Thiophene derivatives for treating disorders caused by IgE - Patent Application 20070229633

Abstract

Thiophene derivatives of formula (I) and pharmaceutically acceptable salts thereof are provided, which have utility for treating or preventing IgE-induced disorders such as allergies, type 1 hypersensitivity, or familial sinusitis.

Description

[Technical field]

[0001] The present invention relates to thiophene derivatives of formula (I), processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of disorders caused by IgE, such as allergic responses, non-allergic mast cell responses or certain autoimmune responses, in particular disorders caused by the interaction of IgE with the FcεRI receptor. [Background technology]

[0002] IgE (immunoglobulin E) is a member of the immunoglobulin family and mediates allergic responses such as asthma, food allergies, type 1 hypersensitivity and familial sinusitis.

[0003] IgE is secreted by B cells and expressed on their surface. IgE synthesized by B cells is anchored in the B cell membrane by a transmembrane domain linked to the mature IgE sequence by a short membrane-binding region. IgE also binds to B cells (as well as monocytes, eosinophils and platelets) via its Fc region to the low affinity IgE receptor (FcεRII). Upon exposure of a mammal to an allergen, B cells are clonally expanded that synthesize IgE that binds to the allergen. This IgE is then released into the circulation by the B cells to which it is bound (via FcεRII) and by mast cells and basophils via the so-called high affinity receptor (FcεRI) found on the surface of mast cells and basophils. Such mast cells and basophils are thereby sensitized to the allergen. Subsequent exposure to the allergen crosslinks the FcεRI on these cells, thus activating the release of histamine and other factors that are responsible for clinical hypersensitivity and anaphylaxis. Currently, allergic diseases, urticaria, and asthma are typically treated with one or more of the following drugs: (1) antihistamines and anti-leukotrienes, which antagonize the inflammatory mediators histamine and leukotrienes; (2) topical or systemic (oral or injectable) corticosteroids or immunosuppressants, which suppress a wide range of inflammatory mechanisms; (3) short- or long-acting bronchodilators, which relax the smooth muscle of the airways constricted in asthma; or (4) mast cell stabilizers, which inhibit mast cell degranulation normally caused by IgE binding at FcεRI; and (5) biologics, which prevent IgE binding at FcεRI. Summary of the Invention [Problem to be solved by the invention]

[0004] However, there remains a need to identify compounds that have therapeutic utility in the treatment or prevention of disorders caused by IgE, particularly disorders caused by the interaction of IgE with the FcεRI receptor. [Means for solving the problem]

[0005] Surprisingly, it has been found that the compounds of formula (I) and their pharma- ceutically acceptable salts can be used for this purpose.

[0006] The present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof: [ka] Provide [In the formula, X is CH, N, or CR 4 and X is CR 4 If R 3 and R 4 may be linked to form a 4- to 6-membered cycloalkyl or heterocyclic ring; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, OH, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy and C 1 ~C 2 substituted by one or more substituents selected from haloalkyl; When X represents N, W, Y and Z are C or one of W, Y and Z is a single bond and the other two are C; X is CH or CR 4 where W, Y and Z are C or one of W, Y or Z is a single bond, O, S, S(O), S(O) 2or N, and the other two are C; When W, Y, or Z is C, each C is H, halogen, SF 5 , =O, =NOH, -OH, -CN, -C(O)Me, -C(O)OH, -C(O)NH 2 , NH-C(O)OC 1 ~C 4 Alkyl, -NO 2 , N.H. 2 , NHMe, NMe 2 , SH, SMe, SOMe, SO 2 Me, C 1 ~C 4 Alkyl, C 3 ~C 4 Cycloalkyl, C 1 ~C 4 Alkoxy, Heterocycle, C 1 ~C 4 heteroalkyl, which may be linked to form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic ring; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic ring; When W, Y or Z is N, N is independently H, C 1 ~C 4 Alkyl, C 3 ~C 4 Cycloalkyl, heterocycle, -C(O)Me, -C(O)NH 2 , -C(O)OH, -S(O)Me, -S(O) 2 Me, -S(O) 2NH 2 any of which may be optionally substituted with halogen, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 may be substituted with one or more substituents selected from W, X, Y and Z may be linked directly or via substituents to form a ring; R 1 is -C(O)OR 5 , -C(O)N(R 6 )(R 7 ), -S(O) 2 N(R 8 )(R 9 ), -S(O) 2 R 10 , -S(O)R 10 and -S(O)(=NR 11 )R 10 Selected from; R 2 is -N(R 12 )C(O)R 13 represents; R 3 is H, -OH, C 1 ~C 8 Alkyl, -NR d R c , -NH-R 14 -NH-R a , -NMe-R 14 -NH-R a , -NH-R 14 -NMe-R a , -CO-NR d R c , -NH-COO-R c , -NH-CO-R c , -COOH, -COO-C 1 ~C 8Alkyl, -CO-C 1 ~C 8 Alkyl, -C 1 ~C 8 Alkylene-COO-C 1 ~C 8 Alkyl, -C 1 ~C 8 Alkylene-NR a , -COO-C 1 ~C 8 Alkyl, -C 1 ~C 8 Alkylene-NR d R c , C 1 ~C 8 Alkylene-NH-R 14 -NH-R a , heteroaryl, -CN, -CH=N-OH, -CF 3 , alkylamino, amino, -NH-SO-C 1 ~C 8 Alkyl, -NH-SO 2 -C 1 ~C 8 Alkyl, Heteroalkyl-amino, Aryl, Heterocycle, C 3 ~C 6 Cycloalkyl, -NHS(O)(=NH)Me, -SO 2 -C 1 ~C 8 Alkyl, -NH-C(CH 3 )=N-CN, -NH-CH=N-CN, -NH-S(=O)(=N)-C 1 ~C 2 alkyl, any of which is optionally halogen, -OH, =O, -COOH, -COH, -CN, SMe, -NR d R c , -OR c , C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, C 1 ~C2 Alkylene-OC 1 ~C 2 Alkyl, C 1 ~C 2 Alkylene-C 3 ~C 4 Cycloalkyl, Heterocycle, C 3 ~C 6 Cycloalkyl, aryl, heteroaryl, C 3 ~C 6 Cycloalkyl-amino, heterocyclo-amino, aryl-amino, heteroaryl-amino, -CONR d R c , -NHCO-R a , -NHCOO-C 1 ~C 4 Alkyl, -CO-C 1 ~C 2 Alkyl, -COO-R a which may be linked to form a ring; d R c and -NR d R c may be linked to form a 7-membered ring fused to a 6-membered aryl group; Aryl, heteroaryl, heterocycle and cycloalkyl are optionally selected from the group consisting of halogen, oxo, cyano, OH, -NOOH, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, Halo~C 1 ~C 6 Alkoxy, C 3 ~C 6 -Cycloalkyl-C 1 ~C 3 -Alkoxy, -O-CO-C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Haloalkyl, C 2 ~C 4 Heterocycle, Acetyl, Acetyl-phenyl, -CONR d R c, COO-C 1 ~C 8 Alkyl, -S(O)NH-C 1 ~C 2 -Alkyl, -S(O) n -C 1 ~C 2 -alkyl, optionally one or more halogen groups, C 1 ~C 2 -heteroaryl optionally substituted with alkyl; n is equal to 0, 1 or 2; R 4 are halogens, OH, CN, NO 2 , N.H. 2 , NHMe, NMe 2 , SH, SMe, SOMe, SO 2 Me, C 1 ~C 4 Alkyl, C 3 ~C 4 Cycloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 heteroalkyl, heterocycle; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R 5 is C 1 ~C 8 Alkyl, C 2 ~C 8 Heteroalkyl, C 2 ~C 8 Alkenyl, C 2 ~C8 Heteroalkenyl, C 2 ~C 8 Alkynyl, C 2 ~C 8 Heteroalkynyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 4 ~C 8 Cycloalkenyl, aryl, heteroaryl, -C 1 ~C 2 Alkylene-C 3 ~C 6 Cycloalkyl, -C 1 ~C 2 Alkylene-heterocycle, -C 1 ~C 2 Alkylene-aryl, -C 1 ~C 2 alkylene-heteroaryl; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, -OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R 6 , R 8 and R 12 are independently H and C 1 ~C 3 alkyl, any of which may be optionally substituted with 1 to 7 halogens; R 7 , R 9 and R 11 are independently, H, C 1 ~C 8 Alkyl, C 2 ~C 8 Heteroalkyl, C2 ~C 8 Alkenyl, C 2 ~C 8 Heteroalkenyl, C 2 ~C 8 Alkynyl, C 2 ~C 8 Heteroalkynyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 Heterocycloalkenyl, aryl, heteroaryl, -C 1 ~C 2 Alkylene-C 3 ~C 6 Cycloalkyl, -C 1 ~C 2 Alkylene-heterocycle, -C 1 ~C 2 Alkylene-aryl, -C 1 ~C 2 Alkylene-heteroaryl, -NC 1 ~C 7 Alky, -NC 3 ~C 8 Cycloalkyl, -N-heterocycle, -N-heteroaryl, C 1 ~C 7 Alkoxy, -OC 3 ~C 8 -cycloalkyl, -O-heterocycle, -O-heteroaryl; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, -OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R10 , H, C 1 ~C 8 Alkyl, C 2 ~C 8 Heteroalkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Heteroalkenyl, C 2 ~C 8 Alkynyl, C 2 ~C 8 Heteroalkynyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 Heterocycloalkenyl, aryl, heteroaryl, -C 1 ~C 3 Alkylene-C 3 ~C 6 Cycloalkyl, -C 1 ~C 3 Alkylene-heterocycle, -C 1 ~C 3 Alkylene-aryl, -C 1 ~C 3 Alkylene-heteroaryl, -NC 1 ~C 8 alkyl, Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, -OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R 13 is C 1 ~C 7 Alkyl, C 1 ~C6 Heteroalkyl, C 3 ~C 8 Cycloalkyl, -C 1 ~C 2 Alkylene-C 3 ~C 6 Cycloalkyl, C 3 ~C 5 heterocycles; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a cycloalkyl or heterocyclic ring; R 6 and R 7 may be linked together to form a ring; R 8 and R 9 may be linked together to form a ring; R 12 and R 13 may be linked together to form a ring; R 14 is C=O, C=S, C=N-OH, C=NR b , C=CH-NO 2 , S.O. 2 , and C 3 ~C 6 cycloalkenyl, which may be optionally substituted with 1 or 2 =O; R a , H, C 1 ~C 8 Alkyl, Heteroalkyl, C 1 ~C 8 Alkoxy, Heterocycle, C 3 ~C 8selected from cycloalkyl, heteroaryl and aryl; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, -OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Heterocycloalkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, aryl, heteroaryl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R b is CN, aryl, heteroaryl, -NO 2 , -OC 1 ~C 2 Alkyl, -CO-OC 1 ~C 2 alkyl, Aryl and heteroaryl are optionally represented by one or more C 1 ~C 2 optionally substituted with alkyl; R c is H, aryl, heteroaryl, C 3 ~C 6 Cycloalkenyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 1 ~C 8 Alkyl, C 1 ~C 8 Heteroalkyl, C 1 ~C 4 Alkylene-C 3 ~C 6 cycloalkyl; Any of these are optional, C(O)(R g ), C(O)N(R f)(R g ), halogens, SF 5 , OH, =O, -COH, -COOH, -CO-OR a , CN, SMe, SO 2 Me, SO 2 R g , C 1 ~C 4 Alkoxy, OC 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 4 Haloalkyl, N(R f )(R g ), N(R f )SO 2 (R g ), SO 2 NH 2 , S.O. 2 NHMe, SO 2 NMe 2 , S(O)(NR f )R g , C 3 ~C 6 Cycloalkyl, Heterocycle, C 1 ~C 4 Alkylene-C 3 ~C 6 optionally substituted with one or more substituents selected from cycloalkyl, aryl and heteroaryl, which may be linked to form a ring; Aryl, heteroaryl, heterocycle and cycloalkyl are optionally selected from halogen, ═O, ═NH, ═NMe, OH, C 1 ~C 2 Alkyl, C 1 ~C 2 Alkoxy, -COOH, -COO-C 1 ~C 2 Alkyl, SO 2 R a , C.O.R. a , SOR a , S(O)(NH)R a ,CONHR aand optionally linked to form a ring; R d is H or C 1 ~C 4 represents alkyl; R c and R d may be linked to form a heterocycle; R e is -C(O)OR a , -C(O)N(R f )(R g ), aryl, heteroaryl, C1-C2 haloalkyl, -CN; R f and R g may be linked to form a ring, Aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C2 haloalkyl, C1-C2 alkyl; R f is H, aryl, heteroaryl, C 3 ~C 6 Cycloalkenyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 1 ~C 8 Alkyl, C 1 ~C 8 Heteroalkyl, C 1 ~C 4 Alkylene-C 3 ~C 6 cycloalkyl; Any of these may optionally be selected from halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C 1 ~C 2 Alkyl, C 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, -COOH, -COO-C 1 ~C 2 Alkyl, SO 2 R a , C.O.R. a, SOR a , S(O)(NH)R a ,CONHR a may be substituted with one or more substituents selected from R g is H, aryl, heteroaryl, C 3 ~C 6 Cycloalkenyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 1 ~C 8 Alkyl, C 1 ~C 8 Heteroalkyl, C 1 ~C 4 Alkylene-C 3 ~C 6 cycloalkyl; Any of these may optionally be selected from halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C 1 ~C 2 Alkyl, C 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, -COOH, -COO-C 1 ~C 2 Alkyl, SO 2 R a , C.O.R. a , SOR a , S(O)(NH)R a ,CONHR a and optionally substituted with one or more substituents selected from R f and R g may be linked to form a ring.

[0007] According to another embodiment, the compound of the present invention has formula (Ia) [ka] It is a compound by [In the formula, X is CH, N, or CR 4 and X is CR 4 If R 3 and R 4 may be linked to form a 4- to 6-membered cycloalkyl or heterocyclic ring; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, OH, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy and C 1 ~C 2 substituted by one or more substituents selected from haloalkyl; When X represents N, W, Y and Z are C or one of W, Y and Z is a single bond and the other two are C; X is CH or CR 4 where W, Y and Z are C or one of W, Y or Z is a single bond, O, S, S(O), S(O) 2 or N, and the other two are C; When W, Y, or Z is C, each C is H, halogen, SF 5 , =O, =NOH, -OH, -CN, -C(O)Me, -C(O)OH, -C(O)NH 2 , NH-C(O)OC 1 ~C 4 Alkyl, -NO 2 , N.H. 2 , NHMe, NMe 2 , SH, SMe, SOMe, SO2 Me, C 1 ~C 4 Alkyl, C 3 ~C 4 Cycloalkyl, C 1 ~C 4 Alkoxy, Heterocycle, C 1 ~C 4 heteroalkyl, which may be linked to form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic ring; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic ring; When W, Y or Z is N, N is independently H, C 1 ~C 4 Alkyl, C 3 ~C 4 Cycloalkyl, heterocycle, -C(O)Me, -C(O)NH 2 , -C(O)OH, -S(O)Me, -S(O) 2 Me, -S(O) 2 NH 2 any of which may be optionally substituted with halogen, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH2 , NHMe, NMe 2 may be substituted with one or more substituents selected from W, X, Y and Z may be linked directly or via substituents to form a ring; R 1 is -C(O)OR 5 , -C(O)N(R 6 )(R 7 ), -S(O) 2 N(R 8 )(R 9 ), -S(O) 2 R 10 , -S(O)R 10 and -S(O)(=NR 11 )R 10 Selected from; R 2 is -N(R 12 )C(O)R 13 represents; R 3 is H, -OH, C 1 ~C 8 Alkyl, -NR d R c , -NH-R 14 -NH-R a , -NMe-R 14 -NH-R a , -NH-R 14 -NMe-R a , -CO-NR d R c , -NH-COO-R c , -NH-CO-R c , -COOH, -COO-C 1 ~C 8 Alkyl, -CO-C 1 ~C 8 Alkyl, -C 1 ~C 8 Alkylene-COO-C 1 ~C 8 Alkyl, -C 1 ~C 8 Alkylene-NR a , -COO-C 1 ~C 8 Alkyl, -C 1 ~C 8Alkylene-NR d R c , -C 1 ~C 8 Alkylene-NH-R 14 -NH-R a , heteroaryl, -CN, -CH=N-OH, -CF 3 , alkylamino, amino, -NH-SO-C 1 ~C 8 Alkyl, -NH-SO 2 -C 1 ~C 8 Alkyl, Heteroalkyl-amino, Aryl, Heterocycle, C 3 ~C 6 Cycloalkyl, -NHS(O)(=NH)Me, -SO 2 -C 1 ~C 8 Alkyl, -NH-C(CH 3 )=N-CN, -NH-CH=N-CN, -NH-S(=O)(=N)-C 1 ~C 2 alkyl, Any of these are optionally halogen, -OH, =O, -COOH, -COH, -CN, SMe, -NR d R c , -OR c , C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkylene-OC 1 ~C 2 Alkyl, C 1 ~C 2 Alkylene-C 3 ~C 4 Cycloalkyl, Heterocycle, C 3 ~C 6 Cycloalkyl, aryl, heteroaryl, C 3 ~C 6Cycloalkyl-amino, heterocycle-amino, aryl-amino, heteroaryl-amino, -CONR d R c , -NHCO-R a , -NHCOO-C 1 ~C 4 Alkyl, -CO-C 1 ~C 2 Alkyl, -COO-R a which may be linked to form a ring; Aryl, heteroaryl, heterocycle and cycloalkyl are optionally substituted with halogen, OH, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -O-CO-C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Haloalkyl and C 2 ~C 4 substituted by one or more substituents selected from heterocycles; R 4 are halogens, OH, CN, NO 2 , N.H. 2 , NHMe, NMe 2 , SH, SMe, SOMe, SO 2 Me, C 1 ~C 4 Alkyl, C 3 ~C 4 Cycloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 heteroalkyl, heterocycle; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R 5 is C 1 ~C 8 Alkyl, C 2 ~C 8 Heteroalkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Heteroalkenyl, C 2 ~C 8 Alkynyl, C 2 ~C 8 Heteroalkynyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 4 ~C 8 Cycloalkenyl, aryl, heteroaryl, -C 1 ~C 2 Alkylene-C 3 ~C 6 Cycloalkyl, -C 1 ~C 2 Alkylene-heterocycle, -C 1 ~C 2 Alkylene-aryl, -C 1 ~C 2 alkylene-heteroaryl; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, -OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R6 , R 8 and R 12 are independently H and C 1 ~C 3 alkyl, any of which may be optionally substituted with 1 to 7 halogens; R 7 , R 9 and R 11 are independently, H, C 1 ~C 8 Alkyl, C 2 ~C 8 Heteroalkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Heteroalkenyl, C 2 ~C 8 Alkynyl, C 2 ~C 8 Heteroalkynyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 Heterocycloalkenyl, aryl, heteroaryl, -C 1 ~C 2 Alkylene-C 3 ~C 6 Cycloalkyl, -C 1 ~C 2 Alkylene-heterocycle, -C 1 ~C 2 Alkylene-aryl, -C 1 ~C 2 Alkylene-heteroaryl, -NC 1 ~C 7 Alky, -NC 3 ~C 8 Cycloalkyl, -N-heterocycle, -N-heteroaryl, C 1 ~C 7 Alkoxy, -OC 3 ~C 8 -cycloalkyl, -O-heterocycle, -O-heteroaryl; Any of these are optional, including halogen, =O, OH, SMe, C1 ~C 2 Alkoxy, -OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R 10 , H, C 1 ~C 8 Alkyl, C 2 ~C 8 Heteroalkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Heteroalkenyl, C 2 ~C 8 Alkynyl, C 2 ~C 8 Heteroalkynyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 Heterocycloalkenyl, aryl, heteroaryl, -C 1 ~C 3 Alkylene-C 3 ~C 6 Cycloalkyl, -C 1 ~C 3 Alkylene-heterocycle, -C 1 ~C 3 Alkylene-aryl, -C 1 ~C 3 Alkylene-heteroaryl, -NC 1 ~C 8 alkyl, Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, -OC 1 ~C 2Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R 13 is C 1 ~C 7 Alkyl, C 1 ~C 6 Heteroalkyl, C 3 ~C 8 Cycloalkyl, -C 1 ~C 2 Alkylene-C 3 ~C 6 Cycloalkyl, C 3 ~C 5 heterocycles; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, NH 2 , NHMe, NMe 2 which may be linked to form a cycloalkyl or heterocyclic ring; R 6 and R 7 may be linked together to form a ring; R 8 and R 9 may be linked together to form a ring; R 12 and R 13 may be linked together to form a ring; R 14is C=O, C=S, C=N-OH, C=NR b , C=CH-NO 2 , S.O. 2 , and C 3 ~C 6 cycloalkenyl, which may be optionally substituted with 1 or 2 =O; R a , H, C 1 ~C 8 Alkyl, Heteroalkyl, C 1 ~C 8 Alkoxy, Heterocycle, C 3 ~C 8 selected from cycloalkyl, heteroaryl and aryl; Any of these are optional, including halogen, =O, OH, SMe, C 1 ~C 2 Alkoxy, -OC 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, aryl, heteroaryl, NH 2 , NHMe, NMe 2 which may be linked to form a ring; R b is CN, aryl, heteroaryl, -NO 2 , -OC 1 ~C 2 Alkyl, -CO-OC 1 ~C 2 alkyl, Aryl and heteroaryl are optionally represented by one or more C 1 ~C 2 is substituted with alkyl; R c is H, aryl, heteroaryl, C 3 ~C 6 Cycloalkenyl, C 3 ~C8 Cycloalkyl, Heterocycle, C 1 ~C 8 Alkyl, C 1 ~C 8 Heteroalkyl, C 1 ~C 4 Alkylene-C 3 ~C 6 cycloalkyl; Any of these are optional, C(O)(R g ), C(O)N(R f )(R g ), halogens, SF 5 , OH, =O, -COH, -COOH, -CO-OR a , CN, SMe, SO 2 Me, SO 2 R g , C 1 ~C 4 Alkoxy, OC 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 4 Haloalkyl, N(R f )(R g ), N(R f )SO 2 (R g ), SO 2 NH 2 , S.O. 2 NHMe, SO 2 NMe 2 , S(O)(NR f )R g , C 3 ~C 6 Cycloalkyl, Heterocycle, C 1 ~C 4 Alkylene-C 3 ~C 6 optionally substituted with one or more substituents selected from cycloalkyl, aryl and heteroaryl, which may be linked to form a ring; Aryl, heteroaryl, heterocycle and cycloalkyl are optionally selected from halogen, ═O, ═NH, ═NMe, OH, C1 ~C 2 Alkyl, C 1 ~C 2 Alkoxy, -COOH, -COO-C 1 ~C 2 Alkyl, SO 2 R a , C.O.R. a , SOR a , S(O)(NH)R a ,CONHR a and optionally linked to form a ring; R d is H or C 1 ~C 4 represents alkyl; R c and R d may be linked to form a heterocycle; R e is -C(O)OR a , -C(O)N(R f )(R g ), aryl, heteroaryl, C1-C2 haloalkyl, -CN; R f and R g may be linked to form a ring, Aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C2 haloalkyl, C1-C2 alkyl; R f is H, aryl, heteroaryl, C 3 ~C 6 Cycloalkenyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 1 ~C 8 Alkyl, C 1 ~C 8 Heteroalkyl, C 1 ~C 4 Alkylene-C 3 ~C 6 cycloalkyl; Any of these may optionally be selected from halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C 1 ~C2 Alkyl, C 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, -COOH, -COO-C 1 ~C 2 Alkyl, SO 2 R a , C.O.R. a , SOR a , S(O)(NH)R a ,CONHR a may be substituted with one or more substituents selected from R g is H, aryl, heteroaryl, C 3 ~C 6 Cycloalkenyl, C 3 ~C 8 Cycloalkyl, Heterocycle, C 1 ~C 8 Alkyl, C 1 ~C 8 Heteroalkyl, C 1 ~C 4 Alkylene-C 3 ~C 6 cycloalkyl; Any of these may optionally be selected from halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C 1 ~C 2 Alkyl, C 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkoxy, OC 1 ~C 2 Haloalkyl, -COOH, -COO-C 1 ~C 2 Alkyl, SO 2 R a , C.O.R. a , SOR a , S(O)(NH)R a ,CONHR a and optionally substituted with one or more substituents selected from R f and Rg may be linked to form a ring.

[0008] In one preferred embodiment of the invention, X, W, Y and Z are preferably C, or alternatively, X, W and Y are preferably C and Z is preferably O, all of which may be optionally substituted as described above.

[0009] More preferably, X is CH and W, Y and Z are independently CH. 2 , CH(C 1 ~C 2 alkyl), CH(C 1 ~C 2 haloalkyl), C(C 1 ~C 2 Alkyl) 2 and spiro-cyclopropyl. Most preferably, X is CH and W, Y and Z are CH 2 It is.

[0010] In this case, preferred compounds have the formula (II): [ka] Characterized by [In the formula, R 1 , R 2 and R 3 is as defined in formula (I) or (Ia)].

[0011] A preferred embodiment according to the present invention is 1 , R 2 and R 3is as defined below. It will be understood by those skilled in the art that the present invention also encompasses compounds of formula (I), (Ia) and (II) and salts thereof, in which the various substituents are independently selected from these embodiments, preferred embodiments, more preferred embodiments, preferably more preferred, even more preferred, most preferred, particular embodiments, preferred particular embodiments, particularly preferred embodiments, particular more preferred embodiments, especially preferred embodiments, best results. This also encompasses compounds of formula (III)-(XXIV) as defined below.

[0012] R 1 But -S(O) 2 R 10 , -S(O)R 10 and -S(O)(=NR 11 )R 10 R 10 is preferably nBu, and R 11 is H.

[0013] R 1 -C(O)OR 5 If R 5 is preferably [ka] It is.

[0014] In a more preferred embodiment, R 1 is -C(O)N(R 6 )(R 7 ) or -S(O) 2 N(R 8 )(R 9 ) and R 6 , R 7 , R 8 and R 9 is as defined above; More preferably, R 1 is -C(O)N(R 6 )(R 7 ) or -S(O) 2 N(R8 )(R 9 ) and R 6 and R 8 H and C 1 ~C 3 alkyl, most preferably R 6 and R 8 is H; R 7 and R 9 is C 1 ~C 8 Alkyl, C 3 ~C 6 Cycloalkyl and -C 1 ~C 2 Alkylene-C 3 ~C 6 cycloalkyl, any of which may be optionally substituted with 1 to 4 halogens; and cycloalkyl is selected from C 1 ~C 8 It may be substituted by alkyl, most preferably R 7 teeth, [ka] and R 9 teeth, [ka] and Even more preferably, R 1 teeth, [ka] and; Most preferably, R 1 teeth, [ka] It is.

[0015] R 2 is preferably -N(R 12)C(O)R 13 represents R 12 H and C 1 ~C 3 alkyl; R 13 is C 1 ~C 7 Alkyl, C 3 ~C 8 Cycloalkyl and -C 1 ~C 2 Alkylene-C 3 ~C 6 cycloalkyl, any of which is optionally selected from halogen and C 1 ~C 2 It is optionally substituted by 1 to 5 substituents selected from alkyl, which may be linked to form a cycloalkyl ring; More preferably, R 2 teeth, [ka] represents; Most preferably, R 2 teeth, [ka] Represents.

[0016] In a preferred embodiment, R 3 -NHR c , -NH-R 14 -NH-R a and heteroaryl; None of them are -NHR c , -C(O)OR a , -C(O)NR d R c , aryl, heteroaryl, C 1 ~C 2 and R is optionally substituted with one or more substituents selected from haloalkyl and -CN. cis selected from H, optionally substituted heteroaryl, optionally substituted heterocycle, and optionally substituted aryl; The substituents of the aryl, heterocyclic and heteroaryl are halogen, -CN, -C(O)OH, -C(O)OC. 1 ~C 2 Alkyl, -C(O)Me, -S(O)Me, -S(O)(O)Me, -S(O)(=NH)Me, heterocycle, C 1 ~C 4 Alkyl, C 1 ~C 2 Heteroalkyl, C 1 ~C 2 Haloalkyl, C 1 ~C 2 Alkoxy, C 1 ~C 2 Haloalkoxy, aryl, heteroaryl, C 3 ~C 8 cycloalkyl.

[0017] In one particularly preferred embodiment, R 3 contains at least one nitrogen as a heteroatom, -NR d R c or -NR d R c and -C(O)OC 1 ~C 2 heteroaryl, optionally substituted with alkyl; R c is selected from H, optionally substituted heteroaryl, optionally substituted heterocycle, and optionally substituted aryl; The substituents of the aryl, heterocyclic and heteroaryl are -CN, -C(O)OC. 1 ~C 2 Alkyl, C 1 ~C 4 Alkyl, C 1 ~C 2 Haloalkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2haloalkoxy, -S(O)Me and -S(O)(O)Me; R d represents H.

[0018] In a particularly preferred embodiment, R 3 contains at least two nitrogen heteroatoms, -NHR c or -NHR c and -C(O)OC 1 ~C 2 heteroaryl, optionally substituted with alkyl; R c is selected from H or optionally substituted heteroaryl containing at least one nitrogen as a heteroatom; The heteroaryl substituents are C 1 ~C 3 Alkyl, C 1 ~C 2 Haloalkyl and C 1 ~C 2 haloalkoxy, wherein at least one halogen is a fluorine atom.

[0019] The best results are R 3 contains three nitrogen heteroatoms, -NHR c is a heteroaryl optionally substituted by R c is an optionally substituted heteroaryl containing at least one nitrogen as a heteroatom; This is obtained when the heteroaryl substituents are selected from methyl, ethyl, difluoromethyl or trifluoromethyl.

[0020] Most preferably, R 3 teeth, [ka] It is.

[0021] In one particularly preferred embodiment of the invention, the compounds of formula (I) or (Ia) or (XXXVI) and their pharma- ceutically acceptable salts are R 1 but, [ka] and; R 2 but [ka] and / or R 3 but, [ka] It is what it is.

[0022] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein X is C or N; Z is C, N, O or S; and Y is C or S.

[0023] In a further embodiment, the compound is R 1However, N-methylaminocarbonyl, (cyclopropylmethyl)aminocarbonyl, cyclopropylcarbonylamino, cyclopropylcarbamoyl, propyl-sulfamoyl, isobutyl-sulfamoyl, [(2-hydroxy-2-methyl)propyl]sulfamoyl, 2-hydroxypropylsulfamoyl, 3-pyrrolidin-1-ylsulfonyl, (3-fluorocyclobutyl)-sulfamoyl, butylsulfonyl, butylsulfinyl, cyclopropylmethylsulfamoyl, butylsulfonimidoyl, 3-fluoropyrrolidine-1-carbonyl, 3-fluoropyrrolidine-1-ylsulfonyl, 3-fluorocyclobutyl-sulfamoyl, butylsulfonyl, butylsulfinyl, cyclopropylmethylsulfamoyl, butylsulfonimidoyl, 3-fluoropyrrolidine-1-carbonyl, 3-fluoropyrrolidine-1-ylsulfon ... and wherein the other substituents are as defined below.

[0024] In another embodiment, the compound is 2 is selected from cyclopropanecarbonylamino, 2-methylpropanoylamino, cyclobutanecarbonylamino, (2-methylcyclopropanecarbonyl)amino, and the other substituents are as defined above and below.

[0025] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein X, Y, W are C, Z is N, and N is substituted with a group selected from methylsulfonyl, acetylethylcarbamoyl, cyano, and the other substituents are as defined above and below.

[0026] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein X, Y, W, Z are C and Z is substituted with a group selected from OH, methyl, ethylcarbamoyl, cyano, oxo, tert-butoxycarbonylamino, 1H-pyrazol-3-yl, and the other substituents are as defined above and below.

[0027] In another embodiment, the compound is such that X, Y, W, and Z are C, W is substituted with a methyl group, and R 3 is H or a methy group, and the other substituents are as defined above and below.

