HK1182389A - Oxadiazole inhibitors of leukotriene production - Google Patents

Description

Biazole inhibitors for inhibiting leukotriene production

Technical Field

The present invention relates to compounds that are useful as inhibitors of pentalipoxygenase activating protein (FLAP) and thus are useful in the treatment of a variety of diseases and disorders mediated or sustained by leukotriene activityOxadiazoles, including asthma, allergy, rheumatoid arthritis, multiple sclerosis, inflammatory pain, acute thoracic syndrome and cardiovascular diseases including atherosclerosis, myocardial infarction and stroke. The invention is also directed to pharmaceutical compositions comprising these compounds, to methods of using these compounds in the treatment of various diseases and disorders, to processes for preparing these compounds and to intermediates useful in these processes.

Prior Art

Leukotriene (LT) and the biosynthetic pathway leading to its production by arachidonic acid have been the target of drug discovery efforts for over twenty years. LT is produced by several cell types including neutrophils, mast cells, eosinophils, basophils, monocytes, and macrophages. The first key step in the intracellular synthesis of LT involves the oxidation of arachidonic acid to LTA by 5-lipoxygenase (5-LO)₄This is a process that requires the presence of the 18kD integral membrane protein 5-lipoxygenase activating protein (FLAP) (D.K. Miller et al, Nature, 1990, 343, 278-. Subsequent metabolism of LTA₄Generating LTB₄And cysteaminoyl LT-LTC₄、LTD₄And LTE₄(B.Samuelsson, Science, 1983, 220, 568-575). Cysteaminoyl LT has potent smooth muscle contraction and bronchoconstriction effects and it can stimulate mucus secretion and vascular leakage. LTB₄Is a potent chemotactic factor for leukocytes and stimulates adhesion, coagulation and enzyme release.

Many early drug discovery efforts in the LT field were directed to the treatment of allergy, asthma and other inflammatory conditions. Research efforts have been directed to multiple targets in this pathway, including LTB₄And cysteinyl leukotriene LTC₄、LTD₄And LTE₄And 5-lipoxygenase (5-LO), LTA₄Inhibitors of hydrolase, and Inhibitors of 5-lipoxygenase activating protein (FLAP) (r.w. friesen and d.riendeau, Leukotriene biosyntheses Inhibitors, ann.rep.med.chem., 2005, 40, 199-. Several commercial products for the treatment of asthma have been available in the above field in many years of endeavour, including 5-LO inhibitors (zileuton) and LT antagonists (montelukast, pranlukast and zafirlukast).

More recent work has demonstrated that LT is involved in cardiovascular disease (including myocardial infarction, stroke, and atherosclerosis) (g.riccioni et al, j.leukoc.biol., 2008, 1374-. FLAP and 5-LO are components of the 5-LO and LT cascade found in atherosclerotic lesions, suggesting their interaction withAtherogenesis is related (r.spanbroek et al, proc.natl.acad.sci.u.s.a., 2003, 100, 1238-. Pharmacological inhibition of FLAP has been reported to reduce atherosclerotic lesion size in animal models. In one study, oral administration of the FLAP inhibitor MK-886 to 2-6 month old knockout apoE/LDL-R two-gene mice fed a high fat diet reduced plaque coverage in the aorta by 56% and in the aortic root by 43% (j.jawien et al, eur.j.clin.invest.2006, 36, 141-one 146). This plaque effect is accompanied by a decrease in plaque-macrophage content, and a simultaneous increase in collagen and smooth muscle content, indicating a shift to a more stable plaque phenotype. In another study, ApoE was reported to be administered by infusion^-/-Administration of xCD4dnT β RII mice (apoE KO mice expressing dominant negative TGF- β receptors, which effectively removes all TGF- β from the system) to MK-886 reduced plaque area in aortic roots by about 40% (m.back et al, circ.res., 2007, 100, 946-949). After the plaque growth has matured slightly (12 weeks), the mice are treated for only four weeks, thereby increasing the likelihood of therapeutic treatment of atherosclerosis by this mechanism. In studies examining human atherosclerotic lesions, it was found that the expression of FLAP, 5-LO and LTA4 hydrolases was significantly increased over healthy controls (h.qiu et al, proc.natl.acad.sci.u.s.a., 103, 21, 8161-. Similar studies indicate that inhibition of the LT pathway by, for example, inhibition of FLAP can be useful in the treatment of atherosclerosis (see, for relevant reviews, m.back curr. athero. reports, 200810, 244-.

In addition to the above work, many other studies have been directed to understanding the biological role of LT and its role in disease. These studies have demonstrated the possible effects of LT on a variety of diseases or conditions (see, for relevant reviews, m.peters-Golden and w.r.henderson, jr., m.d., n.engl.j.med., 2007, 357, 1841-. In addition to the specific diseases mentioned above, LT has been shown to be involved in a variety of allergic, pulmonary, fibrotic, inflammatory and cardiovascular diseases as well as in the possible role of cancer. Inhibition of FLAP has also been reported to be useful in the treatment of renal diseases such as diabetes-induced proteinuria (see, e.g., j. m. valdivieso et al, Journal of neuroprology, 2003, 16, 85-94 and a mono et al, Journal of neuroprology, 2003, 16, 682-.

Many FLAP inhibitors have been reported in the scientific literature (see, e.g., j.f. evans et al, Trends in pharmaceutical Sciences, 2008, 72-78) and U.S. patents. Some FLAP inhibitors have been evaluated in clinical trials for asthma, including MK-886, MK-591, and BAYX1005 (also known as DG-031). Recently, the FLAP inhibitor AM-103(J.H.Hutchinson et al., J.Med.chem.52, 5803-5815) has been evaluated in clinical trials for anti-inflammatory properties (D.S.Lorrain et al., J.pharm.exp.Ther., 2009, DOI: 10.1124/jpeg.109.158089). Subsequently, it was replaced with a support compound (back-up compound) AM-803(GSK-2190915) for the treatment of respiratory diseases. The effect of DG-031 on biomarkers of myocardial infarction risk has also been evaluated in clinical trials and shown to have dose-dependent inhibition of several biomarkers of the disease (H.Hakonason et al, JAMA, 2005, 293, 2245-. MK-591 has been shown in clinical trials to be useful in reducing proteinuria in human glomerulonephritis (see, e.g., A. Guash et al, Kidney International, 1999, 56, 291-267).

However, to date, no FLAP inhibitor has been approved as a commercially available drug.

Disclosure of Invention

The present invention provides novel compounds that inhibit 5-lipoxygenase activating protein (FLAP) and are therefore useful in the treatment of a variety of diseases and disorders mediated or maintained by leukotriene activity, including allergic diseases, pulmonary diseases, fibrotic diseases, inflammatory diseases and cardiovascular diseases and cancer. The invention is also directed to pharmaceutical compositions comprising these compounds, to methods of using these compounds in the treatment of various diseases and disorders, to processes for preparing these compounds and to intermediates useful in these processes.

Detailed Description

In its first broadest embodiment, the present invention relates to compounds of formula I:

wherein:

R¹and R²Each independently is hydrogen, C_1-7Alkyl or C_3-10A carbocyclic ring, provided that R is¹And R²Both are not hydrogen at the same time;

R³is a 5-to 11-membered heteroaryl ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is optionally independently substituted with 1-3 groups selected from: c optionally substituted by 1 to 3 halogen atoms_1-5Alkyl radical, C_1-5Alkoxy radical, C_1-3Hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C_3-6Carbocyclic ring, C_1-6Alkylamino and di-C_1-3An alkylamino group;

R⁴is hydrogen, C_1-3Alkyl, halogen or nitrile;

R⁵is C_1-6Alkyl radical, C_3-10Carbocycle, 3-to 11-membered heterocycle, aryl, 5-to 11-membered heteroaryl, -C (O) -R⁶Hydroxy or-NR⁷R⁸Wherein each R is⁵Optionally independently through 1 to 3 substituents selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁶is C_3-8Heterocycle or-NH-5 to 6 membered heterocycle, each optionally independently selected from R1 to 3⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁷and R⁸Each independently of the others is hydrogen, optionally via C_1-6Alkyl-substituted 5-to 6-membered heterocycle, C optionally substituted by hydroxy_3-10Carbocyclic ring, or C_1-6An alkyl group;

R⁹、R¹⁰and R¹¹Is independently selected from

(a)-H，

(b)-OH，

(c) The halogen(s) are selected from the group consisting of,

(d)-CN，

(e)-CF₃，

(f) c optionally substituted by 1 to 3 groups_1-6Alkyl groups: -OH, -N (R)¹²)(R¹³) 3-to 6-membered heterocycle, C_1-6Alkoxy radical, C_1-6alkoxy-O-C_1-6Alkyl, -CO₂R¹²、-C(O)N(R¹²)(R¹³) or-S (O)_nC_1-6An alkyl group, a carboxyl group,

(g)C_1-6an alkoxy group,

(h)-N(R¹²)(R¹³)，

(i)-S(O)_nC_1-6an alkyl group, a carboxyl group,

(j)-CO₂R¹²，

(k)-C(O)N(R¹²)(R¹³)，

(l)-S(O)₂N(R¹²)(R¹³)，

(m) optionally via 1 to 3C_1-6An alkyl-substituted 3-to 10-membered heterocyclic group,

(n ') an oxo group, and (n'),

(o)-C(O)-C_1-3an alkyl group;

R¹²and R¹³Each independently selected from-H, -C_1-6Alkyl, C (O) C_1-6Alkyl and a 3-to 6-membered heterocyclic group, each of which is optionally independently substituted with 1 to 3 of the following groups: c_1-6Alkyl, -OH, C_1-6Alkoxy, -C (O) N (R)¹⁴)(R¹⁵)、-S(O)_nC_1-6Alkyl, CN, 3-to 6-membered heterocyclic group, -OC_1-6Alkyl, CF₃Or;

R¹²and R¹³Together with the nitrogen ring to which they are attached form an optionally substituted 1 to 3-OH, CN, -OC_1-6An alkyl or oxo substituted heterocyclyl ring;

R¹⁴and R¹⁵Each independently selected from-H and-C_1-6An alkyl group;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

In a second embodiment, the present invention relates to a compound as described in the broadest embodiments above, wherein:

R¹and R²Each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, with the proviso that R is¹And R²Both are not hydrogen at the same time;

R³is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, thienyl, furyl or thiazolyl, wherein each heteroaryl ring is optionally independently substituted with 1 to 3 groups selected from: c optionally substituted by 1 to 3 halogen atoms_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C_3-6Carbocyclic ring, C_1-6Alkylamino and di-C_1-3An alkylamino group; or

R³Is pyridoAzinyl, dihydro-pyridoAzinyl, dihydro-pyrrolopyridinyl, pyrrolopyridinyl or pyrrolopyrazinyl, whichWherein each heteroaryl ring is optionally independently substituted with 1 to 3 groups selected from: c optionally substituted by 1 to 3 halogen atoms_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NHC_3-6Carbocyclic ring, C_1-3Alkylamino and di-C_1-3An alkylamino group;

R⁴is hydrogen, methyl or fluorine;

R⁵is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, pyrrolyl, thienyl, furyl, thiazolyl, thienyl, or the like,Azolyl radical, isoOxazolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, pyrrolopyridyl, pyrrolopyrimidinyl, -C (O) -R⁶Hydroxy or-NR⁷R⁸Wherein each R is⁵Optionally independently through 1 to 3 substituents selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁶is piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or-NH-piperidinyl, each optionally independently selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁷and R⁸Each independently hydrogen, an optionally methyl-substituted 5-to 6-membered heterocycle, optionally hydroxy-substituted C_3-6Carbocyclic ring, or C_1-5An alkyl group;

R⁹、R¹⁰and R¹¹Is independently selected from

(a)-H，

(b)-OH，

(c) The halogen(s) are selected from the group consisting of,

(d)-CN，

(e)-CF₃，

(f) c optionally substituted by 1 to 3 groups_1-6Alkyl groups: -OH, -N (R)¹²)(R¹³) 3-to 6-membered heterocycle, C_1-6Alkoxy radical, C_1-6alkoxy-O-C_1-6Alkyl, -CO₂R¹²、-C(O)N(R¹²)(R¹³) or-S (O)_nC_1-6An alkyl group, a carboxyl group,

(g)C_1-6an alkoxy group,

(h)-N(R¹²)(R¹³)，

(i)-S(O)_nC_1-6an alkyl group, a carboxyl group,

(j)-CO₂R¹²，

(k)-C(O)N(R¹²)(R¹³)，

(l)-S(O)₂N(R¹²)(R¹³)，

(m) optionally via 1 to 3C_1-6An alkyl-substituted 3-to 8-membered heterocyclic group,

(n ') an oxo group, and (n'),

(o)-C(O)-C_1-3an alkyl group;

R¹²and R¹³Each independently selected from-H, -C_1-6Alkyl, C (O) C_1-6Alkyl and a 3-to 6-membered heterocyclic group, each of which is optionally independently substituted with 1 to 3 of the following groups: c_1-6Alkyl, -OH, C_1-6Alkoxy, -C (O) N (R)¹⁴)(R¹⁵)、-S(O)_nC_1-6Alkyl, CN, 3-to 6-membered heterocyclic group, -OC_1-6Alkyl, CF₃(ii) a Or

R¹²And R¹³Together with the nitrogen ring to which they are attached may form an optionally substituted 1 to 3-OH, CN, -OC_1-6An alkyl or oxo substituted heterocyclyl ring;

R¹⁴and R¹⁵Each independently selected from-H and-C_1-4An alkyl group;

n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

In a third embodiment, the present invention relates to a compound as described in any one of the previous embodiments above, wherein:

R¹and R²Each independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl or cyclobutyl, with the proviso that R¹And R²Both are not hydrogen at the same time;

or a pharmaceutically acceptable salt thereof.

In a fourth embodiment, there is provided a compound of formula (I) as described in any one of the previous embodiments above, wherein: r³Is pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each heteroaryl ring is optionally independently substituted with 1 to 2 groups selected from: c optionally substituted by 1 to 3 halogen atoms_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NHC_3-6Carbocyclic ring, C_1-5Alkylamino and di-C_1-3An alkylamino group; or

R³Is pyridoAzinyl, dihydro-pyridoAzinyl, dihydro-pyrrolopyridinyl, pyrrolopyridinyl or pyrrolopyridinylA pyrazinyl group;

or a pharmaceutically acceptable salt thereof.

In a fifth embodiment, there is provided a compound as described in any one of the previous embodiments above, wherein:

R⁵is methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolyl, cyclohexyl, or a salt thereof,Azolyl radical, isoOxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, -C (O) -piperazinyl, -C (O) -piperidinyl, -C (O) -morpholinyl, -C (O) -NH-piperidinyl, hydroxy or-NR⁷R⁸Wherein each R is⁵Optionally independently through 1 to 3 substituents selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁷and R⁸Each independently hydrogen, an optionally methyl-substituted 5-to 6-membered heterocycle, optionally hydroxy-substituted C_3-6Carbocyclic ring, or C₁-C₅An alkyl group;

R⁹、R¹⁰and R¹¹Is independently selected from

(a)-H，

(b)-OH，

(c) The halogen(s) are selected from the group consisting of,

(d)-CN，

(e)-CF₃，

(f) c optionally substituted by 1 to 3 groups_1-6Alkyl groups: -OH, -N (R)¹²)(R¹³) Morpholinyl, piperazinyl, C_1-6Alkoxy radical, C_1-3alkoxy-O-C_1-3Alkyl, -CO₂R¹²or-C (O) N (R)¹²)(R¹³)，

(g)C_1-3An alkoxy group,

(h)-N(R¹²)(R¹³)，

(i)-S(O)_nC_1-6an alkyl group, a carboxyl group,

(j)-CO₂R¹²，

(k)-C(O)N(R¹²)(R¹³)，

(l)-S(O)₂N(R¹²)(R¹³)，

(m) morpholinyl, piperazinyl, piperidinyl or oxetanyl, each optionally substituted with methyl,

(n ') an oxo group, and (n'),

(o)-C(O)-CH₃；

R¹²and R¹³Each independently selected from-H and-C_1-6Alkyl, wherein the alkyl is optionally substituted with 1 to 3-OH, C_1-6Alkoxy, -C (O) N (R)¹⁴)(R¹⁵) or-S (O)_nC_1-6Alkyl substitution;

R¹⁴and R¹⁵Each independently selected from-H and-C_1-4An alkyl group;

n is 2;

or a pharmaceutically acceptable salt thereof.

In a sixth embodiment, there is provided a compound of formula (I) as described in the second embodiment above, wherein:

R¹and R²Each independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl or cyclobutyl, with the proviso that R¹And R²Both are not hydrogen at the same time;

R³is pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each heteroaryl ring is optionally independently substituted with 1 to 2 groups selected from: methyl, methoxy, -CH₂OH, trifluoromethyl, bromo, chloro, fluoro, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C_3-6Carbocyclic ring, C_1-4Alkylamino and di-C_1-3An alkylamino group; or R³Is pyridoAzinyl, dihydro-pyrido(ii) an oxazinyl, dihydro-pyrrolopyridyl, or pyrrolopyrazinyl group;

R⁴is hydrogen;

R⁵is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolyl, or a salt thereof,Azolyl radical, isoOxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, -C (O) -piperazinyl, -C (O) -morpholinyl, -C (O) -NH-piperidinyl, hydroxy or-NR⁷R⁸，

Wherein each R is⁵Optionally independently through 1 to 3 substituents selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁷and R⁸Each independently is hydrogen, piperidinyl optionally substituted with methyl, cyclohexyl optionally substituted with hydroxy, methyl or ethyl;

R⁹、R¹⁰and R¹¹Is independently selected from

(a)-H，

(b)-OH，

(c) The halogen(s) are selected from the group consisting of,

(d)-CN，

(e)-CF₃，

(f) c optionally substituted by 1 to 3 groups_1-6Alkyl groups: -OH, -N (R)¹²)(R¹³) Morpholinyl, piperazinyl, C_1-3Alkoxy radical, C_1-3alkoxy-O-C_1-3Alkyl, -CO₂H or-C (O) N (R)¹²)(R¹³)，

(g)C_1-3An alkoxy group,

(h)-N(R¹²)(R¹³)，

(i)-S(O)₂C_1-2an alkyl group, a carboxyl group,

(j)-CO₂R¹²，

(k)-C(O)N(R¹²)(R¹³)，

(l)-S(O)₂N(R¹²)(R¹³)，

(m) morpholinyl, piperazinyl or oxetanyl, each optionally substituted by methyl,

(n ') an oxo group, and (n'),

(o)-C(O)-CH₃；

R¹²and R¹³Each independently selected from-H and-C_1-6Alkyl, wherein the alkyl is optionally independently substituted with 1 to 3-OH, C_1-6Alkoxy, -C (O) N (R)¹⁴)(R¹⁵) or-S (O)₂C_1-6Alkyl substitution;

R¹⁴and R¹⁵Each independently selected from-H and-C_1-4An alkyl group;

or a pharmaceutically acceptable salt thereof.

