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JP2014513687A - Pyridylaminopyridine as a Syk inhibitor - Google Patents
Pyridylaminopyridine as a Syk inhibitor Download PDF
mmol
アルトマン,マイケル,デイー
デイ・フランチエスコ,マリア・エミリア
ヘイドル,アンドリユー,エム
オツト,ライアン,デイー
エリス,ジヨン・マイケル
チヤイルダーズ,カリーン・コンラツド
ノースラツプ,アラン,ビー
ヤーン,リーピーン
メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp.
2012-05-04 Application filed by メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. filed Critical メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp.
C07D—HETEROCYCLIC COMPOUNDS
C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
The present invention provides novel pyrimidineamines of formula I that are potent spleen tyrosine kinase inhibitors and are useful for the treatment and prevention of diseases mediated by said enzymes, such as asthma, COPD, rheumatoid arthritis and cancer. .
Spleen tyrosine kinase (Syk) is a protein tyrosine kinase that has been described as a key mediator of immune receptor signaling in host inflammatory cells such as mast cells, B cells, macrophages and neutrophils. Such immunoreceptors, such as Fc receptors and B cell receptors, are important for both allergic and antibody-mediated autoimmune diseases, and thus, to the extent possible, due to Syk's pharmacological interference Such disorders can be treated.
Allergic rhinitis and asthma are diseases associated with hypersensitivity reactions and inflammatory events involving many cell types such as mast cells, eosinophils, T cells and dendritic cells. Upon exposure to allergens, high affinity immunoglobulin receptors for IgE and IgG become cross-linked and activate downstream processes in mast cells and other cell types, releasing pro-inflammatory mediators and airway spasmogen Bring. In mast cells, for example, when the IgE receptor is cross-linked by an allergen, release of mediators such as histamine from already formed granules, as well as newly synthesized lipid mediators such as prostaglandins and leukotrienes. Synthesis and release are provided.
Syk kinase is a non-receptor-bound tyrosine kinase that is important in the transmission of downstream intracellular signals associated with Fc ε RI and / or Fc ε RI receptor cross-linking, and exists early in this signaling cascade. In mast cells, for example, the initial sequence of Fc epsilon RI signaling after allergen was crosslinked to receptor -IgE complex, first Lyn (Src family tyrosine kinases) is then Syk is involved. Thus, inhibitors of Syk activity can be expected to inhibit all downstream signaling cascades, thereby alleviating immediate allergic reactions and adverse events caused by the release of pro-inflammatory mediators and spasmogens (Wong et al., 2004, Expert Opin.Investig.Drugs (2004) 13 (7) 743-762).
Recently, the Syk kinase inhibitor R112 (Rigel) has been shown to result in a statistically significant decrease in PGD 2 , a key immune mediator, when administered intranasally in Phase I / II trials for the treatment of allergic rhinitis. This is highly correlated with the improvement of allergic rhinorrhea and is safe within a range of indicators, and therefore the first evidence of clinical safety and efficacy of transsurface Syk kinase inhibitors is Obtained (Meltzer, Eli O .; Berkowitz, Robert B .; Grossbard, Elliott B, Journal of Allergy and Clinical Immunology (2005), 115 (4), 791-796). More recent phase II clinical trials for allergic rhinitis (Clinical Trials. Gov Identifier NCT0015089) have shown that R112 is less effective compared to placebo.
Rheumatoid arthritis (RA) is an autoimmune disease that affects approximately one percent of the population. It is characterized by consumable destruction of bone and cartilage due to inflammation of the joint joint. Recent clinical trials with rituximab leading to reversible B cell depletion (JCW Edwards et al. 2004, New Eng. J. Med. 350: 2572-2582) have shown that B cell function targeting It has been shown to be an appropriate therapeutic strategy in autoimmune diseases such as RA. Clinical benefit correlates with the reduction of autoreactive antibodies (or rheumatoid factors), which indicates that B cell function and indeed autoantibody production is central to the ongoing pathology of the disease Is suggested.
Studies with cells from mice deficient in spleen tyrosine kinase (Syk) showed a non-redundant role for this kinase in B cell function. Syk deficiency is characterized by blockage of B cell development (M. Turner et al. 1995 Nature 379: 298-302 and Cheng et al. 1995, Nature 378: 303-306). This test, along with tests on Syk-deficient mature B cells (Kurasaki et al. 2000, Immunol. Rev. 176: 19-29), shows that Syk is required for B cell differentiation and activation. Thus, inhibiting Syk in RA patients probably blocks B cell function, thereby reducing the production of rheumatoid factor. In addition to the role of Syk in B cell function, more important in the treatment of RA is a prerequisite for Syk activity in Fc receptor (FcR) signaling. It has been suggested that FcR activation by immune complexes in RA contributes to the release of many pro-inflammatory mediators.
U.S. Pat. No. 7,803,801 describes the formula:
(Wherein the variable part is as defined in the patent)
Syk inhibitors having the following are disclosed:
The present invention relates to novel compounds that are inhibitors of Syk kinase activity. Thus, this compound has potential therapeutic benefit in the treatment of disorders associated with inappropriate Syk activity, particularly in the treatment and prevention of disease states mediated by Syk. Such disease states include inflammatory, allergic and autoimmune diseases such as asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, clonal disease, bronchitis, Dermatitis, allergic rhinitis, psoriasis, scleroderma, hives, rheumatoid arthritis, idiopathic thrombocytopenic purpura (ITP), multiple sclerosis, cancer, HIV and lupus.
Wong et al. 2004, Expert Opin. Investig. Drugs (2004) 13 (7) 743-762 Meltzer, Eli O .; Berkowitz, Robert B .; Grossbard, Elliott B, Journal of Allergy and Clinical Immunology (2005), 115 (4), 791-796; J. et al. C. W. Edwards et al. 2004, New Eng. J. et al. Med. 350: 2572-2581 M.M. Turner et al. 1995 Nature 379: 298-302. Cheng et al. 1995, Nature 378: 303-306. Kurasaki et al. 2000, Immunol. Rev. 176: 19-29
The present invention provides novel compounds that are potent Syk inhibitors and pharmaceutical compositions comprising the compounds. The Syk inhibitor compounds of the present invention are useful for the treatment and prevention of diseases and disorders mediated by Syk protein; such diseases and disorders include, but are not limited to, asthma, COPD, rheumatoid arthritis, cancer and idiopathic. Thrombocytopenic purpura can be mentioned.
The present invention provides compounds of formula I:
(Wherein A is a carbocyclic ring or the moiety A- (R 7 ) n (R 8 ) is
Represents;
n is 0, 1, 2 or 3;
p and q are independently selected from 1, 2 and 3;
R 1 is C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl or C 1-4 alkoxy;
R 2 is H or halogen;
R 3 is H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 1-4 hydroxyalkyl;
R 5 is OH, C 1-4 alkoxy, halogen, NH 2 ; or N (H) (C 1-4 alkyl);
R 6 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 1-4 hydroxyalkyl; or R 7 is selected from OH and C 1-4 alkyl;
R 8 is, (CR a R b) n CO 2 R c, CONR d R e, tetrazolyl, OH, CH 2 OH, oxo, CN, is selected from NHCO 2 R f and NHSO 2 R f; R 8 And —C (R 5 ) (R 6 ) — are not bound to the same ring carbon atom;
R a and R b are each independently selected from H and methyl;
R c is H or C 1-4 alkyl;
R d and R e are each independently selected from H and C 1-4 alkyl;
R f is C 1-4 alkyl or benzyl)
Or a pharmaceutically acceptable salt thereof.
In a group of formula I are compounds wherein ring A is a carbocycle. In that subgroup, A is selected from C 3-6 cycloalkyl. In one embodiment, A is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a second embodiment, A is cyclohexyl.
In another group of formula I are compounds wherein R 1 is C 1-4 alkyl or C 1-4 fluoroalkyl. In that subgroup, R 1 is C 1-3 alkyl, such as methyl, ethyl, n-propyl or isopropyl. In its second subset, R 1 is C 1-3 fluoroalkyl, such as difluoromethyl or trifluoromethyl. In one embodiment, R 1 is methyl. In a second embodiment, R 1 is trifluoromethyl. In a third embodiment, R 1 is cyclopropyl.
In another group of formula I are compounds wherein R 2 is H or F.
In another group of formula I are compounds wherein R 3 is C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl. In that subgroup, R 3 is C 1-4 alkyl, C 1-4 fluoroalkyl or C 3-6 cycloalkyl. In one embodiment, R 3 is selected from methyl, difluoromethyl and cyclopropyl. In a second embodiment, R 3 is methyl.
In another group of formula I are compounds wherein R 5 is OH, C 1-4 alkoxy, halogen or NH 2 . In one embodiment, R 5 is OH.
In another group of formula I are compounds wherein R 6 is H, C 1-4 alkyl or C 1-4 haloalkyl. In that subgroup, R 6 is H, C 1-4 alkyl or C 1-4 fluoroalkyl. In another subgroup thereof, R 6 is selected from H, C 1-3 alkyl and fluoro-, difluoro- and trifluoromethyl. In one embodiment, R 6 is methyl.
In another group of formula I are compounds wherein A is a carbocycle and R 8 is selected from (CR a R b ) n CO 2 R c and C (O) NR d R e . In that subgroup, R 8 is selected from CO 2 R c and C (O) NR d R e . In one embodiment, A is C 3-6 cycloalkyl and R 8 is CO 2 R c . In a second embodiment, A is C 3-6 cycloalkyl and R 8 is C (O) NR d R e .
In another group of formula I:
Formula Ia:
Wherein A is a carbocycle;
n is 0, 1 or 2;
R 1 is C 1-4 alkyl or C 1-4 fluoroalkyl;
R 3 is H, C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl;
R 6 is H, C 1-4 alkyl or C 1-4 haloalkyl;
R 7 is C 1-4 alkyl;
R 8 is CO 2 R c or CONR d R e ;
R c is H or C 1-4 alkyl,
A compound or a pharmaceutically acceptable salt thereof.
In one group of formula Ia, R 3 is C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl. In another group thereof, R 3 is H, C 1-4 alkyl, C 1-4 fluoroalkyl or C 3-6 cycloalkyl. In another group R 3 is H, methyl, difluoromethyl and cyclopropyl. In one embodiment, R 3 is H or methyl.
In another group of formula Ia, R 6 is H, C 1-4 alkyl, C 1-4 fluoroalkyl or C 3-4 cycloalkyl.
In another group of formula Ia, R 3 is C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl;
R 6 is H, C 1-4 alkyl or C 1-4 haloalkyl.
Formula Ib:
Where n is 0, 1 or 2;
In one group of formula Ib, R 3 is C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl. In another group thereof, R 3 is H, C 1-4 alkyl, C 1-4 fluoroalkyl or C 3-6 cycloalkyl. In another group R 3 is H, methyl, difluoromethyl and cyclopropyl. In one embodiment, R 3 is H or methyl.
In another group of formula Ib, R 6 is H, C 1-4 alkyl, C 1-4 fluoroalkyl or C 3-4 cycloalkyl.
In another group of formula Ib, R 3 is C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl;
In certain embodiments of the compound having Formula Ib, the moiety
It has the following configuration.
Representative compounds of the invention are as follows, where each named compound is its individual isomer, mixture thereof (eg, racemic and diastereomeric mixtures), and pharmaceutically It is intended to include acceptable salts:
Trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1 -Hydroxypropyl] cyclohexanecarboxylic acid;
Trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1 -Hydroxypropyl] cyclohexanecarboxamide;
Trans-4- [1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl) -1- Hydroxyethyl] cyclohexanecarboxylic acid;
Trans-4- {1-hydroxy-1- [5- (6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl ] Ethyl} cyclohexanecarboxylic acid;
Trans-4- [1- (5- {6-[(5-Fluoro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl ) -1-hydroxyethyl] butyl cyclohexanecarboxylate;
Trans-4- [1- (5- {6-[(5-Fluoro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl ) -1-hydroxyethyl] cyclohexanecarboxylic acid;
1- [5- (4-Methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] -1- ( Pyrrolidin-3-yl) ethanol; and 3- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl ) -1,3-thiazol-2-yl] ethyl} pyrrolidine-1-carboxamide.
Trans-4- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazole -2-yl] ethyl} cyclohexanecarboxylic acid trans-4- [1-hydroxy-1- (5- {4-methyl-6-[(4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylic acid trans-4- [1-hydroxy-1- (5- {6-[(4-methoxypyridin-2-yl) amino] -4-methyl Pyridin-2-yl} -1,3-thiazol-2-yl) ethyl] butyl cyclohexanecarboxylate trans-4- [1-hydroxy-1- (5- {6-[(4-methoxypyridin-2-yl) Ami ] -4-Methylpyridin-2-yl} -1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylic acid trans-4- {1- [5- (6-{[4- (difluoromethyl) pyridine]- 2-yl] amino} -4-methylpyridin-2-yl) -1,3-thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylic acid trans-4- [1- (5- {6- [ (5-Chloro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid trans-4- [1- (5- {6-[(4-Cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] Siku Hexanecarboxylic acid butyl trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2- Yl) -1-hydroxyethyl] cyclohexanecarboxylic acid trans-4- {1-hydroxy-1- [5- (4-methyl-6-{[4- (propan-2-yl) pyridin-2-yl] amino } Pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid trans-4- [1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) ) Amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid 3- {1-hydroxy-1- [5- (4-methyl-) 6 {[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclopentanecarboxylic acid trans-4- {1-hydroxy-1 -[5- (4-Methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] propyl} cyclohexanecarboxylic acid Trans-4- {cyclopropyl (hydroxy) [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol- 2-yl] methyl} cyclohexanecarboxylic acid trans-4- {2,2,2-trifluoro-1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) ) Pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid trans-4- {1-hydroxy-1- [5- (4-methyl-) 6-{[4- (propan-2-yloxy) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] propyl} cyclohexanecarboxylic acid trans-4- {cyclopropyl (Hydroxy) [5- (4-methyl-6-{[4- (propan-2-yloxy) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] methyl } Cyclohexanecarboxylic acid trans-4- {2,2,2-trifluoro-1-hydroxy-1- [5- (4-methyl-6-{[4- (propan-2-yloxy) pyridine] 2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid trans-4- {hydroxy [5- (4-methyl-6-{[4- (tri Fluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] methyl} cyclohexanecarboxylate methyl trans-4- {hydroxy [5- (4-methyl-6- {[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] methyl} cyclohexanecarboxylic acid (1S, 4R) -4- {1- Hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] L} -2,2-dimethylcyclohexanecarboxylic acid (1S, 4S) -4- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] ] Amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} -2,2-dimethylcyclohexanecarboxylic acid (1S, 4S) -4- [1-hydroxy-1- (5- { 4-methyl-6-[(4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl) ethyl] -2,2-dimethylcyclohexanecarboxylic acid (1S, 4S) -4- [1-Hydroxy-1- (5- {6-[(4-methoxypyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2- Yl) ethyl] -2,2-dimethyl Cyclohexanecarboxylic acid (1S, 4S) -4- {1- [5- (6-{[4- (difluoromethyl) pyridin-2-yl] amino} -4-methylpyridin-2-yl) -1,3 -Thiazol-2-yl] -1-hydroxyethyl} -2,2-dimethylcyclohexanecarboxylic acid trans-4- [1-hydroxy-1- (5- {6-[(4-methylpyridin-2-yl)] Amino] pyridin-2-yl} -1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylic acid trans-4- [1-hydroxy-1- (5- {6-[(4-methoxypyridin-2-) Yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylic acid trans-4- {1- [5- (6-{[4- (difluoromethyl) pyridine-2] -Yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylic acid trans-4- {1-hydroxy-1- [5- (6-{[ 4- (propan-2-yl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid (1S, 4S) -4- {1- Hydroxy-1- [5- (6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} -2,2 -Dimethylcyclohexanecarboxylic acid (1S, 4S) -4- [1-hydroxy-1- (5- {6-[(4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3- Thiazol-2-yl) ] -2,2-Dimethylcyclohexanecarboxylic acid (1S, 4S) -4- [1-hydroxy-1- (5- {6-[(4-methoxypyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl) ethyl] -2,2-dimethylcyclohexanecarboxylic acid (1S, 4S) -4- {1- [5- (6-{[4- (difluoromethyl) pyridine-2] -Yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] -1-hydroxyethyl} -2,2-dimethylcyclohexanecarboxylic acid trans-4- {1- [5- (4- Chloro-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl] -1,3-thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylic acid trans- -(1- {5- [4- (Difluoromethyl) -6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl] -1,3-thiazol-2-yl } -1-hydroxyethyl) cyclohexanecarboxylic acid trans-4- {1- [5- (4-cyclopropyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl ) -1,3-thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylic acid (4R) -4-{(1S) -1-hydroxy-1- [5- (4-methyl-6-{[ 4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} pyrrolidin-2-one (4R) -4-{(1R)- 1-hydroxy-1- 5- (4-Methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} pyrrolidin-2-one 4- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2 -Yl] ethyl} -2-methylcyclohexanecarboxylic acid In another embodiment, the compound (including pharmaceutically acceptable salts thereof) is:
Cis-4- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol -2-yl] ethyl} cyclohexanecarboxylic acid;
In another embodiment, the compound (including pharmaceutically acceptable salts thereof) is:
Trans-4-[(1R) -1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2- Yl) -1-hydroxypropyl] cyclohexanecarboxylic acid;
Trans-4-[(1S) -1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2- Yl) -1-hydroxypropyl] cyclohexanecarboxylic acid;
Trans-4-[(1R) -1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2- Yl) -1-hydroxypropyl] cyclohexanecarboxamide;
Trans-4-[(1S) -1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2- Yl) -1-hydroxypropyl] cyclohexanecarboxamide;
Trans-4-{(1R) -1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1 , 3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid;
Trans-4-{(1S) -1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1 , 3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid;
Trans-4-[(1R) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl ) -1-hydroxyethyl] cyclohexanecarboxylic acid;
Trans-4-[(1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl ) -1-hydroxyethyl] cyclohexanecarboxylic acid;
Trans-4-{(1R) -1-hydroxy-1- [5- (6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazole -2-yl] ethyl} cyclohexanecarboxylic acid;
Trans-4-{(1S) -1-hydroxy-1- [5- (6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazole -2-yl] ethyl} cyclohexanecarboxylic acid;
Trans-4-[(1R) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol -2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid; and trans-4-[(1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid.
In this application document, unless otherwise specified, various terms are defined as follows.
"Alkyl" refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms. Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
"Carbocycle" refers to a saturated or partially unsaturated monocyclic non-aromatic ring in which all of the ring atoms are carbon, which may be single, one or two of such rings. Or a condensed type with one or a benzene ring (for example, an ortho condensed type, a spiro condensed type and a bridged type). In the case of polycyclic carbocycles, the point of attachment may be on any ring. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, bicyclo [3.3.0] octane, indane, bicyclo [3.3.1] nonane, Decalin, tetrahydronaphthalene, spiro [3.3] heptane, bicyclo [3.1.0] hexane, adamantane, tricyclo [2.2.1.0 2,6 ] heptane, dispiro [2.1.2.3] Deccan is mentioned.
"Cycloalkyl" refers to a saturated ring containing the specified number of ring carbon atoms and no heteroatoms. In a similar manner, the term "C 3-6 cycloalkyl" refers to a saturated ring having 3-6 ring carbon atoms. Exemplary "cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
"Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
"Haloalkyl" refers to an alkyl group as defined above wherein one to all of the hydrogen atoms have been replaced with a halogen; the halogen is as defined herein. Examples of such branched or straight chain haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, independently substituted with one or more halo, eg, fluoro, chloro, bromo and iodo , Propyl, isopropyl, isobutyl and n-butyl. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and And perfluoro-n-propyl.
"Hydroxyalkyl" refers to an alkyl group that may be the one defined above in which one hydrogen on each carbon atom is replaced with a hydroxy group. Examples of "hydroxyalkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, propane-1,2-diol.
