Carbonylamino pyrrolopyrazoles, potent kinase inhibitors

1. A compound of formula I,

wherein:

R 1 is ethyl, t-butyl, R, -L-(C 3 -C 12 cycloalkyl), -L-phenyl, -L-(5-12 member heteroaryl), -L-(3-12 member heterocyclyl) and -L-(C 3 -C 12 unsaturated nonaromatic carbocyclyl);

each R 2 and R 3 is independently H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 3 alkylene) m -(C 3 -C 12 cycloalkyl) or —(C 1 -C 6 perfluoroalkyl), and each R 2 and R 3 is optionally further substituted by 1-3 groups selected from halide, —CN, oxo, —OH, —NH 2 , C 1 -C 6 monoalkylamino and C 2 -C 8 dialkylamino; or R 2 and R 3 together with the carbon atom that R 2 and R 3 attach to, form a ring selected from 3-5 member nonaromatic carbocyclylene and 3-5 member heterocyclylene, and the said ring is optionally further substituted by 1-3 groups selected from C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl, oxo, —(C 1 -C 3 alkylene) m -halide, —(C 1 -C 3 alkylene) m -CN, —(C 1 -C 3 alkylene) m -OH, —(C 1 -C 3 alkylene) m -NH 2 , —(C 1 -C 3 alkylene) m -(C 1 -C 6 monoalkylamino) and —(C 1 -C 3 alkylene) m -(C 2 -C 8 dialkylamino);

R 4 is selected from —OR 5 , —O—R 6 —R 7 , —O—CH(R 8 )R 9 , —N(R t )—R 6 —R 7 , —N(R t )CH(R 8 )R 9 , —CH(R t )—R 6 —R 7 , —CH(R t )—CH(R 8 )—R 9 , —B—(C 1 -C 3 alkylene)-CH(R 8 )R 9 and —B—(C 1 -C 3 alkylene) m -CH(R 10 )R 9 , and B is —O—, —N(R t )— or —CH(R t )—;

R 5 is R;

R 6 is a divalent radical selected from —(C 3 -C 7 cycloalkylene)-, -(3 to 7 member heterocyclylene)- and -(5 to 7 member heteroarylene)-, provided when R 4 is —CH 2 —R 6 —R 7 and R 7 is unsubstituted phenyl, R 6 is not unsubstituted thiazolylene; R 6 is optionally further substituted by 1-4 groups selected from C 1 -C 3 alkyl, oxo, C 1 -C 3 perfluoroalkyl, —(C 1 -C 3 alkylene) m -halide, —(C 1 -C 3 alkylene) m -(C 1 -C 3 alkylamino), —(C 1 -C 3 alkylene) m -NH 2 , —(C 1 -C 3 alkylene) m -OH and —(C 1 -C 3 alkylene) m -(C 1 -C 3 alkoxy);

R 7 is selected from phenyl, C 10 -C 12 aryl, C 3 -C 12 cycloalkyl, C 4 -C 12 unsaturated nonaromatic carbocyclyl, 3-12 member heterocyclyl and 5-12 member heteroaryl;

R 8 is —(C 1 -C 6 alkylene) n -NR q R q , wherein each R p and R q is independently H or C 1 -C 6 alkyl, or R p and R q , together with the nitrogen atom which R p and R q attach to, form a ring selected from 3-7 member heterocyclyl and 5-7 member heteroaryl, and the said ring is optionally further substituted by 1-6 groups selected from halide, C 1 -C 3 alkyl, oxo and C 1 -C 3 perfluoroalkyl;

R 9 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 perfluoroalkyl, phenyl, -(L 1 )-phenyl, C 10 -C 12 aryl, -(L 1 )-(C 10 -C 12 aryl), C 3 -C 12 cycloalkyl, -(L 1 )—(C 3 -C 12 cycloalkyl), C 4 -C 12 unsaturated nonaromatic carbocyclyl, -(L 1 )-(C 4 -C 12 unsaturated nonaromatic carbocyclyl), 3-12 member heterocyclyl, -(L 1 )-(3-12 member heterocyclyl), 5-12 member heteroaryl and -(L 1 )-(5-12 member heteroaryl);

