SULFONYL AMIDE DERIVATIVES FOR THE TREATMENT OF ABNORMAL CELL GROWTH

Abstract

The present invention relates to a compound of the formula I

##STR00001##

wherein R.sup.1 to R.sup.6, A, B, n and m are as defined herein. Such novel sulfonyl amide derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

Claims

1. A method of making a compound of Formula (1), or a pharmaceutically acceptable salt thereof, the method comprising: ##STR00481## reacting a compound of Formula (C3): ##STR00482## with a compound of Formula (B5): ##STR00483## thereby providing the compound of Formula (1), or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the reaction of the compound of Formula (C3) and the compound of Formula (B5) is performed in the presence of a base.

3. The method of claim 2, wherein the base is diethylamine (DIEA).

4. The method of claim 1, wherein the reaction of the compound of Formula (C3) and the compound of Formula (B5) is performed for 20 hours.

5. The method of claim 1, wherein the reaction is performed in the presence of a solvent.

6. The method of claim 5, wherein the solvent is 1,2-dichloroethane (DCE):t-BuOH.

7. The method of claim 6, wherein the 1,2-dichloroethane (DCE):t-BuOH is 1:1 vol:vol.

8. The method of claim 1, wherein the temperature is 80° C.

9. The method of claim 1, wherein isolating the compound of Formula (1) comprises decreasing the temperature of the reaction mixture to ambient temperature.

10. The method of claim 9, wherein the temperature is 25° C.

11. The method of claim 9, wherein isolating the compound of Formula (1) comprises treating the reaction of the compound of Formula (C3) and the compound of Formula (B5) with EtOAc.

12. The method of claim 9, wherein the reaction of the compound of Formula (C3) and the compound of Formula (B5) is washed with water.

13. The method of claim 9, wherein the reaction of the compound of Formula (C3) and the compound of Formula (B5) is dried over MgSO.sub.4.

14. The method of claim 9, wherein isolating the compound of Formula (1) comprises filtration.

Description

DETAILED DESCRIPTION OF THE INVENTION

Synthesis of 2,4-Diamino Pyrimidines

[0353] The compounds of the invention can be prepared by the following general methods and by methods described in detail in the Experimental Section.

[0354] Non-limiting methods for making the sulfonyl amides of the invention are depicted in Schemes 1-6 below. For sake of clarity, only the pyrimidine derivatives of the compounds of formula I are depicted in the Schemes (i.e., where K of the compound of formula I is CH). However, the same methods can be used for making the 1,2,4-triazine derivatives compounds of formula I (i.e., where K is N).

[0355] Scheme 1 shows one method for preparing 2,4-diamino pyrimidines.

##STR00026##

[0356] In Scheme 1, the amino group of an amino-nitroaryl compound of structure A1-1 is protected (PG=protecting group such as BOC) to form the protected compound A1-2. The nitro group of A1-2 can then be selectively reduced to the corresponding aniline A1-3, using, e.g., hydrogen in the presence of a palladium-supported catalyst. Reaction of aniline A1-3 with 2,4-dichloro-5-(trifluoromethyl)pyrimidine in the presence of an appropriate zinc salt (e.g., ZnBr.sub.2) provides the corresponding C-2 addition product A1-4. Reaction of compounds of formula A1-4 with amines of formula A1-7 under basic conditions provides compound of formula I having the structure A1-5. Other compounds of formula I can be prepared by selectively deprotecting A1-5 to provide the aminoalkyl compound of formula I having the structure A1-6.

[0357] Scheme 2 depicts a non-limiting method for making amide derivatives of the compound of formula I.

##STR00027##

[0358] In Scheme 2, an aminoalkyl such as the compound of formula I having the structure A1-6 can be reacted with an acid halide (e.g., acetyl chloride) under basic conditions to provide the amide derivative of the compound of formula I having the structure A2-1.

[0359] Scheme 3 represents another general non-limiting method of making compounds of formula I.

##STR00028##

[0360] In Scheme 3, an hydroxyalkyl-aniline of formula A3-1 is reacted with 2,4-dichloro-5-(trifluoromethyl) pyrimidine in the presence of a zinc salt (e.g., ZnBr.sub.2) to provide the corresponding C-2 addition product A3-2. Treatment of the A3-2 with an amine of formula A3-6 provides hydroxyalkyl derivatives of the compound of formula I having the structure A3-3. Compound A3-3 may further be selectively converted to a compound of formula I where the hydroxyl group is replaced for another reactive functional group (e.g. alkyl halide or alkyl sulfonate). For example, in Scheme 3, the hydroxylalkyl compound of formula A343 is reacted with thionyl chloride to provide the chloroalkyl compound of formula I having the structure A3-4. Compound A3-4 may further be reacted with amines (e.g., HNR.sup.7R.sup.8) to provide aminoalkyl derivatives of the compounds of formula I having the structure A3-5. If desired, the compounds of structure A3-5 can be used as a starting material to prepare other compounds of formula I.

[0361] Scheme 4 represents yet another general non-limiting method for making compounds of formula I.

##STR00029## ##STR00030##

[0362] In Scheme 4, the acid group of a nitrobenzoate compound of structure A4-1 is protected to form the protected compound A4-2. The nitro group of A4-2 can then be selectively reduced to the corresponding aniline A4-3, using, e.g., hydrogen in the presence of a palladium-supported catalyst. Reaction of aniline A4-3 with 2,4-dichloro-5-(trifluoromethyl)pyrimidine in the presence of an appropriate zinc salt (e.g., ZnBr.sub.2) provides the corresponding C-2 addition product A4-4. Treatment of the chloro-pyrimidine compounds of formula A4-4 with amines of formula A4-7 provides benzoate-protected compounds of formula I having the structure A4-5. Selective deprotection of compound A4-5 can provide benzoic acid derivatives of the compound of formula I having the structure A4-6. The benzoic acid derivatives of formula A4-6 may be further reacted with an amine to provide the amide derivatives of the compound of formula I having the structure A4-6.

[0363] Scheme 5 depicts yet another general non-limiting method for making compounds of formula I.

##STR00031##

[0364] In Scheme 5, an aniline amide compound of structure A5-1 is be reacted with 2,4-dichloro-5-(trifluoromethyl)pyrimidine in the presence of a zinc salt (e.g., ZnBr.sub.2) to provide the corresponding C-2 addition product A5-2. Treatment of the chloro pyrimidine compounds of formula A5-2 with an amine of formula A5-3 provides amide derivatives of the compounds of formula I having the structure A5-4. The amide derivatives of formula A5-4 may be used as a starting material to provide other compounds of formula I.

[0365] In Schemes 1 and 3-5, the 2,4-dichloro-5-(trifluoromethyl)pyrimidine first formed a C-2 addition product (“the C4-chloro intermediate”). The C-4 group was then added by allowing the C4-chloro intermediate to react with an aralkylamino reagent. Scheme 6 depicts another non-limiting method for making the compounds of the invention where the first formed intermediate is the C-4 addition intermediate (“the C2-chloro intermediate”).

##STR00032##

[0366] In Scheme 6, 2,4-dichloro-5-(trifluoromethyl)pyrimidine is reacted with an aralkylamino reagent of formula A6-2 to provide the 2-chloro-pyrimidine addition product A6-3. Reaction of A6-3 with an amino reagent of formula A6-4 provides the compound of formula I having the structure A6-5. Depending on the substituent groups R.sup.1, the compounds of formula A6-5 can be further reacted as described above in Schemes 1-5 to provide additional compounds of formula I.

[0367] Arylalkylamines or heteroarylalkylamines (e.g., A1-7 in Scheme 1) that are attached to the 4 position of the pyrimidine core (or the 5 position of the 1,2,4-triazine core) may be prepared from the corresponding nitrile by catalytic hydrogenation using catalysts such as Pd/C or Raney Nickel or by lithium aluminum hydride reduction, (see Rylander, Catalytic Hydrogenation in Organic Synthesis, Academic Press, 1979); or by methods described herein in the Examples section.

##STR00033##

[0368] The nitrile starting materials can either purchased red from the corresponding aryl/heteroaryl bromide, iodide or triflate and Zn(CN).sub.2 using Pd coupling conditions found in Tschaen, D. M., et. al Synthetic Communications (1994), 24, 6, pp 887-890.

##STR00034##

[0369] Appropriately protected amines may be converted to different amines of formula A1-7 (see Scheme 1) according to methods familiar to those skilled in the art as, for example, N-alkylation of a sulfanilide under phase transfer using conditions as described by Brehme, R. “Synthesis”, (1976), pp 113-114.

##STR00035##

[0370] As understood by those skilled in the art, the chemical transformation to convert an aryl halide or triflate or heteroaryl halide or triflate to an aromatic or heteroaromatic amine may be carried out using conditions currently outlined in the literature, see Hartwig, J. F.: “Angew. Chem. Int. Ed.” (1998), 37, pp. 2046-2067, Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L.; “Acc. Chem. Res.”, (1998), 31, pp 805-818, Wolfe, J. P.; Buchwald, S. L.; “J. Org. Chem.”, (2000), 65, pp 1144-1157, Muci, A. R.; Buchwald, S. L.; “Topics in Current Chemistry” (2002), pp 131-209 and references cited therein. Further, as understood by those skilled in the art, these same aryl or heteroaryl amination chemical transformations may alternatively be carried out on nitrile (or primary amide) precursors which provide amines after nitrile (or amide) reduction.

[0371] Other methods for making the intermediate compounds (e.g. A1-7 in Scheme 1) can be found in U.S. Patent Appl. Publ. No. 20040220177, U.S. Pat. Nos. 7,109,335, 7,109,337, and PCT/IB2006/003349, the entire contents of each of the foregoing references being expressly incorporated herein by reference.

[0372] As noted above, amines comprising the ring moiety A (e.g., A6-4 in Scheme 6) are attached to the 2 position of the pyrimidine core (or the 3 position of the 1,2,4-triazine core). Such amino-ring groups are commercially available or can be made by methods known to those skill in the art. For example, amines comprising alkyl-, hydroxyl-, carboxyl-, and halo-substituted ring moieties are commercially available. In addition, certain of these commercially available amines such as, e.g., the halo- and hydroxyl-substituted ring compounds, can be reacted to form other compounds of the invention using the methods described above, in the Examples section, or known to those skilled in the art. Such reactions can be carried out prior to the reaction with pyrimidine core. Alternatively, such reactions can be carried out after the cyclic amine is attached to the C2 position of the pyrimidine core.

[0373] This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the invention, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth. In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In one embodiment the method comprises comprising administering to a mammal an amount of a compound of the invention that is effective in treating said cancer solid tumor. In one preferred embodiment the solid tumor is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, and bladder cancer.

[0374] In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.

[0375] This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

[0376] This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the invention, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.

[0377] The invention also contemplates a pharmaceutical composition for treating abnormal cell growth wherein the composition includes a compound of the invention, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth, and another anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

[0378] This invention also relates to a method for the treatment of a disorder associated with angiogenesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the invention, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating said disorder in combination with one or more anti-tumor agents listed above. Such disorders include cancerous tumors such as melanoma; ocular disorders such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, hypercalcemia from tumors metastatic to bone, and osteoporosis induced by glucocorticoid treatment; coronary restenosis; and certain microbial infections including those associated with microbial pathogens selected from adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and group A Streptococcus.

[0379] This invention also relates to a method of (and to a composition for) treating abnormal cell growth in a mammal which comprise an amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth.

[0380] Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of the invention in the methods and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX™ (celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), and Arcoxia (etoricoxib). Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Publication No. EP0818442, European Patent Publication No. EP1004578, WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European Patent Publication 606,046 (published Jul. 13, 1994), European Patent Publication 931,788 (published Jul. 28, 1999), WO 90/05719 (published May 331, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCT international Publication No. WO99/007675, European Patent Application No. 99302232.1 (filed Mar. 25, 1999), Great Britain patent application number 9912961.1 (filed Jun. 3, 1999), U.S. Pat. Nos. 7,030,242, 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent Publication 780,386 (published Jun. 25, 1997), all of which are herein incorporated by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

[0381] Some specific examples of MMP inhibitors useful in combination with the compounds of the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in the following list: [0382] 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic acid; [0383] 3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; [0384] (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; [0385] 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide; [0386] 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic acid; [0387] 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxyli acid hydroxyamide; [0388] 3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid hydroxyamide; [0389] (2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; [0390] 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic acid; [0391] 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic acid; [0392] 3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; [0393] 3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; and [0394] 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide;

[0395] and pharmaceutically acceptable salts, solvates and prodrugs of said compounds.

[0396] VEGF inhibitors, for example, SU-11248, SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), can also be combined with a compound of the invention. VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), U.S. Pat. No. 6,653,308 (issued Nov. 25, 2003), WO 99/10349 (published Mar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), all of which are herein incorporated by reference in their entirety. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland, Wash., USA); Avastin, an anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.).

[0397] ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), may be administered in combination with a compound of the invention. Such erbB2 inhibitors include Herceptin, 2C4, and pertuzumab. Such erbB2 inhibitors include those described in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2, 1999), each of which is herein incorporated by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also described in U.S. Pat. No. 6,465,449, and in U.S. Pat. No. 6,284,764, both of which are herein incorporated by reference in their entirety. Other erbb2 receptor inhibitors include TAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome).

[0398] Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some of tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors. More recently, five European patent publications, namely EP 0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1 (published Jun. 22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1 (published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published Nov. 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Applications WO96/16960 (published Jun. 6, 1996), WO 96/09294 (published Mar. 6, 1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434 (published Jan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO 98/02438 (published Jan. 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose. Other patent applications that refer to anti-cancer compounds are World Patent Application WO00/44728 (published Aug. 3, 2000), EP 1029853A1 (published Aug. 23, 2000), and WO01/98277 (published Dec. 12, 2001) all of which are incorporated herein by reference in their entirety.

[0399] Other antiproliferative agents that may be used with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following U.S. patent application Ser. No. 09/221,946 (filed Dec. 28, 1998); 09/454058 (filed Dec. 2, 1999); 09/501163 (filed Feb. 9, 2000); 09/539930 (filed Mar. 31, 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed Aug. 26, 1999); and 09/383755 (filed Aug. 26, 1999); and the compounds disclosed and claimed in the following United States provisional patent applications: 60/168,207 (filed Nov. 30, 1999); 60/170,119 (filed Dec. 10, 1999); 60/177,718 (filed Jan. 21, 2000); 60/168,217 (filed Nov. 30, 1999), and 60/200834 (filed May 1, 2000). Each of the foregoing patent applications and provisional patent applications is herein incorporated by reference in their entirety.

[0400] A compound of the invention may also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the “Background” section, supra. Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Provisional Application 60/113,647 (filed Dec. 23, 1998) which is herein incorporated by reference in its entirety.

[0401] A compound of formula I may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, oxaliplatin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex (tamoxifen) or, for example anti-androgens such as Casodex (4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).

[0402] The compounds of the present invention may be used alone or in combination with one or more of a variety of anti-cancer agents or supportive care agents. For example, the compounds of the present invention may be used with cytotoxic agents, e.g., one or more selected from the group consisting of a camptothecin, irinotecan HCl (Camptosar), edotecarin, SU-11248, epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof. The invention also contemplates the use of the compounds of the present invention together with hormonal therapy, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar, and combinations thereof. Further, the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.

[0403] The compounds of the invention may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers. In this regard, the following is a non-limiting list of examples of secondary agents that may be used with the compounds of the invention. [0404] Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinated alkylating compounds include but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or setrplatin; [0405] Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflomithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; [0406] Antibiotics include but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idanibicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin; [0407] Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide) and combinations thereof; [0408] Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel; [0409] Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCl (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof; [0410] Immunologicals include interferons and numerous other immune enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1. Other agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), moigramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, and Provenge: [0411] Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include krestin, lentinan, sizofiran, picibanil, or ubenimex; [0412] Other anticancer agents include alltretinoin, ampligen, atrasentan, bexarotene, bortezomib, Bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, I-asparaginase, procarbazine, decarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286, Velcade, Tarceva, or tretinoin; [0413] Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revilmid, squalamine, ukrain and Vitaxin; [0414] Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin; [0415] Camptothecin derivatives include but are not limited to camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, Irinotecan, SN-38, edotecarin, and topotecan; [0416] Tyrosine kinase inhibitors are Iressa or SU5416; [0417] Antibodies include Herceptin, Erbitux, Avastin, or Rituximab; and [0418] Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1.

[0419] “Abnormal cell growth”, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (4) any tumors that proliferate by receptor tyrosine kinases; (5) any tumors that proliferate by aberrant serine/threonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs.

[0420] The compounds of the present invention are potent inhibitors of the FAK protein tyrosine kinases, and thus are all adapted to therapeutic use as antiproliferative agents (e.g., anticancer), antitumor (e.g., effective against solid tumors), antiangiogenesis (e.g., stop or prevent proliferationation of blood vessels) in mammals, particularly in humans. In particular, the compounds of the present invention are useful in the prevention and treatment of a variety of human hyperproliferative disorders such as malignant and benign tumors of the liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). It is, in addition, expected that a compound of the present invention may possess activity against a range of leukemias and lymphoid malignancies.

[0421] In one preferred embodiment of the present invention cancer is selected from lung cancer, bone cancer, pancreatic cancer, gastric, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, gynecological, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, squamous cell, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain, pituitary adenoma, or a combination of one or more of the foregoing cancers.

[0422] In a more preferred embodiment cancer is selected a solid tumor, such as, but not limited to, breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, and bladder.

[0423] The compounds of the present invention may also be useful in the treatment of additional disorders in which aberrant expression ligand/receptor interactions or activation or signalling events related to various protein tyrosine kinases, are involved. Such disorders may include those of neuronal, glial, astrocytal, hypothalamic, and other glandular, macrophagal, epithelial, stromal, and blastocoelic nature in which aberrant function, expression, activation or signalling of the erbB tyrosine kinases are involved. In addition, the compounds of the present invention may have therapeutic utility in inflammatory, angiogenic and immunologic disorders involving both identified and as yet unidentified tyrosine kinases that are inhibited by the compounds of the present invention.

[0424] A particular aspect of this invention is directed to methods for treating or preventing a condition that presents with low bone mass in a mammal (including a human being) which comprise administering to a mammal in need of such treatment a condition that presents with low bone mass treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound.

[0425] This invention is particularly directed to such methods wherein the condition that presents with low bone mass is osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, periodontitis or prosthetic ingrowth.

[0426] A particular aspect of this invention is directed to methods for treating osteoporosis in a mammal (including a human being) which comprise administering to a mammal in need of such treatment an osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound.

[0427] Another aspect of this invention is directed to methods for treating a bone fracture or an osteoporotic fracture in a mammal which comprise administering to a mammal in need of such treatment a bone fracture treating or an osteoporotic fracture treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound.

[0428] The term “osteoporosis” Includes primary osteoporosis, such as senile, postmenopausal and juvenile osteoporosis, as well as secondary osteoporosis, such as osteoporosis due to hyperthyroidism or Cushing syndrome (due to corticosteroid use), acromegaly, hypogonadism, dysosteogenesis and hypophospatasemia.

[0429] The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above.

[0430] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0431] The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0432] For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (I)/salt/solvate (active ingredient) may be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg.

[0433] The present invention also encompasses sustained release compositions.

[0434] As noted above, the compounds of the invention are useful for treating abnormal cell growth such, e.g., cancer. Without being limited by theory, Applicants believe that the compounds of the invention are useful for treating or preventing abnormal cell growth by inhibiting the FAK kinases.

In Vitro and In Vivo Assays

[0435] As noted above, the compounds of the invention are useful as inhibitors of receptor tyrosine kinases such as, e.g., FAK, Aurora-1, Aurora-2, HgK and Pyk. Methods for determining the in vitro and in vivo activity of these compounds inhibitors of receptor tyrosine kinases are described below:

A. In-Vitro Activity of FAK:

[0436] The in vitro activity of the compounds of the compounds of the invention may be determined by the following procedure. More particularly, the following assay provides a method to determine whether compounds of the compounds of the invention inhibit the tyrosine kinase activity of the catalytic construct FAK(410-689). The assay is an ELISA-based format, measuring the inhibition of poly-glu-tyr phosphorylation by FAK(410-689).

[0437] The assay protocol has three parts:

I. Purification and cleavage of His-FAK(410-689)
II. FAK410-689 (a.k.a. FAKcd) Activation

III. FAKcd Kinase ELISA

Materials:

[0438] Ni-NTA agarose (Qiagen) [0439] XK-16 column (Amersham-Pharmacia) [0440] 300 mM Imidazole [0441] Superdex 200 HiLoad 16/60 prep grade column (Amersham Biotech.) [0442] Antibody: Anti-Phosphotyrosine HRP-Conjugated Py20 (Transduction labs) [0443] FAKcd: Purified and activated in house [0444] TMB Microwell Peroxidase Substrate (Oncogene Research Products #CL07) [0445] BSA: Sigma #A3294 [0446] Tween-20: Sigma #P1379 [0447] DMSO: Sigma #D-5879 [0448] D-PBS: Gibco #14190-037

Reagents for Purification:

[0449] Buffer A: 50 mM HEPES pH 7.0

[0450] 500 mM NaCl

[0451] 0.1 mM TCEP

[0452] Complete™ protease inhibitor cocktail tablets (Roche) [0453] Buffer B: 25 mM HEPES pH 7.0

[0454] 400 mM NaCl

[0455] 0.1 mM TCEP [0456] Buffer C: 10 mM HEPES pH 7.5

[0457] 200 mM Ammonium Sulfate

[0458] 0.1 mM TCEP

Reagents for Activation:

[0459] FAK(410-689): 3 tubes of frozen aliquots at 150 μl/tube for a total of 450 μl at 1.48 mg/ml (660 μg) [0460] His-Src(249-524): ˜0.74 mg/mi stock in 10 mM HEPES, 200 mM (NH4)2SO4 [0461] Src reaction buffer (Upstate Biotech):

[0462] 100 mM Tris-HCl pH7.2

[0463] 125 mM MgCl2

[0464] 25 mM MnCl2

[0465] 2 mM EDTA

[0466] 250 μM Na3VO4

[0467] 2 mM DTT [0468] Mn2+/ATP cocktail (Upstate Biotech)

[0469] 75 mM MnCl2

[0470] 500 μM ATP

[0471] 20 mM MOPS pH 7.2

[0472] 1 mM Na3VO4

[0473] 25 mM-glycerol phosphate

[0474] 5 mM EGTA

[0475] 1 mM DTT [0476] ATP: 150 mM stock [0477] MgCl2: 1 M Stock [0478] DTT: 1M stock

Reagents for FAKcd Kinase ELISA:

[0479] Phosphorylation Buffer:

[0480] 50 mM HEPES, pH 7.5

[0481] 125 mM NaCl

[0482] 48 mM MgCl2 [0483] Wash Buffer: TBS+0.1% Tween-20. [0484] Blocking Buffer:

[0485] Tris Buffer Saline

[0486] 3% BSA

[0487] 0.05% Tween-20, filtered [0488] Plate Coating Buffer:

[0489] 50 mg/ml Poly-Glu-Tyr (Sigma #P0275) in Phosphate buffer Saline (DPBS). [0490] ATP: 0.1M ATP in H2O or HEPES, pH7

[0491] Note: ATP Assay Buffer:

[0492] Make up as 75 uM ATP in PBS, so that 80 μl in

[0493] 120 μl reaction volume=50 μM final ATP concentration.

