Imidazopyridine Derivatives as IL-17 Modulators

Abstract

A series of substituted fused bicyclic imidazole derivatives, including imidazo[1,2-α]pyridine derivatives and their analogs, are potent modulators of human IL-17 activity and are therefore beneficial in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

Description

[Technical field]

[0001] The present invention relates to heterocyclic compounds and their use in therapy. More particularly, the present invention relates to imidazo[1,2- a ] This invention relates to pharmacologically active substituted fused bicyclic imidazole derivatives, including pyridine derivatives and analogs thereof. These compounds act as modulators of IL-17 activity and are therefore of interest as pharmaceutical agents for treating and / or preventing pathological conditions, including deleterious inflammatory and autoimmune disorders. [Background technology]

[0002] IL-17A (originally named CTLA-8 and also known as IL-17) is a proinflammatory cytokine and the defining member of the IL-17 family (Rouvier et al., J. Immunol., 1993, 150, 5445-5456). Five additional members of the family (IL-17B through IL-17F) have subsequently been identified, including the most closely related IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al., Cytokine Growth Factor Rev., 2003, 14, 155-174). IL-17A and IL-17F are expressed by Th17, a recently defined autoimmune-associated subset of T helper cells, which also expresses signature cytokines such as IL-21 and IL-22 (Korn et al., Ann. Rev. Immunol., 2009, 27, 485-517). IL-17A and IL-17F are expressed as homodimers, but can also be expressed as IL-17A / F heterodimers (Wright et al., J. Immunol., 2008, 181, 2799-2805). IL-17A and F signal through the receptors IL-17R, IL-17RC or the IL-17RA / RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F are associated with several autoimmune diseases.

[0003] The compounds according to the invention, being potent modulators of human IL-17 activity, are therefore beneficial in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

[0004] Additionally, compounds according to the invention may be useful as pharmacological standards for use in the development of new biological tests and in the investigation of new pharmaceutical agents.Thus, compounds of the invention may be useful as radioligands in assays to detect pharmacologically active compounds.

[0005] WO2013 / 116682 and WO2014 / 066726 relate to another class of compounds which are stated to modulate the activity of IL-17 and are useful in the treatment of medical conditions including inflammatory diseases.

[0006] WO2018 / 229079 describes a class of spirocyclic oxoindoline derivatives, and analogues thereof, which are said to act as modulators of IL-17 activity and are therefore of benefit in the treatment of pathological conditions, including deleterious inflammatory and autoimmune disorders.

[0007] Co-pending international patent application PCT / EP2019 / 050594 (published as WO2019 / 138017 on 18 July 2019) describes a class of fused bicyclic imidazole derivatives, including benzimidazole derivatives and analogues thereof, which are stated to act as modulators of IL-17 activity and are therefore of benefit in the treatment of pathological conditions, including deleterious inflammatory and autoimmune disorders. Summary of the Invention [Problem to be solved by the invention]

[0008] However, the prior art available today does not include the substituted imidazo[1,2- a ] None discloses or suggests the exact same structural class of pyridine derivatives and analogs thereof. [Means for solving the problem]

[0009] The present invention provides a compound of formula (I) or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A is CR 1 or N, B is CR 2 or N, D is CR 3 or N, E is CR 4 or N, Z is -CH(R 5 )N(H)C(O)R 6 , -CH(R 5 )N(H)S(O)2R 6 , -C(=CR 5a R 5b )N(H)C(O)R 6 , -CH(R 5 )R 7 , -CH(R 5 )N(H)R 7 or -CH(R 5 )C(O)N(H)R 7 represents R 1 , R 2 , R 3 and R 4 is hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR a , -SR a , -SOR a , -SO2R a , -NR b R c , -NR c COR d , -NR c CO2R d , -NHCONR b R c , -NR c SO2R e , -NHSO2NR b R c, -N=S(O)R b R c , -COR d , -CO2R d , -CONR b R c , -CON(OR a )R b , -SO2NR b R c or -S(O)(NR c )R a , or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, C 4~9 Cycloalkenyl, aryl, aryl(C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) Alkyl, C 3~7 Heterocycloalkenyl, C 4~9 Heterobicycloalkyl, heteroaryl or heteroaryl (C 1~6 ) independently represent alkyl, any of which may be optionally substituted by one or more substituents; R 5 represents hydrogen, or R 5 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, C 4~9 Cycloalkenyl, C 4~12 Bicycloalkyl, C 5~9 Spirocycloalkyl, C 5~9 Spirocycloalkyl(C 1~6 ) Alkyl, C 8~11 Tricycloalkyl, C 8~11 Tricycloalkyl(C 1~6 ) Alkyl, C 7~13 Dispirocycloalkyl, C 7~13 Dispirocycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which may be optionally substituted by one or more substituents; R 5a is C 3~7 Cycloalkyl, C 4~9 Bicycloalkyl, aryl, C 3~7 represents heterocycloalkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; R 5b is hydrogen or C 1~6 represents alkyl, or R 5a and R 5b But when both of them are combined with the carbon atom to which they are bonded, it becomes C 3~7 Cycloalkyl, C 4~9 Bicycloalkyl or C 3~7 any of these groups may be optionally substituted by one or more substituents; R 6 -OR 6a or -NR 6b R 6c or R 6 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which may be optionally substituted by one or more substituents; R 6a is C 1~6 represents alkyl, or R 6a is C3~9 represents a cycloalkyl, which may be optionally substituted by one or more substituents; R 6b is hydrogen or C 1~6 represents an alkyl group, R 6c is hydrogen or C 1~6 represents an alkyl group, R 7 is an aryl, heteroaryl or spiro[(C 3~7 )heterocycloalkyl][heteroaryl], any of which may be optionally substituted by one or more substituents; R a represents trifluoromethyl, or R a is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which may be optionally substituted by one or more substituents; R b and R c is hydrogen or trifluoromethyl, or C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) independently represent alkyl, any of which may be optionally substituted by one or more substituents; or R b and R cwhen taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R d represents hydrogen, or R d is C 1~6 Alkyl, C 3~9 Cycloalkyl, aryl, C 3~7 represents heterocycloalkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; R e is C 1~6 represents alkyl, aryl, or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

[0010] The present invention also provides a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof.

[0011] The present invention also provides a compound of formula (I), or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, as defined above, for use in therapy.

[0012] The present invention also provides a compound of formula (I), or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, as defined above, for use in the treatment and / or prevention of disorders in which the administration of a modulator of IL-17 function is indicated.

[0013] The present invention also provides the use of a compound of formula (I) as defined above, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of a disorder in which the administration of a modulator of IL-17 function is indicated.

[0014] The present invention also provides a method for treating and / or preventing disorders in which the administration of a modulator of IL-17 function is indicated, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof. Although overlapping with others, one aspect of the present invention will be described below. [Invention 1] A compound of formula (I) or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof [C1] JPEG0007623301000002.jpg3533 (In the formula, A is CR 1 or N, B is for CR 2 or N, D is CR 3 or N, E is CR 4 or N, Z is -CH(R 5 )N(H)C(O)R 6 , -CH(R 5 )N(H)S(O) 2 R 6 , -C(=CR 5a R 5b )N(H)C(O)R 6 , -CH(R 5 )R 7 , -CH(R 5 )N(H)R 7 or -CH(R 5 )C(O)N(H)R 7 represents R 1 、R 2 、R 3 and R4 is hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR a , -SR a , -SOR a , -SO 2 R a , -NR b R c , -NR c COR d , -NR c CO 2 R d , -NHCONR b R c , -NR c SO 2 R e , -NHSO 2 NR b R c , -N=S(O)R b R c , -COR d , -CO 2 R d , -CONR b R c , -CON(OR a )R b , -SO 2 NR b R c or -S(O)(NR c )R a , or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, C4~9 Cycloalkenyl, aryl, aryl(C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) Alkyl, C 3~7 Heterocycloalkenyl, C 4~9 Heterobicycloalkyl, heteroaryl or heteroaryl (C 1~6 ) independently represent alkyl, any of which may be optionally substituted by one or more substituents; R 5 represents hydrogen, or R 5 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, C 4~9 Cycloalkenyl, C 4~12 Bicycloalkyl, C 5~9 Spirocycloalkyl, C 5~9 Spirocycloalkyl(C 1~6 ) Alkyl, C 8~11 Tricycloalkyl, C 8~11 Tricycloalkyl(C 1~6 ) Alkyl, C 7~13 Dispirocycloalkyl, C 7~13 Dispirocycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which may be optionally substituted by one or more substituents; R 5a is C 3~7 Cycloalkyl, C 4~9 Bicycloalkyl, aryl, C 3~7 represents heterocycloalkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; R 5b is hydrogen or C 1~6 represents alkyl, or R 5a and R 5b But when both of them are combined with the carbon atom to which they are bonded, it becomes C 3~7 Cycloalkyl, C 4~9 Bicycloalkyl or C 3~7 any of these groups may be optionally substituted by one or more substituents; R 6 -OR 6a or -NR 6b R 6c or R 6 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which may be optionally substituted by one or more substituents; R 6a is C 1~6 represents alkyl, or R 6a is C 3~9 represents a cycloalkyl, which may be optionally substituted by one or more substituents; R 6b is hydrogen or C 1~6 represents an alkyl group, R 6c is hydrogen or C 1~6 represents an alkyl group, R 7 is an aryl, heteroaryl or spiro[(C 3~7 )heterocycloalkyl][heteroaryl], any of which may be optionally substituted by one or more substituents; R a represents trifluoromethyl, or R a is C1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which may be optionally substituted by one or more substituents; R b and R c is hydrogen or trifluoromethyl, or C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) independently represent alkyl, any of which may be optionally substituted by one or more substituents; or R b and R c when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R d represents hydrogen, or R d is C 1~6 Alkyl, C 3~9 Cycloalkyl, aryl, C 3~7 represents heterocycloalkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; R e is C 1~6 represents alkyl, aryl, or heteroaryl, any of which groups may be optionally substituted by one or more substituents. [Invention 2] A compound according to invention 1, represented by formula (I-1), or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof. [Case 2] JPEG0007623301000003.jpg4542 (In the formula, Z, R1 、R 2 、R 3 and R 4 is as defined in Invention 1). [Invention 3] Z is -CH(R 5 )N(H)C(O)R 6 R 5 and R 6 The compound according to Invention 1 or Invention 2, wherein: [Invention 4] R 6 A compound according to any one of claims 1 to 3, wherein represents heteroaryl, which may be optionally substituted by one or more substituents. [Invention 5] A compound according to invention 1, represented by formula (IIA), or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof. [C3] JPEG0007623301000004.jpg5065 (In the formula, R 11 represents hydrogen or halogen; R 16 represents methyl or ethyl; R 2 and R 5 is as defined in Invention 1). [Invention 6] R 11 represents fluoro. [Invention 7] R 2 C 1~6 Alkyl or C 3~7 A compound according to any one of claims 1 to 6, which represents heterocycloalkenyl, any of which may be optionally substituted by one or more substituents. [Invention 8] R 5 C 3~9 8. A compound according to any one of claims 1 to 7, which represents cycloalkyl, which may be optionally substituted by one or more substituents. [Invention 9] A compound according to invention 1 as specifically disclosed in any one of the Examples herein. [Invention 10] A compound of formula (I) as defined in invention 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, for use in therapy. [Invention 11] A compound of formula (I) as defined in invention 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of disorders in which the administration of a modulator of IL-17 function is indicated. [Invention 12] A compound of formula (I) as defined in invention 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of inflammatory or autoimmune disorders. [Invention 13] A pharmaceutical composition comprising a compound of formula (I) according to invention 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier. [Invention 14] 14. The pharmaceutical composition according to claim 13, further comprising an additional pharma- ceutical active ingredient. [Invention 15] Use of a compound of formula (I) as defined in invention 1, or an N-oxide thereof, or a pharma- ceutical acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of a disorder in which the administration of a regulator of IL-17 function is indicated. [Invention 16] 2. Use of a compound of formula (I) according to invention 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating and / or preventing an inflammatory or autoimmune disorder. [Invention 17] A method for treating and / or preventing disorders in which administration of a regulator of IL-17 function is indicated, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in invention 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof. [Invention 18] A method for treating and / or preventing an inflammatory or autoimmune disorder, comprising the step of administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in invention 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] When any of the groups in the compound of formula (I) above is described as being optionally substituted, this group can be unsubstituted or substituted with one or more substituents. Typically, such groups are unsubstituted or substituted with one, two or three substituents. Suitably, such groups are unsubstituted or substituted with one or two substituents.

[0016] In medicine, the salt of the compound of formula (I) is a pharma- ceutically acceptable salt. However, other salts may be useful in the preparation of the compound of formula (I) or its pharma- ceutically acceptable salt. Standard principles underlying the selection and preparation of pharma-ceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharma-ceutically acceptable salts of the compound of formula (I) include, for example, acid addition salts that may be formed by mixing a solution of the compound of formula (I) with a solution of a pharma-ceutically acceptable acid.

[0017] The present invention also includes within its scope co-crystals of the compounds of formula (I) above. The technical term "co-crystal" is used to describe a situation in which 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 active ingredient in crystalline form, which can subsequently alter its physicochemical properties without impairing the intended biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters & L. Quere, RSC Publishing, 2012).

[0018] Suitable alkyl groups which may be present in the compounds of use in the present invention include straight and branched chain C 1~6 Alkyl groups, such as C 1~4 Typical examples include methyl and ethyl groups, as well as straight or branched chain propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl" and "C 1~6 Alkylamino" should be construed accordingly.

[0019] Appropriate C 2~6 Alkenyl groups include vinyl and allyl.

[0020] Appropriate C 2~6 Alkynyl groups include ethynyl and propargyl.

[0021] As used herein, "C 3~9 The term "cycloalkyl" refers to a monovalent radical of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, and may include its benzo-fused analogues. 3~9 Cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononanyl.

[0022] As used herein, "C 4~9 The term "cycloalkenyl" refers to a monovalent radical of 4 to 9 carbon atoms derived from an unsaturated monocyclic hydrocarbon, and may include its benzo-fused analogues. 4~9 Cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0023] As used herein, "C 4~12 The term "bicycloalkyl" refers to a monovalent radical of 4 to 12 carbon atoms derived from a saturated bicyclic hydrocarbon. Exemplary bicycloalkyl groups include bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, and bicyclo[2.2.2]octanyl.

[0024] As used herein, "C 5~9The term "spirocycloalkyl" refers to a saturated bicyclic ring system containing from 5 to 9 carbon atoms, with two rings connected by a common atom. Suitable spirocycloalkyl groups include spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl and spiro[4.4]nonanyl.

[0025] As used herein, "C 8~11 The term "tricycloalkyl" refers to a monovalent group of 8 to 11 carbon atoms derived from a saturated tricyclic hydrocarbon. Exemplary tricycloalkyl groups include adamantanyl.

[0026] As used herein, "C 7~13 The term "dispirocycloalkyl" refers to a saturated tricyclic ring system containing from 7 to 13 carbon atoms and in which three rings incorporate two spiro linkages. Suitable dispirocycloalkyl groups include dispiro[2.0.24.13]heptanyl.

[0027] As used herein, the term "aryl" refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or from multiple fused aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

[0028] Suitable aryl (C 1~6 ) Alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

[0029] As used herein, "C 3~7The term "heterocycloalkyl" refers to a saturated monocyclic ring containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur, and nitrogen, and may include benzo-fused analogs thereof. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[1,2,5]thiadiazolo[2,3- a ]Includes pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl and azocanyl.

