Heteroaryloxycarbocyclyl Compounds as PDE 10 Inhibitors

Abstract

Heteroaryloxycarbocyclyl compounds, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, Huntington's Disease, bipolar disorder, obsessive-compulsive disorder, and the like.

What is claimed is: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         a stereoisomer, or a pharmaceutically-acceptable salt thereof, wherein: 
         each of X 1 , X 2 , and X 3  is independently N or CR 3 ; and X 4  is N; wherein no more than one of X 1 , X 2 , and X 3  are N; 
         optionally, the ring containing X 1 , X 2 , X 3 , and X 4  may be fused to a saturated, partially saturated, or unsaturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from O and S; wherein said monocyclic ring is independently substituted by 0, 1, 2, 3, or 4 R 3  groups; 
         m is 1, 2, 3, or 4; 
         each of p and q is independently 0, 1, 2, 3, 4, 5, or 6; wherein the sum of p and q is 2 to 6; 
         the ring containing p and q is in cis or trans configuration; 
         R 1  is F, Cl, Br, I, C 1-8 alk, C 1-4 haloalk, —OR a , —NR a R a , —N(R a )C(═O)R b , —C(═O)R a , —C(═O)R c , —C(═O)—O—R a , —OR c , —NR a R c , —N(R c )C(═O)R b , —N(R a )C(═O)R c , —C(═O)NR a R b , —C(═O)NR a R c , or C 0-4 alk-L 1 ; wherein said C 1-8 alk group is substituted by 0, 1, 2 or 3 groups selected from halo, C 1-3 haloalk, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk; 
         R 2  is —C(═O)R 5 , —C(═O)OR 5 , —C(═O)NR 5 R 6 , or a group —Y-L 2 ; 
         Y is a C 0-4 alk, O, NR 7 , S, SO, or SO 2 ; 
         R 3  is H, F, Cl, Br, CN, OH, OC 1-4 alk, C 1-4 alk, or C 1-4 haloalk; 
         R 4a  is H, C 1-4 alk, or C 1-4 haloalk; 
         each R 4b  is independently H, F, Cl, Br, CN, OH, OC 1-4 alk, C 1-4 alk, or C 1-4 haloalk; 
         R 4a  is R 4b  when R 2  is —C(═O)R 5 , —C(═O)OR 5 , —C(═O)NR 5 R 6 , or said group —Y-L 2 ; 
         wherein Y is C 0-4 alk, SO, or SO 2 ; 
         R 4a  is R 4a  when R 2  is said group —Y-L 2 , wherein Y is O, NR 7 , or S; 
         each of R 5  and R 6  is independently H, C 1-8 alk, or C 0-8 alk-L 3 ; 
         R 7  is independently H or R b ; 
         R a  is independently H or R b ; 
         R b  is independently phenyl, benzyl, or C 1-6 alk, wherein said phenyl, benzyl, and C 1-6 alk are being substituted by 0, 1, 2 or 3 substituents selected from halo, C 1-4 alk, C 1-3 haloalk, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk; 
         R c  is C 0-4 alk-L 4 ; and 
         each of L 1 , L 2 , L 3 , and L 4  is independently a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a saturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 0 or S atoms; wherein each L 1 , L 2 , L 3 , and L 4  is independently substituted by 0, 1, 2 or 3 R 8  groups which are F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(10C(═NIONR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a , —NR a C 2-6 alkOR a , —C 1-6 alkNR a R a , —C 1-6 alkOR a , —C 1-6 alkN(10C(═O)R b , —C 1-6 alkOC(═O)R b , —C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a  or oxo. 
       
     
     
         2 . The compound as in  claim 1  wherein the group 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound as in  claim 1  wherein the ring containing X 1 , X 2 , X 3 , and X 4  is fused to a saturated, partially saturated, or unsaturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 O or S atoms; wherein said monocyclic ring is independently substituted by 0, 1, 2, 3, or 4 R 3  groups. 
     
     
         4 . The compound as in  claim 3  wherein said monocyclic ring is fused phenyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrazinyl, or piperazinyl. 
     
     
         5 . The compound as in  claim 1  wherein Y is a bond, NH, or N—CH 3 . 
     
     
         6 . The compound as in  claim 1  wherein Y is NH. 
     
     
         7 . The compound as in  claim 1  wherein m is 1. 
     
     
         8 . The compound as in  claim 1  wherein p is 1 and q is 1. 
     
     
         9 . The compound as in  claim 1  wherein the ring containing p and q is in cis configuration. 
     
     
         10 . The compound as in  claim 1  wherein the ring containing p and q is in trans configuration. 
     
