The present invention provides for compounds of Formula I and embodiments and salts thereof for the treatment of diseases (e.g., neurodegenerative diseases). R1, R2, R3, X1, X2, A and Cy variable in Formula all have the meaning as defined herein.

##STR00001##

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Patent
   RE47848
Priority
May 01 2013
Filed
Feb 22 2018
Issued
Feb 11 2020
Expiry
May 01 2034

TERM.DISCL.
Inventors
Patel, Sna…
Assg.orig
Genentech,…
Assg.curr
Genentech,…
Entity
Large
Referenced by
1
References
54
Maint.:
currently ok
CROSS-REFERENCE TO R…
Example 3
0. 56. A compound selected from the group consisting of:
##STR00205##
1. compounds A compound of formula (I)
##STR00197##
or salts a pharmaceutically acceptable salt thereof wherein
R1, R2 and R3 are each independently H, F, Cl, Br, I, CN, C1-6 alkyl or C1-6 haloalkyl;
X1 is N or C—R4, wherein R4 is selected from the group consisting of —F, —Cl, —Br, I -(L1)0-1-C1-6 alkyl, —I, CN, -(L1)0.1-C1-6 alkyl, -(L1)0-1-C1-6 haloalkyl, -(L1)0-1-C1-6 heteroalkyl, -(L2)0-1-C3-8 cycloalkyl, -(L2)0-1-3 to 7 membered heterocycloalkyl, -(L2)0-1-6-10 membered aryl, -(L2)0-1-5-10 membered heteroaryl, wherein L1 is selected from the group consisting of —O—, —N(H)—, —S—, —N(C1-6alkyl)-, ═O and —C(═O)—, and L2 is selected from the group consisting of —O—, —N(H)—, —N(C1-6 alkyl)-, —S—, ═O —C(═O)—, C1-4 alkylene, C1-4 alkenylene, C1-4 alkynylene, C1-4 alkoxylene, C1-4 aminoalkylene, C1-4 thioalkylene and C1-4 heteroalkylene, and wherein R4 is optionally substituted on carbon atoms and heteroatoms with RR4 substituents selected from the group consisting of F, Cl, Br, I, C1-6 alkyl, C1-6 haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 dialkylamino, C1-6 alkylthio, ═O, —NH2, —CN, —NO2 and —SF5;
X2 is N;
A is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 dialkylamino, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, wherein A is optionally substituted with 1-5 RA substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO2, —SF5, C1-8 alkyl, C1-8 haloalkyl, C1-8 heteroalkyl, -(LA)0-1-3-8 membered cycloalkyl, -(LA)0-1-3-8 membered heterocycloalkyl, -(LA)0-1-5 to 6 membered heteroaryl, -(LA)0-1-C6 aryl, -(LA)0-1-NRR1aRR1b, -(LA)0-1-ORR1a, -(LA)0-1-SRR1a, -(LA)0-1-N(RR1a)C(═Y1)ORR1c, -(LA)0-1-OC(═O)N(RR1a)(RR1b), -(LA)0-1-N(RR1a)C(═O)N(RR1a)(RR1b), -(LA)0-1-C(═O)N(RR1a)(RR1b), -(LA)0-1-N(RR1a)C(═O)RR1b, -(LA)0-1-C(═O)ORR1a, -(LA)0-1-OC(═O)RR1a, -(LA)0-1-P(═O)(ORR1a)(ORR1b), -(LA)0-1-S(O)1-2RR1c, -(LA)0-1-S(O)1-2N(RR1a)(RR1b), -(LA)0-1-N(RR1a)S(O)1-2N(RR1a)(RR1b) and -(LA)0-1-N(RR1a)S(O)1-2(RR1c), wherein LA is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C1-4 alkoxylene, C1-4 aminoalkylene, C1-4 thioalkylene, C2-4 alkenylene, and C2-4 alkynylene; wherein RR1a and RR1b are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; RR1c is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein RA is optionally substituted on carbon atoms and heteroatoms with RRA substituents selected from, F, Cl, Br, I, —NH2, —OH, —CN, —NO2, ═O, —SF5, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 (halo)alkyl-C(═O)—, C1-4 (halo)alkyl-S(O)0-2—, C1-4 (halo)alkyl-N(H)S(O)0-2—, C1-4 (halo)alkyl-S(O)0-2N(H)—, (halo)alkyl-N(H)—S(O)0-2N(H)—, C1-4 (halo)alkyl-C(═O)N(H)—, C1-4 (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)2N—C(═O)—, C1-4 (halo)alkyl-OC(═O)N(H)—, C1-4 (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)2N—C(═O)O—, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino; and
Cy is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, 3 to 12 membered cycloalkyl, 3 to 12 membered heterocycloalkyl, wherein Cy is optionally substituted on carbon or heteroatoms with RCy substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO2, —SF5, C1-8 alkyl, C1-8 haloalkyl, C1-8 heteroalkyl, -(LCy)0-1-3-8 membered cycloalkyl, -(LCy)0-1-3-8 membered heterocycloalkyl, -(LCy)0-1-5 to 6 membered heteroaryl, -(LCy)0-1-phenyl, -(LCy)0-1-NRRCaRRCb, -(LCy)0-1-ORRCa, -(LCy)0-1-SRRCa, -(LCy)0-1-N(RRCa)C(═Y1)ORRCc, -(LCy)0-1-OC(═O)N(RRCa)(RRCb), -(LCy)0-1-N(RRCa)C(═O)N(RRCa)(RRCb), -(LCy)0-1-C(═O)N(RRCa)(RRCb), -(LCy)0-1-N(RRCa)C(═O)RRCb, -(LCy)0-1-C(═O)ORRCa, -(LCy)0-1-OC(═O)RRCa, -(LCy)0-1-P(═O)(ORRCa)(ORRCb), -(LCy)0-1-S(O)1-2RRCc, -(LCy)0-1-S(O)1-2N(RRCa)(RRCb), -(LCy)0-1N(RRCa)S(O)1-2N(RRca)(RRCb) -(LCy)0-1N(RRCa)S(O)1-2N(RRCa)(RRCb) and -(LCy)0-1-N(RRCa)S(O)1-2(RRCc), wherein LCy is selected from the group consisting of C1-4 alkylene, C1-4 heteroalkylene, C1-4 alkoxylene, C1-4 aminoalkylene, C1-4 thioalkylene, C2-4 alkenylene, and C2-4 alkynylene; wherein RRCa and RRCb are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 8 membered heterocycloalkyl; RRCc is selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, 3 to 8 membered cycloalkyl, phenyl, benzyl, 5 to 6 membered heteroaryl and 3 to 7 membered heterocycloalkyl, and wherein RCy is optionally substituted on carbon atoms and heteroatoms with from 1 to 5 RRCy substitutents substituents selected from, F, Cl, Br, I, —NH2, —OH, —CN, —NO2, ═O, —SF5, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 (halo)alkyl-C(═O)—, C1-4 (halo)alkyl-S(O)0-2—, C1-4 (halo)alkyl-N(H)S(O)0-2—, C1-4 (halo)alkyl-S(O)0-2N(H)—, (halo)alkyl-N(H)—S(O)0-2N(H)—, C1-4 (halo)alkyl-C(═O)N(H)—, C1-4 (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)2N—C(═O)—, C1-4 (halo)alkyl-OC(═O)N(H)—, C1-4 (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)2N—C(═O)O—, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein either A or Cy is a polycyclic carbocycle or polycyclic heterocycle.
0. 3. A compound according to claim 1, wherein X1 is N.
0. 4. A compound according to claim 1, wherein X1 is C—R4.
5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of —F, —Cl, —CN, -(L2)0-1-C3-8 cycloalkyl, -(L2)0-1-3 to 7 membered heterocycloalkyl, -(L1)0-1-C1-6 alkyl, -(L1)0-1-C1-6 haloalkyl, -(L1)0-1-C1-6 heteroalkyl, -(L2)0-1-6-10 membered aryl and -(L2)0-1-5-10 membered heteroaryl, and is optionally substituted.
6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of —F, —Cl, C3-8 cycloalkyl, 3 to 7 membered heterocycloalkyl, C1-6 alkyl, C1-6 haloalkyl, —(O)—C3-8 cycloalkyl, —(O)—3 to 7 membered heterocycloalkyl, —(O)—C1-6 alkyl and —(O)—C1-6 haloalkyl, and is optionally substituted.
7. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, methyl, monofluoromethyl difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentyl.
8. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of (L2)0-1-phenyl -(L2)0-1-phenyl, -(L2)0-1-pyridyl, -(L2)0-1-pyrimidinyl, -(L2)0-1pyrazinyl, -(L2)0-1-pyridazinyl, -(L2)0-1-pyrrolyl, -(L2)0-1-pyrazolyl, -(L2)0-1-imidazolyl, -(L2)0-1-thienyl, -(L2)0-1-thiazolyl and, -(L2)0-1-thiadiazolyl, -(L2)0-1-triazoloyl, -(L2)0-1-oxazolyl, -(L2)0-1-oxadiazolyl, and -(L2)0-1-furanyl and is optionally substituted.
9. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from the group consisting of -(L2)0-1-phenyl and -(L2)0-1-pyridinyl, and is optionally substituted.
10. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is —OC(H)(CH3)-phenyl wherein said phenyl ring is optionally substituted.
11. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are each independently selected from the group consisting of F, Cl, CN, hydrogen, C1-4 alkyl and C1-4 haloalkyl.
12. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are each hydrogen.
13. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A and Cy are independently selected from the group consisting of pyrrolidine, piperidine, azetidine, azepane, piperazine, 7-azaspiro[3.5]nonane, 3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, morpholine, hexahydro-2H-furo[3,2-c]pyrrole, 2-azabicyclo[2.1.1]hexane, 2,5-diazabicyclo[2.2.1]heptane, 2-aza-tricyclo[3.3.1.1-3,7]decane, 2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane, cyclopropane, cyclopentane, 2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide, 2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran, 8-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane, and is optionally substituted.
14. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of pyrrolidine, piperidine, azetidine, azepane, piperazine, cyclopropane, cyclobutane, cyclopentane, 7-azaspiro[3.5]nonane, 3-oxabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,7-diazaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, morpholine, hexahydro-2H-furo[3,2-c]pyrrole and 2-azabicyclo[2.1.1]hexane, and is optionally substituted.
15. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane, 3oxabicyclo[3.1.0]hexane 3-oxabicyclo[3.1.0]hexane, azetidine, pyrrolidine, cyclopropane, cyclobutane, cyclopentane, and is optionally substituted.
16. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane, (1S,5R)-3-oxabicyclo[3.1.0]hexane, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane and (1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted.
17. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is A is selected from the group consisting of methyl, ethyl, isopropyl,
##STR00198##
18. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from the group consisting of 2,5-diazabicyclo[2.2.1]heptane, piperidine, pyrrolidine, azetidine, 2-aza-tricyclo[3.3.1.1-3,7]decane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo [3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, 2-azabicyclo[2.1.1]hexane, 9-azabicyclo[4.2.1]nonane, 9-azabicyclo[3.3.1]nonane, cyclobutane, 2-Thia-5-aza-bicyclo[2.2.1]heptane 2,2-dioxide, 2-azabicyclo[2.2.1]heptane, tetrahydro-2H-pyran, 8-azabicyclo[3.2.1]octane, and 3-oxa-8-azabicyclo[3.2.1]octane, and is optionally substituted.
19. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from the group consisting of azetidine, (1S ,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, (1R,5S)-3-azabicyclo[3.1.0]hexane, (1S,5R)-3-azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, (1R,5S)-3-oxabicyclo[3.1.0]hexane, (1S,5R)-3-oxabicyclo[3.1.0]hexane, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane and (1R,4R)-2,5-diazabicyclo[2.2.1]heptane, and is optionally substituted.
20. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from the group consisting of
##STR00199##
21. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is C1-6 alkyl or C1-6 dialkylamino, and is optionally substituted.
22. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is methyl or ethyl.
23. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is C1-6 alkyl, and is optionally substituted.
24. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted with from 1 to 5 RA substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO2, —SF5, C1-8 alkyl, C1-8 haloalkyl, C1-8 heteroalkyl, -(LA)0-1-3-8 membered cycloalkyl, -(LA)0-1-3-8 membered heterocycloalkyl, -(LA)0-1-5 to 6 membered heteroaryl, and -(LA)0-1-C6 aryl, wherein LA is selected from the group consisting of —C(O)—, —C(O)CH2—, —OCH2—, —CH2O—, —CH2—, —CH2CH2—, —CH2OCH2—, —N(H)CH2—, —N(C1-3 alkyl)CH2—, CH2N(H)— —CH2N(H)—, and —CH2N(C1-3 alkyl)-; wherein said 3-8 membered cycloalkyl is selected from the group consisting of propane, butane, pentane and hexane; wherein said 3 to 8 membered heterocycloalkyl is selected from the group consisting of oxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine, piperidine and azepane; wherein said 5 to 6 membered heteroaryl is selected from the group consisting of pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, trizole triazole, pyridine, pyrimidine, pyrazine, and pyridazine; wherein said C6 aryl is phenyl; and where in wherein RA is optionally substituted with from 1 to 5 RRA substitutents substituents selected from, F, Cl, Br, I, —NH2, —OH, —CN, —NO2, ═O, —SF5, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 (halo)alkyl-C(═O)—, C1-4 (halo)alkyl-S(O)0-2—, C1-4 (halo)alkyl-N(H)S(O)0-2—, C1-4 (halo)alkyl-S(O)0-2N(H)—, (halo)alkyl-N(H)—S(O)0-2N(H)—, C1-4 (halo)alkyl-C(═O)N(H)—, C1-4 (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)2N—C(═O)—, C1-4 (halo)alkyl-OC(═O)N(H)—, C1-4 (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—(═O)O—, ((halo)alkyl)2N—C(═O)O—, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino.
25. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is optionally substituted with from 1 to 5 RCy substituents selected from the group consisting of F, Cl, Br, I, —OH, —CN, —NO2, —SF5, C1-8 alkyl, C1-8 haloalkyl, C1-8 heteroalkyl, -(LCy)0-1-3-8 membered cycloalkyl, -(LCy)0-1-3-8 membered heterocycloalkyl, -(LCy)0-1-5 to 6 membered heteroaryl, and -(LCy)0-1-C6 aryl, wherein LCy is selected from the group consisting of —C(O)—, —C(O)CH2—, —OCH2—, —CH2O—, —CH2—, —CH2CH2—, —CH2OCH2—, —N(H)CH2—, —N(C1-3 alkyl)CH2—, CH2N(H)—, —CH2N(H)—, and —CH2N(C1-3 alkyl)-; wherein said 3-8 membered cycloalkyl is selected from the group consisting of propane, butane, pentane and hexane; wherein said 3 to 8 membered heterocycloalkyl is selected from the group consisting of oxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine, piperidine and azepane; wherein said 5 to 6 membered heteroaryl is selected from the group consisting of pyrrole, pyrazole, imidazole, thiophene, thiazole, oxazole, trizole triazole, pyridine, pyrimidine, pyrazine, and pyridazine; wherein said C6 aryl is phenyl; and where in RCy is optionally substituted with from 1 to 5 RRCy substitutents substituents selected from, F, Cl, Br, I, —NH2, —OH, —CN, —NO2, ═O, —SF5, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 (halo)alkyl-C(═O)—, C1-4 (halo)alkyl-S(O)0-2—, C1-4 (halo)alkyl-N(H)S(O)0-2—, C1-4 (halo)alkyl-S(O)0-2N(H)—, (halo)alkyl-N(H)—S(O)0-2N(H)—, C1-4 (halo)alkyl-C(═O)N(H)—, C1-4 (halo)alkyl-N(H)—(═O)—, ((halo)alkyl)2N—C(═O)—, C1-4 (halo)alkyl-OC(═O)N(H)—, C1-4 (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—(═O)O—, ((halo)alkyl)2N—C(═O)O—, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino.
26. A compound of claim of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is optionally substituted with 1 to 5 RCy substituents selected from the group consisting of F, Cl, Br, I, CN, OH, 2,3-difluorophen-1-yl-C(═O)—, 4-fluorophen-1-yl-C(═O)—, 3-fluorophen-1-yl-C(═O)—, 3,5-difluorophen-1-yl-C(═O)—, 3-fluoro-4-methyl-phen-1-yl-C(═O)—, 2,5-difluorophen-1-yl-C(═O)—, oxetane, oxetan-3-yl, thiazole, thiazol-2-yl, —CH3CH2C(═O)—, CH3C(═O)—, CF3CH2—, (HO)C(CH3)2CH2—, CH3OCH2CH2—, CH3OC(CH3)2C(═O)—, CH3OCH2C(═O)—, isopropyl, ethyl and methyl.
27. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted with 1 to 5 RA substituents selected from the group consisting of F, Cl, Br, I, CN, CH3O—, CH3, cyclopropylmethyl, CF3 and butyl.
28. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the subformula consisting of
##STR00200## ##STR00201##
29. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the subformula consisting of
##STR00202##
30. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the subformula consisting of
##STR00203## ##STR00204##
wherein RCy if present replaces a hydrogen atom attached to a carbon or nitrogen atom of the Cy ring.
31. A compound of claim 1 selected from the group consisting of:
[3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-yl]pyrrolidin-1-yl]-phenyl-methanone;
[3-[6-(2-aminopyrimidin-5-yl)-2-methyl-pyrimidin-4-yl]-1-piperidyl]-phenyl-methanone;
[3-[6-[2-amino-4-(trifluoromethyl)pyrimidin-5-yl]-2-methyl-pyrimidin-4-yl]-1-piperidyl]-phenyl-methanone;
[3-[6-(2-aminopyrimidin-5-yl)-2-methyl-pyrimidin-4-yl]pyrrolidin-1-yl]-phenyl-methanone
6-((1R,3R,5R,7R)-2-azaadamantan-2-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)-[4,5′-bipyrimidin]-2′-amine;
3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;
5-[2-(3,3-difluoro-1-piperidyl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4-fluoro-1-piperidyl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
1-[(1S,4S)-5-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
5-[2-(3,3-difluoro-1-piperidyl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4-fluoro-1-piperidyl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
1-[(1S,4S)-5-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo-[3.1.0]hexane-3-yl]ethanone;
1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3yl]-ethanone;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2-amine;
5-[2-(3-methoxyazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3,3-dimethylazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)-3-fluoro-1H-pyrrolo[2,3-b]pyridine;
5-[2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-[(1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methoxy-2-methyl-propan-1-one;
[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methoxy-ethanone;
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methoxy-ethanone;
3-(difluoromethoxy)-5-[2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[2.1.1]hexan-4-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(azetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
3-(difluoromethoxy)-5-[2-(3-fluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;
5-[2,6-bis[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3,3-difluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-isopropyl-2,5-diazabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone;
1-[3-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]ethanone;
5-[2-(2-fluoro-7-azaspiro[3.5]nonan-7-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[(1R,5S)-3-methyl-3,6-diazabicyclo[3.2.1]octan-6-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4,4-difluoroazepan-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4-cyclobutylpiperazin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
4-(2-aminopyrimidin-5-yl)-N,N-diethyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-2-amine;
5-[2-(4-methylpip erazin- 1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-(1-piperidyl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(azetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[(3aS,6aR)-5,5-difluoro-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyrrolidin-1-yl-pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3,3-difluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(7,7-difluoro-2-azaspiro[3.3]heptan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[(3aR,6aS)-4,4-difluoro-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(6-azaspiro[2.5]octan-6-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[8-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[6-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
1-[(1S,4S)-2-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-5-yl]-2-methyl-propan-2-ol;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-5-(2-methoxyethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
1-[6-[6-(2-aminopyrimidin-5-yl)-2-cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(9-azabicyclo[3.3.1]nonan-9-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-fluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(4-cyclopropylpiperazin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[(1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-[4-(trifluoromethyl)-1-piperidyl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[2-(2-aminopyrimidin-5-yl)-6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-pyridyl]cyclobutanecarbonitrile;
1-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]cyclobutanecarbonitrile;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-cyclopropyl-pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-isopropoxy-pyridin-2-amine;
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(8-azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine;
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
1-[(1S,4S)-5-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2,2-dioxo-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl]pyrimidin-2-amine;
1-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]cyclobutanecarbonitrile;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-5-fluoro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[3-(oxetan-3-yl)-3-azabicyclo[3.2.1]octan-8-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-cyclopropyl-6[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
8-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-methyl-8-azabicyclo[3.2.1]octan-3-ol;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(2,6-dimethylmorpholin-4-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2,6-bis(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
2-amino-5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridine-3-carbonitrile;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-chloro-pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine;
8-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-8-azabicyclo[3.2.1]octan-3-ol;
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-pyridyl]pyrimidin-2-amine;
5-[4,6-bis(3-azabicyclo[2.1.1]hexan-3-yl)-2-pyridyl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyridyl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(2,2-dimethylmorpholin-4-yl)pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine;
5-[2-(2-methylpyrrolidin-1-yl)-6-tetrahydropyran-4-yl-pyrimidin-4-yl]pyrimidin-2-amine;
5-[6-(3-methoxyazetidin- 1-yl)-4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]-3-(trifluoromethyl)pyridin-2-amine;
5-[6-(3-fluoroazetidin-1-yl)-4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]-3-(trifluoromethyl)pyridin-2-amine;
3-chloro-5-[6-(3-fluoroazetidin- 1-yl)-4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]pyridin-2-amine;
5-[6-(3-fluoroazetidin-1-yl)-4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]pyrimidin-2-amine;
5-(2,6-dimorpholinopyrimidin-4-yl)pyrimidin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo [3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone;
1-[(1R,5S)-6-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine;
5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2-amine;
5-[2-cyclopropyl-6-[(1R,5S)-3-(oxetan-3-yl)-3azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridine-2-amine;
5-[2-cyclopropyl-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-cyclopropyl-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridine-2amine;
5-[2-cyclopropyl-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
5-[2-cyclopropyl-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine;
1-[(1R,5S)-6-[6-[6-amino 5-(difluromethoxy)-3-pyridyl]-2-cyclopropyl-pyrmidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-1one;
1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one;
3-(difluoromethoxy)-5-[2-[(3S)-3-fluoropyrrolodin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5yl]pyrimidin-4-yl]pyridin-2-amine;
3-(difluoromethoxy)-5-[2-[(3S)-3-fluoropyrrolidin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine;
3-(difluoromethoxy)-5-[2-3-methoxypyrrolidin-1-yl)-6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl]pyridin-2-amine;
5-[2-(2-azaspiro[3.3]heptan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)-pyridin-2-amine;
5-[2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5yl)-6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridine-2-amine;
5-[2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; and
3-(difluoromethoxy)-5-[2-(3-methoxy-3-methyl-azetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine; and
6-cyclopropyl-5′-(difluoromethoxy)-4-(1-(oxetan-3-yl)azetidin-3-yl)-[2,3′-bipyridin]-6′-amine
or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
33. A compound of claim 1 which is 3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4]pyridin-2-amine wherein is 3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
34. A compound of claim 1 which is 1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo [3.1.0]hexan-3-yl]-2-methyl-propan-2-ol; or a pharmaceutically acceptable salt thereof.
35. A compound of claim 1 which is 1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]-2-(3-azabicyclo [2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol; or a pharmaceutically acceptable salt thereof.
36. A compound of claim 1 which is [6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol which is 1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol; or a pharmaceutically acceptable salt thereof.
37. A compound of claim 1 which is 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
38. A compound of claim 1 which is 1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methoxy-2-methyl-propan-1-one; or a pharmaceutically acceptable salt thereof.
39. A compound of claim 1 which is [6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methoxy-ethanone which is 1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methoxy-ethanone; or a pharmaceutically acceptable salt thereof.
40. A compound of claim 1 which is 3-(difluoromethoxy)-5-[2-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
41. A compound of claim 1 which is 1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone; or a pharmaceutically acceptable salt thereof.
42. A compound of claim 1 which is 5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
43. A compound of claim 1 which is 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
44. A compound of claim 1 which is 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-isopropoxy-pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
45. A compound of claim 1 which is 5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
46. A compound of claim 1 which is 5-[6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
47. A compound of claim 1 which is 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
48. A compound of claim 1 which is 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
49. A compound of claim 1 which is 1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone; or a pharmaceutically acceptable salt thereof.
0. 50. A compound of claim 1 which is 1-[(1R,5S)-6-[6-(2-aminopyrimidin-5-yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol.
51. A compound of claim 1 which is 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)-6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
52. A compound of claim 1 which is 5-[2-cyclopropyl-6-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
53. A compound of claim 1 which is 1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol; or a pharmaceutically acceptable salt thereof.
54. A compound of claim 1 which is 1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one; or a pharmaceutically acceptable salt thereof.
55. A compound of claim 1 which is 3-(difluoromethoxy)-5-[2-[(3S)-3-fluoropyrrolidin-1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine; or a pharmaceutically acceptable salt thereof.
