Prokineticin 1 receptor antagonists

A compound of Formula (Ia):

• wherein:
• A1 is hydrogen;
• aryl;
• heteroaryl;
• C5-8cycloalkyl;
• or heterocyclyl provided that A1 is other than piperidin-4-yl, N-t-butoxycarbonyl-piperidin-4-yl, or N-methyl-piperidin-3-yl;
• and wherein substituents of A1 other than hydrogen are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, hydroxy(C1-6)alkyl, C1-6alkoxy, halogen, nitro, halogenated C1-6alkyl, halogenated C1-6alkoxy, C1-6alkylthio, C1-6alkoxycarbonyl, amino, cyano, hydroxy, aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, and C1-6alkylcarbonyl;
• L1 is —(CH2)r— optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and halogen;
• provided that when A1 is hydrogen, r is greater than or equal to 4;
• r is an integer of 1 to 5;
• P is —(CH2)4-6— when A2 is hydrogen;
• and P is —(CH2)1-2— or —CH2CH═CH— when A2 is other than hydrogen;
• A2 is hydrogen, heteroaryl other than unsubstituted pyridin-2-yl, C3-8cycloalkyl, or phenyl optionally substituted at the meta and para positions with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, halogenated C1-6alkyl, halogenated C1-6alkoxy, aryl(C1-6)alkoxy, phenyl, C1-6alkylthio, C1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro, aminocarbonyl, C1-6alkylcarbonylamino, and a non fused C3-6cycloalkyloxy;
• wherein heteroaryl other than unsubstituted pyridin-2-yl and C3-8cycloalkyl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, halogenated C1-6alkyl, halogenated C1-6alkoxy, aryl(C1-6)alkoxy, phenyl, C1-6alkylthio, C1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro, aminocarbonyl, C1-6alkylcarbonylamino, and a non fused C3-6cycloalkyloxy;
• provided that no more than two substituents on A2 are aryl(C1-6)alkoxy, phenyl, or a non fused C3-6cycloalkyloxy;
• provided that when A1 is unsubstituted phenyl and L2 is —X1—CH(Rx)—(CRyRz)— wherein X1 is NH and Rx, Ry, and Rz are each hydrogen, A2 is other than unsubstituted phenyl;
• phenyl substituted with aryl(C1-6)alkoxy or phenyl;
• or phenyl substituted at the meta position with cyano;
• and, further provided that when A1 is unsubstituted phenyl and L2 is —X1—CH(Rx)—(CRyRz)2— wherein X1 is NH and Rx, Ry, and Rz are each hydrogen, A2 is other than phenyl substituted with methoxy;
• and, provided that when A1 is 3,4-dichloro-phenyl and P is —CH2—, A2 is other than phenyl substituted at the meta position with trifluoromethyl or trifl uoromethoxy;
• and, further provided that when A1 is 3,4-dichloro-phenyl and P is —(CH2)2—, A2 is other than 4-methoxy-phenyl;
• W is N or CH;
• L2 is a bivalent radical selected from the group consisting of
• —NH—C5-7cycloalkyl—(CH2)0-2—;
• provided that when C5-7cycloalkyl is cyclohexyl, Q is attached at either the 2- or cis-4-position relative to the position of —NH—;
• —X2—(CH2)0-4—;
• —X1—(CH2)2-3—X3—(CH2)2-3—;
• —NH(CH2)1-4C(═O)— provided that at least one of Rb, Rc, or Rd is other than hydrogen and m is 0;
• —NHC(═O)—(CH2)1-4—;
• —C(═O)NH(CRyRz)2-5;
• and
• —X1—CH(Rx)—(CRyRz)1-5—;
• such that when X1 is a direct bond and W is C(Rw), then Rx of CH(Rx) is hydrogen;
• wherein X1 is —NH—, O, S, or a direct bond;
• such that X1 is other than O when W is N;
• X2 is —CH═CH—;
• X3is O, S, NH, or C═O;
• Rx, Ry, and Rz are independently H or C1-4alkyl;
• and provided that L2 in any instance does not exceed 7 atoms in length;
• and further provided that when L2 is —X2—(CH2)0-4— or —C(═O)NH(CRyRz)2-5—, then RW is hydrogen;
• m is 0 or 1;
• G is —C(═NRb)NRcRd;
• Ra and Rd are independently hydrogen or C1-6alkyl, wherein C1-6alkyl is optionally substituted with one to three substituents independently selected from the group consisting of hydroxy, C1-4alkoxy, fluoro, amino, C1-4alkylamino, diC1-4alkylamino, and C1-4alkylcarbonyl;
• or Ra and Rc are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring optionally substituted with oxo;
• Rb is hydrogen, C1-6alkyl, C2-6alkoxycarbonyl, or cyano;
• or, Rb and Rc are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring optionally substituted with oxo;
• Rc is hydrogen, C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, adamantyl, amino, arylcarbonyl, aryl, heteroaryl, or heterocyclyl;
• wherein C1-10alkyl is optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkoxy, trifluoromethyl, aryl, heteroaryl, and heterocyclyl;
• and wherein any aryl- or heteroaryl-containing substituents of Rc are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, fluorinated C1-6alkyl, fluorinated C1-6alkoxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, nitro, methylthio, hydroxy, and cyano;
• or, Rc and Rd are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring that optionally includes 1 to 2 O or S heteroatoms within the ring, and said ring is optionally substituted with oxo;
• with the proviso that in any instance, only one ring optionally exists between Ra and Rb, Rb and Rc, or Rc and Rd;
• and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

