butyl((3K,4K)-4-fluoro-1-(1-((5-methoxypyridine-2 -yl)methyl)-1 H-benzo[d]imidazol-2yl)piperidin-3-yl)carbamate as a colorless oil. (ESI, posit, ion) mass/charge: 456.2 [M+1].

Step 3. (3K,4K)-4-fluoro-1-(1-((5-methoxypyridin-2-yl)methyl)-1H-benzo[b]imidazol-2yl)piperidine-3-amine (Example 425) .

tert-Butyl ((ZK,4K)-4-fluoro-1-(1-((5-methoxypyridin-2-yl)methyl)-1H-benzo[0]imide azol-2yl)piperidin-3-yl)carbamate (32 mg, 1 eq.) was dissolved in DCM (5 ml). HCl in dioxane (10 eq.) was added and the mixture was allowed to stir overnight. The solution was concentrated, then purified using reverse phase HPLC to give the title compound. ^L H NMR (600 MHz, d ₆ -DMSO) δ 7.79 (s, 1H), 7.50 (t, >7.53 Hz, 2H), 7.11 (t, >7.66 Hz, 1H ), 6.96 (d, >7.79 Hz, 1H), 6.886.94 (m, 1H), 6.39-6.49 (m, 1H), 6.19 (t, >8.95 Hz , 1H), 3.54-3.62 (m, 1H), 3.36-3.43 (m, 1H), 3.18-3.24 (m, 3H), 3.00-3.13 (m, 2H), 2.74-2.87 (m, 1H), 2.52-2.63 (m, 1H), 1.91-2.12 (m, 2H), 1.77-1 .89 (m, 1H), 1.47-1.56 (m, 1H). (ESI, posit, ion) mass/charge: 356.2 [M+1].

Table 10

Compounds obtained according to scheme 13 and similarly to the preparation of example 425

Note. No. Alcohol Structure Connection name MS MH+ 423 NC NC % νη ₂ (R)-l-(2-((S)-3aminopiperidin-1 -yl)1 H-benzo[c1] imidazol-1 yl)-2,3-dihydro-1 H-indene5-carbonitrile 358.2

-330043189

424 NC But NC a>o yn ₂ (S)-l-(2-((S)-3aminopiperidin-1 -yl)1 H-benzo[c1] imidazol-1 yl)-2,3-dihydro-1 H-indene5-carbonitrile 358.2 425 c but U o m O (3R,4C)-4-fluoro-1-(1-((5methoxypyridin-2yl)methyl)-1Hbenzo[b]imidazol-2yl)piperidine-3-amine 356.2

Table 11

Characterization data for compounds prepared according to Scheme 13

Note. No. frequency, solvent spruce W NMR data (δppm) Stage divided by nya SFC Terms FOR separating isomers 423 500MHz d ₄ -MeOH 7.79 (s, 1H), 7.50 (t, 7=7.53 Hz, 2H), 7.11 (t, 7=7.66 Hz, 1H), 6.96 (d, 7=7 .79 Hz, 1H), 6.88-6.94 (m, 1H), 6.39-6.49 (m, 1H), 6.19 (t, 7=8.95 Hz, 1H), 3.543 .62 (m, 1H), 3.36-3.43 (m, 1H), 3.183.24 (m, 3H), 3.00-3.13 (m, 2H), 2.742.87 (m, 1H ), 2.52-2.63 (m, 1H), 1.912.12 (m, 2H), 1.77-1.89 (m, 1H), 1.471.56 (m, 1H) IN Phenomenex Lux Cellulose2, 30% MeOH, Chiralcel OD, 25% MeOH, peak 1 424 500MHz d ₄ -MeOH 7.79 (s, 1H), 7.49 (dd, 7=7.91, 11.03 Hz, 2H), 7.06-7.14 (m, 1H), 6.86-6.96 ( m, 2H), 6.45 (br d, 7=5.71 Hz, 1H), 6.19 (br t, 7=8.95 Hz, 1H), 3.53-3.62 (m, 1H ), 3.35-3.44 (m, 2H), 3.11-3.24 (m, 3H), 2.81-2.96 (m, 2H), 2.51-2.65 (m , 1H), 1.90-2.10 (m, 2H), 1.73-1.88 IN Phenomenex Lux Cellulose2, 30% MeOH, peak 3 (m, 1H), 1.42-1.53 (m, 1H) 425 600MHz d ₆ -DMSO 8.22 (d, 7=2.80 Hz, 1H), 7.42 (d, 7=7.79 Hz, 1H), 7.37 (dd, 7=3.11, 8.72 Hz, 1H ), 7.17 (d, 7=8.72 Hz, 1H), 7.11 (d, 7=7.79 Hz, 1H), 7.04-7.09 (m, 1H), 6.98 -7.03 (m, 1H), 5.31 (s, 2H), 4.324.47 (m, 1H), 3.79 (s, 3H), 3.40-3.52 (m, 2H), 2.96-3.09 (m, 2H), 2.84 (dd, 7=8.72, 12.46 Hz, 1H), 2.04-2.14 (m, 1H), 1.73- 1.84(m, 1H) - -

- 331 043189

Scheme 14 Compounds obtained by peptide coupling

LiOH. MeCN

NHBOC

1) amine, .HATUnh ₂

CN < Cs ₂ CO ₃ , MeCN NHBoc

\n ₂

Example 426: 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)acetyl )azetidine-3-carbonitrile

Step 1. Methyl-2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6difluoro-1 H-benzo[d]imidazol- 1-yl)acetate.

The vial was loaded with tert-butyl ((3R,4R)-1-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-yl)carbamate (0.3 g, 0.810 mmol ) Cs ₂ CO ₃ (0.792 g, 2.430 mmol) in acetonitrile (2.70 ml) and methyl 2-bromoacetate (0.149 g, 0.972 mmol) and shaken on a J-Kem block for 16 h. Celite® brand filter media and purified by reverse phase HPLC to give methyl 2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4fluoropiperidin-1-yl)-5.6 -difluoro-1H-benzo[d]imidazol-1-yl)acetate. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.56 (t, J=9.06 Hz, 1H), 7.51 (t, J=8.85 Hz, 1H), 7.19 (br d, J=8.25 Hz, 1H), 4.94-5.03 (m, 2H), 4.51-4.59 (dt, J=4.63, 9.01 Hz, 1H), 3 .68-3.77 (m, 3H), 3.35-3.46 (m, 2H), 3.24-3.30 (m, 1H), 2.95 (br t, J=10.63 Hz, 1H), 2.73-2.89 (m, 1H), 2.13-2.21 (m, 1H), 1.79-1.89 (m, 1H), 1.39 (s, 9H). MS: (ESI positive ion) mass/charge: 443.2 [M+1].

Step 2. 2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6-difluoro-1Hbenzo[d]imidazol-1-yl )acetic acid.

Methyl-2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6-difluoro-1Hbenzo[d]imidazol-1-yl) the acetate was saponified using LiOH (0.097 g, 4.05 mmol) in dioxane (1 ml) and water (1 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was acidified using acetic acid and the resulting off-white precipitate was filtered to give 2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino) -4-fluoropiperidin-1-yl)-5,6difluoro-1H-benzo[d]imidazol-1-yl)acetic acid. MS: (ESI positive ion) mass/charge: 429.2 [M+1].

CN

HN

HATU, DIEA, DMSO\, _U n 25 C, 4 pm

NHBoc

Oh

HN-Boc

Step 3. tert-Butyl((3R,4R)-1-(1-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-5,6-difluoro-1Hbenzo[d]imidazol-2- yl)-4-fluoropiperidin-3-yl)carbamate.

2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6-difluoro-1Hbenzo[d]imidazol-1-yl)acetic solution acid (0.015 g, 0.035 mmol), 3-cyanoazetidine hydrochloride (4.15 mg, 0.035 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.013 g, 0.035 mmol) in dimethyl sulfoxide (0.117 ml) and DIPEA (0.024 ml, 0.140 mmol) were shaken at ambient temperature. The reaction mixture was purified by reverse phase HPLC to give t-butyl((3R,4R)-1-(1-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-5,6-difluoro- 1 H-benzo[d]imidazol-2-yl)- 332 043189

4-fluoropiperidin-3-yl)carbamate. MS: (ESI positive ion) mass/charge: 493.2 [M+1].

Step 4. 1-(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1yl)acetyl)azetidine -3-carbonitrile (example 426).

tert-Butyl ((3R,4R)-1-(1-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-5,6-difluoro-1H-benzo[d]imidazol-2yl)- 4-fluoropiperidin-3-yl)carbamate was treated with TFA (0.5 ml) in DCM (0.5 ml). The mixture was concentrated and purified using reverse phase HPLC to give the title compound. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.34-7.60 (m, 2H), 4.73-4.80 (m, 2H), 4.48-4.60 (m, 2H ), 4.31-4.48 (m, 1H), 4.17-4.28 (m, 1H), 4.06-4.15 (m, 1H), 3.82-3.94 (m , 1H), 2.96-3.06 (m, 2H), 2.74-2.84 (m, 1H), 2.06-2.17 (m, 1H), 1.64-1.88 (m, 3H). MS: (ESI positive ion) mass/charge: 393.2 [M+1].

The following compounds were prepared according to a procedure similar to that described for Example 426 and General Scheme 14 above.

Table 12

Compounds obtained according to scheme 14

Note. No. Amine Structure Connection name MS MN+ 426 HCI CNύ O=S n.h. 1-(2-(2-((3 R,4R)-3-aMHHO-4fluoropiperidin-1 -yl)-5,6difluoro-1Нbenzo[d]imidazol-1 yl)acetyl)azetide in-3 carbonitrile 393.2 427 J _F % ACR nh ₂ 2-(2-((3R,4R)-3-aMHHO-4fluoropiperidin-1-yl)-5,6difluoro-1Нbenzo[(1]imidazol-1-yl)-1 (3-(tert-butoxy)azetidine1- yl) ethane-1-one 440.2

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428 n _F3NH ; 2-(2-((3R,4R)-3-aMHHO-4fluoropiperidin-1-yl)-5,6difluoro-1Нbenzo[(1]imidazol-1-yl)-1 (3,3-difluoroazetidin-1-yl) ethanone 404.2 429 Ϊ n X :χϊη>'ΝΗ _: 2-(2-((3R,4R)-3-aMHHO-4fluoropiperidin-1-yl)-5,6difluoro-1H6eH3o[d]imidazol-1-yl)-1(3-isopropylazetidin-1-yl)ethanone 410.2 430 n _F 3 hH ₂ 2-(2-((3R,4R)-3-aMHHO-4fluoropiperidin-1 -yl)-5,6difluoro-1H- 6eH3o[d]imidazol-1 -yl)-1 (6,6-difluoro-2azaspiro[3.3 ]heptan-2yl)ethanone 444.2 431 Mr. $ .•f I 1 F X _F XN 4 1h n _g 2-(2-((3R,4R)-3-aMHHO-4fluoropiperidin-1 -yl)-5,6difluoro-1H- 6eH3o[d]imidazol-1 -yl)-1 (7-oxa-2azaspiro[3.5]nonan-2yl)ethanone 438.2

Table 13

Characterization data for compounds prepared according to Scheme 14

Note. No. frequency, solvent spruce W NMR data (δ ppm) Stage divided by nya SFC Terms FOR separating isomers 426 600MHz DMSO-d ₆ 7.34-7.60 (m, 2H), 4.73-4.80 (m, 2H), 4.48-4.60 (m, 2H), 4.31-4.48 (m, 1H), 4.17-4.28 (m, 1H), 4.06-4.15 (m, 1H), - -

- 334 043189

3.82-3.94(m, 1H), 2.96-3.06(m, 2H), 2.74-2.84(m, 1H), 2.06-2.17(m, 1H ), 1.64-1.88 (m, 3H). 427 600MHz DMSO-d ₆ 7.46 (dd, /=7.43, 11.17 Hz, 1H), 7.40 (dd, /=7.36, 10.39 Hz, 1H), 4.72-4.79 (m, 2H), 4.56-4.64 (m, 1H), 4.41-4.49 (m, 2H), 4.36 (br s, 1H), 4.16 (dd, /=7.20 , 9.77Hz, 1H), 4.08 (dt, /=4.98, 8.25Hz, 1H), 3.70 (dd, /=4.71, 10.00Hz, 1H), 2 .95-3.06 (m, 2H), 2.78 (ddd, /=5.02, 8.10, 12.73 Hz, 1H), 2.02-2.16 (m, 1H), 1 .89 (br s, 1H), 1.72-1.87 (m, 1H), 1.15 (s, 9H). -- - 428 600MHz DMSO-d ₆ 7.37-7.50(m, 2H), 4.87(s, 1H), 4.764.85(m, 2H), 4.34-4.47(m, 2H), 3.203.27(m, 1H), 3.14-3.19 (m, 1H), 2.983.11 (m, 2H), 2.87-2.97 (m, 1H), 2.79 (dd, /=8.37, 12.57 Hz, 1H), 2.03-2.18 (m, 1H), 1.96 (dt, /=4.67, 9.19 Hz, 1H), 1.78-1.91 (m , 1H) - - 429 600MHz DMSO-d ₆ 7.46 (dd, /=7.47, 11.13 Hz, 1H), 7.38 (dd, /=7.32, 10.67 Hz, 1H), 4.70-4.79 (m, 2H), 4.32-4.47 (m, 1H), 4.25-4.30 (m, 1H), 3.92-3.99 (m, 2H), 3.62 (dd, /= 5.92, 9.65 Hz, 1H), 3.34-3.43(m, 1H), 2.96-3.05(m, 2H), 2.76-2.82(m, 1H) , 2.31-2.47 (m, 1H), 2.08-2.16 (m, 1H), 1.74-1.91 (m, 3H), 0.86 (t, /=5, 57Hz, 6H) - - 430 600MHz DMSO-d ₆ 7.47 (t, /=9.20 Hz, 1H), 7.39 (dd, /=7.36, 10.70 Hz, 1H), 4.74 (d, /=1.79 Hz, 2H ), 4.32-4.46 (m, 3H), 4.03-4.10 (m, 2H), 3.37-3.54 (m, 1H), 2.92-3.05 (m , 3H), 2.88 (t, /=12.38 Hz, 4H), 2.74-2.83 (m, 1H), 2.11 (ddd, /=3.97, - - 8.10, 17.13 Hz, 1H), 1.74-1.93 (m, 1H). 431 600MHz DMSO-d ₆ 7.47 (dd, /=7.43, 11.17 Hz, 1H), 7.39 (dd, /=7.36, 10.70 Hz, 1H), 4.72-4.80 (m, 2H), 4.34-4.47 (m, 1H), 4,O2 (q, /=8.33 Hz, 2H), 3.69 (s, 2H), 3.463.59 (m, 4H), 3.34-3.36 (m, 1H), 2.963.06 (m, 2H), 2.80 (dd, /=8.21, 12.50 Hz, 1H), 2.08-2.16 ( m, 1H), 1.70-1.88 (m, 6H) -- -

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Example 432: (R)-6-((2-(4,4-difluoro-3-(methylamino)piperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile

The vial was loaded with (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol1-yl)methyl)nicotinonitrile (100mg, 0.259 mmol). The vial was fitted with a stirrer, capped and DMF (1.3 ml) was added. Potassium carbonate (53.7 mg, 0.388 mmol) was added followed by iodomethane (40.4 mg, 0.285 mmol). The mixture was allowed to stir at room temperature for 2 hours. The formation of mono- and bis-methylated amines was observed by LCMS. The reaction mixture was worked up by dilution with EtOAc and NH ₄ Cl (aq.). The mixture was extracted with EtOAc, the organic extracts were combined, dried over MgSO ₄ , filtered and concentrated to obtain a crude mixture. The crude material was purified by HPLC to give the title compound. MS: (ESI positive ion) mass/charge: 401.2 [M+1]; ¹ H NMR (600 MHz, d6-DMSO) δ 8.95 (dd, J=0.62, 2.18 Hz, 1H), 8.33 (dd, J=2.18, 8.10 Hz, 1H ), 7.51 (d, J=8.10 Hz, 1H), 7.46 (dd, J=4.98, 8.72 Hz, 1H), 7.11 (dd, J=2.49, 9.03 Hz, 1H), 6.95 (ddd, J=2.49, 8.72, 9.96 Hz, 1H), 5.54 (s,

2H), 3.35-3.41(m, 1H), 3.28-3.32(m, 1H), 3.10-3.16(m, 1H), 2.91-2.96( m, 1H), 2.88 (td, J=3.66, 13.23 Hz, 1H), 2.25 (s, 3H), 2.13-2.23 (m, 1H), 2.01 -2.13 (m, 1H).

Example 433: (R)-6-((2-(4,4-difluoro-3-((2-hydroxyethyl)αmino)piperidin-1-yl)-6-fluoro-1Hbenzo[d]imidazol-1-yl )methyl)nicotinonitrile

Step 1. (R)-6-((2-(3-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-4,4-difluoropiperidin-1-yl)6-fluoro-1H- benzo[d]imidazol-1-yl)methyl)nicotinonitrile.

(R)-6-((2-(3-αmino-4,4-difluoropiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile (89.4 mg , 0.231 mmol) was combined with (tert-butyldimethylsilyloxy)acetaldehyde (63.7 µl, 0.301 mmol) in a vial. Tetrahydrofuran (2.3 ml) and sodium cyanoborohydride (24.2 μl, 0.463 mmol) were added. The mixture was allowed to stir at room temperature for 2 hours, after which the starting material was completely consumed. The reaction mixture was quenched with NH ₄ Cl (aq), extracted into EtOAc, washed with brine, dried over MgSO 4 , filtered and concentrated to give (R)-6-((2-(3-((2(( tert-Butyldimethylsilyl)oxy)ethyl)amino)-4,4-difluoropiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol1-yl)methyl)nicotinonitrile, which was used in the next step without further purification.

(R)-6-((2-(4,4-difluoro-3-((2-hydroxyethyl)αmino)piperidin-1-yl)-6-fluoro-1H step

2.

benzo[d]imidazol-1-yl)methyl)nicotinonitrile (Example 433).

- 336 043189 (R)-6-((2-(3-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-4,4-difluoropiperidin-1-yl)-6-fluoro1H-benzo^ ]imidazol-1-yl)methyl)nicotinonitrile was dissolved in THF (2.3 ml) and tetrabutylammonium fluoride (1.0M solution in THF, 301 μl, 0.301 mmol) was added. The mixture was stirred at rt. within 16 hours Complete removal of the protective group was observed using LCMS. The resulting mixture was treated with dilution with water and EtOAc, extracted into EtOAc, dried over MgSO ₄ , filtered and concentrated. The crude material was purified by column chromatography (4 g SiO ₂ , 0-70% EtOAc in heptane) to give the title compound. MS: (ESI positive ion) mass/charge: 431.2 [M+1]. ¹ H NMR (500 MHz, d4-MeOH) δ 8.82 (br s, 1H), 8.13-8.25 (m, 1H), 7.59 (d, J=8.30 Hz, 1H) , 7.55 (dd, J=4.67, 8.30 Hz, 1H), 6.98-7.06 (m, 2H), 5.58 (s, 2H), 4.17 (dtd, J =4.80, 8.63, 12.98 Hz, 1H), 4.06 (br d, 7=13.23 Hz, 1H), 3.84-3.95 (m, 2H), 3.53 -3.66 (m, 2H), 3.38-3.47 (m, 1H), 3.32-3.37 (m, 2H), 2.25-2.42 (m, 2H).

Example 434: (S)-6-((2-(3-Aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinic acid

The vial was loaded with (S)-6-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile (0.03 g, 0.09 mmol) and 3, 99 N. an aqueous solution of hydrochloric acid (0.075 ml, 0.451 mmol) in 1,4-dioxane (0.301 ml) and shaken at ambient temperature for 1 h. The reaction mixture was concentrated and purified by reverse phase HPLC. 1H

NMR (600 MHz, DMSO-d ₆ ) δ 13.23-13.65 (br s, 1H), 8.98 (d, J=1.40 Hz, 1H), 8.29 (br d, J= 6.85 Hz, 1H), 8.128.19 (m, 1H), 8.11 (br s, 1H), 7.51 (br d, J=7.71 Hz, 1H), 7.21 (br s , 1H), 7.15 (br s, 1H), 5.57-5.61 (br s, 2H), 3.58-3.76 (m, 1H), 3.44-3.57 (m , 1H), 3.16-3.29 (m, 2H), 3.06 (br s, 1H), 2.52-2.55 (m, 1H), 1.95 (br s, 1H), 1.83 (br s, 1H), 1.53-1.64 (m, 1H). MS: (ESI positive ion) mass/charge: 352.2 [M+1].

