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CN-122010947-A - Antagonists of adenosine A2a receptors

CN122010947ACN 122010947 ACN122010947 ACN 122010947ACN-122010947-A

Abstract

The present application relates to compounds having the formula I wherein R 0 、R 1 、R 2 、R 3 and A are each as defined in the application. The application also relates to processes for preparing these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with adenosine A2a receptor activity, such as cancer.

Inventors

  • CLIVE MCCARTHY
  • BENJAMIN MORTON

Assignees

  • 阿道尔克斯治疗有限公司

Dates

Publication Date
20260512
Application Date
20210506
Priority Date
20200507

Claims (17)

  1. 1. A compound, or a pharmaceutically acceptable salt thereof, having the structural formula I as shown below: Wherein: r 0 is hydrogen or deuterium; R 1 is selected from 3-cyanophenyl, furyl, oxazolyl, thiazolyl, isoxazolyl, or oxazolin-2-yl; r 2 is selected from cyano, halo, (1-4C) alkyl, (1-4C) haloalkyl, C (O) OR 2A 、C(O)NR 2A R 2B , phenyl, 5-OR 6-membered heteroaryl, (2-6C) alkenyl, (2-6C) alkynyl OR (1-4C) alkanoyl; Wherein R 2A and R 2B are each independently selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, or in the CONR 2A R 2B group, R 2A and R 2B are linked such that they together with the nitrogen atom to which they are attached form a 3 to 12 membered heterocyclic ring, and Wherein any alkyl, alkenyl, alkynyl, alkanoyl, phenyl, heteroaryl, or heterocyclyl group (formed from R 2A and R 2B ) is optionally substituted with one or more substituents independently selected from (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano 、(CH 2 ) q2 NR 2D R 2E 、(CH 2 ) q2 OR 2D 、(CH 2 ) q2 C(O)R 2D 、(CH 2 ) q2 C(O)OR 2D 、(CH 2 ) q2 OC(O)R 2D 、(CH 2 ) q2 C(O)N(R 2E )R 2D 、(CH 2 ) q2 N(R 2E )C(O)R 2D 、(CH 2 ) q2 S(O) p R 2D （ wherein p is 0, 1, or 2), (CH 2 ) q2 SO 2 N(R 2E )R 2D , or (CH 2 ) q2 N(R 2E )SO 2 R 2D ), wherein q2 is 0, 1, 2, or 3, and wherein R 2D and R 2E are each independently selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, or (3-6C) cycloalkyl (1-2C) alkyl; R 3 is selected from halo, cyano, or a group having the formula: -L-Y-L q -Q Wherein: L is (1-4C) alkylene which is absent or optionally substituted by one or more substituents selected from (1-2C) alkyl or oxo; Y is absent or O、S、SO、SO 2 、N(R a )、C(O)、C(O)O、OC(O)、C(O)N(R a )、C(O)N(R a )O、N(R a )C(O)、N(R a )C(O)N(R b )、N(R a )C(O)O、OC(O)N(R a )、C(=NR y )N(R a )、N(R a )C(=NR y )、N(R a )C(=NR y )N(R b )、S(O) 2 N(R a )、N(R a )SO 2 、N(R a )SO 2 N(R b ) or C (O) N (R a )SO 2 , wherein R a and R b are each independently selected from hydrogen or (1-4C) alkyl, and R y is selected from hydrogen, (1-4C) alkyl, nitro or cyano; L q is (1-4C) alkylene which is absent or is optionally substituted by one or more substituents selected from (1-2C) alkoxy, halo, cyano, amino or oxo, and Q is (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, phenyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, 5-or 6-membered heteroaryl, or 3-to 12-membered heterocyclyl; Wherein Q is optionally further substituted with one or more substituent groups independently selected from oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano 、NR c R d 、OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) p R c （ wherein p is 0, 1 or 2), SO 2 N(R d )R c 、N(R d )SO 2 R c , or (CH 2 ) q NR c R d wherein Q is 1, 2 or 3, wherein R c 、R d and R e are each independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, or (3-6C) cycloalkyl (1-2C) alkyl, or R c and R d are joined such that they together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring which is optionally substituted with one or more substituents selected from (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, di [ (1-4C) alkyl ] amino, cyano or hydroxy, and/or Q is optionally substituted with one or more groups having the formula: -L 1 -L Q1 -W 1 Wherein: L 1 is (1-3C) alkylene which is absent or optionally substituted by one or more substituents selected from (1-2C) alkyl or oxo; L Q1 is absent or selected from O、S、SO、SO 2 、N(R f )、C(O)、C(O)O、OC(O)、C(O)N(R f )、N(R f )C(O)、N(R f )C(O)N(R g )、N(R f )C(O)O、OC(O)N(R f )、S(O) 2 N(R f )、N(R f )SO 2 , wherein R f and R g are each independently selected from hydrogen or (1-2C) alkyl, and W 1 is hydrogen, (1-6C) alkyl, phenyl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, 5-or 6-membered heteroaryl, or 3-to 12-membered heterocyclyl, wherein W 1 is optionally substituted with one or more substituents selected from oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, cyano, phenyl, 5-or 6-membered heteroaryl, 3-to 12-membered heterocyclyl, (3-6C) cycloalkyl 、NR h R i 、OR h 、C(O)R h 、C(O)OR h 、OC(O)R h 、C(O)N(R i )R h 、N(R i )C(O)R h 、S(O) r R h （ wherein R is 0, 1, or 2), SO 2 N(R i )R h 、N(R i )SO 2 R h , or (CH 2 ) s NR i R h ) (wherein s is 1, 2, or 3), wherein R h and R i are each independently selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, or (3-6C) cycloalkyl (1-2C) alkyl; And wherein any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl in the substituent groups present on W 1 is optionally further substituted with one or more halo, (1-4C) alkyl, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, di [ (1-4C) alkyl ] amino, cyano or hydroxy groups, or R h and R i are joined such that they together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more substituents selected from oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, di [ (1-4C) alkyl ] amino, cyano or hydroxy; A is selected from CH and N, And wherein any tertiary amine in the compound having formula I is optionally in the form of an N-oxide and the nitrogen atom in the pyridine ring is optionally in the form of an N-oxide; And wherein any S atom present in the heterocycle may optionally be present as S (=o), S (=o) 2 or S (=o) (=nr z ), wherein R z is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl.
