COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
Cross-Reference to Related Applications
[0001] This application claims the benefit of U.S. provisional application serial no.
60/869,299, filed December 8, 2006, which is incorporated by reference herein in its entirety.
Technical Field
[0002] The invention relates to protein kinase inhibitors, more particularly novel pyrimidine
and pyridine derivatives and pharmaceutical compositions thereof, and their use as
pharmaceuticals.
Background Art
[0003] Anaplastic lymphoma kinase (ALK), a member of the insulin receptor superfamily of
receptor tyrosine kinases, has been implicated in oncogenesis in hematopoietic and nonhematopoietic
tumors. The aberrant expression of full-length ALK receptor proteins has been
reported in neuroblastomas and glioblastomas; and ALK fusion proteins have occurred in
anaplastic large cell lymphoma. The study of ALK fusion proteins has also raised the possibility
of new therapeutic treatments for patients with ALK-positive malignancies. (Pulford et al., Cell.
Mol. Life Sci. 61:2939-2953 (2004)).
[0004] Focal Adhesion Kinase (FAK) is a key enzyme in the integrin-mediated outside-in
signal cascade (D. Schlaepfer et al., Prog Biophys Mol Bioi 1999, 71, 43578). The trigger in the
signal transduction cascade is the autophosphorylation ofY397. Phosphorylated Y397 is a SH2
docking site for Src family tyrosine kinases; the bound c-Src kinase phosphorylates other
tyrosine residues in FAK. Among them, phsophorylated Y925 becomes a binding site for the
SH2 site of Grb2 small adaptor protein. This direct binding of Grb2 to F AK is one of the key
steps for the activation of down stream targets such as the Ras-ERK2/MAP kinase cascade.
[0005] Zeta-chain-associated protein kinase 70 (ZAP-70), a member of the protein tyrosine
kinase family, is of potential prognostic importance in chronic lymphocytic leukemia (CLL).
ZAP-70, known to be of importance in T and NK cell signaling but absent in normal peripheral
B cells, is expressed in the majority of the poorer prognosis unmutated CLL and absent in most
cases with mutated IgVH genes. ZAP-70 is also expressed in a minority of other B cell tumors.
(Orchard et al., Leuk. Lymphoma 46:1689-98 (2005)).
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[0006] Insulin-like growth factor (IGF-1) signaling is highly implicated in cancer, with the
IGF-1 receptor (IGF-1R) as the predominating factor. IGR-1R is important for tumor
transformation and survival of malignant cells, but is only partially involved in normal cell
growth. Targeting of IGF-1R has been suggested to be a promising option for cancer therapy.
(Larsson et al., Br. J. Cancer 92:2097-2101 (2005)).
[0007] Because of the emerging disease-related roles of ALK, FAK, ZAP-70 and IGF-1R,
there is a continuing need for compounds which may be useful for treating and preventing a
disease which responds to inhibition of ALK, FAK, ZAP-70 and/or IGF-1R.
Disclosure of the Invention
[0008] The invention relates to novel pyrimidine and pyridine derivatives and
pharmaceutical compositions thereof, and their use as pharmaceuticals.
[0009] In one aspect, the invention provides a having Formula (1):
or pharmaceutically acceptable salts thereof; wherein
I
.JVV"
R6 .... A R10
~ ~ 4" 7'A1~ ~
R B
Wis or
A1 and A4 are independently CorN;
each A2 and A3 is C, or one of A2 and A3 is N when R6 and R7 form a ring;
B and C are independently an optionally substituted 5-7 membered carbocyclic ring,
aryl, heteroaryl or heterocyclic ring containing N, 0 or S;
Z\ Z2 and Z3 are independently NR11
, C=O, CR-OR, (CR2)1_2 or =C-R12;
R1 and R2 are independently halo, OR12
, NR(R12), SR12
, or an optionally substituted C1_6
alkyl, C2_6 alkenyl or C2_6 alkynyl; or one of R 1 and R2 isH;
R3 is (CR2)o-2S02R12
, (CR2)o-2S02NRR12
, (CR2)o-2C01-2R12
, (CR2)o-2CONRR12 or cyano;
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R4
, R6, R7 and Rio are independently an optionally substituted CI_6 alkyl, C2_6 alkenyl or
C2_6 alkynyl; OR12
, NR(RI2), halo, nitro, S02R12
, (CR2)pR13 or X; or R4
, R7 and Rio are
independently H;
R, R5 and R5
' are independently H or CI_6 alkyl;
R8 and R9 are independently CI-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo or X, or one of R8
and R9 isH when RI and R2 form a ring; and provided one of R8 and R9 is X;
alternatively, RI and R2, or R6 and R7
, R7 and R8
, or R9 and R10
, when attached to a
carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic
ring, aryl, or heteroaryl or heterocyclic ring comprising N, 0 and/or S; or R7
, R8
, R9 and Rio are
absent when attached to N;
R11 isH, CI-6alkyl, C2-6alkenyl, (CR2)pCOI-2R, (CR2)pOR, (CR2)pR13
, (CR2)pNRR12
,
(CR2)pCONRR I2 or (CR2)pSOI_2R I2;
R I2 and R 13 are independently an optionally substituted 3-7 membered saturated or
partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, 0
and/or S; aryl or heteroaryl; or RI2 isH, CI_6 alkyl;
X is (CR2)qY, cyano, COI-2R12
, CONR(RI2), CONR(CR2)pNR(RI2), CONR(CR2)pOR12
,
CONR(CR2)pSRI2, CONR(CR2)pS(O)I-2RI2 or (CR2)I-6NR(CR2)pORI2;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or
a 5-12 membered heteroaryl or heterocyclic ring comprising N, 0 and/or S and attached to A 2 or
A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)q Y is 0; and
n, p and q are independently 0-4,
[0010] In the above Formula (1), RI may be halo or CI_6 alkyl; R2 isH or NH2; or RI and R2
together form an optionally substituted 5-6 membered aryl, or heteroaryl or heterocyclic ring
comprising 1-3 nitrogen atoms, In other examples, R3 in Formula (1) may be S02R12
, S02NH2,
S02NRR12
, C02NH2, CONRR12
, COI-2R12
, or cyano; and RI2 is CI-6 alkyl, an optionally
substituted c3-7 cycloalkyl, c3-7 cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl
or azetidinyL In yet other examples, R5
, R5
', R7 and Rio in Formula (1) are independently H, and
n is 0, In other examples, R6 in Formula (1) may be halo or OR12
, and RI2 is CI_6 alkyL
[0011] In one embodiment, the invention provides compounds having Formula (2):
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wherein R1 is halo or C1_6 alkyl;
R2 isH· or
'
PCT /US2007 /085304
(2)
R1 and R2 together form an optionally substituted 5-6 membered heteroaryl or
heterocyclic ring comprising one or two nitrogen atoms;
R6 is isopropoxy or methoxy;
one of R8 and R9 is (CR2)qY and the other is C1-6 alkyl, cyano, C01-2R12
, CONR(R12) or
CONR(CR2)pNR(R 12);
y is an optionally substituted c3-7 cycloalkyl, c3-7 cycloalkenyl, or phenyl; or y is
pyridyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, benzimidazolyl, pyrrolidinyl, piperazinyl,
piperidinyl, morpholinyl, azetidinyl, heptamethyleneimine or octamethyleneimine, each of
which is attached to the phenyl ring via a carbon atom when q in (CR2)q Y is 0;
n is 0-1; and
q is 0-4.
[0012] In the above Formula (2), one of R8 and R9 may be (CR2)q Y and the other is C1_6
alkyl; and nand q are independently 0. In some examples, Y is pyrrolidinyl, piperidinyl,
azetidinyl. In other examples, R1 is halo or C1_6 alkyl; and R2 is H.
[0013] In another embodiment, the invention provides compounds having Formula (3A) or
(3B):
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(3A)
wherein B and C together form
0
or
Z1
' Z2 and Z3 together form
5
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0
0
\ I 75
0
R1 is halo or C1-6 alkyl;
R2 isH; or
PCT /US2007 /085304
HO or
OH
or tautomers thereof;
R 1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl,
or heteroaryl or heterocyclic ring comprising N, 0 and/or S; and
R6 is isopropoxy or methoxy.
[0014] In the above Formula (3A) or (3B), each R11 may be (CR2)pC01_2R, (CR2)pOR,
(CR2)pR13
, (CR2)pNRR12 or (CR2)pCONRR12;
Rand R12 are independently H or C1_6 alkyl; and
R13 is an optionally substituted piperidinyl, azetidiyl, tetrahydropyranyl, cyclohexyl,
morpholinyl, pyrrolidinyl, heptamethyleneimine, octamethyleneimine, a bicyclic amine or
diamine derivative, quinuclidin-3-yl, 8-methyl-8-aza-bicyclo[3.2.l]oct-6-yl], or 9-methyl-9-azabicyclo[
4.2.l]nonan-7-yl.
[0015] In yet another embodiment, the invention provides compounds having Formula ( 4A)
or Formula (4B):
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wherein R1 is halo or C1-6 alkyl;
R2 isH; or
PCT /US2007 /085304
R8 (4B);
R 1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl,
or heteroaryl or heterocyclic ring comprising N, 0 and/or S;
R6 is isopropoxy or methoxy; and
B2 and B3 are independently an optionally substituted 5-6 membered aryl or heteroaryl
containing N, 0 or S.
[0016] In another aspect, the invention provides compounds having Formula (5):
or pharmaceutically acceptable salts thereof; wherein
I
..JVV'
R6.. ... A R10
~ ~ 4"
7'A1':::,... ~
R B
Wis or
A1 and A4 are independently CorN;
each A2 and A3 is C, or one of A2 and A3 is N when R6 and R7 form a ring;
B and C are independently an optionally substituted 5-7 membered carbocyclic ring,
aryl, heteroaryl or heterocyclic ring containing N, 0 or S;
Z\ Z2 and Z3 are independently NR11
, C=O, CR-OR, (CR2)1_2 or =C-R12;
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RI and R2 are independently halo, OR12
, NR(RI2), SR12
, or an optionally substituted CI_6
alkyl, C2_6 alkenyl or C2_6 alkynyl; or one of R I and R2 isH;
R3 is (CR2)o-2S02R12
, (CR2)o-2S02NRR12
, (CR2)o-2COI-2R12
, (CR2)o-2CONRRI2 or cyano;
R4
, R6, and R7 and Rio when attached to a carbon atom, are independently H, an
optionally substituted CI-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12
, NR(RI2), halo, nitro, S02R12
,
(CR2)pR13 or X; provided R6 and R7 are not both H;
R, R5 and R5
' are independently H or CI_6 alkyl;
R8 and R9 are independently CI-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo or X, or one of R8
and R9 isH; and provided one of R8 and R9 is X;
alternatively, RI and R2, or R6 and R7
, R7 and R8
, or R9 and R10
, when attached to a
carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic
ring, aryl, or heteroaryl or heterocyclic ring comprising N, 0 and/or S; or R7
, R8
, R9 and Rio are
absent when attached to N;
11 , 13 I2
R 1s H, CI-6 alkyl, C2-6 alkenyl, (CR2)pCOI-2R, (CR2)pOR, (CR2)pR , (CR2)pNRR ,
(CR2)pCONRR I2 or (CR2)pSOI_2R I2;
R I2 and R 13 are independently an optionally substituted 3-7 membered saturated or
partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, 0
and/or S; aryl or heteroaryl; or RI2 isH, CI_6 alkyl;
X is (CR2)qY, cyano, COI-2R12
, CONR(RI2), CONR(CR2)pNR(RI2), CONR(CR2)pOR12
,
CONR(CR2)pSRI2, CONR(CR2)pS(O)I-2RI2 or (CR2)I-6NR(CR2)pORI2;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or
a 5-12 membered heteroaryl or heterocyclic ring comprising N, 0 and/or S and attached to A 2 or
A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)q Y is 0; and
n, p and q are independently 0-4,
[0017] In yet another aspect, the present invention provides pharmaceutical compositions
comprising a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), and a
pharmaceutically acceptable excipient
[0018] In yet another aspect, the invention provides methods for modulating ALK, FAK,
ZAP-70 and/or IGF-1R, comprising administering to a system or a subject in need thereof, a
therapeutically effective amount of a compound having Formula (1), (2), (3A), (3B), (4A), (4B)
or (5), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby
modulating said ALK, FAK, ZAP-70 and/or IGF-1R The invention also provides methods to
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treat, ameliorate or prevent a condition which responds to inhibition of ALK, FAK, ZAP-70
and/or IGF-1R, comprising administering to a system or subject in need of such treatment an
effective amount of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), or
pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally in
combination with a second therapeutic agent, thereby treating said condition. Alternatively, the
present invention provides the use of a compound having Formula (1), (2), (3A), (3B), (4A),
(4B) or (5) in the manufacture of a medicament for treating a condition mediated by ALK, FAK,
ZAP-70 and/or IGF-1R. In particular embodiments, the compounds of the invention may be
used alone or in combination with a second therapeutic agent to treat a condition mediated by
ALK, wherein said condition is an autoimmune disease, a transplantation disease, an infectious
disease or a cell proliferative disorder.