Example 435: (S)-6-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinamide

Vial containing (S)-6-((2-(3-aminopiperidin-1-yl)-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile (0.03 g, 0.090 mmol) and NaOH ( 1M in water) (0.271 ml, 0.271 mmol) in methanol (0.30 ml) was shaken at rt. over 3 hours. The reaction mixture was diluted with EtOAc, filtered, concentrated and purified by reverse phase HPLC to give the title compound. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.94 (s, 1H), 8.16 (dd, J=2.22, 8.14 Hz, 1H), 8.11 (br s, 1H ), 7.56 (br s, 1H), 7.43 (d, J=7.79 Hz, 1H), 7.18 (d, J=8.17 Hz, 1H), 6.98-7, 11 (m, 3H), 5.38-5.44 (m, 2H), 3.37-3.43 (m, 1H), 2.76-2.89 (m, 2H), 2.57- 2.66 (m, 1H), 2.52-2.56 (m, 1H), 1.78-1.84 (m, 1H), 1.65-1.74 (m, 1H), 1, 50-1.58(m, 1H), 1.14-1.28(m, 1H). MS: (ESI positive ion) mass/charge: 351.2 [M+1].

- 337 043189

Example

436:

yl)methyl)nicotinamide

6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazole-1-

Vial containing 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile (0.03 g, 0.090 mmol ) and NaOH (1M in water) (0.271 ml, 0.271 mmol) in methanol (0.301 ml) was shaken at ambient temperature for 3 h. The reaction mixture was diluted with EtOAc, filtered, concentrated and purified by reverse phase HPLC with obtaining the connection specified in the header. 1H NMR (500 MHz, MeOH-d ₄ ) δ 8.84-9.04 (m, 1H), 8.088.27 (m, 1H), 7.48-7.58 (m, 1H), 7.06 -7.34 (m, 4H), 5.51 (br d, J=6.75 Hz, 3H), 4.29-4.50 (m, 1H), 3.61 (br dd, J=3 .89, 7.79 Hz, 1H), 3.39-3.50 (m, 1H), 2.87-3.19 (m, 3H), 2.10-2.27 (m, 1H), 1.78-1.97(m, 1H), 0.79-0.98(m,lH). MS: (ESI positive ion) mass/charge: 369.2 [M+1].

Example 437: yl)acetic acid

2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1 H-benzo [d]imidazol-1 -

2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6-difluoro-1Hbenzo[d]imidazol-1-yl)acetic acid treated with TFA (0.5 ml) in DCM (1 ml) and stirred at rt. over 1 h. The reaction mixture was concentrated and purified by reverse phase HPLC to give the title compound. 1H NMR (600 MHz, DMSO-d ₆ ) δ 7.47-7.60 (m, 2H), 4.82-4.92 (m, 2H), 4.51-4.59 (dt, J= 4.63, 9.01 Hz, 1H), 3.35-3.46 (m, 2H), 3.24-3.30 (m, 1H), 2.95 (br t, J=10.63 Hz, 1H), 2.73-2.89 (m, 1H), 2.13-2.21 (m, 1H), 1.79-1.89 (m, 1H). MS: (ESI positive ion) mass/charge: 329.0 [M+1].

Examples 438-441: 6-((R)-1-(4,6-difluoro-2-((3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl)-1Hbenzo[d] imidazol-1-yl)ethyl)nicotinonitrile (Example 596), and 6-((S)-1-(4,6-difluoro-2-((3R,4R)-4-fluoro-3(methylamino)piperidine- 1-yl)-1H-benzo[d]imidazol-1-yl)ethyl)nicotinonitrile (example 597), and 6-((R)-1(5,7-difluoro-2-((3R,4R)- 4-fluoro-3-(methylamino)piperidin-1-yl)-1H-benzo[d]imidazol-1yl)ethyl)nicotinonitrile (Example 598), and 6-((S)-1-(5,7-difluoro -2-((3R,4R)-4-fluoro-3(methylamino)piperidin-1-yl)-1H-benzo[d]imidazol-1-yl)ethyl)nicotinonitrile (Example 599)

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Step 1. tert-Butyl((3R,4R)-1-(1-(1-(5-cyanopyridin-2-yl)ethyl)-4,6-difluoro-1Hbenzo[d]imidazol-2-yl)- 4-fluoropiperidin-3-yl)carbamate (1.05 g, 2.098 mmol, mixture of 4 isomers) and methyl iodide (0.144 ml, 2.308 mmol) were dissolved in THF and cooled to 0°C. A 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (2.203 ml, 2.203 mmol) was added slowly and the reaction mixture was stirred for 1 hour. The conversion stopped so the reaction mixture was quenched with ammonium chloride, then extracted with DCM (3X). The organics were combined, dried over Na ₂ SO ₄ , filtered and concentrated to give a mixture of methylated and NH products.

Step 2 Isomers were separated using chiral SFC: Chiralpak Cel2, 15% MeOH, 0.2% DEA.

Step 3 Each individual isomer (100 mg, 1 eq.) was dissolved in DCM (5 ml), then TFA (0.5 ml) was added. After 1 h, the solutions were poured onto prewetted SCX columns and washed with methanol. The products were eluted with methanolic ammonia.

Peak 1: 6-((R)-1-(4,6-difluoro-2-((3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl)-1Hbenzo[d]imidazole- 1-yl)ethyl)nicotinonitrile (Example 438): 1H NMR (500 MHz, methanol-d ₄ ) δ ppm 1.882.08 (m, 4H) 2.22-2.33 (m, 1H) 2.41-2 .50 (m, 3H) 2.99 (dd, J=12.72, 9.34 Hz, 1H) 3.16-3.30 (m, 2H) 3.50-3.64 (m, 1H) 3.77-3.95 (m, 1H) 4.53-4.76 (m, 1H) 5.97 (q, J=7.01 Hz, 1H) 6.63-6.78 (m, 1H ) 7.04-7.16 (m, 1H) 7.62 (d, J=8.30 Hz, 1H) 8.19 (dd, J=8.30, 2.08 Hz, 1H) 8.84 (d, J=1.56 Hz, 1H). MS: (ESI positive ion) mass/charge: 415.2 [M+1].

Peak 2: 6-((S)-1-(4,6-difluoro-2-((3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl)-1Hbenzo[d]imidazole- 1-yl)ethyl)nicotinonitrile (example 597): 1H NMR (500 MHz, methanol-d ₄ ) δ ppm 1.97 (d, J=7.01 Hz, 3H) 2.03-2.28 (m, 2H) 2.52 (s, 3H) 2.99-3.21 (m, 3H) 3.59 (br d, J=12.98 Hz, 1H) 3.71-3.80 (m, 1H) 4.54-4.75 (m, 1H) 5.97 (q, J=7.01 Hz, 1H) 6.64-6.75 (m, 1H) 7.10 (dd, J=8.82 , 2.08 Hz, 1H) 7.58 (d, J=8.30 Hz, 1H) 8.18 (dd, J=8.30, 2.08 Hz, 1H) 8.76-8.87 ( m, 1H). MS: (ESI positive ion) mass/charge: 415.2 [M+1].

Peak 3: 6-((R)-1-(5,7-difluoro-2-((3R,4R)-4-fluoro-3-(methylamino)n-piperidin-1-yl)-1Hbenzo[d]imidazol- 1-yl)ethyl)nicotinonitrile (Example 598): 1H NMR (500 MHz, methanol-d ₄ ) δ ppm 2.01 (d, J=7.27 Hz, 4H) 2.18-2.33 (m, 1H) 2.49 (s, 3H) 2.98 (dd, J=12.46, 9.34 Hz, 1H) 3.14-3.28 (m, 2H) 3.47 (br dd, J= 12.85, 1.95Hz, 1H) 3.79 (dtd, J=8.40, 4.04, 4.04, 2.47Hz, 1H) 4.57-4.76 (m, 1H) 5.91-6.04 (m, 1H) 6.67-6.85 (m, 2H) 7.63 (d, J=8.30 Hz, 1H) 8.13-8.25 (m, 1H ) 8.84-8.96 (m, 1H). MS: (ESI positive ion) mass/charge: 415.2 [M+1].

Peak 4: 6-((S)-1-(5,7-difluoro-2-((3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl)-1Hbenzo[d]imidazole -1-yl)ethyl)nicotinonitrile (example 599), 1H NMR (500 MHz, methanol-d ₄ ) δ ppm 2.02 (d, J=7.01 Hz, 3H) 2.16-2.35 (m , 1H) 2.51-2.68 (m, 3H) 2.98-3.20 (m, 3H) 3.46-3.60 (m, 1H) 3.65-3.78 (m, 1H ) 4.54-4.78 (m, 1H) 5.99 (q, J=7.27 Hz, 1H) 6.64-6.85 (m, 2H) 7.58 (d, J=8, 30 Hz, 1H) 8.19 (dd, J=8.17, 2.21 Hz, 1H) 8.83-8.96 (m, 1H). MS: (ESI positive ion) mass/charge: 415.2 [M+1].

Scheme 15

Compounds obtained by mixed

Example 607: 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1 H-benzo[d]imidazol-1-yl)- 339 043189

-((1 R,5S)-3-azabicyclo [3.1.0]hexan-3 -yl)ethanone

Step 1. 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)-1(( 1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)ethanone.

2-(2-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-fluoropiperidin-1-yl)-5,6-difluoro-1Hbenzo[d]imidazol-1-yl)acetic acid (110 mg, 0.257 mmol), 1,1'-dimethyltriethylamine (135 μl, 0.770 mmol) and tetrahydrofuran (1284 μl) were combined in a vial and cooled to 0°C. Trimethylacetyl chloride (24.12 µl, 0.282 mmol) was added dropwise and the mixture was stirred for 15 minutes. LCMS showed complete conversion to mixed anhydride (manifested as methyl ester by LCMS by displacement of MeOH). 3-azabicyclo[3.1.0]hexane (1.5 eq) was added and stirred for 1 h. The mixture was concentrated, then redissolved in DCM/TFA (1:1) and allowed to stir for 1 h. concentrated, then redissolved in 1 ml DMSO, filtered and purified by reverse phase HPLC to give the desired product.

Table 14

The following compounds were prepared according to a procedure similar to that described for Example 607 and General Scheme 15 above.

At m. No. Amine Procedure for removing the Boc protection group Structure Connection name MS MN+ 600 Me hn-1 IN _F l I JL Ύ \ l yn ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-1-(2methylazetidin-1 yl)ethanone 382.0 601 L Me Η IN xh? TlH ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-I-(2,2difluoroethyl)-M- 406.2

- 340 043189

methylacetamide 602 Me H IN ^Xl-Me lich nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[0]imidazole-1 - yl)-N-cyclopropyl-Nmethylacetamide 382.2 603 ΜΘ Me. JL & ^CN IN .. ^Me M\ r N—\ J CN _F x&o-nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1 wi)-N-((R)-lcyanoethyl)-Mmethylacetamide 395.2 604 Me V Me Me g _F hъ XGO nh _? 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Нbenzo[(1]imidazol-1 yl)-N-methyl-N-((R) -1 (pyridin-2yl)ethyl)acetamide 447.0 605 Me Me J N H V Me .ώχ nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-H-ethyl-H- methylacetamide 370.2 606 F Me J H V Me , ⁿ Vf _F °sw? _NH2 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro- 1Hbenzo[<1]imidazole-1 - Ηπ)-Ν-(2-φτορ3ΤΗπ)-Ν- methylacetamide 388.2

- 341 043189

607 A n IN g r h ,λαλΆ ΝΗ ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1 Noi)-l-((lR,5S)-3 - azabicyclo[3.1.0]hexan-3-yl)ethanone 394.0 608 Me Ma JL /l hg IN Me Me / Λ _F XXH> \n ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1 - yl)-M-methyl-N-(1 (pyridin-2yl)ethyl)acetamide 447.2 609 O Η V _Γ °δ 'hlHj 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-1-(2- azabicyclo[3.1.0]hexan-2-yl)ethanone 394.2 610 Μθ Me^ JL n ^CN V Me Me * ⁰⁼ S “ w'nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1mi)-N-((S)-lcyanoethyl)-Mmethylacetamide 395.4 611 Me I\ V m\ NX 6 _F °δ :p>a 'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-M-methyl-M(tetrahydrofuran-3 yl) acetamide 412.2

- 342 043189

612 Me 0 ΊΐΆ-ΟΝ IN Me / ^Me ^Aon _F °s ΧΧΑΟ-''nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazole-1 - yl) A-(1-cyanopropan2-yl)-Mmethylacetamide 409.2 613 .. Μθ Me i nA ⁿ Sz V f _F AO ₍ XXrO-''nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-M-methyl-M-(1 (pyridine -4yl)ethyl)acetamide 447.2 614 „ Me Me / Ή-A H \f ₃ V ., Me Me / YA _F °A ^CF1 W? 'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-X-methyl-X-(1,1 ,1trifluoropropan-2yl)acetamide 438.2 615 Me N-V HCN V Me AA ^CN XeH> nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-X-(cyanomethyl)-X- methylacetamide 381.2 616 Me V _F °A XA<>'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-X-methyl-X-propylacetamide 384.2

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617 ^h'V-oh IN _F L ^Γ χζΑ^ ^Ν /—\ ¥ T /)-N >-F p-AD-N X-( 'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazole-1 - yl)-X-cyclopropyl-X(2- hydroxyethyl)acetami e 412.0 618 _F CN Η IN F ^CN _F ft dhnl 'nh ₂ 1-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1-yl)5,6-d iflor- 1Hbenzo[(1]imidazol-1yl)acetyl)-3fluoropyrrolidine-3 carbonitrile 425.2 619 Ή-U Η V ft _F ft XXHft NH? 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1 - silt)-1-(2-oxa-5- azabicyclo[2.2.1]hepta n-5-yl)ethanone 410.0 620 ft) V Zhi? nh? 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-1- (hexahydropyrano[4,3b ] [ 1,4]oxazin-4(7H)yl)ethanone 454.2 621 Me Y^X^SM Me V Me oftr .N Y---< XftCft 'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1 - 409.2

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ηπ)-N-(2cyanopropyl)-Xmethylacetamide 622 A' Me G Η IN ^CF ₃ Me G H χαο νη ₂ -(2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[(1]imidazol-1 yl)^-methyl^-(3,3,3trifluoropropyl)acetam id 438.2 623 X Η V ί ^Η _F °h YthO- ^f _F AAn \—( 'nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazole-1 - m)-1-((1R,5S)-6,6- difluoro-3azabicyclo[3.1.0]hexan-3-yl)ethanone 430.2 624 r- ^N H V nr O _F '> ArssA z—1 I Th h p-AA-n W 'nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(4-(pyrimidin-2yl) piperazin-1 yl)ethanone 475.0 625 H\ V _{F'nh 2} 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-1-(2isopropylazetidin-1 yl)ethanone 410.2

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626 F Xo X IN ^r X _F c 1ch ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(3- (difluoromethoxy)pyrrolidin-1-yl)ethanone 448.2 627 V A _F c X0O * NH ₂ 4-(2-(2-((3 R,4R)-3amino-4fluoropiperidin-1 -yl)5,6-d iftor- 1Hbenzo[c1]imidazol-1 yl)acetyl)morpholine2-carbonitrile 423.0 628 BUT O Η V ⁿ y ^ Ϋ DNE nh. 2-(2-((3 R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-1-(3- hydroxypiperidin-1 yl)ethanone 412.2 629 Me V ^CN ό H V X ^CN X—' _F h ;an> bn ₂ l-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1-yl)5,6-d iftor-1Hbenzo[c1]imidazol-1yl)acetyl)-4methylpiperidine-4carbonitrile 435.2 630 Oe H V sul _F C X0O \|H ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[(1]imidazol-1 yl)-1-(3,4-d ihydro- 1.8- naphthyridine-1 (2H) - 445.0

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silt) ethanone 631 Η IN dh'n> 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[0]imidazole-1 - yl)-T4-cyclopropyl-T4(2,2difluoroethyl)acetamide 432.2 632 O n IN 7 _F c XX%O- ^F '•NHj 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1 - yl)-1 -(5H-pyrrolo[3,4b]pyridin-6(7H)yl)ethanone 431.2 633 Me] n IN 0 Me c joucy NH, 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1 - №ΐ)-Ν-ΜβΤ№Ι-Ν- ((tetrahydrofuran-3yl)methyl)acetamide 426.0 634 Αι Me J H IN Me f'n> XXaO- ^f IsIHj -(2-((3R,4R)-3-aMHHO4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazole-1 Noi)-N-(2,2difluoroethyl)^methylacetamide 406.2 635 Me['W Η IN ^f yJ Ό tiHj 2-(2-((3 R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[(1]imidazol-1 yl)-Namethyl-L1-(2.2, 2trifluoroethyl)acetamide 424.2

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636 TO IN αχ XdS ^z Y ⁿ \ X ¹ Ήη ₂ (R)-1-(2-(2-((3 R,4R)-3amino-4fluoropiperidin-1 -yl)5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)acetyl)pyrrolidine -2- carbonitrile 407.0 637 V Me f W....OH 'nA J _r I J? NHj 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)-N-((lr,4R)-4hydroxycyclohexyl )N-methylacetamide 440.0 638 .. Me Me 1'b V Me Me f , A dhi > Nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-H-methyl->((8)-1 (pyridin-2yl)ethyl)acetamide 447.2 639 Ή - \ / Η ⁴ - ^J V °s nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-1-(octahydro-1Hpyrano[4,3- b]pyridin1 -yl)ethanone 452.2 640 HE Η V OH _F 4 XtH> nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-1-(4- hydroxypiperidin-1 yl)ethanone 412.2

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641 \ 1] 3 H IN Y/? 1-(3-(1H-1,2,4-triazol1-yl)azetidin-1-yl)-2(2-((3R,4R)-3-aMHHO-4fluoropiperidin-1-yl)5,6- difluoro-1Hbenzo[c!]imidazol-1 yl)ethanone 435.2 642 0 GU H V 0 0ΝΗ (Y r Y \n ₂ 7-(2-(2-((3 R,4R)-3amino-4fluoropiperidin-1 -yl)5,6-difluoro-1Hbenzo[c!]imidazol-1 yl)acetyl)hexahydroimidazo[1,5-a ]pyrazine- 3(2Н)-one 452.2 643 xP H V » σ _F 0 h ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-M-(2-cyanoethyl)U-(( tetrahydrofuran3-yl)methyl)acetamide 465.2 644 03-“H V ον _F z jaxy 'nh ₂ 4-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1-yl)5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)acetyl)-Mmethylmorpholine-2carboxamide 455.2 645 MeO ₂ S V MeO ₂ S _F 0 'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-1-(3- 474.2

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((methylsulfonyl)methyl)pyrrolidin-1 yl)ethanone 646 \_zxz V /i th _F a XX ACA f 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Нbenzo[(1]imidazol-1 yl)-1-(5,6-dihydro[1 ,2,4]triazolo[1,5a]pyrazin-7(8H)yl)ethanone 435.2 647 _nOMe cyN—'H V „ OME SU _F X . 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1-(2- (methoxymethyl)morphol ino)ethanone 442.2 648 OH /p-Me N- ^J H V he <Y" _F "A HAAS nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[<1]imidazol-1 yl)-1 -(3-hydroxy-3 methylpyrrolidin- 1 yl)ethanone 412.2 649 SO ₃ Me O H V SO ₂ Me О _F A (HAASA w 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)-1-(4- (methylsulfonyl)piperazin-1-yl)ethanone 475.2

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650 0 JL Z-N^Me A H V 0 JL Z^N^Me K _F l LICH 'νη ₂ N-((lacetylpyrrolidin-3 yl)methyl)-2-(2((3R,4R)-3-aMHHO-4fluoropiperidin-1-yl)5,6-difluoro-1Нbenzo[(1]imidazol-1 yl)L -ethylacetamide 481.2 651 A V .--h >0 Me / si,., AJ _F AND ΧΧ?Ή''nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)N-(1,1dioxidotetrahydro2H-thiopyran-4-yl )-Nmethylacetamide 474.2 652 0 AS'c Me / 'n—' H V C? Me G YA _F X XX?CH 'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)N-((1,1- dioxidotetrahydrothiofen-3-yl)methyl)-Mmethylacetamide 474.0 653 M _e Me sLcn 0 H V Me M® XA.CN 0 X XH? 'nh ₂ 2-(l-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1 -yl)5,6-difluoro-1Hbenzo[c1]imidazol-1 yl)acetyl)piperidin4-yl)-2methylpropanenitrile 463.0

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654 0 Me // l g IN ^M \-< O r Ch rZh? νη ₂ 1-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1-yl)5,6-difluoro-1Hbenzo[(1]imidazol-1yl)acetyl)Omethylpiperide in-3 carboxamide 453.2 655 X But also IN Gu ^H Ci p > yang > \n _; 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro- 1Нbenzo[(1]imidazol-1 yl)О-(2hydroxyethyl)0(pyridine-3 ylmethyl)acetamide 463.2 656 OO IN NC.--. ⁴ \ - \ / p > rGAO 'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-5,6-difluoro- 1Hbenzo[<1]imidazol-1 yl)0-(2-cyanoethyl)- N-(tetrahydro-2Hpyran-4-yl)acetamide 465.2 657 “Ά O n IN Me W O C 'mn ₂ l-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1-yl)5,6-difluoro-1Hbenzo[(1]imidazol-1yl)acetyl)O, Ndimethylpiper idine-3 carboxamide 467.2

