HK1195308A

HK1195308A - Benzoic acid derivatives as eif4e inhibitors

Info

Publication number: HK1195308A
Application number: HK14108723.1A
Authority: HK
Inventors: Paul Gillespie
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2011-09-23
Filing date: 2012-09-17
Publication date: 2014-11-07

Description

benzoic acid derivatives as EIF4E inhibitors

Technical Field

The present invention relates to compounds that inhibit eIF 4E.

Background

Many disease states are characterized by uncontrolled proliferation and differentiation of cells. These disease states encompass many cell types and diseases such as cancer, atherosclerosis, and restenosis.

The term cancer is used to describe a class of diseases characterized primarily by uncontrolled cell growth. Cancer is currently one of the leading causes of death in the world and is expected to become the leading cause of death in the next few years. By 2030, it is expected that there will be over twenty million new cancer diagnoses, at least thirty million deaths, per year.

There are many different types of cancer, and many of these types require different forms of treatment. For cancer, the major treatment modalities at present include surgery, radiation therapy, bone marrow transplantation, immunotherapy, anti-angiogenesis therapy, and treatment with cytotoxic agents (often referred to as chemotherapy). Over the past 70 years, a number of cytotoxic agents have been used to treat cancer, including nitrogen mustards such as the chlorambucil (chlorothiene) and estramustine phosphate; anthracyclines such as doxorubicin, daunorubicin, and idarubicin; platinum-containing compounds such as cisplatin, carboplatin, and oxaliplatin; antimetabolites such as dacarbazine, capecitabine, fludarabine, 5-fluorouracil, gemcitabine, methotrexate, and pemetrexed; topoisomerase inhibitors such as topotecan and irinotecan; tubulin polymerization inhibitors such as vinblastine and vincristine; and tubulin depolymerization inhibitors such as paclitaxel and docetaxel.

Although many anti-cancer drugs are known and have achieved considerable success as therapeutic agents for the treatment of a variety of cancers, there remains an urgent need for new cancer therapies.

Eukaryotic initiation factor 4E (eIF4E) is a 24kDa protein that plays an important role in initiating translation of mRNA. Upon initiation of mRNA translation, eIF4E binds to the 7-methyl guanosine cap structure at the 5' end of the mRNA and forms a complex with scaffolding protein eIF4G and helicase eIF4A (referred to as eIF 4F). Formation of this complex is required to initiate cap-dependent translation, and thus binding of eIF4E to eIF4G is a key event in this process.

eIF4E has been identified as a promising target in the field of oncology because of the large data field involved in transformation and tumorigenesis.

Two small molecule inhibitors of eIF4E-eIF4G interaction have been disclosed by Gerhard Wagner and coworkers (Moerke, n.j.et al. cell2007,128, 257-267). These inhibitors have formulas i and ii. Fixed analogues of the compound of formula ii are disclosed by Wagner team at the 240 th national conference of the american chemical society (8 months, 2010, 22-26 days) (see MEDI-28, MEDI-78, MEDI-94, and MEDI-479, which are excerpted in the chemical abstracts as AN2010:1011638, AN2010:1011687, AN2010:1011703, AN2010:1012083, respectively). The activity of the compound of formula ii was demonstrated in vivo in a fear-consolidated rat model, which was dependent on the formation of the eIF4F complex (hoefer, c.a. et al proc.nat. acad.sci.usa2011,108, 3383-3388). In another study, the compound of formula ii, when combined with the apoptosis-inducing protein TRAIL, inhibited the eIF4E/eIF4G interaction and inhibited growth and induced apoptosis in human lung cancer cells. However, other experiments using siRNA showed that the potentiation of TRAIL activity by 4EGI-1 was independent of cap structure-dependent translation (Fan, S.et al. Neoplasia2010,12, 346-356).

Disclosure of Invention

The present invention provides eIF4E inhibiting compounds of formula I as described below:

wherein R1 is selected fromBromothienyl, thienyl, pyridyl, phenyl, said groups being optionally substituted with one or two members selected from the group consisting of: fluoro, chloro, bromo, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, -S (O)₂-methyl, and cyano;

wherein R2 is selected from:

thienyl, optionally substituted with a member selected from the group consisting of: methyl, acetyl, and chloro;

pyridyl, optionally substituted with one or two members selected from the group consisting of: amido, methoxy, methyl, fluoro, chloro, and cyano;

a pyrimidinyl group optionally substituted with a member selected from: ethoxy, methoxy, hydroxy, and isopropyl; and

phenyl optionally substituted with 1-3 members selected from: methyl, cyano, hydroxy, acetyl, C (O) NH2, methoxy, ethoxy, trifluoromethoxy, C (O) H, chloro, fluoro, trifluoromethyl, nitro, -C (O) OH, -C (O) -X1, wherein X1 is a member selected from:

-NH-X2, wherein X2 is a member selected from: -CH (CH3) -phenyl, and

- (CH2) n-X4 wherein n is 1,2 or 3 and X4 is a member selected from: -N (methyl)₂-N (ethyl)₂Pyridyl, thienyl, morpholinyl, and phenyl, said groups optionally substituted with a member selected from: methyl, methoxy, fluoro, and trifluoromethyl.

Detailed Description

The present invention provides eIF4E inhibiting compounds of formula I:

wherein R2 is selected from:

phenyl optionally substituted with 1-3 members selected from: methyl, cyano, hydroxy, acetyl, C (O) NH2, methoxyYl, ethoxy, trifluoromethoxy, C (O) H, chloro, fluoro, trifluoromethyl, nitro, -C (O) OH, -C (O) -X1, wherein X1 is a member selected from:

-NH-X2, wherein X2 is a member selected from: -CH (CH3) -phenyl, and

In another aspect, the present invention relates to compounds of formula I and pharmaceutically acceptable salts thereof,

wherein R1 is selected fromBromothienyl, thienyl, pyridyl, phenyl, said groups being optionally substituted with one or two members selected from the group consisting of: fluoro, chloro, bromo, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, and cyano;

wherein R2 is selected from:

phenyl optionally substituted by 1 to 3 substituentsA member from the group consisting of: methyl, cyano, hydroxy, acetyl, C (O) NH2, methoxy, ethoxy, trifluoromethoxy, C (O) H, chloro, fluoro, trifluoromethyl, nitro, -C (O) OH, -C (O) -X1, wherein X1 is a member selected from:and-NH-X2, wherein X2 is a member selected from: -CH (CH3) -phenyl, and- (CH2) n-X4, wherein n is 1 or 2 and X4 is a member selected from: pyridyl, thienyl, and phenyl, said groups optionally substituted with a member selected from the group consisting of: methyl, methoxy, fluoro, and trifluoromethyl.

In another aspect, the invention relates to compounds of formula I wherein R1 is phenyl, optionally substituted with one or two members selected from: fluorine, chlorine, bromine, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, and cyano.

In another aspect, the invention relates to compounds of formula I wherein R2 is phenyl, optionally substituted with 1-3 members selected from: methyl, cyano, hydroxy, acetyl, C (O) NH2, methoxy, ethoxy, trifluoromethoxy, C (O) H, chloro, fluoro, trifluoromethyl and nitro.

In another aspect, the invention relates to compounds of formula I wherein R2 is phenyl, optionally substituted with 1-3 members selected from: methyl, cyano, hydroxy, acetyl, C (O) NH2, methoxy, ethoxy, trifluoromethoxy, C (O) H, chloro, fluoro, trifluoromethyl, nitro, -C (O) OH, -C (O) -X1, wherein X1 is a member selected from:and-NH-X2, wherein X2 is a member selected from: -CH (CH3) -phenyl, and- (CH2) n-X4, wherein n is 1 or 2 and X4 is a member selected from: pyridyl, thienyl, and phenyl, said groups optionally substituted with a member selected from the group consisting of: methyl, methoxy, fluoro, and trifluoromethyl.

In another aspect, the present invention relates to compounds of formula I wherein R1 is dichlorophenyl and R2 is phenyl, optionally substituted with 1-3 members selected from: methyl, cyano, hydroxy, acetyl, C (O) NH2, methoxy, ethoxy, trifluoromethoxy, C (O) H, chloro, fluoro, trifluoromethyl, nitro, -C (O) OH, -C (O) -X1, wherein X1 is a member selected from:and-NH-X2, wherein X2 is a member selected from: -CH (CH3) -phenyl, and- (CH2) n-X4, wherein n is 1 or 2 and X4 is a member selected from: pyridyl, thienyl, and phenyl, optionally substituted with a member selected from the group consisting of: methyl, methoxy, fluoro, and trifluoromethyl.

In another aspect, the invention relates to compounds of formula I wherein R1 is selected fromBromothienyl, thienyl, and pyridyl.

In another aspect, the present invention relates to compounds of formula I wherein R1 is dichlorophenyl.

In another aspect, the invention relates to compounds of formula I wherein R1 is 3, 4-dichlorophenyl.

In another aspect, the invention relates to compounds of formula I wherein R1 is2, 3-dihydro-benzo [1,4] dioxin-6-yl, 2, 4-dichloro-phenyl, 2, 4-difluoro-phenyl, 2, 4-dimethyl-phenyl, 2, 5-dichloro-phenyl, 2, 6-difluoro-phenyl, 2-chloro-phenyl, 2-fluoro-4-methoxy-phenyl, 2-fluoro-phenyl, 2-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3, 4-dichloro-phenyl, 3, 4-difluoro-phenyl, 3, 5-bis-trifluoromethyl-phenyl, 3, 5-difluoro-phenyl, 2, 4-dichloro-phenyl, 2, 5-dichloro-phenyl, 2, 4-fluoro-phenyl, 2-fluoro-4-phenyl, 3,5-, 3-bromo-phenyl, 3-chloro-4-fluoro-phenyl, 3-chloro-phenyl, 3-cyano-phenyl, 3-fluoro-phenyl, 3-methoxy-phenyl, 3-trifluoromethyl-phenyl, 4-bromo-phenyl, 4-chloro-3-methyl-phenyl, 4-chloro-phenyl, 4-cyano-phenyl, 4-difluoromethoxy-phenyl, 4-fluoro-phenyl, 4-methanesulfonyl-phenyl, 4-methoxy-phenyl, 4-p-tolyl-, 4-pyridin-2-yl-, 4-pyridin-3-yl-, 4-pyridin-4-yl-, 4-thiophen-2-yl-, 4-thiophen-3-yl-, 4-trifluoromethoxy-phenyl, 4-trifluoromethyl-phenyl, or 5-bromo-thiophen-2-yl.

In another aspect, the invention relates to compounds of formula I wherein R2 is selected from:

pyridyl, optionally substituted with one or two members selected from the group consisting of: amido, methoxy, methyl, fluoro, chloro, and cyano; and

a pyrimidinyl group optionally substituted with a member selected from: ethoxy, methoxy, hydroxy, and isopropyl.

In yet another aspect, the invention relates to compounds of formula I wherein R2 is nitrophenyl.

In yet another aspect, the invention relates to compounds of formula I wherein R2 is 2-nitrophenyl.

In a further aspect, the invention relates to compounds of formula I, wherein R2 is 2- (2-acetyl-thiophen-3-yl) -phenyl, 2- (2-carbamoyl-pyridin-3-yl) -, 2- (2-chloro-thiophen-3-yl) -, 2- (2-ethoxy-pyrimidin-5-yl) -, 2- (2-hydroxy-pyrimidin-5-yl) -, 2- (2-methoxy-pyridin-3-yl) -, 2- (2-methoxy-pyrimidin-5-yl) -, 2- (2-methyl-pyridin-3-yl) -, 2- (3-chloro-thiophen-2-yl) -, 2- (3-methyl-pyridin-4-yl) -, 2- (4-isopropyl-pyrimidin-5-yl) -, 2- (4-methyl-thiophen-3-yl) -, 2- (5-chloro-pyridin-3-yl) -, 2- (5-fluoro-pyridin-2-yl) -, 2- (6-cyano-pyridin-2-yl) -, 2- (6-methoxy-pyridin-2-yl) -, 2',3',5 '-trichloro-phenyl, 2',3',5' -trifluoro-phenyl, 2- (3-chloro-pyrimidin-5-yl) -methyl-, 2- (4-methyl-pyridin-3-yl) -ethyl, 2- (5-fluoro-pyridin-2-yl) -ethyl, 2',3' -dichloro-phenyl, 2',3' -difluoro-phenyl, 2',4' -bis-trifluoromethyl-phenyl, 2',4' -dichloro-phenyl, 2',4' -difluoro-phenyl, 2',5' -dichloro-phenyl, 2',5' -difluoro-phenyl, 2 '-acetyl-phenyl, 2' -carbamoyl-phenyl, 2 '-chloro-2' -fluoro-phenyl, 2 '-chloro-3' -trifluoromethyl-phenyl, 2 '-chloro-4' -ethoxy-phenyl, 2 '-chloro-4' -fluoro-phenyl, 2 '-chloro-4' -methoxy-phenyl, and mixtures thereof, 2' -chloro-4 ' -methyl-phenyl, 2' -chloro-4 ' -trifluoromethyl-phenyl, 2' -chloro-5 ' -cyano-phenyl, 2' -chloro-5 ' -fluoro-phenyl, 2' -chloro-5 ' -hydroxy-phenyl, 2' -chloro-5 ' -methoxy-phenyl, 2' -chloro-5 ' -methyl-phenyl, 2' -chloro-5 ' -trifluoromethoxy-phenyl, 2' -chloro-5 ' -trifluoromethyl-phenyl, 2' -cyano-phenyl, 2' -fluoro-4 ' -carboxy-phenyl, 2' -fluoro-phenyl, 2' -formyl-5 ' -methyl-phenyl, 2' -chloro-5 ' -hydroxy-phenyl, 2' -chloro-5 ' -methyl-phenyl, 2' -chloro-5 ' -hydroxy-phenyl, 2' -fluoro-phenyl, and mixtures thereof, 2 '-formyl-phenyl, 2' -methoxy-6 '-chloro-phenyl, 2' -methoxy-phenyl, 2 '-methyl-4' -cyano-phenyl, 2 '-methyl-phenyl, 2' -nitro-5 '-trifluoromethyl-phenyl, 2' -nitro-phenyl, 2-pyridin-3-yl-, 2-pyridin-4-yl-, 2-pyrimidin-5-yl-, 3 '-acetyl-phenyl, 3' -chloro-4 '-cyano-phenyl, 3' -methoxy-phenyl, 3 '-nitro-phenyl, 4' - (1-acetyl-piperidin-4-ylcarbamoyl) -one Phenyl, 4'- (1-methyl-piperidin-4-ylcarbamoyl) -phenyl, 4' - (1-phenyl-ethylcarbamoyl) -phenyl, 4'- (2-dimethylamino-ethylcarbamoyl) -phenyl, 4' - (2-fluoro-benzylcarbamoyl) -phenyl, 4'- (2-morpholin-4-yl-ethylcarbamoyl) -phenyl, 4' - (2-pyridin-3-yl-ethylcarbamoyl) -phenyl, 4'- (3-diethylamino-propylcarbamoyl) -phenyl, 4' - (3-dimethylamino-propylcarbamoyl) -phenyl, 4' - (3-fluoro-benzylcarbamoyl) -phenyl, 4' - (3-methoxy-benzylcarbamoyl) -phenyl, 4' - (3-methyl-benzylcarbamoyl) -phenyl, 4' - (3-morpholin-4-yl-propylcarbamoyl) -phenyl, 4' - (3-trifluoromethyl-benzylcarbamoyl) -phenyl, 4' - (4-acetyl-piperazine-1-carbonyl) -phenyl, 4' - (4-fluoro-benzylcarbamoyl) -phenyl, 4' - (4-hydroxy-piperidine-1-carbonyl) -phenyl, 4' - (4-methoxy-benzylcarbamoyl) -phenyl, methyl-ethyl-methyl-, 4'- (4-methyl-piperazine-1-carbonyl) -phenyl, 4' - (morpholine-4-carbonyl) -phenyl, 4'- (pyrrolidine-1-carbonyl) -phenyl, 4' - (tetrahydro-furan-3-ylcarbamoyl) -phenyl, 4'- (tetrahydro-pyran-4-ylcarbamoyl) -phenyl, 4' - [ (pyridin-3-ylmethyl) -carbamoyl ] -phenyl, 4'- [ (pyridin-4-ylmethyl) -carbamoyl ] -phenyl, 4' - [ (tetrahydro-furan-2-ylmethyl) -carbamoyl ] -phenyl, 4' - [ (tetrahydro-pyran-4-ylmethyl) -carbamoyl ] -phenyl, 4' - [ (thiophen-2-ylmethyl) -carbamoyl ] -phenyl, 4' -acetyl-phenyl, 4' -benzylcarbamoyl-phenyl, 4' -carbamoyl-2 ' -methyl-phenyl, 4' -carboxy-2 ' -methyl-phenyl, 4' -chloro-3 ' -cyano-phenyl, 4' -chloro-phenyl, 4' -cyano-phenyl, 4' -fluoro-2 ' -trifluoromethyl-phenyl, 4' -fluoro-phenyl, 4' -methoxy-2 ' -nitro-phenyl, m, 4' -methoxy-2 ' -trifluoromethyl-phenyl, 4' -nitro-phenyl, 4' -phenethylcarbamoyl-phenyl, 5' -acetyl-2 ' -chloro-phenyl, 5' -carbamoyl-2 ' -chloro-phenyl, 5' -chloro-2 ' -cyano-phenyl, 6' -chloro-2 ' -fluoro-3 ' -methyl-phenyl, 6' -chloro-2 ' -fluoro-phenyl, 6' -fluoro-3 ' -methyl-phenyl or phenyl.

In another aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, selected from

4- [4- (4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

2' -nitro-4- [4- (4-trifluoromethoxy-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

4- [4- (4-difluoromethoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

2' -nitro-4- [4- (2-trifluoromethyl-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2' -nitro-4- [4- (3-trifluoromethyl-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2' -nitro-4- [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

4- [4- (4-chloro-3-methyl-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (4-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-chloro-4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (5-bromo-thiophen-2-yl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-bromo-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (4-bromo-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2-fluoro-4-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (4-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (4-methanesulfonyl-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-cyano-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (4-cyano-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

2' -nitro-4- (4-pyridin-2-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4-pyridin-3-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4-pyridin-4-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4-p-tolyl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4-thiophen-3-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4-phenyl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4-thiophen-2-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2 '-methyl-biphenyl-2, 4' -dicarboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2 '-fluoro-biphenyl-2, 4' -dicarboxylic acid,

4- [4- (2, 3-dihydro-benzo [1,4] dioxin-6-yl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2, 4-difluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2, 4-dimethyl-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2, 5-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2, 6-difluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2 '-nitro-5' -trifluoromethyl-biphenyl-2-carboxylic acid,

5 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-difluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4 '-methoxy-2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -3' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-diethylamino-propylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-dimethylamino-propylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2-dimethylamino-ethylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (2-methyl-2H-pyrazol-3-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (1-methyl-piperidin-4-ylcarbamoyl) -biphenyl-2-carboxylic acid,

4' - (1-acetyl-piperidin-4-ylcarbamoyl) -4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (4-methyl-piperazine-1-carbonyl) -biphenyl-2-carboxylic acid,

4' - (4-acetyl-piperazine-1-carbonyl) -4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (4-hydroxy-piperidine-1-carbonyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (morpholine-4-carbonyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (pyrrolidine-1-carbonyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-morpholin-4-yl-propylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2-morpholin-4-yl-ethylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (tetrahydro-pyran-4-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (tetrahydro-furan-2-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (tetrahydro-furan-3-ylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (tetrahydro-pyran-4-ylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (4-methoxy-benzylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-methoxy-benzylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2-pyridin-3-yl-ethylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -phenethylcarbamoyl-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (pyridin-3-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (pyridin-4-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-methyl-benzylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-trifluoromethyl-benzylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (4-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (thiophen-2-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid,

4' -benzylcarbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2- (2-carbamoyl-pyridin-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid,

4 '-carbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methyl-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (1-phenyl-ethylcarbamoyl) -biphenyl-2-carboxylic acid,

2' -carbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-ethoxy-pyrimidin-5-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-methoxy-pyrimidin-5-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-hydroxy-pyrimidin-5-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (6-methoxy-pyridin-2-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-methoxy-pyridin-3-yl) -benzoic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4 '-methoxy-2' -trifluoromethyl-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -trifluoromethoxy-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -ethoxy-biphenyl-2-carboxylic acid,

6 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methoxy-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -3' -methoxy-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methoxy-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -methoxy-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -methoxy-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -hydroxy-biphenyl-2-carboxylic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (4-isopropyl-pyrimidin-5-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2-pyrimidin-5-yl-benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-methyl-pyridin-3-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (3-methyl-pyridin-4-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (5-fluoro-pyridin-2-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2-pyridin-3-yl-benzoic acid,

2- (5-chloro-pyridin-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2-pyridin-4-yl-benzoic acid,

2- (6-cyano-pyridin-2-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid,

4 '-cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methyl-biphenyl-2-carboxylic acid,

4' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

3' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2 '-chloro-5' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

5 '-carbamoyl-2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

5 '-chloro-2' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

3 '-chloro-4' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

4 '-chloro-3' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

3' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

5 '-acetyl-2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2- (2-acetyl-thiophen-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid,

4' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2 '-formyl-5' -methyl-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -formyl-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4 '-fluoro-2' -trifluoromethyl-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',4' -bis-trifluoromethyl-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -3' -trifluoromethyl-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -trifluoromethyl-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -trifluoromethyl-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -fluoro-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -fluoro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',5' -difluoro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',4' -difluoro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',3',5' -trifluoro-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -fluoro-biphenyl-2-carboxylic acid,

4 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -fluoro-biphenyl-2-carboxylic acid,

6 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -fluoro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -fluoro-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',3' -difluoro-biphenyl-2-carboxylic acid,

2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -6' -fluoro-3 ' -methyl-biphenyl-2-carboxylic acid,

6' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -fluoro-3 ' -methyl-biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methyl-biphenyl-2-carboxylic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (4-methyl-thiophen-3-yl) -benzoic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -methyl-biphenyl-2-carboxylic acid,

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -methyl-biphenyl-2-carboxylic acid,

2- (2-chloro-thiophen-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid,

2- (3-chloro-thiophen-2-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid,

4' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2',5' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2',3',5' -trichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2',4' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2',3' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

4- [4- (3, 5-bis-trifluoromethyl-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid, and

4- [4- (3, 5-difluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid.

The phrase "a" or "an" entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

The terms "comprising" and "including" when used in this specification, whether in the transition or in the body of a claim, are to be construed in an open-ended sense. That is, the term should be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the listed steps, but may include other steps. The term "comprising" when used in the context of a compound or composition means that the compound or composition includes at least the listed features or components, but may also include additional features or components.

As used in this application, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and/or" and not in the "exclusive" sense of "either.

The term "independently" as used herein means that the variable used in either instance is independent of the presence or absence of variables having the same or different definitions in the same compound. Thus, in a compound where R "occurs twice and is defined as" independent carbon or nitrogen ", two R" may be carbon, two R "may be nitrogen, or one R" may be carbon and the other may be nitrogen.

When any variable occurs more than one time in any moiety or formula shown and described in a compound used or claimed in this invention, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.

Bonds drawn in the ring system (as opposed to at different vertices) indicate that the bond may be attached to any suitable ring atom.

The terms "optional" or "optionally" as used herein mean that the subsequently described event or circumstance may occur, but need not necessarily occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted" means that the optionally substituted moiety may incorporate a hydrogen atom or a substituent.

The phrase "optional bond" means that a bond may or may not be present, and the description includes single, double, triple, or aromatic bonds. If a substituent is designated as "bond" or "absent," the atom attached to the substituent is directly attached.

The term "about" as used herein means approximately, nearby, substantially, or approximately. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the limits above and below the stated value.

Certain compounds of formula I may exhibit tautomerism. A tautomeric compound may exist as two or more species that are interconvertible. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomer compoundAttempts to exist and isolate individual tautomers in constant equilibrium often result in mixtures with chemical and physical properties consistent with mixtures of compounds. The location of equilibrium depends on the chemistry within the molecule and the environment to which it is exposed, e.g., solvent, temperature, pH, etc. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common prototropic tautomers include keto/enolAmide/imide acidsAnd amidinesTautomers. The latter two are particularly common in heteroaryl rings and heterocycles, and the present invention encompasses all tautomeric forms of the compounds.

Technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs, unless otherwise defined. The present application refers to various methods and materials known to those skilled in the art. Standard references describing general principles of pharmacology include the pharmacological Basis of Therapeutics,10, by Goodman and Gilman^thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and/or methods known to those skilled in the art may be used in the practice of the present invention. However, preferred materials and methods are described. Materials, reagents, etc. referred to in the following description and examples may be obtained from commercial sources unless otherwise indicated.

