Tricyclic compounds useful as neurogenic and neuroprotective agents

摘要

The invention disclosed herein is direct to compounds of Formula I and pharmaceutically acceptable salts thereof, which are useful in treating neurodegenerative diseases and promoting the generation or survival of neurons in the mammalian brain. The invention also comprises pharmaceutical compositions comprising a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt thereof. The invention disclosed herein is also directed to a method of promoting the generation or survival of neurons in a patient in need thereof in neurodegenerative and related diseases.;

主权项

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: A1 and A2 are each independently phenyl or a 6 membered heteroaromatic ring having 1, 2 or 3 N atoms in the heteroaromatic ring; Z is selected from the group consisting of S and S(O)2; R is selected from the group consisting of (a) CF3, (b) C1-6alkyl, (c) —S(O)2C1-4alkyl, (d) —C(O)C1-4alkyl, (e) C3-6cycloalkyl, (f) —C(O)C3-6cycloalkyl, (g) —S(O)2C3-6cycloalkyl, (h) —C(O)2C1-4alkyl, (i) —C(O)2C3-6cycloalkyl, (j) aryl, and (k) heteroaryl, wherein the alkyl portion of choices (b), (c), (d) and (h) and the cycloalkyl portion of choices (e), (f), (g) and (i) is optionally substituted with halo, and wherein the aryl of choice (j) and the heteroaryl of choice (k) are each optionally mono or di-substituted with substituents selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, halo C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C1-6alkyl), —NH(C3-6cycloalkyl), —N(C1-6alkyl)2, —N(C3-6cycloalkyl)2, —S(O)nC1-6alkyl, —S(O)nC3-6cycloalkyl and CN; R1, R2, R3 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) CN, (d) CF3, (e) C1-6alkyl, (f) C1-6alkoxy, (g) —S(O)nC1-6alkyl, (h) —NH(C1-6alkyl), (i) —N(C1-6alkyl)2, (j) —NHC(O)(C1-6alkyl), (k) —NHS(O)2C1-6alkyl, (l) —NHS(O)2aryl, (m) —C3-6cycloalkyl, (n) —C3-6cycloalkoxy, (o) —S(O)nC3-6cycloalkyl, (p) —NH(C3-6cycloalkyl), (q) —N(C3-6cycloalkyl)2, (r) —NHS(O)2C3-6cycloalkyl, (s) —C(O)C3-6cycloalkyl, (t) —C(O)C1-6alkyl, (u) aryl, (v) heteroaryl, (w) —S(O)nNR12R13, and (x) —C(O)NR12R13, wherein the alkyl portion of choices (e), (f), (g), (h), (i), (j), (k) and (t) and the cycloalkyl portion of choices (m), (o), (p), (q), (r) and (s) is optionally substituted with halo, and wherein aryl choice (u) and heteroaryl of choice (v) are each optionally mono or di-substituted with substituents selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, halo C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C1-6alkyl), NH(C3-6cycloalkyl), —N(C1-6alkyl)2, —N(C3-6cycloalkyl)2, —S(O)nC1-6alkyl, —S(O)nC3-6cycloalkyl and CN; R5 is selected from the group consisting of: (a) hydrogen, (b) F, (c) C1-6alkyl, and (d) C3-6cycloalkyl; R6 is selected from the group consisting of: (a) hydrogen, (b) F, (c) hydroxyl, (d) —C1-6alkyl, (e) —S(O)nC1-6alkyl, (f) —C(O)C1-6alkyl, (g) —OC1-6alkyl, (h) —NH2, (i) —NH(C1-6alkyl), (j) —N(C1-6alkyl)2, (k) C3-6cycloalkyl, (l) —C(O)C3-6cycloalkyl, (m) —S(O)nC3-6cycloalkyl, (n) —OC3-6cycloalkyl, (o) —NH(C3-6cycloalkyl), and (p) —N(C3-6cycloalkyl)2, or R5 and R6 together with the carbon to which they are attached forms a C3-6cycloalkyl, or an optionally mono-substituted 4, 5 or 6 membered saturated or partially unsaturated heterocycloalkyl ring having 1 or 2 heteroatoms selected from N, S(O)n and O, wherein the substituent is selected from