[0028] In a further embodiment, the compounds of the invention are those in which X is C or N and R 3H, OH, methyl, amino, methylsulfonyl, acetyl, 2-methoxyacetyl, 2-phenylacetyl, 2-(tert-butoxycarbonylamino)ethyl, 2-phenylethyl, pyrimidin-2-ylamino, methanesufonamido, (4-methoxyphenyl)carbamothioylamino, (4-methoxyphenyl)carbamoylamino, ethylcarbamoyl, [N'-cyano-N-(p-tolyl)carbamimidoyl]amino, [N'-cyano no-N-ethyl-carbamimidoyl]amino, (1-oxoisoindolin-5-yl)carbamoyl, (3-sulfamoylphenyl)carbamoyl, (3-methylsulfonylphenyl)carbamoyl, 3-isoxazol-5-ylanilino, (2-ethoxy-3,4-dioxo-cyclobuten-1-yl)amino, ethylcarbonyl, carboxy, (1-oxoisoindolin-5-yl)aminocarbonyl, [(5-oxopyrrolidin-3-yl)phenyl]aminocarbonyl, [3-(3-methyl-5-oxo-4H-pyrazoline (1H-indazol-1-yl)phenyl]carbonylamino, (1H-indazol-4-yl)carbonylamino, 1H-imidazo[4,5-b]pyrazin-2-yl, indan-2-yl, [2-(4-methoxyphenyl)ethylaminocarbonyl, quinoxalin-6-yl, (thiazol-2-yl)aminocarbonyl, (1H-tetrazol-5-yl)aminocarbonyl, (4-pyridyl)aminocarbonyl, pyrazin-2-ylaminocarbonyl, (3-pyridyl)aminocarbonyl, 3-hydroxyazetidine-1-carbonyl, 1,1- Dioxo-1,4-thiazinane-4-carbonyl, 2-(4-hydroxyphenyl)ethylaminocarbonyl, hydroxyiminomethyl, [(4-ethyl-1,2,4-triazol-3-yl)amino]methyl, (4-methylanilino)methyl, 2-amino-3-pyridyl, 5-(p-tolyl)-1H-imidazol-2-yl, cyano, trifluoromethyl, 4-methyloxazol-2-yl, aminomethyl, (p-tolylcarbamoylamino)methyl, 3-methyl-1,2,4-oxadiazol-5-yl, 5-methyl-1,3,4-Oxadiazol-2-yl, pyrrolidine-1-carbonyl, 3-pyridylcarbamothioylamino, 3-(3-pyridylamino)-1,2,4-triazol-4-yl, 1H-pyrazol-3-yl, 5-amino-4-cyano-imidazol-1-yl, 3-(2,2-dimethylpropylamino)-1,2,4-triazol-4-yl, 3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]ami No, [(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl, N'-cyano-N-phenyl-carbamimidoylamino, 3-(isobutylamino)-1,2,4-triazol-4-yl, 3-[(1-methylcyclopropyl)methylamino]-1,2,4-triazol-4-yl, 5-acetamidoimidazol-1-yl, 3-[(5-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-(4-pyridylamino)-1,2,4-triazol-4-yl, N'-cyano -N-(3,4-dimethoxyphenyl)carbamimidoyl]amino, 4-ethoxycarbonyl-5-(ethylamino)imidazol-1-yl, 3-(2-morpholinoethylamino)-1,2,4-triazol-4-yl, (5-oxo-4H-1,2,4-oxadiazol-3-yl)amino, 2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino, [N'-cyano-N-(2,2,2-trifluoroethyl)carbamimidoyl]amino, 3-(ethylamino)-1,2,4-triazol-4-yl, (N-ethyl 3-(3-pyridylamino)-1,2,4-triazol-4-yl, 3-[(1-oxidopyridin-1-ium-3-yl)amino, [N'-nitro-N-(p-tolyl)carbamimidoyl]amino, 2-(3-pyridylamino)imidazol-1-yl, 3-(3-pyridylamino)-1,2,4-triazol-4-yl, 3-(cyclopropylmethylamino, (2,5-dimethylpyrazol-3-yl)carbamothioylamino, 3-(pyrimidin-5-ylamino)-1,2,4-triazol-4-yl, 2-(cyclopropylmethylamino)imidazol-1-yl, [4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino, [1-(4-methylanilino)-2-nitro-vinyl]amino, (N'-cyano-N-ethyl-carbamimidoyl)-methyl-amino, [2-(4-methylanilino)-3,4-dioxo-cyclobuten-1-yl]amino, 3-(2-pyridylamino)-1,2,4-triazol-4-yl, 2-acetamidoimidazol-1-yl, 5-(N-tert-butyloxycarbonylamino)-triazol-1-yl, 5-(3-pyridylamino)triazol-1-yl, ethylcarbamothioylamino, 3-[[(3S)-tetrahydrofuran-3-yl]amino]-1,2,4-triazol-4-yl, [(E)-N-ethyl-N'-nitro-carbamimidoyl]amino, 2-(ethylamino)imidazol-1-yl, 3-[(3,5-dimethylisoxazol-4-yl)amino, [[N'-ethoxycarbonyl-N-(p-tolyl)carbamimidoyl ]amino], [2-[(2-methyl-3-pyridyl)amino]imidazol-1-yl, 1-[(ethylamino)-2-nitro-vinyl]amino, (4-methyl-6-oxo-1H-pyrimidin-2-yl)amino, 5-amino-4-(methylcarbamoyl)imidazol-1-yl, 5-amino-4-carbamoyl-imidazol-1-yl, 2-anilinoimidazol-1-yl, ethylcarbamoylamino, (4-oxo-1H-pyridin-2-yl)amino, [6-(5-methyl-1,3,4-oxadiazol-2-yl)- 3-pyridyl]amino, 5-(ethylamino)tetrazol-1-yl, 1H-1,2,4-triazol-3-ylamino, 4-(1-methylpyrazol-4-yl)-1,2,4-triazol-3-yl]amino, 4-(ethyloxy-carbonyl)imidazol-1-yl, [4-(4-fluorophenyl)-1,2,4-triazol-3-yl]amino, 1H-imidazol-2-ylamino, N'-methoxy-N-(p-tolyl)carbamimidoyl]amino, [4-(4-methylanilino)-1,1-dioxo-1,2,5-Thiadiazol-3-yl]amino, [1-(3-pyridyl)imidazol-2-yl]amino, 5-aminotriazol-1-yl, (2-methoxyphenyl)carbamoylamino, 4-pyridine-carbonylamino, benzylamino, 1H-benzimidazol-2-ylamino, [N'-hydroxycarbamimidoyl]amino, [N'-(1-methylpyrazol-3-yl)-N-(p-tolyl)carbamimidoyl]amino, 3-[(3,5-dimethylpyrazin-2-yl)amino, 3-(ethylamino)-5-(methoxymethyl) )-1,2,4-triazol-4-yl, [5-(3-pyridyl)-1H-1,2,4-triazol-3-yl]amino, p-tolyl-carbonylamino, quinazolin-2-ylamino, 1,3-benzoxazol-2-ylamino, 3-(ethylamino)-5-(hydroxymethyl)-1,2,4-triazol-4-yl, 2-aminoimidazol-1-yl, 3-amino-5-oxo-1,2,4-oxadiazol-4-yl, 3-(ethylamino)-5-methyl-1,2,4-triazol-4-yl, (2-ethyl-3,4- dioxo-cyclobuten-1-yl)amino, 1,3,4-oxadiazol-2-ylamino, 5-oxo-1-(p-tolyl)-4H-imidazol-2-yl]amino, [2-[ethyl(methyl)amino]-3,4-dioxo-cyclobuten-1-yl]amino, (methylsulfonimidoyl)amino, [N-cyano-C-methyl-carbonimidoyl]amino, tetrazol-1-yl, methanesulfinamide, morpholino, 3-(ethylamino)-5-(trifluoromethyl)-1,2,4-triazol-4-yl, (4-oxo -1H-pyrimidin-2-yl)amino, isopropylsulfamoylamino, N'-cyano-N-morpholino-carbamimidoyl]amino, acetamide, methanesulfonamide, [N'-cyano-N-methoxy-carbamimidoyl]amino, (4-methoxyphenyl)carbamoylamino, [4-oxo-6-(trifluoromethyl)-1H-pyrimidin-2-yl]amino, [4-(trifluoromethoxy)phenyl]carbamoylamino, 3-(2-methylpropanoylamino)-1,2,4-triazol-4-yl, 3-[(2,5-Dimethylpyrazol-3-yl)-methyl-amino]-1,2,4-triazol-4-yl, 5-amino-4-(5-methyl-1,3,4-oxadiazol-2-yl)imidazol-1-yl, 3-[(3-methyl-1H-pyrazol-5-yl)amino]-1,2,4-triazol-4-yl, 3-[(1,3-dimethylpyrazol-4-yl)amino]-1,2,4-triazol-4-yl-[(5-cyclopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(5-isopropyl Pyr-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(2-isopropyl-5-methyl-pyrazol-3-yl)amino, 3-[(5-methyl-2-tetrahydrofuran-3-yl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-ethyl -5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-cyclopropyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]-1,2,4-triazol-4-yl, 3-[(5-ethyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino, 3-[(1,4-dimethylpyrazol-4-yl), and 2-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]imidazol-1-yl, [3-[(5-carboxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl], wherein the other substituents are as defined above and below.

[0029] In a further embodiment, the compound is characterized by formula (I) or (Ia), in which W, X, Y, Z are C, Z is optionally substituted with a methyl group, and the other substituents are as defined above and below.

[0030] In a further embodiment, the compound is R 1 are (cyclopropylmethyl)carbamoyl, (3-fluorocyclobutylmethyl)carbamoyl, (2-fluorocyclopropyl)methylcarbamoyl, (2,2-difluorocyclopropyl)methylcarbamoyl, (2,2-dimethylcyclopropyl)methylcarbamoyl, (spiro[2.2]pentan-2-yl)carbamoyl, (spiro[2.2]pentan-2-yl)methylcarbamoyl, (3,3-difluorocyclobutyl)carbamoyl, (3-fluorocyclobutyl)carbamoyl, (2-methylcyclopropyl)methylcarbamoyl, (3 ,3-difluorocyclobutyl)methyl-carbamoyl, ethoxycarbonyl, (3-fluorocyclobutyl)methyl-carbamoyl, (cyclobutyl)methyl-carbamoyl, (3-methylcyclobutyl)carbamoyl, (2,2-difluorocyclobutyl)methyl-carbamoyl, (3-fluorocyclobutyl)methyl-carbamoyl, (2-fluorocyclobutyl)methyl-carbamoyl, (spiro[2.2]pentan-2-yl)carbamoyl, and the other substituents are as defined above and below.

[0031] In a further embodiment, the compound is R 2is selected from (cyclopropyl)acetylamino, (spiro[2.2]pentan-2-yl)carbonylamino, (2-fluorocyclopropyl)carbonylamino, (2,2-difluorocyclopropyl)carbonylamino, (2-methylcyclopropyl)carbonylamino, (3-fluorocyclobutyl)carbonylamino, (3,3-difluorocyclobutyl)carbonylamino, (oxetan-3-yl)carbonylamino, 3,3-difluoropropanoylamino, (cyclobutyl)carbonylamino, 2-(methylpropanoyl)amino, and the other substituents are as defined above and below.

[0032] In a further embodiment, the compound is R 3However, the following compounds are not particularly limited: (1,1-dioxothiolan-3-yl)amino-1,2,4-triazol-4-yl, 3-[3-[methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl, 3-[(1-acetyl-3-methylpyrrolidin-3-yl)amino]-4H-1,2,4-triazol-4-yl, 3-{[1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]amino}-4H-1,2,4-triazol-4-yl, 3-[[-1-pyrazin-2-ylpyrrolidine- 3-[[-1-(6-fluoropyridazin-3-yl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(4-methyl-1-methylsulfonyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(1-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-4H-1,2,4-triazol-4-yl, 3-[[-1-(6-fluoropyridazin-3-yl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[1-pyrimidin-2-ylpyrrolidin Lysin-3-yl]amino]-1,2,4-triazol-4-yl, 5-amino-4-(2-methoxyethoxycarbonyl)imidazol-1-yl, 5-amino-4-(2-morpholinethoxycarbonyl)imidazol-1-yl, 3-(3-methylsulfanylanilino)-1,2,4-triazol-4-yl, 3-(3-methylsulfonylanilino)-1,2,4-triazol-4-yl, 3-(3-methylsulfonylanilino)-1,2,4-triazol-4-yl, 3-(3-methylsulfinylanilino)-1,2,4-triazol-4-yl, 3 -[3-(methylsulfonimidoyl)anilino]-1,2,4-triazol-4-yl, 3-[(6-methylsulfinyl-2-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-methylsulfonyl-2-pyridyl)amino]-1,2,4-triazol-4-yl, 8-methoxy-4-oxo-5,10-dihydroimidazo[4,5-c][1,5]benzodiazepin-1-yl, 8-methoxy-5-methyl-4-oxo-10H-imidazo[4,5-c][1,5]benzodiazepin-1-yl, 5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl, 5-amino-4-[(3R)-3-hydroxypyrrolidine-1-carbonyl]imidazol-1-yl, 5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl, 5-[[4-(dihydroxyamino)-2,5-dimethyl-3H-pyrazol-3-yl]amino]-4-ethoxycarbonyl-imidazol-1-yl, 5-[[4-(dihydroxyamino)-2,5-dimethyl -3H-pyrazol-3-yl]amino]-4-ethoxycarbonyl-imidazol-1-yl, 3-(2-methyl-3-methylsulfinyl-anilino)-1,2,4-triazol-4-yl, 3-(2-methyl-3-methylsulfonyl-anilino)-1,2,4-triazol-4-yl, 3-[(2-methyl-5-oxazol-2-yl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 1-acetylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 1-methylsulfonylpyrrolidine-3- 3-[(2-methylcyclohexyl)amino]-1,2,4-triazol-4-yl, 3-[(5-oxopyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-oxo-4-piperidyl)amino]-1,2,4-triazol-4-yl, 3-[(1-acetyl-2-methyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-methyl-1-methylsulfonyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl -4-yl, -[3-[[3-(6-methyl-3-pyridyl)cyclobutyl]amino]-1,2,4-triazol-4-yl,, 3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, [[1-benzoyl-4,4-difluoro-pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(1-acetyl-4-piperidyl)amino]-1,2,4-triazol-4-yl, 3-[(1-methoxycarbonylpyrrolidin-3-yl)amino]-1,2,4-Triazol-4-yl, 3-[[1-(ethylcarbamoyl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-{[2-(pyrimidin-2-yl)-2-azaspiro[4.4]nonan-7-yl]amino}-4H-1,2,4-triazol-4-yl, 3-[[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[5-[chloro(difluoro)methoxy]-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazo 4-yl, 3-{[1-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-5-yl]amino}-4H-1,2,4-triazol-4-yl, 3-[(5-methoxy-3-methyl-pyrazin-2-yl)amino]-1,2,4-triazol-4-yl, (5-methylthiazolo[5,4-b]pyridin-2-yl)amino, 3-[(5-cyano-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-cyano-2-methyl-3-pyridyl)amino]-1, 2,4-Triazol-4-yl, 3-[(1-methyl-2-oxo-4-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-chloro-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl, 3-[(3-methylpyridazin-4-yl)amino]-1,2,4-triazol-4-yl, 3-[(5-chloro-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl riazol-4-yl, 3-[(3-methylisothiazol-4-yl)amino]-1,2,4-triazol-4-yl, 3-[(3-methylisoxazol-4-yl)amino]-1,2,4-triazol-4-yl, 3-[[5-(cyclopropylmethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(5-ethoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-Triazol-4-yl, (5-amino-4-ethoxycarbonyl-imidazol-1-yl), 3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethyl)-2-(trideuteriomethyl) 5-(5-(difluoromethyl)-2-(trideuteriomethyl)pyrazol-3-yl]amino, 3-[(5-cyano-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2,2-difluoro-1,3-benzodioxol-5-yl)amino]-1,2,4-triazol-4-yl, 3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethyl)-2-(trideuteriomethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(6-fluoro-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[[5-(cyclopropoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[2-methyl-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[6-(trifluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl, 3-[(6-methoxy-3-pyridyl)amino]- 1,2,4-triazol-4-yl, 3-[(2-methoxy-4-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-chloro-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(2-chloro-4-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-methoxy-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, thiazolo[5,4-b]pyridin-2-ylamino, 3-[(3-methyltriazol-4-yl)amino]-1,2,4-triazol-4-yl, the other substituents being as defined above and below, and characterized by formula (I) or (Ia),

[0033] In another particular embodiment, the compound has formula (III) or (IV) [ka] Characterized by [In the formula, R 3 , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 is as defined in formula (I) or (Ia)].

[0034] In another particular embodiment, the compound has formula (V) or (VI) [ka] Characterized by [In the formula, R a , R c , R d , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 and R 14 is as defined in formula (I) or (Ia); R 3 is NR c R d , N.H.-R. 14 -NH-R a , optionally substituted heteroaryl as defined in formula (I) or (Ia).

[0035] In another preferred specific embodiment, the compound has formula (VII) or (VIII) [ka] Characterized by [In the formula, R 6 , R 7 , R 8 , R 9 , R 12 and R 13 is as defined in formula (I) or (Ia); R 3 is heteroaryl, optionally substituted as defined in formula (I) or (Ia).

[0036] In another preferred specific embodiment, the compound has formula (IX) or (X) [ka] Characterized by [In the formula, R c , R d , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 is as defined in formula (I) or (Ia)].

[0037] In another preferred specific embodiment, the compound has formula (XI) or (XII) [ka] Characterized by [In the formula, R c , R d , R e , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 is as defined in formula (I) or (Ia)].

[0038] In another preferred specific embodiment, the compound has formula (XIII) or (XIV) [ka] Characterized by [In the formula, R a , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 is as defined in formula (I) or (Ia)].

[0039] In another preferred specific embodiment, the compound has formula (XV) or (XVI) [ka] Characterized by [In the formula, R a , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 is as defined in formula (I) or (Ia)].

[0040] In another preferred specific embodiment, the compound has formula (XVII) or (XVIII) [ka] Characterized by [In the formula, R c , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 is as defined in formula (I).

[0041] In another preferred specific embodiment, the compound has formula (XIX) or (XX) [ka] Characterized by [In the formula, R c , R e , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 is as defined in formula (I) or (Ia)].

[0042] In another preferred specific embodiment, the compound has formula (XXI) or (XXII) [ka] Characterized by [In the formula, R c , R 6 , R 7 , R 8 , R 9 , and R 13 is as defined in formula (I) or (Ia)].

[0043] In another preferred specific embodiment, the compound has formula (XXIII) or (XXIV) [ka] Characterized by [In the formula, R c , R e , R 6 , R 7 , R 8 , R 9 and R 13 is as defined in formula (I) or (Ia)].

[0044] In another preferred specific embodiment, the compound has formula (XXV) or (XXVI) [ka] It is characterized by:

[0045] In another preferred specific embodiment, the compound has formula (XXVII) or (XXVIII) [ka] It is characterized by:

[0046] In another preferred specific embodiment, the compound has the formula (XXIX) or (XXX) [ka] It is characterized by:

[0047] In another preferred specific embodiment, the compound has formula (XXXI) or (XXXII) [ka] It is characterized by:

[0048] In another preferred specific embodiment, the compound has formula (XXXII) or (XXXIV) [ka] It is characterized by:

[0049] In another preferred specific embodiment, the compound has formula (XXXV) or (XXXVI) [ka] It is characterized by:

[0050] Particular compounds of formula (I) or (XXXVI) according to the invention are [ka] 2-(Cyclopropanecarbonylamino)-N-methyl-5,7-dihydro-4H-thieno[2,3-c]thiopyran-3-carboxamide [ka] 6-(Cyclopropanecarbonylamino)-N-methyl-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxamide; hydrochloride [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methylsulfonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide [ka] 5-Acetyl-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-methylsulfonyl-5,6-dihydro-4H-thieno[2,3-b]pyridine-3-carboxamide [ka] 7-Acetyl-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,6-dihydro-4H-thieno[2,3-b]pyridine-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-methoxyacetyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-phenylacetyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide [ka] Tert-Butyl N-[2-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethyl]carbamate [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-phenylethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide [ka] Methyl 2-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]acetate [ka] (4R)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide (4S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide [ka] N-[3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-[(2-hydroxy-2-methyl-propyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-(2-hydroxypropylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-(3-pyrrolidin-1-ylsulfonyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide [ka] N-[3-[(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-(3-Butylsulfonyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide [ka] N-[3-(isobutylsulfamoyl)-5-(pyrimidin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-(isobutylsulfamoyl)-5-(methanesulfonamido)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[5-[(4-methoxyphenyl)carbamothioylamino]-3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[5-[(4-methoxyphenyl)carbamoylamino]-3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-ethyl-3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-ethyl-3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide [ka] N-(3-Butylsulfinyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide [ka] N-[5-[[N'-cyano-N-(p-tolyl)carbamimidoyl]amino]-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(1-oxoisoindolin-5-yl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-sulfamoylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-methylsulfonylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-isoxazol-5-ylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide [ka] N-[3-(cyclopropylmethylsulfamoyl)-5-[(2-ethoxy-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-(cyclopropylmethylsulfamoyl)-5-[[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-(butylsulfonimidoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] Ethyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate [ka] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1-oxoisoindolin-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[3-(5-oxopyrrolidin-3-yl)phenyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[3-(3-methyl-5-oxo-4H-pyrazol-1-yl)phenyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-indazol-4-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide;2,2,2-trifluoroacetic acid [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-indazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide;2,2,2-trifluoroacetic acid [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-imidazo[4,5-b]pyrazin-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-indan-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[2-(4-methoxyphenyl)ethyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-quinoxalin-6-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-thiazol-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-tetrazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(4-pyridyl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-pyrazin-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(3-pyridyl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(3-hydroxyazetidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[2-(4-hydroxyphenyl)ethyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(hydroxyiminomethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(4-ethyl-1,2,4-triazol-3-yl)amino]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-[(4-methylanilino)methyl]-6,7-dihydro-4H-benzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-2'-oxo-3'-(p-tolyl)spiro[6,7-dihydro-4H-benzothiophene-5,5'-oxazolidine]-3-carboxamide [ka] 5-(2-Amino-3-pyridyl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(p-tolyl)-1H-imidazol-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-Cyano-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide 7-Cyano-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5R)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(4-methyloxazol-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-(aminomethyl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-6,7-dihydro-4H-benzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-[(p-tolylcarbamoylamino)methyl]-6,7-dihydro-4H-benzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-methyl-6,7-dihydro-4H-benzothiophene-3-carboxamide [ka] N-[3-[(3R)-3-fluoropyrrolidine-1-carbonyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-(3-fluoroazetidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] N-[3-(piperidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] 2-(Cyclopropanecarbonylamino)-7-hydroxy-N-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxamide [ka] 2'-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxamide [ka] N-(cyclopropylmethyl)-2-(2-methylpropanoylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclobutanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide 2-(Cyclopropanecarbonylamino)-4,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid [ka] N-(cyclopropylmethyl)-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide diastereomer 1 N-(cyclopropylmethyl)-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide diastereomer 2 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-2',5'-dioxo-spiro[6,7-dihydro-4H-benzothiophene-5,4'-imidazolidine]-3-carboxamide [ka] Cyclopropylmethyl 2-(cyclopropanecarbonylamino)-5-(3-pyridylcarbamothioylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate [ka] Cyclopropylmethyl 2-(cyclopropanecarbonylamino)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate [ka] 2-(Cyclopropanecarbonylamino)-N,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide 2-(Cyclopropanecarbonylamino)-N,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] tert-Butyl N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-7-yl]carbamate [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N7-ethyl-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] N-Methyl-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] Ethyl 2-(cyclopropanecarbonylamino)-7-hydroxy-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate [ka] (5S)-5-(5-amino-4-cyano-imidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2,2-dimethylpropylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(Cyclopropanecarbonylamino)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-isobutyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-Amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-[[N'-cyano-N-phenyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(isobutylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-methylcyclopropyl)methylamino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-5-(5-acetamidoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(4-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-[[N'-cyano-N-(3,4-dimethoxyphenyl)carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] Ethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-morpholinoethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(5-oxo-4H-1,2,4-oxadiazol-3-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-[[N'-cyano-N-(2,2,2-trifluoroethyl)carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(N-ethyl-N'-nitro-carbamimidoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-oxidopyridin-1-ium-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-nitro-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(3-pyridylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] N-[(5S)-3-(5-azaspiro[2.4]heptane-5-carbonyl)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide N-[(5R)-3-(5-azaspiro[2.4]heptane-5-carbonyl)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2,5-dimethylpyrazol-3-yl)carbamothioylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(pyrimidin-5-ylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(cyclopropylmethylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(4-methylanilino)-2-nitro-vinyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-5-[(N'-cyano-N-ethyl-carbamimidoyl)-methyl-amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-(4-methylanilino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-5-(2-acetamidoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] tert-Butyl N-[3-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]triazol-4-yl]carbamate [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(3-pyridylamino)triazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(ethylcarbamothioylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-tetrahydrofuran-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(E)-N-ethyl-N'-nitro-carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5R)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(E)-N-ethyl-N'-nitro-carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(ethylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3,5-dimethylisoxazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] Ethyl N-[[[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]amino]-(4-methylanilino)methylene]carbamate [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-[(2-methyl-3-pyridyl)amino]imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(ethylamino)-2-nitro-vinyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-methyl-6-oxo-1H-pyrimidin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-Amino-1-[(5S)-2-cyclopropanamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-N-methyl-1H-imidazole-4-carboxamide [ka] 5-Amino-1-[(5S)-2-cyclopropanamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-1H-imidazole-4-carboxamide [ka] 5-(2-anilinoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(ethylcarbamoylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-oxo-1H-pyridin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-pyridyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(ethylamino)tetrazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-1,2,4-triazol-3-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5R)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(1-methylpyrazol-4-yl)-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] Ethyl 1-[(5S)-2-cyclopropanamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-1H-imidazole-4-carboxylate [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(4-fluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-imidazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] N-[3-(isopropylmethylsulfamoyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-methoxy-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(4-methylanilino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(3-pyridyl)imidazol-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-(5-aminotriazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-methoxyphenyl)carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]pyridine-4-carboxamide [ka] 5-(Benzylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-(1H-Benzimidazol-2-ylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-hydroxycarbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-(1-methylpyrazol-3-yl)-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;Formic acid [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3,5-dimethylpyrazin-2-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(methoxymethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[5-(3-pyridyl)-1H-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] p-Tolyl N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(quinazolin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-(1,3-Benzoxazol-2-ylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(hydroxymethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(3,3-difluorocyclobutyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-5-(2-aminoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-(3-amino-5-oxo-1,2,4-oxadiazol-4-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-methyl-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5R)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-ethyl-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-ethyl-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(pyrimidin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1,3,4-oxadiazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(3-fluorocyclobutyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[5-oxo-1-(p-tolyl)-4H-imidazol-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-[ethyl(methyl)amino]-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(methylsulfonimidoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-[[N-cyano-C-methyl-carbonimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(tetrazol-1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(methanesulfinamido)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methyl-propyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-morpholino-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(trifluoromethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-oxo-1H-pyrimidin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(isopropylsulfamoylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-[[N'-cyano-N-morpholino-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-Acetamido-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(methanesulfonamido)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-[[N'-cyano-N-methoxy-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-isobutyl-5-[(4-methoxyphenyl)carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-oxo-6-(trifluoromethyl)-1H-pyrimidin-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] N-[5-(methanesulfonamido)-3-(3-methylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] 2-(Cyclopropanecarbonylamino)-N-propyl-5-[[4-(trifluoromethoxy)phenyl]carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-methylpropanoylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)-methyl-amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide [ka] (5S)-5-[5-amino-4-(5-methyl-1,3,4-oxadiazol-2-yl)imidazol-1-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methyl-1H-pyrazol-5-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1,3-dimethylpyrazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-cyclopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-isopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-isopropyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-methyl-2-tetrahydrofuran-3-yl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-ethyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-cyclopropyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-ethyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1,4-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] Methyl 5-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]-1-methyl-pyrazole-3-carboxylate [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ka] 5-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]-1-methyl-pyrazole-3-carboxylic acid; It is selected from the group consisting of these enantiomers and pharma- ceutically acceptable salts thereof.

[0051] According to one embodiment, the compound of the invention is (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S * )-1,1-dioxothiolan-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or R]; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-[3-({3-[imino(methyl)oxo-lambda 6-sulfanyl]-2-methylphenyl}amino)-4H-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[2-methyl-3-[(S)-methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[2-methyl-3-[(R)-methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-{3-[(1-acetyl-3-methylpyrrolidin-3-yl)amino]-4H-1,2,4-triazol-4-yl}-2-cyclopropanamide-N-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[(3S * )-1-acetyl-3-methyl-pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or R]; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-(3-{[(3S)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]amino}-4H-1,2,4-triazol-4-yl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-1-pyrazin-2-ylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(4-methyl-1-methylsulfonyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-{3-[(1-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-4H-1,2,4-triazol-4-yl}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-1-(6-fluoropyridazin-3-yl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; [Example 246] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-1-pyrimidin-2-ylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; 2-Methoxyethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]imidazole-4-carboxylate; 2-morpholin-4-ylethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]imidazole-4-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfanylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfonylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfinylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-(methylsulfonimidoyl)anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-[(S)-methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-[(R)-methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-N-(cyclopropylmethyl)-5-[3-[(6-methylsulfinyl-2-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(spiro[2.2]pentane-2-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(6-methylsulfonyl-2-pyridyl)amino]-1,2,4-triazol-4-yl]-2-[[(2S * )-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(8-methoxy-4-oxo-5,10-dihydroimidazo[4,5-c][1,5]benzodiazepin-1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(8-methoxy-5-methyl-4-oxo-10H-imidazo[4,5-c][1,5]benzodiazepin-1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl]-N-(cyclopropylmethyl)-2-[[(1R * ,2R * )-2-Fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or 1S,2S]; (5S)-5-[5-amino-4-[(3R)-3-hydroxypyrrolidine-1-carbonyl]imidazol-1-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl 1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-5-[(2,5-dimethyl-4-nitro-pyrazol-3-yl)amino]imidazole-4-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-methyl-3-methylsulfinyl-anilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-methyl-3-methylsulfonyl-anilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methyl-5-oxazol-2-yl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[(3S)-1-acetylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-1-methylsulfonylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3R)-1-methylsulfonylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methylcyclohexyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-oxopyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3R * )-5-oxopyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( * or S); 5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-oxo-4-piperidyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(1-acetyl-2-methyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methyl-1-methylsulfonyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[3-(6-methyl-3-pyridyl)cyclobutyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[3-(6-methyl-3-pyridyl)cyclobutyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-[[(1R *)-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or S]; (5S)-2-[[(1R * )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( * or S); (5S)-2-[[(1R * )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or S]; (5S)-2-[[(1S * )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or R]; (5S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-[[(1S *)-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or R]; (5S)-5-[3-[[(3S * )-1-benzoyl-4,4-difluoro-pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or R]; (5S)-5-[3-[(1-acetyl-4-piperidyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Methyl (3S)-3-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]pyrrolidine-1-carboxylate; (3S)-3-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]-N-ethyl-pyrrolidine-1-carboxamide; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-(3-{[2-(pyrimidin-2-yl)-2-azaspiro[4.4]nonan-7-yl]amino}-4H-1,2,4-triazol-4-yl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-[chloro(difluoro)methoxy]-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-[chloro(difluoro)methoxy]-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-(3-{[1-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-5-yl]amino}-4H-1,2,4-triazol-4-yl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-3-methyl-pyrazin-2-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(5-methylthiazolo[5,4-b]pyridin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(5-cyano-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(6-cyano-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-methyl-2-oxo-4-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(6-chloro-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methylpyridazin-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(5-chloro-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2R)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methylisothiazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methylisoxazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(cyclopropylmethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cyclopropylmethyl)-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-ethoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2R *)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or S]; (5S)-N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; Ethyl 5-amino-1-[(5S * )-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate ( * or R); N-[(5S * )-3-(cyclopropylmethylsulfamoyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide ( * or R); N-[(5S *)-3-(cyclopropylmethylsulfamoyl)-5-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide ( * or R); (1R,2S)-N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]-2-fluoro-cyclopropanecarboxamide; (1R,2S)-N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]-2-fluoro-cyclopropanecarboxamide; (1S * )-N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]-2,2-difluoro-cyclopropanecarboxamide[ * or R]; (1S * )-N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]-2,2-difluoro-cyclopropanecarboxamide[ * or R]; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; (1R,2S)-N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R *)-N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2,2-difluorocyclopropane-1-carboxamide ( * or S); (1R * )-N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2,2-difluorocyclopropane-1-carboxamide ( * or S); (5S)-N-(cyclopropylmethyl)-5-[3-[(3-methyl-1,2-thiazol-4-yl)amino]-1,2,4-triazol-4-yl]-2-(spiro[2.2]pentane-2-carbonylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; (1R,2S)-N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; (1R,2S)-N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R * )-N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2,2-difluorocyclopropane-1-carboxamide ( * or S) N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1R * )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( * or S); (5S)-N-(cyclopropylmethyl)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[cis-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1RS,2RS)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1RS,2RS)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-[(5S)-3-(cyclopropylmethylcarbamoyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]oxetane-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(3,3-difluoropropanoylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclobutanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(2-methylpropanoylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1RS,2RS)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (5S)-N-(cyclopropylmethyl)-2-[[(1R * )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( * or S); (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1RS,2SR)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2R)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R * ,2R * )-2-Methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( * or S); (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R * ,2S * )-2-Methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( * 1R,2S or 1S,2R); (5S)-2-(Cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R * )-2,2-Dimethylcyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( * or S); (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-N-[(2R * )-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( * or S); (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[cis-(3-fluorocyclobutyl)methyl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(spiro[2.2]pentan-2-ylmethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(2R)-spiro[2.2]pentan-2-yl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(2S)-spiro[2.2]pentan-2-yl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(3,3-difluorocyclobutyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cis-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(3,3-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1RS,2RS)-2-methylcyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (cis); (5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1RS,2SR)-2-methylcyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (trans); 5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; 5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(2,2-difluorocyclopropyl)methyl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[trans-(3-fluorocyclobutyl)methyl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(trans-3-fluorocyclobutyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-(trideuteriomethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(3,3-difluorocyclobutyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(3,3-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-N-spiro[2.2]pentan-2-yl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-N-[(2S)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(spiro[2.2]pentane-2-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate; Ethyl (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate; (5S)-5-[3-[(5-cyano-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,2-difluoro-1,3-benzodioxol-5-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (4RS,5RS)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (4R * ,5R * )-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[6-(difluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(6-fluoro-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(cyclopropoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cyclopropylmethyl)-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[6-(trifluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(6-methoxy-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methoxy-4-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(6-chloro-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(2-chloro-4-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(6-methoxy-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-fluoro-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methyltriazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(3,3-difluorocyclobutyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(3,3-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[cis-(3-fluorocyclobutyl)methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(spiro[2.2]pentan-2-ylmethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclobutylmethyl)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(3,3-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cis-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(3-methylcyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(3,3-difluorocyclobutyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(2,2-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-spiro[2.2]pentan-2-yl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2-methylcyclopropyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1RS,2RS)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(2R * )-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( * or S); (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-N-[(2R * )-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or S]; (5S)-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[trans-(3-fluorocyclobutyl)methyl]-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[(2S)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R *)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ * or S]; (5S)-N-(cyclobutylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[cis-(3-fluorocyclobutanecarbonyl)amino]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[cis-(3-fluorocyclobutanecarbonyl)amino]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[(2S)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-Cyclopropanamido-5-(3-{[3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl]amino}-4H-1,2,4-triazol-4-yl)-N-{spiro[2.2]pentan-1-yl}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2S)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-[[(1R *)-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( * or S); (5S)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-(spiro[2.2]pentane-2-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(2S * )-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( * or R); (3R * )-6-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-3-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxamide ( * or S); It is selected from these enantiomers and pharma- ceutically acceptable salts thereof.

[0052] According to one embodiment, the compound of the invention is (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-cyclopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-isopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-ethyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-ethoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; ( 5S)-N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(2R * )-Spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( * or S) (5S)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(2R * )-Spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( * or S) It is selected from these enantiomers and pharma- ceutically acceptable salts thereof.

[0053] The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and that are intended to apply uniformly throughout the specification and claims, unless a broader definition is expressly stated.

[0054] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine.

[0055] The term "heterocyclic ring" refers to a saturated ring containing at least one heteroatom, such as oxygen, sulfur, and nitrogen; including heteoaromatic or aromatic rings fused to a heterocycle.

[0056] The term "alkyl" refers to a straight-chain or branched, saturated, aliphatic hydrocarbon group.

[0057] The term "cycloalkyl" refers to a univalent group derived from a saturated cyclic hydrocarbon, and includes fused-ring cycloalkyls and heteroaromatic, heterocyclic, or aromatic rings fused to a carbocycle.

[0058] The term "fused-ring cycloalkyl" refers to a cycloalkyl that contains two or more rings that share at least one bond and two atoms. Examples of fused-ring cycloalkyls include: [ka] Includes:

[0059] The term "heteroalkyl" refers to an alkyl group in which at least one carbon atom is replaced with a heteroatom such as oxygen, sulfur, or nitrogen.

[0060] The term "heterocycle" refers to a ring structure having atoms of at least two different elements as members of the ring, in which some or all of the atoms in the molecule combine into a ring containing at least one atom of an element other than carbon, thus, for example, oxygen, sulfur, and nitrogen; including heteroaromatic or aromatic rings fused to a heterocycle.

[0061] The term "alkylene" refers to a divalent saturated aliphatic radical derived from an unsaturated aliphatic hydrocarbon.

[0062] The term "haloalkyl" refers to an alkyl group, as defined above, in which at least one hydrogen atom is replaced by a halogen atom.

[0063] The term "alkenyl" refers to a univalent group derived from a partially unsaturated straight or branched carbon chain, such as ethenyl, propenyl, butenyl, pentenyl, and the like.

[0064] The term "cycloalkenyl" refers to a monovalent group derived from a partially unsaturated monocyclic hydrocarbon, such as cyclobutenyl.

[0065] The term "heteroalkenyl" refers to a monovalent group derived from a partially unsaturated linear or branched carbon chain containing at least one heteroatom, such as oxygen, sulfur, and nitrogen.

[0066] The term "heterocycloalkenyl" refers to a monovalent group derived from a partially unsaturated monocyclic hydrocarbon containing at least one heteroatom such as oxygen, sulfur, and nitrogen.

[0067] The term "alkynyl" refers to an unsaturated straight or branched carbon chain containing at least one carbon-carbon triple bond, such as ethynyl, propynyl, and butynyl.

[0068] The term "heteroalkynyl" refers to unsaturated linear or branched carbon chains containing at least one carbon-carbon triple bond and containing at least one heteroatom, such as oxygen, sulfur, and nitrogen.

[0069] The term "aryl" refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or multiple condensed aromatic rings; e.g., phenyl, naphthyl.

[0070] The term "heteroaryl" refers to a monovalent aromatic group containing at least five atoms derived from a single ring or multiple fused rings containing at least one heteroatom such as oxygen, sulfur, and nitrogen.

[0071] The term "alkoxy" refers to the group -O-R', where R' is alkyl as defined above.

[0072] The term "alkylamino" refers to the group -NH-alkyl, where alkyl is as defined above. The term "cycloalkyl-amino" refers to the group -NH-cycloalkyl, where cycloalkyl is as defined above.

[0073] The term "heterocycle-amino" refers to a heterocycle as defined above in which one or more carbon atoms are linked to -NH-, thus referring to the group -NH-heterocycle.

[0074] The term "aryl-amino" refers to aryl as defined above where one or more carbon atoms are linked to -NH-, thus referring to the group -NH-aryl.

[0075] The term "heteroaryl-amino" refers to heteroaryl as defined above wherein one or more carbon atoms are linked to -NH-, thus referring to the group -NH-heteroaryl.

[0076] The term "heteroalkyl-amino" refers to the group --NH-heteroalkyl, where heteroalkyl is defined above.

