AU2013201630B2

Aminopyrimidines useful as kinase inhibitors

Abstract

Abstract Disclosed are aminopyrimidine compounds useful as inhibitors of protein kinases. Also disclosed are pharmaceutically acceptable compositions comprising the compounds and methods of using the compounds and compositions in the treatment of various diseases, conditions and disorders. Processes for preparing the compounds are also disclosed.

AU2013201630B2, drawing sheet 1 — Sheet 1 of 254

Term

Projected expiry 19 March 2033.

46 claims: 15 independent, 31 dependent

1
We claim:or a pharmaceutically acceptable salt thereof, wherein: Q is 0, NR' , S, or C (R' ) 2 ;R x is H, Ci- 6 aliphatic, NO 2 , CN, halo, NH 2 , NH (Ci- 4 aliphatic) , N (Ci-4aliphatic) 2 , 0 (Ci_4aliphatic) , OH, or -N (C=O) ( Ci_4aliphatic) ;wherein said aliphatic is optionally substituted with 1-3 fluoro;R 2 and R 2 are independently -R, -T-W-R 6 , or R 8 , or R 2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 is independently optionally substituted by halo, oxo, -CN, -NO 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 is independently optionally substituted by R 4 ;each T and T 4 is independently a Ci_ 4 alkylidene chain or is absent;each R independently is hydrogen, a Ci-χο aliphatic group, a C 6 -io aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from the 161 2013201630 08 Nov 2016 group consisting of nitrogen, oxygen, and sulfur, the aliphatic group and each R being optionally substituted by 0-6 R 9 ;each R 4 is independently -R 7 , -COR 7 , -CO2 (optionally substituted C1-6 aliphatic), -CON(R 7 ) 2 , or -SO2R 7 ;each V is independently -0-, -S-, -SO-, -SO2-, -N(R 6 ) SO2-, SO2N(R 6 )-, -N(R 6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO2N (R 6 )-, -N (R 6 ) N (R 6 )-, -C(O)N(R 6 )-, OC(O)N(R 6 )—, -C (R 6 ) 2O-, -C(R 6 )2S-, -C(R 6 )2SO-, -C (R 6 ) 2SO2, -C(R 6 )2SO 2 N(R 6 )-, C(R 6 )2N(R 6 )-, -C(R 6 )2N(R 6 )C(O), -c (R 6 ) 2N (R 6 ) C (0) 0-, C (R 6 ) =NN (R 6 )-, -C (R 6 ) =N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, or -C (R 6 ) 2N (R 6 ) CON (R 6 )-;each W is independently -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, C(R 6 )2SO 2 -, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -CO-, -CO2, -C (R 6 ) 2OC (0)-, -C(R 6 )2OC(O)N(R 6 ), -C (R 6 ) 2N (R 6 ) CO-, -C (R 6 ) 2N (R 6 ) C (0) 0-, -C (R 6 ) =NN (R 6 )-, -C(R 6 )=N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, -C (R 6 ) 2N (R 6 ) CON (R 6 )-, or -CON (R 6 ) - ;each Z is independently a C1-4 alkylidene chain or is absent;each R 6 is independently hydrogen or Ci_ 6 aliphatic optionally substituted with 0-3 J 6 ;or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 6 ;each R 7 is independently hydrogen;Ci_ 6 aliphatic;a 5-membered heteroaryl containing 0-4 heteroatoms selected from the group consisting of Ο, N, and S;or phenyl;each R 7 is optionally substituted with 0-3 J 7 ;or two R 7 on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 7 ;162 2013201630 08 Nov 2016 each R 8 is independently halogen, -CN, or -NO2;each R 9 is independently -R', -halo, -OR', -C(=O)R', CO 2 R' , -COCOR', COCH2COR' , -NO2, -CN, -S(O)R', -S(O) 2 R' , ~ SR', -N(R') 2 , -CON(r') 2 , -SO 2 N(r') 2 , -OC(=O)R', N(R')COR', -N (R') CO 2 (C1-6 aliphatic), -N (R') N (R') 2 , -N (R') CON (r') 2 < -N (R') SO 2 N (r') 2 < -N (R') S O 2 R' , -OC (=0) N (R') 2 , =NN(r') 2 , =N-OR', =NR' , or =0;each J 6 and J 7 is independently NH 2 , NH (Ci_ 4 aliphatic) , N (C 4 4 aliphatic) 2< halogen, Ci_ 4 aliphat ic, OH, O (Ci_ 4 aliphatic) , NO2, CN, CO2H, CO2 (Ci_ 4 aliphatic) , O (haloCi_ 4 aliphatic) , or haloCi 4 aliphatic;each R is independently hydrogen or a Ci_ 6 aliphatic group optionally substituted with 0-4 occurrences of NH 2 , NH (Ci_ 4 aliphatic) , N (Ci_ 4 aliphatic) 2, halogen, Ci_ 4 aliphatic, OH, O (Ci_ 4 aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_ 4 aliphatic) , CONH 2 , CONH(Ci_ 4 aliphatic) , CON (Ci_ 4 aliphat ic) 2, 0(haloCi_ 4 aliphatic), or haloCi 4 aliphatic;or, two R', together with the atom(s) to which they are attached, form =0, an optionally substituted 3-6 membered carbocyclyl, or heterocyclyl;Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of Ο, N, and S;each substitutable ring carbon of Ring D is independently optionally substituted by oxo, -T 4 -R 5 , or -V-Z-R 5 ;each substitutable ring nitrogen of Ring D is independently optionally substituted by -R 4 ;and R 5 is a C6-10 aryl optionally substituted with R 9 .
6
The compound represented by formula Il-b:R 2 (J)l-6 Il-b;or a pharmaceutically acceptable salt thereof, wherein: Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of Ο, N, and S;each substitutable ring carbon of Ring D is independently optionally substituted by oxo, -T 4 -R 5 , or -V-Z-R 5 ;each substitutable ring nitrogen of Ring D is independently optionally substituted by -R 4 ;R 5 is a Cg-io aryl optionally substituted with R 9 ;each J is independently R, -halo, -OR, -C(=O)R, -CO2R, -COCOR, COCH2COR, -NO2, -CN, -S (0) R, -S(O) 2 R, -SR, -N(R 4 )2, -CON(R 7 )2, SO 2 N(R 7 )2, -OC(=O)R, -N(R 7 )COR, -N (R 7 ) CO2 (C1-6 aliphatic), N(R 4 )N(R 4 )2, =NN(R 4 ) 2 , =N-OR, =NR, =0, -N (R 7 ) CON (R 7 ) 2, -N (R 7 ) SO2N (R 7 ) 2, -N(R 4 )SO2R, -OC (=0) N (R 7 ) 2 , or -OP (=0) (OR) 2 ;2 J groups, on the same atom or on different atoms, together with the atom(s) to which each set of J atoms are 164 2013201630 08 Nov 2016 bound, form a 3-8 membered saturated, partially saturated, or unsaturated ring having 0-2 heteroatoms selected from the group consisting of Ο, N, and S;wherein 1-4 hydrogen atoms on the ring formed by the 2 J groups is optionally replaced with halo, Ci_3alkyl, or -0 (Ci_3alkyl) ;wherein said Ci_3alkyl is optionally substituted with 1-3 fluorine;or two hydrogen atoms on the same atom in the ring formed by the 2 J groups are optionally replaced with oxo;Q is 0, NR' , S, or C (R' ) 2 ;R x is H, Ci_6aliphatic, NO 2 , CN, halo, NH 2 , NH (Ci_ 4 aliphatic) , N (Ci_ 4 aliphatic) 2 , 0 (Ci_ 4 aliphatic) , OH, or -N (C=O) ( Ci_ 4 aliphatic) ;wherein said aliphatic is optionally substituted with 1-3 fluoro;R 2 and R 2 are independently -R, -T-W-R 6 , or R 8 , or R 2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently optionally substituted by halo, oxo, -CN, -NO 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently optionally substituted by R 4 ;each T and T 4 is independently a C 2 - 4 alkylidene chain or is absent;each R is independently hydrogen, a Ci_i 0 aliphatic group, a Cg-io aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the aliphatic group and each R being optionally substituted by 0-6 R 9 ;each R 4 is independently -R 7 , -COR 7 , -CO2 (optionally substituted Ci_6 aliphatic), -CON(R 7 )2, or -SO 2 R 7 ;165 2013201630 08 Nov 2016 each V is independently -0-, -S-, -SO-, -SO2-, -N(R 6 ) SO2-, SO2N(R 6 )-, -N(R 6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO2N (R 6 )-, -N (R 6 ) N (R 6 )-, -C(O)N(R 6 )-, OC(O)N(R 6 )—, -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 ) 2 SO-, -C (R 6 ) 2SO2, -C(R 6 )2SO 2 N(R 6 )-, C(R 6 )2N(R 6 )-, -C(R 6 )2N(R 6 )C(O), -c (R 6 ) 2 N (R 6 ) C (0) 0-, C (R 6 ) =NN (R 6 )-, -C (R 6 ) =N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, or -C (R 6 ) 2N (R 6 ) CON (R 6 )-;each W is independently -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, C(R 6 )2SO 2 -, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -CO-, -CO2, -C (R 6 ) 2OC (0)-, -C(R 6 )2OC(O)N(R 6 ), -C (R 6 ) 2N (R 6 ) CO-, -C (R 6 ) 2N (R 6 ) C (0) 0-, -C (R 6 ) =NN (R 6 )-, -C(R 6 )=N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, -C (R 6 ) 2N (R 6 ) CON (R 6 )-, or -CON (R 6 ) - ;each Z is independently a C1-4 alkylidene chain or is absent;each R 6 is independently hydrogen or Ci_ 6 aliphatic optionally substituted with 0-3 J 6 ;or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 6 ;each R 7 is independently hydrogen;Ci_ 6 aliphatic;a 5-membered heteroaryl containing 0-4 heteroatoms selected from the group consisting of Ο, N, and S;or phenyl;each R 7 is optionally substituted with 0-3 J 7 ;or two R 7 on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 7 ;each R 8 is independently halogen, -CN, or -NO 2 ;each R 9 is independently -R', -halo, -OR', -C(=O)R', CO 2 R' , -COCOR', COCH2COR' , -NO2, -CN, -S(O)R', -S(O) 2 R' , ~ SR', -N(R') 2 , -CON(r') 2 , -SO 2 N(r') 2 , -OC(=O)R', 166 2013201630 08 Nov 2016 N(R')COR', -N (R') CO 2 (Ci-6 aliphatic), -N (R' ) N (R' ) 2 , -N (R') CON (r') 2 , -N (R' ) SO 2 N (r' ) 2 , -N (R' ) S O 2 R' , -OC (=0) N (R') 2 , =NN(R') 2 , =N-OR' , =NR' , or =0;each J 6 and J 7 is independently NH 2 , NH (Ci_4aliphatic) , N (C 2 4 aliphatic) 2 , halogen, Ci-4aliphat ic, OH, O (Ci-4aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_4aliphatic) , O (haloCi_4aliphatic) , or haloCi4aliphatic;and each R is independently hydrogen or a Ci_ 6 aliphatic group optionally substituted with 0-4 occurrences of NH 2 , NH (Ci-4aliphatic) , N (Ci-4aliphatic) 2 , halogen, Ci-4aliphatic, OH, 0 (Ci_4aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci^aliphatic) , CONH 2 , CONH(Ci_ 4aliphatic) , CON (Ci_4aliphat ic) 2 , 0(haloCi- 4 aliphatic), or haloCi4aliphatic;or, two R', together with the atom(s) to which they are attached, form =0, an optionally substituted 3-6 membered carbocyclyl, or heterocyclyl;and each R is independently H or Ci- 2 alkyl.
13
The compound of represented by formula II-c:II-c;or a pharmaceutically acceptable salt thereof, wherein: Q is 0, NR' , S, or C (R' ) 2 ;R x is H, Ci_6aliphatic, NO 2 , CN, halo, NH 2 , N (Ci-4aliphatic) , N (Ci-4aliphatic) 2 , 0 (Ci_4aliphatic) , OH, or -N (C=O) ( Ci-4aliphatic) ;wherein said aliphatic is optionally substituted with 1-3 fluoro;R 2 and R 2 are independently -R, -T-W-R 6 , or R 8 , or R 2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently optionally substituted by halo, oxo, -CN, -NO 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently optionally substituted by R 4 ;each T and T 4 is independently a Ci_ 4 alkylidene chain or is absent;each R is independently hydrogen, a Ci_i 0 aliphatic group, a C6-10 aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or 168 2013201630 08 Nov 2016 heterocyclyl ring having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the aliphatic group and each R being optionally substituted by 0-6 R 9 ;each R 4 is independently -R 7 , -COR 7 , -CO2 (optionally substituted C1-6 aliphatic), -CON(R 7 ) 2 , or -SO2R 7 ;each V is independently -0-, -S-, -SO-, -SO 2 -, -N(R 6 ) SO2-, SO2N(R 6 )-, -N(R 6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO2N (R 6 )-, -N (R 6 ) N (R 6 )-, -C(O)N(R 6 )-, OC(O)N(R 6 )—, -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 ) 2 SO-, -C (R 6 ) 2SO2, -C(R 6 )2SO 2 N(R 6 )-, C(R 6 )2N(R 6 )-, -C(R 6 )2N(R 6 )C(O), -c (R 6 ) 2 N (R 6 ) C (0) 0-, C (R 6 ) =NN (R 6 )-, -C (R 6 ) =N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, or -C (R 6 ) 2N (R 6 ) CON (R 6 )-;each W is independently -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, C(R 6 ) 2 SO 2 -, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -CO-, -CO2, -C(R 6 ) 2 OC (0)-, -C (R 6 ) 2OC (Ο) N (R 6 ) , -C (R 6 ) 2N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (0) 0-, -C (R 6 ) =NN (R 6 )-, -C(R 6 )=N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, -C (R 6 ) 2N (R 6 ) CON (R 6 )-, or -CON (R 6 ) - ;each Z is independently a Ci_ 4 alkylidene chain or is absent;each R 6 is independently hydrogen or C1-6 aliphatic optionally substituted with 0-3 J 6 ;or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 6 ;each R 7 is independently hydrogen;C1-6 aliphatic;a 5-membered heteroaryl containing 0-4 heteroatoms selected from the group consisting of Ο, N, and S;or phenyl;each R 7 is optionally substituted with 0-3 J 7 ;or two R 7 on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-8 membered heterocyclyl or heteroaryl 169 2013201630 08 Nov 2016 ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 7 ;each R 8 is independently halogen, -CN, or -ΝΟ 2 ;each R 9 is independently -R', -halo, -OR', -C(=O)R', CO 2 R', -COCOR', COCH 2 COR' , -NO2, -CN, -S (0) R' , -S (0) 2 R' , ~ SR', -N(R') 2 , -CON(r') 2 , -SO 2 N(r') 2 , -OC(=O)R', N(R')COR', -N (R') CO 2 (C1-6 aliphatic), -N (R') N (R') 2 , -N (R') CON (r') 2 , -N (R') SO 2 N (r') 2 , -N (R') S O 2 R', -OC (=0) N (R') 2 , =NN(r') 2 , =N-OR', =NR' , or =0;each J 6 and J 7 is independently NH 2 , NH (Ci- 4 aliphatic) , N (C 4 4 aliphatic) 2, halogen, Ci_ 4 aliphatic, OH, O (Ci_ 4 aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_ 4 aliphatic) , O (haloCi_ 4 aliphatic) , or haloCi 4 aliphatic;each R is independently hydrogen or a C 4 -6 aliphatic group optionally substituted with 0-4 occurrences of NH 2 , NH (Ci_ 4 aliphatic) , N (Ci- 4 aliphatic) 2 , halogen, Ci_ 4 aliphatic, OH, 0 (Ci_ 4 aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_ 4 aliphatic) , CONH 2 , CONH(Ci_ 4 aliphatic) , CON (Ci- 4 aliphat ic) 2, 0(haloCi- 4 aliphatic), or haloCi 4 aliphatic;or, two R', together with the atom(s) to which they are attached, form =0, an optionally substituted 3-6 membered carbocyclyl, or heterocyclyl;Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of Ο, N, and S;each substitutable ring carbon of Ring D is independently optionally substituted by oxo, -T 4 -R 5 , or -V-Z-R 5 ;each substitutable ring nitrogen of Ring D is independently optionally substituted by -R 4 ;and R 5 is a C1-6 alkyl or C3- 6 cycloaliphatic optionally substituted with R 9 .
18
19. The compound of claim 18, wherein R 5 is optionally substituted with 1-6 halogen or a CF 3 group.
20
21. The compound of claim 20, wherein the azetidine of formula ΙΙ-d is substituted with 2 J groups wherein J is Ci_ 6 aliphatic, C3-6cycloaliphatic, or halogen.
21
22. The compound of claim 21, wherein J is C3 cycloaliphatic.
22
23. The compound of any one of claims 19-21, wherein said halogen of J is F. Il-e; or a pharmaceutically acceptable salt thereof, wherein:Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of Ο, N, and S;Ring D' is a 5 8 aromatic, partially saturated, or fully unsaturated ring containing 0-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;each substitutable ring carbon of Ring D and Ring D' is independently optionally substituted by oxo, -T 4 -R 5 , or -V-Z-R 5 ;each substitutable ring nitrogen of Ring D and Ring D' is independently optionally substituted by -R 4 ;and R 5 is C1-6 aliphatic, C3-6cycloaliphatic, or halogen, wherein said C1-6 aliphatic or C3-6cycloaliphatic is optionally substituted with halogen;175 2013201630 08 Nov 2016 each J is independently R, -halo, -OR, -C(=O)R, -CO2R, -COCOR, COCH 2 COR, -NO2, -CN, -S(O)R, -S(O) 2 R, -SR, -N(R 4 )2, -CON(R 7 )2, SO 2 N(R 7 )2, -OC(=O) R, -N(R 7 )COR, -N (R 7 ) CO2 (Οι-e aliphatic), N(R 4 )N(R 4 )2, =NN(R 4 ) 2 , =N-OR, =NR, =0, -N (R 7 ) CON (R 7 ) 2, -N (R 7 ) SO2N (R 7 ) 2, -N(R 4 )SO2R, -OC (=0) N (R 7 ) 2 , or -OP (=0) (OR) 2 ;2 J groups, on the same atom or on different atoms, together with the atom(s) to which each set of J atoms are bound, form a 3-8 membered saturated, partially saturated, or unsaturated ring having 0-2 heteroatoms selected from the group consisting of Ο, N, and S;wherein 1-4 hydrogen atoms on the ring formed by the 2 J groups is optionally replaced with halo, Ci_3alkyl, or -0 (Ci-3alkyl) ;wherein said Ci_3alkyl is optionally substituted with 1-3 fluorine;or two hydrogen atoms on the same atom in the ring formed by the 2 J groups are optionally replaced with oxo;Q is 0, NR', S, or C(R')2;R x is H, Ci_6aliphatic, NO2, CN, halo, NH 2 , NH (Ci_ 4 aliphatic) , N (Ci_ 4 aliphatic) 2 < 0 (Ci_ 4 aliphatic) , OH, or -N (C=0) ( Ci_ 4 aliphatic) ;wherein said aliphatic is optionally substituted with 1-3 fluoro;R 2 and R 2 ' are independently -R, -T-W-R 6 , or R 8 , or R 2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 is independently optionally substituted by halo, oxo, -CN, -N0 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 is independently optionally substituted by R 4 ;each T and T 4 is independently a C 4 - 4 alkylidene chain or is absent;176 2013201630 08 Nov 2016 each R is independently hydrogen, a Ci-χο aliphatic group, a C 6 -io aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the aliphatic group and each R being optionally substituted by 0-6 R 9 ;each R 4 is independently -R 7 , -COR 7 , -CO2 (optionally substituted Ci_6 aliphatic), -CON(R 7 )2, or -SO 2 R 7 ;each V is independently -0-, -S-, -SO-, -SO2-, -N(R 6 ) SO2-, SO2N(R 6 )-, -N(R 6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO2N (R 6 )-, -N (R 6 ) N (R 6 )-, -C(O)N(R 6 )-, OC(O)N(R 6 )—, -C (R 6 ) 2O-, -C(R 6 )2S-, -C(R 6 )2SO-, -C (R 6 ) 2SO2, -C(R 6 )2SO 2 N(R 6 )-, C(R 6 )2N(R 6 )-, -C(R 6 )2N(R 6 )C(O), -c (R 6 ) 2N (R 6 ) C (0) 0-, C (R 6 ) =NN (R 6 )-, -C (R 6 ) =N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, or -C (R 6 ) 2N (R 6 ) CON (R 6 )-;each W is independently -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, C(R 6 ) 2 SO 2 -, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -CO-, -CO2, -C (R 6 ) 2OC (0)-, -C(R 6 )2OC(O)N(R 6 ), -C (R 6 ) 2N (R 6 ) CO-, -C (R 6 ) 2N (R 6 ) C (0) 0-, -C (R 6 ) =NN (R 6 )-, -C(R 6 )=N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, -C (R 6 ) 2N (R 6 ) CON (R 6 )-, or -CON (R 6 ) - ;each Z is independently a C1-4 alkylidene chain or is absent;each R 6 is independently hydrogen or C1-6 aliphatic optionally substituted with 0-3 J 6 ;or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 6 ;each R 7 is independently hydrogen;Ci_ 6 aliphatic;a 5-membered heteroaryl containing 0-4 heteroatoms selected from the group consisting of Ο, N, and S;or phenyl;each R 7 is optionally substituted with 0-3 J 7 ;or two R 7 on the same 177 2013201630 08 Nov 2016 nitrogen are taken together with the nitrogen to form an optionally substituted 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 7 ;each R 8 is independently halogen, -CN, or -NO 2 ;each R 9 is independently -R', -halo, -OR', -C(=O)R', CO 2 R', -COCOR', COCH 2 COR' , -NO 2 , -CN, -S (0) R', -S (0) 2 R', SR', -N(R') 2 , -CON(R') 2 , -SO 2 N(R') 2 , -OC(=O)R', N(R')COR', -N (R') CO 2 (Ci-6 aliphatic), -N (R') N (R') 2 , -N (R') CON (R') 2 , -N (R') SO 2 N (r') 2 , -N (R') S O 2 R', -OC (=0) N (R') 2 , =NN(R') 2 , =N-OR', =NR' , or =0;each J 6 and J 7 is independently NH 2 , NH (Ci_ 4 aliphatic) , N (C 4 4 aliphatic) 2 , halogen, Ci_ 4 aliphat ic, OH, 0 (Ci_ 4 aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_ 4 aliphatic) , 0 (haloCi_ 4 aliphatic) , or haloCi 4 aliphatic;and each R is independently hydrogen or a Ci-6 aliphatic group optionally substituted with 0-4 occurrences of NH 2 , NH (Ci_ 4 aliphatic) , N (Ci- 4 aliphatic) 2 , halogen, Ci_ 4 aliphatic, OH, 0 (Ci_ 4 aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_ 4 aliphatic) , CONH 2 , CONH(Ci_ 4 aliphatic) , CON (Ci- 4 aliphat ic) 2 , 0(haloCi_ 4 aliphatic), or haloCi 4 aliphatic;or, two R', together with the atom(s) to which they are attached, form =0, an optionally substituted 3-6 membered carbocyclyl, or heterocyclyl;each R is independently H or Ci- 2 alkyl.
