U.S. patent application number 17/124346 was filed with the patent office on 2021-04-08 for compounds and compositions as inhibitors of endosomal toll-like receptors.
The applicant listed for this patent is NOVARTIS AG. Invention is credited to Phillip ALPER, Jonathan DEANE, Songchun JIANG, Tao JIANG, Thomas KNOEPFEL, Pierre-Yves MICHELLYS, Daniel MUTNICK, Wei PEI, Peter SYKA, Guobao ZHANG, Yi ZHANG.
Application Number | 20210101902 17/124346 |
Document ID | / |
Family ID | 1000005287625 |
Filed Date | 2021-04-08 |
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United States Patent
Application |
20210101902 |
Kind Code |
A1 |
ALPER; Phillip ; et
al. |
April 8, 2021 |
COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF ENDOSOMAL TOLL-LIKE
RECEPTORS
Abstract
The invention disclosed herein relates to
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinyl compounds and
4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinyl compounds of Formula
(A), pharmaceutical compositions comprising such compounds and the
use of such compounds in the treatment of autoimmune diseases.
##STR00001##
Inventors: |
ALPER; Phillip; (San Diego,
CA) ; DEANE; Jonathan; (San Diego, CA) ;
JIANG; Songchun; (San Diego, CA) ; JIANG; Tao;
(San Diego, CA) ; KNOEPFEL; Thomas; (Basel,
CH) ; MICHELLYS; Pierre-Yves; (San Diego, CA)
; MUTNICK; Daniel; (Emeryvlle, CA) ; PEI; Wei;
(San Diego, CA) ; SYKA; Peter; (San Diego, CA)
; ZHANG; Guobao; (Shanghai, CN) ; ZHANG; Yi;
(Belmont, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVARTIS AG |
Basel |
|
CH |
|
|
Family ID: |
1000005287625 |
Appl. No.: |
17/124346 |
Filed: |
December 16, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16330820 |
Mar 6, 2019 |
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PCT/IB2017/055375 |
Sep 6, 2017 |
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17124346 |
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62385726 |
Sep 9, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 1/16 20180101; A61P 17/06 20180101; A61K 31/496 20130101; A61P
19/02 20180101; A61K 31/541 20130101; A61K 31/5377 20130101; A61K
31/519 20130101; A61K 31/437 20130101; C07D 471/04 20130101; A61K
31/4375 20130101; A61P 37/06 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61P 17/06 20060101 A61P017/06; A61P 1/16 20060101
A61P001/16; A61P 37/06 20060101 A61P037/06; A61P 19/02 20060101
A61P019/02; A61K 31/437 20060101 A61K031/437; A61K 31/4375 20060101
A61K031/4375; A61K 31/496 20060101 A61K031/496; A61K 31/519
20060101 A61K031/519; A61K 31/5377 20060101 A61K031/5377; A61K
31/541 20060101 A61K031/541; A61K 45/06 20060101 A61K045/06 |
Claims
1. A compound having the structure of Formula (A) or a
pharmaceutically acceptable salt thereof: ##STR00327## wherein:
R.sup.A is ##STR00328## L is --CH.sub.2-- or --CH.sub.2CH.sub.2--;
Y.sub.1 is --CH.sub.2-- or --CH.sub.2CH.sub.2--; Y.sub.2 is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; Y.sub.3 is --CH.sub.2--,
--XCH.sub.2-- or --CH.sub.2X--; X is --CH.sub.2-- or O; R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nOR.sup.9, --NHC(.dbd.O)OR.sup.9,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6,
NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nN(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6, --NHR.sup.6,
--NR.sup.5R.sup.6, --NH.sub.2, --N(R.sup.5).sub.2, --NHR.sup.5,
--NHR.sup.8, --N(R.sup.6R.sup.8),
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CH.sub.2).sub.nR.sup.6, --NH(CHR.sup.9).sub.nR.sup.6,
--N(R.sup.6).sub.2, --NHC(.dbd.O)(CH.sub.2).sub.nN(CD.sub.3).sub.2,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9, --OR.sup.9,
--NR.sup.9C(.dbd.O)R.sup.5,
--NR.sup.9C(.dbd.O)(CH.sub.2).sub.nR.sup.5,
--NR.sup.9C(.dbd.O)OR.sup.5, --NHS(.dbd.O).sub.2R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9C(.dbd.O)R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9S(.dbd.O).sub.2R.sup.5,
##STR00329## an 8-oxa-3-azabicyclo[3.2.1]octanyl, a 5-6 membered
heteroaryl having 1 to 3 ring members independently selected from
N, O and S, or a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 and O which is
unsubstituted or is substituted with 1-2 R.sup.7 groups; R.sup.2 is
H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl or
C.sub.1-C.sub.6alkyl substituted with 1-2 R.sup.15 groups; R.sup.3
is H, C.sub.1-C.sub.6alkyl, --CD.sub.3 or benzyl substituted with
1-2 R.sup.10 groups; R.sup.4 is H, NH.sub.2, C.sub.1-C.sub.6alkyl,
halo or a phenyl substituted with 0-2 R.sup.18 groups; each R.sup.5
is independently selected from C.sub.1-C.sub.6alkyl, --CD.sub.3 and
--(CH.sub.2).sub.nOR.sup.9; R.sup.6 is a C.sub.3-C.sub.6cycloalkyl,
an oxa-3-azabicyclo[3.2.1]octane or a 4-6 membered heterocycloalkyl
having 1 to 2 ring members independently selected from N, NH,
NR.sup.16 and O which is unsubstituted or is substituted with 1-2
R.sup.12 groups; each R.sup.7 is independently selected from
C.sub.1-C.sub.6alkyl, halo, hydroxyl, oxo and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; each R.sup.8 is
independently selected from C.sub.1-C.sub.6haloalkyl,
--(C(R.sup.9).sub.2).sub.nOR.sup.9 and a C.sub.1-C.sub.6alkyl
substituted with 1 to 3 --OH; each R.sup.9 is independently
selected from H and C.sub.1-C.sub.6alkyl; R.sup.10 is
C.sub.1-C.sub.6alkoxy or C.sub.3-C.sub.6cycloalkyl; R.sup.11 is a
C.sub.3-C.sub.6cycloalkyl which is unsubstituted or is substituted
with 1 to 3 C.sub.1-C.sub.6alkyl groups; each R.sup.12 is
independently selected from C.sub.1-C.sub.6alkyl, hydroxyl, halo
and a C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; R.sup.13
is H or C.sub.1-C.sub.6alkyl; R.sup.14 is H or
C.sub.1-C.sub.6alkyl; R.sup.15 is
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nN(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.8, --N(R.sup.6R.sup.8),
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CHR.sup.9).sub.nR.sup.6, --N(R.sup.6).sub.2,
--N(CD.sub.3).sub.2, --NH(CHR.sup.9).sub.nOR.sup.9 or
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9; each R.sup.16 is
C.sub.1-C.sub.6alkyl; each R.sup.7 is independently selected from H
and C.sub.1-C.sub.6alkyl; each R.sup.18 is independently selected
from halo, --CN, C.sub.1-C.sub.6alkoxy and C.sub.1-C.sub.6alkyl; m
is 1, 2, 3, 4, 5 or 6, and n is 1, 2, 3, 4, 5 or 6.
2. The compound of claim 1 having the structure of Formula (I) or
Formula (II), or a pharmaceutically acceptable salt thereof:
##STR00330## wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2
and R.sub.A are as defined in claim 1.
3. The compound of claim 1 or claim 2, wherein the compound of
Formula (A) or compound of Formula (I) has the structure of Formula
(Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie),
Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula
(Ij) or Formula (Ik), or a pharmaceutically acceptable salt
thereof: ##STR00331## ##STR00332## ##STR00333## wherein Y.sub.1,
Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.13
and R.sup.14 are as defined in claim 1.
4. The compound of claim 1 or claim 2, wherein the compound of
Formula (A) or compound of Formula (II) has the structure of
Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula
(IIe), Formula (IIf), Formula (IIg), Formula (IIh), Formula (IIi),
Formula (IIj) or Formula (IIk), or a pharmaceutically acceptable
salt thereof: ##STR00334## ##STR00335## ##STR00336## wherein
Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.13 and R.sup.14 are as defined in claim 1.
5. The compound of any one of claims 1 to 4, wherein: R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nOR.sup.9, --NHC(.dbd.O)OR.sup.9,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6, --NHR.sup.6,
--NR.sup.5R.sup.6, --NH.sub.2, --N(R.sup.5).sub.2, --NHR.sup.5,
--NHR.sup.8, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CH.sub.2).sub.nR.sup.6, --N(R.sup.6).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nN(CD.sub.3).sub.2,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9, --OR.sup.9,
--NR.sup.9C(.dbd.O)R.sup.5, --NR.sup.9C(.dbd.O)OR.sup.5,
--NHS(.dbd.O).sub.2R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9C(.dbd.O)R.sup.5, or
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9S(.dbd.O).sub.2R.sup.5.
6. The compound of any one of claims 1 to 4, wherein: R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.5, --NHR.sup.8,
--NH(CHR.sup.9).sub.nOR.sup.9 or
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9.
7. The compound of any one of claims 1 to 4, wherein: R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6 or --NHR.sup.6.
8. The compound of any one of claims 1 to 4, wherein: L is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; Y.sub.1 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; Y.sub.2 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; Y.sub.3 is --CH.sub.2-- or --XCH.sub.2--; X
is --CH.sub.2-- or O; R.sup.1 is
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6,
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NH(CH.sub.2).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
or --NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9; R.sup.2 is H,
C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6haloalkyl; R.sup.3 is H,
C.sub.1-C.sub.6alkyl or --CD.sub.3; R.sup.4 is H, NH.sub.2,
C.sub.1-C.sub.6alkyl or halo; each R.sup.5 is independently
C.sub.1-C.sub.6alkyl, --CD.sub.3 or --(CH.sub.2).sub.nOR.sup.9;
R.sup.6 is a C.sub.3-C.sub.6cycloalkyl or a 4-6 membered
heterocycloalkyl having 1 to 2 ring members independently selected
from N, NH, NR.sup.16 and O which is unsubstituted or is
substituted with 1-2 R.sup.12 groups; each R.sup.8 is independently
selected from C.sub.1-C.sub.6haloalkyl,
--(C(R.sup.9).sub.2).sub.nOR.sup.9 and a C.sub.1-C.sub.6alkyl
substituted with 1 to 3 --OH; each R.sup.9 is independently
selected from H and C.sub.1-C.sub.6alkyl; R.sup.10 is
C.sub.1-C.sub.6alkoxy or C.sub.3-C.sub.6cycloalkyl; each R.sup.12
is independently selected from C.sub.1-C.sub.6alkyl, hydroxyl, halo
and a C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; R.sup.13
is H or C.sub.1-C.sub.6alkyl; R.sup.14 is H or
C.sub.1-C.sub.6alkyl; each R.sup.16 is C.sub.1-C.sub.6alkyl; each
R.sup.17 is independently H or C.sub.1-C.sub.6alkyl; each R.sup.18
is independently halo, --CN, C.sub.1-C.sub.6alkoxy or
C.sub.1-C.sub.6alkyl; m is 1, 2, 3, 4, 5 or 6, and n is 1, 2, 3, 4,
5 or 6.
9. The compound of any one of claims 1 to 4, wherein: L is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; Y.sub.1 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; Y.sub.2 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; Y.sub.3 is --CH.sub.2-- or --XCH.sub.2--; X
is --CH.sub.2-- or O; R.sup.1 is --NHR.sup.6, --NR.sup.5R.sup.6,
--NH.sub.2, --N(R.sup.5).sub.2, --NHR.sup.5, --NHR.sup.8,
--N(R.sup.6R.sup.8) or --N(R.sup.6).sub.2; R.sup.2 is H,
C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6haloalkyl; R.sup.3 is H,
C.sub.1-C.sub.6alkyl or --CD.sub.3; R.sup.4 is H, NH.sub.2,
C.sub.1-C.sub.6alkyl or halo; each R.sup.5 is independently
C.sub.1-C.sub.6alkyl, --CD.sub.3 or --(CH.sub.2).sub.nOR.sup.9;
R.sup.6 is a C.sub.3-C.sub.6cycloalkyl or a 4-6 membered
heterocycloalkyl having 1 to 2 ring members independently selected
from N, NH, NR.sup.16 and O which is unsubstituted or is
substituted with 1-2 R.sup.12 groups; each R.sup.8 is independently
selected from C.sub.1-C.sub.6haloalkyl,
--(C(R.sup.9).sub.2).sub.nOR.sup.9 and a C.sub.1-C.sub.6alkyl
substituted with 1 to 3 --OH; each R.sup.12 is independently
selected from C.sub.1-C.sub.6alkyl, hydroxyl, halo and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; R.sup.13 is H or
C.sub.1-C.sub.6alkyl; R.sup.14 is H or C.sub.1-C.sub.6alkyl; each
R.sup.16 is C.sub.1-C.sub.6alkyl; each R.sup.17 is independently H
or C.sub.1-C.sub.6alkyl; each R.sup.18 is independently halo, --CN,
C.sub.1-C.sub.6alkoxy or C.sub.1-C.sub.6alkyl; m is 1, 2, 3, 4, 5
or 6, and n is 1, 2, 3, 4, 5 or 6.
10. The compound of any one of claims 1 to 9, wherein R.sup.6 is a
unsubstituted 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH and O.
11. The compound of any one of claims 1 to 9, wherein R.sup.6 is
cyclobutyl, oxetanyl, piperidinyl, pyrrolidinyl, morpholinyl or
azetadinyl.
12. The compound of claim 1 selected from:
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahyd-
ro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahy-
dro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra-
hydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)o-
xetan-3-amine;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(dimethylamino)acetamide
(S)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide;
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide;
6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-oxa-6-azaspiro[3.3]heptane;
4-(1-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,-
3-c]pyridin-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-6,7-dihydro-2H-pyrazolo[4,-
3-c]pyridin-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
4-(1-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-3-methyl-6,7-dihydro-1H-py-
razolo[4,3-c]pyridin-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amin-
e;
4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-3-methyl-6,7-dihydro-2H--
pyrazolo[4,3-c]pyridin-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-am-
ine;
4-((5-(5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-amine;
1,6-dimethyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyraz-
olo[3,4-d]pyrimidine;
1,3,5-trimethyl-7-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]octan-1--
yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[4,3-
-d]pyrimidine;
N-(2-methoxyethyl)-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyri-
midin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyc-
lo[2.2.2]octan-1-amine;
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl-
)morpholine;
2-(ethylamino)-N-(4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4--
yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2-
]octan-1-yl)acetamide;
4-(4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)mor-
pholine;
2-(ethylamino)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-
-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methy-
l)bicyclo[2.2.2]octan-1-yl)acetamide;
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(oxetan-3-ylmethyl)bi-
cyclo[2.2.2]octan-1-amine;
3-(dimethylamino)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]py-
rimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bic-
yclo[2.2.2]octan-1-yl)propanamide;
4-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine;
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-am-
ine;
N-cyclobutyl-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimi-
din-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo-
[2.2.2]octan-1-amine;
N,N-dicyclobutyl-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimi-
din-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo-
[2.2.2]octan-1-amine;
6-methyl-4-(3-methyl-1-((4-(piperidin-1-yl)bicyclo[2.2.2]octan-1-yl)methy-
l)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[3,4-d]pyrim-
idine;
6-methyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]octan-1-y-
l)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[3,4--
d]pyrimidine;
(3-(((4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)amino)methyl)oxetan-3-yl)methanol;
N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)azetidine-3-carboxamide;
(S)--N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-yl)morpholine-3-carboxamide;
(S)--N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-yl)morpholine-2-carboxamide;
(R)--N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-yl)morpholine-3-carboxamide;
(R)--N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-yl)morpholine-2-carboxamide;
3,6-dimethyl-4-(3-methyl-1-((4-morpholinobicyclo[2.2.2]octan-1-yl)methyl)-
-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)isoxazolo[5,4-d]pyrimidine-
;
1,3,5-trimethyl-7-(3-methyl-1-((4-(piperidin-1-yl)bicyclo[2.2.2]octan-1--
yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[4,3-
-d]pyrimidine;
1,6-dimethyl-4-(3-methyl-1-((4-(piperidin-1-yl)bicyclo[2.2.2]octan-1-yl)m-
ethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[3,4-d]p-
yrimidine;
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-y-
l)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(tride-
uteromethyl)bicyclo[22.2]octan-1-amine;
4-((3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-pyr-
azolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethylbicyclo[2.2.2]oc-
tan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-(trifluoromethyl)-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,-
5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-
-1-ol;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5-
,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan--
1-yl)acetamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)m-
ethanesulfonamide; tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)(me-
thyl)carbamate;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]octan--
1-amine; 1-methylcyclopropyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)car-
bamate;
3-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[1.1.1]pentan-1-
-amine;
4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl-
)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicycl-
o[2.2.2]octan-1-amine;
N-cyclobutyl-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-isopropylbicyclo[2.2.2]oct-
an-1-amine;
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)propan-1-ol;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-ethylbicyclo[2.2.2]octan-1-
-amine;
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(py-
rrolidin-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyraz-
olo[4,3-c]pyridine;
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)m-
orpholine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-7,7-dimethy-
l-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]o-
ctan-1-amine;
N-(2,2-difluoroethyl)-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-
-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo-
[2.2.2]octan-1-amine;
-((3-methyl-5-(2-methylquinolin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3--
c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3--
c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
1-((4-(azetidin-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-(1,6-dimethyl-1H--
pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c-
]pyridine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-7,7-dimethy-
l-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]o-
ctan-1-amine;
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)t-
hiomorpholine 1,1-dioxide;
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(piperidin-
-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3--
c]pyridine;
1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)a-
zetidin-3-ol;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)bicyclo[2.-
2.2]octan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-methoxyethyl)bicyc-
lo[2.2.2]octan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-ethoxyethyl)bicyclo[2.2-
.2]octan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-ethoxyethyl)bicycl-
o[2.2.2]octan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-N-methylb-
icyclo[2.2.2]octan-1-amine;
(3S,4R)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)pyrrolidine-3,4-diol;
(S)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)pyrrolidin-3-ol;
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-N,N-dimethylacetamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
N-methyloxetan-3-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-isopropyl-N-methylbicyclo[-
2.2.2]octan-1-amine;
N-cyclobutyl-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo-
[2.2.2]octan-1-amine;
(3S,4S)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)pyrrolidine-3,4-diol;
1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2-oxabicyclo[2.2.2]octan-4-a-
mine;
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(pyrr-
olidin-1-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-p-
yrazolo[4,3-c]pyridine;
4-((5-(6-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-me-
thyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.-
2]octan-1-amine;
4-(4-(1-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-3-methyl-6,7-dihydro-1H-
-pyrazolo[4,3-c]pyridin-5(4H)-yl)pyridin-2-yl)benzonitrile;
3-methyl-5-(2-phenylpyridin-4-yl)-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]oc-
tan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;
2-methyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]octan-1-yl)meth-
yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1,7-naphthyridine;
4-((5-(2-(4-fluorophenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((5-(2-(2-fluoro-4-methylphenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahyd-
ro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((5-(2-(4-methoxyphenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-py-
razolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((3-methyl-5-(2-(p-tolyl)pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4-
,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-(2-(5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-te-
trahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl)bicyclo[2.2.2]octan-1-amine;
4-((5-(2,8-dimethyl-1,7-naphthyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-
-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((3-methyl-5-(2-methyl-6-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyra-
zolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
4-((5-([2,2'-bipyridin]-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(piperidin-
-1-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazol-
o[4,3-c]pyridine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(1-methoxypropan-2-yl)bicy-
clo[2.2.2]octan-1-amine;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-ethyl-N-methylbicyclo[2.2.-
2]octan-1-amine;
1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethyl-2-oxabicyclo[2.-
2.2]octan-4-amine;
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-1-(piperidin-1-yl)ethanone;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(pyrrolidin-1-yl)acetamide;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxy-2-methylpropyl)-
bicyclo[2.2.2]octan-1-amine;
1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-2-oxabicy-
clo[2.2.2]octan-4-amine;
4-((5-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7-te-
trahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine-
;
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
-1-methylpiperazin-2-one;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
3-(dimethylamino)propanamide;
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-1-(pyrrolidin-1-yl)ethanone;
(R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-2-methylmorpholine;
1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
4-methylpiperazin-2-one;
(S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-2-methylmorpholine;
(2S,6R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-2,6-dimethylmorpholine;
(2S,6S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-2,6-dimethylmorpholine;
N-(cyclobutylmethyl)-1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)--
3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2-oxabi-
cyclo[2.2.2]octan-4-amine;
(2R,6R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-2,6-dimethylmorpholine;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(ethylamino)acetamide;
3-amino-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)propanamide;
6-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-oxa-6-azaspiro[3.3]heptane;
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-(methylamino)propanamide;
(S)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-(methylamino)propanamide;
1-((4-(1H-imidazol-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-(1,6-dimethyl--
1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,-
3-c]pyridine;
(1R,5S)-3-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-8-oxa-3-azabicyclo[3.2.1]octane;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(methylamino)acetamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
4-methylmorpholine-3-carboxamide;
1-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-2-methylpropan-2-ol;
2-(ethylamino)-N-(4-((3-methyl-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl-
)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]o-
ctan-1-yl)acetamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)m-
orpholine-2-carboxamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
3-(ethylamino)propanamide;
N-ethyl-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyraz-
olo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
(S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-3-methylmorpholine;
(R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-3-methylmorpholine;
N-(2-methoxyethyl)-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahyd-
ro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)a-
zetidine-3-carboxamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(ethyl(methyl)amino)acetamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(3-fluoroazetidin-1-yl)acetamide;
2-(bis(trideuteromethyl)amino)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]p-
yridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)me-
thyl)bicyclo[2.2.2]octan-1-yl)acetamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-hydroxyacetamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(3-hydroxyazetidin-1-yl)acetamide;
(3-(((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,-
7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-y-
l)amino)methyl)oxetan-3-yl)methanol;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(N-methylmethylsulfonamido)acetamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(N-methylacetamido)acetamide
4-((3-methyl-5-(6-methyl-1-(trideuteromethyl)-1H-pyrazolo[3,4-b]pyridin-4-
-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.-
2]octan-1-amine;
(S)--N-(4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl--
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-
an-1-yl)morpholine-3-carboxamide;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
3-(methylamino)propanamide;
N-cyclobutyl-1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2-oxabicyclo[2.-
2.2]octan-4-amine;
N-cyclobutyl-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H--
pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
tert-butyl
(4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl-
)carbamate; tert-butyl
(4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrah-
ydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbam-
ate; tert-butyl
(4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-py-
razolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate;
tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptan-1-yl)ca-
rbamate;
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,-
5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-
-1-amine, and
4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-ami-
ne.
13. The compound of claim 1 selected from:
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)o-
xetan-3-amine;
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(dimethylamino)acetamide;
(S)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide;
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide, and
6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-oxa-6-azaspiro[3.3]heptane.
14. A pharmaceutical composition comprising a therapeutically
effective amount a compound of any one of claims 1 to 13 and a
pharmaceutically acceptable carrier.
15. Use of a compound of any one of claims 1 to 13 in the
manufacture of a medicament for treating an autoimmune disease
associated with the activity of an endosomal Toll-Like Receptor
selected from TLR7, TLR8 and TLR9, or a combination thereof.
16. Use of a compound of any one of claims 1 to 13 in the
manufacture of a medicament for treating an autoimmune disease
associated with the activity of an endosomal Toll-Like Receptor
pathway selected from TLR7 pathway, TLR8 pathway and TLR9 pathway,
or a combination thereof.
17. Use of a compound of any one of claims 1 to 13 in the
manufacture of a medicament for treating an autoimmune disease
associated with i) TLR7 activity, or ii) TLR7 activity and TLR8
activity, or iii) TLR7 activity and TLR8 activity and TLR9
activity.
18. A method for treating an autoimmune disease associated with the
activity of an endosomal Toll-Like Receptor selected from TLR7,
TLR8 and TLR9, or a combination thereof, wherein the method
comprises administering to a subject in need of such treatment a
therapeutically effective amount of a compound of any one of claims
1 to 13.
19. A method for treating an autoimmune disease associated with the
activity of an endosomal Toll-Like Receptor pathway selected from
TLR7 pathway, TLR8 pathway and TLR9 pathway, or a combination
thereof, wherein the method comprises administering to a subject in
need of such treatment a therapeutically effective amount of a
compound of any one of claims 1 to 13.
20. A method for treating an autoimmune disease associated with i)
TLR7 activity, or ii) TLR7 activity and TLR8 activity, or iii) TLR7
activity and TLR8 activity and TLR9 activity, wherein the method
comprises administering to a subject in need of such treatment a
therapeutically effective amount of a compound of any one of claims
1 to 13.
21. The use of any one of claims 15 to 17 or the method of any one
of claim 18 to 20, wherein the autoimmune disease is systemic lupus
erythematosus, cutaneous lupus, discoid lupus, mixed connective
tissue disease, primary biliary cirrhosis, immune thrombocytopenia
purpura, hidradenitis suppurativa, dermatomyositis, polymyositis,
Sjogren's syndrome, arthritis, rheumatoid arthritis or
psoriasis.
22. A compound of any one of claims 1 to 13 for use in treating an
autoimmune disease.
23. The compound of claim 22, wherein the autoimmune disease is
systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed
connective tissue disease, primary biliary cirrhosis, immune
thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis.
24. A combination comprising a therapeutically effect amount of a
compound of any one of claims 1 to 13 and one or more additional
therapeutic agents, wherein the additional therapeutic agent is
independently selected from anti-inflammatory agents,
immunomodulatory agents, immunosuppressive agents, cytokines,
nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarial
compounds, anti-rheumatic compounds, inhibitors of B-cell
activating factor (BAFF), inhibitors of B-lymphocyte stimulator
(BLyS), and steroid hormones.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/385,726, filed 9 Sep. 2016, which is
incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The invention provides
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine compounds and
4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine compounds, the use
thereof for inhibiting an endosomal Toll-like receptor (e.g. TLR7,
TLR8 or TLR9) and any combinations thereof (including, but not
limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9), the use thereof
for inhibiting an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, and any combinations thereof, and methods of
treating autoimmune diseases using such compounds.
BACKGROUND OF THE INVENTION
[0003] Early detection of specific classes of pathogens is
accomplished by the innate immune system with the help of pattern
recognition receptors (PRRs). Toll-like receptors (TLRs) are
pattern recognition receptors which play an essential role in the
innate immunity, by recognizing invasion of microbial pathogens and
initiating intracellular signal transduction pathways to trigger
expression of genes, the products of which can control innate
immune responses. There are 10 TLRs in the human genome, where
TLR1, TLR2, TLR4, TLR5, and TLR6 respond to extracellular stimuli,
while TLR3, TLR7, TLR8, and TLR9 respond to intracytoplasmic
pathogen associated molecular patterns (PAMPs), being associated
with the endolysosomal compartment.
[0004] Toll-like receptors recognize pathogens associated molecular
patterns present in molecules that are broadly shared by pathogens
but are structurally distinct from host molecules. The ligands for
these receptors are highly conserved microbial molecules such as
lipopolysaccharides (LPS) (recognized by TLR4), lipopeptides (TLR2
in combination with TLR1 or TLR6), flagellin (TLR5),
single-stranded RNA (TLR7 and TLR8), double-stranded RNA (TLR3),
CpG motif-containing DNA (recognized by TLR9), and profilin present
on uropathogenic bacteria (TLR 11). Thus cell-surface TLR dimers
including TLR4-MD-2, TLR1-TLR2, and TLR6-TLR2 recognize microbial
membrane lipids, whereas the endosomal Toll-like receptors TLR3,
TLR7, TLR8, and TLR9 reside in intracellular organelles and
recognize microbial nucleic acids.
[0005] TLR7, TLR8, and TLR9 belong to a subfamily of TLRs based on
their genomic structure, sequence similarities, and homology. TLR7,
TLR8, and TLR9 are located in intracellular endolysosomal
compartments and show a unique pattern of cell type-specific
expression that is thought to be responsible for different pathogen
response profiles.
[0006] In addition to recognizing foreign material, TLRs can
mistakenly respond to self products and cause autoimmune diseases.
TLR7 and 9, innate immune sensors for microbial RNA or DNA,
respectively, have been implicated in autoimmune diseases such as
psoriasis (see Lande et al., "Plasmacytoid dendritic cells sense
self-DNA coupled with antimicrobial peptide", Nature 449, pp
564-569, 2007), arthritis (see Asagiri et al., "Cathepsin
K-dependent toll-like receptor 9 signaling revealed in experimental
arthritis", Science 319, pp 624-627, 2008), and systemic lupus
erythematosus (SLE) (see Pisitkun, P. et al. "Autoreactive B cell
responses to RNA-related antigens due to TLR7 gene duplication",
Science 312, pp 1669-72, 2006; Deane, J. A. et al., "Control of
toll-like receptor 7 expression is essential to restrict
autoimmunity and dendritic cell proliferation", Immunity, 27, pp
801-10, 2007; Christensen, S. R. et al. "Toll-like receptor 7 and
TLR9 dictate autoantibody specificity and have opposing
inflammatory and regulatory roles in a murine model of lupus",
Immunity 25, pp 417-428, 2006; Ehlers, M., et al. "TLR9/MyD88
signaling is required for class switching to pathogenic IgG2a and
2b autoantibodies in SLE", J. Exp. Med. 203, pp 553-561, 2006;
Deane, J. A., and Bolland S. "Nucleic acid-sensing TLRs as
modifiers of autoimmunity", J. Immunol., 117, pp 6573-8, 2006; and
Marshak-Rothstein, A., and Rifkin, I. R., "Immunologically active
autoantigens: the role of toll-like receptors in the development of
chronic inflammatory disease", Annu. Rev. Immunol., 25, pp 419-441,
2007).
[0007] It has been shown that autoimmunity is exacerbated by the
aberrant trafficking of self nucleic acids to endolysosomes (see
Lande et al., 2007; Marshak-Rothstein and Rifkin, 2007; and
Leadbetter et al., "Chromatin-IgG complexes activate B cells by
dual engagement of IgM and Toll-like receptors", Nature, 416, pp
603-607, 2002). In autoimmune diseases like SLE, self-RNA and
self-DNA are complexed with autoantibodies against the nucleic acid
or nucleoproteins, delivered into endosomal compartments via
FcgRII-mediated endocytosis, leading to dendritic cell (DC)
activation and production of type I interferon (IFN) (Barrat et
al., "Nucleic acids of mammalian origin can act as endogenous
ligands for Toll-like receptors and may promote systemic lupus
erythematosus", J. Exp. Med. 202, pp 1131-1139, 2005). While in
psoriasis, self-DNA and -RNA form complexes with the cationic
antimicrobial peptide LL37, gain access to TLR7 and 9 in
endolysosomes of DCs, and induce aberrant production of IFN-a
(Ganguly et al., "Self-RNA-antimicrobial peptide complexes activate
human dendritic cells through TLR7 and TLR8", J. Exp. Med. 206, pp
1983-1994, 2009; and Lande et al., 2007). In rheumatoid arthritis
(RA) the synovial membrane is infiltrated by activated immune
cells, predominantly macrophages and T cells, resulting in the
chronic production of proinflammatory cytokines and matrix
metalloproteinases. TNF plays a central role in RA and the
inhibition of TLR8 has been shown to inhibit TNF production (see
Sandra M. Sacre et al. "Inhibitors of TLR8 Reduce TNF Production
from Human Rheumatoid Synovial Membrane Cultures", J. Immun., 81,
pp 8002-8009, 2008).
[0008] Because of their association with autoimmune diseases, it
has been suggested that TLR7, TLR8 and TLR9 are important
therapeutic targets for the treatment of systemic lupus
erythematosus, rheumatoid arthritis, psoriasis and other autoimmune
diseases.
SUMMARY OF THE INVENTION
[0009] There remains a need for new treatments and therapies for
autoimmune diseases, in particular autoimmune diseases associated
with TLR7, TLR8 and/or TLR9 activity. The invention provides
compounds, pharmaceutically acceptable salts thereof,
pharmaceutical compositions thereof, which may inhibit an endosomal
Toll-like receptor (e.g. TLR7, TLR8 or TLR9) and any combinations
thereof (including, but not limited to, TLR7/8, TLR7/8/9, TLR7/9,
and TLR8/9). Additionally, the compounds of the invention may
inhibit an endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9)
pathway, and any combinations thereof. The invention further
provides methods of treating, preventing, or ameliorating
autoimmune diseases associated with the activity of an endosomal
Toll-like receptor (e.g. TLR7, TLR8 or TLR9), or any combinations
thereof (including, but not limited to, TLR7/8, TLR7/8/9, TLR7/9,
and TLR8/9), comprising administering to a subject in need thereof
an effective amount of a compound of the invention. Various
embodiments of the invention are described herein.
[0010] In one aspect of the invention are compounds having the
structure of Formula (A), and the pharmaceutically acceptable salts
thereof, which may inhibit an endosomal Toll-like receptor (e.g.
TLR7, TLR8 or TLR9) and any combinations thereof (including, but
not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9).
Additionally, the compounds of Formula (A) may inhibit an endosomal
Toll-like receptor (e.g. TLR7, TLR8 or TLR9) pathway, and any
combinations thereof:
##STR00002##
wherein: [0011] R.sup.A is
[0011] ##STR00003## [0012] L is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0013] Y.sub.1 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0014] Y.sub.2 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0015] Y.sub.3 is --CH.sub.2--, --XCH.sub.2--
or --CH.sub.2X--; [0016] X is --CH.sub.2-- or O; [0017] R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nOR.sup.9, --NHC(.dbd.O)OR.sup.9,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6,
NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nN(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6, --NHR.sup.6,
--NR.sup.5R.sup.6, --NH.sub.2, --N(R.sup.5).sub.2, --NHR.sup.5,
--NHR.sup.8, --N(R.sup.6R.sup.8),
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CH.sub.2).sub.nR.sup.6, --NH(CHR.sup.9).sub.nR.sup.6,
--N(R.sup.6).sub.2, --NHC(.dbd.O)(CH.sub.2).sub.nN(CD.sub.3).sub.2,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9, --OR.sup.9,
--NR.sup.9C(.dbd.O)R.sup.5,
--NR.sup.9C(.dbd.O)(CH.sub.2).sub.nR.sup.5,
--NR.sup.9C(.dbd.O)OR.sup.5, --NHS(.dbd.O).sub.2R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9C(.dbd.O)R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9S(.dbd.O).sub.2R.sup.5,
##STR00004##
[0017] an 8-oxa-3-azabicyclo[3.2.1]octanyl, a 5-6 membered
heteroaryl having 1 to 3 ring members independently selected from
N, O and S, and a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 and O which is
unsubstituted or is substituted with 1-2 R.sup.7 groups; [0018]
R.sup.2 is H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl or
C.sub.1-C.sub.6alkyl substituted with 1-2 R.sup.15 groups; [0019]
R.sup.3 is H, C.sub.1-C.sub.6alkyl, --CD.sub.3 or benzyl
substituted with 1-2 R.sup.10 groups; [0020] R.sup.4 is H,
NH.sub.2, C.sub.1-C.sub.6alkyl, halo or a phenyl substituted with
0-2 R.sup.18 groups; [0021] each R.sup.5 is independently selected
from C.sub.1-C.sub.6alkyl, --CD.sub.3 and
--(CH.sub.2).sub.nOR.sup.9; [0022] R.sup.6 is a
C.sub.3-C.sub.6cycloalkyl, an oxa-3-azabicyclo[3.2.1]octane, or a
4-6 membered heterocycloalkyl having 1 to 2 ring members
independently selected from N, NH, NR.sup.16 and O which is
unsubstituted or is substituted with 1-2 R.sup.12 groups; [0023]
each R.sup.7 is independently selected from C.sub.1-C.sub.6alkyl,
halo, hydroxyl, oxo and a C.sub.1-C.sub.6alkyl substituted with 1
to 3 --OH; [0024] each R.sup.8 is independently selected from
C.sub.1-C.sub.6haloalkyl, --(C(R.sup.9).sub.2).sub.nOR.sup.9 and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0025] each
R.sup.9 is independently selected from H and C.sub.1-C.sub.6alkyl;
[0026] R.sup.10 is C.sub.1-C.sub.6alkoxy or
C.sub.3-C.sub.6cycloalkyl; [0027] R.sup.11 is a
C.sub.3-C.sub.6cycloalkyl which is unsubstituted or is substituted
with 1 to 3 C.sub.1-C.sub.6alkyl groups; [0028] each R.sup.12 is
independently selected from C.sub.1-C.sub.6alkyl, hydroxyl, halo
and a C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0029]
R.sup.13 is H or C.sub.1-C.sub.6alkyl; [0030] R.sup.14 is H or
C.sub.1-C.sub.6alkyl; [0031] R.sup.15 is
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nN(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.8, --N(R.sup.6R.sup.8),
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CHR.sup.9).sub.nR.sup.6, --N(R.sup.6).sub.2,
--N(CD.sub.3).sub.2, --NH(CHR.sup.9).sub.nOR.sup.9 or
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9; [0032] each R.sup.16
is C.sub.1-C.sub.6alkyl; [0033] each R.sup.17 is independently
selected from H and C.sub.1-C.sub.6alkyl; [0034] each R.sup.18 is
independently selected from halo, --CN, C.sub.1-C.sub.6alkoxy and
C.sub.1-C.sub.6alkyl; [0035] m is 1, 2, 3, 4, 5 or 6, and [0036] n
is 1, 2, 3, 4, 5 or 6
[0037] In certain embodiments of such compounds of Formula (A) are
compounds of Formula (I) and Formula (II):
##STR00005##
[0038] Another aspect of the invention is a pharmaceutical
compositions that includes a therapeutically effective amount of a
compound of Formula (A), Formula (I) or Formula (II) or subformulae
thereof, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0039] Another aspect of the invention is the use of a compound of
Formula (A), Formula (I) or Formula (II), or subformulae thereof,
or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for treating an autoimmune disease associated with
the activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9), or any combinations thereof (including, but not limited to,
TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9).
[0040] Another aspect of the invention is the use of a compound of
Formula (A), Formula (I) or Formula (II), or subformulae thereof,
or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for treating an autoimmune disease associated with
[0041] i) TLR7 activity, or [0042] ii) TLR7 activity and TLR8
activity, or [0043] iii) TLR7 activity and TLR8 activity and TLR9
activity.
[0044] Another aspect of the invention is the use of a compound of
Formula (A), Formula (I) or Formula (II), or subformulae thereof,
or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for treating an autoimmune disease associated with
the activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, and any combinations thereof.
[0045] Another aspect of the invention is the use of a compound of
Formula (A), Formula (I) or Formula (II), or subformulae thereof,
or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for treating an autoimmune disease.
[0046] Another aspect of the invention is the use of a compound of
Formula (A), Formula (I) or Formula (II), or subformulae thereof,
or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for treating an autoimmune disease is systemic
lupus erythematosus, cutaneous lupus, discoid lupus, mixed
connective tissue disease, primary biliary cirrhosis, immune
thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis. In an embodiment of this aspect
the autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, Sjogren's syndrome or psoriasis.
[0047] Another aspect of the invention is a method for treating an
autoimmune disease associated with the activity of an endosomal
Toll-like receptor (e.g. TLR7, TLR8 or TLR9), or any combinations
thereof (including, but not limited to, TLR7/8, TLR7/8/9, TLR7/9,
and TLR8/9), wherein the method includes administering to a subject
in need of such treatment an effective amount of a compound of
Formula (A), Formula (I) or Formula (II), or subformulae thereof,
or pharmaceutically acceptable salt thereof, thereby treating the
disease.
[0048] Another aspect of the invention is a method for treating an
autoimmune disease associated with: [0049] i) TLR7 activity, or
[0050] ii) TLR7 activity and TLR8 activity, or [0051] iii) TLR7
activity and TLR8 activity and TLR9 activity, wherein the method
includes administering to a subject in need of such treatment an
effective amount of a compound of Formula (A), Formula (I) or
Formula (II), or subformulae thereof, or pharmaceutically
acceptable salt thereof, thereby treating the disease.
[0052] Another aspect of the invention is a method for treating an
autoimmune disease associated with the activity of with the
activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, and any combinations thereof, wherein the method
includes administering to a subject in need of such treatment an
effective amount of a compound of Formula (A), Formula (I) or
Formula (II), or subformulae thereof, or pharmaceutically
acceptable salt thereof, thereby treating the disease.
[0053] Another aspect of the invention is a method for treating an
autoimmune disease associated with TLR7 activity, wherein the
method includes administering to a subject in need of such
treatment an effective amount of a compound of Formula (A), Formula
(I) or Formula (II), or subformulae thereof, or pharmaceutically
acceptable salt thereof, thereby treating the disease.
[0054] Another aspect of the invention is a method for treating an
autoimmune disease associated with TLR7 and TLR8 activity, wherein
the method includes administering to a subject in need of such
treatment an effective amount of a compound of Formula (A), Formula
(I) or Formula (II), or subformulae thereof, or pharmaceutically
acceptable salt thereof, thereby treating the disease.
[0055] Another aspect of the invention is a method for treating an
autoimmune disease associated with TLR7, TLR8 and TLR9 activity,
wherein the method includes administering to a subject in need of
such treatment an effective amount of a compound of Formula (A),
Formula (I) or Formula (II), or subformulae thereof, or
pharmaceutically acceptable salt thereof, thereby treating the
disease.
[0056] In certain embodiments of such methods of treatment the
autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, mixed connective tissue disease, primary
biliary cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis. In another embodiment
the autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, Sjogren's syndrome or psoriasis.
[0057] Another aspect of the invention is a compound of Formula
(A), Formula (I) or Formula (II), or subformulae thereof, or
pharmaceutically acceptable salt thereof, for use in treating an
autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, mixed connective tissue disease, primary
biliary cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis. In an embodiment of
this aspect the autoimmune disease is systemic lupus erythematosus,
cutaneous lupus, discoid lupus, Sjogren's syndrome or
psoriasis.
[0058] Another aspect of the invention is a combination comprising
a therapeutically effect amount of a compound of Formula (A),
Formula (I) or Formula (II), or subformulae thereof, or
pharmaceutically acceptable salt thereof, and one or more
additional therapeutically agents and optionally further comprising
a pharmaceutically acceptable carrier, wherein the additional
therapeutically agent is independently selected from
anti-inflammatory agents, immunomodulatory agents,
immunosuppressive agents, cytokines, nonsteroidal anti-inflammatory
drugs (NSAIDs), antimalarial compounds, anti-rheumatic compounds,
inhibitors of B-cell activating factor (BAFF), inhibitors of
B-lymphocyte stimulator (BLyS), and steroid hormones.
DETAILED DESCRIPTION OF THE INVENTION
[0059] Various enumerated embodiments of the invention are
described herein. It will be recognized that features specified in
each embodiment may be combined with other specified features to
provide further embodiments of the present invention.
Definitions
[0060] The term "C.sub.1-C.sub.6alkyl", as used herein, refers to a
fully saturated branched or straight chain hydrocarbon containing 1
to 6 carbon atoms. Non-limiting examples of "C.sub.1-C.sub.6alkyl"
groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and hexyl.
[0061] The term "C.sub.1-C.sub.6alkoxy", as used herein, refers to
the group --O--C.sub.1-C.sub.6alkyl, wherein the
"C.sub.1-C.sub.6alkyl" group is as defined herein. Non-limiting
examples of "C.sub.1-C.sub.6alkoxy" groups include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
tert-butoxy, n-pentyloxy, isopentyloxy and hexyloxy.