In a seventh embodiment, there is provided a compound as described immediately above in the embodiments wherein:

R¹is a methyl group, and the compound is,

R²selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl and cyclobutyl;

or a pharmaceutically acceptable salt thereof.

In an eighth embodiment, there is provided a compound as described in the sixth embodiment above, wherein:

R³is selected from

Or a pharmaceutically acceptable salt thereof.

In a ninth embodiment, there is provided a compound as described in the sixth embodiment above, wherein:

R⁵is optionally independently selected from 1 to 3R⁹、R¹⁰And R¹¹Pyrazolyl substituted with a group of (a);

or a pharmaceutically acceptable salt thereof.

In a tenth embodiment, there is provided a compound as described in the sixth embodiment above, wherein:

R¹is a methyl group, and the compound is,

R²selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl and cyclobutyl;

R³is selected from

R⁴Is a hydrogen atom, and is,

R⁵is selected from

Or a pharmaceutically acceptable salt thereof.

In an eleventh embodiment, there is provided a compound as described in the tenth embodiment above, wherein:

R²is cyclopropyl or cyclobutyl;

or a pharmaceutically acceptable salt thereof.

In a twelfth embodiment, there is provided a compound as described in the tenth embodiment above, wherein:

R²selected from methyl, ethyl, isopropyl and tert-butyl;

or a pharmaceutically acceptable salt thereof.

In a thirteenth embodiment, there is provided a compound as described in the sixth embodiment above, wherein:

R³is selected from

Or a pharmaceutically acceptable salt thereof.

In a fourteenth embodiment, there is provided a compound as described in the sixth embodiment above, wherein:

R³is selected from

Or a pharmaceutically acceptable salt thereof.

In a fifteenth embodiment, there is provided a compound as described in the tenth embodiment above, wherein:

R¹is a methyl group, and the compound is,

R²is cyclopropyl;

R³is selected from

R⁴Is a hydrogen atom, and is,

R⁵is selected from

Or a pharmaceutically acceptable salt thereof.

In a sixteenth embodiment, compounds of formula I are obtained, wherein

R¹Is a methyl group, and the compound is,

R²is cyclopropyl;

R³is selected from

R⁴Is a hydrogen atom, and is,

R⁵is selected from

Or a pharmaceutically acceptable salt thereof.

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

TABLE 1

In one embodiment, the present invention relates to any one of the compounds described in table 1 above, or a pharmaceutically acceptable salt thereof.

Representative compounds of the invention showed activity in the FLAP binding assay (set forth in the evaluation section of biological properties) as shown in table 2.

TABLE 2

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

The compounds of the present invention also include isotopically labeled forms thereof. The isotopically labeled forms of the active agents of the combinations of the invention are identical to the active agents except that one or more atoms of the active agents are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom usually found in nature. Examples of readily commercially available isotopes that can be incorporated into the combination active agents of the invention in accordance with accepted practice include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as respectively²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Active agents of the combinations of the invention containing one or more of the aforementioned isotopes and/or other isotopes of other atoms, prodrugs thereof or a pharmaceutical of any of the foregoingThe above acceptable salts are all included within the scope of the present invention.

The invention includes the use of any of the above compounds containing one or more asymmetric carbon atoms, which may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers should be defined as enantiomers and diastereomers. All such isomeric forms of these compounds are expressly contemplated herein. Each stereoisomeric carbon may be in the R or S configuration or a combination of configurations.

Some of the compounds of the present invention may exist as more than one tautomer. The invention includes methods of using all of these tautomers.

Unless otherwise indicated, all terms used herein in this specification should be understood in their ordinary meaning as known in the art. For example, "C_1-6Alkoxy "is C having a terminal oxygen_1-6Alkyl radicals, such as methoxy, ethoxy, propoxy, butoxy. When structurally possible and unless otherwise specified, all alkyl, alkenyl and alkynyl groups are understood to be branched or unbranched. Other more specific definitions are as follows:

the term "alkyl" refers to both branched and unbranched alkyl groups. It is to be understood that any combination of terms using the prefix "alkyl" ("alk" or "alkyl") refers to an analog of the above definition of "alkyl". For example, terms such as "alkoxy," "alkylthio," and the like refer to an alkyl group attached to a second group by an oxygen or sulfur atom. "alkanoyl" refers to an alkyl group attached to a carbonyl group (C ═ O).

In all alkyl groups or carbon chains, one or more carbon atoms may optionally be replaced by a heteroatom such as O, S or N. It is understood that if N is unsubstituted, it is NH. It is also understood that heteroatoms may replace terminal or internal carbon atoms within a carbon chain, branched or unbranched. As described above, these groups may be substituted with groups such as oxo to yield groups such as, but not limited to, alkoxycarbonyl, acylAmino and thio (thioxo) and the like. 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-S-C_1-6Alkyl, unless otherwise indicated, is understood to include-S (O) -C_1-6Alkyl and-S (O)₂-C_1-6An alkyl group.

Term C_1-3Hydroxy is also referred to as-C_1-3Alkyl-hydroxy or-C_1-3alkyl-OH.

The term "C_3-10Carbocycle "refers to a non-aromatic 3 to 10 membered (but preferably 3 to 6 membered) monocyclic carbocyclic group or a non-aromatic 6 to 10 membered fused bicyclic, bridged bicyclic or spiro cyclic carbocyclic group. C_3-10Carbocycles may be saturated or partially unsaturated, and the carbocycle may have attached any ring atom that results in a stable structure. Non-limiting examples of 3-to 10-membered monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclohexanone. Non-limiting examples of 6-to 10-membered fused bicyclic carbocyclic groups include bicyclo [3.3.0]Octane, bicyclo [4.3.0]Nonane and bicyclo [4.4.0]Decyl (decahydronaphthyl). Non-limiting examples of 6-to 10-membered bridged bicyclic carbocyclic groups include bicyclo [2.2.2]Heptylalkyl, bicyclo [2.2.2]Octyl and bicyclo [3.2.1]An octyl group. Non-limiting examples of 6-to 10-membered spirocyclic carbocyclic groups include, but are not limited to, spiro [3, 3 ]]Heptalkyl spiro [3, 4 ]]Octyl and spiro [4, 4 ]]A heptalkyl group.

The term "C_6-10Aryl "or" aryl "refers to an aromatic hydrocarbon ring containing 6 to 10 carbon ring atoms. Term C_6-10The aryl group includes monocyclic and bicyclic rings in which at least one ring is aromatic. C_6-10Non-limiting examples of aryl groups include phenyl, indanyl, indenyl, benzocyclobutane, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl, and benzocycloheptenyl.

The term "5-to 11-membered heterocyclic" refers to a stable non-aromatic 4-to 8-membered monocyclic heterocyclic group or a stable non-aromatic 6-to 11-membered fused bicyclic, bridged bicyclic groupCyclic or spiro heterocyclic groups. A 5-to 11-membered heterocyclic ring is composed of carbon atoms and one or more, preferably 1 to 4, heteroatoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring may be saturated or partially unsaturated. Non-limiting examples of non-aromatic 4-to 8-membered monocyclic heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, bisAlkyl, thiomorpholinyl, 1-dioxo-1. lamda⁶-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non-limiting examples of non-aromatic 6-to 11-membered fused bicyclic groups include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothienyl. Non-limiting examples of non-aromatic 6-to 11-membered bridged bicyclic groups include 2-azabicyclo [2.2.1]Heptylalkyl, 3-azabicyclo [3.1.0]Hexane radical and 3-azabicyclo [3.2.1]An octyl group. Non-limiting examples of non-aromatic 6-to 11-membered spirocyclic heterocyclic groups include 7-aza-spiro [3, 3]Heptalkyl, 7-spiro [3, 4 ]]Octyl and 7-aza-spiro [3, 4 ]]An octyl group.

The term "5-to 11-membered heteroaryl" is understood to mean an aromatic 5-to 6-membered monocyclic heteroaryl or an aromatic 7-to 11-membered heteroaryl bicyclic ring, wherein at least one ring is aromatic, wherein the heteroaryl ring contains 1 to 4 heteroatoms such as N, O and S. Non-limiting examples of 5-to 6-membered monocyclic heteroaryl rings include furyl, thienyl, and the like,Azolyl radical, isoAzolyl group,Oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and purinyl. Non-limiting examples of 7-to 11-membered heteroaryl bicyclic heteroaryl ringsIllustrative examples include benzimidazolyl, quinolyl, dihydro-2H-quinolyl, isoquinolyl, quinazolinyl, indazolyl, thieno [2, 3-d ]]Pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxaxolylAzolyl, pyridoAzinyl, dihydro-pyridoOxazinyl, dihydro-pyrrolopyridyl, pyrrolopyrazinyl and benzothiazolyl.

It should be understood that each C_3-10The ring moieties having one to three carbons in the non-aromatic portion of the carbocyclic, 5-to 11-membered heterocyclic, bicyclic aryl ring and bicyclic heteroaryl ring may independently be interrupted by a carbonyl, thiocarbonyl or imino moiety (i.e., -C (═ O) -, -C (═ S) -and-C (═ NR) respectively⁸) -, wherein R⁸As defined above). The term "heteroatom" as used herein is understood to refer to atoms other than carbon, such as O, N and S.

The term "halogen" as used in the present description is understood to mean bromine, chlorine, fluorine or iodine. Definitions "halogenated", "partially or fully fluorinated", "substituted with one or more halogen atoms" include, for example, mono-, di-or trihalo derivatives on one or more carbon atoms. For alkyl, a non-limiting example may be-CH₂CHF₂、-CF₃And the like.

Each alkyl, carbocyclic, heterocyclic or heteroaryl group or analogue thereof as described herein is to be understood as optionally partially or fully halogenated.

It will be appreciated by those skilled in the art that the compounds of the present invention are only those which are expected to be "chemically stable". For example, compounds that may have a "pendant valence ' or a ' carbanion ' are not intended to be encompassed by the inventive methods disclosed herein.

The invention includes pharmaceutically acceptable derivatives of the compounds of formula (I). "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester, or any other compound that, upon administration to a patient, provides (directly or indirectly) a compound for use in the present invention, or a pharmacologically active metabolite or pharmacologically active residue thereof. Pharmacologically active metabolites are understood to mean any compound of the invention which can be metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidatively derivatized 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, p-toluenesulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric, and benzenesulfonic acids. Other acids (e.g., oxalic acid), while not themselves pharmaceutically acceptable, may be used to prepare salts that are useful as intermediates in obtaining compounds and their pharmaceutically acceptable acid addition salts. Salts derived from suitable bases include alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts, and N- (C)₁-C₄Alkyl radical)₄ ⁺And (3) salt.

In addition, the scope of the present invention encompasses the use of prodrugs of the compounds of the present invention. Prodrugs include those compounds which are modified by simple chemical transformation to yield the compounds of the present invention. Simple chemical transformations include hydrolysis, oxidation and reduction. In particular, when a prodrug is administered to a patient, the prodrug can be converted to the compounds disclosed above to impart the desired pharmacological effect.

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

General synthetic methods

The invention also provides a process for preparing compounds of formula (I). In all the formulae, R in the formula below is, unless otherwise stated¹、R²、R³、R⁴And R⁵Should have the formula (I) as defined above for R¹、R²、R³、R⁴And R⁵The meaning of (a).

The optimum reaction conditions and reaction times may depend on the particular reactants used. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art, unless otherwise specified. Specific procedures are provided in the synthesis examples section. Typically, if desired, the reaction progress can be monitored by Thin Layer Chromatography (TLC) or LC-MS, and intermediates and products can be purified by silica gel chromatography, recrystallization, and/or preparative HPLC.

The following examples are illustrative, and as will be understood by those of skill in the art, specific reagents or conditions may be varied as desired for individual compounds without undue experimentation. The starting materials and intermediates used in the following reaction schemes are either commercially available or readily prepared from commercially available materials by one skilled in the art.

Compounds of formula (I) may be synthesized according to reaction scheme 1:

as described in scheme 1, a compound of formula II is reacted with a boronic acid or corresponding boronic ester in a suitable solvent in the presence of a suitable catalyst as shown in the above scheme to give a compound of formula (I). Ra and Rb are hydrogen or Ra and Rb together with the oxygen atom to which they are attached form a 5-to 6-membered ring optionally substituted with 2 to 4 methyl groups. Alternatively, the compound of formula II is reacted with diborane under standard reaction conditions to give the compound of formula III. Reacting an intermediate of formula III with a halide or a triflate R in a suitable solvent in the presence of a suitable catalyst³X-coupling to give the compound of the formula (I). X is chlorine, bromine, trifluoride or iodine.

The compounds of formula (I) may be prepared according to reaction scheme 2:

a compound of formula IV is reacted with an acid chloride R in the presence of a suitable base in a suitable solvent as described in scheme 2⁵COCl reaction to obtain the compound of formula (I).

Alternatively, a compound of formula IV is reacted with an acid R in the presence of carbonyldiimidazole or other suitable amide coupling reagent in a suitable solvent⁵COOH to obtain the compound of formula (I).

The intermediates of formula II can be synthesized as outlined in scheme 3:

a nitrile of formula V is reacted with a halide R in a suitable solvent in the presence of a suitable base, such as sodium hydride or potassium tert-butoxide, as described in scheme 3¹X reacts to give the substituted nitrile of formula VI. Reacting an intermediate of formula VI with a halide R in a suitable solvent in the presence of a suitable base²X is further reacted to give the corresponding substituted nitrile of formula VII. X is chlorine, bromine or iodine. The compound of formula VII is reacted with hydroxylamine under standard reaction conditions to give the compound of formula VIII. Reacting a compound of formula VIII with an acid chloride R in the presence of a suitable base in a suitable solvent⁵COCl reaction to obtain the compound of formula II. Alternatively, a compound of formula VIII is reacted with an acid R in the presence of carbonyldiimidazole or other suitable amide coupling reagent in a suitable solvent⁵COOH to obtain the compound of formula II.

Alternatively, reacting a compound of formula VIII with a reagent such as carbonyldiimidazole to provide a compound of formula II, wherein R is⁵is-OH. Can be used for dredgingThis further transformation of the-OH group is carried out by procedures known in the art to give other compounds of formula II.

The nitrile intermediate of formula VII may also be resolved by resolution techniques known to those skilled in the art to give enantiomers VIIA and VIIA'. Each of these enantiomers can be further converted to compounds of formula I by the reaction sequence shown in scheme 3 above.

The intermediate of formula II can also be synthesized as shown in scheme 4:

as shown in scheme 4, a carbonyl compound of formula IX is reacted with a Grignard reagent R in a suitable solvent²MgX reacts to obtain the hydroxy compound of the formula X. The hydroxy group in the compound of formula X is converted to a cyano group using standard procedures to provide the compound of formula VII. The compound of formula VII is converted to the intermediate of formula II by a reaction as shown in scheme 3. R²X in MgX is chlorine, bromine or iodine.

The intermediate of formula IV can be synthesized according to reaction scheme 5:

as described in scheme 5, a nitrile of formula VII is reacted with a boronic acid or corresponding boronic ester in the presence of a suitable catalyst in a suitable solvent to provide a compound of formula XI, as shown in the above scheme. Ra and Rb are hydrogen or Ra and Rb together with the oxygen atom to which they are attached form a 5-to 6-membered ring optionally substituted with 2 to 4 methyl groups. The compound of formula XI is reacted with hydroxylamine under standard reaction conditions to give the compound of formula IV.

The nitrile intermediate of formula VII may be synthesized according to equation 6:

the ketone of formula XIII is reacted with a methylating agent in a suitable solvent in the presence of a suitable base to provide an enol ether of formula XIV, as described in scheme 6. The enol ether XIV is reacted with an oxidizing agent (e.g., ozone) under suitable conditions to provide an ester of formula XV. Hydrolysis of the ester of formula XV in a suitable solvent in the presence of a suitable base affords the acid of formula XII. The racemic acid can be cleaved to give enantiomers XIIA and XIIA'. Alternatively, the acid XII may be reacted with an organic base (e.g., a primary or secondary amine) in a suitable solvent to provide the corresponding salt.

The carboxylic acid of XII is reacted with a reagent such as ammonia in a suitable solvent to give the amide of formula XVII. The amide of formula XVII is reacted with a suitable dehydrating agent in a suitable solvent to give the nitrile of formula VII. Non-limiting examples of bases that can be used in step (a) include potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydride, potassium hydride, lithium hydride, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, LDA, n-butyllithium, sec-butyllithium, or tert-butyllithium. Non-limiting examples of solvents that may be used in step (a) include dimethylformamide, dichloromethane, ethyl acetate, hexane, heptane, acetonitrile, methyl tert-butyl ether, isopropyl acetate, toluene, and cyclopropyl methyl ether. Non-limiting examples of alkylating agents that may be used in step (a) include dimethyl sulfate, dimethyl carbonate, methyl bromide, methyl triflate and methyl iodide. Non-limiting examples of silylating agents that can be used in step (a) include trimethylchlorosilane, t-butyldimethylchlorosilane, triphenylchlorosilane, and triisopropylchlorosilane, triethylchlorosilane.