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658 MeO-, ABOUT Η IN ^INTER F CN O _F b 'nh ₂ 1-(2-(2-((3 R,4R)-3amino-4fluoropiperidin-1 -yl)5,6-d iftoro-1Hbenzo[c!]imidazol-1 yl)acetyl)-4(methoxymethyl)piperidine -4-carbonitrile 465.2 659 O^O b Η V Yf b _f b 'nh ₂ 7-(2-(2-((3R,4R)-3amino-4fluoropiperidin-1-yl)5,6-d iftor-1Hbenzo[c!]imidazol-1yl)acetyl)tetrahydro1H-oxazolo[3,4a ]pyrazine-3(5Н)-one 453.2 660 ^s Cp ^N nh ₂ V _F Y Jo Μ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-X-(thiazol-2yl)acetamide 393.0 661 Η,Ν-^CF+. V , °Α 'νη ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-X-(2,2,2trifluoroethyl)acetamide 392.2 662 bx V Sgf. _F Y vGg· /—\ TX^CH nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-T4-cyclopropyl-T4(2,2,2trifluoroethyl) acetamide 432.2

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663 Η V F 0 OXOνη ₂ 2-(2-((3 R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-X-(2-methoxyethyl)N-methyl acetamide 382.2 664 V “'νΌ F 0 χχ+ο ΝΗ, 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c1]imidazol-1 yl)-T4-methyl-M-((8)tetrahydrofuran-3 yl)acetamide 394.2 665 Η V μ<α /Ά F X χχχ> νη. 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c1]imidazol-1 yl)-N-methyl-N-((R)tetrahydrofuran-3 yl)acetamide 394.2 666 9 H.N^Me V 9 ΗΝ^ '-Me F XX 4^~Ν \—/ Ίμη ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c1]imidazol-1 nn)-N-((S)-1-(pyridin2-yl )ethyl)acetamide 415.2 667 ^with W and V CF. ____ W _F °7 XXXCX νη ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c1]imidazole-1 - mi)-N-((S)- tetrahydrofuran-3 m)-N-(2,2,2trifluoroethyl)acetamide 462.2

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668 on V Ό=Η> νη ₂ 2-(2-((3 R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-Xcyclobutylacetamide 364.2 669 GN H ₂ N^Me V ^CN HN^'-Me _F X wo nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)->((8)-1cyanopropan-2yl)acetamide 377.2 670 GN H ₂ N^Me V ^CN HN^Me YX sX '---( Kh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazole-1 - m)-N-((R)-1cyanopropan-2yl)acetamide 377.2 671 E ₄ ^OMe H V ( 0 ^s * O LL 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-I-eti l-N-(2methoxyethyl)acetamide 396.2 672 ^with w Y V LL 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c1]imidazol-1 yl)-N-((R)tetrahydrofuran-3 yl)-> (2,2,2trifluoroethyl)acetamide 462.2

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673 V A 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazole-1 ηπ)-N-(3,3,3trifluoropropyl)acetam id 406.2 674 9 V 9 HN^Me _F °h X? hh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazole-1 im)-N-((R)-1 -(pyridine2- yl)ethyl)acetamide 415.2 675 >0° V 0. , °h w nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol-1 iin)-N-((S)tetrahydrofuran-3 yl)acetamide 380.2 676 Η ₃ N'^/ V 0.'NH _F °4 w nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol-1 yl)-N-((R)tetrahydrofuran-3yl)acetamide 380.2 677 ^hn J V (ft Aft Ll. 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol-1 yl)-1-(2methylazetidin-1 yl)ethan-1- He 464.2

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678 α Η V 47 _F 4 Hsnk 'nh ₂ 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Нbenzo[<1]imidazol-1 yl)-1-((8)-3methylmorpholino)ethan1-one 394.2 679 V .....α _F W 'nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol-1 yl)-l-((R)-2methylpyrrolidin-1 yl) ethane-1-he 378.2 680 V / G _F w Kih ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-l-((R)-3(methoxymethyl)morphol ino)ethane-1-one 424.2 681 α Η V .....o _F 4 nh ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazol-1 yl)-l-((R)-3methylmorpholino)ethan1-one 394.2 682 ηΟ V _F G NHBoc 2-(2-((3 R,4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[<1]imidazole-1 - silt)-1-((8)-2- methylpyrrolidin-1 yl)ethan-1-one 378.2

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683 A Η V l ''SY-Оνη ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-1-(3,5dimethylmorpholino)eth an-1- He 408.2 684 Cv Η V A _F A F? NH; 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Нbenzo[(1]imidazol-1 yl)-1-(3ethylmorpholino)ethan1-one 408.2 685 0- ΗV V _f °? LJ ϊνη ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Нbenzo[(1]imidazol-1 yl)-1-((8)-3cyclopropylmorpholine o)ethane- 1-he 420.2 686 ^but A V ^Η% Ό _F Λ zhzh yn ₂ 2-(2-((3 R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c1]imidazol-1 yl)-l-((R)-3(hydroxymethyl)morpholino )ethane-1-one 410.2 687 l ^! Η V g ft liquid νη ₂ 2-(2-((3R, 4R)-3-amino4-fluoropiperidin-1 yl)-6-fluoro-1Hbenzo[c!]imidazol-1 yl)-1-(3,3dimethylmorpholino)eth an-1- He 408.2

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Table 15

Data characterization of the compounds given in table. 14 8.

The Separation step column indicates after which process step the regioisomers formed due to the asymmetric substitution of the benzimidazole at R ¹ in Scheme 15 were separated during the preparation of the final compound shown in the table (I = after the preparation of the acetic acid intermediate (where at least one R ¹ is not hydrogen); B=before deprotection of the Bos group or F=final compound)

Note. No. frequency, solvent spruce W NMR data (δppm) Stage section NIA SFC Terms FOR separating isomers 600 600 MHz, DMSO-d6 7.42-7.56 (m, 1H), 7.38 (dd, J=7.47, 10.59 Hz, 1H), 4.60-4.88 (m, 2H), 4.554.90 ( m, 3H), 4.32-4.52 (m, 2H), 4.114.21 (m, 1H), 3.76-3.90 (m, 1H), 2.963.09 (m, 2H), 2 .71-2.88 (m, 1H), 2.37- 2.46 (m, 1H), 2.12 (dt, J=3.l 1, 13.08 Hz, 1H), 1.73-1.90 (m, 3H), 1.53 (d, J =6.23 Hz, 1H), 1.35 (dd, J=l.87, 6.23 Hz, 2H) - - 601 600 MHz, DMSO-d6 7.44-7.53( _m , 1H), 7.25-7.43(m, 1H), 6.02-6.55(m, 1H), 4.99-5.11(m, 2H ), 4.30-4.48 (m, 1H), 3.93-4.03 (m, 1H), 3.78 (dt, J=3.74, 15.41 Hz, 1H), 3, 22 (s, 2H), 2.94-3.04 (m, 3H), 2.71-2.82 (m, 1H), 2.01-2.15 (m, 1H), 1.70- 1.87(m, 3H) - - 602 600 MHz, DMSO-d6 7.35-7.53 (m, 2H), 4.99-5.15 (m, 2H), 4.30-4.46 (m, 1H), 3.28 (br d, J=3, 43 Hz, 1H), 2.95-3.10 (m, 3H), 2.86 (s, 3H), 2.79 (br dd, J=8.25, 12.61 Hz, 1H), 2 .02-2.18 (m, 1H), 1.71-1.88 (m, 3H), 0.86-1.01 (m, 4H) - -

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603 500MHz d ₄ -MeOH 7.31-7.40 (m, 1H), 7.18-7.30 (m, 1H), 5.58 (q, J=7.18 Hz, 1H), 5.02-5.19 ( m, 2H), 4.42-4.61 (m, 1H), 3.53 (dtd, J=l.56, 4.18, 12.39 Hz, 1H), 3.39 (br d, J =12.98 Hz, 1H), 3.28 (s, 2H), 3.213.30 (m, 1H), 3.04-3.15 (m, 1H), 3.07 (br s, 1H), 2.98 (dd, J=8.82, 12.46 Hz, 1H), 2.17-2.29 (m, 1H), 1.89-2.03 (m, 1H), 1.56 ( d, J=7.01 Hz, ZN) IN Chiralpak OJ, 10% MeOH, peak 2 604 500MHz d ₄ -MeOH Rotamer mixture: 8.68 (d, J=4.67 Hz, 1H), 8.53-8.62 (m, 1H), 7.90 (dt, J=l.82, 7.79Hz, 1H), 7.83 (dt, J=l.82, 7.79Hz, 1H), 7.54 (d, J=7.79Hz, 1H), 7.27-7.46 (m, 3H), 5.83 (q, J=7.01 Hz, 1H), 5.20-5.48 (m, 1H), 5.09 (d, J= 2.34 Hz, 1H), 4.37-4.57 (m, 1H), 3.48-3.57 (m, 1H), 3.34-3.46 (m, 1H), 3.05 -3.21(m, 2H), 3.03(s, 2H), 2.90-3.01(m, 1H), 2.77(s, 1H), 2.12-2.27(m , 1H), 1.88-2.01 (m, 1H), 1.80 (d, J=7.01 Hz, 1H), 1.64 (d, J=7.01 Hz, 2H) IN Chiralpak AD, 20% MeOH, peak 2 605 600 MHz, DMSO-d6 Rotamer mixture: 7.41-7.52 (m, 1H), 7.29-7.40 (m, 1H), 4.94-5.01 (m, 2H), 4.26-4.49 ( m, 1H), 3.42-3.50 (m, 1H), 3.07-3.11 (m, 2H), 2.93-3.05 (m, 2H), 2.85 (s, 1H), 2.75-2.82 (m, 1H), 2.032.15 (m, 1H), 1.64-1.83 (m, 3H), 1.001.24 (m, 3H) - - 606 600 MHz, DMSO-d6 Rotamer mixture: 7.43-7.50 (m, 1H), 7.23-7.41 (m, 1H), 4.98-5.05 (m, 2H), 4.66-4.77 ( m, 1H), 4.49-4.61 (m, 1H), 4.30-4.47 (m, 1H), 3.75-3.86 (m, 1H), 3.60-3, 69 (m, 1H), 3.18 (s, 2H), 2.943.04 (m, 2H), 2.93 (s, 1H), 2.77 (ddd, J=8.56, 12.61, 18.68Hz, 1H), 1.97-2.14 - -

- 360 043189

(m, 1H), 1.71-1.85 (m, 3H) 607 600 MHz, DMSO-d6 7.34-7.50(m, 2H), 4.91(dd, J=14.95, 17.44Hz, 1H), 4.71-4.83(m, 1H), 4.324.48( m, 1H), 3.76 (dd, J=8.25, 9.81 Hz, 1H), 3.56-3.70 (m, 2H), 3.20-3.30 (m, 2H) , 2.91-3.06(m, 2H), 2.73-2.83(m, 1H), 2.06-2.16(m, 1H), 1.82-1.96(m, 1H), 1.73-1.82 (m, 1H), 1.69 (br dd, J=3.74, 7.47 Hz, 1H), 1.57 (td, J=3.62, 7 .40Hz, 1H), 0.70-0.80(m, 1H), 0.20(d, J=4.36Hz, 1H) - - 608 600 MHz, DMSO-d6 Mixture of diastereomers: 8.46-8.53 (m, 2H), 7.68-7.76 (m, 1H), 7.44-7.52 (m, 3H), 5.74-5.81 ( m, 1H), 4.97-5.13 (m, 2H), 4.32-4.48 (m, 1H), 2.94-3.07 (m, 2H), 2.89 (d, J=3.43 Hz, ZN), 2.76-2.84 (m, 1H), 2.04-2.15 (m, 1H), 1.76-1.86 (m, 3H), 1 .68 (br t, J=6.85 Hz, 1H), 1.53 (dd, J=2.49, 7.16 Hz, ZN) - - 609 600 MHz, DMSO-d6 Mixture of diastereomers: 7.43-7.53 (m, 1H), 7.38 (qd, J=7.06, 10.59 Hz, 1H), 5.18 (dd, J=7.63, 17, 59 Hz, 1H), 4.885.03 (m, 1H), 4.27-4.49 (m, 1H), 3.693.78 (m, 1H), 3.62 (dtd, J=2.96.5 .98, 8.76 Hz, 1H), 3.10-3.20 (m, 1H), 2.943.08 (m, 3H), 2.75-2.86 (m, 1H), 2.082.20 ( m, 2H), 1.90 (ddd, J=3.43, 8.88, 12.61 Hz, 1H), 1.71-1.83 (m, 4H), 0.810.90 (m, 1H) - - 610 500MHz d ₄ -MeOH 7.35 (dd, J=7.27, 10.64 Hz, 1H), 7.28 (dd, J=7.14, 10.25 Hz, 1H), 5.48-5.60 (m, 1H), 5.01-5.19 (m, 2H), 4.51-4.66 (m, 1H), 3.56-3.64 (m, 1H), 3.38-3.45 V Chiralpak OJ, 10% MeOH, peak 1

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(m, 2H), 3.28 (s, 3H), 3.03-3.13 (m, 1H), 2.17-2.31 (m, 1H), 1.90-2.05 (m , 1H), 1.56 (d, J=7.27 Hz, ZN) 611 600 MHz, DMSO-d6 7.25-7.58 (m, 2H), 4.90-5.18 (m, 3H), 4.28-4.49(m, 1H), 3.93-4.00(m, 1H), 3.54-3.79 (m, 3H), 2.89-3.08 (m, 4H), 2.71-2.84 (m, 2H), 2.07-2.23 (m, 2H), 1.71-1.89(m, 2H), 1.66-2.00(m, 1H) - - 612 600 MHz, DMSO-d6 Mixture of diastereomers: 7.43-7.51 (m, 1H), 7.28-7.41 (m, 1H), 4.93-5.20 (m, 2H), 4.74-4.85 ( m, 1H), 4.30-4.55 (m, 1H), 3.21-3.29 (m, 2H), 3.01-3.05 (m, 3H), 2.96-3, 00 (m, 1H), 2.75-2.90 (m, 4H), 2.75-2.88 (m, 3H), 2.04-2.20 (m, 1H), 1.70- 1.87 (m, 3H), 1.14-1.35 (m, 3H) -- -- 613 600 MHz, DMSO-d6 8.53-8.60 (m, 2H), 7.43-7.51 (m, 2H), 7.31 (dd, J=5.45, 8.56 Hz, 2H), 5.69 ( quin, J=6.54Hz, 1H), 4.99-5.18(m, 2H), 4.34-4.52(m, 1H), 2.93-3.09(m, 2H) , 2.90 (d, J=4.67 Hz, ZN), 2.75-2.86 (m, 1H), 2.05-2.18 (m, 1H), 1.76-1.88 (m, 3H), 1.51 (dd, J=2.96, 7.01 Hz, ZN) - - 614 600 MHz, DMSO-d6 Mixture of diastereomers: 7.45-7.53 (m, 1H), 7.30-7.43 (m, 1H), 5.17-5.30 (m, 1H), 5.02-5.17 ( m, 2H), 4.30-4.48 (m, 1H), 3.20-3.26 (m, 1H), 3.11 (s, 3H), 2.91-3.04 (m, 2H), 2.73-2.82 (m, 1H), 2.03-2.15 (m, 1H), 1.80-1.86 (m, 1H), 1.68-1.79 ( m, 1H), 1.33-1.53 (m, 3H) - - 615 600 MHz, DMSO-d6 7.40-7.55 (m, 2H), 5.02-5.15 (m, 2H), 4.46 (s, 2H), 4.31-4.44 (m, 1H), 3.273, 30 (m, 2H), 3.23 (s, 3H), 2.97-3.06 (m, 1H), 2.93-3.05 (m, 1H), 2.78 (dd, 1= 8.10, 12.46Hz, 1H), 2.06-2.18(m, - -

- 362 043189

1H), 1.71-1.82 (m, 1H) 616 600 MHz, DMSO-d6 7.41-7.52(m, 1H), 7.29-7.40(m, 1H), 4.94-5.01(m, 2H), 4.26-4.49(m, 1H ), 3.42-3.50 (m, 1H), 3.07-3.11 (m, 2H), 2.93-3.05 (m, 2H), 2.85 (s, 1H), 2.752.82 (m, 1H), 2.03-2.15 (m, 1H), 1.641.83 (m, 3H), 1.00-1.24 (m, 3H) - - 617 600 MHz, DMSO-d6 7.45 (ddd, J=7.47, 10.98, 14.25 Hz, 2H), 5.00-5.14 (m, 2H), 4.31-4.50 (m, 1H), 3.49-3.54( _m , 2H), 3.38-3.48(m, 4H), 3.19-3.24(m, 1H), 2.93-3.06(m, 3H ), 2.77 (dd, J=8.41, 12.46 Hz, 1H), 2.032.21 (m, 1H), 1.73-1.88 (m, 1H), 0.881.03 (m, 4H) - - 618 600 MHz, DMSO-d6 7.45-7.51(m, 1H), 7.33-7.44(m, 1H), 4.82-5.09(m, 2H), 4.42-4.54(m, 1H ), 4.26-4.39 (m, 1H), 3.91-4.21 (m, 2H), 3.71-3.86 (m, 2H), 3.43 (dt, J=7 .32, 10.98 Hz, 1H), 3.16-3.26 (m, 1H), 2.973.07 (m, 2H), 2.75-2.86 (m, 2H), 2.522.73 ( m, 2H), 2.05-2.14 (m, 1H), 1.74- 1.85(m, 1H) - - 619 600 MHz, DMSO-d6 7.44-7.50(m, 1H), 7.32-7.43(m, 1H), 4.84-5.14(m, 2H), 4.61-4.79(m, 2H), 4.33-4.49( _m , 1H), 3.74-3.86(m, 1H), 3.71(s, 1H), 3.60(s, 1H), 3.25-3, 30 (m, 2H), 3.23 (br d, J=11.52 Hz, 1H), 2.913.06 (m, 2H), 2.80 (dd, J=8.25, 12.61 Hz, 1H), 2.07-2.18 (m, 1H), 1.73-1.96 (m, 5H) - - 620 600 MHz, DMSO-d6 Mixture of isomers: 7.39-7.49 (m, 2H), 4.91-5.08 (m, 2H), 4.33-4.52 (m, 2H), 3.87-3.96 ( m, 2H), 3.74-3.85 (m, 2H), - -

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3.58-3.67 (m, 1H), 3.51 (t, J=11.05 Hz, 1H), 3.43 (dt, J=3.l 1, 9.65 Hz, 1H), 3.21-3.27 (m, 2H), 2.94-3.05 (m, 2H), 2.79 (td, J=8.10, 12.46 Hz, 1H), 2.072.17 ( m, 1H), 1.73-1.85 (m, 3H), 1.521.61 (m, 1H) 621 600 MHz, DMSO-d6 Mixture of diastereomers: 7.42-7.51 (m, 1H), 7.38 (dd, J=7.47, 10.59 Hz, 1H), 4.93-5.13 (m, 2H), 4 .29-4.47(m, 1H), 3.65-3.88(m, 1H), 3.40-3.57(m, 1H), 3.19-3.23(m, 3H) , 2.95-3.07(m, 2H), 2.67-2.86(m, 1H), 2.04-2.17(m, 1H), 1.71-1.85(m, 3H) - - 622 600 MHz, DMSO-d6 7.42-7.51(m, 1H), 7.30-7.39(m, 1H), 4.91-5.10(m, 2H), 4.32-4.49(m, 1H ), 3.53-3.74 (m, 2H), 3.26 (br dd, J=5.14, 7.32 Hz, 1H), 3.15 (s, 1H), 3.11-3 .21 (m, 1H), 2.93-3.05 (m, 2H), 2.78 (dd, J=8.25, 12.61 Hz, 1H), 2.52-2.57 (m , 1H), 2.04-2.15 (m, 1H), 1.71-1.82 (m, 3H) - - 623 600 MHz, DMSO-d6 7.43-7.52 (m, 1H), 7.33 (dd, J=7.16, 10.59 Hz, 1H), 4.93-5.01 (m, 1H), 4.814.90 ( m, 1H), 4.31-4.48 (m, 1H), 4.024.12 (m, 1H), 3.91-4.01 (m, 1H), 3.80 (br d, J=12 .46 Hz, 1H), 3.58-3.70 (m, 1H), 3.17-3.26 (m, 1H), 2.91-3.03 (m, 2H), 2.72- 2.85 (m, 2H), 2.56-2.65 (m, 1H), 2.02-2.20 (m, 1H), 1.68-1.81 (m, 2H) - - 624 600 MHz, DMSO-d6 8.32-8.47(m, 2H), 7.35-7.53(m, 2H), 6.61-6.74(m, 1H), 5.03-5.16(m, 2H ), 4.32-4.48 (m, 1H), 3.83-3.93 (m, 2H), 3.77 (br t, J=4.20 Hz, 2H), 3.67-3 .73 (m, 4H), 3.60-3.64 (m, 2H), 2.95-3.06 - -