A compound of Formula (Ia)

• wherein:
• A1 is hydrogen;
• aryl, heteroaryl;
• C5-8cycloalkyl;
• or heterocyclyl other than piperidinyl;
• wherein substituents of A1 other than hydrogen are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, hydroxy(C1-6)alkyl, C1-6alkoxy, halogen, nitro, halogenated C1-6alkyl, halogenated C1-6alkoxy, C1-6alkylthio, C1-6alkoxycarbonyl, amino, cyano, hydroxy, aminocarbonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonyl, and C1-6alkylcarbonyl;
• L1 is —(CH2)r— optionally substituted with a substituent selected from the group consisting of C1-4alkyl, C2-4alkenyl, and C2-4alkynyl;
• provided that r is 1 to 3 when A1 is other than hydrogen;
• or r is 4 or 5 when A1 is hydrogen;
• P is —CH2—;
• A2 is heteroaryl other than unsubstituted pyridin-2-yl, a non fused C3-8cycloalkyl, or phenyl optionally substituted at the meta and para positions with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, halogenated C1-6alkyl, halogenated C1-6alkoxy, C1-6alkylthio, C1-6alkoxycarbonyl, amino, hydroxy, nitro, aminocarbonyl, C1-6alkylcarbonylamino, and a non fused C3-6cycloalkyloxy;
• wherein heteroaryl other than unsubstituted pyridin-2-yl and a non fused C3-8cycloalkyl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, halogenated C1-6alkyl, halogenated C1-6alkoxy, C1-6alkylthio, C1-6alkoxycarbonyl, amino, hydroxy, nitro, aminocarbonyl, C1-6alkylcarbonylamino, and a non fused C3-6cycloalkyloxy;
• provided that no more than two substituents on A2 are non fused C3-6cycloalkyloxy;
• provided that when A1 is unsubstituted phenyl and L2 is —X1—CH(Rx)—(CRyRz)— wherein X1 is —NH— or S and Rx, Ry, and Rz are each hydrogen, A2 is other than unsubstituted phenyl;
• and, further provided that when A, is unsubstituted phenyl and L2 is —X1—CH(Rx)—(CRyRz)2— wherein X1 is NH and Rx, Ry, and Rz are each hydrogen, A2 is other than phenyl substituted with methoxy;
• and, further provided that when A1 is 3,4-dichloro-phenyl, A2 is other than phenyl substituted at the meta position with trifluoromethoxy;
• W is N or CH;
• L2 is a bivalent radical selected from the group consisting of
• —NH—C5-6cycloalkyl—(CH2)0-2—;
• provided that when C5-6cycloalkyl is cyclohexyl, Q is attached at either the 2- or cis-4-position relative to the position of —NH—;
• —X1—CH(Rx)—(CRyRz)1-5—, wherein X1 is —NH—, O, or S;
• and Rx, Ry, and Rz are each hydrogen;
• —C(═O)NH(CH2)2—;
• and
• —X1—(R,R—CH(Rx)CRy(Rz))—;
• wherein X1 is —NH—, and Rx and Rz are methyl, and Ry is hydrogen;
• provided that when L2 is —C(═O)NH(CH2)2—, then RW of W is hydrogen;
• m is 0 or 1;
• G is —C(═NRb)NRcRd;
• Ra and Rd are independently hydrogen or C1-3alkyl, wherein C1-3alkyl is optionally substituted with one to three substituents independently selected from the group consisting of hydroxy, C1-4alkoxy, fluoro, amino, C1-4alkylamino, diC1-4alkylamino, and C1-4alkylcarbonyl;
• or Ra and Rc are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring optionally substituted with oxo;
• Rb is hydrogen or C1-4alkyl;
• or, Rb and Rc are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring, optionally substituted with oxo;
• Rc is hydrogen, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, adamantyl, heterocyclyl, arylcarbonyl, phenyl, or heteroaryl;
• wherein C1-6alkyl is optionally substituted with one to two substituents independently selected from the group consisting of C1-3alkoxy, trifluoromethyl, phenyl, heteroaryl, and heterocyclyl;
• and wherein any aryl-, phenyl-, or heteroaryl-containing substituents of Rc are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, fluorinated C1-6alkyl, fluorinated C1-6alkoxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, nitro, methylthio, hydroxy, and cyano;
• or, Rc and Rd are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring and said ring is optionally substituted with oxo;
• with the proviso that in any instance, only one ring optionally exists between Ra and Rb, Rb and Rc, or Rc and Rd;
• and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