Non-limiting examples of solvents that may be used in step (b) include dimethylformamide, dichloromethane, ethyl acetate, hexane, heptane, acetonitrile, methyl tert-butyl ether, isopropyl acetate, toluene, and cyclopropyl methyl ether. Non-limiting examples of bases that can be used in step (b) include 1, 8-diazabicycloundecen-7-ene (DBU), triethylamine, pyridine, 4-methylmorpholine, diisopropylethylamine, and dimethylamine. Non-limiting examples of dehydrating agents that can be used in step (b) include acetic anhydride, methanesulfonyl chloride, trifluoroacetic anhydride, toluenesulfonyl chloride, sodium hypochlorite, calcium hypochlorite, and tert-butyl hypochlorite.

Non-limiting examples of bases that can be used in step (c) include potassium hydroxide, sodium hydroxide, lithium hydroxide, and cesium hydroxide. Non-limiting examples of solvents that may be used in step (c) include methanol, methanol-water mixtures, dimethylformamide, dichloromethane, ethyl acetate, hexane, heptane, acetonitrile, methyl tert-butyl ether, isopropyl acetate, toluene, and cyclopropyl methyl ether.

The resolution of the racemic acid of formula XII as described in alternative step d) can be carried out using methods known in the art, such as fractional crystallization and chiral chromatography.

In one embodiment, the present invention relates to a process for preparing an intermediate acid XII, XIIA or XIIA' according to scheme 6 above. In another embodiment, the invention relates to an intermediate acid of formula XII, XIIA or XIIA'.

The compounds of formula I prepared by the above methods, as well as intermediates, can be further converted to other intermediates or compounds of formula I by methods known in the art and are exemplified in the synthetic examples section below.

Synthetic examples

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

LCMS retention times and observed m/z data for the following compounds were obtained by one of the following methods:

LC-MS method A

LC-MS method B

LC-MS method C

LC-MS method D

LC-MS method E

LC-MS method F

Synthesis method

The compounds of the present invention can be prepared by the following methods. The optimum reaction conditions and reaction times may depend on the particular reactants used. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art, unless otherwise specified. Specific procedures are provided in the synthesis examples section. Generally, the progress of the reaction can be monitored by Thin Layer Chromatography (TLC) or HPLC-MS, if desired.

The intermediates and products can be purified by silica gel chromatography, recrystallization and/or reverse phase HPLC. The HPLC purification method uses acetonitrile in water at any value between 0 and 100%, and may contain 0.1% formic acid, 0.1% TFA, or 0.2% ammonium hydroxide and use one of the following columns:

a) waters Sunfire OBD C185. mu.M 30X 150mm column

b) Waters Xbridge OBD C185. mu.M 30X 150mm column

c) Waters ODB C85 μ M19X 150mm column

d) Waters Atlantis ODB C185. mu.M 19X 50mm column

e) Waters Atlantis T3 OBD 5. mu.M 30X 100mm column

f) Phenomenex Gemini Axia C185. mu.M 30X 100mm column

g)Waters SunFire C18 Prep OBD 5μm 19x 100mm

h)Waters XBridge Prep C18 5μm 19x 100mm。

Starting materials and reagents are commercially available or can be prepared by one skilled in the art using methods described in the chemical literature.

Synthesis of nitrile intermediates:

synthesis of 2- (4-bromo-phenyl) -2, 3-dimethylbutyronitrile

At 0 ℃ inTo a solution of R-1(20.0g, 0.102mol) in DMF (300mL) was added NaH (60% in oily suspension, 4.28g, 0.107mol) slowly. The mixture was then stirred for a further 15 minutes and 2-bromopropane (9.60mL, 0.107mol) was added. The reaction mixture was allowed to warm to room temperature, stirred for an additional 2 hours, and then concentrated in vacuo. The residue was distributed over CH₂Cl₂And saline. With Na₂SO₄The combined organics were dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂0-15% EtOAc in heptane) to afford I-1(21.3 g); m/z 238.3, 240.2[ M/M +2H]。

I-1(21.3g, 89.6mmol) was dissolved in DMF (300 mL). The mixture was cooled to 0 ℃ and NaH (60% in oily suspension, 3.76g, 94.1mmol) was added slowly. The mixture was then stirred for a further 15 minutes and methyl iodide (5.9mL, 94.1mmol) was added. The reaction mixture was stirred to room temperature at 0 ℃ for 2 hours, then concentrated in vacuo. The residue was partitioned between dichloromethane and brine. With Na₂SO₄The combined organics were dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂0-15% EtOAc in heptane) to afford the title intermediate (21.7 g); m/z252.3, 254.3[ M/M +2H]。

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

synthesis of 2- (4-bromo-phenyl) -2-cyclopropylpropionitrile

To a solution of R-2(5.00g, 22mmol) in THF (30mL) was added a MeMgBr solution (1.0M in butyl ether, 27.0 mL). The solution was stirred for 30 minutes, thenWith saturated NaHCO₃And (4) treating with an aqueous solution. The mixture is distributed to CH₂Cl₂With brine, then collect the organics over MgSO₄Drying, filtration and concentration gave R-3(5.35 g). To the reaction mixture of R-3(5.35g, 22.2mmol) in CH₂Cl₂(100mL) to a solution of TMSCN (5.9mL, 44mmol) and InBr₃(790mg, 2.22 mmol). The reaction was stirred overnight and then poured over 20% Na₂CO₃In aqueous solution. By CH₂Cl₂Extracting the mixture with MgSO₄Dried, filtered, and concentrated in vacuo. By flash chromatography (SiO)₂0-15% EtOAc in heptane) to afford the title intermediate (3.82 g);¹H-NMR，400MHz，DMSO-d6ppm：7.65(2H)(d：J＝12Hz)；7.52(2H)(d：J＝12Hz)；1.69(3H)(s)；1.41(1H)(m)；0.68(1H)(m)；0.58(2H)(m)；0.41(1H)(m)。

the following intermediates were synthesized in a similar manner from the appropriate reagents:

2- (4-bromo-phenyl) -2-cyclopropylpropionitrile may also be prepared in the following manner:

to a solution of R-2(309g, 1.37mol) in THF (3.0L) at-78 deg.C was added MeMgBr (3M in Et) dropwise₂O, 1.37L, 4.12 mol). The mixture was stirred at-78 ℃ for 10 minutes and then at room temperature for 2 hours. With saturated NH₄The reaction mixture was quenched with aqueous Cl and extracted with EtOAc. The combined organic layers were washed with brine, Na₂SO₄The aqueous solution was dried and concentrated to give crude compound R-3(330g), which was used in the next step without further purification.

To R-3(330g, 1.37mol) in CH at-78 deg.C₂Cl₂(2.4L) solution to which BF was added dropwise₃.EtO₂(198g, 1.37 mol). The mixture was stirred at the same temperature for 30 minutes. TMSCN (272g, 2.7) was added dropwise at-78 deg.C4 mol). After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with cold water and the organic layer was separated. By CH₂Cl₂The aqueous phase is extracted. The organic layer was washed with brine, over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by chromatography on silica gel with petroleum ether/EtOAc (50: 1) to give the title intermediate (160 g).

Preparation of (R) -2- (4-bromo-phenyl) -2-cyclopropylpropionitrile (I-6) and (S) -2- (4-bromo-phenyl) -2-cyclopropylpropionitrile (I-7)

Through a ChiralPak AY-H300X 20mm SFC column (elution 85: 15SF CO)₂Ethanol, flow rate 80mL/min) to prepare enantiomers I-6 and I-7. The faster eluting isomer was determined to be I-7;¹H-NMR，400MHz，CDCl₃-d6 ppm: 7.54-7.50(2H) (m); 7.41-7.37(2H) (m); 1.73 (3H)(s); 1.26-1.19(1H) (m); 0.74-0.50(4H) (m); the slower eluting isomer is I-6; 1H-NMR, 400MHz, CDCl₃-d6ppm：7.54-7.50(2H)(m)；7.41-7.37(2H)(m)；1.73(3H)(s)；1.26-1.19(1H)(m)；0.74-0.50(4H)(m)。

Synthesis of 2- (4-bromo-phenyl) -3, 3-dimethylbutyronitrile

To a t-BuMgBr solution (110mL, 1.0M in THF) was added a solution of R-4(10g, 54mmol) in THF (50 mL). The solution was stirred for 10 minutes and then saturated NaHCO₃And (4) treating with an aqueous solution. The mixture was partitioned between dichloromethane and brine, the organics collected, over MgSO₄Dried, filtered, and concentrated. By flash chromatography (SiO)₂Heptane to 15% EtOAc in heptane) toThe crude was purified to give a yellow solid which was further purified by slurrying in heptane to give R-5(4.67g) after filtration. To the solution of R-5(4.63g, 19.0mmol) in CH₃To a solution in CN (100mL) was added imidazole (3.89g, 57.1mmol) followed by pH₃PBr₂(24.1g, 57.1 mmol). The mixture was heated at 40 ℃ for 6 h, then cooled to 23 ℃ and partitioned between EtOAc and saturated NaHCO₃Between aqueous solutions. The organics were collected, washed with water, and MgSO₄Dried, filtered, and concentrated in vacuo. The residue was slurried in heptane and the resulting solid was filtered. The filtrate was collected and the volatiles were removed in vacuo. The residue was dissolved in DMSO (100mL) and treated with NaCN (1.11g, 22.7 mmol). The mixture was heated at 140 ℃ for 3 hours and then cooled to 23 ℃. The mixture was partitioned between Et₂Between O and water. The organics were washed with water, MgSO₄Dried, filtered, and concentrated. By flash chromatography (SiO)₂Heptane to 15% EtOAc in heptane) to give the title intermediate (2.37g)¹H-NMR，400MHz，CDCl₃ppm：7.59(2H)(d：J＝12Hz)；7.33(2H)(d：J＝12Hz)；4.26(1H)(brs)；1.35(9H)(s)。

Synthesis of formamidine intermediates

Synthesis of 2- (4-bromo-phenyl) -N-hydroxy-2, 3-dimethylbutamidine

A solution of I-2(10.0g, 40mmol) in EtOH (50mL) was treated with 50% aqueous hydroxylamine (50 mL). The reaction was heated at 80 ℃ overnight and then concentrated in vacuo. The solid was filtered off and washed with water and then with heptane. The solid was collected and triturated with EtOAc, then filtered, collected and dried to give the title intermediate (10.4 g); m/z 285.4; 287.2[ M/M +2H ]

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

synthesis of 2- [4- (2-aminopyrimidin-5-yl) phenyl ] -N-hydroxy-2, 3-dimethylbutamidine

I-2(2.00g, 7.93mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (2.63g, 11.9mmol) and tetrakis (triphenylphosphine) palladium (0) (459mg, 0.397mmol) in THF (20mL) and saturated Na at 80 deg.C₂CO₃A solution of the aqueous solution (10mL) was heated for 3 hours. The mixture was cooled to 23 ℃ and then partitioned between EtOAc and brine. Collecting the organic matter with MgSO₄Drying, filtering and concentrating to obtain a residue, purifying by flash chromatography (SiO)₂，CH₂Cl₂To the presence in CH₂Cl₂3% MeOH) to give I-20(M/z 267.5[ M + H ]])。

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

i-20 was dissolved in EtOH (30mL) and treated with 50% aqueous hydroxylamine (12 mL). The reaction was heated at 80 ℃ for 48 hoursThen cooled to 23 ℃ and filtered through celite. The filtrate was partitioned between EtOAc and water. Collecting the organic matter with MgSO₄Dried, filtered, and concentrated in vacuo. By flash chromatography (SiO)₂，CH₂Cl₂To the presence in CH₂Cl₂10% MeOH) to afford the title intermediate (1.56 g); m/z: 300.4[ M + H]

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

synthesis of (R) -2- [4- (2-amino-pyrimidin-5-yl) -phenyl ] -2-cyclopropyl-N-hydroxy-propionamidine

To a mixture of I-6(18.5g, 0.074mol) in THF (300mL) was added 5- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ]]Dioxoborolan-2-yl) -pyrimidin-2-ylamine (19.6g, 0.089mol), tetrakis (triphenylphosphine) palladium (0) (8.5g, 0.007mol) and 2M Na₂CO₃(74mL, 0.148 mol). The mixture was heated to 80 ℃ for 24 hours. The solution was cooled to room temperature and extracted with EtOAc and water. With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and the residue was resuspended in CH₂Cl₂In (1). The solid precipitated from the solution was collected by filtration. The solid was dried and confirmed to be I-28(14.8 g); m/z265.4[ M + H ]]。

I-28(14.8g, 0.056mol), KOH (15.7g, 0.28mol) and hydroxylamine H were reacted at 85 deg.C₂A suspension of O solution (50 wt%) (34mL, 0.56mol) was stirred for 48 hours. The mixture was cooled and the solid filtered off and dried to give the title intermediate (12.5 g); m/z 298.4[ M + H ]]。

Synthesis of (R) -2-cyclopropyl-N-hydroxy-2- [4- (2-methylamino-pyrimidin-5-yl) -phenyl ] -propionamidine

5-bromo-2- (methylamino) pyrimidine (451mg, 2.39mmol) and hexamethyldistannane (0.456ml, 2.19mmol) were mixed in toluene (5ml) in a 5ml microwave reaction vessel. The mixture was degassed with argon and then tetrakis (triphenylphosphine) palladium (0) (115mg, 0.10mmol) was added. The reaction was again degassed, capped and warmed to 115 ℃ for 1 hour. After cooling to ambient temperature, I-6(500mg, 1.99mmol) and tetrakis (triphenylphosphine) palladium (0) (115mg, 0.10mmol) were introduced. The vessel was capped and warmed to 115 ℃ overnight. After this time, the reaction was cooled and concentrated. The resulting solid was purified by flash chromatography (silica gel, 0-100% EtOAc/heptane) to give I-29bis (134 mg); m/z 279.4[ M + H ].

To a suspension of I-29bis (134mg, 0.481mmol) in EtOH (3.2ml) was added hydroxylamine H₂O solution (50 wt%) (1.18mL, 19.24mmol) was stirred at 85 deg.C for 72 hours. The mixture was cooled and concentrated, and diluted with water and ethyl acetate. The white solid was filtered off and dried, the organics were purified by flash chromatography and combined with the solid to give the title intermediate (110 mg); m/z 312.4[ M + H ]]。

Synthesis of aryl bromide intermediates

3- [2- (4-bromophenyl) -3-methylbutan-2-yl]-5-cyclopropyl-1, 2, 4-Synthesis of diazoles

A mixture of I-14(150mg, 0.53 mmol 1) and cyclopropylcarbonyl chloride (60mg, 0.58mmol) in pyridine (2mL) was stirred at room temperature for 15 minutes and then heated at 110 ℃ for 18 hours. The reaction mixture was concentrated in vacuo and then partitioned between CH₂Cl₂With saturated NaHCO₃Between aqueous solutions. With Na₂SO₄The organics were dried, filtered and concentrated in vacuo to give the title intermediate (167 mg); m/z 336.0[ M + H ]]。

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

5- {3- [2- (4-bromophenyl) -3-methylbutan-2-yl]-1，2，4-Synthesis of oxadiazol-5-yl pyrimidine

To a solution of pyrimidine-5-carboxylic acid (200mg, 0.70mmol) in pyridine (1.0mL) was added thionyl chloride (61. mu.L, 0.84 mmol). The mixture was stirred at room temperature for 15 min, then I-14(91mg, 0.74mmol) was added. The resulting mixture was heated at 110 ℃ for 18 hours, then concentrated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO₃Between the aqueous solutions, wash with brine, and Na₂SO₄Dried, filtered, and concentrated in vacuo to give the title compound (236 mg); m/z 373.0, 375.0[ M/M +2H]

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

3- [1- (4-bromo-phenyl) -1-cyclopropyl-ethyl]-5- (1H-pyrazol-4-yl) - [1, 2, 4]Synthesis of diazoles

1, 1' -carbonyldiimidazole (4.9g, 30.7mmol) was added to 1H-pyrazole-4-carboxylic acid (3.4g, 30.7mmol) in 1, 4-bisIn a mixture of alkanes (150 ml). The mixture was stirred at 50 ℃ for 30 minutes, I-16 was added and the reaction mixture was heated at 85 ℃ for 48 hours. The reaction mixture was cooled to room temperature and saturated NaHCO was poured in₃To the solution and extracted with EtOAc. Over MgSO₄The organic layer was dried, filtered and concentrated to give the crude product which was purified by flash chromatography (SiO)₂，0-6％MeOH/CH₂Cl₂) This was purified to give the title intermediate (6.9 g); m/z 359, 361[ M/M +2H]。

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

3- [ (R) -1- (4-bromo-phenyl) -1-cyclopropyl-ethyl]-5- (1H-pyrazol-4-yl) - [1, 2, 4]Synthesis of diazoles

Adding the 1, 4-di-compound into a sealed tube1H-pyrazole-4-carboxylic acid (484mg, 4.2mmol) in an alkane (8ml) was added followed by 1, 1' -carbonyldiimidazole (679mg, 4.2 mmol). The reaction mixture was stirred at 55 ℃ for 30 minutes. Then will be stored in 1, 4-twoI-17(1.1g, 4.0mmol) in an alkane (5ml) was added to the above mixture. The reaction mixture was stirred at 120 ℃ for 18 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with water, brine, and anhydrous Na₂SO₄Dried, filtered and concentrated. By flash chromatography (SiO)₂，0-5％MeOH/CH₂Cl₂) To purify the residue to obtain the title intermediate (1.3 g); m/z 359.0, 361.0[ M/M +2H]。

2- (4- {3- [1- (4-bromo-phenyl) -1-cyclopropyl-ethyl]-[1，2，4]Oxadiazol-5-yl } -pyrazol-1-yl radicals) Synthesis of (E) -N, N-dimethyl-acetamide

To a solution of I-59(6.9g, 19mmol) in DMF (80mL) at room temperature was added K₂CO₃(5.3g, 38mmol) and 2-chloro-N, N-dimethylacetamide (2.9g, 28 mmol). The mixture was stirred at the same temperature for 24 hours. Water (200mL) was added and the mixture was extracted with EtOAc (300 mL). With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and subjected to flash column chromatography on silica gel using the solvent in CH₂Cl₂The remaining residue was purified with 8% MeOH as eluent to give the title intermediate (8.3 g); m/z444.2, 446.2[ M/M +2 ]]。

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

a) the reaction mixture was stirred at 80 ℃ for 48 hours

b) The reaction was started with the corresponding iodide and the mixture was stirred at 80 ℃ overnight

3- [ (R) -1- (4-bromo-phenyl) -1-cyclopropyl-ethyl]-5- (1-methyl-1H-pyrazol-4-yl) - [1, 2, 4]IISynthesis of oxazoles

To a vial was added I-61(550mg, 1.531mmol), iodomethane (0.191mL, 3.062mmol) and K in 6mL of DMF₂CO₃(423mg, 3.062 mmol). The reaction mixture was stirred at rt for 2h, then poured into water and brine and extracted with EtOAc (4 × 25 ml). The combined organic portions were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title intermediate (516 mg); m/z 374.0, 376.0[ M/M +2]。

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

2- [4- (3- { 1-cyclopropyl-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ]]Dioxoborolan-2-yl) -phenyl]-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide

1, 4-bis to I-62(2.6g, 5.9mmol) in a pressure vialTo a solution of bis (pinacolato) diboron (2.2g, 8.8mmol), KOAc (2.3g, 23mmol) and tetrakis (triphenylphosphine) palladium (0) (481mg, 0.6mmol) were added. The reaction mixture was stirred at 100 ℃ under Ar atmosphere for 4 hours. The mixture was cooled and concentrated in vacuo. The residue was diluted with EtOAc (100mL) and passed through a plug of celite and rinsed thoroughly with EtOAc (20 mL). The filtrate was dried over magnesium sulfate and filtered to give the title intermediate (1.9 g); m/z 492.3(M + H)

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

a) 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane was used instead of

b) 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane was used instead and the reaction mixture was stirred at 100 ℃ overnight

And (4) synthesis of Boc-piperidine intermediate.

