Claims for Patent: 9,545,405

Summary for Patent: 9,545,405

Title:	Pyrrolo[2,3-D]pyrimidine derivatives
Abstract:	Described herein are pyrrolo{2,3-d}pyrimidine derivatives, their use as Janus Kinase (JAK) inhibitors, and pharmaceutical compositions containing them.
Inventor(s):	Matthew Frank Brown, Ashley Edward Fenwick, Mark Edward Flanagan, Andrea Gonzales, Timothy Allan Johnson, Neelu Kaila, Mark J. Mitton-Fry, Joseph Walter Strohbach, Ruth E. TenBrink, John David Trzupek, Rayomand Jal Unwalla, Michael L. Vazquez, Mihir D. Parikh
Assignee:	Pfizer Corp SRL
Application Number:	US14/691,606
Patent Claims:	1. A compound of formula I having the structure: or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or C1-C4 alkyl, wherein said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl; X is selected from —NH— and —CRaRb—, where (a) Ra and Rb are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (aryl)C1-C6 linear or branched chain alkyl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, (heteroaryl)C1-C6 linear or branched chain alkyl, (heterocyclic)C1-C6 linear or branched chain alkyl, or (b) Ra and Rb together form a chain comprising —(CRcRd)j—, where Rc and Rd are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, CF3, hydroxyl, CONH2, or SO2CH3; Y is -A-R5, where A is a bond, —(CH2)k— or —(CD2)k- and R5 is C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, or —NRa′Rb′, or is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of four to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said alkyl, C3-C6 cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —ORe, —NReRf, —S(O)pRe and C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CONH2, and SO2CH3, where (a) Ra′ and Rb′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, or (C1-C6 linear or branched chain alkyl)heteroaryl, where said alkyl and cycloalkyl may be optionally substituted with one or more Rc′, or (b) Ra′ and Rb′ together form a chain comprising —(CRc′Rd′)j—, where Rc′ and Rd′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF3, CONH2, —ORe, —NReRf, or —S(O)pRe; where Re and Rf are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, or C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF3, and CONH2; j is 2, 3, 4 or 5; k is 1, 2; 3, or 4; p is 0, 1 or 2; and, n is 1 or 2. 2. The compound of claim 1 which is a compound of formula IA having the structure: or a pharmaceutically acceptable salt thereof, wherein Y is -A-R5, where A is a bond, —(CH2)k— or —(CD2)k- and R5 is C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, or —NRa′Rb′, or is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said alkyl, C3-C6 cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —ORe, —NReRf, —S(O)pRe and C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CONH2, and SO2CH3, where (a) Ra′ and Rb′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, or (C1-C6 linear or branched chain alkyl)heteroaryl, where said alkyl and cycloalkyl may be optionally substituted with one or more Rc′, or (b) Ra′ and Rb′ together form a chain comprising —(CRc′Rd′)j—, where Rc′ and Rd′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF3, CONH2, —ORe, —NReRf, or —S(O)pRe; where Re and Rf are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, or C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF3, and CONH2; j is 2, 3, 4 or 5; k is 1, 2; 3, or 4; and, p is 0, 1 or 2. 3. A compound of claim 2 wherein A is a bond and R5 is a C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl or aryl. 4. A compound of claim 2 wherein A is a bond or —(CH2)k—, and R5 is C3-C6 cycloalkyl wherein said C3-C6 cycloalkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 linear or branched chain alkyl, and CN where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CONH2, and SO2CH3; where k is 1, 2, or 3. 5. A compound of claim 2 wherein A is a bond or —(CH2)k—, and R5 is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said alkyl, C3-C6 cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —NRa′Rb′, —ORe, —S(O)pRe and C3-C6 cycloalkyl; where k is 1, 2, or 3. 6. The compound of claim 1 which is a compound of formula IB having the structure: or a pharmaceutically acceptable salt thereof, wherein (a) Ra′ and Rb′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, or (C1-C6 linear or branched chain alkyl)heteroaryl, where said alkyl and cycloalkyl may be optionally substituted with one or more Rc; (b) Ra′ and Rb′ together form a chain comprising —(CRc′Rd′)j—, where Rc′ and Rd′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF3, CONH2, —ORe, —NReRf, or —S(O)pRe; where Re and Rf are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, or C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF3, and CONH2; or, (c) Ra′ and Rb′ together form an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —NReRf, —ORe, —S(O)pRe and C3-C6 cycloalkyl; j is 2, 3, 4 or 5; and, p is 0, 1 or 2. 7. The compound of claim 1 which is a compound of formula IB having the structure: or a pharmaceutically acceptable salt thereof, wherein Ra′ and Rb′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, or (C1-C6 linear or branched chain alkyl)heteroaryl, where said alkyl and cycloalkyl may be optionally substituted with one or more Rc. 8. The compound of claim 1 which is a compound of formula IB having the structure: or a pharmaceutically acceptable salt thereof, wherein Ra′ and Rb′ together form a chain comprising —(CRc′Rd′)j—, where Rc′ and Rd′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF3, CONH2, —ORe, —NReRf, or —S(O)pRe; where Re and Rf are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, or C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF3, and CONH2; and, j is 2, 3, 4 or 5; and, p is 0, 1 or 2. 