U.S. patent application number 17/448013 was filed with the patent office on 2022-03-10 for tyk2 inhibitors and uses thereof.
The applicant listed for this patent is Nimbus Lakshmi, Inc.. Invention is credited to Jeremy Robert GREENWOOD, Geraldine C. HARRIMAN, Silvana M. LEIT DE MORADEI, Craig E. MASSE, Thomas H. MCLEAN, Sayan MONDAL.
Application Number | 20220073527 17/448013 |
Document ID | / |
Family ID | 61906011 |
Filed Date | 2022-03-10 |
United States Patent
Application |
20220073527 |
Kind Code |
A1 |
GREENWOOD; Jeremy Robert ;
et al. |
March 10, 2022 |
TYK2 INHIBITORS AND USES THEREOF
Abstract
The present invention provides compounds, compositions thereof,
and methods of using the same for the inhibition of TYK2, and the
treatment of TYK2-mediated disorders.
Inventors: |
GREENWOOD; Jeremy Robert;
(Brooklyn, NY) ; HARRIMAN; Geraldine C.;
(Charlestown, RI) ; LEIT DE MORADEI; Silvana M.;
(Burlington, MA) ; MASSE; Craig E.; (Cambridge,
MA) ; MCLEAN; Thomas H.; (Cambridge, MA) ;
MONDAL; Sayan; (New York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nimbus Lakshmi, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
61906011 |
Appl. No.: |
17/448013 |
Filed: |
September 17, 2021 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 417/14 20130101;
A61P 35/02 20180101; C07D 487/04 20130101; C07D 471/04 20130101;
C07D 519/00 20130101; A61P 29/00 20180101; C07D 413/14 20130101;
A61P 5/00 20180101; C07D 401/14 20130101; A61P 37/02 20180101; A61P
25/28 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61P 37/02 20060101 A61P037/02; A61P 25/28 20060101
A61P025/28; A61P 35/02 20060101 A61P035/02; A61P 5/00 20060101
A61P005/00; A61P 29/00 20060101 A61P029/00; C07D 519/00 20060101
C07D519/00; C07D 413/14 20060101 C07D413/14; C07D 417/14 20060101
C07D417/14; C07D 471/04 20060101 C07D471/04; C07D 401/14 20060101
C07D401/14 |
Claims
1-57. (canceled)
58. A method of inhibiting TYK2, or a mutant thereof, in a
biological sample comprising contacting the sample with a compound
of formula I: ##STR00589## or a pharmaceutically acceptable salt
thereof, wherein: X is N or C(R.sup.3); R.sup.1 is R, R.sup.D, or
--OR; R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --OCy.sup.2, --SCy.sup.2, or Cy.sup.2;
R.sup.3 is H, halogen, or C.sub.1-6 aliphatic; or R.sup.2 and
R.sup.3 are taken together with their intervening atoms to form a
4-7 membered partially unsaturated or aromatic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; wherein said ring is substituted with m instances of
R.sup.4; each of Cy.sup.1 and Cy.sup.2 is independently phenyl; a
5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; an 8-10
membered bicyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 3-7 membered saturated or partially
unsaturated monocyclic carbocyclic ring; or a 7-12 membered
saturated or partially unsaturated bicyclic heterocyclic ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, wherein Cy.sup.1 is substituted with n
instances of R.sup.5; and; wherein Cy.sup.2 is substituted with p
instances of R.sup.6; L.sup.1 is a covalent bond or a C.sub.1-4
bivalent saturated or unsaturated, straight or branched hydrocarbon
chain wherein one or two methylene units of the chain are
optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--; each instance of R.sup.4, R.sup.5,
R.sup.6, and R.sup.7 is independently R.sup.A or R.sup.B, and is
substituted by q instances of R.sup.C; each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, or --N(R)S(O).sub.2R; each instance of R.sup.B
is independently C.sub.1-6 aliphatic; phenyl; a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; a 3-7 membered
saturated or partially unsaturated carbocyclic ring; a 3-7 membered
saturated or partially unsaturated monocyclic heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; each
instance of R.sup.C is independently oxo, halogen, --CN,
--NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, or --N(R)S(O).sub.2R
or an optionally substituted group selected from C.sub.1-6
aliphatic, phenyl, a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, and a 5-6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; R.sup.D is a C.sub.1-4 aliphatic
group wherein one or more hydrogens are replaced by deuterium; each
R is independently hydrogen, or an optionally substituted group
selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated
or partially unsaturated heterocyclic having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, and a 5-6
membered heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, or: two R groups on the
same nitrogen are taken together with their intervening atoms to
form a 4-7 membered saturated, partially unsaturated, or heteroaryl
ring having 0-3 heteroatoms, in addition to the nitrogen,
independently selected from nitrogen, oxygen, and sulfur; and each
of m, n, p, and q is independently 0, 1, 2, 3, or 4.
59. A method of inhibiting TYK2, or a mutant thereof, in a
biological sample comprising contacting the sample with a compound
of formula VIII: ##STR00590## or a pharmaceutically acceptable salt
thereof, wherein: X is N or C(R.sup.3); Y is N or C(R.sup.1);
R.sup.1 is H, D, or halogen; R, R.sup.D, or --OR; R.sup.2 is H,
R.sup.C, --N(R)C(O)Cy.sup.2, --N(R)S(O).sub.2Cy.sup.2,
--N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2, or Cy.sup.2; R.sup.3 is
H, halogen, or C.sub.1-6 aliphatic; or R.sup.2 and R.sup.3 are
taken together with their intervening atoms to form a 4-7 membered
partially unsaturated or aromatic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; wherein
said ring is substituted with m instances of R.sup.4; each of
Cy.sup.1 and Cy.sup.2 is independently phenyl; a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; a 3-7 membered
saturated or partially unsaturated heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; or a 3-7 membered saturated or partially unsaturated
monocyclic carbocyclic ring; or a 7-12 membered saturated or
partially unsaturated bicyclic heterocyclic ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; wherein Cy.sup.1 is substituted with n instances of
R.sup.5; and; wherein Cy.sup.2 is substituted with p instances of
R.sup.6; Cy.sup.3 is a 5-6 membered monocyclic partially
unsaturated or heteroaromatic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; wherein
Cy.sup.3 is substituted with r instances of R.sup.8; L.sup.1 is a
covalent bond or a C.sub.1-4 bivalent saturated or unsaturated,
straight or branched hydrocarbon chain wherein one or two methylene
units of the chain are optionally and independently replaced by
--C(R.sup.7).sub.2--, --N(R)--, --N(R)C(O)--, --C(O)N(R)--,
--N(R)S(O).sub.2--, --S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--,
--C(O)O--, --OC(O)N(R)--, --N(R)C(O)O--, --S--, --S(O)-- or
--S(O).sub.2--; each instance of R.sup.4, R.sup.5, R.sup.6, R.sup.7
and R.sup.8 is independently R.sup.A or R.sup.B, and is substituted
by q instances of R.sup.C; each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; each instance of R.sup.B is independently
C.sub.1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated carbocyclic ring; a 3-7 membered saturated or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; or a 7-12
membered saturated or partially unsaturated bicyclic heterocyclic
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; each instance of R.sup.C is independently oxo,
halogen, --CN, --NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; R.sup.D is a C.sub.1-4 aliphatic group wherein one or more
hydrogens are replaced by deuterium; each R is independently
hydrogen, or an optionally substituted group selected from
C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially
unsaturated heterocyclic having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, and a 5-6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen
are taken together with their intervening atoms to form a 4-7
membered saturated, partially unsaturated, or heteroaryl ring
having 0-3 heteroatoms, in addition to the nitrogen, independently
selected from nitrogen, oxygen, and sulfur; and each of m, n, p, q,
and r is independently 0, 1, 2, 3, or 4.
60. A method of inhibiting TYK2, or a mutant thereof, in a
biological sample comprising contacting the sample with: (i) a
compound of formula XVI: ##STR00591## or a pharmaceutically
acceptable salt thereof, wherein: X is N or C(R.sup.X); one of
Y.sup.1, Y.sup.2, Z.sup.1, and Z.sup.2 is N, and the other three
are C; R.sup.1 is D, R, R.sup.D, --NR.sub.2, --NRR.sup.D,
--N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)C(O)NRR.sup.D, --N(R)C(NR)NRR.sup.D, --OR, or --OR.sup.D;
R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; R.sup.3 is H, halogen, or C.sub.1-6 aliphatic; or
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 4-7 membered partially unsaturated or aromatic ring
having 0-3 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; wherein said ring is substituted with m
instances of R.sup.4; each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--; each instance of R.sup.4, R.sup.5,
R.sup.6, and R.sup.7 is independently R.sup.A or R.sup.B, and is
substituted by q instances of R.sup.C; each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; each instance of R.sup.B is independently
C.sub.1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated carbocyclic ring; a 3-7 membered saturated or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; or a 7-12
membered saturated or partially unsaturated bicyclic heterocyclic
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; each instance of R.sup.C is independently oxo,
halogen, --CN, --NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; R.sup.D is a C.sub.1-4 aliphatic group wherein one or more
hydrogens are replaced by deuterium; R.sup.X is H, halogen, or
C.sub.1-6 aliphatic each R is independently hydrogen, or an
optionally substituted group selected from C.sub.1-6 aliphatic,
phenyl, a 3-7 membered saturated or partially unsaturated
heterocyclic having 1-2 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, or: two R groups on the same nitrogen are taken
together with their intervening atoms to form a 4-7 membered
saturated, partially unsaturated, or heteroaryl ring having 0-3
heteroatoms, in addition to the nitrogen, independently selected
from nitrogen, oxygen, and sulfur; and each of m, n, p, and q is
independently 0, 1, 2, 3, or 4; or (ii) a compound of formula XVI':
##STR00592## or a pharmaceutically acceptable salt thereof,
wherein: Q is CH or N; X is N or C(R.sup.X); one of Y.sup.1,
Y.sup.2, Z.sup.1, and Z.sup.2 is N, and the other three are C;
R.sup.1 is D, R, R.sup.D, --NR.sub.2, --NRR.sup.D,
--N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)C(O)NRR.sup.D, --N(R)C(NR)NRR.sup.D, --OR, or --OR.sup.D;
R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; R.sup.3 is H, halogen, or C.sub.1-6 aliphatic; or
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 4-7 membered partially unsaturated or aromatic ring
having 0-3 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; wherein said ring is substituted with m
instances of R.sup.4; each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--; each instance of R.sup.4, R.sup.5,
R.sup.6, and R.sup.7 is independently R.sup.A or R.sup.B, and is
substituted by q instances of R.sup.C; each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; each instance of R.sup.B is independently
C.sub.1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated carbocyclic ring; a 3-7 membered saturated or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; or a 7-12
membered saturated or partially unsaturated bicyclic heterocyclic
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; each instance of R.sup.C is independently oxo,
halogen, --CN, --NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; R.sup.D is a C.sub.1-4 aliphatic group wherein one or more
hydrogens are replaced by deuterium; R.sup.X is H, halogen, or
C.sub.1-6 aliphatic; each R is independently hydrogen, or an
optionally substituted group selected from C.sub.1-6 aliphatic,
phenyl, a 3-7 membered saturated or partially unsaturated
heterocyclic having 1-2 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, or: two R groups on the same nitrogen are taken
together with their intervening atoms to form a 4-7 membered
saturated, partially unsaturated, or heteroaryl ring having 0-3
heteroatoms, in addition to the nitrogen, independently selected
from nitrogen, oxygen, and sulfur; and each of m, n, p, and q is
independently 0, 1, 2, 3, or 4.
61. A method of treating a TYK2-mediated disorder, disease, or
condition in a patient comprising administering to said patient a
compound of formula I: ##STR00593## or a pharmaceutically
acceptable salt thereof, wherein: X is N or C(R.sup.3); R.sup.1 is
R, R.sup.D, or --OR; R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)Cy.sup.2, --N(R)S(O).sub.2Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; R.sup.3 is H, halogen, or C.sub.1-6 aliphatic; or
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 4-7 membered partially unsaturated or aromatic ring
having 0-3 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; wherein said ring is substituted with m
instances of R.sup.4; each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--; each instance of R.sup.4, R.sup.5,
R.sup.6, and R.sup.7 is independently R.sup.A or R.sup.B, and is
substituted by q instances of R.sup.C; each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, or --N(R)S(O).sub.2R; each instance of R.sup.B
is independently C.sub.1-6 aliphatic; phenyl; a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; a 3-7 membered
saturated or partially unsaturated carbocyclic ring; a 3-7 membered
saturated or partially unsaturated monocyclic heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; each
instance of R.sup.C is independently oxo, halogen, --CN,
--NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, or --N(R)S(O).sub.2R
or an optionally substituted group selected from C.sub.1-6
aliphatic, phenyl, a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, and a 5-6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; R.sup.D is a C.sub.1-4 aliphatic
group wherein one or more hydrogens are replaced by deuterium; each
R is independently hydrogen, or an optionally substituted group
selected from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated
or partially unsaturated heterocyclic having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, and a 5-6
membered heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, or: two R groups on the
same nitrogen are taken together with their intervening atoms to
form a 4-7 membered saturated, partially unsaturated, or heteroaryl
ring having 0-3 heteroatoms, in addition to the nitrogen,
independently selected from nitrogen, oxygen, and sulfur; and each
of m, n, p, and q is independently 0, 1, 2, 3, or 4.
62. A method of treating a TYK2-mediated disorder, disease, or
condition in a patient comprising administering to said patient a
compound of formula VIII: ##STR00594## or a pharmaceutically
acceptable salt thereof, wherein: X is N or C(R.sup.3); Y is N or
C(R.sup.1); R.sup.1 is H, D, or halogen; R, R.sup.D, or --OR;
R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; R.sup.3 is H, halogen, or C.sub.1-6 aliphatic; or
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 4-7 membered partially unsaturated or aromatic ring
having 0-3 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; wherein said ring is substituted with m
instances of R.sup.4; each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur; wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; Cy.sup.3 is a 5-6 membered monocyclic
partially unsaturated or heteroaromatic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; wherein
Cy.sup.3 is substituted with r instances of R.sup.8; L.sup.1 is a
covalent bond or a C.sub.1-4 bivalent saturated or unsaturated,
straight or branched hydrocarbon chain wherein one or two methylene
units of the chain are optionally and independently replaced by
--C(R.sup.7).sub.2--, --N(R)--, --N(R)C(O)--, --C(O)N(R)--,
--N(R)S(O).sub.2--, --S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--,
--C(O)O--, --OC(O)N(R)--, --N(R)C(O)O--, --S--, --S(O)-- or
--S(O).sub.2--; each instance of R.sup.4, R.sup.5, R.sup.6, R.sup.7
and R.sup.8 is independently R.sup.A or R.sup.B, and is substituted
by q instances of R.sup.C; each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; each instance of R.sup.B is independently
C.sub.1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated carbocyclic ring; a 3-7 membered saturated or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; or a 7-12
membered saturated or partially unsaturated bicyclic heterocyclic
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; each instance of R.sup.C is independently oxo,
halogen, --CN, --NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; R.sup.D is a C.sub.1-4 aliphatic group wherein one or more
hydrogens are replaced by deuterium; each R is independently
hydrogen, or an optionally substituted group selected from
C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially
unsaturated heterocyclic having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, and a 5-6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen
are taken together with their intervening atoms to form a 4-7
membered saturated, partially unsaturated, or heteroaryl ring
having 0-3 heteroatoms, in addition to the nitrogen, independently
selected from nitrogen, oxygen, and sulfur; and each of m, n, p, q,
and r is independently 0, 1, 2, 3, or 4.
63. A method of treating a TYK2-mediated disorder, disease, or
condition in a patient comprising administering to said patient:
(i) a compound of formula XVI: ##STR00595## or a pharmaceutically
acceptable salt thereof, wherein: X is N or C(R.sup.X); one of
Y.sup.1, Y.sup.2, Z.sup.1, and Z.sup.2 is N, and the other three
are C; R.sup.1 is D, R, R.sup.D, --NR.sub.2, --NRR.sup.D,
--N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)C(O)NRR.sup.D, --N(R)C(NR)NRR.sup.D, --OR, or --OR.sup.D;
R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; R.sup.3 is H, halogen, or C.sub.1-6 aliphatic; or
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 4-7 membered partially unsaturated or aromatic ring
having 0-3 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; wherein said ring is substituted with m
instances of R.sup.4; each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--; each instance of R.sup.4, R.sup.5,
R.sup.6, and R.sup.7 is independently R.sup.A or R.sup.B, and is
substituted by q instances of R.sup.C; each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; each instance of R.sup.B is independently
C.sub.1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated carbocyclic ring; a 3-7 membered saturated or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; or a 7-12
membered saturated or partially unsaturated bicyclic heterocyclic
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; each instance of R.sup.C is independently oxo,
halogen, --CN, --NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; R.sup.D is a C.sub.1-4 aliphatic group wherein one or more
hydrogens are replaced by deuterium; R.sup.X is H, halogen, or
C.sub.1-6 aliphatic; each R is independently hydrogen, or an
optionally substituted group selected from C.sub.1-6 aliphatic,
phenyl, a 3-7 membered saturated or partially unsaturated
heterocyclic having 1-2 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, or: two R groups on the same nitrogen are taken
together with their intervening atoms to form a 4-7 membered
saturated, partially unsaturated, or heteroaryl ring having 0-3
heteroatoms, in addition to the nitrogen, independently selected
from nitrogen, oxygen, and sulfur; and each of m, n, p, and q is
independently 0, 1, 2, 3, or 4; or (ii) a compound of formula XVI':
##STR00596## or a pharmaceutically acceptable salt thereof,
wherein: Q is CH or N; X is N or C(R.sup.X); one of Y.sup.1,
Y.sup.2, Z.sup.1, and Z.sup.2 is N, and the other three are C;
R.sup.1 is D, R, R.sup.D, --NR.sub.2, --NRR.sup.D,
--N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)C(O)NRR.sup.D, --N(R)C(NR)NRR.sup.D, --OR, or --OR.sup.D;
R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; R.sup.3 is H, halogen, or C.sub.1-6 aliphatic; or
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 4-7 membered partially unsaturated or aromatic ring
having 0-3 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; wherein said ring is substituted with m
instances of R.sup.4; each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--; each instance of R.sup.4, R.sup.5,
R.sup.6, and R.sup.7 is independently R.sup.A or R.sup.B, and is
substituted by q instances of R.sup.C; each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; each instance of R.sup.B is independently
C.sub.1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated carbocyclic ring; a 3-7 membered saturated or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; or a 7-12
membered saturated or partially unsaturated bicyclic heterocyclic
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; each instance of R.sup.C is independently oxo,
halogen, --CN, --NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; R.sup.D is a C.sub.1-4 aliphatic group wherein one or more
hydrogens are replaced by deuterium; R.sup.X is H, halogen, or
C.sub.1-6 aliphatic; each R is independently hydrogen, or an
optionally substituted group selected from C.sub.1-6 aliphatic,
phenyl, a 3-7 membered saturated or partially unsaturated
heterocyclic having 1-2 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, or: two R groups on the same nitrogen are taken
together with their intervening atoms to form a 4-7 membered
saturated, partially unsaturated, or heteroaryl ring having 0-3
heteroatoms, in addition to the nitrogen, independently selected
from nitrogen, oxygen, and sulfur; and each of m, n, p, and q is
independently 0, 1, 2, 3, or 4.
64. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is selected from an autoimmune disorder, an
inflammatory disorder, a proliferative disorder, an endocrine
disorder, a neurological disorder, and a disorder associated with
transplantation.
65. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is selected from rheumatoid arthritis,
asthma, chronic obstructive pulmonary disease, type 1 diabetes,
ankylosing spondylitis, systemic lupus erythematosus, multiple
sclerosis, systemic sclerosis, psoriasis, Crohn's disease,
ulcerative colitis, and inflammatory bowel disease.
66. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is a leukemia.
67. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is T-cell acute lymphoblastic leukemia
(T-ALL).
68. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is a proliferative disorder associated with
one or more activating mutations in TYK2.
69. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is transplant rejection or graft versus host
disease.
70. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is polycystic ovary syndrome, Crouzon's
syndrome, or type 1 diabetes.
71. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is Alzheimer's disease.
72. The method of claim 61, wherein the TYK2-mediated disorder,
disease, or condition is associated with type I interferon, IL-10,
IL-12, or IL-23 signaling.
73. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is selected from an autoimmune disorder, an
inflammatory disorder, a proliferative disorder, an endocrine
disorder, a neurological disorder, and a disorder associated with
transplantation.
74. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is selected from rheumatoid arthritis,
asthma, chronic obstructive pulmonary disease, type 1 diabetes,
ankylosing spondylitis, systemic lupus erythematosus, multiple
sclerosis, systemic sclerosis, psoriasis, Crohn's disease,
ulcerative colitis, and inflammatory bowel disease.
75. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is a leukemia.
76. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is T-cell acute lymphoblastic leukemia
(T-ALL).
77. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is a proliferative disorder associated with
one or more activating mutations in TYK2.
78. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is transplant rejection or graft versus host
disease.
79. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is polycystic ovary syndrome, Crouzon's
syndrome, or type 1 diabetes.
80. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is Alzheimer's disease.
81. The method of claim 62, wherein the TYK2-mediated disorder,
disease, or condition is associated with type I interferon, IL-10,
IL-12, or IL-23 signaling.
82. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is selected from an autoimmune disorder, an
inflammatory disorder, a proliferative disorder, an endocrine
disorder, a neurological disorder, and a disorder associated with
transplantation.
83. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is selected from rheumatoid arthritis,
asthma, chronic obstructive pulmonary disease, type 1 diabetes,
ankylosing spondylitis, systemic lupus erythematosus, multiple
sclerosis, systemic sclerosis, psoriasis, Crohn's disease,
ulcerative colitis, and inflammatory bowel disease.
84. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is a leukemia.
85. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is T-cell acute lymphoblastic leukemia
(T-ALL).
86. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is a proliferative disorder associated with
one or more activating mutations in TYK2.
87. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is transplant rejection or graft versus host
disease.
88. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is polycystic ovary syndrome, Crouzon's
syndrome, or type 1 diabetes.
89. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is Alzheimer's disease.
90. The method of claim 63, wherein the TYK2-mediated disorder,
disease, or condition is associated with type I interferon, IL-10,
IL-12, or IL-23 signaling.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to compounds and methods
useful for inhibiting non-receptor tyrosine-protein kinase 2
("TYK2"), also known as Tyrosine kinase 2. The invention also
provides pharmaceutically acceptable compositions comprising
compounds of the present invention and methods of using said
compositions in the treatment of various disorders.
BACKGROUND OF THE INVENTION
[0002] The search for new therapeutic agents has been greatly aided
in recent years by a better understanding of the structure of
enzymes and other biomolecules associated with diseases. One
important class of enzymes that has been the subject of extensive
study is the protein kinase family.
[0003] Protein kinases constitute a large family of structurally
related enzymes that are responsible for the control of a variety
of signal transduction processes within the cell. Protein kinases
are thought to have evolved from a common ancestral gene due to the
conservation of their structure and catalytic function. Almost all
kinases contain a similar 250-300 amino acid catalytic domain. The
kinases may be categorized into families by the substrates they
phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,
lipids, etc.).
[0004] In general, protein kinases mediate intracellular signaling
by effecting a phosphoryl transfer from a nucleoside triphosphate
to a protein acceptor that is involved in a signaling pathway.
These phosphorylation events act as molecular on/off switches that
can modulate or regulate the target protein biological function.
These phosphorylation events are ultimately triggered in response
to a variety of extracellular and other stimuli. Examples of such
stimuli include environmental and chemical stress signals (e.g.,
osmotic shock, heat shock, ultraviolet radiation, bacterial
endotoxins, and H.sub.2O.sub.2), cytokines (e.g., interleukin-1
(IL-1), interleukin-8 (IL-8), and tumor necrosis factor .alpha.
(TNF-.alpha.)), and growth factors (e.g., granulocyte
macrophage-colony-stimulating factor (GM-CSF), and fibroblast
growth factor (FGF)). An extracellular stimulus may affect one or
more cellular responses related to cell growth, migration,
differentiation, secretion of hormones, activation of transcription
factors, muscle contraction, glucose metabolism, control of protein
synthesis, and regulation of the cell cycle.
[0005] Many diseases are associated with abnormal cellular
responses triggered by kinase-mediated events. These diseases
include, but are not limited to, autoimmune diseases, inflammatory
diseases, bone diseases, metabolic diseases, neurological and
neurodegenerative diseases, cancer, cardiovascular diseases,
allergies and asthma, Alzheimer's disease, and hormone-related
diseases. Accordingly, there remains a need to find protein kinase
inhibitors useful as therapeutic agents.
SUMMARY OF THE INVENTION
[0006] It has now been found that compounds of this invention, and
pharmaceutically acceptable compositions thereof, are effective as
inhibitors of TYK2 kinase.
[0007] Compounds of the present invention, and pharmaceutically
acceptable compositions thereof, are useful for treating a variety
of diseases, disorders or conditions, associated with regulation of
signaling pathways implicating TYK2 kinases. Such diseases,
disorders, or conditions include those described herein.
[0008] Compounds provided by this invention are also useful for the
study of TYK2 enzymes in biological and pathological phenomena; the
study of intracellular signal transduction pathways occurring in
bodily tissues; and the comparative evaluation of new TYK2
inhibitors or other regulators of kinases, signaling pathways, and
cytokine levels in vitro or in vivo.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
1. General Description of Certain Embodiments of the Invention
[0009] Compounds of the present invention, and compositions
thereof, are useful as inhibitors of TYK2 protein kinase.
[0010] The pseudokinase binding pocket of TYK2 contains a plurality
of hydration sites, each of which is occupied by a single molecule
of water. Each of these water molecules has a stability rating
associated with it. As used herein, the term "stability rating"
refers to a numerical calculation which incorporates the enthalpy,
entropy, and free energy values associated with each water
molecule. This stability rating allows for a measurable
determination of the relative stability of water molecules that
occupy hydration sites in the binding pocket of TYK2.
[0011] Water molecules occupying hydration sites in the binding
pocket of TYK2 having a stability rating of >2.5 kcal/mol are
referred to as "unstable waters."
[0012] Without wishing to be bound by any particular theory, it is
believed that displacement or disruption of an unstable water
molecule (i.e., a water molecule having a stability rating of
>2.5 kcal/mol), or replacement of a stable water (i.e., a water
molecule having a stability rating of <1 kcal/mol), by an
inhibitor results in tighter binding of that inhibitor.
Accordingly, inhibitors designed to displace one or more unstable
water molecules (i.e., those unstable water molecules not displaced
by any known inhibitor) will be a tighter binder and, therefore,
more potent inhibitor as compared to an inhibitor that does not
displace unstable water molecules.
[0013] It was surprisingly found that provided compounds displace
or disrupt one or more unstable water molecules. In some
embodiments, a provided compound displaces or disrupts at least two
unstable water molecules.
[0014] In certain embodiments, the present invention provides a
compound of formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein each of X,
L.sup.1, R.sup.1, R.sup.2, and Cy.sup.1 is as defined below and
described in embodiments herein, both singly and in
combination.
[0015] In some embodiments, the present invention provides a
pharmaceutical composition comprising a compound of formula I, and
a pharmaceutically acceptable carrier, adjuvant, or diluent.
[0016] In some embodiments, the present invention provides a method
of treating a TYK2-mediated disease, disorder, or condition
comprising administering to a patient in need thereof, a compound
of formula I or a pharmaceutically acceptable salt thereof.
[0017] In certain embodiments, the present invention provides a
compound of formula VIII:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein each of X,
L.sup.1, R.sup.1, R.sup.2, and Cy.sup.1 is as defined below and
described in embodiments herein, both singly and in
combination.
[0018] In some embodiments, the present invention provides a
pharmaceutical composition comprising a compound of formula VIII,
and a pharmaceutically acceptable carrier, adjuvant, or
diluent.
[0019] In some embodiments, the present invention provides a method
of treating a TYK2-mediated disease, disorder, or condition
comprising administering to a patient in need thereof, a a compound
of formula VIII or a pharmaceutically acceptable salt thereof.
[0020] In certain embodiments, the present invention provides a
compound of formula XVI':
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein each of Q,
X, Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, L.sup.1, R.sup.1, R.sup.2,
and Cy.sup.1 is as defined below and described in embodiments
herein, both singly and in combination.
[0021] In some embodiments, the present invention provides a
pharmaceutical composition comprising a compound of formula XVI',
and a pharmaceutically acceptable carrier, adjuvant, or
diluent.
[0022] In some embodiments, the present invention provides a method
of treating a TYK2-mediated disease, disorder, or condition
comprising administering to a patient in need thereof, a a compound
of formula XVI' or a pharmaceutically acceptable salt thereof.
2. Compounds and Definitions
[0023] Compounds of the present invention include those described
generally herein, and are further illustrated by the classes,
subclasses, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated. For
purposes of this invention, the chemical elements are identified in
accordance with the Periodic Table of the Elements, CAS version,
Handbook of Chemistry and Physics, 75.sup.th Ed. Additionally,
general principles of organic chemistry are described in "Organic
Chemistry", Thomas Sorrell, University Science Books, Sausalito:
1999, and "March's Advanced Organic Chemistry", 5.sup.th Ed., Ed.:
Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,
the entire contents of which are hereby incorporated by
reference.
[0024] The term "aliphatic" or "aliphatic group", as used herein,
means a straight-chain (i.e., unbranched) or branched, substituted
or unsubstituted hydrocarbon chain that is completely saturated or
that contains one or more units of unsaturation, or a monocyclic
hydrocarbon or bicyclic hydrocarbon that is completely saturated or
that contains one or more units of unsaturation, but which is not
aromatic (also referred to herein as "carbocycle," "cycloaliphatic"
or "cycloalkyl"), that has a single point of attachment to the rest
of the molecule. Unless otherwise specified, aliphatic groups
contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic
groups contain 1-5 aliphatic carbon atoms. In other embodiments,
aliphatic groups contain 1-4 aliphatic carbon atoms. In still other
embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms,
and in yet other embodiments, aliphatic groups contain 1-2
aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or
"carbocycle" or "cycloalkyl") refers to a monocyclic
C.sub.3-C.sub.6 hydrocarbon that is completely saturated or that
contains one or more units of unsaturation, but which is not
aromatic, that has a single point of attachment to the rest of the
molecule. Suitable aliphatic groups include, but are not limited
to, linear or branched, substituted or unsubstituted alkyl,
alkenyl, alkynyl groups and hybrids thereof such as
(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0025] As used herein, the term "bridged bicyclic" refers to any
bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated
or partially unsaturated, having at least one bridge. As defined by
IUPAC, a "bridge" is an unbranched chain of atoms or an atom or a
valence bond connecting two bridgeheads, where a "bridgehead" is
any skeletal atom of the ring system which is bonded to three or
more skeletal atoms (excluding hydrogen). In some embodiments, a
bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur. Such
bridged bicyclic groups are well known in the art and include those
groups set forth below where each group is attached to the rest of
the molecule at any substitutable carbon or nitrogen atom. Unless
otherwise specified, a bridged bicyclic group is optionally
substituted with one or more substituents as set forth for
aliphatic groups. Additionally or alternatively, any substitutable
nitrogen of a bridged bicyclic group is optionally substituted.
Exemplary bridged bicyclics include:
##STR00004##
[0026] The term "lower alkyl" refers to a C.sub.1-4 straight or
branched alkyl group. Exemplary lower alkyl groups are methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
[0027] The term "lower haloalkyl" refers to a C.sub.1-4 straight or
branched alkyl group that is substituted with one or more halogen
atoms.
[0028] The term "heteroatom" means one or more of oxygen, sulfur,
nitrogen, phosphorus, or silicon (including, any oxidized form of
nitrogen, sulfur, phosphorus, or silicon; the quaternized form of
any basic nitrogen or; a substitutable nitrogen of a heterocyclic
ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl) or NR.sup.+ (as in N-substituted pyrrolidinyl)).
[0029] The term "unsaturated," as used herein, means that a moiety
has one or more units of unsaturation.
[0030] As used herein, the term "bivalent C.sub.1-8 (or C.sub.1-6)
saturated or unsaturated, straight or branched, hydrocarbon chain",
refers to bivalent alkylene, alkenylene, and alkynylene chains that
are straight or branched as defined herein.
[0031] The term "alkylene" refers to a bivalent alkyl group. An
"alkylene chain" is a polymethylene group, i.e.,
--(CH.sub.2).sub.n--, wherein n is a positive integer, preferably
from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
A substituted alkylene chain is a polymethylene group in which one
or more methylene hydrogen atoms are replaced with a substituent.
Suitable substituents include those described below for a
substituted aliphatic group.
[0032] The term "alkenylene" refers to a bivalent alkenyl group. A
substituted alkenylene chain is a polymethylene group containing at
least one double bond in which one or more hydrogen atoms are
replaced with a substituent. Suitable substituents include those
described below for a substituted aliphatic group.
[0033] The term "halogen" means F, Cl, Br, or I.
[0034] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic
or bicyclic ring systems having a total of five to fourteen ring
members, wherein at least one ring in the system is aromatic and
wherein each ring in the system contains 3 to 7 ring members. The
term "aryl" may be used interchangeably with the term "aryl ring."
In certain embodiments of the present invention, "aryl" refers to
an aromatic ring system which includes, but not limited to, phenyl,
biphenyl, naphthyl, anthracyl and the like, which may bear one or
more substituents. Also included within the scope of the term
"aryl," as it is used herein, is a group in which an aromatic ring
is fused to one or more non-aromatic rings, such as indanyl,
phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl,
and the like.
[0035] The terms "heteroaryl" and "heteroar-," used alone or as
part of a larger moiety, e.g., "heteroaralkyl," or
"heteroaralkoxy," refer to groups having 5 to 10 ring atoms,
preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 .pi.
electrons shared in a cyclic array; and having, in addition to
carbon atoms, from one to five heteroatoms. The term "heteroatom"
refers to nitrogen, oxygen, or sulfur, and includes any oxidized
form of nitrogen or sulfur, and any quaternized form of a basic
nitrogen. Heteroaryl groups include, without limitation, thienyl,
furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms
"heteroaryl" and "heteroar-", as used herein, also include groups
in which a heteroaromatic ring is fused to one or more aryl,
cycloaliphatic, or heterocyclyl rings, where unless otherwise
specified, the radical or point of attachment is on the
heteroaromatic ring or on one of the rings to which the
heteroaromatic ring is fused. Nonlimiting examples include indolyl,
isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl,
benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,
carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl
group may be mono- or bicyclic. The term "heteroaryl" may be used
interchangeably with the terms "heteroaryl ring," "heteroaryl
group," or "heteroaromatic," any of which terms include rings that
are optionally substituted. The term "heteroaralkyl" refers to an
alkyl group substituted by a heteroaryl, wherein the alkyl and
heteroaryl portions independently are optionally substituted.
[0036] As used herein, the terms "heterocycle," "heterocyclyl,"
"heterocyclic radical," and "heterocyclic ring" are used
interchangeably and refer to a stable 5- to 7-membered monocyclic
or 7-10-membered bicyclic heterocyclic moiety that is either
saturated or partially unsaturated, and having, in addition to
carbon atoms, one or more, preferably one to four, heteroatoms, as
defined above. When used in reference to a ring atom of a
heterocycle, the term "nitrogen" includes a substituted nitrogen.
As an example, in a saturated or partially unsaturated ring having
0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the
nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl), or .sup.+NR (as in N-substituted pyrrolidinyl).
[0037] A heterocyclic ring can be attached to its pendant group at
any heteroatom or carbon atom that results in a stable structure
and any of the ring atoms can be optionally substituted. Examples
of such saturated or partially unsaturated heterocyclic radicals
include, without limitation, tetrahydrofuranyl,
tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl,
oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane,
and quinuclidinyl. The terms "heterocycle," "heterocyclyl,"
"heterocyclyl ring," "heterocyclic group," "heterocyclic moiety,"
and "heterocyclic radical," are used interchangeably herein, and
also include groups in which a heterocyclyl ring is fused to one or
more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl,
3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A
heterocyclyl group may be mono- or bicyclic. The term
"heterocyclylalkyl" refers to an alkyl group substituted by a
heterocyclyl, wherein the alkyl and heterocyclyl portions
independently are optionally substituted.
[0038] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond. The
term "partially unsaturated" is intended to encompass rings having
multiple sites of unsaturation, but is not intended to include aryl
or heteroaryl moieties, as herein defined.
[0039] As described herein, compounds of the invention may contain
"optionally substituted" moieties. In general, the term
"substituted," whether preceded by the term "optionally" or not,
means that one or more hydrogens of the designated moiety are
replaced with a suitable substituent. Unless otherwise indicated,
an "optionally substituted" group may have a suitable substituent
at each substitutable position of the group, and when more than one
position in any given structure may be substituted with more than
one substituent selected from a specified group, the substituent
may be either the same or different at every position. Combinations
of substituents envisioned by this invention are preferably those
that result in the formation of stable or chemically feasible
compounds. The term "stable," as used herein, refers to compounds
that are not substantially altered when subjected to conditions to
allow for their production, detection, and, in certain embodiments,
their recovery, purification, and use for one or more of the
purposes disclosed herein.
[0040] Suitable monovalent substituents on a substitutable carbon
atom of an "optionally substituted" group are independently
halogen; --(CH.sub.2).sub.0-4R.sup..smallcircle.;
--(CH.sub.2).sub.0-4OR.sup..smallcircle.;
--O(CH.sub.2).sub.0-4R.sup..smallcircle.,
--O--(CH.sub.2).sub.0-4C(O)OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4CH(OR.sup..smallcircle.).sub.2;
--(CH.sub.2).sub.0-4SR.sup..smallcircle.; --(CH.sub.2).sub.0-4Ph,
which may be substituted with R.sup..smallcircle.;
--(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1Ph which may be substituted
with R.sup..smallcircle.; --CH.dbd.CHPh, which may be substituted
with R.sup..smallcircle.;
--(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1-pyridyl which may be
substituted with R.sup..smallcircle.; --NO.sub.2; --CN; --N.sub.3;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.).sub.2;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)C(S)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)NR.sup..smallcircle..sub.2;
--N(R.sup..smallcircle.)C(S)NR.sup..smallcircle..sub.2;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)OR.sup..smallcircle.;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)NR.sup..smallcircle..su-
b.2;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)OR.sup..smallcircle-
.; --(CH.sub.2).sub.0-4C(O)R.sup..smallcircle.;
--C(S)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)SR.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)OSiR.sup..smallcircle..sub.3;
--(CH.sub.2).sub.0-40C(O)R.sup..smallcircle.;
--OC(O)(CH.sub.2).sub.0-4SR.sup..smallcircle.;
--SC(S)SR.sup..smallcircle.;
--(CH.sub.2).sub.0-4SC(O)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)NR.sup..smallcircle..sub.2;
--C(S)NR.sup..smallcircle..sub.2; --C(S)SR.sup..smallcircle.;
--SC(S)SR.sup..smallcircle.,
--(CH.sub.2).sub.0-4OC(O)NR.sup..smallcircle..sub.2;
--C(O)N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(O)C(O)R.sup..smallcircle.;
--C(O)CH.sub.2C(O)R.sup..smallcircle.;
--C(NOR.sup..smallcircle.)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4SSR.sup..smallcircle.;
--(CH.sub.2).sub.0-4S(O).sub.2R.sup..smallcircle.;
--(CH.sub.2).sub.0-4S(O).sub.2OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4OS(O).sub.2R.sup..smallcircle.;
--S(O).sub.2NR.sup..smallcircle..sub.2;
--(CH.sub.2).sub.0-4S(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)S(O).sub.2NR.sup..smallcircle..sub.2;
--N(R.sup..smallcircle.)S(O).sub.2R.sup..smallcircle.;
--N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(NH)NR.sup..smallcircle..sub.2; --P(O).sub.2R.sup..smallcircle.;
--P(O)R.sup..smallcircle..sub.2; --OP(O)R.sup..smallcircle..sub.2;
--OP(O)(OR.sup..smallcircle.).sub.2; --SiR.sup..smallcircle..sub.3;
--(C.sub.1-4 straight or branched
alkylene)O--N(R.sup..smallcircle.).sub.2; or --(C.sub.1-4 straight
or branched alkylene)C(O)O--N(R.sup..smallcircle.).sub.2, wherein
each R.sup..smallcircle. may be substituted as defined below and is
independently hydrogen, C.sub.1-6 aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.0-1Ph, --CH.sub.2-(5-6 membered heteroaryl ring),
or a 5-6-membered saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or, notwithstanding the definition above, two
independent occurrences of R.sup..smallcircle., taken together with
their intervening atom(s), form a 3-12-membered saturated,
partially unsaturated, or aryl mono- or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, which may be substituted as defined below.
[0041] Suitable monovalent substituents on R.sup..smallcircle. (or
the ring formed by taking two independent occurrences of
R.sup..smallcircle. together with their intervening atoms), are
independently halogen, --(CH.sub.2).sub.0-2R.sup..cndot.,
-(haloR.sup..cndot.), --(CH.sub.2).sub.0-2OH,
--(CH.sub.2).sub.0-2OR.sup..cndot.,
--(CH.sub.2).sub.0-2CH(OR.sup..cndot.).sub.2;
--O(haloR.sup..cndot.), --CN, --N.sub.3,
--(CH.sub.2).sub.0-2C(O)R.sup..cndot., --(CH.sub.2).sub.0-2C(O)OH,
--(CH.sub.2).sub.0-2C(O)OR.sup..cndot.,
--(CH.sub.2).sub.0-2SR.sup..cndot., --(CH.sub.2).sub.0-2SH,
--(CH.sub.2).sub.0-2NH.sub.2, --(CH.sub.2).sub.0-2NHR.sup..cndot.,
--(CH.sub.2).sub.0-2NR.sup..cndot..sub.2, --NO.sub.2,
--SiR.sup..cndot..sub.3, --OSiR.sup..cndot..sub.3,
--C(O)SR.sup..cndot., --(C.sub.1-4 straight or branched
alkylene)C(O)OR.sup..cndot., or --SSR.sup..cndot. wherein each
R.sup..cndot. is unsubstituted or where preceded by "halo" is
substituted only with one or more halogens, and is independently
selected from C.sub.1-4 aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.0-1Ph, or a 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Suitable divalent
substituents on a saturated carbon atom of R.sup..smallcircle.
include .dbd.O and .dbd.S.
[0042] Suitable divalent substituents on a saturated carbon atom of
an "optionally substituted" group include the following: .dbd.O,
.dbd.S, .dbd.NNR*.sub.2, .dbd.NNHC(O)R*, .dbd.NNHC(O)OR*,
.dbd.NNHS(O).sub.2R*, .dbd.NR*, .dbd.NOR*, --O(C(R*2)).sub.2-3O--,
or --S(C(R*.sub.2)).sub.2-3S--, wherein each independent occurrence
of R* is selected from hydrogen, C.sub.1-6 aliphatic which may be
substituted as defined below, or an unsubstituted 5-6-membered
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur. Suitable divalent substituents that are bound to vicinal
substitutable carbons of an "optionally substituted" group include:
--O(CR*.sub.2).sub.2-3O--, wherein each independent occurrence of
R* is selected from hydrogen, C.sub.1-6 aliphatic which may be
substituted as defined below, or an unsubstituted 5-6-membered
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0043] Suitable substituents on the aliphatic group of R* include
halogen, --R.sup..cndot., -(haloR.sup..cndot.), --OH,
--OR.sup..cndot., --O(haloR.sup..cndot.), --CN, --C(O)OH,
--C(O)OR.sup..cndot., --NH.sub.2, --NHR.sup..cndot.,
--NR.sup..cndot..sub.2, or --NO.sub.2, wherein each R.sup..cndot.
is unsubstituted or where preceded by "halo" is substituted only
with one or more halogens, and is independently C.sub.1-4
aliphatic, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a 5-6-membered
saturated, partially unsaturated, or aryl ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0044] Suitable substituents on a substitutable nitrogen of an
"optionally substituted" group include --R.sup..dagger.,
--NR.sup..dagger..sub.2, --C(O)R.sup..dagger.,
--C(O)OR.sup..dagger., --C(O)C(O)R.sup..dagger.,
--C(O)CH.sub.2C(O)R.sup..dagger., --S(O).sub.2R.sup..dagger.,
--S(O).sub.2NR.sup..dagger..sub.2, --C(S)NR.sup..dagger..sub.2,
--C(NH)NR.sup..dagger..sub.2, or
--N(R.sup..dagger.)S(O).sub.2R.sup..dagger.; wherein each R is
independently hydrogen, C.sub.1-6 aliphatic which may be
substituted as defined below, unsubstituted --OPh, or an
unsubstituted 5-6-membered saturated, partially unsaturated, or
aryl ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or, notwithstanding the definition
above, two independent occurrences of R.sup..dagger., taken
together with their intervening atom(s) form an unsubstituted
3-12-membered saturated, partially unsaturated, or aryl mono- or
bicyclic ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
[0045] Suitable substituents on the aliphatic group of
R.sup..dagger. are independently halogen, --R.sup..cndot.,
-(haloR.sup..cndot.), --OH, --OR.sup..cndot.,
--O(haloR.sup..cndot.), --CN, --C(O)OH, --C(O)OR.sup..cndot.,
--NH.sub.2, --NHR.sup..cndot., --NR.sup..cndot..sub.2, or
--NO.sub.2, wherein each R.sup..cndot. is unsubstituted or where
preceded by "halo" is substituted only with one or more halogens,
and is independently C.sub.1-4 aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.0-1Ph, or a 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0046] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge et al., describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66, 1-19, incorporated herein by reference.
Pharmaceutically acceptable salts of the compounds of this
invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic
acid addition salts are salts of an amino group formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid and perchloric acid or with organic
acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid or malonic acid or by using other
methods used in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, pivalate, propionate, stearate,
succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate,
undecanoate, valerate salts, and the like.
[0047] Salts derived from appropriate bases include alkali metal,
alkaline earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4
salts. Representative alkali or alkaline earth metal salts include
sodium, lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0048] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, Z
and E double bond isomers, and Z and E conformational isomers.
Therefore, single stereochemical isomers as well as enantiomeric,
diastereomeric, and geometric (or conformational) mixtures of the
present compounds are within the scope of the invention. Unless
otherwise stated, all tautomeric forms of the compounds of the
invention are within the scope of the invention. Additionally,
unless otherwise stated, structures depicted herein are also meant
to include compounds that differ only in the presence of one or
more isotopically enriched atoms. For example, compounds having the
present structures including the replacement of hydrogen by
deuterium or tritium, or the replacement of a carbon by a .sup.13C-
or .sup.14C-enriched carbon are within the scope of this invention.
Such compounds are useful, for example, as analytical tools, as
probes in biological assays, or as therapeutic agents in accordance
with the present invention. In certain embodiments, a warhead
moiety, R.sup.1, of a provided compound comprises one or more
deuterium atoms. In certain embodiments, Ring B of a provided
compound may be substituted with one or more deuterium atoms.
[0049] As used herein, the term "inhibitor" is defined as a
compound that binds to and/or inhibits TYK2 with measurable
affinity. In certain embodiments, an inhibitor has an IC.sub.50
and/or binding constant of less than about 50 .mu.M, less than
about 1 .mu.M, less than about 500 nM, less than about 100 nM, less
than about 10 nM, or less than about 1 nM.
[0050] A compound of the present invention may be tethered to a
detectable moiety. It will be appreciated that such compounds are
useful as imaging agents. One of ordinary skill in the art will
recognize that a detectable moiety may be attached to a provided
compound via a suitable substituent. As used herein, the term
"suitable substituent" refers to a moiety that is capable of
covalent attachment to a detectable moiety. Such moieties are well
known to one of ordinary skill in the art and include groups
containing, e.g., a carboxylate moiety, an amino moiety, a thiol
moiety, or a hydroxyl moiety, to name but a few. It will be
appreciated that such moieties may be directly attached to a
provided compound or via a tethering group, such as a bivalent
saturated or unsaturated hydrocarbon chain. In some embodiments,
such moieties may be attached via click chemistry. In some
embodiments, such moieties may be attached via a 1,3-cycloaddition
of an azide with an alkyne, optionally in the presence of a copper
catalyst. Methods of using click chemistry are known in the art and
include those described by Rostovtsev et al., Angew. Chem. Int. Ed.
2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17,
52-57.
[0051] As used herein, the term "detectable moiety" is used
interchangeably with the term "label" and relates to any moiety
capable of being detected, e.g., primary labels and secondary
labels. Primary labels, such as radioisotopes (e.g., tritium,
.sup.32P, .sup.33P, .sup.35S, or .sup.14C), mass-tags, and
fluorescent labels are signal generating reporter groups which can
be detected without further modifications. Detectable moieties also
include luminescent and phosphorescent groups.
[0052] The term "secondary label" as used herein refers to moieties
such as biotin and various protein antigens that require the
presence of a second intermediate for production of a detectable
signal. For biotin, the secondary intermediate may include
streptavidin-enzyme conjugates. For antigen labels, secondary
intermediates may include antibody-enzyme conjugates. Some
fluorescent groups act as secondary labels because they transfer
energy to another group in the process of nonradiative fluorescent
resonance energy transfer (FRET), and the second group produces the
detected signal.
[0053] The terms "fluorescent label", "fluorescent dye", and
"fluorophore" as used herein refer to moieties that absorb light
energy at a defined excitation wavelength and emit light energy at
a different wavelength. Examples of fluorescent labels include, but
are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor
488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor
594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA,
AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR,
BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589,
BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine
6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow,
Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl,
Dapoxyl, Dialkylaminocoumarin,
4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin,
Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD
700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue,
Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green
500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B,
Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green,
2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine
(TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas
Red-X.
[0054] The term "mass-tag" as used herein refers to any moiety that
is capable of being uniquely detected by virtue of its mass using
mass spectrometry (MS) detection techniques. Examples of mass-tags
include electrophore release tags such as
N-[3-[4'-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]ison-
ipecotic Acid,
4'-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methyl
acetophenone, and their derivatives. The synthesis and utility of
these mass-tags is described in U.S. Pat. Nos. 4,650,750,
4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020,
and 5,650,270. Other examples of mass-tags include, but are not
limited to, nucleotides, dideoxynucleotides, oligonucleotides of
varying length and base composition, oligopeptides,
oligosaccharides, and other synthetic polymers of varying length
and monomer composition. A large variety of organic molecules, both
neutral and charged (biomolecules or synthetic compounds) of an
appropriate mass range (100-2000 Daltons) may also be used as
mass-tags.
[0055] The terms "measurable affinity" and "measurably inhibit," as
used herein, means a measurable change in a TYK2 protein kinase
activity between a sample comprising a compound of the present
invention, or composition thereof, and a TYK2 protein kinase, and
an equivalent sample comprising an TYK2 protein kinase, in the
absence of said compound, or composition thereof.
3. Description of Exemplary Embodiments
[0056] As described above, in certain embodiments, the present
invention provides a compound of formula I.
##STR00005## [0057] or a pharmaceutically acceptable salt thereof,
wherein: [0058] X is N or C(R.sup.3) [0059] R.sup.1 is R, R.sup.D,
or --OR; [0060] R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; [0061] R.sup.3 is H, halogen, or C.sub.1-6 aliphatic;
or [0062] R.sup.2 and R.sup.3 are taken together with their
intervening atoms to form a 4-7 membered partially unsaturated or
aromatic ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; wherein said ring is substituted with
m instances of R.sup.4; [0063] each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; [0064] L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--; each instance of R.sup.4, R.sup.5,
R.sup.6, and R.sup.7 is independently R.sup.A or R.sup.B, and is
substituted by q instances of R.sup.C; [0065] each instance of
R.sup.A is independently oxo, halogen, --CN, --NO.sub.2, --OR,
--OR.sup.D, --SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2,
--S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; [0066] each instance of R.sup.B is
independently C.sub.1-6 aliphatic; phenyl; a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; a 3-7 membered
saturated or partially unsaturated carbocyclic ring; a 3-7 membered
saturated or partially unsaturated monocyclic heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; [0067]
each instance of R.sup.C is independently oxo, halogen, --CN,
--NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; [0068] R.sup.D is a C.sub.1-4 aliphatic group wherein one
or more hydrogens are replaced by deuterium; [0069] each R is
independently hydrogen, or an optionally substituted group selected
from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or
partially unsaturated heterocyclic having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, and a 5-6
membered heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, or. [0070] two R groups
on the same nitrogen are taken together with their intervening
atoms to form a 4-7 membered saturated, partially unsaturated, or
heteroaryl ring having 0-3 heteroatoms, in addition to the
nitrogen, independently selected from nitrogen, oxygen, and sulfur;
and [0071] each of m, n, p, and q is independently 0, 1, 2, 3, or
4.
[0072] As defined generally above, X is N or C(R.sup.3). In some
embodiments, X is N. In some embodiments, X is C(R.sup.3). In some
embodiments, X is C(H). In some embodiments, X is C(R.sup.3), where
R.sup.3 is halogen. In some embodiments, X is C(R.sup.3), where
R.sup.3 is fluoro.
[0073] As defined generally above, R.sup.1 is R, R.sup.D, or --OR.
In some embodiments, R.sup.1 is R. In some embodiments, R.sup.1 is
R.sup.D. In some embodiments, R.sup.1 is --OR. In some embodiments,
R.sup.1 is an optionally substituted C.sub.1-6 aliphatic group. In
some embodiments, R.sup.1 is an optionally substituted ethyl group.
In some embodiments, R.sup.1 is hydrogen, methyl or --CD.sub.3. In
some embodiments, R.sup.1 is hydrogen. In some embodiments, R.sup.1
is methyl or --CD.sub.3. In some embodiments, R.sup.1 is methyl. In
some embodiments, R.sup.1 is --CD.sub.3. In some embodiments,
R.sup.1 is --OH.
[0074] As defined generally above, R.sup.2 is H, R.sup.C,
--N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2, or
Cy.sup.2. In some embodiments, R.sup.2 is H. In some embodiments,
R.sup.2 is R.sup.C, --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2,
--OCy.sup.2, --SCy.sup.2, or Cy.sup.2. In some embodiments, R.sup.2
is R.sup.C; In some embodiments, R.sup.2 is --N(R)C(O)R. In some
embodiments, R.sup.2 is --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, or
Cy.sup.2. In some embodiments, R.sup.2 is --N(R)C(O)R,
--N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, or Cy.sup.2. In some
embodiments, R.sup.2 is --N(H)C(O)R, --N(H)C(O)Cy.sup.2,
--N(H)Cy.sup.2, or Cy.sup.2. In some embodiments, R.sup.2 is
--N(H)C(O)R, --N(H)C(O)Cy.sup.2, or --N(H)Cy.sup.2. In some
embodiments, R.sup.2 is --N(H)C(O)R. In some embodiments, R.sup.2
is --N(H)C(O)R wherein R in this instance is optionally substituted
C.sub.1-6 aliphatic. In some embodiments, R.sup.2 is
--N(H)C(O)Cy.sup.2. In some embodiments, R.sup.2 is --N(H)Cy.sup.2.
In some embodiments, R.sup.2 is --N(H)C(O)Cy.sup.2 where Cy.sup.2
is cyclopropyl. In some embodiments, R.sup.2 is
##STR00006##
[0075] As defined generally above, R.sup.3 is H, halogen, or
C.sub.1-6 aliphatic. In some embodiments, R.sup.3 is H. In some
embodiments, R.sup.3 is halogen, or C.sub.1-6 aliphatic. In some
embodiments, R.sup.3 is halogen. In some embodiments, R.sup.3 is
fluoro. In some embodiments, R.sup.3 is C.sub.1-6 aliphatic.
[0076] In some embodiments, R.sup.2 and R.sup.3 are taken together
with their intervening atoms to form a 4-7 membered partially
unsaturated or aromatic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; wherein said ring is
substituted with m instances of R.sup.4. In some embodiments,
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 5-membered partially unsaturated or aromatic ring having
1-3 heteroatoms independently selected from nitrogen, oxygen, and
sulfur; wherein said ring is substituted with m instances of
R.sup.4.
[0077] As defined generally above, Cy.sup.1 is phenyl; a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; an 8-10
membered bicyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 3-7 membered saturated or partially
unsaturated monocyclic carbocyclic ring; or a 7-12 membered
saturated or partially unsaturated bicyclic heterocyclic ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, wherein Cy.sup.1 is substituted with n
instances of R.sup.5.
[0078] In some embodiments, Cy.sup.1 is phenyl. In some
embodiments, Cy.sup.1 is a 5-6 membered heteroaryl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.1 is a 5-membered heteroaryl
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.1 is a 6-membered
heteroaryl having 1-4 nitrogens. In some embodiments, Cy.sup.1 is
pyridyl. In some embodiments, Cy.sup.1 is pyrazinyl. In some
embodiments, Cy.sup.1 is pyrimidinyl. In some embodiments, Cy.sup.1
is triazinyl. In some embodiments, Cy.sup.1 is pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy1 is
furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, In some embodiments,
Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In
some embodiments, Cy.sup.1 is an 8-10 membered bicyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.1 is a 3-7 membered
saturated or partially unsaturated heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.1 is a 3-7 membered saturated
or partially unsaturated monocyclic carbocyclic ring. In some
embodiments, Cy.sup.1 is a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur.
[0079] In some embodiments, Cy.sup.1(R.sup.5).sub.n taken together
is selected from the following:
##STR00007## ##STR00008## ##STR00009## ##STR00010##
wherein each of R, R.sup.C, and q is as defined above and described
in embodiments herein, both singly and in combination.
[0080] In some embodiments, Cy.sup.1(R.sup.5).sub.n taken together
is selected from the groups in the preceding paragraph or the
following:
##STR00011##
[0081] In some embodiments, Cy.sup.1(R.sup.5).sub.n taken together
is selected from the groups in the preceding two paragraph or the
following:
##STR00012## ##STR00013##
[0082] As defined generally above, Cy.sup.2 is phenyl; a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; an 8-10
membered bicyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 3-7 membered saturated or partially
unsaturated monocyclic carbocyclic ring; or a 7-12 membered
saturated or partially unsaturated bicyclic heterocyclic ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, wherein Cy.sup.2 is substituted with p
instances of R.sup.6.
[0083] In some embodiments, Cy.sup.2 is phenyl. In some
embodiments, Cy.sup.2 is a 5-6 membered heteroaryl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.2 is a 5-membered heteroaryl
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.2 is a 6-membered
heteroaryl having 1-4 nitrogens. In some embodiments, Cy.sup.1 is
pyridyl. In some embodiments, Cy.sup.1 is pyrazinyl. In some
embodiments, Cy.sup.2 is pyrimidinyl. In some embodiments, Cy.sup.2
is triazinyl. In some embodiments, Cy.sup.2 is pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy.sup.2
is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, In some
embodiments, Cy.sup.2 is thiophenyl, thiazolyl, isothiazolyl, or
thiadiazolyl. In some embodiments, Cy.sup.2 is an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur. In some embodiments,
Cy.sup.2 is a 3-7 membered saturated or partially unsaturated
heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen, oxygen, and sulfur. In some embodiments, Cy.sup.2 is
a 3-7 membered saturated or partially unsaturated monocyclic
carbocyclic ring. In some embodiments, Cy.sup.2 is C.sub.3-7
cycloalkyl. In some embodiments, Cy.sup.2 is cyclopropyl. In some
embodiments, Cy.sup.2 is a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur.
[0084] In some embodiments, Cy.sup.2 is selected from the
following, each of which is substituted by p instances of
R.sup.6:
##STR00014##
[0085] In some embodiments, Cy.sup.2 is selected from the groups in
the preceding paragraph, or the following, each of which is
substituted by p instances of R.sup.6:
##STR00015##
[0086] In some embodiments, p is 1 or 2 and at least one instance
of R.sup.6 is --CN, --CH.sub.3, --CHF.sub.2, or --CF.sub.3.
[0087] As defined generally above, L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--. In some embodiments, L.sup.1 is a
covalent bond. In some embodiments, L.sup.1 is a C.sub.1-4 bivalent
saturated or unsaturated, straight or branched hydrocarbon chain
wherein one or two methylene units of the chain are optionally and
independently replaced by --C(R.sup.7).sub.2--, --N(R)--,
--N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--, --S(O).sub.2N(R)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --S(O)-- or
--S(O).sub.2--. In some embodiments, L.sup.1 is --N(R)--. In some
embodiments, L.sup.1 is --N(H)--.
[0088] As defined generally above, m is 0, 1, 2, 3, or 4. In some
embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In
some embodiments, m is 1. In some embodiments, m is 2. In some
embodiments, m is 3. In some embodiments, m is 4.
[0089] As defined generally above, n is 0, 1, 2, 3, or 4. In some
embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In
some embodiments, n is 1. In some embodiments, n is 2. In some
embodiments, n is 3. In some embodiments, n is 4.
[0090] As defined generally above, p is 0, 1, 2, 3, or 4. In some
embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In
some embodiments, p is 1. In some embodiments, p is 2. In some
embodiments, p is 3. In some embodiments, p is 4.
[0091] In some embodiments, the present invention provides a
compound of formula I, wherein L.sup.1 is --N(H)--, thereby forming
a compound of formula I-a:
##STR00016##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Cy.sup.1, R.sup.1, and R.sup.2 is as defined above and described in
embodiments herein, both singly and in combination.
[0092] In some embodiments, the present invention provides a
compound of formula I, wherein X is N or C(R.sup.3), thereby
forming a compound of formulas I-b or I-c respectively:
##STR00017##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.1, L.sup.1, R.sup.1, R.sup.2, and R.sup.3 is as defined
above and described in embodiments herein, both singly and in
combination.
[0093] In some embodiments, the present invention provides a
compound of formula I-a, wherein L.sup.1 is N or C(R.sup.3),
thereby forming a compound of formulas II-a or II-b
respectively:
##STR00018##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.1, R.sup.1, R.sup.2, and R.sup.3 is as defined above and
described in embodiments herein, both singly and in
combination.
[0094] In some embodiments, the present invention provides a
compound of formula II-a or II-b wherein Cy.sup.1 is phenyl,
thereby forming a compound of formulas III-a or III-b
respectively:
##STR00019##
or a pharmaceutically acceptable salt thereof, wherein each of
R.sup.1, R.sup.2, R.sup.3, R.sup.5, and n is as defined above and
described in embodiments herein, both singly and in
combination.
[0095] In some embodiments, the present invention provides a
compound of formula III-a or III-b, wherein n is 1, 2 or 3, and at
least one instance of R.sup.5 is ortho to the NH point of
attachment, thereby forming a compound of formulas IV-a or IV-b
respectively:
##STR00020##
or a pharmaceutically acceptable salt thereof, wherein each of
R.sup.1, R.sup.2, R.sup.3, and R.sup.5 is as defined above and
described in embodiments herein, both singly and in
combination.
[0096] In some embodiments, the present invention provides a
compound of formula IV-a or IV-b, wherein the ortho R.sup.5 group
is --OR, --S(O).sub.2R, --C(O)NR.sub.2, or --N(R)S(O).sub.2R,
thereby forming a compound of formulas V-a, V-b, V-c, V-d, V-e,
V-f, V-g, or V-h respectively:
##STR00021## ##STR00022##
or a pharmaceutically acceptable salt thereof, wherein each of R,
R.sup.1, R.sup.2, R.sup.3, and R.sup.5 is as defined above and
described in embodiments herein, both singly and in
combination.
[0097] In some embodiments, the present invention provides a
compound of formula V-a or V-b, wherein a second R.sup.5 group
(R.sup.5b) is meta to the NH point of attachment, thereby forming a
compound of formulas VI-a, or VI-b respectively:
##STR00023##
or a pharmaceutically acceptable salt thereof, wherein each of R,
R.sup.1, R.sup.2, R.sup.3, and R.sup.5 is as defined above and
described in embodiments herein, both singly and in
combination.
[0098] In some embodiments, the present invention provides a
compound of formula VI-a or VI-b, wherein R.sup.5 is R.sup.B. In
some embodiments, the present invention provides a compound of
formula VI-a or VI-b, wherein R.sup.5 is --C(O)NR.sub.2 or a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, said ring
being substituted by q instances of R.sup.C;
[0099] In some embodiments, the present invention provides a
compound of formula VI-a or VI-b, wherein --OR is methoxy,
fluoromethoxy, or difluoromethoxy.
[0100] In some embodiments, the present invention provides a
compound of formula II-a or II-b wherein Cy.sup.1 is pyridyl, n is
2, and one instance of R.sup.5 is oxo, thereby forming a pyridone
compound of formulas VII-a or VII-b respectively:
##STR00024##
or a pharmaceutically acceptable salt thereof, wherein each of
R.sup.1, R.sup.2, R.sup.3, and R.sup.5, is as defined above and
described in embodiments herein, both singly and in
combination.
[0101] As described above, in certain embodiments, the present
invention provides a compound of formula VIII:
##STR00025## [0102] or a pharmaceutically acceptable salt thereof,
wherein: [0103] X is N or C(R.sup.3) [0104] Y is N or C(R.sup.1);
[0105] R.sup.1 is H, D, or halogen; [0106] R, R.sup.D, or --OR;
[0107] R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; [0108] R.sup.3 is H, halogen, or C.sub.1-6 aliphatic;
or [0109] R.sup.2 and R.sup.3 are taken together with their
intervening atoms to form a 4-7 membered partially unsaturated or
aromatic ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; wherein said ring is substituted with
m instances of R.sup.4; [0110] each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur; wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; [0111] Cy.sup.3 is a 5-6 membered
monocyclic partially unsaturated or heteroaromatic ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; wherein Cy.sup.3 is substituted with r instances of
R.sup.8; [0112] L.sup.1 is a covalent bond or a C.sub.1-4 bivalent
saturated or unsaturated, straight or branched hydrocarbon chain
wherein one or two methylene units of the chain are optionally and
independently replaced by --C(R.sup.7).sub.2--, --N(R)--,
--N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--, --S(O).sub.2N(R)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --OC(O)N(R)--,
--N(R)C(O)O--, --S--, --S(O)-- or --S(O).sub.2--; [0113] each
instance of R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is
independently R.sup.A or R.sup.B, and is substituted by q instances
of R.sup.C; [0114] each instance of R.sup.A is independently oxo,
halogen, --CN, --NO.sub.2, --OR, --OR.sup.D, --SR, --NR.sub.2,
--S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2,
--C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R,
--OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2,
--N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2, or
--N(R)S(O).sub.2R; [0115] each instance of R.sup.B is independently
C.sub.1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated carbocyclic ring; a 3-7 membered saturated or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; or a 7-12
membered saturated or partially unsaturated bicyclic heterocyclic
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; [0116] each instance of R.sup.C is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --SR,
--NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R or an optionally substituted group selected
from C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or
partially unsaturated heterocyclic ring having 1-2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, and a 5-6
membered heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; [0117] R.sup.D is a
C.sub.1-4 aliphatic group wherein one or more hydrogens are
replaced by deuterium; [0118] each R is independently hydrogen, or
an optionally substituted group selected from C.sub.1-6 aliphatic,
phenyl, a 3-7 membered saturated or partially unsaturated
heterocyclic having 1-2 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, or. [0119] two R groups on the same nitrogen
are taken together with their intervening atoms to form a 4-7
membered saturated, partially unsaturated, or heteroaryl ring
having 0-3 heteroatoms, in addition to the nitrogen, independently
selected from nitrogen, oxygen, and sulfur; and [0120] each of m,
n, p, q, and r is independently 0, 1, 2, 3, or 4.
[0121] As defined generally above, X is N or C(R.sup.3). In some
embodiments, X is N. In some embodiments, X is C(R.sup.3). In some
embodiments, X is C(H). In some embodiments, X is C(R.sup.3), where
R.sup.3 is halogen. In some embodiments, X is C(R.sup.3), where
R.sup.3 is fluoro.
[0122] As defined generally above, Y is N or C(R.sup.1). In some
embodiments, Y is N. In some embodiments, Y is C(R.sup.1). In some
embodiments, Y is C(H). In some embodiments, Y is C(D). In some
embodiments, Y is C(R.sup.1), where R.sup.1 is halogen. In some
embodiments, X is C(R.sup.1), where R.sup.3 is fluoro.
[0123] As defined generally above, R.sup.1 is H, D, or halogen. In
some embodiments, R.sup.1 is H. In some embodiments, R.sup.1 is D.
In some embodiments, R.sup.1 is halogen. In some embodiments,
R.sup.1 is fluoro.
[0124] As defined generally above, R.sup.2 is H, R.sup.C,
--N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2, or
Cy.sup.2. In some embodiments, R.sup.2 is H. In some embodiments,
R.sup.2 is R.sup.C, --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2,
--OCy.sup.2, --SCy.sup.2, or Cy.sup.2. In some embodiments, R.sup.2
is R.sup.C; In some embodiments, R.sup.2 is --N(R)C(O)R. In some
embodiments, R.sup.2 is --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, or
Cy.sup.2. In some embodiments, R.sup.2 is --N(R)C(O)R,
--N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, or Cy.sup.2. In some
embodiments, R.sup.2 is --N(H)C(O)R, --N(H)C(O)Cy.sup.2,
--N(H)Cy.sup.2, or Cy.sup.2. In some embodiments, R.sup.2 is
--N(H)C(O)R, --N(H)C(O)Cy.sup.2, or --N(H)Cy.sup.2. In some
embodiments, R.sup.2 is --N(H)C(O)R. In some embodiments, R.sup.2
is --N(H)C(O)R wherein R in this instance is optionally substituted
C.sub.1-6 aliphatic. In some embodiments, R.sup.2 is
--N(H)C(O)Cy.sup.2. In some embodiments, R.sup.2 is --N(H)Cy.sup.2.
In some embodiments, R.sup.2 is --N(H)C(O)Cy.sup.2 where Cy.sup.2
is cyclopropyl. In some embodiments, R.sup.2 is
##STR00026##
[0125] In some embodiments, R.sup.2 and R.sup.3 are taken together
with their intervening atoms to form a 4-7 membered partially
unsaturated or aromatic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; wherein said ring is
substituted with m instances of R.sup.4. In some embodiments,
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 5-membered partially unsaturated or aromatic ring having
1-3 heteroatoms independently selected from nitrogen, oxygen, and
sulfur; wherein said ring is substituted with m instances of
R.sup.4.
[0126] As defined generally above, Cy.sup.1 is phenyl; a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; an 8-10
membered bicyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 3-7 membered saturated or partially
unsaturated monocyclic carbocyclic ring; or a 7-12 membered
saturated or partially unsaturated bicyclic heterocyclic ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, wherein Cy.sup.1 is substituted with n
instances of R.sup.5.
[0127] In some embodiments, Cy.sup.1 is phenyl. In some
embodiments, Cy.sup.1 is a 5-6 membered heteroaryl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.1 is a 5-membered heteroaryl
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.1 is a 6-membered
heteroaryl having 1-4 nitrogens. In some embodiments, Cy.sup.1 is
pyridyl. In some embodiments, Cy.sup.1 is pyrazinyl. In some
embodiments, Cy.sup.1 is pyrimidinyl. In some embodiments, Cy.sup.1
is triazinyl. In some embodiments, Cy.sup.1 is pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy1 is
furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, In some embodiments,
Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In
some embodiments, Cy.sup.1 is an 8-10 membered bicyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.1 is a 3-7 membered
saturated or partially unsaturated heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.1 is a 3-7 membered saturated
or partially unsaturated monocyclic carbocyclic ring. In some
embodiments, Cy.sup.1 is a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur.
[0128] In some embodiments, Cy.sup.1(R.sup.5).sub.n taken together
is selected from the following:
##STR00027## ##STR00028## ##STR00029## ##STR00030##
wherein each of R, R.sup.C, and q is as defined above and described
in embodiments herein, both singly and in combination.
[0129] As defined generally above, Cy.sup.2 is phenyl; a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; an 8-10
membered bicyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 3-7 membered saturated or partially
unsaturated monocyclic carbocyclic ring; or a 7-12 membered
saturated or partially unsaturated bicyclic heterocyclic ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, wherein Cy.sup.2 is substituted with p
instances of R.sup.6.
