Antagonists of muscarinic acetylcholine receptor M4
阅读说明：本技术 毒蕈碱性乙酰胆碱受体m4的拮抗剂 (Antagonists of muscarinic acetylcholine receptor M4 ) 是由 C·W·林斯利 T·M·布里奇斯 P·J·康恩 A·M·本德尔 D·W·*** 于 2018-07-12 设计创作，主要内容包括：本文公开了环丙基哌啶化合物,这些化合物作为毒蕈碱性乙酰胆碱受体M4(niAChR M4)的拮抗剂可能是有用的。本文还公开了制造这些化合物的方法、包含这些化合物的药物组合物、以及使用这些化合物和组合物治疗障碍的方法。(Disclosed herein are cyclopropyl piperidine compounds that may be useful as antagonists of muscarinic acetylcholine receptor M4(niachR M4). Also disclosed herein are methods of making these compounds, pharmaceutical compositions comprising these compounds, and methods of treating disorders using these compounds and compositions.)
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
a is a five or six membered heteroaryl group having 1,2 or 3 heteroatoms independently selected from N, O and S, or a nine to ten membered fused bicyclic heteroaryl ring system having 1-4 nitrogen atoms, wherein A is optionally substituted with 1-4 heteroatoms independently selected from halogen, C1-C4Alkyl and C1-C4Substituted with a substituent of haloalkyl;
q is selected from NRaO, and CRbRc；
R1Selected from hydrogen, halogen, -ORd、-N(Rd)2、C1-C4Alkyl, -CH ═ CH-C1-C4Alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and-CH ═ CH-G;
g is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
R2and R3Independently selected from hydrogen, C1-C4Alkyl, and halogen, or R2And R3Together form an oxo group;
each R4Independently selected from halogen, C1-C4Alkyl, and-ORe；
R5And R6Independently selected from hydrogen, C1-C8Alkyl group, and- (CR)fRg)n-Y1；
Each Y1Independently selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
each Ra、Rb、Rc、Rd、Re、RfAnd RgIndependently selected from hydrogen, C1-C4Alkyl, and aryl;
m is 0, 1 or 2; and
n is 0, 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
a is a five or six membered heteroaryl group having 1,2 or 3 heteroatoms independently selected from N, O and S; and
R1selected from hydrogen, halogen, -ORd、C1-C4Alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
Q is NRa(ii) a And
Rais hydrogen or C1-C4An alkyl group.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
Q is NRa(ii) a And
Rais hydrogen.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R1selected from hydrogen, halogen, -CH ═ CH-C1-C4Alkyl, -CH ═ CH-G, C5-C8Cycloalkenyl, four-to eight-membered monocyclic heterocyclyl, six-to twelve-membered aryl, and five-to six-membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein cycloalkenyl, heterocyclyl, aryl and heteroaryl are unsubstituted or 1,2 or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR' are substituted;
g is a six-to twelve-membered aryl group, which may optionally be substituted with 1,2 or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR' are substituted; and
r' is independently at each occurrence C1-C4An alkyl group.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein
R1Is hydrogen, phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, morpholinyl, cyclopentenyl, or-CH ═ CH-G, wherein the phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, morpholinyl, and cyclopentenyl are unsubstituted or substituted with 1,2, or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyano; and
g is phenyl optionally substituted by 1,2, or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR ', wherein R' is C1-C4An alkyl group.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1Selected from the group consisting of halogen, aryl, and five to six membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy and-NHCOR ', wherein R' is C1-C4An alkyl group.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein
R1Is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyano.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R2Is hydrogen; and
R3is hydrogen.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R2And R3Together form an oxo group.
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
m is 0.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R5Is hydrogen.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R6Is selected from C1-C8Alkyl and- (CR)fRg)n-Y1；
RfIs hydrogen;
Rgselected from hydrogen, C1-C4Alkyl and phenyl;
n is 0 or 1; and
Y1selected from: c3-C10-a cycloalkyl group; c5-C10-a cycloalkenyl group; a phenyl group; a five-to six-membered heteroaryl group having 1,2, or 3 heteroatoms independently selected from N, O and S; and a five to eight membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or 1 or 2 independently selected from C1-C4Alkyl, halogen, and C1-C4Substituted by a substituent of a haloalkyl group.
14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
a is a five-membered heteroaryl group having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from N, O and S, a six-membered heteroaryl group having 1-2 nitrogen atoms, a phthalazinyl group, an imidazo [1,2-b ] group]Pyridazinyl radicals, or [1,2,4]]Triazolo [4,3-b]Pyridazinyl, wherein A is optionally substituted with 1-4 substituents independently selected from halogen, C1-C4Alkyl group, and C1-C4Substituted by a substituent of a haloalkyl group.
15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:
a is thiazole-2, 5-diyl, pyridazine-3, 6-diyl, pyrazine-2, 5-diyl, pyridine-2, 5-diyl, phthalazine-1, 4-diyl, imidazo [1,2-b ]]Pyridazin-6-yl, or [1,2,4]]Triazolo [4,3-b]Pyridazin-6-yl wherein A is optionally substituted with 1-4 substituents independently selected from halogen, C1-C4Alkyl group, and C1-C4Substituted by a substituent of a haloalkyl group.
16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is selected from:
wherein
T is selected from O, S and NH; and
u, V, W, X, Y and Z are independently selected from N and CH, wherein 1-3 of the W, X, Y, and Z are N.
17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is selected from
18. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is
19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ia):
wherein:
w, X, Y, and Z are independently selected from N and CH, wherein 1-3 of W, X, Y, and Z are N.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
W, X, Y, and 1 or 2 of Z are N.
21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ib):
22. the compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
R1Selected from: halogen; an aryl group; and a five-to six-membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy and-NHCOR ', wherein R' is C1-C4An alkyl group.
23. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
R2Is hydrogen; and
R3is hydrogen.
24. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
R2And R3Together form an oxo group.
25. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
R5Is hydrogen.
26. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein
R6Is selected from C1-C8Alkyl and- (CR)fRg)n-Y1；
RfIs hydrogen;
Rgselected from hydrogen, C1-C4Alkyl and phenyl;
n is 0 or 1; and
Y1selected from: c3-C10-a cycloalkyl group; c5-C10-a cycloalkenyl group; a phenyl group; with 1,2 or 3 pieces of radix et rhizoma RheiA five-to six-membered heteroaryl group of heteroatoms selected immediately from N, O and S; and a five to eight membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or 1 or 2 independently selected from C1-C4Alkyl, halogen, and C1-C4Substituted by a substituent of a haloalkyl group.
27. The compound of claim 1, wherein the compound is selected from:
6- (2-chloro-5-fluorophenyl) -N- [ [6- [ [3- (trifluoromethyl) -2-pyridinyl ] methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (4-fluorophenyl) pyridazin-3-amine;
n- ((6- (((1R,2R,4S) -7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-amine;
n- [6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-yl ] -6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octane-2-carboxamide;
n- (6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octane-1-carboxamide;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyridin-2-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -N- [6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-yl ] -6-azaspiro [2.5] octane-2-carboxamide;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (2, 2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -N- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] -6-azaspiro [2.5] octane-2-carboxamide;
n- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] -6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octane-2-carboxamide;
6-chloro-N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyrazin-2-amine;
5- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyrazin-2-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyrazin-2-amine;
6- (2-chloro-4-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (4-methyl-3-pyridinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-fluorophenyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3-fluorophenyl) pyridazin-3-amine;
6- (2, 4-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (5-fluoro-2-methyl-phenyl) pyridazin-3-amine;
6- (2, 5-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (5-fluoro-2-methoxy-phenyl) pyridazin-3-amine;
6- (3, 4-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (3, 5-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-phenyl-pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1,3, 5-trimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3, 5-dimethylisoxazol-4-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-methylpyrazol-3-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [ 2-methyl-5- (trifluoromethyl) pyrazol-3-yl ] pyridazin-3-amine;
n- [4- [6- [ [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] amino ] pyridazin-3-yl ] phenyl ] acetamide;
6- (2-chloro-3-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3-methyl-2-thienyl) pyridazin-3-amine;
2- [6- [ [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] amino ] pyridazin-3-yl ] -4-fluoro-benzonitrile;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (7-isoquinolinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (6-quinolinyl) pyridazin-3-amine;
6- (1, 3-benzodioxol-5-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-naphthyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [2- (trifluoromethoxy) phenyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [4- (trifluoromethyl) -3-pyridinyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2-methylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2-methylpentyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ (6-ethyl-6-azaspiro [2.5] octan-2-yl) methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ (6-propyl-6-azaspiro [2.5] octan-2-yl) methyl ] pyridazin-3-amine;
n- [ [6- (cyclopropylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2, 2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- [ [3- (trifluoromethyl) -2-pyridinyl ] methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(S) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(S) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (2-chloro-5-fluoro-phenyl) pyridin-2-amine;
5- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridin-2-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyridin-2-amine;
6- (2, 4-dimethylpyrazol-3-yl) -N- [ [6- (2-tetrahydrofuran-2-ylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5-phenyl-thiazol-2-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5-phenyl-thiazol-2-amine;
5-phenyl-N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] thiazol-2-amine;
6- (2, 4-dimethylpyrazol-3-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (3, 3-difluoropyrrolidin-1-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2, 4-dimethylpyrazol-3-yl) -N-methyl-pyridazin-3-amine;
2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octane;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1-piperidinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
6- (4, 4-difluoro-1-piperidinyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-pyrrolidin-1-yl-pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
6-morpholino-N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6-azaspiro [2.5] octane;
2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6- (cyclohexylmethyl) -6-azaspiro [2.5] octane;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
6- (cyclopenten-1-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- [ (E) -3, 3-dimethylbut-1-enyl ] -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [ (E) -2- (p-tolyl) ethenyl ] pyridazin-3-amine;
4- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] phthalazin-1-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (3-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
2- [ [2- [ [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] amino ] methyl ] -6-azaspiro [2.5] octan-6-yl ] methyl ] benzonitrile;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (4-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (2-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] imidazo [1,2-b ] pyridazin-6-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- (((1R) -6- (bicyclo [2.2.1] hept-5-en-2-ylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazin-3-amine;
(R) -6- (2-chloro-5-fluorophenyl) -N- ((6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazin-3-amine;
n- (((1R) -6- ((7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazin-3-amine;
n- [4- [6- [ [ (2R) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [ [ (2R) -6-benzyl-6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [ (2R) -6- (2-pyridylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [ (2R) -6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [ (2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
n- [4- [6- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] -4, 5-dimethyl-pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] -4, 5-dimethyl-pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- [ (4-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide; or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled.
29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
30. mAChR M for antagonizing subjects4The method of (2), the method comprising the steps of: administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.
31. A method for treating a disorder in a subject, wherein the subject is to be treated from mAChR M4The method comprising the steps of: administering to the mammal a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
32. The method of claim 31, wherein the disorder is a movement disorder.
33. The method of claim 32, wherein the disorder is selected from parkinson's disease, drug-induced parkinson's disease, dystonia, tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, Attention Deficit Hyperactivity Disorder (ADHD), huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
34. A method for treating a motor symptom in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
35. The method of claim 34, wherein the subject has a disorder selected from: parkinson's disease, drug-induced parkinson's disease, dystonia, tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, Attention Deficit Hyperactivity Disorder (ADHD), huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
Technical Field
The present disclosure relates to compounds, compositions, and methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction.
Background
Parkinson's Disease (PD) is the second most common neurodegenerative disease, with an increasing incidence of disease with age. In addition, early onset PD is also increasing. PD is characterized by progressive degeneration and loss of dopaminergic neurons in the Substantia Nigra (SN) and Basal Ganglia (BG), which leads to overt motor symptoms (motorsymptoms) including bradykinesia, tremor, rigidity, gait dysfunction, and postural instability. Currently, levodopa (L-DOPA) is the therapeutic standard for the treatment of motor symptoms, but this is not curative and prolonged use can cause L-DOPA-induced dyskinesia (LID).
Prior to L-DOPA, compounds with anticholinergic activity represented the first choice for PD treatment. Cholinergic neurons provide important neuromodulatory control of the BG motor circuit. Although the effects of cholinergic pathways on basal ganglia pathways are complex, activation of muscarinic acetylcholine receptors (machrs) generally has an opposite effect to Dopamine (DA) signaling. For example, mAChR agonists inhibit DA release and inhibit a variety of behavioral effects of drugs that increase DA levels and signaling. Interestingly, muscarinic acetylcholine receptor (mAChR) antagonists were the first available treatments for PD and are still widely used to treat this disorder. Although many studies of the role of mAChR antagonists have been conducted prior to the introduction of randomized controlled trials, recent double-blind cross-design studies of good controls have shown that patients receiving mAChR antagonists have significant improvements in multiple aspects of motor function. Unfortunately, mAChR antagonists have a number of dose-limiting adverse effects that severely limit their clinical utility, including a variety of peripheral adverse effects, as well as confusion and severe cognitive impairment.
Since adverse effects associated with mAChR antagonists limit the tolerable doses, previous clinical studies may underestimate the efficacy that can be achieved if the dosage of mAChR antagonist can be increased to achieve a more complete blockade of specific mAChR subtypes that are responsible for the anti-parkinson effects of these agents. mAChR comprises 5 subtypes, designated M1-M5. Available mAChR antagonists (e.g. scopolamine) are non-selective among these subtypes and many of their adverse effects are likely to be mediated by mAChR subtypes that are not involved in anti-parkinson's disease activity. Thus, compounds with a stronger selectivity profile for a single mAChR can provide advantages in PD and related disorders (e.g., dystonia). For example, some studies have shown that M4The mAChR subtype may play a dominant role in mAChR regulation of basal ganglia motor function.
Disclosure of Invention
Disclosed are compounds, pharmaceutical compositions comprising these compounds, methods of making these compounds, kits comprising these compounds, and methods of using these compounds, compositions, and kits for the treatment of disorders such as neurological and/or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in a mammal.
In one aspect, compounds of formula (I) are disclosed,
or a pharmaceutically acceptable salt thereof, wherein:
a is a five-or six-membered heteroaryl group having 1,2 or 3 heteroatoms independently selected from N, O and S, or a nine-to ten-membered fused ring having 1-4 nitrogen atomsA bicyclic heteroaryl ring system wherein A is optionally substituted with 1-4 substituents independently selected from halogen, C1-C4Alkyl and C1-C4Substituted with a substituent of haloalkyl;
q is selected from NRaO, and CRbRc；
R1Selected from hydrogen, halogen, -ORd、-N(Rd)2、C1-C4Alkyl, -CH ═ CH-C1-C4Alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and-CH ═ CH-G;
g is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
R2and R3Independently selected from hydrogen, C1-C4Alkyl, and halogen, or R2And R3Together form an oxo group;
each R4Independently selected from halogen, C1-C4Alkyl, and-ORe；
R5And R6Independently selected from hydrogen, C1-C8Alkyl group, and- (CR)fRg)n-Y1；
Each Y1Independently selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
each Ra、Rb、Rc、Rd、Re、RfAnd RgIndependently selected from hydrogen, C1-C4Alkyl, and aryl;
m is 0, 1 or 2; and
n is 0, 1 or 2.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect, the invention provides an mAChR M that antagonizes a subject4The method of (2), the method comprising the steps of: administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
In another aspect, the invention provides a method of treating a disorder in a subject, wherein the subject would benefit from a mAChR M4The method comprising the steps of: administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
In another aspect, the present invention provides a method of treating a motor symptom in a subject, the method comprising the steps of: administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.
In another aspect, the invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.
In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in antagonizing mAChR M4For the treatment by mAChR M4Antagonism to improve the disorder, or for the treatment of motor symptoms.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in antagonizing mAChR M4In the manufacture of a medicament for the treatment of cancer by mAChR M4Antagonism to improve the disorder, or for the treatment of motor symptoms.
Drawings
FIG. 1 shows the structure of Compound O (example 5) obtained by X-ray crystallography.
Detailed Description
Disclosed herein are compounds that are muscarinic acetylcholine receptors M4(mAChR M4) Compounds of (2) and processes for making themMethods of compounds, pharmaceutical compositions comprising these compounds, and methods of treating disorders using these compounds and pharmaceutical compositions. These compounds include functionalized cyclopropyl piperidine compounds.
1. Definition of
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.
As used herein, the terms "comprising," "including," "having," "has," "can," "containing," and variants thereof are intended to be open transition phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The present disclosure also encompasses other embodiments that "comprise," "consist essentially of," and "consist essentially of" the embodiments or elements presented herein, whether or not explicitly stated.
The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., the modifier includes at least the degree of error associated with measurement of the particular quantity). The modifier "about" should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 2 to about 4" also discloses a range of "from 2 to 4". The term "about" may refer to plus or minus 10% of the number indicated. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1" may mean 0.9-1.1. Other meanings of "about" may be apparent from the context, such as rounding off, so, for example, "about 1" may also mean from 0.5 to 1.4.
The definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical Elements are identified according to the Periodic Table of the Elements [ Periodic Table of Elements ], CAS version, Handbook of chemistry and Physics [ Handbook of chemistry and Physics ], 75 th edition, Encapsulated surface, and specific functional groups are generally defined as described therein. In addition, the general principles of Organic Chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Soxhlet (Sausalitio), 1999; smith and March, March's Advanced organic chemistry [ March Advanced organic chemistry ], 5 th edition, John Wiley father corporation (John Wiley & Sons, Inc.), new york, 2001; larock, Comprehensive Organic Transformations [ Integrated Organic Transformations ], VCH Publishers Inc. (VCH Publishers, Inc.), New York, 1989; carruther, Some Modern Methods of organic synthesis [ Some Modern organic synthetic Methods ], 3 rd edition, cambridge university press (cambridge university press), cambridge, 1987; the entire contents of each application are incorporated herein by reference.