[0062] The term "cycloalkyl," as used herein, refers to a
saturated, monocyclic, fused bicyclic, fused tricyclic or bridged
polycyclic ring system. Non-limiting examples of fused bicyclic or
bridged polycyclic ring systems include bicyclo[1.1.1]pentane,
bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane,
bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and adamantanyl. As used
herein, the term "C.sub.3-C.sub.6cycloalkyl", refers to a saturated
monocyclic group having at least 3, and at most 6, carbon atoms.
Non-limiting examples of such "C.sub.3-C.sub.6cycloalkyl" groups
include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl
groups.
[0063] The term "C.sub.1-C.sub.6haloalkyl", as used herein, refer
to the respective "C.sub.1-C.sub.6alkyl", as defined herein,
wherein at least one of the hydrogen atoms of the
"C.sub.1-C.sub.6alkyl" is replaced by a halo atom. The
C.sub.1-C.sub.6haloalkyl groups can be
monoC.sub.1-C.sub.6haloalkyl, wherein such C.sub.1-C.sub.6haloalkyl
groups have one iodo, one bromo, one chloro or one fluoro.
Additionally, the C.sub.1-C.sub.6haloalkyl groups can be
diC.sub.1-C.sub.6haloalkyl wherein such C.sub.1-C.sub.6haloalkyl
groups can have two halo atoms independently selected from iodo,
bromo, chloro or fluoro. Furthermore, the C.sub.1-C.sub.6haloalkyl
groups can be polyC.sub.1-C.sub.6haloalkyl wherein such
C.sub.1-C.sub.6haloalkyl groups can have two or more of the same
halo atoms or a combination of two or more different halo atoms.
Such polyC.sub.1-C.sub.6haloalkyl can be
perhaloC.sub.1-C.sub.6haloalkyl where all the hydrogen atoms of the
respective C.sub.1-C.sub.6alkyl have been replaced with halo atoms
and the halo atoms can be the same or a combination of different
halo atoms. Non-limiting examples of C.sub.1-C.sub.6haloalkyl
groups include fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl.
[0064] The terms "halo" or "halogen" as used herein, refer to
fluoro, chloro, bromo and iodo.
[0065] The term "5-6 membered heteroaryl," as used herein, refers
to a monocyclic aromatic ring structure having 5 or 6 ring members,
wherein 1 to 3 ring members are independently selected from the
heteroatoms N, O and S. Non-limiting examples of 5-6 membered
heteroaryls include 2- or 3-furyl; 2- or 3-thienyl; 1-, 2- or
3-pyrrolyl; 2-, 4-, or 5-oxazolyl; 2-, 4-, or 5-thiazolyl; 1-, 2-,
4-, or 5-imidazolyl; 1-, 3-, 4-, or 5-pyrazolyl; 3-, 4-, or
5-isoxazolyl; 3-, 4-, or 5-isothiazolyl; 4- or 5-1,2,3-oxadiazolyl;
4- or 5-1,2,3-triazolyl; 2- or 5-1,3,4-thiadiazolyl; 2-, 3-, or
4-pyridyl; 3-, 4-, 5- or 6-pyridazinyl; 2-, 4-, 5- or
6-pyrimidinyl, and 2- or 3-pyrazinyl.
[0066] The term "heteroatoms" as used herein, refers to nitrogen
(N), oxygen (O) or sulfur (S) atoms.
[0067] The term "4-6 membered heterocycloalkyl," as used herein
refers to a monocyclic ring structure having 4 to 6 ring members,
wherein one to two of the ring members are independently selected
from N, NH, NR.sup.16, O or --S--, wherein R.sup.16 is
C.sub.1-C.sub.6alkyl. In preferred embodiments a 4-6 membered
heterocycloalkyl is a monocyclic ring structure having 4 to 6 ring
members wherein one to two of the ring members are independently
selected from N, NH, NR.sup.16 and O, wherein R.sup.16 is
C.sub.1-C.sub.6alkyl. Non-limiting examples of 4-6 membered
heterocycloalkyl groups, as used herein, include azetadinyl,
azetadin-1-yl, azetadin-2-yl, azetadin-3-yl, oxetanyl, oxetan-2-yl,
oxetan-3-yl, oxetan-4-yl, thietanyl, thietan-2-yl, thietan-3-yl,
thietan-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl,
pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl,
tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothienyl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-4-yl,
tetrahydrothien-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl,
piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl,
tetrahydropyranyl, tetrahydropyran-2-yl, tetrahydropyran-3-yl,
tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl,
tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl,
tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl,
tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl, piperazinyl,
piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl,
piperazin-5-yl, piperazin-6-yl, morpholinyl, morpholin-2-yl,
morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl,
thiomorpholinyl, thiomorpholin-2-yl, thiomorpholin-3-yl,
thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholin-6-yl,
oxathianyl, oxathian-2-yl, oxathian-3-yl, oxathian-5-yl,
oxathian-6-yl, dithianyl, dithian-2-yl, dithian-3-yl, dithian-5-yl,
dithian-6-yl, dioxolanyl, dioxolan-2-yl, dioxolan-4-yl,
dioxolan-5-yl, thioxanyl, thioxan-2-yl, thioxan-3-yl, thioxan-4-yl,
thioxan-5-yl, dithiolanyl, dithiolan-2-yl, dithiolan-4-yl,
dithiolan-5-yl, pyrazolidinyl, pyrazolidin-1-yl, pyrazolidin-2-yl,
pyrazolidin-3-yl, pyrazolidin-4-yl and pyrazolidin-5-yl.
[0068] The term "hydroxyl" as used herein, refers to a --OH
group.
[0069] The term "oxo" as used herein, refers to a .dbd.O group.
[0070] The term "autoimmune disease," or "autoimmune disorder," as
used herein, refers diseases wherein cells uncontrollably attack
the body's own tissues and organs (autoimmunity), producing
inflammatory reactions and other serious symptoms and diseases.
Non-limiting examples of autoimmune diseases include idiopathic
thrombocytopenic purpura, hemolytic anemia, systemic lupus
erythematosus, cutaneous lupus, discoid lupus, rheumatoid arthritis
(RA), multiple sclerosis (MS), systemic sclerosis, immune-mediated
or type 1 diabetes mellitus, immune mediated glomerulonephritis,
scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus
vulgaris, myasthenia gravis, inflammatory bowel diseases, Crohn's
disease, Graves' disease, psoriasis, autoimmune thyroid diseases,
Hashimoto's disease, Hashimoto's thyroiditis, polymyositis,
dermatomyositis, CREST syndrome, Goodpasture's syndrome, mixed
connective tissue disease myasthenia gravis pseudoparalytica,
ophtalmia sympatica, phakogene uveitis, chronical aggressive
hepatitis, primary billiary cirrhosis, autoimmune hemolytic anemy,
Werlof disease, vitiligo vulgaris, Behcet's disease, collagen
disease, uveitis, Sjogren's syndrome, autoimmune myocarditis,
autoimmune hepatic diseases, autoimmune gastritis, pemphigus,
Guillain-Barre syndrome, atherosclerosis, inflammatory bowel
disease, ankylosing spondylitis, idiopathic thrombocytopenia,
polyarteritis nodosa, primary biliary sclerosis, sarcoidosis,
sclerosing cholangitis, Takayasu's arteritis, temporal arteritis,
Wegener's granulomatosis and HTLV-1-associated myelopathy.
[0071] The terms "combination" or "pharmaceutical combination," as
used herein mean a product that results from the mixing or
combining of more than one active ingredient and includes both
fixed and non-fixed combinations of the active ingredients. The
term "fixed combination" means that the active ingredients, by way
of example, a compound of the invention and one or more additional
therapeutic agent, are administered to a subject simultaneously in
the form of a single entity or dosage. The term "non-fixed
combination" means that the active ingredients, by way of example,
a compound of the invention and one or more additional therapeutic
agent, are administered to a subject as separate entities either
simultaneously, concurrently or sequentially with no specific time
limits, wherein such administration provides therapeutically
effective levels of the active ingredients in the body of the
subject. The latter also applies to cocktail therapy, e.g. the
administration of 3 or more active ingredients.
[0072] The terms "composition" or "pharmaceutical composition," as
used herein, refers to a mixture of a compound of the invention
with at least one and optionally more than one other
pharmaceutically acceptable chemical components, such as carriers,
stabilizers, diluents, dispersing agents, suspending agents,
thickening agents, and/or excipients.
[0073] As used herein, the term "inhibit", "inhibition" or
"inhibiting" refers to the reduction or suppression of a given
condition, symptom, or disorder, or disease, or a significant
decrease in the baseline activity of a biological activity or
process.
[0074] The term "an optical isomer" or "a stereoisomer", as used
herein, refers to any of the various stereo isomeric configurations
which may exist for a given compound of the present invention and
includes geometric isomers. It is understood that a substituent may
be attached at a chiral center of a carbon atom. The term "chiral"
refers to molecules which have the property of
non-superimposability on their mirror image partner, while the term
"achiral" refers to molecules which are superimposable on their
mirror image partner. Therefore, the invention includes
enantiomers, diastereomers or racemates of the compound.
"Enantiomers" are a pair of stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a "racemic" mixture. The term is used to
designate a racemic mixture where appropriate. "Diastereoisomers"
are stereoisomers that have at least two asymmetric atoms, but
which are not mirror-images of each other. The absolute
stereochemistry is specified according to the Cahn-Ingold-Prelog
R-S system. When a compound is a pure enantiomer the
stereochemistry at each chiral carbon may be specified by either R
or S. Resolved compounds whose absolute configuration is unknown
can be designated (+) or (-) depending on the direction (dextro- or
levorotatory) which they rotate plane polarized light at the
wavelength of the sodium D line. Certain compounds described herein
contain one or more asymmetric centers or axes and may thus give
rise to enantiomers, diastereomers, and other stereoisomeric forms
that may be defined, in terms of absolute stereochemistry, as (R)-
or (S)-.
[0075] The term "pharmaceutically acceptable carrier", as used
herein, includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives (e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drug stabilizers, binders,
excipients, disintegration agents, lubricants, sweetening agents,
flavoring agents, dyes, and the like and combinations thereof, as
would be known to those skilled in the art (see, for example,
Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing
Company, 1990, pp. 1289-1329). Except insofar as any conventional
carrier is incompatible with the active ingredient, its use in the
therapeutic or pharmaceutical compositions is contemplated.
[0076] The term "pharmaceutically acceptable salt," as used herein,
refers to a salt which does not abrogate the biological activity
and properties of the compounds of the invention, and does not
cause significant irritation to a subject to which it is
administered.
[0077] The term "subject", as used herein, encompasses mammals and
non-mammals. Examples of mammals include, but are not limited to,
humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats,
swine, rabbits, dogs, cats, rats, mice, guinea pigs, and the like.
Examples of non-mammals include, but are not limited to, birds,
fish and the like. Frequently the subject is a human, and may be a
human who has been diagnosed as in need of treatment for a disease
or disorder associated with the activity of an endosomal Toll-like
receptor (e.g. TLR7, TLR8 or TLR9) and any combinations thereof
(including, but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and
TLR8/9), or associated with an endosomal Toll-like receptor (e.g.
TLR7, TLR8 or TLR9) pathway, and any combinations.
[0078] The term "a subject in need of such treatment", refers to a
subject which would benefit biologically, medically or in quality
of life from such treatment.
[0079] The term "therapeutically effective amount," as used herein,
refers to an amount of a compound of the present invention that
will elicit the biological or medical response of a subject, for
example, reduction or inhibition of an enzyme or a protein
activity, or ameliorate symptoms, alleviate conditions, slow or
delay disease progression, or prevent a disease, etc. In one
non-limiting embodiment, the term "a therapeutically effective
amount" refers to the amount of the compound of the present
invention that, when administered to a subject, is effective to (1)
at least partially alleviate, inhibit, prevent and/or ameliorate a
condition, or a disorder or a disease (i) mediated by an endosomal
Toll-like receptor (e.g. TLR7, TLR8 or TLR9) and any combinations
thereof (including, but not limited to, TLR7/8, TLR7/8/9, TLR7/9,
and TLR8/9), or mediated by an endosomal Toll-like receptor (e.g.
TLR7, TLR8 or TLR9) pathway, and any combinations thereof or (ii)
associated with an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) and any combinations thereof (including, but not limited to,
TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9), or associated with an
endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9) pathway, and
any combinations thereof, or (iii) characterized by activity
(normal or abnormal) of an endosomal Toll-like receptor (e.g. TLR7,
TLR8 or TLR9) and any combinations thereof (including, but not
limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9); or (2) reduce or
inhibit the activity of an endosomal Toll-like receptor (e.g. TLR7,
TLR8 or TLR9) and any combinations thereof (including, but not
limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9); or (3) reduce or
inhibit the expression of an endosomal Toll-like receptor (e.g.
TLR7, TLR8 or TLR9) and any combinations thereof (including, but
not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9). In another
non-limiting embodiment, the term "a therapeutically effective
amount" refers to the amount of the compound provided herein that,
when administered to a cell, or a tissue, or a non-cellular
biological material, or a medium, is effective to at least
partially reducing or inhibiting the activity of an endosomal
Toll-like receptor (e.g. TLR7, TLR8 or TLR9) and any combinations
thereof (including, but not limited to, TLR7/8, TLR7/8/9, TLR7/9,
and TLR8/9), or inhibiting the activity of an endosomal Toll-like
receptor (e.g. TLR7, TLR8 or TLR9) pathway, and any combinations
thereof.
[0080] The terms "TLR7 inhibitors", "TLR7 antagonist", "inhibitor
of TLR7" or "inhibitors of TLR7", as used herein, refer to a
compound of the invention which inhibits Toll-like Receptor 7
(TLR7). Compounds of the invention inhibit both type I Interferon
and proinflammatory cytokines downstream of TLR7.
[0081] The terms "TLR8 inhibitors", "TLR8 antagonist", "inhibitor
of TLR8" or "inhibitors of TLR8", as used herein, refer to a
compound of the invention which inhibits Toll-like Receptor 8
(TLR8).
[0082] The terms "TLR7 and TLR8 inhibitors", "TLR7 and TLR8
antagonists", "inhibitor of TLR7 and TLR8" or "inhibitors of TLR7
and TLR8", as used herein, refer to a compound of the invention
which inhibits Toll-like Receptor 7 (TLR7) and Toll-like Receptor 8
(TLR8). Compounds of the invention inhibit both type I Interferon
downstream of TLR7 and proinflammatory cytokines downstream of
NF-KB in TLR7 and TLR8 signaling. A "TLR7 and TLR8 inhibitor" or
"TLR7 and TLR8 antagonist" can also be represented by the term
"TLR7/8 antagonist".
[0083] The terms "TLR7, TLR8 and TLR9 inhibitors", "TLR7, TLR8 and
TLR9 antagonists", "inhibitor of TLR7, TLR8 and TLR9" or
"inhibitors of TLR7, TLR8 and TLR9", as used herein, refer to a
compound of the invention which inhibits Toll-like Receptor 7
(TLR7), Toll-like Receptor 8 (TLR8) and Toll-like Receptor 9
(TLR9). Compounds of the invention inhibit both type I Interferon
downstream of TLR7 and proinflammatory cytokines downstream of
NF-KB in TLR7 and TLR8 signaling. A "TLR7 and TLR8 and TLR9
inhibitor" or "TLR7 and TLR8 and TLR9 antagonist" can also be
represented by the term "TLR7/8/9 antagonist".
[0084] The terms "treat", "treating" or "treatment" of any disease
or disorder refers in one embodiment, to ameliorating the disease
or disorder (i.e., slowing or arresting or reducing the development
of the disease or at least one of the clinical symptoms thereof).
In another embodiment "treat", "treating" or "treatment" refers to
alleviating or ameliorating at least one physical parameter
including those which may not be discernible by the patient. In yet
another embodiment, "treat", "treating" or "treatment" refers to
modulating the disease or disorder, either physically, (e.g.,
stabilization of a discernible symptom), physiologically, (e.g.,
stabilization of a physical parameter), or both. In yet another
embodiment, "treat", "treating" or "treatment" refers to preventing
or delaying the onset or development or progression of the disease
or disorder.
[0085] The compound names provided herein were obtained using
ChemDraw Ultra version 12.0 (CambridgeSoft.RTM.) or JChem version
5.3.1 (ChemAxon).
[0086] Unless specified otherwise, the term "compounds of the
present invention", "compounds of the invention" or "compounds
provided herein" refers to compounds of formula (A), Formula (I),
Formula (II) and subformulae thereof (such as compounds of Formula
(Ia to Ip) and Formula (IIa to IIk), and pharmaceutically
acceptable salts, stereoisomers (including diastereoisomers and
enantiomers), rotamers, tautomers and isotopically labeled
compounds (including deuterium substitutions), as well as
inherently formed moieties.
[0087] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context.
Compounds of the Invention
[0088] The compounds of the invention are compounds having the
structure of Formula (A), or a pharmaceutically acceptable salt
thereof:
##STR00006##
wherein: [0089] R.sup.A is
[0089] ##STR00007## [0090] L is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0091] Y.sub.1 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0092] Y.sub.2 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0093] Y.sub.3 is --CH.sub.2--, --XCH.sub.2--
or --CH.sub.2X--; [0094] X is --CH.sub.2-- or O; [0095] R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nOR.sup.9, --NHC(.dbd.O)OR.sup.9,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9)C(.dbd.O)R.sup.6,
NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nN(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6, --NHR.sup.6,
--NR.sup.5R.sup.6, --NH.sub.2, --N(R.sup.5).sub.2, --NHR.sup.5,
--NHR.sup.8, --N(R.sup.6R.sup.8),
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CH.sub.2).sub.nR.sup.6, --NH(CHR.sup.9).sub.nR.sup.6,
--N(R.sup.6).sub.2, --NHC(.dbd.O)(CH.sub.2).sub.nN(CD.sub.3).sub.2,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9, --OR.sup.9,
--NR.sup.9C(.dbd.O)R.sup.5,
--NR.sup.9C(.dbd.O)(CH.sub.2).sub.nR.sup.5,
--NR.sup.9C(.dbd.O)OR.sup.5, --NHS(.dbd.O).sub.2R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9C(.dbd.O)R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9S(.dbd.O).sub.2R.sup.5,
##STR00008##
[0095] an 8-oxa-3-azabicyclo[3.2.1]octanyl, a 5-6 membered
heteroaryl having 1 to 3 ring members independently selected from
N, O and S, and a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 and O which is
unsubstituted or is substituted with 1-2 R.sup.7 groups; [0096]
R.sup.2 is H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl or
C.sub.1-C.sub.6alkyl substituted with 1-2 R.sup.15 groups; [0097]
R.sup.3 is H, C.sub.1-C.sub.6alkyl, --CD.sub.3 or benzyl
substituted with 1-2 R.sup.10 groups; [0098] R.sup.4 is H,
NH.sub.2, C.sub.1-C.sub.6alkyl, halo or a phenyl substituted with
0-2 R.sup.18 groups; [0099] each R.sup.5 is independently selected
from C.sub.1-C.sub.6alkyl, --CD.sub.3 and
--(CH.sub.2).sub.nOR.sup.9; [0100] R.sup.6 is a
C.sub.3-C.sub.6cycloalkyl, an oxa-3-azabicyclo[3.2.1]octane or a
4-6 membered heterocycloalkyl having 1 to 2 ring members
independently selected from N, NH, NR.sup.16 and O which is
unsubstituted or is substituted with 1-2 R.sup.12 groups; [0101]
each R.sup.7 is independently selected from C.sub.1-C.sub.6alkyl,
halo, hydroxyl, oxo and a C.sub.1-C.sub.6alkyl substituted with 1
to 3 --OH; [0102] each R.sup.8 is independently selected from
C.sub.1-C.sub.6haloalkyl, --(C(R.sup.9).sub.2).sub.nOR.sup.9 and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0103] each
R.sup.9 is independently selected from H and C.sub.1-C.sub.6alkyl;
[0104] R.sup.10 is C.sub.1-C.sub.6alkoxy or
C.sub.3-C.sub.6cycloalkyl; [0105] R.sup.11 is a
C.sub.3-C.sub.6cycloalkyl which is unsubstituted or is substituted
with 1 to 3 C.sub.1-C.sub.6alkyl groups; [0106] each R.sup.12 is
independently selected from C.sub.1-C.sub.6alkyl, hydroxyl, halo
and a C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0107]
R.sup.13 is H or C.sub.1-C.sub.6alkyl; [0108] R.sup.14 is H or
C.sub.1-C.sub.6alkyl; [0109] R.sup.15 is
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nN(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.8, --N(R.sup.6R.sup.8),
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CHR.sup.9).sub.nR.sup.6, --N(R.sup.6).sub.2,
--N(CD.sub.3).sub.2, --NH(CHR.sup.9).sub.nOR.sup.9 or
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9; [0110] each R.sup.16
is C.sub.1-C.sub.6alkyl; [0111] each R.sup.17 is independently
selected from H and C.sub.1-C.sub.6alkyl; [0112] each R.sup.18 is
independently selected from halo, --CN, C.sub.1-C.sub.6alkoxy and
C.sub.1-C.sub.6alkyl; [0113] m is 1, 2, 3, 4, 5 or 6, and [0114] n
is 1, 2, 3, 4, 5 or 6
[0115] Certain aspects and examples of the compounds of the
invention are provided in the following listing of additional,
enumerated embodiments. It will be recognized that features
specified in each embodiment may be combined with other specified
features to provide further embodiments of the present invention.
[0116] Embodiment 1. The compound having the structure of Formula
(A) is a compound having the structure of Formula (I) or Formula
(II), or a pharmaceutically acceptable salt thereof:
##STR00009##
[0116] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2 and
R.sub.A are as defined herein for compounds of Formula (A). [0117]
Embodiment 2. The compound having the structure of Formula (A) or
Formula (I) is a compound having the structure of Formula (Ia),
Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula
(If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij) or
Formula (Ik), or a pharmaceutically acceptable salt thereof:
[0117] ##STR00010## ##STR00011## ##STR00012## [0118] Formula (Ie)
Formula (If) wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.13, R.sup.14 and R.sup.18 are as
defined herein for compounds of Formula (A). [0119] Embodiment 3.
The compound having the structure of Formula (A) or Formula (I) is
a compound having the structure of Formula (Ia) or Formula (Ig), or
a pharmaceutically acceptable salt thereof:
##STR00013##
[0119] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.13 are as defined herein for compounds
of Formula (A) [0120] Embodiment 4. The compound having the
structure of Formula (A) or Formula (I) is a compound having the
structure of Formula (Ib), Formula (Ic) or Formula (Id), or a
pharmaceutically acceptable salt thereof:
##STR00014##
[0120] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.13 are as defined herein for compounds
of Formula (A). [0121] Embodiment 5. The compound having the
structure of Formula (A) or Formula (I) is a compound having the
structure of Formula (Ie) or Formula (Ih), or a pharmaceutically
acceptable salt thereof:
##STR00015##
[0121] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2 and
R.sup.3 are as defined herein for compounds of Formula (A). [0122]
Embodiment 6. The compound having the structure of Formula (A) or
Formula (I) is a compound having the structure of Formula (If), or
a pharmaceutically acceptable salt thereof:
##STR00016##
[0122] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.14 are as defined herein for compounds
of Formula (A). [0123] Embodiment 7. The compound having the
structure of Formula (A) or Formula (I) is a compound having the
structure of Formula (Ii), or a pharmaceutically acceptable salt
thereof:
##STR00017##
[0123] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.4 and each R.sup.13 are as defined herein for compounds of
Formula (A). [0124] Embodiment 8. The compound having the structure
of Formula (A) or Formula (I) is a compound having the structure of
Formula (Ij) or Formula (Ik), or a pharmaceutically acceptable salt
thereof:
##STR00018##
[0124] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3 and R.sup.18 are as defined herein for compounds of Formula
(A). [0125] Embodiment 9. The compound having the structure of
Formula (A) or Formula (I) is a compound having the structure of
Formula (Im), or a pharmaceutically acceptable salt thereof:
##STR00019##
[0125] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are as defined herein for compounds of Formula
(A). [0126] Embodiment 10. The compound having the structure of
Formula (A) or Formula (I) is a compound having the structure of
Formula (In), or a pharmaceutically acceptable salt thereof:
##STR00020##
[0126] wherein Y.sub.1, X, L, R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are as defined herein for compounds of Formula (A). [0127]
Embodiment 11. The compound having the structure of Formula (A) or
Formula (I) is a compound having the structure of Formula (Io), or
a pharmaceutically acceptable salt thereof:
##STR00021##
[0127] wherein L, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as
defined herein for compounds of Formula (A). [0128] Embodiment 12.
The compound having the structure of Formula (A) or Formula (I) is
a compound having the structure of Formula (Ip), or a
pharmaceutically acceptable salt thereof:
##STR00022##
[0128] wherein R.sup.1 is as defined herein for compounds of
Formula (A). [0129] Embodiment 13. The compound having the
structure of Formula (A) or Formula (II) is a compound having the
structure of Formula (IIa), Formula (IIb), Formula (IIc), Formula
(IId), Formula (IIe), Formula (IIf), Formula (IIg), Formula (IIh),
Formula (IIi), Formula (IIj) or Formula (IIk), or a
pharmaceutically acceptable salt thereof:
##STR00023## ##STR00024## ##STR00025##
[0129] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.13, R.sup.14 and R.sup.18 are as defined
herein for compounds of Formula (A). [0130] Embodiment 14. The
compound having the structure of Formula (A) or Formula (II) is a
compound having the structure of Formula (IIa) or Formula (IIg), or
a pharmaceutically acceptable salt thereof:
##STR00026##
[0130] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.13 are as defined herein for compounds
of Formula (A). [0131] Embodiment 15. The compound having the
structure of Formula (A) or Formula (II) is a compound having the
structure of Formula (IIb), Formula (IIc) or Formula (IId), or a
pharmaceutically acceptable salt thereof:
##STR00027##
[0131] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.13 are as defined herein for compounds
of Formula (A). [0132] Embodiment 16. The compound having the
structure of Formula (A) or Formula (II) is a compound having the
structure of Formula (IIe) or Formula (IIh), or a pharmaceutically
acceptable salt thereof:
##STR00028##
[0132] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2 and
R.sup.3 are as defined herein for compounds of Formula (A). [0133]
Embodiment 17. The compound having the structure of Formula (A) or
Formula (II) is a compound having the structure of Formula (IIf),
or a pharmaceutically acceptable salt thereof:
##STR00029##
[0133] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.14 are as defined herein for compounds
of Formula (A). [0134] Embodiment 18. The compound having the
structure of Formula (A) or Formula (II) is a compound having the
structure of Formula (IIi), or a pharmaceutically acceptable salt
thereof:
##STR00030##
[0134] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.4 and each R.sup.13 are as defined herein for compounds of
Formula (A). [0135] Embodiment 19. The compound having the
structure of Formula (A) or Formula (II) is a compound having the
structure of Formula (IIj) or Formula (IIk), or a pharmaceutically
acceptable salt thereof:
##STR00031##
[0135] wherein Y.sub.1, Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2,
R.sup.3 and R.sup.18 are as defined herein for compounds of Formula
(A). [0136] Embodiment 20. The compounds of Formula (A), Formula
(I), Formula (II), Formula (Ia to Ip) and Formula (IIa to IIk)
wherein, [0137] L is --CH.sub.2-- or --CH.sub.2CH.sub.2--; [0138]
Y.sub.1 is --CH.sub.2-- or --CH.sub.2CH.sub.2--; [0139] Y.sub.2 is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0140] Y.sub.3 is
--CH.sub.2-- or --XCH.sub.2--; [0141] X is --CH.sub.2-- or O;
[0142] R.sup.1 is --NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nOR.sup.9, --NHC(.dbd.O)OR.sup.9,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nN(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NR.sup.9C(.dbd.O)OR.sup.11,
--NHC(.dbd.O)(CH.sub.2).sub.nN(CD.sub.3).sub.2,
--NR.sup.9C(.dbd.O)R.sup.5,
--NR.sup.9C(.dbd.O)(CH.sub.2).sub.nR.sup.5,
--NR.sup.9C(.dbd.O)OR.sup.5, --NHS(.dbd.O).sub.2R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9C(.dbd.O)R.sup.5 or
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9S(.dbd.O).sub.2R.sup.5; [0143]
R.sup.2 is H, C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6haloalkyl;
[0144] R.sup.3 is H, C.sub.1-C.sub.6alkyl or --CD.sub.3; [0145]
R.sup.4 is H, NH.sub.2, C.sub.1-C.sub.6alkyl or halo; [0146] each
R.sup.5 is independently selected from C.sub.1-C.sub.6alkyl,
--CD.sub.3 and --(CH.sub.2).sub.nOR.sup.9; [0147] R.sup.6 is a
C.sub.3-C.sub.6cycloalkyl or a 4-6 membered heterocycloalkyl having
1 to 2 ring members independently selected from N, NH, NR.sup.16
and O which is unsubstituted or is substituted with 1-2 R.sup.12
groups; [0148] each R.sup.8 is independently selected from
C.sub.1-C.sub.6haloalkyl, --(C(R.sup.9).sub.2).sub.nOR.sup.9 and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0149] each
R.sup.9 is independently selected from H and C.sub.1-C.sub.6alkyl;
[0150] R.sup.11 is a C.sub.3-C.sub.6cycloalkyl which is
unsubstituted or is substituted with 1 to 3 C.sub.1-C.sub.6alkyl
groups; [0151] each R.sup.12 is independently selected from
C.sub.1-C.sub.6alkyl, hydroxyl, halo and a C.sub.1-C.sub.6alkyl
substituted with 1 to 3 --OH; [0152] R.sup.13 is H or
C.sub.1-C.sub.6alkyl; [0153] R.sup.14 is H or C.sub.1-C.sub.6alkyl;
[0154] each R.sup.16 is C.sub.1-C.sub.6alkyl; [0155] each R.sup.17
is independently selected from H and C.sub.1-C.sub.6alkyl; [0156]
each R.sup.18 is independently selected from halo, --CN,
C.sub.1-C.sub.6alkoxy and C.sub.1-C.sub.6alkyl; [0157] m is 1, 2,
3, 4, 5 or 6, and [0158] n is 1, 2, 3, 4, 5 or 6. [0159] Embodiment
21. The compounds of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0160] L is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0161] Y.sub.1 is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0162] Y.sub.2 is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0163] Y.sub.3 is
--CH.sub.2-- or --XCH.sub.2--; [0164] X is --CH.sub.2-- or O;
[0165] R.sup.1 is --NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6,
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NH(CH.sub.2).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
or --NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9; [0166] R.sup.2 is
H, C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6haloalkyl; [0167] R.sup.3
is H, C.sub.1-C.sub.6alkyl or --CD.sub.3; [0168] R.sup.4 is H,
NH.sub.2, C.sub.1-C.sub.6alkyl or halo; [0169] each R.sup.5 is
independently selected from C.sub.1-C.sub.6alkyl, --CD.sub.3 and
--(CH.sub.2).sub.nOR.sup.9; [0170] R.sup.6 is a
C.sub.3-C.sub.6cycloalkyl or a 4-6 membered heterocycloalkyl having
1 to 2 ring members independently selected from N, NH, NR.sup.16
and O which is unsubstituted or is substituted with 1-2 R.sup.12
groups; [0171] each R.sup.8 is independently selected from
C.sub.1-C.sub.6haloalkyl, --(C(R.sup.9).sub.2).sub.nOR.sup.9 and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0172] each
R.sup.9 is independently selected from H and C.sub.1-C.sub.6alkyl;
[0173] R.sup.10 is C.sub.1-C.sub.6alkoxy or
C.sub.3-C.sub.6cycloalkyl; [0174] each R.sup.12 is independently
selected from C.sub.1-C.sub.6alkyl, hydroxyl, halo and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0175] R.sup.13
is H or C.sub.1-C.sub.6alkyl; [0176] R.sup.14 is H or
C.sub.1-C.sub.6alkyl; [0177] each R.sup.16 is C.sub.1-C.sub.6alkyl;
[0178] each R.sup.17 is independently selected from H and
C.sub.1-C.sub.6alkyl; [0179] each R.sup.18 is independently
selected from halo, --CN, C.sub.1-C.sub.6alkoxy and
C.sub.1-C.sub.6alkyl; [0180] m is 1, 2, 3, 4, 5 or 6, and [0181] n
is 1, 2, 3, 4, 5 or 6. [0182] Embodiment 22. The compounds of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, [0183] L is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0184] Y.sub.1, is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0185] Y.sub.2 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; [0186] Y.sub.3 is --CH.sub.2-- or
--XCH.sub.2--; [0187] X is --CH.sub.2-- or O; [0188] R.sup.1 is
--NHR.sup.6, --NR.sup.5R.sup.6, --NH.sub.2, --N(R.sup.5).sub.2,
--NHR.sup.5, --NHR.sup.8, --N(R.sup.6R.sup.8) or
--N(R.sup.6).sub.2; [0189] R.sup.2 is H, C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6haloalkyl; [0190] R.sup.3 is H, C.sub.1-C.sub.6alkyl
or --CD.sub.3; [0191] R.sup.4 is H, NH.sub.2, C.sub.1-C.sub.6alkyl
or halo; [0192] each R.sup.5 is independently selected from
C.sub.1-C.sub.6alkyl, --CD.sub.3 and --(CH.sub.2)OR.sup.9; [0193]
R.sup.6 is a C.sub.3-C.sub.6cycloalkyl or a 4-6 membered
heterocycloalkyl having 1 to 2 ring members independently selected
from N, NH, NR.sup.16 and O which is unsubstituted or is
substituted with 1-2 R.sup.12 groups; [0194] each R.sup.8 is
independently selected from C.sub.1-C.sub.6haloalkyl,
--(C(R.sup.9).sub.2).sub.nOR.sup.9 and a C.sub.1-C.sub.6alkyl
substituted with 1 to 3 --OH; [0195] each R.sup.12 is independently
selected from C.sub.1-C.sub.6alkyl, hydroxyl, halo and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0196] R.sup.13
is H or C.sub.1-C.sub.6alkyl; [0197] R.sup.14 is H or
C.sub.1-C.sub.6alkyl; [0198] each R.sup.16 is C.sub.1-C.sub.6alkyl;
[0199] each R.sup.17 is independently selected from H and
C.sub.1-C.sub.6alkyl; [0200] each R.sup.18 is independently
selected from halo, --CN, C.sub.1-C.sub.6alkoxy and
C.sub.1-C.sub.6alkyl; [0201] m is 1, 2, 3, 4, 5 or 6, and [0202] n
is 1, 2, 3, 4, 5 or 6. [0203] Embodiment 23. The compounds of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, [0204] R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nOR.sup.9, --NHC(.dbd.O)OR.sup.9,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6,
NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nN(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6, --NHR.sup.6,
--NR.sup.5R.sup.6, --NH.sub.2, --N(R.sup.5).sub.2, --NHR.sup.5,
--NHR.sup.8, --N(R.sup.6R.sup.8),
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CH.sub.2).sub.nR.sup.6, --NH(CHR.sup.9).sub.nR.sup.6,
--N(R.sup.6).sub.2, --NHC(.dbd.O)(CH.sub.2).sub.nN(CD.sub.3).sub.2,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9, --OR.sup.9,
--NR.sup.9C(.dbd.O)R.sup.5,
--NR.sup.9C(.dbd.O)(CH.sub.2).sub.nR.sup.5,
--NR.sup.9C(.dbd.O)OR.sup.5, --NHS(.dbd.O).sub.2R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9C(.dbd.O)R.sup.5, or
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9S(.dbd.O).sub.2R.sup.5. [0205]
Embodiment 24. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0206]
R.sup.1 is --NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nOR.sup.9, --NHC(.dbd.O)OR.sup.9,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6, --NHR.sup.6,
--NR.sup.5R.sup.6, --NH.sub.2, --N(R.sup.5).sub.2, --NHR.sup.5,
--NHR.sup.8, --NR.sup.9C(.dbd.O)OR.sup.11,
--NH(CH.sub.2).sub.nR.sup.6, --N(R.sup.6).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nN(CD.sub.3).sub.2,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9, --OR.sup.9,
--NR.sup.9C(.dbd.O)R.sup.5, --NR.sup.9C(.dbd.O)OR.sup.5,
--NHS(.dbd.O).sub.2R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9C(.dbd.O)R.sup.5, or
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9S(.dbd.O).sub.2R.sup.5. [0207]
Embodiment 25. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0208]
R.sup.1 is --NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.nOR.sup.9, --NHC(.dbd.O)OR.sup.9,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9)N(R.sup.8).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NR.sup.9C(.dbd.O)OR.sup.11,
--NHC(.dbd.O)(CH.sub.2).sub.nN(CD.sub.3).sub.2,
--NR.sup.9C(.dbd.O)R.sup.5,
--NR.sup.9C(.dbd.O)(CH.sub.2).sub.nR.sup.5,
--NR.sup.9C(.dbd.O)OR.sup.5, --NHS(.dbd.O).sub.2R.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9C(.dbd.O)R.sup.5 or
--NHC(.dbd.O)(CH.sub.2).sub.nNR.sup.9S(.dbd.O).sub.2R.sup.5. [0209]
Embodiment 26. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0210]
R.sup.1 is --NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.5, --NHR.sup.8,
--NH(CHR.sup.9).sub.nOR.sup.9 or
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9. [0211] Embodiment 27.
The compounds of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) and Formula (IIa to IIk) wherein, [0212] R.sup.1 is
--NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, or --NHR.sup.8. [0213] Embodiment 28. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, [0214] R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.5, or --NHR.sup.8. [0215] Embodiment
29. The compounds of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0216] R.sup.1
is --NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6,
--NH(CHR.sup.9).sub.nOR.sup.9 or
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9. [0217] Embodiment 30.
The compounds of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.1 is
--NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2, --NHR.sup.6 or
--NH.sub.2. [0218] Embodiment 31. The compounds of Formula (A),
Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa to
IIk) wherein, R.sup.1 is --NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6 or --NHR.sup.6; [0219]
Embodiment 32. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0220]
R.sup.1 is --NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.mC(.dbd.O)R.sup.6,
--NH(C(R.sup.9).sub.2).sub.nR.sup.10, --NH(CH.sub.2).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nCH.sub.2OR.sup.9,
--NHCH.sub.2(CHR.sup.9).sub.nOR.sup.9,
--NH(CHR.sup.9).sub.nOR.sup.9, --NR.sup.9(CH.sub.2).sub.nOR.sup.9,
or --NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9. [0221] Embodiment
33. The compounds of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0222] R.sup.1
is --NHR.sup.6, --NR.sup.5R.sup.6, --NH.sub.2, --N(R.sup.5).sub.2,
--NHR.sup.5, --NHR.sup.8, --N(R.sup.6R.sup.8) or
--N(R.sup.6).sub.2. [0223] Embodiment 34. The compounds of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa
to IIk) wherein, [0224] R.sup.1 is --NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.8, an
8-oxa-3-azabicyclo[3.2.1]octanyl,
##STR00032##
[0224] or a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 or O which is
unsubstituted or is substituted with 1-2 R.sup.7 groups. [0225]
Embodiment 35. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0226]
R.sup.1 is --NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.5, --NHR.sup.8,
--NH(CHR.sup.9).sub.nOR.sup.9,
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9, an
8-oxa-3-azabicyclo[3.2.1]octanyl,
##STR00033##
[0226] or a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 or O which is
unsubstituted or is substituted with 1-2 R.sup.7 groups. [0227]
Embodiment 36. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0228] L
is --CH.sub.2-- or --CH.sub.2CH.sub.2--; [0229] Y.sub.1 is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0230] Y.sub.2 is
--CH.sub.2-- or --CH.sub.2CH.sub.2--; [0231] Y.sub.3 is
--CH.sub.2-- or --XCH.sub.2--; [0232] X is --CH.sub.2-- or O;
[0233] R.sup.1 is
##STR00034##
[0233] --OR.sup.9, an 8-oxa-3-azabicyclo[3.2.1]octanyl, a 5-6
membered heteroaryl having 1 to 3 ring members independently
selected from N, O and S, or a 4-6 membered heterocycloalkyl having
1 to 2 ring members independently selected from N, NH, NR.sup.16 or
O which is unsubstituted or is substituted with 1-2 R.sup.7 groups;
[0234] R.sup.2 is H, C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6haloalkyl; [0235] R.sup.3 is H, C.sub.1-C.sub.6alkyl
or --CD.sub.3; [0236] R.sup.4 is H, NH.sub.2, C.sub.1-C.sub.6alkyl
or halo; [0237] each R.sup.7 is independently selected from
C.sub.1-C.sub.6alkyl, halo, hydroxyl, oxo and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH; [0238] each
R.sup.9 is independently selected from H and C.sub.1-C.sub.6alkyl;
[0239] R.sup.13 is H or C.sub.1-C.sub.6alkyl; [0240] R.sup.14 is H
or C.sub.1-C.sub.6alkyl; [0241] each R.sup.16 is
C.sub.1-C.sub.6alkyl; [0242] each R.sup.17 is independently
selected from H and C.sub.1-C.sub.6alkyl; [0243] each R.sup.18 is
independently selected from halo, --CN, C.sub.1-C.sub.6alkoxy and
C.sub.1-C.sub.6alkyl; [0244] m is 1, 2, 3, 4, 5 or 6, and [0245] n
is 1, 2, 3, 4, 5 or 6. [0246] Embodiment 37. The compounds of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein,
[0247] R.sup.1 is 8-oxa-3-azabicyclo[3.2.1]octanyl,
##STR00035##
an unsubstituted 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 and O, or a
4-6 membered heterocycloalkyl having 1 to 2 ring members
independently selected from N, NH, NR.sup.16 or O substituted with
1-2 R.sup.7 groups wherein each R.sup.7 is independently selected
from C.sub.1-C.sub.6alkyl, hydroxyl and oxo. [0248] Embodiment 38.
The compounds of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) and Formula (IIa to IIk) wherein, [0249] R.sup.1 is an
unsubstituted 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 and O, or a
4-6 membered heterocycloalkyl having 1 to 2 ring members
independently selected from N, NH, NR.sup.16 or O substituted with
1-2 R.sup.7 groups wherein each R.sup.7 is independently selected
from C.sub.1-C.sub.6alkyl, hydroxyl and oxo. [0250] Embodiment 39.
The compounds of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) and Formula (IIa to IIk) wherein, [0251] R.sup.1 is
azetadinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or
imidazolyl, [0252] or [0253] R.sup.1 is azetadinyl, pyrrolidinyl,
morpholinyl, piperidinyl, piperazinyl or imidazolyl substituted
with 1-2 R.sup.7 groups, wherein and each R.sup.7 is independently
selected from C.sub.1-C.sub.6alkyl, hydroxyl and oxo. [0254]
Embodiment 40. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0255]
R.sup.1 is an unsubstituted 4-6 membered heterocycloalkyl having 1
to 2 ring members independently selected from N, NH, NR.sup.16 and
O, an 8-oxa-3-azabicyclo[3.2.1]octanyl,
##STR00036##
[0255] or a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 or O
substituted with 1-2 R.sup.7 groups. [0256] Embodiment 41. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, [0257] R.sup.1 is a 4-6
membered heterocycloalkyl having 1 to 2 ring members independently
selected from N, NH, NR.sup.16 or O which is unsubstituted or is
substituted with 1-2 R.sup.7 group. [0258] Embodiment 42. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, R.sup.1 is azetadinyl,
pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl. [0259]
Embodiment 43. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.1
is azetadinyl, pyrrolidinyl, morpholinyl, piperidinyl or
piperazinyl, each of which is substituted with 1-2 R.sup.7 groups.