CROSS-REFERENCE TO RELATED APPLICATION

This application I-(LI)0-1-C1-6 alkyl,6((1R,3R,5R,7R)-2-azaadamantan- 2-yl)-2-(2-azabicyclo[2.1.1]hexan- 2-yl)-[4,5′-bipyrimidin]-2′amine  6 0.001 ##STR00068## 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.98 (s, 1H), 7.17 (t, J = 73.9 Hz, 1H), 6.45 (s, 2H), 5.01 (s, 1H), 4.68 (s, 1H), 3.91 (t, 2H), 3.81-3.69 (m, 3H), 3.66 (d, J = 7.4 Hz, 1H), 3.47 (d, J = 10.6, 1.5 Hz, 1H), 3.40-3.23 (m, 1H), 2.46 (q, J = 7.4, 6.9 Hz, 1H), 1.87 (s, 2H). 441 E 3-(difluoromethoxy)-5-[2-(3,3-di- fluoropyrrolidin-1-yl)-6-[(1S,4S)-2- oxa-5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyridin-2-amine  7 0.10 ##STR00069## 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.00 (s, 2H), 4.98 (s, 1H), 4.67 (s, 1H), 4.08 (t, J = 12.1 Hz, 2H), 3.88-3.71 (m, 3H), 3.65 (d, J = 7.4 Hz, 1H), 3.47 (d, J = 10.3 Hz, 1H), 3.37 (s, 1H), 2.17-1.95 (m, 2H), 1.88 (s, 2H), 1.78-1.58 (m, 2H). 390 E 5-[2-(3,3-difluoro-1-piperidyl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine  8 0.22 ##STR00070## 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 5.11- 4.74 (m, 2H), 4.67 (s, 1H), 3.98 (s, 2H), 3.78 (d, J = 7.0 Hz, 1H), 3.73- 3.55 (m, 3H), 3.45 (d, 1H), 2.00-1.76 (m, 4H), 1.76-1.58 (m, 2H). 372 E 5-[2-(4-fluoro-1-piperidyl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine  9 0.11 ##STR00071## 1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 2H), 6.68 (s, 1H), 5.34 (s, 2H), 4.97-4.95 (m, 1H), 4.69-4.62 (m, 4H), 3.83-3.78 (m, 1H), 3.55 (s, 2H), 3.14 (d, J = 8.8 Hz, 2H), 2.94- 2.93 (m, 1H), 2.50 (d, J = 8.4 Hz, 2H), 2.35- 2.33 (m, 1H), 2.13 (s, 2H), 1.99 (s, 2H), 1.46- 1.44 (m, 2H). 392.2 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(oxetan-3-yl)-3- azabicyclo[3.1.0]hexan-6-yl] pyrimidin-4-yl]pyrimidin-2-amine 10 0.01 ##STR00072## 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 7.21 (t, J = 73.6 Hz, 1H), 6.72 (s, 2H), 3.78-3.73 (m, 2H), 3.65-3.60 (m, 1H), 3.40-3.35 (m, 1H), 2.27-2.16 (m, 5H), 1.85 (t, J = 3.2 Hz, 1H), 1.00-0.93 (m, 7H). 416.1 C 1-[(1R,5S)-6-[6-[6-amino-5- (difluoromethoxy)-3-pyridyl]-2- cyclopropyl-pyrimidin-4-yl]- 3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one 11 0.01 ##STR00073## 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 7.21 (t, J = 73.6 Hz, 1H), 6.72 (s, 2H), 3.76-3.73 (m, 2H), 3.69-3.68 (m, 1H), 3.39-3.36 (m, 1H), 2.26-2.24 (m, 1H), 2.18-2.17 (m, 1H), 2.11-2.10 (m, 1H), 1.94 (s, 3H), 1.86 (t, J = 3.2 Hz, 1H), 1.00-0.97 (m, 4H). 402.1 C 1-[(1R,5S)-6-[6-[6-amino-5- (difluoromethoxy)-3-pyridyl]- 2-cyclopropyl-pyrimidin-4- yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone 12 0.01 ##STR00074## 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.36 (s, 1H), 6.79 (s, 2H), 6.53-6.21 (m, 1H), 5.10-4.89 (m, 1H), 4.80-4.78 (m, 1H), 4.74-4.63 (m, 1H), 3.55-3.51 (m, 1H), 3.44-3.35 (m, 2H), 3.23-2.84 (m, 4H), 2.82 (s, 1H), 2.00 (s, 1H), 1.91 (s, 3H), 1.83-1.81 (m, 2H), 1.29 (d, J = 2.0 Hz, 2H). 459.9 B 1-[(1S,4S)-5-[6-[6-amino-5- (trifluoromethyl)-3-pyridyl]-2-(3- azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]- 2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone 13 0.20 ##STR00075## 1H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.02 (s, 1H), 6.72 (s, 1H), 6.58 (t, J = 73.6 Hz, 1H), 4.97- 4.94 (m, 3H), 3.56 (s, 2H), 3.28 (d, J = 8.4 Hz, 2H), 3.15-3.08 (m, 2H), 2.95-2.93 (m, 1H), 2.78 (d, J = 8.4 Hz, 2H), 2.25 (d, J = 2.8 Hz, 1H), 2.12 (s, 2H), 1.99 (s, 2H), 1.49-1.43 (m, 2H). 483.14 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(2,2,2-trifluoroethyl)- 3-azabicyclo[3.1.0]hexan-6-yl] pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine 14 0.43 ##STR00076## 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H), 7.09 (s, 2H), 7.03 (s, 1H), 4.83 (br.s, 1H), 3.43 (s, 2H), 3.26-3.24 (m, 2H), 3.13 (d, J = 8.8 Hz, 2H), 2.89-2.87 (m, 1H), 2.74-2.72 (m, 2H), 2.12-2.11 (m, 1H), 2.03 (s, 2H), 1.93 (s, 2H), 1.30-1.29 (m, 2H). 418.1 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(2,2,2-trifluoroethyl)- 3-azabicyclo[3.1.0]hexan-6-yl] pyrimidin-4-yl]pyrimidin-2-amine 15 0.001 ##STR00077## 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.16 (s, 1H), 7.04 (s, 1H), 6.91 (s, 2H), 4.84-4.82 (m, 1H), 4.05 (s, 1H), 3.45 (s, 3H), 3.19 (d, J = 8.8 Hz, 2H), 2.91-2.89 (m, 1H), 2.35 (s, 2H), 2.26 (s, 1H), 1.98-1.95 (m, 4H), 1.33-1.32 (m, 2H), 1.08 (s, 6H). 491.2 C 1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethoxy)- 3-pyridyl]-2-(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]-3- azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol 16 0.001 ##STR00078## 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.39 (s, 1H), 7.06 (s, 1H), 6.91 (s, 2H), 4.83-4.81 (m, 1H), 4.02 (s, 1H), 3.42 (s, 2H), 3.16-3.14 (m, 2H), 2.87-2.85 (m, 1H), 2.48 (s, 2H), 2.31 (s, 2H), 2.23 (s, 1H), 1.95-1.92 (m, 4H), 1.29 (d, J = 2.8 Hz, 2H), 1.05 (s, 6H). 475.0 C 1-[(1R,5S)-6-[6-[6-amino-5-(trifluoromethyl)-3-pyridyl]- 2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4- yl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-methyl-propan-2-ol 17 0.001 ##STR00079## 1H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.02 (s, 1H), 6.68 (s, 1H), 6.58 (t, J = 73.6 Hz, 1H), 4.98 (s, 3H), 3.56 (s, 2H), 3.31- 3.28 (m, 2H), 3.01- 2.94 (m, 2H), 2.75 (d, J = 8.4 Hz, 2H), 2.50 (s, 2H), 2.26 (s, 1H), 2.10 (s, 2H), 1.99 (s, 2H), 1.80-1.70 (m, 2H), 1.19 (s, 6H). 473.17 C [6-amino-5-(difluoromethoxy)-3-pyridyl]- 2-(3-azabicyclo[2.1.1]hexan- 3-yl)pyrimidin-4-yl]-3-azabicyclo[3.1.0] hexan-3-yl]-2-methyl-propan-2-ol 1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)- 3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)- pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexane-3-yl]-2- methyl-propan-2-ol 18 0.05 ##STR00080## 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.13 (s, 1H), 7.07 (s, 1H), 6.94 (s, 2H), 4.85-4.83 (m, 1H), 3.74-3.65 (m, 3H), 3.45-3.40 (m, 3H), 2.95-2.91 (m, 1H), 2.23-2.17 (m, 2H), 1.96-1.93 (m, 4H), 1.74 (s, 1H), 1.33 (s, 2H), 1.30-1.22 (m, 1H). 460.9 C 1-[(1R,5S)-6-[6-[6-amino-5- (trifluoromethoxy)-3-pyridyl]-2-(3- azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]- 3-azabicyclo[3.1.0]hexan-3-yl]ethanone 19 0.03 ##STR00081## 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.37 (s, 1H), 7.09 (s, 1H), 6.94 (s, 2H), 4.84-4.82 (m, 1H), 3.71-3.64 (m, 3H), 3.43-3.35 (m, 2H), 3.34-3.31 (m, 1H), 3.26-3.21 (m, 1H), 2.89-2.87 (m, 1H), 2.21-2.14 (m, 2H), 1.94-1.90 (m, 4H), 1 73-1.71 (m, 1H), 1.31 (d, J = 4.0 Hz, 2H). 445.0 C 1-[(1R,5S)-6-[6-[6-amino-5- (trifluoromethyl)-3-pyridyl]-2-(3- azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]- 3-azabicyclo[3.1.0]hexan-3-yl]ethanone 20 0.01 ##STR00082## 1H NMR (400 MHz, Methanol-d4) δ 8.62 (s, 1H), 8.17 (s, 1H), 6.85 (s, 1H), 3.80-3.70 (m, 1H), 3.54-3.50 (m, 3H), 3.38 (s, 3H), 3.20 (d, J = 9.6 Hz, 2H), 2.95- 2.90 (m, 1H), 2.71- 2.69 (m, 2H), 2.58- 2.55 (m, 2H), 2.29 (s, 1H), 2.09-2.04 (m, 3H), 1.42-1.41 (m, 1H), 1.29 (s, 3H). 477.14 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(2-methoxyethyl)-3- azabicyclo[3.1.0]hexan-6-yl]pyrimidin- 4-yl]-3-(trifluoromethoxy)pyridin-2-amine 21 0.007 ##STR00083## 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.38 (s, 1H), 7.09 (s, 1H), 6.91 (s, 2H), 4.82-4.81 (m, 1H), 3.42-3.37 (m, 8H), 3.36-3.34 (m, 2H), 3.21 (s, 2H), 3.06 (d, J = 9.2 Hz, 1H), 2.87-2.84 (m, 1H), 2.58-2.57 (m, 1H), 2.39 (d, J = 8.8 Hz, 1H), 2.20 (s, 1H), 1.97- 1.93 (m, 3H), 1.29 (d, J = 2.4 Hz, 1H). 461.0 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(2-methoxyethyl)-3- azabicyclo[3.1.0]hexan-6-yl]pyrimidin- 4-yl]-3-(trifluoromethyl)pyridin-2-amine 22 0.03 ##STR00084## 1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 2H), 6.66 (s, 1H), 5.21 (s, 2H), 4.96 (d, J = 6.8 Hz, 1H), 3.54 (s, 2H), 3.50-3.47 (m, 2H), 3.38 (s, 3H), 3.22 (d, J = 8.8 Hz, 2H), 2.96- 2.94 (m, 1H), 2.72- 2.69 (m, 2H), 2.51 (d, J = 8.4 Hz, 2H), 2.35- 2.32 (m, 1H), 2.09 (s, 2H), 1.99 (s, 2H), 1.46- 1.44 (m, 2H). 393.9 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(2-methoxyethyl)-3- azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4- yl]pyrimidin-2-amine 23 0.02 ##STR00085## 1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.10 (s, 1H), 6.52 (br.s, 1H), 5.08 (br.s, 1H), 4.71 (s, 1H), 3.86 (d, J = 6.8 Hz, 1H), 3.78 (d, J = 7.2 Hz, 1H), 3.52 (d, J = 10.0 Hz, 1H), 3.35-3.31 (m, 1H), 2.06-2.02 (m, 1H), 2.01-1.96 (m, 2H), 1.08-1.05 (m, 2H), 0.95-0.92 (m, 2H). 394.19 A 5-[2-cyclopropyl-6-[(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]-3-(trifluoromethoxy) pyridin-2-amine 24 1.61 ##STR00086## 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.98 (s, 2H), 4.96 (s, 1H), 4.66 (s, 1H), 4.30-4.22 (m, 1H), 4.21-4.13 (m, 2H), 3.86-3.73 (m, 3H), 3.71-3.61 (m, 2H), 3.43 (d, J = 10.4, 2.5 Hz, 1H), 3.24 (s, 3H), 1.89 (s, 2H). 355 E 5-[2-(3-methoxyazetidin-1-yl)-6-[(1S,4S)- 2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]pyrimidin-4-yl]pyrimidin-2-amine 25 1.09 ##STR00087## 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.98 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.76 (d, J = 7.2, 1.5 Hz, 1H), 3.68 (s, 3H), 3.64 (d, J = 7.2 Hz, 1H), 3.43 (d, J = 10.5, 1.4 Hz, 1H), 1.85 (s, 2H), 1.26 (s, 5H). 