The term "alkoxy," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and t-butoxy.
As used herein, the term "alkyl" means a straight or branched saturated hydrocarbon chain containing from 1 to 10 carbon atoms. The term "lower alkyl" or "C1-C6-alkyl "means a linear or branched hydrocarbon containing from 1 to 6 carbon atoms. The term "C1-C3-alkyl "means a linear or branched hydrocarbon containing from 1 to 3 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylPentyl, 2, 3-dimethylpentyl, 4-dimethylpentan-2-yl, n-heptyl, n-octyl, n-nonyl and n-decyl.
As used herein, the term "alkenyl" means a straight or branched hydrocarbon chain containing at least 1 carbon-carbon double bond and from 2 to 10 carbon atoms.
The term "alkoxyalkyl," as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "alkoxyfluoroalkyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
As used herein, the term "alkylene" means a divalent group derived from a straight or branched chain hydrocarbon having from 1 to 10 carbon atoms, for example, from 2 to 5 carbon atoms. Representative examples of alkylene groups include, but are not limited to, -CH2CH2-、-CH2CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH2CH2-、-CH2CH(CH3)CH2CH2-, and-CH2CH2CH2CH2CH2-。
The term "alkylamino" as used herein, means at least one alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.
The term "amide" as used herein means-c (o) NR-or-nrc (o) -wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
The term "aminoalkyl" as used herein, means at least one amino group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
As used herein, the term "amino" means-NRxRyWherein R isxAnd RyCan be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenylOr a heteroalkyl group. In the case of an aminoalkyl group or any other moiety where the amino group is attached to two other moieties, the amino group may be-NRx-, wherein RxCan be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
As used herein, the term "aryl" means a phenyl group, or a bicyclic fused ring system. The bicyclic fused ring system is exemplified by a phenyl group attached to the parent molecular moiety and fused with a cycloalkyl group as defined herein, a phenyl group as defined herein, a heteroaryl group as defined herein, or a heterocycle as defined herein. Representative examples of aryl groups include, but are not limited to, indol-4-yl, naphthyl, phenyl, benzodioxol-5-yl, and tetrahydroquinolin-6-yl.
The term "cyanoalkyl" as used herein, means at least one — CN group attached to the parent molecular moiety through an alkylene group, as defined herein.
As used herein, the term "cyanofluoroalkyl" means at least one-CN group attached to the parent molecular moiety through a fluoroalkyl group as defined herein.
The term "cycloalkyloxy," as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
As used herein, the term "cycloalkyl" refers to a carbocyclic ring system containing three to ten carbon atoms, zero heteroatoms, and zero double bonds. Cycloalkyl groups may be monocyclic, bicyclic, bridged, fused, or spiro. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo [1.1.1] pentyl. "cycloalkyl" also includes carbocyclic ring systems in which a cycloalkyl group is attached to the parent molecular moiety and is fused to an aryl group (e.g., a phenyl group) as defined herein, a heteroaryl group as defined herein, or a heterocycle as defined herein. Representative examples of such cycloalkyl groups include, but are not limited to, 2, 3-dihydro-1H-indenyl (e.g., 2, 3-dihydro-1H-inden-1-yl and 2, 3-dihydro-1H-inden-2-yl), 6, 7-dihydro-5H-cyclopenta [ b ] pyridyl (e.g., 6, 7-dihydro-5H-cyclopenta [ b ] pyridin-6-yl), oxaspiro [3.3] heptanyl (e.g., 2-oxaspiro [3.3] heptan-6-yl), and 5,6,7, 8-tetrahydroquinolyl (e.g., 5,6,7, 8-tetrahydroquinolin-5-yl).
As used herein, the term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic (e.g., bridged) ring system containing at least 1 carbon-carbon double bond, and preferably from 5 to 10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. An exemplary bridged bicyclic ring system is bicyclo [2.2.1] hept-2-enyl.
The term "fluoroalkyl" as used herein means an alkyl group as defined herein in which 1,2,3, 4,5, 6,7 or 8 hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl groups include, but are not limited to, 2-fluoroethyl, 2,2, 2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl, such as 3,3, 3-trifluoropropyl.
The term "fluoroalkoxy," as used herein, means at least one fluoroalkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkoxy groups include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2, 2-trifluoroethoxy.
As used herein, the term "halogen (" halo "or" halo ")" means Cl, Br, I, or F.
The term "haloalkyl" as used herein means an alkyl group as defined herein wherein 1,2,3, 4,5, 6,7 or 8 hydrogen atoms are replaced by halogen.
The term "haloalkoxy," as used herein, means at least one haloalkyl group, as defined herein, is attached to the parent molecular moiety through an oxygen atom.
As used herein, the term "halocycloalkyl" means a cycloalkyl group as defined herein in which one or more hydrogen atoms are replaced by halogen.
The term "heteroalkyl," as used herein, means an alkyl group, as defined herein, wherein one or more carbon atoms are replaced with a heteroatom selected from S, O, P and N. Representative examples of heteroalkyl groups include, but are not limited to, alkyl ethers, secondary alkyl amines, tertiary alkyl amines, amides, and alkyl sulfides.
As used herein, the term "heteroaryl" refers to an aromatic monocyclic or aromatic bicyclic ring system. An aromatic monocyclic ring is a five or six membered ring containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g., 1,2,3, or 4 heteroatoms independently selected from O, S and N). A five-membered aromatic monocyclic ring has two double bonds and a six-membered aromatic monocyclic ring has three double bonds. A bicyclic heteroaryl group is exemplified by a monocyclic heteroaryl ring attached to the parent molecular moiety and fused with a monocyclic cycloalkyl group as defined herein, a monocyclic aryl group as defined herein, a monocyclic heteroaryl group as defined herein, or a monocyclic heterocycle as defined herein. Representative examples of heteroaryl groups include, but are not limited to, indolyl, pyridyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, benzopyrazolyl, 1,2, 3-triazolyl, 1,3, 4-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl, quinazolinyl, 1,2, 4-triazinyl, quinoxalinyl, indazolyl, quinazolinyl, and pyrazinyl, 1,3, 5-triazinyl, isoquinolyl, quinolinyl, 6, 7-dihydro-1, 3-benzothiazolyl, imidazo [1,2-a ] pyridinyl, naphthyridinyl, pyridoimidazolyl, thiazolo [5,4-b ] pyridin-2-yl, thiazolo [5,4-d ] pyrimidin-2-yl, [1,2,4] triazolo [4,3-b ] pyridazinyl, imidazo [1,2-b ] pyridazinyl, phthalazinyl.
As used herein, the term "heterocycle" or "heterocyclic" means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. A monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N and S. The three or four membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The seven-and eight-membered rings contain zero, one, two or three double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1, 3-dioxanyl, 1, 3-dioxolanyl, 1, 3-dithiopentanoyl, 1, 3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxoazepan, oxadiazolinyl, oxadiazolidinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocyclooctyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, thiadiazolidinyl, imidazolidinyl, isothiazolidinyl, imidazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxo-3-azacycloheptanyl, morpholinyl, and, Tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1, 2-thiazinoalkyl, 1, 3-thiazinoalkyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1-thiomorpholinyl (thiomorpholinyl sulfone), thiopyranyl, and trithianyl. A bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiroheterocyclic group, or a bridged monocyclic heterocyclic ring system, wherein two non-adjacent atoms of the ring are connected through an alkylene bridge of 1,2,3, or 4 carbon atoms or an alkenylene bridge of 2,3, or 4 carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2, 3-dihydrobenzofuranyl, 2, 3-dihydrobenzothienyl, 2, 3-dihydroisoquinoline, 2-azaspiro [3.3] heptan-2-yl, 2-oxa-6-azaspiro [3.3] heptan-6-yl, azabicyclo [2.2.1] heptyl (including 2-azabicyclo [2.2.1] heptan-2-yl), azabicyclo [3.1.0] hexanyl (including 3-azabicyclo [3.1.0] hexan-3-yl), 2, 3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta [ c ] pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. The tricyclic heterocycle is exemplified by: a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle, wherein two non-adjacent atoms of the bicyclic ring are connected through an alkylene bridge of 1,2,3, or 4 carbon atoms or an alkenylene bridge of 2,3, or 4 carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2, 5-epoxypentalene, hexahydro-2H-2, 5-endomethylenecyclopenta [ b ] furan, hexahydro-1H-1, 4-endomethylenecyclopenta [ c ] furan, aza-adamantane (1-azatricyclo [3.3.1.13,7] decane), and oxa-adamantane (2-oxatricyclo [3.3.1.13,7] decane). The monocyclic heteroaryl, bicyclic heterocycle and tricyclic heterocycle are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within these rings and may be unsubstituted or substituted.
As used herein, the term "hydroxyl" or "hydroxy" means an — OH group.
The term "hydroxyalkyl" as used herein, means at least one-OH group attached to the parent molecular moiety through an alkylene group, as defined herein.
As used herein, the term "hydroxyalkyl" means at least one — OH group attached to the parent molecular moiety through a hydroxy group, as defined herein.
In some cases, the number of carbon atoms in a hydrocarbyl substituent (i.e., alkyl or cycloalkyl) is preceded by the prefix "Cx-Cy- "indicates where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, "C1-C3-alkyl "means an alkyl substituent containing from 1 to 3 carbon atoms.
As used herein, the term "sulfonamide" means-S (O)2NR-or-NRS (O) -wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.
The term "substituent" refers to a "substituted" group on an aryl, heteroaryl, phenyl or pyridyl group, on any atom on that group. Any atom may be substituted.
The term "substituted" refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, ═ O (oxo), ═ S (thio), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl. For example, if a group is described as "optionally substituted" (e.g., alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, or other group (e.g., R group)), the group can have 0, 1,2,3, 4, or 5 substituents independently selected from the group consisting of: halogen, ═ O (oxo), ═ S (thio), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.
Term(s) for
For the compounds described herein, the groups and substituents may be selected according to the valency allowed for the atoms and substituents, such that the selection and substitution results in a stable compound, e.g., one that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, etc.).
As used herein, the term "mAChR M4Receptor antagonist "refers to a receptor antagonist that directly or indirectly antagonizes a mAChR M (e.g., of an animal, particularly a mammal (e.g., a human))4Any exogenously administered compound or agent of (a).
For the recitation of numerical ranges herein, each intervening number between the two is explicitly contemplated to have the same degree of accuracy. For example, for the range 6-9, the numbers 7 and 8 are considered in addition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly considered.
2. Compound (I)
The compounds of the present invention have formula (I), wherein R1、R2、R3、R4、R5、R6A, Q, and m are as defined herein, including these variables or their subvariates (e.g., Y)1G, etc.).
In one aspect, compounds of formula (I) are disclosed:
or a pharmaceutically acceptable salt thereof, wherein:
a is a five or six membered heteroaryl group having 1,2 or 3 heteroatoms independently selected from N, O and S;
q is selected from NRaO, and CRbRc；
R1Selected from hydrogen, halogen, -ORd、C1-C4An alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycle, an optionally substituted aryl group, and an optionally substituted heteroaryl group;
R2and R3Independently selected from hydrogen, C1-C4Alkyl, and halogen, or R2And R3Together form an oxo group;
each R4Independently selected from halogen, C1-C4Alkyl, and-ORe；
R5And R6Independently selected from hydrogen, C1-C8Alkyl group, and- (CR)fRg)n-Y1；
Each Y1Independently selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
each Ra、Rb、Rc、Rd、Re、RfAnd RgIndependently selected from hydrogen, C1-C4Alkyl, and aryl;
m is 0, 1 or 2; and
n is 0, 1 or 2.
In some embodiments, Q is NRa. In some embodiments, RaIs hydrogen or C1-C4An alkyl group. In some embodiments, RaIs hydrogen.
In some embodiments, R1Selected from hydrogen, halogen (e.g. chlorine), -CH ═ CH-C1-C4Alkyl, -CH ═ CH-G, C5-C8Cycloalkenyl, four-to eight-membered monocyclic heterocyclyl, six-to twelve-membered aryl, and five-to six-membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein cycloalkenyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR' are substituted; g is a six-to twelve-membered aryl group, which may optionally be substituted by 12 or 3 are independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR' are substituted; and R', at each occurrence, is independently C1-C4An alkyl group. In further embodiments, R1Selected from halogen, -CH ═ CH-C1-C4Alkyl, -CH ═ CH-G, C5-C8Cycloalkenyl, four-to eight-membered monocyclic heterocyclyl, six-to twelve-membered aryl, and five-to six-membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein cycloalkenyl, heterocyclyl, aryl and heteroaryl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR' are substituted; g is a six-to twelve-membered aryl group, which may optionally be substituted with 1,2 or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR' are substituted; and R', at each occurrence, is independently C1-C4An alkyl group. In further embodiments, R1Is hydrogen, phenyl, naphthyl (e.g., 2-naphthyl), benzodioxolyl (e.g., benzodioxol-5-yl), pyrazolyl (e.g., pyrazol-3-yl, pyrazol-4-yl), isoxazolyl (e.g., isoxazol-4-yl), thienyl (e.g., 2-thienyl), pyridyl (e.g., pyridin-3-yl), quinolinyl (e.g., quinolin-6-yl), isoquinolinyl (e.g., isoquinolin-7-yl), piperidinyl (e.g., piperidin-1-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl), morpholinyl (e.g., morpholin-4-yl), cyclopentenyl (e.g., cyclopenten-1-yl), or-CH ═ CH-G, wherein phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridyl, quinolyl, isoquinolyl, piperidyl and pyrroleAlkyl, morpholinyl and cyclopentenyl unsubstituted or substituted with 1,2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano; and G is phenyl optionally substituted by 1,2 or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR ', wherein R' is C1-C4An alkyl group. In further embodiments, R1Is phenyl, pyrazolyl, piperidinyl, pyrrolidinyl, morpholinyl, cyclopentenyl or-CH ═ CH-G, wherein phenyl, pyrazolyl, piperidinyl and pyrrolidinyl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano; and G is phenyl optionally substituted by 1,2 or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR ', wherein R' is C1-C4An alkyl group. In still other embodiments, G is via C1-C4Alkyl-substituted phenyl.
In some embodiments, R1Selected from: halogen; an aryl group; and a five-to six-membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy and-NHCOR ', wherein R' is C1-C4An alkyl group. In some embodiments, R1Is halogen (e.g., chlorine). In some embodiments, R1Selected from phenyl, pyrazolyl, thiophene, quinolyl, benzodioxolyl, naphthyl, pyridyl and isoxazolyl, each of which is unsubstituted or substituted by 1,2 or 3 independentlyIs selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy and-NHCOR ', wherein R' is C1-C4An alkyl group. In some embodiments, R1Is phenyl or pyrazolyl, wherein phenyl and pyrazolyl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano. In some embodiments, R1Is phenyl, unsubstituted or substituted by 1 or 2 substituents independently selected from C1-C4Alkyl (e.g., methyl), halogen (e.g., fluoro or chloro), cyano, C1-C4Haloalkyl (e.g. trifluoromethyl), C1-C4Alkoxy (e.g. methoxy), C1-C4Haloalkoxy (e.g., trifluoromethoxy), and-NHCOR ', wherein R' is C1-C4Alkyl (e.g., -NHCOCH)3). In some embodiments, R1Is pyrazolyl, which pyrazolyl is selected from 1 or 2 independently of C1-C4Alkyl (e.g. methyl) and C1-C4Haloalkyl (e.g., trifluoromethyl).
In some embodiments, R1Is composed of
In some embodiments, R2Is hydrogen and R3Is hydrogen. In some embodiments, R2And R3Together form an oxo group.
In some embodiments, m is 0.
In some embodiments, R5Is hydrogen.
In some embodiments, R6Is selected from C1-C8Alkyl and- (CR)fRg)n-Y1。
In some embodiments: r6Is selected from C1-C8Alkyl and- (CR)fRg)n-Y1；RfIs hydrogen; rgSelected from hydrogen, C1-C4Alkyl and phenyl; n is 0 or 1; and Y1Selected from: c3-C10-a cycloalkyl group; c5-C10-a cycloalkenyl group; a phenyl group; a five-to six-membered heteroaryl group having 1,2, or 3 heteroatoms independently selected from N, O and S; and a five to eight membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or 1 or 2 independently selected from C1-C4Alkyl, halogen, and C1-C4Substituted by a substituent of a haloalkyl group. In some embodiments, R6Is C1-C8Alkyl (e.g., methyl, ethyl, isopropyl, sec-butyl, neopentyl, sec-pentyl, 4-dimethylpentan-2-yl). In some embodiments, R6Is- (CR)fRg)n-Y1N is 0 or 1, RfIs hydrogen, RgIs hydrogen, and Y1Is selected from C3-C10Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl), C5-C10Cycloalkenyl (e.g. bicyclo [2.2.1]]Hept-5-en-2-yl), phenyl, a five to eight membered heterocyclic group having 1 or 2 heteroatoms independently selected from N, O and S (e.g., tetrahydrofuryl, tetrahydropyranyl, 7-oxabicyclo [2.2.1] n]Heptadecyl), and five-to six-membered heteroaryl (e.g., pyridyl) having 1,2, or 3 heteroatoms independently selected from N, O and S, wherein cycloalkyl, cycloalkenyl, phenyl, heteroaryl, and heterocyclyl are unsubstituted or 1 or 2 heteroatoms independently selected from C1-C4Alkyl, halogen, and C1-C4Substituted by a substituent of a haloalkyl group.
