U.S. patent application number 15/698771 was filed with the patent office on 2018-03-15 for pyrazolopyrimidine compounds and uses thereof.
The applicant listed for this patent is Incyte Corporation. Invention is credited to Joshua Hummel, Kai Liu, Jun Pan, Alexander Sokolsky, Oleg Vechorkin, Wenqing Yao, Hai Fen Ye, Qinda Ye.
Application Number | 20180072741 15/698771 |
Document ID | / |
Family ID | 59895447 |
Filed Date | 2018-03-15 |
United States Patent
Application |
20180072741 |
Kind Code |
A1 |
Vechorkin; Oleg ; et
al. |
March 15, 2018 |
PYRAZOLOPYRIMIDINE COMPOUNDS AND USES THEREOF
Abstract
Disclosed are compounds of Formula (I), methods of using the
compounds for inhibiting HPK1 activity and pharmaceutical
compositions comprising such compounds. The compounds are useful in
treating, preventing or ameliorating diseases or disorders
associated with HPK1 activity such as cancer.
Inventors: |
Vechorkin; Oleg;
(Wilmington, DE) ; Liu; Kai; (Bel Air, MD)
; Pan; Jun; (Media, PA) ; Sokolsky; Alexander;
(Philadelphia, PA) ; Ye; Hai Fen; (Newark, DE)
; Ye; Qinda; (Claymont, DE) ; Yao; Wenqing;
(Chadds Ford, PA) ; Hummel; Joshua; (Hockessin,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incyte Corporation |
Wilmington |
DE |
US |
|
|
Family ID: |
59895447 |
Appl. No.: |
15/698771 |
Filed: |
September 8, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62385604 |
Sep 9, 2016 |
|
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 487/04 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Claims
1. A compound of Formula I: ##STR00255## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is selected from
Cy.sup.1, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, halo, CN, NO.sub.2, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.a, NR.sup.cC(O)NR.sup.cR.sup.d,
C(.dbd.NR.sup.e)R.sup.b, C(.dbd.NOR.sup.a)R.sup.b,
C(.dbd.NR.sup.e)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.e)NR.sup.cR.sup.d, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.10;
Cy.sup.1 is selected from C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein the 4-10 membered heterocycloalkyl and 5-10 membered
heteroaryl each has at least one ring-forming carbon atom and 1, 2,
3, or 4 ring-forming heteroatoms independently selected from N, O,
and S; wherein the N and S are optionally oxidized; wherein a
ring-forming carbon atom of 5-10 membered heteroaryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form
a carbonyl group; and wherein the C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.10; Cy.sup.A is
selected from C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein
the 5-10 membered heteroaryl has at least one ring-forming carbon
atom and 1, 2, 3, or 4 ring-forming heteroatoms independently
selected from N, O, and S; wherein the N and S are optionally
oxidized; wherein a ring-forming carbon atom of the 5-10 membered
heteroaryl is optionally substituted by oxo to form a carbonyl
group; and wherein the C.sub.6-10 aryl and 5-10 membered heteroaryl
are each optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from R.sup.20; each R.sup.10 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)OR.sup.a1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
C(.dbd.NR.sup.e1)R.sup.b1, C(.dbd.NOR.sup.a1)R.sup.b1,
C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11; or two R.sup.10 substituents
taken together with the carbon atom to which they are attached form
a spiro 3-7-membered heterocycloalkyl ring, or a spiro C.sub.3-6
cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkyl
ring has at least one ring-forming carbon atom and 1, 2 or 3,
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each spiro 3-7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl
ring and spiro C.sub.3-6 cycloalkyl ring are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.11; each R.sup.11 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a3, SR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3,
C(O)OR.sup.a3, NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3,
NR.sup.c3C(O)OR.sup.a3, NR.sup.c3S(O)R.sup.b3,
NR.sup.c3S(O).sub.2R.sup.b3, NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3,
S(O)R.sup.b3, S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12; each R.sup.12 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-7 membered
heterocycloalkyl, halo, CN, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5,
C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5, NR.sup.c5R.sup.d5,
NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,
NR.sup.c5S(O)R.sup.b5, NR.sup.c5S(O).sub.2R.sup.b5,
NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5, S(O)R.sup.b5,
S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, and
S(O).sub.2NR.sup.c5R.sup.d5; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.g; each R.sup.20 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2C(O)NR.sup.c2R.sup.d2,
C(.dbd.NR.sup.e2)R.sup.b2, C(.dbd.NOR.sup.a2)R.sup.b2,
C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.c2)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,
S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl ring;
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
each has at least one ring-forming carbon atom and 1, 2, 3, or 4
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring is optionally substituted by oxo
to form a carbonyl group; and wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring and fused C.sub.3-7 cycloalkyl
ring are each optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.21; each R.sup.21 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a4, SR.sup.a4, C(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4,
C(O)OR.sup.a4, NR.sup.c4R.sup.d4, NR.sup.c4C(O)R.sup.b4,
NR.sup.c4C(O)OR.sup.a4, NR.sup.c4S(O)R.sup.b4,
NR.sup.c4S(O).sub.2R.sup.b4, NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4,
S(O)R.sup.b4, S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, and
S(O).sub.2NR.sup.c4R.sup.d4; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22; or two R.sup.21 substituents
taken together with the carbon atom to which they are attached form
a spiro 3-7-membered heterocycloalkyl ring, or a spiro C.sub.3-6
cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkyl
ring has at least one ring-forming carbon atom and 1, 2 or 3
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each spiro 3-7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl
ring and spiro C.sub.3-6 cycloalkyl ring are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.22; each R.sup.22 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl,
4-7 membered heterocycloalkyl, halo, CN, OR.sup.a6, SR.sup.a6,
C(O)R.sup.b6, C(O)NR.sup.c6R.sup.d6, C(O)OR.sup.a6,
NR.sup.c6R.sup.d6, NR.sup.c6C(O)R.sup.b6, NR.sup.c6C(O)OR.sup.a6,
NR.sup.c6S(O)R.sup.b6, NR.sup.c6S(O).sub.2R.sup.b6,
NR.sup.c6S(O).sub.2NR.sup.c6R.sup.d6, S(O)R.sup.b6,
S(O)NR.sup.c6R.sup.d6, S(O).sub.2R.sup.b6, and
S(O).sub.2NR.sup.c6R.sup.d6; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl,
5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.g; each R.sup.a, R.sup.c, and
R.sup.d is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10; or any R.sup.c
and R.sup.d attached to the same N atom, together with the N atom
to which they are attached, form a 4-10 membered heterocycloalkyl
group optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.10; each R.sup.b is independently
selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.10; each R.sup.e is independently selected from H, CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl; each R.sup.a1, R.sup.c1 and
R.sup.d1 is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11; or any R.sup.c1
and R.sup.d1 attached to the same N atom, together with the N atom
to which they are attached, form a 4-, 5-, 6- or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.11; each R.sup.b1 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11; each R.sup.e1 is
independently selected from H, CN, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkylaminosulfonyl, carbamyl, C.sub.1-6
alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl and di(C.sub.1-6 alkyl)aminosulfonyl;
each R.sup.a2, R.sup.c2 and R.sup.d2 is independently selected from
H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and
5-10 membered heteroaryl are each optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.21; or any
R.sup.c2 and R.sup.d2 attached to the same N atom, together with
the N atom to which they are attached, form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2,
3 or 4 substituents independently selected from R
.sup.21; each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.21; each R.sup.e2 is
independently selected from H, CN, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkylaminosulfonyl, carbamyl, C.sub.1-6
alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl and di(C.sub.1-6 alkyl)aminosulfonyl;
each R.sup.a3, R.sup.c3 and R.sup.d3 is independently selected from
H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-7 membered heterocycloalkyl; wherein said C.sub.1-6 alkyl
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl,
5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12; or any R.sup.c3 and R.sup.d3
attached to the same N atom, together with the N atom to which they
are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group optionally substituted with 1, 2 or 3 substituents
independently selected from R.sup.12; each R.sup.b3 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;
wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl are each optionally substituted with 1,
2, 3, or 4 substituents independently selected from R.sup.12; each
R.sup.a4, R.sup.c4 and R.sup.d4 is independently selected from H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl
and 4-7 membered heterocycloalkyl; wherein said C.sub.1-6 alkyl
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl,
5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22; or any R.sup.c4 and R.sup.d4
attached to the same N atom, together with the N atom to which they
are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group optionally substituted with 1, 2 or 3 substituents
independently selected from R.sup.22; each R.sup.b4 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;
wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl are each optionally substituted with 1,
2, 3, or 4 substituents independently selected from R.sup.22; each
R.sup.a5, R.sup.c5 and R.sup.d5 is independently selected from H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g; each R.sup.b5
is independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6
alkyl C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g; each R.sup.a6, R.sup.c6 and R.sup.d6 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g; each R.sup.b6 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.g; and
each R.sup.g is independently selected from OH, NO.sub.2, CN, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl-C1-2
alkylene, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-3
alkoxy-C.sub.1-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3 alkoxy,
HO--C.sub.1-3 alkoxy, HO--C.sub.1-3 alkyl, cyano-C.sub.1-3 alkyl,
H.sub.2N--C.sub.1-3 alkyl, amino, C.sub.1-6 alkylamino,
di(C.sub.1-6 alkyl)amino, thio, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamyl, C.sub.1-6
alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, carboxy, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl, di(C.sub.1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C.sub.1-6 alkylaminosulfonylamino, di(C.sub.1-6
alkyl)aminosulfonylamino, aminocarbonylamino, C.sub.1-6
alkylaminocarbonylamino, and di(C.sub.1-6 alkyl)aminocarbonylamino;
provided that: 1) R.sup.1 is other than NH.sub.2; 2) R.sup.1 is
other than CH.sub.3; 3) R.sup.1 is other than
CH.sub.2(quinolin-6-yl); 4) R.sup.1 is other than
NHC(O)CH.sub.2CH.sub.2CH.sub.3; and 5) when Cy.sup.A is
unsubstituted or substituted pyrazol-4-yl, then R.sup.1 is other
than pyridin-4-yl substituted by morpholine.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is selected from Cy.sup.1, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, and S(O).sub.2NR.sup.cR.sup.d; wherein said
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10.
3. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is selected from Cy.sup.1, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
and NR.sup.cC(O)R.sup.b; wherein said C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.10.
4. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is selected from Cy.sup.1, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl and OR.sup.a; wherein said C.sub.2-6
alkenyl and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from
R.sup.10.
5. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is selected from Cy.sup.1, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl; wherein said C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.10.
6. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is Cy.sup.1 or C.sub.2-6 alkenyl; wherein
said C.sub.2-6 alkenyl is optionally substituted with 1, 2, or 3
substituents independently selected from R.sup.10.
7. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is C.sub.2-6 alkenyl; wherein said
C.sub.2-6 alkenyl is optionally substituted with 1, 2, or 3
substituents independently selected from R.sup.10.
8. The compound of claim 7, wherein R.sup.1 is CHCH substituted
with R.sup.10, and R.sup.10 is phenyl substituted with
4-methylpiperazin-1-yl.
9. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is Cy.sup.1.
10. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.1 is selected from 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein the 4-10 membered heterocycloalkyl and 5-10 membered
heteroaryl each has at least one ring-forming carbon atom and 1, 2,
3, or 4 ring-forming heteroatoms independently selected from N, O,
and S; wherein the N and S are optionally oxidized; wherein a
ring-forming carbon atom of 5-10 membered heteroaryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form
a carbonyl group; and wherein the 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.10.
11. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.1 is C.sub.6-10 aryl or 5-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein the N and S are
optionally oxidized; wherein a ring-forming carbon atom of 5-10
membered heteroaryl is optionally substituted by oxo to form a
carbonyl group; and wherein the C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.10.
12. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.1 is C.sub.6-10 aryl optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.10.
13. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.1 is 5-10 membered heteroaryl optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.10.
14. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.1 is phenyl, pyrazolyl, pyridinyl,
pyrimidinyl, thiophenyl, and pyridone; wherein the phenyl,
pyrazolyl, pyridinyl, pyrimidinyl, thiophenyl, or pyridone are each
optionally substituted with 1, 2 or 3 substituents independently
selected from R.sup.10.
15. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.10 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)OR.sup.a1, NR.sup.c1S(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1,
S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10
membered heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10
aryl-C.sub.1-3 alkylene and 5-10 membered heteroaryl-C.sub.1-3
alkylene are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11.
16. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.10 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1, and S(O).sub.2R.sup.b1;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene and 5-10 membered
heteroaryl-C.sub.1-3 alkylene are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from
R.sup.11.
17. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.10 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10
membered heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10
aryl-C.sub.1-3 alkylene and 5-10 membered heteroaryl-C.sub.1-3
alkylene are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11.
18. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.10 is independently selected from
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, and
S(O).sub.2R.sup.b1; wherein said C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, and
4-10 membered heterocycloalkyl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, or 3 substituents independently
selected from R.sup.11.
19. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.10 is independently selected from
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, and NR.sup.c1R.sup.d1; wherein
said C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene are each optionally substituted
with 1, 2, or 3 substituents independently selected from
R.sup.11.
20. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.11 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR.sup.c3S(O).sub.2R.sup.b3, and
S(O).sub.2R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12.
21. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.11 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3,
and NR.sup.c3C(O)R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12.
22. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.11 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, 4-10 membered heterocycloalkyl, halo, CN, OR.sup.a3,
C(O)R.sup.b3, NR.sup.c3R.sup.d3, C(O)NR.sup.c3R.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR.sup.c3S(O).sub.2R.sup.b3, and
S(O).sub.2R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, and 4-10
membered heterocycloalkyl are each optionally substituted with 1,
2, or 3 substituents independently selected from R.sup.12.
23. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.11 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, 4-10 membered heterocycloalkyl, halo, CN, C(O)R.sup.b3,
NR.sup.c3R.sup.d3, and NR.sup.c3C(O)R.sup.b3; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally
substituted with 1, 2, or 3 substituents independently selected
from R.sup.12.
24. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.11 is independently selected from
C.sub.1-6 alkyl, 4-10 memberedheterocycloalkyl, CN, OR.sup.a3,
C(O)R.sup.b3, NR.sup.c3R.sup.d3, NR.sup.c3S(O).sub.2R.sup.b3, and
S(O).sub.2R.sup.b3; wherein said C.sub.1-6 alkyl and 4-10 membered
heterocycloalkyl are each optionally substituted with 1, 2, or 3
substituents independently selected from R.sup.12.
25. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.11 is independently selected from
C.sub.1-6 alkyl, 4-10 memberedheterocycloalkyl, CN, C(O)R.sup.b3,
and NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl and 4-10
membered heterocycloalkyl are each optionally substituted with 1,
2, or 3 substituents independently selected from R.sup.12.
26. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.12 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, halo, CN, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5,
C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5, NR.sup.c5R.sup.d5, or
NR.sup.c5C(O)R.sup.b5; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.g.
27. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.12 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, halo, and OR.sup.a5.
28. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.12 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, and halo.
29. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.12 is independently OR.sup.a5.
30. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.12 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl.
31. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.12 is C.sub.1-6 alkyl.
32. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.10 is 4-methylpiperazin-1-yl, fluoro,
methyl, CN, trifluormethyl, methoxy, N,N-dimethylaminocarbonyl,
(4-methylpiperazin-1-yl)methyl, 4-morpholinylmethyl, morpholinyl,
piperazin-1-yl, pyrrolidin-1-yl, N,N-dimethylamine,
morpholinylmethanone, N-cyclopentylaminocarbonyl,
4-(cycloprop-1-yl)morpholine, cyanomethyl, 4-ethylpiperazin-1-yl,
N-methylaminocarbonyl, cyclopropyl, pyridin-1-yl, methylamine,
1-methyl-1-cyanomethyl, tetrahydro-2H-pyran-4-yl, phenyl,
1-(piperazin-1-yl)ethan-1-one, 3-hydroxy-piperidin-1-yl,
4-cyano-piperidin-1-yl, 3-hydroxy-pyrrolidin-1-yl, piperidin-4-yl,
4-(2-methyl-2-hydroxypropyl)piperazin-1-yl,
3-methyl-3(methylhydroxy)piperidin-1-yl,
1-(methylsulfonyl)piperidin-4-amino,
4-(ethylhydroxy)piperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl,
4-((N-methyl-N-ethyl)aminocarbonyl)piperazin-1-yl, piperidin-1-yl,
4-(methylcarbonyl)piperazin-1-yl, 2-cyanophenyl,
1-hydroxyethane-2-amino, (methylsulfonyl)amino-methyl,
azetidin-1-ylsulfonyl, difluoromethoxy,
2-(methoxymethyl)morpholin-4-yl, 4-methyl-4-hydroxypiperidin-1-yl,
or 4-(2-methoxyethyl)piperazin-1-yl.
33. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.10 is 4-methylpiperazin-1-yl, fluoro,
methyl, CN, trifluormethyl, methoxy, N,N-dimethylaminocarbonyl,
(4-methylpiperazin-1-yl)methyl, 4-morpholinylmethyl, morpholinyl,
piperazin-1-yl, pyrrolidin-1-yl, N,N-dimethylamine,
morpholinylmethanone, N-cyclopentylaminocarbonyl,
4-(cycloprop-1-yl)morpholine, cyanomethyl, 4-ethylpiperazin-1-yl,
N-methylaminocarbonyl, cyclopropyl, pyridin-1-yl, methylamine,
1-methyl-1-cyanomethyl, tetrahydro-2H-pyran-4-yl, phenyl, or
1-(piperazin-1-yl)ethan-1-one.
34. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.A is selected from C.sub.6-10 aryl and 6-10
membered heteroaryl; wherein the 6-10 membered heteroaryl has at
least one ring-forming carbon atom and 1 or 2 ring-forming N
heteroatoms; wherein a ring-forming carbon atom of the 6-10
membered heteroaryl is optionally substituted by oxo to form a
carbonyl group; and wherein the C.sub.6-10 aryl and 6-10 membered
heteroaryl are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.20.
35. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.A is phenyl, pyridinyl, isoindolin-1-onyl,
1,2,3,4-tetrahydroisoquinolinyl, quinolinyl,
2,3-dihydro-1H-inden-5-yl, or 1,2,3,4-tetrahydronaphthyl; wherein
the phenyl, pyridinyl, isoindolin-1-onyl,
1,2,3,4-tetrahydroisoquinolinyl, quinolinyl,
2,3-dihydro-1H-inden-5-yl, and 1,2,3,4-tetrahydronaphthyl are each
optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R.sup.20.
36. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.A is phenyl, pyridinyl, isoindolin-1-onyl,
or 1,2,3,4-tetrahydroisoquinolinyl; wherein the phenyl, pyridinyl,
isoindolin-1-onyl, and 1,2,3,4-tetrahydroisoquinolinyl are each
optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R.sup.20.
37. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.20 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, 4-10 membered heterocycloalkyl, halo, CN, OR.sup.a2,
SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2S(O)R.sup.b2, NR.sup.c2S(O).sub.2R.sup.b2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.21; or two adjacent R.sup.20 substituents on the
Cy.sup.A ring, taken together with the atoms to which they are
attached, form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring, or a fused C.sub.3-7 cycloalkyl ring; wherein the fused 4-,
5-, 6- or 7-membered heterocycloalkyl ring each has at least one
ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21.
38. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.20 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, halo, CN, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2,
S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl ring;
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
each has at least one ring-forming carbon atom and 1, 2, 3, or 4
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring is optionally substituted by oxo
to form a carbonyl group; and wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl
ring are each optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.21.
39. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.20 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, 4-10 membered heterocycloalkyl, halo, OR.sup.a2,
SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl ring; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1 or 2 substituents independently selected from R.sup.21.
40. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.20 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, halo, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and
NR.sup.c2C(O)R.sup.b2; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.21; or
two adjacent R.sup.20 substituents on the Cy.sup.A ring, taken
together with the atoms to which they are attached, form a fused
4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring.
41. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.20 is independently selected from
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 4-10 membered
heterocycloalkyl, halo, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2; or two adjacent
R.sup.20 substituents on the Cy.sup.A ring, taken together with the
atoms to which they are attached, form a fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring or a fused C.sub.3-7 cycloalkyl
ring; and wherein the fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl ring are each
optionally substituted with 1 or 2 substituents independently
selected from R.sup.21.
42. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein each R.sup.20 is independently selected from
C.sub.1-6 alkyl, halo, OR.sup.a2, C(O)R.sup.b2, and
C(O)NR.sup.c2R.sup.d2; or two adjacent R.sup.20 substituents on the
Cy.sup.A ring, taken together with the atoms to which they are
attached, form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring.
43. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.20 is fluoro, methyl, methoxy, chloro,
(morpholino)methanone, N-methylaminocarbonyl, aminocarbonyl,
(methylamino)methyl, trifluoromethyl, pyrrolidin-2-yl,
piperidin-2-yl, ((pyrrolidin-1-yl)methyl)carbonylamino,
((N,N-dimethylamino)methyl)carbonylamino, C(O)H,
1-(methylamino)-ethyl, (ethylamino)methyl, cyanomethyl,
N-methylamino, or amino; or two adjacent R.sup.20 substituents on
the Cy.sup.A ring, taken together with the atoms to which they are
attached, form a fused piperidinyl ring.
44. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.20 is fluoro, methyl, methoxy, chloro,
(morpholino)methanone, N-methylaminocarbonyl, or aminocarbonyl; or
two adjacent R.sup.20 substituents on the Cy.sup.A ring, taken
together with the atoms to which they are attached, form a fused
piperidinyl ring.
45. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein Cy.sup.A is 2-fluoro-6-methoxyphenyl.
46. The compound of claim 1 having Formula (IIa1), Formula (IIa2),
Formula (IIa3), Formula (IIa4) or Formula (IIa5): ##STR00256## or a
pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,
or 4.
47. The compound of claim 1 having Formula (IIb1): ##STR00257## or
a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2,
3, 4 or 5.
48. The compound of claim 1 having Formula (IIc1), Formula (IIc2)
or Formula (IIc3): ##STR00258## or a pharmaceutically acceptable
salt thereof, wherein m is 0, 1, 2, 3, or 4; and n is 0, 1, 2, 3,
4, or 5.
49. A compound of Formula I: ##STR00259## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is selected from
Cy.sup.1, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, halo, CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b,
C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.a,
NR.sup.cC(O)NR.sup.cR.sup.d, C(.dbd.NR.sup.e)R.sup.b,
C(.dbd.NOR.sup.a)R.sup.b, C(.dbd.NR.sup.e)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.e)NR.sup.cR.sup.d, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.10; Cy.sup.1 is
selected from C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein the 4-10 membered heterocycloalkyl and 5-10 membered
heteroaryl each has at least one ring-forming carbon atom and 1, 2,
3, or 4 ring-forming heteroatoms independently selected from N, O,
and S; wherein the N and S are optionally oxidized; wherein a
ring-forming carbon atom of 5-10 membered heteroaryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form
a carbonyl group; and wherein the C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.10; Cy.sup.A is
selected from C.sub.6-10 aryl and 6-10 membered heteroaryl; wherein
the 6-10 membered heteroaryl has at least one ring-forming carbon
atom and 1, 2, 3, or 4 ring-forming heteroatoms independently
selected from N, O, and S; wherein the N and S are optionally
oxidized; wherein a ring-forming carbon atom of the 6-10 membered
heteroaryl is optionally substituted by oxo to form a carbonyl
group; and wherein the C.sub.6-10 aryl and 6-10 membered heteroaryl
are each optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from R.sup.20; each R.sup.10 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)OR.sup.a1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
C(.dbd.NR.sup.e1)R.sup.b1, C(.dbd.NOR.sup.a1)R.sup.b1,
C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11; or two R.sup.10 substituents
taken together with the carbon atom to which they are attached form
a spiro 3-7-membered heterocycloalkyl ring, or a spiro C.sub.3-6
cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkyl
ring has at least one ring-forming carbon atom and 1, 2 or 3,
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each spiro 3-7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl
ring and spiro C.sub.3-6 cycloalkyl ring are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.11; each R.sup.11 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a3, SR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3,
C(O)OR.sup.a3, NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3,
NR.sup.c3C(O)OR.sup.a3, NR.sup.c3S(O)R.sup.b3,
NR.sup.c3S(O).sub.2R.sup.b3, NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3,
S(O)R.sup.b3, S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12; each R.sup.12 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-7 membered
heterocycloalkyl, halo, CN, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5,
C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5, NR.sup.c5R.sup.d5,
NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,
NR.sup.c5S(O)R.sup.b5, NR.sup.c5S(O).sub.2R.sup.b5,
NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5, S(O)R.sup.b5,
S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, and
S(O).sub.2NR.sup.c5R.sup.d5; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.g; each R.sup.20 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
NO.sub.2, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2C(O)NR.sup.c2R.sup.d2,
C(.dbd.NR.sup.e2)R.sup.b2, C(.dbd.NOR.sup.a2)R.sup.b2,
C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,
S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl ring;
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
each has at least one ring-forming carbon atom and 1, 2, 3, or 4
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring is optionally substituted by oxo
to form a carbonyl group; and wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl
ring are each optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.21; each R.sup.21 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a4, SR.sup.a4, C(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4,
C(O)OR.sup.a4, NR.sup.c4R.sup.d4, NR.sup.c4C(O)R.sup.b4,
NR.sup.c4C(O)OR.sup.a4, NR.sup.c4S(O)R.sup.b4,
NR.sup.c4S(O).sub.2R.sup.b4, NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4,
S(O)R.sup.b4, S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, and
S(O).sub.2NR.sup.c4R.sup.d4; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22; or two R.sup.21 substituents
taken together with the carbon atom to which they are attached form
a spiro 3-7-membered heterocycloalkyl ring, or a spiro C.sub.3-6
cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkyl
ring has at least one ring-forming carbon atom and 1, 2 or 3
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each spiro 3-7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl
ring and spiro C.sub.3-6 cycloalkyl ring are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.22; each R.sup.22 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl,
4-7 membered heterocycloalkyl, halo, CN, OR.sup.a6, SR.sup.a6,
C(O)R.sup.b6, C(O)NR.sup.c6R.sup.d6, C(O)OR.sup.a6,
NR.sup.c6R.sup.d6, NR.sup.c6C(O)R.sup.b6, NR.sup.c6C(O)OR.sup.a6,
NR.sup.c6S(O)R.sup.b6, NR.sup.c6S(O).sub.2R.sup.b6,
NR.sup.c6S(O).sub.2NR.sup.c6R.sup.d6, S(O)R.sup.b6,
S(O)NR.sup.c6R.sup.d6, S(O).sub.2R.sup.b6, and
S(O).sub.2NR.sup.c6R.sup.d6; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl,
5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.g; each R.sup.a, R.sup.c, and
R.sup.d is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10; or any R.sup.c
and R.sup.d attached to the same N atom, together with the N atom
to which they are attached, form a 4-10 membered heterocycloalkyl
group optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.10; each R.sup.b is independently
selected from C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, and 5-10 membered heteroaryl; wherein said
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10; each R.sup.e is
independently selected from H, CN, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkylaminosulfonyl, carbamyl, C.sub.1-6
alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl and di(C.sub.1-6 alkyl)aminosulfonyl;
each R.sup.a1, R.sup.c1 and R.sup.d1 is independently selected from
H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and
5-10 membered heteroaryl are each optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.11; or any
R.sup.c1 and R.sup.d1 attached to the same N atom, together with
the N atom to which they are attached, form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2,
3 or 4 substituents independently selected from R.sup.11; each
R.sup.b1 is independently selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and
5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11; each R.sup.e1 is
independently selected from H, CN, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkylaminosulfonyl, carbamyl, C.sub.1-6
alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl and di(C.sub.1-6 alkyl)aminosulfonyl;
each R.sup.a2, R.sup.c2 and R.sup.d2 is independently selected from
H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and
5-10 membered heteroaryl are each optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.21; or any
R.sup.c2 and R.sup.d2 attached to the same N atom, together with
the N atom to which they are attached, form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2,
3 or 4 substituents independently selected from R.sup.21; each
R.sup.b2 is independently selected from C
.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and
5-10 membered heteroaryl are each optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.21; each
R.sup.c2 is independently selected from H, CN, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfonyl,
C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkylaminosulfonyl, carbamyl,
C.sub.1-6 alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl,
aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and di(C.sub.1-6
alkyl)aminosulfonyl; each R.sup.a3, R.sup.c3 and R.sup.d3 is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;
wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl are each optionally substituted with 1,
2, 3, or 4 substituents independently selected from R.sup.12; or
any R.sup.c3 and R.sup.d3 attached to the same N atom, together
with the N atom to which they are attached, form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 substituents independently selected from R.sup.12; each
R.sup.b3 is independently selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered
heteroaryl and 4-7 membered heterocycloalkyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.12; each R.sup.a4, R.sup.c4 and R.sup.d4 is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl,
phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;
wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl are each optionally substituted with 1,
2, 3, or 4 substituents independently selected from R.sup.22; or
any R.sup.c4 and R.sup.d4 attached to the same N atom, together
with the N atom to which they are attached, form a 4-, 5-, 6- or
7-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 substituents independently selected from R.sup.22; each
R.sup.b4 is independently selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered
heteroaryl and 4-7 membered heterocycloalkyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.22; each R.sup.a5, R.sup.c5 and R.sup.d5 is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g; each R.sup.b5 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g; each R.sup.a6,
R.sup.c6 and R.sup.d6 is independently selected from H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g; each R.sup.b6
is independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g; and each R.sup.g is independently selected from OH,
NO.sub.2, CN, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C1-2 alkylene, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3
alkoxy, HO--C.sub.1-3 alkoxy, HO--C.sub.1-3 alkyl, cyano-C.sub.1-3
alkyl, H.sub.2N--C.sub.1-3 alkyl, amino, C.sub.1-6 alkylamino,
di(C.sub.1-6 alkyl)amino, thio, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamyl, C.sub.1-6
alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, carboxy, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl, di(C.sub.1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C.sub.1-6 alkylaminosulfonylamino, di(C.sub.1-6
alkyl)aminosulfonylamino, aminocarbonylamino, C.sub.1-6
alkylaminocarbonylamino, and di(C.sub.1-6
alkyl)aminocarbonylamino.
50. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein: R.sup.1 is selected from Cy.sup.1, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, and S(O).sub.2NR.sup.cR.sup.d; wherein said
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10; Cy.sup.1 is selected from 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein the 4-10 membered heterocycloalkyl and 5-10 membered
heteroaryl each has at least one ring-forming carbon atom and 1, 2,
3, or 4 ring-forming heteroatoms independently selected from N, O,
and S; wherein the N and S are optionally oxidized; wherein a
ring-forming carbon atom of 5-10 membered heteroaryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form
a carbonyl group; and wherein the 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.10; Cy.sup.A is selected from C.sub.6-10 aryl and 6-10
membered heteroaryl; wherein the 5-10 membered heteroaryl has at
least one ring-forming carbon atom and 1 or 2 ring-forming N
heteroatoms; wherein a ring-forming carbon atom of the 6-10
membered heteroaryl is optionally substituted by oxo to form a
carbonyl group; and wherein the C.sub.6-10 aryl and 6-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or
substituents independently selected from R.sup.20; each R.sup.10 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
NO.sub.2, OR.sup.a1 SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O)R.sup.b1, NR.sup.c1S(O).sub.2R.sup.b1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11; each R.sup.11 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, halo, CN, OR.sup.a3, SR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, NR.sup.c3R.sup.d3,
NR.sup.c3S(O)R.sup.b3, and NR.sup.c3C(O)OR.sup.a3; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, and
5-10 membered heteroaryl are each optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.12; each
R.sup.12 is independently selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, OR.sup.a5,
SR.sup.a5, C(O)R.sup.b5, C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5,
NR.sup.c5R.sup.d5, NR.sup.c5C(O)R.sup.b5, and
NR.sup.c5C(O)OR.sup.a5; each R.sup.20 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, halo, CN, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2,
S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl ring;
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
each has at least one ring-forming carbon atom and 1, 2, 3, or 4
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring is optionally substituted by oxo
to form a carbonyl group; and wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl
ring are each optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.21; each R.sup.21 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, OR.sup.a4, SR.sup.a4,
C(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4, C(O)OR.sup.a4,
NR.sup.c4R.sup.d4, NR.sup.c4C(O)R.sup.b4, and
NR.sup.c4C(O)OR.sup.a4; each R.sup.a, R.sup.c, and R.sup.d is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered hetero cycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.10; each R.sup.b is independently
selected from C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, and 5-10 membered heteroaryl; wherein said
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10; each R.sup.a1,
R.sup.c1 and R.sup.d1 is independently selected from H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered hetero cycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11; or any R.sup.c1
and R.sup.d1 attached to the same N atom, together with the N atom
to which they are attached, form a 4-, 5-, 6- or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.11; each R.sup.b1 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl; each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl; or any R.sup.c2 and R.sup.d2
attached to the same N atom, together with the N atom to which they
are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.21; each R.sup.b2 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl; each R.sup.a3, R.sup.c3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl; each R.sup.b3 is independently
selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl; each R.sup.a4, R.sup.c4 and
R.sup.d4 is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; each
R.sup.b4 is independently selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; each R.sup.a5,
R.sup.c5 and R.sup.d5 is independently selected from H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl; and each R.sup.b5 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl.
51. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein: R.sup.1 is selected from Cy.sup.1, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
and NR.sup.cC(O)R.sup.b; wherein said C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.10; Cy.sup.1 is
selected from 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and
5-10 membered hetero aryl; wherein the 4-10 membered
heterocycloalkyl and 5-10 membered heteroaryl each has at least one
ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein the N and S are
optionally oxidized; wherein a ring-forming carbon atom of 5-10
membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10; Cy.sup.A is
selected from C.sub.6-10 aryl and 6-10 membered heteroaryl; wherein
the 5-10 membered heteroaryl has at least one ring-forming carbon
atom and 1 or 2 ring-forming N heteroatoms; wherein a ring-forming
carbon atom of the 6-10 membered heteroaryl is optionally
substituted by oxo to form a carbonyl group; and wherein the
C.sub.6-10 aryl and 6-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or substituents independently selected
from R.sup.20; each R.sup.10 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, C.sub.3-10
cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10
membered heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10
aryl-C.sub.1-3 alkylene and 5-10 membered heteroaryl-C.sub.1-3
alkylene are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11; each R.sup.11 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, halo, CN, OR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, NR.sup.c3R.sup.d3, and
NR.sup.c3C(O)R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12; each R.sup.12 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, and halo; each R.sup.20 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN, OR.sup.a2,
C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl ring;
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
each has at least one ring-forming carbon atom and 1, 2, 3, or 4
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring is optionally substituted by oxo
to form a carbonyl group; and wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl
ring are each optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.21; each R.sup.21 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, and
NR.sup.c4R.sup.d4; each R.sup.a, R.sup.c, and R.sup.d is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10 each R.sup.b is independently selected from C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; each R.sup.a1,
R.sup.c1 and R.sup.d1 is independently selected from H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl; or any R.sup.c1 and R.sup.d1 attached to the same N
atom, together with the N atom to which they are attached, form a
4-, 5-, 6- or 7-membered heterocycloalkyl group optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.11; each R.sup.b1 is independently selected from
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, and 4-10 membered
heterocycloalkyl; each R.sup.a2, R.sup.c2 and R.sup.d2 is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; or any R.sup.c2 and
R.sup.d2 attached to the same N atom, together with the N atom to
which they are attached, form a 4-, 5-, 6- or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.21; each R.sup.b2 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, and 4-10 membered
heterocycloalkyl; each R.sup.a3, R.sup.c3 and R.sup.d3 is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; each R.sup.b3 is
independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; and each R.sup.c4 and
R.sup.d4 is independently selected from H and C.sub.1-6 alkyl.
52. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein: R.sup.1 is selected from Cy.sup.1 and C.sub.2-6
alkenyl; wherein said C.sub.2-6 alkenyl is optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.10; Cy.sup.1 is selected from 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein the 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10; Cy.sup.A is
selected from C.sub.6-10 aryl and 6-10 membered heteroaryl; wherein
the 5-10 membered heteroaryl has at least one ring-forming carbon
atom and 1 or 2 ring-forming N heteroatoms; wherein a ring-forming
carbon atom of the 6-10 membered heteroaryl is optionally
substituted by oxo to form a carbonyl group; and wherein the
C.sub.6-10 aryl and 6-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or substituents independently selected
from R.sup.20; each R.sup.10 is independently selected from
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, and NR.sup.c1R.sup.d1; wherein
said C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.11; each R.sup.11 is independently selected from C.sub.1-6
alkyl, 4-10 membered heterocycloalkyl, CN, C(O)R.sup.b3, and
NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl and 4-10 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.12; each R.sup.12 is
independently C.sub.1-6 alkyl; each R.sup.20 is independently
selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halo,
COR.sup.a2, C(O)R.sup.b2, and C(O)NR.sup.c2R.sup.d2; wherein said
C.sub.1-6 alkyl is optionally substituted with 1, 2, or 3,
substituents independently selected from R.sup.21; or two adjacent
R.sup.20 substituents on the Cy.sup.A ring, taken together with the
atoms to which they are attached, form a fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group;
each R.sup.21 is independently selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo,
and NR.sup.c4R.sup.d4; each R.sup.a1, R.sup.c1 and R.sup.d1 is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl; or any R.sup.c1 and
R.sup.d1 attached to the same N atom, together with the N atom to
which they are attached, form a 4-, 5-, 6- or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.11; each R.sup.b1 is
independently C.sub.3-10 cycloalkyl or 4-10 membered
heterocycloalkyl; each R.sup.a2, R.sup.c2 and R.sup.d2 is
independently selected from H and C.sub.1-6 alkyl; or any R.sup.c2
and R.sup.d2 attached to the same N atom, together with the N atom
to which they are attached, form a 4-, 5-, 6- or 7-membered
heterocycloalkyl group; each R.sup.b2 is independently 4-10
membered heterocycloalkyl; each R.sup.c3 and R.sup.d3 is H; each
R.sup.b3 is C.sub.1-6 alkyl; and each R.sup.c4 and R.sup.d4 is
independently selected from H and C.sub.1-6 alkyl.
53. The compound of claim 1 selected from:
5-(2-Fluorophenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-d-
]pyrimidine,
3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-o-tolyl-1H-pyrazolo[4,3-d]pyrimidi-
ne,
5-(2-Methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4-
,3-d]pyrimidine,
5-(2-Chloro-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyraz-
olo[4,3-d]pyrimidine,
3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyridin-3-yl)-1H-pyrazolo[4,3-d]p-
yrimidine,
3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(5-methylpyridin-3-yl)-1-
H-pyrazolo[4,3-d]pyrimidine,
6-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-
isoindolin-1-one,
(5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl-
)pyridin-3-yl)(morpholino)methanone,
N-Methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-5-yl)nicotinamide,
5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-
-1,2,3,4-tetrahydroisoquinoline,
5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyra-
zolo[4,3-d]pyrimidine,
5-(2-Fluoro-6-methoxyphenyl)-3-phenyl-1H-pyrazolo[4,3-d]pyrimidine,
5-(2-Fluoro-6-methoxyphenyl)-3-(2-fluorophenyl)-1H-pyrazolo[4,3-d]pyrimid-
ine,
5-(2-Fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo-
[4,3-d]pyrimidine,
5-(2-Fluoro-6-methoxyphenyl)-3-(pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-
e,
5-(2-Fluoro-6-methoxyphenyl)-3-(pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrim-
idine,
4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)be-
nzonitrile,
5-(2-Fluoro-6-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,-
3-d]pyrimidine,
5-(2-Fluoro-6-methoxyphenyl)-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimi-
dine,
5-(2-Fluoro-6-methoxyphenyl)-3-o-tolyl-1H-pyrazolo[4,3-d]pyrimidine,
5-(2-Fluoro-6-methoxyphenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-d]pyrimidi-
ne,
4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N,N--
dimethylbenzamide,
5-(2-Fluoro-6-methoxyphenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-
-1H-pyrazolo[4, 3-d]pyrimidine,
4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzy-
l)morpholine
5-(2-Fluoro-6-methoxyphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-
-1H-pyrazolo[4,3-d]pyrimidine
4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pheny-
l)morpholine,
5-(2-Fluoro-6-methoxyphenyl)-3-(3-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-
-d]pyrimidine,
5-(2-fluoro-6-methoxyphenyl)-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazolo[4,-
3-d]pyrimidine,
4-(3-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pheny-
l)morpholine,
3-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N,N-dim-
ethylaniline,
(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-
(morpholino)methanone,
N-Cyclopentyl-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-
-3-yl)benzamide,
4-(1-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)ph-
enyl)cyclopropyl)morpholine,
2-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pheny-
pacetonitrile,
5-(2-Fluoro-6-methoxyphenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimi-
dine,
5-(2-Fluoro-6-methoxyphenyl)-3-(4-fluorophenyl)-1H-pyrazolo[4,3-d]py-
rimidine,
3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-
-1H-pyrazolo[4,3-d]pyrimidine,
4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N-methy-
lbenzamide,
3-(4-Cyclopropylphenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]py-
rimidine,
5-(2-Fluoro-6-methoxyphenyl)-3-(4-(piperidin-1-yl)phenyl)-1H-pyr-
azolo[4,3-d]pyrimidine,
(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-
methanamine,
2-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pheny-
l)-2-methylpropanenitrile,
5-(2-Fluoro-6-methoxyphenyl)-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-py-
razolo[4,3-d]pyrimidine,
5-(2,3-Difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4-
,3-d]pyrimidine,
5-(2,3-Difluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H--
pyrazolo[4,3-d]pyrimidine,
2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-5-yl)benzamide,
2-Fluoro-N-methyl-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-
-d]pyrimidin-5-yl)benzamide,
5-(2-Fluoro-6-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-
-d]pyrimidine,
4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-1-methy-
lpyridin-2(1H)-one,
5-(2-Fluoro-6-methoxyphenyl)-3-(2-(piperazin-1-yl)pyridin-4-yl)-1H-pyrazo-
lo[4,3-d]pyrimidine,
5-(2-Fluoro-6-methoxyphenyl)-3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1-
H-pyrazolo[4,3-d]pyrimidine,
5-(2-Fluoro-6-methoxyphenyl)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazo-
lo[4,3-d]pyrimidine,
4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyrid-
in-2-yl)morpholine,
1-(4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)py-
ridin-2-yl)piperazin-1-yl)ethan-1-one,
(E)-5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)styryl)-1H--
pyrazolo[4,3-d]pyrimidine, and
6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-5-yl)-1,2,3,4-tetrahydroisoquinoline, or a pharmaceutically
acceptable salt thereof.
54. The compound of claim 1 selected from:
1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl-
)piperidin-3-ol;
1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl-
)piperidine-4-carbonitrile;
5-(2-Fluoro-6-methylphenyl)-3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidine;
1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl-
)pyrrolidin-3-ol;
5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrim-
idin-3-yl)-N-methylpicolinamide;
4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrim-
idin-3-yl)-2-fluoro-N-methylbenzamide;
1-(3,5-Difluoro-4-(3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)p-
henyl)-N-methylmethanamine;
3-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrim-
idin-3-yl)benzonitrile;
1-(3,5-Difluoro-4-(3-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)phenyl)-N-methylmethanamine;
1-(3,5-Difluoro-4-(3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-pyrazolo[4,3-
-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;
1-(4-(3-(4-(4-Ethylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-y-
l)-3,5-difluorophenyl)-N-methylmethanamine;
5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrim-
idin-3-yl)-2-morpholinonicotinonitrile;
1-(3,5-Difluoro-4-(3-(3-fluoro-2-morpholinopyridin-4-yl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;
1-(4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d-
]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol;
(1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]p-
yrimidin-3-yl)pyridin-2-yl)-3-methylpiperidin-3-yl)methanol;
N-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]py-
rimidin-3-yl)phenyl)-1-(methylsulfonyl)piperidin-4-amine;
2-(4-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d-
]pyrimidin-3-yl)phenyl)piperazin-1-yl)ethanol;
1-(3,5-Difluoro-4-(3-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)-1-
H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;
4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]py-
rimidin-3-yl)pyridin-2-yl)-N-ethyl-N-methylpiperazine-1-carboxamide;
1-(3-Fluoro-4-(3-(6-(piperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrim-
idin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine;
1-(4-(5-(5-(2-Fluoro-4-((methylamino)methyl)-6-(trifluoromethyl)phenyl)-1-
H
-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone;
1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]py-
rimidin-5-yl)phenyl)-N-methylmethanamine;
2-(4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-
-d]pyrimidin-3-yl)-1H-pyrazol-1-yl)benzonitrile;
5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-
-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine;
5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1--
yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine;
N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimid-
in-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide;
N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimid-
in-yl)phenyl)-2-(dimethylamino)acetamide;
1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)phenyl)-N-methylmethanamine;
1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)phenyl)-N-methylethanamine;
1-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]p-
yrimidin-5-yl)phenyl)-N-methylmethanamine;
N-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]p-
yrimidin-5-yl)benzyl)ethanamine;
5-(2-Fluoro-6-methoxyphenyl)-3-(3-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-
-d]pyrimidine;
3-(Benzyloxy)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine;
6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,-
3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
2-(5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-
-d]pyrimidin-3-yl)pyrimidin-2-ylamino)ethanol;
6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[-
4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]-
pyrimidin-3-yl)-N,N-dimethylpyrimidin-2-amine;
5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]-
pyrimidin-3-yl)-N-methylpyrimidin-2-amine;
N-(4-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-
-d]pyrimidin-3-yl)benzyl)methanesulfonamide;
7-(3-(4-(Azetidin-1-ylsulfonyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)--
6,8-difluoro-1,2,3,4-tetrahydroisoquinoline;
7-(3-(6-(Difluoromethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)--
6,8-difluoro-1,2,3,4-tetrahydroisoquinoline;
4-(5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-
-d]pyrimidin-3-yl)pyridin-2-yl)morpholine;
6,8-Difluoro-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]py-
rimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
8-Methoxy-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrim-
idin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
8-Fluoro-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-5-yl)quinoline;
5-(4-Methoxypyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazol-
o[4,3-d]pyrimidine;
5-(4-Methoxypyridin-3-yl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-p-
yrazolo[4,3-d]pyrimidine;
N-Methyl-1-(4-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[-
4,3-d]pyrimidin-5-yl)pyridin-2-yl)methanamine;
2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazo-
lo[4,3-d]pyrimidin-5-yl)phenyl)acetonitrile;
6-Fluoro-5-(3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
6-Fluoro-8-methyl-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H
-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
1-(4-(4-(5-(6-Fluoro-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyra-
zolo[4,3-d]pyrimidin-3-yl)phenyl)piperazin-1-yl)ethanone;
4-(5-(5-(6-Fluoro-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-
o[4,3-d]pyrimidin-3-yl)pyridin-2-yl)morpholine;
6-Fluoro-8-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazo-
lo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
6-Fluoro-8-methyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-
-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
8-Fluoro-6-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazo-
lo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;
4,6-Difluoro-N-methyl-5-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]p-
yrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine;
4,6-Difluoro-N-methyl-5-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H--
pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine;
6,8-Difluoro-N-methyl-7-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]p-
yrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine;
5,7-Difluoro-N-methyl-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]p-
yrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;
5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin--
5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;
5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin--
5-yl)-2,3-dihydro-1H-inden-1-amine;
5-Fluoro-7-methoxy-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyri-
midin-5-yl)-2,3-dihydro-1H-inden-1-amine;
6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazo-
lo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;
6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;
1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]py-
rimidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-ol;
1-(3,5-Difluoro-4-(3-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1H-pyra-
zolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;
1-(4-(3-(4-(4-Ethylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-y-
l)-3-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethanamine;
3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methyl-4-(piperidin-2-y-
l)phenyl)-1H-pyrazolo[4,3-d]pyrimidine; and
(R)-1-(3-Fluoro-4-(3-(6-(2-(methoxymethyl)morpholino)pyridin-3-yl)-1H-pyr-
azolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine-
; or a pharmaceutically acceptable salt thereof.
55. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier or excipient.
56. A method of inhibiting HPK1 activity, said method comprising
administering to a patient a compound of claim 1, or a
pharmaceutically acceptable salt thereof.
57. A method of treating a disease or disorder associated with
inhibition of HPK1 interaction, said method comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof.
58. A method for treating a cancer in a patient, said method
comprising: administering to the patient a therapeutically
effective amount of the compound of claim 1, or a pharmaceutically
acceptable salt thereof.
59. The method of claim 58, wherein the cancer is selected from
breast cancer, colorectal cancer, lung cancer, ovarian cancer, and
pancreatic cancer.
Description
FIELD OF THE INVENTION
[0001] The disclosure provides compounds as well as their
compositions and methods of use. The compounds modulate
hematopoietic progenitor kinase 1 (HPK1) activity and are useful in
the treatment of various diseases including cancer.
BACKGROUND OF THE INVENTION
[0002] Hematopoietic progenitor kinase 1 (HPK1) originally cloned
from hematopoietic progenitor cells is a member of MAP kinase
kinase kinase kinases (MAP4Ks) family, which includes MAP4K1/HPK1,
MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK
(Hu, M. C., et al., Genes Dev, 1996. 10(18): p. 2251-64). HPK1 is
of particular interest because it is predominantly expressed in
hematopoietic cells such as T cells, B cells, macrophages,
dendritic cells, neutrophils, and mast cells (Hu, M. C., et al.,
Genes Dev, 1996. 10(18): p. 2251-64; Kiefer, F., et al., EMBO J,
1996. 15(24): p. 7013-25). HPK1 kinase activity has been shown to
be induced upon activation of T cell receptors (TCR) (Liou, J., et
al., Immunity, 2000. 12(4): p. 399-408), B cell receptors (BCR)
(Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), transforming
growth factor receptor (TGF-.beta.R) (Wang, W., et al., J Biol
Chem, 1997. 272(36): p. 22771-5; Zhou, G., et al., J Biol Chem,
1999. 274(19): p. 13133-8), or G.sub.s-coupled PGE.sub.2 receptors
(EP2 and EP4) (Ikegami, R., et al., J Immunol, 2001. 166(7): p.
4689-96). As such, HPK1 regulates diverse functions of various
immune cells.
[0003] HPK1 is important in regulating the functions of various
immune cells and it has been implicated in autoimmune diseases and
anti-tumor immunity (Shui, J. W., et al., Nat Immunol, 2007. 8(1):
p. 84-91; Wang, X., et al., J Biol Chem, 2012. 287(14): p.
11037-48). HPK1 knockout mice were more susceptible to the
induction of experimental autoimmune encephalomyelitis (EAE) (Shui,
J. W., et al., Nat Immunol, 2007. 8(1): p. 84-91). In human, HPK1
was downregulated in peripheral blood mononuclear cells of
psoriatic arthritis patients or T cells of systemic lupus
erythematosus (SLE) patients (Batliwalla, F. M., et al., Mol Med,
2005. 11(1-12): p. 21-9). Those observations suggested that
attenuation of HPK1 activity may contribute to autoimmunity in
patients. Furthermore, HPK1 may also control anti-tumor immunity
via T cell-dependent mechanisms. In the PGE2-producing Lewis lung
carcinoma tumor model, the tumors developed more slowly in HPK1
knockout mice as compared to wild-type mice (see US 2007/0087988).
In addition, it was shown that adoptive transfer of HPK1 deficient
T cells was more effective in controlling tumor growth and
metastasis than wild-type T cells (Alzabin, S., et al., Cancer
Immunol Immunother, 2010. 59(3): p. 419-29). Similarly, BMDCs from
HPK1 knockout mice were more efficient to mount a T cell response
to eradicate Lewis lung carcinoma as compared to wild-type BMDCs
(Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). These
data, in conjunction with the restricted expression of HPK1 in
hematopoietic cells and lack of effect on the normal development of
immune cells, suggest that HPK1 may be an excellent drug target for
enhancing antitumor immunity. Accordingly, there is a need for new
compounds that modulate HPK1 activity.
SUMMARY
[0004] The present disclosure provides, inter alia, a compound of
Formula (I):
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein constituent
variables are defined herein.
[0005] The present disclosure further provides a pharmaceutical
composition comprising a compound of the disclosure, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier or excipient.
[0006] The present disclosure further provides methods of
inhibiting HPK1 activity, which comprises administering to an
individual a compound of the disclosure, or a pharmaceutically
acceptable salt thereof.
[0007] The present disclosure further provides methods of treating
a disease or disorder in a patient comprising administering to the
patient a therapeutically effective amount of a compound of the
disclosure, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION
Compounds
[0008] The present disclosure provides, a compound of Formula
(I):
##STR00002##
[0009] or a pharmaceutically acceptable salt thereof, wherein:
[0010] R.sup.1 is selected from Cy.sup.1, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo,
CN, NO.sub.2, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.a,
NR.sup.cC(O)NR.sup.cR.sup.d, C(.dbd.NR.sup.e)R.sup.b,
C(.dbd.NOR.sup.a)R.sup.b, C(.dbd.NR.sup.e)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.e)NR.sup.cR.sup.d, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from
R.sup.10;
[0011] Cy.sup.1 is selected from C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10
membered heteroaryl each has at least one ring-forming carbon atom
and 1, 2, 3, or 4 ring-forming heteroatoms independently selected
from N, O, and S; wherein the N and S are optionally oxidized;
wherein a ring-forming carbon atom of 5-10 membered heteroaryl and
4-10 membered heterocycloalkyl is optionally substituted by oxo to
form a carbonyl group; and wherein the C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.10;
[0012] Cy.sup.A is selected from C.sub.6-10 aryl and 5-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein the N and S are
optionally oxidized; wherein a ring-forming carbon atom of the 5-10
membered heteroaryl is optionally substituted by oxo to form a
carbonyl group; and wherein the C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from R.sup.20;
[0013] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, C(.dbd.NR.sup.e1)R.sup.b1,
C(.dbd.NOR.sup.a1)R.sup.b1, C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11;
[0014] or two R.sup.10 substituents taken together with the carbon
atom to which they are attached form a spiro 3-7-membered
heterocycloalkyl ring, or a spiro C.sub.3-6 cycloalkyl ring;
wherein each spiro 3-7-membered heterocycloalkyl ring has at least
one ring-forming carbon atom and 1, 2 or 3, ring-forming
heteroatoms independently selected from N, O, and S; wherein a
ring-forming carbon atom of each spiro 3-7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl
ring and spiro C.sub.3-6 cycloalkyl ring are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.11;
[0015] each R.sup.11 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene,
halo, CN, OR.sup.a3, SR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, NR.sup.c3R.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
NR.sup.c3S(O)R.sup.b3, NR.sup.c3S(O).sub.2R.sup.b3,
NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3, S(O)R.sup.b3,
S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0016] each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
4-7 membered heterocycloalkyl, halo, CN, OR.sup.a5, SR.sup.a5,
C(O)R.sup.b5, C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5,
NR.sup.c5R.sup.d5, NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,
NR.sup.c5S(O)R.sup.b5, NR.sup.c5S(O).sub.2R.sup.b5,
NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5, S(O)R.sup.b5,
S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, and
S(O).sub.2NR.sup.c5R.sup.d5; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.g;
[0017] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, NO.sub.2, OR.sup.a2,
SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, C(.dbd.NR.sup.e2)R.sup.b2,
C(.dbd.NOR.sup.a2)R.sup.b2, C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.c2)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,
S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21;
[0018] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-7 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21;
[0019] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, OR.sup.a4, SR.sup.a4,
C(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4, C(O)OR.sup.a4,
NR.sup.c4R.sup.d4, NR.sup.c4C(O)R.sup.b4, NR.sup.c4C(O)OR.sup.a4,
NR.sup.c4S(O)R.sup.b4, NR.sup.c4S(O).sub.2R.sup.b4,
NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4, S(O)R.sup.b4,
S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, and
S(O).sub.2NR.sup.c4R.sup.d4; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22;
[0020] or two R.sup.21 substituents taken together with the carbon
atom to which they are attached form a spiro 3-7-membered
heterocycloalkyl ring, or a spiro C.sub.3-6 cycloalkyl ring;
wherein each spiro 3-7-membered heterocycloalkyl ring has at least
one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each spiro 3-7-membered heterocycloalkyl ring is
optionally substituted by oxo to form a carbonyl group; and wherein
the spiro 3-7-membered heterocycloalkyl ring and spiro C.sub.3-6
cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.22;
[0021] each R.sup.22 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered
heterocycloalkyl, halo, CN, OR.sup.a6, SR.sup.a6, C(O)R.sup.b6,
C(O)NR.sup.c6R.sup.d6, C(O)OR.sup.a6, NR.sup.c6R.sup.d6,
NR.sup.c6C(O)R.sup.b6, NR.sup.c6C(O)OR.sup.a6,
NR.sup.c6S(O)R.sup.b6, NR.sup.c6S(O).sub.2R.sup.b6,
NR.sup.c6S(O).sub.2NR.sup.c6R.sup.d6, S(O)R.sup.b6,
S(O)NR.sup.c6R.sup.d6, S(O).sub.2R.sup.b6, and
S(O).sub.2NR.sup.c6R.sup.d6; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl,
5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.g;
[0022] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.10;
[0023] or any R.sup.c and R.sup.d attached to the same N atom,
together with the N atom to which they are attached, form a 4-10
membered heterocycloalkyl group optionally substituted with 1, 2, 3
or 4 substituents independently selected from R.sup.10;
[0024] each R.sup.b is independently selected from C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10;
[0025] each R.sup.e is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0026] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.11;
[0027] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0028] each R.sup.b1 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11;
[0029] each R.sup.e1 is independently selected from H, CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0030] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.21;
[0031] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.21;
[0032] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.21;
[0033] each R.sup.e2 is independently selected from H, CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0034] each R.sup.a3, R.sup.b3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said
C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.12;
[0035] or any R.sup.c3 and R.sup.d3 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2 or 3 substituents independently selected from R.sup.12;
[0036] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0037] each R.sup.a4, R.sup.c4 and R.sup.d4 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said
C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.22;
[0038] or any R.sup.c4 and R.sup.d4 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2 or 3 substituents independently selected from R.sup.22;
[0039] each R.sup.b4 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22;
[0040] each R.sup.a5, R.sup.c5 and R.sup.d5 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g;
[0041] each R.sup.b5 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g;
[0042] each R.sup.a6, R.sup.c6 and R.sup.d6 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g;
[0043] each R.sup.b6 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g; and
[0044] each R.sup.g is independently selected from OH, NO.sub.2,
CN, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkylene, C.sub.1-6 alkoxy, C.sub.1-6
haloalkoxy, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.1-3
alkoxy-C.sub.1-3 alkoxy, HO--C.sub.1-3 alkoxy, HO--C.sub.1-3 alkyl,
cyano-C.sub.1-3 alkyl, H.sub.2N--C.sub.1-3 alkyl, amino, C.sub.1-6
alkylamino, di(C.sub.1-6 alkyl)amino, thio, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamyl,
C.sub.1-6 alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, carboxy,
C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl, di(C.sub.1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C.sub.1-6 alkylaminosulfonylamino, di(C.sub.1-6
alkyl)aminosulfonylamino, aminocarbonylamino, C.sub.1-6
alkylaminocarbonylamino, and di(C.sub.1-6
alkyl)aminocarbonylamino;
[0045] provided that:
[0046] 1) R.sup.1 is other than NH.sub.2;
[0047] 2) R.sup.1 is other than CH.sub.3;
[0048] 3) R.sup.1 is other than CH.sub.2(quinolin-6-yl);
[0049] 4) R.sup.1 is other than NHC(O)CH.sub.2CH.sub.2CH.sub.3;
and
[0050] 5) when Cy.sup.A is unsubstituted or substituted
pyrazol-4-yl, then R.sup.1 is other than pyridin-4-yl substituted
by morpholine.
[0051] In some embodiments, R.sup.1 is selected from Cy.sup.1,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo,
CN, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d,
NR.sup.cC(O)R.sup.b, NR.sup.cC(O)OR.sup.a, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, and S(O).sub.2NR.sup.cR.sup.d; wherein said
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10.
[0052] In certain embodiments, R.sup.1 is selected from Cy.sup.1,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo,
CN, OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d,
C(O)OR.sup.a, and NR.sup.cC(O)R.sup.b; wherein said C.sub.2-6
alkenyl and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.10. In
some embodiments, R.sup.1 is selected from Cy.sup.1, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl and OR.sup.a; wherein said C.sub.2-6
alkenyl and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.10.
For example, R.sup.1 can be selected from Cy.sup.1, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl; wherein said C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.10. In certain
embodiments, R.sup.1 is Cy.sup.1 or C.sub.2-6 alkenyl; wherein said
C.sub.2-6 alkenyl is optionally substituted with 1, 2, or 3
substituents independently selected from R.sup.10. In certain
embodiments, R.sup.1 is selected from Cy.sup.1, C(O)NR.sup.cR.sup.d
and NR.sup.cC(O)R.sup.b. In certain embodiments, R.sup.1 is
selected from phenyl, pyridinyl, pyrazolyl, thiazolyl,
C(O)NR.sup.cR.sup.d and NR.sup.cC(O)R.sup.b; wherein the phenyl,
pyridinyl, pyrazolyl, and thiazolyl are each optionally substituted
with 1, 2 or 3 substituents independently selected from
R.sup.10.
[0053] In some embodiments, R.sup.1 is not C.sub.1-6 alkyl that is
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.10 (e.g., CH.sub.3 and
CH.sub.2(quinolin-6-yl)) In certain embodiments, R.sup.1 is not
NR.sup.cR.sup.d (e.g., NH.sub.2). In some embodiments, R.sup.1 is
NR.sup.cC(O)R.sup.b but not including
NHC(O)CH.sub.2CH.sub.2CH.sub.3.
[0054] In some embodiments, R.sup.1 is C.sub.2-6 alkenyl; wherein
said C.sub.2-6 alkenyl is optionally substituted with 1, 2, or 3
substituents independently selected from R.sup.10. For example,
R.sup.1 can be CHCH substituted with R.sup.10, and R.sup.10 is
phenyl substituted with 4-methylpiperazin-1-yl.
[0055] In some embodiments, R.sup.1 is Cy.sup.1.
[0056] In some embodiments, Cy.sup.1 is selected from 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein the 4-10 membered heterocycloalkyl and 5-10 membered
heteroaryl each has at least one ring-forming carbon atom and 1, 2,
3, or 4 ring-forming heteroatoms independently selected from N, O,
and S; wherein the N and S are optionally oxidized; wherein a
ring-forming carbon atom of 5-10 membered heteroaryl and 4-10
membered heterocycloalkyl is optionally substituted by oxo to form
a carbonyl group; and wherein the 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.10.
[0057] In some embodiments, Cy.sup.1 is C.sub.6-10 aryl or 5-10
membered heteroaryl; wherein the 5-10 membered heteroaryl has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl is optionally substituted by oxo to
form a carbonyl group; and wherein the C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10.
[0058] In some embodiments, Cy.sup.1 is C.sub.6-10 aryl optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.10. In certain embodiments, Cy.sup.1 is 5-10 membered
heteroaryl optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.10. For example, Cy.sup.1 can be
phenyl, pyrazolyl, pyridinyl, pyrimidinyl, thiophenyl, and
pyridone; wherein the phenyl, pyrazolyl, pyridinyl, pyrimidinyl,
thiophenyl, or pyridone are each optionally substituted with 1, 2
or 3 substituents independently selected from R.sup.10. In some
embodiments, Cy.sup.1 is phenyl optionally substituted with 1, 2 or
3 substituents independently selected from R.sup.10.
[0059] In some embodiments, each R.sup.10 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
memberedheterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sub.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)OR.sup.a1, NR.sup.c1S(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1,
S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10
membered heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10
aryl-C.sub.1-3 alkylene and 5-10 membered heteroaryl-C.sub.1-3
alkylene are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11.
[0060] In some embodiments, each R.sup.10 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
memberedheterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1, and S(O).sub.2R.sup.b1;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene and 5-10 membered
heteroaryl-C.sub.1-3 alkylene are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from
R.sup.11.
[0061] In some embodiments, each R.sup.10 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
NR.sup.c1R.sup.d1, and NR.sup.c1C(O)R.sup.b1; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10
membered heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10
aryl-C.sub.1-3 alkylene and 5-10 membered heteroaryl-C.sub.1-3
alkylene are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11.
[0062] In some embodiments, each R.sup.10 is independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
S(O).sub.2R.sup.b1, and S(O)NR.sup.c1R.sup.d1; wherein said
C.sub.1-6 alkyl, C.sub.3-.sub.10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene are each optionally substituted
with 1, 2, or 3 substituents independently selected from
R.sup.11.
[0063] In some embodiments, each R.sup.10 is independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, and
S(O).sub.2R.sup.b1; wherein said C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, and
4-10 membered heterocycloalkyl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, or 3 substituents independently
selected from R.sup.11.
[0064] In some embodiments, each R.sup.10 is independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, and NR.sup.c1R.sup.d1; wherein
said C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene are each optionally substituted
with 1, 2, or 3 substituents independently selected from
R.sup.11.
[0065] In some embodiments, each R.sup.10 is 4-10 membered
heterocycloalkyl optionally substituted with 1, 2, or 3
substituents independently selected from R.sup.11.
[0066] In some embodiments, each R.sup.11 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10
memberedheterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR.sup.c3S(O).sub.2R.sup.b3, and
S(O).sub.2R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered hetero aryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12.
[0067] In some embodiments, each R.sup.11 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene, halo, CN,
OR.sup.a3, C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3,
and NR.sup.c3C(O)R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12.
[0068] In some embodiments, each R.sup.11 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo, CN,
OR.sup.a3, C(O)R.sup.b3, NR.sup.c3R.sup.d3, C(O)NR.sup.c3R.sup.d3,
NR.sup.c3C(O)R.sup.b3, NR.sup.c3S(O).sub.2R.sup.b3, and
S(O).sub.2R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, and 4-10
membered heterocycloalkyl are each optionally substituted with 1,
2, or 3 substituents independently selected from R.sup.12.
[0069] In some embodiments, each R.sup.11 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo, CN,
C(O)R.sup.b3, NR.sup.c3R.sup.d3, and NR.sup.c3C(O)R.sup.b3; wherein
said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each
optionally substituted with 1, 2, or 3 substituents independently
selected from R.sup.12.
[0070] In some embodiments, each R.sup.11 is independently selected
from C.sub.1-6 alkyl, 4-10 membered heterocycloalkyl, CN,
OR.sup.a3, C(O)R.sup.b3, NR.sup.c3R.sup.d3,
NR.sup.c3S(O).sub.2R.sup.b3, and S(O).sub.2R.sup.b3; wherein said
C.sub.1-6 alkyl and 4-10 membered heterocycloalkyl are each
optionally substituted with 1, 2, or 3 substituents independently
selected from R.sup.12.
[0071] In some embodiments, each R.sup.11 is independently selected
from C.sub.1-6 alkyl, 4-10 memberedheterocycloalkyl, CN,
C(O)R.sup.b3, and NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl
and 4-10 membered heterocycloalkyl are each optionally substituted
with 1, 2, or 3 substituents independently selected from
R.sup.12.
[0072] In some embodiments, each R.sup.11 is independently selected
from C.sub.1-3 alkyl, 4-10 memberedheterocycloalkyl, CN,
C(O)R.sup.b3, and NR.sup.c3R.sup.d3; wherein said C.sub.1-3 alkyl
and 4-10 membered heterocycloalkyl are each optionally substituted
with 1, 2, or 3 substituents independently selected from R.sup.12.
In some embodiments, each R.sup.11 is C.sub.1-3 alkyl optionally
substituted with 1, 2, or 3 substituents independently selected
from R.sup.12.
[0073] In some embodiments, each R.sup.12 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, halo, CN, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5,
C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5, NR.sup.c5R.sup.d5, or
NR.sup.c5C(O)R.sup.b5; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.g.
[0074] In some embodiments, each R.sup.12 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, halo, and OR.sup.a5. For example, each
R.sup.12 is independently selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, and halo. In some
embodiments, each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl. For example, each
R.sup.12 is C.sub.1-6 alkyl. In some embodiments, each R.sup.12 is
independently OR.sup.a5. In some embodiments, each R.sup.12 is
independently C.sub.1-6 alky.
[0075] In some embodiments, R.sup.10 is 4-methylpiperazin-1-yl,
fluoro, methyl, CN, trifluormethyl, methoxy,
N,N-dimethylaminocarbonyl, (4-methylpiperazin-1-yl)methyl,
4-morpholinylmethyl, morpholinyl, piperazin-1-yl, pyrrolidin-1-yl,
N,N-dimethylamine, morpholinylmethanone,
N-cyclopentylaminocarbonyl, 4-(cycloprop-1-yl)morpholinyl,
cyanomethyl, 4-ethylpiperazin-1-yl, N-methylaminocarbonyl,
cyclopropyl, pyridin-1-yl, methylamine, 1-methyl-1-cyanomethyl,
tetrahydro-2H-pyran-4-yl, phenyl, 1-(piperazin-1-yl)ethan-1-one,
3-hydroxy-piperidin-1-yl, 4-cyano-piperidin-1-yl,
3-hydroxy-pyrrolidin-1-yl, piperidin-4-yl,
4-(2-methyl-2-hydroxypropyl)piperazin-1-yl,
3-methyl-3(methylhydroxy)piperidin-1-yl,
1-(methylsulfonyl)piperidin-4-amino,
4-(ethylhydroxy)piperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl,
4-((N-methyl-N-ethyl)aminocarbonyl)piperazin-1-yl, piperidin-1-yl,
4-(methylcarbonyl)piperazin-1-yl, 2-cyanophenyl,
1-hydroxyethane-2-amino, (methylsulfonyl)amino-methyl,
azetidin-1-ylsulfonyl, difluoromethoxy,
2-(methoxymethyl)morpholin-4-yl, 4-methyl-4-hydroxypiperidin-1-yl,
or 4-(2-methoxyethyl)piperazin-1-yl.
[0076] Examples of R.sup.10 can include 4-methylpiperazin-1-yl,
fluoro, methyl, CN, trifluormethyl, methoxy,
N,N-dimethylaminocarbonyl, (4-methylpiperazin-1-yl)methyl,
4-morpholinylmethyl, morpholinyl, piperazin-1-yl, pyrrolidin-1-yl,
N,N-dimethylamine, morpholinylmethanone,
N-cyclopentylaminocarbonyl, 4-(cycloprop-1-yl)morpholine,
cyanomethyl, 4-ethylpiperazin-1-yl, N-methylaminocarbonyl,
cyclopropyl, pyridin-1-yl, methylamine, 1-methyl-1-cyanomethyl,
tetrahydro-2H-pyran-4-yl, phenyl, and
1-(piperazin-1-yl)ethan-1-one.
[0077] In some embodiments, R.sup.10 is 4-ethylpiperazin-1-yl.
[0078] In some embodiments, Cy.sup.A is selected from C.sub.6-10
aryl and 6-10 membered heteroaryl; wherein the 6-10 membered
heteroaryl has at least one ring-forming carbon atom and 1 or 2
ring-forming N heteroatoms; wherein a ring-forming carbon atom of
the 6-10 membered heteroaryl is optionally substituted by oxo to
form a carbonyl group; and wherein the C.sub.6-10 aryl and 6-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.20.
[0079] In some embodiments, Cy.sup.A is C.sub.6-10 aryl. In some
embodiments, Cy.sup.A is 6-10 membered heteroaryl. In certain
embodiments, Cy.sup.A is not 5-membered heteroaryl (e.g.,
unsubstituted or substituted pyrazol-4-yl).
[0080] In some embodiments, Cy.sup.A is phenyl, pyridinyl,
isoindolin-1-onyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolinyl,
2,3-dihydro-1H-inden-5-yl, or 1,2,3,4-tetrahydronaphthyl; wherein
the phenyl, pyridinyl, isoindolin-1-onyl,
1,2,3,4-tetrahydroisoquinolinyl, quinolinyl,
2,3-dihydro-1H-inden-5-yl, and 1,2,3,4-tetrahydronaphthyl are each
optionally substituted with 1, 2, 3 or 4 substituents independently
selected from R.sup.20.
[0081] In some embodiments, Cy.sup.A is phenyl, pyridinyl,
isoindolin-1-onyl, or 1,2,3,4-tetrahydroisoquinolinyl; wherein the
phenyl, pyridinyl, isoindolin-1-onyl, and
1,2,3,4-tetrahydroisoquinolinyl are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.20.
[0082] In some embodiments, Cy.sup.A is phenyl optionally
substituted with 1, 2, or 3 substituents independently selected
from R.sup.20.
[0083] In some embodiments, Cy.sup.A is phenyl; or two adjacent
R.sup.20 substituents on the Cy.sup.A ring, taken together with the
atoms to which they are attached, form a fused 5- or 6-membered
heterocycloalkyl ring, or a fused C.sub.3-6 cycloalkyl ring;
wherein the fused 5- or 6-membered heterocycloalkyl ring each has
at least one ring-forming carbon atom and 1, 2 or 3 ring-forming
heteroatoms independently selected from N, O, and S; wherein a
ring-forming carbon atom of each fused 5- or 6-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group; and wherein the fused 5- or 6-membered
heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl ring are each
optionally substituted with 1, 2 or 3 substituents independently
selected from R.sup.21.
[0084] In some embodiments, each R.sup.20 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo, CN,
OR.sup.a2, SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,
NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2S(O)R.sup.b2, NR.sup.c2S(O).sub.2R.sup.b2, S(O)R.sup.b2,
S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.21; or two adjacent R.sup.20 substituents on the
Cy.sup.A ring, taken together with the atoms to which they are
attached, form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring, or a fused C.sub.3-7 cycloalkyl ring; wherein the fused 4-,
5-, 6- or 7-membered heterocycloalkyl ring each has at least one
ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21.
[0085] In some embodiments, each R.sup.20 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, halo, CN, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2,
S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl ring;
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
each has at least one ring-forming carbon atom and 1, 2, 3, or 4
ring-forming heteroatoms independently selected from N, O, and S;
wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring is optionally substituted by oxo
to form a carbonyl group; and wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl
ring are each optionally substituted with 1, 2, 3 or 4 substituents
independently selected from R.sup.21.
[0086] In some embodiments, each R.sup.20 is independently selected
from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, 4-10 membered heterocycloalkyl, halo,
OR.sup.a2, SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.21; or two adjacent
R.sup.20 substituents on the Cy.sup.A ring, taken together with the
atoms to which they are attached, form a fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl
ring; and wherein the fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl ring are each
optionally substituted with 1 or 2 substituents independently
selected from R.sup.21.
[0087] In certain embodiments, each R.sup.20 is independently
selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, halo, OR.sup.a2, SR.sup.a2,
C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring, or a fused C.sub.3-7 cycloalkyl ring.
[0088] In some embodiments, each R.sup.20 is independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, 4-10 membered
heterocycloalkyl, halo, OR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2; or two adjacent
R.sup.20 substituents on the Cy.sup.A ring, taken together with the
atoms to which they are attached, form a fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring or a fused C.sub.3-7 cycloalkyl
ring; and wherein the fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring and fused C.sub.3-6 cycloalkyl ring are each
optionally substituted with 1 or 2 substituents independently
selected from R.sup.21.
[0089] In certain embodiments, each R.sup.20 is independently
selected from C.sub.1-6 alkyl, halo, OR.sup.a2, C(O)R.sup.b2, and
C(O)NR.sup.c2R.sup.d2; or two adjacent R.sup.20 substituents on the
Cy.sup.A ring, taken together with the atoms to which they are
attached, form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring.
[0090] In some embodiments, R.sup.20 is fluoro, methyl, methoxy,
chloro, (morpholino)methanone, N-methylaminocarbonyl,
aminocarbonyl, (methylamino)methyl, trifluoromethyl,
pyrrolidin-2-yl, piperidin-2-yl,
((pyrrolidin-1-yl)methyl)carbonylamino,
((N,N-dimethylamino)methyl)carbonylamino, C(O)H,
1-(methylamino)-ethyl, (ethylamino)methyl, cyanomethyl,
N-methylamino, or amino; or two adjacent R.sup.20 substituents on
the Cy.sup.A ring, taken together with the atoms to which they are
attached, form a fused piperidinyl ring. For example, R.sup.20 is
fluoro, methyl, methoxy, chloro, (morpholino)methanone,
N-methylaminocarbonyl, or aminocarbonyl; or two adjacent R.sup.20
substituents on the Cy.sup.A ring, taken together with the atoms to
which they are attached, form a fused piperidinyl ring.
[0091] In some embodiments, each R.sup.20 is independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo; wherein said
C.sub.1-6 alkyl is optionally substituted with 1 or 2 substituents
independently selected from R.sup.21. In some embodiments, R.sup.20
is halo (e.g., fluoro). In some embodiments, R.sup.20 is C.sub.1-6
haloalkyl (e.g., trifluoromethyl). In some embodiments, C.sub.1-6
alkyl is optionally substituted with 1 substituent independently
selected from R.sup.21 (e.g., R.sup.20 is (methylamino)methyl). In
some embodiments, R.sup.20 is fluoro, trifluoromethyl or
(methylamino)methyl.
[0092] In some embodiments, Cy.sup.A is 2-fluoro-6-methoxyphenyl.
In some embodiments, Cy.sup.A is phenyl substituted with halo
(e.g., fluoro), C.sub.1-6 haloalkyl (e.g., trifluoromethyl), and
C.sub.1-6 alkyl substituted with 1 substituent independently
selected from R.sup.21 (e.g., R.sup.20 is (methylamino)methyl). In
some embodiments, Cy.sup.A is phenyl substituted with fluoro,
trifluoromethyl, and (methylamino)methyl.
[0093] In some embodiments, provided herein is a comopund having
Formula (IIa1), Formula (IIa2), Formula (IIa3), Formula (IIa4) or
Formula (IIa5):
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; and variables Cy.sup.A, R.sup.10, and R.sup.11 are as
defined herein.
[0094] In some embodiments, one or more hydrogen atoms in a
compound of the present disclosure can be replaced or substituted
by deuterium. For example, the compound can be a compound of
Formula (IIa1'), Formula (IIa2'), Formula (IIa3'), Formula (IIa4')
or Formula (IIa5'):
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; R.sup.10, R.sup.11 and Cy.sup.A are as defined herein,
and wherein one of more hydrogen atoms of R.sup.10, R.sup.11, and
Cy.sup.A are optionally substituted or replaced with one or more
deuterium.
[0095] In some embodiments, provided herein is a compound having
Formula (IIa1):
##STR00005##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; and variables Cy.sup.A and R.sup.10 are as defined
herein.
[0096] In some embodiments, provided herein is a compound having
Formula (IIa2):
##STR00006##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; and variables Cy.sup.A and R.sup.10 are as defined
herein.
[0097] In some embodiments, provided herein is a compound having
Formula (IIa3):
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; and variables Cy.sup.A and R.sup.10 are as defined
herein.
[0098] In some embodiments, provided herein is a compound having
Formula (IIa4):
##STR00008##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; and variables Cy.sup.A and R.sup.10 are as defined
herein.
[0099] In some embodiments, provided herein is a compound having
Formula (IIa5):
##STR00009##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; and variables Cy.sup.A, R.sup.10, and R.sup.11 are as
defined herein.
[0100] In some embodiments, provided herein is a compound having
Formula (IIb1):
##STR00010##
or a pharmaceutically acceptable salt thereof, wherein n is 0, 1,
2, 3, 4 or 5; and variables R.sup.20 and R.sup.1 are as defined
herein.
[0101] In some embodiments, provided herein is a compound having
Formula (IIc1), Formula (IIc2) or Formula (IIc3):
##STR00011##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; and variables R.sup.10,
R.sup.11, and R.sup.20 are as defined herein.
[0102] In some embodiments, the compound provided herein is a
compound Formula (IIc1):
##STR00012##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; and variables R.sup.10 and
R.sup.20 are as defined herein.
[0103] In some embodiments, the compound provided herein is a
compound Formula (IIc2):
##STR00013##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; and variables R.sup.10 and
R.sup.20 are as defined herein.
[0104] In some embodiments, the compound provided herein is a
compound Formula (IIc3):
##STR00014##
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1,
2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; and variables R.sup.10,
R.sup.11, and R.sup.20 are as defined herein.
[0105] In some embodiments, m is 0.
[0106] In some embodiments, m is 1.
[0107] In some embodiments, m is 2.
[0108] In some embodiments, n is 1.
[0109] In some embodiments, n is 2.
[0110] In some embodiments, n is 3.
[0111] The disclosure also provided herein a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, wherein:
[0112] R.sup.1 is selected from Cy.sup.1, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN, NO.sub.2,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.a, NR.sup.cC(O)NR.sup.cR.sup.d,
C(.dbd.NR.sup.e)R.sup.b, C(.dbd.NOR.sup.a)R.sup.b,
C(.dbd.NR.sup.e)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.e)NR.sup.cR.sup.d, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, NR.sup.cC(O).sub.2NR.sup.cR.sup.d,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.10;
[0113] Cy.sup.1 is selected from C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10
membered heteroaryl each has at least one ring-forming carbon atom
and 1, 2, 3, or 4 ring-forming heteroatoms independently selected
from N, O, and S; wherein the N and S are optionally oxidized;
wherein a ring-forming carbon atom of 5-10 membered heteroaryl and
4-10 membered heterocycloalkyl is optionally substituted by oxo to
form a carbonyl group; and wherein the C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.10;
[0114] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 6-10 membered heteroaryl has at least one
ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein the N and S are
optionally oxidized; wherein a ring-forming carbon atom of the 6-10
membered heteroaryl is optionally substituted by oxo to form a
carbonyl group; and wherein the C.sub.6-10 aryl and 6-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from R.sup.20;
[0115] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 alkylene, 5-10 membered heteroaryl-C.sub.1-3 alkylene,
halo, CN, NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, OC(O)R.sup.b1,
OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)OR.sup.a1, NR.sup.c1C(O)NR.sup.c1R.sup.d1,
C(.dbd.NR.sup.e1)R.sup.b1, C(.dbd.NOR.sup.a1)R.sup.b1,
C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11;
[0116] or two R.sup.10 substituents taken together with the carbon
atom to which they are attached form a spiro 3-7-membered
heterocycloalkyl ring, or a spiro C.sub.3-6 cycloalkyl ring;
wherein each spiro 3-7-membered heterocycloalkyl ring has at least
one ring-forming carbon atom and 1, 2 or 3, ring-forming
heteroatoms independently selected from N, O, and S; wherein a
ring-forming carbon atom of each spiro 3-7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl
ring and spiro C.sub.3-6 cycloalkyl ring are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.11;
[0117] each R.sup.11 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, OR.sup.a3, SR.sup.a3,
C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
NR.sup.c3S(O)R.sup.b3, NR.sup.c3S(O).sub.2R.sup.b3,
NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3, S(O)R.sup.b3,
S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0118] each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
4-7 membered heterocycloalkyl, halo, CN, OR.sup.a5, SR.sup.a5,
C(O)R.sup.b5, C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.a5,
NR.sup.c5R.sup.d5, NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,
NR.sup.c5S(O)R.sup.b5, NR.sup.c5S(O).sub.2R.sup.b5,
NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5, S(O)R.sup.b5,
S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, and
S(O).sub.2NR.sup.c5R.sup.d5; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.g;
[0119] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, NO.sub.2, OR.sup.a2,
SR.sup.a2, C(O)OR.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, C(.dbd.NR.sup.e2)R.sup.b2,
C(.dbd.NOR.sup.a2)R.sup.b2, (.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,
S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21;
[0120] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21;
[0121] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, OR.sup.a4, SR.sup.a4,
S(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4, C(O)OR.sup.a4,
NR.sup.c4R.sup.d4, NR.sup.c4C(O)R.sup.b4, NR.sup.c4C(O)OR.sup.a4,
NR.sup.c4S(O)R.sup.b4, NR.sup.c4S(O).sub.2R.sup.b4,
NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4, S(O)R.sup.b4,
S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, and
S(O).sub.2NR.sup.c4R.sup.d4; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22;
[0122] or two R.sup.21 substituents taken together with the carbon
atom to which they are attached form a spiro 3-7-membered
heterocycloalkyl ring, or a spiro C.sub.3-6 cycloalkyl ring;
wherein each spiro 3-7-membered heterocycloalkyl ring has at least
one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each spiro 3-7-membered heterocycloalkyl ring is
optionally substituted by oxo to form a carbonyl group; and wherein
the spiro 3-7-membered heterocycloalkyl ring and spiro C.sub.3-6
cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.22;
[0123] each R.sup.22 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered
heterocycloalkyl, halo, CN, OR.sup.a6, SR.sup.a6, C(O)R.sup.b6,
C(O)NR.sup.c6R.sup.d6, C(O)OR.sup.a6, NR.sup.c6R.sup.d6,
NR.sup.c6C(O)R.sup.b6, NR.sup.c6C(O)OR.sup.a6,
NR.sup.c6S(O)R.sup.b6, NR.sup.c6S(O).sub.2R.sup.b6,
NR.sup.c6S(O).sub.2NR.sup.c6R.sup.d6, S(O)R.sup.b6,
S(O)NR.sup.c6R.sup.d6, S(O).sup.2R.sup.b6, and
S(O).sub.2NR.sup.c6R.sup.d6; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl,
5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.g;
[0124] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10;
[0125] or any R.sup.c and R.sup.d attached to the same N atom,
together with the N atom to which they are attached, form a 4-10
membered heterocycloalkyl group optionally substituted with 1, 2, 3
or 4 substituents independently selected from R.sup.10;
[0126] each R.sup.b is independently selected from C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl;
wherein said C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and
5-10 membered heteroaryl are each optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.10;
[0127] each R.sup.e is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0128] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.11;
[0129] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0130] each R.sup.b1 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11;
[0131] each R.sup.e1 is independently selected from H, CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0132] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.21;
[0133] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.21;
[0134] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.21;
[0135] each R.sup.e2 is independently selected from H, CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0136] each R.sup.a3, R.sup.c3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said
C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.12;
[0137] or any R.sup.c3 and R.sup.d3 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2 or 3 substituents independently selected from R.sup.12;
[0138] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0139] each R.sup.a4, R.sup.c4 and R.sup.d4 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said
C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.22;
[0140] or any R.sup.c4 and R.sup.d4 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2 or 3 substituents independently selected from R.sup.22;
[0141] each R.sup.b4 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22;
[0142] each R.sup.a5, R.sup.c5 and R.sup.d5 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g;
[0143] each R.sup.b5 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g;
[0144] each R.sup.a6, R.sup.c6 and R.sup.d6 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g;
[0145] each R.sup.b6 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g; and
[0146] each R.sup.g is independently selected from OH, NO.sub.2,
CN, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkylene, C.sub.1-6 alkoxy, C.sub.1-6
haloalkoxy, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.1-3
alkoxy-C.sub.1-3 alkoxy, HO--C.sub.1-3 alkoxy, HO--C.sub.1-3 alkyl,
cyano-C.sub.1-3 alkyl, H.sub.2N--C.sub.1-3 alkyl, amino, C.sub.1-6
alkylamino, di(C.sub.1-6 alkyl)amino, thio, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamyl,
C.sub.1-6 alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, carboxy,
C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl, di(Ci.sub.--6 alkyl)aminosulfonyl,
aminosulfonylamino, C.sub.1-6 alkylaminosulfonylamino, di(C.sub.1-6
alkyl)aminosulfonylamino, aminocarbonylamino, C.sub.1-6
alkylaminocarbonylamino, and di(C.sub.1-6
alkyl)aminocarbonylamino.
[0147] In some embodiments:
[0148] R.sup.1 is selected from Cy.sup.1, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, and S(O).sub.2NR.sup.cR.sup.d; wherein said
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10;
[0149] Cy.sup.1 is selected from 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein the 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10;
[0150] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1 or 2 ring-forming N heteroatoms;
wherein a ring-forming carbon atom of the 6-10 membered heteroaryl
is optionally substituted by oxo to form a carbonyl group; and
wherein the C.sub.6-10 aryl and 6-10 membered heteroaryl are each
optionally substituted with 1, 2, 3, or substituents independently
selected from R.sup.20;
[0151] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, NO.sub.2, OR.sup.a1
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1S(O)R.sup.b1, NR.sup.c1S(O).sub.2R.sup.b1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11;
[0152] each R.sup.11 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, halo, CN, OR.sup.a3, SR.sup.a3,
C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3, and
NR.sup.c3C(O)OR.sup.a3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0153] each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5, C(O)NR.sup.c5R.sup.d5,
C(O)OR.sup.a5, NR.sup.c5R.sup.d5, NR.sup.c5C(O)R.sup.b5, and
NR.sup.c5C(O)OR.sup.a5;
[0154] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, CN, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2,
S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21;
[0155] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21;
[0156] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, OR.sup.a4, SR.sup.a4, C(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4,
C(O)OR.sup.a4, NR.sup.c4R.sup.d4, NR.sup.c4C(O)R.sup.b4, and
NR.sup.c4C(O)OR.sup.a4;
[0157] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10;
[0158] each R.sup.b is independently selected from C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, and
5-10 membered heteroaryl; wherein said C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10;
[0159] R.sup.a1, R.sup.c1 and R.sup.d1 is independently selected
from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.11;
[0160] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0161] each R.sup.b1 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl;
[0162] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0163] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.21;
[0164] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl;
[0165] each R.sup.a3, R.sup.c3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0166] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl;
[0167] each R.sup.a4, R.sup.c4 and R.sup.d4 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0168] each R.sup.b4 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl;
[0169] each R.sup.a5, R.sup.c5 and R.sup.d5 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; and
[0170] each R.sup.b5 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl.
[0171] In some embodiments:
[0172] R.sup.1 is selected from Cy.sup.1, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, and
NR.sup.cC(O)R.sup.b; wherein said C.sub.2-6 alkenyl and C.sub.2-6
alkynyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10;
[0173] Cy.sup.1 is selected from 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered hetero aryl; wherein the 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10;
[0174] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1 or 2 ring-forming N heteroatoms;
wherein a ring-forming carbon atom of the 6-10 membered heteroaryl
is optionally substituted by oxo to form a carbonyl group; and
wherein the C.sub.6-10 aryl and 6-10 membered heteroaryl are each
optionally substituted with 1, 2, 3, or substituents independently
selected from R.sup.20;
[0175] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and
NR.sup.c1C(O)R.sup.b1; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11;
[0176] each R.sup.11 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, halo, CN, OR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, NR.sup.c3R.sup.d3, and
NR.sup.c3C(O)R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0177] each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
and halo;
[0178] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, CN, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2;
[0179] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21;
[0180] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
and halo;
[0181] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl;
[0182] each R.sup.b is independently selected from C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl;
[0183] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0184] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0185] each R.sup.b1 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, and 4-10 membered heterocycloalkyl;
[0186] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0187] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.21;
[0188] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
and 4-10 membered heterocycloalkyl;
[0189] each R.sup.a3, R.sup.c3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl; and
[0190] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl.