I. Purification of His-FAKcd(410-689):

[0494] 1. Resuspend 130 g baculovirus cell paste containing the over expressed His-FAKcd410-689 recombinant protein in 3 volumes (400 ml) of Buffer A.
2. Lyse cells with one pass on a microfluidizer.
3. Remove cell debris by centrifugation at 4° C. for 35 minutes at 14,000 rpm in a Sorval SLA-1500 rotor.
4. Transfer the supernatant to a clean tube and add 6.0 ml of Ni-NTA agarose (Qiagen).
5. Incubate the suspension with gentle rocking at 4° C. for 1 hour.
6. Centrifuge suspension at 700×g in a swinging bucket rotor.
7. Discard the supernatant and resuspend the agarose beads in 20.0 ml of Buffer A.
8. Transfer the beads to an XK-16 column (Amersham-Pharmacia) connected to a FPLCTM.
9. Wash the agarose-beads with 5 column volumes of Buffer A and elute off the column with a step gradient of Buffer A containing 300 mM Imidazole.
10. Perform a buffer exchange of the eluted fractions into Buffer B.
11. Following buffer exchange, pool the fractions and add thrombin at a 1:300 (w/w) ratio and incubated overnight at 13° C. to remove the N-terminal His-tag (His-FAK410-698 a FAK410-689 (a.k.a. FAKcd)).
12. Add the reaction mixture back onto the Ni-NTA column equilibrated with Buffer A and collect the flow-through.
13. Concentrate the flow-through down to 1.7 ml and load directly onto a Superdex 200 HiLoad 16/60 prep grade column equilibrated with Buffer C. The desired protein elutes between 85-95 ml.
14. Aliquot the FAKcd protein and store frozen at −80° C.

II. FAK Activation

[0495] 1. To 450 ul of FAK(410-689) at 1.48 mg/ml (660 μg) add the following:
30 μl of 0.037 mg/ml (1 μM) His-Src(249-524)

30 μl of 7.5 mM ATP

12 μl of 20 mM MgCl2

[0496] 10 μl Mn2+/ATP cocktail (UpState Biotech.)

4 μl of 6.7 mM DTT

60 μl Src Reaction Buffer (UpState Biotech.)

[0497] 2. Incubate Reaction for at least 3 hours at room temperature
At time t0, almost all of the FAK(410-689) is singly phosphorylated. The second phosphorylation is slow. At t120 (t=120 minutes), add 10 μl of 150 mM ATP.
T0=(Start) 90% singly phosphorylated FAK(410-689) (1 PO4)
T43=(43 min) 65% singly phosphorylated (1 PO4), 35% doubly phosphorylated (2 PO4)
T90=(90 min) 45% 1 PO4, 55% 2 PO4

T150=15% 1 PO4, 85% 2 PO4

[0498] T210=<10% 1 PO4, >90% 2 PO4 desalted sample
3. Add 180 μl aliquots of the desalted material to NiNTA spin column and incubate on spin column
4. Spin at 10k rpm (microfuge), for 5 minutes to isolate and collect flow through (Activated FAK(410-689)) and remove His-Src (captured on column)

III. FAKcd Kinase ELISA

[0499] 1. Coat 96-well Nunc MaxiSorp plates with poly-glu-tyr (pGT) at 10 μg/well: Prepare 10 μg/ml of pGT in PBS and aliquot 100 μl/well. Incubate the plates at 37° C. overnight, aspirate the supernatant, wash the plates 3 times with Wash Buffer, and flick to dry before storing at 4° C.
2. Prepare compound stock solutions of 2.5 mM in 100% DMSO. The stocks are subsequently diluted to 60× of the final concentration in 100% DMSO, and diluted 1:5 in Kinase Phosphorylation Buffer.
3. Prepare a 75 μM working ATP solution in Kinase phosphorylation buffer. Add 80 μl to each well for a final ATP concentration of 50 μM.
4. Transfer 10 μl of the diluted compounds (0.5 log serial dilutions) to each well of the pGT assay plate, running each compound in triplicates on the same plate.
5. Dilute on ice, FAKcd protein to 1:1000 in Kinase Phosphorylation Buffer.
Dispense 30 μl per well.
6. Note: Linearity and the appropriate dilution must be pre-determined for each batch of protein. The enzyme concentration selected should be such that quantitation of the assay signal will be approximately 0.8-1.0 at OD450, and in the linear range of the reaction rate.
7. Prepare both a No ATP control (noise) and a No Compound Control (Signal):
8. (Noise) One blank row of wells receives 10 μl of 1:5 diluted compounds in DMSO, 80 μl of Phosphorylation buffer (minus ATP), and 30 μl FAKcd solution.
9. (Signal) Control wells receive 10 μl of 1:5 diluted DMSO (minus Compound) in Kinase phosphorylation buffer, 80 μl of 75 uM ATP, and 30 μl of 1:1000 FAKcd enzyme.
10. Incubate reaction at room temperature for 15 minutes with gentle shaking on a plate shaker.
11. Terminate the reaction by aspirating off the reaction mixture and washing 3 times with wash buffer.
12. Dilute phospho-tyrosine HRP-conjugated (pY20HRP) antibody to 0.250 μg/ml (1:1000 of Stock) in blocking buffer. Dispense 100 μl per well, and incubate with shaking for 30 minutes at 25°.
13. Aspirate the supernatant and wash the plate 3 times with wash buffer.
14. Add 100 μl per well of room temperature TMB solution to initiate color development. Color development is terminated after approximately 15-30 sec. by the addition of 100 μl of 0.09M H2SO4 per well.
15. The signal is quantitated by measurement of absorbance at 450 nm on the BioRad microplate reader or a microplate reader capable of reading at OD450.
16. Inhibition of tyrosine kinase activity would result in a reduced absorbance signal. The signal is typically 0.8-1.0 OD units. The values are reported as IC50s, μM concentration.

FAK Inducible Cell-Based ELISA: Final Protocol

Materials:

[0500] Reacti-Bind Goat Anti-Rabbit Plates 96-well (Pierce Product #15135ZZ @115.00 USD)

[0501] FAKpY397 rabbit polyclonal antibody (Biosource #44624 @315.00 USD)

[0502] ChromePure Rabbit IgG, whole molecule (Jackson Laboratories #001-000-003 @60/25 mg USD)

[0503] UBI aFAK clone 2A7 mouse monoclonal antibody (Upstate #05-182 @ 289.00 USD)

[0504] Peroxidase-conjugated AffiniPure Goat Anti-Mouse IgG (Jackson Labs #115-035-146 @95/1.5 ml USD)

[0505] SuperBlock TBS (Pierce Product #37535ZZ @99 USD)

[0506] Bovine Serum Albumin (Sigma #A-9647 @117.95/100 g USD)

[0507] TMB Peroxidase substrate (Oncogene Research Products #CL07-100 ml @40.00 USD)

[0508] Na3VO4 Sodium Orthovanadate (Sigma #S6508 @43.95/50 g USD)

[0509] MTT substrate (Sigma #M-2128 @25.95/500 mg USD)

[0510] Growth Media: DMEM+10% FBS, P/S, Glu, 750 μg/ml Zeocin and 50 μg/ml Hygromycin (Zeocin InVitrogen #R250-05 @ 725 USD and Hygromycon InVitrogen #R220-05 @ 150 USD)

[0511] Mifepristone InVitrogen #H110-01 @ 125 USD

[0512] Complete™ EDTA-free Protease Inhibitor pellet Boehringer Mannheim #1873580

[0513] FAK cell-based Protocol for selectivity of kinase-dependent phosphoFAKY397

Procedure:

[0514] An inducible FAK cell-based assay in ELISA format for the screening of chemical matter to identify tyrosine kinase specific inhibitors was developed. The cell-based assay exploits the mechanism of the GeneSwitch™ system (InVitrogen) to exogenously control the expression and phosphorylation of FAK and the kinase-dependent autophosphorylation site at residue Y397.

[0515] Inhibition of the kinase-dependent autophosphorylation at Y397 results in a reduced absorbance signal at OD450. The signal is typically 0.9 to 1.5 OD450 units with the noise falling in the range of 0.08 to 0.1 OD450 units. The values are reported as IC50s, μM concentration.

[0516] On day 1, grow A431-FAKwt in T175 flasks. On the day prior to running the FAK cell-assay, seed A431.Math.FAKwt cells in growth media on 96-well U-bottom plates. Allow cells to sit at 37° C., 5% CO2 for 6 to 8 hours prior to FAK induction. Prepare Mifepristone stock solution of 10 μM in 100% Ethanol. The stock solution is subsequently diluted to 10× of the final concentration in Growth Media. Transfer 10 μl of this dilution (final concentration of 0.1 nM Mifepristone) into each well. Allow cells to sit at 37° C., 5% C02 overnight (12 to 16 hours). Also, prepare control wells without Mifepristone induction of FAK expression and phosphorylation.

[0517] On day 2, coat Goat Anti-Rabbit plate(s) with 3.5 μg/ml of phosphospecific FAKpY397 polyclonal antibody prepared in SuperBlock TBS buffer, and allow plate(s) to shake on a plate shaker at room temperature for 2 hours. Optionally, control wells may be coated with 3.5 μg/ml of control Capture antibody (Whole Rabbit IgG molecules) prepared in SuperBlock TBS. Wash off excess FAKpY397 antibody 3 times using buffer. Block Anti-FAKpY397 coated plate(s) with 200 μl per well of 3% BSA/0.5% Tween Blocking buffer for 1 hour at room temperature on the plate shaker. While the plate(s) are blocking, prepare compound stock solutions of 5 mM in 100% DMSO. The stock solutions are subsequently serially diluted to 100× of the final concentration in 100% DMSO. Make a 1:10 dilution using the 100× solution into growth media and transfer 10 μl of the appropriate compound dilutions to each well containing either the FAK induced or uninduced control A431 cells for 30 minutes at 37° C., 5% CO2. Prepare RIPA lysis buffer (50 mM Tris-HCl, pH7.4, 1% NP-40, 0.25% Na-deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM Na3VO4, 1 mM NaF, and one Complete™ EDTA-free protease inhibitor pellet per 50 ml solution). At the end of 30 minutes compound treatment, wash off compound 3 times using TBS-T wash buffer. Lyse cells with 100 μl/well of RIPA buffer.

[0518] To the coated plate, remove blocking buffer and wash 3 times using TBS-T wash buffer. Using a 96-well automated microdispenser, transfer 100 μl of whole cell-lysate (from step 6) to the Goat Anti-Rabbit FAKpY397 coated plate(s) to capture phosphoFAKY397 proteins. Shake at room temperature for 2 hours. Wash off unbound proteins 3 times using TBS-T wash buffer. Prepare 0.5 μg/ml (1:2000 dilution) of UBI aFAK detection antibody in 3% BSA/0.5% Tween blocking buffer. Dispense 100 μl of UBI aFAK solution per well and shake for 30 minutes at room temperature. Wash off excess UBI aFAK antibody 3 times using TBS-T wash buffer. Prepare 0.08 μg/ml (1:5000 dilution) of secondary Anti-Mouse Peroxidase (Anti-2MHRP) conjugated antibody. Dispense 100 μl per well of the Anti-2MHRP solution and shake for 30 minutes at room temperature. Wash off excess Anti-2MHRP antibody 3 times using TBS-T wash buffer. Add 100 μl per well of room temperature TMB substrate solution to allow for color development. Terminate the TMB reaction with 100 μl per well of TMB stop solution (0.09M H2SO4) and quantitate the signal by measurement of absorbance at 450 nm on the BioRad microplate reader.

[0519] Additional FAK cell assays are hereby incorporated by reference from WO2004/027018.

[0520] In a preferred embodiment, the compounds of the present invention have an in vitro activity as determined by a kinase assay, e.g., such as that described herein, of less than 500 nM. Preferably, the compounds have an IC50 of less than 25 nM in the kinase assay, and more preferably less than 10 nM. In a further preferred embodiment, the compounds exhibit an IC50 in a FAK cell based assay, e.g., such as that described herein, of less than 1 μM, more preferably less than 100 nM, and most preferably less than 25 nM.

[0521] Administration of the compounds of the present invention (hereinafter the “active compound(s)”) can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0522] The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

[0523] The active compound may be applied as a sole therapy or may involve one or more other anti-tumour substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex® (tamoxifen) or, for example anti-androgens such as Casodex® (4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide). Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.

[0524] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0525] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0526] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0527] Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

[0528] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

[0529] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated herein by reference in their entireties.

EXAMPLES

General Methods

HPLC:

[0530] Where HPLC chromatography is referred to in the preparations and examples below, the general conditions used, unless otherwise indicated, are as follows. The column used is a ZORBAX™ RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. The samples are run on a Hewlett Packard-1100 system. A gradient solvent method is used running 100 percent ammonium acetate/acetic acid buffer (0.2 M) to 100 percent acetonitrile over 10 minutes. The system then proceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes. The flow rate over this period is a constant 3 mL/minute.

Preparation of Intermediates

[0531] The groups attached to the 4 position of the pyridine core were prepared by the methods described below for compounds B1-B19.

Preparation of N-(3-aminomethyl-phenyl)-N-methyl-methanesulfonamide acetate (B1)

[0532] ##STR00036##

[0533] Step 1. Preparation of N-(3-cyano-phenyl)-methanesulfonamide (B1-1): A solution of 3-amino benzonitrile (10 g, 84.64 mmol) in pyridine (160 mL) was cooled to 0° C. and methane sulphonyl chloride (8.6 mL, 74.8 mmol) was added. The reaction mixture was allowed to warm to 25° C. and stirred for about 20 hours. The reaction mixture was then concentrated, and the resultant residue was dissolved in ethyl acetate (EtOAc) (250 mL), washed with 2N HCl (50 mL), brine (25 mL), and dried over anhydrous Na.sub.2SO.sub.4. The solution was then concentrated to provide (B1-1) as a brown solid. Yield: 17.1 g. .sup.1HNMR (d.sub.6-DMSO) δ: 10.25 (s, 1H), 7.45-7.65 (m, 4H) and 3.1 (s, 3H). Mass: (M−1) 195 calculated for C.sub.8H.sub.8N.sub.2O.sub.2S.

[0534] Step. 2. Preparation of N-(3-cyano-phenyl)-N-methyl-methanesulfonamide (B1-2): A mixture of benzyltriethylammonium chloride (BTEAC) (2.44 g, 10.7 mmol) and B1-1 (21 g, 107.1 mmol) in tetrahydrofuran (THF) (250 mL) and 40% NaOH solution (250 mL) was cooled to 10° C., treated with methyl iodide (8.6 mL, 139.0 mmol), and allowed to warm to 25° C. After about 20 hours the THF was removed by distillation, and the concentrated mixture was extracted with dichloromethane (DCM) (3×200 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resultant residue was then purified by column chromatography (60-120 mesh silica gel; 20% EtOAc in hexane as eluting solvent) to provide B1-2 as a white solid. Yield: 20 g, 89.3%. .sup.1HNMR (d.sub.6-DMSO) δ: 7.9 (s, 1H), 7.7-7.84 (m, 2H), 7.52-7.65 (m, 2H), 3.3 (s, 3H) and 3.02 (s, 3H). Mass: (M+1) 211 calculated for C.sub.9H.sub.10N.sub.2O.sub.2S.

[0535] Step 3. A solution of B1-2 (20 g, 95.12 mmol) in THF (100 ml) and acetic acid (400 mL) was charged to a Parr reactor. The contents of the reactor were then treated with 10% Pd/C (10.12 g) and hydrogenated at 50 Psi hydrogen pressure and 25° C. for 4 hours. The contents of the reactor were filtered through a bed of Celite® and washed with ethanol (50 mL). The combined filtrates were then concentrated under reduced pressure, and the resultant residue was azeotroped with EtOAc (3×50 mL). The resultant oily mass was dissolved in EtOAc and allowed stand at 25° C. for about 20 hours. The resultant white solids were collected by filtration and dried to provide B1 as the acetate salt. Yield: 15.2 g, 60%. .sup.1HNMR (d.sub.6-DMSO) δ: 7.2-7.45 (m, 4H), 4.6-5.65 (broad, 4H), 3.75 (s, 2H), 3.2 (s, 3H), 2.95 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 215 calculated for C.sub.9H.sub.14N.sub.2O.sub.2S. HPLC Purity: 99.1%.

Preparation of N-(3-aminomethyl-pyrazin-2-vi)-N-methyl-methane sulfonamide acetate (B2)

[0536] ##STR00037##

[0537] Step 1. Preparation of N-(3-cyano-pyrazin-2-yl)-N-methyl-methane sulfonamide (B2-1): A solution of chloropyrazine-2-carbonitrile (4.2 g, 30.21 mmol) in acetonitrile (200 mL) at 25° C. was treated sequentially with Cs.sub.2CO.sub.3 (13.7831 g, 42.293 mmol) and N-methyl-methane sulfonamide (3.957 g, 36.25 mmol). The mixture was then heated to 80° C. After about 20 hours the mixture was cooled to 25° and filtered. The solids were washed with EtOAc (3×25 mL) and the combined filtrates were concentrated. The resultant residue was treated with water (50 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with water (50 mL), brine, dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by column chromatography (100-200 mesh silica gel; 40% EtOAc in petroleum ether as eluting solvent) to provide B2-1 as a pale brown liquid. Yield: 4.7 g, 73.43%). .sup.1HNMR (CDCl.sub.3) δ: 8.92 (d, 2H), 3.4 (s, 3H) and 3.25 (s, 3H). Mass: (M+1) 213 calculated for C.sub.7H.sub.8N.sub.4O.sub.2S. (Note: The product contained unreacted N-methanesulfonamide as an impurity. The product was used without further purification to prepare B2 in the step described below.

[0538] Step 2. A suspension of B2-1 (5.345 g, 23.21 mmol) in 2N methanolic NH.sub.3 (566.7 mL) in a Parr reactor was treated with 10% Pd/C (395 mg, 3.78 mmol), and the contents of the reactor were hydrogenated at 45 Psi hydrogen pressure and 25° C. for 3 hours. The contents of the reactor were then filtered through a bed of Celite®, washed with methanol (MeOH), and concentrated. The resultant residue was treated with EtOAc (25 mL) and acetic acid (1.5 g), stirred at 25° C., and concentrated. The resultant residue was treated with EtOAc (100 mL) and allowed to stand at 25° C. for about 20 hours. The resultant solids were collected, washed with EtOAc, and dried to provide B2. Yield: 3.5 g, 64.3%. IR (cm.sup.−1): 3453, 3222, 2937, 3859, 1641, 1560, 1405, 1340 and 1155. .sup.1HNMR (d.sub.6-DMSO) δ: 8.7 (s, 1H), 8.5 (s, 1H), 5.3-5.8 (broad, 2H), 4.0 (s, 2H), 3.2 (s, 3H), 3.12 (s, 3H) and 1.84 (s, 3H). Mass: (M+1) 217 calculated for C.sub.7H.sub.12N.sub.4O.sub.2S.

Preparation of N-(2-aminomethyl-phenyl)-N-methyl-methanesulfonamide acetate (B3)

[0539] ##STR00038##

[0540] Step 1. Preparation of N-(2-cyano-phenyl)-N-dimethanesulfonamide (B3-1): A solution of 2-amino benzonitrile (10 g, 8.46 mmol) in pyridine (250 mL) at 25° C. was treated drop-wise over 30 minutes with methane sulphonyl chloride (21.33 g, 18.62 mmol). The reaction mixture was then stirred at 25° C. for about 20 hours and concentrated The resultant residue was dissolved in EtOAc (200 mL), washed with 2 N HCl (200 mL) and brine (30 mL), and dried over anhydrous sodium sulfate. The solution was then concentrated to provide 83-1 as a yellow solid. Yield: 20.7 g, 89%. .sup.1HNMR (d.sub.6-DMSO) δ: 8.06 (d, 1H), 7.82-7.85 (m, 2H), 7.7-7.75 (m, 1H), 3.62 (s, 6H).

[0541] Step 2. Preparation of N-(2-cyano-phenyl)-N-methyl-methanesulfonamide (B3-2): A solution of 53-1 (4 g, 1.45 mmol) in THF (30 mL) at 25° C. was treated with 40% NaOH solution (30 mL) and BTEAC (0.331 g, 0.145 mmol) and stirred vigorously for 30 minutes. The mixture was then treated with methyl iodide (2.48 g, 1.7 mmol) and stirred at 25° C. for about 20 hours. The THF was removed under reduced pressure and the mixture extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide 53-2 as a pale yellow solid. Yield: 3 g, 96%. .sup.1HNMR (CDCl.sub.3) δ: 7.62-7.8 (m, 2H), 7.55-7.56 (m, 1H), 7.4-7.52 (m, 1H), 3.4 (s, 3H) and 3.15 (s, 3H). Mass: (M−1) 209 calculated for C.sub.9H.sub.10N.sub.2O.sub.2S. The product was used without further purification to prepare B3 in the step described below.

[0542] Step 3. A solution of B3-2 (2 g, 9.5 mmol) in a mixture of acetic acid (100 mL) and THF (25 mL) was charged to a Parr shaker. The contents of the reactor were treated with 10% Pd/C (1.01 g) and hydrogenated at 60 Psi hydrogen pressure and 25° C. for 3.5 hours. The contents of the reactor were then filtered through a bed of Celite® and washed with MeOH (20 mL). The combined filtrates were then concentrated. The resultant residue was azeotroped with toluene (2×20 mL) and EtOAc (20 mL) and dried under vacuum to provide B3 as a white solid. Yield: 1.9 g, 95%. .sup.1HNMR (d.sub.6-DMSO) δ: 7.5-7.62 (m, 1H), 7.25-7.5 (m, 3H), 3.92-5.6 (broad, 3H), 3.8 (s, 2H), 3.16 (s, 3H), 3.04 (s, 3H) and 1.9 (s, 2H). Mass: (M+1) 215 calculated for C.sub.9H.sub.14N.sub.2O.sub.2S. HPLC Purity: 98.8%.

Preparation of N-(2-aminomethyl-pyridin-3-yl)-N-methyl-methanesulfonamide acetate salt (B4)

[0543] ##STR00039##

[0544] Step 1. Preparation of 6-chloro-pyridin-3-ylamine (B4-1): A solution of 2-chloro-5-nitro pyridine (30 g, 189 mmol) in MeOH (600 mL) was charged to a Parr reactor. The contents of the reactor were treated with Raney nickel (2 g) and hydrogenated at 60 Psi hydrogen pressure and 25° C. for 16 hours. The contents of the reactor were then filtered through a Celite® bed and washed with MeOH (100 mL). The combined filtrates were concentrated, and the resultant residue was purified by column chromatography (60-120 mesh silica gel column; 10% MeOH in CHCl.sub.3 as eluting solvent) to provide B4-1 as a pale yellow solid. Yield: 19 g, 78%. .sup.1HNMR (CDCl.sub.3) δ: 7.85 (d, 1H), 7.1 (d, 1H), 6.95 (dd, 1H) and 3.52-3.98 (broad s, 2H).

[0545] Step 2. Preparation of N-(6-chloro-pyridin-3-yl)-methanesulfonamide (B4-2): A solution of B4-1 (38 g, 295.7 mmol) and pyridine (28 g, 354 mm) in DCM (874 mL) at 10° C. was treated drop-wise over 30 minutes with methane sulphonyl chloride (37.2 g, 325 mmol). The reaction mixture was allowed to warm to 25° C., and stirred at 25° C. for 20 hours. The mixture was then treated with DCM (300 mL) and washed with water (1500 mL) and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resultant residue was washed with petroleum ether (80 mL), filtered, and dried to provide B4-2 as an off-white solid. Yield: 36 g, 60%. .sup.1HNMR (d.sub.6-DMSO) δ: 10.12 (s, 1H), 8.22 (d, 1H), 7.65 (dd, 1H), 7.46 (d, 1H) and 3.08 (s, 3H).