R 10 is selected from C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, —(C 1 -C 6 alkylene) m -(C 1 -C 6 alkoxyl), —(C 1 -C 6 alkylene) m -(CONR j R k ) wherein each R j and R k is independently H or C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl) and —(C 1 -C 3 alkylene) m -(3 to 6 member heterocyclyl), and R 10 is optionally further substituted by 1-3 groups selected from halide, —OH, oxo and C 1 -C 3 alkyl, provided that when R 4 is —B—CH(R 10 )R 9 , B is NH or CH 2 and R 9 is unsubstituted —CH 3 or unsubstituted phenyl, R 10 is not unsubstituted CH 3 ;

each R is independently selected from the group consisting of methyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, C 5 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 3 alkylene) m -(C 3 -C 12 cycloalkyl), —(C 1 -C 3 alkylene) m -phenyl, —(C 1 -C 3 alkylene) m -(5-12 member heteroaryl), —(C 1 -C 3 alkylene) m -(3-12 member heterocyclyl), —(C 1 -C 3 alkylene) m —(C 3 -C 12 unsaturated non-aromatic carbocyclyl), —(C 1 -C 6 perfluoroalkyl), —(C 1 -C 3 alkylene) m -halide, —(C 1 -C 3 alkylene) m -CN, —(C 1 -C 3 alkylene) m -C(O)R a , —(C 1 -C 3 alkylene) m -C(O)OR a , —(C 1 -C 3 alkylene) m -C(O)NR a R b , —(C 1 -C 3 alkylene) m -OR a , —(C 1 -C 3 alkylene) m -OC(O)R a , —(C 1 -C 3 alkylene) m -OC(O)NR a R b , —(C 1 -C 3 alkylene) m -O—S(O)R a , —(C 1 -C 3 alkylene) m -OS(O) 2 R a , —(C 1 -C 3 alkylene) m -OS(O) 2 NR a R b , —(C 1 -C 3 alkylene)-(C 1 -C 3 alkylene) m -N 2 , —(C 1 -C 3 alkylene) m -NR a R b , —(C 1 -C 3 alkylene) m -N(R a )C(O)R b , —(C 1 -C 3 alkylene) m -N(R a )C(O)OR b , —(C 1 -C 3 alkylene) m -N(R c )C(O)NR a R b , —(C 1 -C 3 alkylene) m -N(R a )S(O) 2 R b , (C 1 -C 3 alkylene) m -N(R a )S(O)R b , —(C 1 -C 3 alkylene) m -SR a , —(C 1 -C 3 alkylene) m -S(O)R a , —(C 1 -C 3 alkylene) m -S(O) 2 R a , —(C 1 -C 3 alkylene) m -S(O)NR a R b , —(C 1 -C 3 alkylene) m -S(O) 2 NR a R b , —(C 1 -C 3 alkylene) m -O—(C 1 -C 3 alkylene) m -NR a R b and —(C 1 -C 3 alkylene) m -NR a -(C 1 -C 3 alkylene)-OR b ; the said C 3 -C 12 cycloalkyl, the said phenyl, the said 3-12 member heterocyclyl and the said 5-12 member heteroaryl are independently optionally further substituted by 1-3 groups selected from —F, C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl and oxo;

each R a , R b and R c is independently H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 8 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 3 -C 8 cycloalkenyl), C 2 -C 8 alkynyl, —(C 1 -C 3 alkylene) m -phenyl, —(C 1 -C 3 alkylene) m -(5-7 member heteroaryl) or —(C 1 -C 3 alkylene) m -(3-8 member heterocyclyl), and each R a , R b and R c is independently optionally further substituted by 1-3 groups selected from halide, hydroxyl, —CN, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, C 1 -C 6 alkoxyl and C 1 -C 6 alkylamino; or, when connected to the same nitrogen, R a and R b may optionally form a ring selected from -(5-7 member heteroaryl) and -(3-8 member heterocyclyl), and the said ring is optionally further substituted by 1-3 groups selected from halide, hydroxyl, —CN, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, C 1 -C 6 alkoxyl and C 1 -C 6 alkylamino;

