Spirocyclic molecules as protein kinase inhibitors

1. A compound of Formula I

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

the Ring A-Ring B portion is selected from the group consisting of

and each ring is unsubstituted or substituted by one or more R c ;

R 1 is independently chosen from hydrogen, C 1-12 alkyl, C 1-12 alkyl in which one carbon atom is replaced with Si, O, S atom, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —C(O)R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n OR 4 , —(CR 6 R 7 ) n C(O)NR 4 R 5 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 , and wherein each hydrogen in R 1 is unsubstituted or substituted by R c , or one of the hydrogen in R 1 is replaced with —P(O)(OR 9 ) 2 —;

R c is independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —NH 2 , —CN, SF 5 , —OH, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic ring) or —O—(CH 2 ) n (5-12 membered heteroaryl ring);

R 2 is selected from

wherein:

X is N or CR 12 ;

Ar is C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and Ar is unsubstituted or substituted by one or more R c groups;

is selected from C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, wherein

is unsubstituted or substituted by one, two or three R c groups;

R 3 is chosen from hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , SF 5 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 , and each hydrogen in R 3 is unsubstituted or substituted by R 8 ;

R c is independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —S(O) m R 4 , —S(O) 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n OR 4 , —(CR 6 R 7 ) n C(O)NR 4 R 5 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 ,

and wherein each hydrogen in R c is unsubstituted or substituted by R 8 , and wherein R c groups on adjacent atoms are uncombined or combine to form a C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring;

R 4 , R 5 , R 6 and R 7 are independently chosen from hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring;

or any two of R 4 , R 5 , R 6 and R 7 bound to the same nitrogen atom, together with the nitrogen to which they are bound, combine to form a 3 to 12 membered heteroalicyclic ring or a 5-12 membered heteroaryl ring or a 3 to 12 membered heteroalicyclic ring or a 5-12 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S;

or any two of R 4 , R 5 , R 6 and R 7 bound to the same carbon atom combine to form a C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring;

and each hydrogen in R 4 , R 5 , R 6 and R 7 is unsubstituted or substituted by R 8 , or two hydrogen atoms on the same carbon atom in R 4 , R 5 , R 6 and R 7 is unsubstituted or are an oxo substituent;

R 8 is independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —NH 2 , —CN, —OH, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic ring) or —O—(CH 2 ) n (5-12 membered heteroaryl ring); and each hydrogen in R 8 is unsubstituted or substituted by R 11 ;

R 9 is independently chosen from a C 1-12 alkyl, aryl, heteroaryl which is unsubstituted or substituted;

R 10 is independently chosen from a C 1-12 alkyl which is unsubstituted or substituted;

R 11 is independently chosen from halogen, C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic ring), —O—(CH 2 ) n (5-12 membered heteroaryl ring) or —CN, and each hydrogen in R 11 is unsubstituted or substituted by halogen, —OH, —CN, —C 1-12 alkyl which is unsubstituted, or partially halogenated or fully halogenated, —O—C 1-12 alkyl which is unsubstituted or partially halogenated or fully halogenated, or substituted with —CO;

R 12 is chosen from hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 , and each hydrogen in R 12 is unsubstituted or substituted by R 3 ;

R a and R b is independently chosen from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NCR 4 R 5 or —C(O)NR 4 R 5 ; and R a or R b are uncombined or together with the carbon to which they are attached to, R a or R b combine to form a 3-12 membered ring or a 3-12 membered ring which contains one or more heteroatom chosen from NR 4 , O, S, Si; or

R a and R b combine with a ring atom of Ar or a substituent of Ar to form a C 5-12 cycloalkyl, 5-12 membered heteroalicyclic ring fused to Ar; and each hydrogen in R a and R b is unsubstituted or substituted by R c ;

each m is independently 0, 1 or 2;

each n is independently 0, 1, 2, 3 or 4;

q is 1, 2, 3 or 4.

2. The method according to claim 1 , wherein

is selected from

or an aryl, bicyclic aryl, bicyclic heteroaryl, unsubstituted or substituted by one, two or three R c groups.