- 364 043189

(m, 2H), 2.81 (dd, J=7.94, 12.61 Hz, 1H), 2.05-2.19 (m, 1H), 1.75-1.86 (m, 1H ) 625 600 MHz, DMSO-d6 Rotamer mixture: 7.44-7.53 (m, 1H), 7.36 (dd, J=7.32, 10.74 Hz, 1H), 4.664.90 (m, 2H), 4.50-4 .65 (m, 1H), 4.314.48 (m, 1H), 4.10-4.28 (m, 2H), 3.994.09 (m, 1H), 2.91-3.09 (m, 2H ), 2.79 (dt, J=8.56, 13.16 Hz, 1H), 2.20-2.32 (m, 1H), 2.08-2.16 (m, 2H), 2, 00 (td, J=5.61, 15.26 Hz, 1H), 1.69-1.89 (m, 3H), 0.77-0.92 (m, 6H) -- - 626 600 MHz, DMSO-d6 Rotamer mixture: 7.47 (dd, J=7.47, 11.21 Hz, 1H), 7.39 (dd, J=7.16, 10.59 Hz, 1H), 6.61-6.99 (m, 1H), 4.79-5.01 (m, 3H), 4.30-4.48 (m, 1H), 3.63-3.94 (m, 3H), 3.51-3 .61 (m, 2H), 2.96-3.07 (m, 2H), 2.79 (ddd, J=l.25, 8.33, 12.53 Hz, 1H), 2.17-2 .31 (m, 1H), 1.98-2.15 (m, 3H), 1.73-1.81 (m, 1H) - - 627 600 MHz, DMSO-d6 Mixture of diastereomers: 7.43-7.53 (m, 1H), 7.28-7.40 (m, 1H), 4.98-5.28 (m, 3H), 4.30-4.51 ( m, 1H), 4.01-4.26 (m, 1H), 3.74-3.98 (m, 4H), 3.44-3.53 (m, 1H), 3.40-3, 59 (m, 1H), 2.94-3.10 (m, 3H), 2.72-2.87 (m, 1H), 2.06-2.19 (m, 1H), 1.71- 1.94(m, 1H) - - 628 600 MHz, DMSO-d6 Mixture of diastereomers: 7.23-7.49 (m, 2H), 4.91-5.18 (m, 4H), 4.29-4.49 (m, 1H), 3.49-4.15 ( m, 4H), 2.92-3.09 (m, 3H), 2.71-2.82 (m, 1H), 2.04-2.16 (m, 1H), 1.29-1, 90(m, 8H) - - 629 600 MHz, DMSO-d6 7.44-7.52 (m, 1H), 7.41 (dd, J=7.32, 10.74 Hz, 1H), 4.94-5.14 (m, 2H), 4.344.49 ( m, 1H), 4.23-4.32 (m, 1H), 3.97- - -

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4.06 (m, 1H), 3.21 (br d, J=l.25 Hz, 1H), 2.95-3.05 (m, 2H), 2.74-2.91 (m, 2H ), 2.06-2.16 (m, 1H), 2.01 (td, J=2.76, 5.99 Hz, 1H), 1.88-1.96 (m, 2H), 1, 72-1.85 (m, 2H), 1.60-1.72 (m, 1H), 1.43-1.51 (m, 1H), 1.40 (s, 3H) 630 600 MHz, DMSO-d6 8.35-8.57 (m, 1H), 7.59-7.69 (m, 1H), 7.26-7.53 (m, 2H), 7.24 (dd, J=4.83 , 7.63 Hz, 1H), 5.02-5.21 (m, 2H), 4.664.93 (m, 1H), 4.60-4.95 (m, 1H), 4.254.48 (m, 1H), 3.92 (brt, J=5.92 Hz, 1H), 3.80-3.87 (m, 1H), 2.71-3.14 (m, 5H), 1.97-2 .15 (m, 1H), 1.62-1.80 (m, 1H) - - 631 600 MHz, DMSO-d6 7.19-7.28(m, 2H), 6.88-6.96(m, 1H), 6.00-6.28(m, 1H), 5.11-5.23(m, 2H ), 4.31-4.50 (m, 1H), 3.76 (dt, J=3.74, 15.26 Hz, 2H), 2.92-3.08 (m, 3H), 2, 81 (dd, J=8.25, 12.61 Hz, 1H), 2.07-2.18 (m, 1H), 1.70-1.84 (m, 1H), 0.89-1, 07(m, 4H) - - 632 600 MHz, DMSO-d6 8.49-8.55(m, 1H), 7.81-7.90(m, 1H), 7.42-7.51(m, 2H), 7.33-7.40(m, 1H ), 5.00-5.17 (m, 4H), 4.67-4.79 (m, 2H), 4.32-4.47 (m, 1H), 3.36-3.42 (m , 1H), 2.95-3.09 (m, 2H), 2.82 (dd, J=7.94, 12.61 Hz, 1H), 2.05-2.16 (m, 1H), 1.761.87(m, 2H) - - 633 600 MHz, DMSO-d6 Mixture of diastereomers: 7.43-7.52 (m, 1H), 7.29-7.41 (m, 1H), 4.91-5.05 (m, 2H), 4.29-4.50 ( m, 1H), 3.55-3.89 (m, 3H), 3.36-3.49 (m, 2H), 3.19-3.28 (m, 1H), 3.14 (s, 2H), 2.94-3.05(m, 2H), 2.87(s, 1H), 2.73-2.83(m, 1H), 2.512.66(m, 1H), 2.02 -2.15(m, 1H), 1.86- - -

- 366 043189

1.94 (m, 1H), 1.72-1.84 (m, 2H), 1.43- 1.64(m, 1H) 634 600 MHz, DMSO-d6 7.22-7.29(m, 1H), 7.06-7.21(m, 1H), 6.87-6.96(m, 1H), 6.01-6.52(m, 1H ), 4.97-5.13 (m, 2H), 4.29-4.50 (m, 1H), 3.68-4.05 (m, 2H), 3.57 (q, J=7 .16 Hz, 1H), 3.40 (br d, J=7.16 Hz, 1H), 2.933.06 (m, 2H), 2.71-2.89 (m, 1H), 2.062.15 ( m, 1H), 1.78 (ddd, 1=3.58, 6.46, 9.58 Hz, 1H), 1.24 (t, J=7.16 Hz, 2H), 1.06 (t , J=7.01 Hz, 1H) -- -- 635 600 MHz, DMSO-d6 7.21-7.27 (m, 1H), 7.16 (dd, J=4.67, 8.72 Hz, 1H), 7.08 (dd, J=4.67, 8.72 Hz, 1H), 6.88-6.98 (m, 1H), 4.98-5.20 (m, 2H), 4.15-4.52 (m, 1H), 4.21 (q, J= 9.65 Hz, 1H), 3.63 (q, J=7.06 Hz, 2H), 3.42 (br d, 1=6.85 Hz, 1H), 2.89-3.07 (m , 2H), 2.69-2.85 (m, 1H), 2.03-2.13 (m, 1H), 1.69-1.81 (m, 1H), 1.28 (t, J =7.16 Hz, 2H), 1.07 (t, J=7.01 Hz, 1H) - - 636 600 MHz, DMSO-d6 7.39-7.56 (m, 2H), 4.92 (br d, J=3.43 Hz, ZH), 4.81 (dd, J=3.43, 7.47 Hz, 1H), 4 34-4 49 (n ₅ 1H), 3.81 (ddd, J=3.89, 7.71, 9.58 Hz, 1H), 3.56-3.71 (m, 1H), 2, 98-3.09 (m, 3H), 2.80 (dd, J=8.10, 12.77 Hz, 1H), 2.05-2.30 (m, 8H) - - 637 600 MHz, DMSO-d6 7.43-7.50 (m, 1H), 7.37 (dd, J=7.16, 10.59 Hz, 1H), 4.99-5.11 (m, 1H), 4.884.99 ( m, 1H), 4.53-4.62 (m, 1H), 4.304.48 (m, 1H), 4.15 (tt, J=3.89, 11.99 Hz, 1H), 2.98 -3.05(m, 1H), 2.91-2.98(m, 3H), 2.78(td, J=7.43, 12.53Hz, 1H), 2.72(s, 1H ), 2.07-2.14 (m, 1H), 1.86 (br d, J=11.21 Hz, ZN), 1.73-1.80 (m, 1H), - -

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1.66 (br d, J=8.41 Hz, 2H), 1.52-1.60 (m, 1H), 1.48 (br dd, J=3.11, 9.34 Hz, 1H) , 1.29-1.37 (m, 1H), 1.13-1.26 (m, 2H) 638 600 MHz, DMSO-d6 Rotamer mixture: 8.68 (dd, J=0.78, 4.67 Hz, 1H), 8.58 (dd, J=0.78, 4.93 Hz, 1H), 7.79-7.95 (m, 1H), 7.54 (d, J=7.79 Hz, 1H), 7.26-7.46 (m, 3H), 5.83 (q, J=7.18 Hz, 1H), 5.41 (d, J=6.75 Hz, 1H), 5.22-5.37(m, 1H), 5.04-5.14(m, 1H), 4.35-4.61(m, 1H), 3.50-3.61(m, 1H ), 3.35-3.47 (m, 1H), 3.05-3.20 (m, 2H), 3.02 (s, 1H), 2.89-2.98 (m, 1H), 2.76 (s, 1H), 2.12-2.28 (m, 1H), 1.862.01 (m, 1H), 1.80 (d, J=6.75 Hz, 1H), 1.63 (d, 1=7.27Hz, 1H) IN Chiralpak AD, 20% MeOH, peak 1 639 600 MHz, DMSO-d6 7.42-7.52(m, 1H), 7.32-7.41(m, 1H), 5.04-5.26(m, 1H), 4.83-5.02(m, 1H ), 4.55-4.65 (m, 1H), 4.31-4.48 (m, 1H), 4.10-4.26 (m, 1H), 3.85-3.95 (m , 1H), 3.77 (br d, J=11.21 Hz, 1H), 3.58-3.68 (m, 1H), 3.46-3.56 (m, 1H), 3.13 -3.21(m, 1H), 2.92-3.07(m, 2H), 2.76-2.87(m, 1H), 2.59-2.71(m, 1H), 2 .02-2.26 (m, 2H), 1.86-1.93 (m, 1H), 1.66-1.82 (m, 3H), 1.50-1.60 (m, 2H) , 1.21-1.35 (m, 1H) - - 640 600 MHz, DMSO-d6 7.46 (dd, J=7.47, 10.90 Hz, 1H), 7.37 (dd, J=7.47, 10.90 Hz, 1H), 4.91-5.08 (m, 3H), 4.30-4.49(m, 1H), 3.69-3.94(m, 4H), 3.05-3.15(m, 1H), 2.93-3.05( m, 3H), 2.79 (dd, J=8.25, 12.61 Hz, 1H), 2.04-2.17 (m, 2H), 1.67-1.86 (m, 4H) , 1.41-1.50(m, 1H), 1.24-1.33(m, 1H) - -

- 368 043189

641 600 MHz, DMSO-d6 8.66-8.70 (m, 1H), 8.13 (s, 1H), 7.427.51 (m, 2H), 5.44-5.53 (m, 1H), 4.814.90 (m, 2H), 4.77 (q, J=9.03 Hz, 1H), 4.55 (dt, J=5.29, 8.88 Hz, 1H), 4.334.49 (m, 2H), 4, 24 (dd, J=5.29, 10.28 Hz, 1H), 3.15-3.28 (m, 1H), 3.01-3.08 (m, 2H), 2.82 (dd, J=8.41, 12.46 Hz, 1H), 2.10-2.17(m, 1H), 1.90-2.07(m, 1H), 1.79-1.87(m, 1H) -- - 642 600 MHz, DMSO-d6 7.45-7.50(m, 1H), 7.41(brt, J=8.25Hz, 1H), 6.50-6.64(m, 1H), 5.07-5.19( m, 1H), 4.94-5.03 (m, 1H), 4.21-4.50 (m, 2H), 3.91-4.05 (m, 1H), 3.73-3, 85 (m, 1H), 3.53-3.69 (m, 2H), 2.91-3.10 (m, 5H), 2.71-2.86 (m, 2H), 2.56- 2.65 (m, 1H), 2.11-2.18 (m, 1H), 1.74-1.82 (m, 1H) -- - 643 600 MHz, DMSO-d6 7.48 (dd, J=7.47, 11.21 Hz, 1H), 7.35 (ddd, J=5.61, 7.08, 10.67 Hz, 1H), 4.925.18 (m, 2H), 4.30-4.47(m, 1H), 3.743.92(m, 2H), 3.57-3.73(m, 3H), 3.473.53(m, 1H), 3.32 -3.44 (m, 6H), 3.223.27 (m, 1H), 2.93-3.05 (m, 3H), 2.742.80 (m, 2H), 2.01-2.16 (m , 2H), 1.73- 1.91 (m, 3H), 1.47-1.67 (m, 1H) - - 644 600 MHz, DMSO-d6 7.81-8.03 (m, 1H), 7.44-7.50 (m, 1H), 7.40 (dd, J=7.47, 10.59 Hz, 1H), 4.925.22 ( m, 2H), 4.10-4.47 (m, 2H), 3.774.02 (m, 3H), 3.47-3.60 (m, 1H), 3.443.71 (m, 1H), 3 .13-3.25 (m, 2H), 2.993.09 (m, 2H), 2.73-2.86 (m, 2H), 2.592.69 (m, 3H), 2.05-2.19 (m, 1H), 1.701.85 (m, 1H) - -

- 369 043189

645 600 MHz, DMSO-d6 7.42-7.52(m, 1H), 7.31-7.42(m, 1H), 4.72-5.01(m, 2H), 4.32-4.53(m, 1H ), 3.89-4.17 (m, 1H), 3.71-3.85 (m, 1H), 3.53-3.67 (m, 1H), 3.43 (br dd, J= 5.92, 14.01 Hz, 1H), 3.36-3.40 (m, 2H), 3.17 (d, J=4.98 Hz, 1H), 3.11-3.22 (m , 1H), 2.97-3.08 (m, 5H), 2.75-2.83 (m, 1H), 2.59-2.71 (m, 1H), 2.09-2.31 (m, 2H), 1.74-1.88 (m, 2H) - - 646 600 MHz, DMSO-d6 7.96-8.09 (m, 1H), 7.41-7.53 (m, 2H), 5.08-5.27 (m, 2H), 5.03 (s, 1H), 4.754, 86 (m, 1H), 4.33-4.49 (m, 2H), 4.134.22 (m, 2H), 3.96-4.07 (m, 1H), 3.243.28 (m, 1H) , 2.94-3.05 (m, 2H), 2.752.83 (m, 1H), 2.01-2.15 (m, 1H), 1.721.84 (m, 2H) - - 647 600 MHz, DMSO-d6 Mixture of diastereomers: 7.44-7.50 (m, 1H), 7.37-7.43 (m, 1H), 5.13 (dt, J=6.23, 18.22 Hz, 1H), 4 .94 (br dd, J=13.86, 17.28 Hz, 1H), 4.31-4.50 (m, 1H), 4.06-4.21 (m, 1H), 3.80- 3.94 (m, 2H), 3.48-3.69 (m, 2H), 3.39-3.46 (m, 3H), 3.25 (s, 3H), 3.07-3, 11 (m, 1H), 2.94-3.03 (m, 2H), 2.74-2.86 (m, 2H), 2.58-2.64 (m, 1H), 2.06- 2.15 (m, 1H), 1.71-1.87 (m, 1H) - - 648 600 MHz, DMSO-d6 7.46 (dd, J=7.47, 10.90 Hz, 1H), 7.36 (dd, J=7.32, 10.74 Hz, 1H), 4.76-5.01 (m, 3H), 4.29-4.47(m, 1H), 3.67-3.77(m, 1H), 3.42-3.55(m, 2H), 2.95-3.18( m, 3H), 2.74-2.84 (m, 1H), 2.04-2.15 (m, 1H), 1.73-1.98 (m, 4H), 1.28-1, 37(m, 3H) - -

- 370 043189

649 600 MHz, DMSO-d6 7.44-7.51( _m , 1H), 7.32-7.41(m, 1H), 4.99-5.14(m, 2H), 4.29-4.48(m, 1H ), 3.54-3.75 (m, 5H), 3.18-3.26 (m, 3H), 3.11-3.17 (m, 2H), 2.97-3.06 (m, 2H ), 2.94 (s, 3H), 2.74-2.83 (m, 1H), 2.082.19 (m, 1H), 1.75-1.95 (m, 3H) - - 650 600 MHz, DMSO-d6 Mixture of diastereomers: 7.31-7.51 (m, 2H), 4.93-5.22 (m, 2H), 4.49-4.64 (m, 1H), 4.31-4.46 ( m, 1H), 3.73-3.82 (m, 1H), 3.44-3.69 (m, 5H), 2.94-3.06 (m, 3H), 2.72-2, 85 (m, 1H), 2.05-2.30 (m, 4H), 1.97 (d, J=12.46 Hz, ZN), 1.861.92 (m, 2H), 1.25 (q , 1=7.16Hz, 2H), 1.03 (q, J=6.75Hz, 2H) - -- 651 600 MHz, DMSO-d6 7.43-7.51(m, 1H), 7.35-7.43(m, 1H), 5.04-5.19(m, 1H), 4.90-5.03(m, 1H ), 4.57 (tt, J=3.35, 12.22 Hz, 1H), 4.334.48 (m, 1H), 3.35-3.45 (m, 3H), 3.173.28 (m, 3H), 3.06 (br d, J=11.52 Hz, 1H), 3.00 (s, 3H), 2.73-2.83 (m, 2H), 2.06-2.31 ( m, 4H), 1.88 (br d, J=10.90 Hz, 2H), 1.71-1.83 (m, 1H) - - 652 600 MHz, DMSO-d6 Mixture of diastereomers: 7.34-7.49 (m, 2H), 4.93-5.05 (m, 2H), 4.33-4.50 (m, 1H), 3.40-3.60 ( m, 3H), 3.20-3.26 (m, 3H), 3.14-3.18 (m, 3H), 2.95-3.10 (m, 3H), 2.78 (ddd, J=7.32, 8.95, 12.69 Hz, ZN), 2.05-2.24 (m, 2H), 1.65-1.91 (m, 2H) - - 653 600 MHz, DMSO-d6 7.43-7.50(m, 1H), 7.31-7.39(m, 1H), 5.04-5.16(m, 1H), 4.93-5.03(m, 1H ), 4.31-4.50 (m, 2H), 4.02-4.12 (m, 1H), 3.18-3.29 (m, 2H), 3.09 (brt, J=12 .77 Hz, 1H), 2.91-3.04 (m, 2H), 2.80 (td, J=7.63, 12.77 Hz, 1H), 2.55-2.64 (m, - -

- 371 043189

1H), 2.06-2.19 (m, 1H), 1.88 (br s, 1H), 1.75-1.84 (m, 3H), 1.62-1.72 (m, 1H ), 1.31 (brd, J=4.67 Hz, 6H), 1.07-1.15 (m, 1H) 654 600 MHz, DMSO-d6 7.80-7.93(m, 1H), 7.42-7.50(m, 1H), 7.32-7.39(m, 1H), 4.89-5.17(m, 2H ), 4.31-4.48 (m, 1H), 3.74-3.93 (m, 2H), 3.40 (br dd, J=9.34, 13.70 Hz, 1H), 3.11-3.19(m, 1H), 2.94-3.04(m, 3H), 2.72-2.87(m, 2H), 2.53-2.65(m, 3H ), 2.05-2.24 (m, 2H), 1.77-1.90 (m, 4H), 1.59-1.74 (m, 2H) - - 655 600 MHz, DMSO-d6 Rotamer mixture: 8.43-8.56 (m, 2H), 7.69 (td, J=l.87, 7.79 Hz, 1H), 7.47 (dd, J=7.32, 11, 05Hz, 1H), 7.33-7.39(m, 1H), 7.25-7.31(m, 1H), 5.25(s, 2H), 4.62(s, 2H), 4.32-4.50 (m, 1H), 3.643.72 (m, 2H), 3.53 (brt, J=4.98 Hz, 2H), 3.36-3.42 (m, 2H) , 2.93-3.06(m, 2H), 2.71-2.82(m, 1H), 2.01-2.13(m, 1H), 1.72-1.89(m, 1H) - - 656 600 MHz, DMSO-d6 Rotamer mixture: 7.47 (dd, J=7.63, 11.06 Hz, 1H), 7.33-7.42 (m, 1H), 5.045.21 (m, 2H), 4.31-4 .48 (m, 1H), 3.864.07 (m, 3H), 3.51 (t, J=6.85 Hz, 1H), 3.41-3.46 (m, 1H), 3.41 ( br s, 1H), 3.203.28 (m, 1H), 2.94-3.07 (m, 2H), 2.772.84 (m, 1H), 2.72 (t, J=6.85 Hz, 1H), 2.04-2.17(m, 1H), 1.69-1.87(m, 5H) - - 657 600 MHz, DMSO-d6 Rotamer mixture: 7.36-7.50 (m, 2H), 4.92-5.14 (m, 2H), 4.30-4.50 (m, 1H), 4.03-4.24 ( m, 1H), 3.76-3.96 (m, 1H), 3.12-3.24 (m, 1H), 2.98-3.08 (m, 4H), 2.77-2, 89 (m, 5H), 2.61-2.73 (m, 1H), 2.09-2.21 (m, 1H), 1.76-1.94 (m, 4H), - -

