U.S. patent application number 17/564850 was filed with the patent office on 2022-04-21 for compound, compositions, and methods.
This patent application is currently assigned to DENALI THERAPEUTICS INC.. The applicant listed for this patent is DENALI THERAPEUTICS INC.. Invention is credited to Javier de Vicente Fidalgo, Anthony A. Estrada, Jianwen A. Feng, Joseph P. Lyssikatos, Zachary K. Sweeney.
Application Number | 20220119371 17/564850 |
Document ID | / |
Family ID | |
Filed Date | 2022-04-21 |
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United States Patent
Application |
20220119371 |
Kind Code |
A1 |
Estrada; Anthony A. ; et
al. |
April 21, 2022 |
COMPOUND, COMPOSITIONS, AND METHODS
Abstract
Compounds having activity as LRRK2 inhibitors are disclosed. The
compounds are of formula (I) including stereoisomers, tautomers,
pharmaceutically acceptable salts and prodrugs thereof. Methods
associated with preparation and use of such compounds, as well as
pharmaceutical compositions comprising such compounds, are also
disclosed.
Inventors: |
Estrada; Anthony A.; (San
Mateo, CA) ; Feng; Jianwen A.; (San Mateo, CA)
; Lyssikatos; Joseph P.; (South San Francisco, CA)
; Sweeney; Zachary K.; (Redwood City, CA) ; de
Vicente Fidalgo; Javier; (Foster City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DENALI THERAPEUTICS INC. |
SOUTH SAN FRANCISCO |
CA |
US |
|
|
Assignee: |
DENALI THERAPEUTICS INC.
SOUTH SAN FRANCISCO
CA
|
Appl. No.: |
17/564850 |
Filed: |
December 29, 2021 |
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International
Class: |
C07D 403/12 20060101
C07D403/12; C07D 403/14 20060101 C07D403/14; C07D 487/04 20060101
C07D487/04; C07D 417/14 20060101 C07D417/14; C07D 471/04 20060101
C07D471/04; C07D 413/14 20060101 C07D413/14 |
Claims
1. A compound having the following formula (I): ##STR00510## or a
pharmaceutically acceptable salt, stereoisomer, or a mixture of
stereoisomers, tautomer or prodrug thereof, wherein: Z is N or CH;
R.sup.1 is halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkyloxy,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkyloxycarbonyl,
aminocarbonyl, or heterocyclylcarbonyl, wherein each is optionally
substituted; and R.sup.5 is H; or R.sup.1 and R.sup.5 together with
the atom to which they are attached form a 5-membered ring having
the structure: ##STR00511## Y is N or CR.sup.6; R.sup.6 is H, halo,
cyano, C.sub.1-C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 heteroalkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
--S(O).sub.w(C.sub.1-C.sub.6 alkyl), cycloalkyl, heterocyclyl,
heteroaryl, aryl, acyl, or amido, wherein each is optionally
substituted; R.sup.10 is H, halo, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, or cycloalkyl; R.sup.2 is
C.sub.1-C.sub.6 alkyl, cycloalkyl, cycloalkylalkyl, C.sub.1-C.sub.6
alkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy,
heterocyclylalkyloxy, amino, C.sub.1-C.sub.6 alkylamino,
cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, or
heterocyclylalkylamino, wherein each is optionally substituted;
R.sup.3a and R.sup.3b are each independently H, halo, cyano, amino,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 heteroalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, aminocarbonyl, heterocyclylcarbonyl, or
-L.sup.2-R.sup.8, wherein each is optionally substituted; or
R.sup.4 and either R.sup.3a or R.sup.3b when attached to an
adjacent carbon, together with the atoms bound thereto join to form
a heterocyclyl or heteroaryl, wherein each heterocyclyl or
heteroaryl is optionally substituted; or R.sup.3a and R.sup.3b when
attached to an adjacent carbon, together with the atoms bound
thereto join to form a cycloalkyl, heterocyclyl, or heteroaryl,
wherein each cycloalkyl, heterocyclyl, or heteroaryl is optionally
substituted; R.sup.4 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 haloalkoxyalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, heteroarylalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6
alkoxycarbonylalkyl, aminocarbonyl, heterocyclylcarbonyl, or
-L.sup.1-R.sup.7, wherein each is optionally substituted; L.sup.1
is --S(O).sub.p--, --S(O).sub.pN(R.sup.9)--, --(CH.sub.2).sub.m--,
--C(O)--, --C(O)O--, or --C(O)N(R.sup.9)--; each L.sup.2 is
independently --O--, --S(O).sub.m--, --(CH.sub.2).sub.m--,
--C(O)--, --C(O)O--, --OC(O)--, --C(O)N(R.sup.9)--,
--N(R.sup.9)C(O)--, --N(R.sup.9)C(O)--, --OC(O)N(R.sup.9)--,
--N(R.sup.9)C(O)N(R.sup.9)--, --S(O).sub.pN(R.sup.9)--,
--N(R.sup.9)S(O).sub.pN(R.sup.9)-- or --N(R.sup.9)S(O).sub.p--;
R.sup.7 is C.sub.1-C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 heteroalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, wherein each is
optionally substituted; each R.sup.8 is independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
wherein each is optionally substituted; each R.sup.9 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
each p is independently 1 or 2; each w is independently 0, 1 or 2;
and each m is independently 0, 1, 2 or 3; provided that: a) when
R.sup.5 is H, then Z is N, and R.sup.2 is C-heterocyclyl, which is
optionally substituted; and b) when R.sup.1 and R.sup.5 together
with the atom to which they are attached form the 5-membered ring,
then either: i) R.sup.2 is C.sub.1-C.sub.6 alkoxy, cycloalkyloxy,
cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino,
C.sub.1-C.sub.6 alkylamino, cycloalkylamino, cycloalkylalkylamino,
heterocyclylamino, or heterocyclylalkylamino; Z is N; R.sup.5 is H;
Y is N or CR.sup.6; and R.sup.6 is halo, C.sub.1-C.sub.6 haloalkyl
or cycloalkyl; or ii) R.sup.2 is C.sub.1-C.sub.6 alkyl, cycloalkyl
or cycloalkylalkyl, wherein each is optionally substituted.
2. A compound of formula (A-Ic): ##STR00512## or a pharmaceutically
acceptable salt, stereoisomer, mixture of stereoisomers, tautomer,
or prodrug thereof, wherein: R.sup.11 is chloro or --CF.sub.3;
R.sup.12 is H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
C.sub.1-C.sub.6 haloalkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, heteroarylalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6
alkoxycarbonylalkyl, aminocarbonyl or heterocyclylcarbonyl, wherein
each C.sub.1-C.sub.6 alkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or
heteroarylalkyl is optionally substituted; and one of R.sup.13a and
R.sup.13b is H, and the other of R.sup.13a and R.sup.13b is H,
halo, or methyl.
3. The compound of claim 2, wherein R.sup.12 is C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl,
cycloalkyl, heterocyclyl, heteroaryl wherein each cycloalkyl,
heterocyclyl, or heteroaryl is optionally substituted.
4. The compound of claim 2 wherein one of R.sup.13a or R.sup.13b is
H, and the other of R.sup.3a or R.sup.3b is methyl.
5. A compound of formula (B-I): ##STR00513## or a pharmaceutically
acceptable salt, stereoisomer, mixture of stereoisomers, tautomer
or prodrug thereof, wherein: Y is N or CR.sup.21; R.sup.21 is halo,
C.sub.1-C.sub.6 haloalkyl or cycloalkyl; R.sup.22 is
C.sub.1-C.sub.6 alkoxy; cycloalkyloxy, cycloalkylalkyloxy,
heterocyclyloxy, heterocyclylalkyloxy, amino, C.sub.1-C.sub.6
alkylamino, cycloalkylamino, cycloalkylalkylamino,
heterocyclylamino, or heterocyclylalkylamino; R.sup.23a and
R.sup.23b are each independently H, halo, cyano, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, C.sub.1-C.sub.6
alkylcarbonyl, C.sub.1-C.sub.6 alkoxycarbonyl, aminocarbonyl or
heterocyclylcarbonyl; and R.sup.24 is H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,
heteroarylylalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkoxycarbonylalkyl, aminocarbonyl
or heterocyclylcarbonyl.
6. The compound of claim 5, wherein Y is N.
7. The compound of claim 5, wherein Y is CR.sup.21.
8. The compound of claim 7, wherein R.sup.21 is chloro.
9. The compound of claim 7, wherein R.sup.21 is C.sub.1-C.sub.6
haloalkyl or cycloalkyl.
10. The compound of claim 5, wherein R.sup.22 is C.sub.1-C.sub.6
alkoxy or C.sub.1-C.sub.6 alkylamino.
11. The compound of claim 10, wherein R.sup.22 is C.sub.1-C.sub.6
alkoxy.
12. The compound of claim 10, wherein R.sup.22 is C.sub.1-C.sub.6
alkylamino.
13. The compound of any one claim 5, wherein one of R.sup.23a or
R.sup.2b is H, and the other of R.sup.23a or R.sup.23b is halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxyalkyl, C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6
cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl, cycloalkyl,
cycloalkylalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkyloxycarbonyl, aminocarbonyl or heterocyclylcarbonyl.
14. The compound of claim 5, wherein R.sup.24 is C.sub.1-C.sub.6
alkyl.
15. The compound of claim 5, wherein R.sup.24 is C.sub.1-C.sub.6
cyanoalkyl.
16. A compound having the following formula (C-I): ##STR00514## or
a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, tautomer or prodrug thereof, wherein: Y is N or
CR.sup.36; Z is N or CH; R.sup.31 is C.sub.1-C.sub.6 alkyl,
cycloalkyl or cycloalkylalkyl, each of which is optionally
substituted; R.sup.32 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 heteroalkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, or -L.sup.3-R.sup.37,
wherein each C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted; R.sup.33 and R.sup.34 are
each independently H, halo, cyano, amino, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or
-L.sup.4-R.sup.38, wherein each C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl is optionally substituted; or or
R.sup.33 and R.sup.34 together with the atom to which they are
attached form a cycloalkyl, heterocyclyl or heteroaryl, wherein
each cycloalkyl, heterocyclyl and heteroaryl is optionally
substituted; or R.sup.32 and R.sup.33 together with the atom to
which they are attached form a heterocyclyl or heteroaryl, wherein
each heterocyclyl and heteroaryl is optionally substituted;
R.sup.35 is H, halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, or cycloalkyl; R.sup.36 is H, halo, cyano,
C.sub.1-C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 heteroalkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
--S(O).sub.w(C.sub.1-C.sub.6 alkyl), cycloalkyl, heterocyclyl,
heteroaryl, aryl, acyl, or amido, wherein each alkyl, alkoxyl,
haloalkyl, alkoxyalkyl, -cycloalkyl, heterocyclyl, heteroaryl,
aryl, acyl, or amido are independently optionally substituted;
L.sup.3 is --S(O).sub.p--, --S(O).sub.pN(R.sup.39)--,
--(CH.sub.2).sub.m--, --C(O)--, --C(O)O--, or --C(O)N(R.sup.39)--;
each L.sup.4 is independently --O--, --S(O).sub.w--,
--(CH.sub.2).sub.m--, --C(O)--, --C(O)O--, --OC(O)--,
--C(O)N(R.sup.39)--, --N(R.sup.39)C(O)--, --N(R.sup.9)C(O)--,
--OC(O)N(R.sup.39)--, --N(R.sup.39)C(O)N(R.sup.39)--,
--S(O).sub.pN(R.sup.39)--, --N(R.sup.39)S(O).sub.pN(R.sup.39)-- or
--N(R.sup.39)S(O).sub.p--; R.sup.37 is C.sub.1-C.sub.6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 heteroalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl, wherein each C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl is optionally substituted; each
R.sup.38 is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl, wherein each C.sub.1-C.sub.6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl is optionally substituted; each R.sup.39 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
each p is independently 1 or 2; each w is independently 0, 1 or 2;
and each m is independently 0, 1, 2 or 3.
17. The compound of claim 16, wherein R.sup.31 is cycloalkyl.
18. The compound of claim 16, wherein R.sup.32 is C.sub.1-C.sub.6
alkyl, or cycloalkyl, wherein each C.sub.1-C.sub.6 alkyl and
cycloalkyl is optionally substituted.
19. The compound of claim 16, wherein R.sup.32 and R.sup.33 are
each independently C.sub.1-C.sub.6 alkyl.
20. The compound of claim 16, wherein R.sup.32 and R.sup.33
together with the atom to which they are attached form a
heterocyclyl or heteroaryl, wherein each heterocyclyl and
heteroaryl is optionally substituted.
21. The compound of claim 16, wherein R.sup.34 is H.
22. The compound of claim 16, wherein R.sup.33 and R.sup.34
together with the atom to which they are attached form a
cycloalkyl, heterocyclyl or heteroaryl, wherein each cycloalkyl,
heterocyclyl and heteroaryl is optionally substituted.
23. The compound of claim 16, wherein R.sup.35 is H or methyl.
24. The compound of claim 16, wherein Y is N.
25. The compound of claim 16, wherein Y is CR.sup.26.
26. The compound of claim 25, wherein R.sup.36 is C.sub.1-C.sub.6
haloalkyl, cycloalkyl, halo or cyano.
27. The compound of claim 16, wherein Z is N.
28. The compound of claim 16, wherein Z is CH.
29. The compound of claim 16, wherein R.sup.35 is H; one of
R.sup.33 and R.sup.34 is H and the other is halo, cyano, amino,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 heteroalkyl, cycloalkyl, heterocyclyl,
aryl, heteroaryl, or -L.sup.4-R.sup.38, wherein each
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is
optionally substituted.
30-39. (canceled)
40. A compound of Table A-1 or Table A-1A or a pharmaceutically
acceptable salt, stereoisomer, mixture of stereoisomers, prodrug,
or tautomer thereof.
41. A compound of Table B-1 or a pharmaceutically acceptable salt,
stereoisomer, mixture of stereoisomers, prodrug, or tautomer
thereof.
42. A compound selected from Table C-1 or a pharmaceutically
acceptable salt, stereoisomer, mixture of stereoisomers, prodrug,
or tautomer thereof.
43. (canceled)
44. A pharmaceutical composition comprising the compound as in
claim 1, or a pharmaceutically acceptable salt, stereoisomer,
mixture of stereoisomers, prodrug, or tautomer thereof, and a
pharmaceutically acceptable carrier, diluent or excipient.
45. A method for treating a disease or condition mediated, at least
in part, by LRRK2, the method comprising administering an effective
amount of the pharmaceutical composition of claim 1 to a subject in
need thereof.
46. The method of claim 45, wherein the disease or condition is a
neurodegenerative disease.
47. The method of claim 46, wherein the neurodegenerative disease
is Parkinson's disease or dementia.
48. The method of claim 45, wherein the disease or condition is a
central nervous system (CNS) disorder.
49. The method of claim 48, wherein the CNS disorder is Alzheimer's
disease or L-Dopa induced dyskinesia.
50. The method of claim 45, wherein the disease or condition is a
cancer.
51. The method of claim 50, wherein the cancer is kidney cancer,
breast cancer, prostate cancer, blood cancer, papillary cancer,
lung cancer, acute myelogenous leukemia or multiple myeloma.
52. The method of claim 45, wherein the disease or condition is an
inflammatory disease.
53. The method of claim 52, wherein the inflammatory disease is
leprosy, Crohn's disease, inflammatory bowel disease, ulcerative
colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or
ankylosing spondylitis.
54. A method for enhancing cognitive memory, the method comprising
administering an effective amount of the pharmaceutical composition
of claim 44 to a subject in need thereof.
55. A compound of claim 1 for use in therapy.
56. A compound of claim 1 for use in the treatment of a
neurodegenerative disease, cancer, or an inflammatory disease.
57. A compound of claim 1 for use in the treatment of Alzheimer's
disease, L-Dopa induced dyskinesia, Parkinson's disease, dementia,
ALS, kidney cancer, breast cancer, prostate cancer, blood cancer,
papillary cancer, lung cancer, acute myelogenous leukemia, multiple
myeloma, leprosy, Crohn's disease, inflammatory bowel disease,
ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid
arthritis, or ankylosing spondylitis.
58. Use of a compound of claim 1 for the manufacture of a
medicament for treating a neurodegenerative disease, cancer, or an
inflammatory disease.
59. Use of a compound of claim 1 for the manufacture of a
medicament for treating Alzheimer's disease, L-Dopa induced
dyskinesia, Parkinson's disease, dementia, amyotrophic lateral
sclerosis, kidney cancer, breast cancer, prostate cancer, blood
cancer, papillary cancer, lung cancer, acute myelogenous leukemia,
multiple myeloma, leprosy, Crohn's disease, inflammatory bowel
disease, ulcerative colitis, amyotrophic lateral sclerosis,
rheumatoid arthritis, or ankylosing spondylitis.
60. A method of preparing a compound of formula (I) of claim 1,
comprising coupling a compound of formula (b): ##STR00515## wherein
X is halogen, with a compound of formula (c): ##STR00516## under
conditions to provide the compound of formula (I).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. 119(e)
to U.S. Provisional Application Ser. Nos. 62/258,244, filed Nov.
20, 2015, 62/259,165, filed Nov. 24, 2015, 62/307,285, filed Mar.
11, 2016, 62/310,632, filed Mar. 18, 2016, 62/350,927, filed Jun.
16, 2016, 62/350,988, filed Jun. 16, 2016, 62/351,004, filed Jun.
16, 2016, 62/351,083, filed Jun. 16, 2016, 62/411,011, filed Oct.
21, 2016, 62/411,064, filed Oct. 21, 2016, and, where the contents
of each is incorporated herein by reference in its entirety.
FIELD
[0002] The present disclosure relates generally to novel
pyrazole-substituted pyrimidines and their use as therapeutic
agents, for example, as inhibitors of LRRK2.
BACKGROUND
[0003] Neurodegenerative diseases such as Parkinson's disease,
amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Lewy body
dementia, and Huntington's disease affects millions of people.
Parkinson's disease is a chronic, progressive motor system disorder
characterized by selective degeneration and cell death of
dopaminergic neurons in the substantial nigra region of the brain.
This leaves patients with impaired ability to direct and control
their movements. The cause of the disease was generally considered
to be sporatic and unknown, but significant advancements in
understanding have been made in the last 15 years.
[0004] The genetic basis for the disease and associated pathogenic
mechanisms have led exploration of the gene encoding leucine-rich
repeat kinase 2 (LRRK2) protein and its association with hereditary
Parkinson's disease (Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004,
601-607). LRRK2 is a member of the ROCO protein family and shares 5
conserved domains with all other family members. Many mis-sense
mutations to the LRRK2 gene have been linked with autosomal
dominant Parkinson's disease in familial studies Trinh and Farrar,
Nature Reviews in Neurology. Vol. 9, 2013, 445-454; Paisan-Ruiz et
al., J. Parkinson's Disease, Vol. 3, 2013, 85-103). The most common
pathogenic mutation, G2019S, occurs in the highly conserved kinase
domain of LRRK2 (See Gilks et al., Lancet, Vol 365, 2005, 415-416).
In vitro studies indicate Parkinson's disease-associated mutation
leads to increased LRRK2 activity and a decreased rate of GTP
hydrolysis (Guo et al., Experimental Cell Research, Vol. 313(16),
2007, 3658-3670). This evidence suggests the kinase and GTPase
activities of LRRK2 are important for pathogenesis and the LRRK2
kinase domain may regulate overall LRRK2 function (See Cookson,
Nat. Rev. Neurosci., Vol. 11, 2010, 791-797).
[0005] While progress has been made in this field, there remains a
need for improved inhibitors of the LRRK2 receptor which are useful
for treatment of various neurodegenerative diseases, such as
Parkinson's disease, Alzheimer's disease and amyotrophic lateral
sclerosis.
SUMMARY
[0006] Provided herein are compounds that are useful as inhibitors
of LRRK2. The disclosure also provides compositions, including
pharmaceutical compositions, kits that include the compounds, and
methods of using (or administering) and making the compounds. The
disclosure further provides compounds or compositions thereof for
use in a method of treating a disease, disorder, or condition that
is mediated, at least in part, by LRRK2. Moreover, the disclosure
provides uses of the compounds or compositions thereof in the
manufacture of a medicament for the treatment of a disease,
disorder, or condition that is mediated, at least in part, by
LRRK2.
[0007] In one embodiment, provided is a compound of formula
(I):
##STR00001##
[0008] or a pharmaceutically acceptable salt, stereoisomer, or a
mixture of stereoisomers, tautomer or prodrug thereof, wherein:
[0009] Z is N or CH;
[0010] R.sup.1 is halo, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,
cycloalkylalkyloxy, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkyloxycarbonyl, aminocarbonyl, or heterocyclylcarbonyl, wherein
each is optionally substituted; and R.sup.5 is H; or
[0011] R.sup.1 and R.sup.5 together with the atom to which they are
attached form a 5-membered ring having the structure:
##STR00002##
[0012] Y is N or CR.sup.6;
[0013] R.sup.6 is H, halo, cyano, C.sub.1-C.sub.6 alkyl.
C.sub.2-6alkenyl, C.sub.2-6 alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, --S(O).sub.w(C.sub.1-C.sub.6 alkyl),
cycloalkyl, heterocyclyl, heteroaryl, aryl, acyl, or amido, wherein
each is optionally substituted;
[0014] R.sup.10 is H, halo, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, or cycloalkyl;
[0015] R.sup.2 is C.sub.1-C.sub.6 alkyl, cycloalkyl,
cycloalkylalkyl, C.sub.1-C.sub.6 alkoxy, cycloalkyloxy,
cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino,
C.sub.1-C.sub.6 alkylamino, cycloalkylamino, cycloalkylalkylamino,
heterocyclylamino, or heterocyclylalkylamino, wherein each is
optionally substituted;
[0016] R.sup.3a and R.sup.3b are each independently H, halo, cyano,
amino, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6
heteroalkyl, C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6
aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6
alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, heteroaryl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, aminocarbonyl,
heterocyclylcarbonyl, or -L.sup.2-R.sup.8, wherein each is
optionally substituted;
[0017] or R.sup.4 and either R.sup.3a or R.sup.3b when attached to
an adjacent carbon, together with the atoms bound thereto join to
form a heterocyclyl or heteroaryl, wherein each heterocyclyl or
heteroaryl is optionally substituted;
[0018] or R.sup.3a and R.sup.3b when attached to an adjacent
carbon, together with the atoms bound thereto join to form a
cycloalkyl, heterocyclyl, or heteroaryl, wherein each cycloalkyl,
heterocyclyl, or heteroaryl is optionally substituted;
[0019] R.sup.4 is H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 haloalkoxyalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, heteroarylalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6
alkoxycarbonylalkyl, aminocarbonyl, heterocyclylcarbonyl, or
-L.sup.1-R.sup.7, wherein each is optionally substituted;
[0020] L.sup.1 is --S(O).sub.p--, --S(O).sub.pN(R.sup.9)--,
--(CH.sub.2).sub.m--, --C(O)--, --C(O)O--, or
--C(O)N(R.sup.9)--;
[0021] each L.sup.2 is independently --O--, --S(O).sub.m--,
--(CH.sub.2).sub.m--, --C(O)--, --C(O)O--, --OC(O)--,
--C(O)N(R.sup.9)--, --N(R.sup.9)C(O)--, --N(R.sup.9)C(O)--,
--OC(O)N(R.sup.9)--, --N(R.sup.9)C(O)N(R.sup.9)--,
--S(O).sub.pN(R.sup.9)--, --N(R.sup.9)S(O).sub.pN(R.sup.9)--, or
--N(R.sup.9)S(O).sub.p--;
[0022] R.sup.7 is C.sub.1-C.sub.6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
wherein each is optionally substituted;
[0023] each R.sup.8 is independently C.sub.1-C.sub.6 alkyl.
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, wherein each is optionally
substituted;
[0024] each R.sup.9 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-6alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl;
[0025] each p is independently 1 or 2;
[0026] each w is independently 0, 1, or 2; and
[0027] each m is independently 0, 1, 2, or 3;
[0028] provided that:
a) when R.sup.5 is H, then Z is N, and R.sup.2 is C-heterocyclyl,
which is optionally substituted; and b) when R.sup.1 and R.sup.5
together with the atom to which they are attached form the
5-membered ring, then either:
[0029] i) R.sup.2 is C.sub.1-C.sub.6 alkoxy, cycloalkyloxy,
cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino,
C.sub.1-C.sub.6 alkylamino, cycloalkylamino, cycloalkylalkylamino,
heterocyclylamino, or heterocyclylalkylamino; Z is N; R.sup.5 is H;
Y is N or CR.sup.6; and R.sup.6 is halo, C.sub.1-C.sub.6 haloalkyl
or cycloalkyl; or
[0030] ii) R.sup.2 is C.sub.1-C.sub.6 alkyl, cycloalkyl or
cycloalkylalkyl, wherein each is optionally substituted.
[0031] In one aspect, provided is a compound of formula (II):
##STR00003##
[0032] or a pharmaceutically acceptable salt, prodrug,
stereoisomer, or a mixture of stereoisomers thereof, wherein:
[0033] R.sup.41 is halo, cyano, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, cycloalkyl,
cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, or
--C(O)R.sup.45:
[0034] R.sup.42 is: [0035] a fused bicyclic ring system having a
heterocyclyl or cycloalkyl fused to a heteroaryl, wherein the ring
system is attached to the remainder of the molecule via the
heterocyclyl or cycloalkyl and the ring system is independently
optionally substituted with one or more halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, amino, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --C.sub.1-6
alkylene-C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C.sub.1-6
alkylene-SO.sub.2NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46,
--OC(O)R.sup.46, --C(O)R.sup.46, --C.sub.1-6 alkylene-C(O)R.sup.46,
--C.sub.1-6 alkylene-OC(O)R.sup.46, --C.sub.1-6
alkylene-C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, --C.sub.1-6
alkylene-O--C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0036] C.sub.1-6 alkoxyalkyl substituted with one
or more substituents independently selected from halo, amino,
cyano, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl; [0037] C.sub.1-6 haloalkyl
substituted with one or more substituents independently selected
from amino, cyano, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0038] C.sub.1-6 cyanoalkyl optionally substituted
with one or more substituents independently selected from halo,
amino, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl,
C.sub.2-6alkynyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl; [0039] C.sub.3-10 cycloalkyl
substituted with one or more substituents independently selected
from amino, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(C.sub.1-6 alkyl), --S(O)(C.sub.1-6 alkyl),
--S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl substituted with one
or more halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, wherein the
heterocyclyl, heteroaryl, or heteroarylalkyl are optionally
substituted with one or more substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo; or [0040]
--X--C(R.sup.48)(R.sup.49)(R.sup.50), wherein: [0041] X is
C.sub.1-6 alkylene optionally substituted with one or more halo;
[0042] R.sup.48 and R.sup.49, together with the carbon atom to
which they are attached, form an optionally substituted C.sub.3-10
cycloalkyl; and [0043] R.sup.50 is cyanoalkyl, C.sub.1-6
alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6 alkynyl,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
[0044] R.sup.43a and R.sup.43b are each independently H, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, amido, or --C(O)R.sup.45;
[0045] R.sup.44 is cycloalkyl, C-heterocyclyl, --N(R.sup.51).sub.2,
--OR.sup.51, or --SR.sup.51;
[0046] each R.sup.45 is independently C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --N(R.sup.52).sub.2, or heterocyclyl, wherein each
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or heterocyclyl is optionally
substituted;
[0047] each R.sup.46 and R.sup.47 is independently H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl, wherein each
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl is optionally
substituted;
[0048] each R.sup.51 is independently H, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6
alkoxyalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl,
--C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.3-6
cycloalkyl optionally substituted with one or more C.sub.1-6 alkyl,
C.sub.3-6 cycloalkylalkyl optionally substituted with one or more
C.sub.1-6 alkyl, heterocyclyl optionally substituted with one or
more R.sup.53, or heterocyclylalkyl optionally substituted with one
or more R.sup.53; or
[0049] two R.sup.51, together with the nitrogen to which they are
attached, form a three- to six-membered heterocyclyl optionally
substituted with one or more R.sup.53;
[0050] each R.sup.52 is independently H or optionally substituted
C.sub.1-6 alkyl;
[0051] each R.sup.53 is independently C.sub.1-6 alkyl,
C.sub.1-6haloalkyl, halo, oxo, C.sub.1-6 alkoxy, amino,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 alkoxyalkyl, cyano,
heterocyclyl, heterocyclylalkyl, C.sub.3-6cycloalkyl, C.sub.3-6
cycloalkylalkyl, C.sub.3-6 cycloalkylsulfonyl, --C(O)R.sup.54, or
--C.sub.1-6 alkylene-C(O)R.sup.54;
[0052] each R.sup.54 is independently C.sub.1-6 alkyl, C.sub.1-6
alkoxy, amino optionally substituted with halo, C.sub.1-6
haloalkyl, C.sub.1-6 hydroxyalkyl, hydroxy, C.sub.1-6 alkoxyalkyl,
C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6
alkyl), C.sub.1-6 aminoalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; and
[0053] provided that when R.sup.44 is cycloalkyl,
--N(R.sup.51).sub.2, or --OR.sup.51, then R.sup.42 is not an
unsubstituted C.sub.1-6 cyanoalkyl.
[0054] In another embodiment, a pharmaceutical composition is
provided comprising a compound as described herein (e.g., a
compound of Formula I, II, A-I, B-I, C-I, or D-I, or any subformula
thereof), or a stereoisomer, mixture of stereoisomers,
pharmaceutically acceptable salt, tautomer, or prodrug thereof, and
a pharmaceutically acceptable carrier, diluent or excipient.
[0055] In another embodiment, a method for treating a disease or
condition mediated, at least in part, by LRRK2, in a subject in
need thereof is provided, the method comprising administering to
the subject an effective amount of the pharmaceutical composition
comprising a compound as described herein (e.g., a compound of
Formula I, II, A-I, B-I, C-I, or D-I, or any subformula thereof),
or a stereoisomer, mixture of stereoisomers, pharmaceutically
acceptable salt, tautomer, or prodrug thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient.
[0056] In some embodiments, the method is for treatment of a
neurodegenerative disease, a cancer, an inflammatory disease. In
some embodiments, the method is for enhancing cognitive memory.
[0057] In another embodiment, a compound of Formula I, II, A-I,
B-I, C-I, or D-I, or any subformula thereof, is provided for use in
therapy. In some embodiments, the compound is provided for use in
the treatment of a neurodegenerative disease, cancer, or an
inflammatory disease.
[0058] In another embodiment, provided is a method for preparing a
compound of formula (I), comprising coupling a compound of formula
(b):
##STR00004##
[0059] wherein X is halogen, with a compound of formula (c):
##STR00005##
[0060] under conditions to provide the compound of formula (I),
[0061] wherein R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4,
R.sup.5, and Z are as defined herein.
[0062] In another embodiment, provided is a method for preparing a
compound of formula (II), comprising coupling a compound of formula
(II-a):
##STR00006##
[0063] wherein X is a leaving group (e.g., halo), with a compound
of formula (II-b):
##STR00007##
[0064] under conditions to provide the compound of formula
(II),
[0065] wherein R.sup.41, R.sup.42, R.sup.43a, R.sup.43b, and
R.sup.44 are as defined herein.
[0066] These and other aspects of the disclosure will be apparent
upon reference to the following detailed description.
DETAILED DESCRIPTION
[0067] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
embodiments of the disclosure. However, one skilled in the art will
understand that the invention may be practiced without these
details.
1. Definitions
[0068] Unless the context requires otherwise, throughout the
present specification and claims, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is, as "including, but
not limited to".
[0069] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the present disclosure.
Thus, the appearances of the phrases "in one embodiment" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined
in any suitable manner in one or more embodiments.
[0070] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which this disclosure belongs.
[0071] A dash ("-") that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --C(O)NH.sub.2 is attached through the carbon atom. A dash
at the front or end of a chemical group is a matter of convenience;
chemical groups may be depicted with or without one or more dashes
without losing their ordinary meaning. A wavy line or a dashed line
drawn through a line in a structure indicates a specified point of
attachment of a group. Unless chemically or structurally required,
no directionality or stereochemistry is indicated or implied by the
order in which a chemical group is written or named.
[0072] The prefix "Cu-v" indicates that the following group has
from u to v carbon atoms. For example, "C.sub.1-6 alkyl" indicates
that the alkyl group has from 1 to 6 carbon atoms.
[0073] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. In certain embodiments, the term "about" includes
the indicated amount.+-.10%. In other embodiments, the term "about"
includes the indicated amount.+-.5%. In certain other embodiments,
the term "about" includes the indicated amount.+-.1%. Also, to the
term "about X" includes description of "X". Also, the singular
forms "a" and "the" include plural references unless the context
clearly dictates otherwise. Thus, e.g., reference to "the compound"
includes a plurality of such compounds and reference to "the assay"
includes reference to one or more assays and equivalents thereof
known to those skilled in the art.
[0074] "Amino" refers to a NH.sub.2 group or the group
--NR.sup.yR.sup.z wherein R.sup.y and R.sup.z are independently
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,
heteroalkyl, or heteroaryl; each of which may be optionally
substituted, as defined herein.
[0075] "Alkyl" refers to a straight or branched hydrocarbon chain
group consisting solely of carbon and hydrogen atoms, which is
saturated or unsaturated (i.e., contains one or more double bonds
(known as "alkenyl") and/or triple bonds (known as "alkynyl")),
having from one to twelve carbon atoms (C.sub.1-C.sub.12 alkyl),
preferably one to eight carbon atoms (C.sub.1-C.sub.8 alkyl) or one
to six carbon atoms (C.sub.1-C.sub.6 alkyl), and which is attached
to the rest of the molecule by a single bond, e.g., methyl, ethyl,
n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,
1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl,
prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl,
propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated
otherwise specifically in the specification, an alkyl group may be
optionally substituted.
[0076] "Alkylene" or "alkylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a group, consisting solely of carbon and hydrogen,
which is saturated or unsaturated (i.e., contains one or more
double and/or triple bonds), and having from one to twelve carbon
atoms, e.g., methylene, ethylene, propylene, n-butylene,
ethenylene, propenylene, n-butenylene, propynylene, n-butynylene,
and the like. The alkylene chain is attached to the rest of the
molecule through a single or double bond and to the group through a
single or double bond. The points of attachment of the alkylene
chain to the rest of the molecule and to the group can be through
one carbon or any two carbons within the chain. Unless stated
otherwise specifically in the specification, an alkylene chain may
be optionally substituted.
[0077] "Alkylcarbonyl" refers to a group of the formula
--(C.dbd.O)R.sub.a where R.sub.a is an alkyl group as defined above
containing one to twelve carbon atoms. Unless stated otherwise
specifically in the specification, an alkylcarbonyl group is
optionally substituted.
[0078] "Alkoxy" refers to a group of the formula --OR where R is an
alkyl group as defined above containing one to twelve carbon atoms.
A "haloalkoxy" is an alkoxy group as defined above, wherein at
least one carbon-hydrogen bond is replaced with a carbon-halogen
bond. Unless stated otherwise specifically in the specification, an
alkoxy or haloalkoxy group may be optionally substituted.
[0079] "Alkoxyalkyl" refers to a group of the formula
--R.sup.bOR.sup.a where R.sup.a is an alkyl group as defined above
containing one to twelve carbon atoms and R.sub.b is an alkylene
group as defined above. A "haloalkoxyalkyl" group is an
alkoxyalkyl, wherein at least one carbon-hydrogen bond is replaced
with a carbon-halogen bond. Unless stated otherwise specifically in
the specification, an alkoxyalkyl or haloalkoxyalkyl group may be
optionally substituted.
[0080] "Alkoxycarbonyl" refers to a group of the formula
--(C.dbd.O)OR.sup.a where R.sup.a is an alkyl group as defined
above containing one to twelve carbon atoms. Unless stated
otherwise specifically in the specification, an alkoxycarbonyl
group is optionally substituted.
[0081] "Alkoxycarbonylalkyl" refers to a group of the formula
--R.sup.b(C.dbd.O)OR.sup.a where R.sup.a is an alkyl group as
defined above and R.sup.b is an alkylene as defined above. Unless
stated otherwise specifically in the specification, an
alkoxycarbonylalkyl group is optionally substituted.
[0082] "Alkylthio" refers to the group "alkyl-S--".
[0083] "Aminocarbonyl" refers to a group of the formula
--(C.dbd.O)N(R.sup.a).sub.2, where each R.sup.a is independently H
or an alkyl group as defined above. Unless stated otherwise
specifically in the specification, an aminocarbonyl group is
optionally substituted.
[0084] "Aminoalkyl" refers to the group "-alkyl-NR.sup.yR.sup.z,"
wherein R.sup.y and R.sup.z are independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or
heteroaryl; each of which may be optionally substituted, as defined
herein.
[0085] "Alkylsulfonyl" refers to a group of the formula
--S(O).sub.2R.sup.a where R.sup.a is an alkyl group as defined
above. Unless stated otherwise specifically in the specification,
an alkylsulfonyl group may be optionally substituted.
[0086] "Alkylsulfonylalkyl" refers to a group of the formula
--R.sup.bS(O).sub.2R.sup.a where R.sup.a is an alkyl group as
defined above and R is an alkylene group as defined above. Unless
stated otherwise specifically in the specification, an
alkylsulfonylalkyl group may be optionally substituted.
[0087] "Acyl" refers to a group --C(O)R.sup.y, wherein R.sup.y is
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,
heteroalkyl, or heteroaryl; each of which may be optionally
substituted, as defined herein. Examples of acyl include formyl,
acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and
benzoyl.
[0088] "Amido" refers to both a "C-amido" group which refers to the
group --C(O)NR.sup.yR.sup.z and an "N-amido" group which refers to
the group --NR.sup.yC(O)R.sup.z, wherein R.sup.y and R.sup.z are
independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may
be optionally substituted, as defined herein, or R.sup.y and
R.sup.z are taken together to form a cycloalkyl or heterocyclyl;
each of which may be optionally substituted, as defined herein.
[0089] "Amidino" refers to --C(NR.sup.y)(NR.sup.z.sub.2), wherein
R.sup.y and R.sup.z are independently hydrogen, alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or
heteroaryl; each of which may be optionally substituted, as defined
herein.
[0090] "Aryl" refers to a hydrocarbon ring system group comprising
hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For
purposes of this disclosure, the aryl group may be a monocyclic,
bicyclic, tricyclic or tetracyclic ring system, which may include
fused or bridged ring systems. Aryl groups include, but are not
limited to, aryl groups derived from aceanthrylene, acenaphthylene,
acephenanthrylene, anthracene, azulene, benzene, chrysene,
fluoranthene, fluorene, as-indacene, s-indacene, indane, indene,
naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and
triphenylene. Unless stated otherwise specifically in the
specification, the term "aryl" or the prefix "ar-" (such as in
"aralkyl") is meant to include aryl groups that are optionally
substituted. "Arylalkyl" or "Aralkyl" refers to the group
"aryl-alkyl-".
[0091] "Carboxyl ester" or "ester" refer to both --OC(O)R.sup.x and
--C(O)OR.sup.x, wherein R.sup.x is alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of
which may be optionally substituted, as defined herein.
[0092] "Cyanoalkyl" is an alkyl group as defined above, wherein at
least one carbon-hydrogen bond is replaced with a carbon-cyano
bond. Unless stated otherwise specifically in the specification,
cyanoalkyl group may be optionally substituted.
[0093] "Cycloalkyl" or "carbocyclic ring" refers to a stable
non-aromatic monocyclic or polycyclic hydrocarbon group consisting
solely of carbon and hydrogen atoms, which may include fused or
bridged ring systems, having from three to fifteen carbon atoms,
preferably having from three to ten carbon atoms, and which is
saturated or unsaturated and attached to the rest of the molecule
by a single bond. Monocyclic groups include, for example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. Polycyclic groups include, for example, adamantyl,
norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the
like. Unless otherwise stated specifically in the specification, a
cycloalkyl group may be optionally substituted.
[0094] "Cycloalkyloxy" is a cycloalkyl group connected to the
remainder of the molecule via an oxygen atom linker. Unless
otherwise stated specifically in the specification, a cycloalkyloxy
group may be optionally substituted.
[0095] "Cycloalkylalkyl" refers to a group of the formula
--R.sub.bR.sub.d where R.sub.b is an alkylene chain as defined
above and R.sub.d is a cycloalkyl group as defined above. Unless
stated otherwise specifically in the specification, a
cycloalkylalkyl group may be optionally substituted.
[0096] "Cycloalkylalkyloxy" refers to a group of the formula
--OR.sub.bR.sub.d where R.sub.b is an alkylene chain as defined
above and R.sub.d is a cycloalkyl group as defined above. Unless
stated otherwise specifically in the specification, a
cycloalkylalkyloxy group may be optionally substituted.
[0097] "Fused" refers to any ring structure described herein which
is fused to an existing ring structure in the compounds of the
disclosure. When the fused ring is a heterocyclyl ring or a
heteroaryl ring, any carbon atom on the existing ring structure
which becomes part of the fused heterocyclyl ring or the fused
heteroaryl ring may be replaced with a nitrogen atom.
[0098] "Halo" or "halogen" refers to bromo, chloro, fluoro or
iodo.
[0099] "Haloalkyl" refers to an alkyl group, as defined above, that
is substituted by one or more halo groups, as defined above, e.g.,
trifluoromethyl, difluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,
1,2-dibromoethyl, and the like. Unless stated otherwise
specifically in the specification, a haloalkyl group may be
optionally substituted.
[0100] "Heteroalkyl" refers to an alkyl group in which one or more
of the carbon atoms (and any associated hydrogen atoms) are each
independently replaced with the same or different heteroatomic
group, provided the point of attachment to the remainder of the
molecule is through a carbon atom. The term "heteroalkyl" includes
unbranched or branched saturated chain having carbon and
heteroatoms. By way of example, 1, 2, or 3 carbon atoms may be
independently replaced with the same or different heteroatomic
group. Heteroatomic groups include, but are not limited to,
--NR.sup.y--, --O--, --S--, --S(O)--, --S(O).sub.2--, and the like,
wherein R.sup.y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may
be optionally substituted, as defined herein. Examples of
heteroalkyl groups include ethers (e.g., --CH.sub.2OCH.sub.3,
--CH(CH.sub.3)OCH.sub.3, --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3, etc.), thioethers
(e.g., --CH.sub.2SCH.sub.3, --CH(CH.sub.3)SCH.sub.3,
--CH.sub.2CH.sub.2SCH.sub.3,
--CH.sub.2CH.sub.2SCH.sub.2CH.sub.2SCH.sub.3, etc.), sulfones
(e.g., --CH.sub.2S(O).sub.2CH.sub.3,
--CH(CH.sub.3)S(O).sub.2CH.sub.3,
--CH.sub.2CH.sub.2S(O).sub.2CH.sub.3,
--CH.sub.2CH.sub.2S(O).sub.2CH.sub.2CH.sub.2OCH.sub.3, etc.), and
amines (e.g., --CH.sub.2NR.sup.yCH.sub.3,
--CH(CH.sub.3)NR.sup.yCH.sub.3, --CH.sub.2CH.sub.2NR.sup.yCH.sub.3,
--CH.sub.2CH.sub.2NR.sup.yCH.sub.2CH.sub.2NR.sup.yCH.sub.3, etc.,
where R.sup.y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may
be optionally substituted, as defined herein). As used herein,
heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or
1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or
1 heteroatom.
[0101] "Hydroxylalkyl" refers an alkyl group as defined above
containing one to twelve carbon atoms which has been substituted by
one or more hydroxyl groups. Unless stated otherwise specifically
in the specification, hydroxylalkyl group may be optionally
substituted.
[0102] "Heterocyclyl" or "heterocyclic ring" refers to a stable 3-
to 18-membered non-aromatic ring group which consists of two to
twelve carbon atoms and from one to six heteroatoms selected from
the group consisting of nitrogen, oxygen and sulfur. Unless stated
otherwise specifically in the specification, the heterocyclyl group
may be a monocyclic, bicyclic, tricyclic or tetracyclic ring
system, which may include fused or bridged ring systems; and the
nitrogen, carbon or sulfur atoms in the heterocyclyl group may be
optionally oxidized; the nitrogen atom may be optionally
quaternized; and the heterocyclyl group may be partially or fully
saturated. Examples of such heterocyclyl groups include, but are
not limited to, dioxolanyl, thienyl[1,3]dithianyl,
decahydroisoquinolyl, imidazolinyl, imidazolidinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,
thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in
the specification. Unless stated otherwise specifically in the
specification, a heterocyclyl group may be optionally
substituted.
[0103] "C-heterocyclyl" refers to a heterocyclyl group as defined
above where the point of attachment of the heterocyclyl group to
the rest of the molecule is through a carbon atom in the
heterocyclyl group. Unless stated otherwise specifically in the
specification, a C-heterocyclyl group may be optionally
substituted.
[0104] "Heterocyclylcarbonyl" refers to a group of the formula
--C(.dbd.O)R.sub.e where R.sub.e is a heterocyclyl group as defined
above. Unless stated otherwise specifically in the specification, a
heterocyclycarbonyl group may be optionally substituted.
[0105] "Heterocyclylalkyl" refers to a group of the formula
--R.sub.bR.sub.e where R.sub.b is an alkylene chain as defined
above and R.sub.e is a heterocyclyl group as defined above. Unless
stated otherwise specifically in the specification, a
heterocyclylalkyl group may be optionally substituted.
[0106] "Heteroaryl" refers to a 5- to 14-membered ring system group
comprising hydrogen atoms, one to thirteen carbon atoms, one to six
heteroatoms selected from the group consisting of nitrogen, oxygen
and sulfur, and at least one aromatic ring. For purposes of this
disclosure, the heteroaryl group may be a monocyclic, bicyclic,
tricyclic or tetracyclic ring system, which may include fused or
bridged ring systems; and the nitrogen, carbon or sulfur atoms in
the heteroaryl group may be optionally oxidized; the nitrogen atom
may be optionally quaternized. Examples include, but are not
limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl,
benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl,
benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,
benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),
benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,
cinnolinyl, dibenzofuranyl, dibenzothiophenvl, furanyl, furanonyl,
isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,
isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,
isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,
1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl,
phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,
pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl,
isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl).
Unless stated otherwise specifically in the specification, a
heteroaryl group may be optionally substituted.
[0107] "Heteroarylalkyl" refers to a group of the formula
--R.sub.bR.sub.e where R.sub.b is an alkylene chain as defined
above and R.sub.e is a heteroaryl group as defined above. Unless
stated otherwise specifically in the specification, a
heteroarylalkyl group may be optionally substituted.
[0108] "Imino" refers=NH substituent or to a group
--C(NR.sup.y)R.sup.z, wherein R.sup.y and R.sup.z are ach
independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may
be optionally substituted, as defined herein. "Imido" refers to a
group --C(O)NR.sup.yC(O)R.sup.z, wherein R.sup.y and R.sup.z are
each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may
be optionally substituted, as defined herein.
[0109] "Oxime" refers to the group --CR.sup.y(.dbd.NOH) wherein
R.sup.y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may
be optionally substituted, as defined herein.
[0110] "Sulfonyl" refers to the group --S(O).sub.2R.sup.y, where
R.sup.y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may
be optionally substituted, as defined herein. Examples of sulfonyl
are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and
toluenesulfonyl.
[0111] The term "substituted" used herein means any of the above
groups (e.g., alkyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl,
haloalkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
aminylcarbonyl, aminylalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cyanoalkyl, hydroxylalkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, haloalkyl,
heterocyclyl, C-heterocyclyl, heterocyclylcarbonyl,
heterocyclylalkyl, heteroaryl and/or heteroarylalkyl) wherein at
least one hydrogen atom is replaced by a bond to a non-hydrogen
atoms such as, but not limited to: a halogen atom such as F, Cl,
Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy
groups, and ester groups; a sulfur atom in groups such as thiol
groups, thioalkyl groups, sulfone groups, sulfonyl groups, and
sulfoxide groups; a nitrogen atom in groups such as amines, amides,
alkylamines, dialkylamines, arylamines, alkylarylamines,
diarylamines, N-oxides, imides, and enamines; a silicon atom in
groups such as trialkylsilyl groups, dialkylarylsilyl groups,
alkyldiarylsilyl groups, and triarylsilyl groups; and other
heteroatoms in various other groups.
[0112] "Substituted" also means any of the above groups in which
one or more hydrogen atoms are replaced by a higher-order bond
(e.g., a double- or triple-bond) to a heteroatom such as oxygen in
oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups
such as imines, oximes, hydrazones, and nitriles. For example,
"substituted" includes any of the above groups in which one or more
hydrogen atoms are replaced with --NR.sub.gR.sub.h,
--NR.sub.gC(.dbd.O)R.sub.h, --NR.sub.gC(.dbd.O)NR.sub.gR.sub.h,
--NR.sub.gC(.dbd.O)OR.sub.h, --NR.sub.gSO.sub.2R.sub.b,
--OC(.dbd.O)NR.sub.gR.sub.h, --OR.sub.g, --SR.sub.g, --SOR.sub.g,
--SO.sub.2R.sub.g, --OSO.sub.2R.sub.g, --SO.sub.2OR.sub.g,
.dbd.NSO.sub.2R.sub.g, and --SO.sub.2NR.sub.gR.sub.h. Substituted
also means any of the above groups in which one or more hydrogen
atoms are replaced with --C(.dbd.O)R.sub.g, --C(.dbd.O)OR.sub.g,
--C(.dbd.O)NR.sub.gR.sub.h, --CH.sub.2SO.sub.2R.sub.g,
--CH.sub.2SO.sub.2NR.sub.RR.sub.h. In the foregoing, R.sub.g and
R.sub.h are the same or different and independently hydrogen,
alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,
heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
"Substituted" further means any of the above groups in which one or
more hydrogen atoms are replaced by a bond to an amino,
alkylaminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo,
alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,
heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl
group. In addition, each of the foregoing substituents may also be
optionally substituted with one or more of the above
substituents.
[0113] Polymers or similar indefinite structures arrived at by
defining substituents with further substituents appended ad
infinitum (e.g., a substituted aryl having a substituted alkyl
which is itself substituted with a substituted aryl group, which is
further substituted by a substituted heteroalkyl group, etc.) are
not intended for inclusion herein. Unless otherwise noted, the
maximum number of serial substitutions in compounds described
herein is three. For example, serial substitutions of substituted
aryl groups with two other substituted aryl groups are limited to
((substituted aryl)substituted aryl) substituted aryl. Similarly,
the above definitions are not intended to include impermissible
substitution patterns (e.g., methyl substituted with 5 fluorines or
heteroaryl groups having two adjacent oxygen ring atoms). Such
impermissible substitution patterns are well known to the skilled
artisan. When used to modify a chemical group, the term
"substituted" may describe other chemical groups defined herein.
Unless specified otherwise, where a group is described as
optionally substituted, any substituents of the group are
themselves unsubstituted. For example, in some embodiments, the
term "substituted alkyl" refers to an alkyl group having one or
more substituents including hydroxy, halo, alkoxy, acyl, oxo,
amino, cycloalkyl, heterocyclyl, aryl and heteroaryl. In other
embodiments, the one or more substituents may be further
substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy,
cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is
substituted. In other embodiments, the substituents may be further
substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy,
cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is
unsubstituted.
[0114] "Prodrug" is meant to indicate a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound of the disclosure. Thus, the term
"prodrug" refers to a metabolic precursor of a compound of the
disclosure that is pharmaceutically acceptable. A prodrug may be
inactive when administered to a subject in need thereof, but is
converted in vivo to an active compound of the disclosure. Prodrugs
are typically rapidly transformed in vivo to yield the parent
compound of the disclosure, for example, by hydrolysis in blood.
The prodrug compound often offers advantages of solubility, tissue
compatibility or delayed release in a mammalian organism (see,
Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,
Amsterdam)). A discussion of prodrugs is provided in Higuchi, T.,
et al., A.C.S. Symposium Series, Vol. 14, and in Bioreversible
Carriers in Drug Design, Ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987.
[0115] The term "prodrug" is also meant to include any covalently
bonded carriers, which release the active compound of the
disclosure in vivo when such prodrug is administered to a mammalian
subject. Prodrugs of a compound of the disclosure may be prepared
by modifying functional groups present in the compound of the
disclosure in such a way that the modifications are cleaved, either
in routine manipulation or in vivo, to the parent compound of the
disclosure. Prodrugs include compounds of the disclosure wherein a
hydroxy, amino or mercapto group is bonded to any group that, when
the prodrug of the compound of the disclosure is administered to a
mammalian subject, cleaves to form a free hydroxy, free amino or
free mercapto group, respectively. Examples of prodrugs include,
but are not limited to, acetate, formate and benzoate derivatives
of alcohol or amide derivatives of amine functional groups in the
compounds of the disclosure and the like.
[0116] This disclosure is also meant to encompass all
pharmaceutically acceptable compounds of formula (I) being
isotopically-labelled by having one or more atoms replaced by an
atom having a different atomic mass or mass number. Examples of
isotopes that can be incorporated into the disclosed compounds
include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, chlorine, and iodine, such as .sup.2H,
.sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F, .sup.36Cl, .sup.123I, and .sup.125I, respectively. These
radiolabelled compounds could be useful to help determine or
measure the effectiveness of the compounds, by characterizing, for
example, the site or mode of action, or binding affinity to
pharmacologically important site of action. Certain
isotopically-labelled compounds of structure (I), for example,
those incorporating a radioactive isotope, are useful in drug
and/or substrate tissue distribution studies. The radioactive
isotopes tritium. i.e. .sup.3H, carbon-13, i.e. .sup.13C and
carbon-14, i.e. .sup.14C, are particularly useful for this purpose
in view of their ease of incorporation and ready means of
detection.
[0117] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0118] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled compounds of structure (I)
can generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the Preparations and Examples as set out below using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
[0119] This disclosure is also meant to encompass the in vivo
metabolic products of the disclosed compounds. Such products may
result from, for example, the oxidation, reduction, hydrolysis,
amidation, esterification, and the like of the administered
compound, primarily due to enzymatic processes. Accordingly, the
disclosure includes compounds produced by a process comprising
administering a compound of this disclosure to a mammal for a
period of time sufficient to yield a metabolic product thereof.
Such products are typically identified by administering a
radiolabelled compound of the disclosure in a detectable dose to an
animal, such as rat, mouse, guinea pig, monkey, or to human,
allowing sufficient time for metabolism to occur, and isolating its
conversion products from the urine, blood or other biological
samples.
[0120] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0121] "Optional" or "optionally" means that the subsequently
described event of circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl group may or may not be
substituted and that the description includes both substituted aryl
groups and aryl groups having no substitution.
[0122] "Pharmaceutically acceptable carrier, diluent or excipient"
includes without limitation any adjuvant, carrier, excipient,
glidant, sweetening agent, diluent, preservative, dye/colorant,
flavor enhancer, surfactant, wetting agent, dispersing agent,
suspending agent, stabilizer, isotonic agent, solvent, or
emulsifier which has been approved by the United States Food and
Drug Administration as being acceptable for use in humans or
domestic animals.
[0123] "Pharmaceutically acceptable salt" includes both acid and
base addition salts.
[0124] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but are not limited to, hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as, but not limited to, acetic acid,
2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid, and the like.
[0125] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic base or an organic base to the free acid. Salts derived
from inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc,
copper, manganese, aluminum salts and the like. Preferred inorganic
salts are the ammonium, sodium, potassium, calcium, and magnesium
salts. Salts derived from organic bases include, but are not
limited to, salts of primary, secondary, and tertiary amines, such
as alkyl amines (i.e., NH.sub.2(alkyl)), dialkyl amines (i.e.,
HN(alkyl).sub.2), trialkyl amines (i.e., N(alkyl).sub.3),
substituted alkyl amines (i.e., NH.sub.2(substituted alkyl)),
di(substituted alkyl) amines (i.e., HN(substituted alkyl).sub.2),
tri(substituted alkyl) amines (i.e., N(substituted alkyl).sub.3),
alkenyl amines (i.e., NH.sub.2(alkenyl)), dialkenyl amines (i.e.,
HN(alkenyl).sub.2), trialkenyl amines (i.e., N(alkenyl).sub.3),
substituted alkenyl amines (i.e., NH.sub.2 (substituted alkenyl)),
di(substituted alkenyl) amines (i.e., HN(substituted
alkenyl).sub.2), tri(substituted alkenyl) amines (i.e.,
N(substituted alkenyl).sub.3, mono-, di- or tri-cycloalkyl amines
(i.e., NH.sub.2(cycloalkyl), HN(cycloalkyl).sub.2,
N(cycloalkyl).sub.3), mono-, di- or tri-arylamines (i.e.,
NH.sub.2(aryl), HN(aryl).sub.2, N(aryl).sub.3) or mixed amines,
etc., substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, benethamine, benzathine,
ethylenediamine, glucosamine, methylglucamine, theobromine,
triethanolamine, tromethamine, purines, piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particularly
preferred organic bases are isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexylamine, choline and
caffeine.
[0126] Often crystallizations produce a solvate of the compound of
the disclosure. As used herein, the term "solvate" refers to an
aggregate that comprises one or more molecules of a compound of the
disclosure with one or more molecules of solvent. The solvent may
be water, in which case the solvate may be a hydrate.
Alternatively, the solvent may be an organic solvent. Thus, the
compounds of the present disclosure may exist as a hydrate,
including a monohydrate, dihydrate, hemihydrate, sesquihydrate,
trihydrate, tetrahydrate and the like, as well as the corresponding
solvated forms. The compound of the disclosure may be true
solvates, while in other cases, the compound of the disclosure may
merely retain adventitious water or be a mixture of water plus some
adventitious solvent.
[0127] A "pharmaceutical composition" refers to a formulation of a
compound of the disclosure and a medium generally accepted in the
art for the delivery of the biologically active compound to
mammals, e.g., humans. Such a medium includes all pharmaceutically
acceptable carriers, diluents or excipients therefor.
[0128] The compounds of this disclosure, or their pharmaceutically
acceptable salts or tautomers may contain one or more asymmetric
centers 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)- or, as (D)- or (L)- for
amino acids. The present disclosure is meant to include all such
possible isomers, as well as their racemic and optically pure
forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and
(L)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques, for example,
chromatography and fractional crystallization. Conventional
techniques for the preparation/isolation of individual enantiomers
include chiral synthesis from a suitable optically pure precursor
or resolution of the racemate (or the racemate of a salt or
derivative) using, for example, chiral high pressure liquid
chromatography (HPLC). When the compounds described herein contain
olefinic double bonds or other centres of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are also intended to be included.
[0129] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present disclosure contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposcable mirror images
of one another.
[0130] A "tautomer" refers to a proton shift from one atom of a
molecule to another atom of the same molecule, for example, the
conversion of a ketone to an enol via a proton shift. Tautomers are
in equilibrium with one another. For example, amide containing
compounds may exist in equilibrium with imidic acid tautomers.
Regardless of which tautomer is shown and regardless of the nature
of the equilibrium among tautomers, the compounds are understood by
one of ordinary skill in the art to comprise both amide and imidic
acid tautomers. Thus, the amide containing compounds are understood
to include their imidic acid tautomers. Likewise, the imidic acid
containing compounds are understood to include their amide
tautomers. The present disclosure includes tautomers of any said
compounds.
2. Compounds
[0131] In one embodiment, provided is a compound of formula
(I):
##STR00008##
[0132] or a pharmaceutically acceptable salt, stereoisomer, or a
mixture of stereoisomers, tautomer or prodrug thereof, wherein:
[0133] Z is N or CH;
[0134] R.sup.1 is halo, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,
cycloalkylalkyloxy, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkyloxycarbonyl, aminocarbonyl, or heterocyclylcarbonyl, wherein
each is optionally substituted; and R.sup.5 is H; or
[0135] R.sup.1 and R.sup.5 together with the atom to which they are
attached form a 5-membered ring having the structure:
##STR00009##
[0136] Y is N or CR.sup.6;
[0137] R.sup.6 is H, halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
heteroalkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxyalkyl, --S(O).sub.w(C.sub.1-C.sub.6 alkyl), cycloalkyl,
heterocyclyl, heteroaryl, aryl, acyl, or amido, wherein each is
optionally substituted;
[0138] R.sup.10 is H, halo, cyano. C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, or cycloalkyl;
[0139] R.sup.2 is C.sub.1-C.sub.6 alkyl, cycloalkyl,
cycloalkylalkyl, C.sub.1-C.sub.6 alkoxy, cycloalkyloxy,
cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkoxy, amino,
C.sub.1-C.sub.6 alkylamino, cycloalkylamino, cycloalkylalkylamino,
heterocyclylamino, or heterocyclylalkylamino, wherein each is
optionally substituted;
[0140] R.sup.3a and R.sup.3b are each independently H, halo, cyano,
amino, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6
heteroalkyl, C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6
aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6
alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, heteroaryl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, aminocarbonyl,
heterocyclylcarbonyl, or -L.sup.2-R.sup.8, wherein each is
optionally substituted;
[0141] or R.sup.4 and either R.sup.3a or R.sup.3b when attached to
an adjacent carbon, together with the atoms bound thereto join to
form a heterocyclyl or heteroaryl, wherein each heterocyclyl or
heteroaryl is optionally substituted;
[0142] or R.sup.3a and R.sup.3b when attached to an adjacent
carbon, together with the atoms bound thereto join to form a
cycloalkyl, heterocyclyl, or heteroaryl, wherein each cycloalkyl,
heterocyclyl, or heteroaryl is optionally substituted;
[0143] R.sup.4 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 haloalkoxyalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, heteroarylalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6
alkoxycarbonylalkyl, aminocarbonyl, heterocyclylcarbonyl, or
-L.sup.1-R.sup.7, wherein each is optionally substituted;
[0144] L.sup.1 is --S(O).sub.p--, --S(O).sub.pN(R.sup.9)--,
--(CH.sub.2).sub.m--, --C(O)--, --C(O)O--, or
--C(O)N(R.sup.9)--:
[0145] each L.sup.2 is independently --O--, --S(O).sub.m--,
--(CH.sub.2).sub.m--, --C(O)--, --C(O)O--, --OC(O)--,
--C(O)N(R.sup.9)--, --N(R.sup.9)C(O)--, --N(R.sup.9)C(O)--,
--OC(O)N(R.sup.9)--, --N(R.sup.9)C(O)N(R.sup.9)--,
--S(O).sub.pN(R.sup.9)--, --N(R.sup.9)S(O).sub.pN(R.sup.9)--, or
--N(R.sup.9)S(O).sub.9--;
[0146] R.sup.7 is C.sub.1-C.sub.6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
wherein each is optionally substituted;
[0147] each R.sup.8 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, wherein each is optionally
substituted;
[0148] each R.sup.9 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl:
[0149] each p is independently 1 or 2;
[0150] each w is independently 0, 1 or 2; and
[0151] each m is independently 0, 1, 2 or 3;
[0152] provided that:
a) when R.sup.5 is H, then Z is N, and R.sup.2 is C-heterocyclyl,
which is optionally substituted; and b) when R.sup.1 and R.sup.5
together with the atom to which they are attached form the
5-membered ring, then either:
[0153] i) R.sup.2 is C.sub.1-C.sub.6 alkoxy, cycloalkyloxy,
cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino,
C.sub.1-C.sub.6 alkylamino, cycloalkylamino, cycloalkylalkylamino,
heterocyclylamino, or heterocyclylalkylamino; Z is N; R.sup.5 is H;
Y is N or CR.sup.6; and R.sup.6 is halo, C.sub.1-C.sub.6 haloalkyl
or cycloalkyl; or
[0154] ii) R.sup.2 is C.sub.1-C.sub.6 alkyl, cycloalkyl or
cycloalkylalkyl, wherein each is optionally substituted.
[0155] In one embodiment, provided is a compound of formula
(II):
##STR00010##
[0156] or a pharmaceutically acceptable salt, prodrug,
stereoisomer, or a mixture of stereoisomers thereof, wherein:
[0157] R.sup.41 is halo, cyano, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, cycloalkyl,
cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, or
--C(O)R.sup.45;
[0158] R.sup.42 is: [0159] a fused bicyclic ring system having a
heterocyclyl or cycloalkyl fused to a heteroaryl, wherein the ring
system is attached to the remainder of the molecule via the
heterocyclyl or cycloalkyl and the ring system is independently
optionally substituted with one or more halo, cyano, C.sub.1-6
alkyl. C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, amino, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --C.sub.1-6
alkylene-C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C.sub.1-6
alkylene-SO.sub.2NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46,
--OC(O)R.sup.46, --C(O).sub.2R.sup.46, --C.sub.1-6
alkylene-C(O)R.sup.46, --C.sub.1-6 alkylene-OC(O)R.sup.46,
--C.sub.1-6 alkylene-C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, --C.sub.1-6
alkylene-O--C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0160] C.sub.1-6 alkoxyalkyl substituted with one
or more substituents independently selected from halo, amino,
cyano, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6alkenyl, C.sub.2-6
alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl; [0161] C.sub.1-6 haloalkyl
substituted with one or more substituents independently selected
from amino, cyano, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C(O)N.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0162] C.sub.1-6 cyanoalkyl optionally substituted
with one or more substituents independently selected from halo,
amino, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, --S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0163] C.sub.3-10 cycloalkyl substituted with one
or more substituents independently selected from amino, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, cyanoalkyl, --S(C.sub.1-6 alkyl),
--S(O)(C.sub.1-6 alkyl), --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl substituted with one
or more halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, wherein the
heterocyclyl, heteroaryl, or heteroarylalkyl are optionally
substituted with one or more substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo; or [0164]
--X--C(R.sup.48)(R.sup.49)(R), wherein: [0165] X is C.sub.1-6
alkylene optionally substituted with one or more halo; [0166]
R.sup.48 and R.sup.49, together with the carbon atom to which they
are attached, form an optionally substituted C.sub.3-10 cycloalkyl;
and [0167] R.sup.50 is cyanoalkyl, C.sub.1-6 alkoxyalkyl, C.sub.2-6
alkenyl, C.sub.2-6alkynyl, --S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6
haloalkoxy, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl;
[0168] R.sup.43a and R.sup.43b are each independently H, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, amido, or --C(O)R.sup.45;
[0169] R.sup.44 is cycloalkyl, C.sub.1-6 heterocyclyl,
--N(R.sub.51).sub.2, --OR.sup.51, or --SR.sub.51;
[0170] each R.sup.45 is independently C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --N(R.sup.52).sub.2, or heterocyclyl, wherein each
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or heterocyclyl is optionally
substituted;
[0171] each R.sup.46 and R.sup.47 is independently H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl, wherein each
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl is optionally
substituted:
[0172] each R.sup.51 is independently H, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl. C.sub.1-6
alkoxyalkyl. C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl,
--C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl),
C.sub.1-6cycloalkyl optionally substituted with one or more
C.sub.1-6 alkyl, C.sub.3-6 cycloalkylalkyl optionally substituted
with one or more C.sub.1-6 alkyl, heterocyclyl optionally
substituted with one or more R.sup.53, or heterocyclylalkyl
optionally substituted with one or more R.sup.53; or
[0173] two R.sup.51, together with the nitrogen to which they are
attached, form a three- to six-membered heterocyclyl optionally
substituted with one or more R.sup.53;
[0174] each R.sup.52 is independently H or optionally substituted
C.sub.1-6 alkyl;
[0175] each R.sup.53 is independently C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halo, oxo, C.sub.1-6 alkoxy, amino,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 alkoxyalkyl, cyano,
heterocyclyl, heterocyclylalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkylalkyl, C.sub.3-6 cycloalkylsulfonyl, --C(O)R.sup.54, or
--C.sub.1-6 alkylene-C(O)R.sup.54;
[0176] each R.sup.54 is independently C.sub.1-6 alkyl, C.sub.1-6
alkoxy, amino optionally substituted with halo, C.sub.1-6haloalkyl,
C.sub.1-6 hydroxyalkyl, hydroxy, C.sub.1-6 alkoxyalkyl, C.sub.1-6
cyanoalkyl, --C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl),
C.sub.1-6 aminoalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; and
[0177] provided that when R.sup.44 is cycloalkyl,
--N(R.sup.51).sub.2, or --OR.sup.51, then R.sup.42 is not an
unsubstituted C.sub.1-6 cyanoalkyl.
[0178] In some embodiments, are provided compounds having activity
as LRRK2 inhibitors, the compounds are of formula (A-I):
##STR00011##
or a pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, tautomer, or prodrug thereof, wherein: [0179] Cy is
optionally substituted cycloalkyl or optionally substituted
C-heterocyclyl; [0180] R.sup.11 is halo, cyano, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cycloalkyl, cycloalkyloxy,
cycloalkylalkyl, cycloalkylalkyloxy, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkyloxycarbonyl, aminocarbonyl or
heterocyclylcarbonyl; [0181] R.sup.12 is H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 haloalkoxyalkyl
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,
heteroarylylalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkoxycarbonylalkyl, aminocarbonyl
or heterocyclylcarbonyl, wherein each C.sub.1-C.sub.6 alkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, or heteroarylalkyl is optionally substituted; and
[0182] R.sup.13a and R.sup.13b are each independently H, halo,
cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, aminocarbonyl or heterocyclylcarbonyl, wherein each
C.sub.1-C.sub.6 alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl is optionally
substituted [0183] or R.sup.12 and either R.sup.13a or R.sup.13b
when attached to an adjacent carbon, together with the atoms bound
thereto join to form a heterocyclyl or heteroaryl which is
optionally substituted.
[0184] In some embodiments, the compounds are of formula (A-I) or a
pharmaceutically acceptable salt, stereoisomer, mixture of
stereoisomers, tautomer, or prodrug thereof, wherein: [0185] Cy is
optionally substituted cycloalkyl or optionally substituted
C-heterocyclyl; [0186] R.sup.11 is halo, cyano, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cycloalkyl, cycloalkyloxy,
cycloalkylalkyl, cycloalkylalkyloxy, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkyloxycarbonyl, aminocarbonyl or
heterocyclylcarbonyl; [0187] R.sup.12 is H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 haloalkoxyalkyl
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,
heteroarylylalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkoxycarbonylalkyl, aminocarbonyl
or heterocyclylcarbonyl, wherein each C.sub.1-C.sub.6 alkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, or heteroarylalkyl is optionally substituted; and
[0188] R.sup.13a and R.sup.13b are each independently H, halo,
cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, aminocarbonyl or heterocyclylcarbonyl, wherein each
C.sub.1-C.sub.6 alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl is optionally
substituted.
[0189] In some embodiments, the compounds are of compounds having
activity as LRRK2 inhibitors, the compounds of formula (A-I) or a
pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug
thereof, wherein: [0190] Cy is cycloalkyl or C-heterocyclyl; [0191]
R.sup.11 is halo, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkyloxy,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkyloxycarbonyl,
aminylcarbonyl or heterocyclylcarbonyl; [0192] R.sup.11 is H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6
haloalkoxyalkyl C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6
aminylalkyl, C.sub.1-C.sub.6 alkylsulfonyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,
heteroarylylalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkoxycarbonylalkyl, aminylcarbonyl
or heterocyclylcarbonyl; and [0193] R.sup.13a and R.sup.13b are
each independently H, halo, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminylalkyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, heteroaryl. C.sub.1-C.sub.6
alkylcarbonyl, C.sub.1-C.sub.6 alkoxycarbonyl, aminylcarbonyl or
heterocyclylcarbonyl.
[0194] In some embodiments, the compounds are of compounds having
activity as LRRK2 inhibitors, the compounds of formula (A-I) or a
pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug
thereof, wherein: [0195] R.sup.12 is: [0196] a fused bicyclic ring
system having a heterocyclyl or cycloalkyl fused to a heteroaryl,
wherein the ring system is attached to the remainder of the
molecule via the heterocyclyl or cycloalkyl and the ring system is
independently optionally substituted with one or more halo, cyano,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, amino,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6
cyanoalkyl, C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.16R.sup.17, --NR.sup.16C(O)R.sup.17, --C.sub.1-6
alkylene-C(O)NR.sup.16R.sup.17, --C.sub.1-6
alkylene-NR.sup.16C(O)R.sup.17, --SO.sub.2NR.sup.16R.sup.17,
--NR.sup.16SO.sub.2R.sup.17, --C.sub.1-6
alkylene-SO.sub.2NR.sup.16R.sup.17, --C.sub.1-6
alkylene-NR.sup.16SO.sub.2R.sup.17, --C(O)R.sup.16,
--OC(O)R.sup.16, --C(O).sub.2R.sup.16, --C.sub.1-6
alkylene-C(O)R.sup.16, --C.sub.1-6 alkylene-OC(O)R.sup.16,
--C.sub.1-6 alkylene-C(O).sub.2R.sup.16,
--O--C(O)NR.sup.16R.sup.17, --NR.sup.16C(O)OR.sup.17, --C.sub.1-6
alkylene-O--C(O)NR.sup.16R.sup.17, --C.sub.1-6
alkylene-NR.sup.16C(O)OR.sup.17, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl. [0197] C.sub.1-6 alkoxyalkyl substituted with one
or more substituents independently selected from halo, amino,
cyano, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.16R.sup.17, --NR.sup.16C(O)R.sup.17,
--SO.sub.2NR.sup.16R.sup.17, --NR.sup.16SO.sub.2R.sup.16,
--C(O)R.sup.16, --OC(O)R.sup.16, --C(O).sub.2R.sup.16,
--O--C(O)NR.sup.16R.sup.17, --NR.sup.16C(O)OR.sup.17, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl; [0198] C.sub.1-6 haloalkyl
substituted with one or more substituents independently selected
from amino, cyano, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.16R.sup.17,
--NR.sup.16C(O)R.sup.17, --SO.sub.2NR.sup.16R.sup.17,
--NR.sup.16SO.sub.2R.sup.17, --C(O)R.sup.16, --OC(O)R.sup.16,
--C(O).sub.2R.sup.16, --O--C(O)NR.sup.16R.sup.17,
--NR.sup.16C(O)OR.sup.17, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0199] C.sub.1-6 cyanoalkyl optionally substituted
with one or more substituents independently selected from halo,
amino, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl,
C.sub.2-6alkynyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.16R.sup.17, --NR.sup.16C(O)R.sup.17,
--SO.sub.2NR.sup.16R.sup.17, --NR.sup.16SO.sub.2R.sup.17,
--C(O)R.sup.16, --OC(O)R.sup.16, --C(O).sub.2R.sup.16,
--O--C(O)NR.sup.16R.sup.17, --NR.sup.16C(O)OR.sup.17, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl; [0200] C.sub.3-10 cycloalkyl
substituted with one or more substituents independently selected
from amino, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(C.sub.1-6 alkyl), --S(O)(C.sub.1-6 alkyl),
--S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl substituted with one
or more halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, wherein the
heterocyclyl, heteroaryl, or heteroarylalkyl are optionally
substituted with one or more substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo; or [0201]
--X.sup.2--C(R.sup.18)(R.sup.19)(R.sup.20), wherein: [0202] X.sup.2
is C.sub.1-6 alkylene optionally substituted with one or more halo;
[0203] R.sup.18 and R.sup.19, together with the carbon atom to
which they are attached, form an optionally substituted C.sub.3-10
cycloalkyl; and [0204] R.sup.20 is cyanoalkyl, C.sub.1-6
alkoxyalkyl, C.sub.2-6 alkenyl, C.sub.2-6alkynyl,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0205] provided that when Cy is cycloalkyl, then
R.sup.12 is not an unsubstituted C.sub.1-6 cyanoalkyl,
[0206] In some embodiments, the compound is of formula (A-Ia):
##STR00012##
[0207] In some embodiments, the compound is of formula (A-Ib):
##STR00013##
[0208] In some embodiments, Cy is optionally substituted with 1 to
3 substitutents. In some embodiments, the optional substituents
independently are halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6
alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6
aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6
alkylsulfonylalkyl, C.sub.1-C.sub.6 alkylsulfonylalkyl, cycloalkyl,
cycloalkylalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, aminocarbonyl or heterocyclylcarbonyl. In some
embodiments, Cy is optionally substituted with halo. In some
embodiments, Cy is optionally substituted with fluoro.
[0209] In some embodiments, Cy is optionally substituted
cycloalkyl. In some embodiments, Cy is substituted with halo. In
some embodiments, Cy is substituted with fluoro. In some
embodiments, Cy is cycloalkyl.
[0210] In some embodiments, the compound is of formula (A-Ic):
##STR00014##
[0211] or a pharmaceutically acceptable salt, stereoisomer, mixture
of stereoisomers, tautomer, or prodrug thereof, wherein:
[0212] R.sup.11 is chloro or --CF.sub.3;
[0213] R.sup.12 is H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6
alkoxyalkyl, C.sub.1-C.sub.6 haloalkoxyalkyl, C.sub.1-C.sub.6
cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl, C.sub.1-C.sub.6
alkylsulfonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkoxycarbonylalkyl, aminocarbonyl or
heterocyclylcarbonyl, wherein each C.sub.1-C.sub.6 alkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, or heteroarylalkyl is optionally substituted; and
[0214] one of R.sup.13a and R.sup.13b is H, and the other of
R.sup.13a and R.sup.13b is H, halo, or methyl.
[0215] In some embodiments, the compound is of formula (A-I'):
##STR00015##
wherein: [0216] x.sup.1 and y.sup.1 are each independently 1, 2 or
3: [0217] R.sup.14a and R.sup.14b are, at each occurrence,
independently either: [0218] (a) H, halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 alkylsulfonylalkyl, C.sub.1-C.sub.6
alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, C.sub.1-C.sub.6
alkylcarbonyl, C.sub.1-C.sub.6 alkoxycarbonyl, aminocarbonyl or
heterocyclylcarbonyl, or [0219] (b) R.sup.14a is H, halo, cyano or
C.sub.1-C.sub.6 alkyl, and R.sup.14b together with the carbon atom
to which it is bound is taken together with an adjacent R.sup.14b
and the carbon atom to which it is bound to form a carbon-carbon
double bond.
[0220] In some embodiments, the compound is of formula (A-I'a):
##STR00016##
[0221] In some embodiments, the compound is of formula (A-I'b):
##STR00017##
[0222] In some embodiments, Cy is saturated or unsaturated
cyclopropyl, cyclobutyl or cyclopentyl. In some embodiments,
cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted.
In some embodiments, Cy is cyclopropyl or cyclopent-1-en-1-yl.
[0223] In some embodiments, Cy is cyclopropyl, cyclopent-1-en-1-yl,
cyclopentyl, cyclobutyl, trans-2-fluorocyclopropan-1-yl, or
1-fluorocyclopropan-1-yl.
[0224] In some embodiments, Cy is C-heterocyclyl. In one embodiment
C-heterocyclyl is optionally substituted. In some embodiments, Cy
is 1-methyl-1H-pyrazol-4-yl.