24
26. The compound of claim 24 or 25, wherein the azetidine of formula ΙΙ-e is substituted with 1-2 J groups wherein J is Ci_ 6 178 2013201630 08 Nov 2016 aliphatic, C3-6cycloaliphat ic, halogen, OH, OR, NH 2 , NH(Ci_6), N(Ci_ 6 ) 2 , CN, or a 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from the group consisting of Ο, N, and S.
25
27. The compound of any one of claims 24-26, wherein D-D' is benzimidazole, isoquinoline, quinoline, or isoindolinone.
26
28. The compound represented by formula Il-f:Il-f;or a pharmaceutically acceptable salt thereof, wherein: Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of Ο, N, and S;each substitutable ring carbon of Ring D is independently optionally substituted by oxo, -T 4 -R 5 , or -V-Z-R 5 ;each substitutable ring nitrogen of Ring D is independently optionally substituted by -R 4 ;and R 5 is a Cg-io aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;each J is independently R, -halo, -OR, -C(=O)R, -CO 2 R, -COCOR, COCH 2 COR, -NO 2 , -CN, -S (0) R, -S (0) 2 R, -SR, -N(R 4 )2, -CON(R 7 )2, SO 2 N(R 7 )2, -OC(=O)R, -N(R 7 )COR, -N (R 7 ) CO 2 (Ci- 6 aliphatic), 179 2013201630 08 Nov 2016 N(R 4 )N(R 4 )2, =NN(R 4 )2, =n-or, =nr, =0, -N (R 7 ) CON (R 7 ) 2, -N (R 7 ) SO2N (R 7 ) 2, -N(R 4 )SO2R, -OC (=0) N (R 7 ) 2, or -OP (=0) (OR) 2 ;2 J groups, on the same atom or on different atoms, together with the atom(s) to which each set of J atoms are bound, form a 3-8 membered saturated, partially saturated, or unsaturated ring having 0-2 heteroatoms selected from the group consisting of Ο, N, and S;wherein 1-4 hydrogen atoms on the ring formed by the 2 J groups is optionally replaced with halo, Ci-3alkyl, or -0 (Ci-3alkyl) ;wherein said Ci-3alkyl is optionally substituted with 1-3 fluorine;or two hydrogen atoms on the same atom in the ring formed by the 2 J groups are optionally replaced with oxo;Q is 0, NR', S, or -C(R') 2 ;R x is H, Ci_ 6 aliphatic, N0 2 , CN, halo, NH 2 , NH (Ci_ 4 aliphatic) , N (Ci-4aliphatic) 2 < 0 (Ci-4aliphatic) , OH, or -N (C=O) ( Ci-4aliphatic) ;wherein said aliphatic is optionally substituted with 1-3 fluoro;R 2 and R 2 ' are independently -R, -T-W-R 6 , or R 8 , or R 2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 is independently optionally substituted by halo, oxo, -CN, -NO 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 is independently optionally substituted by R 4 ;each T and T 4 is independently a Ci_ 4 alkylidene chain or is absent;each R is independently hydrogen, a C1-10 aliphatic group, a C6-10 aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or 180 2013201630 08 Nov 2016 heterocyclyl ring having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the aliphatic group and each R being optionally substituted by 0-6 R 9 ;each R 4 is independently -R 7 , -COR 7 , -CO2 (optionally substituted C1-6 aliphatic), -CON(R 7 ) 2 , or -SO2R 7 ;each V is independently -0-, -S-, -SO-, -SO 2 -, -N(R 6 ) SO2-, SO2N(R 6 )-, -N(R 6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO2N (R 6 )-, -N (R 6 ) N (R 6 )-, -C(O)N(R 6 )-, OC(O)N(R 6 ) —, -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, -C (R 6 ) 2SO 2 , —C (R 6 ) 2SO2N (R 6 ) —, C (R 6 ) 2N (R 6 ) —, -C (R 6 ) 2N (R 6 ) C (0) , -C (R 6 ) 2N (R 6 ) C (0) 0-, C (R 6 ) =NN (R 6 )-, -C (R 6 ) =N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, or -C (R 6 ) 2N (R 6 ) CON (R 6 )-;each W is independently -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, C(R 6 ) 2 SO 2 -, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -CO-, -CO2, -C (R 6 ) 2 OC (0)-, -C (R 6 ) 2OC (Ο) N (R 6 ) , -C (R 6 ) 2N (R 6 ) CO-, -C (R 6 ) 2 N (R 6 ) C (0) 0-, -C (R 6 ) =NN (R 6 )-, -C(R 6 )=N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, -C (R 6 ) 2N (R 6 ) CON (R 6 )-, or -CON (R 6 ) -;each Z is independently a Ci_ 4 alkylidene chain or is absent;each R 6 is independently hydrogen or C1-6 aliphatic optionally substituted with 0-3 J 6 ;or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 6 ;each R 7 is independently hydrogen;C1-6 aliphatic;a 5-membered heteroaryl containing 0-4 heteroatoms selected from the group consisting of Ο, N, and S;or phenyl;each R 7 is optionally substituted with 0-3 J 7 ;or two R 7 on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-8 membered heterocyclyl or heteroaryl 181 2013201630 08 Nov 2016 ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 7 ;each R 8 is independently halogen, -CN, or -NO 2 ;each R 9 is independently -R', -halo, -OR', -C(=O)R', CO 2 R' , -COCOR', COCH 2 COR', -NO2, -CN, -S (0) R' , -S (0) 2 R' , ~ SR', -N(R') 2 , -CON(r') 2 , -SO 2 N(r') 2 , -OC(=O)R', N(R')COR', —Ν (R' ) CO 2 (C1-6 aliphatic), -N (R') N (R') 2 , -N (R') CON (r') 2 , -N (R') SO 2 N (r') 2 , -N (R') S O 2 R' , -OC (=0) N (R') 2 , =NN(r') 2 , =N-OR', =NR' , or =0;each J 6 and J 7 is independently NH 2 , NH (Ci- 4 aliphatic) , N (C 4 4 aliphatic) 2 < halogen, Ci_ 4 aliphatic, OH, O (Ci_ 4 aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_ 4 aliphatic) , O (haloCi- 4 aliphatic) , or haloCi 4 aliphatic;and each R is independently hydrogen or a C1-6 aliphatic group optionally substituted with 0-4 occurrences of NH 2 , NH (Ci- 4 aliphatic) , N (Ci- 4 aliphatic) 2 , halogen, Ci- 4 aliphatic, OH, 0 (Ci- 4 aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_ 4 aliphatic) , CONH 2 , CONH(Ci_ 4 aliphatic) , CON (Ci- 4 aliphat ic) 2, 0(haloCi_ 4 aliphatic), or haloCi 4 aliphatic;or, two R', together with the atom(s) to which they are attached, form =0, an optionally substituted 3-6 membered carbocyclyl, or heterocyclyl;each R is independently H or Ci-2alkyl. 182 2013201630 08 Nov 2016 or a pharmaceutically acceptable salt thereof, wherein: Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of Ο, N, and S;each substitutable ring carbon of Ring D is independently optionally substituted by oxo, -T 4 -R 5 , or -V-Z-R 5 ;each substitutable ring nitrogen of Ring D is independently optionally substituted by -R 4 ;R 5 is Ci-6 alkyl optionally substituted with R 9 ;Q is 0, NR' , S, or C(R')2;R x is H, Ci_6aliphatic, NO2, CN, halo, NH 2 , NH (Ci_4aliphatic) , N (Ci- 4 aliphatic) 2 < 0 (Ci_ 4 aliphatic) , OH, or -N (C=O) ( Ci- 4 aliphatic) ;wherein said aliphatic is optionally substituted with 1-3 fluoro;R 2 and R 2 are independently -R, -T-W-R 6 , or R 8 , or R 2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently optionally substituted by halo, oxo, -CN, -NO2, -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently optionally substituted by R 4 ;each T and T 4 is independently a C1-4 alkylidene chain or is absent;each R is independently hydrogen, a Ci_i 0 aliphatic group, a C6-10 aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, the aliphatic group and each R being optionally substituted by 0-6 R 9 ;each R 4 is independently -R 7 , -COR 7 , -CO2 (optionally substituted Ci_6 aliphatic), -CON(R 7 )2, or -SO 2 R 7 ;183 2013201630 08 Nov 2016 each V is independently -0-, -S-, -SO-, -SO2-, -N(R 6 ) SO2-, SO2N(R 6 )-, -N(R 6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO2N (R 6 )-, -N (R 6 ) N (R 6 )-, -C(O)N(R 6 )-, OC(O)N(R 6 )—, -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 ) 2 SO-, -C (R 6 ) 2SO2, -C(R 6 )2SO 2 N(R 6 )-, C(R 6 )2N(R 6 )-, -C(R 6 )2N(R 6 )C(O), -c (R 6 ) 2 N (R 6 ) C (0) 0-, C (R 6 ) =NN (R 6 )-, -C (R 6 ) =N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, or -C (R 6 ) 2N (R 6 ) CON (R 6 )-;each W is independently -C(R 6 )2O-, -C(R 6 )2S-, -C(R 6 )2SO-, C(R 6 )2SO 2 -, -C(R 6 )2SO2N(R 6 )-, -C(R 6 )2N(R 6 )-, -CO-, -CO2, -C (R 6 ) 2OC (0)-, -C(R 6 )2OC(O)N(R 6 ), -C (R 6 ) 2N (R 6 ) CO-, -C (R 6 ) 2N (R 6 ) C (0) 0-, -C (R 6 ) =NN (R 6 )-, -C(R 6 )=N-O, -C (R 6 ) 2N(R 6 )N (R 6 )-, -C (R 6 ) 2N (R 6 ) SO2N (R 6 )-, -C (R 6 ) 2N (R 6 ) CON (R 6 )-, or -CON (R 6 ) - ;each Z is independently a C1-4 alkylidene chain or is absent;each R 6 is independently hydrogen or Ci_ 6 aliphatic optionally substituted with 0-3 J 6 ;or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 6 ;each R 7 is independently hydrogen;Ci_ 6 aliphatic;a 5-membered heteroaryl containing 0-4 heteroatoms selected from the group consisting of Ο, N, and S;or phenyl;each R 7 is optionally substituted with 0-3 J 7 ;or two R 7 on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-8 membered heterocyclyl or heteroaryl ring;wherein said heterocyclyl or heteroaryl ring is optionally substituted with 0-4 J 7 ;each R 8 is independently halogen, -CN, or -NO 2 ;each R 9 is independently -R', -halo, -OR', -C(=O)R', CO 2 R' , -COCOR', COCH2COR' , -NO2, -CN, -S(O)R', -S(O) 2 R' , ~ SR', -N(R') 2 , -CON(r') 2 , -SO 2 N(r') 2 , -OC(=O)R', 184 2013201630 08 Nov 2016 N (R' ) COR' , -N (R' ) CO 2 (Ci-6 aliphatic), -N (R') N (R') 2 , -N (R' ) CON (r' ) 2 , -N (R' ) SO 2 N (r' ) 2 , -N (R') S O 2 R', -OC (=0) N (R') 2 , =NN(R')2, =N-OR', =NR', or =0;each J 6 and J 7 is independently NH 2 , NH (Ci_4aliphatic) , N (C 2 4 aliphatic) 2 , halogen, Ci-4aliphat ic, OH, O (Ci_4aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci_4aliphatic) , O (haloCi_4aliphatic) , or haloCi4aliphatic;and each R is independently hydrogen or a Ci_ 6 aliphatic group optionally substituted with 0-4 occurrences of NH 2 , NH (Ci-4aliphatic) , N (Ci-4aliphatic) 2 , halogen, Ci-4aliphatic, OH, 0 (Ci_4aliphatic) , NO 2 , CN, CO 2 H, CO 2 (Ci^aliphatic) , CONH 2 , CONH(Ci_ 4aliphatic) , CON (Ci_4aliphat ic) 2 , 0(haloCi- 4 aliphatic), or haloCi4aliphatic;or, two R', together with the atom(s) to which they are attached, form =0, an optionally substituted 3-6 membered carbocyclyl, or heterocyclyl.
27
30. The compound according to any one of claims 1-29, wherein Q is 0, NR', or S.
30
33. A compound, wherein the compound is:1-1 1-2 1-3 185 2013201630 08 Nov 2016 1-4 1-5 1-6 1-7 1-8 1-9 1-10 1-11 1-12 1-13 1-14 1-15 1-16 1-17 1-18 186 2013201630 08 Nov 2016 N-NH νη ζ Ά~ o 1-22 ν·ΝΗ N'NH 1-20 N-NH 1-23 1-26 1-28 1-29 1-30 187 2013201630 08 Nov 2016 1-37 1-38 1-39 1-40 1-46 or a pharmaceutically acceptable salt thereof.
31
34. A compound, wherein the compound is:188 2013201630 08 Nov 2016 Ji 'N λ ” Jil W A y a .4 ST 'ft λ 8 ,ο r-'K· N s ;A V. S' Ci . ...;U u / 11' BSS|' xFi' 1 H XT a A h £. 3 Cl A A X 1-47 1-48 1-49 H O x 1 Cl T * Ίί „ Λ cr A ” N M' S' “A X _ A 5 (0 „ iz o y s K«T 'IT' '-S- *1A M H l^-N 1 Al A* I Q Y ✓3* X u 1-50 1-51 1-52 H N-'K Ar' Λ ·$| X W Ί o T A R Λ .'Ν' 'N 'S ;A u r -Ό I 9 A η^Α^Α j6 Γ'Γ ΊΓ S A ... g X αι ·χζ * · γ X 1-53 1-54 1-55 189 2013201630 08 Nov 2016 1 « fl rs s s ' X O T ..o Τ' F c (X 1 H Π r« s s A O T OOu Xi Γ'.ϊ J Φ X ,-Χζχ. ιη Cl 1-56 1-57 1-58 1-59 1-60 1-61 r-A „ ΐ.. kh 1 [f ° X'XS v a r H J xO X..«« u .?r4t A ” Π M L u X ,o □: ) li'j r-H’ W XS ‘J Φ X Ci [ij 1-63 190 2013201630 08 Nov 2016 r' J χ/ A Ao A? Λ Y . a n Λ M .., [ B w .1. Γη fv r «ΧΑΧΑ Ύ 1 (AiH ..A·, Ο X-· V W / 1—65 1—66 1—67 0 V .A Y H I ii I 1] A u -Ά·· A. x O mM K Ur A, A .. 5' NH N rA ~ Φ ,L a lijr 0 X κ Λ Mr hrAAA ' }=l4 z 1-68 1 — 69 1-70 H O 1 H A M r ii ίι Ύ n «hAA'M ° H«k Y ,X,, ί I rtl'S'S / 1. O T Η y γί A .. X ην ' n A l! X r«- N‘ A 1 a T M?a ,o H r A 'X. 1-72 191 2013201630 08 Nov 2016 JJ-i? η!(Λγ- Λ r-Ή s λ Ο Y ο £ „ ί·. tiH Δ ΑΝ '£ Λο τ οΝ .Ό φ) Η G Ζ Η Λ Ar Ύ Ν S ·- *4Ν' Υ - / ΐ 1-74 1-75 1-76 1-77 1-78 1-79 1-81 192 2013201630 08 Nov 2016 1-89 1-90 1-91 193 2013201630 08 Nov 2016 1-92 1-93 1-94 Ά £* .. AHoO X M 1 tt wz H X --K. W AAf Ύ* Y W . - . . ..-'Lu . .v-Lx. _,J o „ Δ ζχ Ά' o »A 1 ' ' ' H r X:- 1 AA “Λ \:n 1-95 1 — 96 1-97 H / \ / ’ 7 H V A 'N [ίΛ-*8γΧ u Λν X Χχχ J o 1 7 « ί ιϊ Γ if N Aa N. ΊΤ $ «A L N=( * X A «=4 X 1-98 1-99 1-100 194 2013201630 08 Nov 2016 1-104 1-105 1-106 1-108 195 2013201630 08 Nov 2016 K M Λ nV hA F ,o A V V . f VV HjjL-j 4» hnz·^ 1 H Ji 1 Γ'*τ tr § M ..1. 9 A γ'' V F 1-110 1-111 1-112ΒΥ V ΥΎ Asm H X . f H fLl 1 9 Λ F -Y'-hs η X IL X '1 « F I U 1 □ Λ γϊΎ «AW Of-pf u 1 F . i V AY Μ=ς 1-113 1-114 1-115 ιϊΑ Vf V r ar xinxs IlSl· (Χ .. 5 A* X to ., * L .« -A Π LT ίγ Y;: L· h .,-1-,. -J. ,-L ..-I o Ά si S YY „..D T Ύ A L C3 v L i Π s 1-116 1-117 1-118 196 2013201630 08 Nov 2016 o z\ « U Λ A M jf «.r-’A .'! ;fi 1 « Ji 4 .'-Αύ A C Ji Y AA A -A O Ά’ X M Ο f-·^·· '^4' 'J: ύ .1. v. M Ηγθ 4-. F 1-119 1-120 1-121 **c z V h Π1 u;w ϊφ hN·-^· ’ ί Ν=ς ί £ 6$ Λ Μ *? Λ ΥΑι η jl ^Ν'Ά Η !·!' 'Ν Ji 4 f-'fi- '8 .-1.-. φ ην ..ο Η γ , X .Ν Cr 197 2013201630 08 Nov 2016 1-128 1-129 1-130 4 o... v Λ Li / H : s i: '84 Y4 Φ Li... .$ίττ F f γ « F u V Vy X xx, -n4 X Si:-----1 B \ 1-131 1-132 1-133 1-135 198 2013201630 08 Nov 2016 J p-A A :! ‘ fl » · pi y „ ii Ή Y'ft ί 4 ί- Η •« ' S .1 Γ.Ϊ ^'ST^S A 11 -1 / -'fa Ni -S· -/ k ό V r r· Η^γΡ Ιΐ Ίkr. A V. 1 A, 1-137 1-138 1-139 / ,/'Ί ./ ,, j! ¢, \ ,.‘O k * Γ HrAm· A 1 8 o Il 1 MSi*SAs u 1 p it ή Λ .Λ. Q ..- rt rr ~ V A I otX) ”=\ Y N V Ar F 1-140 1-141 1-142F A r i H ff 74 r-'ti- H5 'S . A iT Ά hK' Ή 1 M F Γ η ΓΎ Ύ79 Y;..1. O T Λ X M »=4 Ii Ί Il X \ r 1-144 199 2013201630 08 Nov 2016 J M XI M A T XV n)rF Λ AiA A A';-,. u? H 1-146 1-147 1-148 „ A* HM ax Ai T lsN . Ό Ft %S/ O **·' ύγ a X fl Ht MjjAs' 1 9 Π ‘-x a □ A. ? * « r A F A A- « I H o A AA^A **=( X 1-149 1-150 1-151 1-153 200 2013201630 08 Nov 2016 !Z' U ,¾f/ F I i I i Η Γ 1» /” F V ίΑγΛν’γ'Μ! f 1 λ Ji if M 7-·' ίΝ Z' ,flA 1-155 1-156 1-157 1-158 1-159 1-160 H Λ x ’ Λ p „54 , J Io IX N- A /''PS' PS - A, p Ya p Ci 9 h?AA;' An 1 x '5 M 1 .-¼. A Ύ« JO 1-162 201 2013201630 08 Nov 2016 Ji J ί~Μ· IT v5 A y Λ ct ix r A Hjj·· μ ,-'-Χν 4 I S w A IX !) Ύ J., ,-S. U - H ΗΗλΖ X O u 1 Q Ύ fl:-- 1-164 1-166 1-165 Ύ „χτ ΠΎΛ h ANr 's-· wH«X? M N?X z V H F r'X xx^xn ^AASAJJ a F hnX, X X, ...:x. J, -A h .£ X X ί I Λ J N- k-4' H X 1-168 1-169 1-170 F N V tl „ f ϊ nr m? ma Ά. vx ΰ Λ An f5s?vX Η I IL A -« X-- ' ΡΛ 1 F ς t 202 2013201630 08 Nov 2016 1-172 F ,Λ 00 λΛ m bAAA· H«A X . 0 J· Λ hk * x •'A'AA ^3'· Ά s. Ογ, / F 1-174 1-175 1-176 o V AAAv :F yr % F .A-* .X A rrVX HX A** 'S·' kA A A Af ^AH q ’ F 1-177 1-178 1-179 A y0- ϊ N F I ft Γ t rr XF hnAA-W ° r A / \ 0 I v X.„ --V ,R ,-- , ' '» 'V' «κΑιΑΑ^Α^ A A 1-180 1-181 1-182 V , A » F [II ¢000 hn A iil={ X Y H p H 0. 0 G. J S F FMlsi-0'0-0s pAn 0^ F . — V A v H L. ... N .- F « Π XT TA 0' 'f'VV A« .A 1-183 1-184 1-185 203 2013201630 08 Nov 2016 Η»γί· , ..-¾. J ο w M A A A I A,j AsAx ·- A I H AhH )=fS 1-186 1-187 1-188 F A X. V' F f AVA Au, F ^Α’ΌΏΦ CS Q 4 . . ΚΝ-· Η·” XS'AA J HfT'N. 1-189 1-190 1-191fXn Φ “ύ F A x j T - y h? a H ri oir HhAj «XF A Ά A rVvA H|S| A N—( 1-192 1-193 1-194 ( / A 1 H F . ¢1 f rMT:A HiA, N={ X M AX Al, φ A 1-195 1-196 1-197 204 2013201630 08 Nov 2016 ί \ Ο L 1 r Α Λ λ Λ Χ„ .8*. 1 Η ? 'Ν: Γ'Χ VP V5 h^A^A.jY.AY 1 „ ri π ϊ xf #Γ -ίΤ ό ·:··! Hr% ?i= ' Η '· υ 1-198 1-199 1-200 fT^M- aL tA l-f ·™ γγ γγ 11 J Υή Μ 1 r Η 1 G γΓ^ *ψ rfW’αΛ «ί AJ A 205 2013201630 08 Nov 2016 «V T Η H JL JL m F H S» Y Y 'dv ' \ 1 ψ U/f [A Η Λ 1-210 1-211 or a pharmaceutically acceptable salt thereof.
32
35. A composition comprising a compound represented by the following structural formula:or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
33
36. A method of inhibiting Aurora protein kinase activity in a biological sample comprising contacting said biological sample with a compound represented by the following structural formula:206 2013201630 08 Nov 2016 or a pharmaceutically acceptable salt thereof.
34
37. A method of treating a proliferative disorder in a patient comprising the step of administering to said patient a compound represented by the following structural formula:or a pharmaceutically acceptable salt thereof.
36
39. A method of treating cancer in a subject in need thereof, comprising the sequential or co-administration of a compound represented by the following structural formula:or a pharmaceutically acceptable salt thereof, and another therapeutic agent.
39
42. The method according to claim 39, wherein said therapeutic agent is camptothecin, doxorubicin, idarubicin, Cisplatin, taxol, taxotere, vincristine, imatinib, the MEK inhibitor, U0126, a KSP inhibitor, vorinostat, erlotinib, dasatinib, or nilotinib.
40
43. A compound represented by the following structural formula:208 2013201630 08 Nov 2016 salt thereof.
41
44 . The compound of claim 43, wherein the compound is
42
45 . , B Η Λ «•As s-ί \ J The compound of claim 43, wherein the compound is a pharmaceutically acceptable salt of
45
48. The method of any one of claims 36-42, wherein the compound
46
49. The method of any one of claims 36-42, wherein the compound is a pharmaceutically acceptable salt of 210 2013201630 08 Nov 2016 211

