| 主权项 |
1. A compound of the formula (I): wherein n=0 or 1; I. when n=1, Z is R1—X—Ar/Het wherein: Ar/Het is: (i) a 5 membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furanyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, and 1,2,4-triazolyl; or (ii) a bicyclic 8-, 9-, or 10-membered heteroaryl selected from the group consisting of benzofuranyl, benzothienyl, benzothiazolyl, indolyl, indazolyl, quinolonyl, naphtyridinyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, triazolothiazolyl, and triazolooxazolyl; X is: (i) —Y—[C(Ra)2]a-A-[C(Rb)2]b—B—; wherein:
Y is bond, CRc═CRd, O, NRe, or S(O)m;each of A and B is, independently, a bond, 0, NR, or S(O)m;a is 1-3;b is 0-3;m is 0-2;each occurrence of Ra and Rb is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or one or more of the following can apply with respect to Ra and Rb:any two Ra, together with the carbons to which each is attached, together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O), and NRg; in these embodiments, any remaining occurrences of Ra and any occurrence of Rb are each independently defined according to any one or more of the preceding or following definitions pertaining to Ra and Rb; orone Ra and one Rb, together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O), and NRg; in these embodiments, the other Ra, the other Rb, and any other remaining occurrences of Ra and Rb are each independently defined according to any one or more of the preceding or following definitions pertaining to Ra and Rb; orany two Rb, together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the ring atoms is selected from O; S(O), and NRg; in these embodiments, each occurrence of Ra and any other remaining occurrences of Rb are each independently defined according to any one or more of the preceding or following definitions pertaining to Ra and Rb;each of Rc and Rd is, independently, selected from H, F, OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;or Rc and Rd, together with the carbons to which each is attached form a C5-C7 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which from 1-2 of the heterocyclyl ring atoms is/are independently selected from O; S(O), and NRg′;each occurrence of Re, Rf, Rg and Rg′ is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)Rh, C(═O)O(C1-C6 alkyl), C(═O)N(Ri)2, SO2—Rh, wherein Rh is selected from C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Ri is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl (in embodiments, the aryl and heteroaryl portion in Rh and Ri can be optionally substituted, e.g., with one or more independently selected substituents such as F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano);further wherein:(a) when each of A and B is a bond, and b is 0, then X has the following formula: —Y—[C(Ra)2]a—;(b) when b is 0 or 1 (e.g., 0), then A and B cannot both be heteroatoms (i.e., as defined in O, NRe, or S(O)m); and(c) when A or B serves as the point of connection of X to Ar/Het, and the Ar/Het is linked to X via a nitrogen ring atom in Ar/Het, then the A or B connector cannot be a heteroatom (i.e., as defined in O, NRe, or S(O)m); or X is: (ii) direct bond; or (iii) C═O, C(Rj)2—C(═O), or C(═O)—C(Rj)2, SO2—NRk, NRk—SO2, C(═O)NRk and NRk—C(═O); wherein:
each occurrence of Rj is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;or Rj—C—Rj together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O), and NRj′;each occurrence of Rj′ and Rk is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)Rm, C(═O)O(C1-C6 alkyl), C(═O)N(Rn)2, and SO2—Rm, wherein Rm is selected from C1-C6 alkyl, CH2-heteroaryl, CH2-aryl, and aryl; and each occurrence of Rn is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl (in embodiments, the aryl and heteroaryl portion in Rm and Rn can be optionally substituted, e.g., with one or more independently selected substituents such as F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano); each of R4 and R5 is, independently, selected from H, C1-C6 alkyl and F; R1 is: (i) hydrogen; or (ii) C6-C10 aryl, which is optionally substituted with from 1-3 Ro; or (iii) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 Ro; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—Ro, and S; or (iv) heterocyclyl including from 4-10 ring atoms, which is optionally substituted with from 1-3 Ro; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—Ro, and S; and each occurrence of Ro is independently selected from the group consisting of (beginning with halogen and through and including nitro below):
halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl;hydroxy(C1-C4)alkyl;C1-C6 alkoxy; fluoro(C1-C6)alkoxy;(C1-C6 alkyl)C(O)—;(C1-C6 alkyl)NH—; (C1-C6 alkyl)2N— (which includes, e.g., —NMe2, —NMe(iPr));—N*(Ro′)2, wherein Ro′—N*—Ro′ together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms (i.e., 1 or 2 ring atoms in addition to the N* ring atom) is/are optionally a heteroatom independently selected from NH, N(alkyl), 0, or S (—N*(Ro′)2 includes cyclic amino such as, e.g., pyrrolidinyl and morpholinyl);formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl;benzyl; benzyloxy;(heterocyclyl)-(C0-C6, e.g., C1-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present (i.e., C1-C6), said alkyl portion serves as the point of attachment to R1 (i.e., the (heterocyclyl)-(C1-C6) alkyl is connected to R1 via the alkyl portion); otherwise in the case of C0 alkyl (i.e., no alkyl portion is present), a heterocyclyl carbon ring atom serves as the point of attachment of the heterocyclyl to R1;phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—Ro″, and S, each of which is optionally substituted with from 1-3 Ro″;SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; andnitro; each occurrence of Ro″ is independently selected from the group consisting of (beginning with halogen and through and including nitro below):
halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl;hydroxy(C1-C4)alkyl;C1-C6 alkoxy; fluoro(C1-C6)alkoxy;(C1-C6 alkyl)C(O)—;(C1-C6 alkyl)NH—; (C1-C6 alkyl)2N— (which includes, e.g., —NMe2, —NMe(iPr));-formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl;benzyl; benzyloxy;heterocyclyl)-(C0-C6, e.g., C1-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present (i.e., C1-C6), said alkyl portion serves as the point of attachment to R1 (i.e., the (heterocyclyl)-(C1-C6) alkyl is connected to R1 via the alkyl portion); otherwise in the case of C0 alkyl (i.e., no alkyl portion is present), a heterocyclyl carbon ring atom serves as the point of attachment of the heterocyclyl to R1;phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—(C1-C6 alkyl), and S;SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; andnitro; II. when n=0, Z is Ri—V-Cy-U—Ar′/Het′ wherein: Ar′/Het′ is: (i) phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with from 1-3 Rp; provided that the point of connection on said phenyl, pyridyl, or pyrimidinyl to U (i.e., the connection U—Ar′/Het′ in formula I) and the point of connection on said phenyl, pyridyl, or pyrimidinyl to the amide carbonyl (i.e., the connection Ar′/Het′-C(═O) in formula I) do not result in 1,2-relation to one another on said phenyl, pyridyl, or pyrimidinyl (i.e., the points of connection to U and C(O) on said phenyl, pyridyl, or pyrimidinyl are not ortho with respect to one another); wherein Rp at each occurrence is, independently, selected from H, F, chloro, CH3, CF3, OCH3, OCF3, and OCHF2; (ii) a 5-membered heteroaryl selected from pyrazolyl, pyrrolyl, thiazolyl, thienyl, furanyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, each of which is optionally substituted with from 1-3 Rp; provided that the point of connection on said 5-membered heteroaryls to U (i.e., the connection U—Ar′/Het′ in formula I) and the point of connection on said 5-membered heteroaryls to the amide carbonyl (i.e., the connection Ar′/Het′-C(═O) in formula I) do not result in 1,2-relation to one another on said 5-membered heteroaryls (i.e., the points of connection to U and C(O) on said 5-membered heteroaryl are not adjacent to one another); (iii) a 8-, 9- or 10-membered bicyclic heteroaryl selected from benzothienyl, benzofuranyl, benzothioazolyl, benzoxazolyl, indolyl, isoindolonyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, quinolinyl, and naphthyridinyl; each of which is optionally substituted with from 1-3 Rp; R1 is: (i) hydrogen; or (ii) C6-C10 aryl, which is optionally substituted with from 1-3 Rq; or (iii) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 Rq; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—Rq, and S; or (iv) heterocyclyl including from 4-10 ring atoms, which is optionally substituted with from 1-3 Rq; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—Rq, and S; and each occurrence of Rq is independently selected from the group consisting of (beginning with halogen and through and including nitro below):
halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl;hydroxy(C1-C4)alkyl;C1-C6 alkoxy; fluoro(C1-C6)alkoxy;(C1-C6 alkyl)C(O)—;(C1-C6 alkyl)NH—; (C1-C6 alkyl)2N— (which includes, e.g., —NMe2, —NMe(iPr));—N*(Rq′)2, wherein Rq′—N*—Rq′ together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms (i.e., 1 or 2 ring atoms in addition to the N* ring atom) is/are optionally a heteroatom independently selected from NH, N(alkyl), O, or S (—N*(Rq′)2 includes cyclic amino such as, e.g., pyrrolidinyl and morpholinyl);formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl;benzyl; benzyloxy;heterocyclyl)-(C0-C6, e.g., C1-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present (i.e., C1-C6), said alkyl portion serves as the point of attachment to R1 (i.e., the (heterocyclyl)-(C1-C6) alkyl is connected to R1 via the alkyl portion); otherwise in the case of C0 alkyl (i.e., no alkyl portion is present), a heterocyclyl carbon ring atom serves as the point of attachment of the heterocyclyl to R1;phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—Rq″, and S, each of which is optionally substituted with from 1-3 Rq″;SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; andnitro; each occurrence of Rq″ is independently selected from the group consisting of (beginning with halogen and through and including nitro below):
halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl;hydroxy(C1-C4)alkyl;C1-C6 alkoxy; fluoro(C1-C6)alkoxy;(C1-C6 alkyl)C(O)—;(C1-C6 alkyl)NH—; (C1-C6 alkyl)2N— (which includes, e.g., —NMe2, —NMe(iPr));-formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl;benzyl; benzyloxy;heterocyclyl)-(C0-C6, e.g., C1-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom independently selected from NH, N(alkyl), O, or S, and when said alkyl portion is present (i.e., C1-C6), said alkyl portion serves as the point of attachment to R1 (i.e., the (heterocyclyl)-(C1-C6) alkyl is connected to R1 via the alkyl portion); otherwise in the case of C0 alkyl (i.e., no alkyl portion is present), a heterocyclyl carbon ring atom serves as the point of attachment of the heterocyclyl to R1;phenyl or heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—(C1-C6 alkyl), and S;SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; andnitro; U is selected from: (i) ═CRr (for purposes of clarification, in these embodiments, the carbon atom in ═CRr is doubly bonded to a ring atom (e.g., ring carbon atom) of Cy, thereby forming an exocyclic double bond, see, e.g., compounds F1-F7); or (ii) —U′—C(Rs)2— or —C(Rs)2—U′—; wherein:
Rr is hydrogen, F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;each occurrence of Rs is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano; orRs—C—Rs together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m (m=0-2) and NRu;each occurrence of Ru is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)Rv, C(═O)O(C1-C6 alkyl), C(═O)N(Rw)2, SO2—Rv, wherein Rv is selected from C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Rw is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl (e.g., in embodiments, the aryl and heteroaryl portion in Rv and Rw can be optionally substituted, e.g., with one or more independently selected substituents such as F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano);U′ is a bond; O; NRu; S(O)m (m=0-2); CH2; and U″—CH2—; wherein U″ is O; NRu; S(O)m (m=0-2); Cy is C4-C10 (e.g., C4-C8, C4-C6) cycloalkyl or saturated heterocyclyl including 4-10 (e.g., 4-8, 4-6) ring atoms, each of which is optionally substituted with from 1-3 Rx (wherein each occurrence of Rx is independently selected from F, OH, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano), in which from 1-3 heteroatoms are independently selected from O, N—H, NRx′ (wherein Rx′ is defined as Rq″), and S(O)m (m=0-2); wherein when the heterocyclyl contains a secondary amine as part of its structure, then: (i) V is linked through the nitrogen of the secondary amine portion of the heterocyclyl; and (ii) U is linked to Cy via a Cy ring carbon atom; wherein the bond between U and the Cy ring carbon is a single or double bond; and (iii) V-Cy and Cy-U do no lead to 1,2 relationship (i.e. the Cy ring carbon atom that is attached to U is not adjacent to Cy ring nitrogen atom that is attached to V); V is selected from:
(i) —V′—C(Ry)2— or —C(Ry)2—V′—; or(ii) O, NRz, or S(O)m (m=0-2); or(iii) —CH═CH—, C═O, C(Ry)2—C(═O), —C(═O)—C(Ry)2—, —SO2NRz, NRzSO2, —C(═O)NRz, and NRzC(═O); wherein:each occurrence of Ry is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano; orRy—C—Ry together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m (m=0-2) and NRaa;each occurrence of Rz and Raa is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)Rv, C(═O)O(C1-C6 alkyl), C(═O)N(Rw)2, SO2—Rv, wherein Rv is selected from C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Rw is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; V′ is a bond; 0; NW; S(O)n, (m=0-2); —C(O)—O—(CRy2)0-2—, —(CRy2)0-2—O—C(O)—, C(Ry)2, C(Ry)2—C(Ry)2; —(Ry)2—V″; and V″—C(Ry)2—; wherein V″ is O; NRz; S(O)m (m=0-2); wherein each occurrence of Ry is independently defined as above; R2 is selected from H, F, Cl, CF3, CF2CF3, CH2CF3, OCF3, OCHF2, phenyl; substituted phenyl (e.g., phenyl substituted with from 1-3 substituents independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6) alkyl C3-C6 cycloalkyl, NH2, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano); thienyl; thiazolyl; and pyrazol-1-yl; and R3 is H, F, or Cl; or a pharmaceutically acceptable salt thereof. |