[0130] In some embodiments, Cy.sup.2 is phenyl. In some
embodiments, Cy.sup.2 is a 5-6 membered heteroaryl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.2 is a 5-membered heteroaryl
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.2 is a 6-membered
heteroaryl having 1-4 nitrogens. In some embodiments, Cy.sup.2 is
pyridyl. In some embodiments, Cy.sup.2 is pyrazinyl. In some
embodiments, Cy.sup.2 is pyrimidinyl. In some embodiments, Cy.sup.2
is triazinyl. In some embodiments, Cy.sup.2 is pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy.sup.2
is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, In some
embodiments, Cy.sup.2 is thiophenyl, thiazolyl, isothiazolyl, or
thiadiazolyl. In some embodiments, Cy.sup.2 is an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur. In some embodiments,
Cy.sup.2 is a 3-7 membered saturated or partially unsaturated
heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen, oxygen, and sulfur. In some embodiments, Cy.sup.2 is
a 3-7 membered saturated or partially unsaturated monocyclic
carbocyclic ring. In some embodiments, Cy.sup.2 is C.sub.3-7
cycloalkyl. In some embodiments, Cy.sup.2 is cyclopropyl. In some
embodiments, Cy.sup.2 is a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur.
[0131] In some embodiments, Cy.sup.2 is selected from the
following, each of which is substituted by p instances of
R.sup.6:
##STR00031##
[0132] In some embodiments, Cy.sup.2 is selected from the groups in
the preceding paragraph, or the following, which is substituted by
p instances of R.sup.6:
##STR00032##
[0133] As defined generally above, Cy.sup.3 is a 5-6 membered
monocyclic partially unsaturated or heteroaromatic ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; wherein Cy.sup.3 is substituted with r instances of
R.sup.8. In some embodiments, Cy.sup.3 is a 5-membered monocyclic
partially unsaturated or heteroaromatic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur. In some
embodiments, Cy.sup.3 is a 5-membered monocyclic partially
unsaturated ring having 1-3 heteroatoms independently selected from
nitrogen, oxygen, and sulfur. In some embodiments, Cy.sup.3 is a
5-membered monocyclic heteroaromatic ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, and sulfur.
[0134] In some embodiments, Cy.sup.3 is selected from the
following, each of which is substituted by r instances of
R.sup.8:
##STR00033##
[0135] As defined generally above, L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--. In some embodiments, L.sup.1 is a
covalent bond. In some embodiments, L.sup.1 is a C.sub.1-4 bivalent
saturated or unsaturated, straight or branched hydrocarbon chain
wherein one or two methylene units of the chain are optionally and
independently replaced by --C(R.sup.7).sub.2--, --N(R)--,
--N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--, --S(O).sub.2N(R)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --S(O)-- or
--S(O).sub.2--. In some embodiments, L.sup.1 is --N(R)--. In some
embodiments, L.sup.1 is --N(H)--.
[0136] As defined generally above, R.sup.8 is independently R.sup.A
or R.sup.B, and is substituted by q instances of R.sup.C; In some
embodiments, R.sup.8 is halogen or C.sub.1-6 aliphatic substituted
by 1-2 R.sup.C; In some embodiments, R.sup.8 is halogen. In some
embodiments, R.sup.8 is C.sub.1-6 aliphatic substituted by 0-2
R.sup.C; In some embodiments, R.sup.8 is chloro or fluoro. In some
embodiments, R.sup.8 is hydroxymethyl. In some embodiments, R.sup.8
is chloro, fluoro, methyl, cyclopropyl, or hydroxymethyl. In some
embodiments, R.sup.8 is chloro, fluoro, or hydroxymethyl.
[0137] As defined generally above, m is 0, 1, 2, 3, or 4. In some
embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In
some embodiments, m is 1. In some embodiments, m is 2. In some
embodiments, m is 3. In some embodiments, m is 4.
[0138] As defined generally above, n is 0, 1, 2, 3, or 4. In some
embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In
some embodiments, n is 1. In some embodiments, n is 2. In some
embodiments, n is 3. In some embodiments, n is 4.
[0139] As defined generally above, p is 0, 1, 2, 3, or 4. In some
embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In
some embodiments, p is 1. In some embodiments, p is 2. In some
embodiments, p is 3. In some embodiments, p is 4.
[0140] As defined generally above, r is 0, 1, 2, 3, or 4. In some
embodiments, r is 0. In some embodiments, r is 1, 2, 3, or 4. In
some embodiments, r is 1. In some embodiments, r is 2. In some
embodiments, r is 3. In some embodiments, r is 4.
[0141] In some embodiments, the present invention provides a
compound of formula VIII, wherein L.sup.1 is --N(H)--, thereby
forming a compound of formula VIII-a:
##STR00034##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Cy.sup.1, R.sup.1, and R.sup.2 is as defined above and described in
embodiments herein, both singly and in combination.
[0142] In some embodiments, the present invention provides a
compound of formula VIII, wherein X is C(R.sup.3) and Y is
C(R.sup.1), or X is C(R.sup.3) and Y is N, or X is N and Y is
C(R.sup.1), or both X and Y are N; thereby forming a compound of
formulas IX-a, IX-b, IX-c, or IX-d respectively:
##STR00035##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.1, Cy.sup.3, L.sup.1, R.sup.1, R.sup.2, and R.sup.3 is as
defined above and described in embodiments herein, both singly and
in combination.
[0143] In some embodiments, the present invention provides a
compound of formulas IX-a, IX-b, IX-c, or IX-d, wherein L.sup.1 is
--N(H)--, thereby forming a compound of formulas X-a or X-b, X-c,
or X-d respectively:
##STR00036##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.1, Cy.sup.3, R.sup.1, R.sup.2, and R.sup.3 is as defined
above and described in embodiments herein, both singly and in
combination.
[0144] In some embodiments, the present invention provides a
compound of formula VIII-a, wherein Cy.sup.1 is phenyl, thereby
forming a compound of formula XI-a:
##STR00037##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Y, R.sup.2, R.sup.5, and n is as defined above and described in
embodiments herein, both singly and in combination.
[0145] In some embodiments, the present invention provides a
compound of formula X-a, X-b, X-c, or X-d wherein Cy.sup.1 is
phenyl, thereby forming a compound of formulas XI-b, XI-c, XI-d, or
XI-e respectively:
##STR00038##
or a pharmaceutically acceptable salt thereof, wherein each of
R.sup.1, R.sup.2, R.sup.3, R.sup.5, and n is as defined above and
described in embodiments herein, both singly and in
combination.
[0146] In some embodiments, the present invention provides a
compound of formula XI-a, wherein n is 1, 2 or 3, and at least one
instance of R.sup.5 is ortho to the NH point of attachment, thereby
forming a compound of formula XII-a:
##STR00039##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Y, Cy.sup.3, R.sup.2, and R.sup.5 is as defined above and described
in embodiments herein, both singly and in combination.
[0147] In some embodiments, the present invention provides a
compound of formula XI-b, XI-c, XI-d, or XI-e wherein n is 1, 2 or
3, and at least one instance of R.sup.5 is ortho to the NH point of
attachment, thereby forming a compound of formula XII-b, XII-c,
XII-d, or XII-e respectively:
##STR00040##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.3, R.sup.1, R.sup.2, R.sup.3, and R.sup.5 is as defined
above and described in embodiments herein, both singly and in
combination.
[0148] In some embodiments, the present invention provides a
compound of formula XII-a, wherein the ortho R.sup.5 group is --OR,
--S(O).sub.2R, --C(O)NR.sub.2, or --N(R)S(O).sub.2R, thereby
forming a compound of formulas XII-a-i, XII-a-ii, XII-a-iii, or
XII-a-iv respectively:
##STR00041##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Y, Cy.sup.3, R, R.sup.1, R.sup.2, R.sup.3, and R.sup.5 is as
defined above and described in embodiments herein, both singly and
in combination.
[0149] In some embodiments, the present invention provides a
compound of formula XII-b, wherein the ortho R.sup.5 group is --OR,
--S(O).sub.2R, --C(O)NR.sub.2, or --N(R)S(O).sub.2R, thereby
forming a compound of formulas XII-b-i, XII-b-ii, XII-b-iii, or
XII-b-iv respectively:
##STR00042##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.3, R, R.sup.1, R.sup.2, R.sup.3, and R.sup.5 is as defined
above and described in embodiments herein, both singly and in
combination.
[0150] In some embodiments, the present invention provides a
compound of formula XII-c, wherein the ortho R.sup.5 group is --OR,
--S(O).sub.2R, --C(O)NR.sub.2, or --N(R)S(O).sub.2R, thereby
forming a compound of formulas XII-c-i, XII-c-ii, XII-c-iii, or
XII-c-iv respectively:
##STR00043##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.3, R, R.sup.2, R.sup.3, and R.sup.5 is as defined above and
described in embodiments herein, both singly and in
combination.
[0151] In some embodiments, the present invention provides a
compound of formula XII-d, wherein the ortho R.sup.5 group is --OR,
--S(O).sub.2R, --C(O)NR.sub.2, or --N(R)S(O).sub.2R, thereby
forming a compound of formulas XII-d-i, XII-d-ii, XII-d-iii, or
XII-d-iv respectively:
##STR00044##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.3, R, R.sup.1, R.sup.2, and R.sup.5 is as defined above and
described in embodiments herein, both singly and in
combination.
[0152] In some embodiments, the present invention provides a
compound of formula XII-e, wherein the ortho R.sup.5 group is --OR,
--S(O).sub.2R, --C(O)NR.sub.2, or --N(R)S(O).sub.2R, thereby
forming a compound of formulas XII-e-i, XII-e-ii, XII-e-iii, or
XII-e-iv respectively:
##STR00045##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.3, R, R.sup.2, and R.sup.5 is as defined above and described
in embodiments herein, both singly and in combination.
[0153] In some embodiments, the present invention provides a
compound of formula XII-a-i, wherein a second R.sup.5 group is meta
to the NH point of attachment, thereby forming a compound of
formula XIII-a:
##STR00046##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Y, Cy.sup.3, R, R.sup.2, and R.sup.5 is as defined above and
described in embodiments herein, both singly and in
combination.
[0154] In some embodiments, the present invention provides a
compound of formula XII-b-i, XII-c-i, XII-d-i, or XII-e-i, wherein
a second R.sup.5 group is meta to the NH point of attachment,
thereby forming a compound of formula XIII-b, XIII-c, XIII-d, or
XIII-e, respectively:
##STR00047##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.3, R, R.sup.1, R.sup.2, R.sup.3, and R.sup.5 is as defined
above and described in embodiments herein, both singly and in
combination.
[0155] In some embodiments, the present invention provides a
compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e
wherein R.sup.5 is R.sup.B. In some embodiments, the present
invention provides a compound of formula XIII-a, XIII-b, XIII-c,
XIII-d, or XIII-e wherein R.sup.5 is --C(O)NR.sub.2 or a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, said ring
being substituted by q instances of R.sup.C;
[0156] In some embodiments, the present invention provides a
compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e
wherein --OR is methoxy, fluoromethoxy, or difluoromethoxy.
[0157] In some embodiments, the present invention provides a
compound of formula I-a, wherein Cy.sup.1 is pyridyl, n is 2, and
one instance of R.sup.5 is oxo, thereby forming a pyridone compound
of formula XIV-a:
##STR00048##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Y, Cy.sup.3, R.sup.2, and R.sup.5 is as defined above and described
in embodiments herein, both singly and in combination.
[0158] In some embodiments, the present invention provides a
compound of formula X-a or X-b, X-c, or X-d, wherein Cy.sup.1 is
pyridyl, n is 2, and one instance of R.sup.5 is oxo, thereby
forming a pyridone compound of formula XV-a, XV-b, XV-c, or
XV-d:
##STR00049##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.3, R.sup.1, R.sup.2, R.sup.3, and R.sup.5 is as defined
above and described in embodiments herein, both singly and in
combination.
[0159] As described above, in certain embodiments, the present
invention provides a compound of formula XVI':
##STR00050## [0160] or a pharmaceutically acceptable salt thereof,
wherein: [0161] Q is CH or N; [0162] X is N or C(R.sup.X); [0163]
one of Y.sup.1, Y.sup.2, Z.sup.1, and Z.sup.2 is N, and the other
three are C; [0164] R.sup.1 is D, R, R.sup.D, --NR.sub.2,
--NRR.sup.D, --N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2,
--N(R)C(NR)NR.sub.2, --N(R)C(O)NRR.sup.D, --N(R)C(NR)NRR.sup.D,
--OR, or --OR.sup.D; [0165] R.sup.2 is H, R.sup.C,
--N(R)C(O)Cy.sup.2, --N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2,
--OCy.sup.2, --SCy.sup.2, or Cy.sup.2; [0166] R.sup.3 is H,
halogen, or C.sub.1-6 aliphatic; or [0167] R.sup.2 and R.sup.3 are
taken together with their intervening atoms to form a 4-7 membered
partially unsaturated or aromatic ring having 0-3 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; wherein
said ring is substituted with m instances of R.sup.4; [0168] each
of Cy.sup.1 and Cy.sup.2 is independently phenyl; a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; a 3-7 membered
saturated or partially unsaturated heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; or a 3-7 membered saturated or partially unsaturated
monocyclic carbocyclic ring; or a 7-12 membered saturated or
partially unsaturated bicyclic heterocyclic ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, wherein Cy.sup.1 is substituted with n instances of
R.sup.5; and; wherein Cy.sup.2 is substituted with p instances of
R.sup.6; [0169] L.sup.1 is a covalent bond or a C.sub.1-4 bivalent
saturated or unsaturated, straight or branched hydrocarbon chain
wherein one or two methylene units of the chain are optionally and
independently replaced by --C(R.sup.7).sub.2--, --N(R)--,
--N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--, --S(O).sub.2N(R)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --S(O)-- or
--S(O).sub.2--; [0170] each instance of R.sup.4, R.sup.5, R.sup.6,
and R.sup.7 is independently R.sup.A or R.sup.B, and is substituted
by q instances of R.sup.C; [0171] each instance of R.sup.A is
independently oxo, halogen, --CN, --NO.sub.2, --OR, --OR.sup.D,
--SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2, --S(O)R,
--S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2, --C(O)N(R)OR,
--OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; [0172] each instance of R.sup.B is
independently C.sub.1-6 aliphatic; phenyl; a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; a 3-7 membered
saturated or partially unsaturated carbocyclic ring; a 3-7 membered
saturated or partially unsaturated monocyclic heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; [0173]
each instance of R.sup.C is independently oxo, halogen, --CN,
--NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; [0174] R.sup.D is a C.sub.1-4 aliphatic group wherein one
or more hydrogens are replaced by deuterium; [0175] R.sup.X is H,
halogen, or C.sub.1-6 aliphatic [0176] each R is independently
hydrogen, or an optionally substituted group selected from
C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially
unsaturated heterocyclic having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, and a 5-6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, or. [0177] two R groups on the same
nitrogen are taken together with their intervening atoms to form a
4-7 membered saturated, partially unsaturated, or heteroaryl ring
having 0-3 heteroatoms, in addition to the nitrogen, independently
selected from nitrogen, oxygen, and sulfur; and [0178] each of m,
n, p, and q is independently 0, 1, 2, 3, or 4.
[0179] As defined generally above, Q is CH or N. In some
embodiments, Q is CH. In some embodiments, Q is N.
[0180] As defined generally above, X is N or C(R.sup.X). In some
embodiments, X is N. In some embodiments, X is C(R.sup.X). In some
embodiments, X is C(H). In some embodiments, X is C(R.sup.X), where
R.sup.X is halogen. In some embodiments, X is C(R.sup.X), where
R.sup.X is fluoro.
[0181] As defined generally above, R.sup.1 is D, R, R.sup.D,
--NR.sub.2, --NRR.sup.D, --N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2,
--N(R)C(NR)NR.sub.2, --N(R)C(O)NRR.sup.D, --N(R)C(NR)NRR.sup.D,
--OR, or --OR.sup.D. In some embodiments, R.sup.1 is D. In some
embodiments, R.sup.1 is R. In some embodiments, R.sup.1 is R.sup.D.
In some embodiments, R.sup.1 is --NR.sub.2. In some embodiments,
R.sup.1 is --NRR.sup.D. In some embodiments, R.sup.1 is
--N(R.sup.D).sub.2. In some embodiments, R.sup.1 is --OR. In some
embodiments, R.sup.1 is --OR.sup.D. In some embodiments, R.sup.1 is
an optionally substituted C.sub.1-6 aliphatic group. In some
embodiments, R.sup.1 is an optionally substituted ethyl group. In
some embodiments, R.sup.1 is hydrogen, methyl or --CD.sub.3. In
some embodiments, R.sup.1 is hydrogen. In some embodiments, R.sup.1
is methyl or --CD.sub.3. In some embodiments, R.sup.1 is methyl. In
some embodiments, R.sup.1 is --CD.sub.3. In some embodiments,
R.sup.1 is --OCH.sub.3. In some embodiments, R.sup.1 is D, R,
R.sup.D, --NR.sub.2, --NRR.sup.D, --N(R.sup.D).sub.2,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)C(O)NRR.sup.D,
--N(R)C(NR)NRR.sup.D, --OR, or --OR.sup.D, wherein R.sup.1 is not
hydrogen. In some embodiments, R.sup.1 is --NR.sub.2, --NRR,
--N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)C(O)NRR.sup.D, --N(R)C(NR)NRR.sup.D, --OR, or --OR.sup.D. In
some embodiments, R.sup.1 is --NR.sub.2, --NRR.sup.D,
--N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)C(O)NRR.sup.D, --N(R)C(NR)NR R.sup.D. In some embodiments,
R.sup.1 is --NR.sub.2, or --NRR.sup.D. In some embodiments, R.sup.1
is optionally substituted C.sub.1-6 aliphatic, --NR.sub.2, or
--NRR.sup.D. In some embodiments, R.sup.1 is --NHR or NHR.sup.D In
some embodiments, R.sup.1 is --NHCH.sub.3 or NHCD.sub.3.
[0182] As defined generally above, R.sup.2 is H, R.sup.C,
--N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2, or
Cy.sup.2. In some embodiments, R.sup.2 is H. In some embodiments,
R.sup.2 is R.sup.C, --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2,
--OCy.sup.2, --SCy.sup.2, or Cy.sup.2. In some embodiments, R.sup.2
is R.sup.C; In some embodiments, R.sup.2 is --N(R)C(O)R. In some
embodiments, R.sup.2 is --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, or
Cy.sup.2. In some embodiments, R.sup.2 is --N(R)C(O)R,
--N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, or Cy.sup.2. In some
embodiments, R.sup.2 is --N(H)C(O)R, --N(H)C(O)Cy.sup.2,
--N(H)Cy.sup.2, or Cy.sup.2. In some embodiments, R.sup.2 is
--N(H)C(O)R, --N(H)C(O)Cy.sup.2, or --N(H)Cy.sup.2. In some
embodiments, R.sup.2 is --N(H)C(O)R. In some embodiments, R.sup.2
is --N(H)C(O)R wherein R in this instance is optionally substituted
C.sub.1-6 aliphatic. In some embodiments, R.sup.2 is
--N(H)C(O)Cy.sup.2. In some embodiments, R.sup.2 is --N(H)Cy.sup.2.
In some embodiments, R.sup.2 is --N(H)C(O)Cy.sup.2 where Cy.sup.2
is cyclopropyl. In some embodiments, R.sup.2 is
##STR00051##
[0183] As defined generally above, R.sup.3 is H, halogen, or
C.sub.1-6 aliphatic. In some embodiments, R.sup.3 is H. In some
embodiments, R.sup.3 is halogen, or C.sub.1-6 aliphatic. In some
embodiments, R.sup.3 is halogen. In some embodiments, R.sup.3 is
fluoro. In some embodiments, R.sup.3 is C.sub.1-6 aliphatic.
[0184] In some embodiments, R.sup.2 and R.sup.3 are taken together
with their intervening atoms to form a 4-7 membered partially
unsaturated or aromatic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; wherein said ring is
substituted with m instances of R.sup.4. In some embodiments,
R.sup.2 and R.sup.3 are taken together with their intervening atoms
to form a 5-membered partially unsaturated or aromatic ring having
1-3 heteroatoms independently selected from nitrogen, oxygen, and
sulfur; wherein said ring is substituted with m instances of
R.sup.4.
[0185] As defined generally above, Cy.sup.1 is phenyl; a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; an 8-10
membered bicyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 3-7 membered saturated or partially
unsaturated monocyclic carbocyclic ring; or a 7-12 membered
saturated or partially unsaturated bicyclic heterocyclic ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, wherein Cy.sup.1 is substituted with n
instances of R.sup.5.
[0186] In some embodiments, Cy.sup.1 is phenyl. In some
embodiments, Cy.sup.1 is a 5-6 membered heteroaryl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.1 is a 5-membered heteroaryl
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.1 is a 6-membered
heteroaryl having 1-4 nitrogens. In some embodiments, Cy.sup.1 is
pyridyl. In some embodiments, Cy.sup.1 is pyrazinyl. In some
embodiments, Cy.sup.1 is pyrimidinyl. In some embodiments, Cy.sup.1
is triazinyl. In some embodiments, Cy.sup.1 is pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy1 is
furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, In some embodiments,
Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In
some embodiments, Cy.sup.1 is an 8-10 membered bicyclic heteroaryl
ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.1 is a 3-7 membered
saturated or partially unsaturated heterocyclic ring having 1-2
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.1 is a 3-7 membered saturated
or partially unsaturated monocyclic carbocyclic ring. In some
embodiments, Cy.sup.1 is a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur.
[0187] In some embodiments, Cy.sup.1(R.sup.5).sub.n taken together
is selected from the following:
##STR00052## ##STR00053## ##STR00054## ##STR00055##
wherein each of R, R.sup.C, and q is as defined above and described
in embodiments herein, both singly and in combination.
[0188] As defined generally above, Cy.sup.2 is phenyl; a 5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; an 8-10
membered bicyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 3-7 membered saturated or partially
unsaturated monocyclic carbocyclic ring; or a 7-12 membered
saturated or partially unsaturated bicyclic heterocyclic ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, wherein Cy.sup.2 is substituted with p
instances of R.sup.6.
[0189] In some embodiments, Cy.sup.2 is phenyl. In some
embodiments, Cy.sup.2 is a 5-6 membered heteroaryl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some embodiments, Cy.sup.2 is a 5-membered heteroaryl
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, Cy.sup.2 is a 6-membered
heteroaryl having 1-4 nitrogens. In some embodiments, Cy.sup.2 is
pyridyl. In some embodiments, Cy.sup.2 is pyrazinyl. In some
embodiments, Cy.sup.2 is pyrimidinyl. In some embodiments, Cy.sup.2
is triazinyl. In some embodiments, Cy.sup.2 is pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy.sup.2
is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, In some
embodiments, Cy.sup.2 is thiophenyl, thiazolyl, isothiazolyl, or
thiadiazolyl. In some embodiments, Cy.sup.2 is an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur. In some embodiments,
Cy.sup.2 is a 3-7 membered saturated or partially unsaturated
heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen, oxygen, and sulfur. In some embodiments, Cy.sup.2 is
a 3-7 membered saturated or partially unsaturated monocyclic
carbocyclic ring. In some embodiments, Cy.sup.2 is C.sub.3-7
cycloalkyl. In some embodiments, Cy.sup.2 is cyclopropyl. In some
embodiments, Cy.sup.2 is a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur.
[0190] In some embodiments, Cy.sup.2 is selected from the
following, each of which is substituted by p instances of
R.sup.6:
##STR00056##
[0191] As defined generally above, L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--. In some embodiments, L.sup.1 is a
covalent bond. In some embodiments, L.sup.1 is a C.sub.1-4 bivalent
saturated or unsaturated, straight or branched hydrocarbon chain
wherein one or two methylene units of the chain are optionally and
independently replaced by --C(R.sup.7).sub.2--, --N(R)--,
--N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--, --S(O).sub.2N(R)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --S(O)-- or
--S(O).sub.2--.
[0192] As defined generally above, m is 0, 1, 2, 3, or 4. In some
embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In
some embodiments, m is 1. In some embodiments, m is 2. In some
embodiments, m is 3. In some embodiments, m is 4.
[0193] As defined generally above, n is 0, 1, 2, 3, or 4. In some
embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In
some embodiments, n is 1. In some embodiments, n is 2. In some
embodiments, n is 3. In some embodiments, n is 4.
[0194] As defined generally above, p is 0, 1, 2, 3, or 4. In some
embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In
some embodiments, p is 1. In some embodiments, p is 2. In some
embodiments, p is 3. In some embodiments, p is 4.
[0195] In some embodiments, the present invention provides a
compound of formula XVI' wherein Q is N, thereby forming a compound
of formula XVI.
##STR00057## [0196] or a pharmaceutically acceptable salt thereof,
wherein: [0197] X is N or C(R.sup.X); [0198] one of Y.sup.1,
Y.sup.2, Z.sup.1, and Z.sup.2 is N, and the other three are C;
[0199] R.sup.1 is D, R, R.sup.D, --NR.sub.2, --NRR.sup.D,
--N(R.sup.D).sub.2, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)C(O)NRR.sup.D, --N(R)C(NR)NRR.sup.D, --OR, or --OR.sup.D;
[0200] R.sup.2 is H, R.sup.C, --N(R)C(O)Cy.sup.2,
--N(R)S(O).sub.2Cy.sup.2, --N(R)Cy.sup.2, --OCy.sup.2, --SCy.sup.2,
or Cy.sup.2; [0201] R.sup.3 is H, halogen, or C.sub.1-6 aliphatic;
or [0202] R.sup.2 and R.sup.3 are taken together with their
intervening atoms to form a 4-7 membered partially unsaturated or
aromatic ring having 0-3 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; wherein said ring is substituted with
m instances of R.sup.4; [0203] each of Cy.sup.1 and Cy.sup.2 is
independently phenyl; a 5-6 membered monocyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; a 3-7 membered saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or a 3-7 membered
saturated or partially unsaturated monocyclic carbocyclic ring; or
a 7-12 membered saturated or partially unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected
from nitrogen, oxygen, and sulfur, wherein Cy.sup.1 is substituted
with n instances of R.sup.5; and; wherein Cy.sup.2 is substituted
with p instances of R.sup.6; [0204] L.sup.1 is a covalent bond or a
C.sub.1-4 bivalent saturated or unsaturated, straight or branched
hydrocarbon chain wherein one or two methylene units of the chain
are optionally and independently replaced by --C(R.sup.7).sub.2--,
--N(R)--, --N(R)C(O)--, --C(O)N(R)--, --N(R)S(O).sub.2--,
--S(O).sub.2N(R)--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--,
--S(O)-- or --S(O).sub.2--; [0205] each instance of R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 is independently R.sup.A or R.sup.B,
and is substituted by q instances of R.sup.C; [0206] each instance
of R.sup.A is independently oxo, halogen, --CN, --NO.sub.2, --OR,
--OR.sup.D, --SR, --NR.sub.2, --S(O).sub.2R, --S(O).sub.2NR.sub.2,
--S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)R,
--N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2, --N(R)S(O).sub.2NR.sub.2,
or --N(R)S(O).sub.2R; [0207] each instance of R.sup.B is
independently C.sub.1-6 aliphatic; phenyl; a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; an 8-10 membered
bicyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; a 3-7 membered
saturated or partially unsaturated carbocyclic ring; a 3-7 membered
saturated or partially unsaturated monocyclic heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; or a 7-12 membered saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; [0208]
each instance of R.sup.C is independently oxo, halogen, --CN,
--NO.sub.2, --OR, --SR, --NR.sub.2, --S(O).sub.2R,
--S(O).sub.2NR.sub.2, --S(O)R, --S(O)NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --C(O)N(R)OR, --OC(O)R, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)R, --N(R)C(O)NR.sub.2, --N(R)C(NR)NR.sub.2,
--N(R)S(O).sub.2NR.sub.2, or --N(R)S(O).sub.2R or an optionally
substituted group selected from C.sub.1-6 aliphatic, phenyl, a 3-7
membered saturated or partially unsaturated heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; [0209] R.sup.D is a C.sub.1-4 aliphatic group wherein one
or more hydrogens are replaced by deuterium; [0210] R.sup.X is H,
halogen, or C.sub.1-6 aliphatic [0211] each R is independently
hydrogen, or an optionally substituted group selected from
C.sub.1-6 aliphatic, phenyl, a 3-7 membered saturated or partially
unsaturated heterocyclic having 1-2 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, and a 5-6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, or: [0212] two R groups on the same
nitrogen are taken together with their intervening atoms to form a
4-7 membered saturated, partially unsaturated, or heteroaryl ring
having 0-3 heteroatoms, in addition to the nitrogen, independently
selected from nitrogen, oxygen, and sulfur; and [0213] each of m,
n, p, and q is independently 0, 1, 2, 3, or 4.
[0214] In some embodiments, the present invention provides a
compound of formula XVI, wherein L.sup.1 is a covalent bond,
thereby forming a compound of formula XVI-a:
##STR00058##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.1, R.sup.2, and
R.sup.3 is as defined above and described in embodiments herein,
both singly and in combination.
[0215] In some embodiments, the present invention provides a
compound of formula XVI, wherein X is N or C(R.sup.X), thereby
forming a compound of formula XVI-b or XVI-c respectively:
##STR00059##
or a pharmaceutically acceptable salt thereof, wherein each of
L.sup.1, Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.X,
R.sup.1, R.sup.2, and R.sup.3 is as defined above and described in
embodiments herein, both singly and in combination.
[0216] In some embodiments, the present invention provides a
compound of formula XVI-b or XVI-c, wherein R.sup.X and R.sup.3 are
both H, thereby forming a compound of formula XVII-a or XVII-b
respectively:
##STR00060##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.1, R.sup.2, and
R.sup.3 is as defined above and described in embodiments herein,
both singly and in combination.
[0217] In some embodiments, the present invention provides a
compound of formula XVII-a or XVII-b, wherein L.sup.1 is a covalent
bond, thereby forming a compound of formula XVIII-a or XVIII-b
respectively:
##STR00061##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.1, and R.sup.2
is as defined above and described in embodiments herein, both
singly and in combination.
[0218] In some embodiments, the present invention provides a
compound of formula XVIII-a or XVIII-b wherein Cy.sup.1 is phenyl,
thereby forming a compound of formula XIX-a or XIX-b
respectively:
##STR00062##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R.sup.1, R.sup.2, and n is as
defined above and described in embodiments herein, both singly and
in combination.
[0219] In some embodiments, the present invention provides a
compound of formula XIX-a or XIX-b, wherein n is 1, 2 or 3, and at
least one instance of R.sup.5 is ortho to the NH point of
attachment, thereby forming a compound of formula XX-a or XX-b
respectively:
##STR00063##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R.sup.1, and R.sup.2 is as
defined above and described in embodiments herein, both singly and
in combination.
[0220] In some embodiments, the present invention provides a
compound of formula XX-a or XX-b, wherein the ortho R.sup.5 group
is --OR, --S(O).sub.2R, --C(O)NR.sub.2, or --N(R)S(O).sub.2R,
thereby forming a compound of formula XXI-a, XXI-b, XXI-c, XXI-d,
XXI-e, XXI-f, XXI-g, or XXI-h respectively:
##STR00064## ##STR00065##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R, R.sup.1, R.sup.2, and
R.sup.5 is as defined above and described in embodiments herein,
both singly and in combination.
[0221] In some embodiments, the present invention provides a
compound of formula XXI-a or XXI-b, wherein a second R.sup.5 group
is meta to the NH point of attachment, thereby forming a compound
of formula XXII-a, or XXII-b respectively:
##STR00066##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R, R.sup.1, R.sup.2, and
R.sup.5 is as defined above and described in embodiments herein,
both singly and in combination.
[0222] In some embodiments, the present invention provides a
compound of formula XXII-a or XXII-b, wherein R.sup.5 is R.sup.B.
In some embodiments, the present invention provides a compound of
formula XXII-a or XXII-b, wherein R.sup.5 is --CN, --C(O)NR.sub.2
or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, said ring
being substituted by q instances of R.sup.C;
[0223] In some embodiments, the present invention provides a
compound of formula XXII-a or XXII-b, wherein --OR is methoxy,
fluoromethoxy, or difluoromethoxy.
[0224] In some embodiments, the present invention provides a
compound of formula XVIII-a or XVIII-b wherein Cy.sup.1 is pyridyl,
n is 2, and one instance of R.sup.5 is oxo, thereby forming a
pyridone compound of formula XXIII-a or XXIII-b respectively:
##STR00067##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R.sup.1, R.sup.2, and R.sup.5,
is as defined above and described in embodiments herein, both
singly and in combination.
[0225] In some embodiments, the present invention provides a
compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b,
XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c,
XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, or
XXIII-b wherein Z.sup.2 is N, and Y.sup.1, Y.sup.2, and Z.sup.1 are
C. In some embodiments, the present invention provides a compound
of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a,
XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d,
XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, or XXIII-b
wherein Y.sup.2 is N, and Y.sup.1, Z.sup.1, and Z.sup.2 are C.
[0226] In some embodiments, the present invention provides a
compound of formula I wherein Z.sup.2 is N, and Y.sup.1, Y.sup.2,
and Z.sup.1 are C; or wherein Y.sup.2 is N, and Y.sup.1, Z.sup.1,
and Z.sup.2 are C, thereby forming a compound of formula XXIV-a or
XXIV-b respectively:
##STR00068##
or a pharmaceutically acceptable salt thereof, wherein each of X,
L.sup.1, Cy.sup.1, R.sup.1, and R.sup.2, is as defined above and
described in embodiments herein, both singly and in
combination.
[0227] In some embodiments, the present invention provides a
compound of formula XXIV-a or XXIV-b wherein L.sup.1 is a covalent
bond, thereby forming a compound of formula XXV-a or XXV-b
respectively:
##STR00069##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Cy.sup.1, R.sup.1, and R.sup.2 is as defined above and described in
embodiments herein, both singly and in combination.
[0228] In some embodiments, the present invention provides a
compound of formula XXV-a or XXV-b wherein X is C, and R.sup.X is
H, thereby forming a compound of formula XXVI-a or XXVI-b
respectively:
##STR00070##
or a pharmaceutically acceptable salt thereof, wherein each of
Cy.sup.1, R.sup.1, and R.sup.2 is as defined above and described in
embodiments herein, both singly and in combination.
[0229] In some embodiments, the present invention provides a
compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b,
XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c,
XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a,
XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b wherein
R.sup.2 is --N(R)C(O)R, --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2, or
Cy.sup.2. In some embodiments, the present invention provides a
compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b,
XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c,
XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a,
XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b wherein
R.sup.2 is --N(H)C(O)R, --N(H)C(O)Cy.sup.2, --N(H)Cy.sup.2, or
Cy.sup.2. In some embodiments, the present invention provides a
compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b,
XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c,
XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a,
XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b wherein
R.sup.2 is --N(H)C(O)R, --N(H)C(O)Cy.sup.2, or --N(H)Cy.sup.2. In
some embodiments, the present invention provides a compound of one
of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b,
XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f,
XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b,
XXV-a, XXV-b, XXVI-a, or XXVI-b wherein R.sup.2 is --N(H)C(O)R. In
some embodiments, the present invention provides a compound of one
of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b,
XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f,
XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b,
XXV-a, XXV-b, XXVI-a, or XXVI-b wherein R.sup.2 is
##STR00071##
In some embodiments, the present invention provides a compound of
one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a,
XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d,
XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b,
XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b wherein R.sup.2 is
--N(H)Cy.sup.2, wherein Cy.sup.2 is selected from the following,
each of which is substituted by p instances of R.sup.6:
##STR00072##
[0230] In some embodiments, the present invention provides a
compound of formula XVI' wherein Q is CH, thereby forming a
compound of formula XVI'':
##STR00073##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Y, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.1, R.sup.2, and
R.sup.3 is as defined above and described in embodiments herein,
both singly and in combination.
[0231] In some embodiments, the present invention provides a
compound of formula XVI'', wherein L.sup.1 is a covalent bond,
thereby forming a compound of formula XVI-a':
##STR00074##
or a pharmaceutically acceptable salt thereof, wherein each of X,
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.1, R.sup.2, and
R.sup.3 is as defined above and described in embodiments herein,
both singly and in combination.
[0232] In some embodiments, the present invention provides a
compound of formula XVI'', wherein X is N or C(R.sup.X), thereby
forming a compound of formula XVI-b' or XVI-c' respectively:
##STR00075##
or a pharmaceutically acceptable salt thereof, wherein each of
L.sup.1, Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.X,
R.sup.1, R.sup.2, and R.sup.3 is as defined above and described in
embodiments herein, both singly and in combination.
[0233] In some embodiments, the present invention provides a
compound of formula XVI-b' or XVI-c', wherein R.sup.X and R.sup.3
are both H, thereby forming a compound of formula XVII-a' or
XVII-b' respectively:
##STR00076##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.1, R.sup.2, and
R.sup.3 is as defined above and described in embodiments herein,
both singly and in combination.
[0234] In some embodiments, the present invention provides a
compound of formula XVII-a' or XVII-b', wherein L.sup.1 is a
covalent bond, thereby forming a compound of formula XVIII-a' or
XVIII-b' respectively:
##STR00077##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, Cy.sup.1, R.sup.1, and R.sup.2
is as defined above and described in embodiments herein, both
singly and in combination.
[0235] In some embodiments, the present invention provides a
compound of formula XVIII-a' or XVIII-b' wherein Cy.sup.1 is
phenyl, thereby forming a compound of formula XIX-a' or XIX-b'
respectively:
##STR00078##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R.sup.1, R.sup.2, and n is as
defined above and described in embodiments herein, both singly and
in combination.
[0236] In some embodiments, the present invention provides a
compound of formula XIX-a' or XIX-b', wherein n is 1, 2 or 3, and
at least one instance of R.sup.5 is ortho to the NH point of
attachment, thereby forming a compound of formula XX-a' or XX-b'
respectively:
##STR00079##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R.sup.1, and R.sup.2 is as
defined above and described in embodiments herein, both singly and
in combination.
[0237] In some embodiments, the present invention provides a
compound of formula XX-a' or XX-b', wherein the ortho R.sup.5 group
is --OR, --S(O).sub.2R, --C(O)NR.sub.2, or --N(R)S(O).sub.2R,
thereby forming a compound of formula XXI-a', XXI-b', XXI-c',
XXI-d', XXI-e', XXI-f', XXI-g', or XXI-h' respectively:
##STR00080## ##STR00081##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R, R.sup.1, R.sup.2, and
R.sup.5 is as defined above and described in embodiments herein,
both singly and in combination.
[0238] In some embodiments, the present invention provides a
compound of formula XXI-a' or XXI-b', wherein a second R.sup.5
group is meta to the NH point of attachment, thereby forming a
compound of formula XXII-a', or XXII-b' respectively:
##STR00082##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R, R.sup.1, R.sup.2, and
R.sup.5 is as defined above and described in embodiments herein,
both singly and in combination.
[0239] In some embodiments, the present invention provides a
compound of formula XXII-a' or XXII-b', wherein R.sup.5 is R.sup.B.
In some embodiments, the present invention provides a compound of
formula XXII-a' or XXII-b', wherein R.sup.5 is --CN, --C(O)NR.sub.2
or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, said ring
being substituted by q instances of R.sup.C;
[0240] In some embodiments, the present invention provides a
compound of formula XXII-a' or XXII-b', wherein --OR is methoxy,
fluoromethoxy, or difluoromethoxy.
[0241] In some embodiments, the present invention provides a
compound of formula XVIII-a' or XVIII-b' wherein Cy.sup.1 is
pyridyl, n is 2, and one instance of R.sup.5 is oxo, thereby
forming a pyridone compound of formula XXIII-a' or XXIII-b'
respectively:
##STR00083##
or a pharmaceutically acceptable salt thereof, wherein each of
Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R.sup.1, R.sup.2, and R.sup.5,
is as defined above and described in embodiments herein, both
singly and in combination.
[0242] In some embodiments, the present invention provides a
compound of one of formulas XVI-a', XVI-b', XVI-c', XVII-a',
XVII-b', XVIII-a', XVIII-b', XIX-a', XIX-b', XX-a', XX-b', XXI-a',
XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a',
XXII-b', XXIII-a', or XXIII-b' wherein Z.sup.2 is N, and Y.sup.1,
Y.sup.2, and Z.sup.1 are C. In some embodiments, the present
invention provides a compound of one of formulas XVI-a', XVI-b',
XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b', XIX-a', XIX-b',
XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f',
XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', or XXIII-b' wherein
Y.sup.2 is N, and Y.sup.1, Z.sup.1, and Z.sup.2 are C.
[0243] In some embodiments, the present invention provides a
compound of formula I' wherein Z.sup.2 is N, and Y.sup.1, Y.sup.2,
and Z.sup.1 are C; or wherein Y.sup.2 is N, and Y.sup.1, Z.sup.1,
and Z.sup.2 are C, thereby forming a compound of formula XXIV-a' or
XXIV-b' respectively:
##STR00084##
or a pharmaceutically acceptable salt thereof, wherein each of Q,
X, L.sup.1, Cy.sup.1, R.sup.1, and R.sup.2, is as defined above and
described in embodiments herein, both singly and in
combination.
[0244] In some embodiments, the present invention provides a
compound of formula XXIV-a' or XXIV-b' wherein L.sup.1 is a
covalent bond, thereby forming a compound of formula XXV-a' or
XXV-b' respectively:
##STR00085##
or a pharmaceutically acceptable salt thereof, wherein each of Q,
X, Cy.sup.1, R.sup.1, and R.sup.2 is as defined above and described
in embodiments herein, both singly and in combination.
[0245] In some embodiments, the present invention provides a
compound of formula XXV-a' or XXV-b' wherein X is C, and R.sup.X is
H, thereby forming a compound of formula XXVI-a' or XXVI-b'
respectively:
##STR00086##
or a pharmaceutically acceptable salt thereof, wherein each of Q,
Cy.sup.1, R.sup.1, and R.sup.2 is as defined above and described in
embodiments herein, both singly and in combination.
[0246] In some embodiments, the present invention provides a
compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b,
XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c,
XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a,
XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI'',
XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b',
XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d',
XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a',
XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a', or XXVI-b'
wherein R.sup.2 is --N(R)C(O)R, --N(R)C(O)Cy.sup.2, --N(R)Cy.sup.2,
or Cy.sup.2. In some embodiments, the present invention provides a
compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b,
XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c,
XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a,
XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI'',
XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b',
XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d',
XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a',
XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a', or XXVI-b'
wherein R.sup.2 is --N(H)C(O)R, --N(H)C(O)Cy.sup.2, --N(H)Cy.sup.2,
or Cy.sup.2. In some embodiments, the present invention provides a
compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b,
XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c,
XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a,
XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI'',
XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b',
XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d',
XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a',
XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a', or XXVI-b'
wherein R.sup.2 is --N(H)C(O)R, --N(H)C(O)Cy.sup.2, or
--N(H)Cy.sup.2. In some embodiments, the present invention provides
a compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b,
XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c,
XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a,
XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI'',
XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b',
XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d',
XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a',
XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a', or XXVI-b'
wherein R.sup.2 is --N(H)C(O)R. In some embodiments, the present
invention provides a compound of one of formulas XVI-a, XVI-b,
XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b,
XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a,
XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a,
XXVI-b, XVI', XVI'', XVI-a', XVI-b', XVI-c', XVII-a', XVII-b',
XVIII-a', XVIII-b', XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b',
XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b',
XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a', or
XXVI-b' wherein R.sup.2 is
##STR00087##
In some embodiments, the present invention provides a compound of
one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a,
XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d,
XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b,
XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI'', XVI-a',
XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b', XIX-a',
XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e',
XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b',
XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a', or XXVI-b' wherein
R.sup.2 is --N(H)Cy.sup.2, wherein Cy.sup.2 is selected from the
following, each of which is substituted by p instances of
R.sup.6:
##STR00088##
[0247] Exemplary compounds of the invention are set forth in Table
1, below.
TABLE-US-00001 TABLE 1 Exemplary Compounds Com- pound Structure I-1
##STR00089## I-2 ##STR00090## I-3 ##STR00091## I-4 ##STR00092## I-5
##STR00093## I-6 ##STR00094## I-7 ##STR00095## I-8 ##STR00096## I-9
##STR00097## I-10 ##STR00098## I-11 ##STR00099## I-12 ##STR00100##
I-13 ##STR00101## I-14 ##STR00102## I-15 ##STR00103## I-16
##STR00104## I-17 ##STR00105## I-18 ##STR00106## I-19 ##STR00107##
I-20 ##STR00108## I-21 ##STR00109## I-22 ##STR00110## I-23
##STR00111## I-24 ##STR00112## I-25 ##STR00113## I-26 ##STR00114##
I-27 ##STR00115## I-28 ##STR00116## I-29 ##STR00117## I-30
##STR00118## I-31 ##STR00119## I-32 ##STR00120## I-33 ##STR00121##
I-34 ##STR00122## I-35 ##STR00123## I-36 ##STR00124## I-37
##STR00125## I-38 ##STR00126## I-39 ##STR00127## I-40 ##STR00128##
I-41 ##STR00129## I-42 ##STR00130## I-43 ##STR00131## I-44
##STR00132## I-45 ##STR00133## I-46 ##STR00134## I-47 ##STR00135##
I-48 ##STR00136## I-49 ##STR00137## I-50 ##STR00138## I-51
##STR00139## I-52 ##STR00140## I-53 ##STR00141## I-54 ##STR00142##
I-55 ##STR00143## I-56 ##STR00144## I-57 ##STR00145## I-58
##STR00146## I-59 ##STR00147## I-60 ##STR00148## I-61 ##STR00149##
I-62 ##STR00150## I-63 ##STR00151## I-64 ##STR00152## I-65
##STR00153## I-66 ##STR00154## I-67 ##STR00155## I-68 ##STR00156##
I-69 ##STR00157## I-70 ##STR00158## I-71 ##STR00159## I-72
##STR00160## I-73 ##STR00161## I-74 ##STR00162## I-75 ##STR00163##
I-76 ##STR00164## I-77 ##STR00165## I-78 ##STR00166## I-79
##STR00167## I-80 ##STR00168## I-81 ##STR00169## I-82 ##STR00170##
I-83 ##STR00171## I-84 ##STR00172## I-85 ##STR00173## I-86
##STR00174## I-87 ##STR00175## I-88 ##STR00176## I-89 ##STR00177##
I-90 ##STR00178## I-91 ##STR00179## I-92 ##STR00180## I-93
##STR00181## I-94 ##STR00182## I-95 ##STR00183## I-96 ##STR00184##
I-97 ##STR00185## I-98 ##STR00186## I-99 ##STR00187## I-100
##STR00188## I-101 ##STR00189## I-102 ##STR00190## I-103
##STR00191## I-104 ##STR00192## I-105 ##STR00193## I-106
##STR00194## I-107 ##STR00195## I-108 ##STR00196## I-109
##STR00197## I-110 ##STR00198## I-111 ##STR00199## I-112
##STR00200## I-113 ##STR00201## I-114 ##STR00202## I-115
##STR00203## I-116 ##STR00204## I-117 ##STR00205## I-118
##STR00206## I-119 ##STR00207## I-120 ##STR00208## I-121
##STR00209## I-122 ##STR00210##
I-123 ##STR00211## I-124 ##STR00212## I-125 ##STR00213## I-126
##STR00214## I-127 ##STR00215## I-128 ##STR00216## I-129
##STR00217## I-130 ##STR00218## I-131 ##STR00219## I-132
##STR00220## I-133 ##STR00221## I-134 ##STR00222## I-135
##STR00223## I-136 ##STR00224## I-137 ##STR00225## I-138
##STR00226## I-139 ##STR00227## I-140 ##STR00228## I-141
##STR00229## I-142 ##STR00230## I-143 ##STR00231## I-144
##STR00232## I-145 ##STR00233## I-146 ##STR00234## I-147
##STR00235## I-148 ##STR00236## I-149 ##STR00237## I-150
##STR00238## I-151 ##STR00239## I-152 ##STR00240## I-153
##STR00241## I-154 ##STR00242## I-155 ##STR00243## I-156
##STR00244## I-157 ##STR00245## I-158 ##STR00246## I-159
##STR00247## I-160 ##STR00248## I-161 ##STR00249## I-162
##STR00250## I-163 ##STR00251## I-164 ##STR00252## I-165
##STR00253## I-166 ##STR00254## I-167 ##STR00255## I-168
##STR00256## I-169 ##STR00257## I-170 ##STR00258## I-171
##STR00259## I-172 ##STR00260## I-173 ##STR00261## I-174
##STR00262## I-175 ##STR00263## I-176 ##STR00264## I-177
##STR00265## I-178 ##STR00266## I-179 ##STR00267## I-180
##STR00268## I-181 ##STR00269## I-182 ##STR00270## I-183
##STR00271## I-184 ##STR00272## I-185 ##STR00273## I-186
##STR00274## I-187 ##STR00275## I-188 ##STR00276## I-189
##STR00277## I-190 ##STR00278## I-191 ##STR00279## I-192
##STR00280## I-193 ##STR00281## I-194 ##STR00282## I-195
##STR00283## I-196 ##STR00284## I-197 ##STR00285## I-198
##STR00286## I-199 ##STR00287## I-200 ##STR00288## I-201
##STR00289## I-202 ##STR00290## I-203 ##STR00291## I-204
##STR00292## I-205 ##STR00293## I-206 ##STR00294## I-207
##STR00295## I-208 ##STR00296## I-209 ##STR00297## I-210
##STR00298## I-211 ##STR00299## I-212 ##STR00300## I-213
##STR00301## I-214 ##STR00302## I-215 ##STR00303## I-216
##STR00304## I-217 ##STR00305## I-218 ##STR00306## I-219
##STR00307## I-220 ##STR00308## I-221 ##STR00309## I-222
##STR00310## I-223 ##STR00311## I-224 ##STR00312## I-225
##STR00313## I-226 ##STR00314## I-227 ##STR00315## I-228
##STR00316## I-229 ##STR00317## I-230 ##STR00318## I-231
##STR00319## I-232 ##STR00320## I-234 ##STR00321## I-235
##STR00322## I-236 ##STR00323## I-237 ##STR00324## I-238
##STR00325## I-239 ##STR00326## I-240 ##STR00327## I-241
##STR00328##
[0248] Exemplary compounds of the invention are set forth in Table
2, below.
TABLE-US-00002 TABLE 2 Exemplary Compounds Compound Structure
VIII-1 ##STR00329## VIII-2 ##STR00330## VIII-3 ##STR00331## VIII-4
##STR00332## VIII-5 ##STR00333## VIII-6 ##STR00334## VIII-7
##STR00335## VIII-8 ##STR00336## VIII-9 ##STR00337## VIII-10
##STR00338## VIII-11 ##STR00339## VIII-12 ##STR00340## VIII-13
##STR00341## VIII-14 ##STR00342## VIII-15 ##STR00343## VIII-16
##STR00344## VIII-17 ##STR00345##
[0249] Exemplary compounds of the invention are set forth in Table
3, below.
TABLE-US-00003 TABLE 3 Exemplary Compounds Compound Structure XVI-1
##STR00346## XVI-2 ##STR00347## XVI-3 ##STR00348## XVI-4
##STR00349## XVI-5 ##STR00350## XVI-6 ##STR00351##
[0250] In some embodiments, the present invention provides a
compound set forth in Table 1, above, or a pharmaceutically
acceptable salt thereof. In some embodiments, the present invention
provides a pharmaceutical composition comprising a compound set
forth in Table 1 above, or a pharmaceutically acceptable salt
thereof, together with a pharmaceutically acceptable carrier,
excipient, or diluent.
[0251] In some embodiments, the method employs a compound set forth
in Table 2, above, or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention provides a compound set
forth in Table 2, above, or a pharmaceutically acceptable salt
thereof. In some embodiments, the present invention provides a
pharmaceutical composition comprising a compound set forth in Table
2 above, or a pharmaceutically acceptable salt thereof, together
with a pharmaceutically acceptable carrier, excipient, or
diluent.
[0252] In some embodiments, the method employs a compound set forth
in Table 3, above, or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention provides a compound set
forth in Table 3, above, or a pharmaceutically acceptable salt
thereof. In some embodiments, the present invention provides a
pharmaceutical composition comprising a compound set forth in Table
3 above, or a pharmaceutically acceptable salt thereof, together
with a pharmaceutically acceptable carrier, excipient, or
diluent.
[0253] Without wishing to be bound by any particular theory, it is
believed that proximity of an inhibitor compound, or pendant moiety
of an inhibitor compound, to the water of interest facilitates
displacement or disruption of that water by the inhibitor compound,
or pendant moiety of an inhibitor compound. In some embodiments, a
water molecule displaced or disrupted by an inhibitor compound, or
pendant moiety of an inhibitor compound, is an unstable water
molecule.
[0254] In certain embodiments, the method employs a complex
comprising TYK2 and an inhibitor, wherein at least one unstable
water of TYK2 is displaced or disrupted by the inhibitor. In some
embodiments, at least two unstable waters selected are displaced or
disrupted by the inhibitor.
4. General Methods of Providing the Present Compounds
[0255] The compounds of this invention may be prepared or isolated
in general by synthetic and/or semi-synthetic methods known to
those skilled in the art for analogous compounds and by methods
described in detail in the Examples, herein.
[0256] In some embodiments, compounds of formula I are prepared
according to the following general procedure, depicted in Scheme
1.
##STR00352##
[0257] In some embodiments, where L.sup.1 is NH, intermediates of
formula Cy.sup.1-NH.sub.2 are prepared according to the methods
described in WO2014074660A1, WO2014074661A1, and WO2015089143A1,
the entirety of each of which is incorporated herein by
reference.
[0258] In some embodiments, compounds of formula VIII are prepared
according to the following general procedure, depicted in Scheme
2.
##STR00353##
[0259] In some embodiments, where L.sup.1 is NH, intermediates of
formula Cy.sup.1-NH.sub.2 are prepared according to the methods
described in WO2014074660A1, WO2014074661A1, and WO2015089143A1,
the entirety of each of which is incorporated herein by
reference.
[0260] In some embodiments, compounds of formula XXIV-b are
prepared according to the following general procedure, depicted in
Scheme 3.
##STR00354##
wherein each of X, L.sup.1, and Cy.sup.1 is as defined above and in
embodiments herein, singly and in combination.
5. Uses, Formulation and Administration
[0261] Pharmaceutically Acceptable Compositions
[0262] According to another embodiment, the invention provides a
composition comprising a compound of this invention or a
pharmaceutically acceptable derivative thereof and a
pharmaceutically acceptable carrier, adjuvant, or vehicle. The
amount of compound in compositions of this invention is such that
is effective to measurably inhibit a TYK2 protein kinase, or a
mutant thereof, in a biological sample or in a patient. In certain
embodiments, the amount of compound in compositions of this
invention is such that is effective to measurably inhibit a TYK2
protein kinase, or a mutant thereof, in a biological sample or in a
patient. In certain embodiments, a composition of this invention is
formulated for administration to a patient in need of such
composition. In some embodiments, a composition of this invention
is formulated for oral administration to a patient.
[0263] The term "patient," as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0264] The term "pharmaceutically acceptable carrier, adjuvant, or
vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that
does not destroy the pharmacological activity of the compound with
which it is formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles that may be used in the compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0265] A "pharmaceutically acceptable derivative" means any
non-toxic salt, ester, salt of an ester or other derivative of a
compound of this invention that, upon administration to a
recipient, is capable of providing, either directly or indirectly,
a compound of this invention or an inhibitorily active metabolite
or residue thereof.
[0266] As used herein, the term "inhibitorily active metabolite or
residue thereof" means that a metabolite or residue thereof is also
an inhibitor of a TYK2 protein kinase, or a mutant thereof.
[0267] Compositions of the present invention may be administered
orally, parenterally, by inhalation spray, topically, rectally,
nasally, buccally, vaginally or via an implanted reservoir. The
term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and
intracranial injection or infusion techniques. Preferably, the
compositions are administered orally, intraperitoneally or
intravenously. Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium.
[0268] For this purpose, any bland fixed oil may be employed
including synthetic mono- or di-glycerides. Fatty acids, such as
oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing
agents that are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0269] Pharmaceutically acceptable compositions of this invention
may be orally administered in any orally acceptable dosage form
including, but not limited to, capsules, tablets, aqueous
suspensions or solutions. In the case of tablets for oral use,
carriers commonly used include lactose and corn starch. Lubricating
agents, such as magnesium stearate, are also typically added. For
oral administration in a capsule form, useful diluents include
lactose and dried cornstarch. When aqueous suspensions are required
for oral use, the active ingredient is combined with emulsifying
and suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
[0270] Alternatively, pharmaceutically acceptable compositions of
this invention may be administered in the form of suppositories for
rectal administration. These can be prepared by mixing the agent
with a suitable non-irritating excipient that is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0271] Pharmaceutically acceptable compositions of this invention
may also be administered topically, especially when the target of
treatment includes areas or organs readily accessible by topical
application, including diseases of the eye, the skin, or the lower
intestinal tract. Suitable topical formulations are readily
prepared for each of these areas or organs.
[0272] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0273] For topical applications, provided pharmaceutically
acceptable compositions may be formulated in a suitable ointment
containing the active component suspended or dissolved in one or
more carriers. Carriers for topical administration of compounds of
this invention include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, provided pharmaceutically acceptable compositions
can be formulated in a suitable lotion or cream containing the
active components suspended or dissolved in one or more
pharmaceutically acceptable carriers. Suitable carriers include,
but are not limited to, mineral oil, sorbitan monostearate,
polysorbate 60, cetyl esters wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
[0274] For ophthalmic use, provided pharmaceutically acceptable
compositions may be formulated as micronized suspensions in
isotonic, pH adjusted sterile saline, or, preferably, as solutions
in isotonic, pH adjusted sterile saline, either with or without a
preservative such as benzylalkonium chloride. Alternatively, for
ophthalmic uses, the pharmaceutically acceptable compositions may
be formulated in an ointment such as petrolatum.
[0275] Pharmaceutically acceptable compositions of this invention
may also be administered by nasal aerosol or inhalation. Such
compositions are prepared according to techniques well-known in the
art of pharmaceutical formulation and may be prepared as solutions
in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or dispersing
agents.
[0276] Most preferably, pharmaceutically acceptable compositions of
this invention are formulated for oral administration. Such
formulations may be administered with or without food. In some
embodiments, pharmaceutically acceptable compositions of this
invention are administered without food. In other embodiments,
pharmaceutically acceptable compositions of this invention are
administered with food.
[0277] The amount of compounds of the present invention that may be
combined with the carrier materials to produce a composition in a
single dosage form will vary depending upon the host treated, the
particular mode of administration. Preferably, provided
compositions should be formulated so that a dosage of between
0.01-100 mg/kg body weight/day of the inhibitor can be administered
to a patient receiving these compositions.
[0278] It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and the
judgment of the treating physician and the severity of the
particular disease being treated. The amount of a compound of the
present invention in the composition will also depend upon the
particular compound in the composition.
[0279] Uses of Compounds and Pharmaceutically Acceptable
Compositions
[0280] Compounds and compositions described herein are generally
useful for the inhibition of kinase activity of one or more
enzymes. In some embodiments the kinase inhibited by the compounds
and methods of the invention is TYK2
[0281] TYK2 is a non-receptor tyrosine kinase member of the Janus
kinase (JAKs) family of protein kinases. The mammalian JAK family
consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins,
including TYK2, are integral to cytokine signaling. TYK2 associates
with the cytoplasmic domain of type I and type II cytokine
receptors, as well as interferon types I and III receptors, and is
activated by those receptors upon cytokine binding. Cytokines
implicated in TYK2 activation include interferons (e.g.
IFN-.alpha., IFN-.beta., IFN-.kappa., IFN-.delta., IFN-.epsilon.,
IFN-.tau., IFN-.omega., and IFN-.zeta. (also known as limitin), and
interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22,
IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor,
cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Velasquez
et al., "A protein kinase in the interferon .alpha./.beta.
signaling pathway," Cell (1992) 70:313; Stahl et al., "Association
and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-60 receptor
components," Science (1994) 263:92; Finbloom et al., "IL-10 induces
the tyrosine phosphorylation of Tyk2 and Jak1 and the differential
assembly of Stat1 and Stat3 complexes in human T cells and
monocytes," J. Immunol. (1995) 155:1079; Bacon et al., "Interleukin
12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2:
differential use of Janus family kinases by IL-2 and IL-12," J.
Exp. Med. (1995) 181:399; Welham et al., "Interleukin-13 signal
transduction in lymphohemopoietic cells: similarities and
differences in signal transduction with interleukin-4 and insulin,"
J. Biol. Chem. (1995) 270:12286; Parham et al., "A receptor for the
heterodimeric cytokine IL-23 is composed of IL-12R.beta.1 and a
novel cytokine receptor subunit, IL-23R," J. Immunol. (2002)
168:5699. The activated TYK2 then goes on to phosphorylate further
signaling proteins such as members of the STAT family, including
STAT1, STAT2, STAT4, and STAT6.
[0282] TYK2 activation by IL-23, has been linked to inflammatory
bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr
et al., "A Genome-Wide Association Study Identifies IL23R as an
Inflammatory Bowel Disease Gene," Science (2006) 314:1461-1463. As
the downstream effector of IL-23, TYK2 also plays a role in
psoriasis, ankylosing spondylitis, and Behcet's disease. Cho et
al., "Genomics and the multifactorial nature of human auto-immune
disease," N. Engl. J. Med (2011) 365:1612-1623; Cortes et al.,
"Identification of multiple risk variants for ankylosing
spondylitis through high-density genotyping of immune-related
loci," Nat. Genet. (2013) 45(7):730-738; Remmers et al.,
"Genome-wide association study identifies variants in the MHC class
I, IL10, and IL23R-IL12RB2 regions associated with Behcet's
disease," Nat. Genet. (2010) 42:698-702. A genome-wide association
study of 2,622 individuals with psoriasis identified associations
between disease susceptibility and TYK2. Strange et al., "A
genome-wide association study identifies new psoriasis
susceptibility loci and an interaction between HLA-C and ERAP1,"
Nat. Genet. (2010) 42:985-992. Knockout or tyrphostin inhibition of
TYK2 significantly reduces both IL-23 and IL-22-induced dermatitis.
Ishizaki et al., "Tyk2 is a therapeutic target for psoriasis-like
skin inflammation," Intl. Immunol. (2013), doi:
10.1093/intimm/dxt062.
[0283] TYK2 also plays a role in respiratory diseases such as
asthma, chronic obstructive pulmonary disease (COPD), lung cancer,
and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucous
hypersecretion is mediated by IL-13-induced activation of TYK2,
which in turn activates STAT6. Zhang et al., "Docking protein Gab2
regulates mucin expression and goblet cell hyperplasia through
TYK2/STAT6 pathway," FASEB J. (2012) 26:1-11.
[0284] Decreased TYK2 activity leads to protection of joints from
collagen antibody-induced arthritis, a model of human rheumatoid
arthritis. Mechanistically, decreased Tyk2 activity reduced the
production of T.sub.h1/T.sub.h17-related cytokines and matrix
metalloproteases, and other key markers of inflammation. Ishizaki
et al., "Tyk2 deficiency protects joints against destruction in
anti-type II collagen antibody-induced arthritis in mice," Intl.
Immunol. (2011) 23(9):575-582.
[0285] TYK2 knockout mice showed complete resistance in
experimental autoimmune encephalomyelitis (EAE, an animal model of
multiple sclerosis (MS)), with no infiltration of CD4 T cells in
the spinal cord, as compared to controls, suggesting that TYK2 is
essential to pathogenic CD4-mediated disease development in MS.
Oyamada et al., "Tyrosine Kinase 2 Plays Critical Roles in the
Pathogenic CD4 T Cell Responses for the Development of Experimental
Autoimmune Encephalomyelitis," J. Immunol. (2009) 183:7539-7546.
This corroborates earlier studies linking increased TYK2 expression
with MS susceptibility. Ban et al., "Replication analysis
identifies TYK2 as a multiple sclerosis susceptibility factor," Eur
J. Hum. Genet. (2009) 17:1309-1313. Loss of function mutation in
TYK2, leads to decreased demyelination and increased remyelination
of neurons, further suggesting a role for TYK2 inhibitors in the
treatment of MS and other CNS demyelination disorders.
[0286] TYK2 is the sole signaling messenger common to both IL-12
and IL-23. TYK2 knockout reduced methylated BSA injection-induced
footpad thickness, imiquimod-induced psoriasis-like skin
inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzene
sulfonic acid-induced colitis in mice.
[0287] Joint linkage and association studies of various type I IFN
signaling genes with systemic lupus erythematosus (SLE, an
autoimmune disorder), showed a strong, and significant correlation
between loss of function mutations to TYK2 and decreased prevalence
of SLE in families with affected members. Sigurdsson et al.,
"Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory
Factor 5 Genes Are Associated with Systemic Lupus Erythematosus,"
Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association
studies of individuals with SLE versus an unaffected cohort showed
highly significant correlation between the TYK2 locus and SLE.
Graham et al., "Association of NCF2, IKZF1, TRF8, IFIH1, and TYK2
with Systemic Lupus Erythematosus," PLoS Genetics (2011)
7(10):e1002341.
[0288] TYK2 has been shown to play an important role in maintaining
tumor surveillance and TYK2 knockout mice showed compromised
cytotoxic T cell response, and accelerated tumor development.
However, these effects were linked to the efficient suppression of
natural killer (NK) and cytotoxic T lymphocytes, suggesting that
TYK2 inhibitors would be highly suitable for the treatment of
autoimmune disorders or transplant rejection. Although other JAK
family members such as JAK3 have similar roles in the immune
system, TYK2 has been suggested as a superior target because of its
involvement in fewer and more closely related signaling pathways,
leading to fewer off-target effects. Simma et al. "Identification
of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated
Tumor Surveillance," Cancer Res. (2009) 69:203-211.
[0289] However, paradoxically to the decreased tumor surveillance
observed by Simma et al., studies in T-cell acute lymphoblastic
leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10
via TYK2 via STAT1-mediated signal transduction to maintain cancer
cell survival through upregulation of anti-apoptotic protein BCL2.
Knockdown of TYK2, but not other JAK family members, reduced cell
growth. Specific activating mutations to TYK2 that promote cancer
cell survival include those to the FERM domain (G36D, S47N, and
R425H), the JH2 domain (V731I), and the kinase domain (E957D and
R1027H). However, it was also identified that the kinase function
of TYK2 is required for increased cancer cell survival, as TYK2
enzymes featuring kinase-dead mutations (M978Y or M978F) in
addition to an activating mutation (E957D) resulted in failure to
transform. Sanda et al. "TYK2-STAT1-BCL2 Pathway Dependence in
T-Cell Acute Lymphoblastic Leukemia," Cancer Disc. (2013)
3(5):564-577.
[0290] Thus, selective inhibition of TYK2 has been suggested as a
suitable target for patients with IL-10 and/or BCL2-addicted
tumors, such as 70% of adult T-cell leukemia cases. Fontan et al.
"Discovering What Makes STAT Signaling TYK in T-ALL," Cancer Disc.
(2013) 3:494-496.
[0291] TYK2 mediated STAT3 signaling has also been shown to mediate
neuronal cell death caused by amyloid-.beta. (A.beta.) peptide.
Decreased TYK2 phosphorylation of STAT3 following A3 administration
lead to decreased neuronal cell death, and increased
phosphorylation of STAT3 has been observed in postmortem brains of
Alzheimer's patients. Wan et al. "Tyk/STAT3 Signaling Mediates
.beta.-Amyloid-Induced Neuronal Cell Death: Implications in
Alzheimer's Disease," J. Neurosci. (2010) 30(20):6873-6881.
[0292] Inhibition of JAK-STAT signaling pathways is also implicated
in hair growth, and the reversal of the hair loss associated with
alopecia areata. Xing et al., "Alopecia areata is driven by
cytotoxic T lymphocytes and is reversed by JAK inhibition," Nat.
Med. (2014) 20: 1043-1049; Harel et al., "Pharmacologic inhibition
of JAK-STAT signaling promotes hair growth," Sci. Adv. (2015)
1(9):e1500973.
[0293] Accordingly, compounds that inhibit the activity of TYK2 are
beneficial, especially those with selectivity over JAK2. Such
compounds should deliver a pharmacological response that favorably
treats one or more of the conditions described herein without the
side-effects associated with the inhibition of JAK2.
[0294] Even though TYK2 inhibitors are known in the art, there is a
continuing need to provide novel inhibitors having more effective
or advantageous pharmaceutically relevant properties. For example,
compounds with increased activity, selectivity over other JAK
kinases (especially JAK2), and ADMET (absorption, distribution,
metabolism, excretion, and/or toxicity) properties. Thus, in some
embodiments, the present invention provides inhibitors of TYK2
which show selectivity over JAK2.
[0295] The activity of a compound utilized in this invention as an
inhibitor of TYK2, or a mutant thereof, may be assayed in vitro, in
vivo or in a cell line. In vitro assays include assays that
determine inhibition of either the phosphorylation activity and/or
the subsequent functional consequences, or ATPase activity of
activated TYK2, or a mutant thereof. Alternate in vitro assays
quantitate the ability of the inhibitor to bind to TYK2. Inhibitor
binding may be measured by radiolabeling the inhibitor prior to
binding, isolating the inhibitor/TYK2 complex and determining the
amount of radiolabel bound. Alternatively, inhibitor binding may be
determined by running a competition experiment where new inhibitors
are incubated with TYK2 bound to known radioligands. Representative
in vitro and in vivo assays useful in assaying a TYK2 inhibitor
include those described and disclosed in, e.g., each of which is
herein incorporated by reference in its entirety. Detailed
conditions for assaying a compound utilized in this invention as an
inhibitor of TYK2, or a mutant thereof, are set forth in the
Examples below.
[0296] As used herein, the terms "treatment," "treat," and
"treating" refer to reversing, alleviating, delaying the onset of,
or inhibiting the progress of a disease or disorder, or one or more
symptoms thereof, as described herein. In some embodiments,
treatment may be administered after one or more symptoms have
developed. In other embodiments, treatment may be administered in
the absence of symptoms. For example, treatment may be administered
to a susceptible individual prior to the onset of symptoms (e.g.,
in light of a history of symptoms and/or in light of genetic or
other susceptibility factors). Treatment may also be continued
after symptoms have resolved, for example to prevent or delay their
recurrence.
[0297] Provided compounds are inhibitors of TYK2 and are therefore
useful for treating one or more disorders associated with activity
of TYK2 or mutants thereof. Thus, in certain embodiments, the
present invention provides a method for treating a TYK2-mediated
disorder comprising the step of administering to a patient in need
thereof a compound of the present invention, or pharmaceutically
acceptable composition thereof.
[0298] As used herein, the term "TYK2-mediated" disorders,
diseases, and/or conditions as used herein means any disease or
other deleterious condition in which TYK2 or a mutant thereof is
known to play a role. Accordingly, another embodiment of the
present invention relates to treating or lessening the severity of
one or more diseases in which TYK2, or a mutant thereof, is known
to play a role. Such TYK2-mediated disorders include but are not
limited to autoimmune disorders, inflammatory disorders,
proliferative disorders, endocrine disorders, neurological
disorders and disorders associated with transplantation.
[0299] In some embodiments, the present invention provides a method
for treating one or more disorders, wherein the disorders are
selected from autoimmune disorders, inflammatory disorders,
proliferative disorders, endocrine disorders, neurological
disorders, and disorders associated with transplantation, said
method comprising administering to a patient in need thereof, a
pharmaceutical composition comprising an effective amount of a
compound of the present invention, or a pharmaceutically acceptable
salt thereof.
[0300] In some embodiments, the disorder is an autoimmune disorder.
In some embodiments the disorder is selected from type 1 diabetes,
systemic lupus erythematosus, multiple sclerosis, psoriasis,
Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative
colitis, and inflammatory bowel disease.
