NZ613786B2 - Compounds and methods for kinase modulation, and indications therefor - Google Patents
Compounds and methods for kinase modulation, and indications therefor Download PDFInfo
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- NZ613786B2 NZ613786B2 NZ613786A NZ61378612A NZ613786B2 NZ 613786 B2 NZ613786 B2 NZ 613786B2 NZ 613786 A NZ613786 A NZ 613786A NZ 61378612 A NZ61378612 A NZ 61378612A NZ 613786 B2 NZ613786 B2 NZ 613786B2
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- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
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Abstract
613786 The disclosure relates to pyrrolopyridine-sulfonamide derivatives of formula (I), wherein the variables are as defined in the specification. These compounds are suitable for treating diseases or conditions mediated by B-Raf protein kinase, wherein said disease or condition is particularly selected from melanomer, thyroid or colon cancer. ly selected from melanomer, thyroid or colon cancer.
Description
—7211
COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS
THEREFOR
FIELD OF THE ION
The present invention relates to kinases and compounds which selectively te kinases,
and uses therefor. Particular embodiments contemplate disease indications which are amenable to
ion.
treatment by modulation of kinase activity by the compounds of the present
OUND OF THE INVENTION
Receptor protein kinases regulate key signal transduction cascades that control or are
involved in the control of a plethora of physiological functions including cellular growth and
proliferation, cell differentiation, cellular development, cell division, cell adhesion, stress response,
short-range contact-mediated axonal guidance, ription regulation, aberrant mitogenesis,
vascular development,
angiogenesis, al endothelial cell-cell or atrix interactions during
inflammation, lymphohematopoietic stem cell activity, protective immunity against specific bacteria,
transduction
allergic asthma, aberrant tissue-specific responses to the activation of the JNK signal
pathway, cell transformation, memory, apoptosis, competitive activity-dependent synapse
calcium
modification at the neuromuscular synapse, immunological mediation of disease, and
regulation.
Specific disease states ated with aberrant regulation of protein kinases include,
example without limitation, acrocephalo-syndactyly type I, acute myeloid leukemia, AIDS-induced
non-Hodgkin's lymphoma, Alzheimer’s disease, amyotrophic lateral sclerosis, arthritis, asthma,
atherosclerosis, atopic dermatitis, autoimmune diseases, bacterial infection, r cancer, cancer
of the endometrium,
the breast, cancer of the central nervous system, cancer of the colon, cancer
cancer of the ovary, heart failure,
cancer of the fallopian tube, cancer of the gastrointestinal tract,
disease
chronic myeloid leukemia, colon carcinoma, ctal cancer, chronic obstructive pulmonary
(COPD), Crouzon Syndrome, diabetes, diabetic nephropathy, emphysema, endometriosis, epidermoid
stromal tumor (GIST), glomerulonephritis, Graves’ disease,
cancer, fibrotic disorders, intestinal
head , cellular carcinoma, Hirschsprung‘s disease. human s, immunodeficiency
diseases, inflammatory disorders, ic stroke, Jackson—Weiss syndrome, leiomyosarccrna,
cell
leukemias, lupus nephritis, malignant melanoma, malignant nephrosclerosis, mastocytosis, mast
metabolic disorders, migraine, multiple sclerosis,
tumors, melanoma of the colon, MEN2 syndromes,
myeloproliferative disorders, nephritis, neurodegenerative diseases, neurotraumatic diseases, non
Pfeiffer
small cell lung cancer, organ lant ion, osteoporosis, pain, son’s disease,
me, poiycystic kidney disease, primary lymphoedema, prostate cancer, psoriasis,
restenosis, rheumatoid arthritis, dermal and tissue scarring, selective T~cell defect (STD), severe
4811—7918—7726.1
combined immunodeficiency , small cell lung cancer, spinal cord injury, squamous
cell carcinoma, systemic lupus erythematosis, testicular cancer, thrombotic microangiopathy
syndromes, Wegener's omatosis, X-linked globulinemia, viral ion,
diabetic retinopathy, alopecia, erectile dysfunction, macular degeneration, chronic
lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), neurofibromatosis, and
tuberous sclerosis. Accordingly, there is a need in the art for compounds and methods of use
thereof for the modulation of receptor protein kinases. The present invention meets this and
other needs.
SUMMARY OF THE INVENTION
[0003A] In a first aspect, the present invention provides a compound having formula (Ig):
Y2 O
R15 HN S Z
s N
N O
H Ig
or a pharmaceutically acceptable salt, a hydrate, a e, a tautomer, or
stereoisomer thereof, wherein
each R15 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl,
C1-6haloalkoxy, C3-8cycloalkyl, C3-8cycloalkyl-C1alkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl or –Ra, wherein Ra is selected
from halogen, -CH=CH2, -CN
-OH, -NH2, -
NO2, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, NH2, -NHC(O)NH2, -NHC(S)NH2,
-NHS(O)2NH2, -C(NH)NH2, -ORb, -SRb, -OC(O)Rb, -OC(S)Rb, -C(O)Rb, b, Rb
, -C(S)ORb, -S(O)Rb, -S(O)2Rb, -C(O)NHRb, HRb, -C(O)NRbRb, -C(S)NRbRb, -S(O)2
NHRb, -S(O)2NRbRb, -C(NH)NHRb, -C(NH)NRbRb, -NHC(O)Rb, -NHC(S)Rb, -NRbC(O)Rb,
-NRbC(S)Rb, -NHS(O)2Rb, -NRbS(O)2Rb, -NHC(O)NHRb, -NHC(S)NHRb, -NRbC(O)NH2, -
NRbC(S)NH2, -NRbC(O)NHRb, -NRbC(S)NHRb, -NHC(O)NRbRb, -NHC(S)NRbRb, -NRbC(O
)NRbRb, -NRbC(S)NRbRb, -NHS(O)2NHRb, -NRbS(O)2NH2, -NRbS(O)2NHRb, -NHS(O)2NRb
Rb, -NRbS(O)2NRbRb, -NHRb or , n each Rb is independently selected from the
group consisting of kyl, halogen, -CN, C1-6alkoxy, C3-8cycloalkyl, C3-8cycloalkyl-C1
alkyl, -OH, C1-6haloalkyl, C1-6haloalkoxy, aryl, aryl-C1-4alkyl, aryl and heteroarylalkyl;
or two Rb substituents when ed to the same nitrogen atom taken together with the
10437476_1
nitrogen atom form a three to eight-membered ring having from 0-2 onal heteroatoms
as ring members selected from N, O or S;
wherein the aliphatic or aromatic portion of R15 is further optionally
substituted with from 1-3 groups selected from C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-
6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl-
C1-4alkyl or -Rc, wherein each Rc is independently selected from halogen, -CH=CH2, -CN, -
OH, -NH2, -NO2,
H, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(
O)2NH2, -C(NH)NH2, -ORd, -SRd, -OC(O)Rd, -OC(S)Rd, -C(O)Rd, d, -C(O)ORd, -C(S)
ORd, -S(O)Rd, -S(O)2Rd, -C(O)NHRd, -C(S)NHRd, -C(O)NRdRd, -C(S)NRdRd, -S(O)2NHRd, -
S(O)2NRdRd, -C(NH)NHRd, -C(NH)NRdRd, )Rd, -NHC(S)Rd, -NRdC(O)Rd, -NRdC(
S)Rd, -NHS(O)2Rd, -NRdS(O)2Rd, -NHC(O)NHRd, -NHC(S)NHRd, -NRdC(O)NH2, -NRdC(S)
NH2, O)NHRd, -NRdC(S)NHRd, -NHC(O)NRdRd, -NHC(S)NRdRd, -NRdC(O)NRdRd,
-NRdC(S)NRdRd, -NHS(O)2NHRd, -NRdS(O)2NH2, -NRdS(O)2NHRd, -NHS(O)2NRdRd, -NRd
S(O)2NRdRd , -NHRd, Rf or -NRdRd,
wherein each Rd is independently selected from C1-6alkyl, arylalkyl, aryl, aryl,
heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or cycloalkylalkyl; and
wherein the aromatic portion of R15 is optionally substituted with from 1-3 substituents
independently ed from Re, wherein Re is selected from the group consisting of n,
-CN, -CH=CH2, -OH, -NH2, -NO2,
-C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(
O)2NH2, -C(NH)NH2, -ORf, -SRf, -OC(O)Rf, -OC(S)Rf, -C(O)Rf, -C(S)Rf, -C(O)ORf, -C(S)O
Rf, -S(O)Rf, Rf, -C(O)NHRf, HRf, -C(O)NRfRf, -C(S)NRfRf, -S(O)2NHRf, -S(O
)2NRfRf, -C(NH)NHRf, -C(NH)NRfRf, -NHC(O)Rf, -NHC(S)Rf, O)Rf,
-NRfC(S)Rf, -NHS(O)2Rf, -NRfS(O)2Rf, -NHC(O)NHRf, -NHC(S)NHRf, -NRfC(O)NH2, -NR
fC(S)NH fC(O)NHRf, -NRfC(S)NHRf, -NHC(O)NRfRf, -NHC(S)NRfRf, O)NRf
2, -NR
Rf, -NRfC(S)NRfRf, -NHS(O)2NHRf, -NRfS(O)2NH2,
-NRfS(O)2NHRf, -NHS(O)2NRfRf, -NRfS(O)2NRfRf , -NHRf, -NRfRf and Rf,
wherein Rf is C1-6alkyl or aryl; or
two adjacent R15 groups on the aryl or heteroaryl ring together with the atoms to
which they are attached form a 5- or 6-membered ring having from 0 to 2 additional
heteroatoms ed from N, O or S, optionally substituted with from 1 to 3 Rd substituents;
Q is selected from H, F, Cl or CH3;
Z is –N(R4)(R5);
10437476_1
R4 and R5 are each independently selected from the group consisting of H, C1-
, C3-8cycloalkyl, C3-8cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,
arylalkyl, heteroaryl and arylalkyl; or
R4 and R5 taken together with the nitrogen atom to which they are attached
form a four to eight-membered ring having from 0-2 additional heteroatoms as ring members
selected from N, O or S;
wherein each of R4 and R5 is optionally substituted with from 1-3 substituents
independently selected from C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, C3-
8cycloalkyl, cloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl,
heteroaryl, arylalkyl, propenyl, Rc, Re or Ra or two adjacent substituents together
with the atom to which they are attached form a 5 or 6-membered ic ring having from
0 to 2 additional atoms as ring members selected from O, N or S, each of which is optionally
substituted with from 1 to 3 substituents independently selected from C1-6alkoxy, C1-
6haloalkyl, C1-6haloalkoxy, C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkylalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, Rd, or Re;
Y2 is H, n, CN, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, C3-8cycloalkyl-C0-4alkyl or (R2)(R3) N-, wherein
R2 and R3 are each independently selected from the group consisting of H, kyl, C1-
6alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C3-8cycloalkyl-C0-4alkyl, heterocycloalkyl
and heterocycloalkyl-C1-4alkyl; or R2 and R3 taken together with the nitrogen atom to which
they are attached form a three to eight-membered ring having from 0-2 additional
heteroatoms as ring members selected from N, O or S; wherein Y2 is ally substituted
with from one to three groups independently ed from Re; and
the subscript s is an integer of 1 to 3,
with the proviso when of formula Ig is 2-methoxypyrimidin
yl, Z is other than dimethylamino, diethylamino, 1-pyrrolidine, 1-piperidinyl, or 4-
morpholinyl.
[0003B] In a second , the present ion provides a compound selected from any of
compounds
10437476_1
(P-0022),
(P-0047),
(P-0051),
(P-0052),
(P-0056),
(P-0057),
(P-0058),
(P-0064),
(P-0077),
10437476_1
(P-0078),
(P-0081),
(P-0084),
(P-0085),
(P-0086),
(P-0091),
(P-0092),
(P-0100),
(P-0106),
10437476_1
(P-0107),
(P-0108),
(P-0109),
(P-0112),
(P-0232),
(P-0233),
(P-0235),
(P-0238),
(P-0240),
10437476_1
(P-0241),
(P-0246),
(P-0249),
(P-0252),
(P-0258),
(P-0260),
(P-0261),
(P-0262),
10437476_1
(P-0263),
(P-0264),
(P-0266),
(P-0267),
(P-0268),
(P-0271),
(P-0272),
10437476_1
(P-0275),
(P-0277),
(P-0280),
(P-0282),
(P-0288),
(P-0289),
(P-0292),
10437476_1
(P-0293),
(P-0294),
(P-0299),
(P-0318),
(P-0320),
(P-0321),
(P-0327),
10437476_1
(P-0338),
(P-0339),
(P-0340), and
(P-0345)
or a pharmaceutically acceptable salt, a e, a solvate, a tautomer, or a stereosiomer
thereof.
[0003C] In a third aspect, the present invention provides a nd selected from any of
compounds
(P-0134),
(P-0135),
(P-0138),
(P-0146),
10437476_1
(P-0147),
(P-0148),
(P-0149),
(P-0185),
(P-0186),
(P-0189),
(P-0197),
(P-0199),
(P-0200), and
10437476_1
(P-0213),
or a ceutically acceptable salt, a hydrate, a solvate, a tautomer, or a
stereoisomer f.
[0003D] In a fourth aspect, the present invention provides a compound of a:
or a pharmaceutically acceptable salt, a hydrate, a solvate, a tautomer, or a
stereosiomer thereof.
[0003E] In a fifth aspect, the present invention provides a pharmaceutical ition
comprising a compound of the first, second, third or fourth aspect, and a pharmaceutically
acceptable excipient or carrier.
[0003F] In a sixth aspect, the present invention provides a pharmaceutical composition
comprising a compound of the first, second, third or fourth aspect, and another therapeutic
agent.
[0003G] In a seventh aspect, the present ion provides a kit comprising a compound of
the first, second, third or fourth .
[0003G] In an eighth aspect, the present invention provides use of a compound the first,
second, third or fourth aspect, in the manufacture of a ment for the treatment of a
protein kinase mediated disease or condition.
Described herein is a compound of formula I:
10437476_1
Y2 O
Y1 HN S Z
N N
H I
and pharmaceutically acceptable salts, hydrates, solvates, tautomers and isomers thereof;
Y1 is selected from the group consisting of CN, halogen, -OH, optionally substituted
C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-6cycloalkyl, optionally
substituted C1-6 haloalkyl, optionally substituted C1-6 haloalkoxy, optionally substituted aryl
and optionally substituted heteroaryl; optionally wherein two adjacent substituents on a
substituted aryl or a substituted heteroaryl ring together with the atoms to which they are
attached form an optionally substituted 5- or 6-membered ring having from 0 to 3 additional
heteroatoms selected from N, O or S;
Y2 is H, halogen, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, aryl,
arylalkyl, heteroaryl, arylalkyl, C3-8 cycloalkyl-C0-4 alkyl or (R2)(R3) N-, wherein R2
and R3 are each independently selected from the group ting of H, C1-6 alkyl, C1-6
alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C3-8 cycloalkyl-C0-4 alkyl,
cycloalkyl and heterocycloalkyl-C1-4 alkyl; or R2 and R3 taken together with the
nitrogen atom to which they are attached form a three to eight-membered ring having from 0-
2 additional heteroatoms as ring members selected from N, O or S; wherein Y2 is optionally
substituted with from one to three groups ndently selected from Re;
Q is selected from H, F, Cl or CH3;
Z is (R5) or –C(R6)(R7)(R8), wherein
R4 and R5 are each ndently ed from the group consisting of H,
ally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally
substituted C3-8 cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally
substituted heterocycloalkylalkyl, optionally substituted aryl, ally substituted
arylalkyl, optionally substituted heteroaryl and optionally substituted arylalkyl;
or R4 and R5 taken together with the nitrogen atom to which they are attached form a
four to eight-membered ring having from 0-2 additional heteroatoms as ring members
selected from N, O or S, wherein the four to eight-membered ring is optionally
substituted;
R6, R7 and R8 are each ndently H, optionally substituted C1-6 alkyl,
optionally substituted, C1-6 haloalkyl, optionally substituted C1-6 haloalkoxy,
optionally substituted C3-8 cycloalkyl, optionally tuted C3-8 cycloalkylalkyl,
10437476_1
optionally substituted aryl, optionally substituted arylalkyl, optionally substituted
heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally tuted
heteroaryl, optionally substituted heteroarylalkyl or -X2R9, wherein X2 is –NR10, O or
S; R10 is H, C1-6 alkyl or aryl; and R9 is H, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy,
C3-8 cycloalkyl, C3-8 cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,
wherein R9 is optionally substituted with from 1 to 3 Re substituents; or
any two of the R6, R7 and R8 groups taken together with the carbon atom to
which they are attached form a 3 to 8-membered optionally substituted non-aromatic
ring having from 0 to 2 heteroatoms selected from N, O or S; provided at each
occurrence, at least two of the R6, R7 and R8 groups are not simultaneously en;
and with the proviso when (i) Y1 is halogen, -CH3, -CN, -OMe or 2-
methoxypyrimidinyl, Z is other than dimethylamino, diethylamino, 1-pyrrolidine,
1-piperidinyl, 4-morpholinyl, isopropyl, -CH(CH3)(CH2CH3), -
CH(CH3)(CH2CH2CH3), cyclobutyl, cyclopentyl or cyclohexyl; and (ii) when Y1 is 1-
methylpyrazolyl, 3-methylsulfonylphenyl or 3-methylsulfonylaminophenyl, Z is
other than cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In some embodiments,
Y1 is CN, halogen, -OH, C1-6 alkyl, C1-6 alkoxy, optionally substituted C3-6cycloalkyl,
C1-6 haloalkyl, C1-6 haloalkoxy, aryl and aryl, wherein the aliphatic or aromatic portion
of Y1 is each independently optionally substituted with from 1-5 R1 substituents;
each R1 is ndently selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6
haloalkoxy, C3-8 cycloalkyl, C3-8 cycloalkyl-C1alkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycloalkyl, heterocycloalkyl-C1-4 alkyl or –Ra, wherein Ra is selected
from halogen, -CH=CH2, -CN, -OH, -NH2, -
NO2, H, H, -C(O)NH2, -C(S)NH2, -S(O)2NH2, )NH2, -NHC(S)NH2, -
NHS(O)2NH2, -C(NH)NH2, -ORb, -SRb, -OC(O)Rb, Rb, -C(O)Rb, -C(S)Rb, -C(O)ORb,
-C(S)ORb, -S(O)Rb, -S(O)2Rb, -C(O)NHRb, -C(S)NHRb, -C(O)NRbRb, -C(S)NRbRb, -S(O)2N
HRb, NRbRb, -C(NH)NHRb, -C(NH)NRbRb, -NHC(O)Rb, )Rb, O)Rb, -
NRbC(S)Rb, -NHS(O)2Rb, -NRbS(O)2Rb, )NHRb, -NHC(S)NHRb, -NRbC(O)NH2, -N
RbC(S)NH2, -NRbC(O)NHRb, S)NHRb, -NHC(O)NRbRb, -NHC(S)NRbRb, -NRbC(O)
NRbRb, -NRbC(S)NRbRb, -NHS(O)2NHRb, -NRbS(O)2NH2, -NRbS(O)2NHRb, -NHS(O)2NRb
Rb, O)2NRbRb, -NHRb or -NRbRb,
10437476_1
each Rb is independently selected from the group consisting of C1-6 alkyl, halogen, -CN, C1-6
alkoxy, C3-8 cycloalkyl, C3-8 cycloalkyl-C1alkyl, -OH, C1-6 haloalkyl, C1-6 haloalkoxy, aryl,
aryl-C1-4 alkyl, heteroaryl and heteroarylalkyl; or two Rb substituents when attached to the
same nitrogen atom taken together with the nitrogen atom form a three to eight-membered
ring having from 0-2 additional heteroatoms as ring s selected from N, O or S;
wherein the aliphatic or aromatic portion of R1 is r ally substituted with from 1-3
groups selected from C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, aryl, arylalkyl,
aryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl or –Rc,
each Rc is independently selected from halogen, -CN, -OH, -CH=CH2, -NH2, -
NO2, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, )NH2, -NHC(S)NH2, -
NHS(O)2NH2, -C(NH)NH2, -ORd, -SRd, -OC(O)Rd, -OC(S)Rd, -C(O)Rd, -C(S)Rd, -C(O)ORd,
-C(S)ORd, d, -S(O)2Rd, -C(O)NHRd, -C(S)NHRd, -C(O)NRdRd, -C(S)NRdRd, N
HRd, -S(O)2NRdRd, -C(NH)NHRd, -C(NH)NRdRd, -NHC(O)Rd, -NHC(S)Rd, -NRdC(O)Rd, -
NRdC(S)Rd, -NHS(O)2Rd, -NRdS(O)2Rd, -NHC(O)NHRd, -NHC(S)NHRd, -NRdC(O)NH2, -N
RdC(S)NH2, -NRdC(O)NHRd, -NRdC(S)NHRd, -NHC(O)NRdRd, -NHC(S)NRdRd, -NRdC(O)
NRdRd, -NRdC(S)NRdRd, -NHS(O)2NHRd, -NRdS(O)2NH2, -NRdS(O)2NHRd, -NHS(O)2NRd
Rd, -NRdS(O)2NRdRd , -NHRd, Rf or -NRdRd,
each Rd is independently selected from kyl, arylalkyl, aryl, heteroaryl,
heteroarylalkyl, lkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; and
wherein the aromatic portion of R1 is ally substituted with from 1-3 substituents
independently selected from Re,
Re is selected from the group consisting of halogen, -CN, -CH=CH2, -OH, -NH2, -
NO2, -C(O)OH, H, -C(O)NH2, -C(S)NH2, -S(O)2NH2, )NH2, -NHC(S)NH2, -
NHS(O)2NH2, -C(NH)NH2, -ORf, -SRf, -OC(O)Rf, -OC(S)Rf, -C(O)Rf, -C(S)Rf, -C(O)ORf, -
C(S)ORf, -S(O)Rf, -S(O)2Rf, -C(O)NHRf, -C(S)NHRf, -C(O)NRfRf, -C(S)NRfRf, -S(O)2NHRf
, -S(O)2NRfRf, -C(NH)NHRf, -C(NH)NRfRf, )Rf, -NHC(S)Rf, -NRfC(O)Rf, -NRfC(S
)Rf, -NHS(O)2Rf, -NRfS(O)2Rf, -NHC(O)NHRf, -NHC(S)NHRf, -NRfC(O)NH2, -NRfC(S)NH
fC(O)NHRf, -NRfC(S)NHRf, -NHC(O)NRfRf, -NHC(S)NRfRf, O)NRfRf, -NRfC
2, -NR
(S)NRfRf, -NHS(O)2NHRf, -NRfS(O)2NH2, -NRfS(O)2NHRf, )2NRfRf, O)2NRf
Rf , -NHRf, -NRfRf and Rf,
Rf is C1-6alkyl or aryl; or two adjacent R1 groups on the aryl or heteroaryl ring
together with the atoms to which they are attached form a 5- or 6-membered ring having from
0 to 2 onal heteroatoms selected from N, O or S, optionally substituted with from 1 to 3
Rd substituents;
10437476_1
R4 and R5 are each independently selected from the group consisting of H, C1-6 alkyl,
C3-8 lkyl, C3-8 cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl,
heteroaryl and heteroarylalkyl, wherein R4 or R5 is optionally substituted with from 1 to 3
members independently selected from C1-6 alkoxy, C1-6 haloalkyl, C1-6 koxy, C1-6 alkyl,
C3-8 cycloalkyl, C3-8 cycloalkylalkyl, cycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl or Rc; or
R4 and R5 taken together with the nitrogen atom to which they are attached form a
four to eight membered ring having from 0-2 additional atoms as ring members
selected from N, O or S, wherein said four to eight membered ring is optionally substituted
with from one to three groups independently selected from C1-6haloalkyl, C1-6 haloalkoxy, C1-
e; and
6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylalkyl, aryl, arylalkyl or R
R6, R7 and R8 are each ndently H, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy,
C3-8 cycloalkyl, C3-8 cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl,
heteroaryl, heteroarylalkyl or -X2R9; wherein the aliphatic or aromatic portion of R6, R7 and
R8 are each optionally substituted with from 1 to 3 members independently selected from the
group consisting of C3-8 cycloalkyl, C3-8 cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,
cycloalkylalkyl, heteroaryl, heteroarylalkyl and Re; or
any two of the R6, R7 and R8 groups taken together with the carbon atom to which
they are attached form a 3 to 8-membered carbocyclic ring or a 4 to 8-membered heterocyclic
ring having from 1 to 2 atoms as ring members selected from N, O or S, n the 3
to ered carbocyclic ring or the 4 to 8-membered heterocyclic ring is optionally
substituted with from one to three groups independently selected from C1-6 haloalkyl, C1-6
haloalkoxy, C1-6 alkyl optionally substituted with Re, C3-8 cycloalkyl, C3-8 cycloalkylalkyl,
aryl, arylalkyl, heteroaryl or heteroarylalkyl or Re.
Also described herein is a composition. The composition includes a compound of
any of formulas I to In, a compound as recited in any of the claims and described herein or a
pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable
excipient or carrier. The invention also provides a composition, which includes a compound
as d in the claims and described herein, a pharmaceutically acceptable excipient or
carrier, and another therapeutic agent.
Also described herein is a kit, which includes a compound of any of as I to
In, a nd as recited in any of the claims
10437476_1
and described , or a pharmaceutically acceptable salt or solvate thereof. The invention
also provides a kit, which includes a composition comprising a compound of formulas I to In,
a compound as recited in any of the claims and described herein, or a pharmaceutically
acceptable salt or solvate thereof.
In r aspect, the invention provides a method for preparing a compound of
formula (I) and any of the subgeneric formulas.
Also described herein is a method for treating a subject suffering from or at risk of
a protein kinase ed diseases or conditions. The method includes administering to the
subject an effective amount of a compound of any of formulas I to In, a compound as recited
in any of the claims and bed herein, or a pharmaceutically acceptable salt or solvate
thereof, or a composition comprising a compound of any of formulas I to In, a compound as
recited in any of the claims and described herein, or a pharmaceutically able salt or
solvate thereof.
10437476_1
039363—721 1
DETAILED DESCRIPTION OF THE INVENTION
1. Definitions
[(1010] As used herein the following definitions apply unless clearly indicated otherwise:
It is noted here that as used in this specification and the appended claims, the singular forms
"a," "an," and "the" include plural reference unless the context y dictates otherwise.
“Halogen” or “halo” refers to all halogens, that is, chloro (Cl), t1uoro(F), bromo (Br), or
iodo (l).
“Hydroxyl” or "hydroxy" refers to the group -OH.
“Thiol” refers to the group —SI-I.
The term ", by itself or as part of another substituent, means, unless otherwise stated, a
straight or ed Chain hydrocarbon, having the number of carbon atoms designated (ie. C 1-6
means one to six carbons). Representative alkyl groups include ht and branched chain alkyl
groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Further representative alkyl groups
include straight and branched chain alkyl groups having I, 2, 3, 4, 5, 6, 7 0r 8 carbon atoms.
Examples of alkyl groups include methyl, ethyl, n—propyl, isopropyl, n—butyl, t—butyl, isobutyl, scc—
butyl, n—pentyl, n—hexyl, n—heptyl, n—octyl, and the like. For each of the definitions herein (e.g., alkyl,
alkoxy, mino, alkylthio, alkylene, haloalkyl, kyl, cycloalkylalkyl, heterocycloalkylalkyl,
heteroarylalkyl), when a prefix is not included to indicate the number of carbon atoms in an alkyl
portion, the alkyl moiety or portion thereof will have 12 or fewer main chain carbon atoms or 8 or
fewer main chain carbon atoms or 6 or fewer main chain carbon atoms. For example, CH; alkyl refers
to a straight or branched hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms and includes, but are not
limited to, CM alkyl, CM alkyl, CM alkyl, C24 alkyl, CM alkyl, C24; alkyl, Cm alkyl, Cm alkyl and
C34, alkyl. “Fluoro substituted alkyl” denotes a alkyl group substituted with one or more fluoro atoms,
such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro
atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any
available atom to produce a stable compound, when optionally substituted alkyl is an R group of a
moiety such as ~~OR (cg. alkoxy), ~SR (e.g. thioalkyl), -NHR (e.g. alkylamino), ~C(O)NHR, and the
like, substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any 0, S,
or N of the moiety (except where N is a hetercaryl ring atom) es substituents that would result
in any 0, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the
alkyl carbon bound to any 0, S, or N of the moiety.
[0016} The term "alkylene" by itself or as part of another substituent means a linear or ed
saturated divalent hydrocarbon moiety d from an alkane having the number of carbon atoms
4811«7918—7726.1
039363—72 ll
indicated in the . For example, (i.e., CM means one to six carbons; Cm nc is meant to
include ene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene and the like). CM
alkylene includes methylene ~CH2‘, ethylene -CH2CH2~, propylene 'CI‘IQCI‘hCHQg and isopropylene
~CH(CH;)CH2~ , -CH2CH(CH3)—, ~CH2-(CH2)3CHg-, ~CHg-CH(CH3)CHg-, -CH2-C(CH3)2-,
—CH2-CH2CH(CH3)- . Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms,
with those groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms being preferred in the
present invention. When a prefix is not included to indicate the number of carbon atoms in an
alkylene portion, the alkylene moiety or portion thereof will have 12 or fewer main chain carbon
atoms or 8 or fewer main chain carbon atoms, 6 or fewer main chain carbon atoms
or 4 or fewer main
chain carbon atoms,
The term "alkenylene" refers to a linear bivalent hydrocarbon moiety or a branched
monovalent hydrocarbon moiety having the number of carbon atoms indicated in the prefix and
containing at least one double bond. For e, i.e., C24, means two to six carbons; C26 lene
is meant to include, but are not limited to, ~CH=CH—, —CH2~CH=CH~, ~CH2—CH=C(CH3)—, —CH=CH—
CH=CH-, and the like). Similarly, the term "alkynylene" refers to a linear bivalent hydrocarbon
moiety or a branched monovalent hydrocarbon moiety containing at least one triple bond and having
the number of carbon atoms indicated in the prefix. For e, (i.e., CM means two to six carbons;
C34, alkynlene is meant to include, but are not limited to, ~CEC~, 2—, ~CH2—CECCH2—, ~
CH3)~, and the like. When a prefix is not included to indicate the number of carbon atoms in
an alkenylene or alkynlene portion, the alkenylene moiety or portion f will have 12
or fewer
main chain carbon atoms or 8 or fewer main chain carbon atoms or 6 or fewer main chain carbon
atoms, or 4 or fewer main chain carbon atoms.
"Cycloalkyl" by itself or as part of r substituent, refers to saturated or unsaturated,
non—aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3—8,
more preferably
3-6, ring members per ring, such as cyclopropyl, cyclopentyl, eyelohexyl, l-cyclohexenyl, adamantyl,
and the like. Cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (eg,
C34; cycloalkyl means three to eight ring carbon atoms)
"Cycloalkylalkyl" refers to an —(alkylene)—cycloalkyl group where alkylene as defined herein
has the indicated number of carbon atoms or if unspecified having six or ferver, preferably four
fewer main chain carbon atoms; and cycloalkyl is as defined herein has the indicated number of
carbon atoms. cloalkylalkyl is meant to have 3 to 8 ring carbon atoms, Exemplary
cycloalkylalkyl include, e.g., cyclopropylmethylcne, cyclobutylethylene, cyclobutylrnethylene, and
the like.
"Haloalkyl," is meant to e alkyl substituted by one to seven halogen atoms. Haloalkyl
includes monohaloalkyl and polyhaloalhyl. For example, the term ” on; haloalkyl" is meant to include
trifluoromethyl, difluoromethyl, 2,2,2—trifluoroethyl, 4vchlorobutyl, 3-bromopropyl, and the like.
48117726.1
—7211
lkoxy" refers to a ~O—haloalkyl group, where haloalkyl is as defined herein, e. g.,
trifiuoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, and the like.
“Alkoxy” refers to a ~O-alkyl group, where alkyl is as defined herein. “Cycloalkoxy” refers
to a ~O-cycloalkyl group, where cycloalkyl is as defined herein. “Fluoro substituted alkoxy” denotes
alkoxy in which the alkyl is substituted with one or more fluoro atoms, where preferably the alkoxy is
substituted with l, 2, 3, 4 or S fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that
substitutions on alkoxy are attached at any available atom to produce a stable compound, substitution
of alkoxy is such that O, S, or N (except where N is a heteroaryl ring atom), are not bound to the alkyl
carbon bound to the alkoxy 0. Further, where alkoxy is described as a substituent of another moiety,
the alkoxy oxygen is not bound to a carbon atom that is bound to an O, S, or \l of the other moiety
(except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.
“Amino” or “amine" denotes the group -NH2.
“Alkylamino” refers to a "NH-alkyl group, where alkyl is as defined herein. Exemplary
alkylamino groups include CH3NH-, ethylamino, and the like.
ylamino” refers to a kyl)(alkyl) group, where each alkyl is independently as
defined herein. Exemplary lamino groups include dimethylamino, lamino,
ethylmethylamino, and the like.
“Cycloalkylamino” denotes the group -NRddR”, where Rdd and R°° combine with the
nitrogen to form a 5-7 membered heteroeycloalkyl ring, where the heterocyeloalkyl may contain an
additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with
alkyl. Alternatively, alkylamino” refers to a ~NH-cycloalkyl group, where cycloalkyl is as
defined herein.
“Alkylthio” refers to -S-alkyl, where alkyl is as defined herein. Exemplary alkylthio groups
include CH3S—, ethylthio, and the like.
“Aryl” by itself or as part of another tuent refers to a monocyclic, bicyclic or
polycyclic polyunsaturated aromatic hydrocarbon moiety containing 6 to 14 ring carbon atoms.
Non-iimiting examples of unsubstituted aryl groups e phenyl, ivnaphthyl, thyi and
4~biphenyl. Exemplary aryl group, such as phenyl or yl, which may be optionally fused with a
cycloalkyl of preferably 5-7, more ably 5-6, ring members.
"Arylalkyl" refers to ~(alkylene)-aryl, where the alkylene group is as defined herein and has
the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms
herein.
or four or fewer main chain carbon atoms; and aryl is as defined Examples of arylalkyl
include benzyl, phenethyl, and the like.
4811—7918-77261
039363-7211
“Heteroaryl” by itself or as part of another substituent refers to a monocyclic aromatic ring
structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to it) atoms, containing
one or more, preferably l—4, more preferably 1-3, even more preferably 1—2, heteroatoms
independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to
include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide ofa tertiary ring nitrogen. A carbon
or nitrogen atom is the point of attachment of the heteroaryl ring ure such that a stable
compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl,
pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl,
pyrimidinyl, pyrrolyl, lyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,
tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl, triazinyl, alinyl, cinnolinyl,
phthalaziniyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,
zofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, pyrimidinyl,
pyrazolopyrimidinyl, imidazopyridines, bcnzothiaxolyl, benzothienyl, quinolyl, nolyl,
lyl, pteridinyl and thiadiazolyl. “Nitrogen containing heteroaryl” refers to heteroaryl wherein
any heteroatoms are N.
"Heteroarylalkyl" refers to —(alkylene)-hetcr0aryl, where the alkylene group is as defined
herein and has the indicated number of carbon atoms, or if unspecified having six or fewer main chain
carbon atoms or four or fewer main chain carbon atoms; and heteroaryl is as defined herein.
Examples of arylalkyl include 2—pyridylmethyl, 2-thiazolylcthyl, and the like.
“lieterocycloalkyl” refers to a saturated or unsaturated non—aromatic cycloalkyl group that
contains from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur
atoms are optionally oxidized, and the nitrogen atom(s) are optionally nized, the remaining ring
atoms being C, where one or two C atoms may optionally be replaced by a yl. The
hcterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ring system of 3 to 12, preferably 4 to
ring atoms, more preferably 5 to 8 ring atoms in which one to five ring atoms are heteroatoms
selected from —N=, —N—, —O—, -S—, —S(O)-, or ~S(O)2— and further wherein one or two ring atoms are
optionally replaced by a -C(O)— group. The heterocycloalkyl can also be a heterocyclic alkyl ring
fused with a cycloalkyl, an aryl or a heteroaryl ring. Non limiting es of heterocycloalkyl
groups include pyrrolidinyl, piperidinyl, imidazolidinyl, lidinyl, butyrolactam ,
lactam moiety, imidazolidinone moiety, hydantoin, dioxolane moiety, phthalimide moiety,
piperidine, l,4~dioxane moiety, morpholinyl, thiomorpholinyl, thiomorpholinyl—S-oxide,
thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridine moiety, olinyl, thiopyranyl, pyrone
, tetrahydrofuranyl, tetrahydrothiophenyl, lidinyl, and the like, A heterocycloalkyl
of the molecule through a ring carbon or a heteroatom.
group can be ed to the remainder
"Heterocycloalkylalkyl" refers to —(all<ylene)-heterocycloalkyl, where the alkylcne group is
or fewer
as defined herein and has the indicated number of carbon atoms, or if unspecified having six
481177261
039363-7211
main chain carbon atoms or four or fewer main chain carbon atoms; and heterocyeloalkyl is as defined
. Examples of heterocycloalkylalkyl include 2—pyridylmethyl, 2—1hiazolylethyl, and the like
The substituents for alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl,
alkylene, lcne, alkynlene include. but are not limited to. R’, halogen, -OH, .NH;, —N02, —CN,
-C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, )2NH2,
—C(NH)NH2, —0R‘, -SR”, -OC(O)R‘, -OC(S)R‘, ’, -C(S)R‘, R’, -C(S)OR', —S(O)R’,
-S(O)2R’, -C(O)NHR’, -C(S)NHR’, -C(O)NR‘R", -C(S)NR'R”, -S(O)2NHR’, -S(O)2NR.R",
-C(NH)NHR‘, -C(NH)NR’R”, -NHC(O)R’, -NHC(S)R1, O)RV, S)R”, -NHS(0)2R’,
O)2R”, )NHR’, )NHR’, -NR’C(O)NH3, -NR’C(S)NH2, -NR!C(O)NHR",
-NR’C(S)NHR”, -NHC(O)NR’R”, -Ni~iC(S)NR‘R”, -NR’C(0)NR”R”’, -NR”’C(S)NR=R",
—NHS(O)2NHR’, -NR’S(O)2NH2, -NR’S(O)3NHR”, -NHS(O)2NR’R”, -NR’S(0)2NR”R”’, NPR, and
—NR’R” in a number ranging from zero to (2m’+l ), where m’ is the total number of carbon atoms in
such group. R’, R” and R’” each independently refer to hydrogen, CH; alkyl, heterocycloalkyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, aryl substituted with 1—3 halogens, Crg alkoxy, haloalkyl,
haloalkoxy or Cl—s thioalkoxy groups, or unsubstituted aryl-Cm alkyl . When R’ and R” are
attached to the same en atom, they can be combined with the nitrogen atom to form a 3-, 4—, 5—,
6—, or 7—membered ring. For example, —NR’R” is meant to include l—pyrrolidinyl and 4-morpholiny1.
R’, R” and R’” can be further substituted with R“, n, —OH, —NH2, —NO;, —CN, —C(O)OH,
—C(S)OH, -C(O)NH3, -C(S)NH2, —S(O)2NH2, -NHC(O)N Hg, —NHC(S)NH2, —NHS(O)2NH3,
—C(NH)NH2, —0Ra‘, —SR"', -OC(O)R“, -OC(S)R“, —C(O)Ra‘, ‘”, —C(O)OR‘”, R"”,
a‘, —S(O)2R‘”, —C(O)NHR“, HR‘”, -C(O)NR"'R”2, —C(S)NRE”R32, —S(O)2NHR“,
—S(O)2N Ra‘R”, —C(NH)NHR3', -C(NH)NR“Ra2, -NHC(O)R“', -NHC(S)R"“, —NR"‘2C(O)R“,
—NR‘”C(S)R"3, —NHS(O)2R“‘, -NRa‘S(O)2Ra2, -NHC(O)N HR“, -NHC(S)NHR"“, —NR“1C(O)NHZ,
—NR‘“C(S)NH2, -NR‘“C(O)NHR32, -NR“C(S)NHRZ‘2, -NHC(O)NR“R32, )NR"“R32,
—NR3‘C(O)NR“2R“3, -NR“3C(S)NR“'R“2, -NHS(O)2NHR”', -NR”‘S(O)3NH2, -N R“S(O)2NHR“2,
-NHS(O)2NR‘“R“2, -NR“S(O)2NR*’2R"3, -NHR“, and ~NR3'Ra2 in a number ranging from zero to
(2n’+l), where n’ is the total number of carbon atoms in such group. R“, R32 and R“3 each
independently refer to hydrogen, Clog alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, aryl substituted with 1-3 halogens, Ci-g alkoxy, haloalkyl, haloalkoxy or (31-3
thioalkoxy groups, or unsubstituted aryl-Cm alkyl groups. R“, R32 and R33 can be further substituted
with R“, halogen, OH. —NH;, ~Noz, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH3, »S(O)2NH2,
-Nncmwng, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR‘”, -512“, carom“, comm“,
-C(O)Rb‘, -C(S)Rb‘, -C(0)0Rb’, -C(S)0R”‘, -S(O)R‘”, -S(O)2Rb’, -C(O)NHR“, HRM,
—C(0)NR"‘R"2, —C(5)NRb‘Rb2, -S(O)2NHR“, —S(O)2NRb'RbZ, —C(NH)NHR“, —C(NH)NR'°‘R“,
—NHC(O)R“, -NHC(S)R“, —NRb2C(O)RN, -NR'“C(S)R"2, -NHS(O)3R“, —NRb‘S(O)2Rb2,
~NHC(O)NHRH, -quswnah', -NR"’C(O)NI~I;, ~NRE'1C(S)NI'12, ~NRh‘C(O)NHRb2,
NRMQSWHRE, -NHuomkmkbi «NHCtSWRMsz, ”NRblquNRbgR“, —NRb3C(S)NR“RW,
481177261
0393 63-721 1
-NHS(O)2NHRb’, —NR"‘S(O)2NH2, -NRh'S(O)2NHRb2, )2NR”‘R"3, —NR“‘S(0)2NRb2Rb3,
—NHRM, and «NRb'RbZ in a number ranging from zero to (2p’+l), where p’ is the total number of
carbon atoms in such group. R“, sz and RB each independently refer to hydrogen, CH; alkyl,
heterocyeloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens! (31-3
alkoxy, haloalkyl, haloalkoxy or Crg thioalkoxy groups, or unsubstituted I-s alkyl groups.
Substituents for the aryl and heteroaryl groups are varied and are generally selected from: R’,
halogen: on, —N H;, -N02, —CN, H3 -C(S)OH, -C(O)NH2, -C(S)NH2¢ -S(O)2NH2,
)NH2, —NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR‘, -SR’, -OC(O)R4, -OC(5)R’., l,
-C(S)R’, -C(O)OR’, -C(S)OR‘, -S(O)R’, -S(O);R’, -C(O)NHR’, -C(S)NHR’, -C(O)NR’R", -C(S)NR'R“,
-S(O)2NHR’, -S(0)2NR’R”, -C(NH)NHR‘, ~C(NH)NR‘R”, )R’, -NHC(S)R’, -NR”C(O)R’,
-NR’C(S)R”, -NHS(O)2R’, -NR’S(O)2R”, -NHC(O)NHR‘, -NHC(S)NHR=, -NR’C(O)NH2,
-NR’C(S)NH2, -NR€C(O)NHR", -NR’C(S)NI-IR”, -NHC(O)NR’R”, -NHC(S)NR’R”,
—NR‘C(0)NR”R”’, —NR”’C(S)NR’R”, -NHS(0)2NHR’, -NR'S(O)2NH2, -NR‘S(0)2NHR",
and ro(C]—
-NHS(O)2N R’R”, 0)2NR”R”’, -NHR’, -NR‘R", -Ng, perfluoro(C1-C4)alk0xy,
aromatic ring
C4)alkyl, in a number ranging from zero to the total number of open valences on the
selected from hydrogen, kyl, haloalkoxy,
system; and where R’, R” and R’” are independently
Cpg alkyl, CM cycloalkyl, cycloalkylalkyl, CM alkenyl, Cm alkynyl, aryl: arylalkyl, heteroaryl,
arylalkyl, aryl-Cm alkyl, and aryloxy-C1-4 alkyl. Other suitable substituents include each of the
1-4 carbon atoms.
above aryl substituents attached to a ring atom by an alkylene tether of from R’, R”
and R’” can be further substituted with R“, halogen, -OH, -NH2, -NO;, —CN, —C(O)OH, I'I,
-C(O)NH2, H2, —S(O)2NH2, )NH2, -NHC(S)NH2, ~NHS(O)2NH3, NH2,-OR31,
511“, -OC(O)R“‘, -OC(S)R“, —C(O)R‘”, -C(S)R‘”, -C(O)OR‘”, -C(S)OR“, -S(O)R“, -S(O)2R“,
-C(O)NHR‘“, -C(S)NIVIR“‘, -C(O)NR“R“2, R‘”R”, -S(0)2NHR“, -S(O)2NR“R32,
NHR‘”, —C(NH)NR81R“2, -NHC(0)R“1, —NHC(S)R“1, -NR1*ZC(O)R“, -NR‘”C(S)R“2,
—NHS(O)2Ra', -NR“’S(O)2Ra2, -NHC(O)NHR‘“, —NI'IC(S)NHR“‘, ~NR“C(O)NH3, -NR“C(S)NH2,
-NR‘”C(O)NHR32, (S)NIVIR“2, -NHC(O)NR“1R32, —NHC(S)NR“R“3, -NR“‘C(O)NR32R”,
—NRa3C(S)NR“Ra2, -NHS(O)2NHR31, -NR“S(O)2NH2, -NR“S(O)ZNHRa2, -NHS(O)3NR3‘Ra2,
—NR“'S(O)2NR“2R33, ,—NR‘”R“Z, .Ng, perfluor0(Cl—C4)alkoxy, and perfluoro(C1-C4)alkyl; in a
number ranging from zero to the total number of open valences on the aromatic ring system;
where R“, R“2 and RaB‘ are each independently selected from hydrogen, haloalkyl, haloalkoxy, C1 -3
alkyl, (13-5 cycloalkyl, cycloalkylalkyl, C24; alkenyl, C13 alkynyl, aryl, arylalkyl, heteroaryl.
heteroarylalkyl, aryl-Cm alkyl, or y-Cm alkyl. Other le substituents include each of the
1-4 carbon atoms.
above aryl substituents attached to a ring atom by an alkylene tether ot‘from
When two substituents are present on adjacent atoms of a substituted aryl or a substituted
formula ~—
heteroaryl ring, such substituents may optionally be replaced with a substituent of the
and q is an
T—C(O)~(CH3)q—U-, wherein T and U are independently ~NH’, ‘Ou, »CH;— er a single bond:
integer of from 0 to 2. Alternatively, when two substituents are present on adjacent atoms of a
4811~7918-7726i1
039363-7211
substituted aryl or a substituted heteroaryl ring, such substituents may optionally be replaced with a
tuent of the formula ~A-(CHg)r-B-, wherein A and B are independently ~Cl"lg-, -O—, —NHo, —S-, —
S(O)o, -S(O)g-, -S(O)3NR’- or a single bond, and r is an r Of from 1 to 3. One of the single
bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, when
two substituents are present on nt atoms of a substituted aryl or a substituted aryl ring,
such substituents may optionally be replaced with a substituent of the formula -(CH3),-X—(CH3),-,
where s and t are independently integers of from 0 to 3, and X is -O-, -NR’-, —S-, -S(O)-, -S(O)2-, or -
S(O)2NR’—. The substituent R’ in -NR’— and -S(O)2NR‘— is selected from hydrogen or unsubstituted
C; as alkyl.
"Protecting group” refers to a grouping Of atoms that when attached to a reactive group in a
molecule masks, s or prevents that reactivity. Examples of protecting groups can be found in
T.W. Greene and PG. Wuts, TIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006),
Beaucage and Iyer, Tezraliedran 3-231 l , and Harrison and Harrison et 61].,
COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols. 1-8 (John Wiley and Sons. 197l~1996).
Representative amino protecting groups include formyl, , trifluoroacetyl, benzyl,
benzyloxycarbonyl (CBZ), I'ert-butoxyearbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-
ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-
fluorenylmethyloxycarbonyl (FMOC), veratryloxycarbonyl (NVOC), tI‘i-isopropylsilyl (TIPS),
phenylsulphonyl and the like (see also, Boyle, A. L. (Editor), carbamates, amides, N—sulfonyl
derivatives, groups of formula -C(O)OR, wherein R is, for example, , ethyl, t-butyl, ,
phenylethyl, CH2=CHCH2—, and the like, groups of the formula ’, wherein R' is, for example,
methyl, phenyl, trifluoromethyl, and the like, groups ofthe formula ~SOZR", wherein R" is, for
example, tolyl, phenyl, tritluoromethyl, 2,2,5,7,8—pentamethylchroman~6~yl, 2,3,6-trimethyl
methoxyphenyl, and the like, and silanyl containing groups, such as 2-trimethylsilylethoxymethyl,
t-butyldimethylsilyl, triisopropylsilyl, and the like, CURRENT PROTOCOLS IN NUCLEIC ACID
CHEMISTRY, John Wiley and Sons, New York,Volume l, 2000).
As used herein, the term “composition” refers to a formulation suitable for administration to
an intended animal subject for therapeutic purposes that contains at least one phamiaceutieally active
compound and at least one ceutically acceptable carrier or excipient.
10039] The term “pharmaceutically acceptable” indicates that the indicated material does not have
properties that would cause a reasonably prudent medical practitioner to avoid administration of the
material to a patient, taking into consideration the disease or conditions to be treated and the
tive route of administration. For example, it is commonly required that such a material be
essentially sterile, eg, for ibles,
[0040} "Pharmaceuticaliy-acceptable salt” refers to a salt which is acceptable for administration to a
patient, such as a mammal (cg, salts having able mammalian safety for a given dosage
48117726.1
039363—7211
regime). Such salts can be derived from pharmaceutically-acceptablc inorganic or c bases and
from pharmaceutically—acceptable inorganic or organic acids= depending on the particular substituents
found on the compounds described herein. When compounds of the present invention n
relatively acidic functionalities, base addition salts can be obtained by contacting the l form of
such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
Salts derived from pharmaceuticaliy— acceptable inorganic bases e aluminum, ammonium,
calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc
and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary,
ary, tertiary and quaternary amines, including substituted amines, cyclic amines, naturallyoccurring
amines and the like, such as arginine, betaine, caffeine, choline, N, N'-
ylethylenediaminc, diethylamine, 2-dicthylaminoethanol, 2- dimethylaminoethanol,
lamine, ethylenediamine, N—ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, metliylglucamine, morpholine, piperazine, piperidine,
polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine,
tromethamine and the like. When nds of the present ion contain relatively basic
functionalities, acid addition salts can be obtained by contacting the neutral form of such nds
with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived
from pharmaceutically—acceptable acids include acetic, ascorbic, esulfonic, benzoic,
camphosulfonic, citric, ethanesulfonic, fumaric, gluconic, glucoronic, glutamic, hippuric,
hydrobromic, hydrochloric, isethionic, lactic, ionic, maleic, malic, mandelic, methanesulfonic,
mucic, naphthalenesulfonic, nicotinic, , pamoic, pantothenic, phosphoric, ic, ic,
tartaric, p—toluenesulfonic and the like.
Also included are salts of amino acids such as te and the like, and salts of organic
acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M. et al,
"Pharmaceutical Salts", J. ceutical Science, 1977, 66:1 -l9). Certain specific compounds of the
present ion contain both basic and acidic functionalilies that allow the compounds to be
converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or
acid and isolating the parent compound in the conventional manner. The parent form of the compound
differs from the various salt forms in certain physical properties, such as solubility in polar solvents,
but otherwise the salts are equivalent to the parent form of the compound for the purposes of the
present invention.
In the present context, the term “therapeutically effective” or "effective amount" indicates
that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more
symptoms of a disease or medical ion, and/or to prolong the survival of the subject being
treated.
4811-7918‘77261
039363—7211
effect” indicate
In the present context, the terms “synergistically effective” or “synergistic
in combinations e
that two or more compounds that are euticaliy effective, when used
based on the
improved therapeutic effects greater than the additive effect that would be expected
effect of each compound used by itself.
of data
By “assaying” is meant the creation of experimental conditions and the gathering
regarding a ular result of the exposure to c experimental conditions. For example,
their ability to act upon a detectable substrate. A compound can be
enzymes can be assayed based on
assayed based on its ability to bind to a particular target molecule or molecules.
refer to a
As used herein, the terms d” and “modulator” are used equivalently to
compound that changes (i.e., increases or ses) the activity of a target biomolecule, eg, an
enzyme such as a kinase. Generally a ligand or modulator will be a small molecule, where “small
1000
molecule refers to a compound with a molecular weight of 1500 daltons or less, or preferably
daltons or less, 800 daltons or less, or 600 daltons or less. Thus, an “improved ligand” is one that
and/or pharmacokinetic properties than a reference compound,
possesses better pharmacological
where “better” can be defined by one skilled in the relevant art for a particular biological system
therapeutic use.
The term “binds” in connection with the interaction between a target and a potential binding
statistically
compound indicates that the potential binding compound associates with the target to a
significant degree as compared to association with ns generally (119., non—specific g).
Thus, the term “binding compound” refers to a compound that has a statistically significant
association with a target molecule. Preferably a binding nd interacts with a specified target
with a dissociation constant (KD) ofl mM or less, 1 LEM or less, 100 nM or less, 10 nM or less, or
nM or less.
and tive"
in the context of compounds binding to a target, the terms “greater affinity”
than the same
indicates that the compound binds more tightly than a reference compound, or
compound in a reference condition, tie“. with a lower iation nt. In some ments,
the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, l000, or 10,000-fold greater
affinity.
{0049] As used herein in connection with compounds of the invention, the term “synthesizing”
materials.
like terms means chemical synthesis from one or more sor Further, by “assaying” is
ofdata regarding a particular result of
meant the creation of experimental conditions and the gathering
the experimental conditions. For example, enzymes can be d based on their ability to act upon
can be assayed based on its ability to bind to a
a detectable substrate. A compound or ligand
particular target molecule or les.
4811491837263
039363-7211
As used herein, the term “modulating” or “modulate” refers to an effect of altering a
ical activity, especially a biological ty associated with a particular ecule such as a
protein kinase. For example, an agonist or antagonist of a particular biomolecule modulates the
activity of that biomolecule, cg, an enzyme, by either increasing (e. g. agonist, activator), or
decreasing (eg. antagonist, inhibitor) the activity of the biomolecule, such as an enzyme. Such
concentration
activity is typically ted in terms of an inhibitory concentration (K350) or excitation
(ECSO) of the compound for an inhibitor or activator, respectively, with respect to, for example, an
enzyme.
"Prodrugs" means any compound which releases an active parent drug according to Formula
l in vivo when such prodrug is administered to a ian subject. Prodrugs of a nd of
such
Formula I are ed by modifying functional groups present in the compound of Formula I in
the parent compound.
a way that the modifications may be cleaved in vivo to release Prodrugs may be
prepared by modifying functional groups present in the compounds in such a way that the
modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
Prodrugs e compounds of Formula I n a hydroxy, amino, carboxyl or sulfhydryl group
be cleaved in vivo to regenerate the free
a compound of Formula I is bonded to any group that may
hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodru gs include, but are not limited
carbamates (cg, N,N-
to esters (e.g, acetate, formate, and benzoate derivatives), amides, ines,
ylaminocarbonyl) of hydroxy functional groups in compounds of Formula l, and the like.
Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as
ed. H.
Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series; "Design ofProdrugs",
Bundgaard, er, 1985; and in Bioreversible rs in Drug , ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby
incorporated by reference in their entirety.
"Tautomer" means compounds produced by the phenomenon wherein a proton of one atom
of a molecule shifts to another atom. See, Jerry March, Advanced Organic Chemistry: Reactions,
Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992). The tautomers
converted
also refer to one of two or more structural s that exist in equilibrium and are readily
from one isomeric form to another. Examples of include keto—enol tautomers, such as acetone/proper»
2~ol, imine~enaminc tautomers and the like, hain tautomers, such as glucose/2,3,45,6—
pentahydroxyhexanal and the like, the tautomerie forms of heteroaryl groups containing a —N=C(I—l)~
tetrazoies.
NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoies, and
tautomeric
Where the compound ns, for example, a keto or oxime group or an aromatic moiety,
isomerism (‘tautomerism’) can occur. The compounds bed herein may have one or more
in the art would ize
tautomers and therefore include various isomers. A person of ry skill
that other tautomeric ring atom arrangements are possibie. All such isomeric forms of these
compounds are expressly included in the present invention.
4311—791847261
—7211
in the nature or
"lsomers" mean compounds having identical molecular formulae but differ
in the arrangement of their atoms in space. lsomers that differ
sequence of bonding of their atoms or
"Stereoisomer" and
in the arrangement of their atoms in space are termed "stereoisomers".
forms if they possess one or
"stereoisomers" refer to compounds that exist in different stereoisomeric
substitution and, therefore, can be
more asymmetric centers or a double bond with asymmetric
produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and
diastereomers. Stereoisomers that are not mirror images of one another are termed “diastereomers”
termed “enantiomers”. When
and those that are non-superimposable mirror images of each other are
for example, it is bonded to four different groups, a pair of
a compound has an asymmetric center,
absolute configuration of its
enantiomers is possible. An omer can be characterized by the
asymmetric center and is described by the R- and S-sequencing rules of Calm and Prelog, or by
of polarized light and designated as rotatory or
manner in which the molecule s the plane
chiral compound can exist as either individual
tatory (119., as (+) or (-)—isomers respectively). A
of the enantiomers is
omer or as a mixture thereof. A mixture ning equal proportions
called a “racemic mixture”. Unless otherwise indicated, the description is intended to e
of stereochemistry
individual stereoisomers as well as mixtures. The methods for the determination
discussion in r 4 of
and the tion of stereoisomers are well—known in the art (see
John Wiley and Sons, New York, 2007)
ADVANCED C CHEMISTRY, 6th n J. March,
differ in the chirality of one or more stereocenters.
well as solvated
Certain compounds of the present invention can exist in unsolvated forms as
forms, including hydrated forms. “Hydrate" refers to a complex formed by combination of water
molecules with les or ions of the solute. "Solvate" refers to a complex formed by combination
solvent can be an organic compound,
of solvent molecules with molecules or ions of the solute. The
e is meant to include hydrate. Some examples of
an inorganic nd, or a mixture of both.
solvents include, but are not limited to, ol, N,N—dimethylformamidc, tetrahydrofuran,
dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms
invention. Certain compounds of the present
are encompassed within the scope of the present
invention may exist in multiple crystalline or amorphous forms. in general, all physical forms are
intended to be within the scope
equivalent for the uses contemplated by the present invention and are
of the present invention)
that are or may be modulators,
In the context of the use, testing, or screening of compounds
be in sufficient proximity to a
the term “contacting” means that the compound(s) are caused to
material that potential binding
particular molecule, complex, cell, , organism, or other specified
other specified material can occur.
ctions and/or chemical reaction between the compound and
that is treated with compounds
{0956} As used herein, the term “subject” refers to a living organism
such as a human, other primates, sports
as described herein, including, but not limted to, any mammal,
481 1191847264
039363—721 1
such as
animals, animals of cial interest such as cattle, farm animals such as horses, or pets
dogs and cats.
of a
“Solid form” refers to a solid preparation (its. a preparation that is neither gas nor liquid)
animal subject for
ceutically active compound that is suitable for administration to an intended
therapeutic es. The solid form includes any complex, such as a salt, co—crystal or an
form may be
amorphous complex, as well as any polymorph of the compound. The solid
form may be
substantially crystalline, semi-crystalline or substantially amorphous. The solid
stered directly or used in the preparation of a suitable composition having improved
pharmaceutical properties. For example, the solid form may be used in a formulation comprising at
least one phannaceutically acceptable carrier or excipient.
without limitation,
{0058] “Pain” or a “pain condition” can be acute and/or chronic pain, including,
back
arachnoiditis; tis (e.g. osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout);
burn pain; cancer pain;
pain (eg. sciatica, ruptured disc, lolisthesis, radiculopathy);
head and facial pain
dysmenorrhea; headaches (e.g. migraine, cluster headaches, tension hes);
inflammatory pain (eg. pain
(cg. l neuralgia, trigeminal neuralgia); hyperalgesia; hyperpathia;
ulcerative colitis, Crohn‘s
associated with irritable bowel me, atory bowel disease,
keloid or scar tissue formation; labor
disease, cystitis, pain from bacterial, fungal or viral infection);
result of polymyositis, dermatomyositis, inclusion body
or delivery pain; muscle pain (e.g. as a
tendonitis,
myositis, repetitive stress injury (e.g. writer’s cramp, carpal tunnel syndrome,
tenosynovitis)); myofascial pain syndromes (e.g. algia); neuropathic pain (e.g. diabetic
neuralgia, gout,
neuropathy, causalgia, entrapment neuropathy, brachial plexus avulsion, occipital
reflex sympathetic dystrophy syndrome, phantom limb or post-amputation pain, rpetic
disease (e. g.
neuralgia, central pain syndrome, or nerve pain resulting from trauma (e.g. nerve injury),
diseases
es, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis, neurodegenerative
l sclerosis, or cancer treatment);
such as Parkinson's disease, Alzheimer's disease, amyotrophic
skin tumors, cysts,
pain ated with skin disorders (e.g. shingles, herpes simplex,
neurotibrmnatosis); sports injuries (eg. cuts, sprains, strains, bruises, dislocations, res, spinal
disorders; vascular
chord, head); spinal stenosis; surgical pain; tactile allodynia; temporomandibular
ischemia,
disease or injury (eg. vasculiiis, coronary artery disease, reperfusion injury (eg, ing
ocular pain, corneal pain,
stroke, or myocardial ts)); other specific organ or tissue pain (eg.
dental pain,
bone pain, heart pain, visceral pain (e. g. kidney, gallbladder, gastrointestinal), joint pain,
other disease associated pain
pelvic hypersensitivity, pelvic pain, renal colic, urinary incontinence);
endometriosis, asthma, chronic obstructive
(eg. sickle cell anemia, AIDS, herpes zoster, psoriasis,
heart burn,
pulmonary disease , silicosis, pulmonary sarcoidosis, esophagitis,
bone tion
gastroesophageal reflux disorder, stomach and duodenal ulcers, functional dyspepsia,
due to graft v. host rejection or
disease, osteoporosis, cerebral malaria, bacterial meningitis); or pain
afi rejections.