each R t is independently H or C 1 -C 3 alkyl;

each R 1 , R 5 , R 7 and R 9 is independently optionally further substituted by 1-6 groups selected from oxo and R x ;

each R x is independently ethyl, t-butyl or R;

each L is independently a bivalent radical selected from —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkylene)-, —(C 2 -C 8 alkenylene)-, —(C 2 -C 8 alkynylene)-, —O—(C 1 -C 3 alkylene) m - and —NH—(C 1 -C 3 alkylene) m -;

each L 1 is independently a bivalent radical selected from —(C 1 -C 3 alkylene)-, —O—, —(C 1 -C 3 alkylene)-O—, —N(R t )— and —(C 1 -C 3 alkylene)-N(R t )—; and

each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted methyl and R 3 is unsubstituted methyl.

3. The compound of claim 2 , or a pharmaceutically acceptable thereof, wherein R 1 is selected from the group consisting of C 1 -C 8 alkyl, —(C 1 -C 3 alkylene) m -phenyl, —(C 3 -C 7 cycloalkylene)-phenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 12 cycloalkyl), —(C 3 -C 7 cycloalkylene)-(C 3 -C 12 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 3 -C 12 unsaturated nonaromatic carbocyclyl), —(C 3 -C 7 cycloalkylene)-(C 3 -C 12 unsaturated nonaromatic carbocyclyl)-(C 1 -C 3 alkylene) m -(5-10 member heteroaryl), —(C 3 -C 7 cycloalkylene)-(5-10 member heteroaryl), —(C 1 -C 3 alkylene) m -(3-10 member heterocyclyl) and —(C 3 -C 7 cycloalkylene)-(3-10 member heterocyclyl), and R 1 is optionally further substituted by 1-6 groups selected from the group consisting of C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 5 cycloalkyl), —(C 1 -C 3 alkylene) m -(3-6 member heterocyclyl optionally further substituted by 1-2 methyl), F, Cl, —CN, C 1 -C 3 perfluoroalkyl, —(C 1 -C 3 alkylene) m -NH 2 , —(C 1 -C 3 alkylene) m -NH(C 1 -C 4 alkyl), —(C 1 -C 3 alkylene) m -N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —(C 1 -C 3 alkylene) m -NH—(C 3 -C 5 cycloalkyl)-(C 1 -C 3 alkylene) m -OH, —(C 1 -C 3 alkylene) m -O—(C 1 -C 4 alkyl), —(C 1 -C 3 alkylene) m -O—(C 3 -C 5 cycloalkyl), —(C 1 -C 3 alkylene) m -C(O)—NH 2 , —(C 1 -C 3 alkylene) m -C(O)—NH—(C 1 -C 4 alkyl) and —(C 1 -C 3 alkylene) m -C(O)—N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl).