Independent claims23

1,684 paragraphs in 354 sections, as filed

FIELD OF THE INVENTION [0001] The present invention relates to compounds useful as inhibitors of kinases. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of the invention, methods of using the compounds and compositions in.the treatment of various disorders, and processes for preparing the compounds.

BACKGROUND OF THE INVENTION [0002] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.

[0003] Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 2.50-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, proteinserine/threonine, lipids, etc.). Sequence motifs have been

WO 2007/056221

PCT/US2006/043096

2013201630 19 Mar 2013 identified that generally correspond to each of these kinase families .

[0004] In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function.

[0005] These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2) , cytokines (e.g., interleukin-3. (IL-1) and tumor necrosis factor a (TNF-a)), and growth factors (e.g., granulocyte macrophage-colonystimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0006] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents. However, considering the lack of currently available treatment options for the majority of the conditions associated with protein kinases, there is

WO 2007/056221

PCT/US2006/043096

2013201630 19 Mar 2013 still a great need tor new therapeutic agents that inhibit these protein targets.

[0007] 'The Aurora proteins are a family of three related serine/threonine kinases (termed Aurora-A, -B and --C) that are essential for progression through the mitotic phase of cell cycle. Specifically Aurora-A plays a crucial role in centrosome maturation and segregation, formation of the mitotic spindle and faithful segregation of chromosomes. Aurora-B is a chromosomal passenger protein that plays a central role in regulating the alignment of chromosomes on the meta-phase plate, the spindle assembly checkpoint and for the correct completion of cytokinesis.

[0008] Overexpression of Aurora-A, -B or -C has been observed in a range of human cancers including colorectal, ovarian, gastric and invasive duct adenocarcinomas.

[0009] A number of studies have now demonstrated that depletion or inhibition of Aurora-A or -B in human cancer cell lines by siRNA, dominant negative antibodies or neutralizing antibodies disrupts progression through mitosis with accumulation of cells with 4N DNA, and in some cases this is followed by endoreduplication and cell death.

[0010] Protein kinases are attractive and proven targets for new therapeutic agents to treat a range of human diseases, with examples of kinase inhibitors including Gleevec® and Tarceva®. The Aurora kinases are especially attractive targets due to their association with numerous human cancers and the roles they play in the proliferation of these cancer cells. Therefore, there is a need for compounds that inhibit protein kinases .

SUMMARY OF THE INVENTION [0011] This invention provides compounds and pharmaceutically acceptable compositions thereof that are useful as inhibitors of protein kinases. These compounds are represented by formula I:

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Σ or a pharmaceutically acceptable salt thereof, wherein R1, Rx, RY, Q, and Ht are as defined herein.

[0012] These compounds and pharmaceutically acceptable compositions thereof are useful for inhibiting kinases' in vitro, in vivo, and ex vivo. Such uses include treating or preventing a variety of diseases, disorders or conditions, including, but not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer’s disease, and hormone-related diseases. Other uses include the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors .

DETAILED DESCRIPTION OF .THE INVENTION [0013] The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ht is thiazole or pyrazole, wherein each Ht is optionally and independently substituted with R2 and R2’ ;

Q is -O-, -NR'-, -S-, or -C(R')2-;

Rx is T1~R3 or Ii-Z-R3;

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Ry is T2-R10 or L-Z-R10;

R1 is T3- (Ring D) ;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring- selected from an aryl or heteroaryl ring, said heteroaryl ring having 1-4 ring heteroatoms selected, from nitrogen, oxygen or sulfur, wherein each substitutable ringcarbon of Ring D is independently substituted by oxo, Τ'3-!!5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by -R4;

each T, T1, T2 , T, and T4 is independently a Ci_4 alkylidene chain or is absent;

Z is a Ci_4 alkylidene chain or is absent;

L· is -O-, -S-, -SO-, -SO2-, -N(R6)SO2-, -SO2N(R6)-,

-N(Re)-, -CO-, -CO2-, -N(RS)CO-, -N (Rs) C (O) O- , -N (Rs) CON (Rs) - ,

-N(R6)SO2N(Re)-, -N(R6}N(Re} -, -C(O)N(Re)~, -OC (Ο) N (Rs) - ,

-C(RG)2O-, -C(Rs)2S-, -C(R6)2SO-, -C(R6) 2SO2~, ~C(Rs)2SO2N(Rs)-,

-C(R6) 2N(R6) - , -C(RS) 2N(RS) C(O)-, -C(R6)2N(R6)C(O)O~,

-C (Rg) =NN (Rs) --, -C(R6)=N-O-f -C (R6) 2N (Rs) N (R6) - ,

-C(Rs)2N(Rs)SO2N(R6)-, or -C(R6) 2N(R6) CON (R6) - ;

R2 and R’’1' are independently -R, -T-W-R6, or R8, or R2 and

R2’ are taken together with their intervening atoms to form a firsed, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2‘ is independently substituted by halo, oxo, -CN, -:NO2f -R'( or -V~RS, and each substitutable ring nitrogen of said ring formed by R2 and R2’ is independently substituted by R4;

each R3 and Rs is independently -R, -halo, -OR, -C(=O)R, -CO2R, -COCOR, COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)s, -SO2N(R7)2, -OC(=O)R, -N(R7)COR, -N(R7) CO2 (C1-6 aliphatic),. -N (R4) N (R4) 2 , -C=NN(R4)2, -*C=N-OR, -N (R7) CON (R7) 2,

-N(R7)SO2N(R7)2, -N(R4)SO2R, or -OC(=O)N(R7) 2;

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2013201630 19 Mar 2013 each R is hydrogen, a Cj_6 aliphatic group, a C6_i0 aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen, or sulfur, the aliphatic group and each R ring being optionally substituted by R9;

each R4 is -R7, -COS', -CO2 (optionally substituted Ci-6 aliphatic), ~CON(R')2, or -SO2R7;

V is -O~, -S-, -SO-, -S02-, -N(Rs)SO2~, -SO2N(R6)-,

-N(R6)-, -CO-, -C02-, -N (R6) CO- , -N (R6) C (O) O-, -N (Rs) CON (Rs) - ,

-N (Re) SO2N(R5) - , -N(R6)N(RS)-, -C(O)N(R6)-, -OC (Ο) N (Rs) - ,

-C(R.S)2O-, -C(R6)2S~, -C(Rs)2SO-, ~C (Re) 2SO2-, -C (Rs) 2SO2N(Rs) ,

C(RS)2N(RS)-, -C (Rs) 2N (Rg) C (O) - , -C (R€) aN (RG) C (O) O-,

C (R6) NN (Rs) - , -C(RS)=N-O~, -C(Rs)2N(Re)N(Rs) -,

-C(Re)2N(Rs)SO2N(Rs) -, or -C(Re) 2N(R6) CON(R6) - ;

W is -C(R6)2O-, -c(r6)2s-, -C(Rs)2SO-, -C(Rs)2SO2-,

-C(Rs)2SO2N(Rs) -, -C(R6)2N(R6) -, -CO-, -CO2-, -C(R6) 2OC(O) -,

-C(Rs)2OC(O)N(R6)-, -C(RS) 2N(RS) CO-, -C (Rs) 2N (R6) C (O) o- , -C(RS) =NN(RS)-, -C(R6)=N-O-, -C(R5)2N(Re)N(R6)-,

-C (R6) 2N (Rs) SO2N(Re)-, -C(Re)2N(Rs)CON(R6)-, or -CON(RS)~;

each R6 is independently hydrogen or an optionally substituted Ci-e aliphatic group, or two Rs groups on the same nitrogen atom are taken together with the nitrogen atom to form an optionally substituted 4-6 membered heterocyclyl or heteroaryl ring; and each R7 is independently hydrogen or an optionally substituted Ci„s aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form an optionally substituted 5-8 membered heterocyclyl or heteroaryl ring;

each R8 is halogen, -CN, or -NO2;

each R9 is —R', -halo, -OR', -C(=O)R', -CO2R', -COCOR' ,

COCH2COR' , ~NO2, -CN, -S(O)R', -S(O)2R', -SR', -N(R')2,

-CON(r')2, -SO2N(r')2, -OC(=O)Rf, -N(R')COR', -N(R') CO2 (Ci-6

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2013201630 19 Mar 2013 aliphatic), -N(R')N(R')2, -C=NN (Rf) 2, . -C=N-OR' , -N (R' ) CON (R') 2, -N(R' )SO2N(R')3< -N(R')SO2R', or -OC (=O) N (R') 2;

each R10 is a 4-membered heterocyclic ring containing 1-2 heteroatoms selected from O, NR11, and S; each R10 is optionally substituted with 0-3 occurrences of J;

each J is independently -halo, -OR, oxo, Ci_s aliphatic, -C(=O)R, -CO2R, -COCOR, COCHsCOR, -no2, -CN, -S(O)R, -S(O)2R, -SR, -N(R4)2, -CON(R7)2f -SO2N(R7)2, -OC(=O)R, -n(r7)cor, -N(R7) CO2 (Ci_e aliphatic), -N (R4) N (R4) 2, == NN (R4 ) 2, =N-OR,

-N(R7) CON(R7)2, -N(R7) SO2N(R7) 2, -N(R4)SO2R, or -OC ( =O) N (R7) 2 ; or

J groups, on the same atom or on different atoms, together with the atom(s) to which they are bound, form a 3-8 membered saturated, partially saturated, or unsaturated ring having 0-2 heteroatoms selected from.O, N, or S;

each Rlj· is ~R', -COR7, -CO2 (optionally substituted Ci_e aliphatic), ~CON(R7)2, or -SO2R?;

each R is independently hydrogen or a Ci_6 aliphatic group optionally substituted with 0~4 occurrences of NH2,

NH (Ci_4aliphatic) , N (Ci_4aliphatic) 2, halogen, Ci_4aliphatic, OH, O(Ci-4aliphatic) , KTO2, CN, CO2H, CO2 (Ci-4aliphatic) , 0(haloCj-4 aliphatic) , or haloCi_4aliphatic; or, two R' , together with the atom(s) to which they are attached, form an optionally substituted 3-6 membered carbocyclyl or heterocyclyl.

[0014] In some embodiments, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

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Ht is thiazole or pyrazole, wherein each ring is optionally and independently substituted with R2 and R2';

Q is -O-, -NR'-, -S-, or -C(R') 2-;

Rx is H, Ci_6aliphatic, NO2, CN, halo, NH2,

N (Ci_4aliphatic) , N (Ci_4aliphatic) 2, O (C1_4aliphatic) , OH, or ~N(C=O)( C^aliphatic) ; wherein said aliphatic is optionally substituted with 1-3 fluoro;

RY is T2-R10 or L-Z-R10;

R“ is T3- (Ring D) ;

Ring D is a 5-7 membered monocyclic aryl or heteroaryl ring, wherein said heteroaryl has 1-4 ring heteroatoms selected from Ο, N, or S; Ring D can optionally be fused with Ring D';

Ring D' is a 5-8 aromatic, partially saturated, or fully unsaturated ring containing 0-4 ring heteroatoms selected front nitrogen, oxygen or sulfur;

each substitutable ring carbon of Ring D and Ring Df is independently substituted by oxo, T4-R5, or V-Z-R5;

each substitutable ring nitrogen of Ring D and Ring Df is independently substituted by ~R4;

each T, T3, and T4 is independently a Ci_4 alkylidene chain or is absent;

Z is a C;L_4 alkylidene chain or is absent;

L is —O-, -S-, -SO-, -SO2-, -N(RG)SO2-f -SO2N (Rs) -,

-N(R6)-, -CO-, -CO2-, -N(RS)CO-, -N (R6) C (O) O- , -N (Rs) CON (Re) - , ~N(R6)SO2N(Rs) -, -N(Re)N(R6) -, -C(O)N(RS)~, -OC (Ο) N (Rs) - ,

-C(R6)2O~, -α(Ηδ)23-, -C(Re)2SO~, -C (Rs) 2so2~, -C(Rs)2SO2N(Re)-, -C(R6)2N(RS) -, -C(Re)2N(R6)C(O)-, -C(Re)2N(Rs)C(O)O-,

-C (Rs) =NN (R6) - , -C (R6) =N-O-, -C (RC) 2N (RS) N (Rs) - , -C(R6)2N(Rs)SO2N(Rs) ·, or -C(RS)2N(RG) CON (Rs) - ;

T2 is independently absent or a Ci-i0 alkylidene chain wherein up to six C units of the alkylidene chain are optionally replaced by -O-, -C(=O)-, -S (O) -, -S(O)2-, -S-, or -N(R4)-; T2 is optionally substituted with O-δ JT groups;

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R2 and R2' are independently -R, -T-W-Rb, or Rs. or R2 and R2' are taken together with their intervening atoms to form a fused, 5--8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R“ and R2' is independently substituted by halo, oxo, -CN, -NO2, -R?, or -V-R6, and each substitutable ring nitrogen of said, ring formed by R2 and R2’ is independently substituted by R4 ;

R5 is -R, -halo, -OR, -C(=O)R, -CO2R, -COCOR, COCH2COR, -NO2, -CN, -S(O)R, -S(O)2R, SR, -N(R4)2, -CON(R7)2, -SO2N(R7)2,

-OC(=O)R, -N(R7)COR, -N(R7) CO2 (Ci-6 aliphatic) , -N (R4) N (R4) 2, -C=NN(R4)2, -C=N-ORf -N (1¾7) CON (R7) 2, -N (R7) SO2N (R7) 2f -N(R4)SO2R, or -OC(=O)N(R7) 2 ;

each R is hydrogen, a Ci_io aliphatic group, a Cs_10 aryl, ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms, the heteroaryl or heterccyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen, or sulfur, the aliphatic group and each R being optionally substituted by 0-6 R9;

each R4 is -R7, -COR7, -CO2 (optionally substituted Cx_s aliphatic), -CON(R7)2, or ~SO2R7;

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2013201630 19 Mar 2013 optionally substituted 5-10 membered aryl ring. In other embodiments, Ring D is an optionally substituted 5-10 membered heteroaryl ring. In some embodiments, Ring D is a 5-6 membered monocyclic aryl or heteroaryl ring. In some embodiments, Ring D' is fused with ring D.

