WO2012082817A1

WO2012082817A1 - Biarylamide inhibitors of leukotriene production

Info

Publication number: WO2012082817A1
Application number: PCT/US2011/064770
Authority: WO
Inventors: Angela Berry; Zhidong Chen; Stephane De Lombaert; Michel Jose Emmanuel; Pui Leng Loke; Chuk Chui Man; Tina Marie Morwick; Hidenori Takahashi
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2010-12-16
Filing date: 2011-12-14
Publication date: 2012-06-21
Also published as: JP2013545810A; JP6097998B2; US20120322795A1; US9073895B2; EP2651930B1; EP2651930A1

Abstract

The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, C, R^1a, R^1b, R², R³, R^4a and R^4b are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

Description

BIARYLAMIDE INHIBITORS OF LEUKOTRIENE PRODUCTION

FIELD OF THE INVENTION

This invention relates to biaryl compounds that are useful as inhibitors of five lipoxygenase activating protein (FLAP) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of leukotrienes including asthma, allergy, rheumatoid arthritis, multiple sclerosis, inflammatory pain, acute chest syndrome and cardiovascular diseases including atherosclerosis, myocardial infarction and stroke. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and

intermediates useful in these processes.

BACKGROUND OF THE INVENTION

Leukotrienes (LTs) and the biosynthetic pathway from arachidonic acid leading to their production have been the targets of drug discovery efforts for over twenty years. LTs are produced by several cell types including neutrophils, mast cells, eosinophils, basophils monocytes and macrophages. The first committed step in the intracellular synthesis of LTs involves oxidation of arachidonic acid by 5-lipoxygenase (5-LO) to LTA4, a process requiring the presence of the 18 kD integral membrane protein 5-lipoxygenase-activating protein (FLAP) (D.K. Miller et al., Nature, 1990, 343, 278-281; R.A.F. Dixon et al., Nature, 1990, 343, 282-284). Subsequent metabolism of LTA₄ leads to LTB₄, and the cysteinyl LTs- LTC₄, LTD₄ and LTE₄ (B. Samuelsson, Science, 1983, 220, 568-575). The cysteinyl LTs have potent smooth muscle constricting and bronchoconstricting effects and they stimulate mucous secretion and vascular leakage. LTB₄ is a potent chemo tactic agent for leukocytes, and stimulates adhesion, aggregation and enzyme release. Much of the early drug discovery effort in the LT area was directed towards the treatment of allergy, asthma and other inflammatory conditions. Research efforts have been directed towards numerous targets in the pathway including antagonists of LTB₄ and the cysteinyl leukotrienes LTC₄, LTD₄ and LTE₄, as well as inhibitors of 5-lipoxygenase (5- LO), LTA₄ hydrolase and inhibitors of 5-lipoxygenase activating protein (FLAP) (R.W. Friesen and D. Riendeau, Leukotriene Biosynthesis Inhibitors, Ann. Rep. Med. Chem., 2005, 40, 199-214). Years of effort in the above areas have yielded a few marketed products for the treatment of asthma including a 5-LO inhibitor, zileuton, and LT antagonists, montelukast, pranlukast and zafirlukast.

More recent work has implicated LTs in cardiovascular disease, including myocardial infarction, stroke and atherosclerosis (G. Riccioni et al., J. Leukoc. Biol., 2008, 1374- 1378). FLAP and 5-LO were among the components of the 5-LO and LT cascade found in atherosclerotic lesions, suggesting their involvement in atherogenesis (R. Spanbroek et al., Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 1238-1243). Pharmacological inhibition of FLAP has been reported to decrease atherosclerotic lesion size in animal models. In one study, oral dosing of the FLAP inhibitor MK-886 to apoE/LDL-R double knockout mice fed a high-fat diet from 2 months of age to 6 months led to a 56% decrease in plaque coverage in the aorta and a 43% decrease in the aortic root (J. Jawien et al., Eur. J. Clin. Invest., 2006, 36, 141-146). This plaque effect was coupled with a decrease in plaque- macrophage content and a concomitant increase in collagen and smooth muscle content which suggests a conversion to a more stable plaque phenotype. In another study, it was reported that administration of MK-886 via infusion to ApoExCD4dnT RII mice (apoE KO mice expressing a dominant-negative TGF-beta receptor which effectively removes all TGF-beta from the system) resulted in about a 40% decrease in plaque area in the aortic root (M. Back et al., Circ. Res., 2007, 100, 946-949). The mice were only treated for four weeks after plaque growth was already somewhat mature (12 weeks) thus raising the possibility of therapeutically treating atherosclerosis via this mechanism. In a study examining human atherosclerotic lesions, it was found that the expression of FLAP, 5-LO and LTA₄ hydrolase was significantly increased compared to healthy controls (H. Qiu et al., Proc. Natl. Acad. Sci. U.S.A., 103, 21, 8161-8166). Similar studies suggest that inhibition of the LT pathway, for example by inhibition of FLAP, would be useful for the treatment of atherosclerosis (for reviews, see M. Back Curr. Athero. Reports, 2008 10, 244-251 and Curr. Pharm. Des., 2009, 15, 3116-3132).

In addition to the work cited above, many other studies have been directed towards understanding the biological actions of LTs and the role of LTs in disease. These studies have implicated LTs as having a possible role in numerous diseases or conditions (for a review, see M. Peters-Golden and W.R. Henderson, Jr., M.D., N. Engl. J. Med., 2007, 357, 1841-1854). In addition to the specific diseases cited above, LTs have been implicated as having a possible role in numerous allergic, pulmonary, fibrotic, inflammatory and cardiovascular diseases, as well as cancer. Inhibition of FLAP is also reported to be useful for treating renal diseases such as diabetes-induced proteinuria (see for example J. M. Valdivieso et al., Journal of Nephrology, 2003, 16, 85-94 and A Montero et al., Journal of Nephrology, 2003, 16, 682-690).

A number of FLAP inhibitors have been reported in the scientific literature (see for example J.F. Evans et al., Trends in Pharmacological Sciences, 2008, 72-78) and in U.S. patents. Some have been evaluated in clinical trials for asthma, including MK-886, MK- 591, and BAY X1005, also known as DG-031. More recently, the FLAP inhibitor AM- 103 (J.H. Hutchinson et al., J. Med. Chem. 52, 5803-5815) has been evaluated in clinical trials, based on its anti-inflammatory properties (D.S. Lorrain et al., J. Pharm. Exp. Ther., 2009, DOI: 10.1124/jpet.109.158089). Subsequently, it was replaced by the back-up compound AM-803 (GSK-2190915) for the treatment of respiratory diseases. DG-031 has also been in clinical trials to evaluate its effect on biomarkers for myocardial infarction risk and showed a dose-dependent suppression of several biomarkers for the disease (H. Hakonarson et al., JAMA, 2005, 293, 2245-2256). MK-591 was shown in a clinical trial to reduce proteinuria in human glomerulonephritis (see for example A. Guash et al., Kidney International, 1999, 56, 291-267).

However, to date, no FLAP inhibitor has been approved as a marketed drug. BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds which inhibit 5-lipoxygenase activating protein (FLAP) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of leukotrienes, including allergic, pulmonary, fibrotic, inflammatory and cardiovascular diseases and cancer. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

DETAILED DESCRIPTION OF THE INVENTION

In its first broadest embodiment, the present invention relates to a compound of formula

I

or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-10 membered heteroaryl ring containing 1 - 3 heteroatoms selected from nitrogen, sulfur and oxygen;

B is a 6-10 membered aryl ring or a 5-6 membered heteroaryl ring containing 1 - 3 heteroatoms selected from nitrogen, sulfur and oxygen;

C is a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring containing 1 - 3 heteroatoms selected from nitrogen, sulfur and oxygen; are each independently selected from -H, C_1-6 alkyl, C_1-6 alkoxyl, -C_1-6 alkyl - OH, hydroxy, -C(O)- C_1-6 alkyl and -NR⁵R⁶;

R 2" and R 3^J are each independently - Ci_6 alkyl or -H, with the proviso that both

R 2 and R 3 cannot be hydrogen; or

R 2 and R 3 together with the carbon atom to which they are attached form a C₃_8 cycloalkyl or C₃_8 heterocyclic ring;

R^4a and R^4b are each independently selected from

-H, Ci-6 alkyl, C_1-6 alkoxyl, -Ci-e alkyl-OH, aryl, -O-aryl, 5-6 membered heteroaryl, C₃_8 cycloalkyl, C₃_g heterocyclyl, -C^alkyl-aryl, -C_1-3 alkyl-heteroaryl, -C_1-3 alkyl- heterocyclyl, -0-C_1-3 alkyl-aryl, , -0-C_1-3 alkyl-heteroaryl, -O Ci_6 alkyl, CF₃ , 0-CF₃, - COO R⁵, -C(O) Ci-3 alkyl -S(0)₂-NR⁵R⁶, -S(0)₂CF₃, -S(0)₂C_1-3 alkyl, -C(O) NR⁷R⁸, hydroxy, halogen, and cyano, wherein each group is optionally independently substituted with 1-3 substituents chosen from C_1-6 alkyl, C_1-6 alkoxyl, hydroxy and halogen;

R⁵and R⁶ are each independently chosen from H, C_1-6 alkyl, - C_1-6 alkylhydroxy and C_1-6 alkyl-O- Ci-6 alkyl;

Or, R⁵and R⁶ together with the nitrogen atom to which they are attached form a 5 - 6 membered heterocyclic ring;

R 7'and R 8" are each independently chosen from H, C_1-6 alkyl, -S(0)₂C_1-3 alkyl, and

-C(NH)-NH_2.

In a seond embodiment, the present invention relates to a compound as described in the broadest embodiment above, or a pharmaceutically acceptable salt thereof, wherein:

A is selected from pyrazolyl, imidazolyl, pyrrolyl, thienyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, imidazopyridinyl, pyrazolopyridinyl and quinolinyl; B is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl;

C is selected from phenyl, indanyl, pyrazolyl, imidazolyl, pyrrolyl, thienyl, thiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, dihydropyrrolopyridinyl,

imidazopyridinyl, pyrazolopyridinyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolanyl, benzodioxolinyl, dihydroindolyl, naphthyridinyl, pyrimidinopyridinyl, thiazolopyridinyl, tetrahydrothiazolopyridinyl and benzothienyl ;

R^la and R^lb are each independently selected from -H, Ci_6 alkyl, C_1-3 alkoxyl, -C_1-3 alkyl - OH, hydroxy, -C(O)- C_1-3 alkyl and -NR⁵R⁶;

R 2" and R 3^J are each independently - C_1-6 alkyl or -H, with the proviso that both

R 2 and R 3 cannot be hydrogen; or

R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or a tetrahydropyranyl ring;

R^4a and R^4b are each independently selected from

-H, C_1-3 alkyl, C_1-3 alkoxyl, -C_1-3 alkyl-OH, phenyl, -O-phenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopropyl, cyclopbutyl, cyclopenyl, cyclohexyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, -C^alkyl-phenyl, -C_1-3 alkyl- pyridinyl, -C_1-3 alkyl- pyrimidinyl, -C_1-3 alkyl- pyridazinyl, -C_1-3 alkyl- pyrazinyl, -C_1-3 alkyl-heterocyclyl, -0-C_1-3 alkyl-phenyl, -0-C_1-3 alkyl-pyridinyl, -O C_1-3 alkyl, CF₃ , O- CF₃, -COO R⁵, -C(O) Ci-3 alkyl -S(0)₂-NR⁵R⁶, -S(0)₂CF₃, -S(0)₂C_1-3 alkyl, -C(O)

NR 7 R 8 , hydroxy, halogen, and cyano, wherein each group is optionally independently substituted with 1-3 substituents chosen from C_1-6 alkyl, C_1-6 alkoxyl, hydroxy and halogen; R⁵and R⁶ are each independently chosen from H, C_1-5 alkyl, - C_1-3 alkylhydroxy and C_1-3 alkyl-O- C_1-3 alkyl;

Or, R⁵and R⁶ together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or thiomorpholinyl ring;

-C(NH)-NH_2.