[0030] As used herein, "C 3~7 The term "heterocycloalkenyl" refers to a mono- or polyunsaturated monocyclic ring containing from 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur and nitrogen, and may include benzo-fused analogs thereof. Suitable heterocycloalkenyl groups include 2,5-dihydropyrrolyl, thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 2,3-dihydro-1,4-oxazinyl and 6,7-dihydro-5H-1,4-oxazepinyl.

[0031] As used herein, "C 4~9 The term "heterobicycloalkyl" refers to a C1-C12 alkyl group in which one or more carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen. 4~9Exemplary heterobicycloalkyl groups are 6-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa-5-azabicyclo-[2.2.2]octanyl, These include oxabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo-[3.3.1]nonanyl and 3,9-diazabicyclo[4.2.1]nonanyl.

[0032] The term "heteroaryl" as used herein refers to a monovalent aromatic group containing at least five atoms from a single ring or multiple condensed rings, in which one or more carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5- a ]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5- a ]pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2- a]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[1,2-b]pyridazinyl, purinyl, imidazo[1,2- a ]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2- a ]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5- a ]pyrimidinyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3- a ]Includes pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups.

[0033] As used herein, the term "halogen" is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.

[0034] When compounds of formula (I) have one or more asymmetric centers, they may exist accordingly as enantiomers. When compounds according to the invention possess two or more asymmetric centers, they may further exist as diastereoisomers. It should be understood that the present invention extends to the use of all such enantiomers and diastereoisomers, as well as mixtures thereof in any ratio, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise specified or indicated. Furthermore, compounds of formula (I) may exist as tautomers, such as keto (CH2C=O)⇔enol (CH=CHOH) tautomers, or amide (NHC=O)⇔hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise specified or indicated.

[0035] It should be understood that each individual atom present in formula (I) or in any formula depicted hereinafter may in fact be present in the form of any of the naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I) or in any formula depicted hereinafter may be: 1 H, 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H. Similarly, by way of example, each individual carbon atom present in formula (I) or any formula depicted hereinafter may be present as: 12 C. 13 C or 14 C atom, preferably 12 It can exist as C.

[0036] In one embodiment, A is CR 1 In another embodiment, A represents N.

[0037] In one embodiment, B is CR 2 In another embodiment B represents N.

[0038] In one embodiment, D is CR 3 In another embodiment, D represents N.

[0039] In one embodiment, E is CR 4 In another embodiment, E represents N.

[0040] In certain embodiments, A is CR 1 B stands for CR 2 and D stands for CR 3 and E stands for CR 4 Represents.

[0041] Suitably, the present invention provides a compound of formula (I-1), or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, Z, R 1 , R 2 , R 3 and R 4 is as defined above).

[0042] In general, R 1 , R 2 , R 3 and R 4 is hydrogen, halogen, cyano, -OR a , -SOR a , -NR b R c , -NR c COR d Or -N=S(O)R b R c , or C 1~6 Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) Alkyl, C 3~7 Heterocycloalkenyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which can be optionally substituted by one or more substituents.

[0043] Appropriately, R 1 , R 2 , R 3 and R 4 is hydrogen or halogen, or C 1~6 Alkyl or C 3~7 represents independently any of these groups may be optionally substituted by one or more substituents.

[0044] Appropriately, R 1 , R 2 , R 3 and R 4 is hydrogen or C 3~7 represents independently a heterocycloalkenyl group which can be optionally substituted by one or more substituents.

[0045] Appropriately, R 1 , R 2 , R 3 and R 4 is hydrogen, fluoro, chloro, cyano, -OR a , -SOR a , -NR b R c , -NR c COR d Or -N=S(O)R b R c or independently represents methyl, ethyl, propyl, phenyl, benzyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, oxazepinyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, 2,5-dihydropyrrolyl, 3,6-dihydro-2H-pyranyl, 1,2,3,4-tetrahydro-pyridinyl, 2,3-dihydro-1,4-oxazinyl, 6,7-dihydro-5H-1,4-oxazepinyl, furyl, pyrazolyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinylmethyl, or pyridinylethyl, any of which groups can be optionally substituted by one or more substituents.

[0046] More specifically, R 1 , R 2 , R 3 and R 4 represents independently hydrogen or fluoro, or propyl or 2,5-dihydropyrrolyl, any of which groups can be optionally substituted by one or more substituents.

[0047] Typically, R 1 , R 2 , R 3 and R 4 independently represents hydrogen or 2,5-dihydropyrrolyl, which can be optionally substituted by one or more substituents.

[0048] R 1 , R 2 , R3 or R 4 Illustrative examples of optional substituents that may be present are halogen, cyano, nitro, C 1~6 Alkyl, trifluoromethyl, difluoroethyl, phenyl, fluorophenyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxadiazolyl, (C 1~6 ) Alkyl-oxadiazolyl, hydroxy, hydroxy(C 1~6 ) Alkyl, oxo, C 1~6 Alkoxy, difluoromethoxy, trifluoro-methoxy, pentafluorothio, C 1~6 Alkylthio, C 1~6 Alkyl sulfinyl, (C 1~6 ) alkyl(imino)sulfinyl, C 1~6 Alkyl sulfonyl, amino, amino(C 1~6 ) Alkyl, C 1~6 Alkylamino, di(C 1~6 ) Alkylamino, C 2~6 Alkylcarbonylamino, C 2~6 Alkylcarbonylamino (C 1~6 ) Alkyl, C 2~6 Alkoxycarbonylamino, C 1~6 Alkyl sulfonylamino, formyl, C 2~6 Alkylcarbonyl, Hydroxy(C 1~6 ) Alkylcarbonyl, Carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, Chloro(C 1~6 ) alkylamino-carbonyl, di(C 1~6 ) alkylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, difluoroazetidinylcarbonyl, (hydroxy)(trifluoromethyl)azetidinylcarbonyl, (hydroxy)-(methyl)azetidinylcarbonyl, morpholinylcarbonyl, (C 1~6 ) Alkylpyrazolylcarbonyl, amino-sulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 ) alkylaminosulfonyl, (C 1~6) alkylsulfoximinyl, trifluoromethylsulfoximinyl, [(C 1~6 )alkyl][N-(C 1~6 )alkyl]sulfoximinyl, [(C 1~6 )Alkyl][N-Carboxy(C 1~6 )alkyl]sulfoximinyl, [N-(C 2~6 )Alkoxycarbonyl (C 1~6 )Alkyl][(C 1~6 ) alkyl]-sulfoximinyl, (C 3~7 )Cycloalkylsulfoximinyl, N-[di(C 1~6 ) alkylsulfoxo] iminyl and di(C 1~6 ) alkylsulfoximinyl. Further examples include trifluoroethylaminocarbonyl.

[0049] R 1 , R 2 , R 3 or R 4 Suitable examples of optional substituents which may be present in are halogen, C 2~6 It contains 1, 2 or 3 substituents independently selected from alkoxycarbonyl, trifluoroethylaminocarbonyl and difluoroazetidinylcarbonyl.

[0050] R 1 , R 2 , R 3 or R 4 Typical examples of optional substituents that may be present in are C 2~6 It contains 1, 2 or 3 substituents independently selected from alkoxycarbonyl and difluoroazetidinylcarbonyl.

[0051] R 1 , R 2 , R 3 or R 4Illustrative examples of specific substituents which may be present are fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, difluoroethyl, phenyl, fluorophenyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxadiazolyl, methyloxadiazolyl, hydroxy, hydroxymethyl, hydroxyisopropyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, pentafluorothio, methylthio, methylsulfinyl, (imino)(methyl)sulfinyl, methylsulfonyl, amino, aminomethyl, amino-ethyl, methylamino, tert-butylamino, dimethylamino, acetylamino, acetylaminoethyl, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, hydroxyacetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl. , aminocarbonyl, methylamino-carbonyl, ethylaminocarbonyl, chloropropylaminocarbonyl, dimethylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, difluoroazetidinylcarbonyl, (hydroxy)-(trifluoromethyl)azetidinylcarbonyl, (hydroxy)(methyl)azetidinylcarbonyl, morpholinyl-carbonyl, ethylpyrazolylcarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylamino-sulfonyl, methylsulfoximinyl, ethylsulfoximinyl, trifluoromethylsulfoximinyl, (methyl)-(N-methyl)sulfoximinyl, (N-carboxymethyl)(methyl)sulfoximinyl, (N-tert-butoxy-carbonylmethyl)(methyl)sulfoximinyl, cyclopropylsulfoximinyl, N-(dimethylsulfoxo)-iminyl and dimethylsulfoximinyl. Further examples include trifluoroethylaminocarbonyl.

[0052] R 1 , R 2 , R 3 or R 4Suitable examples of particular substituents which may be present include 1, 2 or 3 substituents independently selected from fluoro, tert-butoxycarbonyl, trifluoroethylaminocarbonyl and difluoroazetidinylcarbonyl.

[0053] R 1 , R 2 , R 3 or R 4 Representative examples of specific substituents above include 1, 2 or 3 substituents independently selected from tert-butoxycarbonyl and difluoroazetidinylcarbonyl.

[0054] R 1 , R 2 , R 3 or R 4 Specific values ​​of are hydrogen, fluoro, chloro, cyano, -OR a , -SOR a , -NR b R c , -NR c COR d , -N=S(O)R b R c, tert-butoxycarbonylmethyl, dimethyl-aminocarbonylmethyl, acetylaminoethyl, carboxyethyl, tert-butoxycarbonylethyl, methyl-aminocarbonylethyl, dimethylaminocarbonylethyl, acetylaminopropyl, methylsulfonyl-phenyl, methylsulfonylaminophenyl, tert-butoxycarbonylphenyl, dimethylaminocarbonyl-phenyl, ethoxycarbonylbenzyl, carboxytetrahydrofuranyl, methoxycarbonyltetrahydrofuranyl, dimethylaminocarbyl arylcarbonyltetrahydrofuranyl, hydroxyazetidinylcarbonyltetrahydro-furanyl, difluoroazetidinylcarbonyltetrahydrofuranyl, (hydroxy)(trifluoromethyl)-azetidinylcarbonyltetrahydrofuranyl, morpholinylcarbonyltetrahydrofuranyl, methoxycarbonylpyrrolidinyl, tert-butoxycarbonylpyrrolidinyl, dimethylaminocarbonyl-pyrrolidinyl, difluoroazetidinylcarbonylpyrrolidinyl, (ethoxycarbonyl)(methylsulfonyl)-pyrrolidinyl, (acetyl (ethoxycarbonyl)pyrrolidinyl, (tert-butoxycarbonyl)(difluoro-azetidinylcarbonyl)pyrrolidinyl, tetrahydropyranyl, ethoxycarbonyltetrahydropyranyl, dimethylaminocarbonyltetrahydropyranyl, piperidinyl, methylpiperidinyl, acetyl-piperidinyl, hydroxyacetylpiperidinyl, methoxycarbonylpiperidinyl, tert-butoxycarbonyl-piperidinyl, dimethylaminocarbonylpiperidinyl, ethylpyrazolylcarbonylpiperidinyl, methylpiperazinyl nyl, morpholinyl, methyloxadiazolylmorpholinyl, methylsulfonyl-morpholinyl, acetylmorpholinyl, hydroxyacetylmorpholinyl, methoxycarbonyl-morpholinyl, ethoxycarbonylmorpholinyl, tert-butoxycarbonylmorpholinyl, ethylamino-carbonylmorpholinyl, difluoroazetidinylcarbonylmorpholinyl, oxazepinyl, tert-butoxy-carbonyloxazepinyl, oxopyrrolidinylmethyl, carboxypyrrolidinylmethyl, methoxy-carbonylpyrrolidinylmethyl,Dimethylaminocarbonylpyrrolidinylmethyl, methylsulfonyl-piperidinylmethyl, piperazinylmethyl, methylpiperazinylmethyl, oxetanylpiperazinyl-methyl, methylsulfonylpiperazinylmethyl, acetylpiperazinylmethyl, tert-butoxycarbonyl-piperazinylmethyl, (acetyl)(tert-butoxycarbonyl)piperazinylmethyl, morpholinylmethyl, (tert-butoxycarbonyl)(difluoroazetidinyl carbonyl)-2,5-dihydropyrrolyl, 3,6-dihydro-2H-pyranyl, ethoxycarbonyl-3,6-dihydro-2H-pyranyl, dimethylaminocarbonyl-3,6-dihydro-2H-pyranyl, tert-butoxycarbonyl-1,2,3,4-tetrahydropyridinyl, tert-butoxycarbonyl-2,3-dihydro-1,4-oxazinyl, tert-butoxycarbonyl-6,7-dihydro-5H-1,4-oxazepinyl, difluoro -Azetidinylcarbonylfuryl, difluoroazetidinylcarbonylpyrazolyl, acetyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, (imino)(methyl)sulfinylpyridinyl, ethoxycarbonyl-pyridinyl, chloropropylaminocarbonylpyridinyl, dimethylaminocarbonylpyridinyl, azetidinylcarbonylpyridinyl, difluoroazetidinylcarbonylpyridinyl, (hydroxy)(methyl) -azetidinylcarbonylpyridinyl, (dimethylaminocarbonyl)(fluoro)pyridinyl, dimethylamino-carbonylpyrimidinyl, (dimethylaminocarbonyl)(methyl)pyrimidinyl, dimethylamino-carbonylpyrazinyl, pyridinylmethyl, cyanopyridinylmethyl, oxadiazolylpyridinylmethyl, ethoxycarbonylpyridinylmethyl, aminocarbonylpyridinylmethyl, pyridinylethyl and hydroxypyridinylethyl. Further values ​​include (difluoro)(trifluoroethylaminocarbonyl)propyl.

[0055] R 1 , R 2 , R 3 or R 4Selected values ​​of include hydrogen, fluoro, (difluoro)(trifluoroethylaminocarbonyl)propyl, and (tert-butoxycarbonyl)(difluoroazetidinylcarbonyl)-2,5-dihydropyrrolyl.

[0056] R 1 , R 2 , R 3 or R 4 Suitable values ​​for include hydrogen and (tert-butoxycarbonyl)(difluoroazetidinylcarbonyl)-2,5-dihydropyrrolyl.

[0057] Appropriately, R 1 is hydrogen, halogen, cyano or -OR a Represents.

[0058] Appropriately, R 1 represents hydrogen or halogen.

[0059] In the first embodiment, R 1 represents hydrogen. In a second embodiment, R 1 represents a halogen. In one aspect of this embodiment, R 1 represents fluoro. In another aspect of this embodiment, R 1 represents chloro. In a third embodiment, R 1 represents cyano. In a fourth embodiment, R 1 -OR a Represents.

[0060] R 1 Exemplary values ​​of are hydrogen, fluoro, chloro, cyano, and -OR. a Includes.

[0061] R 1 Selected values ​​of include hydrogen and fluoro.

[0062] In general, R 2 is hydrogen, cyano, -OR a , -SOR a , -NR b R c , -NR cCOR d Or -N=S(O)R b R c or R 2 is C 1~6 Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) Alkyl, C 3~7 Heterocycloalkenyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which can be optionally substituted by one or more substituents.

[0063] Appropriately, R 2 is C 1~6 Alkyl or C 3~7 represents heterocycloalkenyl, any of which may be optionally substituted by one or more substituents.

[0064] Appropriately, R 2 is C 3~7 represents a heterocycloalkenyl, which may be optionally substituted by one or more substituents.

