Thiophene derivatives for the treatment of diseases caused by IgE

Abstract

Provided are thiophene derivatives of formula (I) and pharmaceutically acceptable salts thereof. These compounds can be used to treat or prevent diseases caused by IgE, such as allergies, type 1 hypersensitivity reactions, or common sinus inflammation. #imgabs0#

Description

Technical Field

[0001] The present invention relates to thiophene derivatives of formula (I), methods for preparing them, pharmaceutical compositions containing them and their use in treating diseases caused by IgE (e.g., allergic reactions, non-allergic mast cell reactions or certain autoimmune reactions), and in particular in treating diseases caused by the interaction of IgE with the FcεRI receptor. Background of the Invention

[0003] IgE (immunoglobulin E) is a member of the immunoglobulin family that mediates allergic reactions such as asthma, food allergies, type 1 hypersensitivity reactions, and familiar sinus inflammation.

[0004] IgE is secreted by B cells and expressed on the surface of B cells. The IgE synthesized by B cells is anchored in the B cell membrane by a transmembrane domain, which is connected to the mature IgE sequence by a short membrane binding region. IgE also binds to B cells (as well as monocytes, eosinophils and platelets) through its Fc region, forming a low-affinity IgE receptor or (FcεRII). After mammals are exposed to allergens, B cells are cloned and expanded, and they synthesize IgE that binds to the allergen. This IgE is in turn released by B cells into the circulation system and binds to B cells (via FcεRII) and binds to mast cells and basophils through the so-called high-affinity receptor (FcεRI) found on the surface of mast cells and basophils. This makes these mast cells and basophils sensitive to allergens. The next exposure to the allergen will cross-link the FcεRI on these cells, thereby activating them to release histamine and other factors that cause clinical hypersensitivity and allergic reactions.

[0005] Currently, allergic diseases, urticaria and asthma are typically treated with one or more of the following medications: (1) antihistamines and antileukotrienes, which antagonize the inflammatory mediators histamine and leukotrienes, (2) topical or systemic (oral or injectable) corticosteroids or immunosuppressants, which inhibit a wide range of inflammatory mechanisms, (3) short- or long-acting bronchodilators, which relax the smooth muscle that constricts the airways in asthma, or (4) mast cell stabilizers, which inhibit mast cell degranulation normally triggered by IgE binding at FcεRI, (5) biologics, which prevent IgE binding at FcεRI.

[0006] However, there remains a need to identify compounds that have therapeutic effects in the treatment or prevention of diseases caused by IgE, in particular diseases caused by the interaction of IgE with the FcεRI receptor. SUMMARY OF THE INVENTION

[0008] Surprisingly, it has been found that compounds of formula (I) and pharmaceutically acceptable salts thereof can be used for this purpose.

[0009] Detailed description

[0010] The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0011]

[0012] in

[0013] X represents CH, N or CR 4 , where when X is CR 4 When R 3 and R 4 Can be connected to form a 4-6 membered cycloalkyl or heterocyclic ring,

[0014] Any of them may be optionally substituted with one or more substituents selected from the group consisting of halogen, =O, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, aryl and heteroaryl, aryl and heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C1-C6 alkyl, C1-C6 alkoxy and C1-C2 haloalkyl;

[0015] 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;

[0016] When X represents CH or CR 4 When , 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;

[0017] When W, Y or Z is C, each C may be substituted by 1 or 2 groups independently selected from H, halogen, SF5, =O, =NOH, -OH, -CN, -C(O)Me, -C(O)OH, -C(O)NH2, NH-C(O)O-C1-C4 alkyl, -NO2, NH2, NHMe, NMe2, SH, SMe, SOMe, SO2Me, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, heterocycle, C1-C4 heteroalkyl, which may be linked to form a 3-6 membered cycloalkyl or a 4-6 membered heterocycle,

[0018] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a 3-6 membered cycloalkyl or a 4-6 membered heterocyclic ring;

[0019] in

[0020] When W, Y or Z is N, the N may be independently substituted by H, C1-C4 alkyl, C3-C4 cycloalkyl, heterocycle, -C(O)Me, -C(O)NH2, -C(O)OH, -S(O)Me, -S(O)2Me, -S(O)2NH2, any of which may be optionally substituted by one or more substituents selected from halogen, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2;

[0021] and W, X, Y and Z may be linked directly or through substituents to form a ring;

[0022] R 1 Selected from -C(O)OR 5 ,-C(O)N(R 6 )(R 7 ), -S(O)2N(R 8 )(R 9 ), -S(O)2R 10 , -S(O)R 10 and -S(O)(=NR 11 )R 10 ;

[0023] R 2 Represents -N(R 12 )C(O)R 13 ;

[0024] R 3 Selected from H, -OH, C1-C8 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-Rc , -COOH, -COO-C1-C8 alkyl, -CO-C1-C8 alkyl, -C1-C8 alkylene-COO-C1-C8 alkyl, -C1-C8 alkylene-NR a -COO-C1-C8 alkyl, -C1-C8 alkylene-NR d R c , -C1-C8 alkylene-NH-R 14 -NH-R a , heteroaryl, -CN, -CH=N-OH, -CF3, alkylamino, amino, -NH-SO-C1-C8 alkyl, -NH-SO2-C1-C8 alkyl, heteroalkyl-amino, aryl, heterocycle, C3-C6 cycloalkyl, -NHS(O)(=NH)Me, -SO2-C1-C8 alkyl, -NH-C(CH3)=N-CN, -NH-CH=N-CN, -NH-S(=O)(=N)-C1-C2 alkyl,

[0025] Any of them may be optionally substituted by one or more substituents selected from halogen, -OH, =O, -COOH, -COH, -CN, SMe, -NR d R c , -OR c , C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, C1-C2 alkylene-O-C1-C2 alkyl, C1-C2 alkylene-C3-C4 cycloalkyl, heterocycle, C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 cycloalkyl-amino, heterocycle-amino, aryl-amino, heteroaryl-amino, -CONR d R c ,-NHCO-R a , -NHCOO-C1-C4 alkyl, -CO-C1-C2 alkyl, -COO-R a , which can be connected to form a ring, and wherein -CONR d R c and -NR d R c can be linked to form a seven-membered ring fused to a six-membered aryl group;

[0026] Aryl, heteroaryl, heterocycle and cycloalkyl are optionally substituted by one or more substituents selected from halogen, oxo, cyano, OH, -NOOH, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6-cycloalkyl-C1-C3-alkoxy, -O-CO-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C2 haloalkyl, C2-C4 heterocycle, acetyl, acetyl-phenyl, -CONR d R c , COO-C1-C8 alkyl, -S(O)NH-C1-C2-alkyl, -S(O) n - C1-C2-alkyl, heteroaryl, which may optionally be substituted by one or more halogen groups, C1-C2-alkyl,

[0027] n is equal to 0, 1 or 2;

[0028] R 4 Selected from halogen, OH, CN, NO2, NH2, NHMe, NMe2, SH, SMe, SOMe, SO2Me, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C1-C3 heteroalkyl, heterocycle,

[0029] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0030] R 5 Selected from C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C3-C8 cycloalkyl, heterocycle, C4-C8 cycloalkenyl, aryl, heteroaryl, -C1-C2 alkylene-C3-C6 cycloalkyl, -C1-C2 alkylene-heterocycle, -C1-C2 alkylene-aryl, -C1-C2 alkylene-heteroaryl,

[0031] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, -O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0032] R 6 , R 8 and R 12 independently selected from H and C1-C3 alkyl,

[0033] Any of them may be optionally substituted with 1 to 7 halogens;

[0034] R 7 , R 9 and R 11 independently selected from H, C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C3-C8 cycloalkyl, heterocycle, C4-C8 cycloalkenyl, C3-C8 heterocyclealkenyl, aryl, heteroaryl, -C1-C2 alkylene-C3-C6 cycloalkyl, -C1-C2 alkylene-heterocycle, -C1-C2 alkylene-aryl, -C1-C2 alkylene-heteroaryl, -N-C1-C7 alkyl, -N-C3-C8 cycloalkyl, -N-heterocycle, -N-heteroaryl, C1-C7 alkoxy, -O-C3-C8 cycloalkyl, -O-heterocycle, -O-heteroaryl,

[0035] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, -O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0036] R 10 selected from H, C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C3-C8 cycloalkyl, heterocycle, C4-C8 cycloalkenyl, C3-C8 heterocyclealkenyl, aryl, heteroaryl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C1-C3 alkylene-heterocycle, -C1-C3 alkylene-aryl, -C1-C3 alkylene-heteroaryl, -N-C1-C8 alkyl,

[0037] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, -O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0038] R 13 Selected from C1-C7 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, -C1-C2 alkylene-C3-C6 cycloalkyl, C3-C5 heterocycle,

[0039] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a cycloalkyl or heterocycle;

[0040] R 6 and R 7 Can be connected to each other to form a ring;

[0041] R 8 and R 9 Can be connected to each other to form a ring;

[0042] R 12 and R 13 Can be connected to each other to form a ring;

[0043] R 14 C=O, C=S, C=N-OH, C=NR b , C═CH-NO2, SO2 and C3-C6 cycloalkenyl, which may be substituted by 1 or 2 ═O;

[0044] R a is selected from H, C1-C8 alkyl, heteroalkyl, C1-C8 alkoxy, heterocycle, C3-C8 cycloalkyl, heteroaryl and aryl,

[0045] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, -O-C1-C2 haloalkyl, C1-C2 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, aryl, heteroaryl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0046] R b Selected from CN, aryl, heteroaryl, -NO2, -O-C1-C2 alkyl, -CO-O-C1-C2 alkyl,

[0047] Aryl and heteroaryl are optionally substituted with one or more C1-C2 alkyl groups;

[0048] R c Selected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C4 alkylene-C3-C6 cycloalkyl;

[0049] Any of them may be optionally substituted by one or more substituents selected from C(O)(R g), C(O)N(R f )(R g ), halogen, SF5, OH, =O, -COH, -COOH, -CO-OR a ,CN,SMe,SO2Me,SO2R g , C1-C4 alkoxy, O-C1-C4 haloalkyl, C1-C4 alkyl, C1-C2 heteroalkyl, C1-C4 haloalkyl, N(R f )(R g ), N(R f )SO2(R g ), SO2NH2, SO2NHMe, SO2NMe2, S(O)(NR f )R g , C3-C6 cycloalkyl, heterocycle, C1-C4 alkylene-C3-C6 cycloalkyl, aryl and heteroaryl, which may be linked to form a ring;

[0050] Aryl, heteroaryl, heterocycle and cycloalkyl are optionally substituted with one or more substituents selected from halogen, =O, =NH, =NMe, OH, C1-C2 alkyl, C1-C2 alkoxy, -COOH, -COO-C1-C2 alkyl, SO2R a , COR a , SOR a ,S(O)(NH)R a , CONHR a , which can be connected to form a ring;

[0051] R d represents H or C1-C4 alkyl;

[0052] And R c and R d Can be linked to form heterocyclic rings;

[0053] R e Selected from -C(O)OR a ,-C(O)N(R f )(R g ), aryl, heteroaryl, C1-C2 haloalkyl, -CN, wherein R f and R g Can be connected to form a ring,

[0054] Aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C2 haloalkyl, C1-C2 alkyl;

[0055] R fSelected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C4 alkylene-C3-C6 cycloalkyl,

[0056] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, =NH, =NMe, OH, aryl, heteroaryl, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, O-C1-C2 haloalkyl, -COOH, -COO-C1-C2 alkyl, SO2R a , COR a , SOR a ,S(O)(NH)R a , CONHR a ;

[0057] R g Selected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C4 alkylene-C3-C6 cycloalkyl,

[0058] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, =NH, =NMe, OH, aryl, heteroaryl, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, O-C1-C2 haloalkyl, -COOH, -COO-C1-C2 alkyl, SO2R a , COR a , SOR a ,S(O)(NH)R a , CONHR a ,

[0059] R f and R g Can be connected to form a ring.

[0060] According to another embodiment, the compound of the present invention is according to formula (Ia)

[0061]

[0062] in

[0063] X represents CH, N or CR 4 , where when X is CR 4 When R 3 and R 4 Can be connected to form a 4-6 membered cycloalkyl or heterocyclic ring,

[0064] Any of them may be optionally substituted with one or more substituents selected from the group consisting of halogen, =O, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, aryl and heteroaryl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C1-C6 alkyl, C1-C6 alkoxy and C1-C2 haloalkyl;

[0065] 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;

[0066] When X represents CH or CR 4 When , 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;

[0067] When W, Y or Z is C, each C may be substituted by 1 or 2 groups independently selected from H, halogen, SF5, =O, =NOH, -OH, -CN, -C(O)Me, -C(O)OH, -C(O)NH2, NH-C(O)O-C1-C4 alkyl, -NO2, NH2, NHMe, NMe2, SH, SMe, SOMe, SO2Me, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 alkoxy, heterocycle, C1-C4 heteroalkyl, which may be linked to form a 3-6 membered cycloalkyl or a 4-6 membered heterocycle,

[0068] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a 3-6 membered cycloalkyl or a 4-6 membered heterocyclic ring;

[0069] in

[0070] When W, Y or Z is N, the N may be independently substituted by H, C1-C4 alkyl, C3-C4 cycloalkyl, heterocycle, -C(O)Me, -C(O)NH2, -C(O)OH, -S(O)Me, -S(O)2Me, -S(O)2NH2, any of which may be optionally substituted by one or more substituents selected from halogen, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2;

[0071] and W, X, Y and Z may be linked directly or through substituents to form a ring;

[0072] R 1 Selected from -C(O)OR 5 ,-C(O)N(R 6 )(R 7 ), -S(O)2N(R 8 )(R 9 ), -S(O)2R 10 , -S(O)R 10 and -S(O)(=NR 11 )R 10 ;

[0073] R 2 Represents -N(R 12 )C(O)R 13 ;

[0074] R 3 Selected from H, -OH, C1-C8 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-C1-C8 alkyl, -CO-C1-C8 alkyl, -C1-C8 alkylene-COO-C1-C8 alkyl, -C1-C8 alkylene-NR a -COO-C1-C8 alkyl, -C1-C8 alkylene-NR d R c , -C1-C8 alkylene-NH-R 14 -NH-R a , heteroaryl, -CN, -CH=N-OH, -CF3, alkylamino, amino, -NH-SO-C1-C8 alkyl, -NH-SO2-C1-C8 alkyl, heteroalkyl-amino, aryl, heterocycle, C3-C6 cycloalkyl, -NHS(O)(=NH)Me, -SO2-C1-C8 alkyl, -NH-C(CH3)=N-CN, -NH-CH=N-CN, -NH-S(=O)(=N)-C1-C2 alkyl,

[0075] Any of them may be optionally substituted by one or more substituents selected from halogen, -OH, =O, -COOH, -COH, -CN, SMe, -NR d R c , -OR c , C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, C1-C2 alkylene-O-C1-C2 alkyl, C1-C2 alkylene-C3-C4 cycloalkyl, heterocycle, C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 cycloalkyl-amino, heterocycle-amino, aryl-amino, heteroaryl-amino, -CONR d R c ,-NHCO-R a , -NHCOO-C1-C4 alkyl, -CO-C1-C2 alkyl, -COO-R a , which can be connected to form a ring;

[0076] Aryl, heteroaryl, heterocycle and cycloalkyl are optionally substituted with one or more substituents selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, -O-CO-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C2 haloalkyl and C2-C4 heterocycle;

[0077] R 4 Selected from halogen, OH, CN, NO2, NH2, NHMe, NMe2, SH, SMe, SOMe, SO2Me, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C1-C3 heteroalkyl, heterocycle,

[0078] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0079] R 5 Selected from C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C3-C8 cycloalkyl, heterocycle, C4-C8 cycloalkenyl, aryl, heteroaryl, -C1-C2 alkylene-C3-C6 cycloalkyl, -C1-C2 alkylene-heterocycle, -C1-C2 alkylene-aryl, -C1-C2 alkylene-heteroaryl,

[0080] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, -O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0081] R 6 , R 8 and R 12 independently selected from H and C1-C3 alkyl,

[0082] Any of them may be optionally substituted with 1 to 7 halogens;

[0083] R 7 , R 9 and R 11 independently selected from H, C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C3-C8 cycloalkyl, heterocycle, C4-C8 cycloalkenyl, C3-C8 heterocyclealkenyl, aryl, heteroaryl, -C1-C2 alkylene-C3-C6 cycloalkyl, -C1-C2 alkylene-heterocycle, -C1-C2 alkylene-aryl, -C1-C2 alkylene-heteroaryl, -N-C1-C7 alkyl, -N-C3-C8 cycloalkyl, -N-heterocycle, -N-heteroaryl, C1-C7 alkoxy, -O-C3-C8 cycloalkyl, -O-heterocycle, -O-heteroaryl,

[0084] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, -O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0085] R 10 selected from H, C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C3-C8 cycloalkyl, heterocycle, C4-C8 cycloalkenyl, C3-C8 heterocyclealkenyl, aryl, heteroaryl, -C1-C3 alkylene-C3-C6 cycloalkyl, -C1-C3 alkylene-heterocycle, -C1-C3 alkylene-aryl, -C1-C3 alkylene-heteroaryl, -N-C1-C8 alkyl,

[0086] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, -O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0087] R 13 Selected from C1-C7 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, -C1-C2 alkylene-C3-C6 cycloalkyl, C3-C5 heterocycle,

[0088] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, O-C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, NH2, NHMe, NMe2, which may be linked to form a cycloalkyl or heterocycle;

[0089] R 6 and R 7 Can be connected to each other to form a ring;

[0090] R 8 and R 9 Can be connected to each other to form a ring;

[0091] R 12 and R 13 Can be connected to each other to form a ring;

[0092] R 14 C=O, C=S, C=N-OH, C=NR b , C═CH-NO2, SO2 and C3-C6 cycloalkenyl, which may be substituted by 1 or 2 ═O;

[0093] R a is selected from H, C1-C8 alkyl, heteroalkyl, C1-C8 alkoxy, heterocycle, C3-C8 cycloalkyl, heteroaryl and aryl,

[0094] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, OH, SMe, C1-C2 alkoxy, -O-C1-C2 haloalkyl, C1-C2 alkyl, C3-C6 cycloalkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, aryl, heteroaryl, NH2, NHMe, NMe2, which may be linked to form a ring;

[0095] R b Selected from CN, aryl, heteroaryl, -NO2, -O-C1-C2 alkyl, -CO-O-C1-C2 alkyl,

[0096] Aryl and heteroaryl are optionally substituted with one or more C1-C2 alkyl groups;

[0097] R c Selected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C4 alkylene-C3-C6 cycloalkyl,

[0098] Any of them may be optionally substituted by one or more substituents selected from C(O)(R g ), C(O)N(R f )(R g ), halogen, SF5, OH, =O, -COH, -COOH, -CO-OR a ,CN,SMe,SO2Me,SO2R g , C1-C4 alkoxy, O-C1-C4 haloalkyl, C1-C4 alkyl, C1-C2 heteroalkyl, C1-C4 haloalkyl, N(R f )(R g ), N(R f )SO2(R g ), SO2NH2, SO2NHMe, SO2NMe2, S(O)(NR f )R g , C3-C6 cycloalkyl, heterocycle, C1-C4 alkylene-C3-C6 cycloalkyl, aryl and heteroaryl, which may be linked to form a ring;

[0099] Aryl, heteroaryl, heterocycle and cycloalkyl are optionally substituted with one or more substituents selected from halogen, =O, =NH, =NMe, OH, C1-C2 alkyl, C1-C2 alkoxy, -COOH, -COO-C1-C2 alkyl, SO2R a , COR a , SOR a ,S(O)(NH)R a , CONHR a , which can be connected to form a ring;

[0100] R d represents H or C1-C4 alkyl;

[0101] And R c and R d Can be linked to form heterocyclic rings;

[0102] R e Selected from -C(O)OR a ,-C(O)N(R f )(R g), aryl, heteroaryl, C1-C2 haloalkyl, -CN, wherein R f and R g Can be connected to form a ring,

[0103] Aryl and heteroaryl are optionally substituted with one or more substituents selected from C1-C2 haloalkyl, C1-C2 alkyl;

[0104] R f Selected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C4 alkylene-C3-C6 cycloalkyl,

[0105] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, =NH, =NMe, OH, aryl, heteroaryl, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, O-C1-C2 haloalkyl, -COOH, -COO-C1-C2 alkyl, SO2R a , COR a , SOR a ,S(O)(NH)R a , CONHR a ;

[0106] R g Selected from H, aryl, heteroaryl, C3-C6 cycloalkenyl, C3-C8 cycloalkyl, heterocycle, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C4 alkylene-C3-C6 cycloalkyl,

[0107] Any of them may be optionally substituted by one or more substituents selected from halogen, =O, =NH, =NMe, OH, aryl, heteroaryl, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, O-C1-C2 haloalkyl, -COOH, -COO-C1-C2 alkyl, SO2R a , COR a , SOR a ,S(O)(NH)R a , CONHR a ,

[0108] R f and R g Can be connected to form a ring.

[0109] In a preferred embodiment of the present invention, X, W, Y and Z are preferably C, or X, W and Y are preferably C and Z is preferably O, which may all be substituted as described above.

[0110] More preferably, X is CH and W, Y and Z are independently selected from CH2, CH(C1-C2 alkyl), CH(C1-C2 haloalkyl), C(C1-C2 alkyl)2 and spiro-cyclopropyl.Most preferably, X is CH and W, Y and Z are CH2.

[0111] In this case, preferred compounds are characterized by formula (II):

[0112]

[0113] where R 1 , R 2 and R 3 As defined in formula (I) or (Ia).

[0114] A preferred embodiment according to the present invention is a compound of formula (I), (Ia) or (II) and its salts, wherein R 1 , R 2 and R 3 Definitions are as follows. Those skilled in the art will appreciate that the present invention also encompasses compounds of formula (I), (Ia) and (II) and salts thereof, wherein the various substituents are independently selected from these embodiments, preferred embodiments, more preferred embodiments, preferably, more preferably, even more preferably, most preferably specific embodiments, preferred specific embodiments, specifically preferred embodiments, specifically more preferred embodiments, particularly preferred embodiments, and optimal results. This also includes compounds of formula (III) to (XXIV) as defined below.

[0115] If R 1 Selected from -S(O)2R 10 , -S(O)R 10 and -S(O)(=NR 11 )R 10 , then R 10 Preferably nBu and R 11 For H.