The definitions described herein may be appended to form chemically relevant combinations, such as "heteroalkylaryl," "haloalkylheteroaryl," "arylalkyl heterocyclyl," "alkylcarbonyl," "alkoxyalkyl," and the like. When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", this is intended to mean an alkyl group, as defined above, substituted with 1 to 2 substituents selected from the other specifically named groups. Thus, for example, "phenylalkyl" refers to an alkyl group having 1-2 phenyl substituents, and thus includes benzyl and phenylethyl. "alkylaminoalkyl" is an alkyl group having 1-2 alkylamino substituents. "hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2, 3-dihydroxybutyl, hydroxymethyl, 3-hydroxypropyl and the like. Thus, the term "hydroxyalkyl" as used herein is intended to define a subset of heteroalkyl groups as defined above. The term- (ar) alkyl denotes unsubstituted alkyl or aralkyl. The term (hetero) aryl denotes aryl or heteroaryl.

The term "acyl" as used herein denotes a group of formula-C (═ O) R, where R is hydrogen or lower alkyl as defined herein. The term "alkylcarbonyl" as used herein, denotes a group of formula C (═ O) R, wherein R is alkyl as defined herein. Term C_1-6Acyl represents the group-C (═ O) R, where the R group contains up to 6 carbon atoms. The term "arylcarbonyl" as used herein, denotes a group of formula C (═ O) R, wherein R is aryl; the term "benzoyl" as used herein means "arylcarbonyl" wherein R is phenyl.

The term "ester" as used herein denotes a group of formula-C (═ O) OR, where R is lower alkyl as defined herein.

The term "alkyl" as used herein denotes a straight or branched chain, saturated, monovalent hydrocarbon residue containing from 1 to 10 carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. As used herein, "C_1-10Alkyl "means an alkyl group containing 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, and hexyl.

When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", this is intended to mean an alkyl group, as defined above, substituted with 1 to 2 substituents selected from the other specifically named groups. Thus, for example, "phenylalkyl" represents the group R 'R "-, where R' is phenyl, and R" is alkylene as defined herein, it being understood that the attachment point of the phenylalkyl moiety will be on the alkylene. Examples of arylalkyl groups include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The term "arylalkyl" or "aralkyl" is similarly construed, except that R' is aryl. The terms "(hetero) arylalkyl" or "(hetero) aralkyl" are similarly construed, except that R' is optionally aryl or heteroaryl.

The term "haloalkyl" or "halogenated lower alkyl" or "lower haloalkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halogen atoms.

The term "alkylene" as used herein denotes a divalent saturated straight chain hydrocarbon radical having from 1 to 10 carbon atoms (e.g., (CH)₂)_n) Or a branched, saturated, divalent hydrocarbon radical having 2 to 10 carbon atoms (e.g., -CHMe-or-CH)₂CH(i-Pr)CH₂-) unless otherwise specified. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1-dimethyl-ethylene, butylene, 2-ethylbutylene.

The term "alkoxy" as used herein denotes-O-alkyl, wherein alkyl is as defined above, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, hexyloxy, including isomers thereof. "lower alkoxy" as used herein means an alkoxy group having a "lower alkyl" group as described above. As used herein, "C_1-10Alkoxy "denotes-O-alkyl, wherein alkyl is C_1-10。

The term "aryl" denotes a mono-or bicyclic ring system comprising a monovalent aromatic carbocyclic ring of 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.

The term "haloalkoxy" or "halo-lower alkoxy" or "lower haloalkoxy" refers to a lower alkoxy group wherein one or more carbon atoms are substituted with one or more halogen atoms.

The term "hydroxyalkyl" as used herein, denotes an alkyl group as defined herein wherein 1 to 3 hydrogen atoms on different carbon atoms are replaced by a hydroxyl group.

The terms "alkylsulfonyl" and "arylsulfonyl", as used herein, represent the formula-S (═ O)₂R, wherein R is independently alkyl or aryl, and alkyl and aryl are as defined herein.

The terms "alkylsulfonylamino" and "arylsulfonylamino", as used herein, denote the formula-NR' S (═ O)₂R, wherein R is independently alkyl or aryl, R' is hydrogen or C_1-3Alkyl, and alkyl and aryl are as defined herein.

The term "cycloalkyl" as used herein denotes a saturated or unsaturated carbocyclic ring containing from 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. As used herein, "C_3-7Cycloalkyl "or" lower cycloalkyl "denotes cycloalkyl containing 3 to 7 carbons in the carbocyclic ring.

The term carboxy-alkyl as used herein denotes an alkyl moiety wherein one hydrogen atom is replaced by a carboxy group, it being understood that the point of attachment of the heteroalkyl group is through a carbon atom. The term "carboxy" refers to-CO₂And (4) a H part.

The term "heteroaryl" or "heteroaromatic group" as used herein means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring containing at least one heteroatom selected from N, O or an S heteroatom. Thus, for the present invention, the heteroaryl group need only have some degree of aromatic character. Heteroaryl groups may be optionally substituted, as defined directly below. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms, including but not limited to pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl and which may be optionally substituted with one or more, preferably one or two substituents selected from: hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, naphthyridinyl, 5,6,7, 8-tetrahydro- [1,6] naphthyridinyl, and benzisothiazolyl. The bicyclic moiety may be optionally substituted on either ring.

The term "heterocyclyl", "heterocycloalkyl", or "heterocycle" as used herein means a group containing one or more ring heteroatoms (selected from N, O or S (O))_0-2) Is comprised of one or more rings, preferably 1-2 rings, including spirocyclic ring systems, each ring having 3-8 atoms, and which may be optionally independently substituted with one or more, preferably one or two substituents selected from the group consisting of: hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and ionic forms thereof, unless otherwise specified. Examples of heterocyclic groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyranylPyrrolidinyl, hexahydroazepinylAlkyl, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl, and ionic forms thereof.

Preparation of the Compounds of the invention

The compounds of the present invention may be prepared by any conventional method. Methods suitable for synthesizing these compounds are provided in the examples. In general, the compounds of formula 1 may be prepared according to the following scheme.

Scheme 1

One general method for synthesizing the compounds of the present invention is shown in scheme 1. The starting material methyl 2-bromo-5-cyanobenzoate (which has formula 2) for this protocol is commercially available, for example from Ark Pharm, inc.,1840Industrial Drive, Suite820, Libertyville, IL60048, USA and apollo scientific ltd., whitefeleld Road, Bredbury, Stockport, Cheshire 62QR, United SK Kingdom. Such compounds may also be prepared as described below in the examples.

According to the process outlined in scheme 1, a transition metal catalyzed reaction of a compound of formula 2 with a compound of formula 3 gives a biaryl of formula 4, wherein X represents a group that can be used as a leaving group in a noble metal catalyzed coupling reaction such as a Suzuki reaction or Stille reaction. Converting the nitrile of the compound of formula 4 to a thioamide to provide the compound of formula 5. The thioamide of formula 5 is then subjected to Hantzsch thiazole synthesis by reaction with a compound of formula 6 to provide a compound of formula 7. The ester group of the compound of formula 7 is then cleaved to provide the desired compound of formula 1.

Formula 2The reaction of the compound with a compound of formula 3 (wherein X represents boronic acid, boronic ester, potassium trifluoroborate, trimethyltin, or tri-n-butyltin) to give a compound of formula 4 can be carried out using Suzuki or Stille coupling conditions, which are well known to those skilled in the art. For example, the reaction may conveniently be carried out by: in the presence of a catalytic amount of a compound which can be reduced in situ to give palladium (0), e.g. palladium (II) acetate or bis (triphenylphosphine) palladium (II) dichloride, in the presence of a catalytic amount of a phosphine ligand such as tri-o-tolylphosphine or tri-tert-butylphosphine, or alternatively in the presence of a preformed complex of palladium (0) and a phosphine ligand such as bis (tricyclohexylphosphine) palladium, tetrakis (triphenylphosphine) -palladium (0) or [1, 1-bis (diphenylphosphino) ferrocene, in a conventional inert solvent such as a polar aprotic solvent (e.g. N, N-dimethylformamide) or an ether (e.g. dioxane) or water, or indeed in a mixture of said solvents, in the optional additional presence of a catalytic amount of a phosphine ligand such as tri-o-tolylphosphine or tri-tert-butylphosphine]Palladium (II) dichloride) and a compound of formula 2 and a compound of formula 3 (wherein X represents b (oh)) in the presence of an inorganic base such as an alkali metal carbonate, bicarbonate or phosphate (e.g., potassium phosphate or sodium carbonate) at a temperature of between about room temperature and about 100 degrees, and preferably between about room temperature and about 50 degrees₂) And (4) reacting. The Suzuki reaction is well known to those of ordinary skill in the art of organic synthesis and has been reviewed several times, particularly in Miyaura, n.; suzuki, A.Chem.Rev.1995,95,2457-2483, and more recently Alonso, F.; beletskaya, i.p.; yus, M.tetrahedron2008,64, 3047-. Examples of specific conditions for Suzuki coupling can be found in a number of references, including: tiede, S.et al.Angew.chem.Intl.Edn.2010,49, 3972-; schmidt, A. and Rahimi, A.chem.Commun.2010,46, 2995-; lee, s.h.et al.us 20100063281; and Tobisu, M.et al.J.org.chem.2010,75,4835-4840 (supporting information). Stille coupling is well known to those of ordinary skill in the art of organic synthesis and may be used as an alternative to Suzuki coupling, examples of conditions for Stille coupling having been provided above. Stille couplings have been reviewed, including in Farina, V.et al. org. reactions1997,50, 1-652. Examples of specific conditions for Stille coupling can be found in the referencesFor example in Littke, A.F.et al.J.am.chem.Soc.2002,124, 5343-6348; in Alberati-Giani, D.et al, U.S. Pat. No. 7,462,617; and in Robl, j.a. us5,072,023.

The nitrile reaction of formula 4 to give the thioamide of formula 5 can be carried out using a variety of reactions well known to those skilled in the art of organic chemistry. For example, such a reaction may be carried out using sodium hydrosulfide in an inert solvent such as ethanol or water or dimethylformamide at a temperature between about room temperature and about 60 ℃. The precise conditions for such reactions can be found in references such as Guo, X-Z.et al.Bioorg.Med.Chem.2008,16, 10301-; in Ali, a.et al.us 20090137548; in Kim, g.t.et al.wo 2005040127; and in Manaka, A. and Sato, M.Synth. Commun.2005,35, 761-764. Alternatively, the reaction may be carried out by: the compound of formula 4 is treated with ammonium sulfide in a solvent such as a mixture of triethylamine and pyridine, or a mixture of water and methanol, at a temperature between about 50 ℃ and about 100 ℃, optionally under microwave irradiation. The precise conditions for such reactions can be found in references such as in Crane, l.j.et al.tetrahedron2004,60, 5325-; or in Yao, w.et al.us7,776,874. Alternatively, the reaction may be carried out by: hydrogen sulfide gas is added to a solution of the nitrile in triethylamine and optionally in the additional presence of an additional solvent and/or base such as pyridine or dioxane, and the reaction is allowed to proceed at a temperature between about room temperature and about 90 ℃. The precise conditions for such reactions can be found in references, for example in Ash, m.l.et al, us6,329,528; in Jian, f.f.et al.j.fluorine chem.2006,127, 63-67; in Brunck, t.k.et al.us6,342,504; and in Hull, J.W.Jr.et al.org.Process Res.Dedevel.2009, 13, 1125-1129. The reaction may also be carried out using pure diethyl dithiophosphate in an inert solvent such as dichloromethane or hydrogen chloride in ethyl acetate at about room temperature or in a mixture of tetrahydrofuran and water at about 80 ℃. The precise conditions for such reactions can be found in references, for example in Choi, i.y.et al.wo 2006137658; in Bouillot, a.m.j.et al.wo 2009071504; in Stump, B.et al.Heterocycles2007,72, 293-; and in Soh, C.H.et al.J.Comm.chem.2006, 8, 464-. The reaction can also be carried out by the following method: the nitrile of formula 4 is treated with phosphorus pentasulfide in an inert solvent such as methanol or ethanol at a temperature between about room temperature and about 80 ℃. The precise conditions for such reactions can be found in references, for example in Zhang, n.et al.us 20090270363; in Kaboudin, B, and Elhamifar, D.Synthesis2006, 224-226; and in Cummings, c.g.et al.org.lett.2009,11, 25-28.

The reaction of the thioamide of formula 5 with the bromomethyl ketone of formula 6 can be carried out using any conventional method. For example, the reaction can be carried out by: the thioamide of formula 5 is treated with the bromomethyl ketone of formula 6 in an inert solvent such as an alcohol (e.g., ethanol) or an ether (e.g., tetrahydrofuran) at a temperature between about room temperature and about 100 ℃. The precise conditions for such reactions can be found in references, for example in olalmann, c.et al.wo 2009058348; in Saha, a.k.et al.us7,241,812; in Yu, d.t.et al.us6,156,776; in thatB. And Dodic, N.J.Med.chem.1996,39, 1635-1644; and in Wright, S.W.et al.J.Med.chem.2002,45, 3865-3877.

Hydrolysis of a compound of formula 7 to give a compound of the invention of formula 1 can be carried out using conditions well known in the art of Organic Synthesis, many of which are summarized in "Protective Groups in Organic Synthesis" [ T.W.Greene and P.G.M.Wuts,2^nd Edition,John Wiley&Sons,N.Y.1991]In (1). For example, the reaction may be conveniently carried out by: the compound of formula 7 is treated with one or more equivalents of an alkali metal hydroxide, such as potassium hydroxide, sodium hydroxide, or lithium hydroxide, preferably lithium hydroxide, in a mixture of a suitable solvent, such as tetrahydrofuran, methanol, and water. The reaction may be carried out at a temperature between about 100 ℃ and about room temperature, preferably between about room temperature and about 60 ℃.

It will be apparent to those skilled in the art of organic synthesis that any hydrolytically unstable group such as an ester or nitrile in the Ar2 group in the compound of formula 7 will also be cleaved in the hydrolysis reaction described above. This may be a desired result, for example, where the desired compound contains a carboxylate or carboxamide group. It is well known in the art that by judicious choice of reaction conditions, for example using only one equivalent of base or by maintaining a low reaction temperature (e.g., about 0 ℃), the carbomethoxy group is cleaved to give the desired acid of formula 1 without cleaving other groups such as more sterically hindered esters, amides, or nitriles.

Scheme 2

A second general method for synthesizing the compounds of the present invention is shown in scheme 2, wherein the order of the steps outlined in scheme 1 is changed. According to this method, the compound of formula 2 is converted to the thioamide of formula 8 using conditions similar to those described above for the conversion of the compound of formula 4 to the compound of formula 5. The thioamide of formula 8 can then be converted to the thiazole of formula 9 using conditions similar to those described above for the conversion of the compound of formula 5 to the compound of formula 7. The aryl bromide of formula 9 may then be subjected to a transition metal catalyzed reaction with a compound of formula 3 (where X represents a group that may serve as a leaving group in a noble metal catalyzed coupling reaction such as the Suzuki reaction or Stille reaction) to give the biaryl of formula 7. The conditions for the noble metal-catalyzed coupling reaction are similar to those described above for the conversion of the compound of formula 2 to the compound of formula 4. The ester group of the compound of formula 6 is then cleaved to give the desired compound of formula 1, for example using the conditions described above.

In one embodiment of the invention, the compound of the invention is a compound of formula 10. Such compounds can be prepared using the methods outlined in scheme 3.

Scheme 3

According to this method, a compound of formula 9 (which can be prepared as described above) is subjected to a transition metal-catalyzed reaction with a compound of formula 11 (wherein X represents boric acid, a borate ester, potassium trifluoroborate, trimethyltin, or tri-n-butyltin) to give a biaryl of formula 15. Selective cleavage of the tert-butyl ester affords the carboxylic acid of formula 12. The acid is then reacted with a compound of formula HNR₁R₂To give an amide of formula 13, followed by cleavage of the methyl ester to give the compound of the invention of formula 10.

Transition metal-catalyzed reaction of an aryl bromide of formula 9 with a compound of formula 11 (wherein X represents boric acid, a borate ester, potassium trifluoroborate, trimethyltin, or tri-n-butyltin) to provide a compound of formula 15 can be carried out using any conventional method. For example, such conversion may be carried out using conditions similar to those described above for the conversion of the compound of formula 2 to the compound of formula 4.

Cleavage of the tert-butyl ester present in the compound of formula 7 to give the monoester of formula 8 can be carried out using conventional methods. For example, the compound of formula 7 can be carried out with a strong organic acid (preferably trifluoroacetic acid) in an inert solvent such as a halogenated hydrocarbon (preferably dichloromethane or chloroform) at a temperature of about room temperature. The precise conditions for such reactions can be found in references, for example in Bartel, s.et al.us 20100029772; in Thompson, t. and Willis, p.us 20080146612; in Ford, r.et al.us 20080153850; and in Hirashima, S.et al.J.Med.chem.2006,49, 4721-.

According to scheme 3, carboxylic acids of formula 12 with the structure HNR₁R₂The coupling of the amines of (use and preparation of) are described below can be achieved using methods well known to those of ordinary skill in the art. For example, the transformation can be carried out by: reacting a carboxylic acid of formula 12 or a suitable derivative of a carboxylic acid of formula 12, such as an activated ester, with the structure HNR₁R₂Or a corresponding acid addition salt (e.g., hydrochloride salt), if desired, in a coupling agent (many examples areKnown in peptide chemistry). The reaction is conveniently carried out by: in the presence of a suitable base such as diisopropylethylamine, a coupling agent such as O- (benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate or TSTU or N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, and in the optional additional presence of a catalyst such as 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole, in an inert solvent such as a chlorinated hydrocarbon (e.g., dichloromethane) or N, N-dimethylformamide or N-methylpyrrolidinone, at a temperature between about 0 ℃ and about room temperature, preferably at room temperature, with the structure HNR₁R₂The free base or hydrochloride salt of the amine of formula 12.

A source of the compound of formula 3

Many compounds of formula 3 (wherein X represents b (oh)2) are commercially available and examples are shown below.

2-acetylphenylboronic acid from ASDI Incorporated,601 exchange Blvd, Newark, DE19711, USA; phenyl boronic acid.

2-acetyl-3-thienylboronic acid from Aldrich Chemical Company, Inc.,1001West Saint Paul Avenue, Milwaukee, WI53233, USA; 2-methyl-4-cyanophenylboronic acid.

From Alfa Aesar,26Parkridge Road, Ward Hill, MA01835, USA:4- (methane sulfinyl) benzeneboronic acid.

From Chem-Impex International, Inc.,935Dillon Drive, Wood Dale, IL60191, USA 4-methylpyridine-2-boronic acid.

From Combi-Blocks Inc.,7949Silverton Avenue, Suite915, San Diego, CA92126, USA:2,3, 5-trifluorophenylboronic acid; 2, 3-dichlorophenyl boronic acid; 2, 3-difluorophenylboronic acid; 2,4, 6-trichlorophenylboronic acid; 2, 4-dichlorophenyl boronic acid; 2, 5-dichlorophenyl boronic acid; 2, 5-difluorophenylboronic acid; 2-aminocarbonylphenylboronic acid; 2-chloro-4-fluorophenylboronic acid; 2-chloro-5-hydroxyphenylboronic acid; 2-chloro-5-methoxyphenylboronic acid; 2-chloro-5-methylphenylboronic acid; 2-chlorophenylboronic acid; 2-chlorothiophene-3-boronic acid; 2-cyanophenylboronic acid; 2-ethoxypyrimidine-5-boronic acid; 2-fluorophenylboronic acid; 2-methoxypyridine-3-boronic acid hydrate; 2-methoxypyrimidine-5-boronic acid; 2-methylphenylboronic acid; 2-methylpyridine-3-boronic acid hydrochloride; 3-acetylphenylboronic acid; 3-chloro-4-cyanophenylboronic acid; 3-chlorothiophene-2-boronic acid; 3-cyanophenylboronic acid; 3-methoxyphenylboronic acid; 3-methylpyridine-4-boronic acid hydrochloride, 4-acetylphenylboronic acid; 4-chloro-2-fluorophenylboronic acid; 4-chloro-3-cyanophenylboronic acid; 4-chlorophenylboronic acid; 4-cyano-2-fluorophenylboronic acid; 4-cyanophenylboronic acid; 4-isopropylpyrimidine-5-boronic acid; 4-methyl-3-thiopheneboronic acid; 4-nitrophenylboronic acid; 5-chloro-2-cyanophenylboronic acid; 5-chloropyridine-3-boronic acid; 5-fluoropyridine-2-boronic acid; 6-methoxypyridine-2-boronic acid; pyridine-3-boronic acid; pyridine-4-boronic acid; pyrimidine-5-boronic acid.

6-chloropyrazine-2-boronic acid from Combiophos Catalysts, Inc., P.O.Box220, Princeton, NJ08542-0220, USA; 6-cyanopyridine-2-boronic acid.

From Frontier Scientific, Inc., P.O.Box31, Logan, UT84323-0031, USA2, 4-difluorophenylboronic acid; 2-chloro-5-cyanophenylboronic acid; 2-formyl-5-methylphenylboronic acid; 2-formylphenylboronic acid; 2-methoxyphenylboronic acid; 3-nitrophenylboronic acid; 4-fluorophenyl boronic acid.

From Matrix Scientific, P.O.Box25067, Columbia, SC29224-5067, USA 2-cyanopyridine-3-boronic acid.

Several compounds of formula 3 (wherein X represents trialkyltin) are commercially available and examples are shown below.

Trimethyl (phenyl) tin from Aldrich Chemical Company, Inc.,1001West Saint Paul Avenue, Milwaukee, WI53233, USA; tributylphenylstannane; 5- (tributylstannyl) pyrimidine; 2- (tributylstannyl) pyrazine.

From Apollo Scientific Ltd., Whitefield Road, Bredbury, Stockport, CheshireSK62QR, United Kingdom: 4-fluoro- (tributylstannyl) benzene; tributyl (5-fluoro-2-methoxyphenyl) stannane; 5-fluoro-2-methyl- (tributylstannyl) benzene; 3-methoxy (tri-n-butylstannyl) benzene; tributyl (2-methoxyphenyl) stannane; tributyl (3- (trifluoromethyl) phenyl) stannane.

From Matrix Scientific, P.O.Box25067, Columbia, SC29224-5067, USA 4- (tributylstannyl) pyridine.

Except that a commercially available compound of formula 3 (wherein X represents B (OH))₂Or trialkyltin) which can be synthesized by procedures well known to those skilled in the art of organic synthesis. For example, compounds of this type can be conveniently synthesized according to scheme 4 from compounds of formula 14 (wherein Y represents bromo or iodo) by: treatment (to form a grignard reagent) with an alkyllithium (e.g., n-butyllithium) or alkylmagnesium in a suitable inert solvent such as an ether (e.g., tetrahydrofuran or diethyl ether) at a temperature suitable for the reaction (e.g., at about-78 ℃ for reaction with alkyllithium or at about room temperature for reaction with alkylmagnesium) followed by treatment with a trialkyl borate or a trialkyltin chloride to form a compound of formula 3, wherein X represents b (oh)2 or a trialkyltin, respectively. It will be apparent to those of ordinary skill in the art of synthetic organic chemistry that this approach is disadvantageous for preparing compounds of formula 3 from compounds of formula 14 that contain functional groups that are incompatible with the alkyllithium or organomagnesium reagents used in the reaction. Conventional alternatives are outlined below.

Scheme 4

Alternatively, the reaction may be carried out under noble metal catalysis. According to this route, the compound of formula 14 is conveniently reacted with hexa-alkyl-distannane (e.g. hexamethyl-distannane or hexa-n-butyl-di-stannane) or 4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane or 4,4,5,5,4',4',5',5' -octamethyl- [2,2' ] di [ [1,3,2] dioxaborolane ] in the presence of a noble metal catalyst, preferably a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) or palladium (II) chloride or palladium (II) acetate, and in the optional additional presence of a catalytic amount of a phosphine ligand such as tri-o-tolylphosphine or tri-t-butylphosphine. In the case of reaction with hexa-alkyl-distannane, the reaction is optionally carried out in the presence of an organic base such as a tertiary amine (e.g., triethylamine), while in the case of reaction with dioxaborolane, the reaction is carried out in the presence of an inorganic base (e.g., cesium fluoride, or potassium acetate, preferably potassium acetate). The reaction is conveniently carried out in a suitable inert solvent such as a polar aprotic solvent (e.g., N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or acetonitrile) or an aromatic hydrocarbon (e.g., toluene) at a temperature of between about room temperature and about 100 degrees c, and preferably between about room temperature and about 50 degrees c. As an additional example, the specific reaction conditions used in the following disclosure may be followed: baudiin, O.et al.J.org.chem.Soc.2000,65, 9268-9271; ishiyama, T.et al.tetrahedron Lett.1997,38, 3447-3450; hylarides, M.D.J.organomet.chem.1989,367, 259-265; read, M.W.et al.org.Lett.2000,2, 3201-; ishiyama, T.et al.tetrahedron1997,57, 9813-; fuerster, A.et al.org.Lett.2002,4, 541-.

A source of the compound of formula 6

Many compounds of formula 6 are commercially available and examples are shown below.