[0065] Appropriately, R 2 is hydrogen, cyano, -OR a , -SOR a , -NR b R c , -NR c COR d Or -N=S(O)R b R c or R 2represents methyl, ethyl, propyl, phenyl, benzyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, oxazepinyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, 2,5-dihydropyrrolyl, 3,6-dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, 2,3-dihydro-1,4-oxazinyl, 6,7-dihydro-5H-1,4-oxazepinyl, furyl, pyrazolyl, 6,8-dihydro-5H-[1,2,4]-triazolo[4,3-a]pyrazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinylmethyl, or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.

[0066] More specifically, R 2 represents propyl or 2,5-dihydropyrrolyl, either of which groups can be optionally substituted by one or more substituents.

[0067] Typically, R 2 represents 2,5-dihydropyrrolyl, which may be optionally substituted by one or more substituents.

[0068] R 2 Illustrative examples of the optional substituents above are halogen, cyano, nitro, C 1~6 Alkyl, trifluoromethyl, phenyl, fluorophenyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxadiazolyl, (C 1~6 ) alkyl oxadiazolyl, hydroxy, hydroxy (C 1~6 ) Alkyl, oxo, C 1~6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1~6 Alkylthio, C 1~6 Alkyl sulfinyl, (C 1~6 ) alkyl-(imino)sulfinyl, C 1~6 Alkyl sulfonyl, amino, amino(C 1~6 ) Alkyl, C 1~6Alkylamino, di(C 1~6 )-Alkylamino, C 2~6 Alkylcarbonylamino, C 2~6 Alkylcarbonylamino (C 1~6 ) Alkyl, C 2~6 Alkoxy-carbonylamino, C 1~6 Alkyl sulfonylamino, formyl, C 2~6 Alkylcarbonyl, Hydroxy(C 1~6 ) Alkyl-carbonyl, carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, chloro-(C 1~6 ) alkylaminocarbonyl, di(C 1~6 ) alkylaminocarbonyl, azetidinylcarbonyl, hydroxy-azetidinylcarbonyl, difluoroazetidinylcarbonyl, (hydroxy)(trifluoromethyl)azetidinyl-carbonyl, (hydroxy)(methyl)azetidinylcarbonyl, morpholinylcarbonyl, (C 1~6 ) Alkyl-pyrazolylcarbonyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 ) alkylaminosulfonyl and di(C 1~6 ) alkylsulfoximinyl. Further examples include trifluoroethylaminocarbonyl.

[0069] R 2 Suitable examples of the optional substituents above are halogen, C 2~6 It contains 1, 2 or 3 substituents independently selected from alkoxycarbonyl, trifluoroethylaminocarbonyl and difluoroazetidinylcarbonyl.

[0070] R 2 Typical examples of the optional substituents above are C 2~6 It contains 1, 2 or 3 substituents independently selected from alkoxycarbonyl and difluoroazetidinylcarbonyl.

[0071] R2 Illustrative examples of specific substituents above are fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxadiazolyl, methyloxadiazolyl, hydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methyl-thio, methylsulfinyl, (imino)(methyl)sulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, acetylamino, acetylamino-ethyl, methoxycarbonylamino, methylsulfonyl ... and 1, 2, or 3 substituents independently selected from nylamino, formyl, acetyl, hydroxyacetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methyl-aminocarbonyl, ethylaminocarbonyl, chloropropylaminocarbonyl, dimethylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, difluoroazetidinylcarbonyl, (hydroxy)(trifluoromethyl)azetidinylcarbonyl, (hydroxy)(methyl)azetidinylcarbonyl, morpholinylcarbonyl, ethylpyrazolylcarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and dimethylsulfoximinyl. Further examples include trifluoroethylaminocarbonyl.

[0072] R 2 Suitable examples of the above specific substituents include 1, 2 or 3 substituents independently selected from fluoro, tert-butoxycarbonyl, trifluoroethylaminocarbonyl and difluoroazetidinylcarbonyl.

[0073] R 2 Representative examples of specific substituents above include 1, 2 or 3 substituents independently selected from tert-butoxycarbonyl and difluoroazetidinylcarbonyl.

[0074] R 2 Exemplary values ​​of are hydrogen, cyano, -OR a , -SOR a , -NR b R c , -NR c COR d , -N=S(O)R b R c, tert-butoxycarbonylmethyl, dimethylaminocarbonylmethyl, acetylaminoethyl, carboxyethyl, tert-butoxycarbonylethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, acetylaminopropyl, methylsulfonylphenyl, methylsulfonyl-aminophenyl, tert-butoxycarbonylphenyl, dimethylaminocarbonylphenyl, ethoxy-carbonylbenzyl, carboxytetrahydrofuranyl, methoxycarbonyltetrahydrofuranyl, dimethyl-aminocarbonyltetrahydrofuranyl Fluorofuranyl, hydroxyazetidinylcarbonyltetrahydrofuranyl, difluoro-azetidinylcarbonyltetrahydrofuranyl, (hydroxy)(trifluoromethyl)azetidinylcarbonyl-tetrahydrofuranyl, morpholinylcarbonyltetrahydrofuranyl, methoxycarbonylpyrrolidinyl, tert-butoxycarbonylpyrrolidinyl, dimethylaminocarbonylpyrrolidinyl, difluoroazetidinyl-carbonylpyrrolidinyl, (ethoxycarbonyl)(methylsulfonyl)pyrrolidinyl, (acetyl)-(ethoxycarbonyl )pyrrolidinyl, (tert-butoxycarbonyl)(difluoroazetidinylcarbonyl)-pyrrolidinyl, tetrahydropyranyl, ethoxycarbonyltetrahydropyranyl, dimethylamino-carbonyltetrahydropyranyl, piperidinyl, methylpiperidinyl, acetyl piperidinyl, hydroxy-acetyl piperidinyl, methoxycarbonyl piperidinyl, tert-butoxycarbonyl piperidinyl, dimethyl-aminocarbonyl piperidinyl, ethylpyrazolylcarbonyl piperidinyl, methylpiperazinyl, morpholinyl, methyloxa diazolylmorpholinyl, methylsulfonylmorpholinyl, acetyl-morpholinyl, hydroxyacetylmorpholinyl, methoxycarbonylmorpholinyl, ethoxycarbonyl-morpholinyl, tert-butoxycarbonylmorpholinyl, ethylaminocarbonylmorpholinyl, difluoroazetidinylcarbonylmorpholinyl, oxazepinyl, tert-butoxycarbonyloxazepinyl, oxo-pyrrolidinylmethyl, carboxypyrrolidinylmethyl, methoxycarbonylpyrrolidinylmethyl, dimethylaminocarbonylpyrrolidinylmethyl,Methylsulfonylpiperidinylmethyl, piperazinylmethyl, methylpiperazinylmethyl, oxetanylpiperazinylmethyl, methylsulfonyl-piperazinylmethyl, acetylpiperazinylmethyl, tert-butoxycarbonylpiperazinylmethyl, (acetyl)(tert-butoxycarbonyl)piperazinylmethyl, morpholinylmethyl, (tert-butoxy-carbonyl)(difluoroazetidinylcarbonyl)-2,5-dihydropyrrolidinyl aryl, 3,6-dihydro-2H-pyranyl, ethoxycarbonyl-3,6-dihydro-2H-pyranyl, dimethylaminocarbonyl-3,6-dihydro-2H-pyranyl, tert-butoxycarbonyl-1,2,3,4-tetrahydropyridinyl, tert-butoxycarbonyl-2,3-dihydro-1,4-oxazinyl, tert-butoxycarbonyl-6,7-dihydro-5H-1,4-oxazepinyl, difluoro-azetidinylcarbonyl furyl, difluoroazetidinylcarbonylpyrazolyl, acetyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, (imino)(methyl)sulfinylpyridinyl, ethoxycarbonyl-pyridinyl, chloropropylaminocarbonylpyridinyl, dimethylaminocarbonylpyridinyl, azetidinylcarbonylpyridinyl, difluoroazetidinylcarbonylpyridinyl, (hydroxy)(methyl)-azetidinylcarbonylpyridinyl, (dimethylaminocarbonyl)(fluoro)pyridinyl, dimethylamino-carbonylpyrimidinyl, (dimethylaminocarbonyl)(methyl)pyrimidinyl, dimethylamino-carbonylpyrazinyl, pyridinylmethyl, cyanopyridinylmethyl, oxadiazolylpyridinylmethyl, ethoxycarbonylpyridinylmethyl, aminocarbonylpyridinylmethyl, pyridinylethyl and hydroxypyridinylethyl. Further values ​​include (difluoro)(trifluoroethylaminocarbonyl)propyl.

[0075] R 2 Selected values ​​of include (difluoro)(trifluoroethylaminocarbonyl)propyl and (tert-butoxycarbonyl)(difluoroazetidinylcarbonyl)-2,5-dihydropyrrolyl.

[0076] R 2 Suitable values ​​for include (tert-butoxycarbonyl)(difluoroazetidinylcarbonyl)-2,5-dihydropyrrolyl.

[0077] Typically, R 3 is hydrogen, halogen or -NR b R c or R 3 is C 1~6 Alkyl, aryl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl or heteroaryl, either of which groups can be optionally substituted by one or more substituents.

[0078] Appropriately, R 3 is hydrogen, fluoro or -NR b R c or R 3 represents ethyl, phenyl, morpholinyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, or pyridinyl, any of which groups may be optionally substituted by one or more substituents.

[0079] R 3 Typical examples of the optional substituents above are halogen, cyano, nitro, C 1~6 Alkyl, trifluoro-methyl, hydroxy, hydroxy(C 1~6 ) Alkyl, oxo, C 1~6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, amino, amino(C 1~6 ) Alkyl, C 1~6 Alkylamino, di(C 1~6 ) Alkylamino, C 2~6 Alkylcarbonylamino, C 2~6 Alkoxycarbonylamino, C1~6 Alkyl sulfonylamino, formyl, C 2~6 Alkylcarbonyl, Carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, di(C 1~6 ) Alkylaminocarbonyl, difluoroazetidinyl-carbonyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl and di(C 1~6 ) alkylaminosulfonyl.

[0080] R 3 Representative examples of specific substituents in the above include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, difluoroazetidinylcarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

[0081] R 3 Exemplary values ​​of -NR are hydrogen, fluoro, -NR b R c , tert-butoxycarbonylethyl, dimethylaminocarbonylphenyl, morpholinyl, methylsulfonylpiperidinylmethyl, methylsulfonylpiperazinylmethyl, acetylpiperazinylmethyl, morpholinylmethyl and difluoroazetidinylcarbonylpyridinyl.

[0082] In certain embodiments, R 3represents hydrogen.

[0083] Typically, R 4 is hydrogen, halogen or -OR a Represents.

[0084] In the first embodiment, R 4 represents hydrogen. In a second embodiment, R 4 represents a halogen. In one aspect of this embodiment, R 4 represents fluoro. In another aspect of this embodiment, R 4 represents chloro. In a third embodiment, R 4 -OR a Represents.

[0085] R 4 Typical values ​​of are hydrogen, fluoro and -OR. a , especially hydrogen.

[0086] In a first embodiment, Z is -CH(R 5 )N(H)C(O)R 6 Represents.

[0087] In a second embodiment, Z is -CH(R 5 )N(H)S(O)2R 6 Represents.

[0088] In a third embodiment, Z is -C(=CR 5a R 5b )N(H)C(O)R 6 Represents.

[0089] In a fourth embodiment, Z is -CH(R 5 )R 7 Represents.

[0090] In a fifth embodiment, Z is -CH(R 5 )N(H)R 7 Represents.

[0091] In a sixth embodiment, Z is -CH(R 5 )C(O)N(H)R 7 Represents.

[0092] A first subclass of compounds according to the present invention is represented by the compounds of formula (IA) and pharma- ceutically acceptable salts thereof: [ka] (In the formula, A, B, D, E, R 5 and R 6 is as defined above).

[0093] A second subclass of compounds according to the present invention is represented by the compounds of formula (IB) and pharma-ceutically acceptable salts thereof: [ka] (In the formula, A, B, D, E, R 5 and R 6 is as defined above).

[0094] A third subclass of compounds according to the present invention is represented by the compounds of formula (IC) and pharma-ceutically acceptable salts thereof: [ka] (In the formula, A, B, D, E, R 5 and R 7 is as defined above).

[0095] A fourth subclass of compounds according to the present invention is represented by the compounds of formula (ID) and pharma-ceutically acceptable salts thereof: [ka] (In the formula, A, B, D, E, R 5 and R 7 is as defined above).

[0096] A fifth subclass of compounds according to the present invention is represented by the compounds of formula (IE) and pharma- ceutically acceptable salts thereof: [ka] (In the formula, A, B, D, E, R 5 and R 7 is as defined above).

[0097] A sixth subclass of compounds according to the present invention is represented by the compounds of formula (IF) and pharma-ceutically acceptable salts thereof: [ka] (In the formula, A, B, D, E, R 5a , R 5b and R 6 is as defined above).

[0098] Generally, Z is -CH(R 5 )N(H)C(O)R 6 Represents.

[0099] Thus, a particular sub-class of compounds according to the invention is represented by the compounds of formula (IA) as defined above, and the pharma-ceutically acceptable salts thereof.

[0100] Typically, R 5 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, C 4~9 Cycloalkenyl, C 4~12 Bicycloalkyl, C 5~9 Spirocycloalkyl, C 5~9 Spirocycloalkyl(C 1~5 ) Alkyl, C 8~11 Tricycloalkyl, C 8~11 Tricycloalkyl(C 1~6 ) Alkyl, C 7~13Dispirocycloalkyl, aryl, aryl(C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which can be optionally substituted by one or more substituents.

[0101] Appropriately, R 5 is C 3~9 Cycloalkyl, C 4~12 Bicycloalkyl, C 5~9 Spirocycloalkyl or C 7~13 It represents dispirocycloalkyl, any of which may be optionally substituted by one or more substituents.

[0102] Appropriately, R 5 is C 3~9 It represents a cycloalkyl, which may be optionally substituted by one or more substituents.

[0103] In the first embodiment, R 5 represents hydrogen. In a second embodiment, R 5 is optionally replaced by C 1~6 In a third embodiment, R 5 is optionally replaced by C 3~9 In a fourth embodiment, R 5 is optionally replaced by C 3~9 Cycloalkyl(C 1~6 ) alkyl. In a fifth embodiment, R 5 is optionally replaced by C 4~9 In a sixth embodiment, R 5 is optionally replaced by C 4~9 In a seventh embodiment, R 5 is optionally replaced by C 5~9 In an eighth embodiment, R 5is optionally replaced by C 5~9 Spirocycloalkyl(C 1~6 ) alkyl. In a ninth embodiment, R 5 is optionally replaced by C 8~11 In a tenth embodiment, R 5 is optionally replaced by C 8~11 Tricycloalkyl(C 1~6 In an eleventh embodiment, R 5 represents an optionally substituted aryl. In a twelfth embodiment, R 5 is an optionally substituted aryl (C 1~6 In a thirteenth embodiment, R 5 is optionally replaced by C 3~7 In a fourteenth embodiment, R 5 is optionally replaced by C 3~7 Heterocycloalkyl(C 1~6 ) alkyl. In a fifteenth embodiment, R 5 represents an optionally substituted heteroaryl. In a sixteenth embodiment, R 5 is an optionally substituted heteroaryl (C 1~6 ) alkyl. In a seventeenth embodiment, R 5 is optionally replaced by C 7~13 In an eighteenth embodiment, R 5 is optionally replaced by C 7~13 Dispirocycloalkyl(C 1~6 ) alkyl.

[0104] In certain embodiments, R 5 is other than hydrogen.

