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Last Updated: August 13, 2020

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Claims for Patent: 8,680,111

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Summary for Patent: 8,680,111
Title:Macrocyclic derivatives for the treatment of diseases
Abstract: The invention relates to compounds of formula (.PHI.) ##STR00001## 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): Bailey; Simon (San Diego, CA), Burke; Benjamin Joseph (San Diego, CA), Collins; Michael Raymond (San Diego, CA), Cui; Jingrong Jean (San Diego, CA), Deal; Judith Gail (Wildomar, CA), Hoffman; Robert Louis (San Marcos, CA), Huang; Qinhua (San Diego, CA), Johnson; Ted William (Carlsbad, CA), Kania; Robert Steven (San Diego, CA), Kath; John Charles (La Mesa, CA), Le; Phuong Thi Quy (San Diego, CA), McTigue; Michele Ann (Encinitas, CA), Palmer; Cynthia Louise (La Mesa, CA), Richardson; Paul Francis (San Diego, CA), Sach; Neal William (San Diego, CA)
Assignee: Pfizer Inc. (New York, NY)
Application Number:13/786,106
Patent Claims: 1. A compound of formula (V) ##STR00233## wherein: A is a ring selected from C.sub.6-C.sub.12 aryl and 5-6 membered heteroaryl; R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl, wherein each hydrogen on said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --CN, --OR.sup.9, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; each R.sup.2 is independently selected from the group consisting of halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, --S(O).sub.tR.sup.7, --S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2OR.sup.7, --NO.sub.2, --(CR.sup.5R.sup.6).sub.qNR.sup.7R.sup.8, --N(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qNR.sup.7R.sup.8, --OR.sup.7, --O(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qOR.sup.7, --O(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qR.sup.7, --CN, --C(O)R.sup.7, --OC(O)R.sup.7, --O(CR.sup.5R.sup.6).sub.qR.sup.7, --NR.sup.7C(O)R.sup.8, --(CR.sup.5R.sup.6).sub.qC(O)OR.sup.7, --(CR.sup.5R.sup.6).sub.qNR.sup.7R.sup.8, --C(.dbd.NR.sup.7)NR.sup.7R.sup.8, --NR.sup.7C(O)NR.sup.7R.sup.8, --NR.sup.7S(O).sub.2R.sup.8 and --(CR.sup.5R.sup.6).sub.qC(O)NR.sup.7R.sup.8; wherein each hydrogen on said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --OR.sup.9, --CN, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; R.sup.3 and R.sup.4 are each independently selected from hydrogen, C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl, wherein each hydrogen on C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --CN, --OR.sup.9, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; each R.sup.5 and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --CN, --OR.sup.9, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 and --C(O)NR.sup.9R.sup.10; wherein each hydrogen on said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --CN, --OR.sup.9, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; each R.sup.7 and R.sup.8 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --OR.sup.9, --CN, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; each R.sup.9 and R.sup.10 is independently selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 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 R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein each R.sup.2 is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, --S(O).sub.tR.sup.7, --S(O).sub.2NR.sup.7R.sup.8, --OR.sup.7, --O(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qOR.sup.7, --O(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qR.sup.7 and --CN; wherein each hydrogen on said C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --OR.sup.9, --CN, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 and --C(O)NR.sup.9R.sup.10, 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 R.sup.3 is methyl and R.sup.4 is hydrogen, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein R.sup.1 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-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbo- nitrile, 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) ##STR00234## wherein: A is a ring selected from C.sub.6-C.sub.12 aryl and 5-6 membered heteroaryl; R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl, wherein each hydrogen on said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --CN, --OR.sup.9, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; each R.sup.2 is independently selected from the group consisting of halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, --S(O).sub.tR.sup.7, --S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2OR.sup.7, --NO.sub.2, --(CR.sup.5R.sup.6).sub.qNR.sup.7R.sup.8, --N(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qNR.sup.7R.sup.8, --OR.sup.7, --O(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qOR.sup.7, --O(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qR.sup.7, --CN, --C(O)R.sup.7, --OC(O)R.sup.7, --O(CR.sup.5R.sup.6).sub.qR.sup.7, --NR.sup.7C(O)R.sup.8, --(CR.sup.5R.sup.6).sub.qC(O)OR.sup.7, --(CR.sup.5R.sup.6).sub.qNR.sup.7R.sup.8, --C(.dbd.NR.sup.7)NR.sup.7R.sup.8, --NR.sup.7C(O)NR.sup.7R.sup.8, --NR.sup.7S(O).sub.2R.sup.8 and --(CR.sup.5R.sup.6).sub.qC(O)NR.sup.7R.sup.8; wherein each hydrogen on said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --OR.sup.9, --CN, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; R.sup.3 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl and R.sup.4 is hydrogen, wherein each hydrogen on C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --CN, --OR.sup.9, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; each R.sup.5 and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --CN, --OR.sup.9, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 and --C(O)NR.sup.9R.sup.10; wherein each hydrogen on said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --CN, --OR.sup.9, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; each R.sup.7 and R.sup.8 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, --OH, --NH.sub.2, --S(O).sub.tR.sup.9, --S(O).sub.2NR.sup.9R.sup.10, --S(O).sub.2OR.sup.9, --NO.sub.2, --OR.sup.9, --CN, --C(O)R.sup.9, --OC(O)R.sup.9, --NR.sup.9C(O)R.sup.10, --C(O)OR.sup.9, --C(.dbd.NR.sup.9)NR.sup.9R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10 or --C(O)NR.sup.9R.sup.10; each R.sup.9 and R.sup.10 is independently selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.6-C.sub.12 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 R.sup.1 is methyl, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10, wherein each R.sup.2 is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, --S(O).sub.tR.sup.7, --S(O).sub.2NR.sup.7R.sup.8, --OR.sup.7, --O(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qOR.sup.7, --O(CR.sup.5R.sup.6)(CR.sup.5R.sup.6).sub.qR.sup.7 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 R.sup.3 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-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbo- nitrile, 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-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbo- nitrile, 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.

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