  2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is 3-cyanophenyl.
  3. 3. The compound of any one of the preceding claims, OR a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyano, halo, (1-4C) alkyl, (1-4C) haloalkyl, C (O) OR 2A 、C(O)NR 2A R 2B , phenyl, 5-OR 6-membered heteroaryl, (2-6C) alkenyl, (2-6C) alkynyl, OR (1-4C) alkanoyl; Wherein R 2A and R 2B are each independently selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, Or in the CONR 2A R 2B group, R 2A and R 2B are linked such that they form, together with the nitrogen atom to which they are attached, a 4-7 membered heterocyclic ring, and Wherein any alkyl, alkenyl, alkynyl, alkanoyl, phenyl, heteroaryl or heterocyclyl group (formed by R 2A and R 2B ) is optionally substituted with one or more substituents independently selected from (1-4C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano 、(CH 2 ) q2 NR 2D R 2E 、(CH 2 ) q2 OR 2D 、(CH 2 ) q2 C(O)R 2D 、(CH 2 ) q2 C(O)OR 2D 、(CH 2 ) q2 OC(O)R 2D 、(CH 2 ) q2 C(O)N(R 2E )R 2D 、(CH 2 ) q2 N(R 2E )C(O)R 12D 、(CH 2 ) q2 S(O) p R 2D （ wherein p is 0, 1 or 2), (CH 2 ) q2 SO 2 N(R 2E )R 2D or (CH 2 ) q2 N(R 2E )SO 2 R 2D , Wherein q2 is 0,1 or 2, and Wherein R 2D and R 2E are each independently selected from hydrogen, (1-2C) alkyl, (3-4C) cycloalkyl or (3-4C) cycloalkyl (1-2C) alkyl.
  4. 4. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyano, halo, methyl, CF 3 、C(O)OR 2A 、C(O)NR 2A R 2B , 5-or 6-membered heteroaryl, or (2-4C) alkanoyl, Wherein R 2A and R 2B are each independently selected from hydrogen or (1-4C) alkyl, Wherein any heteroaryl group is optionally substituted with one or more substituents independently selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano 、(CH 2 ) q2 NR 2D R 2E 、OR 2D 、C(O)R 2D 、C(O)OR 2D 、OC(O)R 2D 、C(O)N(R 2E )R 2D 、N(R 2E )C(O)R 12D 、S(O) p R 2D （ wherein p is 0, 1 or 2), SO 2 N(R 2E )R 2D , or N (R 2E )SO 2 R 2D wherein q2 is 0 or 1, and wherein R 2D and R 2E are each independently selected from hydrogen or (1-2C) alkyl.
  5. 5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyano or 5-or 6-membered heteroaryl, optionally substituted as defined above in any one of claims 3 or 4.
  6. 6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyano or a group having the formula: , Wherein: (i) R 200 and R 201 are each independently selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, (1-2C) alkanoyl or cyano; (ii) R 200 and R 201 are each independently selected from methyl, hydroxymethyl, halo, difluoromethyl, trifluoromethyl, methoxy, acetyl or cyano; (iii) R 200 is methyl or chloro and R 201 is selected from methyl, hydroxymethyl, halo, difluoromethyl, trifluoromethyl, methoxy, acetyl or cyano; Or alternatively , Wherein: (i) R 201 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) hydroxyalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, (1-2C) alkanoyl or cyano; (ii) R 201 is methyl, hydroxymethyl, halo, difluoromethyl, trifluoromethyl, methoxy, acetyl or cyano; (iii) R 201 is methyl, hydroxymethyl or chlorine; (iv) R 201 is methyl; (v) R 201 is chloro; optionally wherein R 2 is cyano or 2-chloro-6-methylpyridin-4-yl or 2, 6-dimethylpyridin-4-yl.
  7. 7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from halo, cyano, or a group having the formula: -L-Y-L q -Q Wherein: L is absent or (1-4C) alkylene; Y is absent or O、S、SO、SO 2 、N(R a )、C(O)、C(O)O、OC(O)、C(O)N(R a )、C(O)N(R a )O、N(R a )C(O)、N(R a )C(O)N(R b )、N(R a )C(O)O、OC(O)N(R a )、C(=NR y )N(R a )、N(R a )C(=NR y )、N(R a )C(=NR y )N(R b )、S(O) 2 N(R a )、N(R a )SO 2 、C(O)N(R a )SO 2 or N (R a )SO 2 N(R b ), wherein R a and R b are each independently selected from hydrogen or (1-4C) alkyl and R y is selected from hydrogen, (1-4C) alkyl, nitro or cyano; L q is (1-4C) alkylene which is absent or is optionally substituted by one or more substituents selected from (1-2C) alkoxy, halo, cyano, amino or oxo, and Q is hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, phenyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, 5-or 6-membered heteroaryl, or 3-to 12-membered heterocyclyl; Wherein Q is optionally further substituted with one or more substituent groups independently selected from oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano 、NR c R d 、OR c 、C(O)R c 、C(O)OR c 、OC(O)R c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) p R c （ wherein p is 0,1 or 2), SO 2 N(R d )R c 、N(R d )SO 2 R c or (CH 2 ) q NR c R d (wherein Q is 1,2 or 3), wherein R c and R d are each independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, and/or Q is optionally substituted with one or more groups having the formula: -L 1 -L Q1 -W 1 Wherein: l 1 is absent or (1-3C) alkylene; L Q1 is absent or selected from O、S、SO、SO 2 、N(R f )、C(O)、C(O)O、OC(O)、C(O)N(R f )、N(R f )C(O)、N(R f )C(O)N(R g )、N(R f )C(O)O、OC(O)N(R f )、S(O) 2 N(R f )、N(R f )SO 2 , wherein R f and R g are each independently selected from hydrogen or (1-2C) alkyl, and W 1 is hydrogen, (1-6C) alkyl, phenyl (1-2C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, 5-or 6-membered heteroaryl, or 3-to 12-membered heterocyclyl, wherein W 1 is optionally substituted with one or more substituents selected from oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, cyano, phenyl, 5-or 6-membered heteroaryl, 3-to 12-membered heterocyclyl, (3-6C) cycloalkyl 、NR h R i 、OR h 、C(O)R h 、C(O)OR h 、OC(O)R h 、C(O)N(R i )R h 、N(R i )C(O)R h 、S(O) r R h （ wherein R is 0, 1, or 2), SO 2 N(R i )R h 、N(R i )SO 2 R h , or (CH 2 ) s NR i R h ) (wherein s is 1, 2, or 3), wherein R h and R i are each independently selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, or (3-6C) cycloalkyl (1-2C) alkyl; And wherein any tertiary amine or nitrogen atom in the pyridine ring in the R 3 group is optionally in the form of an N-oxide.