5' - (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -2, 3, 5, 6-tetrahydro- [1, 2']Synthesis of t-butyl bipyrazinyl-4-carboxylate

A250 mL round bottom flask was charged with R-7(5.4g, 28.99mmol) in 100mL NMP. R-8(5.00g, 28.99mmol) was added followed by triethylamine (4.85ml, 34.79 mmol). The reaction was heated to 60 ℃ under nitrogen atmosphere overnight. The reaction was cooled to room temperature, poured into ice water and the precipitated I-76(8.60g) isolated by filtration; m/z 323.4[ M + H ]

To a stirred suspension of I-76(8.60g, 26.68mmol) in ethanol (250ml) was added 5M NaOH (26.68ml, 133.39mmol) at room temperature. After successive formation of a precipitate and a solid mass, the mixture became homogeneous. Water (200ml) was added and the mixture was stirred for 4 hours, after which the reaction appeared to be complete. The light brown sludge was poured into a beaker and treated with water. Addition of AcOH to achieveTo acidic pH and the product extracted into DCM (2 ×). Over anhydrous MgSO₄The combined organics were dried, filtered and concentrated to give the product as a solid, which was suspended in heptane. The solid was collected by filtration and washed with heptane to give I-77(7.90 g); m/z 309.4[ M + H ]]。

To a suspension of I-77(3.0g, 9.71mmol) in THF (40ml) was added 1, 1' -carbonyldiimidazole (1.6g, 9.71mmol) at room temperature. The mixture was stirred at 50 ℃ for 30 minutes. Thereafter I-16(2.5g, 8.83mmol) was added and the resulting mixture was heated at 80 ℃ for 3 hours. The mixture was cooled and treated with AcOH (8 ml). The mixture was warmed to 80 ℃ and stirred overnight. After cooling to room temperature, the reaction was concentrated and diluted with water. The product was extracted into DCM (2 ×). The combined organics were washed with brine and over anhydrous MgSO₄And (5) drying. The mixture was filtered and concentrated. The residual crude was purified by flash chromatography (silica gel, 0-5% MeOH/DCM) to give I-78(2.2 g). I-78(0.50g, 0.90mmol) in 15ml DMF was added to a microwave reaction vessel followed by 2-aminopyrimidine-5-boronic acid pinacol ester (0.30g, 1.35mmol), tetrakis (triphenylphosphine) palladium (0) (105mg, 0.09mmol) and Na₂CO₃Aqueous solution (2.0M, 1.8 ml). The reaction mixture was stirred at 85 ℃ for 16 hours. The reaction mixture was then poured into brine and extracted with EtOAc (3 ×). Over anhydrous MgSO₄The combined organic fractions were dried, filtered, and then concentrated in vacuo to give the crude. Purification by flash chromatography (silica gel, 0-5% MeOH/DCM) gave the title intermediate (150 mg); m/z 570.4[ M + H ]]。

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

5' - (3- { (S) -1- [4- (5-amino-pyrazin-2-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -2, 3, 5, 6-tetrahydro- [1, 2']Synthesis of t-butyl bipyrazinyl-4-carboxylate

To a suspension of I-77(1.0g, 3.53mmol) in THF (20ml) was added 1, 1' -carbonyldiimidazole (0.63g, 3.88mmol) at room temperature. The mixture was stirred at 50 ℃ for 30 minutes. I-19(1.2g, 3.88mmol) was then added as a THF solution (15ml) and the resulting mixture was heated at 80 ℃ for 3 h. The mixture was cooled and treated with AcOH (8ml), then warmed to 80 ℃ and stirred overnight. After this time the reaction was cooled to room temperature, concentrated and diluted with water. The product was extracted into DCM (2 ×). The combined organics were washed with brine and dried (MgSO₄) Filtered and concentrated. The residual crude was purified by flash chromatography (silica gel, 0-5% MeOH/DCM) to give I-84(1.2 g). 5-amino-2-bromopyrazine (60mg, 0.34mmol) and hexamethyldistannane (120mg, 0.38mmol) were mixed in toluene (2ml) in a 5ml microwave reaction vessel. The mixture was degassed with argon and then tetrakis (triphenylphosphine) palladium (0) (40mg, 0.03mmol) was added. The reaction was again degassed, capped and warmed to 115 ℃ for 1 hour. After cooling to ambient temperature, I-84(270mg, 0.48mmol) and tetrakis (triphenylphosphine) palladium (0) (30mg, 0.05mmol) were introduced. The vessel was capped and warmed to 115 ℃ overnight. After this time, the reaction was cooled and concentrated. The crude was suspended in DCM/MeOH, treated with silica gel and concentrated. The resulting solid was purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to give the title intermediate (100 mg).

Synthesis of 4-fluoro-pyrimidin-2-ylamine

To R-9(100mg, 0.77mmol) CH at room temperature₃CN (10mL) suspension was added in Et₃HF in N (0.26mL, 1.5 mmol). The solution was heated to 80 ℃ for 48 hours. The solution was cooled and water (10mL) was added. With EtOAc (20mL) and H₂The solution was extracted with O (5 mL). With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated to give I-86(25 mg); m/z 113.9[ M + H ]]。

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

synthesis of 5-bromo-4-fluoro-pyrimidin-2-ylamine

To I-86(280mg, 2.5mmol) CH at room temperature₃CN (20mL) solution was added N-bromosuccinimide (881mg, 4.9 mmol). The solution was stirred at the same temperature for 12 hours. The solid precipitated from the solution was collected and dried to give the title intermediate (250 mg); m/z 191.9, 193.9[ M/M +2H]

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

synthesis of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine

To a stirred solution of R-10(2.70g, 16.66mmol) in DMF (15ml) was added N-bromosuccinimide (3.00g, 16.85mmol) as a DMF solution (15ml, dropwise). After 4 hours the reaction was poured into ice. The precipitate was collected by filtration to give the product as an off-white solid. Dissolved in DCM and washed with brine. The layers were separated and dried (MgSO₄) The organic layer was filtered and concentrated to give the title intermediate (3.8 g); m/z 241.2/243.2[ M/M +2H]。

Synthesis of 5-bromo-3-fluoro-pyridin-2-ylamine

To a round bottom flask was added the solution in CH at 0 deg.C₃R-11(500mg, 4.46mmol) in CN (120ml) followed by the addition of N-bromosuccinimide (397mg, 2.23 mmol). The reaction mixture was stirred vigorously (protected from light) for 15 minutes, then vigorously at room temperature for 1 hour. Another portion of the other N-bromosuccinimide (397mg, 2.23mmol) was added at 0 deg.C, and the reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and taken up with saturated Na₂S₂O₃(20ml), washed with brine and dried over anhydrous Na₂SO₄Dried, filtered and concentrated. By flash chromatography (SiO)₂0-20% EtOAc/heptane) to afford the title intermediate (772 mg); m/z 190.89/192.86[ M/M +2H ]]。

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

synthesis of (5-bromo-pyrimidin-2-yl) -tert-butyl-amine

To a vial was added R-12(200mg, 1.13mmol) in DMF (5ml) followed by addition of K₂CO₃(312mg, 2.26mmol) and isopropylamine (134mg, 2.27 mmol). The reaction mixture was stirred at 70 ℃ for 3 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with water, brine, over anhydrous Na₂SO₄Dried, filtered and concentrated to give the title intermediate (221 mg); m/z 216.0/218.0[ M/M +2H ]]。

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

synthesis of 3-benzyloxy-5-bromo-pyridine

To a vial were added 3-bromo-5-hydroxypyridine (200mg, 1.15mmol), benzyl alcohol (137mg, 1.27mmol), and triphenylphosphine (332mg, 1.27mmol) in THF (5ml) at 0 deg.C, followed by diisopropyl azodicarboxylate (256mg, 1.27 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and saturated NaHCO₃Water, brine washing, anhydrous Na₂SO₄Dried, filtered and concentrated. By flash chromatography (SiO)₂，0-5％MeOH/CH₂Cl₂) To purify the residue to obtain the title compound (97 mg); m/z 264.0, 266.0[ M/M +2H]

Synthesis of 5-bromo-3-trifluoromethyl-pyrazin-2-ylamine

Ferrocene (56mg, 0.3mmol) was added to a DMSO (3ml) solution of 2-amino-5-bromopyrazine (174mg, 1mmol) under Ar with stirring and degassed with Ar for 5 minutes. 2ml of 1N H in DMSO were added₂SO₄Subsequently, CF in DMSO (2ml) was added₃I (0.276ml, 3mmol) gave a pale yellow solution. Slowly add 0.2ml 30% H₂O₂The reaction takes place, the color changing from yellow to dark green. The reaction was heated to 50 ℃ under Ar atmosphere and held for 2 hours. After cooling to room temperature, the reaction mixture was poured into brine and the product was extracted with EtOAc (4 × 20 ml). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated in vacuo. By flash chromatography (SiO)₂Biotage SNAP 10g, 0-50% EtOAc/heptane) to give 70mg of the title compound; m/z 242.0, 244.0(M/M +2H)

Synthesis of 4-benzyloxy-5-bromo-pyrimidin-2-ylamine

A20 ml microwave reaction vessel was charged with benzyl alcohol (7.0ml) and sodium (145mg, 6.33 mmol). The vessel was capped and stirred at ambient temperature until the sodium was depleted. Thereafter, I-90(1.10g, 5.28mmol) was added and the reaction was warmed to 130 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was concentrated to low volume. The remaining residue was diluted with water. The water was poured off and the residual oil was treated with methanol. The precipitated solid was collected by filtration and washed with methanol to give the title intermediate (0.86 g); m/z 282.0[ M + H ].

Synthesis of (5-bromo-pyridin-2-yl) -methyl-amine

A20 ml microwave reaction vessel was charged with 2, 5-dibromo-pyridine (2.00g, 8.44mmol) and treated with methylamine (10.45ml of a 33% solution in ethanol, 84.43mmol) and warmed to 80 ℃ for 3 days. After this time, the reaction was concentrated and the residual solid was treated with 1M HCl (50ml) and DCM. The layers were separated and the aqueous phase was basified using 1N NaOH (to pH about 11). The product was extracted into DCM (2 ×) and dried (MgSO)₄) The combined organics were filtered and concentrated to give the expected product I-96bis (1.20 g).¹H-NMR(400MHz，DMSO-d6)：2.75ppm(d，3H)，6.44ppm(d，1H)，6.72ppm(bs，1H)，7.51ppm(dd，1H)，8.05ppm(s，1H)。

2- [4- (3- { (R) -1- [4- (2-amino-4-benzyloxy-pyrimidin-5-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide

I-97 was prepared according to method 26 (using tetrakis (triphenylphosphine) palladium, 2M Na at 85 deg.C)₂CO₃And DMF for 16 hours); m/z 565.0[ M + H ]]。

2- {2- [4- (3- { (R) -1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]Synthesis of (E) -ethyl) -isoindole-1, 3-dione

With DMF (2.5mL), 2- (2-bromo-ethyl) -isoindole-1, 3-dione (101mg, 0.399mmol) and Cs₂CO₃(83.0mg, 0.599mmol) example 48(100mg, 0.266mmol) was treated and the reaction stirred overnight. The resulting mixture was diluted with water and ethyl acetate and the phases were separated. The organic phase was washed with water and brine, Na₂SO₄Dried, filtered, and concentrated in vacuo. By flash chromatography on silica gel with 0-10% methanol/CH₂Cl₂The resulting residue was purified by elution to give I-98(120 mg).

Synthesis of the final Compound

Method 1

2- (3- {2- [4- (5-methoxypyridin-3-yl) phenyl]-3-methylbut-2-yl } -1, 2, 4-Synthesis of oxadiazol-5-yl) pyrazines (example 1, Table 1)

To a solution of I-27(200mg, 0.64mmol) in DMF (5mL) was added Hunig's base (0.3mL, 1.6mmol), followed by pyrazine-2-carbonyl chloride (110mg, 0.80 mmol). The reaction mixture was heated at 120 ℃ for 2 hours, then the volatiles were removed in vacuo. By flash chromatography (SiO)₂Heptane to 60% EtOAc in heptane) to give the title compound (165 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

examples 2 to 5, Table 1

Example 7, Table 1

Example 117-

Example 120, Table 1

Method 2

[ 2-amino-5- (4- { 3-methyl-2- [5- (pyridin-3-yl) -1, 2, 4-Diazol-3-yl]But-2-yl } phenyl) pyridin-3-yl]Synthesis of methanol (example 6, Table 1)

I-58(0.450g, 1.21mmol) was suspended in 1, 4-bisAlkane (3.0 mL). Bis (pinacolato) diborane (0.364g, 1.43mmol), potassium acetate (0.500g, 5.09mmol) and 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) dichloromethane complex (0.100g, 0.122mmol) were added. The reaction mixture was degassed and heated at 100 ℃ for 4 hours under argon. The mixture was cooled to room temperature, then diluted with EtOAc and washed with water. The organics were collected and concentrated in vacuo to give a residue which was purified by flash chromatography (SiO)₂Hexane to 30% EtOAc in hexane) to give I-99(0.362 g); m/z 420.61[ M +1]]。

I-99(0.100g, 0.238mmol) was dissolved in DMF (2.0mL) and washed with 2-amino-5-bromo-3 (hydroxymethyl) pyridine (0.051g, 0.25mmol), tetrakis (triphenylphosphine) palladium (0) (0.029g, 0.025mmol) and Na₂CO₃Aqueous (2.0M, 1.0mL, 1.0mmol) solution. The reaction mixture was degassed and heated at 100 ℃ for 4 hours under argon atmosphere. The mixture was cooled to room temperature, then diluted with EtOAc and washed with water. The organics were collected and concentrated in vacuo to give a residue which was purified by flash chromatography (SiO)₂In CH₂Cl₂0-10% MeOH) to give the title compound (0.025 g).

Method 3

5- (4- {2- [5- (6-methoxypyridin-3-yl) -1, 2, 4-Diazol-3-yl]Synthesis of (E) -3-methylbut-2-yl } phenyl) pyrimidin-2-amine (example 8, Table 1)

Example 7(35mg, 0.083mmol) was dissolved in MeOH (2.0 mL). A25% (w/w) solution of NaOMe in MeOH (50. mu.L) was added. The reaction mixture was heated at 70 ℃ for 6 hours, then the volatiles were removed in vacuo. By flash chromatography (SiO)₂In CH₂Cl₂0-10% MeOH) to afford the title compound (26 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 9, Table 1

Method 4

3- (3- {2- [4- (2-aminopyrimidin-5-yl) phenyl]-3-methylbut-2-yl } -1, 2, 4-Synthesis of oxadiazol-5-yl) pyridin-2 (1H) -one (example 12, Table 1)

I-21(100mg, 0.255mmol) was dissolved in 1-methyl-2-pyrrolidone (1 mL). Ethyl-diisopropylamine (0.3mL, 1.6mmol) was added followed by 2-chloro-nicotinoyl chloride (62mg, 0.35 mmol). The reaction mixture was heated at 120 ℃ for 1 hour, then cooled to room temperature and partitioned in CH₂Cl₂And water. The organics were collected and the volatiles were removed in vacuo. By flash chromatography (SiO)₂0-100% ethyl acetate in heptane) to afford I-100(78 mg); m/z 421.48[ M +1]]。

Dissolving I-100(35mg, 0.083mmol) in 1, 4-bisAlkane (2.0 mL). A10% (w/w) aqueous LiOH solution (50. mu.L) was added. The reaction mixture was heated at 70 ℃ for 2 hours. The solvent was removed in vacuo and the residue was suspended in water (2.0 mL). The precipitate was collected by filtration, washed with water and air dried. By flash chromatography (SiO)₂In CH₂Cl₂0-10% MeOH) to further purify the solid to give the title compound (28 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 10, Table 1

Method 5

5- (4- {2- [5- (4-methoxypyridin-3-yl) -1, 2, 4-Diazol-3-yl]Synthesis of (E) -3-methylbut-2-yl } phenyl) pyrimidin-2-amine (example 11, Table 1)

4-methoxy-nicotinic acid (54mg, 0.35mmol) was dissolved in 1-methyl-2-pyrrolidone (1mL) and carbonyldiimidazole (57mg, 0.35mmol) was added. The mixture was stirred for 15 min, then I-21(100mg, 0.255mmol) was added. The reaction mixture was heated at 120 ℃ for 1 hour, then cooled to room temperature and diluted with water. The solid was collected by filtration and purified by flash chromatography (SiO)₂0-100% EtOAc in heptane) to yield the title compoundCompound (19 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

examples 13 to 15, Table 1

Examples 18 to 22, Table 1

Examples 25 to 29, Table 1

Examples 33 to 34, Table 1

Example 37, Table 1

Example 58, Table 1

Examples 67 to 69, Table 1

Example 119, Table 1

5- (4- { (R) -1-cyclopropyl-1- [5- (1H-pyrazol-4-yl) - [1, 2, 4]Diazol-3-yl]Synthesis of (E) -Ethyl } -phenyl) -pyrimidin-2-ylamine (example 48, Table 1)

To a suspension of 1H-pyrazole-4-carboxylic acid (7.1g, 0.063mol) in THF (200mL) was added 1, 1' -carbonyldiimidazole (10.2g, 0.063mol) at room temperature. The mixture was stirred at 50 ℃ for 30 minutes. A suspension of I-29(12.5g, 0.042mol) in THF (100mL) was added to the above mixture and the resulting mixture was heated at reflux for 24 h. The mixture was cooled and the solid was collected by filtration. The solid was then suspended in AcOH (150mL) at room temperature. The mixture was heated to 90 ℃ for 2 hours. The solution was cooled and concentrated under vacuum. The residue was dissolved in EtOAc (100mL) and taken up with H₂O (200mL) and saturated NaHCO₃The solution (200mL) was washed. The organic layer was concentrated to give the title compound (14.7g, 0.040 mol).