353 E 5-[2-(3,3-dimethylazetidin-1-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 26 0.01 ##STR00088## 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.86 (s, 1H), 6.92 (t, J = 72.0 Hz, 1H), 6.24 (br.s, 1H), 4.96- 4.90 (m, 3H), 4.79- 4.74 (m, 2H), 4.55 (s, 2H), 4.10 (s, 1H), 3.81 (s, 1H), 3.62 (s, 2H), 3.55-3.52 (m, 1H), 3.04-2.97 (m, 3H), 2.11-2.06 (m, 3H), 1.96-1.94 (m, 1H), 1.51-1.44 (m, 2H). 472.0 B 5-(5-((1R,5S,6s)-3-oxabicyclo[3.1.0] hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)- 3-fluoro-1H-pyrrolo[2,3-b]pyridine 5-[2-(2-azabicyclo[2.1.1]hexan-2-yl)- 6-[(1S,4S)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine 27 0.001 ##STR00089## 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.97 (s, 1H), 7.12 (t, J = 74.0 Hz, 1H), 6.27 (s, 1H), 6.10 (s, 2H), 5.30 (br.s, 1H), 4.97 (s, 1H), 4.86 (d, J = 7.2 Hz, 1H), 3.65-3.57 (m, 2H), 3.48 (s, 3H), 3.44-3.42 (m, 1H), 3.16-3.11 (m, 3H), 2.91-2.89 (m, 1H), 1.95-1.88 (m, 4H), 1.34-1.20 (m, 8H). 516.0 B 1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)- 3-pyridyl]-2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin- 4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]- 2-methoxy-2-methyl-propan-1-one 28 0.001 ##STR00090## 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.97 (s, 1H), 7.18 (t, J = 73.6 Hz, 1H), 6.47 (s, 2H), 6.16 (br.s, 1H), 4.99 (br.s, 1H), 4.84-4.70 (m, 2H), 4.13-4.09 (m, 1H), 3.92-3.91 (m, 1H), 3.56-3.50 (m, 5H), 3.30-3.24 (m, 5H), 2.90-2.88 (m, 1H), 1.94-1.85 (m, 3H), 1.31-1.20 (m 2H). 488.0 B [6-amino-5-(difluoromethoxy)-3- pyridyl]-2-(3-azabicyclo[2.1.1]hexan- 3-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]-2-methoxy-ethanone 1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)-3- pyridyl]-2-(3-azabicycko[2.1.1]hexan-3-yl) pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3- methoxy-ethanone 29 0.005 ##STR00091## 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.99 (s, 1H), 7.39- 6.96 (m, 1H), 6.66- 6.12 (m, 3H), 5.51- 5.39 (m, 1H), 5.38- 5.26 (m, 1H), 5.01 (s, 1H), 4.68 (s, 1H), 4.02- 3.84 (m, 2H), 3.79 (d, J = 7.2, 1.6 Hz, 1H), 3.75- 3.56 (m, 3H), 3.47 (d, J = 10.4, 1.4 Hz, 1H), 3.37 (s, 1H), 1.87 (s, 2H). 441 E 3-(difluoromethoxy)-5-[2-[(3R,4S)- 3,4-difluoropyrrolidin-1-yl]-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan- 5-yl]pyrimidin-4-yl]pyridin-2-amine 30 0.81 ##STR00092## 1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.13 (s, 2H), 7.11 (s, 1H), 4.93 (d, J = 7.0 Hz, 1H), 3.51 (s, 2H), 2.98- 2.91 (m, 3H), 2.76 (t, J = 2.8 Hz, 1H), 2.01 (d, J = 16.4 Hz, 4H), 1.47 (dd, J = 3.9, 1.7 Hz, 2H), 1.36 (dd, J = 4.3, 1.7 Hz, 2H), 1.24 (s, 1H). 336 C 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(3-azabicyclo[2.1.1]hexan-4-yl) pyrimidin-4-yl]pyrimidin-2-amine 31 0.03 ##STR00093## 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.94 (s, 1H), 7.35- 6.93 (m, 1H), 6.43 (s, 2H), 4.96 (s, 1H), 4.66 (s, 1H), 3.99 (t, J = 7.4 Hz, 4H), 3.77 (d, J = 7.5, 1.5 Hz, 1H), 3.64 (d, J = 7.4 Hz, 1H), 3.44 (d, J = 10.0 Hz, 1H), 2.31-2.18 (m, 2H), 1.85 (s, 2H). 391 E 5-[2-(azetidin-1-yl)-6-[(1S,4S)-2- oxa-5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]-3-(difluoromethoxy) pyridin-2-amine 32 0.02 ##STR00094## 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.95 (s, 1H), 7.36- 6.95 (m, 1H), 6.46 (s, 2H), 5.58-5.33 (m, 1H), 4.98 (s, 1H), 4.67 (s, 1H), 4.40-4.26 (m, 2H), 4.06 (d, 1H), 4.00 (d, J = 11.1, 3.2 Hz, 1H), 3.78 (d, J = 7.2, 1.5 Hz, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.45 (d, J = 10.4 Hz, 1H), 1.86 (s, 2H). 409 E 3-(difluoromethoxy)-5-[2-(3- fluoroazetidin-1-yl)-6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyridin-2-amine 33 1.07 ##STR00095## 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.32 (s, 1H), 4.97 (s, 2H), 4.69-4.59 (m, 2H), 3.82-3.74 (m, 2H), 3.67 (dd, J = 7.3, 5.9 Hz, 2H), 3.45 (td, J = 8.6, 7.4, 4.3 Hz, 3H), 3.33 (d, J = 8.9 Hz, 2H), 1.89-1.77 (m, 4H). 368 E 5-[2,6-bis[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4- yl]pyrimidin-2-amine 34 0.024 ##STR00096## 427 E 5-[2-(3,3-difluoroazetidin-1-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3- (difluoromethoxy)pyridin-2-amine 35 0.17 ##STR00097## 1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.10 (s, 2H), 6.99 (s, 1H), 4.91 (d, J = 7.0 Hz, 1H), 3.50 (s, 2H), 3.15 (q, J = 10.2 Hz, 3H), 2.96-2.90 (m, 1H), 2.88-2.80 (m, 1H), 2.01-1.88 (m, 6H), 1.72-1.65 (m, 2H), 1.65-1.56 (m, 2H), 1.35 (dd, J = 4.3, 1.7 Hz, 2H). 446 C 5-[2-(3-azabicyclo[2.1.1]hexan-3- yl)-6-[8-(2,2,2-trifluoroethyl)-8- azabicyclo[3.2.1]octan-3-yl]pyrimidin-4- yl]pyrimidin-2-amine 36 0.22 ##STR00098## 1H NMR (400 MHz, Methanol-d4) δ 8.85 (s, 2H), 6.07 (br.s, 1H), 4.87 (d, J = 6.8 Hz, 1H), 4.54 (br.s, 1H), 3.83 (s, 1H), 3.51 (s, 3H), 3.34- 3.30 (m, 1H), 3.11- 3.08 (m, 1H), 2.89- 2.88 (m, 1H), 2.61- 2.50 (m, 2H), 1.98- 1.92 (m, 4H), 1.38 (d, J = 4.0 Hz, 2H), 1.06 (dd, J = 6.0, 15.2 Hz, 6H). 393.22 B 5-[2-(3-azabicyclo[2.1.1]hexan-3- yl)-6-[(1S,4S)-2-isopropyl-2,5- diazabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 37 0.22 ##STR00099## 1H NMR (400 MHz, Methanol-d4) δ 8.86 (s, 2H), 6.11 (br.s, 1H), 4.88 (d, J = 6.8 Hz, 1H), 4.60 (br.s, 1H), 3.70 (s, 4H), 3.40-3.31 (m, 1H), 2.95-2.91 (m, 2H), 2.66-2.56 (m, 3H), 2.00-1.86 (m, 4H), 1.41-1.40 (m, 2H), 1.10 (t, J = 3.2 Hz, 3H). 379.23 B 5-[2-(3-azabicyclo[2.1.1]hexan-3- yl)-6-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1] heptan-2-yl]pyrimidin-4-yl]pyrimidin-2-amine 38 0.29 ##STR00100## 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.95 (d, J = 6.4 Hz, 2H), 6.25 (br.s, 1H), 4.83 (d, J = 7.6 Hz, 2H), 4.56 (t, J = 6.8 Hz, 2H), 4.35 (t, J = 6.0 Hz, 1H), 4.28 (t, J = 6.4 Hz, 1H), 3.90-3.88 (m, 1H), 3.60-3.50 (m, 1H), 3.45 (s, 2H), 3.20-3.15 (m, 2H), 2.89-2.87 (m, 1H), 2.85-2.81 (m, 1H), 2.68-2.66 (m, 1H), 1.93 (s, 2H), 1.84- 1.82 (m, 1H), 1.80- 1.75 (m, 1H), 1.32- 1.15 (m, 2H). 407.2 B 5-[2-(3-azabicyclo[2.1.1]hexan-3- yl)-6-[(1S,4S)-2-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 39 0.07 ##STR00101## 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 7.04 (s, 2H), 6.31 (s, 1H), 5.49-5.34 (m, 2H), 4.85 (d, J = 6.4 Hz, 1H), 3.91-3.84 (m, 2H), 3.69-3.61 (m, 2H), 3.47 (s, 2H), 2.90- 2.88 (m, 1H), 1.94 (s, 2H), 1.32-1.23 (m, 2H). 359.8 B 5-[2-(3-azabicyclo[2.1.1]hexan-3- yl)-6-[(3S,4R)-3,4-difluoropyrrolidin- 1-yl]pyrimidin-4-yl]pyrimidin-2-amine 40 0.004 ##STR00102## 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.97 (s, 1H), 7.18 (t, J = 74.0 Hz, 1H), 6.47 (s, 2H), 6.17 (br.s, 1H), 4.98 (br.s, 1H), 4.84-4.67 (m, 2H), 3.56-3.54 (m, 1H), 3.50-3.38 (m, 4H), 3.33-3.26 (m, 2H), 2.88 (d, J = 3.2 Hz, 1H), 2.03 (s, 1H), 1.94 (s, 3H), 1.87-1.84 (m, 2H), 1.32-1.31 (m, 2H). 457.9 B 1-[(1S,4S)-5-[6-[6-amino-5-(difluoromethoxy)- 3-pyridyl]-2-(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]- 2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone 41 0.28 ##STR00103## 1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.11 (s, 2H), 7.02 (s, 1H), 4.89 (d, J = 7.0 Hz, 1H), 4.57-4.50 (m, 1H), 4.31-4.21 (m, 1H), 3.48 (s, 2H), 3.18- 3.09 (m, 1H), 2.95- 2.90 (m, 1H), 2.00 (s, 3H), 2.00-1.94 (m, 3H), 1.91-1.70 (m, 7H), 1.34 (dd, J = 4.4, 1.8 Hz, 2H). 406 C 1-[3-[6-(2-aminopyrimidin-5-yl)-2- (3-azabicyclo[2.1.1]hexan-3-yl) pyrimidin-4-yl]-8-azabicyclo[3.2.1] octan-8-yl]ethanone 42 0.17 ##STR00104## 5-[2-(2-fluoro-7-azaspiro[3.5] nonan-7-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 5.91- 5.77 (m, 1H), 5.18- 5.08 (m, 2H), 4.96 (s, 1H), 4.67 (s, 1H), 4.53- 4.44 (m, 2H), 3.77 (d, J = 7.2, 1.5 Hz, 1H), 3.41- 3.32 (m, 1H), 3.65 (d, J = 7.3 Hz, 1H), 3.45 (dd, J = 10.6, 1.5 Hz, 1H), 3.18 (t, J = 12.1 Hz, 2H), 2.43 (d, J = 7.2 Hz, 1H), 2.37 (d, J = 7.4 Hz, 1H), 1.86 (s, 2H), 1.83-1.72 (m, 2H), 1.72-1.51 (m, 2H). 412 E 43 1.61 ##STR00105## 5-[2-[(1R,5S)-3-methyl-3,6-diazabicyclo[3.2.1] octan-6-yl]-6-[(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 3.14- 2.98 (m, 1H), 2.82- 2.72 (m, 1H), 2.41 (s, 1H), 2.13 (d, J = 3.4 Hz, 3H), 1.96 (d, J = 10.5 Hz, 1H), 1.86 (s, 3H), 1.53 (d, J = 10.6 Hz, 1H), 3.38-3.31 (m, 1H), 8.89 (d, J = 10.6 Hz, 2H), 6.94 (s, 2H), 5.02-4.88 (m, 1H), 4.66 (s, 1H), 4.47-4.27 (m, 1H), 3.77 (d, J = 7.2 Hz, 1H), 3.66 (s, 1H), 3.55-3.39 (m, 3H). 395 E 44 0.07 ##STR00106## 5-[2-(4,4-difluoroazepan-1-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 4.96 (s, 1H), 4.67 (s, 1H), 3.87-3.72 (m, 5H), 3.41-3.32 (m, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.46 (d, J = 10.5, 1.4 Hz, 1H), 2.31-2.17 (m, 2H), 2.10-1.96 (m, 2H), 1.92-1.78 (m, 4H). 404 E 45 1.75 ##STR00107## 5-[2-(4-cyclobutylpiperazin-1-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 6.97 (s, 2H), 4.96 (s, 1H), 4.66 (s, 1H), 3.77 (d, J = 7.5, 1.4 Hz, 1H), 3.71 (t, J = 4.9 Hz, 4H), 3.65 (d, J = 7.3 Hz, 1H), 3.44 (d, J = 10.5, 1.4 Hz, 1H), 3.33 (s, 1H), 2.74-2.64 (m, 1H), 2.27 (t, J = 5.0 Hz, 4H), 1.97 (qd, J = 7.2 3.1 Hz, 2H), 1.92-1.72 (m, 4H), 1.72-1.54 (m, 2H). 