[0546] Step 3. Preparation of N-(6-chloro-pyridin-3-yl)-N-methyl-methanesulfonamide (B4-3): A solution of B4-2 (13 g, 62.8 mmol), BTEAC (1.42 g, 6.2 mmol) and 40% aq. NaOH (117 mL) in THF (117 mL) at 0° C. was treated drop-wise over 30 minutes with methyl iodide (10.6 g, 75.3 mmol). The reaction mixture was allowed to warm to 25° C. and stirred for an additional 3 hours. The mixture was then treated with THF (100 mL), and the resultant organic layer was collected. The aqueous layer was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with 1N NaOH and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resultant residue was then triturated with petroleum ether to provide B4-3 as a pale yellow solid. Yield: 12 g, 86%. .sup.1HNMR (CDCl.sub.3) δ: 8.4 (d, 1H), 7.72 (dd, 1H), 7.35 (d, 1H), 3.38 (s, 3H) and 2.88 (s, 3H). Mass: (M+1) 221 calculated for C.sub.7H.sub.9ClN.sub.2O.sub.2S.

[0547] Step 4. Preparation of N-(6-chloro-1-hydroxy-pyridin-3-yl)-N-methyl-methanesulfonamide (B4-4): A solution of B4-3 (15 g, 68.1 mmol) in DCM (172 mL) was cooled to 0° C. and treated slowly over 10 minutes with a solution of 77% m-chloroperoxybenzoic acid (MCPBA) (27.9 g, 124 mm) in DCM (200 mL). The rate of addition was controlled so that the temperature of the reaction mixture did not exceed 3 to 5° C. The reaction mixture was allowed to warm to 25° C. and stirred at 25° C. for 20 hours. The mixture was then cooled to 0° C. and treated with 1N NaOH (300 mL). The resultant organic layer was collected and washed with 1N NaOH (100 mL) and 10% sodium sulfite (100 mL). The organic layer was then dried over anhydrous Na.sub.2SO.sub.4 and concentrated to provide 64-4 as a white crystalline solid. Yield: 8 g, 49%. .sup.1HNMR (d.sub.6-DMSO) δ: 8.55 (s, 1H), 7.85 (d, 1H), 7.46 (dd, 1H), 3.26 (s, 3H) and 3.1 (s, 3H). Mass: (M+1) 237 calculated for C.sub.7H.sub.11ClN.sub.2O.sub.3S.

[0548] Step 5. Preparation of N-(6-chloro-2-cyano-pyridin-3-yl)-N-methyl-methanesulfonamide (B4-5): Dimethylsulfate (3.2 mL) was cooled to 0° C. and treated portion-wise with B4-4 (8 g, 33.6 mmol) over 3 hours. The resultant suspension was allowed to warm to 25° and maintained at 25° C. for 16 hours. The resulted gummy mass was then washed with diethyl ether. The resultant white residue was dissolved in water (37.6 mL) and added drop-wise over 30 minutes to an aqueous solution of sodium cyanide (6.5 g, 134.4 mm) at 10° C. The reaction mixture was allowed to warm to 25° C., and it was maintained at 25° C. for 16 hours. The resultant brown solids were collected and dissolved in EtOAc (200 mL). The organic solution was then washed with water (500 mL) and brine, and dried over anhydrous sodium sulfate. The organic solution was concentrated, and the resultant residue was purified by column chromatography (silica gel; 10% MeOH in CHCl.sub.3 as eluting solvent) to provide B4-5 as a white solid. Yield: 2.5 g, 30%. .sup.1HNMR (d.sub.6-DMSO) δ: 8.38 (d, 1H), 8.02 (d, 1H), 3.3 (s, 3H) and 3.28 (s, 3H).

[0549] Step 6. A solution of B4-5 (2.5 g, 10.2 mmol) in a mixture of THF (80 mL) and acetic acid (200 mL) was charged to a Parr reactor. The contents of the Parr reactor were then treated with 10% Pd/C (2.4 g, 22.4 mmol) and hydrogenated at 60 Psi hydrogen pressure and 25° C. for 16 hours. The contents of the reactor were filtered through a Cellite® bed and washed with MeOH (100 mL). The combined organic filtrates were concentrated, and the resultant residue was azeotroped with EtOAc (2×50 mL). The resultant solids were collected and dried to provide B4 as an off-white solid. Yield: 2.0 g, 95%. IR (cm.sup.−1): 3438, 3245, 2994, 2601, 1590, 1467, 1328, 1151 and 1047. .sup.1HNMR (d.sub.6-DMSO) δ: 8.65 (d, 1H), 8.25-8.55 (broad s, 2H), 8.15 (d, 1H), 7.5-7.7 (m, 1H), 4.0-4.42 (s, 2H), 3.25 (s, 3H) and 3.14 (s, 3H). Mass: (M+1) 216 calculated for C.sub.8H.sub.13N.sub.3O.sub.2S.

Preparation of N-(3-Aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide acetate (B5)

[0550] ##STR00040##

[0551] Step 1. Preparation of N-(3-cyano-pyridin-2-yl)-N-methyl-methanesulfonamide (B5-1): A solution of 2-chloro-3-cyano-pyridine (10 g, 72.4 mmol) in acetonitrile (200 mL) at 25° C. was treated with N-methyl-methanesulfonamide (14 g, 128.2 mmol) and Cs.sub.2CO.sub.3 (33 g, 101.2 mmol). The reaction mixture was slowly heated to 80° C. and maintained at 80° C. for 8 hours. The reaction mixture was then cooled to 25 C, filtered through a Celite® bed, and concentrated. The resultant residue was treated with water (300 ml) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, treated with carbon, and filtered. The filtrate was then concentrated, and the resultant residue was triturated with ether (100 mL). The resultant solids were collected and dried to provide 65-1 as an off-white solid. Yield: 7 g, 46%. .sup.1HNMR (CDCl.sub.3) δ: 8.6-8.72 (m, 1H), 8.02-8.12 (d, 1H), 7.3-7.45 (m, 1H), 3.4 (s, 3H) and 3.2 (s, 3H). Mass: (M+1) 212 calculated for C.sub.8H.sub.9N.sub.3O.sub.2S. HPLC purity: 99.9%.

[0552] Step 2. A solution of 15-1 (10 g, 47.3 mmol) in ethanol was charged to a Parr reactor, and the contents of the reactor were treated with 300 mL of a 2M ammonia solution in ethanol and 5% Pd/C (1.2 g). The contents of the reactor were then hydrogenated at 60 Psi hydrogen pressure and 37° C. for 3 hours and then at 30° C. for 20 hours. The contents of the reactor were filtered through a Celite® bed and concentrated. The resultant residue was treated with EtOAc, cooed to 20° C., and treated with acetic acid (10 mL). The mixture was then stirred for 10 minutes and concentrated. The resultant residue was dissolved in EtOAc (150 ml) in a glass flask. The walls of the flask were then scratched, and white solids began to form. The solids were collected and washed with EtOAc followed by petroleum ether. The solids were then dried to provide B5. Yield: 11 g, 85%. .sup.1HNMR (CDCl.sub.3) δ: 8.3-8.5 (m, 1H), 8.04 (d, 1H), 7.4-7.55 (m, 1H), 6.0?-7.15 (broad, 3H), 3.85 (s, 2H), 3.14 (d, 6H), 1.9 (s, 3H). Mass: (M+1) 216 calculated for C.sub.8H.sub.13N.sub.3O.sub.2S.

Preparation of N-(2-Aminomethyl-phenyl-N-methyl-methanesulfonamide acetate (B6)

[0553] ##STR00041##

[0554] Step 1. Preparation of N-(2-Cyano-phenyl)-N-dimethanesulfonamide (B6-1): A solution of 2-amino benzonitrile (10 g, 8.46 mmol) In pyridine (250 ml) was treated drop-wise at 25° C. over 30 minutes with methane sulphonyl chloride (21.33 g, 18.62 mmol). The reaction mixture was then stirred at 25° C. for 20 hours and concentrated. The resultant residue was dissolved in EtOAc (200 mL) and washed with 2 N HCl (200 mL) and brine (30 mL). The solution was dried over anhydrous sodium sulfate and concentrated to provide B6-1 as a yellow solid. Yield: 20.7 g, 89%. .sup.1HNMR (d.sub.6-DMSO): δ 8.06 (d, 1H), 7.82-7.85 (m, 2H), 7.7-7.75 (m, 1H), 3.62 (s, 6H). The product was used without further purification to prepare B6-2 in the step described below.

[0555] Step 2. Preparation of N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide (B6-2): A solution of B6-1 (4 g, 1.45 mmol) in THF (30 mL) was treated with 40% NaOH (30 mL) and BTEAC (0.331 g, 0.145 mmol) at 25° C. and stirred vigorously for 30 minutes. The mixture was then treated with methyl iodide (2.48 g, 1.7 mmol) and stirred at 25° C. for 20 hours. The THF was removed under reduced pressure, and the concentrated mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide B6-2 as pale yellow solid. Yield: 3 g, 96%. .sup.1H NMR (CDCl.sub.3): δ 7.62-7.8 (m, 2H), 7.55-7.56 (m, 1H), 7.4-7.52 (m, 1H), 3.4 (s, 3H) and 3.15 (s, 3H). Mass: (M−1) 209 calculated for C.sub.9H.sub.10N.sub.2O.sub.2S. The product was used without further purification to prepare B6 in the step described below.

[0556] Step 3. A solution of 56-2 (2 g, 9.5 mmol) in a mixture of acetic acid (100 mL) and THF (25 mL) was charged to a Parr reactor. The contents of the reactor were treated with Pd/C (1.01 g) and hydrogenated at 60 Psi hydrogen pressure and 25° C. for 3.5 hours. The mixture was then filtered through a bed of Celite® and washed with methanol (20 mL). The combined filtrates were concentrated, and the resultant residue was azeotroped with toluene (2×20 mL) followed by EtOAc (20 mL). The residue was then dried under reduced pressure to provide B6 as a white solid. Yield: 1.9 g, 95%. .sup.1HNMR (d.sub.6-DMSO): δ 7.5-7.62 (m, 1H), 7.25-7.5 (m, 3H), 3.92-5.6 (broad, 3H), 3.8 (s, 2H), 3.16 (s, 3H), 3.04 (s, 3H) and 1.9 (s, 2H). Mass: (M+1) 215 calculated for C.sub.9H.sub.14N.sub.2O.sub.2S. HPLC Purity: 98.8%.

Preparation of N-(2-Aminomethyl-phenyl)-methanesulfonamide acetate (B7)

[0557] ##STR00042##

[0558] Step 1. Preparation of N-(2-cyano-phenyl)-methanesulfonamide (B7-1): A solution of B6-1 (4 g, 14.8 mmol) in THF (29.26 ml) was treated with 40% aqueous NaOH (29.26 ml) and BTEAC (0.331 g, 1.45 mmol) and stirred at 25° C. for 20 hours. The reaction mixture was then concentrated, and the resultant residue was diluted with water (100 ml) and neutralized with 6N HCl (30 mL). The mixture was extracted with DCM (200 mL), and the organic layer was washed with water (150 mL) and brine. The organic solution was then dried over anhydrous sodium sulfate and concentrated to provide 57-1 as a white solid. Yield: 2.8 g, 92%. .sup.1HNMR (CDCl3): δ 7.7-7.76 (m, 1H), 7.6-7.65 (m, 1H), 6.8-6.98 (broad, 1H) and 3.14 (s, 3H). Mass: (M−1) 195 calculated for C.sub.8H.sub.8N.sub.2O.sub.2S.

[0559] Step 2. A solution of 17-1 (2 g, 10.19 mmol) in a mixture of THF (133 ml) and acetic acid (250 mL) was charged to a Parr reactor. The contents of the reactor were then treated with 10% Pd/C (2 g) and hydrogenated at 60 Psi hydrogen pressure and 25° C. for 4 hours. The reaction mixture was filtered through Celite) bed and concentrated. The resultant residue was diluted with toluene (20 ml) and concentrated. The resultant residue was then diluted with EtOAc (20 ml) and concentrated to provide 87 as white solid. Yield: 2 g, 98%. .sup.1HNMR (d.sub.6-DMSO): δ 7.32-8.6 (broad, 4H), 7.25-7.32 (m, 1H), 7.1-7.32 (m, 2H), 6.82 (t, 1H), 3.9 (s, 2H), 2.85 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 201 calculated for C.sub.8H.sub.12N.sub.2O.sub.2S. HPLC Purity: 98.9%.

Preparation of N-(2-Aminomethyl-3-methyl-phenyl)-methanesulfonamide acetate (B8)

[0560] ##STR00043##

[0561] Step 1. Preparation of N-(2-cyano-3-methyl-phenyl)-N-dimethanesulfonamide (18-1): A suspension of 2-amino-6-methyl benzonitrile (35 g, 265.5 mmol) in pyridine (600 ml) was cooled to about 0° C. to −5° C. and slowly treated with mesyl chloride (30 mL, 397.71 mmol) over 10 minutes. The reaction mixture was allowed to warm to 26° C. and stirred at 25° C. for 20 hours. The reaction mixture was concentrated and the resultant residue was diluted with EtOAc (600 mL). The organic solution was then washed with water (100 mL), 2N HCl (100 mL), and saturated brine (100 mL). The organic solution was then dried over anhydrous sodium sulfate and concentrated to provide 88-1 as a mixture of di- and mono-mesylated products. Yield: 49 g. The product was used without further purification to prepare 88-2 in the step described below.

[0562] Step 2. Preparation of N-(2-cyano-3-methyl-phenyl)-methanesulfonamide (B8-2): A solution of 88-1 (35 g, 166.6 mmol) in THF (300 ml) was treated with 40% aq. NaOH solution (300 mL) and BTEAC (1.84 g, 8.09 mmol) at 25° C. and stirred for 1 hour. The THF was removed under reduced pressure, and the concentrated mixture was extracted with DCM (500 mL). The aqueous layer was acidified with 2N HCl and extracted with DCM (250 mL). The combined organic layers were washed with water (100 mL) and brine (50 mL). The organic solution was then dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by column chromatography (60-120 mesh silica gel; 3% MeOH in CHCl.sub.3 as eluting solvent) to provide 58-2 as a brown solid. Yield: 24 g. .sup.1HNMR (d.sub.6-DMSO): δ 9.98 (s, 1H), 7.6 (t, 1H), 7.26-7.4 (m, 2H), 3.1 (s, 3H), 2.5 (s, 3H). Mass: (M−1) 209 calculated for C.sub.9H.sub.10N.sub.2O.sub.2S.

[0563] Step 3. A solution of B8-2 (10 g, 47.6 mmol) in acetic acid (75 ml) and THF (250 mL) was charged to a Parr reactor and treated with 10% Pd/C (6 g). The reaction mixture was then hydrogenated at 50 Psi hydrogen pressure and 25° C. for 16 hours. The reaction mixture was filtered through a Celite® bed and washed with ethanol (3×20 mL). The combined filtrates were concentrated, and the resultant residue was co-distilled with EtOAc (100 mL). The resultant brown oil was dissolved in EtOAc (100 ml) and allowed to stand at 25° C. for 20 hours. The resultant white solids were collected and dried to provide 88. Yield: 11 g. .sup.1HNMR (d.sub.6-DMSO): δ 7.65-8.65 (broad, 3H), 7.15 (d, 1H), 7.05 (t, 1H), 6.68 (d, 1H), 3.9 (s, 2H), 2.8 (s, 3H), 2.26 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 215 calculated for C.sub.9H.sub.14N.sub.2O.sub.2S. HPLC Purity: 98.6%.

Preparation of N-(2-Aminomethyl-3-methyl-phenyl)-N-methyl-methanesulfonamide acetate (B9)

[0564] ##STR00044##

[0565] Step 1. Preparation of N-(2-cyano-3-methyl-phenyl-N-methyl-methanesulfonamide (B9-1): A solution of B8-1 (15 g, 71.42 mmol) in THF (150 ml) was treated with 40% aq. NaOH (150 mL) and BTEAC (1.6 g, 7.14 mmol) at 25° C. and stirred for 10 minutes. The reaction mixture was then cooled to 10° C. and treated with methyl iodide (5.78 ml, 85.7 mmol). The reaction mixture was allowed to warm to 25° C. and stirred at 25° C. for 20 hours. The reaction mass was concentrated, and the resultant residue was diluted with DCM (600 mL). The organic solution was then washed with water (100 mL) and brine (50 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated. The resultant residue was then purified by column chromatography (60-120 mesh silica gel; 2% MeOH in CHCl.sub.3 as eluting solvent) to provide B9-1 as pale brown solid. Yield: 20 g, 98%. .sup.1HNMR (d.sub.6-DMSO): δ 7.65 (d, 1H), 7.56 (d, 1H), 7.45 (d, 1H), 3.25 (s, 3H), 3.14 (s, 3H) and 2.5 (s, 3H). Mass: (M+1) 225 calculated for C.sub.10H.sub.12N.sub.2O.sub.2S.

[0566] Step 2. A solution of B9-1 (10 g, 47.6 mmol) in a mixture of THF (100 ml) and acetic acid (300 mL) was charged to a Parr reactor and treated with Pd/C (6 g). The contents of the reactor were then hydrogenated at 50 Psi hydrogen pressure and 25° C. for 6 hours. The reaction mixture was filtered through a bed of Celite® and washed with ethanol (3×30 mL). The combined filtrates were concentrated, and the resultant residue was co-distilled with EtOAc (100 mL). The resultant brown oil was taken Into EtOAc (100 mL) and stirred at 25° C. for 16 hours. The resultant white solids were collected, washed with EtOAc (2×25 mL), and dried to provide B9. Yield: 11.6 g, 89%. .sup.1HNMR (d.sub.6-DMSO): δ 7.15-7.36 (m, 3H), 4.64-5.45 (broad, 3H), 3.76 (d, 2H), 3.15 (s, 3H), 3.05 (s, 3H), 2.42 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 229 calculated for C.sub.10H.sub.16N.sub.2O.sub.2S. HPLC Purity: 97.4%.

Preparation of N-(2-Aminomethyl-5-methyl-phenyl)-methanesulfonamide acetate (B10)

[0567] ##STR00045##

[0568] Step 1. Preparation of 2-amino-4-methyl-benzonitrile (B10-1): A solution of 4-methyl-2-nitrobenzonitrile (10 g, 61.72 mmol) in ethanol (200 ml) was charged to a Parr reactor and treated with 10% Pd/C (1 g). The contents of the reactor were then hydrogenated at 50 Psi hydrogen pressure 25° C. for 90 minutes. The reaction mixture was filtered through a Celite® bed and washed with ethanol. The combined filtrates were the concentrated to provide B10-1. Yield: 8.5 g. .sup.1HNMR (CDCl.sub.3): δ 7.28 (s, 1H), 6.5-6.62 (m, 2H), 4.2-4.42 (broad, 2H) and 2.3 (s, 3H). Mass: (M−1) 132 calculated for C.sub.8H.sub.8N.sub.2. The product was used without further purification to prepare B10-2 in the step described below.

[0569] Step 2. Preparation of N-(2-cyano-5-methyl-phenyl)-methanesulfonamide and N-(2-cyano-5-methyl-phenyl)-N-(methylsulfonyl)methanesulfonamide (B10-2): A solution of B10-1 (8.5 g, 64.39 mmol) in pyridine (50 mL) was cooled to 0° C. and treated drop-wise with mesyl chloride (8.85 g, 77.22 mmol) over 15 minutes. The reaction mixture was allowed to warm to 25° C., and it was stirred at 25° C. for 20 hours. The reaction mixture was then concentrated, and the resultant residue acidified with 2N HCl (50 mL) and extracted with EtOAc (200 mL). The resultant organic layer was washed with water (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated to provide B10-2 as a mixture of both mono and di mesylated product. Yield: 9.2 g. The product was used without further purification to prepare B10-3 in the step described below.

[0570] Step 3. Preparation of N-(2-cyano-5-methyl-phenyl)-methanesulfonamide (B10-3): A solution of B10-2 (17 g, 80.95 mmol) in a mixture of THF (70 mL) and 40% NaOH solution (70 mL) was treated with BTEAC (1.84 g, 8.09 mm) at 25° C. and stirred at 25° C. for 20 hours. The THF was removed under reduced pressure, and the concentrated mixture was extracted with DCM (300 mL). The aqueous layer was acidified with 2N HCl and extracted with DCM (200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was purified by column chromatography (60-120 mesh silica gel; 30% EtOAc in DCM as eluting solvent) to provide B10-3 as a pale brown solid. Yield: 16 g, 97%. .sup.1HNMR (d.sub.6-DMSO): δ 7.9 (d, 1H), 7.7 (s, 1H), 7.55 (d, 1H), 3.62 (s, 6H) and 2.45 (s, 3H). Mass: (M−1) 209 calculated for C.sub.9H.sub.10N.sub.2O.sub.2S.

[0571] Step 4. A solution of B10-3 (17 g, 80.95 mmol) in a mixture of THF (250 mL) and acetic acid (250 mL) was charged to a Parr reactor and treated with 10% Pd/C (8 g). at 25° C. The reaction mixture was then hydrogenated at 50 Psi hydrogen pressure and 25° C. for 4 hours. The mixture was filtered through a Celite® bed and washed with ethanol (3×20 mL). The combined filtrates were concentrated and the resultant residue was azeotroped with EtOAc (2×20 mL). The resultant brown-colored oil was taken into EtOAc (50 mL) and allowed to stand at 25° C. for 20 hours. The resultant white solids were collected and dried to provide B10. Yield: 15.1 g, 71.2%. .sup.1HNMR (d.sub.6-DMSO): δ 7.62-8.2 (broad, 3H), 7.02-7.18 (m, 2H), 6.7 (d, 1H), 3.85 (s, 2H), 2.88 (s, 3H), 2.25 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 215 calculated for C.sub.9H.sub.14N.sub.2O.sub.2S. HPLC Purity: 99.7%.

Preparation of N-(2-Aminomethyl-5-methyl-phenyl)-N-methyl-methanesulfonamide acetate (B11)

[0572] ##STR00046##

[0573] Step 1. Preparation of N-(2-cyano-5-methyl-phenyl)-N-methyl-methanesulfonamide (B11-1): A solution of B10-2 (10 g, 47.61 mmol) in a mixture of THF (100 mL) and 40% aq. NaOH solution (100 mL) at 25° C. was treated with BTEAC (1.1 g, 4.7 mmol) and methyl iodide (8.78 g, 61.89 mmol). The reaction mixture was then stirred at 25° C. for 20 hours. The THF was removed under reduced pressure, and the concentrated mixture was extracted with DCM (300 mL). The organic layer was washed with water (100 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was purified by column chromatography (60-120 mesh silica gel; 10% EtOAc in CHCl.sub.3 as eluting solvent) to provide B11-1 as a brown solid. Yield: 10.3 g, 96%. .sup.1HNMR (CDCl.sub.3): δ 7.62 (d, 1H), 7.38 (s, 1H), 3.38 (s, 3H), 3.1 (s, 3H) and 2.45 (s, 3H). Mass: (M−1) 223 calculated for C.sub.10H.sub.12N.sub.2O.sub.2S.