Method 6

4- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1, 2-dimethyl-propyl } -1, 2, 4-Oxadiazol-5-yl) -piperidine-1-carboxylic acid tert-butyl ester (example 109, Table 1) and 5- (4- { 3-methyl-2- [5- (piperidin-4-yl) -1, 2, 4-Diazol-3-yl]Synthesis of but-2-yl } phenyl) pyrimidin-2-amine (example 110, Table 1)

To a suspension of N-Boc-isohexahydropicotinic acid (115mg, 0.50mmol) in THF (1mL) was added carbonyldiimidazole (81mg, 0.50 mmol). The mixture was heated at 55 ℃ for 20 minutes and then treated with I-21(100mg, 0.33 mmol). The reaction mixture was heated at 55 ℃ for 17 hours and then at 150 ℃ for 20 minutes in a microwave. The mixture was cooled to room temperature and then purified by flash chromatography (SiO)₂15-100% EtOAc in heptane) was used for direct purification to afford example 109(89 mg).

Example 109(83mg, 0.17mmol) was dissolved in CH₂Cl₂(1mL) and HCl in 1, 4-bisA solution in alkane (4.0M, 0.4mL) was treated. The mixture was stirred at room temperature for 3.5 hours, then the resulting solid was filtered and washed with CH₂Cl₂Washed, collected and dried to give the title compound (63 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 111-

Method 7

5- (4- { 3-methyl-2- [5- (1H-pyrazol-4-yl) -1, 2, 4-Diazol-3-yl]Synthesis of but-2-yl } phenyl) pyrimidin-2-amine (example 146, Table 1)

In N₂Next, I-47(70mg, 0.19mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (51mg, 0.23mmol) and 2M Na were reacted₂CO₃A mixture of aqueous solution (0.2mL) in DMF (1mL) was degassed for 5 minutes. To this mixture PdCl was added₂(PPh₃)₂(14mg, 0.02 mmol). The mixture was stirred at 80 ℃ for 18 h, then partitioned between EtOAc and water. Washing the organic with water, Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (13 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 125, Table 1-Synthesis of I-38 with-aminopyrimidine-5-boronic acid, PdCl₂dppf (0.05 eq.) and dppf (0.05 eq.) after reaction, only example 125 was formed instead of example 128

Example 126-

Example 139, Table 1

Example 143, Table 1

Example 146-

Method 8

5- [4- (3-methyl-2- {5- [6- (trifluoromethyl) pyridin-3-yl)]-1，2，4-Oxadiazol-3-yl } but-2-yl) Phenyl radical]Synthesis of pyrimidin-2-amine (example 136, Table 1)

To I-33(156mg, 0.35mmol), 2-aminopyrimidine-5-boronic acid (58mg, 0.42mmol) and 2M Na in a pressure tube₂CO₃To a suspension of aqueous solution (0.53mL) in ethanol/toluene (4: 1, 2mL) was added [1, 1' -bis (diphenylphosphino) -ferrocene]Palladium (II) dichloride (25mg, 0.030mmol) and 1, 1' -bis (diphenylphosphino) ferrocene (15mg, 0.02 mmol). The reaction mixture was stirred at 90 ℃ for 2 hours. The reaction mixture was filtered through a pad of celite, with EtOAc and CH₂Cl₂And (6) washing. The collected filtrate was concentrated in vacuo. Purification by preparative HPLC gave the title compound (72 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 135-138, Table 1

Example 140-

Method 9

2- [4- (3- {1- [4- (2-aminopyrimidin-5-yl) phenyl]-1-cyclopropylethyl } -1, 2, 4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Synthesis of (E) -N, N-dimethylacetamide (example 59, Table 1)

To a solution of example 21(350mg, 0.94mmol) in DMF (1mL) was added K₂CO₃(260mg, 1.9mmol) and 2-chloro-N, N-dimethylacetamide (0.19mL, 1.9 mmol). The reaction mixture was stirred at room temperature for 20 hours, thenBy preparative HPLC (10-60% CH in water with 0.1% TFA)₃CN) was directly purified to give the title compound (200 mg).

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

a) heating the reaction mixture at 50 deg.C

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 30, Table 1

Example 43, Table 1

Example 60, Table 1

Examples 75 to 76, Table 1

Example 79, Table 1

Examples 97 to 99, Table 1

Example 106, Table 1

Example 271, Table 1-reaction carried out at 130 ℃ for 48 hours starting from the corresponding bromide

2- [4- (3- { (R) -1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide (example 115, Table 1)

To a solution of example 48(14.7g, 0.040mol) in DMF (150mL) at room temperature was added 2-chloro-N, N-dimethylacetamide (6)1mL, 0.059mol) and K₂CO₃(10.9g, 0.079 mol). The mixture was stirred at the same temperature for 2 hours. Water (100mL) was added and the mixture was extracted with EtOAc (200 mL). With MgSO₄(20g) The combined organic layers were dried and filtered. The filtrate was concentrated and the residual solid was resuspended in a small amount of acetonitrile (30mL) for 10 minutes. The solid was collected by filtration and washed with cold acetonitrile. The resulting solid was dried under vacuum and confirmed to be the title compound (10 g).

The title compound is further purified by recrystallization from ethanol, methanol or THF, if desired. Alternatively, the title compound is converted to the hydrochloride salt by dissolving the free base in ethanol or isopropanol and subsequently adding aqueous hydrochloric acid to the solution.

Method 10

2- [ (3- {2- [4- (2-aminopyrimidin-5-yl) phenyl)]-3-methylbut-2-yl } -1, 2, 4-Oxadiazol-5-yl) amino]Synthesis of ethanol (example 80, Table 1)

To a solution of I-21(900mg, 3.0mmol) in toluene (35mL) was added trichloroacetic anhydride (0.69mL, 3.6 mmol). The reaction mixture was heated at reflux for 2.5 hours and then cooled to room temperature. The mixture was diluted with EtOAc and saturated NaHCO₃Washing with aqueous solution, and adding Na₂SO₄Drying, filtering and concentrating to give I-101(1.25 g); m/z 426.31/428.22[ M/M +2H ]]。

To a solution of I-101(80mg, 0.19mmol) and KOH (1.9mg, 0.28mmol) in DMSO (1mL) was added ethanolamine (20. mu.L, 0.28 mmol). The reaction mixture was stirred at room temperature for 1 hour and then treated with water. The mixture was extracted with EtOAc, washed with brine, Na₂SO₄Dried, filtered, and concentrated. By fastFast chromatography (SiO)₂In CH₂Cl₂0-10% MeOH) to afford the title compound (45 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

examples 81 to 83, Table 1

Example 84, Table 1-by-products isolated from the reaction to form example 83

Example 86, Table 1-the expected amine derivative was not isolated and the amide by-product was the only isolated product

Example 87, Table 1

Example 89, Table 1

Example 90, Table 1-by-products isolated from the reaction to form example 89

Example 91, Table 1-the expected amine derivative was not isolated and the amide by-product was the only isolated product

Example 134, Table 1

Example 171, Table 1

Method 11

1- { [5- (3- {1- [4- (2-aminopyrimidin-5-yl) phenyl]-1-cyclopropylethyl } -1, 2, 4-Oxadiazol-5-yl) pyrazin-2-yl]Synthesis of amino } -2-methylpropan-2-ol (example 44, Table 1)

To a solution of 5-chloro-pyrazine-2-carboxylic acid (490mg, 3.1mmol) in NMP (3mL) was added carbonyldiimidazole (500mg, 3.1 mmol). The mixture was stirred at 50 ℃ for 0.5 h, then worked up with I-23(830mg, 2.8mmol)Heat and heat at 110 ℃ for 2 hours. The mixture was cooled to room temperature, treated with water, and stirred for 18 hours. The resulting solid was filtered off, dried and collected to give I-102(1.0 g).¹H NMR(DMSO-d6)δppm 9.40(1H，s)，9.20(1H，s)，8.75(1H，s)，8.55(2H，s)，8.10(1H，s)，7.60(2H，d)，7.40(2H，d)，7.20(1H，s)，6.75(2H，s)，1.65-1.75(1H，m)，1.55(3H，s)，0.3-0.75(4H，m)。

I-102(300mg, 0.66mmol) was dissolved in 1-amino-2-methyl-propan-2-ol (1.5mL) and heated at 80 ℃ for 4 h. The mixture was cooled to room temperature and treated with water. The resulting solid was filtered off, collected and passed over CH₃Further purification by recrystallization from CN afforded the title compound (155 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 42, Table 1

Example 45, Table 1

Examples 35 to 36, Table 1

Examples 73 to 74, Table 1

Example 162-

Method 12

5- {4- [ 1-cyclopropyl-1- (5- {6- [ (2-methoxyethyl) amino group]Pyridin-3-yl } -1, 2, 4-Oxadiazol-3-yl) ethyl]Synthesis of phenyl } pyrimidin-2-amine (example 38, Table 1)

To a solution of 6-chloronicotinic acid (500mg, 3.2mmol) in NMP (7mL) was added carbonyldiimidazole (520mg, 2.9 mmol). The mixture was stirred at room temperature for 1 hour, then treated with I-23(860mg, 2.8mmol) and heated at 130 ℃ for 2 hours. The mixture was cooled to room temperature and treated with water. The resulting solid was filtered off, dried and collected to give I-103(350 mg); m/z 419.33[ M + H ]

I-103(150mg, 0.36mmol) was dissolved in 2-methoxyethylamine (0.5mL) and heated at 80 ℃ for 2 hours. The mixture was cooled to room temperature and treated with water to give a residue. The water was poured off and subjected to preparative HPLC (10-60% CH in water with 0.1% TFA)₃CN) to obtain the title compound (98 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

examples 39 to 41, Table 1

Examples 70 to 72, Table 1

Method 13

1- [4- (3- {2- [4- (2-aminopyrimidin-5-yl) phenyl]-3-methylbut-2-yl } -1, 2, 4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Synthesis of (E) -2-methylpropan-2-ol (example 159, Table 1)

To a suspension of I-47(336mg, 0.93mmol) and potassium carbonate (154mg, 1.12mmol) in DMF (6mL) was added 1-chloro-2-methyl-propan-2-ol (100. mu.L, 0.98 mmol). The reaction mixture was stirred at 80 ℃ for 16 h, then concentrated in vacuo. By CH₂Cl₂Extracting the residue with saturated NH₄Washed with aqueous Cl solution and Na₂SO₄Drying, filtration and concentration in vacuo afforded I-104(365 mg); m/z 434[ M + H ]]。

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

in N₂I-104(365mg, 0.84mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (279mg, 1.26mmol) and 2M Na were added₂CO₃A mixture of aqueous solution (0.85mL) in DMF (4mL) was degassed for 5 minutes. To this mixture was added bis (triphenylphosphine) palladium (II) chloride (59mg, 0.08 mmol). The mixture was stirred at 80 ℃ for 18 hours, then concentrated in vacuo. By CH₂Cl₂The residue was extracted with saturated NaHCO₃Washing with an aqueous solution of Na₂SO₄Dried, filtered, and concentrated in vacuo. By flash chromatography (SiO)₂In CH₂Cl₂0-5% MeOH) to afford the title compound (268 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 142, Table 1

Example 144, Table 1

Example 158, Table 1

Example 161, Table 1

Method 14

1- (3- {2- [4- (2-aminopyrimidin-5-yl) phenyl]-3-methylbut-2-yl } -1, 2, 4-Synthesis of oxadiazol-5-yl) cyclopropanecarboxylic acid (example 95, Table 1)

To a solution of I-21(189mg, 0.63mmol) in DMF (1mL) was added a solution of methyl 1-chlorocarbonyl-1-cyclopropanecarboxylate (113mg, 0.69mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 15 minutes and then heated at 120 ℃ for 2 hours. The mixture was cooled, then treated with water and extracted with EtOAc, washed with brine, washed with Na₂SO₄Dried, filtered, and concentrated in vacuo. By flash chromatography (SiO)₂In CH₂Cl₂0-10% MeOH) to afford I-105(30 mg); m/z 408[ M + H]。

To a solution of I-105(30mg, 0.074mmol) in MeOH (0.5mL) was added aqueous NaOH (4.0M, 90. mu.L). The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was partitioned between EtOAc and water, and the aqueous layer was acidified to pH about 4 with 1M aqueous HCl. The aqueous mixture was extracted with EtOAc and concentrated in vacuo to give a residue which was purified by HPLC to give the title compound (20 mg).

Method 15

1- (3- {2- [4- (2-aminopyrimidin-5-yl) phenyl]-3-methylbut-2-yl } -1, 2, 4-Synthesis of oxadiazol-5-yl) cyclohexanecarboxylic acid (example 145, Table 1)

A mixture of monoethyl cyclohexane-1, 1-dicarboxylate (142mg, 0.50mmol), HATU (199mg, 0.52mmol) and triethylamine (80. mu.L, 0.55mmol) in DMF (2.5mL) was stirred for 5 min before addition of I-14(100mg, 0.50 mmol). The mixture was stirred at room temperature for 2 hours, then at 90 ℃ for 18 hours, then concentrated in vacuo. The resulting residue was partitioned between 1M aqueous HCl and EtOAc. The organics were washed with brine, over MgSO₄DryingFiltered and concentrated in vacuo. By flash chromatography (SiO)₂15% EtOAc in cyclohexane) to afford I-106(251 mg); m/z 449/451[ M/M +2H]。

In N₂I-106(223mg, 0.50mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (121mg, 0.55mmol) and 2M Na were reacted under reduced pressure₂CO₃A mixture of (1.9mL) aqueous solution in DMF (5mL) was degassed for 5 minutes. To this mixture was added bis (triphenylphosphine) palladium (II) chloride (35mg, 0.05 mmol). The mixture was stirred at 80 ℃ for 1 hour, then concentrated in vacuo. The residue was extracted with EtOAc, saturated NaHCO₃Washing with an aqueous solution of Na₂SO₄Dried, filtered, and concentrated in vacuo. By flash chromatography (SiO)₂0-20% EtOAc in cyclohexane) to afford I-107(182 mg); m/z 464[ M + H ]]。

To a solution of I-107(175mg, 0.38mmol) in 1: 1 THF/water (3mL) was added LiOH-H₂O (17mg, 0.40 mmol). The reaction mixture was stirred at room temperature for 2 days, then THF was removed in vacuo. The aqueous mixture was washed with EtOAc, saturated NH₄And (4) acidifying the Cl aqueous solution. The aqueous mixture was extracted with EtOAc, washed with brine, and MgSO₄Dried, filtered, and concentrated in vacuo. Et (Et)₂The resulting solid was triturated then filtered, collected and dried to give the title compound (88 mg).

Method 16

3- [4- (3- {2- [4- (2-aminopyrimidin-5-yl) phenyl]-3-methylbut-2-yl } -1, 2, 4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Synthesis of (E) -2, 2-dimethylpropionic acid (example 164, Table 1)

To I-47(407mg, 1.13mmol) and 3-chloro-2, 2-Ethyl dimethylpropionate (557mg, 3.38mmol) in a mixture of DMF (8mL) was added Cs₂CO₃(734mg, 2.25mmol) and tetrabutylammonium iodide (832mg, 2.25 mmol). The mixture was stirred at 80 ℃ for 36 hours, then concentrated in vacuo. The residue was distributed over CH₂Cl₂With saturated NaHCO₃Between aqueous solutions. With Na₂SO₄The organics were dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂10% EtOAc in cyclohexane) to afford I-108(299 mg); m/z 489/491[ M/M +2H]。

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

a) use of K in DMF at 80 ℃₂CO₃The reaction was carried out for 8 hours

In N₂I-108(290mg, 0.46mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (307mg, 1.39mmol) and 2M Na were reacted under reduced pressure₂CO₃A mixture of aqueous solution (0.46mL) in DMF (6mL) was degassed for 5 min. To this mixture was added bis (triphenylphosphine) palladium (II) chloride (65mg, 0.09 mmol). The mixture was stirred at 80 ℃ for 3 hours, then concentrated in vacuo. The residue was extracted with EtOAc, saturated NaHCO₃Washing with an aqueous solution of Na₂SO₄Dried, filtered, and concentrated in vacuo. By flash chromatography (SiO)₂In CH₂Cl₂0-1% MeOH) to afford I-109(171 mg); m/z 504.90[ M + H ]]。

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

i-109(171mg, 0.282mmol), LiOH.H at 40 deg.C₂A mixture of O (12mg, 0.286mmol), methanol (2.5mL), THF (2.5mL), and water (1.3mL) was heated for 8 h, then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (33 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 160, Table 1

Method 17

6- (3- {2- [4- (2-aminopyrimidin-5-yl) phenyl]-3-methylbut-2-yl } -1, 2, 4-Synthesis of oxadiazol-5-yl) -1-methylpyridin-2 (1H) -one (example 165, Table 1)

To a solution of 2-carboxylic acid-6-oxo-pyridine (161mg, 1.16mmol) in DMF (3mL) was added carbonyldiimidazole (188mg, 1.16 mmol). The mixture was stirred at 50 ℃ for 20 minutes, then treated with I-14(300mg, 1.05mmol) and stirred at 110 ℃ for 3 hours. The mixture was concentrated in vacuo and the residue was extracted with EtOAc, saturated NaHCO₃Washing with aqueous solution of MgSO 2₄Dried, filtered and concentrated. By flash chromatography (SiO)₂In CH₂Cl₂2% MeOH in) to afford I-110(223 mg); m/z 389.95[ M +1]]。

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

to a solution of I-110(223mg, 0.41mmol) in THF (3mL) was added K₂CO₃(68mg, 0.49mmol) and MeI (30. mu.L, 0.49 mmol). The mixture was stirred at 40 ℃ for 20 h and treated with additional MeI (30. mu.L, 0.49mmol) at 3h and 15 h. The mixture was treated with saturated aqueous ammonia and MeOH, and then the volatiles were removed in vacuo. The residue was extracted with EtOAc, saturated NaHCO₃Washing with aqueous solution, water, brine, MgSO₄Dried, filtered and concentrated. By flash chromatography (SiO)₂0-10% EtOAc in cyclohexane) to afford I-111(80 mg); m/z 403.85[ M +1]]。

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

in N₂I-111(80mg, 0.19mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (124mg, 0.56mmol) and 2M Na were reacted under reduced pressure₂CO₃A mixture of (0.20mL) aqueous solution in DMF (2mL) was degassed for 5 minutes. To this mixture PdCl was added₂(PPh₃)₂(26mg, 0.094 mmol). The mixture was stirred at 80 ℃ for 3 hours, then concentrated in vacuo. EtOAc extraction residue, saturated NaHCO₃Washing with an aqueous solution of Na₂SO₄Dried, filtered, and concentrated in vacuo. By flash chromatography (SiO)₂In CH₂Cl₂0-1% MeOH) to afford the title compound (30 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 166-. Silica gel column chromatography gave examples 166 and 167.