In a third embodiment, the present invention relates to a compound as described in any of the embodiments above, or a pharmaceutically acceptable salt thereof, wherein:

A is selected from pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolopyridinyl, dihydropyrrolopyridinyl and imidazopyridinyl.

In a fourth embodiment there is provided a compound of formula (I) as described in any of the embodiments above, or a pharmaceutically acceptable salt thereof, wherein:

B is selected from phenyl and pyridinyl.

In a fifth embodiment there is provided a compound as described in any of the embodiments above, or a pharmaceutically acceptable salt thereof, wherein:

C is selected from phenyl, indanyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, imidazopyridinyl, pyrazolopyridinyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzofuranyl,

dihydrobenzofuranyl, benzodioxolanyl, benzodioxolinyl, dihydroindolyl, naphthyridinyl, pyrimidinopyridinyl, thiazolopyridinyl, tetrahydrothiazolopyridinyl and benzothienyl.

In a sixth embodiment there is provided a compound of formula (I) as described in any of the embodiments above, or a pharmaceutically acceptable salt thereof, wherein:

R 2" and R 3^J are each independently H, methyl, ethyl, propyl, isopropyl or tert. butyl, with the proviso that both R 2 and R 3 cannot be hydrogen; or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a tetrahydropyranyl ring.

In a seventh embodiment there is provided a compound as described in the first or second embodiment, or a pharmaceutically acceptable salt thereof, wherein:

A is selected from pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolopyridinyl, dihydropyrrolopyridinyl and imidazopyridinyl;

B is selected from phenyl and pyridinyl;

dihydrobenzofuranyl, benzodioxolanyl, benzodioxolinyl, dihydroindolyl, naphthyridinyl, pyrimidinopyridinyl, thiazolopyridinyl, tetrahydrothiazolopyridinyl and benzothienyl;

R 2" and R 3^J are each independently H, methyl, ethyl, isopropyl or tert. butyl, with the proviso that both R 2 and R 3 cannot be hydrogen; or

R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a tetrahydropyranyl ring;

R^la and R^lb are each independently selected from -H, Ci_6 alkyl, methoxy, -CH₂-OH, hydroxy, -C(O)- CH₃ and -NR⁵R⁶;

R^4a and R^4b are each independently selected from

-H, C_1-3 alkyl, C_1-3 alkoxyl, -C_1-3 alkyl-OH, phenyl, -O-phenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopropyl, cyclopbutyl, cyclopenyl, cyclohexyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, -C^alkyl-phenyl, -C_1-3 alkyl- pyridinyl, -C_1-3 alkyl- pyrimidinyl, -C_1-3 alkyl- pyridazinyl, -C_1-3 alkyl- pyrazinyl, -C_1-3 alkyl-heterocyclyl, -0-C_1-3 alkyl-phenyl, -0-C_1-3 alkyl-pyridinyl, -O C_1-3 alkyl, CF₃ , O- CF₃, -COO R⁵, -C(O) Ci_₃ alkyl -S(0)₂-NR⁵R⁶, -S(0)₂CF₃, -S(0)₂Ci_₃ alkyl, -C(O)

7 8

NR R , hydroxy, halogen, and cyano, wherein each group is optionally independently substituted with 1-3 substituents chosen from C_1-6 alkyl, C_1-6 alkoxyl, hydroxy and halogen;

R⁵and R⁶ are each independently chosen from H, Cis alkyl, - C_1-3 alkylhydroxy and C_1-3 alkyl-O- C_1-3 alkyl;

7 8

R'and R" are each independently chosen from H, C_1-6 alkyl, -S(0)₂C_1-3 alkyl, and -C(NH)-NH_2.

In an eighth embodiment there is provided a compound as described in the seventh embodiment above, or a pharmaceutically acceptable salt thereof, wherein:

2 3

R" and R^J are each independently H, methyl, ethyl, isopropyl or tert. butyl, with the

2 3

proviso that both R and R cannot be hydrogen.

In a ninth embodiment there is provided a compound as described in the seventh embodiment, or a pharmaceutically acceptable salt thereof, wherein:

2 3

R and R together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a tetrahydropyranyl ring.

In a tenth embodiment there is provided a compound as described in the seventh embodiment, or a pharmaceutically acceptable salt thereof, wherein:

B is phenyl.

In an eleventh embodiment there is provided a compound as described in the seventh embodiment, or a pharmaceutically acceptable salt thereof, wherein: B is pyridyl.

The following are representative compounds of the invention which can be made by the general synthetic schemes, the examples, and known methods in the art.

Table 1

H₂N jO Ni v ^F carboxamide

carboxamide

H₂N^ 2H-pyran-4-carboxamide 4- [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(3-oxo-l,3-

71 dihydro-2-benzofuran-5- yl)tetrahydro-2H-pyran-4- carboxamide

4- [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- [3-chloro-4-

72 (morpholin-4- yl)phenyl] tetrahydro-2H-pyran- 4-carboxamide

methyl 3-[({4-[4-(2- aminopyrimidin-5-

HN yl)phenyl] tetrahydro-2H-pyran-

73

4-yl}carbonyl)amino]-5-(4- chlorophenyl)thiophene-2- carboxylate

4- [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(3-tert-

74

butylphenyl)tetrahydro-2H- pyran-4-carboxamide

methyl 6-[({ l-[4-(2- aminopyrimidin-5- yl)phenyl]cyclobutyl}carbonyl)a

mino]pyridine-3-carboxylate

6-[({ l-[4-(2-aminopyrimidin-5- yl)phenyl]cyclobutyl}carbonyl)a

H₂N N mino]pyridine-3-carboxylic acid

O methyl 5-[({ l-[4-(2- aminopyrimidin-5- yl)phenyl]cyclobutyl}carbonyl)a mino] -2-hydroxybenzoate l-[6-(2-aminopyrimidin-5- yl)pyridin-3-yl]-N-(4- cyanophenyl)cyclobutanecarbox amide l-[6-(2-aminopyrimidin-5- yl)pyridin-3-yl]-N-[4- (methylsulfonyl)phenyl] cyclobut anecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-[5-(3-methyl- 1,2,4- oxadiazol-5-yl)pyridin-2- yl]cyclobutanecarboxamide

s y p eny utanam e

— S carboxamide

2-yl]butanamide

tert-butyl 6-[({4-[4-(2- aminopyrimidin-5- yl)phenyl] tetrahydro-2H-pyran- 4-yl}carbonyl)amino]-3,4-

dihydroisoquinoline-2( 1H)- carboxylate

N-[5-(2-methyl-l,3-thiazol-4- yl)pyridin-2-yl]-4-[4-(lH- pyrrolo[2,3-b]pyridin-5- yl)phenyl] tetrahydro-2H-pyran- 4-carboxamide

4-[4-(6-amino-5-methylpyridin- 3-yl)phenyl]-N-[5-(2-methyl- l,3-thiazol-4-yl)pyridin-2-

H₂N N if yl] tetrahydro-2H-pyran-4- carboxamide

4-[4-(2,3-dihydro-lH- pyrrolo[2,3-b]pyridin-5- yl)phenyl]-N-[5-(2-methyl-l,3- thiazol-4-yl)pyridin-2- yl] tetrahydro-2H-pyran-4- carboxamide

4- [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- [4- ( 1 H-imidazol- 1 - yl)phenyl] tetrahydro-2H-pyran- 4-carboxamide

bipyridin-6-yl)-2,3-

carboxamide

carboxamide

N-(pyrimidin-4-yl)-l-[4-(lH- pyrrolo[2,3-b]pyridin-5-

188

yl)phenyl]cyclobutanecarboxami de

N-(2-methylpyridin-4-yl)-l-[4- (lH-pyrrolo[2,3-b]pyridin-5-

189

yl)phenyl]cyclobutanecarboxami de

CH₃

N-(2-methoxypyridin-4-yl)- 1-[4-

(lH-pyrrolo[2,3-b]pyridin-5-

190

yl)phenyl]cyclobutanecarboxami de

H₃C

4- [4- (6- aminopyridin- 3 - yl)phenyl]-N-[5-(2-methyl-l,3-

191 thiazol-4-yl)pyridin-2- yl] tetrahydro-2H-pyran-4- carboxamide l-{4-[2- (methylamino)pyrimidin-5-

192

yl]phenyl}-N-(pyridin-3- yl)cyclobutanecarboxamide

H ^N

— S ^cHa carboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- ( 1 ,3-benzothiazol- 6-yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(4-methyl-l,3-

A thiazol-2-

H₂N N L \ yl)cyclobutanecarboxamide

CH₃

4-{4-[6-(acetylamino)pyridin-3- yl]phenyl}-N-[5-(2-methyl-l,3- thiazol-4-yl)pyridin-2- yl] tetrahydro-2H-pyran-4- carboxamide

4-(4-{2-[(2- methoxyethyl)amino]pyrimidin- 5-yl}phenyl)-N-[5-(2-methyl- l,3-thiazol-4-yl)pyridin-2- yl] tetrahydro-2H-pyran-4- carboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(6'-methoxy-3,3'- bipyridin-6- yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(4,5-dimethyl-l,3- thiazol-2- yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(5-methylpyridin- 2-yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(5-methyl-l,3-

HN s

thiazol-2-

H₂N N yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(2,6- dimethylpyrimidin-4- yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(6- methoxypyridin- 3 - yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- (pyrazin-2- yl)cyclobutanecarboxamide

H (pyridin-4-yl)butanamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-[4- (methylsulfonyl)phenyl] cyclobut

anecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(5-methyl-4,5,6,7- tetrahydro[ 1 ,3]thiazolo[5,4- c]pyridin-2- yl)cyclobutanecarboxamide

2- [4- (2- aminopyrimidin- 5 - yl)phenyl]-2-methyl-N-[5-(2-

H₂N N s methyl- 1 ,3-thiazol-4-yl)pyridin- 2-yl]propanamide

CH₃

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- (2-cyanopyridin-4- yl)cyclobutanecarboxamide

ethyl 6-[({ l-[4-(2- aminopyrimidin-5- yl)phenyl]cyclobutyl}carbonyl)a mino]pyridine-3-carboxylate

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- (3 ,4'-bipyridin-6- yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- (3 ,3 '-bipyridin-6- yl)cyclobutanecarboxamide

5-[({ l-[4-(2-aminopyrimidin-5- yl)phenyl]cyclobutyl}carbonyl)a mino]pyridine-2-carboxamide

NH₂

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(6-cyanopyridin-3- yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(3-phenyl-l,2,4- thiadiazol-5- yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-(5-phenyl- 1H- l,2,4-triazol-3- yl)cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl]-N-[5-(4- methoxyphenyl)- 1H- 1 ,2,4- triazol-3- yl] cyclobutanecarboxamide

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- [3-chloro-4- (morpholin-4- yl)phenyl]cyclobutanecarboxami de

1 - [4- (2- aminopyrimidin- 5 - yl)phenyl] -N- [4- (morpholin-4- yl)phenyl]cyclobutanecarboxami de

2- [4- (2- aminopyrimidin- 5 - yl)phenyl] -2-cyclopentyl-N- (pyridin-4-yl)acetamide

2- [4- (2- aminopyrimidin- 5 - yl)phenyl]-2-cyclopentyl-N-[5- (2-methyl- 1 ,3-thiazol-4- yl)pyridin-2-yl] acetamide

In one embodiment, the invention relates to any of the compounds depicted in Table 1 above and the pharmaceutically acceptable salts thereof.