[0077] The term "pharmaceutically acceptable salts" according to the present invention includes salts of the compounds of formulae (I)-(XXXVI) with pharmaceutically acceptable acids or bases, in particular acid addition salts. The acid addition salt forms of the compounds of formulae (I)-(XXXVI) occurring as bases in their free form can be obtained by treating the free base with a suitable acid such as an inorganic acid, e.g., a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid, e.g., acetic acid, trifluoroacetic acid, oxalic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.

[0078] The present invention also relates to all stereoisomers, such as enantiomers and diastereoisomers of the compounds of formulae (I)-(XXXVI) or mixtures thereof, including all possible mixtures of stereoisomers, such as racemates. In the context of the present invention, reference to a compound or compounds is intended to encompass the compound in each of its possible isomers and mixtures thereof, unless a particular isomeric form is specifically mentioned.

[0079] Some of the compounds of formulas (I)-(XXXVI) may also exist in tautomeric forms, and such forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the invention.

[0080] It should be understood that each individual atom present in formulae (I)-(XXXVI) or in the formulae depicted herein may in fact be present in any of its naturally occurring isotope forms, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formulae (I)-(XXXVI) or in the formulae depicted herein may be present as 1H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, by way of example, each individual carbon atom present in formulae (I)-(XXXVI) or in the formulae depicted herein may be present as 12C, 13C or 14C atom, preferably 12C.

[0081] The present invention includes within its scope solvates of the compounds of formulae (I)-(XXXVI) above. Such solvates may be formed with common organic solvents or with water.

[0082] The present invention also includes within its scope co-crystals of the compounds of formulae (I)-(XXXVI) above. The term "co-crystal" is used to describe a situation in which neutral molecular components are present in a definite stoichiometric ratio within a crystalline compound. The preparation of pharmaceutical co-crystals allows the modification of a pharmaceutical active ingredient into a crystalline form, which can then modify its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0083] The compounds according to the present invention may exist in different polymorphic forms. Although not explicitly stated in the above formula, such forms are intended to be included within the scope of the present invention.

[0084] The present invention also includes within its scope prodrugs of the compounds of formulae (I)-(XXXVI) above. The term "prodrug" refers to a compound that is metabolized in vivo to a compound of the present invention or a salt thereof. A prodrug can be identified by administering the prodrug to a mammal, such as a rat, mouse, monkey or human, and identifying the compound or its salt, for example, in the blood or urine. Another embodiment of the present invention relates to a pharmaceutical composition comprising a detectable amount of a compound of formulae (I)-(XXXVI) or a pharma- ceutically acceptable salt, solvate or co-crystal thereof in combination with a pharma- ceutically acceptable diluent or carrier. In yet another embodiment, the present invention relates to a compound of formula (I)-(XXXVI), a pharma- ceutically acceptable salt, solvate or co-crystal thereof, for use as a medicament, in particular for use in a method for treating or preventing allergies, type 1 hypersensitivity, familial sinusitis, urticaria or related conditions, such as airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, increased vascular permeability, eosinophilic granulomatosis with polyangiitis (also known as Churg-Strauss syndrome), aspirin-exacerbated respiratory disease, or IgE-induced disorders including cutaneous T-cell lymphoma. In a further embodiment, the present invention relates to a method for treating or preventing allergies, type 1 hypersensitivity, familial sinusitis, urticaria or related conditions, comprising administering a therapeutically effective amount of a compound of formula (I)-(XXXVI).

[0085] The following examples illustrate how compounds encompassed by formulae (I)-(XXXVI) can be synthesized. They are presented for illustrative purposes only and are not intended, nor should they be construed, to limit the invention in any manner. Those skilled in the art will appreciate that the following examples can be routinely modified and altered without departing from the spirit or scope of the invention.

[0086] The following examples illustrate how compounds encompassed by Formula I can be synthesized. They are presented for illustrative purposes only and are not intended, nor should they be construed, to limit the invention in any manner. Those skilled in the art will recognize that the following examples can be routinely modified and altered without departing from the spirit or scope of the invention. EXAMPLES

[0087] Abbreviation [Table 1]

[0088] Analysis conditions All NMR were obtained at either 250 MHz, 300 MHz, 400 MHz or 500 MHz. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using anhydrous solvents and glassware. All compound LCMS data was determined using the methods below.

[0089] LCMS method Method 1: 6120B pH10 Long type (Slough) X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: flow rate 1 mL / min [Table 2]

[0090] Method 2: 6140 pH3 Registration (Slough) X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: Pump 1 flow rate: 1 mL / min, Pump 2 flow rate: 0.5 mL / min [Table 3]

[0091] Method 3: 6140 pH10 Registration (Slough) X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: Pump 1 flow rate: 1 mL / min, Pump 2 flow rate: 0.5 mL / min [Table 4]

[0092] Method 4: L102 pH10 Short type 3 minutes (crude type 1?) (Slough) X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: flow rate 1 mL / min [Table 5]

[0093] Method 5: MS17 7 minutes HiRes Evotec Shimadzu(Evotec)MET / CR / 1416 Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Waters Atlantis dC18, Part number 186001295, 2.1mm x 100mm, 3μm column Flow rate: 0.6mL / min Column temperature: 40℃ Injection volume: 3 μL [Table 6] UV 215nM, PDA spectrum 210~420nm, step: 1nm MSD scan positive 100-1000

[0094] Method 6: MS17 METCR1673 Generic 2 minutes (Evotec) Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Supelco Ascentis Express, Part Number: 53802-U, 2.1mm x 30mm, 2.7μm column Flow rate: 1mL / min Column temperature: 40℃ Injection volume: 3 μL [Table 7] UV 215nM, PDA spectrum 210~420nm, step: 1nm MSD scan positive 100-1000

[0095] Method 7: pH10 6120B Short Type (Slough) X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: flow rate 1 mL / min [Table 8]

[0096] Method 8: Braine acidic QDA(Braine) A QDA Waters single quadrupole mass spectrometer is used for LC-MS analysis. The spectrometer is equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (210-400 nm). Data is acquired with a full MS scan from m / z 50-1000 in positive mode using acidic elution. Reverse phase separation is performed at 45° C. on a Waters Acquity UPLC HSS T3 1.8 μm (2.1×50 mm) column with acidic elution. Gradient elution is performed using: Mobile phase A: water Mobile phase B: MeCN Mobile phase C: Water / MeCN / 0.5% formic acid Gradient Program: HPLC flow rate: 0.6mL / min~0.7mL / min Injection volume: 1 μL Total flow rate at MS [Table 9]

[0097] Method 9: Braine Basic QDA (Braine) A QDA Waters single quadrupole mass spectrometer is used for LC-MS analysis. The spectrometer is equipped with an ESI source and a UPLC Acquity Classic with a diode array detector (210-400 nm). Data is acquired with a full MS scan from m / z 50-1000 in positive mode using basic elution. Reverse phase separation is performed at 45° C. on a Waters Acquity UPLC BEH C18 1.7 μm (2.1×50 mm) column with basic elution. Gradient elution is performed using: Mobile phase A:H 2 O / acetonitrile / ammonium formate (95 / 5 / 63 mg / L) + NH 4 OH 50μL Mobile phase B: Acetonitrile / H2 O / Ammonium formate (95 / 5 / 63 mg / L) + NH 4 OH 50μL Gradient Program: HPLC flow rate: 0.4mL / min~0.5mL / min Injection volume: 1 μL Total flow rate in MS [Table 10]

[0098] Method 10: MSQ1 MET-uPLC-AB-101 7 min Low pH (Evotec) Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Phenomenex, Kinetex-XB C18, 2.1 mm x 100 mm, 1.7 μm column Flow rate: 0.6mL / min Column temperature: 40℃ Injection volume: 1 μL [Table 11] UV 215nM, PDA spectrum 200~400nm, step: 1nm MSD scan positive 150~850

[0099] Method 11: MS17 METCR1410 Generic 2 minutes (Evotec) Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Kinetex Core-Shell C18 50 x 2.1 mm, 5 μm column protected by a Phenomenex "Security Guard" column Flow rate: 1.2mL / min Column temperature: 40℃ Injection volume: 3 μL [Table 12] UV 215nM, PDA spectrum 210~420nm, step: 1nm MSD scan positive 100-1000

[0100] Method 12: Agilent 6120 3 min pH3 (Evotec Insourcing lab-UCB machine) Column: Waters X-Bridge, C18, 2.1 x 20 mm, 2.5 μm silica particles Flow rate: 1.0mL / min Mobile phase A: 10 mM ammonium formate + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Column temperature: 40℃ Injection volume: 1-5 μL UV detection: 230-400nm and 215nm Mass spectrum detection: Agilent 6120 mass spectrometer (ES) m / z120~800 Gradient: 5% to 95% B over 1.5 min, hold at 95% B for 0.5 min, re-equilibrate to 5% B

[0101] Method 13: Braine Basic QDA Long Form A QDA Waters single quadrupole mass spectrometer is used for LC-MS analysis. The spectrometer is equipped with an ESI source and a UPLC Acquity Classic with a diode array detector (210-400 nm). Data are acquired with a full MS scan from m / z 70-800 in positive / negative mode using acidic elution. Reverse phase separation is performed at 45° C. on a Waters Acquity UPLC BEH C18 1.7 μm (2.1×100 mm) column with basic elution. Gradient elution is performed using: HO / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μl / L NHOH (solvent A) ACN / H2O / ammonium formate (95 / 5 / 63 mg / L) + 100 μl / L NH4OH (solvent B) HPLC flow rate: 0.4ml / min~0.5ml / min, Injection volume: 1 μL Total flow rate at MS [Table 13]

[0102] Method 14: METCR 1704 (MSQ2 1 minute IPC - Evotec) Column: Waters UPLC CSH C18, 2.1 x 100 mm, 1.7 μm silica particles Flow rate: 0.9mL / min Mobile phase A: Water + 0.1% formic acid Mobile phase B: Acetonitrile + 0.1% formic acid Column temperature: 40℃ Injection volume: 2 μL UV detection: 200-400nm and 215nm Mass spectrum detection: m / z 150-850 Gradient: 5% to 100% B over 1.1 min, hold at 100% B for 0.25 min, re-equilibrate to 5% B.

[0103] Method 15: (Slough crude pH10 short type) [Table 14]

[0104] Method 16: Agilent 6120 6 min pH10 (Evotec Insourcing lab-UCB machine) Column: Waters X-Bridge, C18, 2.1 x 20 mm, 2.5 μm silica particles Flow rate: 1.0mL / min Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Column temperature: 40℃ Injection volume: 1-5 μL UV detection: 230-400nm and 215nm Mass spectrum detection: Agilent 6120 mass spectrometer (ES) m / z120~800 Gradient: 5% to 95% B over 4 min, hold at 95% B for 1 min, re-equilibrate at 5% B.

[0105] Method 17: Agilent 6120 3 min pH10 (Evotec Insourcing lab-UCB machine) Column: Waters X-Bridge, C18, 2.1 x 20 mm, 2.5 μm silica particles Flow rate: 1.0mL / min Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Column temperature: 40℃ Injection volume: 1-5 μL UV detection: 230-400nm and 215nm Mass spectrum detection: Agilent 6120 mass spectrometer (ES) m / z120~800 Gradient: 5% to 95% B over 1.5 min, hold at 95% B for 0.5 min, re-equilibrate to 5% B.

[0106] Method 18: MS10 METCR0990 High pH 2.5 min (Evotec) Mobile phase A: 2 mM ammonium bicarbonate pH 10 Mobile phase B: Acetonitrile Phenomenex Gemini-NX C18 2.0mm x 50mm, 3μm column Flow rate: 1.0mL / min Column temperature: 40℃ Injection volume: 3 μL [Table 15] UV 215nM, PDA spectrum 210~420nm, step: 1nm MSD scan positive 150~850

[0107] Method 19: SFC1AB (Evotec Achiral SFC_1) Column: Synergi 4u Polar RP, 4.6 x 250 mm Mobile phase: 15% ethanol: 85% CO2 Flow rate: 4ml / min Run time: 15 minutes

[0108] Method 20: Braine TOFA Column: Acquity UPLC HSS T3 C18 column (1.7 μm, 2.1 × 100 mm) Flow rate: 0.4ml / min~0.5ml / min Solvent A: Water Solvent B: Acetonitrile Solvent C: 5ml / L formic acid in acetonitrile / water 50 / 50 (pH approx. 3) Column temperature: 45℃ Injection volume: 0.3 μl Total flow rate in MS. [Table 16] UV detection: 210~400nm Mass spectral detection: LCT Waters time-of-flight mass spectrometer, m / z 50-950, positive mode

[0109] Method 21: Braine Acid QDA Long Form A QDA Waters single quadrupole mass spectrometer is used for LC-MS analysis. The spectrometer is equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (210-400 nm). Data is acquired with a full MS scan from m / z 50-1000 in positive mode using acidic elution. Reverse phase separation is performed at 45° C. on a Waters Acquity UPLC HSS T3 1.8 μm (2.1×100 mm) column with acidic elution. Gradient elution is performed using: Water / Formic Acid (Solvent A) Acetonitrile / Formic Acid Ac (Solvent B) HPLC flow rate: 0.4mL / min~0.5mL / min Injection volume: 1 μL Total flow rate at MS [Table 17]

[0110] Method 22: SFC1AB (Evotec Achiral SFC_2) Column: KR60-5 Diol, 4.6 x 250 mm Mobile phase: 25% methanol: 75% CO2 Flow rate: 4ml / min Run time: 8 minutes

[0111] Method 23: Chiral SFCMS analysis (Evotec) Column: Chiralpak AD-H25cm Mobile phase: 15%IPA:85%CO2 Flow rate: 4ml / min Run time: 20 minutes

[0112] Method 24: pH3 UPLC (Slough) Low pH (about pH 3): Column: Waters Acquity UPLC BEH, C18, 2.1 x 50 mm, 1.7 μm Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: Acetonitrile + 5% solvent A + 0.1% formic acid [Table 18] System: Waters Classic Acquity-SQD, Acquity PDAc Column temperature: 40℃ PDA wavelength range: 210~400nm Mass Spectral Detection: ESI on a Waters SQD Flow rate: 0.7mL / min

[0113] Method 25: pH10 UPLC (Slough) High pH (pH approx. 9.5) Column: Waters Acquity UPLC BEH, C18, 2.1 x 50 mm, 1.7 μm Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: Acetonitrile + 5% solvent A + 0.1% ammonia solution [Table 19] System: Waters Classic Acquity-SQD, Acquity PDAc Column temperature: 40℃ PDA wavelength range: 210~400nm Mass Spectral Detection: ESI on a Waters SQD Flow rate: 0.7mL / min

[0114] Method 26: (Slough Registration 6140 pH10, 2018) [Table 20]

[0115] Method 27: (Slough Registration 6140 pH3, 2018) [Table 21]

[0116] Method 28: (Slough, long type, pH3, 2018) [Table 22]

[0117] Method 29: Agilent 6120 6 min pH3 X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: flow rate 1 mL / min [Table 23]

[0118] Method 30: MET / uPLC / AB102 Waters UPLC® CSH™ C18, 2.1 x 100 mm, 1.7 μm column Column temperature: 40℃ Mobile phase A: 2 mM ammonium bicarbonate buffered to pH 10 Mobile phase B: Acetonitrile Gradient program Flow rate 0.6mL / min [Table 24]

[0119] Method 31: MET / CR / 1600 Phenomenex Gemini-NX C18, Part No. 00D-4453-B0, 2.0 x 100 mm, 3 μm column Column temperature: 40℃ Mobile phase A: 2 mM ammonium bicarbonate buffered to pH 10 Mobile phase B: Acetonitrile Gradient program Flow rate 0.5mL / min [Table 25]

[0120] Method 32: MET-uPLC-AB-105 Waters UPLC (registered trademark) BEH (trademark) C18, Part No. 186002352, 2.1 x 100 mm, 1.7 μm Column temperature: 40℃ Mobile phase A: 2 mM ammonium bicarbonate buffered to pH 10 Mobile phase B: Acetonitrile Gradient program Flow rate 0.6mL / min [Table 26]

[0121] Method 33: 6140, pH 10, short pH 3 X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: flow rate 1 mL / min [Table 27]

[0122] Method 34: Agilent 1260-6120B X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: flow rate 1 mL / min [Table 28]

[0123] Chiral SFC Analysis Method Method 1: Use the following conditions unless otherwise stated in the procedure: Column: ChiralPak IC-3, 150 x 4.6 mm, 3 μm Mobile phase A: CO 2 Mobile phase B: Methanol + 0.1% ammonium hydroxide ABPR pressure: 120 bar Detection signal: UV210~600nm, DAD Gradient program: flow rate 3 mL / min [Table 29]

[0124] HPLC method Method 1: General high pH preparative method (standard method) Column: Waters Xbridge C18 Part no. 186003930, 30 x 100 mm, 10 um Column temperature: room temperature Mobile phase A: Water + 0.2% ammonium hydroxide Mobile phase B: Acetonitrile + 0.2% ammonium hydroxide Flow rate: 40ml / min Injection volume: 1500 μl Detection signal: UV215, changeable [Table 30]

[0125] Method 2: General high pH preparative method (initial eluent method) Column: Waters Xbridge C18 Part no. 186003930, 30 x 100 mm, 10 um Column temperature: room temperature Mobile phase A: Water + 0.2% ammonium hydroxide Mobile phase B: Acetonitrile + 0.2% ammonium hydroxide Flow rate: 40ml / min Injection volume: 1500 μl Detection signal: UV215, changeable [Table 31]

[0126] Method 3: General low pH preparative method (standard method) Column: Waters Sunfire C18, Part no. 186003971, 30 x 100 mm, 10 um Column temperature: room temperature Mobile phase A: Water + 0.1% formic acid Mobile phase B: Acetonitrile + 0.1% formic acid Flow rate: 40ml / min Injection volume: 1500 μl Detection signal: UV215, changeable [Table 32]

[0127] Method 4: General low pH preparative method (initial eluent method) Column: Waters Sunfire C18, Part no. 186003971, 30 x 100 mm, 10 um Column temperature: room temperature Mobile phase A: Water + 0.1% formic acid Mobile phase B: Acetonitrile + 0.1% formic acid Flow rate: 40ml / min Injection volume: 1500 μl Detection signal: UV 215, changeable [Table 33]

[0128] Method 5: UCB pH10 Gilson Standard Method Column: Waters XBridge C18, Part no. 186003896, 30 x 150 mm, 10 um Column temperature: room temperature Mobile phase A: water + 0.1% NH 4 OH Mobile phase B: Acetonitrile + 0.1% NH 4 OH Flow rate: 40ml / min Injection volume: 500 μl Detection signal: UV215, changeable [Table 34]

[0129] General Experimental Method General method 1 [ka] A mixture of tricyclic compound and amine (1-10 equiv.) with or without excess base (triethylamine or DIPEA) was dissolved / suspended in either anhydrous DMF or acetonitrile. The reaction was then incubated for 15 min to 1 h in a sealed vial or in N 2 Heat under atmosphere at about 70° C., 90° C., or 140° C. The reaction mixture was then cooled to room temperature and either (1) filtered and purified by reverse phase HPLC or (2) worked up and purified by reverse phase HPLC or normal phase column chromatography unless otherwise indicated.

[0130] General method 2 [ka] To a solution of the amine (1 eq.) in DCM was added 2,4-dimethoxybenzaldehyde (1 eq.) followed by STAB (1.5 eq.). The mixture was stirred at room temperature for 4 h. The mixture was then quenched with saturated sodium bicarbonate. The aqueous layer was extracted with DCM and the organic fractions were combined, dried (Na 2 SO 4 ), and concentrated in vacuo. The resulting residue was purified by column chromatography.

[0131] General method 3 [ka] To a stirred solution of the acid (1 equiv.) in anhydrous DMF was added DIPEA (5-7 equiv.), the relevant amine (2-6 equiv.), and HATU (1-3 equiv.). The reaction mixture was heated at 70° C. (unless otherwise stated) for 1-7 h (unless otherwise stated). Note: In some cases, reagents were added in 2 or 3 portions throughout the course of the reaction. The reaction mixture was then cooled to room temperature and either (1) purified by reverse phase HPLC or (2) worked up and purified by column chromatography.

[0132] General method 4 [ka] To a stirred solution of 2,4-dimethoxybenzyl protected amine (1 eq.) in anhydrous dioxane was added 4M HCl in dioxane (20 eq.). The reaction mixture was stirred at room temperature for 16 h. After removal of the solvent, the crude reaction mixture was used as the HCl salt in the next step. Alternatively, the residue was purified by elution with saturated NaHCO 3 The organic layer was separated and extracted with more DCM. The organic layers were combined, dried (Na 2 SO 4 ), concentrated in vacuo, and then purified by either column chromatography or reverse phase HPLC.

[0133] General method 5 [ka] To a stirred solution of 2,4-dimethoxybenzyl protected amine (1 eq.) in anhydrous DCM was added TFA (10 eq.). The reaction mixture was stirred at room temperature for 16 h. After removal of the solvent, the crude reaction mixture was used as the TFA salt in the next step. Alternatively, the residue was purified by elution with saturated NaHCO 3 The organic layer was separated and extracted with more DCM. The organic layers were combined, dried (Na 2 SO 4 ), concentrated in vacuo, and then purified by either column chromatography or reverse phase HPLC.

[0134] General method 6 [ka] To a mixture of THBT-amine (1 eq.), acid (1 eq.) and pyridine (5 eq.) in DCM (5 mL) was added T3P (1-2 eq.) slowly at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for several hours. The reaction mixture was worked up and purified by reverse phase HPLC.

[0135] General method 7 [ka] To a stirred solution of phenylchloromethanethioate (1.1 eq) in DCM at 0° C. was added THBT-amine (1 eq) and triethylamine (2-3 eq). The reaction was stirred for 1 h while warming to room temperature, then the appropriate amine (1-2 eq) was added as a solution in DCM. The mixture was stirred at room temperature until LCMS showed the reaction was complete. The mixture was then concentrated in vacuo and the residue was purified.

[0136] General method 8 [ka] Thiourea (1 eq.) was dissolved in DMF and formic hydrazide (2-3 eq.) was added followed by mercuric chloride (2-3 eq.). The reaction mixture was stirred at room temperature for 5 min and then triethylamine (3 eq.) was added. The mixture was stirred at 90° C. until the reaction was complete. The mixture was cooled to room temperature, diluted with DCM, filtered through kieselguhr / celite and washed with DCM. The solvent was removed in vacuo and the residue was purified.

[0137] General method 9 [ka] Sodium carbonate (5 eq.) was stirred at 0° C. in a mixture of DCM:water (2:1 respectively). Thiophosgene (1 eq.) was added followed by the amine (1 eq.). The reaction mixture was stirred at 0° C. for 5 min and then at room temperature for 1 h. The mixture was then extracted using DCM and either dried over sodium or magnesium sulfate or passed through a hydrophobic frit. The solvent was removed in vacuo and the residue redissolved in DCM. THBT-amine (1.1 eq.) was added and the mixture was stirred at room temperature until the reaction was complete.

[0138] Abbreviation [Table 35]

[0139] It will be apparent to one skilled in the art that different retention times (RT) may be obtained in LCMS depending on the analytical conditions used.

[0140] Intermediate 1 [ka] Ethyl 6-amino-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxylate To sulfur [7704-34-9] (0.36 g, 11.2 mmol) was added dihydro-2H-pyran-3(4H)-one [23462-75-1] (1.04 g, 10.4 mmol), EtOH (30 mL), ethyl cyanoacetate [105-56-6] (1.2 mL, 11 mmol) and morpholine [110-91-8] (1.4 mL, 16 mmol). The reaction mixture was stirred at room temperature under nitrogen for 15 min and then heated to 50° C. overnight. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc. The crude residue was purified by flash column chromatography on silica (gradient elution from 100% isohexane / EtOAc to 30% EtOAc / isohexane) to give the title compound (1.41 g, 60%) as a pale brown crystalline solid. δ H (300 MHz, DMSO-d 6 ) 7.00 (s, 2H), 4.13 (q, J 7.1 Hz, 2H), 4.09 - 4.03 (m, 2H), 2.56 (t, J 6.4 Hz, 2H), 1.94 - 1.79 (m, 2H), 1.23 (t, J 7.1 Hz, 3H).

[0141] Intermediate 2 [ka] Ethyl 6-(cyclopropanecarbonylamino)-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxylate To intermediate 1 (1.41 g, 6.20 mmol) dissolved in DCM (45 mL) was added DIPEA (3.2 mL, 18 mmol) and cyclopropanecarbonyl chloride [4023-34-1] (0.63 mL, 6.8 mmol) and the reaction mixture was stirred at room temperature under nitrogen for about 2 hours, then quenched with water (15 mL) and diluted with DCM (25 mL). The reaction mixture was filtered through a phase separation cartridge and the mixture was concentrated in vacuo to give the title compound (2.16 g, 118%), which was used crude in the following step. LCMS (ES+) [M+H] + 296.1, RT 3.280 min, purity 94.2% (Method 1).

[0142] Intermediate 3 [ka] 6-(Cyclopropanecarbonylamino)-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxylic acid To intermediate 2 (2.16 g, 7.31 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added lithium hydroxide monohydrate [1310-66-3] (483 mg, 11.5 mmol) and the reaction mixture was heated to 70° C. under nitrogen for 3 h. Further lithium hydroxide monohydrate [1310-66-3] (179 mg, 4.25 mmol) was added and the mixture was heated to 70° C. under nitrogen for 2 h and cooled to room temperature overnight. The mixture was concentrated in vacuo and the residue was left at room temperature for 2 nights. The residue was diluted with water (50 mL) and washed with DCM (2×50 mL). The aqueous phase was acidified to approximately pH 4 with 2 M aqueous hydrochloric acid and the resulting solid was filtered and washed with water to give the title compound (1.28 g, 65%) as a pale brown / orange solid. δ H (300 MHz, DMSO-d 6) 13.06 (s, 1H), 11.31 (s, 1H), 4.14 (dd, J 5.9, 4.2 Hz, 2H), 2.67 (t, J 6.4 Hz, 2H), 2.03 - 1.78 (m, 3H), 0.98 - 0.77 (m, 4H).

[0143] Intermediate 4 and Intermediate 5 [ka] Intermediate 4 O5-tert-Butyl O3-ethyl 2-amino-6,7-dihydro-4H-thieno[3,2-c]pyridine-3,5-dicarboxylate and Intermediate 5 O7-tert-Butyl O3-ethyl 2-amino-5,6-dihydro-4H-thieno[2,3-b]pyridine-3,7-dicarboxylate 1-Boc-3-piperidone [98977-36-7] (10.0 g, 48.7 mmol) was dissolved in EtOH (30 mL) and ethyl cyanoacetate [105-56-6] (6.06 g, 53.6 mmol), morpholine [110-91-8] (6.43 g, 73.0 mmol) and sulfur [7704-34-9] (1.72 g, 53.6 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and heated at 50° C. for 24 h, then filtered and washed with EtOH. The filtrate was partitioned between DCM and water and the organic phase was washed with saturated sodium chloride solution and passed through a phase separation cartridge. The crude material was purified by flash column chromatography on silica (gradient elution with 10-50% EtOAc / hexanes) to give the title compound Intermediate 4 (2.28 g, 14%) as a yellow gum and the title compound Intermediate 5 (1.74 g, 11%) as a pale yellow solid. Intermediate 4 LCMS [MH] - 325.0, RT 2.613 min, purity 83.6% (Method 1). Intermediate 5 LCMS [MH] - 325.0, RT 2.774 min, purity 91.5% (Method 1).

[0144] Intermediate 6 [ka] O5-tert-Butyl O3-ethyl 2-(cyclopropanecarbonylamino)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3,5-dicarboxylate Intermediate 4 (2.28 g, 6.99 mmol) was dissolved in DCM (50 mL) and DIPEA (1.81 g, 14.0 mmol) and cyclopropanecarbonyl chloride [4023-34-1] (0.820 g, 7.68 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was washed with water, passed through a phase separation cartridge and the organic phase was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 5-60% EtOAc / hexanes) to give the title compound (2.55 g, 93%) as an off-white solid. δ H (400 MHz, DMSO-d 6 ) 11.20 (s, 1H), 4.54 (s, 2H), 4.32 (q, J = 7.3 Hz, 2H), 3.60 (t, J = 5.7 Hz, 2H), 2.66 (t, J = 5.8 Hz, 2H), 2.12 - 2.02 (m, 1H), 1.43 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H), 1.01 - 0.83 (m, 4H). LCMS [M-Boc+H] + 295.8, RT 2.904 minutes (Method 2).

[0145] Intermediate 7 [ka] 5-tert-Butoxycarbonyl-2-(cyclopropanecarbonylamino)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxylic acid Intermediate 6 (2.55 g, 6.46 mmol) was dissolved in 1,4-dioxane (100 mL) and a solution of lithium hydroxide monohydrate [1310-66-3] (0.73 g, 17.3 mmol) in water (5 mL) was added. The reaction mixture was stirred at 70° C. for 16 h before being cooled to room temperature and concentrated in vacuo. The reaction was partitioned between water and DCM, the organic phase was separated and the aqueous phase was extracted with DCM (2×). The aqueous phase was acidified to pH<4.5 by addition of aqueous citric acid and the resulting precipitate was filtered off and washed with water (3×) to give the title compound (1.82 g, 77%) as an off-white solid. δ H (400 MHz, DMSO-d 6 ) 13.31 (s, 1H), 11.54 (s, 1H), 4.53 (s, 2H), 3.60 (t, J 5.6 Hz, 2H), 2.72 - 2.60 (m, 2H), 2.07 - 1.93 (m, 1H), 1.42 (s, 9H), 0.99 - 0.81 (m, 4H).

[0146] Intermediate 8 [ka] tert-Butyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylate Intermediate 7 (1.82 g, 4.97 mmol) was suspended in DCM (50 mL), cyclopropylmethylamine [2516-47-4] (0.53 g, 7.5 mmol) and EDCI (1.18 g, 5.96 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with water and saturated sodium chloride solution, passed through a phase separation cartridge and the filtrate concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 10-60% EtOAc / hexanes) to give the title compound (873 mg, 42%) as an off-white solid. δ H (400 MHz, DMSO-d 6) 10.75 (s, 1H), 7.60 (s, 1H), 4.23 (s, 2H), 3.36 (t, J 5.7 Hz, 2H), 2.91 (t, J 6.2 Hz, 2H), 2.52 - 2.31 (m, 2H), 1.81 - 1.60 (m, LCMS [M+H] + 420.8, RT 2.582 min (Method 2). LCMS [MH] - 418.0, RT 2.471 minutes (Method 3).

[0147] Intermediate 9 [ka] O7-tert-Butyl O3-ethyl 2-(cyclopropanecarbonylamino)-5,6-dihydro-4H-thieno[2,3-b]pyridine-3,7-dicarboxylate Intermediate 5 (2.74 g, 8.39 mmol) was dissolved in DCM (50 mL) and DIPEA (2.17 g, 16.8 mmol) and cyclopropanecarbonyl chloride (0.99 g, 9.23 mmol) were added. The reaction mixture was stirred at room temperature for approximately 16 h. The reaction mixture was washed with water and passed through a phase separation cartridge. The organic phase was concentrated in vacuo to give a crude residue which was purified by flash column chromatography on silica (gradient elution with 5-50% EtOAc / hexanes) to give the title compound (3.28 g, 99%) as an off-white solid. δ H (400 MHz, DMSO-d 6) 11.09 (s, 1H), 4.30 (q, J 7.1 Hz, 2H), 3.69 (s, 2H), 2.77 (t, J 6.3 Hz, 2H), 2.06 - 1.93 (m, 1H), 1.93 - 1.82 (m, 2H), 1.49 (s, 9H), 1.33 (t, J 7.1 Hz, 3H), 1.01 - 0.82 (m, 4H). LCMS [M+H] + 395.8, RT 3.141 min, purity 100.0% (Method 2).

[0148] Intermediate 10 [ka] 7-tert-Butoxycarbonyl-2-(cyclopropanecarbonylamino)-5,6-dihydro-4H-thieno[2,3-b]pyridine-3-carboxylic acid Intermediate 9 (3.28 g, 8.31 mmol) was dissolved in 1,4-dioxane (100 mL) and a solution of lithium hydroxide monohydrate [1310-66-3] (0.934 g, 12.5 mmol) in water (5 mL) was added. The reaction mixture was heated to 70° C. and stirred for 16 h before being cooled to room temperature and concentrated in vacuo. The reaction mixture was partitioned between water and DCM, the organic phase separated and the aqueous phase further extracted with DCM (2×). The aqueous phase was acidified to pH<4.5 using aqueous citric acid and the resulting precipitated gum was extracted into EtOAc (3×). The combined organic phase was washed with saturated sodium chloride solution, passed through a phase separation cartridge and the filtrate was concentrated in vacuo to give the title compound (2.85 g, 94%) as a yellow sticky solid. δ H (400 MHz, DMSO-d 6 ) 11.35 (s, 1H), 3.69 (br. s, J 6.2 Hz, 2H), 2.77 (t, J 6.4 Hz, 3H), 1.96 - 1.76 (m, 3H), 1.49 (s, 9H), 0.99 - 0.83 (m, 4H). LCMS [M+H] + 367.2, RT 1.088 min (Method 4). LCMS [MH] -365.0, RT 2.351 min, purity 100.0% (Method 2).

[0149] Intermediate 11 [ka] tert-Butyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-5,6-dihydro-4H-thieno[2,3-b]pyridine-7-carboxylate Intermediate 10 (1.43 g, 3.89 mmol) was suspended in DCM (50 mL) and cyclopropylmethylamine [2516-47-4] (0.42 g, 5.83 mmol) and EDCI (0.92 g, 4.67 mmol) were added and the reaction stirred at room temperature for 16 h. The reaction mixture was partitioned between water and saturated sodium chloride solution, passed through a phase separator and the filtrate concentrated in vacuo to give the crude reaction mixture which was purified by flash column chromatography on silica (gradient elution with 20-80% EtOAc / isohexane) to give the title compound (434 mg, 27%) as a pale yellow gum. δ H (400 MHz, DMSO-d 6 ) 10.76 (s, 1H), 7.44 (s, 1H), 3.46 (s, 2H), 2.90 (t, J 6.2 Hz, 2H), 2.53 - 2.37 (m, 2H), 1.74 - 1.53 (m, 3H), 1.26 (s, 9H), 0.90 - 0.72 (m, 1H), 0.72 - 0.52 (m, 4H), 0.26 - 0.13 (m, 2H), 0.06 - -0.06 (m, 2H). LCMS [M+H] + 420.8, [M+Na] + 442.8, RT 2.645 minutes, purity 100.0% (Method 3).

[0150] Intermediate 12 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[2,3-b]pyridine-3-carboxamide; hydrochloride Intermediate 11 (0.43 g, 1.03 mmol) was dissolved in a 4N solution of hydrochloric acid in 1,4-dioxane (20 mL) and the reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo to give the title compound (370 mg, 101%) as an off-white solid. H (400 MHz, DMSO-d 6 ) 10.98 (s, 1H), 7.41 (s, 1H), 3.05 - 2.94 (m, 2H), 2.90 (t, J 6.2 Hz, 2H), 2.43 (t, J 6.2 Hz, 2H), 1.73 - 1.53 (m, 3H), 0.86 - 0.69 (m, 1H), 0.68 - 0.51 (m, 4H), 0.25 - 0.16 (m, 2H), 0.05 - -0.06 (m, 2H), NH 2 is not permitted.

[0151] Intermediate 13 [ka] Ethyl 2-amino-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate To a solution of 2-methylcyclopentanone [1120-72-5] (3.40 g, 34.6 mmol) in EtOH (10 mL) was added ethyl cyanoacetate [105-56-6] (4.31 g, 38.1 mmol), sulfur [7704-34-9] (1.22 g, 38.0 mmol) and diethylamine (3.82 g, 52.0 mmol). The reaction mixture was stirred at room temperature for 18 h and the mixture was concentrated in vacuo to give the crude product, which was purified by flash column chromatography on silica (gradient elution with 0-15% EtOAc in hexanes) to give the title compound (3.33 g, 43%) as a yellow solid. δ H (400 MHz, DMSO-d 6) 7.21 (s, 2H), 4.26 - 4.04 (m, 2H), 3.14 (ddt, J 8.5, 6.6, 3.3 Hz, 1H), 2.72 (dtd, J 14.3, 8.1, 2.3 Hz, 1H), 2.55 (dd, J 9.3, 2.1 Hz, 1H), 2.44 (ddt, J 12.4, 9.3, 8.1 Hz, 1H), 1.85 (ddt, J 12.2, 8.1, 1.8 Hz, 1H), 1.25 (t, J 7.1 Hz, 3H), 1.09 (d, J 6.8 Hz, 3H).