48117918517261
039363—7211
administration to treat a
”Unit dosage form" refers to a composition intended for a single
subject suffering from a e or medical condition. Each unit dosage form typically comprises
Examples
each of the active ingredients of this invention plus pharmaceutically able exeipients.
bulk powders, liquid solutions,
of unit dosage forms are individual tablets, individual capsules,
Treatment of the disease or
nts, , eye drops, itories, emulsions or suspensions.
for example: one unit dosage
ion may require periodic administration of unit dosage forms.
hours or other interval, or only one
form two or more times a day, one with each meal, one every four
unit dosage form" indicates a unit dosage form designed to be taken
per day. The expression "oral
orally.
of atomic
The compounds of the present invention may also contain ral proportions
For example, the compounds
isotopes at one or more of the atoms that constitute such compounds.
radioactive isotopes, such as for example tritium (3H), iodine-125 (ml) or
may be radiolabeled with
whether
carbon—l4 (MC). All isotopic variations of the compounds of the present invention,
of the present invention.
radioactive or not, are intended to be encompassed within the scope
acid sequence, the term “isolate”
As used herein in connection with amino acid or nucleic
of the amino acid and/or nucleic acid
indicates that the ce is separated from at least a portion
be associated.
sequences with which it would normally
indicates that the
In connection with amino acid or c sequences, the term “purified”
of the biomolecules in a composition
subject molecule constitutes a significantly greater proportion
in a cell culture. The greater proportion can
than the tion observed in a prior composition, e.g.,
the tion found in the prior
be 2—fold, 5—fold, 10—fold, or more than 10—fold, with respect to
composition.
of the present invention which
The invention also embraces ically—labeled compounds
for the fact that one or more atoms are replaced by an atom
are identical to those recited herein, but
atomic mass or mass number usually found
having an atomic mass or mass number different from the
of the ion include
in nature. Examples of isotopes that can be incorporated into compounds
fluorine, and chlorine, such as, but not
isotopes of en, carbon, nitrogen, oxygen= phosphorous,
limited to 2H (deuterium, D), 3H (tritium), ”c, 13C, ”C, ”N, ‘81:, “153213353, 36Ci, and ”51.
Unless
otherwise stated, when a on is designated specifically as "H" or "hydrogen", the position
its isotopes, such as
understood to have hydrogen at its natural abundance isotopic composition or
deuterium (D) or m (3H). Certain isotopically-labeled compounds of the present invention (cg,
in compound andfor substrate tissue distribution
those labeled with .sup.3H and .sup. l4C) are useful
for their case of preparation
assays. Tritiated (i.e., 3H) and carbon-l4 (i.e., MC) isotopes are useful
such as deuterium (i.e., 2H) may afford
and detectability. Further, substitution with heavier isotopes
increased in vivo half-
certain therapeutic advantages resulting from greater metabolic ity (cg,
in some circumstances. lsotopically
life or reduced dosage requirements) and hence may be preferred
4811791817261
039363—7211
labeled compounds of the present invention can generally be prepared by following procedures
analogous to those disclosed in the Schemes and in the Examples herein below, by tuting an
isotopically labeled reagent for a non—isotopically labeled reagent.
II. General
The present invention concerns compounds of Formula I and all sub—generic formulae,
compounds as recited in the claims, and compounds described herein that are modulators of protein
of the kinases
kinases, for example without limitation, the compounds are modulators of at least one
selected from the group consisting of ABLl, ABLZ, ACK, ADRBKl, AKTl, AMPK_A2, A-RAF,
ARKS, Aurora_A-C, BMX, CDC42‘ BPA, CAMK2A, CDK5_p35, CSFlR, DYRKIB, EPl—IAS,
EPHA8, EPHB4, FES, FLT3, FYN,GSK3B,JAK1, KDR, Kl'l‘, MAP4K2, MAPK3, MARKZ,
MARK4, MATK, MET, MINKI, NEK], NEKZ, PAK3, PAK6, PDGFRb, PHKGI, PKC_beta_l,
PKC_beta_II, PKC_delta, PKC_gamma, PKC_zeta, SRC, STK24, STK4, ACVR1B_(ALK4),
ADRBK2_(GRK3), (PKBb), PKBg), ALK, AMPK__Al/B l/Gl, ARKS, ASKI, AXL,
BRSK1_(SAD1), BrSKZ, BTK, CAMK], CAMKID, CAMKZA, CAMKZB, CAMKZD,
CaMKldelta, CaMKllbeta, elta, CaMKIIgamma, CDC42_BPB, CDKl/CyclinB,
CDKZ/CyclinA, CDKZ/cyclinE, CDK3/cyclinE, CDK5_p25, CDK6/cyclinD3,
yclinH/MNAT1, CDK9/CyclinTl, CHEK] , CHEK2, CKldelta, CKlgammal,
CKl gammaz, CKlgamma3, CK2alpha2, CLKl, CLKZ, CLK3, CSNKlAl, CSNKlD, CSNKlE,
CSNKlGl, CSNKIGZ, CSNK1G3, CSNKZAI, CSNK2A2, DAPK], DAPKZ, DAPK3_(ZIPK),
2_(DCK2), DDR2, DMPK, DRAKI, DYRKIA, DYRKZ, DYRKB, DYRK4, EEF2K,
ERBB4, FER,
EGFR, EPHAl, EPHAZ, EPHA3 EPHA4, EphA7, EPHBl, EPHBZ, EPHB3, ERBBZ,
FGFRl, FGFR2, FGFR3, FGFR4, FLT], FLT4, FRAP1,GCK, GRK4, GRKS, GRK6, GRK7,
IGFl R, IGF—l R—
GSK3A, GSK3B, Haspin, HCK, Hck activated, HIPK, HIPK2, HlPKB, HIPK4,
ted, lKBKB, IKBKE, IKKalpha, lKKbeta, INSR, INSRR, IR-activated, IRAKI, IRAK4, lTK,
JAKZ, JAK2__JHlWJH2, JAK3, JNKlalphal, JNK2a|pha2, Lek—activated, LIMKI, LKBl, LOK,
LTK, MAP2K1, MAP2K2, MAP2K6, MAP3K8, MAP3K9, MAP4K4, MAPKl, MAPKIO,
MAPKI l, MAPK12, MAPKlB, MAPKl4, MAPK2, MAPKS, MAPK9, MAPKAPKZ, MAPKAPK3,
MAPKAPKS, MARK}, MARK3, MELK, MERTK, MKK7beta, MLCK, MRCKalpha, ta,
NTRKl,
MS'l‘lR, MST4, mTOR/FKBPlZ, MUSK, NEK3, NEK4, NEKG, NEK7, NEK9, NLK,
NTRKZ, NTRKB, FAKE/3: PAKd, PAK7‘(KIAA1264), lpha. PASK, lpha,
PDGFRbem, PDKI, PIIKGZ, PthammaZ, PIK3CA/PIK3R1. PIK3CG,) Pl‘Ml, PIMZ, Pith-3,
PKBalpha, a, PKBgamma, PKCalpha, PKCbetal, PKCbetall, PKCdelta, ilon,
PKCeta, PKCgamma, PKCiota, PKCmu, PKCtheta, a, PKGlalpha, PKGlbeta, PKNI,
PRKDl,
PLKZ, PLK3, PR'KZ, PRKACA, PRKCA, PRKCE, PRKCH, PRKCI, PRKCN, PRKCQ,
PRKDZ, PRKGl, PRKGB, PRKX, PTKZ, PTKZB, RET, RIPKZ, ROCKl, ROCKZ, ROSl,
RPSGKAL RPS6KA2, RPSéKAS, zt, RPSfiKAS, 6, Rl’SéKBl, SGK, SGKE,
STK33,
SGKL, SlK, SNFlLKQ, Snk, SRPKl, SRPKZ, STKZEB, STK22D, STK23, STK25, STK3,
48117918377261
039363-7211
SYK, TAKI, TAOB, TAOKZ, TBKl, Tee activated, TEK, TLKZ, Txk, TYK2, TYRO3, ULKB,
ULK3, VRK2, WNKZ, WNKB, and ZAP70 and the use of such compounds in the treatment of
es or conditions. In some embodiments, the kinases have less than 20% Inhibition at 1 uM. In
other embodiments, the kinases have less than 10% Inhibition at l uM.
III. Compounds
In one , the present ion provides compounds of formula (I):
Y2 \ /
yl (I?
\ HN—S—Z
[ \ F
N 8
H I
and pharmaceutically able salts, hydrates, solvates, tautomers and isomers thereof; wherein the
substituents are as defined in the Summary of the Invention.
In some embodiments of compounds of a (I), YI is as defined in the summary of the
invention. The All the other substituents of formula (I) are as defined in
any of the embodiments
described herein. In some preferred embodiments, the compounds have molecular s less than
600, more preferably, the compounds have molecular weights less than 550. In other red
ments, the compounds have molecular s less than 500.
In some embodiments of compounds offormula (I), Y’ is CN, halogen, -0H, CH, alkyl, CM
alkoxy, Cgeécycloalkyl, CH, haloalkyl, CH; haloalkoxy, aryl or heteroaryl, wherein the aliphatic or
aromatic portion of Y1 is each independently optionally substituted with from 1-5 RI substituents;
each R1 is independently selected from CH, alkyl, CH, , C14, haloalkyl, CH, haloalkoxy, (33.3
cycloalkyl, C3_g cycloalkyl-C1_4-alkyl, aryl, arylalkyl, heteroaryl, arylalkyl, heterocycloalkyl,
heterocy'cloalky'l-C1.4 alkyl or ~Ra, wherein R3 is selected from halogen, -CH=CH2, -CN, -OH, —NH2, -
N02, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)N H2, NIIZ, —NHC(O)NHZ, -NHC(S)NH2,
-\1_HS(O)2NH2, —C(NH)NH2, on”, -SRb, -OC(O)R", —OC(S)Rb, mom”, -C(S)Rb, ~canon",
-C(S)0Rb, -S(0)R‘”, -S(O)2R.b, HRb, -C(S)NHRb, -C(O)NRbRb, -C(S)NRbR", -stonNHRb,
-S(0)2NRbRb, wC(rnnnnnb, cmnwabn‘l’, -NIIC(O)Rb, -NHC(S)R*’, -Nnbctom’: «nnbcrsmb,
~NHS(O)3Rh, -NR”‘S(O)2Rb, -NHC(O)NHR”, ~NHC(S)NHR", O)NI h, -NR"C(S)NH3,
eNRbC(O)NHRb, -NRbC(S)NHRb, -NHC(O)NR”Rh, -T\'HC(S)NRbRb, —NRbC(O)NRbRb,
—NR"C(S)NR‘-’Rb, —NHS(0)2NHR“, —NRbS(O)2NH2, —NRbS(O)2NHRb, -NHS(O)2NRbRb,
—NR*‘S(0)2NR"R‘; —NHbe or -NRbRb, wherein each Rb is independently selected from the group
consisting of C;_6alkyl, halogen, ~CN, Cwalkoxy, Cnscycloalkyl, Cegcycloalkyl—CM-alkyl, —OH, C1.
nhaloalkyl, thaloalkoxy, aryl, aryl-{33,4alkyl, heteroaryl and heteroarylalkyl; or two Rh substituents
when attached to the same nitrogen atom taken together with the nitrogen atom form
a three to eight
431 1-791837264
039363-7211
membered ring having from 0—2 additional heteroatoms as ring members selected from N O or S;
wherein the aliphatic or aromatic portion of RI is further ally substituted with from 1-3 groups
selected from (71.5 alkyl, CM , C143 haloalkyl, CH, haloalkoxy, aryl, arylalkyl, heteroai’yh
heteroarylalkyl, heterocycloalkyl, heterocycloalkyl—Ci4alky'l or ~R°, n each R6 is
independently selected from n: —CH=CH;, —CN, ~0H, -NH2, -N02, -C(O)OH, —C(S)OH,
-C(O)NH2, H2, -S(O)3NH23 —NHC(O)NH2, -NHC(S)NH3, ~NHS(O)2NH3, -C(NH)NH3, OR“,
-SRd, —OC(0)R‘£ —OC(S)Rd, -C(O)Rd, -C(S)Rd, -C(O)ORd, -C(S)0Rd. -S(O)Rd, swine}, -C(O)NHRd,
-C(S)NHRd, ~C(O)NRde, -C(S)NRde, —S(O)2NHRd, -S(O)2NRde, -C(NH)NHR“, -C(NH)NRde,
-NHC(O)R‘1 —NHC(S)Rd, -NRdC(O)Rd, -NRdC(S)Rd, )2Rd, -NRdS(O)3R“, -NHC(O)Nl-le,
-NHC(S)NH.Rd, —NRdC(O)Nl-l2, -NRdC(S)NH2, -NRdC(O)NHRd, -NRdC(S)Nl-le, -NHC(O)NRde,
-NHC(S)NRde, O)NRde, -NRdC(S)NRde, -NHS(O)2Nl-IRd, -NRdS(O)2NH2,
—NR“S(O)2NHR", -NHS(O)2NR"Rd, -NRdS(O)2NRde Rfor -NRde, wherein each Rd is
, -NHRd,
independently selected from CH5 alkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; and wherein the aromatic portion of RI is
optionally substituted with from 1-3 substituents independently selected from Re, wherein R6 is
selected from the group consisting of halogen, -CH=CH2, -CN, -OH, -NH2, -N03, -C(O)OH,
-C(S)OH, -C(O)NH2, H2, -S(O)ZNH2,, -NHC(O)NH2, —NHC(S)NH2, —NHS(O)2NHZ,
-C(NH)NH2, 0112 —SR", —0C(0)R", -OC(S)Rf, -C(O)Rf, -C(S)Rf, —C(0)0R‘, Rf, —S(O)Rf,
-S(O)2Rf, -C(O)NHRf, -C(S)NHRf, —C(O)NRfRf, -C(S)NRer, NHRE -S(O)2NRFRE
NHR£ -C(NH)NRfRf, )R‘, -NHC(S)Rf, —NR‘C(0)R*‘, —NRfC(S)Rf, —NHS(O)2R£
O)2Rf, —NHC(0)NHR", —NHC(S)NHR’, —NRfC(O)NH2, —NRfC(S)NH2, -NRfC(O)NHRf,
—NRrC(S)NHRf, -NHC(O)NRfRf, -NHC(S)NRer, —NRfC(O)NRrRr, S)NRfR“, )2NHR2
—NRfS(O)2Nllg, —NR"S(O)2NHR2 —NHS(0)2NR‘R€ —NRfS(O)zNRfRf, -NHRf, -NRfRf and R‘", wherein
Rf is Cmalkyl or aryl; or two adjacent R1 groups on the aryl or heteroaryl ring together with the atoms
to which they are attached form a 5- or 6-membered ring having from O to 2 additional heteroatoms
selected from N, O or S, optionally substituted with from 1 to 3 Rd or RC substituents. ln some
instances, Rf is Ci.6all<yl. In other instances, Rf is aryl, such as phenyl. All the other les Y2, Q,
Z of a (I) and R4, R5, R6, R7 and R8 are as defined in any of the embodiments described herein.
[0068} In some embodiments of compounds of formula (1), Y1 is aryl or heteroaryl groups, wherein
the heteroaryl group has from 1 to 4 atoms as ring members selected from N, O or S; and
wherein the aryl or heteroaryl groups are optionally substituted with from I to 3 R.‘ substituents; or
two adjacent RI groups on the phenyl or naphthyl ring together with the atoms to which they are
attached form a 5— or ered ring having from O to 2 additional heteroatoms selected from N, O
or S, optionally substituted with from 1 to 3 Rd substituents. In other embodiments, Y) is CN,
halogen, 10H: CM, alkyl, CH3 alkoxy, C1.6lialoalkyl or C1.6lialoalkoxy'. In some instances, Yl is
phenyl, l-naphthyl or 2-naphthyl, each of which is optionally substituted with from one to three R‘.
In other instances, Y1 is phenyig i-naphthyl or E-naphthyl, each of which is optionally substituted with
4811191847261
039363—721 1
from one to three Ra. In other instances, ‘1" is phenyl, l—naphthyl or thyl, each ot‘which is
optionally substituted with from one to three Rb. In other instances? Y1 is phenyl, l-naphthyl or 2—
naphthyl, each of which is optionally substituted with from one to three RC. In other instances, Y1 is
phenyl, l-naphthyl or 2—naphthyl, each h is optionally substituted with from one to three Rd.
In other instances, Y] is phenyl, l—naphthyl or 2—naphthyl, each of which is optionally substituted with
from one to three Re. In yet other instances, Yl is phenyl, l—naphthyl or 2-naphthyl, each of which is
optionally substituted with from one to three R“. In some instances, Y1 is phenyl, l-naphthyl or 2-
naphthyl, is F, Cl, Br, 1, —CN, —OH, —CF3, NHg, CF;O~, CH5 CHgO, ‘NOz, cyclopropyl,
ropylmethyl, ropylamino, cyclopropylmethylamino, l-cyanocyclopropyl, methylamino,
dimethylaminoa methylthio: acetoxy, acetyl, ycarbonyl, acetamido, l-cyclopropylethyl, 2-
cyclopropylethy], 1-cyclopropylcthylamino, 2-cyclopropylcthylamino or l-hydroxy-l-mcthylcthyl or
methylcarbamoyl. All the other variables Y2, Q, 2 of formula (I) and R4, R5, R6, R7 and R8 are as
defined in any of the embodiments described herein.
In some embodiments of compounds of formula (I), Y1 is lH—4—benzotriazolyl, ll-l—S—
benzotriazolyl, lH—4—benzimidazolyl, enzimidazolyl, ndazolyl, lH—S—indazolyl, lH—6—
indazolyl, lH—7—indazolyl, lH—4—indolyl, ndolyl, lH—6—indolyl, lH—7—indolyl, 2—oxo—6—
nyl, 2—oxo—4—indolinyl, 2—oxo—5—indolinyl, 2—oxo—7—indolinyl, 1,2—benzoxazol—4—yl, 1,2-
benzoxazol-S-yl, 1,2-benzoxazol—6—yl, 1,2—benzoxazol—7—yl, [,3—benzoxazol—4—yl, 1,3—benzoxazol—5—
yl, 1,3-benzoxazol—6—yl, 1,3-benzoxazol—7—yl, 1,2—benzothiazol—4—yl, 1,2—benzothiazolyl, 1,2-
benzothiazol-6—yl, l,2-benzothiazol—7—yl, 5—quinolinyl, 6—quinolinyl, 7—quinolinyl, 8-quinolinyl, 5-
isoquinolinyl, 6—isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl, S—cinnolinyl, 6—cinnolinyl, 7-
inyl, olinyl, S-quinazolinyl, 6—quinazolinyl, azolinyl, 8-quinazolinyl, 5-
quinoxalinyl, 6—quinoxalinyL 7-quinoxalinyl, 8—quinoxalinyl, 4—indanyl, 5-indanyl, 5-tetralinyL 6-
tetralinyl, l,3-dihydroisobenzofuranyl, l,3—dihydroisobcnzofuran-S-yl, 2,3-dihydrobenzofuran-4—
yl, 2,3—dihydrobenzofuran—S—yl, 2,3—dihydrobenzofuran—6—yl, hydrobenzofuranyl, 1,3-
dihydroisobenzothiophen—4-yl, 1,3-dihydroisobenzothiophen-S-yl, 2,3-dihydrobenzothiophen—4-yl,
2,3—dihydrobenzothiophen-S-ylg 2,3—dihydrobenzothiophen—6—yl, 2,3-dihydrobenzothiophen—7-yl, 4-
indolinyl, 5—indolinyl, 6—indolinyl, 7-indolinyl, 5—isochromanyl, hromanyl, 7~isochromanyl, 8—
isochromanyl, S-chromanyl, 6—chromanyl, 7-chromanyl, 8-chromanyl, 2,3-dihydro-l,3-benzothiazo—4—
yl, 2,3adihydro-I33-benzothiazoyl, 2,3—dihydro—l ,3-heiizotliiazo-6—yl, hydro-l ,S—benmthiazo—
7-3/1, 2,3—dihydro-l ,2-bcnzothiazoyl, 2,3-dihydro~l,2-benzothiazo—5~yl, hydro—l,2fi
benzothiazo-o-yl, 2,3‘dihydro—1,2-benzothiazoyl, 2,3-dihydro-1,3-benzoxazol-4uyl, 2,3-dihydro-
1,3-benzoxazol—5-yl, 2,3-dihydro- l ,3 -benzoxazolyl, 2,3-dihydro-l ,3-benzoxazol—7-yl, hydro-
1,2—benzoxazol—4-yl, 2,3—dihydro—l ,2—benzoxazol—S—yl, 2,3—dihydro—l ,2—benzoxazol—6—yl, 2,3—dihydro—
l,2~benzoxazol—7—yl, 4—benzofuranyl, 5—benzofuranyl, 6—benzofuranyl, 7—benzofuranyl, 4-
benzothiophenyl, 5-benzothiophenyl, 6—benzothiophenyl or 7-benzothiophenyl, each of which is
optionally substituted with from I to 3 R1 substiments; or I to 3 R3 substituents; or i to 3 R'0
4811—7918—7726“!
039363-7211
substituents; or 1 to 3 Rc substituents; or 1 to 3 Rd substituents; or i to 3 Re substituents; l to 3 Rf
substituents; or 1 to 3 substituents selected from F, Cl, Br, 1, -CN, -Ol~l, -CF3, NHg, CF3O—, CH3-g
CHgO, -NO:, cyclopropyl, cyclopropylmethyl, cyclopropylamino, eyelopropylmethylamino, l-
cyanocyclopropyl, mothylamino, dimethylamino, methylthio, acctoxy, acetyl, methoxycarbonyl,
acetamido, l-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino, 2-
cyclopropylethylamino or l-hydroxy-l-methylelhy] or methylcarbamoyl. All the other variables Y3,
Q, 2 of formula (I) and R4, R5, R6, R" and R8 are as defined in any ofthe embodiments described
herein.
In some embodiments, Y] is 5 or 6-membered heteroaryl. each ofwhich is ally
independently substituted with from 1-3 Rl groups, wherein the aromatic portion of R1 is optionally
substituted with from 1-3 tuents independently selected from Re; or two adjacent Rl groups on
the phenyl or naphthyl ring together with the atoms to which they are attached form a 5- or 6-
ed ring having from 0 to 2 additional heteroatoms selected from N, O or S, optionally
substituted with from 1 to 3 Rd substituents. All the other variables Y2, Q, Z of formula (1) and R4, R‘,
R6, R7 and R8 are as defined in any ofthe embodiments described herein.
in some embodiments of compounds of formula (D, Y1 is 5-pyrimidinyl, 2-pyrimidinyl, 4-
pyrimidinyl, 2-pyridyl, dyl, 4-pyridyl, 2-pyrazinyl, 2—pyridazinyi, 3-pyridazinyi, olyl, 2—
pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazoiyl, 2-oxazolyl, 4-
oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, azolyl, 4-isoxazolyl, 5-isoxazolyl, 3-
isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2;3-triazol-l—yl, 1,2,3-triazol-2—yl, triazol-3—yl,
triazolyl, 1,2,3-triazol-S-yl, 1,2,4-triazol-l-yl, 1,2,4-triazolyl, l,2,4-triazolyl, 1,2,4-
triazol-élayl2 1,2,4—triazol—5-yl, l~oxa-2,3-diazolyl, l—oxa-2,3—diazol-5—yl, l-oxa—2,4~diazolyl, i»
oxa-2,4—diazol-5—yl, l-oxa-2,5-diazolyl, l-oxa—2,5~diazolyl, l-thia-2,3—diazol-4—yl, l-thia-2,3-
diazol-S-yl, l—thia-2,4-diazol-3—yl, l-thia—2,4-diazolyl, l-thia-2,5-diazolyl, l—thia—2,5—diazol-4—
yl, l-tetrazolyl, 3-tetrazolyl, lH-S-tetrazolyl, etrazolyl, Z-fiiranyl, 3-furanyl, 2-thiopenyl or 3-
thiophenyl, each of which is ally substituted with from 1 to 3 R1 substituents; or i to 3 Ra
substituents; or i to 3 Rb substituents; or I to 3 Rc substituents; or 1 to 3 Rd substituents; or I to 3 Rc
substituents; l to 3 Rf tuents; or 1 to 3 substituents selected from F, Cl, Br, I, ~CN, -OH, -CF3,
NHZ, CF3O-, CH3: CHEO, "N03, cyclopropyl, cyclopropylmethyl, cyclopropylamino,
cyclopropylmethylamino, l—Cyanocyclopropyl, mcthylamino, dimethylamino, thio, acetoxy,
acetyl, methoxycarbonyl, acetamido, l—cyclopropylethyl, Z—cyclopropylethyl, 1w
cyclopropylethylamino, 2-cyclopropylethylamino, l-hydroxy-l-metliylethyl, methylcarbamoyl, i—
ycyclopropyl, l-carbamoylcyciopropyl, l-methoxycarbonylcyclopropyl, l-cyanoisopropyl, l—
hydroxycyclopropyl, l-hydoxyisopropyl, cyclobutoxy, entoxy, eyloxy, 4-morpholino, 4-
hydroxypiperidinyl,1— piperidinyl, piperazinyl, 4-methylpiperazinyl, 4—t—butoxycarbonylpiperazinyl,
azetidinyiy pyrrolidinyl? cyclopropyicarbamoyi, S—Inethyl-1,2,4-oxadiazolyl, S—methyLi 73,4-
zol~2yl 5-dimethylamino~l,3,4~oxadiazol~2yl or S—methylamino—l.3A~thiadiazol«2-yl. All the
481177261
039363-7211
other variables Y2, Q, Z of formula (I) and R4, R5, R6, R7 and R8 are as defined in any of the
embodiments described herein.
In certain embodiments of compounds of a (I), ‘ir’1 is selected from the group
consisting of midinyl, 5-pyrimidinyl, 2-pyrazinyl, zolyl, 4-thiazolyl, S-thiazolyl, 2-
thiophenyl, phenyl, Z-amino-quinazolin-S-yl, o-quinazolin-6»yl, 2-amino-quinazolin-6—
y , 2-amino‘quinazolinyl, Z-amino—quinazolinyl, 2—oxo—6-indolinyl, 2-oxoindolinyl, 2-oxo«5-
indolinyl, 2—oxo—7—indolinylj 2-pyridyl, 3-pyridyl, 4—pyridyl, lH-indazolyl, lH-indazoI-S—yl, 1H-
indazol-6~yl and lH-indazolyl, each of which is substituted with from 1 to 2 susbtituents
independently selected from F, Cl, Br, I, -CN, —OH, -CF3, NHg, CF3O-, CH3-, CH3O, C2H50-, -NOZ,
cyclopropyl, cyclopropylmethyl, ropylamino, cyclopropylmethylamino, l-cyanocyclopropyl, 1-
carboxycyclopropyl, l-carbamoylcyclopropyl, l-methoxycarbonylcyclopropyl, l-cyanoisopropyl, 1—
ycyclopropyl, l—hydoxyisopropyl, cyclobutoxy, entoxy, cycloheyloxy, 4—morpholino, 4-
hydroxypiperidinyl,l— piperidinyl, piperazinyl, 4—methylpiperazinyl, 4—t—butoxycarbonylpiperazinyl,
azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl, 5—methyl—l ,2,4—0xadiazol—3-yl, 5-methyl-l,3,4—
oxadiazol-Zyl, 5-dimethylamino—l,3,4-oxadiazol—2yl, Svmethylamino-I,3,4—thiadiazolyl,
methylamino amino, dimethylamino, methylthio, acetoxy, aeetyl, methoxycarbonyl,
acetamido, methylcarbamoyla isopropyl, l—pyrrolidinyl, l—cyclopropylethyl, 2-cyclopropylethyl, 1—
cyclopropylethylamino, 2-oyclopropylethylamino or l—hydroxy-l—methylethyl. All the other variables
Y2, Q, Z of a (I) and R4, R5, R6, R7 and R8 are as defined in any of the embodiments described
herein
In other embodiments of compounds of formula (I), YI is l-benzotriazolyl, 1-
benzimidazolyl, lI’I—Z—benzimidazolyl, l—indazolyl, 1H—3-indazolyl, l-indolyl, lH—Z-indolyl, 1H
indolyl, 1,2—benzoxazol—3-yl, 1,3-benzoxazolyl, nzothiazolyl, l,3-benzothiazolyl,
quinolinyl, 3-quinolinyl, 4-quinolinyl, l-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 3-einnolinyl,
olinyl, 2-quinazolinyl, 4—quinazolinyl, oxalinyl, 2-benzofuranyl, 3-benzofuranyl, 2-
benzothiophcnyl or 3-benzothiophenyl, each of which is optionally substituted with from 1 to 3 R1
substituents; or 1 to 3 Ra substituents; or i to 3 Rb tuents; or 1 to 3 Rc substituents; or I to 3 Rd
substituents; or I to 3 R“ substituents; l to 3 Rf substituents; or i to 3 substituents selected from F3 Cl,
Br, I3 —CN, -OH, -CF3, NHQ, CF30, CH3—, CHgO, ~N03, cyclopropyl, eyelopropylmethyl,
eyeiopropylamino, eyelopropylmethylamino, l—cyanocyclopropyl, methylamino, dimcthylamino,
methylthio, acetoxy, aeetyl, methoxycarbonyl, ido, i-cyclopropylethyl, 2~cyclopropylethyL l-
eyelopropylethylamino, 2-cyelopropylethylamino, l—hydroxy—l—methylethyl, methylearbamoyl, i-
carboxycyclopropyl, l—earbamoylcyclopropyl, oxyearbonylcyclopropyl, l—eyanoisopropyl, l-
hydroxycyclopropyl, 1-hydoxyisopropyl) cyclobutoxy, cyclopentoxy, cycloheyloxy, 4-morpholino, 4—
hydroxypiperidinyl,1- piperidinyl, piperazinyl, 4—methylpiperazinyl, 4—t—butoxycarbonylpiperazinyl,
axetidinyl, pyrrolidinyi. eye}opropylearbamoyl, 5~methyl—l,234—oxadiazol—3eyl? S-methyl—lfifl—
oxadiazol—le, 5-dimethylamino-l,3,4-oxadiazol-2yl or ylamino—l,3,4-thiadiazol~2—yl. Ail the
481177261
039363—7211
other les Y2, Q, Z of formula (I) and R‘l, R5, R6, R7 and R8 are as defined in any of the
ments described .
In some embodiments of compounds of formula (I), Y1 is selected from:
03““030303é—th/“i-é—zG3N N
AQN“1}“:erJN/”ZNm“:N/Z/X/ yéi/NJfiz/EHI/ NWN
Mf/CDC/N Ci:,each of which is
optionally substituted with from 1 to 3 RI substituents; or 1 to 3 R‘1 substituents; or 1 to 3 Rb
substituents; or 1 to 3 Rc substituents; or 1 to 3 Rd substituents; or 1 to 3 Re tuents; l to 3 Rf
substituents; or I to 3 substituents selected from F, Cl, Br, I, -CN, -OH, -CF3, NHg, CF30—, CHy,
CH30, —NOg, ropyl, cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, 1-
cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl,
acetamido, 1-0;.Iclopropylethyl, 2-cyclopropylethyl, 1-cyelopr0pylethylamino, 2-
cyclopropylethylamino, l—hydroxy—1-methylethyl, methylcarbamoyl, l-carboxycyclopropyl, 1—
earbamoylcyclopropyl, l~methoxycarbonylcyclopropyl, l-cyanoisopropyl, 1-hydroxycyclopropyl, 1-
hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyloxy, 4-morpholino, 4—hydroxypiperidinyl,l—
piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-t—butoxycarbonylpiperazinyI, azetidinyl, pyrrolidinyl,
ropylcarbamoyl, S—niethyl—l,2,4—oxadiazol—3—yl, 5—methyl—l,3,4-oxadiazol—2yl, 5-
dimethylamino-l,3,4-oxadiazol-2yl or 5—methylamino-1,3,4-thiadiazolyl, where the wavy line
indicate the point of attachment to the rest of the molecule. The notation Ԥ_ means Y1 can be
attached to the rest of the molecule at any of the available ons of the Y1 group set forth above.
G31/31”6
For example, 5 3 is meant to e l-indolizinyl, 2-indolizinyl, 3-indolizinyl, 4-
indolizinyl, S-indolizinyl, 6-indolizinyl, 7-indolizinyl, and 8-indolizinyl (Lew substitutions can be at l,
2, 3, 5, 67 7 or 8 positions ofthe indolizine ring):
In some embodiments of compounds of formula (I), Y" is selected from:
H H H
~\ €49 ”2-§—'— \ ”2 \
~§—'~ 'f‘N \
—§~'— ‘3‘N g—aGfi Em
481177261
0393637le
\ S \ S \ \ \ 0t \ N“
~§:N/ ,9 {D Em -%4:N/ MIN-m3: m é-tN/\ ON
\ 3‘ \N\
“E“IR / 'i‘ ‘
”N l‘\ / I
S . .
. . . l
N N N each of which is optionally substituted With from 1 to 3 R or ,
substitucnts; or 1 to 3 Ra tuents; or 1 to 3 Rb substituents; or 1 to 3 R” substituents; or 1 to 3 Rd
tuents; or 1 to 3 Re substituents; 1 to 3 Rf substituents; or 1 to 3 substituents selected from F, Cl,
Br, 1, -CN, -OH, —CF3, NHg, CF30—, CH3-, CHgO, -N03, cyclopropyl, cyclopropylmethyl,
cyclopropylamino, cyclopropylmethylamino, l-cyanocyclopropyl, methylamino, dimethylamino,
methylthio, acetoxy, , methoxycarbonyl, acetamido, l-cyclopropylethyl, 2—cyclopropylethyl,
ropylethylamino, 2-cycl0propylethylamino, l-hydroxy-l-methylethyl, methylcarbamoyl, l-
carboxycyclopropyl, l-carbamoylcyclopropyl, oxycarbonylcycIopropyl, l-cyanoisopropyl, l—
hydroxycyclopropyl, l—hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyloxy, 4—morpholino, 4—
hydroxypiperidinyl,l— piperidinyl, piperazinyl, 4-methylpiperazinyl, 4—t—butoxycarbonylpiperazinyl,
azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl, S—methyl-l,2,4-oxadiazol—3—yl, 5—methyl—l,3,4—
oxadiazol—Zyl, 5—dimethylamino—l ,3,4-oxadiazol-2yl or 5~methylamino~l,3,4—thiadiazol—2—yl, where
the wavy line indicates the point of ment to the rest of the molecule. The notation means
Y1 can be attached to the rest of the molecule at any of the available positions of the Yl group set forth
6: 7\ “1
a H\ / / 2
N 3
above. For example, 4 is meant to include lH—pyrrolo[3,2~b]pyridin—1—yl, 1H-
pyrrolo[3,2—blpyridin—2—yl, lH-pyrrolo[3,2-b]pyridin-3—yl, lH—pyrrolo[3,2—blpyridin—5—yl, 1H—
o[3,2—b]pyridin-6—yl and lH-pyrrolo[3,2-b]pyridinyl (i.e., substitutions can be at l, 2, 3, 5, 6,
variables Y2, Q, Z of formula (I) and
or 7 positions of the pyrrolo[3,2-b]pyridine ring). All the other
R4, R5, R6, R7 and R8 are as defined in any of the embodiments described herein.
In some embodiments of compounds of formula (I), Y' is selected from:
N N N
, ,
’E—NL : «N €411— \ 0/) E‘- \ \ -§—E/§[\/\> \ 8‘ ~§qN>
gm: / N\ ¢ é—l-L
‘N g “K 0 N: /;L\y NtN/ s
9 5 ’
izl O N
“ S S “ \
@4— > gmgm-%——'— ‘~ -§-‘- ‘~ grit
N\N/ NxN/ NNN/ N\N/ N\ /
N S N N, N\N/ OI
’ 7
'8‘ N
-§-—.L r \
,N €4— N
é N‘N/ N or Mei/ks each ofwhich is optienally substituted with From 1 to 3 RE
4811—7918—7726.1
039363—7211
substituents; or 1 to 3 R3 substituents; or 1 to 3 Kb tuents; or 1 to 3 Rc substituents; or 1 to 3 Rd
substituents; or 1 to 3 Re substituents; l to 3 Rr substituents; or 1 to 3 substituents selected from F, Cl,
Br, I, —CN, -OH, -CF3, NI‘IZ, CF30-, CH3-, CH30, -NOZ, cycloprepyl, cyclopropylmethyl,
eyelopropylamino: cyclopropylmethylamino, l-cyanoeyclopropyl, methylamino, dimethylamino,
methylthio, acetoxy, aeetyl, methoxyearbonyl, acetamido, l-cyelopropylethyl, 2-cyclopropylethyl, l-
eyelopropylethylamino, 2-eyelopropylethylamino, l-hydroxy-l—methylethyl, methylcarbamoyl, l-
yeyelopropyl, l-earbamoyleyelopropyl, l-methoxyearbonyleyelopropyl, l-eyanoisopmpyl, l—
yeyclopropyl, l-hydoxyisopropyl, eyelobutoxy, eyelopentoxy, eyeloheyloxy, holino, 4-
hydroxypiperidinyl,l- piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl,
azetidinyl, pyrrolidinyl, eyelopropylcarbamoyl, 5-methyl-1,2,4-oxadiazolyl, 5-methyl-l,3,4-
oxadiazol-Zyl, 5-dimethylamino-l ,3,4-oxadiazol-2yl or 5-methylamino—l ,3,4~thiadiazolyl, where
the wavy line indicates the point of attachment to the rest of the molecule. The notation _§* means
Y1 can be ed to the rest of the molecule at any of the available positions of the Yl group set fot’th
4 H
u 5
a /
2N\ / 7
above. For example, is meant to include SH‘pyrrolo[3,2—e]pyridazin—3—yl, 5H—
pyrrolol3,2—c]pyridazin—4-yl, 5H—pyrrolo[3,2-e]pyridazin—5—yl, SI’I—pyrrolo[3,2—ejpy1‘idazin—6—yl, 5H—
pyrrolo[3,2—e]pyridazin—7-yl (i.e., substitutions can be at 3, 4, 5, 6, or 7 positions ofthe 5H—
pyrrolo[3,2—c]pyridazine ring). All the other variables Y2, Q, 2 of formula (1) and R4, R5, R6, R7 and
R8 are as defined in any of the embodiments bed herein.
In some ments of compounds of formula (I), Y1 is selected from:
N H H o N N \
:2 é—CE 2 2—092 $09“ 2% 2 \
N \ N \ N \ \ N \ x N \ -m,2 1“
N N N N N N O H
, , , ,
2—3?2:2:52:m,1:3? W2Km” N is / 'K is “E":MAS
H N)?
€32»?iii; / éfléiii/Milt“;E gets/N
”t”?N/LNN m: ’NEW;SI
each of which is optionally substituted with from i to 3 R;
, ,
substituents; or i to 3 R“ substituents; or 1 to 3 Rb substituents; or 1 to 3 RC tuents; or 1 to 3 Rd
substituents; or 1 to 3 Re substituents; l to 3 RFSIIbstituents; or 1 to 3 substituents selected from F, Cl,
Br, 1, —CN, -OH, -CF3 NH; CF30-CH3', CHSO ~NOZ, iwopyl cyclopropylmethyl
eyelopropylamino, eyelopropylmethylamino, l—eyanoeyelopropyl, methylamino, dimethylamino,
methylthio, y, acetyl, methoxyearbonyl, acetamido, i-eyeiopropylethyl, opropyletiiyl, l~
4811—7918—7726.1
039363-7211
cyclopropylethylamino, 2-cyclopropylethylamino, 1-hydroxy—1-methylethyl, methylcarbamoyl,
carboxycyclopropyl, l—carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, l-cyanoisopropyl,
hydroxycyclopropyl, 1-hydoxyisopropyl, utoxy, cyclopentoxy, cycloheyloxy, 4-morpholino, 4-
bydroxypiperidinyl,l- piperidinyl, piperazinyl, 4—methylpiperazinyl, 4-t-butoxyearbonylpiperazinyl,
azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl, 5-methyl-l,2,4-oxadiazol-3 -yl, S-methyl-1,3,4-
where
oxadiazolel, 5-dimethylamino-l,3,4-oxadiazol-2yl or ylamino-l,3,4-thiadiazol—2-yl,
notation _i~ means
the wavy line indicates, the point of attachment to the rest of the molecule. The
Y1 can be attached to the rest of the molecule at any of the available positions of the ‘1" group set forth
4 H
3 N
2eCQe N. \
2 N
above. For example, 1 is meant to include SH-pyrrolo[3,2-c]pyrimidin-Z-yl, 5H-
pyrrolo[3,2-c]pyrimidinyl, SH-pyrrolo[3,2-c]pyrimidin-S—yl, 5H-pyrrolo[3,2-c]pyrimidinyl and
SH-pyrrolo[3,2-c]pyrimidin-7—yl (i .e., substitutions can be at 2, 4, 5, 6, or 7 positions ofthe 5H-
o[3,2-clpyrimidine ring). All the other variables Y2, Q, Z of formula (I) and R4, R5, R6, R7 and
R8 are as defined in any of the embodiments described herein.
In some ments of compounds of formula (I), Yl is selected from:
H H H N
eibeiveiheifieihdlbN N N N \
KN/ ,KN/N, N//, KN//,l\N/O, N N,
“ION N “128‘N N
“‘10) N (I) “IS
'E’EN/ Mister /"§1'N/ ”ii—K“ /“I \>’_i—EN/ (ink “N,
iilfiiilfi(N\ Ox (“x S\
N ..
N ...
or N each of which IS optionally substituted Wlth from 1 to 3 R N , ,
substituents; or 1 to 3 Ra substituents; or I to 3 Rb substituents; or 1 to 3 Rc tuents; or 1 to 3 Rd
substituents; or 1 to 3 Re substituents; 1 to 3 Rf substituents; or 1 to 3 substituents ed from F, Cl,
Br, 1, —CN, =OH, —CF3, NI’Ig, CF30-, CH3-, C1130, —N02, ropyl, cyclopropylmethyl,
cyclopropylamino, cyclopropylmethylamino, l—cyanocyclopropyl, methylamino, dimethylamino,
methylthio, y, acetyl, methoxy‘carbonyl, acetamido, I-cyclopropylethyl, Z—cyclopropylethyl,
cyclopropylethylamino, 2-cyclopropylethylamino, l-hydroxy-l—methylethyl, oarbamoyl, i—
carboxycyciopropyl, 1-carbamoylcyclopropyl= 1-methoxycarbonylcyclopropyl, l—cyanoisopropyl,
hydroxycyclopropyl, 1—hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cycloheyioxy, 4»m0rpholino,
hydroxypiperidinyU- piperidinyl, piperazinyl, 4-methylpiperazinyl, 4—t-butoxyearbonylpiperazinyl,
azetidinyl, pyrrolidinyl, ropylcarbamoyl, 5—methyl-l,2,4-oxadiazol-3—yl, yl-l,3,4-
where
oxadiazoLZyL 5—dimethylamino-l ,3,4-oxadiazoi-2yl or S«methylamino-l,3,4—thiadiazol~2~yl,
The notation W5- means
the wavy line indicates the point of attachment to the rest of the moiecuie.
481 11918—77261
039363—7211
Y1 can be attached to the rest of the molecule at any of the available ons of the Y1 group set forth
N\ N 5
é SK
N/ / a
. .
above. For example,,
1 is meant to include 5H«pyitolo[2,3—b]pyrazm-2—yl, 5H-
pyrrolo[2,3~b]pyrazin—3—yl, 5H—pyrrolo[2,3-b}pyrazin—5—yl, 5H-pyrrolo[2,3—b]pyrazinyl, 5H-
pyrrolo[2,3~b]pyrazinyl, (i.e., substitutions can be at 2, 3, 5, 6, or 7 positions of the SH-py’rrolo[2,3—
b]pyrazine ring). All the other variables Y2, Q, 2 of formula (1) and R4, R5, R5, R7 and R8 are as
defined in any ofthe embodiments described herein.
In some embodiments of compounds of formula (I), Y1 is CN, halogen, -OH, optionally
tuted CH, alkyl, optionally substituted CH, alkoxy, optionally substituted thaloalkyl, or
optionally tuted C1.(,haloalkoxy. In other embodiments, YI is CN, halogen, -OH, Cm alkyl, CH;
1 to 3 RI
alkoxy, C1_6haloa|kyl or C1_6haloalkoxy, each of which is optionally tuted with from
substituents; or I to 3 R21 substituents; or 1 to 3 Rb substituents; or 1 to 3 Rc substituents; or
1 to 3 Rd
tuents; or I to 3 Re substituents; 1 to 3 Rr substituents; or I to 3 substitucnts selected from F, Cl,
Br, I, -CN, -OI-l, -CF3, NHZ, CF3O—, CH3-, CH30, —NOZ, ropyl, cyclopropylmethyl,
cyclopropylamino, cyclopropylmethylamino, l-cyanocyclopropyl, methylamino, dimethylamino,
methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido or methylcarbamoyl. In some
embodiments, Yl is CN, halogen, -OI-I, CM alkyl, CH, alkoxy, thaloalkyl or C._6haloalkoxy.
other embodiments, Y1 is CN, Cl, Br, F, I, -OH, —OCH3‘ —CF3, or -OCF3, each of which
is optionally
substituted with from 1 to 3 R1 substituents; or I to 3 Ra substituents; or I to 3 Rb tuents; or
1 to
3 RC substituents; or I to 3 Rd substituents; or I to 3 Re substitucnts; l to 3 Rfsubstituents; or
I to 3
substituents selected from F, Cl, Br, I, —CN, —OH, CH, NHZ, CF3O-, CH3-, CHgO, -N03, cyclopropyl,
cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, l-cyanocyclopropyl, methylamino,
dimethylamino, methylthio, acetoxy, aeetyl, methoxycarbonyl, acetamido, l-eyclopropylethyl, 2—
eyelopropylethyl, l—cyclopropylethylamino, 2-cyclopropylethylamino, 1-hydroxy-l-methylethyl,
methylearbamoyl, l—earboxycyelopropyl, l~carbamoylcyciopropyl, l-methoxycarbonylcyclopropyl,
l-cyanoisopropyl, l-hydroxycyclopropyl, l-hydoxyisopropyl, cyclobutoxy, cyclopentoxy,
cycloheyloxy, 4—morpholino, oxypiperidinyl,l— piperidinyi, piperazinyl, 4-methylpiperazinyl,
4-t-butoxycarbonylpiperazinyl, azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl, hyl-l ,2,4—
oxadiazol—3—yl, 5~methyi~1,3,4-oxadiazol—2yl, 5-dimethylamino-l ,3,4—oxadiazoi~2yl or 5-
methylamino-i,3,4wthiadiazoI—2-yl, In other embodiments, Yl is CN, halogen, ~OH, CH3, CH30—, CFg,
and R“, R5,
CF30, ropyi or cyclopropylmethyl. All the other les Y2, Q, Z of formula (I)
R6, R? and R8 are as defined in any of the embodiments described herein.
where
In any of embodiments of compounds of formula (1) above and described herein,
appropriate, each R1 is independently selected from halogen, ~CN, ~0H, —CF3, CF31}, Chealkyl, Cg,
geikoxy, Cgécyeloalkoxy, —NO;, benzyl, phenyl, cyclopropyi, ropyhnethyl, i»
eycanoeyclopropyl, oxycyelopropyl, l~earbamoyleyclopropyL l-methoxycarbonyleyelopropyl,
4811791877261
039363-7211
l-cyanoisopropyl, 1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, cyclopentoxyg
eyloxy, €1.6alkyl-1,2,4-oxadiazolyl, 5-Cmalkyl-l fiA-oxadiazol—Z‘yl, 5—di(C;_5a1kyl)amin0—
1,3,4-0xadiazol-2yl, 5-C1,6alkyla.mino—1 ,3,4-thiadiazolyl, utyl, utylmethyl,
cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl, -OC(O)Rb, -C(O)Rb, -C(O)0Rb, -
NHC(0)R", -C(O)NHR", NHR" or ~NRbR". In n instances, R‘ is F, (:1, Br, 1, -CN, -0H, -CF3,
N'Hz, CF30, CH3-, CH30, CzHgO-, -N02, cyclopropyl, cyclopropylmethyl, cyclopropylamino,
cyclopropylmethylamino, l-cyanocyclopropyl, l-carboxycyclopropyl, l-carbamoylcyclopropyl, 1-
methoxycarbonylcyclopropyl, l—cyanoisopropyl, 1-hydroxycyclopropyl, 1—hydoxyisopropyl,
cyclobutoxy, cyclopentoxy, eyloxy, holino, 4-hydroxypiperidinyl,1— piperidinyl,
zinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, azetidinyl, pyrrolidinyl,
cyclopropylcarbamoyl, 5-methyl—1,2,4-oxadiazolyl, 5-methyl-1,3,4-oxadiazol-2yl, 5-
dimethylamino—l,3,4—oxadiazol—2yl, 1,3,4—thiadiazol—2—yl, methylamino, dimethylamino, methylthio,
acetoxy, acetyl, ycarbonyl, acetamido, methylcarbamoyl, isopropyl, 1-pyrrolidinyl,
cyclopropylethyl, 2—cyclopropylethyl, l-cyclopropylethylamino, 2-cyclopropylethylamino or
hydroxymethylethy1.
In some ments of compounds of formula (I), Y1 is selected from the group consisting
of 5-pyrimidinyl, 2-pyrimidinyl, midinyl, 2-methoxypyrimidinyl, 2-methoxy-3 -pyrimidinyl,
2-methoxy-4—pyrimidinyl, 4-methoxypyrimidinyl, 4—methoxypyrimidinyl, 4-methoxy—5-
pyrimidinyl, 5-methoxypyrimidinyl, 5—methoxy—4—pyrimidinyl, 2-cyclopropylpyrimidinyl,
cyclopropylpyrimidinyl, 2—cyclopropyI—4-pyrimidinyl, 4-cyclopropyl-2—pyrimidinyl, 4-
cyclopropylpyrimidinyl, 4—cyclopropyl—S-pyrimidinyl, 5-cyclopropyl-2—pyrimidinyl, S~
cyclopropyl—4-pyrimidinyl, 2-cyclopropylmethyl-S-pyrimidinyl, 2-cyclopropylmethyl—3 -pyrimidinyl,
2-cyclopropylmethylpyrimidinyl, 4-cyclopropylmethyl—Z-pyrimidinyl, opropylmethyl-4—
pyrimidinyl, 4-cyclopropylmethyl-S-pyrimidinyl, S-cyclopropylmethyl-2—pyrimidinyl,
cyclopropylmethylpyrimidinyl, ylpyrimidinyl, 2-methylpyrimidinyl, 2-methyl-4—
dinyl, 4-methylpyrimidinyl, 4—methylpyrimidinyl, 4-methyl—5-pyrimidinyl, 5-methyl—2—
2—halo
dinyl, 5-methylpyrimidinyl, 2-halopyrimidinyl, 2-halopyrimidinyl,
pyrimidinyl, 4-haio—2-pyrimidiny1, 4-halo—4-pyrimidinyl, 4-halo-S-pyrimidiny1, 5-halo-2—pyrimidinyl,
—halopyrimidiny1, 2«(1 -cyanocyclopropyl)-5 -pyrimidinyl, 2—(1-cyanocyclopropyl)pyrimidinyl,
2~(1~0yanocyclopropyl)—4~pyrimidinyl, 4—( I —cyanocycl0propyl)—2-pyrimidiny1, 4-(1-
cyanocyciopropy53~4~pyrimidinyi, 4-(1-cyanocyclopropyl)-5—pyrimidinyl, 5-(1 -cyanocyclopropyi)—2~
pyrimidinyl, 5—(1vcyanocyclopropyl)—4-pyrimidinyl, 2-cyclopropylamino—5pyrimidinyi,
cyclopropylaminopyrimidinyl, 2-cyclopropylamino—4—pyrimidinyl, opropylamino
pyrimidinyl, 4-cyclopropy1amino—4—pyrimidinyl, 4—cycIopropylamino—S—pyrimidinyl,
cycIopropylamino-Z—pyrimidinyl, 5—cyclopropylamino-4—pyrimidinyl, 2—dimethylamino
pyrimidinyl, 2-dimethylamino—3-pyrimidinyl, 2—dimethylamino-4—pyrimidinyl, 4-dimethylamino—2'
pyrimidinyi, 4~dimethylamino~4~pyrimidinyL 4wdimethylamino-S—pyrimidinyi, S—dimethylamino—2—
4811-7918—7726.1
39363-7211
pyrimidiny}, 5~dimethylamin0—4—pyrimidinyl, Z—cyano-S-pyrimidinyl, 2-cyanopyrimidinyl, 2—
cyanopyrimidinyl, 4—cyanopyrimidiny], 4-cyanopyrimidinyl, 4-cya1m—5-pyrimidinyl, 5—
cyano-E-pyrimidinyl, S-cyano-él-pyrimidiny], 2-trifluoromethyl-S-pyrimidinyl, 2-trifiuor0methy1~3—
pyrimidinyl, 2~trif1u0romethylpyrimidinyl, luoromethyl-Z-pyrimidinyl, 4-triflu0romethyl
pyrimidinyl, 4- trifluoromethyl-S—pyrimidinyl, S-Irifluoromethyl—IZ-pyrimidinyl, 5-trif1uor0methyI
pyrimidinyl, 2-trifiuorometh0xypyrimidinyl, 2-trifluor0methoxypyrimidinyl, 2-
romethoxy-Ii-pyrimidinyl, 4-trifluoromcthoxy-2—pyrimidinyl, 4-triflu0romethoxy
pyrimidinyl, 4- trifluoromethoxy—S—pyrimidinyl, S-trifiuoromethoxy—Z-pyrimidinyl, 5—
trifluoromethoxypyrimidinyl, 2-hydroxypyrimidinyl, oxypyrimidinyl, 2-hydroxy
pyrimidinyl, 4-hydroxypyrimidinyl, 4-hydroxy-4—pyrimidiny], 4—hydroxypyrimidinyl, 5-
hydroxy-Z-pyrimidinyl, 5-hydroxypyrimidinyl, 2-aminopyrimidinyl, 2-aminopyrimidinyl, 2-
4-pyrimidinyl, 4-aminopyrimidinyl, 4-amino—4-pyrimidiny], 4-amino-5—pyrimidinyl, 5-
aminopyrimidinyl, S-amino—4—pyrimidinyl, 2-methylamino-S-pyrimidinyl, 2-methylamino—3-
pyrimidiny], 2—methylamin0-4—pyrimidinyl, 4—methylamin0pyrimidinyl, 4-methylamin0
pyrimidiny], 4~methylamin0-5~pyrimidinyl, ylaminopyrimidinyl, 5-methylamino—4—
pyrimidinyl, 2-dimethylamino-S-pyrimidinyl, thylaminopyrimidinyl, 2-dimethyIamino
pyrimidiny], 4-dimethylamino—Z—pyrimidiny], 4—dimethylaminopyrimidinyl, 4-dimethylamino
pyrimidinyl, 5-dimethylamino—Z-pyrimidinyl, 5-dimethylaminopyrimidinyl, amido
pyrimidiny]; 2-acetamido-3—pyrimidinyl, 2—acetamido—4-pyrimidinyl, 4-acctamido-2—pyrimidinyl, 4~
acetamido-Zl-pyrimidinyl, 4-acetamido-5—pyrimidinyl, 5-acetamido—2~pyrimidinyl, S—acetamido—4-
pyrimidinyl, 2-methylthio—5—pyrimidiny], 2—methylthio—3—pyrimidinyl, ylthiopyrimidinyl, 4-
methylthio-Z-pyrimidinyl, 4-methylthiopyrimidinyl, 4-methylthio-5~pyrimidinyl, S-methylthiow2-
pyrimidinyl, 5—methy11hiopyrimidinyl, oxy—5-pyrimidinyl, 2-acetoxy~3~pyrimidinyl, 2-
acetoxypyrimidinyl, oxypyrimidiny], 4-acetoxy-4—pyrimidinyl, 4-acetoxy-5~pyrimidinyl,
-acctoxy—2—pyrimidinyl, 5-acetoxy-4—pyrimidiny1, yl—5-pyrimidinyl, 2—acetylpyrimidinyl, 2-
acetylpyrimidinyl, 4—acetyl—2—pyrimidiny], 4-acetyl-4—pyrimidinyl, 4-acetyl-S-pyrimidinyl, 5-
acetylpyrimidinyl, 5-acetylpyrimidinyl, 2-methoxycarbonyl—S-pyrimidinyl, 2—methoxycarbonyl—
3-pyrimidinyl, 2—methoxycarbonyl-4—pyrimidinyl, 4-methoxycarbonyl-Z-pyrimidiny], 4-
methoxycarbonyl—él-pyrimidinyl, 4-methoxycarbony1-S—pyrimidinyl, S—methoxycarbonyl-Z’
pyrimidiny], Svmethoxyaarbonyl-4—pyrimidinyl, 2-methylcarbamoyl—S—pyrimidinyl, 2-
methylcarbamoyl-S-pyrimidinyl, 2-methylcarbamoyl-4—pyrimidinyI, 4-methylcarbamoyl-2—
pyrimidinyl, 4—methy1carbamoy1—4-pyrimidinyi, 4-methylcarbamoylpyrimidinyl, S-
methylcarbamoyI-Z-pyrimidinyl, 5-methylcarbamoyIpyrimidinyi, 2—pyridy}, 3—pyridy1, dyl,
-pyridyl, 3-methoxy—2-pyridyl, 4~methoxy—2-pyridyl, S—methoxy-2—pyridyl, 6—methoxypyridyl, 2-
methoxy—3—pyridyl, 4-methoxy—3-pyridyl, 5~methoxypyridyl, 6—methoxy—3-pyridyl, 0xy—4-
pyridyl, 3-methoxy-4~pyridyl, 3~halo—2—pyridyl, 4-halo-2—pyridyl, 5-hai0—2-pyridyl, 6—halo~2—pyridyl,
2-!1310-3opyridyl, 4-halo-3«pyridyl, S—halcpyridyl, 6—halo-3—pyridyf, 2—halo-4~pyridyl, 4~
pyridyl, 3—cyan0—2~pyridyl, 4~cyano~2~pyridyL 5—cayn0v2~pyridyl, 6-cyano-2—pyridyl, 2~cyan0~3~
4811*7918-77261
039363—7211
pyridyl, 4-cyano-3~pyridyl, S—cyano—3-pyridyl, 6-cyan0—3~pyridyl, 2-cyanopyridyl, 3-cyano—4-
pyridyl, 3-hydr0xypyridyl, 0xypyridyl, 5-hydroxypyridyl, oxy-2~pyridyl,
h}!droxy-3«pyridyl, 4-hydroxypyridyl, S-hydroxypyridyl, 6-hydr0xy-3 -pyridy1, 2-hydroxy
pyridyl, 3-hydr0xypyridyl, uoromethyI-Z-pyridyi, 4-trifluoromethylpyridyI,
trifluoromethyl~2—pyridyl, 6-trif]uoromethylpyridyl, 2-trifluoromethylpyridyI, 4-trifluor0methyl-
3-pyridyl, S-trifluoromethyl-B-pyridyl, 6—trifluoromcthylpyridyl, 2-triflu0romethyl~4-pyridy15
trifluoromethyl—4—pyridyl, 3~amin0pyridyl, opyridyl, S-amino-Z-pyridyl, 6-amino—2-
2-amino
pyridyl, 2-aminopyridyl, 4~amino—3—pyridyl, S-amino-B-pyridyl, 6-amino—3-pyridyl,
pyridyl, 3-aminopyridyl, 3-trifluoromethoxy-Z-pyridy|, 4-trifluoromethoxy-Z-pyridyl,
trifluoromethoxy-Z-pyridyl, 6-trifluoromethoxy-Z-pyridyl, 2-trifluoromethoxy-3 -pyridyl, 4-
trifluoromethoxypyridyl, 5-trifluoromethoxypyridyl, 6-trifluoromethoxypyridyl, 2-
trifluoromethoxypyridyl, 3-trifluoromethoxypyridyl, 3-methylpyridyl, 4-methylpyridyl,
methyl-Z-pyridyl, ylpyridyl, 2-methylpyridyl, ylpyridyl, S-methylpyridyl,
methylpyridyl, 2-methylpyridyl, 3-methyIpyridyl, 3-mcthoxypyridyl, 0xy—2—
pyridyl, 0xy-2—pyridyl, 6-meth0xypyridyl, 2-meth0xypyridyl, 4-meth0xy—3-pyridyl,
ypyridyl, 6-methoxypyridyl, 2-mcthoxy—4-py‘ridyl, 0xypyridyl, 3-cyclopr0pyl-
2-cyclopr0pyl-
2-pyridyl, 4-cyclopropyl-Z-pyridyl, 5-cyclopropyl-Z-pyridyl, 6-cyclopmpylpyridyl,
2-Cyclopropyl~
3-pyridy1, 4-cyclopropylpyridy1, S-cyclopropylpyridyl, 6-cyclopr0pyl—3—pyridyl,
4-pyridyl, 3-cyclopropylpyridyl, 3-cyclopropylmethyl-Z-pyridyl, 4-cyclopropy1methyl—2-pyridyl,
-cyclopmpylmethyl-2~pyridyl, 6-cyclopropylmethyl-Z-pyridyl, 2-cyclopropylmethylpyridyl,
cyclopropylmethyl-3—pyridyl, 5—cyclopropylmelhylpyridyl, 6—cyclopropylmethyl~3-pyridyl,
cyclopropylmethylpyridyl, opr0pylmethylpyridyl, 3~cyclopropylaminopyridyl,
cyclopropyIamino-Z-pyridyl, S-cyclopropylaminoZ—pyridyl, 6—cyclopropylaminopyridyl, 2-
cyclopropylaminopyridy1, 4—Cyclopropylamino—3-pyridyl, S-cyclcpmpylaminopyridyl,
cyclopropylamin0pyridy1, 2-Cyclopropylamin0pyridyl, 3-cyclopropylamino-zl-pyridyl,
cyclopropylmethylamino—Z-pyridyl, 4-cyclopropylmethylamino-Z-pyridyl, 5-
cyclopropylmethylamino—Z-pyridyl, 6—cyclopropylmethylamina-Z-pyridyl, 2-
cyclopropylmethylamino—3-pyridyl, 4-cyclopropylmethylaminopyridyl, 5-
cycIopropylmethylamin0—3-pyridyl, 6-cyclopropylmethylamino—3-pyridy1, 2-
cyclopropylmethylamin0pyridyl, 3—cyclopropylmethylamino-4—pyridyI, 3’1nethylamino-Z-pyridyl,
4-methylaminO-E-pyridyl, ylaminopyridyl, 6-methylamino-Z-pyridyl, 2~methy1amino«3-
pyridyl, 4-methyiamino—3—pyridyl, 5-methy1aminopyridyl, 6—methylamino—B—pyridyl,
amino—4—pyridyl, 3—methylamino-4epyridyl, thylamino—Z-pyridyL 4~dimethylamino«2~
pyridyl, S-dimcthylamino-Z-pyridyl, thylaminopyridyl, 2-dimethylamin0pyridyl,
dimethylamino—B-pyridy}, 5—dimethylaminopyridyL 6-dimethylamino-3—pyridyl, 2-dimethylamin0-
-methylthio—
4-pyridyl, 3-dimethylamino—4—pyridyl, 3—methyithi0—2-pyridyl, 4«methylthio—2—pyridyl,
2upyridylj 6-methylthi0—2—pyridyl, 2—methylthi0pyridyl, 4~methylthiopyridyl, S-methyithi0~3~
fi—acetoxy~2-pyridyi,
pyridyl, 6—methylthio—3-pyridyl, 2~methylthio«4~pyridyl, 3—methyithio~4~pyridyl,
4811-7918J7261
039363—721 1
4—acetoxy—2—pyridyl, 5—acetoxy~2—pyridyl, 6—acetoxy—2—pyridyl, 0xy—pyridyl, 4—acetoxy—3—
3—acety1—
pyridyl, 5—acetoxy-3—pyridyl, 6—acetoxy—3—pyridyl, 2—acetoxy—4—pyridyl, 3—acetoxy—4—pyridyl,
2—pyridyl, 4-acelyl—2—pyridyl, S—acetyl—Z—pyridyl, 6—acetylpyridyl, Z—aceg'l—pyridyl, 4—acetyl—3—
pyridyl, yl-3—pyridyl, 6—acetyl—3—pyridyl, Z—acetyl—4—pyridyl, 3—acetyl—4—pyridyl,
methoxyearbonyl—Z—pyridyl, 4—methoxycarbonyl—2—pyridyl, 5—methoxycarbonyl—2—pyridyl, 6-
methoxycarbonyl—Z—pyridyl, 2—methoxycarbonyl—3—pyridyl, 4—methoxycarbonyl-3—pyridyl, 5—
methoxycarbonyl—B—pyridyl, 6—methoxycarbonyl—3-pyridyl, 2—methoxycarbonyl—4—pyridyl, 3-
methoxycarbonyl—4—pyridyl, 3—methylcarbamoyl—2—pyridyl, 4—methylcarbamoyl—2—pyridyl, 5—
methylcarbamoylpyridyl, 6-methylcarbamoylpyridyl, 2-methylcarbamoylpyridyl, 4-
methylcarbamoyl-3 yl, 5-mcthylcarbamoylpyridyl, 6-methylcarbamoylpyridyl,
methylcarbamoylpyridyl, 3-methylcarbamoyl—4-pyridyl, 3-acetamidopyridyl, 4-acetamido—2—
4—acetamido
pyridyl, S—acetamido—Z—pyridyl, 6-acetamido-2—pyridyl, 2-acetamidopyridyl,
and 3—acetamido—4—
l, 5—acetamido—3 -pyridyl, 6—acetamido—3—pyridyl, 2-acetamido—4—pyridyl
pyridyl, 3—(l—cyanocyclopropyl)—2—pyridyl, 4—(1—cyanocycIopropyl)—2—pyridyl, 5-(1—
cyanocyclopropyl)pyridyl, 6-(1—cyanocyclopropyl)—2—pyridyl, yanocyclopropyl)—3-pyridyl, 4—
(l—cyanocyclopropyl)—3 -pyridyl, 5—(1—cyanocyclopropyl)v3—pyridyl, 6-(1—cyanocyclopropyl)—3—
each of which is
pyridyl, 2—(l—cyanocyclopropyl)—4—pyridyl, 3—(1—cyanocyclopropyl)—4—pyridyl,
optionally tuted with from 1, 2, or 3 susbtituents independently selected from F, Cl, Br,
1, —CN, —
OH, CH, NHZ, CF30—, CH3—, CH3O, —N02, cyclopropyl, l—cyanocyclopropyl, cyclopropylmethyl,
cyclopropylamino, cyclopropylmethylamino, methylamino, ylamino, methylthio, acetoxy,
acctyl, methoxycarbonyl, acetamido, carbamoyl, isopropyl, l—pyrrolidinyl, l—cyclopropylethyl,
2—cyclopropylethyl, l—cyclopropylethylamino, opropylethylamino 0r l—hydroxy—l—methylethyl.