Representative compounds of the invention show activity in the FLAP binding assay and in the human whole blood LTB₄ production inhibition assay, described in the assessment of biological properties section, as shown in Table 2.

Table 2

10 240

11 21 .87 >3000

12 68 2225

13 16.75 3000

14 8.95 2252

15 23.5 >3000

16 10.7 635.75

17 330

18 16 1705

19 120

20 16 1335

21 12 >3000

22 60.5 >3000

23 59.67 >3000

24 95 >3000

25 8.65 501

26 26 >3000

27 5.5 207

28 121 .5

29 190

30 18 2240.5

31 140

32 46.5 1 1 17.5

33 42.5 >3000

34 1 1 .65 160.5

35 390

36 13.33 >3000

37 35 >3000

38 59.5 >3000 39 55 1922

40 29 1219

41 120 >3000

42 310

43 12.25 >3000

44 270

45 6.2 459

46 180 >3000

47 65 3202

48 84 1628

49 27 534.5

50 440

51 18 1694

52 63.5 1810

53 280

54 44.5 1 123.5

55 29 >3000

56 380

57 260

58 170 >3000

59 12.65 >3000

60 3.5 310

61 94 >3000

62 33.5 >3000

63 30.5 81 1 .5

64 48 849.5

65 14 905

66 1 1 .9 1778

67 14.5 1214.5 68 68.5 1213.5

69 260

70 42 >3000

71 190 >3000

72 28.33 244.25

73 53.5 1498

74 97 >3000

75 68 >3000

76 52.5 >3000

77 1 10

78 1 12.5 >3000

79 53.5 >3000

80 60 >3000

81 54 >3000

82 10.5 2776.5

83 14.5 1059.5

84 180

85 12.5 849

86 18.67 412

87 4 192

88 5.65 277.5

89 8.13 202.5

90 31 .5 2075

91 5.45 240

92 15.5 717.5

93 2.05 31 1 .67

94 65 856.67

95 2.35 202.5

96 26 97 4.85 4100

98 12.15 235.5

99 45.5 570

100 1.85 184.5

101 47

102 2.05 330

103 4.1 101.5

104 1.95 155

105 17.5

106 3 195

107 87 1100

108 2 1900

109 9.4 2100

110 120 1100

111 180 2376.5

112 230 2058.5

113 390 10397

114 290 >20000

115 190 17108.5

116 430 10847

117 9.3 1531.25

118 260 10665

119 3.95 985.75

120 11.5 1266

121 19 1884.5

122 9.53 1036.33

123 4 918.75

124 77.5 2171.5

125 173.5 5556.25 126 180 11991.5

127 9 3220.17

128 140 815

129 10.4 8617

130 1.52 224.5

131 2.2 414

132 220 1512.5

133 9.4 4402

134 17.5 650.75

135 11.15 737.5

136 10.25 4688.5

138 300 11803

139 110

140 230

141 190

142 39 11336

143 17.07 646

144 66 1593.25

145 11.3 866.25

146 11.1 752

147 490 2897

148 360 3978.5

149 260 1458.5

150 48 3594

151 2.1 200.25

152 34.5 895.83

153 7.8 508.67

154 63.33 1371.5

155 136 857.25 156 490

157 410

158 36 5267.5

159 420

160 12.95

161 31

162 4.1 896

163 6.75 403.5

164 1 .9 315

165 1 .4 354

166 3 332.5

167 4.7 353.5

168 7.95 616.25

169 5.25 329.75

170 9.8 894

171 2.05 565.5

173 18 929.5

174 18.1 685.75

175 22 1275.5

176 6.65 712

177 5.1 216.75

178 35.5 557

179 24.67 388

180 6.3 401 .67

181 1 10

182 32.5 1056

183 51 .6 480.25

184 39 1470.5

185 17.5 955 186 3.2 334.5

187 5.1 517.25

188 1 .65 129.75

189 1 .45 190.5

190 2.25 148.75

191 27.5 1947

192 32 861

193 10.1 1649

194 19.15 577.25

195 2.7 174.5

196 50.67 2914

197 27 2442.5

198 3.75 180.25

199 5.7 1382

200 19 2006

201 3.75 224.5

202 56.5

203 13.7 3250

204 2.8 415

205 8.4 922

206 270

207 230

208 3.35 459

209 13

210 5.1 791 .5

211 23.5

212 15

213 12.63 333.25

214 24 1070 215 17.67 705.5

216 91 .5 3044

217 8.25 389

218 32.5 958.5

219 5.3 348.5

220 470

221 290 >3000

222 43.5 1229.5

223 7.15 1666.25

224 30 718

225 78 1367.5

226 250

227 40.5 >3000

228 12 1095.5

229 6.65 152.75

230 21 .5 696.5

231 84 121 1 .5

232 7.45 151 .5

233 6.5 159.5

234 32.5 857.75

235 5.4 627

236 3.45 289.75

237 1 .9 43

238 2.35 74.5

239 2.15 144.5

240 4.4

241 5.6 406.5

242 3.95

243 22 244 10.85

245 3.3 46

246 34

247 130

248 240

249 22.5

250 3.2 60.75

251 16

252 7.4 227.5

253 1 .8 270.5

254 1 .6 1 1 1

255 2.5 143.5

The invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of the invention, or the pharmaceutically acceptable derivatives thereof, optionally combined with conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelled forms. An

isotopically-labelled form of an active agent of a combination of the present invention is identical to said active agent but for the fact that one or more atoms of said active agent have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom which is usually found in nature. Examples of isotopes which are readily available commercially and which can be incorporated into an active agent of a combination of the present invention in accordance with well established procedures, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, e.g. , ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. An active agent of a combination of the present invention, a prodrug thereof, or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is

contemplated to be within the scope of the present invention. The invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers shall be defined as being enantiomers and diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.

Some of the compounds of the invention can exist in more than one tautomeric form. The invention includes methods using all such tautomers.

All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, "C_1-6 alkoxy" is a C_1-6 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl, and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:

The term "alkyl" refers to both branched and unbranched alkyl groups. It should be understood that any combination term using an "alk" or "alkyl" prefix refers to analogs according to the above definition of "alkyl". For example, terms such as "alkoxy", "alkythio" refer to alkyl groups linked to a second group via an oxygen or sulfur atom. "Alkanoyl" refers to an alkyl group linked to a carbonyl group (C=0).

In all alkyl groups or carbon chains, one or more carbon atoms can be optionally replaced by heteroatoms such as O, S or N. It shall be understood that if N is not substituted then it is NH. It shall also be understood that the heteroatoms may replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain. Such groups can be substituted as herein above described by groups such as oxo to result in definitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo. As used herein, "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. For example, for a -S-C_1-6 alkyl radical, unless otherwise specified, shall be understood to include -S(0)-C_1-6 alkyl and

-S(0)₂-d_₆ alkyl.

The term "C_3-1o carbocycle" or "cycloalkyl" refers to a nonaromatic 3 to 10-membered (but preferably, 3 to 6-membered) monocyclic carbocyclic radical or a nonaromatic 6 to 10-membered fused bicyclic, bridged bicyclic, or spirocyclic carbocyclic radical. The C_3-1o carbocycle may be either saturated or partially unsaturated, and the carbocycle may be attached by any atom of the cycle which results in the creation of a stable structure. Non-limiting examples of 3 to 10-membered monocyclic carbocycles include

cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, and cyclohexanone. Non-limiting examples of 6 to 10- membered fused bicyclic carbocyclic radicals include bicyclo[3.3.0]octane,

bicyclo[4.3.0]nonane, and bicyclo[4.4.0]decanyl (decahydronaphthalenyl). Non-limiting examples of 6 to 10-membered bridged bicyclic carbocyclic radicals include bicyclo [2.2.2]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.1]octanyl. Non-limiting examples of 6 to 10-membered spirocyclic carbocyclic radicals include but are not limited to spiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl.

The term "Ce-io aryl" refers to aromatic hydrocarbon rings containing from six to ten carbon ring atoms. The term C_6-1o aryl includes monocyclic rings and bicyclic rings where at least one of the rings is aromatic. Non-limiting examples of C₆-io aryls include phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl and benzocycloheptenyl.

The term "5 to 11-membered heterocycle" refers to a stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical. The 5 to 11-membered heterocycle consists of carbon atoms and one or more, preferably from one to four heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be either saturated or partially unsaturated. Non-limiting examples of nonaromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, l, l-dioxo-l ⁶-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non-limiting examples of nonaromatic 6 to 11 -membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limiting examples of nonaromatic 6 to 11 -membered bridged bicyclic radicals include 2- azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of nonaromatic 6 to 11 -membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza- spiro[3,4]octanyl.

The term "5 to 11 -membered heteroaryl" shall be understood to mean an aromatic 5 to 6- membered monocyclic heteroaryl or an aromatic 7 to 11 -membered heteroaryl bicyclic ring where at least one of the rings is aromatic, wherein the heteroaryl ring contains 1-4 heteroatoms such as N, O and S. Non-limiting examples of 5 to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl. Non-limiting examples of 7 to 11- membered heteroaryl bicyclic heteroaryl rings include benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl, benzothiazolyl, benzodioxolanyl, benzodioxolinyl, dihydroindolyl, naphthyridinyl, pyrimidopyridinyl, thiazolopyridinyl, tetrahydrothiazolopyridinyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, imidazopyridinyl, pyrazolopyridinyl,and pyrimidopyridinyl..

It will be understood that one to three carbon ring moieties in the each of the C3.10 carbocyclic rings, the 5 to 11-membered heterocyclic rings, the nonaromatic portion of the bicyclic aryl rings, and the nonaromatic portion of the bicyclic heteroaryl rings can independently be replaced with a carbonyl, thiocarbonyl, or iminyl moiety, i.e., -C(=0)-,

8 8

-C(=S)- and -C(=NR )-, respectively, where R is as defined above. The term "heteroatom" as used herein shall be understood to mean atoms other than carbon such as O, N, and S.

The term "halogen" as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine. The definitions "halogenated", "partially or fully halogenated"; partially or fully fluorinated; "substituted by one or more halogen atoms", includes for example, mono, di or tri halo derivatives on one or more carbon atoms. For alkyl, a non-limiting example would be -CH₂CHF₂, -CF₃ etc.

Each alkyl, carbocycle, heterocycle or heteroaryl, or the analogs thereof, described herein shall be understood to be optionally partially or fully halogenated.

The compounds of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art. For example, a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by the inventive methods disclosed herein.

The invention includes pharmaceutically acceptable derivatives of compounds of formula (I). A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a

pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the invention.

Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,

methanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal

(e.g., magnesium), ammonium and N-(CT -C4 alkyl)4⁺ salts.

In addition, within the scope of the invention is use of prodrugs of compounds of the invention. Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.

The compounds of formula I may be made using the general synthetic methods described below, which also constitute part of the invention.

GENERAL SYNTHETIC METHODS

The compounds of the invention may be prepared by the methods described below. In each of the schemes below, the groups A, B, C, R^la, R^lb, R², R³, R^4a and R^4b are as defined above for general formula I unless noted. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC) or HPLC-MS if desired. Intermediates and products may be purified by chromatography on silica gel, recrystallization, HPLC and/or reverse phase HPLC. Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature and in the Synthetic Examples section below.

Compounds of formula I may be prepared as shown in Scheme 1.

Scheme 1

As illustrated in Scheme 1, reaction of an acid of formula II with an amine of formula III, in a suitable solvent, under standard coupling conditions, provides a compound of formula (I). Standard peptide coupling reactions known in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer- Verlag) may be employed in these syntheses. An example of suitable coupling conditions is treatment of a solution of the carboxylic acid in a suitable solvent such as DMF with EDC, HOBT, and a base such as diisopropylethylamine, followed by the desired amine.