-372 043189

1.48-1.67 (m, 2H) 658 600 MHz, DMSO-d6 7.44-7.50(m, 1H), 7.34-7.42(m, 1H), 4.95-5.13(m, 2H), 4.29-4.47(m, 2H ), 4.00-4.11 (m, 1H), 3.48 (d, 1=1.56 Hz, 2H), 3.36 (s, 3H), 3.22-3.28 (m, 2H), 2.93-3.07(m, 2H), 2.54-2.87(m, 2H), 2.08-2.19(m, 1H), 1.98-2.05( m, 1H), 1.94 (br d, J=13.39 Hz, 1H), 1.76-1.88 (m, 3H), 1.63-1.73 (m, 1H), 1, 44-1.53(m, 1H) - -- 659 600 MHz, DMSO-d6 7.37-7.51(m, 2H), 4.93-5.21(m, 2H), 4.32-4.51(m, 3H), 3.95-4.07(m, 2H ), 3.59-3.69 (m, 1H), 3.09-3.22 (m, 2H), 2.93-3.07 (m, 3H), 2.61-2.83 (m , 2H), 2.04-2.21 (m, 1H), 1.74-1.96 (m, 3H) - - 660 600 MHz, DMSO-d6 7.51 (d, 1=3.58 Hz, 1H), 7.24-7.29 (m, 3H), 6.91-6.97 (m, 1H), 5.07 (s, 2H) , 4.31-4.46(m, 1H), 3.31-3.43(m, 2H), 2.95-3.10(m, 2H), 2.78-2.87(m, 1H), 2.07-2.16 (m, 1H), 1.73-1.84 (m, 1H) I SFC: Chiralpak AYH, 10% IP A, peak 1 661 600 MHz, DMSO- _d6 9.04-9.14(m, 1H), 7.21-7.27(m, 1H), 7.13-7.20(m, 1H), 6.89-6.97(m, 1H ), 4.80 (s, 2H), 4.30-4.51 (m, 1H), 3.934.06 (m, 2H), 3.37-3.47 (m, 2H), 2.973.08 ( m, 2H), 2.77-2.87 (m, 1H), 2.042.16 (m, 1H), 1.72-1.88 (m, 1H) I SFC: Chiralpak AYH, 10% IP A, peak 1 662 600 MHz, DMSO- _d6 7.18-7.27 (m, 2H), 6.93 (ddd, 7=9.85, 8.76, 2.49 Hz, 1H), 5.17-5.28 (m, 2H), 4.32-4.50(m, 1H), 4.13-4.25(m, 2H), 2.95-3.10(m, 3H), 2.62-2.91(m, 2H ), 2.52-2.57 (m, 1H), 2.07-2.18 (m, 1H), 1.71-1.83 (m, 1H), 0.98-1.13 (m , 4H) I SFC: Chiralpak AYH, 10% IP A, peak 1

- 373 043189

663 600 MHz, DMSO- _d6 7.15-7.25 (m, 1H), 7.06 (dd, /=8.68, 4.87 Hz, 1H), 6.91 (t, /=9.22 Hz, 1H), 4 .95-5.03 (m, 2H), 4.38-4.49 (m, 1H), 3.60-3.67 (m, 1H), 3.54-3.60 (m, 1H) , 3.47-3.53(m, 1H), 3.39-3.47(m, 2H), 3.34-3.39(m, 3H), 3.21-3.27(m, 3H), 2.96-3.09 (m, 2H), 2.81 (dt, /=12.53, 9.26 Hz, 2H), 2.06-2.15 (m, 1 H), 1.741.83(m, 1H) I SFC: Chiralpak AYH, 10% IPA, Peak 1 664 500 MHz, METHANOL -d ₄ 7.13-7.24(m, 2H), 6.87-7.00(m, 1H), 4.96-5.14(m, 2H), 4.34-4.55(m, 1H ), 4.04-4.17(m, 1H), 3.64-3.97(m, 3H), 3.47-3.57(m, 1H), 3.38-3.46(m , 1H), 3.30-3.34 (m, 2H), 3.06-3.21 (m, 4H), 2.93 (m, 1H), 2.16-2.44 (m, 2H ), 1.872.10 (m, 2H) F Chiralpak IF, 30% MeOH with 0.2% DEA, peak 2 665 500 MHz, METHANOL -d ₄ 7.13-7.23 (m, 2H), 6.89-6.99 (m, 1H), 5.03 (s, 2H), 4.35-4.54 (m, 1H), 4.054, 16 (m, 1H), 3.65-3.98 (m, 3H), 3.483.58 (m, 1H), 3.35-3.49 (m, 1H), 3.32 (td, /= 1.57, 3.21 Hz, 3H), 3.06-3.14 (m, 2H), 2.89-3.02 (m, 2H), 2.15-2.45 (m, 2H) , 1.85-2.09 (m, 2H) F Chiralpak IF, 30% MeOH with 0.2% DEA, peak 1 666 600 MHz, DMSO- _d6 8.90-9.00(m, 1H), 8.49-8.58(m, 1H), 7.73-7.81(m, 1H), 7.36-7.42(m, 1H ), 7.26-7.31 (m, 1H), 7.16-7.24 (m, 2H), 6.86-6.97 (m, 1H), 4.95-5.09 (m , 1H), 4.70-4.84 (m, 2H), 4.27-4.47 (m, 1H), 3.38-3.48 (m, 1H), 3.33-3.38 (m, 1H), 2.94-3.07 (m, 2H), 2.76-2.84 (m, 1H), 2.03-2.16 (m, 1H), 1.74-1 .81 (m, 1H), 1.38-1.49 (m, 3H) IN Chiralpak IC, 30% MeOH, peak 2 667 500 MHz, METHANOL -d ₄ 7.07-7.25(m, 2H), 6.90-7.01(m, 1H), 5.16-5.32(m, 1H), 5.01-5.16(m, 1H), 4.32-4.55(m, 2H), 4.06-4.32(m, 2H), F Chiralpak ADH, 15% MeOH with 0.2% DEA,

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3.67-4.04 (m, 4H), 3.45-3.55 (m, 1H), 3.36-3.45 (m, 1H), 3.04-3.19 (m, 2H), 2.88-3.02 (m, 1H), 2.00-2.61 (m, 3H), 1.81-1.98(m, 1H) peak 2 668 600 MHz, DMSO- _d6 8.63-8.71(m, 1H), 7.20-7.25(m, 1H), 7.13-7.20(m, 1H), 6.87-6.98(m, 1H ), 4.63 (s, 2H), 4.31-4.48 (m, 1H), 4.164.28 (m, 1H), 3.35-3.47 (m, 1H), 2.953.10 ( m, 2H), 2.76-2.88 (m, 1H), 2.152.24 (m, 2H), 2.05-2.14 (m, 1H), 1.861.99 (m, 3H), 1 .76-1.86 (m, 1H), 1.571.71 (m, 2H) I SFC: Chiralpak AYH, 10% IP A, peak 1 669 600 MHz, DMSO- _d6 8.61-8.72(m, 1H), 7.15-7.29(m, 2H), 6.85-6.97(m, 1H), 4.69(d, 7=9.19 Hz, 2H), 4.31-4.50 (m, 1H), 4.04-4.15 (m, 1H), 3.36-3.49 (m, 2H), 2.96-3, 13 (m, 2H), 2.73-2.88 (m, 2H), 2.63-2.73 (m, 1H), 2.07-2.19 (m, 1H), 1.76- 1.86 (m, 1H), 1.21 (d, 7=6.77 Hz, ZN) I SFC: Chiralpak AYH, 10% IP A, peak 1 670 600 MHz, DMSO- _d6 8.63-8.74(m, 1H), 7.16-7.29(m, 2H), 6.85-6.96(m, 1H), 4.61-4.77(m, 2H ), 4.30-4.50 (m, 1H), 4.04-4.15 (m, 1H), 3.35-3.47 (m, 2H), 2.98-3.11 (m , 2H), 2.81-2.87 (m, 1H), 2.75-2.80 (m, 1H), 2.66-2.71 (m, 1H), 2.08-2.20 (m, 1H), 1.75-1.88 (m, 1H), 1.21 (d, 7=6.77 Hz, ZN) I SFC: Chiralpak AYH, 10% IP A, peak 1 671 600 MHz, DMSO- _d6 7.23-7.34 (m, 1H), 7.12-7.14 (m, 1H), 6.98 (t, 7=9.31 Hz, 1H), 4.95-5.09 ( m, 2H), 4.77-4.86 (m, 1H), 3.66-3.76 (m, 1H), 3.57-3.62 (m, 1H), 3.46-3 .56 (m, 4H), 3.37 (s, 3H), 3.31-3.35 (m, 2H), 3.07-3.12 (m, 2H), 2.91-3.05 (m, 1H), 2.16-2.23 (m, 1H), 1.76-1.88 (m, 1H), 1.04 (t, 7=7.01 Hz, ZN) I SFC: Chiralpak AYH, 10% IP A, peak 1

- 375 043189

672 500 MHz, METHANOL -d ₄ 7.08-7.23(m, 2H), 6.89-7.00(m, 1H), 5.15-5.32(m, 1H), 5.02-5.14(m, 1H ), 4.30-4.55(m, 2H), 4.07-4.28(m, 2H), 3.69-4.05(m, 4H), 3.47-3.57(m , 1H), 3.35-3.44 (m, 1H), 3.03-3.19 (m, 2H), 2.88-2.99 (m, 1H), 1.99-2.61 (m, 3H), 1.82-1.99 (m, 1H) F Chiralpak ADH, 15% MeOH with 0.2% DEA, peak 1 673 600 MHz, DMSO- _d6 8.55-8.63(m, 1H), 7.20-7.27(m, 1H), 7.13-7.19(m, 1H), 6.88-6.99(m, 1H ), 4.63-4.71 (m, 2H), 4.31-4.49 (m, 1H), 3.35-3.47 (m, 4H), 2.96-3.11 (m , 2H), 2.79-2.87 (m, 1H), 2.41-2.48 (m, 2H), 2.07-2.15 (m, 1H), 1.74-1.86 (m, 1H) I SFC: Chiralpak AYH, 10% IP A, peak 1 674 600 MHz, DMSO- _d6 8.86-9.01(m, 1H), 8.49-8.62(m, 1H), 7.71-7.82(m, 1H), 7.34-7.43(m, 1H ), 7.26-7.32(m, 1H), 7.14-7.24(m, 2H), 6.86-6.96(m, 1H), 4.97-5.07(m , 1H), 4.68-4.86 (m, 2H), 4.30-4.48 (m, 1H), 3.35-3.47 (m, 2H), 2.95-3.08 (m, 2H), 2.76-2.86 (m, 1H), 2.03-2.15 (m, 1H), 1.72-1.83 (m, 1H), 1.43 (d , 7=7.01Hz, 3H) I SFC: Chiralpak AYH, 10% IP A, peak 1 675 600 MHz, DMSO- _d6 8.62-8.77(m, 1H), 7.14-7.26(m, 2H), 6.83-6.98(m, 1H), 4.67(d, 7=5.29 Hz, 2H), 4.33-4.48 (m, 1H), 4.26-4.32 (m, 1H), 3.79-3.86 (m, 1H), 3.73-3, 78 (m, 1H), 3.67-3.73 (m, 1H), 3.50-3.56 (m, 1H), 3.37-3.46 (m, 2H), 2.97- 3.09 (m, 2H), 2.76-2.85 (m, 1H), 2.07-2.17 (m, 2H), 1.74-1.85 (m, 2H) IN Chiralpak AZ- H, 35% MeOH, peak 1 676 600 MHz, DMSO- _d6 8.65-8.73 (m, 1H), 7.16-7.27 (m, 2H), 6.89-6.97 (m, 1H), 4.67 (s, 2H), 4.334, 47 (m, 1H), 4.25-4.32 (m, 1H), 3.803.88 (m, 1H), 3.73-3.79 (m, 1H), 3.663.73 (m, 1H) , 3.49-3.57 (m, 1H), 3.37- V Chiralpak AZH, 35% MeOH peak 2

- 376 043189

3.46 (m, 2H), 2.96-3.10 (m, 2H), 2.77- 2.87 (m, 1H), 2.07-2.18 (m, 2H), 1.74- 1.86(m, 2H) 677 600MHz DMSO - d ₆ 8.18 (s, 2H), 7.17-7.25 (m, 2H), 6.93 (t, 7=9.30 Hz, 1H), 4.59-4.76 (m, 2H) , 4X4-4.53 (m, 1H), 4.34-4.43 (m, 1H), 4.07-4.22 (m, 1H), 3.84 (br t, 7=7.75 Hz, 1H), 3.28-3.47 (m, 2H), 3.01-3.21 (m, 4H), 2.79-2.95 (m, 1H), 2.52-2, 57 (m, 1H), 2.40-2.48 (m, 1H), 2.09-2.17 (m, 1H), 1.77-1.90 (m, 2H), 1.53 ( d, 7=6.23Hz, 1H), 1.35 (dd, 7=1.40, 6.31Hz, 1H) I SFC: Chiralpak AYH, 10% IP A, peak 1 678 600MHz DMSO - d ₆ 7.16-7.25(m, 2H), 6.91(t, 7=9.20Hz, 1H), 5.08-5.23(m, 1H), 4.81-4.95( m, 1H), 4.45 (dt, 7=4.17, 7.88 Hz, 1H), 4.30-4.39 (m, 1H), 4.13 (br s, 1H), 4, 00 (br d, 7=13.47 Hz, 1H), 3.82-3.93 (m, 1H), 3.60-3.73 (m, 2H), 3.41-3.53 (m , 2H), 2.96-3.07 (m, 2H), 2.77-2.86 (m, 1H), 2.12 (br s, 2H), 1.75-1.84 (m, 1H), 1.37 (br d, 7=5.61 Hz, 1H), 1.14-1.20 (m, 2H) I SFC: Chiralpak AYH, 10% IP A, peak 1 679 600MHz DMSO - d ₆ 7.15-7.25(m, 2H), 6.91(t, 7=9.32Hz, 1H), 4.87(s, 1H), 4.29-4.39(m, 1H) , 4.05 (dt, 7=2.61, 6.60 Hz, 1H), 3.613.75 (m, 1H), 3.42-3.59 (m, 3H), 2.953.12 (m, 2H ), 2.77-2.85 (m, 1H), 2.5-2.55 (m, 1H), 2.06-2.18 (m, 1H), 1.892.06 (m, 2H), 1.75- 1.87 (m, 1H), 1.451.63 (m, 1H), 1.22-1.29 (m, 1H), 1.11 (d, 7=6.31 Hz, 2H) I SFC: Chiralpak AYH, 10% IP A, peak 1 680 600MHz DMSO - d ₆ 7.15-7.27 (m, 1H), 7.08 (dd, 7=4.79, 8.60 Hz, 1H), 6.92 (t, 7=8.75 Hz, 1H), 5 .11-5.20 (m, 1H), 4.86-4.94 (m, 1H), I SFC: Chiralpak AYH, 10% IP A,

-377 043189

4.41-4.53 (m, 1H), 4.28-4.41 (m, 1H), 4.09-4.25 (m, 1H), 4.01 (br d, 7=11, 83 Hz, 1H), 3.77-3.90 (m, 3H), 3.64 (br dd, 7=3.31, 11.87 Hz, 1H), 3.44-3.60 (m, 2H), 3.34-3.43(m, 3H), 3.32(brs, 2H), 2.97-3.09(m, 3H), 2.75-2.85(m, 1H ), 2.06-2.25(m, 1H), 1.74-1.84(m, 1H). peak 1 681 600MHz DMSO - d ₆ 7.22 (d, 7=9.53 Hz, 1H), 7.18 (t, 7=7.08 Hz, 1H), 6.91 (t, 7=9.33 Hz, 1H), 5, eleven (br d, 7=17.36 Hz, 1H), 4.87 (br d, 7=17.05 Hz, 1H), 4.28-4.40 (m, 1H), 3.78-3, 92 (m, 1H), 3.61-3.76 (m, 2H), 3.38-3.53 (m, 2H), 3.26-3.34 (m, 3H), 2.95- 3.08 (m, 2H), 2.80 (dd, 7=8.29, 12.50 Hz, 1H), 2.02-2.20 (m, 2H), 1.751.85 (m, 1H) , 1.36 (br d, 7=5.76 Hz, 1H), 1.13-1.21 (m, 2H) I SFC: Chiralpak AYH, 10% IP A, peak 1 682 600MHz DMSO - d ₆ 7.14-7.25 (m, 2H), 6.91 (t, 7=9.19 Hz, 1H), 4.87 (q, 7=17.44 Hz, 2H), 4.28- 4.40(m, 1H), 3.97-4.13(m, 1H), 3.613.71(m, 1H), 3.47-3.60(m, 1H), 3.373.46(m, 3H), 2.95-3.11 (m, 2H), 2.752.89 (m, 1H), 2.52-1.91 (m, 4H), 1.491.60 (m, 1H), 1.23 -1.29(m, 1H), 1.11(d, 7=6.31Hz, 2H) I SFC: Chiralpak AYH, 10% IP A, peak 1 683 600MHz DMSO - d ₆ 8.43 (br s, 2H), 7.20-7.30 (m, 2H), 6.947.05 (m, 1H), 4.78-5.18 (m, 2H), 3.954.11 (m , 2H), 3.82-3.93 (m, 1H), 3.683.81 (m, 1H), 3.56-3.68 (m, 2H), 3.323.48 (m, 2H), 2, 99-3.17 (m, 1H), 1.982.21 (m, 1H), 1.40-1.51-2.0 (m, 1H), 1.13-1.30 (m, 7H) I SFC: Chiralpak AYH, 10% IP A, peak 1 684 600MHz DMSO - d ₆ 7.10-7.26(m, 2H), 6.90-6.96(m, 1H), 5.11-5.21 (m, 1H), 4.90-5.00 (m, 1H), 4.41-4.49 (m, 1H), 4.37 (br d, 7=6.07 I SFC: Chiralpak AYH, 10% IP A,

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Hz, 1H), 4.17 (br s, 1H), 3.70-3.87 (m, 2H), 3.61 (dt, 7=2.61, 11.50 Hz, 1H), 3, 38-3.33 (m, 2H), 3.13-3.20 (m, 1H), 2.99-3.05 (m, 2H), 2.87-2.98 (m, 1H), 2.77-2.85(m, 1H), 2.52-2.55(m, 1H), 2.29-2.47(m, 1H), 1.71-1.89(m, 1H ), 0.97 (t, 7=7.40 Hz, 1H), 0.81 (dt, 7=1.40, 7.40 Hz, ZN) peak 1 685 600MHz DMSO - d ₆ 7.22 (br d, 7=9.42 Hz, 1H), 7.16 (br d, 7=4.44 Hz, 1H), 6.92 (br t, 7=9.19 Hz, 1H) , 5.04-5.19 (m, 1H), 4.93 (br d, 7=17.44 Hz, 1H), 4.36-4.38 (br m, 1H), 3.86-3 .95 (m, 1H), 3.77-3.86 (m, 2H), 3.53-3.68 (m, 2H), 3.37-3.51 (m, 3H), 3.14 -3.27(m, 1H), 2.96-3.08(m, 2H), 2.77-2.89(m, 1H), 2.12(brs, 1H), 1.99( br s, 1H), 1.75-1.91 (m, 1H), 1.48 (br s, 1H), 0.62 (br s, 1H), 0.51 (br s, 1H), 0 .42 (br s, 1H), 0.24-0.36 (m, 1H) I SFC: Chiralpak AYH, 10% IP A, peak 1 686 600MHz DMSO - d ₆ 7.14-7.24(m, 1H), 7.11(dd, 7=4.79, 8.60Hz, 1H), 6.85-6.94(m, 1H), 5.15( br d, 7=17.52Hz, 1H), 5.06(d, 7=17.44Hz, 1H), 4.42-4.58(m, 1H), 3.96-4.04( m, 1H), 3.77-3.94 (m, 2H), 3.59-3.74 (m, 2H), 3.44 (br d, 7=9.89 Hz, 1H), 3, 24-3.41 (m, 2H), 2.97-3.23 (m, 1H), 2.65-2.94 (m, 2H), 2.52-2.56 (m, 1H), 2.07-2.16 (m, 1H), 1.74-1.84 (m, 1H), 1.07-1.19 (m, 2H) I SFC: Chiralpak AYH, 10% IP A, peak 1 687 600MHz DMSO - d ₆ 8.29-8.40 (br s, 2H), 7.21-7.30 (m, 1H), 6.99 (t, 7=9.33 Hz, 1H), 4.92-5.06 (m, 1H), 3.70-3.88 (m, 2H), 3.52-3.70 (m, 6H), 3.33-3.39 (m, 2H), 3.05-3 .18 (m, 2H), 3.01 (br t, 7=11.99 Hz, 1H), 2.52- 2.55 (m, 1H), 1.12-1.41 (m, 6H) I SFC: Chiralpak AYH, 10% IP A, peak 1

Biological example 1. Calcium flux analysis in TRPC6.