[0191] In some embodiments:
[0192] R.sup.1 is selected from Cy.sup.1 and C.sub.2-6 alkenyl;
wherein said C.sub.2-6 alkenyl is optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.10;
[0193] Cy.sup.1 is selected from 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein the 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10;
[0194] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1 or 2 ring-forming N heteroatoms;
wherein a ring-forming carbon atom of the 6-10 membered heteroaryl
is optionally substituted by oxo to form a carbonyl group; and
wherein the C.sub.6-10 aryl and 6-10 membered heteroaryl are each
optionally substituted with 1, 2, 3, or substituents independently
selected from R.sup.20;
[0195] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, and NR.sup.c1R.sup.d1; wherein
said C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.11;
[0196] each R.sup.11 is independently selected from C.sub.1-6
alkyl, 4-10 membered heterocycloalkyl, CN, C(O)R.sup.b3, and
NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl and 4-10 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.12;
[0197] each R.sup.12 is independently C.sub.1-6 alkyl;
[0198] each R.sup.20 is independently selected from C.sub.1-6
alkyl, halo, OR.sup.a2, C(O)R.sup.b2, and
C(O)NR.sup.c2R.sup.d2;
[0199] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring; wherein the
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein a
ring-forming carbon atom of each fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group;
[0200] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0201] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0202] each R.sup.b1 is independently C.sub.3-10 cycloalkyl or 4-10
membered heterocycloalkyl;
[0203] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H and C.sub.1-6 alkyl;
[0204] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group;
[0205] each R.sup.b2 is independently 4-10 membered
heterocycloalkyl;
[0206] each R.sup.c3 and R.sup.d3 is H; and
[0207] each R.sup.b3 is C.sub.1-6 alkyl.
[0208] In some embodiments, provided herein is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof,
wherein:
[0209] R.sup.1 is selected from Cy.sup.1, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN, NO.sub.2,
OR.sup.a, SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.a, NR.sup.cC(O)NR.sup.cR.sup.d,
C(.dbd.NR.sup.e)R.sup.b, C(.dbd.NOR.sup.a)R.sup.b,
C(.dbd.NR.sup.e)NR.sup.cR.sup.d,
NR.sup.cC(.dbd.NR.sup.e)NR.sup.cR.sup.d, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, NR.sup.cS(O).sub.2NR.sup.cR.sup.d,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d; wherein said C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.10;
[0210] Cy.sup.1 is selected from C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10
membered heteroaryl each has at least one ring-forming carbon atom
and 1, 2, 3, or 4 ring-forming heteroatoms independently selected
from N, O, and S; wherein the N and S are optionally oxidized;
wherein a ring-forming carbon atom of 5-10 membered heteroaryl and
4-10 membered heterocycloalkyl is optionally substituted by oxo to
form a carbonyl group; and wherein the C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.10;
[0211] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 6-10 membered heteroaryl has at least one
ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein the N and S are
optionally oxidized; wherein a ring-forming carbon atom of the 6-10
membered heteroaryl is optionally substituted by oxo to form a
carbonyl group; and wherein the C.sub.6-10 aryl and 6-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from R.sup.20;
[0212] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1C(O)OR.sup.a1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, C(.dbd.NR.sup.e1)R.sup.b1,
C(.dbd.NOR.sup.a1)R.sup.b1, C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.e1)NR.sup.c1R.sup.d1, NR.sup.c1S(O)R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, NR.sup.c1S(O).sub.2NR.sup.c1R.sup.d1,
S(O)R.sup.b1, S(O)NR.sup.c1d.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11;
[0213] or two R.sup.10 substituents taken together with the carbon
atom to which they are attached form a spiro 3-7-membered
heterocycloalkyl ring, or a spiro C.sub.3-6 cycloalkyl ring;
wherein each spiro 3-7-membered heterocycloalkyl ring has at least
one ring-forming carbon atom and 1, 2 or 3, ring-forming
heteroatoms independently selected from N, O, and S; wherein a
ring-forming carbon atom of each spiro 3-7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl
ring and spiro C.sub.3-6 cycloalkyl ring are each optionally
substituted with 1, 2, 3 or 4 substituents independently selected
from R.sup.11;
[0214] each R.sup.11 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, OR.sup.a3, SR.sup.a3,
C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3, NR.sup.c3C(O)OR.sup.a3,
NR.sup.c3S(O)R.sup.b3, NR.sup.c3S(O).sub.2R.sup.b3,
NR.sup.c3S(O).sub.2NR.sup.c3R.sup.d3, S(O)R.sup.b3,
S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3, and
S(O).sub.2NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0215] each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
4-7 membered heterocycloalkyl, halo, CN, OR.sup.a5, SR.sup.a5,
C(O)R.sup.b5, C(O)NR.sup.c5R.sup.d5, C(O)OR.sup.d5,
NR.sup.c5R.sup.d5, NR.sup.c5C(O)R.sup.b5, NR.sup.c5C(O)OR.sup.a5,
NR.sup.c5S(O)R.sup.b5, NR.sup.c5S(O).sub.2R.sup.b5,
NR.sup.c5S(O).sub.2NR.sup.c5R.sup.d5, S(O)R.sup.b5,
S(O)NR.sup.c5R.sup.d5, S(O).sub.2R.sup.b5, and
S(O).sub.2NR.sup.c5R.sup.d5; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.g;
[0216] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, NO.sub.2, OR.sup.a2,
SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)OR.sup.a2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, C(.dbd.NR.sup.e2)R.sup.b2,
C(.dbd.NOR.sup.a2)R.sup.b2, C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.e2)NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, NR.sup.c2S(O).sub.2NR.sup.c2R.sup.d2,
S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2, and
S(O).sub.2NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21;
[0217] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21;
[0218] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, OR.sup.a4, SR.sup.a4,
C(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4, C(O)OR.sup.a4,
NR.sup.c4R.sup.d4, NR.sup.c4S(O)R.sup.b4, NR.sup.c4C(O)OR.sup.a4,
NR.sup.c4S(O)R.sup.b4, NR.sup.c4S(O).sub.2R.sup.b4,
NR.sup.c4S(O).sub.2NR.sup.c4R.sup.d4, S(O)R.sup.b4,
S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4, and
S(O).sub.2NR.sup.c4R.sup.d4; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22;
[0219] or two R.sup.21 substituents taken together with the carbon
atom to which they are attached form a spiro 3-7-membered
heterocycloalkyl ring, or a spiro C.sub.3-6 cycloalkyl ring;
wherein each spiro 3-7-membered heterocycloalkyl ring has at least
one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each spiro 3-7-membered heterocycloalkyl ring is
optionally substituted by oxo to form a carbonyl group; and wherein
the spiro 3-7-membered heterocycloalkyl ring and spiro C.sub.3-6
cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4
substituents independently selected from R.sup.22;
[0220] each R.sup.22 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered
heterocycloalkyl, halo, CN, OR.sup.a6, SR.sup.a6, C(O)R.sup.b6,
C(O)NR.sup.c6R.sup.d6, C(O)OR.sup.a6, NR.sup.c6R.sup.d6,
NR.sup.c6C(O)R.sup.b6, NR.sup.c6C(O)OR.sup.a6,
NR.sup.c6S(O)R.sup.b6, NR.sup.c6S(O).sub.2R.sup.b6,
NR.sup.c6S(O).sub.2NR.sup.c6R.sup.d6, S(O)R.sup.b6,
S(O)NR.sup.c6R.sup.d6, S(O).sub.2R.sup.b6, and
S(O).sub.2NR.sup.c6R.sup.d6; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl,
5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.g;
[0221] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.10;
[0222] or any R.sup.c and R.sup.d attached to the same N atom,
together with the N atom to which they are attached, form a 4-10
membered heterocycloalkyl group optionally substituted with 1, 2, 3
or 4 substituents independently selected from R.sup.10;
[0223] each R.sup.b is independently selected from C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, and
5-10 membered heteroaryl; wherein said C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10;
[0224] each R.sup.e is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0225] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.11;
[0226] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0227] each R.sup.b1 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.11;
[0228] each R.sup.e1 is independently selected from H, CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0229] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.21;
[0230] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.21;
[0231] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.21;
[0232] each R.sup.e2 is independently selected from H, CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkylaminosulfonyl, carbamyl, C.sub.1-6 alkylcarbamyl, di(C.sub.1-6
alkyl)carbamyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl and
di(C.sub.1-6 alkyl)aminosulfonyl;
[0233] each R.sup.a3, R.sup.c3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said
C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.12;
[0234] or any R.sup.c3 and R.sup.d3 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2 or 3 substituents independently selected from R.sup.12;
[0235] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0236] each R.sup.a4, R.sup.c4 and R.sup.d4 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said
C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.22;
[0237] or any R.sup.c4 and R.sup.d4 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2 or 3 substituents independently selected from R.sup.22;
[0238] each R.sup.b4 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7
membered heterocycloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5-6
membered heteroaryl and 4-7 membered heterocycloalkyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.22;
[0239] each R.sup.a5, R.sup.c5 and R.sup.d5 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g;
[0240] each R.sup.b5 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g;
[0241] each R.sup.a6, R.sup.c6 and R.sup.d6 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.g;
[0242] each R.sup.b6 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl; wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl and
C.sub.2-6 alkynyl are each optionally substituted with 1, 2, 3, or
4 substituents independently selected from R.sup.g; and
[0243] each R.sup.g is independently selected from OH, NO.sub.2,
CN, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkyl-C.sub.1-2 alkylene, C.sub.1-6 alkoxy, C.sub.1-6
haloalkoxy, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, C.sub.1-3
alkoxy-C.sub.1-3 alkoxy, HO--C.sub.1-3 alkoxy, HO--C.sub.1-3 alkyl,
cyano-C.sub.1-3 alkyl, H.sub.2N--C.sub.1-3 alkyl, amino, C.sub.1-6
alkylamino, di(C.sub.1-6 alkyl)amino, thio, C.sub.1-6 alkylthio,
C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, carbamyl,
C.sub.1-6 alkylcarbamyl, di(C.sub.1-6 alkyl)carbamyl, carboxy,
C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6
alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aminosulfonyl,
C.sub.1-6 alkylaminosulfonyl, di(C.sub.1-6 alkyl)aminosulfonyl,
aminosulfonylamino, C.sub.1-6 alkylaminosulfonylamino, di(C.sub.1-6
alkyl)aminosulfonylamino, aminocarbonylamino, C.sub.1-6
alkylaminocarbonylamino, and di(C.sub.1-6
alkyl)aminocarbonylamino.
[0244] In some embodiments, wherein:
[0245] R.sup.1 is selected from Cy.sup.1, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a,
OC(O)R.sup.b, OC(O)NR.sup.cR.sup.d, NR.sup.cC(O)R.sup.b,
NR.sup.cC(O)OR.sup.a, NR.sup.cS(O)R.sup.b,
NR.sup.cS(O).sub.2R.sup.b, S(O)R.sup.b, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, and S(O).sub.2NR.sup.cR.sup.d; wherein said
C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10;
[0246] Cy.sup.1 is selected from 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein the 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10;
[0247] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1 or 2 ring-forming N heteroatoms;
wherein a ring-forming carbon atom of the 6-10 membered heteroaryl
is optionally substituted by oxo to form a carbonyl group; and
wherein the C.sub.6-10 aryl and 6-10 membered heteroaryl are each
optionally substituted with 1, 2, 3, or substituents independently
selected from R.sup.20;
[0248] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1,
OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1, NR.sup.c1R.sup.d1,
NR.sup.c1C(O)R.sup.b1, NR.sup.c1S(O)OR.sup.a1,
NR.sup.c1S(O)R.sup.b1, NR.sup.c1S(O).sub.2R.sup.b1, S(O)R.sup.b1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11;
[0249] each R.sup.11 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, halo, CN, OR.sup.a3, SR.sup.3,
C(O)R.sup.b3, C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3,
NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3, and
NR.sup.c3C(O)OR.sup.a3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0250] each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, OR.sup.a5, SR.sup.a5, C(O)R.sup.b5, C(O)NR.sup.c5R.sup.d5,
C(O)OR.sup.a5, NR.sup.c5R.sup.d5, NR.sup.c5C(O)R.sup.b5, and
NR.sup.c5C(O)OR.sup.a5;
[0251] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, CN, OR.sup.a2, SR.sup.a2, C(O)R.sup.b2,
C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2, OC(O)R.sup.b2,
OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2C(O)OR.sup.a2, NR.sup.c2S(O)R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2,
S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.d2; wherein said
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.21;
[0252] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21;
[0253] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, OR.sup.a4, SR.sup.a4, C(O)R.sup.b4, C(O)NR.sup.c4R.sup.d4,
C(O)OR.sup.a4, NR.sup.c4R.sup.d4, NR.sup.c4C(O)R.sup.b4, and
NR.sup.c4C(O)OR.sup.a4;
[0254] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.10;
[0255] each R.sup.b is independently selected from C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10
cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10 aryl, and
5-10 membered heteroaryl; wherein said C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl are each optionally
substituted with 1, 2, 3, or 4 substituents independently selected
from R.sup.10;
[0256] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl and 5-10 membered heteroaryl;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.11;
[0257] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0258] each R.sup.b1 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl;
[0259] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0260] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.21;
[0261] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl and 5-10 membered heteroaryl;
[0262] each R.sup.a3, R.sup.c3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0263] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl;
[0264] each R.sup.a4, R.sup.c4 and R.sup.d4 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0265] each R.sup.b4 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl;
[0266] each R.sup.a5, R.sup.c5 and R.sup.d5 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl and C.sub.1-6 haloalkyl; and
[0267] each R.sup.b5 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6
haloalkyl.
[0268] In some embodiments, wherein:
[0269] R.sup.1 is selected from Cy.sup.1, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, and
NR.sup.cC(O)R.sup.b; wherein said C.sub.2-6 alkenyl and C.sub.2-6
alkynyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10;
[0270] Cy.sup.1 is selected from 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein the 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10;
[0271] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1 or 2 ring-forming N heteroatoms;
wherein a ring-forming carbon atom of the 6-10 membered heteroaryl
is optionally substituted by oxo to form a carbonyl group; and
wherein the C.sub.6-10 aryl and 6-10 membered heteroaryl are each
optionally substituted with 1, 2, 3, or substituents independently
selected from R.sup.20;
[0272] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and
NR.sup.c1C(O)R.sup.b1; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11;
[0273] each R.sup.11 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, halo, CN, OR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, NR.sup.c3R.sup.d3, and
NR.sup.c3C(O)R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0274] each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
and halo;
[0275] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, CN, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2;
[0276] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21;
[0277] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
and halo;
[0278] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.10
[0279] each R.sup.b is independently selected from C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl;
[0280] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0281] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0282] each R.sup.b1 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, and 4-10 membered heterocycloalkyl;
[0283] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0284] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.21;
[0285] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
and 4-10 membered heterocycloalkyl;
[0286] each R.sup.a3, R.sup.c3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl; and
[0287] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl.
[0288] In some embodiments:
[0289] R.sup.1 is selected from Cy.sup.1, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halo, CN, OR.sup.a,
SR.sup.a, C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, and
NR.sup.cC(O)R.sup.b; wherein said C.sub.2-6 alkenyl and C.sub.2-6
alkynyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.10;
[0290] Cy.sup.1 is selected from 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered hetero aryl; wherein the 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10;
[0291] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1 or 2 ring-forming N heteroatoms;
wherein a ring-forming carbon atom of the 6-10 membered heteroaryl
is optionally substituted by oxo to form a carbonyl group; and
wherein the C.sub.6-10 aryl and 6-10 membered heteroaryl are each
optionally substituted with 1, 2, 3, or substituents independently
selected from R.sup.20;
[0292] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-3
alkylene, 4-10 membered heterocycloalkyl-C.sub.1-3 alkylene,
C.sub.6-10 aryl-C.sub.1-3 alkylene, 5-10 membered
heteroaryl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1, C(O)R.sup.b1,
C(O)NR.sup.c1R.sup.d1, C(O)OR.sup.a1, NR.sup.c1R.sup.d1, and
NR.sup.c1C(O)R.sup.b1; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-3 alkylene, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, C.sub.6-10 aryl-C.sub.1-3
alkylene and 5-10 membered heteroaryl-C.sub.1-3 alkylene are each
optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.11;
[0293] each R.sup.11 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, halo, CN, OR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, NR.sup.c3R.sup.d3, and
NR.sup.c3C(O)R.sup.b3; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl are
each optionally substituted with 1, 2, 3, or 4 substituents
independently selected from R.sup.12;
[0294] each R.sup.12 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
and halo;
[0295] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, CN, OR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, NR.sup.c2R.sup.d2, and NR.sup.c2C(O)R.sup.b2;
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.21;
[0296] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused
C.sub.3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or
7-membered heterocycloalkyl ring each has at least one ring-forming
carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms
independently selected from N, O, and S; wherein a ring-forming
carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl
ring is optionally substituted by oxo to form a carbonyl group; and
wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring
and fused C.sub.3-6 cycloalkyl ring are each optionally substituted
with 1, 2, 3 or 4 substituents independently selected from
R.sup.21;
[0297] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, and NR.sup.c4R.sup.d4;
[0298] each R.sup.a, R.sup.c, and R.sup.d is independently selected
from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
C.sub.1-6 haloalkyl; wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are each optionally substituted with
1, 2, 3, or 4 substituents independently selected from R.sup.10
[0299] each R.sup.b is independently selected from C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6 haloalkyl;
[0300] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0301] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0302] each R.sup.b1 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, and 4-10 membered heterocycloalkyl;
[0303] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0304] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.21;
[0305] each R.sup.b2 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
and 4-10 membered heterocycloalkyl;
[0306] each R.sup.a3, R.sup.c3 and R.sup.d3 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0307] each R.sup.b3 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-6
haloalkyl; and
[0308] each R.sup.c4 and R.sup.d4 is independently selected from H
and C.sub.1-6 alkyl.
[0309] In some embodiments:
[0310] R.sup.1 is selected from Cy.sup.1 and C.sub.2-6 alkenyl;
wherein said C.sub.2-6 alkenyl is optionally substituted with 1, 2,
3, or 4 substituents independently selected from R.sup.10;
[0311] Cy.sup.1 is selected from 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl and 5-10 membered heteroaryl; wherein the 4-10
membered heterocycloalkyl and 5-10 membered heteroaryl each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein the N
and S are optionally oxidized; wherein a ring-forming carbon atom
of 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl is
optionally substituted by oxo to form a carbonyl group; and wherein
the 4-10 membered heterocycloalkyl, C.sub.6-10 aryl and 5-10
membered heteroaryl are each optionally substituted with 1, 2, 3 or
4 substituents independently selected from R.sup.10;
[0312] Cy.sup.A is selected from C.sub.6-10 aryl and 6-10 membered
heteroaryl; wherein the 5-10 membered heteroaryl has at least one
ring-forming carbon atom and 1 or 2 ring-forming N heteroatoms;
wherein a ring-forming carbon atom of the 6-10 membered heteroaryl
is optionally substituted by oxo to form a carbonyl group; and
wherein the C.sub.6-10 aryl and 6-10 membered heteroaryl are each
optionally substituted with 1, 2, 3, or substituents independently
selected from R.sup.20;
[0313] each R.sup.10 is independently selected from C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene, halo, CN, OR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, and NR.sup.c1R.sup.d1; wherein
said C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl, and 4-10 membered
heterocycloalkyl-C.sub.1-3 alkylene are each optionally substituted
with 1, 2, 3, or 4 substituents independently selected from
R.sup.11;
[0314] each R.sup.11 is independently selected from C.sub.1-6
alkyl, 4-10 memberedheterocycloalkyl, CN, C(O)R.sup.b3, and
NR.sup.c3R.sup.d3; wherein said C.sub.1-6 alkyl and 4-10 membered
heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4
substituents independently selected from R.sup.12;
[0315] each R.sup.12 is independently C.sub.1-6 alkyl;
[0316] each R.sup.20 is independently selected from C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, halo, OR.sup.a2, C(O)R.sup.b2, and
C(O)NR.sup.c2R.sup.d2; wherein said C.sub.1-6 alkyl is optionally
substituted with 1, 2, or 3, substituents independently selected
from R.sup.21;
[0317] or two adjacent R.sup.20 substituents on the Cy.sup.A ring,
taken together with the atoms to which they are attached, form a
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring; wherein the
fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring each has at
least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming
heteroatoms independently selected from N, O, and S; wherein a
ring-forming carbon atom of each fused 4-, 5-, 6- or 7-membered
heterocycloalkyl ring is optionally substituted by oxo to form a
carbonyl group;
[0318] each R.sup.21 is independently selected from C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halo, and NR.sup.c4R.sup.d4;
[0319] each R.sup.a1, R.sup.c1 and R.sup.d1 is independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, and C.sub.1-6 haloalkyl;
[0320] or any R.sup.c1 and R.sup.d1 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group optionally substituted with
1, 2, 3 or 4 substituents independently selected from R.sup.11;
[0321] each R.sup.b1 is independently C.sub.3-10 cycloalkyl or 4-10
membered heterocycloalkyl;
[0322] each R.sup.a2, R.sup.c2 and R.sup.d2 is independently
selected from H and C.sub.1-6 alkyl;
[0323] or any R.sup.c2 and R.sup.d2 attached to the same N atom,
together with the N atom to which they are attached, form a 4-, 5-,
6- or 7-membered heterocycloalkyl group;
[0324] each R.sup.b2 is independently 4-10 membered
heterocycloalkyl;
[0325] each R.sup.c3 and R.sup.d3 is H;
[0326] each R.sup.b3 is C.sub.1-6 alkyl; and
[0327] each R.sup.c4 and R.sup.d4 is independently selected from H
and C.sub.1-6 alkyl.
[0328] It is further appreciated that certain features of the
invention, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment (while the embodiments are intended to be
combined as if written in multiply dependent form). Conversely,
various features of the invention which are, for brevity, described
in the context of a single embodiment, can also be provided
separately or in any suitable subcombination. Thus, it is
contemplated as features described as embodiments of the compounds
of Formula (I) can be combined in any suitable combination.
[0329] At various places in the present specification, certain
features of the compounds are disclosed in groups or in ranges. It
is specifically intended that such a disclosure include each and
every individual subcombination of the members of such groups and
ranges. For example, the term "C.sub.1-6 alkyl" is specifically
intended to individually disclose (without limitation) methyl,
ethyl, C.sub.3 alkyl, C.sub.4 alkyl, C.sub.5 alkyl and C.sub.6
alkyl.
[0330] The term "n-membered," where n is an integer, typically
describes the number of ring-forming atoms in a moiety where the
number of ring-forming atoms is n. For example, piperidinyl is an
example of a 6-membered heterocycloalkyl ring, pyrazolyl is an
example of a 5-membered heteroaryl ring, pyridyl is an example of a
6-membered heteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an
example of a 10-membered cycloalkyl group.
[0331] At various places in the present specification, variables
defining divalent linking groups may be described. It is
specifically intended that each linking substituent include both
the forward and backward forms of the linking substituent. For
example, --NR(CR'R'').sub.n-- includes both --NR(CR'R'').sub.n--
and --(CR'R'').sub.nNR-- and is intended to disclose each of the
forms individually. Where the structure requires a linking group,
the Markush variables listed for that group are understood to be
linking groups. For example, if the structure requires a linking
group and the Markush group definition for that variable lists
"alkyl" or "aryl" then it is understood that the "alkyl" or "aryl"
represents a linking alkylene group or arylene group,
respectively.
[0332] The term "substituted" means that an atom or group of atoms
formally replaces hydrogen as a "substituent" attached to another
group. The term "substituted", unless otherwise indicated, refers
to any level of substitution, e.g., mono-, di-, tri-, tetra- or
penta-substitution, where such substitution is permitted. The
substituents are independently selected, and substitution may be at
any chemically accessible position. It is to be understood that
substitution at a given atom is limited by valency. It is to be
understood that substitution at a given atom results in a
chemically stable molecule. The phrase "optionally substituted"
means unsubstituted or substituted. The term "substituted" means
that a hydrogen atom is removed and replaced by a substituent. A
single divalent substituent, e.g., oxo, can replace two hydrogen
atoms.
[0333] The term "C.sub.n-m" indicates a range which includes the
endpoints, wherein n and m are integers and indicate the number of
carbons. Examples include C.sub.1-4, C.sub.1-6 and the like.
[0334] The term "alkyl" employed alone or in combination with other
terms, refers to a saturated hydrocarbon group that may be
straight-chained or branched. The term "C.sub.n-m alkyl", refers to
an alkyl group having n to m carbon atoms. An alkyl group formally
corresponds to an alkane with one C--H bond replaced by the point
of attachment of the alkyl group to the remainder of the compound.
In some embodiments, the alkyl group contains from 1 to 6 carbon
atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to
2 carbon atoms. Examples of alkyl moieties include, but are not
limited to, chemical groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher
homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,
1,2,2-trimethylpropyl and the like.
[0335] The term "alkenyl" employed alone or in combination with
other terms, refers to a straight-chain or branched hydrocarbon
group corresponding to an alkyl group having one or more double
carbon-carbon bonds. An alkenyl group formally corresponds to an
alkene with one C--H bond replaced by the point of attachment of
the alkenyl group to the remainder of the compound. The term
"C.sub.n-m alkenyl" refers to an alkenyl group having n to m
carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2
to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but
are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl,
sec-butenyl and the like.
[0336] The term "alkynyl" employed alone or in combination with
other terms, refers to a straight-chain or branched hydrocarbon
group corresponding to an alkyl group having one or more triple
carbon-carbon bonds. An alkynyl group formally corresponds to an
alkyne with one C--H bond replaced by the point of attachment of
the alkyl group to the remainder of the compound. The term
"C.sub.n-m alkynyl" refers to an alkynyl group having n to m
carbons. Example alkynyl groups include, but are not limited to,
ethynyl, propyn-1-yl, propyn-2-yl and the like. In some
embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3
carbon atoms.
[0337] The term "alkylene", employed alone or in combination with
other terms, refers to a divalent alkyl linking group. An alkylene
group formally corresponds to an alkane with two C--H bond replaced
by points of attachment of the alkylene group to the remainder of
the compound. The term "C.sub.n-m alkylene" refers to an alkylene
group having n to m carbon atoms. Examples of alkylene groups
include, but are not limited to, ethan-1,2-diyl, ethan-1,1-diyl,
propan-1,3-diyl, propan-1,2-diyl, propan-1,1-diyl, butan-1,4-diyl,
butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the
like.
[0338] The term "alkoxy", employed alone or in combination with
other terms, refers to a group of formula --O-alkyl, wherein the
alkyl group is as defined above. The term "C.sub.n-m alkoxy" refers
to an alkoxy group, the alkyl group of which has n to m carbons.
Example alkoxy groups include methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), t-butoxy and the like. In some
embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon
atoms.
[0339] The term "amino" refers to a group of formula
--NH.sub.2.
[0340] The term "carbonyl", employed alone or in combination with
other terms, refers to a --C(.dbd.O)-- group, which also may be
written as C(O).
[0341] The term "cyano" or "nitrile" refers to a group of formula
--C.ident.N, which also may be written as --CN.
[0342] The terms "halo" or "halogen", used alone or in combination
with other terms, refers to fluoro, chloro, bromo and iodo. In some
embodiments, "halo" refers to a halogen atom selected from F, Cl,
or Br. In some embodiments, halo groups are F.
[0343] The term "haloalkyl" as used herein refers to an alkyl group
in which one or more of the hydrogen atoms has been replaced by a
halogen atom. The term "C.sub.n-m haloalkyl" refers to a C.sub.n-m
alkyl group having n to m carbon atoms and from at least one up to
{2(n to m)+1} halogen atoms, which may either be the same or
different. In some embodiments, the halogen atoms are fluoro atoms.
In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4
carbon atoms. Example haloalkyl groups include CF.sub.3,
C.sub.2F.sub.5, CHF.sub.2, CH.sub.2F, CCl.sub.3, CHCl.sub.2,
C.sub.2Cl.sub.5 and the like. In some embodiments, the haloalkyl
group is a fluoroalkyl group.
[0344] The term "haloalkoxy", employed alone or in combination with
other terms, refers to a group of formula --O-haloalkyl, wherein
the haloalkyl group is as defined above. The term "C.sub.n-m
haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of
which has n to m carbons. Example haloalkoxy groups include
trifluoromethoxy and the like. In some embodiments, the haloalkoxy
group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0345] The term "oxo" refers to an oxygen atom as a divalent
substituent, forming a carbonyl group when attached to carbon, or
attached to a heteroatom forming a sulfoxide or sulfone group, or
an N-oxide group. In some embodiments, heterocyclic groups may be
optionally substituted by 1 or 2 oxo (.dbd.O) substituents.
[0346] The term "sulfido" refers to a sulfur atom as a divalent
substituent, forming a thiocarbonyl group (C.dbd.S) when attached
to carbon.
[0347] The term "aromatic" refers to a carbocycle or heterocycle
having one or more polyunsaturated rings having aromatic character
(i.e., having (4n+2) delocalized .pi. (pi) electrons where n is an
integer).
[0348] The term "aryl," employed alone or in combination with other
terms, refers to an aromatic hydrocarbon group, which may be
monocyclic or polycyclic (e.g., having 2 fused rings). The term
"C.sub.n-m aryl" refers to an aryl group having from n to m ring
carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, and the
like. In some embodiments, aryl groups have from 6 to about 10
carbon atoms. In some embodiments aryl groups have 6 carbon atoms.
In some embodiments aryl groups have 10 carbon atoms. In some
embodiments, the aryl group is phenyl. In some embodiments, the
aryl group is naphthyl.
[0349] The term "heteroaryl" or "heteroaromatic," employed alone or
in combination with other terms, refers to a monocyclic or
polycyclic aromatic heterocycle having at least one heteroatom ring
member selected from sulfur, oxygen and nitrogen. In some
embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring
members independently selected from nitrogen, sulfur and oxygen. In
some embodiments, any ring-forming N in a heteroaryl moiety can be
an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms
including carbon atoms and 1, 2, 3 or 4 heteroatom ring members
independently selected from nitrogen, sulfur and oxygen. In some
embodiments, the heteroaryl has 5-10 ring atoms including carbon
atoms and 1, 2, 3 or 4 heteroatom ring members independently
selected from nitrogen, sulfur and oxygen. In some embodiments, the
heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members
independently selected from nitrogen, sulfur and oxygen. In some
embodiments, the heteroaryl is a five-membered or six-membered
heteroaryl ring. In other embodiments, the heteroaryl is an
eight-membered, nine-membered or ten-membered fused bicyclic
heteroaryl ring. Example heteroaryl groups include, but are not
limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl,
pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl,
thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl,
isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-,
1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl, isoindolyl,
benzothiophenyl, benzofuranyl, benzisoxazolyl,
imidazo[1,2-b]thiazolyl, purinyl, and the like. In some
embodiments, the heteroaryl group is pyridone (e.g.,
2-pyridone).
[0350] A five-membered heteroaryl ring is a heteroaryl group having
five ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms
are independently selected from N, O and S. Exemplary five-membered
ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl,
thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,
1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl,
1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
[0351] A six-membered heteroaryl ring is a heteroaryl group having
six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are
independently selected from N, O and S. Exemplary six-membered ring
heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl,
isoindolyl, and pyridazinyl.
[0352] The term "cycloalkyl," employed alone or in combination with
other terms, refers to a non-aromatic hydrocarbon ring system
(monocyclic, bicyclic or polycyclic), including cyclized alkyl and
alkenyl groups. The term "C.sub.n-m cycloalkyl" refers to a
cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl
groups can include mono- or polycyclic (e.g., having 2, 3 or 4
fused rings) groups and spirocycles. Cycloalkyl groups can have 3,
4, 5, 6 or 7 ring-forming carbons (C.sub.3-7). In some embodiments,
the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members,
or 3 to 4 ring members. In some embodiments, the cycloalkyl group
is monocyclic. In some embodiments, the cycloalkyl group is
monocyclic or bicyclic. In some embodiments, the cycloalkyl group
is a C.sub.3-6 monocyclic cycloalkyl group. Ring-forming carbon
atoms of a cycloalkyl group can be optionally oxidized to form an
oxo or sulfido group. Cycloalkyl groups also include
cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl. Also included in the
definition of cycloalkyl are moieties that have one or more
aromatic rings fused (i.e., having a bond in common with) to the
cycloalkyl ring, e.g., benzo or thienyl derivatives of
cyclopentane, cyclohexane and the like. A cycloalkyl group
containing a fused aromatic ring can be attached through any
ring-forming atom including a ring-forming atom of the fused
aromatic ring. Examples of cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,
cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl,
norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl,
and the like. In some embodiments, the cycloalkyl group is
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0353] The term "heterocycloalkyl," employed alone or in
combination with other terms, refers to a non-aromatic ring or ring
system, which may optionally contain one or more alkenylene groups
as part of the ring structure, which has at least one heteroatom
ring member independently selected from nitrogen, sulfur, oxygen
and phosphorus, and which has 4-10 ring members, 4-7 ring members,
or 4-6 ring members. Included within the term "heterocycloalkyl"
are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups.
Heterocycloalkyl groups can include mono- or bicyclic (e.g., having
two fused or bridged rings) or spirocyclic ring systems. In some
embodiments, the heterocycloalkyl group is a monocyclic group
having 1, 2 or 3 heteroatoms independently selected from nitrogen,
sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a
heterocycloalkyl group can be optionally oxidized to form an oxo or
sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or
S(O).sub.2, N-oxide etc.) or a nitrogen atom can be quaternized.
The heterocycloalkyl group can be attached through a ring-forming
carbon atom or a ring-forming heteroatom. In some embodiments, the
heterocycloalkyl group contains 0 to 3 double bonds. In some
embodiments, the heterocycloalkyl group contains 0 to 2 double
bonds. Also included in the definition of heterocycloalkyl are
moieties that have one or more aromatic rings fused (i.e., having a
bond in common with) to the heterocycloalkyl ring, e.g., benzo or
thienyl derivatives of piperidine, morpholine, azepine, etc. A
heterocycloalkyl group containing a fused aromatic ring can be
attached through any ring-forming atom including a ring-forming
atom of the fused aromatic ring. Examples of heterocycloalkyl
groups include azetidinyl, azepanyl, dihydrobenzofuranyl,
dihydrofuranyl, dihydropyranyl, morpholino,
3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl,
piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl,
quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,
1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-inden-5-yl,
isoindolinyl, tropanyl, and thiomorpholino.
[0354] At certain places, the definitions or embodiments refer to
specific rings (e.g., an azetidine ring, a pyridine ring, etc.).
Unless otherwise indicated, these rings can be attached to any ring
member provided that the valency of the atom is not exceeded. For
example, an azetidine ring may be attached at any position of the
ring, whereas an azetidin-3-yl ring is attached at the
3-position.
[0355] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present invention that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically inactive starting materials
are known in the art, such as by resolution of racemic mixtures or
by stereoselective synthesis. Many geometric isomers of olefins,
C.dbd.N double bonds and the like can also be present in the
compounds described herein, and all such stable isomers are
contemplated in the present invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms.
[0356] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. One method
includes fractional recrystallization using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods are,
e.g., optically active acids, such as the D and L forms of tartaric
acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid,
malic acid, lactic acid or the various optically active
camphorsulfonic acids such as .beta.-camphorsulfonic acid. Other
resolving agents suitable for fractional crystallization methods
include stereoisomerically pure forms of .alpha.-methylbenzylamine
(e.g., S and R forms, or diastereomerically pure forms),
2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,
cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
[0357] Resolution of racemic mixtures can also be carried out by
elution on a column packed with an optically active resolving agent
(e.g., dinitrobenzoylphenylglycine). Suitable elution solvent
composition can be determined by one skilled in the art.
[0358] In some embodiments, the compounds of the invention have the
(R)-configuration. In other embodiments, the compounds have the
(S)-configuration. In compounds with more than one chiral centers,
each of the chiral centers in the compound may be independently (R)
or (S), unless otherwise indicated.
[0359] Compounds of the invention also include tautomeric forms.
Tautomeric forms result from the swapping of a single bond with an
adjacent double bond together with the concomitant migration of a
proton. Tautomeric forms include prototropic tautomers which are
isomeric protonation states having the same empirical formula and
total charge. Example prototropic tautomers include ketone-enol
pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine
pairs, and annular forms where a proton can occupy two or more
positions of a heterocyclic system, e.g., 1H- and 3H-imidazole,
1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and
2H-pyrazole. Tautomeric forms can be in equilibrium or sterically
locked into one form by appropriate substitution.
[0360] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates or final compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. For example, isotopes of hydrogen include tritium and
deuterium. One or more constituent atoms of the compounds of the
invention can be replaced or substituted with isotopes of the atoms
in natural or non-natural abundance. In some embodiments, the
compound includes at least one deuterium atom. For example, one or
more hydrogen atoms in a compound of the present disclosure can be
replaced or substituted by deuterium. In some embodiments, the
compound includes two or more deuterium atoms. In some embodiments,
the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
deuterium atoms. Synthetic methods for including isotopes into
organic compounds are known in the art (Deuterium Labeling in
Organic Chemistry by Alan F. Thomas (New York, N.Y.,
Appleton-Century-Crofts, 1971; The Renaissance of H/D Exchange by
Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann,
Angew. Chem. Int. Ed. 2007, 7744-7765). Isotopically labeled
compounds can used in various studies such as NMR spectroscopy,
metabolism experiments, and/or assays.
[0361] Substitution with heavier isotopes such as deuterium, may
afford certain therapeutic advantages resulting from greater
metabolic stability, for example, increased in vivo half-life or
reduced dosage requirements, and hence may be preferred in some
circumstances. (A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210;
R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312).
[0362] The term, "compound," as used herein is meant to include all
stereoisomers, geometric isomers, tautomers and isotopes of the
structures depicted. The term is also meant to refer to compounds
of the inventions, regardless of how they are prepared, e.g.,
synthetically, through biological process (e.g., metabolism or
enzyme conversion), or a combination thereof.
[0363] All compounds, and pharmaceutically acceptable salts
thereof, can be found together with other substances such as water
and solvents (e.g., hydrates and solvates) or can be isolated. When
in the solid state, the compounds described herein and salts
thereof may occur in various forms and may, e.g., take the form of
solvates, including hydrates. The compounds may be in any solid
state form, such as a polymorph or solvate, so unless clearly
indicated otherwise, reference in the specification to compounds
and salts thereof should be understood as encompassing any solid
state form of the compound.
[0364] In some embodiments, the compounds of the invention, or
salts thereof, are substantially isolated. By "substantially
isolated" is meant that the compound is at least partially or
substantially separated from the environment in which it was formed
or detected. Partial separation can include, e.g., a composition
enriched in the compounds of the invention. Substantial separation
can include compositions containing at least about 50%, at least
about 60%, at least about 70%, at least about 80%, at least about
90%, at least about 95%, at least about 97%, or at least about 99%
by weight of the compounds of the invention, or salt thereof.
[0365] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0366] The expressions, "ambient temperature" and "room
temperature," as used herein, are understood in the art, and refer
generally to a temperature, e.g., a reaction temperature, that is
about the temperature of the room in which the reaction is carried
out, e.g., a temperature from about 20.degree. C. to about
30.degree. C.
[0367] The present invention also includes pharmaceutically
acceptable salts of the compounds described herein. The term
"pharmaceutically acceptable salts" refers to derivatives of the
disclosed compounds wherein the parent compound is modified by
converting an existing acid or base moiety to its salt form.
Examples of pharmaceutically acceptable salts include, but are not
limited to, mineral or organic acid salts of basic residues such as
amines; alkali or organic salts of acidic residues such as
carboxylic acids; and the like. The pharmaceutically acceptable
salts of the present invention include the non-toxic salts of the
parent compound formed, e.g., from non-toxic inorganic or organic
acids. The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, non-aqueous media like ether, ethyl
acetate, alcohols (e.g., methanol, ethanol, iso-propanol or
butanol) or acetonitrile (MeCN) are preferred. Lists of suitable
salts are found in Remington's Pharmaceutical Sciences, 17.sup.th
Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et
al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al.,
Handbook of Pharmaceutical Salts: Properties, Selection, and Use,
(Wiley, 2002). In some embodiments, the compounds described herein
include the N-oxide forms.
Synthesis
[0368] Compounds of the invention, including salts thereof, can be
prepared using known organic synthesis techniques and can be
synthesized according to any of numerous possible synthetic routes,
such as those in the Schemes below.
[0369] The reactions for preparing compounds of the invention can
be carried out in suitable solvents which can be readily selected
by one of skill in the art of organic synthesis. Suitable solvents
can be substantially non-reactive with the starting materials
(reactants), the intermediates or products at the temperatures at
which the reactions are carried out, e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected by the skilled artisan.
[0370] Preparation of compounds of the invention can involve the
protection and deprotection of various chemical groups. The need
for protection and deprotection, and the selection of appropriate
protecting groups, can be readily determined by one skilled in the
art. The chemistry of protecting groups is described, e.g., in
Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting
Group Chemistry, (Oxford University Press, 2000); Smith et al.,
March's Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 6.sup.th Ed. (Wiley, 2007); Peturssion et al.,
"Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ.,
1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic
Synthesis, 4th Ed., (Wiley, 2006).
[0371] Reactions can be monitored according to any suitable method
known in the art. For example, product formation can be monitored
by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., .sup.1H or .sup.13C), infrared spectroscopy,
spectrophotometry (e.g., UV-visible), mass spectrometry or by
chromatographic methods such as high performance liquid
chromatography (HPLC) or thin layer chromatography (TLC).
[0372] The Schemes below provide general guidance in connection
with preparing the compounds of the invention. One skilled in the
art would understand that the preparations shown in the Schemes can
be modified or optimized using general knowledge of organic
chemistry to prepare various compounds of the invention.
[0373] Compounds of Formula (I) can be prepared, e.g., using a
process as illustrated in the schemes below.
[0374] Compounds of Formula (I) with a variety of substitution at
position R.sup.1 such as those described herein can be prepared,
using a process as illustrated in Scheme 1. In the process depicted
in Scheme 1, compounds of Formula 1-2 is formed after protection of
the NH group of the pyrazole ring of
5-chloro-1H-pyrazolo[4,3-d]pyrimidine 1-1 with a suitable
protecting group (e.g. SEM or Boc). The chloro substituent in the
compounds of Formula 1-2 can be converted into Cy.sup.A via a
number of different cross-coupling reactions, including Suzuki
(e.g., in the presence of a palladium catalyst, such as Xphos Pd
G2, and a base, such as potassium phosphate), Negishi and Stille
(e.g., in the presence of a palladium(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)), Cu-catalyzed amination
(e.g., in the presence of Cu catalyst and a ligand, such as CuI and
phenanthroline, and a base, such as cesium carbonate or potassium
carbonate), and others, to give the compounds of Formula 1-3.
Deprotection of the protecting group (e.g., under acidic
conditions, such as treatment with HCl or TFA) results in the
formation of compounds of Formula 1-4. These compounds can be
further halogenated with one of the halogenation agents (e.g., NIS
or iodine) to form compounds of Formula 1-5. The NH group of the
pyrazole ring of the compounds of Formula 1-5 is protected with a
suitable protecting group, such as Boc or SEM, to form compounds of
Formula 1-6. The halogen substituent in the compounds of Formula
1-6 can be converted into R.sup.1 via a number of different
cross-coupling reactions, including Stille (ACS Catalysis 2015, 5,
3040-3053) Suzuki (Tetrahedron 2002, 58, 9633-9695), Sonogashira
(Chem. Soc. Rev. 2011, 40, 5084-5121), Negishi (ACS Catalysis 2016,
6, 1540-1552), Buchwald-Hartwig amination (Chem. Sci. 2011, 2,
27-50), Cu-catalyzed amination (Org. React. 2014, 85, 1-688) and
others, to give the compounds of Formula 1-7. Finally, deprotection
of the protecting group under acidic conditions (e.g., treatment
with HCl or TFA) results in the formation of the desired compounds
of Formula (I).
##STR00015##
[0375] Alternatively, to install various substitutions at position
Cy.sup.A, compounds of Formula (I) can be prepared using a process
as illustrated in Scheme 2. Iodination of
5-chloro-1H-pyrazolo[4,3-d]pyrimidine 1-1 with one of the
iodination agents, such as iodine or NIS, forms compounds of
Formula 2-2. The NH group of the pyrazole ring of the compounds of
Formula 2-2 is protected with a suitable protecting group (e.g.,
Boc or SEM) to form compounds of Formula 2-3. The iodo substituent
in the compounds of Formula 2-3 can be converted into R.sup.1 via a
number of different cross-coupling reactions, including Suzuki,
Sonogashira, Negishi, Buchwald-Hartwig amination, Cu-catalyzed
amination and others, to give the compounds of Formula 2-4. The
chloro substituent in the compounds of Formula 2-4 can be further
converted into Cy.sup.A via a number of different cross-coupling
reactions, including Suzuki, Stille, Negishi, Cu-catalyzed
amination and others, to give the compounds of Formula 2-5.
Finally, deprotection of the protecting group, e.g. under acidic
conditions, such as treatment with HCl or TFA, results in the
formation of the desired compounds of Formula (I).
##STR00016##
[0376] Compounds of Formula (Ia) (compounds of Formula I wherein
R.sup.1 is NR.sup.cC(O)R.sup.b) can be prepared, using a process as
illustrated in Scheme 3. In the process depicted in Scheme 3,
compounds of Formula 1-6 reacts with an amine, e.g.
(4-methoxyphenyl)methanamine, under standard Buchwald-Hartwig
amination conditions (e.g. Pd-catalyst, such as Ruphos Pd G2, and a
base, such as cesium carbonate) to form compounds of Formula 3-2.
Deprotection of the protecting groups (e.g., under acidic
conditions, such as treatment with TFA) results in the formation of
compounds of Formula 3-3. The NH group of the pyrazole ring of the
compounds of Formula 3-3 is protected with a suitable protecting
group (e.g., Boc) to form compounds of Formula 3-4. Compounds of
Formula 3-4 react with different acid chlorides in a presence of
base, such as triethylamine or DIPEA, to form compounds of Formula
3-5. Finally, deprotection of the protecting group, e.g. under
acidic conditions, such as treatment with HCl or TFA, results in
the formation of the desired compounds of Formula (Ia).