Alternatively, reaction of the acid of formula II with a reagent such as thionyl chloride or oxalyl chloride, provides the corresponding acid chloride which is then reacted with an amine of formula III, in a suitable solvent, in the presence of a suitable base, to provide a compound of formula (I).

Compounds of formula I may also be made by the sequence outlined in Scheme 2.

Scheme 2

As shown in Scheme 2, reaction of an acid of formula IV, wherein Hal = CI, Br or I, with an amine of formula III, as in Scheme 1, provides an intermediate amide of formula V. Coupling of intermediate of formula V with a boronic acid ester of formula VI or the corresponding boronic acid, in the presence of a siutable base and catalyst, in a suitable solvent, provides a compound of formula I.

Intermediate acid of formula II, wherein R 2 and R 3 together with the carbon atom to which they are attached form a heterocyclic or cycloalkyl ring, may be prepared according to the method shown in Scheme 3.

VII Br— (CH₂)n— Het- (CH₂)n— Br IV

(IX)

Scheme 3

As outlined in Scheme 3, reaction of a nitrile of formula VII with a dibromo or dihalo compound of formula VIII or IX, wherein Het = O, S or N, in a suitable solvent, in the presence of a suitable base, provides the corresponding alkylated nitrile of formula X. Hydrolysis of the nitrile, in a suitable solvent, in the presence of a suitable base, provides the acid of formula IV which may be converted to the corresponding boronic acid of formula XI, under standard reaction conditions. Reaction of the boronic acid of formula XI, under standard coupling conditions, with the halide of formula XII, provides a compound of formula II.

Alternatively, reaction of the acid of formula IV with a boronic acid of formula VI, under standard coupling conditions, provides a compound of formula I.

Intermediate acid of formula IV wherein R 2 and R 3 are acyclic, may be prepared according to Scheme 4.

Scheme 4

As outlined in Scheme 4, reaction of a nitrile of formula VII with R Br (XIII), in a siutable solvent, in the presence of a suitable base, provides a monoalkylated nitrile of formula XIV. Further alkylation with R Br provides a dialkylated nitrile which is then hydrolysed to provide an acid of formula IV. The acid of formula IV may be further converted to an acid of formula II by the sequence of steps shown in Scheme 3.

Another method of preparing intermediate acid of formula II is as shown in Scheme 5

XVI I

Scheme 5 Reaction of 2,5 dibromo pyridine XV, with a nitrile of formula XVI in a suitable solvent, in the presence of a suitable base, provides a nitrile of formula XVII which may be hydrolysed under standard conditions, to provide an acid of formula XVIII. Acid of formula XVIII may be converted to an acid of formula II, via the sequence in Scheme 3

Intermediate acid of formula II, wherein R 2 or R 3 is H, may be prepared starting from a carbonyl compound as shown in Scheme 6 below.

Scheme 6

Reaction of a carbonyl compound of formula XIX with triphenylphosphonium bromide, in a suitable solvent, in the presence of a suitable base, provides an alkene of formula XX. Reaction of alkene XX with a reagent such as BH3 and hydrogen peroxide provides an a hydroxy compound of formula XXI. The hydroxyl group in compound XXI may be oxidized, under standard conditions, to provide an acid of formula XXII which may then be converted to an acid of formula II according to Scheme 3.

Intermediate amine of formula III may be prepared as shown in Scheme 7 below.

XXI I I

Scheme 7

Reduction of a nitro compound of formula XXIII, under standard conditions, provides the corresponding amino compound of formula III.

Syntheses of specific amines are exemplified in the synthetic examples. Compounds of formula I as well as intermediates prepared by the above methods may be further converted to additional intermediates or compounds of formula I by methods known in the art and exemplified in the Synthetic Examples section below.

SYNTHETIC EXAMPLES

Synthesis of Nitrile Intermediates:

S nthesis of l-(4-bromo-phenyl)-cyclobutanecarbonitrile

R-1 1-1

To a solution of R-1 (5.0 g, 26.0 mmol) in DMF (25 mL) at 0 °C is added NaH (60% dispersion in mineral oil, 2.25 g, 56.0 mmol) slowly. The mixture is stirred for 15 minutes, and 1,3-dibromopropane (2.85 mL, 29.0 mmol) is added. The reaction mixture is allowed to warm to room temperature, stirred for 16 hours, and partitioned between EtOAc and H₂0. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-30% EtOAc in heptane) to give the title intermediate 1-1 (2.7 g).

The following intermediates were synthesized in similar fashion from the appropriate reagents:

Synthesis of 4-(4-bromo-phenyl)-tetrahydro-pyran-4-carbonitrile

R-1 I-7

To a solution of NaH (60% dispersion in mineral oil, 2.24 g, 56.0 mmol) in DMSO (10 mL) and THF (10 mL) at -50 °C is added a mixture of R-1 (5.0 g, 25.0 mmol) and 2- bromoethylether (6.5 g, 28.0 mmol) in THF (30 mL). The reaction mixture is allowed to warm to room temperature, stirred for 16 hours, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-20% EtOAc in heptane) to give the title intermediate 1-7 (25.0 g).

Intermediate Structure

Synthesis of l-(4-bromo- henyl)-cyclohexanecarbonitrile

R-1 |-9

To a solution of NaH (60% dispersion in mineral oil, 808 mg, 34.0 mmol) in DMSO (10 mL) and THF (10 mL) at -50 °C is added a mixture of R-1 (3.0 g, 15.0 mmol) and 1,5- dibromopentane (3.9 g, 17.0 mmol) in THF (10 mL). The reaction mixture is allowed to warm to room temperature, stirred for 16 hours, and heated at 70 °C for 40 minutes. The reaction mixture is allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, dried with MgS0₄, filtered, and concentrated in vacuo to give the title intermediate 1-9 (3.7 g).

S nthesis of 2-(4-bromo-phenyl)-2,3-dimethyl-butyronitrile

To a solution of NaH (60% dispersion in mineral oil, 1.42 g, 59.0 mmol) in DMF (20 mL) and THF (10 mL) at -50 °C is added a mixture of 1-3 (14.0 g, 58.0 mmol). The reaction mixture is stirred at -78 °C for 20 minutes, followed by the addition of Mel (8.4 g, 59.0 mmol). The reaction mixture is allowed to warm to room temperature slowly, stirred for 2 hours, and heated at 70 °C for 2 hours. The reaction mixture is allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are dried with Mg₂S0₄, filtered, and concentrated in vacuo to give the title intermediate 1-10 (14.0 g).

Intermediate Structure

1-11

Synthesis of 2-[4-(5-methoxy-pyridin-3-yl)-phenyl]-2,3-dimethyl-butyronitrile

To a mixture of 1-10 (4.0 g, 15.8 mmol) in THF (50 mL) is added R-2 (3.64 g, 23.8 mmol), tetrakis(triphenylphosphine)palladium(0) (1.85 g, 1.6 mmol), and 2M Na₂C0₃ solution (50 mL). The mixture is refluxed for 16 hours, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 25-100% EtOAc in heptane) to give the title intermediate 1-12 (3.1 g).

S nthesis of l-(5-bromo-pyridin-2-yl)-cyclobutanecarbonitrile

To a solution of lithium diisopropylamine (2.0 M in heptane/THF/ethylbenzene, 10 mL, 20.0 mmol) at -78 °C is added R-4 (811 mg, 10.0 mmol). The reaction mixture is stirred at -78 °C for 45 minutes, followed by the addition of R-3 (1.9 g, 8.0 mmol). The reaction mixture is allowed to warm to room temperature slowly, stirred for 16 hours, and heated at 70 °C for 2 hours. The reaction mixture is allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, dried with Mg₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-100% EtOAc in heptane) to give the title intermediate 1-13

(1.1 g).

The following intermediate (methyl ester) was synthesized in similar fashion from the appropriate reagents:

Synthesis of 4-[4-(pyridin-2-ylmethoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile

A mixture of 1-8 (1.5 g, 5.1 mmol), 10% Pd/C in THF (30 mL) is stirred at room temperature under H₂ for 16 hours. The reaction mixture is filtered through celite, and concentrated in vacuo to give 1-15 (1.0 g).

To a solution of 1-15 (1.0 g, 4.9 mmol), triphenylphosphine (2.6 g, 10.0 mmol) in THF (30 mL) is added R-5 (1.1 g, 10.0 mmol). The reaction mixture is cooled to 0 °C, followed by the addition of diisopropyl azodicarboxylate (2.0 g, 10.0 mmol). The reaction mixture is allowed to warm to room temperature, stirred for 2 hours, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, dried with Mg₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 20-90% EtOAc in heptane) to give the title intermediate 1-16 (760 mg). Synthesis of Carboxylic Acid Intermediates:

S nthesis of l-(4-bromo-phenyl)-cyclobutanecarboxylic acid

To a solution of I-l (2.7 g, 11.0 mmol) in EtOH (25 mL) at room temperature is added KOH (1.9 g, 34.0 mmol). The mixture is heated at 110 °C for 48 hours, allowed to cool to room temperature, and concentrated in vacuo. The residue is slurried with 1H HC1 solution, and the resulting solid is filtered, collected, and dried to give the title intermediate 1-17 (2.74 g).

S nthesis of 4-(4-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid

To a solution of 1-7 (2.8 g, 11.0 mmol) in ethylene glycol (30 mL) and H₂0 (15 mL) in a pressure tube at room temperature is added KOH (1.9 g, 56 mmol). The mixture is heated in a pressure tube at 140 C for 48 hours, allowed to cool to room temperature, decanted to ice, acidified with 1H HCl solution, and partitioned between EtOAc and H₂0. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo to give the title intermediate 1-20 (3.0 g).

Synthesis of 2-(4-bromo-phenyl)-3-methyl-butyric acid

1-26 1-27

To a solution of ethyl 4-bromophenyl acetate R-6 (2.0 g, 8.23 mmol) in DMF (25 mL) at -78 °C is added NaH (60% dispersion in mineral oil, 217 mg, 9.05 mmol) slowly. The mixture is stirred for 15 minutes, and 2-bromopropane (1.11 g, 9.05 mmol) is added. The reaction mixture is allowed to warm to room temperature, stirred for 16 hours, and partitioned between EtOAc and H₂0. The combined organics are dried with MgS0₄, filtered, and concentrated in vacuo to give 1-26 (2.0 g).

To a solution of 1-26 (1.5 g, 5.26 mmol) in ethylene glycol (20 mL) and H₂0 (20 mL) in a pressure tube at room temperature is added KOH (0.9 g, 16.0 mmol). The mixture is heated in a pressure tube at 150 °C for 16 hours, allowed to cool to room temperature, decanted to ice, acidified with 1H HCl solution, and partitioned between EtOAc and H₂0. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo to give the title intermediate 1-27 (1.4 g).

S nthesis of (4-bromo-phenyl)-cyclopentyl-acetic acid

To a solution of methyl triphenylphosphonium bromide (1.46 g, 4.1 mmol) in THF (25 mL) at -78 °C is added rc-BuLi (2.5M in hexanes, 1.64 mL, 4.1 mmol) slowly. The mixture is stirred at 0 °C for 30 minutes, and then cooled to -78 °C. To the reaction mixture is added R-7 (1.0 g, 3.95 mmol) in THF (8.0 mL). The reaction mixture is allowed to warm to room temperature, stirred for 16 hours, and partitioned between Et₂0 and saturated NH₄C1 solution. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 100% heptane) to give 1-28 (900 mg).

To a solution of 1-28 (900 mg, 3.58 mmol) in THF (15 mL) at 0 °C is added BH₃ (1.0M in THF, 7.2 mL, 7.2 mmol). The reaction mixture is allowed to warm to room temperature, and stirred for 1 hour. To the reaction mixture is added 1M NaOH solution (8.4 mL), H₂0₂ (30% wt. in H₂0, 1.0 g, 30 mmol). The reaction mixture is stirred at room temperature for 1 hour, and partitioned between Et₂0 and H₂0. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo to give 1-29 (900 mg).