[0301] In some embodiments, the disorder is an inflammatory
disorder. In some embodiments, the inflammatory disorder is
rheumatoid arthritis, asthma, chronic obstructive pulmonary
disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative
colitis, inflammatory bowel disease.
[0302] In some embodiments, the disorder is a proliferative
disorder. In some embodiments, the proliferative disorder is a
hematological cancer. In some embodiments the proliferative
disorder is a leukemia. In some embodiments, the leukemia is a
T-cell leukemia. In some embodiments the T-cell leukemia is T-cell
acute lymphoblastic leukemia (T-ALL). In some embodiments the
proliferative disorder is polycythemia vera, myelofibrosis,
essential or thrombocytosis.
[0303] In some embodiments, the disorder is an endocrine disorder.
In some embodiments, the endocrine disorder is polycystic ovary
syndrome, Crouzon's syndrome, or type 1 diabetes.
[0304] In some embodiments, the disorder is a neurological
disorder. In some embodiments, the neurological disorder is
Alzheimer's disease.
[0305] In some embodiments the proliferative disorder is associated
with one or more activating mutations in TYK2. In some embodiments,
the activating mutation in TYK2 is a mutation to the FERM domain,
the JH2 domain, or the kinase domain. In some embodiments the
activating mutation in TYK2 is selected from G36D, S47N, R425H,
V731I, E957D, and R1027H.
[0306] In some embodiments, the disorder is associated with
transplantation. In some embodiments the disorder associated with
transplantation is transplant rejection, or graft versus host
disease.
[0307] In some embodiments the disorder is associated with type I
interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments
the disorder is associated with type I interferon signaling. In
some embodiments the disorder is associated with IL-10 signaling.
In some embodiments the disorder is associated with IL-12
signaling. In some embodiments the disorder is associated with
IL-23 signaling.
[0308] Compounds of the invention are also useful in the treatment
of inflammatory or allergic conditions of the skin, for example
psoriasis, contact dermatitis, atopic dermatitis, alopecia areata,
erythema multiforma, dermatitis herpetiformis, scleroderma,
vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid,
lupus erythematosus, systemic lupus erythematosus, pemphigus
vulgaris, pemphigus foliaceus, paraneoplastic pemphigus,
epidermolysis bullosa acquisita, acne vulgaris, and other
inflammatory or allergic conditions of the skin.
[0309] Compounds of the invention may also be used for the
treatment of other diseases or conditions, such as diseases or
conditions having an inflammatory component, for example, treatment
of diseases and conditions of the eye such as ocular allergy,
conjunctivitis, keratoconjunctivitis sicca, and vernal
conjunctivitis, diseases affecting the nose including allergic
rhinitis, and inflammatory disease in which autoimmune reactions
are implicated or having an autoimmune component or etiology,
including autoimmune hematological disorders (e.g. hemolytic
anemia, aplastic anemia, pure red cell anemia and idiopathic
thrombocytopenia), systemic lupus erythematosus, rheumatoid
arthritis, polychondritis, scleroderma, Wegener granulamatosis,
dermatomyositis, chronic active hepatitis, myasthenia gravis,
Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory
bowel disease (e.g. ulcerative colitis and Crohn's disease),
irritable bowel syndrome, celiac disease, periodontitis, hyaline
membrane disease, kidney disease, glomerular disease, alcoholic
liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's
disease, sarcoidosis, alveolitis, chronic hypersensitivity
pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis
(anterior and posterior), Sjogren's syndrome, keratoconjunctivitis
sicca and vernal keratoconjunctivitis, interstitial lung fibrosis,
psoriatic arthritis, systemic juvenile idiopathic arthritis,
cryopyrin-associated periodic syndrome, nephritis, vasculitis,
diverticulitis, interstitial cystitis, glomerulonephritis (with and
without nephrotic syndrome, e.g. including idiopathic nephrotic
syndrome or minal change nephropathy), chronic granulomatous
disease, endometriosis, leptospiriosis renal disease, glaucoma,
retinal disease, ageing, headache, pain, complex regional pain
syndrome, cardiac hypertrophy, musclewasting, catabolic disorders,
obesity, fetal growth retardation, hyperchlolesterolemia, heart
disease, chronic heart failure, mesothelioma, anhidrotic ecodermal
dysplasia, Behcet's disease, incontinentia pigmenti, Paget's
disease, pancreatitis, hereditary periodic fever syndrome, asthma
(allergic and non-allergic, mild, moderate, severe, bronchitic, and
exercise-induced), acute lung injury, acute respiratory distress
syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal
sinusitis, ocular allergy, silica induced diseases, COPD (reduction
of damage, airways inflammation, bronchial hyperreactivity,
remodeling or disease progression), pulmonary disease, cystic
fibrosis, acid-induced lung injury, pulmonary hypertension,
polyneuropathy, cataracts, muscle inflammation in conjunction with
systemic sclerosis, inclusion body myositis, myasthenia gravis,
thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or
Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,
blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
cholangitis, cholecystitis, chronic graft rejection, colitis,
conjunctivitis, Crohn's disease, cystitis, dacryoadenitis,
dermatitis, dermatomyositis, encephalitis, endocarditis,
endometritis, enteritis, enterocolitis, epicondylitis,
epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,
Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa,
immunoglobulin A nephropathy, interstitial lung disease,
laryngitis, mastitis, meningitis, myelitis myocarditis, myositis,
nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis,
parotitis, pericarditis, peritonitis, pharyngitis, pleuritis,
phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,
prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,
stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,
uveitis, vaginitis, vasculitis, or vulvitis.
[0310] In some embodiments the inflammatory disease which can be
treated according to the methods of this invention is selected from
acute and chronic gout, chronic gouty arthritis, psoriasis,
psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid
arthritis, Systemic juvenile idiopathic arthritis (SJIA), Cryopyrin
Associated Periodic Syndrome (CAPS), and osteoarthritis.
[0311] In some embodiments the inflammatory disease which can be
treated according to the methods of this invention is a T.sub.h1 or
T.sub.h17 mediated disease. In some embodiments the T.sub.h17
mediated disease is selected from Systemic lupus erythematosus,
Multiple sclerosis, and inflammatory bowel disease (including
Crohn's disease or ulcerative colitis).
[0312] In some embodiments the inflammatory disease which can be
treated according to the methods of this invention is selected from
Sjogren's syndrome, allergic disorders, osteoarthritis, conditions
of the eye such as ocular allergy, conjunctivitis,
keratoconjunctivitis sicca and vernal conjunctivitis, and diseases
affecting the nose such as allergic rhinitis.
[0313] Furthermore, the invention provides the use of a compound
according to the definitions herein, or a pharmaceutically
acceptable salt, or a hydrate or solvate thereof for the
preparation of a medicament for the treatment of an autoimmune
disorder, an inflammatory disorder, or a proliferative disorder, or
a disorder commonly occurring in connection with
transplantation.
[0314] Combination Therapies
[0315] Depending upon the particular condition, or disease, to be
treated, additional therapeutic agents, which are normally
administered to treat that condition, may be administered in
combination with compounds and compositions of this invention. As
used herein, additional therapeutic agents that are normally
administered to treat a particular disease, or condition, are known
as "appropriate for the disease, or condition, being treated."
[0316] In certain embodiments, a provided combination, or
composition thereof, is administered in combination with another
therapeutic agent.
[0317] Examples of agents the combinations of this invention may
also be combined with include, without limitation: treatments for
Alzheimer's Disease such as Aricept.RTM. and Excelon.RTM.;
treatments for HIV such as ritonavir; treatments for Parkinson's
Disease such as L-DOPA/carbidopa, entacapone, ropinrole,
pramipexole, bromocriptine, pergolide, trihexephendyl, and
amantadine; agents for treating Multiple Sclerosis (MS) such as
beta interferon (e.g., Avonex.RTM. and Rebif.RTM.), Copaxone.RTM.,
and mitoxantrone; treatments for asthma such as albuterol and
Singulair.RTM.; agents for treating schizophrenia such as zyprexa,
risperdal, seroquel, and haloperidol; anti-inflammatory agents such
as corticosteroids, TNF blockers, IL-1 RA, azathioprine,
cyclophosphamide, and sulfasalazine; immunomodulatory and
immunosuppressive agents such as cyclosporine, tacrolimus,
rapamycin, mycophenolate mofetil, interferons, corticosteroids,
cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic
factors such as acetylcholinesterase inhibitors, MAO inhibitors,
interferons, anti-convulsants, ion channel blockers, riluzole, and
anti-Parkinsonian agents; agents for treating cardiovascular
disease such as beta-blockers, ACE inhibitors, diuretics, nitrates,
calcium channel blockers, and statins; agents for treating liver
disease such as corticosteroids, cholestyramine, interferons, and
anti-viral agents; agents for treating blood disorders such as
corticosteroids, anti-leukemic agents, and growth factors; agents
that prolong or improve pharmacokinetics such as cytochrome P450
inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4
inhibitors (e.g., ketokenozole and ritonavir), and agents for
treating immunodeficiency disorders such as gamma globulin.
[0318] In certain embodiments, combination therapies of the present
invention, or a pharmaceutically acceptable composition thereof,
are administered in combination with a monoclonal antibody or an
siRNA therapeutic.
[0319] Those additional agents may be administered separately from
a provided combination therapy, as part of a multiple dosage
regimen. Alternatively, those agents may be part of a single dosage
form, mixed together with a compound of this invention in a single
composition. If administered as part of a multiple dosage regime,
the two active agents may be submitted simultaneously, sequentially
or within a period of time from one another normally within five
hours from one another.
[0320] As used herein, the term "combination," "combined," and
related terms refers to the simultaneous or sequential
administration of therapeutic agents in accordance with this
invention. For example, a combination of the present invention may
be administered with another therapeutic agent simultaneously or
sequentially in separate unit dosage forms or together in a single
unit dosage form.
[0321] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0322] In one embodiment, the present invention provides a
composition comprising a compound of formula I, VIII, or XVI', and
one or more additional therapeutic agents. The therapeutic agent
may be administered together with a compound of formula I, VIII, or
XVI', or may be administered prior to or following administration
of a compound of formula I, VIII, or XVI'. Suitable therapeutic
agents are described in further detail below. In certain
embodiments, a compound of formula I, VIII, or XVI' may be
administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1
hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8
hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours,
15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic
agent. In other embodiments, a compound of formula I, VIII, or XVI'
may be administered up to 5 minutes, 10 minutes, 15 minutes, 30
minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7
hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14
hours, 15 hours, 16 hours, 17 hours, or 18 hours following the
therapeutic agent.
[0323] In another embodiment, the present invention provides a
method of treating an inflammatory disease, disorder or condition
by administering to a patient in need thereof a compound of formula
I, VIII, or XVI' and one or more additional therapeutic agents.
Such additional therapeutic agents may be small molecules or
recombinant biologic agents and include, for example,
acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such
as aspirin, ibuprofen, naproxen, etodolac (Lodine.RTM.) and
celecoxib, colchicine (Colcrys.RTM.), corticosteroids such as
prednisone, prednisolone, methylprednisolone, hydrocortisone, and
the like, probenecid, allopurinol, febuxostat (Uloric.RTM.),
sulfasalazine (Azulfidine.RTM.), antimalarials such as
hydroxychloroquine (Plaquenil.RTM.) and chloroquine (Aralen.RTM.),
methotrexate (Rheumatrex.RTM.), gold salts such as gold thioglucose
(Solganal.RTM.), gold thiomalate (Myochrysine.RTM.) and auranofin
(Ridaura.RTM.), D-penicillamine (Depen.RTM. or Cuprimine.RTM.),
azathioprine (Imuran.RTM.), cyclophosphamide (Cytoxan.RTM.),
chlorambucil (Leukeran.RTM.), cyclosporine (Sandimmune.RTM.),
leflunomide (Arava.RTM.) and "anti-TNF" agents such as etanercept
(Enbrel.RTM.), infliximab (Remicade.RTM.), golimumab
(Simponi.RTM.), certolizumab pegol (Cimzia.RTM.) and adalimumab
(Humira.RTM.), "anti-IL-1" agents such as anakinra (Kineret.RTM.)
and rilonacept (Arcalyst.RTM.), canakinumab (Ilaris.RTM.), anti-Jak
inhibitors such as tofacitinib, antibodies such as rituximab
(Rituxan.RTM.), "anti-T-cell" agents such as abatacept
(Orencia.RTM.), "anti-IL-6" agents such as tocilizumab
(Actemra.RTM.), diclofenac, cortisone, hyaluronic acid
(Synvisc.RTM. or Hyalgan.RTM.), monoclonal antibodies such as
tanezumab, anticoagulants such as heparin (Calcinparine.RTM. or
Liquaemin.RTM.) and warfarin (Coumadin.RTM.), antidiarrheals such
as diphenoxylate (Lomotil.RTM.) and loperamide (Imodium.RTM.), bile
acid binding agents such as cholestyramine, alosetron
(Lotronex.RTM.), lubiprostone (Amitiza.RTM.), laxatives such as
Milk of Magnesia, polyethylene glycol (MiraLax.RTM.),
Dulcolax.RTM., Correctol.RTM. and Senokot.RTM., anticholinergics or
antispasmodics such as dicyclomine (Bentyl.RTM.), Singulair.RTM.,
beta-2 agonists such as albuterol (Ventolin.RTM. HFA,
Proventil.RTM. HFA), levalbuterol (Xopenex.RTM.), metaproterenol
(Alupent.RTM.), pirbuterol acetate (Maxair.RTM.), terbutaline
sulfate (Brethaire.RTM.), salmeterol xinafoate (Serevent.RTM.) and
formoterol (Foradil.RTM.), anticholinergic agents such as
ipratropium bromide (Atrovent.RTM.) and tiotropium (Spiriva.RTM.),
inhaled corticosteroids such as beclomethasone dipropionate
(Beclovent.RTM., Qvar.RTM., and Vanceril.RTM.), triamcinolone
acetonide (Azmacort.RTM.), mometasone (Asthmanex.RTM.), budesonide
(Pulmicort.RTM.), and flunisolide (Aerobid.RTM.), Afviar.RTM.,
Symbicort.RTM., Dulera.RTM., cromolyn sodium (Intal.RTM.),
methylxanthines such as theophylline (Theo-Dur.RTM., Theolair.RTM.,
Slo-bid.RTM., Uniphyl.RTM., Theo-24.RTM.) and aminophylline, IgE
antibodies such as omalizumab (Xolair.RTM.), nucleoside reverse
transcriptase inhibitors such as zidovudine (Retrovir.RTM.),
abacavir (Ziagen.RTM.), abacavir/lamivudine (Epzicom.RTM.),
abacavir/lamivudine/zidovudine (Trizivir.RTM.), didanosine
(Videx.RTM.), emtricitabine (Emtriva.RTM.), lamivudine
(Epivir.RTM.), lamivudine/zidovudine (Combivir.RTM.), stavudine
(Zerit.RTM.), and zalcitabine (Hivid.RTM.), non-nucleoside reverse
transcriptase inhibitors such as delavirdine (Rescriptor.RTM.),
efavirenz (Sustiva.RTM.), nevirapine (Viramune.RTM.) and etravirine
(Intelence.RTM.), nucleotide reverse transcriptase inhibitors such
as tenofovir (Viread.RTM.), protease inhibitors such as amprenavir
(Agenerase.RTM.), atazanavir (Reyataz.RTM.), darunavir
(Prezista.RTM.), fosamprenavir (Lexiva.RTM.), indinavir
(Crixivan.RTM.), lopinavir and ritonavir (Kaletra.RTM.), nelfinavir
(Viracept.RTM.), ritonavir (Norvir.RTM.), saquinavir
(Fortovase.RTM. or Invirase.RTM.), and tipranavir (Aptivus.RTM.),
entry inhibitors such as enfuvirtide (Fuzeon.RTM.) and maraviroc
(Selzentry.RTM.), integrase inhibitors such as raltegravir
(Isentress.RTM.), doxorubicin (Hydrodaunorubicin.RTM.), vincristine
(Oncovin.RTM.), bortezomib (Velcade.RTM.), and dexamethasone
(Decadron.RTM.) in combination with lenalidomide (Revlimid.RTM.),
or any combination(s) thereof.
[0324] In another embodiment, the present invention provides a
method of treating rheumatoid arthritis comprising administering to
a patient in need thereof a compound of formula I, VIII, or XVI'
and one or more additional therapeutic agents selected from
non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,
ibuprofen, naproxen, etodolac (Lodine.RTM.) and celecoxib,
corticosteroids such as prednisone, prednisolone,
methylprednisolone, hydrocortisone, and the like, sulfasalazine
(Azulfidine.RTM.), antimalarials such as hydroxychloroquine
(Plaquenil.RTM.) and chloroquine (Aralen.RTM.), methotrexate
(Rheumatrex.RTM.), gold salts such as gold thioglucose
(Solganal.RTM.), gold thiomalate (Myochrysine.RTM.) and auranofin
(Ridaura.RTM.), D-penicillamine (Depen.RTM. or Cuprimine.RTM.),
azathioprine (Imuran.RTM.), cyclophosphamide (Cytoxan.RTM.),
chlorambucil (Leukeran.RTM.), cyclosporine (Sandimmune.RTM.),
leflunomide (Arava.RTM.) and "anti-TNF" agents such as etanercept
(Enbrel.RTM.), infliximab (Remicade.RTM.), golimumab
(Simponi.RTM.), certolizumab pegol (Cimzia.RTM.) and adalimumab
(Humira.RTM.), "anti-IL-1" agents such as anakinra (Kineret.RTM.)
and rilonacept (Arcalyst.RTM.), antibodies such as rituximab
(Rituxan.RTM.), "anti-T-cell" agents such as abatacept
(Orencia.RTM.) and "anti-IL-6" agents such as tocilizumab
(Actemra.RTM.).
[0325] In some embodiments, the present invention provides a method
of treating osteoarthritis comprising administering to a patient in
need thereof a compound of formula I, VIII, or XVI' and one or more
additional therapeutic agents selected from acetaminophen,
non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,
ibuprofen, naproxen, etodolac (Lodine.RTM.) and celecoxib,
diclofenac, cortisone, hyaluronic acid (Synvisc.RTM. or
Hyalgan.RTM.) and monoclonal antibodies such as tanezumab.
[0326] In some embodiments, the present invention provides a method
of treating systemic lupus erythematosus comprising administering
to a patient in need thereof a compound of formula I, VIII, or XVI'
and one or more additional therapeutic agents selected from
acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such
as aspirin, ibuprofen, naproxen, etodolac (Lodine.RTM.) and
celecoxib, corticosteroids such as prednisone, prednisolone,
methylprednisolone, hydrocortisone, and the like, antimalarials
such as hydroxychloroquine (Plaquenil.RTM.) and chloroquine
(Aralen.RTM.), cyclophosphamide (Cytoxan.RTM.), methotrexate
(Rheumatrex.RTM.), azathioprine (Imuran.RTM.) and anticoagulants
such as heparin (Calcinparine.RTM. or Liquaemin.RTM.) and warfarin
(Coumadin.RTM.).
[0327] In some embodiments, the present invention provides a method
of treating Crohn's disease, ulcerative colitis, or inflammatory
bowel disease comprising administering to a patient in need thereof
a compound of formula I, VIII, or XVI' and one or more additional
therapeutic agents selected from mesalamine (Asacol.RTM.)
sulfasalazine (Azulfidine.RTM.), antidiarrheals such as
diphenoxylate (Lomotil.RTM.) and loperamide (Imodium.RTM.), bile
acid binding agents such as cholestyramine, alosetron
(Lotronex.RTM.), lubiprostone (Amitiza.RTM.), laxatives such as
Milk of Magnesia, polyethylene glycol (MiraLax.RTM.),
Dulcolax.RTM., Correctol.RTM. and Senokot.RTM. and anticholinergics
or antispasmodics such as dicyclomine (Bentyl.RTM.), anti-TNF
therapies, steroids, and antibiotics such as Flagyl or
ciprofloxacin.
[0328] In some embodiments, the present invention provides a method
of treating asthma comprising administering to a patient in need
thereof a compound of formula I, VIII, or XVI' and one or more
additional therapeutic agents selected from Singulair.RTM., beta-2
agonists such as albuterol (Ventolin.RTM. HFA, Proventil.RTM. HFA),
levalbuterol (Xopenex.RTM.), metaproterenol (Alupent.RTM.),
pirbuterol acetate (Maxair.RTM.), terbutaline sulfate
(Brethaire.RTM.), salmeterol xinafoate (Serevent.RTM.) and
formoterol (Foradil.RTM.), anticholinergic agents such as
ipratropium bromide (Atrovent.RTM.) and tiotropium (Spiriva.RTM.),
inhaled corticosteroids such as prednisone, prednisolone,
beclomethasone dipropionate (Beclovent.RTM., Qvar.RTM., and
Vanceril.RTM.), triamcinolone acetonide (Azmacort.RTM.), mometasone
(Asthmanex.RTM.), budesonide (Pulmicort.RTM.), flunisolide
(Aerobid.RTM.), Afviar.RTM., Symbicort.RTM., and Dulera.RTM.,
cromolyn sodium (Intal.RTM.), methylxanthines such as theophylline
(Theo-Dur.RTM., Theolair.RTM., Slo-bid.RTM., Uniphyl.RTM.,
Theo-24.RTM.) and aminophylline, and IgE antibodies such as
omalizumab (Xolair.RTM.).
[0329] In some embodiments, the present invention provides a method
of treating COPD comprising administering to a patient in need
thereof a compound of formula I, VIII, or XVI' and one or more
additional therapeutic agents selected from beta-2 agonists such as
albuterol (Ventolin.RTM. HFA, Proventil.RTM. HFA), levalbuterol
(Xopenex.RTM.), metaproterenol (Alupent.RTM.), pirbuterol acetate
(Maxair.RTM.), terbutaline sulfate (Brethaire.RTM.), salmeterol
xinafoate (Serevent.RTM.) and formoterol (Foradil.RTM.),
anticholinergic agents such as ipratropium bromide (Atrovent.RTM.)
and tiotropium (Spiriva.RTM.), methylxanthines such as theophylline
(Theo-Dur.RTM., Theolair.RTM., Slo-bid.RTM., Uniphyl.RTM.,
Theo-24.RTM.) and aminophylline, inhaled corticosteroids such as
prednisone, prednisolone, beclomethasone dipropionate
(Beclovent.RTM., Qvar.RTM., and Vanceril.RTM.), triamcinolone
acetonide (Azmacort.RTM.), mometasone (Asthmanex.RTM.), budesonide
(Pulmicort.RTM.), flunisolide (Aerobid.RTM.), Afviar.RTM.,
Symbicort.RTM., and Dulera.RTM.,
[0330] In another embodiment, the present invention provides a
method of treating a hematological malignancy comprising
administering to a patient in need thereof a compound of formula I,
VIII, or XVI' and one or more additional therapeutic agents
selected from rituximab (Rituxan.RTM.), cyclophosphamide
(Cytoxan.RTM.), doxorubicin (Hydrodaunorubicin.RTM.), vincristine
(Oncovin.RTM.), prednisone, a hedgehog signaling inhibitor, a BTK
inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK
inhibitor, and combinations thereof.
[0331] In another embodiment, the present invention provides a
method of treating a solid tumor comprising administering to a
patient in need thereof a compound of formula I, VIII, or XVI' and
one or more additional therapeutic agents selected from rituximab
(Rituxan.RTM.), cyclophosphamide (Cytoxan.RTM.), doxorubicin
(Hydrodaunorubicin.RTM.), vincristine (Oncovin.RTM.), prednisone, a
hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK
inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations
thereof.
[0332] In another embodiment, the present invention provides a
method of treating a hematological malignancy comprising
administering to a patient in need thereof a compound of formula I,
VIII, or XVI' and a Hedgehog (Hh) signaling pathway inhibitor. In
some embodiments, the hematological malignancy is DLBCL (Ramirez et
al "Defining causative factors contributing in the activation of
hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res.
(2012), published online July 17, and incorporated herein by
reference in its entirety).
[0333] In another embodiment, the present invention provides a
method of treating diffuse large B-cell lymphoma (DLBCL) comprising
administering to a patient in need thereof a compound of formula I,
VIII, or XVI' and one or more additional therapeutic agents
selected from rituximab (Rituxan.RTM.), cyclophosphamide
(Cytoxan.RTM.), doxorubicin (Hydrodaunorubicin.RTM.), vincristine
(Oncovin.RTM.), prednisone, a hedgehog signaling inhibitor, and
combinations thereof.
[0334] In another embodiment, the present invention provides a
method of treating multiple myeloma comprising administering to a
patient in need thereof a compound of formula I, VIII, or XVI' and
one or more additional therapeutic agents selected from bortezomib
(Velcade.RTM.), and dexamethasone (Decadron.RTM.), a hedgehog
signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a
TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination
with lenalidomide (Revlimid.RTM.).
[0335] In another embodiment, the present invention provides a
method of treating or lessening the severity of a disease
comprising administering to a patient in need thereof a compound of
formula I, VIII, or XVI' and a BTK inhibitor, wherein the disease
is selected from inflammatory bowel disease, arthritis, systemic
lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic
purpura (ITP), rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, Still's disease, juvenile arthritis, diabetes,
myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis,
Graves' disease, autoimmune thyroiditis, Sjogren's syndrome,
multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis,
Guillain-Barre syndrome, acute disseminated encephalomyelitis,
Addison's disease, opsoclonus-myoclonus syndrome, ankylosing
spondylosis, antiphospholipid antibody syndrome, aplastic anemia,
autoimmune hepatitis, autoimmune gastritis, pernicious anemia,
celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic
purpura, optic neuritis, scleroderma, primary biliary cirrhosis,
Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm
autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,
alopecia universalis, Behcet's disease, chronic fatigue,
dysautonomia, membranous glomerulonephropathy, endometriosis,
interstitial cystitis, pemphigus vulgaris, bullous pemphigoid,
neuromyotonia, scleroderma, vulvodynia, a hyperproliferative
disease, rejection of transplanted organs or tissues, Acquired
Immunodeficiency Syndrome (AIDS, also known as HIV), type 1
diabetes, graft versus host disease, transplantation, transfusion,
anaphylaxis, allergies (e.g., allergies to plant pollens, latex,
drugs, foods, insect poisons, animal hair, animal dander, dust
mites, or cockroach calyx), type I hypersensitivity, allergic
conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma,
appendicitis, atopic dermatitis, asthma, allergy, blepharitis,
bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,
cholecystitis, chronic graft rejection, colitis, conjunctivitis,
Crohn's disease, cystitis, dacryoadenitis, dermatitis,
dermatomyositis, encephalitis, endocarditis, endometritis,
enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,
fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura,
hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy,
interstitial lung disease, laryngitis, mastitis, meningitis,
myelitis myocarditis, myositis, nephritis, oophoritis, orchitis,
osteitis, otitis, pancreatitis, parotitis, pericarditis,
peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis,
pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis,
vasculitis, or vulvitis, B-cell proliferative disorder, e.g.,
diffuse large B cell lymphoma, follicular lymphoma, chronic
lymphocytic lymphoma, chronic lymphocytic leukemia, acute
lymphocytic leukemia, B-cell prolymphocytic leukemia,
lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic
marginal zone lymphoma, multiple myeloma (also known as plasma cell
myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma,
extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B
cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoid
granulomatosis, breast cancer, prostate cancer, or cancer of the
mast cells (e.g., mastocytoma, mast cell leukemia, mast cell
sarcoma, systemic mastocytosis), bone cancer, colorectal cancer,
pancreatic cancer, diseases of the bone and joints including,
without limitation, rheumatoid arthritis, seronegative
spondyloarthropathies (including ankylosing spondylitis, psoriatic
arthritis and Reiter's disease), Behcet's disease, Sjogren's
syndrome, systemic sclerosis, osteoporosis, bone cancer, bone
metastasis, a thromboembolic disorder, (e.g., myocardial infarct,
angina pectoris, reocclusion after angioplasty, restenosis after
angioplasty, reocclusion after aortocoronary bypass, restenosis
after aortocoronary bypass, stroke, transitory ischemia, a
peripheral arterial occlusive disorder, pulmonary embolism, deep
venous thrombosis), inflammatory pelvic disease, urethritis, skin
sunburn, sinusitis, pneumonitis, encephalitis, meningitis,
myocarditis, nephritis, osteomyelitis, myositis, hepatitis,
gastritis, enteritis, dermatitis, gingivitis, appendicitis,
pancreatitis, cholocystitus, agammaglobulinemia, psoriasis,
allergy, Crohn's disease, irritable bowel syndrome, ulcerative
colitis, Sjogren's disease, tissue graft rejection, hyperacute
rejection of transplanted organs, asthma, allergic rhinitis,
chronic obstructive pulmonary disease (COPD), autoimmune
polyglandular disease (also known as autoimmune polyglandular
syndrome), autoimmune alopecia, pernicious anemia,
glomerulonephritis, dermatomyositis, multiple sclerosis,
scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic
states, Goodpasture's syndrome, atherosclerosis, Addison's disease,
Parkinson's disease, Alzheimer's disease, diabetes, septic shock,
systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic
arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic
thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia
gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative
joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre
syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute
inflammatory responses (such as acute respiratory distress syndrome
and ischemia/reperfusion injury), and Graves' disease.
[0336] In another embodiment, the present invention provides a
method of treating or lessening the severity of a disease
comprising administering to a patient in need thereof a compound of
formula I, VIII, or XVI' and a PI3K inhibitor, wherein the disease
is selected from a cancer, a neurodegenerative disorder, an
angiogenic disorder, a viral disease, an autoimmune disease, an
inflammatory disorder, a hormone-related disease, conditions
associated with organ transplantation, immunodeficiency disorders,
a destructive bone disorder, a proliferative disorder, an
infectious disease, a condition associated with cell death,
thrombin-induced platelet aggregation, chronic myelogenous leukemia
(CML), chronic lymphocytic leukemia (CLL), liver disease,
pathologic immune conditions involving T cell activation, a
cardiovascular disorder, and a CNS disorder.
[0337] In another embodiment, the present invention provides a
method of treating or lessening the severity of a disease
comprising administering to a patient in need thereof a compound of
formula I, VIII, or XVI' and a PI3K inhibitor, wherein the disease
is selected from benign or malignant tumor, carcinoma or solid
tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)),
liver, adrenal gland, bladder, breast, stomach, gastric tumors,
ovaries, colon, rectum, prostate, pancreas, lung, vagina,
endometrium, cervix, testis, genitourinary tract, esophagus,
larynx, skin, bone or thyroid, sarcoma, glioblastomas,
neuroblastomas, multiple myeloma or gastrointestinal cancer,
especially colon carcinoma or colorectal adenoma or a tumor of the
neck and head, an epidermal hyperproliferation, psoriasis, prostate
hyperplasia, a neoplasia, a neoplasia of epithelial character,
adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma,
large cell carcinoma, non-small-cell lung carcinoma, lymphomas,
(including, for example, non-Hodgkin's Lymphoma (NHL) and Hodgkin's
lymphoma (also termed Hodgkin's or Hodgkin's disease)), a mammary
carcinoma, follicular carcinoma, undifferentiated carcinoma,
papillary carcinoma, seminoma, melanoma, or a leukemia, diseases
include Cowden syndrome, Lhermitte-Duclos disease and
Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway
is aberrantly activated, asthma of whatever type or genesis
including both intrinsic (non-allergic) asthma and extrinsic
(allergic) asthma, mild asthma, moderate asthma, severe asthma,
bronchitic asthma, exercise-induced asthma, occupational asthma and
asthma induced following bacterial infection, acute lung injury
(ALI), adult/acute respiratory distress syndrome (ARDS), chronic
obstructive pulmonary, airways or lung disease (COPD, COAD or
COLD), including chronic bronchitis or dyspnea associated
therewith, emphysema, as well as exacerbation of airways
hyperreactivity consequent to other drug therapy, in particular
other inhaled drug therapy, bronchitis of whatever type or genesis
including, but not limited to, acute, arachidic, catarrhal,
croupus, chronic or phthinoid bronchitis, pneumoconiosis (an
inflammatory, commonly occupational, disease of the lungs,
frequently accompanied by airways obstruction, whether chronic or
acute, and occasioned by repeated inhalation of dusts) of whatever
type or genesis, including, for example, aluminosis, anthracosis,
asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis
and byssinosis, Loffler's syndrome, eosinophilic, pneumonia,
parasitic (in particular metazoan) infestation (including tropical
eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa
(including Churg-Strauss syndrome), eosinophilic granuloma and
eosinophil-related disorders affecting the airways occasioned by
drug-reaction, psoriasis, contact dermatitis, atopic dermatitis,
alopecia areata, erythema multiforma, dermatitis herpetiformis,
scleroderma, vitiligo, hypersensitivity angiitis, urticaria,
bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis
bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and
vernal conjunctivitis, diseases affecting the nose including
allergic rhinitis, and inflammatory disease in which autoimmune
reactions are implicated or having an autoimmune component or
etiology, including autoimmune hematological disorders (e.g.
hemolytic anemia, aplastic anemia, pure red cell anemia and
idiopathic thrombocytopenia), systemic lupus erythematosus,
rheumatoid arthritis, polychondritis, scleroderma, Wegener
granulamatosis, dermatomyositis, chronic active hepatitis,
myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue,
autoimmune inflammatory bowel disease (e.g. ulcerative colitis and
Crohn's disease), endocrine opthalmopathy, Grave's disease,
sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,
multiple sclerosis, primary biliary cirrhosis, uveitis (anterior
and posterior), keratoconjunctivitis sicca and vernal
keratoconjunctivitis, interstitial lung fibrosis, psoriatic
arthritis and glomerulonephritis (with and without nephrotic
syndrome, e.g. including idiopathic nephrotic syndrome or minal
change nephropathy, restenosis, cardiomegaly, atherosclerosis,
myocardial infarction, ischemic stroke and congestive heart
failure, Alzheimer's disease, Parkinson's disease, amyotrophic
lateral sclerosis, Huntington's disease, and cerebral ischemia, and
neurodegenerative disease caused by traumatic injury, glutamate
neurotoxicity and hypoxia.
[0338] In some embodiments the present invention provides a method
of treating or lessening the severity of a disease comprising
administering to a patient in need thereof a compound of formula I,
VIII, or XVI' and a Bcl-2 inhibitor, wherein the disease is an
inflammatory disorder, an autoimmune disorder, a proliferative
disorder, an endocrine disorder, a neurological disorder, or a
disorder associated with transplantation. In some embodiments, the
disorder is a proliferative disorder, lupus, or lupus nephritis. In
some embodiments, the proliferative disorder is chronic lymphocytic
leukaemia, diffuse large B-cell lymphoma, Hodgkin's disease,
small-cell lung cancer, non-small-cell lung cancer, myelodysplastic
syndrome, lymphoma, a hematological neoplasm, or solid tumor.
[0339] In some embodiments, the present invention provides a method
of treating or lessening the severity of a disease, comprising
administering to a patient in need thereof a TYK2 pseudokinase
(JH2) domain binding compound and a TYK2 kinase (JH1) domain
binding compound. In some embodiments, the disease is an autoimmune
disorder, an inflammatory disorder, a proliferative disorder, an
endocrine disorder, a neurological disorder, or a disorder
associated with transplantation. In some embodiments the JH2
binding compound is a compound of formula I, VIII, or XVI'. Other
suitable JH2 domain binding compounds include those described in
WO2014074660A1, WO2014074661A1, WO2015089143A1, the entirety of
each of which is incorporated herein by reference. Suitable JH1
domain binding compounds include those described in WO2015131080A1,
the entirety of which is incorporated herein by reference.
[0340] The compounds and compositions, according to the method of
the present invention, may be administered using any amount and any
route of administration effective for treating or lessening the
severity of an autoimmune disorder, an inflammatory disorder, a
proliferative disorder, an endocrine disorder, a neurological
disorder, or a disorder associated with transplantation. The exact
amount required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the infection, the particular agent, its mode of administration,
and the like. Compounds of the invention are preferably formulated
in dosage unit form for ease of administration and uniformity of
dosage. The expression "dosage unit form" as used herein refers to
a physically discrete unit of agent appropriate for the patient to
be treated. It will be understood, however, that the total daily
usage of the compounds and compositions of the present invention
will be decided by the attending physician within the scope of
sound medical judgment. The specific effective dose level for any
particular patient or organism will depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed,
and like factors well known in the medical arts. The term
"patient", as used herein, means an animal, preferably a mammal,
and most preferably a human.
[0341] Pharmaceutically acceptable compositions of this invention
can be administered to humans and other animals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), buccally, as an
oral or nasal spray, or the like, depending on the severity of the
infection being treated. In certain embodiments, the compounds of
the invention may be administered orally or parenterally at dosage
levels of about 0.01 mg/kg to about 50 mg/kg and preferably from
about 1 mg/kg to about 25 mg/kg, of subject body weight per day,
one or more times a day, to obtain the desired therapeutic
effect.
[0342] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, 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, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0343] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0344] Injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0345] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsulated matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0346] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0347] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0348] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0349] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0350] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0351] According to one embodiment, the invention relates to a
method of inhibiting protein kinase activity in a biological sample
comprising the step of contacting said biological sample with a
compound of this invention, or a composition comprising said
compound.
[0352] According to another embodiment, the invention relates to a
method of inhibiting TYK2, or a mutant thereof, activity in a
biological sample comprising the step of contacting said biological
sample with a compound of this invention, or a composition
comprising said compound. In certain embodiments, the invention
relates to a method of irreversibly inhibiting TYK2, or a mutant
thereof, activity in a biological sample comprising the step of
contacting said biological sample with a compound of this
invention, or a composition comprising said compound.
[0353] In another embodiment, the invention provides a method of
selectively inhibiting TYK2 over one or more of JAK1, JAK2, and
JAK3. In some embodiments, a compound of the present invention is
more than 2-fold selective over JAK1/2/3. In some embodiments, a
compound of the present invention is more than 5-fold selective
over JAK1/2/3. In some embodiments, a compound of the present
invention is more than 10-fold selective over JAK1/2/3. In some
embodiments, a compound of the present invention is more than
50-fold selective over JAK1/2/3. In some embodiments, a compound of
the present invention is more than 100-fold selective over
JAK1/2/3.
[0354] The term "biological sample", as used herein, includes,
without limitation, cell cultures or extracts thereof; biopsied
material obtained from a mammal or extracts thereof, and blood,
saliva, urine, feces, semen, tears, or other body fluids or
extracts thereof.
[0355] Inhibition of TYK2 (or a mutant thereof) activity in a
biological sample is useful for a variety of purposes that are
known to one of skill in the art. Examples of such purposes
include, but are not limited to, blood transfusion,
organ-transplantation, biological specimen storage, and biological
assays.
[0356] Another embodiment of the present invention relates to a
method of inhibiting protein kinase activity in a patient
comprising the step of administering to said patient a compound of
the present invention, or a composition comprising said
compound.
[0357] According to another embodiment, the invention relates to a
method of inhibiting activity of TYK2, or a mutant thereof, in a
patient comprising the step of administering to said patient a
compound of the present invention, or a composition comprising said
compound. According to certain embodiments, the invention relates
to a method of reversibly or irreversibly inhibiting one or more of
TYK2, or a mutant thereof, activity in a patient comprising the
step of administering to said patient a compound of the present
invention, or a composition comprising said compound. In other
embodiments, the present invention provides a method for treating a
disorder mediated by TYK2, or a mutant thereof, in a patient in
need thereof, comprising the step of administering to said patient
a compound according to the present invention or pharmaceutically
acceptable composition thereof. Such disorders are described in
detail herein.
[0358] Depending upon the particular condition, or disease, to be
treated, additional therapeutic agents that are normally
administered to treat that condition, may also be present in the
compositions of this invention. As used herein, additional
therapeutic agents that are normally administered to treat a
particular disease, or condition, are known as "appropriate for the
disease, or condition, being treated."
[0359] A compound of the current invention may also be used to
advantage in combination with other therapeutic compounds. In some
embodiments, the other therapeutic compounds are antiproliferative
compounds. Such antiproliferative compounds include, but are not
limited to aromatase inhibitors; antiestrogens; topoisomerase I
inhibitors; topoisomerase II inhibitors; microtubule active
compounds; alkylating compounds; histone deacetylase inhibitors;
compounds which induce cell differentiation processes;
cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;
antineoplastic antimetabolites; platin compounds; compounds
targeting/decreasing a protein or lipid kinase activity and further
anti-angiogenic compounds; compounds which target, decrease or
inhibit the activity of a protein or lipid phosphatase; gonadorelin
agonists; anti-androgens; methionine aminopeptidase inhibitors;
matrix metalloproteinase inhibitors; bisphosphonates; biological
response modifiers; antiproliferative antibodies; heparanase
inhibitors; inhibitors of Ras oncogenic isoforms; telomerase
inhibitors; proteasome inhibitors; compounds used in the treatment
of hematologic malignancies; compounds which target, decrease or
inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG
(17-allylaminogeldanamycin, NSC330507), 17-DMAG
(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),
IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;
temozolomide (Temodal''); kinesin spindle protein inhibitors, such
as SB715992 or SB743921 from GlaxoSmithKline, or
pentamidine/chlorpromazine from CombinatoRX; MEK inhibitors such as
ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461
from Pfizer and leucovorin. The term "aromatase inhibitor" as used
herein relates to a compound which inhibits estrogen production,
for instance, the conversion of the substrates androstenedione and
testosterone to estrone and estradiol, respectively. The term
includes, but is not limited to steroids, especially atamestane,
exemestane and formestane and, in particular, non-steroids,
especially aminoglutethimide, roglethimide, pyridoglutethimide,
trilostane, testolactone, ketokonazole, vorozole, fadrozole,
anastrozole and letrozole. Exemestane is marketed under the trade
name Aromasin.TM.. Formestane is marketed under the trade name
Lentaron.TM.. Fadrozole is marketed under the trade name Afema.TM..
Anastrozole is marketed under the trade name Arimidex.TM. Letrozole
is marketed under the trade names Femara.TM. or Femar.TM..
Aminoglutethimide is marketed under the trade name Orimeten.TM.. A
combination of the invention comprising a chemotherapeutic agent
which is an aromatase inhibitor is particularly useful for the
treatment of hormone receptor positive tumors, such as breast
tumors.
[0360] The term "antiestrogen" as used herein relates to a compound
which antagonizes the effect of estrogens at the estrogen receptor
level. The term includes, but is not limited to tamoxifen,
fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is
marketed under the trade name Nolvadex.TM.. Raloxifene
hydrochloride is marketed under the trade name Evista.TM..
Fulvestrant can be administered under the trade name Faslodex.TM..
A combination of the invention comprising a chemotherapeutic agent
which is an antiestrogen is particularly useful for the treatment
of estrogen receptor positive tumors, such as breast tumors.
[0361] The term "anti-androgen" as used herein relates to any
substance which is capable of inhibiting the biological effects of
androgenic hormones and includes, but is not limited to,
bicalutamide (Casodex.TM.). The term "gonadorelin agonist" as used
herein includes, but is not limited to abarelix, goserelin and
goserelin acetate. Goserelin can be administered under the trade
name Zoladex.TM..
[0362] The term "topoisomerase I inhibitor" as used herein
includes, but is not limited to topotecan, gimatecan, irinotecan,
camptothecin and its analogues, 9-nitrocamptothecin and the
macromolecular camptothecin conjugate PNU-166148. Irinotecan can be
administered, e.g. in the form as it is marketed, e.g. under the
trademark Camptosar.TM.. Topotecan is marketed under the trade name
Hycamptin.TM..
[0363] The term "topoisomerase II inhibitor" as used herein
includes, but is not limited to the anthracyclines such as
doxorubicin (including liposomal formulation, such as Caelyx.TM.)
daunorubicin, epirubicin, idarubicin and nemorubicin, the
anthraquinones mitoxantrone and losoxantrone, and the
podophillotoxines etoposide and teniposide. Etoposide is marketed
under the trade name Etopophos.TM.. Teniposide is marketed under
the trade name VM 26-Bristol Doxorubicin is marketed under the
trade name Acriblastin.TM. or Adriamycin.TM.. Epirubicin is
marketed under the trade name Farmorubicin.TM.. Idarubicin is
marketed. under the trade name Zavedos.TM.. Mitoxantrone is
marketed under the trade name Novantron.
[0364] The term "microtubule active agent" relates to microtubule
stabilizing, microtubule destabilizing compounds and microtubulin
polymerization inhibitors including, but not limited to taxanes,
such as paclitaxel and docetaxel; vinca alkaloids, such as
vinblastine or vinblastine sulfate, vincristine or vincristine
sulfate, and vinorelbine; discodermolides; colchicine and
epothilones and derivatives thereof. Paclitaxel is marketed under
the trade name Taxol.TM. Docetaxel is marketed under the trade name
Taxotere.TM.. Vinblastine sulfate is marketed under the trade name
Vinblastin R.P.TM.. Vincristine sulfate is marketed under the trade
name Farmistin.TM..
[0365] The term "alkylating agent" as used herein includes, but is
not limited to, cyclophosphamide, ifosfamide, melphalan or
nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under
the trade name Cyclostin.TM.. Ifosfamide is marketed under the
trade name Holoxan.TM..
[0366] The term "histone deacetylase inhibitors" or "HDAC
inhibitors" relates to compounds which inhibit the histone
deacetylase and which possess antiproliferative activity. This
includes, but is not limited to, suberoylanilide hydroxamic acid
(SAHA).
[0367] The term "antineoplastic antimetabolite" includes, but is
not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine,
DNA demethylating compounds, such as 5-azacytidine and decitabine,
methotrexate and edatrexate, and folic acid antagonists such as
pemetrexed. Capecitabine is marketed under the trade name
Xeloda.TM.. Gemcitabine is marketed under the trade name
Gemzar.TM..
[0368] The term "platin compound" as used herein includes, but is
not limited to, carboplatin, cis-platin, cisplatinum and
oxaliplatin. Carboplatin can be administered, e.g., in the form as
it is marketed, e.g. under the trademark Carboplat.TM.. Oxaliplatin
can be administered, e.g., in the form as it is marketed, e.g.
under the trademark Eloxatin.TM..
[0369] The term "compounds targeting/decreasing a protein or lipid
kinase activity; or a protein or lipid phosphatase activity; or
further anti-angiogenic compounds" as used herein includes, but is
not limited to, protein tyrosine kinase and/or serine and/or
threonine kinase inhibitors or lipid kinase inhibitors, such as a)
compounds targeting, decreasing or inhibiting the activity of the
platelet-derived growth factor-receptors (PDGFR), such as compounds
which target, decrease or inhibit the activity of PDGFR, especially
compounds which inhibit the PDGF receptor, such as an
N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101,
SU6668 and GFB-111; b) compounds targeting, decreasing or
inhibiting the activity of the fibroblast growth factor-receptors
(FGFR); c) compounds targeting, decreasing or inhibiting the
activity of the insulin-like growth factor receptor I (IGF-IR),
such as compounds which target, decrease or inhibit the activity of
IGF-IR, especially compounds which inhibit the kinase activity of
IGF-I receptor, or antibodies that target the extracellular domain
of IGF-I receptor or its growth factors; d) compounds targeting,
decreasing or inhibiting the activity of the Trk receptor tyrosine
kinase family, or ephrin B4 inhibitors; e) compounds targeting,
decreasing or inhibiting the activity of the Axl receptor tyrosine
kinase family; f) compounds targeting, decreasing or inhibiting the
activity of the Ret receptor tyrosine kinase; g) compounds
targeting, decreasing or inhibiting the activity of the Kit/SCFR
receptor tyrosine kinase, such as imatinib; h) compounds targeting,
decreasing or inhibiting the activity of the C-kit receptor
tyrosine kinases, which are part of the PDGFR family, such as
compounds which target, decrease or inhibit the activity of the
c-Kit receptor tyrosine kinase family, especially compounds which
inhibit the c-Kit receptor, such as imatinib; i) compounds
targeting, decreasing or inhibiting the activity of members of the
c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and
mutants, such as compounds which target decrease or inhibit the
activity of c-Abl family members and their gene fusion products,
such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib
or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from
ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting,
decreasing or inhibiting the activity of members of the protein
kinase C (PKC) and Raf family of serine/threonine kinases, members
of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K,
SYK, BTK and TEC family, and/or members of the cyclin-dependent
kinase family (CDK) including staurosporine derivatives, such as
midostaurin; examples of further compounds include UCN-01,
safingol, BAY 43-9006, Bryostatin 1, Perifosine; ilmofosine; RO
318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196;
isochinoline compounds; FTIs; PD184352 or QAN697 (a PI3K inhibitor)
or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or
inhibiting the activity of protein-tyrosine kinase inhibitors, such
as compounds which target, decrease or inhibit the activity of
protein-tyrosine kinase inhibitors include imatinib mesylate
(Gleevec.TM.) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;
Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490;
Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555;
AG 494; Tyrphostin AG 556, AG957 and adaphostin
(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl
ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing
or inhibiting the activity of the epidermal growth factor family of
receptor tyrosine kinases (EGFR.sub.1 ErbB2, ErbB3, ErbB4 as homo-
or heterodimers) and their mutants, such as compounds which target,
decrease or inhibit the activity of the epidermal growth factor
receptor family are especially compounds, proteins or antibodies
which inhibit members of the EGF receptor tyrosine kinase family,
such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF
related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab
(Herceptin.TM.), cetuximab (Erbitux.TM.), Iressa, Tarceva, OSI-774,
C1-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11,
E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m)
compounds targeting, decreasing or inhibiting the activity of the
c-Met receptor, such as compounds which target, decrease or inhibit
the activity of c-Met, especially compounds which inhibit the
kinase activity of c-Met receptor, or antibodies that target the
extracellular domain of c-Met or bind to HGF, n) compounds
targeting, decreasing or inhibiting the kinase activity of one or
more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK),
including but not limited to PRT-062070, SB-1578, baricitinib,
pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib,
and ruxolitinib; o) compounds targeting, decreasing or inhibiting
the kinase activity of PI3 kinase (PI3K) including but not limited
to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,
buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,
XL-765, and idelalisib; and; and q) compounds targeting, decreasing
or inhibiting the signaling effects of hedgehog protein (Hh) or
smoothened receptor (SMO) pathways, including but not limited to
cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926
(saridegib).
[0370] The term "PI3K inhibitor" as used herein includes, but is
not limited to compounds having inhibitory activity against one or
more enzymes in the phosphatidylinositol-3-kinase family,
including, but not limited to PI3K.alpha., PI3K.gamma.,
PI3K.delta., PI3K.beta., PI3K-C2.alpha., PI3K-C2.beta.,
PI3K-C2.gamma., Vps34, p110-.alpha., p110-.beta., p110-.gamma.,
p110-.delta., p85-.alpha., p85-.beta., p55-.gamma., p150, p101, and
p87. Examples of PI3K inhibitors useful in this invention include
but are not limited to ATU-027, SF-1126, DS-7423, PBI-05204,
GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502,
BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
[0371] The term "BTK inhibitor" as used herein includes, but is not
limited to compounds having inhibitory activity against Bruton's
Tyrosine Kinase (BTK), including, but not limited to AVL-292 and
ibrutinib.
[0372] The term "SYK inhibitor" as used herein includes, but is not
limited to compounds having inhibitory activity against spleen
tyrosine kinase (SYK), including but not limited to PRT-062070,
R-343, R-333, Excellair, PRT-062607, and fostamatinib.
[0373] The term "Bcl-2 inhibitor" as used herein includes, but is
not limited to compounds having inhibitory activity against B-cell
lymphoma 2 protein (Bcl-2), including but not limited to ABT-199,
ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors,
curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors
(Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense
(G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax
(and analogs thereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng
Pharmaceutical University), obatoclax (and analogs thereof, see
WO2004106328), 5-001 (Gloria Pharmaceuticals), TW series compounds
(Univ. of Michigan), and venetoclax. In some embodiments the Bcl-2
inhibitor is a small molecule therapeutic. In some embodiments the
Bcl-2 inhibitor is a peptidomimetic.
[0374] Further examples of BTK inhibitory compounds, and conditions
treatable by such compounds in combination with compounds of this
invention can be found in WO2008039218 and WO2011090760, the
entirety of which are incorporated herein by reference.
[0375] Further examples of SYK inhibitory compounds, and conditions
treatable by such compounds in combination with compounds of this
invention can be found in WO2003063794, WO2005007623, and
WO2006078846, the entirety of which are incorporated herein by
reference.
[0376] Further examples of PI3K inhibitory compounds, and
conditions treatable by such compounds in combination with
compounds of this invention can be found in WO2004019973,
WO2004089925, WO2007016176, U.S. Pat. No. 8,138,347, WO2002088112,
WO2007084786, WO2007129161, WO2006122806, WO2005113554, and
WO2007044729 the entirety of which are incorporated herein by
reference.
[0377] Further examples of JAK inhibitory compounds, and conditions
treatable by such compounds in combination with compounds of this
invention can be found in WO2009114512, WO2008109943, WO2007053452,
WO2000142246, and WO2007070514, the entirety of which are
incorporated herein by reference.
[0378] Further anti-angiogenic compounds include compounds having
another mechanism for their activity, e.g. unrelated to protein or
lipid kinase inhibition e.g. thalidomide (Thalomid.TM.) and
TNP-470.
[0379] Examples of proteasome inhibitors useful for use in
combination with compounds of the invention include, but are not
limited to bortezomib, disulfiram, epigallocatechin-3-gallate
(EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and
MLN9708.
[0380] Compounds which target, decrease or inhibit the activity of
a protein or lipid phosphatase are e.g. inhibitors of phosphatase
1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative
thereof.
[0381] Compounds which induce cell differentiation processes
include, but are not limited to, retinoic acid, .alpha.-.gamma.- or
.delta.-tocopherol or .alpha.-.gamma.- or .delta.-tocotrienol.
[0382] The term cyclooxygenase inhibitor as used herein includes,
but is not limited to, Cox-2 inhibitors, 5-alkyl substituted
2-arylaminophenylacetic acid and derivatives, such as celecoxib
(Celebrex.TM.), rofecoxib (Vioxx.TM.), etoricoxib, valdecoxib or a
5-alkyl-2-arylaminophenylacetic acid, such as
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid,
lumiracoxib.
[0383] The term "bisphosphonates" as used herein includes, but is
not limited to, etridonic, clodronic, tiludronic, pamidronic,
alendronic, ibandronic, risedronic and zoledronic acid. Etridonic
acid is marketed under the trade name Didronel.TM.. Clodronic acid
is marketed under the trade name Bonefos.TM.. Tiludronic acid is
marketed under the trade name Skelid.TM.. Pamidronic acid is
marketed under the trade name Aredia.TM.. Alendronic acid is
marketed under the trade name Fosamax.TM.. Ibandronic acid is
marketed under the trade name Bondranat.TM.. Risedronic acid is
marketed under the trade name Actonel.TM.. Zoledronic acid is
marketed under the trade name Zometa.TM.. The term "mTOR
inhibitors" relates to compounds which inhibit the mammalian target
of rapamycin (mTOR) and which possess antiproliferative activity
such as sirolimus (Rapamune.RTM.), everolimus (Certican.TM.),
CCI-779 and ABT578.
[0384] The term "heparanase inhibitor" as used herein refers to
compounds which target, decrease or inhibit heparin sulfate
degradation. The term includes, but is not limited to, PI-88. The
term "biological response modifier" as used herein refers to a
lymphokine or interferons.
[0385] The term "inhibitor of Ras oncogenic isoforms", such as
H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which
target, decrease or inhibit the oncogenic activity of Ras; for
example, a "farnesyl transferase inhibitor" such as L-744832,
DK8G557 or R115777 (Zarnestra.TM.). The term "telomerase inhibitor"
as used herein refers to compounds which target, decrease or
inhibit the activity of telomerase. Compounds which target,
decrease or inhibit the activity of telomerase are especially
compounds which inhibit the telomerase receptor, such as
telomestatin.
[0386] The term "methionine aminopeptidase inhibitor" as used
herein refers to compounds which target, decrease or inhibit the
activity of methionine aminopeptidase. Compounds which target,
decrease or inhibit the activity of methionine aminopeptidase
include, but are not limited to, bengamide or a derivative
thereof.
[0387] The term "proteasome inhibitor" as used herein refers to
compounds which target, decrease or inhibit the activity of the
proteasome. Compounds which target, decrease or inhibit the
activity of the proteasome include, but are not limited to,
Bortezomib (Velcade.TM.) and MLN 341.
[0388] The term "matrix metalloproteinase inhibitor" or ("MMP"
inhibitor) as used herein includes, but is not limited to, collagen
peptidomimetic and nonpeptidomimetic inhibitors, tetracycline
derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat
and its orally bioavailable analogue marimastat (BB-2516),
prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY
12-9566, TAA211, MMI270B or AAJ996.
[0389] The term "compounds used in the treatment of hematologic
malignancies" as used herein includes, but is not limited to,
FMS-like tyrosine kinase inhibitors, which are compounds targeting,
decreasing or inhibiting the activity of FMS-like tyrosine kinase
receptors (Flt-3R); interferon, 1-.beta.-D-arabinofuransylcytosine
(ara-c) and bisulfan; ALK inhibitors, which are compounds which
target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2
inhibitors.
[0390] Compounds which target, decrease or inhibit the activity of
FMS-like tyrosine kinase receptors (Flt-3R) are especially
compounds, proteins or antibodies which inhibit members of the
Flt-3R receptor kinase family, such as PKC412, midostaurin, a
staurosporine derivative, SU11248 and MLN518.
[0391] The term "HSP90 inhibitors" as used herein includes, but is
not limited to, compounds targeting, decreasing or inhibiting the
intrinsic ATPase activity of HSP90; degrading, targeting,
decreasing or inhibiting the HSP90 client proteins via the
ubiquitin proteosome pathway. Compounds targeting, decreasing or
inhibiting the intrinsic ATPase activity of HSP90 are especially
compounds, proteins or antibodies which inhibit the ATPase activity
of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG),
a geldanamycin derivative; other geldanamycin related compounds;
radicicol and HDAC inhibitors.
[0392] The term "antiproliferative antibodies" as used herein
includes, but is not limited to, trastuzumab (Herceptin.TM.),
Trastuzumab-DM1, erbitux, bevacizumab (Avastin.TM.), rituximab
(Rituxan.RTM.), PR064553 (anti-CD40) and 2C4 Antibody. By
antibodies is meant intact monoclonal antibodies, polyclonal
antibodies, multispecific antibodies formed from at least 2 intact
antibodies, and antibodies fragments so long as they exhibit the
desired biological activity.
[0393] For the treatment of acute myeloid leukemia (AML), compounds
of the current invention can be used in combination with standard
leukemia therapies, especially in combination with therapies used
for the treatment of AML. In particular, compounds of the current
invention can be administered in combination with, for example,
farnesyl transferase inhibitors and/or other drugs useful for the
treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,
Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412. In
some embodiments, the present invention provides a method of
treating AML associated with an ITD and/or D835Y mutation,
comprising administering a compound of the present invention
together with a one or more FLT3 inhibitors. In some embodiments,
the FLT3 inhibitors are selected from quizartinib (AC220), a
staurosporine derivative (e.g. midostaurin or lestaurtinib),
sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib,
NOV-110302, NMS-P948, AST-487, G-749, SB-1317, 5-209, SC-110219,
AKN-028, fedratinib, tozasertib, and sunitinib. In some
embodiments, the FLT3 inhibitors are selected from quizartinib,
midostaurin, lestaurtinib, sorafenib, and sunitinib.
[0394] Other anti-leukemic compounds include, for example, Ara-C, a
pyrimidine analog, which is the 2'-alpha-hydroxy ribose
(arabinoside) derivative of deoxycytidine. Also included is the
purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and
fludarabine phosphate. Compounds which target, decrease or inhibit
activity of histone deacetylase (HDAC) inhibitors such as sodium
butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the
activity of the enzymes known as histone deacetylases. Specific
HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228),
Trichostatin A and compounds disclosed in U.S. Pat. No. 6,552,065
including, but not limited to,
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]--
2E-2-propenamide, or a pharmaceutically acceptable salt thereof and
N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phe-
nyl]-2E-2-propenamide, or a pharmaceutically acceptable salt
thereof, especially the lactate salt. Somatostatin receptor
antagonists as used herein refer to compounds which target, treat
or inhibit the somatostatin receptor such as octreotide, and
SOM230. Tumor cell damaging approaches refer to approaches such as
ionizing radiation. The term "ionizing radiation" referred to above
and hereinafter means ionizing radiation that occurs as either
electromagnetic rays (such as X-rays and gamma rays) or particles
(such as alpha and beta particles). Ionizing radiation is provided
in, but not limited to, radiation therapy and is known in the art.
See Hellman, Principles of Radiation Therapy, Cancer, in Principles
and Practice of Oncology, Devita et al., Eds., 4.sup.th Edition,
Vol. 1, pp. 248-275 (1993).
[0395] Also included are EDG binders and ribonucleotide reductase
inhibitors. The term "EDG binders" as used herein refers to a class
of immunosuppressants that modulates lymphocyte recirculation, such
as FTY720. The term "ribonucleotide reductase inhibitors" refers to
pyrimidine or purine nucleoside analogs including, but not limited
to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,
5-fluorouracil, cladribine, 6-mercaptopurine (especially in
combination with ara-C against ALL) and/or pentostatin.
Ribonucleotide reductase inhibitors are especially hydroxyurea or
2-hydroxy-1H-isoindole-1,3-dione derivatives.
[0396] Also included are in particular those compounds, proteins or
monoclonal antibodies of VEGF such as
1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a
pharmaceutically acceptable salt thereof,
1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;
Angiostatin.TM.; Endostatin.TM.; anthranilic acid amides; ZD4190;
ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or
anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF
aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors,
VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab
(Avastin.TM.).
[0397] Photodynamic therapy as used herein refers to therapy which
uses certain chemicals known as photosensitizing compounds to treat
or prevent cancers. Examples of photodynamic therapy include
treatment with compounds, such as Visudyne.TM. and porfimer
sodium.
[0398] Angiostatic steroids as used herein refers to compounds
which block or inhibit angiogenesis, such as, e.g., anecortave,
triamcinolone, hydrocortisone, 11-.alpha.-epihydrocotisol,
cortexolone, 17.alpha.-hydroxyprogesterone, corticosterone,
desoxycorticosterone, testosterone, estrone and dexamethasone.
[0399] Implants containing corticosteroids refers to compounds,
such as fluocinolone and dexamethasone.
[0400] Other chemotherapeutic compounds include, but are not
limited to, plant alkaloids, hormonal compounds and antagonists;
biological response modifiers, preferably lymphokines or
interferons; antisense oligonucleotides or oligonucleotide
derivatives; shRNA or siRNA; or miscellaneous compounds or
compounds with other or unknown mechanism of action.
[0401] The compounds of the invention are also useful as
co-therapeutic compounds for use in combination with other drug
substances such as anti-inflammatory, bronchodilatory or
antihistamine drug substances, particularly in the treatment of
obstructive or inflammatory airways diseases such as those
mentioned hereinbefore, for example as potentiators of therapeutic
activity of such drugs or as a means of reducing required dosaging
or potential side effects of such drugs. A compound of the
invention may be mixed with the other drug substance in a fixed
pharmaceutical composition or it may be administered separately,
before, simultaneously with or after the other drug substance.
Accordingly the invention includes a combination of a compound of
the invention as hereinbefore described with an anti-inflammatory,
bronchodilatory, antihistamine or anti-tussive drug substance, said
compound of the invention and said drug substance being in the same
or different pharmaceutical composition.
[0402] Suitable anti-inflammatory drugs include steroids, in
particular glucocorticosteroids such as budesonide, beclomethasone
dipropionate, fluticasone propionate, ciclesonide or mometasone
furoate; non-steroidal glucocorticoid receptor agonists; LTB4
antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL
284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and
zafirlukast; PDE4 inhibitors such cilomilast (Ariflo.RTM.
GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp),
BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline
(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281
(Asta Medica), CDC-801 (Celgene), SeICID.TM.CC-10004 (Celgene),
VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko
Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenoceptor
agonists such as albuterol (salbutamol), metaproterenol,
terbutaline, salmeterol fenoterol, procaterol, and especially,
formoterol and pharmaceutically acceptable salts thereof. Suitable
bronchodilatory drugs include anticholinergic or antimuscarinic
compounds, in particular ipratropium bromide, oxitropium bromide,
tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.
[0403] Suitable antihistamine drug substances include cetirizine
hydrochloride, acetaminophen, clemastine fumarate, promethazine,
loratidine, desloratidine, diphenhydramine and fexofenadine
hydrochloride, activastine, astemizole, azelastine, ebastine,
epinastine, mizolastine and terfenadine.
[0404] Other useful combinations of compounds of the invention with
anti-inflammatory drugs are those with antagonists of chemokine
receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7,
CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,
particularly CCR-5 antagonists such as Schering-Plough antagonists
SC-351125, SCH-55700 and SCH-D, and Takeda antagonists such as
N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbony-
l]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium
chloride (TAK-770).
[0405] The structure of the active compounds identified by code
numbers, generic or trade names may be taken from the actual
edition of the standard compendium "The Merck Index" or from
databases, e.g. Patents International (e.g. IMS World
Publications).
[0406] A compound of the current invention may also be used in
combination with known therapeutic processes, for example, the
administration of hormones or radiation. In certain embodiments, a
provided compound is used as a radiosensitizer, especially for the
treatment of tumors which exhibit poor sensitivity to
radiotherapy.
[0407] A compound of the current invention can be administered
alone or in combination with one or more other therapeutic
compounds, possible combination therapy taking the form of fixed
combinations or the administration of a compound of the invention
and one or more other therapeutic compounds being staggered or
given independently of one another, or the combined administration
of fixed combinations and one or more other therapeutic compounds.
A compound of the current invention can besides or in addition be
administered especially for tumor therapy in combination with
chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical
intervention, or a combination of these. Long-term therapy is
equally possible as is adjuvant therapy in the context of other
treatment strategies, as described above. Other possible treatments
are therapy to maintain the patient's status after tumor
regression, or even chemopreventive therapy, for example in
patients at risk.
[0408] Those additional agents may be administered separately from
an inventive compound-containing composition, as part of a multiple
dosage regimen. Alternatively, those agents may be part of a single
dosage form, mixed together with a compound of this invention in a
single composition. If administered as part of a multiple dosage
regime, the two active agents may be submitted simultaneously,
sequentially or within a period of time from one another normally
within five hours from one another.
[0409] As used herein, the term "combination," "combined," and
related terms refers to the simultaneous or sequential
administration of therapeutic agents in accordance with this
invention. For example, a compound of the present invention may be
administered with another therapeutic agent simultaneously or
sequentially in separate unit dosage forms or together in a single
unit dosage form. Accordingly, the present invention provides a
single unit dosage form comprising a compound of the current
invention, an additional therapeutic agent, and a pharmaceutically
acceptable carrier, adjuvant, or vehicle.
[0410] The amount of both an inventive compound and additional
therapeutic agent (in those compositions which comprise an
additional therapeutic agent as described above) that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Preferably, compositions of this invention
should be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of an inventive compound can be administered.
[0411] In those compositions which comprise an additional
therapeutic agent, that additional therapeutic agent and the
compound of this invention may act synergistically. Therefore, the
amount of additional therapeutic agent in such compositions will be
less than that required in a monotherapy utilizing only that
therapeutic agent. In such compositions a dosage of between
0.01-1,000 .mu.g/kg body weight/day of the additional therapeutic
agent can be administered.
[0412] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0413] The compounds of this invention, or pharmaceutical
compositions thereof, may also be incorporated into compositions
for coating an implantable medical device, such as prostheses,
artificial valves, vascular grafts, stents and catheters. Vascular
stents, for example, have been used to overcome restenosis
(re-narrowing of the vessel wall after injury). However, patients
using stents or other implantable devices risk clot formation or
platelet activation. These unwanted effects may be prevented or
mitigated by pre-coating the device with a pharmaceutically
acceptable composition comprising a kinase inhibitor. Implantable
devices coated with a compound of this invention are another
embodiment of the present invention.
EXEMPLIFICATION
[0414] As depicted in the Examples below, in certain exemplary
embodiments, compounds are prepared according to the following
general procedures. It will be appreciated that, although the
general methods depict the synthesis of certain compounds of the
present invention, the following general methods, and other methods
known to one of ordinary skill in the art, can be applied to all
compounds and subclasses and species of each of these compounds, as
described herein.
Example 1. Synthesis of
N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-ox-
o-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-1
##STR00355## ##STR00356##
[0416] Synthesis of compound 1.2. To a solution of 1.1 (50 g, 253.6
mmol, 1.0 eq) in DMF (500 mL), was added K.sub.2CO.sub.3 (70 g,
507.6 mmol, 2.0 eq) at 0.degree. C. and stirred for 15 min. To the
suspension was added Mel (72 g, 507.6 mmol, 2.0 eq) dropwise and
reaction mixture was stirred at 60.degree. C. for 2 h. After
completion of the reaction, reaction mixture was transferred into
ice-water. Precipitated product was filtered, dried to provide 1.2
(50.0 g, 93.0%). MS(ES): m/z 212.2 [M+H].sup.+.
[0417] Synthesis of compound 1.3. To 1.2 (50 g, 236.7 mmol, 1.0 eq)
was added aq. NH40H (300 mL) followed by methanolic NH.sub.3 (1600
mL). Reaction mixture was stirred at room temperature for 16 h.
After completion of the reaction, reaction mixture was concentrated
under reduced pressure and residue was washed with ice cold water.
Precipitate was dried to furnish 1.3 (45.0 g, 96.0%). MS(ES): m/z
197.2 [M+H].sup.+.
[0418] Synthesis of compound 1.4. To a suspension of NaN.sub.3
(21.8 g, 336 mmol, 3.0 eq) in acetonitrile (220 mL) was added
SiCl.sub.4 (28.6 g, 168 mmol, 1.5 eq). To the stirred suspension
was added compound 1.3 (22.0 g, 112 mmol, 1.0 eq) and the reaction
mixture was stirred at 75.degree. C. for 16 h. Reaction mixture was
cooled to room temperature and water was added. Solid precipitated
out was filtered to provide 1.4 (18.0 g, 72.5%). MS(ES): m/z 222.2
[M+H].sup.+.
[0419] Synthesis of compound 1.5. To a stirred solution of 1.4
(15.0 g, 67.8 mmol, 1.0 eq) in DMF (150 mL) was added
K.sub.2CO.sub.3 (23.4 g, 169.7 mmol, 2.5 eq) at 0.degree. C. To
this added Mel (19.1 g, 135.7 mmol, 2.0 eq) dropwise. Reaction
mixture was stirred at room temperature for 24 h. After completion
of the reaction, mixture was transferred into water and extracted
with EtOAc. Organic layers were combined, washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
pressure to obtain crude material. The crude was purified by column
chromatography to provide desired regioisomer 1.5 (10.0 g, 62.7%).
MS(ES): m/z 236.2 [M+H].sup.+.
[0420] Synthesis of compound 1.6. To a solution of 1.5 (10.0 g,
42.5 mmol, 1.0 eq) in MeOH (100 mL), 10% Pd/C (2.0 g) was added.
Hydrogen was purged through reaction mixture for 4 h. After
completion of the reaction, mixture was filtered through Celite-bed
and washed with MeOH. Filtrate was concentrated under reduced
pressure to obtain 1.6. (5.3 g, 60.7%). MS(ES): m/z 206.3
[M+H].sup.+.
[0421] Synthesis of compound 1.8. To 1.7 (1.0 g, 4.42 mmol, 1.0 eq)
was added SOCl.sub.2 (5.0 mL) followed by DMF (catalytic) and
refluxed for 16 h. Reaction mixture was concentrated under reduced
pressure to obtain acyl chloride. Methyl hydrazine (0.20 g, 42.5
mmol, 1.0 eq) was dissolved in CH.sub.2Cl.sub.2 (20.0 mL) followed
by addition of solution of NaOH (0.72 g, 177 mmol, 4.0 eq) in water
(5.0 mL). To the solution was added previously made acyl chloride
solution in CH.sub.2C12 (20.0 mL) dropwise. Reaction mixture was
refluxed for 15 min. After completion of reaction, reaction mixture
was transferred into water and extracted with CH.sub.2Cl.sub.2.