In some casesIn the examples, A is a five-membered heteroaryl group having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from N, O and S, a six-membered heteroaryl group having 1-2 nitrogen atoms, a phthalazinyl group, an imidazo [1,2-b ] group]Pyridazinyl radicals, or [1,2,4]]Triazolo [4,3-b]Pyridazinyl, wherein A is optionally substituted with 1-4 substituents independently selected from halogen, C1-C4Alkyl group, and C1-C4Substituted by a substituent of a haloalkyl group. In further embodiments, A is thiazol-2, 5-diyl, pyridazin-3, 6-diyl, pyrazin-2, 5-diyl, pyridin-2, 5-diyl, phthalazin-1, 4-diyl, imidazo [1,2-b ]]Pyridazin-6-yl, or [1,2,4]]Triazolo [4,3-b]Pyridazin-6-yl wherein A is optionally substituted with 1-4 substituents independently selected from halogen, C1-C4Alkyl group, and C1-C4Substituted by a substituent of a haloalkyl group.
In some embodiments, a is selected from:
wherein T is selected from O, S and NH; and U, V, W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y and Z are N.
In some embodiments, a is selected from:
in some embodiments, A is
In some embodiments, the compound of formula (I) is a compound of formula (Ia):
wherein W, X, Y and Z are independently selected from N and CH, wherein 1-3 of W, X, Y and Z are N.
In some embodiments, 1 or 2 of W, X, Y and Z are N. In some embodiments, W and X are N, and Y and Z are CH. In some embodiments, W, Y and Z are CH and X is N. In some embodiments, X and Y are N, and W and Z are CH.
In some embodiments, the compound of formula (I) is a compound of formula (Ib):
representative compounds of formula (I) include, but are not limited to:
6- (2-chloro-5-fluorophenyl) -N- [ [6- [ [3- (trifluoromethyl) -2-pyridinyl ] methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (4-fluorophenyl) pyridazin-3-amine;
n- ((6- (((1R,2R,4S) -7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-amine;
n- [6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-yl ] -6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octane-2-carboxamide;
n- (6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octane-1-carboxamide;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyridin-2-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -N- [6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-yl ] -6-azaspiro [2.5] octane-2-carboxamide;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine; compound 14
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine; compound 15
N- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (2, 2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -N- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] -6-azaspiro [2.5] octane-2-carboxamide;
n- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] -6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octane-2-carboxamide;
6-chloro-N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyrazin-2-amine;
5- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyrazin-2-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyrazin-2-amine;
6- (2-chloro-4-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (4-methyl-3-pyridinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-fluorophenyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3-fluorophenyl) pyridazin-3-amine;
6- (2, 4-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (5-fluoro-2-methyl-phenyl) pyridazin-3-amine;
6- (2, 5-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (5-fluoro-2-methoxy-phenyl) pyridazin-3-amine;
6- (3, 4-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (3, 5-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-phenyl-pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1,3, 5-trimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3, 5-dimethylisoxazol-4-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-methylpyrazol-3-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [ 2-methyl-5- (trifluoromethyl) pyrazol-3-yl ] pyridazin-3-amine;
n- [4- [6- [ [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] amino ] pyridazin-3-yl ] phenyl ] acetamide;
6- (2-chloro-3-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3-methyl-2-thienyl) pyridazin-3-amine;
2- [6- [ [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] amino ] pyridazin-3-yl ] -4-fluoro-benzonitrile;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (7-isoquinolinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (6-quinolinyl) pyridazin-3-amine;
6- (1, 3-benzodioxol-5-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-naphthyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [2- (trifluoromethoxy) phenyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [4- (trifluoromethyl) -3-pyridinyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2-methylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2-methylpentyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ (6-ethyl-6-azaspiro [2.5] octan-2-yl) methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ (6-propyl-6-azaspiro [2.5] octan-2-yl) methyl ] pyridazin-3-amine;
n- [ [6- (cyclopropylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2, 2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- [ [3- (trifluoromethyl) -2-pyridinyl ] methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(S) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(S) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (2-chloro-5-fluoro-phenyl) pyridin-2-amine;
5- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridin-2-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyridin-2-amine;
6- (2, 4-dimethylpyrazol-3-yl) -N- [ [6- (2-tetrahydrofuran-2-ylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5-phenyl-thiazol-2-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5-phenyl-thiazol-2-amine;
5-phenyl-N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] thiazol-2-amine;
6- (2, 4-dimethylpyrazol-3-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (3, 3-difluoropyrrolidin-1-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2, 4-dimethylpyrazol-3-yl) -N-methyl-pyridazin-3-amine;
2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octane;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1-piperidinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
6- (4, 4-difluoro-1-piperidinyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-pyrrolidin-1-yl-pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
6-morpholino-N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6-azaspiro [2.5] octane;
2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6- (cyclohexylmethyl) -6-azaspiro [2.5] octane;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
6- (cyclopenten-1-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- [ (E) -3, 3-dimethylbut-1-enyl ] -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [ (E) -2- (p-tolyl) ethenyl ] pyridazin-3-amine;
4- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] phthalazin-1-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (3-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
2- [ [2- [ [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] amino ] methyl ] -6-azaspiro [2.5] octan-6-yl ] methyl ] benzonitrile;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (4-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (2-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] imidazo [1,2-b ] pyridazin-6-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- (((1R) -6- (bicyclo [2.2.1] hept-5-en-2-ylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazin-3-amine;
(R) -6- (2-chloro-5-fluorophenyl) -N- ((6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazin-3-amine;
n- (((1R) -6- ((7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazin-3-amine;
n- [4- [6- [ [ (2R) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [ [ (2R) -6-benzyl-6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [ (2R) -6- (2-pyridylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [ (2R) -6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [ (2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
n- [4- [6- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] -4, 5-dimethyl-pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] -4, 5-dimethyl-pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- [ (4-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
or a pharmaceutically acceptable salt thereof.
The experimental part also cites the compounds listed below, which are used as appropriate
The compounds may exist as stereoisomers having asymmetric or chiral centers therein. The stereoisomer is "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used herein are configurations as defined in IUPAC1974Recommendations for Section E, Fundamental Stereochemistry [ IUPAC1974Recommendations for Section E, basic Stereochemistry ], Pure apply. The present disclosure contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers as well as mixtures of enantiomers or diastereomers. The individual stereoisomers of these compounds can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These resolution methods are exemplified by: (1) the enantiomeric mixtures are attached to a chiral auxiliary, the resulting diastereomeric mixtures are separated by recrystallization or chromatography, and the optically pure product is optionally released from the auxiliary, as described by Furniss, Hannaford, Smith and taschell, Vogel's textbook of Practical Organic Chemistry [ woguel, textbook of Organic Chemistry ], 5 th edition (1989), longman scientific & Technical [ langwen scientific Technical press ], Essex (Essex) CM 202 JE, england, or (2) the separation of the mixture of optical enantiomers directly on a chiral chromatographic column, or (3) a fractional recrystallization process.
It is understood that the compounds may have tautomeric forms as well as geometric isomers, and that this also constitutes an embodiment of the disclosure.
The present disclosure also includes isotopically-labeled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as but not limited to those corresponding thereto2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F. And36and (4) Cl. With heavier isotopes such as deuterium (i.e.2H) Certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) may be obtained for substitution, and thus may be preferred in some circumstances. The compounds may be included for use in medical imagingAnd Positron Emission Tomography (PET) studies for determining receptor distribution. Suitable positron-emitting isotopes which may be incorporated in the compounds of formula (I) are11C、13N、15O, and18F. isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labelled reagent in place of a non-isotopically-labelled reagent.
a. Pharmaceutically acceptable salts
The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to salts or zwitterions of the compounds that are water or oil soluble or dispersible, are suitable for treating disorders without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for the intended use. These salts can be prepared during the final isolation and purification of the compound or separately by reacting the amino group of the compound with a suitable acid. For example, the compound can be dissolved in a suitable solvent (such as, but not limited to, methanol and water) and treated with at least one equivalent of an acid (such as hydrochloric acid). The resulting salt may be precipitated and isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, p-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate and the like. The amino groups of the compounds can be quaternized with alkyl chlorides, bromides, and iodides (e.g., methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like).
Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reacting the carboxyl group with a suitable base such as the hydroxide, carbonate or bicarbonate of a metal cation (e.g., lithium, sodium, potassium, calcium, magnesium or aluminum), or with an organic primary, secondary or tertiary amine. Quaternary ammonium salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, proparacaine, dibenzylamine, N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine and N, N' -dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
b. General Synthesis
The compounds of formula (I) may be prepared synthetically or by metabolic methods. The preparation of compounds by metabolic methods includes those that occur in the human or animal body (in vivo) or methods that occur in vitro.
Abbreviations used in the description of the following schemes are:
AcOH acetic acid
Brettphos-Pd-G3 methanesulfonic acid (2-dicyclohexylphosphino-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (CAS number 1470372-59-8)
DCE 1, 2-dichloroethane
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
HATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate
LAH lithium aluminum hydride
NaBH(OAc)3Sodium triacetoxyborohydride
NMP N-methyl-2-pyrrolidone
PyClU 1- (chloro-1-pyrrolidinylmethylene) pyrrolidine hexafluorophosphate
RuPhos-Pd-G3 methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-2-yl) palladium (II) (CAS number 1445085-77-7)
SFC supercritical fluid chromatography
THF tetrahydrofuran
The compounds of formula (I) can be synthesized as shown in the following scheme.
General scheme A
As shown in general scheme a, compound a can be reacted with compound B to produce compound C, which is coupled with an appropriate boronic acid or ester in the presence of a suitable catalyst to produce compound D. Deprotection of Boc yields compound E. This process can be used to prepare precursors of compounds of formula (I), for example, wherein R2And R3Is hydrogen, m is 0, and wherein W is CH, X is N and Z is CH, or wherein W is CH, X is CH and Z is N (i.e. a compound of formula (Ib)).
General scheme B
As shown in general scheme B, compound E can be reacted with a suitable aldehyde and sodium triacetoxyborohydride to yield compound F. This process can be used to prepare compounds of formula (I), for example, wherein R2、R3And R5Is hydrogen, m is 0, and wherein W is CH, X is N and Z is CH, or wherein W is CH, X is CH and Z is N (i.e. a compound of formula (Ib)).
General scheme C
Suitable heteroaryl compounds G (wherein A is a five-or six-membered heteroaryl as defined herein, and R is R) functionalized with a halogen group (e.g., F or Cl), as shown in general scheme C1As defined herein) can be coupled with compound a to yield compound H, which can be deprotected and coupled as described herein or according to other known methods. The process is useful for preparing precursors of compounds of formula (I) wherein R2And R3Is hydrogen, m is 0 and a is as described herein (e.g., wherein a is pyridyl or thiazolyl).
General scheme D
As shown in general scheme D, compound C' (corresponding to compound C, where W is CH, X is CH, and Z is N) can be deprotected and then reacted with 3, 3-dimethylbutyraldehyde and sodium triacetoxyborohydride to produce compound I, which can be coupled with a suitable boronic acid or ester in the presence of a suitable catalyst to produce compound J. This process can be used to prepare certain compounds of formula (I), for example compounds of formula (Ib), wherein R2And R3Is hydrogen, R5Is hydrogen, and R6Is a neopentyl group.
Scheme E
As shown in scheme E, a particular compound can be prepared from compound K (prepared according to general scheme a): compound K can be reduced using lithium aluminum hydride to form compound M by reacting it with rac- (1R,2S,4S) -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid in the presence of HATU and DIPEA to form compound L.
Scheme F
As shown in scheme F, another specific compound can be prepared from compound K. And reacting with 2- (2-bromoethyl) oxolane to generate a compound N.
General scheme G
As shown in general scheme G, if desired, compounds such as compound C' can be subjected to chiral separation to separate enantiomers.
General scheme H
As shown in general scheme H, certain compounds of formula (I) can be prepared by reacting compound Q with 3-amino-6-chloropyridazine and PyClU to form compound R, which can be coupled with a suitable boronic acid or ester in the presence of a suitable catalyst to yield compound S. Deprotection and reaction with the appropriate aldehyde and sodium triacetoxyborohydride gives compound T. This procedure is useful for the preparation of certain compounds of formula (I), for example compounds of formula (Ib), wherein R2And R3Together form an oxo group, and R5Is hydrogen.
General scheme I
As shown in general scheme I, compounds of formula (I) can be prepared by reacting the appropriate amine with chloropyridazine in an organic solvent in the presence of a base and heating, wherein R is1Are amine-containing groups attached through nitrogen. Microwave radiation may facilitate this reaction. In scheme I, L is O, N, S or a methylene group, as defined herein, and R1aIs R1An optional substituent as above. Although in scheme I the p-cyclic amine R1Groups are illustrated, but the method is also applicable to acyclic amines-N (R)d)2。
General scheme J
General scheme J illustrates a preparation sequence analogous to schemes A and B for preparing compounds of formula (I) wherein Q is NRaAnd R isaIs an alkyl group. Suzuki (Suzuki), Boc deprotection, and reductive amination steps are generally similar to those described elsewhere herein.
General scheme K
General scheme K illustrates the sequence for preparing compounds of formula (I) wherein Q is O. Suzuki, Boc deprotection and reductive amination steps are generally similar to those described elsewhere herein.
The compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds may include, but are not limited to: chromatography on solid supports (e.g.silica gel, alumina or silica derivatized with alkylsilane groups), by recrystallization at elevated or low temperatures (optionally pretreated with activated carbon), thin layer chromatography, distillation at various pressures, sublimation under vacuum, and grinding, as described, for example, in "Vogel's Textbook of Practical Organic Chemistry [ Wager's Textbook of Practical Organic Chemistry ]," 5 th edition (1989), Furniss, Hannaford, Smith, and Tatchell, Longman Scientific & Technical [ Langmuir ] publications, Issaki county CM 202 JE, England.
The disclosed compounds may have at least one basic nitrogen so that the compound can be treated with an acid to form the desired salt. For example, the compound may be reacted with an acid at or above room temperature to provide the desired salt, which is precipitated and collected by filtration after cooling. Examples of acids suitable for this reaction include, but are not limited to: tartaric, lactic, succinic, and mandelic, atrolactic (atrolactic), methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.
The reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and the substituents present in the reactants employed. The examples section provides specific procedures. The reaction may be worked up in a conventional manner, for example by removing the solvent from the residue and further purified according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise indicated, starting materials and reagents are commercially available or can be prepared from commercially available materials by one of skill in the art using methods described in the chemical literature. The starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known structurally analogous compounds, or techniques analogous to the procedures described in the schemes above or in the synthetic examples section.
Routine experimentation (including the reaction conditions, reagents, sequence of synthetic routes, protection of any chemical functional groups incompatible with the reaction conditions, and appropriate manipulations of deprotection at appropriate points in the reaction sequence of the process) is included within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples of these methods can be found in the books of PGM Wuts and TWGreene, entitled Protective Groups in organic synthesis (fourth edition), John willy father, inc (John Wiley & Sons), Greene (2006), which is hereby incorporated by reference in its entirety. The synthesis of the compounds of the present invention may be accomplished by methods analogous to those described in the synthetic schemes and specific examples above.
When an optically active form of the disclosed compound is desired, it can be obtained by performing one of the procedures described herein using an optically active starting material (e.g., prepared by asymmetric induction of a suitable reaction step), or by resolving a mixture of stereoisomers of the compound or intermediate using standard procedures, such as chromatographic separation, recrystallization, or enzymatic resolution.
Similarly, when a pure geometric isomer of a compound is desired, it can be obtained by performing one of the above procedures using a pure geometric isomer as the starting material, or by resolving a mixture of geometric isomers of the compound or intermediates using standard procedures such as chromatographic separation.
It is understood that the synthetic schemes and specific examples are illustrative and should not be construed as limiting the scope of the invention as defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are intended to be included within the scope of the claims.
c. Muscarinic acetylcholine receptor M4Activity of
M4Is the mAChR subtype with the highest expression in the striatum, and the M4The expression of (a) is similar in rodents and primates. M due to lack of selectivity4Antagonists, which have been studied biochemically and genetically and which are highly selective for M4Use of Positive Allosteric Modulators (PAM) to direct the action of M4Understanding the mechanism of action. M of high selectivity4PAM causes a dramatic decrease in behavioral response to psychomotor stimulants that act by increasing striatal DA levels. Furthermore, M4The genetic deletion increases exploratory spontaneous activity, increases locomotor response to phenylpropylamine and other stimulants, and eliminates M4Effect of PAM on spontaneous Activity and Selective deletion of M from striatal spinous Process neurons expressing the D1 subtype of DA receptor (D1-SPN)4These effects were also observed. In vivo microdialysis studies have shown that M4Administration of PAM reduced amphetamine-induced release of DA in the dorsal and ventral striatum, and fMRI studies indicate M4PAM reverses amphetamine attractionIncreased cerebral blood flow (CBV) in striatum and other basal ganglia nuclei. Recently, Fast Sweep Cyclic Voltammetry (FSCV) and genetic studies have shown that M is a complex of N and N4PAM acts at least in part by inhibiting presynaptic DA terminal release of DA in the striatum by releasing endogenous cannabinoids from striatal Spinous Process Neurons (SPNs) and activating CB2 cannabinoid receptors at the DA terminal.