     
         11 . The compound as as in  claim 1  wherein R 1  is F, Cl, Br, I, —OR a , —NR a R c , —C(═O)—O—R a , —C(═O)NR a R b , —OR a , or —C(═O)NR a R b . 
     
     
         12 . The compound as in  claim 1  wherein R 1  is C 0-4 alk-L 1 ; wherein said L 1  is a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 4-, 5-, 6-, or 7-membered monocyclic ring, wherein each said ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 0 atoms, and wherein each said ring is substituted by 0, 1, 2 or 3 R 8  groups selected from F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —NR a R a , —C(═O)NR a R a , —SR a , and —C 1-6 alkOR a . 
     
     
         13 . The compound as in  claim 1  wherein R 1  is C 0-4 alk-L 1 ; wherein said L 1  is a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 O atoms, and wherein each said ring is substituted by 0, 1, 2 or 3 R 8  groups selected from F, Cl, Br, C 1 -6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —NR a R a , —C(═O)NR a R a , —SR a , and —C 1-6 alkOR a . 
     
     
         14 . The compound as in  claim 1  wherein R 1  is C 0-4 alk-L 1 ; wherein said L 1  is cyclobutyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl, morpholinyl, pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl, oxaspiro[3.5]nonyl, azepanyl, oxepanyl, or quinolinyl, all of which are substituted by 0, 1, 2 or 3 R 8  groups selected from F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —NR a R a , —C(═O)NR a R a , —SR a , and —C 1-6 alkOR a . 
     
     
         15 . The compound as in  claim 1  wherein R 1  is C 0-4 alk-L 1 ; wherein said L 1  is 3-pyridyl, 4-pyridyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrimidyl, dihydropyranyl, or piperazinyl, all of which are substituted by 0, 1, 2 or 3 R 8  groups selected from F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-4 haloalk, CN, —C(═O)R b , —C(═O)OR a , —NR a R a , —C(═O)NR a R a , —SR a , and —C 1-6 alkOR a . 
     
     
         16 . The compound as as in  claim 1  wherein R 1  is not methyl. 
     
     
         17 . The compound as as in  claim 1  wherein R 1  is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein the dotted bond is an optional double bond. 
     
     
         18 . The compound as in  claim 1  wherein R 3  is H, F, Cl, C 1-4 alk, or C 1-4 haloalk. 
     
     
         19 . The compound as in  claim 1  wherein R 4a  is H. 
     
     
         20 . The compound as in  claim 1  wherein each of R 4a , R 4b , and R 4a  is H. 
     
     
         21 . The compound as in  claim 1  wherein R 5  is C 1-8 alk or C 0-8 alk-L 3 . 
     
     
         22 . The compound as in as in  claim 1  wherein R 6  is C 1-8 alk or C 0-8 alk-L 3 . 
     
     
         23 . The compound as in  claim 1  wherein R 7  is H. 
     
     
         24 . The compound as in  claim 1  wherein R a  is H or C 1-6 alk substituted by 0 or 1 —OH, —OC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk. 
     
     
         25 . The compound as in  claim 1 , wherein R c  is a saturated, partially-saturated or unsaturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0 or 1 N atom and 0 or 1 atom selected from O or S, which is substituted by 0 or 1 R 8  groups which are F, C 1-6 alk, C 1-4 haloalk, or —OR a . 
     
     
         26 . The compound as in  claim 1  wherein R 2  is the group —Y-L 2  which are 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein Y is a NH. 
     
     
         27 . The compound as in  claim 1  wherein R 2  is —C(═O)R 5 , —C(═O)OR 5 , or —C(═O)NR 5 R 6 . 
     
     
         28 . The compound as in  claim 1  wherein each R 2  is the group —Y-L 2  selected from 
       
         
           
           
               
               
           
         
       
       wherein Y is NH; and L 2  is independently substituted by 0, 1, or 2 R 8  groups which are F, Br, Cl, CF 3 , methyl, methoxy, or CN. 
     