The term "composition", in the case of a pharmaceutical composition, includes a product comprising an active ingredient and an inert ingredient (pharmaceutically acceptable excipient) that constitutes the carrier, as well as any two or more combinations of the ingredients. Including any product obtained directly or indirectly by conjugation or aggregation, or by dissociation of one or more of the components, or by other types of reactions or interactions of one or more of the components. Intended to be. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of formula I and a pharmaceutically acceptable excipient.
As used herein, the term "optionally" means that the event described below may or may not occur, both events that occur and events that do not occur Is included.
As used herein, the term "substituted with one or more groups" means substitution with a named substituent, acceptable multiplicity, unless the number of substituents is specified. Substitution (up to all hydrogen atoms replaced with the same or different substituents). When the number of substituents is not specified, one or more is intended.
Each variable part is defined independently for each existence in the definition of the general structural formula. For example, when more than one R 7 substituent is present on the "A" ring, each substituent is independently selected at each occurrence, and each substituent may be the same or different from each other. .
The term "Syk inhibitor" is used to mean a compound that inhibits the Syk enzyme.
The term "Syk-mediated disease" or "disorder or disease or condition mediated by inappropriate Syk activity" is used to mean any disease state mediated or modulated by the Syk kinase mechanism. Such disease states include inflammatory, allergic and autoimmune diseases such as asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDs), ulcerative colitis, clonal disease, bronchitis, Dermatitis, allergic rhinitis, psoriasis, scleroderma, hives, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus, especially asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome ( ARDs), allergic rhinitis and rheumatoid arthritis.
As used herein, "a compound of the invention" means a compound of formula I or a salt, solvate or physiologically functional derivative thereof.
As used herein, the term "solvate" refers to various stoichiometric complexes formed by a solute (in the present invention, a compound of formula I or a salt thereof) and a solvent. Such solvents for the interpretation of the present invention may be those which do not interfere with the biological activity of the solute. Examples of suitable solvents include but are not limited to water, acetone, methanol, ethanol and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably, the solvent is water.
As used herein, the term "physiologically functional derivative" refers to a compound that is transformed in vivo to yield a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound. (Eg, drug precursor). The transformation can occur by various mechanisms (eg, by metabolic or chemical processes), such as hydrolysis in blood. Prodrugs are such derivatives, and a discussion of the use of prodrugs is as follows: C. S. Symposium Series T. Higuchi and W.H. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
A compound of formula I may have the ability to crystallize into more than one form, a characteristic known as polymorphism, such polymorphic forms ("polymorphs") are within the scope of formula I. Please understand that it is included. Polymorphism can generally occur as a response to changes in temperature or pressure or both, and can also occur due to changes in the crystallization process. Polymorphs can be distinguished by various physical properties known in the art, such as x-ray diffraction patterns, solubility, and melting point.
The compounds of formula I may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of formula I, as well as mixtures thereof (eg, racemic mixtures) are intended to form part of the present invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of physical and chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers convert an enantiomer mixture to a diastereomeric mixture by reaction with a suitable optically active compound (eg, a chiral auxiliary such as a chiral alcohol or a Mosher acid chloride), separating the diastereomers and separating the individual diastereomers. Stereomers can be separated by converting (eg, hydrolyzing) the corresponding pure enantiomer. Enantiomers can also be separated by chromatography using a column equipped with a chiral stationary phase. Also, some compounds of formula I may be atropisomers (eg, substituted biaryls) and are considered as part of this invention.
It should also be noted that the compounds of formula I may form tautomers. It is to be understood that all tautomers and tautomeric mixtures of the compounds of the invention are included within the scope of the compounds of the invention. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Although embodiments for each variable part are shown generally above for each variable part separately, the present invention is directed to several embodiments of Formula I or each embodiment selected from each of the above embodiments. Also included are compounds. Accordingly, the present invention is intended to encompass any combination of embodiments of each variable section.
The compounds of the present invention may be in the form of pharmaceutically acceptable salts and / or may be administered in that form. A review on suitable salts can be found in Berge et al, J. MoI. Pharm. Sci. 1977, 66, 1-19. Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Suitable pharmaceutically acceptable salts can include acid addition salts or base addition salts.
Pharmaceutically acceptable acid addition salts include compounds of Formula I and suitable inorganic or organic acids (eg, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, formic acid, acetic acid, propion) Acid, fumaric acid, citric acid, tartaric acid, lactic acid, benzoic acid, salicylic acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid (2-naphthalenesulfonic acid, etc. ), Or hexanoic acid) to obtain and form a salt (which may be in a suitable solvent such as an organic solvent), said salt, usually isolated, for example, by crystallization and filtration, A salt is obtained. Pharmaceutically acceptable acid addition salts of the compounds of formula I are, for example, hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, Propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethane It can be a sulfonate, naphthalenesulfonate (such as 2-naphthalenesulfonate), or hexanoate, or the salt.
Pharmaceutically acceptable base salts are those which can be formed by reaction of the compound of Formula I with a suitable inorganic or organic base. Examples of the salt derived from an inorganic base include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and bases Ion exchange resins such as arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N -Ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine , Tromethamine and the like.
Other non-pharmaceutically acceptable salts, such as oxalate or trifluoroacetate, can also be used, for example, in the isolation of the compounds of the invention and are within the scope of the invention.
The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the compounds of formula I.
In the compounds of general formula I, the atoms may exhibit a natural isotopic abundance, and one or more atoms have the same atomic number, but the atomic weight or mass number is the atomic weight or A specific isotope different from the mass number may be artificially enriched. The present invention is meant to encompass all suitable isotopic variations of the compounds of general formula I. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is an isotope of hydrogen found mainly in nature. Deuterium enrichment may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or compounds useful as standards for characterization of biological samples Can be obtained. Isotopically labeled compounds of general formula I may be prepared by conventional techniques well known to those skilled in the art or without undue experimentation or similar to those described in the schemes and examples herein. Depending on the process, it can be prepared using appropriate reagents and / or intermediates that are isotopically enriched.
Compounds of formula I and salts, solvates and physiologically functional derivatives thereof are considered to be inhibitors of Syk activity, and thus potentially diseases and conditions associated with inappropriate Syk activity. Useful for the treatment of
The compounds of formula I or pharmaceutically acceptable salts thereof and pharmaceutical compositions can be used to treat or prevent a variety of medical conditions or diseases mediated by spleen tyrosine kinase (Syk). Such medical conditions and diseases include, but are not limited to: (1) arthritis, eg rheumatoid arthritis, juvenile arthritis, psoriatic arthritis and osteoarthritis; (2) asthma and other obstructive airway diseases such as chronic asthma Late asthma, airway hypersensitivity, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, adult respiratory distress syndrome, recurrent airway obstruction, and chronic obstructive pulmonary disease such as qi (3) autoimmune diseases or disorders, eg, those designated as autoimmune disorders of single organ or single cell type, eg, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmunity of pernicious anemia Atrophic gastritis, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture disease, autoimmune thrombocytopenia, eg idiopathic thrombocytopenic purpura, sympathetic ophthalmitis, myasthenia , Graves' disease, primary biliary cirrhosis, chronic fulminant hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as related to systemic autoimmune disorders, such as systemic lupus erythematosus, Immune thrombocytopenic purpura, rheumatoid arthritis, Sjogren's syndrome, Reiter syndrome, polymyositis-dermatomyositis, systemic sclerosis, nodular polyarteritis, multiple sclerosis and bullous pemphigoid, and B cells Further autoimmune diseases that can be (humoral) or T cell lines such as Corgan syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I or juvenile onset diabetes, and thyroiditis; (4) Cancer or tumor, eg, gastrointestinal / gastrointestinal cancer, colon cancer, liver cancer, skin cancer, eg mastocytoma and squamous cell carcinoma, breast cancer Breast cancer, ovarian cancer, prostate cancer, lymphoma and leukemia (eg but not limited to acute myeloid leukemia, chronic myelogenous leukemia, mantle cell lymphoma, NHL B cell lymphoma (eg progenitor B-ALL, marginal layer B) Cell lymphoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, mediastinal large cell B cell lymphoma), Hodgkin lymphoma, NK cell and T cell lymphoma; TEL-Syk and ITK-Syk fusion drive Type) myeloma, eg multiple myeloma, myeloproliferative disorder kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma, eg oral melanoma And metastatic melanoma, Kaposi's sarcoma, proliferative diabetic retinopathy, and angiogenesis-related disorders such as solid tumors and pancreatic cancer; (5) diabetes such as Type I diabetes and complications due to diabetes; (6) Eye diseases, disorders or conditions, eg autoimmune diseases of the eye, keratoconjunctivitis, spring conjunctivitis, uveitis, eg uveitis and lenses associated with Behcet's disease Primordial uveitis, keratitis, herpetic keratitis, keratokeratitis, corneal epithelial dystrophy, corneal vitiligo, pemphigus of the eye, Mohren ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, dry horn Conjunctivitis (dry eye), frickten, iridocyclitis, sarcoidosis, endocrine eye disorders, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization; (7) intestinal inflammation, allergy or pathology, eg, clone Disease and / or ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, and mastocytosis; (8) neurodegenerative disease, For example, motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or traumatic, strike, neurodegenerative disease caused by glutamate neurotoxicity or hypoxia; stroke Ischemic / reperfusion injury, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia; (9) associated with platelet aggregation and platelet activation Diseases caused by or caused by this, eg arteriosclerosis, thrombosis, intimal hyperplasia and restenosis after vascular injury; (10) pathologies associated with cardiovascular disease, eg restenosis, acute coronary Syndrome, myocardial infarction, unstable angina, refractory angina, coronary artery after thrombolysis or coronary angioplasty Intravascular thrombotic occlusion, thrombomediated cerebral vascular syndrome, embolic stroke, thrombotic stroke, transient cerebral ischemic attack, venous thrombosis, deep vein thrombosis, pulmonary artery embolization, coagulopathy, disseminated intravascular coagulation syndrome Thrombotic thrombocytopenic purpura, obstructive thrombotic vasculitis, thrombotic diseases associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, device use (heart or other Thrombotic complications associated with intravascular catheterization, intra-aortic balloon pumps, coronary stenting or heart valves, etc., medical conditions requiring the use of prosthetic devices, etc .; (11) skin diseases, medical conditions or disorders Eg, atopic dermatitis, eczema, psoriasis, scleroderma, pruritus and other pruritic conditions; (12) allergic reactions such as anaphylaxis, allergic rhinitis, allergic dermatitis, Guinea urticaria, angioedema, allergic asthma, or insect bites, allergic reaction to food, drugs or pollen; (13) transplant rejection, eg, pancreatic islets rejection, bone marrow transplant rejection, host-host graft disease Organ and cell transplant rejection (bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, and xenogeneic (14) low-grade scar formation such as scleroderma, increased fibrosis, keloid, postoperative scar, pulmonary fibrosis, vasospasm, migraine, reperfusion injury, and post-myocardial infarction Can be mentioned.
Accordingly, the present invention relates to compounds of formula I and salts and solvates thereof and physiologically functional derivatives thereof for use in therapy, in particular in the treatment of diseases and conditions mediated by inappropriate Syk activity. I will provide a. Inappropriate Syk activity as used herein is any Syk activity that deviates from the normal Syk activity expected in a particular mammal. Inappropriate Syk activity can be, for example, an abnormal increase in activity, or a form of abnormal timing and / or control of Syk activity. Thus, such inappropriate activity may be due, for example, to overexpression or mutation of the protein kinase resulting in inappropriate or uncontrollable activation.
In a further embodiment, the present invention relates to methods of modulating, modulating or inhibiting Syk for the prevention and / or treatment of disorders associated with disordered Syk activity.
In a further embodiment, the present invention provides a method of treating a mammal suffering from a disorder mediated by Syk activity, wherein said mammal has an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate thereof. A method comprising administering a product or a physiologically functional derivative.
In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof or a physiologically functional salt thereof in the preparation of a medicament for the treatment of a disorder mediated by Syk activity. Use of a derivative is provided.
In a further embodiment, the disorder mediated by Syk activity is asthma. In a further embodiment, the disorder is rheumatoid arthritis. In another embodiment, the disorder is cancer. In a further embodiment, the disorder is ocular conjunctivitis.
Another aspect of the invention is characterized by being caused by and / or associated with the release or synthesis of Fc receptor signaling cascades, eg chemical mediators of FceRI and / or FcgRI mediated degranulation. As a therapeutic approach to the treatment or prevention of a disease, there is provided a method of treating a disease caused by or associated with such Fc receptor signaling cascade or degranulation. Syk plays an important role in immunotyrosine activation motif (IT AM) signaling, B cell receptor signaling, and T cell receptor signaling. Integrins β (1), β in neutrophils (2) and β (3) are known to be essential components of signal transduction. Thus, the compounds of the present invention can be used to modulate Fc receptors, ITAM, B cell receptors and integrin signaling cascades and the cellular responses elicited by these signaling cascades. Non-limiting examples of cellular responses that can be modulated or inhibited include respiratory burst, cell adhesion, cell degranulation, cell spreading, cell migration, phagocytosis, calcium ion efflux, platelet aggregation and cell maturation.
For use in therapy, it may be envisaged that the compounds of formula I and their salts and solvates, and physiologically functional derivatives thereof, can be administered as is, but the active ingredient is a pharmaceutical composition Can be considered as Accordingly, the present invention further provides a pharmaceutical composition comprising a compound of formula I and salts and solvates thereof, and physiologically functional derivatives thereof and a pharmaceutically acceptable carrier, diluent or excipient. provide. The compounds of formula I and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient thereof. Also according to another aspect of the present invention, the compound of Formula I, or salts and solvates thereof, and physiologically functional derivatives thereof, in one or more pharmaceutically acceptable carriers, diluents or excipients A method of preparing a pharmaceutical composition is provided that comprises mixing with.
The pharmaceutical composition of the invention may be presented in unit dosage form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 5 μg to 3 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of the compound of formula I, depending on the medical condition to be treated, the route of administration and the age, weight and physical condition of the patient. . Thus, such a unit dose may be administered more than once a day. Preferred unit dosage compositions are those containing a daily dose or sub-dose, as described hereinabove (for administration more than once daily), or an appropriate divided amount thereof of an active ingredient. Furthermore, such pharmaceutical compositions can be prepared by any method well known in the pharmaceutical art.
The pharmaceutical composition of the present invention may be any suitable route, for example, oral (eg, buccal or sublingual), rectal, transdermal, inhalation, nasal, ocular or parenteral (eg, intravenous and muscle). Internal) may be adapted for administration by route. Such compositions can be prepared by any method known in the pharmaceutical art, for example, combining the active ingredient with a carrier or excipient. Examples of the dosage form include tablets, troches, dispersions, suspensions, liquids, capsules, creams, ointments, aerosols and the like.
In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the oral route, eg for the treatment of rheumatoid arthritis.
In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the nasal route, for example for the treatment of allergic rhinitis.
In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the inhalation route, eg for the treatment of asthma, COPD or ARDS.
In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by the ophthalmic route for the treatment of eye diseases such as conjunctivitis.
In a further embodiment, the present invention provides a pharmaceutical composition adapted for administration by a parenteral (eg, intravenous) route, eg, for the treatment of cancer.
The pharmaceutical composition of the present invention adapted for oral administration comprises individual units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or It can be presented as a whipping agent; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by grinding the compound to a suitable fine size and mixing with a similarly ground pharmaceutical carrier (such as an edible carbohydrate such as starch or mannitol). In addition, flavoring agents, preservatives, dispersing agents and coloring agents may be present.
Capsules are made by preparing a powder mixture as described above and filling a shaped gelatin sheath. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. Disintegrants or solubilizers such as agar agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the medicament when the capsule is ingested.
In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycols and waxes. Can be mentioned. Lubricants used in such dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate and the like. Examples of the disintegrant include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound (appropriately ground) with a diluent or base as described above, binder (such as carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone), dissolution delay Substances (such as paraffin), absorption accelerators (such as quaternary salts) and / or absorbents (such as bentonite, kaolin or dicalcium phosphate) may be mixed. The powder mixture can be granulated by wetting with a binder (such as syrup, starch paste, gum arabic or a solution of cellulosic or polymeric materials) and pressing through a screen. As an alternative to granulation, the powder mixture may be processed in a tablet machine and the resulting product incompletely slugged to break up into granules. The granules can be smoothed to prevent sticking to the tableting die by means of adding stearic acid, stearate, talc or mineral oil. The smoothed mixture is then compressed into tablets. Alternatively, the compounds of the present invention may be combined with a free flowing inert carrier and compressed directly into tablets without going through the steps of granulating or slugging. A transparent or opaque protective coating consisting of a shellac seal coat, a sugar or polymer coating and a waxed coating may be applied. Dyestuffs may be added to such coatings to distinguish different unit dosages.
Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with the appropriate flavor, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a nontoxic vehicle. Also added solubilizers and emulsifiers (eg ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavor additives (eg peppermint oil or natural sweeteners or saccharin or other artificial sweeteners) etc. May be.
Where appropriate, dosage unit compositions for oral administration may be microencapsulated. The formulation may also be prepared for extended or sustained release, for example, by coating or embedding a particulate material in a polymer, wax or the like.
Also, the compounds of formula I and their salts and solvates, and physiologically functional derivatives thereof can be delivered in liposome delivery systems, for example in the form of small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles May be administered. Liposomes can be formed with a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
In addition, compounds of formula I and salts and solvates thereof, and physiologically functional derivatives thereof may be delivered by using monoclonal antibodies as individual carriers for coupling the compound molecules. The compound may also be coupled with a soluble polymer as a targetable drug carrier. Such polymers may include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds may be of a class of biodegradable polymers useful for obtaining controlled release of drugs, such as polylactic acid, polyε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and It may be coupled to a hydrogel cross-linked or amphiphilic block copolymer.
Dosage forms for inhalation administration can be conveniently formulated as aerosols or dry powders.
In compositions suitable and / or adapted for inhalation administration, it is preferred that the compound or salt of formula I is in particle size size reduction form, more preferably the size reduction form is obtained or obtained by micronization. It can be done. A preferred particle size for a size-reduced (eg, micronized) compound or salt or solvate is defined as having a D50 value of about 0.5 to about 10 microns (eg, as measured using laser diffraction). .
For example, an aerosol formulation for inhalation administration may include a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in a sealed or sealed form in single or repeated doses in a sealed container, which can be in the form of a cartridge or refill for use in an atomizer type device or inhaler. Alternatively, the sealed container may be a unitary medication device, such as a single dose nasal inhaler or an aerosol dispenser (metered dose inhaler) fitted with a throttling valve, which is used for sputum in the container It is intended to be disposed of when it is consumed.
Where the dosage form is equipped with an aerosol dispenser, it preferably contains a suitable propellant under pressure (compressed air, carbon dioxide etc.) or organic propellant (hydrohydrocarbon (HFC) etc.). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. The aerosol dosage form may be in the form of a pump atomizer. Pressurized aerosols can contain a solution or suspension of the active compound. This may require the incorporation of additional excipients such as co-solvents and / or surfactants to improve the dispersion properties and homogeneity of the suspension formulation. Also, liquid preparations may require the addition of a co-solvent such as ethanol. Also, for example, improvers that are other excipients to improve the stability and / or taste and / or particulate mass properties (amount and / or profile) of the formulation may be incorporated.
For pharmaceutical compositions suitable and / or adapted for administration by inhalation, it is preferred that the pharmaceutical composition is a dry powder composition for inhalation. Such compositions comprise a powder base (such as lactose, glucose, trehalose, mannitol or starch), a compound of formula I or a salt or solvate thereof (preferably a particle size reduction form, eg micronized form) And may include performance modifiers such as L-leucine or another amino acid, and / or a metal salt of stearic acid (such as magnesium or calcium stearate). Preferably, the dry powder composition for inhalation comprises a dry powder blend of lactose and a compound of formula I or salt thereof. The lactose is preferably lactose hydrate, such as lactose monohydrate and / or preferably inhalation grade and / or fine powder grade lactose. Preferably, the lactose particle size is 90% or more (weight basis or volume basis) of the lactose particles less than 1000 microns (micrometers) (eg 10 to 1000 microns, eg 30 to 1000 microns), and / or Alternatively, it is defined that 50% or more of the lactose particles have a diameter of less than 500 microns (eg, 10-500 microns). More preferably, the lactose particle size is such that 90% or more of the lactose particles are less than 300 microns in diameter (eg, 10-300 microns, eg, 50-300 microns) and / or 50% or more of the lactose particles are It is defined to be 100 microns in diameter. The lactose particle size may be defined as 90% or more of the lactose particles having a diameter of less than 100 to 200 microns and / or 50% or more of the lactose particles having a diameter of 40 to 70 microns. It is preferred that about 3 to about 30% (eg, about 10%) (by weight or volume) of the particles are less than 50 microns or less than 20 microns in diameter. For example, but not limited, a suitable inhalation grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwoll, Netherlands).
