Spiro derivatives as m4 activators / modulators and uses thereof

Abstract

The present disclosure provides compounds of Formula I: (l) (I), or an N- oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein: A, Y, m, n,p, R1, R2, R3, R3a, R4, R5, R6, R7, and Z are as described herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, N-oxides, or salts, and their uses for treating M4-mediated (or M4-associated) disorders including, e.g., Alzheimer's Disease, Parkinson's Disease, schizophrenia (e.g., its cognitive and negative symptoms), pain, addiction, and a sleep disorder.

Description

This disclosure provides compounds of formula I: or their N-oxides, or pharmaceutically acceptable salts of such compounds or N-oxides, wherein: A, Y, m, n, p, R1, R2, R3, R3a, R4, R5, R6, R7, and Z are as described herein; this disclosure provides methods for preparing such compounds, N-oxides, or salts; intermediates for preparing such compounds, N-oxides, or salts; and compositions containing such compounds, N-oxides, or salts, and their use for treating M4-mediated (or M4-related) conditions, including, for example, Alzheimer's disease, Parkinson's disease, schizophrenia (e.g., its cognitive and negative symptoms), pain, addiction, and sleep disorders. Abstract

Claims

What is claimed is:1 . A compound having a structure of Formula (I):or an W-oxide thereof, or a pharmaceutically acceptable salt of the compound or the W-oxide thereof, wherein:A is a 6-8 membered heterocycle comprising 1 or 2 ring nitrogen atoms and is substituted with 0, 1 , 2, or 3 RA; each RAis independently C1-3alkyl, halogen, =0, OH, C1-3hydroxyalkyl, or C1-3haloalkyl;Y is a bond, S, 0, CH2, CHF, CF2, or C(OH)H; m is 1 or 2; n is 1 or 2; p is 1 or 2;R1is H, halogen, ON, OH, N02, -N(R6)(R7), C1-6alkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, Ci. ealkoxy, -[0]o-1-C3-6cycloalkyl, -[0]o-1-Ce-ioaryi, -[0]o-1-4-8 membered heterocycle or -[0]o-1-5-10 membered heteroaryl, wherein the heterocycle and heteroaryl each comprises 1 , 2, or 3 ring heteroatoms selected from N, 0, and S, and when R1is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, -[0]o-1-C3-6cycloalkyl, -[0]o-1-C6-10aryl, -[0]o- 1-4-8 membered heterocycle, -[0]o-1-5-10 membered heteroaryl, -NH-C3-6cycloalkyl, -NH-C6-10aryl, -NH-4-8 membered heterocycle, -NH-5-10 membered heteroaryl, -N(C1-6alkyl)-C3-6cycloalkyl, -N(C1-6alkyl)-C6-10aryl, -N(Ci. ealkyl)-4-8 membered heterocycle, or -N(C1-6alkyl)-5-10 membered heteroaryl, R1is substituted with 0, 1 , 2, or 3 substituents independently selected from halogen, ON, OH, =0, S02, and C1-3alkyl;R2is H, halogen, ON, OH, -N(R6)(R7), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy , C1-6haloalkoxy, C2. eheteroalkyl, Cs ecycloalkyl, or 4-8 membered heterocycle comprising 1 , 2, or 3 ring heteroatoms selected from N, 0, and S;R3is halogen, Co-6alkylene-CN, OH, -N(R6)(R7), C1-6alkyl, C2-6heteroalkyl, C26alkenyl, C2-6alkynyl, C1- ealkoxy, C1-6alkylene-O-C1-6alkyl, C1-6alkylene-NHC(O)C1-6alkyl, C1-6alkylene-C(O)NHC1-6alkyl, Co-6alky lene-Cyc, O-Co-6alkylene-Cyc, NH-Cyc, N(C1-6alkyl)-Cyc, or C(O)Cyc;Cyc is C3-12cycloalkyl, C3-6heterocycloalkyl, C5-12spirocycloalkyl, C5-12heterospirocycloalkyl, C6-10aryl, 4- 12 membered heterocycle, or 5-10 membered heteroaryl, the heterocycle or heteroaryl comprises 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, and Cyc is substituted with 0, 1 , 2, or 3 R3asubstituents; each R3ais independently selected from halogen, ON, OH, =0, =N(C1-6alkyl), S02, C1-6alkyl, C2.ioalkene, C1-6hydroxyalkyl , C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylene-O-C1-6alkyl, Co-6alkylene-C(0)C1-6alkyl, Co-6alkylene-NH2, Co-6alkylene-NH(C1-6alkyl), Co-6alkylene-N(C1-6alkyl)2, -S-C1-6alkyl, Co-6alkylene-S02C1-6alkyl, Co- 6alkylene-C(O)NH2, Co-6alkylene-C(0)NH(C1-6alkyl), Co-6alkylene-C(0)N(C1-6alkyl)2, Co-6alkylene-NHC(0)C1-6alkyl,Co-6alkylene-COOH, Co-6alkylene-C02C1-6alkyl, Co-6alkylene-C3-6cycloalkyl, and Co-6alkylene-3-6 membered heterocycle comprising 1, 2, or 3 heteroatoms selected from N, 0, and S;R4is H, halogen, CN, OH, C1-6alkyl, C1-6-haloalkyl, or C1-6alkoxy;R5is -CO2-Z, or a bioisostere thereof; each R6and R7is independently H, C1-6alkyl, C(0)-C1-6alkyl, spiro or bicyclic Cs-ucycloalkyl, 8-14 membered heterocycle comprising 1 , 2, or 3 ring heteroatoms selected from N, 0, and S, and when R6or R7is other than H, it is substituted with 0, 1 , 2, or 3 substituents independently selected from the group consisting of halogen, CN, =0, SO2, OH, Co-6alkylene-NH2, Co-6alkylene-NH(C1-6alkyl), Co-6alkylene-N(C1-6alkyl)2, Co-6alkylene- SO2C1-6alkyl, C1-6alkyl and C1-6alkoxy, orR6and R7, together with the nitrogen to which they are attached, form a 4-10 membered heterocycle comprising 0-2 additional ring heteroatoms independently selected from N, 0, and S; andZ is Cualkyl, Cuhaloalkyl, C3-6cycloalkyl, or C2-6alkyne, and Z is substituted with 0, 1, 2, or 3 C1-6alkoxy or C3-6cycloalkyl;then R5is not CO2CH2CH3 or CO2CH(CH3)3.