[0105] R 5Exemplary values ​​of include methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexylmethyl, cyclooctenyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.3]heptanylmethyl, adamantanyl, adamantanylmethyl, dispiro[2.0.24.13]heptanyl, phenyl, benzyl, phenylethyl, naphthylmethyl, thienyl, indolyl, pyridinyl, thienylmethyl, indolylmethyl and pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.

[0106] R 5 Exemplary values ​​of include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptanyl, spiro[2.5]octanyl, and dispiro[2.0.24.13]heptanyl, any of which groups can be optionally substituted by one or more substituents.

[0107] R 5 Suitable values ​​for include cyclohexyl and cyclooctyl, either of which may be optionally substituted by one or more substituents.

[0108] R 5 Suitable values ​​for include cyclohexyl, which may be optionally substituted by one or more substituents.

[0109] R 5 Typical examples of the optional substituents above are halogen, cyano, nitro, C 1~6 Alkyl, trifluoro-methyl, phenyl, hydroxy, oxo, C 1~6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, amino, C 1~6 Alkylamino, di(C1~6 ) Alkyl-amino, C 2~6 Alkylcarbonylamino, C 2~6 Alkoxycarbonylamino, C 1~6 Alkyl sulfonylamino, formyl, C 2~6 Alkylcarbonyl, Carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6 Alkyl-aminocarbonyl, di(C 1~6 ) Alkylaminocarbonyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl and di(C 1~6 ) alkylaminosulfonyl.

[0110] R 5 Suitable examples of the optional substituents above are halogen, cyano, C 1~6 Alkyl, trifluoromethyl, phenyl, hydroxy, C 1~6 1, 2 or 3 substituents independently selected from alkoxy and aminocarbonyl, especially C 1~6 Contains alkyl.

[0111] R 5 Selected examples of the above optional substituents are halogen and C 1~6 1, 2 or 3 substituents independently selected from alkyl, especially C 1~6 Contains alkyl.

[0112] R 5Representative examples of specific substituents in the above include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, hydroxy, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, amino-sulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

[0113] R 5 Suitable examples of particular substituents above include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, phenyl, hydroxy, methoxy, tert-butoxy and aminocarbonyl, especially methyl.

[0114] R 5 Selected examples of specific substituents above include 1, 2 or 3 substituents independently selected from fluoro and methyl, especially methyl.

[0115] R 5Illustrative examples of specific values ​​of are hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclopentyl, indanyl, cyclohexyl, methyl-cyclohexyl, trifluoromethylcyclohexyl, difluorocyclohexyl, dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclohexylmethyl, cyclooctenyl, bicyclo[4.1.0]heptanyl, spiro-[3.3]heptanyl, spiro[2.5]octanyl, dispiro[2.0. 24.13] Includes heptanyl, phenyl, chlorophenyl, benzyl, fluorobenzyl, chlorobenzyl, (chloro)(fluoro)benzyl, dichlorobenzyl, bromobenzyl, cyano-benzyl, methylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, methoxy-benzyl, tert-butoxybenzyl, aminocarbonylbenzyl, phenylethyl, chlorophenylethyl, naphthylmethyl, thienylmethyl, indolylmethyl and pyridinylmethyl.

[0116] R 5 Suitable examples of specific values ​​include cyclopentyl, cyclohexyl, methylcyclohexyl, difluorocyclohexyl, dimethylcyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptanyl, spiro[2.5]octanyl and dispiro[2.0.24.13]heptanyl.

[0117] R 5 Selected examples of specific values ​​of include methylcyclohexyl and difluorocyclohexyl.

[0118] R 5 Representative examples of specific values ​​include methylcyclohexyl and cyclooctyl.

[0119] In the first embodiment, R 5 represents methylcyclohexyl, in particular 4-methylcyclohexyl. In a second embodiment, R 5 represents difluorocyclohexyl, especially 4,4-difluorocyclohexyl. In a third embodiment, R5 represents cyclooctyl.

[0120] In the first embodiment, R 5a is optionally replaced by C 3~7 In a second embodiment, R 5a is optionally replaced by C 4~9 In a third embodiment, R 5a represents an optionally substituted aryl. In a fourth embodiment, R 5a is optionally replaced by C 3~7 In a fifth embodiment, R 5a represents an optionally substituted heteroaryl.

[0121] R 5a Typical values ​​of include cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentanyl, phenyl, dihydrobenzofuranyl and pyrrolyl, any of which may be optionally substituted by one or more substituents.

[0122] R 5a Typical examples of the above optional substituents are C 1~6 Alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkylsulfonyl, C 2~6 Alkylcarbonyl, Amino, C 1~6 Alkylamino and di(C 1~6 ) alkylamino.

[0123] R 5a Selected examples of the above optional substituents are C 1~6 Contains alkyl and halogen.

[0124] R 5aRepresentative examples of particular substituents on the above include methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, amino, methylamino and dimethylamino.

[0125] R 5a Selected examples of specific substituents above include methyl and chloro.

[0126] R 5a Selected values ​​of include cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentanyl, phenyl, chlorophenyl, dihydrobenzofuranyl, and methylpyrrolyl.

[0127] Appropriately, R 5b represents hydrogen, methyl or ethyl.

[0128] In the first embodiment, R 5b represents hydrogen. In a second embodiment, R 5b is C 1~6 It stands for alkyl, especially methyl or ethyl.

[0129] Or, R 5a and R 5b When combined with the carbon atom to which they are both attached, it becomes C 3~7 Cycloalkyl, C 4~9 Bicycloalkyl or C 3~7 It may represent a heterocycloalkyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0130] In the first embodiment, R 5a and R 5b when taken together with the carbon atom to which they are both attached, are appropriately optionally substituted C 3~7Cycloalkyl may represent: Examples include cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, tetrahydronaphthalenyl, cycloheptanyl, benzocycloheptenyl, cyclooctanyl, and cyclononanyl, any of which groups may be optionally substituted by one or more substituents.

[0131] In a second embodiment, R 5a and R 5b when taken together with the carbon atom to which they are both attached, are appropriately optionally substituted C 4~9 Examples include bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptanyl and bicyclo[3.2.1]octanyl, any of which groups may be optionally substituted by one or more substituents.

[0132] In a third embodiment, R 5a and R 5b when taken together with the carbon atom to which they are both attached, are appropriately optionally substituted C 3~7 Examples include tetrahydropyranyl and piperidinyl, either of which may be optionally substituted by one or more substituents.

[0133] Typical examples of optional substituents on such groups are C 1~6 Alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkylsulfonyl, C 2~6 Alkylcarbonyl, Amino, C 1~6 Alkylamino and di(C 1~6 ) alkylamino.

[0134] Selected examples of optional substituents on such groups are C 1~6Alkyl, halogen, trifluoromethyl, trifluoroethyl, phenyl and C 1~6 Contains alkoxy.

[0135] Representative examples of particular substituents on such groups include methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, amino, methylamino and dimethylamino.

[0136] Selected examples of particular substituents on such groups include methyl, chloro, trifluoromethyl, trifluoroethyl, phenyl and methoxy.

[0137] R 5a and R 5b Selected values ​​of, when taken together with the carbon atom to which both are attached, include methylcyclobutyl, dimethylcyclobutyl, phenylcyclobutyl, benzocyclobutenyl, methylbenzocyclobutenyl, chlorobenzocyclobutenyl, methoxy-benzocyclobutenyl, cyclopentyl, methylcyclopentyl, indanyl, chloroindanyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, trifluoromethylcyclohexyl, tetrahydro-naphthalenyl, cycloheptanyl, benzocycloheptenyl, cyclooctanyl, cyclononanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, tetramethyltetrahydropyranyl, and trifluoroethylpiperidinyl.

[0138] Typically, R 6 -OR 6a or -NR 6b R 6c or R 6 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which can be optionally substituted by one or more substituents.

[0139] Appropriately, R 6 -OR 6a or R 6 is C 1~6 It represents alkyl, aryl, or heteroaryl, any of which groups can be optionally substituted by one or more substituents.

[0140] Appropriately, R 6 -OR 6a or R 6 represents heteroaryl, which may be optionally substituted by one or more substituents.

[0141] In the first embodiment, R 6 is optionally replaced by C 1~6 In a second embodiment, R 6 is optionally replaced by C 3~9 In a third embodiment, R 6 is optionally replaced by C 3~9 Cycloalkyl(C 1~6 ) alkyl. In a fourth embodiment, R 6 represents an optionally substituted aryl. In a fifth embodiment, R 6 is an optionally substituted aryl (C 1~6 ) alkyl. In a sixth embodiment, R 6 is optionally replaced by C 3~7 In a seventh embodiment, R 6 is optionally replaced by C 3~7 Heterocycloalkyl(C 1~6 ) alkyl. In an eighth embodiment, R 6 represents an optionally substituted heteroaryl. In a ninth embodiment, R 6is an optionally substituted heteroaryl (C 1~6 In a tenth embodiment, R 6 -OR 6a In an eleventh embodiment, R 6 -NR 6a R 6b Represents.

[0142] R 6 Typical meanings of are -OR 6a or -NR 6a R 6b and methyl, ethyl, propyl, 2-methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, isoxazolyl, oxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.

[0143] R 6 Exemplary values ​​of are -OR 6a and methyl, phenyl, pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.

[0144] R 6 Suitable values ​​for include pyrazolyl, isoxazolyl and oxadiazolyl, any of which may be optionally substituted by one or more substituents.

[0145] R 6 A specific value for includes oxadiazolyl, which may be optionally substituted by one or more substituents.

[0146] R 6 Typical examples of the optional substituents above are halogen, cyano, nitro, C 1~6 Alkyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxy(C 1~6) Alkyl, oxo, C 1~6 Alkoxy, difluoro-methoxy, trifluoromethoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, amino, amino(C 1~6 ) Alkyl, C 1~6 Alkylamino, di(C 1~6 ) Alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C 2~6 Alkylcarbonylamino, C 2~6 Alkylcarbonylamino (C 1~6 ) Alkyl, C 2~6 Alkoxycarbonylamino, C 1~6 Alkyl sulfonylamino, formyl, C 2~6 Alkylcarbonyl, Carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, di(C 1~6 ) Alkylamino-carbonyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 ) alkylaminosulfonyl and di(C 1~6 ) alkylsulfoximinyl.

[0147] R 6 Suitable examples of the optional substituents above are C 1~6 Contains 1, 2 or 3 substituents independently selected from alkyl.

[0148] R 6Representative examples of specific substituents in the above include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl-amino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, methoxycarbonylamino, methylsulfonyl-amino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and dimethylsulfoximinyl.

[0149] R 6 Selected examples of the above specific substituents include 1, 2 or 3 substituents independently selected from methyl and ethyl.

[0150] R 6 Suitable examples of the above specific substituents include 1, 2 or 3 substituents independently selected from methyl.

[0151] R 6Illustrative examples of specific values ​​of are methyl, difluoromethyl, methylsulfonylmethyl, aminomethyl, methylaminomethyl, difluoroethyl, carboxyethyl, difluoropropyl, 2-methylpropyl, butyl, cyanocyclopropyl, methylcyclopropyl, ethyl-cyclopropyl, dimethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chloro-phenyl, cyanophenyl, methylphenyl, hydroxyphenyl, methylsulfonylphenyl, dimethyl-sulfoximinylphenyl, benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, (chloro)(fluoro)-benzyl, dichlorobenzyl, (chloro)(difluoro)benzyl, bromo Includes benzyl, cyanobenzyl, methyl-benzyl, dimethylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, hydroxymethylbenzyl, benzoyl, methoxybenzyl, dimethoxybenzyl, trifluoromethoxy-benzyl, methylsulfonylbenzyl, aminomethylbenzyl, aminoethylbenzyl, dimethylamino-benzyl, pyrrolidinylbenzyl, (dimethyl)(pyrrolidinyl)benzyl, morpholinylbenzyl, (dimethyl)(morpholinyl)benzyl, piperazinylbenzyl, acetylaminoethylbenzyl, phenylethyl, chlorophenylethyl, methylpyrazolyl, ethylpyrazolyl, (methyl)(tetrahydropyranyl)pyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl, pyridinylmethyl and aminopyridinylmethyl.

[0152] R 6 Preferred values ​​of include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyloxadiazolyl.

[0153] R6 Selected values ​​of include methyloxadiazolyl and ethyloxadiazolyl.

[0154] R 6 A specific value for is methyloxadiazolyl.

[0155] In general, R 6a is C 1~6 Represents alkyl.

[0156] In the first embodiment, R 6a is C 1~6 In a second embodiment, R 6a is optionally replaced by C 3~9 It represents cycloalkyl.

[0157] Typically, R 6a is C 1~6 represents alkyl, or R 6a represents cyclobutyl, which can be optionally substituted by one or more substituents.

[0158] R 6a Typical examples of the optional substituents above are halogen, cyano, nitro, C 1~6 Alkyl, trifluoro-methyl, hydroxy, hydroxy(C 1~6 ) Alkyl, oxo, C 1~6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, amino, amino(C 1~6 ) Alkyl, C 1~6 Alkylamino, di(C 1~6 ) Alkylamino, C 2~6 Alkylcarbonylamino, C 2~6 Alkoxycarbonylamino, C 1~6 Alkyl sulfonylamino, formyl, C 2~6 Alkylcarbonyl, Carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6Alkylaminocarbonyl, di(C 1~6 ) Alkylaminocarbonyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl and di(C 1~6 ) alkylaminosulfonyl.

[0159] R 6a Suitable examples of the above optional substituents include 1, 2 or 3 substituents independently selected from halogen.

[0160] R 6a Representative examples of specific substituents in the above include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

[0161] R 6a Suitable examples of the above specific substituents include 1, 2 or 3 substituents independently selected from fluoro.

[0162] R 6a Illustrative examples of particular values ​​include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and difluorocyclobutyl.

[0163] R 6a Suitable examples of particular values ​​include tert-butyl and difluorocyclobutyl.

[0164] Typically, R 6a represents tert-butyl.

[0165] Typically, R 6b represents hydrogen or methyl.

[0166] In the first embodiment, R 6b represents hydrogen. In a second embodiment, R 6b is C 1~6 It stands for alkyl, especially methyl.

[0167] Typically, R 6c represents hydrogen or methyl.

[0168] In the first embodiment, R 6c represents hydrogen. In a second embodiment, R 6c is C 1~6 It stands for alkyl, especially methyl.

[0169] In the first embodiment, R 7 represents aryl, which may be optionally substituted by one or more substituents. In a second embodiment, R 7 represents heteroaryl, which may be optionally substituted by one or more substituents. In a third embodiment, R 7 Spiro[(C 3~7 )heterocycloalkyl][heteroaryl], which can be optionally substituted by one or more substituents.

[0170] R 7 Typical values ​​of are phenyl, pyrazolo[1,5- a ]pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, purinyl, pyridinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl and spiro[tetrahydropyranyl][indole], any of which groups may be optionally substituted by one or more substituents.

[0171] R 7 Typical examples of the optional substituents above are halogen, cyano, nitro, C 1~6 Alkyl, difluoromethyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxy(C 1~6 ) Alkyl, oxo, C 1~6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, amino, amino(C 1~6 ) Alkyl, C 1~6 Alkylamino, di(C 1~6 ) Alkylamino, pyrrolidinyl, morpholinyl, piperazinyl, C 2~6 Alkylcarbonylamino, C 2~6 Alkylcarbonylamino (C 1~6 ) Alkyl, C 2~6 Alkoxycarbonylamino, C 1~6 Alkyl sulfonylamino, formyl, C 2~6 Alkylcarbonyl, Carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, di(C 1~6 ) Alkylaminocarbonyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl and di(C 1~6 ) alkylaminosulfonyl.