To a solution of 1-29 (790 mg, 2.93 mmol) in DMF (10 mL) at room temperature is added pyridinium dichromate (3.4 g, 9.0 mmol). The mixture is stirred at room temperature for 16 hours, diluted with EtOAc, filtered through celite, and partitioned between EtOAc and H₂0. The combined organics are dried with MgS0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-60% EtOAc in heptane) to give the title intermediate 1-30 (265 mg).

Synthesis of 4-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-tetrahydro- pyran-4-carboxylic acid

To a mixture of 1-20 (91 mg, 0.32 mmol), R-8 (95 mg, 0.38 mmol),

bis(triphenylphosphine)palladium(II)dichloride (27 mg, 0.03 mmol) in THF (2.0 mL) at room temperature is added KC0₃ (128 mg, 1.3 mmol), and H₂0 (0.3 mL). The mixture is heated in the microwave at 120 °C for 30 minutes, allowed to cool to room

temperature, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-10% MeOH in CH₂C1₂) to give the title intermediate 1-32 (83 mg).

S nthesis of l-(5-bromo-pyridin-2-yl)-cyclobutanecarboxylic acid

To a solution of 1-13 (380 mg, 1.6 mmol) in H₂0 (5.0 mL) is added acetic acid (5.0 mL), and H₂SO₄ (5.0 mL). The reaction mixture is heated at 85 °C for 3 hours, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, dried with Na₂S0₄, filtered, and concentrated in vacuo to give the title intermediate 1-33 (150 mg).

S nthesis of 4-(5-bromo-pyridin-2-yl)-tetrahydro-pyran-4-carboxylic acid

1-14

I-34 To a solution of 1-14 (1.5 g, 5.0 mmol) in THF (2.5 mL) and MeOH (2.5 mL) at room temperature is added LiOH (1.05 g, 25 mmol) in H₂0 (10 mL). The reaction mixture is concentrated in vacuo, and partitioned between 1M HC1 solution and EtOAc. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo to give the title intermediate 1-34 (1.4 g).

S nthesis of 2-[4-(5-methoxy-pyridin-3-yl)-phenyl]-2,3-dimethyl-butyric acid

To a solution of 1-12 (1.0 g, 3.6 mmol) in H₂0 (10 mL) is added concentrated H₂S0₄ (10.0 mL). The reaction mixture is heated at 85 °C for 16 hours, allowed to cool to room temperature, and partitioned between EtOAc and saturated NaHC0₃ solution. The combined organics are washed with H₂0, filtered, and concentrated in vacuo to give the title intermediate 1-35 (901 mg).

Synthesis of l-{4-[2-(2,5-dimethyl-pyrrol-l-yl)-pyrimidin-5-yl]-phi

c clobutanecarboxylic acid

To MeOH (3.0 mL) at 0 ^UC is added slowly SOCl₂ (0.5 mL), followed by the addition of 1-17 (400 mg, 1.57 mmol). The reaction mixture is heated at 60 °C for 4 hours, allowed to cool to room temperature, and concentrated in vacuo to give the 1-36 (415 mg).

To a mixture of 2-aminopyrimidine-5-boronic acid pinacol ester (221 mg, 1.0 mmol), I- 36 (200 mg, 0.74 mmol), Pd-FibreCat-1007 (75 mg, 0.045 mmol) in THF (2.0 mL) at room temperature is added 2M Na₂C0₃ solution (0.75 mL). The mixture is heated in the microwave at 120 °C for 30 minutes, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-100% EtOAc in heptane) to give 1-37 (75 mg).

A mixture of 1-37 (42 mg, 0.15 mmol), 2,5-hexanedione (82 μί, 0.7 mmol), /?-TsOH (3 mg) in toluene (15 mL) is heated at 140 °C for 5 hours with a Dean-Stark condenser. The reaction mixture is allowed to cool to room temperature, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-100% EtOAc in heptane) to give I- 38 (47 mg).

To a solution of 1-38 (340 mg, 0.94 mmol) in THF (3.0 mL) at room temperature is added a solution of LiOH (72 mg, 3.0 mmol) in H₂0 (1.0 mL). The reaction mixture is heated at 60 °C for 24 hours, allowed to cool to room temperature, acidified with 6M HC1 solution, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, dried with Na₂S0₄, filtered, and concentrated in vacuo to give the title intermediate 1-39 (322 mg).

Synthesis of Amine Intermediates:

Synthesis of 5-phenoxy-pyridin-2-ylamine

To a solution of 5-bromo-2-nitropyridine R-9 (1.0 g, 5.76 mmol) in DMF (10.0 mL) at room temperature is added Cs₂C0₃ (2.5 g, 7.67 mmol). The reaction mixture is stirred at room temperature for 15 minutes, followed by the addition of phenol (1.0 g, 10.62 mmol). The reaction mixture is stirred at room temperature for 72 hours, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash

chromatography (Si0₂, 0-45% EtOAc in heptane) to give 1-40 (664 mg).

A reaction mixture of 1-40 (664 mg, 3.07 mmol), 10% Pd/C (120 mg) in EtOH (25 mL) at room temperature under H₂ is stirred for 16 hours. The reaction mixture is filtered through celite, and concentrated in vacuo to give the title intermediate 1-41 (530 mg).

Synthesis of 5'-methoxy-[3,3']bipyridinyl-6-ylamine

R-10 I-42

To a mixture of 2-aminopyridine-5-boronic acid pinacol ester R-10 (150 mg, 0.68 mmol), 3-bromo-5-methoxypyridine (141 mg, 0.75 mmol),

tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol) in DMF (25 mL) at room temperature is added 2M Na₂C0₃ solution (1.0 mL). The mixture is heated in the microwave at 110 °C for 1 hour, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash

chromatography (Si0₂, 0-3% 2M NH₃ in MeOH in CH₂C1₂) to give the title intermediate 1-42 (95 mg).

93 To a solution of 3-(bromoacetyl)pyridine hydrobromide R-12 (920 mg, 3.27 mmol) in EtOH (10.0 mL) and H₂0 (2.0 mL) at room temperature is added thiourea R-11 (250 mg, 3.27 mmol). The reaction mixture is heated at 80 °C for 2 hours, allowed to room temperature, and taken to pH8 with NH₄OH. The mixture is cooled to 0 °C, and filtered to give the title intermediate 1-51 (536 mg).

S nthesis of 2-(4-methyl-piperazin-l-yl)-pyridin-4-ylamine

I-52

A solution of R-13 (26.7 g, 179 mmol), R-14 (20 mL,179 mmol) in pyridine (42 mL) is heated in the microwave at 220 °C for 30 minutes. The reaction mixture is allowed to cool to room temperature, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-2.5% 2M NH₃ in MeOH in CH₂C1₂) to give the title

intermediate 1-52 (27.3 g).

Synthesis of 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine

R-15 R-16 R-17 R-18 .

l-Oo

To a solution of R-15 (30 mL g, 244 mmol) in cyclohexane (200 mL) at room

temperature is added R-16 (20 mL, 240 mmol), a catalytic amount of /7-TsOH. The reaction mixture is refluxed with a Dean-Stark condenser for 5 hours, allowed to cool to room temperature, and concentrated in vacuo. The residue is dissolved in MeOH (50 mL) followed by the addition of R-17 (7.77 g, 30 mmol), and cooled to 0 °C. To the reaction mixture is added R-18 (10.2 g, 243 mmol) in portions, and stirred for 2 hours. The reaction mixture is allowed to warm to room temperature, filtered, washed with MeOH and Et₂0 to give title intermediate 1-53 (20 g).

Synthesis of 2-butyl-quinolin-6-ylamine

To a solution of R-19 (1.0 g, 6.9 mmol) in THF (10.0 mL) at -30 ^UC is added rc-BuLi (1.6M in hexanes, 33.6 mL, 21.0 mmol). The reaction mixture is stirred at -30 °C for 2 hours, followed by the drop wise addition of acetone (3 mL). The reaction mixture is allowed to warm to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with saturated NH₄C1 solution, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 10-70% EtOAc in heptane) to give title intermediate 1-54 (950 mg).

Synthesis of 3-(2methyl-thiazol-4-yl)-phenylamine

To a solution of R-20 (2.0 g, 10.0 mmol) in EtOH (50.0 mL) at room temperature is added R-21 (750 mg, 10.0 mmol). The solid formed is filtered, and rinsed with cold EtOH to give 1-55 (2.9 g).

To a solution of 1-55 (800 mg, 3.6 mmol) in MeOH (10 mL) at 70 °C is added ammonium formate (2.27 g, 36 mmol) in H₂0 (5 mL), and Zn (300 mg). The reaction mixture is stirred at 70 °C for 15 minutes, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-45% EtOAc in heptane) to give title intermediate 1-56 (664 mg). Synthesis of 4-(pyridin-2-ylmethoxy)-phenylamine

1-57 1-58

To a mixture of R-22 (7.5 g, 50.0 mmol), R-23 (8.2 g, 50 mmol) in DMF (50 mL) at room temperature is added K₂CO₃ (20.7 g, 150 mmol). The reaction mixture is stirred at room temperature for 72 hours, triturated with ice-H₂0, and the resulting solid is filtered to give 1-57 (8.8 g).

A mixture of 1-57 (8.8 g) in EtOH (50 mL) and 12M NaOH solution (12 mL) is heated at 90 °C for 16 hours. The reaction mixture is allowed to cool to room temperature, concentrated in vacuo, and partitioned between EtOAc and H₂0. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo to give title intermediate 1-58 (6.5 g).

Synthesis of Activated Acid Intermediates:

Synthesis of l-(4-bromo-phenyl)-cyclobutanecarboxylic acid l,2,3-triazolo[4,5- Z>]pyridin-3-yl ester

1-59

To a solution of 1-17 (2.74 g, 11.0 mmol), O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (4.5 g, 12.0 mmol) in DMF (25 mL) at room temperature is added DIPEA (2.3 mL, 13 mmol). The mixture is stirred at room temperature for 30 minutes, and partitioned between EtOAc and H₂0. The combined organics are dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-60% EtOAc in heptane) to give the title intermediate 1-59 (2.75 g).

S nthesis of l-(4-bromo-phenyl)-cyclobutanecarbonyl chloride

1-17 I-72

To a solution of 1-17 (400 mg, 1.57 mmol), in CH₂C1₂ (3 mL) at room temperature is added thionyl chloride (1.7 mL, 14.3 mmol). The mixture is heated at 50 °C for 16 h, allowed to cool to room temperature, and concentrated in vacuo to give the title intermediate 1-72 (430 mg).

Synthesis of Final Compounds:

Method 1 - Synthesis of l-[4-(2-aminopyrimidin-5-yl)phenyl]-N-(pyridin-4- l)cyclobutanecarboxamide (example 177)

To a solution of 4-aminopyridine (75 mg, 0.80 mmol) in THF (5.0 mL) at room temperature is added NaH (60% in mineral oil, 40 mg, 1.0 mmol). The reaction mixture is stirred at room temperature for 15 minutes followed by the addition of 1-59 (200mg, 0.54 mmol). The reaction mixture is heated at 80 °C for 2 hours, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo to give the 1-82 (170 mg).

To a mixture of 2-aminopyrimidine-5-boronic acid pinacol ester (85 mg, 0.38 mmol), I- 82 (85 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (30mg, 0.026 mmol) in DMF (2.5 mL) at room temperature is added 2M Na₂C0₃ solution (2.5 mL). The mixture is stirred at 100 °C for 2 hours, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash

chromatography (Si0₂, 0-10% MeOH in CH₂C1₂) to give the title compound 177 (60 mg).