[0152] Intermediate 14 [ka] Ethyl 2-(cyclopropanecarbonylamino)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate To a solution of intermediate 13 (1 g, 4.44 mmol) and triethylamine (1.0 mL, 7.18 mmol) in DCM (10 mL) was added cyclopropanecarbonyl chloride [4023-34-1] (0.6 mL, 6.61 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then diluted with DCM (20 mL). 1 M aqueous hydrochloric acid (20 mL) was added and the aqueous phase was separated, extracted with DCM (2×10 mL) and washed with water (10 mL). The organic phases were combined and dried (MgSO 4 ), filtered and concentrated in vacuo to give the title compound (1.45 g, 89%) as a brown oil which was used without further purification. H(500 MHz, chloroform-d) 11.27 (s, 1H), 4.42 - 4.35 (m, 1H), 4.31 (dq, J 10.8, 7.2 Hz, 1H), 3.39 - 3.28 (m, 1H), 2.91 (dtd, J 15.2, 8.7, 1.8 Hz, 1H), 2.72 (ddd, J 15.1, 9.4, 2.0 Hz, 1H), 2.58 (dq, J 12.6, 8.8 Hz, 1H), 2.00 (ddt, J 12.3, 7.9, 1.9 Hz, 1H), 1.66 (ddd, J 12.5, 7.9, 4.5 Hz, 1H), 1.39 (t, J 7.1 Hz, 3H), 1.16 (d, J 6.8 Hz, 3H), 1.13 (q, J 3.7, 3.2 Hz, 2H), 0.92 (dq, J 6.9, 3.7 Hz, 2H). Purity 80%.

[0153] Intermediate 15 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide Intermediate 14 (80% purity, 1.31 g, 3.57 mmol) was dissolved in a solution of MeOH (10 mL) and 2M aqueous NaOH (3.5 mL) was added. The reaction mixture was heated to reflux for 2 h, the reaction was cooled to room temperature and concentrated in vacuo. The reaction mixture was acidified with 1M aqueous hydrochloric acid and the mixture was extracted with EtOAc (2×20 mL). The combined organic phase was washed with water (10 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo to give the acid: 2-(cyclopropanecarbonylamino)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid (1 g, 74%, 70% pure), which was used without further purification.

[0154] EDCI (180 mg, 0.94 mmol) was added to a solution of 2-(cyclopropanecarbonylamino)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid (200 mg, 0.75 mmol) and 1-cyclopropylmethanamine [2516-47-4] (100 μL, 1.15 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 4 h, then diluted with DCM (10 mL) and washed with 1 M aqueous hydrochloric acid (10 mL). The organic phase was separated and dried (MgSO 4 ), filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography on silica (gradient elution with 0-30% EtOAc / heptane) to give the title compound (40 mg, 16%) as a light brown solid. LCMS [M+H] + 319.1, RT 4.58 minutes (Method 5).

[0155] Intermediate 16 [ka] 2-(Cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Cyclopropanecarbonyl chloride [4023-34-1] (5.44 g, 51.0 mmol) was added to a solution of 2-amino-4,5,6,7-tetrahydro-benzo[B]thiophene-3-carboxylic acid methyl ester [108354-78-5] (10.0 g, 46.4 mmol) and DIPEA (15.0 g, 116 mmol) in DCM (100 mL) and the reaction was stirred at room temperature overnight. The reaction mixture was washed with water and brine, passed through a phase separator and evaporated in vacuum to give a yellow sticky solid, which was dissolved in 1,4-dioxane (100 mL). A solution of lithium hydroxide monohydrate [1310-66-3] (2.92 g, 69.6 mmol) in water (30 mL) was added and the mixture was heated at 70° C. for about 3 hours. The reaction mixture was cooled to room temperature, left to stand overnight and the 1,4-dioxane was removed in vacuo. The aqueous residue was diluted with water and washed with DCM (2x). The aqueous phase was acidified to pH<4 by addition of concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water (3x) and air-dried to give the title compound (12.1 g, 99%) as a cream solid. δ H (400 MHz, DMSO-d 6 ) 13.04 (s, 1H), 11.46 (s, 1H), 2.81 - 2.63 (m, 2H), 2.63 - 2.54 (m, 2H), 1.95 (h, J 5.6 Hz, 1H), 1.80 - 1.60 (m, 4H), 1.02 - 0.76 (m, 4H).

[0156] Intermediate 17 [ka] N-(4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide A suspension of intermediate 16 (500 mg, 1.89 mmol) in toluene (5 mL) was heated in a microwave at 180° C. for 8 h. The solvent was removed in vacuo and the residue was dissolved in hot EtOAc (20 mL). The mixture was filtered to give the title compound (403 mg, 97%). δ H (400 MHz, DMSO-d 6) 11.05 (s, 1H), 6.29 (s, 1H), 2.57 (t, J 5.8 Hz, 2H), 2.45 (t, J 5.9 Hz, 2H), 1.82 - 1.54 (m, 5H), 0.79 (d, J 6.2 Hz, 4H).

[0157] Intermediate 18 [ka] 2,3-Dibromo-4,5,6,7-tetrahydrobenzothiophene To a stirred solution of 4,5,6,7-tetrahydro-1-benzothiophene [13129-17-4] (3 g, 21.7 mmol) in acetic acid (15 mL) and chloroform (15 mL) cooled to -5°C, N-bromosuccinimide [128-08-5] (8.5 g, 47.8 mmol) was added portionwise over 1.5 h and the resulting yellow / orange solution was stirred at -5°C. The reaction mixture was quenched with 10% aqueous sodium sulfite (10 mL) and extracted with DCM (3 x 15 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate (15 mL), brine (15 mL) and dried (MgSO 4 ) and filtered. The crude material was purified by filtration through silica (gradient elution with 0 to 10% DCM in heptane) to give the title compound (260 mg, 64%) as a colorless oil. δ H (250 MHz, chloroform-d) 2.79 - 2.59 (m, 2H), 2.57 - 2.42 (m, 2H), 1.91 - 1.70 (m, 4H).

[0158] Intermediate 19 [ka] 3-Bromo-4,5,6,7-tetrahydrobenzothiophene Intermediate 18 (3.9 g, 13.2 mmol) was cooled to -78 °C and dissolved in Et 2To a stirred solution in O (100 mL) was added 1.6 M n-butyllithium in hexanes (17.3 mL, 27.7 mmol) dropwise over 20 min and the resulting solution was stirred at this temperature for 1.5 h. Water (30 mL) was added, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 2 h. EtOAc (30 mL) was added, the layers were separated and the aqueous phase was extracted with further EtOAc (40 mL). The combined organic phase was washed with brine (20 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo to give the crude material (2.8 g) as an orange oil, which was purified by flash column chromatography on silica (gradient elution with 0 to 10% DCM in heptane) to give the title compound (885 mg, 31%). H (250 MHz, chloroform-d) 7.03 (s, 1H), 2.81 - 2.69 (m, 2H), 2.57 - 2.46 (m, 2H), 1.92 - 1.73 (m, 4H).

[0159] Intermediate 20 [ka] 3-Bromo-2-nitro-4,5,6,7-tetrahydrobenzothiophene To a solution of intermediate 19 (660 mg, 3 mmol) in DCM (15 mL) cooled to -5°C, nitronium tetrafluoroborate [13826-86-3] (460 mg, 3.34 mmol) was added in three portions (200 mg + 200 mg + 60 mg at 5 min intervals). After 1 h, the mixture was poured onto ice, diluted with DCM and allowed to warm to room temperature. The layers were separated and the aqueous phase was extracted with DCM (10 mL). The combined organic phase was washed with brine and dried (MgSO 4 ) and filtered. The crude product was combined with crude material from another run (starting material Intermediate 17, 200 mg, 0.92 mmol), concentrated in vacuo and purified by flash column chromatography on silica (gradient elution with 0 to 50% DCM in heptane) to give the title compound (260 mg, 25%) as a red solid. δ H(500 MHz, chloroform-d) 2.87 - 2.68 (m, 2H), 2.62 - 2.49 (m, 2H), 1.96 - 1.74 (m, 4H).

[0160] Intermediate 21 [ka] 3-Butylsulfanyl-2-nitro-4,5,6,7-tetrahydrobenzothiophene To a solution of intermediate 20 (260 mg, 0.99 mmol) in THF (10 mL) and water (5 mL) was added potassium carbonate (150 mg, 1.01 mmol), followed by dropwise addition of a solution of butane-1-thiol [109-79-5] (0.22 mL, 1.98 mmol) in THF (3 mL) and the resulting mixture was stirred at room temperature. After 2 h, more butane-1-thiol [109-79-5] (0.12 mL, 1.01 mmol) was added and stirring was continued for 1 h. More butane-1-thiol [109-79-5] (0.12 mL, 1.01 mmol) was added and stirring was continued overnight. The reaction mixture was partitioned between water (20 mL) and EtOAc (40 mL), the layers were separated and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with brine (20 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica (gradient elution with 0 to 100% DCM in heptane) to afford the title compound (212 mg, 79%) as a bright yellow solid. δ H (250 MHz, chloroform-d) 3.01 (t, J 7.2 Hz, 2H), 2.86 - 2.71 (m, 2H), 2.68 - 2.54 (m, 2H), 1.91 - 1.80 (m, 4H), 1.60 - 1.32 (m, 4H, partially obscured by water peak), 0.90 (t, J 7.2 Hz, 3H).

[0161] Intermediate 22 [ka] 3-Butylsulfonyl-2-nitro-4,5,6,7-tetrahydrobenzothiophene To a stirred solution of intermediate 21 (195 mg, 0.72 mmol) in DCM (8 mL) was added dropwise a solution of mCPBA (70%, 266 mg, 1.08 mmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred for 1 h and combined with an additional working example (15 mg, 0.055 mmol). The reaction was quenched with saturated aqueous sodium sulfite solution (15 mL), the layers were separated and the aqueous phase was extracted with DCM (2×30 mL). The combined organic layers were washed with 0.5 M aqueous potassium carbonate solution (30 mL), brine (20 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica (gradient elution with 0 to 100% DCM in heptane) to give the title compound (107 mg, 51%). δ H (250 MHz, chloroform-d) 3.69 - 3.47 (m, 2H), 2.95 (t, J 5.4 Hz, 2H), 2.87 - 2.73 (m, 2H), 1.98 - 1.71 (m, 6H), 1.59 - 1.34 (m, 2H, partially obscured by water peak), 0.96 (t, J 7.3 Hz, 3H).

[0162] Intermediate 23 [ka] 3-Butylsulfonyl-4,5,6,7-tetrahydrobenzothiophene-2-amine To a solution of intermediate 22 (35 mg, 0.12 mmol) in EtOH (3 mL) was added 10% Pd on carbon (50% wet, 25 mg, 0.012 mmol) and the mixture was hydrogenated at room temperature and atmospheric pressure. The reaction was placed under hydrogen overnight, filtered through a pad of celite and washed with EtOAc. The reaction mixture was concentrated in vacuo to give the title compound (32 mg, 93%) as a yellow film. LCMS [M+H] + 274, RT 1.37 minutes (Method 6).

[0163] Intermediate 24 [ka] Ethyl 3-(dimethylamino)-2-isocyanoprop-2-enoate To a brown solution of ethyl isocyanoacetate [2999-46-4] (1 g, 8.84 mmol) in dry ethanol (10 mL), DMF-DMA (1.53 mL, 11.49 mmol) was added under N 2 The mixture was added dropwise at 0° C. (ice bath). The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was concentrated in vacuo and the material was purified by flash chromatography on silica (elution gradient using 0-60% ethyl acetate in heptane) to afford the title compound (780 mg, 52%) as a yellow oil that solidified upon cooling. δ H (500 MHz, chloroform-d) δ 7.18 (s, 1H), 4.22 (q, J 7.1 Hz, 2H), 3.23 (s, 6H), 1.30 (t, J 7.1 Hz, 3H).

[0164] Intermediate 25 [ka] Ethyl 5-(tert-butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate To a stirred solution of intermediate 102a (15 g, 44.1 mmol) in DCM (250 mL) and triethylamine (12.3 mL, 88.2 mmol) was added cyclopropanecarbonyl chloride [4023-34-1] (6.9 g, 66.2 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h and then quenched with 0.5 N aqueous hydrochloric acid. The organic phase was separated, washed with brine and dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give the crude product, which was 2Trituration with O and pentane gave the title compound (14 g, 78%). H (400 MHz, DMSO-d 6 ) δ 11.17 (s, 1H), 6.92 (d, J 7.3 Hz, 1H), 4.29 (q, J 7.1 Hz, 2H), 3.62 (s, 1H), 3.04 (dd, J 17.0, 4.3 Hz, 1H), 2.74-2.66 (m, 2H), 2.46 (d, J 9.3 Hz, 1H), 2.06 - 1.88 (m, 2H), 1.68-1.58 (m, 1H), 1.40 (s, 9H), 1.31 (t, J 7.1 Hz, 3H), 0.97 - 0.84 (m, 4H). LCMS [M-Boc+H] + 309.8, RT 2.831 min, purity 96.2% (Method 2).

[0165] Intermediate 26 [ka] 5-(tert-butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid To a stirred solution of intermediate 25 (14 g, 34.3 mmol) in 1,4-dioxane (100 mL) and water (100 mL) was added lithium hydroxide (1.64 g, 68.6 mmol) and the reaction mixture was heated at 100° C. for 3 h. The reaction mixture was acidified to pH 6 with 1N hydrochloric acid solution, stirred for 15 min, and filtered. The resulting residue was dried in vacuum to give the title compound (12 g, 91%). δ H (400 MHz, chloroform-d) 11.31 (s, 1H), 5.80 (s, 1H), 4.70 (s, 1H), 3.99 (s, 1H), 3.22-3.18 (m, 2H), 2.71 (s, 2H), 2.02-2.00 (m, 1H),1.78-1.67 (m, 2H), 1.45 (s, 9H), 1.18-1.12 (m, 2H), 0.96-0.92 (m, 2H). LCMS [MH] -379.0, RT 1.267 min, purity 77.3% (Method 7).

[0166] Intermediate 27 [ka] tert-Butyl N-[2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate To a suspension of intermediate 26 (1.2 g, 2.71 mmol, 86% purity) in quinoline [91-22-5] (10 mL) was added copper powder [7440-50-8] (259 mg, 4.0 mmol). The reaction mixture was heated to 150° C. in a microwave for 1 h and then diluted with DCM (60 mL) and water (60 mL). The organic phase was washed with 0.75 M aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was separated and dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution from 5% to 50% EtOAc in heptane) to give the 5-substituted title compound (640 mg, 50%) as an off-white solid, mixed with the 7-regioisomer (obtained through a presynthetic step from the synthesis of intermediates 102 and 102a). LCMS [M+H] + 337, RT 1.28 min, 71% (5-position isomer), [M+Na] + 359.15, [M-tBu+H] + 280.95, RT 1.38 min, 28% (7-position isomer) (Method 6).

[0167] Intermediate 28 [ka] N-[5-amino-3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide To a suspension of intermediate 27 (1.1 g, 3.3 mmol) in MeCN (9 mL) was added chlorosulfonic acid [7790-94-5] (1 mL, 14.7 mmol). The reaction mixture was stirred at 70° C. for 1 h 40 min and then cooled to 0° C. To chloroform (5 mL) was added isobutylamine [78-81-9] (3 mL, 29.5 mmol) and triethylamine (2 mL, 14.2 mmol) and the mixture was cooled to 0° C. The two solutions were added together and the mixture was stirred at 30° C. for 30 min. Water (25 mL) was added to the reaction mixture and the mixture was diluted with Et 2 The organic phases were combined and dried (MgSO 4 ), filtered and concentrated in vacuo to give the crude product (691 mg) as a yellow oil. The aqueous layer was extracted with EtOAc to give further crude product (0.58 g) as a yellow oil. The crude products were combined and purified by flash column chromatography on silica (100% DCM to 80 / 20 / 2 DCM / MeOH / NH 4 Purification by elution with 0.5% hexanes (gradient elution with 0.5% hexanes, 10% COOH) gave a dark solid (1.05 g) which was dissolved in DCM (ca. 4 mL) and treated with ca. 60 ml of 80 / 20 isopropanol / EtOAc. The insoluble residue was removed and the organic phases were combined and concentrated in vacuo to give the title compound (0.67 g, 55%). LCMS [M+H] + 372.13, [MH] - 370.13, RT 2.52 minutes (Method 9).

[0168] Intermediate 29 [ka] N-(5-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide; hydrochloride Intermediate 27 (640 mg, 1.35 mmol) was dissolved in 1,4-dioxane (5 mL) and 4 M hydrochloric acid in 1,4-dioxane (10 mL, 40.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction was concentrated in vacuo and the crude material (550 mg) was used without further purification. LCMS [M+H] +236.95, RT 0.66 min, purity 31% (Method 6).

[0169] Intermediate 30 [ka] N-[5-(methanesulfonamido)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide Intermediate 29 (550 mg, 2.0 mmol) was dissolved in DCM (5 mL) and DIPEA (0.7 mL, 4.03 mmol) and methanesulfonyl chloride [124-63-0] (0.23 ml, 3.0 mmol) were added. The reaction mixture was stirred at room temperature for 5 h and then diluted with DCM (50 mL) and water (50 mL). The organic phase was separated and dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (gradient elution from 12% to 100% EtOAc in heptane) to afford the title compound (270 mg) as an off-white solid. δ H (500 MHz, CD 3 OD) 6.33 (s, 1H), 3.72 - 3.63 (m, 1H), 2.99 (s, 3H), 2.92 (dd, J 15.9, 5.2 Hz, 1H), 2.83 - 2.76 (m, 2H), 2.49 (dd, J 15.9, 8.7 Hz, 1H), 2.18 - 2.10 (m, 1H), 1.88 - 1.79 (m, 1H), 1.74 - 1.66 (m, 1H), 0.96 - 0.91 (m, 2H), 0.86 (m, 2H). Purity approximately 90%.

[0170] Intermediate 31 [ka] N-[5-amino-3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide To a suspension of intermediate 29 (1.21 g, 3.60 mmol) in MeCN (15 mL) was added chlorosulfonic acid [7790-94-5] (1.85 mL, 27.3 mmol). The reaction mixture was stirred at 70° C. for 1 h and then cooled to 0° C. This solution was slowly added to a cooled solution of chloroform (15 mL), n-propylamine [107-10-8] (5 mL, 60.21 mmol) and triethylamine (10 mL, 71.0 mmol) and the reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution (200 mL) was added to the reaction mixture and the aqueous phase was extracted with Et 2 The organic phases were combined, washed with water (2 x 50 mL), and dried (MgSO 4 ), filtered and concentrated in vacuo to give the crude material (502 mg) as a sticky yellow oil. The combined aqueous phases were extracted with EtOAc (2×100 mL) and the organic phases were combined and dried (MgSO 4 ), filtered and concentrated in vacuo to give a dark yellow oil which was combined with the crude material from the first batch. The combined crude material was purified by flash column chromatography on silica (DCM / MeOH / NH 4 The mixture was purified by elution with a gradient of OH 97.5 / 2.5 / 0.25 to 80 / 20 / 2 to give the title compound (230 mg, 19%). LCMS [M+H] + 358.15, [MH] - 356.12, RT 1.84 minutes (Method 8).

[0171] Intermediate 32 [ka] Ethyl 2'-aminospiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxylate To a mixture of 1,4-dioxaspiro[4.5]decan-7-one [4969-01-1] (5 g, 32.0 mmol), sulfur [7664-93-9] (1.23 g, 38.4 mmol) and ethyl cyanoacetate [105-56-6] (4.34 g, 38.4 mmol) in EtOH (50 mL) was added triethylamine (8.92 ml, 64.0 mmol) and the reaction mixture was stirred at room temperature for 5 days and then concentrated in vacuo. Water was added to the crude product and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine and dried (MgSO 4 ), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography on silica (100% DCM followed by gradient elution from 5% to 50% EtOAc in heptane) to give the title compound (5.47 g, 59%) as a yellow gum. H (500 MHz, CD 3 OD) 4.23 (q, J 7.1 Hz, 2H), 4.05 - 3.96 (m, 4H), 2.87 (s, 2H), 2.63 (tt, J 6.5, 1.6 Hz, 2H), 1.89 (t, J 6.5 Hz, 2H), 1.32 (t, J 7.1 Hz, 3H).LCMS [M+H] + 283.95, RT 1.19 minutes (Method 6).

[0172] Intermediate 33 [ka] Ethyl 2'-(cyclopropanecarbonylamino)spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxylate To a solution of intermediate 32 (5.47 g, 19.3 mmol) and DIPEA (6.7 mL, 38.6 mmol) in DCM (200 mL) was added cyclopropanecarbonyl chloride [4023-34-1] (2.6 ml, 28.9 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then diluted with DCM (200 mL). Water (200 mL) was added and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL) and washed with 0.5 M aqueous hydrochloric acid (100 mL), saturated sodium bicarbonate solution (100 mL) and brine. The organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo to give a crude pale yellow solid, which was purified by flash column chromatography on silica (gradient elution from 5% to 50% EtOAc in heptane) to give the title compound (6.5 g, 96%) as a pale yellow solid. LCMS [M+H] + 352.05, RT 1.38 minutes (Method 6).

[0173] Intermediate 34 [ka] 2'-(Cyclopropanecarbonylamino)spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxylic acid To a suspension of intermediate 33 (6.5 g, 18.5 mmol) in 1,4-dioxane (120 mL) was added 2M lithium hydroxide monohydrate solution [1310-66-3] (18.5 mL, 37.0 mmol) and the reaction mixture was heated to 90° C. for 2 h. The mixture was concentrated in vacuo and the residue was diluted with water (20 mL). The solution was acidified to pH 4-5 with 0.2 M aqueous hydrochloric acid and the material was filtered, washed with water and dried in vacuo to give the title compound (5 g, 84%) as a brown solid. δ H (500 MHz, CD 3OD) 4.03 - 3.99 (m, 4H), 2.99 (s, 2H), 2.80 (t, J 6.5 Hz, 2H), 1.93 (t, J 6.5 Hz, 2H), 1.85 - 1.77 (m, 1H), 1.05 - 0.94 (m, 4H). LCMS [M+H] + 323.95, RT 1.14 minutes (Method 6).

[0174] Intermediate 35 [ka] N-spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-2'-ylcyclopropanecarboxamide To a suspension of intermediate 34 (1.6 g, 4.94 mmol) in quinolone 91-22-5 (15 mL) was added copper powder 7440-50-8 (472 mg, 7.42 mmol) and the mixture was heated to 150° C. in a microwave for 1 h. The reaction mixture was diluted with DCM (100 mL) and water (100 mL). The organic phase was washed with 0.75 M aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (gradient elution from 5% to 50% EtOAc in heptane) to afford the title compound (1.1 g, 80%) as an off-white solid. LCMS [M+H] + 279.95, RT 1.10 minutes (Method 6).

[0175] Intermediate 36 [ka] N-(5-oxo-6,7-dihydro-4H-benzothiophen-2-yl)cyclopropanecarboxamide To intermediate 35 (2 g, 7.15 mmol) dissolved in THF (80 mL) was added 1 M aqueous hydrochloric acid (36 mL). The reaction mixture was heated at 50° C. with stirring under nitrogen for 5 h. After cooling to room temperature, the reaction mixture was basified with saturated sodium bicarbonate solution and diluted with EtOAc. The organic phase was separated and dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give a pale yellow solid which was 2 Trituration with O afforded the title compound (1.42 g, 78%) as a pale yellow solid. LCMS [M+H] + 235.90, RT 1.01 min (Method 6).

[0176] Intermediate 37 [ka] N-(5-amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide Intermediate 36 (1.42 g, 6.0 mmol), ammonium acetate (4.65 g, 60.3 mmol) and Na 2 SO 4 To a mixture of (1.5 g) in MeOH (80 mL) was added sodium triacetoxyborohydride [56553-60-7] (2.55 g, 12.07 mmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was filtered and the filtrate was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with isopropanol / chloroform (1:1). The organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography on silica (gradient elution from 1% to 70% MeOH in DCM) to give the title compound (270 mg, 19%) as a light brown solid. LCMS [M+H] + 236.95 (Method 6).

[0177] Intermediate 38 [ka] N-[5-[(4-methoxyphenyl)carbamoylamino]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide To a solution of intermediate 37 (130 mg, 0.55 mmol) in DCM (7 mL) was added 1-isocyanato-4-methoxybenzene [5416-93-3] (78.4 μL, 0.60 mmol). The solution was stirred at room temperature for 30 min, and the reaction mixture was filtered and washed with DCM to give the title compound (160 mg, 72%) as an off-white solid. LCMS [M+H] + 386.25, RT 1.17 minutes (Method 6).

[0178] Intermediates 39 and 40 [ka] Intermediate 39 O3-tert-Butyl O5-ethyl 2-amino-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxylate Intermediate 40 O3-tert-Butyl O7-ethyl 2-amino-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxylate To a mixture of ethyl 3-oxocyclohexanecarboxylate [17159-79-4] (2 g, 11.75 mmol), sulfur (0.45 g, 14.1 mmol) and tert-butyl cyanoacetate [1116-98-9] (2.15 g, 15 mmol) in EtOH (20 mL) was added triethylamine (3.27 ml, 2.35 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. Water was added and the solution was extracted with EtOAc. The organic phases were combined, washed with brine and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution from 5% to 40% EtOAc in heptane) to give a 79:21 ratio of the title compound intermediate 39 and the title compound intermediate 40 regioisomers (2.84 g, 74%). LCMS [M+H] +326.00, RT 1.49 and 1.52 min (Method 6).

[0179] Intermediates 41 and 42 [ka] Intermediate 41 O3-tert-Butyl O5-ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxylate Intermediate 42 O3-tert-Butyl O7-ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxylate To a 79:21 solution of intermediate 39 and intermediate 40 (8 g, 24.5 mmol) and DIPEA (8.56 ml, 16.0 mmol) in DCM (300 mL) was added cyclopropanecarbonyl chloride (1.08 ml, 49.1 mmol) at 0° C. The reaction was stirred at room temperature for 2 h and then diluted with DCM (200 mL). Water (200 mL) was added and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL) and washed with 0.5 M aqueous hydrochloric acid (100 mL), saturated sodium bicarbonate solution (100 mL) and brine. The organic phase was separated and dried (MgSO 4 ), filtered and concentrated in vacuo to give a pale yellow solid as a mixture of regioisomers, which was purified by flash column chromatography on silica (gradient elution with 5% to 50% EtOAc in heptane) to give the solid product as a mixture of regioisomers. The solid was purified by heptane / Et 2 Trituration with δO afforded the title compound Intermediate 41 (7 g, 72%) and the filtrate was concentrated in vacuo to afford a 40:60 mixture of the title compound Intermediate 41 and the title compound Intermediate 42 (2 g, 21%). Intermediate 41:δ H (500 MHz, CD 3OD) 4.24 - 4.11 (m, 2H), 3.16 (dd, J 17.2, 5.4 Hz, 1H), 2.87 - 2.78 (m, 1H), 2.77 - 2.63 (m, 3H), 2.25 - 2.16 (m, 1H), 1.89 - 1.77 (m, 2H), 1.61 (s, 9H), 1.27 (t, J 7.1 Hz, 3H), 1.05 - 0.94 (m, 4H). LCMS [M+H] + 394.10, RT 1.63 minutes (Method 6).

[0180] Intermediate 43 [ka] 2-(Cyclopropanecarbonylamino)-5-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Intermediate 41 (7.0 g, 17.7 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (88.95 mL). The reaction mixture was stirred at 30° C. for 16 h. The solvent was removed in vacuo and the crude product was extracted with Et 2 Trituration with O afforded the title compound (5.3 g, 88%) as a white solid. LCMS [M+H] + 338, RT 1.28 minutes (Method 6).

[0181] Intermediates 43 and 44 [ka] Intermediate 43 2-(Cyclopropanecarbonylamino)-5-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Intermediate 44 2-(Cyclopropanecarbonylamino)-7-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid A 1:2 mixture of intermediates 41 and 42 (90%, 2.7 g, 6.18 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (30 mL) and stirred at room temperature for 2 h, followed by 6 h at 35° C., then at room temperature for 16 h, then at 35° C. for 3 h. The reaction mixture was concentrated in vacuo and the residue was extracted with Et 2 Trituration with 0 afforded the 5-isomer of the title compound intermediate 43 (220 mg, 11%) as an off-white solid. The filtrate was concentrated under reduced pressure in vacuo to afford a 1:3 mixture of the 5-isomer of the title compound intermediate 43 and the 7-isomer of the title compound intermediate 44 (2 g, 88%) as a sticky yellow foam which was used without further purification. Title compound intermediate 43: δ H (500 MHz, chloroform-d) 11.27 (s, 1H), 4.25 - 4.12 (m, 2H), 3.24 (dd, J 17.4, 5.4 Hz, 1H), 3.03 - 2.90 (m, 1H), 2.82 - 2.63 (m, 3H), 2.28 - 2.18 (m, 1H), 1.96 - 1.84 (m, 1H), 1.80 - 1.71 (m, 2H), 1.29 (t, J 7.1 Hz, 3H), 1.20 - 1.13 (m, 2H), 1.02 - 0.94 (m, 2H).

[0182] Intermediates 45 and 46 [ka] Intermediate 45 2-(Cyclopropanecarbonylamino)-N-ethyl-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide Intermediate 46 2-(Cyclopropanecarbonylamino)-N-ethyl-4,5,6,7-tetrahydrobenzothiophene-7-carboxamide A 1:3 mixture of intermediate 43 and intermediate 44 (2 g, 5.45 mmol, 92% purity) was suspended in quinolone 91-22-5 (15 mL) and copper powder 7440-50-8 (520 mg, 8.18 mmol) was added. The mixture was heated to 150 °C in a microwave for 1 h and the reaction mixture was diluted with DCM (150 mL) and water (150 mL). The organic phase was washed with 1 M aqueous hydrochloric acid (2 × 100 mL), followed by saturated aqueous sodium bicarbonate (100 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. 2 Trituration with 0 afforded a 2:1 mixture of ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate and ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylate (130 mg, 8%) as a light brown solid. The filtrate was concentrated in vacuo and purified by flash column chromatography on silica (gradient elution with 25-50% EtOAc / heptane) to afford a 1:3 mixture of ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate and ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylate (1 g, 47%). 5-isomer: δ H (500 MHz, CD 3 OD) 6.35 (s, 1H), 4.16 (q, J 7.1 Hz, 2H), 2.82 - 2.65 (m, 5H), 2.25 - 2.17 (m, 1H), 1.92 - 1.83 (m, 1H), 1.74 - 1.67 (m, 1H), 1.26 (t, J 7.1 Hz, 3H), 0.96 - 0.91 (m, 2H), 0.89 -0.83 (m, 2H).

[0183] To a 1:3 mixture of ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate and ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylate (1 g, 3.41 mmol, 85% purity) dissolved in THF (20 mL) was added 2 M aqueous lithium hydroxide solution (6 mL, 12 mmol). The reaction mixture was stirred at room temperature for 20 h, the reaction mixture was concentrated in vacuo, the residue was acidified with 1 M aqueous hydrochloric acid, and the precipitate was filtered to give a 1:3 mixture of 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid and 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid (600 mg, 60%). The mixture was used crude.

[0184] A 1:3 mixture of 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid and 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid (300 mg, 1.13 mmol) in DCM (5 mL) was treated with COMU (530 mg, 1.24 mmol) and DIPEA (240 μL, 1.38 mmol) and the mixture was stirred at room temperature for 10 min before adding 2M ethanamine in THF (0.7 mL). The reaction mixture was stirred for a further 30 min, diluted with DCM (20 mL), washed with water (20 mL), followed by 1M aqueous hydrochloric acid, and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 50-100% EtOAc / heptane) to afford the 5-isomer title compound intermediate 45 (100 mg, 20%, approximately 65% ​​pure) as a sticky dark brown oil and the 7-isomer title compound intermediate 46 (150 mg, 45%) as a brown solid. 5-isomer intermediate 45: LCMS [M+H] + 293.00, RT 1.04 min (Method 11). 7-isomeric intermediate 46: δ H (500 MHz, DMSO-d 6) 11.09 (s, 1H), 7.91 (t, J 5.5 Hz, 1H), 6.29 (s, 1H), 3.47 (t, J 6.7 Hz, 1H), 3.16 - 3.00 (m, 2H), 2.44 (t, J 5.5 Hz, 2H), 1.97 - 1.83 (m, 3H), 1.74 - 1.67 (m, 1H), 1.63 - 1.51 (m, 1H), 1.03 (t, J 7.2 Hz, 3H), 0.82 - 0.76 (m, 4H).

[0185] Intermediates 47 and 22 [ka] Intermediate 47 3-Butylsulfinyl-2-nitro-4,5,6,7-tetrahydrobenzothiophene Intermediate 22 3-Butylsulfonyl-2-nitro-4,5,6,7-tetrahydrobenzothiophene To a stirred solution of intermediate 21 (195 mg, 0.72 mmol) in DCM (8 mL) was added dropwise a solution of mCPBA (266 mg, 1.08 mmol, 70%) in DCM (5 mL) at room temperature. The reaction mixture was combined with another run (15 mg, 0.055 mmol starting material) and diluted with saturated Na 2 SO 3 The mixture was quenched with aqueous solution (15 mL). The phases were separated and the aqueous phase was extracted with DCM (2×30 mL). The combined organic phases were washed with 0.5 M potassium carbonate solution (30 mL), brine (20 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica (gradient elution with 0 to 100% DCM in heptane) to give the title compound intermediate 47 (107 mg, 49%) and the title compound intermediate 22 (106 mg, 51%). Intermediate 47: δ H(250 MHz, chloroform-d) 3.35 - 3.02 (m, 3H), 2.96 - 2.75 (m, 3H), 2.12 - 1.71 (m, 6H), 1.67 - 1.44 (m, 2H, obscured by water peak), 0.99 (t, J 7.3 Hz, 3H). LCMS [M+H] + 288, RT 1.38 min (Method 6). Intermediate 22: δ H (250 MHz, chloroform-d) 3.69 - 3.47 (m, 2H), 2.95 (t, J 5.4 Hz, 2H), 2.87 - 2.73 (m, 2H), 1.98 - 1.71 (m, 6H), 1.59 - 1.34 (m, 2H, partially obscured by water peak), 0.96 (t, J 7.3 Hz, 3H). LCMS [M+H] + 304, RT 4.40 minutes (Method 5).

[0186] Intermediate 48 [ka] 2-Amino-2-cyano-N-methylacetamide To a stirred solution of intermediate 131 (77%, 691 mg, 4.15 mmol) in TBME (10 mL) cooled in an ice bath was added 2M CH 3 NH 2 (7 mL) was added. The reaction was stirred for 1.5 h while warming to room temperature to give a yellow solution. The reaction was concentrated in vacuo and the orange residue was sonicated in ethanol:diethyl ether (1:9) to give an orange solid which was collected by vacuum filtration and washed with ethanol:diethyl ether (1:9) to give the title compound (395 mg, 76% at 90% purity) as an orange solid. δ H (250 MHz, DMSO-d 6 ) δ 8.09 (s, 1H), 4.47 (s, 1H), 2.81 (br s, 2H), 2.65 (d, J 4.7 Hz, 3H).