  8. 8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from halo, cyano, or a group having the formula: -L-Y-L q -Q Wherein: L is absent or (1-2C) alkylene; Y is absent or O、N(R a )、C(O)、C(O)O、C(O)N(R a )、C(O)N(R a )O、N(R a )C(O)、N(R a )C(O)N(R b )、N(R a )C(O)O、OC(O)N(R a )、C(=NR y )N(R a )、N(R a )C(=NR y )、N(R a )C(=NR y )N(R b )、S(O) 2 N(R a )、N(R a )SO 2 、C(O)N(R a )SO 2 or N (R a )SO 2 N(R b ), wherein R a and R b are each independently selected from hydrogen or (1-4C) alkyl and R y is selected from hydrogen, (1-4C) alkyl, nitro or cyano; L q is (1-4C) alkylene which is absent or is optionally substituted by one or more substituents selected from (1-2C) alkoxy, halo, cyano, amino or oxo, and Q is hydrogen, (1-6C) alkyl, phenyl, (3-8C) cycloalkyl, 5-or 6-membered heteroaryl, or 3-to 12-membered heterocyclyl; Wherein Q is optionally further substituted with one or more substituent groups independently selected from oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano 、NR c R d 、OR c 、C(O)R c 、C(O)OR c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) p R c （ wherein p is 0,1 or 2), SO 2 N(R d )R c 、N(R d )SO 2 R c or (CH 2 ) q NR c R d wherein Q is1, 2 or 3, wherein R c and R d are each independently selected from hydrogen or (1-6C) alkyl, and/or Q is optionally substituted with one or more groups having the formula: -L 1 -L Q1 -W 1 Wherein: l 1 is absent or (1-2C) alkylene; L Q1 is absent, and W 1 is hydrogen, (1-6C) alkyl, phenyl (1-2C) alkyl, (3-8C) cycloalkyl, 5-or 6-membered heteroaryl, or 3-to 12-membered heterocyclyl, wherein W 1 is optionally substituted with one or more substituents selected from oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, cyano 、NR h R i 、OR h 、C(O)R h 、C(O)OR h 、OC(O)R h 、C(O)N(R i )R h 、N(R i )C(O)R h 、S(O) r R h （ wherein R is 0, 1, or 2, wherein R h and R i are each independently selected from hydrogen or (1-4C) alkyl; And wherein any tertiary amine or nitrogen atom in the pyridine ring in the R 3 group is optionally in the form of an N-oxide.
  9. 9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 is a group having the formula: -L-Y-L q -Q Wherein: l is absent; Y is N (R a ) or C (O) N (R a ); l q is absent, and Q is (1-6C) alkyl or (3-8C) cycloalkyl; Wherein Q is optionally further substituted with one or more substituent groups independently selected from halo, cyano 、NR c R d 、OR c 、C(O)R c 、C(O)OR c 、C(O)N(R d )R c 、N(R d )C(O)R c 、S(O) p R c （ wherein p is 0,1, or 2), SO 2 N(R d )R c 、N(R d )SO 2 R c , or (CH 2 ) q NR c R d wherein Q is 1, 2, or 3, wherein R c and R d are each independently selected from hydrogen or (1-6C) alkyl.
  10. 10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 is a group having the formula: , Wherein R 3a is hydrogen or methyl.
  11. 11. The compound of claim 1, having the formula: , , wherein A, R 0 、R 1 、R 2 、R 3 and R 1z are each as defined in any one of claims 1 to 10; m is 0, 1 or 2; R 200 and R 201 are each independently selected from hydrogen, methyl, hydroxymethyl or halo; Or a pharmaceutically acceptable salt thereof.