In particular, for dry powder compositions for inhalation, the pharmaceutical composition for inhalation administration is a plurality of sealed dose containers (eg, dry powder) mounted longitudinally in strips or ribbons within a suitable inhalation device. The agent composition may be incorporated into the inclusion). The container is ruptureable or peelable when needed, for example, a dose of the dry powder composition can be administered by inhalation from a device such as a DISKUS® device (GlaxoSmithKline). Other dry powder inhalers are well known to those skilled in the art, and many such devices are commercially available, with representative devices being Aerolizer (R) (Novartis), Airmax (TM) (TV AX ), ClickHaler (registered trademark) (Innovata Biomed), Dischaler (registered trademark) (GlaxoSmithKline), Accuhaler (GlaxoSmithKline), Easyhaler (registered trademark) (Orion Pharma), Eclipse registered trademark Hovione), Handihaler (R) (Boehringer Ingelheim), Pulvinal (R) (Chiesi), Rot Haler (registered trademark) (GlaxoSmithKline), Skyhaler (registered trademark) or Certihaler (registered trademark) (SkyPharma), Twishaler (Schering-Plough), Turbohaler (registered trademark) (AstraZeneca), Ulr registered trademark, Ultra registered (Ultar) .
Dosage forms for ophthalmic administration can be formulated as solutions or suspensions using excipients suitable for ophthalmic use.
Dosage forms for nasal administration can be conveniently formulated as aerosols, solutions, drops, gels or dry powders.
Pharmaceutical compositions adapted for administration by inhalation include finely divided powders or mists, which can be produced by various types of metered pressure aerosols, nebulizers or insufflators.
In pharmaceutical compositions suitable and / or adapted for intranasal administration, the compound of formula I or a pharmaceutically acceptable salt or solvate thereof as a liquid agent formulation for delivery from a liquid agent dispenser. It can be formulated. Such a liquid agent dispenser may have, for example, a dispensing nozzle or a dispensing orifice through which a fixed amount of liquid formulation is dispensed when a force is applied by a user to the pump mechanism of the liquid dispenser. Such liquid agent dispensers are typically provided with a number of reservoirs of metered liquid drug formulations that can be dispensed upon sequential actuation of the pump. The dispensing nozzle or orifice may be configured to be inserted into the user's nostril for spray application of the liquid formulation into the nasal cavity. A liquid agent dispenser of the above type is described and illustrated in WO 2005/044354, the entire contents of which are hereby incorporated by reference. The dispenser has a housing, and the housing contains a liquid agent discharge device having a compression pump mounted on a container containing the liquid agent preparation. The housing has at least one side lever that can be operated with a finger. The side lever cams the container upward in the housing and presses the pump, so that a fixed amount of drug is transferred from the pump trunk to the nasal side of the housing. Movable inward relative to the housing for pumping through the nozzle. A particularly preferred liquid agent dispenser is of the general type illustrated in FIGS. 30-40 of WO 2005/044354.
The following is an example of a representative pharmaceutical dosage form of a compound of the invention:
Suspension for injection (IM) mg / ml
Compound of formula I 10
Methylcellulose 5.0
Tween 80 0.5
Benzyl alcohol 9.0
Benzalkonium chloride 1.0
Water tablets for injection to a total volume of 1 ml mg / tablet Compound of formula I 25
Microcrystalline cellulose 415
Povidone 14.0
Starch 43.5
Magnesium stearate 2.5
Capsules mg / Capsules Compound of formula I 25
Lactose powder 573.5
Inhalation aerosol per dose Compound of formula I 100 meg
Oleic acid 5 meg
Ethanol 1mg
HFA 227 (1,1,1,2,3,3,3-heptafluoropropane) 75 mg
Dry powder inhalation aerosol per dose Compound of formula I 100 meg
Lactose 12.5mg
When the compound of the invention is administered in combination with other therapeutic agents usually administered by inhalation, intravenous, oral or intranasal route, the resulting pharmaceutical composition may be administered by the same route Will be recognized.
In addition to the ingredients specifically listed above, it will be understood that the composition may include other agents conventional in the art, taking into account the type of formulation in question (eg, Suitable for oral administration may include flavoring agents).
The therapeutically effective amount of the compounds of the present invention depends on several factors, such as the age and weight of the animal, the exact condition and severity of the treatment requiring treatment, the nature of the formulation and the route of administration, and ultimately Is at the discretion of the attending physician or veterinarian. However, an effective amount of a compound of formula I for treatment of a disease or condition associated with inappropriate Syk activity is generally 5 μg to 100 mg / kg recipient (mammal) body weight / day; More usually in the range of 5 μg to 10 mg / kg body weight / day. This amount may be administered as a single dose per day, or more usually a daily dose with several sub-doses per day (such as 2, 3, 4, 5 or 6 times) Can be administered to be the same. An effective amount of the salt or solvate can be determined as a fraction of the effective amount of the compound of formula I itself.
The compounds of the present invention and salts and solvates thereof, and physiologically functional derivatives thereof may be used alone or otherwise for the treatment of diseases and conditions associated with inappropriate Syk activity. It may be used in combination with other therapeutic agents. Thus, the combination therapy according to the invention comprises the administration of at least one compound of formula I or a pharmaceutically acceptable salt or solvate thereof or a physiologically functional derivative thereof and at least of other pharmaceutically active agents. Use. The compound of formula I and the other pharmaceutically active agent may be administered together or separately, and when administered separately, this may be done simultaneously or sequentially in any order. Good. The amount of the compound of formula I and the other pharmaceutically active agent and the relative timing of administration are selected to achieve the desired combined therapeutic effect.
For the treatment of inflammatory diseases, rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis, compounds of formula I are: (1) TNF-α inhibitors, such as infliximab (Remicade®) Etanercept (Enbrel®), Adalimumab (Humira®), Sertolizumab Pegor (Cimsia®), and Golimumab (Simponi®); (2) Non-selective COX − I / COX-2 inhibitors (eg, piroxicam, diclofenac, propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, phenamates such as mefenamic acid, indomethacin, sulindac, etodolac, azapropazone, pyrazo (3) COX-2 inhibitors (eg, meloxicam, celecoxib, rofecoxib, valdecoxib and etoroxixib); (4) other agents for the treatment of rheumatoid arthritis E.g., methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporine, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, robenzarit, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin or gold for parenteral or oral use , Cyclophosphamide, lymphostat-B, BAFF / APRIL inhibitor and CTLA-4-Ig or mimetics thereof; (5) leukotriene biosynthesis inhibitor, 5-lipoxy Shigenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists such as zileuton; (6) LTD4 receptor antagonists such as zafirlukast, montelukast and pranlukast; (7) PDE4 inhibitors E.g., roflumilast, cilomilast, AWD-12-281 (Elbion), and PD-168787 (Pfizer); (8) antihistamine HI receptor antagonists such as cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, Astemizole, azelastine, levocabastine, olopatidine, metapyrylene and chlorpheniramine; (9) αl- and α2-adrenoceptor agonists Vasoconstrictor sympathomimetic agents such as propylhexedrine, Nilefurin, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethyl norepinephrine hydrochloride; (10) anticholinergic agents such as ipratropium bromide, tiotropium bromide, oxitropi bromide Um, aclindinium bromide, glycopyrrolate, (R, R) -glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenergic receptor agonists such as metaproterenol, isoproterenol, isoprenaline , Albuterol, formoterol (especially fumarate), salmeterol (especially xinafoate), terbutaline, orciprenaline, vitorterol mesylate, fenoterol, and Pyrbuterol, or methylxanthine, such as theophylline and aminophylline, sodium cromoglycate; (12) insulin-like growth factor type I (IGF-1) mimetics; (13) glucocorticosteroids, particularly systemic Less inhaled glucocorticoids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate; (14) kinase inhibitors such as Janus kinase ( Inhibitors of JAK1 and / or JAK2 and / or JAK3 and / or TYK2), for example tofacitinib (Pfizer), varicitinib (Incyte), VX- 09 (Vertex), ASP-015K (Asterellas), GLPG0634 (Galapagos), SB-1578 (SBIO), and AC-430 (Ambit Biosciences); p38 MAPK and IKK2; (15) B cell targeted biologics, such as Rituximab (Rituxan®); (16) selective costimulatory modulators such as abatacept (Orencia); (17) interleukin inhibitors such as IL-1 inhibitor Kineret and IL-6 inhibitors It can be used in combination with one or more other active agents such as tocilizumab (Actemra).
The present invention also provides so-called "triple combination" therapeutics comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a β2-adrenergic receptor agonist and an anti-inflammatory corticosteroid. Preferably the combination is for the treatment and / or prevention of asthma, COPD or allergic rhinitis. The β2-adrenergic receptor agonist and / or the anti-inflammatory corticosteroid can be those described above and / or as described in WO 03/030939. Representative examples of such "triple" combinations include compounds of formula I or pharmaceutically acceptable salts thereof, Advair® (salmeterol xinafoate and fluticasone propionate), Symbicort® (budesonide and fumaric acid) Formoterol), or Dulera® (mometasone furoate and formoterol fumarate), salmeterol or a pharmaceutically acceptable salt thereof (eg salmeterol xinafoate) and fluticasone propionate in combination.
In the treatment of cancer, the compound of formula I may be used in combination with one or more anticancer agents. Examples of such agents are Cancer Principles and Practice of Oncology by V. T.A. Devita and S.M. It can be found in Hellman (editor), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. One skilled in the art will recognize which drug combinations may be useful based on the specific characteristics of the drug and the cancer involved. Examples of such anticancer agents include, but are not limited to: (1) Estrogen receptor modulators such as diethylstibestral, tamoxifen, raloxifene, idoxyphene, LY353811, LY117081, toremifene, fluoxymesterone (Fluoxymestero), and SH646; (2) other hormone agents such as aromatase inhibitors (eg, aminoglutethimide, tetrazole anastrozole, letrozole and exemestane), luteinizing hormone releasing hormone (LHRH) analogs, Ketoconazole, goserelin acetate, leuprolide, megestrol acetate and mifepristone; (3) androgen receptor modulators such as finasteri And other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, riarosol, and abiraterone acetate; (4) retinoid receptor modulators such as bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α -Difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide, and N-4-carboxyphenylretinamide; (5) antiproliferative agents such as antisense RNA and DNA oligonucleotides such as , G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxyfluridine, trimetrex , Fludarabine, capecitabine, galocitabine, cytarabine ocphosphate, hostevine sodium hydrate, raltitrexed, partitrexid, emitefur, thiazofurin, decitabine, nolatrexed, pemetrexed, pemetrexed Methylidene cytidine, 2'-fluoromethylene-2'-deoxycytidine, N6- [4-deoxy-4- [N2- [2 (E), 4 (E) -tetradeca-dienoyl] glycylamino] -L-glycero- B-L-manno-heptopyranosyl] adenine, aplidine, etainacidin, troxacitabine, aminopterin, 5-fluorouracil, floxuridine, methotrexate, leucovorin (leu) covarin), hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine, lometrexol, dexrazoxane , Methioninase, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; (6) prenyl-protein transferase inhibitors such as farnesyl-protein transferase (FPPTase), geranylgeranyl-protein transferase type I (GGPTase-I) And geranylgeranyl-protein transferase type II (also referred to as GGPtase-II, Rab GGPtase); (7) H G-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin and rosuvastatin; (8) angiogenesis inhibitors such as tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1 / KDR (VEGFR2 ) Inhibitors, epithelium-derived, fibroblast-derived or platelet-derived growth factor inhibitors, MMP (matrix metalloproteinase) inhibitors, integrin blockers, interferon-α, interleukin-12, erythropoietin (epoetin) -Α), granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF (sargramostin), polysulfate pentosan, cyclooxygenase inhibitor, steroidal anti-inflammatory drug, carbo Against thiamidol triazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl) -fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonist, heparin, carboxypeptidase U inhibitor, and VEGF Antibody, Endostatin, Ukrain, Lampyrinase, IM862, Acetyldinanaline, 5-amino-1-[[3,5-dichloro-4- (4-chlorobenzoyl) phenyl] methyl] -1H-1,2,3- Triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, and 3-[(2,4-dimethylpyrrol-5-yl) methylene] -2-indolinone ( SU 5416); (9) PPAR-γ agonists, PPAR-δ agonists, thiazolidinedinones (eg, DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl- 1,2-Benzisoxazol-6-yl) oxy] -2-methylpropionic acid (disclosed in USSN 09 / 782,856), and (2R) -7- (3- ( 2-chloro-4- (4-fluorophenoxy) phenoxy) propoxy) -2-ethylchroman-2-carboxylic acid (disclosed in USSN 60 / 235,708 and 60 / 244,697); (9) inherent multidrug resistance Inhibitors of p-glycoprotein (P-gp) such as LY33579, XR9576, OC144-093, R101922, VX853 and PSC833 (Valspodal); (10) inhibitors of cell proliferation and survival signaling For example, inhibitors of EGFR (eg, gefitinib and erlotinib), ERB-2 inhibitors (eg, trastuzumab), inhibitors of IGF1R, eg, MK-0646 (dalotuzumab), inhibitors of CD20 (rituximab) , Cytokine receptor Inhibitors, inhibitors of MET, PI3K family kinases (eg LY294002), inhibitors of serine / threonine kinases (eg but not limited to inhibitors of Akt, eg (WO 03/084064, 03 / 086403, 03/086394, 03/086279, 02/083675, 02/083139, 02/083140, and 02/083138), Raf kinase Inhibitors of (e.g. BAY-43-9006), inhibitors of MEK (e.g. CI-1040 and PD-098059) and inhibitors of mTOR (e.g. Wyeth CCI-779 and Arad AP23573); (11) bisphosphonates, For example, etidronate, pamidro , Alendronate, risedronate, zoledronate, ibandronate, incadronate or simadronate, clodronate, EB-1053, minodronate, neridronate, pyridronate and tiludronate; (12) γ-secretase inhibitor, (13) receptor tyrosine Agents that interfere with kinase (RTK), such as inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met; (14) Agents that interfere with cell cycle checkpoints, such as ATR, ATM, Chkl and Chk2 kinase And inhibitors of cdk and cdc kinase, especially 7-hydroxystaurosporine, flavopiridol, CYC202 (Cyccelel) and BMS-387032; (15) BT K inhibitors such as PCI32765, AVL-292 and AVL-101; (16) PARP inhibitors such as iniparib, olaparib, AGO14699, ABT888 and MK4827; (16) ERK inhibitors; (17) mTOR inhibitors such as Sirolimus, lidaforolimus, temsirolimus, everolimus; (18) cytotoxic agents / cytoproliferative agents.
A "cytotoxic agent / cytoproliferative agent" is a compound that causes cell death or inhibits cell proliferation or inhibits or prevents cell mitosis, mainly by directly impeding cell function. Eg, alkylating agents, tumor necrosis factor, intercalators, hypoxia activatable compounds, microtubule inhibitors / microtubule stabilizers, inhibitors of mitotic kinesin, inhibitors of histone deacetylase, mitotic Kinase inhibitors, antimetabolites; biological response modifiers; hormone / antihormone therapeutics, hematopoietic growth factors, monoclonal antibody targeted therapeutics, topoisomerase inhibitors, proteasome inhibition Refers to drugs and ubiquitin ligase inhibitors.
Examples of cytotoxic agents include, but are not limited to, seltenef, cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechloretamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, tasonermine, lonidamine, carboplatin, Altretamine, dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine, hotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, inprosulfan tosylate, trophosphamide, nimustine, dibrospium chloride, pumitepalo, pumitepalo Satraplatin, profilomycin, cisplatin, ilofulvene, dexifosfamide, cis Aminedichloro (2-methyl-pyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-μ- (hexane-1,6-diamine) -μ- [diamine-platinum ( II)] bis [diamine (chloro) platinum (II)] tetrachloride, dialidinidinylspermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, zorubicin , Doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin, mitomycin C, dactinomycin, pricatomycin, bisantrene, mitozantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino 13-deoxo-10-hydroxy-carminomycin, annamycin, Gararubishin, Erinafido, MEN10755, and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl - include daunorubicin.
An example of a hypoxia activating compound is tirapazamine.
Examples of proteasome inhibitors include but are not limited to lactacystin and bortezomib.
Examples of microtubule inhibitors / microtubule stabilizers include vincristine, vinblastine, vindesine, vinzolidine, vinorelbine, vindesine sulfate, 3 ', 4'-didehydro-4'-deoxy-8'-norvin calleucoblastin, Podophyllotoxins (eg, etoposide (VP-16) and teniposide (VM-26)), paclitaxel, docetaxel, lysoxine, dolastatin, mibobrine isethionate, auristatin, semadine, RPR109881, BMS184476, vinflunine, cryptophycin, anhydro Vinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, epothilone (eg, US Pat. No. 6,284,7) 1 Pat and the second reference Pat 6,288,237) and BMS188797 the like.
Examples of topoisomerase inhibitors include topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ′, 4′-O-exo-benzylidene-shartolucin, roottecan, 7- [2- (N-isopropyl) Amino) ethyl]-(20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) Ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b] carbazole-1-carboxamide, aslacrine, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8 -Metoki Benzo [c] -phenanthridinium, 5- (3-aminopropylamino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] acridine -6-one, N- [1- [2- (diethylamino) ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) Acridine-4-carboxamide, 6-[[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one, and dimesna.
Examples of inhibitors of mitotic kinesins include, but are not limited to, inhibitors of KSP, inhibitors of MKLP1, CENP-E inhibitors, inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosph1 and Rab6- Examples include inhibitors of KIFL.
Examples of "histone deacetylase inhibitors" include, but are not limited to, vorinostat, trichostatin A, oxamflatin, PXD101, MG98, valproic acid and scriptaid.
"Inhibitors of kinases involved in the progression of mitosis" include, but are not limited to, inhibitors of Aurora kinase, inhibitors of Polo-like kinase (PLK) (especially inhibitors of PLK-1), bab -1 inhibitors and bub-R1 inhibitors. An example of an "Aurora kinase inhibitor" is VX-680.
"Antiproliferative agents" include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxyfluridine, trimethrexate , Fludarabine, capecitabine, galocitabine, cytarabine ocphosphate, hosteabin sodium hydrate, raltitrexed, partitrexide, emitefur, thiazofurin, decitabine, nolatrexed, pemetrexed, nerzalabine, 2'-deoxy-2'-methylidendidine Fluoromethylene-2′-deoxycytidine, N6- [4-deoxy-4- [N2- [2,4-tetradecadienoyl] glyci Amino] -L-glycero-B-L-manno-heptopyranosyl] adenine, aplidine, etainacidin, troxacitabine, aminopterin, 5-fluorouracil, floxuridine, methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine, lometrexol, dexrazoxane, methioninase, and 3-aminopyridine-2-carboxaldehyde Semicarbazone is mentioned.