[0225] In some embodiments, the compound is of formula (A-I''):
##STR00018##
wherein: [0226] A is O or NR.sup.15; x.sup.2 is 1, 2, 3, or 4;
y.sup.2 is 0, 1, 2, or 3; [0227] R.sup.14a and R.sup.14b are, at
each occurrence, independently either: [0228] (a) H, halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6
cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl, C.sub.1-C.sub.6
alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl, C.sub.1-C.sub.6
alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, C.sub.1-C.sub.6
alkylcarbonyl, C.sub.1-C.sub.6 alkyloxycarbonyl, aminocarbonyl or
heterocyclylcarbonyl, or [0229] (b) R.sup.14a is H, halo, cyano or
C.sub.1-C.sub.6 alkyl, and R.sup.14b together with the carbon atom
to which it is bound is taken together with an adjacent R.sup.4b
and the carbon atom to which it is bound to form a carbon-carbon
double bond; and [0230] R.sup.15 is H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, aminocarbonyl or
heterocyclylcarbonyl.
[0231] In some embodiments, the compound is of formula
(A-I''a):
##STR00019##
[0232] In some embodiments, the compound is of formula
(A-I''b):
##STR00020##
[0233] In some embodiments, R.sup.11 is halo, cyano,
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl. In some
embodiments, R.sup.11 is C.sub.1-C.sub.6 haloalkyl. In some
embodiments, C.sub.1-C.sub.6 haloalkyl is C.sub.1-C.sub.6
fluoroalkyl. In some embodiments, C.sub.1-C.sub.6 haloalkyl is
trifluoromethyl.
[0234] In some embodiments, R.sup.11 is cyano. In some, R.sup.11 is
halo. In some embodiments, halo is chloro.
[0235] In some embodiments, R.sup.12 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl,
cycloalkyl, heterocyclyl, heteroaryl wherein each cycloalkyl,
heterocyclyl, or heteroaryl is optionally substituted. In some
embodiments. R.sup.12 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6
alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl or C.sub.1-C.sub.6
aminylalkyl. In some embodiments, R.sup.2 is selected from methyl,
ethyl, isopropyl, 2-methylprop-1-yl, 1-methylethyl, sulfonylmethyl,
cyclopentyl, cyclopropyl, cyclobutyl, bicyclo[3.1.0]hexanyl,
oxetanyl, tetrahydropyranyl, piperidinyl, 2-oxopyrrolidinyl,
2-oxopiperidinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl,
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, or
1H,4H,5H,6H-cyclopenta[c]pyrazolyl.
[0236] In some embodiments, R.sup.12 is C.sub.1-C.sub.6 cyanoalkyl.
In some embodiments, R.sup.11 is 2-cyano-prop-2-yl.
[0237] In some embodiments, R.sup.12 is heteroaryl or
heteroarylalkyl. For example in some embodiments, R.sup.12 is
heteroarylalkyl, for example a 5-membered, nitrogen containing
heteroarylalkyl. In some embodiments, R.sup.12 is triazolylalkyl,
for example
2-methyl-2-(1-methyl-1H-1,2,4-triazol-3-yl)propanyl.
[0238] In some embodiments, R.sup.2 may be substituted with 1-3
groups independently selected from deuterium, halo, hydroxy, cyano,
C.sub.1-C.sub.6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
and acyl, aminoacyl. Each of the foregoing groups may also be
further substituted halo, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6
haloalkyl. In some embodiments, R.sup.12 may be substituted with
1-3 groups independently selected from fluoro, hydroxy,
morpholinylmethyl, methyl, ethyl, deuterium, pyrazolyl, pyrrolyl,
1,2,4-triazolyl, 1,2,3-triazolyl, 1-ethyl-1,2,4-triazolyl,
1-methylpyrazolyl, 1-methylimidazolyl,
1-difluoromethyl-1,2,4-triazolyl, 2-difluoromethyl-1,2,4-triazolyl,
2-methyloxadiazolyl, 1-methyl-1,2,4-triazolyl,
2-methyl-1,2,4-triazolyl, acyl, or oxetanyl.
[0239] In some embodiments, R.sup.12 is:
##STR00021## ##STR00022## ##STR00023## ##STR00024##
[0240] In some embodiments, one of R.sup.13a or R.sup.13b is H, and
the other of R.sup.13a or R.sup.13b is halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminoalkyl, cycloalkyl, cycloalkylalkyl,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkyloxycarbonyl,
aminocarbonyl or heterocyclylcarbonyl. In some embodiments, one of
R.sup.13a or R.sup.13b is halo, C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 cyanoalkyl. In some embodiments R.sup.13a is H and
R.sup.13b is halo, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
cyanoalkyl. In some embodiments, R.sup.13b is H and R.sup.13a is
halo, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 cyanoalkyl. In some
embodiments, C.sub.1-C.sub.6 alkyl is methyl. In some embodiments,
C.sub.1-C.sub.6 cyanoalkyl is 2-cyano-prop-2-yl.
[0241] In some embodiments, the compound is selected from a
compound in Table A-1. In various different embodiments, the
compound has one of the structures set forth in Table A-1 below.
The compounds in Table A-1 were each prepared and analyzed by mass
spectrometry, liquid chromatography, and/or .sup.1H NMR. General
methods by which the compounds may be prepared are provided below
and in the Examples. Compounds in the examples were named by using
either ChemBioDraw Ultra 13.0 or Chemaxon.
TABLE-US-00001 TABLE A-1 Exemplary Compounds ##STR00025## A-1
##STR00026## A-2 ##STR00027## A-3 ##STR00028## A-4 ##STR00029## A-5
##STR00030## A-6 ##STR00031## A-7 ##STR00032## A-8 ##STR00033## A-9
##STR00034## A-10 ##STR00035## A-11 ##STR00036## A-12 ##STR00037##
A-13 ##STR00038## A-14 ##STR00039## A-15 ##STR00040## A-16
##STR00041## A-17 ##STR00042## A-18 ##STR00043## A-19 ##STR00044##
A-20 ##STR00045## A-21 ##STR00046## A-22 ##STR00047## A-23
##STR00048## A-24 ##STR00049## A-25 ##STR00050## A-26 ##STR00051##
A-27 ##STR00052## A-28 ##STR00053## A-29 ##STR00054## A-30
##STR00055## A-31 ##STR00056## A-32 ##STR00057## A-33 ##STR00058##
A-34 ##STR00059## A-35 ##STR00060## A-36 ##STR00061## A-37
##STR00062## A-38 ##STR00063## A-39 ##STR00064## A-40 ##STR00065##
A-41 ##STR00066## A-42 ##STR00067## A-43 ##STR00068## A-44
##STR00069## A-45 ##STR00070## A-46 ##STR00071## A-47 ##STR00072##
A-48 ##STR00073## A-49 A-50 Second eluting isomer ##STR00074## A-51
##STR00075## A-52 ##STR00076## A-53 ##STR00077## A-54 ##STR00078##
A-55 ##STR00079## A-56 ##STR00080## A-57 ##STR00081## A-58
##STR00082## A-59 ##STR00083## A-60 ##STR00084## A-61 ##STR00085##
A-62 ##STR00086## A-63 ##STR00087## A-64 ##STR00088## A-65
##STR00089## A-66 ##STR00090## A-67 ##STR00091## A-68 ##STR00092##
A-69 ##STR00093## A-70 ##STR00094## A-71 ##STR00095## A-72
##STR00096## A-73 ##STR00097## A-74 ##STR00098## A-75 ##STR00099##
A-76 ##STR00100## A-77 ##STR00101## A-78 A-79 Second eluting isomer
##STR00102## A-80 ##STR00103## A-81 ##STR00104## A-82 A-83 First
eluting isomer ##STR00105## A-86 A-85 Third eluting isomer
##STR00106## A-87 ##STR00107## A-89 A-90 Second eluting isomer
##STR00108## A-88 A-91 Fourth eluting isomer ##STR00109## A-92 A-84
Fourth eluting isomer ##STR00110## A-93 ##STR00111## A-94 A-95
Second eluting isomer ##STR00112## A-96 A-97 Second eluting isomer
indicates data missing or illegible when filed
[0242] Specific stereoisomers and regioisomers contemplated include
the following in Table A-IA.
TABLE-US-00002 TABLE A-1A ##STR00113## ##STR00114## ##STR00115##
##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120##
##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125##
##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140##
##STR00141## ##STR00142## ##STR00143##
[0243] Also provided herein is a method of preparing a compound of
formula (A-I), comprising coupling a compound of formula (A-a),
comprising coupling a compound of formula (A-b):
##STR00144##
[0244] wherein X is halogen, with a compound of formula (A-b):
##STR00145##
[0245] under conditions to provide the compound of formula
(A-I).
[0246] As noted above, in one embodiment of the present disclosure,
provided are LRRK2 inhibitors of formula (B-I):
##STR00146##
[0247] or a pharmaceutically acceptable salt, stereoisomer, mixture
of stereoisomers, tautomer or prodrug thereof, wherein:
[0248] Y is N or CR.sup.21;
[0249] R.sup.21 is halo, C.sub.1-C.sub.6 haloalkyl or
cycloalkyl;
[0250] R.sup.22 is C.sub.1-C.sub.6 alkoxy; cycloalkyloxy,
cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino,
C.sub.1-C.sub.6 alkylamino, cycloalkylamino, cycloalkylalkylamino,
heterocyclylamino, or heterocyclylalkylamino;
[0251] R.sup.23a and R.sup.23b are each independently H, halo,
cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkyloxycarbonyl, aminocarbonyl or heterocyclylcarbonyl; and
[0252] R.sup.24 is H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6
alkoxyalkyl, C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6
aminoalkyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6
alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, heteroaryl, heteroarylylalkyl,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkoxycarbonylalkyl, aminocarbonyl or
heterocyclylcarbonyl.
[0253] In one embodiment of the present disclosure, provided are
LRRK2 inhibitors of formula (B-I), or a pharmaceutically acceptable
salt, stereoisomer, tautomer or prodrug thereof, wherein:
[0254] Y is N or CR.sup.21:
[0255] R.sup.21 is halo:
[0256] R.sup.22 is C.sub.1-C.sub.6 alkoxy; cycloalkyloxy,
cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino,
C.sub.1-C.sub.6 alkylamino, cycloalkylamino, cycloalkylalkylamino,
heterocyclylamino, or heterocyclylalkylamino;
[0257] R.sup.23a and R.sup.23b are each independently H, halo,
cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkyloxycarbonyl, aminocarbonyl or heterocyclylcarbonyl; and
[0258] R.sup.24 is H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-6 hydroxylalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 aminoalkyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylsulfonylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
heteroaryl, heteroarylylalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6
alkoxycarbonylalkyl, aminocarbonyl or heterocyclylcarbonyl.
[0259] In some embodiments, provided is a compound of formula
(B-Ia):
##STR00147##
[0260] In some embodiments, provided is a compound of formula
(B-Ib):
##STR00148##
[0261] In some embodiments, Y is N. In other embodiments A is
CR.sup.21. In some embodiments, R.sup.21 is chloro. In other
embodiments, R.sup.21 is fluoro.
[0262] In some embodiments, R.sup.21 is C.sub.1-C.sub.6 haloalkyl.
In other embodiments, R.sup.21 is --CF.sub.3. In other embodiments,
R.sup.1 is cycloalkyl. In other embodiments, R.sup.21 is
cyclopropyl.
[0263] In some embodiments, R.sup.22 is C.sub.1-C.sub.6 alkoxy or
C.sub.1-C.sub.6 alkylamino. In some embodiments, R.sup.22 is
C.sub.1-C.sub.6 alkoxy. In some embodiments, R.sup.2 is methoxy or
ethoxy. In some embodiments, R.sup.22 is C.sub.1-C.sub.6
alkylamino. In some embodiments R.sup.22 is methylamino or
ethylamino.
[0264] In some embodiments, one of R.sup.23a or R.sup.23b is H, and
the other of R.sup.23a or R.sup.23b is halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
C.sub.1-C.sub.6 hydroxylalkyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 aminoalkyl, cycloalkyl, cycloalkylalkyl.
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkyloxycarbonyl,
aminocarbonyl or heterocyclylcarbonyl. In some embodiments,
R.sup.23a or R.sup.23b is C.sub.1-C.sub.6 alkyl. In some
embodiments, R.sup.23a is H and R.sup.23b is C.sub.1-C.sub.6 alkyl.
In some embodiments, R.sup.23b is H and R.sup.23a is
C.sub.1-C.sub.6 alkyl. In some embodiments, C.sub.1-C.sub.6 alkyl
is methyl.
[0265] In some embodiments, R.sup.24 is C.sub.1-C.sub.6 alkyl. In
some embodiments, C.sub.1-C.sub.6 alkyl is methyl. In some
embodiments, R.sup.24 is C.sub.1-C.sub.6 cyanoalkyl. In some
embodiments, R.sup.24 is 2-cyano-prop-2-yl.
[0266] In various different embodiments, the compound has one of
the structures set forth in Table B-1 below. The compounds in Table
B-1 were each prepared and analyzed by mass spectrometry, liquid
chromatography, and/or .sup.1H NMR. General methods by which the
compounds may be prepared are provided below and in the
Examples.
TABLE-US-00003 TABLE B-1 B-1 ##STR00149## B-2 ##STR00150## B-3
##STR00151## B-4 ##STR00152## B-5 ##STR00153## B-6 ##STR00154## B-7
##STR00155## B-8 ##STR00156## B-9 ##STR00157## B-10 ##STR00158##
B-11 ##STR00159## B-12 ##STR00160## B-13 ##STR00161## B-14
##STR00162##
[0267] Also provided herein is a method of preparing a compound of
formula (B-I), comprising coupling a compound of formula (B-a),
wherein PG is an optional protecting group and X is halogen:
##STR00163##
[0268] with a compound of formula (B-b):
##STR00164##
[0269] under conditions to provide the compound of formula
(B-I).
[0270] In one embodiment, provided is a compound of Formula
(C-I):
##STR00165##
[0271] or a pharmaceutically acceptable salt, stereoisomer, or a
mixture of stereoisomers, tautomer or prodrug thereof, wherein:
[0272] Y is N or CR.sup.36;
[0273] Z is N or CH;
[0274] R.sup.31 is C.sub.1-C.sub.6 alkyl, cycloalkyl or
cycloalkylalkyl, each of which is optionally substituted;
[0275] R.sup.32 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 heteroalkyl,
cycloalkyl, heterocyclyl, aryl, heteroaryl, or -L.sup.3-R.sup.7,
wherein each C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted;
[0276] R.sup.33 and R.sup.34 are each independently H, halo, cyano,
amino. C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 heteroalkyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, or -L.sup.4-R.sup.38, wherein each
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is
optionally substituted; or
[0277] or R.sub.33 and R.sup.34 together with the atom to which
they are attached form a cycloalkyl, heterocyclyl or heteroaryl,
wherein each cycloalkyl, heterocyclyl, and heteroaryl is optionally
substituted;
[0278] or R.sup.32 and R.sup.33 together with the atom to which
they are attached form a heterocyclyl or heteroaryl, wherein each
heterocyclyl and heteroaryl is optionally substituted:
[0279] R.sup.35 is H, halo, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, or cycloalkyl;
[0280] R.sup.36 is H, halo, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 heteroalkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkoxyalkyl, --S(O).sub.w(C.sub.1-C.sub.6 alkyl),
cycloalkyl, heterocyclyl, heteroaryl, aryl, acyl, or amido, wherein
each alkyl, alkoxyl, haloalkyl, alkoxyalkyl, cycloalkyl,
heterocyclyl, heteroaryl, aryl, acyl, or amido are independently
optionally substituted:
[0281] L.sup.3 is --S(O).sub.p--, --S(O).sub.pN(R.sup.9)--,
--(CH.sub.2).sub.m--, --C(O)--, --C(O)O--, or
--C(O)N(R.sup.39)--;
[0282] each L.sup.4 is independently --O--, --S(O).sub.w--,
--(CH.sub.2).sub.m--, --C(O)--, --C(O)O--, --OC(O)--,
--C(O)N(R.sup.39)--, --N(R.sup.39)C(O)--, --N(R.sup.9)C(O)--,
--OC(O)N(R.sup.39)--, --N(R.sup.39)C(O)N(R.sup.39)--,
--S(O).sub.pN(R.sup.39)--, --N(R.sup.39)S(O).sub.pN(R.sup.39)-- or
--N(R.sup.39)S(O).sub.p--;
[0283] R.sup.37 is C.sub.1-C.sub.6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
wherein each C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl
is optionally substituted;
[0284] each R.sup.38 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, wherein each C.sub.1-C.sub.6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl is optionally substituted;
[0285] each R.sup.39 is independently H, C.sub.1-C.sub.6 alkyl,
C.sup.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
[0286] each p is independently 1 or 2;
[0287] each w is independently 0, 1, or 2; and
[0288] each m is independently 0, 1, 2, or 3.
[0289] In certain embodiments, provided is a compound of Formula
(C-I), or a pharmaceutically acceptable salt, stereoisomer, or a
mixture of stereoisomers, tautomer or prodrug thereof, wherein:
[0290] Y is N or CR.sup.36:
[0291] Z is N or CH;
[0292] R.sup.31 is C.sub.1-C.sub.6 alkyl, cycloalkyl, or
cycloalkylalkyl;
[0293] R.sup.32 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclyl, aryl,
heteroaryl, or -L.sup.3-R.sup.37, wherein each C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted;
[0294] R.sup.33 and R.sup.34 are each independently H, halo, cyano,
amino, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclyl, aryl,
heteroaryl, or -L.sup.4-R.sup.38, wherein each C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted; or
[0295] or R.sup.33 and R.sup.34 together with the atom to which
they are attached form a cycloalkyl, heterocyclyl or heteroaryl,
wherein each cycloalkyl, heterocyclyl, and heteroaryl is optionally
substituted;
[0296] or R.sup.32 and R.sup.33 together with the atom to which
they are attached form a heterocyclyl, or heteroaryl, wherein each
heterocyclyl, and heteroaryl is optionally substituted;
[0297] R.sup.35 is H, halo, cyano. C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, or cycloalkyl;
[0298] R.sup.36 is H, halo, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxyalkyl,
--S(O).sub.2(C.sub.1-C.sub.6 alkyl), cycloalkyl, heterocyclyl,
heteroaryl, aryl, acyl, or amido;
[0299] L.sup.3 is --S(O).sub.2--, --C(O)--, --C(O)O--, or
--C(O)N(R.sup.39)--;
[0300] each L.sup.4 is independently --O--, --S--, --S(O).sub.2--,
--C(O)--, --C(O)O--, --OC(O)--, --C(O)N(R.sup.39)--, or
--N(R.sup.39)C(O)--:
[0301] R.sup.37 is C.sub.1-C.sub.6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
wherein each C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl
is optionally substituted;
[0302] each R.sup.38 is independently C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, wherein each C.sub.1-C.sub.6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl is optionally substituted; and
[0303] each R.sup.39 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl.
[0304] Also provided is a comp und having the formula (C-Ia):
##STR00166##
[0305] Also provided is a compound having the formula (C-Ib):
##STR00167##
[0306] Also provided is a compound having the formula (C-Ic):
##STR00168##
[0307] Also provided is a compound having the formula (C-Id):
##STR00169##
[0308] Also provided is a compound having the formula (C-Ie):
##STR00170##
[0309] Also provided is a compound having the formula (C-If):
##STR00171##
[0310] In one embodiment, R.sup.31 is cycloalkyl. In certain
embodiments, R.sup.31 is cyclopropyl.
[0311] In one embodiment. R.sup.32 is C.sub.1-C.sub.6 alkyl
optionally substituted with one or more halo, cyano, cycloalkyl,
haloalkoxy, or optionally substituted heteroaryl, or cycloalkyl,
optionally substituted with one or more C.sub.1-C.sub.6 alkyl. In
one embodiment. R.sup.32 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, cycloalkylalkyl, or C.sub.1-C.sub.6 cyanoalkyl. In one
embodiment, R.sup.32 is optionally substituted C.sub.1-C.sub.6
alkyl. In one embodiment, R.sup.32 is C.sub.1-C.sub.6 alkyl. In one
embodiment, R.sup.32 is methyl. In one embodiment, R.sup.32 is
optionally substituted cycloalkyl. In one embodiment, R.sup.32 is
cycloalkyl. In one embodiment, R.sup.32 is cyclopropyl.
[0312] In one embodiment, R.sup.32 and R.sup.33 are C.sub.1-C.sub.6
alkyl. In one embodiment, at least one of R.sup.32 and R.sup.33 are
methyl.
[0313] In one embodiment, R.sup.32 and R.sup.33 together with the
atom to which they are attached form a heterocyclyl or heteroaryl,
wherein each heterocyclyl and heteroaryl is optionally substituted.
In certain embodiments, R.sup.32 and R.sup.33 together with the
atom to which they are attached form a heterocyclyl, which is
optionally substituted with cycloalkyl.
[0314] In one embodiment, R.sup.34 is H.
[0315] In one embodiment, R.sup.33 and R.sup.34 together with the
atom to which they are attached form a cycloalkyl, heterocyclyl or
heteroaryl, wherein each cycloalkyl, heterocyclyl and heteroaryl is
optionally substituted.
[0316] In one embodiment, R.sup.35 is H or optionally substituted
C.sub.1-C.sub.6 alkyl. In one embodiment, R.sup.35 is optionally
substituted C.sub.1-C.sub.6 alkyl. In one embodiment, R.sup.33 is H
or C.sub.1-C.sub.6 alkyl. In one embodiment. R.sup.35 is
C.sub.1-C.sub.6 alkyl. In one embodiment, R.sup.35 is methyl. In
one embodiment, R.sup.35 is H. In one embodiment, R.sup.35 is H or
methyl. In one embodiment, R.sup.35 is cycloalkyl. In one
embodiment, R.sup.35 is cyclopropyl. In one embodiment, R.sup.35 is
cycloalkyl and R.sup.32 is cycloalkyl or cycloalkylalkyl.
[0317] In one embodiment, R.sup.35 is H; one of R.sup.33 and
R.sup.34 is H and the other is halo, cyano, amino, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 heteroalkyl, cycloalkyl, heterocyclyl, aryl,
heteroaryl, or -L.sup.4-R.sup.38, wherein each C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted.
[0318] In one embodiment, Y is N. In one embodiment, Y is
CR.sup.36. In one embodiment, R.sup.36 is optionally substituted
C.sub.1-C.sub.6 alkyl, cycloalkyl, halo or cyano. In one
embodiment. R.sup.36 is C.sub.1-C.sub.6 haloalkyl, cycloalkyl, halo
or cyano. In one embodiment, R.sup.36 is H, halo or cyano. In one
embodiment, R.sup.36 is H. In one embodiment, R.sup.36 is halo. In
one embodiment, R.sup.36 is cyano.
[0319] In one embodiment, Z is N. In one embodiment, Z is CH.
[0320] In some embodiments, when R.sup.32 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl, R.sup.32 is optionally
substituted with one or more substituents independently selected
from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido,
amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl
ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine,
hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl,
sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid,
sulfonic acid, sulfonamido, thiol, thioxo, N-oxide, or
--Si(R.sup.102).sub.3, wherein each R.sup.102 is independently
hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl.
[0321] In some embodiments, when R.sup.32 or R.sup.33 together with
the carbon atom to which they are attached, form a heterocyclyl or
heteroaryl optionally substituted with one or more substituents
independently selected from alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido,
carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,
cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or
--Si(R.sup.102).sub.3, wherein each R.sup.102 is independently
hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl.
[0322] In one embodiment, R.sup.32 or R.sup.33 together with the
carbon atom to which they are attached form an optionally
substituted heterocyclyl. In one embodiment, R.sup.32 or R.sup.33
together with the carbon atom to which they are attached form an
optionally substituted heterocyclyl, wherein the heterocylyl is
pyrrolidinyl. In one embodiment, heterocyclyl is optionally
substituted with cycloalkyl.
[0323] In some embodiments, when R.sup.33 or R.sup.34 are each
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl, R.sup.33 or R.sup.34 are each independently optionally
substituted with one or more substituents independently selected
from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido,
amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl
ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine,
hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl,
sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid,
sulfonic acid, sulfonamido, thiol, thioxo. N-oxide, or
--Si(R.sup.102).sub.3, wherein each R.sup.102 is independently
hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl.
[0324] In some embodiments, R.sup.33 and R.sup.34, together with
the carbon atom to which they are attached, form a cycloalkyl,
heterocyclyl or heteroaryl optionally substituted with one or more
substituents independently selected from alkyl, alkenyl, alkynyl,
alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl,
azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,
cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or
--Si(R.sup.102).sub.3, wherein each R.sup.102 is independently
hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl.
[0325] In some embodiments, when R.sup.37 is C.sub.1-C.sub.6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl, R.sup.37 is optionally substituted with one or
more substituents independently selected from alkyl, alkenyl,
alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl,
aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,
cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or
--Si(R.sup.102).sub.3, wherein each R.sup.102 is independently
hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl.
[0326] In some embodiments, when R.sup.38 is C.sub.1-C.sub.6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl, R.sup.38 is optionally substituted with one or
more substituents independently selected from alkyl, alkenyl,
alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl,
aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,
cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or
--Si(R.sup.102).sub.3, wherein each R.sup.102 is independently
hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl,
heteroaryl or heterocyclyl.
[0327] In one embodiment, a compound may be selected from those
compounds in Table C-1. Also included within the disclosure are
pharmaceutically acceptable salt, stereoisomer, or a mixture of
stereoisomers, tautomer or prodrug thereof. In certain embodiments,
provided are compounds of Table C-1 for use in the methods
described herein.
TABLE-US-00004 TABLE C-1 C-1 ##STR00172## C-2 ##STR00173## C-3
##STR00174## C-4 ##STR00175## C-5 ##STR00176## C-6 ##STR00177## C-7
##STR00178## C-8 ##STR00179## C-9 ##STR00180## C-10 ##STR00181##
C-11 ##STR00182## C-12 ##STR00183## C-13 ##STR00184## C-14
##STR00185## C-15 ##STR00186## C-16 ##STR00187## C-17 ##STR00188##
C-18 ##STR00189## C-19 ##STR00190## C-20 ##STR00191## C-21
##STR00192## C-22 ##STR00193## C-23 ##STR00194## C-24 ##STR00195##
C-25 ##STR00196## C-26 ##STR00197## C-27 ##STR00198## C-28
##STR00199## C-29 ##STR00200## C-30 ##STR00201## C-31 ##STR00202##
C-32 ##STR00203## C-33 ##STR00204## C-34 ##STR00205## C-35
##STR00206## C-36 ##STR00207## C-37 ##STR00208## C-38 ##STR00209##
C-39 ##STR00210## C-40 ##STR00211## C-41 ##STR00212## C-42
##STR00213## C-43 ##STR00214## C-44 ##STR00215## C-45 ##STR00216##
C-46 ##STR00217## C-47 ##STR00218## C-48 ##STR00219## C-49
##STR00220## C-50 ##STR00221## C-51 ##STR00222## C-52 ##STR00223##
C-53 ##STR00224## C-54 ##STR00225## C-55 ##STR00226##
[0328] In another embodiment, provided is a method for preparing a
compound of formula (C-1), comprising coupling a compound of
formula (C-a):
##STR00227##
[0329] with a compound of formula (C-b):
##STR00228##
[0330] under conditions to provide the compound of formula (C-I),
wherein R is nitro or an optionally protected amino, and LG is a
leaving group.
[0331] In one embodiment, provided is a compound of Formula
(D-I):
##STR00229##
[0332] or a pharmaceutically acceptable salt, prodrug,
stereoisomer, or a mixture of stereoisomers thereof, wherein:
[0333] R.sup.41 is halo, cyano, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, cycloalkyl,
cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, or
--C(O)R.sup.45;
[0334] R.sup.42 is: [0335] a fused bicyclic ring system having a
heterocyclyl or cycloalkyl fused to a heteroaryl, wherein the ring
system is attached to the remainder of the molecule via the
heterocyclyl or cycloalkyl and the ring system is independently
optionally substituted with one or more halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, amino, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --C.sub.1-6
alkylene-C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C.sub.1-6
alkylene-SO.sub.2NR.sup.46R.sup.47,
--C.sub.1-6alkylene-NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46,
--OC(O)R.sup.46, --C(O).sub.2R.sup.46, --C.sub.1-6
alkylene-C(O)R.sup.46, --C.sub.1-6 alkylene-OC(O)R.sup.46,
--C.sub.1-6 alkylene-C(O).sub.2R.sup.46, --O--C(O)N.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, --C.sub.1-6
alkylene-O--C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0336] C.sub.1-6 alkoxyalkyl substituted with one
or more substituents independently selected from halo, amino,
cyano, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl; [0337] C.sub.1-6 haloalkyl
substituted with one or more substituents independently selected
from amino, cyano, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-6 alkenyl, C.sub.2-6alkynyl, cyanoalkyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0338] C.sub.1-6 cyanoalkyl optionally substituted
with one or more substituents independently selected from halo,
amino, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, --S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0339] C.sub.3-10 cycloalkyl substituted with one
or more substituents independently selected from amino, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, cyanoalkyl, --S(C.sub.1-6 alkyl),
--S(O)(C.sub.1-6 alkyl), --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl substituted with one
or more halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, wherein the
heterocyclyl, heteroaryl or heteroarylalkyl are optionally
substituted with one or more substituents independently selected
from C.sub.1-6 alkyl, C.sup.1-6 haloalkyl, or halo; or [0340]
--X--C(R.sup.48)(R.sup.49)(R.sup.50), wherein: [0341] X is
C.sub.1-6 alkylene optionally substituted with one or more halo;
[0342] R.sup.48 and R.sup.49, together with the carbon atom to
which they are attached, form an optionally substituted C.sub.3-10
cycloalkyl; and [0343] R.sup.50 is cyanoalkyl, C.sub.1-6
alkoxyalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6-hydroxyalkyl, C.sub.1-4 alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl:
[0344] R.sup.43a and R.sup.43b are each independently H, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
hydroxyalkyl, C.sup.1-6 alkoxyalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, amido, or --C(O)R.sup.5;
[0345] R.sup.44 is --N(R.sup.51).sub.2, --OR.sup.51, or
--SR.sup.51;
[0346] each R.sup.45 is independently C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --N(R.sup.52).sub.2, or heterocyclyl, wherein each
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or heterocyclyl is optionally
substituted;
[0347] each R.sup.46 and R.sup.47 is independently H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl, wherein each
C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl is optionally
substituted;
[0348] each R.sup.51 is independently H, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6
alkoxyalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl,
--C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.3-6
cycloalkyl optionally substituted with one or more C.sub.1-6 alkyl,
C.sub.3-6 cycloalkylalkyl optionally substituted with one or more
C.sub.1-6 alkyl, heterocyclyl optionally substituted with one or
more R.sup.13, or heterocyclylalkyl optionally substituted with one
or more R.sup.53; or
[0349] two R.sup.51, together with the nitrogen to which they are
attached, form a three- to six-membered heterocyclyl optionally
substituted with one or more R.sup.53:
[0350] each R.sup.52 is independently H or optionally substituted
C.sub.1-6 alkyl;
[0351] each R.sup.53 is independently C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halo, oxo, C.sub.1-6 alkoxy, amino,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 alkoxyalkyl, cyano,
heterocyclyl, heterocyclylalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkylalkyl, C.sub.3-6 cycloalkylsulfonyl, --C(O)R.sup.54, or
--C.sub.1-6alkylene-C(O)R.sup.54;
[0352] each R.sup.54 is independently C.sub.1-6 alkyl, C.sub.1-6
alkoxy, amino optionally substituted with halo, C.sub.1-6
haloalkyl, C.sub.1-6 hydroxyalkyl, hydroxy, C.sub.1-6 alkoxyalkyl,
C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6
alkyl). C.sub.1-6 aminoalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; and
[0353] provided that when R.sup.44 is --N(R.sup.51).sub.2 or
--OR.sup.51, R.sup.42 is not an unsubstituted C.sub.1-6
cyanoalkyl.
[0354] In one embodiment, provided is a compound of Formula (D-I),
or a pharmaceutically acceptable salt, prodrug, stereoisomer, or a
mixture of stereoisomers thereof, wherein:
[0355] R.sup.41 is halo, cyano, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, cycloalkyl,
cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, or
--C(O)R.sup.45;
[0356] R.sup.42 is: [0357] a fused bicyclic ring system having a
heterocyclyl or cycloalkyl fused to a heteroaryl, wherein the ring
system is attached to the remainder of the molecule via the
heterocyclyl or cycloalkyl and the ring system is independently
optionally substituted with one or more halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, amino, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --C.sub.1-6
alkylene-C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C.sub.1-6
alkylene-SO.sub.2NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46SO.sub.2R.sup.47--, --C(O)R.sup.46,
--OC(O)R.sup.46, --C(O).sub.2R.sup.46,--C.sub.1-6
alkylene-C(O)R.sup.46, --C.sub.1-6 alkylene-OC(O)R.sup.46,
--C.sub.1-6 alkylene-C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, --C.sub.1-6
alkylene-O--C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0358] C.sub.1-6 alkoxyalkyl substituted with one
or more halo, amino, cyano, hydroxy, C.sub.1-6 haloalkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O).sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0359] C.sub.1-6 haloalkyl substituted with amino,
cyano, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-6
alkenyl, C.sub.2-6alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6
alkyl), --C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.4--, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl; [0360] C.sub.1-6 cyanoalkyl
optionally substituted with one or more halo, amino, hydroxy,
C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl. C.sub.2-6 alkynyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl; [0361] C.sub.3-10 cycloalkyl substituted with one
or more amino. C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(C.sub.1-6 alkyl), --S(O)(C.sub.1-6 alkyl),
--S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl substituted with one
or more halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl; or [0362]
--X--C(R.sup.48)(R.sup.49)(R.sup.50), wherein: [0363] X is
C.sub.1-6 alkylene optionally substituted with one or more halo.
[0364] R.sup.48 and R.sup.49, together with the carbon atom to
which they are attached, form an optionally substituted C.sub.3-10
cycloalkyl; and [0365] R.sup.50 is cyanoalkyl, C.sub.1-6
alkoxyalkyl, C.sub.2-6alkenyl, C.sub.2-6 alkynyl,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
[0366] R.sup.43a and R.sup.43b are each independently H, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 cyanoalkyl,
C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, amido, or --C(O)R.sup.45;
[0367] R.sup.44 is --N(R.sup.51).sub.2, --OR.sup.51, and
--SR.sup.51;
[0368] each R.sup.45 is independently C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --N(R.sup.52).sub.2, or heterocyclyl, wherein each
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or heterocyclyl is optionally
substituted;
[0369] each R.sup.46 and R.sup.47 is independently H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl, wherein each
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl is optionally
substituted:
[0370] each R.sup.51 is independently H, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl. C.sub.1-6
alkoxyalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 aminoalkyl,
--C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl),
C.sub.1-6cycloalkyl optionally substituted with one or more
C.sub.1-6 alkyl, C.sub.3-6 cycloalkylalkyl optionally substituted
with one or more C.sub.1-6 alkyl, heterocyclyl optionally
substituted with one or more R.sup.53, or heterocyclylalkyl
optionally substituted with one or more R.sup.53; or
[0371] two R.sup.51, together with the nitrogen to which they are
attached, form a three- to six-membered heterocyclyl optionally
substituted with one or more R.sup.53;
[0372] each R.sup.52 is independently H or optionally substituted
C.sub.1-6 alkyl;
[0373] each R.sup.53 is independently C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halo, oxo, C.sub.1-6 alkoxy, amino,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 alkoxyalkyl, cyano,
heterocyclyl, heterocyclylalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkylalkyl, C.sub.3-6 cycloalkylsulfonyl, --C(O)R.sup.54, or
--C.sub.1-6alkylene-C(O)R.sup.54;
[0374] each R.sup.54 is independently C.sub.1-6 alkyl, C.sub.1-6
alkoxy, amino optionally substituted with halo, C.sub.1-6
haloalkyl, C.sub.1-6 hydroxyalkyl, hydroxy, C.sub.1-6 alkoxyalkyl,
C.sub.1-6 cyanoalkyl, --C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6
alkyl). C.sub.1-6 aminoalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; and
[0375] provided that when R.sup.44 is --N(R.sup.51).sub.2 or
--OR.sup.51, R.sup.42 is not C.sub.1-6 cyanoalkyl.
[0376] Also provided is a compound having the formula (D-Ia):
##STR00230##
[0377] Also provided is a compound having the formula (D-Ib):
##STR00231##
[0378] In certain embodiments, R.sup.44 is --N(R.sup.51).sub.2, and
each R.sup.51 is independently H or C.sub.1-6 alkyl. In certain
embodiments, R.sup.44 is --N(R.sup.51).sub.2, and one R.sup.51 is H
and the other R.sup.51 is C.sub.1-3 alkyl.
[0379] In certain embodiments, R.sup.41 is halo, cyano, C.sub.1-6
alkyl, or C.sub.1-6 haloalkyl. In certain embodiments, R.sup.41 is
C.sub.1-6 haloalkyl. In certain embodiments, R.sup.41 is C.sub.1-6
fluoroalkyl. In curtain embodiments, R.sup.41 is trifluoromethyl.
In certain embodiments, R.sup.41 is cyano. In certain embodiments,
R.sup.41 is halo. In certain embodiments, R.sup.41 is chloro.
[0380] In certain embodiments, one of R.sup.43a or R.sup.43b is H,
and the other of R.sup.43a or R.sup.4b is halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6
alkoxyalkyl, C.sub.1-6 cyanoalkyl, C.sub.1-6 aminoalkyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, amido, or --C(O)R.sup.45.
[0381] In certain embodiments, one of R.sup.41 or R.sup.43b is
halo, C.sub.1-6 alkyl, or C.sub.1-6 cyanoalkyl. In certain
embodiments, R.sup.43a is H, and R.sup.43b is halo, C.sub.1-6
alkyl, or C.sub.1-4 cyanoalkyl. In certain embodiments, C.sub.1-6
alkyl is methyl. In certain embodiments, C.sub.1-6 cyanoalkyl is
2-cyano-prop-2-yl.
[0382] In certain embodiments, R.sup.43b is hydrogen.
[0383] In certain embodiments, R.sup.42 is:
[0384] C.sub.1-6 alkoxyalkyl substituted with one or more halo,
amino, cyano, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl,
C.sub.2-6alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47.
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl:
[0385] C.sub.1-6 haloalkyl substituted with amino, cyano, hydroxy,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-6alkenyl, C.sub.2-6
alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl;
[0386] C.sub.1-6 cyanoalkyl optionally substituted with one or more
halo, amino, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6alkenyl,
C.sub.2-6 alkynyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl;
[0387] C.sub.3-10 cycloalkyl substituted with one or more amino,
C.sub.2-6alkenyl, C.sub.2-6 alkynyl, cyanoalkyl, --S(C.sub.1-6
alkyl), --S(O)(C.sub.1-6 alkyl), --S(O).sub.2(C.sub.1-6 alkyl),
--C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6
haloalkoxy, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl
substituted with one or more halo, cycloalkyl, cycloalkylalkyl,
heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
or
[0388] --X--C(R.sup.48)(R.sup.49)(R.sub.50).
[0389] In certain embodiments, R.sup.42 is:
[0390] C.sub.1-6 alkoxyalkyl substituted with one or more
substituents independently selected from halo, amino, cyano,
hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6alkynyl,
cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
[0391] C.sub.1-6 haloalkyl substituted with one or more
substituents independently selected from amino, cyano, hydroxy,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl;
[0392] C.sub.1-6 cyanoalkyl optionally substituted with one or more
substituents independently selected from halo, amino, hydroxy,
C.sub.1-6 haloalkoxy, C.sub.2-4 alkenyl, C.sub.2-6 alkynyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
[0393] C.sub.3-10 cycloalkyl substituted with one or more
substituents independently selected from amino, C.sub.2-6 alkenyl,
C.sub.2-6alkynyl, cyanoalkyl, --S(C.sub.1-6 alkyl),
--S(O)(C.sub.1-6 alkyl), --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl substituted with one
or more halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, wherein the
heterocyclyl, heteroaryl or heteroarylalkyl are optionally
substituted with one or more substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo; or
[0394] --X--C(R.sup.48)(R.sup.49)(R.sup.50).
[0395] In certain embodiments, R.sup.42 is:
[0396] C.sub.1-6 alkoxyalkyl substituted with one to three
substituents independently selected from halo, amino, cyano,
hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl;
[0397] C.sub.1-6 haloalkyl substituted with one to three
substituents independently selected from amino, cyano, hydroxy,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl;
[0398] C.sub.1-6 cyanoalkyl optionally substituted with one to
three substituents independently selected from halo, amino,
hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, --S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47.
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
[0399] C.sub.3-10 cycloalkyl substituted with one to three
substituents independently selected from amino, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, cyanoalkyl, --S(C.sub.1-6 alkyl),
--S(O)(C.sub.1-6 alkyl), --S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl substituted with one
or three halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, wherein the
heterocyclyl, heteroaryl or heteroarylalkyl are optionally
substituted with one to three substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo; or
[0400] --X--C(R.sup.48)(R.sup.49)(R.sup.50), wherein: [0401] X is
C.sub.1-6 alkylene optionally substituted with one to three halo;
[0402] R.sup.48 and R.sup.49, together with the carbon atom to
which they are attached, form an optionally substituted C.sub.3-10
cycloalkyl; and [0403] R.sup.50 is cyanoalkyl, C.sub.1-6
alkoxyalkyl, C.sub.2-6 alkenyl, C.sub.2-6alkynyl,
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy, C.sub.1-6
hydroxyalkyl, C.sub.1-6 alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl.
[0404] In certain embodiments, R.sup.42 is C.sub.1-6 alkoxyalkyl
substituted with one or more substituents independently selected
from halo, amino, cyano, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6
alkyl), --C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl.
[0405] In certain embodiments, R.sup.42 is C.sub.1-6 alkoxyalkyl
substituted with one to three substituents independently selected
from halo, amino, cyano, hydroxy, C.sub.1-6 haloalkoxy, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6
alkyl), --C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl.
[0406] In certain embodiments, R.sup.42 is C.sub.1-6 alkoxyalkyl
substituted with one or more halo. In certain embodiments, R.sup.42
is C.sub.1-6 alkoxyalkyl substituted with one to three fluoro. In
certain embodiments, R.sup.42 is C.sub.1-6 haloalkyl substituted
with one or more substituents independently selected from amino,
cyano, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, cyanoalkyl, --S(O).sub.2(C.sub.1-6
alkyl), --C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47,
--SO.sub.2NR.sup.46R.sup.47, --NR.sup.46SO.sub.2R.sup.47,
--C(O)R.sup.46, --OC(O)R.sup.46, --C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl.
[0407] In certain embodiments, R.sup.42 is C.sub.1-6 haloalkyl
substituted with one to three substituents independently selected
from amino, cyano, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(O).sub.2(C.sub.1-6 alkyl), --C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)R.sup.47, --SO.sub.2NR.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46, --OC(O)R.sup.46,
--C(O).sub.2R.sup.46, --O--C(O)NR.sup.46R.sup.47,
--NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl.
[0408] In certain embodiments, R.sup.42 is C.sub.1-6 haloalkyl
substituted with --C(O)NR.sup.46R.sup.47 or cyano. In certain
embodiments, R.sup.42 is C.sub.1-3 haloalkyl substituted with
--C(O)NR.sup.46R.sup.47. In certain embodiments, R.sup.42 is
C.sub.1-3 haloalkyl substituted with cyano.
[0409] In certain embodiments, R.sup.42 is C.sub.3-6 cycloalkyl
substituted with one or more cyanoalkyl, --S(C.sub.1-6 alkyl),
--S(O)(C.sub.1-6 alkyl), --S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6
haloalkoxy, C.sub.1-3 alkoxyalkyl substituted with one or more
halo, or heteroaryl.
[0410] In certain embodiments, R.sup.42 is C.sub.3-6 cycloalkyl
substituted with one or more substituents independently selected
from cyanoalkyl, --S(C.sub.1-6 alkyl), --S(O)(C.sub.1-6 alkyl),
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy, C.sub.1-3
alkoxyalkyl substituted with one or more halo, heterocyclyl, or
heteroaryl, wherein the heterocyclyl or heteroaryl is optionally
substituted with one or more substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo.
[0411] In certain embodiments, R.sup.42 is C.sub.1-6 cycloalkyl
substituted with one to three substituents independently selected
from cyanoalkyl, --S(C.sub.1-6 alkyl), --S(O)(C.sub.1-6 alkyl),
--S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-4 haloalkoxy, C.sub.1-3
alkoxyalkyl substituted with one to three halo, heterocyclyl, or
heteroaryl, wherein the heterocyclyl or heteroaryl is optionally
substituted with one to three substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo.
[0412] In certain embodiments, R.sup.42 is a fused bicyclic ring
system having a heterocyclyl fused to a heteroaryl, wherein the
ring system is attached to the remainder of the molecule via the
heterocyclyl. In certain embodiments, R.sup.42 is a fused bicyclic
ring system having a cycloalkyl fused to a heteroaryl, wherein the
ring system is attached to the remainder of the molecule via the
cycloalkyl.
[0413] In certain embodiments, R.sup.42 is a fused bicyclic ring
system having a heterocyclyl fused to a heteroaryl selected from
the group consisting of:
##STR00232##
each of which is optionally substituted with C.sub.1-3 alkyl, and
wherein the wavy line indicates the point of attachment to the
remainder of the molecule. In certain embodiments, C.sub.1-3 alkyl
is methyl.
[0414] In certain embodiments, R.sup.42 is a fused bicyclic ring
system having a heterocyclyl fused to a heteroaryl selected from
the group consisting of:
##STR00233##
each of which is optionally substituted with one to three
substituents independently selected from C.sub.1-3 alkyl or halo,
and wherein the wavy line indicates the point of attachment to the
remainder of the molecule. In certain embodiments, C.sub.1-3 alkyl
is methyl.
[0415] In certain embodiments, R.sup.42 is a fused bicyclic ring
system having a heterocyclyl fused to a heteroaryl selected from
the group consisting of:
##STR00234##
each of which is optionally substituted with one to three
substituents independently selected from C.sub.1-3 alkyl or halo,
and wherein the wavy line indicates the point of attachment to the
remainder of the molecule. In certain embodiments, C.sub.1-3 alkyl
is methyl.
[0416] In certain embodiments, R.sup.42 is a fused bicyclic ring
system having a heterocyclyl fused to a heteroaryl selected from
the group consisting of:
##STR00235##
each of which is optionally substituted with one to three C.sub.1-3
alkyl, and wherein the wavy line indicates the point of attachment
to the remainder of the molecule. In certain embodiments, C.sub.1-3
alkyl is methyl.
[0417] Also provided is a compound having the formula (D-II):
##STR00236##
[0418] wherein each X.sup.1 is independently C or N:
[0419] each X.sup.2 is independently CR.sup.55, N, NR.sup.55, O, or
S,
[0420] each R.sup.55 and R.sup.56 is independently H, halo, cyano.
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, amino,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6
cyanoalkyl, C.sub.1-6 aminoalkyl, --S(O).sub.2(C.sub.1-6 alkyl),
--C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl),
--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)R.sup.47--, --C.sub.1-6
alkylene-C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)R.sup.47, --SO.sub.2N.sup.46R.sup.47,
--NR.sup.46SO.sub.2R.sup.47, --C.sub.1-6
alkylene-SO.sub.2NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46SO.sub.2R.sup.47, --C(O)R.sup.46,
--OC(O)R.sup.46, --C(O).sub.2R.sup.46, --C.sub.1-6
alkylene-C(O)R.sup.46, --C.sub.1-6 alkylene-OC(O)R.sup.46,
--C.sub.1-6 alkylene-C(O).sub.2R.sup.46,
--O--C(O)NR.sup.46R.sup.47, --NR.sup.46C(O)OR.sup.47, --C.sup.1-6
alkylene-O--C(O)NR.sup.46R.sup.47, --C.sub.1-6
alkylene-NR.sup.46C(O)OR.sup.47, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
[0421] m is 0 or 1; and
[0422] n is 0, 1, 2 or 3.
[0423] The remaining variables of formula (D-II) are as defined
herein. Also provided is a compound having the formula (D-II) or a
pharmaceutically acceptable salt, prodrug, stereoisomer, or a
mixture of stereoisomers thereof.
[0424] In some embodiments, at least one X.sup.1 or X.sup.2 is a
heteroatom.
[0425] Also provided is a compound having the formula (D-IIa):
##STR00237##
[0426] Also provided is a compound having the formula (D-IIb):
##STR00238##
[0427] In certain embodiments,
##STR00239##
is:
##STR00240##
[0428] In certain embodiments,
##STR00241##
is:
##STR00242##
[0429] In certain embodiments,
##STR00243##
is selected from:
##STR00244##
[0430] In certain embodiments,
##STR00245##
[0431] In some embodiments, R.sup.42 is not quinuclindinyl,
quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolidinyl,
benzoxazolyl, dihydroquinolinyl, dihydroisoquinolinyl,
tetrahydroquinolinyl, or tetrahydroisoquinolinyl.
[0432] Also provided is a compound having the formula (D-III):
##STR00246##
or a pharmaceutically acceptable salt, prodrug, stereoisomer, or a
mixture of stereoisomers thereof, wherein:
[0433] Cy is C.sub.3-10cycloalkyl:
[0434] y is 1, 2, or 3;
[0435] each R.sup.57 is independently selected from amino,
C.sub.2-6 alkenyl, C.sub.2-6alkynyl, cyanoalkyl, --S(C.sub.1-6
alkyl), --S(O)(C.sub.1-6 alkyl), --S(O).sub.2(C.sub.1-6 alkyl),
--C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6
haloalkoxy, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl
substituted with one or more halo, cycloalkyl, cycloalkylalkyl,
heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
wherein the heterocyclyl, heteroaryl or heteroarylalkyl are
optionally substituted with one or more substituents independently
selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo;
and
[0436] the remaining variables are as defined herein.
[0437] In some embodiments, each R.sup.11 is independently selected
from amino, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cyanoalkyl,
--S(C.sub.1-6 alkyl), --S(O)(C.sub.1-6 alkyl),
--S(O).sub.2(C.sub.1-6 alkyl), --C.sub.1-6
alkylene-S(O).sub.2(C.sub.1-6 alkyl), C.sub.1-6 haloalkoxy,
C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxyalkyl substituted with one
to three halo, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, wherein the
heterocyclyl, heteroaryl or heteroarylalkyl are optionally
substituted with one to three substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo.
[0438] Also provided is a compound having the formula (D-IIIa):
##STR00247##
[0439] Also provided is a om pound having the formula (D-IIIb):
##STR00248##
[0440] Also provided is a compound having the formula (D-IIIc):
##STR00249##
[0441] Also provided is a compound having the formula (D-IIId):
##STR00250##
[0442] Also provided is a compound having the formula (D-IIIe):
##STR00251##
[0443] Also provided is a compound having the formula (D-IIIf):
##STR00252##
[0444] In some embodiments, R.sup.57 is a heteroaryl optionally
substituted with one to three substituents independently selected
from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo.
[0445] In some embodiments, y is 1, and R.sup.57 is a heteroaryl
optionally substituted with one to three substituents independently
selected from C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or halo. In
some embodiments, y is 1, and R.sup.57 is a heteroaryl selected
from the group consisting of pyrazolyl, triazolyl, oxazolyl, or
thiadiazolyl, each of which is optionally substituted with one to
three substituents independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, or halo. In some embodiments, y is 1, and
R.sup.57 is a heterocyclyl optionally substituted with one to three
substituents independently selected from C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, or halo. In some embodiments, R.sup.57 is a heterocyclyl
selected from the group consisting piperazinyl or pyrrolidinyl,
each of which is optionally substituted with one to three
substituents independently selected from C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, or halo.
[0446] In some embodiments, Cy is C.sub.3-6cycloalkyl. In some
embodiments, Cy is cyclobutyl. In some embodiments, Cy is
cyclopentyl.
[0447] In some embodiments, each R.sup.51 is independently H,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6
aminoalkyl, --C.sub.1-6 alkylene-S(O).sub.2(C.sub.1-6 alkyl),
C.sub.3-6 cycloalkyl optionally substituted with one to three
C.sub.1-6alkyl, C.sub.3-6cycloalkylalkyl optionally substituted
with one or three C.sub.1-6 alkyl, heterocyclyl optionally
substituted with one to three R.sup.53, or heterocyclylalkyl
optionally substituted with one to three R.sup.53; or two R.sup.51,
together with the nitrogen to which they are attached, form a
three- to six-membered heterocyclyl optionally substituted with one
to three R.sup.53.
[0448] In some embodiments, when R.sup.45 is C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or heterocyclyl or when R.sup.52 is C.sub.1-6
alkyl, R.sup.45 or R.sup.52 is optionally substituted with one or
more substituents independently selected from alkyl, alkenyl,
alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl,
aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,
cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or --Si(R.sup.y).sub.3,
wherein each R.sup.y is independently hydrogen, alkyl, alkenyl,
alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or
heterocyclyl.
[0449] In some embodiments, when R.sup.45 is C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or heterocyclyl or when R.sup.52 is C.sub.1-6
alkyl, R.sup.45 or R.sup.52 is optionally substituted with one to
three substituents independently selected from alkyl, alkenyl,
alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl,
aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano,
cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfnic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or --Si(R.sup.y).sub.3,
wherein each R.sup.y is independently hydrogen, alkyl, alkenyl,
alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or
heterocyclyl.
[0450] In some embodiments, R.sup.48 and R.sup.49, together with
the carbon atom to which they are attached, form a C.sub.3-10
cycloalkyl optionally substituted with one or more substituents
independently selected from alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido,
carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,
cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or --Si(R.sup.y).sub.3,
wherein each R.sup.y is independently hydrogen, alkyl, alkenyl,
alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or
heterocyclyl.
[0451] In some embodiments, R.sup.48 and R.sup.49, together with
the carbon atom to which they are attached, form a C.sub.3-10
cycloalkyl optionally substituted with one to three substituents
independently selected from alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido,
carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,
cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or --Si(R.sup.y).sub.3,
wherein each R.sup.y is independently hydrogen, alkyl, alkenyl,
alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or
heterocyclyl.
[0452] In some embodiments, when R.sup.48 and R.sup.47 are
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl, R.sup.46 or
R.sup.47 is optionally substituted with one or more substituents
independently selected from alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido,
carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,
cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or --Si(R.sup.y).sub.3,
wherein each R.sup.y is independently hydrogen, alkyl, alkenyl,
alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or
heterocyclyl.
[0453] In some embodiments, when R.sup.46 and R.sup.47 are
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl,
heterocyclyl, aryl, heteroalkyl, or heteroaryl, R.sup.46 or
R.sup.47 is optionally substituted with one to three substituents
independently selected from alkyl, alkenyl, alkynyl, alkoxy,
alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido,
carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,
cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino,
imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,
alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic
acid, sulfonamido, thiol, thioxo, N-oxide, or --Si(R.sup.y).sub.3,
wherein each R.sup.y is independently hydrogen, alkyl, alkenyl,
alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or
heterocyclyl.
[0454] In one embodiment, a compound may be selected from those
compounds in Table D-1. Also included within the disclosure are
pharmaceutically acceptable salts, prodrugs, stereoisomers or a
mixture of stereoisomers thereof. In certain embodiments, provided
are compounds of Table D-1 for use in the methods described
herein.
TABLE-US-00005 TABLE D-1 D-1 ##STR00253## D-2 ##STR00254## D-3
##STR00255## D-4 Second eluting stereoisomer D-5 ##STR00256## D-6
##STR00257## D-7 ##STR00258## D-8 ##STR00259## D-9 ##STR00260##
D-10 ##STR00261## D-11 ##STR00262## D-12 ##STR00263## D-13
##STR00264## D-14 ##STR00265## D-15 ##STR00266## D-16 ##STR00267##
D-17 ##STR00268## D-18 ##STR00269## D-19 ##STR00270## D-20
##STR00271## D-21 ##STR00272## D-22 ##STR00273## D-23 ##STR00274##
D-24 Second eluting stereoisomer D-25 ##STR00275## D-26
##STR00276## D-27 ##STR00277## D-28 ##STR00278## D-29 ##STR00279##
D-30 ##STR00280## D-31 ##STR00281## D-32 ##STR00282## D-33
##STR00283## D-34 ##STR00284## D-35 ##STR00285## D-36 ##STR00286##
D-37 ##STR00287## D-38 ##STR00288## D-39 ##STR00289## D-40
##STR00290## D-41 ##STR00291## D-42 ##STR00292## D-43 ##STR00293##
D-44 ##STR00294## D-45 ##STR00295## D-46 ##STR00296## D-47
##STR00297## D-48 ##STR00298## D-49 ##STR00299## D-50 ##STR00300##
D-51 ##STR00301## D-52 ##STR00302## D-53 ##STR00303## D-54
##STR00304## D-55 ##STR00305## D-56 ##STR00306## D-57 ##STR00307##
D-86 Second eluting stereoisomer D-58 ##STR00308## D-59
##STR00309## D-60 ##STR00310## D-163 Second eluting stereoisomer
D-61 ##STR00311## D-62 ##STR00312##
D-105 Second eluting stereoisomer D-63 ##STR00313## D-64
##STR00314## D-65 ##STR00315## D-122 First eluting stereoisomer
D-66 ##STR00316## D-67 ##STR00317## D-130 Second eluting
stereoisomer D-68 ##STR00318## D-132 First eluting stereoisomer
D-69 ##STR00319## D-143 Fourth eluting stereoisomer D-70
##STR00320## D-96 Second eluting stereoisomer D-71 ##STR00321##
D-72 ##STR00322## D-73 ##STR00323## D-74 ##STR00324## D-102 First
eluting stereoisomer D-75 ##STR00325## D-76 ##STR00326## D-77
##STR00327## D-78 ##STR00328## D-151 Second eluting stereoisomer
D-79 ##STR00329## D-171 First eluting stereoisomer D-80
##STR00330## D-81 ##STR00331## D-82 ##STR00332## D-174 First
eluting stereoisomer D-83 ##STR00333## D-84 ##STR00334## D-85
##STR00335## D-87 ##STR00336## D-88 ##STR00337## D-89 ##STR00338##
D-90 ##STR00339## D-107 Second eluting stereoisomer D-91
##STR00340## D-92 ##STR00341## D-170 Second eluting stereoisomer
D-93 ##STR00342## D-94 ##STR00343## D-95 ##STR00344## D-97
##STR00345## D-98 ##STR00346## D-99 ##STR00347## D-100 ##STR00348##
D-101 ##STR00349## D-103 ##STR00350## D-104 ##STR00351## D-106
##STR00352## D-108 ##STR00353## D-109 ##STR00354## D-110
##STR00355## D-111 ##STR00356## D-112 ##STR00357## D-175 Second
eluting stereoisomer D-113 ##STR00358## D-114 ##STR00359## D-156
Fourth eluting stereoisomer D-115 ##STR00360## D-116 ##STR00361##
D-117 ##STR00362## D-118 ##STR00363## D-119 ##STR00364## D-120
##STR00365## D-121 ##STR00366## D-166 First eluting stereoisomer
D-123 ##STR00367## D-124 ##STR00368##
D-125 ##STR00369## D-126 ##STR00370## D-127 ##STR00371## D-142
Second eluting stereoisomer D-128 ##STR00372## D-129 ##STR00373##
D-131 ##STR00374## D-133 ##STR00375## D-134 Second eluting
stereoisomer D-135 ##STR00376## D-136 ##STR00377## D-137
##STR00378## D-138 ##STR00379## D-139 ##STR00380## D-140
##STR00381## D-141 ##STR00382## D-149 Second eluting stereoisomer
D-144 ##STR00383## D-145 ##STR00384## D-146 ##STR00385## D-147
##STR00386## D-148 ##STR00387## D-150 ##STR00388## D-152
##STR00389## D-172 First eluting stereoisomer D-153 ##STR00390##
D-154 ##STR00391## D-155 ##STR00392## D-157 ##STR00393## D-157a
##STR00394## D-158 ##STR00395## D-159 ##STR00396## D-160
##STR00397## D-161 ##STR00398## D-162 ##STR00399## D-164
##STR00400## D-165 ##STR00401## D-167 ##STR00402## D-168
##STR00403## D-169 ##STR00404## D-173 ##STR00405## D-176
##STR00406## D-177 ##STR00407## D-178 ##STR00408## D-179
##STR00409## D-180 ##STR00410## D-181 ##STR00411## D-182
##STR00412## D-183 ##STR00413## D-184 ##STR00414## D-185
##STR00415## D-186 ##STR00416## D-187 ##STR00417## D-188
##STR00418## D-189 Second eluting stereoisomer D-190 ##STR00419##
D-191 Second eluting stereoisomer D-192 ##STR00420## D-193
##STR00421## D-194 ##STR00422## D-195 ##STR00423## D-196
##STR00424## D-197 ##STR00425## D-198 ##STR00426## D-199
##STR00427## D-200 Second eluting stereoisomer D-201
##STR00428## D-202 Second eluting stereoisomer D-203 ##STR00429##
D-204 ##STR00430## D-205 ##STR00431## D-206 Second eluting
stereoisomer
[0455] Representative stereoisomers of various compounds of Table
D-1 are shown in Table D-2 below. In one embodiment, a compound may
be selected from those compounds in Table D-1 or Table D-2. Also
included within the disclosure are pharmaceutically acceptable
salts, prodrugs, stereoisomers or a mixture of stereoisomers
thereof. In certain embodiments, provided are compounds of Table
D-1 or Table D-2 for use in the methods described herein.
TABLE-US-00006 TABLE D-2 ##STR00432## ##STR00433## ##STR00434##
##STR00435## ##STR00436## ##STR00437## ##STR00438## ##STR00439##
##STR00440## ##STR00441## ##STR00442## ##STR00443## ##STR00444##
##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449##
##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454##
##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459##
##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464##
##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469##
##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474##
##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479##
##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484##
##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489##
##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494##
##STR00495##
[0456] Also provided herein is a method of preparing a compound of
formula (D-I), comprising coupling a compound of formula (D-a):
##STR00496##
[0457] wherein X is a leaving group (e.g., halo), with a compound
of formula (D-b):
##STR00497## [0458] under conditions to provide the compound of
formula (D-I), wherein each of the variables is as defined
herein.
[0459] It is understood that any embodiment of the compounds of a
formula described herein, including substructures thereof, and any
of the specific substituents set forth herein in the compounds of
any of the formulas as set forth above, may be independently
combined with other embodiments and/or substituents of compounds of
any of the formulas to form embodiments of the inventions not
specifically set forth above. In addition, in the event that a list
of substituents is listed for any particular R group in a
particular embodiment and/or claim, it is understood that each
individual substituent may be deleted from the particular
embodiment and/or claim and that the remaining list of substituents
will be considered to be within the scope of the invention. It is
understood that in the present description, combinations of
substituents and/or variables of the depicted formulae are
permissible only if such contributions result in stable
compounds.
3. Pharmaceutical Compositions and Modes of Administration
[0460] For the purposes of administration, the compounds of the
present disclosure may be administered as a raw chemical or may be
formulated as pharmaceutical compositions. Pharmaceutical
compositions of the present disclosure comprise a compound of any
formula described herein and a pharmaceutically acceptable carrier,
diluent or excipient. Accordingly, different embodiments are
directed to pharmaceutical compositions comprising any one or more
of the foregoing compounds or a pharmaceutically acceptable salt,
prodrug or tautomer thereof, and a pharmaceutically acceptable
carrier, diluent or excipient, are also provided in various
embodiments.
[0461] The pharmaceutical compositions of the present disclosure
may be specially formulated for administration in solid or liquid
form, including those adapted for the following: oral
administration, for example, drenches (aqueous or non-aqueous
solutions or suspensions), tablets, e.g., those targeted for
buccal, sublingual, and systemic absorption, boluses, powders,
granules, pastes for application to the tongue; parenteral
administration, for example, by subcutaneous, intramuscular,
intravenous or epidural injection as, for example, a sterile
solution or suspension, or sustained-release formulation; topical
application, for example, as a cream, ointment, or a
controlled-release patch or spray applied to the skin;
intravaginally or intrarectally, for example, as a pessary, cream
or foam; sublingually; ocularly; transdermally; or nasally,
pulmonary and to other mucosal surfaces.
[0462] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0463] The phrase "pharmaceutically-acceptable carrier" as used
herein means a pharmaceutically-acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient, or
solvent encapsulating material, involved in carrying or
transporting the subject compound from one organ, or portion of the
body, to another organ, or portion of the body. Each carrier must
be "acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the patient.
Some examples of materials which can serve as
pharmaceutically-acceptable carriers include: sugars, such as
lactose, glucose and sucrose; starches, such as corn starch and
potato starch; cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate,
powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa
butter and suppository waxes; oils, such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as propylene glycol; polyols, such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters, such as ethyl
oleate and ethyl laurate; agar; buffering agents, such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol; pH buffered
solutions; polyesters, polycarbonates and/or polyanhydrides; and
other non-toxic compatible substances employed in pharmaceutical
formulations. Examples of such formulations include, but are not
limited to DMSO, 10 mM DMSO, 8% hydroxypropyl-beta-cyclodextrin in
PBS, propylene glycol, etc. For example, in a certain embodiment
the compounds of the disclosure can be used as 4 mM solution in 8%
hydroxypropyl-beta-cyclodextrin in PBS for parenteral
administration.
[0464] As set out herein, certain embodiments of the present
compounds may contain a basic functional group, such as amino or
methylamino (NCH.sub.3), and are, thus, capable of forming
pharmaceutically-acceptable salts with pharmaceutically-acceptable
acids. The term "pharmaceutically-acceptable salts" in this respect
refers to the relatively non-toxic, inorganic and organic acid
addition salts of compounds of the present disclosure. These salts
can be prepared in situ in the administration vehicle or the dosage
form manufacturing process, or by separately reacting a purified
compound of the disclosure in its free base form with a suitable
organic or inorganic acid, and isolating the salt thus formed
during subsequent purification. Representative salts include the
hydrobromide, hydrochloride, sulfate, bisulfate, phosphate,
nitrate, acetate, valerate, oleate, palmitate, stearate, laurate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, napthylate, mesylate, glucoheptonate,
lactobionate, and laurylsulphonate salts and the like. (See, for
example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.
66:1-19.)
[0465] The pharmaceutically acceptable salts of the subject
compounds include the conventional nontoxic salts or quaternary
ammonium salts of the compounds, e.g., from non-toxic organic or
inorganic acids. For example, such conventional nontoxic salts
include those derived from inorganic acids such as hydrochloride,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like;
and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isothionic, and the like.
[0466] In other cases, the compounds of the present disclosure may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically-acceptable salts with
pharmaceutically-acceptable bases. The term
"pharmaceutically-acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present disclosure. These salts can likewise be
prepared in situ in the administration vehicle or the dosage form
manufacturing process, or by separately reacting the purified
compound in its free acid form with a suitable base, such as the
hydroxide, carbonate or bicarbonate of a
pharmaceutically-acceptable metal cation, with ammonia, or with a
pharmaceutically-acceptable organic primary, secondary or tertiary
amine. Representative alkali or alkaline earth salts include the
lithium, sodium, potassium, calcium, magnesium, and aluminum salts
and the like. Representative organic amines useful for the
formation of base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine and the
like.
[0467] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0468] Examples of pharmaceutically-acceptable antioxidants
include: water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0469] Formulations of the present disclosure include those
suitable for oral, nasal, topical (including buccal and
sublingual), rectal, vaginal and/or parenteral administration. The
formulations may conveniently be presented in unit dosage form and
may be prepared by any methods well known in the art of pharmacy.
The amount of active ingredient which can be combined with a
carrier material to produce a single dosage form will vary
depending upon the host being treated, the particular mode of
administration. The amount of active ingredient that can be
combined with a carrier material to produce a single dosage form
will generally be that amount of the compound which produces a
therapeutic effect. Generally, this amount will range from about 1%
to about 99% of active ingredient, preferably from about 5% to
about 70%, most preferably from about 10% to about 30%.
[0470] In certain embodiments, a formulation of the present
disclosure comprises an excipient selected from the group
consisting of cyclodextrins, liposomes, micelle forming agents,
e.g., bile acids, and polymeric carriers, e.g., polyesters and
polyanhydrides; and a compound of the present disclosure. In
certain embodiments, an aforementioned formulation renders orally
bioavailable a compound of the present disclosure.
[0471] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present disclosure with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present disclosure with liquid carriers, or finely divided
solid carriers, or both, and then, if necessary, shaping the
product.
[0472] Formulations of the disclosure suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) and/or as mouth washes and the
like, each containing a predetermined amount of a compound of the
present disclosure as an active ingredient. A compound of the
present disclosure may also be administered as a bolus, electuary
or paste.
[0473] In solid dosage forms of the disclosure for oral
administration (capsules, tablets, pills, dragees, powders,
granules and the like), the active ingredient is mixed with one or
more pharmaceutically-acceptable carriers, such as sodium citrate
or dicalcium phosphate, and/or any of the following: fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
and/or silicic acid; binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; humectants, such as glycerol; disintegrating
agents, such as agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate;
solution retarding agents, such as paraffin; absorption
accelerators, such as quaternary ammonium compounds; wetting
agents, such as, for example, cetyl alcohol, glycerol monostearate,
and non-ionic surfactants; absorbents, such as kaolin and bentonite
clay; lubricants, such a talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, and
mixtures thereof; and coloring agents. In the case of capsules,
tablets and pills, the pharmaceutical compositions may also
comprise buffering agents. Solid compositions of a similar type may
also be employed as fillers in soft and hard-shelled gelatin
capsules using such excipients as lactose or milk sugars, as well
as high molecular weight polyethylene glycols and the like.
[0474] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made in a suitable machine in which a mixture
of the powdered compound is moistened with an inert liquid
diluent.
[0475] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present disclosure, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be formulated for rapid release, e.g.,
freeze-dried. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions that
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions that can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0476] Liquid dosage forms for oral administration of the compounds
of the disclosure include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0477] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0478] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0479] Formulations of the pharmaceutical compositions of the
disclosure for rectal or vaginal administration may be presented as
a suppository, which may be prepared by mixing one or more
compounds of the disclosure with one or more suitable nonirritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the rectum or vaginal cavity and release
the active compound.
[0480] Formulations of the present disclosure which are suitable
for vaginal administration also include pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing such carriers
as are known in the art to be appropriate.
[0481] Dosage forms for the topical or transdermal administration
of a compound of this disclosure include powders, sprays,
ointments, pastes, creams, lotions, gels, solutions, patches and
inhalants. The active compound may be mixed under sterile
conditions with a pharmaceutically-acceptable carrier, and with any
preservatives, buffers, or propellants which may be required.
[0482] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this disclosure, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0483] Powders and sprays can contain, in addition to a compound of
this disclosure, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0484] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present disclosure to the
body. Dissolving or dispersing the compound in the proper medium
can make such dosage forms. Absorption enhancers can also be used
to increase the flux of the compound across the skin. Either
providing a rate controlling membrane or dispersing the compound in
a polymer matrix or gel can control the rate of such flux. Such
transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds described herein in
controlled amounts. Such patches may be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
[0485] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this disclosure.
[0486] Pharmaceutical compositions of this disclosure suitable for
parenteral administration comprise one or more compounds of the
disclosure in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain
sugars, alcohols, antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0487] Examples of suitable aqueous and nonaqueous carriers, which
may be employed in the pharmaceutical compositions of the
disclosure include water, ethanol, polyols (such as glycerol,
propylene glycol, polyethylene glycol, and the like), and suitable
mixtures thereof, vegetable oils, such as olive oil, and injectable
organic esters, such as ethyl oleate. Proper fluidity can be
maintained, for example, by the use of coating materials, such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0488] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms upon the subject
compounds may be ensured by the inclusion of various antibacterial
and antifungal agents, for example, paraben, chlorobutanol, phenyl
sorbic acid, and the like. It may also be desirable to include
isotonic agents, such as sugars, sodium chloride, and the like into
the compositions. In addition, prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0489] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution, which in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally-administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0490] Injectable depot forms are made by forming microencapsule
matrices of the subject compounds in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions, which are
compatible with body tissue.
[0491] The compositions that include at least one compound
described herein or a pharmaceutically acceptable salt, tautomer,
stereoisomer, mixture of stereoisomers, prodrug, or deuterated
analog thereof can be formulated so as to provide quick, sustained
or delayed release of the active ingredient after administration to
the subject by employing procedures known in the art. Controlled
release drug delivery systems for oral administration include
osmotic pump systems and dissolutional systems containing
polymer-coated reservoirs or drug-polymer matrix formulations.
4. Treatment Methods and Uses
[0492] "Treatment" or "treating" is an approach for obtaining
beneficial or desired results including clinical results.
Beneficial or desired clinical results may include one or more of
the following: a) inhibiting the disease or condition (e.g.,
decreasing one or more symptoms resulting from the disease or
condition, and/or diminishing the extent of the disease or
condition); b) slowing or arresting the development of one or more
clinical symptoms associated with the disease or condition (e.g.,
stabilizing the disease or condition, preventing or delaying the
worsening or progression of the disease or condition, and/or
preventing or delaying the spread (e.g., metastasis) of the disease
or condition); and/or c) relieving the disease, that is, causing
the regression of clinical symptoms (e.g., ameliorating the disease
state, providing partial or total remission of the disease or
condition, enhancing effect of another medication, delaying the
progression of the disease, increasing the quality of life and/or
prolonging survival.
[0493] "Prevention" or "preventing" means any treatment of a
disease or condition that causes the clinical symptoms of the
disease or condition not to develop. Compounds may, in some
embodiments, be administered to a subject (including a human) who
is at risk or has a family history of the disease or condition.
[0494] "Subject" refers to an animal, such as a mammal (including a
human), that has been or will be the object of treatment,
observation or experiment. The methods described herein may be
useful in human therapy and/or veterinary applications. In some
embodiments, the subject is a mammal. In one embodiment, the
subject is a human.
[0495] The term "therapeutically effective amount" or "effective
amount" of a compound described herein or a pharmaceutically
acceptable salt, tautomer, stereoisomer, mixture of stereoisomers,
prodrug, or deuterated analog thereof means an amount sufficient to
effect treatment when administered to a subject, to provide a
therapeutic benefit such as amelioration of symptoms or slowing of
disease progression. For example, a therapeutically effective
amount may be an amount sufficient to decrease a symptom of a
disease or condition of as described herein. The therapeutically
effective amount may vary depending on the subject, and disease or
condition being treated, the weight and age of the subject, the
severity of the disease or condition, and the manner of
administering, which can readily be determined by one of ordinary
skill in the art.
[0496] The methods described herein may be applied to cell
populations in vivo or ex vivo. "In vivo" means within a living
individual, as within an animal or human. In this context, the
methods described herein may be used therapeutically in an
individual. "Ex vivo" means outside of a living individual.
Examples of ex vivo cell populations include in vitro cell cultures
and biological samples including fluid or tissue samples obtained
from individuals. Such samples may be obtained by methods well
known in the art. Exemplary biological fluid samples include blood,
cerebrospinal fluid, urine, and saliva. In this context, the
compounds and compositions described herein may be used for a
variety of purposes, including therapeutic and experimental
purposes. For example, the compounds and compositions described
herein may be used ex vivo to determine the optimal schedule and/or
dosing of administration of a compound of the present disclosure
for a given indication, cell type, individual, and other
parameters. Information gleaned from such use may be used for
experimental purposes or in the clinic to set protocols for in vivo
treatment. Other ex vivo uses for which the compounds and
compositions described herein may be suited are described below or
will become apparent to those skilled in the art. The selected
compounds may be further characterized to examine the safety or
tolerance dosage in human or non-human subjects. Such properties
may be examined using commonly known methods to those skilled in
the art.
[0497] LRRK2 has been associated with the transition from mild
cognitive impairment to Alzheimer's disease; L-Dopa induced
dyskinesia (Hurley et al., Eur. J, Neurosci., Vol. 26, 2007,
171-177); CNS disorders associated with neuroprogenitor cell
proliferation and migration, and regulation of LRRK2 may have
utility in improving neurological outcomes following ischemic
injury, and stimulating restoration of CNS function following
neuronal injury such as ischemic stroke, traumatic brain injury, or
spinal cord injury (Milosevic et al., Neurodegen., Vol. 4, 2009,
25; See Zhang et al., J. Neurosci. Res. Vol. 88, 2010, 3275-3281);
Parkinson's disease, Alzheimer's disease, multiple sclerosis, and
HIV-induced dementia (See Milosevic et al., Mol. Neurodegen., Vol.
4, 2009, 25); kidney, breast, prostate (e.g. solid tumor), blood
and lung cancer, and acute myeologenouse leukemia (AML); lymphomas
and leukemias (See Ray et al., J. Immunolo., Vol. 230, 2011, 109);
multiple myeoloma (Chapman et al., Nature. Vol. 471, 2011,
467-472); papillary renal and thyroid carcinomas; multiple myeloma
(Chapman et al., Nature, Vol. 471, 2011, 467-472); diseases of the
immune system, including rheumatoid arthritis, systemic lupus
erythematosus autoimmune hemolytic anemia, pure red cell aplasia,
idiopathic thrombocytopenic pupura (ITP), Evans syndrome,
vasculitis, bullous skin disorders, type 1 diabetes mellitus,
Sjogren's syndrome, Delvic's disease, and inflammatory myopathies
(Nakamura et al., DNA Res. Vol. 13(4), 2006, 169-183; See Engel et
al., Pharmacol. Rev. Vol. 63, 2011, 127-156; Homam et al., J. Clin.
Neuromuscular Disease, Vol. 12, 2010, 91-102); ankylosing
spondylitis and leprosy infection (DAnoy et al., PLoS Genetics,
Vol. 6(12), 2010, e1001195, 1-5; see Zhang et al., N. Eng. J. Med.
Vol. 361, 2009, 2609-2618); alpha-synucleinopathies, taupathies
(See Li et al., 2010 Neurodegen. Dis. Vol. 7, 2010, 265-271);
Gaucher disease (See Vestbroek et al., Trends. Mol. Med. Vol. 17,
2011, 485-493); tauopathy diseases characterized by
hyperphosphorylation of Tau such as argyrophilic grain disease,
Pick's disease, corticobasal degeneration, progressive supranuclear
palsy, and inherited frontotemporal dementia and parkinsonism
linked to chromosome 17 (See Goedert, M and Jakes, R, Biochemica et
Biophysica Acta, Vol. 1739, 2005, 240-250); diseases characterized
by diminished dopamine levels such as withdrawal symptoms/relapse
associated with drug addiction (See Rothman et al., og. Brain Res.,
Vol. 172, 2008, 385); microglial proinflammatory responses (See
Moehle et al., J. Neuroscience Vol. 32, 2012, 1602-1611); Crohn's
disease pathogenesis (see Barrett et al., Nature Genetics, Vol. 40,
2008, 955-962); and amyotrophic lateral sclerosis (ALS).
[0498] It is suggested that increased LRRK2 activity may be
characteristic of ALS. Significantly elevated levels of LRRK2 mRNA
have been observed in fibroblasts of Niemann-Pick Type C (NPC)
disease patients, indicating abnormal LRRK2 function may play a
role in lysosomal disorders.