  12. 12. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following: 3- [ 5-amino-3- (4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ 5-amino-3- (1H-pyrazol-4-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- (5-amino-3-pyridazin-4-yl-pyrazolo [1,5-a ] pyrimidin-2-yl) benzonitrile; 3- [ 5-amino-3- (2-ethylpyrazol-3-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ 5-amino-3- (2-chloro-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ 5-amino-3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (2-hydroxy-2-methyl-propyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3-hydroxy-1-bicyclo [1.1.1] pentanyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (8-methyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; (3S) -4- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] morpholine-3-carboxylic acid; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (1-ethyl-4-piperidinyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3 s,4 s) -4-methoxy-1-methyl-pyrrolidin-3-yl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3R) -tetrahydrofuran-3-yl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [3- (hydroxymethyl) -4-methyl-piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3-hydroxyoxetan-3-yl) methylamino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3-hydroxy-3-methyl-butyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3-hydroxycyclobutyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (1-methylsulfonyl-4-piperidinyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] -2, 2-dimethyl-propionic acid; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (5-oxopyrrolidin-3-yl) methylamino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1S) -2-hydroxy-1, 2-dimethyl-propyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ rac- (3 r,4 r) -4-hydroxytetrahydrofuran-3-yl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (quinuclidin-3-ylamino) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3-hydroxycyclobutyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (2-morpholinoethylamino) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1R) -2-hydroxy-1, 2-dimethyl-propyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [2- [2- (dimethylamino) ethyl ] morpholin-4-yl ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1 r,2 s) -2-hydroxycyclobutyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (4H-1, 2, 4-triazol-3-ylmethylamino) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; (2R) -4- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] morpholine-2-carboxylic acid; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3S) -tetrahydrofuran-3-yl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (1-imino-1-oxo-1, 4-thiazinan-4-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (1, 1-dioxosulfan-4-yl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] acetamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5-piperazin-1-yl-pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [2- (dimethylamino) -1-methyl-ethyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5-hydroxy-pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (1H-imidazol-2-ylmethylamino) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5-morpholino-pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] azetidine-2-carboxylic acid; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] azetidine-3-carboxylic acid; (3R) -1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] pyrrolidine-3-carboxylic acid; 4- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] piperazine-1-sulfonamide; 3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] bicyclo [1.1.1] pentane-1-carboxylic acid; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (2R) -2-hydroxypropyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (2S) -2-hydroxypropyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [5- (tert-butylamino) -3- (2-chloro-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1R) -2-hydroxy-1-methyl-ethyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (1-hydroxycyclopropyl) methylamino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (4-piperidinylamino) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3R) -morpholin-3-yl ] methylamino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; Tert-butyl (3R) -3- [ [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] methyl ] morpholine-4-carboxylate; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3R) -3-piperidinyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; Tert-butyl (3R) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] piperidine-1-carboxylic acid ester; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3R) -pyrrolidin-3-yl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; tert-butyl (3R) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] pyrrolidine-1-carboxylic acid ester; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ rac- (4 as,7 as) -3, 4a,5,7 a-hexahydro-2H-pyrrolo [3,4-b ] [1,4] oxazin-6-yl ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; Tert-butylrac- (4 as,7 as) -6- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2,3,4a,5,7 a-hexahydropyrrolo [3,4-b ] [1,4] oxazine-4-carboxylic acid ester; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3S) -morpholin-3-yl ] methylamino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; tert-butyl (3S) -3- [ [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] methyl ] morpholine-4-carboxylate; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3S) -pyrrolidin-3-yl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; tert-butyl (3S) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] pyrrolidine-1-carboxylic acid ester; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3S) -3-piperidinyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; Tert-butyl (3S) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] piperidine-1-carboxylic acid ester; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (3-hydroxy-1-bicyclo [1.1.1] pentanyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; n-tert-butyl-3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (3-hydroxy-3-methyl-butyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [2- (4-phenylpiperazin-1-yl) ethyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (oxetan-3-yl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (morpholine-4-carbonyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; N- (2-amino-2-methyl-propyl) -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (1-hydroxycyclopropyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (1-hydroxycyclobutyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (2R) -2-hydroxypropyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (1R) -2-hydroxy-1-methyl-ethyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3-hydroxyoxetan-3-yl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N-methylsulfonyl-pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (2, 3-dihydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3-hydroxycyclobutyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -N- (1-cyano-2-methoxy-1-methyl-ethyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; N- (4-aminonorbornan-1-yl) -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (2S) -2, 3-dihydroxypropyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3 s,4 s) -4-methoxy-1-methyl-pyrrolidin-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (2R) -2, 3-dihydroxypropyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (1-methylazetidin-3-yl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3 s,4 s) -4-hydroxytetrahydrofuran-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) -N-methyl-pyrazolo [1,5-a ] pyrimidine-5-carboxamide; n- (3-amino-3-methyl-butyl) -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; N- (3-amino-1-bicyclo [1.1.1] pentanyl) -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; Tert-butyl N- [3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] -1-bicyclo [1.1.1] pentanyl ] carbamate; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ cis- (3 s,4 r) -4-hydroxypyrrolidin-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; Tert-butyl (3 s,4 r) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] -4-hydroxy-pyrrolidine-1-carboxylic