[0172] R 7Representative examples of specific substituents in the above include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, isopropoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, pyrrolidinyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, methoxycarbonylamino, methylsulfonyl-amino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

[0173] R 7 Exemplary values ​​of include phenyl, pyrazolo[1,5-a]pyrazinyl, benzoxazolyl, fluorobenzoxazolyl, methylbenzoxazolyl, benzothiazolyl, benzimidazolyl, fluoro-benzimidazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, purinyl, pyridinyl, cyanopyridinyl, methylpyridinyl, methoxypyridinyl, pyridazinyl, chloropyridazinyl, cyanopyridazinyl, methylpyridazinyl, ethylpyridazinyl, isopropylpyridazinyl, difluoro-methylpyridazinyl, trifluoromethylpyridazinyl, methoxypyridazinyl, isopropoxy-pyridazinyl, difluoromethoxypyridazinyl, dimethylaminopyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl, methylpyrazinyl, and spiro[tetrahydropyranyl][oxoindole].

[0174] R a , R b , R c , R d Or R eor the heterocyclic moiety -NR b R c Typical examples of suitable substituents in the above are halogen, C 1~6 Alkyl, C 1~6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1~6 Alkoxy(C 1~6 ) Alkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, hydroxy, hydroxy(C 1~6 ) Alkyl, Amino (C 1~6 ) Alkyl, cyano, trifluoromethyl, oxo, C 2~6 Alkylcarbonyl, Carboxy, C 2~6 Alkoxycarbonyl, C 2~6 Alkylcarbonyloxy, amino, C 1~6 Alkylamino, di(C 1~6 ) Alkylamino, phenylamino, pyridinylamino, C 2~6 Alkylcarbonylamino, C 2~6 Alkylcarbonylamino (C 1~6 ) Alkyl, C 2~6 Alkoxycarbonylamino, C 1~6 Alkyl sulfonyl amino, amino carbonyl, C 1~6 Alkylaminocarbonyl and di(C 1~6 ) alkylaminocarbonyl.

[0175] R a , R b , R c , R d Or R e or the heterocyclic moiety -NR b R cRepresentative examples of specific substituents on the above include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulfinyl, methylsulfonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, tert-butoxycarbonylamino, acetylaminomethyl, methylsulfonylamino, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.

[0176] In general, R a is C 1~6 Alkyl, C 3~9 Cycloalkyl, aryl, aryl(C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which can be optionally substituted by one or more substituents.

[0177] Appropriately, R a is C 1~6 Alkyl, C 3~9 Cycloalkyl, aryl, C 3~7 It represents a heterocycloalkyl or heteroaryl, either of which groups can be optionally substituted by one or more substituents.

[0178] Appropriately, R a is C 1~6 Alkyl, aryl (C 1~6 ) alkyl or heteroaryl (C 1~6 ) alkyl, any of which can be optionally substituted by one or more substituents.

[0179] R aExemplary values ​​of include methyl, ethyl, cyclopropyl, phenyl, benzyl, oxetanyl, tetrahydropyranyl, piperidinyl, pyridinyl, pyridazinyl, and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.

[0180] R a Representative values ​​include methyl, cyclopentyl, phenyl, oxetanyl, tetrahydropyranyl, piperidinyl, pyridinyl and pyridazinyl, any of which may be optionally substituted by one or more substituents.

[0181] R a Selected values ​​of include methyl, ethyl, benzyl and isoindolylpropyl, any of which may be optionally substituted by one or more substituents.

[0182] R a Selected examples of suitable substituents above are C 1~6 Alkoxy, oxo and C 1~6 Including alkylsulfonyl.

[0183] R a Selected examples of specific substituents above include methoxy, oxo and methylsulfonyl.

[0184] In one embodiment, R a is optionally replaced by C 1~6 In one aspect of this embodiment, R a Ideally, the unsubstituted C 1~6 In another aspect of this embodiment, R a Ideally, the substitution C 1~6 In another embodiment, R a represents an optionally substituted aryl. In one aspect of this embodiment, R a represents unsubstituted aryl, especially phenyl. In another aspect of this embodiment, R arepresents a monosubstituted aryl, especially methylphenyl. a is an optionally substituted aryl (C 1~6 ) alkyl, ideally unsubstituted aryl (C 1~6 ) alkyl, especially benzyl. In a further embodiment, R a represents an optionally substituted heteroaryl. In a further embodiment, R a is an optionally substituted heteroaryl (C 1~6 ) alkyl, for example dioxoisoindolylpropyl. In a further embodiment, R a is optionally replaced by C 3~9 In a further embodiment, R a is optionally replaced by C 3~7 It represents heterocycloalkyl.

[0185] R a Particular values ​​for include methyl, methoxyethyl, cyclopentyl, phenyl, benzyl, oxetanyl, tetrahydropyranyl, methylsulfonylpiperidinyl, dioxoisoindolylpropyl, pyridinyl and pyridazinyl.

[0186] In certain embodiments, R b is hydrogen or trifluoromethyl, or C 1~6 Alkyl, C 3~7 Cycloalkyl, C 3~7 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, any of which can be optionally substituted by one or more substituents.

[0187] R b Selected values ​​of are hydrogen, or C 1~6Alkyl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl or C 3~7 Heterocycloalkyl(C 1~6 ) alkyl, any of which can be optionally substituted by one or more substituents.

[0188] R b Typical values ​​of are hydrogen and C 1~6 Contains alkyl.

[0189] As an example, R b is hydrogen or trifluoromethyl, or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl , pyrrolidinylethyl, pyrrolidinylpropyl, thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl, indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.

[0190] R b Representative values ​​of include hydrogen, or methyl, ethyl, n-propyl, benzyl, pyrrolidinyl, or morpholinylpropyl, any of which groups can be optionally substituted by one or more substituents.

[0191] Rb Selected examples of suitable substituents above are C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, hydroxy, cyano, C 2~6 Alkoxycarbonyl, di(C 1~6 ) alkylamino and C 2~6 Includes alkoxycarbonylamino.

[0192] R b Selected examples of specific substituents above include methoxy, methylthio, methylsulfinyl, methylsulfonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.

[0193] R b Particular values ​​for include hydrogen, methyl, methoxyethyl, methylthioethyl, methylsulfinylethyl, methylsulfonylethyl, hydroxyethyl, cyanoethyl, dimethylaminoethyl, tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert-butoxycarbonylpyrrolidinyl and morpholinylpropyl.

[0194] In one embodiment, R b represents hydrogen. In another embodiment, R b is C 1~6 It stands for alkyl, especially methyl.

[0195] R c Selected values ​​of are hydrogen, or C 1~6 Alkyl, C 3~7 Cycloalkyl or C 3~7 Any of these groups, including heterocycloalkyl, can be optionally substituted by one or more substituents.

[0196] Preferably, R c is C 3~7It represents a heterocycloalkyl, which may be optionally substituted by one or more substituents.

[0197] In certain embodiments, R c is hydrogen, C 1~6 Alkyl or C 3~7 It represents cycloalkyl.

[0198] R c Representative values ​​of include hydrogen, or methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, any of which groups may be optionally substituted by one or more substituents.

[0199] R c Selected values ​​of include tetrahydropyranyl and piperidinyl, either of which groups may be optionally substituted by one or more substituents.

[0200] R c Selected examples of suitable substituents above are C 1~6 Alkylsulfonyl, C 2~6 Alkylcarbonyl and C 2~6 Contains alkoxycarbonyl.

[0201] R c Selected examples of specific substituents above include methylsulfonyl, acetyl and tert-butoxycarbonyl.

[0202] R c Particular values ​​for include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, methylsulfonylpiperidinyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl.

[0203] R c Particular values ​​for include tetrahydropyranyl and methylsulfonylpiperidinyl.

[0204] Appropriately, R c is hydrogen or C1~6 In one embodiment, R c is hydrogen. In another embodiment, R c is C 1~6 In a further embodiment, R c is C 3~7 It represents cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0205] Or, partial -NR b R c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may optionally be substituted by one or more substituents.

[0206] Heterocyclic moiety -NR b R c Selected examples of suitable substituents above are C 1~6 Alkyl, C 1~6 Alkyl sulfonyl, hydroxy, hydroxy(C 1~6 ) Alkyl, Amino (C 1~6 ) Alkyl, cyano, oxo, C 2~6 Alkylcarbonyl, Carboxy, C 2~6 Alkoxycarbonyl, Amino, C 2~6 Alkylcarbonylamino, C 2~6 Alkylcarbonylamino (C 1~6 ) Alkyl, C 2~6 Alkoxycarbonylamino, C 1~6 Includes alkylsulfonylamino and aminocarbonyl.

[0207] Heterocyclic moiety -NR b R cSelected examples of specific substituents above include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxycarbonylamino, methylsulfonylamino, and aminocarbonyl.

[0208] Part-NR b R c Particular values ​​for are azetidin-1-yl, hydroxyazetidin-1-yl, hydroxymethylazetidin-1-yl, (hydroxy)(hydroxymethyl)azetidin-1-yl, aminomethyl-azetidin-1-yl, cyanoazetidin-1-yl, carboxyazetidin-1-yl, aminoazetidin-1-yl, aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl, oxopyrrolidin-1-yl, acetylaminomethylpyrrolidin-1-yl, tert-butoxycarbonylaminopyrrolidin-1-yl, oxo-oxazolidin-3-yl, hydroxyisoxazolidin-2-yl, thiazo Includes lysine-3-yl, oxothiazolidin-3-yl, dioxo-isothiazolidin-2-yl, piperidin-1-yl, hydroxypiperidin-1-yl, hydroxymethylpiperidin-1-yl, aminopiperidin-1-yl, acetylaminopiperidin-1-yl, tert-butoxycarbonylaminopiperidin-1-yl, methylsulfonylaminopiperidin-1-yl, morpholin-4-yl, piperazin-1-yl, methylpiperazin-1-yl, methylsulfonylpiperazin-1-yl, oxopiperazin-1-yl, acetylpiperazin-1-yl, ethoxycarbonylpiperazin-1-yl and oxohomopiperazin-1-yl.

[0209] Appropriately, R d is hydrogen, or C 1~6 It represents alkyl, aryl, or heteroaryl, any of which groups can be optionally substituted by one or more substituents.

[0210] R dSelected examples of suitable values ​​for include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.

[0211] R d Selected examples of suitable substituents above are halogen, C 1~6 Alkyl, C 1~6 Alkoxy, oxo, C 2~6 Alkylcarbonyloxy and di(C 1~6 ) alkylamino.

[0212] R d Selected examples of specific substituents above include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.

[0213] In one embodiment, R d represents hydrogen. In another embodiment, R d is optionally replaced by C 1~6 In one aspect of this embodiment, R d Ideally, the unsubstituted C 1~6 In another aspect of this embodiment, R represents an alkyl group, such as methyl, ethyl, isopropyl, 2-methylpropyl or tert-butyl, especially methyl. d Ideally, the substitution C 1~6 In another embodiment, R represents an alkyl group, such as substituted methyl or substituted ethyl, including acetoxymethyl, dimethylaminomethyl, and trifluoroethyl. d represents an optionally substituted aryl. In one aspect of this embodiment, R d represents unsubstituted aryl, especially phenyl. In another aspect of this embodiment, R d represents a monosubstituted aryl, especially methylphenyl. In a further aspect of this embodiment, R d represents a disubstituted aryl, for example dimethoxyphenyl. In a further embodiment, R drepresents an optionally substituted heteroaryl, such as thienyl, chlorothienyl, methylthienyl, methylimidazolyl, or thiazolyl. d is optionally replaced by C 3~7 In a further embodiment, R d is optionally replaced by C 3~7 It represents heterocycloalkyl, for example thiazolidinyl or oxothiazolidinyl.

[0214] R d Selected examples of specific values ​​for include hydrogen, methyl, acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.

[0215] Appropriately, R e is C 1~6 It represents alkyl or aryl, either of which groups can be optionally substituted by one or more substituents.

[0216] R e Selected examples of suitable substituents above are C 1~6 Alkyl, especially methyl.

[0217] In one embodiment, R e is optionally replaced by C 1~6 Alkyl, ideally unsubstituted C 1~6 In another embodiment, R e represents an optionally substituted aryl. In one aspect of this embodiment, R e represents unsubstituted aryl, especially phenyl. In another aspect of this embodiment, R e represents a monosubstituted aryl, especially methylphenyl. In a further embodiment, Re represents an optionally substituted heteroaryl.

[0218] R e Selected values ​​of include methyl, propyl and methylphenyl.

[0219] One subclass of compounds according to the present invention is represented by compounds of formula (IIA) and N-oxides thereof, and pharma-ceutically acceptable salts thereof: [ka] (In the formula, R 11 represents hydrogen or halogen; R 16 represents methyl or ethyl; R 2 and R 5 is as defined above).

[0220] In the first embodiment, R 11 represents hydrogen. In a second embodiment, R 11 represents halogen, especially fluoro.

[0221] Appropriately, R 11 represents hydrogen or fluoro.

[0222] In the first embodiment, R 16 represents methyl. In a second embodiment, R 16 represents ethyl.

[0223] Particular novel compounds according to the invention include those whose preparation is described in the accompanying Examples, and each of the pharma-ceutically acceptable salts and solvates thereof.

[0224] The compounds according to the invention are useful in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

[0225] The compounds according to the invention are useful for the treatment and / or prevention of pathological disorders mediated by the proinflammatory IL-17 cytokine or associated with elevated levels of the proinflammatory IL-17 cytokine. In general, pathological conditions include infections (viral, bacterial, fungal and parasitic), infection-related endotoxic shock, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman's disease, ankylosing spondylitis and other spondyloarthropathy, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, pilonidal disease, peritonitis, psoriasis, atopic dermatitis, vasculitis, surgical adhesions, stroke, autoimmune diabetes, I. type 2 diabetes, Lyme disease arthritis, meningoencephalitis, immune-mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barre syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrotic disorders including pulmonary fibrosis, liver fibrosis, kidney fibrosis, scleroderma or systemic sclerosis, cancer (solid tumors such as melanoma, hepatoblastoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer and hematological malignancies, in particular both acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), ischemic diseases such as myocardial infarction and heart disease including atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydria and pain (particularly pain associated with inflammation).

[0226] WO2009 / 089036 reveals that modulators of IL-17 activity can be administered to inhibit or reduce the severity of ocular inflammatory disorders, particularly ocular surface inflammatory disorders, including dry eye syndrome (DES). As a result, the compounds according to the invention are useful for treating and / or preventing IL-17-mediated ocular inflammatory disorders, particularly IL-17-mediated ocular surface inflammatory disorders, including dry eye syndrome. Ocular surface inflammatory disorders include dry eye syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, artificial keratoplasty surgery, ocular surface corneal inflammatory conditions, conjunctival scarring disorders, ocular autoimmune conditions, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergy, severe allergic (atopic) eye disease, conjunctivitis and microbial keratitis. Specific areas of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjogren's syndrome, Sjogren's syndrome associated keratoconjunctivitis sicca, non-Sjogren's syndrome associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorders, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction and evaporative loss.

[0227] By way of example, the compounds of the invention may be useful for the treatment and / or prevention of pathological disorders selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airways disease, chronic obstructive pulmonary disease, atopic dermatitis, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), ankylosing spondylitis and other spondyloarthropathies, cancer and pain (particularly pain associated with inflammation).

[0228] Suitably the compounds of the invention are useful for the treatment and / or prevention of psoriasis, psoriatic arthritis or ankylosing spondylitis.

[0229] The present invention also provides a pharmaceutical composition comprising a compound according to the invention as described above, or a pharma- ceutically acceptable salt thereof, in association with one or more pharma- ceutically acceptable carriers.