Organic layers were combined, washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to
pressure to obtain crude which was purified by column
chromatography to provide 1.8. (1.1 g, 97.0%). MS(ES): m/z 255.5
[M+H].sup.+.
[0422] Synthesis of compound 1.9. To a suspension of 1.8 (1.0 g,
3.93 mmol, 1.0 eq) in 1-pentanol (15.0 mL) was added
Na.sub.2CO.sub.3 (0.49 g, 3.93 mmol, 1.0 eq) and reaction mixture
was stirred at 120.degree. C. for 16 h. After completion of the
reaction, reaction mixture was cooled to room temperature and
pH=6.0 was adjusted using 1 N HCl. Reaction mixture was
concentrated under reduced pressure to obtain crude which was
purified by preparative HPLC to furnish 1.9. (0.15 g, 17.5%).
MS(ES): m/z 219.2 [M+H].sup.+.
[0423] Synthesis of compound 1.91. To a solution of 1.9 (0.1 g,
0.45 mmol, 1.0 eq) and 1.6 (0.188 g, 0.917 mmol, 2.0 eq) in THE
(2.0 mL) was added 1.0 M solution of LHMDS (1.6 mL, 1.57 mmol, 3.5
eq) in tetrahydrofuran at -78.degree. C. Reaction mixture was
stirred at room temperature for 18 h. After completion of the
reaction, reaction mixture was transferred into water and extracted
with EtOAc. Aqueous layer was acidified with 1.0 N HCl and
extracted with EtOAc. Organic layers were combined, washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to pressure to get pure 1.91. (0.1 g, 56.37%). MS(ES): m/z
387.9 [M+H].sup.+.
[0424] Synthesis of compound I-1. To 1.91 (0.020 g, 0.051 mmol, 1.0
eq) in DMA (0.5 mL) was added cyclopropanecarboxamide (0.005 g,
0.062 mmol, 1.2 eq), Cs.sub.2CO.sub.3 (0.033 g, 0.102 mmol, 2.0
eq). The reaction mixture was degassed for 10 min. under argon
atmosphere, then Pd.sub.2(dba).sub.3 (0.005 g, 0.005 mmol, 0.1 eq)
and Xantphos (0.006 g, 0.01 mmol, 0.2 eq) were added. Suspension
was degassed for additional 5 minutes. The reaction was then heated
at 130.degree. C. for 5 hours. After completion of the reaction,
reaction mixture was diluted with CH.sub.2C12(1 mL) and pass
through silica plug column using 10% methanol in CH.sub.2Cl.sub.2
as eluent. Obtained fractions were combined and concentrated under
reduced pressure to obtain crude material. This was further
purified by reverse phase HPLC to obtain I-1 (0.005 g, 22.2%).
MS(ES): m/z 436.6 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz):
8.92 (s, 1H), 7.79-7.77 (d, 1H), 7.67-7.66 (d, 1H), 7.45-7.40 (m,
1H), 4.45 (s, 3H), 3.88 (s, 3H), 3.47 (s, 3H), 1.69-1.59 (m, 1H),
1.13-1.12 (m, 2H), 0.91-0.90 (m, 2H).
Example 2. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-6-((4-(methoxyme-
thyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3--
one I-2
##STR00357##
[0426] To compound 1.91 (0.040 g, 0.103 mmol, 1.0 eq) in DMF (1.0
ml) was added 4-(methoxymethyl)pyridin-2-amine (0.021 g, 0.155
mmol, 1.5 eq), and K.sub.3PO.sub.4 (0.043 g, 0.206 mmol, 2.0 eq).
The reaction mixture was degassed for 10 minutes using argon, then
[(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-ami-
no-1,1'-biphenyl)]palladium(II)methanesulfonate (0.008 g, 0.01
mmol, 0.1 eq) was added. Suspension was degassed for additional
five minutes. The reaction was stirred at 50.degree. C. for 15 min.
After completion of the reaction, mixture was diluted with
CH.sub.2Cl.sub.2 (1.0 mL) and pass through silica plug column using
8% methanol in CH.sub.2Cl.sub.2 as eluent. Obtained fractions were
combined and concentrated under reduced pressure to obtain crude
which was purified by reverse phase HPLC to obtain I-2 (0.008 g,
15.84%). MS(ES): m/z 489.75 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3,
400 MHz): 9.27 (s, 1H), 8.95 (s, 1H), 8.14-8.12 (d, 1H), 7.70-7.68
(d, 1H), 7.41-7.39 (d, 1H), 7.11-7.08 (t, 1H), 7.00 (s, 1H),
6.89-6.88 (d, 1H), 4.43 (s, 3H), 3.78 (s, 3H), 3.65 (s, 2H), 3.57
(s, 3H), 3.43 (s, 3H).
Example 3. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-m-
ethylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-3
##STR00358##
[0428] Compound I-3 was prepared from compound 1.91 and
5-methylpyridin-2-amine using procedure described in Example 2.
MS(ES): m/z 459.64 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 400
MHz): 10.68 (s, 2H), 9.76 (s, 1H), 8.93 (s, 1H), 8.11 (s, 1H),
7.79-7.77 (d, 1H), 7.65-7.57 (m, 2H), 7.42-7.38 (m, 1H), 7.2 (s,
1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.29 (s, 3H), 2.24 (s, 3H).
Example 4. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-(pyri-
din-2-ylamino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-4
##STR00359##
[0430] Compound I-4 was prepared from compound 1.91 and
pyridin-2-amine using procedure described in Example 2. MS(ES): m/z
445.68 [M+H].sup.+ 1H NMR (DMSO-d.sub.6, 400 MHz): 9.97 (s, 1H),
8.95 (s, 1H), 8.27-8.26 (d, 1H), 8.16 (s, 1H), 7.89 (s, 1H),
7.80-7.78 (d, 1H), 7.74-7.71 (m, 1H), 7.65-7.63 (d, 1H), 7.42-7.38
(t, 1H), 6.97-6.94 (t, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.29 (s,
3H).
Example 5. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((4-m-
ethylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-5
##STR00360##
[0432] Compound I-5 was prepared from compound 1.91 and
4-methylpyridin-2-amine using procedure described in Example 2.
MS(ES): m/z 459.7 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
9.98 (s, 1H), 8.96 (s, 1H), 8.17 (s, 1H), 8.14-8.13 (d, 1H),
7.79-7.77 (d, 1H), 7.65-7.63 (d, 1H), 7.42-7.38 (t, 1H), 6.82-6.81
(d, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H), 2.30 (s,
3H).
Example 6. Synthesis of
6-((4-(hydroxymethyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tet-
razol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3--
one, I-6
##STR00361##
[0434] Compound I-6 was prepared from compound 1.91 and
(2-aminopyridin-4-yl)methanol using procedure described in Example
2. MS(ES): m/z 475.58 [M+H].sup.+; .sup.1H NMR (DMSO-d.sub.6, 400
MHz): 10.01 (s, 1H), 8.97 (s, 1H), 8.20-8.19 (d, 1H), 8.17 (s, 1H),
7.79-7.77 (d, 1H), 7.66-7.64 (d, 1H), 7.42-7.38 (t, 1H), 6.92-6.90
(d, 1H), 5.42 (s, 1H), 4.52 (s, 2H), 4.47 (s, 3H), 3.79 (s, 3H),
3.30 (s, 3H).
Example 7. Synthesis of
N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-ox-
o-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-14
##STR00362## ##STR00363##
[0436] Compound 1.92 was prepared according to the procedure used
for 1.91. Compound I-14 was prepared from compound 1.91 and
cyclopropanecarboxamide using procedure described in Example 2.
(Yield: 22.2%). MS(ES): m/z 436.6 [M+H].sup.+, LCMS purity: 96%,
HPLC purity: 91%, .sup.1H NMR (CDCl.sub.3, 400 MHZ): 8.92 (s, 1H),
7.79-7.77 (d, J=8 Hz, 1H), 7.67-7.66 (d, J=7.2 Hz, 1H), 7.45-7.40
(m, 1H), 4.45 (s, 3H), 3.88 (s, 3H), 3.47 (s, 3H), 1.69-1.59 (m,
1H), 1.13-1.12 (m, 2H), 0.91-0.90 (m, 2H).
Example 13. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-m-
orpholinopyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-7
##STR00364##
[0438] Compound I-7 was prepared from compound 1.91 and
5-morpholinopyridin-2-amine using procedure described in Example 2
(Yield: 8.76%). MS(ES): m/z 530.81 [M+H]+, LCMS purity: 100%, HPLC
purity: 98.59%, 1H NMR (DMSO-d6, 400 MHZ): 9.79-9.75 (bs, 2H), 8.94
(s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.78-7.76 (d, J=8 Hz, 1H),
7.64-7.63 (d, J=7.6 Hz, 1H), 7.46-7.38 (m, 3H), 4.47 (s, 3H), 3.79
(s, 3H), 3.77-3.74 (t, 4H), 3.29 (s, 3H), 3.10-3.08 (t, 4H).
Example 14. Synthesis of
6-((5-fluoro-4-methylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tet-
razol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3--
one, I-8
##STR00365##
[0440] Compound I-8 was prepared from compound 1.91 and
5-fluoro-4-methylpyridin-2-amine using procedure described in
Example 2 (Yield: 16.24%). MS(ES): m/z 477.43 [M+H]+, LCMS purity:
99.71%, HPLC purity: 99.14%, 1H NMR (DMSO-d6, 400 MHZ): 9.87 (s,
1H), 8.92 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.94 (s, 1H),
7.78-7.76 (d, J=8 Hz, 1H), 7.64-7.62 (d, J=7.2 Hz, 1H), 7.42-7.38
(t, 1H), 6.96 (s, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H),
2.28 (s, 3H).
Example 15. Synthesis of
6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetraz-
ol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one-
, I-9
##STR00366##
[0442] Compound I-9 was prepared from compound 1.91 and
2,6-dimethylpyrimidin-4-amine using procedure described in Example
2 (Yield: 11.98%). MS(ES): m/z 474.58 [M+H]+, LCMS purity: 99.76%,
HPLC purity: 96.42%, 1H NMR (MeOD, 400 MHZ): 8.34-8.29 (bs, 2H),
7.86-7.84 (d, J=7.6 Hz, 1H), 7.73-7.71 (d, J=8 Hz, 1H), 7.41-7.37
(t, 1H), 6.89 (s, 1H), 6.25 (s, 1H), 4.48 (s, 3H), 3.85 (s, 3H),
3.53 (s, 3H), 2.64 (s, 3H), 2.42 (s, 3H).
Example 16. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((6-m-
ethylpyridazin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-10
##STR00367##
[0444] Compound I-10 was prepared from compound 1.91 and
6-methylpyridazin-3-amine using procedure described in Example 2
(Yield: 14.03%). m/z 460.43 [M+H]+, LCMS purity: 98.69%, HPLC
purity: 98.00%, 1H NMR (DMSO-d6, 400 MHZ): 10.23 (bs, 1H), 8.93 (s,
1H), 8.29-8.27 (d, J=8.8 Hz, 1H), 8.16 (s, 1H), 7.79-7.77 (d, J=8
Hz, 1H), 7.65-7.64 (d, J=7.2 Hz, 1H), 7.50-7.48 (d, J=9.2 Hz, 1H),
7.40-7.36 (t, J=8 Hz, 1H), 6.99 (bs, 1H), 4.47 (s, 3H), 3.80 (s,
3H), 3.30 (s, 3H), 2.53 (s, 3H).
Example 17. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-(-
piperidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-
-one, I-11
##STR00368##
[0446] Compound I-11 was prepared from compound 1.91 and
5-(piperidin-1-yl)pyridin-2-amine using procedure described in
Example 2 (Yield: 9.78%). MS(ES): m/z 528.68 [M+H]+, LCMS purity:
96.10%, HPLC purity: 98.65%, 1H NMR (CDCl3, 400 MHZ): 9.76 (bs,
1H), 8.89 (s, 1H), 7.71 (s, 1H), 7.66-7.64 (d, J=7.2 Hz, 1H), 7.28
(s, 1H), 7.03-7.00 (m, 2H), 5.72 (s, 1H), 4.40 (s, 3H), 3.77 (s,
3H), 3.54 (s, 3H), 3.17-3.03 (m, 4H), 2.63 (s, 1H), 1.72 (s, 4H),
1.60-1.59 (d, 2H).
Example 18. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-(-
pyrrolidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin--
3-one, I-58
##STR00369##
[0448] Compound I-58 was prepared from compound 1.91 and
5-(pyrrolidin-1-yl)pyridin-2-amine using procedure described in
Example 2 (Yield: 11.08%), MS(ES): m/z 514.46 [M+H]+, LCMS purity:
96.444, PLC purity: 97.390, 1H NMR (DMSO-d6, 400 MHz): 9.96 (s,
1H), 8.68 (s, 1H), 7.72-7.621 (m, 3H), 7.51 (s, 2H), 7.24-6.98 (m,
2H), 6.40 (s, 1H), 4.50 (s, 3H), 3.68 (s, 4H), 3.45 (s, 3H), 3.25
(s, 3H), 1.98 (s, 4H).
Example 19. Synthesis of
6-((5-cyclopropylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazo-
l-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-59
##STR00370##
[0450] Compound I-59 was prepared from compound 1.91 and
5-cyclopropylpyridin-2-amine using procedure described in Example 2
(Yield: 23.28%), MS(ES): m/z 485.53 [M+H]+, LCMS purity: 98.26%,
HPLC purity: 97.44%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s, 1H), 9.74
(s, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 7.95-7.93 (d, J=6.8 Hz, 1H),
7.81-7.79 (d, J=7.6 Hz, 1H), 7.63-7.61 (d, J=7.2 Hz, 1H), 7.43-7.36
(m, 2H), 7.18 (s, 1H), 4.48 (s, 3H), 3.79 (s, 3H), 3.16 (s, 3H),
1.89 (s, 1H), 0.94-0.93 (d, J=6.8 Hz, 2H), 0.69-0.68 (d, J=6.8 Hz,
2H).
Example 20. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((6-(-
trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin--
3-one, I-60
##STR00371##
[0452] 1.91 I-60
[0453] Compound I-60 was prepared from compound 1.91 and
6-(trifluoromethyl)pyridin-2-amine using procedure described in
Example 2 (Yield:39.25%), MS(ES): m/z 513.43 [M+H]+, LCMS purity:
99.01%, HPLC purity: 98.84%, 1H NMR (DMSO-d6, 400 MHz): 10.85 (s,
1H), 10.29 (s, 1H), 9.06 (s, 1H), 8.13-8.11 (d, J=8.8 Hz, 1H),
7.98-7.94 (t, J=8.0 Hz, 1H), 7.82-7.79 (d, J=8.0 Hz, 1H), 7.65-7.64
(d, J=6.8 Hz, 1H), 7.48 (s, 1H), 7.40-7.33 (m, 2H), 4.48 (s, 3H),
3.80 (s, 3H), 3.32 (s, 3H).
Example 21. Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-6-((6-(3-methoxy-
azetidin-1-yl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]p-
yridin-3-one, I-63
##STR00372##
[0455] Compound I-63 was prepared from compound 1.91 and
6-(3-methoxyazetidin-1-yl)pyridin-2-amine using procedure described
in Example 2 (Yield: 19.48%), MS(ES): m/z 530.40 [M+H]+, LCMS
purity: 100.00%, HPLC purity: 98.25%, 1H NMR (CDCl3, 400 MHz): 9.49
(bs, 1H), 8.98 (s, 1H), 7.68-7.66 (d, J=6.8 Hz, 1H), 7.38-7.34 (t,
J=8.0 Hz, 2H), 7.05-7.01 (t, J=8.0 Hz, 1H), 6.26-6.24 (d, J=7.2 Hz,
1H), 5.88-5.86 (d, J=8.0 Hz, 1H), 5.73 (bs, 1H), 4.40 (s, 3H),
4.37-4.32 (m, 1H), 4.29-4.25 (m, 2H), 3.96-3.93 (m, 2H), 3.78 (s,
3H), 3.51 (s, 3H), 3.36 (s, 3H).
Example 22. Synthesis of
6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-o-
xo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitril-
e, I-64
##STR00373##
[0457] Compound I-64 was prepared from compound 1.91 and
6-aminopyrazine-2-carbonitrile using procedure described in Example
2 (Yield: 20.55%), MS(ES): m/z 471.48 [M+H]+, LCMS purity: 100.00%,
HPLC purity: 98.79%, 1H NMR (DMSO-d6, 400 MHz): 10.96 (s, 1H),
10.66 (s, 1H), 9.36 (s, 1H), 9.01 (s, 1H), 8.66 (s, 1H), 7.83-7.81
(d, J=8.0 Hz, 1H), 7.68-7.66 (dd, J=1.2 Hz, 8.0 Hz, 1H), 7.44-7.42
(d, J=8.0 Hz, 1H), 7.40-7.38 (d, J=8.0 Hz, 1H), 4.47 (s, 3H), 3.80
(s, 3H), 3.43 (s, 3H).
Example 23. Synthesis of
6-((6-cyclopropylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazo-
l-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-65
##STR00374##
[0459] Compound I-65 was prepared from compound 1.91 and
6-cyclopropylpyridin-2-amine using procedure described in Example 2
(Yield: 7.98%), MS(ES): m/z 485.53 [M+H]+, LCMS purity: 96.64%,
HPLC purity: 96.85%, 1H NMR (DMSO-d6, 400 MHz): 11.42 (s, 1H), 9.09
(s, 1H), 7.93 (s, 1H), 7.81-7.79 (d, J=6.4 Hz, 1H), 7.66-7.64 (d,
J=6.4 Hz, 1H), 7.41 (s, 1H), 7.09-7.07 (d, J=7.2 Hz, 1H), 6.98-6.96
(d, J=7.2 Hz, 1H), 6.02 (s, 1H), 4.44 (s, 3H), 3.74 (s, 3H), 3.48
(s, 3H), 2.28 (s, 1H), 1.26 (s, 2H), 1.09 (s, 2H).
Example 24. Synthesis of
N-ethyl-6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-me-
thyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinamide,
I-66
##STR00375##
[0461] Compound I-66 was prepared from compound 1.91 and
6-amino-N-ethylpicolinamide using procedure described in Example 2
(Yield: 12.50%), MS(ES): m/z 516.41 [M+H]+, LCMS purity: 96.85%,
HPLC purity: 95.48%, 1H NMR (MeOD, 400 MHz): 8.18 (s, 1H),
7.91-7.86 (t, 1H), 7.82-7.80 (d, J=8.0 Hz, 1H), 7.74-7.72 (m, 1H),
7.68-7.67 (d, 1H), 7.39-7.35 (t, J=8.0 Hz, 1H), 6.19 (s, 1H), 4.48
(s, 3H), 3.84 (s, 3H), 3.53 (s, 3H), 3.52-3.46 (q, J=7.2 Hz, 2H),
1.28-1.25 (t, J=7.2 Hz, 3H).
Example 26. Synthesis of
4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-6--
((5-methylpyridin-2-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one,
I-16
##STR00376##
[0463] Compound I-16 was prepared from compound 1.92 and
5-methylpyridin-2-amine using procedure described in Example 2
(Yield: 19.68%). MS (ES): m/z 458.2 [M+H]+, LCMS purity: 99.65%,
HPLC purity: 99.81%, 1H NMR (DMSO-d6, 400 MHZ): 10.67 (s, 1H), 9.76
(s, 1H), 8.93 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H),
7.68-7.66 (d, J=8 Hz, 1H), 7.59-7.57 (m, 2H), 7.32-7.18 (m, 1H),
3.96 (s, 3H), 3.78 (s, 3H), 3.29 (s, 3H), 2.23 (s, 3H).
Example 27. Synthesis of
6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methy-
l-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile,
I-25
##STR00377##
[0465] Compound I-25 was prepared from compound 1.92 and
6-aminonicotinonitrile using procedure described in Example 2
(Yield: 12.08%). MS (ES): m/z 469.7 [M+H]+, LCMS purity: 99.49%,
HPLC purity: 99.22%, 1H NMR (DMSO-d6, 400 MHZ): 10.39 (s, 1H), 8.95
(s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.25-8.23 (m, 1H), 8.14-8.11
(m, 1H), 7.68-7.66 (d, J=7.2 Hz, 1H), 7.60-7.58 (d, J=8 Hz, 1H),
7.33-7.29 (m, 1H), 7.10 (s, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.31
(s, 3H).
Example 28. Synthesis of
4-((4-chloro-2-methoxyphenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)ami-
no)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-42
##STR00378##
[0467] Synthesis of compound 28.1. Following the procedure used to
prepare 1.91, 28.1 was obtained (Yield: 24%). MS (ES): m/z 340.2
[M+H]+.
[0468] Compound I-42 was prepared from compound 28.1 and
4-methylpyridin-2-amine using procedure described in Example 2
(Yield: 12.53%), MS(ES): m/z 411.52 [M+H]+, LCMS purity: 100.00%,
HPLC purity: 98.32%, 1H NMR (MeOD, 400 MHZ): 8.18-8.17 (d, J=5.2
Hz, 1H), 7.47-7.45 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 7.08-7.06 (d,
J=8.0 Hz, 1H), 6.96-6.94 (d, J=4.8 Hz, 1H), 6.79 (s, 1H), 5.69 (s,
1H), 3.98 (s, 3H), 3.53 (s, 3H), 2.37 (s, 3H).
Example 29. Synthesis of
N-(4-((4-(hydroxymethyl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydr-
o-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-42
##STR00379##
[0470] Synthesis of compound 29.1. Following the procedure used to
prepare 1.91, 29.1 was obtained (Yield: 57.32%). MS (ES): m/z 335.8
[M+H]+.
[0471] Compound I-42 was prepared from compound 29.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield:17.46%), MS(ES): m/z 384.51 [M+H]+, LCMS purity: 95.04%,
HPLC purity: 93.08%, 1H NMR (DMSO-d6, 400 MHZ): 10.67-10.64 (d,
J=1.2 Hz, 2H), 8.41 (s, 1H), 7.64 (s, 1H), 7.38-7.36 (d, J=8.0 Hz,
1H), 7.09 (s, 1H), 6.96-6.94 (d, J=8.0 Hz, 1H), 5.24 (t, J=8.0 Hz,
1H), 4.51-4.49 (d, J=8.0 Hz, 2H), 3.85 (s, 3H), 3.19 (s, 3H), 1.99
(s, 1H), 0.79 (s, 4H).
Example 30. Synthesis of
N-(4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydr-
o-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-45
##STR00380##
[0473] Synthesis of compound 30.1. Following the procedure used to
prepare 1.91, 30.1 was obtained (Yield: 57.51%). MS (ES): m/z 349.8
[M+H]+.
[0474] Compound I-45 was prepared from compound 30.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 23.4%), MS(ES): m/z 398.38 [M+H]+, LCMS purity: 96.46%,
HPLC purity: 95.23%, 1H NMR (DMSO-d6, 400 MHZ): 10.70-10.67 (d,
J=12.4 Hz, 2H), 8.49 (s, 1H), 7.68 (s, 1H), 7.41-7.39 (d, J=8.0 Hz,
1H), 7.07 (s, 1H), 6.96-6.94 (d, J=8.4 Hz, 1H), 4.40 (s, 2H), 3.85
(s, 3H), 3.35 (s, 3H), 3.29 (s, 3H), 1.99 (s, 1H), 0.79-0.78 (d,
J=3.6 Hz, 4H).
Example 31. Synthesis of
N-(4-((3-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-2-methoxyphenyl)amino)-2-me-
thyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxam-
ide, I-46
##STR00381##
[0476] Synthesis of compound 31.1. Following the procedure used to
prepare 1.91, 31.1 was obtained (Yield: 49.08%). MS (ES): m/z 400.7
[M+H]+.
[0477] Compound I-46 was prepared from compound 31.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 5.45%), MS(ES): m/z 449.37 [M+H]+, LCMS purity: 95.95%,
HPLC purity: 97.22%, 1H NMR (MeOD, 400 MHZ): 7.79-7.77 (d, J=8.0
Hz, 1H), 7.43-7.34 (m, 3H), 3.77 (s, 3H), 3.56 (s, 3H), 3.49 (s,
3H), 2.41 (s, 3H), 1.84 (s, 1H), 1.02-0.90 (m, 4H).
Example 32. Synthesis of
4-((2-methoxy-3-(5-methylthiazol-2-yl)phenyl)amino)-2-methyl-6-((4-methyl-
pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-47
##STR00382##
[0479] Synthesis of compound 32.1. Following the procedure used to
prepare 1.91, 32.1 was obtained (Yield: 21.10%). MS (ES): m/z 402.7
[M+H]+.
[0480] Compound I-47 was prepared from compound 32.1 and
4-methylpyridin-2-amine using procedure described in Example 2
(Yield: 27.88%), MS(ES): m/z 474.48 [M+H]+, LCMS purity: 97.47%,
HPLC purity: 95.33%, 1H NMR (CDCl3, 400 MHZ): 8.71 (s, 1H),
8.10-8.09 (d, J=4.8 Hz, 1H), 7.76 (s, 1H), 7.55-7.53 (d, J=8.0 Hz,
1H), 7.46 (s, 1H), 7.35-7.33 (d, J=8.0 Hz, 1H), 6.96-6.92 (d, J=8.0
Hz, 1H), 6.75 (s, 2H), 3.39 (s, 6H), 2.55 (s, 3H), 2.37 (s,
3H).
Example 33. Synthesis of
N-(4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyra-
zolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-48
##STR00383##
[0482] Synthesis of compound 33.1. Following the procedure use to
prepare 1.91, 33.1 was obtained (Yield: 54.05%). MS (ES): m/z 323.7
[M+H]+.
[0483] Compound I-48 was prepared from compound 33.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 18.47%), MS(ES): m/z 372.33 [M+H]+, LCMS purity: 98.91%,
HPLC purity: 95.67%, 1H NMR (DMSO-d6, 400 MHZ): 10.79 (s, 1H), 8.83
(s, 1H), 8.17 (s, 1H), 7.75 (s, 1H), 7.32-7.30 (d, J=8.0 Hz, 1H),
7.21-7.15 (m, 1H), 7.06-7.03 (d, J=10.0 Hz, 1H), 3.88 (s, 3H), 3.31
(s, 3H), 2.03-2.01 (t, J=5.6 Hz, 1H), 0.81-0.81 (d, J=5.6 Hz,
4H).
Example 34. Synthesis of
N-(4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyra-
zolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-49
##STR00384##
[0485] Following the procedure used to prepare 1.91, 34.1 was
obtained (Yield: 47.14%). MS (ES): m/z 340.2 [M+H]+.
[0486] Compound I-49 was prepared from compound 34.1 and
cyclopropanecarboxamide using procedure described in Example 2.
(Yield: 39.36%), MS(ES): m/z 388.13 [M+H]+, LCMS purity: 99.46%,
HPLC purity: 98.93%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (s, 2H), 8.84
(s, 1H), 7.74 (bs, 1H), 7.46-7.43 (t, J=4.8 Hz, 1H), 7.22-7.20 (d,
J=4.8 Hz, 2H), 3.77 (s, 3H), 3.29 (s, 3H), 1.98 (s, 1H), 0.77 (s,
4H).
Example 35: Synthesis of
N-(4-((4-cyclopropyl-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-
-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-50
##STR00385##
[0488] Following the procedure used to prepare 1.91, 35.1 was
obtained (Yield: 54.80%). MS (ES): m/z 345.7 [M+H]+.
[0489] Compound I-50 was prepared from compound 35.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 16.18%), MS(ES): m/z 394.61 [M+H]+, LCMS purity: 94.66%,
HPLC purity: 99.76%, 1H NMR (DMSO-d6, 400 MHz): 10.67-10.62 (d,
J=17.6 Hz, 2H), 8.36 (s, 1H), 7.58 (bs, 1H), 7.29-7.268 (d, J=8.0
Hz, 1H), 6.83-6.83 (d, J=1.6 Hz, 1H), 6.72-6.69 (dd, J=1.6 Hz, 8.0
Hz, 1H), 3.83 (s, 3H), 3.28 (s, 3H), 2.01-1.90 (m, 2H), 0.96-0.90
(m, 2H), 0.79-0.77 (d, J=5.2 Hz, 4H), 0.74-0.72 (dd, J=3.2 Hz, 4.8
Hz, 2H).
Example 36: Synthesis of
N-(4-((4-cyclobutyl-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H--
pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-51
##STR00386##
[0491] Following the procedure used to prepare 1.91, 36.1 was
obtained (Yield: 50.64%). MS (ES): m/z 359.8 [M+H]+.
[0492] Compound I-51 was prepared from compound 36.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 42.27%), MS(ES): m/z 408.37 [M+H]+, LCMS purity: 96.20%,
HPLC purity: 96.45%, 1H NMR (DMSO-d6, 400 MHz): 10.67-10.63 (d,
J=17.2 Hz, 2H), 8.41 (s, 1H), 7.64 (s, 1H), 7.35-7.33 (d, J=8.0 Hz,
1H), 6.97 (s, 1H), 6.88-6.87 (d, J=8.0 Hz, 1H), 3.85 (s, 3H),
3.54-3.48 (q, J=8.8 Hz, 1H), 3.28 (s, 3H), 2.33-2.25 (m, 2H),
2.19-2.09 (m, 2H), 2.02-1.93 (m, 2H), 1.85-1.80 (m, 1H), 0.79-0.78
(d, J=5.2 Hz, 4H).
Example 37: Synthesis of
N-(4-((2-methoxy-3-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-ox-
o-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-52
##STR00387##
[0494] Following the procedure used to prepare 1.91, 37.1 was
obtained (Yield: 68.77%). MS (ES): m/z 387.7 [M+H]+.
[0495] Compound I-52 was prepared from compound 37.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 22.21%), MS(ES): m/z 436.37 [M+H]+, LCMS purity: 97.49%,
HPLC purity: 94.04%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (s, 1H), 8.82
(s, 1H), 8.19 (s, 1H), 7.75-7.73 (d, J=7.6 Hz, 1H), 7.65 (s, 1H),
7.4467.40 (t, J=7.6 Hz, 1H), 7.36-7.34 (d, J=6.4 Hz, 1H), 3.99 (s,
3H), 3.47 (s, 3H), 2.61 (s, 3H), 2.03-2.00 (t, J=6.0 Hz, 1H),
0.81-0.79 (d, J=6.0 Hz, 4H).
Example 38: Synthesis of
N-(4-((3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-2-me-
thyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxam-
ide, I-53
##STR00388##
[0497] Following the procedure used to prepare 1.91, 38.1 was
obtained (Yield: 68.16%). MS (ES): m/z 400.8 [M+H]+.
[0498] Compound I-53 was prepared from compound 38.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 30.67%), MS(ES): m/z 449.37 [M+H]+, LCMS purity: 98.48%,
HPLC purity: 95.33%, 1H NMR (CDCl3, 400 MHz): 9.59 (bs, 1H), 8.89
(s, 1H), 7.59-7.57 (d, J=7.6 Hz, 1H), 7.49-7.47 (d, J=8.0 Hz, 1H),
7.13-7.02 (m, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 3.47 (s, 3H), 2.52
(s, 3H), 1.65 (s, 1H), 1.11 (s, 2H), 0.90 (s, 2H).
Example 39: Synthesis of
N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)amino)-2-methyl-
-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-54
##STR00389##
[0500] Following the procedure used to prepare 1.91, 39.1 was
obtained (Yield: 62.17%). MS (ES): m/z 386.6 [M+H]+.
[0501] Compound I-54 was prepared from compound 39.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 17.76%), MS(ES): m/z 435.32 [M+H]+, LCMS purity: 99.53%,
HPLC purity: 99.60%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (bs, 1H),
8.84 (s, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.68-7.66 (d, J=8.0 Hz,
1H), 7.38-7.34 (m, 1H), 7.25-7.23 (d, J=8.0 Hz, 1H), 3.74 (s, 3H),
3.49 (s, 3H), 3.22 (s, 3H), 2.03-2.00 (m, 1H), 0.81-0.79 (d, J=5.2
Hz, 4H).
Example 40: Synthesis of
N-(4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-2-methyl-3-oxo-
-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-55
##STR00390##
[0503] Following the procedure used to prepare 1.91, 40.1 was
obtained (Yield: 48.16%). MS (ES): m/z 385.7 [M+H]+.
[0504] Compound I-55 was prepared from compound 40.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 20.89%), MS(ES): m/z 434.48 [M+H]+, LCMS purity: 100.00%,
HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400 MHz): 10.76 (bs, 1H),
8.81 (s, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.38-7.33
(t, J=10.0 Hz, 2H), 7.21-7.19 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.61
(s, 3H), 3.32 (s, 3H), 2.02 (s, 1H), 0.80 (s, 4H).
Example 41: Synthesis of
N-(4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihy-
dro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-56
##STR00391##
[0506] Following the procedure used to prepare 1.91, 41.1 was
obtained (Yield: 58.80%). MS (ES): m/z 371.8 [M+H]+.
[0507] Compound I-56 was prepared from compound 41.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 22.10%), MS(ES): m/z 420.48 [M+H]+, LCMS purity: 99.87%,
HPLC purity: 99.66%, 1H NMR (DMSO-d6, 400 MHz): 10.80 (bs, 1H),
8.88 (s, 1H), 8.23-8.22 (d, J=2.0 Hz, 1H), 7.79 (s, 2H), 7.52-7.50
(d, J=7.6 Hz, 1H), 7.39-7.31 (m, 2H), 6.57 (s, 1H), 3.45 (s, 3H),
3.32 (s, 3H), 2.02 (s, 1H), 0.81 (s, 4H).
Example 42: Synthesis of
N-(4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-2-methyl-3-oxo-
-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-57
##STR00392##
[0509] Following the procedure used to prepare 1.91, 42.1 was
obtained (Yield: 37.77%). MS (ES): m/z 385.5 [M+H]+.
[0510] Compound I-57 was prepared from compound 42.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 31.07%), MS(ES): m/z 434.63 [M+H]+, LCMS purity: 100.00%,
HPLC purity: 96.16%, 1H NMR (DMSO-d6, 400 MHz): 10.76 (bs, 2H),
8.83 (s, 1H), 7.79 (s, 2H), 7.62-7.60 (d, J=7.6 Hz, 1H), 7.44-7.42
(d, J=7.6 Hz, 1H), 7.24-7.22 (m, 1H), 6.74-6.73 (d, J=2.4 Hz, 1H),
3.91 (s, 3H), 3.61 (s, 3H), 3.31 (s, 3H), 2.02 (s, 1H), 0.81 (s,
4H).
Example 46: Synthesis of
N-(4-((2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4--
b]pyridin-6-yl)cyclopropanecarboxamide, I-61
##STR00393##
[0512] Following the procedure used to prepare 1.91, 46.1 was
obtained (Yield: 75.13%). MS (ES): m/z 305.7 [M+H].sup.+.
[0513] Compound I-61 was prepared from compound 46.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 19.83%), MS(ES): m/z 354.38 [M+H]+, LCMS purity: 100.00%,
HPLC purity: 98.86%, 1H NMR (DMSO-d6, 400 MHz): 10.69-10.67 (d,
J=10.8 Hz, 2H), 8.53 (s, 1H), 7.69 (s, 1H), 7.45-7.43 (d, J=8.0 Hz,
1H), 7.13-7.12 (d, J=4.0 Hz, 2H), 7.03-6.99 (m, 1H), 3.85 (s, 3H),
3.29 (s, 3H), 1.99 (s, 1H), 0.78 (s, 4H).
Example 51: Synthesis of
4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((6-(trifluoromet-
hyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-67
##STR00394##
[0515] Following the procedure used to prepare 1.91, 51.1 was
obtained (Yield: 78.14%). MS (ES): m/z 349.7 [M+H].sup.+.
[0516] Compound I-67 was prepared from compound 51.1 and
6-(trifluoromethyl)pyridin-2-amine using procedure described in
Example 2 (Yield: 14.70%), MS(ES): m/z 475.35 [M+H].sup.+, LCMS
purity: 100.00%, HPLC purity: 95.73%, 1H NMR (DMSO-d6, 400 MHz):
10.72 (s, 1H), 10.21 (s, 1H), 8.69 (s, 1H), 8.13-8.10 (d, J=8.4 Hz,
1H), 7.96-7.92 (t, J=8.4 Hz, 1H), 7.54-7.52 (d, J=8.0 Hz, 1H),
7.38-7.36 (d, J=7.2 Hz, 1H), 7.32 (s, 1H), 7.06 (s, 1H), 6.95-6.93
(d, J=7.6 Hz, 1H), 4.42 (s, 2H), 3.88 (s, 3H), 3.31 (s, 3H), 3.28
(s, 3H).
Example 52: Synthesis of
6-((4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-3-oxo-2,3-dihyd-
ro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-68
##STR00395##
[0518] Following the procedure used to prepare 1.91, 52.1 was
obtained (Yield: 78.14%). MS (ES): m/z 349.7 [M+H].sup.+.
[0519] Compound I-68 was prepared from compound 52.1 and
6-aminopicolinonitrile using procedure described in Example 2
(Yield: 32.34%), MS(ES): m/z 432.34 [M+H].sup.+, LCMS purity:
97.69%, HPLC purity: 96.47%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s,
1H), 10.24 (s, 1H), 8.64 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H),
7.56-7.53 (d, J=10.0 Hz, 2H), 7.32 (s, 1H), 7.08-7.05 (d, J=10.4
Hz, 2H), 4.41 (s, 2H), 3.88 (s, 3H), 3.33 (s, 3H), 3.28 (s,
3H).
Example 53: Synthesis of
N-(4-((3-bromo-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyraz-
olo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-69
##STR00396##
[0521] Following the procedure used to prepare 1.91, 53.1 was
obtained (Yield: 56.84%). MS (ES): m/z 384.6 [M+H].sup.+.
[0522] Compound I-69 was prepared from compound 53.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 15.53%), MS(ES): m/z 434.27 [M+H].sup.+, LCMS purity:
98.62%, HPLC purity: 98.29%, 1H NMR (DMSO-d6, 400 MHz): 10.79-10.78
(d, J=7.6 Hz, 2H), 8.83 (s, 1H), 7.75 (s, 1H), 7.46-7.44 (t, J=9.6
Hz, 1H), 7.22 (s, 1H), 7.21 (s, 1H), 3.78 (s, 3H), 3.32 (s, 3H),
1.98 (s, 1H), 0.79 (s, 4H).
Example 54: Synthesis of
4-((4-(hydroxymethyl)-2-methoxyphenyl)amino)-2-methyl-6-((6-(trifluoromet-
hyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-72
##STR00397##
[0524] Following the procedure used to prepare 1.91, 54.1 was
obtained (Yield: 65.13%). MS (ES): m/z 335.8 [M+H].sup.+.
[0525] Compound I-72 was prepared from compound 54.1 and
6-(trifluoromethyl)pyridin-2-amine using procedure described in
Example 2 (Yield: 14.54%), MS(ES): m/z 461.38 [M+H].sup.+, LCMS
purity: 98.86%, HPLC purity: 95.52%, 1H NMR (DMSO-d6, 400 MHz):
10.71 (s, 1H), 10.20 (s, 1H), 8.66 (s, 1H), 8.15-8.13 (d, J=9.2 Hz,
1H), 7.96-7.92 (t, J=7.6 Hz, 1H), 7.52-7.49 (d, J=8.0 Hz, 1H),
7.38-7.36 (d, J=7.2 Hz, 1H), 7.27 (s, 1H), 7.08 (s, 1H), 6.95-6.94
(d, J=7.6 Hz, 1H), 5.24-5.22 (t, J=5.6 Hz, 1H), 4.51-4.50 (d, J=5.6
Hz, 2H), 3.87 (s, 3H), 3.28 (s, 3H).
Example 55: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-(piperidin-1-yl)pyridi-
n-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-77
##STR00398##
[0527] Following the procedure used to prepare 1.91, 55.1 was
obtained (Yield: 81.07%). MS (ES): m/z 323.7 [M+H].sup.+.
[0528] Compound I-77 was prepared from compound 55.1 and
5-(piperidin-1-yl)pyridin-2-amine using procedure described in
Example 2 (Yield: 20.89%), MS(ES): m/z 464.53 [M+H].sup.+, LCMS
purity: 100.00%, HPLC purity: 98.80%, 1H NMR (DMSO-d6, 400 MHz):
10.67 (s, 1H), 9.58 (s, 1H), 8.90 (s, 1H), 8.02 (s, 2H), 7.40 (s,
2H), 7.22-7.17 (q, J=8.4 Hz, 1H), 7.01 (s, 2H), 3.89 (s, 3H), 3.27
(s, 3H), 3.08 (s, 4H), 1.64 (s, 4H), 1.23 (s, 2H).
Example 56: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((1-methyl-1H-pyrazol-3-yl-
)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-78
##STR00399##
[0530] Compound I-78 was prepared from compound 55.1 and
1-methyl-1H-pyrazol-3-amine using procedure described in Example 2
(Yield: 37.88%), MS(ES): m/z 384.43 [M+H].sup.+, LCMS purity:
97.80%, HPLC purity: 93.71%, 1H NMR (DMSO-d6, 400 MHz): 10.52 (bs,
1H), 9.52 (bs, 1H), 8.78 (s, 1H), 7.54 (s, 1H), 7.42-7.39 (d, J=8.4
Hz, 1H), 7.21-7.15 (q, J=8.4 Hz, 1H), 7.01-6.97 (d, J=9.6 Hz, 1H),
6.88 (s, 1H), 6.35 (s, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.25 (s,
3H).
Example 57: Synthesis of
6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-79
##STR00400##
[0532] Compound I-79 was prepared from compound 55.1 and
6-aminonicotinonitrile using procedure described in Example 2
(Yield: 39.80%), MS(ES): m/z 406.29 [M+H].sup.+, LCMS purity:
98.61%, HPLC purity: 99.01%, 1H NMR (DMSO-d6, 400 MHz): 10.99 (s,
1H), 10.44 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.23-8.21 (d, J=8.8
Hz, 1H), 8.15-8.13 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.43-7.41 (d, J=8.4
Hz, 1H), 7.25-7.19 (q, J=8.4 Hz, 1H), 7.15 (s, 1H), 7.06-7.01 (d,
J=8.8 Hz, 1H), 3.89 (s, 3H), 3.35 (s, 3H).
Example 58: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-(pyridin-2-ylamino)-1,2-di-
hydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-80
##STR00401##
[0534] Compound I-80 was prepared from compound 55.1 and
pyridin-2-amine using procedure described in Example 2 (Yield:
21.21%), MS(ES): m/z 381.28 [M+H].sup.+, LCMS purity: 97.64%, HPLC
purity: 97.36%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (s, 1H), 9.85 (s,
1H), 8.85 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.44
(s, 1H), 7.21 (s, 2H), 7.06-6.83 (m, 2H), 3.96 (s, 3H), 3.29 (s,
3H).
Example 59: Synthesis of
6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-81
##STR00402##
[0536] Compound I-81 was prepared from compound 55.1 and
6-aminopicolinonitrile using procedure described in Example 2
(Yield:43.78%), MS(ES): m/z 406.43 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400 MHz): 10.84 (s,
1H), 10.32 (s, 1H), 8.95 (s, 1H), 8.05-8.03 (d, J=8.4 Hz, 1H),
7.93-7.89 (t, J=8.4 Hz, 1H), 7.56-7.49 (m, 3H), 7.26-7.20 (q, J=8.0
Hz, 1H), 7.06-7.01 (t, J=9.2 Hz, 1H), 3.91 (s, 3H), 3.30 (s,
3H).
Example 60: Synthesis of
N-(4-((4-(azetidine-1-carbonyl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-
-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-82
##STR00403##
[0538] Following the procedure used to prepare 1.91, 60.1 was
obtained (Yield: 24.74%). MS (ES): m/z 388.8 [M+H].sup.+.
[0539] Compound I-82 was prepared from compound 60.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 21%), MS(ES): m/z 437.37 [M+H].sup.+, LCMS purity: 100.00%,
HPLC purity: 98.68%, 1H NMR (MeOD, 400 MHz): 7.61-7.59 (d, J=8.0
Hz, 2H), 7.39 (s, 1H), 7.34-7.32 (d, J=8.4 Hz, 1H), 4.51-4.47 (t,
J=6.4 Hz, 2H), 4.25-4.21 (t, J=6.4 Hz, 2H), 3.99 (s, 3H), 3.49 (s,
3H), 2.45-2.38 (qui, J=6.4 Hz, 2H), 1.84 (s, 1H), 1.04-0.96 (m,
4H).
Example 61: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)ami-
no)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-83
##STR00404##
[0541] Compound I-83 was prepared from compound 55.1 and
4-methylpyridin-2-amine using procedure described in Example 2
(Yield: 30.68%), MS(ES): m/z 395.28 [M+H].sup.+, LCMS purity:
98.12%, HPLC purity: 97.83%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s,
1H), 9.72 (s, 1H), 8.82 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H),
7.43-7.42 (d, J=7.2 Hz, 1H), 7.20-7.14 (m, 2H), 6.98 (s, 1H), 6.76
(s, 1H), 3.87 (s, 3H), 3.26 (s, 3H), 2.28 (s, 3H).
Example 62: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-methylpyridin-2-yl)ami-
no)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-84
##STR00405##
[0543] Compound I-84 was prepared from compound 55.1 and
5-methylpyridin-2-amine using procedure described in Example 2
(Yield: 20.46%), MS(ES): m/z 395.32 [M+H].sup.+, LCMS purity:
97.72%, HPLC purity: 97.18%, 1H NMR (MeOD, 400 MHz): 8.15 (s, 1H),
7.65-7.62 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.33-7.31 (d, J=8.0 Hz, 1H),
7.18-7.13 (m, 2H), 7.08-7.03 (t, J=8.8 Hz, 1H), 6.89-6.87 (d, J=7.6
Hz, 1H), 3.97 (s, 3H), 3.54 (s, 3H), 2.31 (s, 3H).
Example 63: Synthesis of
6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitrile, I-85
##STR00406##
[0545] Compound I-85 was prepared from compound 55.1 and
6-aminopyrazine-2-carbonitrile using procedure described in Example
2 (Yield: 17.87%), MS(ES): m/z 407.27 [M+H].sup.+, LCMS purity:
99.70%, HPLC purity: 99.67%, 1H NMR (DMSO-d6, 400 MHz): 10.96 (bs,
1H), 10.67 (bs, 1H), 9.31 (s, 1H), 8.92 (s, 1H), 8.65 (s, 1H),
7.47-7.45 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.24-7.18 (q, J=8.0 Hz,
1H), 7.08-7.03 (t, J=6.0 Hz, 1H), 3.91 (s, 3H), 3.35 (s, 3H).
Example 64: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyrid-
in-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-86
##STR00407##
[0547] Compound I-86 was prepared from compound 55.1 and
6-(trifluoromethyl)pyridin-2-amine using procedure described in
Example 2 (Yield: 14.99%), MS(ES): m/z 449.32 [M+H].sup.+, LCMS
purity: 99.81%, HPLC purity: 99.80%, 1H NMR (DMSO-d6, 400 MHz):
10.80 (bs, 1H), 10.24 (bs, 1H), 8.95 (s, 1H), 8.08-8.06 (d, J=8.0
Hz, 1H), 7.95-7.91 (t, J=8.0 Hz, 1H), 7.43-7.35 (m, 3H), 7.14-7.09
(q, J=8.0 Hz, 1H), 7.03-6.98 (t, J=8.0 Hz, 1H), 3.88 (s, 3H), 3.28
(s, 3H).
Example 65: Synthesis of
6-((6-cyclopropylpyridin-2-yl)amino)-4-((3-fluoro-2-methoxyphenyl)amino)--
2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-87
##STR00408##
[0549] Compound I-87 was prepared from compound 55.1 and
6-cyclopropylpyridin-2-amine using procedure described in Example 2
(Yield: 19.19%), MS(ES): m/z 421.32 [M+H].sup.+, LCMS purity:
98.94%, HPLC purity: 94.15%, 1H NMR (DMSO-d6, 400 MHz): 11.46 (s,
1H), 8.99 (s, 1H), 7.95-7.91 (t, J=8.0 Hz, 1H), 7.29-7.27 (d, J=7.2
Hz, 1H), 7.18-7.16 (d, J=8.4 Hz, 2H), 7.08-7.06 (d, J=7.2 Hz, 1H),
6.99-6.97 (d, J=8.4 Hz, 1H), 6.04 (s, 1H), 3.85 (s, 3H), 3.45 (s,
3H), 2.31-2.24 (m, 1H), 1.28-1.23 (m, 2H), 1.11-1.06 (m, 2H).
Example 66: Synthesis of
N-(4-((2-methoxy-3-(2-oxopyrrolidin-1-yl)phenyl)amino)-2-methyl-3-oxo-2,3-
-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-88
##STR00409##
[0551] Following the procedure used to prepare 1.91, 66.1 was
obtained (Yield: 56.22%). MS (ES): m/z 388.7 [M+H].sup.+.
[0552] Compound I-88 was prepared from compound 66.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield:17.06%), MS(ES): m/z 437.37 [M+H].sup.+, LCMS purity:
96.29%, HPLC purity: 95.84%, 1H NMR (DMSO-d6, 400 MHz): 10.77 (s,
1H), 8.77 (s, 1H), 7.79 (s, 1H), 7.44-7.42 (d, J=7.6 Hz, 1H),
7.23-7.19 (t, J=8.0 Hz, 1H), 7.06-7.04 (d, J=7.6 Hz, 1H), 3.74-3.71
(t, J=6.8 Hz, 2H), 3.669 (s, 3H), 3.311 (s, 3H), 2.46-2.42 (d,
J=8.0 Hz, 2H), 2.17-2.10 (qui, J=6.8 Hz, 2H), 2.017 (s, 1H), 0.78
(s, 4H).
Example 67:
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-morpholinopyridin-2-yl-
)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-89
##STR00410##
[0554] Compound I-89 was prepared from compound 55.1 and
5-morpholinopyridin-2-amine using procedure described in Example 2
(Yield: 13.87%), MS(ES): m/z 466.52 [M+H].sup.+, LCMS purity:
95.70%, HPLC purity: 95.05%, 1H NMR (DMSO-d6, 400 MHz): 11.33 (s,
1H), 8.91 (s, 1H), 8.05-8.02 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.83-7.82
(d, J=2.4 Hz, 1H), 7.32-7.11 (m, 5H), 6.09 (s, 1H), 3.86 (s, 3H),
3.75 (s, 4H), 3.38 (s, 3H), 3.12 (s, 4H).
Example 68: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-(pyrrolidin-1-yl)pyrid-
in-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-90
##STR00411##
[0556] Compound I-90 was prepared from compound 55.1 and
5-(pyrrolidin-1-yl)pyridin-2-amine using procedure described in
Example 2 (Yield: 17.95%), MS(ES): m/z 450.42 [M+H].sup.+, LCMS
purity: 97.66%, HPLC purity: 96.95%, 1H NMR (DMSO-d6, 400 MHz):
7.61-7.58 (dd, J=2.4 Hz, 9.6 Hz, 1H), 7.47-7.47 (d, J=2.4 Hz, 1H),
7.30-7.28 (d, J=8.4 Hz, 1H), 7.22-7.19 (d, J=9.6 Hz, 1H), 7.16-7.11
(m, 1H), 7.05-7.00 (d, J=9.6 Hz, 1H), 6.15 (s, 1H), 3.85 (s, 3H),
3.34 (s, 3H), 3.21 (s, 4H), 1.95 (s, 4H).
Example 69: Synthesis of
6-((5-cyclopropylpyridin-2-yl)amino)-4-((3-fluoro-2-methoxyphenyl)amino)--
2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-91
##STR00412##
[0558] Compound I-91 was prepared from compound 55.1 and
5-cyclopropylpyridin-2-amine using procedure described in Example 2
(Yield: 15.99%), MS(ES): m/z 421.29 [M+H].sup.+, LCMS purity:
95.97%, HPLC purity: 95.65%, 1H NMR (DMSO-d6, 400 MHz): 11.50 (s,
1H), 8.93 (s, 1H), 8.17 (s, 1H), 7.85-7.83 (d, J=8.4 Hz, 1H),
7.31-7.29 (d, J=7.2 Hz, 1H), 7.23-7.12 (m, 3H), 6.14 (s, 1H), 3.85
(s, 3H), 3.38 (s, 3H), 2.04 (s, 1H), 1.02 (s, 2H), 0.72 (s,
2H).
Example 70: Synthesis of
4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((5-(pyrrolidine--
1-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo-
[3,4-b]pyridin-3-one, I-92
##STR00413##
[0560] Following the procedure used to prepare 1.91, 70.1 was
obtained (Yield: 78.14%). MS (ES): m/z 349.7 [M+H].sup.+.
[0561] Compound I-92 was prepared from compound 70.1 and
(6-amino-2-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone
using procedure described in Example 2 (Yield: 17.09%), MS(ES): m/z
572.37 [M+H].sup.+, LCMS purity: 94.64%, HPLC purity: 95.10%, 1H
NMR (DMSO-d6, 400 MHz): 10.78 (s, 1H), 10.32 (s, 1H), 8.67 (s, 1H),
8.22-8.20 (d, J=8.8 Hz, 1H), 7.89-7.87 (d, J=8.8 Hz, 1H), 7.53-7.51
(d, J=8.0 Hz, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 6.95-6.93 (d, J=8.0
Hz, 1H), 4.42 (s, 2H), 3.88 (s, 3H), 3.47-3.43 (t, J=6.0 Hz, 2H),
3.31 (s, 3H), 3.28 (s, 3H), 3.13-3.10 (t, J=6.0 Hz, 2H), 1.89-1.81
(m, 4H).
Example 71: Synthesis of
4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((5-methyl-6-(tri-
fluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-o-
ne, I-93
##STR00414##
[0563] Compound I-93 was prepared from compound 70.1 and
5-methyl-6-(trifluoromethyl)pyridin-2-amine using procedure
described in Example 2 (Yield: 26.18%), MS(ES): m/z 489.43
[M+H].sup.+, LCMS purity: 94.92%, HPLC purity: 99.24%, 1H NMR
(DMSO-d6, 400 MHz): 10.68 (s, 1H), 10.01 (s, 1H), 8.63 (s, 1H),
8.10-8.08 (d, J=8.4 Hz, 1H), 7.79-7.77 (d, J=8.4 Hz, 1H), 7.52-7.50
(d, J=7.6 Hz, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.95-6.93 (d, J=7.6
Hz, 1H), 4.41 (s, 2H), 3.88 (s, 3H), 3.34 (s, 3H), 3.27 (s, 3H),
2.29 (s, 3H).
Example 72: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-6-((6-(3-methoxyazetidin-1-yl)pyridin-
-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-94
##STR00415##
[0565] Compound I-94 was prepared from compound 55.1 and
6-(3-methoxyazetidin-1-yl)pyridin-2-amine using procedure described
in Example 2 (Yield: 11.56%), MS(ES): m/z 466.30 [M+H].sup.+, LCMS
purity: 99.23%, HPLC purity: 99.29%, 1H NMR (DMSO-d6, 400 MHz):
10.66 (s, 1H), 9.51 (s, 1H), 8.82 (s, 1H), 7.45-7.36 (m, 1H),
7.17-7.00 (m, 2H), 5.94-5.92 (d, J=7.2 Hz, 1H), 4.28 (s, 1H), 4.04
(s, 2H), 3.87 (s, 3H), 3.67 (s, 2H), 3.26 (s, 3H), 3.22 (s,
3H).
Example 73:
4-((3-chloro-2-methoxyphenyl)amino)-6-((5-fluoro-4-methylpyridin-2-yl)ami-
no)-2-methyl-1,2-dihydro-3H1-pyrazolo[3,4-b]pyridin-3-one, I-95
##STR00416##
[0567] Following the procedure used to prepare 1.91, 73.1 was
obtained (Yield: 70.71%). MS (ES): m/z 340.2 [M+H].sup.+.
[0568] Compound I-95 was prepared from compound 73.1 and
5-fluoro-4-methylpyridin-2-amine using procedure described in
Example 2 (Yield: 15.82%), MS(ES): m/z 429.27 [M+H].sup.+, LCMS
purity: 95.01%, HPLC purity: 95.80%, 1H NMR (DMSO-d6, 400 MHz):
9.84 (s, 1H), 8.86 (s, 1H), 8.17-8.13 (m, 1H), 7.95 (s, 1H),
7.56-7.54 (d, J=8.0 Hz, 1H), 7.25-7.17 (m, 2H), 6.95 (s, 1H), 3.79
(s, 3H), 3.27 (s, 3H), 2.26 (s, 3H).
Example 74: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-
-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-on, I-96
##STR00417##
[0570] Compound I-96 was prepared from compound 73.1 and
2,6-dimethylpyrimidin-4-amine using procedure described in Example
2 (Yield: 14.34%), MS(ES): m/z 426.40 [M+H].sup.+, LCMS purity:
96.62%, HPLC purity: 96.51%, 1H NMR (DMSO-d6, 400 MHz): 10.13 (s,
1H), 8.91 (s, 1H), 8.18 (s, 1H), 7.63-7.60 (d, J=4.8 Hz, 1H), 7.49
(s, 1H), 7.45 (s, 1H), 7.24-7.23 (d, J=4.8 Hz, 2H), 3.82 (s, 3H),
3.31 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H).
Example 75: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-6-((4-(methoxymethyl)pyridin-2-yl)ami-
no)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-97
##STR00418##
[0572] Compound I-97 was prepared from compound 73.1 and
4-(methoxymethyl)pyridin-2-amine using procedure described in
Example 2 (Yield: 12.82%), MS(ES): m/z 441.29 [M+H].sup.+, LCMS
purity: 98.70%, HPLC purity: 98.80%, 1H NMR (DMSO-d6, 400 MHz):
10.78 (s, 1H), 9.83 (s, 1H), 8.88 (s, 1H), 8.21 (s, 1H), 7.97 (s,
1H), 7.59 (s, 1H), 7.25-7.23 (d, J=7.6 Hz, 3H), 6.87 (s, 1H), 4.44
(s, 2H), 3.83 (s, 3H), 3.36 (s, 3H), 3.29 (s, 3H).
Example 76: Synthesis of
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-98
##STR00419##
[0574] Compound I-98 was prepared from compound 73.1 and
6-aminonicotinonitrile using procedure described in Example 2
(Yield: 13.40%), m/z 422.32 [M+H].sup.+, LCMS purity: 98.00%, HPLC
purity: 97.94%, 1H NMR (DMSO-d6, 400 MHz): 11.01 (s, 1H), 10.44 (s,
1H), 8.91 (s, 1H), 8.70 (s, 1H), 8.23-8.16 (m, 2H), 7.59-7.57 (d,
J=8.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.14 (s, 1H), 3.82 (s, 3H), 3.31
(s, 3H).
Example 77: Synthesis of
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-99
##STR00420##
[0576] Compound I-99 was prepared from compound 73.1 and
6-aminopicolinonitrile using procedure described in Example 2
(Yield: 13.14%), m/z 422.35 [M+H].sup.+, LCMS purity: 95.93%, HPLC
purity: 95.55%, 1H NMR (DMSO-d6, 400 MHz): 10.87 (s, 1H), 10.33 (s,
1H), 8.98 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.56
(s, 1H), 7.50 (s, 1H), 7.27-7.24 (m, 2H), 3.83 (s, 3H), 3.31 (s,
3H).
Example 78: Synthesis of
4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-6-((5-methoxy-6-(trifluorome-
thyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3--
one, I-104
##STR00421##
[0578] Compound I-104 was prepared from compound 70.1 and
5-methoxy-6-(trifluoromethyl)pyridin-2-amine using procedure
described in Example 2 (Yield: 11.52%), MS(ES): m/z 505.36
[M+H].sup.+, LCMS purity: 97.99%, HPLC purity: 96.46%, 1H NMR
(DMSO-d6, 400 MHz): 7.82-7.80 (d, J=9.2 Hz, 1H), 7.32-7.23 (m, 3H),
7.10 (s, 1H), 6.98-6.96 (d, J=8.0 Hz, 1H), 4.39 (s, 2H), 3.85 (s,
3H), 3.79 (s, 3H), 3.57 (s, 3H), 3.29 (s, 3H).
Example 79: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((6-methylpyridazin-3-yl)a-
mino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-105
##STR00422##
[0580] Compound I-105 was prepared from compound 73.1 and
6-methylpyridazin-3-amine using procedure described in Example 2
(Yield: 5.49%), m/z 412.29 [M+H].sup.+, LCMS purity: 97.66%, HPLC
purity: 95.98%, 1H NMR (DMSO-d6, 400 MHz): 10.21 (s, 1H), 8.87 (s,
1H), 8.29 (s, 1H), 7.56 (s, 1H), 7.48-7.46 (d, J=9.2 Hz, 1H),
7.21-7.20 (d, J=4.0 Hz, 1H), 7.11-7.09 (d, J=8.8 Hz, 1H), 6.69-6.67
(d, J=9.2 Hz, 1H), 6.10 (s, 1H), 3.81 (s, 3H), 3.27 (s, 3H), 2.34
(s, 3H).
Example 80: Synthesis of
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitrile, I-117
##STR00423##
[0582] Compound I-117 was prepared from compound 73.1 and
6-methylpyridazin-3-amine using procedure described in Example 2
(Yield: 21.39%), m/z 423.27 [M+H].sup.+, LCMS purity: 96.80%, HPLC
purity: 95.08%, 1H NMR (DMSO-d6, 400 MHz): 10.96 (s, 1H), 10.65 (s,
1H), 9.31 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 7.61-7.59 (d, J=4.0
Hz, 1H), 7.35 (s, 1H), 7.27-7.23 (m, 2H), 3.86 (s, 3H), 3.30 (s,
3H).
Example 81: Synthesis of
N-(4-((3,4-difluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H--
pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-127
##STR00424##
[0584] Following the procedure used to prepare 1.91, 81.1 was
obtained (Yield: 63.99%). MS (ES): m/z 341.7 [M+H].sup.+.
[0585] Compound I-127 was prepared from compound 81.1 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 17.5%), m/z 390.27 [M+H].sup.+, LCMS purity: 99.27%, HPLC
purity: 99.63%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s, 2H), 8.55 (s,
1H), 7.49 (s, 1H), 7.29-7.20 (m, 2H), 3.89 (s, 3H), 3.28 (s, 3H),
1.99-1.95 (m, 1H), 0.77-0.75 (d, J=6.4 Hz, 4H).
Example 82:
N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-(methyl-d3)-
-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-100
##STR00425##
[0587] Synthesis of compound 82.1. To 2,4,6-trichloronicotinic acid
(0.25 g, 1.10 mmol, 1.0 eq) was added thionyl chloride (1.2 mL)
followed by N,N-dimethylformamide(catalytic) and refluxed for 16 h.
Reaction mixture was concentrated under reduced pressure to obtain
acid chloride. Methyl hydrazine d3 sulfate (0.16 g, 1.10 mmol, 1.0
eq) was dissolved in dichloromethane (5 mL) followed by addition of
solution of sodium hydroxide (0.18 g, 4.40 mmol, 4.0 eq) in water
(1.2 mL). To this added solution of previously made acid chloride
in dichloromethane (5 mL) dropwise and reaction mixture was
refluxed for 15 min. After completion of reaction, reaction mixture
was transferred into water and extracted with dichloromethane.
Organic layer was combined, washed with brine solution, dried over
sodium sulphate and concentrated under reduced pressure to pressure
to obtain crude material. This was further purified by column
chromatography and the product was eluted in 30% ethyl acetate in
hexane to get pure 1.1. (0.2 g, 70.35%). MS(ES): m/z 258.5
[M+H].sup.+.
[0588] Synthesis of compound 82.2. To a suspension of 83.1 (0.2 g,
0.776 mmol, 1.0 eq) in 1-pentanol (5 mL) was added sodium carbonate
(0.083 g, 0.776 mmol, 1.0 eq) and reaction mixture was stirred at
120.degree. C. for 18 h. After completion of reaction, reaction
mixture was cooled to room temperature and pH=6 was adjusted using
1N hydrochloric acid. Reaction mixture was concentrated under
reduced pressure to obtain crude material. This was further
purified by Preparative HPLC using 0.1% Formic acid in
water/Acetonitrile in gradient method to obtain pure 1.2. (0.085 g,
49.51%). MS(ES): m/z 222.06 [M+H].sup.+.
[0589] Synthesis of compound 82.3 Following the procedure used to
prepare 1.91, 82.3 was obtained (Yield: 30.78%). MS (ES): m/z
390.82 [M+H].sup.+.
[0590] Compound I-100 was prepared from compound 82.3 and
cyclopropanecarboxamide using procedure described in Example 2
(0.025 g, Yield: 23.40%). MS(ES): m/z 439.42 [M+H].sup.+, LCMS
purity: 99.10%, HPLC purity: 97.85%, 1H NMR (DMSO-d6, 400 MHz):
10.79 (s, 2H), 8.89 (s, 1H), 7.81 (s, 1H), 7.68-7.64 (t, J=8.0 Hz,
2H), 7.40-7.36 (t, J=8.0 Hz, 1H), 4.47 (s, 3H), 3.77 (s, 3H), 2.02
(s, 1H), 0.81 (s, 4H).
Example 83: Synthesis of
3-((6-(cyclopropanecarboxamido)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,-
4-b]pyridin-4-yl)amino)-2-methoxybenzamide, I-102
##STR00426##
[0592] Synthesis of compound 83.1. To a solution of methyl
2-hydroxy-3-nitrobenzoate (5.0 g, 25.36 mmol, 1.0 eq) in
N,N-dimethylformamide (50 mL), was added potassium carbonate (7.0
g, 50.76 mmol, 2.0 eq) at 0.degree. C. and stirred for 15 min. To
this added methyl iodide (7.2 g, 50.76 mmol, 2 eq) dropwise and
reaction mixture was stirred at 60.degree. C. for 2 h. After
completion of reaction, reaction mixture was transferred in
ice-water and precipitated product was filtered, dried well to
obtain 83.1 (5.0 g, 93%). MS(ES): m/z 212.2 [M+H].sup.+.
[0593] Synthesis of compound 83.2. To 83.1 (5 g, 23.67 mmol, 1.0
eq) was added aqueous ammonia (30 mL) followed by methanolic
ammonia (160 mL). Reaction mixture was stirred at room temperature
for 16 h. After completion of reaction, reaction mixture was
concentrated under reduced pressure and residue was washed with ice
cold water. Solid was dried well to obtain 83.2 (4.5 g, 96%).
MS(ES): m/z 197.2 [M+H].sup.+.
[0594] Synthesis of compound 83.3. To a solution of 83.2 (4.5 g,
22.94 mmol, 1.0 eq) in methanol (45 mL), 10% palladium on charcoal
(1.0 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 83.3. (3.0 g,
78.69%). MS(ES): m/z 167.18 [M+H].sup.+.
[0595] Synthesis of compound 83.4 Following the procedure used to
prepare 1.91, 84.4 was obtained (Yield: 62.70%). MS (ES): m/z
348.76 [M+H].sup.+.
[0596] Compound I-102 was prepared from compound 83.4 and
cyclopropanecarboxamide using procedure described in Example 2
(Yield: 2.63%). MS(ES): m/z 397.41 [M+H].sup.+, LCMS purity:
98.76%, HPLC purity: 98.65%, 1H NMR (DMSO-d6, 400 MHz): 10.81 (s,
1H), 8.56 (s, 1H), 8.12 (s, 1H), 7.69-7.68 (d, J=6.4 Hz, 1H),
7.65-7.63 (d, J=8.0 Hz, 1H), 7.57-7.55 (d, J=8.0 Hz, 1H), 6.95-6.91
(t, J=8.0 Hz, 1H), 3.29 (s, 3H), 3.27 (s, 3H), 1.49-1.46 (m, 1H),
0.78-0.77 (m, 4H).
Example 84: Synthesis of
3-((6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-p-
yrazolo[3,4-b]pyridin-4-yl)amino)-2-methoxybenzamide, I-103
##STR00427##
[0598] Compound 84.1 was prepared from compound 84 and
2,6-dimethylpyrimidin-4-amine using procedure described in Example
2 (Yield: 19.00%). MS (ES): m/z 417.45 [M+H].sup.+.
[0599] Synthesis of compound I-103. To 84.1 (0.120 g, 0.363 mmol, 1
eq) was added sulfuric acid (2 mL) and stirred at 60.degree. C. for
1 h. After completion of reaction, water and aqueous ammonia was
added to reaction mixture and stirred at room temperature for 10
min. Reaction mixture was concentrated under reduced pressure to
obtain crude material. This was further purified by Preparative
HPLC using 0.1% Formic acid in water/Acetonitrile in gradient
method to obtain pure I-84 (0.02 g, Yield: 15.98%). MS(ES): m/z
435.46 [M+H].sup.+, LCMS purity: 100.00%, HPLC purity: 95.03%, 1H
NMR (DMSO-d6, 400 MHz): 14.19 (s, 1H), 10.15 (s, 1H), 8.61 (s, 2H),
8.15 (s, 1H), 7.73-7.65 (d, J=7.6 Hz, 2H), 7.48 (s, 2H), 6.97-6.93
(t, J=8.0 Hz, 1H), 3.34 (s, 3H), 3.29 (s, 3H), 2.43 (s, 3H), 2.34
(s, 3H).
Example 85: Synthesis of
4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-6-((5-methoxy-6-(trifluorome-
thyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3--
one, I-106
##STR00428##
[0601] Compound 85.1 was prepared from compound 85 and
5-fluoro-4-methylpyridin-2-amine using procedure described in
Example 2 (Yield: 19.65%). MS (ES): m/z 420.42 [M+H].sup.+.
[0602] Synthesis of compound I-106. To 85.1 (0.125 g, 0.298 mmol, 1
eq) was added sulfuric acid (2 mL) and stirred at 60.degree. C. for
1 h. After completion of reaction, water and aqueous ammonia was
added to reaction mixture and stirred at room temperature for 10
min. Reaction mixture was concentrated under reduced pressure to
obtain crude material. This was further purified by Preparative
HPLC using 0.1% Formic acid in water/Acetonitrile in gradient
method to obtain pure I-106 (0.022 g, Yield: 16.88%). MS(ES): m/z
438.44 [M+H].sup.+, LCMS purity: 98.97%, HPLC purity: 96.36%, 1H
NMR (DMSO-d6, 400 MHz): 14.21 (bs, 1H), 9.84 (s, 1H), 8.64 (s, 1H),
8.56 (s, 1H), 8.15-8.11 (m, 2H), 8.02-8.01 (d, J=5.6 Hz, 1H),
7.66-7.61 (d, J=8.0 Hz, 2H), 7.00-6.92 (m, 2H), 3.32 (s, 3H), 3.24
(s, 3H), 2.28 (s, 3H).
Example 86: Synthesis of
6-((5-fluoro-4-methylpyridin-2-yl)amino)-2-methyl-4-((2-(methylsulfonyl)
phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-107
##STR00429##
[0604] Following the procedure used to prepare 1.91, 86.1 was
obtained (Yield: 76.89%). MS (ES): m/z 321.80 [M+H].sup.+.