4. The compound of claim 2 , or a pharmaceutically acceptable thereof, wherein R 1 is selected from the group consisting of C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, phenyl, —(C 1 -C 3 alkylene)-phenyl, -(cyclopropylene)-phenyl, -pyridinyl, —(C 1 -C 3 alkylene)-pyridinyl, —(cyclopropylene)-pyridinyl, -pyrimidinyl, —(C 1 -C 3 alkylene)-pyrimidinyl, -(cyclopropylene)-pyrimidinyl, thiophenyl, —(C 1 -C 3 alkylene)-thiophenyl, -(cyclopropylene)-thiophenyl, pyrazolyl, —(C 1 -C 3 alkylene)-pyrazolyl, -(cyclopropylene)-pyrazolyl, tetrahydrofuranyl, —(C 1 -C 3 alkylene)-tetrahydrofuranyl, —(C 1 -C 3 cyclopropylene)-tetrahydrofuranyl, tetrahydropyranyl, —(C 1 -C 3 alkylene)-tetrahydropyranyl, —(C 1 -C 3 cyclopropylene)-tetrahydropyranyl, morpholinyl, —(C 1 -C 3 alkylene)-morpholinyl, -(cyclopropylene)-morpholinyl, imidazolyl, —(C 1 -C 3 alkylene)-imidazolyl, -(cyclopropylene)-imidazolyl, thiazolyl, —(C 1 -C 3 alkylene)-thiazolyl, -(cyclopropylene)-thiazolyl, isothiazolyl, —(C 1 -C 3 alkylene)-isothiazolyl, -(cyclopropylene)-isothiazolyl, oxazolyl, —(C 1 -C 3 alkylene)-oxazolyl, -(cyclopropylene)-oxazolyl, isoxazolyl, —(C 1 -C 3 alkylene)-isoxazolyl, -(cyclopropylene)-isoxazolyl, benzothiophenyl, —(C 1 -C 3 alkylene)-benzothiophenyl, -(cyclopropylene)-benzothiophenyl, benzothiazolyl, —(C 1 -C 3 alkylene)-benzothiazolyl, -(cyclopropylene)-benzothiazolyl, dihydrobenzofuranyl, —(C 1 -C 3 alkylene)-dihydrobenzofuranyl, -(cyclopropylene)-dihydrobenzofuranyl, pyrazinyl, —(C 1 -C 3 alkylene)-pyrazinyl and -(cyclopropylene)-pyrazinyl, wherein R 1 is optionally further substituted by 1-3 groups selected from F, Cl, C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl and C 1 -C 3 alkoxyl.

5. A compound of formula II,

wherein:

B is —O—, —NR t — or —CHR t —, wherein R t is H or C 1 -C 3 alkyl;

R 1 is selected from the group consisting of C 1 -C 8 alkyl, —(C 1 -C 3 alkylene) m -phenyl, —(C 3 -C 5 cycloalkylene)-phenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 10 cycloalkyl), —(C 1 -C 3 alkylene) m —(C 5 -C 10 cycloalkenyl), —(C 1 -C 3 alkylene) m -(3-10 member heterocyclyl), —(C 3 -C 5 cycloalkylene)-(3-10 member heterocyclyl), —(C 1 -C 3 alkylene) m -(5-12 member heteroaryl) and —(C 3 -C 5 cycloalkylene)-(5-12 member heteroaryl), and R 1 is optionally further substituted by 1-6 groups selected from —(C 1 -C 3 alkylene) m -halide, —(C 1 -C 3 alkylene) m -hydroxyl, —(C 1 -C 3 alkylene) m -CN, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, —(C 1 -C 3 alkylene) m -(C 1 -C 6 alkoxyl), —(C 1 -C 3 alkylene) m -NH 2 , —(C 1 -C 3 alkylene) m -(C 1 -C 6 alkylamino), —(C 1 -C 3 alkylene) m -(C 3 -C 5 cycloalkyl) and —(C 1 -C 3 alkylene) m -(3-5 member heterocyclyl), and the said C 3 -C 5 cycloalkyl and the said 3-5 member heterocyclyl is optionally further substituted by 1-3 group selected from —F, C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl and oxo;

each R 2 and R 3 is independently C 1 -C 3 alkyl, or R 2 and R 3 , together with the carbon atom that R 2 and R 3 attach to, form a C 3 -C 4 cycloalkylene;

R 6 is a divalent radical selected from cyclopropylene, cyclobutylene, cyclopentylene and -(3-6 member heterocyclylene)-, R 6 is optionally further substituted by 1-6 groups selected from halide, C 1 -C 3 alkyl, oxo and C 1 -C 3 perfluoroalkyl;