[0019] Furthermore, the invention provides methods for treating a cell proliferative disorder,
comprising administering to a system or subject in need of such treatment an effective amount of
a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), or pharmaceutically
acceptable salts or pharmaceutical compositions thereof, and optionally in combination with a
second therapeutic agent, thereby treating said condition. Alternatively, the present invention
provides the use of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5) in the
manufacture of a medicament for treating a cell-proliferative disorder. In particular examples,
the compounds of the invention may be used alone or in combination with a chemotherapeutic
agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma,
melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic,
neuronal, lung, uterine or gastrointestinal tumor.
[0020] In the above methods for using the compounds of the invention, a compound having
Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may be administered to a system comprising cells
or tissues, or to a mammalian subject such as a human or animal subject.
Definitions
[0021] "Alkyl" refers to a moiety and as a structural element of other groups, for example
halo-substituted-alkyl and alkoxy, and may be straight-chained or branched. An optionally
substituted alkyl, alkenyl or alkynyl as used herein may be optionally halogenated (e.g., CF3), or
may have one or more carbons that is substituted or replaced with a heteroatom, such as NR, 0
or S (e.g., -OCH2CH20-, alkylthiols, thioalkoxy, alkylamines, etc).
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[0022] "Aryl" refers to a monocyclic or fused bicyclic aromatic ring containing carbon
atoms. "Arylene" means a divalent radical derived from an aryl group. For example, an aryl
group may be phenyl, indenyl, indanyl, naphthyl, or 1,2,3,4-tetrahydronaphthalenyl, which may
be optionally substituted in the ortho, meta or para position.
[0023] "Heteroaryl" as used herein is as defined for aryl above, where one or more of the
ring members is a heteroatom. Examples of heteroaryls include but are not limited to pyridyl,
pyrazinyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl,
benzothiopyranyl, benzo[1,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl,
oxazolyl, isoxazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyrazolyl, thienyl, pyrrolyl,
isoquinolinyl, purinyl, thiazolyl, tetrazinyl, benzothiazolyl, oxadiazolyl, benzoxadiazolyl, etc.
[0024] A "carbocyclic ring" as used herein refers to a saturated or partially unsaturated,
monocyclic, fused bicyclic or bridged polycyclic ring containing carbon atoms, which may
optionally be substituted, for example, with =0. Examples of carbocyclic rings include but are
not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone,
etc.
[0025] A "heterocyclic ring" as used herein is as defined for a carbocyclic ring above,
wherein one or more ring carbons is a heteroatom. For example, a heterocyclic ring may contain
N, 0, S, -N=, -S-, -S(O), -S(Oh-, or -NR- wherein R may be hydrogen, C14alkyl or a protecting
group. Examples of heterocyclic rings include but are not limited to morpholino, pyrrolidinyl,
pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, 1 ,4-dioxa-8-aza-spiro[ 4.5]dec-8-yl,
1,2,3,4-tetrahydroquinolinyl, etc. Heterocyclic rings as used herein may encompass bicyclic
amines and bicyclic diamines.
[0026] The terms "co-administration" or "combined administration" or the like as used
herein are meant to encompass administration of the selected therapeutic agents to a single
patient, and are intended to include treatment regimens in which the agents are not necessarily
administered by the same route of administration or at the same time.
[0027] The term "pharmaceutical combination" as used herein refers to a product obtained
from mixing or combining active ingredients, and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed combination" means that the active
ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient
simultaneously in the form of a single entity or dosage. The term "non-fixed combination"
means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both
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administered to a patient as separate entities either simultaneously, concurrently or sequentially
with no specific time limits, wherein such administration provides therapeutically effective
levels of the active ingredients in the body of the patient. The latter also applies to cocktail
therapy, e.g. the administration of three or more active ingredients.
[0028] The term "therapeutically effective amount" means the amount of the subject
compound that will elicit a biological or medical response in a cell, tissue, organ, system, animal
or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
[0029] The term "administration" or "administering" of the subject compound means
providing a compound of the invention and prodrugs thereof to a subject in need of treatment.
Modes of Carrying Out the Invention
[0030] The invention provides novel pyrimidine and pyridine derivatives and pharmaceutical
compositions thereof, and methods for using such compounds.
[0031] In one aspect, the invention provides a having Formula (1):
or pharmaceutically acceptable salts thereof; wherein
I
.JVV"
R6 .... A R10
~ ~ 4" 7'A1~ ~
R B
Wis or
A1 and A4 are independently CorN;
each A2 and A3 is C, or one of A2 and A3 is N when R6 and R7 form a ring;
B and C are independently an optionally substituted 5-7 membered carbocyclic ring,
aryl, heteroaryl or heterocyclic ring containing N, 0 or S;
Z\ Z2 and Z3 are independently NR11
, C=O, CR-OR, (CR2) 1_2 or =C-R12
;
R1 and R2 are independently halo, OR12
, NR(R12
), SR12
, or an optionally substituted C1_6
alkyl, C2_6 alkenyl or C2_6 alkynyl; or one of R 1 and R2 isH;
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R3 is (CR2)o-2S02R12
, (CR2)o-2S02NRR12
, (CR2)o-2COI-2R12
, (CR2)o-2CONRRI2 or cyano;
R4
, R6, R7 and Rio are independently an optionally substituted CI_6 alkyl, C2_6 alkenyl or
C2_6 alkynyl; OR12
, NR(RI2), halo, nitro, S02R12
, (CR2)pR13 or X; or R4
, R7 and Rio are
independently H;
5 5' R, R and R are independently H or CI_6 alkyl;
R8 and R9 are independently CI_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, halo or X, or one of R8
and R9 isH when RI and R2 form a ring; and provided one of R8 and R9 is X;
alternatively, RI and R2, or R6 and R7
, R7 and R8
, or R9 and R10
, when attached to a
carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic
ring, aryl, or heteroaryl or heterocyclic ring comprising N, 0 and/or S; or R7
, R8
, R9 and Rio are
absent when attached to N;
R11 isH, CI-6alkyl, C2-6alkenyl, (CR2)pCOI-2R, (CR2)pOR, (CR2)pR13
, (CR2)pNRR12
,
(CR2)pCONRR I2 or (CR2)pSOI_2R I2;
R I2 and R 13 are independently an optionally substituted 3-7 membered saturated or
partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, 0
and/or S; aryl or heteroaryl; or RI2 isH, CI_6 alkyl;
X is (CR2)qY, cyano, COI-2R12
, CONR(RI2), CONR(CR2)pNR(RI2), CONR(CR2)pOR12
,
CONR(CR2)pSRI2, CONR(CR2)pS(O)I-2RI2 or (CR2)I-6NR(CR2)PORI2;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or
a 5-12 membered heteroaryl or heterocyclic ring comprising N, 0 and/or S and attached to A 2 or
A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)q Y is 0; and
n, p and q are independently 0-4.
[0032] In one embodiment, the invention provides compounds having Formula (2):
(2)
wherein RI is halo or CI-6 alkyl;
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R2 isH; or
R1 and R2 together form an optionally substituted 5-6 membered heteroaryl or
heterocyclic ring comprising one or two nitrogen atoms;
R6 is isopropoxy or methoxy;
one of R8 and R9 is (CR2)qY and the other is C1-6 alkyl, cyano, C01-2R12
, CONR(R12) or
CONR(CR2)pNR(R 12);
y is an optionally substituted c3-7 cycloalkyl, c3-7 cycloalkenyl, or phenyl; or y is
pyridyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, benzimidazolyl, pyrrolidinyl, piperazinyl,
piperidinyl, morpholinyl, azetidinyl, heptamethyleneimine or octamethyleneimine, each of
which is attached to the phenyl ring via a carbon atom when q in (CR2)q Y is 0;
n is 0-1; and
q is 0-4.
[0033] In another embodiment, the invention provides compounds having Formula (3A) or
(3B):
(3A)
wherein B and C together form
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Z1
' Z2 and Z3 together form
0
0
\ I 75
0
R1 is halo or C1-6 alkyl;
R2 isH· or
'
PCT /US2007 /085304
0
or
HO or
OH
or tautomers thereof;
R 1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl,
or heteroaryl or heterocyclic ring comprising N, 0 and/or S; and
R6 is isopropoxy or methoxy.
[0034] In yet another embodiment, the invention provides compounds having Formula (4A)
or Formula (4B):
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wherein R1 is halo or C1-6 alkyl;
R2 isH; or
PCT /US2007 /085304
R8 (4B);
R 1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl,
or heteroaryl or heterocyclic ring comprising N, 0 and/or S;
R6 is isopropoxy or methoxy; and
B2 and B3 are independently an optionally substituted 5-6 membered aryl or heteroaryl
containing N, 0 or S.