[0605] Synthesis of compound 86.2. To a solution of 86.1 (1.81 g,
5.64 mmol, 1 eq) in acetic acid (2.5 mL) was added 30% hydrogen
peroxide (3.83 g, 112.8 mmol, 20 eq) and sodium tungstate dihydrate
(1.85 g, 5.64 mmol, 1 eq). Reaction mixture was stirred at room
temperature for 2 h. After completion of reaction, reaction mixture
was transferred in ice-water and precipitated product was filtered,
washed with 50% ethyl acetate in hexane and dried well to obtain
86.2 (1.25 g, Yield: 62.80%). MS(ES): m/z 353.79 [M+H].sup.+,
[0606] Compound I-107 was prepared from compound 86.2 and
5-fluoro-4-methylpyridin-2-amine using procedure described in
Example 2 (0.060 g, Yield: 31.89%). MS(ES): m/z 443.47 [M+H].sup.+,
LCMS purity: 99.63%, HPLC purity: 99.37%, 1H NMR (DMSO-d6, 400
MHz): 10.72 (s, 1H), 9.76 (s, 1H), 9.06 (s, 1H), 8.07 (s, 1H),
7.93-7.91 (d, J=7.2 Hz, 2H), 7.84-7.77 (m, 2H), 7.39-7.36 (t, J=7.2
Hz, 1H), 6.94 (s, 1H), 3.25 (s, 3H), 3.16 (s, 3H), 2.25 (s,
3H).
Example I-87: Synthesis of
6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-4-((2-(methylsulfonyl)phen-
yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-109
##STR00430##
[0608] Compound I-109 was prepared from compound 86.2 and
2,6-dimethylpyrimidin-4-amine using procedure described in Example
2 (Yield: 27.52%), MS(ES): m/z 440.40 [M+H].sup.+, LCMS purity:
98.42%, HPLC purity: 95.04%, 1H NMR (DMSO-d6, 400 MHz): 10.84 (bs,
1H), 10.09 (s, 1H), 9.15 (s, 1H), 7.94-7.92 (dd, J=1.2 Hz, 8.0 Hz,
1H), 7.87-7.85 (d, J=8.0 Hz, 1H), 7.81-7.77 (t, J=8.0 Hz, 1H),
7.44-7.34 (m, 3H), 3.27 (s, 3H), 3.16 (s, 3H), 2.37 (s, 3H), 2.29
(s, 3H).
Example 88: Synthesis of
2-methyl-6-((6-methylpyridazin-3-yl)amino)-4-((2-(methylsulfonyl)phenyl)a-
mino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-109
##STR00431##
[0610] Compound I-109 was prepared from compound 86.2 and
6-methylpyridazin-3-amine using procedure described in Example 2
(Yield: 32.58%), MS(ES): m/z 426.19 [M+H].sup.+, LCMS purity:
97.90%, HPLC purity: 96.09%, 1H NMR (DMSO-d6, 400 MHz): 10.59 (bs,
1H), 10.17 (s, 1H), 9.09 (s, 1H), 8.19 (s, 1H), 7.94-7.92 (d, J=8.0
Hz, 1H), 7.84-7.75 (m, 2H), 7.47-7.38 (m, 2H), 6.95 (s, 1H), 3.171
(s, 3H), 3.059 (s, 3H), 2.314 (s, 3H).
Example 89: Synthesis of
6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-4-((2-(methylsulfonyl)p-
henyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-110
##STR00432##
[0612] Compound I-110 was prepared from compound 86.2 and
4-(methoxymethyl)pyridin-2-amine using procedure described in
Example 2 (Yield: 14.42%), MS(ES): m/z 455.20 [M+H].sup.+, LCMS
purity: 94.46%, HPLC purity: 95.28%, 1H NMR (DMSO-d6, 400 MHz):
11.62 (s, 1H), 9.24 (s, 1H), 8.32-8.30 (d, J=6.4 Hz, 1H), 8.00-7.98
(d, J=7.2 Hz, 1H), 7.84-7.80 (m, 2H), 7.51 (t, 1H), 7.24-7.19 (m,
2H), 6.21 (s, 1H), 4.59 (s, 2H), 3.39 (s, 3H), 3.36 (s, 3H), 3.19
(s, 3H).
Example 90: Synthesis of
2-methyl-6-((5-methylpyridin-2-yl)amino)-4-((2-(methylsulfonyl)phenyl)ami-
no)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-111
##STR00433##
[0614] Compound I-111 was prepared from compound 86.2 and
5-methylpyridin-2-amine using procedure described in Example 2
(Yield: 20.78%), MS(ES): m/z 425.19 [M+H].sup.+, LCMS purity:
97.76%, HPLC purity: 96.61%, 1H NMR (MeOD, 400 MHz): 8.14 (s, 1H),
8.06-8.04 (d, J=8.0 Hz, 1H), 7.82-7.76 (m, 2H), 7.63-7.61 (d, J=8.0
Hz, 1H), 7.49-7.46 (t, J=6.8 Hz, 1H), 6.90 (s, 1H), 5.81 (s, 1H),
3.56 (s, 3H), 3.34 (s, 1H), 3.11 (s, 3H), 2.30 (s, 3H).
Example 91: Synthesis of
6-((2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-112
##STR00434##
[0616] Compound I-112 was prepared from compound 86.2 and
6-aminopicolinonitrile using procedure described in Example 2
(Yield: 23.15%), MS(ES): m/z 436.35 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400 MHz): 10.81 (s,
1H), 10.28 (s, 1H), 9.18 (s, 1H), 8.05-8.03 (d, J=8.8 Hz, 1H),
7.94-7.80 (m, 4H), 7.52-7.50 (d, J=7.2 Hz, 1H), 7.41-7.38 (t, J=7.2
Hz, 1H), 7.24 (s, 1H), 3.27 (s, 3H), 3.16 (s, 3H).
Example 92: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5-(pyrrolidine-1-carbony-
l)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]py-
ridin-3-one, I-128
##STR00435##
[0618] Synthesis of compound 92.1. To
5-bromo-6-(trifluoromethyl)pyridin-2-amine (3.0 g, 12.45 mmol, 1.0
eq) in dimethylformamide (1 ml) was added zinc cyanide (1.456 g,
12.45 mmol, 1.0 eq). The reaction mixture was then heated in
microwave at 150.degree. C. for 15 min. After completion of
reaction, water was added to reaction mixture and extracted with
ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 20% ethyl acetate in hexane to obtain 92.1.
(Yield: 68.69%). MS (ES): m/z 188.13 [M+H].sup.+.
[0619] Synthesis of compound 92.2. To compound 92.1 (1.6 g, 8.55
mmol, 1.0 eq) and sodium hydroxide (1.0 g, 25.65 mmol, 3.0 eq) was
added in water (30 mL) The reaction mixture was stirred at
100.degree. C. for 16 h. After completion of reaction, reaction
mixture was extracted with ethyl acetate. Aqueous layer was
acidified with hydrochloric acid and extracted with ethyl acetate.
Organic layer was combined, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 5% methanol in dichloromethane to obtain 93.2. (Yield:
62.41%). MS (ES): m/z 207.12 [M+H].sup.+.
[0620] Synthesis of compound 92.3. To a cooled solution of 92.2
(0.5 g, 2.43 mmol, 1.0 eq) and pyrrolidine (0.19 g, 2.67 mmol, 1.l
eq) in N,N-dimethylformamide (5 mL) at 0.degree. C. was added
((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxi-
d hexafluoro-phosphate)) (1.846 g, 4.86 mmol, 2.0 eq) followed by
N,N-Diisopropylethylamine (0.94 g, 7.29 mmol, 3.0 eq) and the
reaction mixture was stirred at room temperature for 16 h. After
completion of reaction, reaction mixture was transferred into water
and extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 3% methanol in
dichloromethane to obtain pure 92.3 (0.39 g, 62.34%). MS(ES): m/z
260.23 [M+H].sup.+.
[0621] Compound I-128 was prepared from compound 73.1 and compound
93.3 using procedure described in Example 2 (Yield: 10.06%).
MS(ES): m/z 563.35 [M+H].sup.+, LCMS purity: 90.57%, HPLC purity:
94.43%, 1H NMR (DMSO-d6, 400 MHz): 10.91 (bs, 1H), 10.36 (s, 1H),
8.97 (s, 1H), 8.18-8.16 (d, J=8.4 Hz, 1H), 7.89-7.87 (d, J=8.4 Hz,
1H), 7.58-7.55 (dd, J=1.6 Hz, 7.6 Hz, 1H), 7.30 (s, 1H), 7.21-7.14
(m, 2H), 3.81 (s, 3H), 3.45-3.42 (m, 2H), 3.29 (s, 3H), 3.12-3.08
(m, 2H), 1.88-1.79 (m, 4H).
Example 93: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5-(morpholine-4-carbonyl-
)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyr-
idin-3-one, I-130
##STR00436##
[0623] Synthesis of compound 93.1. To a cooled solution of
6-amino-2-(trifluoromethyl)nicotinic acid (0.5 g, 2.43 mmol, 1.0
eq) and morpholine (0.23 g, 2.67 mmol, 1.1 eq) in N,
N-dimethylformamide (5 mL) at 0.degree. C. was added
((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluoro-phosphate)) (1.846 g, 4.86 mmol, 2.0 eq) followed
by N,N-Diisopropylethylamine (0.94 g, 7.29 mmol, 3.0 eq) and the
reaction mixture was stirred at room temperature for 16 h. After
completion of reaction, reaction mixture was transferred into water
and extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 3% methanol in
dichloromethane to obtain pure 93.1 (0.4 g, 59.91%). MS(ES): m/z
276.23 [M+H].sup.+.
[0624] Compound I-130 was prepared from compound 73.1 and compound
93.1 using procedure described in Example 2 (Yield: 30.52%),
MS(ES): m/z 578.41 [M+H].sup.+, LCMS purity: 97.65%, HPLC purity:
97.61%, 1H NMR (DMSO-d6, 400 MHz): 10.89 (s, 1H), 10.38 (s, 1H),
8.97 (s, 1H), 8.17-8.15 (d, J=8.4 Hz, 1H), 7.87-7.84 (d, J=8.8 Hz,
1H), 7.57-7.56 (d, J=7.6 Hz, 1H), 7.32 (s, 1H), 7.22-7.14 (m, 2H),
3.81 (s, 3H), 3.66-3.42 (m, 6H), 3.29 (s, 3H), 3.19-3.15 (m,
2H).
Example 94: Synthesis of
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-methylpicolinonitrile, I-132
##STR00437##
[0626] Synthesis of compound 94.1. To 6-bromopyridin-2-amine (2.0
g, 11.56 mmol, 1.0 eq) in dimethylformamide (1 ml) was added zinc
cyanide (1.35 g, 11.56 mmol, 1.0 eq). The reaction mixture was then
heated in microwave at 150.degree. C. for 15 min. After completion
of reaction, reaction mixture was transferred into water and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 20% ethyl acetate in
hexane to obtain 94.1. (1.0 g, Yield: 72.62%). MS (ES): m/z 120.13
[M+H].sup.+.
[0627] Synthesis of compound 94.2. To compound 94.1 (1.0 g, 8.39
mmol, 1.0 eq) in acetonitrile was added N-Bromosuccinimide (2.24 g,
12.58 mmol, 1.5 eq). The reaction mixture was stirred at room
temperature for 12 h. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Organic layer was combined, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 25% ethyl acetate in hexane to obtain 94.2. (0.42 g,
Yield: 25.27%). MS (ES): m/z 199.02 [M+H].sup.+.
[0628] Synthesis of compound 94.3. To a solution of 94.2 (0.42 g,
2.12 mmol, 1.0 eq) in mixture of water (5 mL) and 1,4-dioxane (15
mL) was added trimethylboroxine (0.4 g, 3.18 mmol, 1.5 eq),
tetrakis (0.073 g, 0.064 mmol, 0.03 eq) and potassium carbonate
(0.878 g, 6.36 mmol, 3.0 eq). The reaction mixture was degassed by
argon for 30 min. Further reaction mixture was stirred at
110.degree. C. for 4 h. After completion of reaction, reaction
mixture was cooled to room temperature transferred into water and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified in 20% ethyl
acetate in hexane to get pure 95.3 (0.1 g, 35.41%). MS(ES): m/z
134.15 [M+H].sup.+.
[0629] Compound I-132 was prepared from compound 73.1 and compound
94.3 using procedure described in Example 2 (Yield: 17.51%).
MS(ES): m/z 436.40 [M+H].sup.+, LCMS purity: 95.36%, HPLC purity:
95.07%, 1H NMR (DMSO-d6, 400 MHz): 10.80 (s, 1H), 10.19 (s, 1H),
8.96 (s, 1H), 7.96-7.94 (d, J=8.0 Hz, 1H), 7.80-7.78 (d, J=8.8 Hz,
1H), 7.64-7.62 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.27-7.18 (m, 2H),
3.81 (s, 3H), 3.28 (s, 3H), 2.39 (s, 3H).
Example 95: Synthesis of
2-methyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-4-((2-(methylsulfonyl)phenyl-
)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-137
##STR00438##
[0631] Compound I-137 was prepared from compound 86.2 and
1-methyl-1H-pyrazol-3-amine using procedure described in Example 2
(Yield: 31.03%), MS(ES): m/z 414.19 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 95.12%, 1H NMR (DMSO-d6, 400 MHz): 10.49 (s,
1H), 9.47 (s, 1H), 9.02 (s, 1H), 7.94-7.92 (d, J=8.0 Hz, 1H),
7.86-7.78 (m, 2H), 7.52 (s, 1H), 7.40-7.37 (m, 1H), 6.76 (bs, 1H),
6.34 (bs, 1H), 3.71 (s, 3H), 3.24 (s, 3H), 3.17 (s, 3H).
Example 96: Synthesis of
2-methyl-6-((4-methylpyridin-2-yl)amino)-4-((2-(methylsulfonyl)phenyl)ami-
no)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-138
##STR00439##
[0633] Compound I-138 was prepared from compound 86.2 and
4-methylpyridin-2-amine using procedure described in Example 2
(Yield: 22.67%), MS(ES): m/z 425.07 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 99.85%, 1H NMR (DMSO-d6, 400 MHz): 10.69 (s,
1H), 9.70 (s, 1H), 9.08 (s, 1H), 8.05 (s, 1H), 7.93-7.91 (d, J=8.0
Hz, 1H), 7.85-7.73 (m, 3H), 7.39 (s, 1H), 7.14 (s, 1H), 6.75 (s,
1H), 3.26 (s, 3H), 3.16 (s, 3H), 2.27 (s, 3H).
Example 97: Synthesis of
6-((2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-139
##STR00440##
[0635] Compound I-139 was prepared from compound 86.2 and
6-aminonicotinonitrile using procedure described in Example 2
(Yield: 16.20%), MS(ES): m/z 436.27 [M+H].sup.+, LCMS purity:
94.62%, HPLC purity: 94.64%, 1H NMR (DMSO-d6, 400 MHz): 10.99 (bs,
1H), 10.43 (s, 1H), 9.18 (s, 1H), 8.66 (s, 1H), 8.14 (s, 2H),
7.97-7.95 (d, J=7.8 Hz, 1H), 7.85 (s, 2H), 7.46-7.42 (m, 1H), 7.09
(s, 1H), 3.31 (s, 3H), 3.19 (s, 3H).
Example 98: Synthesis of
6-((6-(3-methoxyazetidin-1-yl)pyridin-2-yl)amino)-2-methyl-4-((2-(methyls-
ulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-140
##STR00441##
[0637] Synthesis of compound 98.1. To a solution of
2-chloro-6-nitropyridine (2.0 g, 22.96 mmol, 1.5 eq) and
3-methoxyazetidine (2.43 g, 15.30 mmol, 1.0 eq) in dimethyl
sulfoxide (20 mL) was added sodium bicarbonate (2.57 g, 30.60 mmol,
2.0 eq). Reaction mixture was stirred at 80.degree. C. for 4 h.
After completion of reaction, reaction mixture was transferred into
water and extracted with ethyl acetate. Organic layer was combined,
dried over sodium sulphate and concentrated under reduced pressure
to obtain crude material. This was further purified by column
chromatography and compound was eluted in 20% ethyl acetate in
hexane as eluant to obtain pure 98.1 (2.0 g, 62.47%). MS(ES): m/z
210.21 [M+H].sup.+.
[0638] Synthesis of compound 98.2. To a solution of 1.2 (2.0 g,
9.56 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal
(0.4 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 98.2. (1.5 g,
87.55%). MS(ES): m/z 180.22 [M+H].sup.+.
[0639] Compound I-140 was prepared from compound 86.2 and 98.2
using procedure described in Example 2 (Yield: 12.34%), MS(ES): m/z
496.38 [M+H].sup.+, LCMS purity: 99.42%, HPLC purity: 100.00%, 1H
NMR (DMSO-d6, 400 MHz): 10.593 (s, 1H), 9.492 (s, 1H), 8.906 (s,
1H), 7.950-7.932 (d, J=7.2 Hz, 1H), 7.802 (s, 2H), 7.534-7.391 (m,
3H), 6.986 (s, 1H), 5.879-5.860 (d, J=7.6 Hz, 1H), 4.179-4.060 (m,
1H), 3.951-3.722 (m, 2H), 3.590-3.484 (m, 2H), 3.265 (s, 3H), 3.201
(s, 3H), 3.182 (s, 3H).
Example 99: Synthesis of
2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-6-(pyridin-2-ylamino)-1,2-di-
hydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-142
##STR00442##
[0641] Compound I-142 was prepared from compound 86.2 and
pyridin-2-amine using procedure described in Example 2 (Yield:
27.77%), MS(ES): m/z 411.39 [M+H].sup.+, LCMS purity: 93.51%, HPLC
purity: 96.50%, 1H NMR (DMSO-d6, 400 MHz): 10.73 (s, 1H), 9.81 (s,
1H), 9.10 (s, 1H), 8.21 (s, 1H), 7.96-7.94 (d, J=7.6 Hz, 2H),
7.88-7.79 (m, 2H), 7.69 (s, 1H), 7.41 (s, 1H), 7.15 (s, 1H), 6.92
(s, 1H), 3.28 (s, 3H), 3.19 (s, 3H).
Example 100: Synthesis of
6-((5-cyclopropylpyridin-2-yl)amino)-2-methyl-4-((2-(methylsulfonyl)pheny-
l)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-143
##STR00443##
[0643] Synthesis of compound 100.1. To a solution of
5-bromopyridin-2-amine (1 g, 5.78 mmol, 1.0 eq) in mixture of
toluene (12 mL) and water (1 mL) were added cyclopropyl boronic
acid (0.65 g, 7.51 mmol, 1.3 eq) and potassium phosphate (2.45 g,
11.56 mmol, 2.0 eq). The reaction mixture was degassed for 10 min
under argon atmosphere, and palladium acetate (0.13 g, 0.578 mmol,
0.1 eq) and Tricyclohexylphosphine (0.324 g, 1.15 mmol, 0.2 eq)
were added. Reaction mixture was again degassed for 10 min and
stirred at 110.degree. C. for 3 h. After completion of reaction,
reaction mixture was transferred into water and extracted with
ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 20% ethyl acetate in hexane as eluent to
obtain 101.1. (0.5 g, 64.47%). MS(ES): m/z 135.18 [M+H].sup.+.
[0644] Compound I-143 was prepared from compound 86.2 and compound
100.1 using procedure described in Example 2 (0.030 g, Yield:
15.66%). MS(ES): m/z 451.32 [M+H].sup.+, LCMS purity: 97.01%, HPLC
purity: 98.86%, 1H NMR (DMSO-d6, 400 MHz): 10.67 (s, 1H), 9.71 (s,
1H), 9.07 (s, 1H), 8.04 (s, 1H), 7.95-7.93 (d, J=8.8 Hz, 1H),
7.85-7.81 (m, 3H), 7.40-7.33 (m, 2H), 7.07 (s, 1H), 3.26 (s, 3H),
3.18 (s, 3H), 1.88 (m, 1H), 0.93 (m, 2H), 0.67 (m, 2H).
Example 101: Synthesis of
3-(azetidin-1-yl)-6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo--
2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile,
I-144
##STR00444##
[0646] Synthesis of compound 101.1. To 6-bromopyridin-2-amine (2.0
g, 11.56 mmol, 1.0 eq) in dimethylformamide (1 ml) was added zinc
cyanide (1.35 g, 11.56 mmol, 1.0 eq). The reaction mixture was then
heated in microwave at 150.degree. C. for 15 min. After completion
of reaction, reaction mixture was transferred into water and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 20% ethyl acetate in
hexane to obtain 101.1. (1.0 g, Yield: 72.62%). MS (ES): m/z 120.13
[M+H].sup.+.
[0647] Synthesis of compound 101.2. To compound 101.1 (1.0 g, 8.39
mmol, 1.0 eq) in acetonitrile was added N-Bromosuccinimide (2.24 g,
12.58 mmol, 1.5 eq). The reaction mixture was stirred at room
temperature for 12 h. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Organic layer was combined, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 25% ethyl acetate in hexane to obtain 101.2. (0.42 g,
Yield: 25.27%). MS (ES): m/z 199.02 [M+H].sup.+.
[0648] Synthesis of compound 101.3. To a solution of 101.2 (2.0 g,
10.10 mmol, 1.0 eq) 1,4-dioxane (20 mL) was added azetidine
hydrochloride (1.9 g, 20.20 mmol, 2.0 eq) followed by
Tris(dibenzylideneacetone)dipalladium(0) (0.277 g, 0.303 mmol, 0.03
eq), 9,9-Dimethyl-4,5-bis(dI-tert-butylphosphino)xanthene (0.351 g,
0.606 mmol, 0.06 eq) and cesium carbonate (16.4 g, 50.50 mmol, 5.0
eq). The reaction mixture was degassed by argon for 30 min. Further
reaction mixture was stirred at 120.degree. C. for 5 h. After
completion of reaction, water was added to reaction mixture and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 20% ethyl acetate in
hexane to obtain pure 102.3 (0.52 g, 29.95%). MS(ES): m/z 175.21
[M+H].sup.+.
[0649] Compound I-144 was prepared from compound 73.1 and compound
101.3 using procedure described in Example 2 (Yield: 14.22%).
MS(ES): m/z 477.31 [M+H].sup.+, LCMS purity: 97.17%, HPLC purity:
95.19%, 1H NMR (DMSO-d6, 400 MHz): 10.65 (s, 1H), 9.87 (s, 1H),
8.95 (s, 1H), 7.79-7.77 (d, J=8.4 Hz, 1H), 7.62-7.61 (d, J=8.4 Hz,
1H), 7.45 (s, 1H), 7.27-7.13 (m, 3H), 4.10-4.06 (m, 4H), 3.81 (s,
3H), 3.26 (s, 3H), 2.36-2.29 (m, 2H).
Example 102: Synthesis of
(S)-6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-
-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(3-methoxypyrrolidin-1-yl)picolinoni-
trile, I-145
##STR00445##
[0651] Synthesis of compound 102.1. To a solution of
6-amino-3-bromopicolinonitrile (0.5 g, 7.57 mmol, 1.0 eq) in
1,4-dioxane (20 mL) was added (S)-3-methoxypyrrolidine
hydrochloride (2.1 g, 15.14 mmol, 2.0 eq),
Tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.227 mmol, 0.03
eq), 9,9-Dimethyl-4,5-bis(dI-tert-butylphosphino)xanthene (0.26 g,
0.454 mmol, 0.06 eq) and potassium carbonate (3.13 g, 22.71 mmol,
3.0 eq). The reaction mixture was degassed by argon for 30 min.
Further reaction mixture was stirred at 120.degree. C. for 5 h.
After completion of reaction, water was added to reaction mixture
and extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 20% ethyl acetate in
hexane to obtain pure 102.1 (0.055 g, 9.07%). MS(ES): m/z 219.26
[M+H].sup.+.
[0652] Compound I-145 was prepared from compound 73.1 and compound
102.1 using procedure described in Example 2 (Yield: 16.28%).
MS(ES): m/z 522.31 [M+H].sup.+, LCMS purity: 93.16%, HPLC purity:
91.93%, 1H NMR (DMSO-d6, 400 MHz): 10.66 (s, 1H), 9.86 (s, 1H),
8.99 (s, 1H), 7.82-7.81 (d, J=6.4 Hz, 1H), 7.66-7.64 (d, J=7.8 Hz,
1H), 7.46 (s, 1H), 7.39-7.37 (d, J=9.6 Hz, 1H), 7.31-7.27 (t, J=7.8
Hz, 1H), 7.19-7.18 (d, J=7.8 Hz, 1H), 4.10 (s, 1H), 3.84 (s, 3H),
3.73-3.70 (m, 1H), 3.59-3.49 (m, 3H), 3.28 (s, 6H), 2.09-2.03 (m,
2H).
Example 103:
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-cyclopropylpyrazine-2-carbonitrile,
I-146
##STR00446##
[0654] Synthesis of compound 103.1. To a solution of
6-amino-3-bromopyrazine-2-carbonitrile (1 g, 5.02 mmol, 1.0 eq) in
mixture of toluene (12 mL) and water (1 mL) was added Potassium
cyclopropyltrifluoroborate (0.965 g, 6.526 mmol, 1.3 eq), potassium
phosphate (2.13 g, 10.04 mmol, 2.0 eq). The reaction mixture was
degassed for 10 min under argon atmosphere, and then
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride
complex with dichloromethane (0.205 g, 0.251 mmol, 0.05 eq) was
added, again degassed for 10 min. The reaction was then stirred at
110.degree. C. for 3 h. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Organic layer was combined, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 20% ethyl acetate in hexane as eluent to obtain 103.1.
(0.49 g, 60.88%). MS(ES): m/z 161.18 [M+H].sup.+.
[0655] Compound I-146 was prepared from compound 73.1 and compound
103.1 using procedure described in Example 2 (Yield: 15.66%).
MS(ES): m/z 463.25 [M+H].sup.+, LCMS purity: 98.63%, HPLC purity:
96.05%, 1H NMR (DMSO-d6, 400 MHz): 10.53 (bs, 2H), 9.21 (s, 1H),
8.98 (s, 1H), 7.64-7.62 (d, J=6.4 Hz, 1H), 7.29-7.23 (m, 3H), 3.84
(s, 3H), 3.32 (s, 3H), 2.34-2.29 (m, 1H), 1.16-1.13 (m, 2H), 1.01
(m, 2H).
Example 104: Synthesis of
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-ethylpyrazine-2-carbonitrile,
I-147
##STR00447##
[0657] Synthesis of compound 104.1. To a solution of
6-amino-3-bromopyrazine-2-carbonitrile (0.2 g, 1.0 mmol, 1.0 eq) in
mixture of toluene (2.5 mL) and water (0.5 mL) were added
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.201 g, 1.31
mmol, 1.3 eq) and potassium phosphate (0.424 g, 2.0 mmol, 2.0 eq).
The reaction mixture was degassed for 10 min under argon
atmosphere, and palladium acetate (0.022 g, 0.1 mmol, 0.1 eq) and
Tricyclohexylphosphine (0.056 g, 0.2 mmol, 0.2 eq) were added.
Reaction mixture was again degassed for 10 min and stirred at
100.degree. C. for 24 h. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Organic layer was combined, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 15% ethyl acetate in hexane as eluent to obtain 104.1.
(0.12 g, 81.70%). MS(ES): m/z 147.15 [M+H].sup.+.
[0658] Synthesis of compound 104.2. To a solution of 104.1 (0.12 g,
0.821 mmol, 1.0 eq) in ethanol (5 mL), 10% palladium on charcoal
(0.030 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filter through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 104.2 (0.09 g,
73.98%). MS(ES): m/z 149.17 [M+H].sup.+.
[0659] Compound I-147 was prepared from compound 73.1 and compound
104.2 using procedure described in Example (Yield: 20.34%). MS(ES):
m/z 451.25 [M+H].sup.+, LCMS purity: 98.20%, HPLC purity: 96.27%,
1H NMR (DMSO-d6, 400 MHz): 10.92 (s, 1H), 10.54 (s, 1H), 9.27 (s,
1H), 8.96 (s, 1H), 7.63-7.61 (dd, J=2.0 Hz, 7.2 Hz, 1H), 7.33 (s,
1H), 7.27-7.24 (m, 2H), 3.83 (s, 3H), 3.32 (s, 3H), 2.93-2.87 (q,
J=7.2 Hz, 2H), 1.29-1.25 (t, J=7.2 Hz, 3H).
Example 106: Synthesis of
3-ethyl-6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydr-
o-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitrile,
I-148
##STR00448##
[0661] Compound I-148 was prepared from compound 56.1 and
6-amino-3-ethylpyrazine-2-carbonitrile using procedure described in
Example 2 (Yield: 18.57%). MS(ES): m/z 435.24 [M+H].sup.+, LCMS
purity: 96.91%, HPLC purity: 96.60%, 1H NMR (DMSO-d6, 400 MHz):
10.90 (s, 1H), 10.54 (s, 1H), 9.26 (s, 1H), 8.92 (s, 1H), 7.47-7.45
(d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.25-7.20 (m, 1H), 3.05 (t, 1H),
3.90 (s, 3H), 3.31 (s, 3H), 2.91-2.87 (q, J=7.2 Hz, 2H), 1.29-1.25
(t, J=7.2 Hz, 3H).
Example 106: Synthesis of
4-((4-chloro-2-(methylsulfonyl)phenyl)amino)-6-((2,6-dimethylpyrimidin-4--
yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-199
##STR00449##
[0663] Compound I-199 was prepared from
2,6-dimethylpyrimidin-4-amine and 118.4 using procedure described
in Example 2 (Yield: 14.71%). MS(ES): m/z 474.15 [M+H].sup.+, LCMS
purity: 98.47%, HPLC purity: 97.08%, 1H NMR (DMSO-d6, 400 MHz):
11.20 (bs, 2H), 9.23 (s, 1H), 7.93-7.85 (m, 3H), 3.34 (s, 3H), 3.28
(s, 3H), 2.56 (s, 3H), 2.49 (s, 3H).
Example 107: Synthesis of
6-((4-((4-chloro-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo-2,3-dihyd-
ro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-203
##STR00450##
[0665] Compound I-203 was prepared from 6-aminopicolinonitrile and
118.4 using procedure described in Example 2 (Yield: 17.58%).
MS(ES): m/z 470.27 [M+H].sup.+, LCMS purity: 100.00%, HPLC purity:
98.56%, 1H NMR (DMSO-d6, 400 MHz): 10.71 (bs, 1H), 10.29 (s, 1H),
9.18 (s, 1H), 8.04-8.02 (d, J=8.4 Hz, 1H), 7.94-7.85 (m, 3H),
7.54-7.52 (d, J=7.2 Hz, 1H), 7.27 (s, 1H), 3.29 (s, 3H), 3.26 (s,
3H).
Example 108: Synthesis of
4-((4-chloro-2-(methylsulfonyl)phenyl)amino)-6-((5,6-dimethylpyrazin-2-yl-
)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-207
##STR00451##
[0667] Compound I-207 was prepared from 5,6-dimethylpyrazin-2-amine
and 118.4 using procedure described in Example 2 (Yield: 19.06%).
MS(ES): m/z 474.32 [M+H].sup.+, LCMS purity: 100.00%, HPLC purity:
98.78%, 1H NMR (DMSO-d6, 400 MHz): 10.75 (bs, 1H), 9.97 (s, 1H),
9.10 (s, 1H), 8.89 (s, 1H), 7.90-7.86 (m, 3H), 7.09 (s, 1H), 3.29
(s, 3H), 3.26 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H).
Example I-109: Synthesis of
4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-6-((2,6-dimethylpyrimid-
in-4-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-206
##STR00452## ##STR00453##
[0669] Synthesis of compound 109.1. To a solution of
2-fluoro-4-bromonitrobenzene (1.0 g, 4.55 mmol, 1.0 eq) in mixture
of toluene (12 mL) and water (5 mL) were added cyclopropyl boronic
acid (0.51 g, 5.91 mmol, 1.3 eq) and potassium carbonate (1.25 g,
9.1 mmol, 2.0 eq). The reaction mixture was degassed for 10 min
under argon atmosphere, and palladium acetate (0.102 g, 0.455 mmol,
0.1 eq) and Tricyclohexylphosphine (0.255 g, 0.91 mmol, 0.2 eq)
were added. Reaction mixture was again degassed for 10 min and
stirred at 80.degree. C. for 5 h. After completion of reaction,
reaction mixture was transferred into water and extracted with
ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 10% ethyl acetate in hexane as eluent to
obtain 109.1. (0.81 g, 98.36%). MS(ES): m/z 182.17 [M+H].sup.+.
[0670] Synthesis of compound 109.2. To a solution of 109.1 (0.81 g,
4.47 mmol, 1.0 eq) and sodium thiomethoxide (0.313 g, 4.47 mmol,
1.0 eq) in N,N-Dimethylformamide (10 mL) was added. Reaction
mixture was stirred at 150.degree. C. for 5 h. After completion of
reaction, reaction mixture was transferred into water and extracted
with ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 15% ethyl acetate in hexane as eluent to
obtain 110.2. (0.78 g, 83.37%). MS(ES): m/z 210.26 [M+H].sup.+.
[0671] Synthesis of compound 109.3. To a solution of 109.2 (0.78 g,
3.73 mmol, 1.0 eq) in ethanol (10 mL), 10% palladium on charcoal
(0.060 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 109.3 (0.63 g,
94.28%). MS(ES): m/z 180.28 [M+H].sup.+.
[0672] Synthesis of compound 109.4. Compound was synthesized from
109.3 and 1.9 using general procedure A to obtain 109.4 (Yield:
58.41%). MS (ES): m/z 361.86 [M+H].sup.+.
[0673] Synthesis of compound 109.5. To a solution of 109.4 (0.58 g,
1.61 mmol, 1 eq) in acetic acid (1.0 mL) was added 30% hydrogen
peroxide (1.1 g, 32.2 mmol, 20 eq) and sodium tungstate dihydrate
(0.53 g, 1.61 mmol, 1 eq). Reaction mixture was stirred at room
temperature for 2 h. After completion of reaction, reaction mixture
was transferred in ice-water and precipitated product was filtered,
washed with 50% ethyl acetate in hexane and dried well to obtain
109.5. (0.36 g, Yield: 57.01%). MS(ES): m/z 393.86 [M+H].sup.+.
[0674] Compound I-206 was prepared from
2,6-dimethylpyrimidin-4-amine and compound 109.5 using procedure
described in Example 2 (Yield: 5.69%). MS(ES): m/z 480.42
[M+H].sup.+, LCMS purity: 94.51%, HPLC purity: 95.04%, 1H NMR
(DMSO-d6, 400 MHz): 10.81 (s, 1H), 10.08 (s, 1H), 9.01 (s, 1H),
7.74-7.72 (d, J=8.4 Hz, 1H), 7.68-7.67 (d, J=2.0 Hz, 1H), 7.49-7.38
(m, 2H), 7.28 (s, 1H), 3.29 (s, 3H), 3.17 (s, 3H), 2.36 (s, 3H),
2.32 (s, 3H), 2.10-2.13 (m, 1H), 1.05-1.10 (m, 2H), 0.76-1.73 (m,
2H).
Example 110: Synthesis of
4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-6-((5,6-dimethylpyrazin-
-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-211
##STR00454##
[0676] Compound I-211 was prepared from 5,6-dimethylpyrazin-2-amine
and compound 109.5 using procedure described in Example 2 (Yield:
17.07%). MS(ES): m/z 480.25 [M+H].sup.+, LCMS purity: 98.64%, HPLC
purity: 96.56%, 1H NMR (DMSO-d6, 400 MHz): 10.75 (bs, 1H), 9.97 (s,
1H), 9.10 (s, 1H), 8.89 (s, 1H), 7.90-7.86 (m, 3H), 7.09 (s, 1H),
3.29 (s, 3H), 3.26 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 2.12-2.07
(m, 1H), 1.16-1.11 (m, 2H), 0.83-0.79 (m, 2H).
Example 111: Synthesis of
6-((4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo-2,3--
dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitrile,
I-212
##STR00455##
[0678] Compound I-212 was prepared from
6-aminopyrazine-2-carbonitrile and compound 109.5 using procedure
described in Example 2 (Yield: 13.40%). MS(ES): m/z 477.36
[M+H].sup.+, LCMS purity: 97.15%, HPLC purity: 96.84%, 1H NMR
(DMSO-d6, 400 MHz): 10.89 (s, 1H), 10.63 (s, 1H), 9.22 (s, 1H),
9.12 (s, 1H), 8.63 (s, 1H), 7.78-7.76 (d, J=8.8 Hz, 1H), 7.71-7.70
(d, J=1.6 Hz, 1H), 7.48-7.46 (d, J=7.2 Hz, 1H), 7.23 (s, 1H), 3.30
(s, 3H), 3.16 (s, 3H), 2.11-2.07 (m, 1H), 1.05-1.02 (m, 2H),
0.79-1.77 (m, 2H).
Example 112: Synthesis of
N-(4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo-2,3-d-
ihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-201
##STR00456##
[0680] Compound I-112 was prepared from cyclopropanecarboxamide and
compound 109.5 using procedure described in Example 2 (Yield:
3.71%). MS(ES): m/z 442.29 [M+H].sup.+, LCMS purity: 97.07%, HPLC
purity: 95.46%, 1H NMR (MeOD, 400 MHz): 7.77 (s, 1H), 7.72-7.70 (d,
J=8.0 Hz, 1H), 7.51-7.49 (d, J=8.0 Hz, 2H), 3.48 (s, 3H), 3.09 (s,
3H), 2.10-2.06 (m, 1H), 1.83 (m, 1H), 1.13-1.09 (m, 2H), 0.99-0.93
(m, 4H), 0.83-0.79 (m, 2H).
Example 113: Synthesis of
6-((4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo-2,3--
dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile,
I-213
##STR00457##
[0682] Compound I-213 was prepared from 6-aminonicotinonitrile and
compound 109.5 using procedure described in Example 2 (Yield:
15.34%). MS(ES): m/z 476.25 [M+H].sup.+, LCMS purity: 98.48%, HPLC
purity: 95.09%, 1H NMR (DMSO-d6, 400 MHz): 10.91 (s, 1H), 10.37 (s,
1H), 9.02 (s, 1H), 8.66 (s, 1H), 8.13 (s, 2H), 7.72-7.70 (d, J=8.0
Hz, 1H), 7.65-7.64 (d, J=2.0 Hz, 1H), 7.53-7.51 (dd, J=2.0 Hz, 8.0
Hz, 1H), 6.98 (s, 1H), 3.29 (s, 3H), 3.16 (s, 3H), 2.13-2.08 (m,
1H), 1.08-1.03 (m, 2H), 0.79-0.75 (m, 2H).
Example 114: Synthesis of
6-((4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo-2,3--
dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile,
I-33
##STR00458##
[0684] Synthesis of compound 114.1. Compound was synthesized from
3-amino-2-methoxybenzonitrile and 1.9 using general procedure A to
obtain 114.1 (Yield: 66.12%). MS(ES): m/z 330.74 [M+H].sup.+.
[0685] Compound I-33 was prepared from cyclopropanecarboxamide and
compound 115.1 using procedure described in Example 2 (Yield:
11.62%). MS(ES): m/z 379.23 [M+H].sup.+, LCMS purity: 99.15%, HPLC
purity: 96.87%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (bs, 2H), 8.81 (s,
1H), 7.80-7.78 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.58-7.56 (d, J=6.8
Hz, 1H), 7.39-7.35 (t, J=8.0 Hz, 1H), 3.96 (s, 3H), 3.34 (s, 3H),
2.03-2.00 (m, 1H), 0.81-0.80 (m, 4H).
Example 115: Synthesis of
N-(2-methyl-4-((2-(N-methylmethylsulfonamido)phenyl)amino)-3-oxo-2,3-dihy-
dro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-129
##STR00459##
[0687] Synthesis of compound 115.1. To a solution of N-Methyl
methane sulfonamide (0.85 g, 7.79 mmol, 1.1 eq) in acetonitrile (10
mL) was added cesium carbonate (0.608 g, 14.18 mmol, 2.0 eq). The
reaction mixture was stirred at room temperature for 30 min.
1-Fluoro-2-nitrobenzene (1.0 g, 7.09 mmol, 1.0 eq) was added
dropwise into reaction mixture and stirred at room temperature for
3 h. After completion of reaction, reaction mixture was filtered.
Filtered solid was transferred into water, stirred for 30 min and
dried under reduced pressure to obtain pure 115.1. (0.48 g,
29.42%). MS(ES): m/z 231.24 [M+H].sup.+.
[0688] Synthesis of compound 115.2. To a solution of 115.1 (0.48 g,
2.08 mmol, 1.0 eq) in methanol (1 mL), 10% palladium on charcoal
(0.08 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 115.2 (0.322 g,
77.13%). MS(ES): m/z 201.26 [M+H].sup.+.
[0689] Synthesis of compound 115.3. Compound 115.3 was synthesized
from 1.9 and 115.2 using general procedure A (Yield: 34.26%).
[0690] Compound I-129 was prepared from cyclopropanecarboxamide and
compound 115.3 using procedure described in Example 2 (Yield:
18.48%). MS(ES): m/z 431.35 [M+H].sup.+, LCMS purity: 100.00%, HPLC
purity: 98.23%, 1H NMR (DMSO-d6, 400 MHz): 10.74 (s, 2H), 8.84 (s,
1H), 7.70 (s, 1H), 7.61-7.57 (t, J=7.2 Hz, 2H), 7.47-7.45 (t, J=6.8
Hz, 1H), 7.25-7.23 (t, J=6.8 Hz, 1H), 3.34 (s, 6H), 3.16 (s, 3H),
1.24 (m, 1H), 0.87-0.72 (m, 4H).
Example 116: Synthesis of I-133
##STR00460## ##STR00461##
[0692] Synthesis of compound 116.1. To a solution of
5-bromo-1H-imidazole (3.0 g, 20.41 mmol, 1.0 eq) in dichloromethane
(30 mL) were added triethyl amine (5.833 g, 57.76 mmol, 2.83 eq).
Trityl chloride (6.15 g, 22.04 mmol, 1.08 eq) was added dropwise
into reaction mixture at 0.degree. C. The reaction mixture was
stirred at room temperature for 3 h. After completion of reaction,
reaction mixture was transferred into water and product was
extracted with dichloromethane. Combined organic layer washed with
brine solution, dried over sodium sulfate and concentrated under
reduced pressure to obtain crude material. This was further
triturated with diethyl ether to obtain pure 116.1. (6.0 g,
75.51%). MS(ES): m/z 390.30 [M+H].sup.+.
[0693] Synthesis of compound 116.2. A mixture of 116.1 (3.0 g,
12.93 mmol, 1.0 eq), 1-bromo-2-methoxy-3-nitrobenzene (16.42 g,
64.65 mmol, 5.0 eq), Tetrakis(triphenylphosphine)palladium(0)
(0.746 g, 0.646 mmol, 0.05 eq) and potassium acetate (3.80 g, 38.79
mmol, 3.0 eq) in dimethoxyethane (15 mL) was degassed with argon
for 30 min. Further reaction mixture was refluxed for 16 h. After
completion of reaction, reaction mixture was cooled to room
temperature, transferred in water and extracted with ethyl acetate.
Combined organic layer dried over sodium sulfate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted in 20%
ethyl acetate in hexane to obtain pure 116.2 (3.0 g, 83.14%).
MS(ES): m/z 280.10 [M+H].sup.+.
[0694] Synthesis of compound 116.3. A mixture of 116.2 (3.0 g,
10.75 mmol, 1.0 eq), 116.1 (6.28 g, 16.12 mmol, 1.5 eq),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.393
g, 0.537 mmol, 0.05 eq) and potassium carbonate (4.45 g, 32.25
mmol, 3.0 eq) in mixture of toluene (25 mL) and water (09 mL) was
degassed with argon for 30 min. Further reaction mixture was
stirred at 110.degree. C. for 48 h. After completion of reaction,
reaction mixture was cooled to room temperature, transferred in
water and extracted with ethyl acetate. Combined organic layer
dried over sodium sulfate and concentrated under reduced pressure
to obtain crude material. This was further purified by column
chromatography and compound was eluted in 15% ethyl acetate in
hexane to obtain pure 116.3 (2.5 g, 50.39%). MS(ES): m/z 462.52
[M+H].sup.+.
[0695] Synthesis of compound 116.4. To a solution of 116.3 (2.5 g,
5.42 mmol, 1.0 eq) in ethanol (25 mL), 10% palladium on charcoal
(0.2 g) was added. Hydrogen was purged through reaction mixture for
2-3 h. After completion of reaction, reaction mixture was filter
through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 117.4 (1.79 g,
76.57%). MS(ES): m/z 432.54 [M+H].sup.+.
[0696] Synthesis of compound 116.5. Compound 116.5 was synthesized
from 1.9 and 116.4 using general procedure A (Yield: 49.79%).
[0697] Synthesis of compound 116.6. Compound was synthesized from
116.5 and 5-fluoro-4-methylpyridin-2-amine using general procedure
B (Yield: 28.66%).
[0698] Synthesis of compound I-133. To a solution of 116.6 (0.23 g,
0.327 mmol, 1.0 eq) in dichloromethane (3 mL) was added
trifluoroacetic acid (0.373 g, 3.27 mmol, 10.0 eq) at 0.degree. C.
The reaction mixture was stirred at room temperature for 2 h. After
completion of reaction, reaction mixture was transferred into
saturated solution of sodium bicarbonate. Reaction mixture was
extracted with ethyl acetate. Combined organic layer dried over
sodium sulfate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 5% methanol in dichloromethane as eluant to obtain pure I-133
(0.015 g, 9.95%). MS(ES): m/z 461.40 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 99.14%, 1H NMR (DMSO-d6, 400 MHz): 14.62 (bs,
1H), 10.75 (s, 1H), 9.26 (s, 1H), 9.09 (s, 1H), 8.24 (s, 1H), 8.09
(s, 1H), 7.64-7.60 (t, J=8.0 Hz, 2H), 7.44-7.37 (m, 2H), 6.29 (s,
1H), 3.68 (s, 3H), 3.43 (s, 3H), 2.30 (s, 3H).
Example 117: Synthesis of
N-(4-((3-fluoro-2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl)amino)-2-methy-
l-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide-
, I-141
##STR00462## ##STR00463##
[0700] Synthesis of compound 117.1. To a solution of
4-bromo-3-fluoro-2-methoxyaniline (2.0 g, 9.09 mmol, 1.0 eq) in
methanol (40 mL) was added triethyl amine (7.344 g, 72.72 mmol, 8.0
eq) and degassed with argon for 15 min.
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (0.742 g, 0.909 mmol, 0.1 eq) was
added and again degassed for 15 min. The reaction mixture was
stirred at 110.degree. C. under carbon monoxide atmosphere for 10
h. After completion of reaction, reaction mixture was filtered
through pad of celite. Filtrate was concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography and compound was eluted in 20% ethyl acetate
in hexane to obtain pure 117.1 (0.8 g, 44.19%). MS(ES): m/z 200.18
[M+H].sup.+.
[0701] Synthesis of compound 117.2. To a solution of 1.1 (0.8 g,
4.02 mmol, 1.0 eq) in methanol (40 mL) was added aqueous sodium
hydroxide (0.322 g, 8.04 mmol, 2.0 eq). The reaction mixture was
stirred at room temperature for 4 h. After completion of reaction,
reaction mixture was transferred into water and acidified with
citric acid. Obtained solid precipitate was washed with water
followed by hexane. The solid was dried under reduced pressure to
obtain pure 117.2 (0.8 g, 80.68%). MS(ES): m/z 186.15
[M+H].sup.+.
[0702] Synthesis of compound 113.3. To a solution of 117.2 (0.6 g,
3.24 mmol, 1.0 eq) and pyrrolidine (0.230 g, 3.24 mmol, 1.0 eq) in
dichloromethane (10 mL) was added triethylamine (0.981 g, 9.72
mmol, 3.0 eq). The reaction mixture was cooled to 0.degree. C. and
hydroxybenzotriazole (0.991 g, 6.48 mmol, 2.0 eq) was added and
stirred for 10 min followed by addition of
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.0 g, 6.48 mmol,
2.0 eq). Reaction mixture was stirred at room temperature for 4 h.
After completion of reaction, reaction mixture was transferred into
water and extracted with ethyl acetate. Combined organic layer
dried over sodium sulfate and concentrated under reduced pressure
to obtain crude material. This was further purified by column
chromatography and compound was eluted in 2% methanol in
dichloromethane to obtain pure 117.3 (0.485 g, 58.28%). MS(ES): m/z
238.26 [M+H].sup.+.
[0703] Synthesis of compound 117.4. Compound 117.4 was synthesized
from 1.9 and 118.3 using general procedure A (Yield: 51.93%).
[0704] Synthesis of compound I-141. Compound was synthesized from
117.4 and cyclopropanecarboxamide using general procedure B (Yield:
6.73%). MS(ES): m/z 469.42 [M+H].sup.+, LCMS purity: 95.09%, HPLC
purity: 98.20%, 1H NMR (DMSO-d6, 400 MHz): 10.83 (s, 2H), 8.95 (s,
1H), 7.83 (s, 1H), 7.36-7.34 (d, J=8.4 Hz, 1H), 7.22-7.19 (t, J=8.0
Hz, 1H), 3.91 (s, 3H), 3.48-3.45 (t, J=6.8 Hz, 2H), 3.32 (s, 3H),
3.29-3.26 (t, J=6.8 Hz, 2H), 2.03-1.99 (m, 1H), 1.90-1.82 (m, 4H),
0.88-0.80 (m, 4H).
Example 118: Synthesis of
4-((4-chloro-2-(methylsulfonyl)phenyl)amino)-2-methyl-6-((6-methylpyridaz-
in-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-157
##STR00464## ##STR00465##
[0706] Synthesis of compound 118.1. To a solution of
4-chloroaniline (3.0 g, 23.52 mmol, 1.0 eq) in acetic acid (90 mL)
were added Potassium thiocyanate (2.28 g, 23.52 mmol, 1.0 eq). The
reaction mixture was cooled at 10.degree. C. and bromine solution
(3.76 g, 23.52 mmol, 1.0 eq) was added dropwise. Reaction mixture
was further stirred at room temperature for 3 h. After completion
of reaction, reaction mixture was filtered and washed with acetic
acid. Filtered solid was heated in water and then neutralized with
aqueous ammonia to obtain solid which was filtered and dried well
to obtain pure 118.1. (2.5 g, 57.58%). MS(ES): m/z 185.64
[M+H].sup.+.
[0707] Synthesis of compound 118.2. To 118.1 (2.5 g, 13.54 mmol,
1.0 eq) a solution of potassium hydroxide (9.1 g, 162.48 mmol, 12.0
eq) in water (50 mL) was added. Reaction mixture was refluxed for
17 h. Reaction mixture was cooled to room temperature and methyl
iodide was added (2.1 g, 14.89 mmol, 1.1 eq) and stirred for 1 h.
After completion of reaction, reaction mixture was extracted with
ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 20% ethyl acetate in hexane as eluent to
obtain 118.2. (1.3 g, 55.29%). MS(ES): m/z 174.66 [M+H].sup.+.
[0708] Synthesis of compound 118.3. Compound 118.3 was synthesized
from 1.9 and 118.2 using general procedure A. (Yield: 46.03%). MS
(ES): m/z 356.24 [M+H].sup.+.
[0709] Synthesis of compound 118.4. To a solution of 118.3 (0.15 g,
0.422 mmol, 1 eq) in acetic acid (1.0 mL) was added 30% hydrogen
peroxide (0.287 g, 8.44 mmol, 20 eq) and sodium tungstate dihydrate
(0.14 g, 0.422 mmol, 1 eq). Reaction mixture was stirred at room
temperature for 2 h. After completion of reaction, reaction mixture
was transferred in ice-water and precipitated product was filtered,
washed with 5% ethyl acetate in hexane and dried well to obtain
118.4. (0.11 g, Yield: 67.27%). MS(ES): m/z 388.24 [M+H].sup.+.
[0710] Synthesis of compound I-157. Compound was synthesized from
118.4 and 6-methylpyridazin-3-amine using general procedure B to
obtain I-157 (Yield: 27.56%). MS(ES): m/z 460.32 [M+H].sup.+, LCMS
purity: 100.00%, HPLC purity: 99.62%, 1H NMR (DMSO-d6, 400 MHz):
10.94 (bs, 1H), 10.21 (s, 1H), 9.09 (s, 1H), 8.23-8.21 (d, J=8.4
Hz, 1H), 7.89-7.84 (m, 3H), 7.50-7.48 (d, J=8.8 Hz, 1H), 6.94 (s,
1H), 3.28 (s, 3H), 3.27 (s, 3H), 2.56 (s, 3H).
Example 119: Synthesis of
(1S,2S)--N-(4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3--
oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorocyclopropane-1-car-
boxamide, I-210
##STR00466##
[0712] Synthesis of compound 119.1. To a solution of
(1S,2S)-2-fluorocyclopropane-1-carboxylic acid (0.25 g, 2.40 mmol,
1.0 eq) in acetone (4 mL) were added triethyl amine (0.364 g, 3.6
mmol, 1.5 eq) and ethyl chloroformate (0.286 g, 2.64 mmol, 1.1 eq).
The reaction mixture was stirred at room temperature for 1 h.
Reaction mixture was filtered and added aqueous ammonia (4 mL) to
filtrate dropwise. Further, reaction mixture was stirred at room
temperature for 16 h. After completion of reaction, reaction
mixture was filtered. Filtered solid was dried under reduced
pressure to obtain pure 119.1. (0.2 g, 80.76%). MS(ES): m/z 104.10
[M+H].sup.+.
[0713] Synthesis of compound I-210. Compound was synthesized from
119.1 and 109.5 using general procedure B. (Yield: 11.11%). MS(ES):
m/z 460.41 [M+H].sup.+, LCMS purity: 97.95%, HPLC purity: 100.00%,
Chiral HPLC purity: 97%, 1H NMR (DMSO-d6, 400 MHz): 10.82 (s, 2H),
9.01 (s, 1H), 7.65-7.60 (m, 3H), 7.51-7.49 (d, J=7.2 Hz, 1H),
4.98-4.81 (m, 1H), 3.29 (s, 3H), 3.14 (s, 3H), 2.33-2.08 (m, 2H),
1.59-1.54 (m, 2H), 1.20-1.00 (m, 2H), 0.75-1.73 (m, 2H).
Example 120: Synthesis of
(1S,2S)-2-fluoro-N-(2-methyl-4-((2-(N-methylmethylsulfonamido)phenyl)amin-
o)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropane-1-carboxa-
mide, I-216
##STR00467##
[0715] Synthesis of compound I-216. Compound I-216 was synthesized
from 109.5 and 119.1 using general procedure B (Yield: 11.07%).
MS(ES): m/z 449.30 [M+H].sup.+, LCMS purity: 100.00%, HPLC purity:
98.69%, Chiral HPLC: 100%, 1H NMR (DMSO-d6, 400 MHz): 10.79 (s,
1H), 8.86 (s, 1H), 7.76 (s, 1H), 7.62-7.58 (m, 2H), 7.49-7.45 (t,
J=7.2 Hz, 1H), 7.27-7.23 (t, J=8.0 Hz, 1H), 5.01-4.80 (m, 1H), 3.16
(s, 6H), 2.54 (s, 3H), 2.23-2.21 (m, 1H), 1.66-1.55 (m, 1H),
1.19-1.10 (m, 1H).
Example 121: Synthesis of
N-(4-((4-chloro-2-(N-methylmethylsulfonamido)phenyl)amino)-2-methyl-3-oxo-
-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-228
##STR00468##
[0717] Synthesis of compound I-228. Compound I-228 was synthesized
from 118.4 and cyclopropanecarboxamide using general procedure B
(Yield: 27.98%). MS(ES): m/z 465.20 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 99.36%, 1H NMR (DMSO-d6, 400 MHz): 10.76 (s,
1H), 8.81 (s, 1H), 7.75-7.74 (d, J=2.4 Hz, 1H), 7.63-7.53 (m, 4H),
3.34 (s, 3H), 3.20 (s, 3H), 3.18 (s, 3H), 2.03-2.00 (qui, J=6.0 Hz,
1H), 0.81-0.79 (d, J=6.0 Hz, 4H).
Example 122: Synthesis of
N-(2-methyl-4-((4-methyl-2-(N-methylmethylsulfonamido)phenyl)amino)-3-oxo-
-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-229
##STR00469##
[0719] Synthesis of compound 122.1. A mixture of
N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (1.5 g, 4.85
mmol, 1.0 eq), trimethyl boroxine (1.83 g, 14.55 mmol, 3.0 eq),
Tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.242 mmol, 0.05
eq) and potassium carbonate (2.0 g, 14.55 mmol, 3.0 eq) in
1,4-dioxane (15 mL) were degassed with argon for 30 min. Further
reaction mixture was stirred at 110.degree. C. for 4 h. After
completion of reaction, reaction mixture was cooled to room
temperature, transferred in water and extracted with ethyl acetate.
Combined organic layer dried over sodium sulfate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted in 20%
ethyl acetate in hexane to obtain pure 122.1 (0.9 g, 75.93%).
MS(ES): m/z 245.27 [M+H].sup.+.
[0720] Synthesis of compound 122.2. To a solution of 123.1 (0.9 g,
3.68 mmol, 1.0 eq) in ethanol (5 mL), 10% palladium on charcoal
(0.2 g) was added. Hydrogen was purged through reaction mixture for
2-3 h. After completion of reaction, reaction mixture was filter
through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 122.2 (0.7 g,
88.66%). MS(ES): m/z 215.28 [M+H].sup.+.
[0721] Synthesis of compound 122.3. Compound 122.3 was synthesized
from 122.2 and 1.9 using general procedure A (Yield: 41.31%).
[0722] Synthesis of compound I-229. Compound was synthesized from
122.3 and 1.9 using general procedure B. (Yield: 29.69%). MS(ES):
m/z 445.32 [M+H].sup.+, LCMS purity: 99.31%, HPLC purity: 98.78%,
1H NMR (MeOD, 400 MHz): 7.52-7.50 (d, J=8.0 Hz, 1H), 7.45 (s, 2H),
7.33-7.31 (d, J=8.0 Hz, 1H), 3.48 (s, 3H), 3.27 (s, 3H), 3.07 (s,
3H), 2.43 (s, 3H), 1.80 (m, 1H), 1.03-0.94 (m, 4H).
Example 123: Synthesis of
4-((4-chloro-2-(methylsulfonyl)phenyl)amino)-2-methyl-6-((6-(trifluoromet-
hyl)-pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-209
##STR00470##
[0724] Synthesis of compound I-209. Compound I-209 was synthesized
from 118.4 and 6-(trifluoromethyl)pyridin-2-amine using general
procedure B (Yield: 12.58%). MS(ES): m/z 513.34 [M+H].sup.+, LCMS
purity: 98.38%, HPLC purity: 97.15%, 1H NMR (DMSO-d6, 400 MHz):
10.90 (s, 1H), 10.27 (s, 1H), 9.10 (s, 1H), 8.14-8.12 (d, J=8.0 Hz,
1H), 7.97-7.78 (m, 4H), 7.39-7.37 (d, J=8.0 Hz, 1H), 7.19 (s, 1H),
3.30 (s, 3H), 3.27 (s, 3H).
Example 124: Synthesis of
4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-6-((6-(trifluo-
romethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-215
##STR00471##
[0726] Synthesis of compound I-215. Compound I-215 was synthesized
using from 109.5 and 6-(trifluoromethyl)pyridin-2-amine general
using procedure B (Yield: 19.70%). MS(ES): m/z 519.39 [M+H].sup.+,
LCMS purity: 96.47%, HPLC purity: 97.77%, 1H NMR (DMSO-d6, 400
MHz): 10.77 (s, 1H), 10.21 (s, 1H), 8.96 (s, 1H), 8.10-8.08 (d,
J=8.0 Hz, 1H), 7.95-7.91 (t, J=8.0 Hz, 1H), 7.69-7.67 (d, J=8.0 Hz,
2H), 7.42-7.40 (d, J=8.0 Hz, 1H), 7.36-7.34 (d, J=8.0 Hz, 1H), 7.12
(s, 1H), 3.28 (s, 3H), 3.15 (s, 3H), 2.11 (m, 1H), 10.6-1.04 (m,
2H), 0.75-0.74 (m, 2H).
Example 125: Synthesis of
N-(4-((4-chloro-2-(N-methylmethylsulfonamido)phenyl)amino)-2-methyl-3-oxo-
-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-232
##STR00472##
[0728] Synthesis of compound I-232. Compound I-232 was synthesized
using from 125.1 (prepared in a manner analogous to 109.5) and
cyclopropanecarboxamide using procedure B (Yield: 25.62%). MS(ES):
m/z 471.37 [M+H].sup.+, LCMS purity: 98.97%, HPLC purity: 94.23%,
1H NMR (DMSO-d6, 400 MHz): 10.71 (s, 2H), 8.68 (s, 1H), 7.57 (s,
1H), 7.47-7.43 (d, J=8.4 Hz, 1H), 7.32-7.31 (d, J=2.4 Hz, 1H),
7.16-7.14 (d, J=8.0 Hz, 1H), 3.29 (s, 3H), 3.14 (s, 6H), 2.02-1.96
(m, 2H), 1.00-0.98 (m, 2H), 0.79-0.73 (m, 6H).
Example I-126: Synthesis of
4-((4-fluoro-2-(methylsulfonyl)phenyl)amino)-2-methyl-6-((6-methylpyridaz-
in-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-198
##STR00473##
[0730] Synthesis of compound I-198. Compound I-198 was synthesized
using from 126.1 (prepared in a manner analogous to 118.4) and
6-methylpyridazin-3-amine using procedure B (Yield: 9.48%). MS(ES):
m/z 444.32 [M+H].sup.+, LCMS purity: 97.70%, HPLC purity: 97.02%,
1H NMR (DMSO-d6, 400 MHz): 10.19 (s, 1H), 8.92 (s, 1H), 8.23-8.20
(d, J=12 Hz, 1H), 8.17 (s, 1H), 7.90-7.86 (m, 1H), 7.75-7.71 (m,
2H), 7.50-7.48 (d, J=8.0 Hz, 1H), 6.80 (s, 1H), 3.28 (s, 3H), 3.25
(s, 3H), 2.55 (s, 3H).
Example 127: Synthesis of
N-(2-methyl-4-((2-(N-methylmethylsulfonamido)-4-(trifluoromethyl)phenyl)
amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarbo-
xamide, I-235
##STR00474##
[0732] Synthesis of compound 127.1. To a solution of N-Methyl
methane sulfonamide (5.733 g, 52.60 mmol, 1.1 eq) in acetonitrile
(100 mL) were added cesium carbonate (31.18 g, 95.64 mmol, 2.0 eq).
The reaction mixture was stirred at room temperature for 30 min.
Compound 1 (10.0 g, 47.82 mmol, 1.0 eq) was added dropwise into
reaction mixture and stirred at room temperature for 3 h. After
completion of reaction, reaction mixture was filtered. Filtered
solid was transferred into water, stirred for 30 min and dried
under reduced pressure to obtain pure 127.1. (10 g, 70.11%).
MS(ES): m/z 299.24 [M+H].sup.+.
[0733] Synthesis of compound 127.2. To a solution of 128.1 (10.0 g,
33.53 mmol, 1.0 eq) in acetic acid (100 mL) was added zinc powder
(10.9 g, 167.65 mmol, 5.0 eq) portion wise. The reaction mixture
was stirred at room temperature for 20 h. After completion of
reaction, reaction mixture was transferred into saturated solution
of sodium bicarbonate. Reaction mixture was extracted with ethyl
acetate. Combined organic layer dried over sodium sulfate and
concentrated under reduced pressure to obtain crude material. This
was further triturated with diethyl ether to obtain pure 127.2.
(8.0 g, 88.94%). MS(ES): m/z 269.25 [M+H].sup.+.
[0734] Synthesis of compound 127.3. Compound 127.3 was synthesized
from 127.2 using general procedure A (Yield: 56.59%).
[0735] Synthesis of compound 127.4. Compound 127.4 was synthesized
from 128.3 and cyclopropanecarboxamide using procedure B (Yield:
54.99%).
[0736] Synthesis of compound I-235. To a solution of 127.4 (0.18 g,
0.31 mmol, 1.0 eq) in dichloromethane (4 mL) was added
trifluoroacetic acid (0.353 g, 3.1 mmol, 10.0 eq) at 0.degree. C.
The reaction mixture was stirred at room temperature for 2 h. After
completion of reaction, reaction mixture was transferred into
saturated solution of sodium bicarbonate. Reaction mixture was
extracted with ethyl acetate. Combined organic layer dried over
sodium sulfate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
and compound was eluted in 5% methanol in dichloromethane to obtain
pure I-235 (0.12 g, 77.92%). MS(ES): m/z 499.36 [M+H].sup.+, LCMS
purity: 95.31%, HPLC purity: 95.29%, 1H NMR (MeOD, 400 MHz): 7.92
(s, 1H), 7.90-7.88 (d, J=8.4 Hz, 1H), 7.80-7.78 (d, J=8.4 Hz, 1H),
7.45 (s, 1H), 3.48 (s, 3H), 3.34 (s, 3H), 3.18 (s, 3H), 1.87-1.84
(m, 1H), 1.03-0.90 (m, 4H).
Example 128: Synthesis of
N-(4-((2-(dimethylphosphoryl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H--
pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-125
##STR00475##
[0738] Synthesis of compound 128.1. To a solution of diethyl
phosphonate (5.0 g, 36.20 mmol, 1 eq) in tetrahydrofuran was added
methyl magnesium chloride (5.43 g, 72.4 mmol, 2 eq) and potassium
carbonate (14.98 g, 108.6 mmol, 3 eq). The reaction mixture was
stirred at 0.degree. C. for 4 h. After completion of reaction,
reaction mixture was transferred in water and extracted with ethyl
acetate. Organic layer was combined, dried over sodium sulphate and
concentrated under reduced pressure to obtain 128.1. (2.3 g,
81.39%). MS(ES): m/z 79.05 [M+H].sup.+.
[0739] Synthesis of compound 128.2. To a solution of 2-iodoaniline
(1.0 g, 4.57 mmol, 1.0 eq) in dimethylformamide (10 mL) were added
compound 128.1 (0.463 g, 5.94 mmol, 1.3 eq) and potassium phosphate
(1.937 g, 9.14 mmol, 2.0 eq). The reaction mixture was degassed for
10 min under argon atmosphere, and palladium acetate (0.103 g,
0.457 mmol, 0.1 eq) and
4,5-Bis(Diphenylphosphino)-9,9-dimethylxanthene (0.529 g, 0.914
mmol, 0.2 eq) were added. Reaction mixture was again degassed for
10 min and stirred at 120.degree. C. for 6 h. After completion of
reaction, reaction mixture was transferred into water and extracted
with ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 3% methanol in dichloromethane as eluent to
obtain 128.2. (0.48 g, 62.15%). MS(ES): m/z 170.16 [M+H].sup.+.
[0740] Synthesis of compound 128.3. Compound was synthesized from
1.9 and 128.2 using general procedure A to obtain 128.3 (Yield:
5.02%). MS(ES): m/z 351.74 [M+H].sup.+.
[0741] Synthesis of compound I-125. Compound I-125 was synthesized
from 128.3 and cyclopropanecarboxamide using general procedure B
(Yield: 19.32%). MS(ES): m/z 400.39 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 98.05%, 1H NMR (DMSO-d6, 400 MHz): 10.71 (s,
1H), 9.39 (s, 1H), 7.73-7.68 (dd, J=8.0 Hz, 12.0 Hz, 1H), 7.62-7.53
(m, 2H), 7.49 (s, 1H), 7.33-7.29 (t, J=7.6 Hz, 1H), 3.28 (s, 3H),
1.97-1.96 (m, 1H), 1.70 (s, 3H), 1.67 (s, 3H), 0.77-0.75 (m,
4H).
Example 129: Synthesis of
N-(4-((2-methoxy-3-(5-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-
-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-62
##STR00476## ##STR00477##
[0743] Synthesis of compound 129.1. To a solution of 1.4 (0.300 g,
1.28 mmol, 1.0 eq) in tetrahydrofuran (25 mL), was added
dihydropyran (0.430 g, 5.12 mmol, 4.0 eq) and Pyridinium
p-toluenesulfonate (0.032 g, 0.128 mmol, 0.1 eq)under nitrogen
atmosphere and stirred at 90.degree. C. for overnight. After
completion of reaction, reaction mixture was concentrated under
reduced pressure and to obtain crude material. This was further
purified by column chromatography and compound was eluted in 30%
ethyl acetate-hexane to get pure to get 1291.1 (0.325 g, 79.71%).
MS(ES): m/z 319.33 [M+H].sup.+.
[0744] Synthesis of compound 129.2. To a solution of 129.1 (0.325
g, 1.02 mmol, 1.0 eq) in ethanol (5 mL), 10% palladium on charcoal
(0.065 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filter through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 129.2 (0.215 g,
73.03%). MS(ES): m/z 289.35 [M+H].sup.+.
[0745] Synthesis of compound 129.3. To a solution of 1.9 (0.1 g,
0.458 mmol, 1.0 eq) and 129.2 (1.0 g, 1.603 mmol, 3.5 eq) in
Tetrahydrofuran (1 mL) at 0.degree. C. was added Lithium
bis(trimethylsilyl)amide (1M in THF) (2.0 mL, 1.603 mmol, 3.5 eq).
The resulting mixture was stirred at room temperature for 1 h.
After completion of reaction, reaction mixture was transferred in
water and washed with ethyl acetate. Aqueous layer was acidified
with 1N Hydrochloric acid, solid precipitated was filtered and
washed with water, dried well to obtain 129.3 (0.162 g, 75.16%). MS
(ES): m/z 470.93 [M+H].sup.+.
[0746] Synthesis of compound 129.4. To 129.3 (0.162 g, 0.344 mmol,
1.0 eq) in dimethylacetamide (2.5 mL) was added
cyclopropanecarboxamide (0.117 g, 1.376 mmol, 4.0 eq), cesium
carbonate (0.336 g, 1.032 mmol, 3.0 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0)(0.031 g, 0.034 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.0399 g,
0.069 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was then heated at 140.degree. C. under microwave
irradiation. After completion of reaction, reaction mixture was
transferred in water and extracted with ethyl acetate. Combined
organic layer was washed with brine, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by Preparative HPLC using 0.1% Formic acid in
water/Acetonitrile in gradient method. The pure fractions were
concentrated under reduced pressure to obtain pure 129.4 (0.120 g,
67.13%). MS(ES): m/z 519.58 [M+H]+
[0747] Synthesis of compound I-62. To a solution of 129.4 (0.120 g,
0.231 mmol, 1.0 eq) in dichloromethane (5 mL) cooled at 0.degree.
C. was added dropwise 4M HCl in dioxane and stirred for 1 h. After
completion of reaction, reaction mixture was concentrated under
reduced pressure and to obtain crude material which was dissolved
on methanol (5 mL) and neutralized with Tetraalkyl ammonium
carbonate polymer bound. Reaction mixture was filtered and filtrate
was concentrated under reduced pressure to obtain residue which was
triturated with diethyl ether to obtain pure I-62 (0.075 g,
74.60%). MS(ES): m/z 435.37 [M+H].sup.+, LCMS purity: 99.64%, HPLC
purity: 98.47%, 1H NMR (DMSO-d6, 400 MHz): 13.70 (s, 1H), 10.78 (s,
1H), 8.84 (s, 1H), 7.75 (s, 1H), 7.65-7.63 (d, J=7.2 Hz, 1H),
7.57-7.55 (d, J=8.4 Hz, 1H), 7.31-7.27 (d, J=7.2 Hz, 1H), 3.71 (s,
3H), 3.32 (s, 3H), 2.39 (s, 3H), 2.01 (s, 1H), 0.80 (s, 4H).
Example 130: Synthesis of
N-(4-((2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl)amino)-2-methyl-3-oxo-2-
,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-70
##STR00478##
[0749] Synthesis of compound 130.1. To a cooled solution of
3-methoxy-4-nitrobenzoic acid (1.5 g, 7.61 mmol, 1.0 eq) and
pyrrolidine (0.594 g, 8.37 mmol, 1.1 eq) in N,N-dimethylformamide
(15 mL) at 0.degree. C. was added
(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid
hexafluoro-
[0750] phosphate (5.78 g, 15.21 mmol, 2.0 eq) followed by
N,N-Diisopropylethylamine (2.95 g, 22.82 mmol, 3.0 eq). Reaction
mixture was stirred at room temperature for 16 h. After completion
of reaction, reaction mixture was transferred into water and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 50% ethyl acetate in
hexane as eluant to obtain pure 130.1 (1.0 g, 52.52%). MS(ES): m/z
251.25 [M+H].sup.+.