3-chlorobenzoyl methyl bromide from Aldrich Chemical Company, Inc.,1001West Saint Paul Avenue, Milwaukee, WI53233, USA; 4- (trifluoromethyl) phenacyl bromide; 4- (trifluoromethoxy) phenacyl bromide; 2-bromo-1- (3-fluorophenyl) ethan-1-one; 2-bromo-2 ',4' -difluoroacetophenone; 2-bromo-1- (2, 4-dimethylphenyl) ethan-1-one; 2-bromo-4' -iodoacetophenone; 2-bromo-3 '-chloro-4' -fluoroacetophenone; 2,3 '-dibromo-4' -fluoroacetophenone; 2-bromo-1- (3, 5-dichloro-2-fluorophenyl) ethanone; 3, 4-dichlorobenzoyl methyl bromide; 2-bromo-2 ',4' -dichloroacetophenone; 2-bromo-2 ',5' -dimethoxyacetophenone; 2-bromo-4' -methoxyacetophenone; 2,4' -dibromoacetophenone; 2-bromo-4' -chloroacetophenone; 3' -methoxybenzoylmethyl bromide; 2-bromo-4' -fluoroacetophenone; 4-cyanobenzoylmethyl bromide; 3-bromobenzoylmethyl bromide; 2-bromo-2' -chloroacetophenone; 2-bromoacetophenone; 2-bromo-2 ',4' -dimethoxyacetophenone; 2-bromo-4' -methylacetophenone; and 2-bromo-2' -methoxyacetophenone.

2- (2-bromoacetyl) thiophene, available from Alfa Aesar,26Parkridge Road, Ward Hill, MA01835, USA; 3- (trifluoromethyl) phenacyl bromide and 1, 4-benzodioxan-6-ylmethyl ketone.

From Apollo Scientific Ltd., Whitefield Road, Bredbury, Stockport, CheshireSK62QR, United Kingdom: 2-bromo-1- (3-thienyl) -1-ethanone; 3- (2-bromoacetyl) benzonitrile; 2-bromobenzoylmethyl bromide; 2-bromo-1- (4-chloro-3-methylphenyl) ethan-1-one; 2-bromo-1- (4-pentylphenyl) ethan-1-one; 3-ethylbenzoylmethyl bromide; 3, 4-difluorobenzoylmethyl bromide; 3',5' -bis (trifluoromethyl) -2-bromoacetophenone; 4- (difluoromethoxy) phenacyl bromide; 2- (trifluoromethyl) phenacyl bromide; 2-bromo-2' -fluoroacetophenone; 4-fluoro-3- (trifluoromethyl) phenacyl bromide; 2-bromo-1- (4-chloro-2-fluoro-5-methylphenyl) -1-ethanone; 2, 5-difluorobenzoylmethyl bromide; 3, 5-difluorobenzoylmethyl bromide; 2- (trifluoromethoxy) phenacyl bromide; 2-fluoro-4-methoxybenzoylmethyl bromide; 2-bromo-2 ',3' -difluoroacetophenone; 3-fluoro-4-methoxybenzoylmethyl bromide; 2- (difluoromethoxy) phenacyl bromide; 3- (trifluoromethoxy) phenacyl bromide; 2-chloro-5- (trifluoromethyl) phenacyl bromide; 2, 4-bis (trifluoromethyl) phenacyl bromide; 2-fluoro-6- (trifluoromethyl) phenacyl bromide; 2-fluoro-3- (trifluoromethyl) phenacyl bromide; 2-fluoro-4- (trifluoromethyl) phenacyl bromide; 2-fluoro-5- (trifluoromethyl) phenacyl bromide; 3-fluoro-5- (trifluoromethyl) phenacyl bromide; 4-fluoro-2- (trifluoromethyl) phenacyl bromide; 3-fluoro-4- (trifluoromethyl) phenacyl bromide; 4-methoxy-2- (trifluoromethyl) phenacyl bromide; 4-methoxy-3- (trifluoromethyl) phenacyl bromide; 2-bromo-4 '-chloro-3' - (trifluoromethyl) acetophenone; 3,4, 5-trifluorobenzoylmethyl bromide; 2,4, 5-trifluorobenzoylmethyl bromide; 3-fluoro-4-methylbenzoylmethyl bromide; 2-chloro-4-fluorobenzoylmethyl bromide; 2-chloro-5-fluorobenzoylmethyl bromide; 2-bromo-3' - (difluoromethoxy) acetophenone; 2, 3-difluoro-4- (trifluoromethyl) phenacyl bromide; 3, 4-difluoro-5- (trifluoromethyl) phenacyl bromide; 2-bromo-1- (4-bromo-2-fluorophenyl) ethanone; 2-bromo-1- (2-bromo-4-fluorophenyl) ethanone; 2-bromo-1- (3, 5-difluoro-4-methoxyphenyl) ethan-1-one; 2, 4-difluoro-3- (trifluoromethyl) phenacyl bromide; and 2, 3-difluoro-4-methylbenzoylmethyl bromide.

2-bromo-1- (3, 4-dimethoxyphenyl) ethanone from Chontech, Inc.,9Giovanni Drive, Waterford, CT06385, USA; 2-bromo-1- (5-fluoro-2-methoxyphenyl) ethanone; 2-bromo-1- (2, 5-dichlorophenyl) ethanone; 2-bromo-1- (5-chloro-2-methoxy-phenyl) -ethanone; 2-bromo-2 ',3' -dichloroacetophenone; 2-bromo-3 '-chloro-4' -methoxyacetophenone; 2-bromo-1- (4-fluoro-2-methoxyphenyl) ethanone; 2-bromo-2 '-chloro-4' -methoxyacetophenone; 2-bromo-5 '-chloro-2' -fluoroacetophenone; and 2-bromo-4 '-fluoro-3' -methoxyacetophenone.

From Matrix Scientific, p.o. box25067, Columbia, SC29224-5067, USA: 2-bromo-1- (4-methoxy-2, 5-dimethyl-phenyl) -ethanone; 2-bromo-1- (3-bromo-2-thienyl) -1-ethanone; 2-bromo-1- (3-chloro-2-thienyl) -1-ethanone; and 2-bromo-1- (5-chloro-thiophen-2-yl) -ethanone.

2-bromo-1- (5-bromothien-2-yl) ethanone from Oakwood Products, Inc.,1741Old Dunbar Road, West Columbia, SC29172, USA; 2-bromo-1- (5-chloro-2-methoxy-4-methylphenyl) ethanone; 2-bromo-1- (3-bromo-4-methoxyphenyl) ethanone; 2-bromo-1- (5-bromo-2-methoxyphenyl) ethanone; 2-bromo-1- (3, 5-dichloro-2-methoxyphenyl) ethanone; and 2-bromo-1- (2, 6-dimethoxyphenyl) ethanone.

From TimTec LLC, Harmony Business Park Bldg301-A, Newark, DE19711, USA 2-bromo-1- (2-methoxy-5-methyl-phenyl) -ethanone; 2-bromo-1- (2,4, 6-trimethylphenyl) ethan-1-one; 2-bromo-1- (4-ethylphenyl) ethan-1-one; 2-bromo-1- (4-ethoxyphenyl) ethanone; 2-bromo-1- (3,4, 5-trimethylphenyl) ethanone; and 2-bromo-1- (2, 5-dimethylphenyl) ethan-1-one.

Scheme 5

In addition to the use of commercially available compounds of formula 6, such compounds can be synthesized by procedures well known to those skilled in the art of organic synthesis. For example, compounds of this type can be conveniently synthesized according to scheme 5 from the methyl ketone of formula 16, many of the methyl ketones of formula 16 are commercially available, and can be prepared using synthetic procedures well known to those of ordinary skill in the art of organic synthesis (e.g., by Friedel Crafts acetylation of aromatic hydrocarbons, or by Stille coupling of halogenated aromatic hydrocarbons using tributyl (1-ethoxyvinyl) tin followed by hydrolysis). According to this operation, the reaction can be conveniently carried out by: the compound of formula 16 is treated with bromine in an inert solvent such as chloroform or 1, 4-dioxane or acetic acid or diethyl ether or benzene at a temperature between about room temperature and about 40 ℃. Examples of specific conditions for such reactions can be found in references such as in Clive, D.L.J.et al.J.org.chem.2003,68, 9247-9254; in Kourounakis, A.P.et al.Bioorg.Med.chem.2010,18, 7402-; in Laufer, s.a.et al.synthesis2008, 253-266; or in Perrone, r.et al.j.med.chem.1992,35, 3045-3049. It is well known in the art of organic chemistry that other bromination conditions may be used in place of the bromine to carry out the reaction. Examples of such alternative conditions include tetra-n-butylammonium bromide at about room temperature in an inert solvent such as a mixture of methanol and methylene chloride; n-bromosuccinimide in carbon tetrachloride at a temperature between about room temperature and about 80 ℃; and copper (II) bromide in chloroform at about 60 ℃. Examples of specific conditions for such reactions can be found in references, for example in Molino, b.f.et al, us 20060052378; in Kajigaeshi, S.et al. Bull. chem.Soc.Japan1987,60, 1159-Buza 1160; in Tomoda, H.et al.Bull.chem Soc.Japan1999,72, 1327-; in Duan, j.et al.us 20050176716; or in Henry, R.A.et al.J.org.chem.1990,55, 1796-1801.

Scheme 6

Certain compounds of formula 6 can also be prepared by reacting an aromatic hydrocarbon of formula 17 with a Friedel-Crafts of bromoacetyl bromide having formula 18 in the presence of a lewis acid catalyst such as aluminum chloride in an inert solvent such as nitrobenzene or dichloromethane or DMF or carbon disulfide at a temperature of about 0 ℃. It is well known to those of ordinary skill in the art of organic chemistry that the position of the bromoacetyl linkage in such a reaction product of formula 6 depends on the electronics of the aromatic hydrocarbon of formula 17, and therefore such a reaction, while very useful for the preparation of certain compounds of formula 6, is not suitable for the synthesis of all compounds of formula 6. For more information on this reaction and in particular on the regional Chemistry results, reference may be made, for example, to March's advanced organic Chemistry: Reactions, Mechanisms, and Structure,5th Edition (Smith, M.B.; March, J. (2001), New York: Wiley-Interscience; p712et seq.). Examples of specific conditions that can be used in such reactions are found in the references, for example in Yekini, i.et al.bioorg.med.chem.2009,17, 7823-; in Calderwood, d.j.et al.us 20090270402; in Nitz, t.j.et al.us 20090215778; and in perron, m.g. equivalent.bioorg.med.chem.2008, 16, 2473-one 2488.

Scheme 7

Another alternative synthesis of the compound of formula 6 is shown in scheme 7. Such synthesis starts with an arene-carboxylic acid of formula 19, many examples of which are commercially available, or can be synthesized using known procedures. The compound of formula 19 can be treated with a chlorinating agent such as oxalyl chloride or thionyl chloride or phosphorus oxychloride either neat or in an inert solvent such as benzene or methylene chloride at a temperature between about room temperature and the boiling point of the selected solvent to provide the acid chloride of formula 20. The acid chloride may then be treated with diazomethane or trimethylsilyldiazomethane in an inert solvent such as methylene chloride or diethyl ether or a mixture of tetrahydrofuran and acetonitrile at a temperature of about 0 ℃ to provide the diazoketone of formula 21. Without isolation, this compound can then be treated with 30% hydrogen bromide in acetic acid to give the bromomethyl ketone of formula 6. Examples of specific conditions that can be used in such reactions can be found in references such as in illinig, c.r.et al, us6,291,514; in Wager, t.t.et al.wo 2008026046; in Dunn, j.p.et al, us7,166,738; in Melander, c.et al.us 20090270475; and in Huigens, R.W.IIIet al.Bioorg, Med.chem.2010,18, 663-containing 674.

Sources of compounds of formula HNR1R2

Many compounds of formula HNR1R2 are commercially available and examples are shown below.

From Acros Organics BVBA, Janssen Pharmaceuticaan 3A,2440Geel, Belgium:2, 5-dimethylpyrrolidine; piperidine; (tetrahydrofuran-3-yl) methylamine; 4-aminomethyl tetrahydropyran; 4-fluorobenzylamine; 3-methylbenzylamine; 3, 5-difluorobenzylamine; 3-methoxybenzylamine; 2, 5-dimethylbenzylamine; 2-fluoro-5-methylbenzylamine; 3-fluoro-5-methylbenzylamine; 3-fluoro-2-methylbenzylamine; 2-fluoro-4-methylbenzylamine; 4-fluoro-2-methylbenzylamine; 2-bromophenylethylamine; 3-bromophenylethylamine; 2- (3-chlorophenyl) ethylamine; 2-methylphenethylamine; 4-methylphenethylamine; and 3-methylphenethylamine.

Pyrrolidine, available from Aldrich Chemical Company, Inc.,1001West Saint Paul Avenue, Milwaukee, WI53233, USA; morpholine; 4-aminotetrahydropyran; tetrahydrofurfuryl amine; 2-thiophenemethylamine; 4-chlorobenzylamine; benzylamine; 2-chloro-5- (trifluoromethyl) benzylamine; 4- (2-aminoethyl) pyridine; 4-methoxybenzylamine; 4-bromo- α -methylbenzylamine; 1- (4-fluorophenyl) ethylamine; (R) - (+) -1-phenylethylamine; (S) - (-) -1-phenylethylamine; (S) - (-) -1- (4-methoxyphenyl) ethylamine; 4-chloro- α -methylbenzylamine; (S) -1- (3-chlorophenyl) ethylamine; 4-isopropylphenethylamine hydrochloride; 2- (4-trifluoromethyl-phenyl) -ethylamine; 2, 3-dimethoxyphenethylamine; 4-fluorophenethylamine hydrochloride; 3, 4-difluoro-phenethylamine; and 2, 4-difluorophenethylamine.

2-methylpyrrolidine from Alfa Aesar,26Parkridge Road, Ward Hill, MA01835, USA; 1-acetyl-piperazine; (3-methyl-2-thienyl) methylamine; 2, 4-difluorobenzylamine; 2, 6-difluorobenzylamine; 3-chlorobenzylamine; 3- (trifluoromethyl) benzylamine; 3, 5-bis (trifluoromethyl) benzylamine; and 2, 3-difluorobenzylamine.

From Apollo Scientific Ltd., Whitefield Road, Bredbury, Stockport, CheshireSK62QR, United Kingdom:4- (2-aminoethyl) tetrahydropyran; (4-methyl-2-thienyl) methylamine; 2-fluoro-5- (trifluoromethyl) benzylamine; 2-fluoro-5- (trifluoromethyl) benzylamine; 3- (trifluoromethyl) benzylamine; 4- (trifluoromethyl) benzylamine; 1- (2-trifluoromethylphenyl) ethylamine; and 1- (3-trifluoromethylphenyl) ethylamine.

From Matrix Scientific, P.O.Box25067, Columbia, SC29224-5067, USA 1-acetylpiperidin-4-amine; tetrahydro-2H-pyran-3-methanamine; 1- (7-oxabicyclo [2.2.1] hept-2-yl) methylamine; 2- (tetrahydro-pyran-2-yl) -ethylamine; 2-tetrahydrofuran-2-ylethylamine; (5-chlorothien-2-yl) methylamine; 3, 5-dimethylbenzylamine; 3-fluoro-4-methylbenzylamine; 4-cyanobenzylamine; 2, 5-difluorobenzylamine; 3-fluorobenzylamine; 1- (4-methoxyphenyl) ethylamine; 1- (2-methoxy-phenyl) -ethylamine; 1- (3-methoxyphenyl) ethylamine; 1- (3, 4-dichlorophenyl) ethylamine; 1- (3, 4-dimethyl-phenyl) -ethylamine; 1- (4-tert-butylphenyl) ethylamine; and 1- (3-bromophenyl) ethylamine.

From Oakwood Products, Inc.,1741Old Dunbar Road, West Columbia, SC29172, USA (tetrahydrofuran-3-yl) methylamine; tetrahydropyran-2-ylmethylamine; (1-methyl-1H-pyrazol-5-yl) methylamine; 1- (1-ethyl-1H-pyrazol-5-yl) methylamine; 5-fluoro-2-methylbenzylamine; 3, 4-dimethylbenzylamine; 4-isopropyl benzylamine; 2, 3-dimethylbenzylamine; 4-chloro-3- (trifluoromethyl) benzylamine; 1-pyridin-3-yl-ethylamine; 4-fluoro-3-methylbenzylamine; (2- [2- (trifluoromethoxy) phenyl ] ethyl) amine; and 3-ethoxyphenethylamine.

3-aminotetrahydrofuran from TimTec LLC, Harmony Business Park Bldg301-A, Newark, DE19711, USA; 2- (tetrahydro-2H-pyran-3-yl) ethylamine; 2-fluorobenzylamine; 2-methoxybenzylamine; 2, 4-dimethylbenzylamine; 4-ethylbenzylamine; 2,4, 6-trimethylbenzylamine; 2- (aminomethyl) benzonitrile; 4-propylbenzylamine; 2, 6-dimethylbenzylamine; 1-pyridin-4-yl-ethylamine; 3-cyanobenzylamine; 1- (2',4' -difluorophenyl) ethylamine; and 1- [4- (difluoromethoxy) phenyl ] ethylamine.

4-hydroxypiperidine from TCI America,9211 n.harborate Street, Portland, or 97203, USA; 3, 4-difluorobenzylamine; 2-chlorobenzylamine; 4-methylbenzylamine; 2- (aminomethyl) pyridine; 3- (aminomethyl) pyridine; 4- (aminomethyl) pyridine; 3- (2-aminoethyl) pyridine; 2- (2-aminoethyl) pyridine; DL- α -methylbenzylamine; 2-methylbenzylamine; 4-bromophenylethylamine; 2, 6-dichlorophenethylamine; 3, 4-dichlorophenethylamine; 2, 4-dichlorophenethylamine; 2- (3, 4-dimethoxyphenyl) ethylamine; and 2- (2-chlorophenyl) ethylamine.

Many amines of the formula HNR1R2 can be prepared using one of a variety of methods known to those of ordinary skill in the art of organic synthesis. Many of these methods are listed in "The Chemistry of The AminoGroup" [ m.s.gibson; s. Patai Ed.; john Wiley & Sons, Ltd. London1968,37-77, in "Advanced Organic Chemistry" [ J. March,3rd Edition, John Wiley & Sons, Inc. New York,1985], pp 1153-1064, and in "comprehensive Organic Transformations: A Guide to Functional Group Preparations" [ R.C. Larock, VCH Publishers, Inc. New York,1989], pp 1061-1063.

Amines of the formula HNR1R2 (where R1 is hydrogen and R2 is cycloalkyl or heterocycloalkyl) can be prepared from cyclic ketones by the following method: the ketone is treated with hydrogen and ammonia in the presence of a noble metal catalyst such as palladium or ruthenium (both optionally supported on carbon), optionally in the additional presence of ammonium chloride, at a temperature of about 200 ℃. The precise conditions for such reactions are described in the literature, for example in T.Ikenaga et al tetrahedron2005,61, 2105-.

Amines of the formula HNR1R2, which are substituted piperidine derivatives, can be prepared by catalytic hydrogenation of substituted pyridines. The reaction can be conveniently carried out by: the pyridine derivative is treated with hydrogen gas in the presence of a noble metal catalyst such as platinum/carbon or platinum oxide or palladium/carbon in a mixture of ethanol and hydrochloric acid or in acetic acid or ethyl acetate or methanol at a temperature between about room temperature and about 50 ℃ at a hydrogen pressure between about 1 atmosphere and about 30 atmospheres. Examples of the precise conditions that can be used to carry out such reactions are found in references such as Graf, c.d. et al.us 20110015400; in thatEt al.us 20100261755; in Carpenter, a.j.et al.wo 2010014593; or in Motterle, r.et al.wo2010100215.

Amines of formula HNR1R2, which are substituted morpholine derivatives, can be prepared using a number of reaction sequences known in the art of organic synthesis. For example, substituted morpholine derivatives may be prepared from substituted allyloxy-alkyl azides by: the olefin is oxidized by treating the olefin with osmium tetroxide or potassium osmate in a mixture of acetone and water at about room temperature either stoichiometrically or using a stoichiometric oxidizing agent such as N-methylmorpholine N-oxide, then in a mixture of acetone and water at about room temperature with sodium periodate, and then hydrogenated in methanol at about room temperature in the presence of a noble metal catalyst such as palladium on charcoal. Examples of the precise conditions for carrying out such reactions can be found in references such as in Sawant, r.t. and Waghmode, s.b. tetrahedron2010,66, 2010-2014.

Amines of formula HNR1R2 (where R1 is hydrogen and R2 is cycloalkyl or heterocycloalkyl) can be prepared from cycloolefins by: treatment of the cyclic olefin with borane-tetrahydrofuran complex in an inert solvent such as tetrahydrofuran at about room temperature forms the corresponding organoborane, which is then treated with chloramine in the presence of aqueous sodium hydroxide. Alternatively, the organoborane may be treated with hydroxylamine-O-sulfonic acid in diglyme at about 100 ℃ to provide an amine of the formula HNR1R 2. The precise conditions for this reaction can be found in the literature, for example in Brown, H.C. et al tetrahedron1987,43, 4071-4078.

Amines of formula HNR1R2 (where R1 is hydrogen and R2 is cycloalkyl or heterocycloalkyl) can be prepared from alcohols of formula R2OH by: conversion to the corresponding formula R2N₃And then reducing the azide. Replacement of the hydroxyl group of an alcohol of formula R2OH to give the corresponding azido analog can be accomplished by: using 1, 8-diazabicyclo [5.4.0 ] in an inert solvent such as toluene or N, N-dimethylformamide at a temperature of between about 0 ℃ and about 10 ℃ under anhydrous conditions]Undec-7-ene (DBU) treatment of a mixture of an alcohol of formula R2OH and diphenylphosphoryl azide (DPPA) for about 18 hours. The precise conditions for carrying out such reactions can be found in references such as Bremond, p.et al. synthesis2009, 290-296; in Wyrebek, P.et al.tetrahedron2009,65, 1268-; in Ryu, h.et al.j.med.chem.2008,51, 57-67; or in IZQuierdo, I.et al, tetrahedron2006,63, 1440-1447. Hydrogenation of the above azido derivatives to give the corresponding amines of formula HNR1R2 (where R1 is hydrogen and R2 is cycloalkyl or heterocycloalkyl) can be carried out in an organic solvent such as ethyl acetate, methanol, or ethanol in the presence of 5% palladium on charcoal at a hydrogen pressure of between about atmospheric pressure and about 350psi for 1.5 hours at room temperature. The precise conditions for carrying out such reactions can be found in references such as, for example, in Enomoto, m, and Kuwarahara, s.angelw.chem.intl.edn.engl.2009, 48, 1144-; in oii, t.et al.us 2009131716; in Wang, X.et al.tetrahedron2007,63, 6141-6145; or in Ciliberti, N.et al.Bioorg.Med.chem.2007,15, 3065-channel 3081. Alternatively, reduction of the azide group to give an amine of formula HNR1R2 (wherein R1 is hydrogen and R2 is cycloalkyl or heterocycloalkyl) can be achieved by: the azide is treated with triphenylphosphine in an inert solvent such as tetrahydrofuran in the presence of water at a temperature between about room temperature and about 65 ℃. The precise conditions for carrying out such reactions can be found in references such as Han, b.et al.wo 2008148689; in Liu, G.et al.org.Lett.2009,11, 1143-1146; in Wang, X.et al.tetrahedron2007,63, 6141-6145; or Shimada, I.et al.Bioorg.Med.chem.2008,16, 1966-.

Amines of the formula HNR1R2, wherein R1 is hydrogen and R2 is optionally substituted benzyl, can be conveniently prepared by catalytic hydrogenation of benzonitrile. According to this method, a nitrile of formula ArCN, wherein the aryl Ar represents the aromatic moiety of benzyl R2, is treated with hydrogen at about room temperature in the presence of a noble metal catalyst such as palladium, nickel or cobalt in an inert solvent such as ethanol. The precise conditions for carrying out this method can be found in references such as Hegedus, L.et al.appl.Cat.A.2005, 296, 209-215; or in Gould, F.E.et al.J.org.chem.1960,25, 1658-1660. Alternatively, the reduction of a nitrile of formula ArCN, wherein aryl Ar represents the aromatic moiety of benzyl R2, may be carried out using conditions similar to those disclosed in Enthaler, S.et al, chem.Eur.J.2008,14,9491-9494, at an elevated hydrogen pressure, such as at about 50 bar, in the presence of a homogeneous catalyst, such as a mixture of bis (2-methylallyl) -1, 5-cyclooctadieneruthenium (II), 1-bis (diphenylphosphino) ferrocene, and potassium tert-butoxide in toluene, at about 80 ℃. Alternatively, the reduction of a nitrile of formula ArCN (wherein aryl Ar represents the aromatic moiety of benzyl R2) may be carried out by: the nitrile is treated with diisopropylaminomethane borane in the presence of a catalytic amount of lithium borohydride in an inert solvent such as tetrahydrofuran at a temperature of about room temperature using conditions similar to those disclosed in Haddenham, D.et al.J.org.chem.2009,74, 1964-1970.

