SYK INHIBITOR AMINO PYRIMIDINE COMPOUND, E, PHARMACEUTICAL COMPOSITION

专利摘要:
syk inhibitor aminopyrimidine compound, pharmaceutical composition, and use of a compound The present invention provides novel pyrimidine amines of formula (I) which are potent spleen tyrosine kinase inhibitors, and are useful in the treatment and prevention of diseases mediated by said enzyme , such as asthma, copd and rheumatoid arthritis.
公开号:BR112012014703B1
申请号:R112012014703-0
申请日:2010-12-15
公开日:2021-08-03
发明作者:Michael D. Altman；Brian M. Andresen；Kenneth L. Arrington；Kaleen Konrad Childers；Maria Emilia Di Francesco；Anthony Donofrio；John Michael Ellis；Christian Fischer；David Joseph Guerin；Andrew M. Haidle；Solomon Kattar；Sandra Lee Knowles；Chaomin Li；Jongwon Lim；Michelle R. Machacek；Alan B. Northrup；Brendan M. O'boyle；Ryan D. Otte；Joel S. Robichaud；Daniel Guay；Jacques Yves Gauthier；Jean-François Fournier；Kristina Dupont-Gaudet；Bernard Cote；Jason Burch；Hua Zhou；B. Wesley Trotter；Brandon M. Taoka；Tony Siu；Eric Romeo；Michael H. Reutershan；Alessia Petrocchi
申请人:Merck Sharp & Dohme Corp.；Merck Canada Inc.；
IPC主号:

专利说明:

FUNDAMENTALS OF THE INVENTION
Spleen Tyrosine Kinase (Syk) is a protein tyrosine kinase that has been described as a key mediator of immunoreceptor signaling in an inflammatory cell host that includes mastoids, B cells, macrophages and neutrophils. These immunoreceptors, which include Fc receptors and the B cell receptor, are important for both allergic and antibody-mediated autoimmune diseases and thus interfering pharmacologically with Syk could conceivably treat these disorders.
Allergic rhinitis and asthma are diseases associated with hypersensitivity reactions and inflammatory events that involve a multitude of cell types that include mastoids, eosinophils, T cells and dendritic cells. Following exposure to the allergen, high-affinity immunoglobulin receptors for IgE and IgG become cross-linked and activate downstream processes in mastoids and other cell types leading to the release of pro-inflammatory mediators and airway spasmogens. In mastoids, for example, crosslinking of the IgE receptor by the allergen leads to the release of mediators that include histamine from preformed granules, as well as the synthesis and release of newly synthesized lipid mediators that include prostaglandins and leukotrienes.
Syk kinase is a non-receptor-bound tyrosine kinase that is important in transducing downstream cellular signals associated with Fc.épsilon.R1 crosslinkers and/or Fc.épsilon.R1 receptors, and is positioned early in the signaling cascade. In mastoids, for example, the initial sequence of Fc.epsilon.R1 signaling following allergen crosslinking of receptor-IgE complexes involves first Lyn (a tyrosine kinase of the Src family) and then Syk. Inhibitors of Syk 2 activity would therefore be expected to inhibit all downstream signaling cascades thereby alleviating the immediate allergic response and adverse events initiated by the release of pro-inflammatory mediators and spasmogens (Wong ET AL 2004, Expert Opin. Investig. Drugs (2004) 13 (7) 743-762).
It was recently shown that Syk kinase inhibitor R112 (Rigel), dosed intranasally in a phase I/II study for the treatment of allergic rhinitis, gave a statistically significant decrease in PGD2, a key immune mediator that is highly correlated with improvements in allergic rhinorrhea, as well as being safe across a range of indicators, thus providing the first evidence for the safety and clinical efficacy of a topical Syk kinase inhibitor. (Meltzer, Eli O.; Berkowitz, Robert B.; Grossbard, Elliott B, Journal of Allergy and Clinical Immunology (2005), 115(4), 791 - 796). In a more recent phase II clinical trial for allergic rhinitis (Clinical Trials.gov Identifier NCT0015089), R112 was shown to have a lack of efficacy versus placebo.
Rheumatoid Arthritis (RA) is an autoimmune disease that affects approximately 1% of the population. It is characterized by inflammation of the joints leading to debilitating destruction of bone and cartilage. Recent clinical studies with Rituximab, which causes reversible B cell depletion, (JCW Edwards ET AL 2004, New Eng. J. Med. 350: 2572-2581) have shown that targeting B cell function is an appropriate therapeutic strategy in autoimmune diseases such as RA. The clinical benefit correlates with a reduction in autoreactive antibodies (or Rheumatoid Factor) and these studies suggest that B cell function and indeed autoantibody production are central to the chronic pathology of the disease.
Studies using cells from mice deficient in Spleen Tyrosine Kinase (Syk) have demonstrated a non-redundant role of its kinase in B cell function. Syk deficiency is characterized by a block in B cell development (M. Turner ET AL 1995 Nature 379: 298-302 and Cheng ET AL 1995, Nature 378: 303 - 306). These studies, together with studies on Syk-deficient mature B cells (Kurasaki ET AL 2000, Immunol. Rev. 176:19-29), demonstrate that Syk is required for B cell differentiation and activation. Syk in RA patients is likely to block B cell function and thereby reduce Rheumatoid Factor production. In addition to Syk's role in B cell function, and additional relevance for the treatment of RA, is the requirement for Syk activity in Fc receptor (FcR) signaling. Activation of FcR by immune complexes in RA has been suggested to contribute to the release of multiple pro-inflammatory mediators.
The present invention relates to new compounds, which are inhibitors of Syk kinase activity. These compounds therefore have potential therapeutic benefit in the treatment of disorders associated with inappropriate Syk activity, in particular in the treatment and prevention of Syk-mediated disease states. Such disease states can include inflammatory, allergic and autoimmune diseases, for example, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, idiopathic thrombocytopenic purpura (ITP), multiple sclerosis, cancer, HIV and lupus. SUMMARY OF THE INVENTION
The present invention provides new compounds that are potent SYK inhibitors as well as pharmaceutical compositions containing them. Whereas the SYK inhibitor compounds of the present invention are useful in the treatment and prevention of diseases and disorders mediated by the SYK protein; such diseases and disorders include, but are not limited to, asthma, COPD, rheumatoid arthritis, cancer, and idiopathic thrombocytopenic purpura. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides the compounds of formula (I) or a pharmaceutically acceptable salt thereof:
where: p is 0 to 4; q is 0, 1 or 2; Cy is selected from C4-7 cycloalkyl, oxetanyl, pyrrolidinyl, piperidinyl, and azepanyl; R1 is selected from H, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, and C1-4 alkyl; R4 is selected from H, C1-4 alkyl, and C3-4 cycloalkyl; Ry(a) is aminomethyl, OH, OCH3, OCH2CH2OH, F, CN, CO2Ra(a), CONRb(a)Rc(a), NRa(a)Ra(a), NHC(O) C1-3 alkyl (optionally substituted with OH), NHC(O)NH2, NHSO2NH2, NHSO2 C1-3 alkyl, or NHSO2 haloC1-3 alkyl; Rz(a) is selected from (A) C1-4 alkyl optionally substituted with one to three groups independently selected from OH, NH2, CN, CO2Ra(a) and CONH2, (B) C1-3 fluoroalkyl, (C) halogen, (D) CN, (E) CO C1-4 alkyl (optionally substituted with one or two groups independently selected from ORa(a), CN, CO2Ra(a), CONRa(a) Ra(a), and NRa(a) Ra(a)), (F) CO-phenyl (optionally substituted with one or two groups independently selected from ethynyl, CO2Ra(a), CN, F and OH), (G) CO-C3-6 cycloalkyl (optionally substituted with OH or CO2Ra(a)), (H) alkyl C0-3-CO2Ra(a), (I) -C(O)NRb(a)Rc(a), (J) -ORa(a), (K) -OC(O)Ra(a), (L) -NRb(a)Rc(a), (M) -NHC(O) C1-4 alkyl (optionally substituted with one to three OH or a CONRa(a)Ra (a)), (N) -NHSO2 C1-3 alkyl, (O) -NHSO2NH2, (P) oxo, (Q) 1,3,4-oxadiazol-2(3H)-one, (R) 1.2 ,4-oxadiazol-5(4H)-one, (S) SO2NH2, (T) SO2C1-3alkyl, (U) SO2C1-3haloalkyl, and (V) SO2Ph; Ra(a)is H or C1-4 alkyl; Rb(a) and Rc(a) are independently selected from (A) H, (B) C3-6 cycloalkyl optionally substituted with OH, (C) heteroaryl selected from imidazolyl, pyridyl and indolyl, (D) tetrahydrofuranoyl, (E) benzyl, (F) phenyl optionally substituted with one or two groups independently selected from (CH2)0-2OH and F, (G1) C1-4 alkyl and (G2) haloC1-4 alkyl, wherein (G1) and (G2) are each optionally substituted with one to three groups independently selected from (i) OH, (ii) C3-6 cycloalkyl optionally substituted with one or two groups independently selected from C1-4 alkyl, CONH2, CO2H and CH2OH, (iii) CONH2 , (iv) SO2NH2, (v) SO2 C1-4 alkyl, (vi) 4- to 7-membered monocyclic heterocyclyl optionally substituted with one or two groups independently selected from oxo, (CH2)0-2OH, and C1-4 alkyl, (vii) a 5- or 6-membered heteroaryl optionally substituted with one or two groups independently selected from carboxy, (CH2)0-2OH, and C1-4 alkyl, (v iii) CN, (x) OC14 alkyl, (ix) CO2H, (xii) NRa(a)C(O) C1-4 alkyl, (x) phenyl optionally substituted with one or two groups independently selected from (CH2)0- 2OH, SO2NH2, CF3, F and Cl, (xi) 1-pyrrolidinyl optionally substituted with oxo, (xii) 1-imidazolidinyl optionally substituted with oxo, (xiii) 1-piperidinyl optionally substituted with oxo, and (xiv) 4-morpholinyl ; or Rb(a) and Rc(a) together with the nitrogen atom to which they are attached a 6- or 7-membered heterocycle having from 0 to 1 additional heteroatom selected from N, O and S, wherein said heterocycle is optionally substituted with one or two groups independently selected from oxo, CN, (CH2)0-2OH, acetyl, benzyl, SO2 C1-4 alkyl, CONH2, methoxymethyl, carboxymethyl, CO2Ra(a) and C1-4 alkyl. in a subset of formula (I) are compounds where Cy is cyclohexyl. In one aspect the cyclohexyl is substituted with a group selected from CO2Ra(a), CONRb(a)Rc(a) and NHC(O) C 1-4 alkyl optionally substituted with OH, and said e cyclohexyl is optionally further substituted with a or two methyl groups.
In another subset of formula (I) are compounds where Cy is piperidinyl. In one aspect the piperidinyl nitrogen atom is substituted with a group selected from (i) CO C1-4 alkyl (optionally substituted with ORa(a), CN, CO2Ra(a), CONRa(a)Ra(a), and NRa(a)Ra(a)), (ii) CO-phenyl (optionally substituted with one or two groups independently selected from ethynyl, CO2Ra(a), CN, F and OH), (iii) CO-C3-6 cycloalkyl (optionally substituted with OH or CO2Ra(a)), (iv) alkyl C0-3-CO2Ra(a), (v) CONRa(a)Ra(a), (vi) CONH -phenyl (optionally substituted with one or two groups independently selected from C1-4 alkyl, CN, and Cl), (vii) CONH-C3-6 cycloalkyl, (viii) SO2NH2, (ix) SO2C1-3 alkyl, (x) SO2C1-3 haloalkyl, and (xi) SO2Ph.
In another subset of formula (I) are compounds where Cy is azepanil.
In one aspect azepanil is substituted with an oxo group at the 2-position of the ring.
In another subset of formula (I) are compounds where Ry(a) is OH. In one aspect Cy is cyclohexyl. In one embodiment thereof the cyclohexyl is substituted with a group selected from CO2Ra(a), CONHRb(a) and NHC(O) C1-4 alkyl optionally substituted with OH, and said e cyclohexyl is optionally further substituted with one or two methyl groups. In another aspect Cy is 2-oxoazepanil.
In another subset of formula (I) are compounds where Ry(a) is CONH2. In one aspect Cy is cyclohexyl. In one embodiment this cyclohexyl is substituted with a group selected from CO2Ra(a), CONHRb(a) and NHC(O) C1-4 alkyl optionally substituted with OH, and said cyclohexyl is optionally further substituted with one or two methyl groups.
The present invention further provides the compounds of formula (Ia) or a pharmaceutically acceptable salt thereof:
wherein Z is -CRz(b)RZz(c)-, -N(Rz(d))-, -CH 2 -N(Rz(d))-, or -NHC(O)-; p' is from 0 to 3, with the proviso that p is 0 when Z is -NHC(O)-; Rz(b) is selected from (a) H, (B) C1-4 alkyl optionally substituted with one to three groups independently selected from OH, NH2, CN, CO2Ra(a) and CONH2, (C) halogen, (D) CN, (E) -C(O)Ra(a), (F) -C(O)2Ra(a), (G) -C(O)NRb(a)Rc(a), (H) -ORa (a), (I) -OC(O)Ra(a), (J) -NRb(a)Rc(a), (K) -NHC(O) C1-4 alkyl (optionally substituted with OH), ( L) -NHSO2 C1-3 alkyl, (M) -NHSO2NH2, (N) 1,3,4-oxadiazol-2(3H)-one, and (O) 1,2,4-oxadiazol-5(4H)- one; Rz(c)is H or methyl; Rz(d) is selected from (a) H, (B) C1-3 alkyl optionally substituted with a group selected from CO2Ra(a) and CONH2, (C) C1-3 fluoroalkyl, (D) CO C1-4 alkyl ( optionally substituted with one or two groups independently selected from ORa(a), CN, CO2Ra(a), CONRa(a)Ra(a), and NRa(a)Ra(a)), (E) CO-phenyl (optionally substituted with one or two groups independently selected from ethynyl, CO2Ra(a), CN, F and OH), (F) CO-C3-6 cycloalkyl (optionally substituted with OH or CO2Ra(a)), (G) alkyl C0- 3-CO2Ra(a), (H) CONRa(a)Ra(a), (I) CONH-phenyl (optionally substituted with one or two groups independently selected from C1-4 alkyl, CN, and Cl), (J) CONH-C3-6 cycloalkyl, (K) SO2NH2, (L) SO2C1-3alkyl, (M) SO2C1-3haloalkyl, and (N) SO2Ph; and R1, R4, Ry(a), Ra(a), Rb(a) and Rc(a) are as defined under formula I.
In a subset of formula (Ia) are compounds wherein Z is -NHC(O)-. In one embodiment of this Ry(a) is OH.
In another subset of formula (Ia) are compounds wherein Z is -CHRz(b) - and p’ is 0, 1 or 2. In one aspect of this Rz(b) is CO2H. In another aspect of this Rz(b) is CONHRb(a); in one embodiment Rz(b)is CONH2, in another embodiment Rz(b)is CONH(CH2)3-(2-oxo-1-pyrrolidinyl). In another aspect of this Rz(b) is NHC(O) C1-4 alkyl (optionally substituted with OH); in one embodiment Rz(b) is NHC(O)CH 2 OH.
In another subset of formula (Ia) are compounds where Z is -CHRz(b)-, p’ is 0, 1 or 2, and Ry(a)is OH or CONH2. In one aspect of this Rz(b) is CO2H. In another aspect of this Rz(b) is CONHRb(a); in one embodiment Rz(b)is CONH2, in another embodiment Rz(b)is CONH(CH2)3-(2-oxo-1-pyrrolidinyl). In another aspect of this Rz(b) is NHC(O) C1-4 alkyl (optionally substituted with OH); in one embodiment Rz(b) is NHC(O)CH 2 OH.
Representative compounds of the present invention are as follows (each compound is intended to include its pharmaceutically acceptable salts): 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl )-1,3-thiazol-2-yl]-cyclohexanecarbonitrile; 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxamide; (1S,4R)-4-Methoxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid; 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanone; cis-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane-1,4-diol; trans-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane-1,4-diol; trans-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2]cyclohexane-1,4- diol; cis-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane-1, 4-diol; 5-hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one; cis-4-[(hydroxyacetyl)amino]-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]cyclohexanecarboxamide; (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3- thiazol-2-yl]-N-[3-(2-oxopyrrolidin-1-yl)propyl]-cyclohexanecarboxamide; cis-4-Fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; ethyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate; trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile; trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile; trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide; cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide; 3-{cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexyl }-1,2,4-oxadiazol-5(4H)-one;
cis-4-methoxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
trans-4-methoxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
1-Amino-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl] acid cyclohexanecarboxylic acid;
(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid;
(1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3 acid -thiazol-2-yl]cyclohexanecarboxylic acid;
(1S,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid;
(1R,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid; 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate tert-butyl; 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol; 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide; 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-sulfonamide; 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1-(phenylsulfonyl)piperidin-4- ol; 1-{4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]piperidin- 1-yl}ethanone; 4-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]piperidine -1-carboxamide; 2-{3-Hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl]azetidin acid -1-yl}-2-methyl-propanoic; 4-chloro-4-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)piperidine-1-sulfonamide; 5-{cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl] cyclohexyl}-1,3,4-oxadiazol-2(3H)-one; 1-[5-(3-methyl-5-{[4-(propan-2-yl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol; N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoro-methyl)pyrimidin-2-amine; N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}methanesulfonamide ; 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3 -yl}propane-2-sulfonamide;
N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-cyclopropylpyrimidin-2-amine hydrochloride; N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}sulfuric diamide; 1-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}urea; N-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}acetamide; 1-(5-{3-[(4-cyclobutylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol;
cis-4-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylic acid;
trans-4-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylic acid; (1S,4R)-4-(hydroxymethyl)-3,3-dimethyl-1-(5-(3-methyl-5-(4-(trifluoromethyl)-pyrimidin-2-ylamino)phenyl)thiazol-2-yl )cyclohexanol;
(1S, 4R)-4-(5-{3-Cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2 acid ,2-dimethylcyclohexanecarboxylic acid; cis-4-hydroxy-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl ]cyclohexanecarboxamide; cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-N-[ 3-(2-oxopyrrolidin-1-yl)propyl]cyclohexanecarboxamide; (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(propan-2-yloxy)-pyrimidin-2-yl]amino}phenyl) -1,3-thiazol-2-yl]cyclohexanecarboxamide; (1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3- ethyl thiazol-2-yl]cyclohexanecarboxylate; 5-(aminomethyl)-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]azepan-2 -one; 5-(2-hydroxyethoxy)-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan -2-one;
trans-1,4-Dihydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl] acid cyclohexanecarboxylic acid;
cis-1,4-Dihydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid ; 1-{cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl] cyclohexyl}pyrrolidin-2-one;
1,4-trans, 1,5-trans-4,5-dihydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl] acid amino}phenyl)-1,3-thiazol-2-yl]cyclohexane carboxylic;
1,4-cis, 1,5-cis-4,5-dihydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-acid] yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane carboxylic;
cis-4-Fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
trans-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
(1S,4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)-phenyl]-thiazol-2-yl} acid -cyclohexanecarboxylic acid; 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2- one; 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2- one; 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2- one; 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2- one; 5-amino-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one;
(1S,4R)-4-[5-(3-{[4-(Difluoromethyl)pyrimidin-2-yl]amino}-5-methyl-phenyl)-1,3-thiazol-2-yl]-4 acid -hydroxy-2,2-dimethylcyclohexanecarboxylic acid;
(1R,4S)-4-[5-(3-Cyclopropyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl]-4 acid -hydroxy-2,2-dimethylcyclohexanecarboxylic acid;
(1S,4R)-4-[5-(3-Cyclopropyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}-phenyl)-1,3-thiazol-2-yl]- acid 4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; (1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3- thiazol-2-yl]cyclohexanecarboxamide; and (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3 -thiazol-2-yl]cyclohexanecarboxamide.
In a subset of the above representative compounds are:
(1R,4S)-4-[5-(3-Cyclopropyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl]-4 acid -hydroxy-2,2-dimethylcyclohexanecarboxylic acid;
(1S,4R)-4-[5-(3-Cyclopropyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}-phenyl)-1,3-thiazol-2-yl]- acid 4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;
(1S,4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)-phenyl]-thiazol-2-yl} acid -cyclohexanecarboxylic acid;
(1S,4R)-4-[5-(3-{[4-(Difluoromethyl)pyrimidin-2-yl]amino}-5-methyl-phenyl)-1,3-thiazol-2-yl]-4 acid -hydroxy-2,2-dimethylcyclohexanecarboxylic acid; (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(propan-2-yloxy)-pyrimidin-2-yl]amino}phenyl) -1,3-thiazol-2-yl]cyclohexanecarboxamide;
trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;
cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; 5-hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one; cis-4-[(hydroxyacetyl)amino]-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]cyclohexanecarboxamide; and (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1, 3-thiazol-2-yl]-N-[3-(2-oxopyrrolidin-1-yl)-propyl]cyclohexanecarboxamide;
(1S, 4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid;
(1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid;
(1S,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid;
(1R,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid; (1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3 -thiazol-2-yl]cyclohexanecarboxamide; and (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1, 3-thiazol-2-yl]cyclohexanecarboxamide; or a pharmaceutically acceptable salt thereof.
The present invention also includes the compounds (1S, 4R) and (1R, 4S)-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-acid. 1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid, 2-[(2-{3-hydroxy-3-[5-(3-methyl-5-{[4-( trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azetidin-1-yl}-2-methylpropanoyl)oxy]-2-methyl-propanoic and {[4-hydroxy-4 methyl -(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methyl-phenyl}-1,3-thiazol-2-yl)piperidin-1-yl]sulfonyl}carbamate; or a pharmaceutically acceptable salt thereof.
In the application various terms are as defined below: "Alkyl" refers to a straight or branched chain hydrocarbon radical 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. "Alkenyl" refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond, and having the specified number of carbon atoms. Examples of "alkenyl" include, but are not limited to ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl and n-pentenyl. "Alkynyl" refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond, and having the specified number of carbon atoms. Examples of "alkynyl" include, but are not limited to ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Cycloalkyl" refers to a saturated ring that contains the specified number of carbon atoms in the ring, and no heteroatoms. In the same way the term "C3-8 cycloalkyl" refers to a saturated ring having 3 to 8 ring carbon atoms. Exemplary "cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloeptyl and cyclooctyl. "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine. "Haloalkyl" refers to an alkyl group as defined above in which one and up to all of the hydrogen atoms are replaced by a halogen; halogen is as defined herein. Examples of such straight or branched chain alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl independently substituted with one or more halos, e.g., fluorine, chlorine , bromine and iodine. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, trifluoro-methyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and perfluoro-n-propyl . "Hydroxyalkyl" refers to an alkyl group as defined above in which a hydrogen on each carbon atom may be replaced by a hydroxy group. Examples of "hydroxyalkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, propane-1,2-diol. "Heterocyclic" or "heterocyclyl" refers to a non-aromatic saturated or partially unsaturated monocyclic ring in which one to three ring atoms are independently selected from N, S and O. Examples of heterocycle include, but are not limited to , aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, imidazolidine, oxazolidine, thiazolidine, dihydroazepine, tetrahydroazepine, azepane, diazepane, dihydro-diazepine, tetrahydro-diazepine, oxetane, tetrahydrofuran, tetrahydrophene, dihydropyran - hydrothiopyran, dihydrothiopyran, 1,3-dioxane, 1,4-dioxane, 1,3-dioxolane. "Heteroaryl" refers to monocyclic aromatic groups and fused bicyclic aromatic rings that contain 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrazine, pyrimidine.
The term "composition", as in the pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product that results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from other types of reactions or interactions of a or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of formula (I), and pharmaceutically acceptable excipients.
As used herein, the term "optionally" means that the event(s) subsequently described may or may not occur, and includes both event(s) that do occur and events that do not occur.
As used herein, the term "substituted with one or more groups" refers to substitution with the indicated substituent or substituents, multiple degrees of substitution, up to replacement of all hydrogen atoms with the same or different substituents, which are permitted. , unless the number of substituents is explicitly stated. Where the number of substituents is not explicitly stated, one or more are intended.
Each variable is independently defined each time it occurs within the definitions of the generic structural formula. For example, when there is more than one of the Rz(a) substituents on the Cy ring, each substituent is independently selected at each occurrence, and each substituent may be the same or different from one another. As another example, for the group NRa(a)Ra(a), each occurrence of the two groups Ra(a) can be the same or different.
As used herein, where the notation "C0" or "(CH2)0" modifies a substituent, it indicates a bond between the substituent and the rest of the molecule. Thus, the term "alkyl C0-3-CO2H" means the carboxy group is directly attached to the rest of the molecule, or there is a separate C1-3 alkyl group between them.
The term "Syk inhibitor" is used to mean a compound that inhibits the Syk enzyme.
The term "Syk-mediated disease" or a "disorder or disease or condition mediated by the property of inappropriate Syk" is used to mean any disease state mediated or modulated by Syk kinase mechanisms. Such disease states can include inflammatory, allergic and autoimmune diseases, for example, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDs), ulcerative colitis, Crohns disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus, in particular, 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 a variable stoichiometry complex formed by a solute (in this invention, a compound of formula (I), or a salt thereof) and a solvent. such solvents for the purpose of the invention may 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 (e.g., a drug precursor) that is transformed IN VIVO to produce a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. . Transformation can take place by various mechanisms (eg metabolic or chemical processes) such as, for example, through hydrolysis in the blood. Prodrugs are such derivatives, and a discussion of the uses of prodrugs is provided by T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
The compounds of formula (I) may have the ability to crystallize in more than one form, a feature known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism in general can occur in response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various characteristics 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 exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by crystallization and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (eg, chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereomers and converting (eg by hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of formula (I) may be atropisomers (eg substituted biaryls) and are considered to be part of this invention.
It is also mentioned that the compounds of formula (I) can form tautomers. It is understood that all tautomers and mixtures of tautomers of the compounds of the present invention are included within the scope of the compounds of the present invention. Some of the compounds described herein contain olefinic double bonds, and unless otherwise specified, are intended to include both E and Z geometric isomers.
Although embodiments for each variable in general were listed above separately for each variable, this invention also includes those compounds in which several or each embodiment in formula (I) is selected from each of the embodiments listed above. Accordingly, this invention is intended to include all combinations of embodiments for each variable. The compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. For a review on suitable salts see Berge ET AL, J. 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 the non-toxic salts of the compounds of this invention. Suitable pharmaceutically acceptable salts may include acid or base addition salts. A pharmaceutically acceptable acid addition salt can be formed by reacting a compound of formula (I) with an inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic acid , fumaric, citric, tartaric lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, or hexanoic), optionally a suitable solvent such as an organic solvent, to give the salt which is usually isolated, for example, by catalysis and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) comprises or can be, for example, a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate salt , tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (for example, 2-naphthalenesulfonate) or hexanoate.
A pharmaceutically acceptable base salt can be formed by reacting a compound of formula (I) with a suitable inorganic or organic base. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganese, 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 salts of primary, secondary and tertiary amines, substituted amines including substituted amines, cyclic amines, and naturally occurring basic ion exchange resins such as arginine, betaine, caffeine , choline, N,N'-dibenzyl-ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glycamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglycamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
Other, non-pharmaceutically acceptable salts, for example oxalates or trifluoroacetates, may also be used, for example, in the isolation of the compounds of the invention, and are included within the scope of this invention.
The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the compounds of formula (I).
In the compounds of formula (I), atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variations of the compounds of the generic formula (I). For example, isotopic forms other than hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enrichment for deuterium can produce certain therapeutic advantages, such as increasing the IN VIVO half-life or reducing dosage requirements, or can provide a useful compound as a standard for the characterization of biological samples. Isotopically enriched compounds within generic Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically enriched reagents and/or intermediates.
The compounds of formula (I) and salts, solvates and physiologically functional derivatives thereof are believed to be inhibitors of Syk activity, and thus to be potentially useful in the treatment of diseases and conditions associated with inappropriate Syk activity.
The compounds of formula (I) or their pharmaceutically acceptable salts and pharmaceutical compositions can be used to treat or prevent a variety of conditions or diseases mediated by spleen tyrosine kinase (SYK). Such conditions and diseases include, but are not limited to: (1) arthritis, which include rheumatoid arthritis, juvenile arthritis, psoriatic arthritis and osteoarthritis; (2) asthma and chronic obstructive pulmonary disease that includes emphysema; (3) autoimmune diseases or disorders, which include those designated as single organ or single cell type autoimmune disorders, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosus, immune thrombocytopenic purpura, rheumatoid arthritis, multiple sclerosis; (4) cancers or tumors, which include solid tumors, and lymphoma and leukemia; (5) eye diseases including keratoconjunctivitis, vernal conjunctivitis, uveitis, keratitis, keratoconjunctivitis sicca (dry eye), allergic conjunctivitis; (6) intestinal inflammations, allergies or conditions including Crohn's disease and/or ulcerative colitis, inflammatory bowel disease; (7) skin diseases that include atopic dermatitis, eczema, psoriasis, scleroderma, pruritus and other pruritic conditions; (8) allergic reactions that include anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, or allergic reaction to insect bites, food, medications, or pollen; (9) transplant rejection.
The invention thus provides the compounds of formula (I) and salts, solvates and physiologically functional derivatives thereof for use in therapy, and particularly in the treatment of diseases and conditions mediated by the inappropriate Syk property. The inappropriate Syk activity alluded to here is any Syk activity that deviates from the normal Syk activity expected in a particular mammalian individual. Inappropriate Syk activity can take the form of, for example, an abnormal increase in activity, or an aberration in activity in timing and/or controlling Syk activity. Such inappropriate activity may then result, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation.
In another embodiment, the present invention is directed to methods of regulating, modulating, or inhibiting Syk for the prevention and/or treatment of disorders related to unregulated Syk activity.
In another embodiment, the present invention provides a method of treating a mammal suffering from a disorder mediated by Syk activity, which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically salt acceptable, solvate, or a physiologically functional derivative thereof.
In another embodiment, the present invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder. mediated by Syk activity.
In another embodiment said Syk activity-mediated disorder is asthma. In another embodiment said disorder is rheumatoid arthritis. In yet another embodiment, said disorder is cancer. In another embodiment said disorder is ocular conjunctivitis.
While it is possible that, for use in therapy, a compound of formula (I), as well as salts, solvates and their physiological functional derivatives, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides a pharmaceutical composition, which comprises a compound of formula (I) and salts, solvates and physiologically functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The compounds of the formula (I) and salts, solvates and their physiological functional derivatives are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient . According to another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition which comprises mixing a compound of the formula (I), or salts, solvates and physiological functional derivatives thereof, with one or more carriers, diluents or excipients pharmaceutically acceptable.
The pharmaceutical compositions of the present invention may be presented in unit dose form which contain a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 5 µg to 1 g, preferably from 1 mg to 700 mg, more preferably from 5 mg to 100 mg of a compound of the formula (I), depending on the condition that is treated, the route of administration and age, weight and condition of the patient. Such unit doses may consequently be administered more than once a day. Preferred unit dosage compositions are those which contain a daily dose or sub-dose (for administration more than once a day), as indicated hereinabove, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions can be prepared by any of the methods well known in the art of pharmacy.
The pharmaceutical compositions of the present invention may be adapted for administration by any suitable route, for example by the oral route (which includes buccal or sublingual), inhaled, nasal, ocular, or parenteral (which includes intravenous and intramuscular). Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing the active ingredient into association with the carrier(s) or excipient(s).
In another embodiment, the present invention provides a pharmaceutical composition adapted for oral administration to treat, for example, rheumatoid arthritis.
In another embodiment, the present invention provides a pharmaceutical composition adapted for administration via the nasal route, to treat, for example, allergic rhinitis.
In another embodiment, the present invention provides a pharmaceutical composition adapted for administration by the inhaled route, to treat, for example, asthma, COPD or ARDS.
Pharmaceutical compositions of the present invention which are adapted for oral administration may be presented as separate units such as capsules or tablets; powders or granules; aqueous or non-aqueous liquid solutions or suspensions; edible foams or whipped creams; or oil-in-water liquid emulsion or water-in-oil liquid emulsion.
For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an inert, non-toxic, pharmaceutically acceptable oral carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similar comminuted pharmaceutical carrier such as an edible carbohydrate, such as, for example, starch or mannitol. Flavoring, dispersing and coloring preservative agents may also be present.
Capsules are manufactured by preparing a powder mixture as described above and filling formed gelatin shells. 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. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the drug when the capsule is ingested.
Furthermore, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or grinding, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a retarding solution such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by moistening it with a binder such as syrup, starch paste, akkadian mucilage or solutions of cellulosic or polymeric materials and forcing through a sieve. As an alternative to granulation, the powder mixture can be driven through the tabletting machine and the result is imperfectly formed pieces broken into granules. The granules can be lubricated to prevent them from sticking to the tablet-forming matrices by the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulation or crushing steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dye can be added to these coatings to distinguish different unit dosages.
Oral fluids 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 a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
Dosage forms for inhaled administration may conveniently be formulated as aerosols or dry powders.
For compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of formula (I) is in a particle size reduced form, and more preferably the size reduced form is obtained or obtainable by micronization. The preferable particle size of the downsized (e.g., micronized) compound or salt or solvate is defined by a D50 value of about 0.5 to about 10 microns (e.g. as measured using laser diffraction).
Aerosol formulations, for example, for inhaled administration, may comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations may be presented in single or multiple dose amounts in sterile form in a sealed container, which may take the form of a cartridge or refill for use with an atomizing device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted. . Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a hydrofluorocarbon (HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. Aerosol dosage forms can also take the form of a pump atomizer. The pressurized aerosol can contain a solution or a suspension of the active compound. This may require the incorporation of additional excipients eg co-solvents and/or surfactants to improve the characteristic dispersion and homogeneity of suspension formulations. Solution formulations may also require the addition of co-solvents such as ethanol. Other excipient modifiers can also be incorporated to improve, for example, the stability and/or flavor and/or fine particle mass characteristics (amount and/or profile) of the formulation.
For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the pharmaceutical composition is a dry powder inhalable composition. Such a composition may comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, the compound of formula (I) or salt or solvate thereof (preferably in particle size reduced form, for example in micronized form) , and optionally a performance modifier such as L-leucine or another amino acid, and/or metal salts of stearic acid such as magnesium or calcium stearate. Preferably, the dry powder inhalable composition comprises a mixture of lactose dry powder and the compound of formula (I) or salt thereof. The lactose is preferably hydrated lactose eg lactose monohydrate and/or is preferably inhalation grade and/or fine grade lactose. Preferably, the lactose particle size is defined by 90% or more (by weight or by volume) of lactose particles being smaller than 1000 microns (micrometers) (eg from 10 to 1000 microns eg from 30 to 1000 microns) in diameter, and/or 50% or more of lactose particles being less than 500 microns (eg, 10 to 500 microns) in diameter. More preferably, the particle size of lactose is defined as 90% or more of lactose particles being smaller than 300 microns (eg from 10 to 300 microns eg 50 to 300 microns) in diameter, and/or 50% or more of lactose particles being less than 100 microns in diameter. Optionally, the lactose particle size is defined as 90% or more of lactose particles being less than 100 to 200 microns in diameter, and/or 50% or more of lactose particles being less than 40 to 70 microns in diameter. diameter. It is preferred that about 3 to about 30% (for example about 10%) (by weight or by volume) of the particles are less than 50 microns or less than 20 microns in diameter. For example, without limitation, a suitable inhalation grade lactose is lactose E9334 (10% fines) (Borculo Domo Ingredients, Hanzepleem 25, 8017 J D Zwolle, The Netherlands).
Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for inhaled administration may be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally on a strip or tape within. of a suitable inhalation device. The container is breakable or opened by removing the film as needed and the dose, for example, of the dry powder composition can be administered by inhalation via a device such as the DISKUS® (GlaxoSmithKline) device. Other dry powder inhalers are well known to those of ordinary skill in the art, and many such devices are commercially available, with representative devices including Aerolizer® (Novartis), Airmax® (IVAX), ClickHaler® (Innovata Biomed), Diskhaler ® (GlaxoSmithKline), Accuhaler (GlaxoSmithKline), Easyhaler® (Orion Pharma), Eclipse® (Aventis), FlowCaps® (Hovione), Handihaler® (Boehringer Ingelheim), Pulvinal® (Chiesi), Rotahaler® (GlaxoSmithKline), SkyeHaler® or Certihaler® (SkyePharma), Twisthaler (Schering-Plough), Turbuhaler® (AstraZeneca), Ultrahaler® (Aventis), and the like.
Dosage forms for nasal administration may conveniently be formulated as aerosols, solutions, drops, gels or dry powders.
Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators.
For pharmaceutical compositions suitable and/or adapted for intranasal administration, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be formulated as a fluid formation for release from a fluid dispenser. Such a fluid dispenser may have, for example, a dispensing nozzle or dispensing orifice through which a metered dose of fluid formulation is dispensed upon application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir for multiple metered doses of the fluid formulation, the doses being dispensable in sequential pump actuations. The mouthpiece or dispensing orifice can be configured by insertion into the user's nostrils by dispensing by spraying the fluid formulation into the nasal cavity. The following are examples of representative pharmaceutical dosage forms for the compounds of this invention:


It will be appreciated that when the compound of the present invention is administered in combination with other therapeutic agents normally administered by the inhaled, intravenous, oral or intranasal routes, that the resulting pharmaceutical composition can be administered by the same routes.
It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
A therapeutically effective amount of a compound of the present invention will depend on a number of factors including, for example, the age and weight of the animal, the exact condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and ultimately it will be at the discretion of the attending physician or veterinarian. However, an effective amount of a compound of formula (I) for treating diseases or conditions associated with inappropriate Syk activity will generally be in the range of 5 µg to 100 mg/kg of recipient (mammal) body weight per day and more usually in the range of 5 μg to 10 mg/kg body weight per day. This amount can be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of the sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate thereof can be determined as a proportion of the effective amount of the compound of formula (I) itself.
The compounds of the present invention, and their salts and solvates, and their physiologically functional derivatives, can be used alone or in combination with other therapeutic agents for the treatment of diseases and conditions associated with inappropriate Syk activity. Combination therapies according to the present invention thus comprise 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 the use of at least one other pharmaceutically agent active. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected so as to obtain the combined therapeutic effect wanted.
For the treatment of inflammatory diseases, rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of formula (I) may be combined with one or more other active agents such as: (1) TNF-inhibitors α; (2) non-selective COX-1/COX-2 inhibitors; (3) COX-2 inhibitors; (4) other agents for the treatment of rheumatoid arthritis which include methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporine, tacrolimus, penicillamine, bucilamine, actarit, mizoribin, lobenzarit, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, parenteral or aura oral, cyclophosphamide, Linfostat-B, BAFF/APRIL and CTLA-4-Ig inhibitors or their mimetics; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or antagonist of 5-lipoxygenase activating protein (FLAP); (6) LTD4 receptor antagonist; (7) PDE4 inhibitor; (8) antihistamine H1 receptor antagonists; (9) α1 and α2 adrenoceptor agonists; (10) anticholinergic agents; (11) β-adrenoceptor agonists; (12) type I mimetics of insulin-equivalent growth factor (IGF-1); (13) glucocorticosteroids; (14) kinase inhibitors such as are Janus Kinase inhibitors (JAK 1 and/or JAK2 and/or JAK 3 and/or TYK2), p38 MAPK and IKK2; (15) biological products that target the B cell such as rituximab; (16) selective costimulation modulators such as abatacept; (17) interleukin inhibitors such as IL-1 inhibitor anakinra and IL-6 inhibitor tocilizumab.
For the treatment of cancer a compound of formula (I) can be combined with one or more of an anti-cancer agent. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such anti-cancer agents include, but are not limited to the following: (1) estrogen receptor modulator; (2) other hormonal agents that include aromatase inhibitors; (3) androgen receptor modulator; (4) retinoid receptor modulator; (5) antiproliferative agent; (6) prenyl-protein transferase inhibitor; (7) HMG-CoA reductase inhibitor; (8) angiogenesis inhibitor; (9) PPAR-Y agonists, PPAR-δ agonists; (10) inherent multiple drug resistance inhibitor; (11) inhibitor of cell proliferation and survival signaling; (12) a bisphosphonate; (13) y-secretase inhibitors, (14) agents that interfere with receptor tyrosine kinases (RTKs); (14) agent that interferes with a cell cycle checkpoint that include are inhibitors of ATR, ATM, Chk1 and Chk2 kinases, and inhibitors of cdk and cdc kinase; (15) BTK inhibitors; (16) PARP; (17) mTOR inhibitors; and (18) cytotoxic/cytostatic agents classically used in cancer treatment such as anthracyclines, platinum compounds, taxanes, podophyllotoxins, vinca alkaloids, nitrosoureas, bleomycin, mitomycin C, vorinostat, camptothecins and the like.
It will be evident to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal salts or amine or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimize activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will also be apparent that, where appropriate, the therapeutic ingredients can be used in optically pure form.
The combinations alluded to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention. These combinations are of particular interest in respiratory diseases and are conveniently adapted for inhaled or intranasal delivery.
The individual compounds of such combinations can be administered sequentially or simultaneously in separate or combined pharmaceutical compositions. Preferably, the individual compounds will be administered simultaneously in a combined pharmaceutical composition. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art. Biological Test
The Homogeneous Time-Resolved Fluorescence (HTRF) assay for recombinant human SYK enzyme: A recombinant GST-hSYK fusion protein was used to measure the potency of the compounds to inhibit human SYK activity. Recombinant human GST-SYK (Carna Biosciences #08 - 176) (5 pM final concentration) was incubated with various concentrations of the inhibitor diluted in DMSO (0.1 % final concentration) for 10 minutes at room temperature in 15 mM of Tris-HCl (pH 7.5), 0.01% tween 20, 2 mM DTT in 384-well plate format. To initiate the reaction the biotinylated substrate peptide (250 nM final concentration) containing the phosphorylation site for 4SYK was added with magnesium (5 mM final concentration) and ATP (25 mM final concentration). The final volume of the reaction was 10 µL. Peptide phosphorylation was allowed to process for 45’ at room temperature. To quench the reaction and detect the phosphorylated product, 2 nM of a Europium-anti-phosphotyrosine antibody (Perkin Elmer #AD0161) and 70 nM of SA-APC (Perkin-Elmer #CR130-100) were added together in 15 mM of Tris pH 7.5, 40 mM EDTA, 0.01% tween 20. Final volume of quench solution was 10 µL. The resulting HTRF signal was measured after 30 minutes on an EnVision reader (Perkin-Elmer) using a time-resolved fluorescence protocol. The IC50 was determined following dose titration 10 (10 µM to 0.508 nM) and four-parameter logistic curve fit using the Merck Assay Data Analyzer. The activity of rhSYK (IC50) is expressed as +++ (100 nM or less), ++ (between 100 and 1000 nM), + (between 1 and 10 μM).
The compounds of this invention can be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are presented below and then specific compounds of the invention are prepared in the Examples.
The compounds of general formula (I) can be prepared by methods known in the art of organic synthesis as shown in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1991) Protecting groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of protecting groups as well as the reaction conditions and order of reaction steps must be compatible with the preparation of the compounds of formula (I). Those skilled in the art will recognize whether a stereocenter exists in the compounds of formula (I). Consequently, the present invention includes all possible stereoisomers and includes not only mixtures of stereoisomers (such as racemic compounds) but also individual stereoisomers. When a compound is desired as a single enantiomer, it can be obtained by stereospecific synthesis or by resolution of the final product or by any convenient intermediate. Resolution of the final product, an intermediate, or a starting material can be carried out by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).
In the following Schemes R5 represents the portion
"A" and "B" together represent the portion

The ring indicated as "A" represents a suitable ring within the definition of Cy, and is optionally substituted as Cy.
The following abbreviations are used in 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; DIPEA /DIEA = Diisopropylethylamine; DMAP = N,N-dimethylaminopyridine; DME = 1,2-dimethoxyethane; DMF = Dimethyl formamide; DMSO = Dimethyl sulfoxide; Dppf = 1,1'-Bis(diphenylphosphino)ferrocene; EDC = N-(3-dimethyl-aminopropyl)-N'-ethylcarbodiimide; EtOAc = Ethyl acetate; HATU = N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)-uronium hexafluorophosphate; HMDS = Hexamethyldisilazane; HOBT = 1-Hydroxybenzotriazole; IPA = isopropyl alcohol; LDA = Lithium Diisopropylamide; mCPBa = Meta-chloroperoxybenzoic acid; Ms = Methanesulfonyl (mesyl); MTBE = methyl t-butyl ether; NBS = N-bromosuccinimide; Ph = phenyl; TBAF = t-butylammonium fluoride; TBDMS/TBS = t-butyl dimethylsilyl; TFA = Trifluoroacetic/Trifluroacetate; 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 = cycloeptyl. SCHEME 1

The compounds of formula (I) can be prepared by the Suzuki coupling of the boronic esters (1) with one of the thiazole bromides (2). Boronic esters (1) can be obtained by reacting 2-chloropyrimidines (3) and 3-bromoanilines (82) to form the corresponding N-(3-bromophenyl)-pyrimidine-2-amines (83), followed by Miyaura coupling with bis(pinacolato)diboron. The compounds of formula (I) can also be obtained by the reaction of 2-chloropyrimidines (3) and thiazole substituted anilines (4) in the presence of a Pd catalyst or alternatively an SNAr reaction. The thiazole substituted anilines (4), in turn, can be formed under Suzuki coupling conditions using a bromothiazole and nitrophenyl boronic ester, followed by reduction of the nitro group to an amino group using standard conditions known to reduce nitroaromatic compounds for anilines such as Pd-catalyzed hydrogenation. Compounds of formula (I) can also be formed by the Heck reaction between bromine-substituted anilines (83) with substituted thiazoles (84). Bromine-substituted anilines (83) can be prepared by the SNAr reaction between 2-chloropyrimidines (3) and substituted bromo-anilines (82). SCHEME 2

Compounds of formula (I) can also be prepared from compounds (5). The thiazol (5) is treated with a strong base such as LDA, and then with ketones for alcohols (6); with sulphinines to provide 10 sulfinamides (9), which can be cleaved under acidic conditions to provide amines (10). Alcohols (6) can be fluorinated using a fluorinating agent such as DAST or deoxofluor to provide compounds (11). SCHEME 5

Amines (10) can be treated (a) with sulfamide to provide compounds (14); (b) with potassium cyanate in the presence of acetic acid to provide ureas (15); (c) with acylating agents such as acid chlorides and carboxylic acids with a coupling agent to provide 5 amides (17). SCHEME 6

Ketals (18), prepared from compounds (5) and 1,4-dioxaspiro[4,5]decan-8-one, can be treated with HCl to produce ketones (19), which can then be reduced with borohydride. of sodium or 10 treated with methyl Grignard to produce diols (20) or (22), respectively. Alternatively, ketals (18) or ketones (19) are treated with sodium azide and methanesulfonic acid to provide the rearranged lactam (21). Alkylation of compounds (21) followed by deprotection of the silyl ether intermediate produces alcohols (90). SCHEME 8

Compounds (4) can be prepared from 2-amino-1-(3-nitrophenyl)ethanone (23). Linking the amide with an acid provides compounds (24), which are treated with Lawesson's reagent resulting in the formation of nitrophenyls (25). The palladium-mediated reduction of nitroarenes (25) by anilines that produce hydrogen (4). SCHEME 10

Compounds (4) can be prepared from 2-amino-1-(3-nitrophenyl)ethanone (23). Linking the amide with an acid provides compounds (24), which are treated with Lawesson's reagent resulting in the formation of nitrophenyls (25). The palladium-mediated reduction of nitroarenes (25) by anilines that produce hydrogen (4).
Dehydration of compounds (49) with Eaton's reagent provides cycloalkenes (50), which produce diols (93) followed by dehydration. SCHEME 12

Bromides (67) undergo Sonogashira coupling with TMS-acetylene and subsequent silyl deprotection yields acetylene compounds (69), which are reduced to yield compounds (70). Palladium-mediated binding of (67) with cyclopropyl boroate (prepared according to literature; see: JA; Huertas, R.; Leon-Colon, G. Tetrahedron Lett. 2000, 41, 4251-4255) provides the compound of cyclopropyl (68). SCHEME 14

The preparation of 2-chloropyrimidine building blocks starting with 2,4-dichloropyrimidines (71) is illustrated in Scheme 14. Functionalization of pyrimidine via the Suzuki bond yields 2-substituted chloropyrimidines (73), as an SNAr reaction base-mediated with substituted alcohol nucleophile provides ethers (72). Compounds (76) are prepared by an iron-promoted binding of of Grignard reagents to compounds (71). In Scheme R is alkyl or cycloalkyl. SCHEME 15

Coupling of compounds (4) with 2-chloro-4-(methylsulfanyl)pyrimidine (78) provided anilines (79), which are oxidized to the sulfones (8) by mCPBA. Displacement of the sulfone moiety with the alcohols or thiols under basic conditions provided compounds (81). SCHEME 16

Reaction of acids (94) with hydrazine carboxamide produces 1,3,4-oxadiazoles (97). Alternatively, linking the amide with acids (94) produces amides (98). Dehydration of amides (98) with a sulfamoyl salt produces nitriles (99). Cyclization of nitriles (99) with ammonium hydroxide produces 1,2,4-oxadiazoles (100). SCHEME 20
followed by bromination provides (112). The Suzuki connection of (1) with (112) produces (113). Hydrolysis of (113) gives the amide (114), and reduction of (113) with DIBAL gives the amine (115). SCHEME 22