[0116] If R 1 stands for -C(O)OR 5 , then R 5 Preferably

[0117]

[0118] In a more preferred embodiment, R 1 -C(O)N(R 6 )(R 7 ) or -S(O)2N(R 8 )(R 9 ), where R 6 , R 7 , R8 and R 9 As defined above;

[0119] More preferably, R 1 -C(O)N(R 6 )(R 7 ) or -S(O)2N(R 8 )(R 9 );

[0120] where R 6 and R 8 is selected from H and C1-C3 alkyl, and most preferably R 6 and R 8 is H; and

[0121] R 7 and R 9 is selected from C1-C8 alkyl, C3-C6 cycloalkyl and -C1-C2 alkylene-C3-C6 cycloalkyl, any one of which may be optionally substituted by 1-4 halogens and the cycloalkyl may be substituted by C1-C8 alkyl, and most preferably R 7 for

[0122]

[0123] And R 9 for

[0124]

[0125] Even more preferably R 1 for

[0126]

[0127] And the most preferred R 1 for

[0128]

[0129] R 2 Preferably represents -N(R 12 )C(O)R 13 ,

[0130] where R 12 is selected from H and C1-C3 alkyl, and R 13 is selected from C1-C7 alkyl, C3-C8 cycloalkyl and -C1-C2 alkylene-C3-C6 cycloalkyl, any one of which may be optionally substituted with 1-5 substituents selected from halogen and C1-C2 alkyl, which may be linked to form a cycloalkyl ring,

[0131] More preferably, R 2 represent

[0132]

[0133] And most preferably R 2 represent

[0134]

[0135] In a preferred embodiment, R 3 Selected from -NHR c , -NH-R 14 -NH-R a and heteroaryl,

[0136] Any of them may be substituted by one or more substituents selected from -NHR c ,-C(O)OR a , -C(O)NR d R c , aryl, heteroaryl, C1-C2 haloalkyl and -CN, where R c is selected from H, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted aryl,

[0137] The substituents of aryl, heterocycle and heteroaryl are selected from halogen, -CN, -C(O)OH, -C(O)O-C1-C2 alkyl, -C(O)Me, -S(O)Me, -S(O)(O)Me, -S(O)(=NH)Me, heterocycle, C1-C4 alkyl, C1-C2 heteroalkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, aryl, heteroaryl, C3-C8 cycloalkyl.

[0138] In a particularly preferred embodiment, R 3 is a heteroaryl group containing at least one nitrogen as a heteroatom, which may be replaced by -NR d R c or -NR d R c and -C(O)O-C1-C2 alkyl substituted,

[0139] R c is selected from H, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted aryl,

[0140] wherein the substituents of aryl, heterocycle and heteroaryl are selected from -CN, -C(O)O-C1-C2 alkyl, C1-C4 alkyl, C1-C2 haloalkyl, C3-C6 cycloalkyl, C1-C2 haloalkoxy, -S(O)Me and -S(O)(O)Me, and

[0141] R d Represents H.

[0142] In a particularly more preferred embodiment, R 3 is a heteroaryl group containing at least two nitrogen atoms as heteroatoms, which can be replaced by -NHR c or -NHR c and -C(O)O-C1-C2 alkyl substituted,

[0143] R c is selected from H or an optionally substituted heteroaryl group containing at least one nitrogen atom as heteroatom,

[0144] The substituents of the heteroaryl group are selected from C1-C3 alkyl, C1-C2 haloalkyl and C1-C2 haloalkoxy, wherein at least one halogen atom is a fluorine atom.

[0145] R 3 To be available for NHR c The best results were obtained with substituted heteroaryl groups containing 3 nitrogen as heteroatoms,

[0146] R c is an optionally substituted heteroaryl group containing at least one nitrogen as heteroatom,

[0147] The substituents of the heteroaryl group are selected from methyl, ethyl, difluoromethyl or trifluoromethyl.

[0148] Most preferably R 3 for

[0149]

[0150] In a particularly preferred embodiment of the present invention, the compounds of formula (I) or (Ia) or (XXXVI) and pharmaceutically acceptable salts thereof are those wherein:

[0151] R 1 for

[0152]

[0153] R 2 for

[0154] and / or

[0155] R 3 for

[0156]

[0157] 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.

[0158] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein R 1 is selected from 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-fluoroazetidine-1-carbonyl, piperidine-1-carbonyl, cyclopropylmethoxycarbonyl, ethoxycarbonyl, isobutyl-aminocarbonyl, 5-azaspiro[2.4]heptane-5-carbonyl, (3,3-difluorocyclobutyl)carbamoyl, (3-fluorocyclobutyl)carbamoyl, (2-fluoro-2-methyl-propyl)carbamoyl, isobutylcarbamoyl, 3-methylpyrrolidine-1-carbonyl, propylcarbamoyl, and other substituents are defined below.

[0159] In another embodiment, the compounds are characterized by formula (I) or (Ia), wherein R 2 is selected from cyclopropanecarbonylamino, 2-methylpropionylamino, cyclobutanecarbonylamino, (2-methylcyclopropanecarbonyl)amino, and other substituents are as defined above and below.

[0160] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein X, Y, W are C and Z is N, wherein N is substituted by a group selected from methylsulfonyl, acetylethylcarbamoyl, cyano, and the other substituents are as defined above and below.

[0161] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein X, Y, W, Z are C and wherein Z is substituted by a group selected from the group consisting of OH, methyl, ethylcarbamoyl, cyano, oxo, tert-butoxycarbonylamino, 1H-pyrazol-3-yl, and the other substituents are as defined above and below.

[0162] In another embodiment, the compounds are characterized by formula (I) or (Ia), wherein X, Y, W, Z are C, and wherein W is substituted by methyl and R 3 is H or methyl, and the other substituents are as defined above and below.

[0163] In a further embodiment, the compounds of the invention are characterized by formula (I) or (Ia), wherein X is C or N, and R 3selected from H, OH, methyl, amino, methylsulfonyl, acetyl, 2-methoxyacetyl, 2-phenylacetyl, 2-(tert-butoxycarbonylamino)ethyl, 2-phenylethyl, pyrimidin-2-ylamino, methylsulfonylamino, (4-methoxyphenyl)carbamothioylamino, (4-methoxyphenyl)carbamoylamino, ethylcarbamoyl, [N'-cyano-N-(p-tolyl)carbamimidoyl]amino, [N'-cyano-N-ethylcarbamimidoyl]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, carboxyl, (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-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-pyridylcarbamoylaminothioylamino yl, 3-(3-pyridinylamino)-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-carbamimidazol-1-yl, 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-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-(4-pyridinylamino)-1,2,4-triazol-4-yl, N'-cyano-N-(3,4-dimethoxyphenyl)carbamimidazol-4-yl]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)carbamimidazol-4-yl]amino, 3-( 1,2,4-triazol-4-yl, (N-ethyl-N'-nitro-carbamimidino)amino, 3-(3-pyridinylamino)-1,2,4-triazol-4-yl, 3-[(1-oxypyridin-1-ium-3-yl)amino, [N'-nitro-N-(p-tolyl)carbamimidino]amino, 2-(3-pyridinylamino)imidazol-1-yl, 3-(3-pyridinylamino)-1,2,4-triazol-4-yl, 3-(cyclopropylmethylamino, (2,5-dimethylpyrazol-3-yl)aminothiocarboxylamino, 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-pyridinylamino)-1,2,4-triazol-4-yl, 2-acetamidoimidazol-1-yl, 5-(N-tert-butoxycarbonylamino)-triazol-1-yl, 5-(3-pyridinylamino)triazol-1-yl, ethylaminothiocarboxylamino, 3-[[(3S)-tetrahydrofuran-3-yl]amino]-1,2,4-triazol-4-yl, [(E)-N-ethyl-N'-nitro 1-[(ethylamino)-2-nitro-vinyl]amino]-1-yl, (4-methyl-6-oxo-1H-pyrimidin-2-yl)amino, 5-amino-4-(methylcarbamoyl)imidazol-1-yl, 5-amino-4-carbamoyl-imidazol-1-yl, 2-anilinimidazol-1-yl, ethylcarbamoylamino, (4-oxo-1H-pyridin-2-yl)amino, [6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-pyridinyl]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-(ethoxycarbonyl)imidazol-1-yl, [4-(4-fluorophenyl)-1,2,4-triazol-3-yl]amino, 1H-imidazol-2-ylamino, N'-methoxy-N-(p-tolyl)carbamimidyl]amino, [4-(4-methylanilino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino, [1-(3-pyridinyl)imidazol-2-yl]amino, 5-aminotriazol-1-yl, (2-methoxyphenyl)carbamoylamino, 4- Pyridine-carbonylamino, benzylamino, 1H-benzimidazol-2-ylamino, [N'-hydroxycarbamimidino]amino, [N'-(1-methylpyrazol-3-yl)-N-(p-tolyl)carbamimidino]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-oxadiazole oxazol-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, (methylsulfimidoyl)amino, [N-cyano-C-methyl-carbonimidoyl]amino, tetrazol-1-yl, methylsulfimidoyl, morpholino, 3-(ethylamino)-5-(trifluoromethyl)-1,2,4-triazol-4-yl, (4-oxo-1H-pyrimidin-2-yl)amino, isopropyl amino, 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, 2-[(2,5-dimethylpyrazol-3-yl)-methyl-amino]-1,2,4-triazol-4-yl, 2-[(2,5-dimethylpyrazol-3-yl)-methyl-amino]-1,2,4-triazol-4-yl, 3-[(2,5-dimethylpyrazol-3-yl)-methyl-amino]-1,2,4-triazol-4-yl, 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-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, -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- 3-yl)amino]-1,2,4-triazol-4-yl, [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, [3-[(5-carboxy-2-methyl-pyrazol-3-yl)amino]-1,2,4-triazol-4-yl], and other substituents are as defined above and below.

[0164] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein W, X, Y, Z are C and Z is optionally substituted with methyl, and the other substituents are as defined above and below.

[0165] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein R 1Selected from (cyclopropylmethyl)carbamoyl, (3-fluorocyclobutylmethyl)carbamoyl, (2-fluorocyclopropyl)methyl-carbamoyl, (2,2-difluorocyclopropyl)methyl-carbamoyl, (2,2-dimethylcyclopropyl)methylcarbamoyl, (spiro[2.2]pentan-2-yl)carbamoyl, (spiro[2.2]pentan-2-yl)methyl-carbamoyl, (3,3-difluorocyclobutyl)carbamoyl, (3-fluorocyclobutyl)carbamoyl, (2-methylcyclopropyl)methylcarbamoyl )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.

[0166] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein R 2 is 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-difluoropropionylamino, (cyclobutyl)carbonylamino, 2-(methylpropionyl)amino, and the other substituents are as defined above and below.

[0167] In a further embodiment, the compound is characterized by formula (I) or (Ia), wherein R 3Selected from (1,1-dioxothiol-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-ylpyrrolidin-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 oxazol-4-yl, 3-[[1-pyrimidin-2-ylpyrrolidin-3-yl]amino]-1,2,4-triazol-4-yl, 5-amino-4-(2-methoxyethoxycarbonyl)imidazol-1-yl, 5-amino-4-(2-morpholinoethoxycarbonyl)imidazol-1-yl, 3-(3-methylsulfanylanilino)-1,2,4-triazol-4-yl, 3-(3-methylsulfonylanilino)-1,2,4-triazol-4-yl, 3-(3-methylsulfinylanilino)-1,2,4-triazol-4-yl, 1,2,4-triazol-4-yl, 3-[3-(methylsulfinyl)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]benzodiazepine -1-yl, 8-methoxy-5-methyl-4-oxo-10H-imidazo[4,5-c][1,5]benzodiazepine -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-methylsulfonylpyrrolidin-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-piperidinyl)amino]-1,2,4-triazol-4-yl, 3-[(1-acetyl-2-methyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-4-yl -3-yl)amino]-1,2,4-triazol-4-yl, 3-[(2-methyl-1-methylsulfonyl-pyrrolidin-3-yl)amino]-1,2,4-triazol-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-piperidinyl)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-triazol-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-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-[(6-cyano-2-methyl-3-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-[(1-methyl-2-oxo-4-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-[(6-chloro-2-methyl-3-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl ]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, 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- 3-[5-(difluoromethyl)-2-methylpyrazol-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-(trideuteratedmethyl)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-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-[[5-(cyclopropyloxy)-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-pyridinyl]amino]-1,2,4-triazol-4-yl, 3-[(6-methoxy-3-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-[(2-methoxy-4-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-[(6-chloro-3-pyridinyl)amino]-1,2,4-triazol- 4-yl, 3-[(2-chloro-4-pyridinyl)amino]-1,2,4-triazol-4-yl, 3-[(6-methoxy-2-methyl-3-pyridinyl)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, and other substituents are as defined above and below.

[0168] In another embodiment, the compound is characterized by formula (III) or (IV)

[0169]

[0170] where R 3 , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 As defined in formula (I) or (Ia).

[0171] In another embodiment, the compound is characterized by formula (V) or (VI)

[0172]

[0173] where R a , R c , R d , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 and R 14 As defined in formula (I) or (Ia);

[0174] R 3 is an optionally substituted NR as defined in formula (I) or (Ia) c R d , NH-R 14 -NH-R a , heteroaryl.

[0175] In another preferred embodiment, the compound is characterized by formula (VII) or (VIII)

[0176]

[0177] where R 6 , R 7 , R 8 , R 9 , R 12 and R 13 As defined in formula (I) or (Ia);

[0178] R 3 is an optionally substituted heteroaryl group as defined in formula (I) or (Ia).

[0179] In another preferred embodiment, the compound is characterized by formula (IX) or (X)

[0180]

[0181] where R c , R d , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 As defined in formula (I) or (Ia).

[0182] In another preferred embodiment, the compound is characterized by formula (XI) or (XII)

[0183]

[0184] where R c , R d , R e , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 As defined in formula (I) or (Ia).

[0185] In another preferred embodiment, the compound is characterized by formula (XIII) or (XIV)

[0186]

[0187] where R a , R 6 , R 7 , R 8 , R9 , R 12 and R 13 As defined in formula (I) or (Ia).

[0188] In another preferred embodiment, the compound is characterized by formula (XV) or (XVI)

[0189]

[0190] where R a , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 As defined in formula (I) or (Ia).

[0191] In another preferred embodiment, the compound is characterized by formula (XVII) or (XVIII)

[0192]

[0193] where R c , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 As defined in formula (I).

[0194] In another preferred embodiment, the compound is characterized by formula (XIX) or (XX)

[0195]

[0196] where R c , R e , R 6 , R 7 , R 8 , R 9 , R 12 and R 13 As defined in formula (I) or (Ia).

[0197] In another preferred embodiment, the compound is characterized by formula (XXI) or (XXII)

[0198]

[0199] where R c , R 6 , R 7 , R 8, R 9 and R 13 As defined in formula (I) or (Ia).

[0200] In another preferred embodiment, the compound is characterized by formula (XXIII) or (XXIV)

[0201]

[0202] where R c , R e , R 6 , R 7 , R 8 , R 9 and R 13 As defined in formula (I) or (Ia).

[0203] In another preferred embodiment, the compound is characterized by formula (XXV) or (XXVI)

[0204]

[0205] In another preferred embodiment, the compound is characterized by formula (XXVII) or (XXVIII)

[0206]

[0207] In another preferred embodiment, the compound is characterized by formula (XXIX) or (XXX)

[0208]

[0209] In another preferred embodiment, the compound is characterized by formula (XXXI) or (XXXII)

[0210]

[0211] In another preferred embodiment, the compound is characterized by formula (XXXII) or (XXXIV)

[0212]

[0213] In another preferred embodiment, the compound is characterized by formula (XXXV) or (XXXVI)

[0214]

[0215] Specific compounds of formula (I) or (XXXVI) according to the present invention are selected from:

[0216]

[0217] 2-(Cyclopropanecarbonylamino)-N-methyl-5,7-dihydro-4H-thieno[2,3-c]thiopyran-3-carboxamide

[0218]

[0219] 6-(Cyclopropanecarbonylamino)-N-methyl-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxamide

[0220]

[0221] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxamide; hydrochloride

[0222]

[0223] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methylsulfonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide

[0224]

[0225] 5-Acetyl-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide

[0226]

[0227] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-methylsulfonyl-5,6-dihydro-4H-thieno[2,3-b]pyridine-3-carboxamide

[0228]

[0229] 7-Acetyl-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,6-dihydro-4H-thieno[2,3-b]pyridine-3-carboxamide

[0230]

[0231] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-methoxyacetyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide

[0232]

[0233] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-phenylacetyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide

[0234]

[0235] tert-Butyl N-[2-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]ethyl]carbamate

[0236]

[0237] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(2-phenylethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxamide

[0238]

[0239] Methyl 2-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]acetate

[0240]

[0241] (4R)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide

[0242] (4S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide

[0243]

[0244] N-[3-(Cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0245]

[0246] N-[3-(Propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0247]

[0248] N-[3-(Isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0249]

[0250] N-[3-[(2-Hydroxy-2-methyl-propyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0251]

[0252] N-[3-(2-Hydroxypropylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0253]

[0254] N-(3-Pyrrolidin-1-ylsulfonyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide

[0255] N-[3-[(3-Fluorocyclobutyl)sulfamoyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0256]

[0257] N-(3-Butylsulfonyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide

[0258]

[0259] N-[3-(Isobutylsulfamoyl)-5-(pyrimidin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0260]

[0261] N-[3-(Isobutylsulfamoyl)-5-(methylsulfonylamino)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0262]

[0263] N-[5-[(4-Methoxyphenyl)carbamothioylamino]-3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0264]

[0265] N-[5-[(4-Methoxyphenyl)carbamoylamino]-3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0266]

[0267] 2-(Cyclopropanecarbonylamino)-N-ethyl-3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxamide

[0268]

[0269] 2-(Cyclopropanecarbonylamino)-N-ethyl-3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide

[0270]

[0271] N-(3-Butylsulfinyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide

[0272]

[0273] N-[5-[[N'-cyano-N-(p-tolyl)carbamimidoyl]amino]-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0274]

[0275] N-[5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0276]

[0277] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(1-oxoisoindolin-5-yl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide

[0278]

[0279] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-sulfamoylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide

[0280]

[0281] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-methylsulfonylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide

[0282]

[0283] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-N-(3-isoxazol-5-ylphenyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide

[0284]

[0285] N-[3-(Cyclopropylmethylsulfamoyl)-5-[(2-ethoxy-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0286]

[0287] N-[3-(Cyclopropylmethylsulfamoyl)-5-[[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0288]

[0289] N-[3-(Butylsulfimidoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0290]

[0291] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid ethyl ester

[0292]

[0293] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid

[0294]

[0295] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1-oxoisoindolin-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0296]

[0297] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[3-(5-oxopyrrolidin-3-yl)phenyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0298]

[0299] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[3-(3-methyl-5-oxo-4H-pyrazol-1-yl)phenyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0300]

[0301] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-indazol-4-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2,2,2-trifluoroacetic acid

[0302]

[0303] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-indazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide; 2,2,2-trifluoroacetic acid

[0304]

[0305] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-imidazo[4,5-b]pyrazin-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0306]

[0307] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-indan-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0308]

[0309] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[2-(4-methoxyphenyl)ethyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0310]

[0311] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-quinoxalin-6-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0312]

[0313] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-thiazol-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0314]

[0315] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(1H-tetrazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0316]

[0317] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(4-pyridyl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0318]

[0319] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-pyrazin-2-yl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0320]

[0321] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-(3-pyridyl)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0322]

[0323] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(3-hydroxyazetidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0324]

[0325] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0326]

[0327] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-[2-(4-hydroxyphenyl)ethyl]-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[0328]

[0329] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(hydroxyiminomethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0330]

[0331] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(4-ethyl-1,2,4-triazol-3-yl)amino]methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0332]

[0333] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-[(4-methylanilino)methyl]-6,7-dihydro-4H-benzothiophene-3-carboxamide

[0334]

[0335] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-2'-oxo-3'-(p-tolyl)spiro[6,7-dihydro-4H-benzothiophene-5,5'-oxazolidine]-3-carboxamide

[0336]

[0337] 5-(2-amino-3-pyridyl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0338]

[0339] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(p-tolyl)-1H-imidazol-2-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0340]

[0341] 5-Cyano-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0342] 7-Cyano-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0343]

[0344] (5R)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0345] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0346]

[0347] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(4-methyloxazol-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0348]

[0349] 5-(Aminomethyl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-6,7-dihydro-4H-benzothiophene-3-carboxamide

[0350]

[0351] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-[(p-tolylcarbamoylamino)methyl]-6,7-dihydro-4H-benzothiophene-3-carboxamide

[0352]

[0353] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0354]

[0355] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0356]

[0357] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(pyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0358]

[0359] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-hydroxy-5-methyl-6,7-dihydro-4H-benzothiophene-3-carboxamide

[0360]

[0361] N-[3-[(3R)-3-Fluoropyrrolidine-1-carbonyl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0362]

[0363] N-[3-(3-Fluoroazetidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0364]

[0365] N-[3-(Piperidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0366]

[0367] 2-(Cyclopropanecarbonylamino)-7-hydroxy-N-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0368]

[0369] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0370]

[0371] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0372]

[0373] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0374] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0375]

[0376] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxamide

[0377]

[0378] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxamide

[0379]

[0380] 2'-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxamide

[0381]

[0382] N-(Cyclopropylmethyl)-2-(2-methylpropionylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0383]

[0384] 2-(Cyclobutanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0385]

[0386] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0387] 2-(Cyclopropanecarbonylamino)-4,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[0388]

[0389] N-(Cyclopropylmethyl)-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide - diastereomer 1

[0390] N-(Cyclopropylmethyl)-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide - diastereomer 2

[0391]

[0392] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-2',5'-dioxo-spiro[6,7-dihydro-4H-benzothiophene-5,4'-imidazolidine]-3-carboxamide

[0393]

[0394] 2-(Cyclopropanecarbonylamino)-5-(3-pyridylaminothiocarbothioylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid cyclopropylmethyl ester

[0395]

[0396] Cyclopropylmethyl 2-(cyclopropanecarbonylamino)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate

[0397]

[0398] 2-(Cyclopropanecarbonylamino)-N,5-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0399] 2-(Cyclopropanecarbonylamino)-N,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0400]

[0401] tert-Butyl N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-7-yl]carbamate

[0402]

[0403] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N7-ethyl-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxamide

[0404]

[0405] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0406] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-7-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0407]

[0408] N-Methyl-2-[(2-methylcyclopropanecarbonyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0409]

[0410] 2-(Cyclopropanecarbonylamino)-7-hydroxy-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[0411]

[0412] (5S)-5-(5-amino-4-cyano-imidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0413]

[0414] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2,2-dimethylpropylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0415]

[0416] (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

[0417] (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

[0418] (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

[0419]

[0420] 5-amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0421]