[0260] Embodiment 44. The compounds of Formula (A), Formula (I),
Formula (II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein,
R.sup.1 is an 8-oxa-3-azabicyclo[3.2.1]octanyl, or
[0260] ##STR00037## [0261] Embodiment 45. The compounds of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa
to IIk) wherein, R.sup.6 is a C.sub.3-C.sub.6cycloalkyl or an
unsubstituted 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH and O. [0262] Embodiment
46. The compounds of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.6 is a
4-6 membered heterocycloalkyl having 1 to 2 ring members
independently selected from N, NH and O. [0263] Embodiment 47. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, R.sup.6 is an unsubstituted
4-6 membered heterocycloalkyl having 1 to 2 ring members
independently selected from N, NH, NR.sup.16 and O. [0264]
Embodiment 48. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0265]
R.sup.6 is a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH and O substituted with
1-2 R.sup.12 groups, wherein each R.sup.12 is independently
selected from C.sub.1-C.sub.6alkyl, hydroxyl and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH. [0266]
Embodiment 49. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0267]
R.sup.6 is a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 and O
substituted with 1-2 R.sup.12 groups, wherein each R.sup.12 is
independently selected from C.sub.1-C.sub.6alkyl, hydroxyl and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH. [0268]
Embodiment 50. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.6
is a C.sub.3-C.sub.6cycloalkyl. [0269] Embodiment 51. The compounds
of Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, R.sup.6 is cyclobutyl, oxetanyl,
piperidinyl, pyrrolidinyl, morpholinyl or azetadinyl. [0270]
Embodiment 52. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0271]
R.sup.6 is cyclobutyl, oxetanyl, piperidinyl, pyrrolidinyl,
morpholinyl or azetadinyl each of which is substituted with 1-2
R.sup.12 groups, wherein each R.sup.12 is independently selected
from C.sub.1-C.sub.6alkyl, hydroxyl and a C.sub.1-C.sub.6alkyl
substituted with 1 to 3 --OH. [0272] Embodiment 53. The compounds
of Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, R.sup.6 is oxetanyl, piperidinyl,
pyrrolidinyl, morpholinyl or azetadinyl. [0273] Embodiment 54. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, R.sup.6 is cyclobutyl. [0274]
Embodiment 55. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0275] L
is --CH.sub.2--; Y.sub.1 is --CH.sub.2CH.sub.2--; Y.sub.2 is
--CH.sub.2CH.sub.2--; Y.sub.3 is --XCH.sub.2--; and X is
--CH.sub.2-- or O. [0276] Embodiment 56. The compounds of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa
to IIk) wherein, [0277] L is --CH.sub.2--; Y.sub.1 is
--CH.sub.2CH.sub.2--; Y.sub.2 is --CH.sub.2CH.sub.2--; Y.sub.3 is
--XCH.sub.2--; and X is --CH.sub.2--. [0278] Embodiment 57. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, [0279] L is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; Y.sub.1 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; Y.sub.2 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--; Y.sub.3 is --CH.sub.2-- or --XCH.sub.2--; and
X is --CH.sub.2-- or O. [0280] Embodiment 58. The compounds of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, [0281] L is --CH.sub.2--; Y.sub.1 is
--CH.sub.2--; Y.sub.2 is --CH.sub.2--; Y.sub.3 is --CH.sub.2--; and
X is --CH.sub.2--. [0282] Embodiment 59. The compounds of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa
to IIk) wherein, [0283] L is --CH.sub.2--; Y.sub.1 is --CH.sub.2--;
Y.sub.2 is --CH.sub.2CH.sub.2--; Y.sub.3 is --XCH.sub.2--; and X is
--CH.sub.2-- or O. [0284] Embodiment 60. The compounds of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa
to IIk) wherein, [0285] L is --CH.sub.2--; Y.sub.1 is --CH.sub.2--;
Y.sub.2 is --CH.sub.2CH.sub.2--; Y.sub.3 is --XCH.sub.2--; and X is
--CH.sub.2--. [0286] Embodiment 61. The compounds of Formula (A),
Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa to
IIk) wherein, R.sup.2 is C.sub.1-C.sub.6alkyl; R.sup.3 is
C.sub.1-C.sub.6alkyl, and R.sup.4 is C.sub.1-C.sub.6alkyl. [0287]
Embodiment 62. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.2
is methyl; R.sup.3 is methyl, and R.sup.4 is methyl. [0288]
Embodiment 63. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.2
is H, C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6haloalkyl [0289]
Embodiment 64. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.2
is H or C.sub.1-C.sub.6alkyl. [0290] Embodiment 65. The compounds
of Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, R.sup.3 is H, C.sub.1-C.sub.6alkyl or
--CD.sub.3. [0291] Embodiment 66. The compounds of Formula (A),
Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa to
IIk) wherein, R.sup.3 is H or C.sub.1-C.sub.6alkyl. [0292]
Embodiment 67. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.4
is H, NH.sub.2, C.sub.1-C.sub.6alkyl or halo. [0293] Embodiment 68.
The compounds of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.4 is H, NH.sub.2
or C.sub.1-C.sub.6alkyl. [0294] Embodiment 69. The compounds of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, R.sup.4 is H or C.sub.1-C.sub.6alkyl.
[0295] Embodiment 70. The compounds of Formula (A), Formula (I),
Formula (II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein,
each R.sup.5 is independently selected from C.sub.1-C.sub.6alkyl
and --(CH.sub.2).sub.nOR.sup.9. [0296] Embodiment 71. The compounds
of Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, each R.sup.5 is independently
selected from C.sub.1-C.sub.6alkyl and --CD.sub.3. [0297]
Embodiment 72. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, each
R.sup.5 is independently selected from methyl, ethyl, isopropyl,
tert-butyl, --CD.sub.3, --CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 and
--CH.sub.2CH.sub.2OCH.sub.3. [0298] Embodiment 73. The compounds of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, each R.sup.7 is independently
selected from methyl, ethyl and oxo. [0299] Embodiment 74. The
compound of Formula (I), Formula (Ia), Formula (Ib) and Formula
(Ic), wherein, each R.sup.8 is independently selected from
C.sub.1-C.sub.6haloalkyl, --(C(R.sup.9).sub.2).sub.nOR.sup.9 and a
C.sub.1-C.sub.6alkyl substituted with 1 to 3 --OH. [0300]
Embodiment 75. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, each
R.sup.8 is independently selected from --CH.sub.2CHF.sub.2,
--CH.sub.2CF.sub.3, --CH(CH.sub.3)CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OCH.sub.3, --CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 and
--CH.sub.2C(CH.sub.3).sub.2OH. [0301] Embodiment 76. The compounds
of Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, each R.sup.9 is independently
selected from H and C.sub.1-C.sub.6alkyl. [0302] Embodiment 77. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, each R.sup.9 is independently
selected from H, methyl and ethyl. [0303] Embodiment 78. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, R.sup.13 is H. [0304]
Embodiment 79. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.13
is C.sub.1-C.sub.6alkyl. [0305] Embodiment 80. The compounds of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, R.sup.14 is H. [0306] Embodiment 81.
The compounds of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) and Formula (IIa to IIk) wherein, R.sup.13 is H and
R.sup.14 is H. [0307] Embodiment 82. The compounds of Formula (A),
Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa to
IIk) wherein, m is 1, 2 or 3 and n is 1, 2, 3 or 4. [0308]
Embodiment 83. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, m is 1,
2 or 3. [0309] Embodiment 84. The compounds of Formula (A), Formula
(I), Formula (II), Formula (Ia to Ip) and Formula (IIa to IIk)
wherein, n is 1, 2, 3 or 4. [0310] Embodiment 85. The compounds of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) wherein, [0311] R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CH.sub.2).sub.nR.sup.6,
--NH(CH.sub.2).sub.nC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NH(CH.sub.2).sub.mC(.dbd.O)N(R.sup.5).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.5, --NHR.sup.8,
--NH(CHR.sup.9).sub.nOR.sup.9,
--NHCH.sub.2(C(R.sup.9).sub.2).sub.nOR.sup.9, an
8-oxa-3-azabicyclo[3.2.1]octanyl,
##STR00038##
[0311] or a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 or O which is
unsubstituted or is substituted with 1-2 R.sup.7 groups; [0312]
each R.sup.5 is independently selected from C.sub.1-C.sub.6alkyl
and --(CH.sub.2).sub.nOR.sup.9; [0313] R.sup.6 is an unsubstituted
4-6 membered heterocycloalkyl having 1 to 2 ring members
independently selected from N, NH and O, or a
C.sub.3-C.sub.6cycloalkyl; [0314] each R.sup.7 is independently
selected from C.sub.1-C.sub.6alkyl, hydroxyl and oxo; [0315] each
R.sup.8 is independently selected from C.sub.1-C.sub.6haloalkyl,
and --(C(R.sup.9).sub.2).sub.nOR.sup.9; [0316] each R.sup.9 is
independently selected from H and C.sub.1-C.sub.6alkyl; [0317]
R.sup.16 is C.sub.1-C.sub.6alkyl; [0318] m is 1, 2, 3, 4, 5 or 6
[0319] and [0320] n is 1, 2, 3, 4, 5 or 6. [0321] Embodiment 86.
The compounds of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) and Formula (IIa to IIk) wherein, [0322] R.sup.1 is
--NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, --NHR.sup.6, an
8-oxa-3-azabicyclo[3.2.1]octanyl,
##STR00039##
[0322] or a 4-6 membered heterocycloalkyl having 1 to 2 ring
members independently selected from N, NH, NR.sup.16 or O which is
unsubstituted or is substituted with 1-2 R.sup.7 groups; [0323]
each R.sup.5 is independently selected from C.sub.1-C.sub.6alkyl
and --(CH.sub.2).sub.nOR.sup.9; [0324] R.sup.6 is a 4-6 membered
heterocycloalkyl having 1 to 2 ring members independently selected
from N, NH, NR.sup.16 and O, or a C.sub.3-C.sub.6cycloalkyl; [0325]
each R.sup.7 is independently selected from C.sub.1-C.sub.6alkyl,
hydroxyl and oxo; [0326] each R.sup.8 is independently selected
from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, and
--(C(R.sup.9).sub.2).sub.nOR.sup.9; [0327] each R.sup.9 is
independently selected from H and C.sub.1-C.sub.6alkyl; [0328] m is
1, 2, 3, 4, 5 or 6, and [0329] n is 1, 2, 3, 4, 5 or 6. [0330]
Embodiment 87. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0331]
R.sup.1 is --NHC(.dbd.O)R.sup.6,
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6, --NHR.sup.6, --NH.sub.2,
--N(R.sup.5).sub.2, or --NHR.sup.8; [0332] each R.sup.5 is
independently selected from C.sub.1-C.sub.6alkyl and
--(CH.sub.2).sub.nOR.sup.9 [0333] R.sup.6 is an unsubstituted 4-6
membered heterocycloalkyl having 1 to 2 ring members independently
selected from N, NH, NR.sup.16 and O, or a
C.sub.3-C.sub.6cycloalkyl; [0334] each R.sup.8 is independently
selected from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
--(C(R.sup.9).sub.2).sub.nOR.sup.9 and a C.sub.1-C.sub.6alkyl
substituted with 1 to 3 --OH; [0335] each R.sup.9 is independently
selected from H and C.sub.1-C.sub.6alkyl; [0336] m is 1, 2, 3, 4, 5
or 6, and [0337] n is 1, 2, 3, 4, 5 or 6. [0338] Embodiment 88. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, [0339] R.sup.1 is
--NHC(.dbd.O)(CH.sub.2).sub.mN(R.sup.5).sub.2,
--NHC(.dbd.O)(CH.sub.2).sub.mNHR.sup.5,
--NHC(.dbd.O)(CH.sub.2).sub.mNH.sub.2,
--NHC(.dbd.O)(CHR.sup.9).sub.nNHR.sup.8,
--NH(CHR.sup.9).sub.nC(.dbd.O)N(R.sup.8).sub.2, --NH.sub.2,
--N(R.sup.8).sub.2, or --NHR.sup.8; [0340] each R.sup.5 is
independently selected from C.sub.1-C.sub.6alkyl and
--(CH.sub.2).sub.nOR.sup.9; [0341] each R.sup.8 is independently
selected from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
--(C(R.sup.9).sub.2).sub.nOR.sup.9 and a C.sub.1-C.sub.6alkyl
substituted with 1 to 3 --OH; [0342] each R.sup.9 is independently
selected from H and C.sub.1-C.sub.6alkyl; [0343] m is 1, 2, 3, 4, 5
or 6, and [0344] n is 1, 2, 3, 4, 5 or 6. [0345] Embodiment 89. The
compounds of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) and Formula (IIa to IIk) wherein, [0346] R.sup.1 is
--NHC(.dbd.O)R.sup.6, --NHC(.dbd.O)(CHR.sup.9).sub.nR.sup.6,
--NH(CHR.sup.9).sub.nC(.dbd.O)R.sup.6 or --NHR.sup.6; [0347]
R.sup.6 is an unsubstituted 4-6 membered heterocycloalkyl having 1
to 2 ring members independently selected from N, NH, NR.sup.16 and
O, or a C.sub.3-C.sub.6cycloalkyl; [0348] each R.sup.9 is
independently selected from H and C.sub.1-C.sub.6alkyl; [0349] m is
1, 2, 3, 4, 5 or 6, and [0350] n is 1, 2, 3, 4, 5 or 6. [0351]
Embodiment 90. The compounds of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) and Formula (IIa to IIk) wherein, [0352] L
is --CH.sub.2--; [0353] Y.sub.1 is --CH.sub.2CH.sub.2--; [0354]
Y.sub.2 is --CH.sub.2CH.sub.2--; [0355] Y.sub.3 is --XCH.sub.2--;
[0356] X is --CH.sub.2--; [0357] R.sup.1 is --NHC(.dbd.O)R.sup.6;
[0358] R.sup.2 is C.sub.1-C.sub.6alkyl; [0359] R.sup.3 is
C.sub.1-C.sub.6alkyl; [0360] R.sup.4 is C.sub.1-C.sub.6alkyl;
[0361] R.sup.6 is an unsubstituted 4-6 membered heterocycloalkyl
having 1 to 2 ring members independently selected from N, NH, and
O; [0362] R.sup.13 is H; [0363] R.sup.14 is H; and [0364] each
R.sup.17 is H. [0365] Embodiment 91. The compound of Formula (A),
Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa to
IIk), or a pharmaceutically acceptable salt thereof, selected from:
[0366]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0367]
4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amin-
e; [0368]
4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahyd-
ro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0369]
4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-ami-
ne; [0370]
4-((5-(1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl-4,5-
,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan--
1-amine; [0371]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)o-
xetan-3-amine; [0372]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(dimethylamino)acetamide [0373]
(S)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide; [0374]
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide; [0375]
6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-oxa-6-azaspiro[3.3]heptane; [0376]
4-(1-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,-
3-c]pyridin-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
[0377]
4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-6,7-dihydro-2H-pyrazolo[4,-
3-c]pyridin-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
[0378]
4-(1-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-3-methyl-6,7-dihydro-1H-py-
razolo[4,3-c]pyridin-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amin-
e; [0379]
4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-3-methyl-6,7-dihy-
dro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimid-
in-6-amine; [0380]
4-((5-(5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
amine; [0381]
1,6-dimethyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]octan-1-yl)-
methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[3,4-d]-
pyrimidine; [0382]
1,3,5-trimethyl-7-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]octan-1--
yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[4,3-
-d]pyrimidine; [0383]
N-(2-methoxyethyl)-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyri-
midin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyc-
lo[2.2.2]octan-1-amine; [0384]
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl-
)morpholine; [0385]
2-(ethylamino)-N-(4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4--
yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2-
]octan-1-yl)acetamide; [0386]
4-(4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)mor-
pholine; [0387]
2-(ethylamino)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrim-
idin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicycl-
o[22.2]octan-1-yl)acetamide; [0388]
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(oxetan-3-ylmethyl)bi-
cyclo[2.2.2]octan-1-amine; [0389]
3-(dimethylamino)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]py-
rimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bic-
yclo[22.2]octan-1-yl)propanamide; [0390]
4-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine; [0391]
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-am-
ine; [0392]
N-cyclobutyl-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin--
7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2-
.2]octan-1-amine; [0393]
N,N-dicyclobutyl-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimi-
din-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo-
[2.2.2]octan-1-amine; [0394]
6-methyl-4-(3-methyl-1-((4-(piperidin-1-yl)bicyclo[2.2.2]octan-1-yl)methy-
l)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[3,4-d]pyrim-
idine; [0395]
6-methyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]octan-1-yl)meth-
yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[3,4-d]pyri-
midine; [0396]
(3-(((4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)amino)methyl)oxetan-3-yl)methanol; [0397]
N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)azetidine-3-carboxamide; [0398]
(S)--N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-yl)morpholine-3-carboxamide; [0399]
(S)--N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-yl)morpholine-2-carboxamide; [0400]
(R)--N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-yl)morpholine-3-carboxamide; [0401]
(R)--N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-yl)morpholine-2-carboxamide; [0402]
3,6-dimethyl-4-(3-methyl-1-((4-morpholinobicyclo[2.2.2]octan-1-yl)methyl)-
-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)isoxazolo[5,4-d]pyrimidine-
; [0403]
1,3,5-trimethyl-7-(3-methyl-1-((4-(piperidin-1-yl)bicyclo[2.2.2]o-
ctan-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyraz-
olo[4,3-d]pyrimidine; [0404]
1,6-dimethyl-4-(3-methyl-1-((4-(piperidin-1-yl)bicyclo[2.2.2]octan-1-yl)m-
ethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1H-pyrazolo[3,4-d]p-
yrimidine; [0405]
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(trideuteromethy-
l)bicyclo[2.2.2]octan-1-amine; [0406]
4-((3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine; [0407]
4-((3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-pyr-
azolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]octan-1-amine; [0408]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethylbicyclo[2.2.2]oc-
tan-1-amine; [0409]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptan-1-amine;
[0410]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-(trifluorome-
thyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2-
.2]octan-1-amine; [0411]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-ol;
[0412]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,-
5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-
-1-yl)acetamide; [0413]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)m-
ethanesulfonamide; [0414] tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)(me-
thyl)carbamate; [0415]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]octan--
1-amine; [0416] 1-methylcyclopropyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)car-
bamate; [0417]
3-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[1.1.1]pentan-1-amine;
[0418]
4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl-
)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicycl-
o[2.2.2]octan-1-amine; [0419]
N-cyclobutyl-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oc-
tan-1-amine; [0420]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-isopropylbicyclo[2.2.2]oct-
an-1-amine; [0421]
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)propan-1-ol; [0422]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-ethylbicyclo[2.2.2]octan-1-
-amine; [0423]
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(pyrrolidi-
n-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
-c]pyridine; [0424]
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)m-
orpholine; [0425]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-7,7-dimethyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-ami-
ne; [0426]
N-(2,2-difluoroethyl)-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyr-
idin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)meth-
yl)bicyclo[2.2.2]octan-1-amine; [0427]
-((3-methyl-5-(2-methylquinolin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3--
c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine; [0428]
4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3--
c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine; [0429]
1-((4-(azetidin-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-(1,6-dimethyl-1H--
pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c-
]pyridine; [0430]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-7,7-dimethyl-4,5,6,7--
tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]octan-1-ami-
ne;
[0431]
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,-
5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-
-1-yl)thiomorpholine 1,1-dioxide; [0432]
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(piperidin-
-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3--
c]pyridine; [0433]
1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)a-
zetidin-3-ol; [0434]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)bicyclo[2.-
2.2]octan-1-amine; [0435]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-methoxyethyl)bicyc-
lo[2.2.2]octan-1-amine; [0436]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-ethoxyethyl)bicyclo[2.2-
.2]octan-1-amine; [0437]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-ethoxyethyl)bicycl-
o[2.2.2]octan-1-amine; [0438]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-N-methylb-
icyclo[2.2.2]octan-1-amine; [0439]
(3S,4R)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)pyrrolidine-3,4-diol; [0440]
(S)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)pyrrolidin-3-ol; [0441]
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-N,N-dimethylacetamide; [0442]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
N-methyloxetan-3-amine; [0443]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-isopropyl-N-methylbicyclo[-
2.2.2]octan-1-amine; [0444]
N-cyclobutyl-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo-
[2.2.2]octan-1-amine; [0445]
(3S,4S)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)pyrrolidine-3,4-diol; [0446]
1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2-oxabicyclo[2.2.2]octan-4-a-
mine; [0447]
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(pyrrolidi-
n-1-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazo-
lo[4,3-c]pyridine; [0448]
4-((5-(6-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-me-
thyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.-
2]octan-1-amine; [0449]
4-(4-(1-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-3-methyl-6,7-dihydro-1H-
-pyrazolo[4,3-c]pyridin-5(4H)-yl)pyridin-2-yl)benzonitrile; [0450]
3-methyl-5-(2-phenylpyridin-4-yl)-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]oc-
tan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;
[0451]
2-methyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]octan-1-yl)meth-
yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-1,7-naphthyridine;
[0452]
4-((5-(2-(4-fluorophenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-
-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0453]
4-((5-(2-(2-fluoro-4-methylphenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahyd-
ro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0454]
4-((5-(2-(4-methoxyphenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydr-
o-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0455]
4-((3-methyl-5-(2-(p-tolyl)pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine; [0456]
4-(2-(5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-te-
trahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl)bicyclo[2.2.2]octan-1-amine;
[0457]
4-((5-(2,8-dimethyl-1,7-naphthyridin-4-yl)-3-methyl-4,5,6,7-tetrah-
ydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0458]
4-((3-methyl-5-(2-methyl-6-phenylpyridin-4-yl)-4,5,6,7-tetrahydro--
1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0459]
4-((5-([2,2'-bipyridin]-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine; [0460]
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(piperidin-
-1-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazol-
o[4,3-c]pyridine; [0461]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(1-methoxypropan-2-yl)bicy-
clo[2.2.2]octan-1-amine; [0462]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-ethyl-N-methylbicyclo[2.2.-
2]octan-1-amine; [0463]
1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethyl-2-oxabicyclo[2.-
2.2]octan-4-amine; [0464]
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-1-(piperidin-1-yl)ethanone; [0465]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(pyrrolidin-1-yl)acetamide; [0466]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxy-2-methylpropyl)-
bicyclo[2.2.2]octan-1-amine; [0467]
1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-2-oxabicy-
clo[2.2.2]octan-4-amine; [0468]
4-((5-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7-te-
trahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine-
; [0469]
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-1-methylpiperazin-2-one; [0470]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
3-(dimethylamino)propanamide; [0471]
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-1-(pyrrolidin-1-yl)ethanone; [0472]
(R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-2-methylmorpholine; [0473]
1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
4-methylpiperazin-2-one; [0474]
(S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-2-methylmorpholine; [0475]
(2S,6R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-2,6-dimethylmorpholine; [0476]
(2S,6S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-2,6-dimethylmorpholine; [0477]
N-(cyclobutylmethyl)-1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)--
3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2-oxabi-
cyclo[2.2.2]octan-4-amine; [0478]
(2R,6R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-2,6-dimethylmorpholine; [0479]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(ethylamino)acetamide; [0480]
3-amino-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)propanamide; [0481]
6-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-oxa-6-azaspiro[3.3]heptane; [0482]
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-(methylamino)propanamide; [0483]
(S)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-(methylamino)propanamide; [0484]
1-((4-(1H-imidazol-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-(1,6-dimethyl--
1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,-
3-c]pyridine; [0485]
(1R,5S)-3-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)-8-oxa-3-azabicyclo[3.2.1]octane; [0486]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(methylamino)acetamide; [0487]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
4-methylmorpholine-3-carboxamide; [0488]
1-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-2-methylpropan-2-ol; [0489]
2-(ethylamino)-N-(4-((3-methyl-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl-
)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]o-
ctan-1-yl)acetamide; [0490]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)m-
orpholine-2-carboxamide; [0491]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
3-(ethylamino)propanamide; [0492]
N-ethyl-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyraz-
olo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine; [0493]
(S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-3-methylmorpholine; [0494]
(R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-3-methylmorpholine; [0495]
N-(2-methoxyethyl)-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahyd-
ro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0496]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,-
5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-
-1-yl)azetidine-3-carboxamide; [0497]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(ethyl(methyl)amino)acetamide; [0498]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(3-fluoroazetidin-1-yl)acetamide; [0499]
2-(bis(trideuteromethyl)amino)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]p-
yridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)me-
thyl)bicyclo[2.2.2]octan-1-yl)acetamide; [0500]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-hydroxyacetamide; [0501]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(3-hydroxyazetidin-1-yl)acetamide; [0502]
(3-(((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,-
7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-y-
l)amino)methyl)oxetan-3-yl)methanol; [0503]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(N-methylmethylsulfonamido)acetamide; [0504]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(N-methylacetamido)acetamide [0505]
4-((3-methyl-5-(6-methyl-1-(trideuteromethyl)-1H-pyrazolo[3,4-b]pyridin-4-
-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.-
2]octan-1-amine; [0506]
(S)--N-(4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl--
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-
an-1-yl)morpholine-3-carboxamide; [0507]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
3-(methylamino)propanamide; [0508]
N-cyclobutyl-1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-
-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2-oxabicyclo[2.-
2.2]octan-4-amine; [0509]
N-cyclobutyl-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H--
pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine;
[0510] tert-butyl
(4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl-
)carbamate; [0511] tert-butyl
(4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrah-
ydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbam-
ate; [0512] tert-butyl
(4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-py-
razolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate;
[0513] tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptan-1-yl)ca-
rbamate; [0514]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7-te-
trahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine-
, and [0515]
4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-ami-
ne. [0516] Embodiment 92. The compound of Formula (A), Formula (I),
Formula (II), Formula (Ia to Ip) and Formula (IIa to IIk), or a
pharmaceutically acceptable salt thereof, selected from: [0517]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)o-
xetan-3-amine;
[0518]
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,-
5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-
-1-yl)-2-(dimethylamino)acetamide; [0519]
(S)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide; [0520]
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide, and [0521]
6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-oxa-6-azaspiro[3.3]heptane.
[0522] Depending on the choice of the starting materials and
procedures, certain embodiments of the compounds of the present
invention are present in the form of one of the possible isomers or
as mixtures thereof, for example as pure optical isomers, or as
isomer mixtures, such as racemates and diastereoisomer mixtures,
depending on the number of asymmetric carbon atoms. The present
invention is meant to include all such possible isomers, including
racemic mixtures, diasteriomeric mixtures and optically pure forms.
Optically active (R)- and (S)-isomers may be prepared using chiral
synthons or chiral reagents, or resolved using conventional
techniques. If the compound contains a double bond, the substituent
may be E or Z configuration. If the compound contains a
disubstituted cycloalkyl, the cycloalkyl substituent may have a
cis- or trans-configuration. All tautomeric forms are also intended
to be included.
[0523] In certain embodiments, compounds of Formula (A), Formula
(I), Formula (II), Formula (Ia to Ip) and Formula (IIa to IIk) are
prepared as a pharmaceutically acceptable acid addition salt by
reacting the free base form of a compound of Formula (A), Formula
(I), Formula (II), Formula (Ia to Ip) or Formula (IIa to IIk), with
a stoichiometric amount of an appropriate pharmaceutically
acceptable organic acid or inorganic acid or a suitable anion
exchange reagent. Certain compounds of the present invention are
capable of forming acid addition salts by virtue of the presence of
amino groups or groups similar thereto. Alternatively, the salt
forms of compounds of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) and Formula (IIa to IIk) are prepared using
salts of the starting materials or intermediates.
[0524] Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids. The organic acid or
inorganic acids used to form certain pharmaceutically acceptable
acid addition salts of compounds of Formula (A), Formula (I),
Formula (II), Formula (Ia to Ip) and Formula (IIa to IIk) include,
but are not limited to, acetic acid, adipic acid, ascorbic acid,
aspartic acid, benzoic acid, benzenesulfonic acid, carbonic acid,
camphor sulfonic acid, capric acid, chlorotheophyllinate, citric
acid, ethanedisulfonic acid, fumaric acid,
D-glycero-D-gulo-Heptonicacid, galactaric aid, galactaric
acid/mucic acid, gluceptic acid, glucoheptonoic acid, gluconic
acid, glucuronic acid, glutamatic acid, glutaric acid, glycolic
acid, hippuric acid, hydrobromic acid, hydrochloric acid,
hydroiodic acid, isethionic acid, lactic acid, lactobionic acid,
lauryl sulfuric acid, malic acid, maleic acid, malonic acid,
mandelic acid, mesylic acid, methanesulfonic acid, mucic acid,
naphthoic acid, 1-hydroxy-2-naphthoic acid, naphthalenesulfonic
acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid,
octadecanoic acid, oleaic acid, oxalic acid, palmitic acid, pamoic
acid, phosphoric acid, polygalacturonic acid, propionic acid,
sebacic acid, stearic acid, succinic acid, sulfosalicylic acid,
sulfuric acid, tartaric acid, p-toluenesulfonic acid,
trifluoroacetic acid and triphenylacetic acid.
[0525] Lists of additional suitable acid addition salts can be
found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed.,
Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of
Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and
Wermuth (Wiley-VCH, Weinheim, Germany, 2002.
[0526] Salt forms of the compounds of the invention can be
converted into the free compounds by treatment with a suitable
basic agent.
[0527] Pharmaceutically acceptable acid addition salts of compounds
of Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) and
Formula (IIa to IIk) include, but are not limited to, a acetate,
adipate, ascorbate, aspartate, benzoate, besylatye,
benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate,
bromide/hydrobromide, camphor sulfonate, camsylate, caprate,
chloride/hydrochloride, chlorotheophyllinate, citrate, edisylate,
ethanedisulfonate, fumarate, gluceptate, glucoheptonate, gluconate,
glucuronate, glutamate, glutarate, glycolate, hippurate,
hydroiodide/iodide, isethionate, lactate, lactobionate,
laurylsulphate, malate, maleate, malonate, mandelate, mesylate,
methanesulfonate, methylsulfate, mucate, naphthoate, napsylate,
2-napsylate, naphthalenesulfonate, 2-naphthalenesulfonate,
nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate,
pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, sebacate, stearate, succinate,
sulfosalicylate, sulfate, tartrate, tosylate, p-toluenesulfonate,
trifluoroacetate, trifenatate, triphenylacetete and xinafoate salt
forms.
[0528] In one embodiment, the present invention provides
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)o-
xetan-3-amine in an acetate, adipate, ascorbate, aspartate,
benzoate, besylatye, benzenesulfonate, bicarbonate/carbonate,
bisulfate/sulfate, bromide/hydrobromide, camphor sulfonate,
camsylate, caprate, chloride/hydrochloride, chlortheophyllonate,
citrate, edisylate, ethanedisulfonate, fumarate, gluceptate,
glucoheptonate, gluconate, glucuronate, glutamate, glutarate,
glycolate, hippurate, hydroiodide/iodide, isethionate, lactate,
lactobionate, laurylsulphate, malate, maleate, malonate, mandelate,
mesylate, methanesulfonate, methylsulfate, mucate, naphthoate,
napsylate, 2-napsylate, naphthalenesulfonate,
2-naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate,
oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, polygalacturonate, propionate,
sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate,
tosylate, p-toluenesulfonate, trifluoroacetate, trifenatate,
triphenylacetete or xinafoate salt form.
[0529] In one embodiment, the present invention provides
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(dimethylamino)acetamide in an acetate, adipate, ascorbate,
aspartate, benzoate, besylatye, benzenesulfonate,
bicarbonate/carbonate, bisulfate/sulfate, bromide/hydrobromide,
camphor sulfonate, camsylate, caprate, chloride/hydrochloride,
chlortheophyllonate, citrate, edisylate, ethanedisulfonate,
fumarate, gluceptate, glucoheptonate, gluconate, glucuronate,
glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide,
isethionate, lactate, lactobionate, laurylsulphate, malate,
maleate, malonate, mandelate, mesylate, methanesulfonate,
methylsulfate, mucate, naphthoate, napsylate, 2-napsylate,
naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
octadecanoate, oleate, oxalate, palmitate, pamoate,
phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, sebacate, stearate, succinate,
sulfosalicylate, sulfate, tartrate, tosylate, p-toluenesulfonate,
trifluoroacetate, trifenatate, triphenylacetete or xinafoate salt
form.
[0530] In one embodiment, the present invention provides
(S)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide in an acetate, adipate, ascorbate,
aspartate, benzoate, besylatye, benzenesulfonate,
bicarbonate/carbonate, bisulfate/sulfate, bromide/hydrobromide,
camphor sulfonate, camsylate, caprate, chloride/hydrochloride,
chlortheophyllonate, citrate, edisylate, ethanedisulfonate,
fumarate, gluceptate, glucoheptonate, gluconate, glucuronate,
glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide,
isethionate, lactate, lactobionate, laurylsulphate, malate,
maleate, malonate, mandelate, mesylate, methanesulfonate,
methylsulfate, mucate, naphthoate, napsylate, 2-napsylate,
naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
octadecanoate, oleate, oxalate, palmitate, pamoate,
phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, sebacate, stearate, succinate,
sulfosalicylate, sulfate, tartrate, tosylate, p-toluenesulfonate,
trifluoroacetate, trifenatate, triphenylacetete or xinafoate salt
form.
[0531] In one embodiment, the present invention provides
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide in an acetate, adipate, ascorbate,
aspartate, benzoate, besylatye, benzenesulfonate,
bicarbonate/carbonate, bisulfate/sulfate, bromide/hydrobromide,
camphor sulfonate, camsylate, caprate, chloride/hydrochloride,
chlortheophyllonate, citrate, edisylate, ethanedisulfonate,
fumarate, gluceptate, glucoheptonate, gluconate, glucuronate,
glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide,
isethionate, lactate, lactobionate, laurylsulphate, malate,
maleate, malonate, mandelate, mesylate, methanesulfonate,
methylsulfate, mucate, naphthoate, napsylate, 2-napsylate,
naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
octadecanoate, oleate, oxalate, palmitate, pamoate,
phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, sebacate, stearate, succinate,
sulfosalicylate, sulfate, tartrate, tosylate, p-toluenesulfonate,
trifluoroacetate, trifenatate, triphenylacetete or xinafoate salt
form.
[0532] In one embodiment, the present invention provides
6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-oxa-6-azaspiro[3.3]heptane in an acetate, adipate,
ascorbate, aspartate, benzoate, besylatye, benzenesulfonate,
bicarbonate/carbonate, bisulfate/sulfate, bromide/hydrobromide,
camphor sulfonate, camsylate, caprate, chloride/hydrochloride,
chlortheophyllonate, citrate, edisylate, ethanedisulfonate,
fumarate, gluceptate, glucoheptonate, gluconate, glucuronate,
glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide,
isethionate, lactate, lactobionate, laurylsulphate, malate,
maleate, malonate, mandelate, mesylate, methanesulfonate,
methylsulfate, mucate, naphthoate, napsylate, 2-napsylate,
naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
octadecanoate, oleate, oxalate, palmitate, pamoate,
phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, sebacate, stearate, succinate,
sulfosalicylate, sulfate, tartrate, tosylate, p-toluenesulfonate,
trifluoroacetate, trifenatate, triphenylacetete or xinafoate salt
form.
[0533] Any formula given herein is also intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. Isotopically labeled compounds have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, and chlorine, such as .sup.2H, .sup.3H,
.sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18F .sup.31P,
.sup.32P, .sup.35S, .sup.36C, .sup.123I, .sup.124I, .sup.125I
respectively. The invention includes various isotopically labeled
compounds as defined herein, for example those into which
radioactive isotopes, such as .sup.3H and .sup.14C, or those into
which non-radioactive isotopes, such as .sup.2H and .sup.13C are
present. Such isotopically labelled compounds are useful in
metabolic studies (with .sup.14C), reaction kinetic studies (with,
for example .sup.2H or .sup.3H), detection or imaging techniques,
such as positron emission tomography (PET) or single-photon
emission computed tomography (SPECT) including drug or substrate
tissue distribution assays, or in radioactive treatment of
patients. In particular, an .sup.18F or labeled compound may be
particularly desirable for PET or SPECT studies.
Isotopically-labeled compounds of formula (I) can generally be
prepared by conventional techniques known to those skilled in the
art or by processes analogous to those described in the
accompanying Examples and Preparations using an appropriate
isotopically-labeled reagents in place of the non-labeled reagent
previously employed.
[0534] Further, substitution with heavier isotopes, particularly
deuterium (i.e., .sup.2H or D) may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements or an
improvement in therapeutic index. It is understood that deuterium
in this context is regarded as a substituent of a compound of the
formula (I). The concentration of such a heavier isotope,
specifically deuterium, may be defined by the isotopic enrichment
factor. The term "isotopic enrichment factor" as used herein means
the ratio between the isotopic abundance and the natural abundance
of a specified isotope. If a substituent in a compound of this
invention is denoted deuterium, such compound has an isotopic
enrichment factor for each designated deuterium atom of at least
3500 (52.5% deuterium incorporation at each designated deuterium
atom), at least 4000 (60% deuterium incorporation), at least 4500
(67.5% deuterium incorporation), at least 5000 (75% deuterium
incorporation), at least 5500 (82.5% deuterium incorporation), at
least 6000 (90% deuterium incorporation), at least 6333.3 (95%
deuterium incorporation), at least 6466.7 (97% deuterium
incorporation), at least 6600 (99% deuterium incorporation), or at
least 6633.3 (99.5% deuterium incorporation).
[0535] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0536] Compounds of the invention that contain groups capable of
acting as donors and/or acceptors for hydrogen bonds may be capable
of forming co-crystals with suitable co-crystal formers. These
co-crystals may be prepared from compounds of the invention by
known co-crystal forming procedures. Such procedures include
grinding, heating, co-subliming, co-melting, or contacting in
solution compounds of the invention with the co-crystal former
under crystallization conditions and isolating co-crystals thereby
formed. Suitable co-crystal formers include those described in WO
2004/078163. Hence the invention further provides co-crystals
comprising a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) and Formula (IIa to IIk).
[0537] All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed.
[0538] Any asymmetric atom (e.g., carbon or the like) of the
compound(s) of the present invention can be present in racemic or
enantiomerically enriched, for example the (R)-, (S)- or
(R,S)-configuration. In certain embodiments, each asymmetric atom
has at least 50% enantiomeric excess, at least 60% enantiomeric
excess, at least 70% enantiomeric excess, at least 80% enantiomeric
excess, at least 90% enantiomeric excess, at least 95% enantiomeric
excess, or at least 99% enantiomeric excess in the (R)- or
(S)-configuration. Substituents at atoms with unsaturated double
bonds may, if possible, be present in cis- (Z)- or trans-
(E)-form.
[0539] Accordingly, as used herein a compound of the present
invention can be in the form of one of the possible isomers,
rotamers, atropisomers, tautomers or mixtures thereof, for example,
as substantially pure geometric (cis or trans) isomers,
diastereomers, optical isomers (antipodes), racemates or mixtures
thereof.
[0540] Any resulting mixtures of isomers can be separated on the
basis of the physicochemical differences of the constituents, into
the pure or substantially pure geometric or optical isomers,
diastereomers, racemates, for example, by chromatography and/or
fractional crystallization. Any resulting racemates of final
products or intermediates can be resolved into the optical
antipodes by known methods, e.g., by separation of the
diastereomeric salts thereof, obtained with an optically active
acid or base, and liberating the optically active acidic or basic
compound. In particular, a basic moiety may thus be employed to
resolve the compounds of the present invention into their optical
antipodes, e.g., by fractional crystallization of a salt formed
with an optically active acid, e.g., tartaric acid, dibenzoyl
tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric
acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
Racemic products can also be resolved by chiral chromatography,
e.g., high pressure liquid chromatography (HPLC) using a chiral
adsorbent.
[0541] Furthermore, the compounds of the present invention,
including their salts, can also be obtained in the form of their
hydrates, or include other solvents used for their crystallization.
The compounds of the present invention may inherently or by design
form solvates with pharmaceutically acceptable solvents (including
water); therefore, it is intended that the invention embrace both
solvated and unsolvated forms. The term "solvate" refers to a
molecular complex of a compound of the present invention (including
pharmaceutically acceptable salts thereof) with one or more solvent
molecules. Such solvent molecules are those commonly used in the
pharmaceutical art, which are known to be innocuous to the
recipient, e.g., water, ethanol, and the like. The term "hydrate"
refers to the complex where the solvent molecule is water.
[0542] The compounds of the present invention, including salts,
hydrates and solvates thereof, may inherently or by design form
polymorphs.
Processes for Making Compounds of Formula (A) and Subformulae
Thereof
[0543] General procedures for preparing compounds of Formula (A),
Formula (I), Formula (II), Formula (Ia to Ip) and Formula (IIa to
IIk) are described herein. In the reactions described, reactive
functional groups, for example hydroxy, amino, imino, thio or
carboxy groups, where these are desired in the final product, may
be protected to avoid their unwanted participation in the
reactions. Within the scope of this text, only a readily removable
group that is not a constituent of the particular desired end
product of the compounds of the present invention is designated a
"protecting group", unless the context indicates otherwise. The
protection of functional groups by such protecting groups, the
protecting groups themselves, and their cleavage reactions are
described for example in standard reference works, such as J. F. W.
McOmie, "Protective Groups in Organic Chemistry", Plenum Press,
London and New York 1973, in T. W. Greene and P. G. M. Wuts,
"Protective Groups in Organic Synthesis", Third edition, Wiley, New
York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J.
Meienhofer), Academic Press, London and New York 1981, in "Methoden
der organischen Chemie" (Methods of Organic Chemistry), Houben
Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart
1974, in H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide,
Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie,
Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann,
"Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry
of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme
Verlag, Stuttgart 1974. A characteristic of protecting groups is
that they can be removed readily (i.e. without the occurrence of
undesired secondary reactions) for example by solvolysis,
reduction, photolysis or alternatively under physiological
conditions (e.g. by enzymatic cleavage).
[0544] Compounds of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) or Formula (IIa to IIk) are made by processes described
herein and as illustrated in the Examples. Non-limiting examples of
synthetic schemes used to make compounds of the invention are
illustrated in Scheme 1 and Scheme 2.
[0545] Scheme 1 illustrates one embodiment for making compounds of
Formula (A), Formula (I) and Formula (II) using Buchwald-Hartwig
Amination, where Pd catalyzed cross-coupling of protected amine
intermediate (Int-A) or protected amine intermediate (Int-B) with a
heteroaryl halide intermediate (Int-1) followed by deprotection
gives a compound of Formula (Ia) or Formula (IIa), respectively,
where R.sup.1 is NH.sub.2. Further alkylation or acylation results
in compounds of Formula (Ia) or Formula (IIa), where R.sup.1 is as
further defined herein.