Method 18

2- [4- (3- { (1R) -1- [4- (2-aminopyrimidin-5-yl) phenyl]-1-cyclopropylethyl } -1, 2, 4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]-N, N-Dimethylacetamide (example 115) and 2- [4- (3- { (1S) -1- [4- (2-Aminopyrimidin-5-yl) phenyl]-1-cyclopropylethyl } -1, 2, 4-Oxadiazol-5-yl) -1H-pyrazol-1-yl]Synthesis of (E) -N, N-dimethylacetamide (example 116, Table 1)

By using in ChiralpakEnantiomers 115 and 116 were prepared by resolving example 59(100mg) on an AD-H (from Chiral Technologies, Exton, Pa.) semi-preparative (250X 20mm) HPLC column eluting with 95% EtOH in heptane with 0.1% diethylamine. The faster eluting enantiomer 115 had a retention time of about 35 minutes and the slower eluting enantiomer 116 had a retention time of about 73 minutes. The eluate was concentrated to give example 115(32mg) and example 116(27 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

examples 23 to 24, Table 1

Examples 31-32, Table 1-elution with 70% EtOH/heptane containing 0.1% diethylamine

Examples 61 to 62, Table 1

Examples 65 to 66, Table 1

Examples 77 to 78, Table 1

Example 102-103, Table 1

Example 104-

Example 107-108, Table 1

Example 115-116, Table 1-95% EtOH + 0.05% diethylamine in heptane, at 55ml/min

Example 121-122, Table 1-95% EtOH + 0.4% diethylamine in heptane, at 55ml/min

Example 123-

Example 227-

Example 230-

Example 233-

Example 254-

Example 257-

Example 282 Olympic 283, Table 1

Method 19

5- (4- { (2R) -3-methyl-2- [5- (1-methyl-1H-pyrazol-4-yl) -1, 2, 4-Diazol-3-yl]But-2-yl } phenyl) pyrimidin-2-amine (example 46) and 5- (4- { (2S) -3-methyl-2- [5- (1-methyl-1H-pyrazol-4-yl) -1, 2, 4-Diazol-3-yl]Preparation of but-2-yl } phenyl) pyrimidin-2-amine (example 47, Table 1)

By heating at 250 bar in ChiralpakAD-H (available from Chiral Technologies,exton, PA) semi-preparative (250X 30mm) HPLC column (on CO)₂Using 70% MeOH elution) example 15(50mg) was resolved to prepare enantiomers 46 and 47. The faster eluting enantiomer 46 had a retention time of about 5 minutes (Chiralpak)AD-H analytical HPLC column 4.6x 100mm) and the slower eluting enantiomer 47 had a retention time of about 13 minutes. The eluate was concentrated to give example 46(12mg) and example 47(15 mg).

The following compounds were resolved in a similar manner:

examples 16 to 17, Table 1

Examples 48 to 49, Table 1

Method 20

2- { [5- (3- { (1R) -1- [4- (2-Aminopyrimidin-5-yl) phenyl]-1-cyclopropylethyl } -1, 2, 4-Oxadiazol-5-yl) pyrazin-2-yl]Amino } -2-methylpropan-1-ol (example 56, Table 1) and 2- { [5- (3- { (1S) -1- [4- (2-aminopyrimidin-5-yl) phenyl]-1-cyclopropylethyl } -1, 2, 4-Oxadiazol-5-yl) pyrazin-2-yl]Preparation of amino } -2-methylpropan-1-ol (example 57, Table 1)

The column was purified by HPLC (in CO) at 250 bar on a Regispak (from Chiral Technologies, Exton, Pa.) semi-preparative (250X 30mm) HPLC column (in CO)₂Using 70% MeOH elution) example 45(89mg) was resolved to prepare enantiomers 56 and 57. The faster eluting enantiomer 56 had a retention time of about 5 minutes (Chiralpak)AD-H analytical HPLC column 4.6x 100mm) and the slower eluting enantiomer 57 had a retention time of about 13 minutes. The eluate was concentrated to give example 56(12mg) and example 57(15 mg).

The following compounds were resolved in a similar manner:

examples 50 to 51, Table 1-in CO₂Eluted with 55% MeOH

Examples 52 to 53, Table 1-in CO₂Eluted with 45% 3/1/0.1 MeOH/isopropanol/isopropylamine

Examples 54 to 55, Table 1-in CO₂Eluted with 55% EtOH

Examples 56-57, Table 1-elution with 45% 1/1 methanol/isopropanol

Example 100-101, Table 1-elution with 40% cosolvent with 1: 1 methanol: isopropanol with 0.5% isopropylamine at 150 bar

Examples 63 to 64, Table 1

Method 21

5- (4- { 3-methyl-2- [5- (4-methylpiperazin-1-yl) -1, 2, 4-Diazol-3-yl]Synthesis of but-2-yl } phenyl) pyrimidin-2-amine (example 96, Table 1)

To a mixture of I-14(1.029g, 3.61mmol) and carbonyldiimidazole (702mg, 7.33mmol) was added acetonitrile (20 mL). The reaction mixture was heated at 75 ℃ for 18 hours. At this point, the reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO)₂12-100% EtOAc in heptane) to afford I-112 (373)mg)；m/z 311.2/313.2[M/M+2H]。

To a solution of I-112(163mg, 0.523mmol) in pyridine (0.5mL) was added POCl₃(0.479mL, 5.23 mmol). The reaction mixture was heated at 90 ℃ for 18 hours. The reaction mixture was cooled to room temperature and carefully poured into ice water and then extracted 2 times with EtOAc. The organics were combined and washed with brine, Na₂SO₄Dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂12-100% EtOAc in heptane) to afford I-113(59 mg);¹H-NMR(DMSO-d6)δppm 7.50(2H，d)，7.35(2H，d)，2.62(1H，m)，1.60(3H，s)，0.83(3H，d)，0.6(3H，d)。

to a solution of I-113(44mg, 0.133mmol) in DMSO (1mL) was added 1-methylpiperazine (0.148mL, 1.33mmol) and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with water and extracted 2 times with EtOAc. The organics were combined and washed with water, then brine, over Na₂SO₄Dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂In CH₂Cl₂10-100% MeOH) to afford I-114(45 mg); m/z 393.0/395.0[ M/M +2H ]]。

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

a) 1.2 equivalents of amine and 1.2 equivalents of diisopropylethylamine were used.

b) 1.2 equivalents of amine (as free base or hydrochloride salt) and 2.5 equivalents of diisopropylethylamine were used.

c) 1.2 equivalents of amine (as dihydrochloride salt) and 5 equivalents of diisopropylethylamine were used.

A mixture of I-114(45.000mg, 0.114mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (30.286mg, 0.137mmol) and tetrakis (triphenylphosphine) palladium (0) (13.173mg, 0.011mmol) was evacuated and backfilled with Ar 3 times in a vial. THF (1mL) and saturated Na were then added₂CO₃The aqueous solution was heated to 65 ℃ and the mixture was held for 18 hours. After this time, the reaction mixture was quenched with water and extracted 2 times with EtOAc. The organics were combined and washed with brine, Na₂SO₄Dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂12-100% EtOAc in heptane) to afford example 96(12 mg).

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

a) the reaction was carried out in a microwave oven at 110 ℃ for 45 minutes.

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 168, Table 1

Example 169, Table 1-Final procedure is carried out in a microwave oven at 110 ℃ for 1 hour

Example 170, Table 1-Final step 45 minutes at 110 ℃ in a microwave oven

Example 186, Table 1-Final procedure 45 minutes at 110 ℃ in a microwave oven

Example 192, Table 1

Example 198-

Example 208-

Example 212-213, Table 1-Final step carried out in a microwave oven at 110 ℃ for 45 minutes

Example 218, Table 1-Final step 45 minutes at 110 ℃ in a microwave oven

Example 235, Table 1-Final step carried out in a microwave oven at 100 ℃ for 2 hours

Example 236-

Example 260, Table 1

Example 261-

Example 264, Table 1-Final step 45 minutes at 110 ℃ in a microwave oven

Example 266, Table 1-Final step 45 min at 110 ℃ in a microwave oven

Example 269-270, Table 1-Final step carried out in a microwave oven at 110 ℃ for 45 minutes

Method 22

4- (3- {2- [4- (2-aminopyrimidin-5-yl) phenyl]-3-methylbut-2-yl } -1, 2, 4-Synthesis of oxadiazol-5-yl) -2, 2-dimethylbutyric acid (example 85, Table 1)

To a solution of I-21(100mg, 0.334mmol) in DMF (1mL) was added 2, 2-dimethylpentadianhydride (52mg, 0.367 mmol). The reaction mixture was heated at 120 ℃ for 2.5 hours. After this time, the reaction mixture was quenched with water and extracted 2 times with EtOAc. The organics were combined and washed with water, then brine, Na₂SO₄Dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂In CH₂Cl₂10-100% MeOH) was used to purify the residue, which was then triturated in hot MeOH to afford example 85(40 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

examples 92 to 94, Table 1

Method 23

5- (4- { (R) -1-cyclopropyl-1- [5- (3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyrazinyl-5' -yl) - [1, 2, 4]Diazol-3-yl]Synthesis of (E) -Ethyl) -phenyl) -pyrazin-2-ylamine (example 195, Table 1)

Step 1:

to cold (0 ℃) methanol (20ml) was added 1ml acetyl chloride (dropwise). After the addition was complete, I-83(350mg, 0.61mmol) was added as a methanol solution (5 ml). Gradually warm to room temperature and stir overnight. Thereafter, the reaction was basified using 7N ammonia and concentrated to dryness. The remaining residue was purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to afford I-135.

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

the following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 214, Table 1-purification of crude by flash chromatography (silica gel, 0-100% MeOH/DCM)

Example 267, Table 1

Example 268, Table 1-concentrate the crude to dryness and purify it by flash chromatography (silica gel, 0-10% MeOH/DCM, 0.5% NH)₄OH) to purify the crude.

Step 2:

using ChiralPakAn AD-H column (3.0X 25.0cm, available from Chiral Technologies, West Chester PA) was used to perform the Chiral resolution of I-135. Elution with methanol/IPA containing 1% isopropylamine (1: 3) at 150 bar afforded example 195(6 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 196, Table 1-chiral resolution at 125psi

Example 210, Table 1-chiral resolution at 125psi without isopropylamine in the eluate

Method 24

1- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1, 2-dimethyl-propyl } - [1, 2, 4]Synthesis of oxadiazol-5-yl) -2-methyl-propan-2-ol (example 225, Table 1)

To a suspension of R-13(118mg, 1.0mmol) in THF (10ml) was added 1, 1' -carbonyldiimidazole (162mg, 1.0mmol) at room temperature. The mixture was stirred at 50 ℃ for 30 minutes. Thereafter I-21(200mg, 0.67mmol) was added and the resulting mixture was heated at reflux for 3 hours. After this time the reaction was cooled to room temperature, treated with HOAc (1ml) and warmed to 80 ℃. After stirring for 3 days, the mixture was cooled to room temperature and concentrated. The remaining residue was purified by flash chromatography (silica gel, 0-8% MeOH/DCM) to give the title compound (80 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 229, Table 1-No AcOH addition to the reaction mixture

Example 232, Table 1-No AcOH addition to the reaction mixture

Method 25

5- (4- { 1-cyclopropyl-1- [5- (3-oxetan-3-yl-3H-imidazol-4-yl) - [1, 2, 4]Diazol-3-yl]-ethyl } -phenyl) -pyrimidin-2-ylamine (example 206,synthesis of Table 1)

5- (4- { 1-cyclopropyl-1- [5- (1-oxetan-3-yl-1H-imidazol-4-yl) - [1, 2, 4%]Diazol-3-yl]Synthesis of (E) -Ethyl } -phenyl) -pyrimidin-2-ylamine (example 207, Table 1)

To a suspension of 1-trityl-1H-imidazole-4-carboxylic acid (893mg, 2.5mmol) in THF (10mL) at rt was added 1, 1' -carbonyldiimidazole (409mg, 2.5 mmol). The mixture was stirred at 50 ℃ for 30 minutes. A suspension of I-23(500mg, 1.7mmol) in THF (5mL) was added to the above mixture and the resulting mixture was heated in a microwave reactor at 130 ℃ for 2 hours. The mixture was cooled and concentrated in vacuo. By H₂The residue was extracted with O (10mL) and EtOAc (20 mL). With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and subjected to flash column chromatography on silica gel using the solvent in CH₂Cl₂The residue was purified with 10% MeOH in eluent to give I-144(150 mg); m/z 374[ M-trityl ]]. To a solution of I-144(80mg, 0.13mmol) in CH at room temperature₂Cl₂To a solution in (10mL) was added TFA (0.015mL, 0.19 mmol). The solution was stirred at the same temperature for 24 hours. The solution was concentrated under vacuum to give I-145(48 mg); m/z 374[ M + H]。

To a round-bottomed flask were added I-145(100mg, 0.27mmol), 3-iodooxetane (98mg, 0.54mmol) and K in DMF (10mL)₂CO₃(111mg, 0.8 mmol). The reaction mixture was stirred at 80 ℃ for 12 hours. The reaction was cooled and water (10mL) was added. With EtOAc (20mL) and H₂O (10mL) extract solution. With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel using 10% MeOH in TBME as eluent to give the title compound (example 206: 8 m)g; example 207: 10 mg).

Method 26

2- [4- (3- {1- [4- (2-amino-4-fluoro-pyrimidin-5-yl) -phenyl ] -amide derivatives]-1-cyclopropyl-ethyl } - [1, 2, 4]IIAzol-5-yl) -pyrazol-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide (example 275, Table 1)

To a solution of I-69(300mg, 0.6mmol) in DMF (10mL) were added I-87(140mg, 0.7mmol), tetrakis (triphenylphosphine) palladium (0) (70mg, 0.06mmol) and 2M Na₂CO₃(1.5mL, 3.0 mmol). The mixture was heated to 100 ℃ in a microwave reactor for 1 hour. The mixture was cooled and washed with H₂O (20mL) and EtOAc (30 mL). With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and subjected to flash column chromatography on silica gel using the solvent in CH₂Cl₂The residue was purified with 10% MeOH as eluent to give the title compound (200 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 175, Table 1-reaction at 120 ℃

Example 176-180, Table 1-reaction at 120 ℃ -

Example 184-185, Table 1-reaction at 120 ℃ -

Example 187-189, Table 1-reaction carried out at 120 ℃

Example 191, Table 1-reaction at 120 ℃

Example 239-

Example 244-

Example 247, Table 1-6 hours reaction at 100 ℃ in an oil bath

Example 249-250, Table 1-6 hours reaction at 100 ℃ in an oil bath

Example 251, Table 1-reaction at 85 ℃ overnight

Example 253, Table 1-6 hours reaction at 100 ℃ in an oil bath

Example 256, Table 1-6 hours reaction at 100 ℃ in an oil bath

Example 265, Table 1-6 hours reaction at 100 ℃ in an oil bath

Example 273, Table 1-6 hours reaction at 100 ℃ in an oil bath

Example 275, Table 1

Example 279, Table 1

Example 280-281, Table 1-reaction at 80 ℃ for 48 hours

Example 284-

Example 289, Table 1

Example 292, Table 1-reaction at 85 ℃ for 16 h

Example 293-

Example 298, Table 1

Method 27

2- [4- (3- { (R) -1- [4- (6-amino-pyridin-3-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]-N, N-dimethyl-acetamide (example 172, Table 1)

To a microwave vial was added I-63(100mg, 0.225mmol) in DMF (2ml) followed by 2-aminopyridine-5-boronic acid pinacol ester (55mg, 0.25mmol), tetrakis (triphenylphosphine) palladium (0) (26mg, 0.023mmol) and 2M Na₂CO₃Aqueous solution (0.4ml, 0.8 mmol). The reaction mixture was stirred in a microwave reactor at 120 ℃ for 1 hour. The residue was diluted with EtOAc, washed with water, brine, anhydrous Na₂SO₄Dried, filtered and concentrated. By flash chromatography (SiO)₂，0-5％MeOH/CH₂Cl₂) To purify the residue, the title compound (39mg) was obtained.