The efficacy of TRPC6 inhibitors (a family of C6 transient receptor potential channels) was measured by their inhibition of calcium influx initiated by stimulation of OAG (1-oleoyl-2-acetyl-8n-glycerol, Millipore Sigma, 06754) on HEK293 cells stably transfected with human TRPC6 using the FLIPR Tetra system. Cells were grown in humidified medium at 37° C. in 5% CO ₂ using growth medium with the following selective reagents (Dulbecco's Modified Eagle's Medium (DMEM) high glucose, 10% fetal bovine serum, IXPSGlu (penicillin-streptomycin-glutamine ), IX NEAA (non-essential amino acid), IX pyruvate Na and 200 μg/ml hygromycin). For total passage, cells were grown to 70-90% confluency; the medium was removed and the cells were gently washed 2 times with calcium- and magnesium-free PBS (phosphate-buffered saline). Trypsin (3 ml) was used for 5 min at 37°C. The cells were displaced by tapping the flask on the base of the hand and 7 ml of growth medium was added to deactivate the trypsin and resuspend the cells. The usual splitting scheme was 1:5 every 2-3 days.

Cells were seeded the day before assay, cell density at seeding was 1.0-1.5 x 10 ⁴ /25 μl/well in poly-O-lysine (PDL) coated 384-well plates using either multichannel or multipoint pipettes. These cells were first incubated with fluorescent stain.

-379 043189 at room temperature for 90-120 min, after which they were grown in PDL-coated 384-well black plates overnight (example 10 ml dye loading buffer: 9 ml assay buffer, 1 ml, 10X PBX signal enhancer , 10 µl of calcium indicator). Cells were incubated with the compound dose for 25 min prior to stimulation with the TRPC6 OAG agonist. OAG solution was prepared by adding OAG to assay buffer (Ringer's base containing Ca: 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid), 4 mM MgCl ₂ , 120 mM NaCl, 5 mM KCl , pH=7.2 at 25°C) + 0.1%BSA+2 mm CaCl ₂ ) to a concentration of 0.2 mm/2% DMSO, which provided a final cell concentration of 50 μm/0.5% DMSO. 12.5 μl of OAG mixture was added and TRPC6 channel activation was measured by changing intracellular calcium levels on the FLIPR Terra system.

Data was acquired by measuring the fluorescent peak signal subtracted from baseline over a 180 second imaging time interval. Each measurement point was further normalized to 100% of the signal initiated by the OAG compared to the buffer. In table. 16 shows the IC ₅₀ values for each compound, data obtained by plotting peak signal versus compound dose.

Table 16

Note. No. hTRPC6 potency (µM) Note. No. hTRPC6 potency (µM) 1 0.000696 345 0.0015 2 0.0032 346 0.00139 3 0.00199 347 0.00107 4 0.00167 348 0.493 5 0.00292 349 0.215 6 0.0004002 350 0.351 7 0.0011733 351 0.0103 8 0.00028336 352 0.328 9 0.0016133 353 0.0308 10 0.00606 354 0.133 AND 0.00179 355 0.037 12 0.000285 356 0.239 13 0.00687 357 0.0245 14 0.000377 358 0.00647 15 0.00439 359 0.238 16 0.224 360 0.0429 17 0.118 361 0.0668 18 0.00785 362 0.256 19 0.000956 363 0.0313 20 0.00192 364 1.02 21 0.0006585 365 2.96 22 0.00162 366 0.232 23 >3.75 367 0.354 24 0.145 368 0.0992 25 0.23 369 0.00865 26 0.161 370 >50.0 27 0.0735 371 6.83 28 >3.75 372 14.1 29 0.0448 373 5.85 thirty 1.94 374 3.41 31 0.000476 375 2.77 32 0.0472 376 3.05

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33 0.0004325 377 1.65 34 0.0689 378 3.08 35 0.000491 379 4.44 36 0.00613 380 17 37 0.00692 381 5.68 38 0.00071978 382 >50.0 39 0.000867 383 0.319 40 0.00461 384 16 41 0.0184 385 >50.0 42 1.94 386 4.26 43 0.000581 387 5.36 44 0.000952 388 9.75 45 0.00236 389 4.58 46 0.001785 390 3.57 47 0.000686 391 1.82 48 0.002205 392 2.24 49 0.001095 393 5.05 50 0.000759 394 0.732 51 0.00647 395 1.12 52 0.0242 396 18.2 53 0.00152 397 1.58 54 0.00552 398 0.0874 55 0.00397 399 0.0205 56 0.0135 400 16.5 57 0.000784 401 0.00045573 58 0.000469 402 0.00133 59 0.000256 403 0.000395 60 0.000261 404 0.00167 61 0.0027 405 0.000708 62 0.0603 406 0.000447 63 0.000389 407 0.00585 64 0.132 408 0.000924 65 0.000598 409 0.0010356 66 0.237 410 0.0105

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67 0.272 411 0.00268 68 0.0018215 412 0.322 69 0.01471 413 0.221 70 0.002325 414 0.0015 71 0.005615 415 0.274 72 0.000448 416 0.00236 73 0.0010945 417 0.0127 74 0.38 418 0.000584 75 0.0814 419 0.128 76 0.971 420 0.0006 77 0.0109 421 0.0005404 78 0.0707 422 0.00235 79 0.00509 423 0.351 80 0.0793 424 0.000707 81 0.557 425 0.113 82 0.000504 426 0.933 83 0.000906 427 >3.75 84 0.00127 428 0.0183 85 0.00755 429 >3.75 86 0.00137 430 0.88 87 0.000931 431 >3.75 88 0.0006428 432 0.00777 89 0.368 433 >3.75 90 0.068 434 >3.75 91 0.0329 435 1.16 92 0.0438 436 0.0524 93 0.0068533 437 >3.75 94 0.615 438 0.476 95 >3.75 439 0.0367 96 0.134 440 1.34 97 >3.75 441 0.002235 98 >3.75 442 0.000319 99 >3.75 443 0.000471 100 0.06 444 0.00442

- 382 043189

101 >3.75 445 0.0208 102 >3.75 446 0.034 103 >3.75 447 0.119 104 0.0618 448 0.123 105 2.48 449 1.16 106 0.0004496 450 >3.75 107 0.00788 451 0.000613 108 0.000433 452 0.00117 109 0.0438 453 0.00151 110 0.001232 454 0.00152 111 0.0007875 455 0.00656 112 0.00028147 456 0.00844 FROM 0.0002855 457 0.0133 114 0.000382 458 0.0163 115 0.000446 459 0.0164 116 0.00779 460 0.0242 117 >3.75 461 0.0289 118 0.000855 462 0.0294 119 0.00194 463 0.0339 120 0.00321 464 0.0631 121 0.00559 465 0.0867 122 0.0299 466 0.103 123 0.252 467 0.123 124 0.000741 468 0.178 125 0.000389 469 0.19 126 0.00048 470 0.219 127 0.000492 471 0.36 128 0.04935 472 0.383 129 >3.75 473 0.398 130 0.269 474 0.411 131 0.08255 475 0.62 132 0.042 476 0.763 133 0.00698 477 1.03 134 0.00471 478 1.05

- 383 043189

135 > 3.75 [2] 479 1.2 136 0.013945 480 1.2 137 0.0362 481 2.4 138 0.00052 482 2.74 139 0.001905 483 2.74 140 0.132 484 >3.75 141 0.0135 485 >3.75 142 0.0138 486 >3.75 143 0.0068625 487 >3.75 144 0.000462 488 >3.75 145 0.014 489 >3.75 146 0.000631 490 >3.75 147 0.000433 491 >3.75 148 0.0118 492 >3.75 149 0.00109 493 >3.75 150 0.00902 494 0.0126 151 0.00606 495 0.0127 152 0.0677 496 0.0611 153 0.072 497 0.094 154 0.00306 498 0.00188 155 0.0162 499 0.00258 156 0.0617 500 0.005145 157 0.000501 501 0.00621 158 0.00471 502 0.009095 159 0.0164 503 0.0256 160 0.0142 504 0.0393 161 0.133 505 0.0432 162 0.257 506 0.0766 163 2.84 507 0.102 164 0.253 508 0.112 165 2.06 509 0.131 166 0.56 510 0.139 167 0.0019657 511 0.158 168 1.6 512 0.162

- 384 043189

169 0.0142 513 0.183 170 0.0259 514 0.185 171 0.544 515 0.186 172 0.00222 516 0.197 173 0.00138 517 0.319 174 0.564 518 0.4 175 1.7 519 0.476 176 2.33 520 0.686 177 1.54 521 0.757 178 0.0471 522 0.762 179 0.326 523 0.988 180 0.0149 524 1.49 181 0.000907 525 1.78 182 0.314 526 2.85 183 0.655 527 3.01 184 0.143 528 >3.75 185 0.003585 529 >3.75 186 0.278 530 >3.75 187 0.0015905 531 >3.75 188 0.013025 532 >3.75 189 0.0035867 533 >3.75 190 0.004015 534 >3.75 191 0.13985 535 >3.75 192 0.001725 536 >3.75 193 0.0485 537 >3.75 194 0.0142 538 >3.75 195 0.000664 539 >3.75 196 0.00647 540 >3.75 197 0.2555 541 >3.75 198 0.07125 542 >3.75 199 0.0281 543 >3.75 200 0.00218 544 >3.75 201 0.0439 545 >3.75 202 0.002137 546 >3.75

- 385 043189

203 0.598 547 0.0437 204 0.00492 548 0.382 205 0.003 549 0.41 206 0.0123 550 >3.75 207 0.0496 551 0.0061 208 0.0477 552 0.00651 209 0.0038675 553 0.00669 210 0.0691 554 0.0109 211 0.001095 555 0.0116 212 0.0034975 556 0.0119 213 0.00993 557 0.0128 214 0.00042 558 0.0161 215 0.593 559 0.0166 216 0.0114 560 0.0187 217 0.0687 561 0.0198 218 0.00082 562 0.0208 219 0.0159 563 0.0216 220 0.0009855 564 0.0292 221 0.0549 565 0.0322 222 0.002045 566 0.0352 223 0.0515 567 0.0398 224 0.158 568 0.04805 225 0.00281 569 0.0784 226 0.0137 570 0.0854 227 0.00032823 571 0.0932 228 0.00032 572 0.106 229 0.0422 573 0.117 230 0.00049 574 0.153 231 0.737 575 0.155 232 0.00216 576 0.169 233 0.00147 577 0.184 234 0.0269 578 0.251 235 0.15 579 0.312 236 0.0238 580 0.365

- 386 043189

237 0.223 581 0.368 238 0.185 582 0.376 239 0.562 583 0.42 240 0.0107 584 0.546 241 >3.75 585 0.579 242 0.0735 586 0.742 243 1.97 587 0.765 244 >3.75 588 0.811 245 0.0625 589 ι, θι 246 2.92 590 1.44 247 0.0754 591 1.59 248 0.00507 592 1.73 249 0.00765 593 2.12 250 0.0785 594 >3.75 251 0.0172 595 >3.75 252 0.00876 596 >3.75 253 0.406 597 >3.75 254 0.0739 598 >3.75 255 0.10145 599 >3.75 256 0.0194 600 0.00538 257 0.0524 601 0.00556 258 0.0002881 602 0.00575 259 1.43 603 0.00673 260 0.376 604 0.00778 261 >3.75 605 0.0079 262 0.28 606 0.00806 263 0.765 607 0.0143 264 0.217 608 0.0183 265 2.86 609 0.0203 266 15.8 610 0.0212 267 >3.75, >50.0 611 0.0224 268 >3.75, >50.0 612 0.0224 269 0.002045 613 0.0242 270 0.0515 614 0.0248

- 387 043189

271 0.158 615 0.0285 272 0.00281 616 0.0323 273 0.0137 617 0.0332 274 0.00032823 618 0.0483 275 0.00032 619 0.0574 276 0.0422 620 0.0604 277 0.00049 621 0.0753 278 0.737 622 0.0789 279 0.00216 623 0.089 280 0.00147 624 0.102 281 0.0269 625 0.105 282 0.15 626 0.117 283 0.0238 627 0.122 284 0.223 628 0.132 285 0.185 629 0.158 286 0.562 630 0.174 287 0.0107 631 0.225 288 >3.75 632 0.23 289 0.0735 633 0.24 290 1.97 634 0.26 291 >3.75 635 0.304 292 0.0625 636 0.326 293 2.92 637 0.341 294 0.0754 638 0.425 295 0.00507 639 0.657 296 0.00765 640 0.809 297 0.0785 641 1.28 298 0.0172 642 1.65 299 0.00876 643 1.82 300 0.406 644 1.91 301 0.0739 645 2.3 302 0.10145 646 2.31 303 0.0194 647 3.17 304 0.0524 648 3.35

- 388 043189

305 0.0002881 649 >3.75 306 1.43 650 >3.75 307 0.376 651 >3.75 308 >3.75 652 >3.75 309 0.28 653 >3.75 310 0.765 654 >3.75 311 0.217 655 >3.75 312 2.86 656 >3.75 313 15.8 657 >3.75 314 >3.75, >50.0 658 >3.75 315 >3.75, >50.0 659 >3.75 316 0.002045 660 0.005037 317 1.36 661 0.279 318 0.0377 662 0.283 319 0.456 663 0.294 320 0.01205 664 0.555 321 0.00407 665 0.584 322 1.45 666 0.687 323 >3.75 667 0.745 324 >3.75 668 0.778 325 0.743 669 0.901 326 2.93 670 1.12 327 1.37 671 1.43 328 >3.75 672 1.66 329 >3.75 673 >3.75 330 0.669 674 >3.75 331 0.204 675 >3.75 332 3.2 676 >3.75 333 3.25 677 0.0881 334 3.54 678 0.0983 335 >3.75 679 0.15 336 >3.75 680 0.153 337 >3.75 681 0.168 338 >3.75 682 0.259 339 0.00323 683 0.29 340 0.000704 684 0.524 341 0.0258 685 1.16 342 0.0121 686 1.57 343 0.804 687 2.08 344 0.0853

The foregoing is merely illustrative of the present invention and is not intended to limit the present invention to the disclosed compounds. Variations and changes that are obvious to a person skilled in the art are intended to be within the scope and spirit of the present invention, as defined in the appended claims.

From the foregoing description, a person skilled in the art can easily ascertain the main characteristics of the present invention and, without departing from its spirit and scope, is able to make various changes and modifications to the present invention to adapt it to various applications and conditions.

Claims (18)