[0422] 5-[[N'-cyano-N-phenyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0423]

[0424] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(isobutylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0425]

[0426] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-methylcyclopropyl)methylamino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0427]

[0428] (5S)-5-(5-Acetylaminoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0429]

[0430] (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

[0431]

[0432] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(4-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0433]

[0434] 5-[[N'-cyano-N-(3,4-dimethoxyphenyl)carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0435]

[0436] Ethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate

[0437]

[0438] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-morpholinoethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0439]

[0440] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(5-oxo-4H-1,2,4-oxadiazol-3-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0441]

[0442] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-(ethylamino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0443]

[0444] 5-[[N'-cyano-N-(2,2,2-trifluoroethyl)carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0445]

[0446] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0447]

[0448] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(N-ethyl-N'-nitrocarbamimidoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0449]

[0450] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0451]

[0452] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-oxopyridin-1-ium-3-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0453]

[0454] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-nitro-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0455]

[0456] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(3-pyridylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0457]

[0458] N-[(5S)-3-(5-Azaspiro[2.4]heptane-5-carbonyl)-5-[3-(3-pyridinylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0459] N-[(5R)-3-(5-Azaspiro[2.4]heptane-5-carbonyl)-5-[3-(3-pyridinylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0460]

[0461] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(cyclopropylmethylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0462]

[0463] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2,5-dimethylpyrazol-3-yl)aminothiocarboylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0464]

[0465] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(pyrimidin-5-ylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0466]

[0467] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(cyclopropylmethylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0468]

[0469] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(ethylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0470]

[0471] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(4-methylanilino)-2-nitro-vinyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0472]

[0473] (5S)-5-[(N'-cyano-N-ethyl-carbamimidoyl)-methyl-amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0474]

[0475] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-(4-methylanilino)-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0476]

[0477] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-pyridylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0478]

[0479] (5S)-5-(2-Acetylaminoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0480]

[0481] tert-Butyl N-[3-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]triazol-4-yl]carbamate

[0482]

[0483] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(3-pyridylamino)triazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0484]

[0485] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(ethylaminothiocarbothioylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0486]

[0487] (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

[0488]

[0489] 5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0490]

[0491] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(E)-N-ethyl-N'-nitrocarbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0492] (5R)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[(E)-N-ethyl-N'-nitrocarbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0493]

[0494] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-(ethylamino)imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0495]

[0496] (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

[0497]

[0498] Ethyl N-[[[2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]amino]-(4-methylanilino)methylene]carbamate

[0499]

[0500] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[2-[(2-methyl-3-pyridyl)amino]imidazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0501]

[0502] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(ethylamino)-2-nitro-vinyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0503]

[0504] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-methyl-6-oxo-1H-pyrimidin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0505]

[0506] 5-amino-1-[(5S)-2-cyclopropaneamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-N-methyl-1H-imidazole-4-carboxamide

[0507]

[0508] 5-amino-1-[(5S)-2-cyclopropaneamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-1H-imidazole-4-carboxamide

[0509]

[0510] 5-(2-anilinimidazole-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0511]

[0512] (5S)-5-[[N'-cyano-N-ethyl-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0513]

[0514] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(ethylcarbamoylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0515]

[0516] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-oxo-1H-pyridin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0517]

[0518] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-pyridinyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0519]

[0520] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[5-(ethylamino)tetrazol-1-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0521]

[0522] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-1,2,4-triazol-3-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0523]

[0524] (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

[0525]

[0526] (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

[0527]

[0528] 1-[(5S)-2-cyclopropaneamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-1H-imidazole-4-carboxylic acid ethyl ester

[0529]

[0530] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-(4-fluorophenyl)-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0531]

[0532] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-imidazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0533]

[0534] 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

[0535]

[0536] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-methoxy-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0537]

[0538] 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

[0539]

[0540] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[1-(3-pyridyl)imidazol-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0541]

[0542] 5-(5-aminotriazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0543]

[0544] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-methoxyphenyl)carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0545]

[0546] N-[2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]pyridine-4-carboxamide

[0547]

[0548] 5-(Benzylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0549]

[0550] 5-(1H-Benzimidazol-2-ylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0551]

[0552] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-hydroxycarbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0553]

[0554] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-(1-methylpyrazol-3-yl)-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; formic acid

[0555]

[0556] (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

[0557]

[0558] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(methoxymethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0559]

[0560] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[5-(3-pyridyl)-1H-1,2,4-triazol-3-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0561]

[0562] p-Tolyl N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate

[0563]

[0564] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(quinazolin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0565]

[0566] 5-(1,3-Benzoxazol-2-ylamino)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0567]

[0568] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(hydroxymethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0569]

[0570] 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

[0571]

[0572] (5S)-5-(2-aminoimidazol-1-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0573]

[0574] 5-(3-amino-5-oxo-1,2,4-oxadiazol-4-yl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0575]

[0576] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-methyl-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0577]

[0578] (5R)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-ethyl-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0579] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-ethyl-3,4-dioxo-cyclobuten-1-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0580]

[0581] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(pyrimidin-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0582]

[0583] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1,3,4-oxadiazol-2-ylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0584]

[0585] 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

[0586]

[0587] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[5-oxo-1-(p-tolyl)-4H-imidazol-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0588]

[0589] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[2-[ethyl(methyl)amino]-3,4-dioxo-cyclobuten-1-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0590]

[0591] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(methylsulfimidoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0592]

[0593] 5-[[N-cyano-C-methyl-imidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0594]

[0595] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(tetrazol-1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0596]

[0597] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(methanesulfonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0598]

[0599] 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

[0600]

[0601] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-morpholino-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0602]

[0603] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(ethylamino)-5-(trifluoromethyl)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0604]

[0605] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-oxo-1H-pyrimidin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0606]

[0607] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(isopropylsulfamoylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0608]

[0609] 5-[[N'-cyano-N-morpholino-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0610]

[0611] 5-Acetylamino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0612]

[0613] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(methylsulfonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0614]

[0615] 5-[[N'-cyano-N-methoxy-carbamimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0616]

[0617] 2-(Cyclopropanecarbonylamino)-N-isobutyl-5-[(4-methoxyphenyl)carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0618]

[0619] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[4-oxo-6-(trifluoromethyl)-1H-pyrimidin-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0620]

[0621] N-[5-(Methanesulfonylamino)-3-(3-methylpyrrolidine-1-carbonyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[0622]

[0623] 2-(Cyclopropanecarbonylamino)-N-propyl-5-[[4-(trifluoromethoxy)phenyl]carbamoylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0624]

[0625] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-methylpropionylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0626]

[0627] (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

[0628]

[0629] 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

[0630]

[0631] (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

[0632]

[0633] (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

[0634]

[0635] (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

[0636]

[0637] (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

[0638]

[0639] (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

[0640]

[0641] (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

[0642]

[0643] (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

[0644]

[0645] (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

[0646]

[0647] (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

[0648]

[0649] (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

[0650]

[0651] (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

[0652]

[0653] (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

[0654]

[0655] (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

[0656]

[0657] (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

[0658]

[0659] (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

[0660]

[0661] 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 methyl ester

[0662]

[0663] (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

[0664]

[0665] 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;

[0666] their enantiomers and pharmaceutically acceptable salts thereof.

[0667] According to one embodiment, the compound of the invention is selected from:

[0668] (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];

[0669] (5S)-2-Cyclopropaneamido-N-(cyclopropylmethyl)-5-[3-({3-[imino(methyl)oxo-λ6-sulfanyl]-2-methylphenyl}amino)-4H-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide;

[0670] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[2-methyl-3-[(S)-methylsulfimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0671] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[2-methyl-3-[(R)-methylsulfimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0672] (5S)-5-{3-[(1-acetyl-3-methylpyrrolidin-3-yl)amino]-4H-1,2,4-triazol-4-yl}-2-cyclopropanecarboxamido-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];

[0673] (5S)-2-Cyclopropaneamido-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;

[0674] (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;

[0675] (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;

[0676] (5S)-2-Cyclopropaneamido-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;

[0677] (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; [Ex 246]

[0678] (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;

[0679] 2-Methoxyethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]imidazole-4-carboxylate;

[0680] 2-Morpholin-4-ylethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]imidazole-4-carboxylate;

[0681] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfanylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0682] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfonylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0683] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(3-methylsulfinylanilino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0684] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-(methylsulfimidoyl)anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0685] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-[(S)-methylsulfimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0686] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-[(R)-methylsulfimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[0687] (5S)-N-(Cyclopropylmethyl)-5-[3-[(6-methylsulfinyl-2-pyridinyl)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-pyridinyl)amino]-1,2,4-triazol-4-yl]-2-[[(2S*)-spiro[2.2]pentane-2-carbonyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0688] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(8-methoxy-4-oxo-5,10-dihydroimidazo[4,5-c][1,5]benzodiazepine -1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0689] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(8-methoxy-5-methyl-4-oxo-10H-imidazo[4,5-c][1,5]benzodiazepine -1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0690] (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];

[0691] (5S)-5-[5-amino-4-[(3R)-3-hydroxypyrrolidine-1-carbonyl]imidazol-1-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0692] (5S)-5-[5-amino-4-[(2S)-2-methylpyrrolidine-1-carbonyl]imidazol-1-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0693] 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-carboxylic acid ethyl ester;

[0694] (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;

[0695] (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;

[0696] (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;

[0697] (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;

[0698] (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;

[0699] (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;

[0700] (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);

[0701] 5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-oxo-4-piperidinyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0702] (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;

[0703] (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;

[0704] (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;

[0705] (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;

[0706] (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];

[0707] (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);

[0708] (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];

[0709] (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];

[0710] (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;

[0711] (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];

[0712] (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];

[0713] (5S)-5-[3-[(1-acetyl-4-piperidinyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0714] (3S)-3-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]pyrrolidine-1-carboxylic acid methyl ester;

[0715] (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;

[0716] (5S)-2-Cyclopropaneamido-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;

[0717] (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;

[0718] (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;

[0719] (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;

[0720] (5S)-2-Cyclopropaneamido-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;

[0721] (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

[0722] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(5-methylthiazolo[5,4-b]pyridin-2-yl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0723] (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;

[0724] (5S)-5-[3-[(6-cyano-2-methyl-3-pyridinyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0725] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-methyl-2-oxo-4-pyridinyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0726] (5S)-5-[3-[(6-chloro-2-methyl-3-pyridinyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0727] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[2-methyl-6-(trifluoromethyl)-3-pyridinyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0728] (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;

[0729] (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;

[0730] (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;

[0731] (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;

[0732] (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;

[0733] (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;

[0734] (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;

[0735] (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];

[0736] (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;

[0737] (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;

[0738] 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;

[0739] Ethyl 5-amino-1-[(5S*)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate (* or R);

[0740] 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);

[0741] 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);

[0742] (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;

[0743] (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;

[0744] (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];

[0745] (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];

[0746] (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;

[0747] 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;

[0748] 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;

[0749] (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;

[0750] (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;

[0751] (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);

[0752] (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);

[0753] (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;

[0754] 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;

[0755] 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;

[0756] 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

[0757] 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;

[0758] (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;

[0759] (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;

[0760] (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;

[0761] (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;

[0762] 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;

[0763] (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;

[0764] (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;

[0765] (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)

[0766] 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;

[0767] (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;

[0768] (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;

[0769] (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);

[0770] (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;

[0771] (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;

[0772] (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;

[0773] (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;

[0774] (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;

[0775] (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;

[0776] (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;

[0777] (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;

[0778] (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;

[0779] (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;

[0780] 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;

[0781] (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;

[0782] (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(3,3-difluoropropionylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide;

[0783] (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;

[0784] (5S)-N-(cyclopropylmethyl)-5-[3-[[5-(difluoromethyl)-2-methylpyrazol-3-yl]amino]-1,2,4-triazol-4-yl]-2-(2-methylpropionylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide;

[0785] (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;

[0786] (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;

[0787] (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;

[0788] (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

[0789] (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);

[0790] (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;

[0791] (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;

[0792] (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;

[0793] (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;

[0794] (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);

[0795] (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);

[0796] (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);

[0797] (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;

[0798] (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

[0799] (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;

[0800] (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);

[0801] (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;

[0802] (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;

[0803] (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;

[0804] (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;

[0805] (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;

[0806] (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;

[0807] (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;

[0808] (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;

[0809] (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;

[0810] (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;

[0811] (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;

[0812] (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;

[0813] (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;

[0814] (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);

[0815] (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);

[0816] 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;

[0817] (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;

[0818] 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;

[0819] (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;

[0820] (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;

[0821] (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;

[0822] (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;

[0823] (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;

[0824] (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;

[0825] (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;

[0826] (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;

[0827] (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;

[0828] (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;

[0829] (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;

[0830] (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;

[0831] (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;

[0832] (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;

[0833] (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;

[0834] (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;

[0835] (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;

[0836] (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;

[0837] (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;

[0838] (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;

[0839] (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;

[0840] (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-carboxylic acid ethyl ester;

[0841] (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-carboxylic acid ethyl ester;

[0842] (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;

[0843] (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;

[0844] (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;

[0845] (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;

[0846] (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;

[0847] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[6-(difluoromethyl)-3-pyridinyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0848] (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;

[0849] (5S)-5-[3-[[5-(Cyclopropyloxy)-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;

[0850] (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;

[0851] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[6-(trifluoromethyl)-3-pyridinyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0852] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(6-methoxy-3-pyridinyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0853] (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methoxy-4-pyridinyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0854] (5S)-5-[3-[(6-chloro-3-pyridinyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0855] (5S)-5-[3-[(2-chloro-4-pyridinyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide;

[0856] (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;

[0857] (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;

[0858] (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;

[0859] (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;

[0860] (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;

[0861] (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;

[0862] (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;

[0863] (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;

[0864] (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;

[0865] (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;

[0866] (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;

[0867] (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;

[0868] (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;

[0869] (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;

[0870] (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;

[0871] (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;

[0872] (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;

[0873] (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;

[0874] (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;

[0875] (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;

[0876] (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;

[0877] (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;

[0878] (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;

[0879] (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);

[0880] (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;

[0881] (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;

[0882] (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;

[0883] (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;

[0884] (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;

[0885] (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;

[0886] (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;

[0887] (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

[0888] (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;

[0889] (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];

[0890] (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;

[0891] (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;

[0892] (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;

[0893] (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

[0894] (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;

[0895] (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;

[0896] (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];

[0897] (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;

[0898] (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;

[0899] (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;

[0900] (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;

[0901] (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;

[0902] (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;

[0903] (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;

[0904] (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;

[0905] (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;

[0906] (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;

[0907] (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;

[0908] (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;

[0909] (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;

[0910] (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;

[0911] (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;

[0912] (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

[0913] (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;

[0914] (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;

[0915] (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;

[0916] (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;

[0917] (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;

[0918] (5S)-2-Cyclopropaneamido-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;

[0919] (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;

[0920] (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;

[0921] (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;

[0922] (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);

[0923] (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;

[0924] (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);

[0925] (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);

[0926] their enantiomers and pharmaceutically acceptable salts thereof.

[0927] According to one embodiment, the compound of the invention is selected from:

[0928] (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;

[0929] Ethyl 5-amino-1-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]imidazole-4-carboxylate;

[0930] (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;

[0931] (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;

[0932] (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;

[0933] (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;

[0934] (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;

[0935] (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;

[0936] (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;

[0937] (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;

[0938] (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)

[0939] (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)

[0940] their enantiomers and pharmaceutically acceptable salts thereof.

[0941] The following paragraphs provide definitions of the various chemical moieties that make up the compounds of this invention, which are intended to apply equally throughout the specification and claims unless a broader definition is explicitly set forth.

[0942] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine.

[0943] The term "heterocycle" refers to a saturated ring containing at least one heteroatom, such as oxygen, sulfur and nitrogen; and includes heteroaromatic or aromatic rings fused to a heterocycle.

[0944] The term "alkyl" refers to a straight-chain or branched, saturated aliphatic hydrocarbon group.

[0945] The term "cycloalkyl" refers to a monovalent group derived from a saturated cyclic hydrocarbon and includes fused-ring cycloalkyls and heteroaromatic, heterocyclic or aromatic rings fused to a carbocyclic ring.

[0946] The term "fused ring cycloalkyl" refers to a cycloalkyl group having two or more rings wherein the rings have at least one bond and two atoms in common. Examples of fused ring cycloalkyl groups include

[0947]

[0948] The term "heteroalkyl" refers to an alkyl group in which at least one carbon atom has been replaced by a heteroatom such as oxygen, sulfur and nitrogen.

[0949] The term "heterocycle" refers to a ring structure having atoms of at least two different elements as its ring members, so that some or all of the atoms in the molecule are joined in a ring containing at least one atom of an element other than carbon, such as oxygen, sulfur, and nitrogen; and includes heteroaromatic or aromatic rings fused to a heterocycle.

[0950] The term "alkylene" refers to a divalent saturated aliphatic group derived from an unsaturated aliphatic hydrocarbon.

[0951] The term "haloalkyl" refers to an alkyl group as defined above wherein at least one hydrogen atom is replaced by a halogen atom.

[0952] The term "alkenyl" refers to a monovalent group derived from a partially unsaturated straight or branched carbon chain, for example, ethenyl, propenyl, butenyl, pentenyl, and the like.

[0953] The term "cycloalkenyl" refers to a monovalent group derived from a partially unsaturated monocyclic hydrocarbon, for example, cyclobutenyl.

[0954] The term "heteroalkenyl" refers to a monovalent group derived from a partially unsaturated straight or branched carbon chain containing at least one heteroatom such as oxygen, sulfur and nitrogen.

[0955] 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.

[0956] The term "alkynyl" refers to an unsaturated straight or branched carbon chain containing at least one carbon-carbon triple bond, for example, ethynyl, propynyl and butynyl.

[0957] The term "heteroalkynyl" refers to an unsaturated straight or branched carbon chain containing at least one carbon-carbon triple bond and containing at least one heteroatom such as oxygen, sulfur and nitrogen.

[0958] The term "aryl" refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or multiple fused aromatic rings; for example, phenyl, naphthyl.

[0959] The term "heteroaryl" refers to a monovalent aromatic group containing at least 5 atoms derived from a single ring or multiple fused rings containing at least one heteroatom such as oxygen, sulfur and nitrogen.

[0960] The term "alkoxy" refers to the group -O-R', wherein R' is alkyl as defined above.

[0961] The term "alkylamino" refers to the group -NH-alkyl, wherein alkyl is as defined above.

[0962] The term "cycloalkyl-amino" refers to the group -NH-cycloalkyl, wherein cycloalkyl is as defined above.

[0963] The term "heterocycle-amino" refers to a heterocycle as defined above wherein one or more carbon atoms is linked to -NH-, thus referring to the group -NH-heterocycle.

[0964] The term "aryl-amino" refers to an aryl group as defined above wherein one or more carbon atoms is linked to -NH-, thus referring to the group -NH-aryl.

[0965] The term "heteroaryl-amino" refers to a heteroaryl group as defined above wherein one or more carbon atoms are linked to -NH-, thus referring to the group -NH-heteroaryl.

[0966] The term "heteroalkyl-amino" refers to the group -NH-heteroalkyl, where heteroalkyl is as defined above.

[0967] The term "pharmaceutically acceptable salt" according to the present invention includes salts of compounds of formula (I) to (XXXVI) with pharmaceutically acceptable acids or bases, in particular acid addition salts. Acid addition salts of compounds of formula (I) to (XXXVI) that exist in free form as a base can be obtained by treating the free base with an appropriate acid, for example an inorganic acid, for example a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid, for example acetic acid, trifluoroacetic acid, oxalic acid, glycolic acid, propionic 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, cyclohexanesulfamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, or the like.

[0968] The present invention also relates to all stereoisomeric forms of the compounds of formula (I) to (XXXVI), such as enantiomeric and diastereomeric forms, or mixtures thereof (including all possible stereoisomer mixtures, such as racemates). For the purposes of the present invention, reference to one or more compounds is intended to include the compound in every possible isomeric form and mixtures thereof, unless a particular isomeric form is specifically mentioned.

[0969] Certain compounds of formulae (I) to (XXXVI) may also exist in tautomeric forms. These forms, although not explicitly indicated in the above formulae, are intended to be included within the scope of the present invention.

[0970] It will be understood that each individual atom present in Formulas (I) to (XXXVI) or the formulae described herein can actually exist in the form of any of its naturally occurring isotopes, preferably the most abundant isotope. Thus, for example, each individual hydrogen atom present in Formulas (I) to (XXXVI) or the formulae described herein can exist as a 1H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, for example, each individual carbon atom present in Formulas (I) to (XXXVI) or the formulae described herein can exist as a 12C, 13C or 14C atom, preferably 12C.

[0971] The present invention includes within its scope solvates of the compounds of formula (I) to (XXXVI) above. Such solvates may be formed with common organic solvents or water.

[0972] The present invention also includes within its scope co-crystals of compounds of formula (I) to (XXXVI) above. The technical term "co-crystal" is used to describe a situation in which the neutral molecular components are present in a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical co-crystals allows the modification of the crystalline form of the active pharmaceutical ingredient, thereby changing its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0973] The compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, these forms are intended to be included within the scope of the present invention.

[0974] The present invention also includes within its scope prodrugs of the compounds of formula (I) to (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. Prodrugs can be identified by administering the prodrug to a mammal, such as a rat, mouse, monkey, or human, and identifying the compound or a salt thereof in, for example, blood or urine.

[0975] Another embodiment of the present invention relates to a pharmaceutical composition comprising a detectable amount of a compound of Formula (I) to (XXXVI) or a pharmaceutically acceptable salt, solvate or cocrystal thereof and a pharmaceutically acceptable diluent or carrier.

[0976] In another embodiment, the present invention relates to compounds of formula (I) to (XXXVI), pharmaceutically acceptable salts, solvates or cocrystals thereof, for use as medicaments, in particular for the treatment or prevention of diseases caused by IgE, including allergies, type 1 hypersensitivity reactions, common sinus inflammation, 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 cutaneous T-cell lymphoma.

[0977] In another embodiment, the present invention relates to a method for treating or preventing allergy, type 1 hypersensitivity reaction, common sinusitis, urticaria or related conditions, which method comprises administering a compound of formula (I) to (XXXVI) in a therapeutically effective amount.

[0978] The following examples illustrate how to synthesize compounds encompassed by formulas (I) to (XXXVI). They are provided for illustrative purposes only and are not intended to, nor should they be construed as, limiting the present invention in any way. It will be appreciated by those skilled in the art that routine changes and modifications may be made to the following examples without departing from the spirit or scope of the present invention. Example

[0979] The following examples illustrate how to synthesize the compounds shown in Formula I. They are provided for illustrative purposes only and are not intended to or should be construed as limiting the present invention in any way. It will be appreciated by those skilled in the art that routine variations and modifications may be made to the following examples without departing from the spirit or scope of the present invention.