Non-limiting examples of suitable agents used in the treatment of cancer that can be used in combination with a compound of formula I include, but are not limited to, abarelix; aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; Zole; Arsenic trioxide; Asparaginase; Azacitidine; Bendamustine; Bevacucumab; Bexarotene; Bleomycin; Bortezomib; Busulfan; Carsterone; Decarbazine; dactinomycin, actinomycin D; dalteparin; darbepoetin alfa; dasatinib; daunorubicin; Rix; Denileukin diftitox; Dexrazoxane; Docetaxel; Doxorubicin; Dromostanolone propionate; Eculizumab; Eliot B solution; Eltrombopag; Epirubicin; Glastim; floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib; gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelin acetate; hydroxyurea; ibritumomab tiuxetan; idarubicin; ifasfamide; imatinib mesylate; interferon alpha-2b; irinotecan; ixabepilone; lapatinib; lenalidomide; letrozole; Leucovorin; leuprolide acetate; levamisole; lomustine; mechloretamine, nitrogen mustard; megestrol acetate; melphalan, L-PAM; mercaptopurine; mensa; methotrexate; Neralabine; nilotinib; nofetumomab; ofatumumab; oprelbequin; oxaliplatin; paclitaxel; palyfermine; pamidronate; panitumumab; pazopanib; pegademase; Porphymar sodium; Pralatrexate; Procarba Quinacrine; rasburicase; raloxifene hydrochloride; rituximab; romidepsin; lomiprostim; sargrammostine; satragratin; satraplatin; sorafenib; streptozocin; sunitinib maleate; tamoxifen; Trastuzumab; tretinoin; uracil mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; and zoledronate.
Where appropriate, to optimize the activity and / or stability and / or physical properties (such as solubility) of the therapeutic component, the other therapeutic component is in the form of a salt, eg, an alkali metal or amine. It will be apparent to those skilled in the art that they may be used as salts, or as acid addition salts or prodrugs, as esters (eg, lower alkyl esters), or as solvates (eg, hydrates). It will also be apparent that where appropriate, the therapeutic ingredients may be used in optically pure form.
The above concomitant drugs can be conveniently presented for use in the form of a pharmaceutical composition, and thus a pharmaceutical composition comprising a concomitant drug as defined above together with a pharmaceutically acceptable diluent or carrier is provided by the present invention. Represents a further embodiment of Such a combination is particularly important in respiratory diseases and is conveniently adapted for inhalation or intranasal delivery.
The individual compounds of such a combination can be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions. Preferably, the individual compounds are administered simultaneously in a combined pharmaceutical composition. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
Syk inhibition can be measured using the following assay protocol:
Biological Assays Homogeneous Time-Resolved Fluorescence (HTRF) Assay of Recombinant Human Syk Enzyme: Recombinant GST-hSyk fusion protein was used to measure the potency of compounds inhibiting human Syk activity. Recombinant human GST-Syk (Carna Biosciences # 08-176) (5 pM final concentration) with various concentrations of inhibitor (diluted in DMSO (0.1% final concentration)) at room temperature for 10 minutes, 15 mM Tris- Incubated in 384 well plate format in HCl (pH 7.5), 0.01% tween 20, 2 mM DTT. To initiate the reaction, a biotinylated substrate peptide containing a Syk phosphorylation site (250 nM final concentration) was added along with magnesium (5 mM final concentration) and ATP (25 μM final concentration). The final volume of the reaction solution was 10 μL. Phosphorylation of the peptide was allowed to proceed for 45 minutes at room temperature. To quench the reaction and detect phosphorylated products, 2 nM europium-antiphosphotyrosine antibody (Perkin Elmer # AD0161) and 70 nM SA-APC (Perkin-Elmer # CR130-100) were added to 15 mM Tris pH 7.5, They were added together in 40 mM EDTA, 0.01% tween 20. The final volume of the quench solution was 10 μL. The resulting HTRF signal was measured 30 minutes later with an EnVision (Perkin-Elmer) reader using a time-resolved fluorescence protocol. IC 50 was determined using a Merck Assay Data Analyzer according to 10 dose titration (10 μM to 0.508 nM) and 4 parameter logistic curve fitting. The rhSyk activity (IC 50 ) is indicated as ++ (100 nM or less), ++ (100 to 1000 nM), + (1 to 10 μM). Also shown are the IC 50 values of the following representative compounds:
The compounds of the invention can be made by a variety of methods, such as standard chemical reactions. The previously defined variable part (if any) continues to have the previously defined meaning unless otherwise stated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
Compounds of general formula I can be prepared by methods known in the art of organic synthesis, some of which are shown in the following synthetic schemes. In all of the schemes described below, it will be appreciated that protecting groups are used for sensitive or reactive groups where necessary in accordance with the general principles of chemical reactions. Protecting groups are manipulated according to standard organic synthetic methods (TW Green and PGM Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). Such groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The choice of protecting group and the reaction conditions and order of the reaction steps shall be consistent with the preparation of the compound of formula I. One skilled in the art will recognize if an asymmetric center exists in the compound of Formula I. Accordingly, the present invention includes all possible stereoisomers and includes not only mixtures of stereoisomers (such as racemic compounds) but also individual stereoisomers as well. If it is desired that the compound is a single enantiomer, this can be obtained by stereospecific synthesis, stereoselective synthesis or resolution of the final product or convenient intermediate (if any). Resolution of the final product, intermediate or starting material can be done by any suitable method known in the art. For example, Stereochemistry of Organic Compounds by E.E. L. Eliel, S.M. H. Wilen, and L.W. N. See Mander (Wiley-Interscience, 1994).
The following abbreviations are used in the schemes and examples: Ac = acetyl; AcOH = acetic acid; Bn = benzyl; Boc (t-Boc) = t-butyloxycarbonyl; BOP = (benzotriazol-1-yloxy) -Tris (dimethylamino) phosphonium hexafluorophosphate; DAST = (diethylamino) sulfur trifluoride; dba = dibenzylideneacetone; DCE = 1,2-dichloroethane; DCM = dichloromethane; Dibal / Dibal-H = diisobutylaluminum hydride; / DIEA = diisopropylethylamine; DMAP = N, N-dimethyl-aminopyridine; DME = 1,2-dimethoxyethane; DMF = dimethylformamide; DMSO = dimethylsulfoxide; Dppf = 1 1′-bis (diphenylphosphino) ferrocene; EDC = N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide; EtOAc = ethyl acetate; HATU = N, N, N ′, N′-tetramethyl-O -(7-azabenzotriazol-1-yl) uronium hexafluorophosphate; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzo-triazole; IPA = isopropyl alcohol; LDA = lithium diisopropylamide; mCPBA = meta- Ms = methanesulfonyl (mesyl); MTBE = methyl t-butyl ether; NBS = N-bromosuccinimide; Ph = phenyl; TBAF = t-butylammonium fluoride; TBDMS / TBS = t-butyldimethylsilyl; TF = Trifluoroacetic acid / trifluoroacetate; THF = tetrahydrofuran; TLC = thin layer chromatography; TMS = trimethylsilyl; Ts = toluenesulfonyl (tolyl); TSA = p-toluenesulfonic acid. Abbreviations for alkyl / cycloalkyl groups: Me = methyl, Et = ethyl, nPr = n-propyl, iPr = isopropyl, nBu = n-butyl, t-Bu = tertiary butyl, cPr = cyclopropyl, cBu = cyclobutyl, cPen = Cyclopentyl, cHex = cyclohexyl, cHept = cycloheptyl.
Compounds of formula I can be prepared by palladium-mediated coupling of substituted aminopyridines (1) and pyridylthiazoles (2). Alternatively, compounds of formula I can be obtained by reacting a substituted aminobispyridine (3) with a substituted thiazole (4).
Compounds of formula (2) may be prepared by coupling a bis-halopyridine of the type (5) with thiazole and a palladium catalyst. Pyridylthiazole (6) can be deprotonated with a strong base such as LDA and reacted with an electrophile such as (7) to give (2).
As shown in Scheme 3, the compound of formula (2) can be obtained by first deprotonating thiazole with a strong base such as LDA and reacting the resulting species with an electrophile such as (7) to obtain a substituted thiazole (8) Can also be prepared. Reaction of thiazole (8) with bis-halopyridine (5) gives the compound of formula (2).
Aminobispyridine (3) can be synthesized according to Scheme 4. Aminopyridine (9) is coupled with bis-halopyridine (10) using a palladium catalyst to give the compound of formula (3).
An example compound of formula I is represented by a carboxylic acid ester (11). The preparation of carboxylic acid (12) and amide (13) is shown in Scheme 5. Hydrolysis of the carboxylic acid ester of type (11) under basic conditions can give the carboxylic acid (12), which is further derivatized with standard amide coupling reagents and amines to give the formula (13 ) Can be obtained.
As shown in Scheme 6, compound (15) of formula can be prepared by reaction of amine (14) with an electrophile such as potassium cyanate.
Compounds of formula I can be prepared according to the procedures described in the schemes and examples herein using appropriate materials and are further illustrated in the specific examples below. The exemplified compounds are illustrative of the invention, but should not be construed as limiting the scope of the invention in any way. In addition, this example provides details of the preparation of the compounds of the present invention. One skilled in the art will readily appreciate that such compounds can be prepared using protecting groups, reagents and known variations of the conditions and processes of the following preparative procedures. It will also be understood that whenever a chemical reagent is not commercially available, such chemical reagent can be readily prepared by one skilled in the art by either following or adapting known methods described in the literature. . All temperatures are in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured using either electrospray ion-mass spectrometry (ESI) or atmospheric pressure chemical ionization mass spectrometry (APCI).
Intermediate 1. Butyl trans-4-acetylcyclohexanecarboxylate
Aerated CH 2 Cl 2 (150 mL) containing trans-4- (butoxycarbonyl) cyclohexanecarboxylic acid (J. Chem. Soc., Perkin Trans. 1, 1999, 20, 3023) (18.9 g, 83 mmol). A catalytic amount of DMF (30 μL) was added to the cooled solution (0 ° C.) under nitrogen, followed by oxalyl chloride (7.97 mL, 91 mmol). The reaction mixture was then allowed to warm slowly to room temperature when it was stirred for 14 hours, at which point it was concentrated to a yellow oil and dried in vacuo for 3 hours. A residue consisting primarily of butyl trans-4- (chlorocarbonyl) cyclohexanecarboxylate was diluted with THF (200 mL) and cooled in an ice bath. To this solution was added PdCl 2 (dppf) —CH 2 Cl 2 (3.38 g, 4.14 mmol) followed by dimethylzinc (2M in PhCH 3 , 29 mL, 58 mmol) (internal temperature above 15 ° C. Not at such a speed). The cooling bath was then removed and after 2 hours of stirring at room temperature, the reaction mixture was recooled to 0 ° C., at which time it was carefully diluted with H 2 O. After the initial exotherm had subsided, enough 1N HCl and EtOAc were introduced to form a homogeneous biphasic mixture. The layers were separated and a second wash of the organic liquid was performed with H 2 O, then dried over MgSO 4 , filtered and concentrated in vacuo. The crude residue was absorbed onto silica and purified by flash chromatography to give butyl trans-4-acetylcyclohexanecarboxylate as a non-viscous orange oil. MS ESI C 13 H 23 O 3 calculated [M + H] + 227, found 227. 1 H NMR (500 MHz, CDCl 3 ) δ 4.06 (t, J = 6.6 Hz, 2H), 2.37-2.29 (m, 1H), 2.28-2.20 (m, 1H) , 2.14 (s, 3H), 2.11-2.02 (m, 2H), 1.99 (d, J = 13.8 Hz, 2H), 1.66-1.55 (m, 2H) , 1.51-1.40 (m, 2H), 1.39-1.29 (m, 4H), 0.93 (t, J = 7.4 Hz, 3H).
Intermediate 2 Trans-4-[(1R) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] butylcyclohexanecarboxylate and trans-4-[(1S) -1-hydroxy-1- (1 , 3-Thiazol-2-yl) ethyl] butyl cyclohexanecarboxylate
A cooled (0 ° C.) flask containing iPrMgCl—LiCl (1.3 M in THF, 55.2 mL, 71.8 mmol) under nitrogen and thiazole (5.10 mL, 71.71) while maintaining the internal temperature <10 ° C. 8 mmol) was added. The resulting heterogeneous mixture was allowed to warm to RT where it was stirred for 10 minutes and then recooled to -20 ° C. A solution of butyl trans-4-acetylcyclohexanecarboxylate (12.5 g, 55.2 mmol) in THF (20 + 5 mL) was then added via syringe. The cooling bath was then removed and the reaction mixture was allowed to warm slowly to 10 ° C. and was observed to be almost completely homogeneous during this period. After 40 minutes, saturated aqueous NH 4 Cl was added followed by EtOAc, the layers were separated, the organics were dried over MgSO 4 , filtered and concentrated in vacuo. The crude residue was absorbed onto silica and purified by flash chromatography to give butyl trans-4- [1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylate as a pale yellow oil. Obtained. Enantiomers were separated by chiral SFC (Chiral Technology AZ-H, 2.1 × 25 cm, 5 uM, 45/55 MeOH / CO 2 , flow rate: 80 mL / min, 6 min run time, wavelength: 220 nm). Elution was observed at 2.98 and 4.14 minutes. The pooled fractions of each peak were concentrated separately under reduced pressure.
Peak 1 (retention time = 2.98 min): calculated for MS ESI C 16 H 25 NO 3 S [M + H] + 312, found 312. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.67 (d, J = 2.9, 1H), 7.51 (d, J = 2.9, 1H), 5.73 (s, 1H) 3.95 (t, J = 6.5, 2H), 2.16-2.01 (m, 1H), 1.95-1.74 (m, 3H), 1.62 (t, J = 11.1, 1H), 1.54-1.34 (m, 6H), 1.34-1.08 (m, 5H), 1.06-0.91 (m, 1H), 0.85 ( t, J = 7.3, 3H).
Peak 2 (retention time = 4.14 minutes): calculated for MS ESI C 16 H 25 NO 3 S [M + H] + 312, observed 312. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.67 (d, J = 2.9, 1H), 7.51 (d, J = 2.9, 1H), 5.73 (s, 1H) 3.95 (t, J = 6.5, 2H), 2.16-2.01 (m, 1H), 1.95-1.74 (m, 3H), 1.62 (t, J = 11.1, 1H), 1.54-1.34 (m, 6H), 1.34-1.08 (m, 5H), 1.06-0.91 (m, 1H), 0.85 ( t, J = 7.3, 3H).
Intermediate 3.6-Bromo-N- (4-cyclopropylpyridin-2-yl) -4-methylpyridin-2-amine
A dry round bottom flask was charged with 2-amino-4-cyclopropylpyridine (5.00 g, 31.7 mmol) and 2,6-dibromo-4-methylpyridine (7.95 g, 31.7 mmol). The reaction vessel was placed under a nitrogen atmosphere (3 vacuum / N 2 cycles), then 1,4-dioxane (100 mL) was added and the mixture was degassed with a steady stream of nitrogen for 30 minutes. Sodium tert-butoxide (3.35 g, 34.8 mmol) and 1,1′-bis (di-tert-butylphosphino) ferrocenepalladium dichloride (0.49 g, 0.75 mmol) were added to the reaction flask and then the reaction The solution was stirred at room temperature for 15 minutes and then heated to 50 ° C. for 5 hours. After cooling to room temperature for 14 hours, the resulting reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were further washed with water and brine (200 mL aliquots). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oil. The crude product was purified by silica gel chromatography (0-30% ethyl acetate / hexanes) to give the title compound as a brown solid. 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.80 (s, 1H), 8.06 (d, J = 5.3 Hz, 1H), 7.70 (s, 1H), 7.23 (s , 1H), 6.92 (s, 1H), 6.61 (dd, J = 1.4, 5.3 Hz, 1H), 2.25 (s, 3H), 1.91-1.78 (m , 1H), 1.09-0.98 (m, 2H), 0.82-0.66 (m, 2H).
Intermediate 4. Trans-4- {1 (R)-[5- (6-Bromopyridin-2-yl) -1,3-thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylate and trans-4- { 1 (S)-[5- (6-Bromopyridin-2-yl) -1,3-thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylate butyl
Step 1: 2,6-Dibromopyridine (11.13 g, 47.0 mmol), pivalic acid (0.545 mL, 4.70 mmol), potassium carbonate (6.49 g, 47.0 mmol) in N, N-dimethylacetamide ( (45 mL) The suspension was deoxygenated by bubbling argon through this solution for 20 minutes. Thiazole (1.681 mL, 23.49 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.086 g, 0.940 mmol) were added, the flask was sealed and the reaction mixture was heated to 115 ° C. for 18 hours. The reaction mixture was cooled to room temperature and then diluted with water (50 mL), ethyl acetate (50 mL) and diethyl ether (50 mL). The layers were separated then the organic layer was washed with water (2 × 50 mL), saturated aqueous sodium bicarbonate (25 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-60% ethyl acetate / hexane) to give 2-bromo-6- (1,3-thiazol-5-yl) pyridine. Calculated for MS ESI C 8 H 5 BrN 2 S [M + H] + 241 and 243, found 241 and 243. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.19 (s, 1H), 8.64 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.83 (t , J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H).
Step 2: To a solution of 2-bromo-6- (1,3-thiazol-5-yl) pyridine (457 mg, 1.895 mmol) in tetrahydrofuran (20 mL) at −78 ° C. at lithium diisopropylamide (tetrahydrofuran / heptane / ethylbenzene 1 .8M, 1.106 mmol, 1.990 mmol) was added over 3 minutes. After 30 minutes, a solution of butyl trans-4-acetylcyclohexanecarboxylate (450 mg, 1.990 mmol) in tetrahydrofuran (3 mL) was added to the reaction mixture. After an additional 70 minutes, saturated aqueous ammonium chloride (10 mL) was added. The reaction mixture was then warmed to room temperature and diluted with ethyl acetate (50 mL), water (2 mL) and saturated aqueous ammonium chloride (10 mL). The layers were separated and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0 to 20% ethyl acetate / dichloromethane), trans-4- {1- [5- (6-bromopyridin-2-yl) -1,3-thiazol- 2-yl] -1-hydroxyethyl} butylcyclohexanecarboxylate was obtained. MS ESI C 21 H 27 BrN 2 O 3 S calculated [M + H] + 467 and 469, found 467 and 469.2 enantiomers were separated by chiral supercritical liquid chromatography (Chiral Technology IC-H, 2 1 × 25 cm, 5 uM, 70/30 ethanol / CO 2 , flow rate: 70 mL / min, 6 min run time, wavelength: 220 nm). Elution was observed at 3.98 and 4.76 minutes. The pooled fraction of each peak was concentrated under reduced pressure.
Enantiomer 1 (retention time = 3.98 min): 1 H NMR (500 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.61-7.51 (m, 2H), 7.37 (dd, J = 2.7, 5.9 Hz, 1H), 4.04 (t, J = 6.6 Hz, 2H), 3.00 (s, 1H), 2.22-2.16 (m, 1H), 2.08-2.01 (m, 1H), 1.99 (d, J = 13.4 Hz, 2H), 1.83-1.76 (m, 1H), 1.62-1.56 (m , 3H), 1.61 (s, 3H), 144-1.34 (m, 4H), 1.32-1.24 (m, 1H), 1.22-1.15 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H). Enantiomer 2 (retention time = 4.76 min): 1 H NMR (500 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.61-7.51 (m, 2H), 7.37 (dd, J = 2.7, 5.9 Hz, 1H), 4.04 (t, J = 6.6, 2H), 2.99 (s, 1H), 2.25-2.17 (m, 1H), 2.08-2.02 (m, 1H), 1.99 (d, J = 12.8 Hz, 2H), 1.82-1.75 (m, 1H), 1.63 (s, 3H), 1.62-1.56 (m, 3H), 1.43 (m, 1H), 1.40-1.24 (m, 3H), 1.30-1.24 (m, 1H), 1. 21-1.15 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H).
Intermediate 5. 6-Bromo-4-methyl-N- [4- (trifluoromethyl) pyridin-2-yl] pyridin-2-amine
Sodium tert-butoxide (5.87 g, 61.1 mmol) and 1,1′-bis (di-tert-butylphosphino) ferrocenepalladium dichloride (0.905 g, 1.4 mmol) were added to 2,6-dibromo-4. -To a solution of nitrogen spargedioxane (180 mL) containing methylpyridine (13.9 g, 55.5 mmol) and 2-amino-4-trifluoromethylpyridine (9.0 g, 55.5 mmol). The slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25 ° C. for 15 minutes and then heated to 75 ° C. for 12 hours. The reaction mixture was cooled to 25 ° C., water (20 mL) was added and the mixture was extracted with ethyl acetate (2 × 200 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 6-bromo-4-methyl-N- [4- (trifluoromethyl) pyridin-2-yl] pyridin-2-amine as a white solid. MS ESI C 12 H 10 BrF 3 N 3 calculated [M + H] + 332 and 334, found 332 and 334. 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.40 (s, 1 H), 8.46 (d, J = 6.0 Hz, 1 H), 7.90 (s, 1 H), 7.60 (s , 1H), 7.18 (d, J = 6.0 Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).