[0574] Step 2. A solution of B11-1 (4 g, 17.85 mmol) In acetic acid (150 mL) was charged to a Parr reactor and treated with Pd/C (2 g). The contents of the reactor were then hydrogenated at 50 Psi hydrogen pressure and 25° C. for 6 hours. The reaction mixture was filtered through a Celite® bed and washed with ethanol (2×20 mL). The combined filtrates were concentrated, and the resultant brown solid was azeotroped with EtOAc (3×25 mL). The resultant solid was taken into EtOAc (25 mL) at stirred at 25° C. for 20 hours. The resultant solids were collected and dried under reduced pressure to provide B11. Yield: 2.7 g, 53%. .sup.1HNMR (d.sub.6-DMSO): δ 7.45 (d, 1H), 7.3 (s, 1H), 7.2 (d, 1H), 5.04-5.7 (broad, 2H), 3.75-3.92 (broad, 2H), 3.15 (s, 3H), 3.05 (s, 3H), 2.3 (s, 3H) and 1.9 (s, 2H). Mass: (M+1) 229 calculated for C.sub.10H18N.sub.2O.sub.2S. HPLC Purity: 97.7%.

Preparation of N-(2-Aminomethyl-6-methyl-phenyl)-N-methyl-methanesulfonamide trifluoroacetate (B12)

[0575] ##STR00047##

[0576] Step 1. Preparation of potassium di-tert-butyl iminodicarboxylate (B12-1): A solution of di-tert-butyl iminodicarboxylate (56 g, 258 mmol) in ethanol (200 mL) was cooled to 15° C. and treated over 30 minutes with a solution of KOH (17 g) in ethanol (150 mL). The reaction mixture was allowed to warm to 25° C., and it was stirred at 25° C. for 4 hours. The reaction mixture was then concentrated, and the resultant residue was diluted with diethyl ether (300 mL) and stirred for 3 hours. The resultant solids were collected and immediately dried under reduced pressure to provide B12-1 as a white crystalline solid. Yield: 57 g, 82%. .sup.1HNMR (d.sub.6-DMSO): δ 1.35 (s, 18H). Mass: (M−1) 216 calculated for C.sub.10H.sub.19NO.sub.4.

[0577] Step 2. Preparation of 1-chloromethyl-3-methyl-2-nitro-benzene (612-2): A solution of 3-(methyl-2-nitro-phenyl)-methanol (12 g, 71.78 mmol) in DCM (500 mL) was cooled to −5° C. and treated with dimethylaminopyridine (DMAP) (11.4 g, 93.3 mm) followed by treatment with a solution of tosyl chloride (17.79 g, 93.3 mmol) in DCM. The reaction mixture was stirred at −5° C. for 30 minutes. The reaction mixture was then allowed to warm to 25° C., and it was stirred at 25° C. for 20 hours. The reaction mixture was diluted with DCM (100 mL) and washed with 1N HCl (2×50 mL), saturated NaHCO.sub.3 (2×25 mL), and brine. The organic solution was then dried over anhydrous MgSO.sub.4 and concentrated. The resultant residue was purified by column chromatography (silica gel column; 15% EtOAc in hexane as eluting solvent) to provide B12-2 as a pale greenish-yellow oil. Yield: 14 g, 89%. .sup.1HNMR (CDCl.sub.3): δ 7.35-7.46 (m, 2H), 7.26-7.35 (m, 1H), 4.6 (s, 2H) and 2.36 (s, 3H).

[0578] Step 3. Preparation of 3-methyl-2-nitro-benzyl di-tert-butyl iminodicarboxylate (B12-3): A solution of B12-2 (14 g, 75.6 mmol) in N-methylpyrrolidinone (NMP) (135 mL) was cooled to −5° C. and treated with B12-1 (29.7 g, 116.4 mmol) over 20 minutes. The mixture was then heated at 50° C. for 4 hour. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (4×250 mL). The combined organic layers were washed with water (300 mL) and brine. The organic solution was then dried over anhydrous MgSO.sub.4 and concentrated. The resultant residue was purified by column chromatography (silica gel; 20% EtOAc in hexane as eluting solvent) to provide B12-3 as an-off white solid. Yield: 21 g, 76%. .sup.1HNMR (CDCl.sub.3): δ 7.35 (t, 1H), 7.1-7.25 (m, 2H), 4.76 (s, 2H), 2.3 (s, 3H) and 1.42 (s, 18H).

[0579] Step 4. Preparation of 2-amino-3-methyl benzyl di-tert-butyl iminodicarboxylate (B12-4): A solution of B12-3 (20 g, 54.64 mmol) in ethanol (500 mL) was charged to a Parr reactor and treated with 10% Pd/C (7 g). The contents of the reactor were then hydrogenated at 55 Psi hydrogen pressure and 25° C. for 5 hours. The reaction mixture was filtered through a Celite® bed and concentrated to provide B12-4 as a pale greenish-yellow oil (19 g). .sup.1HNMR (CDCl.sub.3): δ 7.1 (d, 1H), 6.96 (d, 1H), 6.6 (t, 1H), 4.7 (s, 2H), 4.3-4.5 (broad, 2H), 2.15 (s, 3H) and 1.45 (s, 18H).

[0580] Step 5. Preparation of di-BOC 3-methyl-2-(methylsulfonamido)benzylamine (B12-5): A solution of B12-4 (20 g, 59.6 mmol) in pyridine (150 mL) was cooled to 0° C. and treated over 25 minutes with mesyl chloride (6.15 mL, 79.4 mmol). The mixture was allowed to warm to 25° C., and it was stirred at 25° C. for 20 hours. The reaction mixture was diluted with EtOAc (300 mL) and washed with 1N HCl solution. The aqueous layer was collected and extracted with EtOAc (100 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO.sub.4. The organic solution was then concentrated, and the resultant residue was taken into petroleum ether and stirred for 1 hour. The resultant solids were collected and dried under reduced pressure to provide B12-5 as an off white solid. Yield: 22 g, 89%. .sup.1HNMR (CDCl.sub.3): δ 7.9 (s, 1H), 7.35 (d, 1H), 7.05-7.25 (m, 2H), 4.9 (s, 2H), 3.1 (s, 3H), 2.45 (s, 3H) and 1.45 (s, 18H). Mass: (M−1) 413 calculated for C.sub.19H.sub.30N.sub.2O.sub.6S.

[0581] Step 6. Preparation of di-BOC 3-methyl-2-(N-methylmethan-2-ylsulfonamido)benzylamine (B12-6): A solution of B12-5 (22 g, 53.14 mmol) in THF (58.6 ml) was cooled to 15° C. and treated with 40% aq NaOH solution (58.6 mL) followed by BTEAC (1.25 g, 5.5 mm). The mixture was stirred for 15 minutes and the treated over 20 minutes with methyl iodide (4.2 mL, 67.4 mmol). The reaction mixture was allowed to warm to 25° C., and it was stirred at 25° C. for 20 hours. The reaction mixture was then diluted with water (300 mL) and extracted with DCM (3×200 mL). The combined organic layers were washed with water (3×400 mL) and brine, dried over anhydrous MgSO.sub.4, and concentrated. The resultant residue was dissolved in petroleum ether in a glass flask, and the wall of the flask was scratched to induce solids formation. The resultant solids were collected and dried to provide B12-6 as a pale yellow solid. Yield: 20 g, 88%. .sup.1HNMR (CDCl.sub.3): δ 7.1-7.25 (m, 2H), 7.04 (d, 1H), 5.05 (d, 1H), 4.8 (d, 1H), 3.25 (s, 3H), 3.1 (s, 3H), 2.36 (s, 3H) and 1.45 (s, 18H).

[0582] Step 7. A solution of B12-6 (13 g, 30.3 mmol) in DCM (35 m) was cooled to 0° C. and treated with trifluoroacetic acid (TFA) (70 mL). The reaction mixture was allowed to warm to 25° C., and it was stirred at 25° C. for 2 hours. The reaction mixture was concentrated, and the resultant residue was azeotroped with EtOAc (2×100 mL). The resultant residue was diluted with a mixture of DCM and pentane (1:1) in a glass flask, and the wall of the flask was scratched. The contents of the flask were stirred for 1 hour, and the resultant precipitate was collected and dried to provide B12 as an off white solid. Yield: 9 g, 87%. .sup.1HNMR (d.sub.6-DMSO): δ 8.3-8.45 (broad, 2H), 7.38-7.5 (m, 3H), 4.2 (s, 2H), 3.14 (s, 6H), and 2.44 (s, 3H). Mass: (M+1) 229 calculated for C.sub.10H.sub.16N.sub.2O.sub.2S. HPLC Purity: 97.5%.

Preparation of N-(2-Aminomethyl-4-methyl-phenyl-N-methyl-methanesulfonamide trifluoroacetate (B13)

[0583] ##STR00048##

[0584] Step 1. Preparation of di-BOC-5-methyl-2-nitrobenzylamine (B13-1): A solution of 2-chloromethyl-4-methyl-1-nitro-benzene (20 g, 107.5 mmol) in NMP (140 mL) was cooled to 0° C. and treated over 30 minutes with potassium di-tert-butyl iminodicarboxylate (40 g, 156 mmol). The reaction mixture was allowed to warm to 25° C., and it was stirred at 25° C. for 20 hours. The reaction mixture was then diluted with water (150 mL) and extracted with EtOAc (2×500 mL). The resultant organic layer was washed with water (250 mL) and brine, and dried over anhydrous MgSO.sub.4 The organic solution was then concentrated, and the resultant residue was purified by column chromatography (silica gel; 20% EtOAc in hexane as eluting solvent) to provide B13-1 as a pale yellow solid. Yield: 29 g, 73%. .sup.1HNMR (CDCl.sub.3): δ 7.98 (d, 1H), 7.2 (d, 1H), 7.1 (s, 1H), 5.15 (s, 2H), 2.4 (s, 3H) and 1.44 (s, 18H).

[0585] Step 2. Preparation of di-BOC 2-amino-5-methylbenzylamine (B13-2): A solution of B13-1 (29 g, 79.23 mmol) in ethanol (500 mL) was charged to a Parr reactor and treated with Pd/C (9 g). The contents of the reactor were then hydrogenated 55 Psi hydrogen pressure and 25° C. for 2 hours. The reaction mixture was filtered through a Celite® bed and concentrated to provide B13-2 as an oil. Yield: 26 g. .sup.1HNMR (CDCl.sub.3): δ 7.02 (s, 1H), 6.85 (d, 1H), 6.55 (d, 1H) 4.7 (s, 2H), 4.02-4.38 (broad, 2H), 2.22 (s, 3H) and 1.46 (s, 18H).

[0586] Step 3. Preparation of di-BOC 5-methyl-2-(methylsulfonamido)benzylamine (B13-3): A solution of 013-2 (26 g, 77.38 mmol) in pyridine (165 mL) was cooled to 0° C. and treated over 20 minutes with mesyl chloride (12.18 g, 106.4 mmol) was added over a period of 20 min. The mixture was allowed to warm to 25° C., and it was stirred at 25° C. for 20 hours. The reaction mixture was then diluted with EtOAc (350 mL) and washed with 1N HCl solution (2×250 mL). The resultant organic layer was washed with brine, dried over anhydrous MgSO.sub.4, and concentrated. The resultant residue was treated with petroleum ether and stirred at 25° C. for 1 hour. The resultant solids were then collected and dried under reduced pressure to provide B13-3 as a pale yellow solid. Yield: 23 g, 71%. .sup.1HNMR (CDCl.sub.3): δ 8.7 (s, 1H), 7.45 (d, 1H), 7.1 (d, 1H), 4.72 (s, 2H), 2.96 (s, 3H), 2.3 (s, 3H) and 1.46 (s, 18H). Mass: (M−1) 413 calculated for C.sub.19H.sub.30N.sub.2O.sub.6S.

[0587] Step 4. Preparation of di-BOC 5-methyl-2-(N-methylmethan-2-ylsulfonamido)benzylamine (B13-4): A solution of B13-3 (22 g, 53.14 mmol) in THF (70 mL) was cooled to 0° C. and treated with 40% aq. NaOH solution (70 mL) followed by BTEAC (1.5 g, 6.6 mmol). After 15 minutes the mixture was treated with methyl iodide (9.51 g, 67.4 mmol) over a period of 20 minutes. The reaction mixture was allowed to warm to 25° C., and it was stirred at 25° C. for 20 hours. The reaction mixture was then diluted with DCM (800 mL). The organic layer was collected and washed with water (2×200 mL) and brine, and dried over anhydrous MgSO.sub.4. The organic solution was concentrated, and the resultant residue was triturated with petroleum ether to provide 813-4 as a pale yellow solid. Yield: 20 g, 88%. .sup.1HNMR (CDCl.sub.3): δ 7.0-7.4 (m, 3H), 4.85-5.1 (d, 2H), 3.25 (s, 3H), 2.92 (s, 3H), 2.35 (s, 3H) and 1.45 (s, 18H).

[0588] Step 5. A solution of B13-4 (15 g, 35.04 mmol) in DCM (45 mL) was cooled to 0° C. and treated over 30 minutes with TFA (90 mL). The mixture was then allowed to warm to 25° C. After 3 hours the mixture was concentrated, and the resultant residue was azeotroped with EtOAc (2×200 mL). The resultant residue was diluted with a mixture of DCM and ether (8:2) and stirred for 1 hour. The resultant precipitate was collected and dried under reduced pressure to provide B13 as an off-white solid. Yield: 12 g, 98%. .sup.1HNMR (d.sub.6-DMSO): δ 7.98-8.2 (broad, 2H), 7.5 (d, 1H), 7.4 (s, 1H), 7.3 (d, 1H), 3.96-4.28 (broad, 2H), 3.2 (s, 3H), 3.05 (s, 3H) and 2.35 (s, 3H). Mass: (M+1) 229 calculated for C.sub.10H.sub.16N.sub.2O.sub.2S.

Preparation of N-(3-Aminomethyl-6-methyl-pyridin-2-yl-N-methyl-methanesulfonamide acetate (B14)

[0589] ##STR00049##

[0590] Step 1. Preparation of N-(3-cyano-6-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide (B14-1): A solution of 2-chloro-6-methyl-nicotinonitrile (20 g, 131.5 mmol) in acetonitrile (300 mL) at 25° C. was treated with HN(CH.sub.3)SO.sub.2Me (13.1 mL, 124.1 mmol) and Cs.sub.2CO.sub.3 (60 g, 184.0 mm). The reaction mixture was then stirred at 80° C. for 15 hours. The reaction mixture was allowed to cool to 25° C. and filtered. The resultant filtrate was concentrated and diluted with EtOAc (600 mL). The organic solution was then washed with water (2×250 mL) and brine, and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was recrystallized with ether to provide B14-1 as an off white solid. Yield: 18.5 g, 62.5%. .sup.1HNMR (CDCl.sub.3): δ 7.9 (d, 1H), 7.16-7.26 (m, 1H), 3.28 (s, 3H), 3.24 (s, 3H) and 2.22 (s, 3H). Mass: (M+1) 226 calculated for C.sub.9H.sub.11N.sub.3O.sub.2S.

[0591] Step 2. A solution B14-1 (10 g, 44.4 mmol) in a mixture of THF (100 mL) and acetic acid (900 mL) was charged to a Parr reactor and treated with 10% Pd/C (9 g, 84.9 mmol). The contents of the reactor were then hydrogenated at 55 Psi hydrogen pressure and 40° C. for 4 hours. The reaction mixture was then filtered through a Celite® bed and concentrated. The resultant residue was diluted with EtOAc (100 mL) and stirred for 3 hours. The resultant solids were collected and dried under reduced pressure to provide B14 as an off-white solid. Yield: 10 g, 98%. .sup.1HNMR (d.sub.6-DMSO): δ 7.9 (d, 1H), 7.3 (d, 1H), 7.0-7.25 (broad, 2H), 3.82 (s, 2H), 3.06-3.18 (d, 5H), 2.45 (s, 3H) and 1.82-1.96 (m, 5H). Mass: (M+1) 230 calculated for C.sub.9H.sub.15N.sub.3O.sub.2S. HPLC Purity: 98.1%.

Preparation of N-(3-Aminomethyl-5-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide acetate (B15)

[0592] ##STR00050##

[0593] Step 1. Preparation of 5-methyl-nicotinic acid (B15-1): A solution of 3.5 lutidine (100 g, 934.57 mmol) in water at 25° C. was treated portion-wise over 5 hours with KMnO.sub.4 (221.1 g, 1401.86 mmol). The reaction mixture was then heated at 45° C. for about 20 hours. The reaction mixture was filtered and washed with water. The resultant filtrates were concentrated, and the resultant residue was diluted with ethanol (3×500 mL), boiled, and filtered. The filtrate was then concentrated under reduced pressure to provide B15-1 as a white solid. Yield: 76 g, 59.4%. .sup.1HNMR (D.sub.2O): δ 8.6-8.7 (s, 1H), 8.3-8.4 (m, 1H), 7.92 (s, 1H) and 2.3 (s, 3H). Mass: (M+1) 138 calculated for C.sub.7H7NO.sub.2.

[0594] Step 2. Preparation of 5-methyl-nicotinamide (B15-2): A suspension of B15-1 (70 g, 510 mmol) in thionyl chloride (350 mL) was heated at 80° C. for 20 hours. The resultant clear solution obtained was allowed to cool to 25° C. and concentrated. The resultant residue was diluted with 1,2 dichloroethane (1.5 L), cooled to −5° C., and treated with NH.sub.3 gas via bubbler until the mixture was saturated. The mixture was allowed to warm to 25° C., stirred for 3 hours, and concentrated. The resultant brown solid was taken in EtOAc (3×800 mL), refluxed for 20 min, and filtered. The resultant filtrate was then concentrated to provide B15-2 as a brown solid. Yield: 52 g, 75%. .sup.1HNMR (d.sub.6-DMSO): δ 8.85-8.9 (s, 1H), 8.55 (s, 1H), 8.05-8.18 (m, 1H), 8.02 (s, 1H), 7.48-7.65 (s, 1H) and 2.35 (s, 3H). Mass: (M+1) 137 calculated for C.sub.7H.sub.8N.sub.2O.

[0595] Step 3. Preparation of 1-Hydroxy-5-methyl-nicotinamide (B15-3): A solution of B15-2 (35 g) in acetic acid (200 mL) was cooled to 10° C. and treated over 10 minutes with H.sub.2O.sub.2 (40% solution in water, 200 mL). The reaction mixture was allowed to warm to 25° C. and then heated at 80° C. for 20 hours. The reaction mixture was cooled to 0° C., treated with 20% sodium sulfite solution (200 mL) and basified with 35% NH.sub.4OH (200 mL). The mixture was then allowed to warm to 25° C. and stirred for an additional 2 hours. The resultant solids were collected and dried under reduced pressure to provide 615-3 as a white solid. Yield: 30.1 g. .sup.1HNMR (d.sub.6-DMSO): δ 8.45 (s, 1H), 8.3 (s, 1H), 7.6 (s, 1H), 4.42-4.7 (broad m, 2H), 2.3 (s, 3H). Mass: (M−1) 153 calculated for C.sub.7H.sub.10N.sub.2O.sub.2.

[0596] Step 4. Preparation of 2-chloro-5-methyl-nicotinonitrile (B15-4): Neat POCl.sub.3 (120 mL) was cooled to about 10° C. and treated portion-wise over 10 minutes with B15-3. The reaction mixture was then heated at 60° C. for 2 hours. The reaction mixture was concentrated, cooled to about 10° C., basified with saturated Na.sub.2CO.sub.3, and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (50 mL), and brine (50 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was purified by column chromatography (silica gel; 35% EtOAc in hexane as eluting solvent) to provide to 615-4 as a white solid. Yield: 3.5 g, 68%. .sup.1HNMR (d.sub.6-DMSO): δ 8.42 (s, 1H), 7.82 (s, 1H) and 2.4 (s, 3H). Mass: (M+1) 153 calculated for C.sub.7H.sub.5ClN.sub.2.

[0597] Step 5. Preparation of N-(3-cyano-5-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide (B15-5): A suspension of B15-4 (16 g, 0.1049 mmol) in acetonitrile (150 mL) at 25° C. was treated with Cs.sub.2CO.sub.3 (51.3 g, 0.157 mmol) and N-methyl methane sulphonamide (12.5 g, 0.115 mmol). The reaction mixture was then heated at 80° C. for 20 hours. The reaction mixture was filtered through a Celite® bed and washed with acetonitrile (3×50 mL). The combined filtrates were concentrated, and the resultant residue was diluted with EtOAc (500 mL) and washed with water (3×100 mL). The resultant organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resultant residue was purified by column chromatography (silica gel; 40% EtOAc in hexane as eluting solvent) to provide B15-5 as pale yellow solid. Yield: 15.1 g, 62.8%. .sup.1HNMR (d.sub.6-DMSO): δ 8.65 (s, 1H), 8.3 (s, 1H), 3 3.22-3.26 (s, 3H), 0.15-3.22 (s, 3H) and 2.36 (s, 3H). Mass: (M+1) 226 calculated for C.sub.9H.sub.11N.sub.3O.sub.2S.

[0598] Step 6. A solution of 815-5 (15 g) in a mixture of acetic acid (200 mL) and THF (200 mL) was charged to a Parr reactor and treated with Pd/C (4 g). The contents of the reactor were then hydrogenated at 50 Psi hydrogen pressure and 25° C. for 5 hours. The mixture was filtered through a Celite® bed and washed with ethanol (50 mL). The filtrate was concentrated under reduced pressure, and the resultant residue was purified by column chromatography (silica gel; 5% MeOH in CHCl.sub.3 as eluting solvent) to provide B15 as a reddish brown solid. Yield: 12.3 g, 98%. IR (cm.sup.−1): 3450, 3264, 2937, 2161, 1706, 1633, 1548, 1413, 1321 and 1151. .sup.1HNMR (d.sub.6-DMSO): δ 8.3 (s, 1H), 7.9 (s, 1H), 7.02-7.25 (broad s, 2H), 3.92 (s, 2H), 3.15 (d, 6H), 2.4 (s, 3H), 1.92 (s, 3H). Mass: (M+1) C.sub.9H.sub.15N.sub.3O.sub.2S. (Note: Few drops of triethylamine was added to the mobile phase during the process of silica gel column purification.)

Preparation of N-(3-Aminomethyl-4-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide (B16)

[0599] ##STR00051##

[0600] Step 1. Preparation of N-(3-cyano-4-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide (B16-1): A suspension of 2-chloro-4-methyl-nicotinonitrile (4 g, 26.2 mmol) (see WO 02/30901), N-methyl methane sulphonamide (3.43 g, 31.4 mmol) and CsCO.sub.3 (12 g, 36.7 mmol) in acetonitrile (40 mL) was heated at 60° C. for 20 hours. The reaction mixture was filtered through a Celite® bed and washed with acetonitrile (40 mL. The combined filtrates were concentrated, and the resultant residue was diluted with EtOAc (100 mL). The organic solution was washed with water (100 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was stirred in methanol. The resultant solids were collected and dried under reduced pressure to provide B16-1 as a white solid. Yield: 1.6 g, 26%. .sup.1HNMR (CDCl.sub.3): δ 8.46 (d, 1H), 7.25 (m, 1H), 3.26 (s, 3H), 3.18 (s, 3H) and 2.6 (s, 3H). Mass: (M+1) 226 calculated for C.sub.9H.sub.11N.sub.3O.sub.2S.

[0601] Step 2. A solution of B16-1 (5 g, 22.1 mmol) in 2N ethanolic ammonia (250 mL) was charged to a Parr reactor and treated with 10% Pd/C (5 g, 47 mm). The contents of the reactor were then hydrogenated at 60 Psi hydrogen pressure and 25° C. for 6 hours. The reaction mixture was filtered through a Celite® bed and washed with ethanol (50 mL). The combined filtrates were concentrated, and the resultant oily residue was triturated with diethyl ether (20 mL). The resultant white solids were collected and dried to provide B16 as a white solid. Yield: 5 g, 90%. .sup.1HNMR (d.sub.6-DMSO): δ 8.46 (d, 1H), 8.2-8.38 (broad s, 2H), 7.42 (d, 1H), 4.55-4.9 (broad s, 4H), 4.15-4.3 (broad s, 2H), 325 (s, 3H), 3.1 (s, 3H) and 2.5 (s, 3H). Mass: (M+1) 230 calculated for C.sub.9H.sub.15N.sub.3O.sub.2S. HPLC Purity: 95.03%.

