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1. A method for the treatment of a disease or condition which benefits from inhibition of p38 MAP kinase activity, comprising administering to a subject in need thereof an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: wherein;
W is N or O, wherein N is substituted with hydrogen, C1-C6 alkyl, or C3-C5-cycloalkyl;Y is a group —S(O)P— wherein p is 0, 1, or 2; a group —O(CR3R4)n—; a group —(CR5R6)n—; a group —NR7—; a group —OC(O)—; a group —OC(O)NH—; or a group —OC(O)O—;R3, R4, R5, and R6 are each independently hydrogen, fluorine, or C1-C6 alkyl; or, respectively, R3 and R4, or R5 and R6 may form, together with the carbon atom to which they are attached, a 3-6 membered saturated carbocyclic monocyclic ring optionally substituted with a C1-C6 alkyl group, hydroxyl group, or halogen;n is 0, 1, 2, or 3;R7 is hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl, wherein such C1-C6 alkyl, or C3-C7 cycloalkyl are optionally substituted with a C1-C3 alkyl group, C3-C6 cycloalkyl group, hydroxyl group, cyano group, or halogen;R1 is a group of formula (IIa), (IIb), or (IIc); whereinR8 is —(C1-C6alkylene)-NRARB, —(C3-C7cycloalkylene)-NRARB, —NRARB, —N(RC)—(C2-C6alkylene)-NRARB, —N(RC)—(C3-C7cycloalkylene)-NRARB, or —RC;RA and RB are at each occurrence independently hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl, said C1-C6 alkyl and C3-C7 cycloalkyl being optionally substituted by a C1-C3 alkyl group, C3-C7cycloalkyl group, —ORD, —SRD, —NRERF, —CN, or halo; alternatively, RA and RB may form, together with the nitrogen atom to which they are attached, a 5-11 membered saturated monocyclic or bicyclic ring system in which said 5-11-membered saturated monocyclic or bicyclic ring is optionally substituted by one or more of —ORD, —CN, halo, C1-C6 alkyl, or C3-C7 cycloalkyl, wherein said C1-C6 alkyl and C3-C7 cycloalkyl may be optionally substituted by a C1-C3 alkyl group, C3-C7cycloalkyl group, —ORD, —CN or halo; and wherein, optionally, said 5-11-membered saturated monocyclic or bicyclic ring contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C1-C6 alkyl or C3-C6 cycloalkyl wherein any of said C1-C6 alkyl or C3-C6 cycloalkyl may be optionally substituted by a C1-C6 alkyl group, C3-C7 cycloalkyl group, —ORD, —CN, or halo;RC is at each occurrence independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, said C1-C6 alkyl and C3-C6 cycloalkyl being optionally substituted by a C1-C3 alkyl group, ORD, CN, or halo;RD is at each occurrence independently hydrogen, —CH3, or —C2H5;RE and RF are at each occurrence independently hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl, said C1-C6 alkyl and C3-C7 cycloalkyl being optionally substituted by a C1-C3 alkyl group, C3-C7cycloalkyl group, —ORD, —SRD, —CN or halo; or RE and RF may form, together with the nitrogen atom to which they are attached, a 5-7 membered saturated ring system in which said 5-7-membered saturated ring is optionally substituted by one or more of —ORD, —CN, halo, C1-C6 alkyl, or C3-C7 cycloalkyl, said C1-C6 alkyl and C3-C7 cycloalkyl being optionally substituted by a C1-C3 alkyl group, C3-C7 cycloalkyl group, —ORD, —CN or halo; and wherein, optionally, said 5-7-membered saturated ring contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C1-C6 alkyl or C3-C6 cycloalkyl wherein any of said C1-C6 alkyl or C3-C6 cycloalkyl may be optionally substituted by a C1-C6 alkyl group, C3-C7 cycloalkyl group, —ORD, —CN, or halo;R26 is hydrogen, —CH3, or —C2H5;X1 and X2 are each