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 173-

Example 181, Table 1

Example 183, Table 1

Example 263, Table 1-reaction at 80 ℃ overnight

Method 28

5- (4- {1, 2-dimethyl-1- [5- (4-methylamino-piperidin-1-yl) - [1, 2, 4 ]]Diazol-3-yl]Synthesis of (propyl) -phenyl) -pyrimidin-2-ylamine (example 217, Table 1)

I-141(138mg, 0.265mmol) was dissolved in DCM (2mL) and added in 1, 4-bis4N HCl in alkane (0.663 m)L, 2.65mmol) and the reaction mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH and passed through PL-HCO₃MP-resin column to obtain free base product. The filtrate was concentrated in vacuo and the crude was purified by preparative TLC using 10% MeOH/DCM as solvent mixture to give the title compound (71 mg); m/z422.4[ M +1]]。

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 222, Table 1

Method 29

2- [4- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl ] -amide derivatives]-1, 2-dimethyl-propyl } - [1, 2, 4]Oxadiazol-5-yl) -piperazin-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide (example 193, Table 1)

2- [4- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl ] -amide derivatives]-1, 2-dimethyl-propyl } - [1, 2, 4]Oxadiazol-5-yl) -piperazin-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide

The synthesis was performed using appropriate reagents under similar conditions as used in method 9.

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

the following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 211, Table 1

Method 30

1- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1, 2-dimethyl-propyl } - [1, 2, 4]Synthesis of oxadiazol-5-yl) -piperidine-4-carboxylic acid (example 219, Table 1)

Synthesis was performed using appropriate reagents under conditions similar to those used in step 2 of method 14; m/z 437.4[ M +1 ]. The compound was purified by trituration in hot MeOH.

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 272, Table 1

Method 31

1- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1, 2-dimethyl-propyl } - [1, 2, 4]Synthesis of oxadiazol-5-yl) -3-methyl-azetidin-3-ol (example 203, Table 1)

1- {3- [1- (4-bromo-phenyl) -1, 2-dimethyl-propyl]-[1，2，4]Synthesis of oxadiazol-5-yl } -azetidin-3-ones

Synthesis was performed using appropriate reagents under similar conditions as used in step 3 of method 21; m/z 364[ M + H ].

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

1- {3- [1- (4-bromo-phenyl) -1, 2-dimethyl-propyl]-[1，2，4]Synthesis of oxadiazol-5-yl } -3-methyl-azetidin-3-ol

To a cooled solution of I-147(132.6mg, 0.364mmol) in THF (1mL) was added 3M methylmagnesium chloride in THF (0.485mL, 1.456mmol) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 10 minutes and then at room temperature for 20 minutes. After this time, the reaction mixture was quenched with water and extracted 2 times with EtOAc. The organics were combined and washed with brine, Na₂SO₄Dried, filtered and concentrated in vacuo to give the title compound (122 mg); m/z 380[ M + H ]]。

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

1- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1, 2-dimethyl-propyl } - [1, 2, 4]Oxadiazol-5-yl) -3-methyl-nitrogenSynthesis of heterocyclic butan-3-ols

The synthesis was performed using appropriate reagents under similar conditions as used in step 4 of method 21.

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 216, Table 1

Example 238, Table 1

Example 276, Table 1

Method 32

2- [4- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl ] -amide derivatives]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -piperazin-1-yl]Synthesis of ethanol (example 252, Table 1)

3- [1- (4-bromo-phenyl) -1-cyclopropyl-ethyl]-[1，2，4]Synthesis of diazol-5-ol

Synthesis was performed using appropriate reagents under conditions similar to those used in step 1 of method 21; m/z 307[ M + H ].

3- [1- (4-bromo-phenyl) -1-cyclopropyl-ethyl]-5-chloro- [1, 2, 4]Synthesis of diazoles

To a solution of I-149(847mg, 2.74mmol) in DCM (8mL) in a microwave vial was added POCl₃(0.401mL, 4.384mmol) and pyridine (1.107mL, 13.7 mmol). The reaction mixture was heated in a microwave oven at 120 ℃ for 1 hour. After that time, the user can select the desired position,quench the reaction mixture with water and CH₂Cl₂The extraction was performed 2 times. The organics were combined and washed with brine, Na₂SO₄Dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂6-50% EA/Hep) to yield the title intermediate (694 mg).¹H-NMR：(DMSO-d6)δppm 7.5(2H，d)，7.3(1H，d)，1.5(1H，m)，1.4(3H，s)，0.6(1H，m)，0.5(1H，m)，0.4(1H，m)，0.3(1H，m)。

2- (4- {3- [1- (4-bromo-phenyl) -1-cyclopropyl-ethyl]-[1，2，4]Synthesis of oxadiazol-5-yl } -piperazin-1-yl) -ethanol

Synthesis was performed using appropriate reagents under conditions similar to those used in step 3 of method 21; m/z421/423[ M/M +2H ].

2- [4- (3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl ] -amide derivatives]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -piperazin-1-yl]-Synthesis of ethanol

In a microwave vial to I-151(193mg, 0.458mmol) and Pd (PPh)₃)₄(53mg, 0.046mmol) to the mixture was added a solution of 2-aminopyrimidine-5-boronic acid pinacol ester (121.6mg, 0.55mmol) in DMF (5mL) and 2M Na₂CO₃Aqueous solution (0.92 mL). The reaction mixture was purged with Ar and then heated in a microwave oven at 110 ℃ for 45 minutes. After this time, the reaction mixture was quenched with water and extracted 2 times with EtOAc. The organics were combined and washed with brine, Na₂SO₄Dried, filtered and concentrated in vacuo. By flash chromatography (SiO)₂1.2-10% MeOH/DCM) to give the title compound (83 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 204-

Example 248, Table 1

Example 252, Table 1

Example 259, Table 1

Example 274, Table 1

Example 287-

Example 297, Table 1

Method 33

1- (3- { (R) -1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1, 2-dimethyl-propyl } - [1, 2, 4]Oxadiazol-5-yl) -piperidin-4-ol (example 223, Table 1) and 1- (3- { (S) -1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1, 2-dimethyl-propyl } - [1, 2, 4]Synthesis of oxadiazol-5-yl) -piperidin-4-ol (example 224, Table 1)

By HPLC on a RegisPak (from Regis Technologies, Morton Grove, Ill.) semi-preparative (30X 250mm) column (on a CO. sup. TM.) at 100 bar₂Example 223 and example 224 were prepared by resolving example 262(90.3mg) on 35% 1: 1MeOH in isopropanol containing 0.1% isopropylamine). The faster eluting enantiomer example 223 had a retention time of 2.07 minutes (RegisPack 4.6x 100mm, available from Regis Technologies, Morton Grove, IL) and the slower eluting enantiomer example 224 had a retention time of 2.68 minutes. The eluate was concentrated to give example 223(36mg) and example 224(34 mg).

The method 34 comprises the following steps:

5-[4- ((R) -1-cyclopropyl-1- {5- [1- (2-dimethylamino-ethyl) -1H-pyrazol-4-yl]-[1，2，4]Oxadiazolyl-ethyl-phenyl]Synthesis of (E) -pyrimidin-2-ylamine (example 182, Table 1)

Using (2-chloro-ethyl) -dimethyl-amine hydrochloride (43.4mg, 0.301mmol), Cs₂CO₃Example 48(75.0mg, 0.201mmol) was treated (147mg, 0.452mmol) with DMF (1.5mL) and the resulting mixture was stirred at 60 ℃ for 1 h. Thereafter, with (2-chloro-ethyl) -dimethyl-amine hydrochloride (14.5mg, 0.100mmol), Cs₂CO₃(32.7mg, 0.100mmol) and stirred for more than 1 hour. The reaction was then directly purified by flash chromatography on C-18 silica gel eluting with 10-60% acetonitrile/water/0.1% trifluoroacetic acid. By CH₂Cl₂And saturated NaHCO₃The resulting semi-pure material was treated with an aqueous solution and the phases were separated. Reuse of CH₂Cl₂The resulting aqueous phase was extracted 5 times and Na was added₂SO₄The combined organic phases were dried, filtered, and concentrated in vacuo to give a residue, which was purified by preparative TLC using 8% methanol/CH₂Cl₂This was further purified by elution to give the title compound (35.0 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 215, Table 1

The method 35 comprises the following steps:

2- [4- (3- { (R) -1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]-1- ((R) -3-methoxy-pyrrolidin-1-yl) -ethylSynthesis of ketones (example 220, Table 1)

[4- (3- { (R) -1- [4- (2-amino-pyrimidin-5-yl) -phenyl ] -amide]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]Synthesis of ethyl acetate

Example 48 was alkylated according to method 9; m/z 460[ M + H ].

[4- (3- { (R) -1- [4- (2-amino-pyrimidin-5-yl) -phenyl ] -amide]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]-Synthesis of acetic acid

Hydrolysis of I-152 according to the final step of method 16; m/z 432[ M + H ].

I-153(94.0mg, 0.218mmol) was treated with (R) -3-methoxy-pyrrolidine (33.1mg, 0.327mmol), HATU (125mg, 0.327mmol), DIEA (114. mu.L, 0.654mmol) and DMF (1.50mL) and the resulting mixture was stirred for 1 h. The reaction was directly purified by reverse phase preparative HPLC eluting with 30-70% acetonitrile/water/0.1% formic acid to give the title compound (16.0 mg).

The following compounds were synthesized in an analogous manner from the appropriate intermediates:

example 194, Table 1

Example 221, Table 1

Method 36

2- [4- (3- { (R) -1- [4- (2-amino-6-oxo-1, 6-dihydro-pyrimidin-5-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide (example 197, Table 1)

I-97(170mg, 0.30mmol) was dissolved in ethanol (10ml) and treated with Poelman's catalyst (palladium hydroxide, 35mg, 50% humidity, 0.12 mmol). The vessel was degassed and placed under hydrogen (balloon). After the conversion was complete, the reaction was filtered through a pad of celite and the solid was washed with methanol. The combined filtrates were concentrated and the residual crude was purified by flash column chromatography (0-10% MeOH/DCM) to give the title compound (100 mg).

Method 37

5- [4- ((R) -1- {5- [1- (2-amino-ethyl) -1H-pyrazol-4-yl]-[1，2，4]Oxadiazol-3-yl } -1-cyclopropyl-ethyl) -phenyl]Preparation of-pyrimidin-2-ylamine (example 190, Table 1).

Intermediate I-98(120mg, 0.22mmol) was treated with ethanol (2.7mL) and THF (0.5mL), followed by the addition of hydrazine (97mg, 1.93 mmol). The resulting mixture was stirred at 50 ℃ for 2 hours. The resulting mixture was filtered, washed with ethanol, diluted with ethyl acetate and water, and the phases were separated. The organic phase is washed with brine, Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC eluting with 10-80% acetonitrile/water/trifluoroacetic acid to give the title compound (33.0 mg).

Method 38

2- [4- (3- {1- [4- (2-amino-6-fluoro-pyridin-3-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]IIAzol-5-yl) -pyrazol-1-yl]-N, N-dimethyl-acetamide (example 277, Table 1) and 2- [4- (3- {1- [4- (6-amino-2-fluoro-pyridin-3-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide (example 278, Table 1)

To a solution of I-69(300mg, 0.68mmol) in 1, 4-bisTo a mixture of alkanes (10mL) were added 2, 6-difluoropyridine-3-boronic acid (128mg, 0.81mmol) and PdCl₂(PPh₃)₂(47mg, 0.068mmol) and 2MNa₂CO₃Solution (2M aqueous solution) (1mL, 02 mmol). The mixture was heated to 100 ℃ in a microwave reactor for 1 hour. The solution was cooled and washed with H₂O and EtOAc extraction. With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and subjected to flash column chromatography on silica gel using the solvent in CH₂Cl₂The residue was purified with 10% MeOH as eluent to give I-154(200mg) (M/z 479.2[ M + + H ]])。

I-154(150mg, 0.31mmol) was dissolved in NH in MeOH₃(2M solution) (10mL) and the solution was heated to 100 ℃ for 72 hours. The solution was cooled and concentrated. The residue was purified by preparative silica gel TLC to give the title compound (example 277: 10 mg; example 278: 14mg)

Method 39

2-[4-(3-{1-[4-(5-Amino-3-cyano-pyrazin-2-yl) -phenyl]-1-cyclopropyl-ethyl } - [1, 2, 4]Oxadiazol-5-yl) -pyrazol-1-yl]Synthesis of (E) -N, N-dimethyl-acetamide (example 295, Table 1)

To a solution of I-69(100mg, 0.2mmol) in DMF was added 2-amino-5-bromo-6-chloropyrazine (51mg, 0.24mmol), tetrakis (triphenylphosphine) palladium (0) (24mg, 0.02mmol) and 2M Na₂CO₃Solution (2M aqueous solution) (0.5mL, 1 mmol). The mixture was heated to 100 ℃ in a microwave reactor for 1 hour. The mixture was cooled and washed with H₂O and EtOAc extraction. With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and subjected to flash column chromatography on silica gel using the solvent in CH₂Cl₂The residue was purified with 10% MeOH as eluent to give I-155(86mg) (M/z 493.2[ M ]⁺+H])。

I-155(80mg, 0.16mmol) was dissolved in DMF (8mL) in a microwave reaction vessel. Zinc cyanide (23mg, 0.19mmol) and Pd (PPh) were added₃)₄(18mg, 0.016mmol) and the solution was heated to 120 ℃ in a microwave for 2 hours. The solution was cooled and poured into water and the product was extracted into EtOAc. With MgSO₄The combined organics were dried, filtered and concentrated. By silica gel flash column chromatography using the buffer in CH₂Cl₂The residue was purified with 10% MeOH as eluent to give the title compound (38 mg).

Method 40

2- [4- (3- {1- [4- (6-amino-2-cyano-pyridin-3-yl) -phenyl]-1-cyclopropyl-ethyl } -1, 2, 4]IIAzol-5-yl) -pyrazol-1-yl]-N, N-dimethylSynthesis of-acetamide (example 296, Table 1)

To a solution of 2-bromo-6-aminopyridine (200mg, 1.2mmol) in DMF (10mL) at room temperature was added Zn (CN)₂(163mg, 1.4mmol) and Pd (PPh)₃)₄(134mg, 0.12 mmol). The solution was heated in a microwave reactor at 120 ℃ for 2 hours. The solution was cooled and water was added. The solution was extracted with EtOAc and MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and subjected to flash column chromatography on silica gel using the solvent in CH₂Cl₂The residue was purified with 10% MeOH in (K) as eluent to give I-156(54mg) (M/z: 119.9[ M ]⁺])。

To I-156(54mg, 0.46mmol) of CH at room temperature₃NBS (162mg, 0.9mmol) was added to a CN (10mL) solution. The solution was stirred at the same temperature for 12 hours. Concentrating the solution and subjecting to flash column chromatography on silica gel using the solution in CH₂Cl₂The residue was purified with 10% MeOH as eluent to give I-157(35mg) (M/z: 197.9[ M ]⁺])。

To a solution of I-69(50mg, 0.1mmol) in DMF (8mL) were added I-157(24mg, 0.12mmol), tetrakis (triphenylphosphine) palladium (0) (11mg, 0.01mmol) and 2M Na₂CO₃(0.25mL, 0.51 mmol). The mixture was heated to 100 ℃ in a microwave reactor for 1 hour. The mixture was cooled and washed with H₂O and EtOAc extraction. With MgSO₄The combined organic layers were dried and filtered. The filtrate was concentrated and subjected to flash column chromatography on silica gel using the solvent in CH₂Cl₂The residue was purified with 10% MeOH as eluent to give the title compound (26 mg).

The method 41 comprises the following steps:

3- {1- [4- (2-amino-pyrimidin-5-yl) -phenyl]-1, 2-dimethyl-propyl } - [1, 2, 4]Synthesis of oxadiazol-5-ol (example 88, Table 1)

To a suspension of morpholine-4-carbonyl chloride (32.907mg, 0.220mmol) in DMF (1ml) was added I-21(60.000mg, 0.200 mmol). The reaction mixture was stirred at room temperature for 20 minutes, then Hunig's base (0.038mL, 0.22mmol) was added and the reaction mixture was heated at 55 ℃ for 1 hour and then in a microwave oven at 150 ℃ for 30 minutes. Thereafter, the reaction mixture was concentrated in vacuo. By flash chromatography (SiO)₂0-10% MeOH in DCM), then the crude was purified by preparative TLC (10% MeOH in DCM) to give example 88(23mg) as a white solid; m/z 326.0[ M + H ]]。

(ii) a final compound; TABLE 3

Evaluation of biological Properties

1. Binding assays

Measurement of iodination in scintillation proximity assay format (¹²⁵I) The ability of a compound to bind FLAP is assessed in a binding assay for compound-specific displacement of FLAP inhibitors (the scintillation proximity assay format is adapted from s. charles et al, mol. pharmacol, 1992, 41, 873-879). Cell pellets prepared from sf9 insect cells expressing recombinant human FLAP protein were resuspended in buffer A [15mM Tris-HCl (pH 7.5), 2mM MgCl₂、0.3mM EDTA、1mM PMSF]In (1). These cells were lysed using a Dounce homogenizer and the material was centrifuged at 10,000x g for 10 minutes. The supernatant was then collected and centrifuged at 100,000x g for 60 minutes. To prepare the membrane proteins for analysis, an aliquot of 100,000x g particles was resuspended in 1ml buffer A, subjected to Dounce homogenization, and finally advancedLine homogenizer (polytron) mixing (30 seconds). Membrane proteins (25. mu.l, 5. mu.g) were mixed with WGA SPA beads (Amersham) and stirred for 1 hour. To an assay plate (Perkin Elmer FlexiPlate) 25. mu.l of test compound (in binding buffer [100mM Tris (pH 7.5), 140mM NaCl, 5% glycerol, 2mM EDTA, 0.5mM TCEP, 0.05% Tween 20)]Prepared in (1), 25. mu.l¹²⁵I]L-691, 831 (iodinated analogue of MK-591, Charleson et al, mol. Pharmacol., 41, 873-879, 1992) and finally 50. mu.l of bead/protein mixture was added. (final concentration: bead: 200. mu.g/well; protein: 5. mu.g/well;)¹²⁵I]Probe, 0.08 nM/well (17 nCi/well). The plates were shaken for 2 hours before being read on a Microbeta plate reader. Nonspecific binding was determined by adding 10. mu.M cold L-691, 831 compound.