3. The compound of claim 1 , wherein said compound is selected from:

wherein:

R 1 is independently chosen from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —C(O)R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n OR 4 , —(CR 6 R 7 ) n C(O)NR 4 R 5 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 , and wherein each hydrogen in R 1 is unsubstituted or substituted by R c ;

X is N or CR 12 ;

Ar is C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and wherein Ar is unsubstituted or substituted by one or more R c groups;

R 3 is chosen from hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , SF 5 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 , and wherein each hydrogen in R 3 is unsubstituted or substituted by R 8 ;

R c is independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —S(O) m R 4 , —S(O) 2 NR 4 R 5 , —S(O) 2 OR 4 , SF 5 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n OR 4 , —(CR 6 R 7 ) n C(O)NR 4 R 5 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 , and wherein each hydrogen in R c is unsubstituted or substituted by R 8 , and wherein R c groups on adjacent atoms are uncombined or combine to form a C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring;

R 4 , R 5 , R 6 and R 7 is independently chosen from hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring; or any two of R 4 , R 5 , R 6 and R 7 bound to the same nitrogen atom, together with the nitrogen to which they are bound, combine to form a 3 to 12 membered heteroalicyclic ring or a 5-12 membered heteroaryl ring or a 3 to 12 membered heteroalicyclic ring or a 5-12 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S; or any two of R 4 , R 5 , R 6 and R 7 bound to the same carbon atom combine to form a C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring or 5-12 membered heteroaryl ring; and each hydrogen in R 4 , R 5 , R 6 and R 7 is unsubstituted or substituted by R 8 , or two hydrogen atoms on the same carbon atom in R 4 , R 5 , R 6 and R 7 is unsubstituted or an oxo substituent;

R 8 is independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —NH 2 , —CN, —OH, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic ring) or —O—(CH 2 ) n (5-12 membered heteroaryl ring); and each hydrogen in R 8 is unsubstituted or substituted by R 11 ;

R 11 is independently chosen from halogen, C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic ring), —O—(CH 2 ) n (5-12 membered heteroaryl ring) or —CN, and each hydrogen in R 11 is unsubstituted or substituted by halogen, —OH, —CN, —C 1-12 alkyl which is unsubstituted or partially halogenated or fully halogenated, —O—C 1-12 alkyl which is unsubstituted or partially halogenated or fully halogenated, or substituted with —CO;

R 12 is chosen from hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 , and each hydrogen in R 12 is unsubstituted or substituted by R 3 ;

R a and R b is independently chosen from hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NCR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) 2 R 5 or —C(O)NR 4 R 5 ; or together with the carbon to which they are attached to, R a or R b combine to form a 3-12 membered ring which may contains one or more heteroatom chosen from NR 4 , O, S, Si, or R a and R b combine with a ring atom of A or a substituent of A to form a C 3-12 cycloalkyl, a 3-12 membered heteroalicyclic ring, C 6-12 aryl or a 5-12 membered heteroaryl ring fused to A; and each hydrogen in R a and R b is unsubstituted or substituted by R c ;

each m is independently 0, 1 or 2;

each n is independently 0, 1, 2, 3 or 4;

q is 1, 2, 3 or 4;

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

4. The compound of claim 3 , wherein said compound is selected from:

5. The compound of claim 4 , wherein said compound has the formula:

6. The compound according to claim 1 , wherein

is selected from the group consisting of:

7. The compounds of claim 5 , wherein said compounds are:

(±)-5-(1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine;

(R)-5-(1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine;

(R)-5-(1-(7-azaspiro[3.5]nonan-2-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine;

(R)-5-(1-(2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine; and

(R)-5-(1-(6-azaspiro[3.5]nonan-2-yl)-1H-pyrazol-4-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine.

8. A composition comprising a combination of a compound of claim 1 and an additional anti-cancer agent.

9. A method treating a cancer in a patient in need thereof by administering to said patient a therapeutically effective amount of a compound of claim 1 , or the composition of claim 8 , wherein said cancer is selected from the group consisting of breast cancer, liver cancer, non-small-cell lung cancer, prostate cancer, and renal cell cancer.

10. The method of claim 9 , further comprising administering radiotherapy.