[0035] In another aspect, the invention provides compounds having Formula (5):
or pharmaceutically acceptable salts thereof; wherein
I
..JVV'
R6.. ... A R10
~ ~ 4"
7'A1':::,... ~
R B
Wis or
A1 and A4 are independently CorN;
each A2 and A3 is C, or one of A2 and A3 is N when R6 and R7 form a ring;
B and C are independently an optionally substituted 5-7 membered carbocyclic ring,
aryl, heteroaryl or heterocyclic ring containing N, 0 or S;
Z\ Z2 and Z3 are independently NR11
, C=O, CR-OR, (CR2)1_2 or =C-R12;
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RI and R2 are independently halo, OR12
, NR(RI2), SR12
, or an optionally substituted CI_6
alkyl, C2_6 alkenyl or C2_6 alkynyl; or one of R I and R2 isH;
R3 is (CR2)o-2S02R12
, (CR2)o-2S02NRR12
, (CR2)o-2COI-2R12
, (CR2)o-2CONRRI2 or cyano;
R4
, R6, and R7 and Rio when attached to a carbon atom, are independently H, an
optionally substituted CI-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12
, NR(RI2), halo, nitro, S02R12
,
(CR2)pR13 or X; provided R6 and R7 are not both H;
R, R5 and R5
' are independently H or CI_6 alkyl;
R8 and R9 are independently CI-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo or X, or one of R8
and R9 isH; and provided one of R8 and R9 is X;
alternatively, RI and R2, or R6 and R7
, R7 and R8
, or R9 and R10
, when attached to a
carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic
ring, aryl, or heteroaryl or heterocyclic ring comprising N, 0 and/or S; or R7
, R8
, R9 and Rio are
absent when attached to N;
11 , 13 I2
R 1s H, CI-6 alkyl, C2-6 alkenyl, (CR2)pCOI-2R, (CR2)pOR, (CR2)pR , (CR2)pNRR ,
(CR2)pCONRR I2 or (CR2)pSOI_2R I2;
R I2 and R 13 are independently an optionally substituted 3-7 membered saturated or
partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, 0
and/or S; aryl or heteroaryl; or RI2 isH, CI_6 alkyl;
X is (CR2)qY, cyano, COI-2R12
, CONR(RI2), CONR(CR2)pNR(RI2), CONR(CR2)pOR12
,
CONR(CR2)pSRI2, CONR(CR2)pS(O)I-2RI2 or (CR2)I-6NR(CR2)pORI2;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or
a 5-12 membered heteroaryl or heterocyclic ring comprising N, 0 and/or S and attached to A 2 or
A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)q Y is 0; and
n, p and q are independently 0-4,
[0036] In each of the above formula, Y orR 13 may independently be heterocyclic rings,
which may be a bicyclic amine or bicyclic diamine, Examples of bicyclic amine and bicyclic
diamines include but are not limited to an optionally substituted hexanemethyleneimine;
heptamethyleneimine; quinuclidine; 3-azabicyclo(3,3,0)octane; 3,8-diazabicyclo[3,2,1]octane;
octahydro-1H-pyrido[3,4-C]azepine; octahydropyrrolizine; 6-azabicyclo[3,2, 1]octane; 3-
azabicyclo[3 ,2, 1 ]octane; 2,5-diazabicyclo[2,2, 1 ]heptane; 1-azabicyclo[2,2, 1 ]heptane; 2-
azabicyclo[2,2, 1 ]heptane; 1 ,4-diazabicyclo[ 4,4,0]decane; 1 ,4-diazabicyclo[ 4,3 ,O]nonane; 1-
azabicyclo[3,2, 1]octane; 3-azabicyclo[3,3,0]octane; 8-azabicyclo[3,2, 1]octane; 3,9-
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diazabicyclo[ 4,2, 1]nonane; octahydropyrrolo[3,4-C]pyrrole; octahydropyrrolo[3,4-B]pyrrole;
hexahydropyrrolo[3,2-B ]pyrrole; hexahydropyrrolo[3,2-C]pyrrole; 1 ,4-diazacyclooctane; 1,5-
diazacyclooctane; 3,7 -diazabicyclo[ 4,2,0]octane; 3, 7 -diazabicyclo[3 ,3, 1 ]nonane;
octahydropyrrolo [3 ,4-C]pyridine; octahydropyrrolo [3 ,4-B ]pyridine;
octahydrocyclopenta[C]pyrrolidine; hexahydrocyclopenta[C]pyrrolidine; 8-
azabicyclo[3,2, 1]octane; decahydroquinoline; decahydroisoquinoline; decahydropyrido[3,4-
B]azepine; decahydropyrido[ 4,3-B]azepine; 9-azabicyclo[3,3, 1]nonane; bispidine; 3-
azabicyclo[3, 1 ,O]hexane; 8-azabicyclo[3 ,2, 1 ]octane; 2-azabicyclo[3 .3 .1 ]nonane;
tetrahydroquinoline; tetrahydroisoquinoline; 2,5-diazabicyclo[2,2,2]octane; decahydro-2,7-
naphthyridine; 1,4-diazepane; azonane; octahydro-1H-indole; octahydro-1H-isoindole; 2-
azabicyclo[3,3,0]octane; 6-azabicyclo[3,2, 1]octane; 7 -aza-bicyclo[2.2.1]heptane;
decahydropyrazino[1 ,2-a]azepine; 3,8-diaza-bicyclo[3,2, 1]octane; 3-azabicyclo[3,2, 1]octane; 3-
aza-tricyclo[ 4,2, 1,0(2,5)]nonane; 2,6-diazaspiro[3,5]nonane; 6-azabicyclo[2, 1 ,O]hexane, etc.
[0037] In each of the above formula, any asymmetric carbon atoms may be present in the
(R)-, (S)-or (R,S)-configuration. The compounds may thus be present as mixtures of isomers or
as pure isomers, for example, as pure enantiomers or diastereomers. The invention further
encompasses possible tautomers of the inventive compounds.
[0038] In each of the above formula, each optionally substituted moiety may be substituted
with C1_6 alkyl, C2_6 alkenyl or C3_6 alkynyl, each of which may be optionally halogenated or
optionally having a carbon that may be replaced or substituted with N, S, 0, or a combination
thereof (for example, hydroxylCrC8alkyl, CrC8alkoxyCrC8alkyl); halo, amino, amidino, C1_6
alkoxy; hydroxyl, methylenedioxy, carboxy; cl-8 alkylcarbonyl, cl-8 alkoxycarbonyl, carbamoyl,
C1_8 alkylcarbamoyl, sulfamoyl, cyano, oxo, nitro, or an optionally substituted carbocyclic ring,
heterocyclic ring, aryl or heteroaryl as previously described.
Pharmacology and Utility
[0039] The compounds of the invention and their pharmaceutically acceptable salts exhibit
valuable pharmacological properties when tested in vitro in cell-free kinase assays and in
cellular assays, and are therefore useful as pharmaceuticals.
[0040] In one aspect, compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may
inhibit the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) and the fusion protein
of NPM-ALK. This protein tyrosine kinase results from a gene fusion of nucleophosmin (NPM)
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and ALK, rendering the protein tyrosine kinase activity of ALK ligand independent. NPM-ALK
plays a key role in signal transmission in a number of hematopoetic and other human cells
leading to hematological and neoplastic diseases, for example in anaplastic large-cell lymphoma
(ALCL) and non-Hodgkin's lymphomas (NHL), specifically in ALK+NHL or Alkomas, in
inflammatory myofibroblastic tumors (IMT) and neuroblastomas. (Duyster et al. 2001
Oncogene 20, 5623-5637). In addition to NPM-ALK, other gene fusions have been identified in
human hematological and neoplastic diseases; for example, TPM3-ALK (a fusion of nonmuscle
tropomyosin with ALK).
[0041] The inhibition of ALK tyrosine kinase activity may be demonstrated using known
methods, for example using the recombinant kinase domain of the ALK in analogy to the
VEGF-R kinase assay described in J. Wood et al. Cancer Res. 60, 2178-2189 (2000). In
general, in vitro enzyme assays using GST-ALK protein tyrosine kinase are performed in 96-
well plates as a filter binding assay in 20 mM Tris HCl, pH= 7.5, 3 mM MgCh, 10 mM MnCh,
1 mM DTT, 0.111Ci/assay (=30 Ill) [y-33P]-ATP, 211M ATP, 3 11g/mL poly (Glu, Tyr 4:1) PolyBY
(Sigma P-0275), 1 % DMSO, 25 ng ALK enzyme. Assays are incubated for 10 min at
ambient temperature. Reactions are terminated by adding 50 111 of 125 mM EDT A, and the
reaction mixture is transferred onto a MAIP Multiscreen plate (Millipore, Bedford, MA, USA),
previously wet with methanol, and rehydrated for 5 min with H20. Following washing (0.5 %
H3P04), plates are counted in a liquid scintillation counter. ICso values are calculated by linear
regression analysis of the percentage inhibition.
[0042] Compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may potently inhibit
the growth of human NPM-ALK overexpressing murine BaF3 cells (DSMZ Deutsche
Sammiung von Mikroorganismen und Zelikulturen GmbH, Germany). The expression of NPMALK
may be achieved by transfecting the BaF3 cell line with an expression vector pClneo ™
(Promega Corp., Madison WI, USA) coding for NPM-ALK and subsequent selection of G418
resistant cells. Non-transfected BaF3 cells depend on IL-3 for cell survival. In contrast, NPMALK
expressing BaF3 cells (named BaF3-NPM-ALK hereinafter) can proliferate in the absence
of IL-3 because they obtain proliferative signal through NPM-ALK kinase. Putative inhibitors of
the NPM-ALK kinase therefore abolish the growth signal and may result in antiproliferative
activity. The antiproliferative activity of putative inhibitors of the NPM-ALK kinase can
however be overcome by addition of IL-3, which provides growth signals through an NPM-
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ALK independent mechanism. An analogous cell system using FL T3 kinase has also been
described (see, E Weisberg et al. Cancer Cell; 1, 433-443 (2002)).
[0043] The inhibitory activity of the compounds of the invention may be determined as
follows. In general, BaF3-NPM-ALK cells (15,000/microtitre plate well) are transferred to 96-
well microtitre plates. Test compounds dissolved in dimethyl sulfoxide (DMSO) are added in a
series of concentrations (dilution series) in such a manner that the final concentration of DMSO
is not greater than 1 % (v/v). After the addition, the plates are incubated for two days during
which the control cultures without test compound are able to undergo two cell-division cycles.
The growth of the BaF3-NPM-ALK cells is measured by means of YO PRO™ staining [T
Idziorek et al. J. Immunol. Methods; 185: 249-258 (1995)]: 25 111 of lysis buffer comprising 20
mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4% NP40, 20 mM EDTA and 20 mM
is added to each well. Cell lysis is completed within 60 min at room temperature and total
amount of YOPRO™ bound to DNA is determined by measurement using the Cytofluor II 96-
well reader (PerSeptive Biosystems) with the following settings: Excitation (nm) 485/20 and
Emission (nm) 530/25.
[0044] ICso values may be determined by a computer-aided system using the formula:
ICso = [(ABStescABSstart)I(ABScontrol-ABSstart)] X 100. (ABS = absorption)
[0045] The ICso value in those experiments is given as that concentration of the test
compound in question that results in a cell count that is 50 % lower than that obtained using the
control without inhibitor. The compounds of the invention in free form or in pharmaceutically
acceptable salt form, may exhibit valuable pharmacological properties, for example, as indicated
by the in vitro tests described in this application. In general, compounds of the invention have
ICso values from 1 nM to 10 11M. In some examples, compounds of the invention have ICso
values from 0.0111M to 5 11M. In other examples, compounds of the invention have ICso values
from 0.01 11M to 111M, or more particularly from 1 nM to 1 11M. In yet other examples,
compounds of the invention have ICso values of less than 1 nM or more than 10 11M. The
compounds of the invention may exhibit a percentage inhibition of greater than 50%, or in other
embodiments, may exhibit a percentage inhibition greater than about 70%, against ALK at 10
!lM.
[0046] The antiproliferative action of the inventive compounds may also be determined in
the human KARPAS-299lymphoma cell line (DSMZ Deutsche Sammiung von
Mikroorganismen und Zelikulturen GmbH, Braunschweig, Germany, described in WG Dirks et
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al. Int. J. Cancer 100, 49-56 (2002)) using the same methodology described above for the BaF3-
NPM-ALK cell line. In some embodiments, compounds of the invention may exhibit inhibitory
activity with an IC50 in the range from approximately 0.01 to 1 11M. The action of the inventive
compounds on autophosphorylation of the ALK may be determined in the human KARPAS-299
lymphoma cell line by means of an immunoblot as described in WG Dirks et al. Int. J. Cancer
100, 49-56 (2002).
[0047] In another aspect, the compounds of the invention may inhibit Focal Adhesion
Kinase (F AK), and may be useful as pharmaceuticals to treat conditions caused by a malfunction
of signal cascades connected with F AK, such as in the treatment of particular tumors. The
inhibition of endogenous FAK signaling results in reduced motility, and in some cases induces
cell death. On the other hand, enhancing F AK signaling by exogenous expression increases cell
motility. In addition, FAK is overexpressed in invasive and metastatic epithelial, mesenchymal,
thyroid and prostate cancers. Consequently, an inhibitor of FAK is likely to be a drug for antitumor
growth and metastasis. The compounds of the invention may thus be useful to prevent
and/or treat a vertebrate and more particularly a mammal, affected by a neoplastic disease, in
particular breast tumor, cancer of the bowel (colon and rectum), stomach cancer and cancer of
the ovary and prostate, non-small cell lung cancer, small cell lung cancer, cancer of liver,
melanoma, bladder tumor and cancer of head and neck.