In general, the preferred potency range (IC) of the compounds in the above assays₅₀) Between 0.1nM and 10. mu.M, more preferably in the range of 0.1nM to 1. mu.M, and most preferably in the range of 0.1nM to 100 nM.

2. Whole blood analysis:

in addition, compounds were tested in human whole blood assays to determine their inhibition of LTB in the cellular system₄The ability to synthesize. Compounds were mixed with heparinized human whole blood and incubated at 37 ℃ for 15 minutes. Then calicheamicin (Calcimycin) (final concentration 20 μ M, prepared in phosphate buffered saline, pH 7.4) was added and the mixture was incubated for another 30 minutes at 37 ℃. The sample was centrifuged at low speed (1500x g) for 5 minutes and the plasma layer discarded. Plasma LTB was then measured using antibody-based homogeneous time-resolved fluorescence₄Concentration (CisBio, Bedford, MA).

Application method

The compounds of the present invention are potent inhibitors of 5-lipoxygenase activating protein (FLAP) and thus are shown to inhibit leukotriene production. Accordingly, in one embodiment of the present invention, there is provided a method of treating leukotriene-mediated disorders using a compound of the invention or a pharmaceutically acceptable salt thereof. In another embodiment, methods of treating cardiovascular, inflammatory, allergic, pulmonary, and fibrotic diseases, renal diseases, and cancer using a compound of the invention or a pharmaceutically acceptable salt thereof are provided.

Without wishing to be bound by theory, the compounds of the present invention block the production of LT by 5-LO oxidation of arachidonic acid and subsequent metabolism by inhibiting FLAP activity. Thus, inhibition of FLAP activity is an attractive means for the prevention and treatment of various LT-mediated diseases. These diseases include:

cardiovascular disease conditions including atherosclerosis, myocardial infarction, stroke, aortic aneurysm, sickle cell crisis, ischemia-reperfusion injury, pulmonary hypertension and sepsis;

allergic diseases including asthma, allergic rhinitis, sinusitis, atopic dermatitis and urticaria;

fibrotic diseases including asthma airway remodeling, 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, inflammatory pain, multiple sclerosis, systemic lupus erythematosus, transplant rejection, inflammatory and allergic eye diseases;

cancer, including solid tumors, leukemias, and lymphomas; and

kidney diseases, such as glomerulonephritis.

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

General administration and pharmaceutical compositions

When used as a pharmaceutical article, the compounds of the present invention are typically administered in the form of a pharmaceutical composition. These compositions may be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the present invention. The compounds of the present invention may also be administered alone or in combination with adjuvants which enhance the stability of the compounds of the present invention, facilitate in certain embodiments the administration of pharmaceutical compositions containing them, promote dissolution or dispersion, elevate antagonist activity, provide adjuvant therapy and the like. The compounds of the invention can be used alone or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances. In general, the compounds of the present invention may be administered in a therapeutically or pharmaceutically effective amount, but may be administered in lower amounts for diagnostic or other purposes.

The compounds of the present invention may be administered in pure form or in the form of a suitable pharmaceutical composition using any of the recognized modes of administration of pharmaceutical compositions. Thus, they may be in solid, semi-solid, lyophilized powder or liquid dosage forms (such as tablets, suppositories, pills, soft and hard gelatin capsules, powders, solutions, suspensions or aerosols or the like), preferably administered in unit dosage forms suitable for convenient administration of precise dosages, for example oral, buccal (e.g. sublingual), nasal, parenteral, topical, transdermal, vaginal or rectal administration. These pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the active agent, and may include, in addition, other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof. These pharmaceutically acceptable excipients, carriers or additives and the preparation of pharmaceutical compositions suitable for various modes of administrationMethods for preparing such compounds are well known to those skilled in the art. The prior art is confirmed, for example, by the following: remington: the Science and Practice of Pharmacy, 20^th Edition，A.Gennaro(ed.)，Lippincott Williams & Wilkins，2000；Handbook of PharmaceuticalAdditives，Michael & Irene Ash(eds.)，Gower，1995；Handbook of PharmaceuticalExcipients，A.H.Kibbe(ed.)，American Pharmaceutical Ass′n，2000；H.C.Anseland N.G.Popovish，Pharmaceutical Dosage Forms and Drug Delivery Systems 5^thed., Lea and Febiger, 1990; the entire contents of each of these documents are incorporated herein by reference in order to better illustrate the prior art.

As one skilled in the art would appreciate, the form (e.g., salt) of the compounds of the present invention employed in a particular pharmaceutical formulation should be selected to have suitable physical characteristics (e.g., water solubility) to effectively effect formulation.

Claims (25)

1. A compound of formula I

Wherein:

R¹and R²Each independently is hydrogen, C_1-7Alkyl or C_3-10A carbocyclic ring, provided that R is¹And R²Both are not hydrogen at the same time;

R³is selected from 1 to 3A 5-to 11-membered heteroaryl ring of heteroatoms of nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is optionally independently substituted with 1 to 3 groups selected from: c optionally substituted by 1 to 3 halogen atoms_1-5Alkyl radical, C_1-5Alkoxy radical, C_1-3Hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C_3-6Carbocyclic ring, C_1-6Alkylamino and di-C_1-3An alkylamino group;

R⁴is hydrogen, C_1-3Alkyl, halogen or nitrile;

R⁵is C_1-6Alkyl radical, C_3-10Carbocycle, 3-to 11-membered heterocycle, aryl, 5-to 11-membered heteroaryl, -C (O) -R⁶Hydroxy or-NR⁷R⁸Wherein each R is⁵Optionally independently through 1 to 3 substituents selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁶is C_3-8Heterocycle or-NH-5 to 6 membered heterocycle, each optionally independently selected from R1 to 3⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁷and R⁸Each independently of the others is hydrogen, optionally via C_1-6Alkyl-substituted 5-to 6-membered heterocycle, C optionally substituted by hydroxy_3-10Carbocyclic ring, or C_1-6An alkyl group;

R⁹、R¹⁰and R¹¹Is independently selected from

(a)-H，

(b)-OH，

(c) The halogen(s) are selected from the group consisting of,

(d)-CN，

(e)-CF₃，

(f) c optionally substituted by 1 to 3 groups_1-6Alkyl groups: -OH, -N (R)¹²)(R¹³) 3-to 6-membered heterocycle, C_1-6Alkoxy radical, C_1-6alkoxy-O-C_1-6Alkyl, -CO₂R¹²、-C(O)N(R¹²)(R¹³) or-S (O)_nC_1-6An alkyl group, a carboxyl group,

(g)C_1-6an alkoxy group,

(h)-N(R¹²)(R¹³)，

(i)-S(O)_nC_1-6an alkyl group, a carboxyl group,

(j)-CO₂R¹²，

(k)-C(O)N(R¹²)(R¹³)，

(l)-S(O)₂N(R¹²)(R¹³)，

(m) optionally via 1 to 3C_1-6An alkyl-substituted 3-to 10-membered heterocyclic group,

(n ') an oxo group, and (n'),

(o)-C(O)-C_1-3an alkyl group;

R¹²and R¹³Each independently selected from-H, -C_1-6Alkyl, C (O) C_1-6Alkyl and a 3-to 6-membered heterocyclic group, each of which is optionally independently substituted with 1 to 3 of the following groups: c_1-6Alkyl, -OH, C_1-6Alkoxy, -C (O) N (R)¹⁴)(R¹⁵)、-S(O)_nC_1-6Alkyl, CN, 3-to 6-membered heterocyclic group, -OC_1-6Alkyl, CF₃Or;

R¹²and R¹³Together with the nitrogen ring to which they are attached form an optionally substituted 1 to 3-OH, CN, -OC_1-6An alkyl or oxo substituted heterocyclyl ring;

R¹⁴and R¹⁵Each independently selected from-H and-C_1-6An alkyl group;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

R¹and R²Each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, with the proviso that R is¹And R²Both are not hydrogen at the same time;

R³is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, thienyl, furyl or thiazolyl, wherein each heteroaryl ring is optionally independently substituted with 1 to 3 groups selected from: optionally taken via 1 to 3 halogen atomsSubstituted C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C_3-6Carbocyclic ring, C_1-6Alkylamino and di-C_1-3An alkylamino group;

or R³Is pyridoAzinyl, dihydro-pyrido(ii) an oxazinyl group, a dihydro-pyrrolopyridyl group, a pyrrolopyrazinyl group, wherein each heteroaryl ring is optionally independently substituted with 1 to 3 groups selected from: c optionally substituted by 1 to 3 halogen atoms_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C_3-6Carbocyclic ring, C_1-3Alkylamino and di-C_1-3An alkylamino group;

R⁴is hydrogen, methyl or fluorine;

R⁵is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, pyrrolyl, thienyl, furyl, thiazolyl, thienyl, or the like,Azolyl radical, isoOxazolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, pyrrolopyridyl, pyrrolopyrimidinyl, -C (O) -R⁶Hydroxy or-NR⁷R⁸Wherein each R is⁵Optionally independently through 1 to 3 substituents selected fromR⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁶is piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or-NH-piperidinyl, each optionally independently selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁷and R⁸Each independently hydrogen, an optionally methyl-substituted 5-to 6-membered heterocycle, optionally hydroxy-substituted C_3-6Carbocyclic ring, or C_1-5An alkyl group;

R⁹、R¹⁰and R¹¹Is independently selected from

(a)-H，

(b)-OH，

(c) The halogen(s) are selected from the group consisting of,

(d)-CN，

(e)-CF₃，

(f) c optionally substituted by 1 to 3 groups_1-6Alkyl groups: -OH, -N (R)¹²)(R¹³) 3-to 6-membered heterocycle, C_1-6Alkoxy radical, C_1-6alkoxy-O-C_1-6Alkyl, -CO₂R¹²、-C(O)N(R¹²)(R¹³) or-S (O)_nC_1-6An alkyl group, a carboxyl group,

(g)C_1-6an alkoxy group,

(h)-N(R¹²)(R¹³)，

(i)-S(O)_nC_1-6an alkyl group, a carboxyl group,

(j)-CO₂R¹²，

(k)-C(O)N(R¹²)(R¹³)，

(l)-S(O)₂N(R¹²)(R¹³)，

(m) optionally via 1 to 3C_1-6An alkyl-substituted 3-to 8-membered heterocyclic group,

(n ') an oxo group, and (n'),

(o)-C(O)-C_1-3an alkyl group;

R¹²and R¹³Each independently selected from-H, -C_1-6Alkyl, C (O) C_1-6Alkyl and a 3-to 6-membered heterocyclic group, each of which is optionally independently substituted with 1 to 3 of the following groups:C_1-6alkyl, -OH, C_1-6Alkoxy, -C (O) N (R)¹⁴)(R¹⁵)、-S(O)_nC_1-6Alkyl, CN, 3-to 6-membered heterocyclic group, -OC_1-6Alkyl, CF₃(ii) a Or the like, or, alternatively,

R¹²and R¹³Together with the nitrogen ring to which they are attached may form an optionally substituted 1 to 3-OH, CN, -OC_1-6An alkyl or oxo substituted heterocyclyl ring;

R¹⁴and R¹⁵Each independently selected from-H and-C_1-4An alkyl group;

n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2, wherein:

R¹and R²Each independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl or cyclobutyl, with the proviso that R¹And R²Both are not hydrogen at the same time;

or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein: r³Is pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each heteroaryl ring is optionally independently substituted with 1 to 2 groups selected from: c optionally substituted by 1 to 3 halogen atoms_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Hydroxy, halogen, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C_3-6Carbocyclic ring, C_1-5Alkylamino and di-C_1-3An alkylamino group; or

R³Is pyridoAzinyl, dihydro-pyridoAzinyl, dihydro-pyrrolopyridinylPyrrolopyridinyl, pyrrolopyrazinyl;

or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein:

R⁵is methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolyl, cyclohexyl, or a salt thereof,Azolyl radical, isoOxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, -C (O) -piperazinyl, -C (O) -piperidinyl, -C (O) -morpholinyl, -C (O) -NH-piperidinyl, hydroxy or-NR⁷R⁸Wherein each R is⁵Optionally independently through 1 to 3 substituents selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁷and R⁸Each independently hydrogen, an optionally methyl-substituted 5-to 6-membered heterocycle, optionally hydroxy-substituted C_3-6Carbocyclic ring, or C₁-C₅An alkyl group;

R⁹、R¹⁰and R¹¹Is independently selected from

(a)-H，

(b)-OH，

(c) The halogen(s) are selected from the group consisting of,

(d)-CN，

(e)-CF₃，

(f) c optionally substituted by 1 to 3 groups_1-6Alkyl groups: -OH, -N (R)¹²)(R¹³) Morpholinyl, piperazinyl, C_1-6Alkoxy radical, C_1-3alkoxy-O-C_1-3Alkyl, -CO₂R¹²or-C (O) N (R)¹²)(R¹³)，

(g)C_1-3An alkoxy group,

(h)-N(R¹²)(R¹³)，

(i)-S(O)_nC_1-6an alkyl group, a carboxyl group,

(j)-CO₂R¹²，

(k)-C(O)N(R¹²)(R¹³)，

(l)-S(O)₂N(R¹²)(R¹³)，

(m) morpholinyl, piperazinyl, piperidinyl or oxetanyl, each optionally substituted with methyl,

(n ') an oxo group, and (n'),

(o)-C(O)-CH₃；

R¹²and R¹³Each independently selected from-H and-C_1-6Alkyl, wherein the alkyl is optionally substituted with 1 to 3-OH, C_1-6Alkoxy, -C (O) N (R)¹⁴)(R¹⁵) or-S (O)_nC_1-6Alkyl substitution;

R¹⁴and R¹⁵Each independently selected from-H and-C_1-4An alkyl group;

n is 2;

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 or 2, wherein:

R¹and R²Each independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl or cyclobutyl, with the proviso that R¹And R²Both are not hydrogen at the same time;

R³is pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein each heteroaryl ring is optionally independently substituted with 1 to 2 groups selected from: methyl, methoxy, -CH₂OH, trifluoromethyl, bromo, chloro, fluoro, hydroxy, -O-benzyl, oxo, cyano, amino, -NH-C_3-6Carbocyclic ring, C_1-4Alkylamino and di-C_1-3An alkylamino group; or

R³Is pyridoAzinyl, dihydro-pyrido(ii) an oxazinyl group, dihydro-pyrrolopyridinyl, pyrrolopyrazinyl group;

R⁴is hydrogen;

R⁵is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolyl, or a salt thereof,Azolyl radical, isoOxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, -C (O) -piperazinyl, -C (O) -morpholinyl, -C (O) -NH-piperidinyl, hydroxy or-NR⁷R⁸Wherein each R is⁵Optionally independently through 1 to 3 substituents selected from R⁹、R¹⁰And R¹¹Substituted with a group of (1);

R⁷and R⁸Each independently is hydrogen, piperidinyl optionally substituted with methyl, cyclohexyl optionally substituted with hydroxy, methyl or ethyl;

R⁹、R¹⁰and R¹¹Is independently selected from

(a)-H，

(b)-OH，

(c) The halogen(s) are selected from the group consisting of,

(d)-CN，

(e)-CF₃，

(f) c optionally substituted by 1 to 3 groups_1-6Alkyl groups: -OH, -N (R)¹²)(R¹³) Morpholinyl, piperazinyl, C_1-3Alkoxy radical, C_1-3alkoxy-O-C_1-3Alkyl, -CO₂H or-C (O) N (R)¹²)(R¹³)，

(g)C_1-3An alkoxy group,

(h)-N(R¹²)(R¹³)，

(i)-S(O)₂C_1-2an alkyl group, a carboxyl group,

(j)-CO₂R¹²，

(k)-C(O)N(R¹²)(R¹³)，

(l)-S(O)₂N(R¹²)(R¹³)，

(m) morpholinyl, piperazinyl or oxetanyl, each optionally substituted by methyl,

(n ') an oxo group, and (n'),

(o)-C(O)-CH₃；

R¹²and R¹³Each independently selected from-H and-C_1-6Alkyl, wherein the alkyl is optionally independently substituted with 1 to 3-OH, C_1-6Alkoxy, -C (O) N (R)¹⁴)(R¹⁵) or-S (O)₂C_1-6Alkyl substitution;

R¹⁴and R¹⁵Each independently selected from-H and-C_1-4An alkyl group;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein:

R¹is a methyl group, and the compound is,

R²selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl and cyclobutyl;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6, wherein: r³Is selected from

Or a pharmaceutically acceptable salt thereof.

9. The compound of claim 6, wherein:

R⁵is optionally independently selected from 1 to 3R⁹、R¹⁰And R¹¹Pyrazolyl substituted with a group of (a);

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 6, wherein:

R¹is a methyl group, and the compound is,

R²selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl and cyclobutyl;

R³is selected from

R⁴Is a hydrogen atom, and is,

R⁵is selected from

Or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10, wherein:

R²is cyclopropyl or cyclobutyl;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10, wherein:

R²selected from methyl, ethyl, isopropyl and tert-butyl;

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 6, wherein:

R³is selected from

Or a pharmaceutically acceptable salt thereof.

14. The compound of claim 6, wherein:

R³is selected from

Or a pharmaceutically acceptable salt thereof.

15. The compound of claim 10, wherein:

R¹is a methyl group, and the compound is,

R²is cyclopropyl;

R³is selected from

R⁴Is a hydrogen atom, and is,

R⁵is selected from

Or a pharmaceutically acceptable salt thereof.

16. A compound selected from:

or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 16, selected from:

or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 17 selected from:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or carrier.

20. A method of treating a leukotriene-mediated disorder comprising administering to a patient in need thereof an effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18.

21. The method of claim 20, wherein the leukotriene-mediated disorder is selected from cardiovascular, inflammatory, allergic, pulmonary, and fibrotic diseases, renal diseases, and cancer.

22. The method of claim 21, wherein the leukotriene-mediated disorder is atherosclerosis.

23. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use as a medicament.

24. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment of a leukotriene-mediated disorder.

25. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment of a leukotriene-mediated disorder selected from cardiovascular, inflammatory, allergic, pulmonary and fibrotic diseases, renal diseases and cancer.