In some embodiments, Ring D is phenyl. In some embodiments, Ring D' is phenyl or imidazole. In some embodiments, the bicyclic ring formed by the fusion of Ring D' and Ring D (Ring D-D? ) is naphthyl, benzimidazole, quinoline, or isoquinoline. In other embodiments, Ring D-D' is benzimidazole, isoquinoline, quinoline, or isoindolinone.

[0019] As would be understood by a skilled practitioner, when two rings are fused, the two rings share two adjacent atoms and. also the bond or bonds between the adjacent atoms. For example, phenyl fused with pyrimidine could form quinazoline.

fused with

[0020] Phenyl fused with pyrrolidine could, form indoline.

fused with-

form

be rotated in any chemically stable orientation. For example, a phenyl fused with an imidazole could form one of

[0022]

4-position some embodiments, Ring with T’5-R5 or V-Z-R5,

D is mono-substituted in the is optionally substituted in the [0023] In some embodiments, V is

In some embodiments, Ring D

4-position with V-Z~RS.

-N (R6) CO-, -C(O)N(RS)-, -O-, embodiments, V is -N(R6jco- or [0024] In some embodiments, T3 is absent.

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2013201630 19 Mar 2013 [0025] In other embodiments, T3 is a Ci_4 alkylidene chain. [0026] In other embodiments, T2 is a Ci_10 alkylidene chain wherein up to six C units of the alkylidene chain are optionally replaced by -O-, -C (=0)-, -S(O)-, --8(0)2-, ~S~, or

-N (R4) - .

[0 027] In some embodiments, Z is a C1-4 alkylidene chain. In other embodiments, Z is absent.

[0028] In certain embodiments, the substituents in Rs and R.7 are independently selected from R9 .

[0029] In another embodiment, the optionally substituted aliphatic group of Re is a C3-4 aliphatic group.

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2013201630 19 Mar 2013 wherein

R2

II~b;

R2, R2' , Rx, Q, and J are as defined, herein;

Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from Of N, or S; and

R!: is a C6-io aryl optionally substituted with R9.

[0048] In some embodiments, Ring D is phenyl.

[0049] In other embodiments, Rb is phenyl optionally substituted with R9. In some embodiments, said phenyl is substituted in the ortho position with R9. In some embodiments, R3 is halogen, CF3, C3_3 alkyl. -S- (Cd^alkyl) , or OCF3 . In other embodiments, J is CI_4alkyl, C3_ealkyl

O (C-3..34alkyl) , OH, CN, or F. In yet other embodiments, J is CH3, OCH3, O(CH2CH3), OCH(CH3) 2,- OC(CH3)3, OH, CN, or F.

[0050] Tn yet another embodiment, a compound of this invention is represented by formula II-C:

II-c;

wherein

R2, R2’ , Rx, and Q, are as defined herein;

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Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from Ο, N, or S; and

R5 is a Cj_6 alkyl optionally substituted with R9 .

[0051] In some embodiments, Rs is optionally substituted with

1-6 halogen groups. In some embodiments, 1-3 halogen groups. In some embodiments, said halogen is fluoro.

[0052] In another embodiment, a compound of this invention is represented by formula II-d:

R2

II-d;

wherein

R7’, R2 , Rx, Q, and J are as defined herein;

Ring D is phenyl or a 6-membered heteroaryl containing 1-2 heteroatoms selected from Ο, N, or S; and

R is Ci-galkyl or C3_6cycloaliphatic, 'wherein said Ci-galkyl or C3_scycloaliphatic is optionally substituted with 0-6 R9.

In some embodiments, Ring D is phenyl.

[0053] In some embodiments, Rs is substituted with 1-6 R9 . In some embodiments, R3 is halogen. In other embodiments, R9 is CF3. In some embodiments, R5 is substituted with a CF3 group.

[0054] In some embodiments, the azetidine of formula II-d is substituted with 1-2 J groups wherein J is selected from Ci_s aliphatic, C3_6cycloaliphatic, halogen, OH, OR, NH2, NH(Ci_s), N(Ci_6)2, CN, or a 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from Ο, N, and S.

[0055] In some embodiments, said heterocyclyl group is a 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from

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Ο, N, or S. In some embodiments, said heterocyclyl is azetidine, morpholine, piperidine, piperazine, or pyrrolidine. [0056] In some embodiments, the azetidine of formula ΙΙ-d is mono-substituted with a 4-7 membered heterocyclyl containing

1-2 heteroatoms selected from Ο, N, and S.

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Table 1

1-2

Ϊ-3

hj-NH m-NH

1-7

O F

1-8

n-nh

1-10

1-11

1-12

1-13

1-14

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N-NH

1-19

1-22 n-NH

n-nh

1-20

1-23

1-26 ki-NH

1-24

N-NH

O

1-27

1-30

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M’NH

O <X

1-32 n-nh

NH'4'/ H I| N f^YNirV'F ° F

1-33

NH N-NH dt/—

N

1-35 fq-NH

/'Ο

NI-NH

O Ci

1-38

1-37

1-41

N-NH

F

1-89 1-90 1-91

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1-101 1-102 1-103

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2013201630 19 Mar 2013

1-161

1-162

1-163

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2013201630 19 Mar 2013 [0075] The term cycloaliphatic (or carbocycle or carbocyclyl or cycloalkyl and the .like) refers to a monocyclic C3-C8 hydrocarbon or bicyclic Cg-Ci2 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

[0076] In the compounds of this invention, rings include linearly-fused, bridged, or spirocyclic rings. Examples of bridged cycloaliphatic groups include, but are not limited to, bicyclo[3.3.2]decane, bicyclo[3.1.1]heptane, and bicyclo[3.2.2]nonane .

[0078] The term heterocycle, heterocyclyl, heterocycloaliphatic, or heterocyclic, and the like, as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the heterocycle, heterocyclyl, heterocycloaliphatic, or heterocyclic group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

Examples of bridged heterocycles include, but are not limited to, 7-aza-bicyclo[2.2.1]heptane and 3-azabicyclo [3.2.2]nonane .

[0079] Suitable heterocycles include, but are not limited to, 3lH-benzimidazol-2One, 3-(1-alkyl)-benzimidazol-2-on.e , 2tetrahydrofuranyl, 3-tetrahydrofuranyl, 2tetrahydrothiophenyl, 3 -tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,

- 4 0

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4- thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, l~tetra.hydropiperazin.yl, 2tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl,.

2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl. 4pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl,

4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro~imidazol-2-one.

[0080] As used herein, the term Ht is interchangeable with

Het and [0081] The term heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon,· the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR+ (as in Nsubstituted pyrrolidinyl)).

[0082] The term unsaturated, as used herein, means that a moiety has one or more units of unsaturation.

[0083] The term alkoxy, or thioalkyl, as used herein, refers to an alkyl group, as previously defined, attached, to the principal carbon chain through an oxygen (alkoxy) or sulfur (thioalkyl) atom.

[0084] The terms haloalkyl, haloalkenyl and haloalkoxy means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term halogen means F, Cl, Br, or 1.

[0085] The term aryl used alone or as part of a larger moiety as in aralkyl, aralkoxy, or aryloxyalkyl, refers to monocyclic, bicyclic, and tricyclic ring systems having a

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2013201630 19 Mar 2013 total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members, · The term aryl. may be used interchangeably with the term aryl ring. The term aryl” also refers to heteroaryl ring systems as defined hereinbelow.

[0086] The term heteroaryl, used alone or as part of a larger moiety as in heteroaralkyl or heteroarylalkoxy, 'refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term heteroaryl may be used interchangeably with the term heteroaryl ring or the term heteroaromatic. Suitable heteroaryl rings include, but are not limited to, 2-furanyl,

3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2pyrimidinyl, 4-pyrimidinyl, 5--pyrimidinyl, pyridazinyl (e.g.,

3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2~triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,

2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3thiadiazolyl, 1, 3,4-thiadiazolyl, 1, 2,5-th.iadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

[0087] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and. the like) group may contain one or more

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2013201630 19 Mar 2013 substituents and thus may be optionally substituted. Unless otherwise defined above and herein, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are generally selected from halogen; -R°; ~OR°; -SR0; phenyl (Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°; - (CH2) i-2 (Ph) , optionally substituted with R°;

-CH=CH(Ph), optionally substituted with R°; a 4-6 membered heteroaryl or heterocyclic ring optionally substituted with R°; -NO2; -CN; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2;

-NR°C(S)N(R°)2; -NR°CO2Ra; -NR°NR°-, -NR°NR°C(O)Rq;

2013201630 19 Mar 2013

312 membered saturated, partially unsaturated,' or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0095] Examples of such rings include, but are not limited to the following: piperidin-l~yl, piperazin-1-yl, or morpholin-

4-yl group.

[0096] Tn some embodiments, a carbon unit (or C unit) of an alkyl, alkylidene, or aliphatic chain is optionally replaced with another atom or group. Examples of such atoms or groups include, but are not limited to, -NR-, -O~s -S~, -CO2-, -OC(O), -C(O)CO~, -C(O)-, -C(O)NR~, -C(=N-CN), -NRCO-, -NRC(O)O-,

-SO2NR-, -NRSOa-, NRC(O)NR, -OC(O)NR~, -NRSO2NR-, -SO-, or SO2-f wherein R is defined herein. Examples of C units include -CH2- and =CH-. Unless otherwise specified, the optional replacements form a chemically stable compound. Optional replacements can occur both within the chain and at either end of the chain; i.e., both at the point of attachment and/or also at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound. Unless otherwise specified, if the replacement occurs at the terminal end, the replacement atom is bound to an H on the terminal end. For example, if a C unit of -CH2CH2CH3 were optionally replaced with -O-, the resulting compound could be -OCH2CH3, -CH2OCH3, or - ch2ch2oh .

[0097] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

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2013201630 19 Mar 2013 [0098] Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

a pyrazole example, possible rotate

As would group can structure

Unless around drawn as substituent be represented in a variety of ways. For drawn as

NH also represents other also represents other possible tautomers, such otherwise indicated, a substituent can freely any rotatable bonds .

drawn as

ents

Likewise, a also represents

-N

are also meant to include compounds enriched atoms. For example, compounds having the present enriched carbon, are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, [00101] The compounds of this invention may be prepared in light of the specification using steps generally known to those of ordinary skill in the art. Those compounds may be

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2013201630 19 Mar 2013 analyzed by known methods, including but not limited to LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance). It should be understood that the specific conditions shown below are only examples, and are not meant to limit the scope of the conditions that can be used for making compounds of this invention. Instead, this . invention also includes conditions that would be apparent to those skilled in that art in light of this specification formaking the compounds of this invention. Unless otherwise indicated, all variables in the following schemes are as defined herein, [00102] The following abbreviations are used:

BOC is t-butyloxycarbonyl

DIPEA is diisopropylethylamine

DMF is dimethylformamide i-PrOH is isopropyl alcohol n-BuOH is n-butano1 t-BuOH is tert-butanol

EtOH is ethanol

MeOH is methanol

EtOAc is ethyl acetate

TFA is trifluoroacetic acid

DMSO is dimethyl sulfoxide

Rt is retention time

Ph is phenyl

DCM is dichloromethane

MeCN is acetonitrile

THF is tetrahydrofuran.

TBTU is 2-(1H-Benzotriazole-1-yl)~1,1,3,3-tetramethyluronium tetrafluoroborate

HPLC is high performance liquid chromatography

LCMS liquid chromatography mass spectrometry

NMR is nuclear magnetic resonance

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General Scheme

Method A [00103] oxidation

r~NH

L|J

Jq-6

HQR‘

..............--.--base, solvent

The general scheme above shows

HQR' base, solvent

HbT

Het

Method B r*NH

Ljj do-6 V

some methods of making compounds of this invention wherein the azetidine is directly attached via a nitrogen atom.

Scheme I

tris(dibenzyiidene acetone)dipailadium, bis(dipher>ylphosphino)9,S-ds'methy!xanthene dioxane, 100 °C, 2H

azetidine derivative base, solvent heat

R2

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2013201630 19 Mar 2013 [00104] Scheme .1 above shows a general route for the preparation of compounds of formula 3 (of Scheme I), wherein Rx, Rx, R2, and J are as defined herein and Q is -O-, -NR'-, or — S—. In some embodiments the dichlorinated'pyrimidine of formula 1 is heated in the presence of a suitable base (e.g. Nal/DIPEA) and a suitable solvent (e.g. DMF) with an optionally substituted aminothiazole to form a compound of formula 2. In other embodiments, the dichlorinated pyrimidine of formula 1 is heated in the presence of a suitable catalyst (see scheme. I) , a suitable solvent (e.g. dioxane) , and an optionally substituted aminothiazole under coupling conditions known to one skilled in the art to form a compound of formula

2. The compound of formula 2 is then heated in the presence of a suitable base (e.g. DIPEA/Nal) and a suitable solvent, (e.g. n-BuOH) of formula 3.

Scheme II ve t.o form a compound

I

axetidine derivative base, soivent heat

base, solvent heat

[00105] Scheme II above shows a general route for the preparation of compounds of formula 7 (of Scheme II), wherein Rx, R,!,f R2, R2< , and J are as defined herein and Q is -O-, -NR'-, or -S-. The dichlorinated pyrimidine of formula 4 is

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2013201630 19 Mar 2013 combined with HQ-R1 to form a compound of formula 5. In some embodiments, the two compounds are heated in the presence of a suitable solvent (e.g. t-BuOH) for 16 hours. In other embodiments, the two compounds are mixed at 0 °C in the presence of acetonitrile and triethylamine for 1 hour. The compound of formula 5 is then heated in the presence of a suitable solvent (e.g. DMF) and a suitable base (e.g. DIPEA/Nal) with an optionally substituted aminopyrazole to form a compound of formula 6, which is heated in the presence of an azetidine derivative in the presence of a suitable solvent (e.g. n-BuOH) to form a compound of formula 7.

Scheme III

urea

NaOMe, MeOH reflux ! 16h

OH

POC!3

DIPEA (1 eq.)

90°C/16H

het - pyrazole:

Nal, DiPEA, DMF, SO’C, 16H het = thiazole:

tris(dibenzylidene acetone)dipaliadium.

HQ—R1 t-BuOH

90°C / 16H

bis{dipheoylphosphirso)-9,S-dimethyl xanthene, dioxans, 100=0, 2H [00106] Scheme III above shows a general route for the preparation of compounds of formula 12 (of Scheme III), wherein Rx, R1, R10f and Ht are as defined herein and Q is -O-, -NR'-, or — S—. The ketoester of formula 8 is cyclized in the presence of urea, a suitable solvent (e.g. MeOH, EtOH), and a suitable base (e.g. NaOMe) to form the dihydroxy pyrimidine of formula 9. The compound of formula 9 is then chlorinated under suitable chlorination conditions, such as heating in the presence of POC13 and DIPEA, to form a dichloropyrimidine of formula 10. The dichloropyrimidine is then heated in the

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2013201630 19 Mar 2013 presence of an appropriate amino-heteroaryl under suitable conditions known to those skilled in the art (see Scheme III for examples) to form a compound of formula 11, which is subsequently heated with HQ-R* in the presence of a suitable solvent (e.g. t-BuOH) to form a compound of formula 12.

Scheme IV

HQ—Ri

t-BuOH reflux 118h

het ~ pyrazole:

Mai. DIPEA, DMF, 90°C, 16H het = thiazols:

irisjdibenzylidene acetonsjdipalladium, ijis(diphenylphosphino).9,9dlmeihyi xanihsne, dioxane, W0°C, 2H

when L is -ONa: MeQH; reflux/16h when L is -ΝΗ2: n-BuOH 30¾ 116H

[00107] Scheme IV above shows a general route for the preparation of compounds of formula 16 (of Scheme IV) , wherein L is an appropriate nucleophile (such as N, O, or S), Q is -O-, -NR'-, or ~S~, and Z, R1, R10, Rx, and. Ht are as defined herein. The dichloropyrimidine of formula 4 is heated in the presence of HQ-R1 to form the substituted dichloropyrimidine of formula 5. The compound of formula 5 is then heated in the presence of an appropriate amino-heteroaryl under suitable conditions known to those skilled in the art (see Scheme IV above for examples) to form a compound of formula 15, which is heated with R10-Z“L, wherein L· is an appropriate nucleophile (such as N, O, or S) , and Z and R10 are as defined herein, to form a compound of formula 16.

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Scheme V

Naoet, etOH

NH.HCI

NH2'^'C(R,)2-R1

C(R')Z-R1 pocs3

DIPEA (1 eq.}

90°C/16H

NH2 het ~ pyrazole:

Nal. DiPEA, DMF. 90°C, 16H het ~ thiazole:

iris(dibenzylidens acetonBjdipaliadium. bis(diphenylphosphlno)-9,9-dimethyi xanthene, dioxane, liiCrC. 2H

[00108] Scheme V above shows a general route for the preparation of compounds of formula 20 (of Scheme V), wherein R1, Rx, RY, R' and Ht are as defined herein. The ketoester of formula 17, together with a substituted amidine, cyclizes to form the hydroxypyrimidine of formula IS . The compound of formula 18 is then chlorinated under suitable chlorination conditions known to those skilled in the art (e. g. POC13/DZPEA), to form the chloropyrimidine of formula 19. The chloropyrimidine is then heated in the presence of an appropriate amino-heteroaryl under suitable conditions known for examples) to form a compound of formula 20.

HN“W

HN \ base, soivem I As·

-----------’

M

Choa

p <

OH

HN-R8

TBTU, DIPEA

DMF

RT 18 h

[00109] Scheme VI above shows a general route for the preparation of compounds of formula 23 (of Scheme VI), wherein Rx, R2, R2', Rb, Rs, Z, J, and Ht are as defined herein. The protected acid of formula 21 is deprotected with a suitable base (e.g. NaOH) in the presence of a suitable solvent or

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2013201630 19 Mar 2013 solvents (e-3· THF/MeOH) to form the acid of formula 22. The acid of formula 22 is then combined, with a suitable amine in the presence of coupling reagents known to one skilled in the art (e.g. TBTU), a suitable base (e.g. DIPEA), and a suitable solvent (e.g. DMF) to form the compound of formula 23.