M4Is abundantly expressed in a subset of SPNs, which also express the D of DA receptors1Subtype (D)1DR), which forms a direct path (D1-SPN) that sends inhibitory projections to the nigral reticular portion (SNr). Interestingly, D1DR activates a unique GTP-binding protein in D1-SPN, designated GαolfG of theαolfAnd D1R is coupled to adenylate cyclase activation, cAMP formation, and protein kinase a (pka) activation. This signaling pathway is critical for many behavioral effects of DA-mediated activation of motor activity. Interestingly, M4Coupling to G αi/oG protein, which inhibits adenylyl cyclase and has direct counteracting inhibition D1Receptor signaling and effects on motor function. These studies suggest the following possibilities: in addition to inhibiting DA release, M4PAM can also inhibit D directly by inhibiting cAMP formation directly1D1R mediated signaling in SPN, and this may also contribute to the selectivity M of DA signaling in the basal ganglia4A strong inhibitory effect on activation. In accordance therewith, M4PAM inhibiting direct action D1The motor stimulating effect of the agonist. In addition, a series of pharmacological, genetic and molecular/cellular studies have shown that this response is through inhibition of D in D1-SPN1DR signaling. Thus, M4PAM to D1The main role of DR signaling is not in the striatum, but rather D in SNr1On the GABAergic end of SPN, where D1Activation of DR induces a strong increase in GABA release. This challenges the general view that cholinergic modulation of striatal function is mediated almost exclusively by ACh released from the tensioactive striatal cholinergic interneurons (ChI), and suggests the possibility of: SN on cholinergic projection from the foot bridge nucleusCholinergic innervation of r may also play a key role in regulating motor activity and other functions of the direct basal ganglia pathway. Taken together, these data indicate that, in addition to inhibiting DA release, M4Activation also in expression D1Act postsynaptic to inhibit motor function in SPN of (a).
And M4The prominent role as the major mAChR subtype involved in the regulation of motor function is consistent and many reports suggest that in M4In knockout mice, the locomotor activation of the mAChR antagonist scopolamine was significantly reduced, but the other four mAChR subtypes (M)1-3,5) Then it is not. Furthermore, M compared to wild-type controls4Haloperidol-induced catalepsy (a model of parkinsonian dyskinesia) was reduced in knockout mice. Evaluation of the antiparkinsonian effect of scopolamine by assessing the effect of this compound on the DA receptor antagonist haloperidol-induced catalepsy showed a robust catalepsy completely reversed by scopolamine in WT mice. Reversal of scopolamine is exceptionally robust and more pronounced than our observed reversal for a number of other agents evaluated for potential anti-parkinson effects, including the metabotropic glutamate (mGlu) receptor mGlu4Or mGlu5、A2A adenosine receptors and NMDA receptors. Importantly, scopolamine is reducing M4The KO mice were not effective in catalepsy, suggesting that anti-catalepsy effects of scopolamine are required at mAChR M4Play a role in the above. M binding to basal ganglia and motor function4Extensive studies of modulation, which provided convincing evidence, suggest that M4Is a major mAChR subtype involved in the anti-Parkinson's disease effects of non-selective mAChR antagonists and in order to discover and develop selective M4Antagonists are useful in the treatment of neurodegenerative diseases (e.g., PD, dystonia, tardive dyskinesia, and other movement disorders) provide support.
Despite advances in mAChR research, there is a lack of M as a potential, effective and selective agent4Compounds that are mAChR antagonists. M of high selectivity4Antagonists represent a novel therapeutic approach and can be used in therapeutic packagesNeurodegenerative diseases including PD, dystonia, tardive dyskinesia and other dyskinesias, and can provide the clinical benefits of scopolamine without adverse effects mediated by pan-mAChR inhibition.
In some embodiments, the disclosed compound is a mAChR M4An antagonist of (1). Such activity can be demonstrated by methods known in the art. For example, the response to Ca loading can be measured2+Co-expression of agonists (e.g., acetylcholine) and chimeric or promiscuous G proteins in cells of sensitive fluorescent dyes (e.g., Fluo-4) calcium flux to determine mAChR M4Antagonism of activity. In some embodiments, calcium flux can be measured as an increase in fluorescence static ratio. In some embodiments, antagonist activity can be assayed as EC80Acetylcholine response (i.e., mAChR M at an acetylcholine concentration that produces 80% of the maximal response4Response) increases in concentration dependence.
In some embodiments, the disclosed compounds antagonize mAChR M in the presence of the compound as compared to the equivalent response of CHO-K1 cells in the absence of the compound4Presented as mAChR M4Calcium fluorescence was reduced in transfected CHO-K1 cells. In some embodiments, the disclosed compounds antagonize mAChR M4Response, IC thereof50Less than about 10 μ M, less than about 5 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, or less than about 50 nM. In some embodiments, the mAChR M is4Transfected CHO-K1 cells Using human mAChR M4And (4) transfection. In some embodiments, the mAChR M is4Transfected CHO-K1 cells with rat mAChR M4And (4) transfection. In some embodiments, the mAChR M is4Transfected CHO-K1 cells were treated with mAChR M from dogs or cynomolgus monkeys4And (4) transfection.
The disclosed compounds antagonize mAChR M4mAChR M in transfected CHO-K1 cells4Response, IC thereof50Less than mAChR M1、M2、M3Or M5IC of one or more of transfected CHO-K1 cells50. That is, relative to mAChRM1、M2、M3Or M5One or more of the receptors, the disclosed compounds may be directed against mAChR M4The receptor is selective. For example, in some embodiments, the disclosed compounds can antagonize mAChR M4Response and antagonism of mAChR M1Response phase, IC thereof50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the disclosed compounds can antagonize mAChR M4Response and antagonism of mAChR M2Response phase, IC thereof50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the disclosed compounds can antagonize mAChR M4Responsive, and antagonistic mAChRM3Response phase, IC thereof50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the disclosed compounds can antagonize mAChR M4Response and antagonism of mAChR M5Response phase, IC thereof50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the disclosed compounds can antagonize mAChR M4Response and antagonism of mAChR M1、M2、M3Or M5Receptor response comparison, IC50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold.
The disclosed compounds are antagonistic to M4mAChR M in transfected CHO-K1 cells4Response, IC thereof50Less than about 10 μ M, and relativeIn mAChR M1、M2、M3Or M5One or more of the receptors, for M4The receptor exhibits selectivity. For example, in some embodiments, the IC of the compound50Can be less than about 10 μ M, less than about 5 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, or less than about 50 nM; and the compounds may also antagonize mAChR M4Response and antagonism of mAChR M1Response phase, IC thereof50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the IC of the compound50Can be less than about 10 μ M, less than about 5 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, or less than about 50 nM; and the compounds may also antagonize mAChR M4Response and antagonism of mAChR M2Response phase, IC thereof50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the IC of the compound50Can be less than about 10 μ M, less than about 5 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, or less than about 50 nM; and the compounds may also antagonize mAChR M4Response and antagonism of mAChR M3Response phase, IC thereof50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the IC of the compound50Can be less than about 10 μ M, less than about 5 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, or less than about 50 nM; and the compounds may also antagonize mAChR M4Response and antagonism of mAChR M5Response phase, IC thereof50About 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the IC of the compound50Can be less thanAbout 10 μ M, less than about 5 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, or less than about 50 nM; and the compounds may also antagonize mAChR M4Responsive to, and antagonistic to M2-M5Receptor response comparison, IC50About 5-fold, about 10-fold, about 20-fold, about 30-fold reduction, and antagonism of M2、M3Or M5Receptor response comparison, IC50About 50-fold decrease, about 100-fold decrease, about 200-fold decrease, about 300-fold decrease, about 400-fold decrease, or antagonism of mAChR M1、M2、M3Or M5Receptor response comparison, IC50The reduction is more than about 500 times.
The in vivo efficacy of the compounds disclosed in the models predictive of anti-parkinson activity can be measured in a number of preclinical rat models. For example, the disclosed compounds can reverse motor function deficits induced by dopamine receptor antagonists in mice or rats. Also, these compounds may have defects in reverse transport function that are observed by other manipulations that reduce dopaminergic signaling (e.g., selective damage to dopamine neurons). In addition, these compounds may have efficacy in animal models of dystonia, and may increase measures of attention, cognitive function and aggressiveness in animal models.
3. Pharmaceutical compositions and formulations
The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to a subject (e.g., a patient, which can be human or non-human). The disclosed compounds can also be provided as formulations (e.g., spray-dried dispersion formulations).
The pharmaceutical compositions and formulations may include a "therapeutically effective amount" or a "prophylactically effective amount" of an agent. "therapeutically effective amount" means an amount effective at the dosage and for the period of time required to achieve the desired therapeutic result. A therapeutically effective amount of the composition can be determined by one of skill in the art and will vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also an amount at which any toxic or adverse effects of the compounds of the present invention (e.g., the compounds of formula (I)) do not outweigh any therapeutically beneficial effects. By "prophylactically effective amount" is meant an amount effective, at the dosage and for the desired period of time, to achieve the desired prophylactic result. Typically, because the prophylactic dose is administered in the subject prior to or early in the disease, such a prophylactically effective amount will be less than the therapeutically effective amount.
For example, a therapeutically effective amount of a compound of formula (I) may be from about 1mg/kg to about 1000mg/kg, from about 5mg/kg to about 950mg/kg, from about 10mg/kg to about 900mg/kg, from about 15mg/kg to about 850mg/kg, from about 20mg/kg to about 800mg/kg, from about 25mg/kg to about 750mg/kg, from about 30mg/kg to about 700mg/kg, from about 35mg/kg to about 650mg/kg, from about 40mg/kg to about 600mg/kg, from about 45mg/kg to about 550mg/kg, from about 50mg/kg to about 500mg/kg, from about 55mg/kg to about 450mg/kg, from about 60mg/kg to about 400mg/kg, from about 65mg/kg to about 350mg/kg, from about 70mg/kg to about 300mg/kg, or, From about 75mg/kg to about 250mg/kg, from about 80mg/kg to about 200mg/kg, from about 85mg/kg to about 150mg/kg, and from about 90mg/kg to about 100 mg/kg.
Pharmaceutical compositions and formulations may include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation aid of any type. Some examples of materials that can be used as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose, and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; astragalus membranaceus gel powder; malt; gelatin; talc powder; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring, mold release, coating, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be included in the composition, according to the judgment of the formulator.
Thus, the compounds and their physiologically acceptable salts can be formulated for administration by, for example, solid administration, eye drops, in topical oil-based formulations, injection, inhalation (through the mouth or nose), implants, or for oral, buccal, parenteral, or rectal administration. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences [ ramsden Pharmaceutical monographs ], (Meade Publishing co., Easton, Pa.), Pa). Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage.
The route of administration of the disclosed compounds and the form of the composition determine the type of carrier to be used. The composition can be in a variety of forms suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant, or parenteral) or topical administration (e.g., skin, lung, nasal, ear, eye, liposome delivery systems, or iontophoresis).
Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavoring agents, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and the like. All carriers are optional in the composition.
Suitable diluents include sugars such as glucose, lactose, dextrose and sucrose; glycols, such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerol; mannitol; and sorbitol. The amount of one or more diluents in the systemic or topical composition is typically from about 50% to about 90%.
Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants, for example, polyethylene glycol and vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter. The amount of one or more lubricants in the systemic or topical composition is typically from about 5% to about 10%.
Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starches, such as corn starch and potato starch; gelatin; gum tragacanth; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose and sodium carboxymethylcellulose. The amount of the one or more binders in the systemic composition is typically from about 5% to about 50%.
Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmellose, crospovidone, sodium starch glycolate, clays and ion exchange resins. The amount of disintegrant(s) in the systemic or topical composition is typically from about 0.1% to about 10%.
Suitable colorants include colorants such as FD & C dyes. When used, the amount of one or more coloring agents in a systemic or topical composition is typically from about 0.005% to about 0.1%.
Suitable flavoring agents include menthol, peppermint, and fruit flavors. When used, the amount of the one or more flavoring agents in the systemic or topical composition is typically from about 0.1% to about 1.0%.
Suitable sweetening agents include aspartame and saccharin. The amount of the one or more sweeteners in the systemic or topical composition is typically from about 0.001% to about 1%.
Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant or antioxidants in the systemic or topical composition is typically from about 0.1% to about 5%.
Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of one or more preservatives in a systemic or topical composition is typically from about 0.01% to about 5%.
Suitable glidants include silicon dioxide. The amount of one or more glidants in a systemic or topical composition is typically from about 1% to about 5%.
Suitable solvents include water, isotonic saline, ethyl oleate, glycerol, hydroxylated castor oil, alcohols (e.g., ethanol), and phosphate buffered solutions. The amount of solvent or solvents in the systemic or topical composition is typically from about 0 to about 100%.
Suitable suspending agents include AVICEL RC-591 (from FMC corporation, Philadelphia, Pa.) and sodium alginate. The amount of suspending agent or agents in the systemic or topical composition is typically from about 1% to about 8%.
Suitable surfactants include lecithin, polysorbate 80 and sodium lauryl sulfate, and TWEENS (Atlas Powder Company, Wilmington, Del.). Suitable surfactants are included in c.t.f.a.cosmetic Ingredient Handbook, 1992, pages 587 and 592; remington's Pharmaceutical Sciences [ Remington's Pharmaceutical Specification ], 15 th edition, 1975, page 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents [ Ma Ka Heng, Vol.1, Emulsifiers and Detergents ],1994, North American edition, p.236-. The amount of surfactant or surfactants in the systemic or topical composition is typically from about 0.1% to about 5%.
Although the amount of components in the systemic composition can vary depending on the type of systemic composition prepared, generally, the systemic composition comprises from 0.01% to 50% of the active compound (e.g., a compound of formula (I)) and from 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically comprise 0.1% to 10% of the active and 90% to 99.9% of a carrier comprising diluents and solvents.
Compositions for oral administration may have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms comprise a safe and effective amount (typically at least about 5%, more specifically about 25% to about 50%) of the active ingredient. Oral dosage compositions comprise from about 50% to about 95% of the carrier, and more specifically, from about 50% to about 75%.
Tablets may be compressed, tablet milled, enteric coated, sugar coated, film coated or multiple compressed. Tablets typically comprise the active ingredient and a carrier comprising an ingredient selected from the group consisting of diluents, lubricants, binders, disintegrants, coloring agents, flavoring agents, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin and sucrose. Specific disintegrating agents include alginic acid and crosslinked carboxymethyl cellulose. Specific lubricants include magnesium stearate, stearic acid and talc. A specific colorant is FD & C dye, which may be added for appearance. Chewable tablets preferably contain sweetening agents (e.g., aspartame and saccharin), or flavoring agents (e.g., menthol, peppermint, fruity flavoring agents), or combinations thereof.
Capsules (including implants, timed release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)) and a carrier comprising one or more diluents within a gelatin-containing capsule as disclosed above. The granules typically comprise the disclosed compounds, preferably a glidant (e.g. silicon dioxide) to improve flow properties. The implant may be of the biodegradable or non-biodegradable type.
The choice of ingredients in the carrier for oral compositions depends on secondary considerations such as taste, cost and storage stability, which are not important for the purposes of the present invention.
The solid compositions may be coated by conventional means (typically with a pH or time dependent coating) such that the disclosed compounds are released in the gastrointestinal tract, either near the desired administration, or at different points and times, to prolong the desired effect. The coating typically comprises one or more components selected from the group consisting of: cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose,
Compositions for oral administration may have a liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent formulations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Compositions for liquid oral administration typically comprise the disclosed compounds and a carrier, i.e., a carrier selected from diluents, coloring agents, flavoring agents, sweetening agents, preservatives, solvents, suspending agents, and surfactants. The oral liquid composition preferably comprises one or more ingredients selected from the group consisting of coloring agents, flavoring agents and sweetening agents.
Other compositions useful for achieving systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more soluble filler materials, such as diluents, including sucrose, sorbitol, and mannitol); and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.
The disclosed compounds may be administered topically. Topical compositions that can be topically administered to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-off conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. The topical composition comprises: disclosed are compounds (e.g., compounds of formula (I)) and carriers. The carrier of the topical composition preferably aids penetration of the compound into the skin. The carrier may further comprise one or more optional components.
The amount of carrier used in combination with the disclosed compounds is sufficient to provide the actual amount of the composition administered per unit dose of the compound. Techniques and compositions for preparing dosage forms useful in the methods of the invention are described in the following references: modern pharmaceuticals chapter 9 and 10, Banker & Rhodes, eds. (1979); lieberman et al, Pharmaceutical Dosage Forms: Tablets [ Pharmaceutical Dosage Forms: tablets ] (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2 nd edition (1976).
The carrier may comprise a single ingredient or a combination of two or more ingredients. In topical compositions, the carrier comprises a topical carrier. Suitable topical carriers include one or more ingredients selected from the group consisting of: phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin a and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide \ castor oil, combinations thereof, and the like. More specifically, carriers for dermal administration include propylene glycol, dimethyl isosorbide and water, even more specifically, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols and symmetrical alcohols.