409 E 46 1.61 ##STR00108## 5-[2-(2-methyl-2,7-diazaspiro[3.5] nonan-7-yl)-6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]pyrimidin- 4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.97 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.76 (d, J = 7.2, 1.5 Hz, 1H), 3.68 (s, 4H), 3.64 (d, J = 7.3 Hz, 1H), 3.43 (d, J = 10.5, 1.4 Hz, 1H), 2.24 (s, 4H), 2.13 (s, 3H), 1.85 (s, 2H), 1.71 (t, J = 5.3 Hz, 4H). 409 E 47 0.07 ##STR00109## 4-(2-aminopyrimidin-5-yl)-N,N- diethyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.94 (s, 2H), 4.93 (s, 1H), 4.66 (s, 1H), 3.77 (d, J = 7.2, 1.6 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.63-3.51 (m, 4H), 3.45 (d, J = 10.5, 1.4 Hz, 1H), 1.87 (t, 2H), 1.14 (t, 6H). 342 E 48 1.61 ##STR00110## 5-[2-(4-methylpiperazin-1-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H), 4.66 (s, 1H), 3.77 (d, J = 7.5, 1.5 Hz, 1H), 3.75-3.68 (m, 4H), 3.41-3.32 (m, 1H), 3.65 (d, J = 7.3 Hz, 1H), 3.45 (d, J = 10.5, 1.4 Hz, 1H), 3.17 (s, 1H), 2.34 (t, J = 5.0 Hz, 4H), 2.20 (s, 3H), 1.86 (s, 2H). 369 E 49 0.54 ##STR00111## 5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]-2-(1-piperidyl) pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 6.96 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.82-3.69 (m, 5H), 3.65 (d, J = 7.3 Hz, 1H), 3.49-3.41 (m, 1H), 3.40-3.32 (m, 1H), 1.92-1.80 (m, 2H), 1.67-1.56 (m, 2H), 1.56-1.45 (m, 4H). 354 E 50 0.41 ##STR00112## 5-[2-(azetidin-1-yl)-6-[(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.97 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.99 (t, J = 7.5 Hz, 4H), 3.77 (dd, J = 7.3, 1.5 Hz, 1H), 3.64 (d, J = 7.3 Hz, 1H), 3.43 (dd, J = 10.5, 1.5 Hz, 1H), 3.40- 3.32 (m, 1H), 3.17 (s, 1H), 2.24 (p, J = 7.5 Hz, 2H), 1.85 (s, 2H). 326 E 51 0.20 ##STR00113## 5-[2-[(3aS,6aR)-5,5-difluoro-1,3,3a,4,6,6a- hexahydrocyclopenta[c]pyrrol-2- yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.97 (s, 2H), 6.31 (s, 1H), 4.97 (s, 1H), 4.66 (s, 1H), 3.84-3.69 (m, 3H), 3.65 (d, J = 7.3 Hz, 1H), 3.51-3.41 (m, 3H), 2.89 (q, J = 9.3, 8.1 Hz, 2H), 2.48-2.31 (m, 2H), 2.16-1.98 (m, 2H), 1.86 (s, 2H). 416 E 52 0.086 ##STR00114## 5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]-2-pyrrolidin-1-yl-pyrimidin-4- yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.95 (s, 2H), 6.27 (s, 1H), 4.96 (s, 1H), 4.66 (s, 1H), 3.77 (d, J = 7.3, 1.5 Hz, 1H), 3.65 (d, J = 7.3 Hz, 1H), 3.58- 3.41 (m, 5H), 1.96- 1.79 (m, 6H). 340 E 53 0.27 ##STR00115## 5-[2-(3,3-difluoroazetidin-1-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.03 (s, 2H), 6.35 (s, 1H), 4.99 (s, 1H), 4.68 (s, 1H), 4.41 (t, J = 12.6 Hz, 4H), 3.78 (dd, J = 7.5, 1.5 Hz, 1H), 3.66 (d, J = 7.4 Hz, 1H), 3.50-3.42 (m, 1H), 3.40-3.31 (m, 1H), 1.87 (s, 2H). 362 E 54 0.16 ##STR00116## 5-[2-(7,7-difluoro-2-azaspiro[3.3] heptan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 7.00 (s, 2H), 4.97 (s, 1H), 4.67 (s, 1H), 4.19 (d, J = 9.3, 3.2 Hz, 2H), 3.94 (d, J = 9.2, 2.8 Hz, 2H), 3.77 (d, J = 7.5, 1.5 Hz, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.44 (d, J = 10.5, 1.5 Hz, 1H), 2.11-1.99 (m, 2H), 1.86 (s, 2H). 402 E 55 0.13 ##STR00117## 5-[2-[(3aR,6aS)-4,4-difluoro-1,3,3a,5,6,6a- hexahydrocyclopenta[c]pyrrol-2- yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H), 4.67 (s, 1H), 3.84-3.58 (m, 5H), 3.49-3.41 (m, 2H), 3.04-2.90 (m, 2H), 2.28-2.08 (m, 2H), 2.08-1.96 (m, 1H), 1.86 (s, 2H), 1.68-1.57 (m, 1H). 416 E 56 1.61 ##STR00118## 5-[2-(5-methyl-2,5-diazaspiro[3.4] octan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 6.98 (s, 2H), 4.96 (s, 1H), 4.66 (s, 1H), 4.08 (d, J = 9.0, 3.2 Hz, 2H), 3.82-3.71 (m, 3H), 3.65 (d, J = 7.2 Hz, 1H), 3.43 (d, J = 10.6, 1.5 Hz, 1H), 3.17 (d, J = 5.0 Hz, 1H), 2.62 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H), 2.05-1.97 (m, 2H), 1.85 (s, 2H), 1.73- 1.62 (m, 2H). 395 E 57 0.12 ##STR00119## 5-[2-(6-azaspiro[2.5]octan-6-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 6.96 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.84-3.79 (m, 4H), 3.77 (d, J = 7.2, 1.4 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.45 (d, J = 10.5, 1.5 Hz, 1H), 1.86 (s, 2H), 1.41-1.28 (m, 4H), 0.34 (s, 4H). 380 E 58 0.21 ##STR00120## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[8-(oxetan-3-yl)-8-azabicyclo[3.2.1] octan-3-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.09 (s, 2H), 6.99 (s, 1H), 4.92 (d, J = 7.0 Hz, 1H), 4.58 (t, J = 6.2 Hz, 2H), 4.35 (t, J = 5.7 Hz, 2H), 3.73-3.65 (m, 1H), 3.50 (s, 2H), 3.13 (s, 2H), 2.93 (dd, J = 6.8, 3.2 Hz, 1H), 2.90- 2.79 (m, 1H), 2.02- 1.81 (m, 6H), 1.69- 1.57 (m, 4H), 1.35 (dd, J = 4.3, 1.8 Hz, 2H) 420 C 59 0.02 ##STR00121## 1-[6-[6-(2-aminopyrimidin-5-yl)-2- (3-azabicyclo[2.1.1]hexan-3-yl) pyrimidin-4-yl]-3-azabicyclo[3.1.0] hexan-3-yl]ethanone 1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 2H), 6.65 (s, 1H), 5.49 (s, 2H), 4.95 (d, J = 6.0 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.72 (s, 2H), 3.54 (s, 3H), 2.95 (s, 1H), 2.30 (s, 2H), 2.06 (s, 3H), 2.00 (s, 2H), 1.70 (s, 1H), 1.45 (s, 2H). 377.8 C 60 0.01 ##STR00122## 1-[(1S,4S)-2-[6-(2-aminopyrimidin- 5-yl)-2-(3-azabicyclo[2.1.1]hexan-3- yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1] heptan-5-yl]-2-methyl-propan-2-ol 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.40- 6.14 (m, 1H), 4.83 (d, J = 6.8 Hz, 1H), 3.99 (s, 1H), 3.68-3.60 (m, 1H), 3.45 (s, 2H), 3.28- 3.27 (m, 2H), 3.04 (d, J = 7.6 Hz, 1H), 2.89- 2.87 (m, 1H), 2.57- 2.54 (m, 1H), 2.45- 2.41 (m, 2H), 1.93- 1.91 (m, 2H), 1.82- 1.71 (m, 2H), 1.32- 1.29 (m, 2H), 1.23- 1.15 (m, 1H), 1.04 (s, 6H). 423.2 B 61 0.01 ##STR00123## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-5-(2-methoxyethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl] pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d4) δ 8.84 (s, 2H), 6.09 (br.s, 1H), 4.95-4.87 (m, 2H), 4.67 (br.s, 1H), 3.71 (s, 1H), 3.62-3.52 (m, 4H), 3.48-3.45 (m, 1H), 3.34-3.31 (m, 3H), 3.00-2.95 (m, 1H), 2.92-2.90 (m, 1H), 2.76-2.74 (m, 2H), 2.67-2.64 (m, 1H), 1.98-1.94 (m, 3H), 1.88-1.82 (m, 1H), 1.42-1.38 (m, 2H). 409.2 B 62 0.003 ##STR00124## 5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3- (difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.96 (s, 1H), 7.17 (t, J = 74.0 Hz, 1H), 6.44 (s, 2H), 6.30 (br.s, 1H), 4.96 (s, 1H), 4.66 (s, 1H), 3.86-3.76 (m, 3H), 3.64 (d, J = 7.2 Hz, 1H), 3.45-3.40 (m, 4H), 1.85 (s, 2H), 1.61- 1.58 (m, 2H), 0.71- 0.66 (m, 1H), 0.14- 0.11 (m, 1H). 416.8 A 63 0.53 ##STR00125## 1-[6-[6-(2-aminopyrimidin-5-yl)-2- cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0] hexan-3-yl]ethanone 1H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 2H), 1.17 (s, 1H), 5.32 (s, 2H), 3.99 (d, J = 12.0 Hz, 1H), 3.74- 3.72 (m, 2H), 3.56 (dd, J = 4.0, 12.4 Hz, 1H), 2.33-2.29 (m, 2H), 2.25-2.20 (m, 1H), 2.07 (s, 3H), 1.80-1.78 (m, 1H), 1.13-1.11 (m, 2H), 1.04-1.02 (m, 2H). 336.9 C 64 0.27 ##STR00126## 5-[2-(3-azabicyclo[2.1.1]hexan-3- yl)-6-(9-azabicyclo[3.3.1]nonan-9-yl) pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.91 (s, 2H), 6.92 (br s, 2H), 6.50 (s, 1H), 5.03 (br s, 1H), 4.80 (d, J = 6.9 Hz, 1H), 4.36 (br s, 1H), 3.44 (s, 2H), 2.85 (m, 1H), 2.18- 1.51 (m, 14H), 1.39- 1.27 (m, 2H). 378 I 65 0.04 ##STR00127## 5-[2-[(3S,4R)-3,4-difluoropyrrolidin- 1-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 6.99 (s, 2H), 5.49- 5.38 (m, 1H), 5.38- 5.26 (m, 1H), 5.00 (s, 1H), 4.68 (s, 1H), 3.44- 3.32 (m, 1H), 4.03- 3.84 (m, 2H), 3.78 (d, J = 7.5, 1.5 Hz, 1H), 3.75- 3.57 (m, 3H), 3.46 (d, J = 10.5, 1.6 Hz, 1H), 3.37 (s, 1H), 1.95- 1.80 (m, 2H). 376 E 66 0.03 ##STR00128## 5-[2-(3,3-difluoropyrrolidin-1-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 6.99 (s, 2H), 5.00 (s, 1H), 4.67 (s, 1H), 3.91 (t, J = 13.5 Hz, 2H), 3.80-3.68 (m, 3H), 3.65 (d, J = 7.3 Hz, 1H), 3.46 (d, 1H), 3.37 (s, 1H), 1.87 (s, 2H). 376 E 67 0.65 ##STR00129## 5-[2-(3-fluoroazetidin-1-yl)-6-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 7.00 (s, 2H), 5.45 (d, J = 57.9, 6.1, 3.2 Hz, 1H), 4.97 (s, 1H), 4.67 (s, 1H), 4.40-4.25 (m, 2H), , 4.12-4.03 (m, 1H), 4.03-3.96 (m, 1H), 3.77 (d, J = 7.3, 1.5 Hz, 1H), 3.65 (d, J = 7.3 Hz, 1H), 3.44 (d, J = 10.5, 1.5 Hz, 1H), 3.41- 3.31 (m, 1H), 3.35 (s, 1H), 1.86 (s, 2H). 395 E 68 1.61 ##STR00130## 5-[2-(4-cyclopropylpiperazin-1-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H), 4.66 (s, 1H), 3.77 (d, J = 7.5, 1.7 Hz, 1H), 3.74-3.61 (m, 5H), 3.45 (d, J = 10.5, 1.5 Hz, 1H), 3.35 (s, 1H), 2.56 (t, J = 5.0 Hz, 4H), 1.86 (s, 2H), 1.68- 1.59 (m, 1H), 0.43 (m, 2H), 0.36 (q, J = 3.2, 2.6 Hz, 2H). 395 E 69 0.11 ##STR00131## 5-[2-[(1R,4R)-5,5-difluoro-2- azabicyclo[2.2.1]heptan-2-yl]-6-[(1S,4S)- 2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 2H), 4.75 (s, 2H), 4.67 (s, 2H), 3.77 (d, J = 7.5, 1.7 Hz, 2H), 3.66 (d, J = 7.4 Hz, 2H), 3.64-3.50 (m, 1H), ), 3.56 (t, J = 8.9 Hz, 1H), 3.50-3.40 (d, 1H), 3.40- 3.35 (m, 3H), 3.45 (d, J = 9.9, 1.7 Hz, 1H), 2.93 (s, 1H), 2.28-2.10 (m, 1H), 2.10-1.96 (m 1H), 1.89 (d, J = 18.5 Hz, 4H). 402 E 70 0.22 ##STR00132## 5-[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]-2-[4-(trifluoromethyl)-1- piperidyl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 4.97 (s, 1H), 4.85 (d, J = 13.2 Hz, 2H), 4.67 (s, 1H), 3.78 (d, J = 7.3, 1.4 Hz, 1H), 2.64-2.52 (m, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.46 (d, J = 10.5, 1.4 Hz, 1H), 3.35 (s, 1H), 2.82 (t, J = 12.8 Hz, 2H), 1.86 (d, J = 11.0 Hz, 4H), 1.45- 1.28 (m, 2H). 