[0751] Synthesis of compound 130.2. To a solution of 130.1 (1.0 g,
3.99 mmol, 1.0 eq) in methanol (10 mL), 10% palladium on charcoal
(0.2 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 130.2. (0.8 g,
90.89%). MS(ES): m/z 221.27 [M+H].sup.+.
[0752] Synthesis of compound 130.3. Compound 130.3 was synthesized
from 1.9 and 130.2 using general procedure A (Yield: 43.41%). MS
(ES): m/z 402.85 [M+H].sup.+.
[0753] Synthesis of compound I-70. Compound I-70 was synthesized
from 130.3 and cyclopropanecarboxamide using general procedure B
(Yield: 44.6%), MS(ES): m/z 451.53 [M+H].sup.+, LCMS purity:
97.09%, HPLC purity: 95.0%, 1H NMR (DMSO-d6, 400 MHz): 10.77 (s,
2H), 8.75 (s, 1H), 7.82 (s, 1H), 7.49-7.47 (d, J=8.0 Hz, 1H), 7.25
(s, 1H), 7.20-7.18 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.48 (s, 4H),
3.30 (s, 3H), 2.02 (s, 1H), 1.85 (s, 4H), 0.81 (s, 4H).
Example 131: Synthesis of
N-(4-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-2-methyl-3-oxo-2,-
3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-71
##STR00479##
[0755] Synthesis of compound 131.1. To a cooled solution of
3-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol, 1.0 eq) and
morpholine (0.485 g, 5.57 mmol, 1.1 eq) in N,N-dimethylformamide
(10 mL) at 0.degree. C. was added
(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxi-
de hexafluorophosphate) (3.85 g, 10.14 mmol, 2.0 eq) followed by
N,N-Diisopropylethylamine (1.96 g, 15.21 mmol, 3.0 eq). Reaction
mixture was stirred at room temperature for 16 h. After completion
of reaction, reaction mixture was transferred into water and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
pressure to obtain crude material. This was further purified by
column chromatography and compound was eluted in 50% ethyl acetate
hexane to obtain pure 131.1 (1.2 g, 88.85%). MS(ES): m/z 267.25
[M+H].sup.+.
[0756] Synthesis of compound 131.2. To a solution of 131.1 (1.2 g,
4.51 mmol, 1.0 eq) in methanol (12 mL), 10% palladium on charcoal
(0.25 g) was added. Hydrogen was purged through reaction mixture
for 4 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 131.2. (0.9 g,
84.52%). MS(ES): m/z 237.27 [M+H].sup.+.
[0757] Synthesis of compound 131.3. Compound was synthesized from
1.9 and 131.2 using general procedure A to obtain 131.3 (Yield:
33.92%). MS (ES): m/z 418.85 [M+H].sup.+.
[0758] Synthesis of compound I-71. Compound I-71 was synthesized
from 131.3 and cyclopropanecarboxamide using general procedure B
(0.005 g, 1.72%). MS (ES): m/z 467.35 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 99.34%, 1H NMR (MeOD, 400 MHz): 7.64-7.62 (d,
J=8.4 Hz, 1H), 7.20 (s, 1H), 7.14-7.12 (d, J=8.0 Hz, 2H), 3.99 (s,
3H), 3.73 (bs, 4H), 3.67 (bs, 4H), 3.48 (s, 3H), 1.83 (s, 1H),
1.04-1.02 (m, 2H), 0.98-0.90 (m, 2H).
Example 132: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-6-((5-fluoro-4-methylpyridin-2-yl)ami-
no)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-73
##STR00480##
[0760] Synthesis of compound 55.1. Compound 55.1 was synthesized
from 1.9 and 3-fluoro-2-methoxyaniline using general procedure A
(Yield: 81.07%). MS (ES): m/z 323.7 [M+H].sup.+.
[0761] Synthesis of compound I-73. Compound I-73 was synthesized
from 55.1 and 5-fluoro-4-methylpyridin-2-amine using general
procedure B (Yield: 46.95%), MS(ES): m/z 413.29 [M+H].sup.+, LCMS
purity: 98.05%, HPLC purity: 96.79%, 1H NMR (DMSO-d6, 400 MHz):
10.86 (bs, 1H), 9.86 (bs, 1H), 8.85 (s, 1H), 8.15 (s, 1H), 7.95
(bs, 1H), 7.43-7.41 (d, J=8.4 Hz, 1H), 7.22-7.17 (m, 1H), 7.03-6.96
(m, 2H), 3.89 (s, 3H), 3.17 (s, 3H), 2.28 (s, 3H).
Example 133: Synthesis of
6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((3-fluoro-2-methoxyphenyl)amino)-
-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-74
##STR00481##
[0763] Synthesis of compound I-74. Compound I-74 was synthesized
from 55.1 and 2,6-dimethylpyrimidin-4-amine using general procedure
B (Yield:39.41%), MS(ES): m/z 410.34 [M+H].sup.+, LCMS purity:
95.95%, HPLC purity: 96.80%, 1H NMR (DMSO-d6, 400 MHz): 10.13 (s,
1H), 8.88 (s, 1H), 8.15 (s, 1H), 7.49-7.45 (t, J=8.0 Hz, 3H),
7.21-7.15 (q, J=8.0 Hz, 1H), 7.06-7.01 (t, J=6.4 Hz, 1H), 3.89 (s,
3H), 2.54 (s, 3H), 2.45 (s, 3H), 2.32 (s, 3H).
Example 134: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((6-methylpyridazin-3-yl)a-
mino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-75
##STR00482##
[0765] Synthesis of compound I-75. Compound I-75 was synthesized
from 55.1 and 6-methylpyridazin-3-amine using general procedure B.
(Yield:32.65%), MS(ES): m/z 396.27 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 97.57%, 1H NMR (DMSO-d6, 400 MHz): 10.85 (s,
1H), 10.22 (s, 1H), 8.85 (s, 1H), 8.32-8.30 (d, J=8.4 Hz, 1H),
7.50-7.47 (d, J=9.2 Hz, 1H), 7.43-7.41 (d, J=8.0 Hz, 1H), 7.20-7.15
(q, J=8.0 Hz, 1H), 7.04-7.01 (d, 2H), 3.90 (s, 3H), 3.28 (s, 3H),
2.67 (s, 3H).
Example 135: Synthesis of
4-((3-fluoro-2-methoxyphenyl)amino)-6-((4-(methoxymethyl)pyridine-2-yl)am-
ino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-76
##STR00483##
[0767] Synthesis of compound I-76. Compound I-76 was synthesized
from 55.1 and 4-(methoxymethyl)pyridin-2-amine using general
procedure B. (Yield: 30.41%), MS(ES): m/z 425.43 [M+H].sup.+, LCMS
purity: 97.57%, HPLC purity: 95.02%, 1H NMR (DMSO-d6, 400 MHz):
10.77 (s, 1H), 9.84 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 7.96 (s,
1H), 7.46-7.37 (m, 2H), 7.23-7.19 (m, 1H), 7.03-7.01 (m, 1H), 6.86
(s, 1H), 4.44 (s, 2H), 3.89 (s, 3H), 3.36 (s, 3H), 3.35 (s,
3H).
Example 136: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-6-((4-(hydroxymethyl)pyridin-2-yl)ami-
no)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-101
##STR00484##
[0769] Synthesis of compound 136.1. To a cooled solution of
(2-aminopyridin-4-yl)methanol (0.5 g, 4.03 mmol, 1.0 eq) in
N,N-dimethylformamide (5 mL) at 0.degree. C., imidazole (0.274 g,
4.03 mmol, 1.0 eq) was added and reaction mixture was stirred for 5
min. To this added tert-Butyldimethylsilyl chloride (0.616 g, 4.03
mmol, 1.0 eq) and stirred at 0.degree. C. for 12 h. After
completion of reaction, reaction mixture was transferred into water
and extracted with ethyl acetate. Organic layer was combined,
washed with brine, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted in 2-3%
ethyl acetate hexane to obtain pure 55.1 (0.6 g, 62.49%). MS(ES):
m/z 239.41 [M+H].sup.+.
[0770] Synthesis of compound 136.2. Compound 136.2 was synthesized
from 73.1 and 136.2 using general procedure B. (Yield: 25.70%). MS
(ES): m/z 542.12 [M+H].sup.+.
[0771] Synthesis of compound I-101. To a solution of 136.2 (0.082
g, 0.151 mmol, 1.0 eq) in tetrahydrofuran (1 mL) at 0.degree. C.
was added Tetrabutyl ammonium fluoride (0.081 g, 0.302 mmol, 2.0
eq) dropwise and reaction mixture was stirred at room temperature
for 2 h. After completion of reaction, reaction mixture was
filtered to obtain crude solid. This crude solid was dissolved in
10% methanol in dichloromethane, washed with brine and concentrated
under reduced pressure to obtain pure I-101 (0.032 g, 49.47%),
MS(ES): m/z 427.86 [M+H].sup.+, LCMS purity: 100.00%, HPLC purity:
99.07%, 1H NMR (DMSO-d6, 400 MHz): 10.752 (s, 1H), 9.78 (s, 1H),
8.85 (s, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.60-7.58 (d, J=8.0 Hz,
1H), 7.25-7.18 (m, 3H), 6.86 (s, 1H), 4.49 (s, 2H), 4.12-4.08 (q,
J=5.2 Hz, 1H), 3.80 (s, 3H), 3.27 (s, 3H).
Example 137: Synthesis of
2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-6-((6-(trifluoromethyl)pyrid-
in-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-113
##STR00485##
[0773] Synthesis of I-113. Compound I-113 was synthesized from 86.2
and 6-(trifluoromethyl)pyridin-2-amine using general procedure B.
(Yield: 21.07%), MS(ES): m/z 479.31 [M+H].sup.+, LCMS purity:
93.97%, HPLC purity: 97.02%, 1H NMR (DMSO-d6, 400 MHz): 10.807 (s,
1H), 10.24 (s, 1H), 9.12 (s, 1H), 8.11-8.09 (d, J=8.4 Hz, 1H),
7.94-7.90 (m, 2H), 7.827-7.737 (m, 2H), 7.21-7.33 (m, 2H), 7.19 (s,
1H), 3.27 (s, 3H), 3.16 (s, 3H).
Example I-138: Synthesis of
4-((6-(cyclopropanecarboxamido)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,-
4-b]pyridin-4-yl)amino)-N-ethyl-3-methoxybenzamide, I-114
##STR00486##
[0775] Synthesis of compound 138.1. To a cooled solution of
3-methoxy-4-nitrobenzoic acid (1.0 g, 5.07 mmol, 1.0 eq) and ethyl
amine (0.296 g, 6.59 mmol, 1.3 eq) in N,N-dimethylformamide (10 mL)
at 0.degree. C. was added
(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid
hexafluoro-phosphate)) (2.9 g, 7.60 mmol, 1.5 eq) followed by
N,N-Diisopropylethylamine (1.96 g, 15.21 mmol, 3.0 eq). Reaction
mixture was stirred at room temperature for 16 h. After completion
of reaction, reaction mixture was transferred into water and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 50% ethyl acetate in
hexane as eluant to obtain pure 138.1 (1.0 g, 87.93%). MS(ES): m/z
225.22 [M+H].sup.+.
[0776] Synthesis of compound 138.2. To a solution of 138.1 (1.0 g,
4.46 mmol, 1.0 eq) in methanol (10 mL), 10% palladium on charcoal
(0.2 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 139.2 (0.85 g,
98.12%). MS(ES): m/z 195.23 [M+H].sup.+.
[0777] Synthesis of compound 138.3. Compound 138.3 was synthesized
from 139.2 and 1.9 using general procedure A. (Yield: 49.31%). MS
(ES): m/z 376.81 [M+H].sup.+.
[0778] Synthesis of compound I-114. Compound I-114 was synthesized
from 138.3 and cyclopropanecarboxamide using general procedure B.
(Yield: 22.13%), MS(ES): m/z 425.46 [M+H].sup.+, LCMS purity:
96.40%, HPLC purity: 95.03%, .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
10.77 (s, 2H), 8.73 (s, 1H), 8.45 (s, 1H), 7.83 (s, 1H), 7.54-7.48
(m, 3H), 3.90 (s, 3H), 3.28-3.26 (m, 5H), 1.99 (m, 1H), 1.13-1.09
(t, J=7.2 Hz, 3H), 0.79 (s, 4H).
Example 139: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5-morpholinopyridin-2-yl-
)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-115
##STR00487##
[0780] Synthesis of compound I-115. Compound I-115 was synthesized
from 5-morpholinopyridin-2-amine and 73.1 using general procedure
B. (Yield: 18.77%), MS(ES): m/z 482.25 [M+H].sup.+, LCMS purity:
96.54%, HPLC purity: 96.43%, 1H NMR (DMSO-d6, 400 MHz): 13.70 (s,
1H), 10.68 (s, 1H), 9.60 (s, 1H), 9.03 (s, 1H), 7.95 (s, 2H),
7.56-7.55 (d, J=6.4 Hz, 1H), 7.42 (s, 1H), 7.32-7.03 (m, 2H), 3.80
(s, 3H), 3.73 (t, 4H), 3.26 (s, 3H), 3.07 (t, 4H).
Example 140: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-6-((6-(3-methoxyazetidin-1-yl)pyridin-
-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-116
##STR00488##
[0782] Synthesis of compound 140.1. To a solution of
3-methoxyazetidine (2.0 g, 22.96 mmol, 1.5 eq) and
2-chloro-6-nitropyridine (2.43 g, 15.30 mmol, 1.0 eq) in dimethyl
sulfoxide (20 mL) was added sodium bicarbonate (2.57 g, 30.60 mmol,
2.0 eq). Reaction mixture was stirred at 80.degree. C. for 4 h.
After completion of reaction, reaction mixture was transferred into
water and extracted with ethyl acetate. Organic layer was combined,
dried over sodium sulphate and concentrated under reduced pressure
to obtain crude material. This was further purified by column
chromatography and compound was eluted in 20% ethyl acetate in
hexane as eluant to obtain pure 141.1 (2.0 g, 62.47%). MS(ES): m/z
210.21 [M+H].sup.+.
[0783] Synthesis of compound 140.2. To a solution of 140.1 (2.0 g,
9.56 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal
(0.4 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 141.2. (1.5 g,
87.55%). MS(ES): m/z 180.22 [M+H].sup.+.
[0784] Synthesis of compound I-116. Compound I-116 was synthesized
from 73.1 and 140.2 using general procedure B (Yield: 3.75%),
MS(ES): m/z 482.94 [M+H].sup.+, LCMS purity: 96.80%, HPLC purity:
95.08%, 1H NMR (DMSO-d6, 400 MHz): 13.98 (s, 1H), 10.65 (s, 1H),
9.44 (s, 1H), 8.75 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.19 (s,
3H), 5.91 (s, 1H), 4.24 (s, 1H), 3.98 (s, 2H), 3.79 (s, 3H), 3.61
(s, 2H), 3.26 (s, 3H), 3.22 (s, 3H).
Example 141: Synthesis of
2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-6-((5-(piperidin-1-yl)pyridi-
n-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-118
##STR00489##
[0786] Synthesis of compound 141.1. To a solution of
5-bromo-2-nitropyridine (2.0 g, 9.85 mmol, 1.0 eq), piperidine
(1.674 g, 19.7 mmol, 2.0 eq) and triethyl amine (1.09 g, 10.83
mmol, 1.1 eq) in dimethyl sulfoxide (20 mL) was added. Reaction
mixture was stirred at 120.degree. C. for 16 h. After completion of
reaction, reaction mixture was transferred into water and extracted
with ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 20% ethyl acetate in hexane as eluant to
obtain pure 141.1 (1.1 g, 53.88%). MS(ES): m/z 208.23
[M+H].sup.+.
[0787] Synthesis of compound 141.2. To a solution of 141.1 (1.1 g,
5.31 mmol, 1.0 eq) in methanol (10 mL), 10% palladium on charcoal
(0.2 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 141.2. (0.7 g,
74.40%). MS(ES): m/z 178.25 [M+H].sup.+.
[0788] Synthesis of compound I-118. Compound I-118 was synthesized
from 86.2 and 141.2 using general procedure B. (Yield: 9.29%),
MS(ES): m/z 494.59 [M+H].sup.+, LCMS purity: 98.43%, HPLC purity:
98.72%, 1H NMR (CDCl3, 400 MHz): 14.41 (bs, 1H), 11.36 (bs, 1H),
9.41 (s, 1H), 7.77-7.73 (m, 2H), 7.44-7.42 (d, J=7.2 Hz, 1H),
7.29-7.28 (d, J=2.8 Hz, 1H), 7.20-7.15 (m, 2H), 7.01-6.97 (t, J=7.2
Hz, 1H), 5.90 (s, 1H), 3.47 (s, 3H), 3.07 (m, 4H), 2.94 (s, 3H),
1.72 (m, 4H), 1.59-1.57 (m, 2H).
Example 142: Synthesis of
6-((2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitrile, I-119
##STR00490##
[0790] Synthesis of compound I-119. Compound I-119 was synthesized
from 6-aminopyrazine-2-carbonitrile and 86.2 using general
procedure B. (Yield: 24.25%), MS(ES): m/z 437.19 [M+H].sup.+, LCMS
purity: 100.00%, HPLC purity: 98.05%, 1H NMR (DMSO-d6, 400 MHz):
10.94 (s, 1H), 10.64 (bs, 1H), 9.29 (s, 1H), 9.22 (s, 1H), 8.62 (s,
1H), 7.95-7.93 (d, J=8.0 Hz, 1H), 7.88-7.79 (m, 2H), 7.44-7.40 (m,
1H), 7.19 (s, 1H), 3.28 (s, 3H), 3.17 (s, 3H).
Example 143:
6-((5-fluoro-4-methylpyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-pyr-
azol-3-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-o-
ne, I-120
##STR00491##
[0792] Synthesis of compound I-120. Compound I-120 was synthesized
from 5-fluoro-4-methylpyridin-2-amine and 42.1 using general
procedure B. (0.040 g, Yield: 27.03%). MS(ES): m/z 475.50
[M+H].sup.+, LCMS purity: 99.34%, HPLC purity: 97.70%, 1H NMR
(DMSO-d6, 400 MHz): 10.71 (s, 1H), 9.77 (s, 1H), 8.83 (s, 1H), 8.11
(s, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.55-7.51 (m, 2H), 7.24-7.20
(t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.73 (s, 1H), 3.90 (s, 3H), 3.62
(s, 3H), 3.27 (s, 3H), 2.26 (s, 3H).
Example 144: Synthesis of
4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-2-methyl-6-((6-me-
thylpyridazin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-121
##STR00492##
[0794] Synthesis of compound I-121. Compound I-121 was synthesized
from 6-methylpyridazin-3-amine and 42.1 using general procedure B.
(0.040 g, Yield: 28.04%). MS(ES): m/z 458.50 [M+H].sup.+, LCMS
purity: 99.36%, HPLC purity: 95.11%, 1H NMR (DMSO-d6, 400 MHz):
10.78 (s, 1H), 10.19 (s, 1H), 8.86 (s, 1H), 8.29 (s, 1H), 7.78 (s,
1H), 7.59-7.46 (m, 3H), 7.23-7.19 (t, J=8.0 Hz, 1H), 7.00 (s, 1H),
6.73 (s, 1H), 3.90 (s, 3H), 3.63 (s, 3H), 3.27 (s, 3H), 2.48 (s,
3H).
Example 145: Synthesis of
6-((4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-2-methyl-3-ox-
o-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile,
I-122
##STR00493##
[0796] Synthesis of compound I-122. Compound I-122 was synthesized
6-aminopicolinonitrile and 42.1 from using general procedure B.
(0.035 g, Yield: 24.01%). MS(ES): m/z 468.37 [M+H].sup.+, LCMS
purity: 99.31%, HPLC purity: 99.49%, 1H NMR (DMSO-d6, 400 MHz):
10.79 (bs, 1H), 10.29 (s, 1H), 8.97 (s, 1H), 8.08-8.05 (d, J=8.0
Hz, 1H), 7.91-7.87 (d, J=8.0 Hz, 1H), 7.78-7.78 (d, J=2.0 Hz, 1H),
7.61-7.52 (m, 3H), 7.46 (s, 1H), 7.29-7.25 (t, J=8.0 Hz, 1H),
6.74-6.73 (d, J=2.0 Hz, 1H), 3.90 (s, 3H), 3.62 (s, 3H), 3.29 (s,
3H).
Example 146: Synthesis of
6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-pyrazo-
l-3-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-123
##STR00494##
[0798] Synthesis of compound I-123. Compound I-146 was synthesized
from 2,6-dimethylpyrimidin-4-amine and 42.1 using general procedure
B (0.039 g, Yield: 26.52%). MS(ES): m/z 472.35 [M+H].sup.+, LCMS
purity: 99.48%, HPLC purity: 95.82%, 1H NMR (DMSO-d6, 400 MHz):
10.83 (bs, 1H), 10.10 (s, 1H), 8.90 (s, 1H), 7.78 (s, 1H),
7.56-7.49 (m, 3H), 7.23 (s, 1H), 6.73 (s, 1H), 3.90 (s, 3H), 3.62
(s, 3H), 3.29 (s, 3H), 2.43 (s, 3H), 2.30 (s, 3H).
Example 147: Synthesis of
4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-2-methyl-6-((5-(p-
iperidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3--
one, I-124
##STR00495##
[0800] Synthesis of compound I-124. Compound I-124 was synthesized
from 5-(piperidin-1-yl)pyridin-2-amine and 42.1 using general
procedure B. (0.055 g, Yield: 33.56%). MS(ES): m/z 526.54
[M+H].sup.+, LCMS purity: 99.19%, HPLC purity: 97.65%, 1H NMR
(DMSO-d6, 400 MHz): 10.60 (bs, 1H), 9.55 (s, 1H), 8.97 (s, 1H),
7.93 (s, 2H), 7.78-7.77 (d, J=4.0 Hz, 1H), 7.58-7.39 (m, 3H),
7.24-7.20 (t, J=8.0 Hz, 1H), 7.04 (s, 1H), 6.73-6.72 (d, J=4.0 Hz,
1H), 3.90 (s, 3H), 3.62 (s, 3H), 3.26 (s, 3H), 3.06 (m, 4H), 1.62
(m, 4H), 1.51 (m, 2H).
Example 148: Synthesis of
3-(difluoromethyl)-6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-
-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile,
I-191
##STR00496##
[0802] Synthesis of compound I-191. Compound I-191 was synthesized
from 55.1 and 6-amino-3-(difluoromethyl)picolinonitrile using
general procedure B. (Yield: 27.26%). MS(ES): m/z 456.36
[M+H].sup.+, LCMS purity: 99.36%, HPLC purity: 97.87%, 1H NMR
(DMSO-d6, 400 MHz): 10.79 (s, 1H), 9.37 (s, 1H), 8.90 (s, 1H),
8.19-8.17 (d, J=7.6 Hz, 1H), 7.79-7.77 (d, J=8.0 Hz, 1H), 7.61-7.62
(t, 1H), 7.50 (s, 2H), 7.26-7.21 (m, 1H), 7.08-7.03 (m, 1H), 3.91
(s, 3H), 3.10 (s, 3H).
Example 149: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-6-((6,7-dihydro-4H-pyrazolo[5,1-c][1,-
4]oxazin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-221
##STR00497##
[0804] Synthesis of compound 149.1. To a solution
5-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.66 mmol, 1.0 eq)
in tetrahydrofuran (30 mL) was added dropwise borane
tetrahydrofuran complex (194 mL, 190.98 mmol, 3.0 eq) at
-0.5.degree. C. The reaction mixture was stirred at room
temperature for 18 h. The reaction mixture was cooled to
-0.5.degree. C., water (30 mL) was added followed by 4N
hydrochloric acid (30 mL). The reaction mixture was stirred at
110.degree. C. for 2 h. After completion of reaction, reaction
mixture was filtered, washed with ethyl acetate. Organic layer was
dried over sodium sulphate and concentrated under reduced pressure
to obtain 149.1 (5.8 g, 63.67%). MS(ES): m/z 144.10
[M+H].sup.+.
[0805] Synthesis of compound 149.2. To a solution of 149.1 (5.8 g,
40.53 mmol, 1.0 eq) in N,N-dimethylformamide (70 mL) was added
cesium carbonate (16.12 g, 49.45 mmol, 1.22 eq). 1,2-dibromoethane
(60.91 g, 324.24 mmol, 1.22 eq) was added dropwise to the reaction
mixture. The reaction mixture was stirred at room temperature for
2.5 h. After completion of reaction, reaction mixture was
transferred in to 10% solution of sodium phosphate (90 mL) and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 35% ethyl acetate in
hexane as eluent to obtain 149.2. (4.0 g, 39.47%). MS(ES): m/z
251.05 [M+H].sup.+.
[0806] Synthesis of compound 149.3. To a solution of 149.2 (3.0 g,
12.00 mmol, 1.0 eq) in N-methyl pyrrolidine (12 mL) was added. The
reaction mixture was stirred at 135.degree. C. for 18 h. After
completion of reaction, reaction mixture was transferred into water
and extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 1% methanol in
dichloromethane as eluent to obtain 149.3. (0.30 g, 14.78%).
MS(ES): m/z 170.14 [M+H].sup.+.
[0807] Synthesis of compound 149.4. To a solution of 149.3 (0.3 g,
1.77 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal
(0.05 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 149.4 (0.22 g,
89.13%). MS(ES): m/z 140.16 [M+H].sup.+.
[0808] Synthesis of compound I-221. Compound I-221 was synthesized
from 149.4 and 73.1 using general procedure B. (Yield: 19.96%).
MS(ES): m/z 442.41 [M+H].sup.+, LCMS purity: 96.79%, HPLC purity:
98.27%, 1H NMR (DMSO-d6, 400 MHz): 10.58 (s, 1H), 9.59 (s, 1H),
8.83 (s, 1H), 7.59-7.57 (d, J=8.0 Hz, 1H), 7.33-7.19 (m, 2H), 6.90
(s, 1H), 6.24 (s, 1H), 4.77 (s, 2H), 4.08-4.00 (m, 4H), 3.83 (s,
3H), 3.18 (s, 3H).
Example 150: Synthesis of
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-(2-oxopyrrolidin-1-yl)picolinonitrile,
I-134
##STR00498##
[0810] Synthesis of compound 150.1. To
6-amino-3-bromopicolinonitrile (0.5 g, 2.52 mmol, 1.0 eq) and
pyrrolidin-2-one (0.258 g, 3.03 mmol, 1.2 eq) in 1,4-dioxane (0.5
mL) was added N-Desmethylclozapine (0.079 g, 0.252 mmol, 0.1 eq),
potassium phosphate (1.07 g, 5.04 mmol, 2.0 eq) and copper iodide
(0.024 g, 0.126 mmol, 0.05 eq). The reaction mixture was degassed
for 10 min. under argon atmosphere. The reaction was refluxed for
48 h. After completion of reaction, reaction mixture was
transferred in water and extracted with ethyl acetate. Combined
organic layer was washed with brine, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography using 40% ethyl
acetate in hexane to obtain pure 150.1 (0.125 g, 29.38%). MS(ES):
m/z 203.22 [M+H].sup.+
[0811] Synthesis of compound I-134. Compound I-134 was synthesized
from 73-1 and 150.1 using general procedure B. (0.028 g, Yield:
37.62%). MS(ES): m/z 505.28 [M+H].sup.+, LCMS purity: 100%, HPLC
purity: 98.40%, 1H NMR (DMSO-d6, 400 MHz): 10.86 (bs, 1H), 10.37
(s, 1H), 8.95 (s, 1H), 8.14-8.11 (d, J=9.2 Hz, 1H), 7.92-7.90 (d,
J=9.6 Hz, 1H), 7.63-7.61 (d, J=6.8 Hz, 1H), 7.36 (s, 1H), 7.27-7.19
(m, 2H), 3.84-3.81 (m, 5H), 3.29 (s, 3H), 3.15-3.14 (d, J=4.4 Hz,
2H), 2.17-2.10 (m, 2H).
Example 151: Synthesis
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-methylpyrazine-2-carbonitrile,
I-135
##STR00499##
[0813] Synthesis of compound 151.1. To a solution of
6-aminopyrazine-2-carbonitrile (1.0 g, 8.33 mmol, 1.0 eq) in
acetonitrile (0.5 mL) was added N-Bromosuccinimide (2.22 g, 12.50
mmol, 1.5 eq). The reaction was stirred at room temperature for 12
h. After completion of reaction, reaction mixture was transferred
in water and extracted with ethyl acetate. Combined organic layer
was washed with brine, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 20% ethyl acetate in hexane
to obtain pure 151.1 (0.75 g, 45.27%). MS(ES): m/z 200.01
[M+H].sup.+
[0814] Synthesis of compound 151.2. To 151.1 (0.75 g, 3.77 mmol,
1.0 eq) in mixture of 1,4-dioxane (0.5 mL) and water (mL) was added
Trimethylboroxine (0.40 g, 7.54 mmol, 2.0 eq). The reaction mixture
was degassed for 10 min. under argon atmosphere. Potassium
carbonate (1.56 g, 11.31 mmol, 3.0 eq) and
tetrakis(triphenylphosphine)palladium(0) (0.435 g, 0.377 mmol, 0.1
eq), again reaction mixture was degassed for 10 min. under argon
atmosphere. The reaction was stirred at 110.degree. C. for 20 h.
After completion of reaction, reaction mixture was transferred in
water and extracted with ethyl acetate. Combined organic layer was
washed with brine, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 15% ethyl acetate in hexane
to obtain pure 151.2 (0.15 g, 29.67%). MS(ES): m/z 135.14
[M+H].sup.+
[0815] Synthesis of compound I-135. Compound was synthesized from
73.1 and 151.2 using general procedure B to obtain I-135 (0.125 g,
Yield: 31.06%). MS(ES): m/z 437.24 [M+H].sup.+, LCMS purity:
93.43%, HPLC purity: 94.00%, 1H NMR (DMSO-d6, 400 MHz): 10.91 (s,
1H), 10.50 (s, 1H), 9.22 (s, 1H), 8.93 (s, 1H), 7.59-7.58 (d, J=6.4
Hz, 1H), 7.35 (s, 1H), 7.23 (m, 2H), 3.88 (s, 3H), 3.29 (s, 3H),
2.57 (s, 3H).
Example 152: Synthesis of
N-(4-((4-ethyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-
-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-152
##STR00500##
[0817] Synthesis of compound 152.1. To a solution of 4-ethylaniline
(3.0 g, 24.76 mmol, 1.0 eq) in acetic acid (30 mL) were added
Ammonium thiocyanate (1.88 g, 24.76 mmol, 1.0 eq). The reaction
mixture was cooled to 0.degree. C. and added dropwise bromine
solution (3.96 g, 24.76 mmol, 1.0 eq). Reaction mixture was stirred
at 10.degree. C. for 3 h. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Organic layer was combined, washed by saturated solution
of sodium bicarbonate, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted in 15%
ethyl acetate in hexane as eluent to obtain 152.1. (1.10 g,
24.93%). MS(ES): m/z 179.25 [M+H].sup.+.
[0818] Synthesis of compound 152.2. To a solution of 152.1 (1.1 g,
6.17 mmol, 1.0 eq) in water (10 mL) was added aqueous solution of
potassium hydroxide (4.14 g, 74.04 mmol, 12.0 eq). Reaction mixture
was refluxed for 48 h. The reaction mixture was maintained at room
temperature, methyl iodide (0.963 g, 6.78 mmol, 1.1 eq) was added,
and the reaction stirred for 1 h. After completion of reaction,
reaction mixture was extracted with ethyl acetate. Organic layer
was combined, dried over sodium sulphate and concentrated under
reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted in 20%
ethyl acetate in hexane as eluent to obtain 152.2. (0.5 g, 48.44%).
MS(ES): m/z 168.27 [M+H].sup.+.
[0819] Synthesis of compound 152.3. Compound 152.3 was synthesized
from 1.9 and 152.2 using general procedure A. (Yield: 68.75%). MS
(ES): m/z 349.85 [M+H].sup.+.
[0820] Synthesis of compound 152.4. To a solution of 152.3 (0.1 g,
0.315 mmol, 1 eq) in acetic acid (0.2 mL) was added 30% hydrogen
peroxide (0.214 g, 6.3 mmol, 20.0 eq) and sodium tungstate
dihydrate (0.104 g, 0.315 mmol, 1 eq). Reaction mixture was stirred
at room temperature for 2 h. After completion of reaction, reaction
mixture was transferred in ice-water and precipitated product was
filtered, washed with 50% ethyl acetate in hexane and dried well to
obtain 152.4 (0.097 g, Yield: 80.77%). MS(ES): m/z 381.85
[M+H].sup.+
[0821] Synthesis of compound I-152. Compound I-152 was synthesized
from 152.4 and cyclopropanecarboxamide using general procedure B
(Yield: 23.77%). MS(ES): m/z 430.24 [M+H].sup.+, LCMS purity:
98.41%, HPLC purity: 100%, 1H NMR (DMSO-d6, 400 MHz): 10.75-10.73
(d, J=7.2 Hz, 2H), 9.03 (s, 1H), 7.77 (s, 1H), 8.69-7.63 (m, 3H),
3.29 (s, 3H), 3.15 (s, 3H), 2.75-2.70 (q, J=7.2 Hz, 2H), 1.99 (s,
1H), 1.25-1.22 (t, J=7.2 Hz, 3H), 0.78-0.76 (m, 4H).
Example 153:
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-(difluoromethyl)picolinonitrile,
I-156
##STR00501##
[0823] Synthesis of compound 153.1. To a cooled suspension of zinc
dust (6.08 g, 93.03 mmol, 7.0 eq) in water (7 mL) at 0.degree. C.
was added difluoromethanesulfinic hypochlorous anhydride (2.0 g,
13.29 mmol, 1.0 eq) dropwise. The reaction mixture was stirred at
room temperature for 2 h. After completion of reaction, reaction
mixture was filtered, washed with ethyl acetate. Organic layer was
dried over sodium sulphate and concentrated under reduced pressure
to obtain 153.1. (2.10 g, 53.48%). MS(ES): m/z 296.53
[M+H].sup.+.
[0824] Synthesis of compound 153.2. To a solution of
6-chloropyridin-2-amine (0.5 g, 3.89 mmol, 1.0 eq) and 153.1 (3.45
g, 11.67 mmol, 3.0 eq) in mixture of dichloromethane (1 mL) and
water (0.4 mL) was added dropwise tert-Butyl hydroperoxide (1.75 g,
19.45 mmol, 5.0 eq). The reaction mixture was stirred at room
temperature for 8 h in closed vessel. After completion of reaction,
reaction mixture was transferred in to saturated solution of sodium
bicarbonate and extracted with dichloromethane. Organic layer was
combined, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography and compound was eluted in 15% ethyl acetate
in hexane as eluent to obtain 153.2. (0.095 g, 13.68%). MS(ES): m/z
179.57 [M+H].sup.+.
[0825] Synthesis of compound 153.3. To a solution of 153.2 (0.095
g, 0.532 mmol, 1.0 eq) and zinc cyanide (0.037 g, 0.319 mmol, 0.6
eq) in N,N-dimethylformamide (2.0 mL). The reaction mixture was
degassed for 10 min. under argon atmosphere.
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride
(0.008 g, 0.011 mmol, 0.02 eq) was added and again degassed for 10
min. under argon atmosphere. The reaction mixture was stirred at
160.degree. C. for 4 h. After completion of reaction, reaction
mixture was transferred in to saturated solution of sodium
bicarbonate and extracted with dichloromethane. Organic layer was
combined, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography and compound was eluted in 15% ethyl acetate
in hexane as eluent to obtain 153.3. (0.06 g, 66.68%). MS(ES): m/z
170.13 [M+H].sup.+.
[0826] Synthesis of compound I-156. Compound I-156 was synthesized
from 73.1 and 153.3 using general procedure B (Yield: 28.75%).
MS(ES): m/z 472.27 [M+H].sup.+, LCMS purity: 98.10%, HPLC purity:
96.85%, 1H NMR (DMSO-d6, 400 MHz): 10.84 (bs, 1H), 9.42 (s, 1H),
8.95 (s, 1H), 8.20-8.18 (d, J=7.2 Hz, 1H), 7.80-7.78 (d, J=7.2 Hz,
1H), 7.67-7.65 (d, J=7.2 Hz, 1H), 7.49 (s, 1H), 7.35-7.25 (m, 2H),
3.84 (s, 3H), 3.32 (s, 3H), 2.10 (s, 1H).
Example 154: Synthesis of
6-((5-fluoro-4-methylpyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2-
,4-triazol-3-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyrid-
in-3-one, I-21
##STR00502##
[0828] Synthesis of compound I-21. Compound I-21 was synthesized
from 5-fluoro-4-methylpyridin-2-amine and 1.92 using general
procedure B. (Yield:22.72%), MS(ES): m/z 476.48 [M+H].sup.+, LCMS
purity: 100.00%, HPLC purity: 99.07%, 1H NMR (DMSO-d6, 400 MHZ):
9.86 (bs, 1H), 8.91 (s, 1H), 8.58 (s, 1H), 8.15 (s, 1H), 7.99 (bs,
1H), 7.67-7.65 (d, J=6.8 Hz, 1H), 7.59-7.57 (d, J=7.6 Hz, 1H),
7.32-7.28 (t, J=8.0 Hz, 1H), 6.98 (bs, 1H), 5.8 (s, 1H), 3.96 (s,
3H), 3.78 (s, 3H), 3.29 (s, 3H), 2.28 (s, 3H).
Example 155: Synthesis of
6-((4-(hydroxymethyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2-
,4-triazol-3-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyrid-
in-3-one, I-19
##STR00503##
[0830] Synthesis of compound I-19. Compound I-19 was synthesized
from (2-aminopyridin-4-yl)methanol and 1.92 using general procedure
B (Yield: 5.43%). MS(ES): m/z 474.58 [M+H].sup.+, LCMS purity:
98.36%, HPLC purity: 96.55%, 1H NMR (DMSO-d6, 400 MHZ): 10.02 (bs,
1H), 8.97 (s, 1H), 8.58 (s, 1H), 8.20 (s, 3H), 7.68-7.59 (m, 3H),
7.30 (s, 1H), 6.92-6.90 (d, J=4.8 Hz, 1H), 4.52 (s, 2H), 3.96 (s,
3H), 3.78 (s, 3H), 3.30 (s, 3H), 2.54 (s, 1H).
Example I-156: Synthesis of
4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-6--
((5-(piperidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyri-
din-3-one, I-24
##STR00504##
[0832] Synthesis of compound I-24. Compound I-24 was synthesized
from 5-(piperidin-1-yl)pyridin-2-amine and 1.92 using general
procedure B. (Yield: 13.68%), MS(ES): m/z 527.76 [M+H].sup.+, LCMS
purity: 99.24%, HPLC purity: 96.02%, 1H NMR (DMSO-d6, 400 MHZ):
9.79 (bs, 2H), 8.94 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.96 (s,
1H), 7.66-7.64 (d, J=8.0 Hz, 1H), 7.59-7.58 (d, J=7.6 Hz, 1H),
7.44-7.43 (d, J=7.2 Hz, 1H), 7.32-7.28 (t, J=8.0 Hz, 1H), 6.77-6.44
(m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.28 (s, 3H), 3.09 (s, 4H),
1.64 (s, 4H), 1.52 (s, 2H).
Example 157: Synthesis of
4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-6--
((5-morpholinopyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3--
one, I-20
##STR00505##
[0834] Synthesis of compound I-20. Compound I-20 was synthesized
from 5-morpholinopyridin-2-amine and 1.92 using general procedure
B. (Yield: 13.68%), MS(ES): m/z 527.76 [M+H].sup.+, LCMS purity:
99.24%, HPLC purity: 96.02%, 1H NMR (DMSO-d6, 400 MHZ): 9.79 (bs,
2H), 8.94 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H),
7.66-7.64 (d, J=8.0 Hz, 1H), 7.59-7.58 (d, J=7.6 Hz, 1H), 7.44-7.43
(d, J=7.2 Hz, 1H), 7.32-7.28 (t, J=8.0 Hz, 1H), 6.77-6.44 (m, 1H),
3.96 (s, 3H), 3.78 (s, 3H), 3.28 (s, 3H), 3.09 (s, 4H), 1.64 (s,
4H), 1.52 (s, 2H).
Example 158: Synthesis of
6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methy-
l-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrimidine-4-carb-
onitrile, I-31
##STR00506##
[0836] Synthesis of compound I-31. Compound I-31 was synthesized
from 6-aminopyrimidine-4-carbonitrile and 1.92 using general
procedure B (Yield: 13.7%) MS(ES): m/z 470.64 [M+H].sup.+, LCMS
purity: 94.47%, HPLC purity: 93.57%, 1H NMR (DMSO-d6, 400 MHZ):
11.17 (bs, 1H), 10.85 (bs, 1H), 8.96 (s, 1H), 8.87 (s, 1H), 8.66
(s, 1H), 8.58 (s, 1H), 7.65-7.61 (t, J=7.6 Hz, 2H), 7.31-7.29 (d,
J=8.0 Hz, 1H), 7.00 (s, 1H), 3.96 (s, 3H), 3.77 (s, 3H), 3.40 (s,
3H).
Example 159: Synthesis of
2-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-o-
xo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)isonicotinonitrile,
I-32
##STR00507##
[0838] Synthesis of compound I-159. Compound I-159 was synthesized
from 2-aminoisonicotinonitrile and 1.91 using general procedure B
(Yield: 24.72%). MS(ES): m/z 470.43 [M+H].sup.+, LCMS purity:
95.52%, HPLC purity: 96.87%, 1H NMR (DMSO-d6, 400 MHZ): 11.01 (s,
1H), 10.27 (s, 1H), 8.93 (s, 1H), 8.61 (s, 1H), 8.48-8.48 (d, J=4.0
Hz, 1H), 7.78-7.76 (d, J=7.6 Hz, 1H), 7.66-7.64 (d, J=7.2 Hz, 1H),
7.48-7.34 (m, 2H), 6.97 (s, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.16
(s, 3H).
Example 160: Synthesis of
6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-o-
xo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile,
I-12
##STR00508##
[0840] Synthesis of compound I-12. Compound I-12 was synthesized
from 1.91 and 6-aminonicotinonitrile using general procedure B.
(Yield: 20.60%). MS(ES): m/z 470.68 [M+H].sup.+, LCMS purity:
97.03%, HPLC purity: 99.75%, 1H NMR (DMSO-d6, 400 MHZ): 10.99 (s,
1H), 10.44 (s, 1H), 8.95 (s, 1H), 8.70 (s, 1H), 8.25-8.22 (d, J=8.8
Hz, 1H), 8.15-8.13 (d, J=8.8 Hz, 1H), 7.79-7.78 (d, J=7.6 Hz, 1H),
7.66-7.64 (d, J=7.6 Hz, 1H), 7.44-7.40 (t, J=7.6 Hz, 1H), 7.17 (s,
1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.39 (s, 3H).
Example 161: Synthesis of
4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((1-m-
ethyl-1H-pyrazol-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-13
##STR00509##
[0842] Synthesis of compound I-13. Compound I-13 was synthesized
from 1-methyl-1H-pyrazol-3-amine and 1.91 using general procedure C
(Yield: 17.29%). MS(ES): m/z 448.43 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 99.64%, 1H NMR (DMSO-d6, 400 MHZ): 10.52 (s,
1H), 9.51 (s, 1H), 8.84 (s, 1H), 7.78-7.76 (d, J=7.6 Hz, 1H),
7.62-7.60 (d, J=7.6 Hz, 1H), 7.55 (s, 1H), 7.40-7.36 (t, J=7.6 Hz,
1H), 6.93 (bs, 1H), 6.36 (s, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.75
(s, 3H), 3.26 (s, 3H).
Example 162: Synthesis of
6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-o-
xo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile,
I-28 ( )
##STR00510##
[0844] Synthesis of compound I-28. Compound I-28 was synthesized
from 6-aminopicolinonitrile and 1.91 using general procedure B.
(Yield: 18.13) MS(ES): m/z 470.43 [M+H].sup.+, LCMS purity: 97.40%,
HPLC purity: 98.61%, 1H NMR (DMSO-d6, 400 MHZ): 10.32 (s, 1H), 9.03
(s, 1H), 8.10-8.08 (d, J=8.8 Hz, 1H), 7.94-7.89 (t, J=8.8 Hz, 1H),
7.86-7.84 (d, J=7.2 Hz, 1H), 7.65-7.63 (d, J=7.2 Hz, 1H), 7.56-7.54
(d, J=7.2 Hz, 1H), 7.49-7.41 (m, 2H), 4.47 (s, 3H), 3.80 (s, 3H),
3.32 (s, 3H).
Example 163: Synthesis of
6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-o-
xo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrimidine-4-carbonitr-
ile, I-29
##STR00511##
[0846] Synthesis of compound I-29. Compound I-29 was synthesized
from 6-aminopyrimidine-4-carbonitrile and 1.91 using general
procedure B. (Yield: 17.27) MS(ES): m/z 471.48 [M+H].sup.+, LCMS
purity: 100.00%, HPLC purity: 99.45%, 1H NMR (DMSO-d6, 400 MHZ):
11.20 (bs, 1H), 10.83 (s, 1H), 8.97 (s, 1H), 8.87 (s, 1H), 8.66 (s,
1H), 7.76-7.74 (d, J=8.0 Hz, 1H), 7.69-7.67 (d, J=8.0 Hz, 1H),
7.43-7.39 (t, J=8.0 Hz, 1H), 6.97 (s, 1H), 4.47 (s, 3H), 3.78 (s,
3H), 3.33 (s, 3H).
Example 164: Synthesis of
4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-6--
((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-18
##STR00512##
[0848] Synthesis of compound I-18. Compound I-18 was synthesized
from 4-methylpyridin-2-amine and 1.92 using general procedure B
(Yield:11.24%), MS(ES): m/z 458.48 [M+H].sup.+, LCMS purity:
99.71%, HPLC purity: 98.00%, 1H NMR (CDCl3, 400 MHZ): 9.49 (bs,
1H), 8.91 (s, 1H), 8.06 (s, 1H), 8.03-8.01 (d, J=6.4 Hz, 1H),
7.60-7.59 (d, J=7.2 Hz, 1H), 7.02-6.98 (t, J=7.6 Hz, 1H), 6.79 (s,
1H), 6.75-6.74 (d, J=5.2 Hz, 1H), 5.70 (s, 1H), 3.96 (s, 3H), 3.73
(s, 3H), 3.58 (s, 3H), 2.29 (s, 3H).
Example 165: Synthesis of
4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((4-(meth-
oxymethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyrid-
in-3-one, I-15
##STR00513##
[0850] Synthesis of compound I-15. Compound I-15 was synthesized
from 4-(methoxymethyl)pyridin-2-amine and 1.92 using general
procedure B. (Yield:15.83%), MS(ES): m/z 488.53 [M+H].sup.+, LCMS
purity: 98.20%, HPLC purity: 98.44%, 1H NMR (MeOD, 400 MHZ): 8.51
(s, 1H), 8.29-8.28 (d, J=5.2 Hz, 1H), 7.76-7.74 (d, J=7.2 Hz, 1H),
7.65-7.63 (d, J=6.8 Hz, 1H), 7.36-7.32 (t, J=8.0 Hz, 1H), 7.05-7.04
(d, J=5.2 Hz, 1H), 6.96 (s, 1H), 5.78 (s, 1H), 4.51 (s, 2H), 4.04
(s, 3H), 3.79 (s, 3H), 3.56 (s, 3H), 3.46 (s, 3H).
Example 166: Synthesis of
6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methy-
l-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile,
I-30
##STR00514##
[0852] Synthesis of compound I-30. Compound I-30 was synthesized
from 6-aminopicolinonitrile and 1.92 using general procedure B.
(Yield:13.73%), MS(ES): m/z 469.48 [M+H].sup.+, LCMS purity:
95.85%, HPLC purity: 96.87%, 1H NMR (DMSO-d6, 400 MHZ): 10.81 (bs,
1H), 10.31 (bs, 1H), 9.02 (s, 1H), 8.58 (s, 1H), 8.10-8.08 (d,
J=8.8 Hz, 1H), 7.93-7.89 (t, J=8.0 Hz, 1H), 7.76-7.74 (d, J=7.6 Hz,
1H), 7.59-7.50 (m, 3H), 7.36-7.32 (t, J=8.0 Hz, 1H), 3.97 (s, 3H),
3.79 (s, 3H), 3.31 (s, 3H).
Example 167: Synthesis of
6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4--
triazol-3-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin--
3-one, I-22
##STR00515##
[0854] Synthesis of compound I-22. Compound I-22 was synthesized
from 2,6-dimethylpyrimidin-4-amine and 1.92 using general procedure
B. (Yield:9.25%), MS(ES): m/z 473.38 [M+H].sup.+, LCMS purity:
94.70%, HPLC purity: 96.65%, 1H NMR (MeOD, 400 MHZ): 8.52 (s, 1H),
7.74-7.64 (m, 3H), 7.36-7.32 (t, J=8.0 Hz, 2H), 4.04 (s, 3H), 3.78
(s, 3H), 3.54 (s, 3H), 2.68 (s, 3H), 2.43 (s, 3H).
Example 168: Synthesis of
4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-6--
((6-methylpyridazin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-on-
e, I-23
##STR00516##
[0856] Synthesis of compound I-23. Compound I-23 was synthesized
from 6-methylpyridazin-3-amine and using general procedure B.
(Yield:7.29%), MS(ES): m/z 459.63 [M+H].sup.+, LCMS purity: 99.85%,
HPLC purity: 95.09%, 1H NMR (MeOD, 400 MHZ): 8.52 (s, 1H),
7.82-7.55 (m, 3H), 7.36-7.32 (t, J=8.0 Hz, 2H), 5.90 (s, 1H), 4.04
(s, 3H), 3.78 (s, 3H), 3.53 (s, 3H), 2.62 (s, 3H).
Example 169: Synthesis of
4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-6--
(pyridin-2-ylamino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-17
##STR00517##
[0858] Synthesis of compound I-17. Compound I-17 was synthesized
from pyridin-2-amine and 1.92 using general procedure B.
(Yield:31.9%), MS(ES): m/z 444.43 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 99.55%, 1H NMR (DMSO-d6, 400 MHZ): 9.96-9.86
(m, 1H), 8.94 (s, 1H), 8.58 (s, 1H), 8.27 (s, 1H), 7.73-7.67 (m,
2H), 7.60-7.58 (d, J=7.6 Hz, 1H), 7.32-7.28 (t, J=8.0 Hz, 1H), 6.96
(s, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.30 (s, 3H).
Example 170: Synthesis of
2-methoxy-3-((6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-3-oxo-2,3-
-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)benzamide, I-126
##STR00518##
[0860] Synthesis of compound 1.2. Compound 170.1 was synthesized
from 114.1 and 4-(methoxymethyl)pyridin-2-amine using general
procedure B. (Yield: 48.91%). MS (ES): m/z 432.46 [M+H].sup.+.
[0861] Synthesis of compound I-126. The solution of compound 170.1
(0.110 g, 0.250 mmol, 1.0 eq) in sulphuric acid (2 mL) is heated at
60.degree. C. for 1 h. After completion of the reaction, the
reaction mixture is cooled to room temperature. Reaction mixture is
transferred to water and the pH of the solution is adjusted to 7 by
using aqueous ammonia to get the solid precipitates which are
filtered to get the crude material. These are further purified by
trituration using pentane to obtain pure I-126. (Yield: 21.28%).
MS(ES): m/z 450.46 [M+H].sup.+, LCMS purity: 100%, HPLC purity:
97.39%, 1H NMR (DMSO-d6, 400 MHz): 14.14 (s, 1H), 10.81 (bs, 1H),
8.63 (s, 2H), 8.29-8.28 (d, J=5.6 Hz, 1H), 8.14 (s, 1H), 7.69-7.62
(m, 3H), 7.04-7.02 (d, J=4.8 Hz, 1H), 6.98-6.94 (t, J=8.0 Hz, 1H),
6.59 (bs, 1H), 4.53 (s, 2H), 3.43 (s, 3H), 3.38 (s, 3H), 3.15 (s,
3H).
Example 171: Synthesis of
N-(4-((3-methoxypyridin-2-yl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazol-
o[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-223
##STR00519##
[0863] Synthesis of compound 171.1. Compound 171.1 was synthesized
from 3-methoxypyridin-2-amine and 1.9 using general procedure A.
(Yield: 89.15%). MS (ES): m/z 306.7 [M+H].sup.+.
[0864] Synthesis of compound I-223. Compound I-223 was synthesized
from 171.1 and cyclopropanecarboxamide using general procedure B
(Yield: 17.25%), MS(ES): m/z 355.17 [M+H].sup.+, LCMS purity:
99.64%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400 MHz): 10.70 (s,
2H), 9.63 (s, 1H), 8.99 (s, 1H), 7.87-7.86 (d, J=4.4 Hz, 1H),
7.38-7.36 (d, J=8.0 Hz, 1H), 6.99-6.96 (m, 1H), 3.91 (s, 3H), 3.29
(s, 3H), 2.02 (m, 1H), 0.83-0.78 (m, 4H).
Example 172: Synthesis of
N-(4-((2-methoxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)amino)-2-methyl--
3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-131
##STR00520## ##STR00521##
[0866] Synthesis of compound 172.1. To a cooled solution
2-methoxy-3-nitrobenzamide of (2.0 g, 10.20 mmol, 1.0 eq) in
1,4-dioxane (80 mL) were added dropwise pyridine (2.417 g, 30.6
mmol, 3.0 eq) and Trifluoromethanesulfonic anhydride (5.75 g, 20.40
mmol, 2.0 eq). The reaction mixture was stirred at room temperature
for 3 h. After completion of reaction, reaction mixture was
transferred into water and extracted with dichloromethane. Combined
organic layer dried over sodium sulfate and concentrated under
reduced pressure to obtain crude material. This was further
triturated in dichloromethane to obtain pure 172.1 (1.0 g, 55.06%).
MS(ES): m/z 179.15 [M+H].sup.+.
[0867] Synthesis of compound 172.2. To a solution of 172.1 (2.5 g,
14.03 mmol, 1.0 eq) in ethanol (40 mL) were added 50% solution of
hydroxyl amine (25 mL). The reaction mixture was stirred at
90.degree. C. for 1 h. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Combined organic layer dried over sodium sulfate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 1% methanol in dichloromethane to obtain pure 172.2 (1.3
g, 43.87%). MS(ES): m/z 212.18 [M+H].sup.+.
[0868] Synthesis of compound 172.3. To a solution of 172.2 (0.7 g,
3.31 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL) were added
potassium phosphate (2.10 g, 9.93 mmol, 3.0 eq). The reaction
mixture was cooled at 0.degree. C. and added acetyl chloride (0.516
g, 6.62 mmol, 2.0 eq). The reaction mixture was stirred at
120.degree. C. for 2 h. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Combined organic layer dried over sodium sulfate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 1% methanol in dichloromethane to obtain pure 172.3 (0.3
g, 38.48%). MS(ES): m/z 236.20 [M+H].sup.+.
[0869] Synthesis of compound 172.4. To a solution of 172.3 (0.1 g,
0.425 mmol, 1.0 eq) in methanol (1 mL), 10% palladium on charcoal
(0.08 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 172.4 (0.04 g,
45.84%). MS(ES): m/z 206.22 [M+H].sup.+.
[0870] Synthesis of compound 172.5. Compound 172.5 was synthesized
from 1.9 and 172.4 using general procedure A to obtain 1.5 (Yield:
26.31%).
[0871] Synthesis of compound I-131. Compound I-131 was synthesized
from 172.5 and cyclopropanecarboxamide using general procedure B.
(Yield: 4.44%).
Example 173: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((1-methyl-1H-pyrazol
3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-136
##STR00522##
[0873] Synthesis of compound I-136. Compound I-136 was synthesized
from 1-methyl-1H-pyrazol-3-amine and 1.9 using general procedure B.
(Yield: 14.14%), MS(ES): m/z 400.27 [M+H].sup.+, LCMS purity:
98.81%, HPLC purity: 98.21%, 1H NMR (DMSO-d6, 400 MHz): 9.72 (bs,
1H), 8.84 (s, 1H), 7.55 (s, 2H), 7.21 (s, 2H), 6.67 (bs, 1H), 6.27
(s, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.28 (s, 3H).
Example 174: Synthesis of
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-isopropylpyrazine-2-carbonitrile,
I-158
##STR00523##
[0875] Synthesis of compound 174.1. To compound
6-aminopyrazine-2-carbonitrile (5.0 g, 41.63 mmol, 1.0 eq) in
acetonitrile was added N-Bromosuccinimide (11.115 g, 62.44 mmol,
1.5 eq). The reaction mixture was stirred at room temperature for 6
h. After completion of reaction, water was added to reaction
mixture and extracted with ethyl acetate. Organic layer was
combined, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography and compound was eluted in 2% methanol in
dichloromethane to obtain 174.1. (5.3 g, Yield: 63.98%). MS (ES):
m/z 200.01 [M+H].sup.+.
[0876] Synthesis of compound 174.2. To a solution of 174.1 (0.5 g,
2.51 mmol, 1.0 eq),
4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.10 g,
6.53 mmol, 2.6 eq) in mixture of toluene (13 mL) and water (2 mL).
The reaction mixture was degassed by argon for 30 min. Palladium
acetate (0.056 g, 0.251 mmol, 0.1 eq), triphenyl phosphine (0.131
g, 0.502 mmol, 0.2 eq) and potassium phosphate (1.59 g, 7.53 mmol,
3.0 eq) was added into reaction mixture and again reaction mixture
was degassed by argon for 30 min. Further reaction mixture was
stirred at 100.degree. C. for 24 h. After completion of reaction,
water was added to reaction mixture and extracted with ethyl
acetate. Organic layer was combined, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 2% methanol in dichloromethane to obtain pure 174.2 (0.3
g, 74.55%). MS(ES): m/z 161.18 [M+H].sup.+.
[0877] Synthesis of compound 174.3. To a solution of 174.2 (0.4 g,
2.50 mmol, 1.0 eq) in methanol (4 mL), 10% palladium on charcoal
(0.016 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 1.3 (0.38 g, 93.82%).
MS(ES): m/z 163.20 [M+H].sup.+.
[0878] Synthesis of compound I-158. Compound I-158 was synthesized
from 174.3 and 1.91 using general procedure B. (Yield: 16.05%).
MS(ES): m/z 465.42 [M+H].sup.+, LCMS purity: 97.37%, HPLC purity:
97.61%, 1H NMR (DMSO-d6, 400 MHz): 10.89 (bs, 1H), 10.55 (s, 1H),
9.28 (s, 1H), 8.96 (s, 1H), 7.64-7.61 (dd, J=2.0 Hz, 7.8 Hz, 1H),
7.34 (s, 1H), 7.29-7.23 (m, 2H), 3.83 (s, 3H), 3.32 (s, 3H),
2.93-2.90 (m, 1H), 1.28 (s, 3H), 1.27 (s, 3H).
Example 175: Synthesis of
N-(4-((3-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-2-methoxyphenyl)amino)-2-me-
thyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxam-
ide, I-149
##STR00524##
[0880] Synthesis of compound 175.1. Compound was synthesized from
3-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-2-methoxyaniline and 1.9
using general procedure B. (Yield: 32.72%). MS(ES): m/z 400.25
[M+H].sup.+.
[0881] Synthesis of compound I-149. Compound I-149 was synthesized
from cyclopropanecarboxamide and 175.1 using general procedure B.
(Yield: 52.71%). MS(ES): m/z 449.46 [M+H].sup.+, LCMS purity:
99.65%, HPLC purity: 95.05%, 1H NMR (DMSO-d6, 400 MHz): 10.67 (bs,
1H), 8.90 (s, 1H), 7.67 (s, 1H), 7.59-7.57 (d, J=8.0 Hz, 1H),
7.32-7.24 (m, 2H), 3.62 (s, 3H), 2.32 (s, 3H), 2.30 (s, 6H),
2.02-1.96 (m, 1H), 1.81-0.78 (m, 4H).
Example 176: Synthesis of
N-(4-((2-(difluoromethoxy)-4-(pyrrolidine-1-carbonyl)phenyl)amino)-2-meth-
yl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamid-
e, I-151
##STR00525## ##STR00526##
[0883] Synthesis of compound 176.1. To a solution of methyl
3-hydroxy-4-nitrobenzoate (3.0 g, 15.2 mmol, 1.0 eq) in
dimethylformamide (50 mL), potassium carbonate (3.14 g, 22.82 mmol,
1.5 eq) was added at 0.degree. C. Then 2-chloro-2,2-difluoroacetate
(3.29 g, 22.82 mmol, 1.5 eq) was added and the reaction mixture was
stirred at 100.degree. C. for 2 h. After completion of the
reaction, the reaction mixture transferred into cooled water to get
solid precipitation. This was filtered to obtain 176.1. (3.0 g,
79.77%). MS(ES): m/z 248.51 [M+H].sup.+.
[0884] Synthesis of compound 176.2. To a solution of compound 176.1
(1.5 g, 6.07 mmol, 1.0 eq) in a mixture of methanol (104 mL) and
water (26 mL), sodium hydroxide (1.94 g, 48.56 mmol, 8.0 eq) was
added. The reaction mixture was stirred at 60.degree. C. for 2 h.
After completion of the reaction, the reaction mixture was cooled
to 0.degree. C. The pH of the solution was adjusted to 6-7 by using
2N HCl to get solid precipitation which was filtered and dried to
obtain 176.2 (1.0 g, 70.68%). MS(ES): m/z 234.76 [M+H].sup.+.
[0885] Synthesis of compound 176.3. To a solution of 176.2 (0.1 g,
0.42 mmol, 1.0 eq) in dimethylformamide (3 mL),
(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (0.195 g, 0.51 mmol, 1.2 eq) and
diisopropylethylamine (0.083 g, 0.64 mmol, 1.5 eq) were added at
0.degree. C. Reaction mixture was stirred at 0.degree. C. for 30
min. Then pyrrolidine (0.045 g, 0.64 mmol, 1.5 eq) was added and
reaction mixture was stirred at room temperature for 24 h. After
completion of the reaction, reaction mixture was transferred to
water and extracted with ethyl acetate. Organic layer was combined,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure to get the crude material. This was further
purified by column chromatography using 1% methanol in
dichloromethane to obtain 176.3 (0.120 g, 56.12%). MS(ES): m/z
229.48 [M+H].sup.+.
[0886] Synthesis of compound 176.4. To a solution of 176.3 (0.48 g,
1.68 mmol, 1.0 eq) in acetic acid (6 mL), iron powder (0.275 g, 5
mmolmmol, 3.0 eq) was added. Reaction mixture was stirred at
70.degree. C. for 2 h. After completion of the reaction, reaction
mixture was transferred to water and extracted with ethyl acetate.
Organic layer was combined, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain 176.4
(0.350 g, 81.11%). MS(ES): m/z 257.29 [M+H].sup.+.
[0887] Synthesis of compound 176.5. To a solution of 176.4 (0.48 g,
1.68 mmol, 1.0 eq) in tetrahydrofuran (6 mL), lithium
bis(trimethylsilyl)amide (0.275 g, 5 mmol, 3.0 eq) was added
dropwise at 0.degree. C. Reaction mixture was stirred at room
temperature for 3 h. After completion of the reaction, reaction
mixture was transferred to water and extracted with ethyl acetate.
Organic layer was combined, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain 176.5
(0.055 g, 10.73%). MS(ES): m/z 438.52 [M+H].sup.+.
[0888] Synthesis of compound I-151. Compound I-151 was synthesized
from 176.5 and cyclopropanecarboxamide using general procedure B.
(Yield: 23.40%). MS(ES): m/z 487.41 [M+H].sup.+, LCMS purity:
96.51%, HPLC purity: 95.50%, 1H NMR (DMSO-d6, 400 MHz): 10.77 (bs,
2H), 8.81 (s, 1H), 7.71 (s, 1H), 7.64-7.62 (d, J=8.4 Hz, 1H),
7.52-7.49 (m, 2H), 7.49-7.15 (t, 1H), 3.49 (m, 4H), 3.18 (s, 3H),
2.03-2.00 (m, 1H), 1.86 (m, 4H), 0.81-0.79 (m, 4H).
Example 177: Synthesis of
N-(4-((4-ethyl-2-(N-methylmethylsulfonamido)phenyl)amino)-2-methyl-3-oxo--
2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-217
##STR00527## ##STR00528##
[0890] Synthesis of compound 177.1. To a suspension of Cesium
carbonate (2.8 g, 0.008 mmol, 1.9 eq) in acetonitrile (28 mL),
N-methyl methane sulfonamide (0.5 g, 0.004 mmol, 1.1 eq) was added
and cooled to 0.degree. C. Then 4-bromo-2-fluoro-1-nitrobenzene (1
g, 0.004 mmol, 1 eq) was added dropwise in the reaction mixture
within 15 min. Reaction mixture was stirred at room temperature for
12 hours. After completion of the reaction, the reaction mixture
was filtered and the filtrate was concentrated under reduced
pressure to obtain 177.1. (0.8 g, 56.93%). MS(ES): m/z 310. 12
[M+H].sup.+.
[0891] Synthesis of compound 177.2. To a solution of compound 177.1
(0.2 g, 0.64 mmol, 1.0 eq) and vinyl boronic acid (0.24 g, 1.61
mmol, 2.5 eq) in a mixture of toluene (5 mL) and water (0.2 mL),
potassium phosphate (0.48 g, 2.26 mmol, 3.5 eq) and tetrakis (0.03
g, 0.12 mmol, 0.2 eq) were added and the reaction mixture was
degassed for 10 min. Then palladium acetate (0.014 g, 0.064 mmol,
0.1 eq) was added and the reaction mixture was again degassed for 5
min. Reaction mixture was stirred at 100.degree. C. for 1 h. After
completion of the reaction, water was added to the reaction mixture
and extracted with ethyl acetate. Organic layer combined, dried
over sodium sulphate and concentrated under pressure to obtain
177.2. (0.8 g, 80.14%). MS(ES): m/z 257.86 [M+H].sup.+.
[0892] Synthesis of compound 177.3. To a solution of 177.2 (0.2 g,
1.77 mmol, 1.0 eq) in methanol (2 mL), 10% palladium on charcoal
(0.06 g) was added. Hydrogen was purged through reaction mixture
for 12 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 177.3 (0.1 g,
56.12%). MS(ES): m/z 229.48 [M+H].sup.+.
[0893] Synthesis of compound 177.4. Compound 177.4 was synthesized
from 177.3 and 1.9 using general procedure A. (Yield: 24.88%).
MS(ES): m/z 410.16 [M+H].sup.+.
[0894] Synthesis of compound I-217. Compound I-217 was synthesized
from 177.4 and cyclopropanecarboxamide using general procedure B.
(Yield: 51.05%). MS(ES): m/z 459.46 [M+H].sup.+, LCMS purity:
96.79%, HPLC purity: 97.19%, 1H NMR (DMSO-d6, 400 MHz): 10.71 (s,
1H), 10.66 (s, 1H), 8.71 (s, 1H), 7.63 (s, 1H), 7.49-7.44 (m, 2H),
7.31-7.29 (d, J=8.0 Hz, 1H), 3.30 (s, 3H), 3.16 (s, 6H), 2.68-2.63
(q, J=7.6 Hz, 2H), 2.02-1.99 (m, 1H), 1.25-1.21 (t, J=7.6 Hz, 3H),
0.79-0.78 (m, 4H).
Example 178: Synthesis of
N-(4-((4-(methoxymethyl)-2-(N-methylmethylsulfonamido)phenyl)amino)-2-met-
hyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxami-
de, I-218
##STR00529## ##STR00530##
[0896] Synthesis of compound 178.1. To a solution of diisopropyl
amine (30.11 g, 298.1 mmol, 2.4 eq) in tetrahydrofuran (150 mL) was
cooled to -78.degree. C. followed by addition of n-butyl lithium
(19.08 g, 298.1 mmol, 2.4 eq) and stirred reaction mixture for 30
min at the same temperature. Tributyltin hydride (86.75 g, 298.1
mmol, 2.4 eq) was added to reaction mixture at same temperature and
then maintained 0.degree. C. and stirred for 30 min. The reaction
mixture was cooled to -78.degree. C., added compound
chloro(methoxy)methane (10 g, 124.21 mmol, 1.0 eq) and reaction
mixture was allowed to warm to room temperature. The reaction
mixture was stirred at room temperature for 5 h. After completion
of reaction, reaction mixture was transferred in to brine solution
and extracted with diethyl ether. Organic layer was combined,
washed with brine, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted hexane as
eluant to obtain 178.1. (7.0 g, 16.82%). MS(ES): m/z 336.12
[M+H].sup.+.
[0897] Synthesis of compound 178.2. To a solution of 177.1 (3.0 g,
9.70 mmol, 1.0 eq) in N-methyl pyrrolidine (35 mL) was added 178.1
(7.0 g, 20.89 mmol, 2.15 eq). The reaction mixture was degassed for
10 min. under argon atmosphere.
Tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.97 mmol, 0.1
eq), again reaction mixture was degassed for 10 min. under argon
atmosphere. The reaction was stirred at 60.degree. C. for 20 h.
After completion of reaction, reaction mixture was transferred in
water and extracted with ethyl acetate. Combined organic layer was
washed with brine, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 15% ethyl acetate in hexane
to obtain pure 178.2 (1.2 g, 45.03%). MS(ES): m/z 275.29
[M+H].sup.+
[0898] Synthesis of compound 178.3. To a solution of 178.2 (1.2 g,
4.37 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal
(0.5 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 178.3. (0.750 g,
70.17%). MS(ES): m/z 245.31 [M+H].sup.+.
[0899] Synthesis of compound 178.4. Compound 178.4 was synthesized
from 178.3 and 1.9 using general procedure A. (Yield: 13.65%).
MS(ES): m/z 426.89 [M+H].sup.+.
[0900] Synthesis of compound I-218. Compound I-218 was synthesized
from 178.4 and cyclopropanecarboxamide using general procedure B
(Yield: 13.46%), MS(ES): m/z 475.42 [M+H].sup.+, LCMS purity:
97.30%, HPLC purity: 99.18%, 1H NMR (DMSO-d6, 400 MHz): 8.82 (s,
1H), 8.25 (s, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.55-7.53 (d, J=6.4
Hz, 1H), 7.40-7.38 (d, J=8.4 Hz, 1H), 4.44 (s, 2H), 3.34 (s, 3H),
3.28 (s, 3H), 3.18 (s, 3H), 3.16 (s, 3H), 2.02-1.99 (m, 1H),
0.87-0.73 (m, 4H).
Example 179: Synthesis of
N-(2-((6-((6,7-dihydro-5H-cyclopenta[b]pyrazin-2-yl)amino)-2-methyl-3-oxo-
-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)phenyl)-N-methylmethanes-
ulfonamide, I-225
##STR00531##
[0902] Synthesis of compound 179.1. 2-chlorocyclopentan-1-one (1.0
g, 4.58 mmol, 1.0 eq) in water (20 mL) was heated to 100.degree.
C., to which a preheated solution of ferric chloride (1.48 g, 9.17
mmol, 2 eq) was added. Reaction mixture was stirred at 100.degree.
C. for 20 min. After completion of the reaction, the reaction
mixture was cooled to room temperature. The pH of the solution was
adjusted to 7 by using ammonium sulfate solution and then extracted
by ethyl acetate. Organic layers were combined, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain 179.1. (0.55 g, 66.47%). MS(ES): m/z 99.25
[M+H].sup.+.
[0903] Synthesis of compound 179.2. To a solution of compound 179.1
(0.100 g, 0.10 mmol, 1.0 eq) in ethanol (5 mL) at 0.degree. C.,
aminoacetamide dihyrobromide (0.23 g, 0.10 mmol, 1.0 eq) was added.