R 7 is selected from phenyl, 5 member heteroaryl, pyridinyl, 6 member heteroaryl containing 2-3 heteroatoms selected from N, S and 0, 7-10 member heteroaryl and 3-12 member heterocyclyl, R 7 is optionally further substituted by 1-6 groups selected from halide, —C 1 -C 3 perfluoroalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, —OH, —NH 2 and —CN;

each m is independently 0 or 1; or

a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , or a pharmaceutically acceptable thereof, wherein R 2 is methyl; R 3 is methyl; B is —O—, —NH— or —CH 2 —; R 1 is selected from the group consisting of C 1 -C 8 alkyl, phenyl, —(C 1 -C 3 alkylene)-phenyl, -(cyclopropylene)-phenyl, C 3 -C 10 cycloalkyl, —(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl), 3-10 member heterocyclyl, —(C 1 -C 3 alkylene)-(3-10 member heterocyclyl), -(cyclopropylene)-(3-10 member heterocyclyl), 5-12 member heteroaryl, —(C 1 -C 3 alkylene)-(5-12 member heteroaryl) and -(cyclopropylene)-(5-12 member heteroaryl), and R 1 is optionally further substituted by 1-6 groups selected from F, Cl, hydroxyl, CN, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl and —(C 1 -C 3 alkylene) m -(C 1 -C 6 alkoxyl).

7. The compound of claim 6 , or a pharmaceutically acceptable thereof, where R 6 is unsubstituted cyclopropylene.

8. The compound of claim 6 , or a pharmaceutically acceptable thereof, wherein R 6 is cyclopropylene substituted by 1-3 groups selected from F, Cl, C 1 -C 3 alkyl and C 1 -C 3 perfluoalkyl.

9. The compound of claim 6 , or a pharmaceutically acceptable thereof, wherein R 7 is selected from the group consisting of phenyl, 5-6 member heteroaryl and 4-7 member heterocyclyl, and R 7 is optionally further substituted by 1-3 groups selected from F, Cl, C 1 -C 3 alkyl, C 1 -C 3 perfluoalkyl and C 1 -C 3 alkoxyl.

10. A compound of formula III,

wherein:

B is —O—, —NR t — or —CHR t —, wherein R t is H or C 1 -C 3 alkyl;

R 1 is selected from C 1 -C 8 alkyl, —(C 1 -C 3 alkylene) m -phenyl, —(C 3 -C 5 cycloalkylene)-phenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 10 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 5 -C 10 cycloalkenyl), —(C 1 -C 3 alkylene) m -(3-10 member heterocyclyl), —(C 3 -C 5 cycloalkylene)-(3-10 member heterocyclyl), —(C 1 -C 3 alkylene) m -(5-12 member heteroaryl) and —(C 3 -C 5 cycloalkylene)-(5-12 member heteroaryl), and R 1 is optionally further substituted by 1-6 groups selected from —(C 1 -C 3 alkylene) m -halide, —(C 1 -C 3 alkylene) m -hydroxyl, —(C 1 -C 3 alkylene) m -CN, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, —(C 1 -C 3 alkylene) m -(C 1 -C 6 alkoxyl), —(C 1 -C 3 alkylene) m -NH 2 , —(C 1 -C 3 alkylene) m -(C 1 -C 6 alkylamino), —(C 1 -C 3 alkylene) m -(C 3 -C 5 cycloalkyl) and —(C 1 -C 3 alkylene) m -(3-5 member heterocyclyl), and the said C 3 -C 5 cycloalkyl and the said 3-5 member heterocyclyl is optionally further substituted by 1-3 group selected from —F, C 1 -C 3 alkyl, C 1 -C 3 perfluoroalkyl and oxo;

each R 2 and R 3 is independently C 1 -C 3 alkyl, or R 2 and R 3 , together with the carbon atom that R 2 and R 3 attach to, form a C 3 -C 4 cycloalkylene;