Preparation of N-(5-aminomethyl-2-methyl-pyridin-4-yl-N-methyl-methanesulfonamide acetate (B17)

[0602] ##STR00052##

[0603] Step 1. Preparation of 2,4-dihydroxy-6-methyl-nicotinic acid ethyl ester (B17-1): Sodium metal pieces (33 g, 1434 mmol) were slowly added to dry ethanol (800 mL) at 25° C. and stirred until all the sodium pieces had reacted. The resultant suspension was then treated over 15 minutes with malonic acid diethyl ester (140 g, 875 mmol) followed by treatment over 15 minutes with ethyl-3-aminocrotonate (110 g, 850 mmol). The reaction mixture was then heated at 110° C. for 20 hours and concentrated. The resultant residue was cooled to 15° C., dissolved in water (800 mL), and stirred for 15 minutes. The mixture was neutralized with a mixture of AcOH:H.sub.2O (1:1) until a pH of 6-7 was achieved. The mixture was then stirred an addition 20 minutes. The resultant solids were collected, washed with petroleum ether (300 mL), and dried under reduced pressure to provide B17-1 as an off-white solid. Yield: 60.3 g, 35%. .sup.1HNMR (d.sub.6-DMSO): δ 12.6 (s, 1H), 11.38 (s, 1H), 5.8 (s, 1H), 4.25 (q, 2H), 2.14 (s, 3H) and 1.25 (t, 3H). Mass: (M+1) 198 calculated for C.sub.9H.sub.11NO.sub.4.

[0604] Step 2. Preparation of 2,4-dichloro-6-methyl-nicotinic acid ethyl ester (B17-2): A suspension of B17-1 (36 g, 182.2 mmol) in N,N-bis(2-hydroxyethyl) 2-propanolamine (DEIPA) (36 mL) was cooled to 0° C. and slowly treated with POCl.sub.3 (250 mL). The resultant clear solution was allowed to warm to 25° C. and then heated at 15° C. for 20 hours. The reaction mixture was concentrated, and the resultant residue was poured into crushed ice. The chilled mixture was then basified with saturated Na.sub.2CO.sub.3 until a pH of 8 was achieved. The organic layer was collected, and the aqueous layer was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resultant residue was purified by chromatography (silica gel; 2% EtOAc in petroleum ether as eluting solvent) to provide B17-2 as a pale yellow solid. Yield: 24 g, 55%. .sup.1HNMR (d.sub.6-DMSO): δ 7.2 (s, 1H), 4.45 (q, 2H), 2.52 (s, 3H) and 1.42 (t, 3H). Mass: (M+1) 236 calculated for C.sub.9H.sub.9Cl.sub.2NO.sub.2.

[0605] Step 3. Preparation of 2-chloro-4-methoxy-6-methyl-nicotinic acid ethyl ester (B17-3): A solution of B17-2 (30 g, 128.2 mmol) in methanol (102 mL) was cooled to 0° C. and treated portion-wise over 30 minutes with NaOMe (8.5 g, 157.4 mmol). The reaction mixture was then heated at 60° C. for 5 hours. The reaction mixture was cooled to 25° C., filtered, and concentrated. The resultant residue was diluted with DCM (350 mL), filtered through a Celite® bed, and washed with DCM. The combined filtrates were concentrated, and the resultant residue was purified by chromatography (silica gel; 6% EtOAc in petroleum ether as eluting solvent) to provide B17-3 as a pale yellow solid. Yield: 20.62 g, 70%. .sup.1HNMR (CDCl.sub.3): δ 6.66 (s, 1H), 4.4 (q, 2H), 3.95 (s, 1H), 3.92 (s, 3H), 2.52 (s, 3H) and 1.38 (t, 3H). Mass: (M+1) 230 calculated C.sub.10H.sub.12ClNO.sub.3.

[0606] Step 4. Preparation of 4-methoxy-6-methyl-nicotinic acid ethyl ester (B17-4): A mixture of B17-3 (27 g, 117.3 mmol) and potassium acetate (11.0 g, 112 mmol) in isopropanol (IPA) (500 mL) was charged to a Parr reactor and treated with Pd/C (9.5 g, 70.15 mmol). The contents of the reactor were then hydrogenated at 55 Psi hydrogen pressure and 25° C. for 4 hours. The mixture was filtered through a Celite® bed and concentrated. The resultant residue was purified by chromatography (silica gel; 8% EtOAc in petroleum ether as eluting solvent) to provide B17.4 as a green viscous liquid. Yield: 23 g, 90%. .sup.1HNMR (CDCl.sub.3): δ 8.84 (s, 1H), 6.75 (s, 1H), 4.35 (q, 2H), 3.98 (s, 3H), 2.6 (s, 3H) and 1.4 (t, 3H). Mass: (M+1) 196 calculated for C.sub.10H.sub.13NO.sub.3.

[0607] Step 5. Preparation of 6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid hydrochloride (B17-5): A suspension of B17-4 (50 g, 256 mmol) in concentrated HCl (600 mL) was heated at 110° C. for 20 hours. The reaction mixture was then concentrated, and the resultant residue was washed in this order with ethanol (150 mL), DCM (2×300 mL), and a mixture of DCM:Et.sub.2O (1:1). The resultant solids were collected and dried to provide B17-5 as an off-white solid. Yield: 40 g. IR (cm.sup.−1): 3449, 3095, 2890, 1674, 1647, 1565, 1470, 1428, 1345, 1257, 1186 and 1028. .sup.1HNMR (d.sub.6-DMSO): δ 11.4-12.7 (b, 2H), 8.45 (s, 1H), 6.64 (s, 1H) and 2.4 (s, 3H). Mass: (M+1) 154 calculated for C.sub.7H7NO.sub.3.

[0608] Step 6. Preparation of 6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid methyl ester (B17-4): A solution of B17-5 (40 g, 261.4 mmol) in methanol (600 ml) was cooled to 0° C. and treated drop-wise over 20 minutes with SOCl.sub.2 (100 mL). The reaction mixture was allowed to warm to 25° C., heated at 70° C. for 20 hours, and concentrated. The resultant residue was washed with ethanol (100 mL), filtered and dried to provide B17-6 as a gummy solid. Yield: 40 g. .sup.1HNMR (CDCl.sub.3): δ 8.8 (s, 1H), 6.7 (s, 1H), 3.9 (s, 3H) and 2.45 (s, 3H). Mass: (M+1) 168 calculated for C.sub.8H.sub.9NO.sub.3. The product was used in the preparation of 617-7 below without further purification.

[0609] Step 7. Preparation of 6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid amide (B17-7): A suspension of B17-6 (40 g, 239.5 mmol) in aqueous NH.sub.3 (800 ml) was heated at 50° C. for 20 hours. The reaction mass was then concentrated, and the resultant residue was washed with a mixture of diethyl ether:DCM (8:2) (300 mL). The resultant solids were collected and dried under reduced pressure to provide 817-7 as an off-white solid. Yield. 40 g. .sup.1HNMR (d.sub.6-DMSO): δ 12.1 (b, 1H), 9.4 (s, 1H), 8.3 (s, 1H), 7.4 (o, 1H), 6.25 (s, 1H) and 2.25 (s, 3H). Mass: (M+1) 153 calculated for C.sub.7H.sub.8N.sub.2O.sub.2.

[0610] Step 8. Preparation of 4-Chloro-6-methyl-nicotinonitrile (117-8): A suspension of B17-7 (20 g, 131.5 mmol) in POCl.sub.3 (62 mL, 580 mmol) was heated at 110° C. for 15 minutes. The mixture was allowed to cool to 25° C. and treated portion-wise over 20 minutes with PCl.sub.5 (38.12 g, 183.4 mmol). The mixture was then heated at 110° C. for 1 hour and concentrated. The resultant residue was diluted with EtOAc (100 mL), cooled to 10° C., and quenched with aqueous Na.sub.2CO.sub.3 (200 mL). The mixture was then extracted with EtOAc (3×250 mL), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resultant residue was purified by chromatography (silica gel; 4-5% EtOAc in petroleum ether as eluting solvent) to provide B17-8 as an off-white puffy solid. Yield: 7.5 g, 37%. .sup.1HNMR (CDCl.sub.3): δ 8.75 (s, 1H), 7.38 (s, 1H), 2.65 (s, 3H). Mass: (M+1) 153 calculated for C.sub.7H.sub.5ClN.sub.2.

[0611] Step 9. Preparation of N-(5-Cyano-2-methyl-pyridin-4-yl)-N-methyl-methanesulfonamide (B17-9): A solution of B17-8 (7 g, 46.8 mmol) in acetonitrile (165 mL) at 25° C. was treated sequentially with Cs.sub.2CO.sub.3 (19 g, 58.2 mmol) and HN(Me)SO.sub.2Me (8.9 mL, 95 mmol). The mixture was heated at 60° C. for 20 hours and concentrated. The resultant residue was diluted with EtOAc (300 mL) and water (100 mL), and stirred for 10 minutes. The organic layer was collected, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over MgSO.sub.4, and concentrated. The resultant residue was purified by chromatography (silica gel; DCM as eluting solvent) to provide B17-9 as a solid. Yield: 9 g, 87%. .sup.1HNMR (CDCl.sub.3): δ 8.8 (s, 1H), 7.3 (d, 1H), 3.4 (s, 3H), 3.18 (s, 3H) and 2.65 (s, 3H). Mass: (M+1) 226 calculated for C.sub.9H.sub.11N.sub.3O.sub.2S.

[0612] Step 10. A solution of B17-9 (7.5 g, 33.3 mmol) in EtOH—NH.sub.3 (300 mL) was charged to a Parr reactor and treated with Pd/C (5 g). The contents of the reactor were hydrogenated at 60 Psi hydrogen pressure and 25° C. for 4 hours. The mixture was filtered through a Celite® bed and concentrated. The resultant residue was diluted with EtOAc:acetic acid (1.1 eq.) and concentrated. The resultant gummy orange-colored liquid was then diluted with a mixture of ether and EtOAc in a glass flask, and the wall of the flaks was scratched. The resultant solids were collected to provide B17 as an off-white solid. Yield: 4.4 g, 42%. IR (cm.sup.−1): 3484, 3343, 3166, 2975, 1644, 1601, 1560, 1505, 1412, 1313, 1136 and 1058. .sup.1HNMR (d.sub.f-DMSO): δ 8.62 (s, 1H), 7.4 (s, 1H), 4.7-5.3 (broad, 3H), 3.82 (s, 2H), 3.14 (d, 2H), 2.45 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 230 calculated 230 for C.sub.9H.sub.15N.sub.3O.sub.2S.

Preparation of N-(3-Aminomethyl-4-methyl-phenyl)-N-methyl-methanesulfonamide acetate (B18)

[0613] ##STR00053##

[0614] Step 1. Preparation of 5-amino-2-methyl-benzonitrile (B18-1): A stirred suspension of 2-methyl-5-nitro benzonitrile (20 g, 123.45 mmol) in a mixture of dioxane (640 mL), ethanol (480 mL) and water (160 mL) at 25° C. was treated with NH.sub.4Cl (26.4 g, 493.8 mmol) followed by treatment with iron powder (34.4 g, 617.2 mmol). The mixture was then heated at 80° C. for 16 hours. The mixture was filtered through a Celite® bed and concentrated. The resultant residue was diluted with EtOAc (600 mL), washed with water (150 ml) and brine (100 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated to provide B18-1 as an orange solid. Yield: 18.2 g. .sup.1HNMR (CDCl.sub.3): δ 7.08 (d, 1H), 6.84-6.9 (m, 1H), 6.75-6.82 (m, 1H), 3.65-3.82 (m, 2H) and 2.4 (s, 3H). Mass: (M+1) 133 calculated for C.sub.8H.sub.8N.sub.2. The product was used below to prepare B18-2 without further purification.

[0615] Step 2. Preparation of N-(3-cyano-4-methyl-phenyl)-methanesulfonamide (B18-2): A solution of B18-1 (18 g, 136.36 mmol) in pyridine (150 mL) was cooled to 0° C. and treated with mesyl chloride (12.6 mL, 163.63 mmol). The mixture was allowed to warm to 25° C., stirred for 20 hours, and concentrated. The resultant residue was diluted with EtOAc (500 mL), and washed with 2N HCl (50 mL), water (100 mL), and brine (50 mL). The organic solution was then dried over anhydrous sodium sulfate and concentrated to provide B18-2 as a yellow solid. Yield: 25.1 g, 87.3%. .sup.1HNMR (CDCl.sub.3): δ 7.5 (s, 1H), 7.3-7.45 (m, 2H), 7.1-7.25 (m, 1H), 3.05 (s, 3H) and 2.5 (s, 3H). Mass: (M+1) 209 calculated for C.sub.9H.sub.10N.sub.2O.sub.2S.

[0616] Step 3. Preparation of N-(3-cyano-4-methyl-phenyl)-N-methyl-methanesulfonamide (B18-3): A solution of B18-2 (25 g, 119.04 mmol) in a mixture of THF (200 ml) and 40% NaOH solution (200 ml) at 25° C. was treated with BTEAC (2.7 g, 11.9 mmol) and stirred vigorously for 20 minutes. The mixture was then treated with methyl iodide (8.89 ml, 142.8 mmol), stirred for 20 hours, and concentrated. The resultant residue was extracted with DCM (500 ml) and washed with water (100 mL) and brine (50 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by column chromatography (60-120 mesh silica gel; 40% EtOAc in hexane as eluting solvent) to provide B18-2 as a white solid. Yield: 26.2 g, 97%. .sup.1HNMR (CDCl.sub.3): δ 7.55-7.65 (m, 1H), 7.5-7.54 (m, 1H), 7.3-7.4 (m, 1H), 3.34 (s, 3H), 2.85 (s, 3H) and 2.55 (s, 3H). Mass: (M+1) 225 calculated for C.sub.10H.sub.12N.sub.2O.sub.2S.

[0617] Step 4. A solution of B18-3 (28 g, 124.4 mmol) in acetic acid (500 ml) and THF (200 ml) was charged to a Parr reactor and treated with 10% Pd/C (8 g). The contents of the reactor were then hydrogenated at 50 PSi hydrogen pressure and 25° C. for 4 hours. The mixture was filtered through a Celite® bed and washed with ethanol (50 mL). The combined filtrates were concentrated, and the resultant residue was azeotroped with EtOAc (3×50 mL). The resultant oily residue was dissolved in EtOAc (200 mL) and maintained at 25° C. for 20 hours. The resultant solids were collected and dried to provide B18 as a white solid. Yield: 2.9 g, 81%. .sup.1HNMR (d.sub.6-DMSO): δ 7.42 (s, 1H), 7.15 (s, 2H), 5.7-5.98 (broad, 3H), 3.72 (s, 2H), 3.2 (s, 3H), 2.95 (s, 3H), 2.25 (s, 3H) and 1.86 (s, 3H). Mass: (M+1) 229 calculated for C.sub.10H.sub.16N.sub.2O.sub.2S. HPLC Purity: 99.9%.

Preparation of N-(5-Aminomethyl-2-methyl-pyrimidin-4-yl)-N-methyl-methanesulfonamide acetate (B19)

[0618] ##STR00054##

[0619] Step 1. Preparation of 4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (B19-1): A mixture of water (410 mL) and a 50% NaOH solution (115.98 g, 2899 mmol) was cooled to 0° C. and treated with 2-methyl 2-thio pseudo urea sulfate (100 g, 359 mmol). The resultant clear solution was treated with a solution of ethoxy methylene malonate (155.38 g, 719 mmol) in ethanol (251 mL) and stirred until the reaction mixture was turbid. The mixture was then allowed to warm to 25°5, and it was allowed to stand at 25° C. for 20 hours. The resultant solids were collected, washed with ethanol (2×50 mL), and dried under reduced pressure to provide 819-1 as a pale yellow solid. Yield: 58 g, 75%. .sup.1HNMR (d.sub.6-DMSO): δ 8.25 (s, 1H), 4.12 (q, 2H), 2.32 (s, 3H) and 1.24 (t, 3H).

[0620] Step 2. Preparation of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (B19-2): Neat POCl.sub.3 (120 mL) was cooled to 10° C. and treated portion-wise over 4 hours with B19-1 (50 g, 232 mmol) without exceeding a temperature of 25° C. The mixture was then heated at 65° C. After 3 hours the mixture was cooled to 10° C., poured into crushed ice (350 g), treated drop-wise with water (676 mL) under vigorous stirring. The resultant solids were collected and dried under reduced pressure to provide B19-2 as a pale yellow solid. Yield: 22 g, 40%. .sup.1HNMR (CDCl.sub.3): δ 8.95 (s, 1H), 4.44 (q, 2H), 2.62 (s, 3H) and 1.42 (t, 3H).

[0621] Step 3. Preparation of 4-chloro-2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester (B19-3): A solution of B19-2 (40 g, 172 mmol) in methanol (720 mL) was cooled to 0° C. and treated with a slurry of oxone (317.9 g, 517 mmol) in distilled water (720 mL). The mixture was allowed to warm to 25° C. and stirred at 5 hours. The mixture was filtered, and the solids were washed with DCM (500 mL). The resultant organic layer was collected, and the aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were then washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide 019-2 as a white solid. Yield: 31 g, 68%. IR (cm.sup.−1): 3015, 2932, 1734, 1550, 1445, 1391, 1325, 1258, 1222, 1142 and 1067. .sup.1HNMR (CDCl.sub.3): δ 9.28 (s, 1H), 4.5 (q, 2H), 3.4 (s, 3H) and 1.45 (t, 3H). Mass: (M+1) 265 calculated for C.sub.8H9ClN.sub.2O.sub.4S.

[0622] Step 3. Preparation of 4-chloro-2-methyl-pyrimidine-5-carboxylic acid ethyl ester (B19-3): A solution of B19-2 (40 g, 151 mmol) in THF (700 mL) was cooled to 0° C. and treated drop-wise over 2 hours with a 3 molar solution of methyl magnesium chloride in THF (54 mL, 166 mmol). The mixture was allowed to warm to 25° C. and maintained for at 25° C. for 4 hours. The mixture was added to water (500 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate, and concentrated to provide B19-2 as a brown liquid. Yield: 30 g, 98%. IR (cm.sup.−1): 2983, 2934, 2868, 1736, 1574, 1523, 1434, 1373, 1269, 1181 and 1070. .sup.1HNMR (CDCl.sub.3): δ 9.1 (s, 1H), 4.5 (q, 2H), 2.74 (s, 3H) and 1.5 (t, 3H).

[0623] Step 3. Preparation of 4-(methanesulfonyl-methyl-amino)-2-methyl-pyrimidine-5-carboxylic acid ethyl ester (B19-3): A solution of N-methyl methane sulphonamide (18.2 g, 180 mmol) in acetonitrile (420 mL) was cooled to 0° C. and treated with cesium carbonate (68 g, 225 mmol). The mixture was then treated over 2 hours with B19-2 (30 g, 150 mmol). The mixture was allowed to warm to 25° C., and it was maintained at 25° C. for 20 hours. The mixture was then filtered, and the solids were washed with washed with EtOAc (200 mL). The combined filtrates were further diluted with EtOAc (500 mL), washed with water (2×500 mL) and brine, and dried over anhydrous sodium sulfate. The organic solution was then concentrated to provide B19-3 as an orange solid. Yield: 18 g, 44%. .sup.1HNMR (d.sub.6-DMSO): δ 8.94 (s, 1H), 4.3 (q, 2H), 3.25-3.3 (m, 6H), 2.65 (s, 3H) and 1.3 (t, 3H). Mass: (M+1) 274 calculated for C.sub.10H.sub.15N.sub.3O.sub.4S.

[0624] Step 4. Preparation of 4-(methanesulfonyl-methyl-amino)-2-methyl-pyrimidine-5-carboxylic acid amide (B19-4): A suspension of B19-3 (10 g, 36 mmol) in 25% NH.sub.4OH (100 mL) was heated at 32° C. for 20 hours. The mixture was concentrated under reduced pressure, and the resultant residue was triturated with EtOAc. The mixture was then filtered and concentrated. The resultant residue was purified by column chromatography (60-120 mesh silica gel; 10% MeOH in CHCl.sub.3 as eluting solvent) to provide 819-4 as a white solid. Yield: 3 g, 33%. .sup.1HNMR (d.sub.6-DMSO): δ 8.75 (s, 1H), 7.95 (s, 1H), 7.7 (s, 1H), 3.3-3.42 (m, 3H), 3.25 (s, 3H) and 2.65 (s, 3H). Mass: (M+1) 245 calculated for C.sub.8H.sub.12N.sub.4O.sub.3S.

[0625] Step 5. Preparation of N-(5-cyano-2-methyl-pyrimidin-4-yl)-N-methyl-methanesulfonamide (B19-5): A solution of B19-4 (5.2 g, 22.3 mmol) and pyridine (3.36 g, 42.6 mmol) in 1,4 dioxane (78 mL) was cooled to 0° C. and treated drop-wise over 10 minutes with TFA (5.8 g, 27.7 mmol). The mixture was allowed to warm to 25° C. After 4 hours the mixture was diluted with EtOAc (100 mL) and washed with water (2×200 mL). The aqueous layer was collected and washed with EtOAc (2×100 mL). The combined organic layers were then washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resultant residue was then washed with petroleum ether and dried to provide B19-5 as a pale yellow solid. Yield: 3.5 g, 76%. .sup.1HNMR (CDCl.sub.3): δ 8.84 (s, 1H), 3.54 (s, 3H), 3.4 (s, 3H) and 2.75 (s, 3H). Mass: (M−1) 225 calculated for C.sub.8H.sub.10N.sub.4O.sub.2S.

[0626] Step 6. A solution of B19-5 (5 g, 22 mmol) in 2N methanolic ammonia (350 mL) was charged to a Parr reactor and treated with 10% Pd/C (3.75 g, 35 mmol). The contents of the reactor were then hydrogenated at 48 Psi hydrogen pressure and 25° C. for 1 hour. The mixture was filtered through a Celite® bed and washed with methanol (200 mL). The combined filtrates were concentrated, and the resultant residue was diluted with EtOAc (25 mL) and acetic acid (1.3 g, 21 mmol). The mixture was stirred for 30 minutes, and the resultant solids were collected to provide B19 as a white solid. Yield: 4.2 g, 80%. IR (cm): 3433, 3381, 3017, 2930, 1720, 1591, 1555, 1446, 1331, 1148 and 1058. .sup.1HNMR (da-DMSO): δ 9.05 (s, 1H), 8.5-8.7 (broad s, 2H), 4.14 (s, 2H), 3.24 (s, 3H), 3.15 (s, 3H) and 2.66 (s, 3H). HPLC Purity: 99.9%.

[0627] 4-Chloro-pyrimidine intermediates were prepared by methods similar to that described below for compound B20.

Preparation of 4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-N-methylbenzamide (B20)

[0628] ##STR00055##

[0629] A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in 1:1 t-BuOH/DCE (10 mL) was cooled to 5° C., treated with solid ZnBr.sub.2 (22.5 mmol), and stirred at 5° C. for 30 minutes. The resultant solution was maintained at 5 C and treated first with solid 4-amino-N-methyl-benzamide (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25° C. and it was mixed at 25° C. for 20 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol/DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20. Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89 (m, 3H), 2.78 (d, J=4.67 Hz, 3H).