[0230] Pharmaceutical compositions according to the invention may be in a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or in a form suitable for administration by inhalation or insufflation.

[0231] For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc or silica), disintegrants (e.g., potato starch or sodium glycolate) or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product which is constituted with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharma-ceutically acceptable excipients, such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavoring agents, coloring agents or sweetening agents, if appropriate.

[0232] Preparations for oral administration can be suitably formulated to provide sustained release of the active compound.

[0233] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0234] The compound according to the present invention can be formulated for parenteral administration by injection, for example bolus injection or injection.The preparation for injection can be presented in unit dosage form, for example in glass ampoules or multi-dose containers, for example glass vials.The composition for injection can take the form of suspension, solution or emulsion in oily or aqueous vehicle, and can contain compounding agents, for example suspending agents, stabilizing agents, preservatives and / or dispersing agents.Alternatively, the active ingredient can be in powder form, which is constituted with suitable vehicle, for example sterile pyrogen-free water, before use.

[0235] In addition to the formulations described above, the compounds according to the present invention can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation or intramuscular injection.

[0236] For administration intranasally or by inhalation, the compounds according to the invention can be conveniently delivered in the form of an aerosol spray presentation for use in pressurized packs or a nebulizer using a suitable propellant, for example dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or gas mixture.

[0237] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.

[0238] For topical administration, the compound according to the present invention can be conveniently formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers.Specific carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.Alternatively, the compound according to the present invention can be formulated into a suitable lotion containing the active ingredient suspended or dissolved in one or more pharma-ceutically acceptable carriers.Specific carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.

[0239] For ophthalmic administration, the compounds according to the invention can be conveniently formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline with or without preservatives, such as bactericidal or fungicidal agents, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration, the compounds according to the invention can be formulated as ointments, such as petrolatum.

[0240] For rectal administration, the compounds according to the present invention can be conveniently formulated as suppositories. These can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will melt in the rectum to release the active ingredient. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.

[0241] The amount of the compound according to the present invention required for the prevention or treatment of a particular condition varies depending on the compound selected and the condition of the patient being treated. In general, however, the daily dosage may range from about 10 ng / kg to 1000 mg / kg, typically 100 ng / kg to 100 mg / kg, for example, about 0.01 mg / kg to 40 mg / kg body weight, for parenteral administration, about 10 ng / kg to 50 mg / kg body weight, for intranasal administration or administration by inhalation or insufflation, about 0.05 mg to about 1000 mg, for example, about 0.5 mg to about 1000 mg.

[0242] If desired, the compounds according to the invention may be co-administered with another pharma- ceutical active agent, for example an anti-inflammatory molecule.

[0243] The compound of formula (IA) above has the formula R 6 It can be prepared by a process comprising reacting a compound of formula (III) with a carboxylic acid of -COH [ka] (In the formula, A, B, D, E, R 5 and R 6 is as defined above).

[0244] The reaction is conveniently accomplished in the presence of a coupling agent and a base. Suitable coupling agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide and 2-chloro-1-methylpyridinium iodide. Suitable bases include organic amines, such as trialkylamines, for example N,N-diisopropylethylamine. The reaction is conveniently carried out at ambient or elevated temperature in a suitable solvent, such as a cyclic ether, for example tetrahydrofuran, or a dipolar aprotic solvent, for example N,N-dimethylformamide, N,N-dimethylacetamide, or a chlorinated solvent, for example dichloromethane.

[0245] R 6 But, C 1~6 When alkyl, e.g. methyl, is represented, the compound of formula (I) above has the formula R 6 It can be prepared by a process comprising reacting a compound of formula (III) as defined above with a compound of -COCl, such as acetyl chloride. The reaction is conveniently accomplished in the presence of a base. Suitable bases include organic amines, such as trialkylamines, for example N,N-diisopropylethylamine. The reaction is conveniently carried out at ambient temperature in a suitable solvent, such as a cyclic ether, for example tetrahydrofuran.

[0246] R 6 -OR 6a wherein the compound of formula (I) above is reacted, ideally in the presence of a base, such as an organic amine, for example triethylamine, with a compound of formula R 6a It may be prepared by a two-step process comprising reacting a compound of -OH with N,N'-disuccinimidyl carbonate, and (ii) reacting the resulting material with a compound of formula (III) as defined above. Steps (i) and (ii) are conveniently carried out at ambient temperature in a suitable solvent, such as a chlorinated solvent, for example dichloromethane.

[0247] The compound of formula (IB) is a compound of formula (III) as defined above, and R 6 is defined above, and L 1 where L represents a suitable leaving group. 1 -S(O)2R 6 The compound may be prepared by a process comprising the step of reacting

[0248] Leaving group L 1 is suitably a halogen atom, for example chloro.

[0249] The reaction is conveniently carried out at ambient temperature in the presence of pyridine. Alternatively, the reaction can be carried out at ambient temperature in the presence of a base, such as an organic amine, for example N,N-diisopropylethylamine, in a suitable solvent, such as a chlorinated solvent, for example dichloromethane.

[0250] The compound of formula (IC) is a compound of formula (III) as defined above, and R 7 is defined above, and L 2 where L represents a suitable leaving group. 2 -R 7 The compound may be prepared by a process comprising the step of reacting

[0251] Leaving group L 2 is suitably a halogen atom, for example chloro or bromo.

[0252] The reaction is conveniently carried out in the presence of a base. Suitable bases include organic amines, such as trialkylamines, for example N,N-diisopropylethylamine. The reaction is typically carried out at elevated temperature in a suitable solvent, such as a cyclic ether, for example 1,4-dioxane, or a cyclic amide, for example 1-methyl-2-pyrrolidinone, or an organic sulfoxide, for example dimethylsulfoxide.

[0253] Alternatively, the reaction may be carried out in the presence of a transition metal catalyst. Suitable transition metal catalysts for use in this procedure include [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (tBuBrettPhos Pd G3). The reaction is conveniently carried out in a suitable solvent or mixture of solvents at elevated temperature in the presence of a base, such as an inorganic base, for example potassium tert-butoxide. The solvent(s) may suitably be selected from cyclic ethers, such as 1,4-dioxane, and sulfoxide solvents, such as dimethylsulfoxide.

[0254] The intermediate of formula (III) can be prepared by the following steps: (i) a compound of formula (IV) and a compound of formula (V) [ka] (Wherein, A, B, D, E and R 5 is as defined above, and L 3 represents a suitable leaving group) to give a compound of formula (VI) [ka] (Wherein, A, B, D, E and R 5 is as defined above, and (ii) It can be prepared by a procedure which includes the step of removing the tert-butylsulfinyl group from compound (VI).

[0255] Leaving group L 3 is suitably a halogen atom, for example bromo.

[0256] Step (i) is suitably carried out by treatment of compound (IV) with a base, such as an organic base, for example n-butyllithium, followed by reaction with compound (V). The reaction is conveniently effected in a suitable solvent, for example a chlorinated solvent, for example dichloromethane, or a cyclic ether, for example tetrahydrofuran.

[0257] Removal of the tert-butylsulfinyl group from compound (VI) in step (ii) may conveniently be achieved by treatment with an acid, such as a mineral acid, for example hydrochloric acid.

[0258] The intermediate of formula (V) above is represented by the formula R 5 It can be prepared by reacting an aldehyde derivative of -CHO with 2-methyl-2-propanesulfinamide. The reaction is suitably carried out in the presence of pyridinium p-toluenesulfonate and magnesium sulfate. The reaction is conveniently carried out at ambient temperature in a suitable solvent, such as a chlorinated solvent, for example dichloromethane.

[0259] In an alternative procedure, the intermediate of formula (III) above may be reacted with an N-protecting group R from a compound of formula (VII) p It can be prepared by removal of [ka] (Wherein, A, B, D, E and R 5 is as defined above, and R p represents an N-protecting group).

[0260] N-protecting group R p is suitably tert-butoxycarbonyl (BOC), in which case its removal may conveniently be accomplished by treatment with an acid, for example a mineral acid, such as hydrochloric acid, or an organic acid, such as trifluoroacetic acid.

[0261] Alternatively, an N-protecting group R pmay be benzyloxycarbonyl, in which case its removal may conveniently be accomplished by catalytic hydrogenation in the presence of a hydrogenation catalyst, such as palladium on carbon or palladium hydroxide on carbon, typically by treatment with hydrogen gas or ammonium formate.

[0262] The intermediate of formula (VII) above may be prepared by reacting a compound of formula (VIII) with a compound of formula (IX) [ka] (In the formula, A, B, D, E, R 5 and R p is as defined above, and L 4 represents the appropriate leaving group).

[0263] Leaving group L 4 is typically a halogen atom, for example bromo.

[0264] The reaction is carried out at elevated temperature in a suitable solvent, e.g. 1~4 This is conveniently carried out in an alkanol, e.g. isopropanol.

[0265] The compound of formula (ID) can be prepared by reacting compound (III) with compound of formula R 6 Under conditions similar to those described above for the reaction between carboxylic acids of formula R 7 -NH2 with a compound of formula (X) [ka] (In the formula, A, B, D, E, R 5 and R 7 is as defined above).

[0266] If they are not commercially available, the starting materials of formulae (IV), (VIII), (IX) and (X) can be prepared by methods analogous to those described in the accompanying examples or by standard methods known in the art.

[0267] It is understood that any compound of formula (I) initially obtained from any of the above processes can, where appropriate, be subsequently synthesized into further compounds of formula (I) by techniques known in the art. For example, a compound of formula (I) containing an N-BOC moiety (BOC is an abbreviation for tert-butoxycarbonyl) can be converted into the corresponding compound containing an NH moiety by treatment with an acid, for example a mineral acid, for example hydrochloric acid, or an organic acid, for example trifluoroacetic acid.

[0268] Compounds of formula (I) containing an NH function may be alkylated, e.g. methylated, typically by treatment with a suitable alkyl halide, e.g. iodomethane, in the presence of a base, e.g. an inorganic carbonate, e.g. sodium carbonate.

[0269] Compounds of formula (I) containing an NH function may be acylated, for example acetylated, typically by treatment with a suitable acyl halide, for example acetyl chloride, in the presence of a base, for example an organic base, for example N,N-diisopropylethylamine or triethylamine.Similarly, compounds of formula (I) containing an NH function may be acylated, for example acetylated, typically by treatment with a suitable acyl anhydride, for example acetic anhydride, in the presence of a base, for example an organic base, for example triethylamine.

[0270] Similarly, compounds of formula (I) containing an NH functionality can be reacted with a suitable C 1~4 Treatment with an alkylsulfonyl chloride reagent, e.g., methylsulfonyl chloride, affords NS(O)Alk 1 Functional group (in the formula, Alk 1 is C 1~4The compound may be converted to the corresponding compound containing an alkyl group, for example methyl.

[0271] Similarly, compounds of formula (I) containing an NH functional group can be converted to the corresponding compounds containing a carbamate or urea moiety, respectively, by treatment with a suitable chloroformate or carbamoyl chloride reagent, typically in the presence of a base, such as an organic base, for example triethylamine. Alternatively, compounds of formula (I) containing an NH functional group can be converted to the corresponding compounds containing a urea moiety, typically in the presence of a base, such as an organic base, for example triethylamine, by treatment with a suitable amine-substituted (3-methylimidazol-3-ium-1-yl)methanone iodide derivative. Alternatively, a suitable isocyanate derivative Alk 1 By treatment with -N=C=O, compounds of formula (I) containing an NH functionality can be converted to the urea moiety NC(O)N(H)Alk, typically in the presence of a base, for example an organic base, for example triethylamine. 1 (In the formula, Alk 1 can be converted to the corresponding compound containing

[0272] Compounds of formula (I) containing an NH functionality may be converted to the corresponding compounds containing an NC(H) functionality by treatment with an appropriate aldehyde or ketone in the presence of a reducing agent, for example sodium triacetoxyborohydride.

[0273] The compounds may be alkylated by treatment with a suitably substituted alkyl trifluoromethanesulfonate, typically in the presence of a base, such as a dialkylamide salt, for example lithium diisopropylamide.

[0274] C 1~4 Alkoxycarbonyl moiety -CO2Alk 1 (In the formula, Alk 1Compounds of formula (I) containing a carboxylic acid (-COH) moiety (-COH) may be converted to the corresponding compounds containing a carboxylic acid (-COH) moiety by treatment with a base, such as an alkali metal hydroxide, for example lithium hydroxide. Alternatively, compounds of formula (I) containing a tert-butoxycarbonyl moiety may be converted to the corresponding compounds containing a carboxylic acid (-COH) moiety by treatment with trifluoroacetic acid.

[0275] Compounds of formula (I) containing a carboxylic acid (-COH) moiety can be reacted with compounds (III) and formula R 6 They can be converted to the corresponding compounds containing an amide moiety by treatment with an appropriate amine under conditions similar to those described above for the reaction of -CO2H with a carboxylic acid.

[0276] C 1~4 Alkoxycarbonyl moiety -CO2Alk 1 (In the formula, Alk 1 Compounds of formula (I) containing a hydroxymethyl (-CHOH) moiety (-CHOH) may be converted to the corresponding compounds containing a hydroxymethyl (-CHOH) moiety by treatment with a reducing agent, for example lithium aluminum hydride.

[0277] C 1~4 Alkylcarbonyloxy moiety -OC(O)Alk 1 (In the formula, Alk 1 is as defined above), for example a compound of formula (I) containing an acetoxy moiety can be converted to the corresponding compound containing a hydroxy (-OH) moiety by treatment with a base, for example an alkali metal hydroxide, for example sodium hydroxide.

[0278] Compounds of formula (I) containing halogen atoms, e.g., bromo, can be converted to the corresponding compounds containing optionally substituted aryl, heterocycloalkenyl or heteroaryl moieties by treatment with substituted aryl, heterocycloalkenyl or heteroaryl boronic acids or cyclic esters thereof, suitably formed with organic diols, e.g., pinacol, 1,3-propanediol or neopentyl glycol. The reaction is typically carried out in the presence of a transition metal catalyst and a base. The transition metal catalyst can be [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Alternatively, the transition metal catalyst can be tris(dibenzylideneacetone)dipalladium(0), which can be advantageously used with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos). Suitably, the base can be an inorganic base, e.g., sodium carbonate or potassium carbonate.

[0279] Compounds of formula (I) containing halogen atoms, such as chloro or bromo, can be converted to corresponding compounds containing optionally substituted aryl, heterocycloalkenyl or heteroaryl moieties via a two-step procedure, which involves (i) reaction with bis(pinacolato)diboron, and (ii) reaction of a compound, thereby obtaining a suitable bromoaryl, heterocycloalkenyl or bromoheteroaryl derivative substituted with a suitable leaving group, such as a halogen atom, e.g., bromo, or a sulfonyloxy moiety, e.g., trifluoromethylsulfonyloxy. Step (i) is conveniently carried out in the presence of a transition metal catalyst and a base, e.g., potassium acetate. Suitably, the transition metal catalyst can be tris(dibenzylideneacetone)dipalladium(0), which can be advantageously used with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos). Alternatively, the transition metal catalyst may be [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Step (ii) is conveniently carried out in the presence of a transition metal catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base, such as an inorganic base, for example sodium carbonate or potassium carbonate.

[0280] Compounds containing a halogen atom, such as bromo, can be converted to the corresponding compounds containing a tert-butoxycarbonylmethyl moiety by treatment with tert-butyl 2-(bromodincio)acetate. The reaction is conveniently carried out in the presence of a transition metal catalyst, such as allylpalladium(II) chloride, which is commonly used with XPhos.