In some instances, the l, 2, 3 substituents are on the aromatic portion of
In other instances, the l,
2, 3 substituents are on the aliphatic portion of Y'. All the other variables Y2, Q, Z of formula (I) and
R4, R5, R6, R7 and R8 are as defined in any of the embodiments described herein.
is phenyl substituted with from 1 to
{0082] In n embodiments of nds of formula (I), Y1
2 susbtituents independently selected from F, Cl, Br, I, —CN, —OH, —CF3, NHz, CF30, CH3—, CH3O,
(bl—1503 —N02, cyclopropyl, cyclopropylmethyl, cyclopropylamino, ropylmethylamino,
cyanoeyclopropyl, l.—carboxycyclopropyl, l-carbamoylcyclopropyl, l-methoxycarbonylcyclopropyl,
l-cyanoiscpt‘opyl, l’hydroxycyclopropyl. l—hydoxyisopropyl, cyclobutoxy, cyclopentoxy,
cycloheyloxy, 4~morpholino, 4-hydroxypiperidinyl,l- piperidinyl, piperazinyl, 4-methylpiperazinyl,
toxyearbonylpiperazinyl, azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl, S-methyl-l,2,4-
zolyl, 5—methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol—2yl, S-nietliylamino-
thiadiazol—2—yl, methylamino methylamino, dimethylamino, methylthio, acetoxy, ,
methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl, l—pyrrolidinyl, l-cyclopropylethyl,
cyclopropylethyl, l-cyclopropylethylamino, 2~cyclopropylethy[amino or l—hydroxy—l«methylethyl.
4811—7918—7726.1
039363-7211
In other embodiments of compounds of formula (1), Y1 is selected from the group consisting
of phenyh 2-halophenyl, 3—halophenyl, 4—halophenyl, Z-fluorophenyl, 3—fluorophenyl, 4-fluorophenyl,
2—cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, oxyphenyl, 3-hydmxyphenyh 4-
hydroxyphenyl, 2—triIluoromethylphenyl, 3-trifluoromethylphenyl, 4—trifluoromethylphenyl, 2—
aminophenyl, 3—aminophenyl, 4—aminophenyl, 2—trif1uoromethylphenyl, 3—trifluoromethylphenyl, 4-
oromethylphenyl, 2—methylphenyl, 3—methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3—
methoxyphenyl, 4—methoxyphenyl, 2~cyelopropylphenyl, 3—cyclopropylphenyl, 4—cyclopropylphenyl,
2-cyclopropylmethylphenyl, 3- cyclopropylmethylphenyI, 4-cyclopropylmethylphenyl, 2-
cyclopropylmethylaminophenyl, 3- cyclopropylmethylaminophenyl, 4-
cyclopropylmethylaminophenyl, 2-cyclopropylaminophenyl, 3-cyclopropylaminophcnyl, 4-
cyclopropylaminophenyl, 2-methylaminophcnyl, 3-methylaminophenyl, 4—methylaminophenyl, 2-
dimethylaminophenyl, 3—dimethylaminophenyl, 4-dimethylaminophenyl, 2-methylthiophenyl, 3—
thiophenyl, 4-methylthiophenyl, oxyphenyl, 3—acetoxyphenyl, 4—aeetoxyphenyl, 2—
acetylphenyl, 3—acetylphenyl, 4-acetylphenyl, 2—mcthoxycarbonylphenyl, 3vmethoxycarbonylphenyl,
4—methoxycarbonylphenyl, amidophenyl, amidophenyl, 4-acetamidophenyl, 2—
methylcarbamoylphenyl, 3—methylcarbamoylphenyl, 4—methylcarbamoylphenyl, 2—(l—
cyanocyclopropyl)phenyl, 3—(1-cyanocyclopropyl)phenyl and 4—(l—cyanocyclopropyl)phenyl, each of
which is optionally substituted with from I, 2 or susbtituents independently selected from F, Cl, Br, I,
—CN, -OH, CH, NHZ, CF3O-, CH3-, CH30, —N02, cyclopropyl, l—cyanocyclopropyl,
cyclopropylmethyl, ropylamino, cyclopropylmethylamino, methylamino, dimethylamino,
methylthio, acetoxy, acetyl, mcthoxycarbonyl, acetamido, l—cyclopropylethyl, 2—cyclopropylethyl, l—
cyclopropylethylamino, 2—cyclopropylethylamino or 1—hydroxy—1-methylethyl or methylcarbamoyl.
In some instances, the l, 2, 3 substituents are on the ic portion of Y1. In other instances, the 1.,
2, 3 substituents are on the tic portion of Y1. All the other les Y2, Q, Z of formula (I) and
R4, R5, R6, R7 and R8 are as defined in any of the embodiments described herein.
In some embodiments of compounds of formula (I), Y2 is as defined in the summary of the
invention and the other variables Y1, Q and Z of formula (I) and R4, R5, R6, R7 and R8 are as defined
in any of the above embodiments and any of the embodiments described herein.
In some embodiments of compounds of formula (i), Y2 is H, halogen, CN, C; 6alkyl, (3:.
(,alkoxy, (33.6cycioalkylamino, C346eycloalkyl-C1.3alkylamino, aryl, heteroaryl. aryialkyl or
arylalkyl, wherein the aliphatic or aromatic portion of Y2 is optionally substituted with 1, 2 or 3
tuents independently selected from H, F, C l, 1, CN, CH3, CH30-, phenyl, CF; or CF30. in
certain instances, Y2 is H, halogen, CN, l, C 1.6alkoxy, C3_6cycloalkylamino or (£3,6cycloalkyl—
C;-3alkylamino, wherein the aliphatic portion of Y2 is optionally substituted with l, 2 or 3 substituents
independently selected from H, F, Cl, 1, CN, CH3, CH30~, phenyl, CF; or CF30. All other variables
Y4, Q and Z of a (I) and R4, R5, Ré, R7 and R8 are as defined in any of the embodiments
described herein‘
4811n7918«7726.1
039363—721 1
In some embodiments of nds of a (I), Y2 is H, F, Cl, 1, CN, CH3, CHgo‘,
formula (I) and
ropylamino or eyelopropylmethylamino. All the other variables Y‘, Q and Z of
R4, R5, R6, R7 and R8 are as defined in any of the embodiments described herein.
Y2 is H and all the other
[0087} In some preferred embodiments of compounds of formula (I),
defined in any of the
variables Y', Q and Z of formula (I) and R4, R5, R“, R7 and R2; are as
embodiments described herein.
In some embodiments of compounds of formula (I), Q is selected from H, F, C1 or CH3.
one embodiment, Q is H. In another embodiment, Q is F. In yet another embodiment, Q is CH3.
still other embodiment, Q is Cl. In another embodiment, Q is H or F. All the other variables Y1, Y2,
the ments described herein.
Z of formula (I) and R4, R5, R", R7 and R8 are as defined in any of
In some embodiments of compounds of formula (I), Z is as defined in the summary of
R8 are as defined in any of the
ion. All the other variables of formula (I) and R4, R5, R6, R7 and
embodiments described herein.
In some embodiments of compounds of formula (I), Z is -—N(R4)(R5) or ~C(R6)(R7)(R3),
of H, optionally
n R4 and R5 are each independently selected from the group consisting
substituted C3.gcycloalkylalkyl,
substituted CMalkyl, optionally substituted C3.gcycloalkyl, optionally
optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally
and optionally
substituted aryl, optionally substituted arylalkyl, optionally tuted heteroaryl
to which they are
substituted heteroarylalkyl; or R4 and R5 taken together with the nitrogen atom
additional atoms as ring members
attached form a four to eightmembered ring having from 0-2
is optionally substituted with from
selected from N, O or S, wherein the four to eight-membered ring
from C16 kyl, CM haloalkoxy, CM alkyl, (33.8
one to three groups independently ed
cycloalkyl, CH lkylalkyl, aryl, arylalkyl or R6. R6, R7 and R8 are each independently H, CH,
arylalkyl,
alkyl, CM haloalkyl, CH, haloalkoxy, C34; cycloalkyl, C34; cycloalkylalkyl, aryl,
~X2R9; wherein the aliphatic or
heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl or
from I to 3 s
ic portion of R6, R7 and R8 are each optionally substituted with
independently selected from the group consisting of C3.3cycloalkyl, C3_gcycloalkylalkyl, aryl,
and Re; or any two of
arylalkyl, heterocyeloalkyl, heterocycloaikylalkyl, heteroaryl, heteroarylalkyl
which they are attached form a 3 to 8—
the Ré, R7 and RE groups taken together with the carbon atom to
from I to 2 heteroatoms as
membered earbocyclie ring or a 4 to 8-membered heterocyclic ring having
8-membered carboeyclie ring or the 4 to 8—
ring members selected from N, O or S, wherein the 3 to
three groups independently
membered heterocyclic ring is optionally substituted with from one to
selected from C;_6haloalkyl, thaloalkoxy, Cl.6alk)'l, cloalkyl, C3-gcycloalkylalkyl, aryl,
least two of the R6, R?
arylalkyl, heteroaryl or heteroaryIalkyl or R“, provided at each occurrence, at
and R8 groups are not simultaneousiy en Ail the other variables 3'”, Y2 and Q of formula (I)
herein.
are as defined in any of the embodiments bed
4811391847261
039363-7211
In some embodiments of compounds of formula (I), Z is ~N(R4)(R5), wherein R4 and R5 are
each independently selected from C,.53lkyl, C3_geycloalkyl, C3_gcycloalkylalkyl, aryl, ai'y'l—C1_4alkyl,
heteroaryl or heteroaiyl-C1_4alkyl, each of which is ally substituted with from ( i) l—3
substituents independently selected from Cmalkoxy, loalkyl, loalkoxy, Cmalkyl, C3.
acycloalkyl, C3_gcyeloalkylalky1, aryl, arylalkyl, heteroaryl, heteroaiylalkyl or R6; or (ii) 1, 2 or 3 R3
substituents; or (iii) 1, 2 or 3 Rb substitnents; or (iv) 1, 2 or 3 RC substituents; or (V) 1, 2 or 3 Rd
substituents; or (vi) 1, 2 or 3 Rf groups. All the other variables Y‘, Y2 and Q of formula (I) are as
defined in any of the embodiments described herein.
In some embodiments ot‘compounds offormula (l), R4 is —CH3 and R5 is C2.(,alkyl, Ct.
scycloalkyl, C3.gcycloalkylalkyl, aryl, malkyl, heteroaryl or heteroai‘yl-C1.4alkyl, each of which
is optionally substituted with from (i) l~3 substituents independently selected from Cmalkoxy, CL
chaloalkyl, C1_(,haloalkoxy, C1_6alkyl, C3_3cycloalkyl, C3,gcycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl or Re; or (ii) 1, 2 or 3 Ra tuents; or (iii) 1, 2 or 3 Rb substituents; or (iv) 1, 2 or 3
RC substituents; or (v) 1, 2 or 3 Rd substituents; or (vi) 1, 2 or 3 Rf groups. In certain instances, R4 is -
CH3 and R5 is C2_6alkyl. All the other variables Y], Y2 and Q of formula (I) are as defined in any of
the embodiments described herein.
in some embodiments of compounds of formula (I), R4 and R5 are each independently
ed from C._6alkyl, C3_gcycloalkyl, cloalkylalkyl, aryl, aryl—C;.4alkyl, heteroaryl or
aryl—C1_4alkyl, each of which is optionally substituted with from 1, 2 or 3 Rx members ed
from F, Cl, Br, 1, —CN, —OH, —CF3, NHQ, CF30-, CH3-, CH3O, —NOZ, cyclopropyl, cyclopropylmethyl,
cyclopropylamino, cyclopropylmethylamino, l—cyanocyclopropyl, methylamino, dimethylamino,
methyithio, acetoxy, acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, dyl, 3—pyridyl, 4-
pyridyl, 2—pyridylmethyl, 3-pyridylmethyl, 4—pyridylmethyl, 2-oxetanyl, 3-oxtetanyl, 2—
oxctanylmethyl, 3—oxtetanylmethyl, Z—tetrahydrofuranyl, 3-tetrahydrofuranyl, 2—
tetrahydrofuranylmethyl, 3-tetrahydrofuranylmethyl, 1—pyrrolidinyl, 2—pyrrolidinyl, 3—pyrrolidinyl, 2—
letrahydrothiophenyl, 3-tetrahydrothiophenyl, 4—morpholinyl, 2-morpholinyl or 3- morpholinyl. In
certain instances, Rx is F, —CN, —OI-I, —CF3, NHz, CF30—, CH3—, CH3O, -NOg, cyclopropyl,
cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, l-cyanocyclopropyl, methylamino,
dimethylamino, methylthio, y, aeetyl, mcthoxycarbonyl, acetamido, carbamoyl, 2-
pyridyl, 3»pyridyi, 4-pyridyl, 2-pyridylmethyl, 3—pyridylmethyl, 4-pyridylmethyl, Z-oxetanyl, 3-
oxtetanyl, anylmethyl, 3~oxtetanylmethyL 2-tetrahydrofuranyl, 3—tetrahydmfuranyl, 2-
tetrahydrofuranylmethyl, 3—telrahydrofnranylmethyl, lupyrrolidinyl, 2—pyrrolidinyl, 3-pyrrolidinyl, 2»
tetraliydrothiophenyl, 3-tetrahydrothiophenyl, 4—morpholinyl, h0linyl or 3— morpholinyl. All
the other variables Y‘, Y2 and Q of formula (I) are as defined in any of the embodiments described
4811-7918‘772611
039363—7211
In some ments of compounds of formula (D, R4 is ~CH3 and R5 is k)'l, C3.
of which
gcyclealkyl, C3_gcycloalkylalkyl, aryl, aryl-C1-4alkyl, heteroaryl or heteroaryl—Cmalkyh each
is optionally substituted with from 1, 2 or 3 RX members selected from F, Cl, Br, I, -CN, —OH, —CF3;
NHL CF30-, CH3—, CHgO, —NO;, cyclopropylf cyclopropylmethyl, mpylamino,
eyelopropylmethylamino, I—Cyanocyclopropyl, methylamino, dimethylamino, methylthio, aeetoxy,
acetylg methoxycarbonylg acetamido, methylcarbamoyl, 2-pyridyl, 3‘pyridyl, 4—pyridyl,
lmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, tanyl, anylmethyl, 3—
oxtetanylmethyl, Z-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2—tetrahyd1'ofuranylmethyl, 3—
tetrahydrofuranylmethyl, l—pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, Z-tetrahydrothiophenyl, 3-
tetrahydrothiophenyl, 4-morpholinyl, 2-morpholinyl or 3- morpholinyl. In certain instances, R" is F, -
CN, -OH, -CF3, NHZ, CF30-, CH3-, CH30, -N02, cyclopropyl, cyclopropylmethyl, ropylamino,
ropylmethylamino, l—cyanocyelopropyl, methylamino, dimethylamino, thio, acetoxy,
acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, dyl, 4-pyridyl,
pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl,
nylmethyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofurany[methyl, 3—
tetrahydrofuranylmethyl, l-pyrrolidinyl, 2—pyrrolidinyl, 3-pyrrolidinyl, Z-tetrahydrothiophenyl, 3-
tetrahydrothiophcnyl, 4-morpholinyl, 2-morpholinyl or 3- morpholinyl. All the other variables Y1, Y2
herein.
and Q of a (I) are as defined in any of the embodiments described
R5 is selected from
In some embodiments of compounds of formula (I), R4 is ~CH3 and
ethyl, propyl, butyl, pcntyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl,
each of which is
cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl,
from F, -CN, -OH, —CF3,
optionally substituted with from 1-3 substituents ndently selected
NHZ, CF3O-, CH3-, CII30, —NO;, cyclopropyl, cyclopropylmethyl, cyclopropylamino,
cyclopropylmethylamino, l—cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,
acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4—pyridyl,
pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2—oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl,
oxtetanylmethyl, 2—tetrahydrofuranyl, ahydrofuranyl, ahydrofuranylmethyl, 3-
ydrcfnranylmethyl, l-pyrrolidinyl, olidinyL 3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-
tetrahydrothiophenyl, 4—morpholinyl, 2-morpholinyl or 3-mcrpholinyl. All the other variables Y1, Y2
herein.
and Q of formula ( I) are as defined in any of the embodiments described
wherein ~NCR“)(R5) is
[0096} In some embodiments of compounds of formula (I), z is —N(R‘)(R5),
selected from ‘indinyl, l—pyi‘rolidinyl, l-piperidinyl, 4-morph0linyl, 4-thiom0rpholinyl,
idinyl, 3~thiazolidinyh 2—isoxazolidinyl, 2-isothiazelidinyl, l-pyrazolidinyl, l-piperazinyl,
l—hexahydropyrimidinyl or l—hexahydropyridazinyl, each of which is (i) optionally substituted with
of halogen, C1-6alkyl,
from I to 3 R26 substituenl‘s independently selected from the group consisting
Cmalkcxy; thaloalkyl, thaloalkexy, Cwelkylé €3,3cyclealkyl, C3_gcyelealkylalkyl,
heteroeyclealkyl, heterecycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and R“; or (ii) two
4811-7918—77261
039363—7211
adjacent R25 substituents together with the atom to which they are ed form a 5 or ered
aromatic ring having from O to 2 additional atoms as ring members selected from O, N or S or (iii)
optionally substituted with from 1 to 8 deuteriums with at least 52.5%, 60%, 70%, 75%, 80%, 90%,
95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium. In certain instances, R26 is
F, Cl, Br, I, -CN, —OH, —CF3, NHZ, CF30«, CH3—, CH30, -N03, cyclopropyl, cyclopropylmethyl,
cyclopropylamino, eyelopropylmethylamino, l—cyanocyclopropyl, methylamino, dimethylamino,
methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido, carbamoyl, 2—pyridyl, 3—pyridyl, 4—
pyridyl, 2~pyridylmethyl, 3cpyridylmcthyl, 4-pyridylmethyl, 2—oxetanyl, 3~oxtetanyl, 2-
oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofi1ranyl, ahydrofuranyl, 2-
tetrahydrofuranylmethyI, 3-tetrahydrofuranylmethyl, l-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2—
tetraliydrothiophenyl, 3-tetrahydrothiophenyl, 4-morpholinyl, 2-morpholinyl or 3- linyl. In
other instances, R26 is F, -CN, -OH, -CF3, NHZ, CF3O-, CH3-, CH3O, -N02, ropyl,
cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, l-cyanocyclopropyl, methylamino,
dimetliylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-
pyridyl, 3-pyridyl, 4—pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2—0xetanyl, 3—
oxtetanyl, 2—oxetanylmethyl, 3-oxtetanylmethyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2—
ydrofuranylmethyl, 3—tetrahydrofuranylmethyl, l-pyrrolidinyl, 2—pyrrolidinyl, 3—pyrrolidinyl, 2—
tetrahydrothiophenyl, 3—tetrahydrothiophenyl, 4-morpholinyl, 2-morpholinyl or 3— morpholinyl. In
other instances, R26 is F, CH3, methoxycarbonyl, carbonyl, —CH3, CH3(CO)NH-, Vinyl, propen—
3-yl or CH3(CO)(CH3)N—. In some embodiments, each hydrogen atom in Z is optionally replaced by a
deuterium atom with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9%
deuterium incorporation for each deuterium. All the other variables Y], Y2 and Q of formula (I) are as
defined in any of the embodiments described herein.
In some embodiments ot‘compounds of formula (I), Z is —C(R6)(R7)(R8), where R6 is H and
R7 and R8 are each independently Cmalkyl, ally substituted with from 1 to 3 Rd or Re. In some
ments, R6, R7 and R8 are each independently C1.6alkyl, optionally tuted with from I to 3
Rd or Re. In some ments, —C(R6)(R7)(R3) is cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,
cyclohcptyl, cyclooctyl, each of which is optionally substituted with from 1-3 R23 substituents
independently selected from F, Cl, Br, 1, -CN, -OH, —CF3, NHZ, 0330-, CH3‘, CH30, —CH;Cll=Cllg, -
N02, cyclopropyl, cyelopropylmetliyl, cyclopropylamino. cyclopropylmethylamino, [—
eyanocyelopmpyl, vinyl, methylamino, dimethylamino, thio, acetoxy, acetyl,
methoxycarbonyi, acetamido, methylcarbamoyl, 2—pyridyl, 3-pyridyl, 4-pyridyl, 2—pyridylmethyl, 3-
pyridylmethyl, dylmethyl, anyl, 3-oxtetanyl, anylmethyl, 3-oxtctanylmethyl, 2-
tetrahydrofuranyl, 3-tetrahydrofiiranyl, 2—tetrahydrofuranylmethyl, 3-tetrahydrofuranylmethyl, l-
pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydtothioplienyl, 4—
linyl, 2-morpholinyl or 3- morpholinyL In some instances, R38 is F, ~CN, DH, «C1633, NHZ,
CF36}, CH3», CHgO, NOE, cyclepropyl, eyelopropylmethyl, cyclopropylamino,
481 17726.1
039363-7211
cyclopropylmethylamino, l—eyanoeyclopropyl, methylamino, dimethylamine, methylthio, acetoxy,
acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2—pyridyl, 3—pyridyl, 4—pyridyl, 2—
pyridylmethyl, 3—pyridylmethyl, 4-pyridylmethyl, 2—0xetanyl, 3-oxtetanyl, 2—oxetanylmethyl, 3—
nylmethyl, 2—tetrahydrofuranyi, 3—tetrahydrofi1ranyl, 2-tctrahydrofuranylmethyl, 3—
tetrahydrofuranylmethyl, l-pyrrolidinyl, 2—pyrrolidinyl, 3—pyrrolidinyl, 2—tetrahydrothiophenyl, 3-
tctrahydrothiophenyl, 4—morpholinyl, 2—morpholinyl or 3— morpholinyl. In some embodiments, —
C(R6)(R7)(R8) is 2-azetindinyl, 3-azetindinyl, 3-pyrrolidinyl, olidinyl, 2—piperidinyl, 3-
piperidinyl, 4-piperidinyl, 2—morpholinyl, 3—morpholinyl, 2-thiomorpholinyl, morpholinyl,
oxazolidinyl, 4-oxazolidinyl, S—oxazolidinyl, 2—thiazolidinyl, 4-thiazolidinyl, S-thiazolidinyl, 3-
isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-
azolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 2-piperazinyl, 2-hexahydropyrimidinyl, 4—
hexahydropyrimidinyl, 5—hexahydropyrimidinyl, 3-hexahydropyridazinyl or hydropyridazinyl,
each of which is optionally substituted with l to 3 R28 substituents. In some embodiments, each
hydrogen atom in Z is optionally replaced by a deuterium atom with at least 52.5%, 60%, 70%, 75%,
All the other
80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium.
herein.
variables Y], Y2 and Q of a (I) are as defined in any of the embodiments described
In some embodiments of compounds of formula (I), Z is selected from the group consisting
of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cycloheptyl, ctyl, l—azetindinyl, l-
pyrrolidinyl, l~piperidinyl, 4-morpholinyl, 4—thiomorpholinyl olidinyl, zolidinyl, 2—
isoxazolidinyl, 2—isothiazolidinyl, l-pyrazolidinyl, l—piperazinyl, l—hexahydropyrimidinyl, l—
hexahydropyridazinyl, )(CF3CH2)N—. cycloproyplmethylamino, sec—butyl, pcntan-Z-yl and
R27 substituents
pentanyl, each of which is (i) ally substituted with from one to three
independently selected from the group consisting of halogen, C._6alkyl, C1_6alkoxy', thaloalkyl, C1.
shaloalkoxy, Cibalkyl, C3_g cycloalkyl, C34; cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,
R27 substituents together with
aiyl, arylalkyl, heteroaryl, arylalkyl and R°; or (ii) two adjacent
0 to 2
the atom to which they are attached form a 5 or 6—membered aromatic ring having from
from 1
additional atoms as ring members selected from O, N or S; or (iii) optionally substituted with
99.5% or 99.9%
to II deuteriums having at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%,
deuterium incorporation for each deuterium. In one embodiment, Z is cyclopropyl optionally
substituted with l to 2 R27 groups. In r embodiment, Z is cyclopentyl optionally substituted
with l to 2 R37 groups. In yet another embodiment Z is l-pyrrolidinyl optionally substituted with t to
2 R27 . In other embodiment, Z is l-piperidinyl optionally substituted with l to 2 R;7 groups.
In another embodiment, Z is l-pyrrolidinyl, 3-fluoro-l—pyrrolidinyl, (3 S)—3—fluoro-l—pyrrolidinyl,
(3 R)~3 ~fluoro— l -pyrrolidinyl, 3,3 —difluoro—l —pyrrolidinyl, 3—C1.6alkyl—C(O)—C1.6alkyl-N—l ~pyrrolidinyl,
3-C16alkyI—C(O)NH-l~pyrrolidinyl, C1-éalkoxycarbonyl~ l lidinyl or 3,3-dimethyl—l ~pyrrolidinyl.
In certain instances, R27 is F, Cl, Br, 1, —CN, on, —CF3, NHQ, CF30, one, CH30, hog, cyclopropyl,
eyelepropyimethyi, ropylamino, cyclopropylmethylamino, I—cyanoeyclopropyl, amino,
4811491847261
039363—721 1
dimethylamino, methylthio, acctoxy, acetyl, ycarbonyl, acetamido, methylcarbamoyl, 2—
pyridyl, 3—pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4—pyridylmethyl, 2—oxetanyl, 3—
oxtetanyl, 2—oxetanylmethyl, 3-oxtetanylmethyl, 2-Ietrahydrofuranyl, 3~tetrahydrofuranyh 2-
tetrahydrofuranylmethyl, 3-tetrahydrofuranylmethyl, l—pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
ahydrothiophenyl, 3-tetrahydrothiophenyl, holinyl, 2-mo1'pholinyl or 3- morpholinyl. In
one instance, R27 is -F, methoxyearbonyl, ethoxycarbonyl, -CH3, )NH-, vinyl, propenyl or
CH3(CO)(CH3)N-. In another instance, R27 is -F, ycarbonyl, ethoxycarbonyl, {TI-13,
CH3(CO)NH- or CH3(CO)(CH3)N—. In yet another instance, R27 is vinyl or propen—3—yl. All the other
variables Y', Y2 and Q of formula (I) are as defined in any ofthe embodiments described herein.
Suigformulae ofFormula I
In one embodiment of the invention, compounds of formula (I) have mula (Ia):
where the substitucnts Y1, Y2, Q, R4 and R5 are as defined in any of the embodiments disclosed
herein. In some embodiments, R4 is CH, and R5 is l optionally substituted with from 1—3
substituents independently selected from F, Cl, Br, I, —CN, —OH, —CF3, NHg, CF3O—, CH3—, CHgO, —
N02, cyclopropyl, cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, l-
cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl,
acetamido, methylearbamoyl, 2-pyridyl, 3-pyridyl, 4—pyridyl, 2-pyridylmethyl, 3—pyridylmethyl, 4—
pyridylmetliyl, 2-oxetanyl, 3-oxtetanyl, Z-oxetanylmethyl, 3-oxtetanylmethyl, 2—tetrahydrofuranyl, 3—
tetrahydrofuranyl, 2-tetrahvdrofuranylmethyl, 3-tetrahydrofuranylmethyl, l—pyrrolidinyl, 2—
pyrrolidinyL olidinyl, 2-tetrahydrothiophenyl, rahydrothiophenyl pholinyl, 2-
morpholinyl or 3- morpholinyl.
In a second embodiment of the ion, compounds of formula (I) have subformuia (lb):
2 // {R“)m
HNw—SN\)})nm
l \g \ F
//‘\N o
H lb
where RH is CMalkyl, C1_balkoxy, (31.5haloalkyl, C]-E,lialoalkoxy, C_;.gcyeloalkyl, C;;-geyeloalkylalkyl,
aryl, aryleikyl, heteroaryl, heteroarylalkyl, heteroeycloalkyli heteroeycloalkylalkyl or R5, each of
48117726.1
039363—7211
which is optionally substituted with from (i) 1-3 substituents independently ed from Ci_6alkoxy,
C 3.6haloalkyl, thaloalkoxy, Cmalkyl, C3_8cycloalkyl, C3_gcycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, Rd or R6; or (ii) 1, 2 or 3 R8 substituents; or (iii) 1, 2 or 3 Rb substituents; or (iv) 1, 2
or 3 Rc substituents; or (v) 1, 2 or 3 Rd substituents; or (vi) 1, 2 or 3 Rf groups; the subscript n is l, 2.
3, 4 or 5 and the subscript m is 0, l, 2 or 3. In some embodiments, R” is Ci_6all(yl, F, Cl, Br, I, -CN, -
OH, —CF3, NHZ, CF30-, CH3-, ethyl, propyl, butyl, CH30, -N03, cyclopropyl, cyclopropylmethyl,
cyclopropylamino, cyclopropylmethylamino, l-cyanocyclopropyl, methylamino, dimcthylamino,
methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2upyridyi, 3-pyridyl, 4-
l, 2—pyridylmethyl, 3—pyridylrnethyl, 4-pyridylmethyl, 2—oxetanyl, 3—oxtelanyl, 2-
oxetanylmethyl, tanylmethyl, 2-tetraliydrofuranyl, 3-tetrahydrofuranyl, 2—
tetrahydrofuraiiylmethyl, 3-tetrahydtofuranylmethyl, l-pyrrolidinyl, 2—pyrrolidinyl, olidinyl, 2-
tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 4-morpholinyl, holinyl or 3- morpholinyl. In
some embodiments, in is 0. In other embodiments, the subscript n is l: 2, 3 or 4. In some
embodiments, n is l, 2 or 3 and m is l or 2. All the other variables Y], Y2 and Q are as defined in any
of the embodiments described herein.
In a third embodiment of the invention, compounds of formula (I) have subformula (1c):
O R7
\ HN.. is
I \ F
/ g R8
N N
H [C
wherein R‘7 and R8 are each independently C._6alkyl, thaloalkyl, Ciréhaloalkoxy, C3_gcycloalkyl, C3.
gcycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or -X2R9, wherein the aliphatic or
aromatic portion of R7 and R8 are each optionally substituted with from 1 to 3 members independently
ed from the group consisting of C3-8cycloalkyl, C3_3cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl and Re; and wherein x2 is —NR'°, 0 or s; R10 is H, Ci_6alkyl or aryl; and R" is H, C._
l, aloalkyl, loalkoxy, C3_gcycloalkyl, C3.gcycloalkylalky‘l, aryl, kyl, aryl or
heteroarylalkyl, wherein R9 is optionally substituted with from I to 3 Re substituents. In some
embodiments, R7 and R8 groups taken together with the carbon atom to which they are attached form
from 1 to 2
a 3 to ered carbocyclic ring or a 4 to 8—membcred heterocyclic ring having
heteroatoms as ring members selected from N, O or S, wherein the 3 to 8-membered carbocyclic ring
from one to three groups
or the 4 to 8—membered heterocyclic ring is optionally substituted with
independently selected from C,.6ha|oalkyl, thaloalkoxy, Citéalkyl, C3.gcycloalkyl, C3.
gcycloalkylalkyl, aryl, kyl, heteroaryl or heteroarylalkyl or R". All the other variables Y‘, Y2 and
Q are as defined in any of the embodiments described herein.
In a fourth embodiment of the invention, compounds of formula (i) have subformuia (Id):
4811—7918—7061
039363-7211
(RWK/ Y2
I \ /HN*“CIS?”‘Z
N N
H Id
wherein R1:2 is H or R'; or two adjacent R12 together with the atoms to which they are attached form a
to 6-memhered ring having 0—2 heteroatoms as ring members selected from O, N or S; wherein the 5
to 6-membered-ring is optionally substituted with from 1-3 Rd or R6 substituents, and the subscript p
is an integer of l to 5. In one ment, p is 1. In another embodiment, p is 2. In yet another
embodiment, p is 5 and two adjacent RI2 tuents together with the atoms to which they are
attached form a 5 t0 ered ring having 0-2 heteroatoms as ring members ed from O, N or
S; wherein the 5 to 6-membered-ring is optionally substituted with from 1-3 Rd or RC substituents, and
each R12 is ndently H, Rd or Re, In some ments, the two adjacent R12 together with the
atoms to which they are attached form an optionally substituted fused carbocyclic ring, including, but
not limiting to, benzene, cyclopentane and cyclohexane rings. The substituents on the carbocyclic
ring can be from I~2 Rd or R’3 groups. In other embodiments, two adjacent R12 together with the atoms
to which they are attached form an optionally substituted fused cyclic ring, including, but not
limiting to, pyrrole, furan, thiophen, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole,
pyridine, pyrazine, pyridazine, tetrahydl'ftiran, tetrahydropyran, ydrothiophene, pyrazolidine, ,
isoxazolidine, imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, and
hexahydropyrimidine rings. All the other variables Y2, Q and Z are as defined in any of the
embodiments described herein.
In a fifth embodiment of the invention, compounds of formula (I) have subformula (Id-l):
n R12 is H or R}; or two adjacent RI2 together with the atoms to which they are attached form a
to 6—membered ring having 052 heteroatoms as ring members selected from O, N or S; wherein the 5
to 6-membered-ring is optionally substituted with from 1-3 Rd or Re substituents, and the subscript p
is an integer of l to 5. In one embodiment, p is I. In r embodiment, p is 2. In yet another
embodiment, p is 5 and two adjacent R12 substitucnts together with the atoms to which they are
attached form a 5 to 6—membered ring having 0—2 atoms as ring members selected from O, N or
; wherein the 5 to 6-membered-ring is optionally substituted with from I—3 Rd or R6 substituents, and
the other three R:2 is each independently H, Rd or R“, In some embodiments, the two nt R12
together with the atoms to which they are attached form an optionally substituted fused carbocyclic
481 17726.1
039363-721]
ring, including, but not limiting to, benzene, cyclopentane, cyclohexane and benzene rings. The
substituents on the carbocyclic ring can be from 1-2 Rd or Re groups. In other embodiments, two
adjacent R12 er with the atoms to which they are. attached form an optionally substituted fused
heterocyclic ring, including, but not limiting to, e, furan, thiophen, pyrazole, imidazole, oxazole,
isoxazole, thiazole, isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran, tetrahydropyran,
tetrahydrothiophene, pyrazolidine, , isoxazoiidine, imidazolidine, oxazolidine, thiamlidine,
isothiazolidine, dine, pipcrazine, and hexahydropyrimidine rings. All the other les Y2, Q,
R‘1 and R5 are as defined in any of the embodiments described herein.
In a sixth embodiment of the invention, compounds of formula (I) have subformula (Id-2):
All the variables R”, p, m, n, Y2, Q, and R” are as defined in any of the embodiments bed
herein. In some embodiments, R” is C1.6alkyl, C3_3cycloalkyl, C3_gcycloalkylalkyl, aryl, arylalkyl,
oaryl, heteroarylalkyl, heterocyeloalkyl, cycloalkylalkyl or Re, the subscript m is an integer
from 0 to 3, and the subscript n is an integer from 1 to 5.
[0105) In a seventh embodiment of the invention, compounds of formula (I) have subformula ):
Id~3
All the variables R”, p, Y2, Q, R7 and R8 are as defined in any of the embodiments described herein.
In some embodiments, R7 and R8 are each independently C1_5all{yl, C;.6haloalkyl, Ciéhaloalkoxy, C3.
alkyl, C3_8cycloalkyialkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or ~X2R9, wherein the
aliphatic or aromatic portion of R'7 and R8 are each optionally substituted with from I to 3 members
independently selected from the group consisting of Ci_gcycloalky'i, C3_gcycloalkyiaikyl, aryl,
arylalkyi, heteroaiyl, heteroarylalkyl and Re, provided at each occurrence, at least two of the R6, R7
and R3 groups are not simultaneously hydrogen; and wherein X2 is 4x112”), 0 or s; R“) is H, kyl
or aryl; and R9 is H, Ci_6alkyl, C;_6haloalkyl, Ci_6haloalkoxy, C3_gcycloalkyl, C3-gcycloalkylalkyl, aryl,
arylalkyl, aryl or heteroarylalkyl, wherein R9 is optionally substituted with from 1 to 3 R‘5
substituents.
In an eighth embodiment cfthe invention, nds of formula (I) have subformula (1e):
481 1—7918-77261
039363-7211
wherein R13 is H or R]; or two adjacent Rl3 together with the atoms to which they are attached form a
S to 6-membered ring having 0-2 heteroatoms as ring members selected from O, N or S; and the
subscript q is an integer of l to 4, where the 5 to ered-ring is Optionally substituted with from
1—3 Rd or Re substituents. In one embodiment, q is I. In r embodiment, q is 2. In yet another
embodiment, q is 4 and two adjacent R‘3 substituents together with the atoms to which they are
attached form a 5 to 6—membered ring having 0-2 heteroatoms as ring members selected from O, N or
S; wherein the 5 to 6—membered-ring is optionally substituted with from 1—3 Rd or Re substituents, and
the other two R13 groups are each independently H, Rd or Re, In some embodiments, the two adjacent
RI3 together with the atoms to which they are attached form an optionally substituted fused
carbocyclic ring, including, but not limiting to, e, cyclopentane and cyclohexane rings. The
substituents on the carbocyclic ring can be from 1—2 Rd or R'3 groups. In other embodiments, two
adjacent R13 groups together with the atoms to which they are attached form an optionally substituted
fused heterocyclie ring, including, but not limiting to, pyrrole, furan, thiophene, pyrazole, imidazole,
oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran,
tetrahydropyran, tetrahydrothiophene, pyrazolidine, , isoxazolidine, imidazolidine, idine,
thiazolidine, isothiazolidine, piperidine, piperazine, and hexahydropyrimidine rings. All the other
variables Y2, Q and Z are as defined in any of the embodiments described herein.
In a ninth embodiment of the invention, compounds of a (I) have subformula (If):
RM is H or R1; or two adjacent RM together with the atoms to which they are attached form a 5 to 6-
ed ring having 0‘2 heteroatoms as ring members selected from U, N or S; and the subscript r
is an integer of i to 3, where the 5 to 6-membered-ring is optionally substituted with from 13 Rd or
R‘6 substituents. In one embodiment, r is l. In another ment, r is 2. in yet another
embodiment, r is 3 and two adjacent Rl4 tucnts er with the atoms to which they are
attached form a 5 to ered ring having 0-2 heteroatoms as ring members selected from O, N or
S; wherein the 5 to 6~membered-ring is optionally substituted with from 1‘3 Rd or Re substituents, and
the other R” is H, RJ or R“. In. some embodiments, the tw0 adjacent RM together with the atoms to
which they are ed form an optionally substituted fused carbocyclie ring, including. but not
48113791877261
039363—7211
limiting to, benzene, cyclopentane and cyclohexane rings. The substituents on the carbocyelic ring
can be from 1—2 Rd or R6 groups. In other embodiments, two adjacent R” groups together with the
atoms to which they are attached form an optionally substituted Fused eyelic ring, including, but
not limiting to, e, Furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole,
isothiazoie, pyridine, pyrazine, pyridazine, tetrahydrt‘uran, tetrahydropyran, tetrahydrothiophene,
pyrazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine,
, isoxazolidine, imidazolidine,
piperazine, and hexahydropyrimidine rings. All the other variables Y3, Q and Z are as defined in any
of the embodiments described herein.
In a tenth embodiment of the invention, compounds of formula (I) have subformula (lg):
(R We'15);. l HN—g—Z
N) \ F H
/ O
H lg
is H or R“; or two adjacent RIS er with the atoms to which they are attached form a 5 to 6-
membered ring having 0-2 heteroatoms as ring members ed from O, N or S; and the subscript s
is an integer of l to 3, where the 5 to 6—membered—ring is optionally substituted with from 1-3 Rd or
R8 substituents. In one embodiment, s is 1. In another embodiment, s is 2. In yet another
embodiment, s is 3 and two adjacent R15 substituents together with the atoms to which they are
attached form a 5 to 6-membercd ring having 0—2 heteroatoms as ring s selected from O, N or
S; wherein the 5 to 6-membered-ring is optionally substituted with from 1-3 Rd or R‘3 substituents, and
the other Rls is H, Rd or Re. In some ments, the two nt R‘5 together with the atoms to
which they are attached form an optionally substituted fused carbocyclic ring, ing, but not
limiting to, e, entane and cyclohexane rings. The substituents on the carbocyclic ring
can be from 1-2 Rd or R“ groups. In other embodiments, two adjacent R'5 groups together with the
atoms to which they are attached form an optionally substituted fused cyelic ring, including, but
not limiting to, pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole,
isothiazole, pyridine, pyrazine, pyridazine, tetrahydrfuran, tetrahydi'opyran, tetrahydrothiophene,
pyrazolidine, olidine, imidazolidine, oxazolidine, thiazolidinc, isothiazolidine, piperidine,
piperazine, and hexahydropyrimidine rings. In other embodiments, R15 is halogen, «CN, OH, -CF3,
CF30, C;.6alkyl, C;_5alkoxy, -N02, benzyl, phenyl, cyclopropyl, cyclopropylmethyl, eyelobutyl,
cyclobutylmethyl, eyelopentyl, cycl0pentylmethyl, cyclohexyl, cyclohexymethyl, -OC(0)Rb, -
C(O)Rb, -C(O)0Rb, -NIIC(O)Rb, HRb, .NHRb or —NRbRb. In some embodiments, R15 is F,
Cl, Br, I, ~CN, DH, ~CF3, NHg, CF3O-, CH3-, CH30, -N03, cyclopropyl, cyclopropylmethyl,
cyclopropylamino, cyclopropylmethylamino, l«cyanocyclopropyl, methylamino, dimethyiamino,
methyithio, acetoxy? acetyl, methoxycarbonyi, aeetamido or methyicarbamoyl, isopropyl, i~
idinyl, l-cyclopropylethyl, Zfieyclopropylethyl, I—cyclopropylethylamino, 2—
481177261
039363-7211
ropylethylamino or l—hy(lroxy—1—methylethyl. All the other variables Y2, Q and Z are as
defined in any of the embodiments bed herein.
In an eleventh embodiment of the invention, compounds of formula (I) have subformule (Ig—
Ig—l
All the other variables R15, Y2, Q and Z are as defined in any of the embodiments bed herein. In
a preferred embodiment, Y2 is H. In some embodiments, R” is H or R‘. In some embodiments, R15. is
Ra, R”, R“, R“ or Re. In other embodiments, R” is halogen, -CN, —OH, 4:13,, (31:30-, C,.6alkyl, Ci.
6alkoxy, —N02, , , cyclopropyl, cyclopropylmethy’l, cyclobutyl, cyclobutylmethyl,
cyclopentyl, cyclopentylmethyl, exyl, cyclohexymethyl, —OC(O)Rb, —C(O)Rb, -C(O)ORh, -
R”, HRb, -NInIRb or ~NR"R". In some embodiments, R15 is F, Cl, Br, I, —CN, —OH, —
CF3, NHg, CF30—, CH3-, CHgO, —N02, cyclopropyl, cyclopropylmethyl, cyclopropylamino,
cyclopropylmethylamino, l—cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,
acetyl, methoxycarbonyl, acetamido or carbamoyl, isopropyl, l—pyrrolidinyl, l-
cyelopropylethyl, 2—cyclopropylethyl, I—cyclopropylethylamino, 2~cyclopropylethylamino or 1‘
hydroxy—l-methylethyl. In some embodiments, z is —N(R4)(R5) H3)(R5). All the other
variables are as defined in any of the embodiments described herein.
In a twelfth embodiment of the invention, compounds of formula (I) have subformula (lg-2):
Ig—2
Ali the variables R15, Y2, Q, R”, m and are as defined in any of the ments described herein. In
a preferred embodiment, Y2 is H. In some embodiments, R15 is H or R‘. In some embodiments, Ris is
R”, Rb, R“, Rd or R6. in one embodiment, R15 is Cmalkyl. In another embodiment, R” is C3.
acycloalkyl. In yet another embodiment, R” is heterocycloalkyl. The subscript m is an integer from 0
to 3. The subscript n is an integer from 1 to 5. In some embodiments, m is 0. In other embodiments,
the subscript n is I, 2, 3 or 4. In some embodiments, n is 1, 2 or 3 and m is l or 2. In some
embodiments, R11 is C;.6alkyl, C3.scycloalkyl, C3_geycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl or Re. In some embodiments, R” is Cngalkyl, Ci_6alkoxy, thaloalkyl, Ciw
481 177261
039363—7211
ghaloalkoxy, C3,gcycloalkyl, C3_3cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyeloalkyl, heterocycloalkylalkyl or R“, each of which is optionally substituted with from (i) 1-3
substitucnts independently selected from Cinalkoxy, Cl-5haloalkyl, Ci,5haloalkoxy, Cinalkyl, C3,
acycloalkyl, C3_gcycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Rd or R6; or (ii) 1, 2 or 3
Ra substituents; or (iii) I, 2 or 3 Rb substituents; or (iv) 1, 2 or 3 Rc substituents; or (v) I, 2 or 3 Rd
substituents; or (vi) 1, 2 or 3 Rf groups; the subscript n is l, 2, 3, 4 or 5 and the subscript m is O, I, 2
or 3. In other embodiments, R” is C,_6alkyl, C3_3cycloalkyl, C3-gcycloalkyialkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl or R? In some embodiments, RH is halogen, C1.6alkyoxycarbonyl, Ci.
galkyl, Ci_5alkyl-(CO)NI-I- or C].6alkyl-(CO)(C1nalkyl)N—. In n embodiments, R” is
methoxycarbonyl, ethoxycarbonyl, -CH3, CH3(CO)NI-l-, vinyl, propenyl or CH3(CO)(CH3)N-. In
one embodiment ofcompounds of formula Ig-2, the subscript n is 1, m is O or I. In another
embodiment of compounds of formula lg-Z, the subscript n is 2, m is 0, I or 2. In yet another
embodiment, ofcompounds of formula Ig-2, the subscript n is 3, m is 0, l or 2. All the other
variables are as defined in any of the embodiments described herein,
In a thirteenth embodiment of the invcntion, compounds of formula (I) have subformula (Ig—
All the variables R15, Y2, Q, R7 and R8 are as defined in any of the ments described herein. In
a preferred embodiment, Y2 is H. In some embodiments, R” is H or R]. In some embodiments, R15
is Ra, Rb, R“, Rd or R”. In one embodiment, R15 is Ci_6alkyl. In another embodiment, R15 is C3,
6cycloalkyl. In yet another ment, R15 is heterocyoloalkyl. In some embodiments, R7 and R8 are
each independently C._6alkyl, C1_6haloalkyl, C|_6haloalkoxy, C3.gcycloalkyl, C3-gcycloalkylall<yl, aryl,
arylalkyl, heteroaryi, heteroarylalkyl or =X2R9, wherein the aliphatic or ic portion of R7 and R3
are each optionally tuted with from I to 3 s independently selected from the group
consisting of cloalkyl, C3-8cy'cloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and Re,
provided at each occurrence, at least two of the R6, R7 and R8 groups are not aneously
hydrogen; and n X2 is wNRm, O or S; R10 is H, Cinalkyl or aryl; and R9 is H, Ci,6aikyl, Ci.
shaloalkyl, thaloalkoxy, y’cloalkyl, C3_3cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, wherein R9 is optionally tuted with from I to 3 Re substituents. In certain
instances, -C(R7)(R8) is a branched CMalkyl. In one embodiment, —C(R7)(R8) is isopropyl. In another
embodiment, )(Rg) is sec—butyl. In yet another embodiment, —C(R7)(Rg) is pentan—2—yl. In still
another ment, -C(R7)(Rg) is pentan~3—yl. All the other variables are as defined in any of the
ments described herein.
4811e7918-7726.1
039363—7211
[0112} In a fourteenth embodiment of the invention, compounds of formula (I) have subformula
(1h):
wherein Z1 is O or S; R16 is H or R]; or two adjacent Rl6 together with the atoms to which they are
attached form a 5 to 6-membered ring having 0-2 heteroatoms as ring members selected from O, N or
S; where the 5 to 6-membered-ring is optionally substituted with from I to 3 Rd or Re substituents; and
the subscriptt is an integer of l to 3. In one embodiment, Z1 is O. In another ment, Z1 is S. In
one embodiment, t is I. In another ment, t is 2. In yet another embodiment, t is 3 and two
adjacent Rm substituents together with the atoms to which they are attached form a 5 to 6—membered
ring having 0—2 heteroatoms as ring members selected from O, N or S; wherein the 5 to 6—membered-
ring is optionally substituted with from 1-3 Rd or Re substituents, and the other R16 is H, Rd or Re. In
some embodiments, the two nt R‘6 together with the atoms to which they are attached form an
optionally substituted fused carbocyclic ring, including, but not limiting to, benzene, cyclopentane
and cyclohexane rings. The substituents on the carbocyclic ring can be from 1—2 Rd or RC groups. In
other ments, two adjacent R‘6 groups together with the atoms to which they are attached form
an optionally substituted fused heterocyclic ring, including, but not limiting to, e, furan,
thiophene, pyrazole, imidazole, e, isoxazole, thiazole, isothiazole, pyridine, pyrazine,
pyridazine, tetrahydrfuran, tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazolidine,
imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, and
hexahydropyrimidine rings. In other embodiments, R16 is halogen, —CN, —OH, CH, CF30, Ciéalkyl,
oxy, —NOZ, benzyl, , cyclopropyl, ropylmethyl, cyclobutyl, cyclobutylmethyl,
cyclopentyl, cyclopentylmetliyl, cyclohexyl, cyclohexymethyl, Rb, —C(O)Rh, —C(O)ORb, —
NHC(0)R", -C(O)NHRb, —NHR” 0r . In some embodiments, R16 is F, Cl, Br, 1, —CN, on, —
CF3, NHg, CF3O-, CH3-, CH3O, —NOZ, cyclopropyl, cyclopropylmethyl, ropylamino,
cyclopropylmethylamino, l-cyanocyclopropyl, amino, dimethylamino, methylthio, acetoxy,
acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl, l-pyirolidinyl, l-cyclopropylethyl,
E-oyclopropylethyl, l-cyclopropyiethylamino. 2—cyclopropyiethylamino or I~hydroxy-l~methylethyl.
All the other variables Y2, Q and Z are as defined in any of the embodiments described herein.
In a fifteenth embodiment of the invention, compounds of formula (I) have mula (Ii):
4811—7918—77261
039363-7211
HN——-sCs‘)—~z
(R17)/adj/7m:/
N N
H 1i
wherein R18 is H, C1_6alkyl, ikyl, C3_6cycloall<yl or C3_5cycloalkyl. R[7 is H or R1; or two
adjacent Rl7 together with the atoms to which they are attached form a 5 to 6-membered ring having
032 heteroatoms as ring members selected from O, N or S; or R17 and R13 taken together with the
atoms to which they are attached form a 5 to 6-membered ring having 0-2 heteroatoms as ring
members selected from O, N or S, where the 5 to 6-membered-ring is optionally substituted with from
1 to 3 Rd or R6 substituents; R[8 is H, Cmalkyl or C._6haloalkyl; and the subscript u is an integer ofl
to 3. In one embodiment, u is I. In another ment, u is 2. In yet another embodiment, u is 3
and two adjacent R17 substituents together with the atoms to which they are attached form a 5 to 6-
membered ring having 0-2 heteroatoms as ring members selected from O, N or S; wherein the 5 to 6-
ed-ring is optionally substituted with from 1-3 Rd or RC substituents, and the other R17 is H, Rd
or Re. In other embodiments, RI7 and R]8 taken together with the atoms to which they are attached
form a 5 to 6~membered ring having 0-2 heteroatoms as ring members selected from O, N or S, where
the S to 6-membered-ring is optionally substituted with from 1 to 3 R“I or R8 substituents. In some
embodiments, (i) the two adjacent Rl7 together with the atoms to which they are attached or (ii) R”
and R18 taken together with the atoms to which they are attached, form an optionally substituted fused
carbocyclic ring, ing, but not limiting to, benzene, cyclopentane and cyclohexane rings. The
substituents on the carbocyclic ring can be from 1-2 Rd or R6 groups. In other embodiments, (i) two
adjacent Rl7 groups together with the atoms to which they are attached or (ii) R17 and R13 taken
together with the atoms to which they are attached, form an optionally substituted fused heterocyclic
ring, including, but not limiting to, pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole,
thiazole, isothiazole, pyridine, pyrazine, zine, tetrahydrfuran, ydropyran,
ydrothiophene, pyrazolidine, isoxazolidine, imidazolidinc, oxazolidine, thiazolidine,
azolidine, piperidine, piperazine, and hexahydropyrimidine rings. In some embodiments, R17 is
halogen, -CN, ~OH, -CF3, CF30—, C1_6alkyl, C,_6alkoxy, -NO;, , phenyl, cyclopropyl,
cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, entyl, cyclopentylmethyl, cyclohexyl,
cyclohexymethyl, coma", -C(O)R‘°‘, Rb, -NHC(O)Rb, -ctomHR", —NHRb or numb. in
some embodiments, R” is F, Cl, Br, I, ~CN, -OH, ~CF3, NHZ, CF30, CH3—, CH30, —N02, cyclopropyi,
ropylmethyl, cyclopropylamino, ropylmethylamino, ocyclopropyl, itiethylamino,
dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, aeetamido, methylcarbamoyl,
isopropyl, l—pyrrolidinyl, l-cyclopropylethyl, 2-cyclopropylethyl, opropylethylamino, 2~
cyclopropylethylamino or l-hydroxy~l-methylethyl. In n instances, R18 is H, C1-6alkyl or C]-
{,haloalkyl. In some embodiments, R13 is H, Ctigalkyl or cyclopropyl, cyclopropylmethyl, cyclobutyl,
cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyciohexyl, or eyelohexylmethyl. In some
48117728.t
039363—7211
ments, R18 is H or CH3. All the other variables Y2, Q and Z are as defined in any of the
embodiments described herein.
In a sixteenth embodiment of the invention, compounds of formula (I) have subformula (1}):
Rl9 is H, C1.6alkyl, C1-6haloalkyl, C3_6cycloalkyl or C3.6cycloalkyl. R20 is H or R1; or two adjacent R20
together with the atoms to which they are attached form a 5 to 6-membered ring having 0-2
heteroatoms as ring members selected from O, N or S; or R20 and R19 taken together with the atoms to
which they are attached form a 5 to 6—membered ring having 0-2 heteroatoms as ring members
selected from O, N or S; R19 is H, Cwalkyl or Cl,6haloalkyl; and the subscript v is an integer of] or 2,
where the 5 to 6-membered-ring is optionally substituted with from 1 to 3 Rd or R° substituents. In
one embodiment, v is 1. In some embodiments, two adjacent R20 substituents together with the atoms
to which they are ed form a 5 to 6-membered ring having 0-2 heteroatoms as ring members
selected from O, N or S; wherein the 5 to 6-membered—ring is optionally substituted with from 1-3 Rd
or Rc substituents. In other embodiments, v is 2. R19 and R20 taken er with the atoms to which
they are ed form a 5 to 6-membered ring having from 0-2 heteroatoms as ring members selected
from O, N or S, where the 5 to 6-membered—ring is optionally substituted with from l to 3 RLi or Rc
substituents, and the other R20 is H, Rd or Rc .
In some embodiments, (i) the two adjacent R20 er
with the atoms to which they are attached or (ii) R19 and R20 taken er with the atoms to which
they are attached, form an ally substituted fused carbocyclic ring, including, but not limiting to,
entane, cyclohexane and benzene rings. The substituents on the carbocyclic ring can be from
1—2 Rd or R6 . In other embodiments, (i) two adjacent R19 groups together with the atoms to
which they are attached or (ii) Rlg and R20 taken together with the atoms to which they are attached,
form an optionally substituted fused heterocyclic ring, including, but not limiting to, pyrrole, furan,
thiophene, le, ole, oxazole, isoxazole. thiazole, isothiazole, pyridine, pyrazine,
pyridazine, tetrahydrfuran, tetrahydropyran, tetrahydrothiophene, pyrazolidine, isoxazclidine,
imidazelidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, zine, and
hexahydropyrimidine rings. In other embodiments, R20 is halogen, ’CN, -OH, CH, CF,O-, Cmalkyl,
C1-5all<oxy', “N02, benzyl, phenyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl,
cyclopentyl, entylmethyl, cyclohexyl, cyclohexymethyl, —OC(O)Rb, -C(O)Rb, —C(O)ORb, -
NI mom", H,Rb, -NHRb or ~NRbRb. In some embodiments, R” is r, (:1, Br, 1, -CN, -OH, —
CF3, NHZ, CFgQw, CH3«, CHgO, ~N03, cyclopropyl, cyclopropylmethyl, cyclopropylamino,
eyeibprepylmethylaminu, l'cyanocyelopropyl, methylamino, dimethylamino, methylthio, aeetoxy,
acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl, Inpyrrolidinyl, l-cycloprepylethyl,
4811—7918—7726.1
039363-7211
2-cyclopropylethyl, l-cyclopropylethylamino, 2—cyclopropylethylamino or l-hydroxy-i -methylethyl.
In certain instances, R19 is H, yl or C1_6haloalkyl. In some embodiments, RI9 is H, Cmalkyl or
cyclopropyl, ropylmethyl, cyciobutyl, cyclobutyimethyl, cyclopentyl, cyclopentylmethyl,
cyclohexyl, or cyclohcxylmcthyl. In some embodiments, R19 is I] or CHg. All the other les Y3,
Q and Z are as defined in any of the ments described herein.
In a seventeenth embodiment of the invention, compounds of a (I) have subformula
(1k):
22 S?
(21(] |\ \ F HN—fi—Z
R WN / O
N N
H Ik
Z2 is O or S. The subscript w is l or 2. R21 is H or R‘; or two adjacent RN together with the atoms to
which they are ed form a 5 to 6-membered ring having 0—2 heteroatoms as ring members
selected from O, N or S, where the 5 to 6-membered-ring is optionally substituted with from 1 to 3 Rd
or R6 substituents. In one embodiment, w is 1. In another embodiment, w is 2. In some
embodiments, two adjacent R21 substituents together with the atoms to which they are attached form a
to ered ring having 0-2 heteroatoms as ring members selected from O, N or S; wherein the 5
to 6-membered-ring is optionally substituted with from 1-3 Rd or Re substituents. In some
embodiments, the two adjacent R21 together with the atoms to which they are attached form an
optionally substituted fused carbocyclic ring, including, but not limiting t0, cyclopentane,
cyclohexane and benzene rings. In n instances, the substituents on the carbocyclic ring can be
from 1-2 Rd or Rc groups. In other embodiments, two adjacent Rm groups together with the atoms to
which they are attachedform an optionally substituted fused heterocyclic ring, including, but not
limiting to, pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole,
pyridine, pyrazine, pyridazine, tetrahydrfuran, tetrahydropyran, ydrothiophene, pyrazolidine,
isoxazolidine, imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, and
dropyrimidine rings. In n ces, the substituents on the heterocyclic ring can be from
1-2 Rd or R3 groups. In other embodiments, R“ is halogen, —CN, -on, or}, one, Ci.6alkyl, c1.
éaikoxy, $102, benzyl, phenyl, cyclopropyl, cyclopropylmcthyl, cyclobutyl, cyclobutylmethyl,
cyclopentyl, entylmethyl, cyclohexyl, cyclohexymethyl, -OC(O)Rb, —C(O)Rb, “CC(3)0125, -
NHCijomb, HR", -NHRb or ~NRbRb. in some embodiments, R“ is F, Cl, Br, i, -CN, on, —
CF3, NH2, (313303 CH3—, CH3O, —NO;, cyclopropyl, cyclopropylmethyl, cyclopropylamino,
cyclopropylmethylamino, l—cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,
acetyl, methoxycarbonyl, acetamido, Inethylcarbamoyl, isopropyl, 1-pyrrolidinyl, l~cyclopropylethyl,
Etcy'ciopropylcthyl, 1-cyciopropyiethyiamino, opropylethyiamino or l—hydroxy—l ~1neti'iylethyi.
All the other les Y2, Q and Z are as defined in any ofthe embodiments described herein.