The carrier of the topical composition may further comprise one or more ingredients selected from the group consisting of: ingredients for emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments and preservatives, all of which are optional.
Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1, 2-diol, butane-1, 3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, carnyl lactate, decyl oleate, Myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and dimethicone. The amount of the one or more emollients in skin-based topical compositions is typically from about 5% to about 95%.
Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide and combinations thereof. The amount of propellant or propellants in the topical composition is typically from about 0 to about 95%.
Suitable solvents include water, ethanol, dichloromethane, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethanol and homotopic alcohols. The amount of the one or more solvents in the topical composition is typically from about 0 to about 95%.
Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in the topical composition is typically from 0 to 95%.
The amount of one or more thickening agents in the topical composition is typically from about 0 to about 95%.
Suitable powders include β -cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silica, sodium polyacrylate, tetraalkyl ammonium montmorillonite, trialkyl aryl ammonium montmorillonite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof.
The amount of fragrance in the topical composition is typically from about 0 to about 0.5%, specifically, from about 0.001% to about 0.1%.
Suitable pH adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.
The pharmaceutical composition or formulation antagonizes mAChR M4IC thereof50Less than about 10 μ M, less than about 5 μ M, less than about 1 μ M, less than about 500nM, or less than about 100 nM. The pharmaceutical composition or formulationThe product can antagonize mAChR M4IC thereof50Between about 10. mu.M and about 1nM, between about 1. mu.M and about 1nM, between about 100nM and about 1nM, or between about 10nM and about 1 nM.
a. Spray-dried dispersion formulations
The disclosed compounds can be formulated as Spray Dried Dispersions (SDD). SDD is a single phase, amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution in which the compound is molecularly "dissolved" in a solid matrix. SDD is obtained by dissolving the drug and polymer in an organic solvent and then spray drying the solution. The use of spray drying for pharmaceutical applications can result in amorphous dispersions with increased solubility of Biopharmaceutical Classification System (BCS) class II (high permeability, low solubility) and class IV (low permeability, low solubility) drugs. The formulation and process conditions are selected to provide rapid evaporation of the solvent from the droplets, thereby providing insufficient time for phase separation or crystallization. SDD has demonstrated long-term stability and manufacturability. For example, SDD demonstrates a shelf life of over 2 years. Advantages of SDD include, but are not limited to, enhanced oral bioavailability of poorly water soluble compounds, delivery using traditional solid dosage forms (e.g., tablets and capsules), repeatable, controllable, and scalable manufacturing processes, and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.
Thus, in one embodiment, the present disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I).
4. Application method
The disclosed compounds, pharmaceutical compositions, and formulations are useful in methods of treating disorders associated with muscarinic acetylcholine receptor dysfunction, such as neurological disorders and/or psychiatric disorders. The disclosed compounds and pharmaceutical compositions may also be used in methods of reducing muscarinic acetylcholine receptor activity in a mammal. The method also includes co-therapeutic methods for improving therapeutic outcome. In the methods of use described herein, one or more additional therapeutic agents can be administered simultaneously or sequentially with the disclosed compounds and compositions.
a. Treatment of disorders
The disclosed compounds, pharmaceutical compositions, and formulations can be used in methods of treating, preventing, ameliorating, controlling, reducing the symptoms of, or reducing the risk of multiple disorders in which patients will receive a mAChRM from an mAChRM4Benefit from antagonism. In some embodiments, the disorder may be a neurodegenerative disorder, a movement disorder, or a brain disorder. The method may comprise administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
Patients would benefit from mAChR M4Disorders of antagonism may include neurodegenerative disorders and movement disorders. For example, exemplary disorders can include parkinson's disease, drug-induced parkinson's disease, dystonia, tourette's syndrome, dyskinesias (e.g., tardive dyskinesia or levodopa-induced dyskinesia), schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness (e.g., narcolepsy), Attention Deficit Hyperactivity Disorder (ADHD), huntington's disease, chorea (e.g., chorea associated with huntington's disease), cerebral palsy, and progressive supranuclear palsy.
In some embodiments, the present disclosure provides a method of treating motor symptoms in a subject with parkinson's disease, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the motor symptom is selected from bradykinesia, tremor, rigidity, gait dysfunction, and postural instability. The method can treat, control and/or reduce motor symptoms in a subject.
In some embodiments, the present disclosure provides a method of treating a motor symptom in a subject suffering from dystonia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. The method can treat, control and/or reduce motor symptoms in a subject. For example, the treatment can reduce muscle contraction or spasm in a subject suffering from dystonia.
In some embodiments, the present disclosure provides a method for treating motor symptoms in a subject with tardive dyskinesia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. The method can treat, control and/or reduce motor symptoms in a subject. For example, treatment can reduce involuntary movements in a subject with tardive dyskinesia.
In some embodiments, the present disclosure provides a method for preventing or delaying tardive dyskinesia in a subject at risk of developing tardive dyskinesia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. For example, the subject may be a subject being treated with a neuroleptic drug (e.g., a typical antipsychotic or an atypical antipsychotic), a dopamine antagonist, or an antiemetic.
In some embodiments, the present disclosure provides a method of treating catalepsy in a subject with schizophrenia, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. For example, the subject with schizophrenia may have catalepsy induced by neuroleptic agents (e.g., typical antipsychotics or atypical antipsychotics).
In some embodiments, the present disclosure provides a method for treating a cancer that may benefit from mAChR M4A method of antagonizing an acting brain disorder characterized by altered dopamine and cholinergic signaling, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the therapy may increase aggressiveness or target-oriented behavior in patients with disorders characterized by reduced aggressiveness of target-oriented behavior, such as schizophrenia and other brain disorders.
In some embodiments, the present disclosure provides a method for increasing wakefulness and/or reducing excessive daytime sleepiness in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a subject with narcolepsy.
In some embodiments, the present disclosure provides a method of increasing attention in a subject in need thereof (e.g., a subject having an attention deficit disorder, e.g., ADHD), the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In some embodiments, the present disclosure provides a method for treating a motor symptom in a subject having a drug-induced movement disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the drug-induced dyskinesia is selected from drug-induced parkinson's disease, tardive dyskinesia, tardive dystonia, akathisia, myoclonus, and tremor. The method can treat, control and/or reduce motor symptoms in a subject.
These compounds and compositions may further be used in methods for preventing, treating, controlling, ameliorating, or reducing the risk of the diseases, disorders, and conditions described herein. These compounds and compositions can be further used in combination with other agents in methods for preventing, treating, controlling, ameliorating, or reducing the risk of the diseases, disorders, and conditions described above.
In situations such as would benefit from mAChR M4In the treatment of the symptoms of antagonism, a suitable dosage level may be about 0.01 to 500mg/kg of patient body weight per day, which may be administered in single or multiple doses. The dosage level may be from about 0.1 to about 250mg/kg per day, or from about 0.5 to about 100mg/kg per day. Suitable dosage levels may be about 0.01 to 250mg/kg per day, about 0.05 to 100mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range, the dose may be 0.05 to 0.5, 0.5 to 5, or 5 to 50mg/kg per day. For oral administration, the composition may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, specifically 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 or 1000 milligrams of the active ingredient for dose modulation of the symptoms in the patient to be treated. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. The dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease and the host undergoing therapy.
Thus, in some embodiments, the present disclosure relates to a method for antagonizing mAChR M in at least one cell4A method for the manufacture of a receptor,the method includes contacting the at least one cell with an effective antagonist of mAChR M in the at least one cell4With at least one disclosed compound or at least one product of a disclosed process. In some embodiments, the cell is mammalian, e.g., human. In some embodiments, the cell has been isolated from the subject prior to the contacting step. In some embodiments, the contacting is by administration to the subject.
In some embodiments, the invention relates to a mAChR M for antagonizing a mAChR M in a subject4A method of receptor, the method comprising antagonizing mAChR M in an effective manner in a subject4A dose and amount of the receptor to a subject of at least one disclosed compound or at least one product of a disclosed method. In some embodiments, the subject is a mammal, e.g., a human. In some embodiments, prior to the administering step, the mammal has been diagnosed as requiring mAChR M4Antagonism is obtained. In some embodiments, prior to the administering step, the mammal has been diagnosed as requiring mAChR M4Antagonism is obtained. In some embodiments, the method further comprises the steps of: identification of the need for mAChR M4Antagonistic subjects.
b. Antagonism of muscarinic acetylcholine receptors
In some embodiments, the present disclosure relates to a mAChR M for antagonizing machms in a mammal4The method of (2), the method comprising the steps of: administering to the mammal an effective amount of at least one of the disclosed compounds or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one of the disclosed compounds or a pharmaceutically acceptable salt thereof.
In some embodiments, the muscarinic acetylcholine receptor antagonistic effect decreases muscarinic acetylcholine receptor activity.
In some embodiments, the administered compound antagonizes mAChR M4IC thereof50Less than about 10 μ M, less than about 5 μ M, less than about 1 μ M, less than about 500nM, or less than about 100 nM. In some embodiments, the administered compound antagonizes mAChR M4Of which IC50Between about 10. mu.M and about 1nM, between about 1. mu.M and about 1nM, between about 100nM and about 1nM, or between about 10nM and about 1 nM.
In some embodiments, the mammal is a human. In some embodiments, prior to the administering step, the mammal has been diagnosed as having a need to decrease muscarinic acetylcholine receptor activity. In some embodiments, the method further comprises the steps of: identifying a mammal in need of reducing muscarinic acetylcholine receptor activity. In some embodiments, antagonism of muscarinic acetylcholine receptors may treat disorders associated with muscarinic acetylcholine receptor activity in mammals. In some embodiments, the muscarinic acetylcholine receptor is a mAChR M4。
In some embodiments, antagonism of muscarinic acetylcholine receptors in mammals is associated with the treatment of disorders associated with muscarinic receptor dysfunction (e.g., the disorders disclosed herein). In some embodiments, the muscarinic receptor is mAChR M4。
In some embodiments, the present disclosure provides a method for antagonizing muscarinic acetylcholine receptors in a cell, comprising the steps of: contacting the cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is mammalian (e.g., human). In some embodiments, the cell has been isolated from the mammal prior to the contacting step. In some embodiments, the contacting is by administration to a mammal.
c. Co-treatment method
The disclosure also relates to mAChR M4Antagonists (e.g. selective mAChR M4Antagonists) to improve treatment outcome. That is, in some embodiments, the present disclosure relates to a method of co-treatment comprising the steps of: an effective amount and dose of at least one of the disclosed compounds, or a pharmaceutically acceptable salt thereof, is administered to a mammal.
In some embodiments, administration improves the therapeutic effect in the context of cognitive or behavioral therapy. Administration in conjunction with cognitive or behavioral therapy may be continuous or intermittent. Administration need not be simultaneous with therapy, and can be performed before, during, and/or after therapy. For example, cognitive or behavioral therapy may be provided within 1,2,3, 4,5, 6,7 days before or after administration of the compound. As another example, cognitive or behavioral therapy may be provided within 1,2,3, or 4 weeks before or after administration of the compound. As still further examples, cognitive or behavioral therapy may be provided before or after administration within a period of 1,2,3, 4,5, 6,7,8, 9, or 10 half-lives of the administered compound.
In some embodiments, administration improves the therapeutic effect in the context of physical or task therapy. Administration in connection with the physical or task therapy may be continuous or intermittent. Administration need not be simultaneous with therapy, and can be performed before, during, and/or after therapy. For example, physical or task therapy may be provided before or after 1,2,3, 4,5, 6,7 days of administration of the compound. As another example, physical or task therapy may be provided before or after 1,2,3, 4 weeks of administration of the compound. As still further examples, physical or task therapy may be provided before or after administration within a period of 1,2,3, 4,5, 6,7,8, 9, or 10 half-lives of the administered compound.
It is to be understood that the disclosed co-treatment methods can be used in conjunction with the disclosed compounds, compositions, kits, and uses.
d. Combination therapy
In the methods of use described herein, one or more additional therapeutic agents can be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, one or more additional therapeutic agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be a time interval between administration of the additional therapeutic agent and the disclosed compound. In some embodiments, administration of additional therapeutic agents with the disclosed compounds may allow for lower doses of the other therapeutic agents and/or administration at lower frequency intervals. When used in combination with one or more other active ingredients, the compounds of the present invention, as well as the other active ingredients, may be used in lower doses than when used alone. Accordingly, the pharmaceutical compositions of the present invention also include pharmaceutical compositions containing one or more other active ingredients in addition to the compound of formula (I). The above combinations include not only combinations of a compound of the present invention with one other active compound, but also combinations of a compound of the present invention with two or more other active compounds.
The disclosed compounds can be used as single agents, or in combination with one or more other drugs, for treating, preventing, managing, ameliorating, or reducing the risk of the aforementioned diseases, disorders, and conditions for which the compound or other drug has utility, where the drugs in combination are safer or more effective than either drug alone. One or more additional agents may be administered by a route and in amounts commonly used therewith, either simultaneously or sequentially with the disclosed compounds. When the disclosed compounds are used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compounds may be used. However, the combination therapy may also be administered on an overlapping schedule. It is also contemplated that combinations of one or more active ingredients and the disclosed compounds may be more effective than as a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds, as well as the other active ingredients, may be used in lower doses than each when used alone.
The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds mentioned herein, which are generally applied for the treatment of the above mentioned pathological conditions.
Combinations above include not only combinations of the disclosed compounds with one other active compound, but also combinations with two or more other active compounds. Likewise, the disclosed compounds can be used in combination with other drugs that are useful for preventing, treating, controlling, ameliorating, or reducing the risk of a disease or disorder for which the disclosed compounds are useful. Such other agents may be administered by one route and in amounts commonly used therefor, either simultaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, the pharmaceutical composition preferably contains such other drugs in addition to the disclosed compound. Thus, in addition to the compounds of the present invention, pharmaceutical compositions also include those that also contain one or more other active ingredients.
The weight ratio of the disclosed compound to the second active ingredient can vary and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the invention is combined with another agent, the weight ratio of the disclosed compound to the other agent typically ranges from about 1000:1 to about 1:1000, preferably from about 200:1 to about 1: 200. Combinations of the compounds of the invention with other active ingredients will generally also be within the above ranges, but in each case an effective dose of each active ingredient should be used.
In such combinations, the disclosed compounds and other active agents can be administered separately or in combination. In addition, administration of one element may be performed before, simultaneously with, or subsequently to the administration of another agent or agents.
Thus, the disclosed compounds can be used alone or in combination with other agents known to be beneficial in a subject's indications or other drugs affecting receptors or enzymes, which can increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compounds and other agents may be co-administered in concomitant therapy or in fixed combination.
In some embodiments, the compounds may be used in combination with any other agent useful for treating the disorders described herein, e.g., for mAChR M that may benefit from4Standard of care therapy for antagonistic disorders (such as those described herein). For example, in some embodiments, the compound may be used in combination with: parkinson's disease drugs (e.g., L-DOPA or carbidopa)Levodopa), mGlu4Positive allosteric modulators, mGlus5Negative allosteric modulators, A2An a inhibitor, a T-type calcium channel antagonist, a VMAT2 inhibitor, a muscle relaxant (e.g., baclofen), an anticholinergic, an antiemetic, a typical or atypical neuroleptic agent (e.g., risperidone, ziprasidone, haloperidol, pimozide, fluphenazine), an antihypertensive agent (e.g., clonidine or guanfacine), a tricyclic antidepressant (e.g., amitriptyline, bupiririne, clomipramine, desipramine, doxepin, imipramine, eprednol, lofepramine, nortriptyline, protiline, or trametamine), an agent that increases the level of extracellular dopamine (e.g., amphetamine, methylphenidate, or rilisamide), an agent used to treat excessive daytime sleepiness (e.g., sodium molybdate or a wakefulness promoter such as amofenib or mofenib), and a norepinephrine reuptake inhibitor (including selective NRI, such as tomoxetine, and non-selective NRIs, such as bupropion).
e. Mode of administration
Methods of treatment can include any number of means for administering the disclosed compositions. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions (e.g., oil-in-water emulsions), liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. To prepare a pharmaceutical composition for oral administration, the agent may be mixed with adjuvants and excipients generally known and used, such as gum arabic, talc, starch, sugars (e.g., such as mannose, methylcellulose, lactose), gelatin, surfactants, magnesium stearate, aqueous or nonaqueous solvents, paraffin derivatives, crosslinking agents, dispersing agents, emulsifying agents, lubricants, preservatives, flavoring agents (e.g., ether oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol), or bioavailability enhancers (e.g., gelucire (tm)). In pharmaceutical compositions, the agent may also be dispersed in microparticles (e.g., nanoparticle compositions).
For parenteral administration, the agent may be dissolved or suspended in a physiologically acceptable diluent, such as water, buffer, oil with or without solubilizing agents, surfactants, dispersants or emulsifiers. As the oil, for example, but not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil may be used. More generally, for parenteral administration, the agent may be in the form of an aqueous, lipid, oily or other kind of solution or suspension, or even administered in the form of liposomes or nanosuspensions.
The term "parenteral" as used herein refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intraarticular injection and infusion.
5. Reagent kit
In one aspect, the present disclosure provides a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, and one or more of:
(a) at least one known to increase mAChR M4An active agent;
(b) at least one known mAChR M-lowering agent4An active agent;
(c) at least one known therapeutic mAChR M4Agents related to disorders, such as the disorders described herein; and
(d) instructions for administering the compound.