Alternatively compounds of Formula 3-5 can be alkylated or arylated
and then deprotected to prepare amides wherein R.sup.c is other
than hydrogen.
##STR00017##
[0377] Compounds of Formula (Ib) (compounds of Formula I wherein
R.sup.1 is C(O)NR.sup.cR.sup.d) can be prepared, using a process as
illustrated in Scheme 4. In the process depicted in Scheme 4,
compounds of Formula 1-6 are converted into compounds of formula
4-2 under Pd-catalyzed carbonylation conditions, such as in a
presence of Pd catalyst (e.g., Pd(dppf)Cl.sub.2*DCM) and base
(e.g., triethylamine) under carbon monoxide atmosphere. Hydrolysis
of the ester group under basic conditions, such as LiOH or NaOH,
forms the compounds of Formula 4-3. Compounds of the Formula 4-3
can be coupled to an amine, HNR.sup.cR.sup.d, using standard amide
coupling agents (e.g., HBTU, HATU or EDC) to give compounds of
Formula 4-4. Finally, deprotection of the protecting group, e.g.
under acidic conditions, such as treatment with HCl or TFA, results
in the formation of the desired compounds of Formula (Ib).
##STR00018##
HPK1 Kinase
[0378] Extensive studies have established that HPK1 is a negative
regulator of T cell and B cell activation (Hu, M. C., et al., Genes
Dev, 1996. 10(18): p. 2251-64; Kiefer, F., et al., EMBO J, 1996.
15(24): p. 7013-25). HPK1-deficient mouse T cells showed
dramatically increased activation of TCR proximal signaling,
enhanced IL-2 production, and hyper-proliferation in vitro upon
anti-CD3 stimulation (Shui, J. W., et al., Nat Immunol, 2007. 8(1):
p. 84-91). Similar to T cells, HPK1 knockout B cells produced much
higher levels of IgM and IgG isoforms after KLH immunization and
displayed hyper-proliferation potentially as a result of enhanced
BCR signaling. Wang, X., et al., J Biol Chem, 2012. 287(14): p.
11037-48. Mechanistically, during TCR or BCR signaling, HPK1 is
activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells)
mediated-Tyr379 phosphorylation and its subsequent binding to
adaptor protein SLP-76 (T cells) or BLNK (B cells) (Wang, X., et
al., J Biol Chem, 2012. 287(14): p. 11037-48). Activated HPK1
phosphorylates SLP-76 on Ser376 or BLNK on Thr152, leading to the
recruitment of signaling molecule 14-3-3 and ultimate
ubiquitination-mediated degradation of SLP-76 or BLNK (Liou, J., et
al., Immunity, 2000. 12(4): p. 399-408; Di Bartolo, V., et al., J
Exp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential
for TCR/BCR-mediated signaling activation (e.g. ERK, phospholipase
C.gamma.1, calcium flux, and NFAT activation), HPK1-mediated
downregulation of these adaptor proteins provide a negative
feedback mechanism to attenuate signaling intensity during T cell
or B cell activation (Wang, X., et al., J Biol Chem, 2012. 287(14):
p. 11037-48).
[0379] The bone marrow-derived dendritic cells (BDMCs) from HPK1
knockout mice showed higher expression of co-stimulatory molecules
(e.g. CD80/CD86) and enhanced production of proinflammatory
cytokines (IL-12, TNF-.alpha. etc), and demonstrated superior
ability to stimulate T cell proliferation in vitro and in vivo as
compared to wild-type DCs (Alzabin, S., et al., J Immunol, 2009.
182(10): p. 6187-94). These data suggest that HPK1 is also an
important negative regulator of dendritic cell activation (Alzabin,
S., et al., J Immunol, 2009. 182(10): p. 6187-94). However, the
signaling mechanisms underlying HPK-1 mediated negative regulation
of DC activation remains to be elucidated.
[0380] In contrast, HPK1 appears to be a positive regulator of
suppressive functions of regulatory T cells (Treg) (Sawasdikosol,
S. et al., The journal of immunology, 2012. 188(supplement 1): p.
163). HPK1 deficient mouse Foxp3+ Tregs were defective in
suppressing TCR-induced effector T cell proliferation, and
paradoxically gained the ability to produce IL-2 following TCR
engagement (Sawasdikosol, S. et al., The Journal of Immunology,
2012. 188(supplement 1): p. 163). These data suggest that HPK1 is
an important regulator of Treg functions and peripheral
self-tolerance.
[0381] HPK1 was also involved in PGE2-mediated inhibition of CD4+ T
cell activation (Ikegami, R., et al., J Immunol, 2001. 166(7): p.
4689-96). Studies published in US 2007/0087988 indicated that HPK1
kinase activity was increased by exposure to physiological
concentrations of PGE2 in CD4+ T cells and this effect was mediated
by PEG2-induced PKA activation. The proliferation of HPK1 deficient
T cells was resistant to the suppressive effects of PGE2 (see US
2007/0087988). Therefore, PGE2-mediated activation of HPK1 may
represent a novel regulatory pathway of modulating immune
response.
[0382] The present disclosure provides methods of modulating (e.g.,
inhibiting) HPK1 activity, said method comprising administering to
a patient a compound provided herein, or a pharmaceutically
acceptable salt thereof. In certain embodiments, the compounds of
the present disclosure, or pharmaceutically acceptable salts
thereof, are useful for therapeutic administration to enhance,
stimulate and/or increase immunity in cancer. For example, a method
of treating a disease or disorder associated with inhibition of
HPK1 interaction can include administering to a patient in need
thereof a therapeutically effective amount of a compound provided
herein, or a pharmaceutically acceptable salt thereof. The
compounds of the present disclosure can be used alone, in
combination with other agents or therapies or as an adjuvant or
neoadjuvant for the treatment of diseases or disorders, including
cancers. For the uses described herein, any of the compounds of the
disclosure, including any of the embodiments thereof, may be
used.
[0383] Examples of cancers that are treatable using the compounds
of the present disclosure include, but are not limited to, bone
cancer, pancreatic cancer, skin cancer, cancer of the head or neck,
cutaneous or intraocular malignant melanoma, uterine cancer,
ovarian cancer, rectal cancer, cancer of the anal region, stomach
cancer, testicular cancer, uterine cancer, carcinoma of the
fallopian tubes, carcinoma of the endometrium, endometrial cancer,
carcinoma of the cervix, carcinoma of the vagina, carcinoma of the
vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the
esophagus, cancer of the small intestine, cancer of the endocrine
system, cancer of the thyroid gland, cancer of the parathyroid
gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer
of the urethra, cancer of the penis, chronic or acute leukemias
including acute myeloid leukemia, chronic myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors
of childhood, lymphocytic lymphoma, cancer of the bladder, cancer
of the kidney or urethra, carcinoma of the renal pelvis, neoplasm
of the central nervous system (CNS), primary CNS lymphoma, tumor
angiogenesis, spinal axis tumor, brain stem glioma, pituitary
adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer,
T-cell lymphoma, environmentally induced cancers including those
induced by asbestos, and combinations of said cancers.
[0384] In some embodiments, cancers treatable with compounds of the
present disclosure include melanoma (e.g., metastatic malignant
melanoma), renal cancer (e.g. clear cell carcinoma), prostate
cancer (e.g. hormone refractory prostate adenocarcinoma), breast
cancer, triple-negative breast cancer, colon cancer and lung cancer
(e.g. non-small cell lung cancer and small cell lung cancer).
Additionally, the disclosure includes refractory or recurrent
malignancies whose growth may be inhibited using the compounds of
the disclosure.
[0385] In some embodiments, cancers that are treatable using the
compounds of the present disclosure include, but are not limited
to, solid tumors (e.g., prostate cancer, colon cancer, esophageal
cancer, endometrial cancer, ovarian cancer, uterine cancer, renal
cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast
cancer, lung cancer, cancers of the head and neck, thyroid cancer,
glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers
(e.g., lymphoma, leukemia such as acute lymphoblastic leukemia
(ALL), acute myelogenous leukemia (AML), chronic lymphocytic
leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle
cell lymphoma, Non-Hodgkin lymphoma (including relapsed or
refractory NHL and recurrent follicular), Hodgkin lymphoma or
multiple myeloma) and combinations of said cancers.
[0386] In some embodiments, diseases and indications that are
treatable using the compounds of the present disclosure include,
but are not limited to hematological cancers, sarcomas, lung
cancers, gastrointestinal cancers, genitourinary tract cancers,
liver cancers, bone cancers, nervous system cancers, gynecological
cancers, and skin cancers.
[0387] Exemplary hematological cancers include lymphomas and
leukemias such as acute lymphoblastic leukemia (ALL), acute
myelogenous leukemia (AML), acute promyelocytic leukemia (APL),
chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia
(CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma,
Non-Hodgkin lymphoma (including relapsed or refractory NHL and
recurrent follicular), Hodgkin lymphoma, myeloproliferative
diseases (e.g., primary myelofibrosis (PMF), polycythemia vera
(PV), essential thrombocytosis (ET)), myelodysplasia syndrome
(MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple
myeloma, cutaneous T-cell lymphoma, Waldenstrom's
Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma
and Burkitt's lymphoma.
[0388] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,
osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma,
liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma,
harmatoma, and teratoma.
[0389] Exemplary lung cancers include non-small cell lung cancer
(NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous
cell, undifferentiated small cell, undifferentiated large cell,
adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial
adenoma, chondromatous hamartoma, and mesothelioma.
[0390] Exemplary gastrointestinal cancers include cancers of the
esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,
lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas
(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma,
carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma,
carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,
neurofibroma, fibroma), large bowel (adenocarcinoma, tubular
adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal
cancer.
[0391] Exemplary genitourinary tract cancers include cancers of the
kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and
urethra (squamous cell carcinoma, transitional cell carcinoma,
adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis
(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,
choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,
fibroadenoma, adenomatoid tumors, lipoma).
[0392] Exemplary liver cancers include hepatoma (hepatocellular
carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma,
hepatocellular adenoma, and hemangioma.
[0393] Exemplary bone cancers include, for example, osteogenic
sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous
histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma
(reticulum cell sarcoma), multiple myeloma, malignant giant cell
tumor chordoma, osteochronfroma (osteocartilaginous exostoses),
benign chondroma, chondroblastoma, chondromyxofibroma, osteoid
osteoma, and giant cell tumors
[0394] Exemplary nervous system cancers include cancers of the
skull (osteoma, hemangioma, granuloma, xanthoma, osteitis
deformans), meninges (meningioma, meningiosarcoma, gliomatosis),
brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma
(pinealoma), glioblastoma, glioblastoma multiform,
oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),
and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as
well as neuroblastoma and Lhermitte-Duclos disease.
[0395] Exemplary gynecological cancers include cancers of the
uterus (endometrial carcinoma), cervix (cervical carcinoma, pre
-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous
cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified
carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell
tumors, dysgerminoma, malignant teratoma), vulva (squamous cell
carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma,
melanoma), vagina (clear cell carcinoma, squamous cell carcinoma,
botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes
(carcinoma).
[0396] Exemplary skin cancers include melanoma, basal cell
carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell
skin cancer, moles dysplastic nevi, lipoma, angioma,
dermatofibroma, and keloids. In some embodiments, diseases and
indications that are treatable using the compounds of the present
disclosure include, but are not limited to, sickle cell disease
(e.g., sickle cell anemia), triple-negative breast cancer (TNBC),
myelodysplastic syndromes, testicular cancer, bile duct cancer,
esophageal cancer, and urothelial carcinoma.
[0397] Exemplary head and neck cancers include glioblastoma,
melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell
carcinomas, adenocarcinomas, oral cancer, laryngeal cancer,
nasopharyngeal cancer, nasal and paranasal cancers, thyroid and
parathyroid cancers.
[0398] In some embodiments, HPK1 inhibitors may be used to treat
tumors producing PGE2 (e.g. Cox-2 overexpressing tumors) and/or
adenosine (CD73 and CD39 over-expressing tumors). Overexpression of
Cox-2 has been detected in a number of tumors, such as colorectal,
breast, pancreatic and lung cancers, where it correlates with a
poor prognosis. Overexpression of COX-2 has been reported in
hematological cancer models such as RAJI (Burkitt's lymphoma) and
U937 (acute promonocytic leukemia) as well as in patient's blast
cells. CD73 is up-regulated in various human carcinomas including
those of colon, lung, pancreas and ovary. Importantly, higher
expression levels of CD73 are associated with tumor
neovascularization, invasiveness, and metastasis and with shorter
patient survival time in breast cancer.
[0399] The terms "individual" or "patient," used interchangeably,
refer to any animal, including mammals, preferably mice, rats,
other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,
or primates, and most preferably humans.
[0400] The phrase "therapeutically effective amount" refers to the
amount of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue, system, animal,
individual or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician.
[0401] As used herein, the term "treating" or "treatment" refers to
one or more of (1) inhibiting the disease; e.g., inhibiting a
disease, condition or disorder in an individual who is experiencing
or displaying the pathology or symptomatology of the disease,
condition or disorder (i.e., arresting further development of the
pathology and/or symptomatology); and (2) ameliorating the disease;
e.g., ameliorating a disease, condition or disorder in an
individual who is experiencing or displaying the pathology or
symptomatology of the disease, condition or disorder (i.e.,
reversing the pathology and/or symptomatology) such as decreasing
the severity of disease.
[0402] In some embodiments, the compounds of the invention are
useful in preventing or reducing the risk of developing any of the
diseases referred to herein; e.g., preventing or reducing the risk
of developing a disease, condition or disorder in an individual who
may be predisposed to the disease, condition or disorder but does
not yet experience or display the pathology or symptomatology of
the disease.
Combination Therapies
[0403] Cancer cell growth and survival can be impacted by multiple
signaling pathways. Thus, it is useful to combine different
enzyme/protein/receptor inhibitors, exhibiting different
preferences in the targets which they modulate the activities of,
to treat such conditions. Examples of agents that may be combined
with compounds of the present disclosure include inhibitors of the
PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway,
inhibitors of JAK-STAT pathway, inhibitors of beta catenin pathway,
inhibitors of notch pathway, inhibitors of hedgehog pathway,
inhibitors of Pim kinases, and inhibitors of protein chaperones and
cell cycle progression. Targeting more than one signaling pathway
(or more than one biological molecule involved in a given signaling
pathway) may reduce the likelihood of drug-resistance arising in a
cell population, and/or reduce the toxicity of treatment.
[0404] The compounds of the present disclosure can be used in
combination with one or more other enzyme/protein/receptor
inhibitors for the treatment of diseases, such as cancer. Examples
of cancers include solid tumors and liquid tumors, such as blood
cancers. For example, the compounds of the present disclosure can
be combined with one or more inhibitors of the following kinases
for the treatment of cancer: Akt1, Akt2, Akt3, TGF-.beta.R, PKA,
PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR,
EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF.alpha.R,
PDGF.beta.R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1,
FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3,
VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src,
Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some
embodiments, the compounds of the present disclosure can be
combined with one or more of the following inhibitors for the
treatment of cancer. Non-limiting examples of inhibitors that can
be combined with the compounds of the present disclosure for
treatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3
or FGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120,
TKI258, lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio1347,
INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or
JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO
inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g.,
GSK2979552, INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta
inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gamma inhibitor
such as a PI3K-gamma selective inhibitor, a CSF1R inhibitor (e.g.,
PLX3397 and LY3022855), a TAM receptor tyrosine kinases (Tyro-3,
Axl, and Mer), an angiogenesis inhibitor, an interleukin receptor
inhibitor, bromo and extra terminal family members inhibitors (for
example, bromodomain inhibitors or BET inhibitors such as OTX015,
CPI-0610, INCB54329 and INCB57643) and an adenosine receptor
antagonist or combinations thereof. Inhibitors of HDAC such as
panobinostat and vorinostat. Inhibitors of c-Met such as
onartumzumab, tivantnib, and INC-280. Inhibitors of BTK such as
ibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,
temsirolimus, and everolimus. Inhibitors of Raf, such as
vemurafenib and dabrafenib. Inhibitors of MEK such as trametinib,
selumetinib and GDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin),
cyclin dependent kinases (e.g., palbociclib), PARP (e.g., olaparib)
and Pim kinases (LGH447, INCB053914 and SGI-1776) can also be
combined with compounds of the present disclosure.
[0405] Compounds of the present disclosure can be used in
combination with one or more immune checkpoint inhibitors.
Exemplary immune checkpoint inhibitors include inhibitors against
immune checkpoint molecules such as CD20, CD27, CD28, CD39, CD40,
CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K
gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR,
B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and
PD-L2. In some embodiments, the immune checkpoint molecule is a
stimulatory checkpoint molecule selected from CD27, CD28, CD40,
ICOS, OX40, GITR and CD137. In some embodiments, the immune
checkpoint molecule is an inhibitory checkpoint molecule selected
from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3,
and VISTA. In some embodiments, the compounds provided herein can
be used in combination with one or more agents selected from KIR
inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors,
2B4 inhibitors and TGFR beta inhibitors.
[0406] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0407] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal
antibody. In some embodiments, the anti-PD-1 monoclonal antibody is
nivolumab, pembrolizumab (also known as MK-3475), pidilizumab,
SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1
monoclonal antibody is nivolumab or pembrolizumab. In some
embodiments, the anti-PD1 antibody is pembrolizumab. In some
embodiments, the anti PD-1 antibody is SHR-1210.
[0408] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal
antibody. In some embodiments, the anti-PD-L1 monoclonal antibody
is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or
MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal
antibody is MPDL3280A or MEDI4736.
[0409] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
In some embodiments, the anti-CTLA-4 antibody is ipilimumab.
[0410] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CSF1R, e.g., an anti-CSF1R antibody. In
some embodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.
[0411] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In
some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525,
IMP321 or GSK2831781.
[0412] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In
some embodiments, the anti-GITR antibody is TRX518, MK-4166,
MK1248, BMS-986156, MEDI1873 or GWN323.
[0413] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or
OX40L fusion protein. In some embodiments, the anti-OX40 antibody
is MEDI0562, MEDI6469, MOXR0916, PF-04518600 or GSK3174998. In some
embodiments, the OX40L fusion protein is MEDI6383.
[0414] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In
some embodiments, the anti-TIM3 antibody is MBG-453.
[0415] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In
some embodiments, the anti-CD20 antibody is obinutuzumab or
rituximab.
[0416] In some embodiments, the compounds of the invention can be
used in combination with one or more metabolic enzyme inhibitors.
In some embodiments, the metabolic enzyme inhibitor is an inhibitor
of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include
epacadostat and NGL919. An example of an arginase inhibitor is
CB-1158.
[0417] The compounds of the present disclosure can be used in
combination with bispecific antibodies. In some embodiments, one of
the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4,
GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGF.beta. receptor.
[0418] Compounds of the present disclosure can be used in
combination with one or more agents for the treatment of diseases
such as cancer. In some embodiments, the agent is an alkylating
agent, a proteasome inhibitor, a corticosteroid, or an
immunomodulatory agent. Examples of an alkylating agent include
bendamustine, nitrogen mustards, ethylenimine derivatives, alkyl
sulfonates, nitrosoureas and triazenes, uracil mustard,
chlormethine, cyclophosphamide (Cytoxan.TM.), ifosfamide,
melphalan, chlorambucil, pipobroman, triethylene-melamine,
triethylenethiophosphoramine, busulfan, carmustine, lomustine,
streptozocin, dacarbazine, and temozolomide. In some embodiments,
the proteasome inhibitor is carfilzomib. In some embodiments, the
corticosteroid is dexamethasone (DEX). In some embodiments, the
immunomodulatory agent is lenalidomide (LEN) or pomalidomide
(POM).
[0419] The compounds of the present disclosure can further be used
in combination with other methods of treating cancers, for example
by chemotherapy, irradiation therapy, tumor-targeted therapy,
adjuvant therapy, immunotherapy or surgery. Examples of
immunotherapy include cytokine treatment (e.g., interferons,
GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine,
monoclonal antibody, adoptive T cell transfer, oncolytic
virotherapy and immunomodulating small molecules, including
thalidomide or JAK1/2 inhibitor and the like. The compounds can be
administered in combination with one or more anti-cancer drugs,
such as a chemotherapeutics. Example chemotherapeutics include any
of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin,
alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole,
arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab,
bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi,
bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan
oral, calusterone, capecitabine, carboplatin, carmustine,
cediranib, cetuximab, chlorambucil, cisplatin, cladribine,
clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine,
dacomitinib, dactinomycin, dalteparin sodium, dasatinib,
dactinomycin, daunorubicin, decitabine, degarelix, denileukin,
denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel,
doxorubicin, droloxafine, dromostanolone propionate, eculizumab,
enzalutamide, epidophyllotoxin, epirubicin, erlotinib,
estramustine, etoposide phosphate, etoposide, exemestane, fentanyl
citrate, filgrastim, floxuridine, fludarabine, fluorouracil,
flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab
ozogamicin, goserelin acetate, histrelin acetate, ibritumomab
tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate,
interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide,
letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,
meclorethamine, megestrol acetate, melphalan, mercaptopurine,
methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane,
mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab,
nelarabine, neratinib, nilotinib, nilutamide, nofetumomab,
oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab,
pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium,
pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib,
prednisone, procarbazine, quinacrine, rasburicase, regorafenib,
reloxafine, rituximab, ruxolitinib, sorafenib, streptozocin,
sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide,
teniposide, testolactone, thalidomide, thioguanine, thiotepa,
topotecan, toremifene, tositumomab, trastuzumab, tretinoin,
triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine,
vincristine, vinorelbine, vorinostat and zoledronate.
[0420] Other anti-cancer agent(s) include antibody therapeutics
such as trastuzumab (Herceptin), antibodies to costimulatory
molecules such as CTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB,
antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10,
TGF-.beta., etc.). Examples of antibodies to PD-1 and/or PD-L1 that
can be combined with compounds of the present disclosure for the
treatment of cancer or infections such as viral, bacteria, fungus
and parasite infections include, but are not limited to, nivolumab,
pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.
[0421] Other anti-cancer agents include inhibitors of kinases
associated cell proliferative disorder. These kinases include but
not limited to Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9,
ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes,
Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC,
Rsk and SGK.
[0422] Other anti-cancer agents also include those that block
immune cell migration such as antagonists to chemokine receptors,
including CCR2 and CCR4.
[0423] The compounds of the present disclosure can further be used
in combination with one or more anti-inflammatory agents, steroids,
immunosuppressants or therapeutic antibodies.
[0424] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be combined with another
immunogenic agent, such as cancerous cells, purified tumor antigens
(including recombinant proteins, peptides, and carbohydrate
molecules), cells, and cells transfected with genes encoding immune
stimulating cytokines. Non-limiting examples of tumor vaccines that
can be used include peptides of melanoma antigens, such as peptides
of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor
cells transfected to express the cytokine GM-CSF.
[0425] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be used in combination with
a vaccination protocol for the treatment of cancer. In some
embodiments, the tumor cells are transduced to express GM-CSF. In
some embodiments, tumor vaccines include the proteins from viruses
implicated in human cancers such as Human Papilloma Viruses (HPV),
Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus
(KHSV). In some embodiments, the compounds of the present
disclosure can be used in combination with tumor specific antigen
such as heat shock proteins isolated from tumor tissue itself. In
some embodiments, the compounds of Formula (I) or any of the
formulas as described herein, a compound as recited in any of the
claims and described herein, or salts thereof can be combined with
dendritic cells immunization to activate potent anti-tumor
responses.
[0426] The compounds of the present disclosure can be used in
combination with bispecific macrocyclic peptides that target Fe
alpha or Fe gamma receptor-expressing effectors cells to tumor
cells. The compounds of the present disclosure can also be combined
with macrocyclic peptides that activate host immune
responsiveness.
[0427] The compounds of the present disclosure can be used in
combination with bone marrow transplant for the treatment of a
variety of tumors of hematopoietic origin.
[0428] Suitable antiviral agents contemplated for use in
combination with the compounds of the present disclosure can
comprise nucleoside and nucleotide reverse transcriptase inhibitors
(NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs),
protease inhibitors and other antiviral drugs.
[0429] Example suitable NRTIs include zidovudine (AZT); didanosine
(ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC);
abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir
(BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also
called beta-L-D4C and named
beta-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD,
((-)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).
Typical suitable NNRTIs include nevirapine (BI-RG-587);
delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721;
AG-1549; MKC-442
(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimid-
inedione); and (+)-calanolide A (NSC-675451) and B. Typical
suitable protease inhibitors include saquinavir (Ro 31-8959);
ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343);
amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623;
ABT-378; and AG-1 549. Other antiviral agents include hydroxyurea,
ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.
11607.
[0430] When more than one pharmaceutical agent is administered to a
patient, they can be administered simultaneously, separately,
sequentially, or in combination (e.g., for more than two
agents).
Formulation, Dosage Forms and Administration
[0431] When employed as pharmaceuticals, the compounds of the
present disclosure can be administered in the form of
pharmaceutical compositions. Thus the present disclosure provides a
composition comprising a compound of Formula (I) or any of the
formulas as described herein, a compound as recited in any of the
claims and described herein, or a pharmaceutically acceptable salt
thereof, or any of the embodiments thereof, and at least one
pharmaceutically acceptable carrier or excipient. These
compositions can be prepared in a manner well known in the
pharmaceutical art, and can be administered by a variety of routes,
depending upon whether local or systemic treatment is indicated and
upon the area to be treated. Administration may be topical
(including transdermal, epidermal, ophthalmic and to mucous
membranes including intranasal, vaginal and rectal delivery),
pulmonary (e.g., by inhalation or insufflation of powders or
aerosols, including by nebulizer; intratracheal or intranasal),
oral or parenteral. Parenteral administration includes intravenous,
intraarterial, subcutaneous, intraperitoneal intramuscular or
injection or infusion; or intracranial, e.g., intrathecal or
intraventricular, administration. Parenteral administration can be
in the form of a single bolus dose, or may be, e.g., by a
continuous perfusion pump. Pharmaceutical compositions and
formulations for topical administration may include transdermal
patches, ointments, lotions, creams, gels, drops, suppositories,
sprays, liquids and powders. Conventional pharmaceutical carriers,
aqueous, powder or oily bases, thickeners and the like may be
necessary or desirable.
[0432] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, the compound of the
present disclosure or a pharmaceutically acceptable salt thereof,
in combination with one or more pharmaceutically acceptable
carriers or excipients. In some embodiments, the composition is
suitable for topical administration. In making the compositions of
the invention, the active ingredient is typically mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier in the form of, e.g., a capsule, sachet, paper, or other
container. When the excipient serves as a diluent, it can be a
solid, semi-solid, or liquid material, which acts as a vehicle,
carrier or medium for the active ingredient. Thus, the compositions
can be in the form of tablets, pills, powders, lozenges, sachets,
cachets, elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), ointments containing,
e.g., up to 10% by weight of the active compound, soft and hard
gelatin capsules, suppositories, sterile injectable solutions and
sterile packaged powders.
[0433] In preparing a formulation, the active compound can be
milled to provide the appropriate particle size prior to combining
with the other ingredients. If the active compound is substantially
insoluble, it can be milled to a particle size of less than 200
mesh. If the active compound is substantially water soluble, the
particle size can be adjusted by milling to provide a substantially
uniform distribution in the formulation, e.g., about 40 mesh.
[0434] The compounds of the invention may be milled using known
milling procedures such as wet milling to obtain a particle size
appropriate for tablet formation and for other formulation types.
Finely divided (nanoparticulate) preparations of the compounds of
the invention can be prepared by processes known in the art see,
e.g., WO 2002/000196.
[0435] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art.
[0436] In some embodiments, the pharmaceutical composition
comprises silicified microcrystalline cellulose (SMCC) and at least
one compound described herein, or a pharmaceutically acceptable
salt thereof. In some embodiments, the silicified microcrystalline
cellulose comprises about 98% microcrystalline cellulose and about
2% silicon dioxide w/w.
[0437] In some embodiments, the composition is a sustained release
composition comprising at least one compound described herein, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable carrier or excipient. In some
embodiments, the composition comprises at least one compound
described herein, or a pharmaceutically acceptable salt thereof,
and at least one component selected from microcrystalline
cellulose, lactose monohydrate, hydroxypropyl methylcellulose and
polyethylene oxide. In some embodiments, the composition comprises
at least one compound described herein, or a pharmaceutically
acceptable salt thereof, and microcrystalline cellulose, lactose
monohydrate and hydroxypropyl methylcellulose. In some embodiments,
the composition comprises at least one compound described herein,
or a pharmaceutically acceptable salt thereof, and microcrystalline
cellulose, lactose monohydrate and polyethylene oxide. In some
embodiments, the composition further comprises magnesium stearate
or silicon dioxide. In some embodiments, the microcrystalline
cellulose is Avicel PH102.TM.. In some embodiments, the lactose
monohydrate is Fast-flo 316.TM.. In some embodiments, the
hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208
K4M (e.g., Methocel K4 M Premier.TM.) and/or hydroxypropyl
methylcellulose 2208 K100LV (e.g., Methocel K00LV.TM.). In some
embodiments, the polyethylene oxide is polyethylene oxide WSR 1105
(e.g., Polyox WSR 1105.TM.).
[0438] In some embodiments, a wet granulation process is used to
produce the composition. In some embodiments, a dry granulation
process is used to produce the composition.
[0439] The compositions can be formulated in a unit dosage form,
each dosage containing from about 5 to about 1,000 mg (1 g), more
usually about 100 mg to about 500 mg, of the active ingredient. In
some embodiments, each dosage contains about 10 mg of the active
ingredient. In some embodiments, each dosage contains about 50 mg
of the active ingredient. In some embodiments, each dosage contains
about 25 mg of the active ingredient. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient.
[0440] The components used to formulate the pharmaceutical
compositions are of high purity and are substantially free of
potentially harmful contaminants (e.g., at least National Food
grade, generally at least analytical grade, and more typically at
least pharmaceutical grade). Particularly for human consumption,
the composition is preferably manufactured or formulated under Good
Manufacturing Practice standards as defined in the applicable
regulations of the U.S. Food and Drug Administration. For example,
suitable formulations may be sterile and/or substantially isotonic
and/or in full compliance with all Good Manufacturing Practice
regulations of the U.S. Food and Drug Administration.
[0441] The active compound may be effective over a wide dosage
range and is generally administered in a therapeutically effective
amount. It will be understood, however, that the amount of the
compound actually administered will usually be determined by a
physician, according to the relevant circumstances, including the
condition to be treated, the chosen route of administration, the
actual compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms and the
like.
[0442] The therapeutic dosage of a compound of the present
invention can vary according to, e.g., the particular use for which
the treatment is made, the manner of administration of the
compound, the health and condition of the patient, and the judgment
of the prescribing physician. The proportion or concentration of a
compound of the invention in a pharmaceutical composition can vary
depending upon a number of factors including dosage, chemical
characteristics (e.g., hydrophobicity), and the route of
administration. For example, the compounds of the invention can be
provided in an aqueous physiological buffer solution containing
about 0.1 to about 10% w/v of the compound for parenteral
administration. Some typical dose ranges are from about 1 .mu.g/kg
to about 1 g/kg of body weight per day. In some embodiments, the
dose range is from about 0.01 mg/kg to about 100 mg/kg of body
weight per day. The dosage is likely to depend on such variables as
the type and extent of progression of the disease or disorder, the
overall health status of the particular patient, the relative
biological efficacy of the compound selected, formulation of the
excipient, and its route of administration. Effective doses can be
extrapolated from dose-response curves derived from in vitro or
animal model test systems.
[0443] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, the
active ingredient is typically dispersed evenly throughout the
composition so that the composition can be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, e.g.,
about 0.1 to about 1000 mg of the active ingredient of the present
invention.
[0444] The tablets or pills of the present invention can be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol and cellulose acetate.
[0445] The liquid forms in which the compounds and compositions of
the present invention can be incorporated for administration orally
or by injection include aqueous solutions, suitably flavored
syrups, aqueous or oil suspensions, and flavored emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil, or
peanut oil, as well as elixirs and similar pharmaceutical
vehicles.
[0446] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions can be nebulized
by use of inert gases. Nebulized solutions may be breathed directly
from the nebulizing device or the nebulizing device can be attached
to a face mask, tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions can be
administered orally or nasally from devices which deliver the
formulation in an appropriate manner.
[0447] Topical formulations can contain one or more conventional
carriers. In some embodiments, ointments can contain water and one
or more hydrophobic carriers selected from, e.g., liquid paraffin,
polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and
the like. Carrier compositions of creams can be based on water in
combination with glycerol and one or more other components, e.g.,
glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl
alcohol. Gels can be formulated using isopropyl alcohol and water,
suitably in combination with other components such as, e.g.,
glycerol, hydroxyethyl cellulose, and the like. In some
embodiments, topical formulations contain at least about 0.1, at
least about 0.25, at least about 0.5, at least about 1, at least
about 2 or at least about 5 wt % of the compound of the invention.
The topical formulations can be suitably packaged in tubes of,
e.g., 100 g which are optionally associated with instructions for
the treatment of the select indication, e.g., psoriasis or other
skin condition.
[0448] The amount of compound or composition administered to a
patient will vary depending upon what is being administered, the
purpose of the administration, such as prophylaxis or therapy, the
state of the patient, the manner of administration and the like. In
therapeutic applications, compositions can be administered to a
patient already suffering from a disease in an amount sufficient to
cure or at least partially arrest the symptoms of the disease and
its complications. Effective doses will depend on the disease
condition being treated as well as by the judgment of the attending
clinician depending upon factors such as the severity of the
disease, the age, weight and general condition of the patient and
the like.
[0449] The compositions administered to a patient can be in the
form of pharmaceutical compositions described above. These
compositions can be sterilized by conventional sterilization
techniques, or may be sterile filtered. Aqueous solutions can be
packaged for use as is, or lyophilized, the lyophilized preparation
being combined with a sterile aqueous carrier prior to
administration. The pH of the compound preparations typically will
be between 3 and 11, more preferably from 5 to 9 and most
preferably from 7 to 8. It will be understood that use of certain
of the foregoing excipients, carriers or stabilizers will result in
the formation of pharmaceutical salts.
[0450] The therapeutic dosage of a compound of the present
invention can vary according to, e.g., the particular use for which
the treatment is made, the manner of administration of the
compound, the health and condition of the patient, and the judgment
of the prescribing physician. The proportion or concentration of a
compound of the invention in a pharmaceutical composition can vary
depending upon a number of factors including dosage, chemical
characteristics (e.g., hydrophobicity), and the route of
administration. For example, the compounds of the invention can be
provided in an aqueous physiological buffer solution containing
about 0.1 to about 10% w/v of the compound for parenteral
administration. Some typical dose ranges are from about 1 .mu.g/kg
to about 1 g/kg of body weight per day. In some embodiments, the
dose range is from about 0.01 mg/kg to about 100 mg/kg of body
weight per day. The dosage is likely to depend on such variables as
the type and extent of progression of the disease or disorder, the
overall health status of the particular patient, the relative
biological efficacy of the compound selected, formulation of the
excipient, and its route of administration. Effective doses can be
extrapolated from dose-response curves derived from in vitro or
animal model test systems.
Labeled Compounds and Assay Methods
[0451] The compounds of the present disclosure can further be
useful in investigations of biological processes in normal and
abnormal tissues. Thus, another aspect of the present invention
relates to fluorescent dye, spin label, heavy metal or
radio-labeled compounds provided herein that would be useful not
only in imaging techniques but also in assays, both in vitro and in
vivo, for localizing and quantitating HPK1 protein in tissue
samples, including human, and for identifying HPK1 ligands by
inhibition binding of a labeled compound. Accordingly, the present
invention includes HPK1 binding assays that contain such labeled
compounds.
[0452] The present invention further includes
isotopically-substituted compounds of the disclosure. An
"isotopically-substituted" compound is a compound of the invention
where one or more atoms are replaced or substituted by an atom
having the same atomic number but a different atomic mass or mass
number. Compounds of the invention may contain isotopes in a
natural abundance as found in nature. Compounds of the invention
may also have isotopes in amounts greater to that found in nature,
e.g., synthetically incorporating low natural abundance isotopes
into the compounds of the invention so they are enriched in a
particularly useful isotope (e.g., .sup.2H and .sup.13C). It is to
be understood that a "radio-labeled" compound is a compound that
has incorporated at least one isotope that is radioactive (e.g.,
radionuclide), e.g., .sup.3H and .sup.14C. Suitable radionuclides
that may be incorporated in compounds of the present invention
include but are not limited to .sup.3H (also written as T for
tritium), .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.18F, .sup.35S, .sup.36Cl,
.sup.82Br, .sup.75Br, .sup.76Br, .sup.77Br, .sup.123I, .sup.124I,
.sup.125I and .sup.131I. The radionuclide that is incorporated in
the instant radio-labeled compounds will depend on the specific
application of that radio-labeled compound. In some embodiments,
the radionuclide is selected from the group consisting of .sup.3H,
.sup.14C, .sup.125I, .sup.35S and .sup.82Br. For in vitro HPK1
labeling and competition assays, compounds that incorporate
.sup.3H, .sup.14C, .sup.82Br, .sup.125I, .sup.131I, or .sup.35S
will generally be most useful. For radio-imaging applications
.sup.11C, .sup.18F, .sup.125I, .sup.123I, .sup.124I, .sup.131I,
.sup.75Br, .sup.76Br or .sup.77Br will generally be most useful.
Synthetic methods for incorporating radio-isotopes into organic
compounds are known in the art.
[0453] Specifically, a labeled compound of the invention can be
used in a screening assay to identify and/or evaluate compounds.
For example, a newly synthesized or identified compound (i.e., test
compound) which is labeled can be evaluated for its ability to bind
a HPK1 protein by monitoring its concentration variation when
contacting with the HPK1, through tracking of the labeling. For
example, a test compound (labeled) can be evaluated for its ability
to reduce binding of another compound which is known to bind to a
HPK1 protein (i.e., standard compound). Accordingly, the ability of
a test compound to compete with the standard compound for binding
to the HPK1 protein directly correlates to its binding affinity.
Conversely, in some other screening assays, the standard compound
is labeled and test compounds are unlabeled. Accordingly, the
concentration of the labeled standard compound is monitored in
order to evaluate the competition between the standard compound and
the test compound, and the relative binding affinity of the test
compound is thus ascertained.
Kits
[0454] The present disclosure also includes pharmaceutical kits
useful, e.g., in the treatment or prevention of diseases or
disorders associated with the activity of HPK1, such as cancer or
infections, which include one or more containers containing a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of Formula (I), or any of the embodiments
thereof. Such kits can further include one or more of various
conventional pharmaceutical kit components, such as, e.g.,
containers with one or more pharmaceutically acceptable carriers,
additional containers, etc., as will be readily apparent to those
skilled in the art. Instructions, either as inserts or as labels,
indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the
components, can also be included in the kit.
[0455] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of non-critical parameters which can be changed or modified
to yield essentially the same results. The compounds of the
Examples have been found to inhibit the activity of HPK1 according
to at least one assay described herein.
EXAMPLES
[0456] Experimental procedures for compounds of the invention are
provided below. Preparatory LC-MS purifications of some of the
compounds prepared were performed on Waters mass directed
fractionation systems. The basic equipment setup, protocols, and
control software for the operation of these systems have been
described in detail in the literature. See e.g. "Two-Pump At Column
Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi.
Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations
and Methods for Parallel Synthesis Purification", K. Blom, R.
Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.
Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved
Compound Specific Method Optimization", K. Blom, B. Glass, R.
Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds
separated were typically subjected to analytical liquid
chromatography mass spectrometry (LCMS) for purity check under the
following conditions: Instrument; Agilent 1100 series, LC/MSD,
Column: Waters Sunfire.TM. C.sub.18 5 .mu.m particle size,
2.1.times.5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and
mobile phase B: acetonitrile; gradient 2% to 80% of B in 3 minutes
with flow rate 2.0 mL/minute.
[0457] Some of the compounds prepared were also separated on a
preparative scale by reverse-phase high performance liquid
chromatography (RP-HPLC) with MS detector or flash chromatography
(silica gel) as indicated in the Examples. Typical preparative
reverse-phase high performance liquid chromatography (RP-HPLC)
column conditions are as follows:
[0458] pH=2 purifications: Waters Sunfire.TM. C.sub.18 5 .mu.m
particle size, 19.times.100 mm column, eluting with mobile phase A:
0.1% TFA (trifluoroacetic acid) in water and mobile phase B:
acetonitrile; the flow rate was 30 mL/minute, the separating
gradient was optimized for each compound using the Compound
Specific Method Optimization protocol as described in the
literature [see "Preparative LCMS Purification: Improved Compound
Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A.
Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate
used with the 30.times.100 mm column was 60 mL/minute.
[0459] pH=10 purifications: Waters XBridge C.sub.18 5 .mu.m
particle size, 19.times.100 mm column, eluting with mobile phase A:
0.15% NH.sub.4OH in water and mobile phase B: acetonitrile; the
flow rate was 30 mL/minute, the separating gradient was optimized
for each compound using the Compound Specific Method Optimization
protocol as described in the literature [See "Preparative LCMS
Purification: Improved Compound Specific Method Optimization", K.
Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883
(2004)]. Typically, the flow rate used with 30.times.100 mm column
was 60 mL/minute.
Example 1
5-(2-Fluorophenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-d]-
pyrimidine
##STR00019##
[0460] Step 1. 5-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyrimidine
##STR00020##
[0462] Potassium hydroxide (2.2 g, 39 mmol) and iodine (4.9 g, 19
mmol) were added to a solution of
5-chloro-1H-pyrazolo[4,3-d]pyrimidine (Astatech, 1.5 g, 9.7 mmol)
in 1,4-dioxane (20 mL). The reaction mixture was stirred at
50.degree. C. for 2 hours. After cooling to r.t., water was added
and the reaction was neutralized to pH 7. The mixture was then
extracted with ethyl acetate and the organic phase was washed with
brine. The organic phase was dried over sodium sulfate and the
solvents were evaporated under reduced pressure. The crude product
was purified by Biotage Isolera.TM. (1 g, 37%). LCMS calculated for
C.sub.5H.sub.3ClIN.sub.4 (M+H).sup.+ m/z=280.9; found 281.0.
Step 2.
5-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4-
,3-d]pyrimidine
##STR00021##
[0464] NaH in mineral oil (150 mg, 3.8 mmol) was slowly added at
0.degree. C. to a solution of
5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine (964 mg, 3.44 mmol)
and [.beta.-(trimethylsilyl)ethoxy]methyl chloride (639 .mu.L, 3.61
mmol) in tetrahydrofuran (10 mL). After stirring at r.t. for 1 h,
the reaction mixture was quenched by the addition of water and the
resulting mixture was extracted with ethyl acetate. The organic
phase was washed with brine and dried over sodium sulfate. The
solvents were evaporated under reduced pressure and the crude
product was purified by Biotage Isolera.TM. (1.2 g, 88%). LCMS
calculated for C.sub.11H.sub.17ClIN.sub.4OSi (M+H).sup.+ m/z=411.0;
found 411.0.
Step 3.
5-Chloro-3-[4-(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsily-
l)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine
##STR00022##
[0466]
5-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,-
3-d]pyrimidine (636 mg, 1.55 mmol),
[4-(4-methylpiperazin-1-yl)phenyl]boronic acid (340 mg, 1.5 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)
complexed with dichloromethane (1:1) (100 mg, 0.2 mmol), potassium
phosphate (430 mg, 2.0 mmol) and a magnet bar were placed in a
vial. The vial was sealed with a Teflon screw-cap, evacuated and
backfilled with nitrogen (this process was repeated a total of
three times). After dioxane (12 mL) and degassed water (2 mL) were
added, the mixture was heated at 100.degree. C. for 16 h. The
reaction mixture was then diluted with ethyl acetate, washed with
brine and dried over sodium sulfate. The solvents were evaporated
under reduced pressure and the crude product was purified by
Biotage Isolera.TM. (520 mg, 74%). LCMS calculated for
C.sub.22H.sub.32ClN.sub.6OSi (M+H).sup.+ m/z=459.2; found
459.3.
Step 4.
5-(2-Fluorophenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazol-
o[4,3-d]pyrimidine
##STR00023##
[0468]
5-Chloro-3-[4-(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsilyl-
)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine (15 mg, 0.033 mmol),
(2-fluorophenyl)boronic acid (6.8 mg, 0.049 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (2.6 mg, 0.0033
mmol), potassium phosphate (21 mg, 0.098 mmol) and a magnet bar
were placed in a vial with septum which was then evacuated and
backfilled with nitrogen three times. 1,4-Dioxane (2.5 mL) and
degassed water (0.3 mL) were added and the reaction mixture was
stirred at 80.degree. C. for 1 h. Then 1M solution of HCl in water
(1 mL) and 4M solution of HCl in dioxane (1 mL) were added and
reaction was stirred at 80.degree. C. for 1 h. Methanol (1 mL) was
added and reaction was further stirred at 80.degree. C. for 30 min.
The reaction mixture was then diluted with acetonitrile and was
purified with prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min). LCMS calculated for C.sub.22H.sub.22FN.sub.6
(M+H).sup.+: m/z=389.2; Found: 389.3.
Example 2
3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-o-tolyl-1H-pyrazolo[4,3-d]pyrimidin-
e
##STR00024##
[0470] This compound was prepared according to the procedures
described in Example 1, using o-tolylboronic acid, instead of
(2-fluorophenyl)boronic acid as starting material. LCMS calculated
for C.sub.23H.sub.25N.sub.6 (M+H).sup.+: m/z=385.2; Found:
385.3.