481177261
039363-7211
In an enth ment of the invention, compounds of a (I) have subfonnula
(ll):
23 is o, s or —N(R3°), where R30 is H, C,_6alkyl, C1_6haloalkyl, C3_6cycloalkyl or C3_6eycloalkyl. The
subscript x is l or 2. R22 is H or R1; or two nt R22 er with the atoms to which they are
attached form a 5 to 6-membered ring having 0-2 heteroatoms as ring members selected from O, N or
S, where the 5 to 6-membered-ring is optionally substituted with from 1 to 3 Rd or RC" substituents. In
one embodiment, x is 1. In another embodiment, x is 2. In some embodiments, two adjacent R22
substituents together with the atoms to which they are attached form a S to 6-membcred ring having 0—
2 heteroatoms as ring members selected from O, N or S; wherein the 5 to 6—membered-ring is
optionally substituted with from 1-3 Rd or R8 substituents. In other embodiments, x is 2, R22 and R30
taken together with the atoms to which they are attached form a S to 6-membered ring having from O-
2 heteroatoms as ring members selected from O, N or S, where the S to ered—ring is optionally
substituted with from I to 3 Rd or Re substituents. In some embodiments, (i) the two nt R22
together with the atoms to Which they are attached or (ii) R22 and R30 taken er with the atoms to
which they are attached, form an optionally tuted fused carbocyclic ring, including, but not
limiting to, cyclopentane, cyclohexane and benzene rings. In certain ces, the substituents on the
yclic ring can be from 1-2 Rd or R6 groups. In other embodiments, (i) two adjacent R22 groups
together with the atoms to which they are attached or (ii) R22 and R30 taken together with the atoms to
which they are attached, form an optionally substituted fused heterocyclie ring, including, but not
limiting to, e, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole,
pyridine, pyrazine, pyridazine, tetrahydrfuran, tetrahydropyran, tetrahydrothiophene, pyrazolidine,
isoxazolidine, imidazolidine, oxazolidine, thiazolidine, azolidine, piperidine, piperazine, and
hexahydropyrimidine rings. In other embodiments, R22 is halogen, -CN, —OH, ~CF3, CF30: C1.6all<yl,
C,.6all<oxy, .NOZ, benzyl, phenyl, eyclopropyl, cyclopropylmethyl, eyeiobutyl, cyclobutylmethyi,
cyclepentyl, cyclopentylmethyl, cyclohexyl, eyelohexymethyl, ~0C(O)Rb, —C(O)Rb, —C(O)0Rb, -
Nnctom", »C(O)NHR", -NHK*’ or . In some embodiments, R22 is F, Cl, Br, i, on, «on, -
(.1133, N'Hg, CF30", CH3—, CH30, -N02, cyclopropyl, cyclopropylmethyl, cyelopropylamino,
eyelopropylmethylamino, l-eyanocyclopropyl, methylamino, dimcthylamino, methylthio, aeetoxy,
acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, pyl, l-pyrrolidinyl, l-cyclopropylethyl,
2-cyelopropylethyl, l~cyclopropylethylamino, 2-cyclopropylethylamino or l—hydroxy-l -methylethyl.
In certain instances, R30 is H, C1,6alk)'l or loalkyl. In some embodiments, R30 is H, C1-6alkyl or
cyclopropyi, cyclopropyimethyl, eyclobutyl, eyelobutylmethyi, cyclepentyl, cyclopentylmethyl,
4811—7918—77261
039363-7211
cyclohexyl, or cyclohexylmethyl. In some embodiments, R30 is H or CH3. All the other variables Y2,
Q and Z are as defined in any of the embodiments described herein.
In a nineteenth embodiment of the invention, compounds of formula (I) have subformula
(1m):
/ O
(R ll
40 } KWl HN—s~—~z
Ne 2’ \ F H
O N [\
/ O
N N
H Im
R40 is H or R1; or two adjacent R40 er with the atoms to which they are ed form a 5 to 6-
membered ring having 0-2 heteroatoms as ring members Selected from O, N or S; and the subscript 0
is an integer of l to 3, where the 5 to 6—membered-ring is optionally substituted with from 1-3 Rd or
R6 substituents. In one embodiment, the subscript o is 1. In another embodiment, the subscriot o is 2.
In yet another embodiment, the subscript 0 is 3 and two adjacent R40 substituents together with the
atoms to which they are attached form a 5 to 6-mcmbered ring having 0-2 heteroatoms as ring
s selected from O, N or S; n the 5 to 6-membered—ring is optionally substituted with
from l~3 R‘3 or RC substituents, and the other R40 is H, Rd, R‘3 or Rf. In some embodiments, the two
adjacent R40 er with the atoms to which they are attached form an optionally substituted fused
carbocyclic ring, including, but not limiting to, benzene, cyclopentane and cyclohexane rings. The
substituents on the carbocyclic ring can be fiom 1-2 Rd or Re . In other embodiments, two
adjacent R“10 groups together with the atoms to which they are ed form an optionally substituted
fused heterocyclic ring, including, but not limiting to, pyrrole, furan, thiophene, pyrazolc, imidazolc,
oxazole, isoxazole, thiazole, isothiazole, pyridine, ne, pyridazine, tetrahydrfixran,
tetrahydropyran, tetrahydrothiophene, pyrazolidine, , isoxazolidine, imidazolidine, idine,
thiazolidine, isothiazolidine, piperidine, piperazine, and hexahydropyrimidine rings. In other
embodiments, R40 is halogen, -CN, on, -CF3, CFgO-, C,.6alkyl, C1-6alkoxy, —NOZ, benzyl, phenyl,
cyclopropyl, ropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl,
exyl, cyclohcxymethyl, -OC(O)Rb, —C(O)Rb, -C(O)OR”, O)Rb, -C(0)NHR*’, NHR" or —
NRbRb. In some embodiments, R4“ is F, (:1, Br, 1, -CN, on, -CFg, NHz, CFsO—, one, enso, nos,
cyclopropyl, cyclopropylmethyl, cyclopropylamino, ropylmethylamino, l~cyanocyclopropyl,
methylamino, dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, aeetamide or
methylcarbamoyl, isopropyl, 1—pyrrolidinyl, l-cyclopropylethyl, 2~cyclopropylcthyL l~
cyclopropylethylamino, 2-cyclopropylethylamino or l-hydroxy-l-methylethyl. All the other variables
Y2, Q and Z are as defined in any of the embodiments described herein,
In a twentieth embodiment of the invention, compounds of formula (I) have mula (In):
481177261
1141 is H or R‘; or two adjacent R“ together with the atoms to which they are attached form a S to 6-
membered ring having 0-2 heteroatoms as ring members selected from O, N or S; and the subscript n’
is an integer of l or 2, where the 5 to 6-membered—ring is optionally substituted with from 1-3 Rd or
Rc substituents. In one embodiment, the subscript n’ is I. In another embodiment, the iot n’ is
2. In some embodiments, the two adjacent R4| substituents er with the atoms to which they are
attached form a 5 to 6-membered ring having 0-2 heteroatoms as ring members selected from O, N or
S; wherein the 5 to 6-membered-ring is optionally substituted with from 1-3 Rd or RC substituents. In
some embodiments, the two adjacent R“ together with the atoms to which they are attached form an
optionally substituted fused carbocyclic ring, including, but not limiting to, benzene, cyclopentane
and cyclohexane rings. The substituents on the carbocyclic ring can be from l-2 Rd or Rc groups. In
other embodiments, two nt R“ groups together with the atoms to which they are ed form
an optionally substituted fused heterocyclic ring, ing, but not limiting to, e, furan,
thiophene, pyrazole, imidazole, oxazole, isoxazole, le, isothiazole, pyridine, ne,
pyridazine, tetrahydrfuran, tetrahydropyran, tetrahydrothiophene, pyrazolidine, , isoxazolidine,
imidazolidine, oxazolidine, thiazolidine, isothiazolidine, piperidine, piperazine, and
hexahydropyrimidine rings. In other ments, R“ is halogen, -CN, ~OH, -CF3, CF3O-, C;_6alkyl,
C1_5alkoxy, -N03, benzyl, phenyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl,
cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl, -OC(O)Rb, -C(O)R", crops", -
NHC(O)R", -C(O)NHR", .NHRb or —NR"R". In some embodiments, R‘“ is F, (:1, Br, 1, -CN, -OH, —
C173, NHg, CF3O-, CH'3-, CH30, -NOg, cyclopropyl, cyclopropylmethyl, cyclopropylamino,
cyclopropylmethylamino, l-cyanocyclopropyl, methylamino, ylamino, methylthio, acetoxy,
acetyl, methoxycarbonyl, acetamido or methylcarbamoyh isopropyl, I-pyrrolidinyl> 1-
eyclopropylethyl, 2-cyclopropy1ethyl, l-cyclopropylethylamino, 2-cyclopropylethylamino or I-
hydroxy- l -methylethyl. All the other variables Y2, Q and Z are as defined in any of the embodiments
bed herein.
In some embodiments, the invention provides a nd selected from the group
consisting of:
N-[3-[5 -(4-chlorophenyl)- l olo[2,3—b]pyridine-3—carbonylI-Z-fluoro—phenylipyrrolidine- l -
sulfonamide (P—0012);
-chloro—3 —[3-[[ethyl(methyl)sulfarnoyi]amino]—2,6-difluoro-benzoyl} l H-pyrrolo[2,3~b]pyridine
(P—OOIS);
481177264
039363-721 1
—(4—chlorophenyl)-3 -[3 -f{ethlemethyl)sulfamoyl]amino]-2,6—difluoro—benzeyl]—1H—pyrrolo[2,3-
b]pyridine (P—0014);
3-[3*[[ethyl(methyl)sulfamoyl]amino]~2,6—difluoro-benzoyl](2—methoxypyrimidin-S—yl)—1H—
pyrrolon,3—b]pyridine (P—OOIS);
N—[2,4-difluoro-3 -(5-f1u0ro-4—i0d0-1 H-pyrrolo[2,3-b]pyridine—3~carbonyl)phenyl]pyrrolidine— I —
sulfonamide (P-0016);
N—[3 -[4—(cyclepropylmethylamino)—S-fluoro— l H—pyrrololZ,3-bjpyridine-3 —carb0nyl]-2,4-difiu0m~
]pyrrolidinesulf0namide (P-0017);
-cyano[3-[[ethyl(methyl)suIfamoyflamino]-2,6-difluoro-benzoy1]-1H-pyrrolo[2,3-b]pyridine
(P-OOIS);
-chloro[3-[[ethy1(methyl)sulfamoyl]amino]fluoro-benzoyl]-1 H-pyrrolo[2,3—b]pyridine (P-
0019);
hlorophenyl)-3—[3-[[ethyI(methyl)sulfamoyljamino]flu0ro—benzoyl]—1I>I—pyrrolo[2,3—
b]pyridine (P-0020);
3 -[3 -[[ethyl(methyl)su lfamoyl]amino]—2-fiuoro-benzoyl]—5—(2-methoxypyrimidin—S—yl)—l H-
pyrrolo[2,3-b]pyridine (P-0021);
N—B-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine—3—carbonyI]—2,4—difluoro—phenyl]pyrrolidine-I-
sulfonamide 2);
N-[3—[5—[2-(dimethylamino)pyrimidinyl]-1H-pyrrolo[2,3—b]pyridine—3 -carbonyI]—2,4-d ifluoro—
phenyl]pyrrolidine—I —sulfonamide (P—0023);
N-[2—fluoro-3 -(5—methyl-1H-pyrrolo[2,3-b]pyridinecarbonyl)phenyl]pyrrolidine—1-sulfonamide
(P-0024);
N-[2,4-difluoro-3 -(5—i0do—1H—pyrrolo[2,3—b]pyridine—3-carbonyl)phenyl]pyrrolidinc-1—sulfonamide
(P-0025);
3 —[3 —[[cyclopropyl(methyl)sulfamoyl]amino]—2-flu0ro-benzoyl]—5-(2-methoxypyrimid in-S—yl)— 1 H—
o[2,3-b]pyridine (P-0026);
[Z-fluoro-3 -(methylsulfamoylamino)phenyl]-[5-(2-methoxypyrimidin—S -yl)-1H—pyrrolo[2,3—
b]pyridinyl]methanone (P—0027);
—(4-cyanophcnyI)-3 -[3 —(dimcthylsulfam0ylam -fluor0-benzoyl]—I I I-pyrrolo[2,3—b]pyrid inc
3-[3 ~(dimethylsulfamoylamino)fluoro-benzoyl]—5-(3-pyridyl)—} H-pyrrolo{2,3-b]pyridine (P—
0029);
3-[3 -(dimethylsulfamoylamino)—2—fluoro~benzoyI](6wmethyi—3-pyridyi)- I H-pyrr0i0[2,3-
b]pyridine (P-0030);
-[6—(dimethylamino)—3-pyridyl]-3—[3—(dimethylsulfamoylamin0)—2-fluoro-benzoyl}— 1 H—
pyrrolo[2,3—b]pyridine (P-0031);
-(4-cyanophenyl)—3 -[3 —[[ethy1(methyl)suIfamoyl]aminoj—Z—f‘luom—benzoyl} l H~pyrrolo[2,3-
b]pyridine (P—0032);
48111918411261
039363—721 I
3-[3-[[ethyl(methyl)sulfamoyl]amino]~2-fiuoro-benzoyl](3 -pyridyl)-I H—pyrrolo[2,3nb]pyridinc
(P—0033);
3 -[3 ~[[ethyl(methyl)sulfamoyl]aminojfiu0ro-benzoyl}5-(6-methyl—3-pyridyl)—1H-pyrrolo[2,3
b]pyridine (P-0034);
3 —[3 -[[ethmeethyl)sulfamoyl ]ami110]—2-fluoro-benzoyl]—5-(4—fluorophenyl)— l H-pyrrolo[2,3 -
b]pyridine (P—0035);
3-[3-(dimethyIsu]famoylamino)fluor0—benzoyl]—5-(4—fluor0phenyl)-1H-pyrrolo[2,3-b]pyridine;
3-[3—[[ethyI(methyl)sulfamoyl]amino]fluoro-benzoy[]~5-phenyl—1H-pyrr010[253-b]pyridine (P-
0036);
3-[3-(dimethylsulfamoylamin0)—2—fluoro-benzoyl]—S—phenyl-1H-pyrrolo[2,3-b]pyridine 7);
~br0mo[3-[[ethyl(methyl)sulfam0y|]amino]fluoro-benzoyl]-1H-pyrrolo[2,3—b]pyridine (P-
0038);
-cyano[3-[[ethyl(methyl)sulfamoyl]amino]w2—fluoro-bcnzoyl]—1H-pyrrolo[2,3—b]pyridine (P-
0039);
3-[2-fluor0—3-[[methyl(propyl)sulfam0yl]amin0]benzoyl]—5—(2-methoxypyrimidin—S-yl)-I H—
o[2,3—b]pyridine (P—0040);
3-benzyloxy-N-[Z-fluoro—3-[5-(2-methoxypyrimidin—5-yl)-1H-pyrrolo[2,3-b]pyridine—3—
carbonyi]phenyl]pyn‘olidinesulf0namide (P-004l);
opropyl—N—[Z—fluoro—3~[5-(1-methylpyrazolyl)-lH-pyrrolo[2,3-b]pyridine
carbonyl]phenyl]methanesulfonamide (P-0042);
N—[2-flu01‘0-3—[5-(3 ~pyridyl)-1 H—pyrro]0[2,3-b]pyridine-3 -carb0nyl]phenyl]pyrrolidine-1 —
sulfonamide (P-0043);
N-[3—[5-(2,4—dimethoxypyrimidin—S—yl)-1H-pyrrolo[2,3—b]pyridine—3-carb0ny!]fluom—
phenyl]pyrr01idinesulf0namide (P—0044);
N-[Z-fluoro—3-[5—(6-methylpyridyl)-IH-pyrm|0[2,3-b]pyridineca‘rb0nyl]phenyl]pyrrolidine
sulfonamide (P—0045);
N-[3-[5-[6-(dimethylamino)pyridyl]-1H-pyrrolo[2,3-b]pyridine-3—carbonyl]f1uoro-
phenyl]pyrrolidinesulf0namide (P-0046);
N—[Z-fluoro—3—[5—(2—isopropylpyrimidin—S—yl)—l H-pyrrolo[2,3-b]pyridine
carbonyl]phenyl]pyrrolidine-1vsulfonamide (P-0047);
N-[3-[5-(2-cyclopmpy1pyrimidin-S-yl)-1 H-pyrrolo[2,3-b]pyridine-3 -carb0nyl]fluoro—
phenyi]pyrrolidine— I ~su1f0namidc (P-0048);
N-[3-[5~(4-Cyano—3-methoxy-phenyl)- I oio[2,3~b]pyridine—3 ~carb0nyIIfluor0-
phenyl]pyn‘olidine-l -sulfonarnide (P-0049);
N~[3—[5-[4-(1-cyanocyclopropyl)phcnyl]—l H—pyrrolo[2,3—b]pyridine-3—carbonyl]-2—fluor0-
phenyl]pyrrolidine~ l -su1fonamide (P—0050);
3-[3-(dinwthylsulfanloylami110)-2—fluoro—benzoyl}—5~(2-isopropylpyrimidin-S—yl}1H—pyrr010[2,3-
b]pyridine I);
481 17918577261
039363~721 1
-(2—cyclopropylpyrimidin-S—yl)-3 ~{3—(dimethylsulfam0ylamino)—2-flu0r0—benzoyl]- I H»
pyrr0[0{2,3—b]pyridine (P-OOSZ);
3~[3 hylsulfamoylam in0)-2—fluoro~benzoyl]—5-[6-(trifiuoromethyl)—3-pyridyI} 1 H-
o[2,3—b]pyridine Q-0053);
-(4-cyan0-3 -methoxy-phenyl)—3 —[3-(dimethylsulfamoylamino)f‘luoro-benzoyl]— l H-pyrroio[2,3~
b]pyrkfine(P-0054L
-[4-(1—cyanocyclopropyl)phenyl]-3 —[3 —(dimethylsulfamoylamino)-2—fluoro-benzoyl]-I H'—
pyrro]0[2,3-b]pyridine (B0055);
3 -[3-[[cthmeethyl)sulfamoyl]amino]fluoro-benzoyl](2-methylpyrimidin-S-yl)- 1 H-
pyrrolo[2,3-b]pyridine (P-0056);
3-[3-[[elhyl(methyl)sulfamoyl]am1'n0]fluoro-benzoyl](2-isopropylpyrimidin-S-yl)-1H-
pyrrolo[2,3-b]pyridine (P-0057);
-(2—cyclopropylpyrimidin-S-yl)-3—[3-[[ethyl(methyl)sulfamoyl]amino]fluoro—benzoyl]—1H-
pyrrolo[2,3-b]pyridine (P-0058);
3- [3 yl(methyl)sulfanmyl]amino]fluoro-benzoyl][6-(trifluoromethyl)‘3~pyridyfl- 1H—
pyrrolo[2,3-b]pyridine (P—0059);
-(4-cyano-3 -methoxy-phenyl)-3 -[3 -Hethyl(methy l)sulfamoyl]amino]—2-fluoro-benzoyl]- 1 H-
pyrrolo[2,3-b]pyridine (P-0060);
1-cyanocyclopropyl)phcnyl][3 -[[ethyl(methyl)sulfamoy]]ami110]—2-fluoro-benzoyl]—I H-
pyrrolo[2,3-b]pyridine (P-006l);
N-[2-fluoro-3—[5-(4-fluorophenyl)-1H—pyrrolo[2,3—b]pyridine—3 -Carb0nyl]phenyl] pyrrolidine— I—
squnanfidc(P-0062L
N-[Z-fluor0—3-(5-phenyl—1H—pyrrolo[2,3—b]pyridine—3-carb0nyl)phcnyl]pyrrolidinesulf0namide
(P-0063);
-[2-(cyclopropylamino)pyrimidin—5-yl]—3 -[3-(dimethylsulfamoylamino)—2-fluoro-benzoyl]-1H-
py1T010[2,3-b]pyridine (P-0064);
N-[2-fluor0[5—(2-methoxypyrimidin-S-yl)-1H—pyrroloI2,3—b]pyridinecarbonyljphcnyl]—2-
methoxy-ethanesulfonamide (P411165);
methyl 3—[[2—fluoro—3—[5—(2-methoxypyrimidin-S—yl)—1H—pyrro]o[2,3-b]pyridine-3—
carbonyl]phenyl]sulfamoyl]propanoate (P-0066);
N—[Z-flumo—3~[5-(2—methoxypyrimidin-S-yi)-1H—pyrrolo[2,3~b]pyridine
carbonyl]phenyl]cyclopropancsulfbnamide (P-0067);
[3«(ethylsuIfamoylamino)—2-fluoro~phenyI]-[5-(2—methoxypyrimMin-53v!)-lH-pyrrolo[2,3—
b]pyridin-3—yl]methanone (P-0068);
hylsulfamoylamino)—2—fluoro-phenyl]—(5-iodo- ] H—pyrmlo[2,3-b]pyridinyl)methanone (P—
0069);
uoro-3~[[isobutyl(methyl)sulfamoyl]amino]benz0yl]iod0-I H—pyrrolo[2.3-b]pyridinc (1’-
0070);
4811—7918—7726‘1
039363-721]
[2-fluoro‘3 -(isopmpylsulfamoylamino)phenyl]-(S-iodo-I H-pyrrolo[2,3—b]pyridin-3 -yl )methauone
(P-0071);
3-{2-flu0r0[[isobutyl(methyl)sulfamoyl]amino]benzoy[](2-me1hoxypyrimidin-5 {VD-1 H»
pyrrolo[2,3-b]pyfidine (P—0072);
3-[2-fiuor0[[2-methoxyethyI(methyl)sulfamoyljamino]benzoyl]-5—(2-methoxypyrimidin—S-yl)-
1H—pyrrolo[2,3-bjpyridine (P—0073);
N-[2-f1u0ro-3 ~[5-(2-methoxypyrimidin—5 -yl)-1H-pyrrolo[2,3-b]pyridinecarbonyI]phenyl]
methyl-pyrrolidine-l -sulfonamide (P—0074);
3-[2-flu0r0[[isopropyl(methyl)sulfamoyl]amino]benzoy!](2-methoxypyrimidin~5 -yl)-1 H-
pyrrolo[2,3-b]pyridine 5);
-[6-(dimethylamino)-3 -pyridyl][3-[[ethyl(methyl)sulfamoy]]amino]fluoro-bcnzoyl]-1H-
pyrrolo[2,3-b]pyridine (P—0076);
-[2-(cyclopropylamino)pyrimidin-5—yl]—3—[3-[[cthyl(methy|)sulfamoy]]amino]fluoro-benzoyl]-
lH-pyrrolo[2,3-b]pyridine (P—0077);
-(2-cyc10propylpyrimidin-S —yl)-3—[2,6—difluoro[[methyl(propyl)sulfamoyl]amino]benzoyl]— 1 H-
pyrrolo[2,3-b]pyridine (P—0078);
-[4-(1-cyanocyclopropyl)phenyl]-3 -[2,6-difluoro-3—[[methyl(propyl)sulfamoyljamino]benzoyl}
1H-pyrmlo[2,3 id ine (P—0079);
-[4-(1-cyanocyclopropyl)phcnyl]-3 -[2-fluoro-3—[[2-
methoxyethyl(methyl)sulfamoyl]amino]benzoyl]- ] H-pyrrolo[2,3-b]pyridine (P—0080);
cycl0propylamino)pyrimidinyl][2-fluoro[[2-
methoxyethyl(methyl)sulfamoyl]amino] l]-1 H-pyrr0|0[2,3-b]pyridine (P—0081);
-[2-(cyclopropylamino)pyrimidin-S~yl][2-fluoro—3-[[methyl(propyl)sulfamoyflamin0]benz0y1]-
1H-pyrrol0[2,3-b]pyridine (P-0082);
3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]fluor0-benzoyl](2-methoxypyrimidin-S-
y1)-1H-pyrrolo[2,3-b]pyridine (P—0083);
3-[3-[[cyclopropylmethyl(methyl)su1famoyl]amino]-2—fluoro—benzoyI](2-cyclopropylpyrimidin-
-yl)- 1 H-pyrr010[2,3-b]pyridine (P—0084);
yclopr0pylpyrimidin-S-yl)[2-fluoro[[2-
methoxyethyl(methyl)sulfamoyl]amino]benzoyl]—1H-pyrrolo[2,3—b]pyridinc (P—0085);
-(2-cyciopmpylpyrimidin-S-yl)-3 -[2-fluoro-3 -[[methyl(propyl)suIfamoyl}amino]benzoyl]~1H-
pyrmlo[2,3-b]pyridine (P-0086);
S-(6»cyclopropyi-3 -pyridyI)—3—[3—[[ethyl(methyl)sulfamoyl]aminoj—Z—fiuoro-benzoyfi—1 H—
pyrrolo[2,3—b]pyridine (P-0087);
3,3-difluoro-N—[2-fluoro—3-[5-(2-methoxypyrimidin-S -y!)-1 olo[2,3 -b]pyridine-3—
carbonyflphenyl]azetidine~1'sulfonamide (P—0088);
4—[[( I S)— 1 —cyclopropylethy11amin01-S -[3~[[ethyf(methyl)sulfamoyljamin0]~2—fluoro—bcnzoylj-7I I—
pyrro]o[2,3-d]pyrimidine 89);
4811-7918J7264
039363-721 1
N-[3-[5-(4-cyanopheny1)~l H-pyrrolo[2,3~b]pyridine~3-carb0nyl}—2-flu0ro-phenyl]pyrro1idine-1 ~
sulfonamide (P~0090);
N-{3-[S—(2-cyanopyrimidiny1)~1H—pyrrolo[2,3-b]pyridinecarb0nyI]flu0r0-
phenyl]pyrmlidine-1 -sulf0namide (P-0091);
N—[Z-fluero—S-[5~(2-methy1pyrimidin-5»yl)-IH—pyrrolo[2,3—b]pyridine—3—
carbonyl]phenyl]pyrrolidinesulf0namide 2);
N-[3-[5-(5~cyam~3-pyridyl)- I H~pyrrolo[2,3-b]pyridinc-3 -carb0ny1]‘2~fluoro-phenyl]pyrrolidine
amide (P—0093);
N-[2-fiuoro-3 -[5-[6-(trifluoromethyl)pyridyl]-1H-pyrrolo[2,3-b]pyridine
carbonyflphenyflpyrrolidine- I -sulfonamide 5);
-(2-cyanopyrimidinyl)[3-(dimethylsulfamoylamin0)fluor0-benzoyl]-lH-pyrrolo[2,3-
b]pyridine (P-0096);
3-[3-(dimethylsulfamoylamino)flu0r0-benzoy1](2-methylpyrimidinyl)-I H-pyrrolo[2,3 -
b]pyridine (P-0097);
S—(S-Cyan0-3—pyridyl)—3 {3-(dimethylsulfam0ylamin0)-2—f1uoro-benzoyl]—1H—pyrrolo[2,3-b]pyridine
(P—0098);
-(6-cyano-3 -pyridyl)-3 -[3-(dimethylsulfamoy]amino)—2-fluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridine
(P—0099);
-(2-cyanopyrimidinyl)[3—[[ethyl(methyl)sulfamoyl]ami110]fluor0-benzoyl]- 1 H-
pyrrolo[2,3-b]pyridine (P—0100);
-(5—cyano-3 -pyridyl)-3—[3—[[ethyl(methyl)su]famoyl]amino]fluoro-benzoyl]-1H-pyrrolo[2,3 -
dine (P—0101);
-(6-cyano-3~pyridyl)[3-[[ethyl(methyl)sulfamoyl]amino]~2-flu0r0-benzoyl]-I H-pyrrolo[2,3-
bprridine 2);
3-[3-(dimethylsulfamoylamino)fluoro-benzoyl][4-( 1-hydroxy-1 -methyl—ethyl)phenyl]— 1 H-
pyrrolo[2,3-b]pyridine (P-0103);
3 -[3 -[[cthyl(mcthyl)sulfamoyl]amino]-2—fluoro-benzoyl]~5-[4-(1~hydroxy—l~methyI-ethyl)phenyl]—
1H-pyrrolo[2,3—b]pyridine (P-0104);
N-[2-flu0r0[5-[4-(1-hydroxy-l -methyl-ethyl)phenyl]-1H-pyrrolo[2,3—b]pyridinc
carbonyl]phenyl]pyrrolidine—1-sulfonamidc (P—0105);
-[2-(dimethylamino)pyrimidin-5vyI]—3{3—(dimethylsulfamoylamino)~2—fluor0~benzoyl]-1H—
pyrrolc[2,3~b]pyridine (P-0106);
3~[3-(dimethylsu!famoylamino)-2—fluoro-benzoyi]—5-(2-pyrr01idinylpyrimidin-Svyi)~1 H«
pyrrolo[2,3-b]pyridine 7);
3—[3—[[ethyl(methyl)sulfamoyl]amino]-2—fluoro-benzoyl](2-pyrrolidin-l —y1pyrimidinyI)-1 H-
0[2§3~b]pyridine (P-OIOS);
N~[2~fluoro—3~[5—(2—pyrrolidin-1~y1pyrimidinAS—yl)—l H~pyrrolo[2,3—b]pyridine~3~
carbonyl]phenyl]pyrr01idine~ I -sulfonamide (P—0109);
4811-7918—7726.1
039363-7211
3»[3 hyfsulfamoylamin0)—2—flu0r0~benzoyl]-5—iodo— l H—pyrrolo{2,3—b}pyridine (P-Ol 10);
3 —[2~flu0r0~3—[[methy1(propyl)sulfamoyl]amino]benzoyl}-5—(2-methy1pyrimidind-y!)~ ] H-
pyn‘o!0[2:3~b]pyridinc (P-01 1 I);
3-[3 -[[eyeIopropylmethyl(methyl)sulfamoyl]amino]-2—fluoro—benzoyl](2—mcthylpyrimidinyl)~
lH—pyrrolo[2,3-b]pyridine (P-0112);
S-(6-cyclopmpyl-3—pyridyl)[3-(dimethylsulfamoylamin0)fluoro—benzoy1]-IH-pyrrolo[2,3—
bjpyridine (P431131;
S-(6-cyclopropylpyridyl)—3 -[2-fluoro—3—[[methyl(propyl)su Ifamoyljamino]benzoyl]~ 1 H-
pyrrolo[2,3»b]pyrid ine (P-0114);
3-[3-[{cyolopropylmethyl(methyl)sulfamoyl]amino]—2-fluoro-benzoy]](6-cyclopropylpyridyl)—
1H‘pyrrolo[2,3-b]pyridine 5);
3—[2,6-diflu0r0—3-[[methyl(pr0pyl)sulfamoyl]amino]benzoyI](2-meth0xypyrimidin-5—yl)- 1 H—
pyrrolo[2,3—b]pyridinc (P-0116);
[2—fluoro-3—(propylsu lfamoylamino)phenyl]-(5-iodo-l H-pyrr010[2,3 idin —3 —yl)methan0ne (P—
0117);
ro—3—(propylsulfamoylamino)phenyI]—(5—methyl-1H—pyrrolo[2,3—b]pyridin—3—yl)methanone
(P-0223);
uore-3 -[5—(2—methoxypyrimidin-S-yl)-1H-pyrrolo[2,3—b]pyridine-3 —carb0nyI]pheny]]butane-
2-sulf0namide (P-0024);
\J—[Z—fluoro-3—[5—(2—pyrrolidin—l—ylpyrimidin—S—yl)—1H-pyrrolo[2,3—b]pyridine—3-
carbonyl]phenyl]butanesulf0namide (P—0225);
\I—[3 -[5—[2-(cyclopropylamino)pyrimidin—5-yl]-lH—pyrmlo[2,3-b]pyridine-3 -carb0nyI]f1uoro-
phenyl]butane-Z-sulfonamide (P-0226);
\ -[3 -[5-[4-( 1 -cyanocyclopropyl)phenyl]—1H—pyrrolo[2,3 -b]pyridine-3 -carbony1]fluoro—
phenyl]butane—2-sulf0namide (P-00227);
\ -[3-[5-(2—cycIopropylpyrimidin-S-yl)-IH-pyrrolo[2,3-b]pyridinc-3—carbony1}fluoro—
phenyl]butanesulfonamide (P-0228);
1\ -[2-fluoro~3-[5-(2-isopropylpyrimidin—S-yl)—1H—pyrrolo[2,3-b]pyridine-3 —carbonyl]phenyl]butane-
2-sulf0namide (P-0229);
I\—[3—[S—[6—(dimethylamino)pyridyl]-1H-pyrrolo[2,3—b]pyridine—3~carbonyl]-2~fluoro—
]butaneu2~sulfonamide (P-0230);
A~[2afi{mm—3~[5~(2-mefl1ylpyrimidin-S—yD—1H-pyrmio[2,3-b]pyridine~3—carbonyl)phenyi]butane~2-
sulfonamide (P~0231);
N-[3 -[5-[2-(cyclopropylamino)pyrimidinyl]— I H-pyrrolo[2,3 -b]pyridinecarbonyI]—2—fluoro—
phenyl]pyrmlidine-1 -su]f'0namide (P-0232);
—(2-cycIopropylpyrimidin—S—yI)—3-[2—fluor0-3—[[isopropyl(mcthyl)sulfamoyl]amino]benzoyl]— 1 H-
pyrrolon,3-b]pyridine 3);
4811—7918—77261
039363721 1
N-[Z-fluoro—B-[S-(2—morpholinopyrimidin-S—yl)-1H-pyrrolo[2,3—b]pyridine-3—
carbonyflpheny]]pyrrolidine-1 -sulf0namide; (P-0235);
N-[Z-fluom-3 -[5-(2morpholinopyrimidin-S—yl)—1II-pyrrolo[2,3-b]pyTidine
carbonyl]phenyl]butane-2—sulf0namide 6);
-[4-(1-cyanocyclopropyl)phenyl]—3-[3{dimethylsulfamoylamino)-2,6-diflu0ro-benzoy1]-1H-
pyrmloiEJ-bjpyridine (P-0237);
-(2-cyclopropylpyrimidin—S—yl)-3 imethylsuIfamoylamin0)-2,6—difluoro~benzoyl]- 1 H-
pyrrolo[2,3—b]pyridine (P-0238);
-[4-(1-cyanocyclopropyl)phenyl][3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-
pyrrolof2,3-b]pyridine (P-0239);
-(2-cyclopropylpyrimidin-S-yl)[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-1H-
pyrrolo[2,3-b]pyridine (P-0240);
N—[3-[5-(2-cyclopropylpyrimidin—S-y!)- l H-pyrrolo[2,3—b]pyridinecarb0nyl]-2,4-difluorophenyl
]pyrrol idinesulf0r1amide (P—024l);
[Z-fluoro—3 ylsulfamoylamino)phenyl]-[5-(1 -methylpyrazolyl)- 1H-pyrrolo[2,3 -b]pyridin—3 -
yl]methanone (P-0242);
1-[4-[3-[2-fluoro(pyrrolidin-I-ylsulfonylamin0)benzoyl]—1H—pyrrolo[2,3—b]pyridin-5—
yl]phenyl]cyclopropanecarboxylic acid (P-0243);
3 -[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]—5-(5-ethoxypyrazin-2—yl)—1H-pyrrolo[2,3 -
b]pyridine (P-0244);
-[4-(1 -cyanomethy1-ethyl)phenyl][3-(dimethylsulfamoylamino)—2-fluoro-benzoyl]-1H-
pyrrolo[2,3-b]pyridine (P-0245);
N-[3 - [5 -(2-cyclopropylpyrimidin-5 -yl)-1 olo[2,3—b]pyridine-3 -carbonyl]fluoro—phenyl]—3 ,3 —
dimethyl-pyrrolidine—I-sulfonamide (P-0246);
N—[3 -[5 -(2-cyclopropylpyrimidin-S—yl)—1H-pyrro10[2,3—b]pyridinc-3 «carbonyl]-2—fluoro-phenyl]-3 -
methyl-pyrrolidinesulfonamide (P-0247);
N-[3-[5—[4-(1«cyanocyclopropyl)phenyl]—I H-pynolo[2,3-b]pyridinc—3 —carb0nyl]-2,4-difluoro-
pheny1]pyrrolidine- 1 ~su1f0namide (P—0248);
3-[3 s[[cyclopropyl(methyl)sulfamoyl] amino]fluoro-benzoyH—S-(Z—cyclopropylpyrimidin-S -yl)- I H’
o{2,3-b]pyridine (P-0249);
[S-(E-cyclopropyipyrimidin—S~yl)-1H-pyrrolo[2,3—b}pyridin—3~yi]-[2-fiuom—3~
(pmpylsuIfamoylamino)phenyl]methanone (P~0251);
3-[3~[[cyclopropyl(methy1)sulfamoyl]amino]~2,6-difluoro-benzoyl]—5—(2-cyclopropylpyrimidin-S-yl)—
rolo[2,3—b]pyridine (P—0252);
l-[4-[3—[2—1‘1uor0-3—(pyrr01idina1-ylsulfonylamino)benzoyl]~lH—pyrrolo[2,3-b]pyridin-5—
yl]phenyl]cyclopropanecarboxamide (P-0253);
4811-‘7918«7726.1
039363-721]
methyl 1-[4-[3-[2-flu0r0-3 olidin—l -ylsulf0nylamino)benzoyl]— I H—pyrr010[2,3 ~b]pyridin
yl]phenyl]cyclopmpanecarboxylate (P—0254);
-[4-(1-cyano-I—mcthyl—cthyl)phenyI]-3~[3—(dimethylsulfamoylamino)-2,6-difluom-benzoy1]—1H-
pyrroio[2,3-b]pyridine (P-OZSS);
S-(Z—ethoxypyrimidin-S—yI)—3—[3{[ethmeethyl)sulfamoyl]amino]-2,6-difluoro-benzoyfi- 1 H-
pyrrolo{2,3-b]pyridine (P-0256);
ethyl 1~[1'2—fluoro—3~[5-(2-methoxypyrimidin—S—yl)— lH—pyrrolo[2,3-b}pyridinc
carbonyl]phenyl]sulfamoyl]pynolidine-Z-carboxylate (P-0257);
4-[5-[3-[3~[[ethy1(metl1yl)sulfamoyl]am ino]—2,6-difluoro—benzoy|]- 1 H-pyrrolo[2,3-b]pyridin-S-
yl]pyrimidinyl]morpholine 8);
4-[3-[3 -[3 -[[etl1yl(methyl)sulfamoyl]amino]-2,6-d ifluoro-benzoyl]-1 H-pyrrolo[2,3-b]pyridin-S -
yl]phenyl]morpholine (P-0259);
N—[2,4-difluoro—3-[5-[2—(4—methylpiperazin—1—yl)pyrimidinyl]-1H—pyrr010[2,3-b]pyridine-3—
carbonyl]phenyl]pyrrolidinesulfonamide 0);
N-[2,4-diflu0r0—3-[5 perazin-I imidinyl)- I H-pyrmlo[2,3-b]pyridine—3—
carbonyl]phenyl]pyrrolidinesulfonamide (P—0261);
N-[2,4-diflu0r0[S-[2-(4—hydroxy-I-piperidyl)pyrimidin-S-yl]—1H—pyrrolo[2,3-b]pyridine—3—
carbonyl]phenyl]pyrmlidine—1-su1fonamide (P-0262);
3 -[3—[[cthyl(mcthyl)sulfamoyl]amino]—2,6-difluoro—bcnzoyl]—5-[2-(4-methylpiperazinyl)pyrimidin-
-yI]-1H-pyrrolo[2,3-b]pyridine (P—0263);
tert—butyl 4-[5-[3-[3—[[ethy1(methyI)sulfam0yl]amin0]—2,6—difluoro-benzoyl]-1H-pyrr0l0[2,3-b]pyridin'
-yljpyrimidinyl]piperazine-l ~carboxylate (P—0264);
-difluoro—3 ~{5—[2-(1-hydroxy-l~methyI-ethyl)thiazoI—4—yl]-lH-pyrrolo[2,3—bprridine
carbonyl]phenyl]pyrrolidine—1~sulfonamide (P-0265);
-difluor0—3-[5 -(2-morplmlinopyrimidin—S—yl)— I H-pyrrolo[2,3-b]pyridine—3-
carbonyl]phenyl]pyrrolidine-1 —su1fonamide (P-0266);
N—[l —[[3-[5-(2-Cyclopropylpyrimidin—S —yI)-I H—pyrrolo[2,3-b]pyridine~3 —carbonyl]—2—fluoro-
phenyl]sulfamoyl]pyrrol idin-3 -methyl—acetamide (P-0267);
3—[3—[[ethyl(methyl)sulfamoyl]amino]-2,6—difluoro—bcnzole—5 -(2—piperazin— 1 -ylpyrimidin-5—yl)-I H—
pyrrolo[2:3«b]pyridine (P-0268);
N-[B-[S—[Z-(azetidin-1—yl)pyrimidin-S-yl]—IH-pyrmlo[2,3-b]pyridine~3 —Carbonyl]-2,4~difluoro-
phenyljpyrmlidinc-I~suifonamide (P—0269);
N-[2,4—diflu0ro~3{S-(Z-methoxythiazolé-yl)— l H—pyrroio[2,3-b]pyridine~3~
carbonyl]phenyl]pyrrolidinesu1fonamide (P-0270);
(3 R)—N-[3 —[5-(2-cyclopr0pylpyrimidin-S-yl)-1H-pyrrolo[2,3-b]pyridine—3-carbonyl]flucro-phenyl]—
3-methy1—pyrrolidine—1-sulfonamide (P—027l):
N—[3 -[5-(2-cyclopropylpyrimidin-S-yl)-I H—pyrr010[2,3~13]pyridinefi-carb0nyl]—2—fluoro—phenyl]v3-
(methylamin0)pyrrolidine» 1-sulfonamide (P-0272);
4811—7918-7726.1
039363—7211
N—[2,4-diflu0ro—3—[S—(4-pyridyl)— I H—pyrrol0[2,3-b]pyridine—3—carbonyl]phcnyl]pyrrolidine— ] —
sulfonamide (P—0273);
N—[B clopropyl-1H-pyrr010[2,3-b]pyridin6-3~carbonyl)fluom-phenyl]pyrrolidine—I —
sulfonamide (P-0274);
3-[3-[[ethmeethyl)sulfamoyl]amin0]-2,6-difl uoro-benzoyl]~5-[2-(4-hydr0xypiperidyl)pyrimidin—5—
yl]- I H-pyrrolo[2,3-b]pyridine (P—0275);
-[3 -(1-cyanocycIopropyl)phenyl]-3 -[3—[[ethyl(methyl)su Ifamoyijamino]—2,6-diflu0ro—benzoyl}1 H*
o[2,3—b]pyridine (P-0276);
-[2-(azctidiny|)pyrimidin-S-yl][3—[[ethyl(methyl)sulfamoyl]amino]~2,6—difluoro-benzoyl]-I H—
pyrrolo[2,3-b]pyridine (P-0277);
N-[3-[5-(2-aminopyrimidin—S-yl)-1H—pyrrolo[2,3—b]pyridinecarbonyl]—2,4—difluoro—
phenyl]pyrrolidine-l —su|fonamide (P—0279);
N-[3 ~[5 ~(2—aminopyrimidin-4—yl)—I H-pyrro|o[2,3-b]pyridine—3 nyI]—2,4-difluoro-
phenyl]pyrrolidine—I -sulfonamide (P-0280);
N-[2—fluoro—3 ~[5—(4—pyridyl)—1H-pyrrolo[2,3—b]pyridine-3—carbonyl]phenyl]pyrrolidine-1 ~su1fonamide
(P~0281);
N—[2,4—difluoro—3—[5—(2—morpholinopyrimidin—4—yl)—l olo[2,3~b]pyridine—3—
carbony1]phenyl]pyrrolidine— ] ~sulfonamide (P-0282);
3—[3~[[ethyl(methyl)sulfamoyl]amino]—2,6-difluoro—benzoyl]—5—(2~fluoro—4—pyridyl)—1H—pyrrolo[2,3-
b]pyridine (P—0283);
N—[2,4—difluoro—3—[5~(2~morpholinopyridyl)—lH—pyrrolo[2,3—b]pyridine—3—
carbonyljphenyljpyrrolidine—1 namide (P-0284);
N-[ZA-difluoro-3 -[5 -methylpiperazin- I -yl)pyridyl]— l H—pyrr010[2,3-bprridine—B—
carbonyl]phenyl]pyrrolidine-1—sulfonamide G’-0285);
N—[3 ~[5 yclobutoxy)pyridyl]-1H—pyrrolo[2,3-b]pyridinecarbony|]-2,4—difluom—
phenyl]pyrrolidinesulf0namidc (P-0286);
N-[2,4-difluoro-3 -[5-(2-methoxypyridyl)—I H-pyrrolo[2,3-b]pyridinecarbonyl]phenyl]pyrrolidine—
l—sulfonamide (P-0287);
N—[3 -[5-(2-cyclopropylpyrimidin-S —yl)—1H-pyrrolo[2,3-b]pyridine-3 —carbonyl]-2,4-difluoro-phenyl}
3,B-difluorO—pyrrolidinesulfonamide (P—0288);
-{3-[S-(2-cyclopropylpyrimidin-S-yl)—IH—pyrrolo[2,3—b}pyridinecarb0r1yl]—2,4—difluorofi
phenyij~3 ~fluoro»pyrrolidine-I -suifonamide (P-0289);
methyl 2~[[3{5~(2—cyclopropylpyrimidin—5~yl)~ I H~pyrrolo[2,3-b]pyridinc—3—carbonyl]~2~fiu0mu
phenyl]sulfam0yl]propanoate (P-0291);
—[2—(dimethylamin0)pyrimidin-5—yl]—3—[3-[[ethy|(methyl)sulfamoyl]amino]—2,6-difluor0-benzoyl]-1 H‘
pyrrolo[2,3~b]pyridine (P—0292);
3-[3—[[ethyl(methyl)sulfamoyl]amin0]—“,6—difluoro-benzoyl1—5-{2«pyrrolidinyIpyrimidin-S~yl}-lH-
pyrmlo[2,3~b]pyridine (P-0293);
4811~7918~7726 1
039363—721 1
N-[2,4-diflu0ro[S—[6—(trifluoromethyl)pyrimidin-4—yl]-1H-pyrrolo[2,3-b]pyridine—3—
carbonyl]phenyl]pyrr01idine- 1 —sulf0namide (P-0294);
N—[3 —[S—(2—cyclopropy]—4-pyridyl)—1H-pyrrolo[2,3 -b]pyridine—3—carbonyl]-2,4—difluoro—
phenyl]pyrrolidine— I -sulfonamide (P—0295);
—cyclobutyl-3—[3-[[ethmeethstulfamoyl]amin0]~2-fluoro—benzoy1]—lH-pyrrolo[2,3—b]pyridine (P-
0297);
S-cyclopropyl-3~[3—[[ethyl(methyl)suIfamoyljamino]fluoro—benzoyl]~I H—pyrrolo[2,3-b]pyridine (P-
0298);
N-[3-[S-(6-aminopyrimidinyl)-1H~pyrrolo[2,3-b]pyridinecarbonyl]fluoro-phenyl]pyrrolidine-
1-sulfonamide (P—0299);
yanophenyl)[3 -[[ethyl(methy|)sulfamoyl]amino]-2,6-difluoro-bcnzoyl]-1H-pyrrolo[2,3-
b]pyridine (P—0300);
3—[3 yl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl][4-(trifluoromethyl)phenyl]- 1 H-
pyrrolo[2,3-b]pyridine (P-0301);
-[3-(dimethylamino)phenyl][3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difiuoro—benzoy1j-I H-
pyrrolo[2,3-b]pyridine (P—0302);
3—[3—[[ethyl(methyl)sulfamoyl]amino]—2,6—difluor0—benzoyl](4-pyrrolidinylphenyl)-1H-
pyrrolo[2,3-b]pyridine (P—0303);
2-[4-[3-[3—[[cthyl(methyl)sulfamoyl]amino]-2,6-difluoro—benzoyl]~1H-pyrrolo[2,3—b]pyridin—5—
yl]phenyl]—5—methyl—l ,3,4—oxadiazole (P—0304);
2— [4—[3 —[3 —[[ethyl(methyl)sulfamoyl]amino]—2,6-difluoro-benzoyl]—1H—pyrrolo[2,3—b]pyridin—5-
yl]phcnyl]—5—(methylamino)— I ,3 ,4-thiadiazole 5);
3-[3-[[ethyl(methyl)sulfamoyl]amino]—2,6—difluoro-benzoyl][S-( l -hydr0xy- 1 amethyl—ethyl)-3—
pyridyl]—1H—pyrrolo[2,3-b]pyridine (P—0306);
3 —[3 —[[ethyl(methyl)sulfamoyl]amino]-2,6—difluoro-benzoyl][6-( 1—hydroxy—1—methyl-ethyl)—3
pyridyl} 1 H—pyrrolo[2,3-b]pyridine (P—0307);
—[4—(diethylamino)phenyI]—3-[3 ‘[[ethyl(1nethyl)sulfamoyl]amin0]-2,6-difluoro-benzoyl}- 1 H-
0[2,3—b]pyridine (P-0308);
3—[3—[[ethyl(methyl)sulfa1n0yl]amino] -2,6-di fl uoro~benzoyl]—5-(2-0xoindolin~6—yl)— I H-pyrrolo[2,3 —
b1pyridine (P413119);
3-[5-[3-[3 -[[ethyl(methyl)sulfamoyl]amincl—2,6—difluoro-ben20yl]-1 oloflj-Mpyridin-S—yl1—2-
thienyl]»5~methyl~l ,2,4-0xadiazole (P-0310);
o~6~{3-[3-[[ethyl(mcthyl)sulfamoyl]amin0]—2,6—d -benzoyl} I H-pyrrolo[2,3-b]pyridin—5-
yl]quinazoline (P-0311);
N-cyclopmpyl-S-[3—[3 -[[ethyl(methyl)su|famoyl]amino]-Z,6-diflu0ro—benzoyl}1H~pyrrolo[2,3-
b]pyridin~5-yl]pyridinc-2~carboxamide (P-0312);
2~(dimethylamino)~6-[3-[3—[[ethyl(methyl)sulfamoyl]amin01~2§6-difluom—benzoyl]— 1 Hapwmloflfim
b]pyridi11‘5u)ll]qt1irlazolirle (P-0313);
4811191817261
039363-7211
3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro—benzoyl]—5-[4-( I -hyd roxycyclopropyl)phenyl]— l H-
pyrr010[2,3-b]pyridine (P’0314);
-[3-[3—{[ethyl(methyl)sulfamoyl]amino]-2,6—difluoro—benzoyl]-I H-pyrrolo[2,3-b]pyridin-S-yl]thiazole
4-[3-[3-Hethyl(methyl)sulfamoyl]amino]—2,6-difluoro-benzoyl]—lH-pyrrolo[2,3-b]pyridinyl](l-
hydroxymethyI-ethy})th i310 Ie (P-0316);
3-[3-[[ethyl(methyl)sulfamoyljamino]-2,6-difluoro-benzoyl]-5~(6—methoxypyridazinyE)~1 Hn
pyrrolo[2,3—b]pyridine (P-0317);
N-[2,4-difluoro[5-(6-morpholinopyrimidinyl)- l H-pyrrolo[2,3-b]pyridine-3—
carbonyl]pheny1]pyrrolidincsulfonamide (P-0318);
N-[2,4-difluoro-3 -[5 -[6—(4-methylpiperazin- l -yl)pyrimidinyl]-I H-py1Tolo[2,3-b]pyridine
carbonyl]phenyl]pyrrolidine—1-sulfonamide (P-0319);
(3 S)—N-[3-[5-(2-cyclopmpylpyrimidin-S-yl)—IH-pyrrolo[2,3-b]pyridine—3-carbonyl]-2,4-diflu0ro—
phenyl]methyl-pyrrolidinc—1—sulfonamide (P-0320);
N-[2-fluoro[5-(6-morpholinopyrimidin—4—yl)—1H—pyrrolo[2,3-b]pyridine‘3-
carbonyl]phenyl]pyrrol id ine— 1 -sulfonamide 1);
N—[2-fluoro-3—[5—[6-(4-mcthylpipcrazin- 1 —y])pyrimidin—4-yl]-l H—pyrrolo[2,3-b]pyridinc
carbonyl]phenyl]pyrrolidine- I -sulfonamide (P—0322);
N-[2-fluor0[5—[6-(4—methylpiperazin—1—yl)—2—pyridyI]—1H—pyn‘Olo[2,3-b]pyridine
carbonyl]phenyl]pyrrolidine-1—sulfonamide (P-0324);
N-[2-fluoro[5-(4-methoxypyrimidiny])-I H-pyrrol0[2,3-b]pyridine
carbonyl]phenyl]pyrrolidine—1—sulfonamidc (P-0325);
N-[2-fiuoro—3~[5~(4-methylpyrimidinyl)—l H-pyrrolo[2,3-b]pyridine—3—carb0nyl]phenyl]pyrrolidine-
1-sulfonamide (P-0326);
(3 R)—N—[3-[5-(2—cyclopropylpyrimidin-S-yl)- I rrolo[2,3-b]pyrid inecarb0nyl]—2-flu0ro-phenyl]—
3—fluoro-pyrrolidine—1-sulfonamide 7);
[5-(2-cyclopropylpyrimidin-S-yl)- I H-pyrrol0[2,3-b]pyridin-3 -y1]—[2,6-difluoro-3 -
(methylsulfamoylamino)phenyl]methanone (P—0334);
[5-(2-cyclopropylpyrimidin-S-yl)-I H—pyrrolo[2,3-b]pyridin-3—yl]—[3—(ethylsulfamoylamino)—2,6-
difluoro-phenyl]methanone (P-0335);
yclopropylpyrimidin—S-yl)~3~[2,6-di Hume-3 -(sulfamoylamino)benzoyl}- i H-pyrrolofla}
b]pyridine (P-0336);
N—[3-[5-(4—ch10rophenyl)-1 olo[2,3-b]pyridine-3—carbonyI]—2.4-difluoro—phcnyljbutane-Z—
sulfbnamide (P-0337);
(3 R)—N-[3«[5—(2—cyc]0pr0pylpyrimidin—S—yl)— l H—pyrrolo[2,3-b]pyridine-3 -carbonyl]—2,4-difluoro—
phenyl]~3—fluor0-pyrrolidine—1-sulfonamide (P-0338);
N-[B {5~(2-cyclopmpylpyrim idiu»5—yl)~l H«pyrw!o[2,3~b]pyridinea nyI}—2,4»difluar0»phenyi}—3 -
pyrrolidine~ I ~su1fonamide (B0339);
431177261
039363—721 l
S-(Z-eyclopropylpyrimidin-5—yI)—3-[236-difluoro—3—[[methyl(2,2,2—
trifluoroethyl)sulfamoyl]amino]benzoyl]— l H-pyrrolo[2;3-b]pyridine (P-0340);
N—[S{5 ~(2-cye Iopropylpyrimidin-S -yl)— I I I—pyrrolo[2,3-b]pyridine—3 nyI]—2,4-difl uoro—
phenyl]butane-2—suIfonamide (P—0342);
-[3 -[3 -[[ethyl(methyl)sulfamoyl]amino]-2,6-d ifluoro—benzoyl}- I H-pyrrolo[2,3—b]pyrid in- 5-le
methoxyuthiazole (P-0343);
3-f3-f{ethyl(methyl)sulfamoyl]amino]-2,6-difluoro—benzoyi]~5-(IH—indazoI—é—yl)-1H-pyrroloI2,3-
b]pyridine (P-0344);
N-[2,4-ditluoro[5-(2-pyrrolidin-l -ylpyrimid in-S-yl)- l H-pyrrolo[2,3-b]pyridine
earbonyIIphenyllpyrrolidine-I-sulfonamide 5);
N-[3-(5-cyclobutyl-1H-pyrrolo[2,3-b]pyridinecarbonyI)fluoro-phenyl]pyrrolidine-I -sulfonamide
N-IZ-fluoro-3 -[5-(2-methoxypyrimid in-S -yl)- I H—pyrrolo[2,3—b]pyridine—3 -
carbonyl]phenyl]cyclopropanesulfonamide (P—0347);
l-allyl-N-[3 -(5-cyano-l H-pyri‘olo[2,3-b]pyridineearb0nyl)—2,4-difluorophenylkyelopropanesulfonamide
(P411548);
N-[2,4-difluoro—3-[5—(2-methoxypyrimidin-S-yl)-lH-pyrrolo[2,3-b]pyridine—3—
carbonyl]phenyl]cyclopropanesulfonamide (P-0349);
N-[2,4—diiluoro[5—(5—methoxy-3—pyridyl)-IIVI-pyrrolo[2,3-b]pyridine
carbonyl]phenyl]cyclopropanesulfonamide 0); and
N-[3-(5-cyano—IH-pyrrolo[2,3-b]pyridine—3—carbonyl)-2,4—difluoro-phenyl]cyclopropanesulfonamide
(P—0351);
or pharmaceutically acceptable salts, hydrates, solvates, tautomers or s thereof. In some
embodiments, the ion provides the above selected compounds and pharmaceutically acceptable
salts f. In other embodiments, the invention es the above selected compounds and
pharmaceutically acceptable salts and ers and isomers f.
In other embodiments, the invention provides a compound selected from any of P—OIOS to P—
0222 as set forth in Table 3 and pharmaceutically acceptable salts, hydrates, solvates, tautomers and
isomers thereof, In some embodiments, the invention provides any of the above selected compounds
and pharmaceutically acceptable salts thereof. In some embodiments the invention provides any of
the above selected compounds and pharmaceutically acceptable salts and tautomers and isomers
{0121] In some embodiments, when Y[ is optionally substituted 2-pyridyl, 3-pyridyl or 4-pyridyl, Z
is other than —N(CH3)(CH3) or —N(R4);, wherein R4 is C..6alkyl. In some embodiments, when Y1 is
phenyli, Z is other than ~N(CH3)(CH3) or ~N(R4)2, wherein R4 is €1-6alkyl. In other embodiments,
when YI is halogen, Z is other than ~N(CH3)(CH3), 2, hpyrrolinyh I-piperidinyl, 4=
4811—7918~7726.1
039363-7211
morpholinyl or g, wherein R‘1 is Cmalkyl. In some embodiments, when Y1 is CH3 or C1.6aIky|,
Z is other than wN(CH3)(CH3), -N(Et)2, olinyl, 1—piperridinyl, 4-morpholinyl or —N(R4)2,
wherein R4 is C1.6alkyl. In some embodiments, when YI is CHgO- or C1-5alkoxy, Z is other than —
N(CH3)(CH3), wN(Et)3, l—pyrrolinyl, I—piperridinyl, 4—morpholinyl or —N(R4)2, wherein Ki is Chgalkyl.
In some ments, when Y1 is CN, Z is other than —N(CH3)(CH3), -N(Et)3, olinyl, I-
piperridinyl, 4-morpholinyl or —N(R4)g, wherein R4 is C1_6alkyl. In certain instances, when Y1 is
halogen, —CH3, -CN3 -OMe or 2-methoxypyrimidin-S—yl, Z is other than Cascycloalkyli In other
instances, when Y1 is I—methyI-éi—pyrazolyl, 3—methylsulfonylphenyl or 3—
methylsulf‘onylarninophenyl, Z is other than C3-6cyc|oalkyl. In other instances, when Y1 is Cmalkyl or
Cmalkoxy, Z is other than C3_6cyc|oalkyl. In other instances, when Y1 is alkylpyrazolyl, Z is
other than cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In other instances, when Y1 is 1-0.
5alkylpyrazolyl, Z is other than C3-6cyc|oalkyl. In other instances, when Y1 is
methylsulfonylphenyl or methylsultonylaminophenyl, Z is other than cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl. In other instances, when Y1 is methylsulfonylphenyl or
methylsulfonylaminophenyl, Z is other than C3-6cycloalkyl. In some instances, when Y1 is 3~C;-
6alkylsulfonylphenyl or 3-C]-621]kylsulfonylaminophenyl, Z is other than cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl. In other instances, when Y1 is alkylsulfonylphenyl or 3—C1-
oalkylsulfonylaminophenyl, Z is other than cloaIkyI.