[0980] Example

[0981] abbreviation

[0982] DCM: dichloromethane

[0983] MTBE: tert-butyl methyl ether

[0984] Et2O: ethyl ether

[0985] THF: Tetrahydrofuran

[0986] EtOAc: ethyl acetate

[0987] MeCN: acetonitrile

[0988] MeOH: methanol

[0989] h: hour

[0990] b s.: broad single peak

[0991] rt: room temperature

[0992] M: Quality

[0993] Brine: saturated sodium chloride solution

[0994] HPLC: High Performance Liquid Chromatography

[0995] LCMS: Liquid chromatography mass spectrometry

[0996] ES+: electrospray positive ionization

[0997] DIPEA: N,N-diisopropylethylamine

[0998] RT: retention time

[0999] DMF: N,N'-dimethylformamide

[1000] NaOH: sodium hydroxide

[1001] COMU: (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholinocarbonium hexafluorophosphate

[1002] mCPBA: 3-chloroperbenzoic acid

[1003] DMAP: 4-dimethylaminopyridine

[1004] NMP: N-methyl-2-pyrrolidone

[1005] CV: column volume

[1006] TFA: trifluoroacetic acid

[1007] DMSO: dimethyl sulfoxide

[1008] EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[1009] TBTU: O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

[1010] CDI: 1,1'-carbonyldiimidazole

[1011] EtOH: ethanol

[1012] Analysis conditions

[1013] All NMR spectra were acquired at 250 MHz, 300 MHz, 400 MHz, or 500 MHz.

[1014] All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dry solvents and glassware.

[1015] All compound LCMS data were determined using the following method.

[1016] LCMS method

[1017] Method 1: 6120B pH10 Long (Slough)

[1018] X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column

[1019] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1020] Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution

[1021] Gradient program: flow rate 1mL / min

[1022]

[1023] Method 2: 6140pH3 Registration (Slough)

[1024] X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column

[1025] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% formic acid

[1026] Mobile phase B: acetonitrile + 5% water + 0.1% formic acid

[1027] Gradient program: flow pump 1: 1 mL / min, flow pump 2: 0.5 mL / min

[1028]

[1029] Method 3: 6140pH10 Registration (Slough)

[1030] X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column

[1031] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1032] Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution

[1033] Gradient program: flow pump 1: 1 mL / min, flow pump 2: 0.5 mL / min

[1034]

[1035] Method 4: L102 pH 10 short 3 min (crude system 1?) (Slough)

[1036] X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column

[1037] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1038] Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution

[1039] Gradient program: flow rate 1mL / min

[1040]

[1041] Method 5: MS17 7min HiRes Evotec Shimadzu (Evotec) MET / CR / 1416

[1042] Mobile phase A: 0.1% formic acid in water

[1043] Mobile phase B: 0.1% formic acid in acetonitrile

[1044] Waters Atlantis dC18, part number 186001295, 2.1 mm x 100 mm, 3 μm column

[1045] Flow rate: 0.6mL / min

[1046] Column temperature: 40°C

[1047] Injection volume: 3 μL

[1048]

[1049] UV 215nM, PDA spectrum 210-420nm, step size: 1nm

[1050] MSD scan positive 100-1000

[1051] Method 6: MS17 METCR1673 Generic 2 min (Evotec)

[1052] Mobile phase A: 0.1% formic acid in water

[1053] Mobile phase B: 0.1% formic acid in acetonitrile

[1054] Supelco Ascentis Express, part number: 53802-U, 2.1mm x 30mm, 2.7μm column

[1055] Flow rate: 1mL / min

[1056] Column temperature: 40

[1057] Injection volume: 3 μL

[1058]

[1059] UV 215nM, PDA spectrum 210-420nm, step size: 1nm

[1060] MSD scan positive 100-1000

[1061] Method 7: pH10 6120B Short (Slough)

[1062] X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column

[1063] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1064] Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution

[1065] Gradient program: flow rate 1mL / min

[1066]

[1067]

[1068] Method 8: Brain Acid QDA (Braine)

[1069] A QDA Waters simple quadrupole mass spectrometer was used for LC-MS analysis.

[1070] The spectrometer was equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (210 to 400 nm).

[1071] Data were acquired in positive mode on a full MS scan from m / z 50 to 1000 under acidic elution.

[1072] Reversed phase separation was performed on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 x 50 mm) column at 45°C for acidic elution.

[1073] Gradient elution was performed as follows:

[1074] Mobile phase A: water

[1075] Mobile phase B: MeCN

[1076] Mobile phase C: water / MeCN / formic acid 0.5%

[1077] Gradient program:

[1078] HPLC flow rate: 0.6 mL / min to 0.7 mL / min

[1079] Injection volume: 1 μL

[1080] Full flow in MS.

[1081]

[1082] Method 9: Braine Alkaline QDA (Braine)

[1083] A QDA Waters simple quadrupole mass spectrometer was used for LC-MS analysis.

[1084] The spectrometer was equipped with an ESI source and a UPLC AcquityClassic with a diode array detector (210 to 400 nm).

[1085] Data were acquired in positive mode on a full MS scan from m / z 50 to 1000 under basic elution.

[1086] Reversed phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 x 50 mm) column at 45°C for basic elution.

[1087] Gradient elution was performed as follows:

[1088] Mobile phase A: H2O / acetonitrile / ammonium formate (95 / 5 / 63 mg / L) + 50 μL NH4OH

[1089] Mobile phase B: acetonitrile / H2O / ammonium formate (95 / 5 / 63 mg / L) + 50 μL NH4OH

[1090] Gradient program:

[1091] HPLC flow rate: 0.4 mL / min to 0.5 mL / min

[1092] Injection volume: 1 μL

[1093] Full flow in MS.

[1094]

[1095] Method 10: MSQ1 MET-uPLC-AB-101 7 min low pH (Evotec)

[1096] Mobile phase A: 0.1% formic acid in water

[1097] Mobile phase B: 0.1% formic acid in acetonitrile

[1098] Phenomenex, Kinetex-XB C18, 2.1 mm x 100 mm, 1.7 μm column

[1099] Flow rate: 0.6mL / min

[1100] Column temperature: 40°C

[1101] Injection volume: 1 μL

[1102]

[1103] UV 215nM, PDA spectrum 200-400nm, step size: 1nm

[1104] MSD scanning positive 150-850

[1105] Method 11: MS17 METCR14 10 Generic 2min(Evotec)

[1106] Mobile phase A: 0.1% formic acid in water

[1107] Mobile phase B: 0.1% formic acid in acetonitrile

[1108] Kinetex Core-Shell C18 50 x 2.1 mm, 5 μm column protected by a Phenomenex "Security Guard" column.

[1109] Flow rate: 1.2 mL / min

[1110] Column temperature: 40°C

[1111] Injection volume: 3 μL

[1112]

[1113] UV 215nM, PDA spectrum 210-420nm, step size: 1nm

[1114] MSD scan positive 100-1000

[1115] Method 12: Agilent 6120 3min pH3 (Evotec Insourcing lab-UCB machine)

[1116] Column: Waters X-Bridge, C18, 2.1 x 20 mm, 2.5 mm silica particles

[1117] Flow rate: 1.0 mL / min

[1118] Mobile phase A: 10 mM ammonium formate + 0.1% formic acid

[1119] Mobile phase B: acetonitrile + 5% water + 0.1% formic acid

[1120] Column temperature: 40°C

[1121] Injection volume: 1-5 μL

[1122] UV detection: 230 to 400 nm and 215 nm

[1123] Mass spectrometry detection: Agilent 6120 mass spectrometer (ES) m / z 120 to 800

[1124] Gradient: 5% to 95% B over 1.5 min, hold at 95% B for 0.5 min, re-equilibrate flow at 5% B

[1125] Method 13: Braine Alkaline QDA Long

[1126] A QDA Waters simple quadrupole mass spectrometer was used for LC-MS analysis.

[1127] The spectrometer was equipped with an ESI source and a UPLC AcquityClassic with a diode array detector (210 to 400 nm).

[1128] Data were acquired in a full MS scan from m / z 70 to 800 in positive / negative mode with basic elution.

[1129] Reversed phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 x 100 mm) column at 45°C for basic elution.

[1130] Gradient elution was performed as follows:

[1131] H2O / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μl / L NH4OH (Solvent A)

[1132] ACN / H2O / ammonium formate (95 / 5 / 63 mg / L) + 100 μl / L NH4OH (Solvent B)

[1133] HPLC flow rate: 0.4ml / min to 0.5ml / min,

[1134] Injection volume: 1 μl

[1135] Full flow in MS.

[1136] Time (min) A(％) B(％) Flow rate (ml / min) 0 99 1 0.4 0.8 99 1 0.4 5.30 0 100 0.4 5.35 0 100 0.5 7.30 0 100 0.5 7.35 99 1 0.4 9 90 1 0.4

[1137] Method 14: METCR 1704 (MSQ2 1min IPC-Evotec)

[1138] Column: Waters UPLC CSH C18, 2.1 x 100 mm, 1.7 mm silica particles

[1139] Flow rate: 0.9 mL / min

[1140] Mobile phase A: water + 0.1% formic acid

[1141] Mobile phase B: acetonitrile + 0.1% formic acid

[1142] Column temperature: 40°C

[1143] Injection volume: 2 μL

[1144] UV detection: 200 to 400 nm and 215 nm

[1145] Mass spectrometry detection: m / z 150 to 850

[1146] Gradient: 5%-100% B over 1.1 min, hold at 100% B for 0.25 min, re-equilibrate flow at 5% B

[1147] Method 15: (Slough crude system pH 10 short)

[1148]

[1149] Flow rate: 1 mL / min

[1150] Solvent A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1151] Solvent B: acetonitrile + 5% water + 0.1% ammonia solution

[1152] Column: XBridge C18, 2.1 x 20 mm, 2.5 μm

[1153] Method 16: Agilent 6120 6 min pH 10 (Evotec Insourcing lab-UCB machine)

[1154] Column: Waters X-Bridge, C18, 2.1 x 20 mm, 2.5 mm silica particles

[1155] Flow rate: 1.0 mL / min

[1156] Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution

[1157] Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution

[1158] Column temperature: 40°C

[1159] Injection volume: 1-5 μL

[1160] UV detection: 230 to 400 nm and 215 nm

[1161] Mass spectrometry detection: Agilent 6120 mass spectrometer (ES) m / z 120 to 800

[1162] Gradient: 5% to 95% B over 4 min, hold at 95% B for 1 min, re-equilibrate flow at 5% B

[1163] Method 17: Agilent 6120 3min pH10 (Evotec Insourcing lab-UCB machine)

[1164] Column: Waters X-Bridge, C18, 2.1 x 20 mm, 2.5 mm silica particles

[1165] Flow rate: 1.0 mL / min

[1166] Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution

[1167] Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution

[1168] Column temperature: 40°C

[1169] Injection volume: 1-5 μL

[1170] UV detection: 230 to 400 nm and 215 nm

[1171] Mass spectrometry detection: Agilent 6120 mass spectrometer (ES) m / z 120 to 800

[1172] Gradient: 5% to 95% B over 1.5 min, hold at 95% B for 0.5 min, re-equilibrate flow at 5% B

[1173] Method 18: MS10 METCR0990 high pH 2.5 min (Evotec)

[1174] Mobile phase A: 2 mM ammonium bicarbonate pH 10

[1175] Mobile phase B: acetonitrile

[1176] Phenomenex Gemini-NX C18 2.0mm x 50mm, 3μm column

[1177] Flow rate: 1.0 mL / min

[1178] Column temperature: 40°C

[1179] Injection volume: 3 μL

[1180]

[1181] UV 215nM, PDA spectrum 210-420nm, step size: 1nm

[1182] MSD scanning positive 150-850

[1183] Method 19: SFC1AB (Evotec achiral SFC_1)

[1184] Column: Synergi 4u Polar RP, 4.6x 250mm

[1185] Mobile phase: 15% ethanol: 85% CO2

[1186] Flow rate: 4ml / min

[1187] Run time: 15 minutes

[1188] Method 20: Braine TOFA

[1189] Column: Acquity UPLC HSS T3 C18 column (1.7 μm, 2.1 x 100 mm)

[1190] Flow rate: 0.4ml / min to 0.5ml / min

[1191] Solvent A: Water

[1192] Solvent B: acetonitrile

[1193] Solvent C: Formic acid 5ml / L in Acetonitrile / water 50 / 50 (pH ~ 3)

[1194] Column temperature: 45°C

[1195] Injection volume: 0.3 μl

[1196] Full flow in MS.

[1197]

[1198] UV detection: 210 to 400 nm

[1199] Mass spectrometry detection: LCT Waters time-of-flight mass spectrometer, m / z 50 to 950, positive mode

[1200] Method 21: Braine Acid QDA Long

[1201] A QDA Waters simple quadrupole mass spectrometer was used for LC-MS analysis.

[1202] The spectrometer was equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (210 to 400 nm).

[1203] Data were acquired in positive mode on a full MS scan from m / z 50 to 1000 under acidic elution.

[1204] Reversed phase separation was performed on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 x 100 mm) column at 45°C for acidic elution.

[1205] Gradient elution was performed as follows:

[1206] Water / formic acid (solvent A)

[1207] Acetonitrile / formic acid (solvent B)

[1208] HPLC flow rate: 0.4ml / min to 0.5ml / min,

[1209] Injection volume: 1 μl

[1210] Full flow in MS.

[1211] Time (min) A(％) B(％) Flow rate (ml / min) 0 99 1 0.4 0.8 99 1 0.4 5.3 5 95 0.4 5.35 5 95 0.5 8.30 5 95 0.5 8.35 99 1 0.4 10 99 1 0.4

[1212] Method 22: SFC1AB (Evotec achiral SFC_2)

[1213] Column: KR60-5DIOL, 4.6 x 250 mm

[1214] Mobile phase: 25% methanol: 75% CO2

[1215] Flow rate: 4ml / min

[1216] Run time: 8 minutes

[1217] Method 23: Chiral SFCMS analysis (Evotec)

[1218] Column: Chiralpak AD-H 25cm

[1219] Mobile phase: 15% IPA: 85% CO2

[1220] Flow rate: 4ml / min

[1221] Run time: 20 minutes

[1222] Method 24: pH 3 UPLC (Slough)

[1223] Low pH (approximately pH 3):

[1224] Column: Waters Acquity UPLC BEH, C18, 2.1x 50mm, 1.7μm

[1225] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% formic acid

[1226] Mobile phase B: acetonitrile + 5% solvent A + 0.1% formic acid

[1227]

[1228] System: Waters Classic Acquity-SQD,Acquity PDAc

[1229] Column temperature: 40°C

[1230] PDA wavelength range: 210-400nm

[1231] Mass spectrometry detection: ESI on Waters SQD

[1232] Flow rate: 0.7 mL / min

[1233] Method 25: pH 10 UPLC (Slough)

[1234] High pH (approximately pH 9.5)

[1235] Column: Waters Acquity UPLC BEH, C18, 2.1x 50mm, 1.7μm

[1236] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1237] Mobile phase B: acetonitrile + 5% solvent A + 0.1% ammonia solution

[1238] System: Waters Classic Acquity-SQD,Acquity PDAc

[1239] Column temperature: 40°C

[1240] PDA wavelength range: 210-400nm

[1241] Mass spectrometry detection: ESI on Waters SQD

[1242] Flow rate: 0.7 mL / min

[1243] Method 26: (Slough Reg 6140pH 10, 2018)

[1244]

[1245] Flow rate: 1mL / min

[1246] Solvent A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1247] Solvent B: acetonitrile + 5% water + 0.1% ammonia solution

[1248] Column: XBridge C18, 2.1 x 20 mm, 2.5 μm

[1249] Method 27: (Slough Register 6140pH 3, 2018)

[1250]

[1251] Flow rate: 1mL / min

[1252] Solvent A: 10 mM ammonium formate aqueous solution + 0.1% formic acid

[1253] Solvent B: acetonitrile + 5% water + 0.1% formic acid

[1254] Column: XBridge C18, 2.1 x 20 mm, 2.5 μm

[1255] Method 28: (Slough Coarse, Long pH 3, 2018)

[1256]

[1257] Flow rate: 1mL / min

[1258] Solvent A: 10 mM ammonium formate aqueous solution + 0.1% formic acid

[1259] Solvent B: acetonitrile + 5% water + 0.1% formic acid

[1260] Column: XBridge C18, 2.1 x 20 mm, 2.5 μm

[1261] Method 29: Agilent 6120 6 min pH 3

[1262] X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column

[1263] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% formic acid

[1264] Mobile phase B: acetonitrile + 5% water + 0.1% formic acid

[1265] Gradient program: flow rate 1mL / min

[1266]

[1267] Method 30: MET / uPLC / AB102

[1268] Waters CSH TM C18, 2.1 x 100 mm, 1.7 μm column

[1269] Column temperature: 40°C

[1270] Mobile phase A: 2 mM ammonium bicarbonate, buffered to pH 10

[1271] Mobile phase B: acetonitrile

[1272] Gradient program: flow rate 0.6mL / Min

[1273]

[1274] Method 31: MET / CR / 1600

[1275] Phenomenex Gemini-NX C18, Part No. 00D-4453-B0, 2.0 x 100 mm, 3 μm column

[1276] Column temperature: 40°C

[1277] Mobile phase A: 2 mM ammonium bicarbonate, buffered to pH 10

[1278] Mobile phase B: acetonitrile

[1279] Gradient program: flow rate 0.5mL / Min

[1280]

[1281] Method 32: MET-uPLC-AB-105

[1282] Waters BEH TM C18, part number 186002352, 2.1 x 100 mm, 1.7 μm

[1283] Column temperature: 40°C

[1284] Mobile phase A: 2 mM ammonium bicarbonate, buffered to pH 10

[1285] Mobile phase B: acetonitrile

[1286] Gradient program: flow rate 0.6mL / Min

[1287]

[1288] Method 33: 6140pH10 short pH 3

[1289] X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column

[1290] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1291] Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution

[1292] Gradient program: flow rate 1mL / min

[1293]

[1294]

[1295] Method 34: Agilent 1260-6120B

[1296] X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μM column

[1297] Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution

[1298] Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution

[1299] Gradient program: flow rate 1mL / min

[1300]

[1301] Chiral SFC analysis method

[1302] Method 1: Unless otherwise specified in the program, use the following conditions

[1303] Column: ChiralPak IC-3, 150 x 4.6 mm, 3 μm

[1304] Mobile phase A: CO2

[1305] Mobile phase B: methanol + 0.1% ammonium hydroxide

[1306] ABPR pressure: 120 bar

[1307] Detection signal: UV 210-600nm, DAD

[1308] Gradient program: flow rate 3mL / min

[1309]

[1310] HPLC method

[1311] Method 1: General high pH preparation method (standard method)

[1312] Column: Waters Xbridge C18 part no. 186003930, 30 x 100 mm, 10 μm

[1313] Column temperature: room temperature

[1314] Mobile phase A: water + 0.2% ammonium hydroxide

[1315] Mobile phase B: acetonitrile + 0.2% ammonium hydroxide

[1316] Flow rate: 40ml / min

[1317] Injection volume: 1500 μl

[1318] Detection signal: UV 215, variable

[1319]

[1320] Method 2: General high pH preparation method (early elution method)

[1321] Column: Waters Xbridge C18 part no. 186003930, 30 x 100 mm, 10 μm

[1322] Column temperature: room temperature

[1323] Mobile phase A: water + 0.2% ammonium hydroxide

[1324] Mobile phase B: acetonitrile + 0.2% ammonium hydroxide

[1325] Flow rate: 40ml / min

[1326] Injection volume: 1500 μl

[1327] Detection signal: UV 215, variable

[1328]

[1329] Method 3: General Low pH Preparation Method (Standard Method)

[1330] Column: Waters Sunfire C18, part no. 186003971, 30 x 100 mm, 10 μm

[1331] Column temperature: room temperature

[1332] Mobile phase A: water + 0.1% formic acid

[1333] Mobile phase B: acetonitrile + 0.1% formic acid

[1334] Flow rate: 40ml / min

[1335] Injection volume: 1500 μl

[1336] Detection signal: UV 215, variable

[1337]

[1338] Method 4: General Low pH Preparation Method (Early Elution Method)

[1339] Column: Waters Sunfire C18, part no. 186003971, 30 x 100 mm, 10 μm

[1340] Column temperature: room temperature

[1341] Mobile phase A: water + 0.1% formic acid

[1342] Mobile phase B: acetonitrile + 0.1% formic acid

[1343] Flow rate: 40ml / min

[1344] Injection volume: 1500 μl

[1345] Detection signal: UV 215, variable

[1346]

[1347] Method 5: UCB pH10 Gilson Standard Method

[1348] Column: Waters XBridge C18, part no. 186003896, 30 x 150 mm, 10 μm

[1349] Column temperature: room temperature

[1350] Mobile phase A: water + 0.1% NH4OH

[1351] Mobile phase B: acetonitrile + 0.1% NH4OH

[1352] Flow rate: 40ml / min

[1353] Injection volume: 500 μl

[1354] Detection signal: UV 215, variable

[1355]

[1356] General experimental methods

[1357] General Method 1

[1358]

[1359] A mixture of the tricycle and the amine (1-10 equivalents) was dissolved / suspended in anhydrous DMF or acetonitrile with or without excess base (triethylamine or DIPEA). The reaction was then heated at 70°C, 90°C, or 140°C for 15 minutes to 1 hour in a sealed vial or under N2 atmosphere. The reaction mixture was then cooled to room temperature and, unless otherwise stated, either (1) filtered and purified by reverse phase HPLC or (2) worked up and purified by reverse phase HPLC or normal phase column chromatography.

[1360] General Method 2

[1361]

[1362] To a solution of the amine (1 equivalent) in DCM was added 2,4-dimethoxybenzaldehyde (1 equivalent), followed by STAB (1.5 equivalents). 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 (Na2SO4), and concentrated under vacuum. The resulting residue was purified by column chromatography.

[1363] General Method 3

[1364]

[1365] To a stirred solution of the acid (1 eq) in anhydrous DMF was added DIPEA (5-7 eq), the relevant amine (2-6 eq) and HATU (1-3 eq). The reaction mixture was heated at 70°C (unless otherwise stated) for a period of 1-7 hours (unless otherwise stated). Note: In some cases, the reagents were added in two or three portions throughout 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.