Reaction mixture was stirred for 10 min. Then, pH of the reaction
mixture was adjusted to 8-9 by using ammonium hydroxide solution.
Reaction mixture was stirred at room temperature overnight. After
completion of the reaction, pH of the reaction mixture was adjusted
to 7 by using 1N HCl and extracted with dichloromethane. Organic
layer was combined, dried over sodium sulfate, filtered and
concentrated to obtain pure 179.2 (0.021 g, 15.83%). MS(ES): m/z
136.48 [M].sup.+.
[0904] Synthesis of compound I-225. Compound I-225 was synthesized
from 115.3 and 179.2 using general procedure B. (Yield: 35.76%).
MS(ES): m/z 481.36 [M+H].sup.+, LCMS purity: 97.58%, HPLC purity:
98.32%, 1H NMR (DMSO-d6, 400 MHz): 10.71 (s, 1H), 9.95 (s, 1H),
8.91 (s, 1H), 8.86 (s, 1H), 7.71-7.69 (d, J=8.0 Hz, 1H), 7.59-7.57
(dd, J=1.2 Hz, 8.0 Hz, 1H), 7.49-7.45 (t, J=8.0 Hz, 1H), 7.25-7.19
(m, 2H), 3.28 (s, 3H), 3.20 (s, 3H), 3.15 (s, 3H), 2.92-2.87 (m,
4H), 2.17-2.09 (qui, J=7.6 Hz, 2H).
Example 180:
N-(4-((4-(3-methoxyazetidin-1-yl)-2-(N-methylmethylsulfonamido)phenyl)ami-
no)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropane-
-carboxamide, I-220
##STR00532##
[0906] Synthesis of compound 180.1. To a solution of
N-(5-fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (2.0 g, 8.06
mmol, 1.0 eq) in N,N-dimethylformamide (20 mL) was added cesium
carbonate (1.35 g, 9.83 mmol, 1.22 eq) followed by addition of
3-methoxyazetidine hydrochloride (1.21 g, 9.83 mmol, 1.22 eq)
dropwise. The reaction mixture was stirred at 60.degree. C. for 48
h. After completion of reaction, reaction mixture was transferred
into 10% solution of sodium phosphate (90 mL) and extracted with
ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 35% ethyl acetate in hexane as eluent to
obtain 180.1. (1.6 g, 62.97%). MS(ES): m/z 316.34 [M+H].sup.+.
[0907] Synthesis of compound 180.2. To a solution of 180.1 (1.6 g,
5.07 mmol, 1.0 eq) in ethanol (20 mL), 10% palladium on charcoal
(0.6 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 180.2. (1.2 g,
82.88%). MS(ES): m/z 286.36 [M+H].sup.+.
[0908] Synthesis of compound 180.3. Compound 180.3 was synthesized
from 180.2 and 1.9 using general procedure A. (Yield: 32.69%).
MS(ES): m/z 467.94 [M+H].sup.+.
[0909] Synthesis of compound I-220. Compound I-220 was synthesized
from 180.3 and cyclopropanecarboxamide using general procedure B
(Yield: 12.51%), MS(ES): m/z 516.31 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 98.39%, 1H NMR (MeOD, 400 MHz): 8.49 (s, 1H),
7.36-7.33 (d, J=8.4 Hz, 1H), 6.70 (s, 1H), 7.59-7.57 (d, J=8.0 Hz,
1H), 4.39 (m, 1H), 4.18-4.15 (m, 2H), 3.82-3.79 (m, 2H), 3.51 (s,
3H), 3.37 (s, 3H), 3.23 (s, 3H), 3.03 (s, 3H), 1.76 (m, 1H),
1.01-0.93 (m, 4H).
Example 181: Synthesis of
N-(4-((4-(azetidin-1-yl)-2-(N-methylmethylsulfonamido)phenyl)amino)-2-met-
hyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxami-
de, I-219
##STR00533##
[0911] Synthesis of compound 181.1. To a solution of
N-(5-fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (5.0 g, 20.14
mmol, 1.0 eq) in N,N-dimethylformamide (50 mL) was added cesium
carbonate (7.98 g, 24.57 mmol, 1.22 eq) followed by addition of
azetidine hydrochloride (1.88 g, 24.57 mmol, 1.22 eq). The reaction
mixture was stirred at 60.degree. C. for 48 h. After completion of
reaction, reaction mixture was transferred in to 10% solution of
sodium phosphate (90 mL) and extracted with ethyl acetate. Organic
layer was combined, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted in 35%
ethyl acetate in hexane as eluent to obtain 181.1. (3.4 g, 59.16%).
MS(ES): m/z 286.32 [M+H].sup.+.
[0912] Synthesis of compound 181.2. To a solution of 181.1 (2.0 g,
7.01 mmol, 1.0 eq) in ethanol (20 mL), 10% palladium on charcoal
(0.8 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 181.2. (1.5 g,
83.84%). MS(ES): m/z 256.34 [M+H].sup.+.
[0913] Synthesis of compound 181.3. Compound 181.3 was synthesized
from 181.2 and 1.9 using general procedure A. (Yield: 39.92%).
MS(ES): m/z 437.92 [M+H].sup.+.
[0914] Synthesis of compound I-219. Compound I-219 was synthesized
from 181.3 and cyclopropanecarboxamide using general procedure B.
(Yield: 37.12%), MS(ES): m/z 486.30 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400 MHz): 10.60 (s,
1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.29-7.18 (m, 2H), 6.82-6.64 (m,
2H), 3.58-3.38 (m, 4H), 3.26 (s, 3H), 3.09 (s, 3H), 3.06 (s, 3H),
3.05-3.00 (m, 2H), 1.92-1.84 (m, 1H), 0.74-0.71 (m, 4H).
Example 182: Synthesis of
4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-6-((4-(methoxymethyl)py-
ridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-214
##STR00534##
[0916] Synthesis of compound I-214. Compound I-214 was synthesized
from 4-(methoxymethyl)pyridin-2-amine using general procedure B
(Yield: 18.91%). MS(ES): m/z 495.26 [M+H].sup.+, LCMS purity:
100.00%, HPLC purity: 96.75%, 1H NMR (DMSO-d6, 400 MHz): 10.79 (bs,
1H), 9.04 (s, 1H), 6.25-6.24 (d, J=8.0 Hz, 1H), 7.59-7.57 (d, J=5.6
Hz, 1H), 7.69-7.67 (m, 2H), 7.51-7.49 (m, 1H), 7.24-7.11 (m, 1H),
7.04-6.99 (m, 1H), 6.45 (s, 1H), 4.52 (s, 2H), 3.44 (s, 3H), 3.32
(s, 3H), 3.18 (s, 3H), 2.15-2.09 (m, 1H), 1.09-1.04 (m, 2H),
0.79-0.75 (m, 2H).
Example 183: Synthesis of
N-(4-((4,5-difluoro-2-(N-methylmethylsulfonamido)phenyl)amino)-2-methyl-3-
-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-230
##STR00535##
[0918] Synthesis of compound 183.1. To a cooled solution of
4,5-difluoro-2-nitroaniline (5.0 g, 0.287 mmol, 1.0 eq) in
dichloromethane (100 mL) was added dropwise triethylamine (9.6 mL,
0.0686 mmol, 2.39 eq) followed by methane sulfonyl chloride (4.8
mL, 0.0619 mmol, 2.16 eq). Reaction mixture was stirred at room
temperature for 18 h. After completion of reaction, reaction
mixture was transferred into water and extracted with
dichloromethane. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted in 20% ethyl acetate in hexane as eluent to
obtain intermediate 5.2 g. To this intermediate was added 1M sodium
hydroxide (50 mL) in mixture of water and tetrahydrofuran. Reaction
mixture was stirred at room temperature for 18 h. After completion
of reaction, reaction mixture was transferred into water and
extracted with ethyl acetate. Organic layer was combined, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 30% ethyl acetate in
hexane as eluent to obtain intermediate 183.1. (2.1 g, 29.00%).
MS(ES): m/z 253.19 [M+H].sup.+.
[0919] Synthesis of compound 183.2. To a solution of 183.1 (2.1 g,
8.33 mmol, 1.0 eq) in dimethyl sulfoxide (10 mL) was added
potassium carbonate (4.6 g, 33.32 mmol, 4.0 eq) and methyl iodide
(3.55 g, 24.99 mmol, 3.0 eq). The reaction mixture was stirred at
80.degree. C. for 24 h. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Organic layer was combined, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 30% ethyl acetate in hexane as eluent to obtain 183.2.
(1.5 g, 67.67%). MS(ES): m/z 267.22 [M+H].sup.+.
[0920] Synthesis of compound 183.3. To a solution of 183.2 (1.5 g,
5.63 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal
(0.2 g) was added. Hydrogen was purged through reaction mixture for
2-3 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 183.3 (0.3 g,
22.54%). MS(ES): m/z 237.24 [M+H].sup.+.
[0921] Synthesis of compound 183.4. Compound 183.4 was synthesized
from 183.3 and 1.9 using general procedure A. (Yield: 31.89%). MS
(ES): m/z 418.82 [M+H].sup.+.
[0922] Synthesis of compound I-230. Compound I-230 was synthesized
from 183.4 and cyclopropanecarboxamide using general procedure B.
(Yield: 21.99%). MS(ES): m/z 467.37 [M+H].sup.+, LCMS purity:
98.04%, HPLC purity: 97.69%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (s,
1H), 8.76 (s, 1H), 8.17 (s, 1H), 7.90-7.85 (dd, J=2.8 Hz, 8.4 Hz,
1H), 7.67-7.62 (dd, J=4.0 Hz, 8.0 Hz, 1H), 7.60 (s, 1H), 3.29 (s,
3H), 3.16 (s, 3H), 3.15 (s, 3H), 2.04-1.97 (m, 1H), 0.80-0.78 (m,
4H).
Example 184: Synthesis of
3-((6-(cyclopropanecarboxamido)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,-
4-b]pyridin-4-yl)amino)-2-methoxybenzoic acid, I-231
##STR00536##
[0924] Synthesis of compound 184.1. Compound 184.1 was synthesized
from 3-amino-2-methoxybenzoic acid and 1.9 using general procedure
A. (Yield: 37.51%). MS (ES): m/z 349.7 [M+H].sup.+.
[0925] Synthesis of compound I-231. Compound I-231 was synthesized
from 184.1 and cyclopropanecarboxamide using general procedure B.
(Yield: 15.80%), MS(ES): m/z 398.43 [M+H].sup.+, LCMS purity:
99.57%, HPLC purity: 94.80%, 1H NMR (DMSO-d6, 400 MHz): 13.08 (bs,
1H), 10.81 (s, 1H), 8.84 (s, 1H), 7.73 (s, 1H), 7.69-7.67 (d, J=8.0
Hz, 1H), 7.48-7.44 (d, J=8.0 Hz, 1H), 7.31-7.27 (t, J=8.0 Hz, 1H),
3.79 (s, 3H), 3.38 (s, 3H), 2.06-1.99 (m, 1H), 0.89-0.80 (m,
4H).
Example 185: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((4,5,6,7-tetrahydropyrazo-
lo[1,5-a]pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-222
##STR00537## ##STR00538##
[0927] Synthesis of compound 185.1. To a solution of
3-nitro-1H-pyrazole (5.0 g, 44.22 mmol, 1.0 eq) in tetrahydrofuran
(50 mL) was added sodium hydride (1.6 g, 66.33 mmol, 1.5 eq) at
0.degree. C. and reaction mixture was stirred for 30 min followed
by 2-(Trimethylsilyl)ethoxymethyl chloride (8.86 g, 53.06 mmol, 1.2
eq) was added at the same temperature. The reaction mixture was
allowed to come at room temperature and stirred for 24 h. After
completion of reaction, reaction mixture was transferred in to ice
cold water and extracted with ethyl acetate. Organic layer was
combined, washed with brine, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted on 15% ethyl acetate in hexane as eluent to obtain 185.1.
(7.9 g, 73.42%). MS(ES): m/z 244.34 [M+H].sup.+.
[0928] Synthesis of compound 185.2. To a cooled solution of
diisopropyl amine (0.622 g, 6.165 mmol, 1.5 eq) in tetrahydrofuran
(10 mL) at -78.degree. C. n-butyl lithium (0.394 g, 6.165 mmol, 1.5
eq) was added and stirred reaction mixture for 30 min. at the same
temperature. Compound 185.1 (1.0 g, 4.11 mmol, 1.0 eq) was added to
reaction mixture and stirred at -78.degree. C. for 1 h. Iodine
solution (0.635 g, 2.50 mmol, 0.5 eq) in tetrahydrofuran was added
at same temperature. After 1 h reaction mixture was brought to room
temperature and stirred for 20 h. After completion of reaction,
reaction mixture was transferred in to aqueous sodium thiosulphate
solution and extracted with ethyl acetate. Organic layer was
combined, washed with brine, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 15% ethyl acetate in hexane as eluent to obtain 185.2.
(1.0 g, 65.90%). MS(ES): m/z 370.23 [M+H].sup.+.
[0929] Synthesis of compound 185.3. To a solution of 185.2 (0.15 g,
0.406 mmol, 1.0 eq) and potassium vinyl trifluoroborate (0.098 g,
0.731 mmol, 1.8 eq) in mixture of tetrahydrofuran (1 mL) and water
(0.2 mL) was added potassium carbonate (0.168 g, 1.22 mmol, 3.0
eq). The reaction mixture was degassed for 10 min. under argon
atmosphere. The [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II)
dichloride dichloromethane complex (0.017 g, 0.020 mmol, 0.05 eq)
was added, again reaction mixture was degassed for 10 min. under
argon atmosphere. The reaction was stirred at 100.degree. C. for 24
h. After completion of reaction, reaction mixture was transferred
in water and extracted with ethyl acetate. Combined organic layer
was washed with brine, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 5% ethyl acetate in hexane
to obtain pure 185.3 (0.080 g, 73.10%). MS(ES): m/z 270.38
[M+H].sup.+.
[0930] Synthesis of compound 185.4. To a solution of 185.3 (0.07 g,
0.259 mmol, 1.0 eq) in mixture of dichloromethane (1 mL) was added
trifluoroacetic acid (1 mL) at 0.degree. C. The reaction was
stirred at room temperature for 6 h. After completion of reaction,
reaction mixture was concentrated under vacuum and basified with
sodium bicarbonate solution then extracted with ethyl acetate to
obtain pure 185.4 (0.025 g, 69.16%). MS(ES): m/z 140.11
[M+H].sup.+.
[0931] Synthesis of compound 185.5. To a solution of 185.4 (0.5 g,
3.59 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL) was added
potassium carbonate (1.486 g, 10.77 mmol, 3.0 eq) at 0.degree. C.
and 4-bromobut-1-ene (0.534 g, 3.95 mmol, 1.1 eq). The reaction
mixture was stirred at room temperature for 20 h. After completion
of reaction, reaction mixture was transferred in water and
extracted with ethyl acetate. Organic layer was combined, washed
with brine, dried over sodium sulphate and concentrated under
reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted on 10%
ethyl acetate in hexane as eluent to obtain 185.5. (0.34 g,
48.96%). MS(ES): m/z 194.21 [M+H].sup.+.
[0932] Synthesis of compound 185.6. To a solution of 185.5 (0.34 g,
1.76 mmol, 1.0 eq) in dichloromethane (7 mL) was added Grubb's
second generation catalyst (0.110 g, 0.176 mmol, 0.1 eq). The
reaction mixture was stirred at 50.degree. C. for 16 h. After
completion of reaction, reaction mixture was concentrated under
reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted on 15%
ethyl acetate in hexane as eluent to obtain 185.6. (0.19 g,
65.37%). MS(ES): m/z 166.15 [M+H].sup.+.
[0933] Synthesis of compound 185.7. To a solution of 185.6 (0.19 g,
1.15 mmol, 1.0 eq) in methanol (2 mL), 10% palladium on charcoal
(0.05 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 185.7 (0.13 g,
82.37%). MS(ES): m/z 138.19 [M+H].sup.+.
[0934] Synthesis of compound I-222. Compound I-222 was synthesized
from 185.7 and 73.1 using general procedure B. (Yield: 11.82%).
MS(ES): m/z 440.32 [M+H].sup.+, LCMS purity: 98.23%, HPLC purity:
97.74%, 1H NMR (DMSO-d6, 400 MHz): 10.52 (s, 1H), 9.45 (s, 1H),
8.81 (s, 1H), 7.57-7.55 (d, J=8.0 Hz, 1H), 7.25-7.17 (m, 2H), 6.95
(s, 1H), 6.14 (s, 1H), 3.94 (t, 2H), 3.82 (s, 3H), 3.25 (s, 3H),
2.72-2.67 (m, 2H), 1.96 (m, 2H), 1.77-1.74 (m, 2H).
Example 186: Synthesis of
N-(2-((6-((1,3-dihydrofuro[3,4-c]pyridin-6-yl)amino)-2-methyl-3-oxo-2,3-d-
ihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)phenyl)-N-methylmethanesulfona-
mide, I-227
##STR00539## ##STR00540##
[0936] Synthesis of compound 181.1. The reaction mixture of
1,3,5-trioxane (12.0 g, 133.22 mmol, 1.0 eq) and trimethylsilyl
iodide (75.9 g, 379.6 mmol, 2.85 eq) was stirred at 40.degree. C.
for 48 h. The reaction progress was monitored by NMR analysis.
After completion of reaction, reaction mixture was purified by
vacuum distillation at 5 mmHg, 105.degree. C. to obtain desired
pure product 186.1. (35 g, 88.20%). 1H NMR (CDCl3, 400 MHz):5.75
(S, 4H).
[0937] Synthesis of compound 186.2. A solution of diisopropyl amine
(16.27 g, 161.16 mmol, 2.4 eq) in tetrahydrofuran (70 mL) was
cooled to -78.degree. C. followed by n-butyl lithium (10.31 g,
161.16 mmol, 2.4 eq) was added and stirred reaction mixture for 30
min. at the same temperature. Tributyltin hydride (46.90 g, 161.16
mmol, 2.4 eq) was added to reaction mixture at same temperature and
then maintained 0.degree. C. and stirred for 30 min. The reaction
mixture was cooled to -78.degree. C., added compound 1 (20 g, 67.15
mmol, 1.0 eq) and reaction mixture was allowed to warm to room
temperature. The reaction mixture was stirred at room temperature
for 5 h. After completion of reaction, reaction mixture was
transferred into brine solution and extracted with diethyl ether.
Organic layer was combined, washed with brine, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography and
compound was eluted hexane as eluent to obtain 186.2. (0.85 g,
2.03%). MS(ES): m/z 625.17 [M+H].sup.+.
[0938] Synthesis of compound 186.3. To a solution of
5-bromo-4-chloropyridin-2-amine (2.0 g, 9.64 mmol, 1.0 eq),
Di-tert-butyl dicarbonate (5.25 g, 24.1 mmol, 2.5 eq) and triethyl
amine (2.423 g, 24.1 mmol, 2.5 eq) in tetrahydrofuran (10 mL) was
added. Then 4-Dimethylaminopyridine (0.117 g, 0.964 mmol, 0.1 eq)
was added and the reaction mixture was stirred at room temperature
for 18 h. After completion of reaction, reaction mixture was
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted in 10% ethyl acetate in hexane as eluent to obtain 186.3.
(2.10 g, 53.43%). MS(ES): m/z 408.69 [M+H].sup.+.
[0939] Synthesis of compound 186.4 To a solution of 186.3 (0.650 g,
1.59 mmol, 1.0 eq), oxybis(methylene)bis(tributylstannane) (0.995
g, 1.59 mmol, 1.0 eq), Tris(dibenzylideneacetone) dipalladium(0)
(0.146 g, 1.59 mmol, 0.1 eq),
2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.152 g,
3.19 mmol, 0.2 eq), in Dioxane (20 mL) was added. The reaction
mixture was degassed for 15 min. under argon atmosphere. The
reaction mixture was stirred at 120.degree. C. for 20 h. After
completion of reaction, reaction mixture was transferred in ethyl
acetate. Organic layer was filtered through celite-bed and washed
with ethyl acetate. Filtrate was concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography using 18% ethyl acetate in hexane to obtain
pure 186.4 (0.250 g, 46.61%). MS(ES): m/z 337.39 [M+H].sup.+.
[0940] Synthesis of compound 186.5. Compound 186.5 was synthesized
from 186.4 using general procedure C. (Yield: 79.06%). MS(ES): m/z
137.15 [M+H].sup.+.
[0941] Synthesis of compound I-227. Compound I-227 was synthesized
from 115.3 and 186.5 using general procedure B. (Yield: 24.78%).
MS(ES): m/z 482.36 [M+H].sup.+, LCMS purity: 98.38%, HPLC purity:
96.23%, 1H NMR (DMSO-d6, 400 MHz): 10.74 (s, 1H), 9.89 (s, 1H),
8.86 (s, 1H), 8.21 (s, 1H), 8.05 (s, 1H), 7.72-7.70 (d, J=8.0 Hz,
1H), 7.59-7.57 (d, J=8.0 Hz, 1H), 1.50-1.48 (d, J=8.0 Hz, 1H), 7.21
(s, 1H), 7.11 (s, 1H), 5.00 (s, 4H), 3.28 (s, 3H), 3.22 (s, 3H),
3.18 (s, 3H).
Example 187: Synthesis of
3-((6-amino-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)ami-
no)-2-methoxybenzoic acid, I-241
##STR00541##
[0943] Synthesis of compound I-241. To a solution of I-33 (0.070 g,
0.184 mmol, 1.0 eq) in ethanol (1 mL) was added 3N aqueous sodium
hydroxide solution (5 mL) dropwise and reaction mixture was stirred
at 90.degree. C. for 3 h. After completion of reaction, reaction
mixture concentrated under reduced pressure to obtain crude
material. This was further purified by Preparative HPLC using 0.1%
Formic acid in water/Acetonitrile in gradient method to obtain pure
I-241 (0.013 g, 21.34%), MS(ES): m/z 330.25 [M+H].sup.+, LCMS
purity: 100.00%, HPLC purity: 98.07%, 1H NMR (DMSO-d6, 400 MHz):
11.89 (s, 1H), 8.77 (s, 1H), 8.19 (s, 1H), 7.64-7.62 (d, J=8.0 Hz,
1H), 7.41-7.39 (d, J=8.0 Hz, 1H), 7.25-7.21 (t, J=8.0 Hz, 1H), 6.53
(s, 2H), 5.78 (s, 1H), 3.80 (s, 3H), 3.18 (s, 3H).
Example 188: Synthesis of
N-(4-((4-cyclobutyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo-2,3-di-
hydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide,
I-182
##STR00542## ##STR00543##
[0945] Synthesis of compound 188.1. To a cooled solution of
3-fluoro-4-nitrophenol (5.0 g, 31.83 mmol, 1.0 eq) in
dichloromethane (50 mL) at 0.degree. C. was added
Trifluoromethanesulfonic anhydride (0.520 g, 4.14 mmol, 2.0 eq),
stirred for 15 min followed by dropwise addition of triethylamine
(0.520 g, 4.14 mmol, 2.0 eq) at the same temperature. The reaction
mixture was stirred at room temperature for 2 h. After completion
of reaction, reaction mixture was transferred in to water and
extracted with dichloromethane. Organic layer was combined, washed
with brine, dried over sodium sulphate and concentrated under
reduced pressure to obtain crude material. This was further
purified by column chromatography in neutral alumina and compound
was eluted on 15% ethyl acetate in hexane as eluent to obtain
188.1. (3.0 g, 32.60%). MS(ES): m/z 290.16 [M+H].sup.+.
[0946] Synthesis of compound 188.2. To a solution of 1.1 (3.0 g,
10.38 mmol, 1.0 eq) and cyclobutyl boronic acid (1.3 g, 12.97 mmol,
1.25 eq) in toluene (30 mL) was added cesium carbonate (6.74 g,
20.76 mmol, 2.0 eq). The reaction mixture was degassed for 10 min.
under argon atmosphere. The
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride
(0.607 g, 0.83 mmol, 0.08 eq) was added, again reaction mixture was
degassed for 10 min. under argon atmosphere. The reaction was
stirred at 90.degree. C. for 4 h. After completion of reaction,
reaction mixture was transferred in water and extracted with ethyl
acetate. Combined organic layer was washed with brine, dried over
sodium sulphate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 5% ethyl acetate in hexane to obtain pure 188.2 (0.32 g,
15.80%). MS(ES): m/z 196.19 [M+H].sup.+.
[0947] Synthesis of compound 188.3. To a solution of 188.2 (0.34 g,
1.64 mmol, 1.0 eq) in mixture of N--N-dimethylformamide (6 mL) and
water (4 mL) was added dropwise sodium thiomethoxide water solution
(0.252 g, 3.61 mmol, 2.2 eq) at 0.degree. C. The reaction was
stirred at 15-20.degree. C. for 1 h. After completion of reaction,
reaction mixture was transferred in water and extracted with ethyl
acetate. Combined organic layer was washed with brine, dried over
sodium sulphate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 5% ethyl acetate in hexane to obtain pure 188.3 (0.24 g,
65.56%). MS(ES): m/z 224.29 [M+H].sup.+.
[0948] Synthesis of compound 188.4. To a solution of 188.3 (0.14 g,
0.623 mmol, 1.0 eq) in methanol (5 mL), 10% palladium on charcoal
(0.05 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 188.4 (0.08 g,
66.01%). MS(ES): m/z 194.31 [M+H].sup.+.
[0949] Synthesis of compound 188.5. Compound 188.5 was synthesized
from 1.9 and 188.4 using general procedure A. (Yield: 58.16%). MS
(ES): m/z 375.89 [M+H].sup.+.
[0950] Synthesis of compound 188.6. To a solution of 188.5 (0.075
g, 0.200 mmol, 1 eq) in acetic acid (1 mL) was added 30% hydrogen
peroxide (0.144 g, 4.0 mmol, 20.0 eq) and sodium tungstate
dihydrate (0.066 g, 0.200 mmol, 1 eq). Reaction mixture was stirred
at room temperature for 2 h. After completion of reaction, reaction
mixture was transferred in ice-water and precipitated product was
filtered, washed with 25% ethyl acetate in hexane and dried well to
obtain 188.6. (0.070 g, Yield: 85.99%). MS(ES): m/z 407.89
[M+H].sup.+.
[0951] Synthesis of compound I-182. Compound I-182 was synthesized
from 188.6 and cyclopropanecarboxamdie using general procedure B.
(Yield: 31.90%). MS(ES): m/z 456.37 [M+H].sup.+, LCMS purity:
95.00%, HPLC purity: 98.84%, 1H NMR (DMSO-d6, 400 MHz): 10.80 (s,
2H), 9.05 (s, 1H), 7.75-7.68 (m, 4H), 3.65 (m, 1H), 3.30 (s, 3H),
3.16 (s, 3H), 2.34 (m, 2H), 2.14 (m, 2H), 2.00 (m, 2H), 1.86 (m,
1H), 0.77 (m, 4H).
Example 189: Synthesis of
4-((4-chloro-2-(methylsulfonyl)phenyl)amino)-2-methyl-6-((5-methyl-6-(tri-
fluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-o-
ne, I-208
##STR00544##
[0953] Synthesis of compound 189.1. To a solution of
5-bromo-6-(trifluoromethyl)pyridin-2-amine (0.500, 2.07 mmol, 1.0
eq) in 1,4-dioxane (0.5 mL) was added Tri methyl boroxine (0.520 g,
4.14 mmol, 2.0 eq). The reaction mixture was degassed for 10 min.
under argon atmosphere. Potassium carbonate (0.858 g, 6.22 mmol,
3.0 eq) and tetrakis(triphenylphosphine)palladium(0) (0.239 g,
0.207 mmol, 0.1 eq), again reaction mixture was degassed for 10
min. under argon atmosphere. The reaction was stirred at
110.degree. C. for 20 h. After completion of reaction, reaction
mixture was transferred in water and extracted with ethyl acetate.
Combined organic layer was washed with brine, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography using
15% ethyl acetate in hexane to obtain pure 189.1 (0.230 g, 62.94%).
MS(ES): m/z 177.14 [M+H].sup.+.
[0954] Synthesis of compound I-208. Compound I-208 was synthesized
from 189.1 and 118.4 using general procedure B (Yield: 7.10%).
MS(ES): m/z 527.34 [M+H].sup.+, LCMS purity: 98.28%, HPLC purity:
96.27%, 1H NMR (DMSO-d6, 400 MHz): 10.83 (s, 1H), 10.09 (s, 1H),
9.06 (s, 1H), 8.04-8.02 (d, J=8.0 Hz, 1H), 7.91-7.90 (d, J=1.0 Hz,
1H), 7.86-7.79 (m, 3H), 7.17 (s, 1H), 3.29 (s, 3H), 3.26 (s, 3H),
2.36 (s, 3H).
Example 190: Synthesis of
6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-(2-methoxypropan-2-yl)pyrazine-2-carboni-
trile, I-155
##STR00545## ##STR00546##
[0956] Synthesis of compound 190.1. To a solution of compound
methyl 3,5-dichloropyrazine-2-carboxylate (0.55 g, 2.6 mmol, 1.0
eq) in dimethylformamide (5 mL), cesium carbonate (0.8 g, 3.1 mmol,
1.2 eq) and dibenzylamine (0.61 g, 3.1 mmol, 1.2 eq) was added.
Reaction mixture was stirred at room temperature for 3 hours. After
completion of the reaction, reaction mixture transferred into water
and extracted with ethyl acetate. Combined organic layer, dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to obtain 190.1. (0.5 g, 51.16%). MS(ES): m/z
368.54 [M+H].sup.+.
[0957] Synthesis of compound 190.2. To a solution of compound 190.1
(0.18 g, 0.4 mmol, 1.0 eq) in tetrahydrofuran (5 mL), methyl
magnesium bromide (0.36 g, 1.09 mmol, 2.2 eq) was added at
0.degree. C. Reaction mixture was stirred at room temperature for 1
h. After completion of the reaction, reaction mixture transferred
into water and extracted with ethyl acetate. Combined organic
layer, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain 190.2. (0.15 g,
83.32%). MS(ES): m/z 368.43 [M+H].sup.+.
[0958] Synthesis of compound 190.3 To a solution of 190.2 (0.15 g,
0.413 mmol, 1.0 eq) in dimethylformamide (1 mL), sodium hydride
(0.025 g, 0.490 mmol, 1.2 eq) was added at 0.degree. C. within 5
min. Then methyl iodide (0.07 g, 0.490 mmol, 1.2 eq) was added and
the reaction mixture was stirred at room temperature for 4 h. After
completion of the reaction, reaction mixture transferred into water
and extracted with ethyl acetate. Combined organic layer, dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to obtain 190.3. (0.1 g, 64.22%). MS(ES): m/z
382.51 [M+H].sup.+.
[0959] Synthesis of compound 190.4. To a solution of 190.3 (0.08 g,
0.29 mmol, 1.0 eq) in dimethylacetamide (1 mL), zinc dust (0.003 g,
0.041 mmol, 0.2 eq) and zinc cyanide (0.012 g, 0.10 mmol, 0.5 eq)
was added. Reaction mixture was degassed for 15 min and then
palladium tris(dibenzylideneacetone)dipalladium(0) (0.02 g, 0.020
mmol, 0.1 eq) was added and the reaction mixture was kept microwave
irradiation for 30 min at 120.degree. C. After completion of the
reaction, reaction mixture transferred into water and extracted
with ethyl acetate. Combined organic layer, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain 190.4. (0.05 g, 64.08%). MS(ES): m/z 373.28 [M+H].sup.+.
[0960] Synthesis of compound 190.5. To a solution of 190.4 (0.08 g,
0.29 mmol, 1.0 eq) in methanol (1 mL), cyclohexene (0.003 g, 0.041
mmol, 0.2 eq) and palladium hydroxide (0.012 g, 0.10 mmol, 0.5 eq)
were added. Reaction mixture was kept in microwave irradiation for
4 h at 100.degree. C. After completion of reaction, reaction
mixture was filtered through celite-bed and washed with methanol.
Filtrate was concentrated under reduced pressure to 190.5 (0.2 g,
38.75%). MS(ES): m/z 193.53 [M+H].sup.+.
[0961] Synthesis of compound I-155. Compound I-155 was synthesized
from 190.5 and 73.1 using general procedure B. (Yield: 29.13%).
MS(ES): m/z 495.58 [M+H].sup.+, LCMS purity: 98.63%, HPLC purity:
98.19%, 1H NMR (DMSO-d6, 400 MHz): 10.95 (s, 1H), 10.65 (s, 1H),
9.28 (s, 1H), 8.99 (s, 1H), 7.64-7.61 (dd, J=1.6 Hz, 8.0 Hz, 1H),
7.32-7.23 (m, 3H), 3.83 (s, 3H), 3.32 (s, 3H), 3.17 (s, 3H), 1.55
(s, 6H).
Example 191: Synthesis of
6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyr-
azolo[3,4-b]pyridin-6-yl)amino)-3-(2-methoxypropan-2-yl)pyrazine-2-carboni-
trile, I-190
##STR00547##
[0963] Synthesis of compound I-190. Compound I-190 was synthesized
from 190.5 and 55.1 using general procedure B. (Yield: 14.92%).
MS(ES): m/z 479.62 [M+H].sup.+, LCMS purity: 95.39%, HPLC purity:
95.38%, 1H NMR (DMSO-d6, 400 MHz): 10.92 (s, 1H), 10.64 (s, 1H),
9.27 (s, 1H), 8.97 (s, 1H), 7.48-7.46 (d, J=8.4 Hz, 1H), 7.33 (s,
1H), 7.27-7.21 (m, 1H), 7.07-7.02 (m, 1H), 3.91 (s, 3H), 3.32 (s,
3H), 3.17 (s, 3H), 1.54 (s, 6H).
Example 192: Synthesis of
N-(4-((4-(3-methoxyazetidin-1-yl)-2-(N-methylmethylsulfonamido)phenyl)ami-
no)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropane-
carboxamide, I-240
##STR00548##
[0965] Synthesis of compound 192.1. To a solution of
N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (0.6 g, 1.94
mmol, 1.0 eq) in mixture of 1,4-dioxane (4 mL) and water (2 mL) was
added
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.611 g, 2.91 mmol, 1.5 eq). The reaction mixture was degassed for
10 min. under argon atmosphere. Potassium carbonate (0.803 g, 5.82
mmol, 3.0 eq) and Tetrakis(triphenylphosphine)palladium(0) (0.224
g, 0.194 mmol, 0.1 eq), again reaction mixture was degassed for 10
min. under argon atmosphere. The reaction was stirred at
100.degree. C. for 20 h. After completion of reaction, reaction
mixture was transferred in water and extracted with ethyl acetate.
Combined organic layer was washed with brine, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography using
15% ethyl acetate in hexane to obtain pure 192.1 (0.5 g, 82.48%).
MS(ES): m/z 313.34 [M+H].sup.+
[0966] Synthesis of compound 192.2. To a solution of 192.1 (0.5 g,
1.6 mmol, 1.0 eq) in ethanol (25 mL), 10% palladium on charcoal
(0.3 g) was added. Hydrogen was purged through reaction mixture for
4 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with methanol. Filtrate was
concentrated under reduced pressure to obtain 192.2. (0.4 g,
87.87%). MS(ES): m/z 285.37 [M+H].sup.+.
[0967] Synthesis of compound 192.3. Compound 192.3 was synthesized
from 1.9 and 192.2 using general procedure A. (Yield: 19.56%).
MS(ES): m/z 466.94 [M+H].sup.+.
[0968] Synthesis of compound I-240. Compound I-240 was synthesized
from 192.3 and cyclopropanecarboxamide using general procedure B.
(Yield: 28.97%), MS(ES): m/z 515.46 [M+H].sup.+, LCMS purity:
97.79%, HPLC purity: 98.19%, Chiral HPLC: (43:57), 1H NMR (DMSO-d6,
400 MHz): 10.73 (s, 1H), 10.68 (s, 1H), 8.79 (s, 1H), 7.69 (s, 1H),
7.51 (s, 2H), 7.37-7.35 (d, J=8.0 Hz, 1H), 3.90-3.87 (m, 2H), 3.40
(m, 2H), 3.30 (s, 3H), 3.17 (s, 3H), 3.15 (s, 3H), 2.84 (m, 1H),
2.00-1.96 (m, 2H), 1.79-1.76 (m, 1H), 1.67 (m, 2H), 0.87-0.80 (m,
4H).
Example 193: Synthesis of
4-((3-chloro-2-methoxyphenyl)amino)-6-((6,7-dihydro-4H-pyrazolo[5,1-c][1,-
4]oxazin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one,
I-234
##STR00549##
[0970] Synthesis of compound 193.1. To a solution of
N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (1.0 g, 3.58
mmol, 1.0 eq) in mixture of tetrahydrofuran (10 mL) and water (5
mL) was added
2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1.51 g, 7.16 mmol, 2.0 eq) and potassium carbonate (1.48 g, 10.74
mmol, 3.0 eq). The reaction mixture was degassed for 10 min. under
argon atmosphere.
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride
(0.262 g, 0.358 mmol, 0.1 eq), again reaction mixture was degassed
for 10 min. under argon atmosphere. The reaction was stirred at
60.degree. C. for 20 h. After completion of reaction, reaction
mixture was transferred in water and extracted with ethyl acetate.
Combined organic layer was washed with brine, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography using
15% ethyl acetate in hexane to obtain pure 193.1 (1.0 g, 98.86%).
MS(ES): m/z 283.36 [M+H].sup.+.
[0971] Synthesis of compound 193.2. To a solution of 193.1 (1 g,
3.54 mmol, 1.0 eq) in methanol (20 mL), 10% palladium on charcoal
(0.15 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 193.2 (0.42 g,
41.70%). MS(ES): m/z 285.37 [M+H].sup.+.
[0972] Synthesis of compound 193.3. Compound 193.3 was synthesized
from 1.9 and 193.2 using general procedure A. (Yield: 22.84%).
MS(ES): m/z 466.95 [M+H].sup.+.
[0973] Synthesis of compound I-234. Compound I-234 was synthesized
from 193.3 and cyclopropanecarboxamide using general procedure B.
(Yield: 51.95%). MS(ES): m/z 515.46 [M+H].sup.+, LCMS purity:
98.21%, HPLC purity: 95.25%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s,
1H), 10.67 (s, 1H), 8.78 (s, 1H), 7.68 (s, 1H), 7.51 (s, 2H),
7.36-7.34 (d, J=8.0 Hz, 1H), 3.99-3.96 (m, 2H), 3.47-3.43 (m, 2H),
3.30 (s, 3H), 3.18 (s, 3H), 3.15 (s, 3H), 2.83 (m, 1H), 2.01 (m,
1H), 1.74 (m, 4H), 0.87-0.79 (m, 4H).
Example 194: Synthesis of
N-(4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo-2,3-d-
ihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2,2-difluorocyclopropane-1-carboxam-
ide, I-239
##STR00550## ##STR00551##
[0975] Synthesis of compound 194.1. To a solution of compound 194
(prepared by reaction of 1.9 with dihydropyran, 0.3 g, 0.25 mmol,
1.0 eq) and 109.4 in tetrahydrofuran (3 mL), Lithium
bis(trimethylsilyl)amide (0.86 g, 0.75 mmol, 3.0 eq) was added.
Reaction mixture was stirred at room temperature to obtain 194.1.
(0.28 g, 63.38%). MS(ES): m/z 445.58 [M+H].sup.+.
[0976] Synthesis of compound 194.2. To a solution of compound 194.1
(0.150 g, 0.33 mmol, 1.0 eq) in 1,4-dioxane (5 mL),
2,2-difluorocyclopropane-1-carboxamide (0.123 g, 1.013 mmol, 3.0
eq) and cesium carbonate (0.44 g, 1.35 mmol, 4.0 eq) was added. The
reaction mixture was degassed for 10 min. under argon atmosphere,
then tris(dibenzylideneacetone)dipalladium(0) (0.031 g, 0.033 mmol,
0.1 eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.040
g, 0.65 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction mixture was then heated in microwave at 130.degree. C. for
60 min. After completion of reaction, reaction mixture was
transferred in water and extracted with ethyl acetate. Combined
organic layer was washed with brine, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography using 13% ethyl
acetate in hexane as eluant to obtain pure 194.2 (0.140 g, 78.42%).
MS(ES): m/z 530.46 [M].sup.+.
[0977] Synthesis of compound 194.3. To a solution of 194.2 (0.2 g,
0.04 mmol, 1.0 eq) in ethyl acetate (3 mL),
meta-chloroperoxybenzoic acid (0.28 g, 0.12 mmol, 3.0 eq) was added
at 0.degree. C. Reaction mixture was stirred at 0.degree. C. for 3
h. After completion of the reaction, water was added to the
reaction mixture and extracted with ethyl acetate. Organic layers
were combined, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain 194.3. (0.15 g,
70.73%). MS(ES): m/z 562.47 [M+H].sup.+.
[0978] Synthesis of compound I-239. To a solution of 194.3 (0.150
g, 0.167 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added
trifluoroacetic acid (1.0 mL) at 0.degree. C. The reaction mixture
was stirred at room temperature for 1 h. After completion of
reaction, reaction mixture transferred in saturated sodium
bicarbonate solution and product was extracted with
dichloromethane. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
trituration with diethyl ether/n-pentane mixture to obtain pure
I-239 (0.080 g, 62.73%). MS(ES): m/z 478.42 [M+H].sup.+, LCMS
purity: 99.70%, HPLC purity: 98.80%, Chiral HPLC: (51:49), 1H NMR
(DMSO-d6, 400 MHz): 10.98 (s, 1H), 10.87 (s, 1H), 9.03 (s, 1H),
7.65-7.63 (d, J=8.0 Hz, 2H), 7.56-7.50 (m, 2H), 3.31 (s, 3H), 3.15
(s, 3H), 3.02-2.94 (m, 1H), 2.14-2.08 (m, 1H), 2.02-1.95 (m, 2H),
1.07-1.02 (m, 2H), 0.79-0.76 (m, 2H).
Example I-195: Synthesis of
(1S,2S)--N-(4-((4-cyclobutyl-2-(N-methylmethylsulfonamido)phenyl)amino)-2-
-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorocyclopro-
pane-1-carboxamide, I-236
##STR00552## ##STR00553##
[0980] Synthesis of compound 195.1. To a cooled solution of
3-fluoro-4-nitrophenol (5.0 g, 31.83 mmol, 1.0 eq) in
dichloromethane (50 mL) at 0.degree. C. was added
Trifluoromethanesulfonic anhydride (0.520 g, 4.14 mmol, 2.0 eq),
stirred for 15 min followed by dropwise addition of triethylamine
(0.520 g, 4.14 mmol, 2.0 eq) at the same temperature. The reaction
mixture was stirred at room temperature for 2 h. After completion
of reaction, reaction mixture was transferred in to water and
extracted with dichloromethane. Organic layer was combined, washed
with brine, dried over sodium sulphate and concentrated under
reduced pressure to obtain crude material. This was further
purified by column chromatography in neutral alumina and compound
was eluted on 15% ethyl acetate in hexane as eluent to obtain
195.1. (3.0 g, 32.60%). MS(ES): m/z 290.16 [M+H].sup.+.
[0981] Synthesis of compound 195.2. To a solution of 1.1 (3.0 g,
10.38 mmol, 1.0 eq) and cyclobutyl boronic acid (1.3 g, 12.97 mmol,
1.25 eq) in toluene (30 mL) was added cesium carbonate (6.74 g,
20.76 mmol, 2.0 eq). The reaction mixture was degassed for 10 min.
under argon atmosphere. The
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride
(0.607 g, 0.83 mmol, 0.08 eq) was added, again reaction mixture was
degassed for 10 min. under argon atmosphere. The reaction was
stirred at 90.degree. C. for 4 h. After completion of reaction,
reaction mixture was transferred in water and extracted with ethyl
acetate. Combined organic layer was washed with brine, dried over
sodium sulphate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 5% ethyl acetate in hexane to obtain pure 195.2 (0.32 g,
15.80%). MS(ES): m/z 196.19 [M+H].sup.+.
[0982] Synthesis of compound 195.3. To a solution of N-Methyl
methane sulfonamide (0.615 g, 5.64 mmol, 1.1 eq) in acetonitrile (6
mL) were added cesium carbonate (3.33 g, 10.24 mmol, 2.0 eq). The
reaction mixture was stirred at room temperature for 30 min.
Compound 195.2 (1.0 g, 5.12 mmol, 1.0 eq) was added dropwise into
reaction mixture and stirred at room temperature for 3 h. After
completion of reaction, reaction mixture was filtered. Filtered
solid was transferred into water, stirred for 30 min and dried
under reduced pressure to obtain pure 195.3. (1.0 g, 68.65%).
MS(ES): m/z 285.33 [M+H].sup.+.
[0983] Synthesis of compound 195.4. To a solution of 195.3 (0.14 g,
0.492 mmol, 1.0 eq) in methanol (5 mL), 10% palladium on charcoal
(0.05 g) was added. Hydrogen was purged through reaction mixture
for 2-3 h. After completion of reaction, reaction mixture was
filtered through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 195.4 (0.08 g,
63.88%). MS(ES): m/z 255.35 [M+H].sup.+.
[0984] Synthesis of compound 195.5. Compound 195.5 was synthesized
from 195.4 and cyclopropanecarboxamide using general procedure A.
(Yield: 22.51%). MS (ES): m/z 436.93 [M+H].sup.+.
[0985] Synthesis of compound 195.6. Compound 195.6 was synthesized
from 195.6 and cyclopropanecarboxamide using general procedure B.
(Yield: 33.32%). MS(ES): m/z 485.58 [M+H].sup.+.
[0986] Synthesis of compound 195.7. To a solution of 195.6 (0.1 g,
0.206 mmol, 1 eq), in methanol (4 mL), and 5M sodium hydroxide (1.5
mL) was added. Reaction mixture stirred at room temperature for 36
h. After completion of reaction, reaction mixture transferred in
water and extracted with ethyl acetate. Combined organic layer
dried over sodium sulfate and concentrated under reduced pressure
to obtain crude material. This was further purified by column
chromatography and compound was eluted in 5% methanol in
Dichloromethane to obtain pure 195.7. (0.070 g, 81.44%). MS(ES):
m/z 417.50 [M+H].sup.+.
[0987] Synthesis of compound I-236 To a solution of 195.7 (0.070 g,
0.168 mmol, 1.0 eq) and (1S, 2S)-2-fluorocyclopropane-1-carboxylic
acid (0.026 g, 0.252 mmol, 1.5 eq) in N,N-dimethylformamide (1 mL)
and cooled at 0.degree. C. Added
((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxi-
d hexafluoro-phosphate)) (0.096 g, 0.252 mmol, 1.5 eq) and
N,N-Diisopropylethylamine (0.065 g, 0.504 mmol, 3.0 eq) and stirred
the reaction mixture at 50.degree. C. for 2 hr. After completion of
reaction, reaction mixture was transferred into water and extracted
with ethyl acetate. Organic layer was combined, dried over sodium
sulphate and concentrated under reduced pressure to pressure to
obtain crude material. This was further purified by column
chromatography and compound was eluted in 5% methanol in
dichloromethane to obtain pure I-236 (0.024 g, 28.41%). MS(ES): m/z
503.41 [M+H].sup.+, LCMS purity: 94.63%, HPLC purity: 99.76%,
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): 8.52 (s, 1H), 7.51-7.46 (m,
2H), 7.35-7.33 (d, J=8.0 Hz, 1H), 6.77 (s, 2H), 5.90 (s, 1H),
5.23-5.06 (m, 1H), 3.64-3.52 (m, 1H), 3.32 (s, 3H), 3.17 (s, 3H),
3.13 (s, 3H), 2.33-2.29 (m, 2H), 2.19-210 (m, 2H), 2.03-1.96 (m,
1H), 1.88-181 (m, 2H), 1.40-1.36 (m, 1H), 1.28-1.25 (m, 1H).
Examples 196/197: Synthesis of
(S)--N-(4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo--
2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2,2-difluorocyclopropane-1-car-
boxamide, I-237 and
(R)--N-(4-((4-cyclopropyl-2-(methylsulfonyl)phenyl)amino)-2-methyl-3-oxo--
2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2,2-difluorocyclopropane-1-car-
boxamide, I-238
##STR00554##
[0989] Synthesis of compound I-237 & I-238. Isomers of I-239
(0.090 g) were separated using column (CHIRAL PAK AD-H
250.times.4.6 mm, 5u) and 0.1 DEA in Methanol as co-solvent with
flow rate of 4 mL/min. to get pure fraction-1 (FR-a) and fraction-2
(FR-b). FR-a was concentrated under reduced pressure at 30.degree.
C. to afford pure I-237 (0.021 g). MS(ES): m/z 478.46 [M+H].sup.+,
LCMS purity: 96.96%, HPLC purity: 96.45%, Chiral HPLC purity:
97.25%, 1H NMR (DMSO-d6, 400 MHz): 10.80 (s, 1H), 8.99 (s, 1H),
7.64-7.61 (m, 2H), 7.49-7.47 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.42 (s,
1H), 3.30 (s, 3H), 3.14 (s, 3H), 2.11-2.07 (m, 1H), 1.99-1.92 (m,
2H), 1.12-1.08 (t, J=7.2 Hz, 1H), 1.05-1.00 (m, 2H), 0.77-0.74 (m,
2H). FR-b was concentrated under reduced pressure at 30.degree. C.
to afford pure I-238 (0.022 g). MS(ES): m/z 478.51 [M+H].sup.+,
LCMS purity: 95.67%, HPLC purity: 96.64%, Chiral HPLC purity: 95%,
1H NMR (DMSO-d6, 400 MHz): 10.79 (s, 1H), 8.98 (s, 1H), 7.64-7.61
(m, 2H), 7.48-7.46 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.36 (s, 1H), 3.30
(s, 3H), 3.14 (s, 3H), 2.12-2.05 (m, 1H), 1.99-1.92 (m, 2H),
1.11-1.08 (t, J=6.8 Hz, 1H), 1.04-1.00 (m, 2H), 0.77-0.74 (m,
2H).
Example 198: Synthesis of
N-(2-((6-((2,3-dihydrofuro[2,3-c]pyridin-5-yl)amino)-2-methyl-3-oxo-2,3-d-
ihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)phenyl)-N-methylmethanesulfona-
mide, I-226
##STR00555## ##STR00556## ##STR00557##
[0991] Synthesis of compound 198.1. To a solution of
4-bromopyridin-3-ol (5.0 g, 28.74 mmol, 1.0 eq) in dichloromethane
(75 mL) was added dropwise triethylamine (11.61 g, 114.96 mmol, 4.0
eq) followed by acetyl chloride (4.512 g, 57.48 mmol, 2.0 eq) at
0.degree. C. The reaction mixture was stirred at room temperature
for 16 h. After completion of reaction, reaction mixture was
filtered by bed of celite. The filtrate was transferred into water
and extracted with ethyl acetate. Organic layer was combined,
washed with brine, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography and compound was eluted on 5%
ethyl acetate in hexane as eluent to obtain 198.1. (4.9 g, 78.93%).
MS(ES): m/z 217.03 [M+H].sup.+.
[0992] Synthesis of compound 198.2. To a solution of 198.1 (16.0 g,
74.06 mmol, 1.0 eq), Trimethylsilylacetylene (9.43 g, 96.78 mmol,
1.3 eq) and triethylamine (112.2 g, 1110.9 mmol, 15 eq) in
tetrahydrofuran (1.6 L). The reaction mixture was degassed for 10
min. under argon atmosphere. The
[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.6
g, 2.22 mmol, 0.03 eq) and copper iodide (0.843 g, 4.44 mmol, 0.06
eq) was added, again reaction mixture was degassed for 10 min.
under argon atmosphere. The reaction was stirred at room
temperature for 24 h. After completion of reaction, reaction
mixture was filtered and residue was concentrated under vacuum. The
residue was diluted with methanol (2.2 L) and potassium fluoride
was added into reaction mixture. The reaction mixture was stirred
at room temperature for 48 h. After completion of reaction,
reaction mixture was filtered through bed of celite and washed with
ethyl acetate. Combined organic layer was washed with brine, dried
over sodium sulphate and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography using 10% ethyl acetate in hexane to obtain pure 1.2
(3.82 g, 43.30%). MS(ES): m/z 120.12 [M+H].sup.+.
[0993] Synthesis of compound 198.3. To a solution of 198.2 (3.82 g,
32.07 mmol, 1.0 eq) in methanol (300 mL), 10% palladium on charcoal
(7.0 g) was added. Hydrogen was purged through reaction mixture for
2-3 h. After completion of reaction, reaction mixture was filtered
through celite-bed and washed with ethanol. Filtrate was
concentrated under reduced pressure to obtain 198.3 (3.5 g,
90.11%). MS(ES): m/z 122.14 [M+H].sup.+.
[0994] Synthesis of compound 198.4. To a solution of 198.3 (3.5 g,
28.89 mmol, 1.0 eq) in dichloromethane (140 mL) was added
meta-chloroperbenzoic acid (5.96 g, 34.66 mmol, 1.2 eq). The
reaction was stirred at room temperature for 18 h. After completion
of reaction, reaction mixture was concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography in basic alumina using 0.1% methanol in
dichloromethane to obtain pure 198.4 (3.4 g, 85.81%). MS(ES): m/z
138.14 [M+H].sup.+.
[0995] Synthesis of compound 198.5. To a solution of 198.4 (1.1 g,
8.02 mmol, 1.0 eq) in chloroform (33 mL) was added phosphoryl
chloride (4.91 g, 32.08 mmol, 4.0 eq). The reaction was stirred at
70.degree. C. for 7 h. After completion of reaction, reaction
mixture was transferred in ice and basified with sodium bicarbonate
solution then extracted with ethyl acetate. Organic layer was
combined, washed with brine, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and compound was
eluted on 15% ethyl acetate in hexane as eluent to obtain 198.5.
(0.3 g, 24.04%). MS(ES): m/z 156.58 [M+H].sup.+.
[0996] Synthesis of compound 198.6. Compound 198.6 was synthesized
from 194 and 115.2 using general procedure A. (Yield: 38.91%).
MS(ES): m/z 466.95 [M+H].sup.+.
[0997] Synthesis of compound 198.7. Compound 198.7 was synthesized
from 198.6 and cyclopropanecarboxamide using general procedure B.
(Yield: 72.44%). MS(ES): m/z 515.60 [M+H].sup.+.
[0998] Synthesis of compound 198.8. To a solution of 198.7 (0.16 g,
0.311 mmol, 1 eq), in methanol (6 mL) and 5N sodium hydroxide (1
mL) was added. Reaction mixture stirred at 50.degree. C. for 24 h.
After completion of reaction, reaction mixture transferred in water
and extracted with ethyl acetate. Combined organic layer dried over
sodium sulfate and concentrated under reduced pressure to obtain
crude material. This was further triturated in 30% diethyl ether in
hexane to obtain pure 198.8. (0.12 g, 86.43%). MS(ES): m/z 447.53
[M+H].sup.+.
[0999] Synthesis of compound 198.9. Compound 198.9 was synthesized
from 198.8 and 198.5 using general procedure B. (Yield: 46.05%).
MS(ES): m/z 566.65 [M+H].sup.+.
[1000] Synthesis of compound I-226. To a solution of 198.9 (0.070
g, 0.123 mmol, 1 eq), in dichloromethane (2 mL) was added
trifluoroacetic acid (0.21 g, 1.845 mmol, 15 eq) at 0.degree. C.
Reaction mixture stirred at room temperature for 30 min. After
completion of reaction, reaction mixture was concentrated under
reduced pressure, transferred into aqueous sodium bicarbonate
solution and extracted with ethyl acetate. Combined organic layer
dried over sodium sulfate and concentrated under reduced pressure
to obtain crude material. This was further triturated in diethyl
ether to obtain pure I-226 (0.05 g, 83.91%). MS(ES): m/z 482.53
[M+H].sup.+. LCMS purity: 100%, HPLC purity: 100%, 1H NMR (DMSO-d6,
400 MHz): 9.05 (s, 1H), 8.91 (s, 1H), 8.40 (s, 1H), 7.70-7.67 (m,
2H), 7.42-7.35 (m, 2H), 7.03-6.99 (t, J=7.6 Hz, 1H), 6.28 (s, 1H),
4.56-4.52 (t, J=8.4 Hz, 2H), 3.33 (s, 3H), 3.29 (s, 3H), 3.26-3.22
(t, J=8.4 Hz, 2H), 3.17 (s, 3H).
Example 199. Synthesis of
N-(5-(5-chlorothiazol-2-yl)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)ph-
enyl)amino)pyridin-2-yl)cyclopropanecarboxamide, VIII-1
##STR00558##
[1002] Synthesis of compound 199.2. To a solution of 199.1 (20.0 g,
96.4 mmol, 1.0 eq) in THF (200 mL) was added Pyridine (15.7 mL,
193.2 mmol, 2.0 eq). Reaction mixture was cooled to 0.degree. C. To
this added DMAP (1.18 g, 9.64 mmol, 0.1 eq) followed by
cyclopropanecarbonyl chloride (15.12 g, 144.6 mmol, 1.5 eq).
Reaction mixture was stirred at room temperature for 3 h. After
completion of the reaction, reaction mixture was quenched with
ice-water. Precipitate was filtered and dried to provide 199.2
(16.5 g, 62.1%). MS(ES): m/z 275.3 [M]+.
[1003] Synthesis of compound 199.3. To a solution of 199.2 (1.0 g,
3.63 mmol, 1.0 eq) in THF (20 mL) was added n-BuLi (7.5 mL, 18.18
mmol, 5.0 eq) at -78.degree. C. and stirred for 30 min. To the
solution was added triisopropyl-borate (3.4 mL, 14.53 mmol, 4.0 eq)
and reaction was stirred at -78.degree. C. for 1 h. After
completion reaction was quenched slowly and solvents were removed
under reduced pressure. Residue was acidified with 1.0 N HCl.
Obtained precipitate was filtered off, washed with ice cold water
to provide 199.3 (0.35 g, 40.1%). MS(ES): m/z 241.5
[M+H].sup.+.
[1004] Synthesis of compound 199.4. To a solution of
2-bromo-5-chlorothiazole (0.068 g, 0.34 mmol, 1.0 eq) in
1,4-dioxane (2.0 mL) was added compound 199.3 (0.10 g, 0.41 mmol,
1.2 eq) followed by addition of 1M aq. Na.sub.2CO.sub.3 (0.68 mL,
0.68 mmol, 2.0 eq). Reaction mixture was degassed with argon for 10
min and Pd(PPh.sub.3).sub.4 (0.037 g, 0.034 mmol, 0.1 eq) was
added. Reaction mixture was stirred at 100.degree. C. for 16 h.
After completion of reaction was quenched with water and extracted
with EtOAc. Organic layers were combined, washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
obtain crude material. The crude was purified by column
chromatography to furnish 1.4. (0.025 g, 23.0%). MS(ES): m/z 314.4
[M]+.
[1005] Synthesis of compound VIII-1. To a solution of 199.4 (0.025
g, 0.079 mmol, 1.2 eq) in i-PrOH (2.5 mL) was added 1.5 (0.014 g,
0.066 mmol, 1.0 eq) followed by addition of TFA (catalytic). The
reaction mixture was heated in microwave at 140.degree. C. for 4
hours. After completion of reaction, mixture concentrated under
reduced pressure to obtain crude material. The crude was purified
by preparative HPLC to furnish VIII-1 (0.0035 g, 10.9%). MS(ES):
m/z 483.7 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz): 10.99 (s,
1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 7.81-7.79 (d, 1H),
7.74-7.72 (d, 1H), 7.37-7.31 (m, 2H), 4.44 (s, 3H), 3.80 (s, 3H),
1.59-1.52 (m, 1H), 1.10-1.08 (m, 2H), 0.90-0.87 (m, 2H).
Example 200. Synthesis of
N-(5-(5-fluorothiazol-2-yl)-4-((2-methoxy-3-(2-methyl-2H1-tetrazol-5-yl)p-
henyl)amino)pyridin-2-yl)cyclopropanecarboxamide, VIII-2
##STR00559##
[1007] Synthesis of compound 2.1. Compound 200.1 was prepared from
compound 199.3 and 2-bromo-5-fluorothiazole using procedure
described in Example 7.
[1008] Synthesis of compound VIII-2. To a solution of 200.1 (0.080
g, 0.268 mmol, 1.0 eq) in 1,4-dioxane (2.0 mL) was added 1.5 (0.055
g, 0.268 mmol, 1.0 eq) and Cs.sub.2CO.sub.3 (0.261 g, 0.804 mmol,
3.0 eq). The reaction mixture was degassed for 10 minutes using
argon, then Pd.sub.2(dba).sub.3 (0.025 g, 0.026 mmol, 0.1 eq) and
XantPhos (0.030 g, 0.053 mmol, 0.2 eq) were added. Suspension was
degassed for additional 5 minutes. The reaction was then heated in
microwave at 175.degree. C. for 1 h. After completion of reaction,
mixture was cooled to room temperature, quenched with water and
extracted with EtOAc. Organic layers were combined, washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to obtain crude which was purified by column
chromatography to provide VIII-2 (0.025 g, 19.94%). MS(ES): m/z
467.48 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz): 11.02 (s,
1H), 8.37 (s, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 7.84-7.81 (dd, 1H),
7.77-7.75 (m, 1H), 7.44-7.34 (m, 2H), 4.47 (s, 3H), 3.82 (s, 3H),
1.58-1.55 (m, 1H), 1.13-1.10 (m, 2H), 0.90-0.87 (m, 2H).
Example 201. Synthesis of
N-(4-((2-methoxy-3-(1-methyl-11H-1,2,4-triazol-3-yl)phenyl)amino)-5-(5-(t-
rifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)cyclopropanecarboxamide,
VIII-3
##STR00560##
[1010] Synthesis of compound 201.2. To compound 202.4 (0.3 g, 0.802
mmol, 1.0 eq) in toluene (3.0 mL) was added TFAA (1.5 mL) and
reaction mixture was refluxed for 1 h. After completion of the
reaction, mixture was concentrated under reduced pressure to obtain
crude which was purified by column chromatography to provide 201.2.
(0.070 g, 19.31%). MS(ES): m/z 452.7 [M].sup.+.
[1011] Synthesis of compound VIII-3. To 201.2 (0.050 g, 0.110 mmol,
1.0 eq) in 1,4-dioxane (2.0 mL) was added cyclopropanecarboxamide
(0.011 g, 0.132 mmol, 1.0 eq) and Cs.sub.2CO.sub.3 (0.080 g, 0.27
mmol, 2.5 eq). The reaction mixture was degassed for 10 minutes
using argon then Pd.sub.2(dba).sub.3 (0.010 g, 0.011 mmol, 0.1 eq)
and XantPhos (0.012 g, 0.022 mmol, 0.2 eq) were added. Suspension
was degassed for additional five minutes. The reaction was then
heated in microwave at 130.degree. C. for 1 h. After completion of
the reaction, mixture was cooled to room temperature, quenched with
water and extracted with EtOAc. Organic layers were combined,
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to obtain the crude product. Crude was
purified by column chromatography to provide VIII-3 (0.019 g,
34.3%). MS(ES): m/z 501.53 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3,
400 MHz): 9.86 (s, 1H), 8.72 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H),
8.13 (s, 1H), 7.86-7.84 (d, 1H), 7.65-7.63 (d, 1H), 7.33-7.28 (m,
1H), 4.03 (s, 3H), 3.81 (s, 3H), 1.48-1.42 (m, 1H), 1.12-1.11 (m,
2H), 0.93-0.91 (m, 2H).
Example 202. Synthesis of methyl
5-(6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-
-3-yl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate,
VIII-4
##STR00561## ##STR00562##
[1013] Synthesis of compound 202.3. To solution of compound 202.1
(2.0 g, 9.09 mmol, 1.0 eq) in EtOH (20.0 mL) was added compound
202.2 (1.86 g, 9.09 mmol, 1.0 eq) followed by the addition of conc.
HCl (catalytic). Reaction mixture was refluxed for 4 h. After
completion of the reaction, mixture was concentrated under reduced
pressure. Residue was dissolved in CH.sub.2C12 washed with satd.
NaHCO.sub.3, brine, then dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to pressure to obtain crude
material. The crude was purified by column chromatography to
provide 202.3. (1.4 g, 39.7%). MS(ES): m/z 388.7 [M]+.
[1014] Synthesis of compound 202.4. To a solution of 202.3 (1.4 g,
3.61 mmol, 1.0 eq) in MeOH (20.0 mL) was added hydrazine hydrate
(g, 2.08 mmol, 3.0 eq). Reaction mixture was stirred at 80.degree.
C. for 3 h. After completion of the reaction, mixture was
concentrated under reduced pressure. Residue obtained was
triturated with diethyl ether to provide 202.4. (0.83 g, 61.51%).
MS(ES): m/z 374.5 [M].sup.+.
[1015] Synthesis of compound 202.5. To solution of 202.4 (0.7 g,
1.87 mmol, 1.0 eq) in CH.sub.2Cl.sub.2 (7.0 mL) was added Et.sub.3N
(0.56 g, 5.63 mmol, 3.0 eq). Solution was cooled to 0.degree. C.,
then methyl oxalyl chloride (0.275 g, 2.25 mmol, 1.2 eq) was added.
Mixture was stirred for 4 h at room temperature. To this was added
p-TsCl (0.73 g, 3.75 mmol, 2.0 eq). Reaction was stirred at room
temperature for 16 h. After completion, of the reaction was
quenched with water and extracted with CH.sub.2Cl.sub.2. Organic
layer were combined, washed with brine, dried over Na.sub.2SO.sub.4
and concentrated under reduced pressure to obtain crude which was
purified by column chromatography to provide 202.5. (0.3 g, 36.3%).
MS(ES): m/z 442.6 [M].sup.+.
[1016] Synthesis of compound VIII-4. To 202.5 (0.10 g, 0.226 mmol,
1.0 eq) in 1,4-dioxane (2.0 mL) was added cyclopropanecarboxamide
(0.021 g, 0.248 mmol, 1.0 eq), Cs.sub.2CO.sub.3 (0.060 g, 0.44
mmol, 2.0 eq). The reaction mixture was degassed for 10 minutes
using argon, then Pd.sub.2(dba).sub.3 (0.022 g, 0.026 mmol, 0.1 eq)
and XantPhos (0.025 g, 0.044 mmol, 0.2 eq) were added, again
degassed for 5 min. The reaction was heated in microwave at
130.degree. C. for 1 h. After completion of the reaction, mixture
was cooled to room temperature, quenched with water and extracted
with EtOAc. Organic layers were combined, washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
obtain crude material. The crude was purified by column
chromatography to furnish VIII-4 (0.04 g, 36.0%). MS(ES): m/z 491.7
[M+H].sup.+; .sup.1H NMR (CDCl.sub.3, 400 MHz): 9.98 (s, 1H), 8.80
(s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.84-7.83 (d,
1H), 7.66-7.64 (d, 1H), 7.34-7.30 (m, 1H), 4.12 (s, 3H), 4.03 (s,
3H), 3.82 (s, 3H), 1.58-1.55 (m, 1H), 1.12-1.10 (m, 2H), 0.92-0.90
(m, 2H).
Example 203. Synthesis of
N-(5-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)-4-((2-methoxy-3-(1-methyl-1-
H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide,
VIII-5
##STR00563##
[1018] To a solution of VIII-4 (0.030 g, 0.061 mmol, 1.0 eq) in
MeOH (1.0 mL) and THE (1.0 mL) was added LiBH.sub.4 (0.004 g, 0.183
mmol, 3.0 eq) at 0.degree. C. Reaction mixture was stirred at room
temperature for 1 hour. After completion of the reaction was
quenched with water and extracted with EtOAc. Organic layers was
combined, washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to obtain crude material. The
crude was purified by column chromatography to provide VIII-5
(0.008 g, 28.2%). MS(ES): m/z 463.53 [M+H].sup.+; .sup.1H NMR
(CDCl.sub.3, 400 MHz): 10.02 (s, 1H), 8.70 (s, 1H), 8.23 (s, 1H),
8.18 (s, 1H), 8.13 (s, 1H), 7.82-7.81 (d, 1H), 7.65-7.63 (d, 1H),
7.33-7.28 (m, 1H), 4.99 (s, 2H), 4.03 (s, 3H), 3.81 (s, 3H),
1.58-1.55 (m, 1H), 1.12-1.11 (m, 2H), 0.92-0.88 (m, 2H).
Example 204. Synthesis of
N-(5-(5-(hydroxymethyl)thiazol-2-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-t-
riazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide,
VIII-6
##STR00564##
[1020] Synthesis of compound 6.1. Compound 6.1 was prepared from
1.3 and (2-bromothiazol-5-yl)methanol using procedure described in
Example 7.
[1021] Synthesis of compound VIII-6. Compound VIII-6 was prepared
from 6.1 and 4.2 using procedure described in Example 8. (0.008 g,
3.71%). MS(ES): m/z 478.69 [M+H].sup.+; .sup.1H NMR (MeOD, 400
MHz): 8.58 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.77
(s, 1H), 7.70-7.68 (d, 1H), 7.65-7.63 (d, 1H), 7.32-7.28 (t, 1H),
4.88 (s, 2H), 4.04 (s, 3H), 3.74 (s, 3H), 1.89 (bs, 1H), 1.31 (bs,
1H), 0.98-0.90 (m, 4H).
Example 205. Synthesis of
N-(4-((2-methoxy-3-(1-methyl-11H-1,2,4-triazol-3-yl)phenyl)amino)-5-(5-me-
thyl-1,3,4-thiadiazol-2-yl)pyridin-2-yl)cyclopropanecarboxamide,
VIII-7
##STR00565##
[1023] Synthesis of compound 205.1. To a solution of
2-bromo-5-methyl-1,3,4-thiadiazole (0.62 g, 3.47 mmol, 1.0 eq) in
DME (10 mL) was added compound 1.3 (1.0 g, 4016 mmol, 1.2 eq)
followed by addition of Na.sub.2CO.sub.3 (0.735 g, 6.94 mmol, 2.0
eq). Reaction mixture was degassed with argon for 10 min and
(dppf)PdCl.sub.2 (0.253 g, 0.347 mmol, 0.1 eq) was added. Reaction
mixture was stirred at 90.degree. C. for 16 hours. After completion
of the reaction, mixture was transferred into water and extracted
with EtOAc. Organic layers were combined, washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure to
obtain crude which was purified by preparative HPLC to furnish 7.1.
(0.08 g, 7.83%). MS(ES): m/z 295.7 [M].sup.+.
[1024] Synthesis of compound VIII-7. Compound VIII-7 was prepared
from 7.1 and 4.2 using procedure described in Example 8. (0.019 g,
15.1%). MS(ES): m/z 463.48 [M+H].sup.+; .sup.1H NMR (CDCl.sub.3,
400 MHz): 10.80 (s, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 8.18 (s, 1H),
8.12 (s, 1H), 7.80-7.78 (d, 1H), 7.66-7.64 (d, 1H), 7.32-7.28 (m,
1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.83 (s, 3H), 1.56-1.54 (m, 1H),
1.12-1.10 (m, 2H), 0.91-0.88 (m, 2H).
Example 206:
N-(5-(isoxazol-3-yl)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)am-
ino)pyridin-2-yl)cyclopropanecarboxamide, VIII-8
##STR00566## ##STR00567##
[1026] Synthesis of compound 206.1. To a solution of 202.1 (10 g,
0.045 mmol, 1.0 eq) in dichloromethane (100 mL) at -78.degree. C.,
diisobutyl aluminium hydride (54 mL, 0.054 mmol, 1.2 eq) was added.
Reaction mixture was stirred at -78.degree. C. for 1 h. After
completion of reaction, methanol was slowly added to the reaction
mixture at -78.degree. C. followed by addition of 1N HCl and
extracted with dichloromethane. Organic layer was combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain 206.1. (7.0 g, 87.52%). MS(ES):
m/z 175.48 [M]+.