Example 1

(R)-tert-butyl 1-(4-(4-((2-(N-methylmethan-5-ylsulfonamido)pyridin-3-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate (1)

[0630] ##STR00056##

Step 1: Preparation of (R tert-butyl 1-(4-nitrophenyl)ethylcarbamate (C1)

[0631] ##STR00057##

[0632] (R)-1-(4-nitrophenyl)ethanamine hydrochloride salt (1.0 g, 4.9 mmol), tert-butoxycarbonyl (BOC) anhydride (1.18 g, 5.43 mmol), and 10.0 mL of 1M sodium bicarbonate solution were dissolved in DCM (15 mL) and allowed to stir at 25° C. for 24 h. The organic layer was collected, and the aqueous layer was washed with DCM. The combined organic layers were then washed with water and 0.1N HCl, dried over MgSO.sub.4, filtered, and concentrated to provide C1 as a white solid. Yield: 1.2 g, 92%. GC-MS=266. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 8.15 (d, 2H), 7.56 (d, 1H), 7.52 (d, 2H), 4.68 (m, 1H), 1.32 (s, 9H), 1.27 (d, 3H).

Step 2: Preparation of (R)-tert-butyl 1-(4-aminophenyl)ethylcarbamate (C2)

[0633] ##STR00058##

[0634] A solution of C1 (1.0 g, 3.8 mmol) in MeOH (20 mL) was charged to a Parr reactor, and the contents of the reactor were treated with 10% Pd/C (800 mg, 0.376 mmol). The contents of the reactor were then hydrogenated at 45 Psi hydrogen pressure and 25° C. for 4 hours. The contents of the reactor were filtered through Celite® and washed with DCM. The combined filtrates were concentrated to provide C2 as a sticky orange residue. Yield: 690 mg, 78% yield. GC_MS=236. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.07 (d, 1H), 6.88 (d, 2H), 6.43 (d, 2H), 4.85 (s, 2H), 4.40 (m, 1H), 1.31 (s, 9H), 1.18 (d, 3H).

Step 3. Preparation of (R)-tert-butyl 1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate (C3)

[0635] ##STR00059##

[0636] C2 (690 mg, 2.92 mmol) was dissolved in 10 mL DCE:t-BuOH (1:1 vol:vol), and the resultant solution was treated with ZnBr.sub.2 (1.97 g, 8.76 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (748 mg, 3.45 mmol). The resultant mixture was then treated drop-wise with TEA (406 ml, 2.92 mmol), and the mixture was allowed to stir at 25° C. for about 20 hours. The reaction mixture was concentrated, and the resultant residue was treated with EtOAc. The resultant solution was washed with water and brine, and dried over MgSO.sub.4. The mixture was then filtered, concentrated, and purified by column chromatography eluting with 22% EtOAc/Heptane. The product-containing eluents were combined and concentrated to provide C3 as a white solid. Yield: 680 mg, 56%. MS-415.2. .sup.1H NMR (500 MHz, DMSO) δ: 10.59 (s, 1H), 8.74 (s, 1H), 7.53 (d, 2H), 7.31 (d, 1H), 7.23 (d, 2H), 4.54 (m, 1H), 1.33 (s, 9H), 1.25 (d, 3H).

Step 4

[0637] Compound C3 (100 mg, 0.24 mmol), B5 (88.5 mg, 0.264 mmol), and diethylamine (DIEA) (0.127 ml, 0.960 mmol) were dissolved in 1,2-dichloroethane (DCE):t-BuOH (1:1 vol:vol) (1.2 mL). The resultant solution was heated at 80° C. for about 20 hours, cooled to 25° C., treated with EtOAc, and washed with water. The organic phase was collected, and the aqueous phase was washed with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated to provide 1 as a sticky residue. MS.sup.+ 596.8. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.50 (s, 1H), 8.41 (m, 1H), 8.22 (s, 1H), 7.61 (m, 2H), 7.35 (m, 3H), 6.99 (d, 2H), 4.76 (d, 2H), 4.47 (m, 1H), 3.14 (s, 3H), 3.11 (s, 3H), 1.33 (s, 9H), 1.21 (d, 3H). The product was used in the preparation of compound 2 in Example 2 below without further purification.

Example 2

Preparation of (R)—N-(3-((2-(4-(1-aminoethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide hydrochloride (2)

[0638] ##STR00060##

[0639] A solution of 1 (143 mg, 0.24 mmol) in THF (0.3 mL) was treated with 4N HCl in dioxane (0.240 ml, 0.96 mmol), and stirred at 25° C. for about 20 hours. The reaction mixture was then triterated with EtOAc and filtered, and the filtrate was concentrated to provide the HCl salt form of 2 as a white solid. Yield: 128 mg, 94% yield. MS.sup.− 494.0. .sup.1H NMR (500 MHz, d.sub.6-DMSO): δ 10.2 (s, 1H), 8.40 (m, 4H), 8.12 (s, 1H), 7.67 (d, 1H), 7.45 (m, 3H), 7.27 (d, 2H), 4.84 (d, 2H), 4.28 (m, 1H), 3.16 (s, 3H), 3.14 (s, 3H), 1.45 (d, 3H). FAK IC.sub.50: <0.000595 μM (Table 1, Example 354)

Example 3

Preparation of tert-butyl 4-(4-((2-(N-methylmethan-5-ylsulfonamido)pyridin-3-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzylcarbamate (3)

[0640] ##STR00061##

Step 1: Preparation of tert-butyl 4-nitrobenzylcarbamate (C4)

[0641] ##STR00062##

[0642] A stirred solution of (4-nitrophenyl)methanamine hydrochloride (10 g, 53.0 mmol) in THF (150 mL) and water (13 mL) was cooled to 0° C. and treated with BOC anhydride (11.6 g, 53.0 mmol) and DIEA (27.7 mL, 159 mmol). The reaction mixture was stirred for about 20 hours as it was allowed to warm to 25° C. The mixture was then concentrated, and the resultant residue was dissolved in EtOAc. The resultant solution was washed with 1N HCl, saturated sodium bicarbonate, and brine. The organic phase was then dried over MgSO.sub.4, filtered, and concentrated to provide C4 as an off white solid. Yield: 14.0 g, 99%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 8.16 (d, 2H), 7.55 (t, 1H), 7.46 (d, 2H), 4.21 (d, 2H), 1.36 (s, 9H).

Step 2. Preparation of tert-butyl 4-aminobenzylcarbamate (C5)

[0643] ##STR00063##

[0644] C4 (7.0 g, 27.7 mmol) was dissolved in dioxane (325 mL), ethanol (240 mL), and water (160 mL). The resultant solution was then treated with Fe(0) powder (7.12 g, 127.4 mmol) and ammonium chloride (5.33 g, 99.7 mmol), and the resultant mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled to 25° C., filtered through Celite®, and washed with EtOAc. The organic solvents were evaporated, and the resultant aqueous residue was extracted with EtOAc. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated to provide C5 as a yellow solid. Yield: 6.52 g, 99% yield. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 7.146 (t, 1H), 6.87 (d, 2H), 6.48 (d, 2H), 4.95 (s, 2H), 3.92 (d, 2H), 1.38 (s, 9H).

Step 3. Tert-butyl 4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)benzylcarbamate (C6)

[0645] ##STR00064##

[0646] Compound C6 was prepared as a white solid in a manner similar to that described in Step 3 of Example 1 except that C5 (1.30 g, 5.86 mmol) was used instead of C2. Yield: 1.37 g, 49%. MS.sup.− 401.1. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 10.6 (s, 1H), 8.75 (s, 1H), 7.56 (d, 2H), 7.34 (t, 1H), 7.18 (d, 2H), 4.05 (d, 2H), 1.36 (s, 9H).

[0647] Step 4. Compound 3 was prepared as a white solid in a manner similar to that described in Step 4 of Example 1 except that C6 (1.2 g, 2.98 mmol) was used instead of C3, and the resultant crude product was purified by column chromatography, eluting with 45-55% EtOAc/Heptane. Yield: 1.17 g, 68%. MS' 582.3. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.57 (s, 1H), 8.42 (s, 1H), 8.58 (s, 1H), 7.64 (m, 2H), 7.35 (m, 4H), 6.94 (d, 2H), 4.80 (d, 2H), 3.98 (d, 2H), 3.16 (s, 3H), 3.14 (s, 3H), 1.39 (s, 9H).

Example 4

Preparation of N-(3-((2-(4-(aminomethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (4)

[0648] ##STR00065##

[0649] The HCl salt form of 4 was prepared as a white solid in a manner similar to that described for preparing 2 in Example 2 except that 3 (1.0 g, 1.72 mmol) was used instead of 1.

[0650] The salt form of 4 was dissolved in DCM, and was washed with saturated sodium bicarbonate. The organic phase was then dried over Na.sub.2SO.sub.4, filtered, and concentrated to provide the free-base form of 4 as a foamy white solid. Yield: 904 mg, 99%. MS.sup.+ 482. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.50 (s, 1H), 8.44 (d, 1H), 8.25 (s, 1H), 7.66 (d, 1H), 7.57 (t, 1H), 7.38 (m, 3H), 7.04 (d, 2H), 4.80 (d, 2H), 3.58 (d, 2H), 3.17 (s, 3H), 3.13 (s, 3H). FAK IC.sub.50: 0.00059 μM (Table 1, Example 104)

Example 5

Preparation of N-(4-(4-((2-(N-methylmethan-5-ylsulfonamido)pyridin-3-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzyl)acetamide (5)

[0651] ##STR00066##

[0652] The free-base form of 4 (80 mg, 0.166 mmol), acetic anhydride (0.019 ml, 0.199 mmol), and DIEA (0.043 ml, 0.249 mmol) were dissolved in THF (0.5 ml) and stirred at 25° C. for 24 hours. The reaction mixture was then treated with EtOAc and washed with 1N NaOH. The resultant organic layer was dried over MgSO.sub.4, filtered, and concentrated to provide 5 as a white solid. Yield: 63 mg, 73%. MS.sup.+ 524.5. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.55 (s, 1H), 8.44 (d, 1H), 8.25 (s, 1H), 8.22 (t, 1H), 7.60 (m, 2H), 7.38 (m, 3H), 6.96 (d, 2H), 4.80 (d, 2H), 4.11 (d, 2H), 3.16 (s, 3H), 3.13 (s, 3H), 1.85 (s, 3H). FAK IC.sub.50: 0.0006 μM

Example 6

Preparation of N-(3-((2-(4-(hydroxymethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (6)

[0653] ##STR00067##

Step 1. Preparation of (4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)methanol (C7)

[0654] ##STR00068##

[0655] Step 1. C7 was prepared in a manner similar to that described in for making C3 in Step 3 of Example 1 except that 4-aminobenzyl alcohol (2.4 g, 19 mmol) was used instead of C2. When the reaction was complete the reaction mixture was concentrated and dissolved in EtOA. The resultant solution was washed with water, brine, dried over MgSO.sub.4, and concentrated. The resultant tan solid was triterated with ether and a small amount of EtOAc, filtered and concentrated to provide C7 as a tan solid. Yield: 2.98 g, 50%. MS 304.1. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 10.61 (s, 1H), 8.76 (s, 1H), 7.59 (d, 2H), 7.26 (d, 2H), 5.10 (bs, 1H), 4.43 (s, 2H).

[0656] Step 2. Compound 6 was prepared in a manner similar to that described for making compound 1 in Step 4 of Example 1, except that C7 (2.5 g, 8.2 mmol) was used instead C3. When the reaction was complete the reaction mixture was concentrated and dissolved in EtOA. The resultant solution was washed with water, brine, and dried over MgSO.sub.4, and concentrated. The resultant solid was triterated with hot EtOAc. and the mixture was cooled to 0° C. and filtered to provide 6 as a white solid. Yield: 2.94 g, 74%. MS.sup.+ 483.4. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.50 (s, 1H), 8.41 (d, 1H), 8.22 (s. 1H), 7.62 (d, 1H), 7.55 (t, 1H), 7.36 (m, 3H), 6.99 (d, 2H), 4.98 (t, 1H), 4.76 (d, 2H), 4.32 (d, 2H), 3.13 (s, 3H), 3.11 (s, 3H). FAK IC.sub.50: <0.000595 μM (Table 1, Example 319)

Example 7

Preparation of N-(3-((2-(4-(chloromethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (7)

[0657] ##STR00069##

[0658] A suspension of 6 (800 mg, 1.66 mmol) in DCM (5 mL) was cooled to 0° C. and treated with a solution of thionyl chloride (0.266 ml, 3.65 mmol) in DCM (2.0 mL). The reaction mixture was allowed to warm to 25° C. and stirred at 25° C. for 20 hours. The reaction mixture was then treated with DCM and washed with water (2×). The aqueous layer was collected and washed with DCM. The combined organic layers were then dried over MgSO.sub.4, filtered and concentrated to provide 7 as a white solid. Yield: 668 mg, 80%. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 6.68 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.64 (m, 2H), 7.42 (m, 3H), 7.14 (d, 2H), 4.82 (d, 2H), 4.66 (s, 2H), 3.17 (s, 3H), 3.15 (s, 3H). FAK IC.sub.50: 0.00155 μM (Table 1, Example 348)

Example 8

Preparation of N-(3-((2-(4-((1,3-dihydroxypropan-2-ylamino)methyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (8)

[0659] ##STR00070##

[0660] A mixture of 7 (100 mg, 0.200 mmol), 2-amino-1,3-propanediol (90.9 mg, 0.998 mmol), sodium hydroxide (7.98 mg, 0.200 mmol) and 2-propanol (0.5 mL) was heated to reflux. After 30 minutes the mixture was cooled, treated with DCM, and washed with water. The organic phase was dried over MgSO.sub.4, filtered and concentrated. The resultant residue was then purified by column chromatography (silica gel; eluting with 6% MeOH/DCM with NH.sub.4OH), and the eluents containing the product were combined and concentrated to provide 8 as a white solid. Yield: 60.9 mg, 55%. MS' 556.2. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 9.48 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.59 (m, 2H), 7.34 (m, 3H), 6.99 (d, 2H), 4.75 (d, 2H), 4.35 (t, 2H), 3.58 (s, 2H), 3.34 (m, 4H), 3.12 (s, 3H), 3.09 (s, 3H), 2.45 (m, 1H). FAK IC.sub.50: <0.000595 μM (Table 1, Example 389)

Example 9

Preparation of tert-butyl 3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl)methyl}amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoate (9)

[0661] ##STR00071##

Step 1. Preparation of tert-butyl 3-({4-chloro-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoate (C8)

[0662] ##STR00072##

[0663] A solution of pyrimidine (24.8 g, 115 mmol) in tert-butanol (150 ml) and DCE (150 ml) was treated with ZnBr.sub.2 (25.8 g, 115 mmol), and the resultant mixture was stirred at 25° C. until all the ZnBr.sub.2 dissolved. The resultant solution was cooled to 0° C. and treated drop-wise with aniline (22.13 g, 115 mmol). The resultant brown mixture was then treated drop-wise with DIEA (40.1 ml, 230 mmol). The mixture was allowed to warm to 25° C. and stirred for 16 hours under N.sub.2 atmosphere. The mixture was concentrated, and the resultant residue was suspended in MeOH. The resultant white solids were collected to provide Ca as a white solid. Yield: 22.7 grams, 53%. APCI m/z 371.8/373.8 (M.sup.−); .sup.1H NMR (d.sub.6-DMSO) δ: 10.84 (bs, 1H), 8.85 (s, 1h), 8.37 (bs, 1H), 7.92 (d, J=7.8 Hz., 1h), 7.62 (d, J=7.8 Hz., 1H), 7.48 (t, J=7.8 Hz., 1H), 1.56 (s, 9H) ppm.

[0664] Step 2. A solution of tert-butanol (20.0 mL), DCE (20.0 mL) and DIEA (3.13 mL, 18.0 mmol) was treated with C.sub.8 (5.60 g, 15.0 mmol) and B5 (5.02 g, 15.0 mmol), and the resulting mixture was stirred at 80° C. under an atmosphere of nitrogen for 16 hours. The mixture was cooled to 25° C. and concentrated. The resultant residue was partitioned between EtOAc and 1 N sodium hydroxide, and the organic phase was collected. The aqueous layer was extracted with EtOAc, and the combined organic phases were dried over MgSO.sub.4 and filtered. The resultant filtrate was concentrated under reduced pressure, and the resultant residue was triturated with hot EtOAc to provide 9 as a white solid. Yield: 7.83 grams, 95%. LC/MS (standard) 25°=3.0 min., m/z 553.6 (MH.sup.+). HPLC (FAK1) 25°=8.14 min. .sup.1H NMR (dg-DMSO) δ: 9.75 (bs, 1H), 8.44 (d, J=5.2 Hz., 1H), 8.29 (s, 1H), 8.05 (bs, 1H), 7.82 (d, J=7.8 Hz., 1H), 7.60 (t, J=5.7 Hz., 1H), 7.44-7.40 (m, 2H), 7.17 (t, J=5.7 Hz, 1H), 4.82 (d, J=5.7 Hz., 2H), 3.16 (s, 3H), 3.13 (s, 3H), 1.51 (s, 9H) ppm. FAK IC.sub.50: 0.0006 μM

Example 10

Preparation of 3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoic acid trifluoroacetic acid salt (10)

[0665] ##STR00073##

[0666] A solution of 9 (7.83 g, 14.1 mmol) in DCE (30.0 mL) was cooled to 0° C. and treated slowly with TFA (45.0 mL). The resultant orange-brown solution was allowed to slowly warm to 25° C. under an N.sub.2 atmosphere and stirred for 4 hours. The mixture was then concentrated, and the resultant residue was treated with EtOAc. The resultant white solids were collected by filtration and washed with EtOAc to provide the trifluoroacetate salt form of 10. Yield: 7.24 grams, 84%. APCI m/z 496.8 (MH.sup.+), HPLC (FAK1) 25°=5.29 min., .sup.1H NMR (d.sub.6-DMSO) &: 9.82 (bs, 1H), 8.44 (d, J=5.2 Hz., 1H), 8.29 (s, 1H), 8.08 (bs, 1H), 7.79 (d, J=7.8 Hz., 1H), 7.60-7.38 (m, 4H), 7.17 (t, J=5.7 Hz, 1H), 4.82 (d, J=5.7 Hz., 2H), 3.16 (s, 3H), 3.13 (s, 3H) ppm. FAK IC.sub.50: 0.0006 μM

Example 11

Preparation of N-cyclopropyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide (11)

[0667] ##STR00074##

[0668] A polymer supported carbodiimide (PS-CDI) (0.326 mmol) was allowed to swell in acetonitrile (volume of 500 μL). The resultant suspension was treated with 10 (100 mg, 0.164 mmol) and DIEA (29 μL, 0.164 mmol). The resultant solution was then treated with cyclopropylamine (19 μL, 0.164 mmol). The resultant suspension was then mixed on a shaker plate for 16 hours. The mixture was then filtered, and the solids washed with 10% MeOH in chloroform. The combined filtrates were concentrated under reduced pressure, and the resultant residue was purified over silica (99:1:0.1 CHCl.sub.3:CH.sub.3OH:NH.sub.4OH) to provide 11 as a white foam. Yield: 14.3 mg, 16%. LC Ret. Time (standard)=2.1 min., m/z 536.2 (MH.sup.+); .sup.1H NMR (CD.sub.3OD) δ: 8.42 (d, J=7.8 Hz., 1H), 8.20 (s, 1h), 7.97 (t, J=7.8 Hz., 1H), 7.81 (d, J=7.8 Hz., 1H), 1.68 (d, J=7.8 Hz., 1H), 7.39-7.34 (m, 2H), 7.26 (t, J=7.8 Hz., 1H), 4.94 (s, 2H), 3.23 (s, 3H), 3.14 (s, 3H), 2.82 (m, 1H), 0.79 (m, 2 h), 0.60 (m, 2H) ppm. FAK IC.sub.50: 0.00186 μM

Example 12

Preparation of N-(3-((2-(4-(1-hydroxyethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (12)

[0669] ##STR00075##

Step 1. N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (C9)

[0670] ##STR00076##

[0671] A solution of B5 and trifluoroethanol (120 mL) was treated with triethylamine (TEA) (16.6 mL) and stirred at 25° C. for 1 hour. In a separate reaction flask, a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (13.2 g, 60.8 mmol) and trifluoroethanol (120 mL) was cooled to −45° C. The cold 2,4-dichloro-5-trifluoromethylpyrimidine solution was then treated drop-wise with the solution containing B5 and stirred at −45° C. for 2 hours. The mixture was allowed to warm to 25° C., and it was stirred at 25° C. for about 20 hours. The reaction mixture was then concentrated and cooled to 0° C. The resultant white mixture was diluted with EtOAc (15 ml), and the solids collected by filtration. The white solids were then washed with water and EtOAc to provide C9. Yield: 0.7 g, 45%. .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 3.07 (s, 3H), 3.29 (s, 3H), 4.68 (d, 2H), 7.39 (m, 1H), 7.72 (d, 1H), 8.40 (s, 1H), 8.50 (t, 1H); ESI-MS: 396.0 (MH.sup.+).

[0672] Step 2. A solution of C9 (0.253 mmol) and anhydrous DMSO (0.5 ml) was treated with 1-(4-aminophenyl)ethanol (0.277 mmol) followed by potassium phosphate dibasic (0.746 mmol). The mixture was stirred at 100° C. for 1.5 days, and treated with additional 1-(4-aminophenyl)ethanol (0.583 mmol). The mixture was stirred at 100° C. for 15 hours and concentrated. The resultant residue was purified first by column chromatography (silica gel; 10% (NH.sub.4OH/MeOH)/CH.sub.2Cl.sub.2) followed by preparatory thin layer chromatography developed in 5% MeOH/CH2Cl2 to provide 12. Yield: 13.6 mg, 10.8%. .sup.1H NMR (CD.sub.3OD) δ: 8.39 (d, 1H), 8.13 (s, 1H), 7.73 (d, 1H), 7.33 (m, 3H), 7.14 (d, 2H), 4.87 (s, 2H), 4.72 (q, 1H), 3.17 (s, 3H), 3.10 (s, 3H), 1.37 (d, 3H). MS: m/z 497 (MH.sup.+).