[0187] Intermediate 49 [ka] 3-Butylsulfinyl-4,5,6,7-tetrahydrobenzothiophene-2-amine To a solution of intermediate 47 (40 mg, 0.14 mmoL) in EtOH (3 mL) was added 10% palladium on carbon (50% wet) (30 mg, 0.014 mmoL) and the mixture was hydrogenated at room temperature and atmospheric pressure. Further 10% palladium on carbon (50% wet) (30 mg, 0.014 mmoL) was added and stirring was continued at room temperature. After stirring for a total of 7 hours, the reaction mixture was filtered through a pad of Celite, washed with EtOAc and concentrated in vacuo to give the title compound (20 mg, 56%) as a yellow film. LCMS [M+H] + 258, RT 1.31 minutes (Method 6).

[0188] Intermediate 50 [ka] 3-Cyano-2-phenyl-1-(p-tolyl)isourea 4-Methylaniline [106-49-0] (40 mg, 0.37 mmol) was dissolved in DCM (2 mL), diphenylcyanocarbonimidate [79463-77-7] (80.0 mg, 0.33 mmol) was added, and the reaction mixture was stirred at room temperature for 6 h. The mixture was concentrated in vacuo, and the title compound (94 mg, 84%) was used without further purification. LCMS [M+H] + 251.95, RT 1.30 min, purity 72% (Method 6).

[0189] Intermediate 51 [ka] N-[5-amino-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide To a suspension of intermediate 27 (500 mg, 1.46 mmol) in MeCN (6 mL) was added chlorosulfonic acid [7790-94-5] (0.49 mL, 7.43 mmol). The reaction mixture was stirred in a sealed tube at 70 °C for 1 h and then cooled to room temperature. This solution was slowly added to a solution of 1-cyclopropylmethanamine [2516-47-4] (1.0 mL, 11.8 mmol) and triethylamine (0.84 mL, 5.94 mmol) in chloroform (5 mL) cooled to 0 °C. The mixture was stirred at room temperature for 3 h, then diluted with EtOAc (70 mL) and washed with water. The aqueous phase was extracted with EtOAc (2 × 40 mL) and the combined organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography on silica (gradient elution from 1% to 20% MeOH in DCM) to give the title compound (210 mg, 38%) as a pale yellow solid. H (500 MHz, chloroform-d) 10.49 (s, 1H), 3.44 - 3.17 (m, 5H), 2.81 - 2.68 (m, 4H), 2.60 (dd, J 15.7, 9.4 Hz, 1H), 2.22 - 2.12 (m, 1H), 1.86 - 1.74 (m, 1H), 1.65 - 1.57 (m, 1H), 1.15 - 1.08 (m, 2H), 0.98 - 0.91 (m, 2H), 0.91 - 0.81 (m, 1H), 0.48 - 0.41 (m, 2H), 0.12 - 0.05 (m, 2H). LCMS [M+H] + 370.10, RT 0.98 minutes (Method 6).

[0190] Intermediate 52 [ka] N-[5-[(N-cyano-C-phenoxy-carbonimidoyl)amino]-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide Intermediate 51 (100 mg, 0.27 mmol) was dissolved in 2-propanol (5 mL), diphenyl cyanocarbonimidate [79463-77-7] (70.9 mg, 0.29 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give the crude product (30 mg), which was purified by preparative HPLC (acidic) followed by preparative HPLC (basic) to give the title compound (130 mg, 89%) as a white solid, a 1:1 mixture of geometric isomers E and Z. δ H (500 MHz, CD 3 OD) 7.52 - 7.38 (m, 2H), 7.34 - 7.26 (m, 1H), 7.24 - 7.11 (m, 2H), 4.32 - 4.13 (m, 1H), 3.46 - 3.36 (m, 1H, isomer 1), 3.31 - 3.24 (m, 1H, isomer 2), 2.90 - 2.74 (m, 4H and 1H, isomer 1), 2.70 - 2.62 (m, 1H, isomer 2), 2.32 - 2.22 (m, 1H, isomer 1), 2.21 - 2.13 (m, 1H, isomer 2), 2.06 - 1.97 (m, 1H, isomer 1), 1.94 - 1.84 (m, 1H, isomer 2), 1.83 - 1.75 (m, 1H), 1.06 - 0.93 (m, 4H), 0.90 - 0.77 (m, 1H), 0.50 - 0.35 (m, 2H), 0.16 - 0.02 (m, 2H).LCMS [M+H] + 514.3, RT 3.70 minutes (Method 10).

[0191] Intermediate 53 [ka] Ethyl 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate Intermediate 43 (4 g, 11.9 mmol) was divided into two equal portions, each suspended in quinoline (15 mL) and copper powder (555 mg, 8.73 mmol) was added. The mixture was heated to 150 °C in a microwave for 1 h. The reaction mixtures were combined, diluted with DCM (250 mL) and washed with 1 M aqueous hydrogen chloride solution (2 x 250 mL), followed by saturated aqueous sodium bicarbonate solution (100 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product was triturated with EtOAc and filtered to give the title compound (3.07 g, 88%) as a grey solid. δ H (500 MHz, DMSO-d 6 ) 11.10 (s, 1H), 6.32 (s, 1H), 4.17 - 4.01 (m, 2H), 2.81 - 2.56 (m, 5H), 2.14 - 2.06 (m, 1H), 1.82 - 1.66 (m, 2H), 1.20 (t, J 7.1 Hz, 3H), 0.83 - 0.75 (m, 4H).LCMS [M+H] + 294.0, RT 1.26 min, purity 98% (Method 6).

[0192] Intermediate 54 [ka] Ethyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate Intermediate 53 (2 g, 6.34 mmol, 93% purity) was suspended in MeCN (120 mL) and sulfonic acid chloride [7790-94-5] (1.45 mL, 21.8 mmol) was added. The solution was heated at 50 °C under nitrogen for 18 h. The solution was cooled to 0 °C and cyclopropylmethanamine [2516-47-4] (4 mL, 46.1 mmol) was added dropwise. The ice bath was removed and the solution was stirred for 30 min. EtOAc (200 mL) was added and the mixture was washed with 1 M aqueous hydrochloric acid (2 × 100 mL) and brine. The organic phase was separated and dried (MgSO 4), filtered and concentrated in vacuo to give the product which was purified by flash column chromatography on silica (gradient elution with 0-30% EtOAc / heptane) to give the title compound (1.4 g, 52%) as an amber oil which solidified to form a beige solid. δ H (500 MHz, DMSO-d 6 ) 10.44 (s, 1H), 7.94 (t, J 5.9 Hz, 1H), 4.18 - 4.02 (m, 2H), 3.08 - 2.98 (m, 1H), 2.80 - 2.63 (m, 6H), 2.14 - 2.05 (m, 1H), 1.94 - 1.86 (m, 1H), 1.81 - 1.71 (m, 1H), 1.21 (t, J 7.1 Hz, 3H), 0.96 - 0.85 (m, 4H), 0.82 - 0.73 (m, 1H), 0.39 - 0.32 (m, 2H), 0.10 - 0.05 (m, 2H).LCMS [M+H] + 449.0, RT 1.43 minutes, 99% purity (Method 6).

[0193] Intermediate 55 [ka] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid Intermediate 54 (1.8 g, 4.22 mmol) was dissolved in 1,4-dioxane (40 mL) and water (10 mL) and 2 M lithium hydroxide monohydrate solution (6 mL) was added. The reaction mixture was heated at 90° C. for 2 h and then cooled to room temperature. The mixture was concentrated in vacuo and the residue was acidified with 1 M aqueous hydrochloric acid. The resulting solid was filtered off, washed with water and dried in vacuo to give the title compound (1.2 g, 71%) as a beige solid. δ H (500 MHz, DMSO-d 6) 12.34 (s, 1H), 10.45 (s, 1H), 7.94 (t, J 5.7 Hz, 1H), 3.03 (dd, J 16.7, 5.0 Hz, 1H), 2.78 - 2.58 (m, 6H), 2.14 - 2.05 (m, 1H), 1.94 - 1.86 (m, 1H), 1.80 - 1.67 (m, 1H), 0.95 - 0.85 (m, 4H), 0.81 - 0.72 (m, 1H), 0.39 - 0.30 (m, 2H), 0.10 - 0.04 (m, 2H). LCMS [M+H] + 399.0, RT 1.24 min, purity 97% (Method 6).

[0194] Intermediate 56 [ka] N-(3-Butylsulfanyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide To a solution of intermediate 21 (930 mg, 3.43 mmoL) and cyclopropanecarboxylic anhydride [33993-24-7] (634 mg, 4.11 mmoL) in EtOAc (120 mL) was added 10% Pd on carbon (50% wet, 730 mg, 0.34 mmoL) and the reaction mixture was hydrogenated at room temperature and atmospheric pressure for 2 h. Further 10% Pd on carbon (50% wet, 730 mg, 0.34 mmoL) was added and stirring was continued at room temperature for 1 h. 10% Pd on carbon (50% wet, 500 mg, 0.24 mmoL) was added and stirring was continued for 1 h. The reaction mixture was filtered through a pad of Celite, washed with EtOAc, and the resulting solution was treated with triethylamine (1.43 mL, 10.3 mmol) followed by cyclopropanecarbonyl chloride [4023-34-1] (0.63 mL, 6.9 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 60 h. The mixture was washed with saturated aqueous ammonium chloride (10 mL) and brine (10 mL) and the organic phase was dried (MgSO 4The organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica (gradient elution with 0 to 50% DCM / heptane) to give the crude product, which was dissolved in EtOAc (15 mL) and washed with saturated aqueous ammonium chloride (10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine. The organic phase was dried (MgSO 4 ). 4 ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (gradient elution with 0 to 50% EtOAc / heptane) to give the title compound (630 mg, 90% purity, 54%) as a pale yellow solid. δ H (250 MHz, chloroform-d) 8.73 (s, 1H), 2.72 - 2.62 (m, 2H), 2.62 - 2.51 (m, 4H), 1.87 - 1.74 (m, 4H), 1.62 - 1.56 (m, 1H), 1.52 - 1.34 (m, 4H), 1.22 - 1.07 (m, 2H), 0.96 - 0.82 (m, 5H). LCMS [M+H] + 310, RT 1.45 min, purity 94% (Method 11).

[0195] Intermediate 57 [ka] N-(3-Butylsulfinyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide To a stirred solution of intermediate 56 (660 mg, 1.9 mmol) in DCM (12 mL) was added a solution of mCPBA (70% pure, 473 mg, 1.9 mmol) in DCM (8 mL) at room temperature for 1.5 h. The mixture was quenched with saturated aqueous sodium sulfite solution (15 mL), the phases were separated and the aqueous phase was extracted with DCM (2×15 mL). The combined organic layers were washed with 1 M potassium carbonate solution (20 mL), water (15 mL), brine (15 mL) and dried (MgSO 4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica (gradient elution with 0 to 50% EtOAc / heptane) to afford the title compound as a yellow oil (576 mg, 92%). δ H (250 MHz, chloroform-d) 11.23 (s, 1H), 3.15 - 2.79 (m, 2H), 2.71 - 2.58 (m, 2H), 2.58 - 2.43 (m, 1H), 2.26 - 2.07 (m, 1H), 1.93 - 1.64 (m, 6H), 1.68 - 1.40 (m, 3H), 1.16 - 1.03 (m, 2H), 0.96 (t, J 7.3 Hz, 3H), 0.94 - 0.80 (m, 2H). LCMS [M+H] + 326, RT 1.28 min, 100% purity (Method 11).

[0196] Intermediate 58 [ka] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-methoxy-N5-methyl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide Example 40 (4 g, 11.04 mmol) was suspended in DCM (100 mL) and EDCI (2.12 g, 11.04 mmol), methoxy(methyl)amine (1.35 g, 22.07 mmol), triethylamine (2.23 g, 22.07 mmol) and catalytic DMAP (30 mg) were added to the mixture. The reaction mixture was stirred at room temperature for 16 h and the reaction mixture was concentrated in vacuo. The crude residue was dissolved in saturated sodium bicarbonate solution (2×10 mL) and extracted with DCM (40 mL). The organic phase was concentrated in vacuo and the residue was purified by flash column chromatography on silica (gradient elution with 0-50% DCM / MeOH) to give the title compound (3.0 g, 60%) as a yellow solid. δ H (500 MHz, methylene chloride-d 2) 12.11 (s, 1H), 6.00 (s, 1H), 3.70 (s, 3H), 3.29 - 3.22 (m, 2H), 3.20 (s, 3H), 2.97 - 2.83 (m, 2H), 2.82 - 2.70 (m, 2H), 2.13-2.08 (m, 1H), 1.89 - 1.76 (m, 1H), 1.65 (tt, J 7.9, 4.6 Hz, 1H), 1.09 - 0.98 (m, 3H), 0.90 - 0.81 (m, 2H), 0.60 - 0.44 (m, 2H), 0.29 - 0.18 (m, 2H). NH proton is unknown. LCMS [M+H] + 406.20, RT 1.78 min, purity 91.76% (Method 12).

[0197] Intermediate 59 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-formyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide Intermediate 58 (2.27 g, 5.6 mmol) was dissolved in DCM (70 mL) and the reaction mixture was stirred at room temperature for 5 min. 1M hydrido[bis(2-methylpropyl)]aluminum in hexanes (11.2 mL, 11.20 mmol) was added dropwise to the reaction mixture and stirred at -78 °C for 1 h. The reaction mixture was removed from the dry ice bath and quenched by the addition of saturated sodium potassium tartrate (100 mL) and the combined organic phase was washed with brine (100 mL) and dried (MgSO 4 ), filtered and the filtrate concentrated in vacuo to give the title compound (1.46 g, 75%) which was used without further purification. LCMS [M+H]+ 347.20, RT 1.79 min, 80% pure (Method 12).

[0198] Intermediate 60 [ka] 5-(Aminomethyl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Formic acid Example 59 (300 mg, 0.83 mmol) was dissolved in MeOH (6 mL) and water (3 mL) and formic acid [64-18-6] (2.94 ml, 78.0 mmol) was added. The reaction mixture was cooled to 0° C. and zinc [7440-66-6] (109 mg, 1.66 mmol) was added. The reaction mixture was stirred at 0° C., warmed to room temperature and stirred for 36 h, the reaction mixture was filtered and the solid was washed with MeOH. The filtrate was concentrated in vacuo to give the desired product, which was purified by flash column chromatography on silica (gradient elution with 0-60% MeOH in DCM) to give the title compound (300 mg, 92%) as a white solid. δ H (250 MHz, methylene chloride-d 2 ) 12.07 (s, 1H), 6.46 (t, J 7.5 Hz, 1H), 3.36-3.33 (m, 1H), 3.21 - 3.08 (m, 1H), 3.07 - 2.85 (m, 3H), 2.73-2.68 (m, 2H), 2.57 - 2.40 (m, 1H), 2.18-2.15 (m, 1H), 2.02-1.96 (m, 1H), 1.71 - 1.46 (m, 2H), 1.14 - 0.96 (m, 3H), 0.90-0.86 (m, 2H), 0.49-0.45 (m, 2H), 0.29-0.23 (m, 2H), As formate salt (1 eq.).

[0199] Intermediate 61 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(ethylcarbamothioylamino)methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide A solution of isothiocyanatoethane [542-85-8] (160.5 mg, 1.84 mmol) in DCM (5 mL) was stirred at room temperature before adding intermediate 60 (320 mg, 0.92 mmol). Triethylamine (128 μl, 0.92 mmol) was added to the reaction mixture and the solution was stirred under nitrogen for 18 h. The reaction mixture was concentrated in vacuo to give a pale yellow solid, which was purified by flash column chromatography on silica (gradient elution from 0% to 100% EtOAc in heptane) to give the title compound (369 mg, 90%) as a white solid. δ H (250 MHz, methylene chloride-d 2 ) 12.16 (s, 1H), 6.07 (s, 1H), 5.80 (br s, 2H), 3.73-3.70 (m, 1H), 3.64 - 3.49 (m, 1H), 3.48 - 3.32 (m, 2H), 3.26 (dd, J 7.0, 5.5 Hz, 2H), 2.90 (dd, J 15.0, 4.9 Hz, 1H), 2.75-2.70 (m, 2H), 2.61 - 2.43 (m, 1H), 2.13-2.08 (m, 1H), 2.03-1.97 (m, 1H), 1.69-1.66 (m, 1H), 1.22 (t, J 7.5 Hz , 3H), 1.11 - 0.96 (m, 3H), 0.91 - 0.81 (m, 2H), 0.63 - 0.50 (m, 2H), 0.30-0.25 (m, 2H); 1H unclear due to solvent.

[0200] Intermediate 62 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-oxo-6,7-dihydro-4H-benzothiophene-3-carboxamide Example 86 (420 mg, 1.12 mmol) was dissolved in THF and 1 M aqueous hydrochloric acid (7.81 mL) was added. The reaction mixture was heated at 70° C. for 3 h and then stirred at room temperature for 18 h. The reaction mixture was heated for an additional 1 h, the solution was cooled to room temperature and the pH was adjusted to pH 9 with saturated sodium bicarbonate solution. The mixture was extracted with EtOAc (2×15 mL) and the combined organic phase was washed with brine (15 mL) and dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give a yellow solid which was purified by flash column chromatography on silica (gradient elution with 0-50% EtOAc / isohexane) to give the title compound (264 mg, 71%) as an off-white solid. LCMS [M+H] + 333.2, RT 1.630 min, purity 92.8% (Method 1).

[0201] Intermediate 63 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)spiro[6,7-dihydro-4H-benzothiophene-5,2'-oxirane]-3-carboxamide Trimethylsulfoxonium iodide [1774-47-6] (2.00 g, 9.09 mmol) was poured into DMSO (13 mL) and cooled to 0° C. Sodium hydride [7646-69-7] (650 mg, 16.3 mmol) was added and the reaction mixture was stirred at room temperature. After 1.5 h, intermediate 62 (1.95 g, 5.87 mmol) and tetrabutylammonium bromide [1643-19-2] (200 mg, 0.620 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was poured into water and ice (50 g) and extracted with EtOAc (3×50 mL). The combined organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo to give a yellow solid which was purified by flash column chromatography on silica (100% DCM to 95 / 5 / 0.5% DCM / MeOH / NH 4OH gradient elution) to give the title compound (1.73 g, 85%) as a yellow solid. LCMS [M+H] + 347.11, RT 2.31 min, purity 96.42% (Method 9).

[0202] Intermediate 64 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-methoxyphenyl)sulfonylhydrazono]-6,7-dihydro-4H-benzothiophene-3-carboxamide Intermediate 62 (200 mg, 0.6 mmol) was added to a solution of 4-methoxybenzenesulfonohydrazide [1950-68-1] (122 mg, 0.6 mmol) in MeOH (1.2 mL) and the suspension was stirred under nitrogen at 20° C. for 60 h. The reaction mixture was diluted with MeOH (10 mL) and the solid was collected by filtration. The solid was washed with MeOH (2×20 mL) and dried in vacuum at 40° C. for 2 h to give the title compound (146 mg, 44%) as a pale yellow powder. δ H (500 MHz, DMSO-d 6 ) 10.96 (s, 1H), 10.16 (s, 1H), 7.90 (t, J 5.5 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.14 - 7.08 (m, 2H), 3.83 (s, 3H), 3.54 (s, 2H), 3.17 (t, J 6.2 Hz, 2H), 2.73 (t, J 6.3 Hz, 2H), 2.49 - 2.44 (unclear, m, 2H), 1.97 - 1.86 (m, 1H), 1.15 - 1.02 (m, 1H), 0.91 - 0.75 (m, 4H), 0.52 - 0.40 (m, 2H), 0.32 - 0.21 (m, 2H). LCMS [M+H] + 517.2, RT 1.87 min, purity 95% (Method 12).

[0203] Intermediate 65 [ka] [2-Oxo-2-(p-tolyl)ethyl]2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate To a stirred solution of Example 40 (100 mg, 0.28 mmol) in DMF (2 mL) was added potassium carbonate (55 mg, 2.26 mmol). The reaction mixture was stirred for 10 min, 2-bromo-1-(4-methylphenyl)ethanone [619-41-0] (65 mg, 0.3 mmol) was added and the mixture was stirred at 40° C. for 1 h. The solvent was removed in vacuo and the remaining residue was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The organic phases were combined, washed with water (3×50 mL), brine (50 mL), separated and dried (Na 2 SO 4 ), filtered and the solvent removed in vacuo to give the crude title compound (120 mg, 62%) as a yellow solid. LCMS [M+H] + 517.10, RT 1.33 min, purity 70.3% (Method 11).

[0204] Intermediate 66 [ka] 2-Cyano-N-(cyclopropylmethyl)acetamide Cyclopropylmethylamine [2516-47-4] (3.63 g, 50.0 mmol) was added dropwise to methyl cyanoacetate [105-34-0] (2.50 g, 25.0 mmol) at 0° C. The reaction mixture was stirred for 90 min, and after 45 min, a white solid precipitated. 1:1Et 2 O / isohexane (40 mL) was added to the reaction mixture, which was stirred at 0° C. for 10 minutes. The solid was filtered and washed with a small amount of isohexane to give the title compound (3.25 g, 95%) as a pure white solid. δ H(300 MHz, chloroform-d) 6.19 (s, 1H), 3.40 (s, 2H), 3.19 (dd, J 7.3, 5.4 Hz, 2H), 1.10 - 0.90 (m, 1H), 0.66 - 0.52 (m, 2H), 0.26 (dt, J 6.2, 4.7 Hz, 2H).

[0205] Intermediate 67 [ka] Ethyl 2-amino-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate To a solution of 3-(trifluoromethyl)cyclohexanone [585-36-4] (0.50 g, 3.0 mmol) in EtOH (3 mL) was added ethyl cyanoacetate [105-56-6] (0.37 g, 3.3 mmol) followed by sulfur [7704-34-9] (0.11 g, 3.4 mmol) and diethylamine (0.33 g, 4.5 mmol). The reaction mixture was stirred at room temperature for 1.5 h, the mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography on silica (gradient elution with 0-15% EtOAc in hexanes) to give the title compound (717 mg, 81%) as an off-white solid. LCMS [M+H] + 294.0, RT 1.532 minutes (Method 4).

[0206] Intermediate 68 [ka] Ethyl 2-(cyclopropanecarbonylamino)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Intermediate 67 (717 mg, 2.45 mmol) was dissolved in DCM (10 mL) and DIPEA (0.75 mL, 4.3 mmol) and cyclopropanecarbonyl chloride [4023-34-1] (0.22 mL, 2.4 mmol) were added. The reaction mixture was stirred at room temperature for approximately 1 h and then washed with saturated sodium bicarbonate solution and brine. The mixture was passed through a phase separation cartridge and the organic layer was concentrated in vacuo to give a yellow gum which was purified by flash column chromatography on silica (gradient elution with 10-50% EtOAc / hexanes) to give the title compound (0.75 g, 85%) as a white solid. δ H (400 MHz, DMSO-d 6 ) 11.17 (s, 1H), 4.32 (qd, J 7.1, 2.0 Hz, 2H), 3.13 (dd, J 16.6, 5.0 Hz, 1H), 2.85 - 2.65 (m, 3H), 2.65 - 2.54 (m, 1H), 2.12 (d, J 12.9 Hz, 1H), 2.04 (tt, J 7.4, 4.9 Hz, 1H), 1.63 (qd, J 11.9, 5.7 Hz, 1H), 1.32 (t, J 7.1 Hz, 3H), 1.04 - 0.83 (m, 4H).

[0207] Intermediate 69 [ka] 2-(Cyclopropanecarbonylamino)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Intermediate 68 (0.73 g, 2.0 mmol) was dissolved in 1,4-dioxane (7 mL), and a solution of lithium hydroxide monohydrate [1310-66-3] (236 mg, 3.15 mmol, 56 mass %) in water (1.5 mL) was added. The mixture was stirred at 50 °C for about 16 h. The mixture was concentrated in vacuo, the residue was dissolved in water and washed with DCM (2×). The aqueous phase was acidified to <pH 2 by addition of 2 M aqueous hydrochloric acid, and the resulting precipitate was filtered off, washed with water (2×), and air-dried to give the title compound (665 mg, 99%) as an off-white solid. LCMS [M-H] - 332.0, RT 2.374 min (Method 2).

[0208] Intermediate 70

Chem.

[0209] Intermediate 71

Chem.

[0210] Intermediate 72 [ka] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(hydrazinecarbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide Example 40 (100 mg, 0.26 mmol) was dissolved in EtOH (3 mL) and hydrazine hydrate (0.12 ml, 2.56 mmol) was added. The reaction mixture was stirred at 70° C. for 20 h. The mixture was concentrated in vacuo to give the title compound (95 mg, 99%) as a white solid. LCMS [M+H] + 377.05, RT 1.13 min, 100% purity (Method 6).

[0211] Intermediate 73 [ka] 2-Cyclopropyl-5,6,7,8-tetrahydrobenzothiopheno[2,3-d][1,3]oxazin-4-one To intermediate 16 (200 mg, 0.75 mmol), DCM (4 mL) and DMF (0.01 mL) was added oxalyl chloride [79-37-8] (105 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo to give the crude product, which was purified by reverse phase LCMS (basic mode) to give the title compound (200 mg, 107%) as a beige solid. δ H (400 MHz, DMSO-d 6 ) 2.75 (dt, J 11.2, 6.0 Hz, 4H), 2.05 - 1.95 (m, 1H), 1.87 - 1.70 (m, 4H), 1.17 - 1.07 (m, 4H).

[0212] Intermediate 74 [ka] Ethyl 2-(cyclopropanecarbonylamino)-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylate To ethyl 2-amino-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate [96334-44-0] (506 mg, 2.12 mmol) was added DCM (15 mL) and DIPEA (1.1 mL, 6.3 mmol). The reaction mixture was stirred under nitrogen, then cyclopropanecarbonyl chloride [4023-34-1] (0.21 mL, 2.30 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen. More DCM (24 mL) was added to dissolve the mixture, followed by more cyclopropanecarbonyl chloride [4023-34-1] (0.21 mL, 2.30 mmol) and the reaction mixture was stirred for 1 hour, then more cyclopropanecarbonyl chloride [4023-34-1] (0.21 mL, 2.30 mmol) was added and the mixture was stirred overnight under nitrogen. Further cyclopropanecarbonyl chloride [4023-34-1] (0.21 mL, 2.30 mmol) was added and the reaction mixture was stirred for 2 h, then further cyclopropanecarbonyl chloride [4023-34-1] (0.85 mL, 9.19 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Water (25 mL) was added to the reaction mixture which was stirred vigorously for 10 min. Further water (25 mL) and DCM (25 mL) were added and the organic layer was separated and then washed with brine (50 mL). The organic layer was separated, passed through a phase separation frit and concentrated in vacuo to give a dark brown oil which was purified by flash column chromatography on silica (gradient elution from 20% EtOAc / isohexane to 95% EtOAc / isohexane) to give the title compound (253 mg, 39%) as a pale yellow solid. LCMS [M+H] + 308.8, RT 2.162 min, purity 100.0% (Method 2). LCMS [M+H] + 308.8, RT 2.205 minutes, purity 100.0% (Method 3).

[0213] Intermediates 74 and 75 [ka] Intermediate 74 Ethyl 2-(cyclopropanecarbonylamino)-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylate Intermediate 75 Methyl 2-(cyclopropanecarbonylamino)-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylate To a stirred solution of cyclopropane carboxylic acid [1759-53-1] (1.00 g, 11.6 mmol) in DCM (3 mL) was added oxalyl chloride [79-37-8] (1.50 g, 11.61 mmol) followed by DMF (1 drop). The reaction immediately evolved gas and was stirred at room temperature for 1 h to form cyclopropane carbonyl chloride [4023-34-1]. A mixture of ethyl 2-amino-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylate and methyl 2-amino-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylate [96334-44-0] (commercially available ASINEX compound is 73% ethyl and 27% methyl) (ratio 0.73:0.27, 2.736 g) was dissolved in 1,4-dioxane (40 mL) by heating and triethylamine (2.38 g, 23.2 mmol) was added. Upon cooling, the amino esters precipitated out of solution and the crude cyclopropanecarbonyl chloride solution was added dropwise over 1 min to this stirred solution at ca. 30° C. After 2 h at room temperature, more commercially available cyclopropanecarbonyl chloride [4023-34-1] (364 mg, 3.48 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was suspended in EtOAc and washed with water (2x), 0.5M aqueous hydrochloric acid, saturated sodium bicarbonate solution (2x) and water (2x). The organic layer was separated and dried (MgSO 4 ), filtered and the mixture was concentrated in vacuo to give a crude mixture of the title products Intermediate 74 and Intermediate 75 (2.84 g, 59%) in approximately 3:1 ratio as a yellow solid. 200 mg was separated by preparative HPLC to give 45 mg and 15 mg of Intermediate 74 and 75, respectively. Intermediate 74: LCMS [M+H] + 308.8, RT 2.162 min, purity 100.0% (Method 2). LCMS [M+H] +308.8, RT 2.205 min, purity 100.0% (Method 3). Intermediate 75: LCMS [M+H] + 294.6, RT 1.940 min, purity 100.0% (Method 2). LCMS [M+H] + 294.6, RT 1.868 min, purity 100.0% (Method 3).

[0214] Intermediate 76 [ka] 2-(Cyclopropanecarbonylamino)-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid A mixture of intermediates 74 and 75 (3:1 ratio) (2.63 g, 8.66 mmol) was dissolved in 1,4-dioxane (40 mL) by heating. Lithium hydroxide monohydrate [1310-66-3] (0.55 g, 13.0 mmol) was dissolved in water (3 mL) by heating and this solution was added to the stirred solution of intermediates 74 and 75. The stirred solution was heated at 60° C. for 2 h followed by room temperature for 18 h. The reaction mixture was heated at 70° C. for 2 h followed by 40° C. for 5 h. Further lithium hydroxide monohydrate [1310-66-3] (0.18 g, 4.33 mmol, 0.5 equiv.) dissolved in water (1 mL) was added and the solution was stirred at room temperature for 3 days. The reaction was heated at 70° C. for 4 h after which the 1,4-dioxane was removed under vacuum. The mixture was diluted with dilute sodium carbonate solution and the suspension was partitioned with EtOAc. The aqueous phase was separated, the organic phase was extracted with dilute sodium carbonate solution and the aqueous extracts were combined. 2M aqueous hydrochloric acid was added to the aqueous extracts until the acid precipitated from solution. The resulting suspension was filtered and the solid was washed with 0.2M aqueous hydrochloric acid and dried in vacuo to give the title compound (890 mg, 37%) as a beige solid. δ H (400 MHz, DMSO-d 6 ) 13.68 (s, 1H), 11.81 (s, 1H), 3.05 (t, J 6.0 Hz, 2H), 2.49 - 2.45 (m, 2H), 2.19 - 1.98 (m, 3H), 1.02 - 0.91 (m, 4H). LCMS [M+H]+ 280.7, RT 1.452 min, purity 96.8% (Method 2). LCMS [M+H] + 280.6, RT 0.600 min, purity 96.9% (Method 3).

[0215] Intermediate 77 [ka] 2-(Cyclopropanecarbonylamino)-N-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxamide To a suspension of intermediate 76 (320 mg, 1.15 mmol) in DCM (12 mL) was added 1-hydroxybenzotriazole hydrate [123333-53-9] (263 mg, 1.72 mmol) followed by EDCI (340 mg, 1.72 mmol). After stirring for 10 min, 2M methylamine in THF (773 mg, 1.72 mmol, 0.86 mL) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc in hexanes) to give the title compound (250 mg, 75%) as a yellow solid. LCMS [M+H] + 293.0, RT 1.092 min, purity 94.0% (Method 4).

[0216] Intermediate 78 [ka] Ethyl 2-amino-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate To a solution of 2-methylcyclohexanone [583-60-8] (1 g, 8.83 mmol) in EtOH (4 mL) was added ethyl cyanoacetate [105-56-6] (1.10 g, 9.71 mmol), sulfur [7704-34-9] (0.31 g, 9.71 mmol) and diethylamine [109-89-7] (0.973 g, 13.24 mmol). The reaction mixture was stirred at room temperature for 18 h, subsequently heated at 50° C. for 7 h, and then left at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica (gradient elution with 0-10% EtOAc in hexanes) to give the title compound (520 mg, 25%) as a yellow solid. δ H (400 MHz, DMSO-d 6 ) 7.23 (s, 2H), 4.27 - 4.07 (m, 2H), 3.22 - 3.10 (m, 1H), 2.47 - 2.32 (m, 2H), 1.87 - 1.62 (m, 3H), 1.61 - 1.47 (m, 1H), 1.26 (t, J 7.1 Hz, 3H), 1.09 (d, J 6.7 Hz, 3H).

[0217] Intermediate 79 [ka] Ethyl 2-(cyclopropanecarbonylamino)-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Cyclopropanecarbonyl chloride [4023-34-1] (0.22 mL, 2.4 mmol) was added to a solution of intermediate 78 (520 mg, 2.17 mmol) and DIPEA (0.75 mL, 4.3 mmol) in DCM (10 mL). The reaction mixture was stirred for 1.5 h before being diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate (2×20 mL). The mixture was passed through a phase separation cartridge and the organic phase was concentrated in vacuo. The crude product was dissolved in DCM and purified by flash chromatography on silica (gradient elution 10% to 40% EtOAc in isohexane) to give the title compound (676 mg, 101%) as a cream solid. δ H (300 MHz, DMSO-d 6 ) 11.23 (s, 1H), 4.22-4.41 (m, 2H), 3.24-3.31 (m, 1H), 2.54-2.68 (m, 2H), 1.94-2.03 (m, 1H), 1.58-1.84 (m, 4H), 1.33 (t, 3H, J 7.1 Hz), 1.12 (d, 3H, J 6.8 Hz), 0.84-0.96 (m, 4H).

[0218] Intermediate 80 [ka] 2-(Cyclopropanecarbonylamino)-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Lithium hydroxide monohydrate [1310-66-3] (236 mg, 3.15 mmol) in water (1.5 mL) was added to a solution of intermediate 79 (646 mg, 2.10 mmol) in 1,4-dioxane (7 mL). The reaction mixture was heated to 70° C. and stirred for 6.5 h, then cooled to room temperature and stirred overnight. The reaction mixture was heated to 70° C. and stirred for a further 6 h, then cooled to room temperature overnight. An additional amount of lithium hydroxide monohydrate [1310-66-3] (80 mg, 1.91 mmol) in water (0.5 mL) was added and the reaction mixture was heated to 70° C. for 6 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, then diluted with water (30 mL) and washed with DCM (2×20 mL). The aqueous phase was acidified to about pH 5 with 2 M aqueous hydrochloric acid. The cream solid that formed was filtered off, washed with water followed by isohexane and dried in vacuo to give the title compound (454 mg, 77%) as a cream solid. H (400 MHz, DMSO-d 6 ) 13.12 (s, 1H), 11.60 (s, 1H), 2.51-2.65 (m, 2H), 1.88-1.95 (m, 1H), 1.66-1.82 (m, 4H), 1.58-1.63 (m, 1H), 1.12 (d, 3H, J 6.8 Hz), 0.85-0.93 (m, 4H).

[0219] Intermediate 81 [ka] Ethyl 2-amino-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Morpholine [110-91-8] (1.04 mL, 11.7 mmol) was added to a suspension of 3,5-dimethylcyclohexanone [2320-30-1] (1.12 mL, 7.76 mmol), sulfur [7704-34-9] (274 mg, 8.55 mmol) and ethyl cyanoacetate [105-56-6] (0.91 mL, 8.5 mmol) in EtOH (30 mL). The reaction was stirred at room temperature overnight. The reaction mixture was heated to 50 °C overnight and then at 50 °C for an additional 6 h. The reaction mixture was cooled to room temperature and stirred overnight. The mixture was concentrated in vacuo, diluted with EtOAc (20 mL), washed with brine (2 x 20 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (gradient elution from 1% to 10% EtOAc in isohexane) to give the title compound (1.23 g, 63%) as a cream solid. δ H (400 MHz, DMSO-d 6 ) 7.18 (s, 2H), 4.15 (q, 2H, J 7.1 Hz), 2.84 (dd, 1H, J 17.2, 5.0 Hz), 2.64-2.74 (m, 1H), 2.00 (ddd, 1H, J 17.4, 11.2, 3.3 Hz), 1.80-1.85 (m, 1H), 1.64-1.77 (m, 1H), 1.24 (t, 3H, J 7.1 Hz), 1.08 (d, 3H, J 6.8 Hz), 1.00 (d, 3H, J 6.5 Hz), 0.91-0.99 (m, 1H).