An example of a different method which can be used to prepare amines of formula HNR1R2 wherein R1 is hydrogen and R2 is optionally substituted benzyl is the conversion of a benzyl halide to a benzyl azide followed by reduction of the azide to give the benzylamine. According to this method, a benzyl halide of the formula R2X, wherein X represents a leaving group such as halogen (e.g., bromine, chlorine, iodine), an alkyl or aryl sulfonate (e.g., methane sulfonate or toluene sulfonate), is reacted with an alkali metal azide salt such as sodium azide in an inert solvent such as dimethyl sulfoxide or ethanol at a temperature between about room temperature and about 80 ℃. The precise conditions for carrying out such reactions can be found in references such as Zhao, y.et al.bioorg.med.chem.2008,16, 6333-; in Compain-Batissou, m.et al.heterocycos2007, 71, 27-38; or in Tegtmeier, f.et al.us 20080044354. The resulting azide group can be reduced using conditions similar to those described above.

Other examples of processes that may be used to prepare amines of formula HNR1R2 wherein R1 is hydrogen and R2 is optionally substituted benzyl include reductive amination of benzaldehyde derivatives, wherein the benzaldehyde derivative is reacted with ammonia or an acid addition salt of ammonia such as ammonium chloride or ammonium acetate and the resulting imine is reduced to give a compound of formula HNR1R 2. The reduction can be carried out using hydrogenation under noble metal catalysis, or can be carried out by: the imine is treated with a reducing agent such as sodium borohydride or sodium cyanoborohydride or preferably sodium triacetoxyborohydride. Imine formation and reduction may be performed as two separate steps, or they may be combined in a single step. The one-step process is convenient and well known to those of ordinary skill in the art of organic synthesis. A review of this reaction, particularly focusing on the use of sodium triacetoxyborohydride as the reducing agent, has recently been published (Abdel-magic, A.F., and Mehrman, S.J.Org.Process Res.Dev.2006,10, 971-ion 1031). The reaction is conveniently carried out by: the benzaldehyde derivative is treated with ammonium acetate in an inert solvent such as a halogenated hydrocarbon (e.g. dichloromethane or 1, 2-dichloroethane) optionally in the additional presence of a water-absorbing agent such as a molecular sieve at about room temperature. A reducing agent such as sodium cyanoborohydride or preferably sodium triacetoxyborohydride is added either simultaneously with the combination of benzaldehyde derivative and ammonium acetate or after a time interval of about 1 hour. Examples of conditions that can be used in such reactions are found in references such as Sallem, w.et al.bioorg.med.chem.2006,14,7999-one 8013; in Brown, w.et al.wo 2006014133; in bogatcleva, e.et al.j.med.chem.2006,49, 3045-assistance 3048; and in Boschelli, d.h.et al.j.med.chem.2004,47, 6666-.

Amines of formula HNR1R2, wherein R1 is hydrogen and R2 is an optionally substituted 2-phenylethyl group, can be conveniently prepared by carrying out the Curtius rearrangement on hydrocinnamic acid derivatives, many examples of which are commercially available or can be readily prepared, for example, by the following method: the Knoevenagel reaction or related reaction of benzaldehyde with a malonate derivative is carried out, and then the resulting intermediate is hydrogenated and decarboxylated. According to this procedure, a hydrocinnamic acid derivative is treated with diphenylphosphoryl azide and an organic base such as triethylamine or diisopropylethylamine in t-butanol at a temperature of about 80 ℃ to give a t-butoxycarbonyl-protected 2-phenylethylamine derivative. Examples of the precise conditions that can be used in such reactions are found in the references, for example in Matsumoto, t.et al, us6,911,468; in Yoshida, i. and Suzuki, s.us7,217,723; in Keil, s.et al.us7,655,679; and in Tsang, K.Y.et al.J.am.chem.Soc.1994,116, 3988-4005. The tert-butoxycarbonyl protecting group may be conveniently removed by treating the intermediate carbamate compound with trifluoroacetic acid in dichloromethane at about room temperature, or may be removed by: tert-butyl carbamate is treated with hydrochloric acid in an alcoholic solvent (e.g., methanol or ethanol) or an ether (e.g., dioxane) or ethyl acetate, also at about room temperature. The precise conditions for such reactions can be found in references, for example in Bartel, s.et.us 20100029772; in Thompson, t. and Willis, p.us 20080146612; in Ford, r.et al.us 20080153850; and in Hirashima, S.et al.J.Med.chem.2006,49, 4721-.

Abbreviations

The following abbreviations are used in the experimental section below:

br broad peak

CDCl₃Deuterated chloroform

CH₂Cl₂Methylene dichloride

cm

Conc concentrated

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d₆Deuterated dimethyl sulfoxide

DTT dithiothreitol

EDTA ethylene diamine tetraacetic acid

EtOAc ethyl acetate

EtOH ethanol

g

h hours

H₂O water

HCl hydrochloric acid

His histidine

HPLC high performance liquid chromatography

HPLC/MS high performance liquid chromatography/Mass Spectrometry

Hz

LCMS liquid chromatography/Mass Spectrometry

LiOH lithium hydroxide

LRMS low resolution mass spectrum

M molarity of

m/z mass divided by charge

mBar (mBar)

MeOH methanol

mg of

MgSO₄Magnesium sulfate

MHz megahertz

min for

mL of

In mM millimolar concentration

mmol millimole

mol mole of

N₂Nitrogen gas

Na2CO₃Sodium carbonate

Na2SO₄Sodium sulfate

NaCl sodium chloride

NaHCO₃Sodium bicarbonate

NaOH sodium hydroxide

nm nanometer

NMR nuclear magnetic resonance

Pd(dppf)Cl₂[1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

Pd(PPh₃)₄Tetrakis (triphenylphosphine) palladium (0)

parts per million ppm

q quartet peak

qd doublet of quadruplicate

quinn quintet peak

s single peak

sat is saturated

spec Spectrum

t triplet peak

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet ray

Microliter of μ L

HPLC purification Condition A

Compounds were purified using a mass-directed HPLC/MS system (mass-directed HPLC/MS system) using a Shimadzu LC-8A pump and Shimadzu 2020 mass spectrometry (Shimadzu Scientific Instruments). The samples were applied on a Sunfire C-18 (3X10 cm) column (Waters Corporation) and eluted using a linear gradient solvent system of (A) 0.05% TFA/H2O and (B) 0.05% TFA/acetonitrile over 20 minutes. The collected fractions were pooled, evaporated and lyophilized.

HPLC purification Condition B

Compounds were purified using a mass-directed HPLC/MS system using a Shimadzu LC-8A pump (Shimadzu Scientific Instruments) and PE Sciex150EX mass spectrometry (Perkin Elmer). Samples were applied on a Varian Pursuit C-18(2X10cm) column (Varian, Inc.) using (A) 0.05% TFA/H₂O and (B) a linear gradient solvent system of 0.05% TFA/acetonitrile over 20 minutes. The collected fractions were pooled, evaporated and lyophilized.

Pharmaceutical compositions and administration

Another embodiment of the invention provides pharmaceutical compositions or medicaments comprising a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, the compounds of the present invention may be formulated for galenic administration by mixing at an appropriate pH at ambient temperature and in the desired purity with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dosages and concentrations used). The pH of the formulation depends primarily on the particular use and compound concentration, but preferably ranges from about 3 to about 8. In one example, the compounds of the invention are formulated in an acetate buffer at pH 5. In another embodiment, the compounds of the invention are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the drug, the method of administration, the timing of administration, and other factors known to physicians.

In one example, a pharmaceutically effective amount of a compound of the invention per dose administered parenterally will be about 0.01-100mg/kg, or about 0.1-20mg/kg, of patient body weight per day, with a typical starting range of 0.3-15mg/kg of compound used per day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 1 to about 100mg of a compound of the present invention.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any conventional form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain conventional ingredients of pharmaceutical preparations such as diluents, carriers, pH adjusting agents, sweeteners, fillers, and other active agents.

A typical formulation was prepared by the following method: the compounds of the present invention are mixed with a carrier or excipient. Suitable carriers and excipientsAgents are well known to those skilled in the art and are described in detail, for example, Ansel, Howard c., et al,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams&Wilkins,2004；Gennaro,AlfonsoR.,et al.Remington:The Science and Practice of Pharmacy.Philadelphia:Lippincott,Williams&wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical ExcipientsChicago, Pharmaceutical Press, 2005. The formulations may also contain one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavors, diluents and other known additives to provide an elegant appearance of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., a drug).

Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, as described above. Other embodiments include pharmaceutical compositions comprising a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Another embodiment includes pharmaceutical compositions comprising a compound of the invention for use in treating hyperproliferative diseases. Another embodiment includes a pharmaceutical composition comprising a compound of the invention for use in the treatment of cancer.

The compounds of the invention inhibit the binding of eIF4E to eIF 4G. Thus, the compounds of the present invention are useful for inhibiting cell proliferation and inducing apoptosis in cancer cells. Accordingly, the compounds of the present invention are useful for treating cancer in mammals, and in particular humans.

Preparation of intermediates

Intermediate 1

2-amino-5-cyano-benzoic acid methyl ester

Copper (I) cyanide (available from Alfa Aesar; 10.71g,0.12mol) was added to a stirred solution of methyl 2-amino-5-bromobenzoate (available from Aldrich Chemical Company, Inc.; 25.0g,0.11mol) in N-methyl-2-pyrrolidone (50mL) and the mixture was stirred at 180 ℃ for 4 hours. The reaction mixture was cooled to room temperature, diluted with aqueous ethylenediamine (water: ethylenediamine ═ 1: 1; 250mL) and filtered through a pad of celite. The filtrate was extracted with EtOAc (3 × 100mL) and the combined organic layers were washed with water (100mL) and brine (100mL), dried over sodium sulfate, filtered, evaporated under reduced pressure, and purified by silica gel chromatography (100-200 mesh) using 5-10% ethyl acetate/hexane as eluent to give methyl 2-amino-5-cyanobenzoate (14.0g, 73%) as a yellow powder.¹H NMR(400MHz,DMSO-d₆)δ8.05(d,J＝1.9Hz,1H),7.57(dd,J＝1.9,8.8Hz,1H),7.44(br s,2H),6.88(d,J＝8.8Hz,1H),3.81(s,3H)。

Intermediate 2

2-bromo-5-cyano-benzoic acid methyl ester

Tert-butyl nitrite (available from Aldrich Chemical Company, Inc.; 13.4mL,0.11mol) was added dropwise to a suspension of copper (II) bromide (available from Aldrich Chemical Company, Inc.; 21.32g,0.10mol) in acetonitrile (300mL) at 0 deg.C and the mixture was stirred for 5 minutes. Methyl 2-amino-5-cyano-benzoate (which may be prepared as described for intermediate 1; 14.0g,79.5mmol) was added in portions and the mixture was stirred at 0 ℃ for 2 hours and then at room temperature for 16 hours. The reaction mixture was concentrated to half volume and then acidified to pH2 (approximate) by addition of 1M HCl. The mixture was extracted with ethyl acetate (3 × 100mL) and the mixture was combinedThe combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give methyl 2-bromo-5-cyano-benzoate (18.0g, 94%) as a yellow solid.¹HNMR(400MHz,DMSO-d₆)δ8.23(d,J＝1.9Hz,1H),8.00(d,J＝8.3Hz,1H),7.93(dd,J＝2.0,8.3Hz,1H),3.89(s,3H).

Intermediate 3

4-cyano-2' -nitro-biphenyl-2-carboxylic acid methyl ester

Methyl 2-bromo-5-cyano-benzoate (which may be prepared as described for intermediate 2; 17.4g,72.6mmol), 2-nitrophenylboronic acid (available from Aldrich Chemical Company, Inc.; 13.2g,79.9mmol), Pd (dppf) Cl₂(available from Aldrich Chemical Company, Inc.; 7g,8.7mmol) and K₂CO₃A mixture of (29.9g,218mmol) in a mixture of water (26.5mL) and dioxane (530mL) was heated at reflux for 3.5 hours. The reaction mixture was cooled and evaporated to dryness. The residue was co-evaporated with toluene and then purified by silica gel chromatography using 20-33% ethyl acetate/petroleum ether as eluent to give methyl 4-cyano-2' -nitro-biphenyl-2-carboxylate (10.4g, 51%).¹H NMR(300MHz,CDCl₃)δ8.38(d,J＝1.7Hz,1H),8.20(d,J＝8.0Hz,1H),7.88-7.83(m,1H),7.71-7.57(m,2H),7.37(d,J＝7.9Hz,1H),7.30-7.22(m,1H),3.71(s,3H).

Intermediate 4

2' -Nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester

O, O' -diethyl dithiophosphate (available from Aldrich Chemical Company, Inc.; 6.85g,36.8mmol) is added to the combined compoundsA solution of the substance 4-cyano-2' -nitro-biphenyl-2-carboxylic acid methyl ester (which can be prepared as described for intermediate 3; 8.62g,30.5mmol) in a mixture of THF (96mL) and water (24 mL). The resulting mixture was stirred at 80 ℃ for 45 hours and then evaporated to a small volume. Ethyl acetate (500mL) was added and the mixture was washed with water (250mL) and saturated NaHCO₃(250mL), dried over anhydrous sodium sulfate, filtered, evaporated, and purified by silica gel chromatography using 17-50% ethyl acetate/petroleum ether as eluent to give methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate (5.0g, 52%).¹H NMR(300MHz,CDCl₃)δ8.50(d,J＝2.1Hz,1H),8.18-8.15(m,2H),7.70-7.54(m,3H),7.32(s,1H),7.30(s,1H),7.24(d,J＝1.2Hz,1H),3.69(s,3H)。

Intermediate 5

2-bromo-5-thiocarbamoyl-benzoic acid methyl ester

Phosphorus pentasulfide (available from Aldrich Chemical Company, inc.; 3.33g,750mmol) in EtOH (1000mL) was stirred at room temperature for 30 minutes, then methyl 2-bromo-5-cyanobenzoate (which can be prepared as described for intermediate 2; 36.0g,150mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and ethyl acetate was added. The mixture was washed three times with water, and the solvent was evaporated from the organic layer to give a mixture of yellow liquid and solid. The solid was filtered off to give methyl 2-bromo-5-thiocarbamoyl-benzoate (36.13g, 83%) as a pale yellow solid.

Intermediate 6

2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid methyl ester

A mixture of methyl 2-bromo-5-thiocarbamoylbenzoate (which may be prepared as described for intermediate 5; 13.7g,50mmol) and 2-bromo-3 ',4' -dichloroacetophenone (available from Aldrich Chemical Company, Inc.; 13.5g,50.5mmol) in EtOH (200mL) was heated at 70 deg.C overnight. The solid was filtered off to give methyl 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoate (18.14g, 82%).

Intermediate 7

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2, 4 '-dicarboxylic acid 4' -tert-butyl 2-methyl ester

The reaction was carried out in two batches. The reaction mixtures were combined and then purified together.

First batch: bubbling argon through 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 6.00g,13.5mmol), 4- (tert-butoxycarbonyl) phenylboronic acid (available from Combi-Blocks Inc.; 5.1g,23mmol), Pd (PPh)₃)₄(available from Aldrich Chemical Company, Inc.; 1.05g,0.91mmol), and a mixture of aqueous potassium carbonate (2M; 31.3mL,62.6mmol) in 1, 4-dioxane (200mL) for 25 minutes. The mixture was heated to 95-100 ℃ overnight. Another portion of 4- (tert-butoxycarbonyl) phenylboronic acid (available from Combi-Blocks Inc.; 1.2g,5.4mmol) was added and the mixture was heated for an additional 4 hours. The mixture was cooled.

Second batch: bubbling argon through 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 2.00g,4.5mmol), 4- (tert-butoxycarbonyl) phenylboronic acid (available from Combi-Blocks Inc.; 2.00g,9.0mmol), Pd (PPh)₃)₄(available from Aldrich Chemical Company, Inc.; 420mg,0.36mmol), and aqueous potassium carbonate (2M; 12.5mL,25mmol) in 1, 4-dioxane (62.7 mL) for 25 minutes. The mixture was heated to 95-100 ℃ overnight and then cooled.

Working up and purification: the two reaction mixtures were combined and water was added. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a brown foam (17.1 g). This material was purified by flash chromatography (silica gel, 220g column, 0-40% CH)₂Cl₂Hexane for 35 min). The fractions containing the product were evaporated to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]4 '-tert-butyl 2-methyl-biphenyl-2, 4' -dicarboxylate (7.6g, 78%) as an off-white solid.¹H NMR(300MHz,DMSO-d₆)δ ppm8.51(s,1H),8.44(s,1H),8.36(s,1H),8.32(d,J＝8.1Hz,1H),8.11(d,J＝6.6Hz,1H),8.00(d,J ＝8.1Hz,2H),7.80(d,J＝8.5Hz,1H),7.66(d,J＝8.1Hz,1H),7.51(d,J＝8.3Hz,2H),3.71(s,3H),1.60(s,9H).

Intermediate 8

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2, 4' -dicarboxylic acid 2-methyl ester

Trifluoroacetic acid (8.3mL,108mmol) was added to 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl at 0-5 deg.C]4 '-tert-Butylester 2-methyl-biphenyl-2, 4' -dicarboxylate (which can be prepared as described for intermediate 7; 5.8g,10.7mmol) in CH₂Cl₂(25 mL). The mixture was warmed to room temperature and stirred for 3 hours. The resulting solution was concentrated under a stream of nitrogen and then dried under high vacuum to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (5.1g, 98%) as a brown solid.¹HNMR(400MHz,DMSO-d₆)δppm13.08(br s,1H),ppm8.49(s,1H),8.42(s,1H),8.35(s,1H),8.30(d,J＝8.0Hz,1H),8.10(d,J＝8.3Hz,1H),8.02(d,J＝8.0Hz,2H),7.77(d,J＝8.5Hz,1H),7.66(d,J＝8.0Hz,1H),7.49(d,J＝8.3Hz,2H).

General operation

General procedure A for Suzuki coupling and hydrolysis in parallel

The 32 reactions were run in parallel as a single run as follows: to each vial was added arylboronic acid or pinacol ester thereof (0.5mmol), methyl 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoate (which can be prepared as described for intermediate 6; 111mg,0.25mmol), palladium (II) acetate (3mg,12.5 μmol), copper (I) chloride (25mg,250 μmol), cesium carbonate (326mg,1.0mmol), bis (diphenylphosphino) ferrocene (available from Aldrich Chemical Company, inc.; 14mg,25 μmol), and DMF (2 mL). The vial was degassed under high vacuum and then the vial was filled twice with N2. The vial was heated in a shaker at 100 ℃ for 24 hours. Using a 48-well filter and plate, the reaction mixture was filtered through DMSO-wet celite, and the celite was washed with DMSO (4mL), each compound was collected on two plates. The filtrate was concentrated at 40 ℃ overnight using HT-12Series II systems (Genevac Inc.) to about half volume at 8mBar, the contents of the wells from the same reaction were combined and then re-evaporated overnight at 40 ℃ under full vacuum. To each vial was added tetrahydrofuran (1mL) and 1M aqueous NaOH (2mL,2 mmol). The vial was then heated on a shaker at 60 ℃ for 24 hours. Concentrated HCl (200 μ L) and DMSO (1mL) were added to each vial, and the contents were analyzed by LC-MS. The contents of each vial were evaporated overnight at 40 ℃ under full vacuum using Genevac Series II HT-12(Genevac Inc.) and then purified by mass directed preparative HPLC using a Shimadzu HPLC system (Shimadzu Scientific Instruments), PE Sciex150EX mass spectrum (Perkin Elmer), LEAP CTC syringe (LEAP Technologies, Inc.) and Gilson215 collector (Gilson, Inc.). The column was Varian Pursuit C-18 phase (2X10cm) (Varian, Inc.) and eluted at 20mL/min using a linear gradient solvent system of (A) 0.05% TFA/H2O and (B) 0.035% TFA/acetonitrile. The collected fractions were evaporated in Genevac Series II HT-12(Genevac Inc.) and lyophilized.

General procedure B for Suzuki coupling and hydrolysis in parallel

The 73 reactions were run in parallel as follows in one run: to each vial was added the aryl boronic acid or its pinacol ester (0.4mmol), 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6; 89mg,0.2mmol), tetrakis (triphenylphosphine) palladium (0) (available from Aldrich Chemical Company, Inc.; 19mg, 16. mu. mol), 3M aqueous potassium carbonate (133. mu.L, 0.4mmol), and DMF (2 mL). The vials were heated on an orbital shaker at 100 ℃ for 20 hours and then cooled to room temperature. To each vial was added tetrahydrofuran (1mL) and 1M aqueous sodium hydroxide (1mL,1 mmol). The vial was then heated on a shaker at 60 ℃ for 24 hours. To each vial was added water (2mL) and dichloromethane (2mL), and the aqueous layer was separated. In several cases, there are solids that are insoluble in either layer. For each reaction, 1M HCl solution (1.5mL) was added to the aqueous layer, and 1M HCl solution (1.5mL) was added to the combination of organic layer and solid. The solid was filtered off. For each reaction, the three fractions (aqueous, organic, and solid) were evaporated separately, then dissolved in DMSO (1mL) and combined. The DMSO solution was filtered through celite and the celite was washed with DMSO (1 mL). The samples were purified by mass-directed preparative HPLC using a Shimadzu HPLC system (Shimadzu Scientific Instruments), PE Sciex150EX mass spectrometry (PerkinElmer), LEAP CTC syringe (LEAP Technologies, Inc.) and Gilson215 collector (Gilson, Inc.). The column was Varian Pursuit C-18 phase (2X10cm) (Varian, Inc.), and (A). 05% TFA/H was used₂O and (B) 035% TFA/acetonitrile linear gradient solvent System at 20mL/min is eluted. The collected fractions were evaporated in Genevac Series II HT-12(Genevac Inc.) and lyophilized.

General procedure C for Suzuki coupling and hydrolysis in parallel

Reacting 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-mixture of methyl benzoate (which can be prepared as described for intermediate 6) and aqueous sodium carbonate solution with CH₂Cl₂Extraction and the organic extracts were dried, filtered and evaporated. 111mg (0.25mmol) of the resulting material was placed in each of a set of 31 vials. To each vial was added arylboronic acid (0.5mmol), palladium (II) acetate (available from Aldrich chemical company, inc.; 2.8mg,0.0125mmol), copper (I) chloride (25mg,0.025mmol), cesium carbonate (326mg,1mmol), bis (diphenylphosphino) ferrocene (available from Aldrich chemical company, inc.; 14mg,25 μmol), and DMF (2 mL). The vial was evacuated and filled twice with nitrogen and then heated at 100 ℃ overnight. The mixture was filtered through celite and washed with DMSO (4 mL). The extent of each reaction was checked by LC-MS and DMSO was evaporated. To each vial was added THF (1mL) and 1M NaOH (1mL,1 mmol). The mixture was heated at 60 ℃ overnight and then cooled. Concentrated HCl (0.2mL) was added to each vial and the contents were mixed. The mixture was evaporated overnight using Genevac Series II HT-12(Genevac Inc.), then DMSO (1mL) was added. The mixture was filtered and purified by mass directed preparative HPLC using a Shimadzu HPLC system (Shimadzu scientific instruments).

General procedure D for amide coupling in parallel

A mixture of 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2, 4 '-dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol), amine of formula HNR1R2 (0.21mmol), triethylamine (42mg,0.41mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (79mg,0.41mmol) and 1-hydroxybenzotriazole hydrate (56mg,0.37mmol) in DMF (3mL) was stirred at room temperature overnight. The reaction mixture was concentrated and 0.1M HCl (2mL) was added. The mixture was centrifuged and the supernatant was discarded from the solid amide product.

General procedure E for amide coupling and hydrolysis in parallel

The 31 reactions were run in parallel as a single run as follows: approximately 0.62mmol of each of the 31 amines of formula HNR1R2 was placed in one of 31 15-mL vials (one amine per vial). Stock solutions were prepared by the following method: 1-hydroxybenzotriazole hydrate (available from Aldrich chemical company, Inc.; 2.6g,17.0mmol) was dissolved in DMF (31mL) and triethylamine (2.2mL,15.8mmol) was added. 1.1mL of this solution was added to each of 31 vials. Stock solutions were prepared by the following method: n- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (available from Alfa Aesar; 3.7g,19.3mmol) was dissolved in DMF (62 mL). The mixture was heated to dissolve the solids. 2.1mL of this solution was added to each of 31 vials. Stock solutions were prepared by the following method: 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 4.7g,9.7mmol) was dissolved in DMF (62 mL). The mixture was heated to dissolve the solids. 2.1mL of this solution was added to each of 31 vials.