acid ester; n- (2-amino-1, 1-dimethyl-ethyl) -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; tert-butyl N- [2- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] -2-methyl-propyl ] carbamate; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3S) -3-piperidinyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; Tert-butyl (3S) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] piperidine-1-carboxylic acid ester; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ trans- (3 s,4 s) -4-hydroxypyrrolidin-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; tert-butyl trans- (3 s,4 s) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] -4-hydroxy-pyrrolidine-1-carboxylic acid ester; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3-hydroxypyrrolidin-3-yl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; Tert-butyl 3- [ [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] methyl ] -3-hydroxy-pyrrolidine-1-carboxylic acid ester; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3R) -3-piperidinyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; tert-butyl (3R) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] piperidine-1-carboxylic acid ester; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (3-methylpyrrolidin-3-yl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; Tert-butyl 3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] -3-methyl-pyrrolidine-1-carboxylic acid ester; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (1 r,2 s) -2, 3-dihydroxy-1-methyl-propyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (1R) -1- [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] ethyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; N- [ (1-amino-3, 3-difluoro-cyclobutyl) methyl ] -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; Tert-butyl N- [1- [ [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] methyl ] -3, 3-difluoro-cyclobutyl ] carbamate; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (morpholin-2-ylmethyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; tert-butyl 2- [ [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] methyl ] morpholine-4-carboxylate; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (piperazine-1-carbonyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; Tert-butyl 4- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] piperazine-1-carboxylic acid ester; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3R) -pyrrolidin-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; tert-butyl (3R) -3- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carbonyl ] amino ] pyrrolidine-1-carboxylic acid ester; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (1-hydroxy-1-methyl-ethyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxylic acid; 2- (3-cyanophenyl) -3- (2-ethylpyrazol-3-yl) -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2-ethyl-5-methyl-pyrazol-3-yl) -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) -3- (2-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2-ethyl-4-methyl-pyrazol-3-yl) -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- [2- (difluoromethyl) -6-methyl-4-pyridinyl ] -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) -3- (2-methylpyrazol-3-yl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) -3-pyrimidin-4-yl-pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3-cyano-2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (2-hydroxy-2-methyl-propoxy) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; n- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] methanesulfonamide; (2S) -2- [ [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] propionic acid; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3R) -pyrrolidin-3-yl ] oxy-pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile formate; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (2-hydroxyethylamino) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (morpholinomethyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [5- (aminomethyl) -3- (2-chloro-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (3-hydroxy-3-methyl-butyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- [2- (difluoromethyl) -6-methyl-4-pyridinyl ] -5- [ (2-hydroxy-2-methyl-propyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [5- [ (2-hydroxy-2-methyl-propyl) amino ] -3- (2-methoxy-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2, 6-dimethyl-4-pyridinyl) -5- [ (2-hydroxy-2-methyl-propyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1S) -2-hydroxy-1-methyl-ethyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (dimethylamino) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (4-piperidinyloxy) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3R) -3-piperidinyl ] oxy ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; tert-butyl (3R) -3- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] oxypiperidine-1-carboxylate; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3S) -pyrrolidin-3-yl ] oxy-pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; Tert-butyl (3S) -3- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] oxypyrrolidine-1-carboxylate; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (3S) -3-piperidinyl ] oxy ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; Tert-butyl (3S) -3- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] oxypiperidine-1-carboxylate; 3- [ 5-amino-3- (6-amino-5-methyl-3-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ 5-amino-3- [2- (difluoromethyl) -6-methyl-4-pyridinyl ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ 5-amino-3- (2-methoxy-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 4- [ 5-amino-2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-3-yl ] -6-methyl-pyridine-2-carbonitrile; 3- [ 5-amino-3- (2-fluoro-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ 5-amino-3- (1-methylpyrazol-4-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ 5-amino-3- (2, 6-dimethyl-1-oxo-pyridin-1-ium-4-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [ 5-amino-3- (2-amino-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 4- [ 5-amino-2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-3-yl ] -6-methyl-pyridine-2-carboxamide; N- [4- [ 5-amino-2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-3-yl ] -6-methyl-2-pyridinyl ] acetamide; 3- [ 5-amino-3- (5-methyl- [1,2,4] triazolo [1,5-a ] pyridin-7-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 4- [ 5-amino-2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-3-yl ] -6-methyl-pyridine-2-carboxylic acid; 3- [ 5-amino-3- [2- (dimethylamino) -6-methyl-4-pyridinyl ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] urea; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -3- (2-hydroxy-2-methyl-propyl) urea; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -3- (1-ethyl-4-piperidinyl) urea; N- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] piperazine-1-carboxamide; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -3- [ (3S) -pyrrolidin-3-yl ] urea; 1- (2-aminoethyl) -3- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] urea; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -3- [ (3R) -pyrrolidin-3-yl ] urea; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2-cyano-guanidine; 3- [3- (2-ethylpyrazol-3-yl) -5- [ (2-hydroxy-2-methyl-propyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-ethylpyrazol-3-yl) -5- [3- (hydroxymethyl) -4-methyl-piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-ethylpyrazol-3-yl) -5- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-ethylpyrazol-3-yl) -5- (8-methyl-3, 8-diazabicyclo [3.2.1] oct-3-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-ethylpyrazol-3-yl) -5- (4-methylsulfonylpiperazin-1-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-ethylpyrazol-3-yl) -5- (4H-1, 2, 4-triazol-3-ylmethylamino) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-ethylpyrazol-3-yl) -5-piperazin-1-yl-pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-ethylpyrazol-3-yl) -5- (1-imino-1-oxo-1, 4-thiazinan-4-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 5- (benzylamino) -2- (2-fluorophenyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [ (3-methyl-2-pyridyl) methylamino ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; Tert-butyl (2S) -2- [ [ [ 3-cyano-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] methyl ] morpholine-4-carboxylate; Tert-butyl (2R) -2- [ [ [ 3-cyano-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] methyl ] pyrrolidine-1-carboxylic acid ester; 5- [4- (2-fluoroethyl) piperazin-1-yl ] -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; Tert-butyl (2S) -2- [ [ [ 3-cyano-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] methyl ] pyrrolidine-1-carboxylic acid ester; tert-butyl (2R) -2- [ [ [ 3-cyano-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] amino ] methyl ] morpholine-4-carboxylate; 2- (2-furyl) -5- [4- (2-phenylethyl) piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [4- (2-pyridylmethyl) piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- (4-methylpiperazin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- [ (1-benzyl-4-piperidinyl) methylamino ] -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; tert-butyl (2R) -4- [ 3-cyano-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2-methyl-piperazine-1-carboxylic acid ester; Tert-butyl (2S) -4- [ 3-cyano-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2-methyl-piperazine-1-carboxylic acid ester; 5- [2- (4-benzylpiperazin-1-yl) ethylamino ] -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [ (3-methyl-2-pyridyl) methylamino ] pyrazolo [1,5-a ] pyrimidine-3-carboxamide; 5- [4- (2-fluoroethyl) piperazin-1-yl ] -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide; 5- [3- (dimethylamino) azetidin-1-yl ] -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide; tert-butyl 4- [ 3-cyano-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -3, 6-dihydro-2H-pyridine-1-carboxylic acid ester; 2- (2-furyl) -5-piperazin-1-yl-pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [ [ (2S) -morpholin-2-yl ] methylamino ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [ [ (2R) -morpholin-2-yl ] methylamino ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- (4-benzylpiperazin-1-yl) -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; N-benzyl-3-bromo-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-amine; 5- (benzylamino) -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- (benzylamino) -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carboxamide; 5- (benzylamino) -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carbaldehyde; 5-amino-2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 3-bromo-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-amine; 2- (2-furyl) -5- [4- [ (3-methyl-2-pyridyl) methyl ] piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [4- [ (2, 4, 6-trifluorophenyl) methyl ] piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [4- [ (1-methylimidazol-2-yl) methyl ] piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [4- (2-hydroxyethyl) piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; N-benzyl-2- (2-furyl) -3- (1-methylpyrazol-4-yl) pyrazolo [1,5-a ] pyrimidin-5-amine; N-benzyl-2- (2-furyl) -3- (2-methylpyrazol-3-yl) pyrazolo [1,5-a ] pyrimidin-5-amine; methyl (E) -3- [5- (benzylamino) -2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-3-yl ] prop-2-enoic acid ester; (E) -3- [5- (benzylamino) -2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-3-yl ] prop-2-enoic acid; 2- (2-furyl) -5- (4-phenylpiperazin-1-yl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- (3-hydroxypropyl amino) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- (2-hydroxyethylamino) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- (3-piperidinylmethylamino) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile hydrochloride; 5- (benzylamino) -2-oxazol-2-yl-pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- (benzylamino) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (3-cyanophenyl) -5- [4- [ (3-methyl-2-pyridinyl) methyl ] piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (3-fluorophenyl) -5- [4- [ (3-methyl-2-pyridyl) methyl ] piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- [4- (2-fluoroethyl) piperazin-1-yl ] -2- (3-fluorophenyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- [4- (2-fluoroethyl) piperazin-1-yl ] -2-oxazol-5-yl-pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- (benzylamino) -2- (4-fluorophenyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- (benzylamino) -2- (5-methyl-2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 5- [4- [ (3-methyl-2-pyridinyl) methyl ] piperazin-1-yl ] -2-oxazol-5-yl-pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; n-benzyl-3-chloro-2- (3-fluorophenyl) pyrazolo [1,5-a ] pyrimidin-5-amine; 3-bromo-5-chloro-2- (3-fluorophenyl) pyrazolo [1,5-a ] pyrimidine; n-benzyl-3-bromo-2- (3-fluorophenyl) pyrazolo [1,5-a ] pyrimidin-5-amine; 5- (benzylamino) -2- (3-fluorophenyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 3-bromo-2- (3-fluorophenyl) pyrazolo [1,5-a ] pyrimidin-5-amine; 5-amino-2- (3-fluorophenyl) pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -N- (thiazol-2-ylmethyl) pyrazolo [1,5-a ] pyrimidin-5-amine; [5- (benzylamino) -2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-3-yl ] methanol; 5- (benzylamino) -2- (2-furyl) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid; n-benzyl-2- (2-furyl) -3-iodo-pyrazolo [1,5-a ] pyrimidin-5-amine; 2- (2-furyl) -3- (4-pyridyl) pyrazolo [1,5-a ] pyrimidin-5-amine; 2- (2-furyl) -5- [ [ (2R) -pyrrolidin-2-yl ] methylamino ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [ [ (2R) -1-methylpyrrolidin-2-yl ] methylamino ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (2-furyl) -5- [ (3R) -3-methylpiperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile hydrochloride; tert-butyl 4- [ 3-cyano-2- (2-furyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] piperidine-1-carboxylic acid ester; 2- (3-cyanophenyl) -5- [4- (2-fluoroethyl) piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 2- (3-cyanophenyl) -5- [2- (4-phenylpiperazin-1-yl) ethylamino ] pyrazolo [1,5-a ] pyrimidine-3-carbonitrile; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (4-fluorophenyl) pyrazolo [1,5-a ] pyrimidin-5-amine; N-tert-butyl-3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamidine; 3- (2-amino-6-methyl-4-pyridinyl) -N-tert-butyl-2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -N- (2, 3-dihydroxy-2-methyl-propyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- (3-hydroxy-1-bicyclo [1.1.1] pentanyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -5- (sulfamoylamino) pyrazolo [1,5-a ] pyrimidine; n- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2-hydroxy-2-methyl-propionamide; n- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2, 2-dimethyl-propionamide; N- (3-amino-3-methyl-butyl) -2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (2-hydroxy-1, 1-dimethyl-ethyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) -3- [ 2-methyl-6- (trifluoromethyl) -4-pyridinyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -N- (1-cyano-1-methyl-ethyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (1 s,2 s) -2, 3-dihydroxy-1-methyl-propyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2-cyano-3-isopropyl-guanidine; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1R) -2-hydroxy-1-methyl-ethyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- (3-cyano-2-methyl-phenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (3-hydroxycyclobutyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (2-oxo-3-piperidinyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (2-hydroxy-1, 2-trimethyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (1-methyl-2-oxo-3-piperidinyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -N- [ (1S) -1, 2-dimethylallyl ] -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; n- (2-acetamido-2-methyl-propyl) -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; n- (3-amino-3-methyl-butyl) -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (1-methyl-4-piperidinyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyano-2-methyl-phenyl) -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1 r,2 s) -2, 