[1366] General Method 4

[1367]

[1368] To a stirred solution of 2,4-dimethoxybenzyl protected amine (1 equivalent) in anhydrous dioxane, a 4M HCl solution in dioxane (20 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. After removing the solvent, the crude reaction mixture was used in the next step as the HCl salt. Alternatively, the residue was dissolved in a saturated NaHCO3 aqueous solution and DCM, the organic layer was separated, and extracted with another DCM. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The product was then purified by column chromatography or reversed-phase HPLC.

[1369] General Method 5

[1370]

[1371] To the stirred anhydrous DCM solution of the amine (1 equivalent) of 2,4-dimethoxybenzyl protection was added TFA (10 equivalents). The reaction mixture was stirred at room temperature for 16 hours. After removing the solvent, the crude reaction mixture was used in the next step as a TFA salt. Alternatively, the residue was dissolved in a saturated NaHCO3 aqueous solution and DCM, the organic layer was separated, and extracted with another DCM. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. Then purified by column chromatography or reversed-phase HPLC.

[1372] General Method 6

[1373]

[1374] THBT-amine

[1375] To a mixture of THBT-amine (1 eq), acid (1 eq) and pyridine (5 eq) in DCM (5 mL) was slowly added T3P (1-2 eq) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for several hours. The reaction mixture was worked up and purified by reverse phase HPLC.

[1376] General Method 7

[1377]

[1378] THBT-amine

[1379] To a stirred solution of phenylthiochloroformate (1.1 equivalents) in DCM at 0°C, THBT-amine (1 equivalent) and triethylamine (2-3 equivalents) were added. The reaction was stirred while warming to room temperature for 1 hour, and then the relevant amine (1-2 equivalents) was added as a DCM solution. 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.

[1380] General Method 8

[1381]

[1382] Thiourea (1 equivalent) is dissolved in DMF, and formic hydrazide (2-3 equivalents) is added, followed by mercuric chloride (2-3 equivalents). The reaction mixture is stirred at room temperature for 5 minutes, then triethylamine (3 equivalents) is added. The mixture is stirred at 90 ° C until the reaction is complete. The mixture is cooled to room temperature, diluted with DCM and filtered through kieselguhr / celite, washed with DCM. The solvent is removed in vacuo, and the residue is purified.

[1383] General Method 9

[1384]

[1385] At 0 ° C, sodium carbonate (5 equivalents) was stirred in a mixture of DCM: water (2: 1, respectively). Thiophosgene (1 equivalent) was added, followed by an amine (1 equivalent). The reaction mixture was stirred at 0 ° C for 5 minutes and then at room temperature for 1 hour. The mixture was then extracted with DCM and dried over sodium sulfate or magnesium sulfate, or passed through a hydrophobic glass frit. The solvent was removed in vacuo, and the residue was redissolved in DCM. THBT-amine (1.1 equivalents) was added, and the mixture was stirred at room temperature until the reaction was complete.

[1386] abbreviation

[1387] sat. saturated

[1388] aq. water

[1389] BOC tert-Butoxycarbonyl

[1390] tBuXPhos Pd G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate

[1391] DCE 1,2-dichloroethane

[1392] TEA triethylamine

[1393] THBT 4,5,6,7-tetrahydrobenzothiophene

[1394] T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphaninane-2,4,6-trioxide

[1395] EDC N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[1396] STAB Sodium triacetoxyborohydride

[1397] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[1398] DPPA diphenylphosphoryl azide

[1399] PTSA p-Toluenesulfonic acid

[1400] DEA Diethylamine

[1401] DMA N,N-dimethylacetamide

[1402] TBME tert-butyl methyl ether (also abbreviated as MTBE)

[1403] hr or hrs hours

[1404] KP-NH SNAP KP-NH, flash chromatography columns

[1405] mCPBA 3-Chloroperbenzoic acid

[1406] o / n Overnight

[1407] It is obvious to a person skilled in the art that different retention times (RT) may be obtained for LCMS if different analytical conditions are used.

[1408] Intermediate 1

[1409]

[1410] 6-Amino-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxylic acid ethyl ester

[1411] 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 for 15 minutes under nitrogen and then heated to 50 ° C overnight. The reaction mixture was cooled to room temperature and filtered, washed with EtOAc. The crude residue was purified by flash column chromatography on silica (eluted with a gradient of 100% isohexane / EtOAc to 30% EtOAc / isohexane) to give the title compound (1.41 g, 60%) as a light brown crystalline solid. H (300MHz, DMSO-d6) 7.00 (s, 2H), 4.13 (q, J 7.1Hz, 2H), 4.09-4.03 (m, 2H), 2.56 (t, J 6.4Hz, 2H), 1.94-1.79 (m, 2H), 1.23 (t, J 7.1Hz, 3H).

[1412] Intermediate 2

[1413]

[1414] Ethyl 6-(cyclopropanecarbonylamino)-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxylate

[1415] 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 ~2 h, 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 carried out in the following steps from the crude product. LCMS (ES+) [M+H] + 296.1, RT 3.280 min, 94.2% purity (Method 1).

[1416] Intermediate 3

[1417]

[1418] 6-(Cyclopropanecarbonylamino)-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxylic acid

[1419] To a solution of 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 for 3 h under nitrogen. Additional lithium hydroxide monohydrate [1310-66-3] (179 mg, 4.25 mmol) was added, and the mixture was heated to 70 ° C for 2 h under nitrogen 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 ~pH 4 with 2M aqueous hydrochloric acid solution, and the solid formed was filtered and washed with water to give the title compound (1.28 g, 65%) as a light brown / orange solid. δ H (300MHz, DMSO-d6) 13.06 (s, 1H), 11.31 (s, 1H), 4.14 (dd, J 5.9, 4.2Hz, 2H), 2.67 (t, J 6.4Hz, 2H), 2.03-1.78 (m, 3H), 0.98-0.77 (m, 4H).

[1420] Intermediate 4 and Intermediate 5

[1421]

[1422] Intermediate 4

[1423] 2-Amino-6,7-dihydro-4H-thieno[3,2-c]pyridine-3,5-dicarboxylic acid O5-tert-butyl O3-ethyl ester and

[1424] Intermediate 5

[1425] 2-Amino-5,6-dihydro-4H-thieno[2,3-b]pyridine-3,7-dicarboxylic acid O7-tert-butyl O3-ethyl ester

[1426] 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 ethanol. The filtrate was distributed between DCM and water, and the organic phase was washed with saturated sodium chloride solution and passed through a phase separation column. The crude product was purified by flash column chromatography on silica (eluting with a 10-50% EtOAc / hexanes gradient) to afford 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 light yellow solid. Intermediate 4 LCMS [MH] - 325.0, RT 2.613 min, 83.6% purity (Method 1). Intermediate 5 LCMS [MH] - 325.0, RT 2.774 min, 91.5% purity (Method 1).

[1427] Intermediate 6

[1428]

[1429] 2-(Cyclopropanecarbonylamino)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3,5-dicarboxylic acid O5-tert-butyl O3-ethyl ester

[1430] Intermediate 4 (2.28 g, 6.99 mmol) was dissolved in DCM (50 mL) and DIPEA (1.81 g, 14.0 mmol) was added, and cyclopropanecarbonyl chloride [4023-34-1] (0.820 g, 7.68 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was washed with water, passed through a phase separation column, and the organic phase was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (eluting with a 5-60% EtOAc / hexane gradient) to give the title compound (2.55 g, 93%) as an off-white solid. H(400MHz, DMSO-d6) 11.20 (s, 1H), 4.54 (s, 2H), 4.32 (q, J = 7.3Hz, 2H), 3.60 (t, J = 5.7Hz, 2H), 2. 66 (t, J=5.8Hz, 2H), 2.12-2.02 (m, 1H), 1.43 (s, 9H), 1.35 (t, J=7.1Hz, 3H), 1.01-0.83 (m, 4H). LCMS[M-Boc+H] + 295.8, RT 2.904 min (Method 2).

[1431] Intermediate 7

[1432]

[1433] 5-tert-Butyloxycarbonyl-2-(cyclopropanecarbonylamino)-6,7-dihydro-4H-thieno[3,2-c]pyridine-3-carboxylic acid

[1434] 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, then 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 (2x). The aqueous phase was acidified to pH <4.5 by adding aqueous citric acid solution, and the resulting precipitate was filtered out and washed with water (3x) to give the title compound (1.82 g, 77%) as an off-white solid. δ H (400MHz, DMSO-d6) 13.31 (s, 1H), 11.54 (s, 1H), 4.53 (s, 2H), 3.60 (t, J 5.6Hz, 2H), 2.72-2.60(m, 2H), 2.07-1.93(m, 1H), 1.42(s, 9H), 0.99-0.81(m, 4H).

[1435] Intermediate 8

[1436]

[1437] tert-Butyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylate

[1438] Intermediate 7 (1.82 g, 4.97 mmol) was suspended in DCM (50 mL) and cyclopropylmethylamine [2516-47-4] (0.53 g, 7.5 mmol) and EDCl (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 column, and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (eluted with a 10-60% EtOAc / hexane gradient) to give the title compound (873 mg, 42%) as an off-white solid. H (400MHz, DMSO-d6) 10.75(s, 1H), 7.60(s, 1H), 4.23(s, 2H), 3.36(t, J5.7Hz, 2H), 2.91(t, J6.2Hz, 2H), 2.52-2.31(m , 2H), 1.81-1.60 (m, 1H), 1.17 (s, 9H), 0.87-0.69 (m, 1H), 0.68-0.48 (m, 4H), 0.26-0.11 (m, 2H), 0.07 to -0.10 (m, 2H). LCMS[M+H] + 420.8, RT 2.582 min (Method 2). LCMS [MH] - 418.0, RT 2.471 min (Method 3).

[1439] Intermediate 9

[1440]

[1441] 2-(Cyclopropanecarbonylamino)-5,6-dihydro-4H-thieno[2,3-b]pyridine-3,7-dicarboxylic acid O7-tert-butyl O3-ethyl ester

[1442] 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 16 h. The reaction mixture was washed with water and passed through a phase separation column. The organic phase was concentrated in vacuo to give a crude residue, which was purified by flash column chromatography on silica (eluting with a 5-50% EtOAc / hexane gradient) to give the title compound (3.28 g, 99%) as an off-white solid. H(400MHz, DMSO-d6) 11.09 (s, 1H), 4.30 (q, J 7.1Hz, 2H), 3.69 (s, 2H), 2.77 (t, J 6.3Hz, 2H), 2.06-1.93(m, 1H), 1.93-1.82(m, 2H), 1.49(s, 9H), 1.33(t, J 7.1Hz, 3H), 1.01-0.82(m, 4H). LCMS[M+H] + 395.8, RT 3.141 min, 100.0% purity (Method 2).

[1443] Intermediate 10

[1444]

[1445] 7-tert-Butyloxycarbonyl-2-(cyclopropanecarbonylamino)-5,6-dihydro-4H-thieno[2,3-b]pyridine-3-carboxylic acid

[1446] 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, then cooled to room temperature and concentrated in vacuo. The reaction mixture was distributed between water and DCM, the organic phase was separated, and the aqueous phase was extracted with additional DCM (2x). The aqueous phase was acidified to pH <4.5 with aqueous citric acid solution, and the resulting precipitated gum was extracted into EtOAc (3x). The combined organic phase was washed with saturated sodium chloride solution, passed through a phase separation column, and the filtrate was concentrated in vacuo to give the title compound (2.85 g, 94%) as a yellow sticky solid. δ H (400MHz, DMSO-d6) 11.35 (s, 1H), 3.69 (br.s, J 6.2Hz, 2H), 2.77 (t, J 6.4Hz, 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, 100.0% purity (Method 2).

[1447] Intermediate 11

[1448]

[1449] tert-Butyl 2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-5,6-dihydro-4H-thieno[2,3-b]pyridine-7-carboxylate

[1450] 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 EDCl (0.92 g, 4.67 mmol) were added and the reaction was 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 was concentrated in vacuo to give a crude reaction mixture which was purified by flash column chromatography on silica (eluting with a 20-80% EtOAc / isohexane gradient) to give the title compound (434 mg, 27%) as a light yellow gum. H (400MHz, DMSO-d6) 10.76 (s, 1H), 7.44 (s, 1H), 3.46 (s, 2H), 2.90 (t, J 6.2Hz, 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 to -0.06(m, 2H). LCMS[M+H] + 420.8, [M+Na] + 442.8, RT 2.645 min, 100.0% purity (Method 3).

[1451] Intermediate 12

[1452]

[1453] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[2,3-b]pyridine-3-carboxamide; hydrochloride

[1454] Intermediate 11 (0.43 g, 1.03 mmol) was dissolved in 4N hydrochloric acid solution in 1,4-dioxane (20 mL), and the reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo to give the title compound (370 mg, 101%) as an off-white solid. H(400 MHz, DMSO-d6) 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 to -0.06 (m, 2H), NH2 not observed.

[1455] Intermediate 13

[1456]

[1457] 2-Amino-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid ethyl ester

[1458] 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 silica flash column chromatography (eluting with a 0-15% EtOAc / hexane gradient) to give the title compound (3.33 g, 43%) as a yellow solid. H (400MHz, DMSO-d6) 7.21 (s, 2H), 4.26-4.04 (m, 2H), 3.14 (ddt, J 8.5, 6.6, 3.3Hz, 1H), 2.72 (dtd, J 14.3, 8.1, 2.3Hz, 1H), 2.55 (dd, J 9.3, 2.1Hz, 1H), 2.44 (ddt, J 12.4, 9.3, 8.1Hz, 1H), 1.85 (ddt, J 12.2, 8.1, 1.8Hz, 1H), 1.25 (t, J 7.1Hz, 3H), 1.09 (d, J 6.8Hz, 3H).

[1459] Intermediate 14

[1460]

[1461] 2-(Cyclopropanecarbonylamino)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid ethyl ester

[1462] 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 solution (20 mL) was added, the aqueous phase was separated, extracted with DCM (2×10 mL) and washed with water (10 mL). The organic phases were combined, 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. δ H m / z, 1H), 1.57 (dt, J 14.7, 1.6 Hz, 3H), 2.76 (dtd, J 15.1, 8.9, 1.8 Hz, 1H), 2.54 (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 (dtd, J 15.2, 8.7, 1.8 Hz, 1H), 1.2 6.8 Hz, 3H), 1.13 (q, J 3.7, 3.2 Hz, 2H), 0.92 (dq, J 6.9, 3.7 Hz, 2H). 80% pure.

[1463] Intermediate 15

[1464]

[1465] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide

[1466] Intermediate 14 (80% purity, 1.31 g, 3.57 mmol) was dissolved in MeOH (10 mL) solution and 2M aqueous NaOH solution (3.5 mL) was added. The reaction mixture was heated to reflux for 2 h, and the reaction was cooled to room temperature and concentrated in vacuo. The reaction mixture was acidified with 1M aqueous hydrochloric acid solution, and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (10 mL), dried (MgSO ), 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% purity), which was used without further purification.

[1467] EDCl (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-cyclopropylmethylamine [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 solution (10 mL). The organic phase was separated, dried (MgSO ), filtered and concentrated in vacuo to give the crude product, which was purified by flash column chromatography on silica (eluted with a 0-30% EtOAc / heptane gradient) to give the title compound (40 mg, 16%) as a light brown solid. LCMS[M+H] + 319.1, RT 4.58 min (Method 5).

[1468] Intermediate 16

[1469]

[1470] 2-(Cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1471] Cyclopropanecarbonyl chloride [4023-34-1] (5.44 g, 51.0 mmol) was added to a solution of methyl 2-amino-4,5,6,7-tetrahydro-benzo[B]thiophene-3-carboxylate [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 vacuo to yield 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 ~3 h. The reaction mixture was cooled to room temperature and allowed to stand overnight, after which 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 adding 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 creamy white solid. H (400MHz, DMSO-d6) 13.04 (s, 1H), 11.46 (s, 1H), 2.81-2.63 (m, 2H), 2.63-2.54 (m, 2H), 1.95 (h, J 5.6Hz, 1H), 1.80-1.60 (m, 4H), 1.02-0.76 (m, 4H).

[1472] Intermediate 17

[1473]

[1474] N-(4,5,6,7-Tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide

[1475] 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%). H (400MHz, DMSO-d6) 11.05 (s, 1H), 6.29 (s, 1H), 2.57 (t, J 5.8Hz, 2H), 2.45 (t, J 5.9Hz, 2H), 1.82-1.54 (m, 5H), 0.79 (d, J 6.2Hz, 4H).

[1476] Intermediate 18

[1477]

[1478] 2,3-Dibromo-4,5,6,7-tetrahydrobenzothiophene

[1479] 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 hours, and the resulting yellow / orange solution was stirred at -5 ° C. The reaction mixture was quenched with 10% aqueous sodium sulfite solution (10 mL) and extracted with DCM (3×15 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate solution (15 mL), brine (15 mL), dried (MgSO4) and filtered. The crude material was purified by filtration on silica (eluting with a 0-10% DCM / heptane gradient) 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).

[1480] Intermediate 19

[1481]

[1482] 3-Bromo-4,5,6,7-tetrahydrobenzothiophene

[1483] To a stirred solution of intermediate 18 (3.9 g, 13.2 mmol) in Et2O (100 mL) cooled to -78°C was added 1.6 M n-butyllithium (17.3 mL, 27.7 mmol) in hexanes over 20 minutes, 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 warmed to room temperature over several hours. EtOAc (30 mL) was added, the layers were separated, and the aqueous phase was extracted with additional EtOAc (40 mL). The combined organic phases were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo to give an orange crude material (2.8 g) as an orange oil, which was purified by flash column chromatography on silica (eluting with a 0-10% DCM / heptane gradient) to give the title compound (885 mg, 31%). δ 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).

[1484] Intermediate 20

[1485]

[1486] 3-Bromo-2-nitro-4,5,6,7-tetrahydrobenzothiophene

[1487] Nitronium tetrafluoroborate [13826-86-3] (460 mg, 3.34 mmol) was added to a solution of intermediate 19 (660 mg, 3 mmol) in DCM (15 mL) cooled to -5 ° C. in three portions (200 mg + 200 mg + 60 mg, 5 minutes apart). After 1 hour, the mixture was poured onto ice, diluted with DCM and heated to room temperature. The layers were separated and the aqueous phase was extracted with DCM (10 mL). The combined organic phases were washed with brine, dried (MgSO 4 ) and filtered. The crude product was combined with a crude material from another experiment (starting material intermediate 17, 200 mg, 0.92 mmol), concentrated in vacuo, and purified by flash column chromatography on silica (eluted with a 0-50% DCM / heptane gradient) 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).

[1488] Intermediate 21

[1489]

[1490] 3-Butylsulfanyl-2-nitro-4,5,6,7-tetrahydrobenzothiophene

[1491] 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 a THF (3 mL) solution of butane-1-thiol [109-79-5] (0.22 mL, 1.98 mmol) was added dropwise, and the resulting mixture was stirred at room temperature. After 2 h, butane-1-thiol [109-79-5] (0.12 mL, 1.01 mmol) was added, and stirring was continued for 1 h. 1-Butanethiol [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 phases were washed with brine (20 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica (eluting with a 0-100% DCM / heptane gradient) 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).

[1492] Intermediate 22

[1493]

[1494] 3-Butylsulfonyl-2-nitro-4,5,6,7-tetrahydrobenzothiophene

[1495] To a stirred solution of intermediate 21 (195 mg, 0.72 mmol) in DCM (8 mL) was added 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 another experiment (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), dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica (eluting with a 0-100% DCM / heptane gradient) to give the title compound (107 mg, 51%). 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).

[1496] Intermediate 23

[1497]

[1498] 3-Butylsulfonyl-4,5,6,7-tetrahydrobenzothiophen-2-amine

[1499] To a solution of intermediate 22 (35 mg, 0.12 mmol) in EtOH (3 mL) was added 10% Pd / C (50% wet, 25 mg, 0.012 mmol) and the mixture was hydrogenated at room temperature and atmospheric pressure. The reaction was left under hydrogen overnight and filtered through a pad of celite, washing 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 min (Method 6).

[1500] Intermediate 24

[1501]

[1502] 3-(Dimethylamino)-2-isocyanatoprop-2-enoic acid ethyl ester

[1503] To a brown solution of ethyl isocyanoacetate [2999-46-4] (1 g, 8.84 mmol) in anhydrous ethanol (10 mL) was added DMF-DMA (1.53 mL, 11.49 mmol) dropwise under N 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 (using an elution gradient of 0-60% ethyl acetate / heptane) to give the title compound (780 mg, 52%) as a yellow oil that solidified upon cooling. 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).

[1504] Intermediate 25

[1505]

[1506] 5-(tert-Butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1507] To a stirred solution of intermediate 102a (15 g, 44.1 mmol) in DCM (250 mL) and triethylamine (12.3 mL, 88.2 mmol) at 0°C was added cyclopropanecarbonyl chloride [4023-34-1] (6.9 g, 66.2 mmol) dropwise. 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, dried (Na2SO4), filtered and concentrated in vacuo to give the crude product, which was triturated with Et2O and pentane to give the title compound (14 g, 78%). H (400MHz, DMSO-d6) δ11.17 (s, 1H), 6.92 (d, J7.3Hz, 1H), 4.29 (q, J 7.1Hz, 2H), 3.62 (s, 1H), 3.04 (dd, J 17.0, 4.3Hz, 1H), 2.74-2.66 (m, 2H), 2.46 (d, J 9.3Hz, 1H), 2.06-1.88 (m, 2H), 1.68-1.58 (m, 1H), 1.40 (s, 9H), 1.31 (t, J 7.1Hz, 3H), 0.97-0.84 (m, 4H). LCMS[M-Boc+H] + 309.8, RT 2.831 min, 96.2% purity (Method 2).

[1508] Intermediate 26

[1509]

[1510] 5-(tert-Butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1511] 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 minutes and filtered. The obtained residue was dried in vacuo to give the title compound (12 g, 91%). 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, 77.3% purity (Method 7).

[1512] Intermediate 27

[1513]

[1514] tert-Butyl N-[2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate

[1515] 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. for 1 h in a microwave 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, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (eluting with a 5%-50% EtOAc / heptane gradient) to give the 5-substituted title compound (640 mg, 50%) as an off-white solid mixed with the 7-regioisomer (performed by previous synthetic steps, derived from the synthesis of intermediates 102 and 102a). LCMS [M+H] + 337, RT 1.28 min, 71% (5-regioisomer), [M+Na] +359.15, [M-tBu+H] + 280.95, RT 1.38 min, 28% (7-regioisomer) (Method 6).