independently a group —(CH)— or a nitrogen atom;R9 and R10 are independently, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl which is optionally substituted, 5- or 6-membered monocyclic heteroaryl which is optionally substituted, or a group of formula (IIIa) or (IIIb): wherein q is 1 or 2; and R24 and R25 are independently hydrogen or C1-C6 alkyl, or R24 and R25 taken together with the nitrogen to which they are attached form a 6-membered heterocyclic ring optionally containing a further heteroatom selected from N and O;R11, R12, and R13 are independently hydrogen, C1-C6 alkyl, or halogen;A is a divalent cycloalkylene radical having 5, 6 or 7 ring atoms; said cycloalkylene ring being attached to W and Y, and fused to a phenyl ring or to a monocyclic heteroaryl ring having 5 or 6 ring atoms, such phenyl or heteroaryl ring being optionally substituted by one or two groups R27;R27 is at each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, and cyano;R2 is a group of formula (IVa), (IVb) or (IVc): whereinR14 is —F, —CH2OMe, or —CF2CF3;R15 and R16 are independently —CH3 or —C2H5;R17 is lone electron pair, hydrogen, —CF3, —NRE1RF1, —(C3-C7cycloalkyl), —(C3-C7heterocycloalkyl), aryl, or heteroaryl wherein any of such —(C3-C7cycloalkyl), —(C3-C7heterocycloalkyl), aryl, or heteroaryl may be optionally substituted by a group C1-C6 alkyl, C3-C7 cycloalkyl, or halo; orR17 is a group of formula (V): whereinR20 is —F, —CH3, —C2H5, —CH2OH, —CH2OMe, —CF2CF3, —CH2SCH3, —SCH3 or —SC2H5;R21 is —CH3 or —C2H5;orR20 and R21 may form, together with the carbon atom to which they are attached, a 3-7-membered monocyclic ring;RE1 and RF1 are each independently C1-C6 alkyl optionally substituted by a C1-C3 alkyl group, —ORG, —CN, or halo; alternatively, RE1 and RF1 may form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated monocyclic or bicyclic ring system in which said 5-11-membered saturated monocyclic or bicyclic ring is optionally substituted by one or more of —ORG, —CN, halo, C1-C6 alkyl, or C3-C7 cycloalkyl, said C1-C6 alkyl and C3-C7 cycloalkyl being optionally substituted by a C1-C3 alkyl group, C3-C7cycloalkyl group, —ORG, —CN, or halo; and wherein, optionally, said 5-11-membered saturated monocyclic or bicyclic ring contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C1-C6 alkyl or C3-C6 cycloalkyl;RG is independently at each occurrence hydrogen, —CH3, or —C2H5;R18 is lone electron pair, hydrogen, aryl, heteroaryl, —(C1-C6alkyl), —(C3-C7cycloalkyl), —(C3-C7heterocycloalkyl), (C5-C7heterocycloalkyl)-(C1-C6alkyl), or (C5-C7heterocycloalkyl)-(C3-C6 cycloalkyl); wherein any of such aryl, heteroaryl, —(C1-C6alkyl), —(C3-C7cycloalkyl), —(C3-C7heterocycloalkyl), (C5-C7heterocycloalkyl)-(C1-C6alkyl), or (C5-C7heterocycloalkyl)-(C3-C6 cycloalkyl) may be optionally substituted by a —CN, —OH, halo, —COORM, C1-C6alkyl, C3-C6cycloalkyl, —O—(C1-C6alkyl), —O—(C3-C6cycloalkyl), —S—(C1-C6alkyl), —S—(C3-C6cycloalkyl), —NRHRJ, —N(RL)(C2-C6alkylene)-NRHRJ, —N(RL)(C3-C7cycloalkylene)-NRHRJ, —(C1-C6alkylene)-NRHRJ, —(C3-C7cycloalkylene)-NRHRJ, —O—(C2-C6alkylene)-NRHRJ, —O—(C3-C7cycloalkylene)-NRHRJ, —S—(C2-C6alkylene)-NRHRJ, —S—(C3-C7cycloalkylene)-NRHRJ, —N(RL)C(O)—(C1-C6alkylene)-NRHRJ, —N(RL)C(O)—(C3-C7cycloalkylene)-NRHRJ, —C(O)N(RL)—(C2-C6alkylene)-NRHRJ, —C(O)N(RL)—(C3-C7cycloalkylene)-NRHRJ, —C(O)N(RL)—(C2-C6alkylene)-ORM, —C(O)N(RL)—(C3-C7cycloalkylene)-ORM, —N(RL)C(O)N(RHRJ), —C(O)N(RHRJ), —N(RL)C(O)N(RL)—(C2-C6alkylene)-NRHRJ, —N(RL)C(O)N(RL)—(C3-C7cycloalkylene)-NRHRJ, —O—(C2-C6alkylene)-ORM, —O—(C3-C7cycloalkylene)-ORM, —S—(C2-C6alkylene)-ORM, —S—(C3-C7cycloalkylene)-ORM, —N(RL)S(O)2—(C1-C6alkylene)-NRHRJ, —N(RL)S(O)2—(C3-C7cycloalkylene)-NRHRJ, —S(O)2N(RL)—(C2-C6alkylene)-NRHRJ, —S(O)2N(RL)—(C3-C7cycloalkylene)-NRHRJ, —S(O)2N(RL)—(C2-C6alkylene)-ORM, —S(O)2N(RL)—(C3-C7cycloalkylene)-ORM, —N(RL)S(O)2—(C2-C6alkylene)-ORM, —N(RL)S(O)2—(C3-C7cycloalkylene)-ORM, —S(O)2N(RHRJ), —N(RL)S(O)2RL, —N(RL)C(O)RL, ORL, SRL, —(C3-C7heterocycloalkyl), (C5-C7heterocycloalkyl)-(C1-C6 