Example 3
5-(2-Methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d-
]pyrimidine
##STR00025##
[0472] This compound was prepared according to the procedures
described in Example 1, using 2-methoxyphenylboronic acid, instead
of (2-fluorophenyl)boronic acid as starting material. LCMS
calculated for C.sub.23H.sub.25N.sub.6O (M+H).sup.+: m/z=401.2;
Found: 401.3.
Example 4
5-(2-Chloro-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazo-
lo[4,3-d]pyrimidine
##STR00026##
[0474] This compound was prepared according to the procedures
described in Example 1, using 2-chloro-6-fluorophenylboronic acid,
instead of (2-fluorophenyl)boronic acid as starting material. LCMS
calculated for C.sub.22H.sub.21ClFN.sub.6 (M+H).sup.+: m/z=423.2;
Found: 423.2.
Example 5
3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyridin-3-yl)-1H-pyrazolo[4,3-d]py-
rimidine
##STR00027##
[0476] This compound was prepared according to the procedures
described in Example 1, using pyridin-3-ylboronic acid, instead of
(2-fluorophenyl)boronic acid as starting material. LCMS calculated
for C.sub.21H.sub.22N.sub.7 (M+H).sup.+: m/z=372.2; Found:
372.3.
Example 6
3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(5-methylpyridin-3-yl)-1H-pyrazolo[-
4,3-d]pyrimidine
##STR00028##
[0478] This compound was prepared according to the procedures
described in Example 1, using 5-methylpyridin-3-ylboronic acid,
instead of (2-fluorophenyl)boronic acid as starting material. LCMS
calculated for C.sub.22H.sub.24N.sub.7 (M+H).sup.+: m/z=386.2;
Found: 386.2.
Example 7
6-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)i-
soindolin-1-one
##STR00029##
[0480] This compound was prepared according to the procedures
described in Example 1, using
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one,
instead of (2-fluorophenyl)boronic acid as starting material. LCMS
calculated for C.sub.24H.sub.24N.sub.7O (M+H).sup.+: m/z=426.2;
Found: 426.2.
Example 8
(5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-
pyridin-3-yl)(morpholino)methanone
##STR00030##
[0482] This compound was prepared according to the procedures
described in Example 1, using
morpholino(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)me-
thanone, instead of (2-fluorophenyl)boronic acid as starting
material. LCMS calculated for C.sub.26H.sub.29N.sub.8O.sub.2
(M+H).sup.+: m/z=485.2; Found: 485.2.
Example 9
N-Methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)nicotinamide
##STR00031##
[0484] This compound was prepared according to the procedures
described in Example 1, using
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide,
instead of (2-fluorophenyl)boronic acid as starting material. LCMS
calculated for C.sub.23H.sub.25N.sub.8O (M+H).sup.+: m/z=429.2;
Found: 429.3.
Example 10
5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)--
1,2,3,4-tetrahydroisoquinoline
##STR00032##
[0486] This compound was prepared according to the procedures
described in Example 1, using tert-butyl
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2-
(1H)-carboxylate, instead of (2-fluorophenyl)boronic acid as
starting material. LCMS calculated for C.sub.25H.sub.28N.sub.7
(M+H).sup.+: m/z=426.2; Found: 426.2.
Example 11
5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyraz-
olo[4,3-d]pyrimidine
##STR00033##
[0488] This compound was prepared according to the procedures
described in Example 1, using 2-fluoro-6-methoxyphenylboronic acid,
instead of (2-fluorophenyl)boronic acid as starting material. LCMS
calculated for C.sub.23H.sub.24FN.sub.6O (M+H).sup.+: m/z=419.2;
Found: 419.3.
Example 12
5-(2-Fluoro-6-methoxyphenyl)-3-phenyl-1H-pyrazolo[4,3-d]pyrimidine
##STR00034##
[0489] Step 1.
5-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidin-
e
##STR00035##
[0491] NaH in mineral oil (570 mg, 14 mmol) was slowly added at
0.degree. C. to a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine
(2.0 g, 13 mmol) and [.beta.-(trimethylsilyl)ethoxy]methyl chloride
(2.40 mL, 13.6 mmol) in tetrahydrofuran (25 mL). After stirring at
r.t. for 1 h, the reaction mixture was quenched by the addition of
water and the resulting mixture was extracted with ethyl acetate.
The organic phase was washed with brine and dried over sodium
sulfate. The solvents were evaporated under reduced pressure and
the crude product was purified by Biotage Isolera.TM. (2.36 g,
64%). LCMS calculated for C.sub.11H.sub.18ClN.sub.4OSi (M+H).sup.+
m/z=285.1; found 285.2.
Step 2.
5-(2-Fluoro-6-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}--
1H-pyrazolo[4,3-d]pyrimidine
##STR00036##
[0493]
5-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyr-
imidine (2.36 g, 8.29 mmol), (2-fluoro-6-methoxyphenyl)boronic acid
(2.1 g, 12 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (400 mg, 0.5
mmol), potassium phosphate (3.6 g, 17 mmol) and a magnet bar were
placed in a flask. The flask was sealed with a rubber cap,
evacuated and backfilled with nitrogen (this process was repeated a
total of three times). After dioxane (20 mL) and degassed water (2
mL) were added, the mixture was heated at 90.degree. C. for 1 h.
The reaction mixture was then diluted with ethyl acetate, washed
with brine and dried over sodium sulfate. The solvents were
evaporated under reduced pressure and the crude product was
purified by Biotage Isolera.TM. (3.27 g, 99%). LCMS calculated for
C.sub.18H.sub.24FN.sub.4O.sub.2Si (M+H) m/z=375.2; found 375.2.
Step 3.
5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine
##STR00037##
[0495] A solution of
5-(2-fluoro-6-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyra-
zolo[4,3-d]pyrimidine (3.27 g, 8.73 mmol) in a mixture of 1.0 M
solution of hydrogen chloride in water (10 mL, 10 mmol) and 4.0 M
solution of hydrogen chloride in dioxane (10 mL, 42 mmol) was
stirred at 80.degree. C. for 1 h. Then methanol (10 mL) was added
and the reaction mixture was further stirred at 80.degree. C. for
30 min. After cooling to r.t., the reaction was neutralized to pH
7. The product was then extracted with ethyl acetate and the
organic phase was washed with brine. The organic phase was dried
over sodium sulfate and the solvents were evaporated under reduced
pressure. The crude product was used in the next step without
further purification. LCMS calculated for C.sub.12H.sub.10FN.sub.4O
(M+H).sup.+ m/z=245.1; found 245.2.
Step 4.
5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidine
##STR00038##
[0497] Potassium hydroxide (2.2 g, 39 mmol) and iodine (4.9 g, 19
mmol) were added to a solution of
5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine (from
previous step) in 1,4-dioxane (20 mL). The reaction mixture was
stirred at 50.degree. C. for 2 hours. After cooling to r.t., water
was added and reaction was neutralized to pH 7. The product was
then extracted with ethyl acetate and the organic phase was washed
with a saturated solution of sodium thiosulfate and brine. The
organic phase was dried over sodium sulfate and the solvents were
evaporated under reduced pressure. The crude product was used in
the next step without further purification. LCMS calculated for
C.sub.12H.sub.9FIN.sub.4O (M+H).sup.+ m/z=371.0; found 371.1.
Step 5.
5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]m-
ethyl}-1H-pyrazolo[4,3-d]pyrimidine
##STR00039##
[0499] NaH in mineral oil (470 mg, 12 mmol) was slowly added at
0.degree. C. to a solution of
5-(2-fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidine
(from previous step) and [.beta.-(trimethylsilyl)ethoxy]methyl
chloride (2.00 mL, 11.3 mmol) in tetrahydrofuran (25 mL). After
stirring at r.t. for 1 h, the reaction mixture was quenched by the
addition of water and the product was extracted with ethyl acetate.
The organic phase was washed with brine and dried over sodium
sulfate. The solvents were evaporated under reduced pressure and
the crude product was purified by Biotage Isolera.TM. (900 mg, 20%
over 3 steps). LCMS calculated for
C.sub.18H.sub.23FIN.sub.4O.sub.2Si (M+H).sup.+ m/z=501.1; found
501.0.
Step 6.
5-(2-Fluoro-6-methoxyphenyl)-3-phenyl-1H-pyrazolo[4,3-d]pyrimidine
##STR00040##
[0501]
5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]me-
thyl}-1H-pyrazolo[4,3-d]pyrimidine (15 mg, 0.030 mmol),
phenylboronic acid (5.5 mg, 0.045 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (2.4 mg, 0.0030
mmol), potassium phosphate (13 mg, 0.062 mmol) and a magnet bar
were placed in a vial with septum which was then evacuated and
backfilled with nitrogen three times. 1,4-Dioxane (1.5 mL) and
degassed water (0.2 mL) were added and the reaction mixture was
stirred at 80.degree. C. for 1 h. Then 1M solution of HCl in water
(1 mL) and 4M solution of HCl in dioxane (1 mL) were added, and
reaction was stirred at 80.degree. C. for 1 h. Methanol (1 mL) was
added and reaction was further stirred at 80.degree. C. for 30 min.
The reaction mixture was then diluted with acetonitrile and was
purified with prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min). LCMS calculated for C.sub.18H.sub.14FN.sub.4O
(M+H).sup.+: m/z=321.1; Found: 321.2.
Example 13
5-(2-Fluoro-6-methoxyphenyl)-3-(2-fluorophenyl)-1H-pyrazolo[4,3-d]pyrimidi-
ne
##STR00041##
[0503] This compound was prepared according to the procedures
described in Example 12, using 2-fluorophenylboronic acid, instead
of phenylboronic acid as starting material. LCMS calculated for
C.sub.18H.sub.13F.sub.2N.sub.4O (M+H).sup.+: m/z=339.1; Found:
339.1.
Example 14
5-(2-Fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3--
d]pyrimidine
##STR00042##
[0505] This compound was prepared according to the procedures
described in Example 12, using
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.16H.sub.14FN.sub.6O (M+H).sup.+: m/z=325.1; Found:
325.2.
Example 15
5-(2-Fluoro-6-methoxyphenyl)-3-(pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine
##STR00043##
[0507] This compound was prepared according to the procedures
described in Example 12, using pyridin-4-ylboronic acid, instead of
phenylboronic acid as starting material. LCMS calculated for
C.sub.17H.sub.13FN.sub.5O (M+H).sup.+: m/z=322.1; Found: 322.2.
Example 16
5-(2-Fluoro-6-methoxyphenyl)-3-(pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidi-
ne
##STR00044##
[0509] This compound was prepared according to the procedures
described in Example 12, using pyrimidin-5-ylboronic acid, instead
of phenylboronic acid as starting material. LCMS calculated for
C.sub.16H.sub.12FN.sub.6O (M+H).sup.+: m/z=323.1; Found: 323.2.
Example 17
4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzonitr-
ile
##STR00045##
[0511] This compound was prepared according to the procedures
described in Example 12, using 4-cyanophenylboronic acid, instead
of phenylboronic acid as starting material. LCMS calculated for
C.sub.19H.sub.13FN.sub.5O (M+H).sup.+: m/z=346.1; Found: 346.2.
Example 18
5-(2-Fluoro-6-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-
-d]pyrimidine
##STR00046##
[0513] This compound was prepared according to the procedures
described in Example 12, using 4-(trifluoromethyl)phenylboronic
acid, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.19H.sub.13F.sub.4N.sub.4O (M+H).sup.+:
m/z=389.1; Found: 389.2.
Example 19
5-(2-Fluoro-6-methoxyphenyl)-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimid-
ine
##STR00047##
[0515] This compound was prepared according to the procedures
described in Example 12, using 3-methoxyphenylboronic acid, instead
of phenylboronic acid as starting material. LCMS calculated for
C.sub.19H.sub.16FN.sub.4O.sub.2 (M+H).sup.+: m/z=351.1; Found:
351.1.
Example 20
5-(2-Fluoro-6-methoxyphenyl)-3-o-tolyl-1H-pyrazolo[4,3-d]pyrimidine
##STR00048##
[0517] This compound was prepared according to the procedures
described in Example 12, using o-tolylboronic acid, instead of
phenylboronic acid as starting material. LCMS calculated for
C.sub.19H.sub.16FN.sub.4O (M+H).sup.+: m/z=335.1; Found: 335.1.
Example 21
5-(2-Fluoro-6-methoxyphenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-
e
##STR00049##
[0519] This compound was prepared according to the procedures
described in Example 12, using thiophen-3-ylboronic acid, instead
of phenylboronic acid as starting material. LCMS calculated for
C.sub.16H.sub.12FN.sub.4OS (M+H).sup.+: m/z=327.1; Found:
327.1.
Example 22
4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N,N-dime-
thylbenzamide
##STR00050##
[0521] This compound was prepared according to the procedures
described in Example 12, using
N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.21H.sub.19FN.sub.5O.sub.2 (M+H).sup.+: m/z=392.2; Found:
392.3.
Example 23
5-(2-Fluoro-6-methoxyphenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)--
1H-pyrazolo[4,3-d]pyrimidine
##STR00051##
[0523] This compound was prepared according to the procedures
described in Example 12, using
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperaz-
ine, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.24H.sub.26FN.sub.6O (M+H).sup.+: m/z=433.2;
Found: 433.3.
Example 24
4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzyl-
)morpholine
##STR00052##
[0525] This compound was prepared according to the procedures
described in Example 12, using
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.23H.sub.23FN.sub.5O.sub.2 (M+H).sup.+: m/z=420.2; Found:
420.3.
Example 25
5-(2-Fluoro-6-methoxyphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)--
1H-pyrazolo[4,3-d]pyrimidine
##STR00053##
[0527] This compound was prepared according to the procedures
described in Example 12, using
1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperaz-
ine, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.24H.sub.26FN.sub.6O (M+H).sup.+: m/z=433.2;
Found: 433.3.
Example 26
4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl-
)morpholine
##STR00054##
[0529] This compound was prepared according to the procedures
described in Example 12, using
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.22H.sub.21FN.sub.5O.sub.2 (M+H).sup.+: m/z=406.2; Found:
406.3.
Example 27
5-(2-Fluoro-6-methoxyphenyl)-3-(3-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidine
##STR00055##
[0531] This compound was prepared according to the procedures
described in Example 12, using tert-butyl
4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-car-
boxylate, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.22H.sub.22FN.sub.6O (M+H).sup.+: m/z=405.2;
Found: 405.2.
Example 28
5-(2-fluoro-6-methoxyphenyl)-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazolo[4,3-
-d]pyrimidine
##STR00056##
[0533] This compound was prepared according to the procedures
described in Example 12, using 3-(pyrrolidin-1-yl)phenylboronic
acid, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.22H.sub.21FN.sub.5O (M+H).sup.+: m/z=390.2;
Found: 390.2.
Example 29
4-(3-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl-
)morpholine
##STR00057##
[0535] This compound was prepared according to the procedures
described in Example 12, using
4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.22H.sub.21FN.sub.5O.sub.2 (M+H).sup.+: m/z=406.2; Found:
406.2.
Example 30
3-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N,N-dime-
thylaniline
##STR00058##
[0537] This compound was prepared according to the procedures
described in Example 12, using 3-(dimethylamino)phenylboronic acid,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.20H.sub.19FN.sub.5O (M+H).sup.+: m/z=364.2; Found:
364.2.
Example 31
(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)(-
morpholino)methanone
##STR00059##
[0539] This compound was prepared according to the procedures
described in Example 12, using
4-(morpholine-4-carbonyl)phenylboronic acid, instead of
phenylboronic acid as starting material. LCMS calculated for
C.sub.23H.sub.21FN.sub.5O.sub.3 (M+H).sup.+: m/z=434.2; Found:
434.2.
Example 32
N-Cyclopentyl-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin--
3-yl)benzamide
##STR00060##
[0541] This compound was prepared according to the procedures
described in Example 12, using
4-(cyclopentylcarbamoyl)phenylboronic acid, instead of
phenylboronic acid as starting material. LCMS calculated for
C.sub.24H.sub.23FN.sub.5O.sub.2 (M+H).sup.+: m/z=432.2; Found:
432.3.
Example 33
4-(1-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phe-
nyl)cyclopropyl)morpholine
##STR00061##
[0543] This compound was prepared according to the procedures
described in Example 12, using
4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)m-
orpholine, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.25H.sub.25FN.sub.5O.sub.2 (M+H).sup.+:
m/z=446.2; Found: 446.3.
Example 34
2-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl-
)acetonitrile
##STR00062##
[0545] This compound was prepared according to the procedures
described in Example 12, using 4-(cyanomethyl)phenylboronic acid,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.20H.sub.15FN.sub.5O (M+H).sup.+: m/z=360.1; Found:
360.1.
Example 35
5-(2-Fluoro-6-methoxyphenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimid-
ine
##STR00063##
[0547] This compound was prepared according to the procedures
described in Example 12, using 4-methoxyphenylboronic acid, instead
of phenylboronic acid as starting material. LCMS calculated for
C.sub.19H.sub.16FN.sub.4O.sub.2 (M+H).sup.+: m/z=351.1; Found:
351.1.
Example 36
5-(2-Fluoro-6-methoxyphenyl)-3-(4-fluorophenyl)-1H-pyrazolo[4,3-d]pyrimidi-
ne
##STR00064##
[0549] This compound was prepared according to the procedures
described in Example 12, using 4-fluorophenylboronic acid, instead
of phenylboronic acid as starting material. LCMS calculated for
C.sub.18H.sub.13F.sub.2N.sub.4O (M+H).sup.+: m/z=339.1; Found:
339.2.
Example 37
3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazo-
lo[4,3-d]pyrimidine
##STR00065##
[0551] This compound was prepared according to the procedures
described in Example 12, using
1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazi-
ne, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.24H.sub.26FN.sub.6O (M+H).sup.+: m/z=433.2;
Found: 433.3.
Example 38
4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N-methyl-
benzamide
##STR00066##
[0553] This compound was prepared according to the procedures
described in Example 12, using 4-(methylcarbamoyl)phenylboronic
acid, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.20H.sub.17FN.sub.5O.sub.2 (M+H).sup.+:
m/z=378.1; Found: 378.2.
Example 39
3-(4-Cyclopropylphenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyr-
imidine
##STR00067##
[0555] This compound was prepared according to the procedures
described in Example 12, using 4-cyclopropylphenylboronic acid,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.21H.sub.18FN.sub.4O (M+H).sup.+: m/z=361.2; Found:
361.2.
Example 40
5-(2-Fluoro-6-methoxyphenyl)-3-(4-(piperidin-1-yl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidine
##STR00068##
[0557] This compound was prepared according to the procedures
described in Example 12, using
1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine,
instead of phenylboronic acid as starting material. LCMS calculated
for C.sub.23H.sub.23FN.sub.5O (M+H).sup.+: m/z=404.2; Found:
404.2.
Example 41
(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)m-
ethanamine
##STR00069##
[0559] This compound was prepared according to the procedures
described in Example 12, using
4-((tert-butoxycarbonylamino)methyl)phenylboronic acid, instead of
phenylboronic acid as starting material. LCMS calculated for
C.sub.19H.sub.17FN.sub.5O (M+H).sup.+: m/z=350.1; Found: 350.0.
Example 42
2-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl-
)-2-methylpropanenitrile
##STR00070##
[0561] This compound was prepared according to the procedures
described in Example 12, using 4-(2-cyanopropan-2-yl)phenylboronic
acid, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.22H.sub.19FN.sub.5O (M+H).sup.+: m/z=388.2;
Found: 388.2.
Example 43
5-(2-Fluoro-6-methoxyphenyl)-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-pyr-
azolo[4,3-d]pyrimidine
##STR00071##
[0563] This compound was prepared according to the procedures
described in Example 12, using
4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,3,2-dioxabor-
olane, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.23H.sub.22FN.sub.4O.sub.2 (M+H).sup.+:
m/z=405.2; Found: 405.2.
Example 44
5-(2,3-Difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,-
3-d]pyrimidine
##STR00072##
[0565] This compound was prepared according to the procedures
described in Example 1, using (2,3-difluorophenyl)boronic acid,
instead of (2-fluorophenyl)boronic acid as starting material. LC-MS
calculated for C.sub.22H.sub.21F.sub.2N.sub.6 (M+H).sup.+:
m/z=407.2; Found 407.2.
Example 45
5-(2,3-Difluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-p-
yrazolo[4,3-d]pyrimidine
##STR00073##
[0567] This compound was prepared according to the procedures
described in Example 1, using
(2,3-difluoro-6-methoxyphenyl)boronic, instead of
(2-fluorophenyl)boronic acid as starting material. LC-MS calculated
for C.sub.23H.sub.23F.sub.2N.sub.6O (M+H).sup.+: m/z=437.2; Found
437.2.
Example 46
2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)benzamide
##STR00074##
[0568] Step 1. Ethyl
2-fltioro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzoate
##STR00075##
[0570] To a solution of
5-chloro-3-[4-(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsilyl)ethox-
y]methyl}-1H-pyrazolo[4,3-d]pyrimidine (Example 1 Step 3, 0.100 g,
0.218 mmol) and (3-(ethoxycarbonyl)-2-fluorophenyl)boronic acid
(0.092 g, 0.436 mmol) in 1,4-dioxane (2.90 ml) and water (0.726 ml)
was added
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (0.017 g, 0.022 mmol) and
potassium phosphate tribasic (0.092 g, 0.436 mmol). The reaction
mixture was degassed and stirred at 90.degree. C. for 2 hours.
After cooling to r.t., the reaction was filtered and concentrated
to dryness under reduced pressure. The residue was purified by
Biotage Isolera.TM. using 0-10% DCM in methanol to afford the
desired product as yellowish oil. LC-MS calculated for
C.sub.31H.sub.40FN.sub.6O.sub.3Si (M+H).sup.+: m/z=591.2; Found
591.2.
Step 2.
2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethyls-
ilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzoic
acid
##STR00076##
[0572] To a solution of the above intermediate in methanol (0.726
ml) was added potassium hydroxide (0.122 g, 2.178 mmol), and the
reaction mixture was stirred at r.t. for 1 hour. After this time
the reaction mixture was concentrated to dryness, diluted with
ethyl acetate and washed with of 1N water solution of HCl (10 mL)
and brine. The organic layer was dried over MgSO.sub.4, filtered
and concentrated to dryness to afford a crude desired product which
was used in the next step without further purification. LC-MS
calculated for C.sub.29H.sub.36FN.sub.6O.sub.3Si (M+H).sup.+:
m/z=563.2; Found 563.2.
Step 3.
2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d-
]pyrimidin-5-yl)benzamide
##STR00077##
[0574] To a solution of
2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)et-
hoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzoic acid (30 mg,
0.053 mmol) in DMF (1 mL) were added 2.0M solution of ammonia in
ethanol (267 .mu.l, 0.533 mmol) and N,N-diisopropylethylamine (37.2
.mu.L, 0.213 mmol), followed by the addition of HATU (81 mg, 0.213
mmol). The reaction mixture was then stirred at. r.t. for 2 hours.
After this time 4M HCl solution in dioxane (1.3 mL, 5.33 mmol) and
1N HCl solution in water (1.1 mL, 1.066 mmol) were added and the
mixture was stirred for another 1 hour at 80.degree. C. It was then
cooled to r.t., diluted with methanol, filterd and purified by
prep-HPLC. (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).
LC-MS calculated for C.sub.23H.sub.23FN.sub.7O (M+H).sup.+:
m/z=432.2; Found 432.2.
Example 47
2-Fluoro-N-methyl-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)benzamide
##STR00078##
[0576] This compound was prepared according to the procedures
described in Example 46, using 2.0M solution of methylamine in THF
instead of 2.0M solution of ammonia in ethanol as starting
material. LC-MS calculated for C.sub.24H.sub.25FN.sub.7O
(M+H).sup.+: m/z=446.2; Found 446.2.
Example 48
5-(2-Fluoro-6-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3--
d]pyrimidine
##STR00079##
[0578] This compound was prepared according to the procedures
described in Example 12, using 1-phenyl-1H-pyrazol-4-ylboronic
acid, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.21H.sub.16FN.sub.6O (M+H).sup.+: m/z=387.1;
Found: 387.2.
Example 49
4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-1-methyl-
pyridin-2(1H)-one
##STR00080##
[0580] This compound was prepared according to the procedures
described in Example 12, using
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one-
, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.18H.sub.15FN.sub.5O.sub.2 (M+H).sup.+:
m/z=352.1; Found: 352.2.
Example 50
5-(2-Fluoro-6-methoxyphenyl)-3-(2-(piperazin-1-yl)pyridin-4-yl)-1H-pyrazol-
o[4,3-d]pyrimidine
##STR00081##
[0582] This compound was prepared according to the procedures
described in Example 12, using
1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-
, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.21H.sub.21FN.sub.7O (M+H).sup.+: m/z=406.2;
Found: 406.2.
Example 51
5-(2-Fluoro-6-methoxyphenyl)-3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-
-pyrazolo[4,3-d]pyrimidine
##STR00082##
[0584] This compound was prepared according to the procedures
described in Example 12, using
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.22H.sub.23FN.sub.7O (M+H).sup.+: m/z=420.2;
Found: 420.2.
Example 52
5-(2-Fluoro-6-methoxyphenyl)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-
o[4,3-d]pyrimidine
##STR00083##
[0586] This compound was prepared according to the procedures
described in Example 12, using tert-butyl
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-
-1-carboxylate, instead of phenylboronic acid as starting material.
LCMS calculated for C.sub.21H.sub.21FN.sub.7O (M+H).sup.+:
m/z=406.2; Found: 406.2.
Example 53
4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridi-
n-2-yl)morpholine
##STR00084##
[0588] This compound was prepared according to the procedures
described in Example 12, using
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine-
, instead of phenylboronic acid as starting material. LCMS
calculated for C.sub.21H.sub.20FN.sub.6O.sub.2 (M+H).sup.+:
m/z=407.2; Found: 407.2.
Example 54
1-(4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyr-
idin-2-yl)piperazin-1-yl)ethan-1-one
##STR00085##
[0590] This compound was prepared according to the procedures
described in Example 12, using
1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperaz-
in-1-yl)ethan-1-one, instead of phenylboronic acid as starting
material. LCMS calculated for C.sub.23H.sub.23FN.sub.7O.sub.2
(M+H).sup.+: m/z=448.2; Found: 448.2.
Example 55
(E)-5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)styryl)-1H-p-
yrazolo[4,3-d]pyrimidine
##STR00086##
[0591] Step 1.
(E)-1-Methyl-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)p-
henyl)piperazine
##STR00087##
[0593] A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane
(135 mg, 0.875 mmol), 1-(4-bromophenyl)-4-methylpiperazine (186 mg,
0.729 mmol), bis(tri-t-butylphosphine)palladium (0) (18.6 mg, 0.036
mmol) and triethylamine (0.203 mL, 1.46 mmol) in toluene (3.0 mL)
was stirred at 80.degree. C. under nitrogen atmosphere for 4 h.
After cooling to room temperature, the mixture was concentrated in
vacuo. The crude was purified by Biotage Isolera.TM. (eluting with
a gradient 0-50% methanol in DCM) to give the desired product as
yellow solid (109 mg, 46%). LCMS calculated for
C.sub.19H.sub.30BN.sub.2O.sub.2 (M+H).sup.+: m/z=329.2; Found:
329.2.
Step 2.
(E)-5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-Astyryl-
)-1H-pyrazolo[4, 3-d]pyrimidine
##STR00088##
[0595] A mixture of
5-(2-fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)--
1H-pyrazolo[4,3-d]pyrimidine (Example 12, Step 5, 56.0 mg, 0.112
mmol),
(E)-1-methyl-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)p-
henyl)piperazine (55.1 mg, 0.168 mmol),
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
complex with dichloromethane (1:1) (4.09 mg, 0.0056 mmol) and
potassium phosphate (47.5 mg, 0.224 mmol) in 1,4-dioxane (2.0 mL)
and water (0.4 mL) was stirred at 80.degree. C. under nitrogen
atmosphere for 18 h. After cooling to room temperature, the mixture
was concentrated in vacuo. The crude mixture was then dissolved in
DCM (2.0 mL) and TFA (2.0 mL) was added to the mixture at room
temperature. After stirring for 2 h, the mixture was concentrated
in vacuo. Then, the crude mixture was dissolved in MeOH (3.5 mL)
and 10% aqueous NH.sub.4OH solution (1.5 mL) was added. After
stirring for 30 min, the reaction mixture was purified with
prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water (pH=2), at flow rate of 60 mL/min) to give the
desired product as yellow solid. LCMS calculated for
C.sub.25H.sub.26FN.sub.6O (M+H).sup.+: m/z=445.2; Found: 445.3.
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 9.89 (br, 1H), 9.40 (s,
1H), 7.86 (d, J=16.5 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.50 (m, 1H),
7.38 (d, J=16.5 Hz, 1H), 7.02 (m, 3H), 6.96 (t, J=8.6 Hz, 1H), 3.93
(m, 2H), 3.73 (s, 3H), 3.45 (m, 2H), 3.14 (m, 2H), 3.02 (m, 2H),
2.86 (s, 3H) ppm.
Example 56
6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00089##
[0596] Step 1. 5-Bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline
##STR00090##
[0598] To a solution of 5-bromo-6-fluoroisoquinoline (1.002 g,
4.433 mmol) in acetic acid (20.0 mL) at room temperature was added
sodium tetrahydroborate (592.0 mg, 15.65 mmol) portionwise. The
mixture was stirred at room temperature for 16 h, and then
concentrated. The residue was diluted with CH.sub.2Cl.sub.2 and
washed with 2 M Na.sub.2CO.sub.3 (aq). The separated organic layer
was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to give a yellow oil, which was used directly in the
next step without further purification. LCMS calculated for
C.sub.9H.sub.10BrFN (M+H).sup.+ m/z=230.0; found 230.1.
Step 2. tert-Butyl
5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00091##
[0600] To a solution of
5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline (1.020 g, 4.433
mmol) in CH.sub.2Cl.sub.2 (12.0 mL) was added di-tert-butyl
dicarbonate (1.617 g, 7.409 mmol). The mixture was stirred at room
temperature for 1 h, and then concentrated. The residue was
purified on silica gel (120 g, 0-100% EtOAc in hexanes) to give the
desired product as a white solid (1.119 g, 76% over two steps).
LCMS calculated for C.sub.14H.sub.17BrFNNaO.sub.2 (M+Na).sup.+
m/z=352.0; found 352.0.
Step 3. tert-Butyl
6-fluoro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxylate
##STR00092##
[0602] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.119
g, 3.389 mmol),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(1.358 g, 5.348 mmol), potassium acetate (1.101 g, 11.22 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (298.6 mg, 0.366 mmol). The vial
was sealed with a Teflon-lined septum, evacuated and backfilled
with nitrogen (this process was repeated a total of three times).
1,4-Dioxane (15.0 mL) was added via syringe. The mixture was heated
at 100.degree. C. for 16 h. After cooling to room temperature, the
reaction mixture was diluted with CH.sub.2Cl.sub.2 and filtered.
The filtrate was concentrated. The residue was purified on silica
gel (40 g, 0-100% EtOAc in hexanes) to give the desired product as
a pale yellow oil (1001 mg, 78%). LCMS calculated for
C.sub.20H.sub.29BFNNaO.sub.4 (M+Na).sup.+ m/z=400.2; found
400.2.
Step 4.
6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d-
]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00093##
[0604] To a screw-cap vial equipped with a magnetic stir bar was
added
5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-pyrazolo[4,3-d]pyrimidine (Example 12, Step 5, 50.9
mg, 0.111 mmol), XPhos Pd G2 (9.5 mg, 0.012 mmol) and
K.sub.3PO.sub.4 (78.2 mg, 0.368 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). A solution of
tert-butyl
6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxylate (44.9 mg, 0.119 mmol) in 1,4-dioxane (2.0
mL) was added via syringe, followed by degassed water (150.0
.mu.L). The mixture was heated at 80.degree. C. for 1 h. After
cooling to room temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated. The
residue was dissolved in methanol (3.00 mL) and treated with 4.0 M
HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirred at
65.degree. C. for 2 h. After cooling to room temperature, the
mixture was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product as a yellow solid
(22.4 mg). LCMS calculated for C.sub.25H.sub.27FN.sub.7
(M+H).sup.+: m/z=444.2; Found: 444.2.
Example 57
1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-
piperidin-3-ol
##STR00094##
[0605] Step 1.
4-(5-Chloro-1-(2-(trimethylsilyl)ethoxy)-1H-pyrazolo[4,3-d]pyrimidin-3-yl-
)phenol
##STR00095##
[0607] To a solution of
5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]py-
rimidine (4.0 g, 9.74 mmol, Example 1, Step 2) in dioxane (39.0 ml)
and water (9.74 ml) was added potassium phosphate (4.13 g, 19.5
mmol) and (4-hydroxyphenyl)boronic acid (1.34 g, 9.74 mmol)
followed by addition of PdCl.sub.2(dppf) (0.795 g, 0.974 mmol).
N.sub.2 was bubbled through the mixture for 5 mins, and then it was
stirred at 90.degree. C. for 2 hours. After this time, the mixture
was cooled to r.t. and then concentrated to dryness. The residue
was purified by silica gel chromatography using 0-10% methanol in
DCM to afford desired product as brownish oil (590 mg, 16.1%).
LC-MS calculated for C.sub.17H.sub.22ClN.sub.4O.sub.2Si
(M+H).sup.+: m/z=377.2; found 377.1.
Step 2.
4-(5-(2-Fluoro-6-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenol
##STR00096##
[0609] To a solution of
4-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimi-
din-3-yl)phenol (660 mg, 1.75 mmol) in dioxane (14 ml) and water
(3.5 ml) was added potassium phosphate (742 mg, 3.50 mmol) and
(2-fluoro-6-methylphenyl)boronic acid (404 mg, 2.63 mmol) followed
by
chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-am-
ino-1,1'-biphenyl-2-yl) palladium(II) (138 mg, 0.175 mmol). N.sub.2
was bubbled through the mixture for 5 mins and then it was stirred
at 80.degree. C. for 2 hours. After this time the mixture was
cooled to r.t. and then concentrated to dryness. The residue was
purified by silica gel chromatography using 0-10% methanol in DCM
to afford desired product as brownish oil (390 mg, 49.4%). LC-MS
calculated for C.sub.24H.sub.28FN.sub.4.sub.2Si (M+H).sup.+:
m/z=451.2; found 451.2.
Step 3.
4-(5-(2-Fluoro-6-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl
trifluoromethanesulfonate
##STR00097##
[0611] To a solution of
4-(5-(2-fluoro-6-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[4,3-d]pyrimidin-3-yl)phenol (990 mg, 2.2 mmol) in DMF (22
ml) was added sodium hydride (132 mg, 3.30 mmol, 60% in mineral
oil). After stirring at r.t. for 10 min,
N-phenyltrifluoromethanesulfonimide (942 mg, 2.64 mmol) was added.
The resulting solution was stirred at r.t. for 30 mins, and then
quenched by NH.sub.4Cl aq. solution. The product was then extracted
with ethyl acetate. The organic layer was washed with water and
brine, and then dried over MgSO.sub.4, filtered and concentrated to
dryness. The residue was purified by silica gel chromatography
using 0-100% ethyl acetate in hexanes to afford desired product as
brownish oil (460 mg, 35.9%). LC-MS calculated for
C.sub.25H.sub.27F.sub.4N.sub.4O.sub.4SSi (M+H).sup.+: m/z=583.1.;
found 583.1
Step 4.
1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl-
)phenyl)piperidin-3-ol
[0612] To a solution of
4-(5-(2-fluoro-6-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[4,3-d]pyrimidin-3-yl)phenyl trifluoromethanesulfonate (30
mg, 0.051 mmol) in dioxane (8 mL) was added cesium carbonate (33.6
mg, 0.103 mmol) and piperidin-3-ol (26.0 mg, 0.257 mmol). The
mixture was degassed and
chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-
-1,1'-biphenyl-2-yl)palladium(II) (4.00 mg, 5.15 .mu.mol) was
added. The resulting mixture was stirred at 90.degree. C. for 2
hours. After this time, the mixture was filtered, and 4.0 M HCl in
dioxane (1 mL, 4 mmol) and 1 mL of water were added. The reaction
mixture was stirred for another 1 hour at 80.degree. C. After this
time, 1 mL of methanol was added and the reaction mixture was
stirred for another 30 min at 80.degree. C. The mixture was then
diluted with acetonitrile, filtered and purified by prep-LCMS
(XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min). LC-MS calculated
for C.sub.23H.sub.23FN.sub.5O (M+H).sup.+: m/z=404.2; found
404.2.
Example 58
1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-
piperidine-4-carbonitrile
##STR00098##
[0614] This compound was prepared according to the procedure
described in Example 57, using piperidine-4-carbonitrile instead of
piperidin-3-ol as starting material. LC-MS calculated for
C.sub.24H.sub.22FN.sub.6 (M+H).sup.+: m/z=413.2; Found 413.2.
Example 59
5-(2-Fluoro-6-methylphenyl)-3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d-
]pyrimidine
##STR00099##
[0616] This compound was prepared according to the procedure
described in Example 57, using piperazine instead of piperidin-3-ol
as starting material. LC-MS calculated for C.sub.22H.sub.22FN.sub.6
(M+H).sup.+: m/z=389.2; Found 389.2.
Example 60
1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-
pyrrolidin-3-ol
##STR00100##
[0618] This compound was prepared according to the procedure
described in Example 57, using pyrrolidin-3-ol instead of
piperidin-3-ol as starting material. LC-MS calculated for
C.sub.22H.sub.21FN.sub.5O (M+H).sup.+: m/z=390.2; Found 390.2.
Intermediate 1. tert-Butyl
3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4-
,3-d]pyrimidin-5-yl)benzyl(methyl)carbamate
##STR00101##
[0619] Step 1. tert-Butyl 3,5-difluorobenzyl(methyl)carbamate
##STR00102##
[0621] To a solution of 3,5-difluorobenzaldehyde (15.0 g, 106 mmol)
in MeOH (528 ml) was added methylamine (79.0 ml, 158 mmol, 2M in
THF), and the reaction mixture was stirred at r.t. for 1 hour.
Sodium borohydride (7.99 g, 211 mmol) was added and the reaction
was stirred until bubbling has stopped. The mixture was
concentrated to dryness, and then dissolved in 300 mL of DCM.
Sodium bicarbonate aq. solution was added and the reaction mixture
was stirred at r.t. for another 1 hour. The organic layer was dried
over MgSO.sub.4, filtered and concentrated to dryness. The residue
was dissolved in DCM (528 ml), then DIPEA (18.4 ml, 106 mmol) and
di-tert-butyl dicarbonate (24.5 ml, 106 mmol) were added. The
resulting solution was stirred at r.t. for 1 hour. The solution was
concentrated to dryness and the residue was purified by silica gel
chromatography using 0-70% ethyl acetate in hexanes to afford
desired product as colorless oil (15.1g, 55.4%). LC-MS calculated
for C.sub.9H.sub.10F.sub.2NO.sub.2 (M+2H-tBu).sup.+: m/z=202.1;
Found 202.2.
Step 2. tert-Butyl
5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2,6-difluorophenyl)-1H-py-
razolo[4,3-d]pyrimidine-1-carboxylate
##STR00103##
[0623] To a solution of tert-butyl
(3,5-difluorobenzyl)(methyl)carbamate (6.67 g, 25.9 mmol) in THF
(120 ml) was added n-butyllithium (13.8 ml, 34.6 mmol) dropwise at
-78.degree. C. and the reaction was stirred at -78.degree. C. for 1
hour. After this time
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.04 g, 43.2
mmol) was added and it was allowed to warm up to r.t. over 1 hour.
The reaction mixture was quenched with water and the desired
product was extracted with ethyl acetate. The organic layer was
washed with brine, dried over MgSO.sub.4, filtered and then
concentrated to dryness. The residue was dissolved in dioxane (40
ml) and water (10.00 ml). To the resulting solution was added
tert-butyl 5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (2.2
g, 8.64 mmol) and potassium phosphate, tribasic (3.01 g, 17.3
mmol). The reaction was degassed and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-am-
ino-1,1'-biphenyl-2-yl) palladium(II) (0.680 g, 0.864 mmol) was
added. The solution was then stirred at 60.degree. C. for 1 hour.
After cooling to r.t. solvents were evaporated in vacuo and the
residue was purified by silica gel chromatography using 0-10%
methanol in DCM to afford desired product as yellowish oil (1.70 g,
41.4%). LC-MS calculated for C.sub.23H.sub.28F.sub.2N.sub.5O.sub.4
(M+H).sup.+: m/z=476.2; found 476.2.
Step 3. tert-Butyl
3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4-
,3-d]pyrimidin-5-yl)benzyl(methyl)carbamate
##STR00104##
[0625] To a solution of tert-butyl
5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2,6-difluorophenyl)-1H--
pyrazolo[4,3-d]pyrimidine-1-carboxylate (1.60 g, 3.36 mmol) in
dioxane (16.8 ml) and water (16.8 ml) was added potassium carbonate
(2.3 g, 16.8 mmol) and the reaction was stirred at 80.degree. C.
for 2 hours. It was then cooled to r.t., diluted with DCM, washed
with water, sodium bicarbonate aq. solution and brine. The organic
layer was dried over MgSO.sub.4, filtered and then concentrated to
dryness. The residue was dissolved in acetonitrile (33.6 ml). To
the resulting solution was added N-iodosuccinimide (643 mg, 2.86
mmol) and the reaction was stirred at 50.degree. C. for 1 hour.
After this time it was cooled to r.t. then DIPEA (588 .mu.l, 3.36
mmol) was added followed by addition of SEM-Cl (507 .mu.l, 2.86
mmol) dropwise. The resulting solution was stirred for 30 mins at
r.t. then concentrated to dryness. The residue was purified by
silica gel chromatography using 0-70% ethyl acetate in hexanes to
afford Intermediate 1 as dark brownish solid (260 mg, 12.2%). LC-MS
calculated for C.sub.24H.sub.33F.sub.2IN.sub.5O.sub.3Si
(M+H).sup.+: m/z=632.2; found 632.2.
Example 61
5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-3-yl)-N-methylpicolinamide
##STR00105##
[0627] To a solution of Intermediate I (20 mg, 0.032 mmol) in
dioxane (1 mL) and water (0.250 mL) was added potassium phosphate,
tribasic (13 mg, 0.063 mmol) and
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
(16 mg, 0.063 mmol). The mixture was degassed and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-am-
ino-1,1'-biphenyl-2-yl) palladium(II) (4.98 mg, 6.33 .mu.mol) was
added. The resulting mixture was stirred at 90.degree. C. for 2
hours. The mixture was filtered, and 4.0 M HCl solution in dioxane
(1 mL, 4.000 mmol) and 1 mL of water were added and the reaction
mixture was stirred for another 1 hour at 80.degree. C. 1 mL of
methanol was added and the reaction mixture was stirred for another
30 mins at 80.degree. C. The mixture was then diluted with
acetonitrile, filtered and purified by prep-LCMS (XBridge C18
column, eluting with a gradient of acetonitrile/water containing
0.1% TFA, at flow rate of 60 mL/min). LC-MS calculated for
C.sub.20H.sub.18F.sub.2N.sub.7O (M+H).sup.+: m/z=410.2; found
410.2.
Example 62
4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-3-yl)-2-fluoro-N-methylbenzamide
##STR00106##
[0629] This compound was prepared according to the procedure
described in Example 61, using
2-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamid-
e instead of
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
as starting material. LC-MS calculated for
C.sub.21H.sub.18F.sub.3N.sub.6O (M+H).sup.+: m/z=427.2; Found
427.2.
Example 63
1-(3,5-Difluoro-4-(3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)ph-
enyl)-N-methylmethanamine
##STR00107##
[0631] This compound was prepared according to the procedure
described in Example 61, using
2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead
of
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
as starting material. LC-MS calculated for
C.sub.20H.sub.18F.sub.2N.sub.5O (M+H).sup.+: m/z=382.2; Found
382.2.
Example 64
3-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-3-yl)benzonitrile
##STR00108##
[0633] This compound was prepared according to the procedure
described in Example 61, using
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile instead
of
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
as starting material. LC-MS calculated for
C.sub.20H.sub.15F.sub.2N.sub.6 (M+H).sup.+: m/z=377.2; Found
377.2.
Example 65
1-(3,5-Difluoro-4-(3-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidi-
n-5-yl)phenyl)-N-methylmethanamine
##STR00109##
[0635] This compound was prepared according to the procedure
described in Example 61, using tert-butyl
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-car-
boxylate instead of
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
as starting material. LC-MS calculated for
C.sub.24H.sub.25F.sub.2N.sub.6 (M+H).sup.+: m/z=435.2; Found
435.2.
Example 66
1-(3,5-Difluoro-4-(3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)phenyl)-N-methylmethanamine
##STR00110##
[0637] This compound was prepared according to the procedure
described in Example 61, using
4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,3,2-dioxabor-
olane instead of
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
as starting material. LC-MS calculated for
C.sub.24H.sub.24F.sub.2N.sub.5O (M+H).sup.+: m/z=436.2; Found
436.2.
Example 67
1-(4-(3-(4-(4-Ethylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl-
)-3,5-difluorophenyl)-N-methylmethanamine
##STR00111##
[0639] This compound was prepared according to the procedure
described in Example 61, using
1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazi-
ne instead of
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
as starting material. LC-MS calculated for
C.sub.25H.sub.28F.sub.2N.sub.7 (M+H).sup.+: m/z=464.2; Found 464.2.
.sup.1H NMR (500 MHz, DMSO) .delta. 9.95 (s, 1H), 9.51 (s, 1H),
9.19 (s, 1H), 8.33 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.20
(d, J=9.0 Hz, 2H), 4.28 (s, 2H), 3.98 (d, J=12.4 Hz, 2H), 3.61 (d,
J=9.8 Hz, 3H), 3.22 (q, J=7.3 Hz, 2H), 3.18-3.02 (m, 3H), 2.66 (s,
3H), 1.27 (t, J=7.2 Hz, 3H).