[0499] In another aspect, the present disclosure relates to a
method of treating a disease or condition mediated, at least in
part, by LRRK2. In particular, the disclosure provides methods for
preventing or treating a disorder associated with LRRK2 in a
mammal, comprising the step of administering to said mammal a
therapeutically effective amount of a compound of structure (I) or
therapeutic preparation of the present disclosure. In some
embodiments the LRRK-mediated disease or condition is a
neurodegenerative disease, for examples a central nervous system
(CNS) disorder, such as Parkinson's disease (PD), Alzheimer's
disease (AD), dementia (including Lewy body dementia and cascular
dementia), amyotrophic lateral sclerosis (ALS), age related memory
dysfunction, mild cognitive impairment (i.e. including the
transition from mild cognitive impairment to Alzheimer's disease),
argyrophilic grain disease, lysosomal disorders (for example,
Niemann-PickType C disease, Gaucher disease) corticobasal
degeneration, progressive supranuclear palsy, inherited
frontotemporal dementia and parkinsonism linked to chromosome 17
(FTDP-17), withdrawal symptoms/relapse associated with drug
addiction, L-Dopa induced dyskinesia, Huntington's disease (HD),
and HIV-associated dementia (HAD). In other embodiments the
disorder is an ischemic disease of organs including but not limited
to brain, heart, kidney, and liver.
[0500] In some other embodiments, the disease or condition
mediated, at least in part, by LRRK2, is cancer. In certain
embodiments, the cancer is thyroid, renal (including papillary
renal), breast, lung, blood, and prostate cancers (e.g. solid
tumor), leukemias (including acute myelogenous leukemia (AML)),
lymphomas, or leukemias. In some embodiments, the cancer is kidney
cancer, breast cancer, prostate cancer, blood cancer, papillary
cancer, lung cancer, acute myelogenous leukemia or multiple
myeloma.
[0501] In other embodiments, the presently disclosed compounds are
used in methods for treatment of inflammatory disorders. In some
embodiments, the disorder is an inflammatory disease of the
intestines such as Crohn's disease or ulcerative colitis (both
generally known together as inflammatory bowel disease). In other
embodiments, the inflammatory disease is leprosy, amyotrophic
lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
In some embodiments, the inflammatory disease is leprosy, Crohn's
disease, inflammatory bowel disease, ulcerative colitis,
amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing
spondylitis.
[0502] In other embodiments, the presently disclosed compounds are
used in methods for treatment of multiple sclerosis, systemic lupus
erythematosus, autoimmune hemolytic anemia, pure red cell aplasia,
idiopathic thrombocytopenic purpura (ITP), Evans syndrome,
vasculitis, bullous skin disorders, type 1 diabetes mellitus,
Sjogren's syndrome, Devic's disease and inflammatory
myopathics.
[0503] Other embodiments include methods for enhancing cognitive
memory of a subject, the method comprising administering an
effective amount of a composition comprising the compound of a
formula described herein to a subject in need thereof.
[0504] The term "trauma" as used herein refers to any physical
damage to the body caused by violence, accident, fracture etc. The
term "ischemia" refers to a cardiovascular disorder characterized
by a low oxygen state usually due to the obstruction of the
arterial blood supply or inadequate blood flow leading to hypoxia
in the tissue. The term "stroke" refers to cardiovascular disorders
caused by a blood clot or bleeding in the brain, most commonly
caused by an interruption in the flow of blood in the brain as from
clot blocking a blood vessel, and in certain embodiments of the
disclosure the term stroke refers to ischemic stroke or hemorrhagic
stroke. The term "myocardial infarction" refers to a cardiovascular
disorder characterized by localized necrosis resulting from
obstruction of the blood supply.
[0505] In certain embodiments, a compound or pharmaceutical
composition is administered orally. In other embodiments, the
compound or pharmaceutical composition is administered
intravenously. Alternative routes of administration include
sublingual, intramuscular, and transdermal administrations.
[0506] In certain embodiments, the present disclosure relates to
compounds for inhibiting cell death, wherein the compounds are
represented by the structure of any formula described herein. In
certain embodiments, the compounds of the present disclosure are
inhibitors of cell death. In any event, the compounds of the
present disclosure preferably exert their effect on inhibiting cell
death at a concentration less than about 50 micromolar, more
preferably at a concentration less than about 10 micromolar, and
most preferably at a concentration less than 1 micromolar.
[0507] The compounds of the disclosure can be tested in standard
animal models of stroke and standard protocols such as described by
Hara, H., et al. Proc Natl Acad Sci USA, 1997. 94(5): 2007-12.
[0508] When the compounds of the present disclosure are
administered as pharmaceuticals, to humans and animals, they can be
given per se or as a pharmaceutical composition containing, for
example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active
ingredient in combination with a pharmaceutically acceptable
carrier.
[0509] The preparations of the present disclosure may be given
orally, parenterally, topically, or rectally. They are of course
given in forms suitable for each administration route. For example,
they are administered in tablets or capsule form, by injection,
inhalation, eye lotion, ointment, suppository, etc. administration
by injection, infusion or inhalation; topical by lotion or
ointment; and rectal by suppositories. Oral administrations are
preferred.
[0510] These compounds may be administered to humans and other
animals for therapy by any suitable route of administration,
including orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracistemally and topically, as by
powders, ointments or drops, including buccally and
sublingually.
[0511] Regardless of the route of administration selected, the
compounds of the present disclosure, which may be used in a
suitable hydrated form, and/or the pharmaceutical compositions of
the present disclosure, are formulated into
pharmaceutically-acceptable dosage forms by conventional methods
known to those of skill in the art.
[0512] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this disclosure may be varied so as
to obtain an amount of the active ingredient that is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0513] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present disclosure employed, or the ester, salt or amide thereof,
the route of administration, the time of administration, the rate
of excretion or metabolism of the particular compound being
employed, the duration of the treatment, other drugs, compounds
and/or materials used in combination with the particular compound
employed, the age, sex, weight, condition, general health and prior
medical history of the patient being treated, and like factors well
known in the medical arts. A daily, weekly, or monthly dosage (or
other time interval) can be used.
[0514] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the disclosure
employed in the pharmaceutical composition at levels lower than
that required to achieve the desired therapeutic effect and then
gradually increasing the dosage until the desired effect is
achieved.
[0515] In general, a suitable daily dose of a compound of the
disclosure will be that amount of the compound that is the lowest
dose effective to produce a therapeutic effect (e.g., inhibit
necrosis). Such an effective dose will generally depend upon the
factors described above. Generally doses of the compounds of this
disclosure for a patient, when used for the indicated effects, will
range from about 0.0001 to about 100 mg per kg of body weight per
day. Preferably the daily dosage will range from 0.001 to 50 mg of
compound per kg of body weight, and even more preferably from 0.01
to 10 mg of compound per kg of body weight.
[0516] If desired, the effective daily dose of the active compound
may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms.
[0517] In another aspect of the disclosure the compounds can be
administered in combination with other agents, including (but not
limited to) compounds that are apoptosis inhibitors; PARP
poly(ADP-ribose) polymerase inhibitors; Src inhibitors; agents for
the treatment of cardiovascular disorders; anti-inflammatory
agents, anti-thrombotic agents; fibrinolytic agents; anti-platelet
agents, lipid reducing agents, direct thrombin inhibitors;
glycoprotein IIb/IIIa receptor inhibitors; calcium channel
blockers; beta-adrenergic receptor blocking agents; cyclooxygenase
(e.g., COX-1 and COX-2) inhibitors; angiotensin system inhibitor
(e.g., angiotensin-converting enzyme (ACE) inhibitors); renin
inhibitors; and/or agents that bind to cellular adhesion molecules
and inhibit the ability of white blood cells to attach to such
molecules (e.g., polypeptides, polyclonal and monoclonal
antibodies).
[0518] The disclosure also provides combinations of two or more
compounds that inhibit cellular necrosis (e.g., a compound as
disclosed herein and an additional agent for inhibiting necrosis).
The disclosure also provides combinations of one or more compounds
that inhibit cellular necrosis combined with one or more additional
agents or compounds (e.g., other therapeutic compounds for treating
a disease, condition, or infection).
5. Kits
[0519] The disclosure also provides kits including one or more
compounds or combinations of the disclosure, or a pharmaceutically
acceptable salt, tautomer, stereoisomer, mixture of stereoisomers,
prodrug, or deuterated analog thereof, and suitable packaging. A
kit can also include one or more additional agents or compounds
described herein. The different components of the kit can be
provided in different containers. The kit can be compartmentalized
to receive the containers in close confinement. The kit can also
contain instructions for using the compounds according to the
disclosure.
[0520] As used herein, a kit such as a compartmentalized kit
includes any kit in which compounds or agents are contained in
separate containers. Illustrative examples of such containers
include, but are not limited to, small glass containers, plastic
containers or strips of plastic or paper. Particularly preferred
types of containers allow the skilled worker to efficiently
transfer reagents from one compartment to another compartment such
that the samples and reagents are not cross-contaminated and the
agents or solutions of each container can be added in a
quantitative fashion from one compartment to another. Such
containers include, but are not limited to, a container that will
accept a compound or combination of compounds and/or other agents
of the disclosure. One or more compounds or agents can be provided
as a powder (e.g. lyophilized powder) or precipitate. Such
compound(s) can be resuspended prior to administration in a
solution that may be provided as part of the kit or separately
available. A kit can contain compounds or agents in other forms
such as liquids, gels, solids, as described herein. Different
compounds and/or agents may be provided in different forms in a
single kit.
[0521] Provided herein are also articles of manufacture that
include a compound described herein or a pharmaceutically
acceptable salt, tautomer, stereoisomer, mixture of stereoisomers,
prodrug, or deuterated analog thereof in a suitable container. The
container may be a vial, jar, ampoule, preloaded syringe, or
intravenous bag.
EXAMPLES
[0522] The examples and preparations provided below further
illustrate and exemplify the compounds of the present disclosure
and methods for testing such compounds. It is to be understood that
the scope of the present disclosure is not limited in any way by
the scope of the following examples. In the following examples, and
throughout the specification and claims, molecules with a single
chiral center (such as compound (I)), unless otherwise noted, exist
as a racemic mixture. Single enantiomers may be obtained by methods
known to those skilled in the art.
[0523] The following examples are provided for purposes of
illustration, not limitation. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques to function well in the practice
of the disclosure, and thus can be considered to constitute
specific modes for its practice. However, those of skill in the art
should, in light of the present disclosure, appreciate that many
changes can be made in the embodiments which are disclosed and
still obtain a like or similar result without departing from the
spirit and scope of the disclosure.
6. General Experimental Methods
[0524] The compounds of the present invention can be prepared
according to any number of methods known in the art, including
those methods specifically described in the Examples below. The
following General Reaction Scheme I illustrates a method of making
compounds of this disclosure, i.e., compounds of formula (I),
wherein R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5 and
Z are as defined above, and X and X' are independently
halogens.
##STR00498##
[0525] Referring to General Reaction Scheme I, compound (a) is
purchased from commercial sources or prepared according to methods
known in the art. Coupling (for example, Buchwald-Hartwig or Suzuki
coupling) of (a) with H--R.sup.2 or an appropriately functionalized
derivative thereof (e.g., boronic acid derivative) yields compound
(b). Amination of compound (b) with pyrazole (c) yields desired
compound of formula I. Modifications to the above General Scheme
are also possible, for example the coupling and amination steps can
be reversed.
[0526] It is understood that one skilled in the art may be able to
make these compounds by similar methods or by combining other
methods known to one skilled in the art. It is also understood that
one skilled in the art would be able to make, in a similar manner
as described below, other compounds of structure (I) not
specifically illustrated below by using the appropriate starting
components and modifying the parameters of the synthesis as needed.
In general, starting components may be obtained from sources such
as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix
Scientific, TCI, and Fluorochem USA, etc. or synthesized according
to sources known to those skilled in the art (see, for example,
Advanced Organic Chemistry: Reactions. Mechanisms, and Structure,
5th edition (Wiley, December 2000)) or prepared as described in
this disclosure.
[0527] It will also be appreciated by those skilled in the art that
in the process described herein the functional groups of
intermediate compounds may need to be protected by suitable
protecting groups. Such functional groups include hydroxy, amino,
mercapto and carboxylic acid. Suitable protecting groups for
hydroxy include trialkylsilyl or diarylalkylsilyl (for example,
t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),
tetrahydropyranyl, benzyl, and the like. Suitable protecting groups
for amino, amidino and guanidino include t-butoxycarbonyl,
benzyloxycarbonyl, and the like. Suitable protecting groups for
mercapto include --C(O)--R'' (where R'' is alkyl, aryl or
arylalkyl), p-methoxybenzyl, trityl and the like. Suitable
protecting groups for carboxylic acid include alkyl, aryl or
arylalkyl esters. Protecting groups may be added or removed in
accordance with standard techniques, which are known to one skilled
in the art and as described herein. The use of protecting groups is
described in detail in Green, T. W. and P. G. M Wutz, Protective
Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill
in the art would appreciate, the protecting group may also be a
polymer resin such as a Wang resin, Rink resin or a
2-chlorotrityl-chloride resin.
[0528] It will also be appreciated by those skilled in the art,
although such protected derivatives of compounds of this disclosure
may not possess pharmacological activity as such, they may be
administered to a mammal and thereafter metabolized in the body to
form compounds of the disclosure which are pharmacologically
active. Such derivatives may therefore be described as "prodrugs".
All prodrugs of compounds of this disclosure are included within
the scope of the disclosure.
[0529] Furthermore, all compounds of the disclosure which exist in
free base or acid form can be converted to their pharmaceutically
acceptable salts by treatment with the appropriate inorganic or
organic base or acid by methods known to one skilled in the art.
Salts of the compounds of the disclosure can be converted to their
free base or acid form by standard techniques.
[0530] Where the preparation of starting materials is not
described, these are commercially available, known in the
literature or readily obtainable by those skilled in the art using
standard procedures. Where it is stated that compounds were
prepared analogously to earlier examples or intermediates, it will
be appreciated by the skilled person that the reaction time, number
of equivalents of reagents and temperature can be modified for each
specific reaction and that it may be necessary or desirable to
employ different work-up or purification techniques.
A: Compound Preparation
[0531] In the following examples, all non-aqueous reactions were
carried out in oven-dried or flame-dried glassware under nitrogen
atmosphere. All chemicals were purchased from commercial vendors
and used as is, unless otherwise specified. Reactions were
magnetically stirred and monitored by thin layer chromatography
(TLC) with 250 .mu.m pre-coated silica gel plates, visualized
either with UV, or in an iodine chamber. Flash column
chromatography was performed using silica gel (100-200 mesh).
Chemical shifts are reported relative to chloroform (.delta.7.26),
methanol (.delta.3.31), or DMSO (.delta.2.50) for .sup.1H NMR. HPLC
analysis was performed on Shimadzu 20AB HPLC system with a
photodiode array detector and Luna-C18(2) 2.0.times.50 mm, 5 .mu.m
column at a flow rate of 1.2 mL/min with a gradient solvent Mobile
phase A (MPA, H.sub.2O+0.037% (v/v) TFA): Mobile phase B (MPB,
ACN+0.018% (v/v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min,
80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS was detected
under 220 and 254 nm or used evaporative light scattering (ELSD)
detection as well as positive electrospray ionization (MS).
Semi-preparative HPLC was performed by either acidic or neutral
condition. Acidic: Luna C18 100.times.30 mm, 5 .mu.m; MPA:
HCl/H.sub.2O=0.04%, or formic acid/H.sub.2O=0.2% (v/v); MPB: ACN.
Neutral: Waters Xbridge 150.times.25, 5 .mu.m; MPA: 10 mM
NH.sub.4HCO, in H.sub.2O; MPB: ACN. Gradient for both conditions:
10% of MPB to 80% of MPB within 12 min at a flow rate of 20 mL/min,
then 100% MPB over 2 min, 10% MPB over 2 min, UV detector.
Example A-1
Synthesis of
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (A-1)
Methyl 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate
[0532] To a solution of 3-methyl-4-nitro-1H-pyrazole (40 g, 314.71
mmol) in DMF (700 mL) was added NaH (18.88 g, 472.06 mmol, 60%
purity) at 0.degree. C. over a period of 30 min under N.sub.2. The
reaction was then stirred at 25.degree. C. for 2 h followed by the
addition of methyl 2-bromo-2-methylpropanoate (85.46 g, 472.06
mmol, 61.04 mL) dropwise at 0.degree. C. The reaction mixture was
warmed to 25.degree. C. and stirred at 25.degree. C. for another 16
h. TLC (petroleum ether/ethyl acetate=5:1) showed the starting
material was consumed completely. The reaction was quenched by ice
water slowly and then extracted with EtOAc (3.times.700 mL). The
combined organic phase was washed with brine (3.times.200 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate=30:1-15:1), to yield the desired
product as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.29 (s, 1H), 3.72 (s, 1H), 2.51 (s, 1H), 1.84 (s, 6H).
2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoic acid
[0533] To a mixture of methyl
2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (69.7 g,
306.75 mmol) in THF (1 L) and H.sub.2O (250 mL) was added LiOH
H.sub.2O (15.45 g, 368.10 mmol) at 25.degree. C. under N.sub.2. The
mixture was then stirred at 25.degree. C. for 16 h. TLC (petroleum
ether/ethyl acetate=5:1) showed the reaction was completed. The
reaction mixture was concentrated in vacuo. The residual aqueous
solution was washed with ethyl acetate (50 mL). The aqueous phase
was then cooled to 0.degree. C., adjusted to approximately pH 1-2,
and filtered to yield the desired product as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 8.65 (s, 1H), 2.48 (s, 1H), 1.83
(s, 6H).
2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide
[0534] To a solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)
propanoic acid (25 g, 117.27 mmol) in DCM (500 mL) was added 8
drops of DMF, followed by oxalyl dichloride (29.77 g, 234.54 mmol)
at 0.degree. C. under N.sub.2. Then the mixture was stirred at
25.degree. C. for a further 2 h. TLC (petroleum ether/ethyl
acetate=3:1) showed reaction was completed. The reaction solution
was concentrated in vacuo. The residue solid was dissolved in THF
(300 mL) and added dropwise into a stirred solution of NH.sub.4OH
(413.61 g, 11.80 mol, 454.52 mL) at 0.degree. C. The reaction was
stirred at 25.degree. C. for 1 h. TLC (ethyl acetate) showed
reaction was completed. The solution was then concentrated in vacuo
and partitioned between EtOAc (100 mL) and water (100 mL), and the
aqueous phase was extracted with ethyl acetate (3.times.80 mL). The
combined organic phase was washed with brine (3.times.40 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo, to yield the desired compound as a yellow solid. .sup.1H NMR
(400 MHz, MeOD): .delta. 8.81 (s, 1H), 7.16-7.26 (m, 2H), 2.42 (s,
3H), 1.71 (s, 3H).
2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile
[0535] A solution of
2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide (22 g, 103.67
mmol) in POCl.sub.3 (132 g, 860.89 mmol, 80 mL) was stirred at
90.degree. C. for 1 h. TLC showed the reaction was completed. The
mixture was cooled to 20.degree. C. and concentrated in vacuo at
50.degree. C. The residue was poured into ice-water (w/w=1/1) (200
mL) and stirred for 10 min. The aqueous phase was adjusted to pH=7
with NaHCO.sub.3 solution, extracted with ethyl acetate (4.times.80
mL). The combined organic phase was washed with brine (40 mL),
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The desired product was afforded as a yellow solid.
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile
[0536] To a mixture of
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (10 g,
51.5 mmol) in EtOH (240 mL) and H.sub.2O (60 mL) was added
NH.sub.4Cl (13.77 g, 257.5 mmol) in one portion at 25.degree. C.,
followed by Fe (14.38 g, 257.5 mmol). The mixture was heated to
80.degree. C. and stirred for 1 h. TLC showed the reaction was
completed. The solution was cooled to 20.degree. C. The mixture was
extracted with ethyl acetate (3.times.100 mL), the combined organic
layers were washed with NaHCO.sub.3 solution (50 mL) and brine (50
mL). The organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated. The desired product was afforded as a dark brown
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.17 (s, 1H),
2.18 (s, 3H), 1.91 (s, 6H).
2-[4-[(5-trifluoromethyl-4-chloro-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-
-yl]-2-methyl-propanenitrile
[0537] A mixture of 2,4-dichloro-5-(trifluoromethyl) pyrimidine
(2.00 g, 9.22 mmol),
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (1.51
g, 9.22 mmol), NaHCO.sub.3 (2.32 g, 27.66 mmol, 1.08 mL) in
acetonitrile (20 mL) was stirred at 25.degree. C. for 3 h under
N.sub.2 atmosphere. LC-MS showed complete reaction of starting
material. Two new peaks were shown in LC-MS and 85% of desired
compound was detected. The reaction mixture was filtered and the
filtrate was concentrated in vacuo to afford the crude desired
product as a brown oil. The crude product was often used in the
next synthetic step without further purification. A portion of the
crude product was purified by prep-HPLC the pure desired product
was afforded as a white solid. .sup.1H NMR (CDCl3 400 MHz): .delta.
8.48-8.68 (m, 1H), 8.15 (s, 1H), 6.97 (bs, 1H), 2.29 (s, 3H), 2.01
(s, 6H).
2-[4-[(5-trifluoromethyl-4-cyclopropyl-pyrimidin-2-yl)amino]-3-methyl-pyra-
zol-1-yl]-2-methyl-propanenitrile (A-1)
[0538] A mixture of
2-[4-[(5-trifluoromethyl-4-chloro-pyrimidin-2-yl)amino]-3-methyl-pyrazol--
1-yl]-2-methyl-propanenitrile (100.00 mg, 290.09 .mu.mol, 1.00 eq),
cyclopropylboronic acid (124.59 mg, 1.45 mmol), Pd(OAc).sub.2 (6.51
mg, 29.01 .mu.mol, 0.10 eq), PCy.sub.3 (16.27 mg, 58.02 .mu.mol,
18.70 .mu.L) and CsF (132.19 mg, 870.27 .mu.mol, 32.09 .mu.L) in
dioxane (5.00 mL) was de-gassed under N.sub.2 and then heated to
90.degree. C. for 12 hours under N.sub.2. LC-MS was used to monitor
reaction progress. The reaction mixture was diluted with H.sub.2O
(20 mL) and extracted with ethyl acetate (3.times.20 mL). The
combined organic layers were washed with brine (5 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a
residue. The residue was purified by column chromatography
(SiO.sub.2, petroleum ether/ethyl acetate=10:1-3:1) followed by
prep-HPLC (neutral condition) to provide the title compound.
.sup.1H NMR (CDCl.sub.3 400 MHz): .delta. 8.45 (s, 1H), 8.12 (s,
1H) 6.73 (bs, 1H), 2.20-2.34 (m, 4H), 2.00 (s, 6H), 1.26-1.35 (m,
2H), 1.11-1.23 (m, 2H). HPLC: RT 3.1 min. MS: m/z: 351.2
[M+H].sup.+.
Example A-2
Synthesis of
2-[4-[(5-chloro-4-cyclopropyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl-
]-2-methyl-propanenitrile (A-2)
2,5-dichloro-4-cyclopropyl-pyrimidine
[0539] A mixture of 2,4,5-trichloropyrimidine (750 mg, 4.09 mmol),
cyclopropylboronic acid (1.76 g, 20.45 mmol), CsF (1.86 g, 12.27
mmol), Pd(OAc).sub.2 (91 mg, 409 u.mu.mol) and PCy.sub.3 (114 mg,
409 .mu.mol) in 1,4-dioxane (20 mL) was degassed and purged with
N.sub.2 for 3 times, and then the mixture was stirred at 90.degree.
C. for 16 h under N.sub.2 atmosphere. The solution was concentrated
in vacuo. To the residue was added water (20 mL), extracted with
ethyl acetate (3.times.15 mL). The organic layers were combined,
washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated to give a crude product. The crude product was
purified by silica gel column chromatography (petroleum ether/ethyl
acetate=100% petroleum ether-10:1) to afford the crude desired
compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.8.38 (s, 1H),
3.72 (s, 1H), 2.44.about.2.49 (m, 1H), 1.23.about.1.32 (m, 4H).
LC/MS: RT 0.833 min, m/z=188.9, 190.9 [M+H].sup.+.
2-[4-[(5-chloro-4-cyclopropyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-yl]-
-2-methyl-propanenitrile (A-2)
[0540] To a solution of 2,5-dichloro-4-cyclopropyl-pyrimidine (230
mg, 547.50 .mu.mol) and
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile
(prepared as described in the examples above; 404 mg, 2.46 mmol) in
1,4-dioxane (10 mL) was added p-TsOH (9 mg, 54.75 .mu.mol). The
mixture was stirred at 100.degree. C. for 16 h. The mixture was
concentrated in vacuo. To the residue was added water (10 mL),
adjusted to pH=7 with NaHCO.sub.3 solution, extracted with ethyl
acetate (3.times.10 mL). The organic layers were combined, washed
with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified by prep-HPLC
(neutral condition) and lyophilized to provide the title compound.
.sup.1H NMR (400 MHz, CDCl3): .delta.8.19 (s, 1H), 8.10 (s, 1H),
6.44 (br, 1H), 2.41.about.2.47 (m, 1H), 2.27 (s, 3H), 2.00 (s, 6H),
1.20.about.1.21 (m, 2H), 1.14.about.1.16 (m, 2H). HPLC: RT 3.34
min. MS: (M+H+) m/z: 317.1.
Example A-3
Synthesis of
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-
-pyrimidine-5-carbonitrile (A-3)
4-chloro-2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]pyrimi-
dine-5-carbonitrile
[0541] To a solution of 2,4-dichloropyrimidine-5-carbonitrile (530
mg, 3.05 mmol) in CH.sub.3CN (10 mL) was added NaHCO.sub.3 (768 mg,
9.15 mmol) and
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (500
mg, 3.05 mmol) at 25.degree. C. The mixture was stirred at
25.degree. C. for 16 h. The solution was concentrated in vacuo to
give a residue. To the residue was added water (20 mL), extracted
with ethyl acetate (3.times.15 mL). The organic layers were
combined, washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
and filtered. The filtrate was concentrated in vacuo to give a
crude product. The crude product was purified by prep-HPLC (neutral
condition). The eluent was extracted with ethyl acetate (3.times.20
mL), washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to afford the desired crude
product as a brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta.8.51.about.8.61 (m, 1H), 8.13 (s, 1H), 7.08.about.7.15 (m,
1H), 2.28.about.2.30 (m, 3H), 2.01 (s, 6H). LC/MS: RT 0.750 min,
m/z=302.0 [M+H].sup.+.
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl--
pyrimidine-5-carbonitrile (A-3)
[0542] A mixture of
4-chloro-2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]pyrim-
idine-5-carbonitrile (140 mg, 463.99 .mu.mol), cyclopropylboronic
acid (199 mg, 2.32 mmol), K.sub.3PO.sub.4 (295 mg, 1.39 mmol),
Pd(dppf)Cl.sub.2 (34 mg, 46.40 .mu.mol) and Ag.sub.2O (11 mg, 46.40
.mu.mol) in 1,4-dioxane (1 mL) was degassed and purged with N.sub.2
for 3 times, and then the mixture was stirred at 80.degree. C. for
16 h under N.sub.2. The solution was concentrated in vacuo to give
a residue. To the residue was added water (10 mL), extracted with
ethyl acetate (3.times.10 mL). The organic layers were combined,
washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The crude product was purified by
prep-HPLC (neutral condition) and lyophilized to afford the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.43.about.8.50 (m, 1H), 8.10 (s, 1H), 6.73.about.6.94 (m, 1H),
2.37 (m, 1H), 2.28 (s, 3H), 1.99 (s, 6H), 1.30 (m, 4H). HPLC: RT 80
min. MS: m/z: 308.2 [M+H].sup.+.
Example A-4
Synthesis of
2-[4-[[4-(cyclopenten-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-me-
thyl-pyrazol-1-yl]-2-methyl-propanenitrile (A-4); and
2-[4-[[4-cyclopentyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-py-
razol-1-yl]-2-methyl-propanenitrile (A-10)
2-[4-[[4-(cyclopenten-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-me-
thyl-pyrazol-1-yl]-2-methyl-propanenitrile (A-4)
[0543]
2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1-
H-pyrazol-1-yl)-2-methylpropanenitrile was prepared according to
the procedures described above. A mixture of
2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyra-
zol-1-yl)-2-methylpropanenitrile (300 mg, 870.27 .mu.mol),
cyclopenten-1-ylboronic acid (584 mg, 5.22 mmol), Cs.sub.2CO.sub.3
(850 mg, 2.61 mmol) and Pd(dppf)Cl.sub.2 (63 mg, 87.03 .mu.mol) in
1,4-dioxane (3 mL), acetonitrile (3 mL) and H.sub.2O (1 mL) was
degassed and purged with N.sub.2 for 3 times, and then the mixture
was stirred at 90.degree. C. for 16 h under N.sub.2. The reaction
mixture was concentrated in vacuo to remove solvent. The residue
was purified by prep-TLC (SiO.sub.2, petroleum ether/ethyl
acetate=4:1) to afford title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta.8.61 (s, 1H), 8.24 (s, 1H), 6.88 (s, 1H), 2.86
(s, 2H), 2.62 (s, 2H), 2.29 (s, 1H), 2.02-2.07 (m, 2H), 2.00 (s,
6H). HPLC: RT 3.69 min. MS: m/z: 399.1 [M+Na].sup.+
2-[4-[[4-cyclopentyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyr-
azol-1-yl]-2-methyl-propanenitrile (A-10)
[0544] To a solution of
2-[4-[[4-(cyclopenten-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-me-
thyl-pyrazol-1-yl]-2-methyl-propanenitrile (200 mg, 0.53 mmol) in
EtOAc (20 mL) was added Pd/C (10%, 0.1 g) under N.sub.2. The
suspension was degassed and purged with H.sub.2 for 3 times. The
mixture was stirred under H.sub.2 (15 psi) at 25.degree. C. for 3
h. The reaction solution was filtered through a pad of celite. The
filtrate was concentrated in vacuo to give a crude product. The
crude product was purified by prep-HPLC (neutral condition) and
lyophilized to afford title compound. .sup.1H NMR (400 MHz,
CDCl.sup.3): .delta. 8.51 (s, 1H), 8.25 (s, 1H), 6.80 (s, 1H), 3.40
(m, 1H), 2.31 (s, 3H), 2.00.about.2.04 (m, 8H), 1.91 (m, 4H), 1.73
(m, 2H). HPLC: RT 3.06 min. NIS: m/z: 379.2 [M+H].sup.+
Example A-5
Synthesis of
2-(5-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1-methyl-1H-
-pyrazol-3-yl)-2-methylpropanenitrile (A-5)
2,2-dimethyl-3-oxopentanedinitrile
[0545] A stirred suspension of NaH (1.3 g, 31.88 mmol, 60% purity)
in THF (25 mL) was heated to 75.degree. C. To this was added a
mixture of 2,2-dimethyl-2-cyanoacetic acid ethyl ester (3 g, 21.25
mmol) and CH.sub.3CN (1.7 mL, 31.88 mmol) in THF (20 mL) dropwise
over a period of 45 min. The resulting pale yellow suspension was
heated at 70.degree. C. for a further 15 h. The reaction mixture
was poured into water (150 mL) and the resulting solution was
extracted with EtOAc (2.times.100 mL). The aqueous layer was
separated, acidified to pH 2 with aqueous 1 M HCl, and extracted
with EtOAc (2.times.100 mL). The combined organic layers were dried
over Na.sub.2SO.sub.4 and then concentrated under reduced pressure
to afford 2,2-dimethyl-3-oxopentanedinitrile as yellow oil. LCMS:
RT 0.213 min, m/z=137.1 [M+H].sup.+.
2-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile
[0546] A mixture of 2,2-dimethyl-3-oxopentanedinitrile (5-2)(500
mg, 3.67 mmol) and methylhydrazine (0.2 mL, 3.67 mmol) in EtOH (20
mL) was treated with cone HCl (0.4 mL, 11 mmol) in at 25.degree. C.
The mixture was stirred at 90.degree. C. for 12 h. The mixture was
poured into ice-water (20 mL) and extracted with EtOAc (20
mL.times.3). The combined organic phase was concentrated under
reduced pressure to give a residue. The residue was purified on a
short silica gel plug eluting with DCM to DCM:MeOH (10:1) to give
2-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile as a
yellow oil. LCMS: RT 0.456 min, m/z=165.2 [M+H].sup.+.
2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine
[0547] To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine
(300 mg, 1.38 mmol) in CH.sub.3CN (9 mL) and H.sub.2O (9 mL) was
added cyclopropane carboxylic acid (357 mg, 4.14 mmol),
(NH.sub.4).sub.2S.sub.2O.sub.8 (1.57 g, 6.90 mmol) and AgNO.sub.3
(940 mg, 5.52 mmol) at 25.degree. C. The reaction mixture was
warmed to 60.degree. C. and stirred for 6 h under N.sub.2. The
reaction was quenched by ice water and then extracted with EtOAc
(20 mL.times.3). The combined organic phase was washed with brine
(20 mL.times.3), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by prep-TLC (PE:EtOAc=20:1), to give
2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine as a colorless
oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.57 (s, 1H),
2.17-2.26 (m, 1H), 1.31-1.40 (m, 2H), 1.16-1.25 (m, 3H).
2-(5-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1-methyl-1H--
pyrazol-3-yl)-2-methylpropanenitrile (A-5)
[0548] To a solution of
2-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (100
mg, 0.6 mmol) in n-BuOH (1 mL) was added
2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (136 mg, 0.6
mmol) and a drop of trifluoroacetic acid (5.00 .mu.L) at 25.degree.
C. The solution was stirred at 100.degree. C. for 1.5 h under
microwave irradiation. The mixture was concentrated under reduced
pressure to give a residue. The residue was purified by prep-HPLC
(column: Luna C8 100*30 5 u; liquid phase: [A-10 mM
NH.sub.4HCO.sub.3 in H.sub.2O; B-ACN] B %: 35%-60%, 12 min]) to
give
2-(5-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1-methyl-1H-
-pyrazol-3-yl)-2-methylpropanenitrile. .sup.1H NMR: (400 MHz,
DMSO): .delta. 8.57 (s, 1H), 7.26 (br. s., 1H), 6.26 (s, 1H), 3.62
(s, 3H), 2.06-2.16 (m, 1H), 1.60 (s, 6H), 1.12 (d, J=6.4 Hz, 4H).
HPLC: RT 3.34 min. MS: m/z: 351.1 [M+H].sup.+.
Example A-6
Synthesis of
2-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-cyclopentylp-
yrimidine-5-carbonitrile (A-6)
[0549] This compound can be synthesized using a method analogous to
Example A-4 or Example A-10.
Example A-7
Synthesis of
4-cyclopropyl-N-(3-methyl-1-methylsulfonyl-pyrazol-4-yl)-5-(trifluorometh-
yl)pyrimidin-2-amine (A-7)
3-methyl-1-methylsulfonyl-4-nitro-pyrazole
[0550] To a mixture of 3-methyl-4-nitro-1H-pyrazole (1 g, 7.87
mmol) and triethylamine (1.59 g, 15.74 mmol) in DCM (50 mL) was
added MsCl (1.35 g, 11.81 mmol) dropwise at 0.degree. C. Then the
mixture was stirred at 25.degree. C. for 12 h. The mixture was
poured into aq. sat. NH.sub.4Cl (10 mL). The aqueous phase was
extracted with ethyl acetate (4.times.20 mL). The combined organic
phase was washed with brine (4.times.20 mL), dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography (petroleum
ether/ethyl acetate=3:1) to afford the desired compound as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.8.760 (s, 1H),
3.468 (s, 3H) 2.651 (s, 3H). LC/MS: RT 0.569 min, m/z=206
[M+H].sup.+.
3-methyl-1-methylsulfonyl-pyrazol-4-amine
[0551] To a solution of 3-methyl-1-methylsulfonyl-4-nitro-pyrazole
(600 mg, 2.92 mmol) in ethanol (10 mL) and water (5 mL) was added
Fe (817 mg, 14.62 mmol) and NH.sub.4Cl (782 mg, 14.62 mmol). The
reaction was stirred at 80.degree. C. for 2 h. The reaction mixture
was filtered and the filtrate was concentrated. The mixture was
added with water (10 mL) and extracted with ethyl acetate
(3.times.20 mL). The combined organic phase was washed with brine
(10 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to afford the desired product. LC/MS: RT
0.094 min, m/z=176 [M+H].sup.+.
4-chloro-N-(3-methyl-1-methylsulfonyl-pyrazol-4-yl)-5-(trifluoromethyl)
pyrimidin-2-amine
[0552] To a mixture of 3-methyl-1-methylsulfonyl-pyrazol-4-amine
(346 mg, 1.97 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine
(427 mg, 1.97 mmol) in acetonitrile (10 mL) was added NaHCO.sub.3
(418 mg, 3.94 mmol) in one portion at 25.degree. C. The mixture was
stirred at 25.degree. C. for 12 h. The reaction mixture was
filtered and the filtrate was concentrated in vacuo. The residue
was purified by prep-HPLC (TFA acidic) to afford the desired
product as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta.8.672 (s, 1H), 8.577 (s, 1H) 7.112 (s, 1H) 3.331 (s, 1H)
2.398 (s, 1H). LC/MS: RT 0.830 min, m/z=356 [M+H].sup.+.
4-cyclopropyl-N-(3-methyl-1-methylsulfonyl-pyrazol-4-yl)-5-(trifluoromethy-
l)pyrimidin-2-amine (A-7)
[0553] To a mixture of
4-chloro-N-(3-methyl-1-methylsulfonyl-pyrazol-4-yl)-5-(trifluoromethyl)
pyrimidin-2-amine (250 mg, 702.80 .mu.mol) and cyclopropylboronic
acid (362 mg, 4.22 mmol) in 1,4-dioxane (5 mL) was added CsF (320
mg, 2.11 mmol), Pd(OAc).sub.2 (15.8 mg, 70.28 .mu.mol) and
PCy.sub.3 (19.7 mg, 70.28 .mu.mol) in one portion at 25.degree. C.
under N.sub.2. The mixture was stirred at 90.degree. C. for 12 h.
The mixture was cooled to 25.degree. C. and concentrated in vacuo
at 35.degree. C. The residue was poured into water (10 mL). The
aqueous phase was extracted with ethyl acetate (3.times.20 mL). The
combined organic phase was washed with brine (3.times.20 mL), dried
with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by prep-HPLC to afford title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.8.524 (s, 2H),
6.757 (s, 1H), 3.300 (s, 3H) 2.400 (s, 3H) 2.290 (s, 1H) 1.333 (s,
2H) 1.229 (s, 2H). HPLC: RT 3.36 min. MS: m/z: 362.1[M+H].sup.+
Example A-8
Synthesis of
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-y-
l)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-8)
(E)-N-((dimethylamino)methylene)-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-
-yl)propanamide
[0554] 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide
used as starting material for this reaction was prepared according
to the procedure described in the above examples. A mixture of
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (5 g,
23.56 mmol) and DMF-DMA (28.07 g, 235.60 mmol) was stirred at
95.degree. C. for 2 h. The mixture was concentrated in vacuo to
give afford the crude desired product as a brown oil. The crude
product was used in the next synthetic step without further
purification. LC/MS: RT 0.655 min, m/z=268 [M+H].sup.+.
3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole
[0555] To a solution of
(E)-N-((dimethylamino)methylene)-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol--
1-yl)propanamide (6.6 g, 24.69 mmol) in acetic acid (50 mL) was
added NH.sub.2--H.sub.2O (18.92 g, 370.35 mmol, 18.37 mL, 98%
purity). The mixture was stirred at 95.degree. C. for 1.5 h. The
reaction mixture was adjusted by addition of sat. NaHCO.sub.3 (200
mL) at 0.degree. C. to pH=9, and then extracted with ethyl acetate
(3.times.100 mL). The combined organic layers were washed with
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to afford the crude desired product as a
brown solid. The crude product was used in the next synthetic step
without further purification. LC/MS: RT 0.581 min, m/z=237
[M+H].sup.+.
1-methyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-tria-
zole
[0556] To a solution of
3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole
(6 g, 25.40 mmol) in acetonitrile (30 mL) was added methyl iodide
(4.33 g, 30.48 mmol) and then Cs.sub.2CO.sub.3 (8.28 g, 25.40
mmol). The mixture was stirred at 50.degree. C. for 12 h. The
reaction mixture was filtered and the filtrate was concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate=5:1-100% ethyl acetate) to
afford the desired product as a yellow oil. .sup.1H NMR (400 MHz,
CDCl3): .delta. ppm 8.18-8.21 (m, 1H) 7.98-8.01 (m, 1H) 3.92 (s,
3H) 2.53 (s, 3H) 2.03 (s, 6H). LC/MS: RT 0.638 min, m/z=251
[M+H].sup.+.
3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-am-
ine
[0557] To a solution of
1-methyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-tri-
azole (2.8 g, 11.19 mmol) in ethanol (50 mL) was added Pd--C (10%,
0.95 g) under N.sub.2. The suspension was degassed in vacuo and
purged with H.sub.2 several times. The mixture was stirred under
H.sub.2 (15 psi) at 50.degree. C. for 2 h. The reaction mixture was
filtered and the filtrate was concentrated in vacuo to afford the
crude desired product as a brown solid. The crude product was used
in the next synthetic step without further purification. .sup.1H
NMR (400 MHz, CDCl3): .delta. 7.90-7.94 (m, 1H) 7.13 (s, 1H) 3.88
(s, 3H) 2.17 (s, 3H) 1.97 (s, 6H).
4-chloro-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H--
pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
[0558] A mixture of
3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-a-
mine (400 mg, 1.82 mmol),
2,4-dichloro-5-(trifluoromethyl)pyrimidine (394.9 mg, 1.82 mmol)
and NaHCO.sub.3 (458.69 mg, 5.46 mmol) in CH.sub.3CN (4 mL) was
stirred at 25.degree. C. for 3 h under N.sub.2. The reaction
mixture was filtered and the filtrate was concentrated in vacuo.
The residue was purified by prep-HPLC (neutral condition) to afford
the desired compound as an off-white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. ppm 8.39-8.62 (m, 1H) 7.89-8.10 (m, 2H)
6.87-7.09 (m, 1H) 3.90 (s, 3H) 2.23 (s, 3H) 2.05 (s, 6H). LC/MS: RT
0.785 min, m/z=401 [M+H].sup.+.
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl-
)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-8)
[0559] A mixture of
4-chloro-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-
-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 249.51
.mu.mol), cyclopropylboronic acid (107.16 mg, 1.25 mmol),
Pd(OAc).sub.2 (5.6 mg, 24.95 .mu.mol), PCy.sub.3 (13.99 mg, 49.90
.mu.mol) and CsF (113.7 mg, 748.53 .mu.mol) in dioxane (2 mL) was
stirred at 90.degree. C. for 12 h under N.sub.2. The mixture was
filtered and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate=10:1-100% ethyl acetate), and further purified by prep-HPLC
(neutral condition) to provide title compound. .sup.1H NMR (400
MHz, CDCl3): .delta. 8.32-8.44 (m, 1H) 7.81-8.02 (m, 2H) 6.59-6.86
(m, 1H) 3.91 (s, 3H) 2.24 (m, 4H) 2.04 (s, 6H) 1.17-1.29 (m, 2H)
1.03-1.14 (m, 2H). LC/MS: RT 2.707 min. MS: m/z: 407.2
[M+H].sup.+
Example A-9
Synthesis of
2-methyl-2-(3-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-
pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile (A-9)
2-methyl-2-(3-methyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)p-
yrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile (A-9)
[0560]
2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1-
H-pyrazol-1-yl)-2-methylpropanenitrile was prepared according to
the procedure described in the above examples. To a solution of
2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyra-
zol-1-yl)-2-methylpropanenitrile (150 mg, 0.4 mmol) in dioxane (8
mL) and water (2 mL) was added
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(109 mg, 0.5 mmol) and K.sub.2CO.sub.3 (180 mg, 1.3 mmol) at
25.degree. C. The solution was degassed with nitrogen for 5 min
followed by addition of Pd(dppf)Cl.sub.2 (32 mg, 0.04 mmol) under
N.sub.2. The mixture was stirred at 90.degree. C. for 12 h. The
mixture was concentrated in vacuo to give a residue. The residue
was purified by prep-HPLC (neutral condition) to provide the title
compound. .sup.1H NMR (400 MHz, DMSO): .delta. 9.36-9.71 (m, 1H),
8.66 (s, 1H), 8.21 (s, 1H), 7.91 (br. s., 1H), 3.91 (s, 3H), 2.18
(br. s., 3H), 1.94 (s, 6H). HPLC: RT 2.92 min. MS: m/z: 391.1
[M+H].sup.+.
Example A-10
Synthesis of
2-[4-[[4-cyclobutyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyr-
azol-1-yl]-2-methyl-propanenitrile (A-11)
2-[4-[[4-cyclobutyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyra-
zol-1-yl]-2-methyl-propanenitrile (A-11)
[0561] To a solution of 2,5-dichloro-4-cyclobutylpyrimidine (200
mg, 845.24 .mu.mol) and
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (139
mg, 845.24 .mu.mol) in 1,4-dioxane (5 mL) was added p-TsOH (87 mg,
507.14 .mu.mol). The mixture was stirred at 100.degree. C. for 12
h. To the solution was added aq. sat. NaHCO.sub.3 solution (15 mL),
stirred for 10 min, the aqueous phase was extracted with EtOAc
(3.times.10 mL). The organic layers were combined, washed with
brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral condition) to give
2-(4-((5-chloro-4-cyclobutylpyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-y-
l)-2-methylpropanenitrile. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.06-8.59 (m, 2H), 6.90 (br. s., 1H), 3.88 (s., 1H),
2.46-2.58 (m, 2H), 2.24-2.40 (m, 5H), 1.91-2.18 (m, 8H). HPLC: RT
3.76 min. MS: (M+H.sup.+) m/z: 365.1.
Example A-11
Synthesis of
2-(4-((4-2-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3--
methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (A-12 and A-13)
4-(2-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine
[0562] To a solution of
2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (500 mg, 2.21
mmol) in CH.sub.3CN (15 mL) and H.sub.2O (15 mL) was added
2-fluorocyclopropanecarboxylic acid (207 mg, 2.0 mmol),
(NH.sub.4).sub.2S.sub.2O.sub.8 (2.5 g, 11 mmol) and AgNO.sub.3 (1.5
g, 8.8 mmol). Then the mixture was stirred at 25.degree. C. for 12
h. The resulting mixture was extracted with EtOAc (3.times.15 mL).
The combined organic extracts were concentrated under reduced
pressure to give residue. The residue was purified by prep-TLC
(PE:EtOAc=1:1) to give
4-(2-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine
as a white solid. LCMS: RT 0.787 min, m/z=285.1 [M+H].sup.+.
2-(4-((4-(2-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3--
methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (A-12 and A-13)
[0563] To a solution of
4-(2-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine
(50 mg, 0.176 mmol) in dioxane (1 mL) was added
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (35 mg,
0.221 mmol) and p-TsOH (9.1 mg, 0.05 mmol) under N.sub.2. Then the
mixture was stirred at 100.degree. C. for 1 h. The mixture was
concentrated under reduced pressure to give a residue. The residue
was purified by prep-HPLC (neutral condition) to give the crude
material, which was further purified by chiral SFC to give two
peaks of
2-(4-((4-(2-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-
-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile; peak 1 and peak
2.
[0564] Peak 1: .sup.1H NMR (400 MHz, CHLOROFORM-d): .delta. 8.49
(br. s., 1H), 8.06 (br. s., 1H), 4.88-5.08 (m, 1H), 2.68 (br. s.,
1H) 2.28 (s, 3H), 1.99 (s, 6H), 1.58-1.60 (m, 2H). HPLC: RT 2.958
min. MS: (M+H.sup.+) m/z: 369.2.
[0565] Peak 2: .sup.1H NMR (400 MHz, CHLOROFORM-d): .delta. 8.49
(br. s., 1H), 8.06 (br. s., 1H), 4.87-5.07 (m, 1H), 2.70 (br. s.,
1H), 2.27 (s, 3H), 1.99 (s, 6H) 1.62 (d, J=6.2 Hz, 2H). HPLC: RT
2.956 min. MS: (M+H.sup.+) m/z: 369.2.
Example A-12
Synthesis of 4-cyclopropyl-N-[3-methyl-1-(oxetan-3-yl)
pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl-
)pyrimidin-2-amine (A-14 and A-15)
3-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and
5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole
[0566] To a solution of PPh.sub.3 (20.64 g, 78.68 mmol) in THF (30
mL) was added DIAD (15.91 g, 78.68 mmol, 15.30 mL),
3-methyl-4-nitro-1H-pyrazole (5 g, 39.34 mmol) and oxetan-3-ol
(2.91 g, 39.34 mmol) at 0.degree. C. Then the mixture was stirred
at 25.degree. C. for 12 h. The mixture was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (SiO.sub.2, PE:EtOAc=50:1 to 5:1). The mixture of
3-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and
5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole was obtained as a yellow
solid.
3-methyl-1-(oxetan-3-yl)pyrazol-4-amine and
5-methyl-1-(oxetan-3-yl)-pyrazol-4-amine
[0567] To a solution of Pd/C (3 g, 10% purity) in MeOH (10 mL) was
added 3-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and
5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole (5 g, 37.3 mmol), then the
mixture was stirred at 25.degree. C. under H.sub.2 (15 psi) for 2
h. The reaction was filtered and the filtrate was concentrated
under reduced pressure to give
3-methyl-1-(oxetan-3-yl)pyrazol-4-amine and
5-methyl-1-(oxetan-3-yl)-pyrazol-4-amine as a dark brown oil.
4-cyclopropyl-N-[3-methyl-1-(oxetan-3-yl)
pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl-
)pyrimidin-2-amine (A-14 and A-15)
[0568] 2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (300
mg, 1.35 mmol), 3-methyl-1-(oxetan-3-yl)pyrazol-4-amine,
5-methyl-1-(oxetan-3-yl)-pyrazol-4-amine (271 mg, 1.77 mmol) and
TEA (273 mg, 2.7 mmol, 374.26 .mu.L) were taken up into a microwave
tube in n-BuOH (8 mL). The sealed tube was heated at 120.degree. C.
for 90 min under microwave. After cooling to 25.degree. C., the
mixture was concentrated under reduced pressure. The residue was
purified by prep-TLC (SiO.sub.2, PE:EtOAc=3:1 to 1:1) to provide
4-cyclopropyl-N-[3-methyl-1-(oxetan-3-yl)
pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl-
)pyrimidin-2-amine (A-14 and A-15).
4-cyclopropyl-N-[3-methyl-1-(oxetan-3-yl)
pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-14)
[0569] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.45 (s, 1H),
8.01 (br. s., 1H), 6.68 (br. s., 1H), 5.38 (quin, J=6.93 Hz, 1H),
5.06 (d, J=6.65 Hz, 4H), 2.29 (s, 3H), 2.25 (br. s., 1H), 1.60 (s,
2H), 1.24-1.33 (m, 2H), 1.15 (br. s., 2H). HPLC: RT 2.97 min MS:
(M+H.sup.+) m/z=340.1.
4-cyclopropyl-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)-
pyrimidin-2-amine (A-15)
[0570] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.39 (s, 1H),
7.75 (br. s., 1H), 6.50 (br. s., 1H), 5.41 (quin, J=7.06 Hz, 1H),
5.24 (t, J=6.40 Hz, 2H), 4.94-5.05 (m, 2H), 2.13-2.24 (m, 4H), 1.24
(br. s., 2H), 1.10 (dd, J=7.50, 3.09 Hz, 2H). HPLC: RT 2.93 min.
MS: (M+H) m/z=340.1.
Example A-13
Synthesis of
4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-tria-
zol-3-yl]ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine
(A-16)
3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1-(trideuteriomethyl)--
1,2,4-triazole
[0571] To a solution of
3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole
(1 g, 4.23 mmol) in CH.sub.3CN (15 mL) was added Cs.sub.2CO.sub.3
(1.38 g, 4.23 mmol) and tridcuterio(iodo)methane (720 mg, 5.08
mmol, 309 .mu.L). The mixture was stirred at 50.degree. C. for 12
h. The reaction mixture was filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=5:1 to 0:1) to give
3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1-(trideuteriome-
thyl)-1,2,4-triazole as an off-white solid. LCMS: RT 0.633 min,
m/z=254 [M+H].sup.+.
3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]pyr-
azol-4-amine
[0572] To a solution of
3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1-(trideuteriomethyl)-
-1,2,4-triazole (300 mg, 1.18 mmol) in EtOH (10 mL) was added Pd--C
(10%, 0.125 g) under N.sub.2. The suspension was degassed under
vacuum and purged with H.sub.2 several times. The mixture was
stirred under H.sub.2 (15 psi) at 50.degree. C. for 2 h. The
reaction mixture was filtered and the filtrate was concentrated to
give
3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]py-
razol-4-amine as a brown solid. The crude product was used into the
next step without further purification. LCMS: RT 0.225 min, m/z=224
[M+H].sup.+.
4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triaz-
ol-3-yl]ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine
(A-16)
[0573] To a solution of
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (346
mg, 1.30 mmol) and
3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]ethyl]py-
razol-4-amine (290 mg, 1.30 mmol) in 1,4-dioxane (10 mL) was added
p-TsOH (67 mg, 390.00 .mu.mol). The mixture was stirred at
100.degree. C. for 2 h. The reaction mixture was diluted with
H.sub.2O (50 mL) and extracted with EtOAc (3.times.20 mL). The
combined organic layers were washed with brine (5 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (neutral condition) to give
title compound
4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-[1-(trideuteriomethyl)-1,2,4-tria-
zol-3-yl]ethyl]pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine
(A-16). .sup.1H NMR: (400 MHz, CHLOROFORM-d): .delta. 8.30-8.56 (m,
1H), 7.79-8.14 (m, 2H), 6.52-6.93 (m, 1H), 2.14-2.30 (m, 4H), 2.04
(s, 6H), 1.18-1.26 (m, 2H), 1.04-1.14 (m, 2H). HPLC: RT 2.429 min.
MS: (M+H.sup.+) m/z: 410.2.
Example A-14
Synthesis of
2-(3-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-
-pyrazol-1-yl)-2-methylpropanenitrile (A-17)
3-chloro-1H-pyrazol-4-amine hydrochloride
[0574] Into a 2 L three-necked round-bottom flask affixed with an
overhead stirrer, a temperature probe, an addition funnel and a
nitrogen inlet were added ethanol (500 mL) and 4-nitro-1H-pyrazole
(40 g, 354 mmol). To this solution was added, in one portion, conc.
HCl (290 mL) (note: rapid exotherm observed from 15.degree. C. to
39.degree. C.) and the resulting mixture was purged with nitrogen
for 5 minutes. Palladium on alumina (5% w/w) (2.1 g) was added to
the mixture and stirred at room temperature while triethylsilane
(208 g, 1789 mmol) was added dropwise over 2 h. The reaction, which
started to slowly exotherm from 35.degree. C. to 45.degree. C. over
1 h, was stirred for a total of 16 h and vacuum filtered through a
plug of celite to give a biphasic mixture. The mixture was
transferred to a separatory funnel. The bottom aqueous layer was
collected and rotary evaporated to dryness with the aid of
acetonitrile (3.times.100 mL). The resulting yellow solid was
suspended in acetonitrile (100 mL) and allowed to stand for 0.5 h
at room temperature followed by 1 h at 0.degree. C. The solids were
filtered and washed with acetonitrile (50 mL) to afford
3-chloro-1H-pyrazol-4-amine hydrochloride as a white solid, which
was used to next step without purification. LCMS: RT 0.1 min,
m/z=118 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6): .delta. 10.49
(br. s, 2H), 8.02 (s, 0.59H), 7.74 (s, 0.31H), 5.12 (br. s,
1H).
tert-butyl (3-chloro-1H-pyrazo4-yl) carbamate
[0575] Into a 2 L round bottom flask was added
3-chloro-1H-pyrazo4-amine hydrochloride (30 g, 195 mmol) and THF
(150 mL). To this mixture were added di-tert-butyldicarbonate (46.8
g, 214 mmol) followed by sodium bicarbonate (36 g, 428.7 mmol) and
water (15 mL). The mixture was stirred for 16 h, diluted with water
(150 mL) and ethyl acetate (150 mL) and transferred to a separatory
funnel. This gave three layers; bottom--a white gelatinous
precipitate, middle-light yellow aqueous, top-auburn organic. The
phases were separated collecting the white gelatinous precipitate
and the aqueous layer together. The aqueous was extracted with
ethyl acetate (2.times.100 mL) and the ethyl acetate extracts were
combined, washed with brine (80 mL), dried over anhydrous sodium
sulfate, filtered and rotary evaporated to give crude product. The
crude product was purified by column chromatography (PE:EtOAc=6:1
to 3:1) to get tert-butyl (3-chloro-1H-pyrazo4-yl) carbamate as a
white solid. LCMS: RT 0.66 min, m z=218 [M+H].sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 11.04 (br. s, 1H), 7.91 (br. s, 1H),
6.28 (br. s, 1H), 1.52 (s, 9H).
Methyl
2-(4-((tert-butoxycarbonyl)amino)-3-chloro-1H-pyrazol-1-yl)-2-methy-
lpropanoate
[0576] To a solution of tert-butyl
N-(3-chloro-1H-pyrazol-4-yl)carbamate (2 g, 9.19 mmol) in DMF (20
mL) was added NaH (404 mg, 10.11 mmol, 60% purity) at 0.degree. C.
The mixture was stirred at 25.degree. C. for 1 h. Methyl
2-bromo-2-methylpropanoate (1.83 g, 10.11 mmol) was added to the
mixture at 0.degree. C. and stirred at 25.degree. C. for 1 h. The
reaction mixture was quenched by addition of ice water (150 mL) and
extracted with EtOAc (3.times.50 mL). The combined organic layers
were washed with saturated brine (3.times.50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give methyl
2-(4-((tert-butoxycarbonyl)amino)-3-chloro-1H-pyrazol-1-yl)-2-methylpropa-
noate as a yellow oil. LCMS: RT 0.849 min, m/z=318.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.92 (s, 1H), 6.25 (s,
1H), 3.70 (s, 3H), 1.81 (s, 6H), 1.52 (s, 9H).
tert-butyl
(1-(1-amino-2-methyl-1-oxopropan-2-yl)-3-chloro-1H-pyrazol-4-yl-
)carbamate
[0577] A solution of methyl
2-[4-(tert-butoxycarbonylamino)-3-chloro-pyrazol-1-yl]-2-methyl-propanoat-
e (3 g, 9.44 mmol) in methanol (50 mL) saturated with NH.sub.3 was
stirred at 80.degree. C. for 16 h in a 100 mL of sealed tube. The
reaction mixture was concentrated under reduced pressure to give
tert-butyl
(1-(1-amino-2-methyl-1-oxopropan-2-yl)-3-chloro-1H-pyrazol-4-yl)carbamate
as a yellow gum. LCMS: RT 0.736 min, m/z=303.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.99 (s, 1H), 6.30 (br. s., 1H),
5.92 (br. s., 1H), 5.58 (br. s., 1H), 1.82 (s, 6H), 1.51 (s,
9H).
tert-butyl
(3-chloro-1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)carbamate
[0578] To a solution of tert-butyl
(1-(1-amino-2-methyl-1-oxopropan-2-yl)-3-chloro-1H-pyrazol-4-yl)carbamate
(200 mg, 660.59 .mu.mol) in pyridine (3 mL) was added POCl.sub.3
(152 mg, 990.89 .mu.mol) at 0.degree. C. The mixture was stirred at
0.degree. C. for 1 h. The reaction mixture was quenched by addition
of water (30 mL) at 0.degree. C. and then extracted with EtOAc
(3.times.10 mL). The combined organic layers were washed with brine
(10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give tert-butyl
(3-chloro-1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)carbamate as a red
solid. LCMS: RT 0.837 min, m/z=285.2 [M+H].sup.+.
2-(3-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H--
pyrazol-1-yl)-2-methylpropanenitrile (A-17)
[0579] A mixture of tert-butyl
(3-chloro-1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)carbamate (150 mg,
526.80 .mu.mol),
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (175
mg, 526.80 .mu.mol) and PTSA (226.79 mg, 1.32 mmol) in 1,4-dioxane
(3 mL) was stirred at 100.degree. C. for 2 h. The reaction mixture
was concentrated under reduced pressure to give a residue. The
residue was diluted with H.sub.2O (20 mL), adjusted to pH=8 by aq.
NaHCO.sub.3 and then extracted with EtOAc (3.times.10 mL). The
combined organic layers were washed with brine (10 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue, which was purified by prep-HPLC (neutral
condition) to give title compound
2-(3-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-
-pyrazol-1-yl)-2-methylpropanenitrile (A-17). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.50 (br. s., 1H), 8.31 (br. s., 1H), 6.95
(br. s., 1H), 2.28 (br. s., 1H), 2.02 (s, 6H), 1.11-1.37 (m, 4H).
HPLC: RT: 3.70 min. MS: m/z: 371.1 [M+H].sup.+.
Example A-15
Synthesis of
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-py-
razol-1-yl]-2-methyl-propan-2-ol and
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-py-
razol-1-yl]-2-methyl-propan-2-ol (A-18 and A-19)
2-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)propan-2-ol and
2-methyl-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol
[0580] To a mixture of 3-methyl-4-nitro-1H-pyrazole (1.50 g, 11.80
mmol) and 2,2-dimethyloxirane (2.43 g, 33.75 mmol, 3 mL) in DMF (19
mL) was added Cs.sub.2CO.sub.3 (7.69 g, 23.60 mmol) at 25.degree.
C. then heated to 100.degree. C. and stirred for 3 h. The mixture
was cooled to 25.degree. C. and poured into water (100 mL) then
extracted with EtOAc (5.times.40 mL), washed with brine (3.times.20
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a mixture of compound
2-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)propan-2-ol and
2-methyl-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol as a red
brown oil. LCMS: RT 0.485 min, m/z=200.2 [M+H].sup.+.
1-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propan-2-ol and
1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol
[0581] A solution of the mixture
2-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)propan-2-ol and
2-methyl-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol (1.00 g,
5.02 mmol) in EtOH (20 mL) was treated with Pd/C (10%, 0.3 g). The
suspension was degassed and purged with H.sub.2 for 3 times. The
mixture was stirred under H.sub.2 (15 PSI) at 25.degree. C. for 16
h. The reaction mixture was filtered and concentrated under reduced
pressure to give the mixture compound
1-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propan-2-ol and
1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a brown
oil. LCMS: RT 0.111 min, m/z=170.2 [M+H].sup.+.
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyr-
azol-1-yl]-2-methyl-propan-2-ol and
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-py-
razol-1-yl]-2-methyl-propan-2-ol
[0582] A mixture of
1-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propan-2-ol and
1-(4-amino-5-methyl-pyrazol-1-yl)-2-methyl-propan-2-ol) (300 mg,
1.77 mmol), 2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine
(591 mg, 1.59 mmol) and Et.sub.3N (537 mg, 5.31 mmol, 736.05 .mu.L)
were taken up into a microwave tube in n-BuOH (3 mL). The sealed
tube was heated at 120.degree. C. for 60 min under microwave. The
reaction mixture was cooled to 25.degree. C. and filtered. The
residue was purified by prep-HPLC (neutral) and further separated
by SFC to provide
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-py-
razol-1-yl]-2-methyl-propan-2-ol as a white solid and
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-py-
razol-1-yl]-2-methyl-propan-2-ol as a white solid.
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyr-
azol-1-yl]-2-methyl-propan-2-ol (A-19)
[0583] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.39 (s, 1H),
7.65 (s, 1H), 6.50 (br. s., 1H), 4.40 (s, 1H), 3.98 (s, 2H), 2.26
(s, 1H), 2.19 (s, 3H), 1.24-1.28 (m, 1H), 1.19 (s, 8H), 1.04-1.12
(m, 2H). HPLC: RT 2.91 min. MS: [M+H].sup.+ m/z: 356.2.
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-pyr-
azol-1-yl]-2-methyl-propan-2-ol (A-18)
[0584] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.42 (br. s.,
1H), 7.78 (br. s., 1H), 6.73 (br. s., 1H), 3.88-4.06 (m, 3H), 2.25
(s, 4H), 1.23-1.28 (m, 2H), 1.19 (s, 6H), 1.09-1.15 (m, 2H). HPLC:
RT 2.91 min. MS: [M+H].sup.+ m/z: 356.2.
Example A-16
Synthesis of
1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-
-pyrazol-1-yl]-1-piperidyl]ethanone and
1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-
-pyrazol-1-yl]-1-piperidyl]ethanone (A-20 and A-21)
1-[4-(5-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone and
1-[4-(3-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone
[0585] To a mixture of 1-(4-hydroxy-1-piperidyl)ethanone (500 mg,
3.49 mmol), 3-methyl-4-nitro-1H-pyrazole (487 mg, 3.84 mmol) and
PPh.sub.3 (1.37 g, 5.24 mmol) in THF (30 mL) was added DIAD (1.06
g, 5.24 mmol) at 0.degree. C. under N.sub.2. The mixture was then
stirred at 25.degree. C. for 16 h. The mixture was poured into
ice-water (100 mL) and extracted with EtOAc (3.times.50 mL). The
combined organic phase was washed with brine, dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel column chromatography (PE:EtOAc=1:1) to
afford a mixture of
1-[4-(5-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone and
1-[4-(3-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone as a
white solid. LCMS: RT 0.603 min, m/z=253.2 [M+H].sup.+.
1-[4-(4-amino-5-methyl-pyrazol-1-yl)-1-piperidyl]ethanone and
1-[4-(4-amino-3-methyl-pyrazol-1-yl)-1-piperidyl]ethanone
[0586] To a mixture of
1-[4-(5-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone and
1-[4-(3-methyl-4-nitro-pyrazol-1-yl)-1-piperidyl]ethanone (400 mg,
1.59 mmol) was in MeOH (20 mL) added Pd--C (0.2 g) under N.sub.2.
The suspension was degassed under vacuum and purged with H.sub.2
three times. The mixture was stirred under H.sub.2 (15 psi) at
25.degree. C. for 1 h. The reaction mixture was filtered and the
filtrate was concentrated to give a mixture
1-[4-(4-amino-5-methyl-pyrazol-1-yl)-1-piperidyl]ethanone and
1-[4-(4-amino-3-methyl-pyrazol-1-yl)-1-piperidyl]ethanone as a
dark-brown solid. LCMS: RT 0.731 min, m/z=223.1 [M+H].sup.+.
1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl--
pyrazol-1-yl]-1-piperidyl]ethanone and
1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-
-pyrazol-1-yl]-1-piperidyl]ethanone (A-20 and A-21)
[0587] To a mixture of
1-[4-(4-amino-5-methyl-pyrazol-1-yl)-1-piperidyl]ethanone and
I-[4-(4-amino-3-methyl-pyrazol-1-yl)-1-piperidyl]ethanone (250 mg,
1.13 mmol) in 1,4-dioxane (2 mL) was added
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (150
mg, 563 .mu.mol) and p-TsOH (29 mg, 169 .mu.mol) at 25.degree. C.
under N.sub.2. The mixture was then heated to 100.degree. C. and
stirred for 2 h. The mixture was cooled to 25.degree. C. and poured
into ice-water (30 mL). The aqueous phase was extracted with EtOAc
(20 mL.times.3). The combined organic phase was washed with brine,
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by prep-HPLC (neutral), which was further
separated by SFC to give
1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl-
-pyrazol-1-yl]-1-piperidyl]ethanone (A-20) and
1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-
-pyrazol-1-yl]-1-piperidyl]ethanone (A-21).
1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-5-methyl--
pyrazol-1-yl]-1-piperidyl]ethanone (A-20)
[0588] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.37 (s, 1H),
7.63 (br. s., 1H), 6.60 (br. s., 1H), 4.76 (d, J=13.43 Hz, 1H),
4.20 (tt, J=4.20, 11.11 Hz, 1H), 4.01 (d, J=13.93 Hz, 1H),
3.18-3.28 (m, 1H), 2.69-2.79 (m, 1H), 2.17-2.31 (m, 5H), 2.12-2.16
(m, 3H), 1.90-2.11 (m, 3H), 1.16-1.25 (m, 2H), 1.03-1.10 (m, 2H).
HPLC: RT 2.413 min. MS: [M+H].sup.+ m/z: 409.2.
1-[4-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl--
pyrazol-1-yl]-1-piperidyl]ethanone (A-21)
[0589] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.43 (br. s.,
1H), 7.81 (br. s., 1H), 6.67 (br. s., 1H), 4.76 (d, J=14.05 Hz,
1H), 4.25 (tt, J=4.00, 11.37 Hz, 1H), 3.96 (d, J=13.80 Hz, 1H),
3.24 (t, J=12.05 Hz, 1H), 2.69-2.84 (m, 1H), 2.16-2.28 (m, 6H),
2.15 (s, 3H), 1.84-2.02 (m, 2H), 1.24-1.28 (m, 2H), 1.14 (br. s.,
2H). HPLC: RT 2.406 min. MS: [M+H].sup.+ m/z: 409.2.
Example A-17
Synthesis of
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H--
pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H--
pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-22 and
A-23)
3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one
[0590] To a solution of 3-methyl-4-nitro-1H-pyrazole (10 g, 78.68
mmol) in DMF (50 mL) was added portionwise NaH (4.72 g, 118.02
mmol, 60% purity) at 0.degree. C. over 30 min. After addition, the
mixture was stirred at 20.degree. C. for 30 min, and then
3-bromo-3-methylbutan-2-one (15.58 g, 94.42 mmol) was added
dropwise at 0.degree. C. The resulting mixture was stirred at
20.degree. C. for 11 h. The reaction mixture was quenched by
addition of H.sub.2O (250 mL) at 0.degree. C., and extracted with
EtOAc (3.times.100 mL). The combined organic layers were washed
with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue. The residue
was purified by column chromatography on silica gel (PE/EtOAc=20/1
to 3/1), 3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one
was obtained as a yellow solid. LCMS: RT 0.674 min, m/z=212 [M+H]+.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.30 (s, 1H) 2.56
(s, 3H) 1.98 (s, 3H) 1.75 (s, 6H).
(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)pent-1--
en-3-one
[0591] A mixture of
3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one (7.5 g,
35.51 mmol) and DMF-DMA (42.31 g, 355.08 mmol, 47.01 mL) was
stirred at 110.degree. C. for 12 hrs under N.sub.2 atmosphere. The
mixture was concentrated under reduced pressure to give
(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)pent-1-
-en-3-one as a yellow solid. The crude product was used in the next
step without further purification. LCMS: RT 0.675 min, m/z=267
[M+H].sup.+.
3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-4-nitro-1H-pyrazole
and
3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-4-nitro-1H-pyraz-
ole
[0592] To a solution of
(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)pent-1-
-en-3-one (10.8 g, 40.56 mmol) in AcOH (100 mL) was added dropwise
methylhydrazine (70.07 g, 608.40 mmol, 79.62 mL) at 0.degree. C.
over 30 min. The resulting mixture was stirred at 100.degree. C.
for 1.5 h. The reaction mixture was quenched by addition H.sub.2O
(100 mL) at 0.degree. C., and then added with sat. NaHCO.sub.3 (200
mL) to pH=8 and extracted with EtOAc (3.times.100 mL). The combined
organic layers were washed with brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(PE/EtOAc=20/1 to 3/1),
3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-4-nitro-1H-pyrazole
was obtained as an off-white solid, confirmed by HNMR and NOE,
3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-4-nitro-1H-pyrazole
was obtained as an off-white solid, confirmed by HNMR and NOE.
3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-4-nitro-1H-pyrazole
[0593] .sup.1H NMR (400 MHz, CDCl.sub.1): .delta. ppm 7.99 (s, 1H)
7.34 (d, J=2.0 Hz, 1H) 6.16 (d, J=2.0 Hz, 1H) 3.91 (s, 3H) 2.54 (s,
3H) 1.96 (s, 6H). LCMS: RT 0.701 min, m/z=250 [M+H].sup.+.
3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-4-nitro-1H-pyrazole
[0594] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.00 (s, 1H)
7.46 (d, J=2.0 Hz, 1H) 6.35 (d, J=2.4 Hz, 1H) 3.47 (s, 3H) 2.56 (s,
3H) 1.98 (s, 6H). LCMS: RT 0.673 min, m/z=250 [M+H].sup.+.
3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-amine
[0595] To a solution of
3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-4-nitro-1H-pyrazole
(3 g, 12.04 mmol) in MeOH (60 mL) was added Pd--C (10%, 1.28 g)
under N.sub.2. The suspension was degassed under vacuum and purged
with H.sub.2 several times. The mixture was stirred under H.sub.2
(15 psi) at 20.degree. C. for 2 hrs. The reaction mixture was
filtered and the filtrate was concentrated under reduced pressure
to give
3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-amine
as a brown solid. The crude product was used in the next step
without further purification. .sup.1H NMR (400 MHz, CDCl3): .delta.
ppm 7.39 (d, J=2.0 Hz, 1H) 6.78 (s, 1H) 6.26 (d, J=2.0 Hz, 1H) 3.37
(s, 3H) 2.19 (s, 3H) 1.86 (s, 6H).
3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine
[0596] To a solution of
3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-4-nitro-1H-pyrazole
(2 g, 8.02 mmol) in MeOH (40 mL) was added Pd--C (10%, 0.85 g)
under N.sub.2. The suspension was degassed under vacuum and purged
with H.sub.2 several times. The mixture was stirred under H.sub.2
(15 psi) at 20.degree. C. for 2 hrs. The reaction mixture was
filtered and the filtrate was concentrated under reduced pressure
to give
3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine
as a brown solid. The crude product was used in the next step
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. ppm 7.23 (d, J=2.0 Hz, 1H) 6.98 (s, 1H) 5.96 (d, J=2.4 Hz,
1H) 3.87 (s, 3H) 2.60-2.73 (bs, 2H) 2.20 (s, 3H) 1.90 (s, 6H).
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-p-
yrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-22)
[0597] To a mixture of
3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H-pyrazol-4-amine
(100 mg, 456.02 .mu.mol) and
2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (67.67 mg,
304.01 .mu.mol) in 1,4-dioxane (3 mL) was added p-TsOH (15.71 mg,
91.20 .mu.mol) in one portion at 25.degree. C. under N.sub.2. The
mixture was heated to 100.degree. C. and stirred for 2 h. The
mixture was added with water (5 mL) and then adjusted to pH=7 by
adding NaHCO.sub.3 (3 mL). The reaction mixture was then extracted
with EtOAc (3.times.4 mL). The combined organic phase was washed
with brine (5 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by prep-HPLC (neutral condition) to give
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan-2-yl)-1H--
pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. ppm 8.35-8.43 (m, 1H) 7.57-7.72 (m,
1H) 7.41-7.48 (m, 1H) 6.63-6.79 (m, 1H) 6.28-6.38 (m, 1H) 3.42 (s,
3H) 2.27 (s, 3H) 2.12-2.23 (m, 1H) 1.95 (s, 6H) 0.90-1.15 (m, 4H).
HPLC: RT 2.821 min. MS: (M+H.sup.+) m/z: 406.
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-p-
yrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-23)
[0598] To a mixture of
3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H-pyrazol-4-amine
(100 mg, 456.02 .mu.mol) and
2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (67.67 mg,
304.01 .mu.mol) in 1,4-dioxane (3 mL) was added p-TsOH (15.71 mg,
91.20 .mu.mol) in one portion at 25.degree. C. under N.sub.2. The
mixture was then heated to 100.degree. C. and stirred for 2 h. The
crude product was added with water (5 mL) and then adjusted to pH=7
by adding NaHCO.sub.3 (3 mL). The reaction mixture was then
extracted with EtOAc (3.times.4 mL). The combined organic phase was
washed with brine (5 mL), dried with anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by prep-HPLC (neutral condition) to give
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-yl)-1H--
pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. ppm 8.30-8.43 (m, 1H) 7.64-7.79 (m,
1H) 7.28-7.32 (m, 1H) 6.57-6.84 (m, 1H) 5.94-6.15 (m, 1H) 3.91 (s,
3H) 2.26 (s, 3H) 2.14-2.22 (m, 1H) 1.97 (s, 6H) 1.10-1.20 (m, 2H)
1.02-1.10 (m, 2H). HPLC: RT 2.817 min. MS: [M+H].sup.+ m/z:
406.
Example A-18
Synthesis of
4-cyclopropyl-N-(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluo-
romethyl)pyrimidin-2-amine and
4-cyclopropyl-N-(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluo-
romethyl)pyrimidin-2-amine (A-24 and A-25)
5-methyl-4-nitro-1-tetrahydropyran-4-yl-pyrazole and
3-methyl-4-nitro-1-tetrahydro-2H-pyran-4-yl-pyrazole
[0599] To a mixture of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.34
mmol) and tetrahydropyran-4-ol (4.82 g, 47.21 mmol, 4.73 mL) in THF
(70 mL) was added PPh.sub.3 (15.48 g, 59.01 mmol) and DIAD (11.93
g, 59.01 mmol, 11.47 mL) in one portion at 0.degree. C. under
N.sub.2. The mixture was stirred at 0.degree. C. for 60 min, then
warmed to 25.degree. C. and stirred for 16 h. The mixture was
poured into the mixture of PE and EtOAc (PE:EtOAc=1:1) (100 mL),
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=5:1) to
afford 5-methyl-4-nitro-1-tetrahydropyran-4-yl-pyrazole and
3-methyl-4-nitro-1-tetrahydro-2H-pyran-4-yl-pyrazole as yellow
solids. LCMS: RT 0.610 min, m/z=212.2 [M+H].sup.+.
5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-amine and
3-methyl-1-tetrahydro-2H-pyran-4-yl-pyrazol-4-amine
[0600] To a mixture of
5-methyl-4-nitro-1-(tetrahydropyran-4-yl)-1H-pyrazole and
3-methyl-4-nitro-1-tetrahydro-2H-pyran-4-yl-pyrazole (3 g, 14.20
mmol) in MeOH (60 mL) was added Pd/C (1 g, 10%) under N.sub.2. The
suspension was degassed under reduced pressure and purged with
H.sub.2 several times. The mixture was stirred under H.sub.2 (15
psi) at 25.degree. C. for 2 h. The reaction mixture was filtered
and the filtrate was concentrated under reduced pressure. The crude
product 5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-amine and
3-methyl-1-tetrahydro-2H-pyran-4-yl-pyrazol-4-amine was used into
the next step without further purification. LCMS: RT 0.482 min,
m/z=182.1 [M+H].sup.+.