##STR00040##
[0546] In additional embodiments, compounds of Formula (A), Formula
(I) and Formula (II) can be obtained by replacing intermediate
(Int-1) with either intermediates Int-2, Int-3, Int-4, Int-5,
Int-6, Int-7, Int-8, Int-9, Int-10 or Int-11, resulting compounds
of Formula (Ic), Formula (b), Formula (If), Formula (Ig), Formula
(Id), Formula (Ie), Formula (Ij), Formula (Ii), Formula (Ik),
Formula (Ih), Formula (IIc), Formula (IIb), Formula (IIf), Formula
(IIg), Formula (IId), Formula (IIe), Formula (IIj), Formula (IIi),
Formula (IIk), and Formula (IIh), respectively. Table 1 shows the
alternative intermediates and the respective products,
where TG.sub.A
##STR00041##
TG.sub.B is
##STR00042##
[0547] X.sub.1 is Br, Cl, I or --SO.sub.3CF.sub.3, and Y.sub.1,
Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.13
and R.sup.14 are as defined herein.
TABLE-US-00001 TABLE 1 Product with Int-A Product with Int-B after
Deprotection and Optional after Deprotection and Optional
Alternative to Int-1 Alkylation or Acylation Alkylation or
Acylation ##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051##
##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##
##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##
##STR00072##
[0548] The Pd catalyst used in the coupling reactions of Scheme 1
is selected from Pd(II) catalysts, for example,
bis(tri-o-tolylphosphine)palladium(II)dichloride,
bis(tri-o-tolylphosphine)Pd(dba).sub.2,
bis(tri-o-tolylphosphine)Pd.sub.2(dba).sub.3, PdCl.sub.2(dppf),
(tri-o-tolylphosphine)Pd(OAc).sub.2, Pd(OAc).sub.2 and a
palladacycle.
[0549] The optional ligand of Scheme 1 is selected from
diphenylphospinobinaphthyl (BINAP), diphenylphospinoferrocene
(DPPF), tri-o-tolylphosphine (P(o-tol).sub.3), triphenylphosphine
(PPh.sub.3), tri-tert-butylphosphine (P(t-Bu).sub.3),
2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-bipheny-
l (BrettPhos),
2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphe-
nyl (t-BuBrettPhos),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos),
2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos),
2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos),
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos),
2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine,
2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl
(t-BuDavePhos),
2-diphenylphosphino-2',6'-bis(dimethylamino)-1,1'-biphenyl
(PhCPhos),
2-Di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbipheny-
l (RockPhos),
2-(di-adamantanylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biph-
enyl (AdBrettPhos),
di-tert-butyl(2',4',6'-tricyclohexyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)p-
hosphine,
di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-bi-
phenyl]-2-yl)phosphine,
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),
2-(2-dicyclohexylphosphanylphenyl)-N1,N1,N3,N3-tetramethyl-benzene-1,3-di-
amine (CPhos),
2'-(Diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine
(PhDavePhos),
2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimethoxy-2',4',6'-t-
riisopropyl-1,1'-biphenyl (JackiePhos),
(2-Biphenyl)di-tert-butylphosphine (JohnPhos),
(2-Biphenyl)dicyclohexylphosphine (CyJohnPhos),
2-Dicyclohexylphosphino-2'-methylbiphenyl (MePhos),
2-Di-t-butylphosphino-2'-methyl)-1,1'-biphenyl (t-BuMePhos),
2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), Sodium
2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate
hydrate (sSPhos), rac-2-(Di-tert-butylphosphino)-1,1'-binaphthyl
(TrixiePhos),
2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbipheny-
l (Me.sub.4 t-BuXPhos),
2'-Dicyclohexylphosphino-2,6-di-i-propyl-4-sulfonato-1,1'-biphenyl
hydrate sodium salt (XPhos-SO.sub.3Na),
di-tert-butyl(2',4',6'-triisopropyl-4,5-dimethoxy-3,6-dimethyl-[1,1'-biph-
enyl]-2-yl)phosphine and
2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-4-amine and
Tricyclohexylphosphine (P(Cy)3).
[0550] The bases used in such coupling reactions of Scheme 1
include, KOAc, NaOAc, K.sub.2CO.sub.3, Na.sub.2CO.sub.3, NaOEt,
KOtBu, NaOtBu, LiHMDS, Cs.sub.2CO.sub.3, K.sub.3PO.sub.4, NaOH,
KOH, tBuOH and NEt.sub.3. Such coupling reactions are stirred at
temperatures in the range of approximately 100-180.degree. C., or
are conducted in a microwave oven. In addition, solvents, for
example benzene, toluene, 1,2-dimethoxyethane, acetonitrile, DCM,
DMF, THF, dioxane and N-methyl-2-pyrrolidone are used. The reaction
may be carried out under an inert gas such as nitrogen or
argon.
[0551] Scheme 2 illustrates another embodiment for making compounds
of Formula (A), Formula (I) and Formula (II) using base catalyzed
cross-coupling of protected amine intermediate (Int-A) or protected
amine intermediate (Int-B) with a heteroaryl halide intermediate
(Int-1) followed by deprotection gives a compound of Formula (Ia)
or Formula (IIa), respectively, where R.sup.1 is NH.sub.2. Further
alkylation or acylation results in compounds of Formula (Ia) or
Formula (IIa), where R.sup.1 is as further defined herein.
##STR00073##
[0552] In additional embodiments, compounds of Formula (A), Formula
(I) and Formula (II) can be obtained by replacing intermediate
(Int-1) with either intermediates Int-2, Int-3, Int-4, Int-5,
Int-6, Int-7, Int-8, Int-9, Int-10 or Int-11, resulting compounds
of Formula (Ic), Formula (Ib), Formula (If), Formula (Ig), Formula
(Id), Formula (Ie), Formula (Ij), Formula (Ii), Formula (Ik),
Formula (Ih), Formula (IIc), Formula (IIb), Formula (IIf), Formula
(IIg), Formula (IId), Formula (IIe), Formula (IIj), Formula (IIi),
Formula (IIk), and Formula (IIh), respectively. Table 2 shows the
alternative intermediates and the respective products,
where TG.sub.A is
##STR00074##
TG.sub.B is
##STR00075##
[0553] X.sub.1 is Br, Cl, I or --SO.sub.3CF.sub.3, and Y.sub.1,
Y.sub.2, Y.sub.3, L, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.13
and R.sup.14 are as defined herein.
TABLE-US-00002 TABLE 2 Product with Int-A Product with Int-B after
Deprotection and Optional after Deprotection and Optional
Alternative for Int-1 Alkylation or Acylation Alkylation or
Acylation ##STR00076## ##STR00077## ##STR00078## ##STR00079##
##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084##
##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089##
##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094##
##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099##
##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104##
##STR00105##
[0554] The bases used in such coupling reactions of Scheme 2
include, DIPEA, Cs.sub.2CO.sub.3, 1,8-diazabicycloundec-7-ene
(DBU), NEt.sub.3, K.sub.2CO.sub.3, CaCO.sub.3, Na.sub.2CO.sub.3,
K.sub.3PO.sub.4, KF, KOAc, NaOEt, KOtBu and NaOH. Such coupling
reactions are stirred at temperatures in the range of approximately
80-180, or are conducted in a microwave oven. The solvent used in
such coupling reactions of Scheme (VII) and Scheme (VII), include
H.sub.2O, 2-methyl-THE, 2-methyl-THF/H.sub.2O (1:1), THE, MeOH,
butanol, t-butanol, EtOAc, CAN, ACN, DMSO, NMP, toluene
dimethylacetamide and DMF. The reaction may be carried out under an
inert gas such as nitrogen or argon.
Intermediates Int-A and Int-B
[0555] Scheme 3 illustrates an embodiment for making intermediates
Int-A and Int-B.
##STR00106##
[0556] Scheme 4 illustrates an embodiment for making intermediates
Int-A and Int-B.
##STR00107##
[0557] The amine protecting group (Prot) in Schemes 1 to 4 is
selected from methyl carbamate, 9-Fluorenylmethyl carbamate (Fmoc),
2,2,2-Trichlorethyl carbamate (Troc), t-butyl carbamate Boc),
2-(Trimethylsilyl)ethyl carbamate (Teoc), allyl carbamate (Alloc),
benzyl carbamate (Cbz), benzylideneamine, p-toluenesulfonamide,
trifluoroacetamide, acetamide, phthalimide, benzylamine,
4-methoxybenzyl amine (PMB), allyl amine and tritylamine.
[0558] The invention further includes any variant of the present
processes, in which an intermediate product obtainable at any stage
thereof is used as starting material and the remaining steps are
carried out, or in which the starting materials are formed in situ
under the reaction conditions, or in which the reaction components
are used in the form of their salts or optically pure material.
[0559] Compounds of the invention and intermediates can also be
converted into each other according to methods generally known to
those skilled in the art.
EXAMPLES
[0560] The compounds of the present invention can be produced as
shown in the following examples. The following examples are
intended to illustrate the invention and are not to be construed as
being limitations thereon. Temperatures are given in degrees
Celsius. If not mentioned otherwise, all evaporations are performed
under reduced pressure, typically between about 15 mm Hg and 100 mm
Hg (=20-133 mbar). The structure of final products, intermediates
and starting materials is confirmed by standard analytical methods,
e.g., microanalysis and spectroscopic characteristics, e.g., MS,
IR, NMR. Abbreviations used are those conventional in the art.
[0561] All starting materials, building blocks, reagents, acids,
bases, dehydrating agents, solvents, and catalysts utilized to
synthesis the compounds of the present invention are either
commercially available or can be produced by organic synthesis
methods known to one of ordinary skill in the art or can be
produced by organic synthesis methods as described herein.
Abbreviations:
[0562] BH.sub.3-DMS borane dimethyl sulfide brine concentrated
aqueous sodium chloride solution CPME cyclopentyl methyl ether d
doublet dd doublet of doublets DCM dichloromethane DMA
dimethylacetamide
DMAP 4-Dimethylaminopyridine
[0563] DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
[0564] DMSO dimethylsulfoxide DIPEA diisopropylethylamine ESI
electrospray ionization ESIMS electrospray ionization mass
spectrometry EtOAc ethyl acetate EtOH ethanol eq equivalent HPLC
high pressure liquid chromatography hr hour hrs hours IPA isopropyl
alcohol LC-MS or LC/MS liquid chromatography and mass spectrometry
MeOH methanol MS mass spectrometry m multiplet mg milligram min
minutes mL milliliter mm millimeter mmol millimol m/z mass to
charge ratio nm nanometer nM nanomolar NMR nuclear magnetic
resonance RT retention time rt room temperature s singlet t triplet
TFA trifluoroacetic acid THE tetrahydrofuran UV ultra violet .mu.m
micrometer
Instrumentation
LC-MS Methods
[0565] Method 1: The instrument was comprised of an Agilent LC/MS
system with a 1200sl HPLC pump and 6100 series single quadrupole
mass spectrometer with electrospray (ESI) ionization. The sample
was injected onto a Waters Acquity.RTM.HSS T3 column C18 1.8 .mu.m
2.1.times.50 mm at 60.degree. C. The gradient pump method used a
flow rate of 0.9 mL/min throughout the 2.25 min run, with mobile
phase A: 0.05% TFA in H2O and mobile phase B: 0.035% TFA in
acetonitrile, 10% B-100% B in 1.36 min. [0566] Method 2:
3.5MIN_10TO100B: The instrument was comprised of an Agilent LC/MS
system with a 1200sl HPLC pump and 6100 series single quadrupole
mass spectrometer with electrospray (ESI) ionization. The sample
was injected onto a Waters Acquity.RTM.HSS T3 column C18 1.8 .mu.m
2.1.times.50 mm at 60.degree. C. The gradient pump method used a
flow rate of 0.9 mL/min throughout the 2.25 min run, with mobile
phase A: 0.05% TFA in H.sub.2O and mobile phase B: 0.035% TFA in
acetonitrile, 10% B-100% B in 1.36 min.
Tail Groups
[0567] The Tail Group intermediates used to obtain compounds of the
invention are shown below and in Table 4, with their respective
synthesis also described below. Unless purchased, the synthesis of
certain reagents used to obtain these intermediates is also
described below.
Purchased Reagents
TABLE-US-00003 [0568] Reagent No. Reagent Structure Reagent Name
i-A0 ##STR00108## 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine
i-A1 ##STR00109## 3-methyl-1H-pyrazolo[4,3-c]pyridine i-A2
##STR00110## 1H-pyrazolo[4,3-c]pyridine i-A3 ##STR00111##
tert-butyl 7,7-dimethyl-1,4,6,7-tetrahydro-5H-
pyrazolo[4,3-c]pyridine-5-carboxylate i-A4 ##STR00112##
3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine i-A6
##STR00113## 3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine i-A7
##STR00114## tert-butyl 3-(trifluoromethyl)-6,7-dihydro-1H-
pyrazolo[4,3-c]pyridin-5(4H)-carboxylate
Synthesis of Certain Intermediates Used in the Synthesis of Various
Tail Groups
Synthesis of
4-((tert-butylcarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B1)
##STR00115##
[0570] Step 1: To a solution of
4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic
acid (4.565 g, 16.9 mmol) in THE (30 mL) was added BH.sub.3-DMS
(5.15 mL, 3.0 eq) at 0.degree. C. After addition, the reaction was
further stirred overnight at rt. LC/MS indicated that the reaction
was complete. The reaction was then treated with dropwise addition
of 10% citric acid. Aqueous work up followed by ISCO purification
(hexane/EtOAc) afforded tert-butyl
(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate as a white
solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 6.31 (s, 1H), 4.31
(t, J=5.4 Hz, 1H), 2.99 (d, J=5.4 Hz, 2H), 1.75-1.61 (m, 6H),
1.41-1.27 (m, 15H). ESIMS (M+H.sup.+) 256.20.
[0571] Step 2: To a mixture of tert-butyl
(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)carbamate (1.021 g, 4.0
mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (1.566 g, 6.4
mmol, 1.6 eq) and DCM (10 mL) was added Et.sub.3N (1.12 mL, 2.0 eq)
and DMAP (49 mg, 0.1 eq) at rt. After addition, the resulting
mixture was further stirred at rt for 4 hrs. LC/MS indicated the
reaction was complete: mainly two peaks, product peak with m/z 408
(M+H.sup.+-56) and intermediate peak with m/z 331. Aqueous work up
followed by ISCO purification (hexane/EtOAc) to get the product
(i-B1) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
8.12 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 6.39 (s, 1H), 3.74
(s, 2H), 1.75-1.57 (m, 6H), 1.42-1.26 (m, 15H). ESIMS calcd. for
C.sub.21H.sub.28F.sub.3NO.sub.5S (M+H.sup.+) 464.17, found 408.00
(M+H+-56).
Synthesis of
(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B2)
##STR00116##
[0573] Step 1: LiAlH.sub.4 (83 mg, 2.188 mmol) was dissolved in THE
(20 mL) at 0.degree. C. Starting material methyl
3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate
(240 mg, 0.995 mmol) was dissolved in 5 mL THF, then was added to
the LiAlH.sub.4 solution at 0.degree. C. After completion of the
reaction, the reaction mixture was warmed up to rt and stirred for
2 hrs. Sat. Na.sub.2SO.sub.4 solution was then added to quench the
reaction. After filtering the solvent was removed to obtain
tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate
for use in the next step.
[0574] Step 2: tert-Butyl
(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (180 mg,
0.844 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (206 mg,
0.844 mmol) and DIPEA (0.295 mL, 1.688 mmol) were mixed in DCM (5
mL) and the reaction mixture was stirred at 25.degree. C. for 5
hrs. After working-up and prep LC-MS,
(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B2) was obtained for use in
the next step. ESIMS (M+H.sup.+) 422.1.
Synthesis of
2-(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)ethyl
methanesulfonate (i-B3)
##STR00117##
[0576]
2-(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)ethyl
methanesulfonate (i-B3) was synthesized by mixing (287 mg, 1.065
mmol) of tert-butyl
(4-(2-hydroxyethyl)bicyclo[2.2.2]octan-1-yl)carbamate and
triethylamine (216 mg, 2.131 mmol) in DCM (10.700 ml). To this
solution was added methanesulfonyl chloride (159 mg, 1.385 mmol) at
0.degree. C. After addition, the resulting mixture was further
stirred at 25.degree. C. for 18 hrs. LC-MS indicated the reaction
was completed. After workup (water addition and extraction in DCM),
the organic layer was dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was used without further
purification. 1H NMR (400 MHz, Chloroform-d) .delta. 4.23 (d, J=6.0
Hz, 1H), 4.15 (t, J=7.3 Hz, 2H), 2.92 (s, 3H), 1.78-1.71 (m, 6H),
1.55-1.50 (m, 2H), 1.50-1.42 (m, 6H), 1.35 (s, 9H). ESIMS
(M+H.sup.+) 348.2.
Synthesis of
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B4)
##STR00118##
[0578]
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyltrif-
luoromethanesulfonate (i-B4) was made by following the synthetic
method for
2-(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)ethyl
methanesulfonate (i-B3), except methyl
4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate
was used in place of tert-butyl
(4-(2-hydroxyethyl)bicyclo[2.2.2]octan-1-yl)carbamate.
4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyl
trifluoromethanesulfonate (i-B4) was typically used as crude.
Synthesis of
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methylmethanesul-
fonate (i-B5)
##STR00119##
[0580]
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methylmeth-
anesulfonate (i-B5) was made by following the synthetic method for
2-(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)ethyl
methanesulfonate (i-B3), except tert-butyl
(4-(2-hydroxyethyl)bicyclo[2.2.1]heptan-1-yl)carbamate was used in
place of tert-butyl
(4-(2-hydroxyethyl)bicyclo[2.2.2]octan-1-yl)carbamate.
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyl
methanesulfonate (i-B5) was typically used as crude.
Synthesis of
(4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B6)
##STR00120##
[0582]
(4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octan-1-yl)methy-
l 4-(trifluoromethyl)benzenesulfonate (i-B6) was made by following
the synthetic method for
(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B2), except methyl
4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-1-carboxylate
was used in place of methyl
3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate.
RT (method 1): 1.84 min. ESIMS calcd. for
C.sub.20H.sub.26F.sub.3NO.sub.6S (M+H.sup.+) 465.5, found 488.5
(M+Na).
Synthesis of Tail Groups
Synthesis of tert-butyl
(4-((4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2-
.2]octan-1-yl)carbamate (TG1) and tert-butyl
(4-((4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2-
.2]octan-1-yl)carbamate (TG2)
##STR00121##
[0584] Step 1: A solution of
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (i-A0) (165 mg, 0.64
mmol) in methanol (13.5 ml) was treated with DIPEA (2.91 ml, 16.66
mmol), followed by dropwise addition of benzyl chloroformate (0.837
ml, 5.95 mmol). The whole mixture was stirred for 18 hrs. LCMS
showed a completed reaction and the reaction mixture was
concentrated in vacuo. The residue was loaded on a 24 g silica gel
column using 10% methanol in DCM to afford benzyl
1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (MS
calculated for C.sub.14H.sub.15N.sub.3O.sub.2 (M+H.sup.+) 258.1,
found 258.1).
[0585] Step 2: To a 20 mL scintillation vial containing benzyl
1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (165
mg, 0.641 mmol), was added
4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B1) (446 mg, 0.962 mmol),
cesium carbonate (418 mg, 1.28 mmol) and anhydrous DMSO (3.2 mL).
The mixture was heated to 110.degree. C. for 18 hr, before diluted
in ethyl acetate and water. Citric acid was added as solid to
neutralize pH. After partition, the aqueous layer was re-extracted
with ethyl acetate three times. All the organic layers were
combined, dried over magnesium sulfate and concentrated in vacuo.
The residue was purified on a 40 g silica gel column using 0-10%
methanol in DCM to afford a mixture of the two desired regioisomers
(MS calculated for C.sub.20H.sub.32N.sub.4O.sub.2 (M+H.sup.+)
361.3, found 361.3.
[0586] Step 3: To a mixture of (TG1a) and (TG2a) (102 mg, 0.21
mmol), was added palladium on carbon (0.0220 g, 0.0207 mmol) and
ethanol (1 ml). The mixture was stirred with hydrogen (65 psi) for
18 hr; LCMS showed .about.90% conversion. The mixture was filtered,
washed with methanol and concentrated in vacuo. The residue was
loaded on a 40 g silica gel column using 0-80% isopropanol in DCM
with 2% ammonia as modifier to afford the pure product directly
used in the separation step (below).
Regioisomer Separation
[0587] 56 mg (0.16 mmol) of TG1 and TG2 from step two were
separated using SFC chromatography on a 21.times.250 mm Cyano
column (phase: 3 .mu.M 4.6.times.50 mm, cyano, solvents mixture:
CO.sub.2: 85%; 1/1 v/v IPA:MeOH+10 mM NH.sub.4OAc -15%; prep
conditions: 80 g/min, 88/6/6 CO.sub.2/IPA/MeOH+10 mM NH40Ac,
.about.115 bar, 2 min stacked injections, 5.25 min elution time) to
afford tert-butyl
(4-((4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2-
.2]octan-1-yl)carbamate (TG1; peak 2, RT 2.1 min., ESIMS calcd. for
C.sub.21H.sub.34N.sub.4O.sub.2(M+H+) 361.3, found 361.3) and
tert-butyl
(4-((4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2-
.2]octan-1-yl)carbamate (TG2; peak 1, RT 1.71 min. ESIMS calcd. for
C.sub.20H.sub.32N.sub.4O.sub.2(M+H+) 361.3, found 361.3.
Synthesis of
tert-butyl(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl-
)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (TG3) and tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG4)
##STR00122##
[0589] Step 1: A suspension of 3-methyl-1H-pyrazolo[4,3-c]pyridine
(i-A1) (2.66 g, 19.98 mmol), in DMSO (80 ml) was treated with
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B1) (9.26 g, 19.98 mmol) and
cesium carbonate (13.02 g, 40.0 mmol). The mixture was heated to
120.degree. C. for 18 hr to complete, before being cooled to rt and
diluted in ethyl acetate and water. After partitioning, the organic
layer was dried over magnesium sulfate and concentrated in vacuo.
The residue was purified on a 120 g silica gel column using 0-80%
ethyl acetate in hexane and extended to 80% ethyl acetate in hexane
to afford the desired products tert-butyl
(4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)carbamate (product 1). The gradient was extended 100% ethyl
acetate to elute the by-product tert-butyl
(4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)carbamate (product 2).
[0590] Product 1: RT (LCMS Method 1): 1.510 min (mass -M+1- 371.2),
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 9.07 (s, 1H), 8.37
(d, J=6.1 Hz, 1H), 7.60 (d, J=6.2 Hz, 1H), 6.18 (broad s, 1H), 4.17
(s, 2H), 2.71 (s, 3H), 1.87 (dd, J=10.0, 5.9 Hz, 6H), 1.66 (dd,
J=10.0, 5.9 Hz, 6H), 1.47 (s, 9H). ESIMS calcd. for
C.sub.21H.sub.30N.sub.4O.sub.2 (M+H+) 371.5, found 371.5.
[0591] Product 2: RT (LCMS Method 1): 1.47 min. ESIMS calcd. for
C.sub.21H.sub.30N.sub.4O.sub.2 (M+H+) 371.5, found 371.5.
[0592] Step 2: Hydrogenation of Product 1
[0593] tert-butyl
(4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)carbamate (product 1) (3.6267 g, 9.79 mmol) was hydrogenated
using a H-cube system. Once complete, the reaction solution was
concentrated and loaded on a 120 g silica gel column using 0-100%
IPA in DCM with 1% ammonia as modifier and then extended to 100%
IPA with 1% ammonia as modifier to elute tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3): .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 3.73 (s, 2H), 3.65 (s, 2H), 3.04 (t, J=5.8 Hz,
2H), 2.65 (t, J=5.9 Hz, 2H), 2.12 (s, 3H), 1.87-1.74 (m, 6H),
1.61-1.47 (m, 6H), 1.39 (s, 9H); ESIMS calcd. for
C.sub.21H.sub.34N.sub.4O.sub.2 (M+H+) 375.5, found 375.5.
[0594] Step 2: Hydrogenation of Product 2
[0595] tert-butyl
(4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)carbamate (1.011 g, 2.73 mmol) was hydrogenated using a H-cube
system. Once complete, the reaction solution was concentrated and
loaded on a 24 g silica gel column using 0-100% IPA in DCM with 3%
NH.sub.3 as modifier to yield tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG4). .sup.1H NMR (400 MHz,
Methanol-d4) .delta. 4.89 (d, J=1.4 Hz, 1H), 3.75 (m 4H), 3.09 (t,
J=5.9 Hz, 2H), 2.72 (m, 2H), 2.15 (s, 3H), 1.79 (m, 6H), 1.54 (m,
6H), 1.40 (s, 9H). ESIMS calcd. for C.sub.21H.sub.34N.sub.4O.sub.2
(M+H+) 375.5, found 375.5.
Synthesis of tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.1]heptan-1-yl)carbamate (TG5)
##STR00123##
[0597] Step 1. A mixture of 3-methyl-1H-pyrazolo[4,3-c]pyridine
(i-A1) (133 mg, 1.0 mmol),
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyl
methanesulfonate (i-B5) (351 mg, 1.1 mmol) and Cs.sub.2CO.sub.3 in
DMSO (2 mL) was stirred at 80.degree. C. overnight. LC-MS showed
completion of the reaction. The reaction mixture was then cooled
down to rt and diluted with EtOAc/water. The layers were separated
and the organic layer was dried over Na.sub.2SO.sub.4 then
concentrated. The crude product was added (solid loading) to a 40 g
silica gel column and was eluted with 0-100% EtOAc in hexanes.
Collected fractions and concentrated to give product 1, tert-butyl
(4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptan--
1-yl)carbamate, and product 2, tert-butyl
(4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.1]heptan--
1-yl)carbamate.
[0598] Step 2. 220 mg (0.617 mmol) of, tert-butyl
(4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptan--
1-yl)carbamate was transformed to the desired product, tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.1]heptan-1-yl)carbamate (TG5) using H-Cube: 90.degree.
C., 20 bar H.sub.2, 10% Pd/C, 1 mL/min flow rate. RT (LCMS Method
2) 1.92 min. MS calculated for C.sub.20H.sub.32N.sub.4O.sub.2
(M+H.sup.+) 361.5, found 361.5. Note: Product 2 was not
hydrogenated.
Synthesis of tert-butyl
1-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-7,7-di-
methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate
(TG6a) and tert-butyl
2-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-7,7-di-
methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate
(TG7a)
##STR00124##
[0600] tert-butyl
7,7-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate
(iA3) (120 mg, 0.477 mmol),
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B1) (220 mg, 0.477 mmol) and
Cs.sub.2CO.sub.3 (156 mg, 0.477 mmol) were mixed in DMA (10 mL) and
stirred at 120.degree. C. for 1 hr. After working-up and prep
LC-MS, tert-butyl
1-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-7,7-di-
methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate
(TG6a) and tert-butyl
2-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-7,7-di-
methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate
TG7a) were obtained.
Synthesis of
4-((7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl-
)bicyclo[2.2.2]octan-1-amine (TG6)
##STR00125##
[0602] tert-butyl
1-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-7,7-di-
methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate
(TG6a) (70 mg, 0.143 mmol) and HCl in dioxane (4N) (0.433 mL, 14.27
mmol) were mixed in MeOH (1 mL) and stirred at 50.degree. C. for 5
hrs. After working-up and prep LC-MS
4-((7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl-
)bicyclo[2.2.2]octan-1-amine (TG6) was obtained.
Synthesis of
4-((7,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl-
)bicyclo[2.2.2]octan-1-amine (TG7)
##STR00126##
[0604] tert-butyl
2-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-7,7-di-
methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate
(TG7a) (70 mg, 0.143 mmol) and HCl in dioxane (4N) (0.433 mL, 14.27
mmol) were mixed in MeOH (1 mL) and stirred at 50.degree. C. for 5
hrs. After working-up and prep LC-MS
4-((7,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl-
)bicyclo[2.2.2]octan-1-amine (TG7) was obtained.
Synthesis of
4-((3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl-
)methyl)bicyclo[2.2.2]octan-1-amine (TG8)
##STR00127##
[0606] Step 1. A mixture of 291 mg (1 mmol) of tert-butyl
3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxyl-
ate (i-A7), 510 mg (1.1 mmol) of
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyl
methanesulfo(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methy-
l methanesulfonate and cesium carbonate (652 mg, 2.0 mmol) in DMSO
(5 mL) was stirred at 80.degree. C. overnight. After cooling to rt
the mixture was diluted with EtOAc/water. The layers were separated
and the aqueous layer was extracted with EtOAc. The combined
organic layers were dried over Na.sub.2SO.sub.4 then concentrated
to give the crude product. The crude product was added (solid
loading) to a 40 g silica gel column and was eluted with 0-50%
EtOAc in hexanes. Collected fractions and concentrated to give the
desired product, tert-butyl
1-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-3-(tri-
fluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate
(TG8a) and a trace amount of tert-butyl
2-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-3-(tri-
fluoromethyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate
(TG9a). TG8a: 1H NMR (500 MHz, Methylene Chloride-d2) .delta.
4.51-4.46 (m, 2H), 4.36 (s, 1H), 3.84 (s, 2H), 3.65 (t, J=5.8 Hz,
2H), 2.70 (t, J=5.9 Hz, 2H), 1.82-1.73 (m, 6H), 1.59-1.52 (m, 6H),
1.46 (s, 9H), 1.38 (s, 9H). MS (ES+): 529.4 (M+1)+. TG9a: Method 1
(RT: 2.07 min), MS (ES+): 529.4 (M+1)+.
[0607] Step 2: To a solution of 66 mg (0.125 mmol) of tert-butyl
1-((4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl)-3-(tri-
fluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate
(TG8a) in dioxane/MeOH (0.5 mL/0.3 mL) was added HCl (4M solution
in dioxane, 0.5 mL). The resulting mixture was stirred at rt for 2
hrs. The reaction mixture was concentrated and lyophilized to give
the final product,
4-((3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyr-
idin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine (TG8), as HCl salt.
Method 1 (RT=0.9 min), MS (ES+): 329.2 (M+1)+.
Synthesis of tert-butyl
methyl(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)met-
hyl)bicyclo[222]octan-1-yl)carbamate (TG10)
##STR00128## ##STR00129##
[0609] Step 1. To a solution of 1.85 g (4.0 mmol) of
(4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate (i-B1) in THF was added 208 mg
(5.2 mmol) of NaH at 0.degree. C. under N.sub.2. The mixture was
warmed up to rt and stirred for 30 min then cooled back to
0.degree. C. before CH.sub.3I (2.84 g, 20.0 mmol) was added
dropwise. The resulting mixture was slowly warmed up to rt and
stirred overnight. LC-MS showed desired product but the reaction
was not complete. Additional NaH (1.0 eq.) and CH.sub.3I (5.0 eq.)
were added and the reaction mixture was stirred at rt overnight.
The reaction was quenched at 0.degree. C. by dropwise adding 2.0 mL
of 2-propanol, then 3.0 mL of cold water. The mixture was then
partitioned between EtOAc and water. The layers were separated and
the aqueous layer was extracted with EtOAc. The combined organic
layers were dried over Na.sub.2SO.sub.4 then concentrated. The
crude product was added to a 80 g silica gel column and was eluted
with 0-30% EtOAc in hexanes. Collected fractions and concentrated
to give
(4-((tert-butoxycarbonyl)(methyl)amino)bicyclo[2.2.2]octan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate. RT: 3.1 min (method 2). 1H NMR
(400 MHz, Methanol-d4) .delta. 8.11 (d, J=8.2 Hz, 2H), 7.98 (d,
J=8.2 Hz, 2H), 3.73 (d, J=1.9 Hz, 2H), 2.82 (s, 3H), 2.04-1.95 (m,
6H), 1.53-1.42 (m, 15H).
[0610] Step 2. A mixture of 133 mg (1.0 mmol) of
3-methyl-1H-pyrazolo[4,3-c]pyridine, 525 mg (1.1 mmol) of
(4-((tert-butoxycarbonyl)(methyl)amino)bicyclo[2.2.2]octan-1-yl)methyl
4-(trifluoromethyl)benzenesulfonate and 652 mg (2.0 mmol) of
Cs.sub.2CO.sub.3 in DMSO was stirred at 80.degree. C. overnight.
After cooling to rt, the mixture was diluted with EtOAc/water. The
layers were separated and the organic layer was dried over
Na.sub.2SO.sub.4, then concentrated. The crude product was added
(solid loading) to a 40 g silica gel column and was eluted with
0-100% EtOAc in hexanes. Collected fractions and concentrated to
give tert-butyl
methyl(4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]o-
ctan-1-yl)carbamate as the major product (eluting first), and
tert-butyl
methyl(4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]o-
ctan-1-yl)carbamate as the minor by-product (eluting second). Major
product (tert-butyl
methyl(4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]o-
ctan-1-yl)carbamate): .sup.1H NMR (400 MHz, Methanol-d4) .delta.
8.99 (d, J=1.1 Hz, 1H), 8.29 (d, J=6.2 Hz, 1H), 7.52 (dd, J=6.2,
1.2 Hz, 1H), 4.10-4.07 (m, 2H), 2.80 (s, 3H), 2.63 (s, 3H),
2.01-1.94 (m, 6H), 1.63-1.56 (m, 6H), 1.43 (s, 9H). MS (ES+): 385.2
(M+1)+. Minor product (tert-butyl
methyl(4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]o-
ctan-1-yl)carbamate): 1H NMR (400 MHz, Methanol-d4) .delta. 9.08
(d, J=1.3 Hz, 1H), 8.14 (d, J=6.4 Hz, 1H), 7.48 (dd, J=6.3, 1.2 Hz,
1H), 4.19 (s, 2H), 2.81 (s, 3H), 2.77 (s, 3H), 2.07-1.97 (m, 6H),
1.70-1.62 (m, 6H), 1.43 (s, 9H). MS (ES+): 385.2 (M+1)+.
[0611] Step 3. tert-butyl
methyl(4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]o-
ctan-1-yl)carbamate (233 mg, 0.606 mmol) was transformed to the
desired product, tert-butyl
methyl(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)met-
hyl)bicyclo[2.2.2]octan-1-yl)carbamate (TG10) using H-Cube:
100.degree. C., 15 bar H.sub.2, 10% Pd/C, 1 mL/min flow rate. The
product was used directly without purification. RT (method 2): 1.7
min, MS (ES+): 389.3 (M+1)+.
TABLE-US-00004 TABLE 4 Additional Tail Groups Tail Group Code Tail
Group Characterization Synthesis Method TG11 ##STR00130## Method 1
(RT = 1.17 min), MS (ES+): 378.3 (M + 1) See Synthesis of TG3 Use
(i-B6) in place of (i-B1) TG12 ##STR00131## Method 1 (RT = 1.25
min.), MS (ES+): 390.2 (M + 1) See Synthesis of TG3 Use (i-B3) in
place of (i-B1) TG13 ##STR00132## Method 1 (RT = 1.09 min.), MS
(ES+): 334.2 (M + 1) See Synthesis of TG4 Use (i-B2) in place of
(i-B1) TG14 ##STR00133## See synthesis of TG3. Use 4-
hydroxybicyclo[2,2,2]octane-1- carboxylic acid as starting material
instead of 4-((tert- butoxycarbonyl)amino)bicyclo[2.2.2]
octane-1-carboxylic acid
Head Groups
[0612] The Head Group intermediates used to obtain compounds of the
invention are shown in Table 5 and their synthesis is described
below. Unless purchased, the synthesis of certain reagents used to
obtain these intermediates is also described below.
TABLE-US-00005 TABLE 5 Head Groups Head Group Synthesis Method or
Code Head Group Head Group Name Purchase HG1 ##STR00134##
4-bromo-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridine Purchased HG2
##STR00135## 4-chloro-1-methyl-1H- pyrazolo[3,4-d]pyrimidiin-
6-amine Purchased HG2a ##STR00136## tert-butyl (4-chloro-1-
methyl-1H-pyrazolo[3,4- d]pyrimidin-6- yl)carbamate Boc Protected
HG2 HG3 ##STR00137## 5,7-dichloro-1-methyl- 1H-pyrazolo[4,3-
d]pyrimidine Purchased HG4 ##STR00138## 7-chloro-1,3,5-trimethyl-
1H-pyrazolo[4,3- d]pyrimidine Purchased HG5 ##STR00139##
4-chloro-3,6- dimethylisoxazolo[5,4- d]pyrimidine Purchased HG6
##STR00140## 4-chloro-1H- pyrazolo[3,4-b]pyridine Purchased HG7
##STR00141## 1-(4-methoxybenzyl)-6- methyl-1H-pyrazolo[3,4-
b]pyridin-4-yl trifluoromethanesulfonate See Below HG8 ##STR00142##
4-chloro-2- methylquinoline Purchased HG9 ##STR00143##
4-chloro-2-methyl-1,7- naphthyridine Purchased HG10 ##STR00144##
4-chloro-2,8-dimethyl- 1,7-naphthyridine See below HG11
##STR00145## 2,4-dichloro-5,7- dihydrofuro[3,4- d]pyrimidine
Purchased HG12 ##STR00146## 7-chloro-5-methyl-1H-
pyrazolo[4,3-b]pyridine Purchased HG13 ##STR00147##
4-chloro-1-ethyl-6- methyl-1H-pyrazolo[3,4- b]pyridine See below
HG14 ##STR00148## 4-chloro-2-methyl-7H- pyrrolo[2,3-d]pyrimidine
Purchased HG15 ##STR00149## 4-chloro-1,6-dimethyl-
1H-pyrrolo[2,3-b]pyridine Purchased HG16 ##STR00150##
4,6-dichloro-1-methyl- 1H-pyrazolo[3,4- d]pyrimidine Purchased HG17
##STR00151## 4-chloro-1,6-dimethyl- 1H-pyrazolo[3,4- d]pyrimidine
Purchased HG18 ##STR00152## 4-chloro-6-methyl-1H-
pyrazolo[3,4-d]pyrimidine Purchased
Synthesis of
1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl
trifluoromethanesulfonate (HG7)
##STR00153##
[0614] Step 1: A solution of 1-(4-methoxybenzyl)-1H-pyrazol-5-amine
and ethyl acetoacetate in acetic acid was stirred at rt overnight.
The reaction was concentrated in vacuo and then taken up in
DOWThermA and heated in a sealed vessel to 230.degree. C. The
reaction was maintained at this temperature for 40 min and then
cooled to rt. The reaction was purified by column chromatography
(SiO.sub.2, ISCO, 0-15% MeOH in dichloromethane) to afford the
desired phenol directly used in the next step.
[0615] Step 2: To the solution of
1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.895
g, 7.04 mmol) in mix solvent of DCM (100 mL, 3.33 parts) and THF
(30 mL, 1 part) at 0.degree. C. was added triethylamine (7.36 mL,
52.8 mmol) followed by triflicAnhydride (2.97 mL, 17.59 mmol). The
reaction was gradually warmed up to rt in 3 hrs. The reaction was
quenched with saturated sodium bicarbonate solution and extracted
with DCM. The organic phase was washed with brine and dried. The
crude product was purified by silica gel chromatography, eluted
with 10% to 50% ethyl acetate in hexane to give
1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl
trifluoromethanesulfonate (HG7). RT (LC/MS method 2): 2.79 min.
ESIMS calcd. for C.sub.16H.sub.14F.sub.3N.sub.3O.sub.4 (M+H+)
402.9, found 402.9.
Synthesis of 4-chloro-2,8-dimethyl-1,7-naphthyridine (HG10)
##STR00154##
[0617] To a solution of 4-chloro-2-methyl-1,7-naphthyridine (405
mg, 2.267 mmol) in THE (10 mL) was intermittently added
methylmagnesium bromide (4.53 mL, 13.60 mmol, 3M in diether ether)
over 30 min at rt. The reaction changed from a light brown to a
dark green suspension. After stirring overnight, the reaction was
stopped and then quenched by addition of saturated NH.sub.4Cl (10
mL), extracted with EtOAc (3.times.25 mL). EtOAc was washed with
brine (5 mL), dried over Na.sub.2SO.sub.4 and evaporated to give
the crude desired product
4-chloro-2,8-dimethyl-7,8-dihydro-1,7-naphthyridine. MS 195.1
(M+1), RT (LC/MS method 1) 0.94 min. Contained byproduct MS 193.1
(M+1), RT (LC/MS method 1) 0.85 min. The crude was used w/o
purification in next step.
[0618] The crude
4-chloro-2,8-dimethyl-7,8-dihydro-1,7-naphthyridine (440 mg, 2.260
mmol) from above was dissolved in DCM (20 mL). DDQ (513 mg, 2.260
mmol) was added. The mixture was sonicated for 2 min. LCMS showed
completion of the reaction. The mixture was diluted with EtOAc (50
mL), filtered through Celite filter cake. The filter cake was
washed with EtOAc (50 mL). The organic was evaporated to give a
dark residue. The crude was purified by flash chromatography
(EtOAc:hex/0-100%) giving 4-chloro-2,8-dimethyl-1,7-naphthyridine
(HG10): MS 193.1 (M+1), RT 0.82 min. (method 1).
Synthesis of 4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine
(HG13)
##STR00155##
[0620] Step 1. A mixture of 2.5 g of 1-ethyl-1H-pyrazol-5-amine
(22.5 mmol), 23.4 g (180 mmol) of ethyl 3-oxobutanoate and 1.35 g
(22.5 mmol) of AcOH was reacted in flow using a Vapourtec R2C+/R4
(trip pressure set to 40 bar; SS tube reactor; solution pressure
set by 250 psi BPR) in dioxane at a flow rate of 0.2 mL/min at
250.degree. C. The reaction was quenched using MeOH (flow rate 0.25
mL/min). The resulting solution was concentrated and triturated in
EtOAc to afford 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol as
an off-white solid. RT 0.95 min (method 2). MS (M+1): 178.2
[0621] Step 2.
[0622] A sealed vessel charged with
1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1 g, 5.64 mmol)
and POCl.sub.3 (0.631 mL, 6.77 mmol) in anisole (8 mL) was heated
at 130.degree. C. for 2 hrs. The reaction was cooled down and the
solvent was removed in vacuo and dried to afford
4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine (HG13). RT
0.52 min (LC/MS method 2). MS (M+1): 196.6.
Synthesis of Exemplary Compounds
Example 1
Synthesis of
4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra-
hydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1)
##STR00156##
[0624] Step 1: To a pressure flask containing tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3) (0.565 g, 42.5 mmol) was
added 4-bromo-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine (HG1) (0.94
g, 2.5 mmol), cesium carbonate (1.63 g, 5.1 mmol),
Pd.sub.2(dba).sub.3 (0.057 g, 0.062 mmol), RuPhos (0.14 g, 0.3
mmol) and THF (25 mL). The mixture was heated at 80.degree. C. for
18 hrs to complete, then cooled to rt. The mixture was diluted in
ethyl acetate and water. After partition, the aqueous layer was
extracted with ethyl acetate once more. Both organic layers were
combined, dried over MgSO.sub.4, filtered and concentrated in
vacuo. The residue was purified via flash chromatography using
0-100% B/A (A=heptane; B=25% ethanol in ethyl acetate) to elute
tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)car-
bamate: .sup.1H NMR (400 MHz, CDCl3) .delta. 7.98 (s, 1H), 6.27 (s,
1H), 4.49 (s, 2H), 4.38-4.25 (m, 1H), 4.11 (s, 3H), 3.94 (t, J=5.5
Hz, 2H), 3.70 (s, 2H), 2.87 (t, J=5.6 Hz, 2H), 2.62 (s, 3H), 2.25
(s, 3H), 1.89-1.75 (m, 6H), 1.58 (m, 6H), 1.42 (s, 9H); MS
calculated for C.sub.29H.sub.72N.sub.7O.sub.2 (M+H.sup.+) 520.34,
found 520.4.