halogen, hydroxyl, nitro, oxo, C1-6alkyl, C1-6cycloalkyl, haloC1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C3-6cycloalkyl), —N(C3-6cycloalkyl)2, —S(O)nC1-6alkyl, —S(O)nC3-6cycloalkyl, aryl, heteroaryl, CN, —NHS(O)nC1-6alkyl, —NHS(O)naryl, —N(R12)(S(O)n)C1-6alkylaryl and —C(O)2NR12R13; the group R9 is hydrogen; and R10 is selected from halogen, hydroxyl, nitro, —C1-6alkylaryl, C1-6alkoxy, haloC1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NR12R13, —NCONR12R13, —NH(C3-6cycloalkyl), —N(C1-6alkyl)2, —N(C3-6cycloalkyl)2, —S(O)nC1-6alkyl, —S(O)nC3-6cycloalkyl, aryl, heteroaryl, CN, aryloxy, —NHS(O)nC1-6alkyl, —NHS(O)2aryl, —N(R12)(S(O)n)alkylaryl, —CONR12R13 and hydroxyC1-6alkyl, wherein said aryl is optionally mono-substituted with halogen, nitro, C1-6alkyl, C1-6alkoxy, halo C1-6alkyl, C3-6cycloalkyl, or C3-6cycloalkoxy; or R9 and R10 are joined together with the atoms connecting R9 and R10 to form a C3-6cycloalkyl, or a 4, 5 or 6 membered saturated or unsaturated monocyclic heterocyclic ring or a 6 to 12 membered saturated or unsaturated bicyclic heterocylic ring, said monocyclic or bicyclic ring having 1 or 2 heteroatoms selected from N, S(O)n and O, and said C3-6cycloalkyl, monocyclic or bicyclic heterocyclic ring is optionally mono or di-substituted with substituents that are independently selected from the group consisting of: (a) halogen, (b) hydroxyl, (c) nitro, (d) oxo, (e) C1-6alkyl, optionally mono, di- or tri-substituted with halogen, (f) C1-6alkoxy, (g) C3-6cycloalkyl, (h) C3-6cycloalkoxy, (i) —NR12R13, (j) —NH(C3-6cycloalkyl), (l) —N(C3-6cycloalkyl)2, (m) —S(O)nC1-6alkyl, (n) —S(O)nC3-6cycloalkyl, (o) —S(O)naryl, (p) —S(O)nheteroaryl, (q) aryl, (r) heteroaryl, (s) CN, (t) —NHS(O)nC1-6alkyl, (u) —NHS(O)naryl, (v) —N(R12)(S(O)n)C1-6alkylaryl, (w) —N(R12)C(O)R13, (x) —N(R12)C(O)OR13, (y) —N(R14)C(O)NR12R13, (z) —C(O)NR12R13, (aa) —C(O)R12, (bb) —C(O)OR12, (cc) —C1-6alkylaryl, and (dd) —C1-6alkylheteroaryl; wherein the alkyl of choices (e), (f), (m), (t), (v), (cc) and (dd) are each optionally mono- or di-substituted with substituents selected from halo, CF3, hydroxyl, C1-6alkoxy, —NHC1-6alkyl and —N(C1-6alkyl)2, and the aryl of choices (o), (q), (u), (v) and (cc) and the heteroaryl of choices (p), (r) and (dd) are each optionally mono or di-substituted with substituents selected halogen, hydroxyl, nitro, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NR12R13, —NH(C3-6cycloalkyl), —N(C3-6cycloalkyl)2, —S(O)nC1-6alkyl, —S(O)nC3-6cycloalkyl, aryl, heteroaryl, and CN; R11 is selected from (a) hydrogen, (b) F, (c) hydroxyl, (d) —C1-4 alkyl, (e) —S(O)nC1-4alkyl, (f) —C(O)C1-4alkyl, (g) —OC1-4alkyl, (h) C3-6cycloalkyl, (i) —S(O)nC3-6cycloalkyl, (j) —OC3-6cycloalkyl, and (k) —C(O)C3-6cycloalkyl R12 and R13 are each independently (a) hydrogen, (b) C1-6alkyl, (c) C3-6cycloalkyl, (d) aryl, (e) heteroaryl, (f) —C1-6alkylphenyl, (g) —C1-6alkylheteroaryl, and (h) —S(O)nphenyl, wherein the alkyl of choices (b), (f) and (g) are each optionally mono, di- or tri-substituted with halo and the aryl of choice (d), the phenyl of choices (f) and (h) and the heteroaryl choices (e) and (g) are each optionally mono or di-substituted with substituents selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, C3-6cycloalkyl, C3-6cycloalkoxy, —NH(C1-3alkyl), NH(C3-6cycloalkyl), —N(C1-3alkyl)2, —N(C3-6cycloalkyl)2, —S(O)nC1-4alkyl, S(O)nC3-6cycloalkyl, aryl, heteroaryl and CN; and R14 is selected from hydrogen, and alkyl optionally mono, di- or tri-substituted with halogen; and n is 0, 1, or 2.