The intermediates in the table below were prepared according to the method described for intermediate 5.
Intermediate 6. 2,6-dichloro-4-cyclopropylpyridine
Cyclopropylzinc bromide (0.5 M in tetrahydrofuran, 15 mL, 7.3 mmol) was added to 2,6-dichloro-4-iodopyridine (1.0 g, 3.65 mmol) and tetrakis (triphenylphosphine) palladium (0). To a mixture of (211 mg, 0.182 mmol) and anhydrous tetrahydrofuran (10 mL) was added at 0 ° C. After stirring at room temperature for 4 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 100: 1) to give 2,6-dichloro-4-cyclopropylpyridine. MS ESI C 8 H 8 Cl 2 N calculated [M + H] + 188, found 188. 1 H NMR: (400 MHz, CDCl 3 ) δ 6.89 (s, 2H), 1.87-1.80 (m, 1H), 1.18-1.13 (m, 2H), 0.84- 0.80 (m, 2H).
Intermediate 7.6-Bromo-N- [4- (difluoromethyl) pyridin-2-yl] -4-methylpyridin-2-amine
Potassium t-butoxide (1.0 M in THF, 198 mL, 198 mmol) was added to 6-bromo-4-methylpyridin-2-amine (37 g, 198 mmol) and 2-chloro-4- (difluoromethyl) pyridine (42.1 g). , 257 mmol) in THF (60 mL). The resulting mixture was heated to reflux for 30 minutes, then cooled to 0 ° C. and a second portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes, cooled to 0 ° C., and a third portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes. After cooling to 0 ° C., a fourth portion of potassium t-butoxide (1.0 M in THF, 20 mL, 20 mmol) was added. After refluxing for 30 minutes, the reaction was allowed to cool to room temperature, then diluted with saturated aqueous NH 4 Cl (500 mL) and diluted with DCM (500 mL). The layers were separated and a second extraction of the aqueous layer was performed with DCM (500 mL). The combined organic layers were dried over Na 2 SO 4 , filtered through a celite pad (150 g) and concentrated in vacuo. The residue was triturated with DCM (100 mL), filtered, washed with hexane (2 × 50 mL) and a portion of 6-bromo-N- [4- (difluoromethyl) pyridin-2-yl] -4. -Methylpyridin-2-amine was obtained. The filtrate was concentrated, absorbed onto silica gel and purified by silica gel column chromatography (EtOAc / hexane), a second portion of 6-bromo-N- [4- (difluoromethyl) pyridin-2-yl]- 4-Methylpyridin-2-amine was obtained. Calc'd for MS ESI C 12 H 11 BrF 2 N 3 [M + H] + 314 and 316, found 314 and 316. 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 7.69 (s, 1H), 7.64 (s , 1H), 7.01 (d, J = 5.1 Hz, 1H), 6.96 (t, J = 22.3 Hz, 1H), 6.95 (s, 1H), 2.24 (s, 3H) ).
Intermediate 8 Methyl trans-4- [cyclopropyl (hydroxy) 1,3-thiazol-2-ylmethyl] cyclohexanecarboxylate
Step 1: Oxalyl chloride (0.26 mL, 2.95 mmol) was added dropwise to a solution of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (500 mg, 2.69 mmol) in dichloromethane (3 mL) at 0 ° C. The solution was stirred at 0 ° C. for 30 minutes, then warmed to room temperature and stirred for 1 hour. The solution was then cooled back to 0 ° C. and 2- (trimethylsilyl) -1,3-thiazole (0.63 mL, 4.03 mmol) was added. The solution was allowed to warm to room temperature and then stirred for 1 hour. The solution was then poured into chilled saturated sodium bicarbonate and then diluted with dichloromethane. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% ethyl acetate / hexanes) to give methyl trans-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate. MS ESI C 12 H 16 NO 3 S calculated [M + H] + 254, found 254. 1 H NMR (500 MHz, CDCl 3 ) δ 8.01 (dd, J = 1.6, 2.9 Hz, 1H), 7.67 (dd, J = 1.7, 2.9 Hz, 1H), 3. 77-3.67 (m, 3H), 3.62 (t, J = 11.1 Hz, 1H), 2.35 (t, J = 10.4 Hz, 1H), 2.18-2.06 (m , 4H), 1.68-1.48 (m, 4H).
Step 2: cyclopropylmagnesium bromide (THF) in a solution of methyl trans-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate (2.59 g, 10.22 mmol) in THF (10 mL) at −78 ° C. 0.5M, 24 mL, 12.00 mmol) was added and the solution was stirred at this temperature for 3 hours. The solution was then warmed for 15 minutes and then quenched with aqueous ammonium chloride. The solution was diluted with dichloromethane and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% ethyl acetate / hexanes). The product was further purified by reverse phase chromatography (25-100% acetonitrile / water with 0.1% TFA modifier) and trans-4- [cyclopropyl (hydroxy) 1,3-thiazol- Methyl 2-ylmethyl] cyclohexanecarboxylate was obtained. MS ESI C 15 H 22 NO 3 S calculated [M + H] + 296, found 296. 1 H NMR (500 MHz, CDCl 3 ) δ 7.77 (d, J = 3.4 Hz, 1H), 7.37 (d, J = 3.4 Hz, 1H), 3.65 (s, 3H), 2 .28-2.17 (m, 1H), 2.13-2.02 (m, 3H), 2.01-1.90 (m, 2H), 1.56-1.48 (m, 1H) , 1.48-1.39 (m, 1H), 1.39-1.32 (m, 1H), 1.33-1.19 (m, 3H), 0.75-0.62 (m, 1H), 0.61-0.50 (m, 1H), 0.42-0.25 (m, 2H).
Intermediate 9 Methyl trans-4- [2,2,2-trifluoro-1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylate
To a solution of methyl trans-4- (thiazole-2-carbonyl) cyclohexanecarboxylate (1.1 g, 4.34 mmol) in THF (20 mL) was added trifluoromethyltrimethylsilane (1.286 mL, 8.68 mmol) at 0 ° C. did. Tetrabutylammonium fluoride trihydrate (1M in THF, 17.37 mL, 17.37 mmol) was added slowly while maintaining the temperature at 0 ° C. The reaction was stirred for 1 hour, then water (30 mL) and ethyl acetate (30 mL) were added to quench the reaction. The organic layer was removed and washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (hexane containing 0 to 20% ethyl acetate) and trans-4- [2,2,2-trifluoro-1-hydroxy-1- (1,3-thiazol- 2-yl) ethyl] methyl cyclohexanecarboxylate was obtained. MS ESI C 13 H 17 F 3 NO 3 S calculated [M + H] + 324, found 324. 1 H NMR (500 MHz, CDCl 3 ) δ 7.79 (d, J = 3.2 Hz, 1H), 7.49 (d, J = 3.2 Hz, 1H), 4.77 (s, 1H), 3 .65 (s, 3H), 2.40 (m, 1H), 2.30-1.90 (m, 3H), 1.50-1.20 (m, 6H).
Intermediate 10 methyl trans-4- [hydroxy (1,3-thiazol-2-yl) methyl] cyclohexanecarboxylate
Sodium borohydride (224 mg, 5.92 mmol) was added to a solution of methyl trans-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate (500 mg, 1.97 mmol) in methanol (20 mL). The solution was stirred for 1 hour. The solution was then diluted with ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography to give methyl trans-4- [hydroxy (1,3-thiazol-2-yl) methyl] cyclohexanecarboxylate. MS ESI C 12 H 18 NO 3 S calculated [M + H] + 256, found 256. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.70 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 6.10 (d, J = 5.2 Hz, 1H), 4.59 (t, J = 5.1 Hz, 1H), 3.54 (s, 3H), 2.21-2.11 (m, 1H), 1.92-1. 83 (m, 2H), 1.75-1.64 (m, 1H), 1.64-1.53 (m, 2H), 1.33-1.11 (m, 4H).
Intermediate 11. (1S, 3R) -3- (Thiazole-2-carbonyl) cyclopentanecarboxylate methyl.
(1S, 3R) -3- (Thiazole-2-carbonyl) cyclopentanecarboxylic acid methyl ester
To a solution of (1R, 3S) -3- (methoxycarbonyl) cyclopentanecarboxylic acid (130 mg, 0.76 mmol) in dichloromethane (3 mL) was added DMF (5.85 μL, 0.08 mmol). The solution was cooled to 0 ° C. and oxalyl chloride (73.0 μL, 0.83 mmol) was added. The mixture was stirred at 0 ° C. for 30 minutes and then allowed to warm to room temperature for 1 hour. The reaction was re-cooled to 0 ° C., 2- (trimethylsilyl) thiazole (178.0 mL, 1.13 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give methyl (1S, 3R) -3- (thiazole-2-carbonyl) cyclopentanecarboxylate. MS ESI C 11 H 14 NO 3 S calculated [M + H] + 240, found 240. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.21 (d, J = 3.0 Hz, 1H), 8.14 (d, J = 3.0 Hz, 1H), 3.58 (s, 3H) 2.96-2.89 (m, 1H), 2.27-2.20 (m, 1H), 1.74-2.04 (m, 6H)
Intermediate 12 (1S, 3R) -3- (1-Hydroxy-1- (thiazol-2-yl) ethyl) methyl cyclopentanecarboxylate
Methyl magnesium bromide (582 mL, 1.75 mmol) was added to a solution of methyl (1S, 3R) -3- (thiazole-2-carbonyl) cyclopentanecarboxylate (148 mg, 1.75 mmol) in THF (6 mL) at −78 ° C. And the solution was stirred at −78 ° C. for 30 minutes. Saturated aqueous ammonium chloride was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was absorbed onto silica and purified by flash chromatography to give methyl (1S, 3R) -3- (1-hydroxy-1- (thiazol-2-yl) ethyl) cyclopentanecarboxylate. MS ESI C 12 H 18 NO 3 S calculated [M + H] + 256, found 256. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.67 (t, J = 3.0 Hz, 1H), 7.50 (d, J = 3.0 Hz, 1H), 3.58-3.57 ( m, 3H), 3.52 (s, 1H), 2.75-2.62 (m, 1H), 2.43-2.35 (m, 1H), 1.97-1.91 (m, 1H), 1.78-1.51 (m, 4H), 1.46-1.44 (m, 3H), 1.25-1.19 (m, 1H).
Intermediate 13. (1S, 4S) -4-[(1S) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] -2,2-dimethylcyclohexanecarboxylate methyl (1S, 4S) -4- [(1R) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] -2,2-dimethylcyclohexanecarboxylate methyl (1S, 4R) -4-[(1S) -1-hydroxy -1- (1,3-thiazol-2-yl) ethyl] -2,2-dimethylcyclohexanecarboxylate methyl (1S, 4R) -4-[(1R) -1-hydroxy-1- (1,3- Thiazol-2-yl) ethyl] -2,2-dimethylcyclohexanecarboxylate methyl ester
Step 1: To a suspension of (methoxymethyl) triphenylphosphonium chloride (38 g, 111 mmol) in THF (300 mL) was added potassium tert-butoxide (1.0 M in THF, 111 mL, 111 mmol) at 0 ° C. Was added at such a rate as not to exceed. After stirring at 0 ° C. for 1 hour, a solution of methyl (1S) -2,2-dimethyl-4-oxocyclohexanecarboxylate (17 g, 92 mmol) in THF (100 mL) was cannulated so that the internal temperature did not exceed 7 ° C. Added at a rate. When complete, the mixture was slowly warmed to room temperature and stirred for 14 hours. The reaction mixture was then cooled to 10 ° C. and diluted with water (100 mL) followed by 6M HCl (250 mL). The resulting mixture was stirred for 3 hours, then more water (400 mL) and EtOAc (500 mL) were added. The organic layer was separated and a second extraction of the aqueous layer was performed with EtOAc (500 mL). The combined organic layers were dried over MgSO 4 , filtered, absorbed onto silica gel, purified by silica gel chromatography, methyl (1R, 4R) -4-formyl-2,2-dimethylcyclohexanecarboxylate and (1R , 4S) -4-formyl-2,2-dimethylcyclohexanecarboxylate methyl mixture was obtained. The product was used directly in the subsequent step. To a cooled (−5 ° C.) solution of iPrMgCl—LiCl (1.3 M in THF, 64 mL, 83 mmol) was added thiazole (6.27 mL, 88 mmol) at a rate such that the internal temperature did not exceed 5 ° C. After the addition was complete, the resulting slurry was warmed to 15 ° C. over 15 minutes and then cooled to −10 ° C. To this slurry was added (1R, 4R) -4-formyl-2,2-dimethylcyclohexanecarboxylate and methyl (1R, 4S) -4-formyl-2,2-dimethylcyclohexanecarboxylate (13.8 g, 69.6 mmol). ) As a THF (30 mL) solution at a rate such that the internal temperature does not exceed 5 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and then quenched with water (50 mL). EtOAc (500 mL) and 1N HCl (300 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The organic layers were combined, dried over MgSO 4 , filtered, absorbed onto silica gel and purified by silica gel chromatography to give a diastereomeric mixture that was used directly in the subsequent step.
Dess-Martin periodinane (25.4 g, 60 mmol) was added to the above mixture of secondary alcohol (16.3 g, 575 mmol) and dichloromethane (150 mL) at 10 ° C. Once the temperature was raised to room temperature, the temperature was controlled so that the internal temperature did not exceed 35 ° C. After 1 hour, the reaction mixture was cooled to room temperature and diluted sequentially with saturated aqueous NaHCO 3 solution (300 mL), 5% aqueous sodium sulfite (200 mL), and additional dichloromethane (350 mL). This heterogeneous mixture was stirred until both layers were clear, then the layers were separated and a second extraction of the aqueous layer was performed with dichloromethane (500 mL). The organic layers were combined, dried over MgSO 4 , filtered, absorbed onto silica, purified by silica gel chromatography and (1S, 4S) -2,2-dimethyl-4- (1,3-thiazol-2). A mixture of methyl -ylcarbonyl) cyclohexanecarboxylate and methyl (1S, 4R) -2,2-dimethyl-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate was obtained. The mixture was further purified by SFC to give the above compound as only one stereoisomer.
Characterization data for (1S, 4S) -2,2-dimethyl-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate: calculated for MS ESI C 14 H 20 NO 3 S [M + H] + 282, measured value 282. 1 H NMR (600 MHz, CD 3 OD) δ 8.04 (d, J = 3.1 Hz, 1H), 7.93 (d, J = 3.0 Hz, 1H), 3.85 (tt, J = 12 .5, 3.4 Hz, 1H), 3.64 (s, 3H), 2.24 (dd, J = 12.8, 3.6 Hz, 1H), 2.00 (ddd, J = 12.7, 5.6, 3.1 Hz, 1H), 1.88 (ddd, J = 26.6, 13.6, 3.9 Hz, 1H), 1.75 (ddd, J = 13.9, 7.0, 3.7 Hz, 1H), 1.69 (ddd, J = 13.2, 3.1, 2.1 Hz, 1H), 1.46-1.35 (m, 2H), 1.05 (s, 3H) ), 1.01 (s, 3H).
Characterization data for (1S, 4R) -2,2-dimethyl-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate: calculated for MS ESI C 14 H 20 NO 3 S [M + H] + 282, measured value 282. 1 H NMR (600 MHz, CD 3 OD) δ 8.02 (d, J = 3.1 Hz, 1H), 7.91 (d, J = 3.1 Hz, 1H), 3.81 (tt, J = 11 .9, 3.8 Hz, 1H), 3.61 (s, 3H), 2.35 (d, J = 3.8 Hz, 1H), 2.03 (t, J = 12.6 Hz, 1H), 1 .99-1.88 (m, 2H), 1.84-1.70 (m, 2H), 1.51-1.45 (m, 1H), 1.10 (s, 3H), 0.91 (S, 3H).
Step 2: (1S, 4R) -2,2-dimethyl-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate (2.3 g, 8.2 mmol) cooled in THF (20 mL) (−40 To the solution, MeMgBr (3.0 M in THF, 3.3 mL, 9.8 mmol) was added at a rate such that the internal temperature did not rise above −30 ° C. The mixture was then stirred at −40 ° C. for 15 minutes, quenched with saturated aqueous ammonium chloride (40 mL) and allowed to warm to room temperature. EtOAc (20 mL) was added, the layers were separated, and a second extraction of the aqueous layer was performed with EtOAc (30 mL). The organic layers were combined, dried over MgSO 4 , filtered, absorbed onto silica and purified by silica gel chromatography to yield (1S, 4R) -4-[(1S) -1-hydroxy-1- (1, 3-Thiazol-2-yl) ethyl] -2,2-dimethylcyclohexanecarboxylate and (1S, 4R) -4-[(1R) -1-hydroxy-1- (1,3-thiazol-2-yl) ) Ethyl] -2,2-dimethylcyclohexanecarboxylate mixture was obtained. Further purification by SFC gave the single diastereomer. MS ESI C 15 H 24 NO 3 S calculated [M + H] + 298, found 298.
Step 3: (1S, 4S) -2,2-dimethyl-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate (11.6 g, 41.1 mmol) cooled in THF (110 mL) (- To the solution was added MeMgBr (3.0 M in THF, 16.5 mL, 49.5 mmol) at a rate such that the internal temperature did not rise above −30 ° C. The reaction mixture was stirred at −40 ° C. for 15 minutes, quenched with saturated aqueous ammonium chloride (200 mL) and allowed to warm to room temperature. EtOAc (110 mL) was added, the layers were separated, and a second extraction of the aqueous layer was performed with EtOAc (110 mL). The organic layers were combined, dried over MgSO 4 , filtered, absorbed onto silica and purified by silica gel chromatography to obtain (1S, 4S) -4-[(1S) -1-hydroxy-1- (1, 3-Thiazol-2-yl) ethyl] -2,2-dimethylcyclohexanecarboxylate and (1S, 4S) -4-[(1R) -1-hydroxy-1- (1,3-thiazol-2-yl) ) ethyl] -2, to obtain a mixture of 2-dimethylcyclohexane carboxylate. Further purification by SFC gave the single diastereomer.
Characterization data of peak 1 by SFC: calculated value of MS ESI C 15 H 24 NO 3 S [M + H] + 298, measured value 298. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.68 (d, J = 3.3 Hz, 1H), 7.50 (d, J = 3.2 Hz, 1H), 5.71 (s, 1H) , 3.53 (s, 3H), 1.98 (dd, J = 3.9, 12.5 Hz, 1H), 1.89 (tt, J = 3.3, 12.3 Hz, 1H), 1. 83-1.75 (m, 1H), 1.65-1.49 (m, 2H), 1.42 (s, 3H), 1.14 (t, J = 12.7 Hz, 1H), 08-1.01 (m, 1H), 0.98-0.88 (m, 1H), 0.84 (s, 3H), 0.77 (s, 3H).
Characterization data of peak 2 by SFC: calculated value of MS ESI C 15 H 24 NO 3 S [M + H] + 298, measured value 298. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.68 (d, J = 3.3 Hz, 1H), 7.51 (d, J = 3.3 Hz, 1H), 5.71 (s, 1H) , 3.53 (s, 3H), 1.98 (dd, J = 3.9, 12.4 Hz, 1H), 1.86 (tt, J = 3.2, 12.5 Hz, 1H), 1. 58-1.51 (m, 1H), 1.51 (s, 2H), 1.43 (s, 3H), 1.41-1.33 (m, 1H), 1.16-1.06 ( m, 1H), 0.93 (t, J = 12.3 Hz, 1H), 0.90 (s, 3H), 0.83 (s, 3H).