The reaction vial was placed on an orbital shaker and shaken at room temperature over the weekend. The solvent was evaporated using Genevac Series II HT-12 and the residue was hydrolyzed without further purification. To each vial were added THF (2mL), MeOH (1mL), and aqueous LiOH (0.5mL solution prepared by dissolving lithium hydroxide monohydrate (1.3g,31mmol) in water (15.5 mL); 1 mmol). The vial was sealed, heated at 60 ℃ for 4 hours, and then stirred at room temperature for two days. If necessary, another portion of lithium hydroxide monohydrate (42mg,1mmol) and THF was added to each solution, dissolving any solids in the vial. The mixture was heated at 60 ℃ for 5 hours. The reaction mixture was cooled, stored in a refrigerator over the weekend, and then concentrated under vacuum using Genevac Series II HT-12. Water (1mL) was added to each vial, the contents mixed and 1M HCl (3mL) added. The vial contents were mixed again, concentrated under vacuum using Genevac Series II HT-12 at 40 ℃, and purified using HPLC purification conditions B to give the product.

Examples

The invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the invention.

Example 1

4- [4- (4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

Step 1: 4- [4- (4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid methyl ester

4-Fluorobenzoylmethyl bromide (available from Alfa Aesar; 35mg,0.16mmol) was added to a suspension of methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate (which may be prepared as described for intermediate 4; 50mg,0.16mmol) in ethanol (2mL) and the resulting mixture was stirred at 45 ℃ for 20 h. The reaction mixture was concentrated to a small volume and cooled. The precipitate was collected by filtration to give 4- [4- (4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid methyl ester (40mg), which was used directly without purification in the subsequent step.

Step 2: 4- [4- (4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

Sodium hydroxide (40mg,1mmol) was added to 4- [4- (4-fluoro-phenyl) -thiazol-2-yl]A suspension of methyl-2' -nitro-biphenyl-2-carboxylate (40mg) in a mixture of water (1mL) and dioxane (1 mL). The resulting mixture was heated at 50 ℃ for 4 hours. The solvent was evaporated and water (5mL) was added. The mixture was filtered and the filtrate was acidified to pH3 by addition of concentrated HCl. The precipitate was collected by filtration and dried to give 4- [4- (4-fluoro-phenyl) -thiazol-2-yl]-2' -nitro-biphenyl-2-carboxylic acid (45mg, 58%, two steps).¹H NMR(300MHz,DMSO-d₆)δ13.21(br s,1H),8.65(s,1H),8.17-8.33(m,5H),7.86(t,J＝7.6Hz,1H),7.73(t,J＝7.8Hz,1H),7.52(t,J＝8.5Hz,2H),7.40(t,J＝8.6Hz,2H)。

Example 2

2' -Nitro-4- [4- (4-trifluoromethoxy-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

2' -Nitro-4- [4- (4-trifluoromethoxy-phenyl) -thiazol-2-yl]Biphenyl-2-carboxylic acid (190mg, 62%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 4- (trifluoromethoxy) phenacyl bromide (available from Matrix Scientific), using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.17(s,1H),8.58(d,J＝2.0Hz,1H),8.13-8.28(m,4H),7.63-7.82(m,2H),7.41-7.51(m,4H)。

Example 3

4- [4- (4-difluoromethoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (4-difluoromethoxy-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (180mg, 61%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 4- (difluoromethoxy) phenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.15(s,1H),8.57(d,J＝1.9Hz,1H),8.11-8.27(m,5H),7.63-7.81(m,2H),7.41-7.48(m,2H),7.30(d,J＝9.2Hz,1H).

Example 4

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2 '-nitro-5' -trifluoromethyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-5- (trifluoromethyl) phenylboronic acid (2-nitro-5-trifluoromethylphenylboronic acid pinacol ester (available from Combi-Blocks inc.; 117mg,0.5 mmol.) the resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2 '-nitro-5' -trifluoromethyl-biphenyl-2-carboxylic acid (31mg, 23%).¹H NMR(300MHz,DMSO-d₆)δ13.48(s,1H),8.55(d,J＝1.7Hz,1H),8.51(s,1H),8.29-8.37(m,2H),8.24(d,J＝8.3Hz,1H),8.10(dd,J＝8.4,2.0Hz,1H),8.03(s,1H),7.97(d,J＝8.5Hz,1H),7.77(d,J＝8.5Hz,1H),7.67(d,J＝8.1Hz,1H).

Example 5

2' -Nitro-4- [4- (2-trifluoromethyl-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

2' -Nitro-4- [4- (2-trifluoromethyl-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (56mg, 19%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2- (trifluoromethyl) phenacyl bromide (available from Maybridge) using the procedure described for the preparation of example 18 except that the total of 4mL of water was added at the start of the hydrolysis step rather than in two portions.¹H NMR(300MHz,DMSO-d₆)δ13.06(br s,1H),8.52(d,J＝1.6Hz,1H),8.20(dd,J＝8.2,1.7Hz,1H),8.13(d,J＝8.0Hz,1H),7.96(s,1H),7.88(d,J＝7.6Hz,1H),7.64-7.80(m,4H),7.40-7.46(m,2H).

Example 6

2' -Nitro-4- [4- (3-trifluoromethyl-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

2' -Nitro-4- [4- (3-trifluoromethyl-phenyl) -thiazol-2-yl]Biphenyl-2-carboxylic acid (53mg, 18%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate (which may be prepared as described for intermediate 4) and 3- (trifluoromethyl) phenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for preparation example 18, except that the entire 4mL of water was added at the beginning of the hydrolysis step, rather than in two portions.¹H NMR(300MHz,DMSO-d₆)δ13.13(br s,1H),8.53-8.58(m,2H),8.38(s,2H),8.27-8.31(m,1H),8.13-8.18(m,1H),7.63-7.82(m,4H),7.41-7.49(m,2H).

Example 7

2' -Nitro-4- [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

2' -Nitro-4- [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl]Biphenyl-2-carboxylic acid (120mg, 40%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate (which may be prepared as described for intermediate 4) and 4- (trifluoromethyl) phenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.16(s,1H),8.59(s,1H),8.51(s,1H),8.27-8.31(m,3H),8.15(d,J＝8.1Hz,1H),7.77-7.87(m,3H),7.66(t,J＝8.0Hz,1H),7.42-7.49(m,2H).

Example 8

4- [4- (3, 5-bis-trifluoromethyl-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3, 5-bis-trifluoromethyl-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (110mg, 32%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 3',5' -bis (trifluoromethyl) -2-bromoacetophenone (available from Oakwood Products, Inc.), using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.20(s,1H),8.79(s,1H),8.72(s,2H),8.55(s,1H),8.32(d,J＝8.1Hz,1H),8.12-8.17(m,2H),7.79(t,J＝7.6Hz,1H),7.66(t,J＝7.6Hz,1H),7.41-7.50(m,2H).

Example 9

4- [4- (4-chloro-3-methyl-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (4-chloro-3-methyl-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (180mg, 63%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-1- (4-chloro-3-methylphenyl) ethan-1-one (available from Maybridge) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.55(d,J＝1.9Hz,1H),8.23-8.28(m,2H),8.13(d,J＝7.9Hz,1H),8.05(d,J＝1.6Hz,1H),7.91(dd,J＝10.1Hz,1H),7.78(t,J＝7.5Hz,1H),7.65(t,J＝7.5Hz,1H),7.40-7.53(m,3H),2.42(s,3H).

Example 10

4- [4- (2, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2, 4-dichloro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (24mg, 8%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate (which may be prepared as described for intermediate 4) and 2-bromo-2 ',4' -dichloroacetophenone (available from Oakwood Products, Inc.), using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.16(s,1H),8.55(d,J＝1.4Hz,1H),8.29(s,1H),8.23(d,J＝8.0Hz,1H),8.14(d,J＝7.9Hz,1H),8.05(d,J＝8.4Hz,1H),7.57-7.78(m,4H),7.43(t,J＝8.3Hz,2H).

Example 11

4- [4- (2-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2-chloro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (116mg, 44%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-chlorobenzoyl methyl bromide (available from Oakwood Products, Inc.) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.55(d,J＝1.7Hz,1H),8.21-8.27(m,2H),8.14(d,J＝8.1Hz,1H),7.99(dd,J＝7.4,1.9Hz,1H),7.78(t,J＝7.4Hz,1H),7.60-7.67(m,2H),7.41-7.52(m,4H)。

Example 12

4- [4- (2, 5-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2, 5-dichloro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (130mg, 44%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-1- (2, 5-dichlorophenyl) ethanone (available from Oakwood Products, Inc.) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.50(d,J＝1.5Hz,1H),8.33(s,1H),8.05-8.19(m,3H),7.74(t,J＝7.6Hz,1H),7.50-7.66(m,3H),7.37(d,J＝7.8Hz,2H).

Example 13

4- [4- (4-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (4-chloro-phenyl) -thiazol-2-yl]-2 '-Nitro-biphenyl-2-carboxylic acid (59mg, 21%) starting from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2Bromo-4' -chloroacetophenone (available from Alfa Aesar) was prepared using the procedure described for the preparation of example 18 except that the entire 4mL of water was added at the beginning of the hydrolysis step instead of adding it in two portions.¹HNMR(300MHz,DMSO-d₆)δ13.12(br s,1H),8.57(s,1H),8.33(s,1H),8.26(d,J＝8.8Hz,1H),8.09-8.16(m,3H),7.41-7.79(m,6H).

Example 14

5 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

5' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid]Methyl benzoate (which can be prepared as described for intermediate 6) and 5-chloro-2-nitrophenylboronic acid (available from Combi-Blocks Inc.) were prepared in 7% yield (for both steps) using general procedure a for Suzuki coupling and hydrolysis in a parallel manner.¹HNMR(300MHz,DMSO-d₆)δ13.29(br s,1H),8.60(d,J＝1.9Hz,1H),8.50(s,1H),8.29-8.37(m,2H),8.20(d,J＝8.9Hz,2H),8.10(dd,J＝8.4,2.0Hz,1H),7.73-7.82(m,2H),7.60(d,J＝2.3Hz,1H),7.53(d,J＝7.9Hz,1H).

Example 15

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2 '-Nitro-biphenyl-2-carboxylic acid (109mg, 37%) starting from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-3 ',4' -dichloroacetophenone (available from Oakwood Pro)Products, Inc.), prepared using the procedure described for preparation example 1. The compound of example 15 has the same formula as the compound of example 16.¹H NMR(300MHz,DMSO-d₆)δ13.18(s,1H),8.56(s,1H),8.47(s,1H),8.26-8.32(m,2H),8.15(d,J＝8.2Hz,1H),8.07(d,J＝8.4Hz,1H),8.03(d,J＝8.6Hz,1H),7.41-7.81(m,5H).

Example 16

Reacting 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6; 608mg,1.4mmol) with Na₂CO₃Treating with saturated aqueous solution, and treating the mixture with CH₂Cl₂And (4) extracting. The organic extracts were dried, filtered and evaporated. 2-Nitrophenylboronic acid (available from Aldrich Chemical Company, Inc.; 194mg,1.2mmol), Pd (PPh) were added₃)₄(available from Aldrich Chemical Company, Inc.; 107mg,0.093mmol) and 1M K₂CO₃Aqueous solution (1M; 3.0mL,3.0mmol) and dioxane (4.6 mL). The mixture was irradiated in a microwave at 150 ℃ for 30 minutes. The mixture was cooled and the solvent was evaporated. The reaction mixture was purified by silica gel chromatography on an 80g column using 0-15% EtOAc/hexanes as the eluent to give a yellow solid (60 mg). Tetrahydrofuran (2.4mL) and 1M aqueous NaOH (2.4mL,2.4mmol) were added. The mixture was heated at 60 ℃ overnight. The pH was brought to 3 by the addition of 1M HCl and the mixture was extracted three times with EtOAc. The organic layers were combined and evaporated. The crude product was first purified by silica gel chromatography (using 50-100% EtOAc/hexanes as eluent) followed by preparative HPLC to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -nitro-biphenyl-2-carboxylic acid (18mg, 3%) as a pale yellow solid. The compound of example 16 has the same chemical formula as the compound of example 15The formula is shown.¹H NMR(300MHz,DMSO-d₆)δ13.11(br s,1H),8.51(d,J＝1.8Hz,1H),8.43(s,1H),8.28(d,J＝1.8Hz,1H),8.24(dd,J＝8.0,1.7Hz,1H),8.10(d,J＝8.2Hz,1H),8.03(dd,J＝8.5,1.8Hz,1H),7.68-7.77(m,2H),7.56-7.65(m,1H),7.42(d,J＝8.2Hz,1H),7.37(d,J＝7.5Hz,1H).

Example 17

4- [4- (3-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3-chloro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (82mg, 30%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 3-chlorobenzoyl methyl bromide (available from Oakwood Products, Inc.) using the procedure described for preparation example 18, except that all 4mL of water was added at the beginning of the hydrolysis step, rather than in two portions.¹H NMR(300MHz,DMSO-d₆)δ13.12(br s,1H),8.56(d,J＝1.7Hz,1H),8.42(s,1H),8.28(dd,J＝8.0,1.9Hz,1H),8.12-8.16(m,2H),8.03-8.07(m,1H),7.76-7.81(m,1H),7.62-7.68(m,1H),7.41-7.55(m,4H).

Example 18

4- [4- (3-chloro-4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

Step 1: 4- [4- (3-chloro-4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid methyl ester

2-bromo-3 ' -chloro-4 ' -fluoroacetophenone (available from Aldrich Chemical Company, Inc.; 80.5mg,0.32mmol) was added to a solution of 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which can be prepared as described for intermediate 4; 100mg,0.32mmol) in THF (2mL) and the resulting mixture was stirred at 40 ℃ for 20 hours. The reaction mixture was evaporated to dryness and the residue was stirred with ethanol (5 mL). The precipitate was collected by filtration (100mg) and used directly in the subsequent step without purification.

Step 2: 4- [4- (3-chloro-4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

Sodium hydroxide (100mg,2.5mmol) was added to 4- [4- (3-chloro-4-fluoro-phenyl) -thiazol-2-yl]A suspension of methyl-2' -nitro-biphenyl-2-carboxylate (100mg) in a mixture of water (2mL) and dioxane (4 mL). The reaction mixture was stirred at 50 ℃ for 2 hours. Another portion of water (2mL) was added and the reaction mixture was stirred at 50 ℃ for an additional 2 hours. The reaction mixture was evaporated to dryness and water (5mL) was added. The mixture was filtered and the filtrate was acidified to pH3-4 by addition of concentrated HCl. The precipitate was collected by filtration and dried to give 4- [4- (3-chloro-4-fluoro-phenyl) -thiazol-2-yl]-2' -nitro-biphenyl-2-carboxylic acid (60mg, 41%, two steps).¹H NMR(300MHz,DMSO-d₆)δ13.18(br s,1H),8.56(s,1H),8.39(s,1H),8.27(d,J＝8.3Hz,1H),8.08-8.16(m,2H),7.79(t,J＝7.4Hz,1H),7.66(t,J＝7.9Hz,1H),7.41-7.58(m,3H)。

Example 19

4- [4- (2, 4-difluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2, 4-difluoro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (66mg, 23%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-2 ',4' -difluoroacetophenone (available from Matrix Scientific) using the procedure described for preparation example 18.¹H NMR(300MHz,DMSO-d₆)δ8.57(d,J＝1.4Hz,2H),8.10-8.35(m,4H),7.21-7.33(m,3H),7.77(t,J＝7.5Hz,1H),7.64(t,J＝7.7Hz,1H),7.23-7.50(m,4H).

Example 20

4- [4- (2, 6-difluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2, 6-difluoro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (45mg, 16%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-2 ',6' -difluoroacetophenone (available from SynQuest Laboratories, Inc.) using the procedure described for preparation example 18, except that all 4mL of water was added at the beginning of the hydrolysis step, rather than in two portions.¹H NMR(300MHz,DMSO-d₆)δ8.45(d,J＝1.9Hz,1H),7.94-8.04(m,3H),7.50-7.70(m,3H),7.19-7.32(m,4H).

Example 21

4- [4- (2-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2-fluoro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (46mg, 18%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-fluorobenzoylmethyl bromide (available from Matrix Scientific) using the procedure described for preparation example 18, except that the total of 4mL of water was added at the beginning of the hydrolysis step, rather than in two portions.¹H NMR(300MHz,DMSO-d₆)δ8.57(d,J＝1.8Hz,1H),8.12-8.30(m,4H),7.61-7.80(m,2H),7.34-7.50(m,5H).

Example 22

4- [4- (3, 5-difluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3, 5-difluoro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (38mg, 14%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate (which may be prepared as described for intermediate 4) and 3, 5-difluorobenzoylmethyl bromide (available from SynQuest Laboratories, Inc.) using the procedure described for preparation example 18.¹H NMR(300MHz,DMSO-d₆)δ8.41-8.50(m,2H),8.03(d,J＝8.1Hz,2H),7.79(d,J＝7.2Hz,2H),7.50-7.68(m,2H),7.21-7.33(m,3H).

Example 23

4- [4- (3, 4-difluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3, 4-difluoro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (114mg, 41%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate (which may be prepared as described for intermediate 4) and 3, 4-difluorobenzoylmethyl bromide (available from Matrix Scientific), using the procedure described for preparation example 18.¹H NMR(300MHz,DMSO-d₆)δ8.56(d,J＝1.7Hz,1H),8.36(s,1H),8.10-8.24(m,3H),7.95-7.99(m,1H),7.75-7.80(m,1H),7.53-7.67(m,2H),7.40-7.43(m,2H).

Example 24

4- [4- (3-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3-fluoro-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (150mg, 57%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 3-fluorobenzoylmethyl bromide (available from Aldrich Chemical Company, Inc.) using the procedure described for preparation example 18, except that all 4mL of water was added at the beginning of the hydrolysis step, rather than in two portions.¹H NMR(300MHz,DMSO-d₆)δ13.14(br s,1H),8.58(d,J＝1.8Hz,1H),8.25-8.28(m,2H),8.10-8.17(m,3H),7.63-7.82(m,2H),7.30-7.48(m,4H).

Example 25

4- [4- (5-bromo-thiophen-2-yl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (5-bromo-thiophen-2-yl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (180mg, 33%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-1- (5-bromothiophen-2-yl) ethanone (available from Oakwood Products, Inc.) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.16(s,1H),8.50(d,J＝1.8Hz,1H),8.13-8.22(m,3H),7.52(d,J＝3.9Hz,1H),7.40-7.48(m,2H),7.28(d,J＝3.9Hz,1H).

Example 26

4- [4- (3-bromo-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3-bromo-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (106mg, 34%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 3-bromobenzoyl methyl bromide (available from Aldrich Chemical Company, Inc.) using the procedures described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.17(s,1H),8.56(d,J＝1.8Hz,1H),8.43(s,1H),8.08-8.29(m,4H),7.41-7.82(m,6H).

Example 27

4- [4- (4-bromo-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (4-bromo-phenyl) -thiazol-2-yl]-2' -nitro-biphenyl-2-carboxylic acid (205mg, 68%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2,4' -dibromoacetophenone (available from Alfa Aesar) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.15(s,1H),8.57(d,J＝1.9Hz,1H),8.34(s,J＝8.3,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.14(dd,J＝8.1,1.1Hz,1H),8.03(d,J＝8.6Hz,1H),7.62-7.81(m,4H),7.40-7.47(m,2H).

Example 28

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4 '-methoxy-2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Preparation of (E) -4 '-methoxy-2' -nitro-biphenyl-2-carboxylic acid from 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-benzoic acid methyl ester (Which can be prepared as described for intermediate 6) and 2- (4-methoxy-2-nitrophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (available from Combi-Blocks Inc.) in 1% yield (for both steps) using general procedure a for Suzuki coupling and hydrolysis in a parallel fashion.¹H NMR(300MHz,DMSO-d₆)δ8.55(s,1H),8.49(s,1H),8.45(s,1H),8.31-8.36(m,1H),8.27(d,J＝7.9Hz,1H),8.03-8.13(m,1H),7.73-7.80(m,1H),7.67(s,1H),7.45(d,J＝8.1Hz,1H),7.37(d,J＝4.5Hz,1H),3.92(s,3H).

Example 29

4- [4- (2-fluoro-4-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2-fluoro-4-methoxy-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (253mg, 89%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-fluoro-4-methoxybenzoylmethyl bromide (available from ASDI Incorporated) using the procedure described for preparative example 1.¹H NMR(300MHz,DMSO-d₆)δ8.54(d,J＝1.8Hz,1H),8.10-8.21(m,3H),7.94(d,J＝2.4Hz,1H),7.59-7.78(m,2H),7.39(d,J＝8.0Hz,2H),6.93-7.02(m,2H),3.83(s,3H).

Example 30

4- [4- (2-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2-methoxy-phenyl) -thiazol-2-yl]-2 '-Nitro-biphenyl-2-carboxylic acid (183mg, 67%) starting from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be as for the intermediate)Prepared as described in figure 4) and 2-bromo-2' -methoxyacetophenone (available from ASDI Incorporated) were prepared using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.13(s,1H),8.57(d,J＝1.9Hz,1H),8.13-8.31(m,4H),7.63-7.81(m,2H),7.35-7.47(m,3H),7.18(d,J＝8.3Hz,1H),7.10(t,J＝7.6Hz,1H).

Example 31

4- [4- (3-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3-methoxy-phenyl) -thiazol-2-yl]-2' -nitro-biphenyl-2-carboxylic acid (148mg, 54%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 3' -methoxybenzoylmethyl bromide (available from Aldrich Chemical Company, Inc.) using the procedures described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.56(d,J＝1.9Hz,1H),8.30(s,1H),8.27(dd,J＝6.0,2.0Hz,1H),8.15(dd,J＝8.1,1.1Hz,1H),7.76-7.82(m,1H),7.61-7.69(m,3H),7.38-7.48(m,3H),6.97(dd,J＝8.2,2.4Hz,1H)。

Example 32

4- [4- (4-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

Step 1: 4- [4- (4-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid methyl ester

2-bromo-4 '-methoxyacetophenone (available from Oakwood Products, inc.; 144.3mg,0.63mmol) was added to a suspension of 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4; 200mg,0.63mmol) in dioxane (4mL) and the resulting mixture was stirred at 40 ℃ for 16 hours. The precipitate was collected by filtration (187mg) and used directly in the next step without purification.

Step 2: 4- [4- (4-methoxy-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

Sodium hydroxide (200mg,5mmol) was added to 4- [4- (4-methoxy-phenyl) -thiazol-2-yl]A suspension of methyl-2' -nitro-biphenyl-2-carboxylate (187mg) in a mixture of water (8mL) and dioxane (8 mL). The reaction mixture was stirred at 50 ℃ for 2 hours. The reaction mixture was evaporated to dryness and water (15mL) was added. The mixture was filtered and the filtrate was acidified to pH3-4 by addition of concentrated HCl. The precipitate was collected by filtration and dried to give 4- [4- (4-methoxy-phenyl) -thiazol-2-yl]-2' -nitro-biphenyl-2-carboxylic acid (100mg, 37%, two steps).¹H NMR(300MHz,DMSO-d₆)δ13.17(br s,1H),8.56(d,J＝1.8Hz,1H),8.24(dd,J＝8.0,1.9Hz,1H),8.11-8.16(m,2H),8.01(d,J＝8.8Hz,2H),7.76-7.81(m,1H),7.63-7.68(m,1H),7.41-7.47(m,2H),7.05(d,J＝8.8Hz,2H),3.82(s,3H)。

Example 33

4- [4- (4-methanesulfonyl-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (4-methanesulfonyl-phenyl) -thiazol-2-yl ] -amide]-2 '-Nitro-biphenyl-2-carboxylic acid (33mg, 11%) starting from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-1- [4- (methylsulfonyl) phenyl]-1-ethanone (available from TCI America) prepared using the procedure described for the preparation of example 1.¹H NMR(300MHz,DMSO-d₆)δ8.57(d,J＝8.3Hz,2H),8.27-8.35(m,3H),8.14(d,J＝7.8Hz,1H),8.03(d,J＝8.1Hz,1H),7.79(t,J＝8.4Hz,1H),7.65(t,J＝7.6Hz,1H),7.41-7.48(m,2H),3.26(s,3H).

Example 34

4- [4- (2, 3-dihydro-benzo [1,4] dioxin-6-yl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2, 3-dihydro-benzo [1,4]]Dioxin-6-yl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (205mg, 71%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) ethan-1-one (available from Alfa Aesar) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.53(d,J＝1.8Hz,2H),8.24(dd,J＝8.0,1.9Hz,1H),8.11-8.16(m,2H),7.78(t,J＝7.8Hz,1H),7.52-7.68(m,3H),7.43(t,J＝8.0Hz,2H),6.95(d,J＝9.0Hz,1H),4.29(s,4H).

Example 35

4- [4- (3-cyano-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (3-cyano-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (150mg, 56%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 3- (2-bromoacetyl) benzonitrile (available from Oakwood Products, Inc.) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.17(s,1H),8.59(d,J＝1.6Hz,1H),8.54(s,1H),8.51(s,1H),8.44(d,J＝7.7Hz,1H),8.31(dd,J＝8.0,1.6Hz,1H),8.16(d,J＝7.5Hz,1H),7.64-7.88(m,4H),7.43-7.49(m,2H).

Example 36

4- [4- (4-cyano-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (4-cyano-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (100mg, 37%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate (which may be prepared as described for intermediate 4) and 4-cyanobenzoyl methyl bromide (available from Oakwood Products, Inc.) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.44-8.47(m,2H),8.27(d,J＝8.5Hz,2H),7.94-8.00(m,4H),7.63-7.68(m,1H),7.47-7.52(m,1H),7.28(dd,J＝7.6,1.4Hz,1H),7.20(d,J＝7.9Hz,1H).