[1516] Intermediate 28

[1517]

[1518] N-[5-Amino-3-(isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[1519] 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 hour and 40 minutes and then cooled to 0° C. Isobutylamine [78-81-9] (3 mL, 29.5 mmol) and triethylamine (2 mL, 14.2 mmol) were added to chloroform (5 mL) and the mixture was cooled to 0° C. The two solutions were added together and the mixture was stirred at 30° C. for 30 minutes. Water (25 mL) was added to the reaction mixture and the mixture was extracted with Et2O (1×50 ml, 2×25 ml). The organic phases were combined, dried (MgSO4), 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 additional crude product (0.58 g) as a yellow oil. The crude products were combined and purified by flash column chromatography on silica (gradient elution from 100% DCM to 80 / 20 / 2 DCM / MeOH / NH4OH) to afford a dark solid (1.05 g), which was dissolved in DCM (~4 mL) and treated with ~60 ml of 80 / 20 isopropanol / ethyl acetate. The insoluble residue was removed, and the combined organic phases were concentrated in vacuo to afford the title compound (0.67 g, 55%). LCMS [M+H] + 372.13, [MH] - 370.13, RT 2.52 min (Method 9).

[1520] Intermediate 29

[1521]

[1522] N-(5-Amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide; hydrochloride

[1523] Intermediate 27 (640 mg, 1.35 mmol) was dissolved in 1,4-dioxane (5 mL) and a 4 M solution of 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 product (550 mg) was used without further purification. LCMS [M+H] + 236.95, RT 0.66 min, purity 31% (Method 6).

[1524] Intermediate 30

[1525]

[1526] N-[5-(Methanesulfonylamino)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[1527] 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, dried (Na2SO4), filtered and concentrated in vacuo. The obtained residue was purified by flash column chromatography on silica (eluted with a 12% to 100% EtOAc / heptane gradient) to give the title compound (270 mg) as an off-white solid. H (500 MHz, CD3OD) 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). ~90% purity.

[1528] Intermediate 31

[1529]

[1530] N-[5-Amino-3-(propylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[1531] 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 Et2O (1×100 mL, 2×50 mL). The organic phases were combined, washed with water (2×50 mL), dried (MgSO4), filtered, and concentrated in vacuo to give the crude material (502 mg) as a viscous yellow oil. The combined aqueous phases were extracted with EtOAc (2 x 100 mL) and the organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to give a dark yellow oil which was combined with the first crude material. The combined crude material was purified by flash column chromatography on silica (gradient elution with DCM / MeOH / NH4OH 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 min (Method 8).

[1532] Intermediate 32

[1533]

[1534] 2'-Aminospiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxylic acid ethyl ester

[1535] To a mixture of 1,4-dioxaspiro[4.5]dec-7-one[4969-01-1](5g, 32.0mmol), sulfur[7664-93-9](1.23g, 38.4mmol) and ethyl cyanoacetate[105-56-6](4.34g, 38.4mmol) in ethanol (50mL) was added triethylamine (8.92ml, 64.0mmol) 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 phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a crude residue, which was purified by flash column chromatography on silica (eluted with 100% DCM followed by a 5%-50% EtOAc / heptane gradient) to give the title compound (5.47g, 59%) as a yellow gum. δ H(500MHz, CD3OD) 4.23 (q, J 7.1Hz, 2H), 4.05-3.96 (m, 4H), 2.87 (s, 2H), 2.63 (tt, J 6.5, 1.6Hz, 2H), 1.89 (t, J 6.5Hz, 2H), 1.32 (t, J 7.1Hz, 3H). LCMS[M+H] + 283.95, RT 1.19 min (Method 6).

[1536] Intermediate 33

[1537]

[1538] 2'-(Cyclopropanecarbonylamino)spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxylic acid ethyl ester

[1539] To a solution of intermediate 32 (5.47 g, 19.3 mmol) and DIPEA (6.7 mL, 38.6 mmol) in DCM (200 mL) at 0°C was added cyclopropanecarbonyl chloride [4023-34-1] (2.6 ml, 28.9 mmol). 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 the crude product as a light yellow solid, which was purified by flash column chromatography on silica (eluting with a 5%-50% EtOAc / heptane gradient) to give the title compound (6.5 g, 96%) as a light yellow solid. LCMS [M+H] + 352.05, RT 1.38 min (Method 6).

[1540] Intermediate 34

[1541]

[1542] 2'-(Cyclopropanecarbonylamino)spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-3'-carboxylic acid

[1543] To a suspension of intermediate 33 (6.5 g, 18.5 mmol) in 1,4-dioxane (120 mL) was added 2 M 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 solution, the collected material was filtered, washed with water and dried in vacuo to give the title compound (5 g, 84%) as a brown solid. H (500MHz, CD3OD) 4.03-3.99 (m, 4H), 2.99 (s, 2H), 2.80 (t, J 6.5Hz, 2H), 1.93 (t, J 6.5Hz, 2H), 1.85-1.77 (m, 1H), 1.05-0.94 (m, 4H). LCMS[M+H] + 323.95, RT 1.14 min (Method 6).

[1544] Intermediate 35

[1545]

[1546] N-Spiro[1,3-dioxolane-2,5'-6,7-dihydro-4H-benzothiophene]-2'-ylcyclopropanecarboxamide

[1547] 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 in a microwave to 150 °C 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 (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica (eluting with a 5%-50% EtOAc / heptane gradient) to give the title compound (1.1 g, 80%) as an off-white solid. LCMS [M+H] + 279.95, RT 1.10 min (Method 6).

[1548] Intermediate 36

[1549]

[1550] N-(5-Oxo-6,7-dihydro-4H-benzothiophen-2-yl)cyclopropanecarboxamide

[1551] To intermediate 35 (2 g, 7.15 mmol) dissolved in 35 mL of THF (80 mL) was added 1 M aqueous hydrochloric acid solution (36 mL). The reaction mixture was heated at 50 ° C for 5 h while stirring under nitrogen. After cooling to room temperature, the reaction mixture was basified with saturated sodium bicarbonate solution and diluted with EtOAc. The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo to give a light yellow solid, which was triturated with DCM / Et2O to give the title compound (1.42 g, 78%) as a light yellow solid. LCMS [M+H] + 235.90, RT 1.01 min (Method 6).

[1552] Intermediate 37

[1553]

[1554] N-(5-Amino-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide

[1555] To a mixture of intermediate 36 (1.42 g, 6.0 mmol), ammonium acetate (4.65 g, 60.3 mmol) and Na2SO4 (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 (MgSO4), filtered and concentrated in vacuo to give a crude residue, which was purified by flash column chromatography on silica (eluting with a 1%-70% MeOH / DCM gradient) to give the title compound (270 mg, 19%) as a light brown solid. LCMS [M+H] + 236.95 (Method 6).

[1556] Intermediate 38

[1557]

[1558] N-[5-[(4-Methoxyphenyl)carbamoylamino]-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[1559] 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 minutes. 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 min (Method 6).

[1560] Intermediates 39 and 40

[1561]

[1562] Intermediate 39

[1563] 2-Amino-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxylic acid O3-tert-butyl O5-ethyl ester

[1564] Intermediate 40

[1565] 2-Amino-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxylic acid O3-tert-butyl O7-ethyl ester

[1566] 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) was added (20 mL) of 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, dried (MgSO 4 ), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (eluting with a 5%-40% EtOAc / heptane gradient) to give the title compound intermediate 39 and the regioisomer of the title compound intermediate 40 in a 79:21 ratio (2.84 g, 74%). LCMS [M+H] + 326.00, RT 1.49 and 1.52 min (Method 6).

[1567] Intermediates 41 and 42

[1568]

[1569] Intermediate 41

[1570] 2-(Cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxylic acid O3-tert-butyl O5-ethyl ester

[1571] Intermediate 42

[1572] 2-(Cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3,7-dicarboxylic acid O3-tert-butyl O7-ethyl ester

[1573] 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) at 0°C was added cyclopropanecarbonyl chloride (1.08 ml, 49.1 mmol). 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 separated. The aqueous phase was extracted with DCM (2 x 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, dried (MgSO₄), filtered, and concentrated in vacuo to afford a light yellow solid as a mixture of regioisomers, which was purified by flash column chromatography on silica (eluting with a 5%-50% EtOAc / heptane gradient) to afford the product as a solid as a mixture of regioisomers. The solid was triturated with heptane / Et2O to give the title compound Intermediate 41 (7 g, 72%) and the filtrate was concentrated in vacuo to give a 40:60 mixture of the title compound Intermediate 41 and the title compound Intermediate 42 (2 g, 21%). Intermediate 41: δ H (500MHz, CD3OD)4.24-4.11(m,2H),3.16(dd,J 17.2, 5.4Hz, 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 7.1Hz, 3H), 1.05-0.94 (m, 4H). LCMS[M+H] + 394.10, RT 1.63 min (Method 6).

[1574] Intermediate 43

[1575]

[1576] 2-(Cyclopropanecarbonylamino)-5-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1577] 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 triturated with Et2O to give the title compound (5.3 g, 88%) as a white solid. LCMS [M+H] + 338, RT 1.28 min (Method 6).

[1578] Intermediates 43 and 44

[1579]

[1580] Intermediate 43

[1581] 2-(Cyclopropanecarbonylamino)-5-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1582] Intermediate 44

[1583] 2-(Cyclopropanecarbonylamino)-7-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1584] A 1:2 mixture of Intermediates 41 and 42 (90%, 2.7 g, 6.18 mmol) was dissolved in 4M hydrochloric acid in 1,4-dioxane (30 mL) and stirred at room temperature for 2 h, then at 35°C for 6 h, then at room temperature for 16 h, and then at 35°C for 3 h. The reaction mixture was concentrated in vacuo and the residue was triturated with Et2O to give the 5-isomer title compound Intermediate 43 (220 mg, 11%) as an off-white solid. The filtrate was concentrated in vacuo under reduced pressure to give a 1:3 mixture of the 5-isomer title compound Intermediate 43 and the 7-isomer 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).

[1585] Intermediates 45 and 46

[1586]

[1587] Intermediate 45

[1588] 2-(Cyclopropanecarbonylamino)-N-ethyl-4,5,6,7-tetrahydrobenzothiophene-5-carboxamide

[1589] Intermediate 46

[1590] 2-(Cyclopropanecarbonylamino)-N-ethyl-4,5,6,7-tetrahydrobenzothiophene-7-carboxamide

[1591] 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), then with saturated aqueous sodium bicarbonate (100 mL), dried (MgSO ), filtered, and concentrated in vacuo. Trituration with Et2O gave 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 (eluting with a 25-50% EtOAc / heptane gradient) to give 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 (500MHz, CD3OD) 6.35 (s, 1H), 4.16 (q, J 7.1Hz, 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 7.1Hz, 3H), 0.96-0.91 (m, 2H), 0.89-0.83 (m, 2H).

[1592] 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 2M aqueous lithium hydroxide solution (6 mL, 12 mmol). The reaction mixture was stirred at room temperature for 20 h, and the reaction mixture was concentrated in vacuo, and the residue was acidified with 1M aqueous hydrochloric acid solution, 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.

[1593] A 1:3 mixture (300 mg, 1.13 mmol) of 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid and 2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid 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 minutes, followed by addition of a 2M solution of ethylamine in THF (0.7 mL). The reaction mixture was stirred for a further 30 minutes and diluted with DCM (20 mL), washed with water (20 mL) and a 1M aqueous hydrochloric acid solution, dried (MgSO ), filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (eluting with a 50-100% EtOAc / heptane gradient) to afford the 5-isomer title compound Intermediate 45 (100 mg, 20%, -65% purity) as a viscous 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-Isomer Intermediate 46: δ H (500MHz, DMSO-d6) 11.09 (s, 1H), 7.91 (t, J 5.5Hz, 1H), 6.29 (s, 1H), 3.47 (t, J 6.7Hz, 1H), 3.16-3.00 (m, 2H), 2.44 (t, J 5.5Hz, 2H), 1.97-1.83(m, 3H), 1.74-1.67(m, 1H), 1.63-1.51(m, 1H), 1.03(t, J 7.2Hz, 3H), 0.82-0.76(m, 4H).

[1594] Intermediates 47 and 22

[1595]

[1596] Intermediate 47

[1597] 3-Butylsulfinyl-2-nitro-4,5,6,7-tetrahydrobenzothiophene

[1598] Intermediate 22

[1599] 3-Butylsulfonyl-2-nitro-4,5,6,7-tetrahydrobenzothiophene

[1600] 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 experiment (15 mg, 0.055 mmol starting material) and quenched with saturated aqueous Na2SO3 (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), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica (eluting with a 0-100% DCM / heptane gradient) 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 min (Method 5).

[1601] Intermediate 48

[1602]

[1603] 2-Amino-2-cyano-N-methylacetamide

[1604] To a stirred solution of intermediate 131 (77%, 691 mg, 4.15 mmol) in TBME (10 mL) cooled in an ice bath was added a 2M solution of CH3NH2 in MeOH (7 mL). 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: ether (1:9) to give an orange solid, which was collected by vacuum filtration and washed with ethanol: ether (1:9) to give the title compound (395 mg, 76% at 90% purity) as an orange solid. H(250MHz, DMSO-d6) δ8.09 (s, 1H), 4.47 (s, 1H), 2.81 (br s, 2H), 2.65 (d, J4.7Hz, 3H).

[1605] Intermediate 49

[1606]

[1607] 3-Butylsulfinyl-4,5,6,7-tetrahydrobenzothiophen-2-amine

[1608] To a solution of intermediate 47 (40 mg, 0.14 mmol) in EtOH (3 mL) was added 10% palladium on charcoal (50% wet) (30 mg, 0.014 mmol), and the mixture was hydrogenated at room temperature and atmospheric pressure. An additional 10% palladium on charcoal (50% wet) (30 mg, 0.014 mmol) was added and stirring was continued at room temperature. After a total of 7 hours of stirring, 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 min (Method 6).

[1609] Intermediate 50

[1610]

[1611] 3-Cyano-2-phenyl-1-(p-tolyl)isourea

[1612] 4-Methylaniline [106-49-0] (40 mg, 0.37 mmol) was dissolved in DCM (2 mL) and diphenyl cyanocarbonimidate [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).

[1613] Intermediate 51

[1614]

[1615] N-[5-amino-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[1616] 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 at 70 ° C for 1 h in a sealed tube and then cooled to room temperature. The solution was slowly added to a chloroform (5 mL) solution of 1-cyclopropylmethylamine [2516-47-4] (1.0 mL, 11.8 mmol) and triethylamine (0.84 mL, 5.94 mmol) 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 x 40 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography on silica (eluting with a 1% to 20% MeOH / DCM gradient) to afford the title compound (210 mg, 38%) as a light yellow solid. H (500MHz, chloroform-d) 10.49 (s, 1H), 3.44-3.17 (m, 5H), 2.81-2.68 (m, 4H), 2.60 (dd, J15.7, 9.4Hz, 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 min (Method 6).

[1617] Intermediate 52

[1618]

[1619] N-[5-[(N-cyano-C-phenoxy-iminoyl)amino]-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide

[1620] Intermediate 51 (100 mg, 0.27 mmol) was dissolved in 2-propanol (5 mL) and diphenyl cyanimidocarbonate [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 a 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. H(500 MHz, CD3OD) 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 min (Method 10).

[1621] Intermediate 53

[1622]

[1623] 2-(Cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid ethyl ester

[1624] Intermediate 43 (4 g, 11.9 mmol) was divided into two equal portions, each suspended in quinoline (15 mL) and then 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 and 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), dried (MgSO4), 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. H (500MHz, DMSO-d6) 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 7.1Hz, 3H), 0.83-0.75 (m, 4H). LCMS[M+H] + 294.0, RT 1.26 min, 98% purity (Method 6).

[1625] Intermediate 54

[1626]

[1627] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid ethyl ester

[1628] Intermediate 53 (2 g, 6.34 mmol, 93% purity) was suspended in MeCN (120 mL) and chlorosulfonic acid [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 cyclopropylmethylamine [2516-47-4] (4 mL, 46.1 mmol) was added dropwise. The ice bath was removed and the solution was stirred for 30 minutes. EtOAc (200 mL) was added and the mixture was washed with 1M aqueous hydrochloric acid (2×100 mL) and brine to separate the organic phase, dried (MgSO 4 ), filtered and concentrated in vacuo to give the product, which was purified by flash column chromatography on silica (eluting with a 0-30% EtOAc / heptane gradient) to give the title compound (1.4 g, 52%) as an amber oil that solidified to form a beige solid. δ H (500MHz, DMSO-d6)10.44(s, 1H), 7.94(t, J 5.9Hz, 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 7.1Hz, 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 min, 99% purity (Method 6).

[1629] Intermediate 55

[1630]

[1631] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid

[1632] Intermediate 54 (1.8 g, 4.22 mmol) was dissolved in 1,4-dioxane (40 mL), and water (10 mL) and 2M lithium hydroxide monohydrate solution (6 mL) were 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 1M aqueous hydrochloric acid solution. 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. H (500MHz, DMSO-d6) 12.34 (s, 1H), 10.45 (s, 1H), 7.94 (t, J5.7Hz, 1H), 3.03 (dd, J 16.7, 5.0Hz, 1H), 2.78-2.58 (m, 6H), 2.14-2.05 (m, 1H), 1.94-1.86 (m, 1H), 1.80-1.6 7 (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, 97% purity (Method 6).

[1633] Intermediate 56

[1634]

[1635] N-(3-Butylsulfanyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide

[1636] 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% palladium on charcoal (50% wet, 730 mg, 0.34 mmol), and the reaction mixture was hydrogenated at room temperature and atmospheric pressure for 2 h. Additional 10% palladium on charcoal (50% wet, 730 mg, 0.34 mmol) was added, and stirring was continued at room temperature for 1 h. 10% palladium on charcoal (50% wet, 500 mg, 0.24 mmol) was added, and stirring was continued for 1 h. The reaction mixture is filtered through a pad of diatomaceous earth, washed with EtOAc, and the gained solution is processed with triethylamine (1.43mL, 10.3mmoL), then processed with cyclopropanecarbonyl chloride [4023-34-1] (0.63mL, 6.9mmoL), and the reaction mixture is stirred at room temperature for 60h under nitrogen. The mixture is washed with saturated aqueous ammonium chloride (10mL) and salt solution (10mL), and the organic phase is dried (MgSO ), filtered and concentrated in vacuo. The crude material is purified by silica flash column chromatography (eluting with 0-50% DCM / heptane gradient), crude product is obtained, which is dissolved in EtOAc (15mL), and washed with saturated aqueous ammonium chloride (10mL), saturated sodium bicarbonate aqueous solution (10mL) and salt solution. The organic phase is dried (MgSO ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (eluting with a 0-50% EtOAc / heptane gradient) to afford the title compound (630 mg, 90% purity, 54%) as a light yellow solid. 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, 94% purity (Method 11).

[1637] Intermediate 57

[1638]

[1639] N-(3-Butylsulfinyl-4,5,6,7-tetrahydrobenzothiophen-2-yl)cyclopropanecarboxamide

[1640] To a stirred solution of intermediate 56 (660 mg, 1.9 mmol) in DCM (12 mL) was added a solution of mCPBA (70% purity, 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 (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), dried (MgSO ), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica (eluting with a 0-50% EtOAc / heptane gradient) to give the title compound as a yellow oil (576 mg, 92%). 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).

[1641] Intermediate 58

[1642]

[1643] 2-(Cyclopropanecarbonylamino)-N3-(cyclopropylmethyl)-N5-methoxy-N5-methyl-4,5,6,7-tetrahydrobenzothiophene-3,5-dicarboxamide

[1644] Example 40 (4 g, 11.04 mmol) was suspended in DCM (100 mL), and EDCl (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 title compound (3.0 g, 60%) was obtained as a yellow solid. H(500 MHz, dichloromethane-d2) 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). Lack of NH protons. LCMS [M+H] + 406.20, RT 1.78 min, 91.76% purity (Method 12).

[1645] Intermediate 59

[1646]

[1647] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-formyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1648] 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 minutes. 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 phases were washed with brine (100 mL), dried (MgSO ), filtered, and the filtrate was 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% purity (Method 12).

[1649] Intermediate 60

[1650]

[1651] 5-(Aminomethyl)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; formic acid

[1652] 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 and heated 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 silica flash column chromatography (eluting with a 0-60% MeOH / DCM gradient) to give the title compound (300 mg, 92%) as a white solid. H (250 MHz, dichloromethane-d2) 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 equiv).

[1653] Intermediate 61

[1654]

[1655] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(ethylaminothiocarbothioylamino)methyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1656] A solution of isothiocyanatoethane [542-85-8] (542.85-8) (160.5 mg, 1.84 mmol) in DCM (5 mL) was stirred at room temperature and intermediate 60 (320 mg, 0.92 mmol) was added. 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 light yellow solid which was purified by flash column chromatography on silica (eluting with a 0%-100% EtOAc / heptane gradient) to give the title compound (369 mg, 90%) as a white solid. Hm / z 7.75-7.80 (m, 1H), 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 was obscured by solvent.

[1657] Intermediate 62

[1658]

[1659] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-oxo-6,7-dihydro-4H-benzothiophene-3-carboxamide

[1660] 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, and 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 phases were washed with brine (15 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a yellow solid, which was purified by flash column chromatography on silica (eluting with a 0-50% EtOAc / isohexane gradient) to give the title compound (264 mg, 71%) as an off-white solid. LCMS [M+H] + 333.2, RT 1.630 min, 92.8% purity (Method 1).

[1661] Intermediate 63

[1662]

[1663] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)spiro[6,7-dihydro-4H-benzothiophene-5,2'-oxirane]-3-carboxamide

[1664] Trimethylsulfoxide 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 hours, 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 hour. The reaction mixture was poured into water and ice (50 g) and extracted with EtOAc (3×50 mL). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford a yellow solid which was purified by flash column chromatography on silica (gradient elution: 100% DCM to 95 / 5 / 0.5% DCM / MeOH / NH4OH) to afford 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).

[1665] Intermediate 64

[1666]

[1667] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(4-methoxyphenyl)sulfonylhydrazine]-6,7-dihydro-4H-benzothiophene-3-carboxamide

[1668] Intermediate 62 (200 mg, 0.6 mmol) was added to a solution of 4-methoxybenzenesulfonylhydrazide [1950-68-1] (122 mg, 0.6 mmol) in MeOH (1.2 mL), and the suspension was stirred at 20 ° C for 60 h under nitrogen. 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 under vacuum at 40 ° C for 2 h to give the title compound (146 mg, 44%) as a light yellow powder. H(500MHz, DMSO-d6) 10.96 (s, 1H), 10.16 (s, 1H), 7.90 (t, J 5.5Hz, 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 6.2Hz, 2H), 2.73(t, J 6.3Hz, 2H), 2.49-2.44(obs.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, 95% purity (Method 12).

[1669] Intermediate 65

[1670]

[1671] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid [2-oxo-2-(p-tolyl)ethyl] ester

[1672] 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 minutes, and 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, dried (Na2SO4), filtered, and the solvent was 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).

