Claims for Patent: 8,680,111

Summary for Patent: 8,680,111

Title:	Macrocyclic derivatives for the treatment of diseases
Abstract:	The invention relates to compounds of formula (Φ) as further defined herein and to the pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof. The compounds and salts of the present invention inhibit anaplastic lymphoma kinase (ALK) and/or EML4-ALK and are useful for treating or ameliorating abnormal cell proliferative disorders, such as cancer.
Inventor(s):	Simon Bailey, Benjamin Joseph Burke, Michael Raymond Collins, Jingrong Jean Cui, Judith Gail Deal, Robert Louis Hoffman, Qinhua Huang, Ted William Johnson, Robert Steven Kania, John Charles Kath, Phuong Thi Quy Le, Michele Ann McTigue, Cynthia Louise Palmer, Paul Francis Richardson, Neal William Sach
Assignee:	Pfizer Corp SRL
Application Number:	US13/786,106
Patent Claims:	1. A compound of formula (V) wherein: A is a ring selected from C6-C12 aryl and 5-6 membered heteroaryl; R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl, wherein each hydrogen on said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —CN, —OR9, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; each R2 is independently selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, —S(O)tR7, —S(O)2NR7R8, —S(O)2OR7, —NO2, —(CR5R6)qNR7R8, —N(CR5R6)(CR5R6)qNR7R8, —OR7, —O(CR5R6)(CR5R6)qOR7, —O(CR5R6)(CR5R6)qR7, —CN, —C(O)R7, —OC(O)R7, —O(CR5R6)qR7, —NR7C(O)R8, —(CR5R6)qC(O)OR7, —(CR5R6)qNR7R8, —C(═NR7)NR7R8, —NR7C(O)NR7R8, —NR7S(O)2R8 and —(CR5R6)qC(O)NR7R8; wherein each hydrogen on said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —OR9, —CN, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; R3 and R4 are each independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, wherein each hydrogen on C1-C6 alkyl and C3-C6 cycloalkyl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —CN, —OR9, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; each R5 and R6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —CN, —OR9, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 and —C(O)NR9R10; wherein each hydrogen on said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —CN, —OR9, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; each R7 and R8 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —OR9, —CN, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; each R9 and R10 is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl; p is 0, 1, 2, 3 or 4; each q is independently 0, 1, 2 or 3; and each t is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1, wherein each R2 is independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, —S(O)tR7, —S(O)2NR7R8, —OR7, —O(CR5R6)(CR5R6)qOR7, —O(CR5R6)(CR5R6)qR7 and —CN; wherein each hydrogen on said C1-C6 alkyl and C3-C6 cycloalkyl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —OR9, —CN, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 and —C(O)NR9R10, or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1, wherein A is a ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrazole, imidazole, triazole, tetrazole, thiazole, isothiazole, oxazole and isoxazole, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, wherein R3 is methyl and R4 is hydrogen, or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1, wherein R1 is methyl, or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, wherein A is a pyrazole ring, or a pharmaceutically acceptable salt thereof. 8. The compound of claim 1, which is (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 10. A compound of formula (XV) wherein: A is a ring selected from C6-C12 aryl and 5-6 membered heteroaryl; R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl, wherein each hydrogen on said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —CN, —OR9, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; each R2 is independently selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, —S(O)tR7, —S(O)2NR7R8, —S(O)2OR7, —NO2, —(CR5R6)qNR7R8, —N(CR5R6)(CR5R6)qNR7R8, —OR7, —O(CR5R6)(CR5R6)qOR7, —O(CR5R6)(CR5R6)qR7, —CN, —C(O)R7, —OC(O)R7, —O(CR5R6)qR7, —NR7C(O)R8, —(CR5R6)qC(O)OR7, —(CR5R6)qNR7R8, —C(═NR7)NR7R8, —NR7C(O)NR7R8, —NR7S(O)2R8 and —(CR5R6)qC(O)NR7R8; wherein each hydrogen on said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —OR9, —CN, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; R3 is C1-C6 alkyl or C3-C6 cycloalkyl and R4 is hydrogen, wherein each hydrogen on C1-C6 alkyl or C3-C6 cycloalkyl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —CN, —OR9, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; each R5 and R6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —CN, —OR9, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 and —C(O)NR9R10; wherein each hydrogen on said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —CN, —OR9, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; each R7 and R8 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, —OH, —NH2, —S(O)tR9, —S(O)2NR9R10, —S(O)2OR9, —NO2, —OR9, —CN, —C(O)R9, —OC(O)R9, —NR9C(O)R10, —C(O)OR9, —C(═NR9)NR9R10, —NR9C(O)NR9R10, —NR9S(O)2R10 or —C(O)NR9R10; each R9 and R10 is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl; p is 0, 1, 2, 3 or 4; each q is independently 0, 1, 2 or 3; and each t is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 11. The compound of claim 10, wherein R1 is methyl, or a pharmaceutically acceptable salt thereof. 12. The compound of claim 10, wherein each R2 is independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, —S(O)tR7, —S(O)2NR7R8, —OR7, —O(CR5R6)(CR5R6)qOR7, —O(CR5R6)(CR5R6)qR7 and —CN, or a pharmaceutically acceptable salt thereof. 13. The compound of claim 10, wherein A is a pyrazole ring, or a pharmaceutically acceptable salt thereof. 14. The compound of claim 10, wherein R3 is methyl, or a pharmaceutically acceptable salt thereof. 15. The compound of claim 10, which is (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 16. A pharmaceutical composition comprising a compound of claim 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 17. A compound which is (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition comprising a compound of claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.