alkyl), and (C5-C7 heterocycloalkyl)-(C3-C6 cycloalkyl); wherein any of said C1-C6alkyl, C3-C6cycloalkyl, —(C2-C6alkylene)-, —(C3-C7cycloalkylene)-, —(C3-C7heterocycloalkyl), (C5-C7heterocycloalkyl)-(C1-C6 alkyl), (C5-C7 heterocycloalkyl)-(C3-C6 cycloalkyl) and (C5-C7heterocycloalkyl)carbonyl portion in the above listed groups may be optionally substituted by a C1-C6 alkyl group, C3-C7 cycloalkyl group, —ORM or halo;RH and RJ are at each occurrence independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, said C1-C6 alkyl or C3-C6 cycloalkyl being optionally substituted by a C1-C3 alkyl group, —ORM, —CN, or halo; alternatively, RH and RJ may form, together with the nitrogen atom to which they are attached, a 5-11 membered saturated monocyclic or bicyclic ring system in which said 5-11-membered saturated monocyclic or bicyclic ring is optionally substituted by one or more of —ORM, —CN, halo, C1-C6 alkyl, or C3-C7 cycloalkyl, said C1-C6 alkyl and C3-C7 cycloalkyl being optionally substituted by a C1-C3 alkyl group, C3-C7 cycloalkyl group, —ORM, —CN, or halo; and wherein, optionally, said 5-11-membered saturated monocyclic or bicyclic ring contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C1-C6 alkyl or C3-C6 cycloalkyl, wherein any of said C1-C6 alkyl or C3-C6 cycloalkyl may be optionally substituted by a C1-C6 alkyl group, C3-C7 cycloalkyl group, —ORM, —CN, or halo; and/or RH and RJ may be linked to one carbon atom of the —(C2-C6alkylene)- or —(C3-C7cycloalkylene)-portion of the group linked to the nitrogen to which they are connected to form a saturated cycle of up to 6 ring atoms;RL is at each occurrence independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, said C1-C6 alkyl or C3-C6 cycloalkyl being optionally substituted by a C1-C3 alkyl group, —ORM, —CN, or halo;RM is at each occurrence independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl, said C1-C4 alkyl or C3-C6 cycloalkyl being optionally substituted by hydroxyl, —CN, or halo;R19 is hydrogen, —CF3, —NRERF, —(C3-C7cycloalkyl), —(C3-C7heterocycloalkyl), aryl, or heteroaryl wherein any of such —(C3-C7cycloalkyl), —(C3-C7heterocycloalkyl), aryl, or heteroaryl may be optionally substituted by a C1-C6 alkyl group, C3-C7 cycloalkyl group, or halo; orR19 is a group of formula (V): wherein R20, R21, RE and RF are as above defined; z1, z2, z3, and z4 are independently selected from the group consisting of C, N, S, O, —CH—, and —NH—, in such a combination that the resulting ring formed is an aromatic system;
T is —N═ or —CR28═;R28 is H, halo, —CH3, or —CN;R22 is H, halo, —CH3, or —CN; with the provisos that:
(1) when z1=—CH—, z2=—C—, z3=—O—, z4=—N—, R18 is an electron lone pair, R17 is a group of formula (V), and R21 is —CH3 or —C2H5;then R20 is —F, —CH2OMe, or —CF2CF3;(2) when z1=—CH—, z2=—C—, z3=—N—, z4=—N—, R17 is a group of formula (V), R21 is —CH3 or —C2H5 and R20 is —CH3, —C2H5; —CH2OH, —CH2SCH3, —SCH3, or —SC2H5, and R18 is a phenyl ring;then:(a) said phenyl ring is substituted by a group which is selected from the group consisting of —CN, —COORM, C3-C6cycloalkyl, —O—(C1-C6alkyl), —O—(C3-C6cycloalkyl), —S—(C1-C6alkyl), —S—(C3-C6cycloalkyl), —NRHRJ, —N(RL)(C2-C6alkylene)-NRHRJ, —N(RL)(C3-C7cycloalkylene)-NRHRJ, —(C3-C7cycloalkylene)-NRHRJ, —O—(C3-C7cycloalkylene)-NRHRJ, —S—(C2-C6alkylene)-NRHRJ, —S—(C3-C7cycloalkylene)-NRHRJ, —N(RL)C(O)—(C1-C6alkylene)-NRHRJ, —N(RL)C(O)—(C3-C7cycloalkylene)-NRHRJ, —C(O)N(RL)—(C2-C6alkylene)-NRHRJ, —C(O)N(RL)—(C3-C7cycloalkylene)-NRHRJ, —C(O)N(RL)—(C2-C6alkylene)-ORM, —C(O)N(RL)—(C3-C7cycloalkylene)-ORM, —N(RL)C(O)NRHRJ, —C(O)NRHRJ, —N(RL)C(O)N(RL)—(C2-C6alkylene)-NRHRJ—N(RL)C(O)N(RL)—(C3-C7cycloalkylene)-NRHRJ, —O—(C2-C6alkylene)-ORM, —O—(C3-C7cycloalkylene)-ORM, —S—(C2-C6alkylene)-ORM, —S—(C3-C7cycloalkylene)-ORM, —N(RL)S(O)2—(C1-C6alkylene)-NRHRJ, —N(RL)S(O)2—(C3-C7cycloalkylene)-NRHRJ, —S(O)2N(RL)—(C2-C6alkylene)-NRHRJ, —S(O)2N(RL)—(C3-C7cycloalkylene)-NRHRJ, —S(O)2N(RL)—(C2-C6alkylene)-ORM, —S(O)2N(RL)—(C3-C7cycloalkylene)-ORM, —N(RL)S(O)2—(C2-C6alkylene)-ORM, —N(RL)S(O)2—(C3-C7cycloalkylene)-ORM, —S(O)2N(RHRJ), —N(RL)S(O)2RL, —N(RL)C(O)RL, SRL, —(C3-C7heterocycloalkyl), (C5-C7heterocycloalkyl)-(C1-C6 alkyl), and (C5-C7 heterocycloalkyl)-(C3-C6 cycloalkyl); wherein any of such C1-C6alkyl, C3-C6cycloalkyl, —(C2-C6alkylene)-, —(C3-C7cycloalkylene)-, —(C3-C7heterocycloalkyl), (C5-C7heterocycloalkyl)-(C1-C6 alkyl), (C5-C7 heterocycloalkyl)-(C3-C6 cycloalkyl), and (C5-C7heterocycloalkyl)carbonyl portion in the above listed groups may be optionally substituted by a C1-C6 alkyl group, C3-C7 cycloalkyl group, —ORM, or halo; or(b) said phenyl ring is substituted by a group which is —(C1-C6alkylene)-NRHRJ or —O—(C2-C6alkylene)-NRHRJ wherein RH and RJ, which are not both hydrogen, are at each occurrence independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, said C1-C6 alkyl or C3-C6 cycloalkyl being substituted by —ORM, —CN or halo; alternatively, RH and RJ may form, together with the nitrogen atom to which they are attached, a 5-11 membered saturated monocyclic or bicyclic ring system in which said 5-11-membered saturated monocyclic or bicyclic ring is substituted by one or more of —ORM, —CN, halo, C1-C6 alkyl, or C3-C7 cycloalkyl, said C1-C6 alkyl and C3-C7 cycloalkyl being optionally substituted by a C1-C3 alkyl group, C3-C7cycloalkyl group, —ORM, —CN, or halo; and wherein, optionally, said 5-11-membered saturated monocyclic or bicyclic ring contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C1-C6 alkyl or C3-C6 cycloalkyl, wherein any of said C1-C6 alkyl or C3-C6 cycloalkyl may be optionally substituted by a C1-C6 alkyl group, C3-C7 cycloalkyl group, —ORM, —CN, or halo; or(c) said phenyl ring is substituted by a group C5-C7heterocycloalkyl)-(C1-C6 alkyl), which is substituted by a C1-C6 alkyl group, C3-C7 cycloalkyl group, —ORM, or halo; or(d) said phenyl ring is substituted by a group —ORL wherein RL is C1-C6 alkyl or C3-C6 cycloalkyl, said C1-C6 alkyl or C3-C6 cycloalkyl being optionally substituted by a C1-C3 alkyl group, —ORM, —CN, or halo; or(e) said phenyl ring is substituted by a group C1-C6 alkyl which is substituted by a C3-C7 cycloalkyl group, ORM, or halo;and(3) when R19 is a morpholine ring and T is —CR28═ or —N═;then R22, if present at position ortho to group T of the aromatic ring, is —CH3 or —CN,and wherein said compound or pharmaceutically acceptable salt thereof is a compound of formula (Ia) in which the carbon stereogenic center on the cycloalkylene portion of ring A which is linked to group W and identified with number (1) herebelow, possesses the absolute configuration herebelow represented: |