3-dihydroxy-1-methyl-propyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- (4-hydroxy-4-methyl-cyclohexyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- [2- (difluoromethyl) -6-methyl-4-pyridinyl ] -5- [ (2-hydroxy-2-methyl-propyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (4-methyl-2-oxo-oxazohdin-4-yl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (2-methyl-5-oxo-pyrrolidin-2-yl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [1- (3-hydroxyoxetan-3-yl) ethyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3-methyl-6-oxo-3-piperidinyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2-cyano-3- (2-hydroxy-2-methyl-propyl) guanidine; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (3-hydroxy-1-bicyclo [1.1.1] pentanyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ rac- (2R) -2-hydroxypropyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyano-2-methyl-phenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (1R) -2-hydroxy-1, 2-dimethyl-propyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ rac- (3 s,4 s) -4-methoxy-1-methyl-pyrrolidin-3-yl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (3-methyl-3-piperidinyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) -3- (2-methoxy-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (4-methyl-2, 5-dioxo-imidazolidin-4-yl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1 s,2 s) -2, 3-dihydroxy-1-methyl-propyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- (3-hydroxy-3-methyl-cyclobutyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ rac- (3R) -3-piperidinyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- (3-cyano-2-methyl-phenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (1S) -2-hydroxy-1, 2-dimethyl-propyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; n- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -3-hydroxy-3-methyl-butyramide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3-hydroxyoxetan-3-yl) methylamino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [1- (2-hydroxyethyl) -4-piperidinyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3-hydroxy-3-methyl-butyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 1- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] guanidine; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamidine; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- (2-hydroxy-2-methyl-propoxy) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (5-oxopyrrolidin-3-yl) methylamino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3S) -3- (1-hydroxy-1-methyl-ethyl) piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2, 6-dimethyl-4-pyridinyl) -5- [ (1-methyl-2-oxo-4-piperidinyl) amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; n- [2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -3-hydroxy-3-methyl-butyramide; N- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] acetamide [2- (3-Cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] urea; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3-hydroxyoxetan-3-yl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1S) -2-hydroxy-1, 2-dimethyl-propyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ rac- (2S) -2-hydroxypropyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ (1 s,3 s) -3-aminocyclopentyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; m- {4- [ ({ [ (3S) -5-oxo-3-pyrrolidinyl ] methyl } amino) carbonyl ] -7- (2, 6-dimethyl-4-pyridinyl) -1.5.9-triazabicyclo [4.3.0] non-2, 4,6, 8-tetraen-8-yl } benzonitrile; 3- [5- [ (2-amino-2-methyl-propyl) amino ] -3- (2-chloro-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- (2-cyano-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ rac- (1R) -2-hydroxy-1, 2-dimethyl-propyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; N- [2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2-hydroxy-2-methyl-propionamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- [ rac- (3S) -3-piperidinyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (3-fluoro-2, 6-dimethyl-4-pyridinyl) -N- (2-hydroxy-2-methyl-propyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (2-oxo-4-piperidinyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (3-fluoro-2, 6-dimethyl-4-pyridinyl) -N- [ (4-methyl-2, 5-dioxo-imidazolidin-4-yl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- (5-oxopyrrolidin-3-yl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3R) -3- (1-hydroxy-1-methyl-ethyl) piperazin-1-yl ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; m- [7- (2, 6-dimethyl-4-pyridinyl) -4- ({ [ (5-oxo-3-pyrrolidinyl) methyl ] amino } carbonyl) -1.5.9-triazabicyclo [4.3.0] non-2, 4,6, 8-tetraen-8-yl ] benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ [ (1 r,2 s) -2-hydroxycyclobutyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; m- {4- [ ({ [ (3R) -5-oxo-3-pyrrolidinyl ] methyl } amino) carbonyl ] -7- (2, 6-dimethyl-4-pyridinyl) -1.5.9-triazabicyclo [4.3.0] non-2, 4,6, 8-tetraen-8-yl } benzonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3-hydroxyazetidin-3-yl) methylamino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 4- [ 5-amino-2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-3-yl ] -6-methyl-pyridine-2-carbonitrile; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- (1-imino-1-oxo-1, 4-thiazinan-4-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [5- [ (1-acetyl-4-piperidinyl) amino ] -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (5-oxomorpholin-2-yl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2-chloro-6-methyl-4-pyridinyl) -5- [ (3R) -pyrrolidin-3-yl ] oxy-pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 1- (2-amino-2-methyl-propyl) -3- [3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] urea; 3- [3- (2, 6-dimethyl-4-pyridinyl) -5- (2, 4-dioxo-1, 3, 8-triazaspiro [4.5] decane-8-carbonyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3 s,4 s) -4-hydroxytetrahydrofuran-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ [ (2R) -5-oxopyrrolidin-2-yl ] methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3R, 4R) -4-hydroxy-4-methyl-tetrahydrofuran-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide 2- (3-Cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3 r,4 s) -4-hydroxy-4-methyl-tetrahydrofuran-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (6-oxo-3-piperidinyl) methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3 s,4 r) -4-hydroxytetrahydrofuran-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3 r,4 r) -4-hydroxytetrahydrofuran-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3R, 4S) -4-hydroxytetrahydrofuran-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3 r,4 r) -4-hydroxy-1-methyl-pyrrolidin-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) -N- [ (3 s,4 r) -4-hydroxy-1-methyl-pyrrolidin-3-yl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 2- (3-cyanophenyl) -N- (2-hydroxy-2-methyl-propyl) -3-thiazol-5-yl-pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [5- [ (2-amino-2-methyl-propyl) amino ] -3- (2-chloro-6-methyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (4-piperidinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) -N- (4-cyano-4-piperidinyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; n- (4-carbamoyl-4-piperidinyl) -3- (2-chloro-6-methyl-4-pyridinyl) -2- (3-cyanophenyl) pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2, 6-dimethyl-4-pyridinyl) -5- (piperazin-1-ylmethyl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 2- (3-cyanophenyl) -N- [ (1S) -2-hydroxy-1, 2-dimethyl-propyl ] -3- [2- (hydroxymethyl) -6-methyl-4-pyridinyl ] pyrazolo [1,5-a ] pyrimidine-5-carboxamide; 3- [3- (2, 6-dimethyl-4-pyridinyl) -5- (3-oxo-2, 8-diazaspiro [4.5] decan-8-yl) pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; 3- [3- (2, 6-dimethyl-4-pyridinyl) -5- [ [1- (2-hydroxy-2-methyl-propyl) -4-piperidinyl ] amino ] pyrazolo [1,5-a ] pyrimidin-2-yl ] benzonitrile; (2S) -N- [2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -3, 3-trifluoro-2-hydroxy-2-methyl-propionamide; n- [2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -2-oxa-6-azaspiro [3.3] heptane-6-carboxamide, or 4-Cyano-N- [2- (3-cyanophenyl) -3- (2, 6-dimethyl-4-pyridinyl) pyrazolo [1,5-a ] pyrimidin-5-yl ] -4-methyl-piperidine-1-carboxamide.