2) NaOMe

MeOH

1) pyridine

O

A X

general route for the

preparation wherein Rx, -N (Rs) -ZR5, of compounds of formula 25 (of Scheme VII),

R2, R2', Rs, and J are as defined herein and ZZ is -O--ZR5, or ~ZR:> wherein R5, Rs, and Z are as defined herein. The compound of 24 is combined with a suitable acid form an intermediate compound that, upon mixing in the presence of sodium methoxide and methanol, forms the compound of formula 25. In some embodiments, X can be OH, in which the

HOST.

Suitable solvents for these coupling reactions include.

but are .not limited to, THF, CH2C12, and dioxane.

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Scheme VIII

Na! (6 eq.), 60%H!

2Θ

H2N-Ht

1) azetidine (1 eq.),

EigN (2eq.), CuCI,

PdCi2(PPh3)2

eq)

[00111]

Scheme VIII above shows a general route for the preparation of compounds of formula 30 (of Scheme VIII) wherein Z is -C ==^C·CH2- . Dichloropyrimidine 2 6 is converted to di-iodinated, pyrimidine 27 in the presence of Nal and HI. Compound 27 is combined with an aminoheteroaryl to form the compound 28. Compound 29 is then combined, with azetidine under basic displacement conditions to form an optionally substituted propynyl-azetidine, which is combined with compound 28 under palladium coupling conditions to form a compound of formula 30.

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Scheme IX

wheeler, H. L, Liddle,

L. M„ JAC. 1908. 30, 1156-1180.

HQR,

POCI3, Toluene, tiipropylamine, reflux

amino pyrazole

Nal, DIPEA

DMF, 6Q°C

chloropyrimidine, t-BuOH, reflux

----------—.»»

1) LIBH4. THF. 70°C

2) P0r3, MeCN, 70“C

[00112] Scheme IX above shows a general route for the preparation of compounds of formula 36 (in Scheme IX) wherein R2., Rx' , r\ and J are as defined herein and Q is -O-, -NR'-, or

-S-. Compound 31 is converted to diohloro pyrimidine 32 by treating 31 with POCI3 in the presence of a suitable solvent (e.g. toluene) and in the presence of suitable base (e.g. tripropylamine). Compound 32 is then heated in the presence of a suitable solvent (e.g. DMF) and a suitable base (e.g. DIPEA/Nal) with, an optionally substituted aminopyrazole to form a compound of formula 33. The chlorinated pyrimidine of formula 33 is combined with HQ-R1 to form a compound of formula 34 and the two compounds are heated in the presence of a suitable solvent (e.g. t-BuOH). Reduction of the ester and treatment of the corresponding alcohol with. PBr3 leads to the formation of bromoderivative 35. Bromoderivative 35 can be then treated with a variety of azetidines at room temperature in the presence of a suitable solvent (e.g. DMF) to yield the final compound 36.

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2013201630 19 Mar 2013 [□0113] The following schemes depict methods for synthesizing various types of azetidiries. Theses azetidines can be used to form compounds of this invention according to the methods described herein.

Scheme A

PG activation

PG base

Ra

PG /

LG [00114]

Rb deprotection

Scheme A above shows a general route for the preparation of N-substituted azetidines wherein at least one J group is bonded to the azetidine via a nitrogen atom. Protected azetidine 31 is activated with a suitable leaving group under suitable conditions upon treatment with NHRARB under amine-substituted azetidine 34.

to form azetidine 32, which,

Azetidine 34 is then nitrogen deprotection conditions to form compound .

i-PrOH, KOH °C

A-ph Pd(OH)2, EtOH, H2 roJJ --------RO-P

J J

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2013201630 19 Mar 2013 [00115] Scheme B above shows a general route for the

<td> preparation</td><td> of</td><td colspan="2"> O-substituted azetidines wherein</td><td> at least one J</td>

<td> group is OR</td><td colspan="2"> wherein. R is· I</td><td> I or Ci_6alkyl.</td><td></td>

<td> Scheme C</td><td></td><td></td><td></td><td></td>

<td colspan="2"> r-NBOC</td><td> LHMDS, THF, -78°C</td><td rowspan="2"> TFA, DCM. rt pNBoc Me</td><td rowspan="2">rNH.TFA nc-H Me</td>

[00116]

Scheme C above shows a general route for the preparation of substituted azetidines wherein J is CN and

Ci-galky! .

Scheme D

[>—-MgBr

THF

-78 0 C

HC!/ether

deoxofluor

DCM, -78 °C

H,, Pd;C

EtOH, rt psi

[00117] Scheme D depicts a general route for the preparation of cyclopropyl-fluoro-substituted azetidines. Compound 42 is oxidized under suitable conditions to form compound 43, which, under suitable Grignard conditions, is combined with cyclopropyl-MgBr to form the cyclopropyl-substituted azetidine 44. Compound 44 is then fluorinated under suitable fluorination conditions to form 45, which is hydrogenated under Pd/C conditions to form the deprotected free azetidine

46.

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Scheme E

ethyl-2-bromoisobutyrate,

In, DMF, 60°C - rt

DiBAL-H, DCM

-78°C - rt

EtOOC48

<td> TsCi, KOlBu, THF. rt</td><td> | pHjlBoc 0) TFA. DCM, rt</td>

! r-^H L-O

2013201630 19 Mar 2013 [00134] In some embodiments, the compounds of this invention are useful for treating cancer, such as colorectal, thyroid, breast, and non-small cell lung cancer; and myeloproliferative disorders, such as polycythemia verst, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile ntv el ©monocytic leukemia, and systemic mast cell disease.

[00135] In some embodiments, the compounds of this invention are useful, for treating hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), acute-promyelocytic leukemia (APL), and acute lymphocytic leukemia (ALL).

[00136] In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the ’ compounds of this invention may also be employed in compositions to treat or prevent the above-identified disorders .

[00137] A pharmaceutically acceptable derivative or prodrug means any pharmaceutically acceptable salt, ester, salt of an ester or other' derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Such derivatives or prodrugs include those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

[00138] Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation,

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2013201630 19 Mar 2013 esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.

[00139] The compounds of this invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt.

[00140] As used herein, the term ’’pharmaceutically acceptable salt” refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.

[00141] Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds. Acid addition salts can be prepared by 1) reacting the purified compound in its free-based form with a suitable organic or inorganic acid, and 2) isolating the salt thus formed.

[00142] Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate,' tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the

[00151] Topical application for the lower intestinal tract can .be effected in a rectal suppository formulation (see

PCT/US2006/043096

2013201630 19 Mar 2013 mitoxantrone; treatments for asthma such as albuterol and Singulair35; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TITF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and antiParkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents,- agents for treating blood disorders such as corticosteroids, antileukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin. Another embodiment provides a simultaneous, separate or sequential use of a combined preparation.

[00171] Those additional agents may be administered separately, as part of a multiple dosage regimen, from the kinase inhibitor-containing compound or composition. Alternatively, those agents may be part of a single, dosage form, mixed together with the kinase inhibitor in a single composition.

[00172] Methods for evaluating the activity of the compounds of this invention (e.g., kinase assays) are known in the art and are also described in the example set forth.

[00173] In order that this invention be more fully understood, the following preparative and testing examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the

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2013201630 19 Mar 2013 invention in any way. All documents cited herein are hereby incorporated by reference.

EXAMPLES [00174] As used herein, the term i!Rt (min) refers to the HPLC retention time, in minutes, associated with the compound. Unless otherwise indicated, the HPLC method utilized to obtain the reported retention time is as follows:

Column: ACE C8 column, 4.6 x 150 mm

Gradient: 0-100% acetonitrile+methanol 60:40 (20mM Tris phosphate)

Flow rate: 1.5 mL/minute

Detection: 225 nm.

[00175] Mass spec, samples were analyzed on a MicroMass Quattro Micro mass spectrometer operated in single MS mode with electrospray ionization. Samples were introduced into the mass spectrometer using chromatography. Mobile phase for all mass spec, analyses consisted of lOmM pH 7 ammonium acetate and a 1:1 acetonitrile-methanol mixture, column gradient conditions were 5%-100% acetonitrile-methanol over

3.5 mins gradient time and 5 mins run time on an ACE C8 3.0 x 75mm column. Flow rate was 1.2 ml/min.

[00176] 1H-NMR spectra were recorded at 400 MHz using a Bruker DPX 400 instrument. The following compounds of formula I were prepared and analyzed as follows.

Example 1

N- (4- (4- (5“Xaethylthiazol-2-ylamino) ~6~chloropyrimidin-2ylthio)phenyl)cyclopropanecarboxamide:

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2013201630 19 Mar 2013 [00177] A suspension of N- (4-(4,6-dichloropyrimidin-2ylthio)phenyl)cyclopropane-carboxamide (5.0g, 14.7 mmol), amino-5-methylthiazole (1.85g, 16.2 mmol), tris(dibenzylideneacetone) dipalladium (0.673g, 0.74mmol), 4,5-bis (diphenylphosphino) --9, .9-dimethyl-xanthene (0.636g, l.lOmmol) and sodium carbonate (2.18g, 20.58mmol) in dioxane (12 0ml) was heated at 100°C for 2h. The reaction mixture was then allowed to cool to room temperature before the tan precipitate was collected by filtration, washed with ethyl acetate (50ml) water (3 x 30 ml) and then diethyl ether (50 ml) and dried to give title compound as a tan solid (4.32g, 70%). 1H NMR (DMSO) 0.81 (4 H, d), 1.83 (1 H, m) , 2.09 (3 H,

s) , 6.35 (1 H, br s) , 6.88 (1 H, s) , 7.53 (2 H, d) , 7.74 (2 H,

d) , 10.48 (1 H, S) . MS(ES+): 418.

Example 2

i (4-(4-(B-methylthiazol-S-ylamino)-6-(3-(dimethylamino) azetidin-l-yl)pyrimidin-2 ylthio)phenyl) cyclopropane carboxamide :

[00178] A suspension of N-(4-(4-(5-methylthiazol-2-ylamino)-

6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (138mg, 0.33mmol), 3~dimethylaminoazetidine dihydrochloride (178mg, l.Ommol), N, JV-diisopropylethylamine CO.34ml, 1.98mmol) in n-butanol (10ml) was heated at 90°C for 17 h. Reaction mixture was then allowed to cool to room temperature, concentrated, in vacuo. The crude product was purified on HPLC to give the title compound as an off-white solid (106mg, 58%).

1H NMR (DMSO) 0.82-0.81 (4 H, m) , 1.87-1.81 (1 H, m) , 2.07 (3 H, s) , 2.78-2.77 (6 H, m) , 4.20 (5 H, s) , 5.56 (1 H, s) , 6.94

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2013201630 19 Mar 2013 (1 H, S) , 7.52 (2 H, d) , 7.76 (2 H, d) , 10.55 (1 H, s) .

MS(ES+): 482.

[00179] Table 3 below depicts data for certain exemplary compounds made according to the method described in Scheme I and in Examples 1--2. Compound numbers correspond to those compounds depicted in Table 1.

Table 3

<td> Compound No</td><td> M+l (obs)</td><td> 1HNMR</td><td> Rt (mins)</td>

2S 6~Difluoro -IV- [4- (4,6-dichloro~pyrimidin~2~ylsulfanyl) phenyl]-benzamide:

[00180] A 250ml round bottom flask equipped with a condenser was charged with 4,6-dichloro-2~methanesulfonyl pyrimidine (4.2g, 18.8mmol), 2 , 6-di fluoro-Ν'- (4-mercapto-phenyl) -benzamide

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2013201630 19 Mar 2013 (4.98g, IS.Sramol) and tert-butanol (75ml) under nitrogen. The reaction mixture was degassed thoroughly and then heated at 90°C for 2h. The reaction mixture was. allowed to cool to room temperature and concentrated in vacuo. The solid residue was taken up in ethyl acetate (50ml) and washed with saturated sodium bicarbonate solution and brine. The organic was dried over magnesium sulfate, filtered and concentrated until the product began to precipitate. The mixture was then cooled and aged for 12 hrs. The product was collected by filtration, washed with cold ethyl acetate and dried. This gave the title compound as an off-white solid (2.7g, 35%). 1H NMR (DMSO) 7.32 (2H, m) , 7.61 (3H, tn), 7.79 (1H, s) , 7.82 (2H, d) , 10.9 (1H, S). MS (ES+): 412.19

Example 4

> 6-Dif luoro-JV-{4 - [4-chloro-6- (5-methyl-SH-pyrazol-3-ylamino) pyrimidin-2-ylsulfanyl]-phenyl}-benzamide s [00181] A 50ml round bottom flask was charged with 2,6difluoro-N- [4-(4,6-dichloro-pyrimidin^2~ylsulfanyl)-phenyl]benzamide (3.. Og, 2.3mmol), 5-methyl~2H-pyrazol-3-ylamine (250mg, 2.58mmol), sodium iodide (351mg, 2.34mmol), diisopropylethyl amine (333mg, 2.58mmol) and dimethylformamide (5ml) under nitrogen. The reaction mixture was stirred at 90°C for 18h, then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (25ml), washed with saturated, sodium bicarbonate solution and brine. The organic was dried over magnesium sulfate, filtered and concentrated in vacuo. The compound was purified by flash chromatography (75 to 80% ethyl acetate/petrol) to give the title compound (l.OSg, 98%). 1H NMR (DMSO) 2.00 (3H, s), 5.25

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2013201630 19 Mar 2013 (1H, brs), 6.48 (1H, brs) , 7.30-7.97 (7H, m) , 10.28 (1H, s) ,

10.89 (1H, S), 11.90 (1H, s); MS(ES+): 473.4.

29-{4- [4-Azetidin-l-yl-6- (5-mefchyl -2H~pyrazol--3-ylamino) pyrimidin-2-ylsulfanyl]-phenyl}-2,6-Difluoro -benzamide;

[00182] A 10ml round bottom flask was charged with 2,6dif luoro-iV-{4- [4-chloro-6- (5-niethyl-2i:f-pyrazol-3-ylamino) pyrimidin-2-ylsulfanyl]-phenyl}-benzamide (150mg, 0.31mmol), azetidine (35mg, 0.62mmol), diisopropyl ethylamine (80mg,

0.62mmol) and n-butanol (1.5ml). The reaction mixture was stirred at 8 0°C for 4h, then cooled and concentrated in vacuo.

The compound was purified by preparative HPLC (MeCN/water +

0.05¾ TEA 10/90 to 100/0 over 10 min) to give the title compound as the trifluoroacetic acid salt (54mg, 29%). 1H NMR (DMSO) 2.05 (3H, s), 2.25-2.36 (2H, m), 3.70-3.98 (4H, m, masked), 5.31 (1H, s), 5.52 (1H, brs), 7.39 (2H, m), 7.46-7.67 (3H, m) , 7.79 (2H, d) , 9.35 (1H, brs), 11.04 (1H, s) , 11.80 (1H, brs)

MS (ES+):494.5.

[00183]

Table 4 below depicts data for certain exemplary compounds made according to the method described in Scheme II and in Examples 3-5. Compound numbers correspond to those compounds depicted in Table 1.

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27-{4- [4-Azetidin-1-yl. - 6 - (5“methyl-2H-pyrazol3~ylamino) pyrimidin-2-ylsulfanyl]-phenyl}-2-chloro-benzamide:

[00186] A 500 mL round bottom flask was charged with 2chloro-W-(4-[4-chloro-6-(5-methyl~2H-pyrazol-3-ylamino)pyrimidin-2-ylsulfanyl]-phenyl}-benzatnide (16.0 g, 34.0 mmol), azetidine (3.87 g, 68.0 mmol), N,JW-diisopropylethylamine (13.0 >

mL, 74.7 mmol) and n-butanol (250 mL). The reaction mixture was stirred at 90°C for 5 h. The reaction mixture was cooled and concentrated in vacuo. Diethyl ether (200 mL) was added and a light brown solid precipitated. The solution was filtered and the solid recrystallized from ethanol to give the pure product as a white solid (9.42 g, 52%) 1H NMR (DMSO): 2.04 (3H, S), 2.32 (2H, m), 3.87 (4H, m), 5.39 (1H, s), 5.66 (1H, br s), 7.48-7.59 (6H, m), 7.82 (2H, m), 9.87 (1H, s),

10.74 (1H, s) , 11.68 (1H, s) ; MS (ES + ) : 492.

[00187] Another method used to prepare example 8 is described below:

[00188] To a suspension of 2-chloro-N-{4-[4-chloro-6~(5methyl-2W-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl] -phenyl}benzamide (169 g, 0.36 mol) in 2-propanol (1.3 L) azetidine (100 g, 1.76 mol) was added portion wise. The reaction mixture was heated to 8 0-82°C. After 24 hours# di-isopropylethylamine (73.4 g, 0.57 mol) was added. The progress of the reaction was monitored by HPLC. The reaction mixture was concentrated under reduce pressure to dryness, azeotroped with methanol three times (3 x 650 mL), stirred for 2 hours in methanol (1 L) at 40°C, and cooled to 10°C. The resulting off-white solid was filtered. The isolated material was slurried in refluxing

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2013201630 19 Mar 2013 acetonitrile for 3 hours, cooled to 20-25°C, filtered and dried in a vacuum oven overnight. The material was slurried again in refluxing acetonitrile for 3 hours, cooled to 2025’C, and filtered. The material was allowed to dry until it was a constant weight. The desired product was isolated as an off-white solid. (154 g, 86%) .

[00189] Table 4 below depicts data for certain exemplary compounds made according to the method described in Scheme II and in Examples 6-8. Compound numbers correspond to those compounds depicted in Table 1.

Table 5

<td> Compound No</td><td> M+l (obs)</td><td> IH NMR</td><td> Rt (mins)</td>

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2013201630 19 Mar 2013 slurried in diethyl ether (300 ml). The solid was again filtered and re-slurried in methanol (100ml). The filtered product was air dried on the sinter, then further dx’ied under vacuum. This affords the title compound as an off-white solid (22.lg, 66% yield). 1H NMR (d6-DMSO) δ 2.22 (3H, S, CH3) , 3.31 (3H, S, CH3) , 6.00-7.50 (2H, br, CH), 10.17 (1H, S, NH) , 12.10 (1H, S, NH) ; MS ES + 256.08, ES - 254-.25.

HN'N

6-chloro-JV- (S-methyl-lH-pyrazol-B-yl) -2- (methyl sulfonyl.) pyrimidin-4-amine [00200] To a stirred suspension of S-chloro-lV-(3-methyl-l.Hpyrazol-5-yl) -2-(methylsulfinyl)pyrimidin-4-amine (8 g, 31.2 mmol) in methanol (200 ml) at 0°C was added a suspension of Oxone (44 g, 71.7 mmol) in water (100 ml) portionwise over 10 minutes. The mixture was stirred for 30 minutes at 0°C then warmed to ambient and stirred for an additional 2 hours. The reaction mixture was filtered and the resulting solid slurried in aqueous sodium bicarbonate. The mixture was filtered and the solid washed with water, then diethyl ether. The solid was slurried in ethyl acetate, filtered and dried. This gave the title product as an off-white solid (7.9 g, 88%); fz NMR (d6DMSO) δ 2.24 (3H, s), 3.35 (3H, s), 5.85 (0.5H, brs), 6.50 (0.5H, brs), 6.95 (0.5H, brs), 8.00 (0.5H, brs), 10.95 (1H,

S), 12.28 (1H, S); MS ES + 288.07, ES - 286.25.