[0048] The relation between FAK inhibition and immuno-system is described e.g. in G.A.
van Seventer et al., Eur. J. Immunol. 2001, 31, 1417-1427. Therefore, the compounds of the
invention are, for example, useful to prevent and/or treat a vertebrate and more particularly a
mammal, affected by immune system disorders, diseases or disorders mediated by T
lymphocytes, B lymphocytes, mast cells and/or eosinophils e.g. acute or chronic rejection of
organ or tissue allo-or xenografts, atherosclerosis, vascular occlusion due to vascular injury such
as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease,
CNS disease such as Alzheimer disease or amyotrophic lateral sclerosis; cancer; infectious
disease such as AIDS; septic shock or adult respiratory distress syndrome, ischemia/reperfusion
injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or
traumatic shock.
[0049] In yet another aspect, the compounds of the invention may inhibit zeta chainassociate
protein 70 (ZAP-70). ZAP-70 protein tyrosine kinase interaction of the agents of the
invention may be demonstrated, for example, by their ability to prevent phosphorylation of
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LA T -11 (linker for activation of T cell) by human ZAP-70 protein tyrosine kinase in aqueous
solution. Therefore, the compounds of the invention may be useful for the prevention or
treatment of disorders or diseases where ZAP-70 inhibition plays a role.
[0050] The compounds of the invention may also inhibit insulin like growth-factor receptor
1 (IGF-1R), and may be useful in the treatment of IGF-1 R mediated diseases. Examples of
IGF-1R mediated diseases include but are not limited to proliferative diseases, such as tumors,
for example breast, renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine
and gastro intestinal tumors, as well as osteosarcomas and melanomas. The efficacy of the
compounds of the invention as inhibitors of IGF-1R tyrosine kinase activity may be
demonstrated using a cellular capture ELISA. In this assay, the activity of the compounds of the
invention against (IGF-1 )-induced autophosphorylation of the IGF-1R is determined.
[0051] The compounds of the invention may also be useful in the treatment and/or
prevention of acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g.
rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis,
multiple sclerosis, myasthenia gravis, diabetes (type I and II) and the disorders associated
therewith, respiratory diseases such as asthma or inflammatory liver injury, inflammatory
glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses,
inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic
contact dermatitis, irritant contact dermatitis and further eczematous dermatitis, seborrhoeic
dermatitis), s inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or
uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.
[0052] In accordance with the foregoing, the present invention provides:
(1) a compound of the invention for use as a pharmaceutical;
(2) a compound of the invention for use as an ALK inhibitor, FAK inhibitor, ZAP-70
inhibitor and/or IGF-1R inhibitor, for example for use in any of the particular indications
hereinbefore set forth;
(3) a pharmaceutical composition, e.g. for use in any of the indications herein before set
forth, comprising a compound of the invention as active ingredient together with one or more
pharmaceutically acceptable diluents or carriers;
( 4) a method for the treatment of any particular indication set forth hereinbefore in a
subject in need thereof which comprises administering an effective amount of a compound of the
invention or a pharmaceutical composition comprising same;
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(5) the use of a compound of the invention for the manufacture of a medicament for the
treatment or prevention of a disease or condition in which ALK, FAK, ZAP-70 and/or IGF-1R
activation plays a role or is implicated;
(6) the method as defined above under (4) comprising co-administration, e.g.
concomitantly or in sequence, of a therapeutically effective amount of a compound of the
invention and one or more further drug substances, said further drug substance being useful in
any of the particular indications set forth hereinbefore;
(7) a combination comprising a therapeutically effective amount of a compound of the
invention and one or more further drug substances, said further drug substance being useful in
any of the particular indications set forth hereinbefore;
(8) use of a compound of the invention for the manufacture of a medicament for the
treatment or prevention of a disease which responds to inhibition of the anaplastic lymphoma
kinase;
(9) the use according to (8), wherein the disease to be treated is selected from anaplastic
large cell lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors,
neuroblastomas and neoplastic diseases;
(10) the use according to (8) or (9), wherein the compound is or a pharmaceutically
acceptable; salt of any one of the examples;
( 11) a method for the treatment of a disease which responds to inhibition of the
anaplastic lymphoma kinase, especially a disease selected from anaplastic large-cell lymphoma,
non Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas and
neoplastic diseases, comprising administering an effective amount of a compound of the
invention or a pharmaceutically acceptable salt thereof.
Administration and Pharmaceutical Compositions
[0053] In general, compounds of the invention will be administered in therapeutically
effective amounts via any of the usual and acceptable modes known in the art, either singly or in
combination with one or more therapeutic agents. A therapeutically effective amount may vary
widely depending on the severity of the disease, the age and relative health of the subject, the
potency of the compound used and other factors known to those of ordinary skill in the art. For
example, for the treatment of neoplastic diseases and immune system disorders, the required
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dosage will also vary depending on the mode of administration, the particular condition to be
treated and the effect desired.
[0054] In general, satisfactory results are indicated to be obtained systemically at daily
dosages of from about 0.01 to about 100 mg/kg per body weight, or particularly, from about
0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g.
humans, may be in the range from about 0.5 mg to about 2000 mg, or more particularly, from
about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to
four times a day or in retard form. Suitable unit dosage forms for oral administration comprise
from ca. 1 to 50 mg active ingredient.
[0055] Compounds of the invention may be administered as pharmaceutical compositions by
any conventional route; for example, enterally, e.g., orally, e.g., in the form of tablets or
capsules; parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g.,
in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
[0056] Pharmaceutical compositions comprising a compound of the present invention in free
form or in a pharmaceutically acceptable salt form in association with at least one
pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner
by mixing, granulating, coating, dissolving or lyophilizing processes. For example,
pharmaceutical compositions comprising a compound of the invention in association with at
least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional
manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for
oral administration contain, for example, from about 0.1 mg to about 500 mg of active
substance.
[0057] In one embodiment, the pharmaceutical compositions are solutions of the active
ingredient, including suspensions or dispersions, such as isotonic aqueous solutions. In the case
of lyophilized compositions comprising the active ingredient alone or together with a carrier
such as mannitol, dispersions or suspensions can be made up before use. The pharmaceutical
compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting
or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or
buffers. Suitable preservatives include but are not limited to antioxidants such as ascorbic acid,
or microbicides, such as sorbic acid or benzoic acid. The solutions or suspensions may further
comprise viscosity-increasing agents, including but not limited to, sodium
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carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or
solubilizers, e.g. Tween 80 (polyoxyethylene(20)sorbitan mono-oleate).
[0058] Suspensions in oil may comprise as the oil component the vegetable, synthetic, or
semi-synthetic oils customary for injection purposes. Examples include liquid fatty acid esters
that contain as the acid component a long-chained fatty acid having from 8 to 22 carbon atoms,
or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include
but are not limited to lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid,
margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for
example oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, and if desired, may
contain antioxidants, for example vitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene.
The alcohol component of these fatty acid esters may have six carbon atoms and may be
monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol. Suitable alcohol
components include but are not limited to methanol, ethanol, propanol, butanol or pentanol or
isomers thereof; glycol and glycerol.
[0059] Other suitable fatty acid esters include but are not limited ethyl-oleate, isopropyl
myristate, isopropyl palmitate, LABRAFIL® M 2375, (polyoxyethylene glycerol),
LABRAFIL® M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis of
apricot kernel oil and comprising glycerides and polyethylene glycol ester), LABRASOL ™
(saturated polyglycolized glycerides prepared by alcoholysis of TCM and comprising glycerides
and polyethylene glycol ester; all available from GaKefosse, France), and/or MIGL YOL® 812
(triglyceride of saturated fatty acids of chain length C8 to C12 from Htils AG, Germany), and
vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or
groundnut oil.
[0060] Pharmaceutical compositions for oral administration may be obtained, for example,
by combining the active ingredient with one or more solid carriers, and if desired, granulating a
resulting mixture, and processing the mixture or granules by the inclusion of additional
excipients, to form tablets or tablet cores.
[0061] Suitable carriers include but are not limited to fillers, such as sugars, for example
lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for
example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as
starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl
methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if
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desired, disintegrators, such as the above-mentioned starches, carboxymethyl starch, crosslinked
polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional
excipients include flow conditioners and lubricants, for example silicic acid, talc, stearic acid or
salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives
thereof.
[0062] Tablet cores may be provided with suitable, optionally enteric, coatings through the
use of, inter alia, concentrated sugar solutions which may comprise gum arable, talc,
polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in
suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings,
solutions of suitable cellulose preparations, such as acetylcellulose phthalate or
hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet
coatings, for example for identification purposes or to indicate different doses of active
ingredient.
[0063] Pharmaceutical compositions for oral administration may also include hard capsules
comprising gelatin or soft-sealed capsules comprising gelatin and a plasticizer, such as glycerol
or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for
example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or
magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be
dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid
polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and
detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
[0064] Pharmaceutical compositions suitable for rectal administration are, for example,
suppositories comprising a combination of the active ingredient and a suppository base. Suitable
suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons,
polyethylene glycols or higher alkanols.
[0065] Pharmaceutical compositions suitable for parenteral administration may comprise
aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble
salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example
sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers. The active
ingredient, optionally together with excipients, can also be in the form of a lyophilizate and can
be made into a solution before parenteral administration by the addition of suitable solvents.
Solutions such as are used, for example, for parenteral administration can also be employed as
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infusion solutions. The manufacture of injectable preparations is usually carried out under
sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the
containers.
[0066] The compounds of the invention may be administered as the sole active ingredient, or
together with other drugs useful against neoplastic diseases or useful in immunomodulating
regimens. For example, the compounds of the invention may be used in accordance with the
invention in combination with pharmaceutical compositions effective in various diseases as
described above, e.g. with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine,
cisplatinum, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel,
rituxan, doxorubicine, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins
or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or
everolimus, corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene, methotrexate,
gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid,
mycophenolate, mofetil, 15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g.
monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD7, CD25, CD28, I
CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or their
ligands, or other immunomodulatory compounds, e.g. CTLA41g.
[0067] The invention also provides for a pharmaceutical combinations, e.g. a kit, comprising
a) a first agent which is a compound of the invention as disclosed herein, in free form or in
pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise
instructions for its administration.
Processes for Making Compounds of the Invention
[0068] Compounds of Formula (1) may be prepared following Reaction Scheme I, in which
each substituent is as defined in the Summary of the Invention:
(1)
Reaction Scheme I
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[0069] A compound of Formula (1) may be synthesized by reacting a compound of formula
(6) with a compound of formula (7) in the presence of palladium catalyst (for example palladium
acetate and the like), ligand (for example xantphos and the like) and base (for example cesium
carbonate and the like) in a suitable solvent (for example, THF, and the like). The reaction
proceeds in a temperature range of about 70°C to about 180°C and can take 10 min. to 8 hours to
complete.
[0070] Alternatively, a compound of Formula (1) may be synthesized by reacting a
compound of formula (6) with a compound of formula (7) in the presence of acid (for example
HCl, TsOH and the like), in a suitable solvent (for example, 2-propanol, and the like). The
reaction proceeds in a temperature range of about 70°C to about 150°C and can take up to 12
hours to complete.
Additional Processes for Making Compounds of the Invention
[0071] The compounds of the invention, including their salts, are also obtainable in the form
of hydrates, or their crystals may include for example the solvent used for crystallization
(present as solvates). Salts can usually be converted to compounds in free form, e.g., by treating
with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen
carbonates, or alkali metal hydroxides, such as potassium carbonate or sodium hydroxide. In
view of the close relationship between the novel compounds in free form and those in the form
of their salts, including those salts that may be used as intermediates, for example in the
purification or identification of the novel compounds, any reference to the free compounds
hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as
appropriate.