  13. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
  14. 14. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the manufacture of a medicament for use in therapy.
  15. 15. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the manufacture of a medicament for use in: (i) Treating a proliferative disorder; (ii) Treating cancer; (iii) Treating cancer wherein the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents; (iv) Treating cancer wherein the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents selected from the group consisting of: 1) Other forms of cancer immunotherapy and anticancer chemotherapeutics; 2) Adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors; 3) anti-PD-1 and PDL-1 antibodies, and 4) Anti-CTLA 4 antibodies.
  16. 16. The use according to claim 15, wherein the anti-PD-1 and PDL-1 antibodies are selected from the group consisting of cetirizine, palbociclib, nal Wu Liyou mab, rivaromycetin You Shan, avermectin and actyly Li Zhushan.
  17. 17. The use of claim 15, wherein the anti-CTLA 4 antibody is ipilimumab.

Description

Antagonists of adenosine A2a receptors The invention is a divisional application of Chinese patent application 202180047824.2 entitled "antagonist of adenosine A2a receptor" with application date 2021, 5 and 6. Technical Field The present invention relates to certain compounds useful as adenosine A2a receptor antagonists. In addition, some of these compounds are also antagonists of the A2b receptor. The invention also relates to processes for preparing these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or conditions associated with adenosine A2a receptor activity, such as cancer. Background Many immunosuppressive pathways are active in the tumor microenvironment, enabling tumor cells to evade elimination by cytotoxic T cells, and reducing the clinical response of patients to anti-checkpoint antibody immunotherapy. The anti-PD-1 antibodies pamte Li Zhushan and nalmefene Wu Liyou mab, as well as the anti-PD-L1 antibodies cervalli You Shan, avistuzumab and atilizumab, are approved for the treatment of a variety of solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. However, only 20% -30% of patients respond to checkpoint blockages, and the side effects of such treatments are apparent (Sukari et al, 2016). Thus, other approaches to enhance the cytotoxic potential of tumor microenvironments are being actively studied. This includes agents that may be used as monotherapy, or more likely to be used in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy. One approach of interest is to interfere with the production and/or action of adenosine in the tumor microenvironment (Vijayan et al, 2017). Adenosine has immunosuppressive properties and is present in high concentrations in tumor microenvironments. Recent studies estimated that the adenosine concentration in human tumors is about 10 μm, whereas the adenosine concentration in normal tissues is <1 μm (Houthuys et al, 2017). Adenosine is formed at intracellular and extracellular sites by two different pathways involving two different substrates. Intracellular adenosine is derived from AMP and S-adenosyl homocysteine, whereas the high extracellular adenosine concentrations observed during metabolic stress are related to the release and degradation of precursor adenine nucleotides (ATP, ADP and AMP) by the synergistic effect of CD39 and CD73 (Vijayan et al, 2017). In response to hypoxia, CD39 and CD73 are upregulated in the tumor microenvironment. CD73 represents a putative stratification method for adenosine antagonist patients, since its expression on tumor cells is also associated with overall poor prognosis for many different cancer types, suggesting that the generation of adenosine contributes to the poor immunosuppressive phenotype of the tumor microenvironment (Gao et al, 2014; loi et al, 2013). CD73 expression by tumor-infiltrating immune cells is also important to promote tumor immunosuppression, as CD73 negative Treg cells fail to suppress effector T cell function (Deaglio et al, 2007; reinhardt et al, 2017). In addition, CD73 levels are elevated in patients resistant to anti-PD 1 treatment (Reinhardt et al, 2017). Adenosine regulates cellular functions through specific GPCRs that occupy the cell surface of the P1 purinergic subtype. The P1 receptor family is further subdivided into A1, A2a, A2b and A3. The A2 receptor is subdivided into A2a and A2b, respectively, based on high and low affinity for adenosine. A2a is expressed by lymphocytes, and activation of A2a results in inhibition of cytokine production and other effector functions. In the syngeneic mouse model, gene ablation of A2a inhibited tumor growth, and this effect has been demonstrated to be due to enhanced lymphocyte activation and cytotoxic function (Ohta et al, 2006; waickman et al, 2012; beavis et al, 2013; mittal et al, 2014; cekic et al, 2014). The A2 a-/-mice have enhanced responses to checkpoint pathway (e.g., PD-1) inhibition, improved tumor-free survival and overall survival. Adenosine mediated A2a activation also limits the efficacy of anti-CTLA 4 therapies (Iannone et al, 2014). The effect of A2a gene deficiency in the mouse model was simulated by pharmacological blockade of A2 a. A2a antagonists have been shown to enhance cytotoxic cd8+ T cells and enhance NK cells' ability to prevent metastasis of CD73 expressing tumors (Beavis et al, 2013). Importantly, A2a antagonists can enhance the therapeutic efficacy of anti-PD 1 antibodies (Beavis et al, 2015). These findings have prompted the development of selective A2a antagonists for cancer immunotherapy and the clinical trial of CPI-444 is being conducted, CPI-444 being the first selective A2a antagonist to evaluate in cancer, both as monotherapy and in combination with the anti-PDL 1 antibody, atilizumab. Preliminary data indicate that the compound is well tolerated and shows early