422 E 71 0.09 ##STR00133## 1-[2-(2-aminopyrimidin-5-yl)-6-(3- azabicyclo[2.1.1]hexan-3-yl)-4- pyridyl]cyclobutanecarbonitrile 1H NMR (400 MHz, DMSO) δ 8.92 (s, 2H), 7.10 (d, J = 1.1 Hz, 1H), 6.91 (br s, 2H), 6.46 (d, J = 1.1 Hz, 1H), 4.88 (d, J = 6.8 Hz, 1H), 3.44 (s, 2H), 3.01-2.90 (m, 1H), 2.75-2.64 (m, 4H), 2.39-2.18 (m, 1H), 2.11-1.92 (m, 3H), 1.41-1.27 (m, 2H). 333 G 72 0.04 ##STR00134## 1-[6-[6-amino-5-(difluoromethoxy)- 3-pyridyl]-2-(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]cyclobutanecarbonitrile 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.05 (s, 1H), 7.23 (t, J = 74.0 Hz, 2H), 7.20 (s, 1H), 6.70 (br s, 2H), 4.95 (m, 1H), 3.54 (s, 2H), 2.99-2.91 (m, 1H), 2.81 (m, 2H), 2.72- 2.60 (m, 2H), 2.32- 2.18 (m, 1H), 2.13- 1.94 (m, 3H), 1.45- 1.38 (m, 2H). 399 I 73 0.002 ##STR00135## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(3-azabicyclo[3.1.0]hexan-3-yl) pyrimidin-4-yl]-3-(difluoromethoxy) pyridin-2-amine 1H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.78 (s, 1H), 6.72 (t, J = 73.6 Hz, 1H), 5.90 (s, 1H), 4.73-4.68 (m, 1H), 3.62 (br.s, 2H), 3.37 (s, 2H), 3.30 (d, J = 10.4 Hz, 2H), 2.75- 2.73 (m, 1H), 1.83 (s, 2H), 1.51-1.50 (m, 2H), 1.24-1.22 (m, 2H), 0.64-0.61 (m, 1H), 0.02-0.01 (m, 1H). 401.0 A 74 0.05 ##STR00136## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-cyclopropyl-pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 1H), 7.91 (s, 1H), 5.92 (s, 1H), 4.96 (d, J = 6.8 Hz, 2H), 4.89 (s, 2H), 4.70 (s, 1H), 3.92- 3.87 (m, 2H), 3.58 (s, 2H), 3.52-4.94 (m, 2H), 2.92-2.90 (m, 1H), 1.96-1.93 (m, 4H), 1.68-1.66 (m, 1H), 1.48-1.46 (m, 2H), 0.96-0.94 (m, 2H), 0.69-0.67 (m, 2H). 390.9 A 75 0.009 ##STR00137## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3-isopropoxy- pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.23 (s, 1H), 6.21 (br.s, 2H), 5.92 (s, 2H), 4.96 (s, 1H), 4.80 (d, J = 7.2 Hz, 1H), 4.67-4.61 (m, 2H), 3.75 (d, J = 6.4 Hz, 1H), 3.63 (d, J = 7.2 Hz, 1H), 3.43-3.42 (m, 4H), 2.87-2.85 (m, 1H), 1.91-1.83 (m, 4H), 1.32-1.21 (m, 8H). 409.2 A 76 0.008 ##STR00138## 5-[2-cyclopropyl-6-[(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]-3-(difluoromethoxy) pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H), 7.99 (s, 1H), 6.58 (t, J = 73.2 Hz, 1H), 6.29 (s, 1H), 5.12 (br.s, 1H), 4.91 (s, 2H), 4.74 (s, 1H), 3.91-3.87 (m, 2H), 3.51-3.44 (m, 2H), 2.12-2.05 (m, 1H), 2.00-1.92 (m, 2H), 1.15-1.07 (m, 2H), 0.97-0.95 (m, 2H). 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.99 (s, 1H), 7.18 (t, J = 74.0 Hz, 1H), 6.80 (br.s, 1H), 6.54 (s, 2H), 5.02 (s, 1H), 4.69 (s, 1H), 3.78 (d, J = 6.8 Hz, 1H), 3.64 (d, J = 7.2 Hz, 1H), 3.48-3.45 (m, 2H), 1.99-1.88 (m, 3H), 0.99-0.88 (m, 4H). 376.1             376.1 A 77 0.16 ##STR00139## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(8-azabicyclo[3.2.1]octan-3-yl) pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.94 (s, 2H), 8.40 (s, 1H), 7.12 (s, 2H), 7.03 (s, 1H), 4.93 (d, J = 7.1 Hz, 1H), 3.81 (s, 2H), 3.04-2.94 (m, 2H), 2.95-2.90 (m, 1H), 2.03-1.95 (m, 4H), 1.94-1.76 (m, 7H), 1.35 (dd, J = 4.4, 1.7 Hz, 2H). 364 C 78 1.61 ##STR00140## 5-[2-[4-(cyclopropylmethyl) piperazin-1-yl]-6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4- yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H), 7.00 (s, 2H), 4.98 (s, 1H), 4.68 (s, 1H), 3.78 (d, J = 6.7 Hz, 1H), 3.65 (d, J = 7.4 Hz, 1H), 3.46 (d, J = 10.1 Hz, 1H), 3.10-2.52 (m, 4H), 1.87 (s, 2H), 0.96 (s, 1H), 0.55 (d, J = 7.5 Hz, 2H), 0.21 (s, 2H), 3.10- 2.52 (m, 4H). 409 E 79 0.06 ##STR00141## 5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)- 4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.15 (t, J = 74.0 Hz, 1H), 6.42 (s, 1H), 6.21 (s, 2H), 5.54 (s, 1H), 4.76- 4.74 (m, 2H), 4.62 (s, 1H), 3.73 (d, J = 6.8 Hz, 1H), 3.63 (d, J = 7.6 Hz, 1H), 3.45 (d, J = 8.8 Hz, 1H), 3.33 (s, 2H), 3.10 (d, J = 10.4 Hz, 1H), 2.88-2.86 (m, 1H), 1.88-1.81 (m, 4H), 1.27-1.26 (m, 2H). 416.1 D 80 0.08 ##STR00142## 5-[6-(3-azabicyclo[2.1.1]hexan-3- yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.99 (s, 2H), 6.38 (br.s, 1H), 4.97-4.91 (m, 2H), 4.62 (s, 1H), 3.78 (d, J = 6.4 Hz, 1H), 3.67 (d, J = 7.2 Hz, 1H), 3.47-3.41 (m, 4H), 2.96-2.90 (m, 1H), 1.98 (s, 2H), 1.87-1.79 (m, 2H), 1.33 (d, J = 2.8 Hz, 2H). 351.8 B 81 0.038 ##STR00143## 5-[2-(3-azabicyclo[3.1.0]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 7.00 (s, 2H), 6.54- 6.10 (br.s, 1H), 5.08- 4.96 (br.s, 1H), 4.66- 4.62 (m, 1H), 3.84- 3.81 (m, 2H), 3.77- 3.75 (m, 1H), 3.63 (d, J = 7.2 Hz, 1H), 3.44- 3.39 (m, 4H), 1.85 (s, 2H), 1.60-1.58 (m, 2H), 0.73-0.66 (m, 1H), 0.14-0.12 (m, 1H). 352.19 B 82 0.034 ##STR00144## 1-[(1S,4S)-5-[6-(2-aminopyrimidin- 5-yl)-2-(3-azabicyclo[2.1.1]hexan-3- yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1] heptan-2-yl]ethanone 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.00 (s, 2H), 6.68- 6.12 (br.s, 1H), 5.11- 4.95 (br.s, 1H), 4.88- 4.65 (m, 2H), 3.55- 3.33 (m, 5H), 3.28- 3.23 (m, 1H), 2.88 (d, J = 6.8 Hz, 1H), 2.02 (s, 2H), 1.93 (s, 3H), 1.86- 1.83 (m, 2H), 1.31 (s, 2H). 393.15 B 83 0.17 ##STR00145## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-2,2-dioxo-2$]{circumflex over ( )}{6}-thia- 5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 2H), 5.92 (s, 1H), 5.22 (s, 3H), 5.00-4.93 (m, 1H), 4.15-4.12 (m, 1H), 3.80 (s, 1H), 3.75- 3.72 (m, 1H), 3.55 (s, 2H), 3.45-3.41 (m, 1H), 3.21-3.18 (m, 1H), 2.95-2.93 (m, 1H), 2.74-2.71 (m, 1H), 2.50-2.47 (m, 1H), 2.00 (s, 2H), 1.47 (d, J = 4.0 Hz, 2H). 399.8 B 5-[2-(3-azabicyclo[2.1.1]hexane-3- yl)-6-[(1S,4S)-2,2-dioxo-2λ6thia-5- azabicyclo[2.2.1]heptain-5-yl]pyrimidin- 4-yl]pyrimidin-2-amine 84 0.051 ##STR00146## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-5-(2,2,2-trifluoroethyl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl] pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.00 (s, 2H), 6.50- 6.15 (m, 1H), 4.83 (d, J = 6.8 Hz, 1H), 3.69 (s, 1H), 3.51-3.48 (m, 3H), 3.45-3.40 (m, 2H), 3.08-3.05 (m, 1H), 2.89-2.88 (m, 1H), 2.68-2.64 (m, 1H), 2.02 (s, 1H), 1.87- 1.86 (m, 1H), 1.82- 1.77 (m, 1H), 1.38 (s, 3H), 1.33-1.32 (m, 2H). 433.1 A 85 0.05 ##STR00147## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(8-azabicyclo[3.2.1]octan-8-yl) pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.94 (s, 2H), 6.39 (s, 1H), 4.78-4.76 (m, 1H), 4.54 (br.s, 2H), 2.84-2.83 (m, 1H), 2.46 (s, 2H), 1.88 (s, 4H), 1.75-1.67 (m, 5H), 1.42-1.27 (m, 5H). 363.9 A 86 0.21 ##STR00148## 1-[6-(2-aminopyrimidin-5-yl)-2-(3- azabicyclo[2.1.1]hexan-3-yl) pyrimidin-4-yl]cyclobutanecarbonitrile 1H NMR (400 MHz, DMSO) δ 9.01 (s, 2H), 7.21 (br s, 2H), 7.20 (s, 1H), 5.06-4.80 (m, 1H), 3.54 (s, 2H), 2.99- 2.89 (m, 1H), 2.85- 2.73 (m, 2H), 2.70- 2.59 (m, 2H), 2.34- 2.14 (m, 1H), 2.14- 1.90 (m, 3H), 1.45- 1.33 (m, 2H). 334 I 87 0.21 ##STR00149## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 5-fluoro-6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 370 B 88 0.41 ##STR00150## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[3-(oxetan-3-yl)-3-azabicyclo[3.2.1] octan-8-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.96 (s, 2H), 7.14-7.02 (m, 3H), 4.90 (d, J = 6.0 Hz, 1H), 4.49 (dt, J = 19.6, 6.2 Hz, 4H), 3.57-3.45 (m, 3H), 2.97-2.87 (m, 1H), 2.76-2.66 (m, 4H), 2.62 (s, 1H), 2.10- 2.03 (m, 2H), 1.98 (s, 2H), 1.62 (s, 4H), 1.40- 1.33 (m, 2H). 420 C 89 0.01 ##STR00151## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3- (trifluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.14 (s, 1H), 6.80 (s, 2H), 6.23 (br.s, 1H), 5.00 (br.s, 1H), 4.82 (d, J = 6.8 Hz, 1H), 4.67 (s, 1H), 3.77 (d, J = 6.4 Hz, 1H), 3.65 (d, J = 7.2 Hz, 1H), 3.47-3.45 (m, 4H), 2.90-2.88 (m, 1H), 1.94-1.86 (m, 4H), 1.32-1.31 (m, 2H). 434.9 A 90 0.13 ##STR00152## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(2,5-diazabicyclo[2.2.1]heptan- 2-yl)pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.98 (s, 2H), 6.43- 6.09 (m, 1H), 4.90- 4.65 (m, 2H), 3.69- 3.61 (m, 1H), 3.50- 3.39 (m, 5H), 2.88 (d, J = 8.0 Hz, 2H), 2.79- 2.76 (m, 1H), 1.93 (s, 2H), 1.73-1.64 (m, 2H), 1.31-1.28 (m, 2H). 351.18 B 91 0.1 ##STR00153## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(3-azabicyclo[3.2.1]octan-8-yl) pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.08 (s, 2H), 7.01 (s, 1H), 4.89 (d, J = 6.7 Hz, 1H), 3.49 (s, 2H), 2.96- 2.90 (m, 1H), 2.81- 2.68 (m, 5H), 2.55 (s, 2H), 1.97 (d, J = 1.2 Hz, 2H), 1.68-1.51 (m, 4H), 1.35 (dd, J = 4.3, 1.8 Hz, 2H) 364 C 92 0.002 ##STR00154## 5-[6-[(1R,4S)-3-azabicyclo[2.2.1] heptan-3-yl]-2-(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]-3- (difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 7.95 (s, 1H), 7.18 (t, J = 73.9 Hz, 1H), 6.38 (br s, 2H), 6.36-6.00 (m, 1H), 4.82 (d, J = 7.0 Hz, 1H), 4.77-4.45 (m, 1H), 3.45 (s, 2H), 3.42- 3.34 (m, 1H), 3.16- 3.04 (m, 1H), 2.88 (dd, J = 6.9, 3.1 Hz, 1H), 2.61 (s, 1H), 1.93 (s, 2H), 1.73-1.44 (m, 5H), 1.41-1.26 (m, 3H). 