The following compounds in Table I are excluded from the generic formulas I and la to In:
Table I
3-[3 -(dimethylsulfamoylamino)-2,6-difluoro—benzoyl]—5-(3 yl)-I olo[2,3 -b]pyridine;
o—3 -[3 -(dimethylsulfamoylam ino)—2,6-difluoro-benzoyl]- I H-pyrroio[2,3 —b]pyridine;
3—[3 -(dimcthylsulfamoylamino)-2,6-difiuoro—benzole—S—phcnyl-I H—pyrrolo[2,3—b]pyridine;
N-[3 -(5—chloro- I H-pyrrolo[2,3-b]pyridine-3—carbonyl)—2,4-difluoro—phenyl]piperidine— I -
sulfonamide;
—(4—chlorophenyl)[3-(dimethylsulfamoylamino)—2,6—ditIuoro-benzoyl]-1H—pyrrol0[2,3-
b]pyridine;
—chloro-3 -[3 -(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]—IH—pyrrolo[2,3—b]pyridine;
(5-chloro— I H-pyrrolo[2,3~b]pyridin—3—yl)-[3~[dimethylsulfamoyl(methyl)amino]-2,6-difluoro-
phenyljmethanone;
N-[ZA-dit‘luorofi -(S -methoxy- I H-pyrrolo[2,3-b]pyridinc—3-carbonyl)phenyl]pyrroiidine- l u
sulfonamide;
N-[3 —(5—chloro-1H—pyrrolo[2,3—b]pyridine—3—carbony|)—2,4—difluoro-phenyljpyrrolidine-I-
sulfonamide;
-d i fluoro~3 —(5vmethyl-l H-pyrrolo[2,3—b]pyrid inc—3~03rbonyl)phenyi]pyrrolidine- l —
sulfonamide;
48117726.1
03 9363—721 1
N-[3-(S-cyan0—1H—pyrrolo[293-b]pyridine—3—carb0nyl)-2,4—difluoro—phenyl]pyrrolidine~1-
sulfonamide;
—cyan0-3 ~[3-(dimethylsulfamoylamino)—2,6-difluoro-benzoyl]—1I"I-pyrr010[2,3 —b]pyridine;
3-[3-(dimethylsulfamoylamino)-2,6-difluoro-benzoyl]methyl-1H-pyrrolo[2,3 —b]pyridinc;
S-ch10m[3-(diethylsuIfamoylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3—b]pyridine;
-cyano—3 —[3 -(dicthylsulfamoylamino)-2,6-difluoro-benzoyl]- I H-pyrmlo[2,3-b]pyridine;
3 -[3-(diethylsulfamoylamin0)~2,6-difluoro-ben20y11methy1- ! H—pyrr010[2,3-b]pyridine;
3~[3-(diethylsulfamoyIamino)-2,6-difluoro-benzoyl]meth0xy~1H-pyrrolo[2,3-b]pyridine;
N -[3 -(5 -chloro-1H-pyn‘olo[2,3-b]pyridine-3 -carbonyl)-2,4-difluoro—phenyl]morphol ine
sulfonamide;
N-[2,4-difluor0-3 -(5-methoxy-1H-pyrrol0[2,3-b]pyridinecarbonyl)phenyl]morpholine—4-
sulfonamide;
—difluoro—3 -(5-methyl—] H—pyrrolo[2,3—b]pyridine-3—c.arbonyl)phenyl]morpholinc
sulfonamide;
N-[3-(5—cyano—1I—I-pyrrolo[2,3 —b}pyridine—3—carbonyl)—2,4-di fluoro-phenyl]morpholine-4—
sulfonamide;
3 -[3 -(dimethylsulfamoylam ,6-difluoro-benzoyl]-5—(2-meth0xypyrimid in-S-yl)- 1 H-
o[2,3-b]pyridine;
N—[2,4-d ifluoro-3 -[5-(2—methoxypyrimidin—S-yl)-1H—pyrrolo[2,3—b]pyridinc
carbonyl]phenyl]pyrrolidine—1—sulf0namide;
3-[3 —(d iethylsulfamoyl amino)—2,6—difluoro-benzoyl](2-methoxypyrimid in-S -yl)-1H-
pyrrolo[2,3-b]pyridine;
-difluoro—3 —[5—(2—meth0xypyrimidinyl)— I H-pyrrolo[2,3-b]pyridine—3-
carbonyl]phenyl]morpholinesulfonamide;
-cyano—3—[3 -(dimethylsulfamoylamino)flu0ro-benzoyl]—1H-pyrrolo[2,3-b]pyridine;
N—[3-(5-cyano—1H—pyrroloI2,3—b]pyridine—3-carbonyl)fluor0-phcnylIpyrrolidinbl-
sulfonamide;
N-[3 —(5-cyano- 1 rrolo[2,3 —b]pyridinecarbonyl)fluor0-phenyl]morpholine
sulfonamide;
N-[2-fluor0[5—(2-methoxypyrimidin-S-yl)—1H-pyrrolo[2,3—b]pyridine
carbonyl]phenyl]pyrmlidine-I -sulfonam ide;
hlorophenyl)—3—[3 ~(dimethylsulfamoylamino)fluoro—benzoyl]— 1 H-pyrmfn[2,3-b]pyridine;
3-[3—(dimethylsuIfamoylamino)fluoro-benzoyl]—5—(2«methoxypyrimidin—S-yl)- i H-pyrrolo[2,3-
h]pyridine;
Propane—2-sulfonic acid [2,4—difluoro—3—(5—methoxy- l II—pyrrolo[2,3—b]pyridinecarbonyl)-
]«amide;
Pyrmlidine-l—sulfonic acid [2,4-diHuoro—3—(5-meth0xy—IH—pyrrolo[2,3-b]pyridine—3-carbonyl)—
phenyiJ—amidc;
481177261
039363-7211
Propane-Z-sulfonic acid [3-(5—chlor0-lH-pyrrolo[2,3-b]pyTidinecarb0nyi)—2,4-difluoro~
phenyl]-amide;
Propane~2—suifonic acid [3-(5-cyano-iH-pyrrolo{2,3-b]pyridinecarb0nyl)-2,4-dif‘iuoro-phenyij-
amide;
e-2~sulf0nic acid {2,4-difluoro—3~[5-(2-methoxy-pyrimidin-S—yl)~IH—pyrmloIZfi-
b]pyridinecarbonyl]-phcnyi}~amide;
Butane-Z-suifonic acid ifluoro-3 ~(5~meth0xy- l H-pyrmlo[2,3—bjpyridinecarbonyi)-
phenyi]-amide;
Péntanc—2-suiibnic acid [2,4-difluoro—3-(5-methoxy-l H-pyrrolo[2,3-b]pyridinecarbonyi)-
]-amide;
Butane-Z-sulfonic acid [3-(5~chloro-1H-pyrrolo[2,3-b]pyridinecarbonyl)—2,4-difluoro-phenyl]—
amide;
Pentane-Z-sulfonic acid [3 ~(5—ch10ro— 1 H—pyrrolo[2,3—b]pyridinecarbonyl)-2,4-difluoro-phenyl]-
amide;
Butanesulf0nic acid [2,4-difluom~3~(5~methyl-l H-pyrroio[2,3-b]pyridine-3~carbonyi)~phenyl]-
amide;
Pentane-Z-sulfonic acid [3-(5-cyan0-1H-pyrrol0[2,3~b]pyridinecarbonyi)-Z,4-difluorO-phenylj-
amide;
Pentane-2~sulf011ic acid [2,4-dif1uoro(5-methyl-1H~pyrrolo[2,3-b]pyridine-3~carb0nyl)-
phenyl]-amide;
Butane-2~sulf0nic acid [3-(5-cyano-iH-pyrrolo[2,3-b]pyridine~3-carbonyl)~2,4-diflu0r0~phenyl]-
amide;
Butane-Z—sulfonic acid {2,4-difluoro[5-(2-methoxy~pyrimidin-5~yl)-I H-pyrroio[2,3-
b]pyridinecarb0nyl]-phenyl}-amide;
Cyclobutancsulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridinecarbonyi)-2,4-diflu0ro-
phenyl]-amide;
Cyclobutanesulfonic acid [3-(5~chloro-1H-pyrrolo[2,3~b]pyridine-3—carbonyi)~2,4-difluoro-
phenylj-amidc;
exanesulfonic acid [2,4-difluor0—3 -(5 —methoxy- l H~pyrrolo[2,3-b]pyridine-3—carbonyi)-
phenyl]-amide;
emanesulfonic acid [2,4—difluom(5—methoxy- l H-pyrroio[2,3-b]pyridine~3 ~carb0nyl)—
phenyi]—amide;
Cyciohexanesuifonic acid [3-(5-chioro- i H-pyrrolo[2,3—b]pyridine—3—carbonyi)—2,4-difluomphenyl
]-amide;
Cyclopentanesulfcnic acid [3~(5-chlor0-1H-pyrrol0[2,3-b]pyridine-3—carbonyi)-2,4-difluoro—
phenyi]~amide;
cntanesuifonic acid [3-(5—cyan0~1H~pyrrolo[2,3-b}pyridinecarb0nyl)—2,4-difiuord
phenyIJ—amidc;
451 17726,1
03 9363-721 1
exanesuifcnic acid [2,4—difluoro—3-(5—methyi— i H—py’rrolo[2,3-b]pyridine-3 carbonyl)-
phenyl]—amidc;
Cyclcbutanesuifonic acid [2,4-difluor0—3«(5-methyI—]H-pyrr010[2,3-b]pyridinecarb0nyi)—
phenyl]-amide;
Cyclopentanesuifonic acid [2,4-difluoro~3—(5‘methyi-1H—pyrroio[2,3-b]pyridinccarbonyl)-
phenyi]-amide;
Cyclohexanesuifonic acid [3 {5 —iH-pyrroiol2,3—b]pyridinecarbonyl)-2,4-diflu0ro-
pimnyi]-amide;
Cyciohexancsulfonic acid ifluoro[5-(2-methoxy-pyrimidin-S-yl)—1H—pyrrolo[2,3-
b]pyridine—3 -carb0nyl]—phenyl} -amide;
Cyclopemanesulfonic acid {2,4-difluoro[5-(2-methoxy-pyrimidin-S-yl)—1H—pyrr010[2,3-
b]pyridinccarbonyl]-phenyl}-amide;
Cyclobutanesulfonic acid {2,4—diflu0ro-3—[5—(2—methoxy—pyrimidin—5—yl)— I H-pyrrolo[2,3—
b]pyridine-3—carbonyl]-phenyl}-amide;
Pyrroiidine- I —suifonic acid [2,4—diflu0ro—3 —(S—methoxy— 1 H-pyrroio[2,3—b]pyridine—3 nyi)—
phenyl]—amide;
Pyrrolidine- i —sulfonic acid [3 -(5—chloro-1H—pyrrolo[2,3—b]pyridine—3-carbonyl)—2,4—difluor0-
phenyl]~amide;
Pyrrolidine— l «sulfonic acid [2,4—difluoro—3 ~(5—methyl—i H-pyrrolo[2,3—b]pyridine—3«carbonyl)n
phenyl]-amide;
Pyrrolidine- 1«sulf0nic acid [2,4~difluoro—3-(5-cyano—1H—pyrrolo[2,3—b]pyridine-3—carbonyl)-
phenyl]-amide;
N,N-dimethylamino~sulfonic acid [2,4—difluoro—3—(5—cyano— i H—pyrroio[2,3—b]pyridine—3-
carbonyi)~phenyl]-amide;
N,N—dimcthylamino-suifonic acid [2,4-difiuoro—3—(5—methyi-1H-pyrrolo[2,3-b]pyridinc—3—
carbonyi)-phenyl]-amide;
NgN-diethyIamino-sulfonic acid [3-(5-chloro—1H—pyrroio[2,3—b]pyridinc—3-carb0nyi)—2,4—diflucro-
phenyij-amide;
N,N—diethylaminmsuifonic acid [3—(5—cyano—l H—pyrroio[2,3—b]pyridinecarbonyl)-2,4-difluoro—
phenyi]-amide;
N,N~diethyiamiim-suifcmic acid [2,4-diflu0r0(5-methyi- i H-pyrro]0[2,3~b]pyridine-3—
carbonyi)-phenyi]-amidc;
ethylamino-suifonic acid [2,4—difluoro—3-(5—methoxy«IH-pyrroio[2?3~b]pyridine
carbonyl)—phenyi]-amidc;
Morpholine—4—suif0nic acid [3~(5—cyan0- i H—pyrrol0[2,3—b]pyridinc—3~carbonyl)—2,4—difluoro-
]—amide;
Morpholine~4-sulfanic acid [3-(5-chior0-iH-pyrroio[2,3~b1pyridine—3‘carbonyi)—234—diflu0mm
phenyij—amidc;
48117361
039363-721 1
Morpholincsulfonic acid [2,4-difluor0(5-mcth0xy-1H-pyrrolo[2,3~b]pyridinc-3—carb0nyl)—
phenyl]—amide;
Morpholincsulfonic acid ifluoro—3-(5-methyl-IH—pyrrolo[2,3-b]pyridinecarbonyl)—
phenyl]—amide;
Propane-2—sulf0nic acid [3-(5-cyan0-1H-pyrroio[2,3—b]pyridinecarbonyl)fluom-phcnyl]~
amide;
Butane-2—sulfonic acid [3-(5-cyano-1II-pyrrolo[2,3:b]pyridine-3—carbonyl)fluoro~phenyl]-
amide;
Cyclohexanesulfonic acid [3—(S-cyano-1H-pyrrolo[2,3-b]pyridinecarb0nyl)—2—fluorO-phcnylj-
amide;
Cyclopentanesulfonic acid [3—(5-cyano—l H—pyrrolo[2,3-b]pyridinccarbonyl)fluoro-phenyl]-
amide;
Cyclobutanesulfonic acid [3—(5—cyano—l H—pyrrolo[2,3-b]pyridine-3—carbonyl)-2—fluor0—phenyl]—
amide;
Cyclopropanesulfonic acid {4—fluoro~3-[5-(1-methyl—1H—pyrazol—4-yI)-1H—pyrrolo[2,3—
b]pyridine—3—carb0nyl]—phenyl}—amide;
Cyclohexanesulfonic acid {4-flu0ro-3—[S—(l —mcthyl—I H—pyrazoI—4—yl)—1H—pyrrolo[2,3—b]pyridine—
3—carbonyl]—phenyl}—amide;
Cyclopropancsulfonic acid [3-(5—chloro-1H—pyrrolo[2,3—b]pyridine—3—carbonyl)—4-fluoro-pheny1]-
amide;
Cyclohexanesulfonic acid [4—fluor0(5—methyl-1H-pyrrolo[2,3-b]pyridine—3-carbonyl)—phenyl]—
amide;
Cyclohexanesulfonic acid {4-fluoro[5-(3-mcthanesulfcnyl-phcnyl)—lH—pyrrolo[2,3-b]pyridine-
3—carbonyl]-phenyl}-amide;
Cyclopentanesulfonic acid {4-Huoro[5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3—
b]pyridinecarbonyl]-phcnyl}-amide;
Cyclohexanesulfonic acid {4-flu0r0[5-(3-methanesulfonylamino-phenyl)—lH-pyrrolo[2,3-
dinecarbonyl]—phenyl}-amide;
Cyclopcntanesulfonic acid {4-fluoro[5-(3-mcthanesulfonylamino-phenyl)-1H—pyrrolo[2,3-
dine—3 -carbonyl]—phcnyl} -amide;
Cyclopentancsulfonic acid [4-fluoro—3-(S—methyl— 1 H-pyrrolo[2,3—b]pyridinc—3 ~carb0ny!}phenyl]—
amide;
Piperidine~I-sulfonic acid chloro-1H—pyrrolo[2,3-b]pyriditie-3¢carbunyl)-4~fluor0-phenyi]-
amide;
N,N—dimethylamino—sulfcnic acid [3-(5—bromo-1H-pyrrolo[2,3~b]pyridinev3~carbonyl)—2—flu0ro—
]-amide;
Pynolidine—I—sulfonic acid [3—(5~bromo~1H~pyrrolo[2,3~b}pyridinc-3~carbonyl)~2»flucrc«phcnyl]-
amide.
481 14918-77261
039363-72ll
[0123} In another aspect, the t invention provides a method for ing a compound of
formulas (I) to (In). The method includes contacting a compound having formula II:
with an agent ed from ‘i’l-GI (III) or AI—S(O),-Z (IV) under conditions ent to form a
compound having formulas (V) or (VI):
Y1 E
\ HN~—'s'.
‘\ z
\ NH?
F I \ F S
N” /
i N r
P1 or P1
(V) (VI)
reacting (i) a compound of formula (V) with a compound of formula (IV), or (ii) a compound of
formula (VI) with a compound of formula (111) under ions sufficient to form the compound of
formula (I); and wherein E1 is halogen, tosylate or mesylate; Gl is —B(OR25)2 or —Sn(Bu)3, wherein
R25 is —OH, alkyl or two ~0st substituents together with the boron atom to which they are attached
to form an ally substituted 5 or 6—membered ring; Al is a leaving group, which can be readily
ced by an arylamino group; and P1 is H or an amino ting group. In some instances, the
substituents for the 5 or 6—membered ring are l to 4 members Re groups. In some embodiments, the
reaction of compounds of formula (II) with In one embodiment, E1 is Cl, Br or I. In another
rembodiment, E1 is tosylate, te or triflate. In one embodiment, G1 is ~B(OH)2. In another
embodiment, G1 is 2—hydroxy-1,3,2-benzodioxaborole or 2-hydroxy-4,4,5,S-tetramcthyl-I ,3,2-
benzodioxaboro. In another embodiment, G] is ~Sn(Bu)3. In one embodiment, A1 is C1 or Br. In
another embodiment, A] is tosylate or mesylate. In one embodiment, P1 is H. The substituents Y1,
Y2, Q and Z are as defined in any of formulas (I) to (In) and any of the embodiments disclosed herein.
In some embodiments, the method includes contacting a compound of formula (II) with an
agent of formula (III): Yl—Gri to form a nd of formula (V), followed by reacting a compound
offernula (V) with an agent of formula (IV): A2~S(O)3-Z to form a compound of formula (I). In other
embodiments, the method includes ting a compound of formula (II) with an agent of formula
(IV): A1~S(O)z-Z to form a compound of formula (VI), ed by reacting a compound of formula
(V1) with an agent of a (III): YI—GI to form a compound of formula (I),
In yet other embodiments, the invention provides a method for preparing a compound of
formulas (I) to (In). The method includes reacting a compound having formula II:
48117726.1
039363-7211
with a compound of formula (IV): Al-S(O)z-Z under conditions sufficient to form a compound having
formula (VI):
\ HN—e—z
I \ F H
N/ 0
(V1)
contacting a compound of formula (VI) with a nd of the formula: 2 and a compound of
the formula: ZB-B(OR3')2 in the presence ofa palladium complex under conditions sufficient to
form the compound of formula (I), wherein R31 is —OH, alkyl or two MGR“ substituents together with
the boron atom to which they are attached to form a 5 or 6-membered ring; and wherein El and E2 are
each independently halogen, tosylate or mesylate; Al is a leaving group; and PI is H or an amino
protecting group. Both Pd(0) and Pd(II) complexes can be used. In some embodiments, E1 is Cl, Br,
I, tosylate or mesylate. In some embodiments, E2 is Cl, Br, I, tosylate or mesylate. In certain
instances, the palladium xes include, but are not limited to, Pd(PPh3)4,
bis(diphenylphosphino)ferrocene]dichloropalladium and the like. The substituents Y1, Y2, Q and Z
are as defined in any of formulas (I) to (In) and any of the embodiments disclosed herein.
In another aspect, the invention provides a compound having fonnula (VIII):
VIII
wherein 13132 and R33 are each independently H. optionally substituted alkyl, optionaily tuted
arylaikyl or ally substituted aryt. In ome embodiements, the aryI or alkyl portion of R32 or R33
is optionally substituted with from I to 4 Re substituents; or R32 and R33 er with the oxygen
atoms to which they are attached form a 5- or 6-membered ring, wherein the S« or 6-membered ring is
optionaliy substituted with from 1 to 4 Re groups or fused with an optionally substituted 5— or 6—
memhered aromatic ring. The substituents Y2, Q and Z in formula VIII are as defined in in any of
formulas (I) to (In) and any ot'the embodiments as described herein.
4811—7918—77261
-7211
In some embodiments, the compounds of formula VIII have sub a VlIIa:
9 Y2W o
R37 6W m—e—z
\;F n
H VIIIa
R34, R35. R36 and R37 are each independently R8 or Rf. In certain instances, R34, R35, R36 and R37 are
each ndently C14, alkyl. In other instances, R34, R35, R36 and R3"7 are CH3. The substituents Y2,
Q and Z in formula VIIIa are as defined in in any offormulas (I) to (In) and any of the embodiments
as described herein.
In some embodiments, the compounds of formula VIII have sub formula VIIIb:
H VII“)
The subscript y is an integer of l to 4. Each R38 is independently H, R° or Rf. The substituents Y2, Q
and Z in formula VIIIb are as defined in any of formulas (I) to (In) and any of the embodiments as
described herein.
In some embodiments, the compounds offormula VIII have subformula VIIIc:
VIIIc
The subscript z is an integer of I to 4. Each R39 is independently H, R8 or Rf. The substituents Y2, Q
and Z in formula VIIIc are as defined in any of formulas (I) to (In) and any of the embodiments as
described herein.
Organic Synthetic Techniques
A Wide array of organic synthetic techniques exist in the art to facilitate the construction of
ial modulators. Many of these organic synthetic methods are described in detail in standard
reference sources utilized by those skilled in the art. One e of such a nce is March, I994,
Advanced Organic Chemistry; Reactions Mechanisms and Structure, New York, McGraw Hill.
Thus, the techniques useful to synthesize a potential modulator of kinase function are readily available
to these d in the art of organic chemical synthesis.
4811791877261
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Alternative nd Farms or Derivatives
Compounds contemplated herein are described with reference to both c formulae and
specific compounds. In addition, invention compounds may exist in a number of different forms or
derivatives, all within the scope of the present invention. Alternative forms or derivatives, e,
for example, (a) prodmgs, and active metabolites (b) tautomers, isomers (including stcrcoisomers and
regioisomers), and racemic es (c) pharmaceutically acceptable salts and (d) solid forms,
including different crystal forms= polymorphic or ous solids, including hydrates and solvates
thereof, and other forms.
(a) Prodrugs and Metabolites
In addition to the present formulae and compounds described herein, the invention also
includes prodrugs (generally pharmaceutically able prodrugs), active lic derivatives
(active metabolites), and their pharmaceutically acceptable salts.
Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when
metabolized under physiological conditions or when converted by solvolysis, yield the desired active
compound. Prodrugs include, without limitation, esters, amides, carbamates, ates, ureides,
solvates, or hydrates of the active compound. Typically, the prodrug is inactive, or less active than
the active compound, but may provide one or more advantageous handling, administration, and/or
metabolic ties. For e, some prodrugs are esters of the active compound; during
metabolysis, the ester group is cleaved to yield the active drug. Esters include, for example, esters of
a carboxylic acid group, or S—acyl or O—acyl derivatives of thiol, alcohol, or phenol groups. In this
context, a common example is an alkyl ester of a carboxylic acid. Prodrugs may also include variants
wherein an -NH group of the compound has undergone ion, such as the l-position of the 1H-
pyrrolo[2,3-b]pyridine ring, or the nitrogen of the sulfonamide group of compounds as described
herein, where cleavage of the acyl group provides the free —NH group of the active drug. Some
prodrugs are activated enzymatically to yield the active compound, or a compound may undergo
further chemical reaction to yield the active compound. Prodrugs may proceed from prodrug form to
active form in a single step or may have one or more intermediate forms which may themselves have
activity or may be inactive.
As described in The Practice ofMedicinal Chemistry, Ch. 31-32 (Ed. Wennuth, ic
Press, San Diego, CA, 2001), gs can be conceptually divided into two non—exciusive ries,
bioprecursor prodrugs and carrier prcdrugs. Generally, bioprecursor prodrugs are nds that are
inactive or have low activity compared to the corresponding active drug compound, that contain one
or more protective groups and are converted to an active form by metabolism or solvolysis. Both the
active drug form and any released metabolic ts shouid have abiy tow ty. 'l‘ypicaliy,
48117726.1
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the formation of active drug compound involves a metabolic process or reaction that is one of the
following types:
Oxidative reactions: Oxidative reactions are exemplified without limitation by reactions
such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons,
hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon—
carbon double bonds, oxidation of nitrogen—containing functional groups, oxidation of silicon,
phosphorus, arsenic, and sulfur, oxidative N-dealkylation, ive O- and S—dealkylation, oxidative
deamination, as well as other oxidative reactions.
Reductive reactions: Reductive reactions are exemplified without limitation by reactions
such as reduction of carbonyl fimctionalitites, reduction of alcohol functionalities and carbon-carbon
double bonds, reduction of en-containing functional groups, and other reduction reactions.
Reactions without change in the ion state: Reactions without change in the state of
oxidation are exemplified without limitation by reactions such as hydrolysis of esters and ethers,
hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non—aromatic
heterocycles, hydration and dehydration at multiple bonds, new atomic linkages ing from
dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other
such reactions.
Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that es
uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier g, the
linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive
or less active than the drug compound, the g and any release ort moiety are acceptably
non—toxic. For gs where the transport moiety is intended to enhance uptake, typically the
release ofthe transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that
provides slow release, e.g., n polymers or other moieties, such as cyclodextrins. (See, e.g.,
Cheng et al., US. Patent Publ. No. 77595, App. No. ,838, incorporated herein by
reference.) Such r prodrugs are often advantageous for orally administered drugs. In some
instances, the transport moiety provides targeted ry of the drug, for example the drug may be
ated to an antibody or antibody fragment. r prodrugs can, for example, be used to
improve one or more of the following properties: increased lipophilicity, increased duration of
cological effects, increased site~specificity, sed toxicity and adverse reactions, andfor
improvement in drug formulation (eg, stability, water solubility, suppression of an undesirable
organoleptic or physiochemical property). For example, lipophilicity can be increased by
esterification of hydroxyi groups with lipophilic carboxylic acids, or of carboxylic acid groups with
alcohols, e.g., aliphatic alcohols. Wermuth, saggy.
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Metabolites, c.g., active lites, overlap with prodrugs as described above, e.g.,
bioprecursor prodrugs. Thus, such metabolites are pharmacologically active compounds or
nds that further metabolize to cologically active nds that are derivatives
resulting from metabolic processes in the body ofa subject. Of these, active metabolites are such
pharmacologically active derivative compounds. For gs, the prodrug compound is generally
inactive or of lower activity than the metabolic product. For active metabolites, the parent compound
may be either an active nd or may be an inactive prodrug. For example, in some compounds,
one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic
activity and/or carboxyl groups can be esterified, e.g., glucuronidation. In some cases, there can be
more than one metabolite, where an intermediate metabolite(s) is further metabolized to provide an
active metabolite. For example, in some cases a derivative compound resulting from metabolic
glucuronidation may be inactive or of low activity, and can be further metabolized to provide an
active metabolite.
Metabolites of a compound may be identified using routine techniques known in the art, and
their activities determined using tests such as those described . See, e.g., Bertolini et al., 1997,
J. Med. Chem, 40:20] 1—2016; Shan et al., l997, JPharm Sci 86(7):756—757; we, 1995, Drug
Dev, Res, 34:220—230; Wermuth, supra.
(b) Tautomers, Stereoisomers, and Regioisomers
It is understood that some compounds may exhibit erism. In such cases, the formulae
provided herein expressly depict only one of the possible tautomeric forms. it is therefore to be
understood that the formulae provided herein are intended to represent any eric form of the
depicted compounds and are not to be limited merely to the specific tautomeric form depicted by the
drawings of the formulae.
Likewise, some of the compounds according to the present invention may exist as
stereoisomers, i.e. having the same atomic conneclivity of covalently bonded atoms yet differing in
the spatial orientation of the atoms. For e, compounds may be optical isomers, which
contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (eg.
enantiomers or diastereomers). Thus, such compounds may be present as single stereoisomers (i.e.,
essentially free of other isomers), racemates, and/or mixtures of enantiomers and/or
reomers. As another example, stereoisomers include geometric s, such as cis« or trans-
orientation ofsubstituents on adjacent carbons of a double bond. All such single stereoisomers,
tes and mixtures thereof are intended to be within the scope of the present invention. Unless
specified to the contrary, all such steroisomeric forms are included within the formulae provided
herein.
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[0143} In some embodiments, a chiral compound of the present invention is in a form that contains
at least 80% of a single isomer (60% enantiomeric excess (“ea”) or diastereomeric excess (“d.e.”)),
or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or (1.6.), 95% (90% cc. or do), 97.5% (95% are. or
d.e.), or 99% (98% e.e. or d.e.). As generally understood by those d in the art, an optically pure
nd having one chiral center is one that consists essentially of one of the two possible
enantiomers (ie., is enantimnerically pure), and an optically pure compound having more than one
chiral center is one that is both diastercomcrically pure and cnantiomcrically pure. In some
embodiments, the compound is present in optically pure form, such lly pure form being
prepared and/or isolated by methods known in the an (eg. by recrystallization techniques, chiral
synthetic ques (including synthesis from optically pure starting materials), and chromatographic
separation using a chiral column.
(c) Pharmaceutically acceptable salts
Unless specified to the contrary, specification of a compound herein includes
ceutically acceptable salts of such nd. Thus, compounds described herein and recited
in any of the claims can be in the form of phatmaceutically acceptable salts, or can be formulated as
pharmaceutically acceptable salts. Contemplated pharmaceutically acceptable salt forms include,
without limitation, mono, bis, tris, tetrakis, and so on. Phannaceutically acceptable salts are non—toxic
in the amounts and concentrations at which they are administered. The preparation of such salts can
facilitate the pharmacological use by altering the physical characteristics of a nd without
preventing it from ng its physiological effect. Useful alterations in physical properties include
lowering the g point to facilitate transmucosal administration and increasing the solubility to
facilitate administering higher concentrations of the drug. A compound of the invention may possess
a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with
any of a number of inorganic or organic bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt.
Pharmaceutically acceptable salts include acid on salts such as those containing
chloride, bromide, iodide, hydrochloride, acetate, acetate, acrylate, ascorbate, ate,
benzoate, 2—phenoxybenzoate, 2—acetoxybenzoate, dinitrobenzoate, hydroxybenzoate,
methoxybenzoate, methylbenzoate, bicarbonate, butyne-l,4 dioate, hexyne—l ate, eaproate,
ate, ehlorobenzoate, cinnamate, e, decanoate, formate, fumarate, ate, glueonate,
glucarate, glucuronate, glucosephosphate, glutamate, heptanoate, hexanoate, onate,
yrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, maleate, ymaleate,
methylmaleate, malonate, mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate, oxalate,
pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate, orthophosphate,
metaphosphate, pyrophosphate, 2—phosphoglycerate, 3—phosphoglycerate, phthalate, propionate,
phenylpropionate, propiolate, pyruvate, quinate, salicylate, 4~aminosalicylate, sebacate, stcaratc,
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subcratc, succinate, sulfate, lfate, bisulfate, sulfitc, bisulfite, sulfamate, sulfonate,
benzenesulfonate (i.e. besylate), ethanesulfonate (i.e. e), ethane-l,2—disulfonate,
2-hydroxyethanesulfonate (i.e. isethionate), methanesulfonale (i.e. mesylate), naphthalene—1—
sulfonate, naphthalene-Lsultonate (i.e. napsylate), propanesulfonate, p—toluenesulfonate (i.e.
te), xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate. These
pharmaceutically acceptable acid addition salts can be prepared using the appropriate corresponding
acid.
When acidic functional groups, such as carboxylic acid or phenol are present,
pharmaceutically able salts also include basic addition salts such as those containing
benzathine, chloroprocaine, choline, ethanolamine, diethanolamine, anolamine, t-butylamine,
dicyclohexylamine, ethylenediamine, N,N’-dibenzylethylenediamine, meglumine,
hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium, copper,
iron, lithium, magnesium, ese, ium, sodium, zinc, ammonium, and mono—, di—, or tri—
alkylamines (e.g. diethylamine), or salts derived from amino acids such as L—histidinc, L-glycine,
L—lysine, and L—arginine. For example, see Remington’s Pharmaceutical Sciences, 19th ed., Mack
Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995. These pharmaceutically acceptable base addition
salts can bc prepared using the appropriate corresponding base.
ceutically acceptable salts can be prepared by rd techniques. For example, the
free—base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous—
alcohol solution ning the appropriate acid and then isolated by evaporating the solution. In
another example, a salt can be ed by reacting the free base and acid in an c solvent. If the
particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any
suitable method, for example, treatment ofthe free acid with an appropriate inorganic or organic base.
(d) Other compoundforms
In the case of agents that are solids, it is understood by those skilled in the art that the
compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co-
crystals, or may be in an amorphous form, or may be any ation thereof (e.g. partially
crystalline, partially amorphous, or mixtures of polymorphs) all of which are intended to be within the
scope of the present invention and specified formulae, Whereas salts are formed by acidlbase
addition, he a free base or free acid of the nd of interest forms an acidease reaction with a
corresponding addition base or addition acid, respectively, resulting in an ionic charge interaction, c0—
crystals are a new al species that is formed between l compounds, resulting in the
compound and an additional lar species in the same crystal structure.
{0149} in some instances, compounds ofthe invention are xed with an acid or a base,
including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine,
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diethanolarnine, t-butylamine, piperazine, meglumine; acid addition salts, such as acetate,
aeetylsalicylate, besylate, camsylate, citrate, formate, fumarate, glutarate, hydrochlorate, maleate,
mesylate, nitrate, oxalate, phosphate, succinate, e, te, thiocyanate and tosylate; and amino
acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutaminc, glutamic acid, glycine,
histidine, isoleueine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan,
ne or valine, In combining the compound of the invention with the acid or base, an amorphous
x is preferably formed rather than a crystalline al such as a typical salt or co-crystal. In
some instances, the amorphous form of the complex is facilitated by additional processing, such as by
spray-diyin g, mechanochemical methods such as roller compaction, or microwave irradiation of the
parent compound mixed with the acid or base. Such methods may also include addition of ionic
and/or non-ionic polymer systems, ing, but not limited to, hydroxypropyl methyl cellulose
acetate ate (HPMCAS) and methacrylic acid copolymer (cg. Eudragit® LIOO—SS), that further
ize the amorphous nature of the complex. Such amorphous complexes provide several
advantages. For example, lowering ofthe melting temperature relative to the free base facilitiates
additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties
ofthe nd. Also, the amorphous complex is readily friable, which es improved
compression for loading of the solid into capsule or tablet form.
onally, the formulae are intended to cover ed or solvated as well as unhydrated
or unsolvated forms of the identified structures. For example, the indicated compounds include both
hydrated and non—hydrated forms. Other examples of solvates include the structures in combination
with a suitable solvent, such as isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate,
acetic acid, or ethanolamine.
IV. Formulations and Administration
In another aspect, the present invention provides pharmaceutical compositions
comprising/including a ceutically acceptable r or excipient and a compound of the
invention described herein or a pharmaceutically acceptable salt or solvatc thereof. in an exemplary
ment, the t invention provides a pharmaceutical formulation comprising’including a
compound as described herein. In one embodiment, the nd has any of formulas I, and la to In.
The methods and compounds will typically be used in therapy for human subjects.
However, they may also be used to treat similar or identical indications in other animal subjects.
Compounds described herein can be administered by ent , including injection (Le.
parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal,
ucosal, rectal, or inhalant. Such dosage forms should allow the compound to reach target cells.
Other factors are well known in the art, and include considerations such as toxicity and dosage forms
that retard the compound or composition from exerting its effects. Techniques and ations
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generally may be found in Remington: The e and Practice ofP/mrmacy, 21St edition,
Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference herein).
In some embodiments, itions will comprise pharmaceutically acceptable rs or
excipients, such as fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizcrs,
and tants, which may be chosen to facilitate administration of the compound by a particular
route. Examples of carriers e calcium carbonate, calcium phosphate, various sugars such as
lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, , liposomes,
nanoparticles, and the like, Carriers also include physiologically compatible liquids as solvents or for
suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution,
dextrose solution, Hank’s solution, Ringer’s solution, vegetable oils, l oils, animai oils,
polyethylene glycols, liquid n, and the like. Bxcipients may also include, for example, colloidal
silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate,
magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross-
linked sodium carboxymethylcellulosc, sodium benzoate, calcium ate, magnesium carbonate,
stearic acid, um stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl
fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceiyl
earate, glyceryl dibehenate, glyceryl palmitostearate, enated vegetable oil,
hydrogenated cotton seed oil, castor seed oil mineral oil, polyethylene glycol (e.g. PEG 4000-8000),
polyoxyethylene glycol, poloxamers, povidone, crospovidone, croscarmellose , alginic acid,
casein, methacrylic acid divinylbenzene copolymer, sodium te, cyclodextrins (e.g. 2-
hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate 80), cetrimide, TPGS (d-alpha—
eryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate,
polyethylene glycol ethers, di—fatty acid ester of polyethylene glycols, or a polyoxyalkylene sorbitan
fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween®), polyoxyethylene sorbitan fatty acid
esters, sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty acid such as oleie, stearic or
palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried,
sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium ate, calcium
sulfate, tes, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, icone,
polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methyl celluloses), HPC (hydroxypropyl
cellulose), hydroxyethyl cellulose, and the like.
Pharmaceutical formulations may be presented in unit dose forms containing a
predetermined amount of active ingredient per unit close. Such a unit may contain, for example, 0.5
mg to 1 g, preferably l mg to 700 mg, more ably 5 mg to 100 mg of a nd of the
invention (as a free-base, solvate ding e) or salt, in any form), ing on the condition
being treated, the route of administration, and the age, weight and condition of the patient. Preferred
unit dosage formulations are those containing a daily dose, weekiy dose, monthly dose, a sub-dose or
48117726.1
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an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical
formulations may be prepared by any of the methods well known in the pharmacy art.
] Pharmaceutical ations may be adapted for administration by any appropriate route, for
example by the oral (including capsules, tablets, liquid-filled capsules, disintegrating tablets,
immediate, delayed and controlled release tablets, oral , solutions, syrups, buccal and
sublingual), rectal, nasal, inhalation, topical (including transdermal), l or parenteral (including
subcutaneous, intramuscular, intravenous or intradeimal) route. Such formulations may be ed
by any method known in the art of pharmacy, for example by bringing into association the active
ingredient with the carrier(s), excipient(s) or diluent. Generally, the carrier, excipient or diluent
employed in the pharmaceutical formulation is "non-toxic," meaning that it/they is/are deemed safe
for consumption in the amount delivered in the ceutical composition, and ”inert" meaning that
y does/do not appreciably react with or result in an undesired effect on the therapeutic activity of
the active ingredient.
In some embodiments, oral administration may be used. Pharmaceutical ations for
oral use can be formulated into conventional oral dosage forms such as discret units capsules, tablets,
and liquid preparations such as syrups, elixirs, and trated drops. Compounds described herein
may be combined with solid cxcipients, optionally grinding a resulting e, and processing the
mixture of granules, after adding suitable auxiliaries, if d, to obtain, for example, tablets, coated
tablets, hard capsules, sofi capsules, ons (e.g. aqueous, alcoholic, or oily solutions) and the like.
Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose,
mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato
starch, gelatin, gum anth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose (CMC), and/or nylpyrrolidone (PVP: povidone); oily ents,
including vegetable and animal oils, such as sunflower oil, olive oil, or codliver oil. The oral dosage
formulations may also contain disintegrating agents, such as the cross-linked nylpyrrolidone,
agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium
stearate; a plasticizer, such as glycerol or sorbitol; a sweetening such as sucrose, fructose, lactose, or
aspartame; a natural or artificial flavoring agent, such as peppermint, oil of Wintergreen, or cherry
ing; or dyestuffs or pigments, which may be used for identification or characterization of
different doses or combinations, such as unit dosages. Also provided are dragee cores with suitabie
gs. For this purpose, concentrated sugar solutions may be used, which may optionally contain,
for example, gum arabic, talc, poly—vinylpyrrolidone, carbopol gel, hylene , and/or
titanium dioxide, lacquer solutions, and suitable c solvents or solvent mixtures. Oral fluids
such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity
contains a predetermined amount of the compound.
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Pharmaceutical preparations that can be used orally include push-tit capsules made of gelatin
(“geicaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or
sorbitol. The t capsules can contain the active ients in admixture with filler such as
lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally,
stabilizers. In soft capsules, the active nds may be dissolved or suspended in suitable liquids,
such as fatty oils, liquid paraffin, or liquid hylene s.
In some embodiments, injection (parenteral administration) may be used, e.g., intramuscular,
enous, intraperitoneal, and/or subcutaneous. Compounds described herein for injection may be
formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions,
such as saline solution, Hank's solution, or Ringer's solution. Dispersions may also be prepared in
non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols,
triacetin, and vegetable oils. Solutions may also contain a preservative, such as methylparaben,
propylpai‘aben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. in addition, the
compounds may be formulated in solid form, including, for example, lyophilized forms, and
redissolved or suspended prior to use. The formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be stored in a freeze—dried (lyophilized)
condition requiring only the addition of the e liquid carrier, for e water for injection,
immediately prior to use.
In some embodiments, transmucosal, topical or transdermal administration may be used. In
such formulations of compounds described herein, penetrants riate to the barrier to be
permeated are used. Such penetrants are generally known in the art, and e, for example, for
ucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be
used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays
or suppositories (rectal or l). Compositions of compounds described herein for topical
administration may be formulated as oils, creams, lotions, ointments, and the like by choice of
appropriate carriers known in the art. Suitable carriers include vegetable or mineral oils, white
petrolatum (white soft n), branched chain fats or oils, animal fats and high molecular weight
alcohol (greater than C12). In some embodiments, carriers are selected such that the active ingredient
is soluble. Emulsifiers, stabilizers, humectants and idants may also be included as well as
agents imparting color or fragrance, if d. Creams for topical ation are preferably
formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the
active ingredient, dissolved in a small amount of solvent (eg, an oil), is admixed. onally,
administration by transdcrmal means may comprise a transdcrmal patch or dressing such as a bandage
impregnated with an active ient and ally one or more carriers or diluents known in the art.
To be administered in the form of a transdermal delivery system, the dosage administration will be
continuous rather than intermittent throughout the dosage regimen.
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In some embodiments, compounds are administered as inhalants. nds described
herein may be formulated as dry powder or a suitable solution, suspension, or aerosol. Powders and
solutions may be formulated with suitable additives known in the art. For example, powders may
e a le powder base such as lactose or starch, and solutions may comprise propylene
glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts.
Such ons or suspensions may be administered by inhaling via spray, pump, er, or
nebulizer, and the like. The nds described herein may also be used in combination with other
inhaled therapies, for example corticosteroids such as fluticasone proprionate, beclomethasone
ionate, triamcinolone acetonide, budesonide, and sone furoate; beta agonists such as
albuterol, salmeterol, and formoterol; anticholinergic agents such as ipratroprium bromide or
tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNAase; therapeutic
proteins; immunoglobulin dies; an oligonucleotide, such as single or double stranded DNA or
RNA, siRNA; antibiotics such as tobramycin; inic receptor antagonists; leukotriene
antagonists; cytokine nists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium
cromoglycate.
The amounts of various compounds to be administered can be determined by rd
procedures taking into account factors such as the compound activity (in vitro, e.g. the compound ICSO
vs. target, or in viva activity in animal efficacy models), pharmacokinetic results in animal models
(e.g. biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder
associated with the subject. The importance of these and other factors are well known to those of
ordinary skill in the art. Generally, a dose will be in the range of about 0.01 to 50 mg/kg, also about
0.] to 20 mg/kg of the subject being d. Multiple doses may be used.
{0162] The compounds described herein may also be used in combination with other therapies for
treating the same disease. Such combination use includes administration of the compounds and one
or more other eutics at different times, or co—administration of the compound and one or more
other therapies. In some embodiments, dosage may be modified for one or more of the compounds
of the invention or other therapeutics used in combination, e.g., reduction in the amount dosed relative
to a compound or therapy used alone, by methods well known to those of ordinary skill in the art.
It is tood that use in combination includes use with other therapies, drugs, medical
procedures etc., where the other therapy or procedure may be administered at different times (eg.
within a short time, such as within hours (e. g. l, 2, 3, 4-24 hours), or within a longer time (eg. 1-2
days, 2-4 days, 4-7 days, 1-4 weeks)) than a compound described herein, or at the same time as a
compound described herein. Use in combination also includes use with a therapy or medical
procedure that is administered once or infrequently, such as surgery, along with a compound
described herein administered within a short time or longer time before or after the other therapy or
procedure. in some embodiments, the t invention provides for delivery of a compound
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described herein and one or more other drug therapeutics delivered by a different route of
administration or by the same route of stration. The use in combination for any route of
administration includes delivery of a nd described herein and one or more other drug
therapeutics delivered by the same route of administration together in any formulation, including
formulations where the two compounds are chemically linked in such a way that they maintain their
therapeutic activity when administered. In one aspect, the other drug therapy may be inistered
with a compound described . Use in combination by co-administration includes administration
of co—formulations or formulations of chemically joined compounds, or administration of two or more
compounds in te formulations within a short time of each other (cg. within an hour, 2 hours, 3
hours, up to 24 hours), administered by the same or ent routes. Co-administration of separate
formulations includes co-administration by delivery via one device, for example the same inhalant
device, the same syringe, etc., or administration from separate s within a short time of each
other. Co-formulations of a compound described herein and one or more additional drug therapies
delivered by the same route includes preparation of the materials together such that they can be
administered by one device, including the separate compounds ed in one formulation, or
nds that are d such that they are chemicallyjoined, yet still maintain their biological
activity Such chemically joined compounds may have a linkage that is substantially maintained in
vivo, or the linkage may break down in viva, separating the two active components.
V. Kinase s and indications of the invention
Protein kinases play key roles in propagating biochemical signals in diverse biological
pathways. More than 500 kinases have been described, and specific kinases have been implicated in a
wide range of es or conditions (i.e., indications), including for example t limitation,
cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases. As
such, kinases represent ant control points for small molecule therapeutic intervention. Specific
target protein kinases contemplated by the present ion are described in the art, including,
without limitation, protein kinases as described in US Patent Application Serial number l “473,347
(see also, PC'l‘ publication W02007002433), the disclosure of which is hereby incorporated by
reference as it relates to such kinase targets, as well as the following:
mg Target kinase A—Raf(i.e., v-rafmurine sarcoma 361 l viral oncogene homoiog l) is
a 67,6 kDa serine/threoninc kinase encoded by chromosome Xpl l.4-pl 1.2 (symbol: ARAF). The
mature protein comprises RBD (i.e., Ras binding ) and l-esterADAG-type zinc finger
domain and is involved in the transduction ofmitogenic signals from the cell membrane to the
nucleus. A—Raf inhibitors may be useful in treating neurologic diseases such as multi-infarct
dementia, head injury, spinal cord injury, mer's disease (AD), Parkinson’s disease; stic
diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (cg. colorectal, lunU,
breast, pancreatic, thyroid, renal, ovarian), lymphoma (cg. histiocytic ma), neurofibromatosis,
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myclodysplastic syndrome, leukemia, tumor angiogenesis; pain of neuropathic or atory
origin, including acute pain, c pain, canceprelated pain and migraine; and diseases associated
with muscle regeneration or degeneration, including, but not d to, vascular restenosis,
sarcopenia, muscular dystrophies (including, but not limited to, Duehennc. Becker, Emery-Dreifuss,
Limb—Girdle, Facioscapulohumeral, ic, Oculopharyngeal, Distal and Congenital Muscular
Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis,
infantile progressive spinal ar atrophy, ediate spinal muscular atrophy, juvenile spinal
muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory
myopathies (including, but not limited to, omyosilis, polymyositis, and inclusion body
myositis), diseases ofthe neuromuscularjunction (including, but not limited to, myasthenia ,
Lambert-Eaton syndrome, and congenital enic syndrome), myopathies due to endocrine
alities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy)
diseases of peripheral nerve (including, but not limited to, Chareot-Marie-Tooth disease, Dejerine-
Sottas disease, and Friedreich’s ataxia), other myopathies (including, but not limited to, myotonia
congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular hy,
and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase
deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency,
phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase
deficiency, and myoadenylate deaminase ncy).
B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogene homolog B1) is a
84.4 kDa serine/threonine kinase encoded by chromosome 7q34 (symbol: BRAF). The mature
protein comprises RBD (i.e., Ras binding domain), Cl (i.e., protein kinase C conserved region I) and
STK (i.e., serine/threonine ) domains.
{0167] Target kinase B—Raf is involved in the uction of mitogenic signals from the cell
membrane to the nucleus and may play a role in the postsynaptic responses of hippocampal neurons.
As such, genes of the RAF family encode s that are regulated by Ras and mediate cellular
responses to growth signals, Indeed, B-Raf kinase is a key component of the af->
MEK->F;RK/NlAP kinase signaling pathway, which plays a fundamental role in the regulation of cell
growth, division and proliferation, and, when constitutively activated, causes tumorigenesis. Among
several isoforms of Raf kinase, the B-type, or B-Raf, is the strongest activator of the downstream
MAP kinase signaling.
The BRA}: gene is frequently mutated in a variety of human tumors, especially in malignant
melanoma and colon carcinoma. The most common reported mutation was a missense e (T) to
e (A) transversion at nucleotide l796 (Tl796A; amino acid change in the RRafprotein is
Vai<600> to 0>) observed in 80% of malignant ma tumors. Funetionai analysis
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reveals that this ersion is the only detected mutation that causes constitutive activation of B—Raf
kinase activity, independent of RAS activation, by converting B—Raf into a dominant transforming
protein. Based on ents, human tumors develop resistance to kinase inhibitors by mutating a
specific amino acid in the catalytic domain as the “gatekeeper”. (Balak, et. al., Clin Cancer Res. 2006,
4-501). Mutation of Thr-529 in BRAF to Ile is thus anticipated as a mechanism of resistance
to BRAF inhibitors, and this can be oned as a transition in codon 529 from ACC to ATC.
Niihori et al., report that in 43 individuals with cardio-facio—cutaneous (CFC) syndrome, they
identified two heterozygous KRAS ons in three individuals and eight BRAF mutations in 16
individuals, suggesting that dysregulation of the RAS-RAF—ERK pathway is a common molecular
basis for the three related ers (Niihori ct al., Nat Gcnct. 2006, 38(3):294-6).
Many cancers associated with dysregulation of the RAS—RAF-ERK pathway, such as s
having B-Raf V600, such as V600E mutations or NRAS mutations, may be treated with Rafkiiiase
inhibitors, such as the Pan Raf kinasc inhibitors as described herein. The ability of these compounds
to inhibit multiple Raf kinase targets, including c—Raf-l, B‘Raf, and B-Raf V600, such as V600E,
provides additional benefits for inhibiting activating mutations in this pathway, with such cancers less
likely to develop resistance to such inhibitors as they are targeting several points in the pathway. Pan
Raf kinase inhibitors as described herein may be useful in treating a variety of cancers, including, but
not limited to, melanoma, glioma, glioblastoma mulitforme, pilocytic astrocytoma, oma (e. g.
gastrointestinal, liver, biliary tract, bile duct (cholangiocarcinoma), colorectal, lung, brain, bladder,
gallbladder, breast, pancreatic, thyroid, kidney, ovarian, adrenocortical, prostate), gastrointestinal
stromal , medullary thyroid cancer, tumor angiogenesis, acute myeloid leukemia, c
myelomonocytic leukemia, childhood acute lymphoblastic leukemia, plasma cell leukemia, and
multiple myeloma. See Mchrmott et al., PNAS, 2007, l04(50): 19936—19941; and Jaiswal et al.,
PLoS One, 2009, 4(5):e5717.
{0171] c-Raf—l: Target kinase c—Raf—l (Le, v-raf murine sarcoma viral oncogene g l) is a
73.0 kDa STK encoded by chromosome 3p25 l: RAFl). c-Raf—l can be targeted to the
mitochondria by BCL2 (i.e., oncogene B—cell leukemia 2) which is a tor of apoptotic cell death.
Active c—Raf—l improves BCLZ-mediated resistance to apoptosis, and c-Raf-I phosphorylates BAD
(i.e., BCl..2-binding protein). c~Raf-l is implicated in carcinomas, including ctal, ovarian, lung
and renal cell carcinoma. c~Rafw1 is also implicated as an ant mediator of tumor angiogenesis
(Hood, 1.13. et al., 2002, Science 296, 2404). c~Raf-l inhibitors may also be useful for the treatment
of acute myeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002,
8(25):2243—8). c—Raf—l activators may be useful as ent for neuroendocrine , such as
medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunnimalaiyaan
et al., ncer Drugs 2006, l7(2):l39«42).
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[01721 Raf inhibitors (A»Raf and/or B-Raf and/or c—Raf—l) may be useful in treating A—Raf~
mediated, B—Raf—mediated or c~Raf— 1 —mcdiatccl diseases or conditions selected from the group
consisting of neurologic es, including, but not limited to, multi—infarct dementia, head injury,
Spinal cord injury, Alzheimer's disease (AD), Parkinson’s disease, seizures and epilepsy; neoplastic
diseases including, but not limited to, melanoma, glioma, glioblastoma multiforme, pilocytie
astrocytoma, sarcoma, carcinoma (cg. gastrointestinal, liver, biliary tract, bile duct
(cholangioearcinoma), colorectal, lung, brain, bladder, gallbladder, breast, pancreatic, thyroid, renal,
ovarian, adrenocortical, prostate), lymphoma (cg. histiocytic lymphoma) neurofibromatosis, acute
mycloid leukemia, myelodysplastic syndrome, ia, chronic myelomonocytic leukemia,
childhood, acute lymphoblastic leukemia, plasma cell leukemia, multiple myeloma, tumor
angiogenesis, gastrointestinal stromal tumors, neuroendocrine tumors such as medullary thyroid
cancer, oid, small cell lung , Kaposi’s a, and pheochromocytoma; pain of
neuropathic or atory origin, including, but not limited to, acute pain, chronic pain, cancer—
related pain, and migraine; cardiovascular diseases ing, but not d to, heart e,
ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes),
atherosclerosis, and reperfusion injury; inflammation and/or proliferation including, but not limited to,
psoriasis, eczema, arthritis and autoimmune diseases and ions, osteoarthritis, endometriosis,
scarring, vascular rcstenosis, fibrotic disorders, rheumatoid tis, inflammatory bowel disease
(IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft
versus host disease, and Kaposi’s a associated with HIV; renal, , or prostatic diseases,
including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclcrosis,
glomerulonephritis, te hyperplasia, polycystic liver disease, tuberous sclerosis, Von Hippel
Lindau disease, ary cystic kidney e, nephronophthisis, and cystic fibrosis; metabolic
disorders, including, but not limited to, obesity; infection, including, but not limited to Helicobacter
pylori, Hepatitis and Influenza viruses, fever, HIV, and sepsis; pulmonary diseases including, but not
d to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome
(ARDS); genetic developmental diseases, including, but not limited to, Noonan’s syndrome, Costello
syndrome, cutaneoskelctal syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome
(CFC), and neural crest syndrome abnormalities causing vascular, al, intestinal, skin, hair
and endocrine diseases; and diseases associated with muscle regeneration or degeneration, including,
but not limited to, enia, muscular phics (including, but not limited to, Duchennc, Becker,
Emery—Dreifuss, Limb—Girdle, Faeioscapulohumeral, Myotonic, Oculopharyngeal, Distal and
Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophie
lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular y,
juvenile spinal muscular atrophy, spinal bulbar ar atrophy, and adult spinal muscular atrophy),
inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion
body rriyositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia
gravis, t-Eaton me, and congenital myasthenic syndrome), myopathies due to endocrine
4811-7918~7726.1
039363-7211
abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy)
es of peripheral nerve (including, but not limited to, Charcot-Marie—Tooth disease, Dejerine‘
Sottas disease, and eich’s ataxia), other myopathies (including, but not limited to, myotonia
ita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy,
and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase
deficiency, acid maltase deficiency, phosphofructokinase deficiency, cher enzyme deficiency,
mitochondrial myopathy, ine deficiency, carnitine pal matyl transferase deficiency,
oglycerate kinasc deficiency, phosphoglycerate mutasc deficiency, lactate dehydrogenasc
deficiency, and myoadenylate ase deficiency).
m Target kinase Erk2 (i.e., extracellular -regulated kinase 2) is a 41.4 kDa dual
function serine/threonine-tyrosine kinase encoded by chromosome 22q1 1.2 (symbol: MAPKl). Erk2
is a member of the n-activated protein (MAP) kinase family and is alternatively known as
mitogen-activated protein kinase 1 (i.e., MAPKl). MAP kinases act as an integration point for
multiple mical signals, and are involved in a wide variety ofcellular processes such as
proliferation, differentiation, transcription regulation and development.
The activation of Erk2 es phosphorylalion by upstream kinases. Upon activation, Erk2
translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets, in addition
to other targets including microtubule associated protein 2, myelin basic protein and ELKl.
MacKenzie et al. state that the CAMP-specific odiesterase family 4, subfamily D, isoform 3
(i.e., PDE4D3) is shown to have FQF (i.e., Phe-Gln-Phe) and KIM (i.e., Kinase Interaction Motif)
docking sites for Erk2. These sites straddle the Ser(579) target residue for Erk2 phosphorylation of
PDE4D3. Mutation of either or both ofthese docking sites prevent Erk2 from being co-
immunoprecipitated with PDE4D3, ablate the ability of epidermal growth factor (EGF) to inhibit
PDE4D3 through Erk2 action in transfected COS cells, and attenuate the ability of Erk2 to
phosphorylate PDE4D3 in vitro. The two ved NH(2)-terminal blocks of ce, called
upstream conserved s 1 and 2 (i.e., UCRl and UCR2), that characterize PDE4 long ms,
are proposed to amplify the small, inherent inhibitory eitect that Erk2 phosphorylation exerts on the
PDE4D catalytic unit. In contrast to this, the lone intact UCR2 region found in PDE4D1 directs
COOH-terminal Erk2 phosphorylation to cause the activation of this short isoform. From the analysis
of PDE4D3 truncates, it is suggested that UCRl and UCR2 e a regulatory signal integration
module that serves to orchestrate the functional consequences of Erk2 phosphorylation. The PDE4D
gene thus encodes a series of ymes that are either inhibited or activated by Erk2
phosphorylation and thereby offers the potential for ERKZ activation either to increase or decrease
CAMP levels in cellular compartments (MacKenzie et al., J Biol Chem 2000, ): 16609— i 7).
According to OMIM, Pleschka et al. (Nature Cell Biol., 2001, 3: 30l—305) proposed that
Erk2 regulates a cellular factor involved in the viral nuclear export protein function, They suggested
48117726.1
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that local application of MEK inhibitors may have only minor toxic effects on the host while
inhibiting viral replication without giving rise to drug-resistant virus variants (OMIM MIM Number:
176948: 10/27/2005). Erk2 is involved in cytokine signaling and is a target for treating inflammation.
Ramesh and Philipp state that lipoproteins are the key inflammatory molecule type of Borrelia
burgdorferi, the spirochete that causes Lyme disease. They investigated whether specific inhibition of
p38 and Erklz’Z MAPK would inhibit TNF-alpha and IL—6 production and thus astrocyte sis,
and proliferation, respectively, Lipoprotein—stimulated lL—6 production was unaffected by the MAPK
tors. In contrast, tion of both p38 and Erkl/Z cantly diminished TNF—alpha
production, and totally abrogated production of this cytokine when both MAPK pathways were
inhibited simultaneously. MAPK inhibition thus may be considered as a strategy to control
inflammation and apoptosis in Lyme neuroborreliosis h and p, Neurosci Lett 2005,
384(1-2):l 12—6). The role of Erk2 in signaling of cell differentiation, proliferation and survival
suggests that inhibition of Erk2 may be eutic for several types of cancer. Husain et a]. studied
the effect of NSAIDS on MAPK activity and phosphorylation in gastric cancer. They de that
NS-398 (a selective COX-2 inhibitor) and indomethacin (a non-selective NSAID) significantly inhibit
proliferation and growth of human gastric cancer cell line MKN28. This effect is mediated by
NSAID-induced inhibition of MAPK (ERKZ) kinase signaling pathway, essential for cell proliferation
(liusain et al., Life Sci 200], 69(25-6):3045—54). Erk2 inhibitors may be useful in treating cancer,
including gastric cancer, and in treating inflammation, including control of inflammation and
apoptosis in Lyme neuroborreliosis.
Kinase Activity Assays
A number of different assays for kinase activity can be utilized for assaying for active
modulators and/or determining specificity ofa modulator for a ular kinase or group or s.
In addition to the assay mentioned in the Examples below, one of ry skill in the art will know of
other assays that can be utilized and can modify an assay for a particular application. For example,
numerous papers concerning kinases describe assays that can be used.
in certain embodiments, compounds as disclosed herein are active in an assay measuring B—
Raf protein kinase ty. In some embodiments, a nd as described herein has an IC50 ofless
than 1,000 nM, less than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10
nM, less than 5 nM, or less than i nM as determined in a generally accepted B-Raf kinase activity
assay. In some embodiments, a nd as described herein has an 1ng of less than 1.000 th less
than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or
less than 1 nM as determined in a generally accepted mutant B-Raf kinase (such as VGOOAE V600M,
V600R. V6OOE, V600K or V6006) activity assay. in some embodiments the assay for measuring 8—
Raf kinase activity and/or mutant B-Raf kinase (such as V600A, V600M, V600R. V600E, V600K or
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VGOOG) activity includes an assay (e.g., biochemical or cell-bases assays) such as described in
Example 9 or an assay well known in the art similar to those described in Example 9.
[0178} In some embodiments, compounds as described herein have little or no activity in an assay
measuring activation of the ERK pathway (i.e., in stimulating the phosphorylation ot‘ERK 1/2). In
some embodiments, compounds as described herein have an EC50 in an ERK activation assay that is
greater than 1 nM; or greater than 2 nM; or greater than 3 nM; or greater than 4 nM; or greater than 5
nM; or greater than 8 nM; or greater than 10 uM. In certain embodiments, the assay for measuring
activation of the ERK pathway includes an assay (e.g., biochemical or cell~bases assays) such as
described in Example 9 or one or more assays well known in the art for ing ERK activity
similar to that bed in Example 9.
In some embodiments, compounds as bed herein are active in an assay measuring BRaf
protein kinase activity and/or an assay for measuring mutant B-Raf (such as V600A, V600M,
V600R, V600E, V600K or V6OOG) protein kinase activity, and have little or no ty in an assay
measuring activation ofthe ERK pathway. in some embodiments a nd as described herein
has an IC50 of less than 1,000 nM, less than 500 nM, less than 100 nM, less than 50 nM, less than 20
nM, less than 10 nM, less than 5 nM, or less than 1 nM as determined in a generally ed B-Raf
kinase activity assay ding a mutant B-Raf kinase activity assay) and an EC50 in an ERK
activation assay that is greater than 1 nM; or greater than 2 uM; or greater than 3 nM; or greater than
4 uM; or greater than 5 nM; or greater than 8 nM; or greater than 10 uM. In some embodiments, a
compound as described herein has an IC50 of less than 100 nM in a V600A, V600M, V600R, V600E,
V600K or V600G mutant B—Raf activity assay and an ECso of greater than 10 in an ERK activation
assay.
VI. Methods for Treating Conditions Mediated by Kinases
In another aspect, the present invention provides a method for treating a subject suffering
from or at risk of a protein kinase mediated diseases or conditions. The method includes
administering to the t an effective amount of a compound of any of formulas I and la to In, or a
compound as described herein, or a composition comprising any of as I and la to In and any of
the nds described herein or a pharmaceutically acceptable salt or a solvate or hydrate thereof.
In certain embodiments, the method involves administering to the subject an effective amount of any
one or more compound(s) as described herein in combination with one or more other ies for the
disease or condition.
In some embodiments, the diseases or conditions treatable with the compounds of the present
invention include, but are not limited to, infarct dementia, head injury, spinal cord injury,
Aizheimer’s disease (AD)2 son’s e, seizures and epilepsy; stic diseases including,
but not limited to, melanoma, glioma, glioblastoma Itiilltiforirie, tic astrocytoma, sarcoma,
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carcinoma (cg. gastrointestinal, liver, biliary tract, bile duct (cholangiocarcinoma), colorectal, lung,
gallbladder, , pancreatic, thyroid, renal, ovarian, adrenocortical, prostate), lymphoma (cg.
histiocytic lymphoma) neurofibromatosis, gastrointestinal stromal tumors, acute myeloid leukemia,
myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as ary
thyroid cancer, carcinoid, small cell lung cancer, Kaposi’s sarcoma, and pheochromocytoma; pain of
neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-
related pain, and migraine; cardiovascular es including, but not limited to, heart e,
ischcmic , cardiac hypertrophy, thrombosis (cg. thrombotic microangiopathy syndromes),
atherosclerosis, and reperfusion injury; inflammation and/or proliferation including, but not limited to,
psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis,
scarring, vascular restenosis, tibrotic- disorders, rheumatoid arthritis, inflammatory bowel disease
(IBD); immunodeficiency diseases, including, but not d to, organ transplant rejection, graft
versus host disease, and Kaposi’s sarcoma associated with HIV; renal, cystic, or prostatic diseases,
including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis,
ulonephritis, prostate lasia, polycystic liver disease, tuberous sclerosis, Von Hippel
Lindau disease, medullary cystic kidney disease, nephronophthisis, and cystic fibrosis; metabolic
disorders, including, but not limited to, obesity; infection, including, but not limited to Helicobacter
pylori, Hepatitis and za Viruses, fever, HIV, and sepsis; pulmonary diseases including, but not
limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome
; genetic developmental diseases, including, but not limited to, Noonan’s syndrome, Costello
syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneous me
(CFC), and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair
and endocrine diseases; and diseases associated with muscle regeneration or degeneration, ing,
but not limited to, enia, muscular dystrophies (including. but not limited to, Duchcnne, Becker,
Emery—Dreifuss, irdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and
Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic
l sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular y,
juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy),
inflammatory myopathies (including, but not limited to, omyositis, polymyositis, and inclusion
body myositis), es ofthe neuromuscular junction (including, but not limited to, myasthenia
, Lambert—Eaton syndrome, and ital myasthenic syndrome), myopathies due to endocrine
abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy)
diseases of eral nerve (including, but not limited to, Chai‘cot~Marie-Tooth disease, Dejerine~
Sottas disease, and Fricdreich’s ataxia), other myopathies (including, but not d to, myotonia
congenita, paramyotonia congenita, central core e, nemaline myopathy, myotubular myopathy,
and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, orylase
deficiency, acid maltase deficiency, phosphofructokinase deficiency, dcbrancher enzyme deficiency,
mitochondrial myopathy, carnitine deficiency, ine palmatyl transferase deficiency,
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phosphoglyceratc kinasc deficiency, phosphoglycerate mutase ncy, lactate dehydrogenase
deficiency, and nylate deaminase deficiency). In one embodiment, the disease or condition is
selected from the group consisting of melanoma, glioma, glioblastoma orme, piiocytic
astrocytoma, sarcoma, liver cancer, biliary tract cancer, cholangiocarcinoma, colorectal , lung
. gallbladder cancer, breast cancer, pancreatic , thyroid cancer, renal cancer, ovarian
cancer, cortical cancer, prostate cancer, cytic lymphoma, neurofibromatosis,
gastrointestinal stromal tumors, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor
angiogcnesis, medullary thyroid cancer, carcinoid, small cell lung cancer, Kaposi’s a,
pheochromocytoma, acute pain, chronic pain, and stic kidney disease. in a red
embodiment, the disease or condition is selected from the group ting of melanoma, glioma,
glioblastoma multiforme, tic astrocytoma, colorectal cancer, thyroid cancer, lung cancer,
ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, intestinal l tumors,
biliary tract , cholangiocarcinoma, acute pain, chronic pain, and polycystic kidney disease.