[0072] Salts of the inventive compounds with a salt-forming group may be prepared in a
manner known per se. Acid addition salts of compounds of Formula (1), (2), (3A), (3B), (4A),
(4B) or (5) may thus be obtained by treatment with an acid or with a suitable anion exchange
reagent. Pharmaceutically acceptable salts of the compounds of the invention may be formed,
for example, as acid addition salts, with organic or inorganic acids, from compounds of Formula
(1), (2), (3A), (3B), (4A), (4B) or (5) with a basic nitrogen atom.
[0073] Suitable inorganic acids include, but are not limited to, halogen acids, such as
hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids include, but are not
limited to, carboxylic, phosphoric, sulfonic or sulfamic acids, for example acetic acid, propionic
27
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acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,
succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,-malic acid, tartaric acid, citric
acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid,
methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid,
salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic
acid, methane-or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 ,2-disulfonic acid,
benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disuifonic acid, 2-, 3-or 4
methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N
cyclohexylsulfamic acid, N-methyl-, N-ethyl-or N-propyl-sulfamic acid, or other organic
protonic acids, such as ascorbic acid.
[0074] For isolation or purification purposes, it is also possible to use pharmaceutically
unacceptable salts, for example picrates or perchlorates. For therapeutic use, only
pharmaceutically acceptable salts or free compounds are employed (where applicable in the
form of pharmaceutical preparations).
[0075] Compounds of the invention in unoxidized form may be prepared from N-oxides of
compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide,
triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride,
tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous
dioxane, or the like) at 0 to 80°C.
[0076] Prodrug derivatives of the compounds of the invention may be prepared by methods
known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994),
Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate
prodrugs may be prepared by reacting a non-derivatized compound of the invention with a
suitable carbamylating agent (e.g., 1, 1-acyloxyalkylcarbanochloridate, para-nitrophenyl
carbonate, or the like).
[0077] Protected derivatives of the compounds of the invention may be made by means
known to those of ordinary skill in the art. A detailed description of techniques applicable to the
creation of protecting groups and their removal may be found in T. W. Greene, "Protecting
Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.
[0078] Compounds of the invention may be prepared as their individual stereoisomers by
reacting a racemic mixture of the compound with an optically active resolving agent to form a
pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically
28
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pure enantiomers. Resolution of enantiomers may be carried out using covalent diastereomeric
derivatives of the compounds of the invention, or by using dissociable complexes (e.g.,
crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting
points, boiling points, solubilities, reactivity, etc.) and may be readily separated by taking
advantage of these dissimilarities. The diastereomers may be separated by fractionated
crystallization, chromatography, or by separation/resolution techniques based upon differences
in solubility. The optically pure enantiomer is then recovered, along with the resolving agent,
by any practical means that would not result in racemization. A more detailed description of the
techniques applicable to the resolution of stereoisomers of compounds from their racemic
mixture may be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers,
Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
[0079] In summary, the compounds of the invention may be made by a process, which
involves:
(a) that of Reaction Scheme I; and
(b) optionally converting a compound of the invention into a pharmaceutically
acceptable salt;
(c) optionally converting a salt form of a compound of the invention to a non-salt form;
(d) optionally converting an unoxidized form of a compound of the invention into a
pharmaceutically acceptable N-oxide;
(e) optionally converting anN-oxide form of a compound of the invention to its
unoxidized form;
(f) optionally resolving an individual isomer of a compound of the invention from a
mixture of isomers;
(g) optionally converting a non-derivatized compound of the invention into a
pharmaceutically acceptable prodrug derivative; and
(h) optionally converting a prodrug derivative of a compound of the invention to its nonderivatized
form.
[0080] Insofar as the production of the starting materials is not particularly described, the
compounds are known or can be prepared analogously to methods known in the art or as
disclosed in the Examples hereinafter. One of skill in the art will appreciate that the above
transformations are only representative of methods for preparation of the compounds of the
present invention, and that other well known methods can similarly be used. The present
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invention is further exemplified, but not limited, by the following and Examples that illustrate
the preparation of the compounds of the invention.
Preparation of Intermediates
Intermediate 1
2-chloro-N-(2-(iso-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine
[0081] To a suspension of 730 mg of NaH in a mixture of DMF/DMSO (25/2.5 ml) is added
drop-wise at 0°C, 2.53 g (12.69 mmol) of 2-(iso-propylsulfonyl)benzenamine in DMF/DMSO
(10 ml, ratio 9/1). The solution is stirred 30 minutes at 0°C and 4.11 g (25.3 mmol, 2 eq.) of 2,4-
dichloro-5-methylpyrimidine diluted in 10 ml of DMF/DMSO (ratio: 9/1) is added dropwise.
The solution is warmed-up to room temperature and stirred overnight. After work-up, the crude
product is directly crystallized from cold CH3CN in several batches to afford 2-chloro-N-(2-(isopropylsulfonyl)
phenyl)-5-methylpyrimidin-4-amine as pale creamy colored crystals: ESMS m/z
326.1 (M + H+).
Intermediate 2
Synthesis of 2,5-dichloro-N-(2-( iso-propy lsulfony 1 )pheny 1 )pyrimidin -4-amine
VCI~
A .. Jl N N Cl yS H
I ((o
[0082] Using the same procedure described for the synthesis of 2-chloro-N-(2-(isopropy
lsulfony 1 )pheny 1 )-5-me thy lpyrimidin -4-amine, 2,5-dichloro-N-(2-( isopropylsulfonyl)
phenyl)pyrimidin-4-amine is isolated as a creamy colored solid: ESMS m/z 346.0
(M + H+).
Intermediate 3
2-chloro-4-fluoro-5- nitrotoluene
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~F
Cl
[0083] To a solution of 100 g (0.7 mol) of 2-chloro-4-fluorotoluene in 250 ml of
concentrated H2S04 is added portion-wise 85 g (0.875 mol) of KN03 at 0°C (addition of the
whole amount of KN03 is finished in about 1 hour). The reddish mixture is slowly warmed-up at
room temperature overnight and quenched over crushed ice and extracted with EtOAc. The
organic layers are combined, dried over MgS04 and concentrated. The crude oil is then purified
over a large silica plug (eluent: 97/3 hexanes/EtOAc) to afford 2-chloro-4-fluoro-5-nitrotoluene
as a pale yellow oil that solidifies upon standing. 1H NMR (CDCb, 400 Mz): 7.97 (d, J = 8.0 Hz,
lH), 7.32 (d, J = 10.4 Hz, lH), 2.43 (s, 3H).
Intermediate 4
2-chloro-4-isopropoxy-5-nitrotoluene
[0084] To a solution of 25 g (0.131 mol) of 2-chloro-4-fluoro-5-nitrotoluene in 250 ml of 2-
propanol is added 208 g (0.659 mol, 5 eq.) of Cs2C03. The mixture is stirred at 60°C overnight
and most of the 2-propanol is evaporated under reduced pressure. Water is added and the
solution is extracted with EtOAc. The organic layers are combined, dried over MgS04 ,
concentrated and the crude product filtrated over a silica plug (eluent: 95/5 hexanes/EtOAc) to
afford 2-chloro-4-isopropoxy-5-nitrotoluene as a pale yellow fluffy solid.
Intermediate 5
2-methyl-4-nitro-5-isopropoxy-phenylboronic acid pinacol ester
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[0085] A mixture of 5.09 g 2-chloro-4-isopropoxy-5-nitrotoluene (0.02216 mol), 6.20 g
(0.02437 mol) of pinacol diborane, 595 mg (0.00212 mol) of PCy3, 1.014 g (0.00108 mol) of
Pd2dba3 and 3.16 g (0.0322 mol) of KOAc in 100 ml of dry dioxane is heated to 100°C
overnight. After cooling toRT, the dark solution is filtered over Celite and the solvent
evaporated under reduced pressure. The crude oil is purified with silica gel column
chromatography (eluent: 95/5 hexanes/EtOAc) to afford 2-methyl-4-nitro-5-isopropoxyphenylboronic
acid pinacol ester as an oil that solidifies upon standing. 1H NMR (CDCb, 400
Mz): 7.51 (s, lH), 7.44 (s, lH), 4.70 (m, lH), 2.48 (s, 3H), 1.36 (d, J = 7.6 Hz, 6H), 1.35 (s,
12H).
Intermediate 6
4-Trifluoromethanesulfony loxy-3, 6-dihydro-2H-pyridine-1-carboxy lie acid tert -buty 1 ester
[0086] A solution of N-tert-Butoxycarbonyl-4-piperidone (10.17 g, 0.05 mol) in THF (100
mL) is added dropwise into a cooled ( -78 °C), vigorously stirring solution of LDA ( 40 mL of 1.5
M solution in cyclohexanes, 0.06 mol) in THF (100 mL), under N2. The reaction mixture is left
at -78 °C for 30 min before adding a solution of phenyl trifluorosulfonimide (19.85 g, 0.055 mol)
in THF (50 mL). Then the reaction mixture is warmed to room temperature and stirred for 3 h.
The reaction is quenched at 0 °C with 100 mL of saturated aqueous NH4Cl and filtered through
Celite. The filtrate is added to 100 mL of EtOAc and the layers are separated. The organic layer
is washed with H20, dried over MgS04 and concentrated. The crude product is purified by silica
flash column chromatography (0-30% EtOAc in Hexanes as eluent and checked by TLC stained
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with 2% of KMn04 in EtOH) to afford 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2Hpyridine-
l-carboxylic acid tert-butyl ester as a yellow oil.
Intermediate 7
4-( 5-Isopropoxy-2-me thy 1-4-nitro-pheny 1 )-3 ,6-dihydro-2H -pyridine-1-carboxy lie acid
tert-butyl ester
[0087] To a solution of 2-methyl-4-nitro-5-isopropoxy-phenylboronic acid pinacol ester
(2.04 g, 6.4 mmol) and 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (3.2 g, 9.6 mmol) in 110 mL of DME/H20 (10:1 V/V) is added Pd(PPh3)4
(365 mg, 0.32 mmol) and Cs2C03 (4.2 g, 12.8 mmol). The reaction mixture is heated under N2 at
80 °C overnight. After cooling to room temperature, the reaction is filtered through Celite and
the filtrate is diluted with 100 mL of EtOAc, sequentially washed with H20, brine, and finally
concentrated in vacuo. The crude product is purified by silica gel flash chromatography (5%-
15% EtOAc in Hexanes as eluent) to afford 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-3,6-
dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CD30D, 400
Mz): 7.59 (s, 1H), 6.96 (s, 1H), 5.67 (broads, 1H), 4.73 (m, 1H), 4.06 (m, 2H), 3.65 (m, 2H),
2.37 (m, 2H), 2.25 (s, 3H), 1.50 (s, 9H), 1.33 (d, J = 6.0 Hz, 6H).
Intermediate 8
2-Chloro-4-isopropoxy-5-nitro-benzoic acid
[0088] A mixture of 2-chloro-4-fluoro-5-nitro-benzoic acid (5.0 g, 22.8 mmol) and cesium
carbonate (29.7 g, 91.1 mmol) in 2-propanol (100 mL) is heated at 50°C overnight. The solvent
33
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is removed in vacuo and 100 mL of water is added. Concentrated aqueous HCl is added
dropwise to this solution at 0 °C until pH=2. The product precipitate which forms is isolated by
filtration, washed by water and dried under vacuum to give 2-chloro-4-isopropoxy-5-nitrobenzoic
acid.