Intermediate 14.4- [1-Hydroxy-1- (1,3-thiazol-2-yl) ethyl] -2-methylcyclohexanecarboxylate ethyl
Step 1: (Methoxymethyl) triphenylphosphonium chloride (155 g, 452 mmol) in THF (700 mL) cooled (0 ° C.) suspension with potassium tert-butoxide (1.0 M in THF, 452 mL, 452 mmol), internal temperature It was added at such a rate that it did not exceed 7 ° C. The mixture was stirred at 0 ° C. for 1 hour, and then a solution of ethyl 2-methyl-4-oxocyclohexanecarboxylate (64 g, 347 mmol) in THF (150 mL) was cannulated at a rate such that the internal temperature did not exceed 7 ° C. Added. The mixture was then allowed to warm slowly to room temperature and stirred for 14 hours. The reaction mixture was then cooled to 10 ° C. and diluted with water (200 mL) followed by 6M HCl (500 mL). The resulting mixture was stirred for 3 hours and then further diluted with water (400 mL) and EtOAc (700 mL). The organic layer was separated and a second extraction of the aqueous layer was performed with EtOAc (700 mL). The organic layers were combined, dried over MgSO 4 , filtered, absorbed onto silica gel and purified by silica gel chromatography to give ethyl 4-formyl-2-methylcyclohexanecarboxylate, which was directly used in the subsequent step. used.
To a cooled solution of iPrMgCl—LiCl (1.3 M in THF, 187 mL, 243 mmol) at −5 ° C. thiazole (17.4 mL, 243 mmol) was added at a rate such that the internal temperature did not exceed 5 ° C. The resulting slurry was warmed to 15 ° C. over 15 minutes and then cooled to −10 ° C. To the reaction mixture, ethyl 4-formyl-2-methylcyclohexanecarboxylate (41 g, 207 mmol) was added as a THF (100 mL) solution at a rate such that the internal temperature did not exceed 5 ° C. The reaction mixture was stirred at 0 ° C. for 30 min, then quenched with water (100 mL) and diluted with EtOAc (500 mL) and 1N HCl (500 mL). The organic layer was separated and the aqueous layer was extracted again with EtOAc (700 mL). The organic layers were combined, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was diluted with DCM (500 mL) and Dess-Martin periodinane (88 g, 208 mmol) was added to the mixture. During the addition, the temperature was controlled so that the internal temperature did not exceed 35 ° C. After 1 hour, the reaction mixture was cooled to room temperature and then diluted with saturated aqueous NaHCO 3 (600 mL), aqueous 5% sodium sulfite (600 mL) and dichloromethane (600 mL). This heterogeneous mixture was stirred until both layers were clear. The layers were separated and a second extraction of the aqueous layer was performed with dichloromethane (600 mL). The organic layers were combined, dried over MgSO 4 , filtered, absorbed onto silica, purified by silica gel chromatography and ethyl 2-methyl-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate. Got. MS ESI C 14 H 20 NO 3 S calculated [M + H] + 282, found 282.
Step 2: MeMgBr (3.0 M in THF) was added to a solution of ethyl 2-methyl-4- (1,3-thiazol-2-ylcarbonyl) cyclohexanecarboxylate (2.8 g, 10 mmol) in THF (28 mL) at −40 ° C. , 4.0 mL, 12 mmol) was added at a rate such that the internal temperature did not exceed −30 ° C. The reaction mixture was stirred at −40 ° C. for 15 minutes, then quenched with saturated aqueous ammonium chloride (50 mL) and allowed to warm to room temperature. EtOAc (20 mL) was added, the layers were separated, and a second extraction of the aqueous layer was performed with EtOAc (50 mL). The organic layers were combined, dried over MgSO 4 , filtered, absorbed onto silica and purified by silica gel chromatography to give 4- [1-hydroxy-1- (1,3-thiazol-2-yl) ethyl]. Ethyl-2-methylcyclohexanecarboxylate was obtained.
The stereoisomer mixture was separated into four fractions in order of elution time by SFC (ES Industries GreenSeppyridine Amide, 21 × 250 mm, 5 microns, 5% MeOH / 95% CO 2 , 50 mL / min). These four fractions were then further separated using the following conditions (Chiralpak AD-H 21X250 mm, 5 microns, 220 nm UV, 100 bar outlet pressure, 70 mL / min. Each solvent used was: As shown in the diagram.
Intermediate 15: (4R) -4-[(1S) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] pyrrolidin-2-one (4R) -4-[(1R)- 1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] pyrrolidin-2-one
Step 1: To a solution of thiazole (3.13 mL, 44 mmol) in THF (50 mL) at −78 ° C. was added nBuLi at a rate such that the internal temperature did not exceed −65 ° C. The reaction mixture was stirred for 15 min and then (4R) -4-acetyl-1-[(1S) -1- (4-methoxyphenyl) ethyl] pyrrolidin-2-one (10 g, 38.3 mmol) in THF ( 50 mL) solution was added via cannula at a rate such that the internal temperature did not exceed -65 ° C. The mixture was stirred for 1 hour, quenched with saturated aqueous ammonium chloride (50 mL) and allowed to warm to room temperature. EtOAc (50 mL) and water (50 mL) were added. The layers were separated and a second extraction of the aqueous layer was performed with EtOAc (50 mL). The organic layers were combined, dried over MgSO 4 , filtered, absorbed onto silica and purified by silica gel chromatography to give (4R) -4-[(1S) -1-hydroxy-1- (1,3- Thiazol-2-yl) ethyl] -1-[(1S) -1- (4-methoxyphenyl) ethyl] pyrrolidin-2-one and (4R) -4-[(1R) -1-hydroxy-1- ( 1,3-thiazol-2-yl) ethyl] -1-[(1S) -1- (4-methoxyphenyl) ethyl] pyrrolidin-2-one was obtained.
The less polar diastereomer (4R) -4-[(1S) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] -1-[(1S) -1- (4 - methoxyphenyl) ethyl] pyrrolidin-2-one characterization data: calculated for MS ESI C 18 H 23 N 2 O 3 S [M + H] + 347, Found 347. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.67 (d, J = 3.2 Hz, 1H), 7.51 (d, J = 3.2 Hz, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.08 (s, 1H), 5.10 (q, J = 7.1 Hz, 1H), 3.70 ( s, 3H), 3.35 (t, J = 9.4 Hz, 1H), 2.89 (dd, J = 9.8, 7.1 Hz, 1H), 2.82-2.72 (m, 1H) ), 2.43 (dd, J = 16.9, 8.2 Hz, 1H), 2.00 (dd, J = 16.9, 9.8 Hz, 1H), 1.37-1.35 (m, 6H).
The more polar diastereomer (4R) -4-[(1R) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] -1-[(1S) -1- (4 - methoxyphenyl) ethyl] pyrrolidin-2-one characterization data: calculated for MS ESI C 18 H 23 N 2 O 3 S [M + H] + 347, Found 347. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.66 (d, J = 3.2 Hz, 1H), 7.51 (d, J = 3.2 Hz, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.08 (s, 1H), 5.14 (dd, J = 14.2, 7.0 Hz, 1H), 3.70 (s, 3H), 2.99-2.90 (m, 1H), 2.88-2.78 (m, 2H), 2.40-2.30 (m, 2H), 1. 33 (s, 3H), 1.30 (d, J = 7.1 Hz, 3H).
Step 2: (4R) -4-[(1S) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] -1-[(1S) -1- (4-methoxyphenyl) ethyl A solution of pyrrolidin-2-one (3.6 g, 10.4 mmol) in TFA (10 mL) was heated to 70 ° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with IPA (30 mL) and stirred until the color disappeared. The reaction mixture was then absorbed onto silica gel and purified by silica gel chromatography to give (4R) -4-[(1S) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] pyrrolidine-2. -Obtained ON. MS ESI C 9 H 13 N 2 O 2 S calculated [M + H] + 213, found 213. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.68 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H), 7.39 (s, 1H) 6.10 (s, 1H), 3.25 (t, J = 9.2 Hz, 1H), 3.19 (dd, J = 9.6, 7.4 Hz, 1H), 2.91-2. 81 (m, 1H), 2.20 (dd, J = 16.7, 8.6 Hz, 1H), 1.77 (dd, J = 16.7, 9.6 Hz, 1H), 1.43 (s , 3H).
Step 3: (4R) -4-[(1R) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] -1-[(1S) -1- (4-methoxyphenyl) ethyl A solution of pyrrolidin-2-one (3.6 g, 10.4 mmol) in TFA (10 mL) was heated to 70 ° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with IPA (30 mL) and stirred until the color disappeared. The reaction mixture was then absorbed onto silica gel and purified by silica gel chromatography to give (4R) -4-[(1R) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] pyrrolidine-2. -Obtained ON. MS ESI C 9 H 13 N 2 O 2 S calculated [M + H] + 213, found 213. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.69 (d, J = 3.2 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H), 7.35 (s, 1H) 6.12 (s, 1H), 3.08 (dd, J = 9.1, 7.3 Hz, 1H), 2.96-2.86 (m, 1H), 2.82 (t, J = 9.0 Hz, 1 H), 2.22 (dd, J = 16.8, 8.7 Hz, 1 H), 2.14 (dd, J = 16.8, 9.6 Hz, 1 H), 1.42 (s , 3H).
Racemic trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl ) -1-hydroxypropyl] cyclohexanecarboxylic acid, trans-4-[(1R) -1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridine-2- Yl} -1,3-thiazol-2-yl) -1-hydroxypropyl] cyclohexanecarboxylic acid, and trans-4-[(1S) -1- (5- {6-[(4-cyclopropylpyridine-2) -Yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxypropyl] cyclohexanecarboxylic acid
Step 1: A dry round bottom flask was charged with trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (2.00 g, 10.74 mmol) and the reaction vessel was placed under an argon atmosphere (3 vacuum / argon cycles). Dichloromethane (11 mL) was added followed by DMF (0.01 mL, 0.129 mmol). The reaction was cooled to 0 ° C. in an ice bath and then oxalyl chloride (1.00 mL, 11.42 mmol) was added dropwise. After 1 hour, when the ice bath was removed, slow gas evolution occurred and the reaction was stirred at ambient temperature for 14 hours. [1,1′-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) (236.0 mg, 0.322 mmol) was then added to the reaction flask followed by tetrahydrofuran (11 mL), followed by diethylzinc in tetrahydrofuran ( 1.0M, 12.9 mL, 12.9 mmol) solution was added. The reaction was stirred at ambient temperature for 2 hours and then poured into cold saturated aqueous ammonium chloride (100 mL). The resulting biphasic solution was diluted with diethyl ether (100 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate / hexane) to give methyl trans-4-propanoylcyclohexanecarboxylate as a clear oil. 1 H NMR (500 MHz, CDCl 3 ) δ 3.67 (s, 3H), 2.47 (q, J = 7.3 Hz, 2H), 2.40-2.21 (m, 2H), 2.12 −2.00 (m, 2H), 1.94 (d, J = 13.9 Hz, 2H), 1.53-1.20 (m, 4H), 1.03 (t, J = 7.3 Hz, 3H).
Step 2: Isopropylmagnesium chloride lithium chloride (1.3M in THF, 6.66 mL, 8.66 mmol) was added dropwise at 0 ° C. to a solution of thiazole (0.675 mL, 9.44 mmol) in THF (5 mL). The reaction was stirred for 30 minutes and the ice bath was removed. Stirring was then continued for 10 minutes before the reaction was re-cooled in an acetone / dry ice bath and then methyl trans-4-propanoylcyclohexanecarboxylate (1.56 g, 7.87 mmol) in THF (15 mL). The solution was transferred by cannula. The reaction was stirred for 1 hour and the cooling bath was removed. When the heating was complete (about 1 hour), the reaction was diluted with saturated aqueous ammonium chloride (75 mL) and the resulting biphasic mixture was transferred to a separatory funnel. The organic phase was diluted with ethyl acetate (125 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate / hexane) and methyl trans-4- [1-hydroxy-1- (1,3-thiazol-2-yl) propyl] cyclohexanecarboxylate was obtained. Obtained. MS ESI C 14 H 22 NO 3 S calculated [M + H] + 284, found 284. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.70 (d, J = 3.3 Hz, 1H), 7.49 (d, J = 3.3 Hz, 1H), 3.53 (s, 3H) , 2.07 (t, J = 12.1 Hz, 1H), 1.95-1.63 (m, 4H), 1.44-1.06 (m, 6H), 1.01-0.81 ( m, 2H), 0.65 (t, J = 7.3 Hz, 3H).
Step 3: 6-Bromo-N- (4-cyclopropylpyridin-2-yl) -4-methylpyridin-2-amine (263 mg, 0.865 mmol), trans-4- [1-hydroxy-1- (1 , 3-thiazol-2-yl) propyl] cyclohexanecarboxylate (245 mg, 0.865 mmol), pivalic acid (151 μl, 1.297 mmol), potassium carbonate (358 mg, 2.59 mmol), π-allyl palladium chloride (II) ) The dimer (31.6 mg, 0.086 mmol) and butyldi-1-adamantylphosphine (124 mg, 0.346 mmol) were combined and the reaction flask was placed under an inert atmosphere (3 vacuum / argon cycles), then Degassed and dimethylacetamide (2 mL) was added. The reaction was heated to 100 ° C. for 5 hours, then cooled to room temperature and poured into diethyl ether (100 mL). The resulting solution was transferred to a separatory funnel and washed sequentially with water (3 × 50 mL) and sodium bicarbonate (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude oil was purified by silica gel chromatography (0 to 100% ethyl acetate / hexanes) and trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl). ) Amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxypropyl] methyl cyclohexanecarboxylate was obtained as a yellow foam. MS ESI C 28 H 35 N 4 O 3 S calculated [M + H] + 507, found 507. 1 H NMR (500 MHz, CDCl 3 ) δ 8.12-8.04 (m, 2H), 7.71 (s, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 6.86 (s, 1H), 6.66 (d, J = 5.2 Hz, 1H), 3.64 (s, 3H), 2.35 (s, 3H), 2.28-2.16 ( m, 1H), 2.16-1.86 (m, 8H), 1.51-1.30 (m, 3H), 1.26 (t, J = 7.1 Hz, 1H), 1.21- 1.06 (m, 3H), 1.03-0.93 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).
Step 4: trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl ) -1-Hydroxypropyl] -cyclohexanecarboxylate (198 mg, 0.391 mmol) and potassium hydroxide (88 mg, 1.563 mmol) were added to a flask of methanol (1 mL) and water (1 mL). The reaction vessel was sealed and heated to 80 ° C. for 14 hours. After the reaction solution was cooled, aqueous hydrochloric acid (1.0 M, 1.56 mL, 1.56 mmol) was added. The cloudy solution was further diluted with water (10 mL) and stirring was continued for 1 hour. Chloroform and isopropanol (4: 1; total volume 20 mL) were added and the biphasic mixture was transferred to a separatory funnel. The organic phase was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4- Methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxypropyl] cyclohexanecarboxylic acid was obtained. MS ESI C 27 H 33 N 4 O 3 S calculated [M + H] + 493, found 493. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.60-10.74 (br s, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 7.75-7. 29 (m, 2H), 7.26 (m, 2H), 5.68-5.47 (m, 1H), 2.42 (s, 3H), 2.29-2.12 (m, 1H) 2.12-1.84 (m, 7H), 1.84-1.73 (m, 1H), 1.54-1.42 (m, 1H), 1.43-1.13 (m, 6H), 1.13-0.97 (m, 3H), 0.88 (t, J = 7.3 Hz, 3H). rhSyk activity = ++.
The two enantiomers were separated by chiral supercritical liquid chromatography (Chiral Technology AS-H, 2.1 × 25 cm, 5 uM, 3/1 MeOH / CO 2 + 0.25% TFA, flow rate: 70 mL / min, 10 Electrophoresis time in minutes, wavelength: 220 nm). Elution was observed at 7.03 minutes and 8.08 minutes. The pooled fraction of each peak was concentrated under reduced pressure.
Enantiomer 1 (retention time = 7.03 min): calculated for MS ESI C 27 H 33 N 4 O 3 S [M + H] + 493, found 493. The 1 H NMR (500 MHz, DMSO-d 6 ) spectrum was consistent with the 1 H NMR spectrum of the racemic material. rhSyk activity = ++.
Enantiomer 2 (Retention time = 8.08 min): MS ESI C 27 H 33 N 4 O 3 Calculated S [M + H] + 493 , Found 493. The 1 H NMR (500 MHz, DMSO-d 6 ) spectrum was consistent with the 1 H NMR spectrum of the racemic material. rhSyk activity = ++.
Trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1 -Hydroxypropyl] cyclohexanecarboxamide, trans-4-[(1R) -1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1 , 3-thiazol-2-yl) -1-hydroxypropyl] cyclohexanecarboxamide, trans-4-[(1S) -1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino]- 4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxypropyl] cyclohexanecarboxamide
Racemic trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl ) -1-Hydroxypropyl] cyclohexanecarboxylic acid (25 mg, 0.051 mmol) in a flask containing O- (7-azabenzotriazol-1-yl) -N, N, N′N′-tetramethyluro. Nitric hexafluorophosphate (25.1 mg, 0.066 mmol) and ammonium chloride (10.9 mg, 0.203 mmol) were added. DMF (1 mL) and N, N-diisopropylethylamine (0.089 mL, 0.507 mmol) were added and the reaction was sealed and stirred for 2 hours. Methanol (0.1 mL) was then added to quench the reaction and the resulting solution was filtered. The filtrate was purified by reverse phase HPLC (10 to 100% acetonitrile / water with 0.1% TFA). Fractions containing the desired product are pooled, frozen, concentrated to dryness in a lyophilizer, and trans-4- [1- (5- {6-[(4-cyclopropylpyridin-2-yl) amino ] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxypropyl] cyclohexanecarboxamide was obtained. MS ESI C 27 H 34 N 5 O 2 S calculated [M + H] + 492, found 492. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.31 (s, 1 H), 8.49 (s, 1 H), 8.30 (d, J = 6.4 Hz, 1 H), 7.53 (s , 1H), 7.38 (s, 1H), 7.15 (s, 1H), 7.04 (d, J = 6.4 Hz, 1H), 6.94 (s, 1H), 6.68 ( s, 1H), 5.84-5.30 (m, 1H), 2.43 (s, 3H), 2.30-2.15 (m, 1H), 2.07-1.87 (m, 4H), 1.87-1.67 (m, 3H), 1.54-1.42 (m, 1H), 1.42-1.18 (m, 6H), 1.12-0.93 ( m, 3H), 0.79 (t, J = 7.3 Hz, 3H) ppm. rhSyk = ++.
The above procedure was used for the enantiopure acid obtained by chiral SFC resolution of the racemic starting material described above (Example 1, Step 4).
(Example 1, Step 4, enantiomer 1, R t = 7.03 min) starting material: MS ESI C 27 H 34 N 5 O 2 Calculated S [M + H] + 492 , Found 492. The 1 H NMR (500 MHz, DMSO-d 6 ) spectrum was consistent with the 1 H NMR spectrum of the racemic material. rhSyk activity = ++.
(Example 1, Step 4, Enantiomer 2, R t = 8.08 min) starting material: calculated for MS ESI C 27 H 34 N 5 O 2 S [M + H] + 492, found 492. The 1 H NMR (500 MHz, DMSO-d 6 ) spectrum was consistent with the 1 H NMR spectrum of the racemic material. rhSyk activity = ++.
Trans-4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid (enantiomer 2)
Step 1: To the flask was added cis-cyclohexane-1,4-dicarboxylic acid (20 g, 116 mmol), n-butyl formate (581 ml, 5066 mmol), Dowex 50Wx2 resin (87 grams) and octane (484 ml). The reaction mixture was heated to 110 ° C. overnight, then cooled and filtered. The resin was washed with 300 mL of 1: 1 hexane: EtOAc. The filtrate was concentrated and then dissolved in toluene and concentrated again. The resulting residue was dissolved in dichloromethane (119 ml) and then thionyl chloride (11.51 ml, 158 mmol) was added. The reaction mixture was heated to 38 ° C. overnight and then concentrated. The residue was dissolved in DCM and concentrated again (3x) to remove residual HCl. The resulting residue was dissolved in 1,4-dioxane (413 ml) and degassed with Ar for 30 minutes. Palladium (II) acetate (0.696 g, 3.10 mmol) was added and the mixture was degassed for an additional 30 minutes. Dimethylzinc (2M in toluene, 31.0 ml, 62.0 mmol) was added. The system was placed under argon by 3 cycles of evacuation / argon flushing and then allowed to react overnight at 38 ° C. The reaction mixture was cooled and diluted with water. The resulting mixture was filtered through a celite plug and the solid was then washed with EtOAc. The filtrate was concentrated and purified by column chromatography on silica gel (0-30% ethyl acetate / hexane) to give butyl cis-4-acetylcyclohexanecarboxylate. 1 H NMR (500 MHz, DMSO-d 6 ) δ 4.07 (t, J = 6.6 Hz, 2H), 2.54-2.48 (m, 1H), 2.44-2.38 (m, 1H), 2.13 (s, 3H), 2.01-1.93 (m, 2H), 1.81-1.57 (m, 9H), 1.41-1.32 (m, 2H) , 0.92 (t, J = 7.5 Hz, 3H).