In other embodiments, the diseases or condictions treatable with the compounds of the
present invention include, but are not limited to, ischemic stroke, cerebrovascular ischemia, multi-
infarct dementia, head , spinal cord injury, Alzheimer's diseasc, Parkinson’s disease,
amyotrophic lateral sclerosis, dementia, senile , Huntington’s disease, neoplastic disease,
complications with neoplastic disease, chemotherapy-induced hypoxia, gastrointestinal stromal
tumors, prostate tumors, mast cell tumors, canine mast cell tumors, acute mycloid leukemia, acute
lymphocytic leukemia, chronic myeloid leukemia, c lymphocytic leukemia, multiple myeloma,
melanoma, mastocytosis, glioma, glioblastoma, astrocytoma, neuroblastoma, sarcomas, sarcomas of
neuroectodermal origin, leiomyosarcoma, lung carcinoma, breast carcinoma, atic carcinoma,
colon carcinoma, hepatocellular carcinoma, renal carcinoma, carcinoma of the female genital tract,
squamous cell oma, carcinoma in situ, lymphoma, histiocytic lymphoma, non-Hodgkin’s
lymphoma, MEN2 syndromes, neurofibromatosis, Schwann cell neoplasia, myelodysplastic
syndrome, leukemia, tumor angiogenesis, thyroid cancer, liver cancer, bone cancer, skin cancer, brain
small cell lung cancer,
cancer, cancer of the central nervous system, atic cancer, lung cancer,
non small cell lung cancer, breast cancer, colon cancer, bladder cancer, prostate cancer,
gastrointestinal tract cancer, cancer of the endometrium, fallopian tubccanccr, testicular cancer,
ovarian cancer, pain of neuropathic , pain of inflammatory origin, acute pain, chronic pain,
migraine, cardiovascular disease, heart failure, cardiac hypertrophy, thrombosis, thrombotic
microangiopathy syndromes, atherosclerosis, reperfusion injury, ischemia, cerebrovascular ischemia,
liver ischemia, inflammation, polycystic kidney disease, age~related macular ration,
rheumatoid tis, ic is, inflammatory bowel disease, ulcerative colitis, Crohn’s disease,
systemic lupus erythematosis, Sjogren’s Syndrome, Wegener’s granulomatosis, psoriasis,
scleroderma, chronic thyroiditis, Grave’s disease, myasthenia gravis, multiple sclerosis, osteoarthritis,
endomctriesis, dermal scarring, tissue scarring, vascular restencsis, fibrotic disorders,
4811-7918~7726.1
-7211
hypereosinophilia, CNS inflammation, pancreatitis, tis, atopic dermatitis, hepatitis,
immunodeficiency diseases, severe combined immunodeficiency, organ transplant rejection, graft
versus host disease, renal disease, prostatic disease, diabetic nephropathy, nephrosclerosis,
glomerulonephritis, interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronic renal failure,
tubular necrosis, diabetes—associated renal complication, associated renal hypertrophy, type 1
diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic sis, insulin resistance,
hyperglycemia, lipolysis obesity, infection, Helicobacter pylori infection, Influenza virus infection,
fever, , pulmonary diseases, chronic obstructive pulmonary disease, acute respiratory distress
syndrome, , allergy, bronchitis, emphysema, pulmonary fibrosis, genetic developmental
diseases, Noonan’s syndrome, Crouzon syndrome, acrocephalo-syndactyly type I, Pfeiffer’s
syndrome, Jackson-Weiss syndrome, Costello syndrome, utaneoskeletal syndrome, leopard
syndrome, -faciocutaneous syndrome, neural crest syndrome abnormalities causing
cardiovascular, skeletal, intestinal, skin, hair or endocrine es, disorders of bone structure or
mineralization, osteoporosis, increased risk of fracture, hypercalcemia, bone metastases, Grave’s
disease, sprung’s disease, lymphoedema, selective T-cell defect, ed
agammaglobulinemia, diabetic retinopathy, alopecia, erectile ction, and tuberous sclerosis
In some embodiments, the disease is a cancer selected from the group ting of
melanoma, glioma, glioblastoma, pilocydic astrocytoma, liver , biliary tract cancer,
cholangiocarcinoma, ctal cancer, lung cancer, bladder cancer, gallbladder , breast cancer,
pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical cancer, prostate
cancer, gastrointestinal stromal tumors, medullary thyroid cancer, tumor angiogenesis, acute myeloid
leukemia, chronic myelomonocytic leukemia, childhood acute lymphoblastic leukemia, plasma cell
leukemia, and multiple a. In certain instances, the disease is a B—Raf V600, such as V600A,
V600E, V6006, V600K V600M or V600R mutant-mediated disease. In one embodiment, the
disease is a V600E mutant mediated disease. In one embodiment, the disease is a cancer, preferably
selected from the group consisting of melanoma, glioma, glioblastoma inultifomie, pilocytic
astrocytoma, colorectal , thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver
cancer, gallbladder cancer, gastrointestinal stromal , biliary tract cancer, and
choiangiocarcinoma. In one embodiment, the cancer is melanoma, colorectal cancer, thyroid cancer
or lung cancer.
In some embodiments, the invention provides methods for treating any B-Raf protein kinase
mediated disease or condition, including any B»Raf mutant kinase mediated e or condition in an
animal t in need f, wherein the method involves stering to the subject an effective
amount of any one or more compound(s) as described herein. In certain embodiments, the method
involves stering to the subject an ive amount of any one or more compoundts) as
described herein in combination with one or more other therapies for the disease or condition,
48117726.1
039363—721 1
In some embodiments, the invention provides s for ng any B-Raf V600 mutant
protein kinase, such as V600A, V6008, V600G, V600K V600M or V600R mutant protein kinase
mediated disease or condition in an animal subject in need f, wherein the method es
administering to the subject an effective amount of any one or more nd(s) as described herein.
In certain embodiments, the method involves administering to the subject an effective amount of any
one or more compound(s) as described herein in combination with one or more other therapies for the
disease or condition.
In some embodiments, a nd as described herein is a Raf kinase inhibitor and has an
ICSO of less than 500 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less
than 5 nM, or less than 1 nM as determined in a generally ed Raf kinasc activity assay. In some
embodiments, a compound as described herein will have an IC5o of less than 500 nM, less than 100
nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than I nM with respect
to B—Raf, c—Raf—l, or B—RafV600E mutant. In some embodiments, a compound as described herein
will selectively inhibit one or more Raf kinases relative to one or more other Raf kinases.
In some embodiments, the invention provides a method for inhibiting a B-Raf V600 mutant
protein kinase, such as V600A, V600E, V6000, V600K , V600M or V600R mutant protein kinase.
The method includes contacting a compound of any of formulas I and Ia to In, or a compound as
described herein, or a composition comprising any of formulas I and la to In and any of the
compounds bed herein or a pharmaceutically acceptable salt or a solvate thereof with a cell or a
B—Raf V600 mutant protein kinase either in vitro or in vivo.
In certain embodiments, the invention provides use of a compound of any of formulas l and
Ia to In, or a compound as described herein, or a ition comprising any of formulas I and la to
In and any of the compounds bed herein or a pharmaceutically acceptable salt or a solvate
thereof in the manufacture of a medicament for the treatment of a disease or condition as described
herein. In other embodiments, the invention provides a compound of any of formulas I and la to In, or
a nd as bed herein, or a composition comprising any of formulas I and la to In and any
of the compounds described herein or a pharmaceutically acceptable salt or a solvate thereof for use in
treating a disease or condition as described herein.
[0189} In some embodiments, the invention provides a method for suppressing UV induced cell
sis. The method includes contacting a cell with a compound of any of formulas I and la to In,
or a compound as described herein, or a composition comprising any of formulas I and la to In and
any of the compounds described herein or a pharmaceutically acceptable salt or a solvate thereof prior
to subject the cell to UV re or radiation.
Combination Theragy
4811791837261
039363—7211
Protein kinase modulators may be ly ed with another pharmacologically active
compound, or with two or more other pharmacologically active compounds, particularly in the
treatment of cancer. In one embodiment, the composition es any one or more compound(s) as
described herein along with one or more compounds that are therapeutically effective for the same
e indication, wherein the compounds have a synergistic effect on the disease indication. In one
embodiment, the composition includes any one or more compound(s) as described herein effective in
treating a cancer and one or more other compounds that are effective in treating the same cancer.
further wherein the compounds are istically effective in treating the cancer.
In some embodiments, the invention provides a composition comprising a compound of any
of formula (I) and formula [a to formula In, or a compound described herein, or a pharmaceutically
acceptable salt or solvate thereof, and one or more . In some embodiments, the one or more
agents are selected from an alkylating agent, including, but not limited to, adozelesin, altretamine,
bendamustine, bizelesin, busulfan, carboplatin, carboquone, carmofur, carmustine, chlorambucil,
tin, hosphamide, dacarbazine, ustine, etoglucid, fotemustine, hepsulfam,
ifosfamide, improsulfan, irofulven, lomustine, mannosulfan, rethamine, melphalan,
mitobronitol, atin, nimustine, oxaliplatin, piposulfan, prednimus’tine, procarbazinc, ranimustinc,
satraplatin, semustine, streptozocin, temozolomide, thiotepa, treosulfan, triaziquone,
triethylenemelamine, triplatin tetranitrate, trofosphamide, and uramustine; an antibiotic, including, but
not limited to, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin,
elsamitrucin, epirubicin, idarubicin, ril, mitomycin, neocarzinostatin, pentostatin, pirarubicin,
plicamycin, valrubicin, and zorubicin; an antimetabolite, including, but not limited to, terin,
azacitidine, azathioprine, capecitabine, cladribine, clofarabine, bine, decitabine, floxuridinc,
fludarabinc, 5—fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, bine,
pemetrexed, azathioprine, rexed, r—uracil, thioguanine, trimethoprim, rexate, and
vidarabine; an immunotherapy, including, but not limited to, alemtuzumab, bevacizumab, cetuximab,
galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, 90 Y
ibritumomab an, ipilimumab, and tremelimumab; a e or hormone antagonist, including,
but not limited to, anastrozole, androgens, buserelin, diethylstilbestro., exemestane, flutamide,
fulvestrant, goserelin, idoxifene, letrozole, leuprolide, rol, raloxifenc, fen, and
toremifene; a taxane, including, but not limited to, DJ-927, docetaxel, TPI 287, xel, ortataxei,
paciitaxel, DHA-paciitaxel, and tesetaxel; a retinoid, including, but not limited to, alitretinoin,
bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid, including, but not limited to,
dcmccolcine, rringtonine, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; an
antiangiogenic agent, including, but not limited to, AE-94l (GW786034, Neovastat), ABT-SIO, 2—
methoxyestradiol, lenalidomide, and thalidomide; a topoisomerase inhibitor, including, but not limited
to, amsacrine, bclotccan, edotecarin, etoposide, etoposide phosphate~ exatecan, irinotecan (also active
metabolite SN-38 (7«ethyl~i 0»hydroxy~camptotheci8)}, lucanthone, mitoxantrone, pixantrene,
48117726.1
039363-721 l
rubitecan, teniposide, topotecan, and 9~aminocamptothecing a kinase inhibitor, including, but not
limited to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinib
mesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafcnib,
sunitinib malate, ABE-788, EMS—599626, UCN—Ol (7—hydroxystaurosporine), and vatalanib; a
targeted signal transduction inhibitor ing, but not limited to bortezomib, geldanamycin, and
rapamycin; a biological response modifier, including, but not limited to, imiquimod, interferon-0t, and
interleukin-2; and other chemotherapeutics, including, but not limited to 3—AP no—2-
carboxyaldehyde thiosemicarbazone), altrasentan, lutethimide, anagrelide, ginase,
bryostatin-l, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, Ionidamine, masoprocol,
mitoguanazone, oblimersen, sulindac, testolactonc, tiazofurin, mTOR tors (eg. temsirolimus,
everolimus, deforolimus), PI3K inhibitors (e.g. BEZ235, GDC-O94], XL147, XL765), Cdk4
inhibitors (e.g. PD-33 2991), Akt tors, I-Isp90 inhibitors (eg. tanespimycin) and
farnesyltransferase inhibitors (e.g. tipifarnib); MEK inhibitors (e.g., AS703026, 4
etinib), AZD8330, BIX02188, CI1040 352), D-87503, GSK] 120212 (HP-74057),
PD03259OI, PD318088, PD98059, PDEAI l9 (BAY 869766), TAK-733). Preferably, the method of
treating a cancer involves administering to the subject an effective amount of a composition including
in combination with a chemotherapeutic agent
any one or more compoundts) as described herein
ed from capecitabine, S-fluorouracil, carboplatin, azine, gefitinib, oxaliplatin, paclitaxel,
SN-3 8, temozolomide, vinblastine, bevacizumab, cetuximab, interferon-0t, interleukin—2, or erlotinib.
In some embodiments, a protein kinase modulator, particularly a nd of any of formula (I) to
formula In, or a compound described herein, or a pharmaceutically acceptable salt or solvate thereof,
as defined above, may be administered simultaneously, sequentially or separately in combination with
one or more agents as described above.
In one embodiment, the invention provides methods for treating a disease or condition
mediated by B-Raf kinase, including mutations thereof, by administering to the subject an effective
amount of a composition including any one or more compound(s) as described herein in combination
with one or more other suitable therapies for treating the disease.
In one embodiment, the invention provides methods for ng a disease or condition
mediated by B~Raf V600 mutant kinases, such as V600A, V600E, V6006, VGOOK V600M or
V600R mutant kinase, by administering to the subject an effective amount of a composition including
with one or more other suitable
any one or more compound(s) as bed herein in combination
therapies for treating the e. In one embodiment, the invention provides methods for treating a
cancer ed by B-Raf mutant s, such as V600A, V600E, V600G, VGOOM or V600R mutant
by administering to the subject an ive amount of a composition including any one or more
compound(s) as described herein. In one embodiment, the invention provides methods for treating a
cancer ed by BtRaf mutant kinases, such as V600A, V60013, V6006, V600K , V600M or
V600R mutant by administering to the t an effective amount of a composition including any
481177261
039363—7211
one or more compound(s) as described herein in combination with one or more suitable anticancer
therapies, such as one or more chemotherapeutic drugs. In one instance, the B-Raf mutant kinase is
VGOOA. In another instance, the B-Rafmutant kinase is V600E. In yet r instance, the B—Raf
mutant kinase is V6006. In another instance, the B—Raf mutant kinase is V600K. In another instance,
the B—Raf mutant kinase is V600M. In another instance, the B—Raf mutant kinase is V600R.
In one embodiment, the invention provides a method of treating a cancer in a subject in need
f by administering to the subject an effective amount of a composition including any one or
more compound(s) as bed herein in combination with one or more other therapies or medical
procedures effective in treating the cancer. Other therapies or medical procedures include suitable
anticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic y) or
medical procedure (e.g. surgery, radiation treatment, hermia heating, bone marrow or stem cell
transplant). In one embodiment, the one or more suitable ncer therapies or medical procedures
is selected from treatment with a chemotherapeutic agent (e.g. chemotherapeutic drug), ion
treatment (e.g. x—ray, y—ray, or electron, proton, neutron, or at particle beam), hyperthermia heating
(e.g. microwave, ultrasound, radiofrequency on), Vaccine therapy (e.g. AFP gene hepatocellular
carcinoma vaccine, AFP adcnoviral vector vaccine, AG—SSS, allogeneic GM—CSF—secretion breast
cancer vaccine, tic cell peptide es), gene therapy (e.g. AdSCMV-p53 vector, adenovector
encoding MDA7, adenovirus S—tumor necrosis factor , photodynamic therapy (eg.
aminolevulinic acid, motcxafin lutctium), y, or bone marrow and stem cell transplantation.
In another aspect, he invention provides kits that e a compound of any of formulas (I)
to (In) or a compound as described herein or composition thereof as described herein. In some
embodiments, the compound or composition is packaged, e.g., in a vial, bottle, flask, which may be
further packaged, e.g., within a box, envelope, or bag; the compound or composition is approved by
the U .8. Food and Drug Administration or similar regulatory agency for administration to a mammal,
e.g., a human; the compound or ition is approved for administration to a mammal, e.g., a
human, for a protein kinase mediated e or condition; the invention kit may include written
instructions for use and/or other indication that the compound or composition is suitable or approved
for stration to a mammal, e.g., a human, for a Raf protein kinasetmediated disease or condition;
and the nd or composition may be packaged in unit dose or single dose form, eg, single dose
pills, capsules, or the like.
VII. Examples
[0196} The following examples are offered to illustrate. but not to limit the claimed invention.
481 1-791 8-7726.1
039363—7211
Compounds within the scope ofthis invention can be synthesized as described below, using
a variety of reactions known to the skilled n. One skilled in the art will also recognize that
alternative methods may be employed to synthesize the target compounds of this invention, and that
the ches described within the body of this document are not exhaustive, but do provide broadly
applicable and practical routes to compounds of interest. In some examples, the mass spectrometry
result indicated for a compound may have more than one value due to the isotope distribution of an
atom in the molecule, such as a compound having a bromo or chloro tuent.
Certain molecules claimed in this patent can exist in different enantiomeric and
diastereomeric forms and all such variants ofthese compounds are claimed.
Those skilled in the art will also recognize that during standard work up procedures in
organic try, acids and bases are frequently used. Salts of the parent compounds are sometimes
produced, if they possess the necessary intrinsic acidity or basicity, during the experimental
procedures described within this patent.
Example 1: Preparation of (3—Amino—2,6—difluorophenyl)(5—i0do-lH—pyrrolo[2,3-b]pyridin—3—
hanone (4)
Scheme 1
O F
SnClg
[0200} Synthesis of 2,6-Difluoro—3—nitrobenzoyl chloride (2): To 2.6-difluoro—3—nitrobenzoic acid
(50 g, 246 mmol) was added thionyl de (185 mL, 2536 mmol). The reaction was heated at 80
OC overnight and d to cool to room ature. The volatiles were removed under reduced
which was used directly in the
pressure and then azeotroped from toluene several times to give an oil
next step.
Synthesis of (2,6-Difluoronitrophenyl)(5—iodo-lH-pyrrolo[2,3-b]pyridin-3—
yl)methanone (3): S-Iodo—l olo[2,3—b]pyridine (32.8 g, 134 mmol) and aluminum chloride
(108 g, 806 mmol) in nitromethane (340 mL) were allowed to stir at room temperature for 1 hour.
Then 2,6—difluoro-3~nitrobenzoyl chloride (44.7 g, 2.02 mmol) in nitromethane (340 mL) was added
and the mixture was heated at :30 0C for 5 days. After cooiing to i} C'C, the reaction was quenched with
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039363-7211
methanol (250 mL) resulting in a ppt. The mixture was diluted with water (500 mL) and then filtered.
The crude product which was triturated with ethyl acetate and filtered washing with onal ethyl
acetate to give (2,6-difluoro—3-nitrophenyl)(5-iodo—l l—I-pyrrolo[2,3-b]pyridinyl)methanone (42 g,
98 mmol, 72.8 0/0 yield) as a brown solid. ]H NMR spectrum is consistent with the structure of the
Synthesis of (3-Amino-2,6-difluorophenyl)(5—iodo—lH-pyrrolo[2,3-h]pyridin~3-
yl)methanone (4): To (2,6-difluoro—3—nitrophenyl)(5-iodo~lH-pyrrolo[2,3—b]pyridin—3-yl)methanone
(44.6 g: 104 mmol) in ethyl e (1732 mL) and THF (1732 mL) was treated portionwise with
tin(II) de dihydrate (82 g, 364 mmol) while heating ()0 °C and held at this temperature
overnight. After cooling to room ature, the reaction mixture was quenched with half sat.
aqueous sodium bicarbonate and filtered through Celite g the cake with ethyl acetate. The
layers were separated and the organic layer was washed with brine then concentrated under reduced
pressure to give the crude product which was triturated with DCM and filtered to give (3 —amino-2,6—
difluorophenyl)(5—iodo—lH-pyrrolo[2,3-b]pyridin-3—yl)methanone (34 g, 85 mmol, 82 % yield) as a
tan solid. 1H NMR spectrum is consistent with the structure of the compound.
Example 2: 5—(4—chlorophenyl)-lH-pyrrolo[2,3—b]pyridine-S-earbonyll-Z,4—difluoro—
phenyl]pyrrolidine—l—sulfonamide (P—002 1).
Scheme 2
Synthesis of N-[2,4—difluoro(5—iodo-lH-pyrroloiZJ-b]pyridine
carbonyl)phenyl]pyrmlidine—l-sulfonamide (6): To (3_amino-2,6-difluoro»phenyl)~(S-iodo-lH—
pyrrolol2,3-b]pyridin-3~yl)methanone (4. 2.9 g, 7.27 mmol) in pyridine (l 1.2 mL), was added
pyrrolidine-l-sulfonyl chloride (5, 1.68 mL, 14.53 mmol). The mixture was stirred at room
temperature for 48 hours, The ing mixture was poured into a saturated NH; Cl aqueous solution
and extracted with cth}l acetate the organic layers were combined and washed with brine dried
4811—7918—7726.1
039363—7211
over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash
chromatography using an 80 g~cartridge (eluted with ethyl acetate and DCM). The desired product
was obtained as a solid (6, 2.06 53.3% yield). ) [ll/HEY]+ = 532.8. 1H NMR spectrum is
consistent with the structure of the compound.
sis of N-[3-[5-(4-chlorophenyl)—lH—pyrrclo[2,3-b]pyridinecarbonyl]~2,4-
difluoro—phenyl]pyrrolidine—1-sulfonamide (P-0021): In a microwave vessel, N—[2,4-difluoro(5-
iodo-1H-pyrrolc[2,3-b}pyridinecarbonyl)phenyllpyrrolidinesulfonamide (6, 0.27g, 0.51 mmol)
and orophenyl)boronic acid (7, 0.1 g, 0.61 mmol) and [1, 1'-
bis(diphenylphosphino)ferrocene]dichloropalladium([l) (27 mg) were mixed in l M of potassium
carbonate in water and acetonitrile (1.31 mL). The mixture was heated at 130 ° C under microwave
for 15 minutes. The resulting e separated into an organic layer and aqueous layer. The
aqueous layer was extracted with ethyl acetate and combined with the organic layer, washed with
brine, dried over sodium sulfate, filtered, and concentrated. The crude t was purified by
chromatography using a 40 g—cartridge (eluted with ethyl acetate and romethane). The purified
t was obtained as a solid (P—0021, 0.071 g, 27% yield). MS (ESI) [M+H+]+ = 517.0 and 519.0.
1H NMR spectrum is consistent with the structure of the compound.
The following compounds were prepared according to the protocols set forth in Examples 1,
2 and 4—9 and Schemes l, 2 and 4—9.
Table 2
—chloro—3—[3—[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro—benzoyll—l H-pyn‘olo[2,3—b]pyridine,
(P-0012),
—(4—chlorophenyl)—3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro—benzoyl]- 1 H-pyrrolo[2,3—
b]pyridine (P—0013),
3-[3—[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro—benzoyl](2-methoxypyrimidin—5—yl)— l H-
pyrrolo[2,3-b]pyridine (P-0014),
N-[2,4-difluoro-3 -(5-fluoroiodo-1H-pyrrolo[2,3-b]pyridinecarbonyl)phenyl]pyrrolidine-l -
sulfcnamide (P~0015),
S-chloro-3«[3~[[ethyl(methyl)sulfamoyl]amino]fluoro—benzoyll~1H~pyrrolo[2,3~b]pyridine (P-
0018L
~(4-chlorophenyl)-3 ~[3 yl(methyl)sulfamoyl]amino]—2-fluoro-benzoyl]-1l‘l-pyrrolofljx
blpyridine (P-0019'),
3-{3 ~[[ethy1(methyl)sulfamoyl]amino]—2—fluoro-benzoyl]~5—(2-methoxypyrimidin-S-syl)— 1 H—
pyrrolo[253-b]pyridine (P-OOZO),
—(4-chlorophenyl)—lH-pyrrolo[2,3~blpyridine~3~carbcnyl]»2,4*difluoro—phenyl]pyrrolidine-
1—sulfenamide (13-0021),
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039363-7211
N—[3-[5—[2-(dimethylamino)pyrimidin—S-yl]—1H-pyrrolo[2,3—b]pyridine—3~0arbonyl]—2,4-diflu0ro—
phenyl]pyrr01idine-} -su1f0namide (P-0022),
N—[2-flu0ro(S-mcthyl-1H-pyrrolo[2,3-b]pyridinccarb0nyl)phcnyl]pyrrolidinc—1—sulfonamide
(P—0023)
N—[ZA-difluom-B-(S-iodo—1H-pyrmlo[2,3-b]pyridinecarb0nyf)phenyl]pyrrolidine-1w
sulfonamide (P-0024),
3-[3-[[cyclopropyl(methyl)sulfamoyl]amin0]—2—fluore—benzoyl](2-methoxypyrimidin-S-yl)—
lH-pyrrolo[2,3-b]pyridine (P-0025),
[2—fluoro-3~(methylsulfamoylamino)phcnyl]-[5—(2-methoxypyrimidiny1)-IH-pyrrolo[2,3-
din—3-yl]methanone (P-0026),
-(4-cyanophenyl)[3 -(dimethy]sulfamoylamino)fiuor0-benzoy1]-l H-pyrrolo[2,3-b]pyridine
3—[3—(dimethylsulfamoylamin0)-2~flu0ro-benzoyl]-5~(3—pyridyl)—1H—pyrrolo[2,3—b]pyridine (P—
0028),
3—[3-(d{methylsulfamoylamino)—2—fluor0-benzoy1]-5~(6-methyl-3—pyridyl)-I H—pyl’rolo[2,3-
b]pyridine (P-0029),
—[6-(dimethy1amino)—3—pyridyl]—3-[3-(dimethylsulfam0ylamino)—2—flu0ro—benzoyl]- I H-
pyrroio[2,3—b]pyridine (P-0030),
S—(4—cyanophenyl)—3 —[3 —[[ethyl(methyl)sulfamoyl]amino]—2—fluoro-benzoy1]—lH—pyrrolo[2,3 —
b]pyridine (P-0031),
3-[3 -[[ethy1(methyl)su]fam0y]]amino]-2—flu0r0-benzoyl]—5—(3—pyridyl)—1H-pyrr010[2,3 -b] pyrid inc
(0032),
3{3—[[ethyl(methy1)sulfamoyl]amino]—2-fluoro-benzoyl]-5—(6—methyIpyridyl)—1H-pyrrolo[2,3—
, b]pyridine (0033),
3 —[3—[[ethmeethstulfamoyl]am inoJ-Z-fluoro-bcnzoyl](4-fluorophcnyl)— 1 H—pyrrolo[2,3-
b]pyridine (0034),
3 -[3-(dimethylsulfamoylamin0)flu0r0-benzoyl]-5 -(4-flu0r0phenyl)- ] H-pyrrolo[2,3-b]pyridine
3-[3—[[ethyl(methyl)sulfamoyl]amino]f1uoro—benzoyl]—5-phenyl—]H-pyrrolo[2,3-b]pyridine (P—
0036),
dimethylsulfamoylamin0)fluoro-benzoyl]—5-pheny1-1H-pyrrolo[2,3-b]pyridine (P-0037),
S—bromo-S-[3-[{ethyl(methyl)sulfamoyl}amino]~2~fluoro~benzoyl]~1prrrolo[2,3-b]pyridine (P—
0038),
3-[2~flu0ro[[methyl(propyl)suIfamoyl]amino]benzoyl](2-methoxypyrimidin~5-yl)fi I H-
pyrrolol2,3-b]pyridine (P—0040)
3~benzyloxy—N«[2~fiu0roa3-={5-(2-meth0xypyrimidinyl)~aIH—pyrrolo[2,3sb]pyridine»3-
carbonyl]phenyl]pyrrolidine-1«sulfonamide (P-0041)
1 02
4811—?918—7726.1
039363-7211
1 —cyclopropyl-N-[2-fiu0ro—3-[5-( ] ~methylpyrazoIyl)-1 H-pyrmlo[2;3-b}pyridin€
carbonyl]phenyl]methanesulfonamide (P—0042)
uoro—S-[S-(S~pyridyi)-1H-pyrrolo[2,3—b]pyridinecarbonyl]phenyl]pyrrolidine—1—
sulfonamide (P~0043)
N~[3-[5-(2,4-dimethaxypyrimidin-S-yD-1H—pyrrolo[2.3-b]pyridinecarb0nyI]fiu0ro-
phenyl]pyrmlidine~l -sulfenamide (P-0044)
N—[Z—fluoro-3—[S—(’6-mcthylpyridyl)-1II—pyrrolo[2,3vb]pyridine-3 -carbonyl]phenyl]pyrrolidine-
l-sulfonamide 5)
N—[3—[5-[6-(dimethylamin0)-3 -pyridyl]-l H-pyrrolo[2,3-b]pyridine-3 -carbonyl]-2—fluoro~
phenyl]pyrrolidinc-l -sulfonamide (P-0046)
N-[Z-fluoro-3 -[5-(2-isopropylpyrimidin-S-yl)- l H-pyrrolo[2,3-b]pyridinc
carbonyl]phenyl]pyrrolidine-l -sulfonamide (P-0047)
N-[3-[5-(2-cyclopropylpyrimidin-S-yl)-I H-pyrrolo[2,3-b]pyridinccarbonyl]—2—fluoro-
phenyl]pyrrolid1'nesulfonamide 8)
N-[3 -[5 -(4-cyan0-3 -methoxy-phenyl)-l H—pyrrolo[2,3—b]pyridine-3 nyl}—2-fluoro—
phenyl]pyrrolidine- 1 —su lfonamide (P-0049)
N-[3 -[5 ~[4—(1-cyan0cyclopropyl)phenyl]—1H-pyrrolo[2,3-b]pyridine-3 —carbonyl]—2-fluoro-
phenyl]pyrrolidinesulfonamide (P-0050)
3 - [3 -(dimethylsulfamoylam ino)fluoro-benz0yl]—5-(2—isopr0pylpyrim idin-S -yl)-1H-pyrrolo[2,3
b]pyridine (P-0051)
S-(2-cyclopropylpyrimidin-S-yl)-3—[3-(dimethylsulfamoylamino)—2-fluoro-benzoylj-1 H—
pyrrolo[2,3-b]pyridine (P-OOSZ)
3-[3 -(dimethylsulfamoylamino)-2—fluoro-benzoyl]—5-[6-(trifluoromethyl )pyridyl]- I H—
pyrrolo[2,3-b]pyridine (P-0053)
S-(4-cyano-3 -methoxy—phenyl)-3—[3 -(d imethylsulfamoylamino)fluoro-benzoyl] -1 H—
pyrrolo[2,3—b]pyridine (P-0054)
1-cyanocyclopropyl)phenyl][3-(dimethylsulfamoylamino)fluoro-benzoyl]-1 H-
pyrrolo[2,3—b]pyridine (P—0055)
[ethyl(methyl)sulfamoyl]amino]—2-fluoro—benzoyl](2-methylpyrimidin-S-yl)—1 H-
o[2,3-b]pyridine (P-0056)
3-[3-[[ethmeethyDSUIfamoyl]amino]fluor0-benzoyl]~5-(2—isopr0pylpyrimidinvS-yl}1 I L
flfi~h]pyridine (P-0057)
~{_2—cyclopropylpyrim idin-S -yl)—3—[3-[[ethyl(methyl)sulfamoyl]amino]-2—fluoro—benzoyl}~ 1 H-
pyrrolo[2,3-b]pyridine (P-0058}
3-[3 -[[ethyl(methyUsulfamoyflamino]fluoro-benzoyl][6-(trifluoromethyl)~3-pyridyl]- 1 H-
pyrrolo[2,3—b]pyridine (P-0059)
-(4—cyanomethoxy-phenyl)-3—[3—[[ethyl(lnethy1)sulfamoyllamino}1‘1u0m-benzoyl]~I H»
pyrmleflfi~bhayridine (£0060)
1 03
4811-7918~7726.1
039363—7211
-[4—(1-cyanocyclopropyl)phenyl][3 -[[ethyl(methyl)sulfamoyl]am ino] ~2—fluor0—benzoyl]~ 1 1+
pyrrolo[2,3—b]pyridine (P-0061)
N—[2—fluom[5—(4-fluomphenyl)-IH-pyrrolo[2,3-b]pyridine—3-carbonyl]phenyl]pyrmlidine—I—
sulfonamide (P—0062)
N-[2—fluor0—3 -(5—phenyl- l H-pyrrolo[2,3-b]pyridinecarbonyl)phenyl]pyrrolidine— l -sulf0namide
(P—0063)
—[2—(c.yclopropylamino)pyrimidin-5—yI]—3-[3-(dimethylsulfamoylamino)-2—flu0r0-bcnzoylj-I H,-
pyrrolo[2,3-b]pyridine (P—0064)
N-[2-fluoro[S-(2-methoxypyrimidin-S-yl)-1H-pyn‘olo[2,3-b]pyridine—3-carbonyl]phenyl]—2—
methoxy—ethanesulfonamide (P-0065)
methyl 3-[[2-fluoro—3-[5-(2-methoxypyrimidinyl)—1H-pyrrolo[2,3-b]pyridine
carbonyl]phenyl]sulfamoyl]propanoate (P-0066)
N—[2~fluoro—3~[S—(2—methoxypyrimidin—S—yl)—1H—pyrrolo[2,3-b]pyridine—3—
yl]phenyl]cyclopropanesulfonamide (P-0067)
[3 sulfamoylamino)-2—fluoro—phenyl]—[5—(2—meth0xypyrimidin—5 -yl)-l 010[2,3—
bjpyridin—3—yljmethanone (P—0068)
[3 -(ethylsulfamoylamino)—2—fluoro—phenyl]-(5—iodo— ] H—pyrrolo[2,3-b]pyridin—3~yl)methan0ne (P—
0069)
3—[2—fluoro—3 butyl(methyl)sulfamoyl]amino]benzoyl]~5—iod0—1H-pyrrolo[2,3—b]pyridine (P—
0070)
[2—Hu0r0-3—(isopropylsulfamoylamin0)phenyl]—(5 -i0d0- l H-pyrrolo[2,3—b]pyridin—3—y1)methanone
(P-0071)
3~[2wfiuoro—3—[[isobutyl(methyl)sulfamoyl]amino]benzoyl]-5—(2—methoxypyrimidin—S—yl)—1H—
pyrrolo[2,3—b]pyridine (P-0072)
3—[2—fluoro[[2-methoxyethyl(methyl)sulfamoyl]amino]benzoyl]—5-(2-methoxypyrimidin—S—yl)—
1H—pyrrolo[2,3-b]pyridine (P—0073)
N—[Z-fluoro-3 —[5 -(2-methoxypyrimidinyl)—1H—pyrrolo[2,3~b]pyridine-3 -carb0nyl]phenyI]—2-
methyl-pyrrolidinesulfonamide (P—0074)
3—[2-fl uor0—3 -[[isopropyl(methyl)sulfamoyl]am ino]benzoyl}5—(2-methoxypyrim idin—S -yl)-1H—
o[2,3—b]pyridine (P—0075)
—[6~(dimelhy1amino)-3‘pyridyU-Ya-[3-[[ethyl(methyl)sulfamoylkmin0]fluoro—benzoyl]-1H-
pyrrolo[2,3—b}pyridine (P—0076)
—[2—(cyciopropylamino)pyrimidin~5—yl]—3{3—[[ethyl(methyUsulfamoyflamino]—2—fiuor0~
benzoyl}!H—pyrrolo[2,3‘b]pyridine (P—0077)
—(2—cyclopr0pylpyrimidin—S—yl)—3—[2,6—difluoro—3—[[methyl(pr0pyl)sulfam0y11an1ino]benzoyl}
1H—pyrrolo[2,3~b]pyridine 8)
—[4-( 1-Cyanocyclopropy1)phenyl]~3{2,641ifluoro’3~[[methyl(pr0pyl)suIfamoylkminobenzoyl}
1H~pyrr010[2,3~b]pyridine (P~0079)
4811791877261
039363-7211
-[4-(1-cyanocyclopropyl)phenyl][2-flu0ro[{2-
methoxyethyl(methyl)sulfamoyl]amino]benmyl]-1H-pyrmlo[2,3—b]pyridine (P-0080)
—[2-(cycIopropylamin0)pyrimidin-5—y[]-3—[2-fluc>ro—3-[[2-
methoxyethyl(methy1)sulfamoyl]amino]benzoyl]-IH-pyrrolo[2,3-b}pyridine (P-0081)
-[2«(eyelopropylamino)pyrimidinyl]—3-[2—fluom
[[methyl(propyl)sulfamoyl]amino]bcnzoylj-l H-pyrrolo[2,3-b]pyridine 2)
3-[3-[[cyclopropylmethyI(methyl)sulfamoyl]aminol-Z-fluoro—benzoyl](2-methoxypyrimidin-5—
y1)-IH-pyrrolo[2,3—b]pyridine (P—0083)
3-[3-[[cyclopropylmethyl(methyl)sulfamoyl]amin0]flu0ro-benzoyl](2-
cyclopropylpyrimidin-S—yl)—1H-pyrrolo[2,3-b]pyridine (P-0084)
-(2-cyclopropylpyrimidin-S-yl)[2-fluoro[[2-
methoxyethyl(methyl)sulfamoylhm in0]benzoyl]- l H-pyrrolo[2,3-b]pyridine (P-0085)
—(2-cyclopr0pylpyrimidin—S —yl)[2-flu0ro[[methyl(propyl)sulfamoyl]amino]benzoyl]—I H-
pyrrolo[2,3—b]pyridine (P-0086)
-(6—cyclopropyl—3—pyridyl)-3—[3—[[ethyl(methyl)sulfamoyl]amin0]—2—fluor0—benzoyl]—1 H—
pyrrolo[2,3-b]pyridine (P-0087)
3,3-difluoro-N-[Z-fluoro-3~[5-(2—methoxypyrimidin—S-yl)-l H-pyrrolo[2,3—b]pyridinc—3-
carbonyi]phenyl]azetidine— I ~sulf0namide (P-0088)
4-[[(1S)—l~cyclopr0pylethyl]amino][3-[[ethyl(methyl)sulfamoyl]amino]—2~fluoro—benzoyl]~7H~
o[2,3-d]pyrimidine (P-0089)
\I—[3~[5-(4-eyan0phenyl)—1H—pyrrolo[2,3—b]pyridinecarbonyI]—2~flu0ro-phenyl]pyrrolidine-l-
sulfonamide (P-0090)
\I-[3~[S—(2~cyanopyrimidinyl)-1H—pyrrolo[2,3-b]pyridine—3—carbonyl]—2-fluor0-
phenyl]pyrrolidine-l-sulfonamide 010091)
\I-[Z—fluoro—3 -[5-(2-methylpyrimidin-S-yl)-1H-pyrrolo[2,3-b]pyridinc-3 —
carbonyl]phenyl]pyrrolidinesulf0namide (P-0092)
\I-[3 - [S-(S-Cyano-3 -pyridyl)— l H-pyrrolo[2,3-b]pyridinecarb0nyl]fluoro-phenyl] pyrrolidine—
l-sulfonamide 3)
N-[3- [5 ‘(6-cyan0—3 -pyridyl)~ I H-pyrrolo[2,3-b]pyridine-3 —carbonyl]fluoro-phenyl]pyrrol idine-
l-sulfonamide 4)
uom[5-[6»(trifluommethy0-3 -pyridyl]—1H-pyrmlo[2,3—b]pyridine-3~
carbonyl]phenyi]pyrrolidinesulf0namide (13-0095,)
-(2—cyanopyrimidin~5-yl)—3-[3—(dimethylsulfamoyiamino)—2-fiu0ro—benzoyl]—1H-pyrrola[2,3—
b]pyridine (P-0096)
3-[3~(dimethylsuIfamoylam1'no)—2—fluoro-benzoyl]—5-(2—methylpyrimidin-S—yl)—1 H—pyrr010[2,3 -
b}pyridine (P-0097)
—(5-Cyan0-3 -pyridyl)[3 -(di1nethylsulfamoylamino)fluor0—benzoyl]— 1 olo[2,3-
b}pyridine 8)
4811—7918—?726.1
O39363 -721 1
S-(6-cyan0-3 -pyridy1)—3 ~[3—(dimethylsulthmoylamin0)fluoro—benzoyl]~ I I I—pyrmlo[2,3-
blpyridine (P—0099)
S~(2—cyanopyrimidinyl)-3— [3-[[ethyl(methy[)sulfamoyl]amino]flu0ro—benzoyl}- 1 H—
pyrrolo[2,3-b]pyridine (P-0100)
‘(5~cyanopyridy1)[3-[[ethmeethstulfamoyHamin0]—2-fluor0-benzoyl]— I olo[2,3—
b]pyridine (P—OlGl)
-(6-cyano—3—pyridyl)[3-[[ethy1(methyl)sulfamoyI]amin0]fluorO—benzoyl]‘1 H—pyrrolo[2,3-
dine (P—0102)
3-[3-(dimethylsulfamoylamino)—2-fluoro-benzoyl][4-(1-hydroxymethyl-ethyl)phenyl]—1H-
pyrrolo[2,3-b]pyridine (P-0103)
3-[3-[[ethyl(methyl)sulfamoyl]amin0]—2-fluoro-benzoyl][4-(1-hydroxymethylethyl
)phenyl]-1H-pyrrolo[2,3-b]pyridine (P-0104)
N—[2-fluoro[5-[4-(1-hydr0xy-I-methy|-ethy|)pheny|]-I H-pyrrolo[2,3-b]pyridine
carbonyl]phenyl]pyrrolidine—l-sulfonamide (P—0105)
-[2-(dimethylamin0)pyrimidina5-yI]-3—[3 -(dimethylsulfamoylamino)-2—fiu0r0—benzoyl]» 1 H-
o[253—b]pyridine (P-0106)
3-[3-(dimcthylsulfamoylamino)-2—flu0ro-benzoyl]—5—(2—pyrrolidin—1-ylpyrimidin—5—yl)-1H—
pyrrolo[2,3-b]pyridine (P—0107)
3-[3-[[ethyl(methyl)sulfamoyl]amino]fluoro-benzoyl]-5—(2-pyrrolidin-1—ylpyrimidinyl)-1H—
pyrrolo[2,3-b]pyridine (P—0108)
N—[2—flu0ro-3—[S—(2-pyrrolidin—1-ylpyrimidin—5-yl)—1H-pyrrolo[2,3—b]pyridine—3—
carbonyl]phenyl]pyrrolidine-1—sulfonamide (P—0109)
3-[3 -(dimethylsulfamoylamino)-2~flu0ro-benzoyl]—5—iodo—1II—pyrrolo[2,3—b]pyridine
(P-OllO)
3—[2—fluor0—3—[[methyl(propyl)sulfamoyl]amino]benzoyl}5-(2—methylpyrimidinyl)-I H-
pyrrolo[2,3—b]pyridine (P-01 1 l)
3—[3-[[cyclopropylmethyl(methyl)sulfamoyl]amino]—2—fluor0-benzoyl](2-methylpyrimidin—5-
y1)—1H—pyrrolo[2,3-b]pyridine (P-0112)
—(6—cyclopr0pyl-3 —pyridyl) [3 -(dimethylsuIfamoylamino)flu0r0-benzoyl]—1H—pyrr010[2,3 -
b]pyridine (P-0113)
—(6ficyclopropyL3‘pyridyIH—[2~flu0ro—3-[[methyl(propyl)su1famoyl]amin01benzoyll—1H—
pyrrolo[2;3—b]pyridine (P-0114)
3-[3-{[cyclopmpylmethyl(methyl)sulfamoyl]amin0]-2—fiuoro-benzoyl](6-cyclopmpylv3-
pyridyl} l H-pyrrolo[2,3-b]pyridine (P-0115)
-difluoro—3-[[methyl(pr0pyl)sulfamoyl]amino]benZQyI]—5—(2-meth0xypyrimidin-S-yl)-1H—
0[2,3~b]pyridine (P-0116)
[2-fluoro~3{propylsulfamoylamin0)phenyl]—(S~iodo— 1 H~pyrrolo[2.3 ab}pyridin—3 «meethanOne
(11-0117)
481177261
039363—7211
[2—fluor0—3 {propylsulfamoylamino)phenyl]~(S—methyI— ] H—pyrrolo[2,3-b]pyridin-3 -yl)methan0ne
(P—0223)
N-[Z—fluoro-B -[S-(B-methoxypyrimidimS -yl)-1H—pyrmlo[2,3~b]pyridine-3 -
carbonyl]phenyl]butane—2—sulfonamide (P~0224)
N-[2-flu0r0[5-(2-pyrrolidin- I imidinyl)- l H-pyrr010[2,3 -b]pyridine
carbonyl]phenyl]butane-2—sulfonamide (P—0225)
N—[3~[5~[2—(cyclopropylamino)pyrimidin—5—yl]— IH—pyrrol0[2,3—b]pyridine-3 -carbonyljflu0ro-
pheny1]butane—2—sulfonamide (P—0226)
-[4-(1-cyanocyclopropyl)phenyl]—IH-pyrrolo[2,3-b]pyridine-3 -carbonyI]fluoro-
phenyl]butane-2—sulfonamide (P-00227)
N-[3-[5-(2-cyclopropylpyrimidin-S-yl)-I H-pyrrolo[2,3-b]pyridine-3 -carbonyl]fluoro—
phenyl]butane-2—sulfonamide (P-0228)
N-[2-fluoro-3 -[5-(2-isopropylpyrimidin—S-yl)- l H—pyrrolo[2,3—b]pyridine—3 -
carbonyl]phenyl]butane—2—sulfonamide (P—0229)
N—[3 —[5 —[6-(dimethy1amino)-3 —pyridy1]-IH—pyrrolo[2,3-b]pyridine—3 nyl]—2—flu0ro—
]butane-2—sulfonamide (P—0230)
N-[Z-fluoro-3—[5—(2—methylpyrimidin-S-yl)-I H—pyrrolo[2,3 —b]pyridine—3~carbonyl]phenyl]butane~
2-sulf0namide (P—023l)
N—[3-[5-[2-(Cyclopropylamino)pyrimidin-S—yl]—1H—pyrrolo[2,3-b]pyridine—3—carb0nyl]flu0r0-
phenyl]pyrrolidine— 1 —sulfonamide (P—0232)
yclopr0pylpyrimidin-S-yl)[2-fluoro—3-[[isopropyl(methy1)sulfam0yl]amino]benzoyl]-1H-
pyrr010[2,3-b]pyridine (P—0233)
N—[2—f1uor0-3~[5—(2-morpholinopyrimidin—S—yl)—lH—pyrrolo[2.,3-b]pyridine—3—
carbonyl]phenyl]pyrrolidinesulfonamide (P—0235)
N-[2-flu0r0-3 -[5-(2-morpholinopyrimidin-S-yl)-l H—pyrrolo[2,3 -b]pyridine-3 ~carb0nyl]phenyl]butane-
2-sulfonamide (P-0236)
-[4-(1-cyanocyclopropyl)phenyl][3-(dimethylsulfamoylamino)-2,6-difluoro—benzoyl]—1H—
o[2,3—b]pyridinc (P-0237)
-(2-cyclopropylpyrimidin—S-yl)—3 —[3 —(dimethylsulfamoylamino)—2,6—difluoro-benzoyl]- I, I I-
pyrrolo[2,3—b]pyridine (P-0238)
—[4-(1~cyanocyclopr0pyl)phenyl][3-[[elhyl(mclhyl)sulfamoyi]amino]~2,6-difluoro-benzoyl]~1Ha
pyrrolo[2,3—b]pyridine (P-0239)
S»(2~cyclopropylpyrimidin—S—yl)—3—[3 ~[[ethyi(methyi)sulfamoyt]amino]—2,6—difluorovbenzoyl} I H
pyrrolo[2,3—b]pyridine (P-0240)
N—[3 -[5 —(2—cyclopropylpyrimidin-5~yl)—1II—pyrrol0[2,3—b]pyridine~3 —carb0nyl]—2,4—difluoro-
phenyflpyrrolidine- 1 —su1f0namide (P-0241)
[Z-fiuoro-B-(pmpylsulfamoylamino)phenyl]-[5-(1—methylpyrazol—4—yl)-I H-pyrrolo[2,3—b]pyridin—3—
yljmethanene (P—0242)
481137918-77261
039363—7211
1-[4-[3 —[2-flu0r0—3—(pyrrolidin—1—yIsulfonylamino)benzoyl]~1H-pyrrolo[2,3—b]pyridin~5-
yl]phenyl]Cyclopropanecarboxylic acid (P-0243)
3—[3{dimethylsulfamoylamino)-2,6—difiuoro—benzoyl}5-(5-ethoxypyrazin—2-yl)-I H-pyrrol0[2,3~
b]pyridine (P-0244)
—[4-(1-Cyano‘1—methy1-ethyl)phenyl]—3-[3—(dimethylsulfamoylamin0)-2—fluoro—benzoy1]-I H-
pyrrolo[2,3-b]pyridine (P-OZ4S)
N—[3{5—(2—cyciopropylpyrimidin-S—yl)—lH—pyrrolo[2,3—b]pyridine—3—carb0nyI]fluoro-phenyl]-3,3-
dimethpryrrolidine—l~sulfonamide (P—0246)
N-[3-[5-(2-cyclopmpylpyrimidin-S-yl)-1H-pyrrolo[2,3-b]pyridinccarbony|]—2-fiuoro—phenyl]-3 -
methyl-pyrrolidine— onamide (P-0247);
N-[3-[5-[4-(1-cyanocyclopropyl)phenyl]—1H-pyrrolo[2,3-b]pyridinecarbonyl]—2,4-difluoro-
phenyl]pyrrolidinesulf0namide 8)
3-[3 -[[cyclopropyl(methyl)sulfamoyl]amino]fluoro-benzoyl]-5—(2—cyclopropylpyrimidin—5—yl)— 1H—
pyrrolo[2,3-b]pyridine (P-0249)
[5-(2-cyclopropyIpyrimidin-S-y1)-1H-pyrrolo[2,3-b]pyridin—3-yl]-[2-fluoro—3—
(propylsulfamoylamino)phenyl]methanone (P-0251)
3—[3—[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]—5—(2—cyclopr0pylpyrimidin-S—yl)-
IH-pyrrolo[2,3—b]pyridine (P-0252)
1—[4—[3 -[2—fluoro-3~(pyrrolidin—l-ylsulfonylamino)benzoyl]-1H—pyrrolo[2,3—b]pyridin—5—
yl]phenyl]cyclopropanecarboxamide (P-0253)
methyl 1—[4—[3~[2-flu0ro(pyrr0lidin—1-ylsulfonylamino)benzoyl]—1H—pyrr010[2,3—b]pyridin
ny1]cyclopropanecarboxylate (P-0254)
-[4-(1-cyano-1—methyl—ethyl)phenyl]—3~[3-(dimethylsulfamoylamino)—2,6—difluoro-benzoyl]-1H—
o[2,3-b]pyridine (P-0255)
-(2-eth0xypyrimidin-S-yl)—3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]—1 H-
pyrrolo[2,3-b]pyridine (P—0256)
ethyl 1-[[2-fluor0[5—(2—meth0xypyrimidin-S—yl)—1H-pyrrolo[2,3-b]pyridine
carbonyl]pheny1]sulfamoyl]pyrrolidine—2-carboxylate (P-0257)
4—[5—[3—[3—[[ethyl(methyl)sulfam0yljamino]-2,6-difluoro—benzoyl]—1H—pyrrolo[2,3—b]pyridin-5—
yl]pyrimidin—2~yl}morpholine (P—0258)
4-[3-[3-{3-[[ethmeethstulfamoyl]amin0]—2,6~difluoro—benzoyH—l H-pyrrolo[2,3-b1pyridin
yijphenylh’mrpholine (P-0259)
N«[2,4~difluoro—3~[5—[2—(4~methylpiperazin—1—yl)pyrimidin~5—yl}-] H~pyrmi0[2,3—b]pyridinew3 -
yl]phenyl]pyrrolidinesulf0namide (P-0260)
N-[2,4—difluoro-3—[5—(2—piperazin-l-ylpyrimidiny1)-1H-pyrroloDJ—b]pyridine-3—
carbonyl]phenyl]pyrrolidine- I ~sulfonamide (P—0261)
N-[2.4—diflu0ro[5-[2-(4-hydroxy-I -piperidyl)pyrimidin-S—yi}1H—pyrr010[2,3-b]pyridine-3—
carbonyl]phenyl}pyn‘olidine—I namidc (P-0262)
1 08
4811491847261
039363-721 1
3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluor0-benzoyl]-5—[2-(4-methylpiperazinyl)pyrimidin-
S-yl}IH-pyrmlo[2,3-b]pyridine (P-0263)
tcrt-butyl 4-[5-[3-[3-[[ethyl(methyl)sulfam0yl]amincl-2,6-difluoro—benzoyl]-1H-pyrrolo[2,3-b]pyridin-
S-yl]pyrimidiny11piperazine-I Acarboxylate (P-0264)
N—[2,4-difluoro[5-[2-(1~hydroxy-I -methyl—ethyl)1hiazol—4—yl]—1H—pyrrolo[2,3-b]pyridine
carbonyl]phenyl]pyrrolidine- I -sulfonamide (P-0265)
N‘[2,4-difluor0«3-[S-(Z-morpholinopyrimidin-S—yl)‘IH-pyrrolo[2,3—b]pyridine
carbonyl]pheny1]pyrrolidinesulf0namide (P-0266)
N-[1-[[3-[5-(2-cycIopropylpyrimidin-S-yl)—1H-pyrrolo[2,3-b]pyridinecarbony1]fluoro-
pheny|]su|famoy|]pyrrolidin-3~y|]-N-methyl—acetamide (P-0267)
3-[3—[[ethy1(methyl)sulfamoy|]amino]—2,6-difluoro-benzoy]](2—piperazinylpyrimidinyl)—1H-
pyrrolo[2,3-b]pyridine (P-0268)
N-[3 -[5-[2-(azetidinyl)pyrimidinyl]- l H-pyrro|o[2,3-b]pyridine-3 -carbonyl]—2,4-difluoro-
phenyl]pyrrolidine-l-sulfonamide (P-0269)
N-[2,4-difluorQ-3 -[5-(2-methoxythiazol-S-y|)- I H-pyrr010[2,3-b]pyridine
carbonyl]phenyl]pyrrolidinesulfonamide (P—0270)
(3 R)-N-[3-[5-(2-cyclopropylpyrimidin-S-yl)-1 H-pyrrolo[2,3-b]pyridine-3 nyl]fluoro-phenyl]-
3 —methy1-pyrrolidine-1—sulfonamide 1)
N-[3-[5—(2-cyclopropylpyrimidin—S-yl)-I H-pyrrol0[2,3-b]pyridine-3 nyl]fluoro-phenyl]-3—
(methylamino)pyrrolidine-1 -sulfonamide (P-0272)
N-[2,4-difluoro[5—(4-pyridyl)-1H-pyrrolo[2,3-b]pyridinecarbonyl]phenyl]pyrrolidine-l-
sulfonamide (P-0273)
N-[3-(5-Cyclop1‘opyl-1 H-pyrrolo[2,3—b]pyridinecarbonyl)—2—fluoro-phenyl]pyrrolidine~l -
sulfonamide (P-0274)
3-[3 -[[ethyl(methyl)sulfamoyl]amino]—2,6—difluoro-benzoyl][2-(4-hydroxy-I -piperidyl)pyrimid in—S-
yl]-1H-pyrrolo[2,3—b]pyridine (P—0275)
-[3-(1 -cyanocyc10propyl)pheny1]—3-[3-[[ethyl(methyl)sulfamoyflamino]-2,6-diflu0r0—benzoyl]- I H-
pyrrolo[2,3-b]pyridine (P-0276)
—[2—(azetidin-1—yl)pyrimidin-5—yl]—3—[3—[[ethyl(methyl)sulfamoyl]amino]—2,6-difluoro—benzoyl]-1H-
o[2,3-b]pyridine (P-0277)
N-[3-[5-(2—aminopyrimidin—S-yl)-1H—pyrrol0[2,3-b]pyridinscarbonyl]—2,4-difluorophenyljpyrrolidine-
I -sulfonamide (P-0279)
N-{3~[5—(2—aminopyrimidin-4—yl)~IH~pyrrolo[2,3—b]pyridine-3—carbonyl]~2,4—difluoro-
]pyrrolidinesulf0namide 0)
N-[E-fluoro—3—[5-(4-pyridy|)-1II-pyrrol0[2,3-b]pyridinecarb0nyl]phenyl]pyn'olidine-I-sulfonamide
(P—UZSI)
N-[2,4—difluoro—3-[5~(2—morpholinopyrimidin—él—yljp-1H-pyrroio[2,3-b1pyridine
carbonyl)phenyfipyrml idine- l usulfonamide (P—GZSZ)
l 09
481177261
039363-721 1
3 —[3 yl(methyl )sulfamoyl]amino]~2,6«difluoro-benzoyl]—5—(2—flu0ro-4—pyridyl)~ 1 H—
pyrr010[2,3—b]pyridine (P-0283)
N—LA—difiuorod-[S-(2-morph01ino—4-pyridyl)- 1 H-pyrr010[2,3 —b]pyridine—3 —
carbonyl]phenyl]pyrrolidinesulfonamide (P-0284)
N—[2,4-difluoro[5-[2-(4-methylpiperazin—1-yI)pyridy1]-1H—pyrrolo[2,3-b]pyridine-3—
carbonyl]phenyl]pyrrolidine-I -sulf0namide (P-0285)
N~[3-[S-[2-(cycl0butoxy)pyridylj- l H-pyrrolo[2,3-b]pyridinecarb0nyl]-2,4-difluoro—
phenyl]pyrrolidinesu1fonamide (P—0286)
N-[2A-difluor0-3 -[5-(2—methoxypyridyl)-1H-pyrrolo[2,3-b]pyridine-3 -carbonyl]phenyl]pyrrolidine-
l-sulfonamidc (P-0287)
N-[3-[5-(2-cyclopropylpyrimidin-S-yl)-1H-pyrrolo[2,3-b]pyridinecarbonyl]-2,4-difluoro-phenyl]-
3,3-difluor0-pyrr0|idine—I namide 8)
(3 S)—N—[3-[5-(2—cyclopr0pylpyrimidin-S-y|)—1H—pyrrolo[2,3—bjpyridine—3—carbonyl]—2,4—difluoro—
phenyl]~3—fluoro—pyrrolidine—I —sulfonamide (P—0289)
methyl 2—[[3—[5-(2—cyclopropylpyrimidin—5-y!)—1H-pyrrolo[2,3—b]pyridine—3—carb0nyI]—2—flu0ro—
]sulfam0y|]propanoate (P-0291)
~[2—(dimethylamino)pyrimidin—S—ylj—3—[3-[[ethyl(methyl)sulfam0yI]amino]~2,6—difluoro—ben20yl]—1H-
pyrrolo[2,3—b]pyridine (P-0292)
3—[3—[[ethyl(methyl)su|famoyl]amino]—2,6—difluoro—benzoyl]—5 —(2—pyrrolidin—I —ylpyrim idin—S—ylH H—
pyrrolo[2,3—b]pyridine (P-0293)
N—[2,4-difluoro—3-[5—[6—(trifluoromethyl)pyrimidin—4—yl]—lH-pyrrolo[2,3—b]pyridine—3—
carbonyl]pheny|]pyrr0|idine- I -sulf0namide (P-0294)
N—[3—[5-(2—cyclopr0pyl—4-pyridyl)—1H-pyrrolo[2,3-b]pyridine—3—carb0nyl]—2,4—difluoro—
phenpryrrolidine—l -sulfonamide (P-0295)
~cyclobutyl[3-[[ethyl(methyl)sulfamoyl]amino]fluoro-benzoyl]-l H—pyrrolo[2g3-b]pyridine (P-
0297)
—cyclopropyl[3-[[ethyl(methyl)sulfamoyl]amino]fluoro—benzoyfl-1H-pyrrolo[2,3-b]pyridine (P-
0298)
N-[3-[5-(6-amin0pyrimidiny|)-l I I-pyrr0|0[2,3 idine—3-carbonyl]-2—fluoro-phenyl]pyrmlidine-
l—sulfonamide (P-0299)
5v(4~cyanopheny1)[3-[[ethyl(methyl)sulfamoyl]amino]-2,6—difluor0-benzoyl]-IH-pyrrolo[2,3-
b]pyridine (P-0300)
3-[3—[[ethyl(lmethyl)sulfamoyl]amino]—2,6—difluoro—benzoyl]—5—[4-(trifluoromethyl)phenyij-IH-
pyrrolo[2,3-b]pyridine (P-0301)
-[3—(dimethylamino)phenyl]—3—[3—[[ethyl(m€thyl)sulfamoyl]amino]—2,6—difluoro—benzcyl]—I H—
pyrr010[2,3—b]pyridinc (P-0302)
[ethmeethyl)wlfamoyI]amino]—2,6-difluoro—ben20y11—S—(4—pyrroiidinylpheny1)— I H
pyrrolo[2,3~b]pyridine (P~0303)
1 10
4811-7918—7726.1
03 9363—721 1
2-[4-[3—[3-[[ethyi(methyl)sulfamoyl]amino]—2.6-difluoro—benzoyl]—1H-pynolo[2,3~b]pyridin—S-
yUphenyU-S-methyl-1,3,4-0xadiazole (P-0304)
2-[4-[3-[3-[[ethmeethyl)suIfamoyl]amino]—2,6-difluoro-henzoyl]-I H-pyrrolo[2,3-b]pyridin-S-
y!1phenyl]-5{methylamino}1,3,4-thiadiazole (P—0305)
3-[3-[[ethy‘l(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]—S-{5-( 1 -hydmxymethyl-ethyl)
pyridyl]—1H-pyr1‘010{2,3-b]pyridine (R0306)
3{3-methyl(methyl)sulfamoyl]aminoj—2,6—difluoro-benzoyl]—5—[6-( 1 —hydroxy— I —methy1-ethyI)—3—
pyridyl]-1H—pyrrolo[2,3-b]pyridine (P—0307)
diethyla.mino)phenyl][3-[[ethyl(methyl)sulFamoyl]amin0]-2,6-difluoro-benzoyl]—IH-
o[2,3-b]pyridine (P-0308)
3-[3-[[ethyl(methyl)sulfamoyl]amino]—2,6—difluoro-benzoyl](2-oxoindolinyl)—1H-pyrrolo[2,3-
b]pyridine (P-0309)
3—[5-[3-[3-[[ethyl(methy1)sulfamoyl]amin0]-2.6-difluoro—benzoyl]-lH-pyrrolo[2,3-b]pyridinyl]
thienyl]methyl- 1 ,2,4-oxadiazo[e (P-0310)
2-amino-6—[3 -[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]- l H-pyrrolo[2,3—b]pyridin-S -
yl]quinazoline (P-0311)
N-cyclopropyI-S-[3-[3-[[ethyl(methyl)sulfamoyl]amin0]—2,6-difluor0—benzoylj-1H-pyrrolo[2,3-
b]pyridin-S-yl]pyridine-Z-carboxamide (P-0312)
2-(dimethylamino)[3-[3-[[ethyl(methyl)sulfamoyl]aminol-Z,6-difluor0-benzoyl]-1H-pyrr010[2,3—
bjpyridin-S-yl]quinazolinc (P-0313)
3-[3—[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyI]-5—[4—( l —hydr0xycycIopropyl)phenyl]—I H-
0[2,3-b]pyridine (P-0314)
-[3-[3«[[ethmeethyl)sulfanloyflamin0]—2,6-difluor0-benzoy]]-1 H—pyrmlo[2,3-b]pyridind-ylhhiazole
(P-0315)
4-[3-[3-[[ethyKmethyl)su1famoyl]amino]—2,6-difluoro-benzoyl]-I H-pyrrolo[2,3-b]pyridinyI]-2‘(1 -
y-l -methyl-cthyl)thiazole (P-0316)
3-[3- nethyflmcthyl)sulfamoyl]amino]-2,6—difluoro—bcnzoyfl—S~(6-methoxypyridazin-3 H-
pyrrolo[2,3-b]pyridine (P-0317)
N-[2,4-difluoro[5-(6-morpholinopyrimidin—4—yl)—1H—pyrrolo[2,3—b]pyridine—3-
carbonyl]phenyl]pyrrolidine-1 -sulfonamide (P-03l8)
N~[2,4-difluom[5-[6—(4-methylpiperazin-1—y!)pyrimidinyl}~1H-pyrroloEZJ—b]pyridine-3—
carbonyUphenyl]pyrrolidine- i -squonamide (P-0319)
(3S)-N-[3~[5-(2~Cyclopropylpyrimidin-S-yl)~ l H-pyrrolo[2,3-b}pyridine—3-carbonyl]—254-diflu0r0-
phenyl]methyl-pyrrolidincsulfonamidc (P-0320)
N-[Z—fluoro—S —[5~(6—m0rpholin0pyrimidin—4—yl)-I olo[2,3—b}pyridine~3—
carbonyl]phenyl]pyrrolidine-1~sulfonamide (P-0321)
N—[Z—fluor0~3 ~[5-[6-(4—methy1piperazin~1-y1)pyrimidin—4»yl}~l olo[2,3-b]pyridine~3-
carbonyl]phenyl]pyrr01idine—1 ~sulfonamide (P—0322)
1 1 1
4811~7918-7726.1
039363-7211
N-[Z-fluoro[5—[6-(4-methylpiperazin—1-yl)—2-pyridyl]—l H—pyrrolo[2,3-b]pyridine
carbonyl]phenyl]pyrr01idine-l-sulfonamidc (P4824)
N-[Z-fluoro-3 -[5-(4-methoxypyrimidin—Z-yl)— I H-pmoloI2,3-b]pyridine-3 -
carbonyl]phenyl]pyrrol id inesulfonamide (P-0325)
N-[2-fiu0ro-3 -[5—(4-mcthylpyrimidin—Z—yl)— I oio[2,3—b]pyridine~3 —carbony1]phenyl]pyrr0lidine-
1—sulfonamide (P-0326)
(3R)-N~[3-[S-(Z—cyclopropylpyrimidin-S—yl)—1H-pyrrolo[2,3-b]pyridine—3—carbonyl]fiuoro-phenyl}~
3—fluoro—pyrrolidine- l -sulf0namide (P-0327)
[S-(Z—cyclopropylpyrimidin-S-yl)—1H-pyrrolo[2,3-b]pyridinyl}~[2,6-difluor0~3-
(methylsulfamoylamino)phenyl]methanone (P-0334)
[5-(2-cyclopropylpyrimidin-S-yI)-1H-pyrrolo[2,3-b]pyridinyl]-[3-(ethylsulfamoylamino)-2,6-
difluoro—phenyl]methanone (P—0335)
-(2-cyclopropylpyrimidin-S-y1)[2,6-difluor0(su Ifamoylamino)benzoyl]- I H-pyrrolo[2,3-
b]pyridine (P-0336)
N-[3 -[5 —(4—chlorophenyl)—1H-pyrrolo[2,3—b]pyridinc—3—carbonyl]—2,4-difluoro-phenyl]butane
sulfonamide 7)
(3 R)-N-[3-[5 -(2-cyclopropylpyrimidin-S-yl)-1 H-pyrrolo[2,3-b]pyridine-3—carb0nyl]-2,4—difluoro—
]—3-fluoro—pyrrolidinesulfonamide (P—0338)
N-[3-[5 -(2-cyclopropylpyrimidinyl)-1H-pyrrolo[2,3-b]pyridinecarbonyl]—2,4—difluoro—phenyl]—3 -
fluoro-pyrrolidine-l -sulf0namide (P—0339)
yclopropylpyrimidinyl)[2,6-difluoro[[methyl(2,2,2-
trifluoroethyl)sulfamoyl]amino]benzoyl]-1H-pyrrolo[2,3—b]pyridine (P—0340)
N~[3{5—(2-cyclopropylpyrimidin-S-yl)-1H-pyrrolo[2,3—b]pyridine-3~carb0nyl]—2,4~diflu0r0-
phenyl]butanesulf0namide (P—0342)
-[3—[3—[[ethyl(methy1)sulfam0yl]amino]—2,6—difluoro-benzoyl]- 1H—pyrrolo[2,3—b]pyridin-S-yl]—2—
methoxy-thiazole 3)
3-[3 -[[ethy1(methyl)sulfamoyl]amin0]-2,6-difluoro—benzoyl]—5—(1H-indazolyl)-1H-pyrrolo[2,3—
b]pyridine (P-0344)
N-[2,4-difluoro-3 —[5—(2-pyrrolidin—I—y1pyrimidin—5 -y1)— 1 H—pyrro10[2,3-b]pyridine
carbonyl]phenyl]pyrrolidine—I namide (P—0345)
N-[3—(5-cyclobutyl-1H-pyrrolo[2,3-b]pyridinc-3 —carbonyl)-Z-fluorOsphenyI]pyrrolidinesulf0namide
(P-0346)
N-[Z-fluom—B-[5-(2-methoxypyrimidin—S~yl)»1H-pyrrolo[2,3-b}pyridine—3—
yI]phenyljcyclopropancsuIfonamide (P-0347)
1“allyLN—[B—(S—cyano-IH-pyn‘olo[2,3—b]pyridine—3-carbonyl)—2,4—diflu0ro~
phenyl]cyclopropanesulfonamide (IF-0348)
N~[2,4-difluom-3{5-(2-methoxypyrimidin~5-yl)~1I'prrroloflfi~b}pyridine—3‘
carbonyl]phenyl]cyclopropanesulfonamide (P—0349)
] 12
48117726.1
039363-7211
N-[2,4-difiuoro—3-[5—(5-methoxy—3—pyridyl)—1H—pyrrolo[2,3-b]pyridinc
carbonyl]phenyl]cyclopropanesulfonamide (P—0350)
N-[3—(5-cyano-l H-pyrrolo[2,3-b]pyridi116carbonyl)—2,4-difluoro-phenyI]eyeIopropanesulfonamide
(P-0351)
The following table provides structures of certain compounds of the present ion and observed
mass. 1H NMR Spectra were tent with the structures of the compounds.