Example 37

2' -Nitro-4- (4-pyridin-2-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid

2 '-Nitro-4- (4-pyridin-2-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid (200mg, 79%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate, which was prepared as described for intermediate 4, and 2- (bromoacetyl) pyridine hydrobromide, available from Oakwood Products, Inc., using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.67(d,J＝4.9Hz,1H),8.60(d,J＝1.9Hz,1H),8.50(s,1H),8.26-8.30(m,2H),8.15(d,J＝7.5Hz,2H),8.00-8.05(m,1H),7.76-7.81(m,1H),7.62-7.68(m,1H),7.41-7.49(m,3H).

Example 38

2' -Nitro-4- (4-pyridin-3-Yl-Thiazol-2-Yl) -Biphenyl-2-Carboxylic acid

2 '-nitro-4- (4-pyridin-3-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid (120mg, 47%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate, which was prepared as described for intermediate 4, and 3- (bromoacetyl) pyridine hydrobromide, available from Oakwood Products, Inc., using the procedure described for preparative example 1.¹H NMR(300MHz,DMSO-d₆)δ9.32(d,J＝1.9Hz,1H),8.64(dd,J＝4.8,1.4Hz,1H),8.55-8.58(m,2H),8.50(s,1H),8.29(dd,J＝8.0,2.0Hz,1H),8.14(dd,J＝8.0,1.2Hz,1H),7.76-7.81(m,1H),7.62-7.68(m,2H),7.41-7.49(m,1H).

Example 39

2' -Nitro-4- (4-pyridin-4-Yl-Thiazol-2-Yl) -Biphenyl-2-Carboxylic acid

2 '-Nitro-4- (4-pyridin-4-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid (195mg, 77%) was prepared from methyl 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylate, which was prepared as described for intermediate 4, and 4- (bromoacetyl) pyridine hydrobromide, available from Oakwood Products, Inc., using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.14(s,1H),8.68(d,J＝5.2Hz,2H),8.61(s,1H),8.58(d,J＝1.1Hz,1H),8.28(dd,J＝7.9,0.9Hz,1H),8.14(d,J＝8.2Hz,1H),8.02(d,J＝5.4Hz,2H),7.78(t,J＝7.5Hz,1H),7.65(t,J＝7.6Hz,1H),7.41-7.49(m,2H).

Example 40

4- [4- (2, 4-dimethyl-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid

4- [4- (2, 4-dimethyl-phenyl) -thiazol-2-yl]-2 '-nitro-biphenyl-2-carboxylic acid (126mg, 47%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-1- (2, 4-dimethylphenyl) ethan-1-one (available from ASDI Incorporated) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.52(d,J＝1.8Hz,1H),8.10-8.18(m,2H),7.85(s,1H),7.76(t,J＝7.7Hz,1H),7.11-7.40(m,4H),2.48(s,3H),2.34(s,3H).

EXAMPLE 41

2' -Nitro-4- (4-p-tolyl-thiazol-2-yl) -biphenyl-2-carboxylic acid

2' -nitro-4- (4-p-tolyl-thiazol-2-yl) -biphenyl-2-carboxylic acid (85mg, 32%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-4 ' -methylacetophenone (available from ASDI Incorporated) using the procedure described for preparation example 39.¹H NMR(400MHz,DMSO-d₆)δ13.15(br s,1H),8.57(d,J＝1.9Hz,2H),8.26(dd,J＝8.0,1.9Hz,1H),8.20(s,1H),8.15(dd,J＝8.1,0.9Hz,1H),7.97(d,J＝8.1Hz,2H),7.77-7.82(m,1H),7.63-7.69(m,1H),7.42-7.48(m,2H),7.30(d,J＝8.0Hz,2H),2.36(s,3H).

Example 42

2' -Nitro-4- (4-thiophen-3-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid

2 '-nitro-4- (4-thiophen-3-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid (50mg, 19%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromo-1- (3-thienyl) -1-ethanone (available from Maybridge) using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ13.13(s,1H),8.54(d,J＝1.7Hz,1H),8.23(dd,J＝7.8,1.8Hz,1H),8.04-8.15(m,3H),7.78(t,J＝6.8Hz,1H),7.62-7.69(m,3H),7.44(t,J＝8.1Hz,2H).

Example 43

2' -Nitro-4- (4-phenyl-thiazol-2-yl) -biphenyl-2-carboxylic acid

2 '-nitro-4- (4-phenyl-thiazol-2-yl) -biphenyl-2-carboxylic acid (100mg, 39%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for intermediate 4) and 2-bromoacetophenone (available from Chem-imprex International, Inc.), using the procedure described for preparation example 18, except that all 4mL of water was added at the beginning of the hydrolysis step, rather than in two portions.¹H NMR(300MHz,DMSO-d₆)δ13.16(br s,1H),8.58(d,J＝1.9Hz,1H),8.06-8.28(m,5H),7.36-7.82(m,7H).

Example 44

2' -Nitro-4- (4-thiophen-2-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid

2 '-Nitro-4- (4-thiophen-2-yl-thiazol-2-yl) -biphenyl-2-carboxylic acid (120mg, 47%) was prepared from 2' -nitro-4-thiocarbamoyl-biphenyl-2Methyl carboxylate (which may be prepared as described for intermediate 4) and 2- (2-bromoacetyl) thiophene (available from Maybridge), prepared using the procedure described for preparation example 1.¹H NMR(300MHz,DMSO-d₆)δ8.51(d,J＝1.7Hz,1H),8.10-8.20(m,3H),7.71(t,J＝8.1Hz,1H),7.57-7.67(m,3H),7.41(t,J＝8.3Hz,2H),7.15(t,J＝4.6Hz,2H).

Example 45

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -nitro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 4-nitrophenylboronic acid (available from Combi-Blocks inc.; 67mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' -nitro-biphenyl-2-carboxylic acid (17mg, 18%).¹H NMR(400MHz,DMSO-d₆)δ13.35(br s,3H),8.50(s,1H)8.47(s,1H),8.34(s,1H),8.27-8.32(m,2H),8.10(d,J＝8.5Hz,1H),7.77(d,J＝6.8Hz,1H),7.68(d,J＝7.0Hz,2H),7.61(d,J＝6.5Hz,1H).

Example 46

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -3' -nitro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) and 3-NitroPhenylboronic acid (available from Aldrich Chemical Company, Inc.; 67mg,0.4mmol) was reacted. The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-3' -nitro-biphenyl-2-carboxylic acid (36mg, 38%).¹H NMR(400MHz,DMSO-d₆)δ8.46-8.51(m,2H),8.18-8.39(m,4H),8.06-8.15(m,1H),7.87(d,J＝7.0Hz,1H),7.73-7.79(m,2H),7.63-7.68(m,1H).

Example 47

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-diethylamino-propylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with N, N-diethyl-1, 3-propanediamine (available from Aldrich chemical company, inc.; 81mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (3-diethylamino-propylcarbamoyl) -biphenyl-2-carboxylic acid (104mg, 87%).¹H NMR(400MHz,DMSO-d₆)δppm13.63(br s,1H),9.48(br s,1H),1H NMR(400MHz,DMF),d ppm9.14(t,J＝5.6Hz,1H),8.92(s,1H),8.83(d,J＝1.8Hz,1H),8.77(d,J＝2.0Hz,1H),8.68(dd,J＝8.0,2.0Hz,1H),8.52(dd,J＝8.3,2.0Hz,1H),8.34(d,J＝8.3Hz,2H),8.20(d,J＝8.5Hz,1H),8.01(d,J＝8.0Hz,1H),7.93(d,J＝8.0Hz,2H),3.77-3.84(m,2H),3.51-3.63(m,6H),2.28-2.38(m,2H),1.62(t,J＝7.2Hz,6H).

Example 48

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-dimethylamino-propylcarbamoyl) -biphenyl-2-carboxylic acid

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl using the conditions of general procedure D for amide coupling in a parallel fashion]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with N, N-dimethyl-1, 3-propanediamine (available from Aldrich chemical company, inc.; 42mg,0.41mmol) to give the crude amide product. The crude amide was hydrolyzed by the addition of THF (2mL), water (0.05mL), MeOH (1mL), and lithium hydroxide monohydrate (12.3mg,0.29mmol), and the mixture was stirred at room temperature overnight. Lithium hydroxide monohydrate (22mg,0.52mmol) was added. The reaction mixture was stirred overnight, then another portion of lithium hydroxide monohydrate (22mg,0.52mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated to dryness under vacuum at 40 ℃.1M HCl (3mL) was added and the mixture was stirred, concentrated to dryness and purified using HPLC purification conditions A to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (3-dimethylamino-propylcarbamoyl) -biphenyl-2-carboxylic acid (102mg, 89%) as a white solid.¹H NMR(400MHz,DMSO-d₆)δppm13.16(br s,1H),8.68(t,J＝5.6Hz,1H),8.48(s,1H),8.40(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,1.8Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.92(d,J＝8.3Hz,2H),7.77(d,J＝8.3Hz,1H),7.58(d,J＝8.0Hz,1H),7.50(d,J＝8.3Hz,2H),3.34-3.40(m,2H),3.08-3.16(m,2H),2.79-2.82(m,6H),1.86-1.95(m,2H).

Example 49

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2-dimethylamino-ethylcarbamoyl) -biphenyl-2-carboxylic acid

4- [4- (3, 4-dichloro-Phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with N, N-dimethylethylenediamine (available from Aldrich Chemical Company, inc.; 55mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (2-dimethylamino-ethylcarbamoyl) -biphenyl-2-carboxylic acid (81mg, 73%).¹H NMR(400MHz,DMSO-d₆)δppm8.73(t,J＝5.4Hz,1H),8.47(s,1H),8.41(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,1.8Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.93(d,J＝8.3Hz,2H),7.77(d,J＝8.5Hz,1H),7.58(d,J＝8.0Hz,1H),7.52(d,J＝8.3Hz,2H),3.63(q,J＝5.8Hz,2H),3.22-3.27(m,2H),2.84(s,6H).

Example 50

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (2-methyl-2H-pyrazol-3-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with (1-methyl-1H-pyrazol-5-yl) methylamine (available from Aldrich chemical company, inc.; 69mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - [ (2-methyl-2H-pyrazol-3-ylmethyl) -carbamoyl]-biphenyl-2-carboxylic acid (100mg, 86%).¹H NMR(400MHz,DMSO-d₆)δppm13.23(br s,1H),9.07(t,J＝5.6Hz,1H),8.48(s,1H),8.38(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,1.8Hz,1H),8.10(dd,J＝8.4,1.9Hz,1H),7.94(d,J＝8.3Hz,2H),7.77(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.50(d,J＝8.3Hz,2H),7.32(d,J＝1.8Hz,1H),6.19(d,J＝1.5Hz,1H),4.55(d,J＝5.5Hz,2H),3.84(s,3H).

Example 51

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (1-methyl-piperidin-4-ylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 4-amino-1-methylpiperidine (available from Aldrich Chemical Company, inc.; 71mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (1-methyl-piperidin-4-ylcarbamoyl) -biphenyl-2-carboxylic acid (135mg, 116%).¹H NMR(400MHz,DMSO-d₆)δppm13.20(br s,1H),8.55(d,J＝7.5Hz,1H),8.49(s,1H),8.40(d,J＝1.8Hz,1H),8.35(d,J＝2.0Hz,1H),8.26(dd,J＝8.2,1.9Hz,1H),8.10(dd,J＝8.3,2.0Hz,1H),7.92(d,J＝8.3Hz,2H),7.78(d,J＝8.3Hz,1H),7.58(d,J＝8.0Hz,1H),7.50(d,J＝8.3Hz,2H),4.01-4.10(m,1H),3.45-3.51(m,2H),3.05-3.18(m,2H),2.78-2.81(m,2H),2.54(s,3H),2.02-2.10(m,2H).

Example 52

4' - (1-acetyl-piperidin-4-ylcarbamoyl) -4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]2-methyl-biphenyl-2, 4' -dicarboxylate (which can be prepared as described for intermediate 8; 100mg,0.21mmol) with 1-acetylPiprolin-4-amine (available from Aldrich Chemical Company, Inc.; 88mg,0.62mmol) was reacted. The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4' - (1-acetyl-piperidin-4-ylcarbamoyl) -4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (5mg, 4%).¹H NMR(400MHz,DMSO-d₆)δppm13.19(br s,1H),8.45(s,1H),8.33(s,3H),8.19(d,J＝7.8Hz,1H),8.09(d,J＝8.5Hz,1H),7.90(d,J＝8.0Hz,2H),7.76(d,J＝8.3Hz,1H),7.55(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,2H),4.35(d,J＝12.3Hz,1H),4.05(br s,1H),3.85(d,J＝13.3Hz,1H),3.16(t,J＝11.8Hz,1H),2.69(d,J＝13.3Hz,1H),2.02(s,3H),1.78-1.93(m,1H),1.18-1.58(m,4H).

Example 53

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (4-methyl-piperazine-1-carbonyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 1-methylpiperazine (available from Aldrich Chemical Company, inc.; 62mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (4-methyl-piperazine-1-carbonyl) -biphenyl-2-carboxylic acid (86mg, 75%).¹H NMR(400MHz,DMSO-d₆)δppm13.20(br s,1H),9.97(br s,1H),8.47(s,1H),8.39(s,1H),8.34(s,1H),8.26(d,J＝8.3Hz,1H),8.09(d,J＝8.3Hz,1H),7.77(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.48-7.57(m,4H),3.25-3.44(m,8H),2.81(br s,3H).

Example 54

4' - (4-acetyl-piperazine-1-carbonyl) -4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 1-acetylpiperazine (available from Aldrich Chemical Company, inc.; 79mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4' - (4-acetyl-piperazine-1-carbonyl) -4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (81mg, 68%).¹H NMR(400MHz,DMSO-d₆)δppm13.24(br s,1H),8.48(s,1H),8.37(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,2.0Hz,1H),8.10(dd,J＝8.3,2.0Hz,1H),7.77(d,J＝8.3Hz,1H),7.60(d,J＝8.0Hz,1H),7.45-7.53(m,4H),3.46-3.59(br s,6H),3.32-3.36(s,6H),2.03(s,3H).

Example 55

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (4-hydroxy-piperidine-1-carbonyl) -biphenyl-2-carboxylic acid

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl using the conditions of general procedure D for amide coupling in a parallel fashion]-biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 4-hydroxypiperidine (available from Aldrich Chemical Company, Inc.; 42mg,0.42mmol) to give the crude amide product. The crude amide was hydrolyzed by the addition of THF (2mL), water (0.05mL), MeOH (1mL), and lithium hydroxide monohydrate (12.3mg,0.29mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under vacuum at 40 ℃. 1MHCl (3mL) was added and the mixture was stirred, concentrated to dryness and HP was usedPurification by LC purification Condition A to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ]]-4' - (4-hydroxy-piperidine-1-carbonyl) -biphenyl-2-carboxylic acid (48mg, 52%) as a white solid.¹H NMR(400MHz,DMSO-d₆) δ ppm13.18(br s,1H),8.47(s,1H),8.37(d, J ═ 1.8Hz,1H),8.34(d, J ═ 2.0Hz,1H),8.24(dd, J ═ 8.0,2.0Hz,1H),8.09(dd, J ═ 8.3,2.0Hz,1H),7.76(d, J ═ 8.5Hz,1H),7.60(d, J ═ 8.0Hz,1H),7.42-7.49(m,4H),3.73-3.79(m,1H),3.36-3.52(m, 2H + water peak), 3.15-3.27(m,2H),1.70-1.82(m,2H),1.32-1.47(m,2H).

Example 56

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (morpholine-4-carbonyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with morpholine (available from Aldrich Chemical Company, inc.; 54mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (morpholine-4-carbonyl) -biphenyl-2-carboxylic acid (76mg, 69%).¹H NMR(400MHz,DMSO-d₆)δppm13.17(br s,1H),8.46(s,1H),8.37(s,1H),8.33(s,1H),8.24(d,J＝8.0Hz,1H),8.09(d,J＝8.3Hz,1H),7.76(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.44-7.51(m,4H),3.60-3.67(m,4H),3.26-3.30(m,4H).

Example 57

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (pyrrolidine-1-carbonyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with pyrrolidine (available from Aldrich Chemical Company, inc.; 44mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (pyrrolidine-1-carbonyl) -biphenyl-2-carboxylic acid (58mg, 54%).¹H NMR(400MHz,DMSO-d₆)δppm13.17(br s,1H),8.46(s,1H),8.35(dd,J＝11.7,1.9Hz,2H),8.23(dd,J＝8.2,1.9Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.76(d,J＝8.5Hz,1H),7.59(dd,J＝8.3,2.3Hz,3H),7.46(d,J＝8.0Hz,2H),3.40-3.54(m,4H),1.73-2.01(m,4H).

Example 58

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-morpholin-4-yl-propylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with N- (3-aminopropyl) morpholine (available from Aldrich Chemical Company, inc.; 89mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (3-morpholin-4-yl-propylcarbamoyl) -biphenyl-2-carboxylic acid (80mg, 65%).¹H NMR(400MHz,DMSO-d₆)δppm13.13(br s,1H),9.60(br s,1H),8.67(br t,1H),8.47(s,1H),8.40(s,1H),8.34(s,1H),8.25(d,J＝8.0Hz,1H),8.09(d,J＝8.5Hz,1H),7.92(d,J＝8.0Hz,2H),7.77(d,J＝8.3Hz,1H),7.58(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,6H),3.60-4.00(m,4H),3.34-3.42(m,3H),2.93-3.21(m,4H),1.87-1.97(m,2H).

Example 59

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2-morpholin-4-yl-ethylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 4- (2-aminoethyl) morpholine (available from Aldrich Chemical Company, inc.; 81mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (2-morpholin-4-yl-ethylcarbamoyl) -biphenyl-2-carboxylic acid (82mg, 68%).¹H NMR(400MHz,DMSO-d₆)δppm13.16(br s,1H),8.47(s,1H),8.41(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,1.8Hz,1H),8.09(dd,J＝8.3,2.0Hz,1H),7.94(d,J＝8.3Hz,2H),7.77(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,2H),3.90-4.10(m,2H),3.50-3.72(m,4H),3.27-3.44(m,4H),3.08-3.23(m,2H).

Example 60

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (tetrahydro-pyran-4-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]2-methyl-biphenyl-2, 4' -dicarboxylate (which may be prepared as described for intermediate 8; 100mg,0.21mmol) and 4-aminomethyltetrahydropyran (available from Aldrich chemical company, Inc.; 71)mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - [ (tetrahydro-pyran-4-ylmethyl) -carbamoyl]-biphenyl-2-carboxylic acid (81mg, 69%).¹H NMR(400MHz,DMSO-d₆)δppm13.22(br s,1H),8.58(t,J＝5.8Hz,1H),8.48(s,1H),8.38(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,1.8Hz,1H),8.10(dd,J＝8.5,2.0Hz,1H),7.91(d,J＝8.3Hz,2H),7.77(d,J＝8.3Hz,1H),7.58(d,J＝8.0Hz,1H),7.48(d,J＝8.3Hz,2H),3.86(dd,J＝11.2,2.6Hz,2H),3.27(t,J＝10.9Hz,2H),3.19(t,J＝6.4Hz,2H),1.77-1.87(m,1H),1.61(d,J＝11.3Hz,2H),1.15-1.27(m,2H).

Example 61

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (tetrahydro-furan-2-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]2-methyl-biphenyl-2, 4' -dicarboxylate (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 3-aminomethyltetrahydrofuran (available from Acros Organics BVBA; 63mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - [ (tetrahydro-furan-2-ylmethyl) -carbamoyl]-biphenyl-2-carboxylic acid (43mg, 38%).¹H NMR(400MHz,DMSO-d₆)δppm8.58(br.t.,1H),8.46(s,1H),8.35(d,J＝15.6Hz,2H),8.23(d,J＝8.0Hz,1H),8.09(d,J＝8.3Hz,1H),7.92(d,J＝7.8Hz,2H),7.76(d,J＝8.3Hz,1H),7.58(d,J＝7.8Hz,1H),7.48(d,J＝7.8Hz,2H),4.01(t,J＝5.9Hz,1H),3.64(q,J＝7.1Hz,1H),3.35(d,J＝5.5Hz,2H),1.77-1.99(m,3H),1.63(d,J＝10.0Hz,1H).

Example 62

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (tetrahydro-furan-3-ylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 3-aminotetrahydrofuran (available from Aldrich Chemical Company, inc.; 54mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (tetrahydro-furan-3-ylcarbamoyl) -biphenyl-2-carboxylic acid (135mg, 121%).¹H NMR(400MHz,DMSO-d₆)δppm13.20(br s,1H),8.62(d,J＝6.5Hz,1H),8.48(s,1H),8.39(d,J＝2.0Hz,1H),8.34(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.10(dd,J＝8.5,2.0Hz,1H),7.93(d,J＝8.3Hz,2H),7.77(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.48(d,J＝8.3Hz,2H),4.43-4.54(m,1H),3.84-3.92(m,2H),3.69-3.77(m,1H),3.61(dd,J＝8.9,4.4Hz,1H),2.12-2.22(m,1H),1.90-2.00(m,1H).

Example 63

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (tetrahydro-pyran-4-ylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 4-aminotetrahydropyran (available from Aldrich Chemical Company, inc.; 63mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions BTo obtain 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (tetrahydro-pyran-4-ylcarbamoyl) -biphenyl-2-carboxylic acid (32mg, 28%).¹H NMR(400MHz,DMSO-d₆)δppm13.08(br s,1H),8.39(s,1H),8.25-8.33(m,3H),8.17(dd,J＝8.0,1.8Hz,1H),8.02(dd,J＝8.3,2.0Hz,1H),7.85(d,J＝8.3Hz,2H),7.69(d,J＝8.5Hz,1H),7.51(d,J＝8.0Hz,1H),7.41(d,J＝8.3Hz,2H),3.91-4.03(m,1H),3.83(d,J＝9.8Hz,2H),3.30-3.38(m,2H),1.68-1.76(m,2H),1.54(qd,J＝11.9,4.3Hz,2H).

Example 64

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (4-methoxy-benzylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 4-methoxybenzylamine (available from Aldrich Chemical Company, inc.; 85mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (4-methoxy-benzylcarbamoyl) -biphenyl-2-carboxylic acid (85mg, 70%).¹H NMR(400MHz,DMSO-d₆)δppm13.20(br s,1H),9.08(t,J＝5.9Hz,1H),8.48(s,1H),8.38(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,1.8Hz,1H),8.10(dd,J＝8.5,2.0Hz,1H),7.95(d,J＝8.3Hz,2H),7.77(d,J＝8.3Hz,1H),7.59(d,J＝8.0Hz,1H),7.49(d,J＝8.3Hz,2H),7.27(d,J＝8.5Hz,2H),6.90(d,J＝8.5Hz,2H),4.44(d,J＝6.0Hz,2H),3.73(s,11H).

Example 65

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-methoxy-benzylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 3-methoxybenzylamine (available from Aldrich Chemical Company, inc.; 85mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (3-methoxy-benzylcarbamoyl) -biphenyl-2-carboxylic acid (94mg, 77%).¹H NMR(400MHz,DMSO-d₆)δppm13.18(br s,1H),9.08(t,J＝5.6Hz,1H),8.46(s,1H),8.38(s,1H),8.33(s,1H),8.24(d,J＝8.0Hz,1H),8.09(d,J＝8.5Hz,1H),7.96(d,J＝7.8Hz,2H),7.76(d,J＝8.3Hz,1H),7.59(d,J＝8.0Hz,1H),7.50(d,J＝7.8Hz,2H),7.26(t,J＝7.9Hz,1H),6.89-6.94(m,2H),6.83(d,J＝8.3Hz,1H),4.49(d,J＝5.8Hz,2H),3.75(s,3H).

Example 66

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2-pyridin-3-yl-ethylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 3- (2-aminoethyl) pyridine (available from Aldrich Chemical Company, inc.; 76mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (2-pyridin-3-yl-ethylcarbamoyl) -biphenyl-2-carboxylic acid (129mg, 109%).¹H NMR(400MHz,DMSO-d₆)δppm13.14(br s,1H),8.63(t,J＝5.5Hz,1H),8.57(s,1H),8.51(d,J＝4.3Hz,1H),8.47(s,1H),8.39(d,J＝1.8Hz,1H),8.33(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.4,1.9Hz,1H),7.83-7.90(m,3H),7.76(d,J＝8.3Hz,1H),7.58(d,J＝8.3Hz,1H),7.45-7.52(m,3H),3.58(q,J＝6.6Hz,2H),2.95(t,J＝6.9Hz,7H).