In some embodiments, the at least one disclosed compound and the at least one pharmaceutical agent are co-formulated. In some embodiments, the at least one disclosed compound and the at least one pharmaceutical agent are co-packaged. Kits may also comprise compounds and/or products co-packaged, co-formulated, and/or co-delivered with other components. For example, a pharmaceutical manufacturer, pharmaceutical distributor, physician, pharmacy, or pharmacist can provide a kit containing the disclosed compounds and/or products, as well as another component for delivery to a patient.
The disclosed kits can be used in conjunction with the disclosed methods of use.
The kit may further comprise information, instructions, or both, such that use of the kit will provide treatment for a medical condition in a mammal, particularly a human. The information and instructions may be in the form of words, pictures, or both. Additionally or alternatively, the kit can include a compound, a composition, or both; and information about the method of administration of the compound or composition, preferably with a benefit of treating or preventing a medical condition in a mammal (e.g., a human), instructions, or both.
The compounds and methods of the present invention will be better understood by reference to the following examples, which are intended to illustrate, but not to limit the scope of the invention.
6. Examples of the invention
All NMR spectra were recorded on a 400MHz AMX Bruker NMR spectrometer. Reported as ppm downfield delta values using deuterated solvents as internal standards1And H chemical shift. The data are reported as follows: chemical shift, multiplicity (s ═ singlet, bs ═ broad singlet, d ═ doublet, t ═ triplet, q ═ quartet, dd ═ doublet, m ═ multiplet, ABq ═ AB quartet), coupling constant, integration. Reverse phase LCMS analysis was performed using an Agilent 1200 system consisting of a binary pump with degasser, high performance autosampler, thermostatted column chamber, C18 column, Diode Array Detector (DAD) and Agilent 6150MSD with the following parameters. Gradient conditions were 5% to 95% acetonitrile and aqueous phase 0.1% TFA in water over 1.4 min. The samples were separated on a WatersAcquity UPLC BEH C18 column (1.7 μm, 1.0X 50mm) at 0.5mL/min and the column temperature and solvent temperature were maintained at 55 ℃. The DAD was set to scan from 190nm to 300nm and the signals used were 220nm and 254nm (both bandwidths were 4 nm). The MS detector was configured with an electrospray ionization source and low resolution mass spectra were obtained by scanning from 140 to 700AMU (step size 0.2AMU at 0.13 cycles/sec, peak width 0.008 min). The drying gas flow rate was set to 13 liters per minute at 300 ℃ and the atomizer pressure was set to 30 psi. The capillary needle voltage was set to 3000V and the fragmentation voltage was set to 100V. Make itData acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.
Abbreviations used in the following examples and reaction schemes are:
AcOH acetic acid
Brettphos-Pd-G3 methanesulfonic acid (2-dicyclohexylphosphino-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (CAS number 1470372-59-8)
DCE 1, 2-dichloroethane
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
EtOAc ethyl acetate
h or hr
HATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate
IPA isopropyl alcohol
LAH lithium aluminum hydride
MeOH methanol
NaBH(OAc)3Sodium triacetoxyborohydride
NMP N-methyl-2-pyrrolidone
PyClU 1- (chloro-1-pyrrolidinylmethylene) pyrrolidine hexafluorophosphate
RP-HPLC reversed-phase high performance liquid chromatography
rt or r.t. Room temperature
RuPhos-Pd-G3 methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-2-yl) palladium (II) (CAS number 1445085-77-7)
SFC supercritical fluid chromatography
THF tetrahydrofuran
Example 1.6- (2-chloro-5-fluorophenyl) -N- ((6- ((3- (trifluoromethyl) pyridin-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazin-3-amine (Compound 1)
Tert-butyl 1- (((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. Reacting tert-butyl 2- (aminomethyl) -6-azaspiro [2.5]]Octane-6-carboxylate (3.0g, 12.5mmol) was dissolved in t-BuOH (14mL) and DIPEA (6.5mL, 37.4mmol) was added followed by 3, 6-dichloropyridazine (4.65g, 31.2 mmol). The resulting suspension was heated to 100 ℃ overnight, then the reaction was cooled to room temperature and quenched with DCM and saturated NaHCO3And (6) diluting. The aqueous layer was extracted with DCM and the organic extract was filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC and the product containing fractions were extracted with DCM. The organic extract was extracted with MgSO4Dried, filtered and concentrated to give the title compound as a white sponge solid. (1.86g, 42%).1H-NMR(400MHz,CDCl3)δ7.16(d,J＝9.2Hz,1H),6.64(d,J＝9.3Hz,1H),4.74(br,1H),3.65(br,2H),3.47-3.35(m,2H),3.26-3.20(m,2H),1.69-1.62(m,1H),1.57-1.51(m,1H),1.46(s,9H),1.40-1.35(m,1H),1.17-1.13(m,1H),1.05-0.98(m,1H),0.63(dd,J＝8.4,4.7Hz,1H),0.30(t,J＝5.0Hz,1H)。ES-MS[M+H]+＝353.2。
Tert-butyl 1- (((6- (2-chloro-5-fluorophenyl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. To a 5mL microwave vial was added tert-butyl 1- (((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [ 2.5%]Octane-6-carboxylate (199mg, 0.56mmol), 2-chloro-5-fluorophenylboronic acid (147mg, 0.85mmol), K2CO3(237mg, 1.69mmol) and RuPhos-Pd-G3(24mg, 0.03 mmol). Then 5:1, 4-dioxane/H was added2O (2.5mL), the resulting suspension was stirred at 120 ℃ for 30 minutes under microwave irradiation, then the reaction mixture was cooled to room temperature and quenched with DCM and saturated NaHCO3And (6) diluting. The aqueous layer was extracted with DCM and the organic extract was filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a colorless oil (100mg, 40%).1H-NMR(400MHz,CDCl3)δ7.61(d,J＝9.2Hz,1H),7.47(d,J＝9.1,3.1Hz,1H),7.40(dd,J＝8.8,5.0Hz,1H),7.06-7.01(m,1H),6.69(d,J＝9.3Hz,1H),4.93(br,1H),3.65(br,2H),3.55-3.42(m,2H),3.28-3.21(m,2H),1.71-1.65(m,1H),1.58-1.52(m,1H),1.46(s,9H),1.43-1.38(m,1H),1.18-1.13(m,1H),1.10-1.03(m,1H),0.64(dd,J＝8.4,4.7Hz,1H),0.32(t,J＝5.0Hz,1H)。ES-MS[M+H]+＝447.2。
N- ((6-azaspiro [ 2.5)]Octane-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazin-3-amine. Tert-butyl 1- (((6- (2-chloro-5-fluorophenyl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (100mg, 0.22mmol) was dissolved in 1, 4-dioxane (2 mL). 4M HCl in 1, 4-dioxane solution (2mL) was then added dropwise. The resulting mixture was stirred at room temperature for 30 minutes, then the solvent was removed under reduced pressure and the resulting white solid was dried under vacuum and used as the HCl salt without further purification. ES-MS [ M + H ]]+＝347.0。
6- (2-chloro-5-fluorophenyl) -N- ((6- ((3- (trifluoromethyl) pyridin-2-yl) methyl) -6-azaspiro [2.5]Octane-1-yl) methyl) pyridazin-3-amine (Compound 1). Reacting N- ((6-azaspiro [2.5]]Octane-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazin-3-amine hydrochloride (11mg, 0.028mmol) was suspended in DCM (1mL) and 3- (trifluoromethyl) pyridine-2-carbaldehyde (24mg, 0.14mmol) was added and allowed to stir at room temperature for 5 minutes, after which sodium triacetoxyborohydride (30mg, 0.14mmol) was added. The resulting solution was stirred at room temperature overnight, and then the reaction mixture was taken up with saturated NaHCO3Quenched and extracted with 3:1 chloroform/IPA. The organic extract was filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC and the product-containing fractions were purified with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The organic extract was filtered through a phase separator and concentrated to give the title compound as a colorless oil (6.2mg, 44%).1H-NMR(400MHz,CDCl3)δ8.80(dd,J＝4.6,0.8Hz,1H),7.95(dd,J＝8.0,1.2Hz,1H),7.61(d,J＝9.3Hz,1H),7.48(dd,J＝9.2,3.1Hz,1H),7.41(dd,J＝8.8,5.0Hz,1H),7.31(dd,J＝7.8,4.8Hz,1H),7.07-7.02(m,1H),6.68(d,J＝9.3Hz,1H),4.83(t,J＝4.6Hz,1H),3.83(s,2H),3.52-3.41(m,2H),2.67-2.62(m,2H),2.50-2.45(m,2H),1.83-1.78(m,1H),1.69-1.65(m,1H),1.49-1.46(m,1H),1.25-1.20(m,1H),1.05-0.97(m,1H),0.61(dd,J＝8.4,4.6Hz,1H),0.28(t,J＝4.9Hz,1H)。ES-MS[M+H]+＝506.2。
Example 2N- ((6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (4-fluorophenyl) pyridazin-3-amine (Compound 2)
6-chloro-N- ((6- (3, 3-dimethylbutyl) -6-azaspiro [ 2.5)]Octane-1-yl) methyl) pyridazin-3-amine. Tert-butyl 1- (((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (prepared as described in example 1) (1.34g, 3.80mmol) was dissolved in 1, 4-dioxane (15mL) and 4M HCl in dioxane solution (15mL) was added dropwise. The resulting cloudy solution was stirred at room temperature for 30 minutes, then the solvent was concentrated to give a white solid, which was dried under vacuum and used as the HCl salt without further purification. The aforementioned HCl salt (1.10g, 3.80mmol) was suspended in DCM (20mL), then 3, 3-dimethylbutyraldehyde (1.14g, 11.39mmol) was added dropwise, followed by sodium triacetoxyborohydride (2.41g, 11.39 mmol). The resulting suspension was stirred at room temperature for 6 hours, then the reaction was cooled to 0 ℃ and saturated NaHCO was used3And (4) quenching. The aqueous layer was extracted with DCM and 3:1 chloroform/IPA. The organic extract was extracted with MgSO4Dry, then filter the solvent and concentrate to give the title compound as a yellow oil, which was used without further purification (1.28g, 100%).1H-NMR(400MHz,CDCl3)δ7.12(d,J＝9.3Hz,1H),6.68(d,J＝9.3Hz,1H),5.05(br,1H),3.41-3.36(m,2H),2.68(br,2H),2.45-2.41(m,4H),1.80-1.38(m,6H),1.00-0.93(m,1H),0.89(s,9H),0.57(dd,J＝8.4,4.7Hz,1H),0.24(t,J＝4.9Hz,1H)。ES-MS[M+H]+＝337.3。
N- ((6- (3, 3-dimethylbutyl) -6-azaspiro [ 2.5)]Octane-1-yl) methyl) -6- (4-fluorophenyl) pyridazin-3-amine (compound 2). Mixing 6-chloro-N- ((6- (3, 3-dimethylbutyl) -6-azaspiro [2.5]]Octane-1-yl) methyl) pyridazin-3-amine (20mg, 0.06mmol), K2CO3(25mg，0.18mmol) 4-fluorophenylboronic acid (10mg, 0.07mmol) and RuPhos-Pd-G3(5mg, 0.006mmol) were combined in a sealed vial and then 5:1, 4-dioxane/H was added by syringe2O (1.2mL, degassed). The resulting suspension was stirred under an inert atmosphere at 100 ℃ for 2 hours, then the reaction was cooled to room temperature and quenched with saturated NaHCO3And 3:1 chloroform/IPA dilution. The aqueous layer was extracted with 3:1 chloroform/IPA and the organic extract was then filtered through a phase separator. The solvent was concentrated and the crude residue was purified by RP-HPLC. The product containing fractions were diluted with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The solvent was filtered through a phase separator and concentrated to give the title compound as a colorless oil (2.7mg, 11%).1H-NMR(400MHz,CDCl3)δ7.95-7.91(m,2H),7.57(d,J＝9.3Hz,1H),7.18-7.12(m,2H),6.74(d,J＝9.3Hz,1H),4.78(t,J＝4.6Hz,1H),3.48(t,J＝6.7Hz,2H),2.67(br,2H),2.45-2.40(m,4H),1.81-1.25(m,6H),1.06-0.99(m,1H),0.91(s,9H),0.61(dd,J＝8.4,4.6Hz,1H),0.29(t,J＝5.0Hz,1H)。ES-MS[M+H]+＝397.4。
Example 3N- ((6- (((1R,2R,4S) -7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-amine (Compound 3)
Tert-butyl 1- (((6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. Tert-butyl 1- (((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (prepared as described in example 1) (68mg, 0.19mmol), 1, 3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (51mg, 0.23mmol), K2CO3(81mg, 0.58mmol) and RuPhos-Pd-G3(8mg, 0.010mmol) in 5:1, 4-dioxane/H2O (2.4mL, degassed), and the resulting solution was heated in a closed flask at 100 ℃ for 1 hour, then the reaction mixture was cooled to room temperature and saturated NaHCO was used3And diluted with DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were passed through a phase separatorFiltered and concentrated. The crude residue was purified by column chromatography (12% -100% EtOAc/hexanes to 0-10% MeOH/EtOAc) to give the title compound as a colorless oil (35mg, 45%). ES-MS [ M + H ]]+＝413.3。
N- ((6-azaspiro [ 2.5)]Octane-1-yl) methyl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-amine dihydrochloride. Tert-butyl 1- (((6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (35mg, 0.086mmol) was dissolved in 1, 4-dioxane (1mL) and 4M HCl in dioxane solution (1mL) was added dropwise. The resulting solution was stirred at room temperature for 30 minutes, then the solvent was concentrated to give a white solid, which was dried under vacuum and used as the HCl salt without further purification. ES-MS [ M + H ]]+＝313.3。
((1R,2S,4S) -7-oxabicyclo [ 2.2.1)]Heptane-2-yl) (1- (((6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-yl) methanone. Reacting N- ((6-azaspiro [2.5]]Octane-1-yl) methyl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-amine dihydrochloride (33mg, 0.086mmol) was dissolved in DMF (1mL), followed by addition of rac- (1R,2S,4S) -7-oxabicyclo [2.2.1]Heptane-2-carboxylic acid (18mg, 0.13mmol) was added followed by DIPEA (0.045mL, 0.26mmol) and HATU (49mg, 0.13 mmol). The resulting solution was stirred at room temperature for 4 hours, after which the reaction was quenched with saturated NaHCO3Quench and extract the aqueous layer with 3:1 chloroform/IPA. The solvent was filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fractions were diluted with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The solvent was filtered through a phase separator and concentrated to give the title compound as a colorless oil (17.3mg, 46%). ES-MS [ M + H ]]+＝437.5。
N- ((6- (((1R,2R,4S) -7-oxabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -6-azaspiro [2.5]Octane-1-yl) methyl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-amine (Compound 3). The reaction product of ((1R,2S,4S) -7-oxabicyclo [ 2.2.1%]Heptane-2-yl) (1- (((6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-yl) methanone (17.3mg, 0.04mmol) was dissolved in THF (1mL) and cooled to 0 deg.C. Then theLAH (0.079mL, 0.08mmol, 1.0M in THF) was added dropwise and the resulting solution was stirred at 0 deg.C for 30 min. With slow addition of saturated NaHCO3The reaction was quenched and the aqueous layer was extracted with DCM and 3:1 chloroform/IPA. The organic extract was filtered and concentrated through a phase separator and the crude residue was purified by RP-HPLC. The product containing fractions were diluted with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The solvent was filtered through a phase separator and concentrated to give the title compound as a colorless oil that solidified upon standing (1.0mg, 6%). ES-MS [ M + H ]]+＝423.5。
Example 4.6- (1, 4-dimethyl-1H-pyrazol-5-yl) -N- ((6- (2- (tetrahydrofuran-2-yl) ethyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazin-3-amine (Compound 4)
Tert-butyl 1- (((6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. Tert-butyl 1- (((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (prepared as described in example 1) (133mg, 0.38mmol), 1, 4-dimethylpyrazole-5-boronic acid pinacol ester (125mg, 0.56mmol), K2CO3(158mg, 1.13mmol) and RuPhos-Pd-G3(16mg, 0.019mmol) were dissolved in 5:1, 4-dioxane/H2O (3mL, degassed), the resulting solution was then heated at 120 ℃ for 20 minutes under microwave irradiation, the reaction mixture was then cooled to room temperature and saturated NaHCO was used3And diluted with DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (12% -100% EtOAc/hexanes to 0-10% MeOH/EtOAc) to give the title compound as a colorless oil (37mg, 24%). ES-MS [ M + H ]]+＝413.2。
N- ((6-azaspiro [ 2.5)]Octane-1-yl) methyl) -6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-amine dihydrochloride. Tert-butyl 1- (((6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (64mg,0.16mmol) was dissolved in 1, 4-dioxane (1mL) and 4M HCl in dioxane solution (1mL) was added dropwise. The resulting solution was stirred at room temperature for 1 hour, then the solvent was concentrated to give a white solid, which was dried under vacuum and used as the HCl salt without further purification. ES-MS [ M + H ]]+＝313.3
6- (1, 4-dimethyl-1H-pyrazol-5-yl) -N- ((6- (2- (tetrahydrofuran-2-yl) ethyl) -6-azaspiro [ 2.5%]Octane-1-yl) methyl) pyridazin-3-amine (Compound 4). Reacting N- ((6-azaspiro [2.5]]Octane-1-yl) methyl) -6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-amine dihydrochloride (12mg, 0.031mmol) was suspended in DCM (1mL), and 2- (2-bromoethyl) oxocyclopentane (11mg, 0.062mmol) was added, followed by K2CO3(8.7mg, 0.062 mmol). The resulting suspension was stirred at room temperature for 4 hours, after which the reaction was quenched with saturated NaHCO3Quench and extract the aqueous layer with 3:1 chloroform/IPA. The solvent was filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fractions were diluted with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The solvent was filtered through a phase separator and concentrated to give the title compound as a white solid (2mg, 16%). ES-MS [ M + H ]]+＝411.4。
Example 5 chiral separation
Tert-butyl 1- (((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate was separated into the individual enantiomers by preparative SFC purification (CHIRALPAK IC 20 × 250mm column) with a 30% isocratic gradient in MeOH as co-solvent. Retention time of enantiomer O eluted earlier: 7.03 min (peak 1), retention time of enantiomer P eluting late: 7.65 min (Peak 2). Peak 1 is the higher affinity enantiomer. X-ray crystallography revealed that compound O has (R) -stereochemistry on cyclopropane, as shown in figure 1.