The ketone (120) is reacted with t-butyl sulfonamide in the presence of titanium ethoxide to produce (121). Deprotection of compound (5) with LDA followed by addition of (121) and then ring expansion by the action of acid and azide gives (122).
The compounds of formula (I), as well as intermediates for their synthesis, can be prepared according to the procedures described in the Schemes, the Preparation of Intermediates, and the Examples herein, using appropriate materials and are further exemplified by the following intermediates and examples specific. The exemplified compounds are representative of the invention, and should not be construed as limiting the scope of the invention in any way. the examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of protecting groups, reagents, as well as the conditions and procedures of the following preparative procedures, can be used to prepare intermediates and compounds of the present invention. It is also understood when a chemical reagent is not commercially available, such a chemical reagent can be easily prepared by those skilled in the art by following or adapting known methods described in the literature. All temperatures are in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion mass spectroscopy (ESI) or atmospheric pressure chemical ionization mass spectroscopy (APCI).
PREPARATION OF INTERMEDIATES AND COMPOUNDS INTERMEDIATE MODEL 1: 1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol Step 1: Isopropylmagnesium chloride/lithium chloride complex (1.3M in HF, 582 ml , 756 mmol) was cooled to 0°C. The thiazole (53.2 ml, 749 mmol) was added in 15 minutes, resulting in an orange/red solution. Stirred for 20 minutes at 0°C, then the cooling bath removed and allowed to warm to room temperature. Stirred for an additional 2 hours, then cooled to 0°C. Cyclobutanone (53.3 ml, 713 mmol) was added in 50 minutes. Removed cooling bath and allowed to warm to room temperature and stirred 20 minutes at this temperature. The reaction mixture was cooled to 0°C and saturated aqueous ammonium chloride was slowly added. The mixture was diluted with EtOAc, the layers separated and the organic portion washed with water. The aqueous layer was washed with ethyl acetate. The combined organic portions were dried over MgSO4 and concentrated in vacuo to provide 127.5 g of material containing 1-(1,3-thiazol-2-yl)cyclobutanol, which was used without further purification. Step 2: The product from Step 1 (171.9 g, 1.107 mol) was dissolved in DMF (860 ml) and cooled to 0°C. Added NBS (236 g, 1.327 mol) and stirred 1 hour at 0°C. Removed cooling bath and allowed to warm to room temperature. Followed by LC until starting material is consumed. The solution was poured into cold water (2 liters) containing Na 2 SO 3 (30 g), washed with MTBE (1 liter)). The mixture was stirred 10 minutes, then diluted with MTBE (1.5 liter) and water (500 ml). Separate the layers and the organic portion washed with water (2 litres). The aqueous portions were extracted with MTBE (2 litres). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to provide an orange oil. Diluted in hexanes at 50°C (1 litre). Stirred while slowly allowed to cool. The seed crystals added, and crystallization started around 35°C. Stirred overnight at room temperature. Cooled to -20°C and stirred 20 min. Filtered, washed with hexanes at -20°C. Dried under a bag of nitrogen to provide 1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol (172.9 g, 739 mmol, 67%). The filtrate and all material remaining in the flask were diluted in CH2Cl2 and concentrated in vacuo. Hexane added, concentrated to ~300 ml, cooled to room temperature and seed crystals were added. They started to crystallize. Cooled to -10°C and filtered, washed with hexanes at -10°C. The second crop of crystals allowed to air dry to provide 1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol (38.8 g, 166 mmol, 15%). The precursor liquid from the second filtration was concentrated and purified by column chromatography on silica gel (Biotage EtOAc/Hex) then dried in vacuo to give 1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol (10 .6 g, 45 mmol, 4%). Everywhere, obtained 1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol (222 g, 948 mmol, 86%). »H NMR (400 MHz, CDCl3 ): δ 7.58 (s, 1H); 3.56 (br s, 1H); 2.69 - 2.60 (m, 2H); 2.47 - 2.36 (m, 2H); 2.09 - 1.87 (m, 2H). INTERMEDIATE 2: N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)-pyrimidin-2-amine
A solution of 3-bromo-5-methylaniline (162.5 g, 873.66 mmol) in 1,4-dioxane (2 litres) was prepared, and 2-chloro-4-(trifluoromethyl)-pyrimidine (182 g, 994.54 mmol) and methanesulfonic acid (97.5 g, 1.02 mol) were added sequentially. The resulting solution was heated to reflux overnight. The resulting mixture was cooled and concentrated in vacuo. The residue was diluted with 2 liters of water, then adjusted to pH 7 - 8 with aqueous sodium bicarbonate solution, followed by extraction with EtOAc (2 x 2 liters). The organic layers were combined, washed with water (2 x 2 liters), dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (200 g, 602 mmol, 69%) as a pale yellow solid. MS(ESI): [M + H]+ 334.0. '11 NMR (400 MHz, CDCl3 ): δ 8.68 (d, J = 4.9 Hz, 1H); 7.79 (s, 1H); 7.30 (s, 2H); 7.10 - 7.06 (m, 2H); 2.36 (s, 3H). INTERMEDIATE 3: N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine
To a solution of Intermediate 2 (250 g, 753.01 mmol,) in 1,4-dioxane (3 litres) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetra - methyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (225 g, 885.83 mmol), KOAc (225 g, 2.30 mol) and Pd(dppf)Cl2 ( 19 g, 25.23 mmol). The resulting solution was heated to reflux overnight. The solid was filtered. The filtrate was decolorized by passing through a silica gel column. Fractions were collected and concentrated in vacuo. This resulted in 110 g of pure product and 150 g of crude product. The crude product was decolorized once more with active carbon to provide an additional 125 g of pure product. This resulted in N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (235 g, 620 mmol, 82%) as a white solid. MS APCI: [M + H]+ m/z 380. 1H NMR (400 MHz, CDCl3, ppm): 1.350 (12H,s), 2.386 (3H,s), 6.993 - 7.006 (1H,d, J = 5.2 Hz), 7.385 - 7.427 (2H, s,), 7.636 (1H, s), 7.753 (1H, s), 8.608 - 8.621 (1H, d, J = 5.2 Hz) . INTERMEDIATE 4: N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoro-methyl)pyrimidin-2-amine
To a solution of Intermediate 3 (80 g, 211.08 mmol) in 1,4-dioxane (800 ml) was added 5-bromo-1,3-thiazole (28 g, 171.78 mmol), Pd(dppf) Cl2 (8 g, 10.62 mmol) and a solution of sodium carbonate (44.7 g, 421.70 mmol) in water (447 ml). The resulting solution was heated to reflux for one hour. Then it was allowed to cool and concentrated in vacuo. The residue was diluted with EtOAc (500 ml) and filtered. The filtrate was washed with brine (2 x 300 ml) and water (2 x 300 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was recrystallized from EtOAc : DCM in a ratio of 1:5 to obtain 34 g of product. The precursor liquid was applied to a silica gel column and eluted with dichloromethane/ethyl acetate (2:1). This resulted in N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoro-methyl)pyrimidin-2-amine (42 g, 125 mmol, 73 %) as a light yellow solid. MS APCI: [M + H]+ m/z 337. 1H NMR (400 MHz, CD3 COCD3, ppm): 2.413 (3H, s), 7.250 - 7.263 (2H, m), 7.636 (1H, s) , 8.204 - 8.213 (2H, m), 8.834 - 8.846 (1H, d, J = 4.8Hz), 8.970 (1H, s), 9.210 (1H, br). Activity of rhSYK = +++. INTERMEDIATE 5: N-(3-bromophenyl)-4-(trifluoromethyl)pyrimidin-2-amine A solution of 3-bromoaniline (250 g, 1.46 mol) in 1,4-dioxane (2.5 liters) was prepared , and 2-chloro-4-(trifluoromethyl)pyrimidine (267 g, 1.47 mol) and methanesulfonic acid (155 g, 1.61 mol) were added sequentially. The resulting solution was heated to 100°C overnight. The resulting mixture was cooled and concentrated in vacuo. The residue was adjusted to pH 7 - 8 with aqueous sodium bicarbonate solution. The solid was filtered, and the filtrate was extracted with EtOAc (4 x 500 ml). The organic layers were combined, washed with water (2 x 2 liters), dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in N-(3-bromophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (200 g, 629 mmol, 43%) as a pale yellow solid. MS APCI: [M + 3]+ m/z 319. 1 H NMR (500 MHz, CDCl 3 ): δ 8.68 (d, J = 4.9 Hz, 1 H); 7.95 (s, 1H); 7.53 - 7.50 (m, 1H); 7.44 (br s, 1H); 7.22 (m, 2H); 7.08 (d, J = 4.9 Hz, 1H). INTERMEDIATE 6: N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-4-(trifluoromethyl)pyrimidin-2-amine
To a solution of Intermediate 5 (200 g, 631 mmol,) in 1,4-dioxane (2 litres) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetra-methyl - 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (177 g, 697 mmol), KOAc (187 g, 1.91 mol) and Pd(dppf)Cl2 (24 g, 32 mmol). The resulting solution was heated to 100°C for 2 hours. The reaction was allowed to cool, and the solid was filtered. The filtrate was concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1 : 10). This resulted in N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (140 g, 384 mmol , 61 %) as a white solid. MS APCI: [M + H]+ m/z 366. 1H NMR (400 MHz, DMSO-d6, ppm): 1.300 (12H, s), 7.237 - 7.249 (1H, m), 7.331 - 7.342 (2 H, m), 7.882 - 7.910 (1H, m), 8,000 (1H, s), 8.796 - 8.806 (1H, m), 10.130 (1H, s). INTERMEDIATE 7: N-[3-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)-pyrimidin-2-amine
Pd(dppf)Cl2 (1.01 g, 1.23 mmol) and Intermediate 6 (9.0 g, 25 mmol) were combined in one flask and were evacuated and backfilled with nitrogen (x 3). Added 2-Me THF (90 ml), 5-bromothiazole (4.45 g, 27.1 mmol), and aqueous sodium carbonate (24.7 ml, 49.3 mmol) sequentially. Sealed the bottle and heated to 80°C for 15 hours. The brown solution was allowed to cool to room temperature, then diluted with water and EtOAc. The layers were separated, and the aqueous portion was extracted with EtOAc (2x). The combined organic portions were washed with saturated aqueous NaHCO3, then brine, then dried over Na2SO4 and concentrated in vacuo. Trituration with CH2Cl2 and collection of the beige solid by filtration provided 5.94 g of the desired product. The parent liquid was concentrated in vacuo and subsequent purification via silica gel column chromatography (CH2Cl2-40% EtOAc:CH2Cl2) provided an additional 1.41 g of the desired product. In total, N-[3-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (7.35 g, 22.8 mmol, 93%) was isolated like a beige solid. MS APCI: [M + H]+ m/z 323. 1H NMR (600 MHz, DMSO-D6, ppm) δ 10.32 (s, 1H), 9.06 (s, 1H), 8.82 (d, J = 4.8, 1 H), 8.20 (d, J = 8.2, 1 H), 8.20 (s, 1 H), 7.64 (d, J = 7.5 , 1H), 7.40 - 7.31 (m, 2H), 7.27 (d, J = 4.9, 1H). Activity of rhSYK = ++. INTERMEDIATE 9: N-[3-(2-bromo-1,3-thiazol-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine
Lithium diisopropylamide (1.8M in THF/heptane/ethylbenzene, 11.4ml, 20.5mmol) was cooled to -70°C. Intermediate 4 (2.3 g, 6.8 mmol) in THF (23 ml) was added slowly over 15 minutes, keeping the temperature at -65°C. The reaction was allowed to stir for 30 minutes following the addition and then bromine (0.53 ml, 10.3 mmol) was added. The reaction was stirred for 30 minutes and then quenched with 20 ml of water and warmed to room temperature. The reaction was diluted with EtOAc (50 ml). The layers were separated and the organic portion was washed with Na2SO3 (10% aqueous), brine, dried over MgSO4 and concentrated in vacuo. Purification via column chromatography (ISCO, dry load with silica gel, Hexane-50% EtOAc : Hexane) to give N-[3-(2-bromo-1,3-thiazol-5-yl)- 5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.88 g, 4.53 mmol, 66%). MS APCI: [M + H]+ m/z 414.8, 416.8. 1H NMR (600 MHz, CDCl 3 ) δ 8.64 (d, J = 4.9, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.33 (s , 1H), 7.05 (t, J = 6.4, 1H), 7.01 (s, 1H), 2.38 (s, 3H). INTERMEDIATE 10: N-[3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine
Step 1: To a solution of 3,5-dibromoaniline (4.47 g, 17.8 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (2.36 ml, 19.6 mmol) was added p-acid toluenesulfonic acid (4.06 g, 21.4 mmol) resulting in the formation of a thick suspension. This mixture was heated to 100°C overnight, during which time it became a deep red solution. The mixture was diluted with 200 ml of EtOAc and washed with 200 ml of sat. (aq) and 200 ml of brine. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by crystallization over silica gel (220 g; load weight/toluene; 100:0 to 85:15 Hexanes:EtOAc in 45 minutes) provided N-(3,5-dibromophenyl)-4-(trifluoromethyl)pyrimidin- 2-amine (5.85 g, 14.7 mmol, 83%) as a light yellow solid. MS APCI: [M + H]+ m/z 397.8. 1 H NMR (400 MHz, CDCl 3 ): δ 8.72 (d, J = 4.9 Hz, 1 H); 7.84 (s, 2H); 7.39 (s, 1H); 7.34 (s, 1H); 7.14 (d, J = 4.9 Hz, 1H).
Step 2: To a solution of the product from Step 1 (2.0 g, 5.0 mmol) in DMSO (10.1 ml) was added 4,4,5,5-tetramethyl-2-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.4 g, 5.5 mmol), KOAc (1.48 g, 15.1 mmol) and Pd(dppf)Cl 2 (123 mg, 0.151 mmol), and the mixture was heated to 125 °C for 30 minutes in the microwave. The mixture was diluted with 100 ml EtOAc and washed with 2 x 100 ml 1:1 H2O:brine. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by silica gel crystallization (80 g; loading weight/CH 2 Cl 2 ; 100 : 0 to 70 : 30 Hexanes : EtOAc in 40 minutes) gave N-[3-bromo-5-(4,4,5,5 - tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (755 mg, 1.70 mmol, 34%) as a yellowish white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.86 (d, J = 4.9, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.36 (s, 1H), 7.32 (d, J = 4.9, 1H), 1.34 (s, 12H). INTERMEDIATE 11: N-[3-bromo-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine A solution of Pd(OAc)2 (19 mg, .085 mmol) and butyl di-1-adamantyl phosphine (61 mg, 0.18 mmol) in THF (12.8 ml) was stirred for 15 minutes. Intermediate 10 (755 mg, 1.70 mmol), 5-bromo-1,3-thiazole (760 µl, 8.50 mmol), potassium fluoride (296 mg, 5.10 mmol), and water (4, 25 ml) were then added, and the mixture was heated to 75°C overnight. After cooling to room temperature, the mixture was diluted with 100 ml of EtOAc and washed with 100 ml of brine. A bright yellow solid remained undissolved on the walls of the separatory funnel, which was thus rinsed with 100 ml of THF. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by crystallization over silica gel (40 g; dry load; 100 : 0 to 50 : 50 Hexanes : EtOAc in 25 minutes) provided N-[3-bromo-5-(1,3-thiazol-5-yl) phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (449 mg, 1.12 mmol, 66%) as a yellowish white solid. MS APCI: [M + H]+ m/z 403.0. 1H NMR (400 MHz,(CD3)2CO): δ 9.46 (s, 1H); 9.03 (s, 1H); 8.89 (d, J = 4.9 Hz, 1H); 8.32 - 8.26 (m, 2H); 8.16 (s, 1H); 7.59 (s, 1H); 7.33 (d, J = 4.9 Hz, 1H). Activity of rhSYK = ++. INTERMEDIATE 15: 1-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]cyclo-butanol
Step 1: Dioxane (720 ml) in a 1 liter three-necked round bottom flask was degassed for 30 minutes. 3-Bromo-5-methylaniline (60 g, 193 mmol), (bispinacolato)diboron (96 g, 377 mmol), potassium acetate (42.7 g, 435 mmol), X-Phos (8.3 g, 17 .41 mmol) and Pd2dba3 (3.99 g, 4.35 mmol) were added to the solvent degassed under N2 (g). After stirring for 10 minutes at room temperature, the reaction mixture was heated to an internal temperature of 80°C. After about 4 hours, the heating mantle was removed and replaced with an ice-water bath. The reaction mixture was cooled to 30°C, and was then filtered through a pad of celite (wash with 500 ml MTBE). This was transferred to a 4 liter separatory funnel containing 500 ml phosphate buffer at pH 8, 500 ml brine, and an additional 500 ml MTBE. The layers were cut and the organics washed with 1 liter of a 1:1 mixture of brine and water. The aqueous layers were combined and sequentially re-extracted with a second 500 ml portion of MTBE. The combined organics were treated with 100 g of MgSO4 and the resulting mixture stirred for 20 minutes. This was then filtered and concentrated in vacuo. The resulting residue was purified by crystallization on silica gel (Biotage, 0 to 25% ethyl acetate in hexanes) to yield 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl)aniline (66 g, 255 mmol, 88%) as a light orange oil. MS APCI: [M + H]+ m/z 234.2.
Step 2: To a 500 ml three-necked round bottom flask were added 2-methyl THF (720 ml) and an aqueous solution of sodium carbonate (2M, 367 ml, 734 mmol). The solution was degassed for 30 minutes. The product from Step 1 (90 g, 367 mmol), Intermediate 1 (86 g, 367 mmol) and PdCl2(dppf) (8.05 g, 11 mmol) were added to the degassed solution under N2 (g). The resulting mixture was stirred for 5 minutes at room temperature and then heated to 80°C. After about 9 hours, the heating mantle was removed and the reaction was cooled to 30°C. The reaction mixture was filtered through a pad of SolkaFloc using water (500 ml) and ethyl acetate (500 ml) to complete the transfer. The filtrate was then transferred to a separatory funnel, using an additional 500 ml of ethyl acetate and 250 ml of brine to complete the transfer. The layers were cut, the organic washed with a mixture of water and brine (500 ml and 250 ml, respectively), and then the aqueous was re-extracted with ethyl acetate (400 ml). The organics were combined, dried over MgSO4 (100 g), filtered and concentrated in vacuo to yield a brown crystalline solid. This material was recrystallized from hot ethyl acetate (250 ml at 60°C), using hexanes as a counter-solvent (750 ml) to yield 1-[5-(3-amino-5-methylphenyl)-1, 3-thiazol-2-yl]cyclobutanol (88 g, 338 mmol, 92%). MS APCI: [M + H]+ m/z 261.2. 1H NMR (500 MHz, DMSO-D6) δ 7.87 (s, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.45 (s, 1H) , 6.34 (s, 1 H), 5.14 (s, 2 H), 2.52 - 2.48 (m, 2 H), 2.31 (q, J = 9.3, 2 H) , 2.17 (s, 3H), 1.93 - 1.80 (m, 2H). INTERMEDIATE 16: 3-Methyl-5-(1,3-thiazol-5-yl)aniline 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (20.98 g, 90 mmol), 5-bromothiazole (8.85 ml, 99 mmol), and sodium carbonate (90 ml, 180 mmol) were combined in one vial. 2-Methyl-THF (326 ml) was added and the flask was degassed with N2 for 1.5 hour before 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (3.67) g, 4.50 mmol) was added. The reaction was heated to 100°C overnight and then cooled to room temperature. The reaction mixture was filtered through a pad of celite, washing with ethyl acetate. The layers were separated and the aqueous layer was re-extracted with ethyl acetate, dried over Na2SO4, and concentrated. The residue was purified by crystallization (0 to 40% ethyl acetate in hexanes). 3-Methyl-5-(1,3-thiazol-5-yl)aniline was isolated as a yellowish brown solid (15.33 g, 81 mmol, 90%). MS ESI: [M + H]+ m/z 191.1. 1H NMR (500 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.02 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6 .50 (s, 1H), 3.71 (s, 2H), 1.79 (s, 3H). INTERMEDIATE 18: 4-methyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine
Step 1: Acetic acid (0.234 ml, 4.08 mmol) was added to 2-chloro-4-methylpyrimidine (0.5 g, 3.89 mmol) and 3-bromo-5-methylaniline (1.096 g, 3, 89 mmol) suspended in dioxane (7.78 ml). The reaction was heated to 120°C overnight. Then, the reaction was cooled to room temperature and was directly purified by column chromatography on silica gel eluting with ethyl acetate/hexanes to give N-(3-bromo-5-methylphenyl)-4-methylpyrimidin-2-amine (1.08 g, 3.89 mmol, quant.) as a white solid. MS ESI: [M + H]+ m/z 278.0 and 280.0.
Step 2: A 40 ml vial was charged with the product from Step 1 (500 mg, 1.798 mmol), bis(pinacolato)diboron (502 mg, 1.977 mmol), 1,1'-bis(diphenylphosphine) dichloride complex ) ferrocene palladium (II) dichloromethane (44.0 mg, 0.054 mmol) and potassium acetate (529 mg, 5.39 mmol). The solid mixture was dissolved with DMSO (7.19 ml) and heated to 120°C. After stirring for 2 hours, the mixture was cooled to room temperature. The reaction was diluted with ethyl acetate, washed with a saturated aqueous solution of NaHCO3 and brine. The organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes to give 4-methyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (331 mg, 1.018 mmol, 56.6% yield) as an orange oil. MS ESI: [M + H]+ m/z 326.2. 1H NMR (500 MHz, DMSO-D6) δ 9.40 (s, 1H), 8.31 (d, J = 5.0Hz, 1H), 7.77 (s, 2H), 7. 07 (s, 1H), 6.70 (d, J = 5.0Hz, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 1.27 (s , 12 h). INTERMEDIATE 19: 4-methyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-pyrimidin-2-amine
A microwave vial was loaded with Intermediate 18 (218 mg, 0.670 mmol), 5-bromo-1,3-thiazole (59.9 µl, 0.670 mmol), Pd2(dba)3 (30.7 mg, 0.034 mmol), X-Phos (32.0 mg, 0.067 mmol) and cesium carbonate (437 mg, 1.341 mmol). The system was purged and flushed with Ar(g) four times before adding dioxane (918 μl) and water (92 μl). Again, the system was purged and flushed five times before sealing the vial and heating to 100°C. LCMS showed ~60% desired product, ~35% debonded product and unreacted starting material remaining. The reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and concentrated. The resulting residue was purified by silica gel column chromatography (Biotage, 0 to 20% ethyl acetate in hexanes) to yield 4-methyl-N-[3-methyl-5-(1,3-thiazol- 5-yl)phenyl]pyrimidin-2-amine (105 mg, 0.372 mmol, 55.5%). MS ESI: [M + H]+ m/z 283.0. 1H NMR (500 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.04 (s, 1H), 8.35 (d, J = 6.6, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.10 (s, 1H), 6.75 (d, J = 6.3, 1 H), 2.37 (s, 3H), 2.30 (s, 3H). INTERMEDIATE 20: 4-Methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine
Step 1: A 10 to 20 ml microwave vial was charged with 2-chloro-4-methoxypyrimidine (0.835 g, 5.78 mmol), 3-bromo-5-methylaniline (1.075 g, 5.78 mmol), acid acetic (0.347 ml, 6.06 mmol) and dioxane (11.55 ml). The system was purged and flushed with Ar(g) three times before sealing and heating to 120°C for 3 hours. The mixture was cooled and stirred overnight. The light brown solids were collected by filtration and dried in a vacuum oven overnight to yield N-(3-bromo-5-methylphenyl)-4-methoxypyrimidin-2-amine (1.7 g, 5.78 mmol , 100% yield) as a brown solid. MS ESI: [M + H]+ m/z 296.0.
Step 2: A 10 to 20 ml microwave vial was charged with the product from Step 1 (1.6 g, 5.44 mmol), bispinacholatediboron (1.519 g, 5.98 mmol), 1.1 dichloride complex α-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (0.133 g, 0.163 mmol), potassium acetate (1.602 g, 16.32 mmol) and DMSO (10.88 ml). The system was flushed and purged five times with Ar(g) before sealing the vial and heating to 120°C for one hour. The reaction was cooled to room temperature, diluted with ethyl acetate, filtered through a pad of celite and concentrated to dryness. The resulting residue was purified by column chromatography on silica gel (Biotage, 5 to 60% ethyl acetate in hexanes) to yield 4-methoxy-N-[3-methyl-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-pyrimidin-2-amine (900 mg, 2.64 mmol, 48.5% yield) as a brown solid. MS ESI: [M + H]+ m/z 342.1. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.17 (d, J = 5.8, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.06 (s, 1H), 6.25 (d, J = 5.8, 1H), 3.92 (s, 3H), 2.26 (s, 3 H), 1.26 (s, 12H). INTERMEDIATE 21: 4-Methoxy-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-pyrimidin-2-amine To a round bottom flask was added 2-chloro-4-methoxypyrimidine (1.58g, 10.93mmol), Intermediate 20 (2g, 10.51mmol), cesium carbonate (6.85g, 21.02mmol) and degassed dioxane (105ml). The system was eluted and purged with Ar(g) and palladium(II) acetate (0.236 g, 1.051 mmol) and Xantfos (0.912 g, 1.577 mmol) were added. The system was flushed and purged again three times with Ar(g) and then heated to 90°C for 2 hours. The reaction was cooled to room temperature and the solvent was removed under reduced pressure and the residue was directly purified by column chromatography on silica gel (0 to 100%, 10:1 ethyl acetate: methanol in hexanes) to yield 4 -methoxy-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (3.1 g, 10.39 mmol, 99%). MS ESI: [M + H]+ m/z 299.1. 1H NMR (600 MHz, CDCl 3 ) δ 8.72 (s, 1H), 8.13 (d, J = 5.7, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.29 (s, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 6.21 (d, J = 5.7, 1H), 3.98 (s, 3H), 2.37 (s, 3H). INTERMEDIATE 24: methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate
Step 1: Methyl 3-oxobutanoate (232 g, 2.00 mol) and paraformaldehyde (30 g, 999.00 mmol) were combined, and to the mixture was added piperidine (10 g, 117.44 mmol). The resulting solution was stirred for 2 hours at 0°C. The solution was heated to 60°C for 2 hours. Extracted with Et2O (3x), and the organic layers were combined and dried over Na2SO4. Filtered and concentrated in vacuum. This resulted in 370 g (crude) of dimethyl 2-methyl-6-oxocyclohex-1-ene-1,3-dicarboxylate as a brown oil. MS: [M + H]+ m/z 227.
Step 2: To a solution of sodium methanolate (90 g, 1.67 mol) in methanol (300 ml) was added the product from Step 1 (150 g, 663.04 mmol) in methanol (150 ml) dropwise with shake in 30 minutes. The resulting solution was heated to 80°C for 30 minutes and the mixture concentrated in vacuo. The reaction mixture was then quenched by the addition of H2O/ice (120 ml), then diluted with acetic acid (130 ml). The resulting solution was extracted with Et2O (3x), and the organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo. The final product was purified by distillation under reduced pressure (5 mm Hg) and the fraction was collected at 110 ~ 120°C. This resulted in 100 g (88%) of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate as a yellow oil. MS: [M + H]+ m/z 169.
Step 3: Copper iodide (121.8 g, 639.54 mmol) was added to Et2O (800 ml). Methyllithium (1.6 M in diethyl ether, 800 ml, 1.28 mol) was added dropwise at -40°C in 3 hours. Added a solution of the product from Step 2 (53.8 g, 319.88 mmol) in Et2O (400 mL) at -40°C in 2 minutes. The resulting solution was stirred 5 hours at -20°C. Quenched by addition of saturated aqueous ammonium chloride (2.5 liters). Extracted with EtOAc (3 x 2 liters). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by eluting through a silica gel column with a 1:20 EtOAc/PE solvent system. This resulted in 45 g (73%) of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate as a yellow oil. MS: [M + H]+ m/z 185. 1H NMR (600 MHz, CDCl3) δ 3.49 (s, 3H), 2.43 - 2.40 (m, 1H), 2.35 - 2 .29 (m, 1H), 2.21 - 2.17 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 - 1.96 (m, 1H) , 1.91 - 1.85 (m, 1H), 0.85 (s, 3H), 0.77 (s, 3H). INTERMEDIATE 25: racemic methyl cis-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate
Step 1: n-Butyllithium (2.2 ml, 5.5 mmol, 2.5 M solution in hexanes) was added dropwise in 12 minutes to a solution of thiazole (0.515 g, 6.05 mmol) in tetrahydrofuran (15 ml) at -78°C. After 30 minutes, the opaque yellow suspension was transferred in 5 minutes via dry ice cooled cannula to a solution of Intermediate 24 (1.013 g, 5.5 mmol) in tetrahydrofuran (15 ml) at -78°C. The resulting yellow solution was kept at -78°C for one hour, moved to a 0°C bath for 15 minutes, and then cooled back to -78°C. Saturated aqueous ammonium chloride solution (10 ml) was added and the mixture was allowed to warm to room temperature. The biphasic mixture was partitioned between ethyl acetate (50 ml) and water (5 ml); the layers were separated and the aqueous layer was extracted with ethyl acetate (15 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (Biotage 100 g SNAP column, 90 : 10 to 65 : 35 Hexane : ethyl acetate) to yield cis-4-hydroxy-2,2-dimethyl-4-( Racemic methyl 1,3-thiazol-2-yl)cyclohexanecarboxylate as a white solid (1.08 g, 73 % yield). MS APCI: [M + H]+ m/z 270.1.
Step 2: To a solution of the product from Step 1 (0.35 g, 1.3 mmol) in N,N-dimethylformamide (1.9 ml) was added N-bromosuccinimide (0.254 g, 1.429 mmol). After three hours an additional portion of N-bromosuccinimide (0.046 g, 0.258 mmol) was added. After an additional one hour, the reaction mixture was partitioned between ethyl acetate (25 ml), saturated aqueous sodium thiosulfate (10 ml), and water (5 ml). The layers were separated, and the organic layer was washed with water (3 x 5 ml) and brine (10 ml), dried over sodium sulfate, filtered, and concentrated. The crude reaction was purified via silica chromatography (Biotage 100 g SNAP column, 95 : 5 to 75 : 25 Hexane : ethyl acetate) to yield cis-4-(5-bromo-1,3-thiazol-2- yl) racemic methyl-4-hydroxy-2,2-dimethylcyclohexanecarboxylate as a white solid (286.8 mg, 63% yield). MS APCI: [M + H]+ m/z 348.0, 350.0. 1H NMR (500 MHz, CDCl 3 ): δ 7.58 (s, 1H); 3.69 (s, 3H); 2.45 (s, 1H); 2.36 (m, 1H); 2.21 (m, 1H); 1.94 (m, 3H); 1.75 (m, 2H); 1.19 (s, 3H); 1.06 (s, 3H). INTERMEDIATE 26: 5-Bromo-2-(1-methoxycyclobutyl)-1,3-thiazole Sodium hydride (60% dispersion in mineral oil) (47.0 mg, 1.175 mmol) was added to a solution at 0° Intermediate 1 C (250 mg, 1.068 mmol) in DMF (3 ml) and THF (3 ml) and the mixture was allowed to react for one hour. Methyl iodide (0.080 ml, 1.281 mmol) was added and the mixture further reacted for 2 hours. The reaction mixture was poured into dilute aqueous NH4Cl and extracted twice with diethyl ether. The organic fraction was concentrated and the residue was passed through a silica plug eluting with 1:10 ethyl acetate:Hexane to yield 2-bromo-5-(1-methoxycyclobutyl)-1,3-thiazole (225mg, 85 %). 1H NMR (500 MHz, (CD3)2CO): δ 7.73 (s, 1H); 3.19 (s, 3H); 2.54 - 2.40 (m, 4H); 1.92 - 1.82 (m, 2H). INTERMEDIATE 27: 2-chloro-4-ethylpyrimidine
Ethylmagnesium bromide (1.0M in THF, 71.4ml, 71.4mmol) was added dropwise to a -78°C solution of 2,4-dichloropyrimidine (10g, 67.1mmol) ) in THF (125 ml). After stirring for 1 hour, saturated aqueous NH4Cl was added at -78°C and the reaction was allowed to reach room temperature with stirring. Then, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO 3 , then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and Hexanes to give 2-chloro-4-ethylpyrimidine (5.031 g, 18.70 mmol, 27.9%) as a 53:47 regioisomeric mixture. . INTERMEDIATE 29: 2-chloro-4-cyclopropylpyrimidine
2,4-Dichloropyrimidine (15 g, 101 mmol), cyclopropyl boronic acid (8.65 g, 101 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.22 g, 10.07 mmol), and phosphate of potassium (53.4 g, 252 mmol) were combined in a 1 liter round bottom flask. THF (503 ml) was added and the suspension was heated to reflux with stirring overnight. The reaction was then cooled to room temperature, concentrated to ~100 ml under reduced pressure, extracted with ethyl acetate, washed with saturated aqueous NaHCO 3 , brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes to give 2-chloro-4-cyclopropylpyrimidine (10.124 g, 58.3 mmol, 57.9%) as a mixture of 89:89 regioisomers: 11. INTERMEDIATE 32: 4-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine
To a vial containing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.50 g, 6.85 mmol) and 2-chloro-4-methylpyrimidine (1.01 g, 7.87 mmol) were added dioxane (69 ml) and methanesulfonic acid (0.51 ml, 7.87 mmol). The reaction was heated at 100°C overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield 4-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (1 .23 g, 3.95 mmol, 58% yield). MS ESI: [M + H]+ m/z 312. 1H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.30 (d, J = 5.0, 1H) , 7.98 (d, J = 8.0, 1H), 7.95 (s, 1H), 7.29 - 7.20 (m, 2H), 6.71 (d, J = 5 .0.1H), 2.33 (s, 3H), 1.28 (s, 12H). INTERMEDIATE 35: 4-Ethyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine
Step 1: To a 1 liter 3-neck flask containing 3-bromo-5-methylaniline (60 g, 290 mmol), bis(pinacolato)diboron (96 g, 377 mmol), 2-dicyclohexylphosphine-2',4 ',6'-triisopropylbiphenyl (8.3 g, 17.4 mmol), dibenzylideneacetone palladium (3.99 g, 4.35 mmol), and potassium acetate (42.7 g, 435 mmol) was added 1, 4-dioxane (720 ml) which was degassed by spraying with nitrogen for 30 minutes. After flushing the flask with nitrogen for 2 minutes, the reaction was heated to an internal temperature of 80°C for 44 hours. On heating, the reaction mixture was filtered through a pad of celite, and then the Celite was washed with tert-butyl methyl ether (500 ml). The resulting solution was diluted with tert-butyl methyl ether (500 ml), pH 8 phosphate buffer (500 ml), and brine (500 ml). The layers were separated and the organic layer was washed with a half-saturated brine solution (1 liter). The aqueous layers, which were kept separately, were sequentially re-extracted with tert-butyl methyl ether (500 ml). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel (0 to 90% ethyl acetate/hexanes) and the resulting pale orange solid was dried overnight under nitrogen to give 3-methyl-5-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (67.7 g, 255 mmol, 88% yield, 90% purity). MS ESI: [M + H]+ m/z 234.1.
Step 2: A solution of 2-chloro-4-ethyl pyrimidine (0.98 g, 7.00 mmol), the product from Step 1 (1.794 g, 7.70 mmol), and methanesulfonic acid (0.50 ml, 7.70 mmol) in 1,4-dioxane (30 ml) was sealed in a screw cap pressure vial and heated at 110°C for 15 hours. The vial was cooled, an additional portion of 2-chloro-4-ethyl pyrimidine (0.145 g, 1.05 mmol) was added, and the vial was resealed and heated for another additional 6.5 hours. The reaction mixture was cooled, diluted with ethyl acetate (70 ml), washed with saturated aqueous sodium bicarbonate solution (25 ml) and brine (25 ml), dried over sodium sulfate, filtered, and concentrated. The resulting reddish brown solid 4-ethyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-pyrimidin-2-amine ( 3.44 g as an 80 : 20 w/w mixture with 1,4-dioxane) was used without further purification. MS ESI: [M + H]+ m/z 340.1 INTERMEDIATE 36: N-[3-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-4-methylpyrimidin-2-amine
Step 1: A solution of 3,5-dibromoaniline (2.93 g, 11.67 mmol), 2-chloro-4-methyl pyrimidine (1.5 g, 11.67 mmol), and acetic acid (0.701 ml, 12.25 mmol) in 1,4-dioxane (23.5 ml) was sealed in a pressure vessel under an argon atmosphere and heated at 120°C for 17 hours. After being cooled to room temperature, the reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (40 ml). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatography on silica gel (10% to 30% ethyl acetate/hexanes) gave N-(3,5-dibromophenyl)-4-methylpyrimidin-2-amine (3.6 g, 9.97 mmol, 85% yield, 95% purity) as a pale yellow solid. MS ESI: [M + H]+ m/z 343.8.
Step 2: A mixture of 1,4-dioxane (40 ml) and aqueous sodium carbonate (2M, 10.50 ml, 20.99 mmol) was sparged with argon for 15 minutes and then poured into a flask containing the product from Step 1 (3.6 g, 9.97 mmol, 85% yield, 95% purity) and the PdCl2(dppf)-CH2Cl2 adduct (0.686 g, 0.840 mmol). Cyclopropyl boronic acid (1.037 g, 12.07 mmol) was added followed by a condenser and the complete system was placed under argon through five cycles of vacuum/argon flow. The reaction mixture was heated to reflux for 18 hours and then cooled to room temperature and diluted with ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by means of reverse phase HPLC (45 to 80% acetonitrile/water with 0.1% TFA buffer). Fractions containing the desired product were diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to give N-(3-bromo-5-cyclopropylphenyl)-4-methylpyrimidin-2-amine (443.6 mg, 1.31 mmol, 13% of yield) as a brown oil. MS ESI: [M + H]+ m/z 306.0.
Step 3: A solution of the product from Step 2 (443.6 mg, 1.458 mmol), Bis(pinacoloate)diboron (407 mg, 1.604 mmol), the PdCl2(dppf)-CH2Cl2 adduct (119 mg, 0.146 mmol), and potassium acetate (429 mg, 4.37 mmol) in dimethyl sulfoxide was heated under argon in a microwave for 10 minutes at 150 °C. The reaction mixture was diluted with diethyl ether (40 ml), ethyl acetate (40 ml), and saturated aqueous sodium bicarbonate solution (30 ml) and then filtered to remove any solids that did not dissolve. The layers were separated and the organic layer was washed with water (3 x 25 ml) and brine (25 ml), dried over sodium sulfate, filtered, and concentrated. The resulting crude product was purified by chromatography on silica (5 to 30% ethyl acetate/hexanes) to give N-[3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)phenyl]-4-methylpyrimidin-2-amine (186.1 mg, 0.53 mmol, 36% yield, about 75% pure) as a white solid. The material was used in subsequent steps in this raw form. MS ESI: [M + H]+ m/z 352.2. INTERMEDIATE 39: (4-Difluoromethyl-pyrimidin-2-yl)-[3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]- the mine
Step 1: To a solution of difluoroacetic anhydride (50 g, 287 mmol) in CH 2 Cl 2 (300 ml) cooled to -20°C was added DMAP (0.351 g, 2.87 mmol) followed by the addition of ethyl vinyl ether (13, 8 ml, 144 mmol) at a rate such that the internal temperature did not exceed -10°C. When complete the flask was stirred at 0°C for 12 hours before slowly warming to room temperature over the next 6 hours. The water along with CH2Cl2 were added, the layers separated and the organic washed sequentially with saturated aqueous NaHCO3 and then brine. The organic layer was dried with MgSO4, filtered, concentrated in vacuo. The residue was subsequently taken up in EtOH (162 ml), immersed in an ice-water bath and then urea (17.25 g, 287 mmol) followed by conc. (43 ml) were added at a rate such that the internal temperature did not exceed 20°C. When the addition was complete, the cooling bath was removed and the resulting mixture stirred for 18 hours before concentrating in vacuo. EtOH was added and the mixture concentrated a second time, then repeated 2x with EtOAc. The residue was diluted with EtOAc (100 ml), the heterogeneous mixture stirred for 10 minutes and then the solvent decanted. This was repeated twice more then the light brown solid was dried under vacuum for 48 hours before diluting with phosphorus oxychloride (215 ml, 2310 mmol). The resulting suspension was heated to 105°C for 90 minutes during which time it was observed that it became homogeneous. The reaction mixture was cooled to room temperature, carefully poured into a cooled 4-liter flask containing 2 liters of ice and a temperature probe. The mixture was stirred for 1 hour until the exotherm had ceased at which time the contents were transferred to a separatory funnel with additional CH2Cl2. The layers were cut, the aqueous layer extracted with CH2Cl2 (2x), then the combined organics were dried over MgSO4, filtered and concentrated in vacuo (200 Torr, 40°C) to an orange oil. The product was placed under vacuum for 1 min to yield 2-chloro-4-difluoromethyl-pyrimidine (31 g, 62.5% by weight solution in CH 2 Cl 2 by 1H NMR, 118 mmol). 1H NMR (600 MHz, CDCl 3 ) δ 8.82 (d, J = 5.0, 1H), 7.57 (d, J = 5.0, 1H), 6.51 (t, J = 54 .4, 1H).
Step 2: The product from Step 1 (4.75 g, 23 mmol) and 3-bromo-5-methylaniline (5.59 g, 30 mmol) were diluted with dioxane (33 ml) to which AcOH (1.32 ml) , 23 mmol) was added. The resulting mixture was heated to reflux and stirring continued for 30 hours after it was cooled to room temperature, diluted with CH2Cl2 and absorbed onto silica prior to purification by flash chromatography to yield N-(3-bromo-5- methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine (5.2 g, 16.6 mmol). 1H NMR (600 MHz, CDCl 3 ) δ 8.58 (d, J = 4.9, 1H), 7.75 (s, 1H), 7.32 (s, 1H), 7.21 (s , 1H), 7.06 - 6.92 (m, 2H), 6.50 - 6.27 (m, 1H), 2.30 (s, 3H).
Step 3: The product from Step 2 (0.5 g, 1.6 mmol), bis(pinacolato)diboron (0.465 g, 1.83 mmol), potassium acetate (0.469 g, 4.78 mmol) and the adduct of PdCl2(dppf)-CH2Cl2 (0.065 g, 0.08 mmol) were diluted with degassed dioxane (3.5 ml) and heated to reflux for 2 hours then re-cooled to room temperature. The mixture was diluted with CH2Cl2 and water was added. The layers were cut, the organic dried over MgSO4, filtered and concentrated in vacuo, and the crude residue purified by flash chromatography to yield (4-difluoromethyl-pyrimidin-2-yl)-[3-methyl-5-(4,4 ,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amine (550 mg, 1.52 mmol) MS ESI: [M + H]+ m/z 362.1. 1H NMR (600 MHz, CDCl 3 ) δ 8.56 (d, J = 4.1, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.45 (s , 1H), 7.35 (s, 1H), 6.94 (d, J = 4.2, 1H), 6.38 (t, J = 55.0, 1H), 2.36 (s, 3H), 1.33 (s, 12H). INTERMEDIATE 41: N-[3-cyclopropyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine
To a flask was added N-[3-(bromomethyl)-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (523mg, 1.30mmol), cyclopropyl boronic acid (336 mg, 3.91 mmol), potassium phosphate (968 mg, 4.56 mmol), Pd(OAc)2 (15 mg, 0.07 mmol) and tricyclohexylphosphine (37 mg, 0.13 mmol). Degassed toluene (10 ml) and water (0.5 ml) were added and the solution was evacuated and then purged with argon 5 times. The mixture was then heated in a microwave at 130°C for 30 minutes. The reaction was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield N-[3-cyclopropyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (384 mg, 1.06 mmol , 81% yield). MS ESI: [M + H]+ m/z 363. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.06 (s, 1H), 8.83 (d) , J = 4.8, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.41 (s, 1H), 7.28 (d, J = 4 0.9, 1H), 7.12 (s, 1H), 2.03 - 1.80 (m, 1H), 1.05 - 0.92 (m, 2H), 0.78 - 0. 61 (m, 2H). INTERMEDIATE 43: 4-cyclopropyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-pyrimidin-2-amine
To a solution of 4-cyclopropyl-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine (750 mg , 2.14 mmol) in 2-methyl tetrahydrofuran (10.7 ml) were added 5-bromo-thiazole (406 mg, 2.35 mmol), PdCl2(dppf)-CH2Cl2 (87 mg, 0.11 mmol), and aqueous sodium carbonate (2M, 2.14 ml). The reaction was sealed and purged with N2 for 5 minutes. The reaction was stirred at 80°C for 16 hours and cooled to room temperature. Water was added and extracted with EtOAc (3x). The combined organic layers were dried (magnesium sulfate), concentrated, and purified by flash chromatography to yield 4-cyclopropyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2 -amine (600 mg, 1.95 mmol, 91% yield) as a yellowish white solid. MS ESI: [M + H]+ m/z 309.1. 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.06 (s, 1H), 8.26 (d, J = 5.0, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 6.82 (d, J = 5.0, 1 H), 2.29 (s, 3H), 2.00 (m, 1H), 1.17 - 0.93 (m, 4H). INTERMEDIATE 44: 4-isopropyl-N-(3-methyl-5-(thiazol-5-yl)phenyl)-pyrimidin-2-amine