1. A compound or a pharmaceutically acceptable salt thereof according to formula (I) R ^{6 R1} b), where p is 0 or 1; if p is 0, then R ¹ is hydrogen, C1-C6 alkyl, halogen or hydroxy; R ² is amino or amino C1- _C4 alkyl; R ³ is hydrogen; and R ⁴ is hydrogen, C ₁ -C ₆ alkyl or phenyl; or if p is 0, then R ¹ and R ³ taken in combination form a fused C3-C6 cycloalkyl ring or a fused 4-6 membered heterocyclic ring containing 1 or 2 ring heteroatoms independently selected from N, O or S , wherein the cycloalkyl or heterocycle is optionally substituted with amino; R ² represents hydrogen, C1-C ₆ -alkyl or amino-C ₁ -C ₄ -alkyl; and R ⁴ is hydrogen; or if p is 1, then R ¹ is NHR ^1a ; R ^1a is hydrogen, C1C4 alkyl, C3-C7 cycloalkyl, hydroxy-C1-C4 alkyl or 4-6 membered heterocycloalkyl containing one ring heteroatom selected from N, O or S; R ² is hydrogen, C1-C4 alkyl, hydroxy-C1-C ₄ alkyl or C(O)NH ₂ ; R ³ is hydrogen, halogen, C1-C4-αkyl, C1-C4-alkoxy or hydroxy; and R ⁴ is hydrogen, C1-C ₄ alkyl or halogen; or if p is 0 or 1, then C(NHR ^1a )R ² taken in combination forms a spirocyclic 4-6 membered heterocycloalkyl; R ³ is hydrogen, halo-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or hydroxy; and R ⁴ is hydrogen or halogen; or if p is 1, then R ¹ and R ³ taken in combination form a fused 4-6 membered heterocycle or a fused 3-7 membered carbocycle, wherein the heterocycle contains a ring nitrogen atom and optionally 0 or 1 additional ring heteroatom, selected from N, O and S, and wherein the carbocycle is substituted with amino; And R ² is hydrogen; and R ⁴ is hydrogen, halogen or hydroxy; R ⁵ represents 1 or 2 substituents independently selected from hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy; R ⁶ is -(CR ⁷ R ⁸ )-A; A is a 5- or 6-membered heteroaryl, wherein the heteroaryl contains one ring heteroatom selected from N, O, or S and 0, 1, or 2 additional ring nitrogen atoms, the heteroaryl being optionally substituted with 0, 1, or 2 groups, independently selected from halogen, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, halogen-C ₁ -C ₆ -αkyl, C ₁ -C ₆ -alkoxy, halogen- C ₁ -C ₆ -alkoxy, C(O)NH ₂ , C(O)NHC ₁ -C ₆ -alkyl, phenyl or 5- or 6-membered heteroaryl containing one ring heteroatom selected from N, O or S, and 0, 1 or 2 additional ring nitrogens, wherein the optional heteroaryl or phenyl substituent is further substituted with 0, 1 or 2 C ₁ -C ₆ alkyl; R ⁷ is hydrogen, C ₁ -C ₄ -alkyl or amino; R ⁸ is hydrogen or C ₁ -C ₄ alkyl; or CR7R ⁸ taken in combination forms a 3-6 membered cycloalkanediyl group; Z ¹ is N or CR ¹¹ ; Z ² is CR ¹² ; Z ³ is CR ¹³ ; Z ⁴ is N or CR ¹⁴ , each of Z ⁵ and Z ⁶ is C; each of R ¹¹ , R ¹² , R ¹³ and R ¹⁴ is independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkynyl, C ₁ - C ₆ -alkoxy, halogen-C ₁ -C ₆ -alkyl, halogen-C ₁ -C ₆ -alkoxy, C ₃ C ₇ -cycloalkyl, cyano, SO ₂ C ₁ -C ₆ -alkyl, phenyl and saturated, partially unsaturated or an aromatic 5- or 6-membered heterocycle containing 1 or 2 ring heteroatoms independently selected from N, O and S, wherein the heterocycle is optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ alkyl and halogen; and provided that the compounds of formula I do not include 1-[7-fluoro6-methoxy-1-[[2-(trifluoromethyl)phenyl]methyl]-1 H-benzimidazol-2-yl]-3-piperidineamine. 2. Connection according to claim 1, where p is 0; R ¹ and R ³ taken in combination form a fused C ₃ -C ₆ cycloalkyl ring or a fused 4-6 membered azacyclic ring, wherein the cycloalkyl or azacycle is optionally substituted with amino; and R ² and R ⁴ are hydrogen. 3. Connection according to claim 1, where p is equal to 1, R ¹ represents NHR ^1a ; R ^1a is water - 390 043189 genus, C 1 -C ₄ -alkyl, C ₃ -C ₇ -cycloalkyl or 4-6-membered heterocycloalkyl containing one ring heteroatom selected from N, O or S; R ² is hydrogen or C1-C4 alkyl; R ³ is hydrogen, halogen, C1-C4 alkyl, C1- _C4 alkoxy or hydroxy; and R ⁴ is hydrogen, halogen, or C ₁ -C ₄ alkyl. 4. Connection according to claim 3, where R ¹ represents NHR ^1a ; R ^1a is hydrogen, methyl, ethyl, propyl, isopropyl or cyclopropyl; R ² is hydrogen or methyl; R ³ is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy or hydroxy; and R ⁴ is hydrogen, halogen, methyl or ethyl. 5. Connection according to claim 3 or 4, where R ¹ represents NH ₂ ; R ² is hydrogen; R ³ is hydrogen, fluorine, methyl or hydroxy; and R ⁴ is hydrogen, fluoro or methyl. 6. The compound according to any one of paragraphs.1-5, where R ⁷ represents hydrogen or methyl; and R ⁸ is hydrogen. 7. A compound according to any one of claims 1-6, wherein A is pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, or pyrazin-2-yl, each of which is substituted with 1-3 groups, independently selected from the group consisting of halo, cyano, C1- _C4 alkyl, halo-C _{g C4} alkyl, C1- _C4 alkoxy, halo-C1- _C4 alkoxy, C(O)NH ₂ , C( O)NHC ₁ -C ₄ -alkyl, phenyl or 5-membered heteroaryl containing one ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms, where the optional heteroaryl or phenyl substituent is additionally substituted with 0 , 1 or 2 C1- _C6 alkyls. 8. Connection according to any one of claims 1-7, where Z ¹ is CR ¹¹ ; Z ² is CR ¹² ; Z ³ is CR ¹³ ; Z ⁴ is N or CR ¹⁴ , each of Z ⁵ and Z ⁶ is C; R ¹¹ represents hydrogen, halogen, cyano or C1-C ₄ -alkyl; each of R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, halogen, cyano, C1- _C4 alkyl, halo-C1- _C4 alkyl, C1- _C4 alkoxy, halo-C _{g C4} alkoxy , C ₃ -C ₆ -cycloalkyl or 5-membered saturated, partially unsaturated or aromatic 5 - or 6-membered heterocycle containing 1 or 2 ring heteroatoms independently selected from N, O and S; And R ¹⁴ is hydrogen, halo, cyano or C1- _C4 alkyl. 9. The compound according to claim 1, which is a compound of formula (III) where X ¹ represents CR ¹⁶ or N; X ² is CR ¹⁷ or N; X ³ is CR ¹⁸ or N; where at least one of X ¹ , X ² and X ³ represents N; Z ⁴ is N or CR ¹⁴ ; R ¹ is NHR ^1a ; R ^1a represents hydrogen or C ₁ -C ₄ -alkyl; R ² represents hydrogen or C ₁ -C ₄ -alkyl; R ³ is hydrogen or halogen; R ⁴ is hydrogen or halogen; R ⁷ is hydrogen, methyl or ethyl; R ¹¹ represents hydrogen, halogen, cyano or C ₁ -C ₄ -alkyl; each of R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, halo- _{C 4} -alkyl, C 1 -C ₄ -alkoxy, or halo-C ₁ -C ₄ -alkoxy; R ¹⁴ is hydrogen, halogen, cyano or C1- _C4 alkyl; R ¹⁵ is hydrogen, halogen, cyano, C1-C ₄ alkyl, C1-C ₄ alkoxy, halo-C _g C ₄ alkyl, halo-C _g C ₄ alkoxy, C(O)NH ₂ , C (O)NH(C ₁ -C ₄ -alkyl) or 5-membered heteroaryl containing one ring heteroatom selected from N, O or S and 0, 1 or 2 additional ring nitrogen atoms; R ¹⁶ is hydrogen, halogen, cyano, C1- _C4 alkyl, C1- _C4 alkoxy, halo-C _{g C4} alkyl, or halo-C1- _C4 alkoxy; R ¹⁷ is hydrogen or halogen; And - 391 043189 R ¹⁸ is hydrogen, halogen, cyano, C1-C4-alkyl, _C1 - _C4 -alkoxy, halo- _C1 - _C4 -alkyl, or halo- _C1 - _C4 -alkoxy, where at least one of R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ is not hydrogen. 10. A compound according to claim 9, wherein R ¹¹ is hydrogen. 11. The compound according to claim 9, where R ^1a represents hydrogen or methyl; R ³ represents hydrogen or fluorine; and R ⁴ is hydrogen or fluorine. 12. A compound selected from the group consisting of: (S)-6-((2-(3-aminopiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-1-yl)-5-chloro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-1-yl)-4-chloro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-5-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-4-chloro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole4-carbonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-chloro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-5-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3S,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (S)-6-((2-(5-amino-3,3-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-6-fluoro-1Hbenzo[d]imidazole-4-carbonitrile ; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethoxy)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-(trifluoromethoxy)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-5-(trifluoromethyl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-6-(trifluoromethyl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3aS,7aR)-hexahydro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3aS,7aS)-hexahydro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3aS,7aS)-hexahydro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3aS,7aR)-hexahydro-1H-pyrrolo[2,3-c]pyridin-6(2H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; (R)-6-((2-(1,6-diazaspiro[3.5]nonan-6-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (S)-6-((2-(1,6-diazaspiro[3.5]nonan-6-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (3R,4R)-1-(1-((5-chloropyridin-2-yl)methyl)-6-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine; (3R,4R)-1-(1-((5-chloropyridin-2-yl)methyl)-5-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1Hbenzo[d]imidazole-4-carbonitrile ; (3R,4R)-1-(5,7-difluoro-1-((5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4 - 392 043189 fluoropiperidine-3-amine; (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine; (3R,4R)-1-(5,7-difluoro-1-((5-fluoropyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine; (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine; 2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1-((5-fluoropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-4-carbonitrile ; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1-((5-fluoropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-4-carbonitrile ; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (3R,4S)-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin3-amine; (3R,4S)-1-(1-((5-chloropyrimidin-2-yl)methyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin3-amine; (R)-2-(3-amino-4,4-difluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-6-carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-5-carbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-dichloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; tert-butyl-((3R,4R)-1-(1-((5-cyanopyridin-2-yl)methyl)-5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin- 3-yl) carbamate; (S)-6-((2-(3-aminopiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; (S)-6-((2-(3-aminopiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; (S)-2-(3-aminopiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole-6carbonitrile; (S)-2-(3-aminopiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole-5carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole6-carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole5-carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole6-carbonitrile; (R)-2-(3-amino-4,4-difluoropiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole5-carbonitrile; (S)-6-((2-(3-aminopiperidin-1-yl)-4,6-dichloro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4,6-dichloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-4,6-dichloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-4,6-dichloro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (S)-6-((2-(3-aminopiperidin-1-yl)-5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,7-difluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1 - 393 043189 yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole6-carbonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1-((5-cyanopyridin-2-yl)methyl)-1H-benzo[d]imidazole5-carbonitrile; (S)-6-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-5-fluoro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; 6-((2-((1R,5S)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((1S,5R)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3aS,4S,6aR)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3aS,4R,6aR)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-(aminomethyl)pyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; (S)-6-((2-(3-(aminomethyl)pyrrolidin-1-yl)-1 H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-5,6-dichloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; (R)-1-(1-((5-chloropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4,4-difluoropiperidin-3-amine hydrochloride; (3R,4S)-1-(1-((5-chloropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-fluoro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-3H-imidazo[4,5-b]pyridin-3yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-N (tert-butyl)nicotinamide; 6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3S,4S)-3-aMUHo-4-rugpoKcununepuguH-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; 6-((2-(2,6-diazaspiro[3.4]octan-6-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; - 394 043189 6-((2-((4aR,7aS)-hexahydroiurrolo[3,4-b][1,4]oxazine-6(2H)-ul)-1H-benzo[d]umidazol-1yl)methyl)nicotinonitrile hydrochloride ; 6-((2-((4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-ul)-1H-benzo[d]umidazol-1yl)methyl)nicotinonitrile hydrochloride ; 6-((2-((4aR,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((4aS,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-ul)-1H-benzo[d]umidazol-1yl)methyl)nicotinonitrile; (S)-3-amino-1-(1-((5-cyanoiiridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)iieridin-3carboxamide; (R)-3-amino-1-(1-((5-cyanoiiridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)iieridin-3carboxamide; (S)-6-((2-(3-amino-3-(hydroxymethyl)iiieridin-1-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-3-(hydroxymethyl)iiieridin-1-yl)-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-fluoro-1-iieridinyl)-6-(trifluoromethyl)-1 H-benzimidazol-1-yl)methyl)-3-iiridinecarbonitrile; 6-((2-((3R,4S)-3-amino-4-fluoro-1-iieridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl)methyl)-3iiridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-1-iieridinyl)-6-(trifluoromethyl)-1 H-benzimidazol-1-yl)methyl)-3iiridincarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-1-iieridinyl)-5-(trifluoromethyl)-1 H-benzimidazol-1-yl)methyl)-3-iiridincarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5-methyl-1H-benzimidazol-1-yl)methyl)-3iiridincarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-6-methyl-1H-benzimidazol-1-yl)methyl)-3iiridincarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-6-chloro-5-methyl-1 H-benzimidazol-1-yl)methyl)-3-yiridincarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5-chloro-6-methyl-1 H-benzimidazol-1-yl)methyl)-3-yiridincarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-6-fluoro-5-methyl-1H-benzimidazol-1-yl)methyl)-3iyridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5-fluoro-6-methyl-1H-benzimidazol-1-yl)methyl)-3iiridincarbonitrile; 6-((2-((3S)-3-(methylamino)-1-iieridinyl)-1 H-benzimidazol-1-yl)methyl)-3-iiridinecarbonitrile; 6-((2-((3R)-3-(methylamino)-1-iieridinyl)-1 H-benzimidazol-1-yl)methyl)-3-iiridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-6-(difluoromethoxy)-1H-benzimidazol-1-yl)methyl)-3iiridincarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5-(difluoromethoxy)-1H-benzimidazol-1-yl)methyl)-3iiridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-4-methoxy-1H-benzimidazol-1-yl)methyl)-3-iiridincarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-4-methyl-1H-benzimidazol-1-yl)methyl)-3iiridincarbonitrile; 5-((2-((3R,4S)-3-amino-4-fluoro-1-iieridinyl)-6-(trifluoromethyl)-1H-benzimidazol-1-yl)methyl)-2iyrazinecarboxamide; 5-((2-((3R,4S)-3-amino-4-fluoro-1-iieridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl)methyl)-2iyrazinecarboxamide; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-6-chloro-5-(trifluoromethoxy)-1H-benzimidazol-1yl)methyl)-3-iiridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5-chloro-6-(trifluoromethoxy)-1H-benzimidazol-1yl)methyl)-3-iiridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1yl)methyl)-3-iiridinecarbonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5-chloro-6-(trifluoromethyl)-1H-benzimidazol-1yl)methyl)-3-iiridinecarbonitrile; 6-((2-((5R)-1,7-diazasiiro[4.5]decan-7-yl)-1H-benzimidazol-1-yl)methyl)-3-yridinecarbonitrile, 6((2-((5S) -1,7-diazasiiro[4.5]decan-7-yl)-1H-benzimidazol-1-yl)methyl)-3-yridinecarbonitrile; 6-((2-((6R)-1,8-diazasiiro[5.5]undecan-8-yl)-1H-benzimidazol-1-yl)methyl)-3-yridinecarbonitrile; 6-((2-((6S)-1,8-diazasiiro[5.5]undecan-8-yl)-1H-benzimidazol-1-yl)methyl)-3-yridinecarbonitrile; - 395 043189 6-((2-((4aR,8aR)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)-yl)-1H-benzimidazol-1-yl)methyl) 3-pyridinecarbonitrile; 6-((2-((4aS,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)-yl)-1H-benzimidazol-1-yl)methyl) 3-pyridinecarbonitrile; 5-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,6-difluoro-1H-benzimidazol-1-yl)methyl)-2pyrazinecarboxamide; 5-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-6-(trifluoromethyl)-1H-benzimidazol-1-yl)methyl)-2pyrazinecarboxamide; 6-((2-((5R)-1,7-diazaspiro[4.5]decan-7-yl)-1H-benzimidazol-1-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((5S)-1,7-diazaspiro[4.5]decan-7-yl)-1H-benzimidazol-1-yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-1-piperidinyl)-5-methoxy-1H-benzimidazol-1-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3R)-3-amino-4,4-difluoro-1-piperidinyl)-6-methoxy-1H-benzimidazol-1-yl)methyl)-3pyridinecarbonitrile; 6-((2-((3S)-3-(methylamino)-1-piperidinyl)-6-(trifluoromethyl)-1H-benzimidazol-1 yl)methyl)-3-pyridinecarbonitrile; 6-((2-((3S)-3-(methylamino)-1-piperidinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl)methyl)-3 pyridinecarbonitrile; 6-((2-((3S)-3-amino-3-methyl-1-piperidinyl)-1 H-benzimidazol-1-yl)methyl)-3-pyridinecarbonitrile; (S)-6-((2-(3-aminopiperidin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile 2,2,2-trifluoroacetate; (S)-6-((2-(3-aminopiperidin-1-yl)-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile 2,2,2-trifluoroacetate; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-6-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile-2, 2,2-trifluoroacetate; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5-methoxy-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-5-methoxy-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile hydrochloride; 2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1Hbenzo[d]imidazole-4-carbonitrile ; (R)-2-(3-Amino-4,4-difluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-5-fluoro-1Hbenzo [d]imidazole-7-carbonitrile ; (R)-2-(3-amino-4,4-difluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1Hbenzo[d]imidazole-4-carbonitrile ; 6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-hydroxypiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; (R)-4-((2-(3-amino-4,4-difluoropiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-1H-benzo[d]imidazol-1yl)methyl)benzonitrile dihydrochloride with 4-((2-((3S ,4S)-3-amino-4-hydroxypiperidin-1-yl)-1H-benzo[d]imidazol-1yl)methyl)benzonitrile (1:1); 4-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,7-difluoro-1 H-benzimidazol-1 yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-4,6-difluoro-1 H-benzimidazol-1 yl)methyl)benzonitrile; 2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-1-(4-cyanobenzyl)-1H-benzimidazole-6-carbonitrile; 2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-1-(4-cyanobenzyl)-1H-benzimidazole-5-carbonitrile; 2-((3R)-3-amino-4,4-difluoro-1-piperidinyl)-1-(4-cyanobenzyl)-1 H-benzimidazole-6-carbonitrile; 2-((3R)-3-amino-4,4-difluoro-1-piperidinyl)-1-(4-cyanobenzyl)-1H-benzimidazole-5-carbonitrile; (R)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-methylpiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-(3-(aminomethyl)-3-methylpyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile and 4-((2-(( 3R,4S)-3-amino-4-phenylpyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (S)-4-((2-(3-aminopyrrolidin-1-yl)-1 H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (S)-4-((2-(3-aminopiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)methyl)benzonitrile; - 396 043189 4-((2-(6-Amino-2-azaspiro[4.4]nonan-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-(4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1H-benzo[d]imidazol-1yl)methyl)benzonitrile; 4-((2-((3S,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3S,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (R)-4-((2-(3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-1 H-benzo[d]imidazol-1-yl)methyl)benzonitrile 2,2,2-trifluoroacetate; (S)-4-((2-(3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile 2,2,2-trifluoroacetate; (R)-4-((2-(3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-1 H-benzo[d]imidazol-1 yl)methyl)benzonitrile-2,2,2-trifluoroacetate; (S)-4-((2-(3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-1 H-benzo[d]imidazol-1 yl)methyl)benzonitrile-2,2,2-trifluoroacetate; (S)-4-((2-(3-(aminomethyl)pyrrolidin-1-yl)-1 H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (R)-4-((2-(3-(aminomethyl)pyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3S,4S)-3-amino-4-methylpiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile 2,2,2-trifluoroacetate; 4-((2-((3S,4R)-3-amino-4-methylpiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile 2,2,2-trifluoroacetate; 4-((2-((3R,4S)-3-amino-4-methylpiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile 2,2,2-trifluoroacetate; 4-((2-((1S,5R)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-1 yl)methyl)benzonitrile; 4-((2-((1R,5S)-1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-1yl)methyl)benzonitrile; (R)-4-((2-(3-aminopiperidin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (R)-4-((2-(3-aminopiperidin-1-yl)-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-6-carbonitrile; (3R,4R)-4-fluoro-1-(1-((5-fluoro-pyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine; (3R,4R)-4-fluoro-1-(1-((5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidine-3-amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazole6-carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazole5-carbonitrile; (3R,4R)-1-(1-((5-bromopyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; (3R,4R)-4-fluoro-1-(1-((5-(trifluoromethyl)pyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2yl)piperidine-3-amine; (3R,4R)-4-fluoro-1-(1-((5-methoxypyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidine-3amine; (3R,4R)-1-(1-((5-chloropyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-fluoro-pyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-6-carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-fluoropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-5-carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-cyanopyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-5-carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-5-carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-bromopyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-6-carbonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-bromopyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-5-carbonitrile; 5-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)pyrazine-2carbonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-Nibenzo[d]imidazole-6-carbonitrile; 2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-Hbenzo[d]imidazole-5-carbonitrile; (3R,4R)-3-amino-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1H-benzo[d]imidazol-2- 397 043189 yl)piperidin-4- ol; (3R,4R)-3-amino-1-(1-((5-chloropyrimidin-2-yl)methyl)-5-fluoro-1H-benzo[d]imidazol-2yl)piperidin-4-ol; 6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; (S)-1-(1-((5-chloropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine; (S)-5-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)picolinonitrile; (3R,4R)-1-(1-((5-chloropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3-amine hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyridin-2-yl)methyl)-1H-benzo[d]imidazole6-carbonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyridin-2-yl)methyl)-1H-benzo[d]imidazole5-carbonitrile hydrochloride; (3R,4R)-1-(1-((R)-1-(5-chloropyridin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine hydrochloride; (3R,4R)-1-(1-((S)-1-(5-chloropyridin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin-3amine hydrochloride; (3R,4R)-1-(1-((R)-1-(5-chloropyridin-2-yl)ethyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-4fluoropiperidine -3-amine hydrochloride; (3R,4R)-1-(1-((S)-1-(5-chloropyridin-2-yl)ethyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-4fluoropiperidine -3-amine hydrochloride; (3R,4R)-1-(5-chloro-1-((R)-1-(5-chloropyridin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3 -amine hydrochloride; (3R,4R)-1-(5-chloro-1-((S)-1-(5-chloropyridin-2-yl)ethyl)-III-benzo[d]imidazol-2-yl)-4fluoropiperidin-3 -amine hydrochloride; (3R,4R)-1-(6-chloro-1-((R)-1-(5-chloropyridin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3 -amine hydrochloride; (3R,4R)-1-(6-chloro-1-((S)-1-(5-chloropyridin-2-yl)ethyl)-III-benzo[d]imidazol-2-yl)-4fluoropiperidin-3 -amine hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((R)-1-(5-cyanopyridin-2-yl)ethyl)-1Нbenzo[d]imidazol-6 -carbonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((R)-1-(5-cyanopyridin-2-yl)ethyl)-1Нbenzo[d]imidazol-5 -carbonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((S)-1-(5-cyanopyridin-2-yl)ethyl)-1Нbenzo[d]imidazol-6 -carbonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((S)-1-(5-cyanopyridin-2-yl)ethyl)-1Нbenzo[d]imidazol-5 -carbonitrile hydrochloride; (3R,4R)-1-(1-((5-chloropyridin-2-yl)methyl)-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine hydrochloride; (3R,4R)-1-(5,6-difluoro-1-((5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine hydrochloride; (R)-1-(1-((5-chloropyridin-2-yl)methyl)-5,7-difluoro-1H-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride; (R)-1-(1-((5-chloropyridin-2-yl)methyl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine hydrochloride; (R)-1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)-2,3-dihydro-1Hinden- 5-carbonitrile hydrochloride; (S)-1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)-2,3-dihydro-Shinden -5-carbonitrile hydrochloride; (R)-5-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)pyrazine-2carbonitrile; (R)-5-((2-(3-amino-4,4-difluoropiperidin-1-yl)-5-chloro-1H-benzo[d]imidazol-1-yl)methyl)pyrazine-2carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)-Nisopropylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)-1-(azetidin1-yl )ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)-N-(2 - 398 043189 cyanopropyl) -N-ethylacetamide; 3 -(2-((3R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1 H-benzo[d]imidazol-1 -yl)-1 methylpyrrolidin-2- He; 3 -(2-((3R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1 H-benzo[d]imidazol-1 -yl)-1 phenylpiperidin-2- He; 3 -(2-((3R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1 H-benzo[d]imidazol-1 -yl)-1 -(4chlorophenyl) pyrrolidin-2-one; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-methoxypyrimidin-2-yl)methyl)-Thbenzo[d]imidazole-5-carbonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-methoxypyrimidin-2-yl)methyl)-Nibenzo[d]imidazole-6-carbonitrile hydrochloride; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1Hbenzo[d]imidazole-6-carbonitrile hydrochloride ; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1Hbenzo[d]imidazole-5-carbonitrile hydrochloride ; (S)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)-1methylpyrrolidin- 2-he; (R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)-1methylpyrrolidin- 2-he; (S)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)-1- (4chlorophenyl)pyrrolidin-2-one; (R)-3-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)-1- (4chlorophenyl)pyrrolidin-2-one; 2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-1-((5-cyano-2-pyrazinyl)methyl)-1H-benzimidazole-6carbonitrile; 2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-1-((5-cyano-2-pyrazinyl)methyl)-1H-benzimidazole-5carbonitrile; 5-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-4,6-difluoro-1H-benzimidazol-1-yl)methyl)-2pyrazinecarbonitrile; 5-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,7-difluoro-1H-benzimidazol-1-yl)methyl)-2pyrazinecarbonitrile; (3S)-1-(1-((5-fluoro-2-pyridinyl)methyl)-1 H-benzimidazol-2-yl)N-methyl-3-piperidineamine; (3S)-1-(1-((5-chloro-2-pyridinyl)methyl)-1 H-benzimidazol-2-yl)-N-methyl-3-piperidineamine; 6-((1R)-1-(2-((3S)-3-(methylamino)-1-piperidinyl)-1 H-benzimidazol-1-yl)ethyl)-3 pyridinecarbonitrile; 6-((1S)-1-(2-((3S)-3-(methylamino)-1-piperidinyl)-1H-benzimidazol-1-yl)ethyl)-3pyridinecarbonitrile; (3R,4R)-1-(1-((5-chloro-2-pyrimidinyl)methyl)-5,7-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-((5-chloro-2-pyrimidinyl)methyl)-4,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-((1-methyl-1H-indazol-4-yl)methyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(5-quinolinylmethyl)-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-((1R)-1-(8-quinolinyl)ethyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(5,6-difluoro-1-((1S)-1-(8-quinolinyl)ethyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-((3-(3-chlorophenyl)-1,2-oxazol-5-yl)methyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4 -fluoro3-piperidineamine; (3R,4R)-1-(5,6-difluoro-1-((1-methyl-1H-indazol-7-yl)methyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-(2,6-dichlorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; 1-(1-azetidinyl)-2-(2-((3S)-3-(methylamino)-1-piperidinyl)-1H-benzimidazol-1-yl)ethanone; 6-((1R)-1 -(4,6-difluoro-2-((4aR,8aR)-hexahydro-2H-pyrido[4,3-b] [ 1,4]oxazin-6(5H)-yl )-1 Nbenzimidazol-1-yl)ethyl)-3-pyridinecarbonitrile; 6-((1R)-1 -(4,6-difluoro-2-((4aS,8aS)-hexahydro-2H-pyrido[4,3-b] [ 1,4]oxazin-6(5H)-yl )-1Hbenzimidazol-1-yl)ethyl)-3-pyridinecarbonitrile; 6-((1S)-1-(4,6-difluoro-2-((4aS,8aS)-hexahydro-2Н-nirido[4,3-b][1,4]oxazin-6(5Н)-yl )-1Hbenzimidazol-1-yl)ethyl)-3-pyridinecarbonitrile; 6-((1S)-1-(4,6-difluoro-2-((4aR,8aR)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)-yl )-1Hbenzimidazol-1-yl)ethyl)-3-pyridinecarbonitrile; - 399 043189 6-((1R)-1-(5,7-difluoro-2-((4aR,8aR)-hexahydro-2H-iirido[4,3-b][1,4]oxazin-6(5H)-yl )-1Hbenzimidazol-1-yl)ethyl)-3-pyridinecarbonitrile; 6-((R)-1-(5,7-difluoro-2-((4aS,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)-yl )-1Hbenzimidazol-1-yl)ethyl)-3-pyridinecarbonitrile; 6-((1S)-1-(5,7-difluoro-2-((4aS,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)-yl )-Hbenzimidazol-1-yl)ethyl)-3-iiridinecarbonitrile; 6-((1S)-1-(5,7-difluoro-2-((4aR,8aR)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-6(5H)-yl )-1Hbenzimidazol-1-yl)ethyl)-3-iiridinecarbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5,6-difluoro-1H-benzimidazol-1-yl)-N-methylacetamide; 2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5,6-difluoro-1H-benzimidazol-1-yl)-1-(4-morpholinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5,6-difluoro-1H-benzimidazol-1-yl)-1-(1-iyrrolidinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5,6-difluoro-1H-benzimidazol-1-yl)-N,Ndimethylacetamide; (2R)-2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5,6-difluoro-1H-benzimidazol-1-yl)-N,Ndimethyliroyanamide; (2S)-2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5,6-difluoro-1H-benzimidazol-1-yl)-N,Ndimethyliroyanamide; 2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5,6-difluoro-1H-benzimidazol-1-yl)-1-(1iiieridinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5,6-difluoro-1H-benzimidazol-1-yl)-N-ethylacetamide; 1-((5-chloro-2-iieridinyl)methyl)-2-((3R,4R)-4-fluoro-3-(methylamino)-1-iieridinyl)-1Hbenzimidazole-6-carbonitrile; 1-((5-chloro-2-iieridinyl)methyl)-2-((3R,4R)-4-fluoro-3-(methylamino)-1-iieridinyl)-1Hbenzimidazole-5-carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-6-chloro-1H-benzimidazol-1-yl)-1-(1azetidinyl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoro-1-iieridinyl)-5-chloro-1H-benzimidazol-1-yl)-1-(1azetidinyl)ethanone; 2-((3R,4S)-3-amino-4-fluoro-1-iieridinyl)-1-(2-(1-azetidinyl)-2-oxoethyl)-1H-benzimidazole-6carbonitrile; 2-((3R,4S)-3-amino-4-fluoro-1-iieridinyl)-1-(2-(1-azetidinyl)-2-oxoethyl)-1H-benzimidazole-5carbonitrile; (3R,4R)-1-(1-((5-chloro-yrimidin-2-yl)methyl)-6-fluoro-1H-benzo[d]imidazol-2-yl)-4-fluoroiyeridin3-amine; (3R,4R)-1-(1-((5-chloro-yrimidin-2-yl)methyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-4-fluoro-iieridin-3-amine; (R)-6-((2-(3-aminoiieridin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (R)-5-((2-(3-aminoiiyeridin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)andcolinonitrile-2,2,2trifluoroacetate; (R)-1-(1-(isoquinolin-7-ylmethyl)-1 H-benzo[d]imidazol-2-yl)-iieridin-3-amine; (R)-1-(1-((1-methyl-1H-indazol-7-yl)methyl)-1H-benzo[d]imidazol-2-yl)iieridin-3-amine; 6-((R)-1-(2-((S)-3-aminoiieridin-1-yl)-1 H-benzo[d]imidazol-1-yl)ethyl)nicotinonitrile hydrochloride; 6-((S)-1-(2-((S)-3-aminoiieridin-1-yl)-1 H-benzo[d]imidazol-1-yl)ethyl)nicotinonitrile hydrochloride; 6-((R)-1-(2-((3R,4R)-3-amino-4-fluoroiyeridin-1-yl)-1 H-benzo[d]imidazol-1 yl)ethyl)nicotinonitrile hydrochloride; 6-((S)-1-(2-((3R,4R)-3-amino-4-fluoroiiyeridin-1-yl)-1H-benzo[d]imidazol-1 yl)ethyl)nicotinonitrile hydrochloride; 6-((R)-1-(2-((S)-3-aminoiiyeridin-1-yl)-1 H-benzo[d]imidazol-1-yl)iroyl)nicotinonitrile hydrochloride; 6-((S)-1-(2-((S)-3-aminoiiyeridin-1-yl)-1 H-benzo[d]imidazol-1-yl)iroyl)nicotinonitrile hydrochloride; (3R,4R)-1-(5,6-difluoro-1-((5-fluoroirimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoroiyeridin-3-amine; 3-(1-(2-((3R,4R)-3-amino-4-fluoroiiyeridin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1yl)ethyl)benzonitrile; (3R,4R)-1-(5,6-difluoro-1-((5-fluoroirimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoroiyeridin-3-amine; - 400 043189 (3R,4S)-1-(5,6-difluoro-1-((5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3- amine; (3R,4S)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2yl)piperidine-3-amine; (3R,4S)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2yl)piperidine-3-amine; (R)-1-(5,6-difluoro-1-((5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4,4difluoropiperidin-3-amine; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-(trifluoromethyl)-III-benzo[d]imidazol-1-yl)-1(azetidin-1 - yl) ethane-1-one; 2-(2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-5-(trifluoromethyl)-1 H-benzo[d]imidazol-1-yl)-1 (azetidin-1 -yl)ethan-1-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1 H-benzo[d]imidazol-1-yl)-1 -(2, 2dimethylpyrrolidin-1-yl)ethan-1-one; 6-((2-((3R,4S)-3-amino-4-hydroxypiperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 6-((2-((3R,4S)-3-amino-4-hydroxypiperidin-1-yl)-5-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 4-((R)-1-(2-((S)-3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)ethyl)benzonitrile hydrochloride; 4-((S)-1-(2-((S)-3-aminopiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)ethyl)benzonitrile hydrochloride; (S)-4-((2-(3-Aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)-3-fluorobenzonitrile hydrochloride; (S)-1-(1-(4-chlorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine hydrochloride; 4-((R)-1-(2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)ethyl)benzonitrile hydrochloride; 4-((S)-1-(2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)ethyl)benzonitrile hydrochloride; 4-((R)-1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)ethyl)benzonitrile hydrochloride; 4-((S)-1-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)ethyl)benzonitrile hydrochloride; (S)-4-((2-(3-Aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)-3-chlorobenzonitrile hydrochloride; (3R,4R)-1-(1-((1R)-1-(2,4-dichlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-((1S)-1-(2,4-dichlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-((1R)-1-(2-chlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-((1S)-1-(2-chlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-((1R)-1-(3-chlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-((1S)-1-(3-chlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-((1R)-1-(2,5-dichlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-((1S)-1-(2,5-dichlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)- 1-(1-((1R)-1 -(2,4-difluorophenyl)ethyl)-5,6-difluoro-1 H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine ; (3R,4R)- 1-(1-((1S)-1 -(2,4-difluorophenyl)ethyl)-5,6-difluoro-1 H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine ; (3R,4R)-1-(1-((1R)-1-(3,4-dichlorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)- 1-(1-((1S)-1 -(3,4-dichlorophenyl)ethyl)-5,6-difluoro-1 H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine ; (3R,4R)- 1-(1-((1R)-1 -(2,5-difluorophenyl)ethyl)-5,6-difluoro-1 H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine ; (3R,4R)-1-(1-((1S)-1-(2,5-difluorophenyl)ethyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3- 401 043189 piperidinamine; (3R,4R)-1 -(5,6-difluoro-1 -((1R)-1 -(4-(trifluoromethyl)phenyl)ethyl)-1H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine ; (3R,4R)-1 -(5,6-difluoro-1 -((1R)-1 -(4-(trifluoromethoxy)phenyl)ethyl)-1 H-benzimidazol-2-yl)-4-fluoro-3 piperidinamine; (3R,4R)-1-(1-(5-chloro-2-(trifluoromethoxy)benzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(4-(III-1,2,4-triazol-1-yl)benzyl)-III-benzimidazol-2-yl)-4-fluoro -3 piperidinamine; 2-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,6-difluoro-1H-benzimidazol-1-yl)methyl)-5chlorobenzonitrile; (3R,4R)-1-(1-(2,4-dichlorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; 4-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,6-difluoro-1H-benzimidazol-1-yl)methyl)-3(difluoromethoxy)benzonitrile; (3R,4R)-1-(1-(2,5-dichlorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(4-(1,1-difluoroethyl)benzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; 4-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,6-difluoro-1H-benzimidazol-1-yl)methyl)-2methylbenzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,6-difluoro-1H-benzimidazol-1-yl)methyl)-2chlorobenzonitrile; 2-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,6-difluoro-1H-benzimidazol-1-yl)methyl)-4chlorobenzonitrile; (3R,4R)-1-(1-(2-(difluoromethoxy)benzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-(3-chloro-4-fluorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(4-chloro-2-methoxybenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(2,4-difluorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(2-(trifluoromethyl)benzyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; 2-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,6-difluoro-1H-benzimidazol-1yl)methyl)benzonitrile; (3R,4R)-1-(1-(2-chlorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(2-chloro-4-fluorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(4-fluoro-2-(trifluoromethyl)benzyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-(3,4-difluorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(4-chloro-2-fluorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(3,4-dichlorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(1-(4-chloro-3-fluorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(4-(trifluoromethyl)benzyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(4-(trifluoromethoxy)benzyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(1-(4-(difluoromethyl)benzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(3-(trifluoromethoxy)benzyl)-1H-benzimidazol-2-yl)-4-fluoro-3piperidinamine; (3R,4R)-1-(5,6-difluoro-1-(3-(trifluoromethyl)benzyl)-1H-benzimidazol-2-yl)-4-fluoro-3-piperidineamine; 3-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-5,6-difluoro-1 H-benzimidazol-1 yl)methyl)benzonitrile; (3R,4R)-1-(1-(3-chlorobenzyl)-5,6-difluoro-1H-benzimidazol-2-yl)-4-fluoro-3-piperidinamine; (S)-1-(1-(4-fluorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (S)-1-(1-(4-(1,2,4-oxadiazol-3-yl)benzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-(methylsulfonyl)benzyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-(1H-1,2,4-triazol-1-yl)benzyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-2-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (R)-1-(1-(2,6-dichlorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(2-chlorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine; - 402 043189 (R)-1-(1-(4-(trifluoromethoxy)benzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-chlorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(3-chlorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-(1,1-difluoroethyl)benzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-2-(4-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-2methylpropanenitrile; (R)-1-(1-(4-(difluoromethyl)benzyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)-N-methylbenzamide; (R)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)-3-fluorobenzonitrile; (R)-2-(4-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)acetonitrile; (R)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)-K,K dimethylbenzenesulfonamide; (R)-1-(1-(4-methylbenzyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-fluorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-((1-methyl-1H-indazol-7-yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(2,4-difluorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(3,4-difluorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-(4-chloro-3-fluorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-1-(1-((3-(3-chlorophenyl)isoxazol-5-yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidine-3-amine; (R)-1-(1-(3-chloro-4-methoxybenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)-3-chlorobenzonitrile; (R)-1-(1-(2,4-dichlorobenzyl)-1 H-benzo[d]imidazol-2-yl)piperidin-3-amine; (R)-4-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)-3-methoxybenzonitrile; (R)-2-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)-5-chlorobenzonitrile; 4-((R)-1-(2-((R)-3-aminopiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)ethyl)benzonitrile; 4-(1-(2-((S)-3-aminopiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)ethyl)benzonitrile; (R)-3-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; 4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1yl)methyl)benzonitrile hydrochloride; (S)-4-((2-(3-aminopiperidin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile hydrochloride; 4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1yl)methyl)benzonitrile; (S)-4-((2-(3-aminopiperidin-1-yl)-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzonitrile hydrochloride; (R)-4-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-chloro-1 H-benzo[d]imidazol-1 yl)methyl)benzonitrile; (R)-4-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-methoxy-1H-benzo[d]imidazol-1 yl)methyl)benzonitrile; (R)-4-((2-(3-amino-4,4-difluoropiperidin-1-yl)-4-chloro-1 H-benzo[d]imidazol-1 yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-1H-benzo[d]imidazol-1yl)methyl)benzonitrile; 4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-4-chloro-1H-benzo[d]imidazol-1yl)methyl)benzonitrile; (R)-4-((2-(3-amino-4,4-difluoropiperidin-1-yl)-4-methoxy-1H-benzo[d]imidazol-1 yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-4-methoxy-1H-benzo[d]imidazol-1yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-imidazo[4,5-c]pyridin-1yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-3H-imidazo[4,5-c]pyridin-3yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-6-ethoxy-1 H-benzimidazol-1 yl)methyl)benzonitrile; 4-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile; 4-((2-((3R)-3-amino-4,4-difluoro-1-piperidinyl)-6-fluoro-1H-benzimidazol-1-yl)methyl)benzonitrile; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-imidazo[4,5-b]pyridin-1yl)methyl)benzonitrile; (S)-4-((2-(3-aminopiperidin-1-yl)-4-chloro-1 H-benzo[d]imidazol-1-yl)methyl)benzonitrile 2,2,2trifluoroacetate; (S)-4-((2-(3-aminopiperidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzonitrile hydrochlo - 403 043189 reed; 4-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1yl)methyl)benzonitrile hydrochloride; (S)-4-((2-(3-aminopiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (S)-4-((2-(3-aminopiperidin-1-yl)-5-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile; (R)-1-(2-((S)-3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)-2,3-dihydro-1H-indene-5carbonitrile; (S)-1-(2-((S)-3-aminopiperidin-1-yl)-1 H-benzo[d]imidazol-1-yl)-2,3-dihydro-1H-indene-5 carbonitrile; (3R,4R)-4-fluoro-1-(1-((5-methoxypyridin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidine-3amine; 1 -(2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1H-benzo[d]imidazol-1 yl)acetyl)azetidine-3 -carbonitrile; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1 H-benzo[d]imidazol-1 -yl)-1 -(3 - (tert-butoxy)azetidin-1-yl)ethan-1-one; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1 H-benzo[d]imidazol-1-yl)-1-(3, 3-difluoroazetidin-1-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1 H-benzo[d]imidazol-1-yl)-1-(3-isopropylazetidine -1-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1 H-benzo[d]imidazol-1-yl)-1-(6, 6difluoro-2-azaspiro[3.3]heptan-2-yl)ethanone; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1 -yl)-5,6-difluoro-1 H-benzo[d]imidazol-1 -yl)-1 -(7- oxa-2azaspiro[3.5]nonan-2-yl)ethanone; (R)-6-((2-(4,4-difluoro-3-(methylamino)piperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; (R)-6-((2-(4,4-difluoro-3-((2-hydroxyethyl)amino)piperidin-1-yl)-6-fluoro-1H-benzo[d]imidazol-1yl)methyl) nicotinonitrile; (S)-6-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinic acid; (S)-6-((2-(3-aminopiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinamide; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinamide; 2-(2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-5,6-difluoro-1H-benzo[d]imidazol-1-yl)acetic acid; 6-((R)-1 -(4,6-difluoro-2-((3R,4R)-4-fluoro-3 -(methylamino)piperidin-1 -yl)-1 H-benzo[d]imidazole- 1 yl)ethyl)nicotinonitrile; 6-((S)-1 -(4,6-difluoro-2-((3R,4R)-4-fluoro-3-(methylamino)piperidin-1 -yl)-1H-benzo[d]imidazole-1 yl)ethyl)nicotinonitrile; 6-((R)-1-(5,7-difluoro-2-((3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl)-1H-benzo[d]imidazol-1yl )ethyl)nicotinonitrile and 6-((S)-1-(5,7-difluoro-2-((3R,4R)-4-fluoro-3-(methylamino)piperidin-1-yl)-1H-benzo[d]imidazol-1yl )ethyl)nicotinonitrile. 13. A compound selected from the group consisting of: 6-((2-((3R,4S)-3-amino-4-fluoropiperidin-1-yl)-6-chloro-1H-benzo[d]imidazol-1yl)methyl)nicotinonitrile; 2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1Hbenzo[d]imidazole-4-carbonitrile ; (3R,4R)-1-(4,6-difluoro-1-((5-fluoropyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)-4fluoropiperidin-3-amine; 6-((2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-4,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile hydrochloride; (R)-6-((2-(3-amino-4,4-difluoropiperidin-1-yl)-6-fluoro-1 H-benzo[d]imidazol-1 yl)methyl)nicotinonitrile; 6-((2-((3R,4R)-3-amino-4-fluoro-1-piperidinyl)-4-methoxy-1H-benzimidazol-1-yl)methyl)-3pyridinecarbonitrile; (2-((3R,4R)-3-amino-4-fluoropiperidin-1-yl)-1-((5-chloropyrimidin-2-yl)methyl)-1Hbenzo[d]imidazole-6-carbonitrile; (3R,4R)-4-fluoro-1-(1-((5-fluoropyrimidin-2-yl)methyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine and (3R,4R )-1-(1-((5-chloropyrimidin-2-yl)methyl)-6-fluoro-1H-benzo[d]imidazol-2-yl)-4-fluoropiperidin3-amine. 14. A compound according to any one of claims 1 to 13 in the form of a pharmaceutically acceptable salt. 15. Pharmaceutical composition containing pharmaceutically acceptable excipients, wear - 404 043189 body or excipient and at least one compound according to any one of claims 1 to 14. 16. A method of treating a TRPC6 mediated disease or disorder in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one compound of any one of claims 1 to 14, or a pharmaceutical salt or pharmaceutical composition thereof. 17. A method for modulating TRPC6 activity in a mammal, the method comprising administering to the mammal an amount of at least one compound of any one of claims 1 to 14, or a pharmaceutical salt or pharmaceutical composition thereof, to modulate TRPC6 activity in the mammal. 18. The use of a compound according to any one of claims 1 to 14 as a drug.