Example 67

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -phenethylcarbamoyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 2-phenylethylamine (available from Aldrich Chemical Company, inc.; 75mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' -phenethylcarbamoyl-biphenyl-2-carboxylic acid (74mg, 62%).¹H NMR(400MHz,DMSO-d₆)δppm13.17(br s,1H),8.62(t,J＝5.4Hz,1H),8.46(s,1H),8.38(s,1H),8.33(s,1H),8.24(d,J＝7.8Hz,1H),8.09(d,J＝8.5Hz,1H),7.88(d,J＝8.0Hz,2H),7.76(d,J＝8.3Hz,1H),7.59(d,J＝8.0Hz,1H),7.48(d,J＝8.0Hz,2H),7.18-7.35(m,5H),3.52(q,J＝6.7Hz,2H),2.88(t,J＝7.4Hz,8H).

Example 68

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (pyridin-3-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid

Using in parallel for acylGeneral procedure for amine coupling the conditions of E were such that 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 3- (aminomethyl) pyridine (available from Aldrich Chemical Company, inc.; 67mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - [ (pyridin-3-ylmethyl) -carbamoyl]-biphenyl-2-carboxylic acid (85mg, 73%).¹H NMR(400MHz,DMSO-d₆)δppm13.16(br s,1H),9.19(t,J＝5.9Hz,1H),8.66(s,1H),8.55(d,J＝3.5Hz,1H),8.47(s,1H),8.40(d,J＝1.8Hz,1H),8.33(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.90-8.01(m,3H),7.76(d,J＝8.3Hz,1H),7.59(d,J＝8.0Hz,1H),7.45-7.55(m,3H),4.57(d,J＝5.8Hz,2H).

Example 69

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (pyridin-4-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which may be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 4- (aminomethyl) pyridine (available from Aldrich Chemical Company, inc.; 67mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - [ (pyridin-4-ylmethyl) -carbamoyl]-biphenyl-2-carboxylic acid (78mg, 68%).¹H NMR(400MHz,DMSO-d₆)δppm13.16(br s,1H),9.25(t,J＝5.8Hz,1H),8.60(d,J＝6.0Hz,2H),8.47(s,1H),8.40(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.3,2.0Hz,1H),7.99(d,J＝8.3Hz,2H),7.77(d,J＝8.3Hz,1H),7.60(d,J＝8.0Hz,1H),7.46-7.55(m,4H),4.60(d,J＝5.8Hz,7H).

Example 70

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-methyl-benzylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 3-methylbenzylamine (available from Aldrich Chemical Company, inc.; 75mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (3-methyl-benzylcarbamoyl) -biphenyl-2-carboxylic acid (46mg, 39%).¹H NMR(400MHz,DMSO-d₆)δppm13.18(br s,1H),9.07(t,J＝5.9Hz,1H),8.46(s,1H),8.38(d,J＝1.8Hz,1H),8.33(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.97(d,J＝8.3Hz,2H),7.76(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.50(d,J＝8.3Hz,2H),7.19-7.26(m,1H),7.11-7.18(m,2H),7.07(d,J＝7.3Hz,1H),4.48(d,J＝5.8Hz,2H),2.30(s,3H).

Example 71

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-trifluoromethyl-benzylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]2-methyl-biphenyl-2, 4' -dicarboxylate (which can be prepared as described for intermediate 8; 100mg,0.21mmol) and 3- (trifluoromethyl) benzylamine (obtainable from A)ldrich Chemical Company, inc; 108mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (3-trifluoromethyl-benzylcarbamoyl) -biphenyl-2-carboxylic acid (53mg, 41%).¹H NMR(400MHz,DMSO-d₆)δppm13.17(br s,1H),9.20(t,J＝6.0Hz,1H),8.46(s,1H),8.39(d,J＝1.8Hz,1H),8.33(d,J＝2.0Hz,1H),8.24(dd,J＝8.2,1.9Hz,1H),8.09(dd,J＝8.3,2.0Hz,1H),7.97(d,J＝8.3Hz,2H),7.76(d,J＝8.5Hz,1H),7.56-7.72(m,5H),7.51(d,J＝8.3Hz,2H),4.60(d,J＝5.8Hz,2H).

Example 72

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (4-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 4-fluorobenzylamine (available from Aldrich Chemical Company, inc.; 78mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (4-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid (88mg, 84%).¹H NMR(400MHz,DMSO-d₆)δppm13.17(br s,1H),9.11(t,J＝5.8Hz,1H),8.46(s,1H),8.38(s,1H),8.33(s,1H),8.24(d,J＝7.8Hz,1H),8.09(d,J＝8.3Hz,1H),7.96(d,J＝8.0Hz,2H),7.76(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,2H),7.35-7.41(m,2H),7.16(t,J＝8.7Hz,2H),4.50(d,J＝5.8Hz,8H).

Example 73

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 3-fluorobenzylamine (available from Aldrich Chemical Company, inc.; 78mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (3-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid (89mg, 74%).¹H NMR(400MHz,DMSO-d₆)δppm13.17(br s,1H),9.14(t,J＝6.0Hz,1H),8.46(s,1H),8.39(d,J＝1.8Hz,1H),8.33(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,1.8Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.97(d,J＝8.3Hz,2H),7.76(d,J＝8.3Hz,1H),7.59(d,J＝8.0Hz,1H),7.51(d,J＝8.3Hz,2H),7.35-7.43(m,1H),7.13-7.23(m,2H),7.04-7.11(m,1H),4.53(d,J＝6.0Hz,8H).

Example 74

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl using the conditions of general procedure D for amide coupling in a parallel fashion]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 2-fluorobenzylamine (available from Aldrich Chemical Company, inc.; 52mg,0.42mmol) to give the crude amide product. The crude amide was hydrolyzed by the addition of THF (2mL), water (0.05mL), MeOH (1mL), and lithium hydroxide monohydrate (12.3mg,0.29mmol), and the mixture was stirred at room temperature overnight. Tetrahydrofuran (2mL) was added to dissolve the solids, and lithium hydroxide monohydrate (22mg, 0) was added.52 mmol). The reaction mixture was stirred overnight, then another portion of lithium hydroxide monohydrate (22mg,0.52mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated to dryness under vacuum at 40 ℃.1M HCl (3mL) was added and the mixture was stirred, concentrated to dryness and purified using HPLC purification conditions A to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (2-fluoro-benzylcarbamoyl) -biphenyl-2-carboxylic acid (75mg, 63%) as a white solid.¹HNMR(400MHz,DMSO-d₆)δppm13.18(br s,1H),9.10(t,J＝5.8Hz,1H),8.47(s,1H),8.39(d,J＝1.8Hz,1H),8.33(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,1.8Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.97(d,J＝8.3Hz,2H),7.76(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.50(d,J＝8.3Hz,2H),7.40(t,J＝7.7Hz,1H),7.29-7.36(m,1H),7.16-7.23(m,2H),4.56(d,J＝5.8Hz,2H).

Example 75

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - [ (thiophen-2-ylmethyl) -carbamoyl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with 2-thiophenemethylamine (available from Aldrich Chemical Company, inc.; 70mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - [ (thiophen-2-ylmethyl) -carbamoyl]-biphenyl-2-carboxylic acid (47mg, 40%).¹H NMR(400MHz,DMSO-d₆)δppm13.24(br s,1H),9.24(t,J＝5.9Hz,1H),8.48(s,1H),8.36(dd,J＝16.8,2.0Hz,2H),8.24(dd,J＝8.0,2.0Hz,1H),8.10(dd,J＝8.4,2.1Hz,1H),7.94(d,J＝8.3Hz,2H),7.77(d,J＝8.5Hz,1H),7.59(d,J＝8.3Hz,1H),7.50(d,J＝8.3Hz,2H),7.40(dd,J＝5.1,1.1Hz,1H),7.04(d,J＝2.5Hz,1H),6.98(dd,J＝5.0,3.5Hz,1H),4.67(d,J＝5.8Hz,2H).

Example 76

4' -Benzylcarbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with benzylamine (available from Aldrich Chemical Company, inc.; 66mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4' -benzylcarbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (73mg, 64%).¹H NMR(400MHz,DMSO-d₆)δppm13.23(br s,1H),9.15(t,J＝6.0Hz,1H),8.48(s,1H),8.39(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,1.8Hz,1H),8.10(dd,J＝8.5,2.0Hz,1H),7.97(d,J＝8.3Hz,2H),7.77(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.50(d,J＝8.3Hz,2H),7.34(d,J＝4.3Hz,4H),7.21-7.29(m,1H),4.52(d,J＝6.0Hz,2H).

Example 77

2- (2-carbamoyl-pyridin-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) and 2-cyanopyridine-3-boronic acid (available from Matrix Scientific; 74mg,0.5mmol)Should be used. The resulting ester was hydrolyzed and the acid was purified to give 2- (2-carbamoyl-pyridin-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Benzoic acid (7mg, 6%).¹H NMR(400MHz,DMSO-d₆)δ13.32(br s,1H),9.02(d,J＝8.8Hz,1H),8.77(d,J＝4.0Hz,1H),8.66(br s,1H),8.40(s,1H),8.28-8.35(m,2H),8.23(d,J＝7.8Hz,1H),8.04-8.14(m,2H),7.69-7.79(m,2H),6.53(s,1H).

Examples 78 and 79

4 '-carbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methyl-biphenyl-2-carboxylic acid and 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2 '-methyl-biphenyl-2, 4' -dicarboxylic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-methyl-4-cyanophenylboronic acid (available from Combi-Blocks inc.; 69mg,0.5 mmol). The resulting ester was hydrolyzed and the product was isolated by preparative HPLC to give 4' -carbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -methyl-biphenyl-2-carboxylic acid (example 78; 24mg, 20%) (Campanula ®)¹H NMR(400MHz,DMSO-d₆) δ 12.99 (brs, 1H)8.50(d, J ═ 1.8Hz,1H)8.48(s,1H)8.34(d, J ═ 2.0Hz,1H)8.25(dd, J ═ 8.0,2.0Hz,1H)8.09(dd, J ═ 8.5,2.0Hz,1H)7.98 (brs, 1H)7.75-7.81(m,2H)7.72(d, J ═ 7.8Hz,1H)7.41(d, J ═ 7.8Hz,1H)7.35 (brs, 1H)7.17(d, J ═ 7.8Hz,1H)2.10(s,3H) } and 4- [4- (3, 4-dichloro-phenyl) -2-thiazolyl-2-yl }]-2 '-methyl-biphenyl-2, 4' -dicarboxylic acid (example 79; 55, 46%). Campanulas¹H NMR(400MHz,DMSO-d₆)δ8.52(s,1H),8.48(s,1H),8.34(s,1H),8.27(d,J＝8.0Hz,1H),8.10(d,J＝8.3Hz,1H),7.85(s,1H),7.75-7.83(m,2H),7.42(d,J＝8.0Hz,1H),7.23(d,J＝7.8Hz,1H),2.11(s,3H)}.

Example 80

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (1-phenyl-ethylcarbamoyl) -biphenyl-2-carboxylic acid

Using the conditions of general procedure E for amide coupling in a parallel fashion, 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2, 4' -dicarboxylic acid 2-methyl ester (which can be prepared as described for intermediate 8; 100mg,0.21mmol) was reacted with DL- α -methylbenzylamine (available from Aldrich Chemical Company, Inc.; 75mg,0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC purification conditions B to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' - (1-phenyl-ethylcarbamoyl) -biphenyl-2-carboxylic acid (69mg, 59%).¹H NMR(400MHz,DMSO-d₆)δppm13.22(br s,1H),8.90(d,J＝8.0Hz,1H),8.48(s,1H),8.38(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.24(dd,J＝8.0,1.8Hz,1H),8.10(dd,J＝8.5,2.0Hz,1H),7.96(d,J＝8.3Hz,2H),7.77(d,J＝8.3Hz,1H),7.59(d,J＝8.0Hz,1H),7.49(d,J＝8.3Hz,2H),7.39-7.45(m,2H),7.34(t,J＝7.7Hz,2H),7.18-7.28(m,1H),5.20(quin,J＝7.3Hz,1H),1.50(d,J＝7.0Hz,3H).

Example 81

2' -carbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-aminocarbonylphenylboronic acid (available from Combi-Blocks inc.; 66mg,0.4 mmol). Hydrolyzing the obtained ester and purifying the acid to obtain2' -carbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (15mg, 8%).¹H NMR(300MHz,DMSO-d₆) δ 13.07(br s,1H),8.46(s,1H),8.36(d, J ═ 14.1Hz,2H),8.04-8.18(m,2H),7.77(d, J ═ 8.5Hz,1H),7.58(d, J ═ 7.2Hz,2H),7.42-7.51(m,2H),7.12-7.34(m, 3H). The compound of example 81 has the same formula as the compound of example 113.

Example 82

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-ethoxy-pyrimidin-5-yl) -benzoic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-ethoxypyrimidine-5-boronic acid (available from Combi-Blocks inc.; 84mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (2-ethoxy-pyrimidin-5-yl) -benzoic acid (3mg, 3%). LCMS analysis indicated the material was-69% pure, as measured by UV at 214 nm. LRMS M/z471.8(M + H)⁺).

Example 83

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-methoxy-pyrimidin-5-yl) -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6; 89mg,0.2mmol) and 2-methoxyPyrimidine-5-boronic acid (available from Combi-Blocks inc.; 62mg,0.4mmol) was reacted. The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (2-methoxy-pyrimidin-5-yl) -benzoic acid (0.9mg, 1%). LCMS analysis indicated the material was-100% pure, as measured by UV at 214 nm. LRMS M/z457.8 and 459.8(M + H)⁺).

Example 84

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-hydroxy-pyrimidin-5-yl) -benzoic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-methoxypyrimidine-5-boronic acid (available from Combi-Blocks inc.; 77mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (2-hydroxy-pyrimidin-5-yl) -benzoic acid (85mg, 76%).¹H NMR(400MHz,DMSO-d₆)δ13.40(br s,1H),8.42-8.62(m,2H),8.20-8.38(m,2H),8.04-8.14(m,1H),7.76(d,J＝8.3Hz,2H),7.61(d,J＝7.5Hz,1H).

Example 85

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (6-methoxy-pyridin-2-yl) -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6; 89mg,0.2mmol)Reacted with 6-methoxypyridine-2-boronic acid (available from Combi-Blocks inc.; 61mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (6-methoxy-pyridin-2-yl) -benzoic acid (23mg, 25%).¹H NMR(400MHz,DMSO-d₆)δ12.95(br s,3H),8.48(s,1H),8.34(d,J＝2.0Hz,1H),8.21(dd,J＝4.3,2.3Hz,2H),8.10(dd,J＝8.3,2.0Hz,1H),7.73-7.94(m,3H),7.39(d,J＝7.3Hz,1H),6.83(d,J＝8.0Hz,1H),3.88(s,3H),2.54(s,9H).

Example 86

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-methoxy-pyridin-3-yl) -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-methoxypyridine-3-boronic acid hydrate (available from Combi-Blocks inc.; 68mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (2-methoxy-pyridin-3-yl) -benzoic acid (11mg, 12%).¹H NMR(300MHz,DMSO-d₆)δ12.94(br s,1H),8.47(s,1H),8.41(d,J＝1.9Hz,1H),8.33(d,J＝2.1Hz,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.18(dd,J＝5.0,1.8Hz,1H),8.09(dd,J＝8.5,2.1Hz,1H),7.77(d,J＝8.3Hz,1H),7.70(dd,J＝7.3,1.8Hz,1H),7.52(d,J＝7.9Hz,1H),7.10(dd,J＝7.2,5.1Hz,1H),3.78(s,3H).

Example 87

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4 '-methoxy-2' -trifluoromethyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 4-methoxy-2- (trifluoromethyl) phenylboronic acid (available from Combi-blocks inc.; 110mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4 '-methoxy-2' -trifluoromethyl-biphenyl-2-carboxylic acid (8mg, 6%).¹HNMR(300MHz,DMSO-d₆)δ12.97(br s,1H),8.54(s,1H),8.48(s,1H),8.34(s,1H),8.23(d,J＝7.5Hz,1H),8.09(d,J＝8.7Hz,1H),7.77(d,J＝8.5Hz,1H),7.41(d,J＝7.9Hz,1H),7.26(s,3H),3.88(s,3H).

Example 88

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -trifluoromethoxy-biphenyl-2-carboxylic acid

Using the conditions of general procedure a for Suzuki coupling and hydrolysis in a parallel manner, methyl 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoate (which can be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-5- (trifluoromethoxy) phenylboronic acid (available from Frontier Scientific, inc.; 120mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -trifluoromethoxy-biphenyl-2-carboxylic acid (1.3mg, 1%). LCMS analysis indicated the material was-100% pure, as measured by UV at 214 nm.

Example 89

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -ethoxy-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-4-ethoxyphenylboronic acid (available from Combi-Blocks inc.; 100mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' -ethoxy-biphenyl-2-carboxylic acid (3mg, 2%).¹H NMR(300MHz,DMSO-d₆)δ13.02(br s,1H),8.48(s,2H),8.33(d,J＝1.9Hz,1H),8.24(d,J＝7.9Hz,1H),8.09(dd,J＝8.4,2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.43(d,J＝7.9Hz,1H),7.25(d,J＝8.5Hz,1H),7.08(d,J＝2.4Hz,1H),6.90-7.02(m,2H),4.10(q,J＝7.0Hz,2H),1.36(t,J＝6.9Hz,3H).

Example 90

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -6' -methoxy-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-6-methoxyphenylboronic acid (available from Aldrich chemical company, inc.; 93mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-6' -methoxy-biphenyl-2-carboxylic acid (5mg, 4%).¹HNMR(300MHz,DMSO-d₆),δ12.87(br s,1H),8.53(d,J＝1.7Hz,1H),8.48(s,1H),8.34(d,J＝1.9Hz,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.4,2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.32-7.41(m,2H),7.10(dd,J＝18.2,8.0Hz,2H),3.67(s,3H).

Example 91

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -3' -methoxy-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 3-methoxyphenylboronic acid (available from Combi-Blocks inc.; 61mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-3' -methoxy-biphenyl-2-carboxylic acid (65mg, 71%).¹H NMR(400MHz,DMSO-d₆)δ13.15(br s,1H),8.46(s,1H),8.28-8.39(m,2H),8.20(d,J＝7.8Hz,1H),8.09(dd,J＝8.5,1.8Hz,1H),7.76(d,J＝8.5Hz,1H),7.59(d,J＝8.0Hz,1H),7.36(t,J＝7.8Hz,1H),6.86-7.06(m,3H),3.80(s,3H).

Example 92

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methoxy-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-methoxyphenylboronic acid (available from Frontier Scientific, inc.; 61mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -methoxy-biphenyl-2-carboxylic acid (36mg, 39%).¹H NMR(400MHz,DMSO-d₆)δ12.75(br s,1H),8.45(s,1H),8.31-8.37(m,2H),8.21(d,J＝8.0Hz,1H),8.09(d,J＝8.3Hz,1H),7.77(d,J＝8.5Hz,1H),7.46(d,J＝8.0Hz,1H),7.36(t,J＝7.8Hz,1H),7.27(d,J＝7.5Hz,1H),7.04(d,J＝7.3Hz,2H),3.69(s,3H).

Example 93

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -methoxy-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-chloro-5-methoxyphenylboronic acid (available from Combi-Blocks inc.; 75mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-5' -methoxy-biphenyl-2-carboxylic acid (29mg, 29%).¹H NMR(400MHz,DMSO-d₆)δ13.04(br s,1H),8.45-8.58(m,2H),8.34(d,J＝2.0Hz,1H),8.26(dd,J＝7.9,1.9Hz,1H),8.09(dd,J＝8.4,1.9Hz,1H),7.77(d,J＝8.5Hz,1H),7.46(d,J＝8.0Hz,1H),7.40(d,J＝8.8Hz,1H),6.98(dd,J＝8.8,3.0Hz,1H),6.92(d,J＝3.0Hz,1H),3.79(m,3H).

Example 94

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -methoxy-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) and 2-chloro-4-methoxyphenylboronic acid (available from Combi-Blocks In)c, carrying out the following steps; 93mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' -methoxy-biphenyl-2-carboxylic acid (6mg, 5%).¹H NMR(300MHz,DMSO-d₆)δ13.00(br s,1H),8.46-8.51(m,2H),8.33(d,J＝2.1Hz,1H),8.24(dd,J＝8.1,1.9Hz,1H),8.09(dd,J＝8.5,2.1Hz,1H),7.77(d,J＝8.5Hz,1H),7.43(d,J＝8.1Hz,1H),7.27(d,J＝8.5Hz,1H),7.10(d,J＝2.4Hz,1H),6.99(dd,J＝8.5,2.6Hz,1H),3.83(s,3H).

Example 95

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -hydroxy-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-chloro-5-hydroxyphenylboronic acid (available from Combi-Blocks inc.; 69mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-5' -hydroxy-biphenyl-2-carboxylic acid (71mg, 74%).¹H NMR(400MHz,DMSO-d₆)δ13.01(br s,1H),9.76(s,1H),8.48(s,2H),8.34(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,1.8Hz,1H),8.09(dd,J＝8.3,2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.43(d,J＝8.0Hz,1H),7.27(d,J＝8.5Hz,1H),6.78(dd,J＝8.7,2.9Hz,1H),6.71(d,J＝2.8Hz,1H).

Example 96

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (4-isopropyl-pyrimidin-5-yl) -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 4-isopropylpyrimidine-5-boronic acid (available from Combi-Blocks inc.; 66mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (4-isopropyl-pyrimidin-5-yl) -benzoic acid (14mg, 14%).¹H NMR(300MHz,DMSO-d₆)δ13.30(br s,1H),9.14(s,1H),8.62(d,J＝1.7Hz,1H),8.50(d,J＝2.4Hz,2H),8.29-8.36(m,2H),8.10(dd,J＝8.4,2.0Hz,1H),7.78(d,J＝8.5Hz,1H),7.55(d,J＝8.1Hz,5H),2.75-2.85(m,1H),1.03-1.19(m,6H).

Example 97

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2-pyrimidin-5-yl-benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with pyrimidine-5-boronic acid (available from Combi-Blocks inc.; 50mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2-pyrimidin-5-yl-benzoic acid (13mg, 16%).¹H NMR(300MHz,DMSO-d₆)δ13.42(br s,1H),9.21(s,1H),8.86(s,2H),8.58(s,1H),8.50(s,1H),8.29-8.37(m,2H),8.10(d,J＝8.5Hz,1H),7.77(d,J＝8.5Hz,1H),7.67(d,J＝7.9Hz,1H).

Example 98

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (2-methyl-pyridin-3-yl) -benzoic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-methylpyridine-3-boronic acid hydrochloride (available from Combi-Blocks inc.; 87mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (2-methyl-pyridin-3-yl) -benzoic acid (65mg, 59%).¹H NMR(400MHz,DMSO-d₆)δ8.56(d,J＝1.8Hz,1H),8.49(s,1H),8.34(d,J＝2.0Hz,1H),8.30(dd,J＝7.9,1.9Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.77(d,J＝8.3Hz,1H),7.43(d,J＝8.0Hz,1H),7.21-7.30(m,1H),2.08(s,3H).

Example 99

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (3-methyl-pyridin-4-yl) -benzoic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 3-methylpyridine-4-boronic acid hydrochloride (available from Combi-Blocks inc.; 87mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (3-methyl-pyridin-4-yl) -benzoic acid (46mg, 42%).¹H NMR(300MHz,DMSO-d₆)δ13.30(br s,1H),8.59-8.66(m,2H),8.50(s,1H),8.30-8.38(m,2H),8.10(dd,J＝8.5,1.9Hz,1H),7.88-7.94(m,1H),7.78(d,J＝8.5Hz,1H),7.56-7.63(m,1H),7.52(d,J＝8.1Hz,1H),2.34(s,3H).

Example 100

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (5-fluoro-pyridin-2-yl) -benzoic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 5-fluoropyridine-2-boronic acid (available from Combi-Blocks inc.; 71mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (5-fluoro-pyridin-2-yl) -benzoic acid (4mg, 4%). LCMS analysis indicated the material was-100% pure, as measured by UV at 214 nm. LRMS M/z444.8(M + H)⁺).

Example 101

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2-pyridin-3-yl-benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with pyridine-3-boronic acid (available from Combi-Blocks inc.; 49mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2-pyridin-3-yl-benzoic acid (12mg, 14%).¹H NMR(300MHz,DMSO-d₆),δ13.27(br s,1H),8.56-8.63(m,2H),8.45-8.51(m,2H),8.34(d,J＝1.9Hz,1H),8.28(dd,J＝7.9,1.9Hz,1H),8.10(dd,J＝8.5,2.1Hz,1H),7.83(d,J＝8.1Hz,1H),7.77(d,J＝8.5Hz,1H),7.61(d,J＝8.1Hz,1H),7.48(dd,J＝7.7,5.1Hz,1H).

Example 102

2- (5-chloro-pyridin-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 5-chloropyridine-3-boronic acid (available from Combi-Blocks inc.; 63mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2- (5-chloro-pyridin-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Benzoic acid (8mg, 8%).¹H NMR(400MHz,DMSO-d₆)δ13.38(br s,1H),8.66(d,J＝2.3Hz,1H),8.47-8.55(m,3H),8.34(d,J＝2.0Hz,1H),8.29(dd,J＝8.0,1.8Hz,1H),8.10(dd,J＝8.5,2.0Hz,1H),8.02(t,J＝2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.64(d,J＝7.8Hz,1H).