To a solution of 4-isopropyl-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine ( 500 mg, 1.42 mmol) in 2-methyl tetrahydrofuran (7.1 ml) was added 5-bromo-thiazole (318 mg, 1.84 mmol), PdCl2(dppf)-CH2Cl2 (58 mg, 0.07 mmol) ), and aqueous sodium carbonate (2M, 1.42 ml). The reaction was sealed and purged with N2 for 5 minutes. The reaction was stirred at 80°C for 16 hours and cooled to room temperature. Water was added and extracted with EtOAc (3x). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo, and purified by flash chromatography to give 4-isopropyl-N-(3-methyl-5-(thiazol-5-yl)phenyl)pyrimidin-2-amine (366 mg, 1.18 mmol, 83% yield) as a yellowish white solid. MS ESI: [M + H]+ m/z 311.1. 1H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.05 (s, 1H), 8.38 (d, J = 4.7, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.51 (s, 1H), 7.11 (s, 1H), 6.77 (d, J = 5.1, 1 H), 2.87 (m, 1H), 2.30 (s, 3H), 1.25 (d, J=6.8, 6H). INTERMEDIATE 46: 3-methyl-N-[3-(pentafluoroethyl)phenyl]-5-(1,3-thiazol-5-yl)aniline
To a solution of 2-chloro-4-(pentafluoroethyl)pyrimidine (61 mg, 0.26 mmol) and 3-methyl-5-(1,3-thiazol-5-yl)aniline (50 mg, 0.26 mmol) ) in degassed 1,4-dioxane (1.1 ml) were added Xantfos (23 mg, 0.039 mmol), Pd(OAc)2 (5.9 mg, 0.026 mmol) and Cs2CO3 (172 mg, 0.53 mmol) and the reaction was heated to 100°C for 30 minutes. After cooling, the reaction was partitioned between EtOAc (10 ml) and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous phase was extracted with EtOAc (10 ml). the combined organic phases were washed with saturated aqueous sodium chloride (10 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification on silica (20 to 60% ethyl acetate in hexanes) gave 3-methyl-N-[3-(pentafluoroethyl)phenyl]-5-(1,3-thiazol-5-yl)aniline (13 mg , 13%) as a colorless foam. MS ESI: [M + H]+ m/z 387.0. INTERMEDIATE 54: 2-chloro-4-(propan-2-yloxy)pyrimidine
To a solution of 2,4-dichloropyrimidine (5.0 g, 34 mmol) in 2-propanol (84 ml) was added Cs2CO3 (12 g, 37 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction was then heated to 65°C for 3 hours, after which time the reaction was filtered and concentrated. Purification on silica using a gradient solvent system of 0 to 10% EtOAc/hexanes provided 2-chloro-4-(propan-2-yloxy)pyrimidine (2.4 g, 41%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 5.7, 1H), 6.56 (d, J = 5.7, 1H), 5.38 (hept, J = 6 .2.1H), 1.34 (d, J=6.2, 6H). INTERMEDIATE 55: 4-tert-butyl-2-chloropyrimidine
To a dry flask containing 2-chloropyrimidine (1.0 g, 8.7 mmol) was added anhydrous Et2O (8.7 ml) and the solution was cooled to -30°C. The tBuLi (1.7 M solution in N-pentane, 5.7 ml, 9.6 mmol) was added dropwise and the reaction was kept at -30°C for 30 minutes. The reaction was warmed to 0°C and stirred at this temperature for 30 minutes, during which time the reaction was quenched by the dropwise addition of a solution of acetic acid (0.60 ml, 10.5 mmol) in THF (3 ml) and water (1 ml). The reaction was kept at 0°C and a solution of DDQ (2.38 g, 10.5 mmol) in THF (8.7 ml) was added. After 15 minutes, NaOH (1M, 1 ml) and water (10 ml) were added, and the dark reaction mixture was transferred to a separatory funnel containing EtOAc (50 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted once with EtOAc (50 ml). The combined organic phases were washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Absorption of the black oily residue onto silica, followed by crystallization on silica using a gradient solvent system of 5→30% EtOAc/Hexanes provided 4-tert-butyl-2-chloropyrimidine (1.00 g, 67%) as a light yellow oil. 1H NMR (500 MHz, CDCl 3 ) δ 8.49 (d, J = 5.2, 1H), 7.24 (d, J = 5.2, 1H), 1.33 (s, 9H). INTERMEDIATE 62: 2-chloro-4-(1-fluoroethyl)pyrimidine
To a solution of 1-(2-chloropyrimidin-4-yl)ethanol (150 mg, 0.950 mmol) in dichloromethane (3 ml) at 0°C was added diethylaminosulfur trifluoride (183 mg, 1.14 mmol) dropwise and stirred for 3 hours. The solution was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated to dryness. Purification on silica gel by flash chromatography (0 to 50% EtOAc/Hexanes) afforded 2-chloro-4-(1-fluoroethyl)pyrimidine (75 mg, 0.467 mmol, 49% yield) as a yellow oil. MS ESI: [M + H]+ m/z 161.0. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 4.2, 1H), 7.46 (d, J = 4.2, 1H), 5.58 (dq, J = 6 0.7, 48, 1H), 1.74-1.57 (m, 3H). INTERMEDIATE 70: 2-chloro-4-(difluoromethyl)pyrimidine
In a 500 ml 3-neck round bottom flask, purged and maintained with an inert nitrogen atmosphere, was placed a solution of 2-chloropyrimidine-4-carbaldehyde (15.0 g, 104 mmol, 1.00 equiv, 98) %) in dichloromethane (200 ml). This was followed by addition of bis[(2-methoxyethyl)amino]sulfur trifluoride (46.0 g, 208 mmol, 2.00 equiv, 100%) dropwise with stirring at 0°C in 30 minutes. The resulting solution was stirred for 2 hours at 0°C, then quenched by the addition of 50 ml of water. The resulting solution was extracted with 3 x 100 ml of dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column and eluted with DCM/Pentane (2:1) to give 2-chloro-4-(difluoromethyl)pyrimidine (2.38 g, 14% yield) as a yellow oil. GC-MS ESI: [M]+ m/z 164. 1H-NMR (300 MHz, CDCl 3 ): 8.87 (t, 1H), 7.61 (d, 1H), 6.55 (m, 1H). 19 F-NMR (300 MHz, CDCl 3 ): -119.37 INTERMEDIATE 71: tert-butyl 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylate
Step 1: To a flask containing THF (82 ml) was added isopropylmagnesium chloride/lithium chloride (1.2 M in THF, 37.7 ml, 45 mmol). A solution of thiazole (3.5 g, 41 mmol) in THF (20 ml) was added slowly. The reaction stirred for an hour. A solution of tert-butyl 4-oxocyclohexanecarboxylate (12.23 g, 62 mmol) in THF (20 ml) was added and the reaction was stirred for 3 hours. The reaction was then slowly quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to produce tert-butyl 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexane carboxylate (9.25 g, 33 mmol, 79% yield). MS ESI: [M + H]+ m/z 284.1.
Step 2: To a flask containing the product from Step 1 (9.25 g, 33 mmol) was added DMF (36 ml) and then n-bromosuccinimide (6.97 g, 32 mmol). The reaction was allowed to stir to completion by LCMS. The reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield tert-butyl 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-cyclohexanecarboxylate (9.24 g, 25.5 mmol, 78% of Yield). MS ESI: [M + H]+ m/z 364.0.
Step 3: To a vial containing 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.6 g, 6.96 mmol), the product from Step 2 (2.52 g, 6.96 mmol), dicyclohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane (0.33 g, 0 .70 mmol), Pd2(dba)3 (0.32 g, 0.35 mmol), cesium carbonate (6.80 g, 20.9 mmol) was added a degassed mixture of dioxane (23 ml) and water ( 2.3 ml). The solution was evacuated and then purged with argon 5 times and then heated to 100°C overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield tert-butyl 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylate. MS ESI: [M + H]+ m/z 389. INTERMEDIATE 72: 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2-methylcyclohexanecarboxylate of ethyl
To a round bottom flask containing 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (402 mg, 1.7 mmol), 4- ethyl (5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxylate (400mg, 1.1mmol), Pd2(dba)3 (105mg, 0.11mmol), X-phos (55 mg, 0.11 mmol) and Cs2CO3 (1.12 g, 3.45 mmol) were added 4.3 ml of degassed 10:1 1.4 dioxane/H2O. The reaction was heated to 100°C for 16 hours, then cooled and partitioned between EtOAc (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The layers were separated and the aqueous phase was extracted once with EtOAc (50 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification of the resulting residue on silica provided ethyl 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2-methylcyclohexanecarboxylate (344 mg, 80%) as a colorless foam. MS ESI: [M + H]+ m/z 375.2. INTERMEDIATE 74: methyl cis-4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylate O cis-4-(5- methyl bromo-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexane-carboxylate (1.372 g, 3.94 mmol), 3-methyl-5-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.918 g, 3.94 mmol), cesium carbonate (3.85 g, 11.82 mmol), X-Phos (0.188 g, 0.394 mmol) and Pd2(dba)3 (0.180 g, 0.197 mmol) were placed in a vial and evacuated/purged with N2 three times. Dioxane (13 ml) and water (1.3 ml) were degassed by bubbling N2 below the surface and added to the reaction vessel. The resulting reaction mixture was stirred at 100°C for 16 hours and then diluted with EtOAc (25 ml), washed with saturated aqueous NaHCO3 (25 ml), brine (25 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. . The residue was purified by flash chromatography (2% to 12% EtOAc in hexanes) to give cis-4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4- methyl hydroxy-2,2-dimethylcyclohexane-carboxylate (1.33 g, 3.54 mmol, 90% yield) as an orange foam. MS ESI: [M + H] + m/z 375.1. 1H NMR (500 MHz, CD3OD) δ 7.80 (s, 1H), 6.78 - 6.74 (m, 2H), 6.53 (br s, 1H), 3.68 (s, 3H ), 2.45 - 2.36 (m, 2H), 2.25 - 2.12 (m, 4H), 2.01 - 1.94 (m, 2H), 1.76 - 1.62 (m , 2H), 1.19 (s, 3H), 1.04 (s, 3H). INTERMEDIATE 75: 8-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4,5]decan-8-ol
Step 1: The thiazole (25.0 ml, 352 mmol) was diluted with THF (300 ml) and cooled to -78°C. The n-BuLi (220 ml, 352 mmol) was added at a rate such that the internal temperature did not exceed -65°C. A yellow slurry formed and the addition took 40 minutes. The reaction was aged for 20 minutes then 1,4-dioxaspiro[4.5]decan-8-one (50 g, 320 mmol) was added as a solution in THF (420 ml) dropwise via the addition funnel. After 2 hours, the reaction was quenched with water, the brake bath removed and the mixture stirred until the internal temperature reached 0°C. The mixture was diluted with EtOAc and the layers were separated followed by extraction of the aqueous portion with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated to a viscous orange oil. EtOAc was added and concentrated to 100 ml. The hexanes were added dropwise via an addition funnel. The mixture was stirred for 1 hour then cooled to -10°C and filtered. The white pie was washed with hexanes (2x) then dried under a bag of nitrogen to yield 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro-[4,5]decan-8-ol (66 g, 85%) as a white solid.
Step 2: The product from Step 1 (60.5 g, 251 mmol) was diluted with DMF (365 ml). N-bromosuccinimide (49.1 g, 276 mmol) was added, and the solution was heated to 50°C and stirred for 2 hours. The reaction was removed from heating and cooled to 45°C and H2O (600 ml) containing 15.8 g of Na2SO3 was added dropwise producing a solid. The mixture was stirred at room temperature for 1 hour, then filtered and washed 2x with H2O (300 ml). The cake was dried overnight under a nitrogen bag to produce 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4,5]-decan-8-ol (68 .2 g, 85%) as a white solid.
Step 3: 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 8.58 mmol), the product from Step 2 (2.75 g, 8.58 mmol), X-Phos (0.409 g, 0.858 mmol), cesium carbonate (8.39 g, 25.7 mmol), and Pd2(dba)3 (0.393 g, 0.429 mmol) ) were placed in an argon-fluxed flask. Degassed dioxane (30 ml) and Water (3 ml) were added and the reaction was heated to 100°C for 40 hours. The reaction was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (3x). The combined organics were dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (40% to 100% EtOAc : Hexanes) gave 8-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4- dioxaspiro[4.5]decan-8-ol (1.93 g, 65%) as a brown foam. MS ESI: [M + H]+ m/z 347. INTERMEDIATE 77: 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2 acid, 2,3-trimethylcyclohexanecarboxylic acid
Lithium diisopropylamide (5110 µl, 9.20 mmol) was added to a -78°C solution of 3-methyl-5-(1,3-thiazol-5-yl)aniline (500 mg, 2.63 mmol) ) in THF (7 ml). The reaction was allowed to warm to -60°C under aging for 30 minutes. The solution was cooled to -78°C and 2,2,3-trimethyl-4-oxocyclohexanecarboxylic acid (600 mg, 3.26 mmol) in THF (6 ml) was added portionwise, maintaining an internal temperature below - 65°C. After 5 minutes at -78°C the reaction was warmed to room temperature, diluted with EtOAc and washed with saturated aqueous ammonium chloride (3x). The combined aqueous portion was extracted with 10% IPA:CHCl3 (3x). The combined organic layers were dried under reduced pressure to yield 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2,3-trimethyl-acid. cyclohexane carboxylic (121 mg, 12%) as a yellow oil. MS ESI: [M + H]+ m/z 375. INTERMEDIATE 78: Cis-1-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-cyclohexane-1,4 -diol
Step 1: The thiazole (25.02 ml, 352 mmol) was diluted with THF (300 ml) and cooled to -78°C. n-BuLi (1.6 M, 220 ml, 532 mmol) was added at a rate such that the internal temperature did not exceed -65°C. The mixture was aged for 20 minutes, then 1,4-dioxaspiro[4.5]decan-8-one (50g, 320mmol) was added as a solution in THF (420ml) dropwise via the addition funnel. The mixture was stirred for 2 hours and then quenched with water. The vial was removed from the cold bath and stirred until it reached 0°C. The mixture was transferred to a separatory funnel with EtOAc and brine and then extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated to a viscous orange oil. The oil was diluted with EtOAc and concentrated to ~100 ml. A stir bar was added to the flask and hexanes were added dropwise via the addition funnel. The mixture was stirred for 1 hour then cooled to -10°C and filtered. The filtrate was washed with hexanes (2x) and dried to yield 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (66 g, 274 mmol, 85% yield).
Step 2: The product from Step 1 (60.5 g, 251 mmol) was diluted with DMF (5 ml). To this solution, NBS (49.1 g, 276 mmol) was added. The reaction was heated to 50°C for 2 hours. The reaction was cooled to 45°C and H2O (600 mL) containing Na2SO3 (15.8 g, 125 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hour then filtered and washed with H2O (2x, 300 ml). The filtrate was dried under nitrogen to yield 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (68.15 g, 213 mmol, 85% yield).
Step 3: The product from Step 2 (15 g, 46.8 mmol) was diluted with THF (10 ml). HCl (6N, 78ml) was added and stirred at 60°C for 3 hours. The reaction was cooled to room temperature and NaOH (6N, 78 ml) was added. The reaction was diluted with EtOAc. The layers were separated and the aqueous layer re-extracted with EtOAc (2x). The combined organic layers were dried (MgSO4 ) and evaporated. The residue was diluted with EtOAc to transfer the concentrate to ~20 ml where Hexanes (60 ml) were added dropwise. The slurry was cooled to room temperature, stirred for 1 hour then filtered, washed with hexanes (2 x 15 ml) and dried to yield 4-(5-bromo-1,3-thiazol-2-yl)-4- hydroxycyclohexanone (11.25 g, 40.8 mmol, 87% yield).
Step 4: The product from Step 3 (6.5 g, 23.54 mmol) was diluted with THF (10 ml) then cooled to -76°C. LiBH4 (2M in THF, 14.1 ml, 28.2 mmol) was added dropwise, keeping the internal temperature < -75°C. The reaction was stirred for 1 hour and quenched with saturated aqueous NH4Cl. The reaction was diluted with EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc (2x). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography and drying under high vacuum gave cis-1-(5-bromo-1,3-thiazol-2-yl)cyclohexane-1,4-diol (5.2 g, 18.69 mmol, 79% of yield) as a white solid.
Step 5: A flask was charged with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.84 g, 3.60 mmol), the product from Step 4 (1.002 g, 3.60 mmol), cesium carbonate (3.52 g, 10.81 mmol), Pd2(dba)3 (0.165 g, 0.180 mmol), x-phos (0.172 g, 0.360 mmol), dioxane (14.62 ml) and water (1.462 ml). The mixture was reacted under argon at 110°C for 5 hours. The reaction was diluted with ethyl acetate and transferred to a separatory funnel. The organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica (0 to 20% MeOH/DCM) to yield cis-1-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl] cyclohexane-1,4-diol (871.5 mg, 2.86 mmol, 79% yield). MS ESI: [M + H]+ m/z 305.1. INTERMEDIATE 80: 4-(5-Bromo-thiazol-2-yl)-4-hydroxy-trans-2-methyl-cyclohexanecarboxylic acid methyl ester
Step 1: To a cooled (-78°C) solution of trans-2-methyl-4-oxo-cyclohexanecarboxylic acid methyl ester (13 g, 76 mmol) and thiazole (10.9 ml, 153 mmol) in THF ( 130 ml) was added nBuLi (2.5 M in Hex, 30.6 ml, 76 mmol) dropwise at a rate such that the internal temperature was maintained < -70°C. The reaction mixture was stirred for 30 minutes, MeOH (3.1 ml, 76 mmol) was introduced, and the reaction warmed to room temperature where it was diluted with water and EtOAc. The layers have been separated; the organic layer dried with MgSO4, filtered and absorbed to silica gel by concentration in vacuo. The crude residue was purified by flash chromatography to yield trans-4-hydroxy-trans-2-methyl-4-thiazol-2-yl-cyclohexanecarboxylic acid methyl ester (4.1 g, 16 mmol) along with the other diastereomer. (7.0 g, 27 mmol).
Step 2: To a solution of the product from Step 1 (4.1 g, 16 mmol) in DMF (30 ml) was added NBS (3.43 g, 19.3 mmol). After the initial exotherm subsided the reaction mixture was heated to 50°C and stirred for 1 hour. It was then cooled to room temperature and water (280 ml containing 7 g of sodium sulphate) was added followed by EtOAc. The layers were cut and the aqueous layer was extracted with EtOAc (2x). The combined organics were washed with H2O, dried over MgSO4, filtered and absorbed onto silica gel by concentration in vacuo. The crude residue was purified by flash chromatography to yield 4-(5-bromo-thiazol-2-yl)-trans-4-hydroxy-trans-2-methyl-cyclohexanecarboxylic acid methyl ester (4.75 g, 16, 1 mmol), MS ESI: [M + H]+ m/z 333.9. INTERMEDIATE 81: propan-2-yl-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,6-dimethylcyclohexanecarboxylate
Step 1: Propan-2-yl 2,6-dimethyl-4-oxocyclohex-2-ene-1-carboxylate (20 g, 95.1 mmol) was prepared according to a literature procedure (J. Org. Chem 2007, 72(4), 1458 - 1453) using isopropyl acetoacetate in place of ethyl acetate and diluted with EtOH (300 ml). To the resulting solution under a blanket of nitrogen was added 5% Pd/C (0.8 g) after the vessel was shaken under an initial hydrogen pressure of 50 psi (345 kPa) for 2 hours. The reaction contents were then filtered through celite using additional EtOH, concentrated in vacuo and purified by flash chromatography to yield propan-2-yl 2,6-dimethyl-4-oxocyclohexanecarboxylate (5.2 g, 24.5 mmol).
Step 2: The product from Step 1 (5.2 g, 24.5 mmol) was diluted with THF (50 ml) to which the thiazole (2.63 ml, 36.7 mmol) was added. The resulting solution was cooled to -78°C and nBuLi (2.5 M in Hex, 10.3 ml, 25.7 mmol) was added dropwise at such a rate to maintain the internal temperature < -65°C. When the addition was complete, the reaction mixture was stirred for an additional 1 hour then quenched by the addition of water and brought to room temperature. EtOAc was added, the layers separated and the organic layer dried over MgSO4, filtered, concentrated in vacuo and the crude residue purified by flash chromatography to yield 4-hydroxy-2,6-dimethyl-4-(1,3-thiazole propan-2-yl-2-yl)cyclohexane carboxylate (2.0 g, 6.7 mmol).
Step 3: To a solution of the product from Step 2 (2.0 g, 6.7 mmol) in DMF (16 ml) was added NBS (1.38 g, 7.73 mmol) and the resulting solution heated to 55° Ç. After 60 minutes the reaction was cooled and a solution of sodium sulfate (500 mg) in water (30 ml) was added followed by EtOAc. The layers were separated, the aqueous layer was re-extracted with EtOAc (2x). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to yield propan-2-yl-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,6-dimethylcyclohexanecarboxylate (2.2 g, 5 .85 mmol) MS ESI: [M + H]+ m/z 375.9. INTERMEDIATE 82: propan-2-yl-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,6-dimethylcyclohexanecarboxylate
Step 1: Propan-2-yl 2,6-dimethyl-4-oxocyclohex-2-ene-1-carboxylate (20 g, 95.1 mmol) was prepared according to a literature procedure (J. Org. Chem 2007, 72(4), 1458 - 1453) using isopropyl acetoacetate in place of ethyl acetate and diluted with EtOH (300 ml). To the resulting solution under a blanket of nitrogen was added 5% Pd/C (0.8 g) after the vessel was shaken under an initial hydrogen pressure of 50 psi (345 kPa) for 2 hours. The reaction contents were then filtered through celite using additional EtOH, concentrated in vacuo and purified by flash chromatography to yield propan-2-yl 2,6-dimethyl-4-oxocyclohexanecarboxylate (6.4 g, 30.1 mmol) .
Step 2: The product from Step 1 (6.4 g, 30.1 mmol) was diluted with THF (65 ml) to which the thiazole (3.24 ml, 45.2 mmol) was added. The resulting solution was cooled to -78°C and nBuLi (2.5 M in Hex, 12.7 ml, 31.7 mmol) was added dropwise at such a rate to maintain the internal temperature < -65°C. When the addition was complete, the reaction mixture was stirred for an additional 1 hour then quenched by the addition of water and brought to room temperature. EtOAc was added, the layers separated and the organic layer dried over MgSO4, filtered, concentrated in vacuo and the crude residue purified by flash chromatography to yield all-cis-propan-2-yl-4-hydroxy-2,6- dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate (4.45 g, 15.0 mmol).
Step 3: To a solution of all-cis-propan-2-yl-4-hydroxy-2,6-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate (4.4 g, 14.8 mmol) in DMF (34 ml) was added NBS (3.03 g, 17.0 mmol) and the resulting solution heated to 55°C. After 60 minutes the reaction was cooled and a solution of sodium sulfate (500 mg) in water (30 ml) was added followed by EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc (2x). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to give the crude product. The product was vortexed in some hexanes, filtered and washed with more hexanes to yield all-cis-propan-2-yl-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2, 6 dimethylcyclohexanecarboxylate (2.4 g, 6.38 mmol) MS ESI: [M + H]+ m/z 375.9. INTERMEDIATE 84(a): Ethyl 4-hydroxy-3-methyl-4-(1,3-thiazol-2-yl)cyclohexane carboxylate INTERMEDIATE 84(b): 4-hydroxy-3,5-dimethyl-4- Ethyl (1,3-thiazol-2-yl)cyclohexanecarboxylate INTERMEDIATE 84(c): Ethyl 4-hydroxy-3,3-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate
Step 1: Lithium bis(trimethylsilyl)amide (41.1 ml, 41.1 mmol) was added to a -78°C solution of ethyl 4-oxocyclohexanecarboxylate (7 g, 41.1 mmol) in THF (153 ml) ensuring that the temperature never exceeds -70°C. After addition, the reaction was aged for 30 minutes before slowly adding iodomethane (15 ml, 240 mmol). The reaction was aged below -70°C for 10 minutes before slowly warming to room temperature over the course of 1 hour. The reaction was then heated to 50°C for 5 hours. The heated source was removed, and the reaction was aged at room temperature for 14 hours. The solution was mixed with water and extracted three times with EtOAc. The combined organic layer was dried under reduced pressure to obtain a dark red oil (9 g). The crude product was used directly in the next step without further purification.
Step 2: The crude dark red oil (9 g) from the previous step was mixed with thiazole (4.41 ml, 61.7 mmol) in THF (150 ml) and cooled to -78°C. n-Butyllithium (2.5M, 16.46 ml, 41.1 mmol) was added, and the solution was kept at -78°C for 1 hour, then allowed to warm to room temperature. The reaction was quenched with water and extracted three times with CH2Cl2. The combined organic layer was dried under reduced pressure and purified by column chromatography on silica gel (5 to 100% EtOAc : Hexanes) to give 4-hydroxy-3-methyl-4-(1,3-thiazol-2 -yl)cyclohexane-ethyl carboxylate (2.69 g, 24%) as a brown oil and a mixture of 4-hydroxy-3,5-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate ethyl and ethyl 4-hydroxy-3,3-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate (1.09 g, 9%) as a brown oil. MS ESI: [M + H]+ m/z 270 (by 84a) + 284 (by 84 b/c) INTERMEDIATE 85: 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy - Ethyl 3-methylcyclohexanecarboxylate N-bromosuccinimide (2222 g, 12.48 mmol) was added to the solution of Intermediate 84(a) (2.69 g, 9.99 mmol) in DMF (10.51 ml). The reaction was aged at room temperature for 2 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate and mixed with water. The mixture was extracted with CH2Cl2 (3x). The combined organic layers were concentrated under reduced pressure and purified by flash chromatography on silica gel (0 to 30% EtOAc:Hexanes) to give 4-(5-bromo-1,3-thiazol-2-yl)-4 ethyl -hydroxy-3-methylcyclohexanecarboxylate (2.27 g, 65%) as a yellow oil. MS ESI: [M + H]+ m/z 348, 350. INTERMEDIATE 86(a): 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-3,5-dimethylcyclohexanecarboxylate Ethyl INTERMEDIATE 86(b): Ethyl N-bromosuccinimide 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-3,3-dimethylcyclohexanecarboxylate (1.01 g, 5.64 mmol) was added to a solution of Intermediate 84(b) and Intermediate 84(c) (1.09 g, 3.85 mmol) in DMF (5.94 ml). The reaction was aged at room temperature for 2 hours and then quenched with saturated aqueous sodium bicarbonate and mixed with water. The mixture was extracted three times with CH2Cl2. The combined organic layers were concentrated under reduced pressure and purified by flash chromatography (0 to 40% Et2O:Heptane) to give 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-3 ethyl ,5-dimethylcyclohexanecarboxylate and ethyl 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-3,3-dimethyl-cyclohexanecarboxylate (1.04 g, 75%) as a yellow oil. MS ESI: [M + H]+ m/z 362, 364. The 240 mg of this material was further purified using chiral HPLC (5% EtOH : Heptane) to give 4-(5-bromo-1,3-thiazole Ethyl-2-yl)-4-hydroxy-3,5-dimethylcyclohexanecarboxylate (71 mg, 30%) (MS ESI: [M + H]+ m/z 362, 364) as a yellow oil and 4- Ethyl (5-bromo-1,3-thiazol-2-yl)-4-hydroxy-3,3-dimethylcyclohexanecarboxylate (110 mg, 46%) (MS ESI: [M + H]+ m/z 362, 364 ) as a yellow oil. INTERMEDIATE 90: 4-(5-Bromo-thiazol-2-yl)-4-hydroxy-2-methyl-cyclohexanecarboxylic acid ester
Step 1: To a cooled (-78°C) solution of cis-2-methyl-4-oxo-cyclohexanecarboxylic acid ester (22g, 119mmol) and thiazole (16.9ml, 239mmol) in THF (154mmol) ml) was added nBuLi (1.6 M in Hex, 74.6 ml, 119 mmol) dropwise at a rate such that the internal temperature was maintained < -65°C. The reaction mixture was stirred for 30 minutes, MeOH (4.83 ml, 119 mmol) was introduced and the reaction warmed to room temperature where it was diluted with water and EtOAc. The layers were separated, the organic layer dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to yield 4-hydroxy-2-methyl-4-thiazol-2-yl-cyclohexane carboxylic acid ethyl acid ester (21 g, 78 mmol).
Step 2: To a solution of the product from Step 1 (20 g, 74.3 mmol) in DMF (140 ml) was added NBS (15.9 g, 89 mmol). After the initial exotherm subsided the reaction mixture was heated to 50°C and stirred for 1 hour. It was then cooled to room temperature and water (280 ml containing 7 g of sodium sulphate) was added followed by EtOAc. The layers were cut and the aqueous layer was re-extracted with EtOAc (2x), then the combined organics washed with H2O. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to yield 4-(5-bromo-thiazol-2-yl)-4-hydroxy-2-methyl-cyclohexane carboxylic acid ester (20 g, 57.4 mmol), MS ESI : [M + H]+ m/z 347.9. INTERMEDIATE 91: 4-(5-Bromo-thiazol-2-yl)-4-hydroxy-2,5-dimethyl-cyclohexanecarboxylic acid ethyl ester
Step 1: Cis-2-methyl-4-oxo-cyclohexanecarboxylic acid ethyl ester (25 g, 136 mmol) was dissolved in tetrahydrofuran (250 ml) and cooled to -78°C in a dry ice/acetone bath. Lithium hexamethyldisilazide (136 ml, 136 mmol) was added dropwise within one hour, keeping the internal reaction temperature at -70°C. The reaction was aged for 30 minutes at -78°C, and then methyl iodide (9.33 ml, 149 mmol) was added. The reaction was aged for 2 hours and then warmed to room temperature and stirred overnight, at which point TLC analysis (staining with KMnO4) indicated complete consumption of the starting ester. The reaction was diluted with water (200 ml) and ethyl acetate (200 ml), and extracted with ethyl acetate (3 x 100 ml). The organic extracts were washed with brine (100m) and dried over MgSO4, filtered and concentrated in vacuo to an orange residue. The crude mixture was taken up in tetrahydrofuran (250 ml) and cooled to -78°C with a dry ice/acetone bath. The thiazole (14.6 ml, 204 mmol) was added, followed by n-butyllithium (54.3 ml, 136 mmol) dropwise, keeping the internal temperature below -70°C. The reaction was aged for 1.25 hours, then quenched with water (100 ml) and warmed to room temperature. The solution was extracted with ethyl acetate (3 x 100 ml) and the organic extracts were washed with brine (100 ml) and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography yielded a 4:6 mixture of two isomers of 4-hydroxy-2,5-dimethyl-4-thiazol-2-yl-cyclohexane carboxylic ethyl acid ester (4.6 g, 16.1 mmol). ) and the impure fractions which were purified a second time by flash chromatography which provided 4-hydroxy-2,5-dimethyl-4-thiazol-2-yl-cyclohexanecarboxylic acid ethyl acid ester (3.84 g (13.6 mmol) ) as a colorless oil MS ESI: [M + H]+ m/z 284.2.
Step 2: To a solution of the product from Step 1 (3.84 g, 8.54 mmol) in dimethylformamide (33.5 ml) was added N-bromosuccinimide (1.75 g, 9.82 mmol) and the solution stirred at 55°C for 3 hours. A solution of sodium sulfate (0.538 g, 4.27 mmol) in water (60 ml) was added dropwise to the reaction. The mixture was diluted with ethyl acetate (100 ml) and the organic extract washed with water (2 x 100 ml). The combined aqueous layers were re-extracted with ethyl acetate (3 x 100 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography provided a solid which was triturated with hexanes to give 4-(5-bromo-thiazol-2-yl)-4-hydroxy-2,5-dimethyl-cyclohexane carboxylic acid ethyl ester ( 1.07g, 2.95mmol). MS ESI: [M]+ m/z 362.1. INTERMEDIATE 92: 4-(5-Bromo-thiazol-2-yl)-4-hydroxy-2,3-dimethyl-cyclohexanecarboxylic acid ethyl ester
To a DMF solution (15.6 ml) of a 4:6 mixture of two isomers of 4-hydroxy-2,5-dimethyl-4-thiazol-2-yl-cyclohexanecarboxylic ethyl acid ester (1.2 g, 4.03 mmol) was added NBS (0.83 g, 4.64 mmol). The resulting solution was heated to 55°C for 1 hour, then cooled to room temperature and a solution of sodium sulfate (0.54 g, 4.27 mmol) in water (30 ml) was added. The mixture was diluted with EtOAc and the layers separated. The aqueous layer was re-extracted with EtOAc (2x). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to yield a 4:6 mixture of the geometric isomer of 4-(5-bromo-thiazol-2-yl)-4-hydroxy-2,3-dimethyl-cyclohexanecarboxylic acid ethyl ester (700) mg, 1.93 mmol). This was further separated by SFC to yield 4-(5-bromo-thiazol-2-yl)-4-hydroxy-2,3-dimethyl-cyclohexane carboxylic acid ethyl ester as shown above. 'H NMR (600 MHz, CDCl 3 ): δ 7.51 (s, 1H), 4.08 (m, 2H), 2.68 (q, J = 4.5Hz, 1H), 2.34 (m, 1H), 2.26 (m, 1H), 2.20 (dd, J = 9.5, 6.7Hz, 1H), 2.09 (td, J = 13.1, 2.5Hz, 1H), 1.94 (dt, J = 13.1, 3.4, 1H), 1.85 (dq, J = 15.0, 3.6Hz, 1H), 1.22 (t, J = 7.5 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H). INTERMEDIATE 93: propan-2-yl-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,6-dimethylcyclohexanecarboxylate
Step 1: Propan-2-yl 2,6-dimethyl-4-oxocyclohex-2-ene-1-carboxylate (20 g, 95.1 mmol) was prepared according to a literature procedure (J. Org. Chem 2007, 72(4), 1458 - 1453) using isopropyl acetoacetate in place of ethyl acetate and diluted with EtOH (300 ml). To the resulting solution under a blanket of nitrogen was added 5% Pd/C (0.8 g) after the vessel was shaken under an initial hydrogen pressure of 50 psi (345 kPa) for 2 hours. The reaction contents were then filtered through celite using additional EtOH, concentrated in vacuo and purified by flash chromatography to yield propan-2-yl 2,6-dimethyl-4-oxocyclohexanecarboxylate (5.2 g, 24.5 mmol) .
Step 2: The product from Step 1 (5.2 g, 24.5 mmol) was diluted with THF (50 ml) to which the thiazole (2.63 ml, 36.7 mmol) was added. The resulting solution was cooled to -78°C and nBuLi (2.5 M in Hex, 10.3 ml, 25.7 mmol) was added dropwise at such a rate to maintain the internal temperature < -65°C. When the addition was complete, the reaction mixture was stirred for an additional 1 hour then quenched by the addition of water and brought to room temperature. EtOAc was added, the layers separated and the organic dried over MgSO4, filtered, concentrated in vacuo and the crude residue purified by flash chromatography to yield propan-2-yl-4-hydroxy-2,6-dimethyl-4-(1 ,3-thiazol-2-yl)cyclohexanecarboxylate (1.4 g, 4.7 mmol).
Step 3: To a solution of the product from Step 2 (1.4 g, 4.7 mmol) in DMF (15 ml) was added NBS (0.963 g, 5.41 mmol) and the resulting solution heated to 55°C. After 60 minutes the reaction was cooled and a solution of sodium sulfate (500 mg) in water (30 ml) was added followed by EtOAc. The layers were separated, the aqueous layer was re-extracted twice with EtOAc and the combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to yield propan-2-yl-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,6-dimethylcyclohexanecarboxylate (1.04 g, 2 .76 mmol) MS ESI: [M + H]+ m/z 375.9. INTERMEDIATE 94: tert-butyl (4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-azepane-1-carboxylate
Step 1: Azepan-4-one (40.0 g, 267 mmol) in DCM (320 ml) was treated with triethylamine (27.0 g, 225 mmol) and then Boc2O (88.0 g, 401 mmol) was added slowly using an ice-water bath to maintain a temperature of 10 to 20°C. Additional triethylamine (27.0 g, 225 mmol) was then added and the solution stirred for 12 hours. The reaction was then treated with saturated aqueous NH 4 Cl (180 ml) and EtOAc (250 ml). The aqueous layer was extracted with EtOAc (150 ml) and the organic layer was concentrated and purified by flash chromatography on silica gel to yield tert-butyl 4-oxoazepane-1-carboxylate as a viscous oil (45.9 g, 233 mmol).
Step 2: The thiazole (21.3 g, 250 mmol) in THF (160 ml) was cooled to -70°C and then n-BuLi (100 ml, 250 mmol) was added slowly in 5 minutes, keeping the temperature at -60°C or lower. The resulting slurry was stirred for 45 minutes at this temperature and then the product from Step 1 (48.55 g, 228 mmol) in THF (50 ml) was added dropwise, keeping the temperature at -60°C. The solution was stirred for an hour and then the brake bath removed. At -20°C, 2M HCl (114 ml) was added and on warming to room temperature the homogeneous solution was diluted with EtOAc (150 ml). The phases were separated and the aqueous layer was extracted with EtOAc (150 ml). The combined organic layers were washed with saturated aqueous NaHCO3 (150 ml), brine (150 ml) and then concentrated to a thick syrup. This was dissolved in EtOAc (140 ml) and then treated with hexane (210 ml) and the slurry filtered to yield tert- 4-hydroxy-4-(1,3-thiazol-2-yl)azepane-1-carboxylate. butyl as a white solid (68.0 g, 220 mmol) and the material was then subjected to chiral chromatography to yield (4R)-4-hydroxy-4-(1,3-thiazol-2-yl)azepane-1- tert-butyl carboxylate (14.5 g, 48.6 mmol).
Step 3: The product from Step 2 (14.5g, 48.6mmol) was dissolved in DMF (58ml) and then treated with NBS (11.24g, 63.2mmol) and heated to 40°C per 3 hours. The reaction was quenched with Na2SO3 (3.0 g, 24.30 mmol) in H2O (50 ml) and the solution was then extracted with EtOAc (100 ml), washed with brine (50 ml) and then subjected to gel chromatography. of silica to yield tert-butyl (4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxyazepane-1-carboxylate (18.3 g, 46 mmol). MS ESI: [M + H-tBu]+ m/z 320. INTERMEDIATE 95: ethyl cis-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylate
Step 1: Isopropylmagnesium chloride/lithium chloride complex (1.3 M, 119 ml, 154 mmol) was added to a flask and cooled to 0°C and then diluted with 50 ml of THF. The thiazole (13.0 g, 154 mmol) was added within 30 minutes ensuring the temperature did not exceed 5°C. The organic slurry was stirred for 45 minutes and then cooled to -20°C and ethyl 4-oxocyclohexanecarboxylate (25.0 g, 147 mmol) in THF (25 ml) was added and then stirred for 50 minutes. The solution was cooled to 5°C and then quenched with HCl (2M, 100ml) and extracted with EtOAc (250ml). The organic layer was washed with saturated aqueous NaHCO3 solution (100 ml), brine (100 ml), evaporated and purified by flash chromatography on silica gel to yield 4-hydroxy-4-(1,3-thiazol-2-yl ) ethyl cyclohexanecarboxylate as an oil (23.6g, 92mmol).
Step 2: The product from Step 1 (23.5g, 92mmol) was dissolved in DMF (94ml) and then treated with NBS (19.66g, 110mmol) and stirred at room temperature for 10 hours. The reaction was then treated with Na 2 SO 3 (5.8 g, 465 mmol) in H 2 O (150 ml) and then extracted with EtOAc (100 ml) and the oil was purified by flash silica gel chromatography to yield 4-(5- ethyl bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexane carboxylate as an oil (31 g, 77 mmol), which was subjected to chiral chromatography to yield cis-4-(5-bromo-1, Ethyl 3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylate as an oil (15g, 33mmol). MS ESI: [M + H]+ m/z 333. INTERMEDIATE 96: 5-(5-bromo-1,3-thiazol-2-yl)-5-hydroxyazepan-2-one
Step 1: To a solution of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (15.0 g, 62.2 mmol) in DMF ( 75 ml) NBS (6.9 g, 55 mmol) was added and the solution heated to 45°C for 48 hours. The solution was treated with Na2SO3 (3.9 g, 31 mmol) in H2O (150 mL) and the resulting slurry was filtered and washed with water (70 mL) to yield 8-(5-bromo-1,3-thiazole) -2-yl)-1,4-dioxaspiro[4.5]decan-8-ol as a white solid (16.8 g, 52.5 mmol).
Step 2: The product from Step 1 (3.0 g, 9.4 mmol) was dissolved in 30 ml of 1:1 THF : HCl (3N) and heated at 50°C for 48 hours and the solution neutralized with solid KHCO 3 and then EtOAc (100 ml) and water (20 ml) were added. The aqueous layer was then extracted with EtOAc (50 ml) and the combined organic layers were washed with brine (50 ml), evaporated to a slurry which was treated with hexanes (20 ml). Filtration and drying yielded 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-cyclohexanone as a white solid (2.1g, 7.7mmol).
Step 3: To the product of Step 2 (10 g, 36.2 mmol) in THF (60.0 ml) was added hydroxylamine hydrochloride (5.0 g, 72.4 mmol) in water (7.0 ml) and Na2CO3 (2M, 36.2ml) added. The solution was stirred for 30 minutes and the resulting slurry was heated to 50°C for 48 hours and then allowed to cool to room temperature in 12 hours. To the slurry, H2O (240.0 ml) was added. Slow filtration yielded 1-(5-bromo-1,3-thiazol-2-yl)4-hydroxyimino)cyclohexanol as a white solid (10.15 g, 35 mmol).
Step 4: The product from Step 3 (10.0g, 34.3mmol) was suspended in acetonitrile (75.0ml) and then TsCl (7.2g, 37.8mmol) and DABCO (4.2mmol) g, 37.8 mmol) were added, keeping the temperature at 20°C with an ice/water bath. The slurry was stirred for 5 hours and then H2O (10.0 ml) added. The slurry was slowly filtered and washed with water. The liquid substances were concentrated and the residue dissolved with heating in MeOH (25 ml). Filtration yielded 5-(5-bromo-1,3-thiazol-2-yl)-5-hydroxyazepan-2-one as a white solid (4.0 g combined, 23 mmol) as a white solid. MS ESI: [M + H]+ m/z 291. INTERMEDIATE 100: (cis) methyl-4-oxo-2-(propan-2-yl)cyclohexane carboxylate
Step 1: Methyl isobutyryl acetate (7.20 g, 49.9 mmol) and sodium methoxide (0.896 g, 4.14 mmol) were cooled to 0°C. Methyl vinyl ketone (4.12 ml, 49.9 mmol) was added dropwise, and the solution was allowed to warm to room temperature and stirred 1 hour at this temperature. Acetic acid (0.249 ml, 4.34 mmol) was added, followed by a mixture of MeOH (6.75 ml): Water (750 µl), and finally a solution of pyrrolidine (0.349 ml, 4.21 mmol) in acid. acetic (0.309 ml, 5.39 mmol). The resulting solution was heated to reflux (115°C) for 2 hours. The reaction was allowed to cool to room temperature and then diluted with Et2O and water. The layers were separated and the aqueous portion extracted once more with Et2O (1x). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to yield methyl 4-oxo-2-(propan-2-yl)cyclohex-2-ene-1-carboxylate (5.11 g, 52%) as an oil. yellow, which was used in the subsequent step without further purification.
Step 2: The product from Step 1 (5.11 g, 26.0 mmol) was dissolved in MeOH (80 ml). Palladium on carbon (0.416 g, 0.391 mmol) was added, and the flask was fitted with a hydrogen balloon. The flask was evacuated and backfilled with hydrogen (3x) and shaken for 15 hours at room temperature. The reaction was then filtered through Celite and the Celite was washed with EtOAc. The filtrate was concentrated in vacuo. Purification by flash silica gel chromatography (0 to 15% EtOAc:Hexanes) gave methyl (cis)-4-oxo-2-(propan-2-yl)cyclohexane carboxylate (2.63 g , 51 %) as a colorless oil. INTERMEDIATE 101: Methyl 2,2-dimethyl-4-oxocycloeptanecarboxylate TMS-Diazomethane (5.97 ml, 11.94 mmol) was added to a stirred mixture cooled to -30°C of 2,2-dimethyl-4-oxocyclohexane - methyl carboxylate (2 g, 10.86 mmol) and BF3-OEt2 (1.513 ml, 11.94 mmol) in CH2Cl2 (65.0 ml). The reaction was aged at -30°C for 2 hours. The reaction was then quenched with water and allowed to warm to room temperature. The mixture was extracted three times with CH2Cl2 and the combined organic layers were concentrated under reduced pressure. The remaining residue was purified by flash chromatography (0 to 100% EtOAc : Hexanes) to yield a mixture of regioisomers, which includes methyl 2,2-dimethyl-4-oxocycloeptanecarboxylate (992 mg, 18%) as a yellow oil . 1H NMR (500 MHz, CDCl3) δ 3.67 - 3.57 (m, 3H), 2.76 (d, J = 12.9, 0.4H), 2.61 (ddd, J = 3.1 , 8.0, 15.5, 0.6H), 2.55 - 2.27 (m, 4H), 1.96 - 1.50 (m, 4H), 0.95 (m, 6H). INTERMEDIATE 119: 4-[5-(3-{(tert-butoxycarbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-4- ethyl hydroxycyclohexane carboxylate
To ethyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (Example 32, 0.15 g, 0.29 mmol) in THF (1.4 ml) was added di-tert-butyl-dicarbonate (0.069 mg, 0.32 mmol), 4-dimethylaminopyridine (0.04 g, 0, 03 mmol), and triethylamine (0.043 g, 0.43 mmol). The reaction was heated at 50 °C overnight. The reaction was cooled, diluted with dichloromethane and washed with water. The organic layer was extracted twice more with dichloromethane and the organic layers were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography was used to give 4-[5-(3-{(tert-butoxycarbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3- ethyl thiazol-2-yl]-4-hydroxycyclohexane carboxylate (0.15 mg, 85% yield). MS ESI: [M + H]+ m/z 607.2. 1H NMR (500 MHz, CDCl 3 ) δ 8.81 (d, J = 5.5, 1H), 7.78 (s, 1H), 7.39 - 7.29 (m, 1H), 7 .27 (d, J = 5.6, 1H), 7.19 (s, 1H), 7.02 (s, 1H), 4.31 - 3.95 (m, 2H), 2, 64 - 2.49 (m, 1H), 2.37 (s, 3H), 2.30 - 2.18 (m, 1H), 2.13 - 1.87 (m, 6H), 1. 87 - 1.74 (m, 1H), 1.49 (s, 9H), 1.26 - 1.23 (m, 4H). Activity of rhSYK = + MODEL COMPOUND 1. 2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan -2-ol