A compound of Formula (Ia)

• wherein:
• A1 is substituted phenyl, benzofuranyl, thiazolyl, or thiophenyl;
• wherein phenyl is substituted with, and benzofuranyl, thiazolyl, and thiophenyl are optionally substituted with, one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, halogen, nitro, halogenated C1-4alkyl, halogenated C1-4alkoxy, methylthio, amino, cyano, and C1-4alkylcarbonyl;
• L1 is —(CH2)r— optionally substituted with a substituent selected from the group consisting of methyl and allyl, and r is 1 to 3;
• P is —CH2—;
• A2 is pyridin-3-yl, pyridin-4-yl, or phenyl optionally substituted at the meta and para positions with one to two substituents independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, hydroxy, aminocarbonyl, and methylcarbonylamino;
• wherein pyridin-3-yl and pyridin-4-yl are optionally substituted with one to two substituents independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, hydroxy, aminocarbonyl, and methylcarbonylamino;
• W is N or CH;
• L2 is a bivalent radical selected from the group consisting of
• —NH-cyclohexyl—(CH2)0-2— and Q is attached at either the 2- or cis-4-position relative to the position of —NH—;
• —X1—CH(Rx)—(CRyRz)1-5—;
• wherein X1 is —NH— or S;
• and Rx, Ry, and Rz are each hydrogen;
• and
• —X1—(R,R—CH(Rx)CRy(Rz))—;
• wherein X1 is —NH—, and Rx and Rz are methyl, and Ry is hydrogen;
• m is 0;
• G is —C(═NRb)NRcRd;
• Ra and Rd are independently hydrogen, methyl or ethyl;
• or Ra and Rc are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring optionally substituted with oxo;
• Rb is hydrogen;
• Rc is hydrogen, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, heterocyclyl, phenylcarbonyl, phenyl, or heteroaryl;
• wherein C1-6alkyl is optionally substituted with one to two substituents independently selected from the group consisting of C1-3alkoxy, phenyl, pyridinyl, furanyl, and tetrahydrofuranyl;
• and wherein any phenyl- or heteroaryl-containing substituents of Rc are optionally substituted with one to two substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, chloro, fluoro, bromo, fluorinated C1-3alkoxy, nitro, methylthio, hydroxy, and cyano;
• or, Rc and Rd are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring;
• and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

A compound of Formula (Ia)

• wherein:
• A1 is phenyl or benzofuranyl;
• wherein phenyl is substituted at either the 4-position or 3- and 4-positions with one to two substituents independently selected from the group consisting of ethyl, methoxy, fluoro, chloro, nitro, difluoromethoxy, and methylthio;
• L1 is —CH2— optionally substituted with methyl or allyl;P is —CH2—;
• A2 is phenyl substituted at the para position with a substituent selected from the group consisting of methoxy, ethoxy, isopropyloxy, difluoromethoxy, hydroxy, and aminocarbonyl;
• or A2 is pyridin-3-yl or pyridin-4-yl substituted with methoxy;
• W is N or CH;
• L2 is a bivalent radical selected from the group consisting of
• —NH-cyclohexyl—(CH2)0-2— and Q is attached at either the 2- or cis4-position relative to the position of —NH—;
• —X1—CH(Rx)—(CRyRz)—;
• wherein X1 is —NH— or S;
• and Rx, Ry, and Rz are each hydrogen;
• and
• —X1—(R,R—CH(Rx)CRy(Rz))—;
• wherein X1 is —NH—, and Rx and Rz are methyl, and Ry is hydrogen;
• m is 0;
• G is —C(═NRb)NRcRd;
• Ra and Rd are independently hydrogen, methyl or ethyl;
• Rb is hydrogen;
• Rc is hydrogen, C1-4alkyl, C2-4alkenyl, cyclohexyl, phenylcarbonyl, phenyl, pyrimidinyl, furanyl, benzo[1,3]dioxolyl, or pyridinyl;
• wherein C1-4alkyl is optionally substituted with one to two substituents independently selected from the group consisting of C1-3alkoxy, phenyl, pyridinyl, furanyl, and tetrahydrofuranyl;
• and wherein any phenyl- or heteroaryl-containing substituents of Rc are optionally substituted with one to two substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, chloro, fluoro, bromo, fluorinated C1-3alkoxy, nitro, methylthio, hydroxy, and cyano;
• or, Rc and Rd are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring;
• and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.