2. The compound or salt of claim 1 , wherein A is3. The compound or salt of claim 2, having a structure of Formula (la), or a pharmaceutically acceptable salt thereof:

4. The compound or salt of any one of claims 1 to 3, wherein Y is CH2, CHF, CF2, or C(OH)H.

5. The compound or salt of claim 4, wherein Y is CH2.

6. The compound or salt of any one of claims 1 to 5, wherein m is 1 .

7. The compound or salt of any one of claims 1 to 6, wherein n is 1 .

8. The compound or salt of any one of claims 1 to 7, wherein p is 1 .

9. The compound or salt of claim 1 , having a structure of Formula (lb):

10. The compound or salt of claim 9, having a structure of Formula (Ic):11 . The compound or salt of claim 9, having a structure of Formula (Id):

12. The compound or salt of claim 1, having a structure of Formula (le), or a pharmaceutically acceptable salt thereof:

13. The compound or salt of any one of claims 1 to 11, wherein R5is a CO2Z bioisostere and is14. The compound or salt of any one of claims 1 to 12, wherein R5is selected from the group consisting of CO2 C2-6alkyl,15. The compound or salt of claim 14, wherein R5is CO2CH2CH3.

16. The compound or salt of any one of claims 1 to 15, wherein R1is H, halogen, CN, OH, -N(R6)(R7), C1-6alkyl, or C1-6alkoxy.

17. The compound or salt of claim 16, wherein R1is H or halogen.

18. The compound or salt of any one of claims 1 to 17, wherein R2is H, halogen, CN, OH, -N(R6)(R7), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy .

19. The compound or salt of claim 18, wherein R2is H, halogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy.

20. The compound or salt of claim 19, wherein R2is H or halogen.21 . The compound or salt of any one of claims 1 to 20, wherein each R6and R7are independentlyH, C1-6alkyl, or C(O)-C1-6alkyl.

22. The compound or salt of claim 21 , wherein each R6and R7are independently H or C1-6alkyl.

23. The compound or salt of any one of claims 1 to 20, wherein at least one R6and R7, together with the nitrogen to which they are attached, form a 4-10 membered heterocycle comprising 0-2 additional ring heteroatoms independently selected from N and O.

24. The compound or salt of any one of claims 1 to 23, wherein R4is H or halogen.

25. The compound or salt of any one of claims 1 to 24, wherein at least one of R1, R2, and R4is halogen.

26. The compound or salt of any one of claims 1 to 25, wherein at least one of R1, R2, and R4is F.

27. The compound or salt of any one of claims 1 to 26, wherein R3is -[C]o-1- C3-6cycloalkyl, -[O]o-1-Ce-ioaryl, -[C]o-1-4-8 membered heterocycle, or -[C]o-1-5-10 membered heteroaryl, and R3is substituted with 0, 1 , 2, or 3 R3a.

28. The compound or salt of claim 27, wherein R3is C3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-8 membered heterocycle, and R3is substituted with 0, 1 , 2, or 3 R3a.

29. The compound or salt of any one of claims 1 to 26, wherein R3is30. The compound or salt of claim 29, wherein R3is31 . The compound or salt of any one of claims 1 to 30, wherein R3is unsubstituted.

32. The compound or salt of any one of claims 1 to 30, wherein R3is substituted with 1 or 2 R3a.

33. The compound or salt of claim 32, wherein R3is substituted with 1 R3a.

34. The compound or salt of any one of claims 1 to 30, 32 and 33, wherein at least one R3ais halogen, CN, OH, =0, SO2, C1-6alkyl, C2-ioalkene, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, Ci. 6alkylene-O-C1-6alkyl, N(C1-6alkyl)2, C1-6alkylene-N(C1-6alkyl)2, -S-C1-6alkyl, NHC(O)C1-6alkyl, C1-6alkylene- NHC(O)C1-6alkyl, or Co-6alkylene-3-6 membered heterocycle comprising 1 , 2, or 3 heteroatoms selected from N, 0, and S.

35. The compound or salt of claim 34, wherein at least one R3ais CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CH2F, CH2CHF2, CH2OH, C(CH3)2OH, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, F, CN, =0, S02, OH, OCH3, OCH2CH3, OCH(CH3)2, OCHF2, CH2OCH3, CH2OCF3, SCH3, N(CH3)2, NHCOCH3, CD3,36. The compound or salt of claim 35, wherein at least one R3ais CH3, CH2CH3, F, CN, OH, OCH3, CF3, CH2OH, or OCHF2.

37. A compound, or pharmaceutically acceptable salt thereof, as recited in Table A.

38. The salt of claim 37, wherein the salt is selected from HOI, HOI ■ H2O, maleate, and maleate' H2O.

39. A pharmaceutical formulation comprising a therapeutically effective amount of the compound or salt of any one of claims 1 to 38, and a pharmaceutically acceptable excipient.

40. A method for treating an M4-mediated (or M4-associated) disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound or salt of any one of claims 1 to 38.41 . The method of claim 40, wherein the M4-mediated (or M4-associated) disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia or psychosis, pain, addiction, a sleep disorder, a cognitive disorder (e.g., mild cognitive impairment), Parkinson's disease, Parkinson's disease- levodopa-induced dyskinesia, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, Trisomy 21 (Down syndrome), cerebral amyloid angiopathy, Alzheimer's disease psychosis, dementia-related psychosis, bipolar, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism, and atherosclerosis42. The method of claim 41 , wherein the M4-mediated (or M4-associated) disease or disorder is selected from the group consisting of Alzheimer's disease, schizophrenia, pain, addiction, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, and sleep disorder.