Example 13

Preparation of 2-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide formic acid salt (13)

[0673] ##STR00077##

[0674] A mixture of 4-amino-2-fluorobenzamide (1.5 eq., 189 μM) In 2-propanol (1.0 mL) was treated with C9 (1 equiv., 130 uM) followed by trifluoroacetic acid (2.7 equiv., 341 μM) and stirred in a sealed vial at 100° C. for about 20 hours. The mixture was then cooled to 25° C., treated with DMSO, filtered, and purified on a Shimadzu using a reverse phase Symmetry C-8 column and eluting with 20-80% B for 10 min at 40 ml/min (A:0.1% formic acid in water, B: 0.1% formic acid in acetonitrile to provide the formic acid salt of 13 as a cream colored solid. Yield: 17.5 mg, 27%. LC-MS M+1=514. NMR (d.sub.6-DMSO) δ: 3.13 (6H, s), 4.81 (2H, s), 7.30-7.40 (6H, m), 7.41-7.73 (2H, m), 8.3 (1H, s), 8.41 (1H, s), 9.96 (1H, s). FAK IC.sub.5n: <0.000595 μM (Table 1, Example 320)

Example 14

Preparation of 3-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide formic acid salt (14)

[0675] ##STR00078##

[0676] Compound 14 was prepared in a manner similar to that described Example 13 for the preparation of 13 except that 4-amino-3-fluorobenzamide (1.5 equ/189 μM) was used instead of 4-amino-2-fluorobenzamide to provide the formic acid salt of 14 as a cream colored solid. Yield: 26 mg, 37%. LC-MS M+1=514. NMR (d.sub.6-DMSO) δ: 2.98 (3H, s), 3.09 (3H, s), 4.65 (2H, s), 7.35-7.66 (7H, m), 7.87 (1H, s), 8.23 (1H, s), 8.38 (1H, s), 9.19 (1H, s). FAK IC.sub.50: <0.000595 μM (Table 1, Example 322)

Example 15

Preparation of 4-(4-{([(3-methanesulfonyl-methyl-amino)-pyrazin-2-ylmethyl]-amino}-5-(trifluoromethyl)-pyrimidin-2-ylamino)-N-methyl-benzamide (15)

[0677] ##STR00079##

[0678] Step 1. A suspension of B20 (0.3 mmol), B2 (0.3 mmol), and diisopropylethyl amine (0.9 mmol) in 1:1 (v:v) DCE/tBuOH was mixed at 80° C. for 9 hours. The mixture was allowed to cool to 25° C., and it was mixed at 25° C. for 20 hours. The mixture was then treated with 9:1 (v:v) ether/ethanol. The solids were collected and washed with water to provide 15. Yield: 0.23 mmol, 78%. HPLC (KDC 10_90) 3.526 min. .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ ppm 9.83 (s, 1H), 8.69 (d, J=2.59 Hz, 1H), 8.58 (d, J=2.59 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J=4.67 Hz, 1H), 7.58-7.70 (m, 3H), 7.41 (t, J=5.18 Hz, 1 H), 5.00 (d, J=5.18 Hz, 2H), 3.23 (s, 3H), 3.20 (s, 3H), 2.75 (d, J=4.15 Hz, 3H). FAK IC.sub.50: <0.000595 μM (Table 1, Example 317)

Example 15A

Preparation of 4-(4-{[(3-methanesulfonyl-methyl-amino)-pyrazin-2-ylmethyl]-amino}-5-(trifluoromethyl)-pyrimidin-2-ylamino)-N-methyl-benzamide hydrochloride salt (15A)

[0679] ##STR00080##

[0680] Step 1. A suspension of B20 (26.3 mmol), B2 (28.9 mmol) and diisopropylethyl amine (105 mmol) was mixed in 1:1 DCE:tBuOH (80 mL) and heated to 88° C. in a sealed flask for 1.5 hour. The mixture turned green and a solid precipitated. The suspension was diluted with Et2O/EtOH (10:1) and filtered to obtain 10.1 g of a white solid (75%). 8 g of this product was slurried in 400 mL of MeOH and to the mixture was added 18 mL 4.0M HCl in dioxane. This was stirred at room temperature for 1 hour, then it was filtered to obtain 15A as an off-white solid HCl salt (˜quant yield). 1H NMR (400 MHz, DMSO-de) 8 ppm 2.75 (d, J=3.74 Hz, 3H), 3.18 (m, 6H), 5.01 (d, J=4.98 Hz, 2H), 7.52 (d, 2H), 7.67 (d, J=8.72 Hz, 2H), 7.98 (br. s., 1H), 8.29 (d, J=4.15 Hz, 1H), 8.42 (s, 1H), 8.59 (d, 1H), 8.68 (d, 1H), 10.38 (s, 1H). ESI-MS: 511.1 (MH.sup.+), 509.2 (M-H). FAK IC.sub.50: 0.00179 μM (Table 1, Example 318)

Examples 16-415

[0681] Compounds 16-415 in Examples 16-415 (see Table 1) were prepared by the methods described above in the Detailed Description of the invention and as described in Examples 1-15A. The amines used in these reactions were obtained commercially and used as received, prepared as described above for compounds B1-B20 or in Examples 1-15A above, or prepared by common synthetic methods for amines known to those skilled in the art. Unless otherwise noted, compounds having chiral centers were prepared as racemic mixtures.

[0682] Table 1 also contains biological kinase inhibition (IC50 values) for compounds 16-415.

[0683] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

TABLE-US-00001 TABLE 1 IC50 values against FAK kinase. Ex. Structure Compound Name FAK IC50, μM 16 [00081] 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzenesulfon-amide (16) 0.00409 17 [00082] 4-({4-[({6-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzene-sulfonamide (17) 0.00126 18 [00083] 4-{[4-{[3-(methylsulfonyl)benzyl]amino}-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzene-sulfonamide (18) 0.0132  19 [00084] 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (19) 0.0034  20 [00085] 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (20), hydrochloride salt 0.0006  21 [00086] 4-({4-[({6-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino) benzamide (21) 0.001   22 [00087] 4-{[4-{[3-(methylsulfonyl)benzyl]amino}-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (22) 0.00356 23 [00088] N-methyl-N-[3-({[2-{[6- (methylsulfonyl)pyridin-3-yl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (23) 0.0686  24 [00089] N-4-[3-(methylsulfonyl)benzyl]-N-2-[6- (methylsulfonyl)pyridin-3-yl]-5- (trifluoromethyl)-pyrimidine-2,4-diamine (24) 0.337   25 [00090] N-methyl-N-[6-methyl-3-({[2-{[6- (methylsulfonyl)pyridin-3-yl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (25) 0.0129  26 [00091] N-methyl-N-[3-({[2-{[6- (methylsulfonyl)pyridin-3-yl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl] methanesulfonamide (26) 0.154   27 [00092] N-[3-({[2-{[4-(1,1-dioxidoisothiazolidin-2- yl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N- rnethylmethane-sulfonamide (27) 0.00138 28 [00093] N-[3-({[2-{[4-(1,1-dioxidoisothiazolidin-2- yl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-6-methylpyridin-2-yl]-N- methylmethanesulfonamide (28) 0.00201 29 [00094] N~2~-[4-(1,1-dioxidoisothiazolidin-2- yl)phenyl]-N~4~-[3- (methylsulfonyl)benzyl]-5- (trifluoromethyl)pyrimidine-2,4-diamine (29) 0.00209 30 [00095] N-methyl-N-{3-[({2-[(4- {[(methylsulfonyl)amino]methyl}phenyl) amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (30) 0.00072 31 [00096] N-[3-({[2-({3- [(aminosulfonyl)methyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (31) 0.00222 32 [00097] N-methyl-N-{3-[({2-[(3- {[(methylsulfonyl)amino]methyl}phenyl) amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (32) 33 [00098] N-methyl-N-{3-[({2-[(3- {[(methylsulfonyl)amino]methyl}phenyl) amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl)pyridin-2- yl}methanesulfonamide (33), hydrochloride salt 0.00133 34 [00099] 4-{[5-bromo-4-({3- [methyl(methylsulfonyl)amino]benzyl} amino)pyrimidin-2- yl]amino}benzenesulfonamide (34) 0.0156  35 [00100] 4-[(5-bromo-4-{[3- (methylsulfonyl)benzyl]amino}pyrimidin-2- yl)amino]benzene-sulfonamide (35) 0.0176  36 [00101] N-methyl-N-[3-({[2-{[1- (methylsulfonyl)piperidin-4-yl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (36) 0.188   37 [00102] N-methyl-N-[3-({[2-{[1- (methylsulfonyl)piperidin-4-yl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (37), trifluoroacetic acid salt 38 [00103] N-[3-({[2-(cyclobutylamino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (38) 0.497   39 [00104] N-[3-({[2-{[(3R)-1-acetylpyrrolidin-3- yl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (39) 1       40 [00105] methyl 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzoate (40) 0.00059 41 [00106] 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzoic acid (41) 42 [00107] 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzoic acid (42), sodium salt 0.188   43 [00108] 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzoic acid (43), trifluoroacetic acid salt 0.0006  44 [00109] N-methyl-N-[3-({[2-(piperidin-4-ylamino)- 5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (44) 0.188   45 [00110] N-{3-[({2-[(1-acetylpiperidin-4-yl)amino]-5 (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (45) 0.188   46 [00111] N-4-[3-(methylsulfonyl)benzyl]-N-2- phenyl-5-(trifluoromethyl)pyrimidine-2,4- diamine (46) 0.00102 47 [00112] 3-methoxy-4-{[4-{[3- (methylsulfonyl)benzyl]amino}-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (47) 0.00059 48 [00113] 3-methoxy-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (48) 0.00059 49 [00114] 3-methoxy-4-({4-[({6-methyl-2- [methyl(methylsulfonyl)-amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (49) 0.00059 50 [00115] N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (50) 0.00059 51 [00116] N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-6-methylpyridin-2-yl]- N-methylmethanesulfonamide (51) 0.00059 52 [00117] N-methyl-4-{[4-{[3- (methylsulfonyl)benzyl]amino}-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (52) 0.00195 53 [00118] N-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (53) 0.00059 54 [00119] N-methyl-4-({4-[({6-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (54) 0.00059 55 [00120] N-[3-({[2-{[1-(methoxyacetyl)piperidin-4- yl]ammo}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (55) 0.188   56 [00121] N-{2-(4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)piperidin-1-yl]-2- oxoethyl}acetamide (56) 0.188   57 [00122] 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)piperidine-1-carboxamide (57) 0.188   58 [00123] N-methyl-N-[3-({[5-(trifluoromethyl)-2-{[1- (3,3,3-trifluoropropanoyl)piperidin-4- yl]amino}pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (58) 0.165   59 [00124] 6-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)nicotinamide (59) 0.00893 60 [00125] ethyl cis-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)cyclohexanecarboxylate (60) 0.188   61 [00126] 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)-N- pyridin-2-ylbenzenesulfonamide (61) 0.00102 62 [00127] N-[2-({[2-anilino-5- (trifluoromelhyl)pyrimidin-4- yl]amino}methyl)-5- methylphenyl]methanesulfonamide (62) 0.0103  63 [00128] N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-4-methylphenyl]-N- methylmethanesulfonamide (63) 0.0006  64 [00129] N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-6-methylphenyl]-N- methylmethanesulfonamide (64) 0.0006  65 [00130] N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-5-methylphenyl]-N- methylmethanesulfonamide (65) 0.0006  66 [00131] N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-4-methylphenyl]-N- methylmethanesulfonamide (66) 0.0006  67 [00132] N-[2-({[2-anilino-5- (trifluorornethyl)pyrimidin-4- yl]amino}methyl)-3-methylphenyl]-N- methylmethanesulfonamide (67) 0.0006  68 [00133] N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl] methanesulfonamide (68) 0.00059 69 [00134] N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-3- methylphenyl]methane-sulfonamide (69) 0.0006 