HN

2- C2-m@thylquin.olin.~6-ylth.io) -6-chloro-Ν'- (3-methyl-IH-pyrazol

5-yl)pyrimidin-4-amine

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2-methyl~6- (2- (2-methylquinolin--6-yl) disulfanyl) quinoline [002 01] To a stirred slurry of 4--aminophenyl disulfide (5.0 g, 0.02 mol) in refluxing 6M HC1 (65 ml) was added crotonaldehyde (4.2 g, 0.06 mol) dropwise over 90 minutes. The resulting mixture was refluxed for an additional 2 hours, then cooled to ambient. Cone aqueous ammonia was added to adjust the pH to neutral and the mixture extracted with ethyl acetate. The combined extracts were washed with water, then saturated aqueous brine, dried (MgSO4) , filtered and concentrated. The crude was purified on silica gel, eluting with 50 to 100% ethyl acetate/petrol. The product was an oil (2.57 g, 37%); MS ES + 349.17.

2-methylqu.inoline-6 -thiol [00202] To a solution of disulfide (886 mg, 2.55 mmol) in DMF (12 ml)/ water (0.5 ml) was added triethylamine (284 mg) followed by tris-(2-carboxyethyl)phosphine hydrochloride (1.52 g, 5.32 mmol). The mixture was stirred for 30 minutes, then diluted with ethyl acetate/water. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) , filtered and concentrated. The crude thiol (870 mg) was used directly without further purification; MS ES +176.02, ES - 174.13

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2- (2-methylquin.olin“6-ylthio) -6-chloro-17- (3-methyl-IH-pyrazol-

5-yl)pyrimidin-4-amine [00203] To a stirred suspension of S-chloro-A7- (3-methyl-lHpyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (2.02 g, 7.03 mmol) in tert-butanol (20 ml) was added 2methylquinoline-6-thiol (1.23 g, 7.03 mmol). The mixture was heated to 70°C for 4 hours, then cooled to ambient and diluted with ethyl acetate/saturated aqueous potassium carbonate. The mixture was filtered to remove unreacted starting material and the organic layer removed form the filtrate. The. aqueous layer was extracted with ethyl acetate and the combined organic extracts washed with brine, dried (MgSO4) , filtered and concentrated. The crude was purified on silica gel, eluting · with 90 to 100% ethyl acetate/petrol. The title compound was further purified by trituration with dichloromethane. This gave the product as a white solid (514 mg, 19%); MS ES

383.25, ES -- 381.36.

2- (2-methyTquinolin-6~ylthio) -6'- (3-cyclopropyl~3~ fluoroazetidin-l-yl) ~N~ (3-methyl - Uf~pyrazol-5~yl) pyrind.din-4amine [00204] 2- (2-methylquinolin-6-ylthio) -6-chloro-N- (3-methyllH-pyrazol-5-yl)pyrimidin-4-amine (50 mg, 0.13 mmol) was slurried in n-butanol (1 ml). Diisopropylamine was added (151 mg, 1.17 mmol) followed by 4-(1-pyrrolidinyl)-piperidine (58 mg, 0.46 mmol). The mixture was heated to 85°C for 14 hours, then allowed to cool to ambient. The reaction mixture was purified by column chromatography (5% MeoH/95% dichloromethane) to give an off-white solid (25 mg, 21%); 1H NMR (400 MHz, (DMSO) δ 0.42-0.46 (2H, m), 0.59 - 0.63 (2H, m),

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2013201630 19 Mar 2013 with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel eluting with 20% ethyl acetate/petrol provide the title compound as a pale yellow oil (0.46 g, 77 %). 1H NMR (CDC13) 1.48 (9H, s) , 1.71 (3H, s) , 3.82 (2H, d) , 4.31 (2H, d) .

3-methylassetidine·-3 -carbonitrile trifluoro acetic acid [00211] To a solution of tert-butyl 3-cyano~3methylazetidine-1-carboxylate (30.0 mg, 0.15 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) and the solution stirred at room temperature for 1 hr. The reaction was concentrated and dried under vacuum to give a viscous oil which was used crude in subsequent chemistry.

HIM

N-(4-((4-(S-methyl-lH-pyraKol-S-ylamino)-6-(3-cyano-3~ methylazetidin-l-yl)pyrimidin~2-yl)sulfanyl)phenyl) propionamide [00212] To a suspension of N- (4-(4-(3-methyl-iH-pyrazol~5ylamino)-6-chloropyrim±din-2-ylthio)phenyl)propionamide (150 mg, 0.387 mmol) in n-butanol (4 ml) was added diispropylamine (500 mg, 3.87 mmol) followed by 3--met.hylazetidine.-3~ carbonitrile hydrochloride (255 mg, 1.94 mmol). The mixture was heated at 85°C for 18 hours then concentrated and the residue purified by mass directed HPLC. This gave the title compound as a TFA salt (72 mg, 41%); 1H NMR (DMSO) 1.05 (3H, t) , 1.65 (3H, s) , 2.03 (3H, s) , 2.37 (2H, q) , 3.88 (2H, d) , 4.18 (2H, d), 5.37 (1H, s), 5.60 (1H, brs), 7.50 (2H, d), 7.71 (2H, d) , 9.50 (1H, brs), 10.11 (1H, brs); MS ES + 449.4, ES 447.6.

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N-Benzhydrylazetidin-3-one [00213] To a stirred slurry of 1-(diphenylmethyl)-3hydroxyazetidine (30g, 0.126 mol) in triethylamine (63g, 0.628 mol) was added a solution of sulfur tfioxide pyridine complex (60g, 0.376 mol) in anhydrous DMSO (300 ml) dropwise over 30 minutes. The resulting mixture was warmed to 50°C for 30 minutes. The reaction mixture was then cooled to ambient and poured into a mixture of water (IL) and ethyl acetate (800 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate (3 x 200 ml). The combined organic solutions were then washed with water (3 x 200ml), then saturated brine (200 ml) , dried (magnesium sulfate), filtered and concentrated. The residue was purified on silica gel, eluting with 5-10% ethyl acetate/petrol. The product was obtained as a white solid (26.2g, 36%); AH NMR CDC13 δ 4.07 (4H, s), 4.62 (1H, S), 7.20-7.39 (6H, m), 7.53 (4H, d).

l-Benzh.ydryl-3-cyclopropylazetidin-3-ol hydrochloride [00214] A solution of cyclopropylmagnesium bromide in THF (0.5M, 600ml, 0.5 mol) was cooled to -78!3C under a nitrogen atmosphere. Precipitation appeared to occur at this

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3,3-Dimethyl-1-oxa-6-aza-spiro[3.3]heptane-6-carboxylic acid tert-butyl ester [00219] To a solution of tert-butyl 3-hydroxy-3-(1-hydroxy2-methylpropan-2-yl)azetidine-l-carboxylate (0.20 g, 0.82 mmol) in THF (4 ml) was added in rapid succession, KOfcBu (0.19 g, 1.72 mmol) and p-toluenesulfonylchloride (0.16 g, 0.82 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.13 g, 70%. 1H NMR

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2013201630 19 Mar 2013 (CDC13, 400 Mhz) 1.25 (6H, s) , 1.45 (9H, s) , 3.89 (2H, d) ,

4.12 (2H, d), 4.20 (2H, s) .

N-{4 -[4-(3,3“Dimethy1-1-oxa-6-aza-spiro[3.3]hept-6-yl) - 6 -(5~ methyl-2jy-pyrazol-3-ylamino) -pyrimidin-2-ylsulfanyl] -phenyl}propionamide [00220] To a solution of 3,3-Dimethyl-l-oxa-6-azaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester (60 mg, 0.27 mmol) in DCM (3 ml) at 0 C was added trifluoroacetic acid and the reaction stirred at room temperature for 1 hr. The reaction was concentrated to give an oil which was used crude in the next step. The oily residue was dissolved .in n-BuOH (3 ml) and diisopropylethylamine (171 mg, 1.35 mmol, 0.24 ml) and N-{4- [4-Chloro-6- (5-methyl-2H-pyrazol-3-ylamino) -pyrimidin-2ylsulfanyl]-phenyl}-propionamide (93 mg, 0.24 mmol) was added. The mixture was heated to 100°C and stirred for 18 hrs. The reaction was allowed to cool to room temperature and diluted with brine (20 ml) and ethyl acetate (20 ml). The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with

2.5 % MeOH in ethyl acetate to give the title compound as a pale orange solid 25 mg, 20%. XH NMR (d6-DMSO, 400MHz) 1.08 (3H, m), 1.20 (6H, s) , 1.98 (3H, s), 2.34 (2H, q), 3.78 (2H,

d), 4.14 - 4.15 (4H, m) , 5.35 (IH, s), 5.61 (IH, brs), 7.47 (2H, d), 7,70 (2H, d), 9.24 (IH, s) , 10.07 (IH, s) , 11.43 (IH,

s). ES+ 480.

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Example 20

OH

EtOoC-NBoc tert-butyl 3-(2-(ethoxycarbonyl)ethynyl)-3-hydroxyazetidine-Ια arboxyl ate [00221] n-butyl lithium (1.17 mmol, 0.47 ml, 2.5 M) was added dropwise to a solution of diisopropylamine (130 mg, 1.29 mmol, 0.18 ml) in THF (8 ml) at --7 8 °C. The solution was warmed to 0°C, stirred for 15 mins, and cooled back to -78°C. Ethyl propiolate (126 mg, 1.29 mmol, 0.13 ml) was added dropwise and the solution stirred for 1 hr at -78°C. A solution of tertbutyl 3-oxoazetidine-1-carboxylate (200 mg, 1.17 mmol) in THF (2 ml) was added dropwise, stirring continued for 30 mins, and the solution warmed to 0cC and stirred for a further 15 mins. The reaction was quenched with Sat NH4C1 (20 ml) and extracted into ethyl acetate (20 ml) , dried (Na2SO4) , and concentrated to give a brown oil. The oil was purified by flash column chromatography eluting with 30% ethylacetate/hexanes to give the title compound as a colorless oil 0.20 g, 64%. ·*Ή NMR (CDC13, 400 MHz) 1.33 (3H, t), 1.48 (9H, s), 2.92 (1H, s),

4.04 (2H, d), 4.22- 4.31 (4H, m).

ΗΟχ

EtO2C'^^ON Soc tert-butyl 3-(2-(ethoxycarbonyl)ethyl)-3-hydroxyaaetidine-lcarboxylate [00222] To palladium on carbon (10 %, 75 mg) under a nitrogen atmosphere was added a solution of tert-butyl 3-(2(ethoxycarbonyl)ethynyl)-3-hydroxyazetidine-l-carboxylate (0.20 g, 0.74 mmol) in ethanol (10 ml), The suspension was subjected to hydrogen (Parr hydrogenation apparatus) at 45 Psi for 3 hrs. The reaction was filtered and concentrated to give an oil. The oil was purified by flash column chromatography

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2013201630 19 Mar 2013 eluting with 30 to 50% ethyl acetate/hexanes to give the title compound as a colorless oil 0.11 g, 50%. 1H NMR (CDC13, 400 MHz) 1.28 (3H, t.) , 1.43 (9H, s) , 2.15 (2H, t) , 2.50 (2H, t) , 3.32 (1H, s) , 3.83 (4H, dd) , 4.18 (2H, q).

HQ tert-butyl 3-hydroxy-3- (3“hydroxypropyl)azetidine-1carboxylate [00223] Diisobutyl aluminium hydride (1.48 mmol, 1.48 ml, 1 M DCM) was added dropwise to a solution of tert-butyl 3-(2(ethoxycarbonyl)ethyl)-3-hydroxyazetidine-1-carboxylate (0.10 g, 0.3 7 mmol) in DCM (3 ml) at -78°C. The solution was allowed to warm to 0°C and stirred for a further 5 hrs. The reaction was quenched with Sat NH4C1 (10 ml) and extracted into ethyl acetate (10 ml), dried (Na2SO4), and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 60% ethylacetate/hexanes to give the title compound as a colorless oil 27 mg, 32%. 1H NMR (CDC13, 400 MHz) 1.48 (9H, s) , 1.69 - 1.75 (2H, m) , 1.93 (2H, t), 3.76 (2H, t.) , 3.82 (4H, s) .

1-oxa- 7- aza-spiro [4.3] octane-7 ·· carboxylic acid terfc-butyl ester [00224] To a solution of tert-butyl 3-hydroxy-3-(3 hydroxypropyl)azetidine-1-carboxylate (27 mg, 0.13 mmol) in THF (2 ml) was added in rapid succession, KOtBu (31 mg, 0.27 mmol) and. p-toluenesulfonylchloride (25 mg, 0.13 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was used crude in the next step.

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2013201630 19 Mar 2013 addition the reaction was allowed to warm to room temperature overnight. A 10 % solution of NaHSO3 (325 ml) and a 10 % solution of K3CO3 (2.6 L) was then added to neutralize the reaction mixture, the solution filtered and the filter cake washed with H2O (3.3 L) . The solid was slurried in H2O (2.6 L) , the solution filtered and the filter cake washed with H2O (3.3 L). The solid was dried under vacuum (72.3 g, 51 %). 1H NMR (DMSO): 0.47 (2H, m) , 0.60 (2H, m), 1.43-1.46 (1H, m) , 2.20 (3H, s), 3.25 (3H, s), 3.97-4.11 (4H, m) , 5.93 (1H, br s),

6.47 (1H, br S). 9.88 (1H, s), 12.01 (1H, hr s). ES+ 367

F

N- (4-(4~(S-methyl-lH-pyrasol-S-ylamiho)-6-(3~cydopropyl-3fluoroazctidin-l-yl)pyrimidin-2-ylthio}phenyl)-3,3,3trifluoropropanami.de (Compound 1-13) (00237] A slurry of 6-(3-cyclopropyl-3-fluoroazetidin-l-yl)N-(3-methyl-lH-pyrazol-5“yl)-2-(methylsulfonyl)pyrimidin-4amine (61g, 170 mmol) and 3f3,3-trifluoro~N-(4~ mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mb) was heated to reflux for 1.5 hours. During this time, the slurry transformed from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0 °C and stirred at this temperature for 15 min. The mixture was then filtered and washed with cold CH3CN (650 mL) . The resulting solid was dried for 20 hours at 38 °C under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3(sat) (1300 mL) . The mixture was stirred until no more solid remained. Then, the aqueous and organic layers were separated and. the aqueous layer was washed with EtOAc (3 90 mL) . The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to a

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2013201630 19 Mar 2013 minimal volume on rotavap. The resulting mixture was recrystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%)IH NMR (MeOD, 400 MHz):

0.40-0.45 (2H, m), 0.60-0.65 (2H, m) , 1.3-1.4 (IH, m), 2.05 (2H, s), 3.25-3.40 (2H, m) , 3.85-3.40 (4H, m), 5.40-5.50 (2H,

m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+ 522.

2-(6-aminopyridin-3-ylthio}-6-(3-cyclopropyl-3-fluoroazetidin1-yl) -N- (3-methyl-lH~pyrazol-5~yl)pyrimidin~4-ainine [00238] A solution of 6-(3-cyclopropyl-3~fluoroazetidin-lyl)-N-(3-methyl-lH-pyrazol~5-yl)-2-(methylsulfonyl)pyrimidin-

4-amine (880 mg, 2.4 mmol) and 6-aminopyridine-3-thiol) (3 00 mg, 2.4 mmol) in DMF (10 ml) was heated to 8 0°C and stirred for 2 hrs. The reaction was diluted with ethylacetate (150 ml) and Sat. NaHCO3 (50 ml) and the organic layer washed with brine (50 ml), dried (MgSO4) and concentrated to give an oil. The residue was purified by flash column chromatography eluting with Pentane/EtOAc (5% MeOH) 0 to 100 %. The resulting compound was triturated in 10:1 DCM:MeOH and filtered to give the title compound as a white solid (300 mg, 30%). IH NMR (DMSO, 400 MHz) 0.42-0.44 (2H, m), 0.55-0.60 (2H, m), 1.35-

1.45 (IH, m), 2.11 (3H, s), 3.81-3.90 (4H, m), 5.55-5.80 (2H,

m), 6.35 (2H, S), 6.49-6.52 (IH, d), 7.46-7.49 (IH, d), 7.97 (IH, s), 9.30-9.35 (IH, s). ES+ 413

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2- ( (4- (2-chlorobenzamido)phenyl) sulfanyl)-6- (5-m.ethyl-lHpyrazol-S-ylamino)-(azetidin-l-yl)pyrimidine-4-carboxamide [00239] To a suspension of methyl 2-((4-(2-chlorobenzamido) phenyl)sulfanyl)-6-(5~methyl-lH-pyrazol“3-ylamino)pyrimidine4-carboxylate (235mg, 0.46 mmol) in ethyl alcohol was added a large excess of azetine (0.5 ml, 7.4 mmol). The tube was then sealed and heated to 90°C for 16 hours, then allowed to cool to room temperature. The volatile components were then removed in vacuo and the residue purified by mass directed preparative HPLC, eluted with acetonitrile / water / TEA to give the product as a white solid after freeze drying (3.5 mg, 1.2 %) . 1H NMR (DMSO-ds) : 2.16 (5H, m) , 3.24 (2H, m) , 3.98 (2H, m) ,

2013201630 19 Mar 2013 off-white powder. Crude product 3.37g (46% yield). NMR (DMSO. 400MHz) 4.02-4.11 (2H, m, alk) , 4..60-4.61 (2H, in, alk), 5.435.46 (H, m, alk), 7.36-7.39 (H, d, ar), 7.55-7.57 (H, m, alk), 7,76 (H, s, ar) and 9.09-9.12 (H, m, NH). F19 NMR (DMSO

400Mhz) —70.59. ES+ 312 ,O

5-bromo-2 - (2,2,2-trifluoroethyl] isoirtdolin-l-one [00244] To a stirred solution of 4-bromo-2-hydroxymethyl-N(2,2,2 -trifluoro-ethyl)-benzamide (3.37g, 10.8 mmol) in anhydrous tetrahydrofuran (50ml), N-methyl-2-pyrrolinone (20mL), cooled to 5oC under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25ml) at a rate to keep the temperature of the reaction mixture under lOoC, After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5oC and a solution of bis(dimethyl amino) phosphoryl chloride (1.85g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified, with IM aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 x 100ml) and the organic layers were combined and dried over Magnesium sulfate powder , filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81g (88% yield). NMR (DMSO 400MHz) 4.36-4.43 (2H, m, alk),

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4.62 (2H, s, alk) , 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar).