[0220] Intermediate 82 [ka] Ethyl 2-(cyclopropanecarbonylamino)-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Cyclopropanecarbonyl chloride [4023-34-1] (0.49 mL, 5.3 mmol) was added to a solution of intermediate 81 (1.23 g, 4.85 mmol) and DIPEA (1.7 mL, 9.8 mmol) in DCM (20 mL). The reaction mixture was stirred for 1.5 h, diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The mixture was passed through a phase separation cartridge and the organic phase was concentrated in vacuo to give the crude product which was purified by flash chromatography on silica (gradient elution 1% to 10% EtOAc in isohexane) to give the title compound (1.43 g, 91%) as a cream solid. δ H (300 MHz, DMSO-d 6 ) 11.17 (s, 1H), 4.30 (q, 2H, J 7.1 Hz), 2.94 (dd, 1H, J 17.2, 5.0 Hz), 2.77-2.89 (m, 1H), 2.11 (ddd, 1H, J 17.1, 11.2, 3.0 Hz), 1.95-2.04 (m, 1H), 1.83-1.90 (m, 1H), 1.69-1.82 (m, 1H), 1.32 (t, 3H, J 7.1 Hz), 1.19 (d, 3H, J 6.8 Hz), 1.03 (d, 3H, J 6.6 Hz), 0.98-1.06 (m, 1H), 0.85-0.96 (m, 4H).

[0221] Intermediate 83 [ka] 2-(Cyclopropanecarbonylamino)-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Lithium hydroxide monohydrate [1310-66-3] (500 mg, 6.67 mmol) in water (5 mL) was added to a solution of intermediate 82 (1.43 g, 4.43 mmol) in 1,4-dioxane (25 mL). The reaction mixture was heated to 70° C. and stirred overnight, then cooled to room temperature, diluted with water (30 mL) and washed with EtOAc (2×20 mL). The aqueous phase was acidified to about pH 5 with 2 M aqueous hydrochloric acid. A pink solid formed, which was filtered off, washed with water and isohexane, and then dried in vacuo. The resulting solid was added to the EtOAc washes, which were washed with the acidic aqueous phase. The acidic aqueous phase was extracted with EtOAc (20 mL) and the combined organic layers were dried (MgSO 4 ), filtered and concentrated in vacuo to give a pink solid (1.40g) which was partially dissolved in EtOAc and triturated with isohexane to give a cream powder which was washed with isohexane and dried. Further compound was obtained by triturating the mother liquor with isohexane, totalling the title compound (1.07g, 82%). δ H (400 MHz, DMSO-d 6 ) 13.07 (s, 1H), 11.49 (s, 1H), 2.98 (dd, 1H, J 17.3, 4.9 Hz), 2.78-2.90 (m, 1H), 2.09 (ddd, 1H, J 17.1, 11.3, 2.9 Hz), 1.90-1.99 (m, 1H), 1.83-1.89 (m, 1H), 1.69-1.82 (m, 1H), 1.18 (d, 3H, J 6.8 Hz), 0.95-1.04 (m, 1H), 1.02 (d, 3H, J 6.6 Hz), 0.85-0.93 (m, 4H).

[0222] Intermediates 84 and 85 [ka] Intermediate 84 Ethyl 2-amino-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Intermediate 85 Ethyl 2-amino-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Morpholine [110-91-8] (1.2 mL, 14 mmol) was added to a suspension of 3-methylcyclohexanone [591-24-2] (1.1 mL, 8.7 mmol), sulfur [7704-34-9] (304 mg, 9.48 mmol) and ethyl cyanoacetate [105-56-6] (1.01 mL, 9.47 mmol) in EtOH (30 mL). The reaction was stirred at room temperature for 30 min and overnight at room temperature before being heated at 50 °C for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with EtOAc (20 mL) and washed with brine (2 x 20 mL). The organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (gradient elution from 1% to 10% EtOAc in isohexane) to give the title compound (1.78 g, 86%) as an off-white solid, which was a ca. 6:1 mixture of the two compound 5-:7-methyl isomers. The major 5-isomer intermediate 84:δ H (300 MHz, DMSO-d 6 ) 7.17 (s, 2H), 4.15 (qd, 2H, J 7.1, 0.6 Hz), 2.82 (ddd, 1H, J 17.3, 5.0, 0.7 Hz), 2.47-2.42 (m, 2H), 2.07 (ddt, 1H, J 17.2, 9.7, Minor 7-isomer intermediate 85: δ H (300 MHz, DMSO-d 6 ) 7.19 (s, 2H), 4.14 (q, 2H, J 7.1Hz), 2.70-2.60 (m, 2H), 1.92-1.61 (m, 3H), 1.59-1.50 (m, 1H), 1.24 (t, 3H, J 7.1Hz), 1.10 (d, 3H, J 6.8 Hz); one proton equivocal.

[0223] Intermediates 86 and 87 [ka] Intermediate 86 Ethyl 2-(cyclopropanecarbonylamino)-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Intermediate 87 Ethyl 2-(cyclopropanecarbonylamino)-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Cyclopropanecarbonyl chloride [4023-34-1] (0.76 mL, 8.2 mmol) was added to a solution of a 6:1 mixture of intermediate 84 and intermediate 85 (1.78 g, 7.42 mmol) and DIPEA (2.6 mL, 15 mmol) in DCM (20 mL) and the reaction was stirred for 1.5 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The mixture was passed through a phase separation cartridge and the organic phase was concentrated in vacuo. The crude product was purified by flash column chromatography on silica (gradient elution from 1% to 10% EtOAc in isohexane) to give the product which was recrystallized from EtOAc / isohexane to give the title compound (141 mg, 0.459 mmol) as a white solid as a 30:1 mixture of 5-:7-methyl isomers. The mother liquor was evaporated and redissolved in EtOAc and the product was seeded and allowed to crystallize overnight. The solid was washed with isohexane and dried under air to give further product (0.52 g) as a white solid, approximately 30:1 mixture of 5-:7-methyl isomers, which was a 30:1 mixture of the title compounds Intermediate 86 and 87 in total (0.66 g, 29%). The mother liquor was evaporated to a cream solid (1.495 g), approximately 4:1 mixture of 5-:7-methyl isomers. The main title compound, Intermediate 86:δ H (400 MHz, DMSO-d 6) 11.17 (s, 1H), 4.26-4.34 (m, 2H), 2.92 (dd, 1H, J 17.2, 5.1 Hz), 2.54-2.68 (m, 2H), 2.15-2.23 (m, 1H), 1.96-2.03 (m, 1H), 1.70-1.86 (m, 2H), 1.29-1.39 (m, 1H), 1.32 (t, 3H, J 7.1 Hz), 1.03 (d, 3H, J 6.6 Hz), 0.86-0.94 (m, 4H).

[0224] Intermediates 88 and 89 [ka] Intermediate 88 2-(Cyclopropanecarbonylamino)-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Intermediate 89 2-(Cyclopropanecarbonylamino)-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Lithium hydroxide monohydrate [1310-66-3] (240 mg, 3.20 mmol) in water (2 mL) was added to a 30:1 solution of intermediate 86 and intermediate 87 (623 mg, 2.03 mmol) in 1,4-dioxane (12 mL). The reaction mixture was heated to 70° C. and stirred overnight. The reaction was cooled to room temperature and concentrated in vacuo to give the crude product, which was treated with water (20 mL) and EtOAc (20 mL). 2M aqueous hydrochloric acid (5 mL) was added and the two phases were separated. The aqueous phase was extracted with EtOAc (20 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The resulting solid was partially dissolved in EtOAc and triturated with isohexane to give a red-brown powder which was washed with isohexane and dried under a stream of air to give the title compound (469 mg, 82%) as a ca. 30:1 mixture of the 5-Me product of Intermediate 88 and the 7-Me product of Intermediate 89. The major title compound, Intermediate 88:δ H (400 MHz, DMSO-d 6) 13.05 (s, 1H), 11.48 (s, 1H), 2.95 (dd, 1H, J 17.3, 5.0 Hz), 2.53-2.67 (m, 2H), 2.17 (dd, 1H, J 17.1, 10.0 Hz), 1.89-1.97 (m, 1H), 1.79-1.84 (m, 1H), 1.68-1.78 (m, 1H), 1.27-1.38 (m, 1H), 1.02 (d, 3H, J 6.6 Hz), 0.84-0.93 (m, 4H).

[0225] Intermediate 90 [ka] Ethyl 2-amino-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxylate To a solution of 3,3-dimethylcyclohexan-1-one [2979-19-3] (500 mg, 3.96 mmol) and ethyl cyanoacetate [105-56-6] (493 mg, 4.36 mmol) in EtOH (15 mL) was added morpholine [110-91-8] (0.5 mL, 5.9 mmol) followed by sulfur [7704-34-9] (140 mg, 4.4 mmol) and the resulting suspension was stirred at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 20 h and then heated to 50 °C for 4.5 h. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc (15 mL) and water (10 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 x 15 mL). The combined organic phase was washed with brine (10 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica (gradient elution with 0 to 50% EtOAc in heptane) followed by flash column chromatography on silica (gradient elution with 0 to 100% DCM in heptane) to afford the title compound (555 mg, 55%) as an off-white solid. δ H(500 MHz, chloroform-d) 5.89 (s, 2H), 4.27 (q, J 7.1 Hz, 2H), 2.61 - 2.39 (m, 4H), 1.54 (t, 2H, partially obscured by water), 1.34 (t, J 7.1 Hz, 3H), 0.98 (s, 6H). LCMS [M+H] + 254, RT 1.51 min, 100% purity (Method 6).

[0226] Intermediate 91 [ka] Ethyl 2-(cyclopropanecarbonylamino)-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxylate To a solution of intermediate 90 (250 mg, 0.99 mmol) and triethylamine (0.2 mL, 1.5 mmol) in DCM (5 mL) cooled to 0° C., cyclopropanecarbonyl chloride [4023-34-1] (0.12 mL, 1.28 mmol) was added and the solution was stirred under an atmosphere of nitrogen. After stirring for 15 min, the mixture was diluted with DCM (15 mL) and 1 M aqueous hydrochloric acid (10 mL) was added. The phases were separated and the aqueous phase was extracted with further DCM (10 mL). The combined organic phase was washed with brine (10 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo to give the title compound (400 mg, quantitative, 80% pure) as a light brown solid. H (500 MHz, chloroform-d) 11.46 (s, 1H), 4.34 (q, J 7.1 Hz, 2H), 2.64 (t, J 6.4 Hz, 2H), 2.55 (s, 2H), 1.69 - 1.61 (m, 1H), 1.59 - 1.50 (m, 2H, partially obscured by water peak), 1.40 (t, J 7.1 Hz, 3H), 1.17 - 1.10 (m, 2H), 0.98 (s, 6H), 0.95 - 0.88 (m, 2H). LCMS [M+H] + 322, [M+Na] +344, RT 1.66 min, 100% purity (Method 6).

[0227] Intermediate 92 [ka] 2-(Cyclopropanecarbonylamino)-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxylic acid To a suspension of intermediate 91 (320 mg, 1 mmol) in 1,4-dioxane (3 mL) and water (3 mL) was added lithium hydroxide monohydrate [1310-66-3] (84 mg, 2 mmol) and the mixture was heated to reflux. After heating for 2 h, the reaction mixture was concentrated in vacuo and the residue was diluted with water (2 mL). The solution was acidified to pH 4-5 with 0.2 M aqueous hydrochloric acid and the off-white precipitate was collected by filtration, washed with water and dried overnight in a vacuum oven at 40° C. to give the title compound (310 mg, quantitative) as an off-white solid. δ H (250 MHz, chloroform-d) 11.27 (s, 1H), 2.72 - 2.56 (m, 4H), 1.80 - 1.63 (m, 1H), 1.57 (t, J 6.3 Hz, 2H), 1.22 - 1.11 (m, 2H), 1.04 - 0.89 (m, 8H). LCMS [M+H] + 294, RT 1.37 min, purity 98% (Method 6).

[0228] Intermediate 93 [ka] Ethyl 2-amino-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylate To a solution of 5-methylcyclohexane-1,3-dione [4341-24-6] (2.46 g, 19.5 mmol, 2.66 mL) in EtOH (10 mL) was added ethyl cyanoacetate [105-56-6] (2.42 g, 21.4 mmol), sulfur [7704-34-9] (0.69 g, 21.4 mmol) and triethylamine (2.96 g, 29.2 mmol, 4.07 mL). The reaction was stirred at room temperature for 18 h and then heated to reflux for 3 days. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica (gradient elution with 0-30% EtOAc in hexanes) to give the title compound (1.28 g, 26%). δ H (400 MHz, DMSO-d 6 ) 8.20 (s, 2H), 4.24 (q, J 7.1 Hz, 2H), 3.23 (dd, J 17.8, 3.7 Hz, 1H), 2.48 - 2.30 (m, 2H), 2.30 - 2.13 (m, 2H), 1.29 (t, J 7.1 Hz, 3H), 1.06 (d, J 5.9 Hz, 3H).

[0229] Intermediate 94 [ka] Ethyl 2-(cyclopropanecarbonylamino)-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylate To a solution of intermediate 93 (1.28 g, 4.80 mmol) and triethylamine (1 mL, 7.18 mmol) in DCM (15 mL) at 0° C. was added cyclopropanecarbonyl chloride [4023-34-1] (0.6 ml, 6.61 mmol). The reaction mixture was stirred at 0° C. for 4 h and then diluted with DCM (20 mL). 1 M aqueous hydrochloric acid (20 mL) was added and the layers were separated. The aqueous phase was further extracted with DCM (2×10 mL) and washed with water (10 mL). The organic phase was separated and dried (MgSO 4), filtered and concentrated in vacuo to give the title compound (1.8 g, 99%, approx. 85% pure) as a red / brown solid which was used in the next step without further purification. H (500 MHz, chloroform-d) 11.73 (s, 1H), 4.41 (q, J 7.1 Hz, 2H), 3.41 - 3.28 (m, 1H), 2.63 - 2.57 (m, 1H), 2.54 (dd, J 17.7, 10.1 Hz, 1H), 2.41 - 2.32 (m, 1H), 2.27 (dd, J 16.0, 12.0 Hz, 1H), 1.70 (tq, J 8.8, 4.5 Hz, 1H), 1.43 (t, J 7.1 Hz, 3H), 1.24 - 1.18 (m, 2H), 1.16 (d, J 6.5 Hz, 3H), 1.06 - 0.96 (m, 2H).

[0230] Intermediate 95 [ka] 2-Amino-N-(cyclopropylmethyl)-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxamide Intermediate 94 (85% pure, 1.8 g, 4.76 mmol) was dissolved in a solution of MeOH (10 mL) and 2M aqueous NaOH (4.5 mL) and heated to reflux for 4 h. After cooling to room temperature, the mixture was allowed to stand over the weekend, then 4M aqueous NaOH (1.25 mL) was added and the mixture was heated to reflux for 4 h. The reaction mixture was cooled to room temperature and MeOH was removed in vacuo. The reaction mixture was acidified with 1M aqueous hydrochloric acid and the product was extracted with EtOAc (2×20 mL). The combined organic phase was washed with water (10 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo to give 2-amino-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid (1.4 g, 78%) as a dark brown solid which was used directly in the next step without further purification.

[0231] EDCI (640 mg, 3.34 mmol) was added to a solution of 1-cyclopropylmethanamine [2516-47-4] (0.29 mL, 3.34 mmol) and 2-amino-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid (500 mg, 2.22 mmol) in DCM (25 mL). After the solution was stirred at room temperature for 16 h, 1-cyclopropylmethanamine [2516-47-4] (0.29 mL, 3.34 mmol) was added followed by EDCI (640 mg, 3.34 mmol) and stirred for an additional 4 h. The reaction mixture was diluted with DCM and poured into 1 M aqueous hydrochloric acid (20 mL). The organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography on silica (gradient elution with 30-80% EtOAc / heptane) to give the title compound (210 mg, 27%, 80% purity) as a bright yellow solid. H (500 MHz, Chloroform-d) 5.67 (s, 1H), 3.30 - 3.24 (m, 2H), 3.05 (dd, J 15.3, 3.9 Hz, 1H), 2.61 (d, J 15.4 Hz, 1H), 2.54 - 2.38 (m, 2H), 2.36 - 2.26 (m, 1H), 1.19 (d, J 6.4 Hz, 3H), 1.07 (m, 1H), 0.58 (m, 2H), 0.28 (q, J 4.9 Hz, 2H).

[0232] Intermediate 96 [ka] 2-Amino-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide To a solution of N1-cyclopropylmethyl-2-cyanoacetamide [114153-25-2] (98%, 660 mg, 4.68 mmol) and cyclohexanone [108-94-1] (0.53 ml, 5.11 mmol) in EtOH (20 mL) was added morpholine [110-91-8] (0.61 ml, 7.05 mmol) and sulfur [7704-34-9] (165 mg, 5.15 mmol). The yellow reaction mixture was stirred at room temperature over the weekend and then heated to 60 °C for 4 h and then to 50 °C for 16 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc (30 mL) and washed with water (2 × 10 mL) followed by brine (10 mL). The organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (gradient elution with 30-60% EtOAc / heptane) followed by flash column chromatography on silica (gradient elution with 0-3% MeOH) to afford the title compound (400 mg, 27%) as a yellow solid; the material was used in the next step without further purification. TLC (1:1 EtOAc / heptane) DP Rf=0.34. δ H (500 MHz, DMSO-d 6 ) 6.79 (t, J 5.6 Hz, 1H), 6.59 (s, 2H), 3.10 - 3.03 (m, 2H), 2.58 (t, J 5.7 Hz, 2H), 2.45 (t, J 5.8 Hz, 2H), 1.78 - 1.62 (m, 4H), 1.05 - 0.95 (m, 1H), 0.43 - 0.36 (m, 2H), 0.22 - 0.16 (m, 2H).

[0233] Intermediate 97 [ka] Cyclopropylmethyl 2-cyanoacetate Cyanoacetic acid [372-09-8] (1.00 g, 12 mmol) was dissolved in cyclopropanemethanol [2516-33-8] (4.20 g, 58 mmol) and hydrochloric acid (42 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was heated to 90° C. for approximately 2 h, then cooled to room temperature and concentrated in vacuo. The crude product was partitioned between water and EtOAc and the organic phase was washed with saturated sodium bicarbonate and brine. The organic layer was concentrated in vacuo to give the title compound (1.58 g, 98%) as a pale yellow oil. δ H (300 MHz, DMSO-d 6 ) 4.03 (s, 2H), 3.96 (d, J 7.3 Hz, 2H), 1.16 - 1.02 (m, 1H), 0.58 - 0.49 (m, 2H), 0.34 - 0.25 (m, 2H).

[0234] Intermediates 98 and 99 [ka] Cyclopropylmethyl 2-amino-5-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Cyclopropylmethyl 2-amino-7-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate 3-N-Boc-aminocyclohexanone [885280-38-6] (2.55 g, 11.4 mmol) was dissolved in 1,4-dioxane (20 mL). Intermediate 97 (1.58 g, 11.4 mmol), morpholine [110-91-8] (1.50 g, 17.0 mmol) and sulfur [7704-34-9] (0.40 g, 12.5 mmol) were added and the reaction mixture was stirred at room temperature for about 2 hours. The mixture was heated at 60° C. for about 3 hours, then at room temperature overnight, followed by heating at 70° C. for an additional 4 hours, then at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica (gradient elution with 5-50% EtOAc / hexanes) to give the 5-isomer intermediate 98 of the title compound (2.34 g, 56%) and the 7-isomer intermediate 99 of the title compound (0.73 g, 18%). Intermediate 98 of the title compound: LCMS [M+H] + 367.2, [M+Na] + 389.2, RT 2.424 min, purity 88.8% (Method 1). Title compound intermediate 99: δ H (400 MHz, DMSO-d 6 ) 7.38 - 7.05 (m, 3H), 4.44 (s, 1H), 3.97 (dd, J 7.3, 3.3 Hz, 2H), 2.58 (s, 2H), 1.96 - 1.74 (m, 2H), 1.69 - 1.57 (m, 2H), 1.40 (d, J 3.89 Hz, 9H), 1.22 - 1.09 (m, 1H), 0.58 - 0.43 (m, 2H), 0.38 - 0.23 (m, 2H).

[0235] Intermediate 100 [ka] Cyclopropylmethyl 5-(tert-butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Intermediate 98 (2.34 g, 6.37 mmol) was dissolved in DCM (50 mL) and DIPEA (1.65 g, 12.75 mmol) and cyclopropanecarbonyl chloride [4023-34-1] (0.75 g, 7.01 mmol) were added. The reaction mixture was stirred at room temperature for about 4 h. The reaction mixture was washed with water and brine, passed through a phase separation cartridge and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient elution with 5-50% EtOAc / Hexanes) to give the product as an off-white solid, which was recrystallized from EtOAc / Hexanes to give the title compound (1.8 g, 65%) as white needles. LCMS [M+H] + 435.2, RT 2.968 min, purity 100.0% (Method 3). LCMS [M+H] + 435.2, RT 2.945 minutes, purity 100.0% (Method 2).

[0236] Intermediate 101 [ka] Cyclopropylmethyl 5-amino-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Intermediate 100 (1.80 g, 4.14 mmol) was dissolved in DCM (12 mL) and TFA (11.95 g, 104.8 mmol) was added. The reaction mixture was stirred at room temperature for about 1 h and then concentrated in vacuo. The residue was partitioned between 5% MeOH / DCM and saturated sodium bicarbonate solution. The organic phase was washed with brine, passed through a phase separation cartridge and the organic layer was concentrated in vacuo to give the title compound (1.40 g, 101%). LCMS [M+H] + 335.0, RT 1.402 minutes, purity 100.0% (Method 4).

[0237] Intermediates 102 and 24 [ka] Intermediate 102 Ethyl 2-amino-7-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate Intermediate 102a Ethyl 2-amino-5-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate To a mixture of tert-butyl N-(3-oxocyclohexyl)carbamate [885280-38-6] (4 g, 18.7 mmol), sulfur [7704-34-9] (0.722 g, 22.5 mmol) and ethyl cyanoacetate [105-56-6] (2.75 g, 24 mmol) in EtOH (40 mL) was added triethylamine (5.22 ml, 37.5 mmol). After stirring at room temperature for 16 h, the reaction mixture was concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The combined organic phase was washed with brine and dried (MgSO 4 ), filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica (gradient elution with 5% to 40% EtOAc in heptane) to give the 7-isomer of the title compound intermediate 102 (700 mg, 11%) and the 5-isomer of the title compound intermediate 102a (4.5 g, 70%) as white solids. H (500 MHz, CD 3 OD) 4.29 - 4.16 (m, 2H), 3.75 - 3.65 (m, 1H), 3.10 (dd, J 17.0, 5.0 Hz, 1H), 2.66 - 2.51 (m, 2H), 2.44 (dd, J 17.1, 9.2 Hz, 1H), 2.05 - 1.93 (m, 1H), 1.73 - 1.63 (m, 1H), 1.46 (s, 9H), 1.32 (t, J 7.1 Hz, 3H). LCMS [M+H] + 341.10, [M+Na] + 361.10, RT 1.35 min, 100% purity (Method 6). 5-isomeric title compound intermediate 102a: δ H (500 MHz, CD 3OD) 4.58 - 4.48 (m, 1H), 4.22 (q, J 7.1 Hz, 2H), 2.76 - 2.58 (m, 2H), 2.01 - 1.92 (m, 1H), 1.92 - 1.80 (m, 1H), 1.77 - 1.64 (m, 2H), 1.46 (s, 9H), 1.32 (t, J 7.1 Hz, 3H). LCMS [M+H] + 341, [M+Na] + 363.10, RT 1.38 min, purity 98% (Method 6).

[0238] Intermediate 103 [ka] Ethyl 7-(tert-butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate To a solution of a mixture of intermediate 102 (710 mg, 2.08 mmol) and DIPEA (0.72 ml, 4.17 mol) in DCM (20 mL) was added cyclopropanecarbonyl chloride [4023-34-1] (0.28 mL, 3.12 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then diluted with DCM (30 mL). Water (20 mL) was added, the layers were separated, extracted with DCM (2×10 mL), washed with 0.5 M aqueous hydrochloric acid (20 mL), saturated sodium bicarbonate solution (20 mL) and brine. The organic phase was separated and dried (MgSO 4 ), filtered and concentrated in vacuo to give the title compound (850 mg, 100%) as a pale yellow solid, which was used in the next step without further purification. H (500 MHz, CD 3OD) 4.73 - 4.67 (m, 1H), 4.36 (q, J 7.1 Hz, 2H), 2.85 - 2.71 (m, 2H), 2.06 - 1.89 (m, 2H), 1.86 - 1.80 (m, 1H), 1.79 - 1.68 (m, 2H), 1.47 (s, 9H), 1.38 (t, J 7.1 Hz, 3H), 1.05 - 1.01 (m, 2H), 1.00 - 0.95 (m, 2H). LCMS [M+Na] + 431.10, RT 1.56 min, purity 92% (Method 6).

[0239] Intermediate 104 [ka] 7-(tert-butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid Intermediate 103 (850 mg, 2.08 mmol) was dissolved in 1,4-dioxane (20 mL) and 2M lithium hydroxide monohydrate [1310-66-3] (2.6 mL, 5.2 mmol) was added. The reaction mixture was heated at 90° C. for 2 h. 1,4-dioxane was removed in vacuo and the residue was acidified with 0.5 M aqueous hydrochloric acid. The resulting solid was filtered off to give the title compound (710 mg, 90%), which was dried and used in the subsequent step without further purification. δ H (500 MHz, CD 3 OD) 4.75 - 4.61 (m, 1H), 2.90 - 2.74 (m, 2H), 2.09 - 1.86 (m, 2H), 1.84 - 1.65 (m, 3H), 1.47 (s, 9H), 1.06 - 0.91 (m, 4H). LCMS [M+Na] + 403.05, RT 1.3 min, 95% purity (Method 6).

[0240] Intermediates 105 and 106 [ka] Intermediate 105 Ethyl 2-amino-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylate Intermediate 106 Ethyl 2-amino-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate To a mixture of ethyl 3-oxocyclohexanecarboxylate [33668-25-6] (1.50 g, 8.81 mmol), sulfur [7704-34-9] (367 mg, 11.4 mmol) and N1-cyclopropylmethyl-2-cyanoacetamide [114153-25-2] (1.46 g, 10.58 mmol) in EtOH (15 mL) was added triethylamine (2.45 ml, 17.63 mmol). The reaction mixture was stirred at room temperature for 5 h and then heated at 60° C. for 24 h. The reaction mixture was concentrated in vacuo, water was added and the solution was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient elution with 5% to 70% EtOAc in heptane) to give the title compound (653 mg, 23%) as a mixture of regioisomers (5-isomer Intermediate 106 and 7-isomer Intermediate 105 in a ratio of 80:20). LCMS [M+H] + 323.05, RT 1.25 minutes (Method 6). Intermediates 105 and 106 were simultaneously developed by LCMS, 1 Both were observed by 1 H NMR.

[0241] Intermediates 107 and 108 [ka] Intermediate 107 Ethyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylate Intermediate 108 Ethyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate To a solution of a mixture of intermediates 105 and 106 (20:80 ratio) (653 mg, 2.02 mmol) and DIPEA (0.71 mL, 4.05 mmol) in DCM (30 mL) at 0° C. was added cyclopropanecarbonyl chloride [4023-34-1] (0.28 mL, 3.08 mmol). The reaction was stirred at room temperature for 2 h and then diluted with DCM (50 mL). Water (50 mL) was added and the layers were separated. The aqueous phase was extracted with DCM (2×50 mL) and washed with 0.5 M aqueous hydrochloric acid (50 mL), saturated sodium bicarbonate solution (50 mL) and brine. The organic layer was separated and dried (MgSO 4 ), filtered and concentrated in vacuo to give a pale yellow solid as a mixture of regioisomers, which was purified by flash column chromatography on silica (gradient elution with 55 to 50% EtOAc in heptane) to give the title compounds as a mixture of 80% 5-isomer of intermediate 108 and 20% 7-isomer of intermediate 107 (600 mg, 76%) as a white solid. LCMS [M+H] + 391.0, RT 1.40 min, 100% purity (Method 6).

[0242] Intermediates 109 and 110 [ka] Intermediate 109 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid Intermediate 110 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid Intermediate 107 and intermediate 108 (20:80 ratio) (600 mg, 1.53 mmol) were dissolved in THF (10 mL) and then 2M aqueous lithium hydroxide [1310-66-3] (2.3 mL, 4.6 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours and THF was removed in vacuo. The residue was acidified with 1M aqueous hydrochloric acid and the resulting solid (75% 5-isomer intermediate 110 and 22% 7-isomer intermediate 109) was filtered off and dried. The mixture was separated by preparative HPLC to give the 5-isomer title compound intermediate 110 (218 mg, 49%) and the 7-isomer title compound intermediate 109 (58.5 mg, 12%) with 6% of the 5-isomer title compound intermediate 110 in 92% purity. 5-isomer title compound intermediate 110: LCMS [M+H] + 363.1, RT 2.78 min, 100% purity (Method 10). 7-isomeric title compound Intermediate 109: LCMS [M+H] + 363.1, RT 2.90 min, 92% purity, 6% of 5-regioisomer present (Method 10).

[0243] Intermediate 111 [ka] 3-(1-Tetrahydropyran-2-ylpyrazol-3-yl)cyclohexanone Hydroxy(cyclooctadiene)rhodium(I) dimer [73468-85-6] (12 mg, 0.025 mmol) and degassed 1,4-dioxane (1.2 mL) were stirred at room temperature for 15 min. Potassium phosphate tribasic acid [7778-53-2] (4 mmol, 2 mL) was added and the mixture was stirred for 15 min. 2-Cyclohexen-1-one [930-68-7] (1.01 mmol, 100 mg) and 1-(tetrahydro-2H-pyran-2-yl)-3-pyrazoleboronic acid MIDA ester (1.21 mmol, 383 mg) were added and the mixture was stirred at 60° C. overnight. The mixture was warmed at 70° C. overnight. The mixture was concentrated in vacuo and the crude product in water was dissolved in Et 2Extraction with 0 (2 x 3 mL) and DCM (2 x 3 mL). The organic phases were combined and concentrated in vacuo to give the crude product, which was purified by preparative TLC (silica plate) (eluted with hexane / EtOAc 6 / 4). The compound was extracted with EtOAc (100 mL) to give the title compound (22 mg, 8.7%) as a yellow oil. GCMS [M+H] + 248.96, RT 14.31 minutes.

[0244] Intermediate 112 [ka] 2-Amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid 2M aqueous NaOH (91 mL, 182 mmol) was added to a suspension of 2-amino-4,5,6,7-tetrahydro-benzo[B]thiophene-3-carboxylic acid methyl ester [108354-78-5] (13.1 g, 60.8 mmol) in EtOH (100 mL). The reaction mixture was heated to 60° C. and stirred for 4 h. The temperature was increased to 80° C. (reflux) and the reaction was stirred overnight. The reaction was stirred at 80° C. for a further 7 h, then cooled to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to remove EtOH. The aqueous solution was washed with DCM (3×200 mL) and then acidified to pH 2 with concentrated hydrochloric acid. A brown solid formed which was filtered off, washed with water then hexane and dried to give the title compound (7.55 g, 63%) as a dark brown solid. δ H (400 MHz, DMSO-d 6 ) 11.8 (br. s, 1H), 7.16 (s, 2H), 2.57 - 2.61 (m, 2H), 2.40 - 2.44 (m, 2H), 1.63 - 1.72 (m, 4H).

[0245] Intermediate 113 [ka] 2-Amino-N-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide EDCI (5.0 g, 26 mmol) was added to a solution of Intermediate 112 (4 g, 20.28 mmol), 1-hydroxybenzotriazole hydrate (3.52 g, 22.3 mmol), DIPEA (14.5 mL, 83.2 mmol) and a 2 M solution of methylamine in THF (31 mL, 62 mmol) in DMF (100 mL) and the reaction was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (100 mL) and water (100 mL) and the organic layer was separated. The organic layer was washed with brine (2×100 mL), filtered to remove an insoluble dark brown solid and dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude product was dissolved in DCM and purified by flash column chromatography on silica (gradient elution from 10% to 40% EtOAc in isohexane). The product was recrystallized from EtOAc / isohexane to give the title compound (1.32 g, 31%) as a brown solid. δ H (300 MHz, DMSO-d 6 ) 6.67 - 6.73 (m, 1H), 6.64 (s, 2H), 2.68 (d, J 4.6 Hz, 3H), 2.53 - 2.58 (m, 2H), 2.42 - 2.47 (m, 2H), 1.62 - 1.74 (m, 4H).

[0246] Intermediate 114 [ka] tert-Butyl N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate To a stirred solution of intermediate 26 (12 g, 31.6 mmol) and cyclopropylmethanamine [2516-47-4] (3.36 g, 47.4 mmol) in DCM (80 mL) was added triethylamine (9.57 g, 94.7 mmol) and EDCI (15.2 g, 78.9 mmol) and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water and extracted with DCM. The organic phase was separated, washed with brine and dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude product obtained was purified by flash column chromatography on silica (eluted with 10% EtOAc / n-hexane) to give the title compound (5.5 g, 40%). δ H (400 MHz, chloroform-d) 12.16 (s, 1H), 5.89 (s, 1H), 4.70 (s, 1H), 4.10 (s, 1H), 3.33 - 3.20 (m, 2H), 3.14 (dd, J 14.6, 5.0 Hz, 1H), 2.77 (d, J 17.3 Hz, 2H), 2.62 - 2.57 (m, 1H), 2.04-2.02 (m, 1H), 1.90-1.84 (m, 1H), 1.73 - 1.60 (m, 1H), 1.48 (s, 9H), 1.46 - 1.36 (m, 1H), 1.04- 0.96 (m, 2H), 0.90-0.89 (m, 2H), 0.61-0.57 (m, 2H), 0.28 - 0.23 (m, 2H).

[0247] Intermediates 115 and 116 [ka] Intermediate 115 tert-Butyl N-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate Intermediate 116 tert-Butyl N-[(5R)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate Intermediate 114 (250 g) was purified by chiral preparative HPLC (Chiralpak AD, 50 × 252 mm, 30 °C, 360 ml / min, CO 2 +35% MeOH) to give the two enantiomers intermediate 115 (126 g) and intermediate 116 (122 g). Intermediate 115 contained about 2% of tert-butyl N-[(5S)-2-(cyclopropanecarbonylamino)-3-(isobutylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate as an impurity, which was obtained from the 2-methylpropan-1-amine impurity in the cyclopropylmethanamine used in the preparation of intermediate 114. Intermediate 115 δ H (300 MHz, DMSO-d 6 ) 11.06 (s, 1H), 7.70 (t, J 5.6 Hz, 1H), 6.94 (d, J 7.5 Hz, 1H), 3.60 (s, 1H), 3.13 (ddq, J 19.8, 13.4, 6.6, 6.0 Hz, 2H), 2.88 (dd, J 16.1, 5.1 Hz, 1H), 2.79 - 2.58 (m, 2H), 2.48 - 2.39 (m, 1H), 1.98 - 1.82 (m, 2H), 1.80 - 1.57 (m, 1H), 1.39 (s, 9H), 1.14 - 0.93 (m, 1H), 0.90 - 0.70 (m, 4H), 0.48 - 0.34 (m, 2H), 0.30 - 0.15 (m, 2H). LCMS [M+H] + 434.0, RT 2.43 min (Method 2). LCMS [M+H] + 434.0, RT 2.37 min (Method 3). Intermediate 116 LCMS [M+H] + 434.0, RT 2.44 min (Method 2). LCMS [M+H] + 434.0, RT 2.36 minutes (Method 3).