The following final compounds were synthesized in similar fashion from the appropriate reagents and intermediates:

173-174, 180, 183-191, 194-196, 198-205, 209-217, 222, 225, 236, 240-241, 249

134-135 (conditions as above except for part 2 where mixture is heated in microwave at 110 °C for l hour)

110 (conditions as above except acid chloride 1-72 was used in the 1^st step as the activated acid)

219 (conditions as above except acid chloride 1-80 was used in the 1^st step as the activated acid)

Method 2 - Synthesis of l-[4-(2-aminopyrimidin-5-yl)phenyl]-N-(pyridin-4-yl) cyclopentanecarboxamide (example 230)

1-64

1-83 230

To a solution of 4-aminopyridine (26 mg, 0.28 mmol) in THF (5.0 mL) at room temperature is added NaH (60% dispersion in mineral oil, 12 mg, 0.5 mmol). The reaction mixture is stirred at room temperature for 15 minutes, followed by the addition of 1-64 (200mg, 0.54 mmol). The reaction mixture is heated in the microwave at 120 °C for 60 minutes, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo to give the 1-83 (89 mg).

To a mixture of 2-aminopyrimidine-5-boronic acid pinacol ester (62 mg, 0.28 mmol), I- 83 (89 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) in THF (2.5 mL) at room temperature is added 2M Na₂C0₃ solution (2.0 mL). The mixture is stirred at 100 °C for 1 hour, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash

chromatography (Si0₂, 0-10% MeOH in CH₂C1₂) to give the title compound 230 (13 mg).

154, 165-168, 206, 208, 218, 223-224, 228-229, 237-239, 245-246

156, 162, 163 (conditions as above except thermal conditions were used for the 1^st step)

90-92, 98-99, 247-248 (conditions as above except acid chloride was used in the 1^st step as the activated acid ) 231 (conditions as above except acid chloride was used in the I^s step as the activated acid and under thermal not microwave conditions)

116-121, 123-126, 133 (conditions as above except acid chloride was used in the 1^st step as the activated acid and the reaction was heated under thermal conditions at 55 deg °C)

147-151 (conditions as above except BEMP, not NaH, was used for the first step)

Method 3 - Synthesis of l-[4-(2-aminopyrimidin-5-yl)phenyl]-N-(2-hydroxypyridin- 4- l)cyclobutanecarboxamide (example 220)

1-84

To a solution of 4-amino-pyridin-2-ol (50 mg, 0.45 mmol) in THF (5.0 mL) at room temperature is added K₂CO₃ (100 mg, 0.72 mmol). The reaction mixture is stirred at room temperature for 15 minutes, followed by the addition of 1-59 (100 mg, 0.27 mmol). The reaction mixture is heated at 60 °C for 2 hours, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo to give the 1-84 (90 mg).

To a mixture of 2-aminopyrimidine-5-boronic acid pinacol ester (90 mg, 0.41 mmol), I- 84 (93 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium(0) (30mg, 0.026 mmol) in DMF (2.5 mL) at room temperature is added 2M Na₂C0₃ solution (2.5 mL). The mixture is stirred at 100 °C for 2 hours, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash

chromatography (Si0₂, 0-10% MeOH in CH₂C1₂) to give the title compound 220 (2 mg). The following final compound(s) were synthesized in similar fashion from the appropriate reagents and intermediates:

221

Method 4- Synthesis of 2-[4-(2-aminopyrimidin-5-yl)phenyl]-2,3-dimethyl-N- ridin-4-yl)butanamide (example 169)

To a solution of 4-aminopyridine (24 mg, 0.25 mmol), and 1-63 (78 mg, 0.20 mmol) in THF (2.0 mL) at room temperature was added 2-ieri-butylimino-2-diethylamino-l,3- dimethylperhydro-l,3,2-diazaphosphorine on polymer support(~2.2 mmol/g loading, 225 mg, 0.45 mmol). The reaction mixture is heated in the microwave at 120 °C for 1 hour, allowed to cool to room temperature, filtered, and concentrated in vacuo to give the 1-85 (70 mg).

To a mixture of 2-aminopyrimidine-5-boronic acid pinacol ester (50 mg, 0.23 mmol), I- 85 (70 mg, 0.20 mmol), bis(triphenylphosphine)palladium(II)dichloride (12 mg, 0.01 mmol) in DMF (2.0 mL) at room temperature is added 2M Na₂C0₃ solution (1.0 mL). The mixture is heated in the microwave at 120 °C for 30 minutes, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, filtered, and concentrated in vacuo. The residue is purified by preparative HPLC (CH₃CN in water containing 0.1% formic acid) to give the title compound 169 (72 mg).

122, 127, 136, 138-146, 155, 158, 160-161, 169, 232-235, 242-244, 251-253, 255 87-89, 94-95, 97, 250, 254 (conditions as above except Pd-FibreCat-1007 was used as the palladium catalyst for step 2)

94 (conditions as above except only step 2 was required, starting from 103. Pd-FibreCat- 1007 was used as the palladium catalyst)

Method 5- Synthesis of 4-[4-(2-aminopyrimidin-5-yl)phenyl]-N-(4-tert- but lphenyl)tetrahydro-2H-pyran-4-carboxamide (example 17)

To a solution of 4-ieri-butylamine (28 mg, 0.18 mmol), and 1-66 (50 mg, 0.12 mmol) in 1,2-dichloroethane (1.5 mL) at room temperature is added 2-ieri-butylimino-2- diethylamino-l,3-dimethylperhydro-l,3,2-diazaphosphorine on polymer support(~2.2 mmol/g loading, 135 mg, 0.30 mmol). The reaction mixture is heated in the microwave at 130 °C for 1 hour, allowed to cool to room temperature, filtered, and concentrated in vacuo to give the 1-86 (51 mg).

To a mixture of 2-aminopyrimidine-5-boronic acid pinacol ester (33 mg, 0.14 mmol), I- 86 (51 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) in THF (1.5 mL) at room temperature is added 2M Na₂C0₃ solution (1.0 mL). The mixture is stirred at 100 °C for 2 hours, allowed to cool to room temperature, and partitioned between 1,2-dichloroethane and H₂0. The combined organics are washed with H₂0, filtered, and concentrated in vacuo. The residue is purified by preparative HPLC (CH₃CN in water containing 0.1% formic acid) to give the title compound 17 (14 mg).

The following final compound(s) were synthesized in similar fashion from the appropriate reagents and intermediates: 1-86

Method 6- Synthesis of 4-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]-N-(5'-methoxy- '-bipyridin-6-yl)tetrahydro-2H-pyran-4-carboxamide (example 132)

To a mixture of 1-19 (50 mg, 0.21 mmol), 1-42 (42 mg, 0.21 mmol), Et₃N (72 μΐ.) in CH₂CI₂ (1.0 mL) at room temperature is added PyBrop (108 mg, 0.21 mmol). The reaction mixture is stirred at room temperature for 24 hours, and partitioned between CH₂CI₂ and H₂0. The combined organics are washed with saturated NaHC0₃ solution, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-10% MeOH in CH₂C1₂) to give 1-87 (18 mg).

To a mixture of 1-87 (59 mg, 0.14 mmol), R-24 (23 mg, 0.17 mmol), PdCl₂dppf (5 mg, 0.07 mmol), dppf (4 mg, 0.07 mmol) in EtOH (0.4 mL) and toluene (0.1 mL) at room temperature is added 2M Na₂C0₃ solution (0.2 mL). The mixture is refluxed for 16 hours, allowed to cool to room temperature, and partitioned between CH₂CI₂ and ¾0. The combined organics are washed with saturated NaHC0₃ solution, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-10% MeOH in CH₂C1₂) to give title compound 132 (15 mg).

129-131

128 (conditions as above except 1-71 was used in the first step and PyBrop was not used) Method 7 - Synthesis of 2-(4-{6-[(2-hydroxyethyl)amino]pyridin-3-yl}phenyl)-2,3- dimethyl-N-(pyridin-4-yl)butanamide (example 226) and 2-{4-[6- (dimethylamino)pyridin-3-yl]phenyl}-2,3-dimethyl-N-(pyridin-4-yl)butanamide example 227)

A solution of 1-88 (prepared using Method 4, step 1, 40 mg, 0.105 mmol), and R-25 (200 μί, 3.31 mmol) in DMF (2.0 mL) was heated at 200 °C in the microwave for 2.5 hours. The reaction mixture is allowed to cool to room temperature, filtered, and purified by preparative HPLC (CH₃CN in water containing 0.1% formic acid) to give the title compounds 226 (4 mg) and 227 (18 mg).

Method 8 - Synthesis of 4-{4-[6-amino-5-(hydroxymethyl)pyridin-3-yl]phenyl}-N-(5- cyanopyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (example 179)

To a mixture of 1-89 (prepared using Method 4, step 1, from intermediate 1-68, 24 mg, 0.37 mmol), R-26 (15 mg, 0.75 mmol), bis(triphenylphosphine)palladium(II)dichloride (8 mg, 0.01 mmol) in THF (2.0 mL) at room temperature is added 2M Na₂C0₃ solution (0.1 mL). The mixture is heated in the microwave at 120 °C for 30 minutes, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-100% EtOAc in heptane) to give the title compound 179 (3.5 mg). Method 9 - Synthesis of 4-[4-(2-aminopyrimidin-5-yl)phenyl]-N-[5-(3-methyl-l,2,4- oxadiazol-5-yl)pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide (example 178)

A mixture of 1-90 (prepared using Method 2, step 1, 240 mg, 0.37 mmol), Amberlyst A- 26 (OH) (1.8g g, 2.5 mmol) in MeOH (10 mL) is stirred at room temperature for 16 hours. The reaction mixture is filtered, and the resin is washed with CH₂Cl₂-MeOH, 20% formic acid in MeOH, and 1M HC1 solution. The combined eluents are concentrated in vacuo to give 1-91 (184 mg).

To a solution of 1-91 (90 mg, 0.22 mmol), O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (95 mg, 0.25 mmol) in THF (25 mL) at room temperature is added DIPEA (75 μΐ,, 0.43 mmol) and R-27 (25 mg, 0.34 mmol). The mixture is stirred at room temperature for 30 minutes, followed by the addition of 2-tert- butylimino-2-diethylamino- 1 ,3-dimethylperhydro- 1 ,3,2-diazaphosphorine on polymer support(~2.2 mmol/g loading, 200 mg, 0.40 mmol), and heated at 120 °C in the microwave for 40 minutes. The reaction mixture is allowed to cool to room temperature, filtered, and concentrated in vacuo to give 1-92 (90 mg).

The final step to prepare the title compound 178 from 1-92 can be prepared according to Method 4, step 2. The following final compound(s) were synthesized in similar fashion from the appropriate reagents and intermediates:

100

Method 10 - Synthesis of 4-[4-(2-aminopyrimidin-5-yl)phenyl]-N-[5-(2- hydroxypropan-2-yl)pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide (example

To a solution of 1-90 (as used in Method 9, 20 mg, 0.048 mmol), in THF (2.0 mL) at -78 °C is added MeMgCl (3.0 M in THF, 0.35 mL, 0.1 mmol). The reaction mixture is stirred at -78 °C for 30 minutes, and allowed to warm to room temperature slowly. The reaction mixture partitioned between EtOAc and saturated NH₄C1 solution. The combined organics are washed with brine, and concentrated in vacuo to give 1-93 (20 mg).

The final step to prepare the title compound 159 from 1-93 can be prepared according to Method 4, step 2.

Method 11 - Synthesis of 6-[({4-[4-(2-aminopyrimidin-5-yl)phenyl]tetrahydro-2H- pyran-4-yl}carbonyl)amino]pyridine-3-carboxylic acid (example 157)

A mixture of 146 (20 mg, 0.046 mmol), Amberlyst A-26 (OH) (350 mg, 0.47 mmol) in MeOH (1 mL) is stirred at room temperature for 16 hours. The reaction mixture is filtered, and the resin is washed with 20% formic acid in MeOH. The combined eluents are concentrated in vacuo to give the title compound 157 (17 mg).