Compounds T M80381) [NH-WT
No. observed
O //\ Q\ //
P-0012 01
/ N/S\(”\ 428.9
I \ F H
CI 0 /
Q //
/ ”Ark
13-0013 0. / 504.9
Qti\ F H
F [-
/o .”\ 0% ‘31 K 9-0014 N /
/ ire/”x 503.0
F H
1 \\/
F i“
. °\ C 0,,0
P-0015 F
. 551.1
1 \> F N111”,“ Q
N S 1
1 l—
0. r/
/ 113%:N\ 410 9
P-OOlB '
1 \ F H
\\N m
c: o
\ [’3 0 K E V -/
1 /\ N \\$\/N\
f T“ 4890
P—0019 F H ‘0 '
i ‘N’AN
H
g E
» J‘! O / ,
i If y E “ ’1\ Q‘s/Hr
i \v’ p I N” \
' 4351
9-0020 1?“? F H ‘o ‘
......... d .1- _- __.._L _._. _
T OX //
Km/fix/QWA‘ FflNH 317.0 and 519.0..
P-Q021 ”WAN? 0:35)“)
. 1
g i H (”\- E
1 i v
1 1
4811-7918—7726.1
-7211
Arm if”? 0
fitéim 528'1
9-0022 p \ F'
J‘N Q ‘\__j
MW "/0 ~
\ 4 ~»5\ 4029
P-0023 .wa "
x A K)
W a
5323
“4......”
497.0
13-0025
m _ .1
/ \S
P0026 /; \> F u“ N, 457.0
i 4635
P-0027
439.5
110028
454.5
P0029
’/ 04%\ '1 M A : 1.4"” S
13-0030 5” '54 483‘”
QNAN/
+—~—-— —r————————-——m~—
4: W K P-0031 x / , m 478.5
4811791847261
-721]
454.5
P—0032
P—0033 468.2
P-0034 471.5
P-003 5 457.5
P—0036 453.1
P—0037 439.2
P-OO4O 499.0
P—0041 603.6
454.0
4811—7918—7726.1
039363—7211
0 KI
\ I
-A ’11 \\All
D1 W ,.
_ 44 N / \NH,OHS“ N\h) A. «Va 75
> Z I: \ aF
/ N ,NH
y...
\ /.
rll Ox
D1_W45 vN \A , 1F / .INxv 4 000 5.
1 1:
NH KYHO
N NH
IN FA
\ \/
:1: \
PAM046
N,V OV/ .N
/ .. 9 6w
/ 3 50
F .NH Arno
\N/ \/_NH
D1my0M 1A3K/V OV/ \ Ox INj» 5 09. 0
/ N,
\ F .L/aHO
D10.0W 507.0
D1nw0m.) 520.0
/v x
DJ nw0m” ous
IF w 0 B0.0
WIN ’HO
K 0
DI0.ON -N .
/ Q!/ ‘ Oncw\, /N\ %3 . I.
/ N
WIN F |
Q A,
K 0V.w/A\ 4
PRuO9. 1
[1:27; ,.
x 1|. 0
A?14 \.N , %
/OHSU /N\ .
> o
N N
_ _ J _
F-..) A,
v 0V1f K \/
P0M3 La 1 OHS\, /N\ mm. 00 0.
/v / ,N
F \o
\ -éN\x
4811—7918—7726.1
-7211
13—0054 494.0
11-0055 504.1
P-0056 \ 469.0
1 § F
A/ \ //
9-0057 4' 21 / 497.0
\414
P-0058 {{ / Hr’K 495.0
P-0059 522.0
P-0060 508.0
P—0061 518.1
/ "j ‘
P-0062 flf ,, E N 5/1412 483.0
1 1
1 4/
P'0063 \\/'\///'\\ /\8 §/N\/I 465.0
4/6 .
P-0064 4,45%“. V4.43 496.0
48117726.1
”Em/”K RACE :3
P0065
"Ami é N-grj 486.0
{N{)\N’ O “K
0 0
/ \r‘ x 7 o
P-OO66 13/
\_ E (‘44; 0 514.0
in/ 0 fl“
/O ‘N\ O O
P-0067 4 ,4 468.0
'10 F, Fifi
P«0068 471.0
1 OVQ 0 P~0069 Mia‘4» 489.0
§N N J—
P-0070 1 LNF< 499 0
(N/Q (3‘00 1
13-0071 1m N481“’K 503.1
N N
/c>\fi,uk 0 Q
9-0072 4 /
. 1.5430 513.5
4 1,} F
19-0073 J1QAQW 515.1
/“ivI r;-
90074- MEI/I 1/; ‘ fig:110,6 5110.
\> F
N N
481177251
039363 _7211
0/ N\ 0 i
i \\ \uUn
P \V/N,
_0m5 N/V1 40/
/ W
«IN .\
Q/ F 08800
\-AN
iN/ V,
\ 1
i vii \ /
Primm6 .N‘xv
/v\l,\,N QnVnO //N A.9
f \/ .F W \
N N O
#V VhN \\E On
P0077 /
x \ l.»/:.\//« \N "Nit 5 1
I \/ \
\N ,N N/\
. M.mmNNm. r w __ i
N 0
P0.0 7 00 aN i J/ fl
/ \ /F N N_
i CHANG \
\N N
P“M079 fi
o ,I \
\ ol/l
0m ////N
P0 I /
i. M.
/ N N\
\ F
i. ovvflio
\N N
II \ 0/,
N N o
P00 00 I #V I /
N \WA rN /!N\ mm
V onvuo
InI\ F N
N N
V ViN \i 0%: r// 0..
PnuOm / w flN\ M).4
,lN \K/ F \V“0
: N
o N o
/ II
Pam0WM. VunN \xi, \./A
x woN\ zlu 1..
,i,\\../inInk
/r/F
\./N
ll. iiv q _M M
wm _ m ,H +,
«Af\ ‘\
N A/\..\
\\ Q /.:.
illiiili C
nu00M iil MUM /03A 1!
v vlkx YLtN
,N ,/N\ mu.
A/ P Lono
4811791817261
039363-7211
AwN o :1. \ j,
D...o0 no 5 IJN \\,2/ / CJ 2 J
V T/
\ w
ILA \
ouyuo
\N M
111!
AW [I
N& o
9 \ 113
Po.O86 (K. 09 .J
A!K:
A rV 5
LIAN \
1:. ,ao
§ N
AW o
, f/
\ \V Q o x,
P0.0 co 7 tN / ,N
4942
l \ F Laoix
N N
0/ o ./ \
v! x F/
/ x
Po08oo IN N
/ W.ouvuo F 5 1 9 5.
I! \ F
\N N
D:mm 0 oo9 46 l J
”\v /
Pmm090 N,
/ NGus“ O 490 5.
IN\ F
”Q /
VIM»ul 0
PoO9 1
/ QuqnuA N O 4MM5
\/ F
\ IN
V1N\ \
V, On
D]n092 IN N,
3/ /«\./N Q
Auo 4
// 8 1 5.
\\ l I
Nflltflil I
x \ ,1
PawO93 \w/ ,N a
11» \\ I Onh/Auo {m \l/ 49 L 5
IL. V
1 \/N
............... \ Fx
aw094 tN of“ 9 ovqfluo,N, P / A
/ N 3 4M. 5
‘L ‘x/ :.
/N w
4811-7918—7726.1
-7211
P—0095 534.5
P-0096 466.5
P-0097 455.5
[3-0098 465.4
P-0099 465.5
480.5
P-OIOI 479.5
479.0
497.5
P-0104
4811391877261
039363—7211
xjsz\, ,A
0}61/10\ \ 5913/03l,’ o
9-0105 523.6
L§ kN; t
-+ L
/N\l,¢N (3le O I
9-0106 #0 *' »% 3%,N 484.5
§ o
§ N}
(:14 2‘
N o
/ /
P0107 I \ ‘9‘ "
" N\ N/E‘J‘J‘K 51., 06
| \ F
\h IN
Wmfl. -.......................
ON ’
N o
/ \ / ’
P—0108 1i A Q IRSJ 524.6
/ N
I\ ‘85 \
\N N»
L m.-
\/N ,
P—OIO9 TA OV’Q
/ 2 ”$53 536.6
k“ 'N§ 0
P—OllO /\ ‘
\ 9 / 489.3
P0111
90112 W
\ ’gm’ 495.5
I \
\ F N
\\ \
N, N, O
AY\ 0\ i»
i ‘y/\ / 2 /
P—Ol 13 NV;\/%> F'r/l N’fi/ \ ' 480.1
Llfiw/JLN’ O
+ +
A /
A O
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P—0224 484.5
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4811~7918~7726 1
039363-7211
[02961 The following compounds are also prepared according to the protocols set forth in Examples
1, 2 and 4—9 and Schemes l, 2 and 4—9. The data from the 1H NMR and mass spectroscopies are
tent with the structures ofthc compounds.
TableS
1 Compound Name ure
1 No. (MS(ESI) [MM-FT)
1.“.
oro-3»— .,,
(phenylsulfamoylamino)phenyl]—[5—(2— ”3/ °
~. :1 9‘ Q7
13-0113 methoxypyrimidin—S—yl)—ll-l—pyrrolo[2,3- /
I“ J WEN»
b]pyridinyl]methanone "h
l 1
3-[2—fluoro—3— {a}
[[mcthyl(phenyl)sulfamoyl]amino]benzoyl] /°\(\ °\ :5)
' ‘1" V
P-Oll‘) (2-methoxypyrimidin—S-yl)—lH- /
I \ F'AQ'E’K
pyrrolo[2,3—b]pyridine ‘N t:
L(533.1)
[2-fluoro-3—(3- /
pyridylsulfamoylamino)phenyl]—[5—(2- /° 1N‘\ O Q
(3‘ Q”
P-Ol20 methoxypyrimidin-5—yl)—lH-pyrrolo[2,3— var
u'i’mu
b]pyridinyl]methanone \
(520.1)
3-[2-fluoro—3—[[methyl(3~ ’AN
pyridyl)sulfamoyl]amino]benzoyl]-S—(2— /° 1-K R (/1 \ 4’
P—OlZl methoxypyrimidin—S—yl)—1l~I-pyrrolo[2,3- ” /
,. |'\ g wik
b]pyridine \
4 (534.1) I
[2-fluoro—3—(thiazol—5- <N§l
amoylamino)phenyl]-[5-(2- ”WT‘ Os C’; 0 Vs
P0122 methoxypyrimidin—S-yl)—lH-pyrrolo[2,3- ' /
1/ |~\> F HN/fi‘H
b]pyridin—3—yl]methanone (526.1) \‘ a
fluoro—3—[5—(2—methoxypyrimidin-S-
yl)-lH—pyrrolo[2,3—b]pyridine-—3- 7
O N O :1
/ Y:
9—0123 carbonyl]phenyl]sulfamoyl—methyl- a \ Q5“
amino]thiazole :XLS H ‘1‘)
112419.11 "
[3-(oyclopentylsulfamoylamino)fluoro-
phenyl]-[5-(2-methoxypyrimidin-S-yl)-lH- /0 1K 0
. (I 1/
b-0124 pyrrolo[2,3-b]pyridin—3-yl]methanone Nx/kf rufiwm
' \> F
(511.1) \N. 5
“743'
l[cyclopcntyl(mcthyl)sulfamoyl]am1no]—2-
/0\T,N% 2384/3“? <1“)”W 1
P-OIZS
1 1 fluoro-benzoyl]—5-(2—mcthoxypyrimidin-5— ,‘EWLW, ~
’ \F’JNM\%,N‘\
yl)—lH—pyrrolo[2,3-h]pyridine Q‘s/Ar} " H
(525.2) H
l .4
clopropylsulfamoylamino)fluoro-
phenyl]—[5-(2-methoxypyrimidin-S-yl)-1H- / \Y«\ \> :/ 0 l7
P3126
1 pyrrolo[2,3—b]pyridin—3—yl]methanone NV ‘/\/\ ”LIE/NH
i \ F H
. 1
(483.0 \‘JW/ D
4811—7918—7726.1
039363—7211
[2—fluor0-3{tetrahyéfiopyran-Zl- fig)
y!su1famoylamino)phenyl]-[5—(2— /0
T3,, 0 V
P—0127 methoxypyrimidin-S—yl)—1H-pyrrolo[2,3— k/
/ Y3 :- Ny‘lsrifi
' H
b]pyridinyl]methan0ne (527.1) 0
\ ,)\
“'MMMW 3
3 M3~[2-fifibro-3133methy1(tetrahydropyran—4— [AK
3y1)sulfamoyl]amino]benzoyl]~5—(2- fovk \lj
P-0128 methoxypyrimidin—S—yl)—IH-pyrrolo[2,3~ 1‘ / >45}
/ “N935”:
idine. m 1., 0
(541.2)
“ 3
3v[2-fiuoro—3-[[2- .
fluoroethyl(methyl)sulfamoyl]amino]benzo ”vg O Q
c: H
3 P'0129 yl]—5-(2-methoxypyrimidin-S-yl)-1H- N ,/
3 \> F1
11 {YER
1 ~pyrrolo[2,3-b]pyridine (503.1) 3 \WN
3-[2-fluoro[[methyl(2,2,2- F
trifluoroethyl)sulfamoyl]amino]benzoyl]—5- ”
/0 . 0
\E/ W\ / 7F
p-0130 (2-methoxypyrimidin-S-yl)—l H-pyrrol0[2,3- is;
b]pyridine > H é
(539.1)
311uoro—3—u3—
fluoropropyl(methy1)sulfamoyl]amino]benz ”OY'K ,
O F2
P—0131 oyl]—5—(2—methoxypyrimidin—5~yl)~1H— W
3 figk
pyrrolo[2,3—b]pyridine
—chloro—3—[2—fluoro[[2— 0,,
methoxyethyl(methyl)sulfamoyl]amino]ben 0‘ /
P'0132 zoyl]-1H-pyrrolo[2,3—b]pyridine 39.33: ”\
(441.1)
-chloro[2-fluoro—3-[[3-
fluoropropyl(methyl)sulfamoyl]amino]benz
P—0133 oyl]-1H-pyrrolo[2,3—b]pyridine
(443. I)
3-[2-fluor0-3 -[[3-
fluoropropyl(methyl)sulfamoyl]an1ino]benz /Rl/
P-O134 oyl](2—isopropylpyrimidin—S—yl)— l H—
pyrro]0[2,3-b]pyridine
(529.2)
3-[2-fluoro[[[ 1 —
(methoxymethyl)cyclopropyl]-methyl- /K®
p.0] 3 5 sulfamoyl]amino]benzoyl}-5—(:2-
isopropylpyrimidin—S—yl)—1H—pyrrolo[2,3-
b]pyridine (553.2)
S-ch10ro—3—[2-fluoro~3-[[[1~ 3
xymethyl)cyc10propy11-methyl—
P-0136 su1famoy1]amino]benzoy11‘1H—pyrr010[2,3— f
3 b]pyridine
3 467.1
-chloro—3-[3-[[2-
cycl0propylethyl(methyl)sulfamoy|]amino]
P-0137 r0—benzoyl]-1H—pyrrolo[2,3-
b]pyridine
3 (45 1 . 1)
4811-7918~7726,1
039363—7211
3—[3-[[2—
cyclopropylethy1(methy1)sulfamoyl]amino] g)
P—0138 { —2—f‘1u0r0-benzoyl}-S-(2-
1 isopropylpyrimidin-S -yl)- l H—pyrr010[2,3-
b]pyridinc (537.2)
”1"5—chloro—3-[2-fluoro-3_[[[1-
(hydroxymethyl)cyclepropyl]methyl- Ox cm» 4
P-0139 methyl~suIfamoyl]amino]benzoy1]—1 H- ‘7
C. 2&4 N513, wk \
pyrrolo[2:3-b]pyridine (467.1) ;m F H ‘5
gm L i H
M...
methyl 1-[[[3—(5-ch10r0-1H-pyrrolo[2,3- O _,
b]pyridine-3*carbonyl)fluoro- ‘
o ’3
’ P-0140 phenyl]sulfam0yl-methy1— \ / N’LK$0
am1110]methyl]cyclopropanecarboxylate L: 1:) F H ‘5
cyanoethyl(methyl)sulfamoyl]amino]—2-
P—0141 benzoy1]-1H-pyrrolo[2,3-b]pyridine
(43 6.1)
L A
r(5—chloro—1H—pyrroloLZ,3—b]pyridinyl)—
ro—3 —(3—
P—0142 ypropylsuIfamoylamino)phenyl]met
hanone
44 I .1
N-[3 —(5 ~chloro-1H—pyrrolo[2,3cb]pyridine~
3—carbonyl)—2—fluoro-phenyl]—4—methyl-
P—0143 zine— 1 -sulfonamide
(452. 1)
—chlor0—3 —[2-flu0r0—3—[[(2—hydroxy—2-
methyl—propyl)—mcthyl-
P—0144 sulfamoyl]amino]benzoyl]- 1 H-pyrrolo[2 ,3 -
b]pyridine
(455.1 g
—chloro—3 -[2-fluoro-3—[[(2-hydroxy- 1 , 1 -
dimcthyl—ethyl)-methyl-
sulfamoyl]amino]bcnzoyl]-1H-pyrrolo12,3-
P-0145
b]pyridine
(455. 1)
N—[3 -[5-(2—cyclopropylpyrim idin-S-yl)-l H-
pyrr010[213-b]pyridine-3 —carbonyl]—2—
P—O 146 fluoro—pheny1]azetidine— l -sulfonam ide
(493 . 1 )
N~[3~[5—(2—Cyclopropylpyrimidiny1)-1H—
pyrrolo[2,3—b]pyridinecarb0nyl]
P-0147 fluoro—phenyl]—3 -flu0ro—azetidine— 1 —
sulfonamide
(51 1.1)
5—(2—cyclopr0pylpyrimidin-S—yl)—3—[2-
fiuoro—B—[{methy1(0xetan—3‘
P—0148 famoylhminojbcnmyl}1H- ‘
pyrrolo[2,3—b}pyridine I?”11.21
3 (523.1)
4811—?918~??26.1
039363-7211
3-[3-
.5. m
[[cyclobutmecthyl)sulfiimoyl]amino] 0\ q
. LAX/“y! \:> [3/5
P-0149 fiuoro—benzoyl]-S~(2~cyclopropylpyrimidin- N /‘
\ F' \N \ffiWNx
I H
. . 2 \3
-y1)-1 H-pyrm10[2,3—b]pyndme ’ \NAN/ ‘r“,
521.2 '
-ch10r0[2-flu0r03-
, /o\‘
[[methyl(tetrahydrofuran—3- 0
C) 0 ;\,.J
P-0150 y])su1famoy1]ami1101benzoyl}1H- 3’
/ {4% F ’g"%&)’”\
pyrr010[2,3-b]pyrldme \N 11
(453.1) 1
—ch10r0-1H-pyrr010[2,3-b]pyridine- \
3-carb0ny1)fluoro-phenyl]methoxy- o 9’) ‘3
P-0151 pyrrolidine-l -su1fonamidc ck)? \ fiu’g’flj
(453.1) \\ " 0
N-[3-(5-chlor0—1H-pyrrolo[2,3-b]pyridine-
3-carbony1)fl uoro-phenyl] NH
0 rp/
P-0152 meth lamino rrolidine-l-sulfonamide . W{KN/m
N—[3—(5-chlor0-1H-pyrrolo[2,3-b]pyridine- 1
3—Carbony1)—2—fluoro—phenyl]-3— «1..
P-0153 (dimethylamino)pyrr01idine—1—su1f0namide c. §\’/4 (LU
(466.1) f L»? F M
—r—- w
N-[3—[5—[6-(1-cyanocycl0propyl)—3-
pyridyl]-1H-pyrrolo[2,3-b]pyridine {’K onO / F’\
P—0154 carbony11—2-fluoro-pheny1]pyrrolidine /
1/ /\> F N’i’k/
sulfonamlde \N/ .11
(531.2) mm“ ”w u,“
3 —[2—fluoro—3 -(pyrrolidin-1 -
ylsulfonylamino)benzoyl]—1H—py1‘r010[2,3- ”2"“ N\ O O
b]pyridin~5-yl]—2— o
“0155 / A MO
pyrl y ]cyc opropanecar exam:'d1 1 b 'd f \ F M
6 "N/LN’
(549.2) H
M""""""""""""""" M1—[5-[3—[2-fluoro(pyrrolidin ‘ ”W”
ylsulfonylamino)benzoyl]~lH-pyrrolo[2,3- ”
HO N\\ O\ / ‘
P-0156 b1pyridiny11 é ' A
/ . Wigs/O
pyridyl]cyclopropanecarboxylic acid K A? F H ‘0
(550.2) N
1-[4—[3-[2-fluor0—3-(pyrrolidin
_ r7
éylsulfonylamino)benzoyl]-lH-pyrrolo[2,3- W
0W0 0 F‘
P-O1S7 ‘b]pyridin-5— o ’/
- /\/< WWMVB H
.. 1 ‘o
* > yuphenyl}cyclopropanecarboxamlde VIN,
4548.2) H
3-[2-fluor0—3-(pyrr01idin
‘ "0);?! ¢\
y1su1fcmylaminofluenzoyl}1H—pyrr010[2,3- '\ O§J\ g‘ g (“”3
MISS 0
I b]pyridin-S- ‘v Ara) F 347%0 ‘ ny1]cyclopropanecarboxylic acid 5:)ij
1548.2) 4
i 3-[3«(dimethylsu1fam0y|amino)fluoro~
{ r?
benzeyl]=5~(5-methoxypyrazinyl)-1H» /’ “jg/N:
, Dir/klzi % :1,
1 13—0139 pyrr010[2,3—b]pyridine ”V/ [mg/g) F, 3’32? \
i ) ‘
, wk»):
481 1‘7918v772611
039363—7211
dimcthylamino)pyrazin-2—y1][3—
hylsulfamoylamino)—2—fluoro-
P—0160 benzoyl]—1 H—pyrmlo[2,3—b]pyridine
(484.2)
3—[3 —(dimethylsulfamoylamino)—2—fiu0r0-
benzoyl]~5—(6-meth0xypyridazin—3 -y1)— 1 H-
P~0161 ! pyrr010[2,3-b]pyridine
(471 . 1)
4—[5-[3—[3—
[[ethyl(mcthyl)sulfamoy1]aminoJfluoro«
13-0162 benzoy1]-1H-pyrrolo[2,3-b]pyridin
yl]pyrimidiny1]morpholine
(540.2)
-chloro[2-f1uoro[[(4-f1uorophenyl)-
methyl-Smfamoyijamino]bcnzoyl]-1H-
P-0163 pyrro1o[2,3-b}pyridine
(477.1)
3 -[3 yl(methy1)sulfamoyl]amino]
fluoro-benzoyl]—5-(1 -methylpyrroly1)—
P-0164 1I‘I-pyrrolo[2,3-b]pyridine
(442.1)
3—[2—fluoro—3 —
[[mcthyl(propy1)sulfamoyl]amino]benzoyl]
P—0165 (1-methylpyrazolyl)—1H-pyrrolo[2,3-
b]pyridine
(47 1 .2)
S—[3—[3—[[ethy1(methy1)sulfamoyl]amino]—2—
fiuoro—benzoyl]—1H-pyrrolo[2,3-b]pyridin— 1
P—0166 5—yl]thiazole (460.1)
3—[3—[[ethyl(methy1)sulfamoyl]amino]—2—
fluoro—benzoy1]-5—(1~methylimidazol—4-yl)—
P-0167 1H-pyrrolo[2,3—b]pyridine
(457. 1)
4-[3—[3—[[ethmecthstulfamoyl]amino]
fluorO—benzoyl]—1H—pyrrolo[2,3-b]pyridin—
P-0168 5-y1]0xazole _
(444.1)
1 ifluom _*T“
(phenylsulfhmoylamin0)phenyl]-[5-(2-
P-0169 methoxypyrimidin-S-yl)-1 H-pyrr010[2,3- 1
J (537.1)b]pyridiny1]melhanone
3-[2,6-di11uoro
[[methyI(phenyl)sulfam0yl]amino]benzoyl]
P-0170 -5—(2~methoxypyrimidin-S-yl)-1H-
. pyx‘rolo[2,3-b]pyridine
, )
48117726.1
039363—7211
[2,6~diflu0ro-3 ‘(3—
pyridylsulfamoylamino)phenyl]-[5~(2-
P—Ol7l methoxypyrimidin-S-yl)-1H—pyrrolo[2,3—
b]pyridin-3—yl]methanone
(538.1)
—diflu0ro[{methyl(3-
pyridyl)sulfamoy1}amino]benzoy1]—5—(2—
P-O l 72 methoxypyrimidin—S-yi)—1I<I-pyrro[o[2,3-
b]pyridine
(5 52.1)
[2,6-dif1uoro—3 —(thiazol-5—
ylsulfamoylamino)phenyI]-[S-(2-
P-O I 73 methoxypyrimidin-S-yl)—I H-pyrrolo[2,3-
b]pyridinyl]methanone
(544.1)
—[[2,4—difluoro-3—[5-(2—methoxypyrimidin—
-y1)-1 H—pyrrolo[2,3-b]pyridine
P-Ol 74 carbonyl]pheny1]su1famoyl-methyl—
amino]thiazole
(55 8. 1)
[3 pentylsulfamoylamino)—2,6—
difiuoro—phenyl]-[5-(2-methoxypyrimidin—
P-0175 5-yl)-1II-pyrro10[2,3—b]pyridin
han0ne
(529. l)
[ 3—[3-
[[cyclopentmeethstulfamoyl]amino]—
P—O I 76 2,6-difiuoro-benzoyl]—5 —(2-
methoxypyrimidin—S -yl)—1H-pyrrolo[2,3-
b]pyridine (543.2)
[3—(cyclopropylsu1famoylamino)—2,6—
difluoro-phenyl]—[5—(2—methoxypyrimidin-
P—O l 77 5—yl)—1H-pyrrolo[2,3-b]pyridin
hanone
(501 . 1)
[2,6-difluoro—3—(tetrahydropyran—4-
ylsulfamoylamino)phenyl]—[5—(2—
P-0178 methoxypyrimidin-S-yl)— 1 olo[2,3- N /
A “kg/m
b]pyridin-3—yl]methanona 1; I») F H “o H
(545.1) H
3—[2,6~difluor0-3—[[methyl(tetrahydropyran~ ?
4-yl)su1famoyl}aminojbenzoyl]—S—(2- if
,, )
O N O
/ 711:1
P—0179 methoxypyrimidin-S—yl)—]I-I—pyrrolo[2,3— V‘ng’g}?
Empyridim: m/ ‘ H ‘3»
j (559.1)
3~{2,6—difluoro-3—[[2- K
fluoroethyl(mcthy1)sulfamoyljamino]bcnzo F
/0 5% o
P-0180 1} y1]-5~(2-methoxypyrimidin—S-yl)—IH- Tfixw 7’ \ JEN/EACJ
pyrr010[2,3»b]pyridine {*m‘ I} F H ‘3)
(521.1) H
3-[2,6-difluoro-3—[[methyl(2,2,2— F
trifluorocthybsult‘ezmoy[Jamino]benzole-S- xi»
P~0181 1 (2»methoxypyrimidin-5—yl)~1I-I-pyrrolo[2,3~ ”CYN‘ 0%”; F
I N’\(//\ Avg ,A-Wg‘m:0
lb]pyridine F
I H b
\\ in;
(556.1,)
L kww
48117918377261
039363—7211
3~[2,6-difluoro~3—[[3—
fiuompropyl(methyl)sulfamoyljaminojbcnz
P-0182 oyl](2-mcth0xypyrimidin—S—yl)-1H—
; pyrmlo[2,3—b]pyridine
(534.1)
r0—3—[2,6-difiu0r0—3—[[2—
methoxyethy1(methyl)sulfamoyl]amino]ben
P—0183 zoyl]—1H—pyrrolo[2,3-b]pyridine
(458.1)
—c-hloro[2,6-difluoro-3—[[3- T
fluoropropy1(methyl)sulfamoy|]amino]benz
P-0184 oyl]-1H-pyrrolo[2,3-b]pyridinc
(561 . 1)
3-[2,6-difluoro-3 -[[3 —
fluoropropyl(methy|)sulfamoyl]amino]benz
oyl]—5—(2-isopropylpyrimidin-S-yl)— 1 H—
pyrrol0[2,3-b]pyridine
______-__.___.__L_____W .
3-[2,6-difluoro[[[1—
(methoxymethyl)cyclopropyl]—methyl—
sulfamoyl]amino]benzoyl](2-
pylpyrimidin-S-yl)—III-pyrrol0[2,3—
b]pyridine (571.2)
S—chlor0—3 -[2,6—diflu0r0-3 -[[[1—
(methoxymethyl)cyclopropyl]-methyl—
P-0187 sulfamoyl]amino]benzoyl]-1H—pyrrol0[2,3-
b]pyridine
(485. 1)
—chloro—3—[3—[[2—
cyclopropylethyl(methyl)sulfamoyl]amino]
P—0188 -2,6—difluoro—benzoyl]—1H—pyrrolo[2,3-
b]pyridine
(469. 1 )
3 ~[3—[[2—
cyclopropylethyl(methyl)sulfamoyl]amino]
P—0189 —2,6-difluoro-benzoyl]-5—(2-
i isopmpylpyrimidin-S«yl)—1H-pyrrolo[2,3-
b]pyridine (555.2)
~chloro~3*[2,6—difluoro»3-[[[1—
(hydroxymethy1)cyclopropyl]methyl-
P-0190 methyl-su1fam0yl]amino]benzoyI]-1H—
pyn‘olo[2,3~b]pyridine
(485.1)
methyl 1»[[{3—(S-Ch10ro~1H-pyrrolo[2,3-
, dinc-3~carb0nyl)-2,4-difluoro-
B0191 phenyl]su1famoyl~methyl—
ami110]methyl]cyc]opropanecarboxylate
(513.1)
ro-3 —[3—[[2—
cyanoethyl(mcthyl)su|fam0yl]amin0}-2,6-
P-Ol 92 difluoro—benzoyl]—1I1~pyrr0l0[2,3~
. {7]pyridine
1 (454.0)
4811391847261
039363—7211
(5—chlor0—1H—pyrrolo[2,3—b]pyridin—3—yl)— F 01
[2,6-difluoro—3-(3-
(km 0 rj’
P-0193 ypropylsulfamoyIamin0)pheny|]met '
C‘w 2;? “33,3'
banana 1%IQ) F H ‘2;
(459.1)
1”N-[3—(5-chlom—1H-pyrmto[2,3—b)pyridine— F
Z 3—carbonyl)-2,4-difluoro‘phenyl]—4—mcthy1—
1 GM / ‘91 F’Nx
P—0194 piperazine- 1 —sulf0namide ; ”rm/g) Fl ‘3 ”EAR/l
(470.1) g \Mfig’
1 1.1
-chlore[2,6-difluoro[[(2-hydroxy R7 0H
methyl-propyl)—methyl- oWNWC‘isrréfiI?)
P-0195 sulfamoyl]amino]benzoy1]I-pyrrolo[2,3- c1
b]pyridine mP H ‘0
(473.1) ‘
-chloro[2,6—dif1uoro[[(2-hydroxy- F
1,1-dimethyl-ethyl)—methyl- o 1") IJ
P—0196 sulfamoyl]amin0]benzoyl]—1Iv’I-pyrrol0[2,3- \
/ \W‘g,1{\
b]pyridine I N\ F H ‘33
(473.1) H
N-[3—[5—(2—cyclopropylpyrimidin—S—yl)—1 H— F
pyrrolo[2,3—b]pyridinc—3-carbonyl]~2,4— Ar \ O \r’”/
P-0197 o—phenyl]azetidine-1—sulf0namide ;
/ \,
/ Mg»?O
1 F
(511.1) H
\N/L 1:
N—[3—[5—(2—cyc10propylpyrimidin—5—yl)—1 H— 1 F‘
pyrrolo[2,3—b]pyridine—3—carbonyl]—2,4- [\(\ 0
\/2 O
difluoro—phenyl]-3~fluor0—azetidine—1— NI / ‘ {Q‘s/10’?
P—0198
/ _
sulfonamide I F H ‘c‘1
N N\
(529.1) H
—(2—cyclopropylpyrimidin—5~yl)—3—[2,6— 1 p
difluoro—3—[[methyl(oxetan—3— %~\ 0
f) 0 5:1
9 yl)sulfamoyl]amino]benzoyl]-1 H— N' / \
/ \ \N/\1§\,~\
pyrrolo[2,3—b]pyridine l F H
\ N‘
(541.1) J. N
3—[3— F
[[cyclobutyl(methyl)sulfamoyl]amino]—2,6- a?) o
\ >4 ’1
‘ /
P—OZOO difluoro—benzoyl]-S—(2-
/ \lkj‘smg/
cyclopropylpyrimidin—S—yl)‘1H— F H '2)
§ L1}
pyrrolo[2,3—b]pyridinc (539.2) H
ro-S{2,6—difluoro—3— 11V 0“,
I[methyl(tetrahydrofuran—3— 0\ C / D
P—0201 yl)su1famoy1]amino]benzoyl]o1H— CI
,\ F; HW‘=%\/N-\
F3;1}*0ic)3[2,3-b]pyridinc ‘ 19/11:: 0
A i
g 1;N*{3’(5-ch1oro-1H—pyrro10[2,3—b]pyridine- a ‘1
3~carb0ny1f)—2,4~difluoro—pheny11—3— 3 0“ 24‘) 4G
,_,~-__1 sulfonamlde' P 0202 1 “M1111
- c1 fly
1 methoxy me 1
\ waf'K/
1(4711) \NJQ F H ‘o
r-------- fl _
N-[3-(5-ch10ro—1H-pyrrolo[2,3-b]pyridine— F \
3—carb0nyI)—2,4—difluom—phenyl]—3~
Rf) 0 #5“
11—0203 (methylamino)pyrrolidine~1—sulf0namide c1 (fix/4 ‘7’ “Lg/k)
W ‘> F H
' i 7 ‘2 ’
g g (4 10,1) haw/AN"11
1 H
WJ AL -
4811—7918—7726.1
O39363~72H
N-[3-(5—chlor0—l H—pyrrolo[2,3—b]pyridine— p \
3—carb0nyl)—2,4—difluoro—phenyl]—3— 01>A? 4 O [MK/NA
P-0204 (dimathylam in0)pyrrolidine— I -sulf‘0namide c:\/\ /\ iI/“ijtsAV}
(484.1) L\ I \/ F H ‘33
N a
N—[3—[5—[6—( l cyclopropyl) F
pyridyIJ—lH-pyrrolo[2,3—b}pyridine-3~ “(/ZKNN 0‘; %> 0 F1
P—0205 yl]—2,4—difluom—phenyl]pyrmlidine- ’
UV; , 7Av3é’K/3
l—sulfonamide QNJES/ r H b
(549.1) ”
, 1-[5-[3-[2,6-difluoro—3~(pyrrolidin-l- F
yIsulfbnylamino)benzoyl]-1Il-pyrrolo[2,3- /
Hz KKK o
P-O206 NY WHY $311st
Eb]pyridin~5-yl]
pyridyl]cyclopropanecarboxamide E \DLN“ F H
(567.2)
1-[5 -[3-[2,6-difluoro(pyrr0lidin- 1-
ylsulfonylamino)benzoyl]-1lI-pyrrolo[2,3- HO
\ \ /
13-0207 b]pyridinyl] 73’ ETC/V
\ 2436.553
pyridyl]cyclopr0panecarboxylic acid K LN
L668- 1)
l-[4-[3 -[2,6—difluor0-3 -(pyrrolidin
ylsulfonylamino)bcnzoyl]-1H-pyrrolo[2,3-
P—0208 b]pyridin
yl]phenyl]cyclopropanecarboxamide
(566.2)
l-[4-[3-[2,6-difluoro(pyrrolidin
ylsulfonylamino)benzoyl]—III-pyrrolo[2,3- "’
HO 0
P-0209 din-5— \
o 1:1,"
yl]phenyl]cyclopropanecarboxylic acid : I? ‘ H ‘2:
(567.1) H
dimcthylsulfamoylamino)—2,6- K
difluoro—benzoyl]—5—(5—methoxypyrazin—2— /0 \N O\ a
l O /
P—O21O yl)-lH—pyrmlo[2,3—b]pyridine /
/ ,
\ \N,‘%\/N\
(489.1)
F H
\N 2N3
_.______..__l_____ ___E
—[5—(d{methylamino)pyrazin—2—yl][3- I F¥A
(dimethylsulfamoylamino)—2,6-difluoro- 2' \N 0\ (j 0 /
P—0211 benzoyl]-1H-pyrr010[2,3-b]pyridine NW1 [
F mfg/{K
(502.1) ;\\N EN\ H
L H
i3—[3—(dimethylsulfamoylamino}2,6~ F.
difluoro—benzoyl](6—methoxypyridazin- /°\(~\ Gym 9‘ !
P—0212 3-y1)-1H—pyrmlo[2,3-b]pyridine “x / Yflrfi F; Era/“K
(489.1) 31L??? °
T 4-[5—(3-(3-
0. .
E kmethylkulfamoyl]amino]-2,6- {V “La, ;
’ o¥flgr o
P-0213 o-benzoyl]— 1 H-pyrrolo[2,3 - {49% Fagin,K b]pyridiny1]pyrimidin-2~yl]m0rpholine kN/LN‘) F H
E(558.2) *‘
S-chloro—3-[2,6-difluoro[[(4- f
fluorophenyI)-methyl» KKK (6”,,
E P~0214 I sulfamoylkmino]benzoyl]-1H-pyrroloprj-
fl 03/),4’ §"’
E / 5’1 x
, b]pyridine \ff‘fi.
E 564950) g ”‘ u
4811—7918~7726.1
039363-7211
3—[3~(dimethylsulfamoylamin0)-2,6- 1
difluoro-benzoyl]—S-( l —methy1pyrrol~3 ~yl)—
P-0215 1 H-pyrroloLZS-b'jpyridine
(460. 1)
1 _____________________
3-[2,6-difluoro
[[methyl(propyl)sulfamoy1]amin0]benzoy1}
P 0216 (1-methylpyrazol—4—y1)—1H—pyrr010[2,3-
b]pyridine
,. $489.1)
‘[3—[3-[[ethyl(methy1)sulfamoyl]ammo]- .1
2,6-difluor0~benzoyl]—1H-pyrrolo[2,3-
P-0217 b]pyridinyljthiazole
(478.1)
3-[3-[[ethyl(methy1)sulfamoyl]amino]-2,6-
difluoro-benzoyl]—5-(1-methy1imidazol
P0218 yl)-1H-pyrrolo[2,3—b]pyridine
(475. 1)
4-[3 -[3 -[[ethy1(methyl)sulfamoyl]amino]-
fluoro—benzoylj—1H—pyrrolonfi—
P-0219 b]pyridiny1]oxazole
(462. 1)
difluoro—benzoyl]—1H-pyrrolo[2,3—
P-0220 bjpyridin-S-y1]quinoline
(508. 1)
WW4.
61513 ~(dimethylsulfamoylamino)-2,6-
difluoro-benzoyl]—1H—pyrrolo[2,3-
P-0221 b]pyridin-S-yquuinazolinc
6—[3—[3 ~(dimethy1sulfamoylamino)—2,6-
difluoro-benzoyl]—1H—pyrrolo[2,3-
P-0222 b] pyridin-S-yl]— 1 ,3-bcnzothiazole
(5 14. 1 )
48117726.1
039363—7211
Example 3: Preparation of S-cyano-S-[S-{[ethyl(methyl)sulfamoyl}amino]-2,6-difluoro»benzoyl}-
1H-pyrrolo[2,3—b]pyridine (P—0017).
Scheme 3
F F F
ok ,0 l
dimethylammopyndmei , , , U
+ C(S:N,j N\H n—BULi
F j pyridine 0:3!20
NH2 /N\/
8 10
Br :©/ / O
\ 1? i-PngCI
N +
0” 0 N11 00 mesutylmagneisum bromide. . .
//S\ //
O N
N\ (ii
\ ,. N/I/
Bess-Marlin Periodinane /l \ F NH’% \
N 1.1’-Bis(diphenylphosphino)-
ferrocene
\ /S \ F
l \ F NH ‘23
\ O W
N N TBAF
\Sao
._.__...____s. N\\
NH/\5,N\ 04 /
i \ F “O
i: :5 \
N NH
p-0017
Synthesis of I-[(ethyl(methy1)sulfamoyl)amino]-2,4-difiuoro-benzene(10): To a on
of2,4~Dii1uoroaniline (2.21 g, 17.13 mmol) in dichloroethane (10 mL) were added 4-
Dimerhyiaminopyridine (0.1 g, 0.82 mmol), I-N-methyi«su1famoy1 chloride (2.7 g, 17:13
mmol) and pyridine (2 g, 25.28 mmoi). The mixture was stirred at room temperature ght. The
resulting mixture was poured into an aqueous potassium carbonate solution, and extracted with ethyl
acetate (EtOAc). The organic layer was washed with brine, dried over sodium sulfate and filtered.
The e was concentrated and d by silica gel column chromatography using 20% to 100%
ethyl acetate in hexane as an eiuent to give th desired product (10, 3.08 g, 718% yield). MS (E51)
[M+H+]* X 250.8. IH NMR spectrum is consistent with the structure of the compound.
48113918317261
039363-721 l
Synthesis of l-[(cthyl(methyl)sulfamoyl)amino]-2,4-difluor0—3-formyl-benzene (11): To
a mixture of l-[(ethyl(methyl)sulfamoyl)amincl—2,4—difluoro—benzene (10. 3.08 g, 12.31 mmol) in
tetrahydrofnran (THF) (25.0 mL) under an atmosphere of nitrogen at -78 °C was added 2.5M nbutyllithium
i) in THF (5 mL). The colorless reaction mixture was kept at -78 °C for one hour
and 2.5M n-BuLi in THF (5.4 ml) was added to the reaction mixture. The reaction was kept at -78 0C
for 1 hr and added methylformamide (DMF) (1.8 mL, 23.25 mmol). The reaction mixture
turned into solid. The solid reaction mixture was shaken For about 5 minutes to obtain a slurry. The
reaction mixture was kept in a dry etone bath for 1 hr and was allowed to warm up to room
temperature for 1 hour. The reaction mixture was poured into an aqueous ammonia chloride solution
and ted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate,
concentrated and purified with silica gel column chromatography using 30% to 100% ethyl acetate in
hexane as an eluent to give the desired product (11, 1.10 g, 32.1% yield). MS (ESI) [M+H+]+ = 278.8.
ll-l NMR spectrum is consistent with the structure of the compound.
Synthesis of 1—(benzenesulfonyl)—5-brom0—3—i0d0—pyrrolol2,3-b} pyridine (12).
/ H
l N
/ \
Br Benzenesulfonyl chloride 043:0
To a solution of 5—bromo—3—iodo—l H-pyrrolo[2,3-b]pyridine (2.7 g, 8.36 mmol) in DMF
(3 0.0 mL) was added sodium hydride (60%, 0.37 g, 9.2 mmol) at room temperature. After 10
s, benzenesulfonyl de (1.13 ml, 8.78 mmol) was added to and the reaction e was
stirred at room temperature for 3 hours. The reaction mixture was poured in to water and ted
with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated, filtered and washed with ethyl acetate to obtain the desired product 12 as a
white solid (2.70 g). The mother liquid was purified with silica gel column chromatography using
% to 100% ethyl acetate in hexane as an eluent to give on product (0.90 g). The combined
yield is 930%. MS (ESI) [MHTT = 464.1. 1H NMR spectrum is consistent with the structure of the
compound.
{0211] Synthesis of 1~(benzenesulfonyi)—5-bromo—3-[[3-[[ethyltmethyl)sulfam0yllamino}-2,6-
difluoro—phenyl]-hydroxy—methyl]pyrrolo[2,3—b] pyridine (13):
Step 1: To a solution of 1—[[ethyl(methyl)sulfamoyl]amino]—2,4~difluoro—3—fonnyl—benzene (11, 0.76
g, 2.73 mmol) in THF (5 mL). under nitrogen at ~78 °C, was added 1M mesitylmagnesium e in
THF (2.8 ml). The reaction solution was stirred for 40 minutes.
48114918-77261
039363—7211
gen”; To 1—(benzenesulfonyl)—5-bromo-3—iodo-pyrro|o[2,3~b]pyridine (17, 1.76 g, 3.79 mmol) in
THF (10 mL), under an atmosphere of nitrogen at -40 °C, was added a solution of i-PngCl (2.0 M
in THF, 1.9 mL). The reaction mixture was allowed to warm up to 5 °C in 1 hour. The reaction
e was cooled to -40 °C and added the reaction solution from step 1. The resulting reaction
mixture was allowed to warm to room temperature in 1 hr, poured into water and extracted with ethyl
acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and
purified by silica gel column chromatography using 20% to 100% ethyl acetate in hexane as an eluent
to give the desired product (13, 1.10g, 65.4%). MS (ESI) [M+H“]+ = 614.7 and 616.7. 1H NMR
spectrum is tent with the ure of the compound.
Synthesis of 1-(bcnzcncsulfonyl)cyano[[3-1[ethyl(methyl)sulfamoyl]amino]-2,6-
difluoro-phenyl]-hydroxy-methyl]pyrrolol2,3-b]pyridine (14): To 1-(benzenesulfonyl)—5—bromo—3—
[[3-[[ethyl(methyl)sulfamoyl]amino]—2,6—difluoro—phenyl]-hydroxy—methyl]pyrrolo[2,3—b]pyridine
(13, 500 mg, 0.81 mmol) were added zinc cyanide (0.05 ml, 0.77 mmol), zinc,
tris(dibenzy|ideneacetone)dipalladium(0) (90 mg, 0.09 mmol), 1,1‘-Bis(diphenylphosphino)ferrocene
(90 mg, 0.16 mmol), and DMF (10 ml) under nitrogen. The reaction mixture was heated to 120 °C
overnight. The resulting reaction mixture was poured into an aqueous potassium carbonate solution
and ted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate
and filtered. The filtrate was concentrated and purified with silica gel column chromatography using
% to 100% ethyl acetate in hexane as an eluent to give the desired product (14, 0.20 g, 43.8%
yield). MS (ESI) [M+H+]+ = 562.0. IH NMR spectrum is consistent with the structure ofthe
compound.
Synthesis of zenesulfonyl)~5~cyano—3—[3-[[ethyl(methyl)sulfamoyl}amino]-2,6—
difluoro—benzoyllpyrrolo[2,3-blpyridine (15): To 1-(benzenesulfonyl)—5—cyano[[3—
[[ethyl(methyl)sulfamoyl]amino]—2,6-difluoro—phenyl]-hydroxy-methyl]pyrrolo[2,3-blpyridine (14,
0.2 g, 0.36 mmol) in methylene chloride (10 mL) was added Bess-Martin Periodinane (0.18
g, 0.43
mmol). The reaction e was stirred at room temperature for 20 minutes. The reaction mixture
was concentrated, and d by silica gel column chromatography using 25% to 100% ethyl acetate
in hexane as an eluent to give th desired product (15, 170 mg, 85.3% yield). MS (EST) [M+H+}T =
560.5. 1H NMR spectrum is consistent with the structure of the nd.
Synthesis of 5~cyano—3~[3-[[ethyl(methyl)sulfamoyl]amino1—2,6~difluoro-benzoyll-IH-
pyrrolo[2,3-b]pyridine (P-0017): To 1-(ben2enesulfonyl)—5—cyano-3{3-
llcthy1(mcthy|)sulfamoyljamino]—2,6-difluoro—benzoyl]pyrrolo[2,3—b]pyridine (15, 0.17 g, 0.3 mmol)
in THF (10 mL) was added tetra—n-butylamonium fluoride (TBAF) (0.19 g, 0.61 mmol). The reaction
mixture was stirred at room temperature overnight. The ing reaction mixture was poured into an
aqueous ammonia de on and extracted with ethyl acetate. The c layer was washed
with, brine, dried over sodium sulfate and filtered The filtrate was concentrated and purified by silica
4811—7918—7726.1
039363-7211
gel column chromatography using 2% to 10% methanol in methylene chloride as an clucnt to give the
product (P«0017, 74.5 mg; 58.5% yield). MS (ESI) + = 420.1. 'H NMR spectrum is
consistent with the structure of the compound.
The ing compounds were prepared according to the protocols set forth in Example 3
and Scheme 3.
S—chloro«3 —[3 -Methyl(methyl)sulfamoyl]amino]—2,6—difluoro—benzoyl]— l H-pyrro lo[2,3 -b]pyridine
(P-0012),
N-[2,4~diflu oro-3 -(S-flttoroiodo- l H-pyrrolo[2,3-b]pyridine-3 -carbonyl)phenyl]pyrrolidine- l -
sulfonamide (P-0013),
-chloro-3—[3—[[ethyl(methyl)sulfamoyl]amino]fluoro-bcnzoyl}- l H-pyrrolo[2,3-b]pyridine (P-
0018),
N—[2—fluoro-3 -(5-methyl- l I~I-pyrrolo[2,3-b]pyridinecarbonyl)phenyl]pyrrolidine-l -sulfonamide
(P-0023),
-bromo-3 -[3-[[ethyl(methyl)sulfamoyl]amino]tluoro-benzoyl]- l H-pyrrolo[2,3-b]pyridine (P—
0038),
—cyano—3 —[3 —[[ethyl(methyl)sulfam0y|]amino]—2-fluoro-bcnzoyl]- l H-pyrrolo[2,3 —b]pyridine (P-
0039).
The following table provides structures of n compounds of the present invention and ed
mass. 1H NMR spectra were consistent with the structures of the compounds.
MS(ESl) [M+Hi]"
Compounds ‘i ed
P-0012
428.9
l s
P—oms F i
I /:\ (8&0
i“ F. fi’s‘m 551.1
‘V‘fi k,
h M
90018
' (EV/7’» G
- f,
"K \L/l
CLYfI\\ F iii/$23 N\ 410};
u” , 2/
13-0023 OV4Q ago
figF rig/SEW 402.9
N/ f: [NV/i
48117726.1
039363—7211
P-0038
Ox //7/\\\
Br ..’< E’Nrf
/’ \\ 455 O
L ”R F {1/27
\NAS
P-0039 flaky/[m
“kw O K
KEN/Ig }%\w.‘js\r~\ 454.9 and 456.9
H '
O I
Example 4: Preparation of N-[3-[4-(cyclopropylmethylamino)-5—fluor0—lH—pyrrolo[2,3-
b] pyridinecarbonyl]-2,4-difluoro-phenyllpyrrolidine-l -sulf0namide (P-0016).
Scheme4.
F F
F o |\ \
F o
, I
G—ISlaep1 N
O F
_.._...... ——-—-———-————-—> p ~02
F \ F
F $32 /
“Q N
~02 H
1 2 18
F F
Step 1 -—Synthessi of 2,6—difluom-S-nitrobenzoyl chloride (2): In a round flask, 2,6—
difluoro—3—nitrobenzoic acid (5.5 g, 0.03 mol) was added 'l‘hionyl chloride (20 mL, 027 mol) and
N,N'Dimethylformamide (100 pl, 0.001 mol). The reaction mixture was placed in an oil bath at 80 ”C
for 4 hrs. All les were d and the residue was stripped from toluene twice and dried in
high vaeuo to give a yellow oily liquid (23 595 g 99%). It will be used as is
4811—7918—77261
039363-7211
Step 2 -- Synthesis of (2,6—diflnoronitro—phenyl)—(5«fluoro—~4—iodo-IH—pyrrolo[2,3—
b]pyridin—3—yl)methanone (18): In a Vial, o~4—iodo-l H-pyrrolo[2,3-b]pyridine (450 mg, 1.72
mmol) was cooled in an ice-water bath and added Trifluoromethanesulfonic acid (1.52 ml, 17.17
mmol). The reaction was stirred in an ice—water bath for 5 minutes and followed by adding 2,6~
difluoro—3—nitrobenzoyl chloride (2, 500mg, 2.26 mmol). The resulting reaction mixture was stirred at
an ice—water bath for 20 min and warmed up to room temperature. After 24 hrs at room temperature,
the reaction mixture was quenched with 5 mL of methanol and stirred at rt. for 1 hr. The mixture was
poured to the ted NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was
washed with water and brine, dried with MgSO4. The les were removed under vacuo. The
residue was suspended in acetonitrile and sonicated for 45 mins. The precipitate al was
collected by filtration and washed with acetonitrile. The desired t (18, 532 mg, 69%) was a tan
solid. MS (ESI) [M+HT= 447.8.
Step 3 — Preparation of (3—amino—2,6—difluoro—phcnyl)—(5—fluoro—4—iodo-lH-pyrrolol2,3—
b]pyridinyl)methanone (19): In a round flask, itluoronitro-phenyl)-(5-fluoro-4—iodo—
lH—pyrrolo[2,3—b]pyridin-3—y|)methanone (0.53 g, 0.001 mol) was added EtOH (50 ml) and TIN(II)
CHLORIDE (788 mg, 4.16 mmol). The reaction mixture was heated at 50 °C for over d. The
reaction mixture treated with 50 mL of water and 50 mL saturated sodium bicarbonate. Additional
ethyl e (20 mL) was added and the milky suspension was treated with celite and mixed well
before filtering. The filtrate was added by brine to give clear layers that were separated. The organic
layer was washed with water and brine and dried with MgSO4. The volatiles were removed under
vacuum. The desired product was isolated by silica gel column chromatography (EtOAc/Hexane, 0—
80% gradient) as an off—white solid (19, 365 mg, 73%). MS (ESI) [M+H+]+= 417.9.
Step 4 « Preparation of N—[2,4—difluoro—3—(S—fluoro—4—iodo—1H—pyrrolol2,3—b]pyridine—3—
carbonyl)phenyl]pyrrolidine—1-sulfonamide (P—0015): In a round flask, (3-amino-2,6-difluoro-
phenyl)—(5—fluoro-4—iodo—l H—pyrrolo[2,3-h]pyridin~3~y1)methan0ne (19, 180 mg, 0.43 mmol) was
dissolved in 4 mL of THF and added PYRIDINE (106 pl, 1.29 mmol) and pyrrolidine- l -sulfonyl
chloride (1 10 mg, 0.65 mmol). The solution was stirred at room temperature for about 90 hrs. The
reaction mixture was added water and extracted with ethyl acetate. The organic layer was washed
with water and brine and dried by Mg-SO4. 'l‘he volatiles were removed under vacuum. The desired
product was isolated by silica gel column chromatography (EtOAc/Hexane, 11-80% gradient) as a light
yellow solid (P-OOIS, 99 mg, 41%). MS ([381) [M+H’]" = 551.1.
Step 5 ~ Preparation of 4-(cyclopropylmethylamino)—5-fluoro—lH—pyrrolo[2,3—
b]pyridine-S—carbonyll~2,4~difluoro—phenyllpyrrolidine—l~sulfonamide (P-0016): To —
ro~3—(5-fluoro~4—iodo~ I H-pyrrolo[2,3 -b]pyridine~3 nyl)phenyl]pyrrolidine— l ~sulfonamide
{95mg 0.17 mmol) in isopropyl l (2 ml) was added cycloprcpylmethanamine (0.5 mL,
49.1 1mg, 0.69 mmol). The resulting solution was stirred at 90 °C overnight. The reaction mixture
4811-7918~7726.1
039363~72ll
was concentrated in vacuo and purified by silica gel on the companion with 8 g-cartridge using
EtOAcfHexane (0-65% gradient) as an . The ing product was further purified by prep
HPLC. The pure fractions were combined and were dried on a lyophilizer. The desired product was
obtained as a tan solid (P—0016, 6.5 mg, 7.6% yield). MS (ES!) [Mi-PT]+ = 494.4. HI NMRtj’l‘HF—dg)
spectrum is consistent with the structure of the compound.