[0625] Step 2: To a 500 mL round bottom flask containing tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)car-
bamate (1.5 g, 1.45 mmol) was added methanol (6 mL), then 4N HCl in
dioxane (7.2 mL, 28.9 mmol). The mixture was stirred at rt for 18
hr then concentrated in vacuo. The residue was treated with
isopropanol portionwise at 70.degree. C. to get all solid
dissolved. The solution was cooled naturally to rt and aged for 18
hrs. Then the solid was filtered and the filtrate was concentrated
and the crystallization process repeated. Both batches were
combined and dried under vacuum at 40.degree. C. for 18 hrs to
afford of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
as HCl salt (Compound No. 1-HCl): .sup.1H NMR (400 MHz, CD.sub.3D)
.delta. 8.51 (s, 1H), 6.88 (s, 1H), 5.06-4.92 (m, 2H), 4.24 (s,
2H), 4.11 (s, 3H), 3.97 (s, 2H), 3.10 (t, J=5.6 Hz, 2H), 2.69 (s,
3H), 2.38 (s, 3H), 1.88-1.59 (m, 12H); MS (M+H.sup.+) found
420.3.
[0626] Step 3: Ambersep 9000H (17 ml, 0.8 meq/mL, prewashed with 60
mL of MeOH) was added into a solution of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
as HCl salt (Compound No. 1-HCl) (1.53 g, 2.7 mmol) in MeOH (100
mL). The mixture was stirred at rt for 1 hr then filtered, washed
with 50 mL of MeOH and concentrated. The crude product was added
(by solid loading) to a 12 g silica gel column and was eluted with
2-9% MeOH (containing small amount of ammonia) in DCM. Collected
fractions and concentrated to give the product,
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine,
as the free base (Compound No. 1): .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.15 (s, 1H), 6.45 (s, 1H), 4.54 (s, 2H), 4.00
(s, 3H), 3.97 (t, J=5.6 Hz, 2H), 3.73 (s, 2H), 2.90 (t, J=5.6 Hz,
2H), 2.55 (s, 3H), 2.23 (s, 3H), 1.55 (s, 12H); MS (M+H.sup.+)
420.3.
Example 2
Synthesis of
4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahyd-
ro-1H-pyrazolo[4,3-c]pyridin-1-yl)methy)bicyclo[2.2.2]octan-1-amine
(Compound No. 2) and
4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-met-
hyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2-
]octan-1-amine (Compound No. 53)
##STR00157## ##STR00158##
[0628] Step 1: tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3) (110 mg, 0.294 mmol),
1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl
trifluoromethanesulfonate (HG7) (118 mg, 0.294 mmol), DIPEA (0.154
mL, 0.881 mmol) and BuOH (0.05 mL) were added to a reaction vial
and then stirred at 120.degree. C. for 3 hrs. The reaction mixture
was purified by HPLC to give tert-butyl
(4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-me-
thyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.-
2]octan-1-yl)carbamate. RT (method 2): 2.29 min, ESIMS m/z 626.4
(M.sup.++1)
[0629] Step 2: To the solution of tert-butyl
(4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-me-
thyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.-
2]octan-1-yl)carbamate (110 mg, 0.176 mmol) in MeOH (1 mL) was
added hydrochloric acid (0.879 mL, 5.27 mmol). The reaction was
stirred for 16 hr at 25.degree. C. and then dried to give
4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-met-
hyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2-
]octan-1-amine (Compound No. 53) as HCl salt. RT (method 1): 1.28
min, ESIMS m/z 526.3 (M.sup.++1)
[0630] Step 3: To a 20 mL pressure tube was added
4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-met-
hyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2-
]octan-1-amine (Compound No. 53) (80 mg, 0.152 mmol), cysteine
(36.9 mg, 0.304 mmol) and TFA (2 mL). The mixture was heated at
75.degree. C. for 2 hr and then cooled to rt and concentrated in
vacuo. The residue was purified by HPLC to give
4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahyd-
ro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 2). ESIMS m/z 406.2 (M.sup.++1); .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.09 (s, 1H), 6.34 (s, 1H), 4.44 (s,
2H), 3.88 (t, J=5.6 Hz, 2H), 3.63 (s, 2H), 3.56 (s, 4H), 2.80 (t,
J=5.6 Hz, 2H), 2.41 (s, 3H), 2.13 (s, 3H), 1.44 (s, 12H).
Example 3
Synthesis of
4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 3) and tert-butyl
(4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-py-
razolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate
(Compound No. 147)
##STR00159##
[0632] Step 1: To the reaction vial were added tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3) (105 mg, 0.280 mmol),
4-chloro-2-methyl-1,7-naphthyridine (HG9) (50 mg, 0.280 mmol),
DIPEA (0.147 mL, 0.840 mmol) and BuOH (0.1 mL). The reaction was
stirred at 120.degree. C. for 3 hr, diluted with methanol and
purified by HPLC. The fractions were pooled, neutralized with
Na.sub.2CO.sub.3 and then extracted with ethyl acetate to give
tert-butyl
(4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-py-
razolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate
(Compound No. 147).sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.53
(s, 1H), 8.73 (d, J=5.9 Hz, 1H), 8.34-7.92 (m, 2H), 7.39 (s, 1H),
4.68 (s, 2H), 4.03 (t, J=5.2 Hz, 2H), 3.72 (s, 2H), 3.08 (s, 2H),
2.78 (s, 3H), 2.51 (s, 9H), 2.12 (s, 3H), 1.80-1.45 (m, 12H). ESIMS
m/z 518.0 (M.sup.++1).
[0633] Step 2: To a solution of tert-butyl
(4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-py-
razolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate
(124 mg, 0.240 mmol) in MeOH (1 mL) was added hydrochloric acid
(1.200 mL, 7.20 mmol). The reaction was stirred for 16 hr at
25.degree. C. The reaction was dried to give
4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 3) as an HCl salt. ESIMS m/z 417.2 (M.sup.++1);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.53 (s, 1H), 8.73 (d,
J=5.9 Hz, 1H), 8.16-8.05 (m, 4H), 7.39 (s, 1H), 4.70 (s, 2H), 4.03
(t, J=5.6 Hz, 2H), 3.72 (s, 2H), 3.13-3.03 (m, 2H), 2.78 (s, 3H),
2.12 (s, 3H), 1.75-1.63 (m, 6H), 1.60-1.49 (m, 6H).
Example 4
Synthesis of
4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahy-
dro-1H-pyrazolo[4,3-c]pyridin-1-yl)methy)bicyclo[2.2.2]octan-1-amine
(Compound No. 4) and tert-butyl
(4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrah-
ydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methy)bicyclo[2.2.2]octan-1-yl)carbama-
te (Compound No. 146)
##STR00160##
[0635] Step 1: To a reaction vial were added tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3) (67.0 mg, 0.179 mmol),
4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG14) (30 mg, 0.179
mmol), DIPEA (0.094 mL, 0.537 mmol) and BuOH (0.1 mL). The reaction
was stirred at 120.degree. C. for 3 hr and then diluted with
methanol and purified by HPLC to give tert-butyl
(4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrah-
ydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbam-
ate (Compound No. 146). RT (method 2): 2.11 min. MS (ES+): 507.3
(M+1)+.
[0636] Step 2: To a solution of tert-butyl
(4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrah-
ydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbam-
ate (35 mg, 0.075 mmol) in MeOH (1 mL) was added hydrochloric acid
(0.445 mL, 2.67 mmol). The reaction was stirred for 16 hr at
25.degree. C. and then dried to give
4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahy-
dro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 4) as an HCl salt. ESIMS m/z 406.2 (M.sup.++1); 1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 7.36 (d, J=3.5 Hz, 1H),
7.08 (d, J=3.6 Hz, 1H), 5.18 (s, 2H), 4.47 (t, J=5.3 Hz, 2H), 4.17
(s, 2H), 3.16 (t, J=5.3 Hz, 2H), 2.71 (s, 3H), 2.52 (s, 3H),
1.90-1.66 (m, 12H).
Example 5
Synthesis of
4-((5-(1,6-dimethyl-H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrah-
ydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methy)bicyclo[2.2.2]octan-1-amine
(Compound No. 5)
##STR00161##
[0638] Step 1: To the reaction vial were added tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3) (62.2 mg, 0.166 mmol),
4-chloro-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (HG15) (30 mg,
0.166 mmol), RuPhos (9.30 mg, 0.020 mmol),
tris(dibenzylideneacetone)dipalladium(0) (7.60 mg, 8.30 .mu.mol),
Cs.sub.2CO.sub.3 (108 mg, 0.332 mmol) and THE (2 mL). The reaction
was stirred @75.degree. C. for 18 hrs. Reaction completed. The
reaction was diluted with ethyl acetate and filtered through celite
to remove salt. The filtrate was dried and the crude product was
directly used in the next step.
[0639] Step 2: To a solution of tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carb-
amate (30 mg, 0.046 mmol) in MeOH (1 mL) was added hydrochloric
acid (0.231 mL, 1.388 mmol). The reaction was stirred for 16 hr at
25.degree. C., then was dried and purified by HPLC to give
-((5-(1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrah-
ydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 5): ESIMS m/z 419.2 (M.sup.++1); .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 7.14 (d, J=3.6 Hz, 1H), 6.80 (d,
J=3.6 Hz, 1H), 6.66 (s, 1H), 4.67 (s, 2H), 4.03 (t, J=5.6 Hz, 2H),
3.79 (s, 3H), 3.69 (s, 2H), 2.86 (t, J=5.6 Hz, 2H), 2.55 (s, 3H),
2.13 (s, 3H), 1.66 (dd, J=10.9, 4.6 Hz, 6H), 1.56 (dd, J=10.8, 4.7
Hz, 6H).
Example 6
Synthesis of
N-(4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-te-
trahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)ox-
etan-3-amine (Compound No. 6)
##STR00162##
[0641] To a solution of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1 from Example 1, 1.68 g, 4.0 mmol) in DCE (40 mL)
was added acetic acid (0.229 mL, 1.0 eq.) and oxetan-3-one (2.94 g,
10 eq.). The mixture was stirred at rt for 30 min before sodium
triacetoxyhydroborate (2.62 g, 3.0 eq.) was added. The mixture was
then stirred at rt overnight. More oxetan-3-one (1.47 g, 5 eq.),
sodium triacetoxyhydroborate (1.3 g, 1.5 eq.) and 20 mL of DCE were
added and the mixture was stirred at rt for additional 5 hrs then
treated with 40 mL of 1N NaOH. The layers were separated and the
aqueous layer was extracted with DCM/MeOH (5:1 v/v, 100
mL.times.3). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the crude
product. The crude product was added to a 40 g gold silica gel
column and was eluted with 0-50% (over 25 min) IPA (containing 0.02
M ammonia) in DCM. Collected fractions and concentrated to give
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)o-
xetan-3-amine (Compound No. 6): 1H NMR (400 MHz, Methanol-d4)
.delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.60 (t, J=6.8 Hz, 2H), 4.43
(s, 2H), 4.34 (t, J=6.6 Hz, 2H), 4.04 (p, J=7.2 Hz, 1H), 3.90 (s,
3H), 3.87 (t, J=5.6 Hz, 2H), 3.61 (s, 2H), 2.79 (t, J=5.6 Hz, 2H),
2.44 (s, 3H), 2.12 (s, 3H), 1.47-1.33 (m, 12H). MS (ES+): 476.3
(M+1)+.
Example 7
Synthesis of
N-(4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-te-
trahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-2-
-(dimethylamino)acetamide (Compound No. 7)
##STR00163##
[0643] To a mixture of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)
-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicycl-
o[2.2.2]octan-1-amine (Compound No. 1 from Example 1, 2.52 g, 6.0
mmol) and 2-(dimethylamino)acetic acid (0.742 g, 1.2 eq.) in DCM
(60 mL) was added DIPEA (2.1 mL, 2.0 eq.) then HATU (2.74 g, 1.2
eq.). The resulting mixture was stirred at rt for 1 hr then washed
with 30 mL of water. The aqueous layer was extracted with DCM (100
mL.times.3) and the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the crude
product. The crude product was added to a 80 g gold silica gel
column and was eluted with 0-50% (over 30 min) IPA (containing 0.02
M of ammonia) in DCM. Collected fractions and concentrated to give
N (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)
-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicycl-
o[2.2.2]octan-1-yl)-2-(dimethylamino)acetamide (Compound No. 7): 1H
NMR (600 MHz, Methanol-d4) .delta. 8.17 (s, 1H), 6.47 (s, 1H), 4.56
(s, 2H), 4.02 (s, 3H), 3.99 (dd, J=6.1, 5.1 Hz. 2H). 3.74 (s. 2H),
2.94 - 2.91 (m, 2H), 2.90 (s. 2H). 2.56 (s. 3H). 2.36 (s, 1H). 2.30
(s. 6H). 2.25 (s. 3H). 1.94 - 1.87 (m. 6H). 1.63 - 1.57 (m. 6H). MS
(ES+): 505.4 (M+1)+.
Example 8
Synthesis of
(S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)
-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicycl-
o[2.2.2]octan-1-yl)morpholine-3-carboxamide (Compound No. 8)
##STR00164##
[0645] A mixture of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)
-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicycl-
o[2.2.2]octan-1-amine (Compound No. 1 from Example 1) (42 mg, 0.1
mmol), (S)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid
(25.4 mg, 0.11 mmol) and DIPEA (0.035 mL, 0.2 mmol) in 1.0 mL of
DMF was added HATU (45.6 mg, 0.12 mmol) then stirred at rt for 30
min. LC-MS confirmed completion of the reaction. The intermediate
was purified by mass-triggered HPLC (10-90% ACN in H.sub.2O over
3.5 min). The collected fractions were concentrated and the residue
was dissolved in MeOH/1,4-dioxane (1.5 mL, 1:2 v/v). 4M HCl in
1,4-dioxane (1.0 mL) was added and the mixture was stirred at rt
for 1 hr then concentrated and lyophilized to give
(S)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide (Compound No. 8), as an HCl salt. 1H
NMR (400 MHz, Methanol-d4) .delta. 8.52 (s, 1H), 7.92 (s, 1H), 6.88
(s, 1H), 5.06-4.91 (m, 2H), 4.25 (s, 2H), 4.19-4.09 (m, 4H),
4.03-3.89 (m, 4H), 3.78-3.56 (m, 4H), 3.22 (ddd, J=12.9, 11.2, 3.7
Hz, 1H), 3.17-3.05 (m, 2H), 2.70 (s, 3H), 2.41 (s, 3H), 1.93 (dd,
J=8.9, 5.0 Hz, 6H), 1.72-1.54 (m, 6H). MS (ES+): 533.3 (M+1)+.
Example 9
Synthesis of
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide (Compound No. 9)
##STR00165##
[0647] A mixture of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1 from Example 1) (42 mg, 0.1 mmol),
(R)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (25.4 mg,
0.11 mmol) and DIPEA (0.035 mL, 0.2 mmol) in 1.0 mL of DMF was
added HATU (45.6 mg, 0.12 mmol) then stirred at rt for 30 min.
LC-MS confirmed completion of the reaction. The intermediate was
purified by mass-triggered HPLC (10-90% ACN in H.sub.2O over 3.5
min). Collectioned fractions were concentrated and the residue was
dissolved in MeOH/1,4-dioxane (1.5 mL, 1:2 v/v). 4M HCl in
1,4-dioxane (1.0 mL) was added and the mixture was stirred at rt
for 1 hr then concentrated and lyophilized to give
(R)--N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)morpholine-3-carboxamide (Compound No. 9), as HCl salt. 1H NMR
(400 MHz, Methanol-d4) .delta. 8.51 (s, 1H), 7.92 (s, 1H), 6.88 (s,
1H), 5.03-4.92 (m, 1H), 4.32-4.18 (m, 2H), 4.20-4.09 (m, 4H),
4.03-3.89 (m, 4H), 3.78-3.54 (m, 4H), 3.22 (ddd, J=13.0, 11.2, 3.8
Hz, 1H), 3.15-3.05 (m, 2H), 2.69 (s, 3H), 2.39 (s, 3H), 1.98-1.85
(m, 6H), 1.62 (dd, J=10.3, 5.9 Hz, 6H). MS (ES+): 533.3 (M+1)+.
Example 10
Synthesis of
6-(4-((3-methyl-5-(1,3,5-trimethyl-H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6-
,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1--
yl)-2-oxa-6-azaspiro[3.3]heptane (Compound No. 10) and
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-am-
ine (Compound No. 26)
##STR00166##
[0649] Step 1. A mixture of
7-chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine (HG4) (263
mg, 1.335 mmol), tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3) (500 mg, 1.335 mmol) and
DIPEA (0.233 mL, 1.335 mmol) in 2-propanol (30 mL) was heated to
100.degree. C. for 1 hr. After working-up and column chromatography
(eluent: 2:1 EtOAc:hexane), tert-butyl
(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,-
7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-y-
l)carbamate was obtained. LC-MS: MS (ES+): 535.4; RT: 1.171 min
(method 1)
[0650] Step 2. tert-butyl
(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,-
7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-y-
l)carbamate was subjected to the same conditions described in step
2 of Example 4 to yield
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-am-
ine (Compound No. 26). .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 4.96 (s, 2H), 4.31 (t, J=5.6 Hz, 2H), 4.24 (s, 3H), 3.77
(s, 2H), 3.04-2.98 (m, 2H), 2.71 (s, 3H), 2.53 (s. 3H), 2.21 (s.
3H), 1.80-1.62 (m. 12H). MS (ES+): 435.4 (M+1)+.
[0651] Step 3. A mixture of (60 mg, 0.138 mmol) of
4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-am-
ine (Compound No. 26), 101 mg (0.414 mmol) of
1,1-bis(bromomethyl)cyclobutane and K.sub.2CO.sub.3 (95 mg, 0.690
mmol) in 2-propanol (10 mL) was heated to 120.degree. C. for 72
hrs. After cooling to rt, the 2-propanol was evaporated, water was
added and the mixture was extracted with EtOAc. The organic layers
were combined, dried (Na.sub.2SO.sub.3) and concentrated. The
residue was purified by preparative LC-MS to give
6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)-2-oxa-6-azaspiro[3.3]heptane (Compound No. 10). .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 4.70 (s, 4H), 4.52 (s, 2H),
4.11 (s, 3H), 3.86 (t, J=5.7 Hz, 2H), 3.71 (s, 2H), 3.39 (s, 4H),
2.99 (t, J=5.5 Hz, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.18 (s, 3H),
1.58-1.40 (m, 12H). MS (ES+): 517.3 (M+1)+.
Example 11
Synthesis of
4-((5-(6-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-me-
thyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.-
2]octan-1-amine (Compound No. 83)
##STR00167##
[0653] Step 1: 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine
(HG16) (40 mg, 0.197 mmol), tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3) (70 mg, 0.187 mmol),
Pd.sub.2dba.sub.3 (10 mg, 10.92 .mu.mol), RuPhos (10 mg, 0.021
mmol) and Cs.sub.2CO.sub.3 (65 mg, 0.199 mmol) were mixed in
dioxane (5 mL) and stirred at 120.degree. C. for 6 hrs. After
working-up and prep LC-MS, tert-butyl
(4-((5-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)carbamate was obtained.
[0654] Step 2: tert-butyl
(4-((5-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,-
6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-
-yl)carbamate (20 mg, 0.037 mmol), (4-fluorophenyl)boronic acid (10
mg, 0.071 mmol), PdCl.sub.2(dppf). CH.sub.2Cl.sub.2 adduct (6 mg,
7.35 .mu.mol) and K.sub.2CO.sub.3 (20 mg, 0.145 mmol) were mixed in
dioxane (3 mL and stirred at 110.degree. C. for 6 hsr. After
working-up and prep LC-MS, tert-butyl
(4-((5-(6-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-m-
ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2-
.2]octan-1-yl)carbamate was obtained.
[0655] Step 3: tert-butyl
(4-((5-(6-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-m-
ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2-
.2]octan-1-yl)carbamate (10 mg, 0.017 mmol) and 4N HCl (0.152 mL,
4.99 mmol) were mixed in MeOH (1 mL) and stirred at 50.degree. C.
for 5 hrs. After working-up and prep LC-MS,
4-((5-(6-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-me-
thyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.-
2]octan-1-amine (Compound No. 83) was obtained. .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.55 (dd, J=8.7, 5.7 Hz, 2H), 8.27
(s, 1H), 7.21 (t, J=8.8 Hz, 2H), 4.97 (s, 2H), 4.38 (brs, 2H), 4.06
(s, 3H), 3.80 (s, 2H), 2.92 (t, J=5.4 Hz, 2H), 2.29 (s, 3H),
1.80-1.60 (m, 12H). MS (ES+): 501.3 (M+1)+.
Example 12
Synthesis of
4-(4-(1-((4-aminobicyclo[2.2.2]octan-1-yl)methy)-3-methyl-6,7-dihydro-1H--
pyrazolo[4,3-c]pyridin-5(4H)-yl)pyridin-2-yl)benzonitrile (Compound
No. 84)
##STR00168##
[0657] Step 1: 2-chloro-4-fluoropyridine (130 mg, 0.988 mmol),
tert-butyl
(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bi-
cyclo[2.2.2]octan-1-yl)carbamate (TG3) (370 mg, 0.988 mmol) and
DIPEA (130 mg, 1.006 mmol) were mixed in DMA (5 mL) and stirred at
150.degree. C. for 4 hrs. After working-up and column
chromatography (2:1 EtOAc:hexane), tert-butyl
(4-((5-(2-chloropyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate was
obtained.
[0658] Step 2: tert-butyl
(4-((5-(2-chloropyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (25 mg,
0.051 mmol), (4-cyanophenyl)boronic acid (15 mg, 0.102 mmol),
PdCl.sub.2(dppf). CH.sub.2Cl.sub.2 adduct (5 mg, 6.12 .mu.mol) and
K.sub.2CO.sub.3 (25 mg, 0.181 mmol) were mixed in dioxane (3 mL)
and stirred at 120.degree. C. for 17 hrs. After working-up and prep
LC-MS, tert-butyl
(4-((5-(2-(4-cyanophenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate
was obtained.
[0659] Step 3: tert-Butyl
(4-((5-(2-(4-cyanophenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate
(20 mg, 0.036 mmol) and 4N HCl (0.220 mL, 7.24 mmol) were mixed in
MeOH (1 mL) and stirred at 50.degree. C. for 3 hrs. After
working-up and prep LC-MS,
4-(4-(1-((4-aminobicyclo[2.2.2]octan-1-yl)methyl)-3-methyl-6,7-dihydro-1H-
-pyrazolo[4,3-c]pyridin-5(4H)-yl)pyridin-2-yl)benzonitrile
(Compound No. 84) was obtained. 1H NMR (400 MHz, Methanol-d4)
.delta. 8.25 (d, J=7.4 Hz, 1H), 8.08-7.97 (m, 4H), 7.56 (brs, 1H),
7.36 (m, 1H), 4.71 (s, 2H), 4.09 (brs, 2H), 3.79 (s, 2H), 2.93 (t,
J=5.4 Hz, 2H), 2.25 (s, 3H), 1.82-1.60 (m, 12H). MS (ES+): 453.3
(M+1)+
Example 13
Synthesis of
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(pyrrolidi-
n-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
-c]pyridine (Compound No. 58)
##STR00169##
[0661]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,-
7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-a-
mine (Compound No. 1 from Example 1) (23 mg, 0.055 mmol) was
treated with potassium carbonate (22.73 mg, 0.164 mmol),
1,4-dibromobutane (59.2 mg, 0.274 mmol) and ethanol (548 .mu.l).
The mixture was heated to 120.degree. C. for 30 min by microwave
irradiation. The mixture was diluted with ethyl acetate and 1N
NaOH. After extraction, the aqueous layer was re-extracted with
ethyl acetate twice. The organic layers were combined, dried with
MgSO.sub.4 and concentrated in vacuo. The residue was loaded on a 4
g silica gel column using 0-50% IPA/DCM with 3% ammonia as modifier
to obtain
5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(pyrrolidi-
n-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
-c]pyridine (Compound 58). 1H NMR (400 MHz, Methanol-d4) .delta.
8.06 (s, 1H), 6.36 (s, 1H), 4.45 (s, 2H), 3.99 (s, 3H), 3.89 (m,
2H), 3.64 (s, 2H), 2.81 (m, 2H), 2.64 (s, 4H), 2.45 (s, 3H), 2.13
(s, 3H), 1.68 (s, 4H), 1.63-1.35 (m, 12H). ESIMS (M+H.sup.+)
475.2.
Example 14
Synthesis of
4-(4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-te-
trahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)mo-
rpholine (Compound No. 59)
##STR00170##
[0663]
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5-
,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan--
1-yl)morpholine was obtained using the method described in Example
13, except 1-bromo-2-(2-bromoethoxy)ethane (63.6 mg, 0.274 mmol)
was used in place of 1,4-dibromobutane. 1H NMR (400 MHz,
Methanol-d4) .delta. 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 3.99
(d, J=9.5 Hz, 5H), 3.73 (s, 2H), 3.68-3.51 (m, 4H), 2.91 (t, J=5.4
Hz, 2H), 2.23 (s, 3H), 1.57 (m, 12H). ESIMS (M+H.sup.+) 491.0.
Example 15
Synthesis of
1-((4-(1H-imidazol-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-(1,6-dimethyl--
1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,-
3-c]pyridine (Compound No. 119)
##STR00171##
[0665]
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,-
7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-a-
mine (Compound No. 1 from Example 1) (55 mg, 0.131 mmol) was taken
in water (807 .mu.l) and 1 drop phosphorous acid was added (pH: 1).
Paraformaldehyde (4.72 mg, 0.157 mmol) and glyoxal (18.04 .mu.l.
0.157 mmol) 40% in water were added and the resulting mixture was
heated to 80.degree. C. A solution of ammonium chloride (8.41 mg,
0.157 mmol) dissolved in water (202 .mu.l) was added dropwise over
10 min and the resulting mixture was heated to 110.degree. C. for
18 hr, LC-MS showed still .about.50% unconverted starting material.
An additional 47 mg of paraformaldehyde, glyoxal (18 mL) and
NH.sub.4Cl (84 mg) were added to the mixture (to get it to go to
completion). The mixture was heated at 110.degree. C. for 18 hrs.
The reaction mixture was adjusted to pH 8-9 using aqueous
Na.sub.2CO.sub.3, extracted twice with DCM. The organic layers were
concentrated and loaded on a 4 g silica gel column using 0-50% IPA
in DCM with 3% NH.sub.3 as modifier to afford
1-((4-(1H-imidazol-1-yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-(1,6-dimethyl--
1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,-
3-c]pyridine (Compound 119). 1H NMR (400 MHz, Methanol-d4) .delta.
8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 4.01 (s, 3H), 3.91 (m,
2H), 3.73 (s, 2H), 3.68-3.51 (m, 4H), 2.91 (m, 2H), 2.55 (m, 4H),
2.52 (s, 3H), 2.23 (s, 3H), 1.57 (m, 12H). ESIMS (M+H.sup.+) found
471.6.
Example 16
Synthesis of
4-((3-methyl-5-(6-methyl-1-(methyl-d3)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,-
5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-
-1-amine (Compound No. 140)
##STR00172##
[0667] To a mixture of tert-butyl
(4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahy-
dro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbama-
te and K.sub.2CO.sub.3 in a 20 mL round-bottomed flask containing 3
mL of DMF was added dropwise CD3I (0.1 mL of a solution of 27.7
.mu.L CD.sub.3I in 1 mL of DMF) at 0.degree. C. The resulting
mixture was slowly warmed up to rt and stirred overnight. The
mixture was then concentrated then purified by ISCO (4 g silica gel
column, 0-10% MeOH in DCM as eluent) to afford tert-butyl
(4-((3-methyl-5-(6-methyl-1-(methyl-d3)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)carbamate. RT=1.13 min (method 1), MS (ES+): 524.3 (M+1)+.
To a solution of 11.5 mg (0.022 mmol) of tert-butyl
(4-((3-methyl-5-(6-methyl-1-(methyl-d3)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)carbamate in 1 mL of dioxane and 0.1 mL of MeOH was added 1
mL of 4M HCl in dioxane. The resulting mixture was stirred at rt
for 1 hr then concentrated and lyophilized to give the desired
product (Compound No. 140) as an HCl salt. 1H NMR (400 MHz,
Methanol-d4) .delta. 8.51 (s, 1H), 6.88 (s, 1H), 5.04-4.94 (m, 2H),
4.25 (s, 2H), 3.98 (s, 2H), 3.78-3.56 (m, 2H), 3.11 (d, J=5.1 Hz,
2H), 2.70 (s, 3H), 2.39 (s, 3H), 1.85-1.66 (m, 12H). MS (ES+):
423.3 (M+1)+.
Example 17
Synthesis of
4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra-
hydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethylbicyclo[2.2.2]oct-
an-1-aminee (Compound No. 43)
##STR00173##
[0669] To a solution of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1 from Example 1) in THF/MeOH (5 mL/1.5 mL) in a 100
mL round-bottomed flask was added DIPEA (0.13 mL, 97 mg, 0.75
mmol). The mixture was stirred at rt for 10 min before formaldehyde
(0.037 mL, 37 wt % in water) was added. The resulting mixture was
stirred at rt for 30 min before NaBH.sub.3CN (157 mg, 2.5 mmol) was
added. Then the mixture was then stirred at rt overnight, quenched
by adding 2.0 mL of water then extracted with DCM. The combined
organic layers were then dried over Na.sub.2SO.sub.4 then
concentrated. The crude product was added to a 4 g silica gel
column and was eluted with 0-8% MeOH (containing very small amount
of ammonia) in DCM. Collected fractions and concentrated then
lyophilized to give the desired product,
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethylbicyclo[2.2.2]oc-
tan-1-amine. 1H NMR (600 MHz, Methanol-d4) .delta. 8.07 (s, 1H),
6.39 (s, 1H), 4.47 (s, 3H), 3.86 (s, 5H), 3.63 (d, J=2.5 Hz, 2H),
2.78 (t, J=5.6 Hz, 2H), 2.58 (s, 6H), 2.41 (s, 3H), 2.07 (s, 3H),
1.71-1.65 (m, 6H), 1.55-1.49 (m, 6H). MS (ES+): 448.4 (M+1)+.
Example 18
Synthesis of
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)m-
ethanesulfonamide (Compound No. 48)
##STR00174##
[0671] To a mixture of 57 mg (0.1 mmol) of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1) and 39 mg (0.052 mL, 0.3 mmol) of DIPEA in 2 mL of
DCM was added 14.9 mg (10.1 .mu.L, 0.13 mmol) of methanesulfonyl
chloride at 0.degree. C. The resulting mixture was slowly warmed up
to rt and stirred for 2 hrs. The crude product was added (by solid
loading) to a 4 g silica gel column and was eluted with 0-7% MeOH
(containing very small amount of ammonia) in DCM, and further
purified by mass-triggered HPLC. Collected fractions, 1.0 mL of 1N
aqueous HCl was added then concentrated and lyophilized to give
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)m-
ethanesulfonamide (Compound No. 48), as HCl salt. 1H NMR (400 MHz,
Methanol-d4) .delta. 8.53 (s, 1H), 6.89 (s, 1H), 5.06-4.94 (m, 2H),
4.25 (s, 2H), 4.12 (s, 3H), 3.98 (s, 2H), 3.18-3.06 (m, 2H), 2.94
(s, 3H), 2.70 (s, 3H), 2.43 (s, 3H), 1.96-1.85 (m, 6H), 1.67-1.57
(m, 6H). MS (ES+): 498.2 (M+1)+.
Example 19
Synthesis of
4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra-
hydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]octan-1-
-amine (Compound No. 50) and tert-buty
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)(me-
thy)carbamate (Compound 49)
##STR00175##
[0673] Step 1. A mixture of
4-bromo-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine (HG1) (67 mg, 0.295
mmol), tert-butyl
methyl(4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)met-
hyl)bicyclo[2.2.2]octan-1-yl)carbamate (TG10) (115 mg, 0.295 mmol),
Pd.sub.2dba.sub.3 (6.8 mg, 0.074 mmol), RuPhos (17 mg, 0.035 mmol)
and Cs.sub.2CO.sub.3 (192 mg, 0.590 mmol) in THE was purged with
argon before being heated to 75.degree. C. for 15 hrs. The reaction
mixture was cooled down to rt then diluted in ethyl acetate and
water. The layers were separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The crude product was added to a 12 g silica gel column and was
eluted with 0-5% methanol in DCM. Collected fractions and
concentrated to give tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)(me-
thyl)carbamate (Compound No. 49). 1H NMR (400 MHz, Methanol-d4)
.delta. 8.16 (s, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 5H),
3.72 (s, 2H), 2.90 (t, J=5.6 Hz, 2H), 2.80 (s, 3H), 2.55 (s, 3H),
2.23 (s, 3H), 2.04-1.91 (m, 6H), 1.60-1.52 (m. 6H), 1.43 (s, 9H).
MS (ES+): 534.4 (M+1)+.
[0674] Step 2. To a solution of 90 mg (0.169 mmol) of tert-butyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)(me-
thyl)carbamate (Compound No. 49) in dioxane/MeOH (1 mL/1 mL) was
added HCl (2 mL of a 4M solution in dioxane). The resulting mixture
was stirred at rt for 2 hrs. LC-MS showed completion of the
reaction. The reaction mixture was concentrated and the residue was
dissolved in 2.0 mL of MeOH then Ambersep 900 OH (0.8 meq/mL, 5.0
eq., prewashed with 5.0 mL of MeOH) was added and the mixture was
stirred at rt for 1 hour. Filtered and washed with 10 mL of MeOH
then concentrated. The crude product was added to a 4 g silica gel
column and was eluted with 2-9% MeOH (containing a small amount of
ammonia) in DCM. Collected fractions and concentrated then
lyophilized to give
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]octan--
1-amine (Compound No. 50). 1H NMR (400 MHz, Methanol-d4) .delta.
8.05 (s, 1H), 6.36 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.88 (t,
J=5.8 Hz, 2H), 3.64 (s, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.44 (s, 3H),
2.17 (s, 3H), 2.13 (s, 3H), 1.49 (s, 12H). MS (ES+): 434.3
(M+1)+.
Example 20
Synthesis of 1-methylcyclopropyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)car-
bamate (Compound No. 51)
##STR00176##
[0676] To a suspension of 57 mg (0.1 mmol) of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1) in 1 mL of DMA was added DIPEA (52 mg, 0.4 mmol)
then 1-methylcyclopropyl (4-nitrophenyl) carbonate (24 mg, 0.1
mmol). The resulting mixture was heated under microwave irradiation
at 150.degree. C. for 2 hrs. The reaction mixture was diluted with
water and extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated.
The crude product was added to a 4 g silica gel column and was
eluted with 0-8% MeOH in DCM. Collected fractions and concentrated
then lyophilized to give 1-methylcyclopropyl
(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)car-
bamate (Compound No. 51). 1H NMR (400 MHz, Methanol-d4) .delta.
8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t,
J=5.6 Hz, 2H), 3.61 (s, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.44 (s, 3H),
2.13 (s, 3H), 1.74-1.63 (m, 6H), 1.50-1.40 (m, 6H), 1.35 (s, 3H),
0.71-0.61 (m, 2H), 0.48-0.41 (m 2H). MS (ES+): 518.3 (M+1)+.
Example 21
Synthesis of
N-(2,2-difluoroethyl)-4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)--
3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[-
2.2.2]octan-1-amine (Compound No. 61)
##STR00177##
[0678] To a mixture of 29.4 mg (0.07 mmol) of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1) and 18.1 mg (0.024 mL, 0.14 mmol) of DIPEA in 1 mL
of THE was added 2,2-difluoroethyl trifluoromethanesulfonate (16.5
mg (10.3 .mu.L, 0.077 mmol). The resulting mixture was stirred at
85.degree. C. for 2 hrs. LC-MS showed desired product and
completion of the reaction. The crude product was directly added to
a 4 g silica gel column and was eluted with 2-9% MeOH (containing a
small amount of ammonia) in DCM. Collected fractions and
concentrated then lyophilized to give
N-(2,2-difluoroethyl)-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-
-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo-
[2.2.2]octan-1-amine (Compound No. 61). 1H NMR (400 MHz,
Methanol-d4) .delta. 8.05 (s, 1H), 6.36 (s, 1H), 5.79 (tt, J=55.9,
4.1 Hz, 1H), 4.44 (s, 2H), 3.89 (m, 5H), 3.64 (s, 2H), 2.94-2.75
(m, 4H), 2.44 (s, 3H), 2.13 (s, 3H), 1.49 (s, 12H). MS (ES+): 484.2
(M+1)+.
Example 22
Synthesis of
4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra-
hydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)bicyclo[2.2-
.2]octan-1-amine (Compound No. 69) and
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-methoxyethyl)bicyc-
lo[2.2.2]octan-1-amine (Compound No. 70)
##STR00178##
[0680] A mixture of 21 mg (0.05 mmol) of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1), 43 mg (0.031 mL, 0.250 mmol) of
1-bromo-2-ethoxyethane and 21 mg (0.150 mmol) of potassium
carbonate in EtOH (1 mL) was heated under microwave irradiation at
120.degree. C. for 30 min. LC-MS showed desired product 1 but the
reaction was not complete. The solvent was changed to IPA and
heated in an oil bath at 110.degree. C. overnight. LC-MS showed two
products. The crude product was added to a 12 g silica gel column
and was eluted with 0-30% IPA (containing 1% of ammonia) in DCM.
Collected fractions and concentrated then lyophilized to give
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-ethoxyethyl)bicyclo[2.2-
.2]octan-1-amine (Compound No. 69) and
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-ethoxyethyl)bicycl-
o[2.2.2]octan-1-amine (Compound No. 70). Compound No. 69: 1H NMR
(400 MHz, Methanol-d4) .delta. 8.16 (s, 1H), 8.05 (d, J=8.2 Hz,
0H), 8.04 (s, 0H), 7.54 (d, J=8.1 Hz, 0H), 6.46 (s, 1H), 4.54 (s,
2H), 4.00 (s, 3H), 3.98 (t, J=5.7 Hz, 2H), 3.73 (s, 2H), 3.35 (s,
2H), 2.98 (s, 3H), 2.94 (s, 3H), 2.90 (t, J=5.6 Hz, 2H), 2.55 (s,
3H), 2.23 (s, 3H), 1.56 (s, 12H). MS (ES+): 505.4 (M+1)+. Compound
No. 70: 1H NMR (400 MHz, Methanol-d4) .delta. 8.15 (s, 1H), 6.45
(s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.97 (t, J=5.5 Hz, 2H), 3.69
(s, 2H), 3.31 (d, J=1.1 Hz, 6H), 2.90 (t, J=5.6 Hz, 2H), 2.75-2.65
(m, 4H), 2.55 (s, 3H), 2.23 (s, 3H), 1.64-1.47 (m, 12H). MS (ES+):
536.4 (M+1)+.
Example 23
Synthesis of
4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra-
hydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-N-methylbi-
cyclo[2.2.2]octan-1-amine. (Compound No. 73)
##STR00179##
[0682] A mixture of 12 mg (0.028 mmol) of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]octan--
1-amine (Compound No. 50), 19 mg (0.013 mL, 0.138 mmol) of
1-bromo-2-methoxyethane and 11.5 mg (0.083 mmol) of K.sub.2CO.sub.3
in IPA was heated under microwave irradiation at 150.degree. C. for
1 hr. The crude product was directly added to a 4 g silica gel
column and was eluted with 0-30% IPA (containing 1% of ammonia) in
DCM. Collected fractions and concentrated then lyophilized to give
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-N-methylb-
icyclo[2.2.2]octan-1-amine (Compound No. 73). 1H NMR (400 MHz,
Methanol-d4) .delta. 8.16 (s, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00
(s, 3H), 3.98 (t, J=5.7 Hz, 2H), 3.72 (s, 2H), 3.43 (t, J=5.8 Hz,
2H), 2.90 (t, J=5.6 Hz, 2H), 2.63 (s, 2H), 2.55 (s, 3H), 2.23 (s,
6H), 1.67-1.49 (m, 12H). MS (ES+): 492.4 (M+1)+.
Example 24
Synthesis of
2-((4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)a-
mino)-N,N-dimethylacetamide (Compound No. 76)
##STR00180##
[0684] A mixture of 42.0 mg (0.1 mmol) of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1), 18.3 mg (0.11 mmol) of
2-bromo-N,N-dimethylacetamide and 65.2 mg (0.2 mmol) of cesium
carbonate in 1 mL DMF was stirred at rt overnight. The crude
product was added to a 4 g silica gel column and was eluted with
0-30% IPA (containing 1% of ammonia) in DCM. Collected fractions
and concentrated then lyophilized to afford
2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7--
tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)-
amino)-N,N-dimethylacetamide (Compound No. 76). 1H NMR (400 MHz,
Methanol-d4) .delta. 8.17 (d, J=1.8 Hz, 1H), 6.47 (s, 1H), 4.56 (s,
2H), 4.02 (s, 3H), 4.00 (t, J=5.7 Hz, 2H), 3.76 (m, 2H), 3.56 (m,
2H), 3.03-2.95 (m, 6H), 2.92 (t, J=5.6 Hz, 2H), 2.56 (s, 3H), 2.25
(s, 3H), 1.73-1.56 (m, 12H). MS (ES+): 505.4 (M+1)+.
Example 25
Synthesis of
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
N-methyloxetan-3-amine (Compound No. 77)
##STR00181##
[0686] To a solution of 2.1 mg (4.4 .mu.mol of
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)o-
xetan-3-amine (Compound No. 6) in THE (1 mL) was added acetic acid
(1.33 mL (1.26 .mu.L, 0.022 mmol) of and 10.9 mg (0.134 mmol) of
formaldehyde. The mixture was stirred at rt for 1 hour before
sodium cyanotrihydroborate was added. The resulting mixture was
then stirred at rt overnight. The reaction was quenched by adding
0.1 mL of water then concentrated. The crude product was added to a
4 g silica gel column and was eluted with 0-50% IPA (containing 1%
of ammonia) in DCM. Collected fractions and concentrated then
lyophilized to afford
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
N-methyloxetan-3-amine (Compound No. 77). 1H NMR (400 MHz,
Methanol-d4) .delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.58 (t, J=6.9 Hz,
2H), 4.47 (t, J=7.0 Hz, 2H), 4.44 (s, 2H), 4.25 (q, J=7.3 Hz, 1H),
3.90 (s, 3H), 3.87 (t, J=5.5 Hz, 2H), 3.61 (s, 2H), 2.79 (t, J=5.6
Hz, 2H), 2.44 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.45 (s, 12H).
MS (ES+): 490.4 (M+1)+.