[0248] Intermediate 117 [ka] (5S)-5-Amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide To a stirred solution of intermediate 115 (20 g, 43.1 mmol) in DCM (100 mL) was added TFA (67 ml, 876 mmol) dropwise over 15 min, maintaining the temperature below 25° C. The reaction mixture was stirred at room temperature for a further 15 min. Toluene (120 mL) was added and the solvent was removed in vacuo. EtOAc (40 mL) was added to the residue followed by diisopropyl ether (1.4 L) to precipitate the product. The slurry was stirred at room temperature for a further 15 min and the precipitate was collected by filtration. The filter cake was washed with diisopropyl ether (180 mL) and Et 2 The precipitate was dissolved in water (800 mL) containing TFA (4 mL) and concentrated to give the crude product (25.4 g) as a beige solid after rinsing with EtO (180 mL) and drying under a stream of nitrogen for 15 min. 2 200 mL of HO and EtOAc (20 mL) were added. The aqueous phase was separated and 2 The organic extracts were combined, dried (NaCl), and washed with 2×O (100 mL). Potassium carbonate (10.2 g, 36.9 mmol) was added and the aqueous phase was extracted with EtOAc (2×400 mL). The aqueous phase was saturated with sodium chloride (250 g) and then further extracted with EtOAc (400 mL). The organic extracts were combined, dried (Na 2 SO 4 ), filtered and the solvent removed in vacuo to give the title compound (14.8 g, 93%) as a beige solid. H(500 MHz, chloroform-d) 12.07 (s, 1H), 6.01 (t, J 5.0 Hz, 1H), 3.34 - 3.23 (m, 3H), 3.04 (dd, J 14.5, 4.8 Hz, 1H), 2.86 - 2.57 (m, 4H), 2.53 (dd, J 14.5, 8.2 Hz, 1H), 2.08 - 2.01 (m, 1H), 1.79 - 1.69 (m, 1H), 1.69 - 1.62 (m, 1H), 1.12 - 1.03 (m, 3H), 0.91 - 0.85 (m, 2H), 0.61 - 0.50 (m, 2H), 0.32 - 0.21 (m, 2H).

[0249] Intermediate 118 [ka] (5S)-5-[[benzyl(2,2-dimethylpropyl)carbamothioyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide To a solution of intermediate 117 (400 mg, 1.20 mmol) in DCM (20 mL) was added DIPEA (234 mg, 1.80 mmol) and phenyl chlorothionocarbonate [1005-56-7] (230 mg, 1.32 mmol). The reaction mixture was stirred for 2 h. DIPEA (239 mg, 1.84 mmol) and N-benzyl-2,2-dimethyl-propan-1-amine (217 mg, 1.23 mmol) were added and the reaction was stirred for 18 h. Water (10 mL) was added to the reaction mixture and the organic layer was separated and passed through a phase separation column. The organic phase was concentrated in vacuo to give a yellow solid which was purified by flash column chromatography on silica (gradient elution with 0-45% EtOAc / isohexane) to give the title compound (539 mg, 80%) as a yellow foam. LCMS [M+H] + 553.0, RT 3.339 minutes, purity approximately 77% (Method 1).

[0250] Intermediate 119 [ka] (5S)-5-[3-[benzyl(2,2-dimethylpropyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide Intermediate 118 (516 mg, 0.93 mmol) was dissolved in DMF (10 mL) and formic hydrazide [624-84-0] (125 mg, 1.87 mmol) was added followed by mercuric chloride [7487-94-7] (507 mg, 1.87 mmol) and finally triethylamine (190 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 2 min and then heated at 60 °C for 3 h. The mixture was cooled, diluted with MeCN (10 mL) and then filtered through a plug of Celite. The Celite pad was washed with excess MeCN (20 mL) and the filtrates were combined and concentrated in vacuo to give a yellow oil. The crude material was purified by flash column chromatography on silica (gradient elution with 0-5% MeOH / EtOAc) to give the title compound (150 mg, 29%) as a white solid. LCMS [M+H] + 561.0, RT 2.936 minutes (Method 1).

[0251] Intermediate 120 [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2,5-dimethylpyrazol-3-yl)carbamothioylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide To a stirred solution of intermediate 117 (33.7 g, 101 mmol) in DCM (300 mL) was added DIPEA (27 mL, 150 mmol) followed by 5-isothiocyanato-1,3-dimethyl-1H-pyrazole [205246-65-7] (23 g, 150 mmol) in DCM (50 mL) and the reaction mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated in vacuo to give the crude product as a tan solid, which was stirred in DCM (100 mL) for 1 h. Et 2 2O (150 mL) was added and the resulting solid was filtered and washed with Et 2 O (100 mL×2) and dried in vacuum to give the title compound (52 g, 100%) as an off-white solid. H (300 MHz, DMSO-d 6 ) 11.09 (s, 1H), 9.11 (s, 1H), 7.95 (d, J 7.5 Hz, 1H), 7.75 (m, 1H), 5.92 (s, 1H), 4.53 (m, 1H), 3.53 (s, 3H), 3.14 (t, J 6.2 Hz, 2H), 3.05 (m, 1H), 2.79 - 2.56 (m, 3H), 2.09 (s, 3H), 2.05 - 1.80 (m, 3H), 1.11 - 0.95 (m, 1H), 0.93 - 0.74 (m, 4H), 0.50 - 0.36 (m, 2H), 0.32 - 0.16 (m, 2H).

[0252] Intermediate 121 [ka] 3-Cyano-1,2-diphenyl-isourea To a solution of aniline [62-53-3] (500 mg, 5.37 mmol) in 2-propanol, diphenyl N-cyanocarbonimidate [79463-77-7] (1.00 g, 6 mmol) and DIPEA (1.0 g, 8 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. The resulting white solid was filtered, washed with hexane, and the solid was dried in vacuum to give the title compound (1.0 g, 100%) as a white powder. LCMS [M+H]+ 238.0, RT 1.313 minutes, purity 100.0% (Method 4).

[0253] Intermediate 122 [ka] 5-Amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; hydrochloride To a solution of intermediate 114 (90% pure, 1.4 g, 2.91 mmol) in 1,4-dioxane (15 mL) was added 4M hydrogen chloride in 1,4-dioxane (11 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the mixture was dissolved in 1,4-dioxane (10 mL). Then further 4M hydrogen chloride in 1,4-dioxane (5 mL) was added. After stirring at room temperature for 3 h, the solvent was removed in vacuo to give the title compound (1.2 g, 95%, 85% pure) as a beige solid. δ H (500 MHz, CD 3 OD) 3.62 - 3.54 (m, 1H), 3.24 (dd, J 7.0, 3.0 Hz, 2H), 3.18 - 3.12 (m, 1H), 2.91 - 2.85 (m, 2H), 2.80 - 2.71 (m, 1H), 2.30 - 2.20 (m, 1H), 2.01 - 1.91 (m, 1H), 1.85 - 1.78 (m, 1H), 1.14 - 1.05 (m, 1H), 1.02 - 0.96 (m, 2H), 0.96 - 0.90 (m, 2H), 0.59 - 0.50 (m, 2H), 0.32 - 0.26 (m, 2H). LCMS [M+H] + 334.1, RT 0.88 min, purity 85% (Method 6).

[0254] Intermediate 123 [ka] (5S)-5-[[benzyl(isobutyl)carbamothioyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide To a solution of intermediate 117 (400 mg, 1.20 mmol) in DCM (20 mL) was added DIPEA (234 mg, 1.80 mmol), phenyl chlorothionocarbonate [1005-56-7] (230 mg, 1.32 mmol) and the reaction mixture was stirred for 2 h. DIPEA (238.7 mg, 1.838 mmol) and N-benzyl-2-methyl-propan-1-amine [42882-36-0] (200 mg, 1.225 mmol) were added and the reaction mixture was stirred for 18 h. Water (10 mL) was added to the reaction mixture and the organic layer was separated and passed through a phase separation column. The organic phase was concentrated in vacuo to give the crude material as a yellow solid which was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc / isohexane) to give the title compound (617 mg, 93%) as a yellow solid. LCMS [M+H] + 539.0, RT 3.24 minutes (Method 1).

[0255] Intermediate 124 [ka] (5S)-5-[3-[benzyl(isobutyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide Intermediate 123 (616 mg, 1.143 mmol) was dissolved in DMF (10 mL) and formic hydrazide [624-84-0] (153 mg, 2.29 mmol) was added followed by mercuric chloride [7487-94-7] (621 mg, 2.29 mmol) and finally triethylamine (233 mg, 2.29 mmol). The reaction mixture was stirred at room temperature for 2 min and then heated at 60 °C for 4 h. The reaction mixture was cooled, diluted with MeCN (10 mL), filtered through Celite and washed with MeCN (20 mL). The filtrate was concentrated in vacuo to give the crude product as a yellow solid which was triturated with EtOAc and filtered. The filtrate was concentrated in vacuo to give a yellow oil which was purified by flash column chromatography on silica (gradient elution with 0-5% MeOH / EtOAc) to give the title compound (270 mg, 43%) as a white solid. LCMS [M+H] + 547.0, RT 2.83 minutes (Method 1).

[0256] Intermediate 125 [ka] (5S)-5-[[benzyl-[(1-methylcyclopropyl)methyl]carbamothioyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide Phenyl chloromethanethioate [1005-56-7] (0.46 mL, 3.3 mmol) was dissolved in DCM (15 mL) with stirring and cooled to 0° C. Intermediate 117 (1 g, 3 mmol) and triethylamine (1.25 mL, 9 mmol) in DCM (15 mL) were added dropwise and the reaction was stirred at 0° C. for 30 min. Benzyl[(1-methylcyclopropyl)methyl]amine (97%, 1.01 g, 5.61 mmol) in DCM (10 mL) was added and the reaction was stirred at room temperature for 2 h. The reaction was stirred for 18 h before being diluted with water (40 mL) and extracted with DCM (3×30 mL). The organic phase was washed with brine and dried (Na 2 SO 4), filtered and concentrated in vacuo to give a brown oil which was purified by flash column chromatography on silica (gradient elution with 0 to 100% EtOAc in heptane). The product-containing fractions were combined and washed with 0.5 M aqueous citric acid (2 × 25 mL) and the organic layer was dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the title compound (1.56 g, 94%) as a white solid. H (500 MHz, DMSO-d 6 ) 11.01 (s, 1H), 7.70 (t, J 5.6 Hz, 1H), 7.31 (t, J 7.4 Hz, 2H), 7.28 - 7.22 (m, 2H), 7.20 (d, J 7.3 Hz, 2H), 5.21 - 5.06 (m, 2H), 4.74 - 4.60 (m, 1H), 3.65 - 3.46 (m, 2H), 3.17 (dt, J 12.7, 6.1 Hz, 1H), 3.10 (dt, J 13.4, 6.0 Hz, 1H), 3.03 (dd, J 15.7, 5.0 Hz, 1H), 2.71 - 2.65 (m, 2H), 2.59 (dd, J 15.7, 9.3 Hz, 1H), 2.03 - 1.95 (m, 1H), 1.95 - 1.87 (m, 1H), 1.87 - 1.78 (m, 1H), 1.04 - 0.96 (m, 4H), 0.89 - 0.78 (m, 4H), 0.44 - 0.38 (m, 2H), 0.39 - 0.31 (m, 2H), 0.32 - 0.27 (m, 2H), 0.24 - 0.17 (m, 2H).

[0257] Intermediate 126 [ka] (5S)-5-[3-[benzyl-[(1-methylcyclopropyl)methyl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide Intermediate 125 (735 mg, 1.33 mmol) was dissolved in DMF (10 mL) and formic hydrazide [624-84-0] (240 mg, 4 mmol) was added followed by mercuric chloride [7487-94-7] (1.09 g, 4 mmol). The reaction was stirred at room temperature for 5 min and triethylamine (0.56 mL, 4.00 mmol) was added. The reaction was heated to 90 °C with stirring for 2 h. Further formic hydrazide [624-84-0] (200 mg) was added and the reaction was heated at 90 °C for 18 h. The reaction was cooled, diluted with DCM, Kieselguhr was added and the mixture was filtered through a plug of Kieselguhr, washing through with DCM. The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with saturated ammonium chloride solution (40 mL), water (40 mL), saturated ammonium chloride solution (40 mL) and brine. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The orange residue was purified by flash column chromatography on silica (gradient elution with 0-10% MeOH in DCM) to give the title compound (485 mg, 41% with 64% UV purity) as a yellow foam, which contained 31% urea starting material. LCMS [M+H] + 559.2, RT 1.986 min, purity 64% (Method 12).

[0258] Intermediate 127 [ka] Methyl N-(cyanomethyl)methanimidate To a stirred solution of potassium carbonate (1.74 g, 12.6 mmol) in water (2 mL) was added cyanomethanaminium chloride [6011-14-9] (2.3 g, 25.1 mmol) in portions with stirring. The aqueous mixture was extracted with EtOAc (5 x 30 mL). The organic phases were combined, dried (potassium carbonate), filtered, and the solvent removed in vacuo to give the free base (766 mg, 54%) as a pale yellow oil which was used without further purification. The oil was diluted with trimethyl orthoformate [149-73-5] (2 mL) and the solution was diluted with Na 2 SO 4 (2.0 g) and sulfuric acid (1 drop) in trimethyl orthoformate [149-73-5] (18 mL) was added dropwise over 5 min. Stirring was continued for an additional 30 min, by which point the reaction had turned yellow-orange in color. The mixture was concentrated in vacuo to give the title compound (894 mg, 31%) as an orange oil. δ H (500 MHz, DMSO-d 6 ) 7.91 (s, 1H), 4.37 (d, J 0.9 Hz, 2H), 3.65 (s, 3H) [purity approximately 85%w / w].

[0259] Intermediate 128 [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(5-methyl-3-pyridyl)carbamothioylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide Intermediate 117 (200 mg, 0.60 mmol) was dissolved in DCM (10 mL) and DIPEA (117 mg, 0.90 mmol) was added followed by 3-isothiocyanato-5-methyl-pyridine (135 mg, 0.90 mmol). The reaction was stirred for 2 h before being concentrated in vacuo to give the crude product which was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc / isohexane) to give the title compound (290 mg, 100%) as a white solid. LCMS [M+H]+ 483.9, RT 1.348 min, purity 100.0% (Method 4).

[0260] Intermediate 129 [ka] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(4-pyridylcarbamothioylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide To a solution of pyridin-4-amine [90-25-5] (0.4 ml, 5.31 mmol) in THF (10 mL) was added di-1H-imidazol-1-ylmethanethione [6160-65-2] (1.14 g, 6.38 mmol) portionwise at 0° C. DCM (10 mL) was added and the mixture was allowed to warm to room temperature and stirred for 18 h. Intermediate 117 (1.75 g, 5.25 mmol) in DCM (10 mL) was added to the reaction mixture and the mixture was allowed to stir at room temperature for 18 h. The mixture was diluted with DCM (20 mL), filtered and the filtrate was concentrated in vacuo to give the crude product which was purified by flash column chromatography on silica (gradient elution from 0% to 100% EtOAc in heptane, 0-50% MeOH in DCM) to give the title compound (900 mg, 60%) as a brown solid. LCMS [M+H] + 468.20 / 470.20, RT 1.67 min, purity 84% (Method 12).

[0261] Intermediate 130 [ka] 3-Cyano-1-(3,4-dimethoxyphenyl)-2-phenyl-isourea Diphenyl N-cyanocarbonimidate [79463-77-7] (200 mg, 0.81 mmol) and 3,4-dimethoxyaniline [6315-89-5] (137 mg, 0.89 mmol) were dissolved in DCM (2 mL), 2-propanol (2 mL) and DIPEA (159 mg, 1.22 mmol) were added, and the reaction mixture was stirred at room temperature for about 1 h. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica (gradient elution with 15-100% EtOAc / hexanes) to give the title compound (198 mg, 82%) as a white solid. δ H (300 MHz, DMSO-d 6 ) 10.65 (s, 1H), 7.51 - 7.37 (m, 2H), 7.36 - 7.22 (m, 3H), 7.09 (d, J 1.8 Hz, 1H), 7.03 - 6.91 (m, 2H), 3.75 (s, 6H).

[0262] Intermediate 131 [ka] Ethyl 2-amino-2-cyanoacetate Ethyl (2E)-cyano(hydroxyimino)ethanoate [3849-21-6] (5 g, 35.2 mmol) was suspended in water (30 mL) and the reaction mixture was stirred. Saturated aqueous sodium bicarbonate (36 mL) was added slowly in portions to give an orange solution (pH = 5). Sodium dithionite [7631-94-9] (85%, 17 g, 83.0 mmol) was added in portions over 20 min and the reaction was stirred for an additional 30 min (the temperature of the solution rose to 39 °C). The reaction was extracted with DCM (4 x 50 mL) and the organics were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the title compound (2.82 g, 53% at 85% purity) as a red / brown oil which was stored in the refrigerator. H(250 MHz, chloroform-d) 4.44 (s, 1H), 4.34 (q, J 7.1 Hz, 2H), 2.55 (s, 2H), 1.35 (t, J 7.1 Hz, 3H.

[0263] Intermediate 132 [ka] (5S)-5-[[benzyl(2-morpholinoethyl)carbamothioyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide To a solution of intermediate 117 (400 mg, 1.20 mmol) in DCM (20 mL) was added DIPEA (234 mg, 1.80 mmol) and phenyl chlorothionocarbonate [1005-56-7] (230 mg, 1.32 mmol) and the solution was stirred for 2 h. DIPEA (239 mg, 1.84 mmol) and N-benzyl-2-morpholino-ethanamine [2038-05-3] (270 mg, 1.23 mmol) were added and the reaction was stirred for 18 h. Water (10 mL) was added to the reaction mixture and the organic layer was separated and passed through a phase separation column. The organic phase was concentrated in vacuo to give a yellow solid which was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc / isohexane) to give the title compound (505 mg, 69%) as a yellow gum. LCMS [M+H] + 596.0, RT 2.75 min, purity 80.1% (Method 1).

[0264] Intermediate 133 [ka] (5S)-5-[3-[benzyl(2-morpholinoethyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide Intermediate 132 (758 mg, 1.27 mmol) was dissolved in DMF (10 mL) and formic acid hydrazide [624-84-0] (153 mg, 2.29 mmol) was added followed by mercuric chloride [7487-94-7] (621 mg, 2.29 mmol) and finally triethylamine (233 mg, 2.29 mmol). The mixture was stirred at room temperature for 2 min and then heated at 80° C. for 5 h. The mixture was cooled and diluted with MeCN (10 mL) and then filtered through a plug of Celite, which was washed with excess MeCN (20 mL). The reaction mixture was concentrated in vacuo to give a yellow solid which was purified by flash column chromatography on silica (gradient elution with [10% MeOH / DCM with ca. 2% aqueous ammonia] / DCM) to give the title compound (300 mg, 39%) as a white solid. LCMS [M+H] + 604.0, RT 2.340 minutes (method 1).

[0265] Intermediate 134 [ka] 5-(Cyanoamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide To a stirred solution of intermediate 122 (250 mg, 0.68 mmol) and DIPEA (0.29 mL, 1.69 mmol) in anhydrous DCM (3 mL) cooled to 0° C. in an ice bath was added a solution of cyanogen bromide [506-68-3] (75 mg, 0.71 mmol) in anhydrous DCM (2 mL) dropwise and the mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with DCM (20 mL) and washed with saturated aqueous ammonium chloride (10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL) then dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (gradient elution with 0-100% EtOAc in heptane) to afford the title compound (150 mg, 62%) as an off-white solid. δ H(2...

Claims

1. Compounds of formula (I) and pharma- ceutically acceptable salts thereof: 【Chemistry 1】 [In the formula, X is CH, N, or C-R ４ X represents C-R ４ If R ３ and R ４ may be linked to form a 4- to 6-membered cycloalkyl or heterocyclic ring; Any of these may optionally be halogen, ═O, OH, SMe, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, NH ２ , NHMe, NMe ２ , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy and C １ ~C ２ substituted by one or more substituents selected from haloalkyl; When X represents N, W, Y and Z are C or one of W, Y and Z is a single bond and the other two are C; X is CH or C-R ４ where W, Y and Z are C or one of W, Y or Z is a single bond, O, S, S(O), S(O) ２ or N, and the other two are C; When W, Y, or Z is C, each C is H, halogen, SF ５ , =O, =NOH, -OH, -CN, -C(O)Me, -C(O)OH, -C(O)NH ２ ,NH-C(O)OC １ ~C ４ Alkyl, -NO ２ , N.H. ２ , NHMe, NMe ２ , SH, SMe, SOMe, SO ２ Me, C １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, C １ ~C ４ Alkoxy, heterocycle, C １ ~C ４ heteroalkyl, which may be linked to form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic ring; Any of these may optionally be halogen, ═O, OH, SMe, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, NH ２ , NHMe, NMe ２ which may be linked to form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic ring; When W, Y or Z is N, N is independently H, C １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, heterocycle, -C(O)Me, -C(O)NH ２ , -C(O)OH, -S(O)Me, -S(O) ２ Me, -S(O) ２ N.H. ２ any of which may be optionally substituted with halogen, OH, SMe, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, NH ２ , NHMe, NMe ２ may be substituted with one or more substituents selected from W, X, Y and Z may be linked directly or via substituents to form a ring; R １ teeth, 【Chemistry 2】 represents; R ２ teeth, 【Chemistry 3】 represents; R ３ is H, -OH, C １ ~C ８ Alkyl, -NR ｄ R ｃ , -NH-R １４ -NH-R ａ , -NMe-R １４ -NH-R ａ , -NH-R １４ -NMe-R ａ , —CO—NR ｄ R ｃ , -NH-COO-R ｃ , —NH—CO—R ｃ , -COOH, -COO-C １ ~C ８ Alkyl, —CO—C １ ~C ８ Alkyl, -C １ ~C ８ Alkylene-COO-C １ ~C ８ Alkyl, -C １ ~C ８ Alkylene -NR ａ , -COO-C １ ~C ８ Alkyl, -C １ ~C ８ Alkylene -NR ｄ R ｃ , C １ ~C ８ Alkylene -NH-R １４ -NH-R ａ , heteroaryl, -CN, -CH=N-OH, -CF ３ , alkylamino, amino, -NH-SO-C １ ~C ８ Alkyl, -NH-SO ２ -C １ ~C ８ Alkyl, Heteroalkyl-amino, Aryl, Heterocycle, C ３ ~C ６ Cycloalkyl, -NHS(O)(=NH)Me, -SO ２ -C １ ~C ８ Alkyl, -NH-C(CH ３ )=N-CN, -NH-CH=N-CN, -NH-S(=O)(=N)-C １ ~C ２ alkyl, Any of these may optionally be halogen, -OH, =O, -COOH, -COH, -CN, SMe, -NR ｄ R ｃ , -OR ｃ , C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Alkylene -O-C １ ~C ２ Alkyl, C １ ~C ２ Alkylene-C ３ ~C ４ Cycloalkyl, Heterocycle, C ３ ~C ６ Cycloalkyl, aryl, heteroaryl, C ３ ~C ６ Cycloalkyl-amino, heterocyclo-amino, aryl-amino, heteroaryl-amino, -CONR ｄ R ｃ , -NHCO-R ａ , -NHCOO-C １ ~C ４ Alkyl, —CO—C １ ~C ２ Alkyl, -COO-R ａ which may be linked to form a ring; ｄ R ｃ and -NR ｄ R ｃ may be linked to form a 7-membered ring fused to a 6-membered aryl group; Aryl, heteroaryl, heterocycle and cycloalkyl are optionally selected from the group consisting of halogen, oxo, cyano, OH, —NOOH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, halo-C １ ~C ６ Alkoxy, C ３ ~C ６ -Cycloalkyl-C １ ~C ３ -alkoxy, -O-CO-C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ２ Haloalkyl, C ２ ~C ４ Heterocycle, acetyl, acetyl-phenyl, -CONR ｄ R ｃ , COO-C １ ~C ８ Alkyl, -S(O)NH-C １ ~C ２ -alkyl, -S(O) ｎ -C １ ~C ２ - alkyl, optionally one or more halogen groups, C １ ~C ２ -heteroaryl, optionally substituted with alkyl; n is equal to 0, 1 or 2; R ４ is halogen, OH, CN, NO ２ , N.H. ２ , NHMe, NMe ２ , SH, SMe, SOMe, SO ２ Me, C １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ heteroalkyl, heterocycle; Any of these may optionally be halogen, ═O, OH, SMe, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, NH ２ , NHMe, NMe ２ which may be linked to form a ring; R １４ are C=O, C=S, C=N-OH, C=NR ｂ , C=CH-NO ２ , S.O. ２ , and C ３ ~C ６ cycloalkenyl, which may be optionally substituted with 1 or 2 =O; R ａ is H, C １ ~C ８ Alkyl, Heteroalkyl, C １ ~C ８ Alkoxy, heterocycle, C ３ ~C ８ selected from cycloalkyl, heteroaryl and aryl; Any of these may optionally be halogen, ═O, OH, SMe, C １ ~C ２ Alkoxy, —O—C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Heterocycloalkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, aryl, heteroaryl, NH ２ , NHMe, NMe ２ which may be linked to form a ring; R ｂ is CN, aryl, heteroaryl, -NO ２ , -O-C １ ~C ２ Alkyl, —CO—O—C １ ~C ２ alkyl, Aryl and heteroaryl optionally include one or more C １ ~C ２ may be substituted with alkyl; R ｃ is H, aryl, heteroaryl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ８ Cycloalkyl, Heterocycle, C １ ~C ８ Alkyl, C １ ~C ８ Heteroalkyl, C １ ~C ４ Alkylene-C ３ ~C ６ cycloalkyl; Any of these may optionally be C(O)(R ｇ ), C(O)N(R ｆ ) (R ｇ ), halogen, SF ５ , OH, =O, -COH, -COOH, -CO-O-R ａ ,CN,SMe,S.O. ２ Me, SO ２ R ｇ , C １ ~C ４ Alkoxy, O-C １ ~C ４ Haloalkyl, C １ ~C ４ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ４ Haloalkyl, N(R ｆ ) (R ｇ ), N(R ｆ ) S.O. ２ (R ｇ ), S.O. ２ N.H. ２ , S.O. ２ NHMe, SO ２ NMe ２ , S(O)(NR ｆ ) R ｇ , C ３ ~C ６ Cycloalkyl, Heterocycle, C １ ~C ４ Alkylene-C ３ ~C ６ may be substituted with one or more substituents selected from cycloalkyl, aryl and heteroaryl, which may be linked to form a ring; Aryl, heteroaryl, heterocycle and cycloalkyl are optionally selected from halogen, ═O, ═NH, ═NMe, OH, C １ ~C ２ Alkyl, C １ ~C ２ Alkoxy, -COOH, -COO-C １ ~C ２ Alkyl, SO ２ R ａ , C.O.R. ａ , SOR ａ , S(O)(NH)R ａ , C.O.N.R. ａ and optionally linked to form a ring; R ｄ is H or C １ ~C ４ represents an alkyl group, R ｃ and R ｄ may be linked to form a heterocycle; R ｆ is H, aryl, heteroaryl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ８ Cycloalkyl, Heterocycle, C １ ~C ８ Alkyl, C １ ~C ８ Heteroalkyl, C １ ~C ４ Alkylene-C ３ ~C ６ cycloalkyl; Any of these may optionally be selected from the group consisting of halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, -COOH, -COO-C １ ~C ２ Alkyl, SO ２ R ａ , C.O.R. ａ , S.O.R. ａ ,S(O)(NH)R ａ , C.O.N.R. ａ may be substituted with one or more substituents selected from R ｇ is H, aryl, heteroaryl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ８ Cycloalkyl, Heterocycle, C １ ~C ８ Alkyl, C １ ~C ８ Heteroalkyl, C １ ~C ４ Alkylene-C ３ ~C ６ cycloalkyl; Any of these may optionally be selected from the group consisting of halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, -COOH, -COO-C １ ~C ２ Alkyl, SO ２ R ａ , C.O.R. ａ , S.O.R. ａ ,S(O)(NH)R ａ , C.O.N.R. ａ may be substituted by one or more substituents selected from R ｆ and R ｇ may be linked to form a ring.

2. Compounds of formula (Ia) and pharma- ceutically acceptable salts thereof: 【Chemistry 4】 [In the formula, X is CH, N, or C-R ４ X represents C-R ４ If R ３ and R ４ may be linked to form a 4- to 6-membered cycloalkyl or heterocyclic ring; Any of these may optionally be halogen, ═O, OH, SMe, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, NH ２ , NHMe, NMe ２ , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from halogen, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy and C １ ~C ２ substituted by one or more substituents selected from haloalkyl; When X represents N, W, Y and Z are C or one of W, Y and Z is a single bond and the other two are C; X is CH or C-R ４ where W, Y and Z are C or one of W, Y or Z is a single bond, O, S, S(O), S(O) ２ or N, and the other two are C; When W, Y, or Z is C, each C is H, halogen, SF ５ , =O, =NOH, -OH, -CN, -C(O)Me, -C(O)OH, -C(O)NH ２ ,NH-C(O)OC １ ~C ４ Alkyl, -NO ２ , N.H. ２ , NHMe, NMe ２ , SH, SMe, SOMe, SO ２ Me, C １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, C １ ~C ４ Alkoxy, heterocycle, C １ ~C ４ heteroalkyl, which may be linked to form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic ring; Any of these may optionally be halogen, ═O, OH, SMe, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, NH ２ , NHMe, NMe ２ which may be linked to form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocyclic ring; When W, Y or Z is N, N is independently H, C １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, heterocycle, -C(O)Me, -C(O)NH ２ , -C(O)OH, -S(O)Me, -S(O) ２ Me, -S(O) ２ N.H. ２ any of which may be optionally substituted with halogen, OH, SMe, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, NH ２ , NHMe, NMe ２ may be substituted with one or more substituents selected from W, X, Y and Z may be linked directly or via substituents to form a ring; R １ teeth, 【Chemistry 5】 represents; R ２ teeth, R ２ teeth, 【Chemistry 6】 represents; R ３ is H, -OH, C １ ~C ８ Alkyl, -NR ｄ R ｃ , -NH-R １４ -NH-R ａ , -NMe-R １４ -NH-R ａ , -NH-R １４ -NMe-R ａ , —CO—NR ｄ R ｃ , -NH-COO-R ｃ , —NH—CO—R ｃ , -COOH, -COO-C １ ~C ８ Alkyl, —CO—C １ ~C ８ Alkyl, -C １ ~C ８ Alkylene-COO-C １ ~C ８ Alkyl, -C １ ~C ８ Alkylene -NR ａ , -COO-C １ ~C ８ Alkyl, -C １ ~C ８ Alkylene -NR ｄ R ｃ , -C １ ~C ８ Alkylene -NH-R １４ -NH-R ａ , heteroaryl, -CN, -CH=N-OH, -CF ３ , alkylamino, amino, -NH-SO-C １ ~C ８ Alkyl, -NH-SO ２ -C １ ~C ８ Alkyl, Heteroalkyl-amino, Aryl, Heterocycle, C ３ ~C ６ Cycloalkyl, -NHS(O)(=NH)Me, -SO ２ -C １ ~C ８ Alkyl, -NH-C(CH ３ )=N-CN, -NH-CH=N-CN, -NH-S(=O)(=N)-C １ ~C ２ alkyl, Any of these may optionally be halogen, -OH, =O, -COOH, -COH, -CN, SMe, -NR ｄ R ｃ , -OR ｃ , C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Alkylene -O-C １ ~C ２ Alkyl, C １ ~C ２ Alkylene-C ３ ~C ４ Cycloalkyl, Heterocycle, C ３ ~C ６ Cycloalkyl, aryl, heteroaryl, C ３ ~C ６ Cycloalkyl-amino, heterocycle-amino, aryl-amino, heteroaryl-amino, -CONR ｄ R ｃ , -NHCO-R ａ , -NHCOO-C １ ~C ４ Alkyl, —CO—C １ ~C ２ Alkyl, -COO-R ａ which may be linked to form a ring; Aryl, heteroaryl, heterocycle and cycloalkyl are optionally selected from the group consisting of halogen, OH, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, —O—CO—C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ２ Haloalkyl and C ２ ~C ４ substituted by one or more substituents selected from heterocycles; R ４ is halogen, OH, CN, NO ２ , N.H. ２ , NHMe, NMe ２ , SH, SMe, SOMe, SO ２ Me, C １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ heteroalkyl, heterocycle; Any of these may optionally be halogen, ═O, OH, SMe, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, NH ２ , NHMe, NMe ２ which may be linked to form a ring; R １４ is C=O, C=S, C=N-OH, C=NR ｂ , C=CH-NO ２ , S.O. ２ , and C ３ ~C ６ cycloalkenyl, which may be optionally substituted with 1 or 2 =O; R ａ is H, C １ ~C ８ Alkyl, Heteroalkyl, C １ ~C ８ Alkoxy, heterocycle, C ３ ~C ８ selected from cycloalkyl, heteroaryl and aryl; Any of these may optionally be halogen, ═O, OH, SMe, C １ ~C ２ Alkoxy, —O—C １ ~C ２ Haloalkyl, C １ ~C ２ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ２ Heteroalkyl, C １ ~C ２ Haloalkyl, aryl, heteroaryl, NH ２ , NHMe, NMe ２ which may be linked to form a ring; R ｂ is CN, aryl, heteroaryl, -NO ２ , -O-C １ ~C ２ Alkyl, —CO—O—C １ ~C ２ alkyl, Aryl and heteroaryl optionally include one or more C １ ~C ２ is substituted with alkyl; R ｃ is H, aryl, heteroaryl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ８ Cycloalkyl, Heterocycle, C １ ~C ８ Alkyl, C １ ~C ８ Heteroalkyl, C １ ~C ４ Alkylene-C ３ ~C ６ cycloalkyl; Any of these may optionally be C(O)(R ｇ ), C(O)N(R ｆ ) (R ｇ ), halogen, SF ５ , OH, =O, -COH, -COOH, -CO-O-R ａ ,CN,SMe,S.O. ２ Me, SO ２ R ｇ , C １ ~C ４ Alkoxy, O-C １ ~C ４ Haloalkyl, C １ ~C ４ Alkyl, C １ ~C ２ Heteroalkyl, C １ ~C ４ Haloalkyl, N(R ｆ ) (R ｇ ), N(R ｆ ) S.O. ２ (R ｇ ), S.O. ２ N.H. ２ , S.O. ２ NHMe, SO ２ NMe ２ , S(O)(NR ｆ ) R ｇ , C ３ ~C ６ Cycloalkyl, Heterocycle, C １ ~C ４ Alkylene-C ３ ~C ６ optionally substituted with one or more substituents selected from cycloalkyl, aryl and heteroaryl, which may be linked to form a ring; Aryl, heteroaryl, heterocycle and cycloalkyl are optionally selected from halogen, ═O, ═NH, ═NMe, OH, C １ ~C ２ Alkyl, C １ ~C ２ Alkoxy, -COOH, -COO-C １ ~C ２ Alkyl, SO ２ R ａ , C.O.R. ａ , S.O.R. ａ ,S(O)(NH)R ａ , C.O.N.R. ａ and optionally linked to form a ring; R ｄ is H or C １ ~C ４ represents alkyl; R ｃ and R ｄ may be linked to form a heterocycle; R ｆ is H, aryl, heteroaryl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ８ Cycloalkyl, Heterocycle, C １ ~C ８ Alkyl, C １ ~C ８ Heteroalkyl, C １ ~C ４ Alkylene-C ３ ~C ６ cycloalkyl; Any of these may optionally be selected from the group consisting of halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, -COOH, -COO-C １ ~C ２ Alkyl, SO ２ R ａ , C.O.R. ａ , SOR ａ , S(O)(NH)R ａ , C.O.N.R. ａ may be substituted with one or more substituents selected from R ｇ is H, aryl, heteroaryl, C ３ ~C ６ Cycloalkenyl, C ３ ~C ８ Cycloalkyl, Heterocycle, C １ ~C ８ Alkyl, C １ ~C ８ Heteroalkyl, C １ ~C ４ Alkylene-C ３ ~C ６ cycloalkyl; Any of these may optionally be selected from the group consisting of halogen, ═O, ═NH, ═NMe, OH, aryl, heteroaryl, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, C １ ~C ２ Alkoxy, O-C １ ~C ２ Haloalkyl, -COOH, -COO-C １ ~C ２ Alkyl, SO ２ R ａ , C.O.R. ａ , S.O.R. ａ ,S(O)(NH)R ａ , C.O.N.R. ａ may be substituted by one or more substituents selected from R ｆ and R ｇ may be linked to form a ring.