R 8 is —(C 1 -C 6 alkylene) m -NR p R q , wherein each R p and R q is independently H, C 1 -C 3 alkyl, or R p and R q , together with the nitrogen atom they attach to, form a ring selected from 3-7 member heterocyclyl and 5-7 member heteroaryl, the said ring is optionally further substituted by 1-6 groups selected from halide, C 1 -C 3 alkyl and C 1 -C 3 perfluoroalkyl;

R 9 is selected from C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, phenyl, —(C 1 -C 3 alkylene)-phenyl, C 10 -C 12 aryl, C 3 -C 12 cycloalkyl, —(C 1 -C 3 alkylene)-(C 3 -C 12 cycloalkyl), C 4 -C 12 unsaturated nonaromatic carbocyclyl, —(C 1 -C 3 alkylene)-(C 4 -C 12 unsaturated nonaromatic carbocyclyl), 3-12 member heterocyclyl, —(C 1 -C 3 alkylene)-(3-12 member heterocyclyl), 5-12 member heteroaryl and —(C 1 -C 3 alkylene)-(5 to 12 member heteroaryl), and each R 9 is independently optionally further substituted by 1-6 groups selected from halide, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, —OH, C 1 -C 6 alkoxy, —(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy)-NH 2 , —(C 1 -C 6 alkylene)-NH 2 , —(C 1 -C 6 alkylene)-(C 1 -C 6 alkylamino), C 1 -C 6 alkylamino and CN; and

each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , or a pharmaceutically acceptable thereof, wherein R 2 is methyl; R 3 is methyl; B is —O—, —NH— or —CH 2 —; R 1 is selected from the group consisting of C 1 -C 8 alkyl, phenyl, —(C 1 -C 3 alkylene)-phenyl, -(cyclopropylene)-phenyl, C 3 -C 10 cycloalkyl, —(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl), 3-10 member heterocyclyl, —(C 1 -C 3 alkylene)-(3-10 member heterocyclyl), -(cyclopropylene)-(3-10 member heterocyclyl), 5-12 member heteroaryl, —(C 1 -C 3 alkylene)-(5-12 member heteroaryl) and -(cyclopropylene)-(5-12 member heteroaryl), and R 1 is optionally further substituted by 1-6 groups selected from F, Cl, hydroxyl, CN, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl and —(C 1 -C 3 alkylene) m -(C 1 -C 6 alkoxyl).

12. The compound of claim 11 , or a pharmaceutically acceptable thereof, wherein R 8 is —(C 1 -C 6 alkylene) m -NR p R q , wherein each R p and R q is independently H or C 1 -C 3 alkyl.

13. The compound of claim 12 , or a pharmaceutically acceptable thereof, wherein R 8 is selected from —CH 2 —N—(CH 3 ) 2 , —CH 2 —NH—CH 3 and —CH 2 —NH 2 .

14. The compound of claim 11 , or a pharmaceutically acceptable thereof, wherein R 8 is —(C 1 -C 6 alkylene) m -NR p R q , and R p and R q , together with the nitrogen atom they attach to, form a 3-7 member heterocyclyl, the said 3-7 member heterocyclyl is optionally further substituted by 1-6 groups selected from halide, C 1 -C 3 alkyl and C 1 -C 3 perfluoroalkyl.

15. The compound of claim 11 , or a pharmaceutically acceptable thereof, wherein R 9 is selected from the group consisting of C 1 -C 8 alkyl, phenyl, —(C 1 -C 3 alkylene)-phenyl, 5-6 member heteroaryl and 3-7 member cycloalkyl, and R 9 is optionally further substituted with 1-6 groups selected from F, Cl, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, —OH, C 1 -C 6 alkoxy, —(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy) and CN.

16. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

17. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

18. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20. A method to treat abnormal cell growth in a mammal, comprising administering to the mammal the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

21. A method of inhibiting a PAK4 protein kinase comprising contacting the PAK4 kinase with the compound of claim 1 or with a pharmaceutically acceptable salt thereof.

22. A compound of the formula

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising the compound of claim 22 , or a pharmaceutically acceptable salt thereof.