Example 68
5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-3-yl)-2-morpholinonicotinonitrile
##STR00112##
[0641] This compound was prepared according to the procedure
described in Example 61, using
2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitri-
le instead of
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
as starting material. LC-MS calculated for
C.sub.23H.sub.21F.sub.2N.sub.8O (M+H).sup.+: m/z=463.2; Found
463.2.
Example 69
1-(3,5-Difluoro-4-(3-(3-fluoro-2-morpholinopyridin-4-yl)-1H-pyrazolo[4,3-d-
]pyrimidin-5-yl)phenyl)-N-methylmethanamine
##STR00113##
[0643] This compound was prepared according to the procedure
described in Example 61, using
4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)m-
orpholine instead of
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide
as starting material. LC-MS calculated for
C.sub.22H.sub.21F.sub.3N.sub.7O (M+H).sup.+: m/z=456.2; Found
456.2.
Example 70
1-(4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]-
pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol
##STR00114##
[0644] Step 1. tert-Butyl
4-(3-(6-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyraz-
olo[4,3-d]pyrimidin-5-yl)-3,5-difluorobenzyl(methyl)carbamate
##STR00115##
[0646] To a solution of Intermediate 1 (500 mg, 0.792 mmol) in
dioxane (6 ml) and water (1.5 ml) was added
(6-chloropyridin-3-yl)boronic acid (112 mg, 0.713 mmol) followed by
addition of potassium phosphate, tribasic (336 mg, 1.58 mmol). The
resulting solution was degassed, PdCl.sub.2(dppf) (64 mg, 0.079
mmol) was added and the reaction mixture was stirred at 90.degree.
C. for 2 hours. The reaction mixture was cooled to r.t. and
concentrated to dryness. The residue was purified by silica gel
chromatography using 0-100% ethyl acetate in hexanes to afford
desired product as brownish oil (310 mg, 63.4%). LC-MS calculated
for C.sub.29H.sub.36ClF.sub.2N.sub.6O.sub.3Si (M+H).sup.+:
m/z=618.2; found 618.2.
Step 2.
1-(4-(5-(5-(2,6-Dilltioro-4-((methylamino)methyl)phenyl)-1H-pyrazo-
lo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol
[0647] To a solution of tert-butyl
(4-(3-(6-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra-
zolo[4,3-d]pyrimidin-5-yl)-3,5-difluorobenzyl)(methyl)carbamate
(100 mg, 0.162 mmol) in dioxane (5 mL) was added cesium carbonate
(106 mg, 0.324 mmol) and 2-methyl-1-(piperazin-1-yl)propan-2-ol
(128 mg, 0.810 mmol). The resulting mixture was degassed and
chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-
-1,1'-biphenyl-2-yl)palladium(II) (12 mg, 0.016 mmol) was added.
The resulting mixture was stirred at 90.degree. C. for 2 hours. The
reaction mixture was filtered, and 4.0 M HCl solution in dioxane (1
mL, 4.0 mmol) and 1 mL of water were added. The resulting mixture
was stirred for another 1 hour at 80.degree. C. 1 mL of methanol
was added and the reaction mixture was stirred for another 30 mins
at 80.degree. C. The solution was then diluted with acetonitrile,
filtered and then purified by prep-LCMS (XBridge C18 column,
eluting with a gradient of acetonitrile/water containing 0.1% TFA,
at flow rate of 60 mL/min). LC-MS calculated for
C.sub.26H.sub.31F.sub.2N.sub.8O (M+H).sup.+: m/z=509.2; found
509.2. .sup.1H NMR (600 MHz, DMSO) .delta. 9.54 (s, 1H), 9.22 (d,
J=2.3 Hz, 1H), 9.08 (bs, 1H), 8.50 (dd, J=8.9, 2.4 Hz, 1H), 7.46
(d, J=8.0 Hz, 2H), 7.14 (d, J=8.9 Hz, 1H), 4.31 (d, J=18.8 Hz, 2H),
4.28 (t, J=5.6 Hz, 2H), 3.71-3.61 (m, 2H), 3.59-3.49 (m, 2H),
3.30-3.21 (m, 2H), 3.20 (s, 2H), 2.65 (t, J=5.1 Hz, 3H), 1.29 (s,
6H).
Example 71
(1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]py-
rimidin-3-yl)pyridin-2-yl)-3-methylpiperidin-3-yl)methanol
##STR00116##
[0649] This compound was prepared according to the procedure
described in Example 70, using (3-methylpiperidin-3-yl)methanol
instead of 2-methyl-1-(piperazin-1-yl)propan-2-ol as starting
material. LC-MS calculated for C.sub.25H.sub.28F.sub.2N.sub.7O
(M+H).sup.+: m/z=480.2; Found 480.2.
Example 72
N-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyr-
imidin-3-yl)phenyl)-1-(methylsulfonyl)piperidin-4-amine
##STR00117##
[0650] Step 1. tert-Butyl
4-(3-(4-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,-
3-d]pyrimidin-5-yl)-3,5-clifluorobenzyl(methyl)carbamate
##STR00118##
[0652] To a solution of Intermediate 1 (1 g, 1.583 mmol) in dioxane
(12 ml) and water (3 ml) was added (4-chlorophenyl)boronic acid
(173 mg, 1.11 mmol) followed by addition of potassium phosphate,
tribasic (672 mg, 3.17 mmol). The resulting solution was degassed,
PdCl.sub.2(dppf) (129 mg, 0.158 mmol) was added and the reaction
mixture was stirred at 90.degree. C. for 2 hours. The mixture was
cooled to r.t. and then concentrated to dryness. The residue was
purified by silica gel chromatography using 0-100% ethyl acetate in
hexanes to afford desired product as brownish oil (450 mg, 46.1%).
LC-MS calculated for C.sub.30H.sub.37ClF.sub.2N.sub.5O.sub.3Si
(M+H).sup.+: m/z=616.2; found 616.2.
Step 2.
N-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4-
,3-d]pyrimidin-3-yl)phenyl)-1-(methylsulfonyl)piperidin-4-amine
[0653] To a solution of tert-butyl
(4-(3-(4-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4-
,3-d]pyrimidin-5-yl)-3,5-difluorobenzyl)(methyl)carbamate (30 mg,
0.049 mmol) in dioxane (1 ml) was added cesium carbonate (79 mg,
0.24 mmol) and 1-(methylsulfonyl)piperidin-4-amine (43.4 mg, 0.243
mmol). The mixture was degassed and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-am-
ino-1,1'-biphenyl-2-yl) palladium(II) (7.66 mg, 9.74 .mu.mol) was
added. The resulting mixture was stirred at 90.degree. C. for 2
hours. The mixture was filtered, and 4.0 M HCl solution in dioxane
(1 mL, 4.0 mmol) and 1 mL of water were added. The reaction was
stirred for another 1 hour at 80.degree. C. 1 mL of methanol was
added, and the reaction mixture was stirred for another 30 mins at
80.degree. C. The solution was then diluted with acetonitrile,
filtered and then purified by prep-LCMS (XBridge C18 column,
eluting with a gradient of acetonitrile/water containing 0.1% TFA,
at flow rate of 60 mL/min). LC-MS calculated for
C.sub.25H.sub.28F.sub.2N.sub.7O.sub.2S (M+H).sup.+: m/z=528.2;
found 528.2.
Example 73
2-(4-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]-
pyrimidin-3-yl)phenyl)piperazin-1-yl)ethanol
##STR00119##
[0655] This compound was prepared according to the procedure
described in Example 72, using 2-(piperazin-1-yl)ethanol instead of
1-(methylsulfonyl)piperidin-4-amine as starting material. LC-MS
calculated for C.sub.25H.sub.28F.sub.2N.sub.7O (M+H).sup.+:
m/z=480.2; Found 480.2. .sup.1H NMR (400 MHz, DMSO) .delta. 9.78
(s, 1H), 9.50 (s, 1H), 9.10 (s, 1H), 8.30 (d, J=8.5 Hz, 2H),
7.53-7.38 (m, 2H), 7.23-7.12 (m, 2H), 4.27 (s, 2H), 3.94 (d, J=12.4
Hz, 2H), 3.79 (t, J=5.2 Hz, 2H), 3.68-3.56 (m, 3H), 3.27 (t, J=4.9
Hz, 2H), 3.23-3.12 (m, 3H), 2.66 (s, 3H).
Example 74
1-(3,5-Difluoro-4-(3-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)-1H-
-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine
##STR00120##
[0656] Step 1. tert-Butyl
3,5-difluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl(methyl)carbamate
##STR00121##
[0658] To a solution of tert-butyl
(3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
4,3-d]pyrimidin-5-yl)benzyl)(methyl)carbamate (Intermediate 1, 300
mg, 0.475 mmol) in dioxane (3 mL) and water (0.750 mL) was added
potassium phosphate, tribasic (202 mg, 0.950 mmol) and
1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine
(165 mg, 0.570 mmol). The resulting mixture was degassed and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-am-
ino-1,1'-biphenyl-2-yl) palladium(II) (74 mg, 0.095 mmol) was
added. The resulting mixture was stirred at 90.degree. C. for 2
hours. The mixture was concentrated to dryness. The residue was
purified by silica gel chromatography using 0-10% methanol in DCM
to afford desired product as brownish oil (220 mg, 69.5%). LC-MS
calculated for C.sub.33H.sub.45F.sub.2N.sub.8O.sub.3Si (M+H).sup.+:
m/z=667.2; found 667.2.
Step 2.
1-(3,5-Dilltioro-4-(3-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-
-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine
[0659] To a solution of tert-butyl
(3,5-difluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)-1-((2-(trimethylsilyl-
)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl)(methyl)carbamate
(25 mg, 0.037 mmol) in DCM (750 .mu.l) was added DIPEA (32.7 .mu.l,
0.187 mmol) followed by addition of methanesulfonyl chloride (22
mg, 0.19 mmol). The resulting solution was stirred at r.t. for 1
hour. 1 mL of TFA was added, and the reaction mixture was stirred
at r.t. for another 1 hour. The solvent was then removed, and the
residue was dissolved in methanol and stirred at 60.degree. C. for
15 mins. The solution was diluted with acetonitrile, filtered and
then purified by prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min). LC-MS calculated for
C.sub.23H.sub.25F.sub.2N.sub.8O.sub.2S (M+H).sup.+: m/z=515.2;
found 515.2.
Example 75
4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyr-
imidin-3-yl)pyridin-2-yl)-N-ethyl-N-methylpiperazine-1-carboxamide
##STR00122##
[0661] This compound was prepared according to the procedure
described in Example 74, using ethyl(methyl)carbamic chloride
instead of methanesulfonyl chloride as starting material. LC-MS
calculated for C.sub.26H.sub.30F.sub.2N.sub.9O (M+H).sup.+:
m/z=522.2; Found 522.2.
Example 76
1-(3-Fluoro-4-(3-(6-(piperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimi-
din-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine
##STR00123##
[0662] Step 1. tert-Butyl
3-fluoro-5-(trifluoromethyl)benzyl(methyl)carbamate
##STR00124##
[0664] To a solution of 3-fluoro-5-(trifluoromethyl)benzaldehyde
(20.0 g, 104 mmol) in MeOH (500 ml) was added methylamine solution
(104 ml, 208 mmol, 2M in THF) and the reaction mixture was stirred
at r.t. for 1 hour. Sodium borohydride (7.88 g, 208 mmol) was
added, and the reaction mixture was stirred for additional 30 mins.
The mixture was concentrated to dryness and 300 mL of DCM was
added. Aqueous solution of sodium bicarbonate was added, and the
reaction mixture was stirred at r.t. for another 1 hour. The
organic layer was separated, and it was dried over MgSO.sub.4,
filtered and concentrated to dryness. To a solution of the
resulting residue in DCM (521 ml) was added triethylamine (14.5 ml,
104 mmol) and di-tert-butyl dicarbonate (22.7 g, 104 mmol). The
resulting solution was stirred at r.t. for 1 hour. After this time
it was concentrated to dryness and the residue was purified by
silica gel chromatography using 0-70% ethyl acetate in hexanes to
afford desired product as colorless oil (15.1 g, 47.0%). LC-MS
calculated for C.sub.10H.sub.10F.sub.4NO.sub.2
(M+H--C.sub.4H.sub.8).sup.+: 252.1; found 252.2.
Step 2. tert-Butyl
5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-(trifluorometh-
yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate
##STR00125##
[0666] To a solution of tert-butyl
(3-fluoro-5-(trifluoromethyl)benzyl)(methyl)carbamate (2.3 g, 7.5
mmol) in THF (33.3 ml) was added n-butyllithium (8.98 ml, 22.5
mmol) dropwise at -78.degree. C., and the reaction mixture was
stirred at -78.degree. C. for 1 hour.
2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.57 g, 29.9
mmol) was added. The resulting mixture was allowed to warm up to
r.t. over 1 hour. The resulting solution was quenched with water,
neutralized to pH=6, and the desired product was extracted with
ethyl acetate. The organic layer was washed with brine, dried over
MgSO.sub.4, filtered and then concentrated to dryness. To a
solution of the resulting residue in dioxane (33.3 ml) and water
(8.32 ml) was added potassium phosphate (1.30 g, 7.48 mmol) and
tert-butyl 5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate
(0.953 g, 3.74 mmol). The mixture was degassed with N.sub.2,
chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-am-
ino-1,1'-biphenyl-2-yl) palladium(II) (0.118 g, 0.150 mmol) was
added, and the reaction mixture was stirred at 60.degree. C. for 1
hour. After this time it was concentrated to dryness. The residue
was purified by silica gel chromatography using 0-100% ethyl
acetate in hexanes to afford desired product as yellowish oil (850
mg, 43.2%). LC-MS calculated for
C.sub.24H.sub.28F.sub.4N.sub.5O.sub.4 (M+H).sup.+: m/z=526.2; Found
526.2.
Step 3. tert-Butyl
3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d-
]pyrimidin-5-yl)-5-(trifluoromethyl)benzyl(methyl)carbamate
##STR00126##
[0668] To a solution of tert-butyl
5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-(trifluorome-
thyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (250 mg,
0.476 mmol) in dioxane (2.5 ml) and water (2.5 ml) was added
potassium carbonate (329 mg, 2.38 mmol), and the reaction mixture
was stirred at 80.degree. C. for 2 hours. The mixture was cooled to
r.t., diluted with DCM and washed with water, sodium bicarbonate
and brine. The organic layer was dried over MgSO.sub.4, filtered
and then concentrated to dryness. To a solution of the resulting
residue in acetonitrile (5 ml) was added N-iodosuccinimide (91 mg,
0.40 mmol) and the reaction was stirred at 50.degree. C. for 1
hour. The mixture was cooled to r.t., DIPEA (83 .mu.l, 0.476 mmol)
was added followed by the dropwise addition of SEM-Cl (71.7 .mu.l,
0.404 mmol). The resulting solution was stirred at r.t. for 30
mins, then concentrated to dryness. The residue was purified by
silica gel chromatography using 0-70% ethyl acetate in hexanes to
afford desired product as dark brownish solid (260 mg, 80.0%).
LC-MS calculated for C.sub.25H.sub.33F.sub.4IN.sub.5O.sub.3Si
(M+H)+: m/z=682.2; found 682.2.
Step 4.
1-(3-Fluoro-4-(3-(6-(piperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine
[0669] To a solution of tert-butyl
(3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)-5-(trifluoromethyl)benzyl)(methyl)carbamate (20
mg, 0.029 mmol) in dioxane (800 .mu.l) and water (200 .mu.l) was
added (6-(piperidin-1-yl)pyridin-3-yl)boronic acid (6.1 mg, 0.029
mmol) followed by the addition of potassium phosphate, tribasic
(12.4 mg, 0.058 mmol). The resulting solution was degassed,
PdCl.sub.2(dppf) (2.4 mg, 2.93 .mu.mol) was added, and the reaction
mixture was stirred at 90.degree. C. for 2 hours. The mixture was
cooled to r.t. and then HCl, 4.0 M in dioxane (1 ml, 4.00 mmol) was
added, followed by the addition of 1 ml of water. The resulting
solution was stirred at 80.degree. C. for 2 hours. The solution was
cooled to r.t., diluted with acetonitrile, filtered and purified by
prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).
LC-MS calculated for C.sub.24H.sub.24F.sub.4N.sub.7 (M+H).sup.+:
m/z=486.2; found 486.2.
Example 77
1-(4-(5-(5-(2-Fluoro-4-((methylamino)methyl)-6-(trifluoromethyl)phenyl)-1H-
-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone
##STR00127##
[0671] This compound was prepared according to the procedure
described in Example 76, using
6-(4-acetylpiperazin-1-yl)pyridin-3-ylboronic acid instead of
(6-(piperidin-1-yl)pyridin-3-yl)boronic acid as starting material.
LC-MS calculated for C.sub.25H.sub.25F.sub.4N.sub.8O (M+H).sup.+:
m/z=529.2; Found 529.2.
Example 78
1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyr-
imidin-5-yl)phenyl)-N-methylmethanamine
##STR00128##
[0672] Step 1. tert-Butyl
5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate
##STR00129##
[0674] In a 50 mL round-bottom flask with a stir bar,
5-chloro-1H-pyrazolo[4,3-d]pyrimidine (Oxchem, 600 mg, 3.88 mmol)
and triethylamine (649 .mu.l, 4.66 mmol) were dissolved in
CH.sub.2Cl.sub.2 (12.9 mL). Di-tert-butyl dicarbonate (991 .mu.l,
4.27 mmol) was added, and the reaction mixture was stirred at r.t.
for 1 h. The reaction mixture was then diluted with water,
extracted with CH.sub.2Cl.sub.2, and the combined organic layers
were dried over magnesium sulfate and concentrated under reduced
pressure. The crude product was purified by Biotage Isolera.TM.
(860 mg, 87%). LCMS calculated for C.sub.10H.sub.12ClN.sub.4O.sub.2
(M+H).sup.+ m/z=255.1; found 255.2.
Step 2. 4-Bromo-3-fluoro-5-methylaniline
##STR00130##
[0676] N-Bromosuccinimide (15.8 g, 89 mmol) was added to a solution
of 3-fluoro-5-methylaniline (Combi-Blocks, 11 g, 88 mmol) in DMF
(80 mL) cooled to 0.degree. C. in an ice bath. The reaction mixture
was stirred at 0.degree. C. for 30 minutes. After warming to r.t.,
the reaction was stirred for an additional 1 hour. Water and EtOAc
were then added, and the organic phase was washed with saturated
aqueous NaHCO.sub.3 and brine. The organic phase was then dried
over magnesium sulfate and the solvents were evaporated under
reduced pressure. The crude product was purified by Biotage
Isolera.TM. (17.2 g, 96%). LCMS calculated for C.sub.7H.sub.8BrFN
(M+H).sup.+ m/z=203.9; found 204.0.
Step 3. 2-Bromo-1-fluoro-5-iodo-3-methylbenzene
##STR00131##
[0678] To a solution of 4-bromo-3-fluoro-5-methylaniline (7.28 g,
36 mmol) in acetonitrile (190 mL) cooled to 0.degree. C. in an ice
bath was added sulfuric acid (4.75 mL, 89 mmol) dissolved in
H.sub.2O (10 mL). After stirring for 5 minutes, a solution of
sodium nitrite (4.92 g, 71.4 mmol) in water (10 mL) was added
dropwise, and the reaction mixture was stirred for an additional 15
minutes at 0.degree. C. Potassium iodide (23.7 g, 143 mmol) in
water (20 mL) was then added, and the ice-bath was removed. After
warming to r.t., the reaction was stirred for an additional 20
minutes before the reaction was quenched via the addition of
aqueous Na.sub.2S.sub.2O.sub.3. The mixture was then extracted with
ethyl acetate and the combined organic phases were washed with
brine, dried over magnesium sulfate, and concentrated under reduced
pressure. The crude product was purified by Biotage Isolera.TM.
(10.3 g, 94%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (br
s, 1H), 7.29 (m, 1H), 2.38 (s, 3H) ppm.
Step 4. 2-Bromo-1-fluoro-3-methyl-5-vinylbenzene
##STR00132##
[0680] To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene
(10.3 g, 32.8 mmol) in 1,4-dioxane (80 mL) and water (13.3 mL) was
added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,
6.16 mL, 34.5 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(Pd(dppf)Cl.sub.2) (2.40 g, 3.3 mmol), and potassium phosphate
tribasic (13.9 g, 65.7 mmol). The reaction mixture was degassed
with nitrogen and heated to 70.degree. C. for 1 h. After cooling to
r.t., the reaction was filtered over a pad of Celite, diluted with
water, and extracted with ethyl acetate. The combined organic
phases were washed with brine, dried over magnesium sulfate, and
concentrated under reduced pressure. The crude product was purified
by Biotage Isolera.TM. (5.46 g, 77%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.05 (br s, 1H), 7.01 (dd, J=2.0, 9.4 Hz, 1H),
6.60 (dd, J=10.9, 17.5 Hz, 1H), 5.75 (d, J=17.5 Hz, 1H), 5.31 (d,
J=10.9 Hz, 1H), 2.42 (s, 3H) ppm.
Step 5. 4-Bromo-3-fluoro-5-methylbenzaldehyde
##STR00133##
[0682] To a solution of 2-bromo-1-fluoro-3-methyl-5-vinylbenzene
(5.46 g, 25.4 mmol) in acetone (46 mL) and water (4.6 mL) was
sequentially added sodium periodate (21.7 g, 102 mmol) and a 4%
aqueous solution of osmium tetroxide (8.07 mL, 1.27 mmol). The
reaction was stirred at r.t. for 2 h. The reaction mixture was then
filtered over a pad of celite, diluted with water, and extracted
with ethyl acetate. The combined organic phases were washed with
brine, dried over magnesium sulfate, and concentrated under reduced
pressure. The crude product was purified by Biotage Isolera.TM.
(3.22 g, 58%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.93 (d,
J=1.8 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.44 (dd, J=1.8, 7.8 Hz,
1H), 2.52 (s, 3H) ppm.
Step 6. 1-(4-Bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine
##STR00134##
[0684] In a 20 mL scintillation vial equipped with a magnetic stir
bar, 4-bromo-3-fluoro-5-methylbenzaldehyde (1.46 g, 6.70 mmol) was
dissolved in MeOH (6.70 mL) and the reaction was placed under a
nitrogen environment. Following this, a 33% solution of methanamine
(3.15 g, 33.5 mmol) in ethanol and titanium(IV) isopropoxide (0.982
mL, 3.35 mmol) were added, and the reaction mixture was stirred at
r.t. for 3 hours. Sodium borohydride (1.01 g, 26.8 mmol) was then
added to the reaction mixture portion wise and stirring was
continued at r.t. for an additional 1.5 hours. NH.sub.4OH (30%
aqueous solution) was added to the reaction mixture and stirring
continued for another 15 minutes. The reaction was then acidified
with 1 N HCl and extracted with ethyl acetate. The water layer was
then made basic and extracted with ethyl acetate. The combined
organic phases were washed with brine, dried over magnesium
sulfate, and concentrated under reduced pressure to afford
1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g,
85%) as a light yellow oil. The crude product was used in the next
step without further purification. LCMS calculated for
C.sub.9H.sub.12BrFN (M+H).sup.+ m/z=232.0; found 231.9.
Step 7. tert-Butyl
4-bromo-3-fluoro-5-methylbenzyl(methyl)carbamate
##STR00135##
[0686] To a solution of
1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g,
5.67 mmol) and triethylamine (1.58 mL, 11.34 mmol) in THF (18.9 mL)
was added di-tert-butyl dicarbonate (1.58 mL, 6.80 mmol). The
reaction mixture was then stirred at ambient temperature for 1
hour. The reaction mixture was then diluted with water and
extracted with ethyl acetate. The combined organic layers were then
dried with magnesium sulfate and concentrated under reduced
pressure. The crude product was purified by Biotage Isolera.TM.
(1.42 g, 78%). LCMS calculated for C.sub.10H.sub.12BrFNO.sub.2
(M+H--C.sub.4H.sub.8).sup.+ m/z=276.0; found 276.0.
Step 8. tert-Butyl
3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(m-
ethyl)carbamate
##STR00136##
[0688] In an oven-dried 20 mL scintillation vial with a stir bar,
tert-butyl (4-bromo-3-fluoro-5-methylbenzyl)(methyl)carbamate (573
mg, 1.73 mmol) was dissolved in THF (11.5 mL). The reaction mixture
was then cooled to -78.degree. C. in a dry ice/acetone bath and
n-BuLi (1.6 M solution in hexanes, 1.19 mL, 1.90 mmol) was added
dropwise. The reaction mixture was then allowed to stir for 3
minutes before 2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(427 .mu.L, 2.25 mmol) was added dropwise. The mixture was warmed
to r.t and stirred for an additional 5 hours. The reaction mixture
was quenched by the addition of water, acidified to pH 5-6 using 1
N HCl, and extracted with ethyl acetate. The combined organic
layers were then washed with brine, dried over magnesium sulfate,
and concentrated to afford tert-butyl
3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(m-
ethyl)carbamate. The crude product was used in the next step
without further purification. LCMS calculated for
C.sub.16H.sub.24BrFNO.sub.4 (M+H--C.sub.4H.sub.8).sup.+ m/z=324.2;
found 324.1.
Step 9. tert-Butyl
5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)--
1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate
##STR00137##
[0690] In a 20 mL scintillation vial equipped with a magnetic stir
bar, tert-butyl 5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate
(340 mg, 1.34 mmol) and tert-butyl
(3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-
(methyl)carbamate (557 mg, 1.47 mmol) were dissolved in 1,4-dioxane
(8.0 mL) and water (2.0 mL). To this mixture was added
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (158 mg, 0.20
mmol) and potassium phosphate tribasic (567 mg, 2.67 mmol). The
reaction mixture was then degassed by bubbling nitrogen through the
resulting mixture, and the reaction mixture was sealed and heated
to 75.degree. C. for 1 h. After cooling to r.t., the reaction was
diluted with water and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over magnesium
sulfate, and concentrated under reduced pressure. The crude product
was purified by Biotage Isolera.TM. (532 mg, 84%). LCMS calculated
for C.sub.24H.sub.31FN.sub.5O.sub.4 (M+H).sup.+ m/z=472.2; found
472.3.
Step 10. tert-Butyl
3-fltioro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)-5-methylbenzyl(methyl)carbamate
##STR00138##
[0692] In a 20 mL scintillation vial with a stir bar, tert-butyl
5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl-
)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (817 mg, 1.73 mmol)
and potassium carbonate (958 mg, 6.93 mmol) were dissolved in
1,4-dioxane (6.06 mL) and water (6.06 mL). The reaction was then
purged under a nitrogen environment and heated to 80.degree. C. for
2 hours. The reaction was diluted with water and extracted with
ethyl acetate. The combined organic phases were then washed with
brine, dried over magnesium sulfate, and concentrated. The crude
intermediate was dissolved in acetonitrile (10 mL) and
N-iodosuccinimide (507 mg, 2.25 mmol) was added, and the reaction
mixture heated to 60.degree. C. for 1 hour.
N,N-diisopropylethylamine (393 .mu.l, 2.25 mmol) and
[2-(trimethylsilyl)ethoxy]methyl chloride (369 .mu.L, 2.08 mmol)
were added to the reaction mixture was stirred at r.t for an
additional 1 h. The reaction mixture was then concentrated under
reduced pressure and the crude product was purified by Biotage
Isolera.TM. (412 mg, 38%). LCMS calculated for
C.sub.25H.sub.36FIN.sub.5O.sub.3Si (M+H).sup.+ m/z=628.2; found
628.1.
Step 11.
1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[-
4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine
[0693] In a 4 dram vial equipped with a magnetic stir bar,
tert-butyl
(3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)-5-methylbenzyl)(methyl)carbamate (20 mg, 0.032
mmol) was dissolved in 1,4-dioxane (0.5 mL) and water (0.08 mL). To
this solution was added
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyr-
azole (9.28 mg, 0.045 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (2.5 mg, 0.0032
mmol), and potassium phosphate (13.5 mg, 0.064 mmol). The reaction
mixture was then degassed, sealed, and stirred at 85.degree. C. for
1 h. The reaction was then concentrated and CH.sub.2Cl.sub.2 (0.25
mL) followed by TFA (0.25 mL) were added, and the mixture was
stirred at 30.degree. C. for 90 minutes. The reaction was then
concentrated and methanol (1.0 mL) followed by 7 drops of
NH.sub.4OH (30% aqueous solution) was added and stirring was
continued at 30.degree. C. for 1 hour. The reaction mixture was
then concentrated, dissolved in methanol and purified with
prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).
LCMS calculated for C.sub.18H.sub.19FN.sub.7 (M+H).sup.+:
m/z=352.2; Found: 352.2.
Example 79
2-(4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidin-3-yl)-1H-pyrazol-1-yl)benzonitrile
##STR00139##
[0695] In a 4 dram vial equipped with a magnetic stir bar,
tert-butyl
(3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)-5-methylbenzyl)(methyl)carbamate (18.9 mg, 0.030
mmol) was dissolved in 1,4-dioxane (0.5 mL) and water (0.08 mL). To
this solution was added
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzon-
itrile (12.4 mg, 0.042 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2) (3.6 mg, 0.0032
mmol), and potassium phosphate (16.0 mg, 0.064 mmol). The reaction
mixture was then degassed, sealed, and stirred at 80.degree. C. for
1 h. Following this, a 4 N solution of HCl in 1,4-dioxane (2 mL)
was added and the reaction was stirred at r.t. for 1 hour. The
reaction mixture was then concentrated, dissolved in methanol and
purified with prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min). LCMS calculated for C.sub.24H.sub.20FN.sub.8
(M+H).sup.+: m/z=439.2; Found: 439.1.
Example 80
5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1--
yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine
##STR00140##
[0696] Step 1. tert-Butyl
4-(4-bromo-3-fluoro-5-methylphenyl)-4-oxobutylcarbamate
##STR00141##
[0698] To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene
(1.34 g, 4.25 mmol, Example 78, Step 3) in THF (30 mL) was added a
solution of isopropylmagnesium chloride in THF (2.13 mL, 4.25 mmol,
2 M) dropwise at -40 C. After stirring at -40.degree. C. for 1 h,
the mixture was cooled to -78.degree. C. and tert-butyl
2-oxopyrrolidine-1-carboxylate (0.726 mL, 4.25 mmol) was added. The
mixture was then slowly warmed to RT over 1.5 h. The mixture was
quenched by 1 M HCl, extracted with ethyl acetate and concentrated
in vacuo. The obtained crude product was purified by Biotage
Isolera.TM. to give the desired product. LCMS calculated for
C.sub.11H.sub.14BrFNO (M-Boc+2H).sup.+: m/z=274.0; Found:
274.0.
Step 2. tert-Butyl
2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate
##STR00142##
[0700] To a solution of tert-butyl
4-(4-bromo-3-fluoro-5-methylphenyl)-4-oxobutylcarbamate (1.30 g,
3.47 mmol) in DCM (15 mL) was added 15 mL TFA, and the mixture was
stirred at RT for 30 min. The mixture was concentrated in vacuo and
then dissolved in 30 mL THF. To this solution was added
triethylamine (0.593 mL, 4.25 mmol) and sodium
triacetoxyborohydride (1.80 g, 8.51 mmol). The mixture was stirred
at RT for 18 h and then quenched by 1 M NaOH. The mixture was
extracted by ethyl acetate and concentrated in vacuo. The obtained
crude product was dissolved in THF (20 mL). To this solution was
added di-tert-butyl dicarbonate (1.86 g, 8.51 mmol) and
triethylamine (0.513 mL, 3.68 mmol) at RT. After stirring for 1 h,
the solvents were evaporated under reduced pressure and the
obtained crude product was purified by Biotage Isolera.TM. to give
the desired product. LCMS calculated for
C.sub.12H.sub.14BrFNO.sub.2 (M-C.sub.4H.sub.8+H).sup.+: m/z=302.0;
Found: 302.0.
Step 3.
5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(4-(4-methylpipe-
razin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine
[0701] A mixture of tert-butyl
2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate (65
mg, 0.181 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (69.1
mg, 0.272 mmol), potassium acetate (53.4 mg, 0.544 mmol) and
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
complex with dichloromethane (1:1) (29.6 mg, 0.036 mmol) in dioxane
(10 mL) was stirred at 110.degree. C. for 24 h. After cooling to
room temperature, the mixture was concentrated in vacuo. A mixture
of this crude material,
5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-pyrazolo[4,3-d]pyrimidine (25.8 mg, 0.056 mmol,
Example 1, Step 3), XPhos Pd G2 (4.14 mg, 5.61 .mu.mol) and cesium
carbonate (54.9 mg, 0.168 mmol) in dioxane (10 mL) and water (2 mL)
was stirred at 70.degree. C. for 18 h. After cooling to room
temperature, the mixture was concentrated in vacuo. The crude
mixture was then dissolved in DCM (2.0 mL) and TFA (2.0 mL) was
added dropwise at room temperature. After stirring for 2 h, the
mixture was concentrated in vacuo. The crude mixture was dissolved
in MeOH (3.5 mL) and 10% aqueous NH.sub.4OH (1.5 mL) was added. The
mixture was purified with prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to give the desired product. LCMS calculated for
C.sub.27H.sub.31FN.sub.7 (M+H).sup.+: m/z=472.3; Found: 472.3.
Example 81
5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-y-
l)phenyl)-1H-pyrazolo[4,3-d]pyrimidine
##STR00143##
[0702] Step 1. tert-Butyl
6-(4-bromo-3-fluoro-5-methylphenyl)-3,4-dihydropyridine-1(2H)-carboxylate
##STR00144##
[0704] A solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (526
mg, 1.67 mmol, Example 78, Step 3), tert-butyl
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-
-carboxylate (516 mg, 1.67 mmol),
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
complex with dichloromethane (1:1) (136 mg, 0.167 mmol) and
potassium carbonate (461 mg, 3.34 mmol) in dioxane (10 mL) and
water (2mL) was stirred at 65.degree. C. for 18 h. After cooling to
room temperature, the mixture was concentrated in vacuo. The
obtained crude product was purified by Biotage Isolera.TM. to give
the desired product. LCMS calculated for
C.sub.13H.sub.14BrFNO.sub.2 (M-C.sub.4H.sub.8+H).sup.+: m/z=314.0;
Found: 313.9.
Step 2. tert-Butyl
2-(4-bromo-3-fluoro-5-methylphenyl)piperidine-1-carboxylate
##STR00145##
[0706] To a solution of tert-butyl
6-(4-bromo-3-fluoro-5-methylphenyl)-3,4-dihydropyridine-1(2H)-carboxylate
(530 mg, 1.42 mmol) in DCM (10 mL) was added 10 mL TFA, and the
mixture was stirred at RT for 30 min. The mixture was concentrated
in vacuo and then dissolved in 20 mL THF. To this solution was
added triethylamine (0.233 mL, 1.67 mmol) and sodium
triacetoxyborohydride (707 mg, 3.34 mmol). The mixture was stirred
at RT for 18 h and then quenched by 1 M NaOH. The mixture was
extracted by ethyl acetate and concentrated in vacuo. The obtained
crude product was dissolved in THF (20 mL). To this solution was
added di-tert-butyl dicarbonate (364 mg, 1.67 mmol) at RT. After
stirring for 3 h, the solvents were evaporated under reduced
pressure and the obtained crude product was purified by Biotage
Isolera to give the desired product. LCMS calculated for
C.sub.13H.sub.16BrFNO.sub.2 (M-C.sub.4H.sub.8+H).sup.+: m/z=316.0;
Found: 315.9.
Step 3.
5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(4-(4-methylpiper-
azin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine
[0707] A mixture of tert-butyl
2-(4-bromo-3-fluoro-5-methylphenyl)piperidine-1-carboxylate (65 mg,
0.175 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (66.5
mg, 0.262 mmol), potassium acetate (51.4 mg, 0.524 mmol) and
(1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)
complex with dichloromethane (1:1) (28.5 mg, 0.035 mmol) in dioxane
(10 mL) was stirred at 105.degree. C. for 24 h. After cooling to
room temperature, the mixture was concentrated in vacuo. The crude
boronic ester intermediate was treated with
5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-pyrazolo[4,3-d]pyrimidine (24.9 mg, 0.054 mmol,
Example 1, Step 3), XPhos Pd G2 (4.0 mg, 5.43 .mu.mol) and cesium
carbonate (53.0 mg, 0.163 mmol) in dioxane (10 mL)/water (2 mL) and
stirred at 70.degree. C. for 18 h. After cooling to room
temperature, the mixture was concentrated in vacuo. The crude Pd
coupling product mixture was then dissolved in DCM (2.0 mL) and
treated with TFA (2.0 mL) dropwise at room temperature. After
stirring for 2 h, the mixture was concentrated in vacuo. The crude
product mixture was dissolved in MeOH (3.5 mL) and 10% aqueous
NH.sub.4OH (1.5 mL) was added. The mixture was purified with
prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min)
to give the desired product. LCMS calculated for
C.sub.28H.sub.33FN.sub.7 (M+H).sup.+: m/z=486.3; Found: 486.4.
Example 82
N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidi-
n-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide
##STR00146##
[0708] Step 1.
5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-pyrazolo[4,3-d]pyrimidine
##STR00147##
[0710] To a mixture of
5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]py-
rimidine (3.25 g, 7.91 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(1.646 g, 7.91 mmol), dppf-PdCl.sub.2 (0.323 g, 0.396 mmol) and
potassium carbonate (2.187 g, 15.83 mmol) were added 1,4-dioxane
(15.83 ml) and water (3.96 ml), and the reaction flask was
evacuated, back filled with nitrogen, then stirred at 90.degree. C.
overnight. The mixture was diluted with DCM and filtered through a
pad of Celite. The filtrate was concentrated and purified by
Biotage Isolera.TM. (flash purification system with ethyl
acetate/hexanes at a ratio from 0 to 100%) to provide the desired
product as a dark oil (2.08 g, 72%). LC-MS calculated for
C.sub.15H.sub.22ClN.sub.6OSi [M+H].sup.+ m/z: 365.2, found
365.2.
Step 2.
3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilin-
e
##STR00148##
[0712] To a mixture of 4-bromo-3,5-difluoroaniline (3.30 g, 15.9
mmol), dppf-PdCl.sub.2 (0.648 g, 0.793 mmol),
bis(pinacolato)diboron (6.04 g, 23.8 mmol) and potassium acetate
(3.11 g, 31.7 mmol) was added 1,4-dioxane (31.7 ml) and the
reaction flask was evacuated, back filled with nitrogen, then
stirred at 100.degree. C. overnight. The reaction mixture was then
diluted with DCM and filtered through a pad of Celite. The filtrate
was concentrated and purified by Biotage Isolera.TM. (flash
purification system with ethyl acetate/hexanes at a ratio from 0 to
100%) to provide the desired product as a brown solid (2.4 g, 59%).
LC-MS calculated for C.sub.12H.sub.17BF.sub.2NO.sub.2 [M+H].sup.+
m/z: 256.1, found 256.1.
Step 3. Preparation of
3,5-clifluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)aniline
##STR00149##
[0714] To a mixture of
5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-pyrazolo[4,3-d]pyrimidine (475 mg, 1.302 mmol),
3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(432 mg, 1.692 mmol), Xphos Pd G2 (102 mg, 0.130 mmol) and
potassium phosphate, tribasic (553 mg, 2.60 mmol) were added
1,4-dioxane (4.75 ml) and water (0.950 ml) and the reaction mixture
was evacuated, back filled with nitrogen, then stirred at
80.degree. C. for 1 hr. The mixture was then diluted with DCM and
filtered through a plug of Celite. The filtrate was concentrated
and purified by Biotage Isolera.TM. (flash purification system with
dichloromethane/methanol at a ratio from 2 to 10%) to provide the
desired product as a brown solid. LC-MS calculated for
C.sub.21H.sub.26F.sub.2N.sub.7OSi [M+H].sup.+ m/z: 458.2, found
458.2.
Step 4. Preparation of
2-chloro-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethyl-
silyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)acetamide
##STR00150##
[0716] To a mixture of
3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy-
)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)aniline (100 mg, 0.219
mmol), 2-chloroacetic acid (41.3 mg, 0.437 mmol) and HATU (125 mg,
0.328 mmol) in DMF (1093 .mu.l) was added hunig's base (115 .mu.l,
0.656 mmol) and the reaction mixture stirred at r.t. for 1 hr. The
mixture was then quenched with water and extracted with ethyl
acetate. The organic layer was washed with water and brine, dried
over sodium sulfate and concentrated. The residue was used in the
next step without further purification. LC-MS calculated for
C.sub.23H.sub.27ClF.sub.2N.sub.7O.sub.2Si [M+H].sup.+ m/z: 534.2,
found 534.2.
Step 5. Preparation of
N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide
[0717] To a solution of
2-chloro-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethyl-
silyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)acetamide
(25 mg, 0.047 mmol) in DMF (468 .mu.l) was added pyrrolidine (7.83
.mu.l, 0.094 mmol) and the reaction mixture was stirred at
80.degree. C. for 2 hrs. It was then quenched with water and
extracted with ethyl acetate. The organic layer was washed with
water and brine, dried over sodium sulfate and concentrated. To the
residue were added methanol (1 mL) and 4N HCl (1 mL) and the
reaction mixture heated to 80.degree. C. for 30 mins, then cooled
to r.t., diluted with methanol and purified directly on prep-LCMS
(XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to provide the
desired product. LC-MS calculated for
C.sub.21H.sub.21F.sub.2N.sub.8O [M+H].sup.+ m/z: 439.2, found
439.2.
Example 83
N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidi-
n-5-yl)phenyl)-2-(dimethylamino)acetamide
##STR00151##
[0719] This compound was prepared using procedures analogous to
those for example 82, with dimethyl amine replacing pyrrolidine.
LCMS calculated for C.sub.19H.sub.19F.sub.2N.sub.8O [M+H].sup.+
m/z: 413.2; Found: 413.2.
Preparation of
3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy-
)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde
##STR00152##
[0720] Step 1. Preparation of
(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)metha-
nol
##STR00153##
[0722] To a solution of
3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
(4.0 g, 14.92 mmol) in tetrahydrofuran (149 ml) was added sodium
borohydride (0.677 g, 17.91 mmol). After 2 hrs, the reaction was
quenched with sat. sodium bicarbonate and extracted with ethyl
acetate. The organic layer was washed with brine, dried over sodium
sulfate and concentrated. The crude product was used in the next
step without further purification.
Step 2. Preparation of
(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)methanol
##STR00154##
[0724] To a mixture of
5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-pyrazolo[4,3-d]pyrimidine (425 mg, 1.165 mmol),
(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)metha-
nol (472 mg, 1.747 mmol), Xphos Pd G2 (92 mg, 0.116 mmol) and
potassium phosphate (494 mg, 2.329 mmol) were added 1,4-dioxane (3
ml) and water (776 .mu.l), and the reaction flask was evacuated,
back filled with nitrogen, then stirred at 95.degree. C. for 2 hrs.
The mixture was diluted with DCM and filtered through a pad of
Celite. The filtrate was concentrated and purified by Biotage
Isolera.TM. (flash purification system with
dichloromethane/methanol at a ratio from 2 to 10%) to provide the
desired product as a dark oil. LCMS calculated for
C.sub.22H.sub.27F.sub.2N.sub.6O.sub.2Si [M+H].sup.+ m/z: 473.2;
Found: 473.2.
Step 3. Preparation of
3,5-clifluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde
[0725] To a solution of
(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)methanol (550 mg,
1.164 mmol) in DCM (6 mL) was added manganese dioxide (1.9 g, 22.11
mmol). The reaction mixture was heated to 60.degree. C. for 1 hr,
and then filtered through a plug of Celite. The filtrate was
concentrated and purified by Biotage Isolera.TM. (flash
purification system with hexanes/ethyl acetate at a ratio from 0 to
100%) to provide the desired product as an oil. LCMS calculated for
C.sub.22H.sub.25F.sub.2N.sub.6O.sub.2Si [M+H].sup.+ m/z: 471.2;
Found: 471.2.
Example 84
1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidi-
n-5-yl)phenyl)-N-methylmethanamine
##STR00155##
[0727] To a solution of
3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy-
)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde (25 mg,
0.053 mmol) and methanamine (2M in THF, 0.133 ml, 0.266 mmol) in
toluene (1 ml) was added acetic acid (9.12 .mu.l, 0.159 mmol) and
the reaction mixture was stirred at 80.degree. C. overnight. The
mixture was then concentrated and redissolved in methanol (1 mL).
Sodium borohydride (2.010 mg, 0.053 mmol) was then added and the
mixture was stirred at r.t. for 30 mins. Then 4 N HCl in dioxane
was added (1 mL), and the reaction mixture was heated to 80 degrees
for 30 mins. The mixture was then diluted with methanol and
purified directly on prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to provide the desired product. LC-MS calculated for
C.sub.17H.sub.16F.sub.2N.sub.7 [M+H].sup.+ m/z: 356.2, found
356.2.
Example 85
1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidi-
n-5-yl)phenyl)-N-methylethanamine
##STR00156##
[0728] Step 1.
1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)eth-
oxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)ethanone
##STR00157##
[0730] To a solution of
3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy-
)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde (100 mg,
0.213 mmol) in THF (2.1 mL) at 0.degree. C. was added
methylmagnesium bromide (1 M in THF, 213 .mu.l, 0.638 mmol). The
reaction mixture was warmed up to r.t. and stirred for 1 hr, and
then quenched with sat. ammonium chloride and extracted with ethyl
acetate. The organic layer was dried over sodium sulfate and
concentrated. To the residue was added DCM (2 mL) and manganese
dioxide (185 mg, 2.125 mmol). After stirring at 60.degree. C. for 1
hr, the mixture was filtered through a plug of Celite and
concentrated. The residue was purified by Biotage Isolera.TM.