4-cyclopropyl-N-(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluor-
omethyl)pyrimidin-2-amine and
4-cyclopropyl-N-(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluo-
romethyl)pyrimidin-2-amine (A-24 and A-25)
[0601] 5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-amine,
3-methyl-1-tetrahydro-pyran-4-yl-pyrazol-4-amine (200 mg, 1.31
mmol), 2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (251
mg, 1.13 mmol) and TEA (398 mg, 3.93 mmol, 544.77 .mu.L) were taken
up into a microwave tube in n-BuOH (2 mL). The sealed tube was
heated at 120.degree. C. for 90 min under microwave. The mixture
was cooled to 25.degree. C. and concentrated under reduced
pressure. The residue was poured into ice-water (5 mL). The aqueous
phase was extracted with EtOAc (3.times.2 mL). The combined organic
phase was washed with brine (5 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-TLC (SiO.sub.2, PE:EtOAc=1:1) to
provide
4-cyclopropyl-N-(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluo-
romethyl)pyrimidin-2-amine and
4-cyclopropyl-N-(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluo-
romethyl)pyrimidin-2-amine was obtained.
4-cyclopropyl-N-(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluor-
omethyl)pyrimidin-2-amine (A-24)
[0602] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.39 (s, 1H),
7.66 (br. s., 1H), 6.28-6.92 (m, 1H), 4.12-4.26 (m, 3H), 3.49-3.62
(m, 2H), 2.33 (qd, J=12.40, 4.58 Hz, 2H), 2.23 (s, 3H), 1.87 (dd,
J=12.80, 2.13 Hz, 2H), 1.23 (br. s., 2H), 1.04-1.12 (m, 2H). HPLC:
RT 3.06 min. MS: [M+H].sup.+ m/z=368.2.
4-cyclopropyl-N-(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)-5-(trifluor-
omethyl)pyrimidin-2-amine (A-25)
[0603] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.42 (br. s.,
1H), 7.83 (br. s., 1H), 4.23-4.33 (m, 1H), 4.12 (d, J=11.04 Hz,
2H), 3.56 (t, J=11.73 Hz, 2H), 2.26 (s, 3H), 1.98-2.17 (m, 4H),
1.25-1.31 (m, 2H), 1.16 (br. s., 2H). HPLC: RT 3.15 min. MS:
[M+H].sup.+ m/z=368.2.
Example A-19
Synthesis of
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-
-pyrazol-1-yl)-1-methylpiperidin-2-one and
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-
-pyrazol-1-yl)-1-methylpiperidin-2-one (A-26 and A-27)
5-((tert-butyldiphenylsilyl)oxy)piperidin-2-one
[0604] To a solution of 5-hydroxypiperidin-2-one (4.5 g, 39.09
mmol) in DMF (60 mL) was added imidazole (7.98 g, 117.27 mmol),
followed by TBDPSCl (16.11 g, 58.64 mmol) at 0.degree. C. The
mixture was stirred at 25.degree. C. for 12 h. The solution was
added with water (120 mL), extracted with EtOAc (3.times.30 mL).
The organic layers were combined, washed with brine (3.times.20
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to get a residue, which was purified by silica gel
chromatography (PE:EtOAc=10:1 to 1:1) to give
5-((tert-butyldiphenylsilyl)oxy)piperidin-2-one as an off-white
solid. LCMS: RT 0.943 min, m/z=354.3 [M+H].sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 7.62-7.69 (m, 4H), 7.42-7.48 (m, 2H),
7.36-7.42 (m, 4H), 6.19 (br. s., 1H), 4.06-4.12 (m, 1H), 3.15-3.27
(m, 2H), 2.66 (ddd, J=17.42, 9.48, 6.17 Hz, 1H), 2.27 (dt, J=17.86,
5.84 Hz, 1H), 1.74-1.95 (m, 2H), 1.02-1.12 (m, 9H).
5-((tert-butyldiphenylsilyl)oxy)-1-methylpiperidin-2-one
[0605] To a solution of
5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one (1 g, 2.83 mmol) in
DMF (15 mL) at 0.degree. C. was added NaH (158.4 mg, 3.96 mmol),
the mixture was stirred at 25.degree. C. for 1 h and then CH.sub.3I
(802.99 mg, 5.66 mmol) was added. The mixture was stirred at
25.degree. C. for 11 h. The reaction mixture was quenched by
addition of H.sub.2O (50 mL), extracted with EtOAc (3.times.50 mL).
The combined organic layers were washed with brine (2.times.50 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give a residue, which was purified by silica
gel chromatography (PE:EtOAc=1:1 to 1:3) to give
5-((tert-butyldiphenylsilyl)oxy)-1-methylpiperidin-2-one as a
yellow oil. LCMS: RT 0.924 min, m/z=368.2 [M+H].sup.+.
5-hydroxy-1-methylpiperidin-2-one
[0606] To a solution of
5-[tert-butyl(diphenyl)silyl]oxy-1-methyl-piperidin-2-one (400 mg,
1.09 mmol) in MeOH (15 mL) was added KF (633.29 mg, 10.90 mmol).
The mixture was stirred at 85.degree. C. for 12 h. The reaction
mixture was concentrated under reduced pressure to get a residue,
which was slurried with DCM/MeOH (V/V, 10/1, 40 mL), the suspension
was filtered and the filtrate was concentrated to get a residue,
which was dissolved in H.sub.2O (20 mL). The solution was extracted
with MTBE (2.times.25 mL), the aqueous phase was concentrated under
reduced pressure to give 5-hydroxy-1-methyl-piperidin-2-one as a
white solid.
1-methyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one and
1-methyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one
[0607] To a solution of 5-hydroxy-1-methyl-piperidin-2-one (175 mg,
1.35 mmol), 3-methyl-4-nitro-1H-pyrazole (5) (205.9 mg, 1.62 mmol)
and PPh.sub.3 (531.14 mg, 2.03 mmol) in THF (15 mL) was added DIAD
(409.48 mg, 2.03 mmol) at 0.degree. C. The mixture was stirred at
25.degree. C. for 12 h. The reaction mixture was concentrated under
reduced pressure to get a residue, which was purified by prep-TLC
(SiO.sub.2, DCM:MeOH=20:1) to give a mixture of
1-methyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one and
1-methyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one as
yellow solid. LCMS: RT 0.577 min, m/z=239.1 [M+H].sup.+.
5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one and
5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one
[0608] To a mixture of
1-methyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one and
1-methyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one (180
mg, 755.54 .mu.mol) in MeOH (10 mL) was added Pd/C (10%, 60 mg)
under N.sub.2. The suspension was degassed and purged with H.sub.2
for 3 times. The mixture was stirred under H.sub.2 (15 Psi) at
25.degree. C. for 4 h. It was filtered over celite, the filter cake
was washed with MeOH (20 mL.times.2), the filtrate was combined and
concentrated under reduced pressure to give a mixture of
5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one and
5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one (as
yellow oil. LCMS: RT 0.194 min, m/z=209.1 [M+H].sup.+.
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H--
pyrazol-1-yl)-1-methylpiperidin-2-one and
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-
-pyrazol-1-yl)-1-methylpiperidin-2-one (A-26 and A-27)
[0609] A mixture of
5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one and
5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one (107
mg, 513.78 .mu.mol),
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (137
mg, 513.78 .mu.mol) and TsOH.H.sub.2O (49 mg, 256.89 .mu.mol) in
1,4-dioxane (15 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 100.degree. C. for 2 h
under N.sub.2. It was poured into H.sub.2O (15 mL), adjusted to
pH=8 with aq. NaHCO.sub.3, extracted with EtOAc (2.times.30 mL).
The combined organic phase was dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to get a residue,
which was purified by prep-HPLC (neutral) first and then it was
re-purified by SFC to give
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-
-pyrazol-1-yl)-1-methylpiperidin-2-one (14 mg) and
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-
-pyrazol-1-yl)-1-methylpiperidin-2-one.
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H--
pyrazol-1-yl)-1-methylpiperidin-2-one (A-26)
[0610] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.39 (s, 1H),
7.67 (br. s., 1H), 6.51 (br. s., 1H), 4.42-4.60 (m, 1H), 3.91 (dd,
J=11.69, 9.92 Hz, 1H), 3.46 (ddd, J=12.13, 5.51, 1.76 Hz, 1H), 3.00
(s, 3H), 2.65 (d, J=3.97 Hz, 1H), 2.42-2.59 (m, 2H), 2.25 (s, 3H),
2.17 (d, J=1.76 Hz, 2H), 1.22 (br. s., 2H), 1.09 (dd, J=7.72, 3.31
Hz, 2H). HPLC: Retention Time: 2.87 min. MS: (M+H.sup.+) m/z:
395.2.
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H--
pyrazol-1-yl)-1-methylpiperidin-2-one (A-27)
[0611] .sup.1H NMR (400 MHz, CDCl.sub.1): .delta. 8.43 (s, 1H),
7.86 (br. s., 1H), 6.49-6.87 (m, 1H), 4.56 (d, J=6.62 Hz, 1H), 3.71
(d, J=7.06 Hz, 2H), 3.00 (s, 3H), 2.48-2.64 (m, 2H), 2.34-2.45 (m,
1H), 2.17-2.34 (m, 4H), 1.22-1.30 (m, 2H), 1.15 (br. s., 2H). HPLC:
Retention Time: 2.86 min. MS: (M+H.sup.+) m/z: 395.2.
Example A-20
Synthesis of
4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl-
]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl-
]-5-(trifluoromethyl)pyrimidin-2-amine (A-28 and A-29)
1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-4-nitro-pyrazole and
1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-4-nitro-pyrazole
[0612] To a mixture of 5-methyl-4-nitro-1H-pyrazole (727 mg, 5.72
mmol) and 1,3-difluoropropan-2-ol (500 mg, 5.20 mmol) in THF (50
mL) was added PPh.sub.3 (2.05 g, 7.80 mmol) and DIAD (1.58 g, 7.80
mmol) at 0.degree. C. under N.sub.2. Then the mixture was stirred
at 25.degree. C. for 16 h. The mixture was poured into ice-water
(100 mL) and extracted with EtOAc (3.times.50 mL). The combined
organic phase was washed with brine, dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel column chromatography (PE:EtOAc=10:1) to
afford a mixture of
1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-4-nitro-pyrazole and
1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-4-nitro-pyrazole as a
colorless oil. LCMS: RT 0.620 min, m/z=206.1 [M+H].sup.+.
1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-amine and
1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-amine
[0613] To a mixture of
1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-4-nitro-pyrazole and
1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-4-nitro-pyrazole (1 g,
4.87 mmol) in EtOH (36 mL) and H.sub.2O (9 mL) was added NH.sub.4Cl
(783 mg, 14.64 mmol) and Fe (817 mg, 14.64 mmol) at 25.degree. C.
under N.sub.2. The mixture was then heated to 80.degree. C. and
stirred for 2 h. The mixture was cooled to 25.degree. C., filtered
and the filtrate was concentrated to afford a mixture of
1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-amine and
1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-amine as a
black-brown solid. LCMS: RT 0.228 min, m/z=176.1 [M+H].sup.+.
4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]-
-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl-
]-5-(trifluoromethyl)pyrimidin-2-amine (A-28 and A-29)
[0614] To a mixture of
1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-amine and
1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-amine (157
mg, 901 .mu.mol) in 1,4-dioxane (3 mL) was added
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (120
mg, 450 .mu.mol) and p-TsOH (23 mg, 135 .mu.mol) at 25.degree. C.
under N.sub.2. The mixture was then heated to 100.degree. C. and
stirred for 2 h. The mixture was cooled to 25.degree. C. and poured
into ice-water (30 mL). The aqueous phase was extracted with EtOAc
(3.times.20 mL). The combined organic phase was washed with brine,
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated.
The residue was separated by prep-TLC (PE:EtOAc=3:1) to give
desired products, which were further purified by prep-HPLC
(neutral) to give
4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl-
]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl-
]-5-(trifluoromethyl)pyrimidin-2-amine.
4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl]-
-5-(trifluoromethyl)pyrimidin-2-amine (A-28)
[0615] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.39 (s, 1H),
7.72 (s, 1H), 6.56 (br. s., 1H), 4.77-4.91 (m, 4H), 4.67-4.76 (m,
1H), 2.24 (s, 3H), 2.19 (dd, J=1.57, 4.71 Hz, 1H), 1.22 (br. s.,
2H), 1.04-1.13 (m, 2H). HPLC: RT 2.870 min. MS: [M+H].sup.+ m/z:
362.1.
4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-
-5-(trifluoromethyl)pyrimidin-2-amine (A-29)
[0616] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.43 (br. s.,
1H), 7.96 (s, 1H), 6.71 (br. s., 1H), 4.75-4.94 (m, 4H), 4.62-4.72
(m, 1H), 2.26 (s, 4H), 1.26-1.30 (m, 2H), 1.14-1.15 (m, 2H). HPLC:
Retention Time: 2.871 min. MS: [M+H].sup.+ m/z: 362.1.
Example A-21
Synthesis of
4-cyclopropyl-N-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluoro-
methyl)pyrimidin-2-amine and
4-cyclopropyl-N-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoro-
methyl)pyrimidin-2-amine (A-30 and A-31)
1-(2-fluoroethyl)-5-methyl-4-nitro-1H-pyrazole and
1-(2-fluoroethyl)-3-methyl-4-nitro-1H-pyrazole
[0617] To a solution of 5-methyl-4-nitro-1H-pyrazole (2 g, 15.74
mmol) in DMF (10 mL) was added Cs.sub.2CO.sub.4 (9.74 g, 29.90
mmol) and 1-bromo-2-fluoroethane (5.99 g, 47.21 mmol). The mixture
was stirred at 100.degree. C. for 3 h. The reaction mixture was
diluted with H.sub.2O (70 mL) and extracted with EtOAc (3.times.30
mL). The combined organic layers were washed with brine (30 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give
1-(2-fluoroethyl)-5-methyl-4-nitro-1H-pyrazole and
1-(2-fluoroethyl)-3-methyl-4-nitro-1H-pyrazole as a pale-yellow
oil. The crude product was used into the next step without further
purification. LCMS: RT 0.377, 0.464 min, m/z=174 [M+H].sup.+.
1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-amine and
1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-amine
[0618] To a solution of
1-(2-fluoroethyl)-5-methyl-4-nitro-1H-pyrazole and
1-(2-fluoroethyl)-3-methyl-4-nitro-1H-pyrazole (2 g, 11.55 mmol) in
EtOH (48 mL) was added H.sub.2O (12 mL) and NH.sub.4Cl (3.09 g,
57.75 mmol), then Fe (3.23 g, 57.75 mmol). Then the mixture was
heated to 80.degree. C. and stirred at 80.degree. C. for 1 h. The
mixture was cooled to 25.degree. C., filtered and concentrated. The
aqueous phase was extracted with EtOAc (3.times.5 mL). The combined
organic phase was washed with brine (10 mL), dried with anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure, to give
the crude product 1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-amine and
1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-amine, which was used into
the next step without further purification. LCMS: RT 0.114 min,
m/z=144.2 [M+H].sup.+.
4-cyclopropyl-N-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluorom-
ethyl)pyrimidin-2-amine and
4-cyclopropyl-N-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoro-
methyl)pyrimidin-2-amine (A-30 and A-31)
[0619] To a solution of
1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-amine and
1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-amine (161 mg, 1.13 mmol)
and 4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine
(150 mg, 563.40 .mu.mol) in 1,4-dioxane (3 mL) was added p-TsOH (29
mg, 169.02 .mu.mol) under N.sub.2. The mixture was stirred at
100.degree. C. for 2 h. The reaction mixture was quenched by
addition of H.sub.2O (15 mL) at 0.degree. C., and then added with
sat. NaHCO.sub.3 (10 mL) to pH=8 and extracted with EtOAc
(3.times.10 mL). The combined organic layers were washed with brine
(5 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified by prep-HPLC
(neutral condition),
4-cyclopropyl-N-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluoro-
methyl)pyrimidin-2-amine and
4-cyclopropyl-N-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoro-
methyl)pyrimidin-2-amine were obtained.
4-cyclopropyl-N-(1-(2-fluoroethyl)-5-methyl-1H-pyrazol-4-yl)-5-(trifluorom-
ethyl)pyrimidin-2-amine (A-30)
[0620] .sup.1H NMR: (400 MHz, CHLOROFORM-d) .delta. 8.39 (s, 1H),
7.66 (s, 1H), 6.51 (br, s, 1H), 4.68-4.89 (m, 2H), 4.27-4.43 (m,
2H), 2.12-2.30 (m, 4H), 1.18-1.29 (m, 2H), 1.02-1.12 (m, 2H). HPLC:
RT 3.07 min. MS: [M+H].sub.+ m/z: 330.2.
4-cyclopropyl-N-(1-(2-fluoroethyl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluorom-
ethyl)pyrimidin-2-amine (A-31)
[0621] .sup.1H NMR: (400 MHz, CHLOROFORM-d) .delta. 8.43 (s, 1H),
7.86 (s, 1H), 6.66 (br, 1H), 4.65-4.86 (m, 2H), 4.27-4.43 (m, 2H),
2.15-2.30 (m, 4H), 1.23-1.33 (m, 3H), 1.08-1.18 (m, 2H). HPLC: RT
3.13 min. MS: [M+H].sup.+ m/z: 330.2.
Example A-22
Synthesis of
2-(4-((5-chloro-4-cyclobutylpyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-y-
l)-2-methylpropanenitrile (A-32)
2-(4-((5-chloro-4-cyclobutylpyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl-
)-2-methylpropanenitrile (A-32)
[0622] To a mixture of
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (150
mg, 0.94 mmol) in 1,4-dioxane (2 mL) was added
2,5-dichloro-4-cyclobutylpyrimidine (186 mg, 0.91 mmol) and p-TsOH
(315 mg, 1.83 mmol) at 25.degree. C. under N.sub.2. The mixture was
stirred at 100.degree. C. for 12 h. The reaction mixture was
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral) to give
2-(4-((5-chloro-4-cyclobutylpyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-y-
l)-2-methylpropanenitrile. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.31 (s, 1H), 8.19 (s, 1H), 6.61 (s, 1H), 3.87-3.91 (m,
1H), 2.33-2.47 (m, 4H), 2.30 (s, 3H), 2.09-2.11 (m, 1H), 1.94-1.99
(m, 7H). HPLC: RT 3.63 min. MS: [M+H].sup.+ m/z: 331.1.
Example A-23
Synthesis of
5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)propan--
2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (33) and
5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan--
2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (A-34)
5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-pyrazol-3-yl)propan-2-
-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (A-34)
[0623] To a mixture of
3-methyl-1-[1-methyl-1-(1-methylpyrazol-3-yl)ethyl]pyrazol-4-amine
(100 mg, 456.02 .mu.mol) and 2,5-dichloro-4-cyclopropyl-pyrimidine
(57 mg, 304.01 .mu.mol) in 1,4-dioxane (3 mL) was added p-TsOH (15
mg, 91.20 .mu.mol) at 25.degree. C. Then the mixture was heated to
100.degree. C. and stirred for 2 h. The mixture was added to water
(5 mL) and adjusted to pH=7 by adding aq. NaHCO.sub.3 (2 mL). Then
it was extracted with EtOAc (3 mL.times.3), washed with brine (5
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral) to give compound
5-chloro-4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-(1-methylpyrazol-3-yl)et-
hyl]pyrazol-4-yl]pyrimidin-2-amine. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. ppm 8.12 (s, 1H), 7.71 (s, 1H), 7.28 (d,
J=1.51 Hz, 1H), 6.42 (br. s., 1H), 6.04 (s, 1H), 3.91 (s, 3H),
2.35-2.42 (m, 1H), 2.25 (s, 3H), 1.96 (s, 6H), 1.02-1.10 (m, 4H).
HPLC: RT 2.641 min. MS: [M+H].sup.+ m/z: 372.2.
[0624] Compound A-33 was prepared in analogous manner.
Example A-24
Synthesis of
5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)p-
ropan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (A-35)
5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)pr-
opan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (A-35)
[0625] To a solution of 2,5-dichloro-4-cyclopropylpyrimidine (200
mg, 1.06 mmol) and
3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-p-
yrazol-4-amine (280 mg, 1.27 mmol) in 1,4-dioxane (2 mL) was added
TFA (36 mg, 318.00 .mu.mol) under N.sub.2. The mixture was stirred
at 100.degree. C. for 2 h. The reaction mixture was quenched by
addition sat. NaHCO.sub.3 (10 mL) at 0.degree. C., and then diluted
with H.sub.2O (10 mL) and extracted with EtOAc (3.times.10 mL). The
combined organic layers were washed with brine (5 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (neutral condition) to give
5-chloro-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)p-
ropan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine. .sup.1H NMR (400
MHz, CHLOROFORM-d): .delta. 8.13 (s, 1H), 7.97 (s, 1H), 7.88 (s,
1H), 6.42 (br, 1H), 3.91 (s, 3H), 2.33-2.45 (m, 1H), 2.23 (s, 3H),
2.04 (s, 6H), 1.11-1.16 (m, 2H), 1.04-1.10 (m, 2H). HPLC: RT 2.68
min. MS: [M+H].sup.+ m/z: 373.1.
Example A-25
Synthesis of
N-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol--
4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine and
N-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol--
4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-36 and
A-37)
(E)-tert-butyl
(3-chloro-1-(1-(((dimethylamino)methylene)amino)-2-methyl-1-oxopropan-2-y-
l)-1H-pyrazol-4-yl)carbamate
[0626] A solution of tert-butyl
N-[1-(2-amino-1,1-dimethyl-2-oxo-ethyl)-3-chloro-pyrazol-4-yl]carbamate
(2 g, 6.61 mmol) in DMF-DMA (20 mL) was degassed and purged with
N.sub.2 for 3 times, and then the mixture was stirred at
110.degree. C. for 2 h under N.sub.2. The reaction mixture was
concentrated under reduced pressure to give (E)-tert-butyl
(3-chloro-1-(1-(((dimethylamino)methylene)amino)-2-methyl-1-oxopropan-2-y-
l)-1H-pyrazol-4-yl)carbamate as a yellow gum. LCMS: RT 0.738 min,
m/z=358.2 [M+H].sup.+.
tert-butyl
(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H--
pyrazol-4-yl)carbamate and tert-butyl
(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4--
yl)carbamate
[0627] To a solution of (E)-tert-butyl
(3-chloro-1-(1-(((dimethylamino)methylene)amino)-2-methyl-1-oxopropan-2-y-
l)-1H-pyrazol-4-yl)carbamate (2 g, 5.59 mmol) in AcOH (20 mL) was
added methylhydrazine (3.86 g, 33.54 mmol, 4.39 mL, 40% purity).
The mixture was stirred at 95.degree. C. for 1 h. The reaction
mixture was concentrated under reduced pressure. The residue was
diluted with water (20 mL), adjusted to pH=8 by aq. NaHCO.sub.3 and
extracted with EtOAc (3.times.20 mL). The combined organic layers
were washed with saturated brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue. The residue was purified by silica gel column
chromatography (PE:EtOAc=1:1 to 1:2) to give tert-butyl
(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4--
yl)carbamate and tert-butyl
(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4--
yl)carbamate as a yellow oil. LCMS: RT 0.728 min, m/z=341.2
[M+H].sup.+.
N-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-
-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-36)
[0628] A mixture of
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (219
mg, 821.57 .mu.mol), tert-butyl
(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4--
yl)carbamate (700 mg, 40% purity, 328.6 .mu.mol) and PTSA (354 mg,
2.05 mmol) in 1,4-dioxane (8 mL) was degassed and purged with
N.sub.2 for 3 times, and then the mixture was stirred at
100.degree. C. for 2 h under N.sub.2. The reaction mixture was
concentrated under reduced pressure. The residue was diluted with
H.sub.2O (60 mL), adjusted to pH=8 by aq. NaHCO.sub.3 and then
extracted with EtOAc (3.times.20 mL). The combined organic layers
were washed with brine (30 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue,
which was purified by prep-HPLC (neutral condition) to give
N-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyr-
azol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.42 (br. s., 1H), 7.99
(br. s., 1H), 7.91 (br. s., 1H), 7.01 (br. s., 1H), 3.92 (s, 3H),
2.23 (br. s., 1H), 2.04 (s, 6H), 1.21 (br. s., 2H), 1.12 (d, J=7.03
Hz, 2H). HPLC: RT: 3.22 min. MS: m/z: 427.2 [M+H].sup.+.
N-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4-
-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-37)
[0629] A mixture of
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (117
mg, 440.13 .mu.mol), tert-butyl
(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol-4--
yl)carbamate (150 mg, 440.13 .mu.mol) and PTSA (189.48 mg, 1.1
mmol) in dioxane (3 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 100.degree. C. for 3 h
under N.sub.2. The reaction mixture was concentrated under reduced
pressure. The residue was diluted with H.sub.2O (60 mL), adjusted
to pH=8 by aq. NaHCO.sub.3 and then extracted with EtOAc
(3.times.20 mL). The combined organic layers were washed with brine
(30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a residue, which was purified by
prep-HPLC (neutral condition) to give
N-(3-chloro-1-(2-(1-methyl-1H-1,2,4-triazol-5-yl)propan-2-yl)-1H-pyrazol--
4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 0.95-1.27 (m, 4H), 2.05 (s, 6H),
2.22 (br. s., 1H), 3.43 (br. s., 3H), 7.07 (br. s., 1H), 7.84 (s,
1H), 8.44 (br. s., 1H). HPLC: RT: 3.24 min. MS: m/z: 427.2
[M+H].sup.+.
Example A-26
Synthesis of
2-(4-((4-(1-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-
-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (A-38)
4-(1-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine
[0630] To a solution of
2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (300 mg, 1.33
mmol) in CH.sub.3CN (9.00 mL) and H.sub.2O (9.00 mL) was added
1-fluorocyclopropanecarboxylic acid (125 mg, 1.2 mmol),
(NH.sub.4).sub.2S.sub.2O.sub.8 (1.5 g, 6.65 mmol) and AgNO.sub.3
(904 mg, 5.32 mmol). Then the mixture was stirred at 20.degree. C.
for 12 h. The resulting mixture was extracted with EtOAc (3.times.5
mL). The combined organic extracts were concentrated under reduced
pressure. The residue was purified by prep-TLC (SiO.sub.2,
PE:EtOAc=1:1) to give
4-(1-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine
as a white solid. LCMS: RT 1.28 min, m/z=285.0 [M+H].sup.+.
2-(4-((4-(1-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3--
methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (A-38)
[0631] To a solution of
4-(1-fluorocyclopropyl)-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine
(45 mg, 0.158 mmol) in 1,4-dioxane (1 mL) was added
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (26 mg,
0.158 mmol) and p-TsOH (8.2 mg, 0.05 mmol) under N.sub.2. Then the
mixture was stirred at 100.degree. C. for 1 h. The mixture was
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral) to give
2-(4-((4-(1-fluorocyclopropyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-
-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile. .sup.1H NMR (400
MHz, CHLOROFORM-d): .delta. 8.67 (br. s., 1H), 7.89-8.21 (m, 1H),
6.60-6.96 (m, 1H), 2.27 (s, 3H), 1.99 (s, 6H), 1.56 (br. s., 2H),
1.55-1.59 (m, 2H), 1.53 (s, 2H), 1.50-1.55 (m, 1H). HPLC: RT 3.49
min. MS: (M+H.sup.+) m/z: 369.2.
Example A-27
Synthesis of
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-y-
l)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-39)
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-1-ol
[0632] To a solution of ethyl
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoate (20 g, 82.9
mmol) in MeOH (200 mL) was added NaBH.sub.4 (6.3 g, 165.8 mmol) at
0.degree. C. The reaction mixture was stirred at 0.degree. C. for 2
h. The mixture was cooled to 20.degree. C. and poured into sat.
NH.sub.4Cl (400 mL). The aqueous phase was extracted with EtOAc
(3.times.200 mL). The combined organic phase was washed with brine
(200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue, which was
purified by silica gel column chromatography (PE:EtOAc=20:1 to 1:1)
to give 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-1-ol as
a yellow solid. .sup.1H NMR (400 MHz, CHLOROFORM-d): .delta.
8.20-8.24 (m, 1H), 3.73-3.81 (m, 2H), 3.11 (br. s., 1H), 2.42-2.54
(m, 3H), 1.54 (s, 6H).
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanal
[0633] To a solution of
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-1-ol (5 g, 25
mmol) in DCM (350 mL) was added DMP (11.7 g, 27.6 mmol, in DCM (40
mL) portionwise at 0.degree. C. The reaction mixture was stirred at
20.degree. C. for 12 h under N.sub.2. Sat. NaHCO.sub.3 and
Na.sub.2S.sub.2O.sub.3 were added into the reaction mixture. The
resulting mixture was stirred for 0.5 h. The organic phase was
separated, washed with NaHCO.sub.3, brine (20 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give a residue, which was purified by silica gel column
chromatography (PE:EtOAc=5:1) to give
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanal as a yellow
solid. .sup.1H NMR (400 MHz, CHLOROFORM-d): .delta.9.56-9.63 (m,
1H), 8.28 (s, 1H), 2.55 (s, 3H), 1.70 (s, 6H).
3-methyl-1-(2-methylbut-3-yn-2-yl)-4-nitro-1H-pyrazole
[0634] To a solution of
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanal (1.6 g, 8.1
mmol) in MeOH (50 mL) was added dimethyl
(1-diazo-2-oxopropyl)phosphonate (3.2 g, 16.2 mmol) and K.sub.2CO
(2.3 mg, 16.2 mmol) in one portion at 25.degree. C. The reaction
mixture was stirred at 25.degree. C. for 16 h under N.sub.2. The
mixture was cooled to 20.degree. C. and poured into ice-water (40
mL). The aqueous phase was extracted with EtOAc (3.times.40 mL).
The combined organic phase was washed with brine (20 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give a residue, which was purified by silica
gel column chromatography (PE:EtOAc=10:1) to give
3-methyl-1-(2-methylbut-3-yn-2-yl)-4-nitro-1H-pyrazole as a yellow
oil. .sup.1H NMR (400 MHz, CHLOROFORM-d): .delta. 8.55 (s, 1H),
2.73 (s, 1H), 2.54 (s, 3H), 1.84 (s, 6H).
1-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,3-tria-
zole
[0635] To a solution of
3-methyl-1-(2-methylbut-3-yn-2-yl)-4-nitro-1H-pyrazole (200 mg, 1.0
mmol) in t-BuOH (0.5 mL) and water (2 mL) was added CuI (40 mg, 0.2
mmol), CH.sub.3I (177 mg, 0.08 mL, 1.3 mmol) and NaN.sub.3 (75 mg,
1.1 mmol). The reaction mixture was stirred at 70.degree. C. for 2
h. The reaction mixture was diluted with EtOAc and 35% ammonia (5
mL). The mixture was stirred for 30 min and the two phase
separated. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and evaporated to give a residue, which was purified by
prep-TLC (SiO.sub.2, EtOAc) to give
1-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,3-tri-
azole as a light yellow solid. LCMS: RT 0.645 min, m/z=251.1
[M+H].sup.+.
3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-am-
ine
[0636] To a solution of
1-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,3-tri-
azole (150 mg, 0.6 mmol) in EtOH (8 mL) and water (2 mL) was added
Fe (100 mg, 1.8 mmol) and NH.sub.4Cl (96 mg, 1.8 mmol), then the
mixture was stirred at 100.degree. C. for 2 h. The reaction was
concentrated under reduced pressure to give residue, which was
diluted with EtOAc (2.times.10 mL) and filtered. The filtrate was
concentrated under reduced pressure to give the title
3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-a-
mine as a yellow oil. LCMS: RT 0.098 min, m/z=221.2
[M+H].sup.+.
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl-
)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-39)
[0637] To a solution of
3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-a-
mine (79 mg, 0.36 mmol) in 1,4-dioxane (2 mL) was added
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (105
mg, 0.39 mmol) and TFA (82 mg, 0.05 mL, 0.72 mmol). Then the
mixture was stirred at 100.degree. C. for 2 h. The mixture was
concentrated under reduced pressure to give a residue, which was
purified by prep-HPLC (neutral) to give
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,3-triazol-4-yl)propan-2-y-
l)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H
NMR (400 MHz, CHLOROFORM-d): .delta.8.39 (br. s., 1H), 7.92 (br.
s., 1H), 7.20 (s, 1H), 6.71 (br. s., 1H), 4.03 (s, 3H), 2.25 (s,
3H), 2.20 (d, J=5.6 Hz, 1H), 2.03 (s, 6H), 1.19 (br. s., 2H),
1.07-1.13 (m, 2H). HPLC: RT 2.88 min. MS: [M+H].sup.+ m/z:
407.1.
Example A-28
Synthesis of
4-cyclopropyl-N-(3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-y-
l)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-40)
4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole
[0638] To a solution of TMSN.sub.3 (984 mg, 8.5 mmol, 1.2 mL) in
MeOH (2.5 mL) and DMF (20 mL) was added
3-methyl-1-(2-methylbut-3-yn-2-yl)-4-nitro-1H-pyrazole (1.1 g, 5.7
mmol) and CuI (109 mg, 0.7 mmol). The reaction mixture was stirred
at 110.degree. C. for 12 h under N.sub.2. The mixture was cooled to
20.degree. C. and poured into ice-water (100 mL). The aqueous phase
was extracted with EtOAc (3.times.50 mL). The combined organic
phase was washed with brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue, which was purified by silica gel column
chromatography (PE:EtOAc=1:1) to give
4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole
as a yellow oil. LCMS: RT 0.691 min, m/z=237.2 [M+H].sup.+.
2-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-tria-
zole
[0639] To a solution of
4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole
(1 g, 4.23 mmol) in MeOH (20 mL) was CH.sub.3I (902 mg, 0.4 mL,
6.35 mmol) and Cs.sub.2CO.sub.3 (4.2 g, 12.7 mmol) under N.sub.2,
then the mixture was stirred at 50.degree. C. for 12 h. The mixture
was filtered and filtrate was concentrated under reduced pressure
to give residue, which was purified by prep-TLC (SiO.sub.2,
PE:EtOAc=5:1) to give
2-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-tri-
azole as a yellow solid. LCMS: RT 0.775 min, m/z=251.2
[M+H].sup.+.
3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-am-
ine
[0640] To a solution of Pd/C (20 mg) in THF (10 mL) was added
2-methyl-4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-tri-
azole (100 mg, 0.4 mmol) under H.sub.2, then the mixture was
stirred at 30.degree. C. for 12 h. The reaction was concentrated
under reduced pressure to give a residue, which was diluted with
EtOAc (2.times.15 mL) and filtered. The filtrate was concentrated
under reduced pressure to give
3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazo-
l-4-amine as a brown solid. LCMS: RT 0.112 min, m/z=221.2
[M+H].sup.+.
4-cyclopropyl-N-(3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl-
)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-40)
[0641] To a solution of
3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-yl)-1H-pyrazol-4-a-
mine (90 mg, 0.41 mmol) in 1,4-dioxane (1 mL) was added
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (30
mg, 0.11 mmol) and TFA (23 mg, 0.02 mL, 0.20 mmol). Then the
mixture was stirred at 100.degree. C. for 2 h. The mixture was
concentrated under reduced pressure to give a residue, which was
purified by prep-HPLC (neutral) to give
4-cyclopropyl-N-(3-methyl-1-(2-(2-methyl-2H-1,2,3-triazol-4-yl)propan-2-y-
l)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H
NMR (400 MHz, CHLOROFORM-d): .delta. 8.39 (br. s., 1H), 7.81 (br.
s., 1H), 7.34 (br. s., 1H), 6.69 (br. s., 1H), 4.17 (s, 3H), 2.25
(s, 3H), 2.16-2.23 (m, 1H), 1.98 (s, 6H), 1.16 (br. s., 2H), 1.10
(d, J=8.0 Hz, 2H). HPLC: RT 2.25 min. MS: [M+H].sup.+ m/z:
407.2.
Example A-29
Synthesis of
4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]py-
razol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]py-
razol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-41 and
A-42)
Ethyl
1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylate
[0642] To a mixture of 3-methyl-4-nitro-1H-pyrazole (2.33 g, 18.35
mmol) in DMF (10 mL) was added NaH (927 mg, 23.18 mmol, 60%) in one
portion at 0.degree. C. under N.sub.2. After that ethyl
1-bromocyclobutanecarboxylate (4 g, 19.32 mmol) was added and the
mixture was stirred at 100.degree. C. for 12 h. The mixture was
poured into ice-water (70 mL) and stirred for 5 min. The aqueous
phase was extracted with EtOAc (3.times.30 mL). The combined
organic phase was washed with brine (2.times.20 mL), dried with
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=10:1 to 2:1) to give ethyl
1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylate as a
white solid. .sup.1H NMR (400 MHz, CDCl3): .delta. ppm 8.08-8.20
(m, 1H) 4.00-4.22 (m, 2H) 2.54-2.93 (m, 3H) 2.48 (s, 3H) 2.09-2.36
(m, 1H) 1.92-2.05 (m, 1H) 1.14-1.25 (m, 3H).
1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylic acid
[0643] To a mixture of ethyl
1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate (600 mg,
2.37 mmol) in THF (10 mL) and water (10 mL) was added LiOH.H.sub.2O
(298.34 mg, 7.11 mmol) in one portion at 25.degree. C. under
N.sub.2. The mixture was stirred at 25.degree. C. for 12 h. The
mixture was extracted with EtOAc (2.times.10 mL). And the aqueous
phase was adjusted to pH=3 with 1 N HCl, then extracted with EtOAc
(3.times.10 mL). The combined organic phase was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure, to give
1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylic acid as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 9.94
(br. s., 1H) 8.14-8.29 (m, 1H) 2.89-3.01 (m, 2H) 2.73-2.84 (m, 2H)
2.59-2.69 (m, 1H) 2.55 (s, 2H) 2.22-2.48 (m, 1H) 2.03-2.17 (m,
1H).
1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide
[0644] To a solution of
1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylic acid (2.4 g,
10.66 mmol) and DMF (30 .mu.L) in DCM (30 mL) was added oxalyl
chloride (2.71 g, 21.32 mmol) at 0.degree. C. under N.sub.2. The
reaction was stirred at 25.degree. C. for 2 h. Then the mixture was
concentrated. The residue was taken up in THF (50 mL) and added
into NH.sub.3.H.sub.2O (50 mL) at 0.degree. C., and then the
reaction mixture was stirred at 25.degree. C. for another 12 h. The
mixture was extracted with MTBE (3.times.50 mL). The combined
organic phase was washed with brine (2.times.50 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=10:1 to 1:1) to give
1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide as a
white solid.
(E)-N-((dimethylamino)methylene)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclo-
butanecarboxamide
[0645] A mixture of
1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide (1 g,
4.46 mmol) in DMF-DMA (15 mL) was stirred at 95.degree. C. for 2 h.
The mixture was concentrated under reduced pressure. And the crude
product was used directly in next step as is. LCMS: RT 0.667 min,
m/z=280 [M+H].sup.+.
1-methyl-3-[1-(4-nitropyrazol-1-yl)cyclobutyl]-1,2,4-triazole and
1-methyl-5-[1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]-1,2,4-triazole
[0646] To a mixture of
(E)-N-((dimethylamino)methylene)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cycl-
obutanecarboxamide (1.25 g, 4.46 mmol) in AcOH (10 mL) was added
methyl hydrazine (1.23 g, 26.76 mmol, 1.40 mL) in one portion at
25.degree. C. under N.sub.2. The mixture was stirred at 95.degree.
C. for 2 h. The mixture was concentrated and added with water (20
mL). The aqueous phase was extracted with EtOAc (2-10 mL). The
combined organic phase was washed with aq. NaHCO.sub.3 (20 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (PE:EtOAc=50:1 to 1:1) to give
1-methyl-3-[1-(4-nitropyrazol-1-yl)cyclobutyl]-1,2,4-triazole and
1-methyl-5-[1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]-1,2,4-triazole
as a white solid. LCMS: RT=0.667 min, m/z=263 [M+H].sup.+.
3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine
[0647] To a solution of
1-methyl-3-[1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]-1,2,4-triazole
(500 mg, 1.91 mmol) in MeOH (20 mL) was added Pd/C (50 mg, 10%
purity) under N.sub.2. The suspension was degassed under vacuum and
purged with H.sub.2 three times. The mixture was stirred under
H.sub.2 (15 psi) at 25.degree. C. for 2 h. The reaction mixture was
filtered and the filtrate was concentrated under reduced pressure
to give
3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine
as a yellow oil. LCMS: RT 0.945 min, m/z=263 [M+H].sup.+. .sup.1H
NMR (400 MHz, CDCl3): .delta. ppm 7.93 (s, 1H) 7.08 (s, 1H) 3.86
(s, 4H) 2.86 (dt, J=6.37, 3.15 Hz, 2H) 2.17-2.22 (m, 3H) 2.16 (s,
3H) 1.98-2.02 (m, 2H).
4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyr-
azol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-41)
[0648] To a mixture of
3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine
(50 mg, 215.26 .mu.mol) and
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (57.31
mg, 215.26 .mu.mol) in 1,4-dioxane (3 mL) was added p-TsOH (11.12
mg, 64.58 .mu.mol) in one portion at 25.degree. C. under N.sub.2.
The mixture was stirred at 110.degree. C. for 5 h. The residue was
poured into ice-water (5 mL) and stirred for 5 min. The aqueous
phase was extracted with EtOAc (2.times.10 mL). The combined
organic phase was washed with brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The product was purification by prep-HPLC (NH.sub.4HCO.sub.3) to
give
4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclobutyl]py-
razol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. ppm 8.32 (br. s., 1H) 7.84-7.94 (m, 1H)
7.75 (br. s., 1H) 6.44-6.68 (m, 1H) 3.78-3.89 (m, 3H) 2.85-3.05 (m,
5H) 2.19 (s, 3H) 2.13 (br. s., 1H) 1.91-2.03 (m, 2H) 1.51 (s, 2H)
1.15 (br. s., 2H) 0.96-1.05 (m, 2H). HPLC: Retention Time: 2.563
min. MS: [M+H].sup.+ m/z: 419.
3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine
[0649] To a solution of
1-methyl-5-[1-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]-1,2,4-triazole
(200 mg, 762.57 .mu.mol) in MeOH (10 mL) was added Pd/C (50 mg, 10%
purity) under N.sub.2. The suspension was degassed under vacuum and
purged with H.sub.2 three times. The mixture was stirred under
H.sub.2 (15 psi) at 25.degree. C. for 2 h. The reaction mixture was
filtered and the filtrate was concentrated under reduced pressure
to give
3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine
as a yellow oil.
4-cyclopropyl-N-[3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyr-
azol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-42)
[0650] To a mixture of
3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyrazol-4-amine
(50 mg, 215.26 .mu.mol) and
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (57.31
mg, 215.26 .mu.mol) in 1,4-dioxane (5 mL) was added p-TsOH (37.07
mg, 215.26 .mu.mol) in one portion at 25.degree. C. under N.sub.2.
The mixture was stirred at 110.degree. C. for 5 h. The residue was
poured into ice-water (10 mL) and stirred for 5 min. The aqueous
phases were extracted with EtOAc (2.times.10 mL). The combined
organic phase was washed with brine (10 mL), dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The product was purification by HPLC (NH.sub.4HCO.sub.3) to give
4-cyclopropyl-N-[3-methyl-1-[1-(2-methyl-1,2,4-triazol-3-yl)cyclobutyl]py-
razol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine. 1H NMR (400 MHz,
CDCl3): .delta. ppm 8.39 (s, 1H) 7.89 (s, 1H) 7.49-7.67 (m, 1H)
6.65 (br. s., 1H) 3.58 (s, 3H) 3.08-3.18 (m, 2H) 2.97-3.06 (m, 2H)
2.29 (s, 3H) 1.96-2.22 (m, 3H) 1.10 (dd, J=7.72, 2.87 Hz, 4H).
HPLC: RT 3.19 min. MS: [M+H].sup.+ m/z: 419.
Example A-30
Synthesis of
5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyr-
azol-4-yl]pyrimidin-2-amine and
5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyr-
azol-4-yl]pyrimidin-2-amine (A-43 and A-44)
5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyra-
zol-4-yl]pyrimidin-2-amine and
5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyr-
azol-4-yl]pyrimidin-2-amine (A-43 and A-44)
[0651] To a solution of 2,5-dichloro-4-cyclopropylpyrimidine (120
mg, 634.79 .mu.mol) and a mixture
1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-amine and
1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-amine (56 mg,
317.4 .mu.mol) in 1,4-dioxane (5 mL) was added p-TsOH (164 mg,
952.19 .mu.mol). The mixture was stirred at 100.degree. C. for 4 h.
The reaction mixture was concentrated under reduced pressure. The
residue was basified to pH=7 with aq. Na.sub.2HCO.sub.3 solution,
extracted with EtOAc (3-10 mL). The organic layers were combined,
washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to give a crude product,
which was purified by prep-TLC (PE:EtOAc=1:1), to give two
separated crude product, which was further purified by prep-HPLC
(neutral) to give
5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyr-
azol-4-yl]pyrimidin-2-amine and
5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyr-
azol-4-yl]pyrimidin-2-amine.
5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyra-
zol-4-yl]pyrimidin-2-amine (A-43)
[0652] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.13 (s, 1H),
7.72 (s, 1H), 6.21 (br. s., 1H), 4.90 (d, J=6.02 Hz, 2H), 4.67-4.81
(m, 3H), 2.34-2.42 (m, 1H), 2.23 (s, 3H), 1.11-1.17 (m, 2H),
1.03-1.10 (m, 2H). HPLC: RT 3.09 min. MS: [M+H].sup.+ m/z:
328.2.
5-chloro-4-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyra-
zol-4-yl]pyrimidin-2-amine (A-44)
[0653] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.17 (s, 1H),
7.94 (s, 1H), 6.41 (br. s., 1H), 4.76-4.93 (m, 4H), 4.60-4.75 (m,
1H), 2.37-2.47 (m, 1H), 2.25 (s, 3H), 1.17-1.23 (m, 2H), 1.09-1.16
(m, 2H). HPLC: RT 3.14 min. MS: [M+H].sup.+ m/z: 328.2.
Example A-31
Synthesis of
N-[5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-
-5-(trifluoromethyl)pyrimidin-2-amine and
N-[3-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-
-5-(trifluoromethyl)pyrimidin-2-amine (A-45 and A-46)
N-[5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl--
5-(trifluoromethyl)pyrimidin-2-amine and
N-[3-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-
-5-(trifluoromethyl)pyrimidin-2-amine (A-45 and A-46)
[0654] To a mixture of
5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-amine and
3-chloro-1-(1,3-difluoropropan-2-yl)-1H-pyrazol-4-amine (110 mg,
562.37 .mu.mol) and
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (100
mg, 374.91 .mu.mol) in 1,4-dioxane (3 mL) was added p-TsOH (19 mg,
112.47 .mu.mol) at 25.degree. C. under N.sub.2. The mixture was
heated to 100.degree. C. and stirred for 2 h. The mixture was
cooled to 25.degree. C. and adjusted to pH=7-8 with a solution of
NaHCO.sub.3 then extracted with EtOAc (3.times.5 mL). The combined
organics were washed with brine (5 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (neutral) to give
N-[5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyc-
lopropyl-5-(trifluoromethyl)pyrimidin-2-amine and
N-[3-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl-
-5-(trifluoromethyl)pyrimidin-2-amine.
N-[5-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl--
5-(trifluoromethyl)pyrimidin-2-amine (A-45)
[0655] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.45 (s, 1H)
8.11 (s, 1H) 6.72 (br. s., 1H) 4.75-5.02 (m, 5H) 2.24 (br. s., 1H)
1.27-1.32 (m, 2H) 1.15 (dd, J=7.72, 3.31 Hz, 2H). HPLC: RT 3.113
min. MS: [M+H] m z: 382.1.
N-[3-chloro-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrazol-4-yl]-4-cyclopropyl--
5-(trifluoromethyl)pyrimidin-2-amine (A-46)
[0656] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.48 (br. s.,
1H) 8.10 (br. s., 1H) 6.91 (br. s., 1H) 4.64-4.95 (m, 5H) 2.26 (br.
s., 1H) 1.27-1.33 (m, 2H) 1.18 (br. s., 2H). HPLC: RT 3.159 min.
MS: [M+H].sup.+ m/z: 382.2.
Example A-32
Synthesis of
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-py-
razol-1-yl]cyclopropanecarbonitrile (A-47)
1-(4-amino-3-methyl-pyrazol-1-yl)cyclopropanecarbonitrile
[0657] To a mixture of
1-(3-methyl-4-nitro-pyrazol-1-yl)cyclopropanecarbonitrile (100 mg,
520.37 .mu.mol) in EtOH (2 mL) and H.sub.2O (500 .mu.L) was added
NH.sub.4Cl (139 mg, 2.60 mmol) and Fe (145 mg, 2.60 mmol) at
20.degree. C. The mixture was then heated to 80.degree. C. and
stirred for 1 h. The mixture was cooled to 20.degree. C., filtered
and concentrated. The residue was added with water (10 mL) and then
extracted with EtOAc (3.times.3 mL), washed with brine (5 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure, to give
1-(4-amino-3-methyl-pyrazol-1-yl)cyclopropanecarbonitrile as a
brown oil. LCMS: RT 0.107 min, m/z=163.2 [M+H].sup.+.
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyr-
azol-1-yl]cyclopropanecarbonitrile (A-47)
[0658] To a mixture of
1-(4-amino-3-methyl-pyrazol-1-yl)cyclopropanecarbonitrile (11 mg,
684.38 .mu.mol) and
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (121
mg, 456.25 .mu.mol) in 1,4-dioxane (3 mL) was added p-TsOH (23 mg,
136.88 .mu.mol) at 25.degree. C. under N.sub.2. The mixture was
heated to 100.degree. C. and stirred for 2 h. The mixture was
cooled to 25.degree. C. and adjusted pH=7-8 by adding
aq.NaHCO.sub.3. Then the mixture was extracted with EtOAc
(3.times.5 mL), washed with brine (5 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (neutral) to give compound
1-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3--
methyl-pyrazol-1-yl]cyclopropanecarbonitrile. LCMS: RT 0.898 min,
m/z=349.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
ppm 8.46 (br. s., 1H), 8.02 (br. s., 1H), 6.68 (br. s., 1H), 2.26
(s, 4H), 1.80 (d, J=5.73 Hz, 4H), 1.29 (br. s., 2H), 1.17 (br. s.,
2H). HPLC: RT 2.826 min. MS: [M+H].sup.+ m/z: 349.2.
Example A-33
Synthesis of
N-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-
-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine
(A-48)
5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-a-
mine
[0659] To a solution of
(3S,4S)-4-(5-chloro-4-nitro-pyrazol-1-yl)-3-fluoro-1-(oxetan-3-yl)piperid-
ine (150 mg, 492.27 .mu.mol) in EtOH (2 mL) and water (500 .mu.L)
was added Fe (82.48 mg, 1.48 mmol) and NH.sub.4Cl (79 mg, 1.48
mmol). The reaction was stirred at 90.degree. C. for 2 h. The
reaction solution was concentrated under reduced pressure to give
residue, which was washed with EtOAc (2.times.5 mL) and filtered.
The filtrate was concentrated under reduced pressure to give
5-chloro-1-[(3S,4S)-3-fluoro-1-(oxetan-3-yl)-4-piperidyl]pyrazol-4-amine
as a brown solid, which was used without further purification.
N-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol--
4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-48)
[0660] To a solution of
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (130
mg, 0.5 mmol) in 1,4-dioxane (2 mL) was added
5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4--
amine (134 mg, 0.5 mmol) and p-TsOH (25 mg, 0.15 mmol) at
25.degree. C. The solution was heated at 100.degree. C. for 1 h.
The mixture was concentrated under reduced pressure. The residue
was purified by prep-HPLC (neutral condition) to give
N-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-
-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H
NMR (400 MHz, CHLOROFORM-d): .delta. 8.43 (s, 1H), 8.07 (s, 1H),
6.70 (br. s., 1H), 4.93-5.14 (m, 1H), 4.56-4.74 (m, 4H), 4.24-4.36
(m, 1H), 3.66 (quin, J=6.39 Hz, 1H), 3.16-3.26 (m, 1H), 2.85 (d,
J=9.70 Hz, 1H), 2.28-2.43 (m, 1H), 2.22 (br. s., 1H), 1.97-2.17 (m,
4H), 1.23-1.34 (m, 3H), 1.09-1.17 (m, 2H). HPLC: RT 2.851 min. MS:
[M+H].sup.+ m/z: 461.1.
Example A-34
Synthesis of
2-(5-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-
-pyrazol-1-yl)-1-methylcyclopentanol (A-49 and A-50)
2-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-methylcyclopentanol
(A-34-2)
[0661] To a solution of
2-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-methylcyclopentanol (150 mg,
0.61 mmol) in EtOH (2 mL) and H.sub.2O (500 .mu.L) was added Fe
(102 mg, 1.83 mmol) and NH.sub.4Cl (98 mg, 1.83 mmol). The reaction
mixture was stirred at 90.degree. C. for 1 h. The reaction mixture
was concentrated under reduced pressure to give a residue, which
was diluted with EtOAc (2.times.3 mL) and filtered. The filtrate
was concentrated to give
2-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-methylcyclopentanol as brown
solid. LCMS: RT 0.113 min, m/z=216.1 [M+H].sup.+.
2-(5-chloro-4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H--
pyrazol-1-yl)-1-methylcyclopentanol (A-49, A-50)
[0662] To a solution of
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (150
mg, 0.56 mmol) in dioxane (2 mL) was added
2-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-methylcyclopentanol (122 mg,
0.56 mmol) and p-TsOH (29 mg, 0.17 mmol) at 25.degree. C. Then the
mixture was stirred at 100.degree. C. for 1 h. The mixture was
concentrated under reduced pressure to give a residue, which was
purified by prep-HPLC (NH.sub.4HCO.sub.3) to give 48 mg of crude
product, which was further purified by chiral SFC to give two peaks
of target isomers, peak 1 and peak 2.
[0663] .sup.1H NMR (400 MHz, CHLOROFOR-d): .delta. 8.42 (s, 1H),
7.99 (s, 1H), 6.81 (br. s., 1H), 4.63 (t, J=7.2 Hz, 1H), 2.35-2.48
(m, 2H), 2.22 (br. s., 1H), 1.90-2.07 (m, 3H), 1.71-1.81 (m, 1H),
1.25-1.30 (m, 2H), 1.12 (dd, J=8.0, 3.09 Hz, 2H), 0.97 (s, 3H).
HPLC: RT 3.043 min. MS: [M+H].sup.+ m/z: 402.1.
[0664] .sup.1H NMR (400 MHz, CHLOROFOR-d): .delta. 8.42 (s, 1H),
8.00 (s, 1H), 6.77 (br. s., 1H), 4.63 (t, J=7.2 Hz, 1H), 2.35-2.48
(m, 2H), 2.22 (br. s., 1H), 1.87-2.08 (m, 3H), 1.72-1.81 (m, 1H),
1.24-1.30 (m, 2H), 1.12 (dd, J=7.2, 3.31 Hz, 2H), 0.97 (s, 3H).
HPLC: Retention Time: 3.045 min. MS: [M+H].sup.+ m/z: 402.1.
Example A-35
Synthesis of
4-cyclopropyl-N-(1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methy-
l-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-51)
1-ethyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triaz-
ole
[0665] To a solution of
3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole
(2 g, 8.47 mmol) in CH.sub.3CN (30 mL) was added EtI (1.59 g, 10.16
mmol, 813 .mu.L) and Cs.sub.2CO.sub.3 (2.76 g, 8.47 mmol). The
mixture was stirred at 50.degree. C. for 12 h. The reaction mixture
was filtered and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (PE:EtOAc=5:1 to
0:1) to give
1-ethyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-tria-
zole as a yellow solid. LCMS: RT 0.684 min, m/z=265 [M+H]+.
1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-ami-
ne
[0666] To a solution of
I-ethyl-3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-tria-
zole (1.67 g, 6.32 mmol) in EtOH (35 mL) was added Pd--C (10%, 0.67
g) under N.sub.2. The suspension was degassed under vacuum and
purged with H.sub.2 several times. The mixture was stirred under
H.sub.2 (15 psi) at 50.degree. C. for 2 h. The reaction mixture was
filtered and the filtrate was concentrated to give
1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-am-
ine as a brown solid. The crude product was used into the next step
without further purification.
4-cyclopropyl-N-(1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-
-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-51)
[0667] To a solution of
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (70
mg, 262.92 .mu.mol) and
1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-am-
ine (62 mg, 262.92 .mu.mol) in 1,4-dioxane (3 mL) was added p-TsOH
(14 mg, 78.88 .mu.mol). The mixture was stirred at 100.degree. C.
for 2 h. The reaction mixture was diluted with H.sub.2O (15 mL) and
adjusted with sat. NaHCO.sub.3 to pH=9 and extracted with EtOAc
(3.times.10 mL). The combined organic layers were washed with brine
(5 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified by prep-HPLC
(neutral condition) to give
4-cyclopropyl-N-(1-(2-(1-ethyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methy-
l-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H
NMR: (400 MHz, CHLOROFORM-d) .delta. 8.38 (s, 1H), 7.99 (s, 1H),
7.86 (s, 1H), 6.78 (br, s, 1H), 4.20 (q, J=14.4, 7.2 Hz, 2H),
2.14-2.28 (m, 4H), 2.04 (s, 6H), 1.53 (t, J=7.2 Hz, 3H), 1.17-1.25
(m, 2H), 1.02-1.12 (m, 2H). HPLC: RT 2.626 min. MS: [M+H].sup.+
m/z: 421.2.
Example A-36
Synthesis of
4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]p-
yrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-52)
3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]pyrazol-4-amine
[0668] To a solution of
1-methyl-3-(1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclopropyl)-1H-1,2,4-tri-
azole (150 mg, 604.25 .mu.mol) in EtOH (20 mL) was added Pd--C
(10%, 20 mg) under N.sub.2. The suspension was degassed under
reduced pressure and purged with H.sub.2 several times. The mixture
was stirred under H.sub.2 (15 psi) at 45.degree. C. for 6 h. The
reaction mixture was filtered and the filtrate was concentrated, to
give the crude
3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]pyrazol-4-amine
which was used into the next step without further purification.
LCMS: RT 0.822 min, m/z=219.3 [M+H].sup.+.
4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]py-
razol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-52)
[0669] To a mixture of
1-methyl-3-(1-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclopropyl)-1H-1,2,4-tri-
azole (87 mg, 326.77 .mu.mol) and
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (71
mg, 326.77 .mu.mol) in 1,4-dioxane (4 mL) was added TFA (112 mg,
980.31 .mu.mol, 73 .mu.L) at 20.degree. C. under N.sub.2. The
mixture was heated to 80.degree. C. and stirred for 5 h. The
mixture was cooled to 20.degree. C. and was adjusted to pH=8 by
adding aq.NaHCO.sub.3 and extracted with EtOAc (3.times.5 mL). The
combined organic phase was washed with brine (10 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by prep-HPLC (neutral) to give
4-cyclopropyl-N-[3-methyl-1-[1-(1-methyl-1,2,4-triazol-3-yl)cyclopropyl]p-
yrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 8.41 (br. s., 1H), 8.00 (br. s., 1H),
7.88 (s, 1H), 6.71 (br. s., 1H), 3.82 (s, 3H), 2.28 (s, 3H),
2.17-2.25 (m, 1H), 1.74 (d, J=4.64 Hz, 4H), 1.26 (br. s., 2H),
1.08-1.14 (m, 2H). HPLC: Retention Time: 2.362 min. MS: (M+H.sup.+)
m/z=405.2.
Example A-37
Synthesis of
5-bromo-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)pr-
opan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (A-53)
5-bromo-2-chloro-4-cyclopropylpyrimidine
[0670] To a solution of 5-bromo-2-chloropyrimidine (5 g, 25.9 mmol)
in H.sub.2O (150 mL) and CH.sub.3CN (150 mL) was added
cyclopropanecarboxylic acid (2.2 g, 25.9 mmol),
(NH.sub.4).sub.2S.sub.2O.sub.8 (14.8 g, 164.6 mmol) and AgNO.sub.3
(8.8 g, 8.8 mmol). The reaction mixture was stirred at 20.degree.
C. for 72 h. The reaction was quenched by ice water slowly and then
extracted with EtOAc (3.times.150 mL). The combined organic phase
was washed with brine (150 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue, which was purified by prep-TLC (SiO.sub.2,
PE:EtOAc=10:1) to give 5-bromo-2-chloro-4-cyclopropylpyrimidine as
a pale yellow oil. MS: m/z=234.9 [M+H].sup.+.
5-bromo-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)pro-
pan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine (A-23)
[0671] To a solution of 5-bromo-2-chloro-4-cyclopropylpyrimidine
(120 mg, 0.51 mmol) in 1,4-dioxane (1 mL) was added
3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)-1H-pyrazol-4-a-
mine (113 mg, 0.51 mmol) and p-TsOH (27 mg, 0.15 mmol). The
reaction mixture was stirred at 100.degree. C. for 2 h. The mixture
was concentrated under reduced pressure to give a residue, which
was purified by prep-TLC (SiO.sub.2, PE:EtOAc=1:1) to give
5-bromo-4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-1,2,4-triazol-3-yl)pr-
opan-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine. .sup.1HNMR (400 MHz,
CHLOROFORM-d): .delta. 8.22 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H),
6.39 (br. s., 1H), 3.90 (s, 3H), 2.34-2.43 (m, 1H), 2.22 (s, 3H),
2.03 (s, 6H), 1.10-1.14 (m, 2H), 1.03-1.08 (m, 2H). HPLC: RT 2.70
min. MS: [M+H].sup.+ m/z: 417.1.
Example A-38
Synthesis of
4-cyclopropyl-N-[5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-yl]-5-
-(trifluoromethyl)pyrimidin-2-amine (A-54)
5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-amine
[0672] To a solution of
5-methyl-1-[(1-methylpyrazol-3-yl)methyl]-4-nitro-pyrazole (540 mg,
2.44 mmol) in MeOH (30 mL) was added Pd--C (10%, 250 mg) under
N.sub.2 at 20.degree. C. The suspension was degassed under vacuum
and purged with H.sub.2 several times. The mixture was stirred
under H.sub.2 (15 psi) at 40.degree. C. for 5 h. The mixture was
cooled to 20.degree. C. and concentrated to give
5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-amine as a white
solid. LCMS: RT 0.882 min, m/z=192.3 [M+H].sup.+.
4-cyclopropyl-N-[5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-yl]-5--
(trifluoromethyl)pyrimidin-2-amine (A-54)
[0673] To a mixture of
5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-amine (80 mg,
418.34 .mu.mol) and
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (123
mg, 460.17 .mu.mol) in 1,4-dioxane (1.00 mL) was added TFA (95 mg,
836.68 .mu.mol, 61 .mu.L) at 20.degree. C. The mixture was then
heated to 100.degree. C. and stirred for 3 h. The mixture was
cooled to 20.degree. C. and concentrated. The residue was adjusted
pH=7-8 by adding aq. NaHCO.sub.3, then was extracted with EtOAc
(3.times.3 mL), washed with brine (3 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (neutral) to give
4-cyclopropyl-N-[5-methyl-1-[(1-methylpyrazol-3-yl)methyl]pyrazol-4-yl]-5-
-(trifluoromethyl)pyrimidin-2-amine. LCMS: RT 0.882 min, m/z=192.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.37
(s, 1H), 7.64 (br. s., 1H), 7.28-7.29 (m, 1H), 6.51 (br. s., 1H),
6.08 (br. s., 1H), 5.27 (s, 2H), 3.87 (s, 3H), 2.13-2.25 (m, 4H),
1.20 (br. s., 2H), 1.02-1.09 (m, 2H). HPLC: RT 2.489 min. MS:
[M+H].sup.+ m/z: 378.1.
Example A-39
Synthesis of
4-cyclopropyl-N-(3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-
-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-55)
3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-amine
[0674] To a solution of
5-methyl-1-[(1-methylpyrazol-3-yl)methyl]-4-nitro-pyrazole (120 mg,
542.45 .mu.mol) in MeOH (4 mL) was added Pd--C (10%, 0.05 g) under
N.sub.2. The suspension was degassed under vacuum and purged with
H.sub.2 several times. The mixture was stirred under H.sub.2 (15
psi) at 40.degree. C. for 2 h. The reaction mixture was filtered
and the filtrate was concentrated to get
3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-amine as
a black brown oil. LCMS: RT 0.765 min, m/z=214.2 [M+Na].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.00 (s, 1H), 6.14 (d,
J=2.21 Hz, 1H), 5.12 (s, 2H), 3.87 (s, 3H), 2.71 (d, J=7.06 Hz,
2H), 2.18 (s, 3H).
4-cyclopropyl-N-(3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol--
4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-55)
[0675] To a mixture of
3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-amine
(100 mg, 522.93 .mu.mol) and
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (139
mg, 522.93 .mu.mol) in 1,4-dioxane (2 mL) was added TFA (119 mg,
1.05 mmol) and then the mixture was stirred at 100.degree. C. for 2
h under N.sub.2. The reaction mixture was concentrated under
reduced pressure to give a residue, which was purified by prep-HPLC
(neutral condition) to give
4-cyclopropyl-N-(3-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-
-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR (400 MHz,
CDCl3): .delta. 8.38 (br. s., 1H), 7.74 (br. s., 1H), 7.30 (br. s.,
1H), 6.76 (br. s., 1H), 6.19 (s, 1H), 5.23 (s, 2H), 3.90 (s, 3H),
2.24 (s, 3H), 2.18 (d, J=8.16 Hz, 1H), 1.19 (br. s., 2H), 1.07 (dd,
J=7.53, 3.26 Hz, 2H). HPLC: RT 2.93 min. MS: [M+H].sup.+
m/z=378.1.
Example A-40
Synthesis of
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-
-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-56)
3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one
[0676] To a solution of 3-methyl-4-nitro-1H-pyrazole (10 g, 78.68
mmol) in DMF (50 mL) was added portionwise NaH (4.72 g, 118.02
mmol, 60% purity) at 0.degree. C. over a period of 30 min under
N.sub.2. The reaction mixture was warmed to 20.degree. C. and
stirred at 20.degree. C. for 1 h. Then
3-bromo-3-methyl-butan-2-on56e (15.58 g, 94.41 mmol) was added
dropwise at 0.degree. C. over a period of 30 min. The reaction
mixture was warmed to 20.degree. C. and stirred at 20.degree. C.
for another 5 h. The reaction mixture was quenched by pouring into
ice water (350 mL) slowly and then extracted with EtOAc
(3.times.100 mL). The combined organic layers were washed with
brine (2.times.50 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=10:1 to 3:1)
to give 3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one as
a light yellow solid. LCMS: RT 0.670 min, m/z=212.2
[M+H].sup.+.
1-bromo-3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one
[0677] A mixture of
3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one (6.7 g, 31.72
mmol), CuBr.sub.2 (12.04 g, 53.92 mmol) in EtOAc (80 mL) and
CHCl.sub.3 (80 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 80.degree. C. for 24 h
under N.sub.2. The reaction mixture was filtered and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (PE:EtOAc=10:1 to 3:1) to give
1-bromo-3-methyl-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)butan-2-one as
a yellow solid. LCMS: RT 1.035 min, m/z=290.0 [M+H].sup.+.
3-methyl-1-(2-(2-(methylthio)-1H-imidazol-4-yl)propan-2-yl)-4-nitro-1H-pyr-
azole
[0678] To a mixture of
1-bromo-3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one (10
g, 34.47 mmol) and 2-Methyl-2-thiopseudourea sulfate (2:1) (11.51
g, 41.36 mmol) in EtOH (200 mL) was added AcONa (8.48 g, 103.41
mmol) at 20.degree. C. Then the mixture was heated to 90.degree. C.
and stirred for 12 h. The mixture was cooled to 20.degree. C.,
quenched by pouring into ice-water (50 mL), concentrated under
reduced pressure, and extracted with EtOAc (3.times.20 mL). The
combined organic phase was washed with brine (20 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=10:1 to 3:1) to give
3-methyl-1-(2-(2-(methylthio)-1H-imidazol-4-yl)propan-2-yl)-4-nitro--
1H-pyrazole as a yellow solid. LCMS: RT 0.664 min, m/z=282.1
[M+H].sup.+.
1-(2-(1H-imidazol-4-yl)propan-2-yl)-3-methyl-4-nitro-1H-pyrazole
[0679] To a solution of
3-methyl-1-[1-methyl-1-(2-methylsulfanyl-1H-imidazol-4-yl)ethyl]-4-nitro--
pyrazole (1 g, 3.55 mmol) in THF (20 mL) was added Et.sub.3SiH
(1.24 g, 10.66 mmol) and Pd/C (756 mg, 710.91 .mu.mol, 10% purity)
at 0.degree. C. The mixture was stirred at 20.degree. C. for 60 h.
The reaction mixture was filtered and concentrated under reduced
pressure. The residue was purified by flash silica gel
chromatography (ISCO.RTM.; 20 g SepaFlash.RTM. Silica Flash Column,
Eluent of 0-100% EtOAc/PE gradient at 100 mL/min) to give
1-(2-(1H-imidazol-4-yl)propan-2-yl)-3-methyl-4-nitro-1H-pyrazole as
a yellow solid. LCMS: RT 0.186 min, m/z=236.2 [M+H].sup.+.
3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-4-nitro-1H-pyrazole
[0680] To a solution of
1-[1-(1H-imidazol-4-yl)-1-methyl-ethyl]-3-methyl-4-nitro-pyrazole
(120 mg, 510.12 .mu.mol) in CH.sub.3CN (2 mL) was added Mel (87 mg,
612.14 .mu.mol) and Cs.sub.2CO.sub.3 (166 mg, 510.12 .mu.mol). The
mixture was stirred at 20.degree. C. for 12 h. The reaction mixture
was filtered and concentrated under reduced pressure. The residue
was purified by prep-TLC (SiO.sub.2, EtOAc) to give
3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-4-nitro-1H-pyrazole
as a yellow solid. LCMS: RT 0.236 min, m/z=250.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.05-8.11 (m, 1H),
7.41-7.48 (m, 1H), 6.82-6.89 (m, 1H), 3.70 (s, 3H), 2.54 (s, 3H),
1.94 (s, 6H).
3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-pyrazol-4-amine
[0681] To a solution of
3-methyl-1-[1-methyl-1-(1-methylimidazol-4-yl)ethyl]-4-nitro-pyrazole
(150 mg, 601.76 .mu.mol) in MeOH (10 mL) was added Pd--C (10%, 128
mg) under N.sub.2. The suspension was degassed under vacuum and
purged with H.sub.2 several times. The mixture was stirred under
H.sub.2 (15 psi) at 30.degree. C. for 2 h. The reaction mixture was
filtered and the filtrate was concentrated to give
3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-pyrazol-4-amine
as a brown oil. LCMS: RT 0.387 min, m/z=220.3 [M+H].sup.+.
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H--
pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-56)
[0682] To a solution of
3-methyl-1-[1-methyl-1-(1-methylimidazol-4-yl)ethyl]pyrazol-4-amine
(120 mg, 547.22 .mu.mol) and
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (146
mg, 547.22 .mu.mol) in 1,4-dioxane (5 mL) was added TFA (31 mg,
273.61 .mu.mol). The mixture was stirred at 100.degree. C. for 1 h.
The reaction mixture was diluted with H.sub.2O (20 mL) and aq.
NaHCO.sub.3 (20 mL), extracted with EtOAc (3.times.10 mL). The
combined organic layers were washed with brine (10 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (neutral condition) to give
4-cyclopropyl-N-(3-methyl-1-(2-(1-methyl-1H-imidazol-4-yl)propan-2-yl)-1H-
-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. ppm 8.30-8.47 (m, 1H), 7.74-7.94 (m,
1H), 7.36-7.45 (m, 1H), 6.53-6.78 (m, 2H), 3.65 (s, 3H), 2.26 (s,
3H), 2.14-2.23 (m, 1H), 1.96 (s, 6H), 1.15-1.28 (m, 2H), 1.03-1.12
(m, 2H). HPLC: RT 2.467 min. MS: m/z: 406.2 [M+H].sup.+.
Example A-41
Synthesis of
1-[5-chloro-4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyr-
azol-1-yl]-2-methyl-propan-2-ol (A-57)
[0683] To a mixture of
1-(4-amino-5-chloro-1H-pyrazol-1-yl)-2-methylpropan-2-ol (70 mg,
369.12 .mu.mol) and
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (98
mg, 369.12 .mu.mol) in 1,4-dioxane (5 mL) was added TFA (84 mg,
738.24 .mu.mol, 55 .mu.L) at 20.degree. C. under N.sub.2. The
mixture was heated to 90.degree. C. and stirred for 5 h. The
mixture was cooled to 20.degree. C. and adjusted to pH=8 by adding
aq. NaHCO.sub.3. The aqueous phase was extracted with EtOAc
(3.times.10 mL). The combined organic phase was washed with brine
(10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral) to give
1-[5-chloro-4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyr-
azol-1-yl]-2-methyl-propan-2-ol. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.11 (d, J=9.66 Hz, 2H), 7.87 (s, 1H), 6.68 (br. s., 1H),
5.13-5.25 (m, 1H), 3.81 (s, 3H), 3.05 (d, J=4.14 Hz, 3H), 2.28 (s,
3H), 1.73 (s, 4H). HPLC: RT 2.723 min. MS: [M+H].sup.+
m/z=376.1.
Example A-42
Synthesis of
N-(1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-c-
yclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-58)
1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine
[0684] To a solution of
3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1H-1,2,4-triazole
(2 g, 8.47 mmol) in EtOH (40 mL) was added Pd--C (10%, 0.9 g) under
N.sub.2. The suspension was degassed under vacuum and purged with
H.sub.2 several times. The mixture was stirred under H.sub.2 (15
psi) at 50.degree. C. for 2 h. The reaction mixture was filtered
and the filtrate was concentrated to give
1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine
as a brown solid. The crude product was used into the next step
without further purification.
N-(1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-cy-
clopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-58)
[0685] To a solution of
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (129
mg, 484.85 .mu.mol) and
1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine
(100 mg, 484.85 .mu.mol) in 1,4-dioxane (5 mL) was added TFA (110
mg, 969.70 .mu.mol). The mixture was stirred at 100.degree. C. for
2 h. The reaction mixture was diluted with H.sub.2O (20 mL),
adjusted with sat. NaHCO.sub.3 (10 mL) to pH=8-9 and extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
brine (5 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue, which was
purified by prep-HPLC (FA condition) to give an FA salt of the
product (36 mg). The salt was purified by prep-HPLC (neutral) to
give
N-(1-(2-(1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-c-
yclopropyl-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR: (400
MHz, CDCl3): (400 MHz, CHLOROFORM-d) .delta. 11.39 (bs, 1H), 8.41
(s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.03 (bs, 1H), 2.27 (s, 3H),
2.18-2.25 (m, 1H), 2.05 (s, 6H), 1.20-1.30 (m, 2H), 1.07-1.18 (m,
2H). HPLC: RT 2.301 min. MS: [M+H].sup.+ m/z: 393.2.
Example A-43
Synthesis of
(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,
(R)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,
(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one, and
(R)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one (A-59, A-60, A-61, and
A-62)
5-((tert-butyldiphenylsilyl)oxy)-1-ethylpiperidin-2-one
[0686] To a solution of
5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one (2 g, 5.66 mmol) in
DMF (10 mL) was added portionwise NaH (340 mg, 8.49 mmol, 60%
purity) at 0.degree. C. over 20 min. After addition, the mixture
was stirred at 20.degree. C. for 40 min, and then EtI (1.32 g, 8.49
mmol) was added dropwise at 0.degree. C. The resulting mixture was
stirred at 20.degree. C. for 11 h. The reaction mixture was poured
into ice-water (80 mL) and extracted with EtOAc (3.times.30 mL).
The combined organic layers were washed with brine (3.times.10 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=5:1 to 0:1) to give
5-((tert-butyldiphenylsilyl)oxy)-1-ethylpiperidin-2-one as a yellow
oil. LCMS: RT 1.008 min, m/z=382.2 [M+H].sup.+.
1-ethyl-5-hydroxypiperidin-2-one
[0687] To a solution of
5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl-piperidin-2-one (1.5 g,
3.93 mmol) in MeOH (30 mL) was added KF (4.57 g 78.60 mmol) at
25.degree. C. under N.sub.2. The mixture was then heated to
70.degree. C. and stirred for 48 h. The mixture was cooled to
25.degree. C. and concentrated under reduced pressure. The residue
was poured into DCM:MeOH=10:1 (50 mL) and stirred for 30 min,
followed by filtration. The filtrate was concentrated under reduced
pressure. The residue was dissolved in water (50 mL) and extracted
with MTBE (2.times.20 mL). The aqueous phase was concentrated under
reduced pressure to give 1-ethyl-5-hydroxypiperidin-2-one as a
colorless oil. LCMS: RT 0.206 min, m/z=144.2 [M+H].sup.+.
1-ethyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one &
1-ethyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one
[0688] To a solution of 1-ethyl-5-hydroxy-piperidin-2-one (530 mg,
3.70 mmol), 3-methyl-4-nitro-1H-pyrazole (706 mg, 5.55 mmol) and
PPh, (146 g, 5.55 mmol) in THF (20 mL) was added dropwise DIAD
(1.12 g, 5.55 mmol) at 0.degree. C. over 20 min. After addition,
the mixture was stirred at this temperature for 40 min, and then
the resulting mixture was stirred at 20.degree. C. for 11 h. The
reaction mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(PE:EtOAc=5:1 to 0:1) to give a mixture of
1-ethyl-5-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one and
1-ethyl-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidin-2-one as a
yellow solid. LCMS: RT 0.881 min, m/z=253.1 [M+H].sup.+.
5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one and
5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one
[0689] To a solution of
1-ethyl-5-(5-methyl-4-nitro-pyrazol-1-yl)piperidin-2-one and
1-ethyl-5-(3-methyl-4-nitro-pyrazol-1-yl)piperidin-2-one (420 mg,
1.66 mmol) in MeOH (40 mL) was added Pd/C (10%, 176 mg) under
N.sub.2. The suspension was degassed under vacuum and purged with
H.sub.2 several times. The mixture was stirred under H.sub.2 (15
psi) at 20.degree. C. for 2 h. The reaction mixture was filtered
and the filtrate was concentrated to give a mixture of
5-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one and
5-(4-amino-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one as a
brown oil. LCMS: RT 0.566 min, m/z=223.3 [M+H].sup.+.