Example 26
Synthesis of
4-((5-(1,6-dimethyl-H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra-
hydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxy-2-methylpropyl)b-
icyclo[2.2.2]octan-1-amine (Compound No. 101)
##STR00182##
[0688] Step 1. To a solution of 14.2 mg (0.12 mmol) of
2-methoxy-2-methylpropanoic acid in DMF (2 mL) was added HATU (45.6
mg, 0.12 mmol) and DIPEA (0.035 mL, 25.8 mg, 0.2 mmol). The mixture
was stirred at rt for 5 min before of 42.0 mg (0.1 mmol)
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1) was added. The resulting mixture was then stirred
at rt for 1 hour. LC-MS showed completion of the reaction. The
mixture was partitioned between EtOAc and water. The layers were
separated and the aqueous layer was extracted with EtOAc. The
combined organic layer was dried over Na.sub.2SO.sub.4 then
concentrated. The crude product was added to a 4 g silica gel
column and was eluted with 0-50% IPA (containing 1% of ammonia) in
DCM. Collected fractions and concentrated then lyophilized to
afford
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-methoxy-2-methylpropanamide. 1H NMR (400 MHz, Methanol-d4)
.delta. 8.19 (s, 1H), 6.77 (s, 1H), 6.51 (s, 1H), 4.58 (s, 2H),
3.96 (t, J=5.4 Hz, 2H), 3.94 (s, 3H), 3.64 (s, 2H), 3.12 (s, 3H),
2.84 (t, J=5.6 Hz, 2H), 2.49 (s, 3H), 2.14 (s, 3H), 1.83-1.73 (m,
6H), 1.53-1.43 (m, 6H), 1.17 (s, 6H). MS (ES+): 520.3 (M+1)+.
[0689] Step 2. To a stirred solution of 17 mg (0.033 mmol) of
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-methoxy-2-methylpropanamide in THE (1 mL) was added 6.5 mg (0.164
mmol) of LiAlH.sub.4 at 0.degree. C. The resulting mixture was then
slowly warmed up to rt and stirred overnight. After cooling at
0.degree. C. the reaction was quenched with IPA then water and
concentrated. The crude product was added (by solid loading) to a 4
g silica gel column and was eluted with 0-30% IPA (containing 1% of
ammonia) in DCM. Collected fractions and concentrated then further
purified by mass-triggered HPLC to afford
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,-
5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxy-2-met-
hylpropyl)bicyclo[2.2.2]octan-1-amine (Compound No. 101), which was
neutralized using Ambersep 900 OH (Strong Base Anion Exchanger). 1H
NMR (600 MHz, Methanol-d4) .delta. 8.05 (d, J=1.1 Hz, 1H), 6.35 (s,
1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.90-3.85 (m, 2H), 3.64 (d, J=6.3
Hz, 2H), 3.07 (s, 2H), 2.83-2.77 (m, 2H), 2.44 (s, 3H), 2.13 (s,
3H), 1.57-1.46 (m, 12H), 1.07 (s, 6H). MS (ES+): 506.4 (M+1)+.
Example 27
Synthesis of
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
1-methylpiperazin-2-one (Compound No. 104)
##STR00183##
[0691] Step 1: To a solution of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1) (121 mg, 0.246 mmol) in CPME (12.3 mL) was added
tert-butyl methyl(2-oxoethyl)carbamate (63.8 mg, 0.369 mmol). The
mixture was stirred at 25.degree. C. for 30 min before sodium
triacetoxyborohydride (156 mg, 0.737 mmol) was added. Then the
mixture was stirred at 25.degree. C. for 3 hrs. The mixture was
concentrated and purified on a 4 g silica gel column using 0-40%
IPA in DCM with 2% NH.sub.3 as modifier to elute 88.6 mg (0.154
mmol) of tert-butyl
(2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl-
)amino)ethyl)(methyl)carbamate. RT (method 1): 1.26 min, MS (ES+):
577.4 (M+1)+.
[0692] Step 2: A mixture of 40 mg (0.069 mmol) of tert-butyl
(2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl-
)amino)ethyl)(methyl)carbamate, 35.5 mg (0.024 mL, 0.208 mmol) of
ethyl 2-bromoacetate and 10.5 mg (0.076 mmol) of potassium
carbonate in EtOH (1 mL) was heated under microwave irradiation at
150.degree. C. for 1 hour. LC-MS showed completion of the reaction.
The reaction was cooled down to rt, 1N aqueous NaOH was added and
the mixture was stirred at rt for 3 hrs. The reaction mixture was
then diluted with 2 mL of water and the organic solvent was removed
on the rotorvap, and washed with Et.sub.2O (3 mL). The aqueous
layer was then acidified carefully with 1N aqueous HCl to .about.pH
3. Extracted with EtOAc then DCM/MeOH but most product remained in
the aqueous phase based on LC-MS. Both aqueous and organic phase
were concentrated then purified by mass-triggered HPLC to afford
2-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(4-((5-(1,6-dimethyl-1H-p-
yrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]-
pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)amino)acetic acid. RT
(method 2): 1.72 min, MS (ES+): 634.8 (M+1)+.
[0693] Step 3. To a mixture of 27.0 mg (0.043 mmol) of
2-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(4-((5-(1,6-dimethyl-1H-p-
yrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]-
pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)amino)acetic acid in 1
mL of 1,4-dioxane was added 0.3 mL of MeOH to get a clear solution.
4 M HCl in dioxane was added dropwise and the resulting mixture was
stirred at rt for 1 hr. LC-MS showed completion of the reaction.
The mixture was concentrated and the residue was dissolved in 2.0
mL of DMF and DIPEA (38 .mu.L, 5 eq.) then added dropwise into a
solution of HATU (21 mg, 1.3 eq.) in 3.0 mL of DMF at 0.degree. C.
The resulting mixture was stirred at 0.degree. C. for 30 min. LC-MS
showed completion of the reaction. The crude product was purified
by mass-triggered HPLC (10-20% ACN in H2O over 3.5 min) then
neutralized using basic resin to afford
4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
1-methylpiperazin-2-one (Compound No. 104). 1H NMR (400 MHz,
Methanol-d4) .delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90
(s, 3H), 3.87 (t, J=5.5 Hz, 2H), 3.62 (s, 2H), 3.17 (dd, J=6.3, 4.5
Hz, 2H), 3.08 (s, 2H), 2.80 (m, 5H), 2.66 (dd, J=6.3, 4.5 Hz, 2H),
2.44 (s, 3H), 2.13 (s, 3H), 1.48 (tq, J=9.4, 6.4, 4.7 Hz, 12H). MS
(ES+): 517.3 (M+1)+.
Example 28
Synthesis of
1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
4-methylpiperazin-2-one (Compound No. 108)
##STR00184##
[0695] Step 1: To a mixture of 80 mg (0.139 mmol) of tert-butyl
(2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-
-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl-
)amino)ethyl)(methyl)carbamate (Example 27, Step 1) and 36 mg
(0.048 .mu.L, 0.277 mmol) of DIPEA in 1.0 mL of DCM was added
dropwise into a solution of 2-bromoacetyl bromide (0.062 mL, 0.694
mmol) in DCM (1.0 mL) at 0.degree. C. The resulting mixture was
slowly warmed up to rt and stirred for 1 hr. Then quenched the
reaction by adding 0.1 mL of water and concentrated. The crude
product was added to a 4 g silica gel column and was eluted with
0-30% IPA (containing 0.02 M ammnia) in DCM. Collected fractions
and concentrated to afford tert-butyl
(2-(2-bromo-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-meth-
yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]-
octan-1-yl)acetamido)ethyl)(methyl)carbamate. RT (method 1): 1.45
min. MS (ES+): 701.2, 700.3 (M+1)+.
[0696] Step 2: To a mixture of 40.0 mg (0.057 mmol) of tert-butyl
(2-(2-bromo-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-meth-
yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[222]oc-
tan-1-yl)acetamido)ethyl)(methyl)carbamate in 1 mL of 1,4-dioxane
was added 0.5 mL of MeOH to get a clear solution. 4 M HCl in
dioxane (0.5 mL, 2.0 mmol) was added dropwise and the resulting
mixture was stirred at rt for 30 min. LC-MS showed completion of
the reaction. The mixture was concentrated and to the residue were
added 5.0 mL of DMF and cesium carbonate. The resulting mixture was
stirred at rt for 1 hr and concentrated. The crude product was
purified by mass-triggered HPLC (10-20% ACN in H2O over 3.5 min)
then 1N aqueous HCl was added and lyophilized to afford
1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
4-methylpiperazin-2-one, as HCl salt (Compound No. 108). 1H NMR
(400 MHz, Methanol-d4) .delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s,
2H), 3.90 (s, 3H), 3.87 (t, J=5.5 Hz, 2H), 3.62 (s, 2H), 2.80 (t,
J=5.5 Hz, 2H), 2.45 (m, 5H), 2.17 (dd, J=7.9, 6.9 Hz, 2H), 2.14 (s,
6H), 2.13 (s, 3H), 1.80-1.73 (m, 6H), 1.50-1.43 (m, 6H). MS (ES+):
519.3 (M+1)+.
Example 29
Synthesis of
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(3-fluoroazetidin-1-yl)acetamide (Compound No. 133)
##STR00185##
[0698] Step 1: To a mixture of 16.7 mg (0.120 mmol) of
2-bromoacetic acid and 42.0 mg (0.1 mmol) of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1) in DCM (1 mL) were added HATU (45.6 mg, 0.12 mmol)
and DIPEA (25.8 mg, 0.035 mL, 0.2 mmol). The resulting mixture was
stirred at rt for 1 hr. LC-MS confirmed the completion of the
reaction and the mixture was concentrated. The crude product was
added to a 4 g silica gel column and was eluted with 0-50% IPA
(containing 0.02 M of ammonia) in DCM. Collected fractions and
concentrated to afford
2-bromo-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)acetamide. RT (method 1): 1.26 min. MS (ES+): 540.2 and
542.1 (M+1)+.
[0699] Step 2: A mixture of 27 mg (0.05 mmol) of
2-bromo-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4-
,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octa-
n-1-yl)acetamide, 7.3 mg (0.065 mmol) of 3-fluoroazetidine and 20.7
mg (0.15 mmol) of potassium carbonate in DMA (1 mL) was heated at
120.degree. C. under microwave irradiation for 40 min. After
concentration, the crude product was purified by mass-triggered
HPLC (10-30% ACN in H.sub.2O over 3.5 min) then 1N aqueous HCl was
added and lyophilized to afford
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(3-fluoroazetidin-1-yl)acetamide (Compound No. 133), as HCl salt.
RT (method 1): 1.04 min. MS (ES+): 535.3 (M+1)+.
Example 30
Synthesis of
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-hydroxyacetamide (Compound No. 135) and
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(3-hydroxyazetidin-1-yl)acetamide (Compound No. 136)
##STR00186##
[0701] Step 1: To a mixture of 10.1 mg (0.11 mmol) of 2-oxoacetic
acid and 42 mg (0.1 mmol) of
4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetr-
ahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-amine
(Compound No. 1) in DCM was added HATU (41.8 mg, 0.11 mmol) and
DIPEA (25.8 mg, 0.035 mL, 0.2 mmol). The resulting mixture was then
stirred at rt for 1 hr then loaded to a 4 g silica gel column and
was eluted with 0-50% IPA (containing 0.02 M of ammonia) in DCM.
Collected fractions and concentrated. The residue was dissolved in
2 mL of DCE, azetidin-3-ol (HCl salt) was added and the mixture was
stirred at rt for 30 min before sodium triacetoxyhydroborate was
added. The mixture was then stirred at rt overnight. LC-MS showed
some desired product 1 but mainly byproduct 2. The crude product
was purified by mass-triggered HPLC (10-30% ACN in H2O over 3.5
min) then 1N aqueous HC was added and lyophilized to give
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-(3-hydroxyazetidin-1-yl)acetamide (Compound No. 136) [RT (method
1): 1.05 min. MS (ES+): 478.3 (M+1)+] and
N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-t-
etrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)--
2-hydroxyacetamide (Compound No. 135) [RT (method 1): 0.98 min. MS
(ES+): 533.3 (M+1)+], both as HC salt.
TABLE-US-00006 TABLE 6 Additional Exemplary Compounds Compound
Synthesis No. Structure and Name Characterization Method 11
##STR00187## See Example 1 Replace (HG1) in step 1 with (HG2) and
(TG3) with (TG1) 12 ##STR00188## See Example 1 Replace (HG1) in
step 1 with (HG2) and (TG3) with (TG2) 13 ##STR00189## RT (method
2): 1.13 min. MS (ES+): 423.3 (M + 1)+. See Example 1 Replace (HG1)
in step 1 with (HG2) 14 ##STR00190## RT (method 2): 1.17 min. MS
(ES+): 423.3 (M + 1)+. See Example 1 Replace (HG1) in step 1 with
(HG2) and (TG3) with (TG4) 15 ##STR00191## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.00 (s, 1H), 4.64 (s, 2H), 4.25 (s, 3
H), 4.10-3.87 (m, 2H), 3.78 (s, 2H), 3.03 (t, J = 5.5 Hz, 2H), 2.19
(s, 3H), 1.96-1.40 (m, 12H). MS (ES+): 441.3 (M + 1)+. See Example
1 Replace (HG1) in step 1 with (HG3) 16 ##STR00192## .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.26 (s, 1H), 4.83 (s, 2H),
4.22 (brs, 2H), 3.91 (s, 3H), 4.10-3.87 (m, 2H), 3.69 (s, 2H), 3.09
(m, 2H), 2.82 (m, 2H), 2.52 (s, 3H), 2.15 (s, 3H), 1.98- 1.52 (m,
16H). MS (ES+): 475.4 (M + 1)+. See Example 13 Replace Compound No.
1 with Compound No. 149 17 ##STR00193## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 4.96 (s, 2H), 4.27 (m, 2H), 4.24 (s, 3H),
3.77 (s, 2H), 3.63-3.55 (m, 2H), 3.38 (m, 2H), 3.21 (m, 2H),
3.06-2.98 (m, 2H), 2.71 (s, 3H), 2.53 (s, 3H), 2.21 (s, 3H),
2.08-1.92 (m, 4H), 1.91-1.83 (m, 6H), 1.72-1.60 (m, 6H). MS (ES+):
489.4 (M + 1)+. See Example 13 Replace Compound No. 1 with Compound
No. 26 18 ##STR00194## .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 4.95 (s, 2H), 4.31 (t, J = 6.6 Hz, 2H), 4.24 (s, 3H), 3.78
(s, 2H), 3.63- 3.55 (m, 2H), 3.39 (s, 3H), 3.14-3.07 (m, 2H),
3.06-2.98 (m, 2H), 2.71 (s, 3H), 2.53 (s, 3H), 2.20 (s, 3H),
1.86-1.77 (m, 6H), 1.72-1.62 (m, 6H). MS (ES+): 493.4 (M + 1)+. See
Example 17 Replace Compound No. 1 with Compound No. 26 and replace
formaldehyde with 2- methoxyacetal- dehyde 19 ##STR00195## .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.22 (s, 1H), 4.87 (s, 2H),
4.26 (brs, 2H), 3.96 (s, 3H), 3.73 (s, 2H), 3.69 (m, 4H), 2.86 (t,
J = 5.5 Hz, 2H), 2.68 (m, 4H), 2.55 (s, 3H), 2.24 (s, 3H), 1.68-
1.50 (m, 12H). MS (ES+): 491.4 (M + 1)+. See Example 14 Replace
Compound No. 1 with Compound No. 149 20 ##STR00196## .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.98 (s, 1H), 5.02 (s, 2H),
4.55 (s, 2H), 3.73 (brs, 2H), 3.63 (s, 2H), 3.03 (q, J = 7.3 Hz,
2H), 2.93 (brs, 2H), 2.66 (s, 3H), 2.27 (s, 3H), 1.89 (dd, J = 9.8,
6.0 Hz, 6H), 1.58 (dd, J = 9.7, 6.1 Hz, 6H), 1.28 (t, J = 7.3 Hz,
3H). MS (ES+): 492.4 (M + 1)+. See Example 7 Replace Compound No. 1
with Compound No. 58 and replace 2- (dimethylamino) acetic acid
with ethylglycine 21 ##STR00197## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.99 (s, 1H), 5.01 (s, 2H), 4.56 (s, 2H),
4.06 (m, 2H), 3.84- 3.68 (m, 4H), 3.41 (m, 2H), 3.14-2.90 (m, 4H),
2.66 (s, 3H), 2.26 (s, 3H), 1.88 (dd, J = 9.3, 5.6 Hz, 6H), 1.69
(dd, J = 9.4, 5.4 Hz, 6H). MS (ES+): 477.4 (M + 1)+. See Example 14
and Example 1 Replace (HG1) in step 1 with (HG18) 22 ##STR00198##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 4.98 (s, 2H), 4.32
(m, 2H), 4.25 (s, 3H), 3.75 (s, 2H), 3.67 (s, 3H), 3.64 (s, 2H),
3.08-3.00 (m, 4H), 2.72 (s, 3H), 2.48 (s, 3H), 1.93-1.87 (m, 6H),
1.61- 1.57 (m, 6H), 1.30 (m, 3H). MS (ES+): 520.4 (M + 1)+. See
Example 7 Replace Compound No. 1 with Compound No. 26 and replace
2- (dimethylamino) acetic acid with ethylglycine 23 ##STR00199##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 4.96 (s, 2H), 4.31
(t, J = 5.6 Hz, 2H), 4.24 (s, 3H), 3.78 (s, 2H), 3.72-3.45 (m, 4H),
3.12-2.98 (m, 4H), 2.71 (s, 3H), 2.53 (s, 3H), 2.21 (s, 3H),
2.06-1.97 (m, 1H), 1.88-1.72 (m, 6H), 1.72-1.63 (m, 6H). MS (ES+):
505.4 (M + 1)+. See Example 17 Replace Compound No. 1 with Compound
No. 26 and replace formaldehyde with oxetane- 3- carbaldehyde 24
##STR00200## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 4.97
(s, 2H), 4.31 (t, J = 5.7 Hz, 2H), 4.24 (s, 3H), 3.73 (s, 2H), 3.33
(m, 2H), 3.02 (t, J = 5.5 Hz, 2H), 2.86 (s, 6H), 2.71 (s, 3H), 2.61
(t, J = 6.6 Hz, 2H), 2.53 (s, 3H), 2.22 (s, 3H), 1.94- 1.86 (m,
6H), 1.62-1.53 (m, 6H). MS (ES+): 534.4 (M + 1)+. See Example 7
Replace Compound No. 1 with Compound No. 26 and replace 2-
(dimethylamino) acetic acid with 3- (dimethylamino) propanoic acid
25 ##STR00201## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta.
4.53 (s, 2H), 4.11 (s, 3H), 3.87 (t, J = 5.7 Hz, 2H), 3.76-3.64 (m,
6H), 3.01 (J = 5.6 Hz, 2H), 2.65 (brs, 4H), 2.60 (s, 3H), 2.50 (s,
3H), 2.18 (s, 3H), 1.70-1.50 (m, 12H). MS (ES+): 505.4 (M + 1)+.
See Example 14 Replace Compound No. 1 with Compound No. 26 26
##STR00202## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 4.96
(s, 2H), 4.31 (t, J = 5.6 Hz, 2H), 4.24 (s, 3H), 3.77 (s, 2H),
3.04-2.98 (m, 2H), 2.71 (s, 3H), 2.53 (s, 3H), 2.21 (s, 3H),
1.80-1.62 (m, 12H). MS (ES+): 435.4 (M + 1)+. See Example 10 27
##STR00203## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 4.96
(s, 2H), 4.31 (t, J = 5.6 Hz, 2H), 4.24 (s, 3H), 3.77 (s, 2H), 3.01
(t, J = 5.5 Hz, 2H), 2.79 (d, J = 7.4 Hz, 2H), 2.71 (s, 3H), 2.53
(s, 3H), 2.20 (s, 3H), 1.80- 1.60 (m, 12H), 1.16-0.96 (m, 1H),
0.74-0.65 (m, 2H), 0.41-0.31 (m, 2H). MS (ES+): 489.4 (M + 1)+. See
example 6 Replace Compound No. 1 with Compound No. 26 and replace
oxetan-3-one with 1- cyclobutanone 28 ##STR00204## .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 4.94 (s, 2H), 4.30 (t, J = 5.6 Hz,
2H), 4.24 (s, 3H), 3.76 (s, 2H), 3.21-2.98 (m, 6H), 2.69 (s, 3H),
2.53 (s, 3H), 2.20 (s, 3H), 1.96-1.86 (m, 6H), 1.72-1.62 (m, 6H),
1.26-1.18 (m, 2H), 0.84-0.75 (m, 4H), 0.54- 0.38 (m, 4H). MS (ES+):
543.4 (M + 1)+. See example 6 Replace Compound No. 1 with Compound
No. 26 and replace oxetan-3-one with cyclobutanone 29 ##STR00205##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.99 (s, 1H), 5.01
(s, 2H), 4.56 (brs, 2H), 3.81 (s, 2H), 3.58-3.50 (m, 2H), 3.06-
2.88 (m, 2H), 2.86-2.76 (m, 2H), 2.66 (s, 3H), 226 (brs, 3H),
2.00-1.62 (m, 18H). MS (ES+): 475.3 (M + 1)+. See Example 13 and
Example 1 Replace (HG1) in step 1 with (HG18) and replace 1,4-
dibromobutane with 1,5- dibromopentane 30 ##STR00206## .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.85 (s, 1H), 4.92 (s, 2H),
4.43 (brs, 2H), 3.70 (s, 2H), 3.28-3.30 (m, 2H), 3.16- 3.05 (m,
2H), 2.94-2.77 (m, 2H), 2.56 (s, 3H), 2.16 (brs, 3H), 1.98-1.52 (m,
16H). MS (ES+): 461.4 (M + 1)+. See Example 13 and Example 1
Replace (HG1) in step 1 with (HG18) 31 ##STR00207## .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 4.52 (s, 2H), 4.50 (s, 2H),
4.45- 4.35 (m, 4H), 4.11 (s, 3H), 3.87 (t, J = 5.6 Hz, 2H), 3.75
(s, 2H), 3.01 (t, J = 5.5 Hz, 2H), 2.87 (s, 2H), 2.60 (s, 3H), 2.50
(s, 3H), 2.18 (s, 3H), 1.64- 1.52 (m, 12H). MS (ES+): 535.4 (M +
1)+. See Example 17 This is a by- product from example 17 32
##STR00208## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 5.03
(s, 2H), 4.34 (t, J = 5.5 Hz, 2H), 4.25 (s, 3H), 4.15- 4.10 (m,
4H), 3.87 (s, 2H), 3.62-3.56 (m, 1H), 3.09 (t, J = 5.5 Hz, 2H),
2.74 (s, 3H), 2.55 (s, 3H), 2.32 (s, 3H), 1.96-1.88 (m, 6H),
1.66-1.56 (m, 6H). MS (ES+): 518.4 (M + 1)+. See Example 7 Replace
Compound No. 1 with Compound No. 26 and replace 2- (dimethylamino)
acetic acid with azetidine- 3-carboxylic acid 33 ##STR00209##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 4.53 (s, 2H), 4.11
(s, 3H), 3.90- 3.78 (m, 3H), 3.72-3.66 (m, 3H), 3.50-3.38 (m, 3H),
3.00 (t, J = 5.5 Hz, 2H), 2.90-2.78 (m, 2H), 2.59 (s, 3H), 2.50 (s,
3H), 2.18 (s, 3H), 1.92-1.84 (m, 6H), 1.62-1.52 (m, 6H). MS (ES+):
548.4 (M + 1)+. See Example 7 Replace Compound No. 1 with Compound
No. 26 and replace 2- (dimethylamino) acetic acid with (S)-
morpholine-3- carboxylic acid 34 ##STR00210## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 4.52 (s, 2H), 4.11 (s, 3H), 3.95- 3.76
(m, 4H), 3.72 (s, 2H), 3.66-3.56 (m, 1H), 3.15-3.09 (m, 1H), 3.00
(t, J = 5.5 Hz, 2H), 2.80-2.75 (m, 2H), 2.59 (s, 3H), 2.54 (m, 1H),
2.50 (s, 3H), 2.18 (s, 3H), 1.92- 1.84 (m, 6H), 1.62-1.52 (m, 6H).
MS (ES+): 548.4 (M + 1)+. See Example 7 Replace Compound No. 1 with
Compound No. 26 and replace 2- (dimethylamino) acetic acid with
(S)- morpholine-2- carboxylic acid 35 ##STR00211## .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 4.53 (s, 2H), 4.11 (s, 3H), 3.90-
3.80 (m, 3H), 3.74-3.67 (m, 3H), 3.50-3.38 (m, 3H), 3.00 (t, J =
5.5 Hz, 2H), 2.90-2.78 (m, 2H), 2.60 (s, 3H), 2.50 (s, 3H), 2.18
(s, 3H), 1.92-1.84 (m, 6H), 1.62-1.52 (m, 6H). MS (ES+): 548.4 (M +
1)+. See Example 7 Replace Compound No. 1 with Compound No. 26 and
replace 2- (dimethylamino) acetic acid with (R)- morpholine-3-
carboxylic acid 36 ##STR00212## 1H NMR (400 MHz, Methanol-d4)
.delta. 4.53 (s, 2H), 4.12 (s, 3H), 3.96- 3.76 (m, 4H), 3.72 (s,
2H), 3.66-3.56 (m, 1H), 3.16-3.07 (m, 1H), 3.00 (t, J = 5.5 Hz,
2H), 2.82-2.75 (m, 2H), 2.59 (s, 3H), 2.54 (m, 1H), 2.50 (s, 3H),
2.18 (s, 3H), 1.92- 1.84 (m, 6H), 1.62-1.52 (m, 6H). MS (ES+):
548.4 (M + 1)+. See Example 7 Replace Compound No. 1 with Compound
No. 26 and replace 2- (dimethylamino) acetic acid with (R)-
morpholine-2- carboxylic acid 37 ##STR00213## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 4.76 (s, 2H), 4.18 (t, J = 5.6 Hz, 2H),
4.10-4.02 (m, 2H), 3.81 (s, 2H), 3.78-3.68 (m, 2H), 3.46-3.38 (m,
2H), 3.16-3.06 (m, 2H), 2.96-2.90 (m, 2H), 2.73 (s, 3H), 2.56 (s,
3H), 2.23 (s, 3H), 1.92-1.84 (m, 6H), 1.72-1.60 (m, 6H). MS (ES+):
492.4 (M + 1)+. See Example 14 and See Example 1 Replace (HG1) in
step 1 with (HG5) 38 ##STR00214## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 4.96 (s, 2H), 4.31 (t, J = 5.7 Hz, 2H),
4.24 (s, 3H), 3.78 (s, 2H), 3.58- 3.52 (m, 2H), 3.02 (t, J = 5.3
Hz, 2H), 2.88-2.76 (m, 2H), 2.71 (s, 3H), 2.53 (s, 3H), 2.20 (s,
3H), 2.00-1.42 (m, 18H). MS (ES+): 503.4 (M + 1)+. See Example 13
Replace Compound No. 1 with Compound No. 26 and replace 1,4-
dibromobutane with 1,5- dibromopentane 39 ##STR00215## .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.42 (s, 1H), 4.92 (s, 2H),
4.35 (brs, 2H), 4.04 (s, 3H), 3.82 (s, 2H), 3.58- 3.50 (m, 2H),
2.98-2.90 (m, 2H), 2.86-2.76 (m, 2H), 2.66 (s, 3H), 2.26 (s, 3H),
2.00-1.62 (m, 18H). MS (ES+): 489.4 (M + 1)+. See Example 13
Replace Compound No. 1 with Compound No. 149 and replace 1,4-
dibromobutane with 1,5- dibromopentane 40 ##STR00216## .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 4.95 (s, 2H), 4.31 (t, J = 5.6
Hz, 2H), 4.24 (s, 3H), 3.78 (s, 2H), 3.01 (t, J = 5.5 Hz, 2H), 2.78
(s, 3H), 2.53 (s, 3H), 2.20 (s, 3H), 1.90-1.80 (m, 6H), 1.72-1.62
(m, 6H). MS (ES+): 469.4 (M + 1)+. See Example 17 Replace Compound
No. 1 with Compound No. 26 and replace then treat with CD.sub.3I 41
##STR00217## 1H NMR (400 MHz, DMSO-d6) .delta. 8.23 (s, 1H), 8.03
(s, 1H), 7.70 (s, 3H), 4.44 (s, 2H), 3.85 (s, 2H), 3.62 (s, 2H),
2.07 (s, 3H), 1.69-1.29 (m, 14H). MS (ES+): 393.2 (M + 1)+. See
Example 1 Replace (HG1) in step 1 with (HG6) 42 ##STR00218##
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.20 (s, 1H), 8.00 (d,
J = 5.6 Hz, 1H), 6.39 (d, J = 5.7 Hz, 1H), 4.45 (s, 2H), 3.84 (t, J
= 5.7 Hz, 2H), 3.61 (s, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.13 (s,
3H), 1.78 (s, 1H), 1.36 (q, J = 9.8 Hz, 12H). MS (ES+): 393.2 (M +
1)+. See Example 1 Replace (HG1) in step 1 with (HG6) and (TG3)
with (TG2) 43 ##STR00219## 1H NMR (600 MHz, Methanol-d4) .delta.
8.07 (s, 1H), 6.39 (s, 1H), 4.47 (s, 3H), 3.86 (s, 5H), 3.63 (d, J
= 2.5 Hz, 2H), 2.78 (t, J = 5.6 Hz, 2H), 2.58 (s, 6H), 2.41 (s,
3H), 2.07 (s, 3H), 1.71-1.65 (m, 6H), 1.55-1.49 (m, 6H). MS (ES+):
448.4 (M + 1)+. See example 17 44 ##STR00220## 1H NMR (600 MHz,
Methanol-d4) .delta. 8.52 (s, 1H), 6.90 (s, 1H), 4.97 (s, 2H), 4.37
(s, 2H), 4.27 (d, J = 8.2 Hz, 2H), 4.12 (s, 3H), 3.13 (t, J = 5.5
Hz, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 1.92-1.73 (m, 8H), 1.67-1.54
(m, 2H). MS (ES+): 406.3 (M + 1)+. See Example 1 Replace (TG3) in
step 1 with (TG5) 45 ##STR00221## 1H NMR (600 MHz, Methanol-d4)
.delta. 8.37 (s, 1H), 6.83 (s, 1H), 5.08 (s, 2H), 4.36-4.16 (m,
2H), 4.11 (s, 3H), 4.02 (s, 2H), 3.08 (s, 2H), 2.69 (s, 3H),
1.82-1.68 (m, 12H). MS (ES+): 474.3 (M + 1)+. See Example 1 Replace
(TG3) in step 1 with (TG8) 46 ##STR00222## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.53 (s, 1H), 6.89 (s, 1H), 4.97 (d, J = 10.,7
Hz, 2H), 4.24 (d, J = 11.9 Hz, 2H), 4.12 (s, 3H), 3.99 (s, 2H),
3.14 (td, J = 5.1, 4.6, 2.6 Hz, 2H), 2.70 (s, 3H), 2.45 (s, 3H),
1.64 (s, 12H). MS (ES+): 421.2 (M + 1)+. See Example 1 Replace TG3
with TG14 47 ##STR00223## RT (method 1): 1.18 min. MS (ES+): 462.2
(M + 1)+. See Example 7 Replace Compound No. 1 with Compound No. 26
and replace 2- (dimethylamino) acetic acid with acetic acid 48
##STR00224## 1H NMR (400 MHz, Methanol-d4) .delta. 8.53 (s, 1H),
6.89 (s, 1H), 5.06- 4.94 (m, 2H), 4.25 (s, 2H), 4.12 (s, 3H), 3.98
(s, 2H), 3.18-3.06 (m, 2H), 2.94 (s, 3H), 2.70 (s, 3H), 2.43 (s,
3H), 1.96-1.85 (m, 6H), 1.67-1.57 (m, 6H). MS (ES+): 498.2 (M +
1)+. See Example 18 49 ##STR00225## 1H NMR (400 MHz, Methanol-d4)
.delta. 8.16 (s, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 5H),
3.72 (s, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.80 (s, 3H), 2.55 (s, 3H),
2.23 (s, 3H), 2.04- 1.91 (m, 6H), 1.60-1.52 (m, 6H), 1.43 (s, 9H).
MS (ES+): 534.4 (M + 1)+. See Example 19 50 ##STR00226## 1H NMR
(400 MHz, Methanol-d4) .delta. 8.05 (s, 1H), 6.36 (s, 1H), 4.44 (s,
2H), 3.90 (s, 3H), 3.88 (t, J = 5.8 Hz, 2H), 3.64 (s, 2H), 2.80 (t,
J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 1.49 (s,
12H). MS (ES+): 434.3 (M + 1)+. See Example 19
51 ##STR00227## 1H NMR (400 MHz, Methanol-d4) .delta. 8.05 (s, 1H),
6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t, J = 5.6 Hz, 2H),
3.61 (s, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.13 (s, 3H),
1.74-1.63 (m, 6H), 1.50-1.40 (m, 6H), 1.35 (s, 3H), 0.71-0.61 (m,
2H), 0.48-0.41 (m, 2H). MS (ES+): 518.3 (M + 1)+. See Example 20 52
##STR00228## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.47
(s, 1H), 6.81 (s, 1H), 4.32 (s, 2H), 4.25-4.18 (m, 2H), 4.10 (s,
3H), 3.02-2.97 (m, 2H), 2.66 (s, 3H), 2.28 (s, 3H), 1.99 (s, 6H).
MS (ES+): 378.2 (M + 1)+. See Example 1 Replace (TG3) in step 1
with (TG13) 53 ##STR00229## RT (method 1), 1.28 min. MS (ES+):
528.4 (M + 1)+. See Example 2 54 ##STR00230## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 4.01
(s, 3H), 3.98 (t, J = 5.6 Hz, 2H), 3.72 (s, 2H), 3.32 (m, 1H), 2.90
(t, J = 5.5 Hz, 2H), 2.55 (s, 3H), 2.23 (s, 3H), 2.19 (tt, J =
11.1, 5.3 Hz, 2H), 1.93-1.77 (m, 2H), 1.68 (dd, J = 11.1, 5.7 Hz,
2H), 1.63-1.51 (m, 12H). MS (ES+): 474.4 (M + 1)+. See example 6
Replace oxetan-3-one with cyclobutanone 55 ##STR00231## 1H NMR (400
MHz, Methanol-d4) .delta. 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H),
4.01 (s, 3H), 3.98 (t, J = 5.7 Hz, 2H), 3.74 (s, 2H), 3.18 (m, 1H),
2.91 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.23 (s, 3H), 1.66 (q, J =
5.6, 4.5 Hz, 6H), 1.63- 1.54 (m, 6H), 1.11 (d, J = 6.3 Hz, 6H). MS
(ES+): 462.4 (M + 1)+. See example 6 Replace oxetan-3-one with
propan-2- one 56 ##STR00232## RT (method 1): 0.21 min. MS (ES+):
478.4 (M + 1)+. See example 6 Replace oxetan-3-one with 1-
hydroxypropan- 2-one 57 ##STR00233## 1H NMR (400 MHz, Methanol-d4)
.delta. 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 4.01 (s, 3H),
3.98 (t, J = 5.7 Hz, 2H), 3.75 (s, 2H), 2.91 (t, J = 5.5 Hz, 2H),
2.69 (q, J = 6.5, 5.9 Hz, 2H), 2.55 (s, 3H), 2.24 (s, 3H), 1.63 (H,
J = 6.4, 5.8 Hz, 12H), 1.14 (t, J = 7.1 Hz, 3H). MS (ES+): 448.4 (M
+ 1)+. See example 6 Replace oxetan-3-one with acetaldehyde 58
##STR00234## 1H NMR (400 MHz, Methanol-d4) .delta. 8.06 (s, 1H),
6.36 (s, 1H), 4.45 (s, 2H), 3.99 (s, 3H), 3.89 (m, 2H), 3.64 (s,
2H), 2.81 (m, 2H), 2.64 (s, 4H), 2.45 (s, 3H), 2.13 (s, 3H), 1.68
(s, 4H), 1.63- 1.35 (m, 12H). ESIMS calcd. for C28H39N7 (M + H+)
475.2, found 475.2. See Example 13 59 ##STR00235## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 3.99
(d, J = 9.5 Hz, 5H), 3.73 (s, 2H), 3.68- 3.51 (m, 4H), 2.91 (t, J =
5.4 Hz, 2H), 2.23 (s, 3H), 1.57 (m, 12H). ESIMS calcd. for
C28H39N7O (M + H+) 491.0, found 491.0 See Example 14 60
##STR00236## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.51
(s, 1H), 7.47 (s, 1H), 6.83 (s, 1H), 5.02 (s, 2H), 4.13 (s, 3H),
3.97 (s, 2H), 3.95 (s, 2H), 2.66 (s, 3H), 1.79 (brs, 12H), 1.49 (s,
6H). MS (ES+): 434.3 (M + 1)+. See Example 1 Repalce (TG3) in step
1 with (TG6) 61 ##STR00237## 1H NMR (400 MHz, Methanol-d4) .delta.
8.05 (s, 1H), 6.36 (s, 1H), 5.79 (tt, J = 55.9, 4.1 Hz, 1H), 4.44
(s, 2H), 3.89 (m, 5H), 3.64 (s, 2H), 2.94- 2.75 (m, 4H), 2.44 (s,
3H), 2.13 (s, 3H), 1.49 (s, 12H). MS (ES+): 484.2 (M + 1)+. See
Example 21 62 ##STR00238## 1H NMR of HCl salt (400 MHz,
Methanol-d4) .delta. 8.25 (d, J = 8.6 Hz, 1H), 7.98 (ddd, J = 8.2,
6.9, 1.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.25
(d, J = 5.0 Hz, 1H), 4.75 (d, J = 2.9 Hz, 2H), 4.11 (t, J = 5.4 Hz,
2H), 3.92 (s, 2H), 3.20 (s, 3H), 2.80 (d, J = 1.7 Hz, 3H), 2.28 (d,
J = 3.3 Hz, 2H), 1.88-1.62 (m, 12H); 416.2 (M + 1), rt = 1.18 min
See Example 1 Repalce (HG1) in step 1 with (HG8) 63 ##STR00239## 1H
NMR (400 MHz, Chloroform-d) .delta. 8.38 (d, J = 5.9 Hz, 1H), 7.93
(dt, J = 6.4, 1.4 Hz, 2H), 7.51- 7.34 (m, 3H), 7.13 (d, J = 2.6 Hz,
1H), 6.71 (dd, J = 6.0, 2.6 Hz, 1H), 4.30 (s, 2H), 3.73 (t, J = 5.6
Hz, 2H), 3.67 (s, 2H), 2.76 (t, J = 5.7 Hz, 2H), 2.23 (s, 3H), 1.50
(m, 12H); MS 428.3 (M + 1), rt-1.02 min See Example 12 Repalce-4-
cyanophenyl) boronic acid in step 2 with phenylboronic acid 64
##STR00240## 1H NMR (400 MHz, Methanol-d4) .delta. 8.03 (d, J = 0.9
Hz, 1H), 6.33 (s, 1H), 4.42 (s, 2H), 3.89 (s, 3H), 3.85 (q, J = 5.6
Hz, 2H), 3.61 (s, 2H), 3.33- 3.23 (m, 4H), 2.79 (t, J = 5.6 Hz,
2H), 2.43 (s, 3H), 2.12 (s, 3H), 1.95 (dt, J = 15.3, 7.6 Hz, 2H),
1.49- 1.36 (m, 12H). MS (ES+): 460.4 (M + 1)+. See Example 13
Replace 1,4- dibromobutane with 1,3- dibromopropane 65 ##STR00241##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.49 (s, 1H), 7.47
(s, 1H), 6.83 (s, 1H), 5.08 (s, 2H), 4.09 (s, 3H), 3.95 (s, 2H),
3.92 (s, 2H), 2.66 (s, 3H), 1.80-1.70 (m, 6H), 1.68- 1.58 (m, 6H),
1.41 (s, 6H). MS (ES+): 434.3 (M + 1)+. See Example 1 Replace (TG3)
in step 1 with (TG7) 66 ##STR00242## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.39 (s, 1H), 6.75 (s, 1H), 4.12 (s, 2H),
4.00 (s, 4H), 3.79 (s, 3H), 3.74-3.32 (m, 7H), 2.95 (s, 2H), 2.58
(s, 3H), 2.20 (s, 3H), 1.89 (dd, J = 9.8, 5.0 Hz, 6H), 1.78- 1.50
(m, 6H). MS (ES+): 538.4 (M + 1)+. See Example 13 Replace 1,4-
dibromobutane with 1- bromo-2-((2- bromoethyl)sul- fonyl)ethane 67
##STR00243## .sup.1H NMR (400 MHz, Methaol-d.sub.4) .delta. 8.40
(s, 1H), 6.76 (s, 1H), 4.13 (s, 2H), 4.01 (s, 3H), 3.82 (s, 2H),
3.45 (d, J = 11.6 Hz, 2H), 2.97 (s, 2H), 2.73 (t, J = 12.3 Hz, 2H),
2.58 (s, 3H), 2.23 (s, 3H), 1.99- 1.49 (m, 18H), 1.38 (dd, J =
14.9, 5.7 Hz, 2H). MS (ES+): 488.3 (M + 1)+. See Example 13 Replace
1,4- dibromobutane- with 1,5- dibromopentane 68 ##STR00244##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.50 (s, 1H), 6.87
(s, 1H), 4.61- 4.34 (m, 2H), 4.24 (s, 1H), 4.06 (d, J = 6.9 Hz,
1H), 3.94 (d, J = 10.1 Hz, 3H), 3.92-3.71 (m, 2H), 3.34 (m, 2H),
3.11 (m, 2H), 2.69 (s, 3H), 2.34 (s, 3H), 1.74 (m, 12H). MS (ES+):
476.9 (M + 1)+. See Example 13 Replace 1,4- dibromobutane with 1,3-
dibromopropan- 2-ol 69 ##STR00245## 1H NMR (400 MHz, Methanol-d4)
.delta. 8.16 (s, 1H), 8.05 (d, J = 8.2 Hz, 0H), 8.04 (s, 0H), 7.54
(d, J = 8.1 Hz, 0H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.98
(t, J = 5.7 Hz, 2H), 3.73 (s, 2H), 3.35 (s, 2H), 2.98 (s, 3H), 2.94
(s, 3H), 2.90 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.23 (s, 3H), 1.56
(s, 12H). MS (ES+): 505.4 (M + 1)+. See Example 22 70 ##STR00246##
1H NMR (400 MHz, Methanol-d4) .delta. 8.15 (s, 1H), 6.45 (s, 1H),
4.54 (s, 2H), 4.00 (s, 3H), 3.97 (t, J = 5.5 Hz, 2H), 3.69 (s, 2H),
3.31 (d, J = 1.1 Hz, 6H), 2.90 (t, J = 5.6 Hz, 2H), 2.75-2.65 (m,
4H), 2.55 (s, 3H), 2.23 (s, 3H), 1.64-1.47 (m, 12H). MS (ES+):
536.4 (M + 1)+. See Example 22 71 ##STR00247## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.15 (s, 1H), 6.45 (s, 1H), 4.54 (s, 2H), 4.00
(s, 3H), 3.97 (dd, J = 7.4, 4.1 Hz, 2H), 3.73 (s, 2H), 3.52-3.46
(m, 4H), 2.90 (t, J = 5.6 Hz, 2H), 2.67 (t, J = 5.5 Hz, 2H), 2.54
(s, 3H), 2.23 (s, 3H), 1.57 (s, 12H), 1.19-1.15 (m, 3H). MS (ES+):
492.4 (M + 1)+. See Example 22 Replace 1- bromo-2- methoxyethane
with 1- bromo-2- ethoxyethane 72 ##STR00248## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.16 (s, 1H), 6.45 (s, 1H), 4.54 (s, 2H), 4.00
(s, 3H), 3.99- 3.95 (m, 2H), 3.70 (s, 2H), 3.47 (q, J = 7.0 Hz,
4H), 3.38 (t, J = 6.8 Hz, 4H), 2.90 (t, J = 5.6 Hz, 2H), 2.71 (d, J
= 7.3 Hz, 4H, 2.55 (s, 3H), 2.23 (s, 3H), 1.65-1.49 (m, 12H), 1.16
(t, J = 7.0 Hz, 6H). MS (ES+): 564.4 (M + 1)+. See Example 22
Replace 1- bromo-2- methoxyethane with 1- bromo-2- ethoxyethane 73
##STR00249## 1H NMR (400 MHz, Methanol-d4) .delta. 8.16 (s, 1H),
6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.98 (t, J = 5.7 Hz, 2H),
3.72 (s, 2H), 3.43 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H),
2.63 (s, 2H), 2.55 (s, 3H), 2.23 (s, 6H), 1.67- 1.49 (m, 12H). MS
(ES+): 492.4 (M + 1)+. See Example 23 74 ##STR00250## .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.50 (s, 1H), 6.87 (s, 1H),
4.95 (m, 2H), 4.21 (m, 4H), 4.11 (s, 3H), 3.95 (d, J = 6.5 Hz, 2H),
3.66-3.35 (m, 2H), 3.32 (m, 2H), 3.18 (m, 1H), 3.08 (s, 2H), 2.69
(s, 3H), 2.36 (d, J = 6.4 Hz, 3H), 1.88 (m, 6H), 1.79-1.57 (m, 6H).