Example 5: Synthesis of N-(2—Chloro{3-[2,6-difluoro-3—(propanesnlfonylamino)—benzoyl]-
IH-pyrrololz,3—bIpyridin-S-yl}-pyridinyl)—benzenesulfonamide 25
N—(Z-Chloro{3-[2,6-difluoro—3—(propanesu[fony1amino)-benzoyl]-1H-
pyrrolo[2,3-b]pyridin—5-yl}-pyridin—3 -yl)-benzenesulfonamide 7 was prepared in six steps from
S-Bromo-lH'pyrrolo[2,3-b]pyridine 1 as shown in Scheme ].
Schemes
F F F
0 °
a r Step2 \/ SteP 3 0y o
’\ \ Step1
B B r m’ —* r Br ;
\ \ N“ Isl/’0
‘Ng N i \“ N02 W . F NH?
F I \ F H H
H / I
/ \ ,/ I
N N N N N
H H H
21 23
F F
Step 1 « Preparation of2, 6-Difluoro-3~nitr0—phenyl)—(5-br0m0-1H—12vrroio[2.3-1)jpyridin-3—ylj-
methanone (21).'
To S—Bromo—lH-pyrrolo[2,3-b]pyridine (20, 0.5 g, 2 mmol) in nitromethane (l 1 mL) was
added aluminum trichloride (1.64 g, 12 mmol). The mixture became clear instantly. The resulting
solution was stirred at room temperature for 1 hour. To this mixture was then added 2,6—difluoro-3—
nitro-benzoyl chloride (0.681 g, 3 mmol) in nitromethane. The reaction mixture was stirred at 45 °C
ght. The on was quenched with ol. After a few minutes, some solids were crashed
out. Solids were collected by filtration, and it was clean t {21, 0.58 g). Additional product was
obtained from filtrate through chromatography (eluted with ethyl acetate and dichloromethane).
{0223} Preparation of 2,6—Difluoro—3-nitro—benzoyl chloride: To t‘luoror3~nitro~benzoic acid
(2 g, 1 mmol) was added thionyl chloride (0.9 mL. 12 mmol). The reaction mixture was stirred at 57
°C ght. After removal of solvent, the residue was stripped once from toluene. This gave brown
oil was checked by NMR which indicated complete conversion to the acid chloride (18 g, 99%). This
material was used as is, without purification.
4811~7918—7726.1
039363-721 1
Step 2 A Preparation of (3—Amino—2,6-difluor0-pheny0—(5-br0mo—IH-pyrrol0[2,3-bjpyridiizy0-
methanone (22):
To a suspension of 2,,6-difluoronitro~phenyl)—(S-bromo-l H-pyrrolo[2,3-b]pyridin~3—yl)-
methanone (0.123 g, 0.287 mmol) in ethyl acetate (5 mL) and ydroturan (5 mL) was added
stannous chloride, ate (0.223 g, 1 mmol). The reaction mixture was stirred at 60 °C for 24
hours. The reaction e was poured into a mixture of 25 mL of water and 25 mL of saturated
sodium bicarbonate. This milky mixture was filtered through a bed of Celite, and the Celite bed wast
washed with some ethyl acetate. The two layers of the filtrate were separated. The organic layer were
collected, washed with brine, and dried over anhydrous sodium sulfate. After removal of drying agent
and solvent, the residue was purified by chromatography (eluted with ethyl e and
dichloromethane) to provide solid product (22, 0.1 g, 87%).
Step 3 —— Preparation ofisobulane- I-sulfonic acid [3-(5-brom0-1H-pyrro!0[2,3-b]pyridine
car!)onyl)-2, 4-difluoro-phenyl]-amide (23) .'
{0225] A mixture of (3-Amino-2,6-difluoro-phenyl)—(S-bromo-1H-pyrrolo[2,3—b]pyridinyl)-
methanone (47 mg, 0.13 mmol), isobutane-l-sulfonylchloride (62 mg, 0.4 mmol), and pyridine (0.5
mL, 6 mmol), in tetrahydrofuran (3 mL) was irradiated in microwave at 130°C for 10 minutes. The
mixture was diluted by ethyl acetate and then washed with water, brine, and dried over anhydrous
sodium sulfate. After removal of drying agent and solvent, the residue was purified by
chromatography (eluted with s and ethyl acetate) to provide desired product (23, 24 mg, 36%).
Step 4 — Preparation ofisobztlane—I—sulfonic acid {2, 4-difluoro[5—(4, 4, 5. 5-telramethyl-
[1, 3, 2]diuxab0rolanyl)- 1H—pyrrolo[2, ridinecarbonyl]-phenyl}~amide (24) .‘
To a suspension of compound 23, an appropriate amount of bis(pinacolato)diboron, and
potassium acetate in ous 1,4-dioxane or an appropriate solvent is added [1,1’-
phenylphosphino)ferroeene]dichloropalladium ([1) (complex with dichloromethane 1:1). The
suspension is heated in an oil bath for 2 to 24 hours. After cooling to room temperature, the mixture is
diluted with ethyl acetate, filtered through a Cclitc pad, and concentrated. The residue is purification
by chromatography to e ane-l-sulfonic acid {2,4—difluoro—3~[5-(4,4,5,5-tetramcthyl-
[1 ioxaborolan—2—yl)— l H—pyrrolo[2,3 idine-3 —carbonyl]-phenyl}-amide (24).
Step 5 _ Preparation ofisobutane-I-suljonic acid {3-[5-plzenyl-IIprrrolofl,3-b]pyridme
carbonylj-Z aaro-phenyi}amide (’25):
{0227] To a mixture of compound 24, phenyl bromide and an appropriate amount of cesium
carbonate in anhydrous 1,4-dioxane or an appropriate solvent is added an appropriate amount of
tetrakis(triphenylphosphine)palladium. The mixture is then heated in an oil bath for 2 to 48 hours.
After cooling to room temperature, the e is diluted with ethyl acetate or an appropriate solvent,
filtered through Celite, and concentrated. The residue is purified by chromatography to provide
481 11918-77261
039363-7211
isobutanel -sulfonic acid {3-[5—phenyl—1H-pyrrolof2,3-b]pyridine-3~carbonyl]—2,4—difluoro—phenyl)—
amide (25).
Example 6: Preparation of compound 30
Compound 30 is prepared in four steps from S-Bromo—lH-pyrrolo[2,3-b]pyridine l as shown
in Scheme 2.
Scheme6
R R R
Er a1 Sepz 3
fi 1\\Fl\02A B'\\E/\\\>FN-b \ N”
[L/\FHR
/N /N
H H a
2) 27 m a
—gr\rr\w/N
Step I ~ Preparation afcumpozmd 27:
To S—Bromo-lH-pyrrolo[2,3-b]pyridine (20) in nitromethane or an appropriate solvent is
added an appropriate amount of aluminum trichloride. The resulting solution is stirred at room
temperature for l to 24 hour (heated in an oil bath if necessary). To this mixture is then added
appropriate amount of benzoyl chloride in nitromethane or an appropriate solvent. The reaction
e is heated in an oil bath for 2 to 48 hours. The reaction is quenched with methanol or an
appropriate solvent. Precipitate is collected by filtration, and it is purified by chromatography to
provide compound 27.
Step — Preparation ofcompound 28:
To a suspension of nd 20 in an appropriate solvent is added an appropriate amount of
stannous de. The reaction mixture is heated in an oil bath for 2 to 48 hours, The reaction mixture
is poured into a mixture of water and saturated sodium bicarbonate. This milky mixture was filtered
through a bed of Celite, and the Celite bed was washed with an appropriate solvent, The organic
layers were collected, washed with brine, and dried over anhydrous sodium sulfate. After l of
drying agent and t, the e is d by chromatography to provide compound 28.
Step 3 m Preparation ofcompound 29:
{0231} A mixture of compound 28, an riate sulfonyl chloride, and an appropriate amount of
pyridine in an appropriate solvent is irradiated in microwave at over 50°C for EU to 60 minutes. The
481177251
039363-7211
mixture is diluted by an appropriate solvent and then washed with water, brine, and dried over
anhydrous sodium sulfate After removal of drying agent and t, the residue is purified by
chromatography to e nd 29.
Step 4 — Preparation ound 30:
To a mixture of compound 29 an appropriate boronic acid or a boronic ester, and an
appropriate amount of cesium carbonate in anhydrous l,4-dioxane or an appropriate solvent is added
an appropriate amount of tetrakis(triphenylphosphine)palladium. The mixture is then heated in an oil
bath for 2 to 48 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate or
an appropriate solvent, filtered through Celite, and concentrated. The residue is purification by
chromatography to provide compound 30. When boronic acid or a boronic ester is not cially
available, boronic acid or ester of nd 29 is prepared by following the procedure described at
Example 1, step 4. Compound 30 is then prepared by following the abovementioned procedure from
boronic acid or ester of compound 29 and an appropriate halide.
Example 7: Preparation of compound 30
nd 30 can also be prepared in three steps from o-lH—pyrrolo[2,3-b]pyridine
11 as shown in Scheme 3.
Scheme7
R / R
/ _::‘:L \‘
Sepz 86m
\ \ /
F [\ma 3 "
I\ 1
\) F N32 \> \
/ \\ F “*2
/ N’ N l >
H H
27 31 32
Step I —— Preparation ofcompound 31:
To a mixture of compound 27 an appropriate boronic acid or a boronic ester, and an
appropriate amount of cesium carbonate in anhydrous 1,4-dioxane or an appropriate solvent is added
an appropriate amount of is(triphenylphosphine)palladium. The e is then heated in an oil
bath for 2 to 48 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate or
an appropriate solvent, filtered through Celite, and concentrated. The residue is purification by
tography to provide compound 31. When boronic acid or a boronic ester is not cially
available, boronic acid or ester of compound 27 is prepared by following the procedure described at
Example 1, step 4, Compound 31 is then prepared by following the abovementioned procedure from
boronic acid or ester of compound 27 and an appropriate halide.
481 11918-77261
039363—7211
Step 2 w Preparation ofcompound 32:
[0235} To a sion of compound 31 in an appropriate soivent is added an appropriate amount of
stannous chloride. The reaction mixture is heated in an oil bath for 2 to 48 hours. The reaction mixture
is poured into a mixture of water and saturated sodium bicarbonate. This milky mixture was filtered
through a bed of celite, and the celite bed was washed with an appropriate solvent. The organic layers
were collected, washed with brine, and dried over anhydrous sodium sulfate. After removal of drying
agent and solvent, the residue is purified by chromatography to provide compound 32.
Step 3 — Preparation ound 30:
A mixture of nd 32, an appropriate yl chloride, and an appropriate amount of
pyridine in an appropriate solvent is irradiated in microwave at over 50°C for 10 to 60 s. The
mixture is diluted by an appropriate solvent and then washed with water, brine, and dried over
anhydrous sodium sulfate. After removal of drying agent and solvent, the residue is purified by
chromatography to provide compound 30.
e 8: ation of compound 34
Compound 34 is prepared in two steps from 5—Bromc-lH—pyrrolo[2,3-b]pyridine l as shown
in Scheme 8.
Scheme 8.
arm Step1 3&32
/ B I \ R
Q }\ R F
\ F i
/ I:
N H
33
Step I — Preparation ound 33:
To S-Bromo-lH-pyrrolo[2,3-b]pyridine (20) in ethane or an appropriate solvent is
added appropriate amount of aluminum trichloride. The resulting solution is stirred at room
temperature for l to 48 hour (heated in an oil bath if necessary). To this mixture is then added
appropriate amount of benzoyl chloride in nitromethane or an appropriate solvent. The reaction
mixture is heated in an oil bath for 2 to 48 hours. The reaction is quenched with an appropriate
solvent. Precipitate is colleCIed by filtration, and it is purified by chromatography to provide
compound 33,
Step 2 — ation ofcompound 34.'
To a mixture of compound 33 an appropriate boronic acid or a boronic ester, and an
appropriate amount of cesium carbonate in anhydrous l,4~dioxane or an appropriate solvent is added
an appropriate amount of tetrakisfiriphenylphosphine)palladium. The mixture is then heated in an oil
4811-7918—77261
039363-721 1
bath for 2 to 48 hours, After cooling to room temperature, the mixture is diluted with ethyl acetate or
an riate solvent, filtered through Celite, and concentrated. The residue is purification by
chromatography to provide compound 34.
When boronic acid or a boronic ester is not commercially available, boronic acid or ester of
compound 33 is prepared by following the procedure described at Example 6, step 4. Compound 34 is
then prepared by following the abovementioned procedure from boronic acid or ester of compound 33
and an appropriate halide.
Example 9: Prepartion of 3-[3-(dimethylsulfamoylamino)—2,6-difluoro-benzoyl](5-
ethoxypyrazin-Z-yl)—1H-pyrrolo[2,3-b]pyridine (37).
Scheme 9.
F F
° QL O 3
° 0
O I /
| \ O
\ HN—§~N/ ————»Step1 O’B \ HN—E—N/
1 \ F “ O‘B/B\O
ll \ I [ \ F u \
/ O O / O
N N N N
H H
Step2
Step 1.
Into a microwave vial o-3—[3-(dimethylsulfamoylamino)—2,6-difluoro—benzoyl]-l H-
pyrrolo[2,3-b]pyridine 35 (70% pure: 200 mg, 0.3 mmol) was placed with 4,4,535—tetramethyl
(4,4,5,5—tetramcthyl—1,3,2—dioxaborolan—2—yl)—l,3,2—dioxaborolane (2} 6.75 mg, 0.85 mmol) and
potassium acetate (100 mg, 1.02 mmol) was added ed by l,1’-bis(diphenylphosphino)ferrocene—
palladium(H) dichloride dichloromethane complex (50 mg, 0.06 mmol). 1,4-dioxane (3 mL) was
added and the mixture was ated in microwave reactor at 145 °C for 45 minutes. The formation of
the intermediate 36 was confirmed by LCMSK MS 1381 [M+H+l+ = 506.95 [M—H+l~ = 504.85.
Step 2.
2-Bromo—5-ethoxypyrazine (200 mg, 0.99 mmol) in 1.5 mL of 1,4-dioxane was added into
the reaction e, made in Step 1, followed by the addition of 1,1"
bis(diphenylphosphino)ferrocene-palladium(]l)dichloride romethane complex (50 mg, 0.06
mmol) and 1M potassium carbonate in water (1.3 ml). The reaction was ated in microwave
r at 135°C for 10 minutes. After cooling the reaction was placed into brine and 1N HCI; the
48117918-77261
039363~7211
aqueous were extracted with ethyl acetate. The organic layers were ed and dried over
anhydrous sodium sulfate. After removal of drying agent and solvent, the residue was purified by
silica gel chromatography eluting with a gradient of ethyl acetate: hexanes (IO-100%) to provide 3—[3~
(dimethylsulfamoylamino)‘2,6~dif1uoro—benzoyl]—5—(5-ethoxypyrazin-2—yl)- l olo[2,3-b]pyridine
37 (16 mg, 10.2%). ESI [M+H+]+ = 503.0 [M-H+]— = 501.1.
Example 10: Compound Properties
While the inhibitory activity of the compounds on any Raf kinase is ant to their
activity in ng of disease, the compounds bed herein show favorable properties that provide
advantages as a pharmaceutical as well.
Assays for biochemical and cell based activity are known in the art, for example, as
described in PCT publication , the disclosure of which is hereby incorporated by
reference as it relates to such assays. For example, the biochemical activity ICSO values are
determined with respect to inhibition of B—RafVGOOE kinase activity or p—Erk kinase ty, where
tion of orylation of a peptide substrate is measured as a function of compound
concentration. Compounds to be tested are diluted in dimethyl sulfoxide to a concentration of 0.1
mM. These are serially diluted 15 pL into 30 pL thyl sulfoxide seven times in 96 well plates
for a total of8 dilution points, and for each dilution point 1 uL is added to a well of an assay plate.
Plates are prepared such that each well in a 384 well plate contains 1 uL of compound in 10 uL
volume with 0.1 ng Rafenzyme (i.e. any of B-Raf, c-Raf-l or B-RafVGOOE, Upstate Biotechnology
or ead by methods known to one ofskill in the art), 50 mM HEPES, pH 7.0, 50 mM NaCl, 2
mM MgC12, 1 mM MnClz, 0.01% Tween-20, 1 mM DTT, and 100 nM biotin-MEKl as substrate. The
reaction is started with addition of 10 pL of 200 uM ATP (i.e. final 100 uM ATP). After incubation
of the kinase reaction for 45 minutes at room ature, 5 uL/well of Stop Solution is added (25
mM Hepes pH 7.5 100 mM EDTA, 0.01% BSA with donor beads (Streptavidin coated beads, Perkin
Elmer), acceptor beads (Protein A coated, Perkin Elmer), and anti phosphor MEKI/Z antibody
(CellSignal), each at final concentration 10 pg/mL). The plates are ted for 3 hours at room
temperature and read on Envision reader (Perkin Elmer). Phosphorylation of Mekl results in binding
of the anti-phosphor-MEK1/2antibody and ation of the donor and acceptor beads such that
signal correlates with kinase activity. The signal vs. compound concentration is used to determine the
ICso.
Compounds are assessed in a variety of cell based assays. For example human cell lines
with B—Raf VGOOE on (A375 melanoma, SKMEL3 melanoma, and COL0205 colon
adenocarcinoma), as well as tumorigenic cell lines with wild—type B—RAF (SW620 colon
adenocarcinoma) or with R35 mutations (SKMEL2 melanoma and IPC298 melanoma). Similar
assays may be used to assess additional tumorigenic cell lines with Ras mutations, including, but not
limited to, M202, MZO7, M243, MZ44, M296, SI 17, l-ICT116, HUN 5, DLDI, MiaPaCa, A549, NCL
4811—7918—7726.1
039363-7211
H23, NCl-H460, HOP62, MDA—MB231, T, 111,60, MOLT—4, and CCRF-CEMi
On day 1, cells are counted, then centrifuged in a conical tube for 5 minutes at 1000 rpm.
The supernatant is removed and cells are re-suspended as follows:
SW620 (ATCC catalog # ): resuspend in Leibovitz’s L-15 medium, 2 mM L-
glutamine, 10% fetal bovine serum to 6 X 104 cells/mL,
A375 (ATCC catalog # CRL-l6l9): resuspcnd in co’s modified Eagle’s medium, 4
mM amine, 4.5 g/L D-glucose, 10% fetal bovine serum to 6 X 104 cells/mL.
COLO2OS (ATCC catalog # CCL-222): resuspend in RPMI 1640, 2 mM L-glutamine, 1.5 g/L
sodium bicarbonate, 4.5 g/L D-glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 10% fetal
bovine serum to 6 X 104 cells/mL.
SKMEL2 (ATCC catalog # HTB—68): resuspend in Minimum Eagle essential medium, 2 mM
L—glutamine, 1.5 g/L sodium bicarbonate, 0.1 mM non—essential amino acids, 1.0 mM sodium
pyruvate, 10% fetal bovine serum to 6 X 10" cells/mL.
SKMEL3 (ATCC catalog # HTB—69): resuspend in McCoy’s 5A medium, 1.5 mM L-
glutamine, 15% fetal bovine serum to 6 X 104 cells/mL.
IPC298 (DSMZ g # ACC 251): end in RPMI 1640, 2 mM L-glutamine, 10% fetal
bovine serum to 6 X 104 cells/mL.
The cells are plated, 50 uL in each well ofa 96-well dish (Coming 3610) and incubated at 37
0C in 5% C02 overnight, cells plated to a final concentration of cells as follows:
SW620: 5,000 cells per well.
A375: 2,000 cells per well.
COLOZOS: 2,000 cells per well.
SKMELZ: 2,000 cells per well.
: 3,000 cells per well.
1PC298: 2,000 cells per well.
[02.43] On day 2, nd at a maximum concentration of 5 mM is serially diluted 1:3 (eg. 10 pl,
with 30 iLL dimethyl sulfoxide) for a total of 8 point ion with DMSO as a. control, A 1 11L aliquot
of each dilution point and control is added to 249 uL growth media and 50 uL is added to a well
containing cells, providing 10 uM compound at the maximum concentration point. The cells are
incubated for 3 days at 37 0C in 5% C02.
{0249] On day 5, ATPlite 1 step Luminescence Assay System (Perkin Elmer # 6016739) is brought
to room ature along with the cell cultures. ATPlite is added 25 nL to each well, shake for 2
minutes, and the cells are incubated at room temperature for 10 minutes, then luminescence is read on
48115791847261
039363-7211
Satire reader. The measured luminescence correlates ly with cell number, such that the reading
as a function of compound tration is used to determine the IC50 value.
B9 is a squamous cell carcinoma cell line expressing ted HRAS that was isolated from
a DMBA/TPA-induced mouse model of skin carcinogenesis (Stoler, et at. The l Q/Cell
Biology, 1993, 122(5), 1103-17). lPC-298 is a human melanoma cell line that expresses activated
NRAS (Aubert, et al. International Journal ofCancer, 1993, 54(5), 784-92). To determine whether
compounds induce phosphorylated ERK and MEK, cells are plated in a l dish and treated with
an t titration of compound for one hour at 37 0C. The media is then removed and the cells are
incubated with lysis buffer containing protease and phosphatase inhibitors. Phosphorylated ERK and
MEK in the resulting lysates is detected using AlphaScreenTM technology. To detect phosphorylated
ERK, cell lysates are incubated with streptavidin-coated donor beads, anti-mouse IgG acceptor beads,
a biotinylated anti-ERK1/2 rabbit antibody, and a mouse antibody that recognizes ERK] /2 only when
it is phosphorylated on Thr202 and Tyr204. The biotinylated ERKl/2 antibody will bind to both the
streptavidin-coated donor beads and to ERKl/Z (regardless of its phosphorylation state), and the
phospho-ERKl/2 antibody will bind to the or beads and to ERK 1/2 that is phosphorylated at
Thr202/Tyr204. Excitation of the beads with laser light at 680 nm produces singlet oxygen, which is
rapidly quenched unless the beads are in close proximity. When ERK is phosphorylated, both
antibodies can bind the same n, ng the donor and acceptor beads into Close proximity,
producing a signal that can be measured at 580 nm. MEK phosphorylation is detected using a similar
approach, only with antibodies directed against total MEK1/2 and MEKl/Z that is phosphorylated at
Ser217 and Ser221.
It is understood that the results of these assays may vary as assay conditions are varied.
Inhibition levels determined under the conditions described herein represent a relative activity for the
compounds tested under the c conditions employed. The cell based assays are likely to show
ility due to the complexity of the system and the sensitivity f to any changes in the assay
ions. As such, some level of tion in the cell based assays is indicative of the compounds
having some inhibitory ty for those cells, whereas lack of inhibition below the threshold of the
highest concentration tested does not necessarily indicate that the compound has no inhibitory ty
on the cells, only that under the conditions tested, no inhibition is observed. In some instances, the
compounds were not tested in all of the assays, or assay results were not valid, as indicated by NA. in
the tables below.
The following table provides data indicating the B-Raf V600E and IPC-298_P-ERK cell
activation activity, A3 75_P—ERK and COLOZOS cell growth inhibitory activity for exemplary
compounds as described herein:
1 Compound Biochemical i Cell activity J Cell activity (le0 uM) i
number activitv (:1ng uM) i (ECw M) l
l i V600E i “JG—298 [LERK l A375 COLO205 a 5
13—0012 < 0.1 i > 10 l < 1
l > L-
,,,,,,,,,,, l
48117726.1
039363-7211
Compound Biochemical T Cell ty Cell activity (IC50 11M)
number (13ng 11M)
1 activity (ICSO 11M) fl“ NW..." .1,
V600E 1P02983—ERK A375 C0L0205
1 P0013 <0.1 > 10 <1 >1
; P0014 <0.1 >8 <1 <1
P0015 <0.1 > 10 <1 >1
AAAAAA
P0016 ‘M ‘
< 0.1. NA < 1 < 1
P-0017 <0.1 I > 10 <1 >1
P0018 < 0.1 > 10 <1 >1
P0019 <0.1 > 10 <1 >1
fl h 1
P0020 <0.1 I >10 <1 <1
P0021 <0.1 > 10 <1 <1
P0022 <0.1 > 10 <1 <1
P0023 <0.1 : > 10 <1 >1
P0024 <0.1 '
> 10 <1 >1
P0025 <0.1 > 10 <1 <1
P0026 >10 >1
P0027 < 0.1 NA < 1 < 1
P-0028 <0.1 > 10 <1 <1
P0029 <0.1 I > 10 <1 <1
_._1_
P-0030 <0.1 > 10 <1 <1
F ._._
P0031 <0.1 > 10 <1 <1
P0032 <0.1 > 10 <1 <1
P0033 <0.1 > 10 <1 <1
P0034 <0.1 > 10 <1 >1
P0035 I <0.1 > 10 <1 >1
P0036 <0.1 > 10 <1 >1
P0037 <0.1 I > 10 <1 >1
P0038 <0.1 > 10 <1 >1
P0039 <0.1 > 10 <1 >1
P0040 <0.1 I > 10 ”L <1 <1
P0041 >0.1 > 10 >1
P0042 <0.1 >10 <1 <1
1 __1 I 1
P0043 <0.1 > 10 <1 <1
P0044 <0.1 > 10 <1 <1
' 1
P0045 <0.1 > 10 <1 <1
P0046 <0.1 I > 10 <1 <1
P0047 < 0.1 > 10 < 1 < 1
P0048 < 0.1 > 10 < 1
P0049 L < 0.1 > 4 < 1 < 1
P0050 < 0.1 I > 10 < 1 < 1
__P0051 < 0.1 > 10 < 1
fl 1 __ _<-__1 _
P0052 <0.1 > 10 <1 <1
P0053 <0.1 I” > 10 <1 <1 1
1 P0054 1 <0.1 >1 <1 f >1
1 ‘
_ P011151 30.1 51 1<11
P0056 <0.1 > 10 <1 I <1
« P-0057 <0.1 >10 <1 <1
< 0.1 > 10
,_.._,P_:99_52.................1 < 011 > 10
I P0060 I < 0.1 > 2
P0061 <0.1 > 10
P0062 < 011 11 > 10
1 P0063 <01 1 > 10
‘‘‘‘‘‘‘‘
P0064 1 < 011 > 10
48113918772611
039363—7211
Compound Biochemical Cell activity Cell activity (IC50 11M)
number activity (leo 11M) (ECSO 11M)
V600E IPC-298 P-ERK A375 COLOZOS
P411165 L < 0.1 [ < 1 > 1
P-0066 < 0.1 < 1 < 1
1 L
P-0067 < 01 < 1 > 1
P-0068 < 0.1
1 L
P—0069 < 0.1
P-01170 > 0.1 L: <1 > 1
P411171 1 > 0.1 < 1 > 1
w > 0-1 < 1 J > 1
WP-0073 > 0.1 < I > 1
> 0.1 < 1 > 1
P-0076 ' '
._1 11111111
P41077 .
P-0078 < 0.1 < 1 > 1
, l l
P411179 < 0.1 < 1 < 1
"“— l
P-0080 < 0.1 >
L LLLLLL -1 - ,,,,, <_1 ,........ .1
1 P—0081 <0.1 <1 <1
P411182 < 0.1 < 1 < 1
P-0083 __L < 0.1 < 1 < 1
P41084 < 0.1 < 1
_ _ 11*; 1W
P-0085 < 0.1 < 1 > 1
P-0086 < 0.1 ___L__L_<_1____L___<__1__L
P411187 < 0.1 1: < 1 < 1
P41088 < 0.1L_M__W_ j" < 1 L- 13-11,“ 1
P411189 < 0.1 < 1 > 1
P-0090 < 0.1 < 1 < 1
P411191 < 0.1 < 1 < 1
P-0092 < 1 1
< 0.1 < 1
P—0093 <0.1 L____ 1 <1 <1
P411194 < 0.1 < 1 < 1
P411195 I < 011 < 1 < 1
P-0096 < 0.1 < 1
.1 “1,511-1 _ _
P41097 < 0.1 < 1 < 1
P41098 < 11.1 [ < 1 < 1
P-0099 < 0.1 < 1 > 1
1 1
P-0100 <0,.1 l A g __1 _ fl “P1 W
P—0101 < 0.1 < 1 > 1
P411112 "”1 <01 L <1 >1
1 1
P-0103 < 0.1 < 1 < 1
P411114 < 0.1 T < 1 < 1
7 4
11-0105 T“. < 01 < 1 < 1
P411116 i
; < 0.1 < 1 < 1
4 i
1 7 < 0.1 l < 1 < 1
i ‘
P411118 < 0.1 < 1 > 1
P411119
4811772611
039363-7211
Compound l Biochemical I Cell activity Cell activity (K350 pM)
number activity (ICSO HM) (ECso EM)
i V600E IPC-298 P-ERK A375 COL-0205
P—0242 < 0.1 > 1 > l
P-0243 < 0.1 > 1 f > 1
P-0244 < 0.} > 1 > 1
11-0245 <1 <1
__L, W.< 0-1. W ,; _ _ W A . 7“ i
P—0246 < 0.1 g > 1 > 1
48117726.1
039363—721 ]
Compound Biochemical Cell activity Cell activity {ICSO 11M)
number
2 actixity (ICso EM)
(13ng 11M)
V6OOE A375 COL0205
W IPC-298_P—ERK
P-0297 < 0.1 > 1 > 1
P-0298 < 0.1 > 1 > 1
W 1 W
< 0.1 > 1 1
_ 9 - 2 ___>
P-0300 <01 >4 <1 >1
P-0301 < 0.1 < 1 > 1
4 J
P-0302 < 0.1 < 1 < 1
<0.1 >1
2 _ P19§§3_ >1“ __T >_
P—0304 < 0.1 < 1 < 1
P0305 < 0.1 < 1 < 1
P-0306 < 0.1 > 1 < 1
< 0.1 < 1 <
__ _ 30319.7 1-2.-.-
P0308 < 0.1 < 1 < 1
P-0309 < 0.1 < 1 < 1
P0310 < 0.1 < 1 < 1
P-0311_ < 0.1 1
_ _____- <_1 ___<
P0312 < 0.1 < 1 < 1
P0313 i < 0.1 < 1 < 1
P-0314 < 0.1 < 1 < 1
P031; < 0.1 < 1 < 1
.. W _
P—0316 I < 0.1 [ < 1 < 1
P0317 < 0.1 < 1 < 1
W _:
P—0318 < 0.1 < 1 < 1
17:99.12- < 0-1 < 1 < 1
P0320 > 0.1
P0321 < 0.1 < 1 < 1
P0322 < 0.1 < 1 1 < 1
P0323” < 0.1 <1 < 1
P0325 < 0.1 < 1 > 1
P-0326 < 0.1 > 1 > 1
P0327 < 0.1 < 1 < 1
P-0334 > 2 > 1 > 1
<01 - I
P0335 T < 0.1 < 1 < 1
P-0336 > 0.1 > 4
W W W
P0337 < 0.1 1 > 1 > 1
P0338 < 0.1 < 1
W W “:12 W
P0339 < 0.1 < 1 < 1
TP0340 < 0.1 < 1 < 1
P0223 > 0.1
481177261
039363—7211
Compound Biochemical Cell activity Cell activity (IC50 pM)
number swollen 9M) {Ecso PM)- s__ W“. .s.__,_...__m_
V6005 gr lPC-298 P-ERK A3 75 COLO205
9—0113 T < 0.1 3 < 1 < 1
P—0112 < 0.1 f < 1 < I
P-Oll 1 f < 0.1 < 1 < 1
P—0110 < 0.1 < 1 < l
The table below provides the IPC—298_P—ERK cell activation activity, A3 75KP—ERK and
COLO205 cell growth tory activity data for a few exemplary compounds known in the art.
nd Cell activity Cell activity
ECSO M) (1050 M
IPC-298 P-ERK A375 ECOLOZOS
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridinecarbonyl)- < 0.5 < 0.8 < 1
2,4-difluoro-phenyl]proganesulfonamide
N—[2,4-difluoro—3—[5—(2—methoxypyrimidin~5~yl)~1H-
pyrrolol2,3—b]pyridine—3 -carbonyl]phenyl]—2-fluoro—
benzenesulfonamide
N—[2,4—difluoro—3—[5—(2-methoxypyrimidin—S—yl)—1H- l
pyrrolo[2,3—b]pyridine—3—carbonyl]phenyl]—2,5-
difluoro—benzenesulfonamide
Pharmacokinetic properties of compounds (including any solid forms or formulations
thereof) are assessed in male Sprague Dawley rats or male Beagle dogs. Rats are dosed daily with
compound either by IV injections via surgically implanted jugular catheters or by oral gavage (PO).
Each compound is prepared as a 20 mg/mL stock solution in dimethyl sulfoxide, which is further
diluted to provide the dosing stock at the desired concentration for the 1V or PO formulations. For IV
dosing, the dosing stock is d into a 1:1:8 mixture of Solutol ®:ethanol:water. For PO dosing, the
dosing stock is diluted into 1% methylcellulose. In a cassette format (or each compound, solid form
thereof or formulation thereof is done individually), compounds are diluted to 0.5 mg/mL each for IV
dosing and 0.4 mg/mL each for P0 dosing and closed at 1 mg/kg (2mL/kg) or 2 mg/kg (5 mL/kg),
respectively. For IV dosed animals, tail vein blood samples are collected with lithium heparin
anticoagulant at 5, 15, 30, and 60 minutes and 4, 8, and 24 hours post dosing each day. For PO dosed
animals, tail vein blood samples are collected with lithium n anticoagulant at 30 minutes, 1, 2,
4, 8 and 24 hours post dosing each day. Dogs are closed daily by oral capsules in a suitable
ation at 50 mgx’mL. Cephalic vein blood samples are collected with lithium heparin
anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hours post dosing each day. All samples are processed
to plasma and frozen for later analysis of each compound by MS. Plasma levels as a function
of time are plotted to assess the AUC (ng*hr/mL). nds according to the present invention
preferably Show ed cokinetic properties ve to previously described compounds,
i.e. they have substantially higher values for one or more of AUC, Cmax and half—life relative to
previously described compounds.
All patents, patent ations and other references cited in the specification are indicative
4811~7918-7726.1
039363-7211
of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by
reference in their ties, including any tables and figures, to the same extent as if each nce
had been incorporated by reference in its entirety individually.
One d in the art would y appreciate that the present invention is well adapted to
obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variances,
and compositions described herein as presently representative of preferred embodiments are
exemplary and are not intended as limitations on the scope of the invention. Changes therein and
other uses will occur to those skilled in the art, which are encompassed within the spirit of the
invention, are defined by the scope of the claims.
While this invention has been disclosed with reference to specific embodiments, it is apparent
that other embodiments and variations of this invention may be d by others d in the art
t departing from the true spirit and scope of the invention.
in addition, where features or aspects of the ion are described in terms of Markush
groups or other grouping of alternatives, those skilled in the art will recognize that the invention is
also thereby described in terms of any individual member or subgroup of members of the Markush
group or other group.
Also, unless indicated to the contrary, where various numerical values are provided for
embodiments, additional embodiments are described by taking any two different values as the
endpoints of a range. Such ranges are also within the scope of the described invention.
4811-7918—7726.1
Claims (32)
1. A compound having formula (Ig): Y2 O R15 HN S Z s N N N O H Ig or a pharmaceutically acceptable salt, a hydrate, a e, a tautomer, or stereoisomer thereof, wherein each R15 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-8cycloalkyl, C3-8cycloalkyl-C1alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl-C1-4alkyl or –Ra, wherein Ra is selected from halogen, -CH=CH2, -CN -OH, -NH2, - NO2, -C(O)OH, -C(S)OH, -C(O)NH2, H2, NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -ORb, -SRb, -OC(O)Rb, -OC(S)Rb, -C(O)Rb, -C(S)Rb, -C(O)ORb , -C(S)ORb, -S(O)Rb, -S(O)2Rb, -C(O)NHRb, -C(S)NHRb, -C(O)NRbRb, -C(S)NRbRb, -S(O)2 NHRb, -S(O)2NRbRb, -C(NH)NHRb, -C(NH)NRbRb, -NHC(O)Rb, -NHC(S)Rb, -NRbC(O)Rb, -NRbC(S)Rb, )2Rb, -NRbS(O)2Rb, -NHC(O)NHRb, -NHC(S)NHRb, -NRbC(O)NH2, - NRbC(S)NH2, -NRbC(O)NHRb, S)NHRb, -NHC(O)NRbRb, -NHC(S)NRbRb, -NRbC(O , -NRbC(S)NRbRb, )2NHRb, -NRbS(O)2NH2, -NRbS(O)2NHRb, -NHS(O)2NRb Rb, -NRbS(O)2NRbRb, -NHRb or -NRbRb, wherein each Rb is independently selected from the group consisting of C1-6alkyl, n, -CN, C1-6alkoxy, C3-8cycloalkyl, C3-8cycloalkyl-C1 alkyl, -OH, C1-6haloalkyl, C1-6haloalkoxy, aryl, aryl-C1-4alkyl, heteroaryl and heteroarylalkyl; or two Rb substituents when attached to the same nitrogen atom taken together with the nitrogen atom form a three to eight-membered ring having from 0-2 additional heteroatoms as ring s selected from N, O or S; wherein the tic or aromatic portion of R15 is r optionally substituted with from 1-3 groups selected from C1-6 alkyl, C1-6 , C1-6haloalkyl, C1- 6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkyl- C1-4alkyl or -Rc, wherein each Rc is independently selected from halogen, -CH=CH2, -CN, - OH, -NH2, -NO2, 10437476_1 -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS( O)2NH2, -C(NH)NH2, -ORd, -SRd, -OC(O)Rd, -OC(S)Rd, d, -C(S)Rd, -C(O)ORd, -C(S) ORd, -S(O)Rd, -S(O)2Rd, -C(O)NHRd, -C(S)NHRd, -C(O)NRdRd, -C(S)NRdRd, -S(O)2NHRd, - RdRd, -C(NH)NHRd, -C(NH)NRdRd, -NHC(O)Rd, -NHC(S)Rd, -NRdC(O)Rd, -NRdC( S)Rd, -NHS(O)2Rd, -NRdS(O)2Rd, -NHC(O)NHRd, -NHC(S)NHRd, -NRdC(O)NH2, -NRdC(S) NH2, -NRdC(O)NHRd, -NRdC(S)NHRd, -NHC(O)NRdRd, )NRdRd, -NRdC(O)NRdRd, -NRdC(S)NRdRd, -NHS(O)2NHRd, -NRdS(O)2NH2, -NRdS(O)2NHRd, -NHS(O)2NRdRd, -NRd S(O)2NRdRd , -NHRd, Rf or , wherein each Rd is independently selected from C1-6alkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; and wherein the aromatic portion of R15 is optionally substituted with from 1-3 substituents independently selected from Re, wherein Re is selected from the group consisting of halogen, -CN, -CH=CH2, -OH, -NH2, -NO2, -C(O)OH, H, -C(O)NH2, H2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS( , -C(NH)NH2, -ORf, -SRf, -OC(O)Rf, -OC(S)Rf, -C(O)Rf, -C(S)Rf, Rf, -C(S)O Rf, -S(O)Rf, -S(O)2Rf, -C(O)NHRf, -C(S)NHRf, -C(O)NRfRf, -C(S)NRfRf, -S(O)2NHRf, -S(O )2NRfRf, -C(NH)NHRf, -C(NH)NRfRf, -NHC(O)Rf, -NHC(S)Rf, -NRfC(O)Rf, -NRfC(S)Rf, -NHS(O)2Rf, -NRfS(O)2Rf, -NHC(O)NHRf, -NHC(S)NHRf, O)NH2, -NR fC(S)NH fC(O)NHRf, -NRfC(S)NHRf, -NHC(O)NRfRf, )NRfRf, -NRfC(O)NRf 2, -NR Rf, -NRfC(S)NRfRf, -NHS(O)2NHRf, -NRfS(O)2NH2, -NRfS(O)2NHRf, -NHS(O)2NRfRf, -NRfS(O)2NRfRf , -NHRf, -NRfRf and Rf, wherein Rf is C1-6alkyl or aryl; or two adjacent R15 groups on the aryl or heteroaryl ring together with the atoms to which they are attached form a 5- or ered ring having from 0 to 2 additional heteroatoms selected from N, O or S, optionally substituted with from 1 to 3 Rd substituents; Q is selected from H, F, Cl or CH3; Z is (R5); R4 and R5 are each independently selected from the group consisting of H, C1- 6alkyl, C3-8cycloalkyl, C3-8cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; or R4 and R5 taken er with the nitrogen atom to which they are attached form a four to membered ring having from 0-2 additional heteroatoms as ring members selected from N, O or S; 10437476_1 wherein each of R4 and R5 is optionally substituted with from 1-3 substituents independently selected from C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, C3- 8cycloalkyl, C3-8cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, propenyl, Rc, Re or Ra or two adjacent substituents together with the atom to which they are attached form a 5 or ered aromatic ring having from 0 to 2 onal atoms as ring members selected from O, N or S, each of which is optionally substituted with from 1 to 3 substituents independently selected from C1-6alkoxy, C1- 6haloalkyl, C1-6haloalkoxy, C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Rd, or Re; Y2 is H, halogen, CN, kyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C3-8cycloalkyl-C0-4alkyl or (R2)(R3) N-, wherein R2 and R3 are each independently selected from the group consisting of H, C1-6alkyl, C1- y, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C3-8cycloalkyl-C0-4alkyl, heterocycloalkyl and cycloalkyl-C1-4alkyl; or R2 and R3 taken together with the nitrogen atom to which they are attached form a three to eight-membered ring having from 0-2 additional atoms as ring s selected from N, O or S; wherein Y2 is ally substituted with from one to three groups independently selected from Re; and the subscript s is an integer of 1 to 3, with the proviso when of formula Ig is 2-methoxypyrimidin yl, Z is other than dimethylamino, diethylamino, 1-pyrrolidine, 1-piperidinyl, or 4- morpholinyl.
2. The compound of claim 1 having formula (Ig-1): R15 N O Y2 O N HN S Z N O H Ig-1.
3. The compound of claim 1 or 2, wherein Z is: 10437476_1 wherein R11 is C1-6alkyl, C1-6alkoxy, loalkyl, C1-6haloalkoxy, C3- 8cycloalkyl, C3-8cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, or Re; each of which is optionally substituted with from 1 to 3 substituents ndently selected from C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, C3- d, or Re; alkyl, C3-8cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, R the ipt m is an integer from 0 to 3; the ipt n is an integer from 1 to 5; and the wavy line indicates the point of attachment to the SO2 group of formulas Ig or Ig-1.
4. The compound of claim 1, wherein each R15 is ndently halogen, -CN, -OH, -CF3, CF3O-, C1-6alkyl, C1-6alkoxy, C3-6cycloalkoxy, -NO2, benzyl, phenyl, cyclopropyl, cyclopropylmethyl, 1-cyanocyclopropyl, 1-carboxycyclopropyl, 1- carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1- hydroxycyclopropyl, 1-hydroxyisopropyl, cyclobutoxy, entoxy, cyclohexyloxy, C1- 6alkyl-1,2,4-oxadiazolyl, 5-C1-6alkyl-1,3,4-oxadiazol-2yl, 1-6alkyl)amino-1,3,4- oxadiazol-2yl, 5-C1-6alkylamino-1,3,4-thiadiazolyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexymethyl, -OC(O)Rb, -C(O)Rb, - C(O)ORb, -NHC(O)Rb, -C(O)NHRb, -NHRb or .
5. The compound of claim 1, wherein R15 is F, Cl, Br, I, -CN, -OH, -CF3, NH2, CF3O-, CH3-, CH3O, C2H5O-, -NO2, cyclopropyl, cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl, 1-carboxycyclopropyl, 1- carbamoylcyclopropyl, 1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1- hydroxycyclopropyl, oxyisopropyl, cyclobutoxy, cyclopentoxy, cyclohexyloxy, 4- morpholino, 4-hydroxypiperidinyl, 1-piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-tbutoxycarbonylpiperazinyl , azetidinyl, idinyl, cyclopropylcarbamoyl, 5-methyl-1,2,4- oxadiazolyl, 5-methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl, 5- methylamino-1,3,4-thiadiazolyl, methylamino, dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, ido, methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1- cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or 1-hydroxymethylethyl.
6. The compound of claim 1, wherein (i) 10437476_1 of formula Ig is selected from the group consisting of 2- methoxypyrimidinyl, 2-methoxypyrimidinyl, oxypyrimidinyl, 4-methoxy pyrimidinyl, 4-methoxypyrimidinyl, 4-methoxypyrimidinyl, 5-methoxypyrimidinyl, 5-methoxypyrimidinyl, 2-cyclopropylpyrimidinyl, 2-cyclopropylpyrimidinyl, 2- cyclopropylpyrimidinyl, 4-cyclopropylpyrimidinyl, 4-cyclopropylpyrimidinyl, 4- cyclopropylpyrimidinyl, opropylpyrimidinyl, 5-cyclopropylpyrimidinyl, 2- cyclopropylmethylpyrimidinyl, 2-cyclopropylmethylpyrimidinyl, 2-cyclopropylmethyl- 4-pyrimidinyl, 4-cyclopropylmethylpyrimidinyl, 4-cyclopropylmethylpyrimidinyl, 4- cyclopropylmethylpyrimidinyl, 5-cyclopropylmethylpyrimidinyl, 5-cyclopropylmethyl- 4-pyrimidinyl, 2-methylpyrimidinyl, 2-methylpyrimidinyl, 2-methylpyrimidinyl, 4- methylpyrimidinyl, 4-methylpyrimidinyl, 4-methylpyrimidinyl, 5-methyl pyrimidinyl, 5-methylpyrimidinyl, 2-halopyrimidinyl, 2-halopyrimidinyl, 2-halo pyrimidinyl, 4-halopyrimidinyl, 4-halopyrimidinyl, 4-halopyrimidinyl, 5-halo pyrimidinyl, 5-halopyrimidinyl, yanocyclopropyl)pyrimidinyl, 2-(1- cyanocyclopropyl)pyrimidinyl, 2-(1-cyanocyclopropyl)pyrimidinyl, 4-(1- cyanocyclopropyl)pyrimidinyl, 4-(1-cyanocyclopropyl)pyrimidinyl, 4-(1- cyanocyclopropyl)pyrimidinyl, yanocyclopropyl)pyrimidinyl, 5-(1- cyanocyclopropyl)pyrimidinyl, 2-cyclopropylaminopyrimidinyl, opropylamino- 3-pyrimidinyl, 2-cyclopropylaminopyrimidinyl, opropylaminopyrimidinyl, 4- cyclopropylaminopyrimidinyl, 4-cyclopropylaminopyrimidinyl, 5-cyclopropylamino pyrimidinyl, 5-cyclopropylaminopyrimidinyl, 2-dimethylaminopyrimidinyl, 2- dimethylaminopyrimidinyl, 2-dimethylaminopyrimidinyl, 4-dimethylamino pyrimidinyl, 4-dimethylaminopyrimidinyl, 4-dimethylaminopyrimidinyl, 5- dimethylaminopyrimidinyl, 5-dimethylaminopyrimidinyl, 2-cyanopyrimidinyl, 2- cyanopyrimidinyl, 2-cyanopyrimidinyl, 4-cyanopyrimidinyl, 4-cyanopyrimidinyl, 4-cyanopyrimidinyl, opyrimidinyl, 5-cyanopyrimidinyl, 2-trifluoromethyl pyrimidinyl, 2-trifluoromethylpyrimidinyl, 2-trifluoromethylpyrimidinyl, 4- trifluoromethylpyrimidinyl, 4-trifluoromethylpyrimidinyl, 4- trifluoromethyl pyrimidinyl, 5-trifluoromethylpyrimidinyl, 5-trifluoromethylpyrimidinyl, 2- oromethoxypyrimidinyl, 2-trifluoromethoxypyrimidinyl, luoromethoxy pyrimidinyl, 4-trifluoromethoxypyrimidinyl, 4-trifluoromethoxypyrimidinyl, 4- trifluoromethoxypyrimidinyl, 5-trifluoromethoxypyrimidinyl, 5-trifluoromethoxy 10437476_1 pyrimidinyl, oxypyrimidinyl, 2-hydroxypyrimidinyl, 2-hydroxypyrimidinyl, 4-hydroxypyrimidinyl, 4-hydroxypyrimidinyl, 4-hydroxypyrimidinyl, 5-hydroxy pyrimidinyl, 5-hydroxypyrimidinyl, opyrimidinyl, 2-aminopyrimidinyl, 2- aminopyrimidinyl, 4-aminopyrimidinyl, 4-aminopyrimidinyl, 4-amino pyrimidinyl, 5-aminopyrimidinyl, 5-aminopyrimidinyl, 2-methylaminopyrimidinyl, 2-methylaminopyrimidinyl, 2-methylaminopyrimidinyl, 4-methylaminopyrimidinyl, 4-methylaminopyrimidinyl, 4-methylaminopyrimidinyl, 5-methylaminopyrimidinyl, 5-methylaminopyrimidinyl, 2-dimethylaminopyrimidinyl, 2-dimethylamino pyrimidinyl, 2-dimethylaminopyrimidinyl, 4-dimethylaminopyrimidinyl, 4- dimethylaminopyrimidinyl, 4-dimethylaminopyrimidinyl, 5-dimethylamino pyrimidinyl, 5-dimethylaminopyrimidinyl, 2-acetamidopyrimidinyl, 2-acetamido pyrimidinyl, 2-acetamidopyrimidinyl, 4-acetamidopyrimidinyl, 4-acetamido pyrimidinyl, 4-acetamidopyrimidinyl, 5-acetamidopyrimidinyl, 5-acetamido pyrimidinyl, 2-methylthiopyrimidinyl, 2-methylthiopyrimidinyl, 2-methylthio pyrimidinyl, 4-methylthiopyrimidinyl, ylthiopyrimidinyl, 4-methylthio pyrimidinyl, 5-methylthiopyrimidinyl, ylthiopyrimidinyl, 2-acetoxy pyrimidinyl, 2-acetoxypyrimidinyl, 2-acetoxypyrimidinyl, 4-acetoxypyrimidinyl, 4- acetoxypyrimidinyl, 4-acetoxypyrimidinyl, 5-acetoxypyrimidinyl, 5-acetoxy dinyl, ylpyrimidinyl, 2-acetylpyrimidinyl, 2-acetylpyrimidinyl, 4-acetyl- 2-pyrimidinyl, 4-acetylpyrimidinyl, ylpyrimidinyl, 5-acetylpyrimidinyl, 5- acetylpyrimidinyl, oxycarbonylpyrimidinyl, oxycarbonylpyrimidinyl, 2-methoxycarbonylpyrimidinyl, 4-methoxycarbonylpyrimidinyl, 4-methoxycarbonyl pyrimidinyl, 4-methoxycarbonylpyrimidinyl, 5-methoxycarbonylpyrimidinyl, 5- methoxycarbonylpyrimidinyl, 2-methylcarbamoylpyrimidinyl, 2-methylcarbamoyl pyrimidinyl, ylcarbamoylpyrimidinyl, 4-methylcarbamoylpyrimidinyl, 4- methylcarbamoylpyrimidinyl, 4-methylcarbamoylpyrimidinyl, 5-methylcarbamoyl pyrimidinyl, 5-methylcarbamoylpyrimidinyl, each of which is optionally substituted with from 1 to 2 substituents independently ed from F, Cl, Br, I, -CN, -OH, -CF3, NH2, CF3O-, CH3-, CH3O, -NO2, cyclopropyl, 1-cyanocyclopropyl, cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, methylamino, dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido or methylcarbamoyl; or 10437476_1 (ii) of a Ig is selected from the group consisting of 4- pyrimidinyl, and 5-pyrimidinyl, each of which is substituted with from 1 to 2 substituents independently selected from F, Cl, Br, I, -CN, -OH, -CF3, NH2, CF3O-, CH3-, CH3O, C2H5O-, -NO2, cyclopropyl, cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, 1- cyanocyclopropyl, 1-carboxycyclopropyl, 1-carbamoylcyclopropyl, 1- methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl, 1-hydoxyisopropyl, cyclobutoxy, entoxy, cyclohexyloxy, 4-morpholino, oxypiperidinyl,1- piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, azetidinyl, pyrrolidinyl, cyclopropylcarbamoyl, 5-methyl-1,2,4-oxadiazolyl, 5-methyl-1,3,4- oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl, ylamino-1,3,4-thiadiazolyl, methylamino methylamino, ylamino, methylthio, acetoxy, , methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl, 2- cyclopropylethyl, 1-cyclopropylethylamino, opropylethylamino or 1-hydroxy methylethyl.
7. The compound of any of claims 1-6, wherein Y2 is H, halogen, CN, C1-6alkyl, C1-6alkoxy, C3-6cycloalkylamino, C3-6cycloalkyl-C1-3alkylamino, aryl, heteroaryl, arylalkyl or heteroarylalkyl.
8. The compound of claim 7, wherein Y2 is H, F, Cl, I, CN, CH3, CH3O-, cyclopropylamino or cyclopropylmethylamino.
9. The compound of any of claims 1-8, wherein R4 is –CH3 and R5 is C2- 6alkyl, C3-8cycloalkyl, C3-8cycloalkylalkyl, aryl, aryl-C1-4alkyl, heteroaryl or heteroaryl-C1- 4alkyl, each of which is optionally tuted with from 1-3 substituents independently selected from C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, C3-8cycloalkyl, C3- 8cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or R
10. The compound of claims 1-8, wherein R4 and R5 are each independently selected from CH3, ethyl, propyl, butyl, pentyl, cyclopropyl, ropylmethyl, cyclobutyl, cyclobutylmethyl, entyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl, each of which is optionally substituted with from 1-3 substituents independently selected from F, Cl, Br, I, -CN, -OH, -CF3, NH2, CF3O-, CH3-, CH3O, -NO2, ropyl, cyclopropylmethyl, cyclopropylamino, 10437476_1 cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, dylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl, 2- oxetanylmethyl, 3-oxtetanylmethyl, ahydrofuranyl, 3-tetrahydrofuranyl, 2- tetrahydrofuranylmethyl, 3-tetrahydrofuranylmethyl, olidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 4-morpholinyl, 2-morpholinyl or 3-morpholinyl.
11. The compound of claims 1-8, wherein R4 is CH3 and R5 is ed from ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl or , each of which is optionally substituted with from 1-3 substituents independently selected from F, Cl, Br, I, -CN, -OH, -CF3, NH2, CF3O-, CH3-, CH3O, -NO2, cyclopropyl, cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy, , methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4- pyridylmethyl, 2-oxetanyl, 3-oxtetanyl, 2-oxetanylmethyl, 3-oxtetanylmethyl, 2- tetrahydrofuranyl, 3-tetrahydrofuranyl, ahydrofuranylmethyl, 3- tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2- ydrothiophenyl, ahydrothiophenyl, 4-morpholinyl, 2-morpholinyl or 3- morpholinyl.
12. The compound of claim 1, wherein Z is selected from the group consisting of 1-azetindinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl 3-oxazolidinyl, 3-thiazolidinyl, 2-isoxazolidinyl, 2-isothiazolidinyl, 1-pyrazolidinyl, 1- piperazinyl, 1-hexahydropyrimidinyl and 1-hexahydropyridazinyl, each of which is optionally substituted with from one to three R24 substituents independently selected from the group consisting of n, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3- 8cycloalkyl, C3-8cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, kyl, heteroaryl, heteroarylalkyl and Rc; or two nt R24 substituents together with the atom to which they are attached form a 5 or ered aromatic ring having from 0 to 2 additional atoms as ring members selected from O, N or S.
13. The compound of claim 1, wherein Z is selected from the group consisting of 1-pyrrolidinyl, (CH3)(CH3CH2)N-,(CH3)(CF3CH2)N-, and 10437476_1 cycloproyplmethylamino, each of which is optionally substituted with from 1-2 members selected from -F, methoxycarbonyl, ethoxycarbonyl, -CH3, CH3(CO)NH-, vinyl, propenyl or )(CH3)N-.
14. The compound of claim 3, wherein n is 1, 2, 3 or 4.
15. The compound of claim 3, wherein the subscript m is 0.
16. The compound of claim 3, wherein R11 is H, F, Cl, Br, I, -CN, -OH, - CF3, NH2, CF3O-, CH3-, CH3O, -NO2, cyclopropyl, cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl, phenyl, benzyl, methylamino, dimethylamino, thio, acetoxy, acetyl, methoxycarbonyl, ethyoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl, dyl, 4-pyridyl, dylmethyl, 3-pyridylmethyl, 4- pyridylmethyl, 2-oxetanyl, 3-oxtetanyl, anylmethyl, 3-oxtetanylmethyl, 2- tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl, 3- tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2- tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 4-morpholinyl, holinyl, 3- morpholinyl, olidinyl, 2-pyrrolidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2- thiophenyl, 3-thiophenyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl¸ 5-imidazolyl or 2- thiazolyl.
17. The compound of claim 1, wherein each R15 is F, Cl, Br, I, -CN, -OH, -CF3, NH2, CF3O-, CH3-, CH3O, -NO2, cyclopropyl, cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino, thio, acetoxy, acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1- ropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or 1-hydroxymethylethyl.
18. A compound selected from any of compounds (P-0022), 10437476_1 (P-0047), (P-0048), (P-0051), (P-0052), (P-0056), (P-0057), (P-0058), (P-0077), (P-0078), 10437476_1 (P-0081), (P-0082), (P-0084), (P-0085), (P-0091), (P-0092), (P-0100), (P-0106), (P-0107), 10437476_1 (P-0108), (P-0109), (P-0111), (P-0112), (P-0232), (P-0233), (P-0235), (P-0238), (P-0241), 10437476_1 (P-0247), (P-0249), (P-0252), (P-0258), (P-0260), (P-0261), (P-0262), (P-0263), 10437476_1 (P-0266), (P-0267), (P-0268), (P-0269), (P-0271), (P-0272), (P-0275), 10437476_1 (P-0277), (P-0279), (P-0280), (P-0282), (P-0289), (P-0292), (P-0293), 10437476_1 (P-0294), (P-0318), (P-0320), (P-0321), (P-0322), (P-0327), (P-0338), 10437476_1 (P-0339), (P-0340), and (P-0345) or a pharmaceutically able salt, a hydrate, a solvate, a tautomer, or a stereosiomer thereof.
19. A compound selected from any of compounds (P-0134), (P-0135), (P-0138), (P-0146), (P-0147), 10437476_1 (P-0148), (P-0149), (P-0185), (P-0186), (P-0197), (P-0198), (P-0199), (P-0200), and (P-0213), 10437476_1 or a pharmaceutically acceptable salt, a hydrate, a e, a tautomer, or a stereoisomer thereof.
20. The compound of claim 1, wherein each R15 is independently selected from halogen, -CN, -OH, -CF3, CF3O-, C1-6alkyl, C1-6alkoxy, -NO2, benzyl, phenyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, entyl, cyclopentylmethyl, cyclohexyl, exymethyl, -OC(O)Rb, -C(O)Rb, -C(O)ORb, - NHC(O)Rb, -C(O)NHRb, -NHRb or –NRbRb.
21. A compound of formula: or a pharmaceutically acceptable salt, a hydrate, a solvate, a tautomer, or a siomer thereof.
22. A pharmaceutical composition comprising a compound of any of claims 1-21 and a pharmaceutically able excipient or carrier.
23. A pharmaceutical composition comprising a compound of any of claims 1-21 and another therapeutic agent.
24. A kit sing a compound of any of claims 1-21.
25. Use of a compound of claims 1-21 in the manufacture of a medicament for the treatment of a protein kinase mediated disease or condition.
26. The use of claim 25, wherein the protein kinase is B-Raf or a mutation thereof.
27. The use of claim 25, n said disease or condition is selected from the group consisting of ic stroke, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson’s disease, amyotrophic lateral 10437476_1 sclerosis, dementia, senile chorea, gton’s disease, neoplastic disease, complications with neoplastic disease, chemotherapy-induced hypoxia, gastrointestinal stromal , prostate , mast cell tumors, canine mast cell tumors, acute myeloid ia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic ia, multiple a, melanoma, mastocytosis, glioma, glioblastoma, astrocytoma, neuroblastoma, sarcomas, sarcomas of neuroectodermal origin, leiomyosarcoma, lung carcinoma, breast carcinoma, pancreatic carcinoma, colon carcinoma, hepatocellular carcinoma, renal carcinoma, carcinoma of the female genital tract, squamous cell carcinoma, carcinoma in situ, lymphoma, histiocytic lymphoma, non-Hodgkin’s lymphoma, MEN2 syndromes, neurofibromatosis, Schwann cell neoplasia, myelodysplastic syndrome, leukemia, tumor angiogenesis, thyroid cancer, liver cancer, bone cancer, skin cancer, brain cancer, cancer of the central nervous system, pancreatic cancer, lung cancer, small cell lung cancer, non small cell lung cancer, breast cancer, colon cancer, bladder cancer, prostate cancer, gastrointestinal tract cancer, cancer of the endometrium, fallopian tubecancer, testicular cancer, ovarian cancer, pain of neuropathic origin, pain of matory origin, acute pain, chronic pain, migraine, cardiovascular disease, heart failure, cardiac hypertrophy, thrombosis, thrombotic microangiopathy syndromes, atherosclerosis, reperfusion injury, ischemia, cerebrovascular ischemia, liver ischemia, mation, polycystic kidney e, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease, tive s, Crohn’s disease, systemic lupus erythematosis, Sjogren’s me, Wegener’s granulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave’s disease, myasthenia gravis, multiple sis, osteoarthritis, endometriosis, dermal scarring, tissue scarring, vascular restenosis, fibrotic disorders, hypereosinophilia, CNS inflammation, atitis, nephritis, atopic dermatitis, hepatitis, immunodeficiency es, severe combined immunodeficiency, organ transplant rejection, graft versus host e, renal disease, prostatic disease, diabetic nephropathy, nephrosclerosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronic renal failure, tubular necrosis, diabetes-associated renal complication, ated renal hypertrophy, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, c steatosis, insulin resistance, hyperglycemia, lipolysis obesity, infection, Helicobacter pylori infection, Influenza virus infection, fever, sepsis, pulmonary diseases, chronic ctive pulmonary disease, acute respiratory distress me, , allergy, bronchitis, emphysema, ary fibrosis, genetic developmental diseases, Noonan’s syndrome, Crouzon syndrome, acrocephalo-syndactyly type I, Pfeiffer’s syndrome, Jackson-Weiss syndrome, Costello syndrome, 10437476_1 faciocutaneoskeletal syndrome, leopard syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair or endocrine diseases, ers of bone structure or mineralization, osteoporosis, increased risk of fracture, hypercalcemia, bone metastases, Grave’s disease, Hirschsprung’s disease, lymphoedema, selective T-cell defect, X-linked agammaglobulinemia, diabetic retinopathy, alopecia, erectile dysfunction, and tuberous sclerosis.
28. The use of claim 25, wherein said disease or ion is ma, thyroid cancer or colon cancer.
29. The use of claim 25, wherein said disease or condition is melanoma.
30. The use of claim 25, wherein said e or condition is thyroid cancer.
31. The use of claim 25, wherein said disease or ion is colon cancer.
32. The use of claim 25, wherein said disease or condition is leukemia.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161440339P | 2011-02-07 | 2011-02-07 | |
| US61/440,339 | 2011-02-07 | ||
| PCT/US2012/023543 WO2012109075A1 (en) | 2011-02-07 | 2012-02-01 | Compounds and methods for kinase modulation, and indications therefor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ613786A NZ613786A (en) | 2015-09-25 |
| NZ613786B2 true NZ613786B2 (en) | 2016-01-06 |
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