[0281] Compounds of formula (I) containing a cyano (-CN) moiety can be converted to the corresponding compounds containing a 1-aminoethyl moiety by a two-step process that involves (i) reaction with methylmagnesium chloride, ideally in the presence of titanium(IV) isopropoxide, and (ii) treatment of the resulting material with a reducing agent, such as sodium borohydride. If an excess of methylmagnesium chloride is used in step (i), the corresponding compounds containing a 1-amino-1-methylethyl moiety are obtained.

[0282] Compounds of formula (I) containing the moiety -S- may be converted to the corresponding compounds containing the moiety -S(O)(NH)- by treatment with (diacetoxyiodo)benzene and ammonium carbamate.

[0283] Compounds of formula (I) containing a C═C double bond may be converted to the corresponding compounds containing a CH—CH single bond by treatment with hydrogen gas in the presence of a hydrogenation catalyst, such as palladium on carbon.

[0284] Compounds of formula (I) containing an aromatic nitrogen atom may be converted to the corresponding compounds containing an N-oxide moiety by treatment with a suitable oxidizing agent, for example 3-chloroperbenzoic acid.

[0285] When a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product may be separated therefrom at a suitable stage by conventional methods, such as preparative HPLC or column chromatography, for example employing silica and / or alumina with a suitable solvent system.

[0286] When the process described above for the preparation of the compounds according to the invention results in a mixture of stereoisomers, these isomers can be separated by conventional techniques. In particular, when it is desired to obtain a particular enantiomer of the compound of formula (I), this can be produced from the corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereoisomeric derivatives, e.g. salts, can be produced by reaction of a mixture of an enantiomer of formula (I), e.g. a racemate, and a suitable chiral compound, e.g. a chiral base. The diastereoisomers can then be separated by any convenient means, e.g. by crystallization, e.g. in the case where the diastereoisomer is a salt, treatment with an acid to recover the desired enantiomer. In another resolution process, the racemate of formula (I) can be separated using chiral HPLC. Furthermore, if necessary, a particular enantiomer can be obtained by using a suitable chiral intermediate in one of the above-mentioned processes. Alternatively, a specific enantiomer can be obtained by enantiomer-specific enzymatic biotransformation, such as ester hydrolysis using an esterase, followed by purification of only the enantiomerically pure hydrolyzed acid from the unreacted ester enantiomer. Chromatography, recrystallization and other conventional separation procedures may also be used on intermediates or final products when it is desired to obtain a specific geometric isomer of the invention.

[0287] During any of the above synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules. This may be achieved by conventional protecting groups, such as those described in Greene's Protective Groups in Organic Synthesis, edited by PGM Wuts, John Wiley & Sons, 5th Edition, 2014. The protecting groups may be removed at any convenient subsequent stage using methods known in the art.

[0288] Compounds according to the invention potently inhibit the ability of IL-17A to bind to IL-17RA. When tested in the IL-17 FRET assay described below, compounds of the invention have IC values ​​of 10 μM or less, generally 5 μM or less, usually 1 μM or less, typically 500 nM or less, suitably 100 nM or less, ideally 50 nM or less, and preferably 25 nM or less. 50 values ​​(those skilled in the art may 50 (Recognize that lower values ​​indicate more active compounds.)

[0289] Moreover, certain compounds according to the invention potently inhibit IL-17-induced IL-6 release from human dermal fibroblasts. Indeed, when tested in the HDF cell line assay described below, the compounds of the invention have IC values ​​of 10 μM or less, generally 5 μM or less, usually 1 μM or less, typically 500 nM or less, suitably 100 nM or less, ideally 50 nM or less, and preferably 25 nM or less. 50 (As mentioned above, those skilled in the art will appreciate that IC 50 (Recognize that lower values ​​indicate more active compounds.)

[0290] IL-17 FRET assay The purpose of this assay is to test the ability of compounds to interfere with the interaction between IL-17A and soluble IL-17 receptor A (IL-17RA). The ability of compounds to inhibit the binding of IL-17A to IL-17RA is measured in this assay.

[0291] The IL-17AA-TEV-human Fc construct was expressed in a CHO SXE cell line and purified by protein A chromatography and size exclusion. Proteins were labeled with amine-reactive AlexaFluor 647 dye (Thermo Fisher #A20006) according to the manufacturer's instructions.

[0292] Soluble IL-17RA(33-317)-HKH-TEV-Fc was expressed in the Expi HEK293 cell line and purified by protein A chromatography and size exclusion. The Fc tag was cleaved with TEV to generate IL-17RA(33-317)-HKH, and the protein was labeled with amine-reactive terbium (Thermo Fisher #PV3581).

[0293] The following solutions were prepared in assay buffer [Dulbecco's PBS (Sigma #14190-094), 0.05% P20 (Thermo Scientific #28320), 1 mg / mL BSA (Sigma #A2153-500G)]: For IL-17A assay IL-17A-Fc-AF647, 5nM IL-17RA-HKH-Tb, 5 nM

[0294] Compounds were serially diluted in DMSO and the aqueous dilutions were then placed into a 384-well dilution plate (Greiner #781281) to give a 25% DMSO solution.

[0295] IL-17A (10 μL) was added to a black low volume assay plate (Costar #4511) and diluted compounds (5 μL) were transferred from the aqueous diluent plate. Cytokines and compounds were incubated for 1 h, then IL-17RA (10 μL) was added. Plates were wrapped in foil and incubated with gentle shaking (<400 rpm) at room temperature for 18-20 h before being read on a Perkin Elmer Envision plate reader (excitation: 330 nm, emission 615 / 645 nm).

[0296] Final assay concentrations were IL-17A-AF647, 2 nM and IL-17RA-Tb, 2 nM, 5% DMSO.

[0297] When tested in the IL-17 FRET assay, all of the compounds in the accompanying examples had IC 50It has been found to exhibit value.

[0298] When tested in the IL-17 FRET assay, the compounds of the accompanying examples generally have an IC in the range of about 0.01 nM to about 10 μM, usually in the range of about 0.01 nM to about 5 μM, typically in the range of about 0.01 nM to about 1 μM, suitably in the range of about 0.01 nM to about 500 nM, suitably in the range of about 0.01 nM to about 100 nM, ideally in the range of about 0.01 nM to about 50 nM, and preferably in the range of about 0.01 nM to about 25 nM. 50 It presents value.

[0299] Inhibition of IL-17A-induced IL-6 release from a dermal fibroblast cell line The purpose of this assay is to test the ability to neutralize IL-17 protein in a human primary cell line. Stimulation of normal human dermal fibroblasts (HDFs) with IL-17 alone produces a very weak signal, but in combination with certain other cytokines, such as TNFα, it has a synergistic effect on the production of the proinflammatory cytokine, IL-6.

[0300] HDFs were stimulated with IL-17A (50 pM) in combination with TNF-α (25 pM). The resulting IL-6 response was then measured using a homogeneous time-resolved FRET kit from Cisbio. The kit utilizes two monoclonal antibodies, the first labeled with Eu-Cryptate (donor) and the second labeled with d2 or XL665 (acceptor). The intensity of the signal is proportional to the concentration of IL-6 present in the sample (the ratio is calculated by 665 / 620×104).

[0301] The ability of compounds to inhibit IL-17-induced IL-6 release from human dermal fibroblasts is measured in this assay.

[0302] HDF cells (Sigma #106-05n) were cultured in complete medium (DMEM + 10% FCS + 2 mM L-glutamine) and maintained in tissue culture flasks using standard techniques. Cells were harvested from the tissue culture flasks the morning of the assay using TrypLE (Invitrogen #12605036). TrypLE was neutralized using complete medium (45 mL) and cells were centrifuged at 300 x g for 3 min. Cells were resuspended in complete medium (5 mL), counted and a total of 3.125 x 10 4 The concentration was adjusted to 10 cells / mL and then added to a 384-well assay plate (Corning #3701) at 40 μL per well. Cells were left at 37° C. / 5% CO2 for a minimum of 3 hours to adhere to the plate.

[0303] Compounds were serially diluted in DMSO before the aqueous dilutions were placed into a 384-well dilution plate (Greiner #781281) and 5 μL from the titration plate was transferred to 45 μL of complete medium and mixed to give a solution containing 10% DMSO.

[0304] A mixture of TNFα and IL-17 cytokines was prepared in complete medium to a final concentration of TNFα 25 pM / IL-17A 50 pM, then 30 μL of the solution was added to a 384-well reagent plate (Greiner #781281).

[0305] 10 μL was transferred from the aqueous dilution plate to the reagent plate containing 30 μL of diluted cytokines to give a 2.5% DMSO solution. Compounds were incubated with the cytokine mixture for 1 h at 37° C. After incubation, 10 μL was transferred to the assay plate to give a 0.5% DMSO solution, which was then incubated for 18-20 h at 37° C. / 5% CO2.

[0306] Europium cryptate and Alexa 665 from Cisbio IL-6 FRET kit (Cisbio#62IL6PEB) were diluted in reconstitution buffer and mixed 1:1 as per kit instructions. FRET reagent (10 μL) was added to a white low volume 384-well plate (Greiner#784075) and then the supernatant (10 μL) was transferred from the assay plate to the Greiner reagent plate. The mixture was incubated at room temperature with gentle shaking (<400 rpm) for 3 h before being read on a Synergy Neo 2 plate reader (excitation: 330 nm, emission: 615 / 645 nm).

[0307] When tested in the above assay, the compounds of the accompanying examples had IC 50 It has been found to exhibit value.

[0308] When tested in the above assay, the compounds of the accompanying examples generally have an IC in the range of about 0.01 nM to about 10 μM, usually in the range of about 0.01 nM to about 5 μM, typically in the range of about 0.01 nM to about 1 μM, suitably in the range of about 0.01 nM to about 500 nM, suitably in the range of about 0.01 nM to about 100 nM, ideally in the range of about 0.01 nM to about 50 nM, and preferably in the range of about 0.01 nM to about 25 nM. 50 It presents value.

[0309] The following examples illustrate the preparation of compounds according to the invention. EXAMPLES

[0310] Abbreviation DCM: dichloromethane EtOAc: ethyl acetate MeOH: Methanol THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide DIPEA: N,N-diisopropylethylamine TBME: tert-butyl methyl ether IPA: isopropyl alcohol DMA: N,N-Dimethylacetamide HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl h: time rt: room temperature M: Mass RT: Retention time FCC: flash column chromatography HPLC: High-performance liquid chromatography LCMS: Liquid Chromatography Mass Spectrometry

[0311] Analysis conditions Compounds were named using ACD / Name Batch (Network) version 11.01, and / or Accelrys Draw 4.2, and / or Elemental, Dotmatics, and / or ChemAxon.

[0312] All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dry solvents and glassware.

[0313] NMR spectra were recorded on Bruker Avance III HD 500 MHz, 400 MHz, 300 MHz or 250 MHz spectrometers.

[0314] Column chromatographic separations were performed using a Biotage® Isolera 4 system equipped with a Biotage® SNAP KP-Sil prepacked silica gel column.

[0315] HPLC-MS was performed on an Agilent 1200-6120 LC-MS system coupled to an Agilent 6120 mass spectrometer (ES) with UV Detection (230 to 400 nm and 215 nm) and Mass Spec Detection, m / z 120 to 800.

[0316] Method 1 Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Mobile phase A: 10 nM ammonium formate in water + 0.1% NH3 (pH 10) Mobile phase B: Acetonitrile + 5% water + 0.1% NH3 (pH 10) Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0317] Method 2 Acquity UPLC BEH C18 1.7μm, 2.1×50mm column Mobile phase A: 10 mM ammonium formate + 0.1% NH3 (pH 10) Mobile phase B: Acetonitrile + 5% H2O + 0.1% NH3 (pH 10) Flow rate: 1.5mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 0.10 95.00 5.00 3.50 5.00 95.00 4.00 5.00 95.00 4.05 95.00 5.00

[0318] Method 3 XBridge Prep C18 (19 x 100 mm, 5 μm) column Mobile phase A: 10 mM ammonium bicarbonate + 0.1% NH3 in water (pH 10) Mobile phase B: Acetonitrile + 5% water + 0.1% NH3 (pH 10) Flow rate: 19mL / min Gradient Program: Time A% B% 0.00 65.00 35.00 2.50 65.00 35.00 11.00 50.00 50.00 11.50 5.00 95.00 13.00 65.00 35.00

[0319] Method 4 Stationary phase: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Mobile phase A: 10 nM ammonium formate in water + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0320] Method 5 uPLC-MS was performed on a Waters Acquity UPLC system coupled to a Waters Acquity PDA detector, an ELS detector and an MSD (scan positive: 150-850). Stationary phase: Phenomenex Kinetex-XB, C18 2.1×100mm, 1.7μm column Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Flow rate: 0.6mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 5.30 0.00 100.0 5.80 0.00 100.0 5.82 95.00 5.00 7.00 95.00 5.00

[0321] Intermediate 1 (NE)-2-Methyl-N-[(4-trans-methylcyclohexyl)methylene]propane-2-sulfinamide trans-4-Methylcyclohexanecarbaldehyde (8.7 g, 69 mmol), 2-methylpropane-2-sulfinamide (9.2 g, 76 mmol), pyridinium p-toluenesulfonate (870 mg, 3.4 mmol) and magnesium sulfate (41 g, 340 mmol) were suspended in DCM (140 mL). The mixture was stirred at ambient temperature for 18 h, then filtered and concentrated in vacuo. The resulting material was purified by flash column chromatography using a gradient of EtOAc (0-20%) in isohexane to afford the title compound (4.1 g, 26%) as a pale yellow oil.

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[0322] Intermediate 2 (7-Chloroimidazo[1,2- a ]pyridin-2-yl)(4-trans-methylcyclohexyl)methanamine hydrochloride 2-Bromo-7-chloroimidazo[1,2- a]pyridine (500 mg, 2.2 mmol) was dissolved in DCM (20 mL) and cooled to -78°C, then a solution of n-butyllithium (1.6 M in hexanes, 1.6 mL, 2.5 mmol) was added. The mixture was stirred at -78°C, then a solution of intermediate 1 (495 mg, 2.2 mmol) in DCM (20 mL) was added over 5 min. The solution was stirred at -78°C for 1 h, then warmed to ambient temperature and stirred for 4 h. A 4N solution of HCl in 1,4-dioxane (10 mL) was added. The mixture was stirred at ambient temperature for 30 min, then concentrated in vacuo to give the title compound (600 mg), which was used without further purification.

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[0323] Intermediate 3 N-[(7-chloroimidazo[1,2- a ]pyridin-2-yl)(4-trans-methylcyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 2 (600 mg, 2.16 mmol) was dissolved in DCM (20 mL) and then 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (277 mg, 2.16 mmol), DIPEA (1.51 mL, 8.64 mmol) and HATU (1 g, 2.59 mmol) were added. The mixture was stirred at ambient temperature for 18 h then diluted with DCM (50 mL) and washed with water (50 mL). The aqueous layer was further extracted with DCM (50 mL) and then the combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography eluting with a gradient of MeOH / DCM (0-10%) to give the title compound (636 mg, 76%).

number

[0324] Intermediate 4 O 1 -tert-ButylO 3-Ethyl 4-(trifluoromethylsulfonyloxy)-2,5-dihydropyrrole-1,3-dicarboxylate 1-tert-Butyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (15.0 g, 55.4 mmol) was dissolved in DCM (80 mL) and cooled to −78° C. in a dry ice / acetone bath under nitrogen. DIPEA (10.6 mL, 61.0 mmol) was added. The reaction mixture was stirred under nitrogen and then a 1 M solution of trifluoromethanesulfonic anhydride in DCM (58 mL, 58 mmol) was added. The reaction mixture was stirred under nitrogen at −78° C. for 30 min, then allowed to warm to room temperature and stirred for 18 h. Saturated aqueous sodium bicarbonate (50 mL) was added. The mixture was stirred at rt for 5 min and then filtered through a hydrophobic PTFE frit, washing with DCM (25 mL). The combined filtrates were concentrated in vacuo. The resulting oil was dissolved in diethyl ether (150 mL) and the resulting white solid was filtered off and washed with diethyl ether (2×25 mL). The filtrate was concentrated in vacuo and the crude material was purified by flash column chromatography using a gradient of EtOAc (0-20%) in isohexane to afford the title compound (14.3 g, 66%) as a colorless oil that solidified on standing.