415 E 93 0.01 ##STR00155## 5-[6-[(1R,4S)-3-azabicyclo[2.2.1] heptan-3-yl]-2-(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.88 (s, 2H), 6.93 (s, 2H), 6.35-6.10 (m, 1H), 4.82 (d, J = 7.0 Hz, 1H), 4.77-4.42 (m, 1H), 3.44 (s, 2H), 3.37 (d, J = 8.4 Hz, 1H), 3.21- 2.98 (m, 1H), 2.91- 2.83 (m, 1H), 2.61 (d, J = 1.9 Hz, 1H), 1.92 (s, 2H), 1.72-1.52 (m, 4H), 1.51-1.43 (m, 1H), 1.36 (t, J = 8.6 Hz, 1H), 1.31 (dd, J = 4.3, 1.6 Hz, 2H). 350 E 94 0.028 ##STR00156## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(3-azabicyclo[3.1.0]hexan-3-yl) pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 6.97 (s, 2H), 6.19 (s, 1H), 4.82 (d, J = 6.4 Hz, 1H), 3.74 (br.s, 2H), 3.44-3.38 (m, 4H), 2.88-2.87 (m, 1H), 1.92-1.87 (m, 2H), 1.65 (s, 2H), 1.31 (s, 2H), 0.73-0.72 (m, 1H), 0.13-0.12 (m, 1H). 335.8 A 95 0.68 ##STR00157## 5-[2-cyclopropyl-6-[(1S,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d4) δ 8.76 (s, 2H), 6.45 (br.s, 1H), 5.02-4.98 (m, 1H), 4.63 (s, 1H), 3.78-3.77 (m, 1H), 3.70-3.68 (m, 1H), 3.43-3.42 (m, 1H), 3.38-3.30 (m, 1H), 1.98-1.97 (m, 1H), 1.88-1.85 (m, 2H), 1.18-0.97 (m, 2H), 0.86-0.83 (m, 2H). 311.19 A 96 0.14 ##STR00158## 8-[6-(2-aminopyrimidin-5-yl)-2-(3- azabicyclo[2.1.1]hexan-3-yl) pyrimidin-4-yl]-3-methyl-8- azabicyclo[3.2.1]octan-3-ol 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.41 (s, 1H), 4.81-4.79 (m, 1H), 4.70-4.44 (m, 2H), 3.43 (s, 2H), 2.70- 2.69 (m, 2H), 2.25- 2.24 (m, 2H), 1.92 (s, 2H), 1.80-1.73 (m, 4H), 1.64-1.61 (m, 2H), 1.31-1.30 (m, 2H), 0.95 (s, 3H). 394.2 A 97 0.32 ##STR00159## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(2,6-dimethylmorpholin-4-yl) pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 2H), 6.08 (s, 1H), 5.70 (s, 2H), 4.94 (d, J = 7.2 Hz, 1H), 4.21 (d, J = 12.8 Hz, 2H), 3.72- 3.64 (m, 2H), 3.57 (s, 2H), 2.94-2.91 (m, 1H), 2.62-2.56 (m, 2H), 1.98 (d, J = 2.0 Hz, 2H), 1.47 (dd, J = 2.0, 4.4 Hz, 2H), 1.28 (d, J = 6.8 Hz, 6H). 368.0 A 98 0.101 ##STR00160## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(8-oxa-3-azabicyclo[3.2.1] octan-3-yl)pyrimidin-4-yl]pyrimidin-2- amine 1H NMR (400 MHz, Methanol-d4) δ 8.85 (s, 2H), 6.30 (s, 1H), 4.88- 4.86 (m, 1H), 4.44- 4.43 (m, 2H), 4.12- 4.06 (m, 2H), 3.53 (s, 2H), 3.10 (dd, J = 2.0, 12.8 Hz, 2H), 2.92- 2.90 (m, 1H), 2.00 (s, 1H), 1.95-1.91 (m, 2H), 1.87-1.79 (m, 3H), 1.40 (dd, J = 2.0, 4.4 Hz, 2H). 365.9 A 99 0.043 ##STR00161## 5-[2,6-bis(3-azabicyclo[2.1.1] hexan-3-yl)pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.34 (s, 1H), 4.84-4.82 (m, 2H), 3.40 (s, 4H), 2.96- 2.86 (m, 2H), 1.95 (d, J = 19.6 Hz, 4H), 1.32- 1.31 (m, 4H). 336.1 A 100  0.001 ##STR00162## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3- (difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.97 (s, 1H), 7.18 (t, J = 73.6 Hz, 1H), 6.47 (s, 2H), 6.25 (br.s, 1H), 5.00-4.97 (m, 1H), 4.85-4.83 (m, 1H), 4.68 (s, 1H), 3.78 (d, J = 6.4 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.52- 3.46 (m, 4H), 2.90- 2.89 (m, 1H), 1.95-1.87 (m, 4H), 1.32 (s, 2H). 416.9 A 101  0.026 ##STR00163## 2-amino-5-[2-(3-azabicyclo[2.1.1] hexan-3-yl)-6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]pyrimidin- 4-yl]pyridine-3-carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.54 (s, 1H), 7.26 (br.s, 2H), 6.50 (br.s, 1H), 5.04-5.01 (m, 1H), 4.86 (s, 1H), 4.68 (s, 1H), 3.78 (d, J = 7.2 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.47-3.44 (m, 4H), 2.92-2.89 (m, 1H), 1.95-1.87 (m, 4H), 1.35-1.33 (m, 2H). 375.9 A 102  0.024 ##STR00164## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3- chloro-pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.23 (s, 1H), 6.66 (s, 2H), 6.30-6.20 (m, 1H), 5.04-4.98 (m, 1H), 4.93-4.83 (m, 1H), 4.71-4.67 (m, 1H), 3.77 (d, J = 6.0 Hz, 1H), 3.66 (d, J = 7.2 Hz, 1H), 3.52-3.44 (m, 4H), 2.90-2.88 (m, 1H), 1.94-1.91 (m, 2H), 1.90-1.86 (m, 2H), 1.33-1.31 (m, 2H). 385.0 A 103  0.018 ##STR00165## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3- (trifluoromethyl)pyridin-2-amine 1H NMR (400 MHz, DMSO + H2O-d6) δ 8.76- 8.75 (m, 1H), 8.32- 8.28 (m, 1H), 6.60- 6.10 (m, 1H), 5.20- 5.00 (m, 1H), 4.90- 4.88 (m, 1H), 4.69- 4.70 (m, 1H), 3.79- 3.77 (m, 2H), 3.51- 3.48 (m, 4H), 2.93- 2.91 (m, 1H), 2.02- 1.99 (m, 2H), 1.95- 1.89 (m, 2H), 1.35 (s, 2H). 419.0 A 104  0.069 ##STR00166## 8-[6-(2-aminopyrimidin-5-yl)-2-(3- azabicyclo[2.1.1]hexan-3-yl) pyrimidin-4-yl]-8-azabicyclo[3.2.1]octan-3-ol 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 6.97 (s, 2H), 6.42 (s, 1H), 4.82-4.80 (m, 1H), 4.59-4.54 (m, 4H), 3.90-3.86 (m, 1H), 2.89-2.87 (m, 1H), 2.26-2.25 (m, 2H), 1.99-1.86 (m, 7H), 1.65-1.61 (m, 2H), 1.32-1.30 (m, 2H). 380.1 A 105  1.36 ##STR00167## 5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)- 4-(3-oxa-8-azabicyclo[3.2.1]octan- 8-yl)-2-pyridyl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.86 (s, 2H), 6.75 (s, 2H), 6.61 (d, J = 1.7 Hz, 1H), 5.81 (d, J = 1.7 Hz, 1H), 4.82-4.72 (m, 1H), 4.35 (s, 2H), 3.68 (d, J = 10.8 Hz, 2H), 3.44 (d, J = 10.9 Hz, 2H), 3.37 (s, 2H), 2.95-2.87 (m, 1H), 1.97-1.91 (m, 6H), 1.30 (dd, J = 4.3, 1.8 Hz, 2H). 365 D 106  0.98 ##STR00168## 5-[4,6-bis(3-azabicyclo[2.1.1] hexan-3-yl)-2-pyridyl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.84 (s, 2H), 6.73 (s, 2H), 6.49 (d, J = 1.6 Hz, 1H), 5.67 (d, J = 1.6 Hz, 1H), 4.77 (dd, J = 5.4, 1.6 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 3.36 (s, 2H), 2.96-2.88 (m, 2H), 1.92 (dd, J = 16.5, 1.6 Hz, 4H), 1.35-1.25 (m, 4H). 335 D 107  0.13 ##STR00169## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(3-oxa-8-azabicyclo[3.2.1]octan- 8-yl)pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H), 7.00 (s, 2H), 6.52 (s, 1H), 4.82 (d, J = 6.8 Hz, 1H), 4.65-4.50 (m, 2H), 3.62 (d, J = 10.8 Hz, 4H), 3.53 (d, J = 10.4 Hz, 2H), 2.89- 2.87 (m, 1H), 1.96- 1.86 (m, 6H), 1.32 (dd, J = 2.0, 4.4 Hz, 2H). 366.1 A 108  0.32 ##STR00170## 5-[6-(3-azabicyclo[2.1.1] hexan-3-yl)-4-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]-2- pyridyl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 6.75 (s, 2H), 6.44 (s, 1H), 5.57 (s, 1H), 4.78- 4.76 (m, 2H), 4.65 (s, 1H), 3.75 (dd, J = 7.3, 1.1 Hz, 1H), 3.66 (d, J = 7.4 Hz, 1H), 3.47 (dd, J = 9.7, 1.3 Hz, 1H), 3.36 (s, 2H), 3.12 (d, J = 9.8 Hz, 1H), 2.90 (dt, J = 6.2, 2.8 Hz, 1H), 1.93- 1.82 (m, 4H), 1.33- 1.27 (m, 2H). 351 D 109  0.48 ##STR00171## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-(2,2-dimethylmorpholin-4-yl) pyrimidin-4-yl]pyrimidin-2-amine No NMR 368 C 110  0.02 ##STR00172## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.99 (s, 2H), 6.30- 6.10 (m, 1H), 5.10- 4.90 (m, 1H), 4.83 (d, J = 6.8 Hz, 1H), 4.70- 4.64 (m, 1H), 3.85- 3.76 (m, 1H), 3.66- 3.64 (m, 1H), 3.45- 3.38 (m, 4H), 2.91- 2.87 (m, 1H), 1.93- 1.86 (m, 4H), 1.34- 1.29 (m, 2H). 352.1 A 111  0.15 ##STR00173## 5-[2-(2-methylpyrrolidin-1-yl)-6- tetrahydropyran-4-yl-pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.08 (s, 2H), 6.98 (s, 1H), 4.29-4.21 (m, 1H), 3.96-3.91 (m, 2H), 3.63-3.48 (m, 2H), 3.43 (td, J = 11.2, 3.4 Hz, 2H), 2.78-2.70 (m, 1H), 2.09-1.96 (m, 2H), 1.92-1.85 (m, 1H), 1.82-1.73 (m, 4H), 1.71-1.64 (m, 1H), 1.25 (d, J = 6.2 Hz, 3H). 341 C 112 0.06 ##STR00174## 5-[2-(2-methylpyrrolidin-1-yl)-6- tetrahydropyran-4-yl-pyrimidin-4-yl]pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 7.08 (s, 2H), 6.98 (s, 1H), 4.25 (dd, J = 6.1, 4.2 Hz, 1H), 3.94 (dd, J = 9.7, 2.3 Hz, 2H), 3.64- 3.49 (m, 2H), 3.43 (td, J = 11.3, 3.1 Hz, 2H), 2.79-2.69 (m, 1H), 2.10-1.95 (m, 2H), 1.91-1.72 (m, 5H), 1.72-1.63 (m, 1H), 1.25 (d, J = 6.3 Hz, 3H). 341 C 113 0.74 ##STR00175## 5-[6-(3-methoxyazetidin-1-yl)-4-[1- (oxetan-3-yl)-4-piperidyl]-2-pyridyl]- 3-(trifluoromethyl)pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.36 (s, 1H), 6.96 (s, 1H), 6.11 (s, 1H), 5.64 (s, 2H), 4.74- 4.67 (m, 4H), 4.38- 4.23 (m, 3H), 3.93- 3.90 (m, 2H), 3.63- 3.56 (m, 1H), 3.35 (s, 3H), 2.98 (d, J = 10.8 Hz, 2H), 2.54-2.46 (m, 1H), 2.06-1.99 (m, 2H), 1.93-1.88 (m, 4H). 464.0 F 114 0.69 ##STR00176## 5-[6-(3-fluoroazetidin-1-yl)-4-[1- (oxetan-3-yl)-4-piperidyl]-2-pyridyl]- 3-(trifluoromethyl)pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.36 (s, 1H), 6.89 (s, 1H), 6.14 (s, 1H), 5.53 (s, 2H), 4.74- 4.69 (m, 5H), 4.38- 4.31 (m, 2H), 4.20- 4.11 (m, 2H), 3.63- 3.60 (m, 1H), 3.00- 2.98 (m, 2H), 2.54- 2.49 (m, 1H), 2.04- 1.90 (m, 6H). 452.0 F 115 0.49 ##STR00177## 3-chloro-5-[6-(3-fluoroazetidin-1-yl)- 4-[1-(oxetan-3-yl)-4-piperidyl]-2-pyridyl]pyridin-2-amine 1H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.20 (s, 1H), 7.01 (s, 1H), 6.24 (s, 1H), 5.66-5.34 (m, 1H), 4.72-4.71 (m, 2H), 4.66-4.62 (m, 2H), 4.40-4.31 (m, 2H), 4.14-4.11 (m, 1H), 4.08-4.05 (m, 1H), 3.56-3.53 (m, 1H), 2.94-2.92 (m, 2H), 2.61-2.52 (m, 1H), 2.03-2.00 (m, 2H), 1.97-1.78 (m, 4H). 418.15 F 116 1.61 ##STR00178## 5-[6-(3-fluoroazetidin-1-yl)-4-[1- (oxetan-3-yl)-4-piperidyl]-2-pyridyl]pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d4) δ 8.86 (s, 2H), 7.01 (s, 1H), 6.26 (s, 1H), 5.53-5.36 (m, 1H), 4.74-4.71 (m, 2H), 4.65-4.62 (m, 2H), 4.40-4.31 (m, 2H), 4.14-4.05 (m, 2H), 3.56-3.52 (m, 1H), 2.93 (d, J = 12.0 Hz, 2H), 2.64-2.56 (m, 1H), 2.03-1.99 (m, 2H), 1.97-1.81 (m, 4H). 385.16 F 117 0.71 ##STR00179## 5(2,6-dimorpholinopyrimidin-4-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO) δ 8.93 (s, 2H), 7.00 (s, 2H), 6.60 (s, 1H), 3.70-3.60 (m, 16H). 