F19 NMR (DMSO 400Mhz) -69.03. ES+ 296

-(2,2,2-trifluoroethyl)-5-((triisopropylsilyl)sulfanyl) isoindolin-1-one [00245] To a, stirred solution of triisopropyls.ilane thiol (6'48 mg, 3.4 mmol in anhydrous THF(lOml), cooled to SoC under nitrogen atmosphere was added 60% sodium hydride powder ( 143mg, 3.57 mmol) portion wise over 10 minutes. The resulting yellow solution was stirred for 20 minutes and then, a solution of 5-bromo-2-¢2,2,2- trifluoro-ethyl)-2,3-dihydro-isoindol-1one (Ig, 3-4 mmol) in anhydrous THF (10ml) and tetrakis palladium triphenylphosphine (393mg 0.34 mmol)was added. The reaction mixture was degassed with nitrogen and heated at 90°C for 2 hours. The mixture was concentrated and the reside was purified using column chromatography eluting with 30% ethyl acetate 70% petroleum ether to isolate both the protected (406mg, 30% yield based on FW) and non-protected thiol (171 mg, 20% yield based on FW). ES+ 248.14

US'

2-(2,2,2-trifluoroethyl)-5-mercaptoisoindolin-l-one [00246] 2-(2,2,2-trifluoroethyl)-5-(( triisopropylsilyl) sulfanyl)isoindolin-1-one was dissolved in a solution of hydrochloric acid in methanol (2ml) and tetrahydrofuran (2ml) and stirred at room temperature for 2 hours or until

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Compound c

F

2~(2,2,2-trifluoroethyl)-7-mercaptoisoquinolin-1(2H)-one o

7-bromo-2-(2,2,2-trifluoroethyl)isoquinolin-1(2H)-one [00247] To a stirred solution of 7-bromoisoquinolin-1(2H)one (5g, 22.3 mmol) and iodotrifluoroethane (4.9g, 23.4mmol) in dimethylacetimide cooled to 5oC was added sodium hydride 60% wt (0.89g 22.3 mmol) portion wise over 5 minutes. After complete addition reaction mixture allowed to warm up to room temperature over 2 hours and then heated at 50oC for 24 hours. Reaction mixture was evaporated to leave a residue, which was diluted with ethyl acetate (200 ml) and water (200ml). The aqueous layer was further extracted with ethyl acetate (2 x 50ml) and organic layers were combined and washed with saturated aqueous bicarbonate (200ml), brine (200ml) and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure to leave a residue and purified using column chromatography eluting with 50% ethyl acetate/petrol ether to give a yellow solid which was still impure by LCMS (1.53g, 22% yield)

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2- (2s2,2-trifluoroethyl)-7-((triisopropylsilyl)sulfanyl) isoquinolin-1 (2H) -one [00248] 7-bromo-2-(2,2,2-trifluoroethyl)isoquinolin-1(2H)one (O.Sg, 1.63 mmol), cesium carbonate ( 0.693g 2.1 mmol), Palladium acetate (0.018g, 0.08 mmol) and triphenylphoshine (0.094g, 0.36 mmol) in anhydrous toluene in a microwave vessel was degassed with nitrogen, trisiopropylsilane thiol (0.404g 0.36 mmol) was added to the vessel and the vessel was then subjected to heating at lOOoC in a microwave reactor for 2 hours. The reaction mixture was diluted with petroleum ether and the solid precipitate was removed by filtration and the filtrate was evaporated and the residue was purified, by column chromatography eluting with ethyl acetate/petroleum (3:7) ether to give an oil (1.05g, 50% yield).

O

2-(2,2,2-trifluoroethyl)-7-mercaptoisoquinolin-1(2H)-one [00249] 2-(2,2,2-trifluoroethyl)-7-((triisopropylsilyl) sulfanyl)isoquinolin-1(2H)-one was dissolved in a solution of hydrochloric acid in methanol (2ml) and tetrahvdrofuran (2ml) and stirred at room temperature for 2 hours or until disappearance of starting material. Reaction mixture was concentrated to give the desired material (quant yield).

Compound d

HS

2-Chloro-Ν'- (4-mercaptophenyl) benzamide

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S~4~(2-chlorobenzafflido)phenyl 2-chlorobenzothioate [00250] Degassed EtOAc (3.2 L) is charged in a flask. The solvent is cooled to 0°C under nitrogen. 4-aminobenzenethiol (435 g, 3.48 mol) is melted and added directly to the flask. Triethylamine (773 g, 7.65 mol) is added over 30 minutes forming a precipitate. Then, 2-chlorobenzoyl chloride (1340 g, 7.65 mol) is added neat keeping the temperature below 5°C. After complete addition, the mixture is heated to 20°C for one hour. The slurry is filtered and the cake washed with EtOAc (780 mL). The material is dried at 50°C under vacuum with a nitrogen sweep until a constant weight is obtained and carried to the next reaction without further purification.

- chiorcs · if·· (4-mercaptophenyl)benzamide [00251] 8-4-(2-chlorobenzamido)phenyl 2-chlorobenzothioate (305 g, 0.76 mol), EtOAc (325 mL), and water (65 mL·) are charged to a flask fitted with reflux condenser. A solution of NaOH (3 eq., 50% aq.) is added and the mixture heated to 70°C for 30-40 minutes. EtOAc was removed by distillation sit 100mm Hg and the mixture cooled to 5°C. The mixture was acidified with 6N HC1 to pH 2. The solid is collected by vacuum filtration and washed with water (390 mb). The solid is taken up in CH2C12 (520 mb) and washed with saturated aqueous NaHCO3. The organic layer is dried over Na2SO4, filtered, and concentrated to give the desired material (174 g, 87%) .

Compound e

H

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3,3,3 - trifluoro-2(/- (4 -mercaptoph.en.yl) propanamide

S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3trifluoroprcpanethioate [00252] 4-Aminothiophenol is melted and charged to a flask.

Degassed EtOAc (1950 mL) was added. A solution of K2CO3 (92g, 67 0 mmol) in degassed H2O (13 0 0 vol) was then added. The solution was cooled to 0 °C and the 3,3,3-trifluoropropanoyl chloride (55.2 g, 600 mmol) was slowly added to keep the temperature below 10 °C). The reaction was then warmed to room temperature. The oiganic layer was separated and washed xvith brine (1300 mL). The organic layer was then concentrated on the rotary evaporator. The solid was slurried in Heptane/EtOAc (390 mL/390 mL) for 30 min. Heptane (780 mL) was then added and the slurry was cooled to 0 °C for 30 min. The slurry was filtered and the filter cake was dried under vacuum to give the desired compound (51.3 g, 87.2%).

fyA.

HS>W o

3,3,3-trif luoro-.V- (4-mercaptophenyl)propanamide [00253] S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) are charged to a flask. Concentrated HC1 (22.5 mL·) is slowly added, to keep the temp below 30 °C. The reaction is then heated to 50 °C for 17.5 h. The reaction mixture is reduced to 41 mL by vacuum distillation at 50 °C. Cool the reaction to room temperature and H20 (51 mL) is added. The slurry is filtered and the filter cake is washed with H2O (3 x 35 mL).

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The solid is dried under vacuum to produce the desired compound (19.9 g, 58%).

[00254] Table 8 depicts data for additional exemplary compounds of this invention.

<td colspan="2"> [00255]</td><td colspan="2"> Compounds</td><td> 47 ,</td><td> 48 ,</td><td> 4 9 , 5 0 , 51,</td><td> 52,</td><td> 53 ,</td><td colspan="2"> 54, 55, 56,</td>

according to the method described in Scheme II and in Examples

6-8 .

[00256] Compounds 68, 70, 96, 100, 110, 112, 113, 119, 141,

170, 172, 173, 175, 177, 186, 194, 195 and 202 were made according to the method described in General Scheme (method B) and in example 14.

[00257] Compounds 171, 179, 188, 189, 190, 201, 206 and 210 were made according to the method described in General Scheme (method A) and in example 24.

[00258] Compounds 72, 73, 74, 83, 87, 108, 114, 116, 117, 120, 121, 137, 138, 139, 14Q, 152, 158, 161, 162, 163, 164, 165, 166, 167, 207 and 211 were made according to the method described in Scheme VII and in Example 11.

[00259] Compound 181 was made according to the method described in. Scheme I and. in Example 1-2.

[00260] Compound 132 was made according to the method described in Scheme IX and in Example 23.

[00261] Compound 192 was made according to the method described in Scheme II and in Example 21.

[00262] Compounds 183, 196 were made according to the method described in Example 22.

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2013201630 19 Mar 2013 [00263] Compound 205 was made according to the method described in Example 9--10.

Table 8

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<td> Compound No</td><td> Vl+l (obs)</td><td> 1HNMR</td><td> Rt | (mins)</td>

<td> 1-133</td><td> 478.00</td><td> (DMSO-d6) 0.30 - 0.34 (IH, m), 0.39 - 0.44 (2H. m), 1.15-1.21 (IH, m), 2.00 (3H, s), 2.09 (2H. q), 3.66 (4H, q), 3.88 (2H, t), 5.42 (IH, s), 5.58 (IH, s) 5.60 (IH, brs), 7.55 (2H. d), 7.78 (2H, d), 9.18 (IH, s), 11.68 (IH, s). 2 hydrogens masked by solvent</td><td> 8.063</td>

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<td> Compound No</td><td colspan="2"> M+l (obs)ilHNMR</td><td> Rt (mins)</td>

Example 28; &urora-2 {Aurora A) Inhibition Assay [00264] Compounds were screened for their ability to inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of lOOmM Hepes (pH7.5), lOrnM MgClz, ImM DTT, 25mM NaCl, 2.5mM phosphoenolpyruvate, 300 μΜ NADH, 30 pg/ml pyruvate kinase and 10 pg/ml lactate dehydrogenase. Final substrate concentrations in the assay are 400μΜ ATP (Sigma Chemicals) and 570μΜ peptide (Kemptide, American Peptide, Sunnyvale, CA). Assays were carried out at 30 ‘C and in the presence of 40nM Aurora--2 .

[00265] An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of Aurora-2 and the test compound of interest. SS μΐ of the stock solution was placed in a 96 well plate followed by addition of 2 μΐ of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 7.5pM). The plate was preincubated for 10 minutes at 30'C and the reaction initiated by addition of 10 μΐ of Aurora-2. Initial reaction rates were determined with a Molecular Devices SpectraMax Plus plate reader over a 10

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2013201630 19 Mar 2013 minute time course. IC50 and. Ki data were calculated from non-linear regression analysis using the Prism software package (GraphPad Prism version 3.Ocx for Macintosh, GraphPad Software, San Diego California, USA) .

[00266] Compounds 1-15, 16-17, 19, 21-22, 23-48, 50-68, 7072, 76-90, 92-136, 141-165, 167-211 were found to have Aurora

A kinase activity at <

5nM Ki.

[00267]

Compounds 1,

52, 63, 69, 72-75, 82,

2, 6, 10, 11, 18-24, 26, 41, 47, 49,

91, 108, 124, 132, 137-140, 145, 150,

166, 167, 174-175, 188, 197, 200-201, and 209 were found to inhibit Aurora A kinase at a Ki value of between 0.005 uM and 0.2 uM.

[00268] Compounds 3, 4, 7-9, 14-15, 17, 25, 27-30, 32-33,

35, 39, 43-45, 48, 53-54, 58-60, 62, 70-71, 76-77, 79-80, 9496’, 98-99, 112, 114, 117, 120-121, 123, 125, 127-128, 130,

134, 141-142, 147-149, 158-159, 165, 176, 182, 189, 190,

192-193,

210 were found to inhibit

Aurora A between 0.001 uM and 0.005

UM .

126, 129,

136, 143-144,

177-181,

194, 196, 199, 203-206,

208, and 211 were found to inhibit Aurora A kinase at a Ki value of < 0.001 uM.

Example 29: Aurora-1 (Aurora B) Inhibition Assay(radiometric) [00270] .An assay buffer solution was prepared which consisted of 25 mM HEPES (pH 7.5), 10 mM MgCl2, 0.1% BSA and 10% glycerol. A 22 nM Aurora-B solution, also containing 1.7 mM DTT and 1.5 mM Kemptide (URRASLG), was prepared in assay buffer. To 22 pL· of the Aurora-B solution, in a 96-well plate, was added 2 μΐ of a compound stock solution in DMSO and the mixture allowed to equilibrate for 10 minutes at 25°C. The

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2013201630 19 Mar 2013 enzyme reaction was initiated by the addition of 16 μΐ stock [y-j3P] -ATP solution (-20 nCi/pL) prepared in assay buffer, to a final assay concentration of 800 μΜ. The reaction was stopped after 3 hours by the addition of 16 pL· 500 mM phosphoric acid and the levels of j3P incorporation into the peptide substrate were determined by the following method. [00271] A phosphocellulose 96-well plate (Millipore, Cat no. MAPHNOB50) was pre-treated with 100 pL of a 100 mM phosphoric acid prior to the addition of the enzyme reaction mixture (40 pL). The solution was left to soak on to the phosphocellulose membrane for 30 minutes and the plate subsequently washed four times with 200 pL of a 100 mM phosphoric acid. To each well of the dry plate was added 30 pL of Optiphase ’SuperMix'· liquid scintillation cocktail (Perkin Elmer) prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac). Levels of non-enzyme catalyzed background radioactivity were determined by adding 16 pL of the 500 mM phosphoric acid to control wells, containing all assay components (which acts to denature the enzyme), prior to the addition of the [y-Yp] -ATP solution. Levels of enzyme catalyzed Ύ incorporation were calculated by subtracting mean background counts from those measured at each inhibitor concentration. For each Ki determination. 8 delta points, typically covering the concentration range 0 -- 10 pM compound, were obtained in duplicate (DMSO stocks were prepared from an initial compound stock, of 10 mM with subsequent 1:2.5 serial dilutions). Ki values were calculated from initial rate data by non-linear regression using the Prism software package (Prism 3.0, Graphpad Software, San Diego, CA) .

[00272] Compounds 2, 4, 10-11, 21-27, 41, 47, 49, 52, 54, 62, 67-70, 72-75, 77, 82, 93, 108, 124-125, 131, 136-141, 145,

148, 150-151, 166-167, 174-175, 189, 193, 197, 200-201, 203,

209-210 were found to inhibit Aurora B kinase at a Ki value of between 0.05 uM and 2.0 uM.

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<td> [00273] Compounds</td><td> 1,</td><td> 6, 14-15,</td><td> 17-18</td><td> , 20, 28-32,</td><td> 34-36,</td><td> 39,</td>

190, 192, 194, 198, 202, and 205-207 were found to inhibit

Aurora B kinase at a Ki value of between 0.01 uM and 0.05 uM.

[00274] Compounds 3, 5, 7-9, 12-13, 16, 19, 33, 37-38, 40, 42, 46, 48, 50-51, 55-57, 59, 61, 64-66, 76, 78, 81, 83-90,

97, 100-106, 110-111, 113, 115-116, 118-119, 122-123, 126,

129, 135, 142-143, 146, 152-153, 155, 158-161, 163-165,

168-169, 172, 177, 179, 183, 185-187, 191, 195-196, 199, 204,

208, and 211 were found to inhibit Aurora B kinase at a Ki value of < 0.01 uM.

[00275] Compounds 3, 5-9, 12-16, 18-19, 29, 31, 33-34, 3640, 42, 46, 48, 50-51, 53, 55-59, 61, 64-66, 76, 78-79, 81,

83-90, 94-106, 110-113, 115-116, 118-123, 126-130, 133-135,

142-144, 146-147, 152-165, '168-173, 176-177, 179, 182-187,

191, 194-196, 198-199, 202, 204-205, 207-208, and 211 were found to inhibit Aurora B kinase at a Ki value of < 0.025 uM.

Example 30: Itk Inhibition Assay [00276] The compounds of the present invention were evaluated as inhibitors of human Itk kinase using a radioactivity-based assay. These compounds can also be evaluated using a spectrophotometric or alphascreen assay.

Itk Inhibition Assay: Radioactivity-based Assay [00277] Assays were carried out in a mixture of 20 mM MOPS (pH 7.0), lOmM MgCl2, 0.1% BSA and ImM DTT. Final substrate concentrations in the assay were 7.5 μΜ [γ-33P]ATP (400μΟ1 33P ATP/ μπιοί ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 3uM peptide (SAM68 protein Δ332-443). Assays were carried out at 25 °C. in the presence of 50 nM Itk, An assay stock buffer solution was prepared containing all of the reagents

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2013201630 19 Mar 2013 listed above, with the exception of ATP and the test compound of interest. 50 pL of the stock solution was placed in a 96 well plate followed by addition of 2p.L of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 50μΜ with 2-fold serial dilutions), in duplicate (final DMSO concentration 2%). The plate was pre-incubated for 10 minutes at 25°C and the reaction initiated by addition of 50u.L [γ-33Ρ] ATP (final concentration 7.5pM).

[00278] The reaction was stopped after 10 minutes by the ’addition of 100pL 0.2M phosphoric acid + 0.01% TWEEN 20. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with 100pL 0.2M phosphoric acid + 0.01%- TWEEN 20 prior* to the addition of 170μΒ of the stopped assay mixture. The plate was washed with 4 x 200pL 0.2M phosphoric acid + 0.01% TWEEN 20. After drying, 30pL Optipha.se 'SuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

[00279] Ki(app) data were calculated from non-linear regression analysis of the initial rate data using the Prism software package (GraphPad Prism version 3.Ocx for Macintosh, GraphPad Software, San Diego California, USA).

2013201630 19 Mar 2013

Example 33 JAK3 Inhibition Assay [00290] Compounds were screened for their ability to inhibit JAK using the assay shown below. Reactions were carried out in a kinase buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, mM MgCl2, 25 mM NaCl, and 0.01% BSA.

Substrate concentrations in the assay were 5 μΜ ATP (200 uCi/pmole ATP) and 1 μΜ poly (Glu) «Tyr. Reactions were carried out at 25 °C and 1 nM JAK3.

[00291] To each well of a 96 well polycarbonate plate was added 1.5 μΐ of a candidate JAK3 inhibitor along with 50 pl of kinase buffer containing 2 μΜ poly (Glu) «Tyr and 10 μΜ ATP.

This was then mixed and 50μ1 of kinase buffer containing 2 nM JAK3 enzyme was added to start the reaction. After 20 minutes at room temperature (25C), the reaction was stopped with 50μ1 of 20% trichloroacetic acid (TCA) that also contained 0.4 mM ATP. The entire contents of each well were then transferred to a 96 well glass fiber filter plate using a TomTek Cell Harvester. After washing, 60 μΐ of scintillation fluid was added and 33P incorporation detected on a Perkin Elmer TopCount.

[00292] Compounds 12-13, 21, 25, 37, 50, 65, 76, 78, 81, 88,

92, 99, 102, 105, 108, 110, 112-113, 115, 131, 135, 150-151, 158-161, 164, 172-173, 180-181, 183, 185, 1.99, 202, 206, 209, and 211 were found to have a Ki value of < 0.01 uM.

[00293] ‘ Compounds 1, 3, 5, 7-11, 14-17, 19-20, 22, 28-31,

33, 38-40, 44, 46, 48-49, 51-57, 60-61, 64, 66-68, 71, 74, 79, 80, 83, 85, 89-90, 94-97, 100, 103-104, 109, 116-117, 119-121, 126, 128, 134, 144-146, 148-149, 155, 162-163, 166-170, 1.75,

177, 179, 182, 184, 186, 188-191, 194-195, 198, 204-205, and 207 were found to have a Ki value of > 0.01 uM and <_ 0.5 uM. [00294] Compounds 2, 4, 23-24, 26-27, 32, 34-35, 58, 69, 73,

77, 82, 87, 114, 124, 127, 132, 137-138, 152, 171, 178, 192,

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Example 34: JAK2 Inhibition Assay [00295] Ths assays are as described above in Example 33 except that JAK-2 enzyme was used, the final poly(Glu) 4Tyr concentration was 15 uM, and final ATP concentration was 12 μΜ.

Example 35: FLT-3 Inhibit i on Assay [00296] Compounds were screened for their ability to inhibit FLT-3 activity using a radiometric filter-binding assay. This assay monitors the 33P incorporation into a substrate poly(Glu, Tyr) 4:1 (pE4¥). Reactions were carried out in a solution containing 100 mM HEPES (pH 7.5}, 10 mM MgCl2, 25 mM NaCl, 1 mM DTT, 0.01% BSA and 2.5% DMSO. Final substrate concentrations in the assay were 90 μΜ ATP and 0.5mg/ml pE4Y (both from Sigma Chemicals, St Louis, MO). The final concentration of a compound of the present invention was generally between 0.01 and 5 μΜ. Typically, a 12~point titration was conducted by preparing serial dilutions from 10 mM DMSO stock of test compound. Reactions were carried out at room temperature .