Example 6N- (6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octane-1-carboxamide. (Compound 5)
Tert-butyl 1- ((6-chloropyridazin-3-yl) carbamoyl) -6-azaspiro [2.5]Octane-6-carboxylate. Reacting 6-Boc-6-azaspiro [2.5]]Octane-1-carboxylic acid (100mg,0.39mmol) and 3-amino-6-chloropyridazine (101mg,0.78mmol) were dissolved in DCE (3mL) and DIPEA (0.14mL, 0.78mmol) and PyClU (261mg, 0.78mmol) were added. The resulting suspension was heated to 110 ℃ under microwave irradiation for 20 minutes, then the reaction was cooled to room temperature and quenched with DCM and H2And (4) diluting with oxygen. The aqueous layer was extracted with DCM and the organic extract was filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a white solid (61mg, 43%).1H-NMR(400MHz,CDCl3)δ10.4(br,1H),8.60(d,J＝9.4Hz,1H),7.51(d,J＝9.3Hz,1H),3.58-3.48(m,2H),3.42-3.35(m,1H),3.25-3.19(m,1H),2.18(dd,J＝7.6,5.6Hz,1H),1.75(t,J＝5.7Hz,2H),1.59-1.53(m,1H),1.48-1.46(m,1H),1.44(s,9H),1.36(t,J＝4.9Hz,1H),1.08(dd,J＝7.6,4.5Hz,1H)。ES-MS[M+H]+＝367.2。
Tert-butyl 1- ((6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) carbamoyl) -6-azaspiro [2.5]Octane-6-carboxylate. Tert-butyl 1- ((6-chloropyridazin-3-yl) carbamoyl) -6-azaspiro [2.5]Octane-6-carboxylate (61mg,0.17mmol), 1, 4-dimethylpyrazole-5-boronic acid pinacol ester (44mg,0.20mmol), K2CO3(70mg,0.50mmol) and RuPhos-Pd-G3(7mg, 0.008mmol) were combined in a sealed vial and 5: 11, 4-dioxane/H was added2O solution (1.2mL, degassed). The resulting suspension was stirred at 100 ℃ for 1 hour under an inert atmosphere, then the reaction mixture was cooled to room temperature and quenched with H2And (4) diluting with oxygen. The aqueous layer was extracted with DCM and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a colorless oil (55mg, 78%). ES-MS [ M + H ]]+＝427.2。
N- (6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) -6- (3, 3-dimethylMethylbutyl) -6-azaspiro [2.5]Octane-1-carboxamide (Compound 5). Tert-butyl 1- ((6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) carbamoyl) -6-azaspiro [2.5]Octane-6-carboxylate (55mg,0.13mmol) was dissolved in 1, 4-dioxane (1 mL). 4M HCl in 1, 4-dioxane solution (1mL) was then added dropwise. The resulting mixture was stirred at room temperature for 1 hour, then the solvent was removed under reduced pressure and the resulting white solid was dried under vacuum and used as the HCl salt without further purification. The HCl salt previously mentioned (17mg, 0.043mmol) was suspended in DCM (1mL) and 3, 3-dimethylbutyraldehyde (22mg, 0.22mmol) was added and allowed to stir at room temperature for 5 minutes before sodium triacetoxyborohydride (46mg, 0.22mmol) was added. The resulting solution was stirred at room temperature overnight, and the reaction mixture was taken up in H2Quench O and extract with DCM. The organic extract was filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC and the product-containing fractions were purified with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The organic extract was filtered through a phase separator and concentrated to give the title compound as a colorless oil (7.6mg, 43%). ES-MS [ M + H ]]+＝411.4。
Example 7N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyridin-2-amine (Compound 6)
Tert-butyl 1- (((5-bromopyridin-2-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. In a 2mL microwave vial, tert-butyl 1- (aminomethyl) -6-azaspiro [2.5]]Octane-6-carboxylate (150mg, 0.62mmol) and 5-bromo-2-fluoropyridine (275mg, 1.56mmol) were dissolved in NMP (1.5 mL). DIPEA (0.33mL, 1.87mmol) was then added and the resulting solution was heated at 180 ℃ for 1 hour under microwave irradiation, then the reaction mixture was directly purified by RP-HPLC and extracted with 3:1 chloroform/IPA. The organic extract was extracted with MgSO4Dried, filtered and concentrated to give the title compound as a colourless oil (125mg, 50%).1H-NMR(400MHz,CDCl3)δ8.10(d,J＝2.4Hz,1H),7.47(dd,J＝8.8,2.5Hz,1H),6.29(d,J＝8.8Hz,1H),4.51(br,1H),3.64(br,2H),3.27-3.21(m,4H),1.68-1.61(m,1H),1.56-1.49(m,1H),1.46(s,9H),1.39-1.35(m,1H),1.18-1.13(m,1H),1.01-0.94(m,1H),0.61(dd,J＝8.4,4.7Hz,1H),0.27(t,J＝4.9Hz,1H)。ES-MS[M+H]+＝396.4。
Tert-butyl 1- (((5- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridin-2-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. Reacting tert-butyl 1- (((5-bromopyridin-2-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (51mg, 0.13mmol), 1, 3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (34mg, 0.15mmol), K2CO3(54mg, 0.39mmol) and RuPhos-Pd-G3(5mg, 0.006mmol) in 5:1, 4-dioxane/H2O (2.4mL, degassed), and the resulting solution was heated in a closed flask at 100 ℃ for 1 hour, then the reaction mixture was cooled to room temperature and saturated NaHCO was used3And diluted with DCM. The aqueous layer was extracted with DCM (3 ×), and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (12% -100% EtOAc/hexanes to 0-10% MeOH/EtOAc) to give the title compound as a light brown oil (48mg, 90%). ES-MS [ M + H ]]+＝412.3。
N- ((6-azaspiro [ 2.5)]Octane-1-yl) methyl) -5- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridin-2-amine dihydrochloride. Tert-butyl 1- (((5- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridin-2-yl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (48mg, 0.12mmol) was dissolved in 1, 4-dioxane (1mL) and 4M HCl in dioxane solution (1mL) was then added dropwise. The resulting solution was stirred at room temperature for 30 minutes, then the solvent was concentrated to give a brown solid, which was dried under vacuum and used as the HCl salt without further purification. ES-MS [ M + H ]]+＝312.3。
N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5]]Octane-2-yl]Methyl radical]-5- (1, 3-dimethylpyrazol-4-yl) pyridin-2-amine (compound 6). Reacting N- ((6-azaspiro [2.5]]Octane-1-yl) methyl) -5- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridin-2-amine dihydrochloride (15mg, 0.039mmol) was suspended in DCM (1mL), and then 3, 3-dimethylbutyraldehyde (19mg, 0.19mmol) was added, followed by triethylenebutanalSodium acyloxyborohydride (41mg, 0.19 mmol). The resulting suspension was stirred at room temperature for 5 hours, after which the reaction was quenched with saturated NaHCO 3. The aqueous layer was extracted with 3:1 chloroform/IPA (3X). The organic extract was filtered and concentrated through a phase separator and the crude residue was purified by RP-HPLC. The product containing fractions were diluted with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The organic extract was filtered through a phase separator and concentrated to give the title compound as a colorless oil (3.4mg, 22%). ES-MS [ M + H ]]+＝396.6。
The compounds shown in table 1 were prepared in analogy to the compounds described above using suitable starting materials. In table 1, the "schemes" column indicates general reaction schemes for preparing the compounds, wherein these schemes are shown in the "detailed description" section.
TABLE 1
Example 8.6- (3, 3-difluoropyrrolidin-1-yl) -N- ((6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazin-3-amine (Compound 75)
Mixing 6-chloro-N- ((6- (3, 3-dimethylbutyl) -6-azaspiro [2.5]]Octane-1-yl) methyl) pyridazin-3-amine (24mg, 0.071mmol) and 3, 3-difluoropyrrolidine hydrochloride (51mg, 0.36mmol) were combined in a microwave vial and NMP (1mL) was added followed by DIPEA (0.062mL, 0.36 mmol). The reaction mixture was heated at 200 ℃ for 1 hour under microwave irradiation and then purified directly by RP-HPLC. The product containing fractions were diluted with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a light orange oil (12.3mg, 42%).1H NMR(400MHz,CDCl3)δ6.67-6.61(m,2H),4.13(t,J＝4.8Hz,1H),2.84(t,J＝13.3Hz,2H),3.66(t,J＝7.2Hz,2H),3.40-3.36(m,2H),2.67(br,2H),2.53-2.42(m,6H),1.80-1.49(m,3H),1.47-1.43(m,2H),1.32(br,1H),1.03-0.96(m,1H),0.90(s,9H),0.55(dd,J＝8.4,4.6Hz,1H),0.23(t,J＝4.9Hz,1H)。[M+H]+＝408.3。
Example 9.6- (1, 4-dimethyl-1H-pyrazol-5-yl) -N- ((6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-1-yl) methyl) -N-methylpyridazin-3-amine (Compound 76)
Tert-butyl 1- (((6-chloropyridazin-3-yl) (methyl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. To tert-butyl 1- (((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] at 0 deg.C]To a solution of octane-6-carboxylate (58mg,0.16mmol) in DMF (1mL) was added sodium hydride (7.8mg,0.33mmol, 60% dispersion in mineral oil), and the resulting mixture was stirred for 5 minutes. Methyl iodide (3. mu.L, 0.25mmol) was then added and the resulting solution was stirred at 0 ℃ for 1 hour, after which the reaction mixture was washed with DCM and saturated NaHCO3And (6) diluting. The aqueous layer was extracted with DCM, and the combined organic extracts were passed through a phase separator and concentrated under reduced pressure. The crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound (37mg, 62%). [ M + H ]]+＝367.2。
Tert-butyl 1- (((6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) (methyl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. Reacting tert-butyl 1- (((6-chloropyridazin-3-yl) (methyl) amino) methyl) -6-azaspiro [ 2.5%]Octane-6-carboxylate (37mg, 0.10mmol), 1, 4-dimethylpyrazole-5-boronic acid pinacol ester (40mg, 0.18mmol), K2CO3(42mg, 0.30mmol) and Brettphos-Pd-G3(4.6mg, 0.005mmol) were combined in a microwave vial and 5:1, 4-dioxane/H was added under an inert atmosphere2O solution (1mL, degassed). The resulting mixture was heated at 120 ℃ for 20 minutes under microwave irradiation, and the reaction mixture was then washed with DCM and saturated NaHCO3And (6) diluting. The aqueous layer was extracted with DCM, and the combined organic extracts were passed through a phase separator and concentrated under reduced pressure. The crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a yellow oil (32mg, 74%). [ M + H ]]+＝427.4。
6- (1, 4-dimethyl-1H-pyrazol-5-yl) -N- ((6- (3, 3-dimethylbutyl) -6-azaspiro [ 2.5)]Octane-1-yl) methyl) -N-methylpyridazin-3-amine. Tert-butyl 1- (((6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) (methyl) amino) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (32mg, 0.074mmol) was dissolved in 1, 4-dioxane (1mL) and 4M HCl in dioxane solution (1mL) was added dropwise. The resulting solution was stirred at room temperature for 1 hour, and then the solvent was concentrated under reduced pressure to give a HCl salt which was free of HCl saltFurther purification is required for direct use. The HCl salt (30mg, 0.074mmol) was suspended in DCM (1mL) and 3, 3-dimethylbutyraldehyde (37mg, 0.37mmol) was added, followed by sodium triacetoxyborohydride (79mg, 0.37 mmol). After stirring at room temperature overnight, the reaction mixture was heated to 55 ℃ and stirred overnight, followed by addition of AcOH (3 drops) and stirring overnight. The reaction mixture was cooled to room temperature and quenched with 3:1 chloroform/IPA and saturated NaHCO3And (6) diluting. The aqueous layer was extracted with 3:1 chloroform/IPA. The combined organic extracts were filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fractions were diluted with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (9.3mg, 30%). [ M + H ]]+＝411.5。
EXAMPLE 10.1- (((6- (2-chloro-5-fluorophenyl) pyridazin-3-yl) oxy) methyl) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octane (Compound 77)
Tert-butyl 1- (((6-chloropyridazin-3-yl) oxy) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. Reacting tert-butyl 1- (hydroxymethyl) -6-azaspiro [2.5]]Octane-6-carboxylate (466mg, 1.93mmol) was dissolved in THF (10mL) and NaH (93mg, 3.86mmol, 60% dispersion in mineral oil) was added at 0 deg.C. After stirring for 5 minutes, 3, 6-dichloropyridazine (432mg, 2.90mmol) was added. The resulting solution was warmed to room temperature and stirred overnight, then the reaction mixture was taken up with DCM and H2And (4) diluting with oxygen. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hexanes/EtOAc) to give the title compound as a white solid (541mg, 79%). [ M + H-Boc]+＝254.4。
Tert-butyl 1- (((6- (2-chloro-5-fluorophenyl) pyridazin-3-yl) oxy) methyl) -6-azaspiro [2.5]Octane-6-carboxylate. Tert-butyl 1- (((6-chloropyridazin-3-yl) oxy) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (541mg, 1.53mmol), 2-chloro-5-fluorophenylboronic acid (320mg, 1.83 mmol)mmol)、K2CO3(643mg, 4.59mmol) and RuPhos-Pd-G3(128mg, 0.15mmol) were combined in a microwave vial and 5:1, 4-dioxane/H was added under an inert atmosphere2O solution (12mL, degassed). The resulting mixture was heated at 120 ℃ for 20 minutes under microwave irradiation, and the reaction mixture was then washed with DCM and saturated NaHCO3And (6) diluting. The aqueous layer was extracted with DCM and the combined organic extracts were then extracted with MgSO4And (5) drying. The solvent was filtered under reduced pressure and concentrated, then the crude residue was purified by column chromatography (hexane/EtOAc) to give the title compound as a white foamy solid (290mg, 42% (purity 89%)). [ M + H-Boc]+＝348.2。
1- (((6- (2-chloro-5-fluorophenyl) pyridazin-3-yl) oxy) methyl) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5]Octane. Tert-butyl 1- (((6- (2-chloro-5-fluorophenyl) pyridazin-3-yl) oxy) methyl) -6-azaspiro [2.5]Octane-6-carboxylate (290mg, 0.65mmol) was dissolved in 1, 4-dioxane (5mL) and 4M HCl in dioxane solution (4mL) was added dropwise. The resulting solution was stirred at room temperature for 1 hour, then the solvent was concentrated under reduced pressure to give the HCl salt, which was used directly without further purification. The HCl salt was suspended in DCM (1mL) and 3, 3-dimethylbutyraldehyde (27mg, 0.27mmol) was added, followed by sodium triacetoxyborohydride (57mg, 0.27 mmol). After stirring overnight at room temperature, the reaction mixture was taken up with saturated NaHCO3Quench and extract the aqueous layer with 3:1 chloroform/IPA. The combined organic extracts were filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fractions were diluted with saturated NaHCO3Basified and extracted with 3:1 chloroform/IPA. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (4.2mg, 18%). [ M + H ]]+＝432.4。
The compounds shown in table 1.1 were prepared in analogy to the compounds described above using suitable starting materials. In table 1.1, the "schemes" column indicates general reaction schemes for preparing compounds, wherein these schemes are shown in the "detailed description" section.
TABLE 1.1
Example 11 biological Activity
A. Cell lines expressing muscarinic acetylcholine receptors
Human, rat or mouse M using Lipofectamine20004cDNA and chimeric G protein Gqi5Were co-transfected into Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection. M4/Gqi5CHO cells were grown in Ham's F-12 medium containing 10% heat-inactivated Fetal Bovine Serum (FBS), 20mM HEPES, 500. mu.g/mLG 418 sulfate and 200. mu.g/mL hygromycin B.