MS (ES+): 507.4 (M + 1)+. See Example 13 Replace 1,4- dibromobutane
with (2R,3S)-1,4- dichlorobutane- 2,3-diol 75 ##STR00251## .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.51 (s, 1H), 6.88 (s, 1H),
4.50 (m, 1H), 4.25 (s, 2H), 4.11 (s, 3H), 3.97 (d, J = 5.3 Hz, 2H),
3.52-3.36 (m, 4H), 3.27 (s, 2H), 3.10 (s, 2H), 2.69 (s, 3H), 2.38
(d, J = 4.8 Hz, 3H), 2.21-1.95 (m, 2H), 1.96- 1.80 (m, 6H), 1.80-
1.63 (m, 6H). MS (ES+): 491.3 (M + 1)+. See Example 13 Replace 1,4-
dibromobutane with (S)-1,4- dibromobutane- 2-ol 76 ##STR00252## 1H
NMR (400 MHz, Methanol-d4) .delta. 8.17 (d, J = 1.8 Hz, 1H), 6.47
(s, 1H), 4.56 (s, 2H), 4.02 (s, 3H), 4.00 (t, J = 5.7 Hz, 2H), 3.76
(m, 2H), 3.56 (m, 2H), 3.03-2.95 (m, 6H), 2.92 (t, J = 5.6 Hz, 2H),
2.56 (s, 3H), 2.25 (s, 3H), 1.73-1.56 (m, 12H). MS (ES+): 505.4 (M
+ 1)+. See Example 24 77 ##STR00253## 1H NMR (400 MHz, Methanol-d4)
.delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.58 (t, J = 6.9 Hz, 2H), 4.47
(t, J = 7.0 Hz, 2H), 4.44 (s, 2H), 4.25 (q, J = 7.3 Hz, 1H), 3.90
(s, 3H), 3.87 (t, J = 5.5 Hz, 2H), 3.61 (s, 2H), 2.79 (t, J = 5.6
Hz, 2H), 2.44 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.45 (s, 12H).
MS (ES+): 490.4 (M + 1)+. See Example 25 78 ##STR00254## 1H NMR
(400 MHz, Methanol-d4) .delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s,
2H), 3.90 (s, 3H), 3.87 (t, J = 5.6 Hz, 2H), 3.61 (s, 2H),
3.38-3.27 (m, 1H), 2.80 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.13 (s,
3H), 2.05 (s, 3H), 1.58 (dd, J = 10.0, 5.4 Hz, 6H), 1.49- 1.40 (m,
6H), 0.92 (d, J = 6.5 Hz, 6H). MS (ES+): 476.4 (M + 1)+. See
Example 25 Replace Compound No. 6 with Compound No. 55 79
##STR00255## 1H NMR (400 MHz, Methanol-d4) .delta. 8.00 (s, 1H),
6.30 (s, 1H), 4.39 (s, 2H), 3.85 (s, 3H), 3.82 (t, J = 5.6 Hz, 2H),
3.56 (s, 2H), 3.41-3.27 (m, 1H), 2.75 (t, J = 5.6 Hz, 2H), 2.40 (s,
3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.91 (td, J = 9.8, 2.4 Hz, 2H),
1.85- 1.76 (m, 2H), 1.53-1.34 (m, 14H). MS (ES+) 48.4 (M + 1)+. See
Example 25 Replace Compound No. 6 with Compound No. 54 80
##STR00256## RT (method 1): 0.97 min. MS (ES+): 507.3 (M + 1)+. See
Example 13 Replace 1,4- dibromobutane with (2S,3S)-2,3-
dihydroxybutane- 1,4-diyl bis(4- methylbenzene- sulfonate) 81
##STR00257## RT (method 2): 1.21 min. MS (ES+): 423.3 (M + 1)+. See
Example 1 Replace (TG3) in step 1 with (TG11) 82 ##STR00258## RT
(method 2): 1.23 min. MS (ES+): 477.4 (M + 1)+. See Example 13
Replace Compound No. 1 with Compound No. 81 83 ##STR00259## .sup.1H
NMR (400 MHz, Methanol-d.sub.4) .delta. 8.55 (dd, J = 8.7, 5.7 Hz,
2H), 8.27 (s, 1H), 7.21 (t, J = 8.8 Hz, 2H), 4.97 (s, 2H), 4.38
(brs, 2H), 4.06 (s, 3H), 3.80 (s, 2H), 2.92 (t, J = 5.4 Hz, 2H),
2.29 (s, 3H), 1.80-1.60 (m, 12H). MS (ES+): 501.3 (M + 1)+. See
Example 11 84 ##STR00260## .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.25 (d, J = 7.4 Hz, 1H), 8.08-7.97 (m, 4H), 7.56 (brs,
1H), 7.36 (m, 1H), 4.71 (s, 2H), 4.09 (brs, 2H), 3.79 (s, 2H), 2.93
(t, J = 5.4 Hz, 2H), 2.25 (s, 3H), 1.82-1.60 (m, 12H). MS (ES+):
453.3 (M + 1)+. See Example 12 85 ##STR00261## 1H NMR (400 MHz,
Chloroform-d) .delta. 8.27 (d, J = 6.0 Hz, 1H), 7.86-7.79 (m, 2H),
7.42 (m, 2H), 7.41-7.34 (m, 1H), 7.05 (d, J = 2.6 Hz, 1H), 6.69
(dd, J = 6.1, 2.6 Hz, 1H), 4.27 (s, 2H), 3.71 (t, J = 5.6 Hz, 2H),
3.62 (s, 2H), 2.73 (t, J = 5.7 Hz, 2H), 2.53 (m, 4H), 2.19 (s, 3H),
1.68 (s, 4H), 1.63- 1.38 (m, 12H); MS 482.3 (M + 1), rt = 1.13 min
See Example 13 Replace Compound No. 1 with Compound No. 63 86
##STR00262## 1H NMR (400 MHz, Chloroform-d) .delta. 9.31 (d, J =
0.8 Hz, 1H), 8.47 (d, J = 5.8 Hz, 1H), 7.70 (dd, J = 5.8, 0.9 Hz,
1H), 6.93 (s, 1H), 4.17 (s, 2H), 3.68 (s, 2H), 3.58 (t, J = 5.6 Hz,
2H), 2.90 (t, J = 5.7 Hz, 2H), 2.70 (s, 3H), 2.62- 2.50 (m, 4H),
2.20 (s, 3H), 1.71 (t, J = 3.2 Hz, 4H), 1.67-1.47 (m, 12H); MS
471.3 (M + 1), rt = 0.77 min See Example 13 Replace Compound No. 1
with Compound No. 3 87 ##STR00263## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.25-8.16 (m, 1H), 7.96- 7.88 (m, 2H),
7.48-7.29 (m, 4H), 4.70 (s, 2H), 4.07 (brs, 2H), 3.79 (s, 2H), 2.92
(t, J = 5.4 Hz, 2H), 2.25 (s, 3H), 1.86- 1.60 (m, 12H). MS (ES+):
446.3 (M + 1)+. See Example 12 Replace (4- cyanophenyl) boronic
acid in step 2 with (4- fluorophenyl) boronic acid 88 ##STR00264##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.22 (d, J = 7.4
Hz, 1H), 7.59-7.41 (m, 3H), 7.36- 7.22 (m, 2H), 4.68 (s, 2H), 4.06
(t, J = 5.6 Hz, 2H), 3.79 (s, 2H), 2.91 (t, J = 5.3 Hz, 2H), 2.45
(s, 3H), 2.24 (s, 3H), 1.86- 1.56 (m, 12H). MS (ES+): 460.3 (M +
1)+. See Example 12 Replace (4- cyanophenyl) boronic acid in step 2
with (2-fluoro-4- methylphenyl) boronic acid 89 ##STR00265##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.14 (d, J = 7.4
Hz, 1H), 7.86-7.80 (m, 2H), 7.41 (brs, 1H), 7.29-7.14 (m, 3H), 4.68
(s, 2H), 4.06 (brs, 2H), 3.91 (s, 3H), 3.79 (s, 2H), 2.92 (t, J =
5.4 Hz, 2H), 2.25 (s, 3H), 1.82-1.60 (m, 12H). MS (ES+): 458.3 (M +
1)+. See Example 12 Replace (4- cyanophenyl) boronic acid in step 2
with (4- methoxyphenyl) boronic acid 90 ##STR00266## .sup.1H NMR
(400 MHz, Methanol-d.sub.4) .delta. 8.16 (d, J = 7.4 Hz, 1H), 7.76
(d, J = 8.2 Hz, 2H), 7.52-7.40 (m, 3H), 7.32- 7.26 (m, 1H), 4.69
(s, 2H), 4.07 (brs, 2H), 3.79 (s, 2H), 2.92 (t, J = 5.4 Hz, 2H),
2.47 (s, 3H), 2.25 (s, 3H), 1.84-1.54 (m, 12H). MS (ES+): 442.4 (M
+ 1)+. See Example 12 Replace (4- cyanophenyl) boronic acid in step
2 with p-tolylboronic acid 91 ##STR00267## RT (method 2): 1.33 min.
MS (ES+): 435.3 (M + 1)+. See Example 1 Replace (TG3) in step 1
with (TG12) 92 ##STR00268## .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.48 (d, J = 6.3 Hz, 1H), 8.11 (d, J = 6.3 Hz, 1H), 7.42
(s, 1H), 4.56 (s, 2H), 3.92 (t, J = 5.3 Hz, 2H), 3.82 (s, 2H), 3.11
(d, J = 11.5 Hz, 8H), 2.22 (s, 3H), 1.75 (dd, J = 30.1, 8.1 Hz,
12H). MS (ES+): 431.3 (M + 1)+. See Example 1 Replace (HG1) in step
1 with (HG10)
93 ##STR00269## 1H NMR (400 MHz, Methanol-d4) .delta. 7.86- 7.76
(m, 2H), 7.50-7.40 (m, 3H), 7.04 (d, J = 2.4 Hz, 1H), 6.80 (d, J =
2.3 Hz, 1H), 4.36 (s, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.72 (s, 2H),
2.80 (t, J = 5.6 Hz, 2H), 2.49 (s, 3H), 2.22 (s, 3H), 1.57 (s,
12H); MS 442.2 (M + 1), rt = 1.00 min See Example 12 Replace 2-
chloro-4- fluoropyridine in step 1 with 2-chloro-4- fluoro-6-
methylpyridine Repalce 4- cyanophenyl) boronic acid in step 2 with
phenylboronic acid 94 ##STR00270## 1H NMR (400 MHz, Chloroform-d)
.delta. 8.60 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 8.34-8.25 (m, 2H),
7.85 (d, J = 2.7 Hz, 1H), 7.73 (td, J = 7.7, 1.8 Hz, 1H), 7.26-7.19
(m, 1H), 6.68 (dd, J = 5.9, 2.7 Hz, 1H), 4.27 (s, 2H), 3.71 (t, J =
5.6 Hz, 2H), 3.59 (s, 2H), 2.69 (t, J = 5.7 Hz, 2H), 2.16 (s, 3H),
1.51- 1.37 (m, 12H); MS 429.2 (M + 1), rt = 0.95 min See Example 12
Repalce 4- cyanophenyl) boronic acid in step 2 with pyridin-2-
ylboronic acid 95 ##STR00271## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.39 (s, 1H), 6.76 (s, 1H), 4.12 (s, 2H),
4.01 (m, 5H), 3.88 (s, 2H), 3.39 (m, 3H), 3.02 (m, 2H), 2.81 (m,
2H), 2.58 (s, 3H), 2.23 (s, 3H), 2.13-1.50 (m, 14H), 1.38 (m, 1H).
RT (method 2): 1.39 min. MS (ES+): 491.4 (M + 1)+. See Example 13
Replace Compound No. 1 with Compound No. 81 and replace 1,4-
dibromobutane with 1,5- dibromopentane 96 ##STR00272## 1H NMR (400
MHz, Methanol-d4) .delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H),
3.90 (s, 3H), 3.87 (t, J = 5.7 Hz, 2H), 3.62 (s, 2H), 3.06 (dq, J =
7.7, 3.4 Hz, 2H), 3.01-2.91 (m, 1H), 2.80 (t, J = 5.6 Hz, 2H), 2.44
(s, 3H), 2.13 (s, 3H), 1.51-1.42 (m, 12H), 0.91 (d, J = 6.3 Hz,
3H). MS (ES+): 492.4 (M + 1)+. See Example 17 Replace Compound No.
1 with Compound No. 26 and replace formaldehyde with 2- 1-
methoxypropan- 2-one 97 ##STR00273## 1H NMR (400 MHz, Methanol-d4)
.delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H),
3.89- 3.85 (m, 2H), 3.63 (s, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.48
(d, J = 7.9 Hz, 2H), 2.44 (s, 3H), 2.14 (d, J = 6.6 Hz, 6H), 1.60-
1.41 (m, 12H), 0.99 (t, J = 7.1 Hz, 3H). MS (ES+): 462.4 (M + 1)+.
See Example 25 Replace Compound No. 6 with Compound No. 57 98
##STR00274## RT (method 2): 1.27 min. MS (ES+): 451.3 (M + 1)+. See
Example 17 Replace Compound No. 1 with Compound No. 81 99
##STR00275## 1H NMR (600 MHz, Methanol-d4) .delta. 8.16 (s, 1H),
6.46 (s, 1H), 4.55 (s, 2H), 4.01 (s, 3H), 4.00- 3.95 (m, 2H), 3.74
(s, 2H), 3.54 (dd, J = 6.7, 4.5 Hz, 2H), 3.41-3.38 (m, 2H), 3.36
(d, J = 0.8 Hz, 2H), 2.91 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.24
(s, 3H), 1.67 (ddd, J = 12.5, 7.2, 4.0 Hz, 2H), 1.57 (m, 16H). MS
(ES+): 545.4 (M + 1)+. See Example 24 Replace 2- bromo-N,N-
dimethylaceta- mide with 2- bromo-1- (piperidin-1- yl)ethan-1-one
100 ##STR00276## 1H NMR (600 MHz, Methanol-d4) .delta. 8.05 (s,
1H), 6.36 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.90- 3.86 (m, 2H),
3.63 (s, 2H), 3.03 (s, 2H), 2.83- 2.77 (m, 2H), 2.62-2.53 (m, 4H),
2.45 (s, 3H), 2.14 (s, 3H), 1.81-1.76 (m, 6H), 1.75-1.71 (m, 4H),
1.51-1.46 (m, 6H). MS (ES+): 531.4 (M + 1)+. See Example 24 Replace
2- bromo-N,N- dimethylaceta- mide with 2- bromo-1- (pyrrolidin-1-
yl)ethan-1-one 101 ##STR00277## 1H NMR (600 MHz, Methanol-d4)
.delta. 8.05 (d, J = 1.1 Hz, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90
(s, 3H), 3.90-3.85 (m, 2H), 3.64 (d, J = 6.3 Hz, 2H), 3.07 (s, 2H),
2.83-2.77 (m, 2H), 2.44 (s, 3H), 2.13 (s, 3H), 1.57-1.46 (m, 12H),
1.07 (s, 6H). MS (ES+): 506.4 (M + 1)+. See Example 26 102
##STR00278## RT (method 2): 0.18 min. MS (ES+): 502.1 (M + Na)+.
See Example 21 Replace Compound No. 1 with Compound No. 81 and
Replace 2,2- difluoroethyl trifluromethane- sulfonate with 2-
bromomethoxy- ethane 103 ##STR00279## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 5.34 (t, J = 2.6 Hz, 2H), 4.84 (t, J =
2.5 Hz, 2H), 4.60 (s, 2H), 3.89 (brs, 2H), 3.76 (s, 2H), 2.79 (t, J
= 5.5 Hz, 2H), 2.20 (s, 3H), 1.82-1.58 (m, 12H). MS (ES+): 429.3 (M
+ 1)+. See Example 1 Replace (HG1) in step 1 with (HG11) 104
##STR00280## 1H NMR (400 MHz, Methanol-d4) .delta. 8.05 (s, 1H),
6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t, J = 5.5 Hz, 2H),
3.62 (s, 2H), 3.17 (dd, J = 6.3, 4.5 Hz, 2H), 3.08 (s, 2H), 2.80
(m, 5H), 2.66 (dd, J = 6.3, 4.5 Hz, 2H), 2.44 (s, 3H), 2.13 (s,
3H), 1.48 (tq, J = 9.4, 6.4, 4.7 Hz, 12H). MS (ES+): 517.3 (M +
1)+. See Example 27 105 ##STR00281## 1H NMR (400 MHz, Methanol-d4)
.delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H),
3.87 (t, J = 5.5 Hz, 2H), 3.62 (s, 2H), 2.80 (t, J = 5.5 Hz, 2H),
2.45 (m, 5H), 2.17 (dd, J = 7.9, 6.9 Hz, 2H), 2.14 (s, 6H), 2.13
(s, 3H), 1.80-1.73 (m, 6H), 1.50- 1.43 (m, 6H). MS (ES+): 519.3 (M
+ 1)+. See Example 7 Replace 2- (dimethylamino) acetic acid with 3-
(dimethylamino) propanoic acid 106 ##STR00282## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.47 (s, 1H), 6.82 (s, 1H), 4.87 (s, 2H), 4.20
(t, J = 5.5 Hz, 2H), 4.10 (s, 3H), 3.84 (s, 2H), 3.81 (s, 2H), 3.46
(t, J = 6.8 Hz, 4H), 3.00 (t, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.25
(s, 3H), 2.01 (p, J = 6.6 Hz, 2H), 1.92 (q, J = 6.7 Hz, 2H),
1.87-1.78 (m, 6H), 1.68 (dt, J = 8.1, 5.9 Hz, 6H). MS (ES+): 531.3
(M + 1)+ See Example 21. Replace 2,2- difluoroethyl
trifluoromethane- sulfonate with 2-bromo- 1-(pyrrolidin-1-
yl)ethan-1-one 107 ##STR00283## RT (method 1): 0.14 min. MS (ES+):
505.3 (M + 1)+. See Example 14 Replace 1- bromo-2-(2- bromoethoxy)
ethane with (R)-1-bromo- 2-(2- bromoethoxy) propane 108
##STR00284## 1H NMR (400 MHz, Methanol-d4) .delta. 8.53 (s, 1H),
6.90 (s, 1H), 4.99 (s, 2H), 4.27 (s, 2H), 4.12 (s, 3H), 4.02 (s,
2H), 3.92 (d, J = 12.1 Hz, 1H), 3.75 (dd, J = 35.3, 18.9 Hz, 5H),
3.20-3.11 (m, 2H), 2.94 (s, 3H), 2.71 (s, 3H), 2.46 (s, 3H), 2.16
(d, J = 7.8 Hz, 6H), 1.67 (d, J = 6.7 Hz, 6H). MS (ES+): 517.3 (M +
1)+. See Example 29 109 ##STR00285## RT (method 1): 1.09 min. MS
(ES+): 505.4 (M + 1)+. See Example 14 Replace 1- bromo-2-(2-
bromoethoxy) ethane with (S)-2-(2- (tosyloxy)eth- oxy)propyl 4-
methylbenzene- sulfonate 110 ##STR00286## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.06 (s, 1H), 6.36 (s, 1H), 4.45 (s, 2H), 3.89
(d, J = 9.6 Hz, 5H), 3.63 (s, 2H), 3.56- 3.41 (m, 2H), 2.81 (t, J =
5.5 Hz, 2H), 2.71 (m, 2H), 2.45 (s, 3H), 2.13 (s, 3H), 1.81 (m,
2H), 1.60-1.30 (m, 12H), 1.01 (d, J = 6.2 Hz, 6H). MS (ES+): 518.4
(M + 1)+. See Example 14 Replace 1- bromo-2-(2- bromoethoxy) ethane
with (S)-2-(((R)-1- tosyloxypropan- 2- yl)oxy)propyl 4-
methylbenzene- sulfonate 111 ##STR00287## RT (method 1): 1.12 min.
MS (ES+): 518.4 (M + 1)+. See Example 14 Replace 1- bromo-2-(2-
bromoethoxy) ethane with (S)-2-(((S)-1- tosyloxypropan- 2-
yl)oxy)propyl 4- methylbenzene- sulfonate 112 ##STR00288## RT
(method 1): 1.13 min. MS (ES+): 490.4 (M + 1)+. See Example 13
Replace Compound No. 1 with Compound No. 81 and replace 1,4-
dibromobutane with (bromomethyl) cyclobutane 113 ##STR00289## RT
(method 1): 1.12 min. MS (ES+): 518.4 (M + 1)+. See Example 14
Replace 1- bromo-2-(2- bromoethoxy) ethane with (R)-2-(((R)-1-
tosyloxypropan- 2- yl)oxy)propyl 4- methylbenzene- sulfonate 114
##STR00290## 1H NMR (400 MHz, Methanol-d4) .delta. 8.51 (s, 1H),
6.88 (s, 1H), 5.03- 4.91 (m, 2H), 4.24 (s, 2H), 4.11 (s, 3H), 3.93
(s, 2H), 3.65 (s, 2H), 3.15- 3.07 (m, 2H), 3.04 (q, J = 7.3 Hz,
2H), 2.69 (s, 3H), 2.39 (s, 3H), 2.00-1.88 (m, 6H), 1.68-1.56 (m,
6H), 1.29 (t, J = 7.3 Hz, 3H). MS (ES+): 505.3 (M + 1)+ See Example
7 Replace dimethylglycine with ethylglycine 115 ##STR00291## 1H NMR
(400 MHz, Methanol-d4) .delta. 8.52 (s, 1H), 6.89 (s, 1H), 5.08-
4.91 (m, 2H), 4.25 (s, 2H), 4.12 (s, 3H), 3.98 (s, 2H), 3.18-3.05
(m, 4H), 2.70 (s, 3H), 2.52 (t, J = 6.5 Hz, 2H), 2.43 (s, 3H),
1.99-1.87 (m, 6H), 1.67- 1.54 (m, 6H). MS (ES+): 491.3 (M + 1)+.
See example 7. Replace dimethylglycine with 3-((tert-
butoxycarbonyl) amino)propa- noic acid 116 ##STR00292## 1H NMR (400
MHz, Methanol-d4) .delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.59 (s, 4H),
4.44 (s, 2H), 3.88 (d, J = 10.9 Hz, 5H), 3.62 (s, 2H), 3.40 (s,
4H), 2.79 (t, J = 5.4 Hz, 2H), 2.44 (s, 3H), 2.12 (s, 3H), 1.60-
1.27 (m, 12H). MS (ES+): 503.1 (M + 1)+. See Example 10 Replace
Compound No. 26 with Compound No. 1 117 ##STR00293## 1H NMR (400
MHz, Methanol-d4) .delta. 8.52 (s, 1H), 6.89 (s, 1H), 5.06- 4.92
(m, 2H), 4.25 (s, 2H), 4.12 (s, 3H), 3.98 (s, 2H), 3.69 (q, J =
6.2, 5.6 Hz, 1H), 3.20-3.06 (m, 2H), 2.70 (s, 3H), 2.62 (s, 3H),
2.42 (s, 3H), 2.00- 1.88 (m, 6H), 1.69-1.57 (m, 6H), 1.44 (d, J =
6.9 Hz, 3H). MS (ES+): 505.3 (M + 1)+. See example 7. Replace
dimethylglycine with N-(tert- butoxycarbonyl)- N-methyl-D- alanine
118 ##STR00294## 1H NMR (400 MHz, Methanol-d4) .delta. 8.53 (s,
1H), 6.90 (s, 1H), 5.10- 4.92 (m, 2H), 4.26 (s, 2H), 4.12 (s, 3H),
4.02 (s, 2H), 3.73-3.66 (m, 1H), 3.19-3.09 (m, 2H), 2.70 (s, 3H),
2.62 (s, 3H), 2.45 (s, 3H), 2.00-1.90 (m, 6H), 1.70-1.57 (m, 6H),
1.44 (d, J = 6.9 Hz, 3H). MS (ES+): 505.3 (M + 1)+ See example 7.
Replace dimethylglycine with N-(tert- butoxycarbonyl)- N-methyl-L-
alanine 119 ##STR00295## .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.06 (s, 1H), 7.66 (s, 1H), 7.13 (s, 1H), 6.85 (s, 1H),
6.36 (s, 1H), 4.45 (s, 2H), 3.90 (s, 5H), 3.71 (s, 2H), 2.83 (s,
2H), 2.45 (s, 3H), 2.14 (s, 3H), 1.93 (dd, J = 9.7, 6.0 Hz, 6H),
1.63 (dd, J = 9.7, 6.0 Hz, 6H). MS (ES+): 472.3 (M + 1)+ See
Example 15 120 ##STR00296## .sup.1H NMR (400 MHz, Methanol-d.sub.4)
.delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 4.11 (s, 2H), 4.0
(s, 3H), 3.81 (m, 2H), 3.60 (s, 2H), 2.80 (dd, J = 10.6, 5.2 Hz,
2H), 2.44 (s, 5H), 2.29 (d, J = 10.7 Hz, 2H), 2.13 (s, 3H), 1.74
(d, J = 6.4 Hz, 2H), 1.41 (s, 12H). MS (ES+): 517.0 (M + 1)+ See
Example 13 Replace 1,4- dibromobutane with ((2R,5S)-
tetrahydrofuran- 2,5- diyl)bis(methyl- ene)bis(4- methylbenzene-
sulfonate) 121 ##STR00297## 1H NMR (400 MHz, Methanol-d4) .delta.
8.52 (s, 1H), 6.89 (s, 1H), 5.07- 4.93 (m, 2H), 4.25 (s, 2H), 4.12
(s, 3H), 3.98 (s, 2H), 3.66 (s, 2H), 3.13 (dt, J = 8.1, 3.2 Hz,
1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.42 (s, 3H), 2.00-1.87 (m, 6H),
1.69-1.57 (m, 6H). MS (ES+): 491.3 (M + 1)+. See example 7. Replace
dimethylglycine with N-(tert- butoxycarbonyl)- N- methylglycine 122
##STR00298## 1H NMR (400 MHz, Methanol-d4) .delta. 8.07 (s, 1H),
6.37 (s, 1H), 4.45 (s, 2H), 3.89 (d, J = 7.9 Hz, 5H), 3.72 (dd, J =
11.7, 3.2 Hz, 2H), 3.62 (s, 2H), 3.50 (td, J = 11.6, 2.4 Hz, 1H),
3.29 (dd, J = 11.6, 10.2 Hz, 1H), 2.80 (t, J = 5.6 Hz, 2H), 2.74
(d, J = 12.0 Hz, 1H), 2.68 (s, 1H), 2.45 (s, 3H), 2.30 (d, J = 10.0
Hz, 1H), 2.19 (s, 3H), 2.13 (s, 3H), 1.83- 1.72 (m, 6H), 1.53-1.42
(m, 6H). MS (ES+): 547.3 (M + 1)+. See example 7. Replace
dimethylglycine with 4- methyl- morpholine-3- carboxylic acid 123
##STR00299## 1H NMR (400 MHz, Methanol-d4) .delta. 8.52 (s, 1H),
6.89 (s, 1H), 5.06- 4.92 (m, 2H), 4.25 (s, 2H), 4.12 (s, 3H), 3.98
(s, 2H), 3.12 (q, J = 5.7, 3.9 Hz, 2H), 2.90 (s, 2H), 2.70 (s, 3H),
2.39 (s, 3H), 1.96-1.81 (m, 6H), 1.79- 1.63 (m, 6H), 1.29 (s, 6H).
MS (ES+): 492.3 (M + 1)+ See Example 14 Replace 1- bromo-2-(2-
bromoethoxy) ethane with 2,2- dimethyloxirane 124 ##STR00300##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.20 (s, 1H), 6.65
(s, 1H), 4.83 (m, 4H), 3.63 (s, 2H), 3.53 (s, 2H), 3.01- 2.84 (m,
4H), 2.54 (s, 3H), 2.15 (s, 3H), 1.84- 1.74 (m, 6H), 1.52-1.42 (m,
6H), 1.17 (t, J = 7.3 Hz, 3H). MS (ES+): 491.4 (M + 1)+. See
Example 6 Replace HG1 with HG12 125 ##STR00301## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.15 (s, 1H), 6.45 (s, 1H), 4.53 (s, 2H), 4.00
(s, 3H), 3.97 (t, J = 5.6 Hz, 2H), 3.90 (dt, J = 11.5, 2.4 Hz, 1H),
3.78 (dd, J = 10.7, 2.8 Hz, 1H), 3.72 (s, 2H), 3.63-3.54 (m, 1H),
3.10 (dd, J = 12.7, 2.8 Hz, 1H), 2.90 (t, J = 5.6 Hz, 2H),
2.78-2.72 (m, 2H), 2.54 (s, 4H), 2.23 (s, 3H), 1.92- 1.84 (m, 6H),
1.61- 1.54 (m, 6H). MS (ES+): 533.3 (M + 1)+. See Example 7 Replace
dimethylglycine with 4-(tert- butoxycarbonyl) morpholine-
2-carboxylic acid 126 ##STR00302## 1H NMR (400 MHz, Methanol-d4)
.delta. 8.51 (s, 1H), 6.87 (s, 1H), 5.04- 4.93 (m, 1H), 5.03-4.95
(m, 0H), 4.95 (dddd, J = 5.4, 2.7, 2.1, 1.3 Hz, 1H), 4.24 (s, 2H),
4.11 (s, 3H), 3.91 (s, 2H), 3.17 (t, J = 6.6 Hz, 2H), 3.07 (p, J =
7.3, 6.7 Hz, 4H), 2.69 (s, 3H), 2.56 (t, J = 6.6 Hz, 2H), 2.37 (s,
3H), 1.97- 1.86 (m, 6H), 1.66-1.53 (m, 6H), 1.30 (t, J = 7.3 Hz,
3H). MS (ES+): 591.3 (M + 1)+. See Example 7 Replace
dimethylglycine with 3- (ethylamino)pro- panoic acid 127
##STR00303## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.19
(d, J = 7.4 Hz, 1H), 7.90-7.83 (m, 2H), 7.72- 7.59 (m, 3H), 7.48
(s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 4.70 (s, 2H), 4.08 (s, 2H), 3.79
(s, 2H), 3.03- 2.88 (m, 4H), 2.25 (s, 3H), 1.84-1.62 (m, 12H), 1.26
(t, J = 7.3 Hz, 3H). MS (ES+): 456.3 (M + 1)+. See example 6
Replace Compound No. 1 with Compound No. 63 and replace
oxetan-3-one with acetaldehyde 128 ##STR00304## RT (method 1): 1.27
min. MS (ES+): 505.3 (M + 1)+. See Example 14 Replace 1-
bromo-2-(2- bromoethoxy) ethane with (S)-1-chloro-3- (2-
chloroethoxy)- 2- methylpropane 129 ##STR00305## NMR (DMSO-D.sub.6,
400 MHz, .sup.1H) .delta. 8.72 (d, J = 5.2, 1H), 8.16 (d, J = 1.2,
1H), 8.00 (d, J = 2.3, 1H), 7.97 (dd, J = 1.8, 5.2, 1H), 7.93 (s,
3H), 7.84 (dd, J = 2.3, 8.7, 1H), 7.50 (s, 2H), 7.29 (d, J = 8.8,
1H), 3.81 (s, 2H), 1.82-1.55 (m, 12H); ESIMS MS (ES+): 505.3 (M +
1)+. See Example 14 Replace 1- bromo-2-(2- bromoethoxy) ethane with
(R)-1-chloro-3- (2- chloroethoxy)- 2- methylpropane 130
##STR00306## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.19
(d, J = 7.4 Hz, 1H), 7.88-7.83 (m, 2H), 7.68- 7.62 (m, 3H), 7.48
(s, 1H), 7.32 (brs, 1H), 4.70 (s, 2H), 4.08 (brs, 2H), 3.79 (s,
2H), 3.58 (t, J = 5.0 Hz, 2H), 3.39 (s, 3H), 3.10 (t, J = 5.5 Hz,
2H), 2.92 (t, J = 5.4 Hz, 2H), 2.25 (s, 3H), 1.86-1.78 (m, 6H),
1.72-1.62 (m, 6H). MS (ES+): 486.4 (M + 1)+. See example 6 Replace
Compound No. 1 with Compound No. 63 and replace oxetan-3-one with
2- methoxyacetal- dehyde 131 ##STR00307## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.47 (s, 1H), 6.82 (s, 1H), 4.88 (s, 2H),
4.19 (t, J = 4.8 Hz, 2H), 4.15-4.06 (m, 7H), 3.76 (s, 2H),
3.60-3.50 (m, 1H), 3.00 (t, J = 5.4 Hz, 2H), 2.69
(s, 3H), 2.26 (s, 3H), 1.93- 1.84 (m, 6H), 1.63-1.53 (m, 6H). MS
(ES+): 503.4 (M + 1)+. See Example 7 Replace dimethylglycine with
1-(tert- butoxycarbonyl) azetidine-3- carboxylic acid 132
##STR00308## 1H NMR (400 MHz, Methanol-d4) .delta. 8.16 (s, 1H),
6.46 (s, 1H), 4.55 (s, 2H), 4.00 (s, 3H), 3.98 (t, J = 5.5 Hz, 2H),
3.73 (s, 2H), 2.91 (t, J = 5.6 Hz, 2H), 2.88 (s, 2H), 2.55 (s, 3H),
2.47 (q, J = 7.2 Hz, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.93-1.85 (m,
6H), 1.63-1.55 (m, 6H), 1.05 (t, J = 7.2 Hz, 3H). MS (ES+): 519.3
(M + 1)+. See Example 7 Replace dimethylglycine with N-ethyl- N-
methylglycine 133 ##STR00309## RT (method 10: 1.04 min. MS (ES+):
535.3 (M + 1)+. See Example 29 134 ##STR00310## 1H NMR (400 MHz,
Methanol-d4) .delta. 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90
(s, 3H), 3.87 (t, J = 5.6 Hz, 2H), 3.62 (s, 2H), 2.80 (t, J = 5.6
Hz, 2H), 2.73 (s, 2H), 2.44 (s, 3H), 2.13 (s, 3H), 1.82- 1.73 (m,
6H), 1.51-1.45 (m, 6H). MS (ES+): 511.3 (M + 1+. See Example 7
Replace dimethylglycine with N,N- Dimethyl-d6- glycine HCl salt 135
##STR00311## RT (method 1): 1.05 min. MS (ES+): 478.3 (M + 1)+. See
Example 30 136 ##STR00312## RT (method 10: 0.98 min. MS (ES+):
533.3 (M + 1)+. See Example 30 137 ##STR00313## .sup.1H NMR (400
MHz, Methanol-d.sub.4) .delta. 8.15 (s, 1H), 6.45 (s, 1H), 4.54 (s,
2H), 4.50-4.34 (m, 4H), 4.03-3.94 (m, 5H), 3.76 (s, 2H), 3.73 (s,
2H), 2.96-2.81 (m, 4H), 2.55 (s, 3H), 2.23 (s, 3H), 1.57 (m, 12H).
MS (ES+): 520.4 (M + 1)+. See Example 14 Replace 1- bromo-2-(2-
bromoethoxy) ethane with (3- (bromomethyl) oxetan-3- yl)methanol
138 ##STR00314## 1H NMR (400 MHz, Methanol-d4) .delta. 8.53 (s,
1H), 6.90 (s, 1H), 4.97 (d, J = 15.5 Hz, 2H), 4.26 (s, 2H), 4.12
(s, 3H), 4.01 (s, 2H), 3.77 (s, 2H), 3.20- 3.09 (m, 2H), 2.95 (s,
3H), 2.88 (s, 3H), 2.70 (s, 3H), 2.45 (s, 3H), 1.98- 1.88 (m, 6H),
1.62 (dd, J = 10.1, 5.8 Hz, 6H). MS (ES+): 569.2 (M + 1)+. See
Example 18 Replace Compound No. 1 with Compound No. 126 139
##STR00315## 1H NMR (400 MHz, Methanol-d4) .delta. 8.54 (s, 1H),
6.91 (s, 1H), 5.07- 4.95 (m, 2H), 4.27 (s, 2H), 4.12 (s, 3H), 4.03
(s, 2H), 3.94 (d, J = 14.3 Hz, 2H), 3.16 (q, J = 4.1, 2.9 Hz, 2H),
3.05 (s, 2H), 2.87 (s, 1H), 2.71 (s, 3H), 2.47 (s, 3H), 2.12 (s,
2H), 2.01 (s, 1H), 1.93 (ddd, J = 9.2, 5.5, 2.9 Hz, 6H), 1.62 (dt,
J = 11.0, 5.3 Hz, 6H). MS (ES+): 533.3 (M + 1)+. See Example 7
Replace Compound No. 1 with Compound No. 126 and replace 2-
(dimethylamino) acetic acid with acetic acid 140 ##STR00316## 1H
NMR (400 MHz, Methanol-d4) .delta. 8.51 (s, 1H), 6.88 (s, 1H),
5.04- 4.94 (m, 2H), 4.25 (s, 2H), 3.98 (s, 2H), 3.78- 3.56 (m, 2H),
3.11 (d, J = 5.1 Hz, 2H), 2.70 (s, 3H), 2.39 (s, 3H), 1.85-1.66 (m,
12H). MS (ES+): 423.3 (M + 1)+. See Example 16 141 ##STR00317##
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.49 (s, 1H), 6.82
(s, 1H), 4.87 (s, 2H), 4.47 (q, J = 7.2 Hz, 2H), 4.22-4.10 (m, 3H),
4.02-3.86 (m, 2H), 3.77-3.53 (m, 4H), 3.31-3.16 (m, 2H), 2.99 (t, J
= 5.2 Hz, 2H), 2.67 (s, 3H), 2.25 (s, 3H), 1.93- 1.82 (m, 6H),
1.64-1.46 (m, 9H). MS (ES+): 547.4 (M + 1)+. See Example 8 Replace
HG1 with HG13 142 ##STR00318## 1H NMR (400 MHz, Methanol-d4)
.delta. 8.53 (s, 1H), 6.90 (s, 1H), 5.06- 4.93 (m, 2H), 4.26 (s,
2H), 4.12 (s, 3H), 3.99 (s, 2H), 3.15 (dt, J = 10.7, 5.8 Hz, 4H),
2.69 (d, J = 5.5 Hz, 6H), 2.56 (t, J = 6.4 Hz, 2H), 2.44 (s, 3H),
1.99-1.88 (m, 6H), 1.67- 1.56 (m, 6H). MS (ES+): 505.3 (M + 1)+.
See Example 7 Replace dimethylglycine with 3- (methylamino)
propanoic acid 143 ##STR00319## .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.96 (s, 1H), 6.27 (s, 1H), 4.36 (s, 2H),
3.84 (s, 3H), 3.72 (m, 2H), 3.64 (m, 2H), 3.41 (s, 2H), 3.14 (m,
1H), 2.80 (m, 2H), 2.36 (s, 3H), 2.04 (s, 3H), 1.69- 1.26 (m, 11H).
MS (ES+): 476.4 (M + 1)+. See example 6 Replace Compound No. 1 with
Compound No. 81 and replace oxetan-3-one with cyclobutanone 144
##STR00320## 1H NMR (400 MHz, Methanol-d4) .delta. 8.22 (d, J = 6.1
Hz, 1H), 7.55 (d, J = 7.0 Hz, 2H), 7.46 (m, 3H), 7.25 (d, J = 2.4
Hz, 1H), 6.92 (dd, J = 6.1, 2.5 Hz, 1H), 4.39 (s, 2H), 3.82 (t, J =
5.5 Hz, 2H), 3.70 (s, 2H), 3.43 (m, 1H), 2.81 (t, J = 5.4 Hz, 2H),
2.23 (s, 3H), 2.11-2.01 (m, 2H), 1.78-1.64 (m, 2H), 1.62- 1.51 (m,
2H), 1.54 (m, 12H); MS 482.3 (M + 1), rt = 1.05 min See example 6
Replace Compound No. 1 with Compound No. 63 and replace
oxetan-3-one with cyclobutanone 145 ##STR00321## RT (method 2):
2.24 min. MS 535.1 (M + 1) See Compound No. 157 Product of Step 1
146 ##STR00322## MS (ES+): 507.3 (M + 1)+ See Example 4 147
##STR00323## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.53 (s,
1H), 8.73 (d, J = 5.9 Hz, 1H), 8.34-7.92 (m, 2H), 7.39 (s, 1H),
4.68 (s, 2H), 4.03 (t, J = 5.2 Hz, 2H), 3.72 (s, 2H), 3.08 (s, 2H),
2.78 (s, 3H), 2.51 (s, 9H), 2.12 (s, 3H), 1.80-1.45 (m, 12H). ESIMS
m/z 518.0 (M.sup.+ + 1) See Exmaple 3 148 ##STR00324## 1H NMR (600
MHz, Methanol-d4) .delta. 8.16 (s, 1H), 6.47 (s, 1H), 4.56 (s, 2H),
4.08 (s, 2H), 4.00 (d, J = 4.9 Hz, 5H), 2.92 (t, J = 5.7 Hz, 2H),
2.55 (s, 3H), 2.24 (s, 3H), 1.80 (s, 2H), 1.7-1.59 (m, 7H), 1.40
(s, 10H). MS (ES+): 506.3 (M + 1)+. See Compound No. 44 Product of
Step 1 149 ##STR00325## RT (method 1): 1.78 min. MS (ES+): 421.4 (M
+ 1)+ See Example 1 Replace (HG1) in step 1 with (HG17) 150
##STR00326## .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 8.39
(s, 1H), 6.71 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.09 (t, J = 5.1
Hz, 2H), 3.70 (s, 2H), 3.25 (m, 2H), 2.89 (t, J = 5.3 Hz, 2H), 2.56
(s, 3H), 2.15 (s, 3H), 1.78- 1.28 (m, 15H). MS (ES+): 434.6 (M +
1)+. See Example 1 Replace (HG1) in step 1 with (HG14)
Administration and Pharmaceutical Compositions
[0702] For the therapeutic uses of compounds of the invention, such
compounds are administered in therapeutically effective amounts
either alone or as part of a pharmaceutical composition.
Accordingly, the present invention provides a pharmaceutical
composition, which comprises a compound of the invention, or
pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable carriers, diluents, or excipients. For
purposes of the present invention, unless designated otherwise,
solvates and hydrates are generally considered compositions.