[1027] Synthesis of compound 206.2. To a solution of 206.1 (8.0 g,
0.045 mmol, 1.0 eq) in methanol (150 mL) was added hydroxylamine
(70 mL, 0.045 mmol, 1.0 eq) at 0.degree. C. Reaction mixture was
stirred at 40.degree. C. for 24 h. After completion of reaction,
reaction mixture was transferred into water slowly and extracted
with dichloromethane. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain 206.2. (2.0 g, 23.03%). MS(ES): m/z 192.38
[M].sup.+.
[1028] Synthesis of compound 206.3. To a solution of compound 206.2
(2.0 g, 10.4 mmol, 1.0 eq) in dichloromethane (20 mL) at 0.degree.
C., pyridine (4.2 mL, 41.88 mmol, 5.0 eq), N-chloro succinimide
(7.0 g, 52.35 mmol, 5.0 eq) was added. Reaction mixture was stirred
at room temperature for 3 h. Then, trimethylsilane acetylene (4.11
g, 41.8 mmol, 4.0 eq) and triethylamine (5.9 mL, 41.8 mmol, 4.0 eq)
was added. Reaction mixture was stirred at room temperature for 16
h. After completion of reaction, reaction mixture was transferred
into water and extracted with ethyl acetate. Organic layer was
combined, washed with brine solution, dried over sodium sulphate
and concentrated under reduced pressure to obtain crude material.
This was further purified by column chromatography and the product
was eluted in 3% ethyl acetate in hexane to obtain 206.3. (1.0 g,
33.25%). MS(ES): m/z 288.41 [M].sup.+.
[1029] Synthesis of compound 206.4. To a solution of compound 206.3
(0.4 g, 1.3 mmol, 1.0 eq) in isopropyl alcohol (4 mL), potassium
carbonate (0.192 mL, 1.3 mmol, 1.0 eq) was added. Reaction mixture
was stirred at room temperature for 24 h. After completion of
reaction, reaction mixture was transferred into water and extracted
with ethyl acetate. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography and the product was eluted in 5% ethyl
acetate in hexane to obtain 206.4. (0.150 g, 50.09%). MS(ES): m/z
216.53 [M].sup.+.
[1030] Synthesis of compound 206.5. To a solution of compound 206.4
(0.150 g, 0.69 mmol, 1.0 eq) in dimethylformamide (1 mL), sodium
azide (0.045 g, 0.69 mmol, 1.0 eq) was added. Reaction mixture was
stirred at 90.degree. C. for 3 h. After completion of reaction,
reaction mixture was transferred into water and extracted with
ethyl acetate. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography and the product was eluted in 10% ethyl
acetate in hexane to obtain 206.5. (0.060 g, 38.81%). MS(ES): m/z
222.53 [M].sup.+.
[1031] Synthesis of compound 206.6. To a solution of compound 206.5
(0.060 g, 0.26 mmol, 1.0 eq) in a mixture of tetrahydrofuran (2.4
mL) and water (0.4 mL), triphenylphosphine (0.14 g, 0.54 mmol, 2.0
eq) was added. Reaction mixture was stirred at 75.degree. C. for 3
h. After completion of reaction, reaction mixture was transferred
into water and extracted with ethyl acetate. Organic layer was
combined, washed with brine solution, dried over sodium sulphate
and concentrated under reduced pressure to obtain crude material.
This was further purified by column chromatography and the product
was eluted in 10% ethyl acetate in hexane to get 1.6. (0.050 g,
68.41%). MS(ES): m/z 196.35 [M].sup.+.
[1032] Synthesis of compound 206.7. To a solution of compound 206.6
(0.050 g, 0.2 mmol, 1.0 eq) in pyridine (0.5 mL),
4-dimethylaminopyridine (0.071 mL, 0.27 mmol, 2.0 eq) and
cyclopropyl carbonyl chloride (0.1 mL, 1.22 mmol, 5 eq) was added.
Reaction mixture was heated in microwave at 90.degree. C. for 1 h.
After completion of reaction, reaction mixture was transferred into
water and extracted with ethyl acetate. Organic layer was combined,
washed with brine solution, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and the product was
eluted in 10% ethyl acetate in hexane to obtain 206.7. (0.050 g,
74.15%). MS(ES): m/z 264.53 [M].sup.+.
[1033] Synthesis of VIII-8. To a solution of compound 206.7 (0.05
g, 0.11 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added 1.5 (0.058 g,
0.22 mmol, 1.5 eq), potassium carbonate (0.065 g, 0.47 mmol, 2.5
eq). The reaction mixture was degassed for 10 min. under argon
atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.017 g,
0.019 mmol, 0.1 eq) and
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.021 g, 0.037
mmol, 0.2 eq) were added, again degassed for 5 min. The reaction
was stirred at 100.degree. C. for 30 min. After completion of
reaction, reaction mixture was cooled to room temperature,
transferred in water and product was extracted with ethyl acetate.
Organic layer was combined, washed with brine solution, dried over
sodium sulphate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 5% methanol in dichloromethane as eluant to obtain pure
VIII-8 (0.023 g, 28.05%). MS(ES): m/z 433.25 [M+H].sup.+, LCMS
purity: 97.99%, HPLC purity: 96.22%, .sup.1H NMR (CDCl.sub.3, 400
MHZ): 10.59 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.46-8.40 (d,
J=10.2 Hz, 1H), 8.34 (s, 1H), 7.71-7.69 (d, J=3.2 Hz, 1H), 7.36 (s,
1H), 7.33 (s, 1H), 6.84 (s, 1H), 4.49 (s, 3H), 3.87 (s, 3H),
1.19-1.16 (m, 2H), 1.00-0.98 (m, 2H), 0.90 (s, 1H).
Example 207:
N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-4-((2-methoxy-3-(1-methyl-1-
H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide,
VIII-9
##STR00568## ##STR00569##
[1035] Synthesis of compound 207.2. To a solution of compound 4.2
(2 g, 9.8 mmol, 1.0 eq) in 1,4-dioxane (20 mL) was added 207.1 (1.7
g, 9.8 mmol, 1.0 eq), potassium carbonate (3.38 g, 24.5 mmol, 2.5
eq). The reaction mixture was degassed for 10 min. under argon
atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.89 g,
0.098 mmol, 0.1 eq) and
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (1.13 g, 1.9 mmol,
0.2 eq) were added, again degassed for 5 min. The reaction was
stirred at 110.degree. C. for 2 h. After completion of reaction,
reaction mixture was cooled to room temperature, transferred in
water and product was extracted with ethyl acetate. Organic layer
was combined, washed with brine solution, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography using
1% methanol in dichloromethane as eluant to obtain pure 207.2 (0.9
g, 22.84%). MS(ES): m/z 341.45 [M+H].sup.+.
[1036] Synthesis of compound 207.3. To a solution of 207.2 (0.270
g, 0.79 mmol, 1.0 eq) in 1,4-dioxane (3 mL) was added cyclopropane
carboxamide (0.101 g, 1.19 mmol, 1.5 eq), potassium carbonate (0.27
g, 1.98 mmol, 2.5 eq). The reaction mixture was degassed for 10
min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.072 g, 0.079 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.091 g,
0.158 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 130.degree. C. for 2 h under microwave
irradiation. After completion of reaction, reaction mixture was
cooled to room temperature, transferred in water and product was
extracted with ethyl acetate. Organic layer was combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 2% methanol in
dichloromethane as eluant to obtain pure 207.3 (0.250 g, 81.03%).
MS(ES): m/z 390.25 [M+H].sup.+.
[1037] Synthesis of compound 207.4. To a solution of 207.3 (0.250
g, 0.64 mmol, 1.0 eq) in ethanol (2 mL) was added hydroxylamine (2
mL). Reaction mixture was stirred at 80.degree. C. for 3 h. After
completion of the reaction, the reaction mixture was cooled to room
temperature and solvent was evaporated to get the crude material.
This was further transferred into ice water to get the solid
precipitate which was filtered, dried well to obtain pure 207.4
(0.220 g, 81.81%). MS(ES): m/z 423.58 [M+H].sup.+.
[1038] Synthesis of VIII-9. To a solution of 207.4 (0.150 g, 0.35
mmol, 1.0 eq) in a mixture of toluene (0.9 mL) and
dimethylformamide (0.1 mL), potassium carbonate (0.058 g, 0.42
mmol, 1.2 eq) and ethyl-2-hydroxy acetate (0.055 g, 0.53 mmol, 1.5
eq) was added. Reaction mixture was stirred at 110.degree. C. for 3
h. After completion of reaction, reaction mixture concentrated
under reduced pressure to obtain crude material. This was further
purified by Preparative HPLC to obtain VIII-9 (0.028 g, 17.05%).
MS(ES): m/z 463.59 [M+H].sup.+, LCMS purity: 98.10%, HPLC purity:
98.82%, .sup.1H NMR (DMSO-d.sub.6, 400 MHZ): 10.33 (s, 1H), 8.93
(s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.04-7.99 (m, 2H), 7.52-7.50
(d, J=7.6 Hz, 1H), 7.19-7.15 (t, J=16.0 Hz, 1H), 6.15 (s, 1H), 4.85
(s, 2H), 3.94 (s, 3H), 3.67 (s, 3H), 1.84-1.79 (m, 1H), 0.93-0.91
(m, 4H).
Example 208:
N-(5-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2-
,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide,
VIII-10
##STR00570## ##STR00571##
[1040] Synthesis of compound 208.2. To a solution of 208.1 (20 g,
96.4 mmol, 1.0 eq) in Tetrahydrofuran (200 mL) was added Pyridine
(15.7 mL, 193.2 mmol, 2.0 eq) and reaction mixture was cooled to
0.degree. C. To this added dimethylaminopyridine (1.18 g, 9.64
mmol, 0.1 eq) followed by cyclopropanecarbonyl chloride (15.12 g,
144.6 mmol, 1.5 eq) and reaction mixture was stirred at room
temperature for 3 h. After completion of reaction, reaction mixture
was transferred in ice-water and precipitated product was filtered,
dried well to obtain 208.2 (16.5 g, 62.1%). MS(ES): m/z 275.3
[M].sup.+.
[1041] Synthesis of compound 208.3. To a solution of compound 208.2
(4.5 g, 16.36 mmol, 1.0 eq) in tetrahydrofuran (60 mL) at 0.degree.
C., compound 4.2 (4.0 g, 19.63 mmol, 1.2 eq) was added. Then,
lithium-bis(trimethylsilyl)amide (49 mL, 49.09 mmol, 3 eq) was
added dropwise at 0.degree. C. Reaction mixture was stirred at
50.degree. C. for 24 h. After completion of the reaction, the
reaction mixture was cooled to room temperature, transferred to
water and extracted with ethyl acetate. Organic layer combined,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure to get the crude material. This was further
purified by column chromatography using 30% ethyl acetate in hexane
to obtain pure 208.3. (3.5 g, 48.34%). MS(ES): m/z 444.25
[M].sup.+.
[1042] Synthesis of compound 208.4. To a solution of compound 208.3
(0.5 g, 1.12 mmol, 1.0 eq) in dimethylformamide (5 mL), pyrazole
ethyl ester (0.48 g, 3.35 mmol, 3 eq) was added. Reaction mixture
was degassed with argon for 15 min. Then, copper iodide (0.010 g,
0.05 mmol, 0.05 eq) and potassium carbonate (0.4 g, 2.84 mmol, 2.5
eq) was added. Reaction mixture was stirred in microwave at
180.degree. C. for 40 min. After completion of reaction, reaction
mixture was transferred into water and extracted with ethyl
acetate. Organic layer was combined, washed with brine solution,
dried over sodium sulphate and concentrated under reduced pressure
to obtain crude material. This was further purified by column
chromatography and the product was eluted in 0.5% methanol in
dichloromethane to obtain 208.4. (0.045 g, 7.94%). MS(ES): m/z
502.64 [M].sup.+.
[1043] Synthesis of VIII-10. To a solution of 208.4 (0.040 g, 0.07
mmol, 1.0 eq) in a mixture of methanol (1 mL) and tetrahydrofuran
(1 mL) at 0.degree. C., lithium borohydride (0.008 g, 0.39 mmol,
5.0 eq) was added. The reaction mixture was stirred at 40.degree.
C. for 24 h. After completion of reaction, reaction mixture was
transferred into water and extracted with ethyl acetate. Organic
layer was combined, washed with brine solution, dried over sodium
sulphate and concentrated under reduced pressure to obtain crude
material. This was further purified by preparative thin layer
chromatography using 5% methanol in dichloromethane as mobile phase
to obtain pure VIII-10 (0.014 g, 33.95%). MS(ES): m/z 461.53
[M+H].sup.+, LCMS purity: 100%, HPLC purity: 99.77%, .sup.1H NMR
(MeOD, 400 MHZ): 8.49 (s, 1H), 8.26-8.21 (d, J=8.0 Hz, 2H), 8.06
(s, 1H), 7.88 (s, 1H), 7.62-7.57 (t, J=11.2 Hz, 2H), 7.28-7.24 (t,
J=1.6 Hz, 1H), 4.64 (s, 2H), 4.03 (s, 3H), 3.72 (s, 3H), 1.88 (s,
1H), 0.98-0.90 (bs, 4H).
Example 209:
N-(4-((2-methoxy-3-(1-methyl-11H-1,2,4-triazol-3-yl)phenyl)amino)-5-(pyri-
dazin-3-yl)pyridin-2-yl)cyclopropanecarboxamide, VIII-11
##STR00572##
[1045] Synthesis of compound 209.1 To a solution of compound 208.3
(2.0 g, 4.50 mmol, 1.0 eq) in 1,4-dioxane (40 mL) was added
bis-pinacolato-diboron (4.59 g, 18.02 mmol, 4.0 eq). Reaction
mixture was degassed with argon for 15 min. Then, potassium acetate
(0.88 g, 9.05 mmol, 2.0 eq) was added and again degassed with argon
for 10 min. Then,
1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
complex with dichloromethane (0.36 g, 0.45 mmol, 0.1 eq) was added
and the reaction mixture was heated at 120.degree. C. for 2 h.
After completion of reaction, reaction mixture was transferred into
water and extracted with ethyl acetate. Organic layer was combined,
washed with brine solution, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by trituration using diethyl ether and hexane
to obtain 209.1 (1.7 g, 76.84%). MS(ES): m/z 491.26 [M].sup.+.
[1046] Synthesis of VIII-11. To a solution of compound 209.1 (1.0
g, 0.204 mmol, 1.0 eq) in a mixture of water (0.5 mL) and
dimethylformamide (1.5 mL) was added bromopyridazine (0.48 g, 0.306
mmol, 1.5 eq) and potassium carbonate (0.098 g, 0.714 mmol, 3.5
eq). Reaction mixture was degassed with argon for 15 min. Then,
bis(Tri-tert butyl Phosphine) palladium (0) (0.028 g, 0.040 mmol,
0.2 eq) was added. Reaction mixture was stirred at 125.degree. C.
for 30 min under microwave irradiation. After completion of
reaction, reaction mixture was transferred into water and extracted
with ethyl acetate. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography and the product was eluted in 3% methanol in
dichloromethane to obtain VIII-11 (0.020 g, 22.16%). MS(ES): m/z
443.43 [M+H].sup.+, LCMS purity: 98.78%, HPLC purity: 99.38%,
.sup.1H NMR (CDCl.sub.3, 400 MHZ): 11.48 (s, 1H), 9.14 (s, 1H),
8.75 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.97-7.95
(d, J=8.8 Hz, 1H), 7.66-7.64 (d, J=8 Hz, 1H), 7.63-7.59 (m, 2H),
4.02 (s, 3H), 3.90 (s, 3H), 1.61 (s, 1H), 1.12-1.11 (m, 2H),
0.91-0.89 (m, 2H).
Example 210:
(5-(4-((2-methoxy-3-(1-methyl-11H-1,2,4-triazol-3-yl)phenyl)amino)-6-((6--
methylpyridazin-3-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methanol,
VIII-12
##STR00573##
[1048] Synthesis of compound 210.1. To a solution of compound 202.5
(0.15 g, 1.13 mmol, 1.0 eq) in a mixture of water (5 mL) and
tetrahydrofuran (5 mL) at 0.degree. C., lithium borohydride (2.93
mL, 20.9 mmol, 3 eq) was added. Reaction mixture was stirred at
room temperature for 3 h. After completion of the reaction, the
reaction mixture was concentrated, transferred to water and
extracted with ethyl acetate. Organic layer combined, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to get the crude material. This was further purified by
column chromatography using 10% ethyl acetate in hexane to obtain
pure 210.1. (0.1 g, 71.18%). MS(ES): m/z 414.57 [M].sup.+.
[1049] Synthesis of VIII-12. To a solution of compound 210.1 (0.150
g, 0.12 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added
methylpyridazinamine (0.015 g, 0.14 mmol, 1.2 eq), cesium carbonate
(0.05 g, 0.36 mmol, 3.0 eq). The reaction mixture was degassed for
10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.011 g, 0.012 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.013 g,
0.024 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction mixture was stirred at 130.degree. C. for 1 h under
microwave irradiation. After completion of reaction, reaction
mixture was cooled to room temperature, transferred in water and
product was extracted with ethyl acetate. Organic layer was
combined, washed with brine solution, dried over sodium sulphate
and concentrated under reduced pressure to obtain crude material.
This was further purified by column chromatography using 1.5%
methanol in dichloromethane as eluant to obtain pure VIII-12 (0.037
g, 20.98%). MS(ES): m/z 487.43 [M+H].sup.+, LCMS purity: 100%, HPLC
purity: 99.01%, .sup.1H NMR (DMSO-d.sub.6, 400 MHZ): 10.24 (s, 1H),
9.84 (s, 1H), 8.65 (s, 1H), 8.58 (s, 2H), 7.96-7.93 (d, J=8.8 Hz,
1H), 7.87 (s, 1H), 7.72-7.68 (t, J=11.5 Hz, 2H), 7.47-7.44 (d,
J=6.8 Hz, 1H), 7.33-7.29 (t, J=15.6 Hz, 1H), 4.77 (s, 2H), 3.96 (s,
3H), 3.76 (s, 3H), 2.50 (s, 3H).
Example 211:
6-((5-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)-4-((2-methoxy-3-(1-methyl--
1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-2-yl)amino)picolinonitrile,
VIII-13
##STR00574##
[1051] Synthesis of VIII-13. To a solution of compound 210.1 (0.150
g, 0.36 mmol, 1.0 eq) in 1,4-dioxane (5 mL) was added
6-aminopicolinonitrile (0.051 g, 0.43 mmol, 1.2 eq), potassium
carbonate (0.15 g, 1.08 mmol, 3.0 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.032 g, 0.036 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.041 g,
0.072 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 130.degree. C. for 1 h under microwave
irradiation. After completion of reaction, reaction mixture was
cooled to room temperature, transferred in water and product was
extracted with ethyl acetate. Organic layer was combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 1.5% methanol in
dichloromethane as eluant to obtain pure VIII-13 (0.027 g, 15.00%).
MS(ES): m/z 497.65 [M+H].sup.+, LCMS purity: 97.91%, HPLC purity:
97.55%, .sup.1H NMR (DMSO-d.sub.6, 400 MHZ): 10.47 (s, 1H), 10.04
(s, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 7.91-7.89 (d,
J=8.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.77-7.47 (m, 1H), 7.67-7.65 (m,
1H), 7.53-7.4 (m, 1H), 6.03-6.00 (t, J=12.4 Hz, 1H), 4.77 (s, 2H),
3.96 (s, 3H), 3.76 (s, 3H).
Example 212:
(5-(6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,-
2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methanol,
VIII-14
##STR00575##
[1053] Synthesis of VIII-14. To a solution of compound 210.1 (0.150
g, 0.36 mmol, 1.0 eq) in 1,4-dioxane (5 mL) was added
dimethylpyrimidinamine (0.059 g, 0.43 mmol, 1.2 eq), potassium
carbonate (0.15 g, 1.08 mmol, 3.0 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.032 g, 0.036 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.041 g,
0.072 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 130.degree. C. for 1 h under microwave
irradiation. After completion of reaction, reaction mixture was
cooled to room temperature, transferred in water and product was
extracted with ethyl acetate. Organic layer was combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 1.5% methanol in
dichloromethane as eluant to obtain pure VIII-14 (0.021 g, 11.57%).
MS(ES): m/z 501.58 [M+H].sup.+, LCMS purity: 98.90%, HPLC purity:
98.6%, .sup.1H NMR (DMSO-d.sub.6, 400 MHZ): 10.27 (s, 1H), 9.87 (s,
1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.76-7.69 (m, 2H),
7.36-7.33 (m, 1H), 7.03 (s, 1H), 6.03-6.00 (t, J=8.0 Hz, 1H), 4.77
(s, 2H), 3.96 (s, 3H), 3.74 (s, 3H), 2.37 (s, 3H), 2.96 (s,
3H).
Example 213:
6-((5-(5-chlorothiazol-2-yl)-4-((2-methoxy-3-(2-methyl-2H1-tetrazol-5-yl)-
phenyl)amino)pyridin-2-yl)amino)picolinonitrile, VIII-15
##STR00576##
[1055] Synthesis of compound 213.1. To a solution of compound
VIII-1 (0.3 g, 0.62 mmol, 1.0 eq) in ethanol (5 mL) was added 4M
sodium hydroxide solution (4.1 mLg, 3.11 mmol, 5.0 eq). Reaction
mixture was stirred at 60.degree. C. for 3 h. After completion of
reaction, reaction mixture concentrated under reduced pressure to
obtain residue which was transferred into water and extracted with
dichloromethane. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain 213.1 (0.25 g, 83.15%). MS(ES): m/z 416.57
[M].sup.+.
[1056] Synthesis of VIII-15. To a solution of compound 213.1 (0.08
g, 0.19 mmol, 1.0 eq) in 1,4-dioxane (1 mL) was added
6-bromopicolinonitrile (0.04 g, 0.231 mmol, 1.2 eq), cesium
carbonate (0.187 g, 0.57 mmol, 3.0 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.017 g, 0.019 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.027 g,
0.037 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 100.degree. C. for 30 min. After completion
of reaction, reaction mixture was cooled to room temperature,
transferred in water and product was extracted with ethyl acetate.
Organic layer was combined, washed with brine solution, dried over
sodium sulphate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 2% methanol in dichloromethane as eluant to obtain pure
VIII-15 (0.018 g, 18.06%). MS(ES): m/z 517.43 [M+H].sup.+, LCMS
purity: 91.32%, HPLC purity: 95.86%, .sup.1H NMR (DMSO-d.sub.6, 400
MHZ): 11.05 (s, 1H), 10.39 (s, 1H), 8.59 (s, 1H), 8.14 (s, 1H),
8.06 (s, 1H), 7.92-7.86 (m, 2H), 7.78-7.76 (d, J=8.8 Hz, 1H),
7.67-7.65 (d, J=7.2 Hz, 1H), 7.54-7.48 (m, 2H), 4.45 (s, 3H), 3.76
(s, 3H).
Example 214:
5-(5-chlorothiazol-2-yl)-N4-(2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)pheny-
l)-N2-(6-methylpyridazin-3-yl)pyridine-2,4-diamine, VIII-16
##STR00577##
[1058] Synthesis of VIII-16. To a solution of compound 213.1. (0.08
g, 0.19 mmol, 1.0 eq) in 1,4-dioxane (1 mL) was added
methylchloropyridazine (0.04 g, 0.231 mmol, 1.2 eq), cesium
carbonate (0.187 g, 0.57 mmol, 3.0 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.017 g, 0.019 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.027 g,
0.037 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 100.degree. C. for 30 min. After completion
of reaction, reaction mixture was cooled to room temperature,
transferred in water and product was extracted with ethyl acetate.
Organic layer was combined, washed with brine solution, dried over
sodium sulphate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 2% methanol in dichloromethane as eluant to obtain pure
VIII-16 (0.020 g, 20.46%). MS(ES): m/z 507.31 [M+H].sup.+, LCMS
purity: 97.53%, HPLC purity: 97.31%, .sup.1H NMR (DMSO-d.sub.6, 400
MHZ): 10.84 (s, 1H), 10.18 (s, 1H), 8.56 (s, 1H), 8.03-7.98 (m,
2H), 7.83-7.81 (d, J=7.6 Hz, 2H), 7.69-7.67 (d, J=6.8 Hz, 1H),
7.46-7.43 (d, J=9.2 Hz, 1H), 7.40-7.36 (t, J=13.2 Hz, 1H), 4.47 (s,
3H), 3.77 (s, 3H), 2.49 (s, 3H).
Example 215:
5-(5-chlorothiazol-2-yl)-N4-(2-methoxy-3-(2-methyl-2H1-tetrazol-5-yl)phen-
yl)-N2-(4-(methoxymethyl)pyridin-2-yl)pyridine-2,4-diamine,
VIII-17
##STR00578##
[1060] Synthesis of compound 215.2. To a solution of 215.1 (2 g,
9.9 mmol, 1.0 eq) in tetrahydrofuran (30 mL) at 0.degree. C., boron
trifluoride etherate (4.18 g, 29.7 mmol, 3.0 eq) was added
dropwise. Reaction mixture was stirred at room temperature for 3 h.
After completion of reaction, reaction mixture was transferred in
ice-water and product was extracted with ethyl acetate. Organic
layer was combined, washed with brine solution, dried over sodium
sulphate and concentrated under reduced pressure to obtain 1.1 (1.4
g, 75.21%). MS(ES): m/z 189.65 [M].sup.+.
[1061] Synthesis of compound 215.3. To a solution of 215.2 (1.4 g,
7.4 mmol, 1.0 eq) in tetrahydrofuran (15 mL) at 0.degree. C.,
sodium hydride (0.35 g, 14.8 mmol, 2.0 eq) was added. Reaction
mixture was stirred at 0.degree. C. for 20 min. Then, methyl iodide
(1.57 g, 11.2 mmol, 1.5 eq) was added. Reaction mixture was stirred
at room temperature for 3 h. After completion of reaction, reaction
mixture was transferred in ice-water and product was extracted with
ethyl acetate. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain 215.3 (0.7 g, 46.53%). MS(ES): m/z 203.58
[M].sup.+.
[1062] Synthesis of VIII-17. To a solution of compound 215.3 (0.046
g, 0.23 mmol, 1.2 eq) in 1,4-dioxane (1 mL) was added 213.1 (0.080
g, 0.19 mmol, 1.0 eq), cesium carbonate (0.187 g, 0.57 mmol, 3.0
eq). The reaction mixture was degassed for 10 min. under argon
atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.017 g,
0.019 mmol, 0.1 eq) and
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.027 g, 0.037
mmol, 0.2 eq) were added, again degassed for 5 min. The reaction
was stirred at 110.degree. C. for 30 min. After completion of
reaction, reaction mixture was cooled to room temperature,
transferred in water and product was extracted with ethyl acetate.
Organic layer was combined, washed with brine solution, dried over
sodium sulphate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 2% methanol in dichloromethane as eluant to obtain pure
VIII-17 (0.016 g, 15.48%). MS(ES): m/z 536.35 [M+H].sup.+, LCMS
purity: 96.59%, HPLC purity: 98.40%, .sup.1H NMR (CDCl.sub.3, 400
MHZ): 10.84 (s, 1H), 9.91 (s, 1H), 8.55 (s, 1H), 8.16-8.15 (d,
J=5.60 Hz, 2H), 8.12 (s, 1H), 7.88-7.86 (d, J=7.6 Hz, 1H),
7.67-7.65 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.55 (s, 1H), 6.82 (s,
1H), 4.47 (s, 3H), 4.42 (s, 2H), 3.71 (s, 3H), 3.34 (s, 3H).
Example 216:
N-(1-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3-(methylamino)-
-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropanecarboxamide, XVI-1
##STR00579## ##STR00580##
[1064] Synthesis of compound 216.2. To a solution of compound 216.1
(2.0 g, 7.4 mmol, 1.0 eq) in toluene (10 mL), compound benzophenone
hydrazone (1.5 g, 7.4 mmol, 1.0 eq) and sodium-tert-butoxide (1.8
g, 18.50 mmol, 2.5 eq) were added. Reaction mixture was degassed
with argon for 15 min. Then,
tris(dibenzylideneacetone)dipalladium(0) (0.68 g, 0.74 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.86 g,
1.49 mmol, 0.2 eq) were added. Reaction mixture was stirred at
110.degree. C. for 4 h. After completion of reaction, reaction
mixture was transferred into water and product was extracted with
ethyl acetate. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography using 11% methanol in dichloromethane as
eluant to obtain 216.2 (1.5 g, 52.44%). MS(ES): m/z 384.15
[M+H].sup.+.
[1065] Synthesis of compound 216.3. To a suspension of 216.2 (1.5
g, 3.91 mmol, 1.0 eq) in water (3 mL) was added 4M hydrogen
chloride in dioxane (15 mL) and stirred at room temperature for 24
h. After completion of the reaction, the reaction mixture was
concentrated under reduced pressure to obtain the crude material.
This was further purified by trituration with dichloromethane and
diethyl ether to obtain 216.3 (0.7 g, 69.98%). MS(ES): m/z 256.46
[M+H].sup.+.
[1066] Synthesis of compound 216.4. To a solution of compound 216.3
(0.4 g, 1.8 mmol, 1.0 eq) in ethanol (5 mL), dichloropyridine
carbonitrile (0.35 g, 1.8 mmol, 1.0 eq) was added. Reaction mixture
was heated in microwave at 140.degree. C. for 5 h. After completion
of the reaction, the reaction mixture was concentrated under
reduced pressure to obtain the crude product. This was further
purified by column chromatography using 5% methanol in
dichloromethane to obtain pure 216.4. (0.09 g, 16.17%). MS(ES): m/z
356.48 [M].sup.+.
[1067] Synthesis of compound 216.5. To a solution of compound 216.4
(0.050 g, 0.14 mmol, 1.0 eq) in methanol (5 mL), paraformaldehyde
(0.025 g, 0.84 mmol, 6.0 eq) and sodium methoxide (0.023 g, 0.43
mmol, 3.0 eq) were added. Reaction mixture was stirred at
60-65.degree. C. for 3 h. Reaction mixture was cooled to room
temperature and sodium borohydride (0.005 g, 0.35 mmol, 2.5 eq) was
added in portions. Reaction mixture was again stirred at
60-65.degree. c. for 24 h. After completion of the reaction, the
reaction mixture was transferred into water and extracted with
dichloromethane. Organic layer combined, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
get 216.5. (0.04 g, 76.97%). MS(ES): m/z 370.28 [M].sup.+.
[1068] Synthesis of XVI-1. To a solution of compound 216.5 (0.040
g, 0.10 mmol, 1.0 eq) in 1,4-dioxane (3 mL) was added
cyclopropanecarboxamide (0.010 g, 0.10 mmol, 1.0 eq), cesium
carbonate (0.08 g, 0.25 mmol, 2.5 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.016 g, 0.010 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.013 g,
0.020 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 130.degree. C. for 1 h under microwave
irradiation. After completion of reaction, reaction mixture was
cooled to room temperature, transferred into water and product was
extracted with ethyl acetate. Organic layer was combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 1.5% methanol in
dichloromethane as eluant to obtain pure XVI-1 (0.010 g, 22.09%).
MS(ES): m/z 419.48 [M+H].sup.+, LCMS purity: 99.86%, HPLC purity:
99.81%, .sup.1H NMR (MeOD, 400 MHZ): 8.99 (s, 1H), 8.53 (s, 1H),
8.04-8.02 (d, J=6.8 Hz, 1H), 7.77 (s, 1H), 7.61-7.59 (d, J=8.8 Hz,
1H), 7.46-7.42 (t, J=11.5 Hz, 1H), 4.04 (s, 3H), 3.47 (s, 3H), 3.28
(s, 3H), 1.90 (s, 1H), 1.02 (s, 2H), 0.92 (s, 2H).
Example 217: tert-butyl
(6-chloro-3-(2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)imidazo[1,5-a]-
pyrazin-1-yl)carbamate XVI-2
##STR00581## ##STR00582##
[1070] Synthesis of compound 217.2. To a solution of compound 217.1
(0.1 g, 0.37 mmol, 1.0 eq) in diethyl ether (1 mL), n-butyl lithium
(0.7 mL, 0.74 mmol, 2.0 eq) was added dropwise under argon
atmosphere at -78.degree. C. Reaction mixture was stirred at
-78.degree. C. for 40 min and carbon dioxide was bubbled through
the reaction mixture for 45 min. After completion of the reaction,
the reaction mixture was transferred in 1N hydrochloric acid,
neutralized using 1N sodium hydroxide solution and extracted with
dichloromethane. Organic layer combined, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain 217.2 (0.070 g, 80.43%). MS(ES): m/z 235.48 [M+H].sup.+.
[1071] Synthesis of compound 217.3. To a solution of 217.2 (0.083
g, 0.35 mmol, 1.0 eq) in N,N-dimethylformamide (1.5 mL) was added
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (0.1 g, 24.6 mmol, 1.0 eq) at 0.degree.
C. Reaction mixture was stirred at 0.degree. C. for 40 min. Then,
compound 1.2 and di-isopropylethylamine was added at 0.degree. C.
Reaction mixture was stirred at room temperature for 4 h. After
completion of reaction, reaction mixture was transferred into water
and extracted with ethyl acetate. Organic layer combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography and the product was eluted in 10%
ethyl acetate in hexane to obtain 217.3 (0.080 g, 38.46%). MS(ES):
m/z 360.54 [M+H].sup.+.
[1072] Synthesis of compound 217.4. To a solution of compound 217.3
(0.1 g, 0.27 mmol, 1.0 eq) in N,N-dimethylformamide (0.7 mL),
phosphorous oxychloride (0.7 mL) was added. Reaction mixture was
stirred at 55.degree. C. for 3 h. After completion of the reaction,
the reaction mixture was quenched using aqueous ammonia solution
and extracted with dichloromethane. Organic layer combined, dried
over anhydrous sodium sulphate, filtered and concentrated under
reduced pressure to get the crude material. This was further
purified by column chromatography using 1% methanol in
dichloromethane to obtain pure 217.4. (0.070 g, 73.69%). MS(ES):
m/z 342.52 [M].sup.+.
[1073] Synthesis of compound 217.5. To a solution of compound 217.4
(0.050 g, 0.14 mmol, 1.0 eq) in N,N-dimethylformamide (1 mL),
N-iodo succinimide (0.035 mL, 0.15 mmol, 1.05 eq) was added.
Reaction mixture was stirred at 60.degree. C. for 3 h. After
completion of the reaction, the reaction mixture was transferred
into water and extracted with ethyl acetate. Organic layer
combined, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography using 0.2% methanol
in dichloromethane to obtain pure 217.5. (0.045 g, 65.77%). MS(ES):
m/z 468.51 [M].sup.+.
[1074] Synthesis of compound 217.6. To a solution of compound 217.5
(0.16 g, 0.34 mmol, 1.0 eq) in 1,4-dioxane (10 mL), tert-butyl
carbamate (0.4 g, 3.42 mmol, 10.0 eq) was added. Reaction mixture
was degassed with argon for 15 min followed by addition of
N,N-dimethylcyclohexylamine (0.097 g, 0.68 mmol, 2.0 eq) and again
degassed with argon for 5 min. Then, copper iodide (0.067 g, 0.34
mmol, 2.0 eq) was added. Reaction mixture was stirred 75.degree. C.
for 6 h. After completion of the reaction, the reaction mixture was
concentrated, transferred into water and extracted with ethyl
acetate. Organic layer combined, dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to obtain
the crude material. This was further purified by column
chromatography using 40% ethyl acetate in hexane to obtain pure
217.6. (0.055 g, 35.18%). MS(ES): m/z 457.82 [M].sup.+.
[1075] Synthesis of compound 217.7. To a solution of compound 217.6
(0.055 g, 0.12 mmol, 1.0 eq) in dichloromethane (1 mL),
trifluoroacetic acid (0.2 mL) was added. Reaction mixture was
stirred at room temperature under nitrogen atmosphere for 30 min.
After completion of the reaction, reaction mixture was transferred
into water, neutralized using sodium bicarbonate solution and then
extracted with ethyl acetate. Organic layer combined, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain 217.7. (0.037 g, 86.15%). MS(ES): m/z 357.28
[M].sup.+.
[1076] Synthesis of compound 217.8. To a solution of compound 217.7
(0.037 g, 0.10 mmol, 1.0 eq) in methanol (2.3 mL), paraformaldehyde
(0.020 g, 0.62 mmol, 6.0 eq) and sodium methoxide (0.017 g, 0.312
mmol, 3.0 eq) was added. Reaction mixture was stirred at 65.degree.
C. for 2 h. Then, reaction mixture was cooled to room temperature
and sodium borohydride (0.011 g, 0.270 mmol, 2.6 eq) was added.
Reaction mixture was stirred at 65.degree. C. for 45 min. After
completion of the reaction, reaction mixture was concentrated,
transferred into water and extracted with dichloromethane. Organic
layer combined, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain 217.8. (0.025 g,
65.01%). MS(ES): m/z 371.47 [M].sup.+.
[1077] Synthesis of XVI-2. To a solution of compound 217.8 (0.025
g, 0.067 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added
cyclopropanecarboxamide (0.040 g, 0.47 mmol, 7.0 eq), cesium
carbonate (0.087 g, 0.26 mmol, 4.0 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.006 g, 0.006 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.008 g,
0.013 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 150.degree. C. for 1 h under microwave
irradiation. After completion of reaction, reaction mixture was
cooled to room temperature, transferred into water and product was
extracted with ethyl acetate. Organic layer was combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 1.5% methanol in
dichloromethane as eluant to obtain pure XVI-2 (0.006 g, 21.22%).
MS(ES): m/z 420.53 [M+H].sup.+, LCMS purity: 99.42%, HPLC purity:
96.00%, .sup.1H NMR (DMSO-d.sub.6, 400 MHZ): 8.65 (s, 1H), 8.13 (s,
2H), 7.74-7.73 (d, J=4.0 Hz, 1H), 7.45 (s, 1H), 4.48 (s, 3H), 3.41
(s, 3H), 3.09 (s, 3H), 1.81 (s, 1H), 1.30 (s, 2H), 0.92-0.82 (m,
4H).
Example 218:
N-(1-(2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)-3-(methylamino)-1H-p-
yrazolo[4,3-c]pyridin-6-yl)cyclopropanecarboxamide, XVI-3
##STR00583## ##STR00584##
[1079] Synthesis of compound 218.2. To a solution of compound 218.1
(2.0 g, 7.4 mmol, 1.0 eq) in toluene (15 mL), compound
benzophenonehydrazone (1.8 g, 8.9 mmol, 1.2 eq) and
sodium-tert-butoxide (1.8 g, 18.5 mmol, 2.5 eq) were added.
Reaction mixture was purged with argon for 15 min. Then,
tris(dibenzylideneacetone)dipalladium(O) (0.68 g, 0.74 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.86 g,
1.49 mmol, 0.2 eq) were added. Reaction mixture was stirred at
110.degree. C. for 4 h. After completion of reaction, reaction
mixture was transferred into water and product was extracted with
ethyl acetate. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography using 20% ethyl acetate in hexane as eluant
to obtain 218.2 (1.6 g, 65.78%). MS(ES): m/z 384.15
[M+H].sup.+.
[1080] Synthesis of compound 218.3. To a suspension of 218.2 (1.7
g, 4.4 mmol, 1.0 eq) in water (2 mL) was added 4M hydrogen chloride
in dioxane (17 mL) dropwise. Reaction mixture was stirred at room
temperature for 24 h. After completion of the reaction, the
reaction mixture was concentrated under reduced pressure to obtain
crude material. This was further purified by trituration with
dichloromethane and ether to obtain 218.3 (0.8 g, 70.48%). MS(ES):
m/z 256.46 [M+H].sup.+.
[1081] Synthesis of compound 218.4. To a solution of
dichloropyridinecarbonitrile (0.3 g, 1.3 mmol, 1.0 eq) in butanol
(2 mL), compound 218.3 (0.23 g, 1.3 mmol, 1.0 eq) was added.
Reaction mixture was heated in microwave at 120.degree. C. for 5 h.
After completion of the reaction, the reaction mixture was
concentrated to get the crude product. This was further purified by
column chromatography using 5% methanol in dichloromethane to
obtain pure 218.4. (0.17 g, 4.77%). MS(ES): m/z 357.48
[M].sup.+.
[1082] Synthesis of compound 218.5. To a solution of compound 218.4
(0.2 g, 0.56 mmol, 1.0 eq) in methanol (2 mL), paraformaldehyde
(0.1 g, 3.3 mmol, 6.0 eq) and sodium methoxide (0.09 g, 1.6 mmol,
3.0 eq) were added. Reaction mixture was stirred at 60-65.degree.
C. for 3 h, cooled to room temperature and sodium borohydride
(0.005 g, 0.14 mmol, 2.5 eq) was added in portions. Reaction
mixture was again stirred at 60-65.degree. c. for 24 h. After
completion of the reaction, the reaction mixture was transferred
into water and extracted with dichloromethane. Organic layer
combined, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain 218.5. (0.12 g,
57.73%). MS(ES): m/z 371.48 [M].sup.+.
[1083] Synthesis of XVI-3. To a solution of compound 218.5 (0.050
g, 0.13 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added
cyclopropanecarboxamide (0.057 g, 0.67 mmol, 5.0 eq), cesium
carbonate (0.1 g, 3.3 mmol, 2.5 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.015 g,
0.021 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 110.degree. C. for 1 h under microwave
irradiation. After completion of reaction, reaction mixture was
cooled to room temperature, transferred in water and product was
extracted with ethyl acetate. Organic layer combined, washed with
brine solution, dried over sodium sulphate and concentrated under
reduced pressure to obtain crude material. This was further
purified by column chromatography using 1.5% methanol in
dichloromethane as eluant to obtain pure XVI-3 (0.015 g, 26.52%).
MS(ES): m/z 420.38 [M+H].sup.+, LCMS purity: 100%, HPLC purity:
100%, .sup.1H NMR (MeOD, 400 MHZ): 8.99 (s, 1H), 8.18-8.17 (m, 2H),
7.67-7.65 (m, 2H), 7.53-7.49 (m, 1H), 4.48 (s, 3H), 3.54 (s, 3H),
3.27 (s, 3H), 1.92-1.87 (m, 1H), 1.04-1.01 (m, 2H), 0.99-0.90 (m,
2H).
Example 219:
N-(3-ethyl-1-(2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)-1H-pyrazolo[-
4,3-c]pyridin-6-yl)cyclopropanecarboxamide, XVI-4
##STR00585##
[1085] Synthesis of compound 219.2. To a solution of compound 219.1
(0.5 g, 2.61 mmol, 1.0 eq) in tetrahydrofuran (10 mL),
1,1'-carbonyldiimidazole (0.63 g, 3.91 mmol, 1.5 eq) was added.
Reaction mixture was stirred for 30 min at room temperature. Then,
di-isopropylethylamine (0.67 g, 5.22 mmol, 2.0 eq) and
N,O-dimethylhydroxyamine hydrochloride (0.30 g, 3.13 mmol, 1.2 eq)
was added and the reaction mixture was stirred for 18 h. After
completion of the reaction, the reaction mixture was transferred
into water and extracted with ethyl acetate. Organic layer
combined, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain the crude material.
This was further purified by column chromatography using 20% ethyl
acetate in hexane to obtain pure 219.2 (0.3 g, 49.01%). MS(ES): m/z
236.06 [M+H].sup.+.
[1086] Synthesis of compound 219.3. To a solution of 219.2 (0.1 g,
0.42 mmol, 1.0 eq) in tetrahydrofuran (0.5 mL) was added ethyl
magnesium bromide (1M in THF) (0.84 mL, 0.84 mmol, 2.0 eq) at
0.degree. C. Reaction mixture was stirred at room temperature for
18 h. After completion of reaction, the reaction mixture was
transferred to ammonium chloride and product was extracted with
ethyl acetate. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain crude material. This was further purified by
column chromatography and the product was eluted in 10% ethyl
acetate in hexane to get 219.3 (0.8 g, 92.16%). MS(ES): m/z 205.48
[M+H].sup.+.
[1087] Synthesis of compound 219.4. To a solution of compound 219.3
(0.028 g, 0.13 mmol, 1.0 eq) in dimethylformamide (0.5 mL),
di-isopropylethylamine (0.084 g, 0.65 mmol, 5 eq) and hydrazine
hydrate (0.022 g, 0.45 mmol, 3.5 eq) were added. Reaction mixture
was stirred at 80.degree. C. for 18 h. After completion of the
reaction, the reaction mixture was transferred into water and
extracted with ethyl acetate. Organic layer combined, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain 1.3 (0.023 g, 99.99%). MS(ES): m/z 182.37
[M+H].sup.+.
[1088] Synthesis of compound 219.6. To a solution of compound 219.4
(0.07 g, 0.38 mmol, 1.0 eq) in dioxane (5 mL), compound 219.5 (0.18
mL, 0.77 mmol, 2.0 eq) was added. Reaction mixture was degassed for
5 min. Then, 4-dimethylaminopyridine (0.188 g, 1.54 mmol, 4.0 eq)
and cesium carbonate (0.32 g, 0.98 mmol, 2.5 eq) was added and
again degassed for 15 min. Then, copper acetate (0.07 g, 0.42 mmol,
1.1 eq) was added. Reaction mixture was stirred at 50.degree. C.
for 1 hour. After completion of the reaction, the reaction mixture
was concentrated, transferred to water and extracted with ethyl
acetate. Organic layers were combined, dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to get
the crude material. This was further purified by column
chromatography using 12% ethyl acetate in hexane to obtain pure
219.6. (0.05 g, 41.45%). MS(ES): m/z 370.48 [M].sup.+.
[1089] Synthesis of XVI-4. To a solution of compound 219.6 (0.05 g,
0.14 mmol, 1.0 eq) in N--N'-dimethylacetamide (1 mL) was added
cyclopropane carboxamide (0.038 g, 0.44 mmol, 3.0 eq), cesium
carbonate (0.14 g, 0.44 mmol, 3.0 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.013 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.017 g,
0.029 mmol, 0.2 eq) were added, again degassed for 5 min. Reaction
mixture was stirred at 130.degree. C. for 1 h under microwave
irradiation. After completion of reaction, reaction mixture was
cooled to room temperature, transferred into water and product was
extracted with ethyl acetate. Organic layer was combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 1.5% methanol in
dichloromethane as eluant to obtain pure XVI-4 (0.020 g, 32.14%).
MS(ES): m/z 419.63 [M+H].sup.+, LCMS purity: 100%, HPLC purity:
100%, .sup.1H NMR (DMSO-d.sub.6, 400 MHZ): 10.99 (s, 1H), 8.99 (s,
1H), 8.06-8.04 (d, J=6.8 Hz, 1H), 7.92 (s, 1H), 7.71-7.69 (d, J=8.8
Hz, 1H), 7.53-7.49 (t, J=11.5 Hz, 1H), 4.47 (s, 3H), 3.29 (s, 3H),
3.10-3.05 (m, 2H), 2.01 (s, 1H), 1.42-1.39 (t, J=11.5 Hz, 3H),
0.77-0.74 (m, 4H).
Example 220:
N-(1-ethyl-3-(2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)-1H-pyrazolo[-
3,4-c]pyridin-5-yl)cyclopropanecarboxamide, XVI-5
##STR00586## ##STR00587##
[1091] Synthesis of compound 220.2. To a solution of compound 220.1
(0.5 g, 1.85 mmol, 1.0 eq) in 1,4-dioxane (1 mL), compound
bispinacolato diboron (0.70 g, 2.2 mmol, 1.2 eq),
(1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride
(0.04 g, 0.05 mmol, 0.03 eq) and potassium acetate (0.54 g, 5.52
mmol, 3 eq) was added. Reaction mixture was degassed with argon for
15 min and then stirred at 120.degree. C. for 5 h. After completion
of the reaction, the reaction mixture was transferred into water
and extracted with ethyl acetate. Organic layer combined, dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to obtain crude material. This was further
purified by column chromatography using 20% ethyl acetate in hexane
as eluent to obtain pure 220.2 (0.4 g, 68.09%). MS(ES): m/z 317.58
[M+H].sup.+.
[1092] Synthesis of compound 220.4. To a solution of 220.3 (1.0 g,
0.50 mmol, 1.0 eq) in dimethylformamide (10 mL) was added potassium
hydroxide (0.54 g, 0.75 mmol, 1.5 eq) and iodine (2.2 g, 0.75 mmol,
1.5 eq) at room temperature. Reaction mixture was stirred at room
temperature for 2 h. After completion of reaction, to the reaction
mixture was added solution of sodium carbonate slowly and extracted
with ethyl acetate. Organic layer was combined, washed with brine
solution, dried over sodium sulphate and concentrated under reduced
pressure to obtain 220.4 (1.3 g, 71.44%). MS(ES): m/z 280.53
[M+H].sup.+.
[1093] Synthesis of compound 220.5. To a solution of compound 220.5
(1.5 g, 5.30 mmol, 1.0 eq) in dimethylformamide (15 mL) at
0.degree. C., ethyl iodide (0.32 g, 6.3 mmol, 1.2 eq) was added.
Then, sodium hydride (1.0 g, 7.9 mmol, 1.5 eq) was added in
portions at 0.degree. C. Reaction mixture was stirred at room
temperature for 2 h. After completion of the reaction, the reaction
mixture was transferred to water and extracted with ethyl acetate.
Organic layer combined, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain crude
material. This was further purified by column chromatography using
10% ethyl acetate in hexane to obtain pure 220.5. (1.0 g, 60.58%).
MS(ES): m/z 308.56 [M].sup.+.
[1094] Synthesis of compound 220.6. To a solution of compound 220.5
(0.1 g, 0.32 mmol, 1.0 eq) in a mixture of toluene (1.0 mL),
ethanol (0.5 mL) and water (0.5 mL), compound 220.2 (0.12 g, 0.39
mmol, 1.2 eq) was added. Then, sodium bicarbonate (0.08 g, 0.9
mmol, 3.0 eq) and Tetrakis(triphenylphosphine)palladium(0) (0.030
g, 0.032 mmol, 0.1 eq) was added. Reaction mixture was stirred at
room temperature for 2 h. After completion of the reaction, the
reaction mixture was transferred into water and extracted with
dichloromethane. Organic layer combined, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain crude material. This was further purified by column
chromatography using 60% ethyl acetate in hexane to obtain pure
220.6 (0.033 g, 27.44%). MS(ES): m/z 370.43 [M].sup.+.
[1095] Synthesis of XVI-5. To a solution of compound 220.6 (0.150
g, 0.40 mmol, 1.0 eq) in 1,4-dioxane (1.5 mL) was added
cyclopropane carboxamide (0.052 g, 0.60 mmol, 1.5 eq), cesium
carbonate (0.26 g, 0.81 mmol, 2.0 eq). The reaction mixture was
degassed for 10 min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.037 g, 0.040 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.047 g,
0.081 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 130.degree. C. for 5 h under microwave
irradiation. After completion of reaction, reaction mixture was
cooled to room temperature, transferred in water and product was
extracted with ethyl acetate. Organic layer was combined, washed
with brine solution, dried over sodium sulphate and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 1.5% methanol in
dichloromethane as eluant to obtain pure XVI-5 (0.030 g, 17.67%).
MS(ES): m/z 419.48 [M+H].sup.+, LCMS purity: 98.63%, HPLC purity:
96.58%, .sup.1H NMR (DMSO-d.sub.6, 400 MHZ): 10.77 (s, 1H), 9.04
(s, 1H), 8.34 (s, 1H), 7.95-7.93 (d, J=8.8 Hz, 1H), 7.78-7.76 (d,
J=11.5 Hz, 1H), 7.44-7.42 (m, 1H), 7.42-7.40 (m, 1H), 4.64-4.59 (m,
2H), 4.45 (s, 3H), 3.39 (s, 3H), 1.99-1.96 (d, J=13.2 Hz, 1H),
1.52-1.48 (m, 2H), 0.74 (s, 4H).
Example 221:
N-(1-ethyl-3-(2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)-1H-pyrrolo[2-
,3-c]pyridin-5-yl)cyclopropanecarboxamide, XVI-6
##STR00588##
[1097] Synthesis of compound 221.2. To a solution of compound 221.1
(2 g, 11.62 mmol, 1.0 eq) in dimethylformamide (10 mL),
dimethylformamide dimethyl acetal (2 mL) was added. Reaction
mixture was stirred at 90.degree. C. for 2 h. After completion of
the reaction, the reaction mixture was transferred into water and
extracted with ethyl acetate. Organic layer combined, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain 221.2 (1.2 g, 45.48%). MS(ES): m/z 228.15
[M+H].sup.+.
[1098] Synthesis of compound 221.3. To a solution of 221.2 (1.0 g,
4.4 mmol, 1.0 eq) in acetic acid (10 mL) was added iron powder (1.2
g, 22.0 mmol, 5.0 eq) at room temperature. Reaction mixture was
stirred at 90.degree. C. for 2 h. After completion of reaction, to
the reaction mixture was added solution of sodium carbonate slowly
and extracted with ethyl acetate. Organic layer was combined,
washed with brine solution, dried over sodium sulphate and
concentrated under reduced pressure to obtain crude material. This
was further purified by column chromatography and the product was
eluted in 30% ethyl acetate in hexane to obtain 221.3 (0.65 g,
96.98%). MS(ES): m/z 153.47 [M+H].sup.+.
[1099] Synthesis of compound 221.4. To a solution of compound 221.3
(1.2 g, 7.7 mmol, 1.0 eq) in dimethylformamide (5 mL), bromine
solution (1.2 g, 7.7 mmol, 1.0 eq) was added. Reaction mixture was
stirred at room temperature for 1 h. After completion of the
reaction, the reaction mixture was transferred into water to obtain
the precipitate which was filtered, washed with water and dried
well under vacuum to obtain 221.4. (1.1 g, 60.42%). MS(ES): m/z
232.53 [M].sup.+.
[1100] Synthesis of compound 221.5. To a solution of compound 221.4
(1.1 g, 7.2 mmol, 1.0 eq) in dimethylformamide (20 mL) at 0.degree.
C., sodium hydride (0.5 mL, 10.8 mmol, 1.5 eq) was added. Reaction
mixture was stirred at 0.degree. C. for 20 min. Then, ethyl iodide
(1.6 mL, 10.8 mmol, 1.5 eq) was added. Reaction mixture was stirred
at room temperature for 3 h. After completion of the reaction, the
reaction mixture was transferred into water to obtain the
precipitate which was filtered, washed with water and dried well
under vacuum to obtain 221.5. (0.9 g, 72.97%). MS(ES): m/z 260.37
[M].sup.+.
[1101] Synthesis of compound 221.6. To a solution of compound 221.5
(0.4 g, 1.5 mmol, 1.0 eq) in a mixture of water (2 mL), ethanol (4
mL) and toluene (4 mL), compound 220.2 (0.63 mL, 2.0 mmol, 1.3 eq)
and sodium bicarbonate (0.3 g, 3.6 mmol, 3.0 eq) was added.
Reaction mixture was degassed with argon for 15 min. Then,
tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol, 0.1
eq) was added and again degassed for 5 min. Reaction mixture was
stirred at 110.degree. C. for 24 h. After completion of the
reaction, the reaction mixture was concentrated, transferred to
water and extracted with ethyl acetate. Organic layer combined,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure to obtain crude material. This was further
purified by column chromatography using 55% ethyl acetate in hexane
to obtain pure 221.6. (0.15 g, 26.39%). MS(ES): m/z 369.43
[M].sup.+.
[1102] Synthesis of XVI-6. To a solution of compound 221.6 (0.150
g, 0.40 mmol, 1.0 eq) in 1,4-dioxane (5 mL) was added cyclopropane
carboxamide (0.052 g, 0.61 mmol, 1.5 eq), potassium carbonate (0.1
g, 1.92 mmol, 3.0 eq). The reaction mixture was degassed for 10
min. under argon atmosphere, then
tris(dibenzylideneacetone)dipalladium(0) (0.058 g, 0.040 mmol, 0.1
eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.036 g,
0.080 mmol, 0.2 eq) were added, again degassed for 5 min. The
reaction was stirred at 130.degree. C. for 5 h. After completion of
reaction, reaction mixture was cooled to room temperature,
transferred in water and product was extracted with ethyl acetate.
Organic layer combined, washed with brine solution, dried over
sodium sulphate and concentrated under reduced pressure to obtain
crude material. This was further purified by column chromatography
using 2% methanol in dichloromethane as eluant to obtain pure XVI-6
(0.050 g, 29.45%). MS(ES): m/z 418.48 [M+H].sup.+, LCMS purity:
99.91%, HPLC purity: 100%, .sup.1H NMR (DMSO-d.sub.6, 400 MHZ):
10.58 (s, 1H), 8.72 (s, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.79-7.76
(d, J=8.8 Hz, 1H), 7.69-7.67 (d, J=7.6 Hz, 1H), 7.41-7.37 (t,
J=15.6 Hz, 1H), 4.46 (s, 3H), 4.41-4.35 (m, 2H), 3.40 (s, 3H), 1.99
(s, 1H), 1.48-1.44 (t, J=14.4, 3H), 0.77-0.74 (m, 4H).
Example 222. TYK2 JH2 Domain Binding Assay
[1103] Binding constants for compounds of the present invention
against the JH2 domain were determined by the following protocol
for a KINOMEscan.RTM. assay (DiscoveRX). A fusion protein of a
partial length construct of human TYK2 (JH2domain-pseudokinase)
(amino acids G556 to D888 based on reference sequence NP_003322.3)
and the DNA binding domain of NFkB was expressed in transiently
transfected HEK293 cells. From these HEK 293 cells, extracts were
prepared in M-PER extraction buffer (Pierce) in the presence of
Protease Inhibitor Cocktail Complete (Roche) and Phosphatase
Inhibitor Cocktail Set II (Merck) per manufacturers' instructions.
The TYK2(JH2domain-pseudokinase) fusion protein was labeled with a
chimeric double-stranded DNA tag containing the NFkB binding site
(5'-GGGAATTCCC-3') fused to an amplicon for qPCR readout, which was
added directly to the expression extract (the final concentration
of DNA-tag in the binding reaction is 0.1 nM).
[1104] Streptavidin-coated magnetic beads (Dynal M280) were treated
with a biotinylated small molecule ligand for 30 minutes at room
temperature to generate affinity resins the binding assays. The
liganded beads were blocked with excess biotin and washed with
blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM
DTT) to remove unbound ligand and to reduce nonspecific
binding.
[1105] The binding reaction was assembled by combining 16 .mu.l of
DNA-tagged kinase extract, 3.8 .mu.l liganded affinity beads, and
0.18 .mu.l test compound (PBS/0.05% Tween 20/10 mM DTT/0.1% BSA/2
.mu.g/ml sonicated salmon sperm DNA)]. Extracts were used directly
in binding assays without any enzyme purification steps at a
>10,000-fold overall stock dilution (final DNA-tagged enzyme
concentration <0.1 nM). Extracts were loaded with DNA-tag and
diluted into the binding reaction in a two step process. First
extracts were diluted 1:100 in 1.times. binding buffer (PBS/0.05%
Tween 20/10 mM DTT/0.1% BSA/2 .mu.g/ml sonicated salmon sperm DNA)
containing 10 nM DNA-tag. This dilution was allowed to equilibrate
at room temperature for 15 minutes and then subsequently diluted
1:100 in 1.times. binding buffer. Test compounds were prepared as
111.times. stocks in 100% DMSO. K.sub.ds were determined using an
11-point 3-fold compound dilution series with three DMSO control
points. All compounds for K.sub.d measurements are distributed by
acoustic transfer (non-contact dispensing) in 100% DMSO. The
compounds were then diluted directly into the assays such that the
final concentration of DMSO was 0.9%. All reactions performed in
polypropylene 384-well plates. Each was a final volume of 0.02 mL.
Assays were incubated with shaking for 1 hour at room temperature.
Then the beads were pelleted and washed with wash buffer
(1.times.PBS, 0.05% Tween 20) to remove displaced kinase and test
compound. The washed based were re-suspended in elution buffer
(1.times.PBS, 0.05% Tween 20, 0.5 .mu.M non-biotinylated affinity
ligand) and incubated at room temperature with shaking for 30
minutes. The kinase concentration in the eluates was measured by
qPCR. qPCR reactions were assembled by adding 2.5 .mu.L of kinase
eluate to 7.5 .mu.L of qPCR master mix containing 0.15 .mu.M
amplicon primers and 0.15 .mu.M amplicon probe. The qPCR protocol
consisted of a 10 minute hot start at 95.degree. C., followed by 35
cycles of 95.degree. C. for 15 seconds, 60.degree. C. for 1
minute.
[1106] Test compounds were prepared as 111.times. stocks in 100%
DMSO. K.sub.ds were determined using an 11-point 3-fold compound
dilution series with three DMSO control points. All compounds for
K.sub.d measurements are distributed by acoustic transfer
(non-contact dispensing) in 100% DMSO. The compounds were then
diluted directly into the assays such that the final concentration
of DMSO was 0.9%. The K.sub.ds were determined using a compound top
concentration of 30,000 nM. K.sub.d measurements were performed in
duplicate.
[1107] Binding constants (K.sub.ds) were calculated with a standard
dose-response curve using the Hill equation:
Response = Background + ( Signal - Background ) ( 1 + ( K .times. d
Hill .times. .times. Slope Dose Hill .times. .times. Slope )
##EQU00001##
[1108] The Hill Slope was set to -1. Curves were fitted using a
non-linear least square fit with the Levenberg-Marquardt algorithm
(Levenberg, K., A method for the solution of certain non-linear
problems in least squares, Q. Appl. Math. 2, 164-168 (1944)). In
some cases
[1109] Results of the JH2 binding assay are reported in Table 4.
Compounds described as "A" have a K.sub.d less than 100 .mu.M.
Compounds described as "B" have a K.sub.d equal to or greater than
100 .mu.M and less than 500 .mu.M. Compounds described as "C" have
a K.sub.d equal to or greater than 500 .mu.M and less than 1 nM.
Compounds described as "D" have a K.sub.d equal to or greater than
1 nM and less than 10 nM. Compounds described as "E" have a K.sub.d
equal to or greater than 10 nM.
TABLE-US-00004 TABLE 4 JH2 binding assay. Compound JH2 K.sub.d I-1
A I-2 B I-3 B I-4 B I-5 E I-6 E I-7 D I-8 A I-9 A I-10 A I-11 E
I-12 A I-13 A I-14 B I-15 B I-16 B I-17 A I-18 B I-19 D I-20 B I-21
B I-22 C I-23 E I-24 B I-25 B I-27 E I-28 D I-29 B I-30 E I-31 A
I-32 E I-33 E I-34 E I-35 E I-36 E I-37 E I-38 E I-39 E I-40 E I-41
E I-42 E I-43 E I-44 D I-45 D I-46 C I-47 E I-48 C I-49 C I-50 D
I-51 E I-52 D I-53 B I-54 C I-55 C I-56 C I-57 A I-58 E I-59 B I-60
B I-61 D I-62 A I-63 B I-64 A I-65 B I-66 C I-67 D I-68 B I-69 D
I-70 B I-71 C I-72 D I-73 D I-74 B I-75 B I-76 D I-77 D I-78 D I-79
D I-80 D I-81 B I-82 B I-83 D I-84 D I-85 C I-86 D I-87 D I-88 D
I-89 D I-90 E I-91 D I-92 B I-93 D I-94 D I-95 D I-96 B I-97 C I-98
C I-99 C I-100 A I-101 D I-102 E I-103 E I-104 E I-105 D I-106 D
I-107 B I-108 B I-109 B I-110 D I-111 B I-112 A I-113 B I-114 D
I-115 D I-116 E I-117 E I-118 E I-119 D I-120 D I-121 C I-122 B
I-123 B I-124 D I-125 E I-126 E I-127 E I-128 B I-129 B I-130 B
I-131 B I-132 B I-133 B I-134 B I-135 D I-136 D I-137 C I-138 C
I-139 B I-140 D I-141 D I-142 B I-143 B I-144 B I-145 B I-146 E
I-147 E I-148 E I-149 E I-151 E I-152 C I-155 C I-156 E I-157 C
I-158 E I-182 B I-190 C I-191 E I-198 B I-199 B I-201 A I-203 C
I-206 C I-207 D I-208 C I-209 C I-210 B I-211 C I-212 E I-213 B
I-214 B I-215 B I-216 B I-217 A I-218 A I-219 B I-220 B I-221 B
I-222 D I-223 D I-225 A I-226 B I-227 A I-228 B I-229 A I-230 C
I-231 D I-232 A I-234 B I-235 B I-236 E I-237 D I-238 B I-239 B
I-240 B I-241 E
[1110] Results of the JH2 binding assay are listed in Table 5,
below. Compounds designated as "A" had a K.sub.d between 100 .mu.M
and 1 nM. Compounds designated as "B" had a K.sub.d between 1 nM
and 10 nM. Compounds designated as "C" had a K.sub.d between 10 nM
and 100 nM. Compounds designated as "D" had a K.sub.d greater than
100 nM.
TABLE-US-00005 TABLE 5 Results of Tyk2 JH2 Domain Binding Assay
Compound JH2 K.sub.d VIII-1 B VIII-2 C VIII-3 D VIII-4 B VIII-5 B
VIII-6 C VIII-7 B VIII-8 D VIII-9 D VIII-10 D VIII-11 C VIII-12 A
VIII-13 A VIII-14 A VIII-15 B VIII-16 A VIII-17 A XVI-1 C XVI-2 D
XVI-3 D XVI-4 A XVI-5 C XVI-6 C
[1111] Results of the Tyk2 JH2 Domain Binding Assay indicate that
compounds XVI-1 and XVI-3 have a K.sub.d between 7-10 uM, and
compounds XVI-2 and XVI-4 through XVI-6 have a K.sub.d between
10-185 nM.
Example 223. Tyk2 & JAK2 Radioactive Kinase Assay
[1112] Peptide substrate, [KKSRGDYMTMQIG], (20 .mu.M) is prepared
in reaction buffer (20 mM Hepes pH 7.5, 10 mM MgCl.sub.2, 1 mM
EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na.sub.3PO.sub.4, 2 mM
DTT, 1% DMSO. TYK2 (Invitrogen) kinase is added, followed by
compounds in DMSO. 33PATP is added to initiate the reaction in ATP
at 10 .mu.M. Kinase reaction is incubated for 120 min at room temp
and reactions are spotted onto P81 ion exchange paper (Whatman
#3698-915), and then washed extensively in 0.75% phosphoric acid,
prior to reading the radioactivity counts. For JAK2 (Invitrogen)
kinase assay the peptide substrate poly[Glu:Tyr](4:1), 0.2 mg/ml is
used, in the reaction carried out the same as for TYK2.
[1113] Results of the active kinase assay indicate that compounds
I-1 and I-2 have no detectable inhibitory activity against TYK2 JH1
kinase function.
[1114] Results of the active kinase assay indicate that compounds
VIII-1, VIII-2, VIII-3, and VIII-4 have no detectable inhibitory
activity against TYK2 or JAK2 JH1 kinase function.
Example 224. Tyk2 & JAK2 Caliper Assay
[1115] The caliper machine employs an off chip mobility shift assay
to detect phosphorylated peptide substrates from kinase assays,
using microfluidics technology. The assays are carried out at ATP
concentration equivalent to the ATP Km, and at 1 mM ATP. Compounds
are serially diluted in DMSO then further diluted in assay buffer
(25 mM HEPES, pH 7.5, 0.01% Brij-35, 0.01% Triton, 0.5 mM EGTA). 5
ul of diluted compound was added into wells first, then 10 ul of
enzyme mix was added into wells, followed by 10 uL of substrate mix
(peptide and ATP in 10 mM MgCl.sub.2) to start reaction. Reaction
was incubated at 28.degree. C. for 25 min and then added 25 ul stop
buffer (100 mM HEPES, 0.015% Brij-35, 50 mM EDTA), followed by
reading with Caliper. JAK2 at 1 nM final concentration and TYK2 at
9.75 nM are from Carna, and substrates used are ATP at 20 and 16
uM, respectively. JAK2 assay uses peptide 22 and TYK2 uses peptide
30 (Caliper), each at 3 uM.
Example 225. IL-12 Induced pSTAT4 in Human PBMC
[1116] Human PBMC are isolated from buffy coat and are stored
frozen for assays as needed. Cells for assay are thawed and
resuspended in complete media containing serum, then cells are
diluted to 1.67 E6 cells/ml so that 120 .mu.l per well is 200,000
cells. 15 .mu.l of compound or DMSO is added to the well at the
desired concentrations and incubated at 1 hr at 37 C. 15 .mu.l of
stimulus (final concentration of 1.7 ng/mL IL-12) is added for 30
minutes prior to pSTAT4 and total STAT4 analysis using cell lysates
prepared and analyzed by MSD reagents as per manufacturer protocol.
The final DMSO concentration of compound in the assay is 0.1%.
[1117] Results of the IL-12 induced pSTAT4 assay in human PBMC
indicate that each of compounds VIII-1 through VIII-17 inhibited
pSTAT4 production with an IC.sub.50 of between 100 nM and 10
uM.
Example 226. GM-CSF Induced pSTAT5 in Human PBMC
[1118] Cells are prepared for analysis as in the above procedure
and 15 .mu.l of GM-CSF (final concentration 5 ng/mL) is added for
20 minutes prior to pSTAT5 and total STAT5 analysis using cell
lysates prepared and analyzed by MSD reagents as per manufacturer
protocol. The final DMSO concentration of compound in the assay is
0.1%.
[1119] Results of the GM-CSF Induced pSTAT5 assay in human PBMC
indicate that compound VIII-1 inhibits pSTAT5 production with an
IC.sub.50 of greater than 50 uM.
Example 227. Ex Vivo Mouse IL-12 Induced IFN.gamma. Studies
[1120] C57/BL6 mice are given a single oral dose of either vehicle
or different doses of compound at a volume of 10 mL/kg. 30 minutes
to 1 hour after dosing, animals are euthanized and blood was
collected via vena cava into sodium heparin blood collection tubes
and inverted several times. Blood is then plated on anti-CD3 coated
plates and stimulated with 2 ng/ml of mouse IL-12 in RPMI media for
24 hours at 37.degree. C. in humidified incubator with 5% CO.sub.2.
At the end of the incubation, blood is centrifuged at 260 g for 5
minutes to collect supernatant. IFN.gamma. concentration in the
supernatant is determined with mouse IFN.gamma. MSD kit per
manufacture's instruction (Meso Scale Discovery). At the time of
the blood collection, plasma is collected for drug level analysis
by LC-MS/MS.
Example 228. T-ALL Cell Proliferation Assay
[1121] T-ALL cell lines KOPT-K1, HPB-ALL, DND-41, PEER, and
CCRF-CEM are cultured in RPMI-1640 medium with 10% fetal bovine
serum and penicillin/streptomycin. Cells are plated in triplicate
at 1.times.10.sup.4 cells per well in 96-well plates. T-ALL cell
lines DU.528, LOUCY, and SUP-T13 are cultured in the same medium
and plated at a density of 1.5.times.10.sup.4 cells per well. The
cells are treated with DMSO or different concentrations of each
compound of the invention. Cell viability at 72 hour exposure to
the drug is assessed by CellTiter-Glo Luminescent Cell Viability
Assay (Promega). CellTiter-Glo Reagent is added into the well and
incubated for 10 minutes. Luminescence is measured subsequently
using a 96-well plate luminescence reader. Cell viability is
calculated by using the DMSO treated samples as 100%. IC.sub.50
value is calculated by nonlinear regression using GraphPad Prism
software.
[1122] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments that utilize the compounds and methods of
this invention. Therefore, it will be appreciated that the scope of
this invention is to be defined by the appended claims rather than
by the specific embodiments that have been represented by way of
example.
Sequence CWU 1
1
2110DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1gggaattccc 10213PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 2Lys
Lys Ser Arg Gly Asp Tyr Met Thr Met Gln Ile Gly1 5 10
* * * * *