[1673] Intermediate 66

[1674]

[1675] 2-Cyano-N-(cyclopropylmethyl)acetamide

[1676] To cyclopropylmethylamine [2516-47-4] (3.63 g, 50.0 mmol) was added methyl cyanoacetate [105-34-0] (2.50 g, 25.0 mmol) dropwise at 0°C. The reaction mixture was stirred for 90 minutes, and a white solid precipitated after 45 minutes. 1:1 Et2O / 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. 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).

[1677] Intermediate 67

[1678]

[1679] 2-Amino-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1680] 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, and the mixture was concentrated in vacuo, and the crude residue was purified by flash column chromatography on silica (eluting with a 0-15% EtOAc / hexane gradient) to give the title compound (717 mg, 81%) as an off-white solid. LCMS [M+H] + 294.0, RT 1.532 min (Method 4).

[1681] Intermediate 68

[1682]

[1683] 2-(Cyclopropanecarbonylamino)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1684] 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 ~1 h and then washed with saturated sodium bicarbonate solution and brine. The mixture was passed through a phase separation column, and the organic layer was concentrated in vacuo to give a yellow gum, which was purified by flash column chromatography on silica (eluting with a 10 - 50% EtOAc / hexane gradient) to give the title compound (0.75 g, 85%) as a white solid. δ H (400 MHz, DMSO - d6) 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).

[1685] Intermediate 69

[1686]

[1687] 2 - (Cyclopropanecarbonylamino) - 5 - (trifluoromethyl) - 4,5,6,7 - tetrahydrobenzothiophene - 3 - carboxylic acid

[1688] Intermediate 68 (0.73 g, 2.0 mmol) was dissolved in 1,4 - dioxane (7 mL), and an aqueous solution (1.5 mL) of lithium hydroxide monohydrate [1310 - 66 - 3] (236 mg, 3.15 mmol, 56 mass%) was added, and the mixture was stirred at 50 °C for ~16 h. The mixture was concentrated in vacuo and the residue was dissolved in water and washed with DCM (2x). The aqueous phase was acidified to <pH 2 by addition of 2 M aqueous hydrochloric acid, and the resulting precipitate was filtered off and washed with water (2x) to give the title compound (665 mg, 99%) as a pale grey - white solid, which was air dried. LCMS [M - H] - 332.0, RT 2.374 min (Method 2).

[1689] Intermediate 70

[1690]

[1691] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1692] To intermediate 69 (100 mg, 0.30 mmol) was added a suspension of cyclopropylmethylamine [2516-47-4] (32 mg, 0.45 mmol) and EDCl (71.2 mg, 0.36 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature overnight and then heated at 40 ° C for ~1 h. The mixture was diluted with DCM (5 mL), washed with water and passed through a phase separation column, and the filtrate was then concentrated in vacuo. The crude product was purified by flash column chromatography on silica (eluting with a 10-50% EtOAc / hexane gradient) and then freeze-dried from MeCN / water to give the title compound (35 mg, 30%) as a white solid. LCMS [M+H] + 387.8, RT 2.637 min (Method 2).

[1693] Intermediate 71

[1694]

[1695] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid acetonate

[1696] Example 40 was dissolved in DMF (3 mL) and triethylamine (0.046 ml, 0.33 mmol) and chloroacetone [78-95-5] (0.026 ml, 0.33 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water and the resulting solid was filtered to give the title compound (80 mg, 63%), which was used without further purification. LCMS [M+H] + 419.05, RT 1.38 min, purity 91% (Method 6).

[1697] Intermediate 72

[1698]

[1699] 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(hydrazinocarbonyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1700] 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 afford the title compound (95 mg, 99%) as a white solid. LCMS [M+H] + 377.05, RT 1.13 min, purity 100% (Method 6).

[1701] Intermediate 73

[1702]

[1703] 2-Cyclopropyl-5,6,7,8-tetrahydrobenzothieno[2,3-d][1,3]oxazin-4-one

[1704] 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 LCMS reverse phase (basic mode) to give the title compound (200 mg, 107%) as a beige solid. H (400MHz, DMSO-d6) 2.75 (dt, J 11.2, 6.0Hz, 4H), 2.05-1.95 (m, 1H), 1.87-1.70 (m, 4H), 1.17-1.07 (m, 4H).

[1705] Intermediate 74

[1706]

[1707] 2-(Cyclopropanecarbonylamino)-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid ethyl ester

[1708] 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, and then cyclopropanecarbonyl chloride [4023-34-1] (0.21 mL, 2.30 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen overnight. Additional DCM (24 mL) was added to dissolve the mixture, followed by additional cyclopropanecarbonyl chloride [4023-34-1] (0.21 mL, 2.30 mmol), and the reaction mixture was stirred for 1 h. Additional cyclopropanecarbonyl chloride [4023-34-1] (0.21 mL, 2.30 mmol) was then added and the mixture was stirred under nitrogen overnight. Additional cyclopropanecarbonyl chloride [4023-34-1] (0.21 mL, 2.30 mmol) was added and the reaction mixture was stirred for 2 h, then additional 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 and stirred vigorously for 10 minutes. Water (25 mL) and DCM (25 mL) were added, the organic layer was separated, and then washed with brine (50 mL). The organic layer was separated, passed through a phase separation glass frit, and concentrated in vacuo to give a dark brown oil, which was purified by flash column chromatography on silica (eluted with a gradient of 20% EtOAc / isohexane to 95% EtOAc / isohexane) to give the title compound (253 mg, 39%) as a light yellow solid. LCMS [M+H] + 308.8, RT 2.162 min, 100.0% purity (Method 2). LCMS [M+H] + 308.8, RT 2.205 min, 100.0% purity (Method 3).

[1709] Intermediates 74 and 75

[1710]

[1711] Intermediate 74

[1712] 2-(Cyclopropanecarbonylamino)-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid ethyl ester

[1713] Intermediate 75

[1714] 2-(Cyclopropanecarbonylamino)-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid methyl ester

[1715] To a stirred solution of cyclopropanecarboxylic 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 produced gas and was stirred at room temperature for 1 hour to form cyclopropanecarboxylic acid 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, 73% ethyl and 27% methyl) (ratio 0.73:0.27, 2.736 g) was dissolved in 1,4-dioxane (40 mL added) with heating, and triethylamine (2.38 g, 23.2 mmol) was added. Upon cooling, the aminoester precipitated from the solution, and the crude cyclopropanecarbonyl chloride solution was added dropwise to the stirred ~30°C solution over 1 minute. After 2 hours at room temperature, additional commercially available cyclopropanecarbonyl chloride [4023-34-1] (364 mg, 3.48 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was suspended in EtOAc and washed with water (2x), 0.5 M aqueous hydrochloric acid solution, saturated sodium bicarbonate solution (2x) and water (2x). The organic layer was separated, dried (MgSO4), filtered and the mixture was concentrated in vacuo to give a crude mixture of the title product Intermediate 74 and Intermediate 75 (2.84 g, 59%) as a yellow solid in a ratio of ~3:1. 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, 100.0% purity (Method 2). LCMS [M+H] + 308.8, RT 2.205 min, 100.0% purity (Method 3). Intermediate 75: LCMS [M+H] + 294.6, RT 1.940 min, 100.0% purity (Method 2). LCMS [M+H] + 294.6, RT 1.868 min, 100.0% purity (Method 3).

[1716] Intermediate 76

[1717]

[1718] 2-(Cyclopropanecarbonylamino)-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid

[1719] A mixture of Intermediates 74 and 75 (3:1 ratio) (2.63 g, 8.66 mmol) was dissolved in 1,4-dioxane (40 mL) with heating. Lithium hydroxide monohydrate [1310-66-3] (0.55 g, 13.0 mmol) was dissolved in water (3 mL) with 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, then at room temperature for 18 h. The reaction mixture was heated at 70°C for 2 h, then at 40°C for 5 h. Lithium hydroxide monohydrate [1310-66-3] (0.18 g, 4.33 mmol, 0.5 equiv) dissolved in water (1 mL) was further added, and the solution was stirred at room temperature for 3 days. The reaction was heated at 70°C for 4 h, and then 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 and the organic phase was extracted with dilute sodium carbonate solution and the aqueous extracts were combined. 2M aqueous hydrochloric acid solution was added to the aqueous extract until the acid precipitated from the solution. The resulting suspension was filtered and the solid was washed with 0.2M aqueous hydrochloric acid solution and dried under vacuum to give the title compound (890 mg, 37%) as a beige solid. H (400MHz, DMSO-d6) 13.68 (s, 1H), 11.81 (s, 1H), 3.05 (t, J 6.0Hz, 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, 96.8% purity (Method 2). LCMS [M+H] + 280.6, RT 0.600 min, 96.9% purity (Method 3).

[1720] Intermediate 77

[1721]

[1722] 2-(Cyclopropanecarbonylamino)-N-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxamide

[1723] 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 EDCl (340 mg, 1.72 mmol). After stirring for 10 minutes, 2M methylamine (773 mg, 1.72 mmol, 0.86 mL) in THF 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 (eluted with a 0-100% EtOAc / hexane gradient) to give the title compound (250 mg, 75%) as a yellow solid. LCMS [M+H] + 293.0, RT 1.092 min, 94.0% purity (Method 4).

[1724] Intermediate 78

[1725]

[1726] 2-Amino-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1727] To a solution of 2-methylcyclohexanone [583-60-8] (1 g, 8.83 mmol) in EtOH (4 mL) were 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, then 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 silica flash column chromatography (eluting with a 0-10% EtOAc / hexane gradient) to give the title compound (520 mg, 25%) as a yellow solid. H (400MHz, DMSO-d6) 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 7.1Hz, 3H), 1.09 (d, J 6.7Hz, 3H).

[1728] Intermediate 79

[1729]

[1730] 2-(Cyclopropanecarbonylamino)-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1731] 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, then diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate solution (2 × 20 mL). The mixture was passed through a phase separator column, and the organic phase was concentrated in vacuo. The crude product was dissolved in DCM and purified by flash chromatography on silica (eluting with a 10%-40% EtOAc / isohexane gradient) to give the title compound (676 mg, 101%) as a creamy white solid. H (300MHz, DMSO-d6) 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 7.1Hz), 1.12 (d, 3H, J 6.8Hz), 0.84-0.96 (m, 4H).

[1732] Intermediate 80

[1733]

[1734] 2-(Cyclopropanecarbonylamino)-4-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1735] A solution of 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 another 6 h, then cooled to room temperature overnight. Another portion 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 ~pH 5 with 2M aqueous hydrochloric acid. The cream solid formed was filtered off, washed with water then isohexane and dried in vacuo to give the title compound (454 mg, 77%) as a cream solid. H(400MHz, DMSO-d6) 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 6.8Hz), 0.85-0.93(m, 4H).

[1736] Intermediate 81

[1737]

[1738] 2-Amino-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1739] 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 heated at 50 ° C for another 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 (2×20 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (eluting with a gradient of 1% to 10% EtOAc in isohexane) to afford the title compound (1.23 g, 63%) as a cream solid. H (400MHz, DMSO-d6) 7.18 (s, 2H), 4.15 (q, 2H, J7.1Hz), 2.84 (dd, 1H, J 17.2, 5.0Hz), 2.64-2.74 (m, 1H), 2.00 (ddd, 1H, J 17.4, 11.2, 3.3Hz), 1.80-1.85 (m, 1H), 1.64-1.77 (m, 1H), 1.24 (t, 3H, J 7.1Hz), 1.08 (d, 3H, J 6.8Hz), 1.00 (d, 3H, J 6.5Hz), 0.91-0.99(m, 1H).

[1740] Intermediate 82

[1741]

[1742] 2-(Cyclopropanecarbonylamino)-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1743] 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 solution (20 mL). The mixture was passed through a phase separator column, and the organic phase was concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica (eluting with a 1%-10% EtOAc / isohexane gradient) to give the title compound (1.43 g, 91%) as a creamy white solid. H (300MHz, DMSO-d6) 11.17 (s, 1H), 4.30 (q, 2H, J 7.1Hz), 2.94 (dd, 1H, J 17.2, 5.0Hz), 2.77-2.89 (m, 1H), 2.11 (ddd, 1H, J 17.1, 11.2, 3.0Hz), 1.95-2.04 (m, 1H), 1.83-1.90 (m, 1H), 1.69-1.82 (m, 1H), 1.32 (t, 3H, J7.1Hz), 1.19 (d, 3H, J 6.8Hz), 1.03 (d, 3H, J 6.6Hz), 0.98-1.06(m, 1H), 0.85-0.96(m, 4H).

[1744] Intermediate 83

[1745]

[1746] 2-(Cyclopropanecarbonylamino)-5,7-dimethyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1747] A solution of 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 ~pH 5 with 2M aqueous hydrochloric acid. A pink solid formed, which was filtered off and washed with water and isohexane, then dried in vacuo. The obtained 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 (1.40 g), which was partially dissolved in EtOAc and triturated with isohexane to give a cream-colored powder, which was washed with isohexane and dried. Trituration of the mother liquor with isohexane provided additional compound; the overall title compound (1.07 g, 82%). δ H (400MHz, DMSO-d6) 13.07 (s, 1H), 11.49 (s, 1H), 2.98 (dd, 1H, J 17.3, 4.9Hz), 2.78-2.90 (m, 1H), 2.09 (ddd, 1H, J 17.1, 11.3, 2.9Hz), 1.90-1.99 (m, 1H), 1.83-1.89 (m, 1H), 1.69-1.82 (m, 1H), 1.18 (d, 3H, J6.8Hz), 0.95-1.04 (m, 1H), 1.02 (d, 3H, J 6.6Hz), 0.85-0.93(m, 4H).

[1748] Intermediates 84 and 85

[1749]

[1750] Intermediate 84

[1751] 2-Amino-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1752] Intermediate 85

[1753] 2-Amino-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1754] 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 minutes, stirred at room temperature overnight, and then heated at 50 ° C for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, diluted with EtOAc (20 mL) and washed with brine (2 × 20 mL). The organic phase was dried (MgSO ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (eluting with a 1%-10% EtOAc / isohexane gradient) to afford the title compound (1.78 g, 86%) as an off-white solid as a ~6:1 mixture of the two 5:7-methyl isomers of the compound. H (300 MHz, DMSO-d6) 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, 2.2 Hz), 1.84-1.63 (m, 2H), 1.37-1.27 (m, 1H), 1.24 (t, 3H, J 7.1 Hz), 1.00 (d, 3H, J 6.6 Hz). Minor 7-isomer intermediate 85: δ H (300 MHz, DMSO-d6) 7.19 (s, 2H), 4.14 (q, 2H, J 7.1 Hz), 2.70-2.60 (m, 2H), 1.92-1.61 (m, 3H), 1.59-1.50 (m, 1H), 1.24 (t, 3H, J 7.1 Hz), 1.10 (d, 3H, J 6.8 Hz); 1 proton is obscured.

[1755] Intermediates 86 and 87

[1756]

[1757] Intermediate 86

[1758] 2-(Cyclopropanecarbonylamino)-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1759] Intermediate 87

[1760] 2-(Cyclopropanecarbonylamino)-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1761] Cyclopropanecarbonyl chloride [4023-34-1] (0.76 mL, 8.2 mmol) was added to 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 solution (20 mL). The mixture was passed through a phase separator column, and the organic phase was concentrated in vacuo. The crude product was purified by flash column chromatography on silica (eluting with a 1%-10% EtOAc / isohexane gradient) to give the product, which was recrystallized from EtOAc / isohexane to give the title compound (141 mg, 0.459 mmol) as a white solid of a 30:1 mixture of 5-:7-methyl isomers. The mother liquor was evaporated, redissolved in EtOAc, seeded with the product, and allowed to crystallize overnight. The solid was washed with isohexane and dried in air to give additional product (0.52 g) as a white solid, a ~30:1 mixture of 5-:7-methyl isomers; a 30:1 mixture of the main title compound Intermediates 86 and 87 (0.66 g, 29%). The mother liquor was evaporated to a cream solid (1.495 g) to give a ~4:1 mixture of 5-:7-methyl isomers. The main title compound, Intermediate 86: δ H (400MHz, DMSO-d6)11.17(s,1H),4.26-4.34(m,2H),2.92(dd,1H,J 17.2, 5.1Hz), 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 7.1Hz), 1.03 (d, 3H, J 6.6Hz), 0.86-0.94 (m, 4H).

[1762] Intermediates 88 and 89

[1763]

[1764] Intermediate 88

[1765] 2-(Cyclopropanecarbonylamino)-5-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1766] Intermediate 89

[1767] 2-(Cyclopropanecarbonylamino)-7-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1768] 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 solution (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 (Na2SO4), filtered and concentrated in vacuo. The solid obtained was partially dissolved in EtOAc and triturated with isohexane to give a reddish-brown powder which was washed with isohexane and dried under a stream of air to give the title compound (469 mg, 82%) as a 30:1 mixture of Intermediate 88 5-Me and Intermediate 89 7-Me products. H (400MHz, DMSO-d6) 13.05 (s, 1H), 11.48 (s, 1H), 2.95 (dd, 1H, J 17.3, 5.0Hz), 2.53-2.67 (m, 2H), 2.17 (dd, 1H, J 17.1, 10.0Hz), 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 6.6Hz), 0.84-0.93 (m, 4H).

[1769] Intermediate 90

[1770]

[1771] 2-Amino-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxylic acid ethyl ester

[1772] 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 a nitrogen atmosphere. 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 extracted with additional EtOAc (2×15 mL). The combined organic phases were washed with brine (10 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (eluting with a gradient of 0-50% EtOAc in heptane) and then further purified by flash column chromatography on silica (eluting with a gradient of 0-100% DCM in heptane) to afford the title compound (555 mg, 55%) as an off-white solid. 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).

[1773] Intermediate 91

[1774]

[1775] 2-(Cyclopropanecarbonylamino)-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxylic acid ethyl ester

[1776] 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 was added cyclopropanecarbonyl chloride [4023-34-1] (0.12 mL, 1.28 mmol) and the solution was stirred under a nitrogen atmosphere. After stirring for 15 minutes, the mixture was diluted with DCM (15 mL) and 1 M aqueous hydrochloric acid solution (10 mL) was added. The phases were separated and the aqueous phase was extracted with additional DCM (10 mL). The combined organic phases were washed with brine (10 mL), dried (MgSO ), filtered and concentrated in vacuo to give the title compound (400 mg, quantitative, 80% purity) 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).

[1777] Intermediate 92

[1778]

[1779] 2-(Cyclopropanecarbonylamino)-5,5-dimethyl-6,7-dihydro-4H-benzothiophene-3-carboxylic acid

[1780] 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 heated to reflux. After heating for 2 hours, the reaction mixture was concentrated in vacuo and the residue was diluted with water (2 mL). The solution was acidified to a pH of 4-5 with 0.2 M aqueous hydrochloric acid, and the off-white precipitate was collected by filtration, washed with water, and dried in a vacuum oven at 40 ° C overnight 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, 98% purity (Method 6).

[1781] Intermediate 93

[1782]

[1783] 2-Amino-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid ethyl ester

[1784] 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 (eluting with a 0-30% EtOAc / hexane gradient) to give the title compound (1.28 g, 26%). H (400MHz, DMSO-d6) 8.20 (s, 2H), 4.24 (q, J7.1Hz, 2H), 3.23 (dd, J 17.8, 3.7Hz, 1H), 2.48-2.30 (m, 2H), 2.30-2.13 (m, 2H), 1.29 (t, J7.1Hz, 3H), 1.06 (d, J 5.9Hz, 3H).

[1785] Intermediate 94

[1786]

[1787] 2-(Cyclopropanecarbonylamino)-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxylic acid ethyl ester

[1788] 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 solution (20 mL) was added and the layers were separated. The aqueous phase was extracted with additional DCM (2 x 10 mL) and washed with water (10 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo to give the title compound (1.8 g, 99%, ~85% purity) as a red / brown solid which was used in the next step without further purification. H(500MHz, chloroform-d) 11.73 (s, 1H), 4.41 (q, J 7.1Hz, 2H), 3.41-3.28 (m, 1H), 2.63-2.57 (m, 1H), 2.54 (dd, J 17.7, 10.1Hz, 1H), 2.41-2.32 (m, 1H), 2.27 (dd, J 16.0, 12.0Hz, 1H), 1.70 (tq, J 8.8, 4.5Hz, 1H), 1.43 (t, J 7.1Hz, 3H), 1.24-1.18 (m, 2H), 1.16 (d, J 6.5Hz, 3H), 1.06-0.96 (m, 2H).

[1789] Intermediate 95

[1790]

[1791] 2-amino-N-(cyclopropylmethyl)-5-methyl-7-oxo-5,6-dihydro-4H-benzothiophene-3-carboxamide

[1792] Intermediate 94 (85% purity, 1.8 g, 4.76 mmol) was dissolved in a solution of MeOH (10 mL) and 2M aqueous NaOH solution (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 solution (1.25 mL) was added and the mixture was heated to reflux for 4 h. The reaction mixture was allowed to cool to room temperature and the MeOH was removed in vacuo. The reaction mixture was acidified with 1M aqueous hydrochloric acid solution and the product was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (10 mL), 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%), which was used directly in the next step without further purification.

[1793] EDCl (640 mg, 3.34 mmol) is added to a solution of 1-cyclopropylmethylamine [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). The solution is stirred at room temperature for 16 h, then 1-cyclopropylmethylamine [2516-47-4] (0.29 mL, 3.34 mmol) is added, followed by EDCI (640 mg, 3.34 mmol), and stirred for another 4 h. The reaction mixture is diluted with DCM and poured into a 1 M aqueous hydrochloric acid solution (20 mL). The organic phase was dried (MgSO 4 ), filtered and concentrated in vacuo to afford the crude product which was purified by flash column chromatography on silica (eluting with a 30-80% EtOAc / heptane gradient) to afford the title compound (210 mg, 27%, 80% purity) as a bright yellow solid. δ H (500MHz, chloroform-d) 5.67 (s, 1H), 3.30-3.24 (m, 2H), 3.05 (dd, J15.3, 3.9Hz, 1H), 2.61 (d, J 15.4Hz, 1H), 2.54-2.38(m, 2H), 2.36-2.26(m, 1H), 1.19(d, J6.4Hz, 3H), 1.07(m, 1H), 0.58(m, 2H), 0.28(q, J 4.9Hz, 2H).