Preferably, pharmaceutically acceptable carriers are sterile.
[0703] The pharmaceutical composition of the present invention can
be in unit dosage of about 1-1000 mg of active ingredient(s) for a
subject of about 50-70 kg. The therapeutically effective dosage of
a compound, the pharmaceutical composition, or the combinations
thereof, is dependent on the species of the subject, the body
weight, age and individual condition, the disorder or disease or
the severity thereof being treated. A physician, clinician or
veterinarian of ordinary skill can readily determine the effective
amount of each of the active ingredients necessary to prevent,
treat or inhibit the progress of the disorder or disease.
[0704] The above-cited dosage properties are demonstrable in vitro
and in vivo tests using advantageously mammals, e.g., mice, rats,
dogs, monkeys or isolated organs, tissues and preparations thereof.
The compounds of the present invention can be applied in vitro in
the form of solutions, e.g., aqueous solutions, and in vivo either
enterally, parenterally, advantageously intravenously, e.g., as a
suspension or in aqueous solution. The dosage in vitro may range
between about 10-3 molar and 10-9 molar concentrations. A
therapeutically effective amount in vivo may range depending on the
route of administration, between about 0.1-500 mg/kg. The activity
of a compound according to the present invention can be assessed by
the following in vitro & in vivo methods.
[0705] The pharmaceutical compositions of the invention can be
prepared using processes which include admixing a compound of the
invention, or pharmaceutically acceptable salts thereof, with one
or more pharmaceutically acceptable carriers, diluents or
excipients. By way of example, the pharmaceutical compositions of
the inventions are manufactured by mixing, granulating and/or
coating methods using a compound of the invention in free form, or
in a pharmaceutically acceptable salt form, in association with at
least one pharmaceutically acceptable carrier, diluent or
excipient.
[0706] The present invention further provides anhydrous
pharmaceutical compositions and dosage forms comprising the
compounds of the present invention as active ingredients, since
water may facilitate the degradation of certain compounds.
[0707] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
An anhydrous pharmaceutical composition may be prepared and stored
such that its anhydrous nature is maintained. Accordingly,
anhydrous compositions are packaged using materials known to
prevent exposure to water such that they can be included in
suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastics, unit
dose containers (e. g., vials), blister packs, and strip packs.
[0708] The invention further provides pharmaceutical compositions
and dosage forms that comprise one or more agents that reduce the
rate by which the compound of the present invention as an active
ingredient will decompose. Such agents, which are referred to
herein as "stabilizers," include, but are not limited to,
antioxidants such as ascorbic acid, pH buffers, or salt buffers,
etc.
[0709] The pharmaceutical composition can be formulated for
particular routes of administration such as oral administration,
rectal administration, transdermal administration, parenteral,
intravenous administration, intramuscular administration, pulmonary
administration, inhalation administration, intranasal
administration, ophthalmic administration and topical
administration.
Oral Administration Dosage Forms
[0710] The pharmaceutical compositions of the invention can be
administered orally as discrete dosage forms, wherein such dosage
forms include, but are not limited to, capsules, gelatin capsules,
caplets, tablets, chewable tablets, lozenges, dispersible powders,
granules, syrups, flavored syrups, solutions or suspensions in
aqueous or non-aqueous liquids, edible foams or whips, and
oil-in-water liquid emulsions or water-in-oil liquid emulsions.
[0711] Accordingly, for oral administration the pharmaceutical
compositions of the invention comprising an effective amount of a
compound of the invention can be made up in a solid form (including
without limitation capsules, gelatin capsules, hard or soft
capsules, tablets, chewable tablets, lozenges, caplets, pills,
granules or dispersible powders), or in a liquid form (including
without limitation solutions, aqueous or oily suspensions, syrups,
elixirs, foams, whips or emulsions). The pharmaceutical
compositions can be subjected to conventional pharmaceutical
operations such as sterilization and/or can contain conventional
inert diluents, lubricating agents, or buffering agents, as well as
adjuvants, such as preservatives, stabilizers, wetting agents,
emulsifiers and buffers, etc.
[0712] Compositions intended for oral use are prepared according to
any method known in the art for the manufacture of pharmaceutical
compositions and such compositions can contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations.
[0713] Typically, the pharmaceutical compositions are tablets or
gelatin capsules comprising the active ingredient together with one
or more of: [0714] a) diluents, e.g., lactose, dextrose, sucrose,
mannitol, sorbitol, cellulose and/or glycine; [0715] b) lubricants,
e.g., silica, talcum, stearic acid, its magnesium or calcium salt
and/or polyethyleneglycol; for tablets also [0716] c) binders,
e.g., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose and/or
polyvinylpyrrolidone; if desired [0717] d) disintegrants, e.g.,
starches, agar, alginic acid or its sodium salt, or effervescent
mixtures; and [0718] e) absorbents, colorants, flavors and
sweeteners.
[0719] Tablets may contain the active ingredient in admixture with
nontoxic pharmaceutically acceptable excipients which are suitable
for the manufacture of tablets. These excipients are, for example,
inert diluents, such as calcium carbonate, sodium carbonate,
lactose, calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example, starch, gelatin or acacia; and
lubricating agents, for example magnesium stearate, stearic acid or
talc. Tablets may be either film coated or enteric coated according
to methods known in the art. The tablets are uncoated or coated by
known techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate can be employed.
Formulations for oral use can be presented as hard gelatin capsules
wherein the active ingredient is mixed with an inert solid diluent,
for example, calcium carbonate, calcium phosphate or kaolin, or as
soft gelatin capsules wherein the active ingredient is mixed with
water or an oil medium, for example, peanut oil, liquid paraffin or
olive oil.
Parenteral Dosage Forms
[0720] In certain embodiments pharmaceutical compositions of the
invention are administered parenterally by various routes
including, but not limited to, subcutaneous, intravenous (including
bolus injection), intramuscular, and intraarterial.
[0721] Certain injectable compositions are aqueous isotonic
solutions or suspensions, and suppositories are advantageously
prepared from fatty emulsions or suspensions. Said compositions may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively,
and contain about 0.1-75%, or contain about 1-50%, of the active
ingredient.
Topical Dosage Forms
[0722] In certain embodiments pharmaceutical compositions of the
invention are administered by topical application of a
pharmaceutical composition containing a compound of the invention
in the form of a lotion, gel, ointment, solution, emulsion,
suspension or cream.
[0723] Suitable compositions for topical application, e.g., to the
skin and eyes, include aqueous solutions, suspensions, ointments,
creams, gels or sprayable formulations, e.g., for delivery by
aerosol or the like. Such topical delivery systems will in
particular be appropriate for dermal application, e.g., for the
treatment of skin cancer, e.g., for prophylactic use in sun creams,
lotions, sprays and the like. They are thus particularly suited for
use in topical, including cosmetic, formulations well-known in the
art. Such may contain solubilizers, stabilizers, tonicity enhancing
agents, buffers and preservatives.
[0724] As used herein a topical application may also pertain to an
inhalation or to an intranasal application. They may be
conveniently delivered in the form of a dry powder (either alone,
as a mixture, for example a dry blend with lactose, or a mixed
component particle, for example with phospholipids) from a dry
powder inhaler or an aerosol spray presentation from a pressurized
container, pump, spray, atomizer or nebulizer, with or without the
use of a suitable propellant.
Rectal Administration
[0725] In certain embodiments pharmaceutical compositions of the
invention of the invention are administered rectally in the form of
suppositories, enemas, ointment, creams rectal foams or rectal
gels. In certain embodiments such suppositories are prepared from
fatty emulsions or suspensions, cocoa butter or other
glycerides.
Depot Administration
[0726] In certain embodiments pharmaceutical compositions of the
invention of the invention are formulated as a depot preparation.
Such formulations are administered by implantation (for example
subcutaneously or intramuscularly) or by intramuscular injection.
In certain embodiments, such formulations include polymeric or
hydrophobic materials (for example, as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
Combination Treatment
[0727] Compounds of the invention and pharmaceutical compositions
provided herein are administered singly or in combination with one
or more additional therapeutic agents.
[0728] The combination of the present invention can be in unit
dosage of about 1-1000 mg of active ingredient(s) for a subject of
about 50-70 kg. The therapeutically effective dosage of the
combinations is dependent on the species of the subject, the body
weight, age and individual condition, the disorder or disease or
the severity thereof being treated. A physician, clinician or
veterinarian of ordinary skill can readily determine the effective
amount of each of the active ingredients necessary to prevent,
treat or inhibit the progress of the disorder or disease.
[0729] The above-cited dosage properties are demonstrable in vitro
and in vivo tests using advantageously mammals, e.g., mice, rats,
dogs, monkeys or isolated organs, tissues and preparations thereof.
The compounds of the present invention can be applied in vitro in
the form of solutions, e.g., aqueous solutions, and in vivo either
enterally, parenterally, advantageously intravenously, e.g., as a
suspension or in aqueous solution. The dosage in vitro may range
between about 10-3 molar and 10-9 molar concentrations. A
therapeutically effective amount in vivo may range depending on the
route of administration, between about 0.1-500 mg/kg. The activity
of a compound according to the present invention can be assessed by
the following in vitro & in vivo methods.
[0730] The compound of the present invention may be administered
either simultaneously with, or before or after, one or more other
therapeutic agent. The compound of the present invention may be
administered separately, by the same or different route of
administration, or together in the same pharmaceutical composition
as the other agents. A therapeutic agent is, for example, a
chemical compound, peptide, antibody, antibody fragment or nucleic
acid, which is therapeutically active or enhances the therapeutic
activity when administered to a patient in combination with a
compound of the invention.
[0731] The invention provides a pharmaceutical composition
comprising a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk), and another therapeutic
agent(s). Optionally, the pharmaceutical composition may comprise a
pharmaceutically acceptable carrier, as described above.
[0732] The invention provides a product comprising a compound of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) or
Formula (IIa to IIk), and at least one other therapeutic agent as a
combined preparation for simultaneous, separate or sequential use
in therapy. In one embodiment, the therapy is the treatment of an
autoimmune disease or condition mediated by activity of an
endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9), or any
combinations thereof (including, but not limited to, TLR7/8,
TLR7/8/9, TLR7/9, and TLR8/9). Products provided as a combined
preparation include a composition comprising the compound of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) or
Formula (IIa to IIk) and the other therapeutic agent(s) together in
the same pharmaceutical composition, or the compound of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) or Formula (IIa
to IIk) and the other therapeutic agent(s) in separate form, e.g.
in the form of a kit.
[0733] In an embodiment, the invention provides a product
comprising a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk), and at least one other
therapeutic agent as a combined preparation for simultaneous,
separate or sequential use in therapy. In one embodiment, the
therapy is the treatment of an autoimmune disease or condition
mediated by TLR7, TLR7 and TLR8 or TLR7, TLR8 and TLR9 activity.
Products provided as a combined preparation include a composition
comprising the compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk) and the other
therapeutic agent(s) together in the same pharmaceutical
composition, or the compound of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) or Formula (IIa to IIk) and the other
therapeutic agent(s) in separate form, e.g. in the form of a
kit.
[0734] The invention provides a product comprising a compound of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) or
Formula (IIa to IIk), and at least one other therapeutic agent as a
combined preparation for simultaneous, separate or sequential use
in therapy. In one embodiment, the therapy is the treatment of an
autoimmune disease or condition mediated by activity of an
endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9) pathway, or
any combinations thereof. Products provided as a combined
preparation include a composition comprising the compound of
Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) or
Formula (IIa to IIk) and the other therapeutic agent(s) together in
the same pharmaceutical composition, or the compound of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) or Formula (IIa
to IIk) and the other therapeutic agent(s) in separate form, e.g.
in the form of a kit.
[0735] In one embodiment, the invention provides a kit comprising
two or more separate pharmaceutical compositions, at least one of
which contains a compound of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) or Formula (IIa to IIk). In one
embodiment, the kit comprises means for separately retaining said
compositions, such as a container, divided bottle, or divided foil
packet. An example of such a kit is a blister pack, as typically
used for the packaging of tablets, capsules and the like.
[0736] The kit of the invention may be used for administering
different dosage forms, for example, oral and parenteral, for
administering the separate compositions at different dosage
intervals, or for titrating the separate compositions against one
another. To assist compliance, the kit of the invention typically
comprises directions for administration.
[0737] In the combination therapies of the invention, the compound
of the invention and the other therapeutic agent may be
manufactured and/or formulated by the same or different
manufacturers. Moreover, the compound of the invention and the
other therapeutic may be brought together into a combination
therapy: (i) prior to release of the combination product to
physicians (e.g. in the case of a kit comprising the compound of
the invention and the other therapeutic agent); (ii) by the
physician themselves (or under the guidance of the physician)
shortly before administration; (iii) in the patient themselves,
e.g. during sequential administration of the compound of the
invention and the other therapeutic agent.
[0738] In certain embodiments of the combination therapies
described herein, the compound of the invention and the additional
therapeutics agent(s) act additively. In certain embodiments of the
combination therapies described herein, the compound of the
invention and the additional therapeutics agent(s) act
synergistically.
[0739] The additional therapeutic agents used in combination with a
compound of the invention, include, but are not limited to
anti-inflammatory agents, immunomodulatory agents,
immunosuppressive agents, cytokines, nonsteroidal anti-inflammatory
drugs (NSAIDs), antimalarial compounds, anti-rheumatic compounds,
inhibitors of B-cell activating factor (BAFF), inhibitors of
B-lymphocyte stimulator (BLyS), and steroid hormones.
[0740] Nonsteroidal anti-inflammatory drugs (NSAIDs) used in
combination with compounds of the invention, include, but are not
limited to, salicylic acid, acetylsalicylic acid, methyl
salicylate, diflunisal, salsalate, olsalazine, sulfasalazine,
acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid,
meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen,
naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen,
oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,
tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine,
aminopyrine, apazone and nimesulide.
[0741] Anti-rheumatic compound used in combination with compounds
of the invention, include, but are not limited to,
methotrexate.
[0742] Antimalarial compound used in combination with compounds of
the invention, include, but are not limited to, chloroquine and
hydroxycloroquine.
[0743] Inhibitors of B-cell activating factor (BAFF), also known as
inhibitors of B-lymphocyte stimulator (BLyS), used in combination
with compounds of the invention, include, but are not limited to,
belimumab (Benlysta.RTM.), Blisibimod and BR3-Fc.
[0744] Immunosuppressive agents used in combination with compounds
of the invention, include, but are not limited to, mycophenolate
mofetil (MMF), mycophenolic acid, cyclophosphamide, azathioprine
and Laquinimod
(5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline--
3-carboxamide).
[0745] Steroid hormones used in combination with compounds of the
invention, include, but are not limited to, dehydroepiandrosterone
(DHEA).
[0746] Certain aspects of the pharmaceutical compositions and
combinations of the invention are provided in the following listing
of additional, enumerated embodiments. It will be recognized that
features specified in each embodiment may be combined with other
specified features to provide further embodiments of the present
invention. [0747] Embodiment 93. A pharmaceutical composition
comprising a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk), or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.
[0748] Embodiment 94. A pharmaceutical composition comprising a
compound of Formula (I) or Formula (Ia to Ip), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier. [0749] Embodiment 95. A pharmaceutical
composition comprising a compound of Formula (II) or Formula (IIa
to IIk), or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier. [0750] Embodiment 96. A
pharmaceutical composition comprising a compound of Formula (A), or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier. [0751] Embodiment 97. A pharmaceutical
composition comprising a therapeutically effective amount of a
compound of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) or Formula (IIa to IIk), or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier. [0752]
Embodiment 98. A pharmaceutical composition comprising a
therapeutically effective amount of a compound of Formula (I) or
Formula (Ia to Ip), or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable carrier. [0753] Embodiment 99. A
pharmaceutical composition comprising a therapeutically effective
amount of a compound of Formula (II) or Formula (IIa to IIk), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier. [0754] Embodiment 100. A pharmaceutical
composition comprising a therapeutically effective amount of a
compound of Formula (A), or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier. [0755]
Embodiment 101. The pharmaceutical composition of the invention
further comprising one or more additional therapeutically agents
independently selected from anti-inflammatory agents,
immunomodulatory agents, immunosuppressive agents, cytokines,
nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarial
compounds, anti-rheumatic compounds, inhibitors of B-cell
activating factor (BAFF), inhibitors of B-lymphocyte stimulator
(BLyS), and steroid hormones. [0756] Embodiment 102. A combination
comprising a therapeutically effect amount of a compound of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) or Formula (IIa
to IIk), or a pharmaceutically acceptable salt thereof, and one or
more additional therapeutically agents and optionally further
comprising a pharmaceutically acceptable carrier, wherein the
additional therapeutically agent is independently selected from
anti-inflammatory agents, immunomodulatory agents,
immunosuppressive agents, cytokines, nonsteroidal anti-inflammatory
drugs (NSAIDs), antimalarial compounds, anti-rheumatic compounds,
inhibitors of B-cell activating factor (BAFF), inhibitors of
B-lymphocyte stimulator (BLyS), and steroid hormones.
Pharmacology and Utility
[0757] Compounds of the invention are generally inhibitors of an
endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9), or any
combinations thereof (including, but not limited to, TLR7/8,
TLR7/8/9, TLR7/9, and TLR8/9), and may therefore be useful in the
treatment of autoimmune diseases associated with the activity of an
endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9), or any
combinations thereof (including, but not limited to, TLR7/8,
TLR7/8/9, TLR7/9, and TLR8/9). Accordingly, compounds of the
invention may be useful in the treatment of autoimmune diseases,
including systemic lupus erythematosus, cutaneous lupus, discoid
lupus, mixed connective tissue disease, primary biliary cirrhosis,
immune thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis.
[0758] Compounds of the invention are typically inhibitors of TLR7,
TLR7 and TLR8, or TLR7 and TLR8 and TLR9, and may therefore useful
in the treatment of autoimmune diseases associated with TLR7
activity, TLR7 and TLR8 activity, or TLR7 and TLR8 and TLR9
activity. Accordingly, compounds of the invention may be useful in
the treatment of autoimmune diseases, including systemic lupus
erythematosus, cutaneous lupus, discoid lupus, mixed connective
tissue disease, primary biliary cirrhosis, immune thrombocytopenia
purpura, hidradenitis suppurativa, dermatomyositis, polymyositis,
Sjogren's syndrome, arthritis, rheumatoid arthritis or
psoriasis.
[0759] In addition, compounds of the invention are generally
inhibitors of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, or any combinations thereof, and may therefore be
useful in the treatment of autoimmune diseases associated with the
activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, or any combinations thereof. Accordingly, compounds
of the invention may be useful in the treatment of autoimmune
diseases, including systemic lupus erythematosus, cutaneous lupus,
discoid lupus, mixed connective tissue disease, primary biliary
cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis.
[0760] The compounds of the invention, in free form or in
pharmaceutically acceptable salt form, exhibit valuable
pharmacological properties, e.g. as indicated in vitro and in vivo
tests as provided herein, and are therefore indicated for therapy
or for use as research chemicals, e.g. as tool compounds.
[0761] Thus, as a further embodiment, the present invention
provides the use of a compound of the invention in therapy, wherein
the therapy is the treatment of an autoimmune disease which may be
treated by inhibition of an endosomal Toll-like receptor (e.g.
TLR7, TLR8 or TLR9), or any combinations thereof (including, but
not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9). In another
embodiment, the autoimmune disease is systemic lupus erythematosus,
cutaneous lupus, discoid lupus, mixed connective tissue disease,
primary biliary cirrhosis, immune thrombocytopenia purpura,
hidradenitis suppurativa, dermatomyositis, polymyositis, Sjogren's
syndrome, arthritis, rheumatoid arthritis or psoriasis.
[0762] In a further embodiment, the therapy is the treatment of an
autoimmune disease which may be treated by inhibition of TLR7, TLR7
and TLR8, or TLR7 and TLR8 and TLR9. In another embodiment, the
autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, mixed connective tissue disease, primary
biliary cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis.
[0763] A further embodiment, the present invention provides the use
of a compound of the invention in therapy, wherein the therapy is
the treatment of an autoimmune disease which may be treated by
inhibition of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, and any combinations thereof. In another embodiment,
the autoimmune disease is selected from an autoimmune disease like
systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed
connective tissue disease, primary biliary cirrhosis, immune
thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis.
[0764] In another embodiment, the invention provides a method of
treating an autoimmune disease which is treated by inhibition of an
endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9), or any
combinations thereof (including, but not limited to, TLR7/8,
TLR7/8/9, TLR7/9, and TLR8/9), wherein the method comprises
administration of a therapeutically acceptable amount of a compound
of Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) or
Formula (IIa to IIk). In a further embodiment, the autoimmune
disease is systemic lupus erythematosus, cutaneous lupus, discoid
lupus, mixed connective tissue disease, primary biliary cirrhosis,
immune thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis.
[0765] In another embodiment, the invention provides a method of
treating an autoimmune disease which is treated by inhibition of
TLR7, TLR7 and TLR8 or TLR7 and TLR8 and TLR9, wherein the method
comprises administration of a therapeutically acceptable amount of
a compound of Formula (A), Formula (I), Formula (II), Formula (Ia
to Ip) or Formula (IIa to IIk). In a further embodiment, the
autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, mixed connective tissue disease, primary
biliary cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis.
[0766] In another embodiment, the invention provides a method of
treating an autoimmune disease which is treated by inhibition of an
endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9) pathway, or
any combinations thereof, wherein the method comprises
administration of a therapeutically acceptable amount of a compound
of Formula (A), Formula (I), Formula (II), Formula (Ia to Ip) or
Formula (IIa to IIk). In a further embodiment, the autoimmune
disease is systemic lupus erythematosus, cutaneous lupus, discoid
lupus, mixed connective tissue disease, primary biliary cirrhosis,
immune thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis.
[0767] Thus, as a further embodiment, the present invention
provides the use of a compound of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) or Formula (IIa to IIk) in the manufacture
of a medicament for the treatment of an autoimmune disease
associated the activity of an endosomal Toll-like receptor (e.g.
TLR7, TLR8 or TLR9), or any combinations thereof (including, but
not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9). In another
embodiment, the autoimmune disease is systemic lupus erythematosus,
cutaneous lupus, discoid lupus, mixed connective tissue disease,
primary biliary cirrhosis, immune thrombocytopenia purpura,
hidradenitis suppurativa, dermatomyositis, polymyositis, Sjogren's
syndrome, arthritis, rheumatoid arthritis or psoriasis.
[0768] In a further embodiment, the present invention provides the
use of a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk) in the manufacture of a
medicament for the treatment of an autoimmune disease associated
with the activity of TLR7, TLR7 and TLR8 or TLR7 and TLR8 and TLR9.
In another embodiment, the autoimmune disease is systemic lupus
erythematosus, cutaneous lupus, discoid lupus, mixed connective
tissue disease, primary biliary cirrhosis, immune thrombocytopenia
purpura, hidradenitis suppurativa, dermatomyositis, polymyositis,
Sjogren's syndrome, arthritis, rheumatoid arthritis or
psoriasis.
[0769] As a further embodiment, the present invention provides the
use of a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk) in the manufacture of a
medicament for the treatment of an autoimmune disease associated
the activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, or any combinations. In another embodiment, the
autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, mixed connective tissue disease, primary
biliary cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis.
[0770] Certain aspects of the uses of the compounds of the
invention and of the methods of treatment of the invention are
provided in the following listing of additional, enumerated
embodiments. It will be recognized that features specified in each
embodiment may be combined with other specified features to provide
further embodiments of the present invention. [0771] Embodiment
103. A method for treating an autoimmune disease associated with
the activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9), or any combinations thereof (including, but not limited to,
TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9), wherein the method includes
administering to a subject in need of such treatment an effective
amount of a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk), or pharmaceutically
acceptable salt thereof, thereby treating the disease. [0772]
Embodiment 104. A method for treating an autoimmune associated with
the activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9), or any combinations thereof (including, but not limited to,
TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9), wherein the method includes
administering to a subject in need of such treatment an effective
amount of a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk), or pharmaceutically
acceptable salt thereof and wherein the autoimmune disease is
systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed
connective tissue disease, primary biliary cirrhosis, immune
thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis. [0773] Embodiment 105. A method
for treating an autoimmune disease associated with the activity of
an endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9) pathway,
or any combinations thereof, wherein the method includes
administering to a subject in need of such treatment an effective
amount of a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk), or pharmaceutically
acceptable salt thereof, thereby treating the disease. [0774]
Embodiment 106. A method for treating an autoimmune disease
associated with the activity of an endosomal Toll-like receptor
(e.g. TLR7, TLR8 or TLR9) pathway, or any combinations thereof,
wherein the method includes administering to a subject in need of
such treatment an effective amount of a compound of Formula (A),
Formula (I), Formula (II), Formula (Ia to Ip) or Formula (IIa to
IIk), or pharmaceutically acceptable salt thereof and wherein the
autoimmune is systemic lupus erythematosus, cutaneous lupus,
discoid lupus, mixed connective tissue disease, primary biliary
cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis. [0775] Embodiment
107. A method for treating an autoimmune disease associated with
[0776] i) TLR7 activity, or [0777] ii) TLR7 activity and TLR8
activity, or [0778] iii) TLR7 activity and TLR8 activity and TLR9
activity, wherein the method includes administering to a subject in
need of such treatment an effective amount of a compound of Formula
(A), Formula (I), Formula (II), Formula (Ia to Ip) or Formula (IIa
to IIk), or pharmaceutically acceptable salt thereof, thereby
treating the disease. [0779] Embodiment 108. A method for treating
an autoimmune disease associated with [0780] i) TLR7 activity, or
[0781] ii) TLR7 activity and TLR8 activity, or [0782] iii) TLR7
activity and TLR8 activity and TLR9 activity, [0783] wherein the
method includes administering to a subject in need of such
treatment an effective amount of a compound of Formula (A), Formula
(I), Formula (II), Formula (Ia to Ip) or Formula (IIa to IIk), or
pharmaceutically acceptable salt thereof, and wherein the
autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, mixed connective tissue disease, primary
biliary cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis. [0784] Embodiment
109. A compound of Formula (A), Formula (I), Formula (II), Formula
(Ia to Ip) or Formula (IIa to IIk), or pharmaceutically acceptable
salt thereof, for treating an autoimmune disease associated with
the activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9), or any combinations thereof (including, but not limited to,
TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9. [0785] Embodiment 110. A
compound of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) or Formula (IIa to IIk), or pharmaceutically acceptable salt
thereof, for treating an autoimmune disease associated with the
activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9), or any combinations thereof (including, but not limited to,
TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9), wherein the autoimmune
disease is systemic lupus erythematosus, cutaneous lupus, discoid
lupus, mixed connective tissue disease, primary biliary cirrhosis,
immune thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis. [0786] Embodiment 111. A
compound of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) or Formula (IIa to IIk), or pharmaceutically acceptable salt
thereof, for treating an autoimmune disease associated with the
activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, or any combinations thereof. [0787] Embodiment 112.
A compound of Formula (A), Formula (I), Formula (II), Formula (Ia
to Ip) or Formula (IIa to IIk), or pharmaceutically acceptable salt
thereof, for treating an autoimmune disease associated with the
activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, or any combinations thereof, wherein the autoimmune
disease is systemic lupus erythematosus, cutaneous lupus, discoid
lupus, mixed connective tissue disease, primary biliary cirrhosis,
immune thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis. [0788] Embodiment 113. A
compound of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) or Formula (IIa to IIk), or pharmaceutically acceptable salt
thereof, for treating an autoimmune disease associated with [0789]
i) TLR7 activity, or [0790] ii) TLR7 activity and TLR8 activity, or
[0791] iii) TLR7 activity and TLR8 activity and TLR9 activity,
wherein the autoimmune disease is systemic lupus erythematosus,
cutaneous lupus, discoid lupus, mixed connective tissue disease,
primary biliary cirrhosis, immune thrombocytopenia purpura,
hidradenitis suppurativa, dermatomyositis, polymyositis, Sjogren's
syndrome, arthritis, rheumatoid arthritis or psoriasis. [0792]
Embodiment 114. A compound of Formula (A), Formula (I), Formula
(II), Formula (Ia to Ip) or Formula (IIa to IIk), or
pharmaceutically acceptable salt thereof, for use in treating an
autoimmune disease associated with the activity of an endosomal
Toll-like receptor (e.g. TLR7, TLR8 or TLR9), or any combinations
thereof (including, but not limited to, TLR7/8, TLR7/8/9, TLR7/9,
and TLR8/9. [0793] Embodiment 115. A compound of Formula (A),
Formula (I), Formula (II), Formula (Ia to Ip) or Formula (IIa to
IIk), or pharmaceutically acceptable salt thereof, for use in
treating an autoimmune disease associated with the activity of an
endosomal Toll-like receptor (e.g. TLR7, TLR8 or TLR9), or any
combinations thereof (including, but not limited to, TLR7/8,
TLR7/8/9, TLR7/9, and TLR8/9), wherein the autoimmune disease is
systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed
connective tissue disease, primary biliary cirrhosis, immune
thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis. [0794] Embodiment 116. A
compound of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) or Formula (IIa to IIk), or pharmaceutically acceptable salt
thereof, for use in treating an autoimmune disease associated with
the activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, or any combinations thereof. [0795] Embodiment 117.
A compound of Formula (A), Formula (I), Formula (II), Formula (Ia
to Ip) or Formula (IIa to IIk), or pharmaceutically acceptable salt
thereof, for use in treating an autoimmune disease associated with
the activity of an endosomal Toll-like receptor (e.g. TLR7, TLR8 or
TLR9) pathway, or any combinations thereof, wherein the autoimmune
disease is systemic lupus erythematosus, cutaneous lupus, discoid
lupus, mixed connective tissue disease, primary biliary cirrhosis,
immune thrombocytopenia purpura, hidradenitis suppurativa,
dermatomyositis, polymyositis, Sjogren's syndrome, arthritis,
rheumatoid arthritis or psoriasis. [0796] Embodiment 114. A
compound of Formula (A), Formula (I), Formula (II), Formula (Ia to
Ip) or Formula (IIa to IIk), or pharmaceutically acceptable salt
thereof, for use in treating a disease associated with [0797] i)
TLR7 activity, or [0798] ii) TLR7 activity and TLR8 activity, or
[0799] iii) TLR7 activity and TLR8 activity and TLR9 activity,
wherein the disease is an autoimmune disease. [0800] Embodiment
115. Use of a compound of Formula (A), Formula (I), Formula (II),
Formula (Ia to Ip) or Formula (IIa to IIk), or pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for
treating an autoimmune disease where TLR7 activity, TLR7 and TLR8
activity, or TLR7 and TLR8 and TLR9 activity, are implicated.
[0801] Embodiment 116. Use of a compound of Formula (A), Formula
(I), Formula (II), Formula (Ia to Ip) or Formula (IIa to IIk), or
pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for treating an autoimmune disease, wherein the
autoimmune disease is systemic lupus erythematosus, cutaneous
lupus, discoid lupus, mixed connective tissue disease, primary
biliary cirrhosis, immune thrombocytopenia purpura, hidradenitis
suppurativa, dermatomyositis, polymyositis, Sjogren's syndrome,
arthritis, rheumatoid arthritis or psoriasis.
Assays
[0802] Compounds of the invention were assayed in the assays
described in the following paragraphs.
Test Compound Preparation
[0803] Compounds were generally serially diluted (1/3) in DMSO and
plated on sterile 384 well tissue culture plates and stored until
ready for use. Each ten-point dilution was typically plated in
triplicate in parallel rows.
TLR7, TLR8 and TLR9 Antagonist Assays in Human PBMC's
PBMC Isolation
[0804] Fresh blood was collected from normal human donors under
written informed consent in heparinized syringes on the morning of
the assay. The blood was diluted in RPMI-1640 medium and the white
blood cells were separated from red blood cells by centrifugation
(800 g 15'0 acceleration, 0 brake) on a Ficoll cushion. Peripheral
blood mononuclear cells (PBMCs) were separated from platelets by a
series of low-speed centrifugations (1000 RPM 10') in PBS+5% HI-FBS
and 1 mM EDTA. Purified PBMCs were re-suspended in assay medium
(RPMI-1640 w Glutamax (Invitrogen) supplemented with 5% HI-FBS, 10
mM HEPES, 50 uM .beta.-mercaptoethanol, and 100 mG/L
penicillin/streptomycin cocktail). Viable PBMCs were counted on a
hemacytometer and kept on ice until ready for plating.
Agonist Treatment Bulk Transfection
[0805] A 4.times. concentration (4 ug/ml or 40 ug/ml for TLR8 or
TLR7 assays, respectively) of the TLR7/8 agonist ssRNA40 (IDT) was
complexed with 10% DOTAP (Roche) in assay medium for 30 min prior
to addition to the PBMC suspension (5 million cells/ml). After
addition, the final concentration of ssRNA40 in the TLR7/8
stimulated PBMC suspension was 1 .mu.g/ml for TLR8 assay, and 10
g/mL for the TLR7 assay. The final DOTAP concentration was 2.5%.
Diluted PBMCs (5 million cells/ml) were treated with 4.times.TLR9
agonist ODN2216 (Invivogen). Final concentration of ODN2216 in TLR9
stimulated PBMC suspension was 0.3 .mu.M.
PBMC Plating and Compound Treatment
[0806] Agonist stimulated PBMCs were plated on the compound treated
384 well plates at 150,000 cells/well. Un-stimulated PBMCs were
plated as controls on each plate. Plating volume was 40 .mu.L per
well. DMSO concentration in each well was 0.25%.
[0807] A separate plate, without compounds, with titrations of
ssRNA40 and ODN2216 was included in every assay to measure agonist
response of each donor's PBMC prep. Assay plates were placed in a
tissue culture incubator (37.degree. C., 5% CO.sub.2) for 14-16
hrs. After this incubation, the plates were centrifuged and stored
at -20.degree. C. until they were assayed.
IL-6 TR-FRET Assay for TLR8 Activity:
[0808] 1) Cisbio Human IL-6 kit, 20,000 tests (62TNFPEC), and GNF
High-Base TC 384 well plates (cat #789163G) were used; 2) the
Anti-TIL-6 Cryptate conjugate and the Anti-IL-6 XL665 conjugate
were diluted 1:20 in Reconstitution Buffer; 3) a 1:1 mixture of 3
.mu.l/well Anti-IL-6 Cryptate conjugate and 3 .mu.l/well Anti-IL-6
XL665 conjugate was prepared; 4) 6 .mu.l/well HTRF dilution
mastermix was added to 6 .mu.l of transferred supernatant samples
in proxiplates; 5) The plates were incubated for 3 hrs at rt in the
dark; and 6) the levels of IL-6 production was measured using an
Envision plate reader (665 nm (emmission)/590 nm (excitation)) with
HTRF settings and ratiometric read-out: (XL665 emission/Eu Cryptate
emission).times.10,000.
IFN.alpha..sub.2b AlghaLISA Assay for TLR7 or TLR9 Activity
[0809] After thawing the assay plates, 6 .mu.L of supernatant
samples were transferred to a low-volume AlphaPlate 384SW
(Perkin-Elmer). The concentration of IFN.alpha. in supernatants was
measured using the IFN.alpha..sub.2b AlphaLISA Assay (Perkin-Elmer:
AL297F). 3 .mu.L of IFN.alpha. acceptor beads/biotinylated antibody
solution was added first, using laboratory automation. After an
hour incubation, 3 .mu.L of streptavidin acceptor bead solution was
added. The plates containing this mixture were incubated in the
dark for an hour and read on an appropriate plate reader at reading
parameters set by the manufacturer. (Envision, EnSpire:
Perkin-Elmer).
THP-1 TLR8 Antagonist TNFalpha TR-FRET Assay
Cell-Based Assay:
[0810] 1) THP-1 cells were cultured in RPMI 1640 with 10% FBS, 10
mM HEPES, 1 mM Sodium Pyruvate, 1% Penicillin-Streptomycin
L-glutamine, and 1% Non-Essential Amino Acids; 2) 3 sets of
different passages of THP-1 cells in assay media were pooled,
counted, and resuspended in the same media as culture media, but
with 5% FBS; 3) Cells were diluted to 100,000 cells/well (30
.mu.l/well) and the R848 agonist was diluted to 25 .mu.M in 10
ul/well in media; 4) The cell and agonist dilutions were combined
and 40 .mu.l/well were added to 384-well flat bottom Greiner assay
plates containing test compounds in DMSO, which were Echo
pre-spotted at 50 nL per well with a 8 mM top dose and 10 point 1:3
serial dilutions--10 M final top dose; 5) The plates were incubated
overnight for 18-20 hrs at 37 degrees with 5% CO.sub.2; 6) The
plates were then centrifuged at 1000 rpm for 2 min at rt; 7) 10
g/well of supernatants were transferred to 384-well low volume
white Greiner proxiplates; and 8) TNF.alpha. levels were measured
using the TR-FRET assay described below.
TNFalpha TR-FRET Assay:
[0811] 1) Cisbio Human TNFalpha kit, 20,000 tests (62TNFPEC), and
Greiner Bio-One LIA-white TC 384 well small volume plates (cat
#784080) were used; 2) the Anti-TNFalpha Cryptate conjugate and the
Anti-TNFalpha XL665 conjugate were diluted 1:20 in Reconstitution
Buffer; 3) a 1:1 mixture of 5 .mu.l/well Anti-TNFalpha Cryptate
conjugate and 5 .mu.l/well Anti-TNFalpha XL665 conjugate was
prepared; 4) 10 .mu.l/well HTRF dilution mastermix were added to 10
g of transferred supernatant samples in proxiplates; 5) The plates
were incubated for 3 hrs at rt in the dark; and 6) the levels of
TNFalpha production was measured using an Envision plate reader
(665 nm (emmission)/590 nm (excitation)).
[0812] Various compounds of the invention, in free form or in
pharmaceutically acceptable salt form, exhibit pharmacological
properties, for example, as indicated by the assay results
presented in Table 7. The IC.sub.50 values are given as the
concentration of the test compound in question that provoke a
response halfway between the baseline and maximum responses. Dashes
(---) in Table 7 mean that no tests were conducted.
TABLE-US-00007 TABLE 7 Assay Results huPBMC TLR7 huPBMC TLR8 huPBMC
TLR9 Antagonist Antagonist Antagonist Compound IFN.alpha. Assay
IL-6 TR-FRET Assay IFN.alpha. Assay No. IC.sub.50 (.mu.M) IC.sub.50
(.mu.M) IC.sub.50 (.mu.M) 1 0.025 0.236 1.519 2 0.038 >10 3.134
3 0.054 0.055 1.934 4 -- 0.511 -- 5 0.397 0.433 -- 6 0.019 0.135
1.386 7 -- 0.061 -- 8 0.004 0.166 4.28 9 0.015 0.201 5.1 10 0.056
0.048 >10 11 0.318 -- >6.58 12 0.841 -- >4.96 13 0.042
1.348 7.75 14 0.241 -- >9.09 15 0.288 0.203 1.27 16 0.025 0.443
>10 17 0.258 0.199 >10 18 0.245 0.077 >10 19 0.055 0.186
>10 20 0.025 0.031 >9.38 21 0.024 0.036 >10 22 0.033 0.014
>10 23 0.666 0.373 >10 24 0.201 0.01 >7.38 25 0.565 0.017
>8.08 26 0.644 0.289 >10 27 0.015 0.014 >10 28 0.84 0.641
>10 29 0.073 0.016 >10 30 0.01 0.324 >10 31 0.013 0.027
2.34 32 0.124 0.125 -- 33 0.055 0.072 >10 34 0.013 0.029 5.7 35
0.014 >10 >10 36 0.007 0.08 4.97 37 0.159 0.079 >10 38
0.042 0.031 >10 39 0.06 0.119 >10 40 0.07 0.314 2.517 41
0.006 4.59 0.817 42 0.017 >10 0.472 43 0.016 0.051 0.511 44
0.038 0.861 1.214 45 0.038 0.63 2.056 46 0.056 >10 >10 47
0.004 >10 >10 48 0.013 >10 >10 49 0.02 >10 3.95 50
0.006 0.308 0.376 51 0.007 >10 7.55 52 0.304 >10 4.86 53
0.843 1.14 1.73 54 0.004 0.074 0.489 55 0.005 0.42 1.054 56 0.007
0.292 0.68 57 0.007 0.11 0.497 58 0.003 0.053 0.639 59 0.004 0.052
2.168 60 1.028 0.277 -- 61 0.012 0.129 62 -- 0.699 -- 63 0.034
0.568 -- 64 0.004 0.115 0.443 65 -- 2.356 -- 66 -- 1.13 -- 67 0.005
0.011 -- 68 -- 0.155 -- 69 0.009 0.031 0.442 70 -- 0.379 -- 71
0.005 0.014 0.488 72 0.037 0.102 0.815 73 -- 0.139 -- 74 0.007
0.158 1.542 75 0.011 0.134 0.963 76 -- 0.201 -- 77 0.01 0.316 0.179
78 -- 0.474 -- 79 0.004 0.136 0.064 80 0.002 0.466 0.249 81 --
0.395 -- 82 -- 0.486 -- 83 -- 0.865 -- 84 0.302 0.831 1.836 85
0.046 0.224 0.569 86 0.081 0.048 2.741 87 -- 1.095 -- 88 -- 0.715
-- 89 -- 0.622 -- 90 -- 1.007 -- 91 0.022 0.377 0.215 92 0.16 0.04
0.094 93 -- 0.983 -- 94 -- 1.106 -- 95 -- 0.085 -- 96 -- 0.775 --
97 -- 0.089 -- 98 -- 0.718 -- 99 0.04 0.13 2.841 100 0.005 0.015
1.365 101 0.039 0.071 2.642 102 0.022 0.366 1.239 103 -- 1.421 --
104 0.061 0.389 >10 105 0.014 0.027 1.63 106 0.063 0.168 2.661
107 0.011 0.006 1.71 108 0.021 0.044 8.64 109 0.012 0.016 0.515 110
0.007 0.016 1.901 111 0.028 0.039 1.409 112 0.024 0.056 1.186 113
0.053 0.016 1.407 114 0.01 0.015 1.554 115 0.01 0.245 >10 116
0.009 0.068 1.574 117 0.002 0.236 0.954 118 0.002 0.197 0.775 119
0.006 1.182 0.608 120 0.004 0.02 -- 121 0.005 0.039 1.438 122 --
0.922 -- 123 0.024 0.121 2.226 124 1.038 >10 >10 125 0.004
0.043 0.909 126 0.02 0.153 9.53 127 0.259 1.428 0.545 128 0.006
0.013 0.792 129 0.008 0.012 1.055 130 1.327 2.832 0.672 131 0.003
0.361 >10 132 <0.000508 0.008 0.26 133 0.012 0.806 1.14 134
0.001 0.093 0.299 135 0.01 8.44 >10 136 0.006 0.178 1.169 137
0.072 0.068 1.279 138 0.006 2.792 -- 139 0.067 3.54 -- 140 0.027
0.331 1.803 141 0.032 2.289 5.17 142 0.047 0.932 >6.59 143 0.041
0.687 0.841 144 0.073 0.105 0.139 145 0.061 >10 -- 146 0.236 --
-- 147 0.033 >10 6.24 148 0.054 >10 >10 149 -- 0.695 --
150 -- 4.203 --
TABLE-US-00008 TABLE 8 Assay Results THP-1 TLR8 Antagonist Compound
TR-FRET Assay No. IC.sub.50 (.mu.M) 11 8.23 12 >10 14 >10
[0813] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended
claims.
* * * * *