(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-
-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,
(R)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,
(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one, and
(R)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one (A-59, A-60, A-61, and
A-62)
[0690] To a solution of
5-(4-amino-5-methyl-pyrazol-1-yl)-1-ethyl-piperidin-2-one and
5-(4-amino-3-methyl-pyrazol-1-yl)-1-ethyl-piperidin-2-one (310 mg,
1.39 mmol), and
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (370
mg, 1.39 mmol) in 1,4-dioxane (10 mL) was added TFA (317 mg, 2.78
mmol). The mixture was stirred at 100.degree. C. for 2 h. The
reaction mixture was diluted with H.sub.2O (30 mL), adjusted with
aq. NaHCO.sub.3 (30 mL) to pH=8 and extracted with EtOAc
(3.times.30 mL). The combined organic layers were washed with brine
(30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give crude product. The crude product was
triturated with DMF (5 mL). The undissolved solid was filtered to
give crude product as a solid. This crude product was separated by
SFC to give
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-
-pyrazol-1-yl)-1-ethylpiperidin-2-one as a single enantiomer (Peak
1 in SFC) and
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3--
methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one as a single
enantiomer (Peak 2 in SFC). The DMF filtrate was concentrated to
give crude product. This crude product was purified by prep-HPLC
(TFA) and then twice of SFC to give
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-m-
ethyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one as a single
enantiomer (Peak 1 in SFC) and
5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-
-pyrazol-1-yl)-1-ethylpiperidin-2-one as a single enantiomer (Peak
2 in SFC).
First Eluting Isomer (Peak 1):
(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one (A-59)
[0691] .sup.1H NMR (400 MHz, MD.sub.3OD): .delta. ppm 8.25-8.45 (m,
1H), 7.48-7.67 (m, 1H), 4.64-4.79 (m, 1H), 3.72-3.84 (m, 1H),
3.56-3.63 (m, 1H), 3.44-3.54 (m, 1H), 3.35-3.43 (m, 1H), 2.50-2.61
(m, 2H), 2.32-2.44 (m, 1H), 2.25 (s, 3H), 2.09-2.21 (m, 2H),
0.98-1.34 (m, 7H). HPLC: RT 2.480 min. MS: m/z: 409.2 [M+H].sup.+.
SFC: RT 5.72 min, ee=100%.
Second Eluting Isomer (Peak 2):
(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one (A-60)
[0692] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 8.21-8.48 (m,
1H), 7.43-7.71 (m, 1H), 4.67-4.80 (m, 1H), 3.72-3.83 (m, 1H),
3.56-3.62 (m, 1H), 3.44-3.54 (m, 1H), 3.34-3.43 (m, 1H), 2.49-2.60
(m, 2H), 2.33-2.44 (m, 1H), 2.25 (s, 3H), 2.08-2.21 (m, 2H),
0.97-1.34 (m, 7H). HPLC: RT 2.487 min. MS: m/z: 409.1 [M+H].sup.+.
SFC: RT 6.33 min, ee=100%.
First Eluting Isomer (Peak 1):
(S)-5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methy-
l-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one (A-61)
[0693] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 8.34-8.43 (m,
1H), 7.84-7.94 (m, 1H), 4.54-4.69 (m, 1H), 3.69-3.79 (m, 2H),
3.38-3.52 (m, 2H), 2.46-2.57 (m, 2H), 2.32-2.43 (m, 1H), 2.22-2.30
(m, 1H), 2.19 (s, 4H), 1.18-1.31 (m, 2H), 1.07-1.17 (m, 5H). HPLC:
RT 2.468 min. MS: m/z: 409.1 [M+H].sup.+. SFC: RT 4.87 min,
ee=100%.
Second Eluting Isomer (Peak
2):5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-
-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one (A-62)
[0694] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 8.34-8.42 (m,
1H), 7.83-7.95 (m, 1H), 4.56-4.71 (m, 1H), 3.68-3.80 (m, 2H),
3.37-3.53 (m, 2H), 2.45-2.58 (m, 2H), 2.32-2.43 (m, 1H), 2.23-2.30
(m, 1H), 2.19 (s, 4H), 1.19-1.30 (m, 2H), 1.06-1.18 (m, 5H). HPLC:
RT 2.464 min. MS: m/z: 409.1 [M+H].sup.+. SFC: RT 5.67 min,
ee=98.02%.
Example A-44
Synthesis of
N-[5-chloro-1-[[1-(morpholinomethyl)cyclopropyl]methyl]pyrazol-4-yl]-4-cy-
clopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-63)
N-[5-chloro-1-[[1-(morpholinomethyl)cyclopropyl]methyl]pyrazol-4-yl]-4-cyc-
lopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-63)
[0695] To a mixture of
5-chloro-1-((1-(morpholinomethyl)cyclopropyl)methyl)-1H-pyrazol-4-amine
(70 mg, 258.53 .mu.mol) and
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine
(75.71 mg, 284.38 .mu.mol) in 1,4-dioxane (3 mL) was added TFA
(58.96 mg, 517.06 .mu.mol) in one portion at 20.degree. C. under
N.sub.2. The mixture was stirred at 90.degree. C. for 6 h. The
mixture was concentrated under reduced pressure. The residue was
poured into aq. NaHCO.sub.3 (10 mL) and stirred for 5 min. The
aqueous phase was extracted with EtOAc (3.times.5 mL). The combined
organic phase was washed with brine (10 mL), dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (NH.sub.4HCO.sub.3) to give
N-(5-chloro-1-((1-(morpholinomethyl)cyclopropyl)methyl)-1H-pyrazol-4-
-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.43 (s, 1H) 7.98 (s, 1H)
6.70 (br. s., 1H) 4.19 (s, 2H) 3.67 (t, J=4.52 Hz, 4H) 2.43 (br.
s., 4H) 2.15-2.28 (m, 3H) 1.26-1.36 (m, 2H) 1.08-1.20 (m, 2H)
0.68-0.79 (m, 2H) 0.38-0.48 (m, 2H). HPLC: RT 2.44 min. MS:
[M+H].sup.+ m/z: 457.
Example A-45
Synthesis of
N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-y-
l)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (64) and
N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-y-
l)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-65)
5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-amine
[0696] To a mixture of
3-(5-chloro-4-nitro-1H-pyrazol-1-yl)-4,4-difluoro-1-(oxetan-3-yl)piperidi-
ne (1.1 g, 3.41 mmol) in EtOH (48 mL) and H.sub.2O (12 mL) was
added NH.sub.4Cl (911 mg, 17.05 mmol) and Fe (951 mg, 17.05 mmol)
at 20.degree. C. Then the mixture was heated to 80.degree. C. and
stirred for 2 h. The mixture was cooled to 20.degree. C., filtered
and concentrated under reduced pressure. The residue was added with
water (10 mL) then extracted with EtOAc (3.times.5 mL). The
combined organic phase was washed with brine (5 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure, to give
5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-amin-
e as a red brown solid. LCMS: RT 0.103 min, m/z=293.1
[M+H].sup.+.
N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl-
)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine and
N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-y-
l)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-64 and
A-65)
[0697] A mixture of
5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-amin-
e (200 mg, 683.27 .mu.mol),
2-chloro-4-cyclopropyl-5-(trifluoromethyl)pyrimidine (167 mg,
751.60 .mu.mol), Pd.sub.2(dba).sub.3 (63 mg, 68.33 .mu.mol), XPhos
(65 mg, 136.65 .mu.mol) and Cs.sub.2CO.sub.3 (534 mg, 1.64 mmol) in
1,4-dioxane (10 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 100.degree. C. for 12 h
under N.sub.2. The residue was purified by prep-TLC (SiO.sub.2,
PE/Ethyl acetate=1/1) to give crude product. The crude was further
separated by SFC to provide
N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-y-
l)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine as a single
enantiomer (peak 1) and
N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-y-
l)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine as a single
enantiomer (peak 2).
First Eluting Isomer (Peak 1):
N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-y-
l)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-64)
[0698] .sup.1H NMR: (400 MHz, CHLOROFORM-d) .delta. ppm 8.44 (s,
1H), 8.12 (s, 1H), 6.74 (bs, 1H), 4.66-4.81 (m, 3H), 4.56-4.64 (m,
2H), 3.64-3.76 (m, 1H), 3.04-3.14 (m, 1H), 2.93-3.02 (m, 1H),
2.79-2.89 (m, 1H), 2.10-2.41 (m, 4H), 1.24-1.35 (m, 2H), 1.07-1.18
(m, 2H). HPLC: RT 2.914. MS: [M+H].sup.+ m/z: 479.2. SFC: ee:
99.66%.
Second Eluting Isomer (Peak 2):
N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-y-
l)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-65)
[0699] .sup.1H NMR: (400 MHz, CHLOROFORM-d) .delta. ppm 8.44 (s,
1H), 8.12 (s, 1H), 6.73 (bs, 1H), 4.66-4.82 (m, 3H), 4.54-4.65 (m,
2H), 3.63-3.79 (m, 1H), 3.05-3.16 (m, 1H), 2.92-3.03 (m, 1H),
2.78-2.89 (m, 1H), 2.09-2.42 (m, 4H), 1.23-1.37 (m, 2H), 1.04-1.20
(m, 2H). HPLC: RT 2.911. MS: [M+H].sup.+ m/z: 479.1. SFC: ee:
98.9%.
Example A-46
Synthesis of
4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4--
yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-67)
3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one
[0700] To a solution of 3-methyl-4-nitro-1H-pyrazole (6.42 g, 50.51
mmol) in DMF (100 mL) was added NaH (2.42 g, 60.61 mmol) at
0.degree. C. under N.sub.2. The mixture was allowed to warmed to
25.degree. C. and stirred for 2 h. Then the mixture was cooled to
0.degree. C. and added with 3-bromo-3-methyl-butan-2-one (10 g,
60.61 mmol). The mixture was then stirred at 25.degree. C. for 16
h. The mixture was poured into ice-water (600 mL). The aqueous
phase was extracted with EtOAc (3.times.200 mL). The combined
organic phase was washed with brine (2.times.200 mL), dried with
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by silica gel column chromatography (PE:EtOAc=10:1) to
afford 3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one as
light yellow solid. LCMS: RT 0.704 min, m/z=212.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d): .delta. 8.30 (s, 1H), 2.56 (s,
3H), 1.98 (s, 3H), 1.74 (s, 611).
(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-pyrazol-1-yl)pent-1-en--
3-one
[0701] A mixture of
3-methyl-3-(3-methyl-4-nitro-pyrazol-1-yl)butan-2-one (6.2 g, 29.35
mmol) and DMF-DMA (34.98 g, 293 mmol, 38.86 mL) was heated to
110.degree. C. and stirred for 6 h. The mixture was cooled to
0.degree. C. and yellow solid was precipitated out. The mixture was
filtered to give
(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-pyrazol-1-yl)pent-1-en-
-3-one as a yellow solid. LCMS: RT 0.691 min, m/z=267.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.28 (s,
1H), 7.65 (d, J=12.17 Hz, 1H), 4.55 (d, J=12.30 Hz, 1H), 3.09 (br.
s., 3H), 2.72 (br. s., 3H), 2.55 (s, 3H), 1.76 (s, 6H).
3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]-4-nitro-pyrazole
[0702] To a mixture of
(E)-1-(dimethylamino)-4-methyl-4-(3-methyl-4-nitro-pyrazol-1-yl)pent-1-en-
-3-one (2 g, 7.51 mmol) in AcOH (10 mL) was added hydrazine hydrate
(1.88 g, 37.55 mmol, 1.83 mL). The mixture was then heated to
100.degree. C. and stirred for 2 h. The mixture was cooled to
25.degree. C. and concentrated under reduced pressure. The residue
was poured into saturated aqueous NaHCO.sub.3 (100 mL). The aqueous
phase was extracted with EtOAc (3.times.50 mL). The combined
organic phase was washed with brine (100 mL), dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to give
3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]4-nitro-pyrazole as a
yellow solid, which was used for next step directly. LCMS: RT 0.692
min, m/z=236.1 [M+H].sup.+.
3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-amine
[0703] To a solution of
3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]-4-nitro-pyrazole
(1.87 g, 7.95 mmol) in MeOH (30 mL) was added Pd--C (10%, 0.6 g)
under N.sub.2. The suspension was degassed under vacuum and purged
with H.sub.2 three times. The mixture was stirred under H.sub.2 (15
psi) at 25.degree. C. for 2 h. The reaction mixture was filtered
and the filtrate was concentrated to give
3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-amine as
black-brown oil. LCMS: RT 0.109 min, m/z=206.1 [M+H].sup.+.
4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-y-
l]-5-(trifluoromethyl)pyrimidin-2-amine (A-67)
[0704] To a mixture of
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (100
mg, 375 .mu.mol) and
3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4-amine (77
mg, 375.60 .mu.mol) in 1,4-dioxane (2 mL) was added TFA (85 mg, 751
.mu.mol) at 25.degree. C. under N.sub.2. The mixture was then
heated to 90.degree. C. and stirred for 3 h. The mixture was cooled
to 25.degree. C. and poured into saturated aqueous NaHCO.sub.3 (30
mL). The aqueous phase was extracted with EtOAc (3.times.10 mL).
The combined organic phase was washed with brine (10 mL), dried
with anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give
a residue. The residue was purified by prep-HPLC (neutral) to
afford
4-cyclopropyl-N-[3-methyl-1-[1-methyl-1-(1H-pyrazol-5-yl)ethyl]pyrazol-4--
yl]-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR (400 MHz,
CDCl.sup.3): .delta. 8.39 (br. s., 1H), 7.83 (br. s., 1H), 7.51
(br. s., 1H), 6.80 (br. s., 1H), 6.19 (br. s., 1H), 2.28 (s, 3H),
2.20 (br. s., 1H), 2.00 (s, 6H), 1.19 (d, J=9.70 Hz, 2H), 1.05-1.13
(m, 2H). HPLC: RT 2.589 min. MS: [M+H].sup.+ m/z: 392.2.
Example A-47
Synthesis of
4-cyclopropyl-N-(3-methyl-1-((1R,3r,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-3-
-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidi-
n-2-amine (A-69) and
4-cyclopropyl-N-(3-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-
-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidi-
n-2-amine (A-70) and
4-cyclopropyl-N-(5-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-
-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidi-
n-2-amine (A-68)
1-(cyclopent-3-en-1-yl)-5-methyl-4-nitro-1H-pyrazole and
1-(cyclopent-3-en-1-yl)-3-methyl-4-nitro-1H-pyrazole
[0705] To a solution of 3-methyl-4-nitro-1H-pyrazole (20 g, 157.36
mmol), cyclopent-3-en-1-ol (15.88 g, 188.83 mmol) and PPh, (61.91
g, 236.04 mmol) in THF (300 mL) was added DIAD (47.73 g, 236.04
mmol) at 0.degree. C. The mixture was stirred at 25.degree. C. for
12 h. The reaction mixture was concentrated under reduced pressure
to give a residue, which was purified by silica gel chromatography
(PE:EtOAc=50:1 to 20:1) to give a mixture of
1-(cyclopent-3-en-1-yl)-5-methyl-4-nitro-1H-pyrazole and
1-(cyclopent-3-en-1-yl)-3-methyl-4-nitro-1H-pyrazole as a yellow
oil. LCMS: RT 1.301 min, m/z=194.1 [M+H].sup.+.
Ethyl
3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxyla-
te and ethyl
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylate
[0706] To a mixture of
I-cyclopent-3-en-1-yl-5-methyl-4-nitro-pyrazole and
1-cyclopent-3-en-1-yl-3-methyl-4-nitro-pyrazole (10 g, 51.76 mmol),
bis [(Z)-1-methyl-3-oxo-but-1-enoxy]copper (948 mg, 3.62 mmol) in
DCE (300 mL) was added a solution of ethyl 2-diazoacetate (23.6 g,
207.04 mmol) in DCE (600 mL) over a period of 12 h at 90.degree. C.
The mixture was stirred at 90.degree. C. for 4 h. The reaction
mixture was concentrated under reduced pressure to give a residue,
which was purified by silica gel column chromatography
(PE:EtOAc=20:1 to 5:1) to give a mixture of ethyl
3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxyl-
ate and ethyl
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylate
as a yellow solid. LCMS: RT 0.831 min, m/z=280.1 [M+H].sup.+.
3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylic
acid and
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylic
acid
[0707] To a mixture of ethyl
3-(5-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylate
(4) and ethyl
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carb-
oxylate (4A) (2.6 g, 9.31 mmol) in THF (40 mL) and H.sub.2O (10 mL)
was added LiOH.H.sub.2O (781 mg, 18.62 mmol). The mixture was
stirred at 25.degree. C. for 12 h. The reaction mixture was poured
into H.sub.2O (30 mL) and extracted with MTBE (20 mL.times.2), the
aqueous layer was separated and adjusted to pH=3 by 1 N HCl, then
it was extracted with EtOAc (2.times.30 mL), dried over
Na.sub.2SO.sub.4, concentrated under reduced pressure to give a
mixture of
3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylic
acid and
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carbo-
xylic acid as a white solid. LCMS: RT 1.072 min, m/z=252.1
[M+H].sup.+.
3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide
and
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide
[0708] To a mixture of
3-(5-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylic
acid and
3-(5-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxylic
acid (800 mg, 3.18 mmol) in DCM (20 mL) was added DMF (200 .mu.L)
and (COCl).sub.2 (807 mg, 6.36 mmol) drop-wise at 0.degree. C. over
a period of 10 min under N.sub.2. The reaction mixture was then
stirred at 25.degree. C. for 1 h, concentrated under reduced
pressure to give a residue. Then the residue was dissolved in THF
(20 mL) and added dropwise to NH.sub.3.H.sub.2O (7.8 g, 222.6 mmol)
at 25.degree. C. The resulting mixture was stirred at 25.degree. C.
for 3 h. The reaction mixture was concentrated under reduced
pressure and extracted with EtOAc (50 mL 2). The combined organic
phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a mixture
of
3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide
and
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamid-
e. LCMS: RT 1.158 min, m/z=251.1 [M+H].sup.+.
(E)-N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyc-
lo[3.1.0]hexane-6-carboxamide and
(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicy-
clo[3.1.0]hexane-6-carboxamide
[0709] A mixture of
3-(5-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide
and
3-(3-methyl-4-nitro-pyrazol-1-yl)bicyclo[3.1.0]hexane-6-carboxamide
(800 mg, 3.2 mmol) in DMF-DMA (3.81 g, 32 mmol) was heated to
95.degree. C. and stirred for 2 h. The mixture was cooled to
25.degree. C., concentrated under reduced pressure to give a
residue, which was slurried with MTBE (10 mL), filtered to give
pure
(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicy-
clo[3.1.0]hexane-6-carboxamide (0.6 g) as a white solid. The
filtrate was concentrated under reduced pressure to give a mixture
of
(E)-N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicy-
clo[3.1.0]hexane-6-carboxamide and
(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicy-
clo[3.1.0]hexane-6-carboxamide. LCMS: RT 1.16 min, m/z=306.1
[M+H].sup.+.
3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H-1,2,4--
triazole
[0710] To a solution of
(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicy-
clo[3.1.0]hexane-6-carboxamide (800 mg, 2.62 mmol) in AcOH (8 mL)
was added NH.sub.2NH.sub.2.H.sub.2O (1.97 g, 39.3 mmol). The
mixture was stirred at 95.degree. C. for 2 h. The reaction mixture
was concentrated under reduced pressure and poured into ice-water
(20 mL), adjusted to pH=9 with aq. NaHCO.sub.3, and extracted with
EtOAc (50 mL.times.2). The combined organic layers were washed with
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure, to give
3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-1H--
1,2,4-triazole. LCMS: RT 0.633 min, m/z=275.1 [M+H].sup.+.
1-methyl-3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)--
1H-1,2,4-triazole and
1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole
[0711] To a solution of
3-[3-(3-methyl-4-nitro-pyrazol-1-yl)-6-bicyclo[3.1.0]hexanyl]-1H-1,2,4-tr-
iazole (8) (400 mg, 1.46 mmol) in MeCN (20 mL) was added Mel (248
mg, 1.75 mmol) and Cs.sub.2CO.sub.3 (476 mg, 1.46 mmol). The
mixture was stirred at 50.degree. C. for 12 h. The reaction mixture
was filtered and concentrated under reduced pressure to give a
residue, which was purified by prep-TLC (SiO.sub.2, DCM:MeOH=10:1)
to give a mixture of
1-methyl-3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole and
1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole. LCMS: RT 0.677 min, m/z=289.1 [M+H].sup.+.
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1H-
-pyrazol-4-amine and
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine
[0712] A mixture of
1-methyl-3-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole and
1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole (300 mg, 1.04 mmol), NH.sub.4Cl (278 mg, 5.2
mmol) and Fe (290 mg, 5.2 mmol) in EtOH (25 mL) and H.sub.2O (5 mL)
was stirred at 90.degree. C. for 2 h. It was filtered and the
filtrate was concentrated under reduced pressure to give a residue,
which was slurried with DCM:MeOH (V:V, 10:1, 15 mL), filtered and
the filtrate was concentrated under reduced pressure to give a
mixture of
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine and
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine. LCMS: RT 0.369 min, m/z=259.2 [M+H].sup.+.
4-cyclopropyl-N-(3-methyl-1-((1R,3r,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-3--
yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-
-2-amine (A-69) and
4-cyclopropyl-N-(3-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-
-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidi-
n-2-amine (A-70)
[0713] A mixture of
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-3-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine and
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine (200 mg, 774.23 .mu.mol),
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (247
mg, 929 .mu.mol) and TFA (177 mg, 1.55 mmol) in 1,4-dioxane (30 mL)
was degassed and purged with N.sub.2 for 3 times, and then the
mixture was stirred at 95.degree. C. for 4 h under N.sub.2. It was
poured into H.sub.2O (15 mL), adjusted to pH=8 with aq.NaHCO.sub.3,
extracted with EtOAc (30 mL.times.2). The combined organic phase
was dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to get a residue, which was purified by prep-HPLC
(neutral) to give
4-cyclopropyl-N-(3-methyl-1-((1R,3r,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-3-
-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidi-
n-2-amine (69) and
4-cyclopropyl-N-(3-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5-
-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidi-
n-2-amine (70).
4-cyclopropyl-N-(3-methyl-1-((1R,3r,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-3--
yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-
-2-amine (A-69)
[0714] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.41 (d, J=18.96
Hz, 1H), 7.76-7.91 (m, 2H), 6.55-6.71 (m, 1H), 4.30-4.45 (m, 1H),
3.85 (s, 3H), 2.33-2.59 (m, 4H), 2.15-2.29 (m, 4H), 1.96-2.04 (m,
3H), 1.22-1.30 (m, 2H), 1.05-1.17 (m, 2H). HPLC: RT 2.96 min. MS:
[M+H].sup.+=m/z: 445.2.
4-cyclopropyl-N-(3-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5--
yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-
-2-amine (A-70)
[0715] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.43 (br. s.,
1H), 7.74-7.93 (m, 1H), 7.71 (s, 1H), 6.58-6.81 (m, 1H), 4.41 (t,
J=8.16 Hz, 1H), 3.90 (s, 3H), 2.36-2.60 (m, 4H), 2.25 (s, 3H),
2.05-2.21 (m, 3H), 1.77 (br. s., 1H), 1.27 (br. s., 2H), 1.04-1.19
(m, 2H). HPLC: RT 2.60 min. MS: [M+H].sup.+ m/z: 445.2.
1-methyl-5-(3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)--
1H-1,2,4-triazole and
1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole
[0716] To a mixture of
(E)-N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicy-
clo[3.1.0]hexane-6-carboxamide and
(E)-N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicy-
clo[3.1.0]hexane-6-carboxamide (200 mg, crude) in AcOH (8 mL) was
added methylhydrazine (1.32 g, 11.50 mmol). The mixture was stirred
at 95.degree. C. for 2 h. The reaction mixture was concentrated
under reduced pressure and poured into ice-water (20 mL), adjusted
to pH=9 with aq. NaHCO.sub.3, and extracted with EtOAc (50
mL.times.2). The combined organic layers were washed with brine (50
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give a mixture of
1-methyl-5-(3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole and
1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-v)--
1H-1,2,4-triazole as yellow oil. LCMS: RT 0.950 min, m/z=289.1
[M+H].sup.+.
5-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-
-pyrazol-4-amine and
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine
[0717] A mixture of
1-methyl-5-(3-(5-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole and
1-methyl-5-(3-(3-methyl-4-nitro-1H-pyrazol-1-yl)bicyclo[3.1.0]hexan-6-yl)-
-1H-1,2,4-triazole (0.2 g, crude), NH.sub.4Cl (195 mg, 3.64 mmol)
and Fe (203 mg, 3.64 mmol) in EtOH (25 mL) and H.sub.2O (5 mL) was
stirred at 90.degree. C. for 2 h. It was filtered and the filtrate
was concentrated under reduced pressure to give a residue, which
was slurry with DCM:MeOH (V:V, 10:1, 15 mL), filtered and the
filtrate was concentrated under reduced pressure to give a mixture
of
5-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine and
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine as a yellow oil. LCMS: RT 0.320 min, m/z=259.2
[M+H].sup.+.
4-cyclopropyl-N-(5-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-triazol-5--
yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-
-2-amine (A-68)
[0718] A mixture of
5-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine and
3-methyl-1-(6-(1-methyl-1H-1,2,4-triazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1-
H-pyrazol-4-amine (188 mg, crude),
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (235
mg, 883 .mu.mol) and TFA (168 mg, 1.47 mmol) in 1,4-dioxane (30 mL)
was degassed and purged with N.sub.2 for 3 times, and then the
mixture was stirred at 95.degree. C. for 4 h under N.sub.2. It was
poured into H.sub.2O (15 mL), adjusted to pH=8 with aq.NaHCO.sub.3,
extracted with EtOAc (30 mL.times.2). The combined organic phase
was dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to get a residue, which was purified by prep-HPLC
(neutral) and then it was separated by SFC to give
4-cyclopropyl-N-(5-methyl-1-((1R,3s,5S,6r)-6-(1-methyl-1H-1,2,4-tria-
zol-5-yl)bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyr-
imidin-2-amine (68). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.38 (s, 1H), 7.55-7.74 (m, 2H), 6.44-6.70 (m, 1H), 4.37 (br. s.,
1H), 3.92 (s, 3H), 2.66 (br. s., 2H), 2.40 (dd, J=13.16, 7.89 Hz,
2H), 2.21 (s, 3H), 2.16 (br. s., 2H), 1.73 (br. s., 1H), 1.19-1.25
(m, 2H), 1.08 (d, J=4.38 Hz, 2H). HPLC: RT 2.86 min. MS:
[M+H].sup.+ m/z: 445.2.
Example A-48
Synthesis of
N-(1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-c-
yclopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-71)
1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine
[0719] To a solution of
4-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-2H-1,2,3-triazole
(100 mg, 0.42 mmol) in EtOH (2 mL) and water (0.5 mL) was added
NH.sub.4Cl (68 mg, 1.27 mmol) and Fe (71 mg, 1.27 mmol), then the
mixture was stirred at 100.degree. C. for 1 h. The reaction mixture
was concentrated under reduced pressure, then diluted with EtOAc (5
mL.times.2) and filtered. The filtrate was concentrated under
reduced pressure to give
1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine
as a brown solid. LCMS: RT 0.11 min, m/z=207.2 [M+H].sup.+.
N-(1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-cy-
clopropyl-5-(trifluoromethyl)pyrimidin-2-amine (A-71)
[0720] To a solution of
1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-amine
(40 mg, 0.19 mmol) in 1,4-dioxane (2 mL) was added
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (57
mg, 0.21 mmol) and TFA (44 mg, 0.029 mL, 0.39 mmol). Then the
mixture was stirred at 100.degree. C. for 1 h. The mixture was
concentrated under reduced pressure to give a residue, which was
purified by prep-HPLC (neutral) to give
N-(1-(2-(2H-1,2,3-triazol-4-yl)propan-2-yl)-3-methyl-1H-pyrazol-4-yl)-4-c-
yclopropyl-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR 400
MHz, CHLOROFORM-d): .delta. 8.40 (br. s., 1H), 7.90 (br. s., 1H),
7.47 (br. s., 1H), 6.88 (br. s., 1H), 2.27 (s, 3H), 2.21 (br. s.,
1H), 2.03 (s, 6H), 1.19 (br. s., 2H), 1.11 (d, J=7.6 Hz, 2H). HPLC:
Retention Time: 2.81 min. MS: [M+H].sup.+ m/z: 393.1.
Example A-49
Synthesis of
4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2--
yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
(A-72) and
4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propa-
n-2-yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
(A-73)
1-(difluoromethyl)-3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,2-
,4-triazole and
1-(difluoromethyl)-5-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,-
2,4-triazole
[0721] To a mixture of
3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1H-1,2,4-triazole
(5 g, 21.17 mmol) in DMF (50 mL) was added K.sub.2CO.sub.3 (8.78 g,
63.51 mmol) at 20.degree. C. The mixture was heated to 90.degree.
C. then chloro(difluoro)methane was bubbled into the mixture at
90.degree. C. for 1 h. The mixture was cooled to 20.degree. C. and
poured into ice-water (300 mL). The aqueous phase was extracted
with EtOAc (3.times.100 mL). The combined organics were washed with
brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (PE:EtOAc=10:1 to 0:1) to give
1-(difluoromethyl)-3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,-
2,4-triazole as a yellow oil and
1-(difluoromethyl)-5-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,-
2,4-triazole as a yellow oil. LCMS: RT 0.735 min, m/z=287.2
[M+H].sup.+.
1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-py-
razol-4-amine
[0722] To a mixture of
1-(difluoromethyl)-3-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,-
2,4-triazole (2.37 g, 8.28 mmol) in EtOH (96 mL) and H.sub.2O (24
mL) was added NH.sub.4Cl (2.21 g, 41.40 mmol) and Fe (2.31 g, 41.40
mmol) at 20.degree. C. The mixture was heated to 80.degree. C. and
stirred for 1 h. The mixture was cooled to 20.degree. C. and
concentrated under reduced pressure. The residue was added with
water (30 mL). The aqueous phase was extracted with EtOAc (3-10
mL), washed with brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give
1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-p-
yrazol-4-amine as a brown oil. LCMS: RT 1.012 min, m/z=257.2
[M+H].sup.+.
4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-y-
l)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
[0723] To a mixture of
1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2-yl)-3-methyl-1H-p-
yrazol-4-amine (100 mg, 390.24 .mu.mol) and
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (86
mg, 325.20 .mu.mol) in 1,4-dioxane (1 mL) was added TFA (74 mg,
650.40 .mu.mol, 48.16 .mu.L) at 20.degree. C. The mixture was
heated to 90.degree. C. and stirred for 2 h. The mixture was cooled
to 20.degree. C. and adjusted pH=7-8 by adding aq. NaHCO.sub.3. The
aqueous phase was extracted with EtOAc (3.times.5 mL), washed with
brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral) to give
4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)propan-2--
yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
as a brown solid. LCMS: RT 0.855 min, m/z=443.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.45 (br. s., 1H),
8.40 (br. s., 1H), 7.97 (br. s., 1H), 7.04-7.42 (m, 2H), 6.73 (br.
s., 1H), 2.25 (s, 4H), 2.06 (s, 6H), 1.18-1.29 (m, 2H), 1.03-1.16
(m, 2H). HPLC: RT 2.871 min. MS: [M+H].sup.+ m/z: 443.1.
1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-py-
razol-4-amine
[0724] To a mixture of
1-(difluoromethyl)-5-[1-methyl-1-(3-methyl-4-nitro-pyrazol-1-yl)ethyl]-1,-
2,4-triazole (1.97 g, 6.88 mmol) in EtOH (48 mL) and H.sub.2O (12
mL) was added NH.sub.4Cl (1.84 g, 34.41 mmol) and Fe (1.92 g, 34.41
mmol) at 20.degree. C. The mixture was heated to 80.degree. C. and
stirred for 1 h. The mixture was cooled to 20.degree. C. and
concentrated under reduced pressure. The residue was added with
water (20 mL) and extracted with EtOAc (3.times.8 mL). The combined
organic phase was washed with brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give
1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-p-
yrazol-4-amine as a brown solid. LCMS: RT 0.924 min, m/z=257.2
[M+H].sup.+.
4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-y-
l)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
(A-73)
[0725] To a mixture of
1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2-yl)-3-methyl-1H-p-
yrazol-4-amine (100 mg, 390.24 .mu.mol) and
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (86
mg, 325.20 .mu.mol) in 1,4-dioxane (1 mL) was added TFA (74 mg,
650.40 .mu.mol, 48.16 L) at 20.degree. C. The mixture was heated to
90.degree. C. and stirred for 2 h. The mixture was cooled to
20.degree. C. and adjusted pH=7-8 by adding sat. aq. NaHCO.sub.3
then was extracted with EtOAc (3.times.5 mL), washed with brine (5
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral) to give
4-cyclopropyl-N-(1-(2-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)propan-2--
yl)-3-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.
LCMS: RT 0.829 min, m/z=443.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl3) .delta. ppm 8.45 (s, 1H), 8.43 (br. s., 1H), 8.01 (br. s.,
1H), 6.76 (br. s., 1H), 6.19-6.54 (m, 1H), 2.20-2.30 (m, 4H),
2.05-2.15 (m, 6H), 1.14 (d, J=7.53 Hz, 4H). HPLC: RT 2.671 min. MS:
[M+H].sup.+ m/z: 443.2.
Example A-50
Synthesis of
4-cyclopropyl-N-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl-
)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-74)
N'-acetyl-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanehydrazide
[0726] To a solution of
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (2 g,
9.38 mmol) in DCM (80 mL) was added acetohydrazide (834 mg, 11.3
mmol), HATU (7.13 g, 18.8 mmol) and DIPEA (2.4 g, 3.3 mL, 18.8
mmol). The reaction mixture was stirred at 20.degree. C. for 1 h.
The mixture was concentrated under reduced pressure to give a
residue, which was purified by silica gel column chromatography
(PE:EtOAc=10:1 to EtOAc) to give
N'-acetyl-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanchydrazide
as a yellow oil. LCMS: RT 0.627 min, m/z=270.2 [M+H].sup.+.
2-(4-((4-cyclopropyl-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)meth-
yl)-7H-pyrrolo
2-methyl-5-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1,3,4-oxadia-
zole
[0727] A solution of
N'-acetyl-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanchydrazide
(200 mg, 0.74 mmol) in POCl.sub.3 (0 mL) was stirred at 100.degree.
C. for 2 h. The reaction mixture was poured into ice-water (2 mL),
and extracted with EtOAc (3.times.2 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to give a residue, which was purified by prep-TLC
(SiO.sub.2, PE:EtOAc=1:1) to give
2-(4-((4-cyclopropyl-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)met-
hyl)-7H-pyrrolo
2-methyl-5-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1,3,4-oxadia-
zole as a white solid. LCMS: RT 0.662 min, m/z=252.2
[M+H].sup.+.
3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-ami-
ne
[0728] To a solution of Pd/C (80 mg) in MeOH (20 mL) was added
2-methyl-5-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-1,3,4-oxadia-
zole (170 mg, 0.68 mmol), then the mixture was stirred at
20.degree. C. for 2 h under H.sub.2 (15 psi). The reaction mixture
was concentrated under reduced pressure to give residue, which was
diluted with EtOAc (3.times.20 mL). The filtrate was concentrated
under reduced pressure to give
3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-
-4-amine as a yellow solid. LCMS: RT 0.102 min, m/z=222.2
[M+H].sup.+.
4-cyclopropyl-N-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-
-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-74)
[0729] To a solution of
3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl)-1H-pyrazol-4-am-
ine (130 mg, 0.59 mmol) in 1,4-dioxane (3 mL) was added
4-cyclopropyl-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine (157
mg, 0.59 mmol) and TFA (67 mg, 0.04 mL, 0.59 mmol). Then the
mixture was stirred at 80.degree. C. for 2 h. The mixture was
concentrated under reduced pressure to give a residue, which was
purified by prep-HPLC (neutral) to give
4-cyclopropyl-N-(3-methyl-1-(2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl-
)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H
NMR (400 MHz, CHLOROFORM-d): .delta.8.42 (br. s., 1H), 7.96 (br.
s., 1H), 6.67 (br. s., 1H), 2.51 (s, 3H), 2.24 (s, 3H), 2.20-2.24
(m, 1H), 2.07 (s, 6H), 1.23 (br. s., 2H), 1.14 (br. s., 2H). HPLC:
RT 3.10 min. MS: [M+H].sup.+ m/z: 408.2.
Example A-51
Synthesis of
(R)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-met-
hyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine and
(S)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-met-
hyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-78 and
A-79)
(R)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-meth-
yl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine and
(S)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-met-
hyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-78 and
A-79)
[0730] To a solution of
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-amine
(200 mg, 984.06 .mu.mol) and
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amine
and 4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine
(262 mg, 984.06 .mu.mol) in 1,4-dioxane (5 mL) was added TFA (56
mg, 492.03 .mu.mol). The mixture was stirred at 100.degree. C. for
1 h. The reaction mixture was diluted with H.sub.2O (20 mL), and
adjusted with aq. NaHCO.sub.3 (10 mL) to pH=8 and extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue. The residue
was purified by prep-HPLC (neutral) to give 70 mg mixture of
product, which was purified by SFC to give
(R)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-met-
hyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (peak 1
in SFC, stereochemistry randomly assigned), and
(S)-4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-met-
hyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (peak 2
in SFC, stereochemistry randomly assigned).
First Eluting Isomer (Peak 1):
4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl--
1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-78)
[0731] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 8.40 (s, 1H),
7.60-8.05 (m, 1H), 7.23-7.34 (m, 1H), 7.10-7.22 (m, 1H), 5.73-5.85
(m, 1H), 4.27-4.44 (m, 1H), 4.11-4.25 (m, 1H), 3.18-3.31 (m, 1H),
2.76-2.93 (m, 1H), 2.20 (br. s., 4H), 1.01-1.39 (m, 4H). HPLC: RT
2.373 min. MS: me: 390.2 [M+H].sup.+. SFC: RT 2.52 min.
Second Eluting Isomer (Peak 2):
4-cyclopropyl-N-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl--
1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-79)
[0732] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 8.41 (s, 1H),
7.69-8.07 (m, 1H), 7.29-7.41 (m, 1H), 7.18-7.27 (m, 1H), 5.77-5.93
(m, 1H), 4.31-4.49 (m, 1H), 4.14-4.28 (m, 1H), 3.21-3.30 (m, 1H),
2.77-2.93 (m, 1H), 2.20 (br. s., 4H), 1.03-1.38 (m, 4H). HPLC: RT
2.369 min. MS: m/z: 390.1 [M+H].sup.+ SFC: RT 2.58 min.
Example A-52
Synthesis of
4-cyclopropyl-N-(1-(difluoro(1-methyl-1H-1,2,4-triazol-3-yl)methyl)-3-met-
hyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-77),
4-cyclopropyl-N-[1-[difluoro(1H-1,2,4-triazol-3-yl)methyl]-3-methyl-pyraz-
ol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-75) and
4-cyclopropyl-N-[1-[difluoro-(2-methyl-1,2,4-triazol-3-yl)methyl]-3-methy-
l-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-76)
N'-acetyl-2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanehydrazide
[0733] To a solution of tert-butyl
N-[1-(2-amino-1,1-difluoro-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]carbamate
(653 mg, 2.25 mmol) and
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (599
mg, 2.25 mmol) in 1,4-dioxane (10 mL) was added p-TsOH (387 mg,
2.25 mmol). The mixture was stirred at 100.degree. C. for 10 h. The
reaction solution was concentrated under reduced pressure. The
residue was added with water (20 mL), adjusted to pH=7 with
aq.NaHCO.sub.3. The aqueous phase was extracted with EtOAc
(3.times.10 mL). The organic layers were combined, washed with
brine (5 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give
2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-py-
razol-1-yl]-2,2-difluoro-acetamide as a yellow solid. LCMS: RT
0.822 min, m/z=377.1 [M+H].sup.+.
2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyr-
azol-1-yl]-N-(dimethylaminomethylene)-2,2-difluoro-acetamide
[0734] A mixture of
2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-py-
razol-1-yl]-2,2-difluoro-acetamide (720 mg, 1.91 mmol), DMF-DMA
(3.25 g, 27.27 mmol, 3.61 mL) was degassed and purged with N.sub.2
for 3 times, and then the mixture was stirred at
10.about.30.degree. C. for 12 h under N.sub.2. The reaction mixture
was concentrated under reduced pressure to give
2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-meth-
yl-pyrazol-1-yl]-N-(dimethylaminomethylene)-2,2-difluoro-acetamide
as a yellow oil. LCMS: RT 0.807 min, m/z=432.1 [M+H].sup.+.
4-cyclopropyl-N-(1-(difluoro(1H-1,2,4-triazol-3-yl)methyl)-3-methyl-1H-pyr-
azol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A-77)
[0735] To a solution of
(NE)-2-[4-[[4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-meth-
yl-pyrazol-1-yl]-N-(dimethylaminomethylene)-2,2-difluoro-acetamide
(200 mg, 463.65 .mu.mol) in AcOH (2 mL) was added
NH.sub.2NH.sub.2.H.sub.2O (23 mg, 463.65 .mu.mol, 22.53 .mu.L). The
mixture was stirred at 15.degree. C. for 2 h. The reaction solution
was poured into ice-water (5 mL), adjusted to pH=7 with aq.
NaHCO.sub.3, extracted with EtOAc (3.times.5 mL). The organic
layers were combined, washed with brine (5 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC(FA) to give
4-cyclopropyl-N-[1-[difluoro(1H-1,2,4-triazol-3-yl)methyl]-3-methyl-pyraz-
ol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine. .sup.1H NMR 400 MHz,
CHLOROFORM-d): .delta. 8.40 (s., 1H), 8.28 (s., 2H), 6.51-6.97 (br,
1H), 2.21 (s, 4H), 1.17-1.26 (m, 2H), 1.09 (m, 2H). HPLC: RT 2.76
min. MS: (M+H.sup.+) m/z: 401.1
4-cyclopropyl-N-[1-[difluoro(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-3-meth-
yl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[1-[difluoro-(2-methyl-1,2,4-triazol-3-yl)methyl]-3-methy-
l-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-75 and
A-76)
[0736] To a solution of
4-cyclopropyl-N-[1-[difluoro(1H-1,2,4-triazol-3-yl)methyl]-3-methyl-pyraz-
ol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (500 mg, 1.25 mmol,
crude) in MeCN (10 mL) was added Mel (532 mg, 3.75 mmol, 233.27
.mu.L) and K.sub.2CO.sub.3 (518 mg, 3.75 mmol). The mixture was
stirred at 15.degree. C. for 10 h. The mixture was filtered and the
filtrate was concentrated under reduced pressure. The residue was
purified by prep-HPLC (FA) to give
4-cyclopropyl-N-[1-[difluoro-(1-methyl-1,2,4-triazol-3-yl)methyl]-3-methy-
l-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[1-[difluoro-(2-methyl-1,2,4-triazol-3-yl)methyl]-3-methy-
l-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.
4-cyclopropyl-N-[1-[difluoro(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-3-meth-
yl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-75)
[0737] .sup.1H NMR (400 MHz, CHLOROFORM-d): .delta.8.46 (s., 1H),
8.29 (s., 1H), 8.17 (s, 1H), 6.89 (br. s., 1H), 4.04 (s, 3H),
2.16-2.33 (m, 4H), 1.24-1.32 (m, 2H), 1.15 (m, 2H). HPLC: RT 3.23
min. MS: [M+H].sup.+ m/z: 415.1.
4-cyclopropyl-N-[1-[difluoro-(2-methyl-1,2,4-triazol-3-yl)methyl]-3-methyl-
-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-76)
[0738] .sup.1H NMR (400 MHz, CHLOROFORM-d): .delta.8.49 (s., 1H),
8.25-8.43 (m, 1H), 7.99 (s, 1H), 6.79 (br. s., 1H), 4.02 (s, 3H),
2.17-2.33 (m, 4H), 1.29 (m, 2H), 1.19 (m, 2H). HPLC: RT 3.47 min.
MS: [M+H].sup.+ m/z: 415.1.
Example A-53
Synthesis of
4-cyclopropyl-N-(5-methyl-1-((1R,3S)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cy-
clobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-(3-methyl-1-((1R,3S)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cy-
clobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
(A-80 and A-81)
3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide and
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide
[0739] To a mixture of
3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylic acid and
3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylic acid (I g,
4.44 mmol) in DCM (15 mL) was added a solution of oxalyl chloride
(1.13 g, 8.88 mmol, 777.34 .mu.L) and DMF (162.26 mg, 2.22 mmol)
dropwise at 0.degree. C. and stirred at 15.degree. C. for 1 h. The
reaction mixture was concentrated to get a residue. A mixture of
the residue in THF (10 mL) was added to NH.sub.3.H.sub.2O (20 mL)
and stirred at 15.degree. C. for 1 h. The mixture was concentrated
to get 3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide
and 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide (1.2
g, crude). LCMS: RT 0.53 min, m/z=225.2 [M+H].sup.+.
N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobuta-
necarboxamide and
N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobut-
anecarboxamide
[0740] A solution of
3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide and
3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxamide (500 mg,
2.23 mmol) in DMF-DMA (5 mL) was stirred at 80.degree. C. for 2 h.
The reaction mixture was concentrated under reduced pressure to get
N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobut-
anecarboxamide and
N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobut-
anecarboxamide as a yellow gum. LCMS: RT 0.548 mn, m/z=280.2
[M+H].sup.+.
1-methyl-5-((1r,3r)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,2-
,4-triazole and
1-methyl-5-((1r,3r)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,-
2,4-triazole
[0741] To a solution of
N-((dimethylamino)methylene)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobut-
anecarboxamide and
N-((dimethylamino)methylene)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobut-
anecarboxamide (620 mg, 2.23 mmol) in CH--COOH (6 mL) was added
methylhydrazine (2.57 g, 22.30 mmol, 2.92 mL, 40% purity). The
mixture was stirred at 90.degree. C. for 2 h. The reaction mixture
was concentrated under reduced pressure. The residue was diluted
with water (60 mL), adjust to pH=8 by aq. NaHCO.sub.3, and
extracted with EtOAc (3.times.30 mL). The combined organic layers
were washed with brine (20 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue.
The residue was purified by prep-TLC (SiO.sub.2, DCM:MeOH=20:1), to
give
1-methyl-5-((1r,3r)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,-
2,4-triazole and
1-methyl-5-((1r,3r)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,-
2,4-triazole. LCMS: RT 0.881 mn, m/z=263.1[M+H].sup.+.
5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyraz-
ol-4-amine
[0742] To a solution of
1-methyl-5-((1r,3r)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,-
2,4-triazole (40 mg, 152.51 .mu.mol) in MeOH (4 mL) was added Pd--C
(10%, 0.02 g) under N.sub.2. The suspension was degassed under
vacuum and purged with H.sub.2 several times. The mixture was
stirred under H.sub.2 (15 psi) at 15.degree. C. for 2 h. The
reaction mixture was filtered and the filtrate was concentrated to
give
5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyra-
zol-4-amine as a yellow solid. LCMS: RT 0.173 mn,
m/z=233.1[M+H].sup.+.
3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyraz-
ol-4-amine
[0743] To a solution of
1-methyl-5-((1r,3r)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)-1H-1,-
2,4-triazole (60 mg, 228.78 .mu.mol) in EtOH (2 mL) and H.sub.2O
(0.5 mL) was added Fe (64 mg, 1.14 mmol) and NH.sub.4Cl (61 mg,
1.14 mmol). The mixture was stirred at 80.degree. C. for 2 h. The
reaction mixture was filtered and the filtrate was concentrated.
The residue was added with EtOAc and filtered. The filtrate was
concentrated to give
3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyra-
zol-4-amine as a yellow gum.
4-cyclopropyl-N-(5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyc-
lobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
(A-80)
[0744] A mixture of
5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyra-
zol-4-amine (35 mg, 150.68 .mu.mol),
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (32
mg, 120.54 .mu.mol) and TsOH.H.sub.2O (29 mg, 150.68 .mu.mol) in
1,4-dioxane (3 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 90.degree. C. for 6 h
under N.sub.2. The residue was diluted with H.sub.2O (20 mL),
adjusted to pH=8 by aq. NaHCO.sub.3 and then extracted with EtOAc
(3.times.10 mL). The combined organic layers were washed with brine
(10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a residue, which was purified by
prep-HPLC (FA) to give
4-cyclopropyl-N-(5-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cy-
clobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.38 (s, 1H), 7.87 (s,
1H), 7.74 (br. s., 1H), 5.11 (t, J=7.59 Hz, 1H), 3.81 (s, 3H), 3.76
(dt, J=9.47, 4.67 Hz, 1H), 3.22 (q, J=9.62 Hz, 2H), 2.85 (t, J=8.47
Hz, 2H), 2.19 (s, 4H) 1.25 (d, J=2.51 Hz, 2H), 1.09 (dd, J=7.59,
3.20 Hz, 2H). HPLC: RT: 3.06 min. MS: m/z: 419.2 [M+H].sup.+.
4-cyclopropyl-N-(3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyc-
lobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
(A-81)
[0745] A mixture of
3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)-1H-pyra-
zol-4-amine (50 mg, 215.25 .mu.mol),
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (46
mg, 172.20 .mu.mol), TsOH.H.sub.2O (61 mg, 322.88 .mu.mol) in
ethylene glycol monomethyl ether (2 mL) was degassed and purged
with N.sub.2 for 3 times, and then the mixture was stirred at
110.degree. C. for 5 h under N.sub.2. The reaction mixture was
concentrated under reduced pressure. The residue was diluted with
H.sub.2O (20 mL), adjusted to pH=8 by aq. NaHCO.sub.3 and then
extracted with EtOAc (3.times.10 mL). The combined organic layers
were washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue,
which was purified by prep-HPLC (FA) to give
4-cyclopropyl-N-(3-methyl-1-((1r,3r)-3-(1-methyl-1H-1,2,4-triazol-5-yl)cy-
clobutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.
.sup.1H NMR (400 MHz, CDCl.sub.1): S 8.42 (br. s., 1H), 7.86 (s,
1H), 7.80 (br. s., 1H), 5.07 (t, J=7.72 Hz, 1H), 3.81 (s, 3H), 3.73
(dt, J=9.22, 4.80 Hz, 1H), 3.11-3.20 (m, 2H), 2.87 (br. s., 2H),
2.30 (s, 3H), 2.23 (br. s., 1H), 1.23-1.30 (m, 2H), 1.06-1.19 (m,
2H). HPLC: RT: 2.90 min. MS: m/z: 419.1 [M+H].sup.+.
Example A-54
Synthesis of
4-cyclopropyl-N-[1-[(7R)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl-
]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[1-[(7S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl-
]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-82
and A-83)
3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidin-2-one
[0746] To a solution of 3-methyl-4-nitro-1H-pyrazole (4.15 g, 32.64
mmol), 3-hydroxypyrrolidin-2-one (3 g, 29.67 mmol) and PPh3 (11.67
g, 44.51 mmol) in THF (100 mL) was added DIAD (9 g, 44.51 mmol) at
0.degree. C. under N2. The mixture was stirred at 25.degree. C. for
6 h. The mixture was filtered and filtrate was concentrated to give
a residue. The residue was purified by silica gel column
chromatography (PE:EtOAc=1:1) to give a crude product, which was
triturated with MTBE (20 mL), to give
3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidin-2-one as a white solid.
LCMS: RT 0.226 min, m/z=211.2 [M+H]+, 0.1H NMR (400 MHz, DMSO-d6):
.delta. 8.89 (s, 1H), 8.25 (br. s., 1H), 5.09 (t, J=9.10 Hz, 1H),
3.27-3.42 (m, 3H), 2.53-2.60 (m, 2H), 2.43 (s, 3H).
3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidine-2-thione
[0747] To a mixture of
3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidin-2-one (1.1 g, 5.23
mmol) in toluene (20 mL) was added Lawesson's reagent (1.06 g, 2.62
mmol). The mixture was then heated to 110.degree. C. and stirred
for 2 h. The mixture was concentrated under reduced pressure to
give a residue. The residue was added with EtOAc (10 mL) and
filtered. The filtrate was concentrated to afford
3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidine-2-thione as a white
solid. LCMS: RT 0.458 min, m/z=227.1 [M+H].sup.+, 1H NMR (400 MHz,
DMSO-d6): .delta. 10.75 (br. s., 1H), 8.92 (s, 1H), 5.33 (t, J=8.60
Hz, 1H), 3.59-3.72 (m, 2H), 2.59-2.69 (m, 3H), 2.43 (s, 3H).
3-methyl-1-(5-methylsulfanyl-3,4-dihydro-2H-pyrrol-4-yl)-4-nitro-pyrazole
[0748] To a mixture of
3-(3-methyl-4-nitro-pyrazol-1-yl)pyrrolidine-2-thione (1.07 g, 4.73
mmol) and K2CO3 (3.27 g, 23.65 mmol) in THF (20 mL) was added
CH.sub.3I (3.36 g, 23.65 mmol, 1.47 mL). The mixture was then
stirred at 25.degree. C. for 16 h. The reaction mixture was
filtered and the filtrate was concentrated to give
3-methyl-1-(5-methylsulfanyl-3,4-dihydo-2H-pyrrol-4-yl)-4-nitro-pyrazole)
as a white solid. LCMS: RT 0.839 min, m/z=241.1 [M+H].sup.+.
7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]tria-
zole
[0749] To a solution of
3-methyl-1-(5-methylsulfanyl-3,4-dihydro-2H-pyrrol-4-yl)-4-nitro-pyrazole
(800 mg, 3.33 mmol) in HCOOH (2 mL) and triethoxymethane (2 mL) was
added formohydrazide (199 mg, 3.33 mmol) at 25.degree. C. under N2.
The mixture was then heated to 150.degree. C. and stirred for 2 h.
The mixture was cooled to 25.degree. C. and concentrated under
reduced pressure. The residue was poured into ice-water (100 mL).
The aqueous phase was extracted with EtOAc (3.times.50 mL). The
combined organic phase was washed with brine (50 mL), dried with
anhydrous Na2SO.sub.4, filtered and concentrated. The residue was
purified by prep-TLC (SiO2, CH2C12:MeOH=10:1) to afford
7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]tri-
azole as a yellow solid. LCMS: RT 0.218 min, m/z=235.1 [M+H]+. 1H
NMR (400 MHz. DMSO-d6): .delta. 9.03 (s, 1H), 8.56 (s, 1H), 6.03
(dd, J=3.97, 8.38 Hz, 1H), 4.27 (ddd, J=6.40, 7.94, 10.81 Hz, 1H),
4.15 (ddd, J=4.41, 8.38, 11.03 Hz, 1H), 3.24-3.30 (m, 1H),
2.86-2.95 (m, 1H), 2.39 (s, 3H).
1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)-3-methyl-pyrazol-4-am-
ine
[0750] To a solution of
7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]tri-
azole (123 mg, 525.17 .mu.mol) in MeOH (10 mL) was added Pd--C
(10%, 20 mg) under N2. The suspension was degassed under vacuum and
purged with H2 three times. The mixture was stirred under H2 (15
psi) at 25.degree. C. for 2 h. The reaction mixture was filtered
and the filtrate was concentrated to afford
1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)-3-methyl-pyrazol-4-a-
mine as a yellow gum. LCMS: RT 0.085 min, m/z=205.1 [M+H]+.
4-cyclopropyl-N-[1-[(7R)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl]-
-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[1-[(7S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl-
]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine (A-82
and A-83)
[0751] To a mixture of
1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)-3-methyl-pyrazol-4-a-
mine (81 mg, 396.61 .mu.mol) and
4-cyclopropyl-2-methylsulfonyl-5-(trifluoromethyl)pyrimidine (105
mg, 396.61 .mu.mol) in ethylene glycol monomethyl ether (2 mL) was
added TFA (4 mg, 39.66 .mu.mol). The mixture was then heated to
100.degree. C. and stirred for 2 h. The mixture was cooled to
25.degree. C. and poured into saturated aqueous NaHCO.sub.3 (30
mL). The aqueous phase was extracted with EtOAc (3.times.10 mL).
The combined organic phase was washed with brine (10 mL), dried
with anhydrous Na2SO.sub.4, filtered and concentrated to give a
residue. The residue was purified by prep-HPLC (neutral) and
further separated by SFC to afford
4-cyclopropyl-N-[1-[(7R)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl-
]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine and
4-cyclopropyl-N-[1-[(7S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl-
]-3-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidin-2-amine.
First Eluting Isomer (A-83)
[0752] 1H NMR (400 MHz, CDCl3): .delta. 8.40 (br. s., 1H), 8.22 (s,
1H), 7.91 (br. s., 1H), 6.59-6.94 (m, 1H), 5.64-5.75 (m, 1H),
4.34-4.46 (m, 1H), 4.12-4.23 (m, 1H), 3.18-3.38 (m, 2H), 2.19 (s,
4H), 1.23 (br. s., 2H), 1.13 (d, J=6.17 Hz, 2H). HPLC: RT 2.45 min.
MS: [M+H]+ m/z: 391.1. SFC: RT 2.46 min.
Second Eluting Isomer (A-82)
[0753] 1H NMR (400 MHz, CDCl3): .delta. 8.38 (d, J=5.73 Hz, 1H),
8.20 (d, J=6.62 Hz, 1H), 7.87 (br. s., 1H), 6.74-7.12 (m, 1H), 5.66
(br. s., 1H), 4.37 (br. s., 1H), 4.15 (br. s., 1H), 3.11-3.40 (m,
2H), 1.97-2.34 (m, 4H), 1.19 (br. s., 2H), 1.09 (br. s., 2H). HPLC:
RT 2.46 min. MS: [M+H]+ m/z: 391.1. SFC: RT 3.78 min.
Example A-55
[0754] The following compounds were made according to similar
procedures described above. The LCMS conditions used to isolate the
compounds are as provided above in the general method.
TABLE-US-00007 MS No. [M + H].sup.+ A-84 390.2 A-85 367.1 A-86
367.1 A-87 377.1 A-88 367.1 A-89 390.2 A-90 390.2 A-91 367.1 A-92
390.2 A-93 381.2 A-94 381.1 A-95 381.2 A-96 405.2 A-97 405.2
B: Compound Preparation
[0755] In the following Examples, all non-aqueous reactions were
carried out in oven-dried or flame-dried glassware under nitrogen
atmosphere. All chemicals were purchased from commercial vendors
and used as is, unless otherwise specified. Reactions were
magnetically stirred and monitored by thin layer chromatography
(TLC) with 250 .mu.m pre-coated silica gel plates, visualized
either with UV, or in an iodine chamber. Flash column
chromatography was performed using silica gel (100-200 mesh).
Chemical shifts are reported relative to chloroform (.delta. 7.26),
methanol (S 3.31), or DMSO (S 2.50) for .sup.1H NMR HPLC analysis
was performed on Shimadzu 20AB HPLC system with a photodiode array
detector and Luna-C18(2) 2.0.times.50 mm, 5 .mu.m column at a flow
rate of 1.2 mL/min with a gradient solvent Mobile phase A (MPA,
H.sub.2O+0.037% (v/v) TFA): Mobile phase B (MPB, ACN+0.018% (v/v)
TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92
min, 10% MPB: 5.5 min, 10% MPB). LCMS was detected under 220 and
254 nm or used evaporative light scattering (ELSD) detection as
well as positive electrospray ionization (MS). Semi-preparative
HPLC was performed by either acidic or neutral condition. Acidic:
Luna C18 100.times.30 mm, 5 .mu.m; MPA: HCl/H.sub.2O=0.04%, or
formic acid/H.sub.2O=0.2% (v/v); MPB: ACN. Neutral: Waters Xbridge
150.times.25, 5 .mu.m; MPA: 10 mM NH.sub.4HCO.sub.3 in H.sub.2O;
MPB: ACN. Gradient for both conditions: 10% of MPB to 80% of MPB
within 12 min at a flow rate of 20 mL/min, then 100% MPB over 2
min, 10% MPB over 2 min, UV detector. SFC analysis was performed on
Thar analytical SFC system with a UV/Vis detector and series of
chiral columns including AD-3, AS-H, OJ-3, OD-3, AY-3 and IC-3,
4.6.times.100 mm, 3 um column at a flow rate of 4 mL/min with a
gradient solvent Mobile phase A (MPA, CO.sub.2): Mobile phase B
(MPB, MeOH+0.05% (v/v) IPAm) (0.01 min, 10% MPB; 3 min, 40% MPB;
3.5 min, 40% MPB; 3.56-5 min, 10% MPB). SFC preparative was
performed on Thar 80 preparative SFC system with a UV/Vis detector
and series of chiral preparative columns including AD-H, AS-H,
OJ-H, OD-H, AY-H and IC-H, 30.times.250 mm, Sum column at a flow
rate of 65 mL/min with a gradient solvent Mobile phase A (MPA,
CO.sub.2): Mobile phase B (MPB, MeOH+0.1% (v/v) NH.sub.3H.sub.2O)
(0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1-10 min, 10%
MPB).
Example B-1
Synthesis of
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile
Methyl 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate
[0756] To a solution of 3-methyl-4-nitro-1H-pyrazole (40 g, 314.71
mmol) in DMF (700 mL) was added NaH (18.88 g, 472.06 mmol, 60%
purity) at 0.degree. C. over a period of 30 min under N.sub.2. The
reaction was then stirred at 25.degree. C. for 2 h followed by the
addition of methyl 2-bromo-2-methylpropanoate (85.46 g, 472.06
mmol, 61.04 mL) dropwise at 0.degree. C. The reaction mixture was
warmed to 25.degree. C. and stirred at 25.degree. C. for another 16
h. TLC (petroleum ether/ethyl acetate=5:1) showed the starting
material was consumed completely. The reaction was quenched by ice
water slowly and then extracted with EtOAc (3.times.700 mL). The
combined organic phase was washed with brine (3-200 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate=30:1-15:1), to yield the desired
product as a light yellow solid (69.70 g, 97.47%). .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 8.29 (s, 1H), 3.72 (s, 1H), 2.51 (s, 1H),
1.84 (s, 6H).
2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoic acid
[0757] To a mixture of methyl
2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (69.7 g,
306.75 mmol) in THF (1 L) and H.sub.2O (250 mL) was added LiOH
H.sub.2O (15.45 g, 368.10 mmol) at 25.degree. C. under N.sub.2. The
mixture was then stirred at 25.degree. C. for 16 h. TLC (petroleum
ether/ethyl acetate=5:1) showed the reaction was completed. The
reaction mixture was concentrated in vacuo. The residual aqueous
solution was washed with ethyl acetate (50 mL). The aqueous phase
was then cooled to 0.degree. C., adjusted to approximately pH 1-2,
and filtered to yield the desired product as a white solid (53 g,
81.04%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.65 (s, 1H),
2.48 (s, 1H), 1.83 (s, 6H).
2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide
[0758] To a solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)
propanoic acid (25 g, 117.27 mmol) in DCM (500 mL) was added 8
drops of DMF, followed by oxalyl dichloride (29.77 g, 234.54 mmol)
at 0.degree. C. under N.sub.2. Then the mixture was stirred at
25.degree. C. for a further 2 h. TLC (petroleum ether/ethyl
acetate=3:1) showed reaction was completed. The reaction solution
was concentrated in vacuo. The residue solid was dissolved in THF
(300 mL) and added dropwise into a stirred solution of NH.sub.4OH
(413.61 g, 11.80 mol, 454.52 mL) at 0.degree. C. The reaction was
stirred at 25.degree. C. for 1 h. TLC (ethyl acetate) showed
reaction was completed. The solution was then concentrated in vacuo
and partitioned between EtOAc (100 mL) and water (100 mL), and the
aqueous phase was extracted with ethyl acetate (3.times.80 mL). The
combined organic phase was washed with brine (3.times.40 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo, to yield the desired compound as a yellow solid (22 g,
103.67 mmol, 88.4%). .sup.1H NMR (400 MHz, MeOD): .delta. 8.81 (s,
1H), 7.16-7.26 (m, 2H), 2.42 (s, 3H), 1.71 (s, 3H).
2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile
[0759] A solution of
2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide (22 g, 103.67
mmol) in POCl.sub.3 (132 g, 860.89 mmol, 80 mL) was stirred at
90.degree. C. for 1 h. TLC showed the reaction was completed. The
mixture was cooled to 20.degree. C. and concentrated in vacuo at
50.degree. C. The residue was poured into ice-water (w/w=1/1) (200
mL) and stirred for 10 min. The aqueous phase was adjusted to pH=7
with NaHCO.sub.3 solution, extracted with ethyl acetate (4-80 mL).
The combined organic phase was washed with brine (40 mL), dried
with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The desired product was afforded as a yellow solid (20 g,
99.35%).
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile
[0760] To a mixture of
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (10 g,
51.5 mmol) in EtOH (240 mL) and H.sub.2O (60 mL) was added
NH.sub.4Cl (13.77 g, 257.5 mmol) in one portion at 25.degree. C.,
followed by Fe (14.38 g, 257.5 mmol). The mixture was heated to
80.degree. C. and stirred for 1 h. TLC showed the reaction was
completed. The solution was cooled to 20.degree. C. The mixture was
extracted with ethyl acetate (3.times.100 mL), the combined organic
layers were washed with NaHCO.sub.3 solution (50 mL) and brine (50
mL). The organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated to afford the desired product. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 7.17 (s, 1H), 2.18 (s, 3H), 1.91 (s,
6H).
Example B-2
Synthesis of
2-[4-[[5-Chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3--
methyl-pyrazol-1-yl]-2-methyl-propanenitrile (B-6)
2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine
[0761] To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1
g, 5.32 mmol) in THF (3 mL) and DCM (12 mL) was added NCS (852 mg,
6.38 mmol) in one portion at 25.degree. C. The mixture was stirred
under microwave at 90.degree. C. for 2.5 h. LC/MS showed the
reaction was completed. Two new peaks were shown on LC/MS and 74%
of desired (M+H.sup.+=221.9) was detected. The mixture was added to
brine and extracted with DCM. The organics were dried over
anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate=50:1-5:1), to yield the desired
product as a yellow solid (750 mg, 63.37%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 10.70 (s., 1H) 8.16 (s, 1H) 4.14 (s, 3H).
2,5-Dichloro-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine
[0762] To a mixture of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine
(600 mg, 2.7 mmol) and triethylamine (272.92 mg, 2.7 mmol, 373.86
uL) in methanol (2 mL) was added MeNH.sub.2 (EtOH solution, 1 mL)
in one portion. The solution was stirred at 25.degree. C. for 12 h.
LC/MS showed the reaction was completed. The mixture was
concentrated in vacuo, washed by MTBE and filtered to yield the
desired product (493 mg, 84.12%). MS: m/z: 215.1 [M+H].sup.+
2-[4-[[5-Chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-m-
ethyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0763] To a solution of
2,5-dichloro-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg,
691.05 umol) in t-BuOH (5 mL) was added TFA (78.79 mg, 691.05 umol,
51.16 uL) and
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (113 mg,
691.05 umol). The mixture was stirred at 80.degree. C. for 16 h.
LC/MS showed starting material was consumed and a main peak of
desired MS observed. The mixture was concentrated in vacuo. The
residue was purified by prep-HPLC (HCl condition), to yield the
desired product. .sup.1H NMR (400 MHz, MeOD): .delta. 8.21 (s, 1H),
6.96 (s, 1H), 3.19 (s, 1H), 2.27 (s, 1H). HPLC: RT 1.91 min. MS:
m/z: 345.1 [M+H].sup.+.
Example B-3
Synthesis of
2-[4-[(5-chloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-
-pyrazol-1-yl]-2-methyl-propanenitrile (B-5)
2,5-dichloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine
[0764] To a solution of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine
(300 mg, 1.35 mmol) in MeOH (5 mL) was added NaOMe (145.85 mg, 2.7
mmol) in one portion at 25.degree. C. The mixture was stirred at
60.degree. C. for 12 h. LC/MS showed the reaction was completed.
The residue was poured into water (10 mL) and stirred for 5 min.
The aqueous phase was extracted with ethyl acetate (3.times.10 mL),
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to give the crude
2,5-dichloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (280 mg crude)
which was used in the next step without further purification.
2-[4-[(5-chloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl--
pyrazol-1-yl]-2-methyl-propanenitrile
[0765] To a mixture of
2,5-dichloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 687.95
.mu.mol) and
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (135.56
mg, 825.54 .mu.mol) in t-BuOH (5 mL) was added TFA (156.88 mg, 1.38
mmol, 101.87 L) in one portion at 25.degree. C. under N.sub.2. The
mixture was stirred at 100.degree. C. for 12 h. The mixture was
concentrated when HPLC indicated the reaction had reached
completion. The crude product was purified by prep-HPLC (neutral)
to yield the desired product. .sup.1H NMR (400 MHz, MeOD): .delta.
8.249 (s, 1H), 6.827 (s, 1H), 4.072 (s, 3H), 2.274 (s, 3H), 2.274
(s, 6H). HPLC: RT 2.58 min. MS: m/z: 345.1 [M+H].sup.+.
Example B-4
Synthesis of
5-chloro-N-(1,5-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidi-
n-2-amine (B-8) and
5-chloro-N-(1,3-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidi-
n-2-amine (B-9)
Trimethyl-[2-[(2,4,5-trichloropyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]s-
ilane
[0766] To a solution of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine
(800 mg, 3.60 mmol) in DMF (8 mL) was added NaH (158 mg, 3.96 mmol,
60% purity) at 0.degree. C. under N.sub.2. The solution was stirred
at 0.degree. C. for 30 min. Then SEM-Cl (719 mg, 4.32 mmol) was
added to the solution at 0.degree. C. The solution was stirred at
25.degree. C. for 2.5 h. To the mixture was poured into NH.sub.4Cl
solution. The solution was extracted with ethyl acetate (3.times.15
mL). The organic layers were combined, washed with brine (10 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated to afford
the desired product as a brown oil (1.20 g, 94.5%). The product was
used in the next reaction without further purification. LC/MS: RT
1.897 min, m/z=352.1, 354.1 [M+H].sup.+.
2-[(2,5-dichloro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trim-
ethyl-silane
[0767] To a solution of
trimethyl-[2-[(2,4,5-trichloropyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]-
silane (850 mg, 2.41 mmol) in methanol (5 mL) was added NaOMe (260
mg, 4.82 mmol) in one portion at 25.degree. C. under N.sub.2. The
mixture was stirred at 25.degree. C. for 2 h. The mixture was
poured into water (10 mL), extracted with ethyl acetate (3-3 mL).
The combined organic phase was washed with brine (10 mL), dried
with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by prep-TLC (SiO.sub.2, petroleum
ether/ethyl acetate=5:1) to afford the desired product as a white
solid (500 mg, 59.57%).
5-chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrim-
idin-2-amine
[0768] To a mixture of
2-[(2,5-dichloro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-tri-
methyl-silane (250 mg, 718 umol) and
1,5-dimethyl-1H-pyrazol-4-amine and 1,3-dimethyl-1H-pyrazol-4-amine
(88 mg, 790 umol) in 1,4-dioxane (5 mL) was added
Pd.sub.2(dba).sub.3 (66 mg, 71.8 umol), BINAP (45 mg, 71.8 umol)
and Cs.sub.2CO.sub.3 (702 mg, 2.15 mmol) in one portion at
25.degree. C. under N.sub.2. The mixture was stirred at 90.degree.
C. for 12 h. The mixture was concentrated in vacuo at 35.degree. C.
The residue was poured into water, extracted with EtOAc (3.times.20
mL). The combined organic phase was washed with brine (2.times.10
mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified by prep-TLC
(SiO.sub.2, petroleum ether/ethyl acetate=3:1) to afford the
desired compounds as a white solid (250 mg, 82.34%).
5-chloro-N-(1,5-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-
-2-amine &
5-chloro-N-(1,3-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3--
d]pyrimidin-2-amine
[0769] To a solution of
5-chloro-N-(1,5-dimethyl-1H-pyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyri-
midin-2-amine (250 mg, 591.04 .mu.mol) in DCM (10 mL) was added TFA
(2 mL) in one portion at 25.degree. C. The mixture was stirred at
40.degree. C. for 3 hours. The mixture was concentrated in vacuo at
35.degree. C. The crude product was dissolved in THF (10 mL) and
sat. NaHCO.sub.3 solution (10 mL) was added. The mixture was
stirred at 25.degree. C. for 12 h. The aqueous phase was extracted
with ethyl acetate (3.times.20 mL). The combined organic phase was
washed with brine (2.times.10 mL), dried with anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by prep-HPLC (HCl acidic condition) to give
5-chloro-N-(1,5-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidi-
n-2-amine and
5-chloro-N-(1,3-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidi-
n-2-amine.
5-chloro-N-(1,5-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-
-2-amine
[0770] .sup.1H NMR (400 MHz, MeOD): .delta.7.816 (s, 1H), 7.023 (s,
1H), 4.208 (s, 3H), 3.929 (s, 3H) 2.337 (s, 3H). HPLC: RT 2.29 min.
MS: m/z: 293.1 [M+H].sup.+.
5-chloro-N-(1,3-dimethylpyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-
-2-amine
[0771] .sup.1H NMR (400 MHz, MeOD): .delta.8.014 (s, 1H), 7.019 (s,
1H), 4.207 (s, 3H), 3.961 (s, 3H) 2.276 (s, 3H). HPLC: RT 2.18 min.
MS: m/z: 293.1 [M+H].sup.+.
Example B-5
Synthesis of
5-chloro-N.sup.2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]py-
rimidine-2,4-diamine (B-1) and
5-chloro-N.sup.2-(1,3-dimethylpyrazol-4-yl)-N'-methyl-7H-pyrrolo[2,3-d]py-
rimidine-2,4-diamine &
5-chloro-N.sup.2-(1,3-dimethyl-1H-pyrazol-4-yl)-N'-methyl-7H-pyrrolo[2,3--
d]pyrimidine-2,4-diamine (B-4)
2,5-dichloro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimi-
din-4-amine
[0772] To a solution of
trimethyl-[2-[(2,4,5-trichloropyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]-
silane (1.20 g, 3.40 mmol) in ethanol (20 mL) was added MeNH.sub.2
(640 mg, 6.80 mmol, 33% purity in EtOH). The mixture was stirred at
25.degree. C. for 24 h. TLC (petroleum ether:ethyl acetate=5:1)
showed the reaction was completed. The mixture was concentrated in
vacuo. The residue was purified by column chromatography
(SiO.sub.2, petroleum ether/ethyl acetate=100:1-ethyl acetate) to
afford the desired product as a colorless gum (600 mg, 50.81%).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta.6.93 (s, 1H), 5.95 (br,
1H), 5.47 (s, 2H), 3.50-3.54 (t, 2H), 3.17-3.18 (d, 3H), 0.90-0.94
(t, 2H), 0.02 (s, 9H). LC/MS: RT 0.954 min, m/z=347.1, 349.1
[M+H].sup.+.
5-chloro-N2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7-(2-trimethylsilylethoxy-
methyl)pyrrolo[2,3-d]pyrimidine-2,4-diamine
[0773] A mixture of
2,5-dichloro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrim-
idin-4-amine (400 mg, 1.15 mmol), 1,5-dimethylpyrazol-4-amine (89
mg, 805 umol), Cs.sub.2CO.sub.3 (1.12 g, 3.45 mmol), XPhos (55 mg,
115 umol) and Pd.sub.2(dba).sub.3 (105 mg, 115 umol) in 1,4-dioxane
(20 mL) was degassed and purged with N.sub.2 for 3 times, and then
the mixture was stirred at 110.degree. C. for 16 h under N.sub.2.
TLC (petroleum ether/ethyl acetate=10:1) showed the reaction was
completed. The solution was concentrated in vacuo to give a
residue. To the residue was added water (10 mL), extracted with
ethyl acetate (3.times.15 mL). Organic layers were combined, washed
with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated to give a crude product. The crude was purified by
column chromatography (SiO.sub.2, petroleum ether/ethyl
acetate=30:1-10:1) to afford a mixture that contained the two
desired products as a colorless gum (260 mg, ratio-1:1, 53.6%). The
mixture was used in the next step without further purification.
LC/MS: RT 1.449 min, m/z=422.3 [M+H].sup.+.
5-chloro-N2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimidi-
ne-2,4-diamine and
5-chloro-N2-(1,3-dimethylpyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimid-
ine-2,4-diamine &
5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyr-
imidine-2,4-diamine
[0774] To a solution of a mixture of
5-chloro-N2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7-(2-trimethylsilylethox-
ymethyl)pyrrolo[2,3-d]pyrimidine-2,4-diamine (260 mg, 616 .mu.mol,
also containing
5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methyl-7-((2-(trimethylsily-
l)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine) in DCM
(20 mL) was added TFA (6.16 g, 54.03 mmol). The mixture was stirred
at 50.degree. C. for 3 h. TLC (petroleum ether/ethyl acetate=1:1)
showed the reaction was completed. The solution was concentrated in
vacuo. The residue was dissolved in THF (20 mL) and 20 mL of sat.
NaHCO.sub.3 solution was added to the solution. Then the solution
was stirred at 25.degree. C. for 6 h. The solution was extracted
with ethyl acetate (3.times.20 mL), organic layers were combined,
washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated to give a crude product. The crude product was
purified by prep-HPLC (neutral condition) and lyophilized to afford
the desired products.
5-chloro-N2-(1,5-dimethylpyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyrimidi-
ne-2,4-diamine
[0775] .sup.1H NMR (400 MHz, CDCl3): .delta.9.19 (br, 1H), 7.59 (s,
1H), 6.34 (s, 1H), 6.03 (br, 1H), 5.69 (br, 1H), 3.73 (s, 3H),
3.10-3.13 (d, 3H), 2.17 (s, 3H). HPLC: RT 1.691 min. MS: m/z: 292.1
[M+H].sup.+.
5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-methyl-7H-pyrrolo[2,3-d]pyri-
midine-2,4-diamine
[0776] .sup.1H NMR (400 MHz, CDCl3): .delta.9.13 (br, 1H), 7.73 (s,
1H), 6.42 (s, 1H), 6.18 (br, 1H), 5.73 (br, 1H), 3.80 (s, 3H),
3.10-3.13 (d, 3H), 2.25 (s, 3H). HPLC: RT 1.770 min. MS: m/z: 292.1
[M+H].sup.+.
Example B-6
Synthesis of
2-[4-[[5-chloro-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-m-
ethyl-pyrazol-1-yl]-2-methyl-propanenitrile (B-2)
2,5-dichloro-N-ethyl-7-(2-trimethylsilylethoxymethyl)
pyrrolo[2,3-d]pyrimidin-4-amine
[0777] To a solution of
2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyr-
imidine (400 mg, 1.13 mmol) in ethanol (10 mL) was added ethanamine
(61 mg, 1.36 mmol) dropwise at 25.degree. C. The mixture was
stirred at 25.degree. C. for 2 h. The mixture was concentrated in
vacuo at 35.degree. C. The residue was poured into water (10 mL).