3. Compound of formula (II): 【Chemistry 7】 [In the formula, R １ , R ２ and R ３ is as defined in claim 1.

3. The compound of claim 1 or 2, wherein:

4. 3. The compound of claim 1 or 2, wherein X is C or N; Z is C, N, O or S; and Y is C or S; or a pharma- ceutically acceptable salt thereof.

5. 3. The compound according to claim 1 or 2, wherein X, Y, and W are C, Z is N, and N is substituted with a group selected from methylsulfonyl, acetylethylcarbamoyl, and cyano, or a pharma- ceutically acceptable salt thereof.

6. The compound according to any one of claims 1 and 2, wherein X, Y, W, and Z are C, and Z is substituted with a group selected from OH, methyl, ethylcarbamoyl, cyano, oxo, tert-butoxycarbonylamino, and 1H-pyrazol-3-yl, or a pharma- ceutically acceptable salt thereof.

7. X, Y, W, and Z are C, W is substituted with a methyl group, and R ３ 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is H or a methyl group.

8. X is C or N, and R ３ is H, OH, methyl, amino, methylsulfonyl, acetyl, 2-methoxyacetyl, 2-phenylacetyl, 2-(tert-butoxycarbonylamino)ethyl, 2-phenylethyl, pyrimidin-2-ylamino, methanesulfonamido, (4-methoxyphenyl)carbamothioylamino, (4-methoxyphenyl)carbamoylamino, ethylcarbamoyl, [N'-cyano-N-(p-tolyl)carbamimidoyl]amino, [N'-cyano-N-ethyl-carbamimidoyl]amino, (1-oxoisoindolin-5-yl)carbamoyl , (3-sulfamoylphenyl)carbamoyl, (3-methylsulfonylphenyl)carbamoyl, 3-isoxazol-5-ylanilino, (2-ethoxy-3,4-dioxo-cyclobuten-1-yl)amino, ethylcarbonyl, carboxy, (1-oxoisoindolin-5-yl)aminocarbonyl, [(5-oxopyrrolidin-3-yl)phenyl]aminocarbonyl, [3-(3-methyl-5-oxo-4H-pyrazol-1-yl)phenyl]carbonylamino, (1H-indazol-4-yl)carbonylamino, 1H-imidazolidin-4-yl 2-(4-methoxyphenyl)ethylaminocarbonyl, quinoxalin-6-yl, (thiazol-2-yl)aminocarbonyl, (1H-tetrazol-5-yl)aminocarbonyl, (4-pyridyl)aminocarbonyl, pyrazin-2-ylaminocarbonyl, (3-pyridyl)aminocarbonyl, 3-hydroxyazetidine-1-carbonyl, 1,1-dioxo-1,4-thiazinane-4-carbonyl, 2-(4-hydroxyphenyl)ethylaminocarbonyl, hydroxyiminocarbonyl ethyl, [(4-ethyl-1,2,4-triazol-3-yl)amino]methyl, (4-methylanilino)methyl, 2-amino-3-pyridyl, 5-(p-tolyl)-1H-imidazol-2-yl, cyano, trifluoromethyl, 4-methyloxazol-2-yl, aminomethyl, (p-tolylcarbamoylamino)methyl, 3-methyl-1,2,4-oxadiazol-5-yl, 5-methyl-1,3,4-oxadiazol-2-yl, pyrrolidine-1-carbonyl, 3-pyridylcarbamoylamino, 3-(3-pyridylamino)-1,2,4-Triazol-4-yl, 1H-pyrazol-3-yl, 5-amino-4-cyano-imidazol-1-yl, 3-(2,2-dimethylpropylamino)-1,2,4-triazol-4-yl, 3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino, [(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl, N'-cyano-N-phenyl-carbamimi doylamino, 3-(isobutylamino)-1,2,4-triazol-4-yl, 3-[(1-methylcyclopropyl)methylamino]-1,2,4-triazol-4-yl, 5-acetamidoimidazol-1-yl, 3-[(5-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-(4-pyridylamino)-1,2,4-triazol-4-yl, N'-cyano-N-(3,4-dimethoxyphenyl)carbamimidoyl]amino, 4-ethoxycarbonyl-5-(ethylamino)imidazol-1-yl, 3- (2-morpholinoethylamino)-1,2,4-triazol-4-yl, (5-oxo-4H-1,2,4-oxadiazol-3-yl)amino, 2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino, [N'-cyano-N-(2,2,2-trifluoroethyl)carbamimidoyl]amino, 3-(ethylamino)-1,2,4-triazol-4-yl, (N-ethyl-N'-nitro-carbamimidoyl)amino, 3-(3-pyridylamino)-1,2,4-triazol-4-yl, 3-[(1-oxidopyridylamino)-1,2,4-triazol-4-yl, Lysin-1-ium-3-yl)amino, [N'-nitro-N-(p-tolyl)carbamimidoyl]amino, 2-(3-pyridylamino)imidazol-1-yl, 3-(3-pyridylamino)-1,2,4-triazol-4-yl, 3-(cyclopropylmethylamino, (2,5-dimethylpyrazol-3-yl)carbamothioylamino, 3-(pyrimidin-5-ylamino)-1,2,4-triazol-4-yl, 2-(cyclopropylmethylamino)imidazol-1-yl, [4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino, [1-(4-methylanilino)-2-nitro-vinyl]amino, (N'-cyano-N-ethyl-carbamimidoyl)-methyl-amino, [2-(4-methylanilino)-3,4-dioxo-cyclobuten-1-yl]amino, 3-(2-pyridylamino)-1,2,4-triazol-4-yl, 2-acetamidoimidazol-1-yl, 5-(N-tert-butyloxycarbonylamino)-triazol-1-yl, 5-(3-pyridylamino) Triazol-1-yl, ethylcarbamothioylamino, 3-[[(3S)-tetrahydrofuran-3-yl]amino]-1,2,4-triazol-4-yl, [(E)-N-ethyl-N'-nitro-carbamimidoyl]amino, 2-(ethylamino)imidazol-1-yl, 3-[(3,5-dimethylisoxazol-4-yl)amino, [[N'-ethoxycarbonyl-N-(p-tolyl)carbamimidoyl]amino], [2-[(2-methyl-3-pyridyl)amino]imidazole -1-yl, 1-[(ethylamino)-2-nitro-vinyl]amino, (4-methyl-6-oxo-1H-pyrimidin-2-yl)amino, 5-amino-4-(methylcarbamoyl)imidazol-1-yl, 5-amino-4-carbamoyl-imidazol-1-yl, 2-anilinoimidazol-1-yl, ethylcarbamoylamino, (4-oxo-1H-pyridin-2-yl)amino, [6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-pyridyl]amino, 5-(ethyl amino)tetrazol-1-yl, 1H-1,2,4-triazol-3-ylamino, 4-(1-methylpyrazol-4-yl)-1,2,4-triazol-3-yl]amino, 4-(ethyloxy-carbonyl)imidazol-1-yl, [4-(4-fluorophenyl)-1,2,4-triazol-3-yl]amino, 1H-imidazol-2-ylamino, N'-methoxy-N-(p-tolyl)carbamimidoyl]amino, [4-(4-methylanilino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino, [1-(3-pyridyl)imidazol-2-yl]amino, 5-aminotriazol-1-yl, (2-methoxyphenyl)carbamoylamino, 4-pyridine-carbonylamino, benzylamino, 1H-benzimidazol-2-ylamino, [N'-hydroxycarbamimidoyl]amino, [N'-(1-methylpyrazol-3-yl)-N-(p-tolyl)carbamimidoyl]amino, 3-[(3,5-dimethylpyrazin-2-yl)amino, 3-(ethylamino)-5-(methoxymethyl )-1,2,4-triazol-4-yl, [5-(3-pyridyl)-1H-1,2,4-triazol-3-yl]amino, p-tolyl-carbonylamino, quinazolin-2-ylamino, 1,3-benzoxazol-2-ylamino, 3-(ethylamino)-5-(hydroxymethyl)-1,2,4-triazol-4-yl, 2-aminoimidazol-1-yl, 3-amino-5-oxo-1,2,4-oxadiazol-4-yl, 3-(ethylamino)-5-methyl-1,2,4-triazol-4-yl, (2-ethyl-3,4- dioxo-cyclobuten-1-yl)amino, 1,3,4-oxadiazol-2-ylamino, 5-oxo-1-(p-tolyl)-4H-imidazol-2-yl]amino, [2-[ethyl(methyl)amino]-3,4-dioxo-cyclobuten-1-yl]amino, (methylsulfonimidoyl)amino, [N-cyano-C-methyl-carbonimidoyl]amino, tetrazol-1-yl, methanesulfinamide, morpholino, 3-(ethylamino)-5-(trifluoromethyl)-1,2,4-triazol-4-yl, (4-oxo -1H-pyrimidin-2-yl)amino, isopropylsulfamoylamino, N'-cyano-N-morpholino-carbamimidoyl]amino, acetamide, methanesulfonamide, [N'-cyano-N-methoxy-carbamimidoyl]amino, (4-methoxyphenyl)carbamoylamino, [4-oxo-6-(trifluoromethyl)-1H-pyrimidin-2-yl]amino, [4-(trifluoromethoxy)phenyl]carbamoylamino, 3-(2-methylpropanoylamino)-1,2,4-triazol-4-yl, 3-[(2,5-dimethylpyrazol-3-yl)-methyl-amino]-1,2,4-triazol-4-yl, 5-amino-4-(5-methyl-1,3,4-oxadiazol-2-yl)imidazol-1-yl, 3-[(3-methyl-1H-pyrazol-5-yl)amino]-1,2,4-triazol-4-yl, 3-[(1,3-dimethylpyrazol-4-yl)amino]-1,2,4-triazol-4-yl-[(5-cyclopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(5-isopropyl propyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(2-isopropyl-5-methyl-pyrazol-3-yl)amino, 3-[(5-methyl-2-tetrahydrofuran-3-yl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2- ethyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-cyclopropyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]-1,2,4-triazol-4-yl, 3-[(5-ethyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino, 3-[(1,4- The compound according to any one of claims 1, 2 and 4, which is selected from [3-[(5-methoxycarbonyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl], [2-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]imidazol-1-yl, and [3-[(5-carboxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl], or a pharma- ceutically acceptable salt thereof.

9. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein W, X, Y, and Z are C, and Z is optionally substituted with a methyl group.

10. R ３ (1,1-dioxothiolan-3-yl)amino-1,2,4-triazol-4-yl, 3-[3-[methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl, 3-[(1-acetyl-3-methylpyrrolidin-3-yl)amino]-4H-1,2,4-triazol-4-yl, 3-{[1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]amino}-4H-1,2,4-triazol-4-yl, 3-[[-1-pyrazin-2-ylpyrrolidine- 3-[[-1-(6-fluoropyridazin-3-yl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[-1-(6-fluoropyridazin-3-yl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[-1-(6-fluoropyridazin-3-yl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[-1-pyrimidin-2-ylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, Lysin-3-yl]amino]-1,2,4-triazol-4-yl, 5-amino-4-(2-methoxyethoxycarbonyl)imidazol-1-yl, 5-amino-4-(2-morpholinethoxycarbonyl)imidazol-1-yl, 3-(3-methylsulfanylanilino)-1,2,4-triazol-4-yl, 3-(3-methylsulfonylanilino)-1,2,4-triazol-4-yl, 3-(3-methylsulfonylanilino)-1,2,4-triazol-4-yl, 3-(3-methylsulfinylanilino)-1,2,4-triazol-4-yl, 3 -[3-(methylsulfonimidoyl)anilino]-1,2,4-triazol-4-yl, 3-[(6-methylsulfinyl-2-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-methylsulfonyl-2-pyridyl)amino]-1,2,4-triazol-4-yl, 8-methoxy-4-oxo-5,10-dihydroimidazo[4,5-c][1,5]benzodiazepin-1-yl, 8-methoxy-5-methyl-4-oxo-10H-imidazo[4,5-c][1,5]benzodiazepin-1-yl, 5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl, 5-amino-4-[(3R)-3-hydroxypyrrolidine-1-carbonyl]imidazol-1-yl, 5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl, 5-[[4-(dihydroxyamino)-2,5-dimethyl-3H-pyrazol-3-yl]amino]-4-ethoxycarbonyl-imidazol-1-yl, 5-[[4-(dihydroxyamino)-2,5-dimethyl-3H-pyrazol-3-yl]amino] 3-(2-methyl-3-methylsulfinyl-anilino)-1,2,4-triazol-4-yl, 3-(2-methyl-3-methylsulfonyl-anilino)-1,2,4-triazol-4-yl, 3-[(2-methyl-5-oxazol-2-yl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 1-acetylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 1-methylsulfonylpyrrolidine-3 -yl]amino]-1,2,4-triazol-4-yl, 3-[(2-methylcyclohexyl)amino]-1,2,4-triazol-4-yl, 3-[(5-oxopyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-oxo-4-piperidyl)amino]-1,2,4-triazol-4-yl, 3-[(1-acetyl-2-methyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-methyl-1-methylsulfonyl-pyrrolidin-3-yl)amino]-1,2,4-triazo -4-yl, -[3-[[3-(6-methyl-3-pyridyl)cyclobutyl]amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, [[1-benzoyl-4,4-difluoro-pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(1-acetyl-4-piperidyl)amino]-1,2,4-triazol-4-yl, 3-[(1-methoxycarbonylpyrrolidin-3-yl)amino]-1,2,4-Triazol-4-yl, 3-[[1-(ethylcarbamoyl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 3-{[2-(pyrimidin-2-yl)-2-azaspiro[4.4]nonan-7-yl]amino}-4H-1,2,4-triazol-4-yl, 3-[[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[5-[chloro(difluoro)methoxy]-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazo 4-yl, 3-{[1-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-5-yl]amino}-4H-1,2,4-triazol-4-yl, 3-[(5-methoxy-3-methyl-pyrazin-2-yl)amino]-1,2,4-triazol-4-yl, (5-methylthiazolo[5,4-b]pyridin-2-yl)amino, 3-[(5-cyano-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-cyano-2-methyl-3-pyridyl)amino]-1, 2,4-triazol-4-yl, 3-[(1-methyl-2-oxo-4-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-chloro-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl, 3-[(3-methylpyridazin-4-yl)amino]-1,2,4-triazol-4-yl, 3-[(5-chloro-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl riazol-4-yl, 3-[(3-methylisothiazol-4-yl)amino]-1,2,4-triazol-4-yl, 3-[(3-methylisoxazol-4-yl)amino]-1,2,4-triazol-4-yl, 3-[[5-(cyclopropylmethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(5-ethoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-Triazol-4-yl, (5-amino-4-ethoxycarbonyl-imidazol-1-yl), 3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethyl)-2-(trideuteriomethyl) 5-(5-(difluoromethyl)-2-(trideuteriomethyl)pyrazol-3-yl]amino, 3-[(5-cyano-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2,2-difluoro-1,3-benzodioxol-5-yl)amino]-1,2,4-triazol-4-yl, 3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl, 3-[[5-(difluoromethyl)-2-(trideuteriomethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[(6-fluoro-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[[5-(cyclopropoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[2-methyl-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl, 3-[[6-(trifluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl, 3-[(6-methoxy-3-pyridyl)amino]- 1,2,4-triazol-4-yl, 3-[(2-methoxy-4-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-chloro-3-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(2-chloro-4-pyridyl)amino]-1,2,4-triazol-4-yl, 3-[(6-methoxy-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl, thiazolo[5,4-b]pyridin-2-ylamino, 3-[(3-methyltriazol-4-yl)amino]-1,2,The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, selected from 4-triazol-4-yl.

11. 2-(cyclopropanecarbonylamino)-N-methyl-5,7-dihydro-4H-thieno[2,3-c]thiopyran-3-carboxamide; 6-(cyclopropanecarbonylamino)-N-methyl-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxamide hydrochloride; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methylsulfonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide; 5-acetyl-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-methylsulfonyl-5,6-dihydro-4H-thieno[2,3-b]pyridine-3-carboxamide; 7-Acetyl-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,6-dihydro-4H-thieno[2,3-b]pyridine-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-methoxyacetyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-phenylacetyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide; Tert-butyl N-[2-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethyl]carbamate; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-phenylethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide; Methyl 2-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]acetate; (4R)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide; (4S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide; N-[3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-[(2-hydroxy-2-methyl-propyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-(2-hydroxypropylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-(3-pyrrolidin-1-ylsulfonyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide; N-[3-[(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-(3-butylsulfonyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide; N-[3-(isobutylsulfamoyl)-5-(pyrimidin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-(isobutylsulfamoyl)-5-(methanesulfonamido)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[5-[(4-methoxyphenyl)carbamothioylamino]-3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[5-[(4-methoxyphenyl)carbamoylamino]-3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; 2-(cyclopropanecarbonylamino)-N-ethyl-3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxamide; 2-(cyclopropanecarbonylamino)-N-ethyl-3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide; N-(3-butylsulfinyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide; N-[5-[[N'-cyano-N-(p-tolyl)carbamimidoyl]amino]-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(1-oxoisoindolin-5-yl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide; 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-sulfamoylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide; 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-methylsulfonylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide; 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-isoxazol-5-ylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide; N-[3-(cyclopropylmethylsulfamoyl)-5-[(2-ethoxy-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-(cyclopropylmethylsulfamoyl)-5-[[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-(butylsulfonimidoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; Ethyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylate; 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1-oxoisoindolin-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[3-(5-oxopyrrolidin-3-yl)phenyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[3-(3-methyl-5-oxo-4H-pyrazol-1-yl)phenyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2,2,2-trifluoroacetic acid salt of 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-indazol-4-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2,2,2-trifluoroacetic acid salt of 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-indazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-imidazo[4,5-b]pyrazin-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-indan-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[2-(4-methoxyphenyl)ethyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-quinoxalin-6-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-thiazol-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-tetrazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(4-pyridyl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-pyrazin-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(3-pyridyl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(3-hydroxyazetidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[2-(4-hydroxyphenyl)ethyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(hydroxyiminomethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(4-ethyl-1,2,4-triazol-3-yl)amino]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-[(4-methylanilino)methyl]-6,7-dihydro-4H-benzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-2'-oxo-3'-(p-tolyl)spiro[6,7-dihydro-4H-benzothiophene-5,5'-oxazolidine]-3-carboxamide; 5-(2-amino-3-pyridyl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(p-tolyl)-1H-imidazol-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-cyano-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 7-cyano-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5R)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(4-methyloxazol-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-(aminomethyl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-6,7-dihydro-4H-benzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-[(p-tolylcarbamoylamino)methyl]-6,7-dihydro-4H-benzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-methyl-6,7-dihydro-4H-benzothiophene-3-carboxamide; N-[3-[(3R)-3-fluoropyrrolidine-1-carbonyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-(3-fluoroazetidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[3-(piperidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; 2-(cyclopropanecarbonylamino)-7-hydroxy-N-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxamide; 2'-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxamide; N-(cyclopropylmethyl)-2-(2-methylpropanoylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclobutanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-4,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid; N-(cyclopropylmethyl)-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide diastereomer 1; N-(cyclopropylmethyl)-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide diastereomer 2; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-2',5'-dioxo-spiro[6,7-dihydro-4H-benzothiophene-5,4'-imidazolidine]-3-carboxamide; Cyclopropylmethyl 2-(cyclopropanecarbonylamino)-5-(3-pyridylcarbamothioylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate; Cyclopropylmethyl 2-(cyclopropanecarbonylamino)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate; 2-(cyclopropanecarbonylamino)-N,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; tert-Butyl N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-7-yl]carbamate; 2-(cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N7-ethyl-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; N-methyl-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl 2-(cyclopropanecarbonylamino)-7-hydroxy-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate; (5S)-5-(5-amino-4-cyano-imidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2,2-dimethylpropylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-isobutyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[N'-cyano-N-phenyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(isobutylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-methylcyclopropyl)methylamino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-(5-acetamidoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(4-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[N'-cyano-N-(3,4-dimethoxyphenyl)carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-morpholinoethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(5-oxo-4H-1,2,4-oxadiazol-3-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[N'-cyano-N-(2,2,2-trifluoroethyl)carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(N-ethyl-N'-nitro-carbamimidoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-oxidopyridin-1-ium-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-nitro-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(3-pyridylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; N-[(5S)-3-(5-azaspiro[2.4]heptane-5-carbonyl)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[(5R)-3-(5-azaspiro[2.4]heptane-5-carbonyl)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2,5-dimethylpyrazol-3-yl)carbamothioylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(pyrimidin-5-ylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(cyclopropylmethylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(4-methylanilino)-2-nitro-vinyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[(N'-cyano-N-ethyl-carbamimidoyl)-methyl-amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-(4-methylanilino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-(2-acetamidoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; tert-Butyl N-[3-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]triazol-4-yl]carbamate; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(3-pyridylamino)triazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(ethylcarbamothioylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-tetrahydrofuran-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(E)-N-ethyl-N'-nitro-carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5R)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(E)-N-ethyl-N'-nitro-carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(ethylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3,5-dimethylisoxazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl N-[[[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]amino]-(4-methylanilino)methylene]carbamate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-[(2-methyl-3-pyridyl)amino]imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(ethylamino)-2-nitro-vinyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-methyl-6-oxo-1H-pyrimidin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-amino-1-[(5S)-2-cyclopropanamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-N-methyl-1H-imidazole-4-carboxamide; 5-amino-1-[(5S)-2-cyclopropanamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-1H-imidazole-4-carboxamide; 5-(2-anilinoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(ethylcarbamoylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-oxo-1H-pyridin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-pyridyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(ethylamino)tetrazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-1,2,4-triazol-3-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5R)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(1-methylpyrazol-4-yl)-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl 1-[(5S)-2-cyclopropanamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-1H-imidazole-4-carboxylate; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(4-fluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-imidazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; N-[3-(isopropylmethylsulfamoyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-methoxy-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(4-methylanilino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(3-pyridyl)imidazol-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-(5-aminotriazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-methoxyphenyl)carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]pyridine-4-carboxamide; 5-(benzylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-(1H-benzoimidazol-2-ylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-hydroxycarbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Formic acid salt of 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-(1-methylpyrazol-3-yl)-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3,5-dimethylpyrazin-2-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(methoxymethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[5-(3-pyridyl)-1H-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; p-Tolyl N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(quinazolin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-(1,3-benzoxazol-2-ylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(hydroxymethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(3,3-difluorocyclobutyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-(2-aminoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-(3-amino-5-oxo-1,2,4-oxadiazol-4-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-methyl-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5R)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-ethyl-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-ethyl-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(pyrimidin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1,3,4-oxadiazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(3-fluorocyclobutyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[5-oxo-1-(p-tolyl)-4H-imidazol-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-[ethyl(methyl)amino]-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(methylsulfonimidoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[N-cyano-C-methyl-carbonimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(tetrazol-1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(methanesulfinamido)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-fluoro-2-methyl-propyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-morpholino-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(trifluoromethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-oxo-1H-pyrimidin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(isopropylsulfamoylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[N'-cyano-N-morpholino-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-acetamido-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(methanesulfonamido)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[N'-cyano-N-methoxy-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-isobutyl-5-[(4-methoxyphenyl)carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-oxo-6-(trifluoromethyl)-1H-pyrimidin-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; N-[5-(methanesulfonamido)-3-(3-methylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; 2-(cyclopropanecarbonylamino)-N-propyl-5-[[4-(trifluoromethoxy)phenyl]carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-methylpropanoylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)-methyl-amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; (5S)-5-[5-amino-4-(5-methyl-1,3,4-oxadiazol-2-yl)imidazol-1-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methyl-1H-pyrazol-5-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1,3-dimethylpyrazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-cyclopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-isopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-isopropyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-methyl-2-tetrahydrofuran-3-yl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-ethyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-cyclopropyl-5-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-ethyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1,4-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Methyl 5-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]-1-methyl-pyrazole-3-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]-1-methyl-pyrazole-3-carboxylic acid; These enantiomers and their pharma- ceutically acceptable salts or a pharma- ceutically acceptable salt thereof, selected from:

12. (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S ＊ )-1,1-dioxothiolan-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or R]; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-[3-({3-[imino(methyl)oxo-lambda 6-sulfanyl]-2-methylphenyl}amino)-4H-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[2-methyl-3-[(S)-methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[2-methyl-3-[(R)-methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-{3-[(1-acetyl-3-methylpyrrolidin-3-yl)amino]-4H-1,2,4-triazol-4-yl}-2-cyclopropanamide-N-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[(3S ＊ )-1-acetyl-3-methyl-pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or R]; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-(3-{[(3S)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]amino}-4H-1,2,4-triazol-4-yl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-1-pyrazin-2-ylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(4-methyl-1-methylsulfonyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-{3-[(1-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-4H-1,2,4-triazol-4-yl}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-1-(6-fluoropyridazin-3-yl)pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-1-pyrimidin-2-ylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; 2-Methoxyethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]imidazole-4-carboxylate; 2-morpholin-4-ylethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]imidazole-4-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfanylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfonylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfinylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-(methylsulfonimidoyl)anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-[(S)-methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-[(R)-methylsulfonimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(6-methylsulfinyl-2-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(spiro[2.2]pentane-2-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(6-methylsulfonyl-2-pyridyl)amino]-1,2,4-triazol-4-yl]-2-[[(2S ＊ )-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(8-methoxy-4-oxo-5,10-dihydroimidazo[4,5-c][1,5]benzodiazepin-1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(8-methoxy-5-methyl-4-oxo-10H-imidazo[4,5-c][1,5]benzodiazepin-1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl]-N-(cyclopropylmethyl)-2-[[(1R ＊ , 2R ＊ )-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or 1S,2S]; (5S)-5-[5-amino-4-[(3R)-3-hydroxypyrrolidine-1-carbonyl]imidazol-1-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl 1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-5-[(2,5-dimethyl-4-nitro-pyrazol-3-yl)amino]imidazole-4-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-methyl-3-methylsulfinyl-anilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-methyl-3-methylsulfonyl-anilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methyl-5-oxazol-2-yl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[(3S)-1-acetylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3S)-1-methylsulfonylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3R)-1-methylsulfonylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methylcyclohexyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-oxopyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[(3R ＊ )-5-oxopyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( ＊ or S); 5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-oxo-4-piperidyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(1-acetyl-2-methyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methyl-1-methylsulfonyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[3-(6-methyl-3-pyridyl)cyclobutyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[3-(6-methyl-3-pyridyl)cyclobutyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-[[(1R ＊ )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or S]; (5S)-2-[[(1R ＊ )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( ＊ or S); (5S)-2-[[(1R ＊ )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or S]; (5S)-2-[[(1S ＊ )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ ＊ or R]; (5S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-[[(1S ＊ )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide[ ＊ or R]; (5S)-5-[3-[[(3S ＊ )-1-benzoyl-4,4-difluoro-pyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or R]; (5S)-5-[3-[(1-acetyl-4-piperidyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Methyl (3S)-3-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]pyrrolidine-1-carboxylate; (3S)-3-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]-N-ethyl-pyrrolidine-1-carboxamide; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-(3-{[2-(pyrimidin-2-yl)-2-azaspiro[4.4]nonan-7-yl]amino}-4H-1,2,4-triazol-4-yl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-[chloro(difluoro)methoxy]-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-5-(trifluoromethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-[chloro(difluoro)methoxy]-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-Cyclopropanamido-N-(cyclopropylmethyl)-5-(3-{[1-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-5-yl]amino}-4H-1,2,4-triazol-4-yl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-3-methyl-pyrazin-2-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(5-methylthiazolo[5,4-b]pyridin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(5-cyano-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(6-cyano-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-methyl-2-oxo-4-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(6-chloro-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-6-(trifluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methylpyridazin-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(5-chloro-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2R)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methylisothiazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methylisoxazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(cyclopropylmethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cyclopropylmethyl)-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-ethoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2R ＊ )-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or S]; (5S)—N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; Ethyl 5-amino-1-[(5S ＊ )-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate ( ＊ or R); N-[(5S ＊ )-3-(cyclopropylmethylsulfamoyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide ( ＊ or R); N-[(5S ＊ )-3-(cyclopropylmethylsulfamoyl)-5-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide ( ＊ or R); (1R,2S)-N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]-2-fluoro-cyclopropanecarboxamide; (1R,2S)-N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]-2-fluoro-cyclopropanecarboxamide; (1S ＊ )-N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]-2,2-difluoro-cyclopropanecarboxamide [ ＊ or R]; (1S ＊ )-N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]-2,2-difluoro-cyclopropanecarboxamide [ ＊ or R]; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; (1R,2S)-N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R ＊ )-N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2,2-difluorocyclopropane-1-carboxamide ( ＊ or S); (1R ＊ )-N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2,2-difluorocyclopropane-1-carboxamide ( ＊ or S); (5S)-N-(cyclopropylmethyl)-5-[3-[(3-methyl-1,2-thiazol-4-yl)amino]-1,2,4-triazol-4-yl]-2-(spiro[2.2]pentane-2-carbonylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[cis-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; (1R,2S)-N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; (1R,2S)-N-[(5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R,2S)-N-[(5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3-[trans-(3-fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2-fluorocyclopropane-1-carboxamide; (1R ＊ )-N-[(5S)-3-[(3,3-difluorocyclobutyl)sulfamoyl]-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]-2,2-difluorocyclopropane-1-carboxamide ( ＊ or S); N-[(5S)-3-(cyclopropylmethylsulfamoyl)-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]cyclopropanecarboxamide; (5S)—N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1R ＊ )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( ＊ or S); (5S)—N-(cyclopropylmethyl)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[cis-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1RS,2RS)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-2-[[(1RS,2RS)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; N-[(5S)-3-(cyclopropylmethylcarbamoyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]oxetane-3-carboxamide; (5S)—N-(cyclopropylmethyl)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(3,3-difluoropropanoylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclobutanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(2-methylpropanoylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1RS,2RS)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (5S)-N-(cyclopropylmethyl)-2-[[(1R ＊ )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( ＊ or S); (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1RS,2SR)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2R)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R ＊ , 2R ＊ )-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( ＊ or S); (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R ＊ , 2S ＊ )-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( ＊ 1R,2S or 1S,2R); (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R ＊ )-2,2-dimethylcyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( ＊ or S); (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-N-[(2R ＊ )-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide ( ＊ or S); (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[cis-(3-fluorocyclobutyl)methyl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(spiro[2.2]pentan-2-ylmethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(2R)-spiro[2.2]pentan-2-yl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(2S)-spiro[2.2]pentan-2-yl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(3,3-difluorocyclobutyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cis-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(3,3-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1RS,2RS)-2-methylcyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (cis); (5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1RS,2SR)-2-methylcyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (trans); 5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; 5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-[(2,2-difluorocyclopropyl)methyl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[trans-(3-fluorocyclobutyl)methyl]-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1S,2S)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(trans-3-fluorocyclobutyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-(trideuteriomethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(3,3-difluorocyclobutyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(3,3-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-N-spiro[2.2]pentan-2-yl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-N-[(2S)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(spiro[2.2]pentane-2-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate; Ethyl (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate; (5S)-5-[3-[(5-cyano-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,2-difluoro-1,3-benzodioxol-5-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-2-[[(2S)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (4RS,5RS)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (4R ＊ , 5R ＊ )-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[6-(difluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(6-fluoro-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(cyclopropoxy)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cyclopropylmethyl)-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[6-(trifluoromethyl)-3-pyridyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(6-methoxy-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methoxy-4-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(6-chloro-3-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(2-chloro-4-pyridyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(6-methoxy-2-methyl-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-fluoro-3-pyridyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3-methyltriazol-4-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(3,3-difluorocyclobutyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(3,3-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[cis-(3-fluorocyclobutyl)methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(spiro[2.2]pentan-2-ylmethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)—N-(cyclobutylmethyl)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(3,3-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(cis-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(3-methylcyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(3,3-difluorocyclobutyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(2,2-difluorocyclobutyl)methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-spiro[2.2]pentan-2-yl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2-methylcyclopropyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1RS,2RS)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(2R ＊ )-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( ＊ or S); (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[(2,2-difluorocyclopropyl)methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; and (5S)-2-(cyclopropanecarbonylamino)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-N-[(2R ＊ )-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or S]; (5S)-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[trans-(3-fluorocyclobutyl)methyl]-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1S,2S)-2-methylcyclopropanecarbonyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[(2S)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R ＊ )-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ ＊ or S]; (5S)—N-(cyclobutylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[cis-(3-fluorocyclobutanecarbonyl)amino]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[cis-(3-fluorocyclobutanecarbonyl)amino]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[[(1R,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[(2S)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-[trans-(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1R)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-N-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-[trans-(3-fluorocyclobutanecarbonyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1S,2S)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-(trans-3-fluorocyclobutyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-Cyclopropanamido-5-(3-{[3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl]amino}-4H-1,2,4-triazol-4-yl)-N-{spiro[2.2]pentan-1-yl}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2S)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(2R)-spiro[2.2]pentan-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[(3-fluorocyclobutyl)methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-[[(1R ＊ )-2,2-difluorocyclopropanecarbonyl]amino]-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-N-[[(1R,2R)-2-fluorocyclopropyl]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( ＊ or S); (5S)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-(spiro[2.2]pentane-2-carbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(2S ＊ )-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( ＊ or R); (3R ＊ )-6-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-3-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxamide ( ＊ Or S) or a pharma- ceutically acceptable salt thereof, selected from:

13. (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-cyclopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-isopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-ethyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-ethoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(1R,2S)-2-fluorocyclopropanecarbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)—N-(cyclopropylmethyl)-2-[[(1R,2R)-2-fluorocyclopropanecarbonyl]amino]-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-N-(cyclopropylmethyl)-5-[3-[(5-methoxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-2-[[(2R ＊ )-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide ( ＊ or S); or a pharma- ceutically acceptable salt thereof, selected from:

14. Formula (XXV) or (XXVI) 【Chemistry 8】 3. The compound according to claim 1 or 2, characterized in that:

15. Formula (XXVII) or (XXVIII) 【Chemistry 9】 3. The compound according to claim 1 or 2, characterized in that:

16. Formula (XXIX) or (XXX) 【Chemistry 10】 3. The compound according to claim 1 or 2, characterized in that:

17. Formula (XXXII) 【Chemistry 11】 3. The compound according to claim 1 or 2, characterized in that:

18. Formula (XXXII) or (XXXIV) 【Chemistry 12】 3. The compound according to claim 1 or 2, characterized in that:

19. Formula (XXXV) or (XXXVI) 【Chemistry 13】 3. The compound according to claim 1 or 2, characterized in that:

20. (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2,5-dimethylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; Ethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-cyclopropyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(5-ethyl-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methyl-pyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; and (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethoxy)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide or a pharma- ceutically acceptable salt thereof, selected from:

21. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof.

22. 22. A pharmaceutical composition according to claim 21 for use in a method for treating or preventing an IgE-induced disorder.

23. 22. The pharmaceutical composition of claim 21 for use in a method for treating or preventing allergy, non-allergic mast cell responses, type 1 hypersensitivity, urticaria, or familial sinusitis.

24. 22. The pharmaceutical composition of claim 21 for use in a method for treating or preventing airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, urticaria, or increased vascular permeability.

25. 22. The pharmaceutical composition of claim 21 for use in a method for treating or preventing eosinophilic granulomatosis with polyangiitis (also known as "Churg-Strauss syndrome"), aspirin-exacerbated respiratory disease, or cutaneous T-cell lymphoma.

26. 22. The pharmaceutical composition of claim 21 for use in a method for treating or preventing allergy, non-allergic mast cell responses, type 1 hypersensitivity, urticaria, familial sinusitis, eosinophilic granulomatosis with polyangiitis (also known as "Churg-Strauss syndrome"), aspirin-exacerbated respiratory disease, or cutaneous T-cell lymphoma.

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