Example 1
6-{ 5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino 1-pyrimidin-2-ylamino} -5-isopropoxy-2-
piperidin-4-yl-2,3-dihydro-isoindol-1-one (178)
oO
(1CIX'Jt )j
~N N N~ s-::::.0 H H 0 l'a )-
steps 1 and 2: 4-(2-Chloro-4-isopropoxy-5-nitro-benzoylamino )-piperidine-1-carboxylic acid
tert-butyl ester
[0089] To a solution of 2-chloro-4-isopropoxy-5-nitro-benzoic acid (Intermediate 8, 10 g,
38.5 mmol) in DCM (200 mL) and DMF (1mL), is slowly added thionyl chloride (9.17 g, 77
mmol) via a syringe. The mixture is stirred for 3 hours, and is then concentrated to dryness. The
obtained white solid, 2-chloro-4-isopropoxy-5-nitro-benzoyl chloride, is dried under vacuum.
To a mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.44g, 7.2 mmol) and
triethylamine (3 mL, 21.6 mmol) in DCM (100 mL), is slowly added 2-chloro-4-isopropoxy-5-
nitro-benzoyl chloride (2g, 7.2 mmol) dissolved in DCM (10 mL) via syringe. The mixture is
stirred at room temperature for 3 hours, and then is concentrated. The obtained solid is dissolved
in ethyl acetate and is washed with water and brine respectively. After evaporation of the
solvent, the title compound is obtained as light yellow solid, and is directly used for the next step
without further purification.
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Step 3: 4-( 4-Isopropoxy-5-nitro-2-vinyl-benzoylamino )-piperidine-1-carboxylic acid tert-butyl
ester
[0090] To a mixture of 4-(2-chloro-4-isopropoxy-5-nitro-benzoylamino )-piperidine-1-
carboxylic acid tert-butyl ester (7.2 mmol) obtained in the previous step, vinylboronic acid
dibutyl ester (1.72 g, 9.4 mmol) and sodium carbonate (5.34 g, 50.4 mmol) in THF/H20 (100/25
mL) is added dichlorobis(triphenylphospine) palladium (II) ( 442 mg, 5% mmol). The mixture is
purged with N2 for 3 min and heated at 90°C under N2 for overnight in a round bottom flask
equipped with a condenser. The mixture is cooled to room temperature and poured into
saturated aqueous ammonia chloride solution. The mixture is extracted with ethyl acetate (3 x
100 mL). The organic extracts are combined, washed with brine and concentrated. The crude
product is purified with silica gel column chromatography (40% ethyl acetate in hexanes) to
afford 4-( 4-isopropoxy-5-nitro-2-vinyl-benzoylamino )-piperidine-1-carboxylic acid tert-butyl
ester as white solid.
Steps 4, 5 and 6: 4-(5-Isopropoxy-6-nitro-1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-1-
carboxylic acid tert-butyl ester
[0091] 4-( 4-Isopropoxy-5-nitro-2-vinyl-benzoylamino )-piperidine-1-carboxylic acid tertbutyl
ester obtained from previous step (1.9 g, 4.38mmol) is dissolved in DCM (100 mL) and is
cooled to -78 °C. 0 3 (g) is bubbled into the solution until the solution's color turns blue/gray.
The solution is then purged with N2 (g) until the blue color disappears. The solution is warmed
to room temperature and treated with triphenylphosphine resin (5 g) pre-swelled in DCM (100
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mL). After 30 min, the mixture is filtered, the filtrate is concentrated, and the resulting residue
dissolved in DCM/TFA (100mL I 25 mL). To this mixture is added triethyl silane ( 4.6 mL, 17.5
mmol). The resulting mixture is stirred at room temperature overnight. The reaction mixture is
concentrated and re-dissolved in DCM. The DCM solution is washed with IN aqueous HCI (3 x
20 mL). The combined aqueous layer is treated with cone. aqueous NaOH until pH =12. The
aqueous layer is extracted with ethyl acetate (3 x 30 mL). The combined organic layers are
washed with brine, and dried over sodium sulfate. A light yellow solid is obtained after
evaporation of the organic solvent.
[0092] The solid is dissolved in a mixture of methanol and triethylamine (100mL, 9:1 v/v).
To this mixture is added di-tert-butyl dicarbonate (680 mg, 3.lmmol). After stirring at 50 °C for
30 minutes, the mixture is concentrated and purified by silica gel flash column chromatography
(eluent: 40-50% ethyl acetate in hexanes) to afford 4-(5-Isopropoxy-6-nitro-1-oxo-1 ,3-dihydroisoindol-
2-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. 1H NMR ( 400 MHz,
CDCb) 8 8.19 (s, 1H), 7.11 (s, 1H), 4.74 (q, 1H), 4.45-4.38 (m, 1H), 4.35 (s, 2H), 2.90-2.80
(m, 2H), 1.85-1.81 (m, 2H), 1.66-1.63 (m, 2H), 1.48 (s, 9H), 1.42 (d, 6H).
Steps 7, 8 and 9
[0093] To a solution of 4-(5-isopropoxy-6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)piperidine-
1-carboxylic acid tert-butyl ester from the previous step (850 mg, 2mmol) in
methanol, is added Pd/C (10% on carbon, 100 mg). The mixture is hydrogenated under 1 atm of
hydrogen gas. After 4 hours, the mixture is filtered and concentrated. The obtained aniline, as
yellow solid, is used for next step without additional purification. To a mixture of the crude
product (2 mmol) from previous step, (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)phenyl]-
amine (Intermediate 2, 770mg, 2.2 mmol), cesium carbonate (1.3g, 4mmol), and
xantphos (115 mg, 0.2mmol) in THF (20 mL), is added palladium acetate (22mg, 5% mmol) in a
microwave tube. The mixture is purged with N2 for 3 min. The sealed tube is heated at 150°C
for 20 min under microwave irradiation. The mixture is cooled, filtered and concentrated. The
residue is purified by silica gel flash column chromatography (eluent: 65% ethyl acetate in
hexanes) to afford a yellow solid. The solid is treated with DCM/TFA (111, 10mL) for 1 hour
followed by concentration under vacuum. Final purification using preparative RP LC-MS
affords 6-{ 5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino ]-pyrimidin-2-ylamino} -5-
isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (178) as a white solid. 1H NMR (400
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MHz, CDCb) 8 10.38 (s, 1H), 10.13 (s, 1H), 9.60-9.50 (br, 1H), 9.34-9.21 (br, 1H), 8.46 (d,
1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.91 (dd, 1H), 7.71 (m, 1H), 7.34 (t, 1H), 7.03 (s, 1H), 4.30 (m,
1H), 4.53 (m, 1H), 4.33 (s, 2H), 3.62 (m, 2H), 3.21-3.09 (m, 3H), 2.31-2.21 (m, 2H), 2.09-2.05
(m, 2H), 1.41 (d, 6H), 2.30 (d, 6H); ESMS m/z 599.2 (M + H+).
Example 2
6-{ 5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino ]-pyrimidin-2-ylamino} -5-isopropoxy-2-( 1-
methyl-piperidin-4-yl)-2,3-dihydro-isoindol-1-one (181)
I oO
(1ciX'Jt
~N N N
s-.:::::0 H H 0 l'a ;----
Step 1: 5-Isopropoxy-2-(1-methyl-piperidin-4-yl)-6-nitro-indan-1-one
I
N
0 A
[0094] To a solution of 5-isopropoxy-6-nitro-2-piperidin-4-yl-indan-1-one (Example 1, Step
5) in THF (5 mL) and methanol (5 mL) is added formaldehyde (104.2 uL, 1.39 mmol) and 10
drops of AcOH sequentially. The reaction mixture is stirred at room temperature for 1h, then
sodium cyanoborohydride (175.1 mg, 2.78 mmol) is added in one portion, and the reaction is
stirred for an additional30 min. The reaction is quenched by saturated aqueous NH4Cl and
concentrated in vacuo to give an oily residue. This oil is partitioned between EtOAc and brine,
the organic extract is dried over Na2S04, filtered and concentrated under vacuum. Silica gel
chromatography (5% MeOH in DCM) affords 5-isopropoxy-2-(1-methyl-piperidin-4-yl)-6-nitroindan-
1-one; MS m/z 333.2 (M+1).
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Steps 2 and 3
[0095] Following the procedures previously described (Example 1, Steps 7 and 8) using the
product from Step 1 generates the title compound 6-{5-Chloro-4-[2-(propane-2-sulfonyl)phenylamino
]-pyrimidin-2-ylamino} -5-isopropoxy-2-( 1-methyl-piperidin-4-yl)-2,3-dihydroisoindol-
1-one (181) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D20) 8 8.46 (d,
1H), 8.35 (s, 1H), 8.09(s, 1H), 7.82(d, 1H), 7.74(t, 1H), 7.36(t,1H), 7.33(s, 1H), 4.75 (m, 1H),
4.41(s, 2H), 4,29(m, 1H), 3.65(m, 2H), 3.44(m, 1H), 3.17(t, 2H), 2,79(s, 3H), 2.07(m, 2H),
1,98(d, 2H), 1.28(d, 6H), 1.14(d, 6H); MS m/z 613 (M+1).
Example 3
5-Methyl-N2
- [ 4-methyl-S-( 1-methyl-1H -pyrazol-4-yl)-2-(piperidin-4-yloxy)-phenyl]-N4
- [2-
(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (35)
Step 1: 4-( 4-Chloro-5-me thy 1-2-nitro-phenoxy)-piperidine-1-carboxy lie acid tert -buty 1 ester
[0096] To a mixture of 4-Chloro-5-methyl-2-nitro-phenol (3.752 g, 20.0 mmol), 4-Hydroxypiperidine-
1-carboxylic acid tert-butyl ester (4.83 g, 24 mmol), and triphenylphosphine (6.23 g,
24 mmol) in 75 mL THF is added diisopropyl asodicarboxylate (4.73 mL, 245 mmol) in several
portions at 22 °C for 1 h. The reaction is stirred at the same temperature for an additional 2 hrs.
The reaction mixture is concentrated in vacuo. The residue is taken up in 50 mL ether, and let
stand at 22 °C for 14 hrs. The resulting crystals are removed by filtration. The filtrate is
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concentrated in vacuo, and the residue is purified over a 330 g Si02 column (ISCO) using a
gradient of 20 to 40% ethyl acetate in hexanes as eluent, affording 4-(4-Chloro-5-methyl-2-
nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as dark yellow viscous oil. MS
(ES+); 315.1 (MH+- C4H8), 393.1 (MNa+).
Step 2: 4-[5-Methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-nitro-phenoxy ]-piperidine-1-carboxylic
acid tert-butyl ester
[0097] A mixture of 4-( 4-Chloro-5-methyl-2-nitro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester from the previous step (375.8 mg, 1.01 mmol), 1-Methyl-4-( 4,4,5,5-tetramethyl[
1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Boron Molecular, 224.4 mg 1.08 mmol), potassium
phosphate tribasic monohydrate (392 mg), Pd2(dba)3 (45 mg), and dicyclophosphinobiphenyl
(43 mg) in 4 mL of 1,4-dioxane/H20 (3/1) is heated in a sealed tube at 150 °C for 20 min under
microwave radiation. The reaction mixture is filtered through a small plug of Celite, dried over
Na2S04 and concentrated. The residue is purified using a Si02 column (ISCO), affording 4-[5-
Methyl-4-(1-methyl-1H-pyrazol-4-yl)-2-nitro-phenoxy ]-piperidine-1-carboxylic acid tert-butyl
ester. MS (ES+); 417.3 (MH+), 439.2 (MNa+).
Steps 3, 4 and 5
[0098] Utilizing the same procedures described in the synthesis of Example 1 (Steps 7, 8
and 9) and final purification using preparative RP LC-MS affords 5-Methyl-N2-[4-methyl-5-(1-
methyl-1H-pyrazol-4-yl)-2-(piperidin-4-yloxy)-phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]pyrimidine-
2,4-diamine (35). MS (ES+ ): 576.3 (MH+ ).