The aqueous phase was extracted with EtOAc (3.times.20 mL). The
combined organic phase was washed with brine (2.times.10 mL), dried
with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by prep-TLC (SiO.sub.2, petroleum
ether/ethyl acetate=5:1) to afford the desired product as a white
solid (250 mg, 61.23%). LC/MS: RT 1.015 min, m/z=361
[M+H].sup.+.
2-[4-[[5-chloro-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-me-
thyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0778] To a mixture of 2,
5-dichloro-N-ethyl-7-(2-trimethylsilylethoxymethyl)
pyrrolo[2,3-d]pyrimidin-4-amine (240 mg, 664.19 umol) and
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (120
mg, 730.61 umol) in 1,4-dioxane (5 mL) was added
Pd.sub.2(dba).sub.3 (61 mg, 66.42 umol), X-Phos (32 mg, 66.42 umol)
and Cs.sub.2CO.sub.3 (650 mg, 1.99 mmol) in one portion at
25.degree. C. under N.sub.2. The mixture was stirred at 90.degree.
C. for 12 h. The mixture was cooled to 25.degree. C. and
concentrated in vacuo at 35.degree. C. The residue was poured into
water (10 mL). The aqueous phase was extracted with ethyl acetate
(3.times.20 mL). The combined organic phase was washed with brine
(2.times.10 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The residue was purified by TLC
(petroleum ether/ethyl acetate=3:1) to afford the desired product
as a white solid (250 mg, quantitative). LC/MS: RT 0.883 min,
m/z=489 [M+H].sup.+.
2-[4-[[5-chloro-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-me-
thyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0779] To a mixture of
2-[4-[[5-chloro-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-m-
ethyl-pyrazol-1-yl]-2-methyl-propanenitrile (150 mg, 306.69
.mu.mol) in DCM (10 mL) was added TFA (2 mL) in one portion at
25.degree. C. The mixture was stirred at 25.degree. C. for 3 h. The
reaction mixture was concentrated in vacuo to remove DCM. The crude
product was dissolved in THF (10 mL) and aq. NaHCO.sub.3 (10 mL)
was added. The mixture was stirred at 25.degree. C. for 12 h. The
mixture was extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a
residue. The residue was purified by prep-HPLC (neutral condition)
to afford the desired product. .sup.1H NMR (400 MHz, CDCl3):
.delta. 8.518 (s, 1H), 8.232 (s, 1H), 6.602 (s, 1H), 6.224 (s, 1H)
5.747 (s, 1H) 3.673-3.606 (m, 2H) 2.288 (s, 3H) 1.968 (s, 6H)
1.363-1.327 (t, 3H, J=7.2 Hz). HPLC: RT 2.609 min. MS: [M+H].sup.+
m/z: 359.1
Example B-7
Synthesis of
2-[4-[[5-chloro-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl--
pyrazol-1-yl]-2-methyl-propanenitrile (B-3)
2-[(2,5-dichloro-4-ethoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trime-
thyl-silane
[0780] To a mixture of
2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyr-
imidine (500 mg, 1.42 mmol) in ethanol (5 mL) was added freshly
prepared NaOEt (193.26 mg, 2.84 mmol) in one portion at 25.degree.
C. The mixture was stirred at 25.degree. C. for 3 h. The reaction
mixture was quenched by water, extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a
residue. The residue was purified by prep-TLC (SiO.sub.2, petroleum
ether/ethyl acetate=8:1) to afford the desired product (280 mg,
54.42%). LC/MS: RT 1.016 min, m/z=362 [M+H].sup.+.
2-[4-[[5-chloro-4-ethoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyr-
imidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0781] To a mixture of
2-[(2,5-dichloro-4-ethoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trim-
ethyl-silane (280 mg, 773 umol) and
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (140
mg, 850 umol) in dioxane (5 mL) was added Pd.sub.2(dba).sub.3 (71
mg, 77.3 umol), Cs.sub.2CO.sub.3 (755 mg, 2.32 mmol) and BINAP (48
mg, 77 umol) in one portion at 25.degree. C. under N.sub.2. The
mixture was heated to 120.degree. C. and stirred for 16 h. The
mixture was cooled to 25.degree. C. and concentrated in vacuo at
35.degree. C. The residue was poured into water, extracted with
ethyl acetate. The combined organic phase was washed with brine,
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by prep-TLC (SiO.sub.2,
PE:EtOAc=5:1) to afford the desired product as a white solid (315
mg, 83.18%). LC/MS: RT 0.993 min, m/z=490 [M+H].sup.+.
2-[4-[[5-chloro-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methyl-p-
yrazol-1-yl]-2-methyl-propanenitrile
[0782] To a mixture of
2-[4-[[5-chloro-4-ethoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]py-
rimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
(315 mg, 643 mmol) in DCM (10 mL) was added TFA (2 mL) in one
portion at 25.degree. C. The mixture was stirred at 25.degree. C.
for 3 h. The reaction mixture was concentrated in vacuo to remove
DCM. The residue was dissolved in THF (10 mL) and added with aq.
NaHCO.sub.3 (10 mL). The mixture was stirred at 25.degree. C. for
12 h, and extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo, purified by prep-HPLC (neutral condition) to
afford the desired product. .sup.1H NMR (400 MHz, CDCl3): .delta.
8.720 (s, 1H), 8.222 (s, 1H), 6.703-6.698 (d, 1H, J=2 Hz), 6.327
(s, 1H), 4.608-4.555 (m, 2H), 2.314 (s, 3H), 1.990 (s, 6H),
1.535-1.500 (t, 3H, J=7 Hz). HPLC: RT 2.847 min. MS: m/z: 360.1
[M+H].sup.+.
Example B-8
Synthesis of
2-(4-((6-methoxy-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylp-
ropanenitrile (B-7)
2,6-dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine
[0783] To a solution of 2,6-dichloro-9H-purine (3 g, 15.87 mmol) in
DMF (10 mL) was added NaH (698 mg, 17.46 mmol) at 0.degree. C. The
mixture was stirred at 0.degree. C. for 1 h. Then SEM-Cl (3.18 g,
19.05 mmol) was added to the suspension, the mixture was stirred at
25.degree. C. for 2 h. The reaction mixture was quenched by
addition of H.sub.2O (10 mL) at 25.degree. C. and extracted with
ethyl acetate (3-330 mL). The combined organic layers were washed
with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to get a residue. The residue was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate=5:1-3:1) to afford the desired product was a white solid
(3.8 g, 75%). LC/MS: RT 0.89 min, m/z=319 [M+H].sup.+.
2-chloro-6-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine
[0784] To a solution of
2,6-dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (1.3 g,
4.07 mmol) in MeOH (20 mL) was added sodium methoxide (330 mg, 6.11
mmol). The mixture was stirred at 25.degree. C. for 10 h. The
reaction mixture was concentrated in vacuo to remove MeOH. The
residue was diluted with H.sub.2O (30 mL) and extracted with DCM
(3.times.30 mL). The combined organic layers were washed with brine
(25 mL.times.2), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give a residue. The residue was purified
by prep-TLC (SiO.sub.2, petroleum ether/ethyl acetate=3:1) to
afford the desired compound as a white solid (600 mg, 47%). LC/MS:
RT 0.88 min, m/z=315 [M+H].sup.+.
2-(4-((6-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)amino)-
-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile
[0785] To a solution of
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (203
mg, 1.24 mmol),
2-chloro-6-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine
(300 mg, 952.86 umol) in 1,4-dioxane (25 mL) was added
Pd.sub.2(dba).sub.3 (87 mg, 95.29 umol), Cs.sub.2CO.sub.3 (621 mg,
1.91 mmol) and X-Phos (91 mg, 190.57 umol) under N.sub.2. The
mixture was stirred at 110.degree. C. for 10 h. The reaction
mixture was concentrated in vacuo to remove 1,4-dioxane. The
residue was diluted with H.sub.2O (20 mL) and extracted with ethyl
acetate (2.times.25 mL). The combined organic layers were washed
with brine (2.times.15 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo to give a residue. The residue was
purified by prep-TLC (SiO2, petroleum ether/ethyl acetate=1:1) to
afford the desired product as a white solid (320 mg, 76%). LC/MS:
RT 0.82 min, m/z=443 [M+H].sup.+.
2-(4-((6-methoxy-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylpr-
opanenitrile
[0786] To a solution of
2-(4-((6-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)amino-
)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (162 mg, 366.03
umol) in DCM (10 mL) was added TFA (3.34 g, 29.28 mmol) in one
portion at 25.degree. C. The mixture was heated to 40.degree. C.
and stirred for 6 h. The reaction mixture was concentrated in vacuo
to get a residue. The residue was dissolved in THF (10 mL) and
added with aq. NaHCO.sub.3 (10 mL). The mixture was stirred at
25.degree. C. for 12 h. The mixture was extracted with ethyl
acetate (30 mL). The organic layer was washed with brine (15 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
get a residue. The residue was purified by prep-TLC (SiO.sub.2,
DCM:MeOH=10:1) to afford the desired product. .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 12.64 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.91
(s, 1H), 4.04 (s, 3H), 2.19 (s, 3H), 1.94 (s, 6H). HPLC: RT 1.59
min. MS: [M+H].sup.+ m/z: 313.2.
Example B-9
Synthesis of
2-(4-((5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3--
methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile
2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine
[0787] A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (7 g,
37.23 mmol) and selectfluor (13.19 g, 37.23 mmol) in CH.sub.3CN
(360 mL) and AcOH (72 mL) was degassed and then the mixture was
stirred at 60.degree. C. for 16 h under N.sub.2. The reaction
mixture was concentrated under reduced pressure. The residue was
diluted with water (200 mL), adjusted to pH=7 with aq. NaHCO.sub.3,
and extracted with EtOAc (3.times.300 mL). The combined organic
layers were washed with brine (300 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue, which was purified by silica gel column
chromatography (PE:EtOAc=10:1 to 5:1) to give
2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 22.82%)
as a yellow oil. LCMS: RT 0.732 min, m/z=206.0 [M+H].sup.+.
2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3--
d]pyrimidine
[0788] To a solution of
2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 12.14
mmol) in DMF (25 mL) was added NaH (582 mg, 14.57 mmol) at
0.degree. C. The mixture was stirred at this temperature for 1 h,
and then SEM-Cl (2.43 g, 14.57 mmol) was added dropwise at
0.degree. C. The resulting mixture was stirred at 25.degree. C. for
1 h. The reaction was slowly poured into ice-water, and then
extracted with EtOAc (3.times.80 mL). The combined organic phase
was washed with brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give
2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-
-d]pyrimidine (2.5 g, 61.24%) as a yellow oil. LCMS: RT 0.975 min,
m/z=336.1 [M+H].sup.+.
2-chloro-5-fluoro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]p-
yrimidin-4-amine
[0789] To a mixture of
2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-
-d]pyrimidine (1.1 g, 3.27 mmol) in EtOH (15 mL) was added
MeNH.sub.2 (522 mg, 5.55 mmol, 33% purity) at 0.degree. C. under
N.sub.2 and stirred at 25.degree. C. for 8 h. The mixture was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (SiO.sub.2, PE:EtOAc=50:1) to give
2-chloro-5-fluoro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]-
pyrimidin-4-amine (645 mg, 59.61%) as a yellow syrup. LCMS: RT
0.912 min, m/z=331.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.29 (s, 1H), 6.75 (d, J=2.51 Hz, 1H), 5.48
(s, 2H), 3.49-3.56 (m, 2H), 3.19 (d, J=5.02 Hz, 2H), 0.90-0.97 (m,
2H).
2-[4-[[5-fluoro-4-(methylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,-
3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0790] To a solution of
2-chloro-5-fluoro-N-methyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]-
pyrimidin-4-amine (350 mg, 1.06 mmol) in 1,4-dioxane (5 mL) was
added Pd.sub.2(dba).sub.3 (97 mg, 106 umol), Cs.sub.2CO.sub.3 (1.04
g, 3.18 mmol) and
dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (505 mg,
1.06 mmol) under N.sub.2. The mixture was stirred at 120.degree. C.
for 16 h. The mixture was concentrated under reduced pressure. The
residue was purified by prep-TLC (SiO.sub.2, PE:EtOAc=2:1), to give
2-[4-[[5-fluoro-4-(methylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2-
,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
(310 mg, 63.77%) as a brown syrup. LCMS: RT 0.807 min, m/z=459.3
[M+H].sup.+.
2-(4-((5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-m-
ethyl-1H-pyrazol-1-yl)-2-methylpropanenitrile
[0791] To a solution of
2-[4-[[5-fluoro-4-(methylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2-
,3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
(120 mg, 261.66 umol) in DCM (5 mL) was added dropwise SnCl.sub.4
(886 mg, 3.40 mmol) at 0.degree. C. over 30 min. After addition,
the mixture was stirred at this temperature for 30 min. The
resulting mixture was stirred at 20.degree. C. for 2 h. The
reaction mixture was quenched by addition of H.sub.2O (20 mL) at
0.degree. C., and then added with sat. NaHCO.sub.3 (20 mL) to pH=8
and extracted with DCM (3.times.20 mL). The combined organic layers
were washed with brine (10 mL), and concentrated under reduced
pressure at 20.degree. C. The residue was dissolved with
THF/H.sub.2O (4/1, 20 mL) and added with excessive K.sub.2CO.sub.3.
The resulting mixture was stirred at 20.degree. C. for 2 h. The
reaction mixture was diluted with H.sub.2O (40 mL) at 0.degree. C.,
and extracted with EtOAc (3.times.20 mL). The combined organic
layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure at 20.degree. C.
The residue was purified by prep-HPLC (neutral) to give
2-(4-((5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3--
methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile. .sup.1H NMR: (400
MHz. CDCl3): .delta. ppm 8.87 (br, 1H), 8.21 (s, 1H), 6.31-6.37 (m,
1H), 6.25-6.30 (m, 1H), 5.13-5.25 (m, 1H), 3.15 (d, J=4.8 Hz, 3H),
2.28 (s, 3H), 1.92 (s, 6H). HPLC: RT 1.992 min. MS: [M+H].sup.+
m/z: 329.2.
Example B-10
Synthesis of
2-[4-[(5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl-
-pyrazol-1-yl]-2-methyl-propanenitrile (B-11)
2-[(2-chloro-5-fluoro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-
-trimethyl-silane
[0792] To a mixture of
2-[(2,4-dichloro-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trim-
ethyl-silane (1.16 g, 3.45 mmol) in MeOH (13 mL) was added NaOMe
(559 mg, 10.35 mmol) at 0.degree. C. under N.sub.2 and stirred at
25.degree. C. for 2 h. The mixture was concentrated under reduced
pressure and poured into ice water (12 mL). The aqueous phase was
extracted with EtOAc (3.times.4 mL). The combined organic phase was
washed with brine (4 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=50:1) to
afford
2-[(2-chloro-5-fluoro-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethy-
l-trimethyl-silane (1.08 g, 94.20%) as a yellow solid. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 6.88-6.91 (m, 1H), 5.52 (s, 2H),
4.17 (s, 3H), 3.48-3.54 (m, 2H), 0.89-0.95 (m, 2H).
2-[4-[[5-fluoro-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]py-
rimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0793] To a solution of
2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (327 mg,
1.99 mmol) in 1,4-dioxane (7 mL) was added Pd.sub.2(dba).sub.3 (166
mg, 181 umol), Cs.sub.2CO.sub.3 (1.77 g, 5.43 mmol) and XPhos (86
mg, 181 umol) under N.sub.2. The mixture was stirred at 120.degree.
C. for 16 h. The mixture was concentrated under reduced pressure.
The residue was purified by prep-TLC (SiO.sub.2, PE:EtOAc=2:1), to
give
2-[4-[[5-fluoro-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]p-
yrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
(294 mg, 35.34%) as a yellow solid. LCMS: RT 0.947 min, m/z=460.3
[M+H].sup.+.
2-[4-[(5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-methyl--
pyrazol-1-yl]-2-methyl-propanenitrile
[0794] To a solution of
2-[4-[[5-fluoro-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]p-
yrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
(250 mg, 543.96 umol) in DCM (10 mL) was added SnCl.sub.4 (1.84 g,
7.07 mmol, 826.13 uL) at 0.degree. C. under N.sub.2. The mixture
was stirred at 25.degree. C. for 2 h. The mixture was poured into
ice-water (10 mL) and adjusted to pH=8 by adding aq. NaHCO.sub.3.
The reaction mixture was extracted with EtOAc (3.times.4 mL). The
combined organic phase was washed with brine (10 mL), and
concentrated under reduced pressure. The residue was dissolved in
THF (7.5 mL) and H.sub.2O (2.5 mL), then added with K.sub.2CO.sub.3
(3.38 g, 24.48 mmol). The mixture stirred at 25.degree. C. for 3 h.
The reaction mixture was extracted with EtOAc (3.times.4 mL). The
combined organic phase was washed with brine (10 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by prep-HPLC (neutral), to give
2-[4-[(5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-m-
ethyl-pyrazol-1-yl]-2-methyl-propanenitrile. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.23 (s, 2H), 6.49 (t, J=2.51 Hz, 1H), 6.34
(s, 1H), 4.11 (s, 3H), 2.30 (s, 3H), 1.98 (s, 6H). HPLC: RT: 2.68
min. MS: [M+H].sup.+ m/z=330.2.
Example B-11
Synthesis of
2-[4-[(6-ethoxy-9H-purin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-prop-
anenitrile (B-12)
2-[(2-chloro-6-ethoxy-purin-9-yl)methoxy]ethyl-trimethyl-silane
[0795] To a mixture of
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (3.00 g,
9.40 mmol) in EtOH (30 mL) was added fresh EtONa (216 mg, 3.18
mmol, 273 uL) at 25.degree. C. The mixture was stirred at
25.degree. C. for 3 h. The reaction mixture was quenched by adding
water (10 mL) at 25.degree. C. and concentrated. Then the mixture
was extracted with EtOAc (3.times.5 mL). The combined organic phase
was washed with brine (5 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give
2-[(2-chloro-6-ethoxy-purin-9-yl)methoxy]ethyl-trimethyl-silane
(2.82 g, 91.22%) as a white solid. LCMS: RT 0.922 min, m/z=329.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.03
(s, 1H), 5.58 (s, 2H), 4.68 (q, J=7.06 Hz, 2H), 3.58-3.64 (m, 2H),
1.52 (t, J=7.06 Hz, 3H), 0.91-0.96 (m, 2H) -0.03 (s, 9H).
2-[4-[[6-ethoxy-9-(2-trimethylsilylethoxymethyl)purin-2-yl]amino]-3-methyl-
-pyrazol-1-yl]-2-methyl-propanenitrile
[0796] To a mixture of
2-[(2-chloro-6-ethoxy-purin-9-yl)methoxy]ethyl-trimethyl-silane
(200 mg, 608.14 umol) and
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (119.84
mg, 729.77 umol) in 1,4-dioxane (2 mL) was added Cs.sub.2CO.sub.3
(475 mg, 1.46 mmol), XPhos (57 mg, 121.63 umol) and
Pd.sub.2(dba).sub.3 (56 mg, 60.81 umol) at 20.degree. C. under
N.sub.2. The mixture was heated to 110.degree. C. and stirred for 5
h. The mixture was cooled to 20.degree. C. and added with water (10
mL), then extracted with EtOAc (3.times.5 mL), washed with brine (5
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-TLC (PE:EtOAc=1:1) to give
2-[4-[[6-ethoxy-9-(2-trimethylsilylethoxymethyl)purin-2-yl]amino]-3-methy-
l-pyrazol-1-yl]-2-methyl-propanenitrile (259 mg, 93.27%) as a
yellow oil. LCMS: RT 0.874 min, m/z=457.3 [M+H]+
2-[4-[(6-ethoxy-9H-purin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-propa-
nenitrile
[0797] To a mixture of
2-[4-[[6-ethoxy-9-(2-trimethylsilylethoxymethyl)purin-2-yl]amino]-3-methy-
l-pyrazol-1-yl]-2-methyl-propanenitrile (256 mg, 560.64 umol) in
DCM (20 mL) was added TFA (6.16 g, 54.03 mmol, 4 mL) at 20.degree.
C. under N.sub.2. The mixture was heated to 40.degree. C. and
stirred for 5 h. The mixture was cooled to 20.degree. C. and
concentrated. The residue was adjusted pH=7-8 by adding
aq.NaHCO.sub.3. The mixture was extracted with EtOAc (10
mL.times.3), washed with brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (neutral) to give
2-[4-[(6-ethoxy-9H-purin-2-yl)amino]-3-methyl-pyrazol-1-yl]-2-methyl-prop-
anenitrile. LCMS: RT 0.629 min, m/z=327.2 [M+H].sup.+. .sup.1H NMR
(400 MHz, MeOD): .delta. ppm 8.25 (s, 1H), 7.90 (s, 1H), 4.59 (q,
J=7.06 Hz, 2H), 2.25-2.29 (m, 3H), 1.99 (s, 6H), 1.48 (t, J=7.06
Hz, 3H). HPLC: RT: 1.652 min. MS: [M+H].sup.+ m/z: 327.2.
Example B-12
Synthesis of
2-[4-[(5-cyclopropyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-m-
ethyl-pyrazol-1-yl]-2-methyl-propanenitrile (B-13)
2-[(2,4-dichloro-5-cyclopropyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl--
trimethyl-silane
[0798] A mixture of
2-[(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimet-
hyl-silane (3 g, 6.75 mmol), cyclopropylboronic acid (928 mg, 10.80
mmol), Pd(dppf)Cl.sub.2 (494 mg, 675 umol), Ag.sub.2O (782 mg, 3.38
mmol) and K.sub.3PO.sub.4 (4.3 g, 20.25 mmol) in 1,4-dioxane (30
mL) was degassed and purged with N.sub.2 for 3 times. The mixture
was stirred at 90.degree. C. for 16 h under N.sub.2. The mixture
was cooled to 20.degree. C. and poured into ice-water (30 mL). The
aqueous phase was extracted with EtOAc (3-20 mL). The combined
organic phase was washed with brine (3.times.20 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=5:1), to give
2-[(2,4-dichloro-5-cyclopropyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-
-trimethyl-silane (2 g, 82.69%) as a yellow solid. LCMS: RT 1.069
min, m/z=358.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 6.97 (d, J=1.13 Hz, 1H), 5.51-5.53 (m, 2H), 3.49-3.53 (m,
2H), 2.11-2.20 (m, 1H), 0.96-1.00 (m, 2H), 0.90-0.94 (m, 2H), 0.64
(dd, J=5.21, 1.57 Hz, 2H), -0.04 (s, 9H).
2-[(2-chloro-5-cyclopropyl-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]-
ethyl-trimethyl-silane
[0799] To a mixture of
2-[(2,4-dichloro-5-cyclopropyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-
-trimethyl-silane (1 g, 2.79 mmol) in MeOH (2 mL) was added
CH.sub.3ONa (880 mg, 16.29 mmol) in one portion at 0.degree. C.,
warmed to 20.degree. C. and stirred for 16 h. The mixture was
poured into ice-water (10 mL). The aqueous phase was extracted with
EtOAc (3.times.10 mL). The combined organic phase was washed with
brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure, to give
2-[(2-chloro-5-cyclopropyl-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)me-
thoxy]ethyl-trimethyl-silane (1 g, crude) as a yellow oil. LCMS: RT
1.051 min, m/z=354.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.1): .delta. 6.71 (s, 1H), 5.47 (s, 2H), 4.14 (s, 3H),
3.44-3.53 (m, 2H), 2.06-2.15 (m, 1H), 0.89-0.95 (m, 4H), 0.58-0.64
(m, 2H), -0.05 (s, 9H).
2-[4-[[5-cyclopropyl-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-
-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0800] A mixture of
2-[(2-chloro-5-cyclopropyl-4-methoxy-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy-
]ethyl-trimethyl-silane (300 mg, 847.65 umol),
2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (278 mg,
1.70 mmol), Pd.sub.2(dba).sub.3 (78 mg, 84.77 umol), XPhos (81 mg,
169.53 umol) and Cs.sub.2CO.sub.3 (690 mg, 2.12 mmol) in
1,4-dioxane (5 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 110.degree. C. for 16 h
under N.sub.2. The mixture was cooled to 20.degree. C. and poured
into ice-water (5 mL). The aqueous phase was extracted with EtOAc
(3.times.4 mL). The combined organic phase was washed with brine (4
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-TLC (SiO.sub.2, PE:EtOAc=3:1), to give
2-[4-[[5-cyclopropyl-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,-
3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
(279 mg, 68.34%) as a yellow oil. LCMS: RT 1.021 min, m/z=482.4
[M+H].sup.+.
2-[4-[(5-cyclopropyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-me-
thyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0801] To a mixture of
2-[4-[[5-cyclopropyl-4-methoxy-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,-
3-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
(279 mg, 579.25 umol) in DCM (20 mL) was added TFA (6.16 g, 54.03
mmol, 4 mL) at 0.degree. C. under N.sub.2. The mixture was stirred
at 20.degree. C. for 8 h and concentrated under reduced pressure.
The residue in THF (20 mL) and H.sub.2O (5 mL) was added with
K.sub.2CO.sub.3 (7 g, 50.65 mmol). The mixture was stirred at
20.degree. C. for 12 h. The mixture was poured into ice-water (10
mL). The aqueous phase was extracted with EtOAc (3.times.10 mL).
The combined organic phase was washed with brine (10 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by prep-HPLC (neutral),
to give
2-[4-[(5-cyclopropyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)am-
ino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 8.71 (br. s., 1H), 8.24 (s, 1H),
6.33 (s, 2H), 4.10 (s, 3H), 2.29 (s, 3H), 2.03-2.12 (m, 1H), 1.93
(s, 6H), 0.84-0.90 (m, 2H), 0.58 (dd, J=5.21, 1.69 Hz, 2H). HPLC:
RT: 2.77 min. MS: [M+H]J m/z=352.2.
Example B-13
Synthesis of
2-(4-((4-methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amin-
o)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (B-14)
2-chloro-4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl-
)-7H-pyrrolo[2,3-d]pyrimidine
[0802] To a solution of CuI (146 mg, 0.77 mmol), KF (668 mg, 11.5
mmol) and 1,10-phenanthroline (138 mg, 0.77 mmol) in DMSO (2 mL)
was added (MeO).sub.3B (1.2 g, 11.5 mmol),
2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d-
]pyrimidine (1.7 g, 3.83 mmol) and TMSCF.sub.3 (1.63 g, 11.5 mmol).
The reaction mixture was stirred at 60.degree. C. for 12 h under
N.sub.2. The mixture was cooled to 20.degree. C. and poured into
ice-water (20 mL). The aqueous phase was extracted with EtOAc (2-20
mL). The combined organic phase was washed with brine (20 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a residue, which was purified by
silica gel column chromatography (PE:EtOAc=20:1 to 1:1) to give
2-chloro-4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methy-
l)-7H-pyrrolo[2,3-d]pyrimidine (900 mg, 61.54%) as a yellow solid.
LCMS: RT 1.222 min, m/z=382.1 [M+H].sup.+.
2-(4-((4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)--
7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methylp-
ropanenitrile
[0803] To a solution of
2-chloro-4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methy-
l)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.52 mmol) in 1, 4-dioxane
(5 mL) was added
2-(4-amino-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (94 mg,
0.57 mmol), XPhos (248 mg, 0.52 umol), Cs.sub.2CO (170 mg, 0.52
mmol) and Pd.sub.2(dba), (477 mg, 0.52 umol) under N.sub.2, then
the mixture was stirred at 100.degree. C. for 2 h. The reaction
mixture was cooled to ambient temperature and poured into ice-water
(5 mL), and extracted with EtOAc (3.times.5 mL). Combined organic
layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to give a residue, which
was purified by prep-TLC (SiO.sub.2, PE:EtOAc=1:1) to give
2-(4-((4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-
-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methyl-
propanenitrile (200 mg, 75.33%) as a yellow solid. LCMS: RT 1.412
min, m/z=510.4 [M+H].sup.+.
2-(4-((4-methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino-
)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile
[0804] To a solution of
2-(4-((4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-
-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-methyl-
propanenitrile (150 mg, 0.29 mmol) in DCM (4 mL) was added TFA (671
mg, 0.44 mL, 5.89 mmol) at 0.degree. C., then the mixture was
stirred at 40.degree. C. for 24 h. The reaction mixture was
concentrated under reduced pressure. The residue in THF (4 mL) and
water (4 mL) was added with K.sub.2CO.sub.3 (540 mg, 3.91 mmol) at
20.degree. C. Then the mixture was stirred at 50.degree. C. for 4
h. The mixture was concentrated under reduced pressure to give a
residue, which was purified by prep-HPLC (FA) to give
2-(4-((4-methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amin-
o)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile. .sup.1H NMR
(400 MHz, CHLOROFORM-d): .delta. 8.74 (br. s., 1H), 8.22 (s, 1H),
7.14 (br. s., 1H), 6.37 (s, 1H), 4.10 (s, 3H), 2.30 (s, 3H), 1.98
(s, 6H). HPLC: RT: 2.98 min. MS: [M+H].sup.+ m/z: 380.1.
[0805] Other compounds of structure (B-I) were prepared according
to the above procedures.
C: Compound Preparation
[0806] In the following Examples, all non-aqueous reactions were
carried out in oven-dried or flame-dried glassware under nitrogen
atmosphere. All chemicals were purchased from commercial vendors
and used as is, unless otherwise specified. Reactions were
magnetically stirred and monitored by thin layer chromatography
(TLC) with 250 .mu.m pre-coated silica gel plates, visualized
either with UV, or in an iodine chamber. Flash column
chromatography was performed using silica gel (100-200 mesh).
Chemical shifts are reported relative to chloroform (87.26),
methanol (63.31), or DMSO (82.50) for 1H NMR. HPLC analysis was
performed on Shimadzu 20AB HPLC system with a photodiode array
detector and Luna-C18(2) 2.0.times.50 mm, 5 .mu.m column at a flow
rate of 1.2 mL/min with a gradient solvent Mobile phase A (MPA,
H2O+0.037% (v/v) TFA): Mobile phase B (MPB, ACN+0.018% (v/v) TFA)
(0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10%
MPB; 5.5 min, 10% MPB). LCMS was detected under 220 and 254 nm or
used evaporative light scattering (ELSD) detection as well as
positive electrospray ionization (MS). Semi-preparative HPLC was
performed by either acidic or neutral condition. Acidic: Luna C18
100.times.30 mm, 5 .mu.m: MPA: HCl/H.sub.2O=0.04%, or formic
acid/H.sub.2O=0.2% (v/v); MPB: ACN. Neutral: Waters Xbridge
150.times.25, 5 .mu.m; MPA: 10 mM NH.sub.4HCO.sub.3 in H.sub.2O;
MPB: ACN. Gradient for both conditions: 10% of MPB to 80% of MPB
within 12 min at a flow rate of 20 mL/min, then 100% MPB over 2
min, 10% MPB over 2 min, UV detector. Compounds were named by using
either ChemBioDraw Ultra 13.0 or Chemaxon.
Example C-1 and C-2
Synthesis of
6-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl-
]-9H-purin-2-amine (C-1) and
6-cyclopropyl-N-(1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-9H-
-purin-2-amine (C-2)
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane
[0807] To a solution of compound 2,6-dichloro-9H-purine (10.00 g,
52.91 mmol) in DMF (100 mL) was added NaH (2.54 g, 63.49 mmol, 60%
purity) at 0.degree. C. over a period of 15 min under N.sub.2. The
mixture was then warmed up to 20.degree. C. and stirred at
20.degree. C. for 30 min. Then compound SEMCl (11.35 g, 63.49 mmol)
was dropwise at 0.degree. C. over a period of 15 min under N.sub.2.
The mixture was then warmed up to 20.degree. C. and stirred at
20.degree. C. for 3 h. The reaction was quenched by pouring into
ice-water (500 mL) and extracted with MTBE (3.times.200 mL), washed
with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=20:1 to 2:1)
to give compound
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane as a
light yellow solid.
2-[(2-chloro-6-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane
[0808] To a mixture of compound
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (5.00 g,
15.66 mmol) and cyclopropaneboronic acid (4.04 g, 46.98 mmol) in
1,4-dioxane (50 mL) was added Ag2O (1.81 g, 7.83 mmol), K3PO4 (9.97
g, 46.98 mmol) and Pd(dppf)Cl2 (1.15 g, 1.57 mmol) in one portion
at 20.degree. C. under N2. The mixture was then heated to
90.degree. C. and stirred for 5 h. The mixture was cooled to
20.degree. C., filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(PE:EtOAc=10:1 to 1:1) to give compound
2-[(2-chloro-6-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane
as a light yellow solid.
6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-yl]-9-{-
[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine and
6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl]-9--
{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine
[0809] To a mixture of compound
2-[(2-chloro-6-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane
(500 mg, 1.54 mmol) and
1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-amine and
1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-amine (405 mg,
2.31 mmol, mixture) in 1,4-dioxane (15 mL) was added XPhos (147 mg,
308 umol), Cs2CO3 (1.20 g, 3.70 mmol) and Pd2(dba)3 (141 mg, 154
umol) in one portion at 20.degree. C. under N2. The mixture was
then heated to 110.degree. C. and stirred for 16 h. The mixture was
cooled to 20.degree. C., added with EtOAc (5 mL), filtered and the
filtrate was concentrated under reduced pressure. The residue was
purified by prep-TLC (PE:EtOAc=1:1) to give crude product compound
6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-yl]-9--
{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine and
6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl]-9--
{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine as a red brown
oil which was used into the next step without further
purification.
6-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-
-9H-purin-2-amine and
6-cyclopropyl-N-(1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-9H-
-purin-2-amine
[0810] To a mixture of compound
6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-yl]-9--
{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine and
6-cyclopropyl-N-[1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl]-9--
{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-2-amine (220 mg, 474
umol) in DCM (20 mL) was added TFA (6.16 g, 54.03 mmol) at
0.degree. C. The mixture was heated to 40.degree. C. and stirred
for 3.5 h. The mixture was cooled to 25.degree. C. and adjusted pH
to 7 by adding aq. NaHCO3 and stirred for 10 min. The mixture was
then extracted with EtOAc (3.times.5 mL). The combined organic
phase was washed with brine (5 mL), dried over anhydrous
Na2SO.sub.4, filtered and concentrated under reduce pressure. The
residue was purified by prep-HPLC (FA condition) to give
6-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl-
]-9H-purin-2-amine and
6-cyclopropyl-N-(1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-9H-
-purin-2-amine.
6-cyclopropyl-N-[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl]-
-9H-purin-2-amine
[0811] .sup.1H NMR (400 MHz, CDCl3): .delta. ppm 7.95 (s, 1H), 7.68
(s, 1H), 6.50 (br. s., 1H), 4.38-5.08 (m, 5H), 2.66 (d, J=4.52 Hz,
1H), 2.26 (s, 3H), 1.33-1.47 (m, 2H), 1.14-1.24 (m, 2H). HPLC: RT
1.574 min. MS: m/z: 334.2 [M+H]+.
6-cyclopropyl-N-(1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-yl)-9H--
purin-2-amine
[0812] .sup.1H NMR (400 MHz, CDCl3): .delta. ppm 11.66 (br. s.,
1H), 7.67 (s, 1H) 7.21 (s, 1H), 6.23 (s, 1H), 4.57-4.83 (m, 5H),
2.59 (br. s., 1H), 2.11-2.24 (m, 3H), 1.29 (br. s., 2H), 1.03-1.14
(m, 2H). HPLC: RT 1.556 min. MS: m/z: 334.2 [M+H]+.
Example C-3
Synthesis of
6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9H-purin-2--
amine (C-3)
6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9-((2-(trime-
thylsilyl)ethoxy)methyl)-9H-purin-2-amine
[0813] To a solution of
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (180 mg,
554.05 .mu.mol) in 1,4-dioxane (10 mL) was added compound
1-(difluoromethyl)-3-methyl-1H-pyrazol-4-amine (98 mg, 664.86
umol), XPhos (53 mg, 110.81 umol), Cs.sub.2CO.sub.3 (361 mg, 1.11
mmol) and Pd.sub.2(dba).sub.3 (51 mg, 55.41 umol). The mixture was
stirred at 110.degree. C. for 6 h under N.sub.2. The mixture was
concentrated under reduced pressure to give a residue, which was
purified by prep-TLC (SiO.sub.2, PE:EtOAc=1:1) to give compound
6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9-((2-(trim-
ethylsilyl)ethoxy)methyl)-9H-purin-2-amine as a yellow solid. LCMS:
RT 0.880 min, m/z=436.1 [M+H].sup.+.
6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9H-purin-2-a-
mine
[0814] To a solution of
6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9H-purin-2--
amine (205 mg, 476.67 umol) in DCM (20 mL) was added TFA (6.8 g,
59.65 mmol) in one portion at 25.degree. C. The mixture was stirred
at 40.degree. C. for 4 h. The reaction mixture was concentrated
under reduced pressure to get a residue, which was dissolved in THF
(20 mL) and treated with aq. NaHCO.sub.3 (20 mL). The mixture was
stirred at 25.degree. C. for 12 h. The mixture was extracted with
EtOAc (30 mL). The organic layer was separated and washed with
brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to get a residue, which was
purified by prep-HPLC (neutral) to get
6-cyclopropyl-N-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)-9H-purin-2--
amine. .sup.1H NMR (400 MHz, MeOD): .delta. 8.40 (s, 1H), 8.07 (s,
1H), 7.12-7.48 (m, 1H), 2.56-2.66 (m, 1H), 2.29 (s, 3H), 1.27-1.35
(m, 2H), 1.12-1.21 (m, 2H). HPLC: RT 1.96 min. MS: m/z: 306.2
[M+H].sup.+.
Example C-4
Synthesis of
6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2--
amine (C-4)
6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trime-
thylsilyl)ethoxy)methyl)-9H-purin-2-amine
[0815] To a solution of
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (180 mg,
554.05 umol) in 1,4-dioxane (10 mL) was added
1-(difluoromethyl)-5-methyl-1H-pyrazol-4-amine (98 mg, 664.86
umol), XPhos (53 mg, 110.81 umol), Cs.sub.2CO.sub.3 (361 mg, 1.11
mmol) and Pd.sub.2(dba).sub.3 (51 mg, 55.41 umol). The mixture was
stirred at 110.degree. C. for 6 h under N.sub.2. The mixture was
concentrated under reduced pressure to give a residue, which was
purified by prep-TLC (SiO.sub.2, PE:EtOAc=1:1) to give
6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trim-
ethylsilyl)ethoxy)methyl)-9H-purin-2-amine as a yellow solid. LCMS:
RT 2.831 min, m/z=436.1 [M+H].sup.+.
6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2-a-
mine
[0816] To a solution of
6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(trim-
ethylsilyl)ethoxy)methyl)-9H-purin-2-amine (140 mg, 321.43 umol) in
DCM (20 mL) was added TFA (6.8 g, 59.65 mmol) in one portion at
25.degree. C. The mixture was heated to 40.degree. C. and stirred
for 4 h. The reaction mixture was concentrated under reduced
pressure to get a residue, which was dissolved in THF (20 mL) and
added with aq.NaHCO.sub.3 (20 mL). The mixture was stirred at
25.degree. C. for 12 h. The mixture was extracted with EtOAc (30
mL). The organic layer was separated and washed with brine (15 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to get a residue, which was purified by prep-HPLC
(neutral) to get
6-cyclopropyl-N-(1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-2--
amine. .sup.1H NMR (400 MHz, MeOD): .delta. 8.02 (br. s., 1H), 7.93
(s, 1H), 7.24-7.57 (m, 1H), 2.59 (br. s., 1H), 2.39 (s, 3H),
1.23-1.32 (m, 2H), 1.08-1.18 (m, 2H). HPLC: RT: 1.87 min. MS: m/z:
306.1 [M+H].sup.+.
Example C-5 and C-6
Synthesis of
6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9H-purin-2-amine (C-5)
and 6-cyclopropyl-N-(1,3-dimethylpyrazol-4-yl)-9H-purin-2-amine
(C-6)
6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9-(2-trimethylsilylethoxymethyl-
)purin-2-amine
[0817] 2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane
(400 mg, 1.23 mmol), 1,3-dimethyl-1H-pyrazol-4-amine and
1,5-dimethyl-1H-pyrazol-4-amine (205 mg, 1.85 mmol, mixture), XPhos
(117 mg, 246.24 umol), Cs.sub.2CO.sub.3 (963 mg, 2.95 mmol) and
Pd.sub.2(dba).sub.3 (112 mg, 123.12 umol) in 1,4-dioxane (10 mL)
were taken up into a microwave tube. The sealed tube was heated at
110.degree. C. for 14 h under microwave irradiation. After cooled
to 25.degree. C., EtOAc (10 mL) was added. The mixture was then
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=10:1 to 0:1)
to give
6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)-9-{[2-(trimethylsilyl)etho-
xy]methyl}-9H-purin-2-amine and
6-cyclopropyl-N-(1,5-dimethyl-1H-pyrazol-4-yl)-9-{[2-(trimethylsilyl)etho-
xy]methyl}-9H-purin-2-amine as a yellow oil.
6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9H-purin-2-amine and
6-cyclopropyl-N-(1,3-dimethylpyrazol-4-yl)-9H-purin-2-amine
[0818] To a solution of
6-cyclopropyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)-9-{[2-(trimethylsilyl)etho-
xy]methyl}-9H-purin-2-amine and
6-cyclopropyl-N-(1,5-dimethyl-1H-pyrazol-4-yl)-9-{[2-(trimethylsilyl)etho-
xy]methyl}-9H-purin-2-amine (200 mg, 500.54 .mu.mol, mixture) in
DCM (20 mL) was added TFA (6.16 g, 54.02 mmol) in one portion at
0.degree. C. Then the mixture was heated to 40.degree. C. and
stirred for 6 h. The mixture was adjusted pH to 7-8 by adding aq.
sat. NaHCO.sub.3 and stirred for 10 min. The aqueous phase was
extracted with EtOAc (3.times.5 mL). The combined organic phase was
washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by prep-HPLC (FA condition) and further separated by SFC
to give 6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9H-purin-2-amine
and 6-cyclopropyl-N-(1,3-dimethylpyrazol-4-yl)-9H-purin-2-amine.
LCMS: RT 0.148 min, m/z=270.2 [M+H].sup.+.
6-cyclopropyl-N-(1,5-dimethylpyrazol-4-yl)-9H-purin-2-amine
[0819] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 11.89 (br.
s., 1H), 7.58 (s, 1H), 7.17 (s, 1H), 6.32 (br. s., 1H), 3.83 (s,
1H), 3.75 (s, 3H), 2.60-2.70 (m, 1H), 2.23 (s, 1H), 2.17 (s, 3H),
1.37 (br. s., 2H), 1.17 (d, J=4.52 Hz, 2H), 0.08 (s, 1H). HPLC: RT:
1.287 min. MS: m/z: 270.2 [M+H].sup.+.
6-cyclopropyl-N-(1,3-dimethylpyrazol-4-yl)-9H-purin-2-amine
[0820] .sup.1H NMR (400 MHz, CDCl3): .delta. ppm 10.46 (br. s.,
1H), 7.69 (s, 1H), 7.53 (s, 1H), 6.34 (s, 1H), 3.84 (s, 3H),
2.63-2.72 (m, 1H), 2.25 (s, 3H), 1.34-1.41 (m, 2H), 1.18 (dd,
J=8.16, 3.31 Hz, 2H). HPLC: RT: 1.262 min. MS: m/z: 270.1
[M+H].sup.+.
Example C-7
Synthesis of
6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-
-2-amine (C-7)
6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(tr-
imethylsilyl)ethoxy)methyl)-9H-purin-2-amine
[0821] To a solution of
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (232 mg,
714.14 umol) in 1,4-dioxane (10 mL) was added
1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-amine (90 mg, 595.20
umol), XPhos (57 mg, 119.04 umol), Cs.sub.2CO.sub.3 (388 mg, 1.19
mmol) and Pd.sub.2(dba).sub.3 (55 mg, 59.52 umol). The mixture was
stirred at 110.degree. C. for 6 h under N.sub.2. The mixture was
concentrated under reduced pressure to give a residue, which was
purified by prep-TLC (SiO.sub.2, PE:EtOAc=1:1) to give
6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(t-
rimethylsilyl)ethoxy)methyl)-9H-purin-2-amine as a yellow solid.
LCMS: RT 0.839 min, m/z=440.3 [M+H].sup.+.
6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin--
2-amine
[0822] To a solution of
6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9-((2-(t-
rimethylsilyl)ethoxy)methyl)-9H-purin-2-amine (160 mg, 363.94 umol)
in DCM (20 mL) was added TFA (7.7 g, 67.53 mmol) in one portion at
25.degree. C. The mixture was heated to 40.degree. C. and stirred
for 4 h. The reaction mixture was concentrated under reduced
pressure to get a residue, which was dissolved in THF (20 mL) and
added with aq. NaHCO.sub.3 (20 mL). The mixture was stirred at
25.degree. C. for 12 h. The mixture was extracted with EtOAc (30
mL). The organic layer was separated and washed with brine (15 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to get a residue, which was purified by prep-HPLC
(neutral) to get
6-cyclopropyl-N-(1-(cyclopropylmethyl)-5-methyl-1H-pyrazol-4-yl)-9H-purin-
-2-amine. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 11.82-12.27
(m, 1H), 7.62 (s, 1H), 7.19 (s, 1H), 6.30 (s, 1H), 3.88 (d, J=6.90
Hz, 2H), 2.63 (d, J=4.14 Hz, 1H), 2.21 (s, 3H), 1.36 (br. s., 2H),
1.15 (dd, J=7.65, 2.89 Hz, 3H), 0.53 (d, J=7.53 Hz, 2H), 0.33 (d,
J=5.02 Hz, 2H). HPLC: RT 1.74 min. MS: m/z: 310.2 [M+H].sup.+.
Example C-8
Synthesis of
N-(6-cyclopropyl-9H-purin-2-yl)spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,-
1'-cyclopropane]-3-amine (C-8)
[1-[(4-nitropyrazol-1-yl)methyl]cyclopropyl]methanol
[0823] To a solution of 3-nitropyrazole (16.61 g, 146 mmol),
[1-(hydroxymethyl) cyclopropyl] methanol (15 g, 146 mmol) and
PPh.sub.3 (38.52 g, 146 mmol) in THF (300 mL) was added DIAD (29.7
g, 146 mmol) dropwise at 0.degree. C. over a period of 30 min under
N.sub.2. The reaction mixture was stirred at 25.degree. C. for
another 12 h. The reaction was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(PE:EtOAc=50:1 to 2:1) to give
[1-[(4-nitropyrazol-1-yl)methyl]cyclopropyl]methanol as a white
solid.
1-[[1-(bromomethyl)cyclopropyl]methyl]-4-nitro-pyrazole
[0824] To a mixture of
[1-[(4-nitropyrazol-1-yl)methyl]cyclopropyl]methanol (7 g, 35.5
mmol) in DCM (100 mL) was added PBr.sub.3 (19.22 g, 71 mmol) at
0.degree. C. over a period of 15 min. The mixture was stirred at
0.degree. C. for 2 h. The mixture was poured into ice-water (100
mL) and stirred for 5 min. The aqueous phase was extracted with DCM
(50 mL.times.2). The combined organic phase was washed with brine
(100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (SiO.sub.2, PE:EtOAc=100:1 to
10:1) to give
1-[[1-(bromomethyl)cyclopropyl]methyl]-4-nitro-pyrazole as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.24 (s, 1H),
8.11 (s, 1H), 4.23, (s, 2H), 3.23, (s, 2H), 1.03-1.08 (m, 2H),
0.82-0.87 (m, 2H).
3-nitrospiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]
[0825] To a solution of
1-[[1-(bromomethyl)cyclopropyl]methyl]-4-nitro-pyrazole (560 mg,
2.15 mmol) in THF (500 mL) was added a solution of LiHMDS (4.3
mmol, 1 M, 4.3 mL) dropwise at -78.degree. C. under N.sub.2. After
addition the reaction was allowed to warm to 25.degree. C. over a
period of 2 h, and stirred at 60.degree. C. for 4 h. The five
parallel reactions were combined to workup. The mixture was
quenched by aq. NH.sub.4Cl (100 ml) and extracted with MTBE
(3.times.100 mL). The combined organic phase was washed with brine
(2.times.100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The product was purified
by prep-HPLC (TFA) to give
3-nitrospiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]
as a yellow solid. LCMS: RT 0.986 min, m/z=180 [M+H].sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.09 (s, 1H), 4.15 (s, 2H),
3.24 (s, 2H), 0.92 (s, 4H).
Spiro
[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]-3-amine
[0826] To a solution of
3-nitrospiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]
(90 mg, 502 umol) in MeOH (5 mL) was added Pd/C under N.sub.2. The
suspension was degassed under vacuum and purged with H.sub.2 three
times. The mixture was stirred under H.sub.2 (20 psi) at 25.degree.
C. for 2 h. The reaction mixture was filtered and the filtrate was
concentrated under reduced pressure to give spiro
[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]-3-amine as a
brown solid. LCMS: RT 0.911 min, m, =150 [M+H].sup.+. .sup.1H NMR
(400 MHz, CDCl3): .delta. ppm 7.24 (s, 1H), 4.01 (s, 2H), 2.81 (s,
2H), 2.72 (br. s., 1H), 0.77-0.86 (m, 4H).
N-[6-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-2-yl]spiro[4,6-dihy-
dropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]-3-amine
[0827] To a mixture of spiro
[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]-3-amine (80
mg, 536.23 umol) and
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (261 mg,
804.35 umol) in 1,4-dioxane (1 mL) was added XPhos (51 mg, 107.25
umol), Cs.sub.2CO.sub.3 (419 mg, 1.29 mmol) and Pd.sub.2(dba).sub.3
(49 mg, 53.62 umol) at 20.degree. C. under N.sub.2. The mixture was
heated to 110.degree. C. and stirred for 5 h. The mixture was
cooled to 20.degree. C. then added with water (5 mL). The aqueous
phase was extracted with EtOAc (3.times.3 mL). The combined organic
phase was washed with brine (3 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-TLC (PE:EtOAc=1:1) to give
N-[6-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-2-yl]spiro[4,6-dih-
ydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]-3-amine as a yellow
oil.
N-(6-cyclopropyl-9H-purin-2-yl)spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1-
'-cyclopropane]-3-amine
[0828] To a mixture of
N-[6-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-2-yl]spiro[4,6-dih-
ydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]-3-amine (230 mg,
525.58 umol) in DCM (20 mL) was added TFA (6.16 g, 54.02 mmol) in
one portion at 20.degree. C. The mixture was heated to 40.degree.
C. and stirred for 5 h. The mixture was then cooled to 20.degree.
C. and concentrated under reduced pressure. The residue was added
with THF (10 mL) and aq. K.sub.2CO.sub.3 (10 mL) then stirred for 2
h. The mixture was filtered and the filtrate was concentrated,
extracted with EtOAc (3.times.5 mL). The combined organic phase was
washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by prep-HPLC (neutral condition) to give
N-(6-cyclopropyl-9H-purin-2-yl)spiro[4,6-dihydropyrrolo[1,2-b]pyrazo-
le-5,1'-cyclopropane]-3-amine. LCMS: RT 0.212 min, m/z=308.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3): .delta. ppm 12.53 (br.
s., 1H), 7.64 (s, 1H), 7.06 (s, 1H), 6.48 (s, 1H), 3.94 (s, 2H),
2.77 (s, 2H), 2.60-2.69 (m, 1H), 1.36 (br. s., 2H), 1.17 (dd,
J=7.53, 3.01 Hz, 2H), 0.39-0.60 (m, 4H). HPLC: RT: 1.658 min. MS:
m/z: 308.2 [M+H].sup.+.
Example C-9
Synthesis of
2-(4-((6-cyclopropyl-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-met-
hylpropanenitrile (C-9)
Methyl 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate
[0829] To a solution of 3-methyl-4-nitro-1H-pyrazole (40 g, 314.71
mmol) in DMF (700 mL) was added NaH (18.88 g, 472.06 mmol, 60%
purity) at 0.degree. C. over a period of 30 min under N.sub.2. The
reaction was then stirred at 25.degree. C. for 2 h followed by the
addition of methyl 2-bromo-2-methylpropanoate (85.46 g, 472.06
mmol, 61.04 mL) dropwise at 0.degree. C. The reaction mixture was
warmed to 25.degree. C. and stirred at 25.degree. C. for another 16
h. TLC (petroleum ether/ethyl acetate=5:1) showed the starting
material was consumed completely. The reaction was quenched by ice
water slowly and then extracted with EtOAc (3.times.700 mL). The
combined organic phase was washed with brine (3.times.200 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate=30:1-15:1), to yield the desired
product as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.29 (s, 1H), 3.72 (s, 1H), 2.51 (s, 1H), 1.84 (s, 6H).
2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoic acid
[0830] To a mixture of methyl
2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (69.7 g,
306.75 mmol) in THF (1 L) and H.sub.2O (250 mL) was added
LiOH.H.sub.2O (15.45 g, 368.10 mmol) at 25.degree. C. under
N.sub.2. The mixture was then stirred at 25.degree. C. for 16 h.
TLC (petroleum ether/ethyl acetate=5:1) showed the reaction was
completed. The reaction mixture was concentrated in vacuo. The
residual aqueous solution was washed with ethyl acetate (50 mL).
The aqueous phase was then cooled to 0.degree. C., adjusted to
approximately pH 1-2, and filtered to yield the desired product as
a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.65 (s,
1H), 2.48 (s, 1H), 1.83 (s, 6H).
2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide
[0831] To a solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)
propanoic acid (25 g, 117.27 mmol) in DCM (500 mL) was added 8
drops of DMF, followed by oxalyl chloride (29.77 g, 234.54 mmol) at
0.degree. C. under N.sub.2. The mixture was then stirred at
25.degree. C. for a further 2 h. TLC (petroleum ether/ethyl
acetate=3:1) showed reaction was completed. The reaction solution
was concentrated in vacuo. The residue solid was dissolved in THF
(300 mL) and added dropwise into a stirred solution of NH.sub.4OH
(413.61 g, 11.80 mol, 454.52 mL) at 0.degree. C. The reaction was
stirred at 25.degree. C. for 1 h. TLC (ethyl acetate) showed
reaction was completed. The solution was then concentrated in vacuo
and partitioned between EtOAc (100 mL) and water (100 mL), and the
aqueous phase was extracted with ethyl acetate (3.times.80 mL). The
combined organic phase was washed with brine (3.times.40 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo, to yield the desired compound as a yellow solid. .sup.1H NMR
(400 MHz, MeOD): .delta. 8.81 (s, 1H), 7.16-7.26 (m, 2H), 2.42 (s,
3H), 1.71 (s, 3H).
2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile
[0832] A solution of
2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide (22 g, 103.67
mmol) in POCl.sub.3 (132 g, 860.89 mmol, 80 mL) was stirred at
90.degree. C. for 1 h. TLC showed the reaction was completed. The
mixture was cooled to 20.degree. C. and concentrated in vacuo at
50.degree. C. The residue was poured into ice-water (w/w=1/1) (200
mL) and stirred for 10 min. The aqueous phase was adjusted to pH=7
with NaHCO.sub.3 solution, extracted with ethyl acetate (4.times.80
mL). The combined organic phase was washed with brine (40 mL),
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The desired product was afforded as a yellow solid.
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile
[0833] To a mixture of
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (10 g,
51.5 mmol) in EtOH (240 mL) and H.sub.2O (60 mL) was added
NH.sub.4Cl (13.77 g, 257.5 mmol) in one portion at 25.degree. C.,
followed by Fe (14.38 g, 257.5 mmol). The mixture was heated to
80.degree. C. and stirred for 1 h. TLC showed the reaction was
completed. The solution was cooled to 20.degree. C. The mixture was
extracted with ethyl acetate (3-100 mL), the combined organic
layers were washed with NaHCO.sub.3 solution (50 mL) and brine (50
mL). The organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated. The desired product was afforded as a dark brown
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.17 (s, 1H),
2.18 (s, 3H), 1.91 (s, 6H).
2-(4-((6-cyclopropyl-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)am-
ino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile
[0834] To a solution of
2-[(2,6-dichloropurin-9-yl)methoxy]ethyl-trimethyl-silane (450 mg,
1.39 mmol) and
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (342 mg,
2.09 mmol) in 1,4-dioxane (20 mL) was added Pd.sub.2(dba).sub.3
(127 mg, 139 umol), Cs.sub.2CO.sub.3 (1.13 g, 3.47 mmol) and X-Phos
(132 mg, 278 umol) under N.sub.2. The mixture was stirred at
110.degree. C. for 12 h. The reaction mixture was concentrated
under reduced pressure to get a residue, which was diluted with
H.sub.2O (20 mL) and extracted with EtOAc (2.times.25 mL). The
combined organic layers were washed with brine (15 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue, which was purified by prep-TLC (SiO.sub.2,
PE:EtOAc=3:1) to give
2-(4-((6-cyclopropyl-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)a-
mino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile as a white
solid. LCMS: RT 0.843 min, m/z=453.2 [M+H].sup.+.
2-(4-((6-cyclopropyl-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-meth-
ylpropanenitrile
[0835] To a solution of
2-(4-((6-cyclopropyl-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)a-
mino)-3-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile (350 mg,
773.26 umol) in DCM (20 mL) was added TFA (7.05 g, 61.86 mmol) in
one portion at 25.degree. C. The mixture was heated to 40.degree.
C. and stirred for 5 h. The reaction mixture was concentrated under
reduced pressure to get a residue, which was dissolved in THF (20
mL) and added with aq. NaHCO.sub.3 (20 mL). The mixture was stirred
at 25.degree. C. for 10 h. The mixture was extracted with EtOAc (40
mL). The organic layer was washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to get a residue, which was purified by prep-HPLC (neutral) to give
of
2-(4-((6-cyclopropyl-9H-purin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2-met-
hylpropanenitrile. .sup.1H NMR (400 MHz, DMSO-d6): .delta.12.27
(br. s, 1H), 8.44 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 2.53-2.57
(m, 1H), 2.18 (s, 3H), 1.94 (s, 6H), 1.25 (br. s., 2H), 1.12 (dd,
J=7.72, 3.31 Hz, 2H). HPLC: RT: 1.87 min. MS: m z: 323.2
[M+H].sup.+.
Example C-10
Synthesis of
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (C-10)
2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
[0836] To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (7
g, 37.23 mmol) in DMF (37 mL) was added NIS (8.79 g, 39.09 mmol) in
one portion at 0.degree. C. under N.sub.2. The mixture was stirred
at 25.degree. C. for 1.5 h. The reaction solution was poured into
ice-water (100 mL), and the resulting precipitate was isolated by
filtration. The filter cake was washed with ice water (2.times.50
mL) and dried under reduced pressure to give
2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid.
LCMS: RT 0.771 min, m/z=313.9 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO): .delta. 13.12 (br. s., 1H), 7.97 (d, J=2.01 Hz, 1H).
2-[(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimeth-
yl-silane
[0837] To a mixture of
2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5 g, 15.93 mmol)
in DMF (40 mL) was added NaH (764 mg, 19.11 mmol, 60% purity) in
one portion at 0.degree. C. under N.sub.2. The mixture was stirred
at 25.degree. C. for 30 min, SEMCl (3.19 g, 19.12 mmol, 3.39 mL)
was added to the mixture at 0.degree. C. and stirred for 1.5 h at
25.degree. C. The mixture was poured into ice-water (40 mL),
extracted with EtOAc (3.times.30 mL). The combined organic phase
was washed with brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(PE:EtOAc=10:1) to afford
2-[(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimet-
hyl-silane as a yellow solid. LCMS: RT 0.996 min, m/z=444
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO): .delta. 8.15 (s, 1H),
5.55 (s, 2H), 3.49-3.56 (m, 2H), 0.81-0.87 (m, 2H), -0.08 (s,
9H).
2,4-dichloro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-ca-
rbonitrile
[0838] To a mixture of
2-[(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimet-
hyl-silane (2 g, 4.50 mmol) in NMP (32 mL) was added CuCN (806.54
mg, 9.01 mmol, 1.97 mL) in one portion at 25.degree. C. under
N.sub.2. The mixture was heated to 120.degree. C. and stirred for
4.5 h. The mixture was cooled to 25.degree. C. and poured into
ice-water (150 mL). The aqueous phase was extracted with EtOAc
(3.times.60 mL). The combined organic phase was washed with brine
(3.times.60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (PE:EtOAc=15:1) to afford
2,4-dichloro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyri-
midine-5-carbonitrile as a yellow solid. LCMS: RT 0.912 min,
m/z=343.1 [M+H].sup.+.
2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrim-
idine-5-carbonitrile
[0839] To a solution of
2,4-dichloro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-c-
arbonitrile (1.48 g, 4.31 mmol) and cyclopropylboronic acid (630
mg, 7.33 mmol) in 1,4-dioxane (30 mL) was added K.sub.3PO.sub.4
(2.74 g, 12.93 mmol), Ag.sub.2O (499 mg, 2.15 mmol),
Pd(dppf)Cl.sub.2 (315 mg, 431 umol) under N.sub.2. The mixture was
stirred at 90.degree. C. for 4.5 h. The mixture was cooled to
25.degree. C. and poured into ice-water (30 mL). The aqueous phase
was extracted with EtOAc (3-20 mL). The combined organic phase was
washed with brine (20 mL.times.3), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(PE:EtOAc=30:1) to afford
2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[-
2,3-d]pyrimidine-5-carbonitrile as a yellow solid. LCMS: RT 1.023
min, m/z=349.2 [M+H]r. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.82-7.83 (m, 1H), 5.60-5.62 (m, 2H), 3.55-3.61 (m, 2H), 2.73-2.81
(m, 1H), 1.45-1.48 (m, 2H), 1.30-1.34 (m, 2H), 0.92-0.97 (m, 2H),
-0.01 (s, 9H).
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl--
7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile
[0840] To a solution of
2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyri-
midine-5-carbonitrile (100 mg, 286.62 umol) and
2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (56 mg,
343.94 umol) in 1,4-dioxane (10 mL) was added Pd.sub.2(dba).sub.3
(26 mg, 28.66 umol), Cs.sub.2CO.sub.3 (233 mg, 716.55 umol) and
X-Phos (27 mg, 57.32 umol) under N.sub.2. The mixture was stirred
at 110.degree. C. for 16 h. The mixture was cooled to 25.degree. C.
and poured into ice-water (16 mL). The aqueous phase was extracted
with EtOAc (3-8 mL). The combined organic phase was washed with
brine (3.times.8 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by prep-TLC (SiO.sub.2, PE:EtOAc=5:1) to give
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-
-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile
as a yellow solid. LCMS: RT 1.722 min, m/z=477.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.28-8.32 (m, 1H), 7.57
(s, 1H), 5.52 (s, 2H), 3.80 (s, 1H), 3.54-3.61 (m, 2H), 2.68-2.76
(m, 1H), 2.31 (s, 3H), 2.00 (s, 6H), 1.33-1.37 (m, 2H), 1.21-1.24
(m, 2H), 0.92-0.97 (m, 2H), -0.04 (s, 9H).
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
[0841] To a mixture of
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-
-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile
(95 mg, 199.31 umol) in DCM (20 mL) was added TFA (6.16 g, 54.02
mmol, 4 mL) in one portion at 0.degree. C. under N.sub.2. The
mixture was stirred at 20.degree. C. for 8 h. The mixture was
concentrated under reduced pressure. The residue in THF (10 mL) was
added with NaHCO.sub.3 (12.96 g, 154.27 mmol, 6 mL), stirred at
20.degree. C. for 16 h. The mixture was poured into ice-water (10
mL). The aqueous phase was extracted with EtOAc (3.times.8 mL). The
combined organic phase was washed with brine (3.times.8 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by prep-HPLC (neutral
condition) to provide
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-cyclopropyl-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile. .sup.1H NMR (400 MHz,
DMSO): .delta. 8.60 (br. s., 1H), 8.10 (d, J=12.80 Hz, 2H), 2.17
(s, 3H), 1.94 (s, 6H), 1.15-1.25 (m, 4H). HPLC: RT: 2.498 min. MS:
m/z=347.2 [M+H].sup.+.
Example C-11 and C-12
Synthesis of
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-y-
l]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (C-11) and
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-y-
l]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (C-12)
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl-
]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carboni-
trile and
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-py-
razol-4-yl]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-
-5-carbonitrile
[0842] To a solution of
2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyri-
midine-5-carbonitrile (300 mg, 859.85 umol), mixture of
1-(1,3-difluoropropan-2-yl)-3-methyl-1H-pyrazol-4-amine and
1-(1,3-difluoropropan-2-yl)-5-methyl-1H-pyrazol-4-amine (196 mg,
1.12 mmol) in 1,4-dioxane (10 mL) was added Pd.sub.2(dba).sub.3 (79
mg, 85.99 umol), Cs.sub.2CO3 (700 mg, 2.15 mmol) and XPhos (82 mg,
171.97 umol). The mixture was stirred at 110.degree. C. for 16 h.
The mixture was cooled to 20.degree. C. and concentrated under
reduced pressure. The residue was poured into ice-water (20 mL).
The aqueous phase was extracted with EtOAc (3.times.10 mL). The
combined organic phase was washed with brine (3.times.10 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by prep-TLC (SiO2,
PE:EtOAc=3:1) and two products were separated.
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-y-
l]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbon-
itrile was obtained as a yellow oil.
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-y-
l]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbon-
itrile was obtained as a yellow oil. LCMS: RT 0.926 min, m/z=488.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.1): .delta. 8.10-8.12
(m, 1H), 7.55 (s, 1H), 6.49 (s, 1H), 5.50 (s, 2H), 4.87-4.93 (m,
2H), 4.77-4.82 (m, 2H), 4.13 (q, J=7.15 Hz, 1H), 3.55 (t, J=8.16
Hz, 2H), 2.65-2.75 (m, 1H), 2.29 (s, 3H), 1.30-1.36 (m, 2H), 1.21
(dd, J=7.53, 3.14 Hz, 2H), 0.88-0.95 (m, 2H), -0.05 (s, 9H)
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-yl-
]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
[0843] To a solution of
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-y-
l]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbon-
itrile (124 mg, 254.30 umol) in DCM (20 mL) was added TFA (6.16 g,
54.03 mmol, 4 mL) in one portion at 0.degree. C. under N.sub.2. The
mixture was stirred at 20.degree. C. for 8 h. The mixture was
concentrated under reduced pressure. The residue in THF (10 mL) was
added with aq. NaHCO.sub.3 (12.96 g, 154.27 mmol, 6 mL). The
mixture was stirred at 20.degree. C. for 16 h. The mixture was
poured into ice-water (10 mL). The aqueous phase was extracted with
EtOAc (3.times.8 mL). The combined organic phase was washed with
brine (3.times.8 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by prep-HPLC (neutral condition) to give
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-5-methyl-pyrazol-4-y-
l]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile. .sup.1H NMR
(400 MHz, DMSO): .delta. 8.35-8.40 (m, 1H), 8.01-8.04 (m, 1H),
7.63-7.67 (m, 1H), 4.89-5.02 (m, 1H), 4.85 (br. s., 2H), 4.70-4.76
(m, 2H), 2.18 (s, 3H), 1.09-1.21 (m, 4H). HPLC: RT: 2.333 min. MS:
m/z=358.2 [M+H].sup.+.
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-yl-
]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
[0844]
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyraz-
ol-4-yl]amino]-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5--
carbonitrile (209 mg, 428.61 .mu.mol) was treated with TFA (48.87
mg, 428.61 umol, 31.73 .mu.L) in one portion at 0.degree. C. under
N.sub.2. The mixture was stirred at 20.degree. C. for 8 h. The
mixture was concentrated under reduced pressure. The residue in THF
(10 mL) was added with aq. NaHCO.sub.3 (12.96 g, 154.27 mmol). The
mixture was stirred at 20.degree. C. for 16 h. The mixture was
poured into ice-water (10 mL). The aqueous phase was extracted with
EtOAc (3.times.38 mL). The combined organic phase was washed with
brine (3-38 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by prep-HPLC (neutral condition) to give
4-cyclopropyl-2-[[1-[2-fluoro-1-(fluoromethyl)ethyl]-3-methyl-pyrazol-4-y-
l]amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile. .sup.1H NMR
(400 MHz, DMSO): .delta. 8.39 (br. s., 1H), 8.03 (s, 1H), 7.94 (s,
1H), 4.70-4.89 (m, 5H), 2.12 (s, 3H), 1.21 (br. s., 2H), 1.14 (d,
J=7.78 Hz, 2H). HPLC: RT: 2.63 min. MS: m/z=358.2 [M+H].sup.+.
Example C-13
Synthesis of
4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropan-
e]-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (C-13)
4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane-
]-3-ylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-ca-
rbonitrile
[0845] A mixture of spiro
[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane]-3-amine (135
mg, 904.89 umol),
2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyri-
midine-5-carbonitrile (379 mg, 1.09 mmol), Cs.sub.2CO.sub.3 (737
mg, 2.26 mmol), Pd.sub.2(dba).sub.3 (83 mg, 90.49 umol) and XPhos
(86 mg, 180.98 umol) in 1,4-dioxane (5 mL) was degassed and purged
with N.sub.2 for 3 times, and then the mixture was stirred at
110.degree. C. for 16 h under N.sub.2. The mixture was cooled to
20.degree. C. and concentrated under reduced pressure. The residue
was poured into ice-water (5 mL). The aqueous phase was extracted
with EtOAc (4 mL.times.3). The combined organic phase was washed
with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by prep-TLC (SiO.sub.2, PE:EtOAc=1:1) to give
4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropan-
e]-3-ylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-c-
arbonitrile as a yellow oil. LCMS: 1.019 min, m/z=462.3
[M+H].sup.+.
4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropane-
]-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
[0846] To a solution of
4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropan-
e]-3-ylamino)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-c-
arbonitrile (352 mg, 762.50 umol) in DCM (20 mL) was added TFA
(6.16 g, 54.02 mmol, 4 mL) in one portion at 0.degree. C. under
N.sub.2. The mixture was stirred at 20.degree. C. for 8 h. The
mixture was concentrated under reduced pressure. The residue in THF
(20 mL) and water (4 mL) was added with K.sub.2CO.sub.3 (5 g, 36.18
mmol). The mixture was stirred at 20.degree. C. for 16 h. The
mixture was poured into ice-water (10 mL) and extracted with EtOAc
(3.times.8 mL). The combined organic phase was washed with brine
(3.times.8 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral condition) to give
4-cyclopropyl-2-(spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,1'-cyclopropan-
e]-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 11.68 (br. s., 1H), 7.63 (s,
1H), 6.71 (s, 1H), 6.43 (s, 1H), 3.93 (s, 2H), 2.80 (s, 2H),
2.65-2.73 (m, 1H), 1.30-1.35 (m, 2H), 1.16-1.22 (m, 2H), 0.60-0.65
(m, 2H), 0.48-0.53 (m, 2H). HPLC: RT: 2.402 min. MS: m/z=332.2
[M+H].sup.+.
Example C-14
Synthesis of
2-[4-[(4-cyclopropyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-me-
thyl-pyrazol-1-yl]-2-methyl-propanenitrile (C-14)
2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine
[0847] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine
(50 g, 0.27 mol) in CH.sub.3CN (1 L) and AcOH (200 mL) was added
selectfluor (131.9 g, 0.37 mol) in one portion. The reaction
mixture was stirred at 60.degree. C. for 12 h under Ar. The
reaction mixture was poured into cold water (1 L) and crystallized
for 30 min, filtrated to give
2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine as a brown solid.
LCMS: RT 1.268 min, m/z=206.0 [M+H].sup.+.
2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3--
d]pyrimidine
[0848] To a solution of
2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (2.17 g, 10.53
mmol) in DMF (22 mL) was added NaH (843 mg, 21.06 mmol, 60% purity)
at 0.degree. C., then the mixture was warmed to 25.degree. C. and
stirred for 30 min. A solution of SEMCl (1.84 g, 11.06 mmol, 1.96
mL) in DMF (10 mL) was added dropwise to the mixture and stirred
continuously for 3 h. The reaction mixture was quenched by pouring
into ice water (150 mL). The resulting aqueous layer was extracted
with EtOAc (3.times.100 mL). The combined organics were washed with
brine (two times) and dried over Na.sub.2SO.sub.4, concentrated
under reduced pressure to give a residue, which was purified with a
short silica gel plug eluting with PE:EtOAc=200:1 to 50:1 to give
2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-
-d]pyrimidine as a yellow oil. .sup.1H NMR (400 MHz, CHLOROFORM-d):
.delta.7.17 (d, J=2.8 Hz, 1H), 5.61 (s, 2H), 3.50-3.63 (m, 2H),
0.94-1.01 (m, 2H), -0.02-0.03 (m, 9H).
2-[(2-chloro-4-cyclopropyl-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]e-
thyl-trimethyl-silane
[0849] To a mixture of
2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-
-d]pyrimidine (2.9 g, 8.62 mmol) and cyclopropylboronic acid (1.26
g, 14.65 mmol) in 1,4-dioxane (40 mL) was added Ag.sub.2O (999 mg,
4.31 mmol), Pd(dppf)Cl.sub.2 (631 mg, 862 umol) and K.sub.3PO.sub.4
(5.49 g, 25.86 mmol) at 20.degree. C. under N.sub.2. The mixture
was stirred at 90.degree. C. for 4.5 h, then cooled to 20.degree.
C. and poured into ice-water (80 mL). The aqueous phase was
extracted with EtOAc (40 mL.times.3). The combined organic phase
was washed with brine (40 mL.times.3), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(PE:EtOAc=30:1) to give
2-[(2-chloro-4-cyclopropyl-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]-
ethyl-trimethyl-silane as a yellow solid. LCMS: RT 1.006 min,
m/z=342.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
6.99 (d, J=2.51 Hz, 1H), 5.53 (s, 2H), 3.48-3.54 (m, 2H), 2.48-2.56
(m, 1H), 1.40-1.44 (m, 2H), 1.19-1.25 (m, 2H), 0.90-0.94 (m, 2H),
-0.03 (s, 9H).
2-[4-[[4-cyclopropyl-5-fluoro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3--
d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0850] A mixture of
2-[(2-chloro-4-cyclopropyl-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]-
ethyl-trimethyl-silane (200 mg, 585 umol),
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (134 mg,
819.00 .mu.mol), Pd.sub.2(dba).sub.3 (54 mg, 58.50 .mu.mol), XPhos
(56 mg, 117 .mu.mol) and Cs.sub.2CO.sub.3 (477 mg, 1.46 mmol) in
1,4-dioxane (15 mL) was degassed and purged with N.sub.2 for 3
times, then the mixture was stirred at 110.degree. C. for 16 h
under N.sub.2. The mixture was cooled to 20.degree. C. and poured
into ice-water (30 mL). The aqueous phase was extracted with EtOAc
(3.times.15 mL). The combined organic phase was washed with brine
(15 mL.times.3), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by prep-TLC (SiO.sub.2, PE:EtOAc=3:1) to give
2-[4-[[4-cyclopropyl-5-fluoro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-
-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
as a yellow oil. LCMS: RT 1.005 min, m, =470.3 [M+H].sup.+.
2-[4-[(4-cyclopropyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-met-
hyl-pyrazol-1-yl]-2-methyl-propanenitrile
[0851] To a solution of
2-[4-[[4-cyclopropyl-5-fluoro-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-
-d]pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-propanenitrile
(169 mg, 359.86 .mu.mol) in DCM (20 mL) was added SnCl.sub.4 (1.22
g, 4.68 mmol, 546.53 uL) at 0.degree. C. under N.sub.2. The mixture
was stirred at 20.degree. C. for 4 h, poured into ice-water (10
mL). The mixture was neutralized with aq. NaHCO.sub.3 (21.6 g,
257.11 mmol, 10 mL) to pH=8. The mixture was extracted with EtOAc
(3.times.10 mL). The combined organic phase was washed with brine
(10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. To a solution of the residue
in THF (20 mL) and Water (4 mL) was added K.sub.2CO.sub.3 (3.00 g,
21.71 mmol), and the mixture stirred at 20.degree. C. for 16 h. The
reaction mixture was poured into ice-water (10 mL) and extracted
with EtOAc (3.times.10 mL). The combined organic phase was washed
with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by prep-HPLC (neutral condition) to give
2-[4-[(4-cyclopropyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-3-me-
thyl-pyrazol-1-yl]-2-methyl-propanenitrile. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.26-8.32 (m, 1H), 8.18 (s, 1H), 6.58 (t,
J=2.45 Hz, 1H), 6.38 (s, 1H), 2.44-2.53 (m, 1H), 2.29 (s, 3H), 1.97
(s, 6H), 1.31-1.36 (m, 2H), 1.11-1.18 (m, 2H). HPLC: RT: 2.731 min.
MS: m/z=340.2 [M+H].sup.+.
Example C-15 and C-16
Synthesis of
4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo-
[2,3-d]pyrimidine-5-carbonitrile (C-15) and
4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo-
[2,3-d]pyrimidine-5-carbonitrile (C-16)
2,4-dichloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrro-
lo[2,3-d]pyrimidine
[0852] To a solution of
2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 22.5 mmol)
in THF (400 mL) was added LDA (113 mL, 0.23 mol, 2M) at -78.degree.
C., the mixture was stirred at -20.degree. C. for 2 h. Then
re-cooled to -78.degree. C., to the reaction solution was added
CH.sub.3I (32 g, 225.1 mmol, 14 mL), then the mixture stirred at
-20.degree. C. for 2 h. The reaction mixture was quenched with sat.
NH.sub.4Cl (300 mL), and extracted with EtOAc (3.times.300 mL). The
combined organic phase was washed with brine (3.times.200 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a residue, which was purified by
silica gel column chromatography (PE:EtOAc=10:1) to give
2,4-dichloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrr-
olo[2,3-d]pyrimidine as a yellow solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d: .delta. 5.59-5.67 (m, 2H), 3.47-3.56 (m, 2H), 2.57
(s, 3H), 0.89-0.96 (m, 2H), -0.03 (s, 9H).
2,4-dichloro-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3--
d]pyrimidine-5-carbonitrile
[0853] To a solution of
2,4-dichloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrr-
olo[2,3-d]pyrimidine (5 g, 10.9 mmol) in NMP (50 mL) was added CuCN
(1.95 g, 21.8 mmol) at 25.degree. C. under N.sub.2. The reaction
mixture was heated to 120.degree. C. and stirred for 12 h. Then the
reaction was poured into ice-water (200 mL), and extracted with
EtOAc (3.times.200 mL). The combined organic phase was washed with
brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (PE:EtOAc=10:1) to give
2,4-dichloro-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-
-d]pyrimidine-5-carbonitrile as a yellow oil. LCMS: RT 1.006 min,
m/z=357.2 [M+H].sup.+.