Step 2: A solution of thiazole (800 mg, 9.40 mmol) in THF (94 mL) was cooled to −78 ° C. n-BuLi (2.5 M in THF, 3759 μl, 9.40 mmol) was added and the solution was stirred at −78 ° C. for 30 minutes. THF (5 mL) containing butyl cis-4-acetylcyclohexanecarboxylate (2552 mg, 11.28 mmol) was added in one portion and the solution was stirred at −78 ° C. for 1 hour. The reaction was diluted with water and then allowed to warm to room temperature. The mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5 to 30% ethyl acetate / hexane) and cis-4- [1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylic Acid butyl was obtained. Calculated value [M + H + ] 312 for MS ESI C 16 H 25 NO 3 S, measured 312.
Step 3: In a vial, add 2,6-dibromo-4-methylpyridine (121 mg, 0.482 mmol), cis-4- [1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] cyclohexanecarboxyl Acid butyl (75 mg, 0.241 mmol), potassium carbonate (100 mg, 0.722 mmol), pivalic acid (5.59 μl, 0.048 mmol), tetrakis (triphenylphosphine) palladium (0) (11.1 mg, 9.63 μmol) ) And N, N-dimethylacetamide (760 μl) were added. The vial was sealed and placed under argon by 3 cycles of evacuation / argon flushing and then allowed to react overnight at 80 ° C. The resulting mixture was cooled, diluted with ethyl acetate, filtered through a celite plug and concentrated. The residue was purified by column chromatography on silica gel (0 to 100% ethyl acetate / hexane) and racemic -cis-4- {1- [5- (6-bromo-4-methylpyridine-2- Yl) -1,3-thiazol-2-yl] -1-hydroxyethyl} -cyclohexanecarboxylate butyl was obtained.
The two enantiomers were separated by chiral supercritical liquid chromatography (Chiral Technology IC-H, 2.1 × 25 cm, 5 uM, 70/30 ethanol / CO 2 , flow rate: 70 mL / min, 8 min run time, Wavelength: 220 nm). Elution was observed at 5.20 and 6.08 minutes. The pooled fraction of each peak was concentrated under reduced pressure.
Enantiomer 1 (retention time 5.20 minutes): Calculated for MS ESI C 22 H 29 BrF 3 N 2 O 3 S [M + H + ] 481 and 483, found 481 and 483.
Enantiomer 2 (retention time 6.08 min): Calculated for MS ESI C 22 H 29 BrF 3 N 2 O 3 S [M + H + ] 481 and 483, found 481 and 483.
Step 4: In a vial, 4- (trifluoromethyl) pyridin-2-amine (10 mg, 0.062 mmol), cis-4- {1- [5- (6-bromo-4-methylpyridin-2-yl) -1,3-thiazol-2-yl] -1-hydroxyethyl} -cyclohexanecarboxylate (step 3, enantiomer 1, R t = 5.20 min) (14.9 mg, 0.031 mmol), palladium acetate ( II) (0.7 mg, 3 μmol), xanthophos (2.7 mg, 4.6 μmol), cesium carbonate (20.1 mg, 0.062 mmol) and 1,4-dioxane (308 μl) were added. The vial was sealed and placed under argon by 3 cycles of evacuation / argon flushing and then heated at 100 ° C. for 2 hours 30 minutes. The mixture was cooled, diluted with EtOAc, filtered through a celite plug and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0 to 100% ethyl acetate / hexane) and 4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6- { [4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} butylcyclohexanecarboxylate was obtained. MS ESI C 28 H 33 F 3 N 4 O 3 S calculated [M + H + ] 563, found 563.
Step 5: 4-{(1R or 1S) -1- [5- (6-Bromo-4-methylpyridin-2-yl) -1,3-thiazol-2-yl] -1-hydroxyethyl in a vial } Butylcyclohexanecarboxylate (10 mg, 0.018 mmol), MeOH (178 μl) and NaOH (1M in water, 89 μl, 0.089 mmol) were added. The vial was sealed and heated in the microwave at 100 ° C. for 10 minutes. An additional 25 uL NaOH was added and then heated in the microwave for 20 minutes. The pH was then adjusted to 3-4 with 1M aqueous HCl. The solution was diluted with 10% IPA / CHCl 3 and washed with water and brine. The organic layer is separated by passing through a hydrophobic membrane cartridge, concentrated, and trans-4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6-{[4- (tri Fluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid was obtained. MS ESI C 24 H 25 F 3 N 4 O 3 S calculated [M + H + ] 507, found 507. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.19 (s, 1 H), 8.64 (s, 1 H), 8.48 (d, J = 5.0 Hz, 1 H), 8.26 (s , 1H), 7.34 (s, 1H), 7.21 (d, J = 5.0 Hz, 1H), 7.08 (s, 1H), 2.31 (s, 3H), 2.06- 1.67 (m, 3H), 1.67-1.34 (m, 5H), 1.31-0.96 (m, 5H). rhSyk activity = ++.
Step 1: In a vial, 4- (trifluoromethyl) pyridin-2-amine (8 mg, 0.049 mmol), cis-4- {1- [5- (6-bromo-4-methylpyridin-2-yl) -1,3-thiazol-2-yl] -1-hydroxyethyl} -cyclohexanecarboxylate (Example 3, Step 3, Enantiomer 2, R t = 6.08 min) (11.9 mg, 0.025 mmol) , Palladium (II) acetate (0.6 mg, 2.47 μmol), xanthophos (2.1 mg, 3.7 μmol), cesium carbonate (16.1 mg, 0.049 mmol) and 1,4-dioxane (247 μl) were added. . The vial was sealed and placed under argon by 3 cycles of evacuation / argon flushing and then allowed to react overnight at 100 ° C. The resulting mixture was cooled, diluted with EtOAc, filtered through a celite plug and concentrated. The residue was purified by column chromatography on silica (0 to 100% ethyl acetate / hexane) and 4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6- { [4- (Trifluoromethyl) pyridin-2-yl] amino} -pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} butylcyclohexanecarboxylate was obtained. MS ESI C 28 H 33 F 3 N 4 O 3 S calculated [M + H + ] 563, found 563.
Step 2: 4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridine- in a vial 2-yl) -1,3-thiazol-2-yl] ethyl} -cyclohexanecarboxylate butyl (10 mg, 0.018 mmol), MeOH (178 μl) and NaOH (1M in water, 89 μl, 0.089 mmol) were added. The vial was sealed and placed under argon by 3 cycles of evacuation / argon flushing and then heated in a microwave at 100 ° C. for 10 minutes. The pH was then adjusted to pH 3-4 with 1M HCl. The solution was diluted with 10% IPA / CHCl 3 and washed with water and brine. The organic layer is separated by passing through a hydrophobic membrane cartridge, concentrated, and trans-4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6-{[4- (tri Fluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid was obtained. MS ESI C 24 H 25 F 3 N 4 O 3 S calculated [M + H + ] 507, found 507. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.18 (s, 1 H), 8.64 (s, 1 H), 8.48 (d, J = 5.3 Hz, 1 H), 8.26 (s , 1H), 7.34 (s, 1H), 7.20 (d, J = 5.5 Hz, 1H), 7.08 (s, 1H), 2.31 (s, 3H), 2.15 1.72 (m, 3H), 1.72-1.32 (m, 5H), 1.31-0.87 (m, 5H). rhSyk activity = ++.
Trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2 -Yl) -1-hydroxyethyl] cyclohexanecarboxylic acid (enantiomer 1)
Step 1: 5-fluoro-4-methylpyridin-2-amine (16.2 mg, 0.128 mmol), trans-4- {1- [5- (6-bromopyridin-2-yl) -1,3- Thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylate (intermediate 4, step 2, enantiomer 1, R t = 3.98 min) (57 mg, 0.122 mmol), xanthophos (10.6 mg, 0 0.018 mmol), 1,4-dioxane (0.8 mL) containing cesium carbonate (79 mg, 0.244 mmol) and palladium (II) acetate (2.7 mg, 0.012 mmol) (under an argon atmosphere) at 115 ° C. Until 1.5 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (25 to 45% ethyl acetate / hexane) and trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4- Methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] butyl cyclohexanecarboxylate was obtained. MS ESI C 27 H 33 FN 4 O 3 S calculated [M + H] + 513, found 513. 1 H NMR (500 MHz, CDCl 3 ) δ 8.10 (s, 1H), 8.01 (s, 1H), 7.88 (d, J = 5.8 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.04 (T, J = 6.6 Hz, 2H), 3.03 (s, 1H), 2.38 (s, 3H), 2.24-2.17 (m, 1H), 2.10-1.98 (M, 3H), 1.83-1.75 (m, 1H), 1.73-1.67 (m, 1H), 1.65 (s, 3H), 1.62-1.56 (m , 2H), 1.48-1.38 (m, 2H), 1.40-1.32 (m, 2H), 1.32-1.25 (m, 1H), 1.23-1.15 (M, 1H), 0.91 (t, J = 7.4 Hz, 3H).
Step 2: trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3- Thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylate (54.7 mg, 0.107 mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) in a solution of sodium hydroxide (1 in water 0 M, 0.427 mL, 0.427 mmol) was added. The reaction mixture was heated in a microwave oven at 110 ° C. for 5 minutes, then hydrochloric acid (2.0 M in water, 0.220 mL, 0.440 mmol) was added. The mixture was diluted with 10% IPA: CHCl 3 (25 mL), ethyl acetate (100 mL) and brine. The layers are separated and the organic layer is washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and trans-4-[(1R or 1S) -1- (5- {6-[(5- Fluoro-4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid was obtained. MS ESI C 23 H 25 FN 4 O 3 S calculated [M + H] + 457, found 457. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.95 (br s, 1 H), 9.74 (s, 1 H), 8.26 (s, 1 H), 8.15 (d, J = 6. 1 Hz, 1H), 8.11 (s, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 5.82 (s, 1H), 2.32 (s, 3H), 2.07-1.94 (m, 1H), 1.92-1.83 (m, 3H), 1.67-1.60 (m, 1H), 1.54-1.48 (m, 1H), 1.48 (s, 3H), 1.26-1.14 (m, 3H) 1.08-1.02 (m, 1H). rhSyk activity = ++.
Step 1: 5-Fluoro-4-methylpyridin-2-amine (15.6 mg, 0.124 mmol), trans-4-{(1R or 1S) -1- [5- (6-bromopyridin-2-yl) ) -1,3-thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylate (intermediate 4, step 2, enantiomer 2, R t = 4.76 min) (55 mg, 0.118 mmol), xanthophos (10.2 mg, 0.018 mmol), a solution of 1,4-dioxane (0.8 mL) containing cesium carbonate (77 mg, 0.235 mmol) and palladium (II) acetate (2.6 mg, 0.012 mmol) (argon Atmosphere) was heated to 115 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (25 to 45% ethyl acetate / hexane) and trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4- Methylpyridin-2-yl) amino] pyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] butyl cyclohexanecarboxylate was obtained. MS ESI C 27 H 33 FN 4 O 3 S calculated [M + H] + 513, found 513. 1 H NMR (500 MHz, CDCl 3 ) δ 8.10 (s, 1H), 8.01 (s, 1H), 7.88 (d, J = 5.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.17 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 4.04 (T, J = 6.7 Hz, 2H), 3.03 (s, 1H), 2.38 (s, 3H), 2.22-2.16 (m, 1H), 2.10-1.96 (M, 3H), 1.83-1.77 (m, 1H), 1.69-1.64 (m, 1H), 1.65 (s, 3H), 1.62-1.55 (m , 2H), 1.48-1.39 (m, 2H), 1.39-1.32 (m, 2H), 1.32-1.27 (m, 1H), 1.21-1.15 (M, 1H), 0.91 (t, J = 7.4 Hz, 4H).
Step 2: trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] pyridin-2-yl} -1,3- Thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylate (48.5 mg, 0.095 mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) in a solution of sodium hydroxide (1 in water 0.0M, 0.378 mL, 0.378 mmol) was added. The reaction mixture was heated in a microwave oven at 110 ° C. for 5 minutes, then hydrochloric acid (2.0 M in water, 0.192 mL, 0.384 mmol) was added. The resulting suspension was diluted with water, filtered and trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino ] Pyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid was obtained. MS ESI C 23 H 25 FN 4 O 3 S calculated [M + H] + 457, found 457. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.95 (br s, 1 H), 9.74 (s, 1 H), 8.26 (s, 1 H), 8.15 (d, J = 5. 7 Hz, 1 H), 8.11 (s, 1 H), 7.66 (t, J = 7.9 Hz, 1 H), 7.36 (d, J = 7.4 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1H), 5.82 (s, 1H), 2.34 (s, 1H), 2.32 (s, 3H), 2.07-1.94 (m, 1H), 1 .91-1.83 (m, 3H), 1.67-1.61 (m, 1H), 1.53-1.47 (m, 1H), 1.48 (s, 3H), 1.26 -1.14 (m, 3H), 1.08-1.02 (m, 1H). rhSyk activity = ++.
Trans-4-{(1R or 1S) -1-hydroxy-1- [5- (6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3 -Thiazol-2-yl] ethyl} cyclohexanecarboxylic acid (enantiomer 1)
Step 1: 4- (trifluoromethyl) pyridin-2-amine (20.8 mg, 0.128 mmol), trans-4-{(1R or 1S) -1- [5- (6-bromopyridin-2-yl) ) -1,3-thiazol-2-yl] -1-hydroxyethyl} -cyclohexanecarboxylate butyl (intermediate 4, step 2, enantiomer 1, R t = 3.98 min) (57 mg, 0.122 mmol), A solution of 1,4-dioxane (0.8 mL) containing xanthophos (10.6 mg, 0.018 mmol), cesium carbonate (79 mg, 0.244 mmol) and palladium (II) acetate (2.7 mg, 0.012 mmol) ( (Under an argon atmosphere) was heated to 115 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (25 to 45% ethyl acetate / hexane) and trans-4-{(1R or 1S) -1-hydroxy-1- [5- (6-{[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylate butyl was obtained. MS ESI C 27 H 31 F 3 N 4 O 3 S calculated [M + H] + 549, found 549. 1 H NMR (500 MHz, CDCl 3 ) δ 8.61 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.65 (t, J = 7.9 Hz, 1 H), 7.48 (s, 1 H), 7.28 (d, J = 7.5 Hz, 1 H), 7.11 (d, J = 4.9 Hz, 1 H), 6.94 (D, J = 8.2 Hz, 1H), 4.04 (t, J = 6.6 Hz, 2H), 3.20 (s, 1H), 2.22-2.16 (m, 1H), 2 10-1.98 (m, 3H), 1.79 (m, 1H), 1.69-1.64 (m, 1H), 1.65 (s, 3H), 1.62-1.57 (M, 3H), 1.49-1.39 (m, 2H), 1.38-1.33 (m, 1H), 1.32-1.24 (m, 1H), 1.21-1 .18 (m, 1H), 0.91 (T, J = 7.4 Hz, 3H).
Step 2: trans-4-{(1R or 1S) -1-hydroxy-1- [5- (6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl)- 1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylate (59.6 mg, 0.109 mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) in a solution of sodium hydroxide (1. 0M, 0.435 mL, 0.435 mmol) was added. The reaction mixture was heated in a microwave oven at 110 ° C. for 5 minutes, then hydrochloric acid (2.0 M in water, 0.220 mL, 0.440 mmol) was added. The resulting mixture was diluted with 10% IPA: CHCl 3 and brine and the layers were separated. The aqueous layer was extracted with 10% IPA: CHCl 3 and the combined organic layers were then dried over sodium sulfate, filtered, concentrated in vacuo, and trans-4-{(1R or 1S) -1-hydroxy-1- [5- (6-{[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid was obtained. MS ESI C 23 H 23 F 3 N 4 O 3 S calculated [M + H] + 493, found 493. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.95 (s, 1 H), 10.27 (s, 1 H), 8.64 (s, 1 H), 8.49 (d, J = 5.2 Hz) , 1H), 8.28 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 5.75 (d, J = 10.1 Hz, 1H), 2.01 (m, 1H), 1.94 -1.82 (m, 2H), 1.64 (m, 1H), 1.53 (m, 1H), 1.48 (s, 3H), 1.24-1.14 (m, 4H), 1.02 (m, 1H). rhSyk activity = ++.
Step 1: 4- (Trifluoromethyl) pyridin-2-amine (20.0 mg, 0.124 mmol), trans-4-{(1R or 1S) -1- [5- (6-bromopyridin-2-yl) ) -1,3-thiazol-2-yl] -1-hydroxyethyl} cyclohexanecarboxylate (intermediate 4, step 2, enantiomer 2, R t = 4.76 min) (55 mg, 0.118 mmol), xanthophos (10.2 mg, 0.018 mmol), a solution of 1,4-dioxane (0.8 mL) containing cesium carbonate (77 mg, 0.235 mmol) and palladium (II) acetate (2.6 mg, 0.012 mmol) (argon Atmosphere) was heated to 115 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (25 to 45% ethyl acetate / hexane) and trans-4-{(1R or 1S) -1-hydroxy-1- [5- (6-{[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylate butyl was obtained. MS ESI C 27 H 31 F 3 N 4 O 3 S calculated [M + H] + 549, found 549. 1 H NMR (500 MHz, CDCl 3 ) δ 8.61 (s, 1H), 8.41 (d, J = 4.7 Hz, 1H), 8.10 (s, 1H), 7.65 (t, J = 7.9 Hz, 1 H), 7.47 (s, 1 H), 7.28 (d, J = 7.0 Hz, 1 H), 7.11 (d, J = 4.3 Hz, 1 H), 6.94 (D, J = 8.1 Hz, 1H), 4.04 (t, J = 6.6 Hz, 2H), 3.20 (s, 1H), 2.22-2.17 (m, 1H), 2 10-1.98 (m, 3H), 1.82-1.76 (m, 1H), 1.70-1.65 (m, 1H), 1.65 (s, 3H), 1.62 -1.57 (m, 3H), 1.48-1.39 (m, 2H), 1.38-1.33 (m, 1H), 1.32-1.24 (m, 1H), 1 20-1.14 (m, 1H) , 0.91 (t, J = 7.4 Hz, 3H).
Step 2: trans-4-{(1R or 1S) -1-hydroxy-1- [5- (6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl)- 1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylate (58.5 mg, 0.107 mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) in a solution of sodium hydroxide (1. 0M, 0.427 mL, 0.427 mmol) was added. The reaction mixture was heated in a microwave oven at 110 ° C. for 5 minutes, then hydrochloric acid (2.0 M in water, 0.215 mL, 0.430 mmol) was added. The resulting mixture was diluted with 10% IPA: CHCl 3 and brine and the layers were separated. The aqueous layer was extracted with 10% IPA: CHCl 3 and the combined organic layers were then dried over sodium sulfate, filtered, concentrated in vacuo, and trans-4-{(1R or 1S) -1-hydroxy-1- [5- (6-{[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid was obtained. MS ESI C 23 H 23 F 3 N 4 O 3 S calculated [M + H] + 493, found 493. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.95 (br s, 1 H), 10.27 (s, 1 H), 8.64 (s, 1 H), 8.49 (d, J = 5. 1 Hz, 1 H), 8.28 (s, 1 H), 7.73 (t, J = 7.9 Hz, 1 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.26 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 5.76 (s, 1H), 2.02-1.95 (m, 1H), 1.94−. 1.92 (m, 2H), 1.66-1.61 (m, 1H), 1.54-1.49 (m, 1H), 1.48 (s, 3H), 1.24-1. 14 (m, 4H), 1.05-0.99 (m, 1H). rhSyk activity = ++.