INTERMEDIATE 4 (100 mg, 0.297 mmol) in THF (1.5 ml) was added slowly to LDA (496 µl, 0.892 mmol) pre-cooled to -78°C in 5 minutes with stirring. The reaction mixture was allowed to stir for 30 minutes and treated with acetone (32.7 µl, 0.446 mmol). After 1 hour the reaction mixture was treated with 5 ml sat NH 4 Cl and allowed to warm to room temperature. The mixture was extracted with EtOAc, and the organic layer washed with saturated aqueous NaHCO3 . The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash chromatography to give 2-[5-(3-methyl-5-{[4-(trifluoro-methyl)pyrimidin-2-yl]-amino }phenyl)-1,3-thiazol-2-yl]propan-2-ol (95 mg, 0.241 mmol, 81% yield) as a colorless oil. APCI: [M + H]+ m/z 395.0. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.45 (s, 1H), 7.28 (d, J = 4.9, 1H), 7.14 (s, 1H), 6.03 (s, 1 H), 2.31 (s, 3H), 1.51 (s, 6H). rhSYK activity = +++
EXAMPLE 1 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile

Step 1: To a solution of cyclohexanecarbonitrile (0.913 g, 8.36 mmol) in toluene (25 ml) at 0°C was added sodium bis(trimethylsilyl)amide (1M solution in THF, 10.0 ml, 10, 0 mmol) and the resulting mixture was stirred for 1 hour at 0°C. 2-Chlorothiazole (1 g, 8.36 mmol) was then added dropwise as a solution in toluene (0.5 ml) over a period of 5 minutes and the resulting mixture was allowed to warm from 0°C to room temperature in 16 hours. The reaction mixture was quenched with saturated aqueous NH 4 Cl (20 ml), and extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (60 ml, dried (Na2SO4), filtered and concentrated under reduced pressure.The residue was purified by column chromatography over silica (gradient elution from 2% to 12% EtOAc in hexanes) to yield 1-(1,3-thiazol-2-yl)cyclohexanecarbonitrile (686 mg, 3.57 mmol, 42.7% yield) as a pale yellow oil which solidified on standing MS ESI: [M + H]+ m/z 193.
Step 2: N-Bromosuccinimide (0.33 g, 1.87 mmol) was added to a solution of the product from Step 1 (300 mg, 1.56 mmol) in DMF (5 ml) and the resulting reaction mixture was stirred at room temperature for 2 hours. 2 aliquots of N-bromosuccinimide (0.33 g, 1.87 mmol) were added over a 23 hour period prior to the addition of the saturated aqueous Na2S2O3 (10 mL). The mixture was then extracted with EtOAc (2 x 20 ml) and the combined organic layers were washed with brine (50 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution from 7% to 60% EtOAc in hexanes) to yield 1-(5-bromo-1,3-thiazol-2-yl)cyclohexanecarbonitrile (96 mg, 0 .35 mmol, 22.7% yield) as a pale yellow oil. MS ESI: [M + H]+ m/z 272.
Step 3: N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3. 134 mg, 0.35 mmol), the compound from Step 2 (96 mg, 0.35 mmol), cesium carbonate (346 mg, 1.06 mmol), X-Phos (16.9 mg, 0.035 mmol) ) and Pd2(dba)3 (16.2 mg, 0.018 mmol) were placed in a vial and evacuated/purged with N2 three times. Dioxane (1.5 ml) and water (0.15 ml) were degassed by bubbling N2 below the surface and added to the reaction vessel. The resulting reaction mixture was stirred at 100°C for 5 hours and then diluted with EtOAc (5 ml), washed with brine (5 ml), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution from 7% to 60% EtOAc in hexanes) to give the title compound (128 mg, 0.289 mmol, 82% yield) as a yellowish foam. MS ESI: [M + H]+ m/z 444.1. 1H NMR (500 MHz, CD3-OD) δ 8.72 (d, J = 5.0, 1H), 8.06 (bs, 1H), 8.00 (s, 1H), 7.48 (bs, 1H), 7.16 (bs, 1H), 7.14 (d, J = 4.9, 1H), 2.41 - 2.37 (m, 5H), 2.06 - 2.00 (m, 2H), 1.94 - 1.89 (m, 2H), 1.85 - 1.73 (m, 3H), 1.40 (m, 1H). Activity of rhSYK = ++.
EXAMPLE 2 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide

A mixture of 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile (45mg, 0, 10 mmol) and NaOH (1M in MeOH, 0.5 ml, 0.50 mmol) was heated at 100°C in microwave for 16 hours. The mixture was brought to pH = 3 by the addition of HCl (1.0N in H2O) and then partitioned between EtOAc (5 ml) and brine (5 ml). The organic layer was separated, dried (Na2SO4), filtered and volatiles were removed under reduced pressure. The residue was purified by HPLC (gradient elution from 40% to 100% CH 3 CN in H 2 O / 0.1% TFA, 20 minutes, 20 ml/min) to give the title compound (4.0 mg, 8.67 µmol, 8.5% yield) as a white solid. MS ESI: [M + H]+ m/z 462.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 5.3, 1H), 7.97 (s, 2H), 7.46 ( bs, 1H), 7.28 (d, J = 5.2, 1H), 7.20 (bs, 1H), 7.15 (bs, 2H), 2.31 - 2.24 (m , 5H), 2.00 - 1.94 (m, 2H), 1.51 - 1.41 (m, 5H), 1.33 (m, 1H). Activity of rhSYK = +++.
EXAMPLE 3 (1S,4R)-4-Methoxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-acid 1,3-thiazol-2-yl]cyclohexanecarboxylic acid

Step 1: A mixture of methyl cis-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylate (416 mg, 1.195 mmol) and iodomethane (112 µl, 1.792 mmol) in DMF (5500 µl) was cooled to 0°C and aged while stirring for 10 minutes. Sodium hydride (47.8 mg, 1.195 mmol) was then added and the reaction aged at 0°C for 5 minutes before warming to room temperature. The reaction was aged at room temperature for 2 hours. The reaction was cooled to 0°C and quenched with methanol. The mixture was warmed back to room temperature, mixed with water, and extracted with CH2Cl2 (3X). The combined organic layers were dried under reduced pressure and purified by column chromatography on silica gel (0 to 100% EtOAc : Hexanes) yielded cis-4-(5-bromo-1,3-thiazol-2-yl) methyl-4-methoxycyclohexane carboxylate (306 mg, 71 %) as a colorless oil. ESI: [M + H - MeOH]+ m/z 330, 332.
Step 2: N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 3, 320 mg, 0.845 mmol), the product from Step 1 (306 mg, 0.845 mmol), and sodium carbonate (845 µl, 1.689 mmol) in 2-methyl THF (5631 µl) were degassed by sparging with Ar for 5 minutes. PdCl2(dppf)-CH2Cl2 adduct (34.5 mg, 0.042 mmol) was added and the temperature raised to 85°C. The reaction was aged for 5 hours. The cooled reaction was mixed with water and extracted with CH2Cl2 (3X). The organic layers were dried under reduced pressure. The crude product was purified by column chromatography on silica gel (0 to 100% EtOAc : Hexanes) yielded (1S,4R)-4-methoxy-2,2-dimethyl-4-[5-(3-methyl) Methyl -5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (156 mg, 29%) as a colorless oil. MS ESI: [M + H]+ m/z 535.
Step 3: Potassium hydroxide in methanol (3.0 ml, 3.0 mmol) was added to the product from Step 2 (150 mg, 0.23 mmol) and the reaction mixture heated to 65°C for 110 hours. The reaction mixture was cooled and then quenched with HCl (2N in H2O). The mixture was filtered and washed with ~20 ml of water to obtain a yellowish white solid. The solid was dried under reduced pressure at 40°C in a vacuum oven for 1.5 hour to furnish the title compound (95mg, 79%) as a yellow solid. ESI: [M + H]+ m/z 521. 1H NMR (500 MHz, DMSO-d6) δ 12.15 - 11.94 (m, 1H), 10.26 (s, 1H), 8. 83 (d, J = 4.9, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.45 (s, 1H), 7.28 (d, 1H), J = 4.9, 1H), 7.16 (s, 1H), 3.07 (s, 3H), 2.31 (s, 3H), 2.22 - 2.09 (m, 2H) , 1.99 - 1.80 (m, 3H), 1.72 (d, J = 14.5, 1H), 1.62 (s, 1H), 1.07 (s, 3H), 1 .01 (s, 3H). rhSYK activity = +++
The following compounds were prepared in a manner analogous to that described for Model Compound 1. In this and all subsequent Tables without the explicitly reported stereochemistry (absolute or relative) are single isomers of an unknown configuration or a mixture of isomers. Indicators of stereochemistry (cis or trans) refer to the relative relationships of the corresponding substituents with the highest CIP priority respectively. EXAMPLES 4B/4C/4D TABLE 4B
Table 4C

4D TABLE
EXAMPLE 7 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanone
To a stirred solution of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4 -dioxaspiro[4.5]decan-8-ol (prepared in a manner analogous to that described for Compound Model 1, 785 mg, 1.59 mmol) in THF (6 ml) was added HCl (6M, 5.3 ml, 32 mmol) and the reaction was allowed to stir for 6 hours. The mixture was brought to pH 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (x 3), and the combined organic portion washed with saturated aqueous sodium bicarbonate. The solution was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography to yield 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino} phenyl)-1,3-thiazol-2-yl]cyclohexanone (625 mg, 1.39 mmol) as a white foam. APCI: [M + H]+ m/z 449.1. 1H NMR (600 MHz, CDCl 3 ) δ 8.64 (d, J = 4.9, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.46 (s , 1H), 7.26 (s, 1H), 7.06 (s, 1H), 7.04 (d, J = 4.9, 1H), 2.92 - 2.82 (m , 2H), 2.49 - 2.29 (m, 6H), 2.38 (s, 3H). rhSYK activity = +++
EXAMPLES 8(1) AND 8(2) cis-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2- yl]cyclohexane-1,4-diol trans-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]cyclohexane-1,4-diol

To a stirred solution of 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]cyclohexanone (500 mg, 1.115 mmol) in MeOH (11 ml) was added sodium borohydride (63.3 mg, 1.672 mmol) at -20°C and the reaction was aged for 20 minutes. The mixture was treated with water and extracted with ethyl acetate. The combined organics were dried, filtered, concentrated, and purified by flash chromatography to yield cis-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl) -1,3-thiazol-2-yl]cyclohexane-1,4-diol (250 mg, 0.56 mmol). APCI: [M + H]+ m/z 451.1. 1H NMR (600 MHz, CDCl 3 ) δ 8.63 (d, J = 4.9, 1H), 7.89 - 7.79 (m, 2H), 7.45 (s, 1H), 7. 26 (s, 1H), 7.06 (s, 1H), 7.02 (d, J = 4.9, 1H), 3.81 - 3.72 (m, 1H), 2, 98 (s, 1H), 2.37 (s, 3H), 2.11 - 1.72 (m, 8H). Activity of rhSYK = +++ trans-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane -1,4-diol (40 mg, 0.09 mmol) APCI: [M + H]+ m/z 451.1. 1H NMR (600 MHz, CDCl 3 ) δ 8.63 (d, J = 4.9, 1H), 7.88 - 7.79 (m, 2H), 7.46 (s, 1H), 7. 27 (s, 1H), 7.06 (s, 1H), 7.02 (d, J = 4.9, 1H), 3.67 (t, J = 6.3, 1H), 3.56 (m, 1H), 2.43 - 1.62 (m, 8H), 2.37 (s, 3H). rhSYK Activity = +++ The compounds in the following Table(s) were prepared in a manner analogous to that described in Example 8(1)/8(2): TABLE 8A
TABLE 8B

EXAMPLES 9(1) AND 9(2) trans-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3 -thiazol-2-yl]cyclohexane-1,4-diol cis-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)- 1,3-thiazol-2-yl]cyclohexane-1,4-diol

To a stirred solution of 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]cyclohexanone (104 mg, 0.232 mmol) in THF (4 ml) was added MeMgCl (3.0 M, 0.464 ml, 1.39 mmol) at 0°C. The resulting organic suspension was stirred for 1 hour at 0°C, treated with saturated aqueous ammonium chloride, and extracted with ethyl acetate (x 3). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography gave: trans-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol- 2-yl]cyclohexane-1,4-diol (6mg, 0.013mmol) as a white solid. APCI: [M + H]+ m/z 465.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J = 4.9, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.43 (s, 1H), 7.25 (d, J = 4.9, 1H), 7.12 (s, 1H), 5.74 (s, 1 H), 4.03 (s, 1H), 2.29 (s, 3H), 2.21 (td, J = 3.9, 13.3, 2H), 1.71 - 1.36 (m , 6H), 1.10 (s, 3H). Activity of rhSYK = +++) cis-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol- 2-yl]cyclohexane-1,4-diol (23 mg, 0.050 mmol) as a colorless oil. APCI: [M + H]+ m/z 465.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.8, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.45 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.13 (s, 1H), 2.31 (s, 3H ), 1.96 - 1.40 (m, 8H), 1.13 (s, 3H). Activity of rhSYK = +++.
EXAMPLE 10 5-hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2- whoa

A mixture of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[ 4.5]decan-8-ol (60 mg, 0.122 mmol), sodium azide (23.76 mg, 0.365 mmol) and methanesulfonic acid (95 µl, 1.462 mmol) in CHCl3 (1.2 ml) was heated to 65°C for 1 hour and cooled to room temperature. The mixture was treated with water, and extracted with ethyl acetate. The combined organics were dried, filtered, concentrated and purified by flash chromatography to yield 5-hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)- 1,3-thiazol-2-yl]azepan-2-one (36 mg, 0.078 mmol). APCI: [M + H]+ m/z 464.2. 1H NMR (600 MHz, CDCl 3 ): δ 8.63 (d, J = 4.9, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.62 ( s, 1H), 7.26 (s, 1H), 7.05 (s, 1H), 7.03 (d, J = 5 4.9, 1H), 6.21 (s, 1 H), 3.81 (s, 1H), 3.46 (s, 1H), 3.21 - 3.03 (m, 2H), 2.41 (dd, J = 7.5, 14, 4.1H), 2.37 (s, 3H), 2.24 (t, J = 13.3, 1H), 2.18 - 2.04 (m, 3H). rhSYK activity = +++
The following compounds were prepared as the free base in a manner analogous to that described in Example 10: TABLE 10

EXAMPLE 14 cis-4-[(hydroxy-acetyl)amino]-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole -2-yl]cyclohexanecarboxamide

Step 1: To a solution of ethyl 4-oxocyclohexanecarboxylate (5.0 g, 40.6 mmol) in benzene (20 ml) were added ethylene glycol (2.83 ml, 50.8 mmol) and catalytic sulfuric acid (772 mg, 4.1 mmol) and the mixture was refluxed under a Dean-Stark siphon for 18 hours. The mixture was cooled to 23°C, diluted with saturated aqueous NaHCO 3 (85 ml) and extracted with EtOAc (2 x 75 ml). The organic layer was dried over Na2SO4, filtered and concentrated and the crude product was purified by flash column chromatography to yield 1,4-di-oxaspiro[4.5]decane-8-carbonitrile (6.15 g, 34, 9 mmol, 86% yield) as a colorless oil. IU NMR (500 MHz, CDCl 3 ): δ 3.85 - 3.3.80 (m, 4H), 2.61 - 2.53 (m, 1H), 1.90 - 1.77 (m, 4H) ), 1.75 - 1.69 (m, 2H), 1.56 - 1.48 (m, 2H).
Step 2: To a solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (3 g, 17.9 mmol) in anhydrous toluene (95 ml) at 0°C, was added bis(trimethyl-silyl sodium amide (1M in toluene, 21.5 ml, 21.5 mmol). The resulting organic solution was kept at 0°C for 1 hour, before introducing a solution of 2-Chlorotriazole (2.14 g, 17.9 mmol) in anhydrous toluene (10 ml) via cannulation. The resulting dark brown solution was allowed to slowly warm to 23°C in 16 hours. The reaction was diluted with saturated aqueous NH 4 Cl (100 ml) and extracted with EtOAc (2 x 80 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified by flash column chromatography (SiO2 : 100% Hex to 80 : 20 Hex : EtOAc) to give 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4 ,5]decane-8-carbonitrile (1.78 g, 6.74 mmol, 37.5% yield) as a fluffy yellowish white solid. MS ESI: [M + H]+ m/z 251.1. 1H NMR (500 MHz, CDCl 3 ): δ 7.79 (d, 1H, J = 3.2 Hz), 7.35 (d, 1H, J = 3.5 Hz), 4.01 - 3, 95 (m, 4H), 2.44 - 2.31 (m, 4H), 2.09 - 2.03 (m, 2H), 1.89 - 1.86 (m, 2H).
Step 3: To a solution of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.78 g, 7.11 mmol) in anhydrous DMF (25 ml) was added N-bromosuccinimide (1.52 g, 8.53 mmol). The solution was heated at 50°C for 2 hours. The reaction was cooled to 23°C then diluted with saturated aqueous NaS 2 O 3 (175 ml) and extracted with EtOAc (2 x 130 ml). The combined organic layers were washed with brine (150 ml), dried over Na2SO4, filtered and concentrated. The yellow crude oil was purified by flash column chromatography (SiO2 : 100% Hex to 60 : 40 Hex : EtOAc) to yield 8-(5-bromo-1,3-thiazol-2-yl)-1 ,4-dioxa-spiro[4.5]decane-8-carbonitrile (1.43 g, 4.13 mmol, 58% yield) as a yellowish white solid. MS ESI: [M + H]+ m/z 331.1. 1H NMR (500 MHz, CDCl 3 ): δ 7.66 (s, 1H), 4.01 - 3.93 (m, 4H), 2.39 - 2.26 (m, 4H), 2.07 - 2.01 (m, 2H), 1.88 - 1.86 (m, 2H).
Step 4: N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1 .60 g, 4.22 mmol), 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.40 g, 4 .22 mmol), cesium carbonate (4.12 g, 12.6 mmol), Pd2(dba)3 (193 mg, 0.21 mmol) and X-Phos (201 mg, 0.42 mmol) were added to a flame-dried flask, deoxygenated, and diluted with anhydrous 1,4-dioxane (15 ml) and water (1.5 ml). The resulting dark mixture was heated to 100°C for 5 hours. The reaction mixture was diluted with 1:1 aqueous saturated NaHCO3 : brine (100 ml) and extracted with EtOAc (2 x 85 ml). The organic layers were dried over Na2SO4, filtered and concentrated. The crude dark brown oil was purified by flash column chromatography (SiO2 : 100% Hex to Hex : EtOAc 60 : 40) which gave 8-[5-(3-methyl-5-{[4-(trifluoromethyl) pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxa-spiro[4,5]decane-8-carbonitrile (1.77 g, 3.35 mmol, 79% yield) as a yellowish white solid. MS ESI: [M + H]+ m/z 502.1. 1H NMR (500 MHz, CD3OD): δ 11.1 (s, 1H), 9.65 (d, 1H, J = 4.9Hz), 8.93 (s, 1H), 8.83 (s, 1H), 8.30 (s, 1H), 8.10 (d, 1H, J = 4.9 Hz), 8.02 (s, 1H), 4.73 - 4, 72 (m, 4H), 3.21 - 3.18 (m, 2H), 3.13 (s, 3H), 3.01 - 2.97 (m, 2H), 2.69 - 2.61 ( m, 4H). rhSYK activity = +++
Step 5: To a solution of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1, 4-dioxaspiro[4.5]decane-8-carbonitrile (250 mg, 0.50 mmol) in anhydrous DMSO (4 ml) was added potassium carbonate (172 mg, 1.25 mmol) and hydrogen peroxide (218 µl , 2.49 mmol). The resulting solution was stirred at 70°C for 1.5 hour, cooled to room temperature and diluted with water (70 ml) and washed with EtOAc (2 x 60 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude oil was triturated with diethyl ether and Hexanes, and the resulting brown solid was collected by filtration and air dried to give 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2 -yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro - [4,5]decane-8-carboxamide (171 mg, 0.31 mmol, 63% yield) as a brown solid. MS ESI: [M + H]+ m/z 520.1. 1H NMR (500 MHz, CD3OD): δ 11.0 (s, 1H), 9.64 (d, 1H, J = 4.9Hz), 8.79 (s, 1H), 8.76 (bs, 1H), 8.28 (bs, 1H), 8.12 - 8.05 (m, 3H), 7.97 (s, 1H), 4.68 - 4.64 (m, 4H), 3.23 - 3.15 (m, 2H), 3.12 (s, 3H), 2.95 - 2.85 (m, 2H), 2.44 - 2.38 (m, 4H) .
Step 6: To a suspension of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1 ,4-dioxaspiro[4.5]decane-8-carboxamide (700 mg, 1.35 mmol) in anhydrous THF (2 ml) and concentrated HCl (5.53 ml, 67.4 mmol) was added. The resulting dark yellow solution was stirred at 23°C for 6 hours. The mixture was diluted with saturated aqueous NaHCO3 (80 ml) and extracted with EtOAc (2 x 70 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude oil was triturated with Hexanes and diethyl ether which afforded 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2- yl]-4-oxocyclohexanecarboxamide (683 mg, 1.01 mmol, 74.6%) as a brown solid. MS APCI: [M + H]+ m/z 476.1.
Step 7: To a solution of 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-4- oxocyclohexanecarboxamide (683 mg, 1.44 mmol) in anhydrous MeOH (6 mL) were added ammonium acetate (221 mg, 2.87 mmol) and sodium cyanoborohydrite (95 mg, 1.508 mmol). The resulting mixture was stirred at 23°C for 46 d. The reaction was quenched with 0.5 M NaOH (100 ml) and extracted with EtOAc (2 x 75 ml). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to an orange oil, which was purified by reverse phase HPLC (C18 column, gradient of acetonitrile/water with 0.1% TFA present). Purification yielded a mixture of diastereomers, which were separated via separation on a chiral stationary phase (SFC, 35% / 65% Methanol /CO2 (no other modifiers) to provide both cis-4-amino-1-[ 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxamide (92 mg, 0.18 mmol, 29% yield) for trans-4-amino-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2- yl]cyclohexanecarboxamide (103 mg, 0.21 mmol, 32 % yield) as yellowish white solids. MS ESI: [M + H]+ m/z 477.1. For molecule A, rhSYK activity = +++ ; for molecule B, rhSYK activity = +++
Step 8: To a solution of cis-4-amino-1-[5-(3-methyl-5-{[4-(trifluoro-methyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole -2-yl]cyclohexanecarboxamide (30mg, 0.06mmol) in anhydrous DMF (1.5ml) were sequentially added glycolic acid (7.18mg, 0.09mmol), EDC (18.1mg, 0, 09 mmol), HOBT (14.5 mg, 0.09 mmol), and Et3N (0.03 ml, 0.19 mmol). The mixture was stirred at 23°C for 16 hours, then diluted with water (55 ml) and washed with EtOAc (2 x 40 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase HPLC (gradient acetonitrile/water with 0.1% TFA present) and the fractions containing the product were diluted with saturated aqueous NaHCO3 (50 ml) and washed with EtOAc (45 ml). The organic layer was dried over Na2SO4, filtered and concentrated to yield cis-4-[(hydroxy-acetyl)amino]-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl ]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide (16.5 mg, 0.03 mmol, 47% yield) as a yellowish white solid. MS ESI: [M + H]+ m/z 535.1. 1H NMR (500 MHz, DMSO) δ 10.26 (s, 1H), 8.83 (d, J = 4.9, 1H), 7.96 (s, 1H), 7.94 (s , 1H), 7.55 (d, J = 8.2, 1H), 7.45 (m, 2H), 7.32 - 7.22 (m, 2H), 7.14 (s, 1 H), 5.29 (t, J = 5.9, 1H), 3.75 (d, J = 6.0, 2H), 3.70 - 3.60 (m, 1H), 2, 67 - 2.58 (m, 2H), 2.31 (s, 3H), 1.82 - 1.68 (m, 4H), 1.54 - 1.41 (m, 2H). rhSYK activity = +++
EXAMPLES 25 (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 ,3-thiazol-2-yl]-N-[3-(2-oxopyrrolidin-1-yl)-propyl]cyclohexanecarboxamide

To the acid (1S, 4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1, 3-thiazol-2-yl]cyclohexane carboxylic (102 mg, 0.20 mmol), N-(3-aminopropyl)-2-pyrrolidinone (85 µl, 0.60 mmol), EDC (58 mg, 0.30 mmol), and HOBt (46 mg, 0.30 mmol) was added N,N-dimethylformamide (2 ml) and triethylamine (140 µl, 1.01 mmol). The mixture was stirred at room temperature for 16 hours, quenched with 1:1 water:brine, and extracted with EtOAc. The organic layer was washed with 1:1 water:brine (3x). The organic layer was dried over magnesium sulfate, filtered and purified by reverse phase HPLC (C-18, eluting with a gradient 45 : 55 to 80 : 20 acetonitrile : water + 0.1% TFA). The combined fractions were diluted with ethyl acetate and dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to yield the title compound (97 mg, 0.15 mmol, 76% yield) as a white solid. MS ESI: [M + H]+ m/z 631.2. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.68 (t, J = 5.6, 1H), 7.46 (s, 1H), 7.28 (d, J = 4.9, 1H), 7 .14 (s, 1H), 5.86 (s, 1H), 3.29 (s, 1H), 3.24 - 3.12 (m, 2H), 3.12 - 3.03 ( m, 1H), 2.99 - 2.88 (m, 1H), 2.31 (s, 3H), 2.19 (m, 2H), 2.02 (m, 2H), 1.86 (m, 5H), 1.66 - 1.50 (m, 3H), 1.40 (m, 1H), 1.11 (s, 3H), 0.92 (s, 3H).
EXAMPLE 26 cis-4-Fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl] acid cyclohexanecarboxylic

Step 1: To the solution of 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl tert-Butyl]cyclohexanecarboxylate (400mg, 0.748mmol) in dichloromethane (3.74ml) and ethanol (2.2µl, 0.037mmol) was added Deoxofluor (690µl, 3.74mmol). The reaction was complete after stirring for one hour at room temperature. The reaction was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Column chromatography was used for purification to furnish the two isomers of 4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1, tert-butyl 3-thiazol-2-yl]cyclohexanecarboxylate. The cis isomer (141 mg, 0.210 mmol, 28.1%). MS ESI: [M + H]+ m/z 537.2. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (d, J = 5.2, 1H), 8.07 (d, J = 2.9, 1 H), 8.03 (s, J = 8.3, 1H), 7.47 (s, 1H), 7.29 (d, J = 5.1, 1H), 7.20 (s , 1H), 2.32 (s, 5H), 2.20 - 1.93 (m, 3H), 1.93 - 1.78 (m, 2H), 1.76 - 1.57 (m, 2H), 1.40 (s, 9H). The trans isomer (175 mg, 0.326 mmol, 43.6%). MS ESI: [M + H]+ m/z 537.2. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.83 (d, J = 5.3, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.47 (s, 1H), 7.29 (d, J = 5.2, 1H), 7.20 (s, 1H), 2.53 (s, 3H ), 2.32 (s, 4H), 2.08 - 1.93 (m, 2H), 1.93 - 1.82 (m, 2H), 1.84 - 1.61 (m, 1H) , 1.39 (s, 9H).
Step 2: To a solution of cis-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoro-methyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole tert-butyl-2-yl]cyclohexanecarboxylate (67 mg, 0.125 mmol) in dichloromethane (2.50 ml) was added 2,6-lutidine (145 µl, 1.249 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (860 µl, 3 .75 mmol). The reaction was completed after 1 hour at room temperature. The reaction was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Column chromatography was used for purification to produce a mixture of the fluorocarboxylic acid and the des-fluorocarboxylic acid. SFC was then used for further purification (Berger Multigram II SFC, column: Chiral Technology OJ 2.1 X 25 cm, 5 µM, mobile phase: 40% to 60% methanol in CO2(1), flow rate: 70 ml /min, 7.5 minutes driving time) to produce cis-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)- acid 1,3-thiazol-2-yl]cyclohexane carboxylic (17 mg, 0.035 mmol, 28.3%). MS ESI: [M + H]+ m/z 481.1. 1H NMR (600 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.82 (d, J = 4.9, 1H), 8.06 (d, J = 2.8, 1 H), 8.00 (s, 1H), 7.45 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.18 (s, 1H), 2 .40 (t, J = 12.1, 1H), 2.30 (s, 3H), 2.16 (t, J = 11.8, 2H), 2.05 (dtd, J = 4.4 , 14.0, 40.0, 2H), 1.91 (d, J = 13.3, 2H), 1.68 (tt, J = 6.5, 12.9, 2H). rhSYK activity = +++
The following examples were prepared in a manner analogous to that described in Example 26. TABLE 26
EXAMPLE 32
ethyl 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate

The tetrahydrofuran was placed in a flask and cooled to -78°C. Lithium diisopropylamide (9.91 ml, 17.84 mmol) was added and the mixture was allowed to cool to -78°C. INTERMEDIATE 4 (2.0 g, 5.95 mmol) was dissolved in tetrahydrofuran (60 ml) and added to the reaction mixture in one portion and stirred for 30 minutes. Ethyl 4-oxo-cyclohexanecarboxylate (1.52 g, 8.92 mmol) was dissolved in tetrahydrofuran (60 ml) and added in one portion. After 1 hour, the reaction was quenched with saturated ammonium chloride and allowed to warm to room temperature. The solution was diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography was used for purification to produce a 1:1 mixture of 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino diastereomers ethyl }phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxylate (1.96 g, 65.1%). MS ESI: [M + H]+ m/z 507.2. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 5.2, 1H), 8.02 - 7.85 (m, 2H), 7.46 (s, 1H), 7.27 (d, J = 5.0, 1H), 7.14 (s, 1H), 5.97 (m, 1H), 4.12 - 4.01 (m, 2H), 2.62 - 2.54 (m, 1H), 2.31 (s, 3H), 2.12 - 1.99 (m, 1H), 1.93 - 1.58 (m, 7H), 1.24 - 1.05 (m, 3H). rhSYK activity = +++ EXAMPLES 33(1) AND 33(2)
trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid
cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid
Part A: 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate ethyl (3.72 g, 7.3 mmol) was suspended in methanol (42 ml) and sodium hydroxide (1M in water, 15 ml) was added. The solution was divided between 3 20 ml microwave tubes. The reaction was irradiated at 100°C in microwave for 15 minutes. On completion, the solution was acidified with HCl (1M in water, 18 ml). The solution was extracted with ethyl acetate and a small amount of CHCl3 : isopropanol 9:1. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated.
Part B: Supercritical fluid separation was used for purification with a 2.1 X 25 cm, 5 µM OJ-H column. The mobile phase used was a methanol/CO2 3 : 7 with a flow rate of 70 ml/min with a conduction time of 7 minutes, to produce:
Isomer 1: trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl acid ]cyclohexane carboxylic (1.11 g, 32 % yield). MS ESI: [M + H]+ m/z 479.1. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J = 4.9, 1H), 8.00 - 7.75 (m, 2H), 7.44 (s, 1H), 7.25 (d, J = 4.9, 1H), 7.12 (s, 1H), 5.92 (s, 1H), 2.62 ( s, 1H), 2.29 (s, 3H), 2.11 - 1.95 (m, 2H), 1.92 - 1.75 (m, 4H), 1.71 - 1.54 (m , 2H). rhSYK activity = +++
Isomer 2: cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl acid ]cyclohexanecarboxylic acid (1.13 g, 32%). MS ESI: [M + H]+ m/z 479.1. 1H NMR (500 MHz, DMSO-d6) δ 12.1 (s, 1H), 10.25 (s, 1H), 8.83 (d, J = 5.2, 1H), 8.04 - 7.83 (m, 2H), 7.46 (s, 1H), 7.27 (d, J = 5.0, 1H), 7.15 (s, 1H), 5.95 ( s, 1H), 2.31 (s, 3H), 2.13 - 1.99 (m, 1H), 1.91 - 1.73 (m, 2H), 1.71 - 1.53 ( m, 6H). rhSYK activity = +++
EXAMPLES 33(1) - NA cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol- sodium 2-yl]cyclohexanecarboxylate
cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid ( 15 mg, 0.031 mmol) was dissolved in acetonitrile (272 µl) and water (54 µl). Sodium hydroxide (31 µl, 0.031 mmol) was added, and the mixture was heated to 40°C for 1 hour. The reaction was allowed to cool to room temperature, before freezing and lyophilizing to dryness to yield cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl sodium ]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M + H]+ m/z 479.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (s, 1H), 8.06 - 7.73 (m, 2H), 7.46 (s, 1H), 7.27 (s, 1H), 7.13 (s, 1H), 5.89 - 5.60 (m, 1H), 2.31 (s, 3H), 1.91 - 1.54 (m, 9H). rhSYK activity = +++
EXAMPLES 33(1) - K cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol- potassium 2-yl]cyclohexanecarboxylate
cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid ( 15 mg, 0.031 mmol) was dissolved in acetonitrile (272 µl) and water (54 µl). Potassium hydroxide (31 µl, 0.031 mmol) was added, and the mixture was heated to 40°C for 1 hour. The reaction was allowed to cool to room temperature, before freezing and lyophilizing to dryness to yield cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl potassium ]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M + H]+ m/z 479.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H), 7.99 - 7.83 (m, 2H), 7.46 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.13 (s, 1H), 5.88 - 5.63 (m, 1H), 2.31 (s, 3H), 1.88 - 1.59 (m, 9H). rhSYK activity = +++
EXAMPLES 33(2) - NA trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol- sodium 2-yl]cyclohexanecarboxylate
trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid ( 15 mg, 0.031 mmol) was dissolved in acetonitrile (272 µl) and water (54 µl). Sodium hydroxide (31 µl, 0.031 mmol) was added, and the mixture was heated to 40°C for 1 hour. The reaction was allowed to cool to room temperature, before freezing and lyophilizing to dryness to yield trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl sodium ]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M + H]+ m/z 479.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H), 8.04 - 7.76 (m, 2H), 7.46 (s, 1 H), 7.27 (d, J = 4.9, 1 H), 7.14 (s, 1 H), 5.68 (s, 1 H), 2.31 ( s, 3H), 2.21 - 1.96 (m, 3H), 1.90 - 1.63 (m, 4H), 1.62 - 1.42 (m, 2H). rhSYK activity = +++
EXAMPLES 33(2) - K trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol- potassium 2-yl]cyclohexanecarboxylate
trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid ( 15 mg, 0.031 mmol) was dissolved in acetonitrile (272 µl) and water (54 µl). Potassium hydroxide (31 µl, 0.031 mmol) was added, and the mixture was heated to 40°C for 1 hour. The reaction was allowed to cool to room temperature, before freezing and lyophilizing to dryness to yield trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl potassium ]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M + H]+ m/z 479.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H), 8.02 - 7.78 (m, 2H), 7.46 (s, 1 H), 7.27 (d, J = 4.9, 1 H), 7.14 (s, 1 H), 5.69 (s, 1 H), 2.31 ( s, 3H), 2.19 - 2.07 (m, 2H), 1.99 - 1.85 (m, 1H), 1.81 - 1.60 (m, 4H), 1.57 - 1 .42 (m, 2H). rhSYK activity = +++
The compounds in the following Tables 33A to 33D were prepared in an analogous manner to that described in Examples 32 - 33. TABLE 33-A
TABLE 33A

TABLE 33B


EXAMPLES 37(1) AND 37(2) cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3 -thiazol-2-yl]cyclohexanecarbonitrile trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazole -2-yl]cyclohexanecarbonitrile

To a flask was added tetrahydrofuran (3.0 ml) and the flask was cooled to -78°C. Lithium diisopropylamide (1.0 ml, 1.78 mmol) was added and the mixture was cooled to -78°C. INTERMEDIATE 4 (0.20 g, 0.60 mmol) was dissolved in tetrahydrofuran (3.0 ml) and added to the reaction mixture in one portion and stirred for 30 minutes. The 4-oxocyclohexanecarbonitrile (0.073 g, 0.60 mmol) was dissolved in THF (3.0 ml) and then added over a five minute period and the solution was then allowed to warm to room temperature. The reaction was diluted with ethyl acetate, washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and concentrated. Column chromatography was used to produce: cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3- thiazol-2-yl]cyclohexanecarbonitrile (0.72 g, 26%) Analysis for cis isomer: MS ESI: [M + H]+ m/z 460.1. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J = 4.9, 1H), 7.93 (m, 2H), 7.44 ( s, 1H), 7.26 (d, J = 4.9, 1H), 7.13 (s, 1H), 6.11 (s, 1H), 2.82 (s, 1H) ), 2.29 (s, 3H), 1.99 - 1.72 (m, 8H). Activity of rhSYK = +++ trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol- 2-yl]cyclohexanecarbonitrile (0.78 g, 29%). MS ESI: [M + H]+ m/z 460.1. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J = 4.9, 1H), 8.00 - 7.89 (m, 2H), 7.45 (s, 1 H), 7.25 (d, J = 4.9, 1 H), 7.14 (s, 1 H), 6.11 (s, 1 H), 3.13 ( s, 1H), 2.30 (s, 3H), 2.07 (m, 2H), 2.00 - 1.89 (m, 2H), 1.77 (m, 4H). rhSYK activity = +++
EXAMPLES 38(1) AND 38(2) trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3 -thiazol-2-yl]cyclohexanecarboxamide cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazole -2-yl]cyclohexanecarboxamide

To trans-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile ( 0.78 g, 0.17 mmol) was added DMSO (1.4 ml). Potassium carbonate (0.13 mg, 0.92 mmol) and 30% hydrogen peroxide (0.17 ml, 1.70 mmol) were added and the reaction was heated to 70°C. On completion, the solution was cooled and filtered. The filtrate was purified by reverse phase HPLC (10 to 100% gradient acetonitrile with water in 12 minutes with a 0.05% trifluoroacetic acid buffer) to yield trans-4-hydroxy-4-[5- (3 ) -methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxamide (0.040 g, 49%). MS ESI: [M + H]+ m/z 478.1. 1H NMR (500 MHz, CD3OD) δ 8.72 (d, J = 5.3, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.45 (s , 1H), 7.22 - 6.90 (m, 2H), 2.57 - 2.40 (m, 3H), 2.38 (s, 3H), 2.00 - 1.69 (m, 6H). rhSYK activity = +++
In an analogous manner to that, cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2 -yl]cyclohexanecarboxamide described above was prepared as the free base. [M + H]+ Found: 478.1. rhSYK activity: +++
EXAMPLE 39 3-{cis-4-Hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2- yl]cyclohexyl}-1,2,4-oxadiazol-5(4H)-one

Step 1: cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl] acid cyclohexanecarboxylic acid (500 mg, 1.05 mmol), ammonium chloride (112 mg, 2.09 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (795 mg, 2.09 mmol), and diisopropylethylamine (730 µl, 4.18 mmol) were absorbed in dimethylformamide (4.2 ml) under argon. The vessel was sealed and shaken at 65°C for 4 hours. On heating, the reaction mixture was diluted with water, and the resulting precipitate was collected by filtration. The solids were washed with water and diethyl ether and dried in vacuo overnight to yield cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl] amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide (437.6 mg, 0.916 mmol, 88% yield) as a white solid. MS ESI: [M + H]+ m/z 478.1.
Step 2: In a dry vessel, the product from Step 1 (350 mg, 0.733 mmol) was taken up in dichloromethane (4.9 ml) and tetrahydrofuran (2.4 ml) under argon. (Methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, inner salt (218 mg, 0.916 mmol) was added, and the resulting mixture was sealed and stirred at room temperature for 18 hours. A further portion of (methoxy-carbonylsulfamoyl)triethyl-ammonium hydroxide, inner salt (218 mg, 0.916 mmol) was then added, and the resulting mixture was sealed and stirred at room temperature for 18 hours. The reaction mixture was quenched with water and directly concentrated. Purification by reverse phase HPLC (water-acetonitrile, trifluoroacetic acid modifier) gave cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl] amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile (28.6 mg, 0.062 mmol, 8.5% yield) as a white solid. MS ESI: [M + H]+ m/z 460.1.
Step 3: The product from Step 2 (25 mg, 0.054 mmol), hydroxylamine hydrochloride (18.90 mg, 0.272 mmol), and potassium carbonate (41.4 mg, 0.299 mmol) were absorbed in Ethanol (0.5 ml) under argon. The vessel was sealed and shaken at 80°C for 18 hours. The reaction mixture was directly concentrated, and the solids were taken up in tetrahydrofuran (0.5 ml). Triethylamine (22.8 µl, 0.163 mmol) was added, and the mixture was cooled to 0°C. Carbonyldiimidazole (13.2 mg, 0.082 mmol) was added, and the resulting mixture was allowed to warm to room temperature in 18 hours. The reaction was quenched with trifluoroacetic acid and diluted with 1 ml of DMSO. The resulting mixture was filtered and directly subjected to reverse phase HPLC (water-acetonitrile, trifluoroacetic acid modifier). This purification gave the title compound (14.7 mg, 0.028 mmol, 52% yield) as a white solid. MS ESI: [M + H]+ m/z 519.1. 1H NMR (500 MHz, dmso) δ 12.23 (s, 1H), 10.26 (s, 1H), 8.83 (d, J = 4.8, 1H), 7.94 (d , J = 10.8, 2H), 7.46 (s, 1H), 7.28 (d, J = 4.9, 1H), 7.15 (s, 1H), 6.06 ( s, 1H), 2.68 (m, 1H), 2.31 (s, 3H), 2.03 - 1.79 (m, 8H). rhSYK activity = +++
EXAMPLE 40(1) AND 40(2) 2-({3-[2-(cis-4-carboxy-1-methoxy-cyclohexyl)-1,3-thiazol-5-yl]-5-methylphenyl} trifluoroacetate amino)-4-(trifluoromethyl)pyrimidin-1-yl 2-({3-[2-(trans-4-carboxy-1-methoxy-cyclohexyl)-1,3-thiazol-5-yl]-5 trifluoroacetate -methylphenyl}amino)-4-(trifluoromethyl)pyrimidin-1-ium

Step 1: To a solution of 4-[5-(3-{(tert-butoxy-carbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2 Ethyl -yl]-4-hydroxy-cyclohexanecarboxylate (Intermediate 119, 0.148 g, 0.24 mmol) and DMF (1.2 ml) was added iodomethane (0.042 g, 0.29 mmol). The solution was cooled to 0°C and then 60% sodium hydride in mineral oil (0.011 g, 0.27 mmol) was added and the reaction was allowed to warm overnight. The next morning, iodomethane (1.14 g, 8.03 mmol) was added and the mixture was cooled to 0 °C. Sodium hydride in mineral oil (60%, 0.011 g, 0.27 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was complete after heating. The solution was cooled to 0°C and carefully quenched with methanol and then water. The mixture was extracted with dichloromethane. The organic layer was washed three times with water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography was used to yield 4-[5-(3-{(tert-butoxy-carbonyl)[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1, ethyl 3-thiazol-2-yl]-4-methoxy-cyclohexanecarboxylate. MS ESI: [M + H]+ m/z 621.2.
Step 2: To the product from Step 1 (0.15 g, 0.243 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1.48 g, 12.98 mmol) and the reaction was stirred to completion. The reaction was diluted with water and the mixture extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 4-methoxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl) ethyl -1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M + H]+ m/z 521.2.
Step 3: To the product from Step 2 (0.13, 0.24 mmol) in methanol (1 ml) was added potassium hydroxide (1 M in water, 0.24 ml, 0.24 mmol) and the reaction was stirred at room temperature overnight. The reaction was quenched with hydrochloric acid (2N in water) and the solution was extracted 3 times with dichloromethane. The combined organic layer was concentrated and the residue was subjected to purification by supercritical fluid chromatography with a 2.1 X 25 cm OJ-H, 5 µM column. The mobile phase was a 2:8 methanol/CO2 with a flow rate of 70 ml/min with a 12 minute lead time to produce: 2-({3-[2-(cis-4-carboxy-) trifluoroacetate 1-methoxy-cyclohexyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)-4-(trifluoromethyl)pyrimidin-1-yl (0.03 g, 19% yield). MS ESI: [M + H]+ m/z 493.1. 1H NMR (500 MHz, CDCl 3 ) δ 8.64 (s, 1H), 7.93 (m, 2H), 7.28 (s, 1H), 7.12 (s, 1H), 7. 07 (d, J = 4.9, 1H), 3.27, (s, 3H), 2.41 (s, 3H), 2.29 (m, 1H), 1.96 (m, 8H) ). Activity of rhSYK = +++. 2-({3-[2-(trans-4-carboxy-1-methoxy-cyclohexyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)-4-(trifluoromethyl)pyrimidin-trifluoroacetate 1-10 (0.02 g, 15% yield). MS ESI: [M + H]+ m/z 493.1. 1H NMR (600 MHz, CDCl 3 ) δ 8.58 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7 .08 (s, 1H), 7.04 (d, J = 5.0, 1H), 3.16 (s, 3H), 2.64 (s, 1H), 2.37 (s, 3H), 2.05 - 1.89 (m, 8H). Activity of rhSYK = +++.
EXAMPLE 41 1-Amino-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl acid ]cyclohexanecarboxylic

Step 1: 1-{[(9H-fluoren-9-yloxy)carbomyl]amino}-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl acid ]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxylic acid (0.079 g, 0.11 mmol) was dissolved in DMF (1.0 ml). Piperidine (0.086 g, 1.01 mmol) was added. After 15 minutes, the reaction mixture was directly purified by reverse phase HPLC to yield 1-amino-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin- acid] 2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane carboxylic (0.005 g, 0.01 mmol) as its TFA salt. MS ESI: [M + H]+ m/z 494.1. 1H NMR (600 MHz, CD3OD) δ 8.70 (d, J = 4.9, 1H), 8.04 (s, 1H), 7.94 - 7.80 (m, 2H), 7. 69 (d, J = 7.6, 1H), 7.52 - 7.42 (m, 1H), 7.42 - 7.34 (m, 1H), 7.18 - 7.00 ( m, 2H), 2.60 - 2.42 (m, 2H), 2.36 (s, 3H), 2.28 - 2.07 (m, 4H), 2.05 - 1.89 (m, 2H). rhSYK activity = +++. The starting material was prepared generally following the procedures described in Examples 32 and 33 using commercially available 1-{[{9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxocyclohexane carboxylic acid.
EXAMPLES 42(1) AND 42(2) AND 42(3) AND 42(4) (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{ acid) [4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (1R,4S)-4-hydroxy-2,2-dimethyl-4-[5 -(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (1S,4S)-4-hydroxy- 2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (1R,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3- thiazol-2-yl]cyclohexane-carboxylic

Method 1
Lithium diispropylamide (1.31 M, 10.0 ml, 13.1 mmol) was cooled to -78°C and N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]- 4-(trifluoromethyl)-pyrimidin-2-amine (INTERMEDIATE 4, 2.0 g, 5.95 mmol) in THF (20 ml) was added portionwise. Under stirring at -78°C more lithium diisopropylamide (1.31M, 4.55ml, 5.95mmol) was added. In a separate flask, lithium diisopropylamide (1.31 M, 10.0 ml, 13.1 mmol) was cooled to 0°C and 2,2-dimethyl-4-oxocyclohexanecarboxylic acid (2.02 g, 11, 9 mmol) in THF (20 ml) was added. The resulting carboxylate anion solution was transferred via cannula to the previously prepared thiazole anion solution, maintaining an internal reaction temperature below -68°C. The resulting mixture was stirred at -78°C for 1 hour, then methanol (5 ml) was added and the reaction mixture allowed to warm to room temperature. The reaction mixture was poured into water (200 ml) and extracted with MTBE (2x). The layers were separated and the aqueous portion was acidified to pH = 3 with 2N aqueous HCl then extracted with ethyl acetate (2x). The combined organic portions were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give a yellow foam. The foam was then purified and the enantiomers separated via supercritical fluid chromatography (30% MeOH:CO2) to give the acid (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-( 3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic (Example 42(1), 12.9 g, 25.5 mmol, 21 %) as a yellow solid. MS ESI: [M + H]+ m/z 507.1. 1H NMR (500 MHz, DMSO-d6) δ 12.13 - 11.86 (br s, 1H), 10.24 (s, 1H), 8.82 (m, 1H), 7.94 ( s, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.27 (m, 1H), 7.14 (s, 1H), 5.89 ( s, 1H), 2.31 (s, 3H), 2.16 (d, J = 12.7, 1H), 2.02 (m, 1H), 1.86 (m, 3H), 1.64 (d, J = 13.8, 1H), 1.57 (d, J = 13.1.1H), 1.11 (s, 3H), 0.99 (s, 3H). Activity of rhSYK = +++. (1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1 acid, 3-thiazol-2-yl]cyclohexanecarboxylic acid, (1S,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2 -yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid and (1R,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{ [4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (Examples 42(2), 42(3), 42(4)) were prepared from a in a manner analogous to that described above for the (1S,4R) isomer. MS ESI: [M + H]+ m/z 507. rhSYK activity: +++ Method 2 for preparing Example 42(1)
Step 1: Methyl (1S)-2,2-dimethyl-4-oxocyclohexanecarboxylate
NADPH-dependent ketoreductase KRED-119 (668 mg, 3% w/w, available from Codexis, Inc., Redwood City, CA), NADP (668 mg, 3% w/w), glucose dehydrogenase CDX-901 (668 mg, 3% w/w, available from Codexis, Inc., Redwood City, CA) and D-(+)-glucose (11.16 g, 61.9 mmol) were dissolved in KH2PO4/K2HPO4 buffer solution (0, 1 M aqueous, pH = 6.8, 445 ml) at room temperature. In a separate vial, racemic methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (INTERMEDIATE 24, 22.26 g, 113 mmol) was dissolved in DMSO (6 ml) and the resulting solution was added to the buffered KH2PO4/K2HPO4 solution. described above. The pH of the combined mixture was adjusted to 6.9 with 17.6 M aqueous NaOH solution and the reaction mixture stirred for 19 hours at pH 6.9. The pH was adjusted to 4 using 11.7 M HCl solution (aq.) and the reaction mixture was stirred for 30 minutes, then MTBE (100 ml), 2-propanol (100 ml) and sodium chloride (40 ml). .0 g) were added. The phases were separated and the organic layer was filtered through a pad of Solka Floc 200. The aqueous layer and the residual aqueous layer from the filtrate were combined and then extracted with MTBE (100 ml). The combined organic layers were concentrated in vacuo to 100 ml, and treated twice with sodium bisulfite (7.03 g, 67.6 mmol) and water (100 ml), each time the biphasic mixture was stirred vigorously for 30 minutes. The combined aqueous phase was treated with potassium carbonate (22.0 g, 159.2 mmol) then diluted with MTBE (100 ml) and the layers were separated. The combined organic layers were concentrated in vacuo to yield (1S)-2,2-dimethyl-4-oxo-cyclohexanecarboxylate (9.66 g, 96.2% ee) as an oil. MS ESI: M+. m/z 184. 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3H), 2.62 (t, J = 6.6, 1H), 2.57 (m, 1H), 2 .44 (dd, J = 13.7.1.8, 1 H), 2.29 (m, 1 H), 2.19 (d, J = 13.7, 1 H), 2.11 (m , 2H), 1.07 (s, 3H), 1.00 (s, 3H).
Step 2: (1S,4R)-4-hydroxy-2,2-dimethyl-4-(1,3-thiazol-2-yl) cyclohexanecarboxylic acid hydrate
To a solution of methyl (1S)-2,2-dimethyl-4-oxocyclohexanecarboxylate (10 g, 54.28 mmol)) in THF (16.3 g) was added more THF (184 ml) followed by thiazole (6.93 g, 81.42 mmol). The resulting solution was then cooled to -78°C. Boron trifluoride diethyletherate (9.24g, 65.14 mmol) was added in 24 minutes and the resulting mixture aged at -78°C for 5 minutes. n-Butyllithium (2.5M in hexanes, 20.05 g, 71.98 mmol) was added to the subsurface of the mixture in 4 hours and the mixture was aged for 15 mins. Sodium hydroxide (1M aqueous solution, 54.3 ml, 54.3 mmol) was added followed by MTBE (54 ml) and the mixture was warmed to 20°C. The aqueous layer was separated and the organic layer was washed with a semi-saturated aqueous solution of sodium chloride (54 ml) resulting in a pale yellow solution of (1S,4R)-4-hydroxy-2,2-dimethyl-4- methyl (1,3-thiazol-2-yl)cyclohexane carboxylate, which was then concentrated under partial vacuum to a low volume. Methanol (124 ml) was added and the solution concentrated to an oil under partial vacuum. The solution was then diluted with methanol (124 ml) and heated to 40°C. A 1M sodium hydroxide solution (92ml, 92.0mmol) was added in 5 minutes and the resulting mixture heated to 50°C then aged for 16 hours before being cooled to 20°C. The solution was washed three times with dichloromethane (124 ml, 62 ml, 62 ml) and the aqueous methanol solution of the product was crystallized by the addition of 6M aqueous HCl (15.3 ml, 92 mmol) in 30 mins. The slurry was aged for 2 hours after which the mixture was concentrated under partial vacuum to a total volume of 124 ml. The solid was collected by filtration and washed with water-methanol (1:1 v:v, 62 ml) then water (62 ml) to give the title compound (11.44 g, 41.86 mmol, 99.9% and e) as a light yellow solid. MS ESI : [M + H]+ 256.1 1H NMR (400 MHz, DMSO-d6) : 11.89 - 12.09 (br s, 1H), 7.67 (d, J = 3.5 Hz , 1H), 7.53 (d, J = 3.5Hz, 1H), 5.79 (s, 1H), 3.36 (br s, 2H), 2.13 - 2.20 ( m, 2H), 1.95 - 2.09 (m, 1H), 1.76 - 1.91 (m, 3H), 1.53 - 1.65 (m, 2H), 1.11 (s , 3H), 0.99 (s, 3H).
Step 3: N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine
To a solution of 3-bromo-5-methylaniline (45.77 g, 246 mmol) in toluene (500 ml) were sequentially added 2-chloro-4-(trifluoromethyl)pyrimidine (53.9 g, 295 mmol) and acid methanesulfonic acid (28.4 g, 295 mmol). The resulting solution was heated to 105 °C overnight. The resulting mixture was cooled, diluted with water (500 ml) and adjusted to pH 14 by the addition of a concentrated aqueous solution of sodium hydroxide (26.6 g of a solution containing 320 mmol of sodium hydroxide). The resulting solution was extracted with MTBE (500 ml), the layers separated, and the organic layer subsequently washed with water (300 ml) then 50% saturated brine solution (200 ml). The organic layer was concentrated in vacuo to 200 ml resulting in crystallization of the product. To the slurry, heptane (660 ml) was added in 40 minutes followed by a 2 hour aging at 20°C. The solid was isolated by filtration, washed with heptane (200 ml) and dried in a vacuum oven at 40°C overnight to give the title compound (69.5 g, 209 mmol) as a pale yellow solid. . MS ESI: [M + H]+ m/z 334.0. 'H NMR (400 MHz, CDCl3): δ 8.68 (d, J = 4.9 Hz, 1H); 7.79 (s, 1H); 7.30 (s, 2H); 7.10 - 7.06 (m, 2H); 2.36 (s, 3H).
Step 4: (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-acid 1,3-thiazol-2-yl]cyclohexane carboxylic A mixture of the product from Step 2 (8.5 g, 31.2 mmol), the product from Step 3 (11 g, 33.4 mmol), palladium acetate (II) (0.15 g, 0.68 mmol), pivalic acid (3.5 g, 35.3 mmol), potassium carbonate (15.1 g, 109 mmol) and diadamantyl n-butyl phosphine (0, 74 g, 2.1 mmol) was purged with nitrogen. Dimethyl acetamide (60 ml) was added and the suspension was purged with nitrogen. The mixture was stirred at 120°C for 20 hours, cooled and poured into water (90 ml) and MTBE (40 ml). The aqueous phase was separated and washed with MTBE (2x). The aqueous phase was acidified with 6N HCl to pH <1 and extracted with MTBE (1x). The organic phase was washed with water (2x) then MBTE was distilled off to concentrate the solution. Acetonitrile was added to the residue resulting in crystallization of the title compound, which was isolated by filtration and dried in vacuo. The crude product was recrystallized from MeCN:THF (3:1) to give the acid (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[ 4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexane carboxylic (11.9 g, 23.4 mmol) as a yellow solid. MS ESI: [M + H]+ m/z 507.1. 1H NMR (400 MHz, DMSO-d6) δ 12.03 - 11.95 (br s, 1H), 10.24 (s, 1H), 8.84 (d, J = 4.7, 1H ), 7.94 (s, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.27 (d, J = 4.8, 1H), 7. 13 (s, 1H), 5.89 (s, 1H), 2.32 (s, 3H), 2.16 (d, J = 12.7, 1H), 2.10 - 1.95 (m, 1H), 1.86 (m, 3H), 1.65 (d, J = 13.8, 1H), 1.59 (d, J = 13.1.1H), 1. 13 (s, 3H), 1.01 (s, 3H). rhSYK activity: +++
EXAMPLE 42(1)-Na(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino sodium }phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate Method 1
(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3 acid -thiazol-2-yl]cyclohexane carboxylic (9.8 mg, 0.019 mmol) was dissolved in acetonitrile (20 µl) and water (20 µl). Sodium hydroxide (19 µl, 0.019 mmol) was added, and the mixture was heated at 35°C for 10 minutes. The mixture was allowed to cool to room temperature, diluted with water, frozen to a solid, and lyophilized to dryness to yield (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3- sodium methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxylate. Method 2
(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3 acid -thiazol-2-yl]cyclohexane carboxylic (7.15 g, 14.12 mmol) was dissolved in tetrahydrofuran (35 ml). Sodium hydroxide (10 M, 1.383 ml, 13.83 mmol) was added, and the mixture was aged for 15 minutes. Ethyl acetate (50 ml) was slowly added over 45 minutes and the mixture was aged for 1 hour at 20°C. Another aliquot of ethyl acetate (25 ml) was added and 55 ml of solvent was removed in vacuo. The slurry was filtered and washed with ethyl acetate (35 ml). The solid was dried in vacuo at 70°C to yield the title compound (7.02 g, 13.28 mmol). MS ESI: [M + H]+ m/z 507.1. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J = 4.9, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.48 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.12 (s, 1H), 5.82 (br s, 1H), 2.31 (s, 3H), 1.96 - 1.85 (m, 1H), 1.84 - 1.68 (m, 4H), 1.60 - 1.45 (m, 2H), 1.12 (s, 3H), 1.01 (s, 3H). rhSYK activity = +++
EXAMPLE 42(1)-K (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino} potassium phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-( trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane carboxylic (9.8 mg, 0.019 mmol) was dissolved in acetonitrile (20 µl) and water (20 µl). Potassium hydroxide (19 µl, 0.019 mmol) was added, and the mixture was heated at 35°C for 10 minutes. The mixture was allowed to cool to room temperature, diluted with water, frozen to a solid, and lyophilized to dryness to yield (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3- potassium methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M + H]+ m/z 507.1. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J = 4.9, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.12 (s, 1H), 5.97 (s, 2H ), 2.31 (s, 3H), 1.92 - 1.82 (m, 2H), 1.81 - 1.65 (m, J = 13.8, 5H), 1.54 - 1.48 (m, 1H), 1.47 - 1.39 (m, 1H), 1.05 (s, 3H), 0.95 (s, 3H). rhSYK activity = +++
EXAMPLE 45 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1- tert-butyl carboxylate

At -78°C, INTERMEDIATE 4 (200 mg, 0.595 mmol) in THF (3.0 ml) was added to LDA (892 µl, 1.784 mmol) and the reaction aged for 10 minutes followed by the addition of 4-oxopiperidino- tert-butyl 1-carboxylate (474 mg, 2.379 mmol). The reaction was allowed to warm slowly to -20°C in 4 hours. To the mixture, saturated aqueous ammonium chloride solution was added, and the product was extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layer was dried, filtered and the solvent reduced by rotovap. The residue was purified by column chromatography on silica gel (0 to 50% ethyl acetate in DCM) to give 260 mg (0.485 mmol, 82%) of 4-hydroxy-4-[5-(3-methyl-). tert-butyl 5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate as yellowish white solid. MS ESI: [M + H]+ m/z 536.2. '11 NMR (600 MHz, CDCl3 ): δ 8.60 (d, J = 4.8 Hz, 1H); 7.81 (apr s, 2H); 7.74 (br s, 1H); 7.28 (s, 1H); 7.02 (s, 1H); 7.00 (d, J = 4.8 Hz, 1H); 4.0 (br s, 2H); 3.28 (br s, 2H); 2.34 (s, 3H); 2.09 (m, 2H); 1.88 (m, 2H); 1.41 (s, 9H). rhSYK = ++
The compounds in the following Table(s) were prepared as the free base in a manner analogous to that described in Example 45: TABLE 45

EXAMPLE 46 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol
To 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate of tert-butyl (50 mg, 0.093 mmol) in DCM (1 ml) was added 144 µL of TFA (20 eq) and the reaction stirred at room temperature for 4 h. To the mixture, saturated aqueous NaHCO3 was added and extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layer was dried, filtered. The solvent was reduced in vacuo to give 40 mg (0.092 mmol, 98%) of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1. 3-thiazol-2-yl]piperidin-4-ol. MS ESI: [M + H]+ m/z 436.2. »H NMR (600 MHz, DMSO-d6): δ 8.81 (d, J = 4.7 Hz, 1H); 7.93 (m, 2H), 7.44 (s, 1H); 7.25 (d, J = 4.9 Hz, 1H); 7.13 (s, 1H); 5.97 (br s, 1H), 2.78 - 2.98 (m, 4H); 2.29 (s, 3H); 1.93 - 1.98 (m, 2H), 1.63 - 1.65 (m, 2H). rhSYK activity = +++
The compounds in the following Table(s) were prepared in a manner analogous to that described in Examples 45/46: TABLE 46

EXAMPLE 47 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1- carboxamide

To 15 mg (0.034 mmol) of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin- 4-ol in THF/Water (3:1, 1 ml) was added 4.2 mg (0.052 mmol, 1.5 eq) of potassium cyanate and 2N hydrochloric acid (22 µL, 1.3 eq). The mixture was heated at 50°C for 6 h and then a further 1.5 eq of potassium cyanate and 1.5 eq of HCl were added and the mixture stirred at 50°C overnight. The reaction was diluted with saturated aqueous NaHCO3 and was partitioned with ethyl acetate. The organic layer was washed with water and dried, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) to give 12 mg (0.025 mmol, 73%) of 4-hydroxy-4-[5-(3-methyl- 5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide as yellowish white solid. MS ESI: [M + H]+ m/z 479.2. Ul1 NMR (600 MHz, CD3OD): δ 8.68 (d, J = 4.8 Hz, 1H); 7.99 (s, 1H); 7.87 (s, 1H); 7.40 (s, 1H); 7.10 (m, 2H); 3.91 (m,2H); 3.28 (m, 2H); 2.34 (s, 3H); 2.16 (m, 2H); 1.83 (m, 2H). rhSYK activity = +++
EXAMPLE 49 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1- sulfonamide

To a solution of ({4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2- tert-butyl yl]piperidin-1-yl}sulfonyl)-carbamate (45 mg, 0.073 mmol) in DCM (0.7 ml) was added TFA (0.120 ml, 1.5 mmol) and the reaction was stirred at temperature for 80 minutes, then more TFA (0.120 ml, 1.5 mmol) was added. After 90 minutes most volatiles were removed by N2 flow and vacuum. The residue was diluted with saturated aqueous NaHCO3 and ethyl acetate. The combined organic layers were dried and evaporated to give 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole -2-yl]-piperidine-1-sulfonamide (31 mg, 0.06 mmol, 82% yield). MS ESI: [M + H]+ m/z 515.2. 'II NMR (600 MHz, CDCl 3 ): δ 8.59 (d, J = 4.8 Hz, 1H); 7.87 (s, 1H); 7.81 (s, 1H); 7.25 (s, 1H); 7.02 (s, 1H); 7.00 (d, J = 4.8 Hz, 1H); 3.59 (d, J = 12 Hz, 2H); 3.14 (m, 2H); 2.34 (s, 3H); 2.26 (m, 2H); 1.94 (d, J = 12 Hz, 2H). rhSYK activity = +++
EXAMPLE 50 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1-(phenylsulfonyl)piperidin- 4-ol
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH 2 Cl 2 (1 ml). N,N-diisopropylethylamine (50 µl, 0.287 mmol) and benzenesulfonyl chloride (29 µl, 0.230 mmol) were added sequentially. The solution was stirred overnight at room temperature, then concentrated in vacuo in a Genevac. The resulting residue was dissolved in DMSO and purified by HPLC (48 to 82 % CH3CN:H2O) to give 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl] amino}phenyl)-1,3-thiazol-2-yl]-1-(phenylsulfonyl)piperidin-4-ol. MS ESI: [M + H]+ m/z 576.1. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 9.2 Hz , 2H), 7.75 (dd, J = 8.7, 10.3 Hz, 2H), 7.73 (s, 1H), 7.65 (t, J = 8.1 Hz, 1H) , 7.43 (s, 1H), 7.25 (d, J = 5.1Hz, 1H), 7.12 (s, 1H), 6.10 (s, 1H), 3, 54 (d, J = 12.3 Hz, 1H), 2.58 (t, J = 12.3 Hz, 2H), 2.54 - 2.37 (m, 1H), 2.28 (s , 3H), 2.08 (t, J = 16.1 Hz, 2H), 1.80 (d, J = 14.6 Hz, 2H). rhSYK activity = ++
EXAMPLE 51 1-{4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl] piperidin-1-yl}ethanone