2-chloro-4-cyclopropyl-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-py-
rrolo[2,3-d]pyrimidine-5-carbonitrile
[0854] To a solution of
2,4-dichloro-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-
-d]pyrimidine-5-carbonitrile (300 mg, 0.84 mmol) and
cyclopropylboronic acid (87 mg, 1.01 mmol) in dioxane (2 mL) was
added K.sub.3PO.sub.4 (535 mg, 2.52 mmol), Ag.sub.2O (98 mg, 0.42
mmol) and Pd(dppf)Cl.sub.2 (61 mg, 84 umol) under N.sub.2. The
reaction mixture was stirred at 90.degree. C. for 12 h. The mixture
was cooled to 20.degree. C. and poured into ice-water (w/w=1/1) (2
mL). The aqueous phase was extracted with EtOAc (3.times.2 mL). The
combined organic phase was washed with brine (2 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give a residue, which was purified by silica gel column
chromatography (PE:EtOAc=1:1) to give
2-chloro-4-cyclopropyl-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-p-
yrrolo[2,3-d]pyrimidine-5-carbonitrile as a brown oil. LCMS: RT
1.05 min, m/z=363.1 [M+H].sup.+.
4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(trim-
ethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
and
4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(tri-
methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
[0855] To a solution of
2-chloro-4-cyclopropyl-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-p-
yrrolo[2,3-d]pyrimidine-5-carbonitrile (200 mg, 0.55 mmol) in 1,
4-dioxane (4 mL) was added a mixture of
1,3-dimethyl-1H-pyrazol-4-amine and 1,5-dimethyl-1H-pyrazol-4-amine
(49 mg, 0.44 mmol), Cs.sub.2CO.sub.3 (450 mg, 1.38 mmol), XPhos (53
mg, 0.11 umol) and Pd.sub.2(dba).sub.3 (51 mg, 55 umol) under
N.sub.2, then the mixture was stirred at 110.degree. C. for 12 h.
The reaction mixture was concentrated under reduced pressure to
give residue, which was purified by prep-TLC (SiO.sub.2,
PE:EtOAc=1:1) to give a mixture of compound
4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(tri-
methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
and
4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(tri-
methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
as a yellow oil. MS: m/z=438.2 [M+H].sup.+.
4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[-
2,3-d]pyrimidine-5-carbonitrile and
4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo-
[2,3-d]pyrimidine-5-carbonitrile
[0856] To a solution of mixture of
4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(tri-
methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
and
4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7-((2-(tri-
methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile
(70 mg, 0.16 mmol) in DCM (4 mL) was added TFA (365 mg, 0.24 mL,
3.2 mmol) at 0.degree. C., then the mixture was stirred at
40.degree. C. for 24 h. The reaction mixture was concentrated under
reduced pressure to give a yellow oil. LCMS: RT 1.075 min,
m/z=338.2 [M+H].sup.+. To a solution of this crude material in THF
(4 mL) and water (4 mL) was added K.sub.2CO.sub.3 (225 mg, 1.63
mmol) at 20.degree. C. Then the mixture was stirred at 50.degree.
C. for 4 h. The mixture was concentrated under reduced pressure to
give a residue, which was purified by prep-HPLC (FA) to give
4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo-
[2,3-d]pyrimidine-5-carbonitrile and
4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo-
[2,3-d]pyrimidine-5-carbonitrile.
4-cyclopropyl-2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[-
2,3-d]pyrimidine-5-carbonitrile
[0857] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.23 (br. s.,
1H), 8.25 (s, 1H), 7.69 (s, 1H), 3.68-3.73 (m, 3H), 2.43 (s, 4H),
2.05 (s, 3H), 1.16 (d, J=4.0 Hz, 2H), 1.06-1.12 (m, 2H). HPLC: RT:
2.34 min. MS: m/z: 308.1 [M+H].sup.+.
4-cyclopropyl-2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-6-methyl-7H-pyrrolo[-
2,3-d]pyrimidine-5-carbonitrile
[0858] .sup.1H NMR (400 MHz, DMSO-d6): .delta. 12.19 (br. s., 1H),
8.21 (s, 1H), 7.42 (s, 1H), 3.68 (s, 3H), 2.42 (s, 4H), 2.11 (s,
3H), 1.13 (br. s., 2H), 1.09 (d, J=7.94 Hz, 2H). HPLC: RT: 2.25
min. MS: m/z: 308.2 [M+H].sup.+.
Example C-17
Synthesis of
7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-ami-
ne (C-17)
4-chloropyridine-2,3-diamine
[0859] To a solution of 4-chloropyridine-2,3-diamine (6 g, 34.57
mmol) in i-PrOH (60 mL) and H.sub.2O (15 mL) was added Fe (9.65 g,
172.85 mmol) and NH.sub.4Cl (9.25 g, 172.85 mmol). The mixture was
stirred at 80.degree. C. for 2 h. The reaction mixture was filtered
and to the filtrate was added H.sub.2O (100 mL) at 0.degree. C.
Then it was extracted with DCM/i-PrOH (60 mL.times.4). The combined
organic layers were washed with brine (60 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give 4-chloropyridine-2,3-diamine as a dark brown solid. LCMS:
RT 0.107 min, m/z=144.1 [M+H].sup.+.
7-chloro-3H-imidazo[4,5-b]pyridine
[0860] A solution of 4-chloropyridine-2,3-diamine (I g, 6.97 mmol)
in CH(OEt).sub.3 (20 mL) and HCOOH (0.5 mL) was degassed and purged
with N.sub.2 for 3 times, and then the mixture was stirred at
100.degree. C. for 3 h under N.sub.2. The reaction mixture was
concentrated under reduced pressure. The residue was diluted with
water (20 mL) and extracted with DCM/i-PrOH (20 mL.times.3). The
combined organic layers were washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give 7-chloro-3H-imidazo[4,5-b]pyridine as a dark brown solid.
LCMS: RT 0.140 min, m/z=154.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 13.43 (br. s, 1H), 8.52 (d, J=5.14 Hz, 1H), 8.29
(d, J=5.14 Hz, 1H), 7.39 (d, J=5.15 Hz, 1H).
7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine
[0861] To a solution of 7-chloro-3H-imidazo[4,5-b]pyridine (1 g,
6.51 mmol) in DMF (10 mL) was added NaH (312 mg, 7.81 mmol, 60%
purity) in three portions at 0.degree. C. The mixture was stirred
at 20.degree. C. for 1 h. SEM-Cl (1.3 g, 7.81 mmol, 1.39 mL) was
added at 0.degree. C. and the mixture was stirred at 20.degree. C.
for 1 h. The reaction mixture was quenched by addition of water (60
mL) at 0.degree. C., and then extracted with EtOAc (30 mL.times.3).
The combined organic layers were washed with brine (20 mL.times.3),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give a residue, which was purified by silica
gel column chromatography (PE:EtOAc=6:1) to give
7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine
as a yellow oil. LCMS: RT 0.901 min, m/z=284.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, CDCl3): .delta. 8.32 (d, J=5.27 Hz, 1H), 8.24 (s,
1H), 7.32 (d, J=5.27 Hz, 1H), 5.69 (s, 2H), 3.58-3.66 (m, 2H),
0.91-0.96 (m, 2H), -0.04 (s, 9H).
7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridi-
ne
[0862] A mixture of cyclopropylboronic acid (181 mg, 2.12 mmol),
7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine
(400 mg, 1.41 mmol), Cs.sub.2CO.sub.3 (918 mg, 2.82 mmol),
Pd.sub.2(dba).sub.3 (64 mg, 70.5 umol) and DavePhos (55 mg, 141
umol) in toluene (20 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 120.degree. C. for 3 h
under N.sub.2. The reaction mixture was concentrated under reduced
pressure to give a residue, which was purified by silica gel column
chromatography (PE:EtOAc=8:1) to give
7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyrid-
ine. LCMS: RT 0.835 min, m/z=290.1 [M+H].sup.+.
7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridi-
ne 4-oxide
[0863] To a solution of
7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyrid-
ine (6.7 g, 23.15 mmol) in CHCl.sub.3 (70 mL) was added m-CPBA (9.4
g, 46.3 mmol, 85% purity). The mixture was stirred at 75.degree. C.
for 16 h. The reaction mixture was quenched by addition of H.sub.2O
(120 mL) and Na.sub.2S.sub.2O.sub.3 (12 g) at 0.degree. C., and
then extracted with DCM (50 mL.times.3). The combined organic
layers were washed with saturated NaHCO.sub.3 solution (60 mL) and
brine (60 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give a residue, which was
purified by silica gel column chromatography (DCM:MeOH=10:1) to
give
7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyrid-
ine 4-oxide as a dark brown gum. LCMS: RT 0.765 min, m/z=306.2
[M+H].sup.+
5-chloro-7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-
-b]pyridine (Intermediate 15)
[0864] To a solution of
7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyrid-
ine 4-oxide (3 g, 9.82 mmol) in DMF (30 mL) was added MsCl (4.50 g,
39.29 mmol, 3.04 mL). The mixture was stirred at 80.degree. C. for
20 min. The reaction mixture was quenched by addition of H.sub.2O
(180 mL) at 0.degree. C., alkalified with aq. NaHCO.sub.3 to pH=8
and extracted with EtOAc (60 mL.times.3). The combined organic
layers were washed with brine (3.times.30 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give
5-chloro-7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,-
5-b]pyridine. LCMS: RT 0.953 min, m/z=324.1[M+H].sup.+.
7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3-((2-(trimethylsilyl)ethoxy)me-
thyl)-3H-imidazo[4,5-b]pyridin-5-amine
[0865] A mixture of
5-chloro-7-cyclopropyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,-
5-b]pyridine (170 mg, 524.87 umol), 1-methylpyrazol-3-amine (102
mg, 1.05 mmol), Cs.sub.2CO.sub.3 (427 mg, 1.31 mmol),
Pd.sub.2(dba).sub.3 (48 mg, 52.49 umol) and XPhos (50 mg, 104.97
umol) in 1,4-dioxane (4 mL) was degassed and purged with N.sub.2
for 3 times, and then the mixture was stirred at 110.degree. C. for
16 h under N.sub.2. The reaction mixture was concentrated under
reduced pressure. The residue was diluted with H.sub.2O (20 mL) and
extracted with DCM (3.times.10 mL). The combined organic layers
were washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue,
which was purified by prep-TLC (SiO.sub.2, EtOAc) to give
7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3-((2-(trimethylsilyl)ethoxy)m-
ethyl)-3H-imidazo[4,5-b]pyridin-5-amine as a yellow gum. LCMS: RT
0.832 min, m/z=385.3 [M+H].sup.+.
7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amin-
e)
[0866] To a solution of
7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3-((2-(trimethylsilyl)ethoxy)m-
ethyl)-3H-imidazo[4,5-b]pyridin-5-amine (80 mg, 208.04 umol) in DCM
(9 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL). The mixture was
stirred at 40.degree. C. for 6 h. The reaction mixture was
concentrated under reduced pressure to get a residue, which was
purified by prep-HPLC (neutral condition) to give
7-cyclopropyl-N-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-ami-
ne. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.89 (s, 1H), 7.33
(d, J=2.26 Hz, 1H), 6.62 (s, 1H), 6.27 (d, J=2.26 Hz, 1H), 3.94 (s,
3H), 2.44-2.54 (m, 1H), 1.15-1.20 (m, 4H). HPLC: RT: 2.65 min. MS:
m/z: 255.1 [M+H].sup.+.
Example C-18 and C-19
Synthesis of
4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimi-
dine-5-carbonitrile (C-18) and
4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimi-
dine-5-carbonitrile (C-19)
4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilylethox-
ymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile and
4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilyletho-
xymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile
[0867] To a mixture of
2-chloro-4-cyclopropyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyri-
midine-5-carbonitrile (400 mg, 1.15 mmol) and
1,3-dimethyl-1H-pyrazol-4-amine and 1,5-dimethyl-1H-pyrazol-4-amine
(217 mg, 1.95 mmol, mixture) in 1,4-dioxane (15 mL) was added
Pd.sub.2(dba).sub.3 (105 mg, 115 umol) in one portion at 20.degree.
C. under N.sub.2. The mixture was heated to 110.degree. C. and
stirred for 16 h, cooled to 20.degree. C. and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=1:1) to afford
4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilyletho-
xymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile and
4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilyletho-
xymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile as a yellow oil.
LCMS: RT 1.589 min, m/z=424.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.81 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.52
(s, 1H), 5.51 (s, 1H), 5.46 (s, 2H), 3.86 (s, 2H), 3.79-3.83 (m,
3H), 3.54 (dt, J=12.05, 8.22 Hz, 4H), 2.63-2.74 (m, 2H), 2.27 (s,
2H), 2.22 (s, 3H), 1.13-1.22 (m, 4H), 0.91 (dt, J=11.45, 8.27 Hz,
4H), -0.05 (s, 9H).
4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimid-
ine-5-carbonitrile and
4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimi-
dine-5-carbonitrile
[0868] To a solution of
4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilyletho-
xymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile (297 mg, 701.15
umol, mixture) and
4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7-(2-trimethylsilyletho-
xymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonitrile in DCM (20 mL) was
added TFA (6.16 g, 54.03 mmol, 4 mL) in one portion at 0.degree. C.
under N.sub.2. The mixture was stirred at 20.degree. C. for 8 h.
The mixture was concentrated under reduced pressure. The residue in
THF (10 mL) was added with aq. NaHCO.sub.3 (12.96 g, 154.27 mmol, 6
mL). The mixture was stirred at 20.degree. C. for 16 h, and poured
into ice-water (10 mL) and extracted with EtOAc (3.times.8 mL). The
combined organic phase was washed with brine (3.times.8 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by prep-HPLC (FA
condition) to provide
4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimi-
dine-5-carbonitrile was as a white solid and
4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimi-
dine-5-carbonitrile.
4-cyclopropyl-2-[(1,5-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimid-
ine-5-carbonitrile
[0869] .sup.1H NMR (400 MHz, DMSO): .delta. 12.29 (br. s., 1H),
8.30 (s, 1H), 8.01 (s, 1H), 7.44 (s, 1H), 3.69 (s, 3H), 2.12 (s,
3H), 1.10-1.20 (m, 4H). HPLC: RT: 2.17 min. MS: m/z=294.2
[M+H].sup.+.
4-cyclopropyl-2-[(1,3-dimethylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimid-
ine-5-carbonitrile
[0870] .sup.1H NMR (400 MHz, DMSO): .delta. 12.31 (br. s., 1H),
8.34 (s, 1H), 8.03 (s, 1H), 7.72 (s, 1H), 3.72 (s, 3H), 2.07 (s,
3H), 1.20 (br. s., 2H), 1.14 (d, J=7.40 Hz, 2H). HPLC: RT: 2.20
min. MS: m/z=294.2 [M+H].sup.+.
Example C-20
Synthesis of
4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonitrile (C-20)
4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine
[0871] To a solution of 4-chloro-7-azaindole (20 g, 131.08 mmol) in
AcOH (200 mL) was added NIS (30.96 g, 137.63 mmol) in portions at
0.degree. C. under N.sub.2. The mixture was stirred at 20.degree.
C. for 16 h. The reaction mixture was diluted with water (500 mL)
and extracted with DCM (3.times.400 mL). The combined organic
layers were washed with saturated aq. NaHCO.sub.3 (300 mL) and
brine (400 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give
4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine as a black brown solid
crude material. LCMS: RT 0.83 min, m/z=279.0 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 12.53 (br. s., 1H), 8.18 (d, J=5.14
Hz, 1H), 7.79 (d, J=2.13 Hz, 1H), 7.18 (d, J=5.02 Hz, 1H).
4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyri-
dine
[0872] To a mixture of 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine
(50 g, 179.55 mmol) in DMF (500 mL) was added NaH (8.62 g, 215.46
mmol, 60% purity) in portions at 0.degree. C. under N.sub.2. The
mixture was stirred at 20.degree. C. for 1 h. Then SEM-Cl (35.92 g,
215.46 mmol) was added to the mixture and stirred at 20.degree. C.
for 2 h. The mixture was poured into ice-water (1000 mL) and
stirred for 5 min. The aqueous phase was extracted with ethyl
acetate (3.times.500 mL). The combined organic phase was washed
with brine (3-500 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue,
which was purified by silica gel column chromatography
(PE:EtOAc=20:1) to give
4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyr-
idine as a black brown solid.
4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3--
carbonitrile
[0873] A mixture of
4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyr-
idine (3 g, 7.34 mmol) and CuCN (1.31 g, 14.68 mmol) in NMP (20 mL)
was degassed and purged with N.sub.2 for 3 times, and then the
mixture was stirred at 120.degree. C. for 4.5 h under N.sub.2
atmosphere. The mixture was cooled to 20.degree. C. and poured into
ice-water (20 mL). The aqueous phase was extracted with ethyl
acetate (3.times.15 mL). The combined organic phase was washed with
brine (3.times.15 mL), dried with anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give a residue, which was purified by
silica gel column chromatography (PE:EtOAc=15:1) to afford
4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonitrile as a yellow solid. LCMS: RT 0.938 min,
m/z=308.1 [M+H].sup.+.
4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridi-
ne-3-carbonitrile
[0874] A mixture of
4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-
-carbonitrile (1.03 g, 3.35 mmol), cyclopropylboronic acid (575 mg,
6.70 mmol), Pd.sub.2(dba).sub.3 (460 mg, 502.50 umol),
Cs.sub.2CO.sub.3 (2.18 g, 6.70 mmol) and DavePhos (132 mg, 335
umol) in toluene (15 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 120.degree. C. for 8 h
under N.sub.2. The mixture was concentrated under reduced pressure
to give a residue, which was purified by silica gel column
chromatography (PE:EtOAc=30:1) to give
4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonitrile as a yellow solid. LCMS: RT 0.937 min, m/z=314.2
[M+H].sup.+.
3-cyano-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3--
b]pyridine 7-oxide
[0875] To a solution of
4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyrid-
ine-3-carbonitrile (3.3 g, 10.53 mmol) in CHCl.sub.3 (40 mL) was
added m-CPBA (6.41 g, 31.59 mmol, 85% purity). The mixture was
stirred at 75.degree. C. for 16 h. The reaction mixture was
quenched by addition of water (150 mL) and Na.sub.2S.sub.2O.sub.3
(8 g) at 0.degree. C., and then extracted with DCM (3.times.50 mL).
The combined organic layers were washed with saturated NaHCO.sub.3
solution (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give a residue,
which was purified by silica gel column chromatography
(DCM:MeOH=10:1) to give
3-cyano-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-
-b]pyridine 7-oxide as a white solid. LCMS: RT 1.015 min, m/z=330.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.09 (d,
J=6.53 Hz, 1H), 7.87 (s, 1H), 6.67 (d. J=6.53 Hz, 1H), 6.35 (s,
2H), 3.65-3.73 (m, 2H), 2.57-2.68 (m, 1H), 1.23-1.28 (m, 2H),
0.93-0.98 (m, 2H), 0.87-0.92 (m, 2H), -0.02 (s, 9H).
6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-
-b]pyridine-3-carbonitrile
[0876] To a solution of
3-cyano-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-
-b]pyridine 7-oxide (1.78 g, 5.40 mmol) in DMF (18 mL) was added
MsCl (2.47 g, 21.60 mmol) and the mixture was stirred at 80.degree.
C. for 20 min. The reaction mixture was quenched by addition
H.sub.2O (120 mL) at 0.degree. C. and treated with saturated aq.
NaHCO.sub.3 solution to pH=8 and extracted with EtOAc (3.times.40
mL). The combined organic layers were washed with brine (3.times.30
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give
6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,-
3-b]pyridine-3-carbonitrile as a black brown gum. LCMS: RT 1.004
min, m/z=348.1 [M+H].sup.+.
3-iodo-1,4-dimethyl-pyrazole
[0877] To a solution of 1,4-dimethyl-pyrazole (10 g, 104.03 mmol)
in DMF (150 mL) was added NIS (21.06 g, 93.63 mmol) in one portion
at 25.degree. C. under N.sub.2. The mixture was stirred at
60.degree. C. for 12 h. The mixture was poured into ice-water (300
mL) and stirred for 5 min. The aqueous phase was extracted with
MTBE (3.times.300 mL). The combined organic phase was washed with
brine (3.times.200 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=10:1-1:1) to
give 3-iodo-1,4-dimethyl-pyrazole as a brown solid. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. ppm 7.05 (s, 1H), 3.86 (s, 3H), 1.98
(s, 3H).
Tert-butyl N-(1,4-dimethylpyrazol-3-yl)carbamate
[0878] A mixture of 3-iodo-1,4-dimethyl-pyrazole (5 g, 22.52 mmol),
tert-butyl carbamate (3.43 g, 29.28 mmol), CuI (2.14 g, 11.26
mmol), K.sub.2CO.sub.3 (6.22 g, 45.04 mmol) and
(1S,2S)--N1,N2-dimethylcyclohexane-1,2-diamine (1.6 g, 11.26 mmol)
in 1,4-dioxane (60 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture solution was stirred at 110.degree. C.
for 12 h under N.sub.2. To the reaction solution was added water
(80 mL), extracted with EtOAc (30 mL.times.3), organic layers were
combined, washed with brine (30 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=5:1 to 3:1)
to give tert-butyl N-(1,4-dimethylpyrazol-3-yl)carbamate as a light
brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 7.06
(s, 1H), 6.44 (br. s., 1H), 3.71-3.81 (m, 3H), 1.98 (s, 3H), 1.48
(s, 9H).
1,4-dimethylpyrazol-3-amine
[0879] To a mixture of tert-butyl
N-(1,4-dimethylpyrazol-3-yl)carbamate (700 mg, 3.31 mmol) in
1,4-dioxane (10 mL) was added HCl/dioxane (15 mL) at 20.degree. C.
The mixture was stirred at 20.degree. C. for 5 h. The mixture was
concentrated under reduced pressure to give
1,4-dimethylpyrazol-3-amine (HCl salt) as a brown oil. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 10.21 (br. s., 2H), 7.58 (s,
1H), 3.74 (s, 3H), 3.39 (s, 1H), 1.98 (s, 3H).
4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsily-
l)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile
[0880] A mixture of
6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,-
3-b]pyridine-3-carbonitrile (250 mg, 718.56 umol),
1,4-dimethylpyrazol-3-amine (160 mg, 1.44 mmol), Cs.sub.2CO.sub.3
(1.05 g, 3.23 mmol), Pd.sub.2(dba).sub.3 (66 mg, 71.86 umol) and
XPhos (68 mg, 143.71 umol) in 1,4-dioxane (6 mL) was degassed and
purged with N.sub.2 for 3 times, and then the mixture was stirred
at 110.degree. C. for 16 h under N.sub.2. The reaction mixture was
concentrated under reduced pressure. The residue was diluted with
H.sub.2O (60 mL) and extracted with EtOAc (3.times.20 mL). The
combined organic layers were washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue, which was purified by prep-TLC (SiO.sub.2,
PE:EtOAc=1:1) to give
4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsil-
yl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile as a
yellow gum. LCMS: RT 0.902 min, m/z=423.3 [M+H].sup.+. .sup.1H NMR
(400 MHz, CDCl3): .delta. ppm 7.59 (s, 1H), 7.12 (s, 1H), 6.69 (s,
1H), 6.33 (s, 1H), 5.54 (s, 2H), 3.82 (s, 3H), 3.53-3.58 (m, 2H),
2.52-2.64 (m, 1H), 1.96 (s, 3H), 1.14 (dd, J=8.34, 2.07 Hz, 2H),
0.90-0.95 (m, 2H), 0.86 (dd, J=4.77, 1.63 Hz, 2H), -0.03 (s,
9H).
4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonitrile
[0881] To a solution of
4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsil-
yl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (210 mg,
496.92 umol) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3
mL). The mixture was stirred at 40.degree. C. for 6 h and
concentrated under reduced pressure to get a residue.
K.sub.2CO.sub.3 (15 g, 108.53 mmol) was added to the residue in THF
(12 mL) and water (12 mL). The mixture was stirred at 40.degree. C.
for 16 h. The mixture was poured into ice-water (30 mL) and
extracted with EtOAc (10 mL.times.3). The combined organic phase
was washed with brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was triturated with CH.sub.3CN to give
4-cyclopropyl-6-((1,4-dimethyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonitrile. .sup.1H NMR (400 MHz, MeOD): .delta. 7.70
(s, 1H), 7.33 (s, 1H), 6.35 (s, 1H) 3.78 (s, 3H), 2.47-2.55 (m,
1H), 1.92 (s, 3H), 1.09-1.15 (m, 2H), 0.79-0.85 (m, 2H). HPLC: RT
2.22 min. MS: m/s: 293.1 [M+H].sup.+.
Example C-21
Synthesis of
4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridi-
ne-3-carbonitrile (C-21)
4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsilyl)et-
hoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile
[0882] A mixture of
6-chloro-4-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,-
3-b]pyridine-3-carbonitrile (250 mg, 718.56 umol),
1-methylpyrazol-3-amine (70 mg, 718.56 umol), Cs.sub.2CO3 (585 mg,
1.80 mmol), Pd.sub.2(dba).sub.3 (66 mg, 71.86 umol) and XPhos (68
mg, 143.71 umol) in 1,4-dioxane (4 mL) was degassed and purged with
N.sub.2 for 3 times, and then the mixture was stirred at
110.degree. C. for 16 h under N.sub.2. The reaction mixture was
concentrated under reduced pressure. The residue was diluted with
H.sub.2O (20 mL) and extracted with DCM (3.times.10 mL). The
combined organic layers were washed with brine (10 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give a residue, which was purified by prep-TLC (SiO.sub.2,
PE:EtOAc=1:1). LCMS: RT 0.974 min, m/z=409.3 [M+H].sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.60 (s, 1H), 6.92 (s, 1H), 6.51
(d, J=1.76 Hz, 1H), 6.39 (s, 1H), 5.58 (s, 2H), 3.83 (s, 3H),
3.53-3.60 (m, 2H), 2.53-2.61 (m, 1H), 1.17 (dd, J=8.16, 1.98 Hz,
2H), 0.90-0.94 (m, 2H), 0.87 (dd, J=4.85, 1.76 Hz, 2H), -0.06 (s,
9H).
4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonitrile
[0883] To a solution of
4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (200 mg,
489.51 umol) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3
mL). The mixture was stirred at 40.degree. C. for 4 h. The mixture
was concentrated under reduced pressure to give a residue.
K.sub.2CO.sub.3 (15 g, 108.53 mmol) was added to the residue in THF
(10 mL) and water (10 mL) and stirred at 40.degree. C. for 16 h.
The mixture was poured into ice-water (30 mL) and extracted with
EtOAc (10 mL.times.3). The combined organic phase was washed with
brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral condition) to give
4-cyclopropyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridi-
ne-3-carbonitrile. .sup.1H NMR (400 MHz, DMSO-d6): .delta. 9.14 (s,
1H), 7.95 (s, 1H), 7.50 (d, J=2.13 Hz, 1H), 6.56 (d, J=2.13 Hz,
1H), 6.53 (s, 1H), 3.72 (s, 3H), 2.37-2.44 (m, 1H) 1.06-1.14 (m,
2H), 0.77 (dd, J=4.89, 2.01 Hz, 2H). HPLC: RT: 2.12 min. MS:
m/z=279.1 [M+H].sup.+.
[0884] The following compounds were prepared according to the
Examples above and/or general procedures described herein.
TABLE-US-00008 No. [M + H].sup.+ C-22 356.1 C-23 322.2 C-24 269.1
C-25 269.1 C-26 403.2 C-27 378.2 C-28 412.2 C-29 396.2 C-30 333.2
C-31 333.2 C-32 367.1 C-33 284.1 C-34 284.1 C-35 269.1 C-36 310.2
C-37 378.2 C-38 330.1 C-39 330.1 C-40 330.1 C-41 362.2 C-42 390.1
C-43 360.1 C-44 360.2 C-45 334.1 = [M - H].sup.- C-46 336.2 C-52
310.1 C-53 319.1 C-54 319.1 C-55 367.1
D: Compound Preparation
[0885] In the following examples, all non-aqueous reactions were
carried out in oven-dried or flame-dried glassware under nitrogen
atmosphere. All chemicals were purchased from commercial vendors
and used as is, unless otherwise specified. Reactions were
magnetically stirred and monitored by thin layer chromatography
(TLC) with 250 .mu.m pre-coated silica gel plates, visualized
either with UV, or in an iodine chamber. Flash column
chromatography was performed using silica gel (100-200 mesh).
Chemical shifts are reported relative to chloroform (87.26),
methanol (63.31), or DMSO (82.50) for .sup.1H NMR. HPLC analysis
was performed on Shimadzu 20AB HPLC system with a photodiode array
detector and Luna-C18(2) 2.0-50 mm, 5 um column at a flow rate of
1.2 mL/min with a gradient solvent Mobile phase A (MPA,
H.sub.2O+0.037% (v/v) TFA): Mobile phase B (MPB. ACN+0.018% (v/v)
TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92
min, 10% MPB: 5.5 min, 10% MPB). LCMS was detected under 220 and
254 nm or used evaporative light scattering (ELSD) detection as
well as positive electrospray ionization (MS). Semi-preparative
HPLC was performed by either acidic or neutral condition. Acidic:
Luna C18 100.times.30 mm, 5 .mu.m; MPA: HCl/H.sub.2O=0.04%, or
formic acid/H.sub.2O=0.2% (v/v); MPB: ACN. Neutral: Waters Xbridge
150.times.25, 5 .mu.m; MPA: 10 mM NH.sub.4HCO: in H.sub.2O; MPB:
ACN. Gradient for both conditions: 10% of MPB to 80% of MPB within
12 min at a flow rate of 20 mL/min, then 100% MPB over 2 min, 10%
MPB over 2 min, UV detector. SFC analysis was performed on Thar
analytical SFC system with a UV/Vis detector and series of chiral
columns including AD-3, AS-H, OJ-3, OD-3. AY-3 and IC-3,
4.6.times.100 mm, 3 um column at a flow rate of 4 mL/min with a
gradient solvent Mobile phase A (MPA, CO.sub.2): Mobile phase B
(MPB, MeOH+0.05% (v/v) IPAm) (0.01 min, 10% MPB; 3 min, 40% MPB;
3.5 min, 40% MPB; 3.56-5 min, 10% MPB). SFC preparative was
performed on Thar 80 preparative SFC system with a UV/Vis detector
and series of chiral preparative columns including AD-H, AS-H,
OJ-H, OD-H, AY-H and IC-H, 30.times.250 mm, Sum column at a flow
rate of 65 mL/min with a gradient solvent Mobile phase A (MPA,
CO.sub.2): Mobile phase B (MPB, MeOH+0.1% (v/v) NH.sub.3H.sub.2O)
(0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1-10 min, 10%
MPB).
[0886] Compounds were named by using either ChemBioDraw Ultra 13.0
or Chemaxon.
Example D-1
Synthesis of
2-methyl-2-[3-methyl-4-[[4-methylsulfanyl-5-(trifluoromethyl)pyrimidin-2--
yl]amino]pyrazol-1-yl]propanenitrile (D-46)
Methyl 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate
[0887] To a solution of 3-methyl-4-nitro-1H-pyrazole (1-1, 40 g,
314.71 mmol) in DMF (700 mL) was added NaH (18.88 g, 472.06 mmol,
60% purity) at 0.degree. C. over a period of 30 min under N.sub.2.
The reaction was then stirred at 25.degree. C. for 2 h followed by
the addition of methyl 2-bromo-2-methylpropanoate (85.46 g, 472.06
mmol, 61.04 mL) dropwise at 0.degree. C. The reaction mixture was
warmed to 25.degree. C. and stirred at 25.degree. C. for another 16
h. TLC (petroleum ether/ethyl acetate=5:1) showed the starting
material was consumed completely. The reaction was quenched by ice
water slowly and then extracted with EtOAc (3.times.700 mL). The
combined organic phase was washed with brine (3.times.200 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate=30:1-15:1), to yield the desired
product as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.29 (s, 1H), 3.72 (s, 1H), 2.51 (s, 1H), 1.84 (s, 6H).
2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl) propanoic acid
[0888] To a mixture of methyl
2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (69.7 g,
306.75 mmol) in THF (1 L) and H.sub.2O (250 mL) was added LiOH
H.sub.2O (15.45 g, 368.10 mmol) at 25.degree. C. under N.sub.2. The
mixture was then stirred at 25.degree. C. for 16 h. TLC (petroleum
ether/ethyl acetate=5:1) showed the reaction was completed. The
reaction mixture was concentrated in vacuo. The residual aqueous
solution was washed with ethyl acetate (50 mL). The aqueous phase
was then cooled to 0.degree. C., adjusted to approximately pH 1-2,
and filtered to yield the desired product as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 8.65 (s, 1H), 2.48 (s, 1H), 1.83
(s, 6H).
2-Methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide
[0889] To a solution of 2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)
propanoic acid (25 g, 117.27 mmol) in DCM (500 mL) was added 8
drops of DMF, followed by oxalyl chloride (29.77 g, 234.54 mmol) at
0.degree. C. under N.sub.2. The mixture was then stirred at
25.degree. C. for a further 2 h. TLC (petroleum ether/ethyl
acetate=3:1) showed reaction was completed. The reaction solution
was concentrated in vacuo. The residue solid was dissolved in THF
(300 mL) and added dropwise into a stirred solution of NH.sub.4OH
(413.61 g, 11.80 mol, 454.52 mL) at 0.degree. C. The reaction was
stirred at 25.degree. C. for 1 h. TLC (ethyl acetate) showed
reaction was completed. The solution was then concentrated in vacuo
and partitioned between EtOAc (100 mL) and water (100 mL), and the
aqueous phase was extracted with ethyl acetate (3.times.80 mL). The
combined organic phase was washed with brine (3.times.40 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo, to yield the desired compound as a yellow solid. .sup.1H NMR
(400 MHz, MeOD): .delta. 8.81 (s, 1H), 7.16-7.26 (m, 2H), 2.42 (s,
3H), 1.71 (s, 3H).
2-Methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile
[0890] A solution of
2-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)propanamide (22 g, 103.67
mmol) in POCl.sub.3 (132 g, 860.89 mmol, 80 mL) was stirred at
90.degree. C. for 1 h. TLC showed the reaction was completed. The
mixture was cooled to 20.degree. C. and concentrated in vacuo at
50.degree. C. The residue was poured into ice water (w/w=1/1) (200
mL) and stirred for 10 min. The aqueous phase was adjusted to pH=7
with NaHCO.sub.3 solution, extracted with ethyl acetate (4.times.80
mL). The combined organic phase was washed with brine (40 mL),
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The desired product was afforded as a yellow solid.
2-(4-Amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile
[0891] To a mixture of
2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (10 g,
51.5 mmol) in EtOH (240 mL) and H.sub.2O (60 mL) was added
NH.sub.4Cl (13.77 g, 257.5 mmol) in one portion at 25.degree. C.,
followed by Fe (14.38 g, 257.5 mmol). The mixture was heated to
80.degree. C. and stirred for 1 h. TLC showed the reaction was
completed. The solution was cooled to 20.degree. C. The mixture was
extracted with ethyl acetate (3.times.100 mL), the combined organic
layers were washed with NaHCO.sub.3 solution (50 mL) and brine (50
mL). The organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated. The desired product was afforded as a dark brown
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.17 (s, 1H),
2.18 (s, 3H), 1.91 (s, 6H).
2-chloro-4-methylsulfanyl-5-(trifluoromethyl)pyrimidine and
4-chloro-2-methylsulfanyl-5-(trifluoromethyl)pyrimidine
[0892] To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine
(1-6, 1 g, 4.61 mmol) in THF (10 mL) was added a solution of NaSMe
(2.42 g, 6.92 mmol, 2.20 mL) dropwise at -25.degree. C. under
N.sub.2. The reaction mixture was then stirred at -25.degree. C.
for 1 hour followed by stirred at 25.degree. C. for 15 h. The
reaction mixture was diluted with CH.sub.2Cl.sub.2 (20 mL) and
washed with 1 N HCl (3.times.10 mL). The organic phase was dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to
afford a mixture of
2-chloro-4-methylsulfanyl-5-(trifluoromethyl)pyrimidine and
4-chloro-2-methylsulfanyl-5-(trifluoromethyl)pyrimidine as yellow
oil.
2-methyl-2-[3-methyl-4-[[4-methylsulfanyl-5-(trifluoromethyl)pyrimidin-2-y-
l]amino]pyrazol-1-yl]propanenitrile and
2-methyl-2-[3-methyl-4-[[2-methylsulfanyl-5-(trifluoromethyl)pyrimidin-4--
yl]amino]pyrazol-1-yl]propanenitrile
[0893] To a mixture of
2-chloro-4-methylsulfanyl-5-(trifluoromethyl)pyrimidine and
4-chloro-2-methylsulfanyl-5-(trifluoromethyl)pyrimidine (150 mg,
656.12 .mu.mol) in n-BuOH (3 mL) was added
2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (161 mg,
984.18 .mu.mol) and TEA (99 mg, 984.18 .mu.mol) at 25.degree. C.
under N.sub.2. The mixture was then heated under microwave at
120.degree. C. and stirred for 1 h. The mixture was cooled to
25.degree. C. poured into water (10 mL) and extracted with ethyl
acetate (3-10 mL). The combined organic phase was washed with brine
(10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by prep-HPLC (HCl) to give
2-methyl-2-[3-methyl-4-[[4-methylsulfanyl-5-(trifluoromethyl)pyrimidin-2--
yl]amino]pyrazol-1-yl]propanenitrile and
2-methyl-2-[3-methyl-4-[[2-methylsulfanyl-5-(trifluoromethyl)pyrimidin-4--
yl]amino]pyrazol-1-yl]propanenitrile.
2-methyl-2-[3-methyl-4-[[4-methylsulfanyl-5-(trifluoromethyl)pyrimidin-2-y-
l]amino]pyrazol-1-yl]propanenitrile (D-46)
[0894] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.45 (br. s.,
1H), 8.18 (br. s., 2H), 2.68 (br. s., 3H), 2.35 (br. s., 3H),
1.88-2.02 (m, 6H); HPLC: RT 3.48 min; MS: m/z: 357.1
[M+H].sup.+.
2-methyl-2-[3-methyl-4-[[2-methylsulfanyl-5-(trifluoromethyl)pyrimidin-4-y-
l]amino]pyrazol-1-yl]propanenitrile
[0895] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.74 (s, 1H),
8.41 (s, 1H), 8.09 (s, 1H), 2.33 (s, 3H), 2.06 (s, 3H), 1.94 (s,
6H); HPLC: RT 3.19 min: MS: m/z: 357.1 [M+H].sup.+.
Example D-2
Synthesis of
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-ethylsulfan-
yl-pyrimidine-5-carbonitrile (D-47)
2-chloro-4-ethylsulfanyl-pyrimidine-5-carbonitrile and
4-chloro-2-ethylsulfanyl-pyrimidine-5-carbonitrile
[0896] NaH (172 mg, 4.31 mmol, 60%) was added to a solution of EtSH
(178 mg, 2.87 mmol) in dry THF (5 mL) at 0.degree. C. under
N.sub.2. The resulting suspension was slowly added to a solution of
2, 4-dichloropyrimidine-5-carbonitrile (2-1, 500 mg, 2.87 mmol) in
dry THF (10 mL). The reaction was stirred at -20.degree. C. for 1
h. The reaction mixture was quenched by addition of aqueous
NH.sub.4Cl (20 mL) at 0.degree. C., and then extracted with EtOAc
(3.times.20 mL). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to afford a mixture of
2-chloro-4-ethylsulfanyl-pyrimidine-5-carbonitrile and
4-chloro-2-ethylsulfanyl-pyrimidine-5-carbonitrile as yellow oil.
LCMS: RT 0.793 min, m/z=199.9 [M+H].sup.+.
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-ethylsulfany-
l-pyrimidine-5-carbonitrile (47) and
4-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-2-ethylsulfan-
yl-pyrimidine-5-carbonitrile
[0897] To a mixture of
2-chloro-4-ethylsulfanyl-pyrimidine-5-carbonitrile and
4-chloro-2-ethylsulfanyl-pyrimidine-5-carbonitrile (200 mg, 1 mmol)
in n-BuOH (2 mL) was added
2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (246 mg,
1.5 mmol) and TEA (50 mg, 500.85 .mu.mol) at 25.degree. C. under
N.sub.2. The mixture was then heated at 120.degree. C. under
microwave for 1.5 h. The reaction mixture was concentrated under
reduced pressure. The residue was purified by prep-HPLC (neutral)
to give
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-ethylsulfan-
yl-pyrimidine-5-carbonitrile and
4-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-2-ethylsulfan-
yl-pyrimidine-5-carbonitrile.
2-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-4-ethylsulfany-
l-pyrimidine-5-carbonitrile (D-47)
[0898] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.26-8.39 (m,
1H), 8.09-8.18 (m, 1H), 6.75-6.97 (m, 1H), 3.25 (q, J=7.06 Hz, 2H),
2.29 (br. s., 3H), 1.93-2.05 (m, 6H), 1.42 (t, J=7.50 Hz, 3H);
HPLC: RT 2.597 min: MS: m/z: 328.2 [M+H].sup.+.
4-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-2-ethylsulfany-
l-pyrimidine-5-carbonitrile
[0899] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.36 (s, 1H),
8.12 (br. s., 1H), 6.70 (br. s., 1H), 3.11 (q, J=7.35 Hz, 2H), 2.28
(s, 3H), 1.97-2.03 (m, 6H), 1.38 (t, J=7.28 Hz, 3H); HPLC: RT 2.382
min; MS: m/z: 328.2 [M+H].sup.+.
Example D-3
Synthesis of
2-[4-[(5-chloro-4-ethylsulfanyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1--
yl]-2-methyl-propanenitrile (D-44)
2,5-dichloro-4-ethylsulfanyl-pyrimidine
[0900] NaH (654 mg, 16.35 mmol, 60%) was added to a solution of
ethanethiol (677 mg, 10.90 mmol) in dry THF (10 mL) at 0.degree. C.
under N.sub.2. The resulting suspension was slowly added to a
solution of 2,4,5-trichloropyrimidine (2 g, 10.90 mmol) in dry THF
(15 mL) at -20.degree. C. under N.sub.2. The reaction was then
stirred at -20.degree. C. for 1 h. The mixture was poured into
aqueous NH.sub.4Cl (50 mL), extracted with EtOAc (3.times.20 mL).
The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, concentrated to afford
2,5-dichloro-4-ethylsulfanyl-pyrimidine as yellow solid. LCMS: RT
0.876 min, m/z=209.0 [M+H].sup.+.
2-[4-[(5-chloro-4-ethylsulfanyl-pyrimidin-2-yl)amino]-3-methyl-pyrazol-1-y-
l]-2-methyl-propanenitrile (D-44)
[0901] To a mixture of 2,5-dichloro-4-ethylsulfanyl-pyrimidine (200
mg, 956.48 .mu.mol) and
2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (235 mg,
1.43 mmol) in n-BuOH (3 mL) was added TEA (290 mg, 2.87 mmol) at
25.degree. C. under N.sub.2. The mixture was heated under microwave
at 120.degree. C. for 1.5 h. The mixture was cooled to 25.degree.
C. and concentrated under reduced pressure. The residue was
purified by prep-HPLC (neutral) to afford
2-[4-[(5-chloro-4-ethylsulfanyl-pyrimidin-2-yl)amino]-3-methyl-pyr-
azol-1-yl]-2-methyl-propanenitrile (D-44). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.13 (s, 1H), 8.03 (s, 1H), 6.53 (br. s., 1H),
3.20 (q, J=7.50 Hz, 2H), 2.28 (s, 3H), 1.99 (s, 6H), 1.41 (t,
J=7.28 Hz, 3H); HPLC: RT 3.47 min: MS: m/z: 337.1 [M+H].sup.+.
Example D-4
Synthesis of
2-[4-[[4-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl--
pyrazol-1-yl]-2-methyl-propanenitrile (D-45)
2-chloro-4-ethylsulfanyl-5-(trifluoromethyl)pyrimidine and
4-chloro-2-ethylsulfanyl-5-(trifluoromethyl)pyrimidine
[0902] NaH (138 mg, 3.45 mmol, 60%) was added to a solution of
ethanethiol (143 mg, 2.30 mmol, 170.12 .mu.L) in dry THF (5 mL) at
0.degree. C. under N.sub.2. The resulting suspension was slowly
added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine
(500 mg, 2.30 mmol) in dry THF (10 mL) at -20.degree. C. under
N.sub.2. The reaction was then stirred at -20.degree. C. for 1 h.
The mixture was poured into aqueous NH.sub.4Cl (50 mL), extracted
with EtOAc (3-20 mL). The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, concentrated to afford a
mixture of 2-chloro-4-ethylsulfanyl-5-(trifluoromethyl)pyrimidine
and 4-chloro-2-ethylsulfanyl-5-(trifluoromethyl)pyrimidine as
yellow oil.
2-[4-[[4-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-p-
yrazol-1-yl]-2-methyl-propanenitrile (D-45) and
2-[4-[[2-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]-3-methyl--
pyrazol-1-yl]-2-methyl-propanenitrile
[0903] To a mixture of
2-chloro-4-ethylsulfanyl-5-(trifluoromethyl)pyrimidine and
4-chloro-2-ethylsulfanyl-5-(trifluoromethyl)pyrimidine (300 mg,
1.24 mmol) in n-BuOH (3 mL) was added
2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-propanenitrile (305 mg,
1.86 mmol) and TEA (375 mg, 3.71 mmol) at 25.degree. C. under
N.sub.2. The mixture was heated in microwave at 120.degree. C. for
1.5 h. The reaction mixture was concentrated under reduced pressure
to give a residue. The residue was purified by prep-HPLC (neutral)
to give
2-[4-[[4-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl--
pyrazol-1-yl]-2-methyl-propanenitrile (45) and
2-[4-[[2-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]-3-methyl--
pyrazol-1-yl]-2-methyl-propanenitrile.
2-[4-[[4-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-p-
yrazol-1-yl]-2-methyl-propanenitrile (D-45)
[0904] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.31 (br. s.,
1H), 8.12 (s, 1H), 6.73 (br. s., 1H), 3.23 (q, J=7.53 Hz, 2H), 2.29
(s, 3H), 1.95-2.06 (m, 6H), 1.40 (t, J=7.28 Hz, 3H); HPLC: RT 3.60
min: MS: m z: 371.2 [M+H].sup.+.
2-[4-[[2-ethylsulfanyl-5-(trifluoromethyl)pyrimidin-4-yl]amino]-3-methyl-p-
yrazol-1-yl]-2-methyl-propanenitrile
[0905] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.33 (s, 1H),
8.14 (s, 1H), 6.53 (br. s., 1H), 3.10 (q, J=7.20 Hz, 2H), 2.25 (s,
3H), 2.00 (s, 6H), 1.37 (t, J=7.28 Hz, 3H); HPLC: RT 3.30 min; MS:
m/z: 371.2 [M+H].sup.+.
Example D-5
Synthesis of
2-(1-((3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)ami-
no)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile (D-1)
2-(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile
[0906] To a mixture of PPh.sub.3 (2.63 g, 10 mmol) in THF (30 mL)
was added DIAD (2 mL, 10 mmol), 3-methyl-4-nitro-1H-pyrazole (850
mg, 6.7 mmol) and 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile (982
mg, 8 mmol) at 25.degree. C. The mixture was stirred at 25.degree.
C. for 12 h. The reaction mixture was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=50:1 to 5:1) to give
2-(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitr-
ile.
2-(1-((4-amino-3-methyl-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile
[0907] To a mixture of
2-(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile
(400 mg, 1.82 mmol) in EtOH (2 mL) was added Fe (507 mg, 9.08 mmol)
and NH.sub.4Cl (486 mg, 9.08 mmol) in one portion at 25.degree. C.
under N.sub.2. The mixture was heated to 90.degree. C. and stirred
for 1 h. The mixture was concentrated under reduced pressure. The
residue was purified by prep-TLC (SiO.sub.2, PE:EtOAc=1:1) to give
2-(1-((4-amino-3-methyl-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile
as pale yellow oil.
2-(1-((3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amin-
o)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile (D-1)
[0908] To a mixture of
2-(1-((4-amino-3-methyl-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile
(100 mg, 0.53 mmol) and
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (110 mg,
0.53 mmol) in n-BuOH (2 mL) was added TEA (0.2 mL) in one portion
at 25.degree. C. under N.sub.2. The mixture was stirred at
25.degree. C. for 1 h. The reaction mixture was concentrated under
reduced pressure to remove n-BuOH. The residue was purified by
prep-HPLC (neutral) to give
2-(1-((3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)ami-
no)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile (D-1). .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.98-8.27 (m, 1H), 7.90 (d, J=20
Hz, 1H), 4.11 (s, 2H), 3.09 (d, J=16 Hz, 3H), 2.41-2.61 (m, 2H),
2.10-2.32 (m, 3H), 0.89 (br. s., 2H), 0.73 (br. s., 2H); HPLC: RT
1.63 min; MS: m/z: 366.1 [M+H].sup.+.
Example D-6, D-7, and D-8
Synthesis of
N2-[1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-2),
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyrazol-4--
yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (First
eluting stereoisomer, D-3), and
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyrazol-4--
yl]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Second
eluting stereoisomer, D-4)
7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole
and
7-(5-methyl-4-nitro-1H-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imi-
dazole
[0909] To a mixture of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol
(1 g, 8.06 mmol) and 3-methyl-4-nitro-1H-pyrazole (1.13 g, 8.87
mmol) in THF (20 mL) was added PPh.sub.3 (3.17 g, 12.09 mmol) and
then DIAD (2.44 g, 12.09 mmol, 2.4 mL) dropwise at 0.degree. C.
over a period of 30 min under N.sub.2. The mixture was warmed to
20.degree. C. and stirred for 12 h, then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (gradient PE:EtOAc from 10:1 to 0:1) to give the
mixture of
7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole
and
7-(5-methyl-4-nitro-1H-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imi-
dazole as a white solid. LCMS: RT 0.112 min, m/z=234.1
[M+H].sup.+.
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amine
and
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4--
amine
[0910] To a solution of
7-(3-methyl-4-nitro-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole
and
7-(5-methyl-4-nitro-1H-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imi-
dazole (650 mg, 2.79 mmol) in MeOH (20 mL) was added Pd--C (10%,
0.3 g) under N.sub.2. The suspension was degassed under vacuum and
purged with H.sub.2 several times. The mixture was stirred under
H.sub.2 (15 psi) at 20.degree. C. for 4 h, then filtered and
concentrated under reduced pressure, to give the mixture of
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amine
and
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4--
amine as a light yellow solid. LCMS: RT 0.62-0.878 min, m/z=204.2
[M+H].sup.+.
N2-[1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]--
N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-2),
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-3), and
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-4)
[0911] To a solution of the mixture
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amine
and
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4--
amine (220 mg, 1.08 mol) and
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (251.35 mg,
1.19 mol, 1.10 eq) in 1,4-dioxane (2 mL) was added TFA (246 mg,
2.16 mol, 0.16 mL) at 20.degree. C. The mixture was heated to
90.degree. C. and stirred for 1 h. The mixture was cooled to
20.degree. C. and concentrated under reduced pressure. To the
residue was added aq. sat. NaHCO.sub.3, extracted with EtOAc
(3.times.5 mL). The combined organics were washed with brine (5
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
prep-HPLC (neutral) to give
N2-[1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-2) and
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, which was
further purified by chiral SFC to give the corresponding enantiomer
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (First eluting
stereoisomer. D-3) and
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-pyrazol-4-yl]-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Second
eluting stereoisomer, D-4).
N2-[1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-yl]--
N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-2)
[0912] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.09 (s, 1H),
7.76 (br. s., 1H), 7.12 (s, 1H), 6.96 (s, 1H), 6.44 (br. s., 1H),
5.55-5.66 (m, 1H), 5.13 (br. s., 1H), 4.39-4.51 (m, 1H), 4.10 (t,
J=11.04 Hz, 1H), 3.08-3.26 (m, 2H), 3.00 (d, J=4.52 Hz, 3H), 2.40
(s, 3H); HPLC: RT: 1.703 min; MS: m/z: 379.1 [M+H].sup.+.
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyrazol-4-y-
l]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (First
eluting stereoisomer, D-3)
[0913] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.09 (br. s.,
1H), 7.89 (s, 1H), 7.18 (s, 1H), 6.99 (s, 1H), 6.72 (br. s., 1H),
5.57-5.68 (m, 1H), 5.19 (br. s., 1H), 4.22 (br. s., 1H), 3.99-4.12
(m, 1H), 3.02-3.24 (m, 2H), 2.97 (d, J=3.09 Hz, 3H), 2.25 (s, 3H);
HPLC: RT 1.769 min; MS: m/z: 379.1 [M+H].sup.+; SFC: RT 2.71
min.
N2-[1-[6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl]-3-methyl-1H-pyrazol-4-y-
l]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Second
eluting stereoisomer, D-4)
[0914] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.09 (br. s.,
1H), 7.88 (br. s., 1H), 7.18 (s, 1H), 6.99 (s, 1H), 6.66 (br. s.,
1H), 5.58-5.67 (m, 1H), 5.18 (br. s., 1H), 4.22 (br. s., 1H),
4.03-4.12 (m, 1H), 3.04-3.24 (m, 2H), 2.97 (br. s., 3H) 2.24 (s,
3H); HPLC: RT 1.768 min; MS: m/z: 379.1 [M+H].sup.+; SFC: RT 3.21
min.
Example D-9 and D-10
Synthesis of
N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H--
pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-5) and
N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-
-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-6)
(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol
and
(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol
[0915] To a solution of [1-(hydroxymethyl)cyclopropyl]methanol
(9-1, 3 g, 29.37 mmol), 3-methyl-4-nitro-1H-pyrazole (3.39 g, 26.70
mmol) and PPh.sub.3 (7 g, 26.70 mmol) in THF (30 mL) was added
dropwise DIAD (5.4 g, 26.70 mmol) at 0.degree. C. over 30 min.
After addition, the mixture was stirred at this temperature for 30
min. The resulting mixture was stirred at 25.degree. C. for 11 h.
The reaction mixture was diluted with H.sub.2O (90 mL) and
extracted with EtOAc (3.times.30 mL). The combined organic layers
were washed with brine (20 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 0:1)
to give a mixture of
(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol
and
(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol
as an off-white solid, which was used into the next step without
further purification. LCMS: RT 0.568 min, m/z=212.2
[M+H].sup.+.
(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl
methanesulfonate and
(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl
methanesulfonate
[0916] To a solution of
(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol
and
(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methanol
(5.2 g, 24.62 mmol) and Et.sub.3N (7.47 g, 73.86 mmol) in DCM (50
mL) was added dropwise MsCl (3.38 g, 29.54 mmol) at 0.degree. C.
for 0.5 h. The mixture was stirred at 0.degree. C. for 0.5 h. The
reaction mixture was diluted with H.sub.2O (50 mL) and extracted
with DCM (3.times.10 mL). The combined organic layers were washed
with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give
(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl
methanesulfonate and
(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl
methanesulfonate as a yellow oil. The crude product was used into
the next step without further purification. LCMS: RT 1.018 min, m
z=290.0 [M+H].sup.+.
1-((1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,2-
,4-triazole and
1-((1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,-
2,4-triazole
[0917] To a solution of 1H-1,2,4-triazole (2.01 g, 29.04 mmol) in
DMF (30 mL) was added NaH (1.16 g, 29.04 mmol, 60% purity) at
0.degree. C. After addition, the mixture was stirred at this
temperature for 0.5 h, and then
(1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl
methanesulfonate and
(1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl
methanesulfonate (7 g, 24.20 mmol) in DMF (20 mL) was added
dropwise at 0.degree. C. The resulting mixture was stirred at
50.degree. C. for 3.5 h. The reaction mixture was quenched by
addition H.sub.2O (150 mL) at 0.degree. C., and extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 0:1) to give a
mixture of
1-((1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,-
2,4-triazole and
1-((1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,-
2,4-triazole as a pale-yellow solid, which was used into the next
step without further purification. LCMS: RT 0.604 min, m/z=263.2
[M+H].sup.+.
1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyraz-
ol-4-amine and
1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyra-
zol-4-amine
[0918] To a solution of
1-((1-((3-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,-
2,4-triazole and
1-((1-((5-methyl-4-nitro-1H-pyrazol-1-yl)methyl)cyclopropyl)methyl)-1H-1,-
2,4-triazole (1 g, 3.81 mmol) in MeOH (20 mL) was added Pd--C (10%,
0.32 g) under N.sub.2. The suspension was degassed under vacuum and
purged with H.sub.2 several times. The mixture was stirred under
H.sub.2 (15 psi) at 25.degree. C. for 2 h. The reaction mixture was
filtered and the filtrate was concentrated to give a mixture of
1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyra-
zol-4-amine and
1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyra-
zol-4-amine as a brown oil, which was used into the next step
without further purification.
N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-p-
yrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-5) and
N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H--
pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-6)
[0919] A mixture of
1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-pyra-
zol-4-amine and
1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-pyra-
zol-4-amine (200 mg, 861.03 .mu.mol),
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (164 mg,
774.93 .mu.mol) and Et.sub.3N (261 mg, 2.58 mmol) were taken up
into a microwave tube in n-BuOH (5 mL). The sealed tube was heated
at 120.degree. C. for 1.5 h under microwave. The reaction mixture
was concentrated under reduced pressure. The residue was purified
by prep-HPLC (neutral) to give
N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H--
pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-6) and
N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-
-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-5).
N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-3-methyl-1H-p-
yrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-5)
[0920] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.25-8.34 (m,
1H), 8.08-8.20 (m, 1H), 7.98-8.04 (m, 1H), 7.96 (m, 1H), 6.49-6.78
(m, 1H), 5.10-5.37 (m, 1H), 3.99-4.06 (m, 2H), 3.82-3.92 (m, 2H),
3.04-3.16 (m, 3H), 2.29 (s, 3H), 0.85-0.89 (m, 2H), 0.81-0.85 (m,
2H): HPLC: RT 1.973 min; MS: m/z: 408.2 [M+H].sup.+.
N2-(1-((1-((1H-1,2,4-triazol-1-yl)methyl)cyclopropyl)methyl)-5-methyl-1H-p-
yrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-6)
[0921] .sup.1H NMR (400 MHz. CDCl.sub.3): .delta. ppm 8.32 (s, 1H),
8.07-8.14 (m, 1H), 7.97 (s, 1H), 7.69-7.90 (m, 1H), 6.38-6.62 (m,
1H), 5.09-5.24 (m, 1H), 4.12 (s, 2H), 3.90 (s, 2H), 3.02 (d, J=4.52
Hz, 3H), 2.12 (s, 3H), 0.85-0.91 (m, 2H), 0.77-0.83 (m, 2H); HPLC:
RT 1.913 min: MS: m/z: 408.2 [M+H].sup.+.
Example D-11 and D-12
Synthesis of
N4-methyl-N2-[5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-
-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-7) and
N4-methyl-N2-[3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]tr-
iazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4--
diamine (D-8)
5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one
[0922] To a solution of 5-hydroxypiperidin-2-one (4.5 g, 39.09
mmol) in DMF was added imidazole (7.98 g, 117.27 mmol), followed by
TBDPSCl (16.11 g, 58.64 mmol) at 0.degree. C. The mixture was
stirred at 20.degree. C. for 16 h. The solution was added with
water (120 mL), extracted with EtOAc (3.times.30 mL). The organic
layers were combined, washed with brine (3.times.20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(PE:EtOAc=10:1 to 1:1) to give compound
5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one as an off-white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.62-7.69 (m,
4H), 7.42-7.48 (m, 2H), 7.36-7.42 (m, 4H), 6.19 (br. s., 1H),
4.06-4.12 (m, 1H), 3.15-3.27 (m, 2H), 2.66 (ddd, J=17.42, 9.48,
6.17 Hz, 1H), 2.27 (dt, J=17.86, 5.84 Hz, 1H), 1.74-1.95 (m, 2H),
1.02-1.12 (m, 9H).
5-[tert-butyl(diphenyl)silyl]oxypiperidine-2-thione
[0923] To a solution of
5-[tert-butyl(diphenyl)silyl]oxypiperidin-2-one (3 g, 8.49 mmol) in
toluene (5 mL) was added lawesson's reagent (1.72 g, 4.25 mmol).
The mixture was stirred at 110.degree. C. for 2 h. The reaction
solution was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=10:1 to 3:1)
to give 5-[tert-butyl(diphenyl)silyl]oxypiperidine-2-thione as a
yellow gum. LCMS: RT 0.940 min, m/z=370.2 [M+H].sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 7.64 (dd, J=6.46, 5.08 Hz, 4H),
7.44-7.50 (m, 2H), 7.38-7.43 (m, 4H), 4.13 (q, J=6.86 Hz, 2H),
3.11-3.29 (m, 3H), 2.89 (dt, J=18.95, 5.46 Hz, 1H), 1.70-1.90 (m,
2H), 1.07 (s, 9H).
Tert-butyl-[(6-methylsulfanyl-2,3,4,5-tetrahydropyridin-3-yl)oxyl]-dipheny-
l-silane
[0924] To a solution of
5-[tert-butyl(diphenyl)silyl]oxypiperidine-2-thione (2.2 g, 5.95
mmol) in THF (50 mL) was added K.sub.2CO.sub.3 (4.11 g, 29.75 mmol)
and Mel (4.22 g, 29.75 mmol). The mixture was stirred at 20.degree.
C. for 16 h. The reaction mixture was filtered through a pad of
celite. The cake was washed with EtOAc (50 mL), and the filtrate
was washed with water (20 mL) and brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give
Tert-butyl-[(6-methylsulfanyl-2,3,4,5-tetrahydropyridin-3-yl)oxyl]-diphen-
yl-silane as yellow gum, which was used in next step without
further purification. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.66 (m, 4H), 7.33-7.49 (m, 6H), 3.93 (quin, J=5.02 Hz, 1H),
3.54-3.73 (m, 2H), 2.53-2.64 (m, 1H), 2.27 (s, 3H), 2.15-2.24 (m,
1H), 1.74 (q, J=6.40 Hz, 2H), 1.00-1.16 (s, 9H).
Tert-butyl-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-y-
l)oxyl]-diphenyl-silane
[0925] To a solution of
Tert-butyl-[(6-methylsulfanyl-2,3,4,5-tetrahydropyridin-3-yl)oxyl]-diphen-
yl-silane (1.9 g, 4.95 mmol) in EtOH (20 mL) was added
acetohydrazide (477 mg, 6.44 mmol). The mixture was stirred at
80.degree. C. for 16 h. The reaction was concentrated under reduced
pressure. The residue was added with water (20 mL), extracted with
EtOAc (3.times.10 mL). The organic layers were combined, washed
with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated to give a crude of
tert-butyl-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6--
yl)oxyl]-diphenyl-silane as a colorless gum, which was used in next
step without further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.66-7.68 (m, 2H), 7.54-7.56 (m, 2H),
7.36-7.47 (m, 6H), 4.36 (d, J=3.26 Hz, 1H), 3.49-3.65 (m, 2H),
2.91-3.29 (m, 2H), 2.18-2.24 (m, 3H), 1.75-2.15 (m, 2H), 1.03 (s,
9H).
3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-ol
[0926] To a solution of
Tert-butyl-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6--
yl)oxyl]-diphenyl-silane (1.9 g, 4.85 mmol) in MeOH (30 mL) was
added KF (4.23 g, 72.75 mmol). The mixture was stirred at
80.degree. C. for 16 h. The reaction mixture was concentrated under
reduced pressure. The residue was added with DCM:MeOH (50 mL,
ratio=10:1), stirred for 10 min, filtered and the filtrate was
concentrated under reduced pressure. The residue was added with
MTBE (15 mL), stirred for 10 min, filtered and the solid was dried
under reduced pressure to give
3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-ol as a
yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 4.35 (dd,
J=6.17, 2.21 Hz, 1H), 3.73-3.96 (m, 2H), 2.78-2.90 (m, 2H),
2.18-2.29 (m, 3H), 1.83-2.07 (m, 2H).
(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)
methanesulfonate
[0927] To a solution of
3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-ol (400
mg, 2.61 mmol) in DCM (50 mL) was added TEA (528 mg, 5.22 mmol) and
followed by MsCl (448 mg, 3.92 mmol). The mixture solution was
stirred at 0.degree. C. for 2 h. The reaction was added with water
(5 mL), extracted with DCM (5.times.10 mL). The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a crude
(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)
methanesulfonate as a yellow oil, which was used in next step
without further purification. .sup.1H NMR (400 MHz, CDCl3): .delta.
5.36-5.43 (m, 1H), 3.99-4.25 (m, 2H), 3.05-3.18 (m, 5H), 2.36-2.52
(m, 4H), 2.03-2.14 (m, 1H).
3-methyl-6-(3-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triaz-
olo[4,3-a]pyridine and
3-methyl-6-(5-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]tria-
zolo[4,3-a]pyridine
[0928] To a solution of 3-methyl-4-nitro-1H-pyrazole (1-1, 398 mg,
3.13 mmol) in DMF (10 mL) was added NaH (125 mg, 3.13 mmol, 60%
purity) at 0.degree. C., then the reaction was stirred at
20.degree. C. for 1 h. Then,
(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)
methanesulfonate (604 mg, 2.61 mmol, 70% purity) in DMF (4 mL) was
added to the solution at 20.degree. C. Then, the mixture was
stirred at 80.degree. C. for 12 h. The reaction solution was added
with NH.sub.4Cl solution (20 mL), extracted with DCM:MeOH (20
mL.times.3, ratio=3:1). The organic layers were combined, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The crude product was purified by prep-TLC (DCM:MeOH=5:1)
to give a mixture of
3-methyl-6-(3-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]tria-
zolo[4,3-a]pyridine and
3-methyl-6-(5-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]tria-
zolo[4,3-a]pyridine as a yellow gum. LCMS: RT 0.925 min, m/z=263.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.25 (s,
0.6H), 8.13 (s, 0.3H), 4.68-4.81 (m, 1H), 4.14-4.42 (m, 2H),
3.02-3.31 (m, 2H), 2.77 (s, 1H), 2.55 (s, 2H), 2.44-2.53 (m, 4H),
2.43 (s, 1H).
5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl-
)pyrazol-4-amine and
3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-y-
l)pyrazol-4-amine
[0929] To a mixture of
3-methyl-6-(3-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]tria-
zolo[4,3-a]pyridine and
3-methyl-6-(5-methyl-4-nitro-pyrazol-1-yl)-5,6,7,8-tetrahydro-[1,2,4]tria-
zolo[4,3-a]pyridine (100 mg, 381.29 .mu.mol) in MeOH (10 mL) was
added Pd/C (10%, 50 mg) under N.sub.2. The suspension was degassed
and purged with H.sub.2 for 3 times. The mixture was stirred under
H.sub.2 (15 psi) at 20.degree. C. for 5 h. The reaction solution
was filtered through a pad of celite, the filtrate was concentrated
under reduced pressure to give a crude
5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-y-
l)pyrazol-4-amine and
3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-y-
l)pyrazol-4-amine. LCMS: RT 0.173 min, m/z=233.1 [M+H].sup.+.
N4-methyl-N2-[5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3--
a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-7) and
N4-methyl-N2-[3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]tr-
iazolo[4,3-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4--
diamine (D-8)
[0930] A mixture of
5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-y-
l)pyrazol-4-amine and
3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-y-
l)pyrazol-4-amine (70 mg, 301.36 .mu.mol),
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (64 mg,
301.36 .mu.mol) and TEA (91 mg, 904.08 .mu.mol) in 1,4-dioxane (10
mL) was degassed and purged with N.sub.2 for 3 times, and then the
mixture was stirred at 110.degree. C. for 12 h under N.sub.2. The
reaction solution was concentrated under reduced pressure. The
crude product was purified by prep-HPLC (HCOOH) to give
N4-methyl-N2-[5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-
-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-7, HCOOH salt) and
N4-methyl-N2-[3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-
-a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-8, HCOOH salt).
N4-methyl-N2-[5-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3--
a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-7)
[0931] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.24 (s, 0.39H),
8.07 (s, 1H), 7.90 (s, 1H), 5.50 (br. s., 0.14H), 5.28 (br. s.,
0.8H), 4.65 (br. s., 1H), 4.39 (dd, J=12.11, 9.22 Hz, 1H), 4.15
(dd, J=12.36, 5.58 Hz, 1H), 3.20-3.31 (m, 1H), 2.97-3.09 (m, 4H),
2.39-2.45 (m, 4H), 2.33-2.42 (m, 4H); HPLC: RT 2.754 min; MS: m/z:
408.2 [M+H].sup.+.
N4-methyl-N2-[3-methyl-1-(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3--
a]pyridin-6-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-8)
[0932] .sup.1H NMR (400 MHz. CDCl.sub.3): .delta. 8.22 (s, 0.52H),
8.09 (s, 1H), 7.96 (s, 1H) 5.34 (br. s., 1H), 4.71 (s, 1H)
4.18-4.35 (m, 2H) 3.22 (d, J=17.07 Hz, 1H), 3.00-3.13 (m, 3H), 2.43
(m, 5H), 2.29 (s, 3H); HPLC: RT 2.847 min; MS: m/z: 408.2
[M+H].sup.+.
Example D-13
Synthesis of
N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trif-
luoromethyl)pyrimidine-2,4-diamine (D-9)
1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine
[0933] To a solution of
1-[2-(difluoromethoxy)ethyl]-5-methyl-4-nitro-pyrazole (13-1, 100
mg, 452.16 .mu.mol) in MeOH (10 mL) was added Pd--C (10%, 50 mg)
under N.sub.2 at 20.degree. C. The suspension was degassed under
vacuum and purged with H.sub.2 several times. The mixture was
stirred under H.sub.2 (15 psi) at 40.degree. C. for 5 h. The
reaction mixture was filtered and the filtrate was concentrated, to
give 1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine was
obtained as a yellow oil. LCMS: RT 1.037 min, m/z=192.2
[M+H].sup.+.
N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-9)
[0934] 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (5-5,
54 mg, 253.69 .mu.mol),
1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine (97 mg,
507.38 .mu.mol) and TEA (51 mg, 507.38 .mu.mol, 7 .mu.L) were taken
up into a microwave tube in 1,4-dioxane (1.00 mL) at 20.degree. C.
The sealed tube was heated at 120.degree. C. for 1.5 h under
microwave. The mixture was cooled to 20.degree. C. and
concentrated. The residue was purified by prep-HPLC (neutral) to
give compound
N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-(trif-
luoromethyl)pyrimidine-2,4-diamine (D-9). LCMS: RT 0.605 min,
m/z=367.2 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD): .delta. ppm
7.97 (br. s., 1H), 7.62 (br. s., 1H), 6.12-6.52 (m, 1H), 4.31-4.36
(m, 2H), 4.16-4.22 (m, 2H), 2.91 (br. s., 3H), 2.24 (s, 3H); HPLC:
RT 2.216 min. MS: m/z: 367.1[M+H].sup.+.
Example D-14
Synthesis of
N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trif-
luoromethyl)pyrimidine-2,4-diamine (D-10)
1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine
[0935] To a solution of
1-[2-(difluoromethoxy)ethyl]-3-methyl-4-nitro-pyrazole (14-1, 100
mg, 452.16 .mu.mol) (100 mg, 452.16 .mu.mol) in MeOH (10 mL) was
added Pd--C (10%, 50 mg) under N.sub.2. The suspension was degassed
under vacuum and purged with H, several times. The mixture was
stirred under H.sub.2 (15 psi) at 40.degree. C. for 5 h. The
reaction mixture was filtered and the filtrate was concentrated to
give compound 1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine
as a black brown oil. LCMS: RT 0.802 min, m/z=192.3
[M+H].sup.+.
N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-10)
[0936] 1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine (73
mg, 381.84 .mu.mol),
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (40 mg,
190.92 .mu.mol) and TEA (38 mg, 381.84 .mu.mol, 52.93 .mu.L) were
taken up into a microwave tube in 1,4-dioxane (1.00 mL) at
20.degree. C. The sealed tube was heated at 120.degree. C. for 1.5
h under microwave. The mixture was cooled to 20.degree. C. and
concentrated. The residue was purified by prep-HPLC (neutral) to
give compound
N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-(trif-
luoromethyl)pyrimidine-2,4-diamine (D-10). LCMS: RT 0.671 min,
m/z=367.1 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): .delta. ppm
8.02 (s, 1H), 7.90 (br. s., 1H), 6.14-6.55 (m, 1H), 4.27-4.34 (m,
2H), 4.15-4.22 (m, 2H), 2.97 (s, 3H), 2.22 (s, 3H); HPLC: RT 2.277
min; MS: m/z: 367.1 [M+H].sup.+.
Example D-15
Synthesis of
N2-[5-chloro-1-[2-(difluoromethoxy)ethyl]pyrazol-4-yl]-N4-methyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-11)
N2-[5-chloro-1-[2-(difluoromethoxy)ethyl]pyrazol-4-yl]-N4-methyl-5-(triflu-
oromethyl)pyrimidine-2,4-diamine (D-11)
[0937] Compound
5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-amine (80 mg,
378.07 .mu.mol), compound
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (80 mg,
378.07 .mu.mol) and TEA (115 mg, 1.13 mmol, 157 .mu.L) were taken
up into a microwave tube in 1,4-dioxane (10 mL). The sealed tube
was heated at 120.degree. C. for 90 min under microwave. After
cooling to 20.degree. C., the mixture was concentrated under
reduced pressure. The residue was purified by prep-HPLC (neutral)
to give
N2-[5-chloro-1-[2-(difluoromethoxy)ethyl]pyrazol-4-yl]-N4-methyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-11). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.14 (br. s., 2H), 6.60-6.79 (m, 1H),
5.99-6.40 (m, 1H), 5.22 (br. s., 1H), 4.36-4.41 (m, 2H), 4.23-4.29
(m, 2H), 3.07 (d, J=4.64 Hz, 3H): HPLC: RT 2.521 min; MS: m/z=387.0
[M+H].sup.+.
Example D-16
Synthesis of
N2-[5-chloro-1-[[1-(methoxymethyl)cyclopropyl]methyl]pyrazol-4-yl]-N4-met-
hyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-12)
N2-[5-chloro-1-[[1-(methoxymethyl)cyclopropyl]methyl]pyrazol-4-yl]-N4-meth-
yl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-12)
[0938] To a mixture of compound
5-chloro-1-((1-(methoxymethyl)cyclopropyl)methyl)-1H-pyrazol-4-amine
(70 mg, 324.55 .mu.mol) and compound
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (68.67 mg,
324.55 .mu.mol) in 1,4-dioxane (10 mL) was added TFA (74 mg, 649.10
.mu.mol, 48 .mu.L) at 20.degree. C. under N.sub.2. The mixture was
heated to 90.degree. C. and stirred for 5 h. The mixture was cooled
to 20.degree. C. and was adjusted to pH=8 by adding aq. sat.
NaHCO.sub.3 and extracted with EtOAc (3-8 mL). The combined organic
phase was washed with brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (neutral) to give
N2-[5-chloro-1-[[1-(methoxymethyl)cyclopropyl]methyl]pyrazol-4-yl-
]-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-12).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.13 (s, 2H), 6.79 (br.
s., 1H), 5.18-5.26 (m, 1H), 4.16 (s, 2H), 3.34 (s, 3H), 3.16 (s,
2H), 3.07 (d, J=4.64 Hz, 3H), 0.74-0.78 (m, 2H), 0.55-0.60 (m, 2H);
HPLC: RT 2.574 min; MS: m/z=391.1 [M+H].sup.+.
Example D-17 and D-18
Synthesis of
2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-
-2-yl]amino]pyrazol-1-yl]acetamide (D-14) and
2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-
-2-yl]amino]pyrazol-1-yl]acetonitrile (D-13)
Ethyl 2,2-difluoro-2-(3-methyl-4-nitro-pyrazol-1-yl)acetate
[0939] To a solution of 5-methyl-4-nitro-1H-pyrazole (20 g, 157.36
mmol) in DMF (300 mL) was added NaH (9.44 g, 236.04 mmol, 60%
purity) at 0.degree. C. under N.sub.2. After addition, the mixture
was allowed to 25.degree. C. and stirred for 2 h,
1-bromo-3-ethoxy-1,1-difluoro-propan-2-one (51.22 g, 236.04 mmol)
was then added at 0.degree. C. The mixture was stirred at
25.degree. C. for 16 h. The mixture was poured into aqueous
NH.sub.4Cl (900 mL). The aqueous phase was extracted with MTBE
(3.times.300 mL). The combined organic phase was washed with brine
(2.times.200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (PE:EtOAc=20:1) to give ethyl
2,2-difluoro-2-(3-methyl-4-nitro-pyrazol-1-yl)acetate as a light
yellow liquid. LCMS: RT 1.190 min, m/z=250.1 [M+H].sup.+.
Ethyl 2-(4-amino-3-methyl-pyrazol-1-yl)-2,2-difluoro-acetate
[0940] To a solution of ethyl
2,2-difluoro-2-(3-methyl-4-nitro-pyrazol-1-yl)acetate (10 g, 40.13
mmol) in EtOH (100 mL) was added Pd/C (1 g, 10% purity) under
N.sub.2. The suspension was degassed under vacuum and purged with
H.sub.2 for three times. The mixture was stirred under H.sub.2 (15
psi) at 15.degree. C. for 3 h. The reaction solution was filtered
and the filtrate was concentrated under reduced pressure to give
ethyl 2-(4-amino-3-methyl-pyrazol-1-yl)-2,2-difluoro-acetate as a
brown oil. LCMS: RT 0.23 min, m/z=220 [M+H].sup.+
Ethyl
2-[4-[bis(tert-butoxycarbonyl)amino]-3-methyl-pyrazol-1-yl]-2,2-difl-
uoro-acetate
[0941] A mixture of ethyl
2-(4-amino-3-methyl-pyrazol-1-yl)-2,2-difluoro-acetate (8.3 g,
37.87 mmol), Boc.sub.2O (12.4 g, 56.81 mmol, 13.05 mL), TEA (6.9 g,
68.17 mmol, 9.45 mL) and DMAP (4.63 g, 37.87 mmol) in DCM (160 mL)
was degassed and purged with N.sub.2 for 3 times, and then the
mixture was stirred at 25.degree. C. for 12 h under N.sub.2. The
reaction mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(PE:EtOAc=5/1 to 3:1) to give ethyl
2-[4-[bis(tert-butoxycarbonyl)amino]-3-methyl-pyrazol-1-yl]-2,2-difluoro--
acetate as a yellow oil. LCMS: RT 0.23 min, m/z=320
[M+H].sup.+.
Tert-butyl
N-[1-(2-amino-1,1-difluoro-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]c-
arbamate
[0942] To a solution of ethyl
2-[4-(tert-butoxycarbonylamino)-3-methyl-pyrazol-1-yl]-2,2-difluoro-aceta-
te (4 g, 12.53 mmol) in MeOH (10 mL) was added a methanolic
solution of NH.sub.3 (70 mL). The mixture was stirred at 50.degree.