Trans-4-[(1R) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol -2-yl) -1-hydroxyethyl] butylcyclohexanecarboxylate and trans-4-[(1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] -4-Methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] butyl cyclohexanecarboxylate
Step 1: 2,6 dibromo-4-methylpyridine (10.0 g, 40.0 mmol), sodium tert-butoxide (4.4 g, 46.0 mmol), 2-amino-4-methyl-5-fluoro in the flask Pyridine (5.8 g, 45.8 mmol) and 1,1′-bis (di-tert-butylphosphino) ferrocenepalladium dichloride (1.3 g, 1.9 mmol) were added followed by nitrogen sparged 1,4-dioxane. (100 mL) was added. The slurry was evacuated and refilled with nitrogen three times and then heated to 88 ° C. for 5 hours. After cooling to 25 ° C., ethyl acetate (100 mL) and water (20 mL) were added and the layers were separated. The organic layer was washed with 10% aqueous sodium chloride solution (25 mL) and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10 to 50% ethyl acetate / hexane) and N- (6-bromo-4-methylpyridin-2-yl) -5-fluoro-4-methylpyridine-2. -Amine was obtained. 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.07 (d, J = 0.8 Hz, 1H), 7.61 (s, 1H), 7.32 (d , J = 5.6 Hz, 1H), 6.87 (s, 1H), 2.20 (s, 3H), 2.19 (s, 3H).
Step 2: In a flask, butyldiadamantylphosphine (0.133 g, 0.37 mmol), palladium (II) acetate (0.04 g, 2.2 mmol), potassium carbonate (0.77 g, 5.6 mmol), pivalic acid ( 0.23 g, 2.2 mmol), butyl trans-4- [1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylate (0.69 g, 60.0 mmol) and N- ( 6-Bromo-4-methylpyridin-2-yl) -5-fluoro-4-methylpyridin-2-amine (0.55 g, 1.86 mmol) was added followed by nitrogen sparge dimethylacetamide (4.4 mL). Was added. The slurry was evacuated and refilled with nitrogen three times and then slowly heated to 130 ° C. for 15 hours. The slurry was cooled to 35 ° C. and diluted with ethyl acetate (100 mL). The slurry was then filtered through celite, washed with 10% aqueous NaCl (3 × 100 mL) and concentrated in vacuo. The residue was purified by chromatography on silica gel (ethyl acetate / hexane) and racemic trans-4- [1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] -4-Methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] butyl cyclohexanecarboxylate was obtained as a foam. 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.62 (s, 1H), 8.21 (s, 1H), 8.12 (d, J = 5.8 Hz, 1H), 8.08 (s , 1H), 7.21 (s, 1H), 7.04 (s, 1H), 5.79 (s, 1H), 3.93 (t, J = 6.5 Hz, 2H), 2.29 ( s, 3H), 2.25 (s, 3H), 2.14 to 2.05 (m, 1H), 1.93-1.80 (m, 3H), 1.65 to 1.60 (m, 1H), 1.53-1.47 (m, 3H), 1.45 (s, 3H), 1.31-1.16 (m, 5H), 1.08-0.99 (m, 1H) , 0.83 (t, J = 7.4 Hz, 3H).
The two enantiomers were separated by chiral supercritical liquid chromatography (Chiral Technology AS-H, 2.1 × 25 cm, 5 uM, 20/80 ethanol / CO 2 , flow rate: 70 mL / min, 11 min run time, Wavelength: 275 nm). Elution was observed at 5.77 and 7.36 minutes. The pooled fraction of each peak was concentrated under reduced pressure.
Enantiomer 1 (Retention time = 5.77 min): MS ESI C 28 H 35 FN 4 O 3 Calculated S [M + H] + 527 , Found 527. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.65 (s, 1 H), 8.24 (s, 1 H), 8.15 (d, J = 5.9 Hz, 1 H), 8.10 (s , 1H), 7.24 (s, 1H), 7.06 (s, 1H), 5.82 (s, 1H), 3.96 (t, J = 6.5 Hz, 2H), 2.31 ( s, 3H), 2.27 (s, 3H), 2.14-2.08 (m, 1H), 1.95-1.80 (m, 3H), 1.68-1.63 (m, 1H), 1.57-1.48 (m, 3H), 1.48 (s, 3H), 1.33-1.14 (m, 5H), 1.08-1.01 (m, 1H) , 0.85 (t, J = 7.4 Hz, 3H). rhSyk activity = ++
Enantiomer 2 (Retention time = 7.36 min): MS ESI C 28 H 35 FN 4 O 3 Calculated S [M + H] + 527 , Found 527. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.65 (s, 1 H), 8.24 (s, 1 H), 8.14 (d, J = 5.7 Hz, 1 H), 8.10 (s , 1H), 7.24 (s, 1H), 7.06 (s, 1H), 5.82 (s, 1H), 3.96 (t, J = 6.5 Hz, 2H), 2.31 ( s, 3H), 2.27 (s, 3H), 2.11 (s, 1H), 1.95-1.80 (m, 3H), 1.68-1.63 (m, 1H), 1 .57-1.48 (m, 3H), 1.48 (s, 3H), 1.33-1.17 (m, 5H), 1.05 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H). rhSyk activity = ++
Trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3 -Thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid (enantiomer 1)
Trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3 - thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid butyl (example 9, step 2, enantiomer 1, R t = 5.77 min) (725mg, 1.377mmol) and tetrahydrofuran (8 mL) containing To a methanol (16 mL) solution was added sodium hydroxide (1.0 M in water, 5.51 mL, 5.51 mmol). The reaction mixture was heated to 70 ° C. for 90 minutes and then allowed to cool to room temperature. Hydrochloric acid (2.0 M in water, 2.75 mL, 5.50 mmol) and water (30 mL) were added and the resulting precipitate was collected by filtration. The solid was washed with water (2 × 10 mL) and then dried under reduced pressure to give trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridine-2- Yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylate. MS ESI C 24 H 27 FN 4 O 3 S calculated [M + H] + 471, found 471. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.96 (br s, 1 H), 9.65 (s, 1 H), 8.24 (s, 1 H), 8.14 (d, J = 6. 0 Hz, 1H), 8.10 (s, 1H), 7.24 (s, 1H), 7.06 (s, 1H), 5.81 (s, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.04-1.98 (m, 1H), 1.94-1.82 (m, 3H), 1.66-1.61 (m, 1H), 1. 53-1.48 (m, 1H), 1.48 (s, 3H), 1.28-1.14 (m, 3H), 1.07-1.02 (m, 1H). rhSyk activity = ++.
Trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridin-2-yl) amino] -4-methylpyridin-2-yl} -1,3 - thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylic acid butyl (example 9, step 2, enantiomer 2, R t = 7.36 min) (725mg, 1.377mmol) and tetrahydrofuran (8 mL) containing To a solution of methanol (16 mL) was added sodium hydroxide (1.0 M in water, 5.51 mL, 5.51 mmol). The reaction mixture was heated to 70 ° C. for 90 minutes and then allowed to cool to room temperature. Hydrochloric acid (2.0 M in water, 2.75 mL, 5.50 mmol) and water (30 mL) were added and the resulting precipitate was collected by filtration. The solid was washed with water (2 × 10 mL) and then dried under reduced pressure to give trans-4-[(1R or 1S) -1- (5- {6-[(5-fluoro-4-methylpyridine-2- Yl) amino] -4-methylpyridin-2-yl} -1,3-thiazol-2-yl) -1-hydroxyethyl] cyclohexanecarboxylate. MS ESI C 24 H 27 FN 4 O 3 S calculated [M + H] + 471, found 471. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.96 (br s, 1 H), 9.65 (s, 1 H), 8.24 (s, 1 H), 8.14 (d, J = 6. 0 Hz, 1H), 8.10 (s, 1H), 7.24 (s, 1H), 7.06 (s, 1H), 5.81 (s, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.04-1.98 (m, 1H), 1.94-1.82 (m, 3H), 1.66-1.61 (m, 1H), 1. 53-1.48 (m, 1H), 1.48 (s, 3H), 1.28-1.14 (m, 3H), 1.07-1.02 (m, 1H). rhSyk activity = ++.
1- [5- (4-Methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] -1- ( Pyrrolidin-3-yl) ethanol
Step 1: Lithium isopropylmagnesium chloride (1.3 M in tetrahydrofuran, 0.6 mL, 0.780 mmol) was added dropwise at room temperature to a flask containing a solution of thiazole (0.050 mL, 0.705 mmol) in tetrahydrofuran (5 mL). A water bath was provided around the flask. After 40 minutes, tetrahydrofuran (5 mL) containing tert-butyl 3-acetylpyrrolidine-1-carboxylate (160 mg, 0.750 mmol) was added dropwise. After stirring at room temperature for 35 minutes, the mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (0 to 60% ethyl acetate / hexane) and 3- [1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] pyrrolidine-1-carboxyl Tert-butyl acid was obtained as a 1: 1 diastereomeric mix. 1 H NMR (500 MHz, CDCl 3 ) δ 7.69-7.55 (m, 1H, two sets of doublet overlap derived from two diastereomers), 7.23-7.14 (m , 1H, two sets of doublet overlap derived from two diastereomers), 3.59-2.98 (m, 4H), 2.80-2.60 (m, 1H), 1. 98-1.70 (m, 2H), 1.59 (s, 3H), 1.45-1.30 (m, 9H, two sets of peak overlap derived from two diastereomers).
Step 2: tert-Butyl 3- [1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] pyrrolidine-1-carboxylate (100 mg, 0.335 mmol), 6-bromo-4-methyl- N- [4- (trifluoromethyl) pyridin-2-yl] pyridin-2-amine (112 mg, 0.337 mmol), butyldi-1-adamantylphosphine (25 mg, 0.070 mmol), tris (dibenzylideneacetone) Palladium (0) (16.3 mg, 0.018 mmol), pivalic acid (0.018 mL, 0.157 mmol), potassium carbonate (140 mg, 1.013 mmol) and N, N-dimethylacetamide (1 mL) were combined and the mixture was Evacuate, purge with nitrogen 3 times, then heat to 130 ° C for 7 hours It was. The mixture was filtered and then extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, concentrated in vacuo, and 3- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl)- Pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} pyrrolidine-1-carboxylate was obtained, which was obtained in a subsequent step without further purification. used. MS ESI C 26 H 30 F 3 N 5 O 3 S calculated [M + H] + 550, found 550.
Step 3: Trifluoroacetic acid (0.4 mL, 5.19 mmol) was added to 3- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl]. Amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} pyrrolidine-1-carboxylate tert-butyl (100 mg, 0.182 mmol) was added to a solution of dichloromethane (0.8 mL). The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by reverse phase HPLC (Sunfire preparative C18 OBD 5 uM, acetonitrile / water + 0.1% TFA), 1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridine- 2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] -1- (pyrrolidin-3-yl) ethanol was obtained as a 1: 1 diastereomeric mix. MS ESI C 21 H 22 F 3 N 5 OS calculated [M + H] + 450, found 450. 1 H NMR (500 MHz, CD 3 OD) δ 8.55 (d, J = 5.6 Hz, 1H), 8.37 (d, 1H, two singlets derived from two diastereomers), 8 .12 (s, 1H), 7.46 (s, 1H), 7.37 (d, J = 5.5 Hz, 1H), 7.05 (s, 1H), 3.58-2.95 (m , 5H, two sets of peaks derived from two diastereomers), 2.45 (s, 3H), 2.30-1.79 (m, 2H, two sets of two diastereomers Peak), 1.69 (d, 3H, two singlets from two diastereomers). rhSyk activity = ++.
3- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2 -Yl] ethyl} pyrrolidine-1-carboxamide
1- [5- (4-Methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] -1- ( Pyrrolidin-3-yl) ethanol (20 mg, 0.044 mmol, 1: 1 diastereomeric mix) in tetrahydrofuran (0.4 mL) in potassium cyanate (25 mg, 0.308 mmol), water (1.2 mL) and HCl (2M in water, 0.14 mL, 0.280 mmol) was added. The mixture was stirred at 55 ° C. for 3 hours and then cooled to room temperature. The mixture was purified by reverse phase HPLC (Sunfire preparative C18 OBD 5 uM, acetonitrile / water + 0.1% TFA) and 3- {1-hydroxy-1- [5- (4-methyl-6-{[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} pyrrolidine-1-carboxamide was obtained as a 1: 1 diastereomeric mixture. MS ESI C 22 H 23 F 3 N 6 O 2 Calculated S [M + H] + 493 , Found 493. 1 H NMR (500 MHz, CD 3 OD) δ 8.65-8.60 (m, 1H, two sets of doublet overlap derived from two diastereomers), 8.39 (d, 1H, Two singlets from two diastereomers), 7.86 (s, 1H), 7.51 (d, 1H, two singlets from two diastereomers), 7.46 -7.42 (m, 1H, two sets of doublet overlap derived from two diastereomers), 7.05 (s, 1H), 3.65-2.82 (m, 5H, 2 2 sets of peaks derived from different kinds of diastereomers), 2.50 (s, 3H), 2.20-2.00 (m, 2H), 1.69 (s, 3H). rhSyk activity = ++.
Alternative preparation of Examples 4 and 3; Preparation of related compounds of formula I trans-4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6-{[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid (enantiomer 1, same stereoisomer as in Example 4)
Step 1: Palladium acetate (10 mg, 0.045 mmol), butyl di-1-adamantylphosphine (32 mg, 0.090 mmol) and dioxane (1 mL) were added to the vial under nitrogen and the mixture was stirred for 10 minutes. In a separate flask, 6-bromo-4-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) pyridin-2-amine (75 mg, 0.23 mmol), cesium fluoride (103 mg, 0. 3). 68 mmol), pivalic acid (35 mg, 0.34 mmol) and butyl trans-4-[(1R or 1S) -1-hydroxy-1- (1,3-thiazol-2-yl) ethyl] cyclohexanecarboxylate (intermediate) 2, peak 2, R t = 4.14 min) (70 mg, 0.23 mmol) in dioxane (1 mL) was added. The mixture in Flask 1 was added to the mixture in Flask 2, the resulting mixture was evacuated and then purged with argon five times. The mixture was then heated to 100 ° C. for 24 hours. The mixture was then diluted with ethyl acetate, filtered through celite, and the celite was washed with ethyl acetate. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel to obtain trans-4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6-{[4- (Trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylate butyl was obtained. MS ESI C 28 H 34 F 3 N 4 O 3 S calculated [M + H] + 563, found 563 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.65 ( s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.34 (s, 1H), 7.19 (t, J = 12.4 Hz, 1H), 7.06 (d, J = 16.9 Hz, 1H), 5.76 (s, 1H), 3.95 (t, J = 6.5 Hz, 2H), 2.31 (s, 3H), 2.17-2.05 ( m, 1H), 1.96-1.80 (m, 3H), 1.72-1.59 (m, 1H), 1.59-1.44 (m, 5H), 1.35-1. 14 (m, 6H), 1.11-0.96 (m, 1H), 0.84 (t, J = 7.4 Hz, 3H). rhSyk = ++
Step 2: trans-4-{(1R or 1S) -1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridine-2 -Yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylate (76 mg, 0.14 mmol) in methanol (3 mL) was added to aqueous sodium hydroxide (1 M in water, 2 0.0 mL, 2.0 mmol) was added and the mixture was heated in a microwave at 140 ° C. for 60 minutes. The mixture was allowed to cool to room temperature and acidified to about pH 3 with aqueous hydrochloric acid. The mixture is diluted with ethyl acetate and the organic layer is separated, dried over magnesium sulfate, filtered and concentrated to trans-4-{(1R or 1S) -1-hydroxy-1- [5- (4- Methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2-yl] ethyl} cyclohexanecarboxylic acid (enantiomer 1) was obtained. . MS ESI C 24 H 26 F 3 N 4 O 3 S calculated [M + H] + 507, found 507. 1 H NMR (500 MHz, CD 3 OD) δ 8.62 (d, J = 5.6 Hz, 1H), 8.38 (s, 1H), 7.92 (s, 1H), 7.51 (s, 1H), 7.40 (t, J = 16.4 Hz, 1H), 7.05 (s, 1H), 2.50 (s, 3H), 2.24-2.11 (m, 1H), 2 10-1.93 (m, 3H), 1.89-1.76 (m, 1H), 1.66-1.58 (m, 4H), 1.47-1.31 (m, 3H) , 1.26-1.11 (m, 1H). rhSyk = ++
The following compounds were prepared in a manner similar to that described in Example 14, Step 1, and where appropriate in Step 2. Unless otherwise specified, the terms cis and trans indicate the stereochemical configuration around the cycloalkyl ring.
For compound 3, compounds 14-1 to 14-10, compounds 14-39 to 14-43, and compounds 14-52 to 14-54, enantiomer 1 is prepared from intermediate 2, peak 2, while enantiomer 2 is intermediate Prepared from body 2, peak 1.
For compounds 14-30 to 14-38 and 14-44 to 14-51, isomer 1 is prepared from intermediate 13, step 3, peak 1, while isomer 2 is intermediate 13, step 3, peak 2. Prepared from Compound 14-30 was prepared from the diastereomeric mixture of Intermediate 13, Step 4. Compounds 14-11-14, 14 were prepared from Intermediate 12. Compounds 14-15, 14-16, 14-21 and 14-22 were prepared from Example 1, Step 2. Compounds 14-17, 14-18, 14-23 and 14-24 were prepared from Intermediate 8. Compounds 14-19, 14-20, 14-25 and 14-26 were prepared from Intermediate 9. Compounds 14-27 through 14-29 were prepared from Intermediate 10. Compounds 14-55 were prepared from Intermediate 15, Step 2. Compounds 14-56 were prepared from Intermediate 15, Step 3.
4- {1-hydroxy-1- [5- (4-methyl-6-{[4- (trifluoromethyl) pyridin-2-yl] amino} pyridin-2-yl) -1,3-thiazol-2 -Il] ethyl} -2-methylcyclohexanecarboxylic acid stereoisomer in the same manner as described in Example 14, Steps 1 and 2 using the product of Intermediate 14, Step 2. Prepared. In step 2, isomerization occurred in some cases. If isomerization occurred, the isomers were separated and then tested. The following table shows the case where isomerization is observed.
Formula I:
The compound according to claim 1, wherein ring A is a carbocycle, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is C3-6 cycloalkyl.
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is cyclohexyl.
The compound according to claim 1, wherein R 5 is OH, or a pharmaceutically acceptable salt thereof.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a carbocycle and R 8 is selected from (CR a R b ) n CO 2 R c and C (O) NR d R e. salt.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is C 3-6 cycloalkyl and R 8 is CO 2 R c .
The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
R 3 is C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl;
R 6 is H, C 1-4 alkyl or C 1-4 haloalkyl,
The compound according to claim 8, or a pharmaceutically acceptable salt thereof.
R 8 is CO 2 R c ,
The compound according to claim 10 or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
A method for the treatment or prevention of a Syk mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. .
15. A method according to claim 14, wherein the disease is asthma or COPD.
15. The method of claim 14, wherein the disease is rheumatoid arthritis.
The method of claim 14, wherein the disease is cancer.
Use of a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of a Syk mediated disease.
JP2014510372A 2011-05-10 2012-05-04 Pyridylaminopyridine as a Syk inhibitor Pending JP2014513687A (en)
PCT/US2012/036426 WO2012154520A1 (en) 2011-05-10 2012-05-04 Pyridyl aminopyridines as syk inhibitors
JP2014510372A Pending JP2014513687A (en) 2011-05-10 2012-05-04 Pyridylaminopyridine as a Syk inhibitor
AU (1) AU2012253886A1 (en)
TW (1) TW201249839A (en)
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redpajama_set_name: RedPajamaCommonCrawl