[00297] Two assay solutions were prepared. Solution 1 contains 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 1 mg/ml pS4Y and 180 mM ATP (containing 0.3mCi of [γ-33ρ]ΆΤΡ for each reaction). Solution 2 contains 100 mM HEPES (pH 7.5), 10 mM MgClz, 25 mM NaCl, 2 mM DTT, 0.02% BSA and 3 nM FLT-3. The assay was run on a 96 well plate by mixing 50μ1 each of Solution 1 and 2.5 ml of the compounds of the present invention. The reaction was initiated with Solution 2. After incubation for 20 minutes at room temperature, the reaction was stopped with 50μ1 of 20% TCA containing 0.4mM of ATP. All of the reaction volume was then transferred to a filter plate

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2013201630 19 Mar 2013 and washed with 5% TCA by a Harvester 9600 from TOMTEC (Hamden, CT) . The amount of 33P incorporation into pE4y was analyzed by a Packard Top Count Microplate Scintillation Counter (Meriden, CT). The data was fitted using Prism software to get an IC50 or Ki.

[00298] Compounds 2, 3, 25, 50, 76, 78-79, 81, 85, 88-90,

92, 94, .97, 99-100, 102-103, 105, 108-110, 112-113, 119, 128,

131, 144, 150-151, 159-160, 168-169, 173, 181, 183, 199, 202,

206, and 209 were found to have a Ki value of <_ 0.05 uM.

[00299] Compounds 1, 4-5, 8, 10, 12, 14-17, 20, 22, 26-27,

31-32, 35, 37, 39-40, 46, 51, 60, 64-65, 67, 68, 71, 73-74, 80, 95-96, 104, 115, 121, 126, 134-135, 137, 148, 155, 158, 171-172, 182, 184-186, 188-18.9, 194, 198, '204-205, and 211 were found to have a Ki value > 0.05 uM and < .15 uM.

[00300] Compounds 6-7, 9, 11, 19, 23-24, 28-30, 33-34, 38,

44, 48-49, 52-59, 61, 66, 69, 77, 82-83, 114, 117, 120, 124,

127, 132, 139, 142, 145-146, 149, 152, 161-1.64, 166-167, 170,

175, 177-178, 190-191, 193, 195, 203, and 207 were found to have a Ki > .15 uM and < 1.0 uM.

Example 36: Microsomal Stability Assay [00301] Microsomal stability was monitored by generation of depletion-time profiles in microsomes from a range of species (male CD-I mouse, male Sprague-Dawley rat, male Beagle dog, male Cynomolgus monkey and pooled mixed gender human). Compound spiking solutions were made up by diluting down the compound stock solution in DMSO (typically 10 mM) .to give a solution in acetonitrile (0.5 mM). Compound (to give final concentration of 5 μΜ) was incubated with a final reaction mixture (1000 pL) consisting of liver microsome protein (1 mg/oiL) and a β-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-regenerating system (RGS) [consisting of 2 mM β-nicotinamide adenine dinucleotide phosphate (NADP),

20.5 mM isocitric acid, 0.5 ϋ of isocitrate dehydrogenase/mL, · 154

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2013201630 19 Mar 2013 mM magnesium chloride, and 0.1 M phosphate buffer (PB) pH 7.4] in the presence of 0.1 M PB (pH 7.4).

[00302] The reaction was initiated.by the addition (250 μΒ) of the pre-incubated RGS to the pre-incubated microsome/VRT/PB mixture (pre-incubation in both instances was fox* 10 minutes at 37 °C). Samples were incubated 'within Eppendorf vials (1.5 ml) on a heater shaker (DPC Micromix 5 (settings; form 20, amplitude 4) modified to be heated, to 37 °C, by two plate heaters fixed to the deck and controlled by a Packard Manual Heater) attached to a Multiprobe II HT Ex automated liquid handler. The liquid handler was programmed (WinPREP software) to sample the microsomal incubation mixture after 0, 2, 10, 30 and 60 minutes of incubation and transfer an aliquot (100 μΒ) to a stop block (96-well block) containing 100 μΒ of chilled methanol. The % organic in the stop mixture was optimized for analysis by addition of appropriate volumes of aqueous/organic (typically 100 μΒ of 50:50 methanol: water).

[00303] Prior to analysis the stop block was placed on a shaker (DPC Micromix 5; 10 min, form 20, amplitude 5) to precipitate out proteins. The block was then centrifuged (Jouan GR412; 2000 rpm, 15 min, 4 °C). A sample aliquot (200 μΒ) was then transferred to an analysis block and the block was centrifuged again (Jouan GR412; 2000 rpm, 5 min, 4 °C) prior to being sent for analysis. Depletion profiles were determined by monitoring the disappearance of VRT by liquid chromatography-tandem, mass spectrometry (LC-MS/MS). Samples were injected (20 μΒ; Agilent 1100 liquid chromatographic system equipped with autosampler) onto an analytical column. Mobile phase consisted of Water + 0.05% (v/v) formic acid (A) and methanol + 0.05% (v/v) formic acid (B).

[00304] Running a gradient method optimized for the compound of interest carried out the compound elution from analytical column. The total run time was 6 minutes with a flow rate of

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0.35 mL/min. The entire column effluent entered, the electrospray ionization source (positive mode) of a Micromass Quattro L>C tandem mass spectrometer between 0.5 and 5.9 min of the run. The mass spectrometry was optimized for the compound of interest. All incubations were conducted in duplicate and results were expressed as % parent remaining at either 30 minutes or 60 minutes relative to 0 minutes sample.

[00305] Compounds 5, 7, 9-17, 20-22, 25-35, 37-40, 44,

48-50, 52-61, 64-66, 68-69, 71, 75-76, 78-80, 82-83, 85,

87-99, 94, 97, 99-100, 102-105, 108-110, 112-117, 120-121,

126-128, 132, 134-135, 137-139, 142, 144-146, 148-153, 155, 159-163, 166-173, 175, 177-178, 180-181, 183-184, 186, 188, 190-192, 194-195, 199-200, 202, 205-206, 209, and 211 were found to have stability to human liver microsomes at > 50%

<td colspan="2"> remain!</td><td> ng after 30</td><td colspan="2"> minutes .</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2"> [00306]</td><td> Compounds</td><td> 5,</td><td> 7, 9,</td><td> 12-</td><td> 14,</td><td> 16,</td><td> 18,</td><td> 31,</td><td> 33,</td><td> 36</td><td> , 37,</td>

194, and 202 were found to have stability to human liver microsomes at > 50% remaining after 60 minutes.

Example 37; Analysis of cell proliferation and viability [00307] Compounds were screened for their ability to inhibit cell proliferation and their effects on cell viability using Colo205 cells obtained from ECACC and using the assay shown below.

[00308] Colo205 cells were seeded in 96 well plates and serially diluted compound was added to the wells in duplicate. Control groups included untreated cells, the compound diluent (0.1% DMSO alone) and culture medium without cells. The cells were then incubated for 72 or 96 hrs at 37C in an atmosphere of 5% CO2/95% humidity.

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2013201630 19 Mar 2013 [00309] To measure proliferation, 3 h prior to the end of the experiment 0.5 pci of 3H thymidine was added to each well. Cells were then harvested and the ineox-porated radioactivity counted on a Wallac microplate beta-counter, Cell viability was assessed using Promega CellTiter 96AQ to measure MTS conversion. Dose response curves were calculated using either Prism 3.0 (GraphPad) · or SoftMax Pro 4.3.1 LS (Molecular Devices) software.

Hours Incubation [00310] The following compounds were incubated for 72 hours and were found to have an IC50 value of _< 0.03 uM; Compounds 50-51, 81, 85, 89, 97, 113, 118, 133, 135, 143-144, 146, 157, 159-160, 170, 172, 176, 182-183, 185, 187, 191, 194, 196, 1.98-199, 204-205, and 211.

[00311] The following compounds were incubated for 72 hours and were found, to have an IC50 value > 0.03 uM and < 0.20 uM:

<td> Compounds 5, 16, 40, 56,</td><td> 83,</td><td> 87, 103,</td><td> 115,</td><td> 119, 121-123,</td>

[00312] The following compounds were incubated for 72 hours and were found to have an TC50 value > 0.20 uM: Compounds 59, 112, 114, 116-117, 120, 124-125, 129, 131-132, 136, 141, 145,

148-150, 158, 174-175, 188-189, 192-193, 197, 200, 206-207,

209-210.

Hours Incubation [00313] The following compounds were incubated for 96 hours and were found to have an IC50 value of < 0.05 uM: Compounds 7, 12, 38, 50-51, 56, 70-71, 78, 80-81, 84-85, 88-90, 92, 9596, 99-105, 107, 110-111, 128, 135, 153, 155, 157, and. 164.

[00314] The following compounds were incubated for 96 hours and were found to have an IC50 value of > 0.05 uM and < 1.0 UM: Compounds 1-2, 4-6, 8-9, 11, 13-18, 20, 28-37, 39-46, 48,

52-55, 57-61, 64-68, 76-77, 79, 86, 93-94, 98, 106, 109, 132,

137-140, 154, 156, 1.61-163, 165, and 201.

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2013201630 19 Mar 2013 [00315] The following compounds were incubated for 96 hours and were found to have an IC50 value of > 1.0 uM: Compounds 3, 19, 21-27, 47, 49, 62-63, 72-74, 97, 108, 166, and 167.

Example 38: Abl Kinase Activity Inhibition Assay and Determination of the Inhibition Constant Ki [00316] Compounds were screened for their ability to inhibit N~terminally truncated (Δ 27) Abl kinase activity using a standard coupled enzyme system (Fox et al., Protein Sci., 7, pp. 2249 (1998)). .Reactions were carried out in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgC12, 25 mM NaCl, 300 μΜ NADH, 1 mM DTT and 3% DMSO. Final substrate concentrations in the assay were 110 μΜ ATP (Sigma Chemicals, St'Louis, MO) and 70 μΜ peptide (EAT YAAP FAKKK, American Peptide, Sunnyvale, CA). Reactions were carried out at 30 °C and 21 nM Abl kinase. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 200 μΜ NADH, SO pg/ml pyruvate kinase and 20 pg/ml lactate dehydrogenase.

[00317] An assay stock buffer· solution was prepared containing all of the reagents .listed above with the exception of ATP and the test compound of interest. The assay stock buffer solution (60 μΐ) was incubated in a 96 well plate with 2 μΐ of the test compound of interest at final concentrations typically spanning 0,002 μΜ to 30 μΜ at 30 °C for 10 min. Typically, a 12 point titration was prepared by serial dilutions (from 1 mM compound stocks) with DMSO of the test compounds in daughter plates. The reaction was initiated by the addition of 5 μΐ of ATP (final concentration 110 μΜ). Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at 30 °C. The Ki values were determined from the residual rate data as a function of inhibitor concentration, using nonlinear regression (Prism 3.0, Graphpad Software, San Diego, CA).

- 158 WO 2007/056221

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2013201630 19 Mar 2013

Example 39; Mutant Abl Kinase (T3151) Activity inhibition Assay and Determination of the Inhibition Constant IC50 [00318] Compounds were screened for their ability to inhibit the T315I mutant form of human Abl at Upstate Cell Signaling Solutions (Dundee, UK). In a final reaction volume of 25 μΐ, the T315I mutant of human Abl (5-10 mU) was incubated with 8 mM MOPS .pH 7.0, 0.2 mM EDTA, 50 μΜ EAIYAAPFAKKK, 10 mM Mg Acetate, [γ-^Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol, lOmM final assay concentration) and the test compound of interest at final concentrations over the range 0~4μπΜ. The reaction was initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped, by the addition of 5 μΐ of a 3% phosphoric acid solution. 10 μΐ of the reaction was then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting, Inhibition IC50 values were determined from non-linear regression analysis of the residual enzyme activities as a function of inhibitor concentration (Prism 3.0, Graphpad Software, San Diego, CA).

Example 40: Plk4 Inhibition Assay:

[00319] Compounds were screened for their ability to inhibit Plk4 using a radioactive-phosphate incorporation assay.

Assays were carried out in a mixture of 8mM MOPS (pH 7.5), lOmM MgCl2, 0.1% BSA and 2mM DTT. Final substrate concentrations were 15μΜ [γ~33Ρ]ΑΤΡ (227mCi 3 3P ATP/ mmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 300μΜ peptide (KKKMDATFADQ) . Assays were carried out at 25 °C in the presence of 25nM Plk4. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test, compound of interest. 30pL of the stock solution was placed in a 96 well plate followed by addition of 2μΕ of DMSO stock containing serial dilutions of

159

2013201630 11 Feb 2016 the test compound (typically starting from a final concentration of ΙΟμΜ with 2-fold serial dilutions) in duplicate (final DMSO concentration 5%). The plate was pre-incubated for 10 minutes at 25°C and the reaction initiated by addition of 8pL [ y-33P] ATP (final concentration 15μΜ).

The reaction was stopped after 180 minutes by the addition of lOOpL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with lOOpL 0.2M phosphoric acid prior to the addition of 125pL of the stopped assay mixture. The plate was washed with 4 x 200pL 0.2M phosphoric acid. After drying, lOOpL Optiphase 'SuperMix' liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac). After removinq mean backqround values for all of the data points, Ki(app) data were calculated from non-linear regression analysis of the initial rate data usinq the Prism software packaqe (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Dieqo California, USA).

[ 00320] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize or encompass the compounds, methods, and processes of this invention.

Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims.

[ 00321] Any discussion of the prior art throuqhout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common qeneral knowledqe of the field.

[ 00322] Unless the context clearly requires otherwise, the words comprise, comprisinq and the like, throuqhout the description and the claims, are to be construed in an inclusive sense as opposed to an exclusive sense, that is to say, in the sense of includinq, but not limited to.

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Every citation, both ways

Citations
Document	Relation	Office	Cited during
US2003225073A1	Cites	United States of America	Search report
WO2004000833A1	Cites	World Intellectual Property Organization (WIPO)	Search report
US2004224944A1	Cites	United States of America	Search report
WO2007041358A2	Cites	World Intellectual Property Organization (WIPO)	Search report
US20030225073	Cites	United States of America	–
US20040224944	Cites	United States of America	–
WO2004000833	Cites	World Intellectual Property Organization (WIPO)	–
WO2007041358	Cites	World Intellectual Property Organization (WIPO)	–

91 members in 18 offices

This recordMember, by publication datePriority claim8 more offices are in the list below

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Priority claims
Document	Office	Kind	Date
60732951	United States of America	–	2005-11-03
60733557	United States of America	–	2005-11-04
2006311797	Australia	A	2006-11-03

Members91

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AU2006311797A1	Australia	A1	2007-05-18
AU2006311830A1	Australia	A1	2007-05-18
AU2006311831A1	Australia	A1	2007-05-18
CA2627808A1	Canada	A1	2007-05-18
CA2627830A1	Canada	A1	2007-05-18
CA2627857A1	Canada	A1	2007-05-18
WO2007056163A2	World Intellectual Property Organization (WIPO)	A2	2007-05-18
WO2007056164A2	World Intellectual Property Organization (WIPO)	A2	2007-05-18
WO2007056221A2	World Intellectual Property Organization (WIPO)	A2	2007-05-18
TW200734327A	Taiwan Province of China	A	2007-09-16
TW200736249A	Taiwan Province of China	A	2007-10-01
TW200736250A	Taiwan Province of China	A	2007-10-01
AR056763A1	Argentina	A1	2007-10-24
AR056764A1	Argentina	A1	2007-10-24
US2007249031A1	United States of America	A1	2007-10-25
US2007259869A1	United States of America	A1	2007-11-08
WO2007056221A3	World Intellectual Property Organization (WIPO)	A3	2007-12-06
WO2007056164A3	World Intellectual Property Organization (WIPO)	A3	2007-12-13
AR057874A1	Argentina	A1	2007-12-26
US2008032963A1	United States of America	A1	2008-02-07
WO2007056163A3	World Intellectual Property Organization (WIPO)	A3	2008-03-27
KR20080066069A	Republic of Korea	A	2008-07-15
NO20082514L	Norway	L	2008-07-18
NO20082517L	Norway	L	2008-07-18
KR20080067693A	Republic of Korea	A	2008-07-21
KR20080067694A	Republic of Korea	A	2008-07-21
EP1948193A2	European Patent Office (EPO)	A2	2008-07-30
NO20082508L	Norway	L	2008-07-31
EP1951715A2	European Patent Office (EPO)	A2	2008-08-06
EP1954277A2	European Patent Office (EPO)	A2	2008-08-13
MX2008005717A	Mexico	A	2008-10-15
MX2008005814A	Mexico	A	2008-10-15
MX2008005818A	Mexico	A	2008-10-15
CN101316597A	China	A	2008-12-03
CN101316843A	China	A	2008-12-03
CN101321530A	China	A	2008-12-10
JP2009514880A	Japan	A	2009-04-09
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US7528142B2	United States of America	B2	2009-05-05
US2009181938A1	United States of America	A1	2009-07-16
RU2008122046A	Russian Federation	A	2009-12-10
RU2008122048A	Russian Federation	A	2009-12-10
RU2008122070A	Russian Federation	A	2009-12-10
ZA200804599B	South Africa	B	2010-03-31
ZA200804600B	South Africa	B	2010-06-30
ZA200804768B	South Africa	B	2010-07-28
US7767672B2	United States of America	B2	2010-08-03
US7820685B2	United States of America	B2	2010-10-26
US2010310675A1	United States of America	A1	2010-12-09
SG166827A1	Singapore	A1	2010-12-29
SG166828A1	Singapore	A1	2010-12-29
US2011020469A1	United States of America	A1	2011-01-27
RU2423361C2	Russian Federation	C2	2011-07-10
RU2427578C2	Russian Federation	C2	2011-08-27
BRPI0619704A2	Brazil	A2	2011-10-11
BRPI0619706A2	Brazil	A2	2011-10-11
BRPI0619708A2	Brazil	A2	2011-10-11
EP1948193A4	European Patent Office (EPO)	A4	2011-11-09
EP1951715A4	European Patent Office (EPO)	A4	2011-11-09
EP1954277A4	European Patent Office (EPO)	A4	2011-11-09
US8129399B2	United States of America	B2	2012-03-06
US2012142660A1	United States of America	A1	2012-06-07
RU2011112948A	Russian Federation	A	2012-10-10
RU2011118227A	Russian Federation	A	2012-11-10
CN101316843B	China	B	2013-01-02
NZ594385A	New Zealand	A	2013-02-22
AU2006311830B2	Australia	B2	2013-03-14
JP2013049731A	Japan	A	2013-03-14
AU2013201058A1	Australia	A1	2013-03-21
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AU2013201630A1	Australia	A1	2013-04-18
JP2013075904A	Japan	A	2013-04-25
NZ594383A	New Zealand	A	2013-05-31
CN103145702A	China	A	2013-06-12
JP5249770B2	Japan	B2	2013-07-31
JP5249771B2	Japan	B2	2013-07-31
EP1951715B1	European Patent Office (EPO)	B1	2013-09-04
US8557833B2	United States of America	B2	2013-10-15
JP5328361B2	Japan	B2	2013-10-30
AU2006311831C1	Australia	C1	2013-11-07
ES2435081T3	Spain	T3	2013-12-18
US8637511B2	United States of America	B2	2014-01-28
NZ606263A	New Zealand	A	2014-03-28
NZ606259A	New Zealand	A	2014-06-27
EP1948193B1	European Patent Office (EPO)	B1	2015-01-07
ES2533241T3	Spain	T3	2015-04-08
AU2016203378A1	Australia	A1	2016-06-23
AU2013201630B2This record	Australia	B2	2016-12-01
EP1954277B1	European Patent Office (EPO)	B1	2017-01-18

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