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[0325] Intermediate 5 O 1 -tert-ButylO 3 -Ethyl 4-(2-{(4-trans-methylcyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2- a ]pyridin-7-yl)-2,5-dihydropyrrole-1,3-dicarboxylate Intermediate 3 (280 mg, 0.722 mmol), bis(pinacolato)diboron (220 mL, 0.866 mmol), potassium acetate (143 mg, 1.44 mmol) and XPhos (35 mg, 0.0722 mmol) were suspended in 1,4-dioxane (5 mL) and sealed in a vial, which was degassed with three cycles of vacuum and nitrogen. Pd2(dba)3 (34 mg, 0.0361 mmol) was added. The reaction mixture was heated at 100 °C for 7 h, then cooled, filtered through Celite and concentrated in vacuo. The crude material was dissolved in a mixture of 1,4-dioxane (5 mL) and water (5 mL) and then intermediate 4 (422 mg, 1.08 mmol) and potassium carbonate (302 mg, 2.17 mmol) were added. The mixture was sealed in a vial, which was degassed with three cycles of vacuum and nitrogen. Pd(dppf)Cl2 (28 mg, 0.0361 mmol) was added. The mixture was heated at 100 °C for 2 h, then cooled to ambient temperature and diluted with DCM (20 mL). The organic phase was separated using a hydrophobic PTFE frit and then concentrated in vacuo. The crude material was purified by flash column chromatography eluting with MeOH (0-10%) in DCM to give the title compound (291 mg, 68%), which was used without further purification.

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[0326] Intermediate 6 1-tert-Butoxycarbonyl-4-(2-{(4-trans-methylcyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2- a ]pyridin-7-yl)-2,5-dihydropyrrole-3-carboxylic acid Intermediate 5 (291 mg, 0.491 mmol) was dissolved in a mixture of THF (5 mL) and water (5 mL) then lithium hydroxide (24 mg, 0.982 mmol) was added. The mixture was stirred at ambient temperature for 3 h then 2N hydrochloric acid (2 mL) was added. The mixture was extracted into DCM (2×25 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound (347 mg, 100%) which was used without further purification.

number

[0327] Intermediate 7 Benzyl N-{(1S)-1-(4,4-difluorocyclohexyl)-2-[methoxy(methyl)amino]-2-oxoethyl}-carbamate To a stirred solution of (2S)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (9.00 g, 27.5 mmol) and N-methoxymethanamine hydrochloride (3.22 g, 33.0 mmol) in DCM (90 mL) was added HATU (12.55 g, 33.0 mmol) in portions at ambient temperature, followed by dropwise addition of DIPEA (12 mL, 68.7 mmol). The reaction mixture was stirred at ambient temperature for 45 min. Saturated aqueous sodium carbonate (50 mL) and water (50 mL) were added to the reaction mixture and stirring was continued for 5 min. The organic phase was collected and the aqueous phase was back extracted with DCM (100 mL). The organic layers were combined and washed with brine (100 mL) then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by automated chromatography (350 g SFAR-duo column) eluting with a gradient of TBME (5-70%) in heptane to give the title compound (10.01 g, 92%) as a clear gum.

number

[0328] Intermediate 8 Benzyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate To a stirred solution of intermediate 7 (10.0 g, 25.4 mmol) in anhydrous THF (132 mL) pre-cooled to -20°C was added dropwise 3M methylmagnesium bromide in diethyl ether (25 mL, 76.1 mmol), maintaining the temperature below -10°C. The reaction mixture was stirred for 4.5 h, allowing the temperature to rise gently to ambient temperature. The reaction mixture was cooled to 0°C and added dropwise to ice-cold saturated aqueous ammonium chloride solution (300 mL). Stirring was continued at 0°C for a further 5 min, then the reaction mixture was extracted with ethyl acetate (2 x 200 mL). The organic layers were combined, washed with brine (140 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the title compound (7.98 g, 95%) as an off-white solid.

number

[0329] Intermediate 9 Benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate To a stirred solution of intermediate 8 (1.18 g, 3.63 mmol) in chloroform (12 mL) cooled to 0 °C was added bromine (0.2 mL, 3.63 mmol) dropwise over 5 min. The reaction mixture was stirred at ambient temperature for 3 h and then the solvent was removed in vacuo. The residue was partitioned between water (5 mL) and ethyl acetate (10 mL). The organic layer was further washed with saturated aqueous sodium carbonate (5 mL) and brine (5 mL) then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography (Isolera 4, 50 g SFAR Duo column) eluting with a gradient of TBME (5-50%) in heptane to give the title compound (0.35 g, 24%) as an off-white solid.

number

[0330] Intermediate 10 Benzyl N-[(S)-(7-bromo-8-fluoroimidazo[1,2- a ]pyridin-2-yl)(4,4-difluorocyclohexyl)methyl]carbamate A suspension of 4-bromo-3-fluoropyridin-2-amine (520 mg, 2.72 mmol) and intermediate 9 (912 mg, 2.26 mmol) in IPA (9 mL) was sealed under nitrogen and heated at 80 °C for 24 h. After cooling, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, and concentrated in vacuo. The resulting crude brown viscous oil (1.54 g) was purified by FCC (100 g Biotage Isolera Sfar Duo column) eluting with 0-50% EtOAc in heptane to give the title compound (632 mg, 57%) as a tan powder.

number

[0331] Intermediate 11 tert-Butyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-8-fluoroimidazo[1,2- a ]pyridin-7-yl}acetate To a solution of intermediate 10 (90%, 100 mg, 0.18 mmol) in anhydrous THF (1.8 mL) was added allylpalladium(II) chloride (3.3 mg, 9.02 μmol) and XPhos (8.6 mg, 0.018 mmol). The mixture was sonicated and purged with nitrogen for 5 min. tert-Butyl 2-(bromodincio)acetate (0.5 M in THF, 1.1 mL, 0.55 mmol) was added. The mixture was sonicated and purged with nitrogen for 5 min. The reaction mixture was sealed under nitrogen and heated at 50° C. for 3 h, then stirred at rt overnight. Additional allylpalladium(II) chloride (3.3 mg, 9.02 μmol) and XPhos (8.6 mg, 0.018 mmol) were added, followed by tert-butyl 2-(bromodincio)acetate (0.5 M in THF, 2.2 mL, 1.10 mmol) and the mixture was sealed under nitrogen and heated at 50° C. for an additional 18 h. After cooling to rt, the mixture was quenched with saturated aqueous ammonium chloride (20 mL) and partitioned with ethyl acetate (20 mL). The mixture was filtered through a Celite® pad and washed with ethyl acetate (2×10 mL). The biphasic filtrate was separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo. The resulting crude brown powder (137 mg) was purified by FCC (25 g Biotage Isolera Sfar Duo column) eluting with 10-100% EtOAc in heptane to afford the title compound (56 mg, 48%) as an off-white wax.

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[0332] Intermediate 12 tert-Butyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-8-fluoroimidazo[1,2- a ]pyridin-7-yl]-4,4-difluorobutanoate A solution of lithium diisopropylamide (2.0 M in THF / heptane / ethylbenzene, 0.62 mL, 1.24 mmol) was added dropwise to a stirred solution of intermediate 11 (93%, 281 mg, 0.49 mmol) in anhydrous THF (10 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 1 h. 2,2-Difluoroethyl trifluoromethanesulfonate (0.1 mL, 0.75 mmol) was added dropwise and stirring was continued at −78° C. under nitrogen for 1.5 h. The reaction mixture was quenched at −78° C. by adding saturated aqueous ammonium chloride solution (10 mL). The mixture was allowed to warm to rt, then diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, and concentrated in vacuo. The resulting crude brown viscous oil (380 mg) was purified by FCC (25 g, Biotage Isolera Sfar HC Duo column) eluting with 10-60% EtOAc in heptane to afford the title compound (174 mg, 56%) as a tan viscous oil.

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[0333] Intermediate 13 tert-Butyl 2-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]-8-fluoroimidazo[1,2- a ]-Pyridin-7-yl}-4,4-difluorobutanoate A suspension of intermediate 12 (93%, 174 mg, 0.27 mmol) and 10% palladium on carbon (50% water wet) (40 mg, 0.019 mmol) in ethanol-water (9:1, 4 mL) was placed under a hydrogen atmosphere and stirred at 20° C. for 20 h. The flask was evacuated and backfilled with nitrogen three times, then the solids were removed by filtration through a Celite® pad and washed with ethanol (4×20 mL). The filtrate was concentrated in vacuo to give the title compound (1:1 mixture of diastereoisomers) (132 mg, 98%) as a brown viscous oil which was used without further purification.

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[0334] Intermediate 14 tert-Butyl 2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-ethyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-8-fluoroimidazo[1,2- a ]pyridin-7-yl)-4,4-difluorobutanoate DIPEA (125 μL, 0.72 mmol) was added to a stirred solution of 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (49 mg, 0.34 mmol) and HATU (141 mg, 0.37 mmol) in DCM (1.5 mL) at 20° C. The mixture was stirred under nitrogen at 20° C. for 10 min. The resulting orange solution was added to a stirred solution of intermediate 13 (93%, 132 mg, 0.27 mmol) in DCM (1.5 mL) at 20° C. The mixture was stirred under nitrogen for 20 h, then quenched with saturated aqueous sodium carbonate (5 mL), extracted with DCM (4×5 mL) using a hydrophobic frit and the phases separated. The organic filtrate was concentrated in vacuo. The resulting crude orange viscous oil (234 mg) was separated by FCC (25 g Biotage isolera Sfar Duo column, eluent: 0-60% ethyl acetate in heptane) to afford the title compound (1:1 mixture of diastereoisomers) (118 mg, 68%) as an orange powder which was used without further purification.

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[0335] Intermediate 15 2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-ethyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}-8-fluoroimidazo[1,2- a ]pyridin-7-yl)-4,4-difluorobutanoic acid Trifluoroacetic acid (0.54 mL, 7.27 mmol) was added to a stirred solution of Intermediate 14 (90%, 118 mg, 0.18 mmol) in DCM (2 mL). The mixture was stirred at 20° C. for 20 h then concentrated in vacuo. The residue was azeotroped with DCM (3×10 mL) and chloroform (1×5 mL) then dried under high vacuum at 40° C. for 2 h to afford the title compound (TFA salt) (1:1 mixture of diastereoisomers) (118 mg, 91%) as a tan powder which was used without further purification.

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[0336] (Example 1) [ka] tert-Butyl 3-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{(4-trans-methylcyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2- a ]pyridin-7-yl)-2,5-dihydropyrrole-1-carboxylate Intermediate 6 (316 mg, 0.615 mmol) was dissolved in DCM (20 mL) then DIPEA (0.15 mL, 2.15 mmol), HATU (214 mg, 0.738 mmol) and 3,3-difluoroazetidine hydrochloride (72 mg, 0.738 mmol) were added. The mixture was stirred at ambient temperature for 1 h then diluted with DCM (50 mL) and brine (25 mL). The organic layer was separated using a hydrophobic PTFE frit and then concentrated in vacuo. The crude material was purified by flash column chromatography eluting with EtOAc (0-100%) in isohexane. The residue was further purified by preparative HPLC (Method 3) to give the title compound (5 mg, 2%) as a white solid.

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[0337] (Example 2) [ka] N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-8-fluoroimidazo[1,2- a ]pyridin-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide A solution of intermediate 15 (117 mg, 0.18 mmol) in DMA (1.2 mL) was added dropwise to a stirred solution of 2,2,2-trifluoroethylamine (25.7 μL, 0.33 mmol), 2-chloro-1-methylpyridinium iodide (60.3 mg, 0.24 mmol) and DIPEA (158 μL, 0.91 mmol) in DMA (1.2 mL). The mixture was heated at 40° C. for 40 min in a sealed vial. After cooling, the mixture was partitioned between brine (5 mL), water (20 mL) and ethyl acetate (30 mL). The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (2×20 mL), dried over magnesium sulfate and concentrated in vacuo. The resulting crude brown viscous oil (118 mg) was separated by low pH preparative HPLC (formic acid-water-acetonitrile) to give, after freeze-drying, the title compound (1:1 mixture of diastereoisomers) (57 mg, 51%) as an off-white powder.

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Claims

1. A compound of formula (I-1), or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 (In the formula, Z is -CH(R ５ )N(H)C(O)R ６ represents R １ represents hydrogen or halogen; R ２ is C １～６ Alkyl or C ３～７ heterocycloalkenyl, any of which may be optionally substituted by one or more substituents; R ３ represents hydrogen, R ４ represents hydrogen, R ５ is C ３～９ represents a cycloalkyl, which may be optionally substituted by one or more substituents; R ６ represents heteroaryl, which may be optionally substituted by one or more substituents.

2. R ６ 2. The compound of claim 1, wherein represents oxadiazolyl, which may be optionally substituted by one or more substituents.

3. C １～６ one, two or three substituents independently selected from alkyl, R ６ The compound of claim 1 or 2, wherein is optionally substituted.

4. 2. The compound of claim 1 represented by formula (IIA): or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 2】 (In the formula, R １１ represents hydrogen or halogen; R １６ represents methyl or ethyl; R ２ and R ５ is as defined in claim 1).

5. R １１ 5. The compound of claim 4, wherein represents fluoro.

6. Halogen, C ２～６ the group R ２ The compound of any one of claims 1 to 5, wherein is optionally substituted.

7. R ５ A compound according to any one of claims 1 to 6, wherein represents cyclohexyl, which may be optionally substituted by one or more substituents.

8. Halogen and C １～６ one, two or three substituents independently selected from alkyl, R ５ The compound of any one of claims 1 to 7, wherein is optionally substituted.

9. The compound of claim 1 selected from the following: tert-butyl 3-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{(4-trans-methylcyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-a]pyridin-7-yl)-2,5-dihydropyrrole-1-carboxylate; and N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-8-fluoroimidazo[1,2-a]pyridin-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide.

10. A composition for use in therapy comprising a compound of formula (I-1) according to claim 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof.

11. A composition for use in the treatment and / or prevention of disorders in which administration of a regulator of IL-17 function is indicated, comprising a compound of formula (I-1) according to claim 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof.

12. A composition comprising a compound of formula (I-1) according to claim 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, for use in the treatment and / or prevention of inflammation or autoimmune disorders.

13. The composition of any one of claims 10 to 12, further comprising an additional pharma- ceutical active ingredient.

14. A pharmaceutical composition comprising a compound of formula (I-1) according to claim 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier.

15. 15. The pharmaceutical composition of claim 14 further comprising an additional pharma- ceutical active ingredient.

16. Use of a compound of formula (I-1) according to claim 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of a disorder in which administration of a regulator of IL-17 function is indicated.

17. 2. Use of a compound of formula (I-1) according to claim 1, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating and / or preventing an inflammatory or autoimmune disorder.

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