96 (prepared from 95) and purified by preparative HPLC (CH₃CN in water containing 0.1% formic acid)

101 (prepared from 97) and purified by preparative HPLC (CH₃CN in water containing 0.1% formic acid)

Method 12 - Synthesis of 6-[({l-[4-(2-aminopyrimidin-5- yl)phenyl]cyclobutyl}carbonyl)amino]-N-carbamimidoylpyridine-3-carboxamide example 108)

1-94

To a solution of R-28 (176 mg, 1.85 mmol) in NMP (10 mL) at room temperature is added NaH (60% dispersion in mineral oil, 42 mg, 1.83 mmol). The reaction mixture is stirred for 30 minutes, followed by the addition of 1-90 (97 mg, 0.025 mmol) in NMP (1 mL). The reaction mixture is heated at 75 °C for 4 hours. The reaction mixture is allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-10% 2M NH₃ in MeOH in CH₂C1₂) to give I- 94 (52 mg).

The final step to prepare the title compound 108 from 1-94 can be prepared according to Method 4, step 2. Method 13 - Synthesis of l-[4-(2-aminopyrimidin-5-yl)phenyl]-N-[5-(l-methyl-lH- l 2,4-triazol-5-yl)pyridin-2-yl]cyclobutanecarboxamide (example 103)

103

I-98

A mixture of 1-95 (prepared using Method 2, step 1, 100 mg, 0.28 mmol), H₂S0₄ (15 drops) in TFA (1.0 mL) is stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo, and the reaction mixture partitioned between EtOAc and H₂0. The combined organics are washed with saturated NaHC0₃ solution, dried with Na₂S0₄, filtered, and concentrated in vacuo to give the 1-96 (118 mg).

A mixture of 1-96 (118 mg) in N,N'-dimethylformamide dimethyl acetal (1.0 mL) is heated at 110 °C for 1 hour. The reaction mixture is allowed to cool to room temperature, and concentrated in vacuo to give the 1-97 (139 mg).

To a solution of 1-97 (66 mg, 0.15 mmol) in acetic acid (2.0 mL) at room temperature is added methylhydrazine (0.53 mL, 10 mmol). The reaction mixture is stirred for 1 hour, concentrated in vacuo, and the reaction mixture partitioned between EtOAc and H₂0. The combined organics are washed with saturated NaHC0₃ solution, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-100% EtOAc in heptane) to give 1-98 (21 mg).

The final step to prepare the title compound 103 from 1-98 can be prepared according to Method 4, step 2.

The following final compounds(s) were synthesized in similar fashion from the appropriate reagents and intermediates: 102

Method 14 - Synthesis of 6-[({l-[4-(2-aminopyrimidin-5- yl)phenyl]cyclobutyl}carbonyl)amino]-N-(methylsulfonyl)pyridine-3-carboxamide (example 105)

105

To a solution of 1-99 (prepared using Method 2, stepl, 100 mg, 0.26 mmol) in THF (1.0 mL) at room temperature is added a solution of LiOH (24 mg, 1.0 mmol) in H₂0 (0.5 mL). The reaction mixture is stirred at room temperature for 16 hours, and partitioned between EtOAc and H₂0. The combined aqueous layers are acidified with 6M HC1 solution to form a white solid which is filtered to give 1-100 (70 mg).

To a solution of I- 100 (70 mg, 0.19 mmol) in THF (1.0 mL) at room temperature is added Ι,Γ-carbonyldiimidazole (68 mg, 0.42 mmol). The mixture is stirred at room

temperature for 30 minutes, heated at 55 °C for 30 minutes, and allowed to cool to room temperature. To the reaction mixture is added R-29 (44 mg, 0.46 mmol), and DBU (75 μί, 0.48 mmol), stirred at room temperature for 16 hours, and partitioned between EtOAc and H₂0. The combined organics are dried with Na₂S0₄, and concentrated in vacuo to give 1-101 (70 mg).

The final step to prepare the title compound 105 from I- 101 can be prepared according to Method 4, step 2, with FibreCat-1007 as the palladium catalyst. Method 15 - Synthesis of l-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]-N-[5-(l-methyl- lH- razol-4-yl)pyridin-2-yl]cyclobutanecarboxamide (example 109)

To a solution of 1-17 (45 mg, 0.176 mmol), 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (67 mg, 0.18 mmol) in DMF (1.0 mL) at room temperature is added 4-methylmorpholine (25 μί, 0.22 mmol), and the reaction mixture is stirred at room temperature for 30 minutes. To a solution of 1-48 (50 mg, 0.29 mmol) in THF (1.0 mL) at room temperature is added NaH (60% dispersion in mineral oil, 7 mg, 0.3 mmol), and the reaction mixture is stirred at room temperature for 15 minutes. The two reaction mixtures are combined and heated at 55 °C for 1 hour. The reaction mixture is allowed to cool to room temperature, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-10% MeOH in CH₂C1₂) to give the 1-102 (10 mg).

The final step to prepare the title compound 109 from 1-102 can be prepared according to Method 4, step 2, with FibreCat-1007 as the palladium catalyst.

The following final compound(s) were synthesized in similar fashion from the

appropriate reagents and intermediates

107

Method 16 - Synthesis of l-[4-(2-aminopyrimidin-5-yl)phenyl]-N-[5-(l-methyl-lH- pyrazol-5-yl)pyridin-2-yl]cyclobutanecarboxamide (example 106)

The first step to prepare 1-103 from 1-69 can be prepared according to Method 1, step 1. The second step to prepare 1-104 from 1-103 can be prepared according to Method 4, step 2, with FibreCat-1007 as the palladium catalyst.

To a solution of 1-104 (35 mg, 0.069 mmol) in EtOH (2.0 mL) and dioxane (1.0 mL) is added NH₂OH.HCl (48 mg, 0.7 mmol) in H₂0 (0.5 mL), and Et₃N (10 μΐ,, 0.07 mmol). The reaction mixture is heated at 90 °C for 24 hours, allowed to cool to room

temperature, and partitioned between EtOAc and saturated NaHC0₃ solution. The combined organics are washed with brine, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by preparative HPLC (CH₃CN in water containing 0.1% formic acid) to give the title compound 106 (10 mg).

The following final compound(s) were synthesized in similar fashion from the appropriate reagents and intermediates:

104

Method 17 - Synthesis of 4-[4-(2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)phenyl]- N-[5-(2-methyl-l,3-thiazol-4-yl)pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide (example 153)

153

R-30

To a solution of 1-105 (prepared using Method 1, step 1, 143 mg, 0.31 mmol), KOAc (128 mg, 1.3 mmol), PdCl₂(dppf).CH₂Cl₂ (27 mg, 0.04 mmol) in dioxane (5.0 mL) at room temperature is added R-8 (95 mg, 0.38 mmol). The reaction mixture is heated at 100 °C in a sealed tube for 4 hours. The reaction mixture is allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with brine, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 30-70% EtOAc in heptane) to give 1-106 (120 mg).

To a solution of 1-106 (60 mg, 0.12 mmol) in THF (3.0 mL), is added R-30 (20 mg, 0.1 mmol), 20% Na₂C0₃ solution (2.0 mL), and Pd(PPh₃)₄. The reaction mixture is heated at 100 °C for 60 minutes, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combine organics are dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-10% MeOH in EtOAc) to give the title compound 153 (25 mg).

152 170, 171, 175 (conditions as above except

bistricylcohexylphosphinepalladium(II)chloride was used as the palladium

step 2)

Method 18 - Synthesis of 4-(4-{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}phenyl)-N- [5-(2-methyl-l,3-thiazol-4-yl)pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide (example 207)

To a solution of 1-105 (75 mg, 0.16 mmol), KOAc (157 mg, 1.6 mmol),

PdCi₂(dppf).CH₂Ci₂ (33 mg, 0.04 mmol) in dioxane (2.0 mL) at room temperature is added R-8 (115 mg, 0.46 mmol). The reaction mixture is heated at 100 °C in a sealed tube for 16 hours. The reaction mixture is allowed to cool to room temperature, followed by the addition R-31 (88 mg, 0.38 mmol) in THF (2.0 mL), 20% Na₂C0₃ solution (2.0 mL), and Pd(PPh₃)₄ (23 mg, 0.20 mmol). The reaction mixture is heated in the microwave at 120 °C for 60 minutes, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-10% MeOH in EtOAc) to give the title compound 207 (36 mg).

164, 181-182, 192-193, 197

Method 19 - Synthesis of 4-{4-[6-amino-5-(hydroxymethyl)pyridin-3-yl]phenyl}-N- [5-(2-methyl-l,3-thiazol-4-yl)pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide (example 176)

176

To a solution of 1-105 (125 mg, 0.27 mmol) in dioxane (5.0 mL) is added R-8 (380 mg, 1.50 mmol), Pd(OAc)₂ (10 mg, 0.045 mmol), 2-(dicyclohexylphosphino)biphenyl (36 mg, 0.10 mmol) at room temperature. The reaction mixture is heated at 80 °C for 1 hour, and allowed to cool to room temperature. To the reaction mixture is added Ba(OH)₂ (257 mg, 1.5 mmol), R-26 (102 mg, 0.50 mmol), and H₂0 (0.5 mL). The reaction mixture is heated at 120 °C for 4 hours, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash

chromatography (Si0₂, 0-10% MeOH in EtOAc) to give the title compound 176 (35 mg).

Method 20 - Synthesis of N-(2-butylquinolin-6-yl)-2-[4-(5-methoxypyridin-3- l)phenyl]-2,3-dimethylbutanamide (example 115)

To a solution of 1-54 (950 mg, 0.5 mmol) in DMA (2.0 mL) is added DIPEA (116 mg, 0.9 mmol), and 1-81 (150mg, 0.47 mmol). The reaction mixture is heated at 90 °C for 4 hours, allowed to cool to room temperature, and partitioned between EtOAc and H₂0. The combined organics are washed with H₂0, dried with Na₂S0₄, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si0₂, 0-20% EtOAc in heptane) to give the title compound 115 (84 mg). The following final compounds were synthesized in similar fashion from the appropriate reagents and intermediates:

111-114

Table of final compounds

ı22

130

ı42

ı64

LC-MS Method A

LC-MS Method B

Column Agilent SB-C18

1.8 μιη, 3x50mm column Ambient temperature

Mobile phase A = Formic acid (aq) 0.1%

B = Formic acid (acetonitrile) 0.1%

Flow rate 1.5 ml/min

Injection volume 3 μΐ

Detector 220 and 254 nm (nominal)

Gradient Time (mins) % B

0 12

0.25 30

0.3 40

1.19 95

1.75 100

LC-MS Method C

Column Waters BEH C18

Ambient temperature

Mobile phase A = Formic acid (aq) 0.05%

B = Formic acid (acetonitrile) 0.05%

Flow rate 0.8 ml/min

Injection volume 1 μΐ

Detector 254 nm (nominal)

Gradient Time (mins) % B

0 10

1.19 95

1.7 95

LC-MS Method D

Column Agilent Zorbax C18 SB

Ambient temperature

Mobile phase A = Formic acid (aq) 0.1%

B = Formic acid (acetonitrile) 0.1%

Flow rate 2.5 ml/min

Injection volume 7 μΐ Detector 200-600 nm (nominal)

Gradient Time (mins) % B

0 5

1.7 95

2 95

2.1 5

2.3 5

LC-MS Method E

LC-MS Method F

LC-MS Method G

Assessment of Biological Properties

1. Binding Assay

Compounds are assessed for the ability to bind to FLAP in a binding assay that measures compound-specific displacement of an iodinated ( 125 I) FLAP inhibitor via a Scintillation Proximity Assay format (adapted from S. Charleson et al., Mol. Pharmacol., 1992, 41, 873-879).