9. The compound of claim 1 which is a compound of formula IB having the structure: or a pharmaceutically acceptable salt thereof, wherein Ra′ and Rb′ together form an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —NReRf, —ORe, —S(O)pRe and C3-C6 cycloalkyl; and, p is 0, 1 or 2. 10. The compound of claim 1 which is a compound of formula IC having the structure: or a pharmaceutically acceptable salt thereof, wherein (a) Ra′ and Rb′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, or (C1-C6 linear or branched chain alkyl)heteroaryl, where said alkyl and cycloalkyl may be optionally substituted with one or more Rc; (b) Ra′ and Rb′ together form a chain comprising —(CRc′Rd′)j—, where Rc′ and Rd′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF3, CONH2, —ORe, —NReRf, or —S(O)pRe; where Re and Rf are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, or C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF3, and CONH2; or, (c) Ra′ and Rb′ together form an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —NReRf, —ORe, —S(O)pRe and C3-C6 cycloalkyl; j is 2, 3, 4 or 5; and, p is 0, 1 or 2. 11. The compound of claim 1 which is a compound of formula IC having the structure: or a pharmaceutically acceptable salt thereof, wherein Ra′ and Rb′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, or (C1-C6 linear or branched chain alkyl)heteroaryl, where said alkyl and cycloalkyl may be optionally substituted with one or more Rc. 12. The compound of claim 1 which is a compound of formula IC having the structure: or a pharmaceutically acceptable salt thereof, wherein Ra′ and Rb′ together form a chain comprising —(CRc′Rd′)j—, where Rc′ and Rd′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF3, CONH2, —ORe, —NReRf, or —S(O)pRe; where Re and Rf are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, or C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF3, and CONH2; j is 2, 3, 4 or 5; and, p is 0, 1 or 2. 13. The compound of claim 1 which is a compound of formula IC having the structure: or a pharmaceutically acceptable salt thereof, wherein Ra′ and Rb′ together form an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —NReRf, —ORe, —S(O)pRe and C3-C6 cycloalkyl; and, p is 0, 1 or 2. 14. The compound of claim 1 which is a compound of formula ID having the structure: or a pharmaceutically acceptable salt thereof, wherein Y is -AR5, where A is a bond or —(CH2)k—, and R5 is C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, or is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said alkyl, C3-C6 cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —NRa′Rb′, —ORe, —S(O)pRe and C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CONH2, and SO2CH3, where (a) Ra′ and Rb′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (aryl)C1-C6 linear or branched chain alkyl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, (heteroaryl)C1-C6 linear or branched chain alkyl, (heterocyclic)C1-C6 linear or branched chain alkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more Rc′, or (b) Ra′ and Rb′ together form a chain comprising —(CRc′Rd′)j—, where Rc′ and Rd′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF3, CONH2, —ORe, —NReRf, or —S(O)pRe; where Re and Rf where are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, or C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF3, and CON H2; j is 2, 3, 4 or 5; k is 1, 2, or 3; and, p is 0, 1 or 2. 15. The compound of claim 1 which is a compound of formula ID having the structure: or a pharmaceutically acceptable salt thereof, wherein Y is -AR5, where A is a bond or —(CH2)k—, and R5 is C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, or is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said alkyl, C3-C6 cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —NRa′Rb′, —ORe, —S(O)pRe and C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CON H2, and SO2CH3, where Ra′ and Rb′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, (aryl)C1-C6 linear or branched chain alkyl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, (heteroaryl)C1-C6 linear or branched chain alkyl, (heterocyclic)C1-C6 linear or branched chain alkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more Rc′, k is 1, 2, or 3; and, p is 0, 1 or 2. 16. The compound of claim 1 which is a compound of formula ID having the structure: or a pharmaceutically acceptable salt thereof, wherein Y is -AR5, where A is a bond or —(CH2)k—, and R5 is C1-C6 linear or branched chain alkyl, C3-C6 cycloalkyl, aryl, or is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said alkyl, C3-C6 cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C1-C6 linear or branched chain alkyl, CN, hydroxyl, CF3, —NRa′Rb′, —ORe, —S(O)pRe and C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CONH2, and SO2CH3, where Ra′ and Rb′ together form a chain comprising —(CRc′Rd′)j—, where Rc′ and Rd′ are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, aryl, (C1-C6 linear or branched chain alkyl)aryl, heteroaryl, (C1-C6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF3, CONH2, —ORe, —NReRf, or —S(O)pRe; where Re and Rf where are independently hydrogen, deuterium, C1-C6 linear or branched chain alkyl, or C3-C6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF3, and CONH2; j is 2, 3, 4 or 5; k is 1, 2, or 3; and, p is 0, 1 or 2. 17. The compound of claim 1 which is a compound of formula ID having the structure: or a pharmaceutically acceptable salt thereof, wherein Y is -AR5, where A is a bond or —(CH2)k—, and R5 is C1-C6 linear or branched chain alkyl, where said alkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, and SO2CH3; and, k is 1, 2, or 3. 18. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.