(flash purification system with dichloromethane/methanol at a ratio
from 2 to 10%) to provide the desired product as a white solid.
LCMS calculated for C.sub.23H.sub.27F.sub.2N.sub.6O.sub.2Si
[M+H].sup.+ m/z: 485.2; Found: 485.2.
Step 2.
1-(3,5-Dilltioro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d-
]pyrimidin-5-yl)phenyl)-N-methylethanamine
[0731] A solution of
1-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)eth-
oxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)ethan-1-one (25
mg, 0.052 mmol), methanamine (0.129 ml, 0.258 mmol) in toluene (1
ml) was stirred at 80.degree. C. overnight. The reaction mixture
was then concentrated and redissolved in methanol (1 ml). Sodium
borohydride (5.86 mg, 0.155 mmol) was then added, and the mixture
was stirred at r.t. for 30 mins. 4N HCl in dioxane was then added
and stirring was continued at 80.degree. C. for 30 mins. The
mixture was then diluted with methanol and purified directly on
prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min)
to provide the desired product. LC-MS calculated for
C.sub.18H.sub.18F.sub.2N.sub.7 [M+H].sup.+ m/z: 370.2, found
370.2.
Example 86
1-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]py-
rimidin-5-yl)phenyl)-N-methylmethanamine
##STR00158##
[0732] Step 1.
(3-Fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)methanol
##STR00159##
[0734] To a solution of (3-fluoro-5-methoxyphenyl)methanol (575 mg,
3.68 mmol) in THF (18 mL) at -78.degree. C. was added n-BuLi (1.6 M
in hexanes, 4.8 mL, 7.73 mmol) and the reaction mixture was stirred
at -78.degree. C. for 1 hr. Then
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1581 .mu.l,
7.73 mmol) was added dropwise and stirring was continued at
-78.degree. C. for 0.5 hrs, then the mixture was warmed to r.t. by
removal from the cold bath. When room temperature was reached, the
reaction mixture was then quenched with 1N HCl until acidic and
extracted with ethyl acetate. The organic layer was dried over
sodium sulfate and concentrated. The crude residue was used in the
next step without further purification.
Step 2.
(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimeth-
ylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yhphenyl)methanol
##STR00160##
[0736] To a mixture of
5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-pyrazolo[4,3-d]pyrimidine (500 mg, 1.370 mmol),
(3-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)methanol (1160 mg, 4.11 mmol), XPhos Pd G2 (108 mg, 0.137 mmol)
and potassium phosphate (582 mg, 2.74 mmol) were added 1,4-dioxane
(3.6 mL) and water (900 .mu.l). The reaction flask was evacuated,
back filled with nitrogen, and the reaction mixture was then
stirred at 95.degree. C. for 2 hours. The mixture was diluted with
DCM and filtered through a pad of Celite. The filtrate was
concentrated and purified by Biotage Isolera.TM. (flash
purification system with dichlromethane/methanol at a ratio from 2
to 10%) to provide the desired product as an oil. LCMS calculated
for C.sub.23H.sub.30FN.sub.6O.sub.3Si [M+H].sup.+ m/z: 485.2;
Found: 485.2.
Step 3.
3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethy-
lsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde
##STR00161##
[0738] To a solution of
(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl-
)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)methanol
(309 mg, 0.638 mmol) in DCM (6.4 mL) was added manganese dioxide
(554 mg, 6.38 mmol) and the reaction mixture was heated to
60.degree. C. for 1 h, then cooled, filtered through a plug of
Celite and concentrated. The residue was purified by Biotage
Isolera.TM. (flash purification system with dichlromethane/methanol
at a ratio from 2 to 10%) to provide the desired product as an oil.
LCMS calculated for C.sub.23H.sub.28FN.sub.6O.sub.3Si [M+H].sup.+
m/z: 483.2; Found: 483.2.
Step 4.
1-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[-
4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine
[0739] To a solution of
3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde (25
mg, 0.052 mmol) and methanamine (2 M in THF, 0.130 ml, 0.259 mmol)
in toluene (1 ml) was added acetic acid (8.90 .mu.l, 0.155 mmol)
and the reaction mixture was heated to 80.degree. C. overnight. The
mixture was then cooled down to r.t. and concentrated. The residue
was redissolved in MeOH (1 ml) and sodium borohydride (1.960 mg,
0.052 mmol) was added. After 30 mins, 4 N HCl in dioxane was added
(1 mL) and the mixture heated to 80.degree. C. for 30 mins, then
diluted with methanol and purified directly on prep-LCMS (XBridge
C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to provide the
desired product. LC-MS calculated for C.sub.18H.sub.19FN.sub.7O
[M+H].sup.+ m/z: 368.2, found 368.2.
Example 87
N-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]py-
rimidin-5-yl)benzyl)ethanamine
##STR00162##
[0741] This compound was prepared using procedures analogous to
those for example 86, with ethyl amine (88% in water) replacing
methylamine. LCMS calculated for C.sub.19H.sub.21FN.sub.7O
[M+H].sup.+ m/z: 382.2; Found: 382.2.
Example 88
5-(2-Fluoro-6-methoxyphenyl)-3-(3-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3--
d]pyrimidine
##STR00163##
[0743] This compound was prepared using procedures analogous to
those for Example 12, with
3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
replacing phenylboronic acid as starting material. LCMS calculated
for C.sub.16H.sub.14FN.sub.6O [M+H].sup.+ m/z: 325.2; Found:
325.2.
Example 89
3-(Benzyloxy)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine
##STR00164##
[0745] To a mixture of
5-(2-fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)--
1H-pyrazolo[4,3-d]pyrimidine (30 mg, 0.060 mmol, Example 12, Step
5), benzyl alcohol (62.3 .mu.L, 0.600 mmol), cesium carbonate (58.6
mg, 0.180 mmol) and t-BuBrettPhos Pd G3 (4 mg) was added
1,4-dioxane (700 .mu.L). The reaction flask was evacuated, back
filled with nitrogen, and the reaction mixture was then stirred at
100.degree. C. overnight. The reaction mixture was quenched with
water and extracted with ethyl acetate. The organic layer was dried
over sodium sulfate and concentrated. To the residue were added
methanol (1 mL) and HCl (4M in dioxane, 1 mL). After stirring at
80.degree. C. for 1 hr, the mixture was diluted with methanol and
purified directly on prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to provide the desired product. LC-MS calculated for
C.sub.19H.sub.16FN.sub.4O.sub.2 [M+H].sup.+ m/z: 351.2, found
351.2.
Example 90
6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-
-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00165##
[0746] Step 1.
N-(3,5-Difluorophenethyl)-2,2,2-trifluoroacetamide
##STR00166##
[0748] To a solution of 2-(3,5-difluorophenyl)ethan-1-amine (AURUM
Pharmatech, 5.023 g, 32.0 mmol) in CH.sub.2Cl.sub.2 (100.0 mL) was
added triethylamine (9.90 mL, 71.0 mmol). The mixture was cooled to
-15.degree. C. Then trifluoroacetic anhydride (6.15 mL, 43.6 mmol)
was added dropwise. The mixture was allowed to warm to room
temperature. After stirring at room temperature for 30 mins, the
reaction mixture was poured into ice and extracted with
CH.sub.2Cl.sub.2. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to give the crude
product as a pale yellow solid that was used directly in the next
step without further purification (8.96 g). LCMS calculated for
C.sub.10H.sub.9F.sub.5NO (M+H).sup.+ m/z=254.1; found 254.2.
Step 2.
1-(6,8-Difluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet-
hanone
##STR00167##
[0750] To a solution of
N-(3,5-difluorophenethyl)-2,2,2-trifluoroacetamide (6.29 g, 24.84
mmol) in acetic acid (80.0 ml) at 0.degree. C. was added sulfuric
acid (50.0 ml) slowly. Then paraformaldehyde (1.967 g, 65.5 mmol)
was added. The mixture was allowed to warm to room temperature and
stirred for 5 h. The mixture was poured into ice, and extracted
with EtOAc. The organic layer was washed with 2 M
K.sub.2CO.sub.3(aq), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified on silica gel
(120 g, 0-100% EtOAc in hexanes) to give the desired product as a
white solid (3.867 g, 59%). LCMS calculated for
C.sub.11H.sub.9F.sub.5NO (M+H).sup.+ m/z=266.1; found 266.1.
Step 3. tert-Butyl
6,8-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00168##
[0752] To a solution of
1-(6,8-difluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-o-
ne (3.867 g, 14.58 mmol) in MeOH (70.0 ml) was added potassium
carbonate (6.56 g, 47.5 mmol) followed by H.sub.2O (25.0 ml). The
mixture was stirred at 50.degree. C. for 2 h. After cooling to room
temperature, the mixture was diluted with CH.sub.2Cl.sub.2 and
washed with brine. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
dissolved in CH.sub.2Cl.sub.2 (50 ml). Boc-anhydride (3.56 g, 16.31
mmol) was added followed by DMAP (548.6 mg, 4.49 mmol). The
reaction mixture was stirred at room temperature for 30 mins and
MeOH (50 ml) was added. The reaction was concentrated. The residue
was purified on silica gel (120 g, 0-50% EtOAc in hexanes) to give
the desired product as a colorless oil (3.77 g, 96%). LCMS
calculated for C.sub.10H.sub.10F.sub.2NO.sub.2
(M+H--C.sub.4H.sub.8).sup.+: m/z=214.1; found: 214.1.
Step 4. tert-Butyl
6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroi-
soquinoline-2(1H)-carboxylate
##STR00169##
[0754] To a solution of tert-butyl
6,8-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.76 g,
13.96 mmol) in THF (100.0 ml) under N.sub.2 at -78.degree. C. was
added a solution of LDA (1.0 M in THF/hexanes) (36.0 ml, 36.0 mmol)
dropwise via syringe over a period of 40 mins. The reaction was
allowed to warm to -60.degree. C. and stirred for 60 mins. The
reaction was then cooled back to -78.degree. C.
2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.52 ml,
51.5 mmol) was added slowly over a period of 20 min. After stirring
at -78.degree. C. for 20 min, the reaction mixture was allowed to
warm to room temperature and stirred for 2 h. The reaction mixture
was quenched with sat. NaHCO.sub.3, and extracted with Et.sub.2O.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified on silica gel
(120 g, 0-50% EtOAc in hexanes) to give the desired product as a
white solid (4.11 g, 75%). LCMS calculated for
C.sub.16H.sub.21BF.sub.2NO.sub.4 (M+H--C.sub.4H.sub.8).sup.+:
m/z=340.2; found: 340.1.
Step 5. tert-Butyl
5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate
##STR00170##
[0756] To a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine
(3.034 g, 19.63 mmol) in CH.sub.2Cl.sub.2 (100.0 ml) was added
boc-anhydride (7.15 ml, 30.8 mmol) followed by DMAP (728.8 mg, 5.97
mmol). The reaction was stirred at room temperature for 16 h. MeOH
(50 ml) was added. The mixture was stirred at room temperature for
2 h, and then concentrated. The residue was purified on silica gel
(120 g, 0-100% EtOAc in hexanes) to give the desired product as a
white solid (3.78 g, 76%). LCMS calculated for
C.sub.10H.sub.12ClN.sub.4O.sub.2 (M+H).sup.+ m/z=255.1; found
255.1.
Step 6. tert-Butyl
7-(1-(tert-butoxycarbonyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-difluoro-
-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00171##
[0758] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (1388 mg, 5.45
mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 807.5 mg, 1.026
mmol) and cesium carbonate (4851 mg, 14.89 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroi-
soquinoline-2(1H)-carboxylate (2.054 g, 5.20 mmol) in 1,4-dioxane
(15.00 ml) was added via syringe, followed by water (6.00 ml). The
reaction was stirred at 60.degree. C. for 2 h. The separated
organic layer was concentrated. The residue was purified on silica
gel (120 g, 0-100% EtOAc in hexanes) to give the desired product as
a yellow foamy solid (2.410 g, 95%). LCMS calculated for
C.sub.24H.sub.27F.sub.2N.sub.5NaO.sub.4 (M+Na).sup.+ m/z=510.2;
found 510.2.
Step 7. tert-Butyl
6,8-difluoro-7-(1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxylate
##STR00172##
[0760] To a mixture of tert-butyl
7-(1-(tert-butoxycarbonyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-difluoro-
-3,4-dihydroisoquinoline-2(1H)-carboxylate (2410 mg, 4.94 mmol),
potassium carbonate (4755 mg, 34.4 mmol) was added 1,4-dioxane
(25.0 ml) followed by water (25.0 ml). The mixture was stirred at
80.degree. C. for 10 h. After cooling to room temperature, the
mixture was diluted with CH.sub.2Cl.sub.2, and washed with brine.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give the crude product as a yellow
solid that was used directly in the next step without further
purification. LCMS calculated for
C.sub.19H.sub.20F.sub.2N.sub.5O.sub.2 (M+H).sup.+ m/z=388.2; found
388.1.
Step 8. tert-Butyl
7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-d-
ifluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00173##
[0762] To a solution of tert-butyl
6,8-difluoro-7-(1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxylate (step 7) in DMF (30.0 ml) was added
N-iodosuccinimide (1342 mg, 5.96 mmol). The mixture was stirred at
80.degree. C. for 90 mins, and then cooled to room temperature.
Boc-anhydride (1753 mg, 8.03 mmol) was added followed by DMAP
(243.4 mg, 1.992 mmol). The reaction was stirred at room
temperature for 20 mins. The mixture was diluted with
CH.sub.2Cl.sub.2, and washed with sat. NaHCO.sub.3 (aq). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified on silica gel (120 g,
0-100% EtOAc in hexanes) to give the desired product as a white
foamy solid (2041 mg, 67% over 2 steps). LCMS calculated for
C.sub.24H.sub.27F.sub.2IN.sub.5O.sub.4 (M+H).sup.+ m/z=614.1; found
614.1.
Step 9.
6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyra-
zolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
[0763] To a screw-cap vial equipped with a magnetic stir bar was
added
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine (22.5 mg, 0.074 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 6.0 mg, 7.63
.mu.mol) and cesium carbonate (56.7 mg, 0.174 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-d-
ifluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (30.0 mg, 0.049
mmol) in 1,4-dioxane (2.00 ml) was added via syringe, followed by
water (200.0 .mu.l). The reaction was heated to 50.degree. C. for
16 h. The reaction was concentrated. To the residue was added
CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room temperature for 15 mins, and then concentrated. The
residue was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product. LCMS calculated
for C.sub.24H.sub.25F.sub.2N.sub.8 (M+H).sup.+: m/z=463.2; found:
463.3.
Example 91
2-(5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3--
d]pyrimidin-3-yl)pyrimidin-2-ylamino)ethanol
##STR00174##
[0765] This compound was prepared according to the procedure
described in Example 90 (step 9), using
2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylamino)eth-
anol instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.20H.sub.19F.sub.2N.sub.8O (M+H).sup.+: m/z=425.2; found:
425.2.
Example 92
6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4-
,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00175##
[0767] This compound was prepared according to the procedure
described in Example 90 (step 9), using
2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)pyrimidine instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.23H.sub.24F.sub.2N.sub.9 (M+H).sup.+: m/z=464.2; found:
464.3.
Example 93
5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]p-
yrimidin-3-yl)-N,N-dimethylpyrimidin-2-amine
##STR00176##
[0769] This compound was prepared according to the procedure
described in Example 90 (step 9), using
N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-a-
mine instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.20H.sub.19F.sub.2N.sub.8 (M+H).sup.+: m/z=409.2; found:
409.3.
Example 94
5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]p-
yrimidin-3-yl)-N-methylpyrimidin-2-amine
##STR00177##
[0771] This compound was prepared according to the procedure
described in Example 90 (step 9), using
N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine
instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.19H.sub.17F.sub.2N.sub.8 (M+H).sup.+: m/z=395.2; found:
395.2.
Example 95
N-(4-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3--
d]pyrimidin-3-yl)benzyl)methanesulfonamide
##STR00178##
[0773] This compound was prepared according to the procedure
described in Example 90 (step 9), using
4-(methylsulfonamidomethyl)phenylboronic acid instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.22H.sub.21F.sub.2N.sub.6O.sub.2S (M+H).sup.+: m/z=471.1;
found: 471.2.
Example 96
7-(3-(4-(Azetidin-1-ylsulfonyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-
,8-difluoro-1,2,3,4-tetrahydroisoquinoline
##STR00179##
[0775] This compound was prepared according to the procedure
described in Example 90 (step 9), using
4-(azetidin-1-ylsulfonyl)phenylboronic acid instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.23H.sub.21F.sub.2N.sub.6O.sub.2S (M+H).sup.+: m/z=483.1;
found: 483.2.
Example 97
7-(3-(6-(Difluoromethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-
,8-difluoro-1,2,3,4-tetrahydroisoquinoline
##STR00180##
[0777] This compound was prepared according to the procedure
described in Example 90 (step 9), using
2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
ne instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.20H.sub.15F.sub.4N.sub.6O (M+H).sup.+: m/z=431.1; found:
431.2.
Example 98
4-(5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3--
d]pyrimidin-3-yl)pyridin-2-yl)morpholine
##STR00181##
[0779] This compound was prepared according to the procedure
described in Example 90 (step 9), using
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.23H.sub.22F.sub.2N.sub.7O (M+H).sup.+: m/z=450.2; found:
450.2. .sup.1H NMR (TFA salt, 500 MHz, DMSO) .delta. 9.50 (s, 1H),
9.30 (br, 2H), 9.17 (d, J=2.2 Hz, 1H), 8.44 (dd, J=9.0, 2.2 Hz,
1H), 7.25 (d, J=9.9 Hz, 1H), 7.04 (d, J=9.0 Hz, 1H), 4.35 (s, 2H),
3.76-3.66 (m, 4H), 3.57-3.49 (m, 4H), 3.44 (m, 2H), 3.11 (t, J=6.1
Hz, 2H).
Example 99
6,8-Difluoro-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyr-
imidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00182##
[0781] This compound was prepared according to the procedure
described in Example 90 (step 9), using
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperaz-
ine instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.25H.sub.26F.sub.2N.sub.7 (M+H).sup.+: m/z=462.2; found:
462.3. .sup.1H NMR (TFA salt, 600 MHz, DMSO) .delta. 10.12 (br,
1H), 9.48 (s, 1H), 9.42 (br, 2H), 8.30 (d, J=8.9 Hz, 2H), 7.25 (d,
J=9.8 Hz, 1H), 7.16 (d, J=8.9 Hz, 2H), 4.34 (s, 2H), 3.95 (m, 2H),
3.53 (m, 2H), 3.45 (m, 2H), 3.17 (m, 2H), 3.11 (t, J=6.1 Hz, 2H),
3.06 (m, 2H), 2.86 (s, 3H).
Example 100
8-Methoxy-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimi-
din-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00183##
[0782] Step 1. tert-Butyl
5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate
##STR00184##
[0784] To a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (4.97
g, 32.2 mmol) in DMF (120.0 ml) was added N-iodosuccinimide (7.967
g, 35.4 mmol). The mixture was stirred at 80.degree. C. for 1 h.
After cooling to room temperature, boc-anhydride (11.32 ml, 48.8
mmol) was added followed by DMAP (1.296 g, 10.61 mmol). The
reaction was stirred at room temperature for 20 mins. The mixture
was diluted with Et.sub.2O and washed with water. The organic layer
was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified on silica gel (120 g, 0-100%
EtOAc in hexanes) to give the desired product as a white solid
(4.435 g, 49%). LCMS calculated for
C.sub.10H.sub.11ClIN.sub.4O.sub.2 (M+H).sup.+ m/z=381.0; found
381.0.
Step 2. tert-Butyl
5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-
e-1-carboxylate
##STR00185##
[0786] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (700.0
mg, 1.839 mmol), (4-(4-methylpiperazin-1-yl)phenyl)boronic acid
(509.0 mg, 2.313 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (300.1 mg, 0.367 mmol) and
cesium carbonate (1991 mg, 6.11 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). 1,4-Dioxane (10.0 ml)
was added, followed by water (3.0 ml). The reaction mixture was
stirred at 50.degree. C. for 16 h. After cooling to room
temperature, the mixture was diluted with CH.sub.2Cl.sub.2, and
washed with brine. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes then 10% MeOH
in CH.sub.2Cl.sub.2) to give the desired product as a brown solid
(752.2 mg, 95%). LCMS calculated for
C.sub.21H.sub.26ClN.sub.6O.sub.2 (M+H).sup.+ m/z=429.2; found
429.2.
Step 3. tert-Butyl
5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00186##
[0788] To a solution of
5-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinoline, HCl salt (857.7
mg, 3.08 mmol) in CH.sub.2Cl.sub.2 (10.0 ml) was added
N,N-diisopropylethylamine (1.209 ml, 6.92 mmol). The mixture was
stirred at room temperature for 10 mins, and then a solution of
boc-anhydride (828.2 mg, 3.79 mmol) in CH.sub.2Cl.sub.2 (5.0 ml)
was added. After stirring at room temperature for 30 mins, the
reaction was concentrated. The residue was purified on silica gel
(40 g, 0-100% EtOAc in hexanes) to give the desired product as an
oil (1.048 g, 99%). LCMS calculated for C.sub.11H.sub.13BrNO.sub.3
(M+H--C.sub.4H.sub.8).sup.+: m/z=286.0; found: 286.0.
Step 4. tert-Butyl
8-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoq-
uinoline-2(1H)-carboxylate
##STR00187##
[0790] To a screw-cap vial equipped with a magnetic stir bar was
added
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(1174 mg, 4.62 mmol), potassium acetate (1214 mg, 12.37 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (500.3 mg, 0.613 mmol). The
vial was sealed with a Teflon-lined septum, evacuated and
backfilled with nitrogen (this process was repeated a total of
three times). A solution of tert-butyl
5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1048
mg, 3.06 mmol) in 1,4-dioxane (15.0 mL) was added via syringe. The
mixture was stirred at 100.degree. C. for 16 h. After cooling to
room temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes)
to give the desired product (959.8 mg, 81%). LCMS calculated for
C.sub.17H.sub.25BNO.sub.5 (M+H--C.sub.4H.sub.8).sup.+: m/z=334.2;
found: 334.1.
Step 5.
8-Methoxy-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
[0791] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-
e-1-carboxylate (39.7 mg, 0.093 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 9.0 mg, 0.011
mmol) and cesium carbonate (81.5 mg, 0.250 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
8-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoq-
uinoline-2(1H)-carboxylate (29.7 mg, 0.076 mmol) in 1,4-dioxane
(2.00 ml) was added via syringe, followed by water (200.0 .mu.l).
The reaction was heated to 50.degree. C. for 16 h. The reaction was
concentrated. To the residue was added CH.sub.2Cl.sub.2 (2.0 mL)
followed by TFA (2.0 mL). The mixture was stirred at room
temperature for 15 min, and then concentrated. The residue was
purified using prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to afford the desired product. LCMS calculated for
C.sub.26H.sub.30N.sub.7O (M+H).sup.+: m/z=456.3; found: 456.2.
Example 101
8-Fluoro-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)quinoline
##STR00188##
[0793] This compound was prepared according to the procedure
described in Example 100 (step 5), using
8-fluoroquinolin-7-ylboronic acid instead of tert-butyl
8-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoq-
uinoline-2(1H)-carboxylate as the starting material. LCMS
calculated for C.sub.25H.sub.23FN.sub.7 (M+H).sup.+: m/z=440.2;
found: 440.2.
Example 102
5-(4-Methoxypyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo-
[4,3-d]pyrimidine
##STR00189##
[0795] This compound was prepared according to the procedure
described in Example 100 (step 5), using
4-methoxypyridin-3-ylboronic acid instead of tert-butyl
8-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoq-
uinoline-2(1H)-carboxylate as the starting material. LCMS
calculated for C.sub.22H.sub.24N.sub.7O (M+H).sup.+: m/z=402.2;
found: 402.2.
Example 103
5-(4-Methoxypyridin-3-yl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-py-
razolo[4,3-d]pyrimidine
##STR00190##
[0796] Step 1. tert-Butyl
5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyr-
imidine-1-carboxylate
##STR00191##
[0798] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (900.0
mg, 2.365 mmol),
1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine (732.2 mg, 2.415 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complexed with dichloromethane (1:1) (386.1 mg, 0.473 mmol) and
cesium carbonate (2621 mg, 8.04 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). 1,4-Dioxane (10.0 ml)
was added, followed by water (3.0 ml). The reaction was stirred at
50.degree. C. for 16 h. After cooling to room temperature, the
mixture was diluted with CH.sub.2Cl.sub.2, and washed with brine.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified on silica gel
(40 g, 0-100% EtOAc in hexanes then 10% MeOH in CH.sub.2Cl.sub.2)
to give the desired product as a yellow solid (746.2 mg, 73%). LCMS
calculated for C.sub.20H.sub.25ClN.sub.7O.sub.2 (M+H).sup.+
m/z=430.2; found 430.2.
Step 2.
5-(4-Methoxypyridin-3-yl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-y-
l)-1H-pyrazolo[4,3-d]pyrimidine
[0799] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyr-
imidine-1-carboxylate (24.7 mg, 0.057 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 7.0 mg, 8.90
.mu.mol) and cesium carbonate (66.2 mg, 0.203 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of (4-methoxypyridin-3-yl)boronic acid (23.6 mg, 0.154
mmol) in 1,4-dioxane (2.00 ml) was added via syringe, followed by
water (200.0 .mu.l). The reaction was heated to 50.degree. C. for
16 h. The reaction was concentrated. To the residue was added
CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room temperature for 15 min, and then concentrated. The
residue was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product. LCMS calculated
for C.sub.21H.sub.23N.sub.8O (M+H).sup.+: m/z=403.2; found:
403.2.
Example 104
N-Methyl-1-(4-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4-
,3-d]pyrimidin-5-yl)pyridin-2-yl)methanamine
##STR00192##
[0800] Step 1. tert-Butyl
(5-bromo-4-methylpyridin-2-yl)methyl(methyl)carbamate
##STR00193##
[0802] To a solution of 5-bromo-4-methylpicolinaldehyde (1.044 g,
5.22 mmol) in MeOH (20.0 ml) was added 2.0 M methylamine in MeOH
(8.0 ml, 16.00 mmol) followed by sodium cyanoborohydride (1.313 g,
20.89 mmol) and acetic acid (1.00 ml, 17.47 mmol). After stirring
at room temperature for 90 mins, the reaction was quenched with HCl
(6.0 N in water) (25.0 ml, 150 mmol). The mixture was stirred at
room temperature for 30 mins, and treated with NaOH (4 N in water)
until pH reached 10. The mixture was extracted with Et.sub.2O. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated. The residue was dissolved in CH.sub.2Cl.sub.2 (30
mL), and treated with Boc-anhydride (1.198 g, 5.49 mmol). After
stirring at room temperature for 30 mins, the reaction was
concentrated. The residue was purified on silica gel (40 g, 0-100%
EtOAc in hexanes) to give the desired product as a yellow oil
(1.101 g, 67%). LCMS calculated for
C.sub.13H.sub.20BrN.sub.2O.sub.2 (M+H).sup.+ m/z=315.1; found
315.0.
Step 2. tert-Butyl
methyl((4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-
-yl)methyl)carbamate
##STR00194##
[0804] To a screw-cap vial equipped with a magnetic stir bar was
added
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(1.216 g, 4.79 mmol), potassium acetate (1.143 g, 11.65 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (450.3 mg, 0.551 mmol). The
vial was sealed with a Teflon-lined septum, evacuated and
backfilled with nitrogen (this process was repeated a total of
three times). A solution of tert-butyl
((5-bromo-4-methylpyridin-2-yl)methyl)(methyl)carbamate (1.101 g,
3.49 mmol) in 1,4-dioxane (17.0 ml) was added via syringe. The
mixture was stirred at 80.degree. C. for 16 h. After cooling to
room temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes
then 10% MeOH in CH.sub.2Cl.sub.2) to give the desired product
(461.0 mg, 36%).
Step 3.
N-Methyl-1-(4-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-py-
razolo[4,3-d]pyrimidin-5-yl)pyridin-2-yl)methanamine
[0805] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-
e-1-carboxylate (47.0 mg, 0.110 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 13.0 mg, 0.017
mmol) and cesium carbonate (115.5 mg, 0.354 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
methyl((4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-
-yl)methyl)carbamate (59.8 mg, 0.165 mmol) in 1,4-dioxane (3.00 ml)
was added via syringe, followed by water (300.0 .mu.l). The
reaction was heated to 50.degree. C. for 16 h. The reaction was
concentrated. To the residue was added CH.sub.2Cl.sub.2 (2.0 mL)
followed by TFA (2.0 mL). The mixture was stirred at room
temperature for 15 mins, and then concentrated. The residue was
purified using prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to afford the desired product. LCMS calculated for
C.sub.24H.sub.29N.sub.8 (M+H).sup.+: m/z=429.3; found: 429.3.
Example 105
2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazol-
o[4,3-d]pyrimidin-5-yl)phenyl)acetonitrile
##STR00195##
[0806] Step 1. 4-(4-Bromo-3,5-difluorophenyl)isoxazole
##STR00196##
[0808] To a screw-cap vial equipped with a magnetic stir bar was
added 2-bromo-1,3-difluoro-5-iodobenzene (1360.8 mg, 4.27 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (828.0 mg,
4.25 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium
(II) dichloromethane adduct (727.0 mg, 0.890 mmol) and cesium
carbonate (2843 mg, 8.73 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). 1,4-Dioxane (12.0 ml)
was added via syringe followed by water (2.0 ml). The reaction was
heated to 50.degree. C. for 16 h. After cooling to room
temperature, the organic layer was separated and concentrated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes)
to give the desired product as a pale yellow solid (502.9 mg,
46%).
Step 2. 2-(4-Bromo-3,5-difluorophenyl)acetonitrile
##STR00197##
[0810] To a mixture of 4-(4-bromo-3,5-difluorophenyl)isoxazole
(489.4 mg, 1.882 mmol) and potassium fluoride (584.8 mg, 10.07
mmol) was added DMF (5.0 ml) followed by water (5.0 ml). The
reaction was heated to 90.degree. C. for 3 h. After cooling to room
temperature, the mixture was diluted with CH.sub.2Cl.sub.2, and
washed with brine. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the
desired product as an off-white solid (363.4 mg, 83%).
Step 3.
2-(3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl)acetonitrile
##STR00198##
[0812] To a screw-cap vial equipped with a magnetic stir bar was
added
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(607.8 mg, 2.393 mmol), potassium acetate (643.7 mg, 6.56 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complexed with dichloromethane (1:1) (256.1 mg, 0.314 mmol). The
vial was sealed with a Teflon-lined septum, evacuated and
backfilled with nitrogen (this process was repeated a total of
three times). A solution of
2-(4-bromo-3,5-difluorophenyl)acetonitrile (363.4 mg, 1.566 mmol)
in 1,4-dioxane (10.0 mL) was added via syringe. The mixture was
stirred at 100.degree. C. for 16 h. After cooling to room
temperature, the reaction mixture was diluted with CH.sub.2Cl.sub.2
and filtered. The filtrate was concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes then 10% MeOH
in CH.sub.2Cl.sub.2) to give the desired product (229.4 mg, 53%).
LCMS calculated for C.sub.14H.sub.17BF.sub.2NO.sub.2 (M+H).sup.+:
m/z=280.1; found: 280.0.
Step 4. tert-Butyl
5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]p-
yrimidine-1-carboxylate
##STR00199##
[0814] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (1026.0
mg, 2.70 mmol),
2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)pyrimidine (816.5 mg, 2.68 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (440.2 mg, 0.539 mmol) and
cesium carbonate (2693 mg, 8.27 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). 1,4-Dioxane (12.0 ml)
was added, followed by water (4.0 ml). The reaction was stirred at
50.degree. C. for 16 h. After cooling to room temperature, the
mixture was diluted with CH.sub.2Cl.sub.2, and washed with brine.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified on silica gel
(40 g, 0-100% EtOAc in hexanes then 10% MeOH in CH.sub.2Cl.sub.2)
to give the desired product as a yellow solid (877.3 mg, 76%). LCMS
calculated for C.sub.19H.sub.24ClN.sub.8O.sub.2 (M+H).sup.+
m/z=431.2; found 431.1.
Step 5.
2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-
-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)acetonitrile
[0815] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]p-
yrimidine-1-carboxylate (33.3 mg, 0.077 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (9.0 mg, 0.011 mmol) and cesium
carbonate (83.0 mg, 0.255 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). A solution of
2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ace-
tonitrile (34.6 mg, 0.124 mmol) in 1,4-dioxane (2.0 ml) was added
via syringe, followed by water (200.0 .mu.l). The reaction was
heated to 50.degree. C. for 16 h. The reaction was concentrated. To
the residue was added CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA
(2.0 mL). The mixture was stirred at room temperature for 15 mins,
and then concentrated. The residue was purified using prep-LCMS
(XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to afford the
desired product. LCMS calculated for C.sub.22H.sub.20F.sub.2N.sub.9
(M+H).sup.+: m/z=448.2; found: 448.2.
Example 106
6-Fluoro-5-(3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d-
]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00200##
[0816] Step 1. 5-Bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline
##STR00201##
[0818] To a solution of 5-bromo-6-fluoroisoquinoline (1.002 g,
4.433 mmol) in acetic acid (20.0 mL) at room temperature was added
sodium tetrahydroborate (592.0 mg, 15.65 mmol) portion wise. The
mixture was stirred at room temperature for 16 h, and then
concentrated. The residue was diluted with CH.sub.2Cl.sub.2 and
washed with 2 M Na.sub.2CO.sub.3 (aq). The separated organic layer
was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to give a yellow oil that was used directly in the
next step without further purification. LCMS calculated for
C.sub.9H.sub.10BrFN (M+H).sup.+ m/z=230.0; found 230.1.
Step 2. tert-Butyl
5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00202##
[0820] To a solution of
5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline (1.020 g, 4.433
mmol) in CH.sub.2Cl.sub.2 (12.0 mL) was added di-tert-butyl
dicarbonate (1.617 g, 7.409 mmol). The mixture was stirred at room
temperature for 1 h, and then concentrated. The residue was
purified on silica gel (120 g, 0-100% EtOAc in hexanes) to give the
desired product as a white solid (1.119 g, 76% over two steps).
LCMS calculated for C.sub.14H.sub.17BrFNNaO.sub.2 (M+Na).sup.+
m/z=352.0; found 352.0.
Step 3. tert-Butyl
6-fluoro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxylate
##STR00203##
[0822] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.119
g, 3.389 mmol),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(1.358 g, 5.348 mmol), potassium acetate (1.101 g, 11.22 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (298.6 mg, 0.366 mmol). The
vial was sealed with a Teflon-lined septum, evacuated and
backfilled with nitrogen (this process was repeated a total of
three times). 1,4-Dioxane (15.0 mL) was added via syringe. The
mixture was heated at 100.degree. C. for 16 h. After cooling to
room temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes)
to give the desired product as a pale yellow oil (1001 mg, 78%).
LCMS calculated for C.sub.20H.sub.29BFNNaO.sub.4 (M+Na).sup.+
m/z=400.2; found 400.2.
Step 4. tert-Butyl
5-chloro-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d]p-
yrimidine-1-carboxylate
##STR00204##
[0824] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (1126.0
mg, 2.96 mmol),
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperaz-
ine (949.2 mg, 3.00 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (450.5 mg, 0.552 mmol) and
cesium carbonate (2892.3 mg, 8.88 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). 1,4-Dioxane (12.0 ml)
was added via syringe, followed by water (4.0 ml). The reaction was
stirred at 50.degree. C. for 16 h. After cooling to room
temperature, the mixture was diluted with CH.sub.2Cl.sub.2, and
washed with brine. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes then 10% MeOH
in CH.sub.2Cl.sub.2) to give the desired product as a yellow solid
(927.3 mg, 71%). LCMS calculated for
C.sub.22H.sub.28ClN.sub.6O.sub.2 (M+H).sup.+ m/z=443.2; found
443.2.
Step 5.
6-Fluoro-5-(3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazo-
lo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
[0825] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d]p-
yrimidine-1-carboxylate (26.5 mg, 0.060 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 7.0 mg, 8.90
.mu.mol) and cesium carbonate (68.0 mg, 0.209 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxylate (22.6 mg, 0.060 mmol) in 1,4-dioxane (2.0
ml) was added via syringe, followed by water (200.0 .mu.l). The
reaction was heated to 50.degree. C. for 16 h. The reaction mixture
was concentrated. To the residue was added CH.sub.2Cl.sub.2 (2.0
mL) followed by TFA (2.0 mL). The resulting mixture was stirred at
room temperature for 15 min, and then concentrated. The residue was
purified using prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to afford the desired product. LCMS calculated for
C.sub.26H.sub.29FN.sub.7 (M+H).sup.+: m/z=458.2; found: 458.3.
Example 107
6-Fluoro-8-methyl-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazol-
o[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00205##
[0826] Step 1. (3-Bromo-4-fluoro-2-methylphenyl)methanol
##STR00206##
[0828] To a solution of ethyl 3-bromo-4-fluoro-2-methylbenzoate
(Enamine, 6.535 g, 25.03 mmol) in THF (60.0 ml) was added
BH.sub.3*THF (1.0 M in THF) (125 ml, 125 mmol). The mixture was
stirred at 65.degree. C. for 16 h. The reaction was cooled to room
temperature, and MeOH (100.0 ml) was added. After stirring at room
temperature for 2 h, the mixture was cooled to 0.degree. C. HCl
(4.0 M in water) (100 ml, 400 mmol) was added. The mixture was
extracted with Et.sub.2O. The separated organic layer was washed
with sat. NaHCO.sub.3, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give the crude product as a white
solid (5.35 g, 98%).
Step 2. 3-Bromo-4-fluoro-2-methylbenzaldehyde
##STR00207##
[0830] To a solution of (3-bromo-4-fluoro-2-methylphenyl)methanol
(5.35 g, 24.42 mmol) in CH.sub.2Cl.sub.2 (120.0 ml) was added
manganese dioxide (activated) (36.6 g, 379 mmol). The mixture was
stirred at room temperature for 16 h. The mixture was filtered
through a pad of Celite. The Celite pad was further rinsed with
CH.sub.2Cl.sub.2. The combined filtrate was concentrated. The
residue was purified on silica gel (120 g, 0-100% EtOAc in hexanes)
to give the desired product as a yellow solid (4.427 g, 84%).
Step 3.
N-(3-Bromo-4-fluoro-2-methylbenzylidene)-2,2-dimethoxyethanamine
##STR00208##
[0832] To a solution of 3-bromo-4-fluoro-2-methylbenzaldehyde
(6.086 g, 28.0 mmol) in toluene (100.0 ml) was added
2,2-dimethoxyethan-1-amine (3.13 mL, 28.6 mmol). The mixture was
refluxed for 16 h with a Dean-Stark trap. After cooling to room
temperature, the mixture was concentrated to give the crude product
that was used directly in next step without further purification.
LCMS calculated for C.sub.12H.sub.16BrFNO.sub.2 (M+H).sup.+
m/z=304.0; found 304.0.
Step 4. 7-Bromo-6-fluoro-8-methylisoquinoline
##STR00209##
[0834] To a solution of
1-(3-bromo-4-fluoro-2-methylphenyl)-N-(2,2-dimethoxyethyl)methanimine
(crude in step 3) in THF (100.0 ml) at -10.degree. C. was added
ethyl chloroformate (3.126 g, 28.8 mmol) dropwise. The mixture was
stirred at -10.degree. C. for 10 mins, and then allowed to warm to
room temperature and stirred for 2 h. Trimethyl phosphite (4.562 g,
36.8 mmol) was added. The mixture was stirred at room temperature
for 24 h, and then concentrated. The resulting oil was
re-evaporated three times with toluene to remove traces of
trimethyl phosphite. The residue was dissolved in CH.sub.2Cl.sub.2
(100.0 ml). A solution of TiCl.sub.4 (1.0 M in CH.sub.2Cl.sub.2)
(200.0 ml, 200 mmol) was added. The mixture was refluxed under
N.sub.2 for 72 h. After cooling to room temperature, the mixture
was poured into ice and treated with ammonium hydroxide (14.8 M in
water) until pH reached 10. The mixture was filtered through a pad
of Celite. The pad was rinsed with CH.sub.2Cl.sub.2. The organic
layer was separated, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified on silica gel
(120 g, 0-100% EtOAc in hexanes) to give the desired product as a
white solid (3.378 g, 50% over 2 steps). LCMS calculated for
C.sub.10H.sub.8BrFN (M+H).sup.+ m/z=240.0; found 240.0.
Step 5. tert-Butyl
7-bromo-6-fluoro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00210##
[0836] To a solution of 7-bromo-6-fluoro-8-methylisoquinoline
(3.378 g, 14.07 mmol) in acetic acid (100.0 ml) at room temperature
was added sodium tetrahydroborate (2042.3 mg, 54.0 mmol) portion
wise. The mixture was stirred at room temperature for 1 h, and MeOH
(100 ml) was added. The mixture was concentrated. The residue was
diluted with CH.sub.2Cl.sub.2, and washed with 2 M K.sub.2CO.sub.3
(aq). The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was dissolved in
CH.sub.2Cl.sub.2. Boc-anhydride (4.27 g, 19.56 mmol) was added
followed by DMAP (534.8 mg, 4.38 mmol). After stirring at room
temperature for 40 min, the mixture was treated with MeOH (20 ml)
and stirred for 2 h. The mixture was then concentrated. The residue
was purified on silica gel (120 g, 0-50% EtOAc in hexanes) to give
the desired product as a pale yellow solid (2.13 g, 44%). LCMS
calculated for C.sub.11H.sub.12BrFNO.sub.2
(M+H--C.sub.4H.sub.8).sup.+: m/z=288.0; found: 288.0.
Step 6. tert-Butyl
6-fluoro-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxylate
##STR00211##
[0838] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
7-bromo-6-fluoro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
(1083.9 mg, 3.15 mmol),
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(1076 mg, 4.24 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (514 mg, 0.630 mmol) and
potassium acetate (982.3 mg, 10.01 mmol). The vial was sealed with
a Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). 1,4-Dioxane (12.0 mL)
was added via syringe. The mixture was stirred at 100.degree. C.
for 16 h. After cooling to room temperature, the reaction mixture
was filtered. The filtrate was used directly in the next step.
Step 7. tert-Butyl
7-(1-(tert-butoxycarbonyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-fluoro-8-m-
ethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00212##
[0840] To a screw-cap vial equipped waft a magnetic stir oar was
added tert-butyl
5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (882.4 mg, 3.46
mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 372.5 mg, 0.473
mmol) and cesium carbonate (3138 mg, 9.63 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
6-fluoro-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxylate (step 6) in 1,4-dioxane (12.0
ml) was added via syringe, followed by water (4.0 ml). The reaction
was stirred at 50.degree. C. for 16 h. After cooling to room
temperature, the mixture was diluted with CH.sub.2Cl.sub.2 and
washed with brine. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the
desired product as a yellow foamy solid (735.5 mg, 48% over two
steps). LCMS calculated for C.sub.25H.sub.31FN.sub.5O.sub.4
(M+H).sup.+: m/z=484.2; found: 484.2.
Step 8. tert-Butyl
6-fluoro-8-methyl-7-(1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,4-dihydroisoquin-
oline-2(1H)-carboxylate
##STR00213##
[0842] To a solution of tert-butyl
7-(1-(tert-butoxycarbonyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-fluoro-8-m-
ethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (735.5 mg, 1.521
mmol) in 1,4-dioxane (8.0 ml) was added potassium carbonate (1552
mg, 11.23 mmol) followed by water (8.0 ml). The mixture was stirred
at 80.degree. C. for 10 h. After cooling to room temperature, the
mixture was diluted with Et.sub.2O and washed with brine. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated to give the crude product as a yellow solid that
was used directly in the next step without further purification.
C.sub.20H.sub.23FN.sub.5O.sub.2 (M+H).sup.+: m/z=384.2; found:
384.1.
Step 9. tert-Butyl
7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-flu-
oro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
##STR00214##
[0844] To a solution of tert-butyl
6-fluoro-8-methyl-7-(1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,4-dihydroisoquin-
oline-2(1H)-carboxylate (step 8) in DMF (10.0 ml) was added
N-iodosuccinimide (412.4 mg, 1.833 mmol). The mixture was stirred
at 60.degree. C. for 90 mins, and cooled to room temperature.
Boc-anhydride (494.2 mg, 2.264 mmol) was added followed by DMAP
(77.8 mg, 0.637 mmol). The reaction was stirred at room temperature
for 30 mins. The mixture was diluted with CH.sub.2Cl.sub.2 and
washed with sat. NaHCO.sub.3(aq). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give
the desired product (198.1 mg, 21% over 2 steps). LCMS calculated
for C.sub.25H.sub.30FIN.sub.5O.sub.4 (M+H).sup.+: m/z=610.1; found:
610.1.
Step 10.
6-Fluoro-8-methyl-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1-
H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
[0845] To a screw-cap vial equipped with a magnetic stir bar was
added
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine (18.0 mg, 0.059 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 5.0 mg, 6.35
.mu.mol) and cesium carbonate (50.1 mg, 0.154 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-flu-
oro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (25.0 mg,
0.041 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,
followed by water (200.0 .mu.l). The reaction was heated to
50.degree. C. for 16 h. The reaction was concentrated. To the
residue was added CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0
mL). The mixture was stirred at room temperature for 15 mins, and
then concentrated. The residue was purified using prep-LCMS
(XBridge C18 column, eluting with a gradient of acetonitrile/water
containing 0.1% TFA, at flow rate of 60 mL/min) to afford the
desired product. LCMS calculated for C.sub.25H.sub.28FN.sub.8
(M+H).sup.+: m/z=459.2; found: 459.2.