To a mixture of acetic acid (9 µl, 0.15 mmol) and Si-carbonyl diimidazole (266 mg, 0.287 mmol) was added a solution of 4-[5-(3-methyl-5-{[4-(trifluoromethyl) )pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50mg, 0.115mmol) and hydroxy-benzotriazole (26mg, 0.17mmol) dissolved in N,N-dimethylformamide, and the resulting suspension was stirred in a Bohdan block overnight at room temperature. The reaction mixture was filtered and concentrated in vacuo, and the resulting residue was dissolved in DMSO and purified by HPLC (30 to 64% CH3CN:H2O) to give 1-{4-hydroxy-4-[5- (3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone. MS ESI: [M + H]+ m/z 478.1. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J = 5.2Hz, 1H), 7.95 (s, 2H), 7.44 (s, 1H), 7.26 (d, J = 5.1Hz, 1H), 7.14 (s, 1H), 6.30 (s, 1H), 4.25 - 3.99 (m, 1H), 3.73 (m, 1H), 3.41 - 3.34 (m, 1H), 3.07 - 2.97 (m, 1H), 2.47 (s , 3H), 2.32 (s, 3H), 2.25 - 2.14 (m, 1H), 1.93 (m, 2H), 1.75 (m, 1H). rhSYK activity = +++
EXAMPLE 52 4-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl] piperidine-1-carboxamide
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH 2 Cl 2 (1 ml). N,N-diisopropylethylamine (30 µl, 0.172 mmol) and methyl isocyanate (7 µl, 0.130 mmol) were added sequentially. The solution was stirred overnight at room temperature, then concentrated in vacuo in a Genevac. The resulting residue was dissolved in DMSO and purified by HPLC (30 to 64% CH3CN:H2O) to give 4-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-piperidine-1-carboxamide (36 mg, 0.073 mmol). MS ESI: [M + H]+ m/z 493.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J = 5.2Hz, 1H), 7.93 (s, 2H), 7.44 (s, 1H), 7.25 (d, J = 5.1Hz, 1H), 7.13 (s, 1H), 6.43 (d, J = 4.8Hz, 1H) , 6.15 (s, 1H), 3.83 - 3.74 (m, 2H) (d, J = 14.0 Hz, 2H), 3.07 (t, J = 14.5 Hz, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.98 - 1.82 (m, 2H), 1.65 (d, J = 13.9 Hz, 2H). rhSYK activity = +++
EXAMPLES 53(1) AND 53(2) 2-{3-Hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1, acid 3-thiazol-2-yl]azetidin-1-yl}-2-methyl-propanoic acid 2-[(2-{3-Hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl) ) pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azetidin-1-yl}-2-methylpropanoyl)oxy-]-2-methyl-propanoic OH

A solution of 3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azetidin-3-ol (50 mg, 0.123 mmol), 2-bromo-2-methyl propionic acid (20.5 mg, 0.123 mmol), and triethylamine (0.043 ml, 0.307 mmol) in tetrahydrofuran (1 ml) was heated in a microwave for 100 minutes for 5 minutes. An additional amount of 2-bromo-2-methyl propionic acid (8 mg, 0.048 mmol), triethylamine (0.060 ml, 0.428 mmol), and tetrahydrofuran (1 ml) were added and the reaction was heated in a microwave oven for a additional 10 minutes. The reaction was concentrated and then purified by reverse phase HPLC (15% to 50% acetonitrile in water). Fractions containing the desired product were lyophilized to produce:
2-{3-Hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azetidin- acid 1-yl}-2-methyl-propanoic (Example 53(1), 32.5 mg). MS ESI: [M + H]+ m/z 494.1. 'II NMR (500 MHz, d6-DMSO): δ 10.30 (s, 1H); 8.85 (d, J = 4.9 Hz, 1H); 8.19 (s, 1H); 8.04 (s, 1H); 7.73 (s, 1H); 7.47 (s, 1H); 7.29 (d, J = 4.9 Hz, 1H); 7.22 (s, 1H); 4.82 - 4.50 (m, 2H); 4.33 - 4.11 (m, 2H); 2.33 (s, 3H); 1.53 (s, 6H). rhSYK activity = +++
2-[(2-{3-Hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-acid yl]azetidin-1-yl}-2-methylpropanoyl)oxy-]-2-methyl-propanoic (Example 53(2), 8 mg). MS ESI: [M + H]+ m/z 580.2. »H NMR (500 MHz, d6-DMSO): δ 10.29 (s, 1H); 8.83 (d, J = 4.6 Hz, 1H); 8.18 (s, 1H); 8.03 (s, 1H); 7.81 (s, 1H); 7.46 (s, 1H); 7.29 (d, J = 5.1 Hz, 1H); 7.21 (s, 1H); 4.83 (br s, 1H); 4.72 - 4.41 (m, 2H); 4.34 - 4.12 (m, 1H); 2.32 (s, 3H); 1.52 (brs, 12H). rhSYK activity = +++
EXAMPLES 54(1) AND 54(2) {[4-hydroxy-4-(5-{3-[(4-methoxy-pyrimidin-2-yl)amino]-5-methyl-phenyl}-1,3- thiazol-2-yl)piperidin-1-yl]sulfonyl}carbamate methyl 4-Chloro-4-(5-{3-[(4-methoxy-pyrimidin-2-yl)amino]-5-methylphenyl}-1 ,3-thiazol-2-yl)piperidine-1-sulfonamide

At 0°C, chlorosulfonyl isocyanate (16.38 µl, 0.189 mmol) in dichloromethane was added methanol (7.63 µl, 0.189 mmol). After stirring for 30 min, to the mixture were added 4-(5-{3-[(4-methoxy-pyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)piperidine -4-ol (50 mg, 0.126 mmol) and triethylamine (52.6 µl, 0.377 mmol). The reaction was aged for 20 minutes and the ice bath removed, and stirred for 3 hours. LCMS indicates product formation. The material was directly subjected to column chromatography on silica gel (0 to 100% 10:1 ethyl acetate: methanol in hexanes) to yield: {[4-hydroxy-4-(5-{3-[(4- methyl methoxy-pyrimidin-2-yl)amino]-5-methyl-phenyl}-1,3-thiazol-2-yl)piperidin-1-yl]sulfonyl}carbamate (7 mg, 0.013 mmol, 10%). MS ESI: [M + H]+ m/z 535.1. '11 NMR (600 MHz, CD3 OD): δ 8.09 (d, J = 6.0 Hz, 1H); 7.91 (s, 1H); 7.88 (s, 1H); 7.38 (s, 1H); 7.08 (s, 1H); 6.23 (d, J = 6.0 Hz, 1H); 3.98 (s, 3H); 3.73 (m, 3H); 3.34 (m, 2H); 3.19 (m, 2H); 2.35 (s, 3H); 2.25 (m, 2H); 1.90 (m, 2H). Activity of rhSYK = +++ 4-Chloro-4-(5-{3-[(4-methoxy-pyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)piperidine -1-sulfonamide (18 mg, 0.036 mmol, 28%). MS ESI: [M + H]+ m/z 495.2. 'II NMR (500 MHz, CD3 OD): δ 8.09 (d, J = 6.0 Hz, 1H); 7.89 (s, 2H); 7.38 (s, 1H); 7.09 (s, 1H); 6.24 (d, J = 6.0 Hz, 1H); 4.37 (m, 1H); 3.99 (s, 3H); 3.97 (m, 1H); 3.68 (m, 1H); 3.36 (m, 1H); 2.35 (s, 3H); 2.19 (m, 2H); 1.94 (m, 2H). Activity of rhSYK = +++ The following examples were prepared in a manner analogous to that described in Examples 47 to 54 by N,N-disubstituted urea (Example 47), disubstituted t-butyl sulfamoyl carbamate (Example 48), N sulfuric diamide ,N,N'-trisubstituted (Example 49), N,N-disubstituted sulphonamide or sulfamic acid (Example 50), amide (Example 51), N,N,N'-trisubstituted urea (Example 52), N-alkylated azetidine , pyrrolidine, piperidine or azepane (Example 53), and N,N,N'-trisubstituted sulfamoyl carbamate (Example 54). TABLE 54A

TABLE 54D

TABLE 54E

Example 55 5-{cis-4-Hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]cyclohexyl}-1,3,4-oxadiazol-2(3H)-one

Step 1: cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl] acid cyclohexanecarboxylic acid (150 mg, 0.313 mmol), hydrazinecarboxamide hydrochloride (52.4 mg, 0.470 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (149 mg) , 0.392 mmol), and diisopropylethylamine (164 µl, 0.940 mmol) were absorbed in dimethylformamide (1.3 ml) under argon. The vessel was sealed and sealed at 125°C for 18 hours. The reaction mixture was cooled to room temperature, filtered, and directly subjected to reverse phase HPLC (water-acetonitrile, trifluoroacetic acid modifier). This purification yielded 5-{cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2- yl]cyclohexyl}-1,3,4-oxadiazol-2(3H)-one as a white solid (39.1 mg, 0.075 mmol, 24% yield). MS ESI: [M + H]+ m/z 519.1. 1H NMR (500 MHz, dmso) δ 12.10 (s, 1H), 10.25 (s, 1H), 8.82 (d, J = 4.8, 1H), 8.02 - 7 .88 (m, 2H), 7.45 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.15 (s, 1H), 6.06 (s, J = 27.1, 1H), 2.67 (s, 1H), 2.31 (s, 3H), 2.09 - 1.75 (m, 8H). rhSYK activity = +++
Example 56 1-[5-(3-Methyl-5-{[4-(propan-2-yl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl] HCl salt cyclobutanol

Step 1: Acetic acid (0.192 ml, 3.35 mmol) was added to commercially available 2-chloro-4-(propan-2-yl)pyrimidine (0.5 g, 3.19 mmol) and 3-bromo-5 -methylaniline (0.900 g, 3.19 mmol) suspended in dioxane (6.39 ml). The reaction was heated to 120°C (bath temperature) overnight. Then, the reaction was cooled to room temperature and purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give N-(3-bromo-5-methylphenyl)-4-(propan-2-yl) pyrimidin-2-amine (959.8 mg, 3.13 mmol, 98%) as a white solid.
Step 2: A 40 ml vial was charged with the product from Step 1 (500 mg, 1.633 mmol), bis(pinacolato)diboron (456 mg, 1.796 mmol), 1,1'-bis(diphenyl-dichloride) complex phosphino)ferrocene-palladium(II) - dichloromethane (40.0 mg, 0.049 mmol) and potassium acetate (481 mg, 4.90 mmol). The solid mixture was dissolved with DMSO (6.5 ml) and heated to 120°C. After stirring for 2 hours, the mixture was extracted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes to give N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)phenyl]-4-(propan-2-yl)pyrimidin-2-amine (249 mg, 0.705 mmol, 43.2% yield) as a white solid.
Step 3: A 2 gram vial (120 g) was charged with the product from Step 2 (100 mg, 0.283 mmol) 1-(5-bromo-1,3-thiazol-2-yl)cyclobutanol (INTERMEDIATE 1.72 0.9 mg, 0.311 mmol), butyldi-1-adamantylphosphine (14.21 mg, 0.040 mmol), palladium(II) acetate (4.45 mg, 0.020 mmol), potassium fluoride (49.3 mg, 0.849 mmol) ), THF (1166 μl) then water (348 μl). The vial was sealed and then heated to 80°C overnight. Then the reaction was cooled to room temperature. The reaction mixture was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes. Fractions were combined, concentrated and redissolved in acetonitrile/water + HCl (1 M, 200 µl) and lyophilized to give the HCl salt of 1-[5-(3-methyl-5-{[4-(propan-2 -yl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclobutanol (16.8 mg, 0.040 mmol, 14.23 % yield) as a white solid. MS ESI: [M + H]+ m/z 381.1. 'H NMR (500 MHz, CDCl 3 ): δ 9.66 (s, 1H); 8.38 (d, J = 5.5 Hz, 1H); 8.02 (s, 1H); 7.97 (s, 1H); 7.50 (s, 1H); 7.07 (m, 1H); 6.79 (m, 1H); 2.90 (m, 1H); 2.53 (m, 2H); 2.33 (m, 2H); 2.30 (s, 3H); 1.88 (m, 2H); 1.25 (d, J = 7Hz, 6H). rhSYK activity = +++
The following examples were prepared in a manner analogous to that described in Example 56. TABLE 56

Example 59 N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)-pyrimidin-2-amine

Step 1: To a solution of oxetan-3-one (600 mg, 8.33 mmol) and 2-methylpropane-2-sulfinamide (1.01 g, 8.33 mmol) in tetrahydrofuran (14 ml), titanium ethoxide (3.45 ml, 16.65 mmol) was added. The mixture was stirred at 50°C overnight. The reaction mixture was poured into brine. the suspension was filtered through celite and washed with ethyl acetate. The solution was partitioned between ethyl acetate and brine. The organics were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (0 to 70% ethyl acetate in hexanes) to yield 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (692 g, 3.20 mmol, 38% yield) as a clear oil. MS ESI: [M + H]+ m/z 176.1.
Step 2: A solution of lithium diisopropylamine (1.8 M, 4.96 ml, 8.92 mmol) in THF (8 ml) was placed under an argon atmosphere and cooled to -78°C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 1200 mg, 3.57 mmol) in THF (8 ml) was cooled to -78°C and added dropwise to the LDA solution. The reaction mixture was stirred 30 minutes at -78°C. The product from Step 1 (625 mg, 3.57 mmol) in THF (8 ml) was added dropwise and the reaction was allowed to warm to room temperature overnight. The mixture was quenched with brine, diluted with ethyl acetate. The organics were washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (20 to 100% ethyl acetate in hexanes) to yield 2-methyl-N-{3-[5-(3-methyl-5-{[4-( trifluoromethyl)pyrimidin-2-yl]-amino}-phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfinamide (1.10 g, 2.140 mmol, 60.0% of Yield). MS ESI: [M + H]+ m/z 512.1.
Step 3: To a solution the product from Step 2 (1.01g, 1.964mmol) in methanol (9.8ml), 4M HCl in Dioxane (1.97ml, 7.86mmol) was added. The mixture was stirred at room temperature for 15 minutes. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (40 to 100% ethyl acetate in hexanes) to yield N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5 - yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (386.6 mg, 0.954 mmol, 53.5% yield) as a pale yellow solid. MS ESI: [M + H]+ m/z 408.0. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J = 4.8, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.47 (s, 1H), 7.28 (d, J = 4.9, 1H), 7.17 (s, 1H), 4.87 (d, J =5.6, 2H), 4.58 (d, J = 5.7, 2H), 2.32 (s, 3H).
Example 60 N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl }methanesulfonamide

Step 4: To a solution of N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2- amine (200 mg, 0.491 mmol) and Et3N (82 µl, 0.589 mmol) in dichloromethane (3.9 ml), methanesulfonyl chloride (57 µl, 0.736 mmol) was added. The reaction mixture was stirred at room temperature for 495 minutes. The mixture was then diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10 to 100% ethyl acetate in hexanes) and lyophilized to yield N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)- pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}-methanesulfonamide (113 mg, 0.233 mmol, 47.4% yield) as a white powder. MS ESI: [M + H]+ m/z 486.0. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (m, 2H), 8.11 (s, 1H), 7.99 (s, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 7.21 (s, 1H), 4.91 (dd, J = 6.6, 16.1, 4H), 2 .98 (s, 3H), 2.33 (s, 3H). rhSYK activity = +++
Example 61 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan -3-yl}propane-2-sulfonamide

Step 5: A solution of 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2 -yl]oxetan-3-yl}propane-2-sulfinamide (Example 59, Step 2, 75mg, 0.147mmol) in dichloromethane (1.5ml) was cooled to 0°C. m-CPBA (37.8 mg, 0.219 mmol) was added and the resulting mixture was warmed to room temperature. The reaction mixture was diluted with dichloromethane, washed with 2M NaOH (2x), saturated NaHCO3 (1x), brine (1x), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10 to 100% ethyl acetate in hexanes) and lyophilized to yield 2-methyl-N-{3-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfonamide (45.6 mg, 0.086 mmol, 59.0% yield ) as a light yellow solid. MS ESI: [M + H]+ m/z 510.1. 1H NMR (500 MHz, dmso) δ 10.29 (s, 1H), 8.83 (d, J = 4.9, 1H), 8.29 (s, 1H), 8.09 (s , 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.28 (d, J = 4.9, 1H), 7.18 (s, 1H) , 4.90 (dd, J = 6.6, 33.0, 4H), 2.33 (s, 3H), 1.35 (s, 9H). rhSYK activity = +++
The following examples were prepared in a manner analogous to that described in Examples 59 to 61. TABLE 61B

Example 62
N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-cyclo-propylpyrimidin-2-amine hydrochloride

Step 1: A 20 ml microwave vial was charged with 3-methyl-5-(1,3-thiazol-5-yl)aniline (500 mg, 2.63 mmol), cesium carbonate (2.99 g, 9.20 mmol), 2-chloro-4-cyclopropylpyrimidine (INTERMEDIATE 29, 406 mg, 2.63 mmol), and dioxane (10.4 ml). The system was purged and flushed with argon (3x) before adding XantPhos (228 mg, 0.394 mmol) and palladium(II) acetate (59 mg, 0.263 mmol). The system was then purged and flushed with argon (3 x) before sealing and heating to 100°C for 2 hours. On completion the mixture was cooled to room temperature, diluted with ethyl acetate, filtered through celite washing with ethyl acetate, and concentrated under reduced pressure. Purification by column chromatography on silica gel (0 to 60% ethyl acetate in hexanes) provided 603 mg (1.96 mmol, 74%) of 4-cyclopropyl-N-[3-methyl-5-( 1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine as a yellow solid. MS ESI: [M + H]+ m/z 309.2.
Step 2: To a solution of the product from Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 ml) at -78°C was added LDA (1.62 ml, 2.0 M, 3.24 mmol). The mixture was stirred for 15 minutes at -78°C. N-Cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 ml) was added dropwise at -78°C and the reaction was allowed to warm to room temperature and stirred at 2°C. hours. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3 x 200 ml). The combined organic fractions were washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[ (4-cyclopropyl-pyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M + H]+ m/z 482.2.
Step 3: To a solution of the product from Step 2 (182 mg, 0.38 mmol) in dioxane (3.8 ml) was added 4.0 M hydrochloric acid in dioxane (0.95 ml, 3.78 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to provide 170 mg (0.41 mmol, 109%) of N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-hydrochloride methylphenyl}-4-cyclopropylpyrimidin-2-amine. MS ESI: [M + H]+ m/z 378.2. 1H NMR (600 MHz, d6-DMSO) δ 9.54 (s, 1H), 8.95 (s, 2H), 8.25 (d, J = 4.8, 1H), 8.16 ( s, 1H), 8.10 (s, 1H), 7.40 (s, 1H), 7.11 (s, 1H), 6.83 (d, J = 4.8, 1H ), 2.66 (m, 2H), 2.57 (m, 2H), 2.28 (s, 3H), 2.14 (m, 1H), 2.03 (m, 2H), 1, 10 - 1.04 (m, 4H). rhSYK activity = +++
The following examples were prepared in a manner analogous to that described in Example 62. TABLE 62

Example 63 N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3 diamide -yl} sulfuric

To a solution of N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 59, 25mg, 0.061mmol) in dioxane (600ul), sulfamide (70mg, 0.725mmol) was added. The reaction mixture was stirred at 100°C. The resulting mixture was stirred at 100°C for 4 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10 to 100% ethyl acetate in hexanes) and lyophilized to yield N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl) diamide )pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}sulfuric (16.3 mg, 0.034 mmol, 54.6% yield) as a yellow solid clear. MS ESI: [M + H]+ m/z 487.0. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 2H), 8.85 (m, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H), 7.28 (m, 1H), 7.17 (s, 1H), 6.98 (s, 2H), 5 .02 (m, 2H), 4.84 (m, 2H), 2.32 (s, 3H). rhSYK activity = +++
The compounds in the following Tables were prepared in a manner analogous to that described in Example 63: TABLE 63

Example 64 1-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclobutyl}urea

To a solution of N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 61B-1, 50mg, 0.123mmol) and acetic acid (7µl, 0.123mmol) in THF/water (1.6:1, 2.1ml), potassium cyanate (10mg, 0.123mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was purified by column chromatography on silica (50 to 100% ethyl acetate in hexanes, 0 to 20% methanol in dichloromethane) and lyophilized to yield 1-{1-[5-(3-methyl-5) -{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}urea (31.3 mg, 0.068 mmol, 54.9%) as a white powder . MS ESI: [M + H]+ m/z 449.1. 1H NMR (500 MHz, DMSO-d6 δ 10.23 (s, 1H), 8.82 (d, J = 4.9, 1H), 7.93 (s, 1H), 7.90 ( s, 1H), 7.47 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.15 - 7.00 (m, 2H), 5.58 (s , 2H), 2.63 - 2.51 (m, 2H), 2.32 (m, 5H), 1.96 (m, 2H) rhSYK activity = +++
The following examples were prepared in a manner analogous to that described in Example 64. TABLE 64

Example 66 N-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclobutyl}acetamide

To a solution of N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methyl-phenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 61B- 1.75 mg, 0.185 mmol) and Et3N (25.8 µl, 0.185 mmol) in THF (1000 µl), acetyl chloride (13.15 µl, 0.185 mmol) was added. The mixture was stirred at room temperature for 70 minutes. Additional acetyl chloride (6 µl) was added to drive the reaction to completion. The mixture was stirred for an additional 10 minutes, then diluted with ethyl acetate, washed with saturated 5 NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated to yield N-{1-[5-(3-methyl-5) -{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}acetamide (80.8 mg, 0.171 mmol, 92%). MS ESI: [M + H]+ m/z 480.0. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.93 (s, 1H), 8.83 (d, J = 4.9Hz, 1H), 8. 00 (s, 1H), 7.94 (s, 1H), 7.42 (s, 1H), 7.28 (d, J = 4.9Hz, 1H), 7.14 (s , 1H), 3.32 - 2.60 (m, 2H), 2.43 - 2.41 (m, 2H), 2.31 (s, 3H), 1.99 - 1.95 (m, 2H), 1.88 (s, 3H). rhSYK activity = +++
The compounds in the following Tables were prepared in a manner analogous to that described in Example 66:

Example 107 1-(5-{3-[(4-cyclobutylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol

Step 1: 2,4-Dichloropyrimidine (250mg, 1.68mmol) and ferric acetylacetonate (30mg, 0.08mmol) were taken up in tetrahydrofuran (3.4ml) and the reaction was cooled to -78°C. Cyclobutylmagnesium chloride (0.5M, 3.4ml, 1.68mmol) was added dropwise and the mixture was stirred at -78°C for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic fractions were washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 5% ethyl acetate in hexanes) to provide 121 mg (0.72 mmol, 43%) of 2-chloro-4-cyclobutylpyrimidine as a colorless oil . MS ESI: [M + H]+ m/z 169.1.
Step 2: 2-Chloro-4-cyclobutylpyrimidine (65 mg, 0.39 mmol), INTERMEDIATE 15 (100 mg, 0.39 mmol), and acetic acid (22 µl, 0.39 mmol) were combined in dioxane (1.9 ml) and the mixture was stirred at 120°C for 3 hours. The mixture was cooled to room temperature and directly purified by chromatography on Combíflash silica gel, eluting with ethyl acetate/isohexane to provide 66 mg (0.17 mmol, 44%) of 1-(5-{3-[( 4-cyclobutyl-pyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol. MS ESI: [M + H]+ m/z 393.2. 1H NMR (600 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.33 (d, J = 4.8, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 6.68 (d, J = 5.4, 1H), 6.46 (s, 1H) H), 3.53 - 3.50 (m, 1H), 2.52 - 2.46 (m, 2H), 2.33 - 2.22 (m, 9H), 1.99 (m, 1H), 1.87 - 1.83 (m, 3H). rhSYK activity = +++
The compounds in the following Tables were prepared in a manner analogous to that described in Example 107:

EXAMPLES 110(1) and 110(2) cis-4-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-5-methylphenyl}-1,3-thiazol-2-yl) acid -4-hydroxycyclohexanecarboxylic
trans-4-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylic acid

Step 1: To a vial containing tert-butyl trans-4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylate (125 10 mg, 0, 32 mmol) was added a solution of 2-chloro-4-cyclopropylpyrimidine (INTERMEDIATE 29.57 mg, 0.37 mmol) in dioxane (1.0 ml). Acetic acid (19 µl, 0.33 ml) was added and the reaction was heated at 100°C overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate (10 ml), washed with water (10 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography to give trans-4-(5-{3-[(4-cyclopropyl-pyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl) tert-butyl-4-hydroxycyclohexanecarboxylate (36 mg, 0.071 mmol, 22% yield). ESI: [M + H]+ m/z 507.2.
Step 2: To a flask containing the product from Step 1 (36 mg, 0.071 mmol) was added methanol (0.80 ml) and aqueous sodium hydroxide (1M, 0.14 ml, 0.14 mmol). The reaction was heated at 100°C overnight. The reaction was cooled, acidified with HCl (1M, 0.2 ml, 0.20 mmol) and diluted with water (5 ml) and ethyl acetate (5 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. During the reaction, the starting material is isomerized. The mixture of syn and anti isomers was diluted in DMSO and purified by HPLC to yield: cis-4-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3 acid -thiazol-2-yl)-4-hydroxycyclohexanecarboxylic (example 110(1)). MS ESI: [M + H]+ m/z 451.1. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.48 (s, 1H), 8.26 (d, J = 5.0Hz, 1H), 7. 94 (s, 1H), 7.92 (s, 1H), 7.45 (s, 1H), 7.02 (s, 1H), 6.81 (d, J = 5.0Hz , 1H), 5.90 (s, 1H), 2.28 (s, 3H), 2.20 (m 1H), 2.01 (m, 1H), 1.88 - 1.85 (m 2H), 1.82 - 1.74 (m, 6H), 1.08 - 1.05 (m, 4H). rhSYK activity = +++ trans-4-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylic acid (example 110(2). ESI: [M + H]+ m/z 451.1. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.47 (s, 1 H), 8.26 (d, J = 5.0Hz, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.44 (s, 1H), 7.03 (s, 1H), 6.81 (d, J = 5.0Hz, 1H), 5.90 (s, 1H), 2.42 (m, 1H), 2.28 (s, 3H), 2.09 - 2.06 (m, 2H), 2.02 - 2.00 (m, 1H), 1.84 - 1.82 (m, 4H), 1.66 - 1.63 (m, 2H), 1.08 - 1.05 (m, 4H) rhSYK activity = +++
Example 112 (1S, 4R)-4-(hydroxymethyl)-3,3-dimethyl-1-(5-(3-methyl-5-(4-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)thiazol-2- il) cyclohexanol

Step 1: (1S,4R)-methyl 4-(5-bromothiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (110 mg, 0.316 mmol) was placed in a 25 ml flask under nitrogen and THF (3 ml) was added. LiAlH4 (1M in THF, 0.6 ml, 0.600 mmol) was added in 1 portion and the reaction mixture became a suspension with white gel. After 2 hours methanol was added and solvents were evaporated. The residue was purified by reverse phase HPLC (gradient from 10 to 50% acetonitrile with water + 0.1% TFA) to yield TFA salt (1S, 4R)-4-(hydroxymethyl)-3,3-dimethyl -1-(thiazol-2-yl)cyclohexanol (40 mg, 0.113 mmol, 35.6% yield) as a colorless oil.
Step 2: A 4 ml screw cap pressure flask was charged with N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 2, 74.8 mg, 0.225 mmol ), stir bar, pivalic acid (2.61 µl, 0.023 mmol), potassium carbonate (46.7 mg, 0.338 mmol), TFA salt (1S, 4R)-4-(hydroxymethyl)-3,3-dimethyl -1-(thiazol-2-yl)cyclohexanol (40 mg, 0.113 mmol), and Pd(PPh3)4 (13.01 mg, 0.011 mmol). The flask was closed, evacuated and backfilled with nitrogen 3 times. DMA (0.5 ml) (dry, over molecular sieves, Fluka) was added and the reaction mixture heated to 120°C for 16 hours. LCMS showed product formation and some starting materials remaining. Vacuum filtered and concentrated. The residue was purified by reverse phase HPLC (gradient from 10 to 60% acetonitrile with water + 0.1% TFA) to yield (1S,4R)-4-(hydroxymethyl)-3,3-dimethyl-1- (5-(3-methyl-5-(4-(trifluoromethyl)-pyrimidin-2-ylamino)phenyl)thiazol-2-yl)cyclohexanol (14 mg, 0.023 mmol, 20.51% yield over 2 steps) as a yellow solid. MS ESI: [M + H]+ m/z 492.2. 1H NMR (500 MHz, DMSO-d6) : δ 10.24 (s, 1H), 8.83 (d, J = 4.9Hz, 1H), 7.94 (s, 1H), 7 .92 (d, J = 6.8 Hz, 1 H), 7.46 (s, 1 H), 7.28 (d, J = 4.9 Hz, 1 H), 7.14 (s, 1 H), 3.66 (dd, J = 10.2, 3.5 Hz, 1 H), 3.08 (ap t, J = 10.2 Hz, 1 H), 2.31 (s, 3H) , 1.98 - 1.44 (m, 7H), 0.96 (s, 3H), 0.93 (s, 3H). rhSYK activity = +++
Example 113 (1S, 4R)-4-(5-{3-Cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy acid -2,2-dimethylcyclohexanecarboxylic acid

Step 1: A reaction mixture containing N-[3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylpyrimidin-2- amine (60 mg, 0.171 mmol), (1S, 4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (62.5 mg, 0.179 mmol), the PdCl2(dppf)-CH2Cl2 adduct (27.9 mg, 0.034 mmol), 1,4-dioxane (1.2 ml), water (0.1 ml), and the aqueous bicarbonate solution. sodium (2M, 0.171 ml, 0.342 mmol) were microwaved for 15 minutes at 160°C. The reaction mixture was partitioned between ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate solution (15 ml). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (25 to 50% ethyl acetate/hexanes) to yield (1S, 4R)-4-(5-{3-cyclopropyl-5-[(4 -methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (41.3 mg, 0.084 mmol, 49% yield) as a yellowish white solid.
Step 2: To a solution of the product from Step 1 (41.3 mg, 0.084 mmol) in tetrahydrofuran (0.4 ml) and methanol (0.8 ml) was added sodium hydroxide (1 M in water, 0.153 ml , 0.153 mmol). The reaction mixture was heated to 120°C for 10 minutes in a microwave oven. An additional charge of sodium hydroxide was added (1M in water, 0.300 ml, 0.300 mmol) and the flask was heated once more for 10 minutes at 120°C. On cooling aqueous hydrogen chloride (2M in water, 0.235 ml, 0.470 mmol) was added and the resulting mixture was diluted with 10% v/v isopropanol/chloroform (20 ml), brine (10 ml), and water ( 1 ml). The layers were separated and the aqueous layer was re-extracted with 10% v/v isopropanol/chloroform (10 ml). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. Lyophilization of the residue from methanol/water furnished the acid (1S, 4R)-4-(5-{3-cyclopropyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol- 2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic (34.3 mg, 0.072 mmol, 84% yield) as a yellowish white solid. MS ESI: [M + H]+ m/z 461.1.
The compounds in the following Tables were prepared in a manner analogous to that described in Example 113: TABLE 113A

TABLE 113B
TABLE 113C

EXAMPLE 116
(1S,4R) and (1R,4S)-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methyl-phenyl}-1,3-thiazole acid -2-yl)-4-hydroxy-2,2-5-dimethylcyclohexanecarboxylic acid

Step 1: 2-chloro-5-fluoro-4-methylpyrimidine (50.0 mg, 0.341 mmol), 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]- Racemic methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate (128 mg, 0.341 mmol), Pd(OAc)2 (15.3 mg, 0.0680 mmol), Xantphos (59.2 mg, 0.102 mmol), and Cs2CO3 (222 mg, 0.682 mmol) were combined in a vial and degassed with argon. To this solid mixture was added dioxane (2.0 ml), and the resulting mixture was degassed with argon for 5 minutes. The reaction mixture was heated to 110°C for 1.5 hours. The reaction was cooled to room temperature, then diluted with saturated aqueous NaCl and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica (10 to 30% gradient EtOAc/Hexanes) to yield -4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino Racemic methyl]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (143 mg, 0.295 mmol, 86% yield). MS ESI: [M + H]+ m/z 485.
Step 2: To a solution of (1S,4R)-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)-amino]-5-methylphenyl}-1,3-thiazol- Racemic methyl 2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (70mg, 0.14mmol) in methanol (1ml) was added sodium hydroxide (1M, 0.87ml, 0.87mmol) ). The resulting suspension was heated to 110°C for 10 minutes under microwave irradiation. The reaction was cooled to room temperature, and the pH was adjusted to a range of 3 - 4 (pH paper) using HCl (1N in water). The resulting mixture was extracted with 10% IPA:CHCl3 (3x). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3- acid thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexane carboxylic racemic (58 mg, 0.12 mmol, 58% yield). The racemate was subjected to purification by chiral supercritical fluid chromatography (35% / 65% Methanol/CO2, with a flow rate of 70 ml/min and a conduction time of 4 minutes).
Enantiomer 1 (26 mg, 0.055 mmol, 38% yield). MS ESI: [M + H]+ m/z 471. 1H NMR (500 MHz, DMSO) δ 12.00 (br s, 1H), 9.68 (s, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.47 (s, 1H), 7.05 (m, 1H), 5.89 (br s , 1H), 2.41 (s, 3H), 2.29 (s, 3H), 2.16 (br d, J = 12.5, 1H), 2.02 (m, 1H), 1.84 (br m, 3H), 1.64 (br d, J = 14.0, 1H), 1.58 (br d, J = 13.5, 1H), 1.11 (s, 3H), 1.01 (s, 3H).
Enantiomer 2 (27 mg, 0.057 mmol, 40% yield). MS ESI: [M + H]+ m/z 471. 1H NMR (500 MHz, DMSO) δ 12.00 (br s, 1H), 9.68 (s, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.47 (s, 1H), 7.05 (m, 1H), 5.89 (br s , 1H), 2.41 (s, 3H), 2.29 (s, 3H), 2.16 (br d, J = 12.5, 1H), 2.02 (m, 1H), 1.84 (br m, 3H), 1.64 (br d, J = 14.0, 1H), 1.58 (br d, J = 13.5, 1H), 1.11 (s, 3H), 1.01 (s, 3H).
The compounds in the following Tables were prepared in a manner analogous to that described in Example 116: TABLE 116A