C. for 12 h in an autoclave. The reaction solution was concentrated
under reduced pressure to give tert-butyl
N-[1-(2-amino-1,1-difluoro-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]carbamate
as a yellow solid. LCMS: RT 0.705 min, m/z=291.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, chloroform-d): .delta. 8.01-8.21 (m, 1H),
6.83 (s, 1H), 6.01-6.31 (br, 2H), 3.49 (s, 1H), 2.23 (s, 3H),
1.50-1.55 (m, 9H),
2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-
-2-yl]amino]pyrazol-1-yl]acetamide (D-14)
[0943] To a solution of tert-butyl
N-[1-(2-amino-1,1-difluoro-2-oxo-ethyl)-3-methyl-pyrazol-4-yl]carbamate
(500 mg, 1.72 mmol) and
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (400 mg,
1.89 mmol) in 1,4-dioxane (30 mL) was added p-TsOH (296 mg, 1.72
mmol). The mixture was stirred at 100.degree. C. for 10 h. The
reaction solution was concentrated under reduced pressure. The
residue was adjusted to pH 7 with aq. NaHCO.sub.3, extracted with
EtOAc (3.times.10 ml). The organic layers were combined, washed
with brine (5 ml), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude product was washed
with MeCN (5 mL), the solid was filtered and dried under reduced
pressure to give
2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-
-2-yl]amino]pyrazol-1-yl]acetamide (14). Additional crude compound
14 was obtained by concentration of the MeCN mother liquor. .sup.1H
NMR (400 MHz, chloroform-d): .delta. 9.33 (br. s., 1H), 8.58 (s,
1H), 8.34 (br. s., 2H), 8.17 (s, 1H), 7.16 (br. s., 1H), 2.90 (d,
J=4.27 Hz, 3H), 2.24 (s, 3H); HPLC: RT 2.49 min; MS: m/z: 366.0
[M+H].sup.+.
2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin--
2-yl]amino]pyrazol-1-yl]acetonitrile (D-13)
[0944] The solution of
2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-
-2-yl]amino]pyrazol-1-yl]acetamide (100 mg, 273.78 .mu.mol) in
POCl.sub.3 (3.3 g, 21.52 mmol, 2.00 mL) was heated at 90.degree. C.
for 10 h. The reaction solution was concentrated under reduced
pressure. The residue was adjusted to pH 7 with aq. NaHCO.sub.3,
extracted with EtOAc (3.times.10 mL), organic layers were combined,
washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The crude product was
purified by prep-TLC (PE:EtOAc=1:1) and further purified by
prep-HPLC (FA) to give
2,2-difluoro-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-
-2-yl]amino]pyrazol-1-yl]acetonitrile (D-13). .sup.1H NMR (400 MHz,
chloroform-c): .delta. 8.42 (s, 1H), 8.19 (s., 1H), 6.71 (br. s.,
1H), 5.30 (br. s., 1H), 3.10 (d, J=4.27 Hz, 3H), 2.37 (s, 3H);
HPLC: RT 2.48 min; MS: m/z: 348.2 [M+H].sup.+
Example D-19 and D-20
Synthesis of
N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-15) and
N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-16)
2-(5-methyl-4-nitro-pyrazol-1-yl)ethanol and
2-(3-methyl-4-nitro-pyrazol-1-yl)ethanol
[0945] A mixture of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.34 mmol),
2-bromoethanol (9.83 g, 78.68 mmol, 5.59 mL) and K.sub.2CO.sub.3
(16.31 g, 118.02 mmol) in CH.sub.3CN (50 mL) was degassed and
purged with N.sub.2 for 3 times, and then the mixture was stirred
at 80.degree. C. for 16 h under N.sub.2. The mixture was cooled to
20.degree. C. and concentrated under reduced pressure. The residue
was poured into ice water (100 mL). The aqueous phase was extracted
with EtOAc (3.times.35 mL). The combined organic phase was washed
with brine (35 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (PE:EtOAc=2:1), to give
2-(5-methyl-4-nitro-pyrazol-1-yl)ethanol and
2-(3-methyl-4-nitro-pyrazol-1-yl)ethanol as a yellow oil. LCMS: RT
0.161 min, m/z=172.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.20 (s, 1H), 8.03 (s, 1H), 4.14-4.22 (m, 4H),
3.94-4.03 (m, 4H), 3.07 (d, J=5.27 Hz, 2H), 2.64 (s, 3H), 2.47 (s,
3H).
1-[2-(difluoromethoxy)ethyl]-5-methyl-4-nitro-pyrazole and
1-[2-(difluoromethoxy)ethyl]-3-methyl-4-nitro-pyrazole
[0946] To a solution of 2-(5-methyl-4-nitro-pyrazol-1-yl)ethanol
(19-2, 4.26 g, 24.89 mmol),
2-(3-methyl-4-nitro-pyrazol-1-yl)ethanol and CuI (948 mg, 4.98
mmol) in CH.sub.3CN (100 mL) was added a solution of
2,2-difluoro-2-fluorosulfonyl-acetic acid (6.65 g, 37.34 mmol, 3.87
mL) in CH.sub.3CN (10 mL) dropwise at 55.degree. C. over a period
of 30 min under N.sub.2. The reaction mixture was stirred at
55.degree. C. for another 2 h. The mixture was cooled to 20.degree.
C. and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=5:1), to
give a mixture of
1-[2-(difluoromethoxy)ethyl]-5-methyl-4-nitro-pyrazole and
1-[2-(difluoromethoxy)ethyl]-3-methyl-4-nitro-pyrazole as a yellow
oil. LCMS: RT 0.707 min, m/z=222.1 [M+H].sup.+.
1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine and
1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine
[0947] To a mixture of
1-[2-(difluoromethoxy)ethyl]-5-methyl-4-nitro-pyrazole and
1-[2-(difluoromethoxy)ethyl]-3-methyl-4-nitro-pyrazole (800 mg,
1.81 mmol) and NH.sub.4Cl (484 mg, 9.05 mmol) in EtOH (20 mL) and
H.sub.2O (5 mL) was added Fe (505 mg, 9.05 mmol). The mixture was
stirred at 80.degree. C. for 2 h. The mixture was cooled to
20.degree. C. and concentrated in reduced pressure. The residue was
poured into ice water (10 mL). The aqueous phase was extracted with
EtOAc (5.times.5 mL). The combined organic phase was washed with
brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure, to give the crude product
1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine and
1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine, which was
used in the next step without further purification. LCMS: RT 0.095
min, m/z=192.2 [M+H].sup.+.
N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-ethyl-5-(triflu-
oromethyl)pyrimidine-2,4-diamine (D-15) and
N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-16)
[0948] To a mixture of
1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-amine and
1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-amine (100 mg,
523.07 .mu.mol), and
2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (130 mg,
575.38 .mu.mol) in 1,4-dioxane (5.00 mL) was added TEA (159 mg,
1.57 mmol) under N.sub.2. The mixture was stirred at 120.degree. C.
for 2 h. The mixture was cooled to 20.degree. C. and concentrated
under reduced pressure. The residue was purified by prep-HPLC (FA
condition), to give
N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-15) and
N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-ethyl-5-(trifl-
uoromethyl)pyrimidine-2,4-diamine (D-16, peak 2).
N2-[1-[2-(difluoromethoxy)ethyl]-5-methyl-pyrazol-4-yl]-N4-ethyl-5-(triflu-
oromethyl)pyrimidine-2,4-diamine (D-15)
[0949] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.09 (s, 1H),
7.75 (br. s., 1H), 5.91-6.36 (m, 1H), 5.06 (br. s., 1H), 4.27-4.32
(m, 2H), 4.22-4.27 (m, 2H), 3.44-3.53 (m, 2H), 2.24 (s, 3H), 1.66
(br. s., 1H), 1.20-1.27 (m, 3H); HPLC: RT 1.75 min; MS: m/z=381.1
[M+H].sup.+.
N2-[1-[2-(difluoromethoxy)ethyl]-3-methyl-pyrazol-4-yl]-N4-ethyl-5-(triflu-
oromethyl)pyrimidine-2,4-diamine (D-16)
[0950] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.12 (br. s.,
1H), 7.87 (s, 1H), 5.94-6.39 (m, 1H), 5.13 (br. s., 1H), 4.26-4.33
(m, 2H), 4.17-4.24 (m, 2H), 3.48-3.59 (m, 2H), 2.26 (s, 3H), 1.90
(br. s., 1H), 1.28 (t, J=7.28 Hz, 3H); HPLC: RT 2.508 min; MS:
m/z=381.1 [M+H].sup.+.
Example D-21 and D-22
Synthesis of
N2-[1-[(2R)-2-(difluoromethoxy)propyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-
-(trifluoromethyl)pyrimidine-2,4-diamine (D-19) and
N2-[1-[(2R)-2-(difluoromethoxy)propyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-
-(trifluoromethyl)pyrimidine-2,4-diamine (D-20)
(R)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol and
(R)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol
[0951] To a mixture of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.34
mmol) and (R)-2-methyloxirane (3.43 g, 59.01 mmol, 4.13 mL) in DMF
(50 mL) was added Cs.sub.2CO.sub.3 (19.23 g, 59.01 mmol) at
20.degree. C. The mixture was heated to 80.degree. C. and stirred
for 15 h then cooled to 20.degree. C. and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=10:1 to 0:1) to give the mixture of
(R)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol and
(R)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol as a yellow
liquid. LCMS: RT 0.133 min, m/z=186.1 [M+H].sup.+.
(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-4-nitro-1H-pyrazole and
(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-4-nitro-1H-pyrazole
[0952] To a solution of the mixture
(R)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol and
(R)-1-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol (3 g, 16.2
mmol) in CH.sub.3CN (150 mL) was added CuI (617 mg, 3.24 mmol),
then a solution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (4.33
g, 24.30 mmol, 2.5 mL) in CH.sub.3CN (150 mL) dropwise at
20.degree. C. over a period of 30 min under N.sub.2. The reaction
mixture was warmed to 55.degree. C. and stirred for 2 h then cooled
to 20.degree. C. and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(PE:EtOAc=10:1 to 0:1) to give the mixture of
(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-4-nitro-1H-pyrazole and
(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-4-nitro-1H-pyrazole as a
yellow oil. LCMS: RT 0.873 min, m/z=236.1 [M+H].sup.+.
(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-1H-pyrazol-4-amine and
(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-1H-pyrazol-4-amine
[0953] To a solution of the mixture
(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-4-nitro-1H-pyrazole and
(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-4-nitro-1H-pyrazole (4
g, 17.01 mmol) in EtOH (96 mL) and H.sub.2O (24 mL) was added
NH.sub.4Cl (4.55 g, 85.04 mmol, 2.97 mL) and Fe (4.75 g, 85.04
mmol) at 20.degree. C. The mixture was heated to 80.degree. C. and
stirred for 2 h then cooled to 20.degree. C. and concentrated under
reduced pressure. The residue was washed with DCM:MeOH=10:1
(3.times.10 mL) then filtered and the filtrate was concentrated
under reduced pressure to give the mixture compound
(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-1H-pyrazol-4-amine and
(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-1H-pyrazol-4-amine as a
light yellow oil. LCMS: RT 1.046 min, m/z=206.2 [M+H].sup.+.
N2-[1-[(2R)-2-(difluoromethoxy)propyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5--
(trifluoromethyl)pyrimidine-2,4-diamine (D-19) and
N2-[1-[(2R)-2-(difluoromethoxy)propyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-
-(trifluoromethyl)pyrimidine-2,4-diamine (D-20)
[0954] To a solution of the mixture
(R)-1-(2-(difluoromethoxy)propyl)-5-methyl-1H-pyrazol-4-amine and
(R)-1-(2-(difluoromethoxy)propyl)-3-methyl-1H-pyrazol-4-amine (300
mg, 1.46 mmol) and
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (238 mg,
1.12 mmol) in 1,4-dioxane (3 mL) was added p-TsOH (97 mg, 562.30
.mu.mol) at 20.degree. C. The mixture was heated to 90.degree. C.
and stirred for 2 h, then cooled to 20.degree. C. and adjusted to
pH 7-8 by aq. NaHCO.sub.3. The mixture was extracted with EtOAc
(3.times.5 mL), washed with brine (5 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by prep-HPLC (FA) to give compound
N2-[1-[(2R)-2-(difluoromethoxy)propyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5-
-(trifluoromethyl)pyrimidine-2,4-diamine (D-19) and
N2-[1-[(2R)-2-(difluoromethoxy)propyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5-
-(trifluoromethyl)pyrimidine-2,4-diamine (D-20).
N2-[1-[(2R)-2-(difluoromethoxy)propyl]-5-methyl-pyrazol-4-yl]-N4-methyl-5--
(trifluoromethyl)pyrimidine-2,4-diamine (D-19)
[0955] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.08 (br. s.,
1H), 7.76 (br. s., 1H), 6.85 (br. s., 1H), 5.80-6.24 (m, 1H), 5.15
(br. s., 1H), 4.59-4.75 (m, 1H), 4.04-4.24 (m, 2H), 2.99 (d, J=4.02
Hz, 3H), 2.24 (s, 3H), 1.34 (d, J=6.53 Hz, 3H); HPLC: RT 2.406 min;
MS: (M+H.sup.+) m/z: 381.1; SFC: RT 3.15 min.
N2-[1-[(2R)-2-(difluoromethoxy)propyl]-3-methyl-pyrazol-4-yl]-N4-methyl-5--
(trifluoromethyl)pyrimidine-2,4-diamine (D-20)
[0956] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.13 (br. s.,
1H), 7.89 (br. s., 1H), 6.58 (br. s., 1H), 5.85-6.31 (m, 1H), 5.19
(br. s., 1H), 4.55-4.69 (m, 1H), 4.13 (d, J=5.52 Hz, 2H), 3.06 (d,
J=4.52 Hz, 3H), 2.26 (s, 3H), 1.30 (d, J=6.53 Hz, 3H); HPLC: RT:
2.463 min; MS: (M+H.sup.+) m/z: 381.1; SFC: RT: 3.44 min.
Example D-23 and D-24
Synthesis of
N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-yl]-5-(difl-
uoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine (D-48) and
N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-yl]-N4-meth-
yl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-21)
Ethyl 2-(5-methyl-4-nitro-pyrazol-1-yl)propanoate and ethyl
2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate
[0957] To a solution of 3-methyl-4-nitro-1H-pyrazole (5 g, 39.34
mmol) in DMF (50 mL) was added NaH (1.89 g, 47.21 mmol, 60% purity)
at 0.degree. C. under N.sub.2. The mixture was stirred at
20.degree. C. for 1 h, then added with ethyl 2-chloropropanoate
(10.75 g, 78.68 mmol, 10.05 mL) and stirred for 15 h. The mixture
was poured into ice water (250 mL). The aqueous phase was extracted
with EtOAc (3.times.100 mL). The combined organic phase was washed
with brine (3-100 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (PE:EtOAc=2:1), to
give a mixture of ethyl 2-(5-methyl-4-nitro-pyrazol-1-yl)propanoate
and ethyl 2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate as a yellow
oil. LCMS: RT 0.745 min, m/z=228.2 [M+H].sup.+.
2-(5-methyl-4-nitro-pyrazol-1-yl)propan-1-ol and
2-(3-methyl-4-nitro-pyrazol-1-yl)propan-1-ol
[0958] To a mixture of ethyl
2-(5-methyl-4-nitro-pyrazol-1-yl)propanoate and ethyl
2-(3-methyl-4-nitro-pyrazol-1-yl)propanoate (9.3 g, 40.93 mmol) in
MeOH (90 mL) was added NaBH.sub.4 (3.87 g, 102.33 mmol) at
0.degree. C. under N.sub.2. The mixture was stirred at 0.degree. C.
for 2 h. The mixture was concentrated under reduced pressure and
purified by silica gel column chromatography (PE:EtOAc=3:1), to
give a mixture of 2-(5-methyl-4-nitro-pyrazol-1-yl)propan-1-ol and
2-(3-methyl-4-nitro-pyrazol-1-yl)propan-1-ol was obtained as a
yellow solid. LCMS: RT 0.707 min, m/z=222.1 [M+H].sup.+.
1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-4-nitro-pyrazole
and
1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-4-nitro-pyrazole
[0959] To a solution of
2-(5-methyl-4-nitro-pyrazol-1-yl)propan-1-ol,
2-(3-methyl-4-nitro-pyrazol-1-yl)propan-1-ol (2.08 g, 11.23 mmol)
and CuI (428 mg, 2.25 mmol) in CH:CN (20 mL) was added a solution
of 2,2-difluoro-2-fluorosulfonyl-acetic acid (3 g, 16.85 mmol, 1.74
mL) in CH.sub.3CN (10 mL) dropwise at 55.degree. C. over a period
of 30 min under N.sub.2. The reaction mixture was stirred at
55.degree. C. for 2.5 h. The mixture was concentrated under reduced
pressure and purified by silica gel column chromatography
(PE:EtOAc=6:1), to give a mixture of
1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-4-nitro-pyrazole
and
1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-4-nitro-pyrazole
was obtained as a yellow oil. LCMS: RT 0.758 min, m/z=236.52
[M+H].sup.+.
1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-amine and
1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-amine
[0960] To a mixture of
1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-4-nitro-pyrazole
and
1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-4-nitro-pyrazole
(760 mg, 3.23 mmol) in EtOH (20 mL) was added Fe (902.38 mg, 16.15
mmol) and NH.sub.4Cl (864 mg, 16.15 mmol, 564.87 .mu.L). The
mixture was stirred at 80.degree. C. for 2 h. The mixture was
cooled to 20.degree. C. and concentrated under reduced pressure.
The residue was poured into ice water (10 mL). The aqueous phase
was extracted with EtOAc (3.times.10 mL). The combined organic
phase was washed with brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure,
to give a crude
1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-amine and
1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-amine,
which was used into the next step without further purification.
LCMS: RT 1.026 min, m/z=186.1 [M+H].sup.+
N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-yl]-5-(diflu-
oromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine (D-48) and
N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-yl]-N4-meth-
yl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-21)
[0961] To a mixture of
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (372 mg,
1.75 mmol),
1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-amine and
1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-amine
(300 mg, 1.46 mmol) in 1,4-dioxane (10 mL) was added TEA (295 mg,
2.92 mmol, 404.75 .mu.L) in one portion under N.sub.2. The mixture
was stirred at 120.degree. C. for 2 h. The mixture was concentrated
under reduced pressure. The residue was purified by prep-HPLC
(FA).
N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-5-methyl-pyrazol-4-yl]-5-(diflu-
oromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine (D-48)
[0962] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.10 (s, 1H),
7.85 (br. s., 1H), 6.62 (br. s., 1H), 5.86-6.31 (m, 1H), 5.14 (br.
s., 1H), 4.44-4.55 (m, 1H), 4.22 (t, J=9.48 Hz, 1H), 4.08 (dd,
J=10.36, 5.07 Hz, 1H), 3.00 (d, J=4.85 Hz, 3H), 2.18-2.30 (m, 3H),
1.53 (d, J=7.06 Hz, 3H); HPLC: RT 1.94 min; MS: m/z=381.1
[M+H].sup.+
N2-[1-[2-(difluoromethoxy)-1-methyl-ethyl]-3-methyl-pyrazol-4-yl]-N4-methy-
l-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-21)
[0963] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.12 (br. s.,
1H), 7.92 (br. s., 1H), 6.97 (br. s., 1H), 5.88-6.38 (m, 1H), 5.21
(br. s., 1H), 4.47 (d, J=5.52 Hz, 1H), 3.99-4.20 (m, 2H), 3.06 (d,
J=2.89 Hz, 3H), 2.26 (s, 3H), 1.56 (d, J=6.78 Hz, 3H). HPLC: RT
1.93 min; MS: m/z: 381.1 [M+H].sup.+.
Example D-25, D-26, and D-27
Synthesis of
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (First
eluting stereoisomer, D-23),
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Second
eluting stereoisomer, D-24), and
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-22)
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-y-
l)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (First
eluting stereoisomer, D-23),
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Second
eluting stereoisomer, D-24), and
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-22)
[0964] To a solution of
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-pyrazol-4-amine
(200 mg, 984.06 .mu.mol) and
1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-pyrazol-4-amine
and 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (222 mg,
984.06 .mu.mol) in 1,4-dioxane (5 mL) was added TFA (56 mg, 492.03
.mu.mol). The mixture was stirred at 100.degree. C. for 1 h. The
reaction mixture was diluted with H.sub.2O (20 mL), and adjusted
with aq. NaHCO.sub.3 (10 mL) to pH 8 and extracted with EtOAc
(3.times.10 mL). The combined organic layers were washed with brine
(5 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The residue was purified by prep-HPLC (TFA)
to give crude
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Peak 1 in
HPLC) and racemic
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Peak 2 in
HPLC).
[0965] Crude
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine was further
purified by prep-HPLC (FA) to give
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-22, FA
salt, racemers). Racemic
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine was
separated by SFC to give
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-23, First
eluting stereoisomer in SFC), and
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4--
yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-24,
Second eluting stereoisomer in SFC).
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-y-
l)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (First
eluting stereoisomer, D-23)
[0966] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 7.99-8.07 (m,
1H), 7.77-7.87 (m, 1H), 7.20-7.27 (m, 1H), 7.08-7.17 (m, 1H),
5.70-5.79 (m, 1H), 4.26-4.36 (m, 1H), 4.08-4.22 (m, 1H), 3.38-3.52
(m, 2H), 3.18-3.30 (m, 1H), 2.74-2.90 (m, 1H), 2.22 (s, 3H),
1.07-1.24 (m, 3H); HPLC: RT 2.018 min; MS: m/z: 393.2 [M+H].sup.+;
SFC: RT 2.47 min.
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-1H-pyrazol-4-y-
l)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Second
eluting stereoisomer, D-24)
[0967] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 7.99-8.08 (m,
1H), 7.77-7.87 (m, 1H), 7.19-7.26 (m, 1H), 7.09-7.16 (m, 1H),
5.70-5.78 (m, 1H), 4.26-4.38 (m, 1H), 4.09-4.20 (m, 1H), 3.38-3.51
(m, 2H), 3.19-3.29 (m, 1H), 2.72-2.88 (m, 1H), 2.22 (s, 3H),
1.05-1.25 (m, 3H); HPLC: RT 2.016 min; MS: m/z: 393.2 [M+H].sup.+;
SFC: RT 2.67 min.
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-5-methyl-1H-pyrazol-4-y-
l)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-22)
[0968] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 8.11-8.24 (m,
1H), 7.95-8.07 (m, 1H), 7.49-7.75 (m, 1H), 7.25 (br. s., 1H),
7.09-7.21 (m, 1H), 5.88-6.01 (m, 1H), 4.35-4.51 (m, 1H), 4.12-4.29
(m, 1H), 3.41-3.57 (m, 2H), 3.22-3.31 (m, 1H), 2.84-3.04 (m, 1H),
2.34 (s, 3H), 1.18 (m, 3H); HPLC: RT 1.967 min: MS: m/z: 393.2
[M+H].sup.+.
Example D-28 and D-29
Synthesis of
trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-met-
hyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-25) and
trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-N4-met-
hyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-26)
cis-3-benzyloxycyclobutanol
[0969] To a solution of 3-benzyloxycyclobutanone (28-1, 19.7 g,
111.8 mmol) in MeOH (200 mL) was added NaBH.sub.4 (6.77 g, 178.9
mmol) at 0.degree. C., and the mixture was stirred at 15.degree. C.
for 2 h. The reaction mixture was poured into water (100 mL)
slowly. The methanol was removed under reduced pressure. The
residue was extracted with EtOAc (3.times.50 mL). The organic phase
was washed with brine (30 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated to give cis-3-benzyloxycyclobutanol as
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm
7.29-7.35 (m, 5H), 4.43 (s, 2H), 3.90-3.95 (m, 1H), 3.62-3.66 (m,
1H), 2.71-2.75 (m, 2H), 1.83-1.96 (m, 3H).
trans-1-(3-benzyloxycyclobutyl)-5-methyl-4-nitro-pyrazole and
trans-1-(3-benzyloxycyclobutyl)-3-methyl-4-nitro-pyrazole
[0970] To a solution of cis-3-benzyloxycyclobutanol (17 g, 95.4
mmol) and 3-methyl-4-nitro-1H-pyrazole (12.1 g, 95.4 mmol) in THF
(350 mL) was added PPh.sub.3 (37.5 g, 143 mmol). Then, DIAD (28.9
g, 143 mmol) was added slowly at 0.degree. C., and the mixture was
stirred at 15.degree. C. for 20 h. The mixture was quenched with
H.sub.2O (100 mL), then filtered. The filtrate was then extracted
with EtOAc (3.times.70 mL). The organic phase was washed with brine
(30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by silica gel column
chromatography (PE:EtOAc=10:1 to 7:1), to give
trans-1-(3-benzyloxycyclobutyl)-5-methyl-4-nitro-pyrazole and
trans-1-(3-benzyloxycyclobutyl)-3-methyl-4-nitro-pyrazole.
trans-3-[5-methyl-4-nitro-pyrazol-1-yl]cyclobutanol and
trans-3-[3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol
[0971] To a solution of
trans-1-(3-benzyloxycyclobutyl)-5-methyl-4-nitro-pyrazole and
trans-1-(3-benzyloxycyclobutyl)-3-methyl-4-nitro-pyrazole (19.5 g,
67.9 mmol) in DCM (200 mL) was added BCl.sub.3 (1 M, 26.5 mL) at
0.degree. C., and the mixture was stirred at 0.degree. C. for 2 h.
The mixture was poured into water (200 mL) slowly, then extracted
with DCM (2.times.100 mL). The organic phase was washed with
aqueous NaHCO.sub.3 (50 mL), brine (40 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel column chromatography (PE/EtOAc=2:1 to 1:1),
to give trans-3-[5-methyl-4-nitro-pyrazol-1-yl]cyclobutanol and
trans-3-[3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol as a mixture as
a white solid.
trans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-4-nitro-pyrazole
and
trans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-4-nitro-pyrazole
[0972] To a mixture of
trans-3-[5-methyl-4-nitro-pyrazol-1-yl]cyclobutanol and
trans-3-[3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol (1.4 g, 7.1
mmol) in CH.sub.3CN (100 mL) was added CuI (541 mg, 2.84 mmol) and
2,2-difluoro-2-fluorosulfonyl-acetic acid (1.9 g, 10.65 mmol) at
15.degree. C., and the mixture was stirred at 55.degree. C. for 2
h. The mixture was quenched with water (5 mL). The solvent was
filtered through celite and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (PE:EtOAc=10:1), to give
trans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-4-nitro-pyrazole
and
trans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-4-nitro-pyrazole
as a yellow solid.
trans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-amine
and
trans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-amine
[0973] To a mixture of
trans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-4-nitro-pyrazole
and
trans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-4-nitro-pyrazole
(350 mg, 1.42 mmol) and NH.sub.4Cl (379 mg, 7.08 mmol) in EtOH (8.8
mL) and H.sub.2O (2.2 mL) was added powder Fe (395 mg, 7.08 mmol)
at 15.degree. C., then the mixture was stirred at 80.degree. C. for
2 h. The mixture was filtered through celite, and the filtrate was
concentrated under reduced pressure. The mixture was extracted with
EtOAc (2.times.30 mL). The organic phase was washed with brine (10
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to give
trans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-amine
and
trans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-amine as
a brown oil. LCMS: RT 2.06 min, m/z=393.1 [M+H].sup.+.
trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-meth-
yl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-25) and
trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-N4-met-
hyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-26)
[0974] To a mixture of
trans-1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-amine
and
trans-1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-amine
(270 mg, 1.24 mmol) in 1,4-dioxane (10 mL) was added
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (262 mg,
1.24 mmol) and TsOH-H.sub.2O (236 mg, 1.24 mmol) at 15.degree. C.
The mixture was warmed to 90.degree. C. and stirred for 2 h. The
reaction was quenched with H.sub.2O (1 mL), then concentrated under
reduced pressure. The crude was purified by prep-HPLC (FA) to give
trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-met-
hyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (25) and
trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-N4-met-
hyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (26).
trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-5-methyl-pyrazol-4-yl]-N4-meth-
yl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-25)
[0975] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.08 (s, 1H)
7.71-7.98 (br. s., 1H), 6.23 (t, J=3.2 Hz, 1H), 5.20 (t, J=3.2 Hz,
1H), 4.1 (t, J=3.2 Hz, 1H), 4.75 (br. s., 1H), 3.03 (s, 3H),
2.97-3.03 (m, 2H), 2.68-2.73 (m, 2H), 2.20 (s, 3H): HPLC: RT 2.06
min; MS: m/z: 393.1 [M+H].sup.+.
trans-N2-[1-[3-(difluoromethoxy)cyclobutyl]-3-methyl-pyrazol-4-yl]-N4-meth-
yl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-26)
[0976] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.21 (s, 1H),
8.07 (br. s., 1H), 7.89 (s, 1H), 6.22 (t, J=3.2 Hz, 1H), 5.34 (br.
s., 1H), 4.96-5.02 (m, 1H), 4.81-4.90 (m, 1H) 3.04-3.15 (m, 3H),
2.84-2.96 (m, 2H), 2.65-2.78 (m, 2H), 2.31 (s, 3H); HPLC: RT 2.06
min; NIS: m/z: 393.1 [M+H].sup.+.
Example D-30 and D-31
Synthesis of
cis-N4-methyl-N2-[5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(t-
rifluoromethyl)pyrimidine-2,4-diamine (D-49) and
cis-N4-methyl-N2-[3-methyl-1-(3-pyrazol-1-ylcyclo
butyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-27)
cis-[3-[(1R)-5-methyl-4-nitro-pyrazol-1-yl]cyclobutyl]
methanesulfonate and
cis-[3-[(1S)-3-methyl-4-nitro-pyrazol-1-yl]cyclobutyl]
methanesulfonate
[0977] To a mixture of
3-[(1R)-5-methyl-4-nitro-pyrazol-1-yl]cyclobutanol and
3-[(1R)-3-methyl-4-nitro-pyrazol-1-yl]cyclobutanol (2 g, 10.14
mmol) in DCM (20 mL) was added TEA (2.05 g, 20.29 mmol) and MsCl
(1.74 g, 15.21 mmol) at 0.degree. C., then stirred at 20.degree. C.
for 30 min. The reaction mixture was quenched by water (100 mL) at
0.degree. C., and extracted with DCM (2.times.50 mL). The combined
organic layers were washed with brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give the crude product, which was used to the next step directly
without purification. The mixture of
[3-[(1R)-5-methyl-4-nitro-pyrazol-1-yl]cyclobutyl] methanesulfonate
and [3-[(1S)-3-methyl-4-nitro-pyrazol-1-yl]
cyclobutyl]methanesulfonate was obtained as a yellow solid. LCMS:
RT 0.715 min, m/z=276.2 [M+H].sup.+.
cis-5-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole and
cis-3-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole
[0978] To a mixture of 1H-pyrazole (30-3, 297 mg, 4.36 mmol) in DMF
(10 mL) was added NaH (174 mg, 4.36 mmol, 60% purity) at 0.degree.
C. and stirred for 30 min, then added the mixture of
[3-[(1R)-5-methyl-4-nitro-pyrazol-1-yl] cyclobutyl]
methanesulfonate and
[3-[(1S)-3-methyl-4-nitro-pyrazol-1-yl]cyclobutyl] methanesulfonate
(1 g, 3.63 mmol) in DMF (1 mL), then heated to 60.degree. C. and
stirred for 16 h. Then, a mixture of 1H-pyrazole (297 mg, 4.36
mmol) and NaH (174 mg, 4.36 mmol) in DMF (3 mL) was added into the
reaction at 0.degree. C., then heated to 60.degree. C. and stirred
for 16 h. The reaction mixture was quenched by aq. sat. NH.sub.4Cl
(100 mL) at 0.degree. C., and extracted with EtOAc (3.times.50 mL).
The combined organic layers were washed with brine (50 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give a residue, which was purified by silica gel column
chromatography (EtOAc/PE=0-50%). The mixture of
cis-5-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole and
cis-3-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole was
obtained as a yellow solid. LCMS: RT 0.730 min, m/z=248.2
[M+H].sup.+.
cis-5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine and
cis-3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine
[0979] To a mixture of
5-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole and
(1S)-3-methyl-4-nitro-1-(3-pyrazol-1-ylcyclobutyl)pyrazole (400 mg,
1.62 mmol) in EtOH (8 mL) and H.sub.2O (2 mL) was added Fe (271 mg,
4.86 mmol) and NH.sub.4Cl (260 mg, 4.86 mmol) at 0.degree. C. The
mixture was heated to 90.degree. C. for 1 h. The mixture was
filtered and the filtrate was concentrated under reduced pressure
to give a residue. The residue was dissolved in acetonitrile (10
mL), and then filtered. The filtrate was concentrated under reduced
pressure to give crude mixture of
cis-5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine and
cis-3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine as a brown
oil, which was used to the next step without purification. LCMS: RT
1.126 min, m/z=218.2 [M+H].sup.+.
cis-N4-methyl-N2-[5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(tr-
ifluoromethyl)pyrimidine-2,4-diamine (D-49) and
cis-N4-methyl-N2-[3-methyl-1-(3-pyrazol-1-ylcyclo
butyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-27)
[0980] To a mixture of
cis-5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine and
cis-3-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-amine (180 mg,
828 .mu.mol) in 1,4-dioxane (5 mL) was added TsOH.H.sub.2O (48 mg,
249 .mu.mol) and
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (175 mg, 828
.mu.mol) at 20.degree. C. The mixture was heated to 80.degree. C.
and stirred for 2 h. The mixture was added with water (1 mL) and
stirred for 2 min, then concentrated under reduced pressure to give
a residue, which was purified by prep-HPLC (FA condition) to give
cis-N4-methyl-N2-[5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(t-
rifluoromethyl)pyrimidine-2,4-diamine (D-49) and
cis-N4-methyl-N2-[3-methyl-1-(3-pyrazol-1-ylcyclo
butyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-27).
cis-N4-methyl-N2-[5-methyl-1-(3-pyrazol-1-ylcyclobutyl)pyrazol-4-yl]-5-(tr-
ifluoromethyl)pyrimidine-2,4-diamine (D-49)
[0981] .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 2.24 (s, 3H)
2.96-3.18 (m, 5H) 3.22-3.36 (m, 2H) 4.50-4.61 (m, 1H) 4.68-4.80 (m,
1H) 5.18 (br. s., 1H) 6.31 (d, J=2.20 Hz, 1H) 6.84 (br. s., 1H)
7.54 (s, 1H) 7.67 (br. s., 1H) 7.90 (br. s., 1H) 8.09 (br. s., 1H);
HPLC: RT 1.72 min; MS: m/z: 393.1 [M+H].sup.+.
cis-N4-methyl-N2-[3-methyl-1-(3-pyrazol-1-ylcyclo
butyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-27)
[0982] .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 2.28 (s, 3H)
3.13 (t, J=8.16 Hz, 7H) 4.53-4.75 (m, 2H) 5.25 (br. s., 1H) 6.29
(s, 1H) 6.99 (d, J=13.23 Hz, 1H) 7.55 (br. s., 2H) 8.13 (br. s.,
1H) 8.21 (br. s., 1H); HPLC: RT 1.91 min: MS: m/z: 393.1
[M+H].sup.+.
Example D-32 and D-33
Synthesis of
cis-N4-methyl-N2-[5-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5--
(trifluoromethyl)pyrimidine-2,4-diamine (D-50) and
cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfonyl
cyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-28)
cis-5-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole and
cis-3-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole
[0983] To a mixture of
cis-[3-[5-methyl-4-nitro-pyrazol-1-yl]cyclobutyl] methanesulfonate
and
cis-[3-[-3-methyl-4-nitro-pyrazol-1-yl]cyclobutyl]methanesulfonate
(1 g, 3.63 mmol) in NMP (10 mL) was added NaSMe (1.02 g, 14.52
mmol) at 20.degree. C. The mixture was heated to 100.degree. C. and
stirred for 16 h. The reaction mixture was quenched by aq. sat.
NH.sub.4Cl (100 mL) at 0.degree. C., and extracted with EtOAc
(3.times.50 mL). The combined organic phases were washed with brine
(50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give a residue. The residue was purified
by silica gel column chromatography (PE:EtOAc=30:1 to 10:1), to
give a mixture of
cis-5-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole and
cis-3-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole as a
yellow oil. LCMS: RT 0.798 min, m/z=228.2 [M+H].sup.+.
cis-5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine and
cis-3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine
[0984] To a mixture of
cis-5-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole and
cis-3-methyl-1-(3-methylsulfanylcyclobutyl)-4-nitro-pyrazole (200
mg, 879.97 .mu.mol) in EtOH (4 mL) and H.sub.2O (1 mL) was added Fe
(148 mg, 2.64 mmol) and NH.sub.4Cl (141 mg, 2.64 mmol) at 0.degree.
C. The mixture was heated to 90.degree. C. for 1 h. The mixture was
filtered and the filtrate was concentrated under reduced pressure
to give a residue. Then, the residue was dissolved by MeCN (5 mL)
and filtered. The filtrate was concentrated under reduce pressure
to give crude
cis-5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine and
cis-3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine as brown
oil, which was used in the next step without purification. LCMS: RT
1.113 min, m/z=198.1 [M+H].sup.+.
cis-N4-methyl-N2-[(5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5--
(trifluoromethyl)pyrimidine-2,4-diamine and
cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5--
(trifluoromethyl)pyrimidine-2,4-diamine
[0985] To a mixture of
cis-5-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine and
cis-3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-amine (190 mg,
963 .mu.mol) in 1,4-dioxane (4 mL) was added
2-chloro-N-methyl-5-(trifluormethyl)pyrimidin-4-amine (204 mg, 963
.mu.mol) and TsOH-H.sub.2O (55 mg, 289 .mu.mol) at 20.degree. C.
The mixture was heated to 80.degree. C. and stirred for 2 h. The
mixture was added with water (1 mL) and stirred for 3 min, then
concentrated under reduced pressure to give a residue, which was
purified by silica gel column chromatography (DCM:MeOH=20:1 to
5:1), to give a mixture of
cis-N4-methyl-N2-[-5-methyl-1-(3-methylsulfanylcyclobutyl)
pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine and
cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5--
(trifluoromethyl)pyrimidine-2,4-diamine as a yellow oil. LCMS: RT
2.747 min, m/z=373.1 [M+H].sup.+.
cis-N4-methyl-N2-[5-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(-
trifluoromethyl)pyrimidine-2,4-diamine (D-50) nd
cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfonyl
cyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-28)
[0986] To a mixture of
N4-methyl-N2-[(1R)-5-methyl-1-(3-methylsulfanyl
cyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
and
N4-methyl-N2-[(1S)-3-methyl-1-(3-methylsulfanylcyclobutyl)pyrazol-4-yl]-5-
-(trifluoromethyl)pyrimidine-2,4-diamine (280 mg, 752 .mu.mol) in
THF (5 mL) and H.sub.2O (1 mL) was added oxone (229 mg, 1.5 mmol)
at 0.degree. C. The mixture was stirred at 20.degree. C. for 2 h.
The mixture was quenched by aq. Na.sub.2S.sub.2O.sub.3 (60 mL) and
extracted with EtOAc (3.times.20 mL). The organic phase was washed
by brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated
under reduced pressure to give a residue, which was purified by
prep-HPLC (FA condition) to give
cis-N4-methyl-N2-[5-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5--
(trifluoromethyl)pyrimidine-2,4-diamine (D-50) and
cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfonyl
cyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-28).
cis-N4-methyl-N2-[5-methyl-1-(3-methylsulfonylcyclobutyl)pyrazol-4-yl]-5-(-
trifluoromethyl)pyrimidine-2,4-diamine (D-50)
[0987] .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 2.23 (br.
s., 3H) 2.79-2.86 (m, 2H) 2.94 (s, 3H) 3.04 (d, J=4.85 Hz, 3H) 3.27
(q, J=9.70 Hz, 2H) 3.57-3.67 (m, 1H) 4.69 (quint., J=8.05 Hz, 1H)
5.20 (br. s., 1H) 6.27 (br. s., 1H) 7.94 (br. s., 1H) 8.07 (br. s.,
1H); HPLC: RT 1.24 min: MS: m/z: 405.1 [M+H].sup.+.
cis-N4-methyl-N2-[3-methyl-1-(3-methylsulfonyl
cyclobutyl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-28)
[0988] .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 2.27 (s, 3H)
2.88 (s, 3H) 2.90-3.04 (m, 4H) 3.14 (br. s., 3H) 3.61 (quint.
J=8.60 Hz, 1H) 4.80 (br. s., 1H) 5.32 (br. s., 1H) 7.46 (br. s.,
1H) 8.10 (br. s., 1H) 8.23 (s, 1H): HPLC: RT 2.58 min; MS: m/z:
405.1 [M+H].sup.+.
Example D-34 and D-35
Synthesis of
trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-y-
l]amino]-5-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile (D-29) and
trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-y-
l]amino]-3-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile (D-30)
trans-methyl
3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate and
trans-methyl
3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate
[0989] To a solution of methyl 3-hydroxycyclobutanecarboxylate (2
g, 15.37 mmol), 5-methyl-4-nitro-1H-pyrazole (1.95 g, 15.37 mmol)
and PPh: (6.05 g, 23.06 mmol) in THF (30 mL) was added dropwise
DIAD (4.66 g, 23.06 mmol, 4.48 mL) at 0.degree. C. and degassed and
purged with N.sub.2 for 3 times, and then the mixture was stirred
at 25.degree. C. for 16 h under N.sub.2. The reaction mixture was
concentrated under reduced pressure to remove THF. The residue was
washed with PE:EtOAc (1:1, 30 mL), filtered and concentrated under
reduced pressure to give a residue. The residue was purified by
column chromatography (SiO.sub.2. PE:EtOAc=10:1 to 5:1) to give the
mixture of trans-methyl
3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate and
trans-methyl
3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate as a white
solid. LCMS: RT 0.729 min, m/z=240.2 [M+H].sup.+.
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol and
trans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol
[0990] To a solution of methyl
3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate and methyl
3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate (1.7 g,
7.11 mmol, mixture) in MeOH (20 mL) was added NaBH.sub.4 (672 mg,
17.77 mmol) at 0.degree. C. The mixture was stirred at 25.degree.
C. for 2 h. The reaction mixture was quenched by addition of aq.
NH.sub.4Cl (20 mL) at 0.degree. C., and extracted with EtOAc
(3.times.10 mL), washed with brine (5 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography (SiO.sub.2,
PE:EtOAc=5:1 to 1:1) to give the mixture of
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol and
trans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol as a
yellow solid. LCMS: RT 0.645 min, m/z=212.2 [M+H].sup.+.
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methyl
methanesulfonate and
trans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methyl
methanesulfonate
[0991] To a solution of
[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol and
[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol (300 mg, 1.42
mmol, mixture) in DCM (10 mL) was added MsCl (243 mg, 2.13 mmol,
164.86 L) and TEA (287 mg, 2.84 mmol) at 0.degree. C. Then the
mixture was stirred at 25.degree. C. for 20 min. The reaction
mixture was concentrated under reduced pressure to remove
CH.sub.3CN (10 mL). The reaction mixture was quenched by addition
water (20 mL) at 0.degree. C., and then extracted with DCM
(3.times.10 mL). The combined organic layers were washed with brine
10 mL, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to give the mixture of
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methyl
methanesulfonate and
trans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methyl
methanesulfonate as a yellow oil. LCMS: RT 0.746 min, m/z=290
[M+H].sup.+.
trans-2-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile
and
trans-2-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile
[0992] A mixture of
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methyl
methanesulfonate and
trans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methyl
methanesulfonate (500 mg, 1.73 mmol), KCN (563 mg, 8.65 mmol) in
DMF (10 mL) was degassed and purged with N.sub.2 for 3 times, and
then the mixture was stirred at 65.degree. C. for 12 h under
N.sub.2. The reaction mixture was quenched by addition H.sub.2O 50
mL at 0.degree. C. and then extracted with EtOAc (3.times.10 mL).
The combined organic layers were washed with brine 10 mL, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give the mixture compound
trans-2-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile
and
trans-2-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile
as a red oil. LCMS: RT 0.792 min, m/z=221 [M+H].sup.+.
trans-2-[3-(4-amino-5-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile
and
trans-2-[3-(4-amino-3-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile
[0993] A mixture of
2-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile, and
2-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]acetonitrile (300
mg, 1.36 mmol), Fe (379 mg, 6.80 mmol), NH.sub.4Cl (363 mg, 6.80
mmol) in EtOH (4 mL) and H.sub.2O (1 mL) was degassed and purged
with N.sub.2 for 3 times, and then the mixture was stirred at
80.degree. C. for 2 h under N.sub.2 atmosphere. The reaction
mixture was concentrated under reduced pressure to remove EtOH. The
residue was diluted with H.sub.2O (20 mL) and extracted with EtOAc
(3.times.10 mL). The combined organic layers were washed with
aqueous brine 10 mL, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give the mixture compound
trans-2-[3-(4-amino-5-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile
and
trans-2-[3-(4-amino-3-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile
as a red oil. LCMS: RT 0.099 min, m/z=191 [M+H].sup.+.
trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl-
]amino]-5-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile (D-29) and
trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-y-
l]amino]-3-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile (D-30)
[0994] To a solution of
2-[3-(4-amino-5-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile, and
2-[3-(4-amino-3-methyl-pyrazol-1-yl)cyclobutyl]acetonitrile (100
mg, 525.62 .mu.mol) in 1,4-dioxane (3 mL) was added TsOH (45 mg,
262.81 .mu.mol) and
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (89 mg,
420.50 .mu.mol). The mixture was stirred at 80.degree. C. for 2 h.
The reaction mixture was concentrated under reduced pressure, and
then purified by twice of prep-HPLC (FA condition, followed by
neutral condition), to give desired compound
trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-y-
l]amino]-5-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile (D-29) and
compound
trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-y-
l]amino]-3-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile (D-30).
LCMS: RT 0.765 min, m/z=366.1 [M+H].sup.+.
trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl-
]amino]-5-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile (D-29)
[0995] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.18 (s, 3H)
2.42 (ddd, J=12.57, 8.38, 3.75 Hz, 2H) 2.62 (d, J=6.62 Hz, 2H)
2.89-3.01 (m, 3H) 3.03 (d, J=4.85 Hz, 3H) 4.82-4.94 (m, 1H) 5.15
(br. s., 1H) 8.10 (s, 1H); HPLC: RT 2.71 min; MS: m/z: 366.1
[M+H].sup.+.
trans-2-[3-[4-[[5-(difluoromethyl-fluoranyl)-4-(methylamino)pyrimidin-2-yl-
]amino]-3-methyl-pyrazol-1-yl]cyclobutyl]acetonitrile (D-30)
[0996] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.28 (s, 3H)
2.42 (t, J=8.38 Hz, 2H) 2.60 (d, J=5.73 Hz, 2H) 2.79-2.93 (m, 3H)
2.99-3.14 (m, 3H) 4.77-4.90 (m, 1H) 5.18 (br. s., 1H) 6.54 (br. s.,
1H) 7.88 (br. s., 1H) 8.14 (br. s., 1H); HPLC: RT 1.55 min; MS:
m/z: 366.1 [M+H].sup.+.
Example D-36 and D-37
Synthesis of
trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-yl]--
5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine
(D-31) and
trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-yl]--
5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine
(D-32)
trans-methyl
3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate and
trans-methyl
3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate
[0997] To a solution of methyl 3-hydroxycyclobutanecarboxylate (2
g, 15.37 mmol), 5-methyl-4-nitro-1H-pyrazole (1.95 g, 15.37 mmol)
and PPh.sub.3 (6.05 g, 23.06 mmol) in THF (30 mL) was added
dropwise DIAD (4.66 g, 23.06 mmol, 4.48 mL) at 0.degree. C. and
degassed and purged with N.sub.2 for 3 times, and then the mixture
was stirred at 25.degree. C. for 16 h under N.sub.2. The reaction
mixture was concentrated under reduced pressure to remove THF. The
residue was washed with PE:EtOAc (1:1, 30 mL), filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (SiO.sub.2, PE:EtOAc=10:1 to 5:1) to give the
mixture of trans-methyl
3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate and
trans-methyl
3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate as a white
solid. LCMS: RT 0.729 min, m/z=240.2 [M+H].sup.+.
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol and
trans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol
[0998] To a solution of trans-methyl
3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate, and
trans-methyl
3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarboxylate (1.7 g,
7.11 mmol, mixture) in MeOH (20 mL) was added NaBH.sub.4 (672 mg,
17.77 mmol) at 0.degree. C. The mixture was stirred at 25.degree.
C. for 2 h. The reaction mixture was quenched by addition of aq.
NH.sub.4Cl (20 mL) at 0.degree. C., and extracted with EtOAc
(3.times.10 mL), washed with brine (5 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography (SiO.sub.2,
PE:EtOAc=5:1 to 1:1) to give the mixture of
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol and
trans-[3-(3-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol as a
yellow solid. LCMS: RT 0.645 min, m/z=212.2 [M+H].sup.+.
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-4-nitro-pyrazole
and
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-4-nitro-pyrazo-
le
[0999] A mixture of
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol, and
trans-[3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutyl]methanol (500
mg, 2.37 mmol, mixture), CuI (90 mg, 474.00 .mu.mol),
2,2-difluoro-2-(fluorosulfonyl)acetic acid (633 mg, 3.56 mmol, 368
.mu.L) in CH.sub.3CN (10 mL) was degassed and purged with N.sub.2
for 3 times, and then the mixture was stirred at 55.degree. C. for
2 h under N.sub.2. The reaction mixture was concentrated under
reduced pressure to remove CH.sub.3CN (10 mL). The residue was
purified by prep-TLC (SiO.sub.2. PE:EtOAc=3:1) to give the mixture
of
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-4-nitro-pyrazole
and
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-4-nitro-pyrazo-
le as a colorless oil. LCMS: RT 0.834 min, m/z=262 [M+H].sup.+.
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-amine
and
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-amine
[1000] To a solution of
1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-4-nitro-pyrazole,
and
1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-4-nitro-pyrazole
(300 mg, 1.15 mmol, mixture) in EtOH (4 mL) and H.sub.2O (1 mL) was
added Fe (321 mg, 5.75 mmol) and NH.sub.4Cl (307 mg, 5.75 mmol).
The mixture was stirred at 80.degree. C. for 2 h. The reaction
mixture was concentrated under reduced pressure to remove EtOH. The
residue was diluted with H.sub.2O (10 mL) and extracted with EtOAc
(3.times.10 mL). The combined organic layers were washed with brine
(10 mL, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give the mixture compound
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-amine
and
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-amin-
e as a red oil. LCMS: RT 0.266 min, m/z=232 [M+H].sup.+.
trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-yl]-5-
-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine (D-31)
and
trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-yl]--
5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine
(D-32)
[1001] A mixture of
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (123 mg,
583.81 .mu.mol),
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-amine,
and
trans-1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-amin-
e (150 mg, 648.68 .mu.mol, mixture), TsOH (11 mg, 648.68 .mu.mol)
in 1,4-dioxane (2 mL) was degassed and purged with N.sub.2 for 3
times, and then the mixture was stirred at 80.degree. C. for 2 h
under N.sub.2. The reaction mixture was concentrated under reduced
pressure. The residue was purified by prep-HPLC (FA condition), to
give desired compound
trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-yl]--
5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine
(D-31) and compound
trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyraz-
ol-4-yl]-5-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine
(D-32). LCMS: RT 0.720 min, m/z=407.3 [M+H].sup.+.
trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-5-methyl-pyrazol-4-yl]-5-
-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine
(D-31)
[1002] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.19 (s, 3H)
2.32-2.41 (m, 2H) 2.69-2.81 (m, 1H) 2.84-2.96 (m, 2H) 3.03 (d,
J=4.85 Hz, 3H) 3.95-4.04 (m, 2H) 4.78 (quin, J=7.94 Hz, 1H) 5.18
(br. s., 1H) 6.08-6.51 (m, 2H) 8.08 (s, 1H): HPLC: RT 2.07 min; MS:
m/z: 407.1 [M+H].sup.+.
trans-N2-[1-[3-(difluoromethoxymethyl)cyclobutyl]-3-methyl-pyrazol-4-yl]-5-
-(difluoromethyl-fluoranyl)-N4-methyl-pyrimidine-2,4-diamine
(D-32)
[1003] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.29 (s, 3H)
2.40 (t, J=8.82 Hz, 2H) 2.62-2.80 (m, 3H) 3.08 (br. s., 3H) 3.97
(d, J=5.73 Hz, 2H) 4.67-4.84 (m, 1H) 5.30 (br. s., 1H) 6.06-6.49
(m, 2H) 7.89 (br. s., 1H) 8.09 (br. s., 1H); HPLC: RT 2.06 min; MS:
m/z: 407.3.
Example D-38
Synthesis of
2-(1-((5-chloro-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)ami-
no)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile (D-33)
[1004] A mixture of
2-[1-[(4-amino-5-chloro-pyrazol-1-yl)methyl]cyclopropyl]acetonitrile
(70 mg, 332.29 .mu.mol),
2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (70 mg,
332.29 .mu.mol) and TFA (76 mg, 664.58 .mu.mol) in dioxane (3 mL)
was degassed and purged with N.sub.2 for 3 times, and then the
mixture was stirred at 100.degree. C. for 2 h under N.sub.2. The
reaction mixture was concentrated under reduced pressure. The
residue was diluted with H.sub.2O (20 mL), adjusted pH to 8 by
adding aq. NaHCO.sub.3 and then extracted with EtOAc (3.times.10
mL). The combined organic layers were washed with brine (10 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by prep-HPLC (neutral
condition) to give
2-(1-((5-chloro-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)ami-
no)-1H-pyrazol-1-yl)methyl)cyclopropyl)acetonitrile (D-33). .sup.1H
NMR (400 MHz. CDCl.sub.3): .delta. ppm 8.26 (s, 1H), 8.20 (s, 1H),
7.16 (br. s., 1H), 5.30 (br. s., 1H), 4.32 (s, 2H), 3.43 (s, 2H),
3.11 (d, J=4.77 Hz, 3H), 0.97-1.02 (m, 2H), 0.78-0.82 (in, 2H):
HPLC: RT 2.50 min; MS: m/z: 386.0 [M+H].sup.+.
Example D-39
Synthesis of
N.sub.1-methyl-N.sup.2-(3-methyl-1-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrid-
in-8-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-34)
##STR00499##
[1006] Compound 39-1 was combined with BnBr and CsCO.sub.3 mn DMF
to give compound 39-2. Compound 39-2 was combined with
2-chloroacetaldehyde and K.sub.2CO.sub.3 in DMF to give compound
39-3. To compound 39-3 in MeOH was added Pd/C, and the mixture was
stirred under H.sub.2 to produce compound 39-4. Compound 39-4 was
combined with compound 1-1, PPh.sub.3, and DIAD in THF to give
compound 39-5. To compound 39-5 in MeOH was added Pd/C, and the
mixture was stirred under H.sub.2 to produce compound 39-6.
Compound 39-6, compound 5-5, and TsOH were combined in 1,4-dioxane
to give compound D-34. MS m/z=393.1 [M+H].sup.+.
Example D-40
Synthesis of
N.sup.2-(1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-yl)-3-methyl-1H-pyrazo-
l-4-yl)-N.sup.1-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-36)
##STR00500##
[1008] Compound 40-1 is first combined with methyl acrylate, and
the subsequent product is then combined with potassium t-butoxide
to give compound 40-2. To Compound 40-2 is added HCl to give
compound 40-3. Compound 40-3 is combined with NaBH.sub.4 in MeOH to
produce compound 40-4. Compound 40-4 is combined with compound 1-1,
PPh.sub.3, and DIAD in THF to give compound 40-5. To compound 40-5
in MeOH is added Pd/C, and the mixture is stirred under H.sub.2 to
produce compound 40-6. Compound 40-6, compound 5-5, and TsOH are
combined in 1,4-dioxane to give compound D-36.
[1009] Compound D-36 can also be synthesized according to the
scheme below.
##STR00501##
[1010] Compound 40-7 was combined with trityl chloride and TEA in
DMF to give compound 40-8. Compound 40-8 was combined with
vinylmagnesium bromide in THF to give compound 40-9. Compound 40-9
was combined with MnO.sub.2 in dioxane to give compound 40-10.
Compound 40-10 was combined with HBr and acetic acid to give
Compound 40-11. Compound 40-11 was combined with Cs.sub.2CO.sub.3
in acetonitrile to give compound 40-3. Compound 40-3 was combined
with NaBH.sub.4 in MeOH to produce compound 40-4. Compound 40-4 was
combined with compound 1-1, PPh.sub.3, and DIAD in THF to give
compound 40-5. To compound 40-5 in MeOH was added Pd/C. and the
mixture is stirred under H.sub.2 to produce compound 40-6. Compound
40-6, compound 5-5, and TsOH were combined in 1,4-dioxane to give
compound D-36. MS m/z=379.2 [M+H].sup.+.
Example D-41
Synthesis of
N.sup.2-(1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-3-methyl-1H-pyraz-
ol-4-yl)-N.sup.1-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-38)
##STR00502##
[1012] Compound 41-1 was combined with trityl chloride and TEA in
DMF, and vinylmagnesium bromide was subsequently added to give
compound 41-2. Compound 41-2 was combined with MnO.sub.2, and HBr
was subsequently added to give compound 41-3. Compound 41-3 was
combined with TEA in MeCN, and NaBH.sub.4 was subsequently added to
give compound 41-4. Compound 41-4 was combined with compound 1-1,
PPh.sub.3, and DIAD in THF to give compound 41-5. To compound 41-5
in MeOH was added Pd/C, and the mixture was stirred under H.sub.2
to produce compound 41-6. Compound 41-6, compound 5-5, and TsOH
were combined in 1,4-dioxane to give compound D-38.
Example D-42
Synthesis of
N.sup.1-methyl-N.sup.2-(3-methyl-1-(3-methyl-5,6-dihydro-4H-cyclopenta[d]-
isoxazol-6-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-35)
##STR00503##
[1014] Compound 42-1 was combined with acetaldehyde oxime,
N-chlorosuccinimide, and NaHCO.sub.3 to give compound 42-2.
Compound 42-2 was combined with NaBH.sub.4 in MeOH to provide
compound 42-3. Compound 42-3 was combined with compound 1-1,
PPh.sub.3, and DIAD in THF to give compound 42-4. To compound 42-4
in MeOH was added Pd/C, and the mixture was stirred under H.sub.2
to produce compound 42-5. Compound 42-5, compound 5-5, and TsOH
were combined in 1,4-dioxane to give compound D-35. MS m/z=394.1
[M+H].sup.+.
Example D-43
Synthesis of
N.sup.1-methyl-N.sup.2-(3-methyl-1-(1-methyl-1,4,5,6-tetrahydrocyclopenta-
[c]pyrazol-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamin-
e (D-37)
##STR00504##
[1016] Compound 43-1 was combined with methyl hydrazine to give
compound 43-2. Compound 43-2 was combined with NaBH.sub.4 in MeOH
to give compound 43-3. Compound 43-3 was combined with compound
1-1, PPh.sub.3, and DIAD in THF to give compound 43-4. To compound
43-4 in MeOH was added Pd/C, and the mixture was stirred under
H.sub.2 to produce compound 43-5. Compound 43-5, compound 5-5, and
TsOH were combined in 1,4-dioxane to give compound D-37. MS
m/z=393.1 [M+H].sup.+.
Example D-44
Synthesis of
N2-(1-(5,6-dihydro-4H-cyclopenta[d]thiazol-6-yl)-3-methyl-1H-pyrazol-4-yl-
)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-53),
N2-(1-(5,6-dihydro-4H-cyclopenta[d]oxazol-6-yl)-3-methyl-1H-pyrazol-4-yl)-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-54),
N2-(1-(5,6-dihydro-4H-cyclopenta[d]oxazol-4-yl)-3-methyl-1H-pyrazol-4-yl)-
-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-51), and
N.sup.1-methyl-N.sup.2-(3-methyl-1-(1,4,5,6-tetrahydrocyclopenta[c]pyrazo-
l-6-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-39)
[1017] Compounds D-53, D-43, D-51, and D-39 can be prepared
according to the following general scheme, wherein: X is S, Y is
CH, and Z is N for compound D-53; X is O, Y is CH, and Z is N for
compound D-54; X is N. Y is CH, Z is O for compound D-51; and X is
NH, Y is N, and Z is CH for compound D-39.
##STR00505## ##STR00506##
[1018] Compound 44-1 is combined with methyl acrylate.
Pd(PPh.sub.3).sub.4, and TEA. Then, to the subsequent product is
added Pd/C, and the mixture is stirred under H.sub.2 to produce
compound 44-2. Compound 44-2 is combined with potassium t-butoxide,
followed by HCl, to give compound 44-3. Compound 44-3 is combined
with NaBH.sub.4 in MeOH to give compound 44-4. Compound 44-4 is
combined with compound 1-1, PPh.sub.3, and DIAD in THF to give
compound 44-5. To compound 44-5 in MeOH is added Pd/C, and the
mixture is stirred under H.sub.2 to produce compound 44-6. Compound
44-6, compound 5-5, and TsOH are combined in 1,4-dioxane to give
compound 44-7.
Example D-45
Synthesis of
N.sup.2-(1-(2-chloro-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)-3-methyl-
-1H-pyrazol-4-yl)-N.sub.1-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine
(D-41)
##STR00507##
[1020] Compound 45-1 is combined with compound 1-1, PPh.sub.3, and
DIAD in THF to give compound 45-2. Compound 45-2 is combined with
N-chlorosuccinimide to give compound 45-3. To compound 45-3 in MeOH
is added Pd/C, and the mixture is stirred under H.sub.2 to produce
compound 45-4. Compound 45-4, compound 5-5, and TsOH are combined
in 1,4-dioxane to give compound D-41.
Example D-46
Synthesis of
N2-(1-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-5-methyl-1H-pyrazol-4--
yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-55)
##STR00508##
[1022] Compound 46-1 is combined with TBSCl and imidazole in DMF,
and then Et.sub.3OBF.sub.4 is subsequently added to give compound
46-2. Compound 46-2 is combined with 2,2-diethoxyethan-1-amine and
HCl in EtOH to give compound 46-3. Compound 46-3 is combined with
HCl in 1,4-dioxane to give compound 46-4. Compound 46-4 is combined
with compound 1-1, PPh.sub.3, and DIAD in THF to give compound
46-5. To compound 46-5 in MeOH is added Pd/C, and the mixture is
stirred under H.sub.2 to produce compound 46-6. Compound 46-6,
compound 5-5, and TsOH are combined in 1,4-dioxane to give compound
D-55.
Example D-47
Synthesis of
N2-(1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-5-yl)-5-methyl-1H-pyrazol-4-y-
l)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (D-52)
##STR00509##
[1024] Compound 30-3 and 3-bromo-2-(bromomethyl)prop-1-ene are
combined with K.sub.2CO.sub.3 in DMF to give compound 47-1.
Compound 47-1 is combined with lithium bis(trimethylsilyl)amide to
give compound 47-2. Compound 47-2 is combined with NaBH.sub.4 in
MeOH to give compound 47-3. Compound 47-3 is combined with compound
1-1, PPh, and DIAD in THF to give compound 47-4. To compound 47-4
in MeOH is added Pd/C, and the mixture is stirred under H.sub.2 to
produce compound 47-5. Compound 47-5, compound 5-5, and TsOH are
combined in 1,4-dioxane to give compound D-52.
[1025] Compounds D-17 (MS: (M+H.sup.+) m/z: 381.1) and D-18 (MS:
(M+H.sup.+) m/z: 381.1) were prepared according to Example D-21 and
D-22. Compounds D-40, D-42, and D-43, are prepared according to the
Examples above and/or general procedures described herein.
Compounds D-176 to D-187 are also prepared according to the
Examples above and/or general procedures described herein.
[1026] Compounds listed in Table D-3 were prepared according to the
Examples above and/or general procedures described herein. Further,
compound numbers of Table D-3 correspond to the compound numbers of
Table D-1.
TABLE-US-00009 TABLE D-3 MS No. [M + H].sup.+ D-56 393.1 D-57 410.1
D-58 408.2 D-59 408.1 D-60 393.1 D-61 476.2 D-62 413.1 D-63 443.2
D-64 411.2 D-65 393.7 D-66 408.1 D-67 379.1 D-68 394.1 D-69 408.2
D-70 381.2 D-71 393.1 D-72 408.2 D-73 408.1 D-74 393.1 D-75 444.1
D-76 408.2 D-77 394.2 D-78 407.2 D-79 408.1 D-80 395.1 D-81 426.2
D-82 395.1 D-83 411.1 D-84 408.2 D-85 420.1 D-86 410.1 D-87 443.2
D-88 425.2 D-89 425.2 D-90 408.2 D-91 408.1 D-92 407.2 D-93 407.2
D-94 393.1 D-95 407.2 D-96 381.2 D-97 410.1 D-98 407.1 D-99 413.1
D-100 394.1 D-101 380 D-102 393.1 D-103 424.2 D-104 413.1 D-105
413.1 D-106 419.2 D-107 408.2 D-108 408.2 D-109 408.1 D-110 393.1
D-111 403.1 D-112 408.1 D-113 408.2 D-114 408.2 D-115 394.2 D-116
407.1 D-117 408.2 D-118 476.2 D-119 420.1 D-120 381.1 D-121 379.1
D-122 393.1 D-123 408.1 D-124 408.2 D-125 408.2 D-126 393.2 D-127
380.1 D-128 404.1 D-129 407.1 D-130 379.1 D-131 393.1 D-132 394.2
D-133 408.2 D-134 408.2 D-135 476.2 D-136 4082 D-137 379.1 D-138
407.1 D-139 424.2 D-140 420.1 D-141 408.1 D-142 380.1 D-143 408.2
D-144 352.2 D-145 393.1 D-146 393.1 D-147 419.2 D-148 408.1 D-149
408.2 D-150 379.1 D-151 407.2 D-152 393.2 D-153 426.2 D-154 374.2
D-151 366.1 D-156 408.2 D-157 393.1 D-157a 366.1 D-158 380.2 D-159
380.1 D-160 394.1 D-161 381 D-162 394.2 D-163 393.1 D-164 400 D-165
411.2 D-166 379.1 D-167 411.1 D-168 411.1 D-169 393.1 D-170 407.2
D-171 408.2 D-172 393.1 D-173 394.1 D-174 395.1 D-175 408.2 D-178
406.1 D-183 377.1 D-184 405.0 D-185 404.1 D-186 361.1 D-187 439.3
D-188 393.1 D-189 393.1 D-190 358.1 D-191 358.1 D-192 421.1 D-193
421.2 D-194 439.3 D-195 428.3 D-196 428.3 D-197 428.3 D-198 428.3
D-199 376.2 D-200 376.1 D-201 384.2 D-202 384.2 D-203 372.2 D-204
390.3 D-205 407.2 D-206 407.2
Biological Example
Biochemical Assay of the Compounds
[1027] Materials: LRRK2 G2019S enzyme, Substrate (LRRKtide), ATP,
TR-FRET dilution buffer, pLRRKtide antibody, 384-well assay plate,
and DMSO.
[1028] Enzyme reaction conditions: 50 mM Tris pH 7.5, 10 mM
MgCl.sub.2, 1 mM EGTA, 0.01% Brij-35, 2 mM DTT, 5 nM LRRK2, 134
.mu.M ATP, 60 minute reaction time, 23.degree. C. reaction
temperature, and 10 .mu.L total reaction volume.
[1029] Detection reaction conditions: 1.times.TR-FRET dilution
buffer, 10 mM EDTA, 2 nM antibody, 23.degree. C. reaction
temperature, and 10 .mu.L total reaction volume.
[1030] Compound solutions were prepared by initially diluting to 1
mM with DMSO. 35 .mu.L of reference compound solution, 35 .mu.L of
test compound solution, and 35 .mu.L HPE were successively added to
the source plate (384-well assay plate, Labcyte). The plates were
centrifuged at 2500 rpm for 1 minute and sealed in foil. POD was
used to perform a 3.162 fold serial dilution and 100 nL of
reference compound solution, test compound solution, HPE and ZPE
were transferred to assay plates. The assay plate was centrifuged
at 2500 rpm for 1 minute, and sealed with foil.
[1031] To perform the enzyme reaction, 5 .mu.L of LRRKtide
substrate and kinase mixture in assay buffer was added to all wells
of the assay plate. The plate was centrifuged to concentrate the
mixture at the bottom of the wells. The assay plate was incubated
at 23.degree. C. for 20 minutes. Following incubation, 5 .mu.L of
2.times.ATP in assay buffer was added to each well, and plates were
centrifuged to concentrate the mixture at the bottom of the wells.
The plate was incubated at 23.degree. C. for 60 minutes.
[1032] To perform the detection of the reaction, EDTA completely
mixed in TR-FRET dilution buffer was added to antibody reagent. 10
.mu.L of detection reagent was added to all wells of each well of
the assay plate and the plate was centrifuged to concentrate the
mixture at the bottom of the wells. The plate was then incubated at
23.degree. C. for 60 minutes. Plates were read on Perkin Elmer
Envision 2104 instrument in TR-FRET mode using a 340 nm excitation
filter, 520 nm fluorescence emission filter, and 490 or 495 nm
terbium emission filter.
[1033] Representative compounds found in Table A-1, B-1, C-1, and
D-1 were tested according to the above methods and found to exhibit
an LRRK2 G2019S IC.sub.50 as indicated in Table A-2, B-2, C.sub.2,
and D-4 respectively.
TABLE-US-00010 TABLE A-2 Activity of Representative Compounds No.
IC.sub.50 No. IC.sub.50 No. IC.sub.50 No. IC.sub.50 A-1 +++ A-2 +++
A-3 + A-4 ++ A-5 ++ A-7 +++ A-8 +++ A-9 ++ A-10 + A-11 ++ A-12 +
A-13 + A-14 +++ A-15 +++ A-16 +++ A-17 ++ A-18 ++ A-19 ++ A-20 +++
A-21 ++ A-22 + A-23 +++ A-24 +++ A-25 ++ A-26 +++ A-27 + A-28 +++
A-29 +++ A-30 +++ A-31 +++ A-32 + A-33 + A-34 +++ A-35 +++ A-36 +++
A-37 + A-38 + A-39 +++ A-40 +++ A-41 +++ A-42 + A-43 +++ A-44 +++
A-45 +++ A-46 +++ A-47 +++ A-48 +++ A49 + A-50 +++ A-51 +++ A-52 +
A-53 +++ A-54 +++ A-55 +++ A-56 +++ A-57 + A-58 +++ A-59 +++ A-60
+++ A-61 ++ A-62 + A-63 ++ A-64 ++ A-65 +++ A-66 + A-67 +++ A-68
+++ A-69 +++ A-70 +++ A-71 +++ A-72 + A-73 +++ A-74 ++ A-75 +++
A-76 + A-77 +++ A-78 + A-79 +++ A-80 +++ A-81 +++ A-82 +++ A-83 +++
A-84 +++ A-85 +++ A-86 +++ A-87 +++ A-88 + A-89 +++ A-90 +++ A-91
++ A-92 +++ A-93 +++ A-94 +++ A-95 +++ A-96 +++ A-97 ++ +++ =
IC.sub.50 less than 30 nM; ++ = IC.sub.50 between 30 nM and 60 nM;
+ = IC.sub.50 greater than 60 nM
TABLE-US-00011 TABLE B-2 Activity of Representative Compounds No.
IC.sub.50 No. IC.sub.50 No. IC.sub.50 No. IC.sub.50 B-1 ++ B-2 +++
B-3 +++ B-4 + B-5 ++ B-6 +++ B-7 + B-8 ++ B-9 + B-10 ++ B-11 ++
B-12 + B-13 + B-14 + + = IC.sub.50 greater than 2 nm to 20 nm; ++ =
IC.sub.50 greater than 1 nm to 2 nM; +++ = IC.sub.50 1 nM or
less
TABLE-US-00012 TABLE C-2 Activity and MS data of Representative
Compounds No. IC.sub.50 [M + H].sup.+ C-1 +++ 334.2 C-2 +++ 334.2
C-3 ++ 306.2 C-4 +++ 306.1 C-5 +++ 270.2 C-6 +++ 270.1 C-7 +++
310.2 C-8 +++ 308.2 C-9 +++ 323.2 C-10 +++ 347.2 C-11 +++ 358.2
C-12 +++ 358.2 C-13 +++ 337.2 C-14 +++ 340.2 C-15 + 308.1 C-16 +
308.2 C-17 + 255.1 C-18 +++ 294.2 C-19 +++ 294.2 C-20 +++ 293.1
C-21 +++ 279.1 C-22 +++ 356.1 C-23 +++ 322.2 C-24 +++ 269.1 C-25
+++ 269.1 C-26 +++ 403.2 C-27 +++ 378.2 C-28 +++ 412.2 C-29 +++
396.2 C-30 +++ 333.2 C-31 +++ 333.2 C-32 +++ 367.1 C-33 + 284.1
C-34 + 284.1 C-35 + 269.1 C-36 +++ 310.2 C-37 +++ 378.2 C-38 +++
330.1 C-39 +++ 330.1 C-40 +++ 330.1 C-41 +++ 362.2 C-42 +++ 390.1
C-43 +++ 360.1 C-44 +++ 360.2 C-45 +++ 334.1 = [M - H].sup.- C-46
+++ 336.2 C-47 +++ 374.1 C-48 +++ 350.1 C-49 +++ 296.1 C-50 +++
296.1 C-51 +++ 310.1 C-52 +++ 310.1 C-53 +++ 319.1 C-54 +++ 319.1
C-55 +++ 367.1
TABLE-US-00013 TABLE D-4 Activity of Representative Compounds No.
IC.sub.50 D-1 + D-2 +++ D-3 + D-4 +++ D-5 + D-6 +++ D-7 +++ D-8 +
D-9 +++ D-10 ++ D-11 +++ D-12 +++ D-13 +++ D-14 +++ D-15 +++ D-16
+++ D-17 +++ D-18 + D-19 +++ D-20 + D-21 ++ D-22 +++ D-23 + D-24
+++ D-25 +++ D-26 +++ D-27 +++ D-28 +++ D-29 +++ D-30 +++ D-31 +++
D-32 +++ D-33 +++ D-34 +++ D-35 +++ D-36 + D-37 ++ D-44 +++ D-45
+++ D-46 ++ D-47 + D-48 +++ D-49 +++ D-50 +++ D-56 +++ D-57 +++
D-58 +++ D-59 +++ D-60 +++ D-61 +++ D-62 + D-63 +++ D-64 +++ D-65
+++ D-66 +++ D-67 + D-68 + D-69 +++ D-70 +++ D-71 +++ D-72 + D-73
+++ D-74 +++ D-75 +++ D-76 +++ D-77 +++ D-78 + D-79 +++ D-80 +++
D-81 +++ D-82 +++ D-83 +++ D-84 +++ D-85 +++ D-86 +++ D-87 +++ D-88
+++ D-89 +++ D-90 +++ D-91 +++ D-92 ++ D-93 +++ D-94 +++ D-95 +
D-96 +++ D-97 +++ D-98 +++ D-99* +++ D-100 +++ D-101 +++ D-102 +++
D-103 +++ D-104 +++ D-105 +++ D-106 +++ D-107 +++ D-108 +++ D-109
+++ D-110 +++ D-111 +++ D-112 +++ D-113 +++ D-114 +++ D-115 + D-116
+++ D-117 +++ D-118 +++ D-119 +++ D-120 +++ D-121 +++ D-122 +++
D-123 +++ D-124 +++ D-125 +++ D-126 + D-127 +++ D-128 +++ D-129 +++
D-130 ++ D-131 +++ D-132 +++ D-133 +++ D-134 +++ D-135 +++ D-136
+++ D-137 +++ D-138 +++ D-139 +++ D-140 +++ D-141 +++ D-142 + D-143
++ D-144 +++ D-145 +++ D-146 +++ D-147 +++ D-148 +++ D-149 ++ D-150
+++ D-151 +++ D-152 +++ D-153 +++ D-154 +++ D-155 +++ D-156 +++
D-157 +++ D-157a +++ D-158 +++ D-159 +++ D-160 +++ D-16I +++ D-162
+++ D-163 +++ D-164 +++ D-165 +++ D-166 +++ D-167 +++ D-168 +++
D-169 + D-170 +++ D-171 +++ D-172 +++ D-173 + D-174 +++ D-175 +++
D-178 +++ D-183 +++ D-184 +++ D-185 +++ D-186 +++ D-187 +++ D-188 +
D-189 +++ D-190 +++ D-191 +++ D-192 +++ D-193 +++ D-194 +++ D-195
+++ D-196 +++ D-197 +++ D-198 +++ D-199 +++ D-200 +++ D-201 +++
D-202 +++ D-203 +++ D-204 +++ D-205 + D-206 +++ +++ = IC.sub.50
less than 30 nM; ++ = IC.sub.50 between 30 nM and 60 nM; + =
IC.sub.50 greater than 60 nM *Data for D-99 either refers to D-99,
D-41, or a mixture of D-41 and D-99.
[1034] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs.
[1035] The inventions illustratively described herein may suitably
be practiced in the absence of any element or elements, limitation
or limitations, not specifically disclosed herein. Thus, for
example, the terms "comprising", "including," "containing", etc.
shall be read expansively and without limitation. Additionally, the
terms and expressions employed herein have been used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the invention claimed.
[1036] Thus, it should be understood that although the present
invention has been specifically disclosed by preferred embodiments
and optional features, modification, improvement and variation of
the inventions embodied therein herein disclosed may be resorted to
by those skilled in the art, and that such modifications,
improvements and variations are considered to be within the scope
of this invention. The materials, methods, and examples provided
here are representative of preferred embodiments, are exemplary,
and are not intended as limitations on the scope of the
invention.
[1037] The invention has been described broadly and generically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
invention. This includes the generic description of the invention
with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material
is specifically recited herein.
[1038] In addition, where features or aspects of the invention are
described in terms of Markush groups, those skilled in the art will
recognize that the invention is also thereby described in terms of
any individual member or subgroup of members of the Markush
group.
[1039] All publications, patent applications, patents, and other
references mentioned herein are expressly incorporated by reference
in their entirety, to the same extent as if each were incorporated
by reference individually. In case of conflict, the present
specification, including definitions, will control.
[1040] It is to be understood that while the disclosure has been
described in conjunction with the above embodiments, that the
foregoing description and examples are intended to illustrate and
not limit the scope of the disclosure. Other aspects, advantages
and modifications within the scope of the disclosure will be
apparent to those skilled in the art to which the disclosure
pertains.
* * * * *