[1794] Intermediate 96

[1795]

[1796] 2-Amino-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1797] 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, 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) and then brine (10 mL). The organic phase was dried (MgSO ), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica (eluting with a 30-60% EtOAc / heptane gradient) and then by flash column chromatography on silica (eluting with a 0-3% MeOH gradient) to afford the title compound (400 mg, 27%) as a yellow solid, which was used in the next step without further purification. TLC (1:1 EtOAc / heptane) DP Rf = 0.34. δ H (500MHz, DMSO-d6) 6.79 (t, J 5.6Hz, 1H), 6.59 (s, 2H), 3.10-3.03 (m, 2H), 2.58 (t, J 5.7Hz, 2H), 2.45 (t, J 5.8Hz, 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).

[1798] Intermediate 97

[1799]

[1800] Cyclopropylmethyl 2-cyanoacetate

[1801] 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 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 light yellow oil. H(300MHz, DMSO-d6) 4.03 (s, 2H), 3.96 (d, J 7.3Hz, 2H), 1.16-1.02 (m, 1H), 0.58-0.49 (m, 2H), 0.34-0.25 (m, 2H).

[1802] Intermediates 98 and 99

[1803]

[1804] 2-Amino-5-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid cyclopropylmethyl ester

[1805] 2-Amino-7-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid cyclopropylmethyl ester

[1806] 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 ~2 h. The mixture was heated at 60°C for ~3 h, then at room temperature overnight, then heated at 70°C for another 4 h, then at room temperature overnight. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica (eluting with a 5-50% EtOAc / hexane gradient) to provide the title compound 5-isomer Intermediate 98 (2.34 g, 56%) and the title compound 7-isomer. Intermediate 99 (0.73 g, 18%). Title compound Intermediate 98: LCMS [M+H] + 367.2, [M+Na] + 389.2, RT 2.424 min, 88.8% purity (Method 1). Title compound Intermediate 99: δ H (400MHz, DMSO-d6) 7.38-7.05(m, 3H), 4.44(s, 1H), 3.97(dd, J 7.3, 3.3Hz, 2H), 2.58(s, 2H), 1.96-1.74(m, 2H), 1.69-1.57(m, 2H), 1.40(d, J 3.89Hz, 9H), 1.22-1.09(m, 1H), 0.58-0.43(m, 2H), 0.38-0.23(m, 2H).

[1807] Intermediate 100

[1808]

[1809] Cyclopropylmethyl 5-(tert-Butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate

[1810] 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 ~4 h. The reaction mixture was washed with water and brine, passed through a phase separation column, and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography on silica (eluting with a 5-50% EtOAc / hexane gradient) to give the product as an off-white solid, which was recrystallized from EtOAc / hexane to give the title compound (1.8 g, 65%) as white needles. LCMS [M+H] + 435.2, RT 2.968 min, 100.0% purity (Method 3). LCMS [M+H] + 435.2, RT 2.945 min, 100.0% purity (Method 2).

[1811] Intermediates 101

[1812]

[1813] 5-Amino-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid cyclopropylmethyl ester

[1814] 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 ~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 min, 100.0% purity (Method 4).

[1815] Intermediates 102 and 24

[1816]

[1817] Intermediate 102

[1818] 2-Amino-7-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1819] Intermediate 102a

[1820] 2-Amino-5-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1821] To a mixture of tert-butyl N-(3-oxocyclohexyl)carbamate [885280-38-6] (4 g, 18.7 mmol), sulphur [7704-34-9] (0.722 g, 22.5 mmol) and ethyl cyanoacetate [105-56-6] (2.75 g, 24 mmol) in EtOH (40 mL), triethylamine (5.22 ml, 37.5 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo. Water was added to the residue, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo, and the residue was purified by flash column chromatography on silica (eluting with a gradient of 5% to 40% EtOAc / heptane) to afford the 7-isomer title compound Intermediate 102 (700 mg, 11%) and the 5-isomer title compound Intermediate 102a (4.5 g, 70%) as white solids. 7-Isomer title compound Intermediate 102: δ H (500MHz, CD3OD) 4.29-4.16 (m, 2H), 3.75-3.65 (m, 1H), 3.10 (dd, J 17.0, 5.0Hz, 1H), 2.66-2.51 (m, 2H), 2.44 (dd, J17.1, 9.2Hz, 1H), 2.05-1.93 (m, 1H), 1.73-1.63 (m, 1H), 1.46 (s, 9H), 1.32 (t, J 7.1Hz, 3H). LCMS[M+H] + 341.10, [M+Na] + 361.10, RT 1.35 min, 100% purity (Method 6). 5-Isomer title compound Intermediate 102a: δ H (500MHz, CD3OD)4.58-4.48(m, 1H), 4.22(q, J 7.1Hz, 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 7.1Hz, 3H). LCMS[M+H] + 341, [M+Na] + 363.10, RT 1.38 min, 98% purity (Method 6).

[1822] Intermediate 103

[1823]

[1824] 7-(tert-Butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester

[1825] To 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 and the layers were separated, extracted with DCM (2×10 mL) and washed with 0.5 M aqueous hydrochloric acid solution (20 mL), saturated sodium bicarbonate solution (20 mL) and brine. The organic phase was separated, dried (MgSO ), filtered and concentrated in vacuo to give the title compound (850 mg, 100%) as a light yellow solid which was used in the next step without further purification. H (500MHz, CD3OD)4.73-4.67(m, 1H), 4.36(q, J 7.1Hz, 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 7.1Hz, 3H), 1.05-1.01(m, 2H), 1.00-0.95(m, 2H). LCMS[M+Na] + 431.10, RT 1.56 min, 92% purity (Method 6).

[1826] Intermediate 104

[1827]

[1828] 7-(tert-Butoxycarbonylamino)-2-(cyclopropanecarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1829] 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 to give the title compound (710 mg, 90%), which was dried and used in the next step without further purification. H(500MHz, CD3OD) 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).

[1830] Intermediates 105 and 106

[1831]

[1832] Intermediate 105

[1833] 2-Amino-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid ethyl ester

[1834] Intermediate 106

[1835] 2-Amino-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid ethyl ester

[1836] 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, dried (MgSO ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica (eluting with a gradient of 5% to 70% EtOAc / heptane) to afford 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 min (Method 6). Intermediates 105 and 106 were run together on LCMS, but both were observable by 1H NMR.

[1837] Intermediates 107 and 108

[1838]

[1839] Intermediate 107

[1840] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid ethyl ester

[1841] Intermediate 108

[1842] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid ethyl ester

[1843] To 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, dried (MgSO4), filtered and concentrated in vacuo to afford a light yellow solid as a mixture of regioisomers, which was purified by flash column chromatography on silica (eluting with a 55 to 50% EtOAc / heptane gradient) to afford the title compound as a mixture of 80% 5-isomer Intermediate 108, 20% 7-isomer Intermediate 107 (600 mg, 76%) as a white solid. LCMS [M+H] + 391.0, RT 1.40 min, 100% purity (Method 6).

[1844] Intermediates 109 and 110

[1845]

[1846] Intermediate 109

[1847] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-7-carboxylic acid

[1848] Intermediate 110

[1849] 2-(Cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophene-5-carboxylic acid

[1850] 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 solution [1310-66-3] (2.3 mL, 4.6 mmol) was added. The reaction mixture was stirred at room temperature for 20 h, and the THF was removed in vacuo. The residue was acidified with 1M aqueous hydrochloric acid, and the resulting solid (75% of the 5-isomer intermediate 110 and 22% of the 7-isomer intermediate 109) was filtered and dried. The mixture was separated by preparative HPLC to obtain the 5-isomer title compound intermediate 110 (218 mg, 49%) and the 7-isomer title compound intermediate 109 (58.5 mg, 12%) with 92% purity and 6% of the 5-isomer title compound intermediate 110. 5-isomer title compound intermediate 110: LCMS [M+H] + 363.1, RT 2.78 min, 100% purity (Method 10). 7-Isomer title compound Intermediate 109: LCMS [M+H] + 363.1, RT 2.90 min, 92% purity, 6% 5-regioisomer present (Method 10).

[1851] Intermediate 111

[1852]

[1853] 3-(1-tetrahydropyran-2-ylpyrazol-3-yl)cyclohexanone

[1854] 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 minutes. Tripotassium phosphate [7778-53-2] (4 mmol, 2 mL) was added, and the mixture was stirred for 15 minutes. 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, 383 100 mg) were added, and the mixture was stirred at 60°C overnight. The mixture was heated at 70°C overnight. The mixture was concentrated in vacuo, and the crude product was extracted into water with Et2O (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 plates) eluting 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.

[1855] Intermediate 112

[1856]

[1857] 2-Amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid

[1858] 2M NaOH aqueous solution (91mL, 182mmol) was added to a solution of 2-amino-4,5,6,7-tetrahydro-benzo[B]thiophene-3-carboxylic acid methyl ester [108354-78-5] (13.1g, 60.8mmol) in EtOH (100mL). The reaction mixture was heated to 60°C and stirred for 4h. The temperature was raised to 80°C (reflux), and the reaction was stirred overnight. The reaction was stirred at 80°C for another 7h, 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 (3×200mL) and then acidified to pH 2 with concentrated hydrochloric acid. A brown solid was formed, which was filtered off, washed with water, then washed with hexane, and dried to give the title compound (7.55g, 63%) as a dark brown solid. H (400MHz, DMSO-d6) 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).

[1859] Intermediate 113

[1860]

[1861] 2-Amino-N-methyl-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1862] 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 2M 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 insoluble dark brown solids, 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 (eluting with a 10%-40% EtOAc / isohexane gradient). The product was recrystallised from EtOAc / isohexane to give the title compound (1.32 g, 31%) as a tan solid.H (300MHz, DMSO-d6) 6.67-6.73(m, 1H), 6.64(s, 2H), 2.68(d, J 4.6Hz, 3H), 2.53-2.58(m, 2H), 2.42-2.47(m, 2H), 1.62-1.74(m, 4H).

[1863] Intermediate 114

[1864]

[1865] tert-Butyl N-[2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate

[1866] To a stirred solution of intermediate 26 (12 g, 31.6 mmol) and cyclopropylmethylamine [2516-47-4] (3.36 g, 47.4 mmol) in DCM (80 mL) were 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, dried (Na2SO4), 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%). 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 17.3Hz, 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, 9 H), 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).

[1867] Intermediates 115 and 116

[1868]

[1869] Intermediate 115

[1870] tert-Butyl N-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate

[1871] Intermediate 116

[1872] tert-Butyl N-[(5R)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate

[1873] Intermediate 114 (250 g) was separated by chiral preparative HPLC (Chiralpak AD, 50×252 mm, 30° C., 360 ml / min, CO 2 + 35% MeOH) to give two enantiomers, Intermediate 115 (126 g) and Intermediate 116 (122 g). Intermediate 115 contained 2% of tert-butyl N-[(5S)-2-(cyclopropanecarbonylamino)-3-(isobutylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]carbamate, which was caused by the 2-methylpropan-1-amine impurity in the cyclopropylmethylamine used in the preparation of Intermediate 114. Intermediate 115δ H (300MHz, DMSO-d6) 11.06 (s, 1H), 7.70 (t, J 5.6Hz, 1H), 6.94 (d, J 7.5Hz, 1H), 3.60 (s, 1H), 3.13 (ddq, J 19.8, 13.4, 6.6, 6.0Hz, 2H), 2.88 (dd, J16.1, 5.1Hz, 1H), 2.79-2.58 (m, 2H), 2.48-2.39 (m, 1H), 1.98-1.82 (m, 2 H), 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 min (Method 3).

[1874] Intermediate 117

[1875]

[1876] (5S)-5-amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1877] In 15 minutes, TFA (67ml, 876mmol) was added dropwise to a stirred solution of intermediate 115 (20g, 43.1mmol) in DCM (100mL), while keeping the temperature below 25°C. The reaction mixture was stirred for another 15 minutes at room temperature. Toluene (120mL) was added, and the solvent was removed in vacuo. EtOAc (40mL) was added to the residue, and diisopropyl ether (1.4L) was then added to cause product precipitation. The slurries were stirred for another 15 minutes at room temperature, and the precipitate was collected by filtration. The filter cake was rinsed with diisopropyl ether (180mL) and Et2O (180mL), and dried under a stream of nitrogen for 15 minutes to obtain a crude product (25.4g), which was a beige solid. The precipitate was dissolved in water (800mL) containing TFA (4mL) and Et2O (200mL) and EtOAc (20mL) were added. The aqueous phase was separated, and washed with Et2O (100mL). Potassium carbonate (10.2 g, 36.9 mmol) was added and the aqueous phase was extracted with EtOAc (2 x 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 (Na2SO4), filtered and the solvent removed in vacuo to afford the title compound (14.8 g, 93%) as a beige solid. H (500MHz, chloroform-d) 12.07 (s, 1H), 6.01 (t, J 5.0Hz, 1H), 3.34-3.23 (m, 3H), 3.04 (dd, J 14.5, 4.8Hz, 1H), 2.86-2.57 (m, 4H), 2.53 (dd, J 14.5, 8.2Hz, 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).

[1878] Intermediate 118

[1879]

[1880] (5S)-5-[[Benzyl(2,2-dimethylpropyl)carbamoylthioyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1881] 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 chlorothiocarbonate [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-propane-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, the organic layer was separated, and passed through a phase separator column. The organic phase was concentrated in vacuo to give a yellow solid, which was purified by flash column chromatography on silica (eluted with a 0-45% EtOAc / isohexane gradient) to give the title compound (539 mg, 80%) as a yellow foam. LCMS [M+H] + 553.0, RT 3.339 min, purity -77% (Method 1).

[1882] Intermediate 119

[1883]

[1884] (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

[1885] Intermediate 118 (516 mg, 0.93 mmol) was dissolved in DMF (10 mL) and formic hydrazide [624-84-0] (624 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 minutes and then heated at 60 ° C for 3 h. The mixture was cooled and diluted with MeCN (10 mL) and then filtered through a celite plug. The celite pad was washed with excess MeCN (20 mL), the filtrate was combined and concentrated in vacuo to give a yellow oil. The crude material was purified by silica flash column chromatography (eluted with a 0-5% MeOH / EtOAc gradient) to give the title compound (150 mg, 29%) as a white solid. LCMS [M+H] + 561.0, RT 2.936 min (Method 1).

[1886] Intermediate 120

[1887]

[1888] (5S)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2,5-dimethylpyrazol-3-yl)aminothiocarboylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1889] 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 a solution of 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. Et2O (150 mL) was added, and the resulting solid was filtered, washed with Et2O (100 mL×2), and dried in vacuo to give the title compound (52 g, 100%) as an off-white solid. H (300MHz, DMSO-d6) 11.09 (s, 1H), 9.11 (s, 1H), 7.95 (d, J 7.5Hz, 1H), 7.75 (m, 1H), 5.92 (s, 1H), 4.53 (m, 1H), 3.53 (s, 3H), 3.14 (t, J 6.2Hz, 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).

[1890] Intermediate 121

[1891]

[1892] 3-Cyano-1,2-diphenyl-isourea

[1893] To a solution of aniline [62-53-3] (500 mg, 5.37 mmol) in 2-propanol was added diphenyl N-cyanimidocarbonate [79463-77-7] (1.00 g, 6 mmol) and DIPEA (1.0 g, 8 mmol), and the reaction mixture was stirred at room temperature for 3 h. The resulting white solid was filtered and washed with hexane, and the solid was dried under vacuum to give the title compound (1.0 g, 100%) as a white powder. LCMS [M+H] + 238.0, RT 1.313 min, 100.0% purity (Method 4).

[1894] Intermediate 122

[1895]

[1896] 5-Amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; hydrochloride

[1897] To a solution of intermediate 114 (90% purity, 1.4 g, 2.91 mmol) in 1,4-dioxane (15 mL) was added a 4 M solution of 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). An additional 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was then added. After stirring at room temperature for 3 hours, the solvent was removed in vacuo to give the title compound (1.2 g, 95%, 85% purity) as a beige solid. H (500MHz, CD3OD)3.62-3.54(m, 1H), 3.24(dd, J 7.0, 3.0Hz, 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, 85% purity (Method 6).

[1898] Intermediate 123

[1899]

[1900] (5S)-5-[[Benzyl(isobutyl)carbamothioyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1901] To a solution of intermediate 117 (400 mg, 1.20 mmol) in DCM (20 mL) was added DIPEA (234 mg, 1.80 mmol), phenyl chlorothiocarbonate [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-methylpropan-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, the organic layer was separated, and passed through a phase separator column. The organic phase was concentrated in vacuo to give a crude material as a yellow solid, which was purified by flash column chromatography on silica (eluting with a 0-100% EtOAc / isohexane gradient) to give the title compound (617 mg, 93%) as a yellow solid. LCMS [M+H] + 539.0, RT 3.24 min (Method 1).

[1902] Intermediate 124

[1903]

[1904] (5S)-5-[3-[Benzyl(isobutyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1905] 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 minutes and then heated at 60 ° C for 4 h. The reaction mixture was cooled and diluted with MeCN (10 mL) and 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 ground with EtOAc and filtered. The filtrate was concentrated in vacuo to give a yellow oil, which was purified by flash column chromatography on silica (eluted with a 0-5% MeOH / EtOAc gradient) to give the title compound (270 mg, 43%) as a white solid. LCMS [M+H] + 547.0, RT 2.83 min (Method 1).

[1906] Intermediate 125

[1907]

[1908] (5S)-5-[[Benzyl-[(1-methylcyclopropyl)methyl]carbothioylamino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

[1909] Phenyl chlorothioformate [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) in DCM (15 mL) and triethylamine (1.25 mL, 9 mmol) was added dropwise and the reaction was stirred at 0°C for 30 minutes. 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 hours. The reaction was stirred for 18 hours, then diluted with water (40 mL) and extracted with DCM (3×30 mL). The organic phase was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give a brown oil, which was purified by flash column chromatography on silica (eluting with a 0-100% EtOAc / heptane gradient). The product-containing fractions were combined, washed with 0.5 M aqueous citric acid solution (2 x 25 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (1.56 g, 94%) as a white solid. δ H (500MHz, DMSO-d6) 11.01 (s, 1H), 7.70 (t, J 5.6Hz, 1H), 7.31 (t, J 7.4Hz, 2H), 7.28-7.22 (m, 2H), 7.20 (d, J 7.3Hz, 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, 6.1Hz, 1H), 3.10 (dt, J 13.4, 6.0Hz, 1H), 3.03 (dd, J 15.7, 5.0Hz, 1H), 2.71-2.65 (m, 2H), 2.59 (dd, J 15.7, 9.3Hz, 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)...

Claims

1. A compound of formula (V) or a pharmaceutically acceptable salt thereof: in R 1 represent R 2 represent R 3 Selected from:

2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: N-[3-(Isobutylsulfamoyl)-4,5,6,7-tetrahydrobenzothiophen-2-yl]cyclopropanecarboxamide; 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(1H-imidazo[4,5-b]pyrazin-2-yl)-4,5,6,7-tetrahydrobenzothiophene-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; 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(4-methyloxazol-2-yl)-4,5,6,7-tetrahydrobenzothiophene-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-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (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-pyridinylamino)-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-pyridinylamino)-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(1-oxopyridin-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; (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)aminothiocarboylamino]-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-pyridinylamino)-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-(ethylaminothiocarbothioylamino)-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-cyclopropaneamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-N-methyl-1H-imidazole-4-carboxamide; 5-amino-1-[(5S)-2-cyclopropaneamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-1H-imidazole-4-carboxamide; 5-(2-anilinimidazole-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-pyridinyl]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; 1-[(5S)-2-cyclopropaneamido-3-[(cyclopropylmethyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-5-yl]-1H-imidazole-4-carboxylic acid ethyl ester; 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; 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-Benzimidazol-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; 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[[N'-(1-methylpyrazol-3-yl)-N-(p-tolyl)carbamimidoyl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; formic acid; (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; (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)-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-[(methylsulfimidoyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 5-[[N-cyano-C-methyl-imidoyl]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-(methanesulfonamido)-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-Acetylamino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; 2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-(methylsulfonylamino)-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-(cyclopropylmethyl)-5-[[4-oxo-6-(trifluoromethyl)-1H-pyrimidin-2-yl]amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-(2-methylpropionylamino)-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; (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; 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 methyl ester; (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; their enantiomers and pharmaceutically acceptable salts thereof.

3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (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-Cyclopropaneamido-N-(cyclopropylmethyl)-5-[3-({3-[imino(methyl)oxo-λ6-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)-methylsulfimidoyl]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)-methylsulfimidoyl]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-cyclopropaneamido-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-Cyclopropaneamido-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-Cyclopropaneamido-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-(methylsulfimidoyl)anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-[(S)-methylsulfimidoyl]anilino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[3-[(R)-methylsulfimidoyl]anilino]-1,2,4-triazol-4-yl]-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]benzodiazepine -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]benzodiazepine -1-yl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (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; 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-carboxylic acid ethyl ester; (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-piperidinyl)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)-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-piperidinyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (3S)-3-[[4-[(5S)-2-(cyclopropanecarbonylamino)-3-(cyclopropylmethylcarbamoyl)-4,5,6,7-tetrahydrobenzothiophen-5-yl]-1,2,4-triazol-3-yl]amino]pyrrolidine-1-carboxylic acid methyl ester; (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-Cyclopropaneamido-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)-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-Cyclopropaneamido-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-pyridinyl)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-pyridinyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(6-chloro-2-methyl-3-pyridinyl)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-pyridinyl]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)-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)-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; (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)-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-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)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[6-(difluoromethyl)-3-pyridinyl]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)-2-(Cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[[6-(trifluoromethyl)-3-pyridinyl]amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(6-methoxy-3-pyridinyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(2-methoxy-4-pyridinyl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(6-chloro-3-pyridinyl)amino]-1,2,4-triazol-4-yl]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; (5S)-5-[3-[(2-chloro-4-pyridinyl)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.

4. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (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.

5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by formula (XXV) or (XXVI) 6. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by formula (XXVII) or (XXVIII) 7. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by formula (XXIX) or (XXX) 8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by formula (XXXII) 9. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by formula (XXXII) or (XXXIV) 10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by formula (XXXV) or (XXXVI) 11. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (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-pyridinylamino)-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.

12. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is (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.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing a disease caused by IgE.

15. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of allergy, non-allergic mast cell reaction, type 1 hypersensitivity reaction, urticaria or common sinusitis.

16. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis, urticaria or increased vascular permeability.

17. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing eosinophilic granulomatosis with polyangiitis (also known as "Hulsch-Strauss syndrome"), aspirin-exacerbated respiratory disease or cutaneous T-cell lymphoma.

18. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of allergy, non-allergic mast cell reaction, type 1 hypersensitivity reaction, urticaria, common sinus inflammation, eosinophilic granulomatosis with polyangiitis (also known as "Hulsch-Strauss syndrome"), aspirin-exacerbated respiratory disease or cutaneous T-cell lymphoma.

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