TABLE-US-00002 Ex. Structure Compound Name FAK IC50, μM  70 [00135] N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-5- methylpyridin-2-yl]-N- methylmethanesulfonamide (70) 0.0006   71 [00136] 4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (71) 0.0006   72 [00137] 4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (72), hydrochloride salt  73 [00138] 4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (73) 0.0006   74 [00139] 4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (74), hydrochloride salt  75 [00140] N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]- N-methylmethane-sulfonamide (75) 0.0006   76 [00141] N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-3-yl]- N-methylmethane-sulfonamide (76) 0.093    77 [00142] N-ethyl-4-{[4-{[3- (methylsulfonyl)benzyl]amino}- 5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (77) 0.0006   78 [00143] N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-4- methylpyridin-2-yl]-N- methylmethanesulfonamide (78) 0.0006   79 [00144] N-[5-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-2- methylpyrimidin-4-yl]-N- methylmethanesulfonamide (79) 0.00262   80 [00145] N-[5-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-2- methylpyridin-4-yl]-N- methylmethanesulfonamide (80) 0.00059   81 [00146] N-methyl-N-[3-({[5- (trifluoromethyl)-2-{[6- (trifluoromethyl)pyridin-3- yl]amino}pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (81) 0.0158   82 [00147] 4-({4-[({5-methyl-2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (82) 0.0006   83 [00148] 4-({4-[({4-methyl-2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (83) 0.0006   84 [00149] 4-({4-[({2-methyl-4- [methyl(methylsulfonyl)amino] pyrimidin-5-yl}methyl)amino]- 5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (84) 0.00171   85 [00150] 4-({4-[({6-methyl-4- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (85) 0.00084   86 [00151] N-methyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (86) 0.00161   87 [00152] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethy)pyrimidin-2- yl}amino)-N-[3- (trifluoromethyl)phenyl] benzamide (87)  88 [00153] 3-({4-[({2- [methyl(tnethylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-[3- (trifluoromethyl)phenyl] benzamide (88), hydrochloride salt 0.0215   89 [00154] N-ethyl-4-({4-[({6-methyl-2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (89) 0.0006   90 [00155] N-[3-({[2-({3-[(3- hydroxyazetidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (90) 0.00072   91 [00156] N-{3-[({2-[(1-ethyl-1H- pyrazol-5-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (91) 0.188    92 [00157] N-{3-[({2-[(2-chloropyridin-4- yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (92) 0.00192   93 [00158] N-{3-[({2-[(2-methoxypyridin- 4-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (93) 0.0006   94 [00159] N-methyl-N-{3-[({2-[(3- methylpyridin-4-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (94) 0.00801   95 [00160] N-{3-[({2-[(4- cyanophenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (95) 0.0006   96 [00161] N-methyl-4-{[4-({2- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (96) 0.00059   97 [00162] N-ethyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (97) 0.00059   98 [00163] ethyl [4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]acetate (98) 0.00059   99 [00164] 4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (99) 0.00038  100 [00165] 4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (100), hydrochloride salt 101 [00166] N-methyl-4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (101) 0.00059  102 [00167] N-[5-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)pyridin-2- yl]acetamide (102) 0.00233  103 [00168] N-methyl-4-({4-[({6-methyl-4- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (103) 0.00059  104 [00169] N-[3-({[2-([4- (aminomethyl)phenyl]amino}- 5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (104) 0.00059  105 [00170] [4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]acetic acid (105) 0.00094  106 [00171] 4-{[4-({2-methyl-5- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (106) 0.00096  107 [00172] 4-{[4-({2-methyl-6- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (107) 0.00059  108 [00173] 4-{[4-({3-methyl-2- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (108) 0.0006  109 [00174] 4-{[4-({4-methyl-2- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (109) 0.0006  110 [00175] 4-{[4-({5-methyl-2- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (110) 0.0006  111 [00176] 4-{[4-({2- [(methylsulfonyl)amino]benzyl} amino)-5- (trifluoromethy)pyrimidin-2- yl]amino}benzamide (111) 0.0006  112 [00177] 4-{[4-({4-methyl-2- [(methylsulfonyl)amino]benzyl} amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (112) 0.0006  113 [00178] 4-{[4-({2-methyl-6- [(methylsulfonyl)amino]benzyl} amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (113) 0.0006  114 [00179] N-(2-hydroxyethyl)-N-methyl- 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (114) 115 [00180] N-(2-hydroxyethyl)-N-methyl- 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (115), trifluoroacetic acid salt 0.00088  116 [00181] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-[(2R)- tetrahydrofuran-2- ylmethyl]benzamide (116) 117 [00182] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-[(2R)- tetrahydrofuran-2- ylmethyl]benzamide (117), trifluoroacetic acid salt 0.00147  118 [00183] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(tetrahydro-2H- pyran-3-yl)benzamide (118) 119 [00184] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(tetrahydro-2H- pyran-3-yl)benzamide (119), trifluoroacetic acid salt 0.00114  120 [00185] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(tetrahydro-2H- pyran-4-yl)benzamide (120) 121 [00186] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(tetrahydro-2H- pyran-4-yl)benzamide (121), trifluoroacetic acid salt 0.00094  122 [00187] N-methyl-N-[3-({[2-{[3- (morpholin-4- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (122) 123 [00188] N-methyl-N-[3-({[2-{[3- (morpholin-4- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (123), trifluoroacetic acid salt 0.00215  124 [00189] N-[3-({[2-{[3-(azetidin-1- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (124) 125 [00190] N-[3-({[2-{[3-(azetidin-1- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethanesulfon-amide (125), trifluoroacetic acid salt 0.00127  126 [00191] N-[(1- hydroxycyclobutyl)methyl]-3- ({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (126) 127 [00192] N-[(1- hydroxycyclobutyl)methyl]-3- ({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (127), trifluoroacetic acid salt 0.00211  128 [00193] N,N-bis(2-hydroxyethyl)-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (128) 129 [00194] N,N-bis(2-hydroxyethyl)-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (129), trifluoroacetic acid salt 0.00076  130 [00195] N-cyclopentyl-N-methyl-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (130) 131 [00196] N-cyclopentyl-N-methyl-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (131), trifluoroacetic acid salt 0.0108  132 [00197] N-[2-(dimethylamino)-2- oxoethyl]-3-({1-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (132) 133 [00198] N-[2-(dimethylamino)-2- oxoethyl]-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (133), trifluoroacetic acid salt 0.00195  134 [00199] N-[3-({[2-({3-[(3-hydroxy-3- methylpyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (134) 135 [00200] N-[3-({[2-({3-[(3-hydroxy-3- methylpyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (135), trifluoroacetic acid salt 0.00333  136 [00201] N-[2-(dimethylamino)ethyl]-N- methyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (136) 137 [00202] N-[2-(dimethylamino)ethyl]-N- methyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (137), trifluoroacetic acid salt 0.00433  138 [00203] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(pyridin-2- ylmethyl)benzamide (138) 139 [00204] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(pyridin-2- ylmethyl)benzamide (139), trifluoroacetic acid salt 0.00191  140 [00205] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-[(3-methyloxetan- 3-yl)methyl]benzamide (140) 141 [00206] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-[(3-methyloxetan- 3-yl)methyl]benzamide (141), trifluoroacetic acid salt 0.00084  142 [00207] N-methyl-N-{3-[({2-[(3-{[(3S)- 3-methylmorpholln-4- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (142) 143 [00208] N-methyl-N-{3-[({2-[(3-{[(3S)- 3-methylmorpholin-4- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (143), trifluoroacetic acid salt 0.0024  144 [00209] N-[3-(dimethylamino)propyl]- 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (144) 145 [00210] N-[3-(dimethylamino)propyl]- 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (145), trifluoroacetic acid salt 0.00254  146 [00211] N-{3-[({2-[(3-{[2- (hydroxymethyl)pyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (146) 147 [00212] N-{3-[({2-[(3-{[2- (hydroxymethyl)pyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (147), trifluoroacetic acid salt 0.00474  148 [00213] N-(3-methoxypropyl)-3-({4- [({2-[methyl(methylsulfonyl)- amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (146) 149 [00214] N-(3-methoxypropyl)-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (149), trifluoroacetic acid salt 0.00151  150 [00215] N-(1-cyclopropylethyl)-3-({4- [({2-[methyl(methylsulfonyl)- amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (150) 151 [00216] N-(1-cyclopropylethyl)-3-({4- [({2-[methyl(methylsulfonyl)- amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (151), trifluoroacetic acid salt 0.00524  152 [00217] N-{3-[({2-[(3-{[(3R,4R)-3,4- difluoropyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (152) 153 [00218] N-{3-[({2-[(3-{[(3R,4R)-3,4- difluoropyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (153), trifluoroacetic acid salt 0.00335  154 [00219] N-methyl-N-[3-({[2-({3-[(2- methylpyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (154) 155 [00220] N-mothyl-N-[3-({[2-({3-[(2- methylpyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (155), trifluoroacetic acid salt 0.00975  156 [00221] N-{3-[({2-[(3-{[(3S)-3- hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (156) 157 [00222] N-{3-[({2-[(3-{[(3S)-3- hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (157), trifluoroacetic acid salt 0.00424  158 [00223] N-{3-[({2-[(3-{[(3S)-3- hydroxypiperidin-1- yl]carbonyl}phenyl)amino]-5- (tritluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (158) 159 [00224] N-{3-[({2-[(3-{[(3S)-3- hydroxypiperidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (159), trifluoroacetic acid salt 0.00614  160 [00225] N-[(1R)-1-(hydroxymethyl)-2- methylpropyl]-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (160) 161 [00226] N-[(1R)-1-(hydroxymethyl)-2- methylpropyl]-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (161), trifluoroacetic acid salt 0.00374  162 [00227] N-cyclopentyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (162) 163 [00228] N-cyclopentyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (163), trifluoroacetic acid salt 0.0051  164 [00229] N-{3-[({2-[(3-{[3- (dimethylamino)azetidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (164) 165 [00230] N-{3-[({2-[(3-{[3- (dimethylamino)azetidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (165), trifluoroacetic acid salt 0.00493  166 [00231] N-[2-(acetylamino)ethyl]-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (166) 167 [00232] N-[2-(acetylamino)ethyl]-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (167), trifluoroacetic acid salt 0.00344  168 [00233] N-[(1R)-1- (hydroxymethyl)propyl]-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (168) 169 [00234] N-[(1R)-1- (hydroxymethyl)propyl]-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (169), trifluoroacetic acid salt 0.00247  170 [00235] N-methyl-N-[3-({[2-{[3- (piperidin-1- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (170) 171 [00236] N-methyl-N-[3-({[2-{[3- (piperidin-1- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (171), trifluoroacetic acid salt 0.00791  172 [00237] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(1- methylpiperidin-4-yl)benzamide (172) 173 [00238] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(1- methylpiperidin-4-yl)benzamide (173), trifluoroacetic acid salt 0.00096  174 [00239] N-{3-[({2-[(3-{[(3R)-3- hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (174) 175 [00240] N-{3-[({2-[(3-{[(3R)-3- hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methyl-methanesulfonamide (175), trifluoroacetic acid salt 0.00408  176 [00241] N-[3-({[2-({3-[(3,3- difluoropyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (176) 177 [00242] N-[3-({[2-({3-[(3,3- difluoropyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (177), trifluoroacetic acid salt 0.00593  178 [00243] N-[(1S)-1-(hydroxymethyl)-2- methylpropyl]-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (178) 179 [00244] N-[(1S)-1-(hydroxymethyl)-2- methylpropyl]-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (179), trifluoroacetic acid salt 0.00109  180 [00245] N-(3-methoxypropyl)-N- methyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (180) 181 [00246] N-(3-methoxypropyl)-N- methyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (181), trifluoroacetic acid salt 0.00918  182 [00247] N-[(1S)-1- (hydroxymethyl)propyl]-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (182) 183 [00248] N-[(1S)-1- (hydroxymethyl)propyl]-3-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (183), trifluoroacetic acid salt 0.00196  184 [00249] N-cyclobutyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (184) 185 [00250] N-cyclobutyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (185), trifluoroacetic acid salt 0.00217  186 [00251] N-cyclohexyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (186) 187 [00252] N-cyclohexyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (187), trifluoroacetic acid salt 0.00584  188 [00253] N-isopropyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (188) 189 [00254] N-isopropyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (189), trifluoroacetic acid salt 0.0043  190 [00255] N-benzyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (190) 191 [00256] N-benzyl-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (191), trifluoroacetic acid salt 0.0055  192 [00257] N-(2-hydroxyethyl)-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-propylbenzamide (192) 193 [00258] N-(2-hydroxyethyl)-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-propylbenzamide (193), trifluoroacetic acid salt 0.0011  194 [00259] N-ethyl-N-(2-methoxyethyl)-3- ({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (194) 195 [00260] N-ethyl-N-(2-methoxyethyl)-3- ({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (195), trifluoroacetic acid salt 0.00681  196 [00261] N-methyl-N-[3-({[2-({3-[(4- methylpiperidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (196) 197 [00262] N-methyl-N-[3-({[2-({3-[(4- methylpiperidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (197), trifluoroacetic acid salt 0.00447  198 [00263] N-methyl-N-[3-({[2-({3-[(4- methylpiperazin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (198) 199 [00264] N-methyl-N-[3-({[2-({3-[(4- methylpiperazin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (199), trifluoroacetic acid salt 0.00256  200 [00265] N-(2-hydroxy-1,1- dimethylethyl)-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (200) 201 [00266] N-(2-hydroxy-1,1- dimethylethyl)-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (201), trifluoroacetic acid salt 0.00164  202 [00267] N-[1-(hydroxymethyl)propyl]- 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (202) 203 [00268] N-[1-(hydroxymethyl)propyl]- 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)berizamicie (203), trifluoroacetic acid salt 0.00113  204 [00269] N-[2-(dimethylamino)ethyl]-3- ({4-[({2- [methyl(methylsulfonyl)amino] pyridIn-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (204) 205 [00270] N-[2-(dimethylamino)ethyl]-3- ({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (205), trifluoroacetic acid salt 0.0032  206 [00271] N-methyl-N-{3-[({2-[(3-{[(3R)- 3-methylmorpholin-4- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (206) 207 [00272] N-methyl-N-{3-[({2-[(3-{[(3R)- 3-methylmorpholin-4- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (207), trifluoroacetic acid salt 0.00278  208 [00273] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(1- propylcyclopropyl)benzamide (208) 209 [00274] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(1- propylcyclopropyl)benzamide (209), trifluoroacetic acid salt 0.00368  210 [00275] N-[(1S)-2-hydroxy-1- methylethyl]-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (210) 211 [00276] N-[(1S)-2-hydroxy-1- methylethyl]-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}ainino)benzamide (211), trifluoroacetic acid salt 0.00106  212 [00277] N-methyl-N-[3-({[2-({3-[(3- oxopiperazin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (212) 213 [00278] N-methyl-N-[3-({[2-({3-[(3- oxopiperazin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (213), trifluoroacetic acid salt 0.00288  214 [00279] N-[3-({[2-{[3- (aminomethyl)phenyl]amino}- 5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (214) 0.0007  215 [00280] N~2~-acetyl-N-[4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzyl]glycinamide (215) 0.0006  216 [00281] N-{3-[({2-[(4- {[(aminocarbonyl)amino]- methyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (216) 0.0006  217 [00282] N-cyclopropyl-2-[4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]acetamide (217) 0.0006  218 [00283] N-[3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}mothyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzyl]acetamide (218) 0.0006  219 [00284] tert-butyl 4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzoate (219) 0.0006  220 [00285] N-{3-[({2-[(5-cyano-2- methylphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (220) 0.0006  221 [00286] N-methyl-N-{3-[({2-[(2- methylpyridin-4-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (221) 0.188   222 [00287] N-{3-[({2-[(3- {[(aminocarbonyl)amino]- methyllphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethanesulfonamide (222) 0.0006  223 [00288] N-2-acetyl-N-[3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzyl]glycinamide (223) 0.0006  224 [00289] N,N-dimethyl-4-{[4-({2- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (224) 0.0006  225 [00290] N,N-dimethyl-4-{[4-({2- [(methylsulfonyl)amino]benzyl} amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (225) 0.00098  226 [00291] N,N-dimethyl-4-{[4-({4- methyl-2- [(methylsulfonyl)amino]benzyl} amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (226) 0.00292  227 [00292] N,N-dimethyl-4-{[4-({2- methyl-6- [(methylsulfonyl)amino]benzyl} amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (227) 0.00343  228 [00293] N,N-dimethyl-4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (228) 0.00219  229 [00294] N,N-dimethyl-4-{[4-{[3- (methylsulfonyl)benzyl]amino}- 5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (229) 0.00493  230 [00295] N,N-dimethyl-4-({4-[({2- [methyl(alethylsulfonyl)amino] pyridin-3-yl]methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (230) 0.00238  231 [00296] N,N-dimethyl-4-({4-[({6- methyl-2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (231) 0.0006  232 [00297] N-{3-[({2-[(4-{[(3R,4R)-3,4- difluoropyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (232) 0.00262  233 [00298] N-[3-(dimethylamino)propyl]- 4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (233) 0.00133  234 [00299] N-(2-hydroxyethyl)-N-methyl- 4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (234) 0.00232  235 [00300] N-[3-({[2-({4-[(3- fluoropyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (235) 0.0006  236 [00301] N-{3-[({2-[(4-{[(3S)-3- fluoropyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (236) 0.00141  237 [00302] N-methyl-N-[3-({[2-{[4- (pyrrolidin-1- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (237) 0.00205  238 [00303] 4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-[(2R)- tetrahydrofuran-2- ylmethyl]benzamide (238) 0.00125  239 [00304] N-[3-({[2-({4-[(4- hydroxypiperidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (239) 0.0006  240 [00305] N-cyclobutyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (240) 0.00069  241 [00306] N-[1-(hydroxymethyl)-2- methylpropyl]-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (241) 0.0006  242 [00307] N-isopropyl-4-({4-[({2- [methyl(methylsulfortyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethy)pyrimidin-2- yl}amino)benzamide (242) 0.001   243 [00308] N-(cyclopropylmethyl)-N- methyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (243) 0.0021  244 [00309] N-(2-hydroxyethyl)-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (244) 0.00111  245 [00310] N-[2-(acetylamino)ethyl]-4-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amina)benzamide (245) 0.00262  246 [00311] N-[(1- hydroxycyclobutyl)methyl]-4- ({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (246) 0.0006  247 [00312] N-[3-({[2-({4-[(3- hydroxypiperidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (247) 0.00063  248 [00313] 4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(pyridin-2- ylmethyl)benzamide (248) 0.00935  249 [00314] N-{3-[({2-[(4-{[(3R)-3- hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (249) 0.00191  250 [00315] 4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluormethyl)pyrimidin-2- yl}amino)-N-(1- methylpiperidin-4-yl)benzamide (250) 0.00069  251 [00316] N-[2-(dimethylamino)ethyl]-4- ({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (251) 0.00121  252 [00317] N-(cyclopropylmethyl)-4-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (252) 0.00148  253 [00318] N-[3-({[2-{[4-(azetidin-1- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (253) 0.0006  254 [00319] N-methyl-N-[3-({[2-({4-[(3- oxopiperazin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (254) 0.00133  255 [00320] N-(3-hydroxypropyl)-4-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (255) 0.00082  256 [00321] N-(3-hydroxy-2,2- dimethylpropyl)-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (256) 0.00157  257 [00322] N-[(1R)-1- (hydroxymethyl)butyl]-4-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (257) 0.0058  258 [00323] N-methyl-N-[3-({[2-{[4- (piperidin-1- ylcarbonyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (258) 0.00179  259 [00324] N-[2-(dimethylamino)-2- oxoethyl]-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (259) 0.00157  260 [00325] N-{3-[({2-[(4-{[(3S)-3- hydroxypiperidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethanesulfonamide (260) 0.0023  261 [00326] N-methyl-N-{3-[({2-[(4-{[(3S)- 3-methylmorpholin-4- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (261) 0.00113  262 [00327] N-cyclopentyl-N-methyl-4-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethy)pyrimidin-2- yl}amino)benzamide (262) 0.0058  263 [00328] 4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-(tetrahydro-2H- pyran-3-yl)benzamide (263) 0.00081  264 [00329] N-[2-hydroxy-1- (hydroxymethyl)ethyl]-4-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (264) 0.0046  265 [00330] N-methyl-N-[3-({[2-({4-[(4- methylpiperidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethy)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (265) 0.0006  266 [00331] N-[3-({[2-({4-[(3,3- difluoropyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (266) 0.0006  267 [00332] N-{3-[({2-[(4-{[(3S)-3- hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (267) 0.00115  268 [00333] N-[3-(1[2-({4-[(3-hydroxy-3- methylpyrrolidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (268) 0.00262  269 [00334] N-(2-hydroxyethyl)-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-propylbenzamide (269) 0.00869  270 [00335] N-(5-hydroxypentyl)-4-({4- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (270) 0.00099  271 [00336] N-benzyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (271) 0.00114  272 [00337] N-[3-({[2-({4-[(3- fluoroazetidin-1- yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (272) 0.00264  273 [00338] N-{[(1R,2R)-2- (hydroxymethyl)cyclopropyl] methyl}-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (273) 0.00269  274 [00339] N-[2-(dimethylamino)ethyl]-N- methyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (274) 0.00466  275 [00340] N-{3-[({2-[(4-{[(3R)-3- hydroxypiperidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (275) 0.00236  276 [00341] N-(2-methoxyethyl)-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (276) 0.0006  277 [00342] N-(3-methoxypropyl)-N- methyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (277) 0.00236  278 [00343] N-methyl-N-{3-[({2-[(4-{[(3R)- 3-methylmorpholin-4- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}mothanesulfonamide (278) 0.00664  279 [00344] N-{3-[({2-[(4-{[3- (dimethylamino)azetidin-1- yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (279) 0.00397  280 [00345] N-{3-[({2-[(4- methoxyphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (280) 0.0006  281 [00346] N-{3-[({2-[(3- methoxyphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (281) 0.0006  282 [00347] N-{3-[({2-[(3,4- dimethoxyphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (282) 0.0006  283 [00348] N-[3-({[2-{[3- (hydroxymethyl)phenyl]amino} -5-(trifluoromethyl)pyrimidin- 4-yl]amino}methyl)pyridin-2- yl]-N-methylmethane- sulfonamide (283) 0.0006  284 [00349] N-methyl-N-[3-({[2-{[4- (trifluoromethoxy)phenyl] amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (284) 0.00183  285 [00350] N-methyl-N-[3-({[2-(pyridin-4- ylamino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl}methanesulfonamide (285) 0.00127  286 [00351] N-{3[({2-[(3- cyanophenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethanesulfonamide (286) 0.00164  287 [00352] N-{3-methyl-2-({[2-{[4-(1H- tetrazol-5-yl)phenyl]amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl] methanesulfonamide (287) 0.00195  288 [00353] N-methyl-N-{3-[({2-[(3- methylisoxazol-5-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (288) 289 [00354] N-methyl-N-{3-[({2-[(3- methylisoxazol-5-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (289), formic acid salt 0.0182  290 [00355] N-methyl-N-{3-[({2-[(4- morpholin-4-ylphenyl)amino]- 5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (290) 291 [00356] N-methyl-N-{3-[({2-[(4- morpholin-4-ylphenyl)amino]- 5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (291), hydrochloride salt <0.000595   292 [00357] N-{3-[({2-[(6-cyanopyridin-3- yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}aniino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (292), trifluoroacetic acid salt 0.0233  293 [00358] N-methyl-N-{3-[({2-[(5- morpholin-4-ylpyridin-2- yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (293), trifluoroacetic acid salt <0.000595   (n = 2) 294 [00359] 3-({4-[({6-methyl-2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (294) <0.000595   295 [00360] 3-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (295) 0.00133  296 [00361] 3-({4-[({2-methyl-4- [methyl(methylsulfonyl)amino] pyrimidin-5-yl}methyl)amino]- 5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (296) 0.00389  297 [00362] 3-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (297) 0.00226  298 [00363] N-{3-[({2-[(4-aminopyrimidin- 2-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (298) 0.0328  299 [00364] N-{3-[({2-[(2-aminopyrimidin- 4-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (299) >0.188     300 [00365] 4-{[(7R)-8-cyclopentyl-7-ethyl- 5-methyl-6-oxo-5,6,7,8- tetrahydropteridin-2-yl]amino}- 3-methoxy-N-(1- methylpiperidin-4-yl)benzamide (300) 0.121   301 [00366] N-[3-({[2-{[3-(1- hydroxyethyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (301) <0.000595   302 [00367] 1,1,1-trifluoro-N-[4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzyl] methanesulfonamide (302) 0.00100  303 [00368] 1,1,1-trifluoro-N-[3-({4-[({2- [({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzyl] methanesulfonamide (303) 0.000727 304 [00369] 4-methoxy-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (304) 0.000777 305 [00370] 4-methoxy-3-({4-[({6-methyl- 2-[methyl(methylsulfonyl)- amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethy)pyrimidin-2- yl}amino)benzamide (305) 0.000646 306 [00371] 4-methoxy-3-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (306) 0.000696 307 [00372] 4-methoxy-3-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (307) 0.00111  308 [00373] 4-methoxy-3-({4-[({2-mothyl- 4-[methyl(methylsulfonyl)- amino]pyrimidin-5- yl}methyl)amino}-5- (trifluoromethy)pyrimidin-2- yl}amino)benzamide (308) 0.00350  309 [00374] 4-methyl-3-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (309) 0.00351  310 [00375] 4-methyl-3-({4-[({2-methyl-4- [methyl(methylsulfonyl)amino] pyrimidin-5-yl}methyl)amino]- 5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (310) 0.00504  311 [00376] N-{3-[({2-[(4- acetylphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (311) 0.00100  312 [00377] N-{3-[({2-[(3- acetylphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (312) 0.00126  313 [00378] N-methyl-N-{3-[({2-[(3- morpholin-4-ylphenyl)amino]- 5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yl}methanesulfonamide (313) 0.00202  314 [00379] N-methyl-N-[3-({[2-{[4-(1H- tetrazol-5-yl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (314) <0.000595   315 [00380] N-[3-({[2-{[3-(4,5-dihydro-1,3- oxazol-2-yl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (315) 0.000914 316 [00381] N-methyl-4-[{4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (316) 0.000965 317 [00382] N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (317) <0.000595   318 [00383] N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (318), hydrochloride salt 0.00179  319 [00384] N-[3-({[2-{[4- (hydroxymethyl)phenyl]amino} -5-(trifluoromethyl)pyrimidin- 4-yl]amino}methyl)pyridin-2- yl]-N-methylmethane- sulfonamide (319) <0.000595   320 [00385] 2-fluoro-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (320), formic acid salt <0.000595   321 [00386] 4-{[4-({3- [(difluoromethyl)(methyl- sulfonyl)amino]benzyl}amino)- 5-(trifluoromethyl)pyrimidin-2- yl]amino}benzoate (321) 0.119   (0.0159-0.883 n = 2) 322 [00387] 3-fluoro-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (322), formic acid salt <0.000595   323 [00388] N-[3-({[2-{[4-(1-hydroxy-1- methylethyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (323) 0.00150  324 [00389] N-[3-({[2-{[4-(1-hydroxy-1- methylethyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]- methylmethanesulfonamide (324) 0.00187  325 [00390] N-[2-({[2-{[4-(1-hydroxy-1- methylethyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-3-yl]- N-methylmethane-sulfonamide (325) 0.00266  326 [00391] N-[3-({[2-{[4-(1-hydroxy-1- methylethyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]- N-methylmethane-sulfonamide (326) 0.00162  327 [00392] 2-fluoro-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (327), formic acid salt 0.00169  328 [00393] N-[3-({[2-{[4-(1- hydroxyethyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]- methylmethanesulfonamide (328) 0.000619 329 [00394] N-[2-({[2-{[4-(1- hydroxyethyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-3-yl]- N-methylmethane-sulfonamide (329) 0.000914 330 [00395] N-[3-({[2-{[4-(1- hydroxyethyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]- N-methylmethane-sulfonamide (330) 0.000750 331 [00396] 2-fluoro-4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (331), hydrochloride salt 0.00177  332 [00397] 2-fluoro-4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (332), formic acid 0.000863 333 [00398] 2-fluoro-4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (333) 0.00214  334 [00399] 2-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (334) <0.000595   (n = 2) 335 [00400] 2-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (335), hydrochloride salt <0.000595   (n = 2) 336 [00401] 2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (336) <0.000595   337 [00402] 2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (337), hydrochloride salt <0.000595   338 [00403] 2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (338) <0.000595   339 [00404] 2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (339), hydrochloride salt <0.000595   340 [00405] 2-methyl-4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (340) <0.000595   341 [00406] 3-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (341) <0.000595   342 [00407] 3-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (342), hydrochloride salt 0.00103  343 [00408] 3-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (343) 0.000993 344 [00409] 3-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (344) 0.000900 345 [00410] 3-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (345), hydrochloride salt 0.000981 346 [00411] 3-methyl-4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (346) 0.000886 347 [00412] N-[3-({[2-{[4- (isopropoxymethyl)phenyl] amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (347) 0.00215  348 [00413] N-[3-({[2-{[4- (chloromethyl)phenyl]amino)- 5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (348) 0.00155  349 [00414] N-methyl-N-[3-({[2-{[4- (morpholin-4- ylmethyl)phenyl]amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (349) <0.000595   350 [00415] 4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}oxy)benzamide (350) 0.0637  351 [00416] N-[3-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]- N-methylmethane-sulfonamide (351), hydrochloride salt 0.000616 352 [00417] N-[2-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-3-yl]- N-methylmethane-sulfonamide (352), hydrochloride salt <0.000595   353 [00418] N-[3-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N- methylmethanesulfonamide (353), hydrochloride salt <0.000595   354 [00419] N-[3-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (354), hydrochloride salt <0.000595   355 [00420] N-[3-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]- N-methylmethane-sulfonamide (355), hydrochloride salt <0.000595   356 [00421] N-[2-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-3-yl]- N-methylmethane-sulfonamide (356), hydrochloride salt 0.000593 357 [00422] 2-chloro-4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (357) 0.00147  358 [00423] 2-chloro-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (358) <0.000595   359 [00424] 2-chloro-4-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (359) <0.000595   360 [00425] 2-chloro-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (360) <0.000595   361 [00426] 3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)-N-piperidin-4- ylbenzamide (361), hydrochloride salt 0.00870  362 [00427] N-[2-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N- methylmethanesulfonamide (362), hydrochloride salt <0.000595   363 [00428] N-[2-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N- methylmethanesulfonamide (363), hydrochloride salt <0.000595   364 [00429] N-[3-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (364), hydrochloride salt 0.000644 365 [00430] N-[3-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N- methylmethanesulfonamide (365), hydrochloride salt 0.000976 366 [00431] N-[3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]acetamide (366) <0.000595   367 [00432] N-methyl-N-[3-({[2-{[3-(3- methyl-2-oxoimidazolidin-1- yl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (367) 0.00164  368 [00433] 3-fluoro-N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (368) <0.000595   369 [00434] 3-fluoro-N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (369), hydrochloride salt 0.00149  370 [00435] 2-fluoro-N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (370) 0.000600 371 [00436] N-[3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]propanamide (371) 0.00194  372 [00437] 5-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)pyridine-2- carboxamide (372), formic acid salt 0.00400  373 [00438] 4-fluoro-3-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (373) 0.00749  374 [00439] 4-fluoro-3-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (374) 0.0155  375 [00440] 4-fluoro-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (375) 0.00629  376 [00441] 5-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}pyridine-2- carboxamide (376), formic acid salt 0.00815  377 [00442] 5-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)pyridine-2- carboxamide (377), formic acid salt 0.0153  378 [00443] 4-fluoro-3-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (378) 0.00194  379 [00444] 2-fluoro-5-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (379), hydrochloride salt 0.00478  380 [00445] 2-fluoro-5-({4-[({2- [methyl(methylsulfonyl)aminc] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (380), hydrochloride salt 0.00160  381 [00446] 2-fluoro-5-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (381), hydrochloride salt 0.00455  382 [00447] 2-fluoro-5-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (382), hydrochloride salt 0.0107  383 [00448] N-{3-[({2-[(4-{[(2- hydroxyethyl)amino]methyl} phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (383) <0.000595   384 [00449] N-[3-({[2-({4- [(isopropylamino)methyl] phenyl}amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (384) <0.000595   385 [00450] N-[3-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]acetamide (385) 0.00144  386 [00451] N-[3-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]acetamide (386) 0.00165  387 [00452] N-(3-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}phenyl)acetamide (387) 0.00295  388 [00453] N-{3-[({2-[(4-{[(2- methoxyethyl)amino]methyl} phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}- N-methylmethane-sulfonamide (388) <0.000595   389 [00454] N-[3-({[2-([4-({[2-hydroxy-1- (hydroxymethyl)ethyl]amino} methyl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (389) <0.000595   390 [00455] N-{3-[({2-[(4-cyano-3- hydroxyphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethane-sulfonamide (390) 0.000746 391 [00456] N-{3-[({2-[(4-cyano-3- hydroxyphenyl)amino]-5- (trifluoromethyl)pyrimidln-4- yl}amino)methyl]pyrazin-2-yl}- N-methylmethane-sulfonamide (391), hydrochloride salt 0.00124  392 [00457] N-{3-[({2-[(4-cyano-3- hydroxyphenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]phenyl}-N- methylmethanesulfonamide (392) 0.00451  393 [00458] 2-hydroxy-4-{[4-{[3- (methylsulfonyl)benzyl]amino}- 5-(trifluoromethyl)pyrimidin-2- yl]amino}benzonitrile (393) 0.00741  394 [00459] 2-hydroxy-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (394), formic acid salt <0.000595   395 [00460] 2-hydroxy-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (395), formic acid salt 0.000849 396 [00461] 2-hydroxy-4-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]amino}benzamide (396), formic acid salt 0.00313  397 [00462] N-2-acetyl-N-[3-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]glycinamide (397) 0.00151  398 [00463] N~2~-acetyl-N-[3-({4-[({3- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)phenyl]glycinamide (398) 0.00218  399 [00464] N-2-acetyl-N-(3-{[4-({3- [methyl(methylsulfonyl)amino] benzyl}amino)-5- (trifluoromethyl)pyrimidin-2- yl]aminolphenyl)glycinamide (399) 0.00557  400 [00465] N,2-dimethyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (400), hydrochloride salt 0.000660 401 [00466] N,3-dimethyl-4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (401), hydrochloride salt 0.00117  402 [00467] N,2-dimethyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (402), hydrochloride salt <0.000595   403 [00468] N,3-dimethyl-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (403), hydrochloride salt 0.00109  404 [00469] 4-({4-[({4- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (404), formic acid salt 0.00207  405 [00470] 3-methyl-4-({4-[({4- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (405), formic acid salt 0.0173  406 [00471] 2-methyl-4-({4-[({4- [methyl(methylsulfonyl)amino] pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (406), formic acid salt 0.000784 407 [00472] N′-hydroxy-4-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzenecarboximida mide (407), formic acid salt <0.000595   408 [00473] N′-hydroxy-3-({4-[({2- [methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino) benzenecarboximidamide (408), formic acid salt 0.00229  409 [00474] N-[3-({[2-{[4-(2,2-dimethyl- 1,3-dioxolan-4- yl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]- N-methylmethane-sulfonamide (409) 0.00475  410 [00475] N-[3-({[2-{[4-(2,2-dimethyl- 1,3-dioxolan-4- yl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (410) 0.00119  411 [00476] N-[3-({[2-{[4-(1,2- dihydroxyethyl)phenyl]amino}- 5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]- N-methylmethane-sulfonamide (411), hydrochloride salt 0.000941 412 [00477] N-[3-({[2-{[4-(1,2- dihydroxyethyl)phenyl]amino)- 5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]- N-methylmethane-sulfonamide (412), hydrochloride salt <0.000595   413 [00478] N-{3-[({2-[(4-{[(2-hydroxy-2- methylpropyl)amino]methyl} phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]- N-methylmethanesulfonamide (413) <0.000595   414 [00479] N-methyl-N-[3-({[2-({4- [(methylamino)methyl]phenyl} amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide (414), hydrochloride salt <0.000595   415 [00480] N-methyl-N-[2-({[2-({4- [(methylamino)methyl]phenyl} amino)-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl] methanesulfonamide (415), hydrochloride salt <0.000595