Example 117 cis-4-hydroxy-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2 -yl]cyclohexanecarboxamide

To a stirred solution of cis-4-hydroxy-1-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3- thiazol-2-yl]cyclohexane-carboxylic (442mg, 0.90mmol) in DMF (9.0ml) was added ammonium chloride (144mg, 2.69mmol), EDC (344mg, 1.80mmol) ), HOBt (243 mg, 1.80 mmol) and diisopropylethyl amine (0.94 ml, 5.38 mmol). The solution was allowed to stir at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with saturated aqueous sodium bicarbonate, brine, then dried (magnesium sulfate), filtered and concentrated. The residue was purified by column chromatography to give the title compound as a white solid. ESI: [M + H]+ m/z 492.2. 1H NMR (500 MHz, CD3OD) δ 8.71 (d, J = 4.9, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.44 (s , 1H), 7.13 (s, 2H), 2.37 (s, 3H), 2.22 (d, J = 13.0, 2H), 2.15 (d, J = 12.2, 2H), 1.84 (d, J = 14.1, 2H), 1.63 (d, J = 13.4, 2H), 1.30 (s, 3H).
The compounds in the following Tables were prepared in a manner analogous to that described in Example 117: TABLE 117


Example 118 cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-N -[3-(2-oxopyrrolidin-1-yl)propyl]cyclohexanecarboxamide

To N-(3-aminopropyl)-2-pyrrolidinone (14.1 µl, 0.12 mmol) was added a solution of cis-4-hydroxy-4-[5-(3-methyl-5-{[4] acid -(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane carboxylic (48 mg, 0.1 mmol) in N,N-dimethylformamide (1 ml). N,N-diisopropylethylamine (35 µl, 0.2 mmol) was added and the solution was then cooled to 0°C.
1-Propanephosphonic acid cyclic anhydride (70 µl, 0.12 mmol) was added and the mixture was warmed to room temperature and stirred for 16 hours, filtered, then purified by mass-flared reverse phase C18 HPLC to give the product of the title (21.5 mg, 0.036 mmol, 36% yield) as a pale yellow solid. MS ESI: [M + H]+ m/z 603.2. 1H NMR (600 MHz, DMSO) δ 10.22 (s, 1H), 8.80 (d, J = 4.9, 1H), 7.91 (s, 2H), 7.73 (s, 1H), 7.43 (s, 1H), 7.25 (d, J = 4.9, 1H), 7.12 (s, 1H), 3.29 (t, J = 7. 0.1H), 3.13 (t, J = 7.2, 2H), 2.98 (d, J = 6.0, 2H), 2.29 (s, 3H), 2.17 (t , J = 8.1, 3H), 1.91 - 1.75 (m, 9H), 1.60 - 1.50 (m, 5H).
Example 119 (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(propan-2-yloxy)pyrimidin-2-yl]-amino} phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide

To a solution of (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(propan-2-yloxy)pyrimidin-2-yl] acid amino}phenyl)-1,3-thiazol-2-yl]cyclohexane-carboxylic (30 mg, 0.060 mmol) in DMF (3.0 ml) was added ammonium chloride (19 mg, 0.36 mmol), HATU ( 35 mg, 0.09 mmol) and Hunig's base (0.13 ml, 0.72 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was then partitioned between 10 ml each of EtOAc and water and the layers were separated. The aqueous layer was extracted once with 10 mL of EtOAc, and the combined organic layers were washed with 10 mL of saturated aqueous sodium chloride, dried over anhydrous MgO4, filtered, and concentrated under reduced pressure. Purification by reverse phase HPLC (gradient from 10 to 100% MeCN in H2O, 0.1% TFA) gave (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5 trifluoroacetate -(3-methyl-5-{[4-(propan-2-yloxy)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-cyclohexanecarboxamide (12mg, 33%) as a colorless foam. MS ESI: [M + H]+ m/z 496.2. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.18 (d, J = 5.6Hz, 1H), 7.92 (s, 1H), 7. 86 (s, 1H), 7.45 (s, 1H), 7.14 (s, 1H), 7.11 (s, 1H), 6.71 (s, 1H), 6, 24 (d, J = 5.9 Hz, 1 H), 5.40 (septet, J = 6.1 Hz, 1 H), 2.30 (s, 3H), 2.04 - 1.60 (m , 6H), 1.34 (d, J = 6.1 Hz, 6H), 1.34 (s, 3H), 1.11 (s, 3H) rhSTK activity = +++
The compounds in the following Tables were prepared in a manner analogous to those described in Examples 117 (Method A), 118 (Method B) and 119 (Method C). The particular method used is indicated in the Table(s): TABLE 119



* synthetic method A, B, or C
Example 120 (1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl)-1 ethyl ,3-thiazol-2-yl]cyclohexanecarboxylate
(1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoro-methyl)pyrimidin-2-yl]amino}phenyl)-acid 1,3-thiazol-2-yl]cyclohexane carboxylic (100 mg, 0.197 mmol) was dissolved in ethanol (3 ml) and concentrated sulfuric acid (10.52 µl, 0.197 mmol) added. The reaction mixture was stirred for 16 hours. The reaction mixture was extracted with ethyl acetate (3x) and washed with saturated aqueous sodium bicarbonate. evaporation of solvent gave the title compound (88 mg, 0.165 mmol, 83% yield). ESI: [M + H]+ m/z 535.2. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.82 (d, J = 4.9, 1H), 7.93 (d, J = 9.6, 2H ), 7.46 10 (s, 1 H), 7.27 (d, J = 4.9, 1 H), 7.14 (s, 1 H), 4.07 (dt, J = 10.8 , 17.9, 2H), 2.31 (s, 3H), 2.05 (s, 3H), 1.96 - 1.78 (m, 3H), 1.65 (m, 2H), 1. 18 (m, 3H), 1.09 (s, 3H), 0.97 (s, 3H). rhSYK activity = +++
Example 126 5-(aminomethyl)-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-15 2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan -2-one

Step 1: Diisobutylaluminum dihydride (1M in hexanes, 0.239 ml, 0.239 mmol, 1.2 equiv) was added to a solution of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin- 2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decane-8-carbonitrile (100 mg, 0.20 mmol) at -10°C and the resulting cloudy mixture was stirred at -10°C for 1 hour. A second addition of DIBAL (1M in hexanes, 0.239 ml, 0.239 mmol, 1.2 equiv) was made at -10°C and the reaction was allowed to slowly warm to 23°C and then stir for 4 days. The reaction was quenched with a 1 : 1 : 3 mixture of water : 6N aqueous NaOH and the particulate matter was removed by filtration. The remaining filtrate was partitioned between EtOAc (2 x 55 ml) and water (65 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield N-(3-{2-[8-(aminomethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-1,3- thiazol-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (39 mg, 39%) as a yellowish white solid. MS ESI: [M + H]+ m/z 506.1. 1H NMR (500 MHz, CDCl 3 ) δ 8.66 (d, J = 4.6 Hz, 1H), 7.93 (s, 1H), 7.45 (bs, 1H), 7.28 ( s, 1H), 7.08 - 7.04 (m, 2H), 4.06 - 3.95 (m, 6H), 2.51 - 2.35 (m, 7H), 1.95 - 1 .71 (m, 4H).
Step 2: Sodium Azide (20.45 mg, 0.315 mmol, 3.0 equiv) was added to a stirred solution of the product from Step 1 (53 mg, 0.11 mmol) in chloroform (5 mL). Methanesulfonic acid (0.082 ml, 1.258 mmol, 12 equiv) was added and the reaction was capped and stirred at 65°C for 1 hour. The yellow mixture was partitioned between EtOAc (2 x 85 ml) and saturated aqueous NaHCO3 (90 ml), and the combined organic layers were dried over MgSO4 and concentrated. The residual colorless oil was purified by means of reverse phase HPLC (acetonitrile/water gradient with 0.1% TFA present). The desired fractions were partitioned between EtOAc (2 x 55 ml) and saturated aqueous NaHCO3 (65 ml). The combined organic layers were dried over Na 2 SO 4 and concentrated, giving the desired title compound (1.3 mg, 2.5%) as a colorless solid oil. MS ESI: [M + H]+ m/z 477.21. 1H NMR (500 MHz, CD3OD) δ 8.72 (d, 1H, J = 4.6 Hz), 8.19 (bs, 1H), 7.98 (s, 1H), 7.44 (s , 1H), 7.16 (s, 1H), 7.13 (d, 1H, J = 4.6 Hz), 3.45 (s, 2H), 2.95 (m, 2H), 2 .05 (s, 3H), 1.90 - 1.57 (m, 6H). rhSYK activity = +++
Example 127 5-(2-hydroxyethoxy)-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl] azepan-2-one

Step 1: A flame dried microwave vessel was charged with a solution of sodium hydride (4.26 mg, 0.106 mmol, 2.0 equiv) in anhydrous DMF (1 ml). {3-[2-(4-hydroxy-7-oxoazepan-4-yl)-1,3-thiazol-5-yl]-5-methylphenyl}[4-(trifluoromethyl)-pyrimidin-2-yl]carbamate tert-butyl (30 mg, 0.05 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (19.1 mg, 0.08 mmol, 1.5 equiv) were added causing an exotherm and color change. brown to dark orange. This mixture was heated at 125°C for 30 minutes. The resulting mixture of products was purified via reverse phase HPLC (gradient acetonitrile/water with 0.05% TFA present) to yield (3-{2-[4-(2-hydroxy-ethoxy)-7 tert-butyl -oxoazepan-4-yl]-1,3-thiazol-5-yl}-5-methylphenyl)[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (14mg, 33%) as a orange oil. MS ESI: [M + H]+ m/z 722.2
Step 2: A biphasic mixture of the product from Step 1 (15 mg, 0.02 mmol) in acetonitrile and water with 0.05% TFA (reverse phase HPLC solvent system) was heated to 125 °C for 10 minutes. The reaction was concentrated in vacuo, and the residual oil was partitioned between EtOAc (2 x 40 ml) and saturated aqueous NaHCO3 (55 ml). The combined organic layers were dried over MgSO4, filtered and concentrated to yield the desired title product (8.1 mg, 77%) as a yellow oil. MS ESI: [M + H]+ m/z 508.2 1H NMR (500 MHz, DMSO) δ 10.3 (m, 1H), 8.82 (m, 1H), 8.04 (m, 1H), 7.98 (s, 1H), 7.54 (m, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 4.68 (m, 1H), 1H), 3.98 (m, 2H), 3.55 (m, 2H), 3.00-2.79 (m, 2H), 2.38 (s, 3H), 2.37 - 1, 82 (m, 3H), 1.37 - 1.01 (m, 3H). rhSYK activity = +++
Examples 140(1) and 140(2) trans-1,4-Dihydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)- acid 1,3-thiazol-2-yl]cyclohexanecarboxylic acid and cis-1,4-dihydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl acid )-1,3-thiazol-2-yl]cyclohexane carboxylic

To a suspension of 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl] cyclohexanone (77 mg, 0.17 mmol) and zinc iodide (10 mg, 0.033 mmol) in CH 2 Cl 2 (1 ml), was added trimethylsilyl cyanide (115 µl, 0.858 ml). The resulting suspension was stirred for 14 hours at room temperature. Additional zinc iodide (10 mg, 0.033 mmol) and trimethylsilyl cyanide (115 µl, 0.858 ml) were added, and the resulting suspension was stirred for 5 d at room temperature. HCl (1 ml, 12 N) was then added and stirring continued for 14 hours at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with EtOAc (3x), dried over Na 2 SO 4 and concentrated in vacuo. Cis and trans isomers were separated by HPLC (20 to 75% CH3CN:H2O with 0.1% TFA modifier). Fractions containing the desired product were diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated to yield trans-1,4-dihydroxy-4-[5-(3- methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic provided (6 mg, 7%) as a white solid and the acid cis- 1,4-dihydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (5 mg, 6%) as a white solid. Characterization data for the trans isomer: MS ESI: [M + H]+ m/z 495. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.8, 1H), 7.93 (d, J = 14.9, 2H), 7.46 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.14 (s, 1H), 2.31 (s, 3H), 2.07 - 1.91 (m, 4H), 1.85 (s, 2H), 1.72 (d, J = 9 .9, 2H). Activity of rhSYK = +++. Characterization data for cis isomer: MS ESI: [M + H]+ m/z 495. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.8, 1H), 7.94 (s, 2H), 7.46 (s, 1H), 7.27 (d, J = 4.9, 1H), 7.15 (s, 1H), 2.31 (s, 3H), 2.20 (d, J = 13.0, 2H), 2.09 (d, J = 10.4, 2H), 1.57 (m, 4H) ). rhSYK activity = +++
Example 141 1-{Cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]cyclohexyl}pyrrolidin-2-one

Step 1: To a solution of cis-4-amino-1-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol- 2-yl]cyclohexanol (50 mg, 0.111 mmol) in dichloromethane (1 ml) was added triethylamine (0.047 ml, 0.334 mmol) and 4-chlorobutyryl chloride (0.015 ml, 0.133 mmol) sequentially. The resulting white suspension was stirred 1 hour at room temperature, filtered, washed with THF, and concentrated in vacuo to yield 4-chloro-N-{cis-4-hydroxy-4-[5-(3-methyl-5-{ [4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexyl}butanamide as a yellowish white solid (61 mg) which was used in the subsequent reaction without further purification.
Step 2: To a solution of the product from Step 1 (61 mg, 0.110 mmol) in THF (2 ml) was added sodium hydride (14.5 mg, 0.363 mmol) at 0°C. The suspension was stirred 15 minutes at 0°C, then allowed to warm to room temperature and stirred 14 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride, extracted with EtOAc (3x), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (0% to 10% MeOH : CH 2 Cl 2 ) gave the title compound (33 mg, 58%) as a white solid. ESI: [M + H]+ m/z 518. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H), 7.95 (d, J = 6.4, 2H), 7.46 (s, 1H), 7.28 (d, J = 4.9, 1H), 7.15 (s, 1H) , 6.03 (s, 1H), 3.83 (s, 1H), 2.31 (s, 3H), 2.21 (m, 3H), 1.91 (m, 9H), 1. 45 (m, 2H). rhSYK activity = +++
Examples 142(1) and 142(2) 1,5-trans-4,5-Dihydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin acid] -2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid 1,4-Trans and 1,5-cis-4,5-dihydroxy-2,2-dimethyl-4-[ 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic 1,4-cis, OH
cis-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2- Methyl yl]cyclohexanecarboxylate (570mg, 1.095mmol) was suspended in Eaton's Reagent (4.14ml, 21.9mmol) and heated to 60°C for 1.5 hour. The reaction mixture was allowed to cool to room temperature, and the reaction quenched by the slow addition of aqueous sodium bicarbonate. The reaction mixture was extracted with EtOAc (3x), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (10% to 35% EtOAc: Hexanes) and separation of diastereomers via HPLC gave 6,6-dimethyl-4-[5-(3-methyl) acid -5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohex-3-ene-1-carboxylic (127 mg, 23 %) as a foam colorless. ESI: [M + H]+ m/z 503.
Step 2: The product from Step 1 (41 mg, 0.082 mmol) was dissolved in acetone (800 µl) and water (100 µl). Osmium tetroxide (4% in water, 199 µl, 0.033 mmol) and 4-methylmorpholine n-oxide (38.2 mg, 0.326 mmol) were added, and the suspension was stirred 1 hour at room temperature. The reaction was quenched with 5% aqueous Na2S2O5 and stirred for 15 minutes at room temperature, extracted with EtOAc (3x), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (20% to 75% EtOAc: Hexanes) gave 1,4-trans, 1,5-trans-4,5-dihydroxy-2,2-dimethyl-4 -[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate and 1,4-cis, 1 ,5-cis-4,5-dihydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1 Methyl ,3-thiazol-2-yl]cyclohexanecarboxylate (28 mg, 64%) as a colorless oil as an apparent ~4:1 mixture of diastereomers. ESI: [M + H]+ m/z 537.
Step 3: 4,5-Dihydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole -2-yl]cyclohexanecarboxylate (43 mg, 0.080 mmol) was dissolved in methanol (500 µl). Sodium hydroxide (1.0 M in water, 481 µl, 0.481 mmol) was added, and the suspension was heated in a microwave to 100°C for 20 minutes. The mixture was acidified to pH 3 to 4 with HCl (1M in water) and diluted with water and 10% IPA:CHCl3. The layers were separated and the aqueous layer was re-extracted with 10% IPA:CHCl3 (2x). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Purification by reverse phase HPLC (40 to 90% CH3CN:H2O) gave 1,5-trans-4,5-dihydroxy-2,2-dimethyl-4-[5-(3-methyl) acid 1,4-trans -5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexane carboxylic, (13 mg, 31%) as a white solid and 1,5-cis-4,5-dihydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]-amino}phenyl) acid 1,4-cis -1,3-thiazol-2-yl]cyclohexanecarboxylic acid (17 mg, 41 %) as a white solid. Characterization data for the 1.4-cis, 1.5-cis compound: MS ESI: [M + H]+ m/z 523. 1H NMR (500 MHz, CD3OD) δ 8.71 (d, J = 4 9.9, 1H), 8.01 (s, 1H), 7.97 (s, 2H), 7.45 (s, 1H), 7.13 (d, J = 4.8, 2H) , 4.06 (dd, J = 4.5, 11.9, 1H), 2.50 (dd, J = 3.0, 13.1, 1H), 2.37 (s, 3H), 2.24 (q, J = 13.0, 1H), 2.01 (d, J = 14.7, 1H), 1.84 (d, J = 14.7, 2H), 1.22 (s, 3H), 1.10 (s, 3H). Activity of rhSYK = +++. Characterization data for 1.4-trans, 1.5-trans compound: MS ESI: [M + H]+ m/z 523. 1H NMR (500 MHz, CD3OD) δ 8.71 (d, J = 4 0.9, 1H), 8.01 (s, 1H), 7.96 (s, 2H), 7.46 (s, 1H), 7.13 (d, J = 5.0, 2H) , 4.61 (dd, J = 4.5, 10.9, 1H), 2.58 - 2.44 (m, 2H), 2.38 (s, 3H), 2.28 - 2.16 (m, 1H), 1.96 (d, J = 13.7, 1H), 1.75 (d, J = 14.0, 1H), 1.30 (s, 3H), 0, 98 (s, 3H). rhSYK activity = +++
Examples 151(a) and 151(b) Cis-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1 acid ,3-thiazol-2-yl]cyclohexanecarboxylic acid
trans-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid
Step 1: To a flask containing 4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2- tert-butyl yl]cyclohexanecarboxylate (400mg, 0.75mmol) dichloromethane (3.7ml) and ethanol (2.2ml) were added. Deoxofluor (0.69 ml, 3.74 mmol) was added and the reaction was stirred for one hour. The reaction was then diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield trans-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole tert-butyl-2-yl]cyclohexanecarboxylate (175 mg, 0.33 mmol, 44% yield) and cis-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl) tert-butyl pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (140 mg, 0.21 mmol, 28% yield). ESI of trans isomer: [M + H]+ m/z 537. ESI of cis isomer: [M + H]+ m/z 537.
Step 2 with cis isomer: To a solution of cis-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3- tert-butyl thiazol-2-yl]cyclohexanecarboxylate (67 mg, 0.13 mmol) in dichloromethane (2.5 ml) were added 2,6-lutidine (0.15 ml, 1.25 mmol) and TBSOTf (0 .86 ml, 3.75 mmol). The reaction stirred for an hour. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Supercritical fluid chromatography (from 40%/60% methanol/CO2) was used for purification to yield cis-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl) acid pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic (17 mg, 0.035 mmol, 28% yield). MS ESI: [M + H]+ m/z 461. 1H NMR (600 MHz, DMSO-d6) δ 12.20 (s, 1H), 10.26 (s, 1H), 8.81 (d) , J = 4.8, 1H), 8.05 (d, J = 2.7, 1H), 8.00 (s, 1H), 7.45 (s, 1H), 7.26 (d, J = 4.9, 1H), 7.18 (s, 1H), 2.40 (t, J = 12.1, 1H), 2.16 (s, 3H), 2, 12 - 1.97 (m, 4H), 1.94 - 1.87 (m, 2H), 1.67 (dt, J = 9.5, 12.9, 2H). rhSYK activity = +++
Step 2 with trans isomer: To a solution of trans-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3- tert-butyl thiazol-2-yl]cyclohexanecarboxylate (175 mg, 0.33 mmol) in dichloromethane (6.5 ml) and 2,6-lutidine (0.38 ml, 3.26 mmol) was added TBSOTf (2 .25 ml, 9.78 mmol). The reaction stirred for an hour. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica and then reverse phase HPLC were used for purification to yield trans-4-fluoro-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl acid] ]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic (70 mg, 0.15 mmol, 45% yield. ESI MS: [M + H]+ m/z 461. 1H NMR (600 MHz) , DMSO-d6) δ 10.25 (s, 1H), 8.81 (d, J = 4.8, 1H), 8.05 (s, 1H), 8.00 (s, 1H) ), 7.45 (s, 1H), 7.26 (d, J = 4.7, 1H), 7.17 (s, 1H), 2.38 (s, 1H), 2, 29 (s, 5H), 2.03 - 1.87 (m, 2H), 1.88 - 1.71 (m, 4H) rhSYK activity = +++
Example 152 (1S,4R)-4-Hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)-phenyl]-thiazol-2- acid yl}-cyclohexanecarboxylic

Step 1: To a mixture of (4-methyl-pyrimidin-2-yl)-[3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -phenyl]-amine (20.0 g, 56.9 mmol), (1S, 4R)-4-(5-Bromo-thiazol-2-yl)-4-hydroxy-2,2-dimethyl acid methyl ester -cyclohexanecarboxylic acid (19.8 g, 56.9 mmol), and PdCl2(dppf)2 (2.33 g, 2.85 mmol) in degassed 2-methyltetrahydrofuran (237 ml), was added sodium carbonate (2 M in H2O, 56.9 ml, 114 mmol). The reaction flask was purged with nitrogen and then heated to 70°C for 5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and filtered through celite. The solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. Purification by crystallization on silica gel (Isco CombiFlash 100 : 0 to 40 : 60, Hexanes : ethyl acetate), then crystallization on silica gel (2 : 98, methanol : dichloromethane) gave 17.5 g (37, 4 mmol 66%) of (1S, 4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)- acid methyl ester phenyl]-thiazol-2-yl}-cyclohexane-carboxylic acid as a light brown foam.
Step 2: To a solution of the product from Step 1 (16.5 g, 35.3 mmol) in methanol (115 ml) was added sodium hydroxide (1 M, 123 ml, 123 mmol) and the mixture was heated to 70°C. °C for 2.5 hours. The reaction was cooled to 30°C and hydrochloric acid (1N, 123 ml, 123 mmol) was added. The reaction was aged for 1.5 hours and filtered to provide 15.3 g (33.7 mmol, 96%) of the title compound as a white solid. MS ESI: [M + H]+ m/z 453.0. 1H NMR (600 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.55 (s, 1H), 8.32 (d, J = 5.0, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.49 (s, 1H), 7.02 (s, 1H), 6.72 (d, J = 5.0, 1 H), 5.86 (s, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.14 (dd, J = 12.7, 3.1, 1H) , 2.00 (ddd, J = 18.6, 13.2, 6.0, 1H), 1.88 - 1.77 (m, 3H), 1.62 (d, J = 14.1, 1H), 1.55 (dq, J = 13.5, 3.3, 1H), 1.09 (s, 3H), 0.97 (s, 3H). rhSYK activity = +++
EXAMPLES 160(a) and 160(b) 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3- thiazol-2-yl]azepan-2-one 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3 -thiazol-2-yl]azepan-2-one

Step 1: 5-Hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2 -one (example 10, 300 mg, 0.65 mmol) was suspended neat in the phosphorus pentoxide (1.2 ml, 12.9 mmol) and stirred at 65°C for 2 hours, then cooled to room temperature , and carefully poured into saturated aqueous sodium bicarbonate. After the exotherm ceased, the mixture was extracted with ethyl acetate (2x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (45 : 55 to 85 : 15 acetonitrile : water with 0.1% trifluoroacetic acid modifier) to yield 5-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,3,6,7-tetrahydro-2H-azepin-2-one and 5-[5- (3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,3,4,7-tetrahydro-2H-azepin- 2-one (70 : 30 mixture, 119 mg, 0.26 mmol, 41% yield) as a yellow solid. MS ESI: [M + H]+ m/z 446.1.
Step 2: The 70 : 30 mixture of the products from Step 1 (100 mg, 0.22 mmol) was dissolved in acetone (1 ml) and water (125 µl). Osmium tetroxide (4% in H2O, 548 µl, 0.09 mmol) and 4-methylmorpholine N-oxide (105 mg, 0.90 mmol) were added and the suspension was stirred for 1 hour at room temperature. The reaction was quenched with 5% aqueous sodium thiosulfate and stirred for 15 minutes. The mixture was washed with ethyl acetate (3x), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a mixture of 4,5-dihydroxy-5-[5-(3-methyl- 5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one and 5,6-dihydroxy-5-[5-(3- methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one (70:30, 40 mg, 0.084 mmol 37% yield) as a yellow-brown solid. MS ESI: [M + H]+ m/z 480.1, 1H NMR (600 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.80 (d, J = 4.9, 1 H), 7.93 (s, 1H), 7.90 (s, 1H), 7.53 - 7.36 (m, 2H), 7.23 (d, J = 4.9, 1H ), 7.11 (s, 1H), 5.92 (s, 1H), 5.86 (s, 1H), 5.12 - 5.01 (m, 1H), 4.04 - 3.99 (m, 1H), 3.58 - 3.36 (m, 1H), 3.19 - 3.09 (m, 1H), 2.96 - 2.75 (m, 1H) ), 2.30 (s, 3H), 2.04 - 1.82 (m, 2H) rhSYK activity = +++ Examples 161(a), 161(b), 161(c) and 161(d) 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2- 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2 one -one
Two stereoisomers each
Step 1: The 70 : 30 mixture of 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole -2-yl]azepan-2-one and 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3 - thiazol-2-yl]azepan-2-one (30 mg; Examples 160(a) and 160(b)) were subjected to purification by chiral supercritical fluid chromatography (4/6 2-propanol/CO2 at a rate of flow of 50 ml/min and a lead time of 19 minutes) to produce the stereoisomers of 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl] -amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one and 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin - 2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one. Enantiomer 1 [cis] 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]azepan-2-one (3.2 mg, 6.25 µmol, 10% yield). MS ESI: [M + H]+ m/z 480. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H) , 7.96 (s, 1H), 7.93 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.27 (d, J = 4 0.9, 1H), 7.13 (s, 1H), 6.01 (s, 1H), 5.17 (d, J = 5.9, 1H), 3.81 - 3.73 (m, 1H), 3.54 (m, 1H), 2.82 (m, 2H), 2.31 (s, 3H), 2.04 - 1.93 (m, 2H), 1. 93 - 1.86 (m, 1H). rhSYK activity = +++
Enantiomer 2 [cis] 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]azepan-2-one (9.0 mg, 0.019 mmol, 30% yield). MS ESI: [M + H]+ m/z 480. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H) , 7.96 (s, 1H), 7.93 (s, 1H), 7.61 (s, 1H), 7.47 (s, 1H), 7.27 (d, J = 4 0.9, 1H), 7.13 (s, 1H), 6.06 (s, 1H), 5.18 (d, J = 5.7, 1H), 4.04 - 4.00 (m, 1H), 3.47-3.40 (m, 1H), 3.15 (d, J = 5.3, 1H), 2.90 (s, 1H), 2.31 (s, 3H), 2.18 (s, 1H), 1.97 - 1.82 (m, 2H). rhSYK activity = +++
Enantiomer 3 [cis] 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]azepan-2-one (3.3 mg, 6.88 µmol, 11% yield). MS ESI: [M + H]+ m/z 480. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J = 4.9, 1H) , 7.96 (s, 1H), 7.93 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.28 (d, J = 4 0.9, 1H), 7.14 (s, 1H), 6.01 (s, 1H), 5.17 (d, J = 5.9, 1H), 3.82 - 3.71 (m, 1H), 3.53 (m, 1H), 2.91 - 2.75 (m, 2H), 2.31 (s, 3H), 2.04 - 1.93 (m, 2H ), 1.93 - 1.86 (m, 1H). rhSYK activity = +++
Enantiomer 4[cis]4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl ]azepan-2-one (5.1 mg, 0.011 mmol, 17% yield). MS ESI: [M + H]+ m/z 480. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J = 4.9, 1H) , 7.96 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1H), 7.27 (d, J = 4 0.9, 1H), 7.13 (s, 1H), 6.06 (s, 1H), 5.18 (d, J = 5.7, 1H), 4.05 - 4.00 (m, 1H), 3.44 (s, 1H), 3.15 (d, J = 5.2, 1H), 2.90 (s, 1H), 2.31 (s, 3H ), 2.18 (s, 1H), 1.97 - 1.84 (m, 2H). rhSYK activity = +++
Example 162 5-amino-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2- whoa
stirred from (S)-(-)-2-methyl-2-propanesulfinamide (854 mg, 7 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (1 g, 6.40 mmol) in tetrahydrofuran (13 ml) was added titanium(IV) ethoxide (5.11 ml, 16 mmol). The mixture was stirred for 4 hours at room temperature, poured into saturated aqueous sodium bicarbonate (10 ml) and acetonitrile (10 ml) with stirring, and stirred for 20 minutes. Magnesium sulfate was added and the mixture was stirred for 20 minutes, filtered through celite and concentrated. The residue was purified by column chromatography on silica gel (gradient ethyl acetate 10 : 90 to 70:30 : Hexanes) to yield N-(1,4-dioxaspiro[4.5]dec-8-ylidene)- 2-methyl-propane-2-sulfinamide (466 mg, 1.8 mmol, 28% yield) as a white solid. MS ESI: [M + H]+ m/z 260.
Step 2: To diisopropyl amine (318 µl, 2.23 mmol) in tetrahydrofuran (3.7 ml) at 0°C was added N-butyllithium (2.5 M in hexanes, 892 µl, 2.23 mmol). The mixture was stirred for 15 minutes, then cooled to -78°C. INTERMEDIATE 4 (250 mg, 0.74 mmol) dissolved in tetrahydrofuran (1 ml) was added dropwise within 5 minutes. The mixture was stirred for 30 minutes at -78°C, then the product from Step 1 (212 mg, 0.82 mmol) dissolved in tetrahydrofuran (1 ml) was added dropwise. The reaction mixture was stirred for 2 hours, then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3x), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate gradient: Hexanes, then 0:100 to 15:85 methanol gradient: dichloromethane) yielded 2-methyl-N-(8 -[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5] dec-8-yl}propane-2-sulfinamide (318 mg, 0.40 mmol, 75% yield) as brown solid. MS ESI: [M + H]+ m/z 596.
Step 3: To the product from Step 2 (100 mg, 0.13 mmol) were added chloroform (630 µl), sodium azide (24.5 mg, 0.38 mmol), and methanesulfonic acid (98 µl, 1.51 mmol). The mixture was heated to 65°C for 1.5 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate (2x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (acetonitrile 35 : 65 to 70 : 30 : water with 0.1% trifluoroacetic acid modifier). Fractions containing the desired product were diluted with ethyl acetate and free of base with saturated aqueous sodium bicarbonate. The separated organic layer was dried over magnesium sulfate, filtered and concentrated to yield the title compound (38 mg, 0.083 mmol, 66% yield) as an orange oil. MS ESI: [M + H]+ m/z 463. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (s, 1H), 8.75 (s , 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.49 (s, 1H), 7.28 (d, J = 4.7, 1H) , 7.16 (s, 1H), 2.39 - 2.08 (m, 9H), 1.30 - 0.99 (m, 4H). rhSYK activity = +++

权利要求:
Claims (11)
[0001]
1. Compound characterized in that it is selected from the group consisting of: (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-() acid trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; (1S,4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-pyrimidin-2-ylamino)-phenyl]-1,3-thiazol- acid 2-yl}-cyclohexanecarboxylic acid; 4-hydroxy-2,5-dimethyl-4-(5-{3-methyl-5-[4-methylpyrimidin-2-yl)amino)phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid; and 4-hydroxy-2,5-dimethyl-4-(5-{3-methyl-5[4-trifluoromethyl)pyrimodin-2-yl]amino}phenyl}-1,3-thiazol-2-yl}cyclohexanecarboxylic acid ; or a pharmaceutically salt thereof.
[0002]
2. Compound according to claim 1, characterized in that it is (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-( trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid or a pharmaceutically acceptable salt thereof.
[0003]
3. Compound according to claim 2, characterized in that it is in the form of free acid.
[0004]
4. Compound according to claim 1, characterized in that it is (1S,4R)-4-hydroxy-2,2-dimethyl-4-{5-[3-methyl-5-(4-methyl-acid) pyrimidin-2-ylamino)-phenyl]-thiazol-2-yl}-cyclohexanecarboxylic acid, or a pharmaceutically acceptable salt thereof.
[0005]
5. A compound according to claim 1, characterized in that it is 4-hydroxy-2,5-dimethyl-4-(5-{3-methyl-5-[4-methylpyrimidin-2-yl)amino acid) phenyl]-1,3-thiazol-2-yl} cyclohexanecarboxylic acid, or a pharmaceutically salt thereof.
[0006]
6. A compound according to claim 1, characterized in that it is 4-hydroxy-2,5-dimethyl-4-(5-{3-methyl-5[4-trifluoromethyl)pyrimodin-2-yl]amino} phenyl}-1,3-thiazol-2-yl} cyclohexanecarboxylic acid, or a pharmaceutically salt thereof.
[0007]
7. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[0008]
8. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound as defined in claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[0009]
9. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound as defined in claim 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[0010]
10. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound as defined in claim 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[0011]
11. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound as defined in claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-05-21| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-06-04| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2021-05-18| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-08-03| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/12/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US28726709P| true| 2009-12-17|2009-12-17|

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US61/287,267|2009-12-17|

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PCT/US2010/060463|WO2011075517A1|2009-12-17|2010-12-15|Aminopyrimidines as syk inhibitors|

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