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Example 4
1-(5-{ 5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino ]-pyrimidin-2-ylamino} -4-isopropoxy-2-
methyl-phenyl)-ethanone (36)
Step 1: 2-( 4-Isopropoxy-2-methyl-5-nitro-phenyl)-2-methyl- [1,3]dioxolane
[0100] A mixture of 1-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-ethanone (0.788 g, 3.32
mmol), ethyleneglycol (1.8 mL), and p-toluenesulfonic acid monohydrate (6.3 mg) in 60 mL of
benzene is heated at reflux with a Dean-Stark trap for 18 hrs. The reaction mixture is diluted
with 100 mL of ethyl acetate and successively washed with 100 mL each of aqueous saturated
NaHC03, H20, and saturated brine. The organic phase is dried over anhydrous Na2S04, filtered
and concentrated in vacuo, affording 2-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-2-methyl[
1,3]dioxolane as yellow crystals. MS (ES+): 282.2 (MH+).
Steps 2 and 3: 5-Chloro-N2-[2-isopropoxy-4-methyl-5-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]N
4-[2-(propane-2-sulfony 1 )-pheny 1] -pyrimidine-2,4-diamine
[0101] Utilizing the same procedures described in the synthesis of Example 1 (Steps 7 and
8), using 2-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-2-methyl-[1,3]dioxolane from the previous
40
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step as starting material and purification using silica gel chromatography (gradient 2% to 20%
EtOAc in hexanes) affords 5-Chloro-N2-[2-isopropoxy-4-methyl-5-(2-methyl-[1,3]dioxolan-2-
yl)-phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine as a white solid. MS
(ES+ ): 561.2 (MH+ ).
Step 4
[0102] A solution of 5-Chloro-N2-[2-isopropoxy-4-methyl-5-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-
N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine from the previous step (84
mg, 0.15 mmol) in 5 mL 1,4-dioxane is treated with 1 mL of aqueous IN HCI at 22 °C for 2 hrs.
The reaction is worked up and affords 1-(5-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]pyrimidin-
2-ylamino }-4-isopropoxy-2-methyl-phenyl)-ethanone (36). MS (ES+ ): 517.2 (MH+ ).
Example 5
N2
- { 2-Isopropoxy-4-methyl-5-[ 1-(2-morpholin-4-yl-ethyl)-1H -pyrazol-4-yl]-phenyl} -5-methylN4-[
2-(propane-2-sulfony 1 )-pheny 1] -pyrimidine-2,4-diamine (37)
Step 1: 4-Bromo-5-methyl-2-nitro-phenol
[0103] 4-Bromo-3-methyl-phenol (1.122 g, 6.00 mmol) and Yb(CF3S03) 3 (372 mg) in 30
mL dichloromethane is treated with 0.38 mL of cone. HN03 at 22 °C. After stirring at the same
temperature for 1 hr, an additional 0.1 mL of cone. HN03 is added, and the reaction is stirred for
an additional hour. The reaction mixture is washed with H20, dried over anhydrous magnesium
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sulfate, filtered and concentrated. The residue is purified using a Si02 column (ISCO), affording
a mixture of 4-Bromo-5-methyl-2-nitro-phenol as yellow crystals and its regioisomer by-product
as orange crystals.
Step 2: 1-Bromo-4-isopropoxy-2-methyl-5-nitro-benzene
[0104] To a mixture of 4-Bromo-5-methyl-2-nitro-phenol from the previous step (0.66 g,
2.84 mmol), 2-propanol (0.262 mL), and triphenylphosphine (894 mg) in 10 mL THF is added
diisopropyl asodicarboxylate (0.671 mL) at 22 °C. The reaction mixture is concentrated in
vacuo. The residue is purified using a Si02 column (ISCO), affording 1-Bromo-4-isopropoxy-2-
methyl-5-nitro-benzene as a bright yellow solid.
Step 3: 5-Bromo-2-isopropoxy-4-methyl-phenylamine
[0105] To 1-Bromo-4-isopropoxy-2-methyl-5-nitro-benzene from the previous step (0.734 g,
2.68 mmol) and iron (powder, 325 mesh, 1.05 g) in 20 mL ethanol is added 1 mL of 1N aqueous
HCl with cooling in an ice bath. Following this addition, the reaction is heated at reflux for 2
hrs. Then an additional 0.5 g of iron is added and the reaction is heated at reflux for an
additional 2 hrs. The reaction mixture is cooled down and filtered though a pad of Celite. The
filtrate is concentrated in vacuo, affording 5-Bromo-2-isopropoxy-4-methyl-phenylamine as an
orange oil. The product is used for the next step without further purification.
42
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Step 4: N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)pheny
1] -pyrimidine-2,4-diamine
[0106] 5-Bromo-2-isopropoxy-4-methyl-phenylamine from the previous step (537 mg, 2.20
mmol) and 2-chloro-N-(2-(iso-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine
(Intermediate 1, 652 mg, 2.00 mmol) in the presence of methanesulfonic acid (0.143 mL) in 4
mL 2-propanol are condensed at 140 °C for 30 min in a sealed tube under microwave irradiation.
Following workup, N2-( 5-Bromo-2-isopropoxy-4-me thy 1-pheny 1 )-5-me thy 1-N 4- [2-(propane-2-
sulfonyl)-phenyl]-pyrimidine-2,4-diamine is obtained. MS (ES+ ): 535.1 (MH+ ).
Step 5
[0 107] A mixture of N2-( 5-Bromo-2-isopropoxy-4-meth y 1-pheny 1 )-5-me thy 1-N 4- [2-
(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine from the previous step (53 mg, 0.099
mmol), 4-{ 2-[ 4-( 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl }-morpholine
(Boron Molecular, 61 mg 0.20 mmol), K3P04 (58 mg), Pd2(dba)3 (10 mg), and
tricyclohexylphosphine (8 mg) in 1 mL of 1,4-dioxane/H20 (3/1 v/v) is heated in a sealed tube
at 150 °C for 20 min under microwave radiation. The reaction mixture is filtered through a
small plug of Celite and concentrated. Final purification using preparative RP LC-MS affords
N2-{ 2-Isopropoxy-4-methyl-S-[ 1-(2-morpholin-4-yl-ethyl)-1H -pyrazol-4-y 1]-phenyl} -5-methylN4-[
2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (37). MS (ES+ ): 634.3 (MH+ ).
Example 6
5-Chloro-N2-(2-isopropoxy-5-methyl-4-morpholin-4-ylmethyl-phenyl)-N4-[2-(propane-2-
sulfonyl)-phenyl]-pyrimidine-2,4-diamine (60)
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Steps 1 and 2: 1-Chloro-5-isopropoxy-2-methyl-4-nitro-benzene
[0108] To a mixture of 1-chloro-2-methyl-4-nitro-5-isopropoxy-benzene (Intermediate 4,
870 mg, 3.77mmol), vinylboronic acid dibutyl ester (1.24 mL, 5.6 mmol), and sodium carbonate
(2.8 g, 26.4mmol) in THF/H20 (20/5 mL) is added dichlorobis(triphenylphospine) palladium
(II) (132 mg, 5% mmol). The reaction tube is sealed, the mixture is purged with N2 for 3 min
and then heated at 90°C under N2 for overnight. The reaction is cooled to room temperature and
poured into saturated aqueous ammonia chloride solution. The crude reaction mixture is
extracted with ethyl acetate (3 x 100 mL). The organic extracts are combined, washed with brine
and concentrated. The crude product is purified with silica gel column chromatography (10%
ethyl acetate in hexanes) to afford 1-methyl-5-nitro-4-propoxy-2-vinyl-benzene as a yellow
solid. 1-Methyl-5-nitro-4-propoxy-2-vinyl-benzene obtained from the previous step (360 mg,
1.63mmol) is dissolved in DCM (20 mL) and is cooled to -78 °C. 0 3 (g) is bubbled into the
solution until the solution's color turns blue/gray. The solution is then purged with N2 (g) until
the blue color disappears. The solution is warmed to room temperature and treated with
triphenylphospine resin (2 g) pre-swelled in DCM (30 mL). After 30 min, the mixture is filtered,
and the filtrate is concentrated to afford 2-methyl-4-nitro-5-propoxy-benzaldehyde as yellow
solid.
Steps 3 and 4: 2-Isopropoxy-5-methyl-4-morpholin-4-ylmethyl-phenylamine
[0109] To a solution of 2-methyl-4-nitro-5-propoxy-benzaldehyde obtained in the previous
step (34 mg, 0.152 mmol) in MeOH/THF (0.5/0.5 mL), is added acetic acid (5 drops). The
mixture is stirred at room temperature for 1 hour. Sodium cyanoborohydride (20 mg, 0.30
mmol) is then added. After stirring for 30 min, the reaction is quenched by adding saturated
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aqueous ammonium chloride solution. The reaction mixture is extracted with ethyl acetate (3 x 5
mL). The organic phases are combined and concentrated to afford the amine product as an
yellow oil which is directly used for the next step without further purification. To a solution of
the product obtained in the previous step in methanol (5 mL), is added Pd/C (10% on carbon, 2
mg). The mixture is hydrogenated under 1 atm hydrogen. After 4 hours, the mixture is filtered
and concentrated. The aniline product obtained (yellow solid), is used in the next step without
further purification.
Step 5
[0110] To a mixture of the aniline product obtained in the previous step (0.152 mmol), (2,5-
dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (Intermediate 2, 52 mg, 0.152
mmol), cesium carbonate (99 mg, 0.30 mmol) and xantphos (8 mg, 0.02mmol) in THF (2 mL),
is added palladium acetate (2 mg, 5% mmol) in a microwave tube. The mixture is purged with
N2 for 3 min and then the sealed tube is heated at 150 °C for 20 min. under microwave
irradiation. The reaction is filtered, concentrated, and purified by mass-trigger preparative RP
LC-MS to afford the title compound 5-Chloro-N2-(2-isopropoxy-5-methyl-4-morpholin-4-
ylmethyl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (60) as a yellow
solid: 1H NMR (400 MHz, CDCb) 810.35(s, 1H), 8.38 (d, 1HO, 7.93 (d, 1H), 7.59 (m, 2H),
7.41-7.36 (m, 2H), 4.70-4.63(br, 1H), 4.30-4.18 (br, 2H), 4.15-4.10 (br, 2H), 4.00-3.97 (br, 2H),
3.52-3.46 (br, 2H), 3.20 (m, 1H), 2.95-2.84 (br, 2H), 2.24 (s, 3H), 1.31 (d, 12H); ESMS m/z
574.2 (M + H+).
Example 7
5 -Chloro-N2 -(2-isopropoxy-5-methyl-4-piperidin -4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)pheny
1]-pyrimidine-2,4-diamine ( 66)
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Step 1: 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine
[0111] 4-Pyridineboronic acid (147 mg, 1.20 mmol, 1.1 equiv.) is dissolved in a 2:1 v/v
mixture of dioxane and H20 (15 mL) and N2 is bubbled through for 5 minutes.
Tris(dibenzylidene acetone)dipalladium (0) (100 mg, 0.109 mmol, 0.1 equiv.), 2-
dicyclohexylphosphine-2' -6' -dimethoxy biphenyl (112 mg, 0.272 mmol, 0.25 equiv.), 1-chloro-
5-isopropoxy-2-methyl-4-nitro-benzene (Intermediate 4, 250 mg, 1.09 mmol, 1.0 equiv.) and
K3P04 (462 mg, 2.18 mmol, 2.0 equiv.) are added under a N2 blanket. The reaction vessel is
sealed and heated with microwave irradiation to 150 °C for 20 min. After cooling to room
temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (2x),
the organic layer is then dried over Na2S04 and filtered. After concentration, the crude product
is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes)
to give 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine as a brown solid: ESMS m/z 273.1
(M + H+).
Steps 2 and 3: 4-( 4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tertbutyl
ester
H2N-9--()-{+
)-
[0112] 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine from the previous step(438 mg,
1.61 mmol) dissolved in acetic acid (30 mL) is treated with TFA (0.24 mL, 3.22 mmol) and Pt02
(176 mg, 40% w/w). The reaction mixture is vigorously stirred under 1 atm. H2 for 36 hours.