344 G 118 0.001 ##STR00180## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(2-methoxyethyl)-3- azabicyclo[3.1.0]hexan-6-yl]pyrimidin- 4-yl]-3-(difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.01 (s, 1H), 6.71 (s, 1H), 6.57 (t, J = 73.6 Hz, 1H), 4.97- 4.93 (m, 3H), 3.55 (s, 2H), 3.50-3.47 (m, 2H), 3.38 (s, 3H), 3.22 (d, J = 8.4 Hz, 2H), 2.94- 2.92 (m, 1H), 2.72- 2.69 (m, 2H), 2.52- 2.50 (m, 2H), 2.32 (s, 1H), 2.09 (s, 2H), 1.98 (s, 2H), 1.46-1.44 (m, 2H). 459.15 C 119 0.002 ##STR00181## 1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2- (3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]- 3-azabicyclo[3.1.0]hexan-3-yl]ethanone 1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.03 (s, 1H), 6.71 (s, 1H), 6.58 (t, J = 73.2 Hz, 1H), 4.96 (s, 3H), 3.97 (d, J = 12.0 Hz, 1H), 3.73 (s, 2H), 3.56 (s, 2H), 3.00-2.95 (m, 1H), 2.31 (s, 2H), 2.07-2.00 (m, 5H), 1.72 (s, 1H), 1.60 (d, J = 3.6 Hz, 1H), 1.47 (s, 2H). 443.15 C 120 0.01 ##STR00182## 1-[(1R,5S)-6-[6-(2-aminopyrimidin-5- yl)-2-(3-azabicyclo[2.1.1]hexan-3-yl) pyrimidin-4-yl]-3-azabicyclo[3.1.0] hexan-3-yl]-2-methyl-propan-2-ol 1H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 2H), 6.65 (s, 1H), 5.31 (s, 2H), 4.97 (d, J = 7.2 Hz, 1H), 3.56 (s, 2H), 3.30 (d, J = 9.2 Hz, 2H), 2.98-2.93 (m, 2H), 2.75 (d, J = 8.8 Hz, 2H), 2.50 (s, 2H), 2.10 (s, 1H), 2.02 (s, 2H), 1.99 (s, 2H), 1.46-1.45 (m, 2H), 1.19 (s, 6H). 408.15 C 121 0.003 ##STR00183## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0] hexan-6-yl]pyrimidin-4-yl]-3-(difluoromethoxy) pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.03 (s, 1H), 6.72 (s, 1H), 6.58 (t, J = 73.2 Hz, 1H), 4.97- 4.93 (m, 3H), 4.71- 4.67 (m, 2H), 4.69- 4.61 (m, 2H), 3.82- 3.79 (m, 1H), 3.56 (s, 2H), 3.14 (d, J = 8.8 Hz, 2H), 2.95-2.93 (m, 1H), 2.50 (d, J = 8.4 Hz, 2H), 2.35-2.34 (m, 1H), 2.13 (s, 2H), 1.99 (s, 2H), 1.49-1.45 (m, 2H). 457.12 C 122 0.02 ##STR00184## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl] pyrimidin-4-yl]-3-(trifluoromethyl)pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.41 (s, 1H), 6.71 (s, 1H), 4.98-4.92 (m, 1H), 4.69-4.62 (m, 2H), 4.62-4.59 (m, 2H), 3.82-3.75 (m, 1H), 3.55 (s, 2H), 3.12 (d, J = 8.8 Hz, 2H), 2.93- 2.92 (m, 1H), 2.49 (d, J = 8.4 Hz, 2H), 2.35- 2.33 (m, 1H), 2.12 (s, 2H), 2.00-1.98 (m, 2H), 1.45-1.43 (m, 2H). 458.9 C 123 0.02 ##STR00185## 5-[2-(3-azabicyclo[2.1.1]hexan-3-yl)- 6-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl] pyrimidin-4-yl]-3-(trifluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.15 (s, 1H), 7.10 (s, 1H), 6.92 (s, 2H), 4.85-4.83 (m, 1H), 4.57-4.54 (m, 2H), 4.46-4.43 (m, 2H), 3.72-3.69 (m, 1H), 3.45 (s, 2H), 3.06 (d, J = 8.8 Hz, 2H), 2.91-2.89 (m, 1H), 2.40 (d, J = 8.4 Hz, 2H), 2.29 (s, 1H), 2.05 (s, 2H), 1.96 (s, 2H), 1.33-1.32 (m, 2H). 474.9 C 124 0.02 ##STR00186## 5-[2-cyclopropyl-6-[(1R,5S)-3-(oxetan-3-yl)-3- azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3- (difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.04 (s, 1H), 7.19 (s, 1H), 6.58 (t, J = 73.2 Hz, 1H), 4.97 (s, 2H), 4.69-4.59 (m, 4H), 3.81-3.75 (m, 1H), 3.12 (d, J = 8.8 Hz, 2H), 2.49 (d, J = 8.4 Hz, 2H), 2.42-2.40 (m, 1H), 2.18-2.15 (m, 1H), 2.11 (s, 2H), 1.11- 1.08 (m, 2H), 1.00- 0.97 (m, 2H). 416.1 C 125 0.11 ##STR00187## 5-[2-cyclopropyl-6-[(1R,5S)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3- (difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 7.97 (s, 1H), 7.14 (s, 1H), 6.52 (t, J = 73.6 Hz, 1H), 4.93 (s, 2H), 3.26-3.20 (m, 2H), 3.05-3.00 (m, 2H), 2.71 (d, J = 8.8 Hz, 2H), 2.27-2.25 (m, 1H), 2.11-2.10 (m, 1H), 2.04 (s, 2H), 1.18- 1.03 (m, 2H), 0.96- 0.91 (m, 2H). 442.1 C 126 0.003 ##STR00188## 5-[2-cyclopropyl-6-[(1R,5S)-3-(2-methoxyethyl)-3- azabicyclo[3.1.0]hexan-6-yl]pyrimidin-4-yl]-3- (difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.02 (s, 1H), 7.17 (s, 1H), 6.58 (t, J = 73.2 Hz, 1H), 4.96 (s, 2H), 3.46 (t, J = 6.4 Hz, 2H), 3.36 (s, 3H), 3.21 (d, J = 9.2 Hz, 2H), 2.70- 2.67 (m, 2H), 2.49 (d, J = 8.8 Hz, 2H), 2.38 (s, 1H), 2.17-2.15 (m, 1H), 2.06 (s, 2H), 1.11- 1.18 (m, 2H), 0.99- 0.96 (m, 2H). 418.2 C 127 0.001 ##STR00189## 1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]-2- cyclopropyl-pyrimidin-4-yl]-3-azabicyclo[3.1.0]hexan-3- yl]-2-methyl-propan-2-ol 1H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.05 (s, 1H), 7.18 (s, 1H), 6.60 (t, J = 73.2 Hz, 1H), 4.99 (s, 2H), 3.30 (d, J = 8.8 Hz, 2H), 2.92-2.85 (m, 1H), 2.75 (d, J = 8.4 Hz, 2H), 2.51 (s, 2H), 2.34 (s, 1H), 2.20-2.16 (m, 1H), 2.10 (s, 2H), 1.19 (s, 6H), 1.14-1.11 (m, 2H), 1.10-1.00 (m, 2H). 432.2 C 128 0.008 ##STR00190## 1-[(1R,5S)-6-[6-[6-amino-5-(difluoromethoxy)-3-pyridyl]- 2-(3-azabicyclo[2.1.1]hexan-3-yl)pyrimidin-4-yl]- 3-azabicyclo[3.1.0]hexan-3-yl]propan-1-one 1H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.02 (s, 1H), 6.69 (s, 1H), 6.58 (t, J = 73.6 Hz, 1H), 5.01- 4.94 (m, 3H), 3.98 (d, J = 8.4 Hz, 1H), 3.75- 3.66 (m, 2H), 3.57- 3.55 (m, 3H), 2.95- 2.94 (m, 1H), 2.32- 2.26 (m, 4H), 2.00 (s, 2H), 1.70-1.68 (m, 1H), 1.46-1.45 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H). 457.15 C 129 0.001 ##STR00191## 3-(difluoromethoxy)-5-[2-[(3S)-3- fluoropyrrolidin-1-yl]-6-[(1S,4S)-2- oxa-5-azabicyclo[2.2.1]heptan-5-yl] pyrimidin-4-yl]pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.99 (s, 1H), 7.17 (t, J = 73.8 Hz, 1H), 6.43 (s, 2H), 5.51-5.30 (m, 1H), 4.99 (s, 1H), , 4.67 (s, 1H), 3.93-3.74 (m, 3H), 3.74-3.44 (m, 4H), 3.35 (s, 1H), 2.28- 2.01 (m, 2H), 1.92- 1.82 (m, 2H). 423 E 130 0.022 ##STR00192## 3-(difluoromethoxy)-5-[2-(3- methoxypyrrolidin-1-yl)-6-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4- yl]pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.98 (s, 1H), 7.16 (t, 1H), 6.41 (s, 2H), 4.98 (s, 1H), 4.66 (s, 1H), 4.06-3.99 (m, 1H), 3.78 (d, J = 7.4 Hz, 1H), 3.70-3.53 (m, 4H), 3.46 (d, J = 10.1 Hz, 2H 3.35 (s, 1H), 3.26 (s, 3H), 2.06-1.93 (m, 2H), 1.86 (s, 2H). 435 E 131 0.01 ##STR00193## 5-[2-(2-azaspiro[3.3]heptan-2-yl)-6- [(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]-3- (difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.94 (s, 1H), 7.15 (t, 1H), 6.43 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.95 (s, 4H), 3.77 (d, J = 7.3 Hz, 1H), 3.64 (d, J = 7.3 Hz, 1H), 3.43 (d, J = 10.4 Hz, 1H), 3.35 (s, 1H), 2.15 (t, J = 7.6 Hz, 4H), 1.91-1.71 (m, 4H). 431 E 132 0.014 ##STR00194## 5-[2-(2,3,3a,4,6,6a-hexahydrofuro[2,3-c]pyrrol-5-yl)-6- (2-oxa-5-azabicyclo[2.2.1]heptan-5-yl) pyrimidin-4-yl]-3-(difluoromethoxy)pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.97 (s, 1H), 7.16 (t, J = 73.8 Hz, 1H), 6.42 (s, 2H), 4.98 (s, 1H), 4.66 (s, 1H), 4.50 (t, J = 5.6 Hz, 1H), 3.85 (q, J = 7.4 Hz, 1H), 3.81- 3.68 (m, 4H), 3.65 (d, J = 7.3 Hz, 1H), 3.59- 3.50 (m, 1H), 3.45 (d, J = 10.1 Hz, 1H), 3.35 (s, 1H), 2.99-2.87 (m, 1H), 2.14-1.98 (m, 1H), 1.93-1.73 (m, 3H). 447 E 133 0.08 ##STR00195## 3-(difluoromethoxy)-5-[2-(3-methoxy-3-methyl- azetidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.94 (s, 1H), 7.37- 6.94 (m, 1H), 6.45 (s, 2H), 4.97 (s, 1H), 4.67 (s, 1H), 3.97-3.89 (m, 2H), 3.85-3.73 (m, 3H), 3.65 (d, J = 7.3 Hz, 1H), 3.44 (d, J = 10.4 Hz, 1H), 3.40-3.30 (m, 1H), 3.20 (s, 3H), 1.86 (s, 2H), 1.44 (s, 3H). 435 E 134 0.02 ##STR00196## 6-cyclopropyl-5′-(difluoromethoxy)- 4-(1-(oxetan-3-yl)azetidin-3-yl)-[2,3′-bipyridin]-6′-amine 1H NMR (400 MHz, DMSO) δ 8.53 (d, J = 1.9 Hz, 1H), 7.94 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.17 (t, J = 74.0 Hz, 1H), 7.16 (s, 1H), 6.35 (br s, 2H), 4.62- 4.50 (m, 2H), 4.45- 4.32 (m, 2H), 3.82- 3.70 (m, 1H), 3.70- 3.60 (m, 3H), 3.28- 3.23 (m, 2H), 2.17- 2.03 (m, 1H), 1.05- 0.85 (m, 4H) J

Example 3

DLK TR-FRET inhibition assay: DLK kinase reactions (20 μL) containing 5 nM N-terminally GST-tagged DLK (catalytic domain amino acid 1-520) (Carna Bioscience), 40 nM N-terminally HIS-tagged MKK4 K131M substrate, and 30 μM ATP in kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01% Triton X-100, 0.01% Bovine γ-Globulins, 2 mM DTT, 10 mM MgCl2 and 1 mM EGTA), and testing compound 1:3 serial diluted starting at 20 uM were incubated at ambient temperature for 60 minutes in 384 well OptiPlate (Perkin Elmer). To quench kinase reactions and detect phosphorylated MKK4, 15 μL of TR-FRET antibody mixture containing 2 nM anti-phosphorylated MKK4 labeled with Europium cryptate (Cisbio) and 23 nM anti-HIS labeled with D2 (Cisbio) in detection buffer (25 mM Tris pH 7.5, 100 mM NaCl, 100 mM EDTA, 0.01% Tween-20, and 200 mM KF) was added to the reaction mixture. The detection mixture was incubated for 3 hours at ambient temperature and the TR-FRET was detected with an EnVision multilabel plate reader (Perkin-Elmer) using the LANCE/DELFIA Dual Enh label from Perkin-Elmer (excitation filter: UV2 (TRF) 320 and emission filters: APC 665 and Europium 615). Compounds of formula I as set forth in Table 1 in Example 1 inhibited the DLK kinase with the Kis in micromolar (μM).

INVENTORS:

Patel, Snahel, Estrada, Anthony, Siu, Michael, Lyssikatos, Joseph, Olivero, Alan G., Huestis, Malcolm, Kellar, Terry

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