     
         29 . A compound of formula II: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically-acceptable salt thereof, wherein:
 each of X 1 , X 2 , and X 3  is independently N or CR 3 ; and X 4  is N; wherein no more than one of X 1 , X 2 , and X 3  are N; and wherein any adjacent X 1 , X 2 , and X 3  may optionally form an optionally substituted -saturated, -partially saturated, or -unsaturated-heterocyclic or -heteroaryl ring fused to the ring containing X 1 , X 2 , X 3 , and X 4 ; 
 m is 1, 2, 3, or 4; 
 each of p and q is independently 0, 1, 2, 3, 4, 5, or 6; wherein the sum of p and q is 2 to 6; 
 the ring containing p and q is in cis or trans configuration; 
 Ring D is L 1;    
 R 2  is —C(═O)R 5 , —C(═O)OR 5 , —C(═O)NR 5 R 6 , or a group —Y-L 2 ; 
 Y is a C 0-4 alk, O, NR 7 , S, SO, or SO 2 ; 
 R 3  is H, F, Cl, Br, CN, OH, OC 1-4 alk, C 1-4 alk, or C 1-4 haloalk; 
 R 4a  is H, C 1-4 alk, or C 1-4 haloalk; 
 each R 4b  is independently H, F, Cl, Br, CN, OH, OC 1-4 alk, C 1-4 alk, or C 1-4 haloalk; 
 R 4a  is R 4b  if R 2  is —C(═O)R 5 , —C(═O)OR 5 , —C(═O)NR 5 R 6 , or said group —Y-L 2 ; wherein Y is C 0-4 alk, SO, or SO 2 ; 
 R 4a  is R 4a  if R 2  is said group —Y-L 2 , wherein Y is O, NR 7 , or S; 
 each of R 5  and R 6  is independently H, C 1-8 alk, or C 0-8 alk-L 3 ; 
 R 7  is independently H or R b ; 
 R a  is independently H or R b ; 
 R b  is independently phenyl, benzyl, or C 1-6 alk, wherein said phenyl, benzyl, and C 1-6 alk are being substituted by 0, 1, 2 or 3 substituents which are halo, C 1-4 alk, C 1-3 haloalk, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk, —OC(═O)C 1-4 alk, or —N(C 1-4 alk)C 1-4 alk; and 
 each of L 1 , L 2 , L 3 , and L 4  is independently a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a saturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S atoms; wherein each L 1 , L 2 , L 3 , and L 4  is independently substituted by 0, 1, 2 or 3 R 8  groups which are F, Cl, Br, C 1-6 alk, C 1-4 haloalk, —OR a , —OC 1-A haloalk, CN, —C(═O)R b , —C(═O)OR a , —C(═O)NR a R a , —C(=NR a )NR a R a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a )C(═O)R b , —N(R a )C(═O)OR b , —N(R a )C(═O)NR a R a , —N(10C(=NIONR a R a , —N(R a )S(═O) 2 R b , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a , —NR a C 2-6 alkOR a , —C 1-6 alkNR a R a , —C 1-6 alkOR a , —C 1-6 alkN(10C(═O)R b , —C 1-6 alkOC(═O)R b , -C 1-6 alkC(═O)NR a R a , —C 1-6 alkC(═O)OR a  or oxo. 
 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound as in  claim 29 , wherein the group is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound as in  claim 29 , wherein the group is in trans configuration. 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound as in  claim 29 , wherein the group is in cis configuration. 
     
     
         33 . A method of treating conditions that may be treated with PDE10 inhibitors comprising the step of administering a pharmaceutically effective amount of a compound as in  claim 1  to a patient in need thereof 
     
     
         34 . A method of  claim 33  wherein said condition is selected from the group consisting of psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention deficit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease, dementia and mania with caudate and pallidal diseases, and compulsions with pallidal disease. 
     
     
         35 . The method of  claim 33  wherein said condition is selected from the group consisting of schizophrenia, Huntington's Disease, bipolar disorder, and obsessive-compulsive disorder. 
     
     
         36 . A pharmaceutical composition comprising a compound as in  claim 1  and a pharmaceutically acceptable excipient thereof 
     