Cell pellets produced from sf9 insect cells expressing recombinant human FLAP protein are resuspended in buffer A [15 mM Tris-HCl (pH 7.5), 2 mM MgCl₂, 0.3 mM EDTA, 1 mM PMSF]. The cells are lysed with a Dounce homogenizer and the material is centrifuged at 10,000 x g for 10 minutes. The supernatant is then collected and centrifuged at 100,000 x g for 60 minutes. To prepare membrane protein for an assay, an aliquot of the 100,000 x g pellet is resuspended in 1 ml of buffer A, Dounce

homogenized, and finally subjected to polytron mixing (30 seconds). Membrane protein (25 μΐ, 5 μg) is mixed with WGA SPA beads (Amersham) and stirred for lh. To an assay plate (Perkin Elmer FlexiPlate) is added 25 μΐ of test compound prepared in Binding buffer [100 niM Tris (pH 7.5), 140 niM NaCl, 5% glycerol, 2 niM EDTA, 0.5 niM TCEP, 0.05% Tween 20], 25 μΐ of [¹²⁵I]L-691,831 (an iodinated analog of MK-591, Charleson et al. Mol. Pharmacol., 41, 873-879, 1992) and finally 50 μΐ of the

bead/protein mixture, (final concentrations: beads, 200 μg/well; protein, 5μg/well; [ 125 I] probe, 0 08 nM/well(17 nCi/well). The plates are shaken for 2h before reading on a Microbeta plate reader. Non-specific binding is determined by the addition of 10 μΜ cold L-691,831 compound.

2. Whole Blood Assay

Compounds are additionally tested in a human whole blood assay to determine their ability to inhibit the synthesis of LTB₄ in a cellular system. Compounds are combined with heparinized human whole blood and incubated for 15 minutes at 37°C. Calcimycin (20μΜ final, prepared in phosphate-buffered saline, pH 7.4) is then added and the mixture is incubated for another 30 minutes at 37°C. The samples are centrifuged for 5 min at low speed (1500 x g) and the plasma layer is removed. Plasma LTB₄

concentrations are then measured using an antibody-based homogenous time-resolved fluorescence method (CisBio, Bedford, MA).

In general, the preferred potency range (IC₅₀) of compounds in the above assay is between 0.1 nM to 10 μΜ, the more preferred potency range is 0.1 nM to 1 μΜ, and the most preferred potency range is 0.1 nM to 100 nM.

METHOD OF USE

The compounds of the invention are effective inhibitors of 5-lipoxygenase activating protein (FLAP) and thus inhibit leukotriene production. Therefore, in one embodiment of the invention, there is provided methods of treating leukotriene-mediated disorders using compounds of the invention. In another embodiment, there is provided methods of treating cardiovascular, inflammatory, allergic, pulmonary and fibrotic diseases, renal diseases and cancer using compounds of the invention. Without wishing to be bound by theory, by inhibiting the activity of FLAP, the compounds of the invention block the production of LTs resulting from the oxidation of arachidonic acid by 5-LO and subsequent metabolism. Thus, the inhibition of FLAP activity is an attractive means for preventing and treating a variety of diseases mediated by LTs. These include:

Cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, aortic aneurysm, sickle cell crisis, ischemia-reperfusion injury, pulmonary arterial hypertension and sepsis;

Allergic diseases including asthma, allergic rhinitis, rhinosinusitis, atopic dermatitis and urticaria;

Fibrotic diseases including airway remodeling in asthma, idiopathic pulmonary fibrosis, scleroderma, asbestosis;

Pulmonary syndromes including adult respiratory distress syndrome, viral bronchiolitis, obstructive sleep apnea, chronic obstructive pulmonary disease, cystic fibrosis, and bronchopulmonary dysplasia;

Inflammatory diseases including rheumatoid arthritis, osteoarthritis, gout,

glomerulonephritis, interstitial cystitis, psoriasis, inflammatory bowel disease systemic lupus erythematosus, transplant rejection, multiple sclerosis, inflammatory pain, inflammatory and allergic ocular diseases;

Cancer including solid tumors, leukemias and lymphomas; and

Renal diseases such as glomerulonephritis.

For treatment of the above-described diseases and conditions, a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20 mg/kg of body weight per dosage. For example, for administration to a 70 kg person, the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern. The active ingredient may be administered from 1 to 6 times a day.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention are typically

administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The compounds of the invention may also be administered alone or in combination with adjuvants that enhance stability of the compounds of the invention, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increased antagonist activity, provide adjunct therapy, and the like. The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. In general, the compounds of this invention are administered in a therapeutically or pharmaceutically effective amount, but may be administered in lower amounts for diagnostic or other purposes.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted modes of administration of pharmaceutical compositions. Thus, administration can be, for example, orally, buccally (e.g., sublingually), nasally, parenterally, topically,

transdermally, vaginally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof. Such pharmaceutically acceptable excipients, carriers, or additives as well as methods of making pharmaceutical compositions for various modes or administration are well-known to those of skill in the art. The state of the art is evidenced, e.g., by Remington: The Science and Practice of Pharmacy, 20th Edition, A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook of Pharmaceutical Excipients, A.H. Kibbe (ed.), American Pharmaceutical Ass'n, 2000; H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger, 1990; each of which is incorporated herein by reference in their entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds of the invention utilized in a particular pharmaceutical formulation will be selected (e.g., salts) that possess suitable physical characteristics (e.g., water solubility) that are required for the formulation to be efficacious.

Claims

CLAIMS What is claimed is:

1. A compound of formula I

I

or a pharmaceutically acceptable salt thereof, wherein:

C is a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring containing 1 - 3 heteroatoms selected from nitrogen, sulfur and oxygen;

R^la and R^lb are each independently selected from -H, Ci_6 alkyl, C_1-6 alkoxyl, -C_1-6 alkyl - OH, hydroxy, -C(O)- C_1-6 alkyl and -NR⁵R⁶;

R 2 and R 3 cannot be hydrogen; or

R 2 and R 3 together with the carbon atom to which they are attached form a C₃_g cycloalkyl or C₃-8 heterocyclic ring; R ^a and R are each independently selected from

-H, C_1-6 alkyl, Ci-e alkoxyl, -C_1-6 alkyl-OH, aryl, -O-aryl, 5-6 membered heteroaryl, C₃_g cycloalkyl, C₃_g heterocyclyl, -C^alkyl-aryl, -C_1-3 alkyl-heteroaryl, -C_1-3 alkyl- heterocyclyl, -0-C_1-3 alkyl-aryl, , -0-C_1-3 alkyl-heteroaryl, -O C_1-6 alkyl, CF₃ , 0-CF₃, - COO R⁵, -C(O) Ci-3 alkyl -S(0)₂-NR⁵R⁶, -S(0)₂CF₃, -S(0)₂C_1-3 alkyl, -C(O) NR⁷R⁸, hydroxy, halogen, and cyano, wherein each group is optionally independently substituted with 1-3 substituents chosen from C_1-6 alkyl, C_1-6 alkoxyl, hydroxy and halogen;

R⁵and R⁶ are each independently chosen from H, C_1-6 alkyl, - C_1-6 alkylhydroxy and C_1-6 alkyl-0- Ci_₆ alkyl;

R 7'and R 8" are each independently chosen from H, C_1-6 alkyl, -S(0)₂C_1-3 alkyl, and -C(NH)-NH_2.

2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

A is selected from pyrazolyl, imidazolyl, pyrrolyl, thienyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, imidazopyridinyl, pyrazolopyridinyl and quinolinyl;

B is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl;

2 3

R" and R^J are each independently - Ci_6 alkyl or -H, with the proviso that both

2 3

R and R cannot be hydrogen; or

2 3

R and R together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or a tetrahydropyranyl ring;

R^4a and R^4b are each independently selected from

7 8

3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

4. A compound of formula (I) according to any of the claims 1 - 3, or a

pharmaceutically acceptable salt thereof, wherein:

B is selected from phenyl and pyridinyl.

5. A compound of formula (I) according to any of the claims 1-4, or a pharmaceutically acceptable salt thereof, wherein:

6. A compound of formula (I) according to any of the claims 1-5, or a pharmaceutically acceptable salt thereof, wherein:

IT 2 and R 3^J are each independently H, methyl, ethyl, propyl, isopropyl or tert. butyl, with the proviso that both R 2 and R 3 cannot be hydrogen; or

R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a tetrahydropyranyl ring.

7. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

A is selected from pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolopyridinyl, dihydropyrrolopyridinyl and imidazopyridinyl; B is selected from phenyl and pyridinyl;

IT 2 and R 3^J are each independently H, methyl, ethyl, isopropyl or tert. butyl, with the proviso that both R 2 and R 3 cannot be hydrogen; or

R^4a and R^4b are each independently selected from

-H, C_1-3 alkyl, C_1-3 alkoxyl, -C_1-3 alkyl-OH, phenyl, -O-phenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopropyl, cyclopbutyl, cyclopenyl, cyclohexyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, -Ci^alkyl-phenyl, -C_1-3 alkyl- pyridinyl, -C_1-3 alkyl- pyrimidinyl, -C_1-3 alkyl- pyridazinyl, -C_1-3 alkyl- pyrazinyl, -C_1-3 alkyl-heterocyclyl, -0-C_1-3 alkyl-phenyl, -0-C_1-3 alkyl-pyridinyl, -O C_1-3 alkyl, CF₃ , O- CF₃, -COO R⁵, -C(O) Ci-3 alkyl -S(0)₂-NR⁵R⁶, -S(0)₂CF₃, -S(0)₂C_1-3 alkyl, -C(O)

NR 7 R 8 , hydroxy, halogen, and cyano, wherein each group is optionally independently substituted with 1-3 substituents chosen from C_1-6 alkyl, C_1-6 alkoxyl, hydroxy and halogen;

R⁵and R⁶ are each independently chosen from H, C_1-5 alkyl, - C_1-3 alkylhydroxy and C_1-3 alkyl-O- Ci_₃ alkyl; or, R⁵and R⁶ together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or thiomorpholinyl ring;

R 7'and R 8" are each independently chosen from H, C_1-6 alkyl, -S(0)₂C₁_3 alkyl, and -C(NH)-NH_2.

8. A compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein:

R 2" and R 3^J are each independently H, methyl, ethyl, isopropyl or tert. butyl, with the proviso that both R 2 and R 3 cannot be hydrogen.

9. A compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein:

10. A compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein:

B is phenyl.

11. A compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein:

B is pyridyl.

12. A compound of formula (I), selected from a group consisting of:

or pharmaceutically acceptable salts thereof.

13. A compound of formula (I) according to claim 12, selected from a group consisting of:

210

or pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising a compound according to any of the claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or carrier.

15. A method of treating a leukotriene-mediated disorder comprising administering an effective amount of a compound according to any of claims 1 to 13 or a

pharmaceutically acceptable salt thereof, to a patient in need thereof.

16. The method of claim 15, wherein said leukotriene-mediated disorder is selected from cardiovascular, inflammatory, allergic, pulmonary and fibrotic diseases, renal diseases and cancer.

17. The method of claim 16, wherein said leukotriene-mediated disorder is Atherosclerosis.

18. A compound of any of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use as a medicament.

19. A compound of any of claims 1 to 13 or a pharmaceutically acceptable salt thereof for treatment of a leukotriene-mediated disorder.

20. A compound of any of claims 1 to 13 or a pharmaceutically acceptable salt thereof for treatment of a leukotriene-mediated disorder selected from cardiovascular, inflammatory, allergic, pulmonary and fibrotic diseases, renal diseases and cancer.