B. Cell-based functional assays for muscarinic acetylcholine receptor activity
For high-throughput measurement of agonist-induced increases in intracellular calcium, CHO-K1 cells stably expressing muscarinic receptors were plated in G418 and G418-deficient wells at 15,000 cells/20 μ L/well in Griner 384-well Black-wall Tissue Culture (TC) -treated clear-bottom plates (VWR)Growth medium for hygromycin. At 37 ℃ and 5% CO2Cells were incubated overnight. The next day, cells were washed with assay buffer using ELX 405 (BioTek); the final volume was then pipetted to 20 μ L. Then, 20 μ L of 2.3 μ M Fluo-4/acetoxymethyl ester feedstock (Invitrogen, Calsbad, Calif.) prepared as 2.3mM feedstock in DMSO mixed with 10% (w/v) Pluronic F-127 in a 1:1 ratio and diluted in assay buffer was added to the wells and the cell plates were incubated at 37 ℃ and 5% CO2Incubate for 50 minutes. The dye was removed by washing with ELX 405 and the final volume was pipetted to 20. mu.L. Compound master plates were set up in 10 point concentration-response curve (CRC) format (1:3 dilution) in 100% DMSO at starting concentrations of 10 or 1mM using BRAVO liquid handler (Agilent). The test compound CRC was then transferred to daughter boards (240nL) using an Echo plate recombiner (Labcyte corporation, sinerval, ca), and the test buffer (40 μ L) was diluted into 2 × stock using Thermo Fisher Scientific (volser feishi technologies), waltham, massachusetts.
Calcium flux was measured using a Functional Drug Screening System (FDSS)6000 or 7000 (hamamatsu corporation, Tokyo, Japan) and was shown as an increase in the fluorescence static ratio. Compounds were applied to cells (20 μ L, 2X) using an automated system of FDSS for 2 seconds and data collected at 1 Hz. At 143s, 10. mu.L of EC was added20Concentration of muscarinic receptor agonist acetylcholine (5X) followed by 12 μ L EC addition at 268s time point80Acetylcholine (5X) at concentration. Agonist activity was assayed as the concentration-dependent increase in calcium mobilization upon compound addition. Analysis of Positive allosteric Modulator Activity as EC20The concentration-dependent increase in acetylcholine response. Analysis of antagonist Activity as EC80A concentration-dependent decrease in acetylcholine response; for purposes of the tables herein, the IC will be50(inhibitory concentration 50) calculated as EC80The concentration dependence of the response by acetylcholine concentration is reduced. Using a software for Excel (Microsoft corporation, Redmond, Washington) or Prism (graphics software)The concentration-response curves were generated by four-parameter logistic equations in XLFit curve fitting Software (IDBS corporation, bridgwad, new jersey) or in the Dotmatics Software platform (Dotmatics corporation, Bishop's Stortford, uk) by GraphPad Software, Inc (san diego, california).
The above assay also operates in a second mode, in which an appropriate fixed concentration of a compound of the invention is added to the cells about 3 seconds after the fluorescence baseline is established, and the response in these cells is measured. After 140s, the full concentration-response range consisting of increasing concentrations of agonist was added and the calcium response (maximal-local minimal response) was measured. Determining EC for agonist in the presence or absence of test compound by non-linear curve fitting50The value is obtained. EC of agonists decreasing with increasing concentration of the compounds of the invention50Values (left shift of agonist concentration-response curve) indicate the extent of muscarinic type positive allosteric modulation at a given concentration of a compound of the invention. EC of agonists increasing with increasing concentration of the Compounds of the invention50The values (right shift of the agonist concentration-response curve) indicate the extent of muscarinic antagonism at a given concentration of a compound of the invention. The second mode also indicates whether the compounds of the invention also affect the maximal response of muscarinic receptors to agonists.
C. Based on mAChR M4Activity of compounds in assays of cells
The compounds were synthesized as described above. As mentioned above, in mAChR M based4Determination of Activity (IC) in functional assays of cells50And Emin) The data are shown in tables 2 and 3. The compound numbers correspond to the compound numbers used in the examples and tables 1 and 1.1.
Table 2.
Maximum% ACh at 30 μ M.
ND is uncertain
Table 3.
Maximum% ACh at 30 μ M.
7. Further aspects and embodiments of the invention
E1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
a is a five or six membered heteroaryl group having 1,2 or 3 heteroatoms independently selected from N, O and S, or a nine to ten membered fused bicyclic heteroaryl ring system having 1-4 nitrogen atoms, wherein A is optionally substituted with 1-4 heteroatoms independently selected from halogen, C1-C4Alkyl and C1-C4Substituted with a substituent of haloalkyl;
q is selected from NRaO, and CRbRc；
R1Selected from hydrogen, halogen, -ORd、-N(Rd)2、C1-C4Alkyl, -CH ═ CH-C1-C4Alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and-CH ═ CH-G;
g is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl;
R2and R3Independently selected from hydrogen, C1-C4Alkyl, and halogen, or R2And R3Together form an oxo group;
each R4Independently selected from halogen, C1-C4Alkyl, and-ORe；
R5And R6Independently selected from hydrogen, C1-C8Alkyl group, and- (CR)fRg)n-Y1；
Each Y1Independently selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
each Ra、Rb、Rc、Rd、Re、RfAnd RgIndependently selected from hydrogen, C1-C4Alkyl, and aryl;
m is 0, 1 or 2; and
n is 0, 1 or 2.
E2. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein:
a is a five or six membered heteroaryl group having 1,2 or 3 heteroatoms independently selected from N, O and S; and
R1selected from hydrogen, halogen, -ORd、C1-C4Alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.
E3. The compound of E1 or E2, or a pharmaceutically acceptable salt thereof, wherein
Q is NRa(ii) a And
Rais hydrogen or C1-C4An alkyl group.
E4. The compound of E1 or E2, or a pharmaceutically acceptable salt thereof, wherein
Q is NRa(ii) a And
Rais hydrogen.
E5. The compound of any one of E1-E4, or a pharmaceutically acceptable salt thereof, wherein:
R1selected from hydrogen, halogen, -CH ═ CH-C1-C4Alkyl, -CH ═ CH-G, C5-C8Cycloalkenyl, four-to eight-membered monocyclic heterocyclyl, six-to twelve-membered aryl, and five-to six-membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein cycloalkenyl, heterocyclyl, aryl and heteroaryl are unsubstituted or 1,2 or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR' are substituted;
g is a six-to twelve-membered aryl group, which may optionally be substituted with 1,2 or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR' are substituted; and
r' is independently at each occurrence C1-C4An alkyl group.
E6. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein
R1Is hydrogen, phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridyl, quinolyl, isoquinolyl, piperidinyl, pyrrolidinyl, morpholinyl, cyclopentenyl, or-CH ═ CH-G, wherein phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridinyl, quinolyl, isoquinolyl, piperidinyl, pyrrolidinyl, morpholinyl, and cyclopentenyl are unsubstituted or substituted with 1,2, or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyanoSubstituted; and
g is phenyl optionally substituted by 1,2, or 3 independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, and-NHCOR ', wherein R' is C1-C4An alkyl group.
E7. The compound of any one of E1-E4, or a pharmaceutically acceptable salt thereof, wherein
R1Selected from the group consisting of halogen, aryl, and five to six membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy and-NHCOR ', wherein R' is C1-C4An alkyl group.
E8. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein
R1Is phenyl or pyrazolyl, wherein phenyl and pyrazolyl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, and cyano.
E9. The compound of any one of E1-E8, or a pharmaceutically acceptable salt thereof, wherein R2Is hydrogen; and
R3is hydrogen.
E10. The compound of any one of E1-E8, or a pharmaceutically acceptable salt thereof, wherein R2And R3Together form an oxo group.
E11. The compound of any one of E1-E10, or a pharmaceutically acceptable salt thereof, wherein m is 0.
E12. The compound of any one of E1-E11, or a pharmaceutically acceptable salt thereof, wherein R5Is hydrogen.
E13. The compound of any one of E1-E12, or a pharmaceutically acceptable salt thereof, wherein
R6Is selected from C1-C8Alkyl and- (CR)fRg)n-Y1；
RfIs hydrogen;
Rgselected from hydrogen, C1-C4Alkyl and phenyl;
n is 0 or 1; and
Y1selected from: c3-C10-a cycloalkyl group; c5-C10-a cycloalkenyl group; a phenyl group; a five-to six-membered heteroaryl group having 1,2, or 3 heteroatoms independently selected from N, O and S; and a five to eight membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or 1 or 2 independently selected from C1-C4Alkyl, halogen, and C1-C4Substituted by a substituent of a haloalkyl group.
E14. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein:
a is a five-membered heteroaryl group having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from N, O and S, a six-membered heteroaryl group having 1-2 nitrogen atoms, a phthalazinyl group, an imidazo [1,2-b ] group]Pyridazinyl radicals, or [1,2,4]]Triazolo [4,3-b]Pyridazinyl, wherein A is optionally substituted with 1-4 substituents independently selected from halogen, C1-C4Alkyl group, and C1-C4Substituted by a substituent of a haloalkyl group.
E15. The compound of E14, or a pharmaceutically acceptable salt thereof, wherein:
a is thiazole-2, 5-diyl, pyridazine-3, 6-diyl, pyrazine-2, 5-diyl, pyridine-2, 5-diyl, phthalazine-1, 4-diyl, imidazo [1,2-b ]]Pyridazin-6-yl, or [1,2,4]]Triazolo [4,3-b]Pyridazin-6-yl wherein A is optionally substituted with 1-4 substituents independently selected from halogen, C1-C4Alkyl group, and C1-C4Substituted by a substituent of a haloalkyl group.
E16. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein
A is selected from:
wherein
T is selected from O, S and NH; and
u, V, W, X, Y and Z are independently selected from N and CH, wherein 1-3 of the W, X, Y, and Z are N.
E17. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein
A is selected from
E18. the compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein A is
E19. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ia):
wherein:
w, X, Y, and Z are independently selected from N and CH, wherein 1-3 of the W, X, Y, and Z are N.
E20. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein
1 or 2 of the W, X, Y, and Z are N.
E21. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ib):
E22. the compound of any one of E19-E21, or a pharmaceutically acceptable salt thereof, wherein
R1Selected from: halogen; an aryl group; and a five-to six-membered monocyclic heteroaryl having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein the aryl and heteroaryl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from C1-C4Alkyl, halogen, cyano, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy and-NHCOR ', wherein R' is C1-C4An alkyl group.
E23. The compound of any one of E19-E22, or a pharmaceutically acceptable salt thereof, wherein
R2Is hydrogen; and
R3is hydrogen.
E24. The compound of any one of E19-E22, or a pharmaceutically acceptable salt thereof, wherein R2And R3Together form an oxo group.
E25. The compound of any one of E19-E24, or a pharmaceutically acceptable salt thereof, wherein R5Is hydrogen.
E26. The compound of any one of E19-E25, or a pharmaceutically acceptable salt thereof, wherein R6Is selected from C1-C8Alkyl and- (CR)fRg)n-Y1；
RfIs hydrogen;
Rgselected from hydrogen, C1-C4Alkyl and phenyl;
n is 0 or 1; and
Y1selected from: c3-C10-a cycloalkyl group; c5-C10-a cycloalkenyl group; a phenyl group; a five-to six-membered heteroaryl group having 1,2, or 3 heteroatoms independently selected from N, O and S; and a five to eight membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; wherein the cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or 1 or 2 independently selected from C1-C4Alkyl, halogen, and C1-C4Substituted by a substituent of a haloalkyl group.
E27. The compound of E1, wherein the compound is selected from:
6- (2-chloro-5-fluorophenyl) -N- [ [6- [ [3- (trifluoromethyl) -2-pyridinyl ] methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (4-fluorophenyl) pyridazin-3-amine;
n- ((6- (((1R,2R,4S) -7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) pyridazin-3-amine;
n- [6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-yl ] -6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octane-2-carboxamide;
n- (6- (1, 4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octane-1-carboxamide;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyridin-2-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -N- [6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-yl ] -6-azaspiro [2.5] octane-2-carboxamide;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (2, 2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -N- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] -6-azaspiro [2.5] octane-2-carboxamide;
n- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] -6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octane-2-carboxamide;
6-chloro-N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyrazin-2-amine;
5- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2,3, 3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyrazin-2-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyrazin-2-amine;
6- (2-chloro-4-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (4-methyl-3-pyridinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-fluorophenyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3-fluorophenyl) pyridazin-3-amine;
6- (2, 4-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (5-fluoro-2-methyl-phenyl) pyridazin-3-amine;
6- (2, 5-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (5-fluoro-2-methoxy-phenyl) pyridazin-3-amine;
6- (3, 4-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (3, 5-difluorophenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-phenyl-pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2, 4-dimethylpyrazol-3-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1,3, 5-trimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3, 5-dimethylisoxazol-4-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-methylpyrazol-3-yl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [ 2-methyl-5- (trifluoromethyl) pyrazol-3-yl ] pyridazin-3-amine;
n- [4- [6- [ [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] amino ] pyridazin-3-yl ] phenyl ] acetamide;
6- (2-chloro-3-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (3-methyl-2-thienyl) pyridazin-3-amine;
2- [6- [ [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] amino ] pyridazin-3-yl ] -4-fluoro-benzonitrile;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (7-isoquinolinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (6-quinolinyl) pyridazin-3-amine;
6- (1, 3-benzodioxol-5-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-naphthyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [2- (trifluoromethoxy) phenyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [4- (trifluoromethyl) -3-pyridinyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2-methylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2-methylpentyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ (6-ethyl-6-azaspiro [2.5] octan-2-yl) methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ (6-propyl-6-azaspiro [2.5] octan-2-yl) methyl ] pyridazin-3-amine;
n- [ [6- (cyclopropylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -6- (1, 3-dimethylpyrazol-4-yl) pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (2, 2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- [ [3- (trifluoromethyl) -2-pyridinyl ] methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(S) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(S) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (2-chloro-5-fluoro-phenyl) pyridin-2-amine;
5- (2-chloro-5-fluoro-phenyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridin-2-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5- (1, 3-dimethylpyrazol-4-yl) pyridin-2-amine;
6- (2, 4-dimethylpyrazol-3-yl) -N- [ [6- (2-tetrahydrofuran-2-ylethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5-phenyl-thiazol-2-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -5-phenyl-thiazol-2-amine;
5-phenyl-N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] thiazol-2-amine;
6- (2, 4-dimethylpyrazol-3-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (3, 3-difluoropyrrolidin-1-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2, 4-dimethylpyrazol-3-yl) -N-methyl-pyridazin-3-amine;
2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octane;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (1-piperidinyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
6- (4, 4-difluoro-1-piperidinyl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-pyrrolidin-1-yl-pyridazin-3-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6-morpholino-pyridazin-3-amine;
6-morpholino-N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6-azaspiro [2.5] octane;
2- [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] oxymethyl ] -6- (cyclohexylmethyl) -6-azaspiro [2.5] octane;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
6- (cyclopenten-1-yl) -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- [ (E) -3, 3-dimethylbut-1-enyl ] -N- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- [ (E) -2- (p-tolyl) ethenyl ] pyridazin-3-amine;
4- (1, 3-dimethylpyrazol-4-yl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] phthalazin-1-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -4- (1, 3-dimethylpyrazol-4-yl) phthalazin-1-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (3-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
2- [ [2- [ [ [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl ] amino ] methyl ] -6-azaspiro [2.5] octan-6-yl ] methyl ] benzonitrile;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (4-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [6- [ (2-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ (6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] imidazo [1,2-b ] pyridazin-6-amine;
n- [ [6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
n- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
n- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] - [1,2,4] triazolo [4,3-b ] pyridazin-6-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N- [ [6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- (((1R) -6- (bicyclo [2.2.1] hept-5-en-2-ylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazin-3-amine;
(R) -6- (2-chloro-5-fluorophenyl) -N- ((6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazin-3-amine;
n- (((1R) -6- ((7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazin-3-amine;
n- [4- [6- [ [ (2R) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [ [ (2R) -6-benzyl-6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [ (2R) -6- (2-pyridylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
6- (2-chloro-5-fluoro-phenyl) -N- [ [ (2R) -6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methyl ] pyridazin-3-amine;
n- [ [ (2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methyl ] -6- (2-chloro-5-fluoro-phenyl) pyridazin-3-amine;
n- [4- [6- [ [6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] -4, 5-dimethyl-pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] -4, 5-dimethyl-pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- [ (3-methyl-2-pyridinyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2R) -6- [ (4-fluorophenyl) methyl ] -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (3, 3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide;
n- [4- [6- [ [ (2S) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl ] methylamino ] pyridazin-3-yl ] phenyl ] acetamide; or a pharmaceutically acceptable salt thereof.
E28. The compound of any one of E1-E27, or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled.
E29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of E1-E28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
E30. mAChR M for antagonizing subject4The method of (2), the method comprising the steps of: administering to the subject a therapeutically effective amount of a compound of any one of E1-E28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E29.
E31. A method for treating a disorder in a subject, wherein the subject is to be treated with a mAChR M4The method comprising the steps of: administering to the mammal a therapeutically effective amount of a compound of any one of E1-E28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E29.
E32. The method of E31, wherein the disorder is a movement disorder.
E33. The method of E32, wherein the disorder is selected from parkinson's disease, drug-induced parkinson's disease, dystonia, tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, Attention Deficit Hyperactivity Disorder (ADHD), huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
E34. A method for treating a motor symptom in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of E1-E28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E29.
E35. The method of E34, wherein the subject has a disorder selected from: parkinson's disease, drug-induced parkinson's disease, dystonia, tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, Attention Deficit Hyperactivity Disorder (ADHD), huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.
It should be understood that the foregoing detailed description and accompanying examples are illustrative only, and should not be taken as limiting the scope of the invention, which is defined only by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope of the invention.
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