Example 108
1-(4-(4-(5-(6-Fluoro-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyraz-
olo[4,3-d]pyrimidin-3-yl)phenyl)piperazin-1-yl)ethanone
##STR00215##
[0847] This compound was prepared according to the procedure
described in Example 107 (step 10), using
1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-y-
l)ethanone instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.27H.sub.29FN.sub.7O (M+H).sup.+: m/z=486.2; found: 486.3.
Example 109
4-(5-(5-(6-Fluoro-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo-
[4,3-d]pyrimidin-3-yl)pyridin-2-yl)morpholine
##STR00216##
[0849] This compound was prepared according to the procedure
described in Example 107 (step 10), using
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.24H.sub.25FN.sub.7O (M+H).sup.+: m/z=446.2; found: 446.3.
Example 110
6-Fluoro-8-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazol-
o[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00217##
[0851] This compound was prepared according to the procedure
described in Example 107 (step 10), using
1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.25H.sub.28FN.sub.8 (M+H).sup.+: m/z=459.2; found: 459.2.
Example 111
6-Fluoro-8-methyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3--
d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00218##
[0853] This compound was prepared according to the procedure
described in Example 107 (step 10), using
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperaz-
ine instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)p-
iperazine as the starting material. LCMS calculated for
C.sub.26H.sub.29FN.sub.7 (M+H).sup.+: m/z=458.2; found: 458.3.
.sup.1H NMR (TFA salt, 500 MHz, DMSO) .delta. 10.14 (br, 1H), 9.46
(s, 1H), 9.36 (br, 2H), 8.29 (d, J=8.9 Hz, 2H), 7.14 (m, 3H), 4.25
(s, 2H), 3.93 (m, 2H), 3.52 (m, 2H), 3.40 (m, 2H), 3.16 (m, 2H),
3.09 (t, J=6.1 Hz, 2H), 3.03 (m, 2H), 2.86 (s, 3H), 1.98 (s,
3H).
Example 112
8-Fluoro-6-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazol-
o[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
##STR00219##
[0854] Step 1. tert-Butyl
8-fluoro-6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxylate
##STR00220##
[0856] This compound was prepared according to the procedures
described in Example 107 (step 3 to step 6), using
3-bromo-2-fluoro-4-methylbenzaldehyde (AstaTech) instead of
3-bromo-4-fluoro-2-methylbenzaldehyde (step 2 in Example 107) as
the starting material. LCMS calculated for
C.sub.21H.sub.31BFNNaO.sub.4 (M+Na).sup.+: m/z=414.2; found:
414.2.
Step 2.
8-Fluoro-6-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-
-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline
[0857] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyr-
imidine-1-carboxylate (42.8 mg, 0.100 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 9.0 mg, 0.011
mmol) and cesium carbonate (84.3 mg, 0.259 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
8-fluoro-6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxylate (31.7 mg, 0.081 mmol) in
1,4-dioxane (2.00 ml) was added via syringe, followed by water
(200.0 .mu.l). The reaction was heated to 50.degree. C. for 16 h.
The reaction was concentrated. To the residue was added
CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room temperature for 15 min, and then concentrated. The
residue was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product. LCMS calculated
for C.sub.25H.sub.28FN.sub.8 (M+H).sup.+: m/z=459.2; found: 459.2.
.sup.1H NMR (TFA salt, 600 MHz, DMSO) .delta. 10.09 (br, 1H), 9.49
(s, 1H), 9.29 (br, 2H), 9.20-9.18 (m, 1H), 8.48 (dd, J=8.8, 2.3 Hz,
1H), 7.13 (d, J=8.8 Hz, 1H), 7.11 (s, 1H), 4.48 (m, 2H), 4.31 (s,
2H), 3.52 (m, 2H), 3.46-3.36 (m, 2H), 3.20 (m, 2H), 3.06 (m, 4H),
2.84 (s, 3H), 2.17 (s, 3H).
Example 113
4,6-Difluoro-N-methyl-5-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]py-
rimidin-5-yl)-2,3-dihydro-1H-inden-1-amine
##STR00221##
[0858] Step 1. tert-Butyl
4,6-difluoro-2,3-dihydro-1H-inden-1-yl(methyl)carbamate
##STR00222##
[0860] To a solution of 4,6-difluoro-2,3-dihydro-1H-inden-1-one
(Ark Pharm, 4.015 g, 23.88 mmol) in 2-propanol (90.0 ml) was added
methylamine (2.0 M in methanol) (60.0 ml, 120 mmol) followed by
titanium(IV) isopropoxide (15.31 ml, 51.7 mmol). The mixture was
stirred at 35.degree. C. for 16 h before it was cooled to room
temperature. Sodium borohydride (1.312 g, 34.7 mmol) was added. The
reaction was stirred at room temperature for 1 h, and was quenched
with HCl (6.0 N in water) (60.0 ml, 360 mmol). The mixture was
stirred at room temperature for 2 h, and was treated with NaOH (4.0
N in water) until pH reached 10. The mixture was extracted with
Et.sub.2O. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
dissolved in CH.sub.2Cl.sub.2 (100 mL), and treated with
boc-anhydride (5.21 g, 23.88 mmol). After stirring at room
temperature for 30 min, the reaction was concentrated. The residue
was purified on silica gel (120 g, 0-100% EtOAc in hexanes) to give
the desired product as an oil (5.27 g, 78%). LCMS calculated for
C.sub.11H.sub.12F.sub.2NO.sub.2 (M+H--C.sub.4H.sub.8).sup.+:
m/z=228.1; found: 228.1.
Step 2. tert-Butyl
4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro--
1H-inden-1-yl(methyl)carbamate
##STR00223##
[0862] To a solution of tert-butyl
(4,6-difluoro-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (5.27 g,
18.60 mmol) in THF (100.0 ml) at -78.degree. C. under N.sub.2 was
added a solution of n-BuLi (2.5 M in hexanes) (15.00 ml, 37.5 mmol)
slowly over a period of 20 min. The reaction was allowed to warm to
-60.degree. C. and stirred for 90 min. The reaction was then cooled
back to -78.degree. C.
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.79 g, 58.0
mmol) was added slowly over a period of 20 min. After stirring at
-78.degree. C. for another 10 min, the reaction was allowed to warm
to room temperature and stirred for 1 h. The reaction was then
quenched with sat. NaHCO.sub.3, and extracted with Et.sub.2O. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified on silica gel (120 g, 0-100%
EtOAc in hexanes) to give the desired product as an oil (1.74 g,
23%). LCMS calculated for C.sub.17H.sub.23BF.sub.2NO.sub.4
(M+H--C.sub.4H.sub.8).sup.+: m/z=354.2; found: 354.1.
Step 3. tert-Butyl
5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carb-
oxylate
##STR00224##
[0864] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (463.9
mg, 1.219 mmol),
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
(468.2 mg, 1.614 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complexed with dichloromethane (1:1) (149.2 mg, 0.183 mmol) and
cesium carbonate (1.2 g, 3.69 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). 1,4-Dioxane (10.0 ml)
was added, followed by water (3.0 ml). The reaction was stirred at
50.degree. C. for 4 h. After cooling to room temperature, the
mixture was diluted with CH.sub.2Cl.sub.2, and washed with brine.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified on silica gel
(40 g, 0-100% EtOAc in hexanes) to give the desired product as a
yellow solid (395.2 mg, 78%). LCMS calculated for
C.sub.19H.sub.22ClN.sub.6O.sub.3 (M+H).sup.+ m/z=417.1; found
417.1.
Step 4.
4,6-Dilltioro-N-methyl-5-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo-
[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine
[0865] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carb-
oxylate (24.8 mg, 0.059 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 5.6 mg, 7.12
.mu.mol) and cesium carbonate (58.6 mg, 0.180 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
(4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-
-1H-inden-1-yl)(methyl)carbamate (24.8 mg, 0.061 mmol) in
1,4-dioxane (2.00 ml) was added via syringe, followed by water
(200.0 .mu.l). The reaction was heated to 50.degree. C. for 16 h.
The reaction was concentrated. To the residue was added
CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room temperature for 15 min, and then concentrated. The
residue was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product. LCMS calculated
for C.sub.24H.sub.24F.sub.2N.sub.7O (M+H).sup.+: m/z=464.2; found:
464.2.
Example 114
4,6-Difluoro-N-methyl-5-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-p-
yrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine
##STR00225##
[0866] Step 1. tert-Butyl
5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]p-
yrimidine-1-carboxylate
##STR00226##
[0868] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (1026.0
mg, 2.70 mmol),
2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)pyrimidine (816.5 mg, 2.68 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (330.2 mg, 0.404 mmol) and
cesium carbonate (2.693 g, 8.27 mmol). The vial was sealed with a
Teflon-lined septum, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). 1,4-Dioxane (12.0 ml)
was added, followed by water (4.0 ml). The reaction was stirred at
50.degree. C. for 16 h. After cooling to room temperature, the
mixture was diluted with CH.sub.2Cl.sub.2, washed with brine. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified on silica gel (40 g,
0-100% EtOAc in hexanes, then 10% MeOH in CH.sub.2Cl.sub.2) to give
the desired product as a yellow foamy solid (877.3 mg, 76%). LCMS
calculated for C.sub.19H.sub.24ClN.sub.8O.sub.2 (M+H).sup.+
m/z=431.2; found 431.1.
Step 2.
4,6-Difluoro-N-methyl-5-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5--
yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine
[0869] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]p-
yrimidine-1-carboxylate (81.4 mg, 0.189 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 28.4 mg, 0.036
mmol) and cesium carbonate (110.9 mg, 0.340 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
(4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-
-1H-inden-1-yl)(methyl)carbamate (64.0 mg, 0.156 mmol) in
1,4-dioxane (3.00 ml) was added via syringe, followed by water
(300.0 .mu.l). The reaction was heated to 50.degree. C. for 16 h.
The reaction was concentrated. To the residue was added
CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room temperature for 15 mins, and then concentrated. The
residue was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product. LCMS calculated
for C.sub.24H.sub.26F.sub.2N.sub.9 (M+H).sup.+: m/z=478.2; found:
478.2.
Example 115
6,8-Difluoro-N-methyl-7-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]py-
rimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine
##STR00227##
[0870] Step 1. tert-Butyl
6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl(methyl)carbamate
##STR00228##
[0872] To a solution of
6,8-difluoro-3,4-dihydronaphthalen-2(1H)-one (Ark Pharm, 1.316 g,
7.22 mmol) in MeOH (30.0 ml) was added methylamine hydrochloride
(5.38 g, 80 mmol), sodium cyanoborohydride (2.398 g, 38.2 mmol) and
THF (30.0 ml). The mixture was heated to 50.degree. C. for 16 h.
After cooling to room temperature, the mixture was quenched with
HCl (6.0 N in water) (30.0 ml, 180 mmol). The mixture was stirred
at room temperature for 2 h, and was treated with NaOH (4.0 N in
water) until pH reached 10. The mixture was extracted with
Et.sub.2O. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
dissolved in CH.sub.2Cl.sub.2 (100 mL), and treated with
Boc-anhydride (1.548 g, 7.09 mmol). After stirring at room
temperature for 30 min, the reaction was concentrated. The residue
was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give
the desired product as a white solid (1.177 g, 55%). LCMS
calculated for C.sub.12H.sub.14F.sub.2NO.sub.2
(M+H--C.sub.4H.sub.8).sup.+: m/z=242.1; found: 242.1.
Step 2. tert-Butyl
6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetr-
ahydronaphthalen-2-yl(methyl)carbamate
##STR00229##
[0874] To a solution of tert-butyl
(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)carbamate
(1.177 g, 3.96 mmol) in THF (30.0 ml) at -78.degree. C. under
N.sub.2 was added a solution of n-BuLi (2.5 M in hexanes) (3.20 ml,
8.00 mmol) slowly over a period of 20 mins. The reaction was
allowed to warm to -60.degree. C. and stirred for 60 mins. The
reaction was then cooled back to -78.degree. C.
2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.425 ml,
11.89 mmol) in THF (10.0 mL) was added slowly over a period of 20
mins. After stirring at -78.degree. C. for 20 mins, the reaction
was allowed to warm to room temperature and stirred for 1 h. The
reaction was quenched with sat. NaHCO.sub.3, and extracted with
Et.sub.2O. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the
desired product as a white solid (922.0 mg, 55%). LCMS calculated
for C.sub.22H.sub.32BF.sub.2NNaO.sub.4 (M+Na).sup.+: m/z=446.2;
found: 446.2.
Step 3.
6,8-Difluoro-N-methyl-7-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[-
4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine
[0875] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carb-
oxylate (24.8 mg, 0.059 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 7.0 mg, 8.90
.mu.mol) and cesium carbonate (58.5 mg, 0.180 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
(6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tet-
rahydronaphthalen-2-yl)(methyl)carbamate (22.3 mg, 0.053 mmol) in
1,4-dioxane (2.00 ml) was added via syringe, followed by water
(200.0 .mu.l). The reaction was heated to 50.degree. C. for 16 h.
The reaction was concentrated. To the residue was added
CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room temperature for 15 mins, and then concentrated. The
residue was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product. LCMS calculated
for C.sub.25H.sub.26F.sub.2N.sub.7O (M+H).sup.+: m/z=478.2; found:
478.3.
Example 116
5,7-Difluoro-N-methyl-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]py-
rimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine
##STR00230##
[0876] Step 1. tert-Butyl
5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate
##STR00231##
[0878] To a solution of
5,7-difluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm, 1.325 g,
7.27 mmol) in 2-propanol (30.0 ml) was added methylamine (2.0 M in
methanol) (15.00 ml, 30.0 mmol) followed by titanium(IV)
isopropoxide (4.06 ml, 13.73 mmol) and THF (15.0 ml). The mixture
was stirred at 35.degree. C. for 16 h before it was cooled to room
temperature. Sodium borohydride (418.4 mg, 11.06 mmol) was added.
The reaction was stirred at room temperature for 1 h, and was
quenched with HCl (6.0 N in water) (40.0 ml, 240 mmol). The mixture
was stirred at room temperature for 2 h, and was treated with NaOH
(4.0 N in water) until pH reached 10. The mixture was extracted
with Et.sub.2O. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
dissolved in CH.sub.2Cl.sub.2 (40 mL), and treated with
Boc-anhydride (1.709 g, 7.83 mmol). After stirring at room
temperature for 30 mins, the reaction was concentrated. The residue
was purified on silica gel (120 g, 0-100% EtOAc in hexanes) to give
the desired product (1.873 g, 87%). LCMS calculated for
C.sub.12H.sub.14F.sub.2NO.sub.2 (M+H--C.sub.4H.sub.8).sup.+:
m/z=242.1; found: 242.1.
Step 2. tert-Butyl
5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetr-
ahydronaphthalen-1-yl(methyl)carbamate
##STR00232##
[0880] To a solution of tert-butyl
(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate
(1.872 g, 6.30 mmol) in THF (40.0 ml) at -78.degree. C. under
N.sub.2 was added a solution of n-BuLi (2.5 M in hexanes) (5.00 ml,
12.50 mmol) slowly over a period of 20 mins. The reaction was
allowed to warm to -60.degree. C. and stirred for 60 mins. The
reaction was then cooled back to -78.degree. C.
2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.85 ml,
18.89 mmol) in THF (10.0 mL) was added slowly over a period of 20
mins. After stirring at -78.degree. C. for 20 mins, the reaction
was allowed to warm to room temperature and stirred for 1 h. The
reaction was quenched with sat. NaHCO.sub.3, and extracted with
Et.sub.2O. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the
desired product as a yellow foamy solid (989.9 mg, 37%). LCMS
calculated for C.sub.22H.sub.32BF.sub.2NNaO.sub.4 (M+Na).sup.+:
m/z=446.2; found: 446.2.
Step 3.
5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyr-
imidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine
[0881] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carb-
oxylate (24.8 mg, 0.059 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 7.0 mg, 8.90
.mu.mol) and cesium carbonate (59.7 mg, 0.183 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tet-
rahydronaphthalen-1-yl)(methyl)carbamate (23.3 mg, 0.055 mmol) in
1,4-dioxane (2.00 ml) was added via syringe, followed by water
(200.0 .mu.l). The reaction was heated to 50.degree. C. for 16 h.
The reaction was concentrated. To the residue was added
CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room temperature for 15 min, and then concentrated. The
residue was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product. LCMS calculated
C.sub.25H.sub.26F.sub.2N.sub.7O (M+H).sup.+: m/z=478.2; found:
478.2
Example 117
5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-
-yl)-1,2,3,4-tetrahydronaphthalen-1-amine
##STR00233##
[0882] Step 1. tert-Butyl
5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate
##STR00234##
[0884] To a mixture of 5,7-difluoro-3,4-dihydronaphthalen-1(2H)-one
(Ark Pharm, 1636.4 mg, 8.98 mmol), sodium cyanoborohydride (6.064
g, 96 mmol) and ammonium acetate (16.51 g, 214 mmol) was added
2-propanol (50.0 ml). The reaction was stirred at 70.degree. C. for
16 h. After cooling to room temperature, the mixture was diluted
with water and extracted with Et.sub.2O. The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated.
The residue was dissolved in THF (100 ml), and HCl (6.0 N in water)
(50.0 ml, 300 mmol) was added. The mixture was stirred at room
temperature for 16 h, and was treated with NaOH (4.0 N in water)
until pH reached 10. The mixture was extracted with Et.sub.2O. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated. The residue was dissolved in CH.sub.2Cl.sub.2 (40
ml), and was treated with boc-anhydride (1.982 g, 9.08 mmol). After
stirring at room temperature for 30 mins, the reaction was
concentrated. The residue was purified on silica gel (120 g, 0-100%
EtOAc in hexanes) to give the desired product as a white solid
(1.836 g, 72%). LCMS calculated for C.sub.11H.sub.12F.sub.2NO.sub.2
(M+H--C.sub.4H.sub.8).sup.+: m/z=228.1; found: 228.1.
Step 2. tert-Butyl
5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetr-
ahydronapthalen-1-ylcarbamate
##STR00235##
[0886] To a solution of tert-butyl
(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (1.836 g,
6.48 mmol) in THF (40.0 ml) at -78.degree. C. under N.sub.2 was
added a solution of n-BuLi (2.5 M in hexanes) (7.00 ml, 17.50 mmol)
slowly via syringe over a period of 20 mins. The reaction was
allowed to warm to -60.degree. C. and stirred for 60 mins. The
reaction was then cooled back to -78.degree. C.
2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.04 ml,
24.72 mmol) in THF (10.0 ml) was added via syringe slowly over a
period of 20 mins. After stirring at -78.degree. C. for 20 mins,
the reaction was allowed to warm to room temperature and stirred
for 1 h. The reaction was quenched with sat. NaHCO.sub.3, and
extracted with Et.sub.2O. The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give
the desired product as a white foamy solid (1.632 g, 62%). LCMS
calculated for C.sub.21H.sub.30BF.sub.2NNaO.sub.4 (M+Na).sup.+:
m/z=432.2; found: 432.2.
Step 3.
5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyr-
imidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine
[0887] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carb-
oxylate (28.5 mg, 0.068 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17
.mu.mol) and cesium carbonate (66.8 mg, 0.205 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tet-
rahydronaphthalen-1-yl)carbamate (24.7 mg, 0.060 mmol) in
1,4-Dioxane (2.00 ml) was added via syringe, followed by water
(200.0 .mu.l). The reaction was heated to 50.degree. C. for 16 h.
The reaction was concentrated. To the residue was added
CH.sub.2Cl.sub.2 (2.0 mL) followed by TFA (2.0 mL). The mixture was
stirred at room temperature for 15 mins, and then concentrated. The
residue was purified using prep-LCMS (XBridge C18 column, eluting
with a gradient of acetonitrile/water containing 0.1% TFA, at flow
rate of 60 mL/min) to afford the desired product. LCMS calculated
for C.sub.24H.sub.24F.sub.2N.sub.7O (M+H).sup.+: m/z=464.2; found:
464.2.
Example 118
5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-
-yl)-2,3-dihydro-1H-inden-1-amine
##STR00236##
[0888] Step 1. tert-Butyl
5,7-dilltioro-2,3-dihydro-1H-inden-1-ylcarbamate
##STR00237##
[0890] To a solution of boc-anhydride (1.398 g, 6.41 mmol) in
CH.sub.2Cl.sub.2 (15.0 ml) was added
5,7-difluoro-2,3-dihydro-1H-inden-1-amine, HCl salt (AstaTech,
1.002 g, 4.87 mmol) followed by N,N-diisopropylethylamine (2.93 ml,
16.78 mmol). The mixture was stirred at room temperature for 30
min, and then concentrated. The residue was purified on silica gel
(40 g, 0-100% EtOAc in hexanes) to give the desired product as a
white solid (1.178 g, 90%).
Step 2. tert-Butyl
5,7-dilltioro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-
-1H-inden-1-ylcarbamate
##STR00238##
[0892] To a solution of tert-butyl
(5,7-difluoro-2,3-dihydro-1H-inden-1-yl)carbamate (1.168 g, 4.34
mmol) in THF (40.0 ml) at -78.degree. C. under N.sub.2 was added a
solution of n-BuLi (2.5 M in hexanes) (4.60 ml, 11.50 mmol) slowly
via syringe over a period of 20 mins. The reaction was allowed to
warm to -60.degree. C. and stirred for 60 mins. The reaction was
then cooled back to -78.degree. C.
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.01 ml,
14.77 mmol) was added slowly via syringe over a period of 20 mins.
After stirring at -78.degree. C. for 20 min, the reaction was
allowed to warm to room temperature and stirred for 1 h. The
reaction was quenched with sat. NaHCO.sub.3, and extracted with
Et.sub.2O. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give the
desired product as a white foamy solid (893.5 mg, 52%). LCMS
calculated for C.sub.20H.sub.28BF.sub.2NNaO.sub.4 (M+Na).sup.+:
m/z=418.2; found: 418.2.
Step 3.
5,7-Dilltioro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]py-
rimidin-5-yl)-2,3-dihydro-1H-inden-1-amine
[0893] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carb-
oxylate (28.5 mg, 0.068 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17
.mu.mol) and cesium carbonate (70.0 mg, 0.215 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-
-1H-inden-1-yl)carbamate (24.9 mg, 0.063 mmol) in 1,4-dioxane (2.00
ml) was added via syringe, followed by water (200.0 .mu.l). The
reaction was heated to 50.degree. C. for 16 h. The reaction was
concentrated. To the residue was added CH.sub.2Cl.sub.2 (2.0 mL)
followed by TFA (2.0 mL). The mixture was stirred at room
temperature for 15 min, and then concentrated. The residue was
purified using prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to afford the desired product. LCMS calculated for
C.sub.23H.sub.22F.sub.2N.sub.7O (M+H).sup.+: m/z=450.2; found:
450.3.
Example 119
5-Fluoro-7-methoxy-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrim-
idin-5-yl)-2,3-dihydro-1H-inden-1-amine
##STR00239##
[0894] Step 1. tert-Butyl
5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-ylcarbamate
##STR00240##
[0896] To a mixture of
5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-one (NetChem, 1742.0 mg,
9.67 mmol), sodium cyanotrihydroborate (6212.9 mg, 99 mmol) and
ammonium acetate (18.12 g, 235 mmol) was added 2-propanol (60.0
ml). The reaction was stirred at 70.degree. C. for 16 h. After
cooling to room temperature, the mixture was diluted with 2 N
NaOH(aq) and extracted with CH.sub.2Cl.sub.2 (.times.10). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated. The residue was dissolved in CH.sub.2Cl.sub.2 (40
ml), and was treated with boc-anhydride (2.156 g, 9.88 mmol). After
stirring at room temperature for 30 mins, the reaction was
concentrated. The residue was purified on silica gel (120 g, 0-100%
EtOAc in hexanes) to give the desired product as a white solid
(1.886 g, 69%). LCMS calculated for C.sub.11H.sub.13FNO.sub.3
(M+H--C.sub.4H.sub.8).sup.+: m/z=226.1; found: 226.1.
Step 2. tert-Butyl
5-fluoro-7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-di-
hydro-1H-inden-1-ylcarbamate
##STR00241##
[0898] To a solution of tert-butyl
(5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-yl)carbamate (1.886 g,
6.70 mmol) in THF (40.0 ml) at -78.degree. C. under N.sub.2 was
added a solution of n-BuLi (2.5 M in hexanes) (7.50 ml, 18.75 mmol)
slowly via syringe over a period of 20 mins. The reaction was
allowed to warm to -60.degree. C. and stirred for 60 mins. The
reaction was then cooled back to -78.degree. C.
2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.00 ml,
24.51 mmol) was added slowly via syringe over a period of 20 mins.
After stirring at -78.degree. C. for 20 mins, the reaction was
allowed to warm to room temperature and stirred for 1 h. The
reaction was quenched with sat. NaHCO.sub.3, and extracted with
Et.sub.2O. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified on silica gel (40 g, 0-50% EtOAc in hexanes) to give the
desired product as a white foamy solid (1.063 g, 39%). LCMS
calculated for C.sub.21H.sub.31BFNNaO.sub.5 (M+Na).sup.+:
m/z=430.2; found: 430.2.
Step 3.
5-Fluoro-7-methoxy-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-
-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine
[0899] To a screw-cap vial equipped with a magnetic stir bar was
added tert-butyl
5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carb-
oxylate (28.5 mg, 0.068 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17
.mu.mol) and cesium carbonate (69.8 mg, 0.214 mmol). The vial was
sealed with a Teflon-lined septum, evacuated and backfilled with
nitrogen (this process was repeated a total of three times). A
solution of tert-butyl
(5-fluoro-7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-d-
ihydro-1H-inden-1-yl)carbamate (25.8 mg, 0.063 mmol) in 1,4-dioxane
(2.00 ml) was added via syringe, followed by water (200.0 .mu.l).
The reaction was heated to 50.degree. C. for 16 h. The reaction was
concentrated. To the residue was added CH.sub.2Cl.sub.2 (2.0 mL)
followed by TFA (2.0 mL). The mixture was stirred at room
temperature for 15 min, and then concentrated. The residue was
purified using prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to afford the desired product. LCMS calculated for
C.sub.24H.sub.25FN.sub.7O.sub.2 (M+H).sup.+: m/z=462.2; found:
462.1. .sup.1H NMR (TFA salt, 600 MHz, DMSO) .delta. 9.49 (s, 1H),
9.17-9.14 (m, 1H), 8.44 (dd, J=9.0, 2.4 Hz, 1H), 8.15 (br, 3H),
7.10 (d, J=8.9 Hz, 1H), 7.04 (d, J=9.0 Hz, 1H), 4.91 (m, 1H),
3.72-3.69 (m, 4H), 3.55-3.51 (m, 4H), 3.46 (s, 3H), 3.17 (m, 1H),
3.01-2.89 (m, 1H), 2.59-2.52 (m, 1H), 2.08 (m, 1H).
Example 120
6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazol-
o[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine
##STR00242##
[0900] Step 1. tert-Butyl
5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate
##STR00243##
[0902] To a solution of
5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm, 312.6
mg, 1.286 mmol) in 2-propanol (10.0 ml) was added methylamine (2.0
M in methanol) (2.50 ml, 5.00 mmol) followed by titanium(IV)
isopropoxide (596.0 mg, 2.097 mmol). The mixture was stirred at
35.degree. C. for 16 h before it was cooled to room temperature.
Sodium borohydride (53.4 mg, 1.412 mmol) was added. The reaction
was stirred at room temperature for 1 h, and was treated with HCl
(1.0 N in water) (30.0 ml, 30 mmol). The mixture was stirred at
room temperature for 2 h, and was treated with NaOH (4.0 N in
water) until the pH reached 10. The mixture was extracted with
Et.sub.2O. The organic phase was separated, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
dissolved in CH.sub.2Cl.sub.2 (10 ml), and treated with
boc-anhydride (426.4 mg, 1.954 mmol). After stirring at room
temperature for 30 min, the reaction was concentrated. The residue
was purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give
the desired product (461.0 mg, 89%). LCMS calculated for
C.sub.12H.sub.14BrFNO.sub.2 (M+H--C.sub.4H.sub.8).sup.+: m/z=302.0;
found: 302.1.
Step 2. tert-Butyl
6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahyd-
ronaphthalen-1-yl(methyl)carbamate
##STR00244##
[0904] A vial was charged with
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(517.4 mg, 2.037 mmol), potassium acetate (416.8 mg, 4.25 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complexed with dichloromethane (1:1) (210.2 mg, 0.257 mmol). The
vial was sealed, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). A solution of
tert-butyl
(5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate
(461.0 mg, 1.287 mmol) in 1,4-dioxane (6.0 ml) was added, and the
mixture was heated at 100.degree. C. for 16 h. After cooling to
room temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes)
to give the desired product (337.4 mg, 65%). LCMS calculated for
C.sub.22H.sub.33BFNNaO.sub.4 (M+Na).sup.+ m/z=428.2; found
428.2.
Step 3.
6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-
-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine
[0905] A vial was charged with tert-butyl
5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyr-
imidine-1-carboxylate (34.0 mg, 0.079 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17
.mu.mol) and cesium carbonate (81.4 mg, 0.250 mmol). The vial was
sealed, evacuated and backfilled with nitrogen (this process was
repeated a total of three times). A solution of tert-butyl
(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahy-
dronaphthalen-1-yl)(methyl)carbamate (28.1 mg, 0.069 mmol) in
1,4-dioxane (2.0 ml) was added, followed by water (200.0 .mu.l).
The reaction mixture was heated to 50.degree. C. for 16 h., cooled
and concentrated. To the residue was added CH.sub.2Cl.sub.2 (2.0
mL) followed by TFA (2.0 mL). The mixture was stirred at room
temperature for 15 mins, and then concentrated. The residue was
purified using prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to afford the desired product. LCMS calculated
C.sub.26H.sub.30FN.sub.8 (M+H).sup.+: m/z=473.3; found: 473.3.
Example 121
6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimid-
in-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine
##STR00245##
[0906] Step 1. tert-Butyl
5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate
##STR00246##
[0908] To a mixture of
5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (Ark Pharm, 309.5
mg, 1.273 mmol), sodium cyanoborohydride (824.0 mg, 13.11 mmol) and
ammonium acetate (2.184 g, 28.3 mmol) was added 2-propanol (10.0
ml). The reaction was stirred at 70.degree. C. for 16 h. After
cooling to room temperature, the mixture was diluted with 2 M
K.sub.2CO.sub.3 (aq) and extracted with Et.sub.2O. The organic
phase was separated, was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was dissolved in
CH.sub.2Cl.sub.2 (20 ml), and was treated with Boc-anhydride (425.9
mg, 1.951 mmol). After stirring at room temperature for 30 min, the
reaction mixture was concentrated. The residue was purified on
silica gel (40 g, 0-100% EtOAc in hexanes) to give the desired
product as a white solid (316.3 mg, 72%). LCMS calculated for
C.sub.11H.sub.12BrFNO.sub.2 (M+H--C.sub.4H.sub.8).sup.+: m/z=288.0;
found: 288.0.
Step 2. tert-Butyl
6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahyd-
ronaphthalen-1-ylcarbamate
##STR00247##
[0910] A vial was charged with
4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl]
(319.0 mg, 1.256 mmol), potassium acetate (272.1 mg, 2.77 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complexed with dichloromethane (1:1) (150.1 mg, 0.184 mmol). The
vial was sealed, evacuated and backfilled with nitrogen (this
process was repeated a total of three times). A solution of
tert-butyl
(5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate
(316.3 mg, 0.919 mmol) in 1,4-dioxane (6.0 ml) was added. The
mixture was heated at 100.degree. C. for 16 h. After cooling to
room temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated. The
residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes)
to give the desired product (200.0 mg, 56%). LCMS calculated for
C.sub.17H.sub.24BFNO.sub.4 (M+H--C.sub.4H.sub.8).sup.+: m/z=336.2;
found: 336.3.
Step 3.
6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d-
]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine
[0911] A vial was charged with tert-butyl
5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-
e-1-carboxylate (30.0 mg, 0.070 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17
.mu.mol) and cesium carbonate (72.8 mg, 0.223 mmol). The vial was
sealed, evacuated and backfilled with nitrogen (this process was
repeated a total of three times). A solution of tert-butyl
(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahy-
dronaphthalen-1-yl)carbamate (25.0 mg, 0.064 mmol) in 1,4-dioxane
(2.00 ml) was added, followed by water (200.0 .mu.l). The reaction
was heated to 50.degree. C. for 16 h. The reaction was cooled and
concentrated. To the residue was added CH.sub.2Cl.sub.2 (2.0 mL)
followed by TFA (2.0 mL). The mixture was stirred at room
temperature for 15 min, and then concentrated. The residue was
purified using prep-LCMS (XBridge C18 column, eluting with a
gradient of acetonitrile/water containing 0.1% TFA, at flow rate of
60 mL/min) to afford the desired product. LCMS calculated for
C.sub.26H.sub.29FN.sub.7 (M+H).sup.+: m/z=458.3; found: 458.3.
Example 122
1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyr-
imidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-ol
##STR00248##
[0913] This compound was prepared according to the procedure
described in Example 70, using 4-methylpiperidin-4-ol instead of
2-methyl-1-(piperazin-1-yl)propan-2-ol as starting material. LC-MS
calculated for C.sub.24H.sub.26F.sub.2N.sub.7O (M+H).sup.+:
m/z=466.2; Found 466.2.
Example 123
1-(3,5-Difluoro-4-(3-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1H-pyraz-
olo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine
##STR00249##
[0915] This compound was prepared according to the procedure
described in Example 72, using 1-(2-methoxyethyl)piperazine instead
of 1-(methylsulfonyl)piperidin-4-amine as starting material. LC-MS
calculated for C.sub.26H.sub.30F.sub.2N.sub.7O (M+H).sup.+:
m/z=494.2; Found 494.2.
Example 124
1-(4-(3-(4-(4-Ethylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl-
)-3-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethanamine
##STR00250##
[0917] This compound was prepared according to the procedure
described in Example 76, using
1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazi-
ne instead of (6-(piperidin-1-yl)pyridin-3-yl)boronic acid as
starting material. LC-MS calculated for
C.sub.26H.sub.28F.sub.4N.sub.7 (M+H).sup.+: m/z=514.2; Found 514.2.
.sup.1H NMR (500 MHz, DMSO) .delta. 9.50 (s, 1H), 9.27 (bs, 1H),
8.30 (d, J=8.9 Hz, 2H), 7.97 (s, 1H), 7.90 (dd, J=9.7, 1.6 Hz, 1H),
7.19-7.14 (m, 2H), 4.38 (s, 2H), 4.02-3.90 (m, 2H), 3.59 (d, J=10.3
Hz, 2H), 3.26-3.17 (q, J=7.3 Hz, 2H), 3.17-3.10 (d, J=20.8 Hz, 2H),
3.08 (s, 2H), 2.69 (s, 3H), 1.27 (t, J=7.2 Hz, 3H).
Example 125
3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methyl-4-(piperidin-2-yl-
)phenyl)-1H-pyrazolo[4,3-d]pyrimidine
##STR00251##
[0919] This compound was prepared according to the procedures
described in Example 81, using
1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazi-
ne, instead of
1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperaz-
ine as starting material. LCMS calculated for
C.sub.29H.sub.35FN.sub.7 (M+H).sup.+: m/z=500.3; Found: 500.3.
Example 126
(R)-1-(3-Fluoro-4-(3-(6-(2-(methoxymethyl)morpholino)pyridin-3-yl)-1H-pyra-
zolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine
##STR00252##
[0920] Step 1.
5-Chloro-3-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazolo[4,3-d]pyrimidine
##STR00253##
[0922] To a solution of
5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]py-
rimidine (Example 1, step 2. 2.60 g, 6.33 mmol) in dioxane (24 ml)
and water (6 ml) were added potassium phosphate, tribasic (2.60 g,
12.7 mmol) and (6-fluoropyridin-3-yl)boronic acid (981 mg, 6.96
mmol). Nitrogen gas was bubbled through the reaction mixture for 10
minutes and PdCl.sub.2(dppf) (517 mg, 0.633 mmol) was added. The
reaction mixture was stirred at 90.degree. C. for 2 hours. After
cooling to r.t. it was concentrated to dryness. The residue was
purified by silica gel chromatography using 0-100% ethyl acetate in
hexanes to afford desired product as brownish oil. LC-MS calculated
for C.sub.16H.sub.20ClFN.sub.5OSi (M+H).sup.+: m/z=380.2; found
380.2.
Step 2. tert-Butyl
3-fluoro-4-(3-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-
-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)benzyl(methyl)carbam-
ate
##STR00254##
[0924] To a solution of tert-butyl
(3-fluoro-5-(trifluoromethyl)benzyl)(methyl)carbamate (Step 1,
example 76, 4.50 g, 14.6 mmol) in THF (45.8 ml) was added 2.5M
solution of n-butyllithium in hexane (7.03 ml, 17.6 mmol) dropwise
at -78.degree. C. over 60 mins. The resulting solution was stirred
at -78.degree. C. for 30 mins before
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.48 ml, 22.0
mmol) was added. The reaction mixture was stirred for another 1
hour, allowing it to warm up to r.t. It was acidified to pH=5 by 1N
HCl solution. The resulting solution was diluted with ethyl acetate
and washed with water and brine. The organic layer was dried over
MgSO.sub.4, filtered and concentrated to dryness. The residue was
dissolved in dioxane (20 ml) and water (4 ml) and
5-chloro-3-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazolo[4,3-d]pyrimidine (1.39 g, 3.66 mmol) was added followed
by potassium phosphate, tribasic (6.22 g, 29.3 mmol). Nitrogen gas
was bubbled through the reaction mixture for 10 minutes.
Chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-am-
ino-1,1'-biphenyl-2-yl) palladium(II) (Xphos-Pd-G2, 0.691 g, 0.879
mmol) was added and the reaction mixture was stirred at 60.degree.
C. for 1 hour. After cooling to r.t., the reaction mixture was
diluted with ethyl acetate and washed with water and brine. The
organic layer was dried over MgSO.sub.4, filtered and concentrated
to dryness. The residue was purified by silica gel chromatography
using 0-100% ethyl acetate in hexanes to afford the desired product
as light yellowish oil. LC-MS calculated for
C.sub.30H.sub.36F.sub.5N.sub.6O.sub.3Si (M+H).sup.+: m/z=651.2;
found 651.2.
Step 3.
(R)-1-(3-Fluoro-4-(3-(6-(2-(methoxymethyl)morpholino)pyridin-3-yl)-
-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trilltioromethyl)phenyl)-N-methylmet-
hanamine
[0925] To a solution of tert-butyl
3-fluoro-4-(3-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-
-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)benzyl(methyl)carbam-
ate (15 mg, 0.024 mmol) in DMSO (1 ml) was added
(R)-2-(methoxymethyl)morpholine (31.7 mg, 0.242 mmol) followed by
DIPEA (0.021 mL, 0.121 mmol). The resulting mixture was stirred at
120.degree. C. for 15 hours. The reaction mixture was then cooled
to r.t., diluted with DCM and washed with water and brine. 1 mL of
TFA was added to the separated organic phase and the resulting
solution was stirred at 40.degree. C. for 2 hours. It was
concentrated to dryness, diluted with methanol and purified using
prep-LCMS (XBridge C18 column, eluting with a gradient of
acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min)
to afford the desired product. LC-MS calculated for
C.sub.25H.sub.26F.sub.4N.sub.7O.sub.2 (M+H).sup.+: m/z=532.2; found
532.2.
Example A
HPK1 Kinase Binding Assay
[0926] A stock solution of 1 mM test compound was prepared in DMSO.
The compound plate was prepared by 3-fold and 11-point serial
dilutions. 0.1 .mu.L of the compound in DMSO was transferred from
the compound plate to the white 384 well polystyrene plates. The
assay buffer contained 50 mM HEPES, pH 7.5, 0.01% Tween-20, 5 mM
MgCl.sub.2, 0.01% BSA, and 5 mM DTT. 5 .mu.l of 4 nM active HPK1
(SignalChem M23-11G) prepared in the buffer was added to the plate.
The enzyme concentration given was based on the given stock
concentration reported by the vender. 5 .mu.l of 18 nM tracer 222
(ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody
(ThermoFisher PV5595) were added. After one hour incubation at
25.degree. C., the plates were read on a PHERAstar FS plate reader
(BMG Labtech). Ki values were determined.
[0927] Compounds of the present disclosure, as exemplified in
Examples, showed the K.sub.i values in the following ranges:
+=Ki.ltoreq.100 nM; ++=100 nM<Ki.ltoreq.500 nM; +++=500
nM<Ki.ltoreq.5000 nM.
TABLE-US-00001 TABLE 1 Example HPK1 Ki, nM 1 + 2 + 3 + 4 + 5 + 6 +
7 + 8 + 9 + 10 + 11 + 12 + 13 ++ 14 + 15 + 16 ++ 17 + 18 ++ 19 + 20
+++ 21 + 22 ++ 23 + 24 + 25 + 26 + 27 + 28 ++ 29 + 30 + 31 + 32 +
33 ++ 34 + 35 + 36 + 37 + 38 + 39 + 40 + 41 + 42 + 43 + 44 + 45 +
46 + 47 ++ 48 + 49 + 50 + 51 + 52 + 53 + 54 + 55 + 56 + 57 + 58 +
59 + 60 + 61 + 62 + 63 + 64 + 65 + 66 + 67 + 68 + 69 + 70 + 71 + 72
+ 73 + 74 + 75 + 76 + 77 + 78 + 79 + 80 + 81 + 82 + 83 + 84 + 85 +
86 + 87 + 88 + 89 + 90 + 91 + 92 + 93 + 94 + 95 + 96 + 97 + 98 + 99
+ 100 + 101 + 102 + 103 + 104 + 105 + 106 + 107 + 108 + 109 + 110 +
111 + 112 + 113 + 114 + 115 + 116 + 117 + 118 + 119 + 120 + 121 +
122 + 123 + 124 + 125 + 126 +
Example B
p-SLP76S376 HTRF Assay
[0928] One or more compounds of the invention can be tested using
the p-SLP76S376 HTRF assay described as follows. Jurkat cells
(cultured in RPMI1640 media with 10% FBS) are collected and
centrifuged, followed by resuspension in appropriate media at
3.times.10.sup.6 cells/ml. The Jurkat cells (35 ul) are dispensed
into each well in a 384 well plate. Test compounds are diluted with
cell culture media for 40-fold dilution (adding 39 ul cell culture
media into 1 ul compound). The Jurkat cells in the well plate are
treated with the test compounds at various concentrations (adding 5
ul diluted compound into 35 ul Jurkat cells and starting from 3 uM
with 1:3 dilution) for 1 hour at 37.degree. C., 5% CO.sub.2),
followed by treatment with anti-CD3 (5 ug/ml, OKT3 clone) for 30
min. A 1:25 dilution of 100.times. blocking reagent (from p-SLP76
ser376HTRF kit) with 4.times. Lysis Buffer (LB) is prepared and 15
ul of the 4.times. LB buffer with blocking reagent is added into
each well and incubated at room temperature for 45 mins with gentle
shaking. The cell lysate (16 ul) is added into a Greiner white
plate, treated with p-SLP76 ser376HTRF reagents (2 ul donor, 2 ul
acceptor) and incubated at 4.degree. C. for overnight. The
homogeneous time resolved fluorescence (HTRF) is measured on a
PHERAstar plate reader the next day. IC.sub.50 determination is
performed by fitting the curve of percent inhibition versus the log
of the inhibitor concentration using the GraphPad Prism 5.0
software.
Example C
Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement
[0929] Blood samples are collected from healthy donors. CD4+ or
CD8+ T cells are isolated by negative selection using CD4+ or CD8+
enrichment kits (lifetech, USA). The purity of the isolated CD4+ or
CD8+ T cells is determined by flow cytometry and is routinely
>80%. Cells are cultured in RPMI 1640 supplemented with 10% FCS,
glutamine and antibiotics (Invitrogen Life Technologies, USA). For
cytokine measurement, Jurkat cells or primary CD4+ or CD8+ T cells
are plated at 200 k cells/well and are stimulated for 24 h with
anti-CD3/anti-CD28 beads in the presence or absence of testing
compounds at various concentrations. 16 .mu.L of supernatants are
then transferred to a white detection plate and analyzed using the
human IL2 or IFN.gamma. assay kits (Cisbio).
Example D
Treg Assay
[0930] One or more compounds can be tested using the Regulatory
T-cell proliferation assay described as following. Primary
CD4+/CD25- T-cells and CD4+/CD25+ regulatory T-cells are isolated
from human donated Peripheral Blood Mononuclear Cells, using an
isolated kit from Thermo Fisher Scientific (11363D). CD4+/CD25-
T-cells are labeled with CFSE (Thermo Fisher Scientific, C34554)
following the protocol provided by the vendor. CFSE labeled T-cells
and CD4+/CD25+ regulatory T-cells are re-suspended at the
concentration of 1.times.106 cells/ml in RPMI-1640 medium. 100
.mu.l of CFSE-labeled T-cells are mixed with or without 50 .mu.l of
CD4+/CD25+ regulatory T-cells, treated with 5 .mu.l of
anti-CD3/CD28 beads (Thermo Fisher Scientific, 11132D) and various
concentrations of compounds diluted in 50 .mu.l of RPMI-1640
medium. Mixed populations of cells are cultured for 5 days
(37.degree. C., 5% CO.sub.2) and proliferation of CFSE-labeled
T-cells is analyzed by BD LSRFortessa X-20 using FITC channel on
the 5th day.
[0931] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference,
including without limitation all patent, patent applications, and
publications, cited in the present application is incorporated
herein by reference in its entirety.
* * * * *