     
         37 . A compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, which is:
 N-(3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   5-methyl-N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)pyridin-2-amine;   5-methyl-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)pyridin-2-amine;   1-(4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidin-1-yl)ethanone;   1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;   N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)-1H-benzo[d]imidazol-2-amine;   N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)-1H-benzo[d]imidazol-2-amine;   1-(4-(3-((1R,3R)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;   N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1R,3R)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   1-(4-(3-((1S,3S)-3-((5-methylpyridin-2-yl)amino)cyclobutoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;   1-(4-(3-((1R,3R)-3-((5-methylpyridin-2-yl)amino)cyclobutoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;   N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)-5-(trifluoromethyl)pyridin-2-amine;   N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)-5-(trifluoromethyl)pyridin-2-amine;   6-(((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)amino)nicotinonitrile;   6-(((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)amino)nicotinonitrile;   5-chloro-N-((1R,3R)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)pyridin-2-amine;   5-chloro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)pyridin-2-amine;   N-((1S,3S)-3-((3-(2-methylpyridin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   5-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   6-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   4-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1S,3S)-3-((3-(2-methoxypyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   7-fluoro-N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   (1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-4-yl)methanol;   1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperazin-1-yl)ethanone;   N-((1S,3S)-3-((3-(3-methylpyridin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-4-one;   N-((1S,3S)-3-((3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   6-fluoro-N-((1S,3S)-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   4-fluoro-N-((1S,3S)-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidine-1-carboxylate;   5-fluoro-N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   7-fluoro-N-((1S,3S)-3-((5-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   methyl 3-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)azetidine-1-carboxylate;   N-((1S,3S)-3-((3-(3-fluoro-4-methylphenyl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1R,3R)-3-((5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)oxy)cyclobutyl)-5-(trifluoromethyl)pyridin-2-amine;   N-((1S,3S)-3-((5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)oxy)cyclobutyl)-5-(trifluoromethyl)pyridin-2-amine;   N-((1R,3R)-3-((3-(1-acetylpiperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide;   N-((1S,3S)-3-((3-(1-acetylpiperidin-4-yl)pyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide;   N-((1R,3R)-3-((3-(3-fluoro-4-methylphenyl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   2′-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-[3,3′-bipyridine]-6-carbonitrile;   N-(3-((3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   (1-(3-(3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-3-yl)methanol;   2’-((1R,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-[3,3′-bipyridine]-6-carbonitrile;   N-((1S,3S)-3-((3-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   tert-butyl 4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidine-1-carboxylate;   tert-butyl 2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-5′,6′-dihydro -[3,4′-bipyridine]-1′(2′H)-carboxylate;   1-(3-(3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;   N-((1S,3S)-3-((3-(2-methylpyrimidin-5-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1S,3S)-3-((3-(6-chloropyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1S,3S)-3-((3-(6-fluoropyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)picolinonitrile;   1-(4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidin-1-yl)ethanone;   5-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)picolinonitrile;   (1-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-4-yl)methanol;   methyl 4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidine-1-carboxylate;   2-methoxy-1-(4-(2-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidin-1-yl)ethanone;   N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)oxy)cyclobutyl)quinolin-2-amine;   1-(4-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidin-1-yl)-2-methoxyethanone;   ((R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-3-yl)methanol;   ((S)-1-(3-((1S,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-3-yl)methanol;   2′-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-[3,3′-bipyridine]-6-carbonitrile;   1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperazin-1-yl)ethanone;   2-methoxy-1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;   N-((1S,3S)-3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)quinolin-2-amine;   N-((1S,3S)-3-((3-morpholinopyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   (R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrrolidin-3-ol;   1-(1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-4-yl)ethanol;   1-(4-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;   (S)-1-(3-((1S,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrrolidin-3-ol;   N-(3-((3-(3-methylpiperidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1S,3S)-3-((3-((R)-3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1R,3S)-3-((3-((S)-3-methylpyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidine-4-carbonitrile;   1-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidine-4-carbonitrile;   N-((1S,3S)-3-((6-chloro-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)picolinamide;   (R)-1-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;   (S)-1-(3-((1S,3R)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;   5-(3-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)picolinamide;   1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-1-yl)-2-hydroxyethanone;   N-((1S,3S)-3-((3-(3,3-difluoropyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-(3-((3-(3-fluoropyrrolidin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   2’-((1S,3S)-3-(quinolin-2-ylamino)cyclobutoxy)-[3,3′-bipyridine]-6-carboxamide;   N-((1S,3S)-3-((3-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   5-fluoro-N-((1S,3S)-3-((3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   1-(4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-1-yl)-2-methoxyethanone;   N-((1S,3S)-3-((6-fluoro-5-iodopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   4-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)thiomorpholine 1,1-dioxidecyclobutyl}-amine;   2′-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)-[3,3′-bipyridine]-6-carboxamide;   N-((1S,3S)-34(3-(6-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)quinazolin-2-amine;   N-((1S,3S)-3-46-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   5-(3-((1S,3S)-3-(quinazolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)picolinonitrile;   N-((1S,3S)-3-((3-(2-methylpyridin-3-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   1-(2-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyridin-3-yl)piperidine-4-carbonitrile;   1-(5-(3-((1S,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutoxy)pyrazin-2-yl)pyridin-2-yl)ethanone;   N-((1S,3S)-3-((3-(1-methylpiperidin-4-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1S,3S)-3-((3-(5,6-dihydroimidazo [1,5-a]pyrazin-7(8H)-yl)pyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine;   N-((1S,3S)-3-((3-(4-methylpiperazin-1-yl)pyrazin-2-yl)oxy)cyclobutyl)quinazolin-2-amine; or   (1-(3-((1S,3S)-3-(quinazolin-2-ylamino)cyclobutoxy)pyrazin-2-yl)piperidin-4-yl)methanol.