The reaction mixture is filtered and the filtrate is concentrated under vacuum. The resulting
residue is diluted with ethyl acetate and washed with 1 N aqueous NaOH (2x), the organic layer
is then dried over Na2S04 and filtered. After concentration, the crude product (391 mg) is
dissolved in anhydrous CH2Ch (30 mL). TEA is added (0.44 mL, 3.15, 2 equiv.) followed by
Boc20 (344 mg, 1.57 equiv, 1 equiv.). The reaction is stirred at room temperature for 30 min.
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The reaction is concentrated under vacuum. The resulting residue is purified by silica gel
chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-amino-5-
isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a sticky foam:
ESMS m/z 293.1 (M-tBu+Ht.
Steps 4 and 5
[0113] 4-( 4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-1-carboxylic acid tert-butyl
ester (170 mg, 0.488 mmol) from the previous step, (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-
2-sulfonyl)-phenyl]-amine (Intermediate 2, 169 mg, 0.488 mmol, 1 equiv.), xantphos (28 mg,
0.049 mmol, 0.1 equiv.), palladium acetate (5.5 mg, 0.024 mmol, 0.05 equiv.), and Cs2C03 (477
mg, 1.46 mmol, 3 equiv.) are dissolved in anhydrous THF (6 mL). N2 is bubbled through the
reaction mixture for 5 minutes and then the reaction vessel is sealed and heated with microwave
irradiation to 150 °C for 20 min. The reaction is filtered and the filtrate concentrated under
vacuum. After concentration, the crude product is purified by silica gel chromatography
(gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-{5-chloro-4-[2-(propane-2-
sulfonyl)-phenylamino ]-pyrimidin-2-ylamino} -5-isopropoxy-2-methyl-phenyl)-piperidine-1-
carboxylic acid tert-butyl ester as a yellow film: ESMS m/z 658.3 (M + H+). This product (105
mg, 0.160 mmol) is dissolved in CH2Ch (3 mL) and treated with TFA (3 mL). After 45 min.,
the reaction is concentrated under vacuum. 1 N HCl in Et20 (5 mL x 2) is added causing the
product HCl salt to precipitate. The solvent is removed by decantation. The resulting 5-
Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)phenyl]-
pyrimidine-2,4-diamine (66) is dried under high vacuum, generating an off-white
powder: 1H NMR (400 MHz, DMSO-d6 +trace D20) 8 8.32 (s, 1H), 8.27 (d, 1H), 7.88 (d, 1H),
7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56-4.48 (m, 1H), 3.49-3.32 (m, 3H),
3.10-2.91 (m, 3H), 2.09 (s, 3H), 1.89-1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1
(M + H+).
Example 8
5-Chloro-N2-[2-isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenyl]-N4 -[2-(propane-2-
sulfonyl)-phenyl]-pyrimidine-2,4-diamine (67)
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Step 1: 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-1-methyl-pyridinium iodide
[0114] 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine (Example 7, Step 1, 217 mg,
0.797 mmol) is dissolved in anhydrous THF (9 mL). Iodomethane (0.10 mL, 1.61 mmol, 2
equiv.) is added and the reaction is stirred at 40 °C in a sealed tube for 2 days. The volatiles are
removed under vacuum generating 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-1-methylpyridinium
iodide as a brown solid: ESMS m/z 287.1 (M+).
Steps 2 and 3: 2-Isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenylamine
[0115] 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-1-methyl-pyridinium iodide from the
previous step (0.697 mmol) is dissolved in CH30H (20 mL) and cooled to 0 °C. NaBH4 (264
mg, 6.97 mmol, 10 equiv.) is slowly added. After this addition is complete, the cooling bath is
removed and the reaction is stirred at room temperature for 1 h. The reaction is quenched by the
slow addition of 1N aqueous HCl (14 mL). The CH30H is partially removed by vacuum. The
resulting residue is partitioned between EtOAc and 1 N aqueous NaOH. Additional 50 %
aqueous NaOH is added until the aqueous layer pH> 12. The EtOAc layer is washed with 1 N
aqueous NaOH (2x), the organic layer is then dried over Na2S04. filtered, and concentrated
under vacuum. After concentration, the crude product (175 mg) is dissolved in acetic acid (10
mL). TFA (0.15 mL, 3 equiv.) and Pt02 (53 mg, 30% w/w) are added and the reaction is placed
48
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under 50 psi H2 gas in a Parr Shaker for 14 h. The reaction mixture is filtered and the filtrate is
concentrated under vacuum. The resulting residue is partitioned between EtOAc and 1 N
aqueous NaOH. Additional 50% aqueous NaOH is added until the aqueous layer pH >12. The
EtOAc layer is washed with 1 N aqueous NaOH (2x), the organic layer is then dried over
Na2S04. filtered, and concentrated under vacuum to give 2-Isopropoxy-5-methyl-4-(1-methylpiperidin-
4-yl)-phenylamine which is used in Step 4 without further purification: ESMS m/z
263.2 (M + H+).
Step 4
[0116] Utilizing the same procedures described in the synthesis of Example 7 (Step 4) and
final purification using preparative RP LC-MS affords 5 -Chloro-N 2
- [2-isopropoxy-5-me thy l-4-
(1-methyl-piperidin-4-yl)-phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine
(67) as a pale yellow powder: (HCl salt, DMSO-d6 +trace D20) 8 8.28 (s, 1H), 8.19 (d, 1H),
7.86 (d, 1H), 7.66 (dd, 1H), 7.45 (dd, 1H), 7.37 (s, 1H), 6.77 (s, 1H), 4.56-4.49 (m, 1H), 3.51-
3.37 (m, 3H), 3.16-3.08 (m, 2H), 2.98-2.88 (m, 1H), 2.77 (s, 3H), 2.05 (s, 3H), 1.90-1.81 (m,
4H), 1.19 (d, 6H), 1.11 (d, 6H); ESMS m/z 572.2 (M + H+).
Example 9
2-[ 4-( 4-{ 5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino ]-pyrimidin-2-ylamino} -5-
isopropoxy-2-methyl-phenyl)-piperidin-1-yl]-ethanol (72)
[0117] 5-Chloro-N2 -(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4 -[2-(propane-2-
sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 7, 0.087 mmol) is dissolved in anhydrous
DMF (1 mL). TEA (0.04 mL, 0.262 mmol, 3 equiv.) is added followed by 2-bromo-ethanol
(0.019 mL, 0.262 mmol, 3 equiv.) dissolved in anhydrous DMF (0.7 mL). The reaction vessel
is sealed and heated at 70 °C for 12 h. After cooling to room temperature, the reaction is diluted
with ethyl acetate and washed with 1 N aqueous NaOH (5x), the organic layer is then dried over
Na2S04 and filtered. After concentration, the crude product is purified using preparative RP

We Claim:
1. A novel pyrimidine compound of Formula (1)
N
N
R2
N N
R3
R5
R1
R5'
(R4)n
W (1)
or pharmaceutically acceptable salts thereof; wherein
W is
A1
A2
A3
A4
R6
R7 R9
R10
R8 ;
A1 and A4 are independently C;
each A2 and A3 is C;
R1 is halo or C1-6 alkyl;
R2 is H;
R3 is (CR2)0-2SO2R12;
R4 is H, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro,
SO2R12, (CR2)pR13 or X;
R5, R5’, R7 and R10 are H;
R6 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12,
(CR2)pR13 or X;
R8 and R9 are independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo or X; and
provided one of R8 and R9 is X;
R is H or C1-6 alkyl;
X is (CR2)qY;
Y is a 5-12 membered heterocyclic ring comprising N, O and/or S, and
optionally substituted with C1-6 alkyl, hydroxylC1-C8alkyl, C1-C8alkoxyC1-C8alkyl or a 5-
12 membered heterocyclic ring comprising N, O and/or S; and wherein Y is attached
to A2 or A3 or both via a carbon atom of said heterocyclic ring when q in (CR2)qY is 0;
R12 and R13 are independently 3-7 membered saturated or partially
unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O
and/or S; aryl or heteroaryl; or R12 is H, C1-6 alkyl;
p is 0-4; and
n and q are 0.
147
2. The novel pyrimidine compound as claimed in claim 1, wherein R3 is SO2R12 and R12 is
C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl or
morpholinyl.
3. The novel pyrimidine compound as claimed in claim 1, wherein R6 is halo or OR12,
wherein R12 is C1-6 alkyl.
4. The novel pyrimidine compound as claimed in claim 1, wherein said compound is
selected from the group consisting of
67
O
NH
N
N
Cl
NH
S
O
O
N
5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-
methylpiperidin-4-yl)phenyl)-N4-[2-
(propane-2-sulfonyl)phenyl]-pyrimidine-
2,4-diamine;
69
O
NH
N
N
Cl
NH
S
O
O
N
N
5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-
(1-methylpiperidin-4-yl)piperidin-4-
yl)phenyl)-N4-(2-(isopropylsulfonyl)
phenyl)pyrimidine-2,4-diamine;
71
O
NH
N
N
Cl
NH
S
O
O
NH
5-chloro-N2-(2-cyclobutoxy-5-methyl-4-
(piperidin-4-yl)phenyl)-N4-(2-
(isopropylsulfonyl)phenyl)pyrimidine-2,4-
diamine;
72
O
NH
N
N
Cl
NH
S
O
O
N
OH
148
2-[4-(4-{5-Chloro-4-[2-(propane-2-
sulfonyl)-phenylamino]-pyrimidin-2-
ylamino}-5-isopropoxy-2-methyl-phenyl)-
piperidin-1-yl]-ethanol;
73
O
NH
N
N
Cl
NH
S
O
O
N
O
5-chloro-N2-(2-isopropoxy-4-(1-(2-
methoxyethyl)piperidin-4-yl)-5-
methylphenyl)-N4-(2-(isopropylsulfonyl)
phenyl)pyrimidine-2,4-diamine;
74
O
NH
N
N
NH
S
O
O
N
N2-(2-isopropoxy-5-methyl-4-(1-
methylpiperidin-4-yl)phenyl)-N4-(2-
(isopropylsulfonyl)phenyl)-5-
methylpyrimidine-2,4-diamine;
75
O
NH
N
N
Cl
NH
S
O
O
N
5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-
methylpiperidin-4-yl)phenyl)-N4-(2-
(propylsulfonyl)phenyl)pyrimidine-2,4-
diamine;
77
O
NH
N
N
Cl
NH
S
O
O
N
N
5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-
methylpiperidin-4-yl)phenyl)-N4-(2-
(pyrrolidin-1-ylsulfonyl)phenyl) pyrimidine-
2,4-diamine;
149
82
O
NH
N
N
Cl
NH
S
O
N
O
5-chloro-N2-(2-isopropoxy-5-methyl-4-(1-
methylpiperidin-4-yl)phenyl)-N4-(2-
(methylsulfonyl)phenyl)pyrimidine-2,4-
diamine; and
84
O
NH
N
N
Cl
NH
S
O
N
O
5-chloro-N4-(2-(cyclobutylsulfonyl)phenyl)-
N2-(2-isopropoxy-5-methyl-4-(1-
methylpiperidin-4-yl)phenyl)pyrimidine-
2,4-diamine;
or pharmaceutically acceptable salts thereof.
5. The novel pyrimidine compound as claimed in claim 1, wherein said compound is N2-
(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-
(isopropylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine.
6. A pharmaceutical composition comprising a therapeutically effective amount of a
compound as claimed in any one of claims 1-5 and a pharmaceutically acceptable
carrier.
7. The pharmaceutically compound as claimed in any one of claims 1-5, or
pharmaceutically acceptable salts thereof, as and when used as therapeutic agent for
the treatment of a cell proliferative