Example 103

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2-pyridin-4-yl-benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with pyridine-4-boronic acid (available from Combi-Blocks inc.; 49mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2-pyridin-4-yl-benzoic acid (7mg, 8%).¹H NMR(300MHz,DMSO-d₆),δ13.35(br s,1H),8.69(d,J＝6.0Hz,2H),8.50(s,1H),8.48(d,J＝1.7Hz,1H),8.34(d,J＝1.9Hz,1H),8.30(dd,J＝7.9,1.9Hz,1H),8.10(dd,J＝8.5,2.1Hz,1H),7.77(d,J＝8.5Hz,1H),7.61(d,J＝8.1Hz,1H),7.54(d,J＝5.8Hz,2H).

Example 104

2- (6-cyano-pyridin-2-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 6-cyanopyridine-2-boronic acid (available from CombiPhos catalsys, inc.; 59mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2- (6-cyano-pyridin-2-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Benzoic acid (14mg, 16%).¹H NMR(300MHz,DMSO-d₆)δ13.14(br s,1H),8.50(s,1H),8.40(s,1H),8.35(s,1H),8.24-8.32(m,1H),8.00-8.16(m,3H),7.73-7.88(m,3H).

Example 105

4 '-cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-methyl-4-cyanophenylboronic acid (available from Aldrich chemical company, inc.; 64mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -methyl-biphenyl-2-carboxylic acid (13mg, 14)％)。¹HNMR(400MHz,DMSO-d₆)δ13.14(br s,1H),8.54(d,J＝2.0Hz,1H),8.49(s,1H),8.34(d,J＝2.0Hz,1H),8.28(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.75-7.83(m,2H),7.71(d,J＝7.8Hz,1H),7.41(d,J＝8.0Hz,1H),7.31(d,J＝8.0Hz,1H).

Example 106

4' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 4-cyanophenylboronic acid (available from Combi-Blocks inc.; 59mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (20mg, 22%).¹H NMR(400MHz,DMSO-d₆)δ13.31(br s,1H),8.49(s,1H),8.43(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.26(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.4,2.1Hz,1H),7.92(d,J＝8.3Hz,2H),7.77(d,J＝8.5Hz,1H),7.56-7.64(m,3H).

Example 107

3' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6; 89mg,0.2mmol) and 3-cyanophenylboronic acid (obtainable from Combi-Blocks inc; 59mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 3' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (19mg, 21%).¹H NMR(400MHz,DMSO-d₆)δ13.30(br s,1H),8.48(s,1H),8.45(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.26(dd,J＝8.0,1.8Hz,1H),8.10(dd,J＝8.3,2.0Hz,1H),7.85-7.92(m,2H),7.71-7.81(m,2H),7.57-7.69(m,2H).

Examples 108 and 109

2 '-chloro-5' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid and 5 '-carbamoyl-2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-chloro-5-cyanophenylboronic acid (available from Frontier Scientific, inc.; 73mg,0.4 mmol). Hydrolyzing the resulting ester and purifying the acid to obtain 2 '-chloro-5' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-Biphenyl-2-carboxylic acid (example 108; 27mg, 28%) (Campylo ®)¹HNMR(400MHz,DMSO-d₆) δ 13.12(br s,1H),8.57(d, J ═ 1.8Hz,1H),8.50(s,1H),8.26-8.39(m,2H),8.04-8.15(m,2H),7.85-7.96(m,2H),7.78(d, J ═ 8.5Hz,1H),7.61(d, J ═ 8.3Hz,1H),7.50(d, J ═ 8.3Hz,2H) } and 5 '-carbamoyl-2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-Biphenyl-2-carboxylic acid (example 109; 14mg, 14%) (Campylo ®)¹HNMR(400MHz,DMSO-d₆)δ8.57(d,J＝2.0Hz,1H),8.50(s,1H),8.34(d,J＝2.0Hz,1H),8.32(s,1H),8.30(d,J＝2.0Hz,1H),8.10(dd,J＝8.3,2.0Hz,1H),8.06(br s,1H),7.95(dd,J＝8.3,2.0Hz,1H),7.83(d,J＝2.3Hz,1H),7.78(d,J＝8.2Hz,1H),7.67(d,J＝8.5Hz,1H),7.51(d,J＝7.7Hz,1H)。

Example 110

5 '-chloro-2' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 5-chloro-2-cyanophenylboronic acid (available from Combi-Blocks inc.; 73mg,0.4 mmol). Hydrolyzing the resulting ester and purifying the acid to give 5 '-chloro-2' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (12mg, 12%).¹H NMR(400MHz,DMSO-d₆)δ13.38(br s,1H),8.63(d,J＝2.0Hz,1H),8.52(s,1H),8.31-8.37(m,2H),8.10(dd,J＝8.5,2.0Hz,1H),7.97(d,J＝8.3Hz,1H),7.78(d,J＝8.5Hz,1H),7.65-7.73(m,2H),7.59(d,J＝8.0Hz,1H).

Example 111

2' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-cyanophenylboronic acid (available from Aldrich Chemical Company, inc.; 59mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (2mg, 1%). The compound of example 111 has the same chemical formula as the compound of example 112. LCMS analysis showed the material to be 94% pure by UV214 nm. LRMS M/z450.8(M + H)⁺).

Examples 112 and 113

2 '-cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid and 2' -carbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-cyanophenylboronic acid (available from Aldrich Chemical Company, inc.; 74mg,0.5 mmol). The resulting ester was hydrolyzed and the hydrolyzate was separated by preparative HPLC to give 2' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-Biphenyl-2-carboxylic acid (example 112; 48mg, 43%) (Campylo ®)¹H NMR(300MHz,DMSO-d₆) δ 13.25(br s,1H),8.60(d, J ═ 1.7Hz,1H),8.51(s,1H),8.30-8.37(m,2H),8.10(dd, J ═ 8.4,2.0Hz,1H),7.91(d, J ═ 7.5Hz,1H),7.73-7.81(m,2H),7.47-7.63(m,3H) } and 2' -carbamoyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-Biphenyl-2-carboxylic acid (example 113; 16mg, 14%) (Campylo ®)¹HNMR(300MHz,DMSO-d₆) δ 13.10(br s,1H),8.46(s,1H),8.39(s,1H),8.33(s,1H),8.13-8.19(m,1H),8.09(d, J ═ 8.3Hz,1H),7.77(d, J ═ 8.5Hz,1H),7.53-7.62(m,2H),7.46(t, J ═ 5.7Hz,2H),7.26-7.35(m,2H),7.19(d, J ═ 6.2Hz, 1H). The compound of example 112 has the same chemical formula as the compound of example 111. The compound of example 113 has the same chemical formula as the compound of example 81.

Example 114

3 '-chloro-4' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 3-chloro-4-cyanophenylboronic acid (available from Combi-Blocks inc.; 73mg,0.4 mmol). Hydrolyzing the resulting ester and purifying the acid to give 3 '-chloro-4' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (42mg, 43%).¹H NMR(400MHz,DMSO-d₆)δ13.40(br s,1H)8.44-8.55(m,2H),8.34(d,J＝1.8Hz,1H),8.28(dd,J＝8.0,2.0Hz,1H),8.07-8.13(m,1H),8.05(d,J＝8.0Hz,1H),7.81(d,J＝1.3Hz,1H),7.77(d,J＝8.1Hz,1H),7.61(d,J＝8.0Hz,1H),7.56(dd,J＝8.0,1.5Hz,1H).

Example 115

4 '-chloro-3' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 4-chloro-3-cyanophenylboronic acid (available from Combi-Blocks inc.; 73mg,0.4 mmol). Hydrolyzing the resulting ester and purifying the acid to give 4 '-chloro-3' -cyano-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (18mg, 19%).¹H NMR(400MHz,DMSO-d₆)δ13.35(br s,1H),8.44-8.51(m,2H),8.34(d,J＝2.0Hz,1H),8.28(dd,J＝8.0,1.8Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),8.06(d,J＝2.3Hz,1H),7.82(d,J＝8.5Hz,1H),7.77(d,J＝8.5Hz,1H),7.74(dd,J＝8.5,2.3Hz,1H),7.61(d,J＝8.0Hz,1H).

Example 116

3' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 3-acetylphenylboronic acid (available from Combi-Blocks inc.; 66mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 3' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (21mg, 23%).¹H NMR(400MHz,DMSO-d₆)δ8.48(s,1H),8.40(d,J＝1.8Hz,1H),8.34(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.10(dd,J＝8.5,2.0Hz,1H),8.00(d,J＝7.8Hz,1H),7.96(s,1H),7.77(d,J＝8.5Hz,1H),7.55-7.71(m,3H),2.63(s,3H).

Example 117

2' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-acetylphenylboronic acid (available from ASDI Incorporated; 66mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (14mg, 15%).¹H NMR(400MHz,DMSO-d₆)δ12.97(br s,1H),8.44-8.50(m,2H),8.34(d,J＝1.8Hz,1H),8.20(dd,J＝7.9,1.9Hz,1H),8.09(dd,J＝8.3,2.0Hz,1H),7.81-7.88(m,1H),7.77(d,J＝8.5Hz,1H),7.55-7.64(m,1H),7.45-7.54(m,1H),7.34(d,J＝8.0Hz,1H),7.19-7.28(m,1H),6.52(s,1H),2.32(s,3H).

Example 118

5 '-acetyl-2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

5 '-acetyl-2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid starting from 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6) and 5-acetyl-2-chlorophenylboronic acid (available from Combi-Blocks Inc.) were prepared in 7% yield (for both steps) using general procedure a for Suzuki coupling and hydrolysis in a parallel manner.¹HNMR(300MHz,DMSO-d₆)δ13.14(s,1H),8.58(d,J＝1.9Hz,1H),8.50(s,1H),8.30-8.38(m,2H),8.10(dd,J＝8.4,2.0Hz,1H),7.98(dd,J＝8.3,2.1Hz,1H),7.90(d,J＝2.1Hz,1H),7.78(d,J＝8.5Hz,1H),7.69(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),2.62(s,3H).

Example 119

2- (2-acetyl-thiophen-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-acetyl-3-thienylboronic acid (available from Aldrich chemical company, inc.; 68mg,0.4 mmol). Hydrolyzing the obtained ester and purifying the acid to obtain 2- (2-acetyl group)-thiophen-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Benzoic acid (19mg, 20%).¹H NMR(400MHz,DMSO-d₆)δ13.12(br s,1H),8.52(d,J＝1.8Hz,1H),8.49(s,1H),8.34(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.94(d,J＝5.0Hz,1H),7.77(d,J＝8.3Hz,1H),7.52(d,J＝8.0Hz,1H),7.10(d,J＝5.0Hz,1H),2.08(s,3H).

Example 120

4' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 4-acetylphenylboronic acid (available from Combi-Blocks inc.; 66mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4' -acetyl-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (28mg, 30%).¹H NMR(400MHz,DMSO-d₆)δppm13.23(br s,1H),8.48(s,1H),8.40(d,J＝1.5Hz,1H),8.34(d,J＝2.0Hz,1H),8.25(dd,J＝8.0,2.0Hz,1H),8.10(dd,J＝8.3,2.0Hz,1H),8.03(d,J＝8.3Hz,2H),7.77(d,J＝8.5Hz,1H),7.60(d,J＝8.0Hz,1H),7.55(d,J＝8.3Hz,2H),2.63(s,3H).

Example 121

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2 '-fluoro-biphenyl-2, 4' -dicarboxylic acid

2-bromo-5- [4-, (S-B) using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 4-cyano-2-fluorophenylboronic acid (available from Combi-Blocks inc.; 83mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2 '-fluoro-biphenyl-2, 4' -dicarboxylic acid (49mg, 40%).¹H NMR(400MHz,DMSO-d₆)δ13.27(br s,1H),8.53(d,J＝1.8Hz,1H),8.50(s,1H),8.30-8.36(m,2H),8.10(dd,J＝8.3,2.0Hz,1H),7.87(dd,J＝7.9,1.4Hz,1H),7.77(d,J＝8.5Hz,1H),7.69(dd,J＝10.4,1.4Hz,1H),7.55-7.62(m,2H).

Example 122

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2 '-formyl-5' -methyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-formyl-5-methylphenylboronic acid (available from Frontier Scientific, inc.; 66mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2 '-formyl-5' -methyl-biphenyl-2-carboxylic acid (18mg, 19%).¹H NMR(400MHz,DMSO-d₆)δ13.10(br s,1H),9.72(s,1H),8.52(d,J＝1.8Hz,1H),8.49(s,1H),8.34(d,J＝2.0Hz,1H),8.26(dd,J＝8.0,2.0Hz,1H),8.10(dd,J＝8.5,2.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.49(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.17(s,1H),2.43(s,3H).

Example 123

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -formyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-formylphenylboronic acid (available from Frontier Scientific, inc.; 60mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -formyl-biphenyl-2-carboxylic acid (45mg, 49%).¹H NMR(400MHz,DMSO-d₆)δ13.11(br s,1H),9.80(br s,1H),8.54(s,1H),8.49(s,1H),8.34(s,1H),8.27(d,J＝7.8Hz,1H),8.10(d,J＝8.5Hz,1H),7.93(d,J＝7.5Hz,1H),7.78(d,J＝8.5Hz,1H),7.73(t,J＝7.2Hz,1H),7.61(t,J＝7.3Hz,1H),7.51(d,J＝7.8Hz,1H),7.36(d,J＝7.5Hz,1H).

Example 124

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4 '-fluoro-2' -trifluoromethyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 4-fluoro-2- (trifluoromethyl) benzeneboronic acid (available from Frontier Scientific, inc.; 87mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4 '-fluoro-2' -trifluoromethyl-biphenyl-2-carboxylic acid (4mg, 3%).¹HNMR(300MHz,DMSO-d₆)δ13.14(br s,1H),8.58(s,1H),8.49(s,1H),8.34(d,J＝1.9Hz,1H),8.26(d,J＝6.6Hz,1H),8.10(d,J＝8.3Hz,1H),7.77(d,J＝8.5Hz,1H),7.71(d,J＝9.4Hz,1H),7.57(d,J＝8.1Hz,2H),7.44(d,J＝8.3Hz,1H).

Example 125

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',4' -bis-trifluoromethyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2, 4-bis (trifluoromethyl) phenylboronic acid (available from Combi-Blocks inc.; 129mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2',4' -bis-trifluoromethyl-biphenyl-2-carboxylic acid (7mg, 5%).¹H NMR(300MHz,DMSO-d₆)δ13.17(br s,1H),8.62(s,1H),8.50(s,1H),8.27-8.37(m,2H),8.05-8.15(m,3H),7.77(d,J＝8.3Hz,1H),7.64(d,J＝7.9Hz,1H),7.48(d,J＝8.1Hz,1H).

Example 126

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -3' -trifluoromethyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-3- (trifluoromethyl) phenylboronic acid (available from Combi-Blocks inc.; 112mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-3' -trifluoromethyl-biphenyl-2-carboxylic acid (3mg, 2%).¹H NMR(300MHz,DMSO-d₆)δ13.22(br s,1H),8.58(br.s.,1H),8.50(s,1H),8.27-8.36(m,2H),8.10(d,J＝7.3Hz,1H),7.87-7.93(m,1H),7.78(d,J＝8.5Hz,1H),7.61-7.70(m,2H),7.47-7.53(m,1H).

Example 127

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -trifluoromethyl-biphenyl-2-carboxylic acid

Methyl 2-bromo-5- [4- (34-dichloro-phenyl) -thiazol-2-yl ] -benzoate (which can be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-4- (trifluoromethyl) phenylboronic acid (available from Combi-Blocks inc.; 100mg,0.5mmol) using the conditions of general procedure a for Suzuki coupling and hydrolysis in a parallel fashion. The resulting ester was hydrolyzed and the acid was purified to give 2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -trifluoromethyl-biphenyl-2-carboxylic acid (2mg, 2%). LCMS analysis indicated the material was-100% pure, as measured by UV at 214 nm.

Example 128

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -trifluoromethyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-5- (trifluoromethyl) phenylboronic acid (available from Combi-Blocks inc.; 112mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-5' -trifluoromethyl-biphenyl-2-carboxylic acid (5mg, 4%).¹H NMR(300MHz,DMSO-d₆)δ13.19(br s,1H),8.59(s,1H),8.50(s,1H),8.28-8.36(m,2H),8.10(d,J＝8.5Hz,1H),7.71-7.82(m,4H),7.52(d,J＝8.1Hz,1H).

Example 129

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -fluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 4-fluorophenylboronic acid (available from Frontier Scientific, inc.; 56mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' -fluoro-biphenyl-2-carboxylic acid (63mg, 71%).¹H NMR(400MHz,DMSO-d₆)δ13.18(br s,1H),8.46(s,1H),8.35(d,J＝8.5Hz,2H),8.22(d,J＝8.0Hz,1H),8.09(d,J＝8.3Hz,1H),7.73-7.81(m,1H),7.56(d,J＝8.0Hz,1H),7.40-7.48(m,2H),7.24-7.34(m,2H).

Example 130

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -fluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-5-fluorophenylboronic acid (available from Combi-Blocks inc.; 87mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-5' -fluoro-biphenyl-2-carboxylic acid (12mg, 10%).¹H NMR(300MHz,DMSO-d₆)δ13.14(br s,1H),8.55(d,J＝1.7Hz,1H),8.49(s,1H),8.34(d,J＝1.9Hz,1H),8.29(dd,J＝8.1,1.9Hz,1H),8.09(dd,J＝8.5,2.1Hz,1H),7.77(d,J＝8.5Hz,1H),7.56(dd,J＝8.6,5.7Hz,1H),7.48(d,J＝8.1Hz,1H),7.30(d,J＝8.7Hz,2H).

Example 131

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',5' -difluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2, 5-difluorophenylboronic acid (available from Combi-Blocks inc.; 63mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2',5' -difluoro-biphenyl-2-carboxylic acid (71mg, 77%).¹H NMR(400MHz,DMSO-d₆)δ13.22(br s,1H),8.48-8.52(m,2H),8.34(s,1H),8.29(d,J＝8.0Hz,1H),8.09(d,J＝8.3Hz,1H),7.75-7.79(m,1H),7.59(d,J＝6.8Hz,1H),7.27-7.37(m,3H).

Example 132

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',4' -difluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) and 2, 4-difluorophenylboronic acid (available from Frontier Scientific, Inc.; 79 mg)0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2',4' -difluoro-biphenyl-2-carboxylic acid (19mg, 17%).¹H NMR(400MHz,DMSO-d₆)δ13.17(br s,1H),8.46-8.52(m,2H),8.33(d,J＝2.0Hz,1H),8.26-8.31(m,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.55(d,J＝8.0Hz,1H),7.44-7.52(m,1H),7.27-7.36(m,1H),7.15-7.24(m,1H).

Example 133

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',3',5' -trifluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2,3, 5-trifluorophenylboronic acid (available from Combi-Blocks inc.; 70mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2',3',5' -trifluoro-biphenyl-2-carboxylic acid (23mg, 24%).¹H NMR(400MHz,DMSO-d₆)δ13.36(br s,1H),8.55(s,1H),8.50(s,1H),8.28-8.39(m,2H),8.10(d,J＝8.3Hz,1H),7.77(dd,J＝8.4,1.6Hz,1H),7.54-7.66(m,2H),7.22-7.28(m,1H).

Example 134

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -fluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-benzylMethyl ester of acid (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-chloro-4-fluorophenylboronic acid (available from Combi-Blocks inc.; 70mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' -fluoro-biphenyl-2-carboxylic acid (8mg, 8%). LCMS analysis indicated the material was 93% pure, as measured by UV at 214 nm. LRMS M/z479.7(M + H)⁺).

Example 135

4 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -fluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 4-chloro-2-fluorophenylboronic acid (available from Combi-Blocks inc.; 70mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -fluoro-biphenyl-2-carboxylic acid (0.6mg, 0.3%). When 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]When methyl benzoate (which can be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 4-chloro-2-fluorophenylboronic acid (available from Combi-Blocks inc.; 87mg,0.5mmol), the same compound was also prepared using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner. The resulting ester was hydrolyzed and the acid was purified to give 4' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -fluoro-biphenyl-2-carboxylic acid (63.6mg, 53%). A second sample is passed through¹H NMR characterization: (300MHz, DMSO-d₆)δ13.22(br s,1H),8.50(d,J＝4.9Hz,2H),8.26-8.37(m,2H),8.09(d,J＝8.3Hz,1H),7.77(d,J＝8.5Hz,1H),7.37-7.60(m,4H).

Example 136

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -6' -fluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-6-fluorophenylboronic acid (available from Combi-Blocks inc.; 87mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-6' -fluoro-biphenyl-2-carboxylic acid (3mg, 3%).¹H NMR(300MHz,DMSO-d₆)δ13.18(br s,1H),8.61(d,J＝1.9Hz,1H),8.50(s,1H),8.28-8.38(m,2H),8.10(dd,J＝8.4,2.0Hz,1H),7.78(d,J＝8.5Hz,1H),7.39-7.57(m,3H),7.33(d,J＝9.2Hz,1H).

Example 137

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -fluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-fluorophenylboronic acid (available from Combi-Blocks inc.; 56mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -fluoro-biphenyl-2-carboxylic acid (30mg, 34%).¹H NMR(400MHz,DMSO-d₆)δ13.11(br s,1H),8.48(s,2H),8.34(s,1H),8.28(d,J＝7.8Hz,1H),8.09(d,J＝8.3Hz,1H),7.77(d,J＝6.5Hz,1H),7.56(d,J＝6.5Hz,1H),7.39-7.48(m,2H),7.20-7.35(m,2H).

Example 138

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2',3' -difluoro-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2, 3-difluorophenylboronic acid (available from Combi-Blocks inc.; 63mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2',3' -difluoro-biphenyl-2-carboxylic acid (64mg, 69%).¹H NMR(400MHz,DMSO-d₆)δ13.26(br s,1H),8.52(s,1H),8.50(d,J＝1.5Hz,1H),8.34(s,1H),8.31(d,J＝8.0Hz,1H),8.10(d,J＝8.5Hz,1H),7.74-7.81(m,1H),7.59(d,J＝8.0Hz,1H),7.42-7.53(m,1H),7.19-7.36(m,2H).

Example 139

2' -chloro-4- [4- (34-dichloro-phenyl) -thiazol-2-yl ] -6' -fluoro-3 ' -methyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-4-methylphenylboronic acid (available from Combi-Blocks inc.; 94mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-6 '-fluoro-3' -methyl-biphenyl-2-carboxylic acid (4mg, 3%).¹H NMR(300MHz,DMSO-d₆)δ13.14(br s,1H),8.60(s,1H),8.50(s,1H),8.28-8.36(m,2H),8.10(d,J＝8.1Hz,1H),7.77(d,J＝8.3Hz,1H),7.37-7.53(m,2H),7.16-7.27(m,1H),2.36(s,3H).

Example 140

2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -6' -fluoro-5 ' -methyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-6-fluoro-5-methylphenylboronic acid (available from Combi-Blocks inc.; 94mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-6 '-fluoro-5' -methyl-biphenyl-2-carboxylic acid (3mg, 2%).¹H NMR(400MHz,DMSO-d₆)δ13.18(br s,1H),8.60(d,J＝2.0Hz,1H),8.48-8.56(m,1H),8.26-8.37(m,2H),8.10(dd,J＝8.5,2.0Hz,1H),7.78(d,J＝8.5Hz,1H),7.49(d,J＝7.8Hz,1H),7.27-7.39(m,2H),2.54(s,8H).

Example 141

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2' -methyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-methylphenylboronic acid (available from Combi-Blocks inc.; 54mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2' -methyl-biphenyl-2-carboxylic acid (63mg, 72%).¹H NMR(400MHz,DMSO-d₆)δ12.92(br s,1H),8.46(d,J＝4.8Hz,2H),8.34(s,1H),8.22(d,J＝8.0Hz,1H),8.09(d,J＝8.5Hz,1H),7.77(d,J＝8.3Hz,1H),7.39(d,J＝8.0Hz,1H),7.17-7.32(m,3H),7.09(d,J＝7.0Hz,1H),2.08(s,3H).

Example 142

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (4-methyl-thiophen-3-yl) -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 4-methyl-3-thiopheneboronic acid (available from Combi-Blocks inc.; 57mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-2- (4-methyl-thiophen-3-yl) -benzoic acid (49mg, 55%).¹H NMR(400MHz,DMSO-d₆)δ13.04(br s,1H),8.47(s,1H),8.41(d,J＝1.8Hz,1H),8.33(d,J＝2.0Hz,1H),8.20(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.3,2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.45(d,J＝8.0Hz,1H),7.35(d,J＝3.3Hz,1H),7.13-7.26(m,1H),2.54(s,3H).

Example 143

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' -methyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which can be prepared as described for intermediate 6; 111mg,0.25mmol) and 2-chloro-4-methylbenzeneBoronic acid (available from Combi-Blocks inc.; 85mg,0.5mmol) was reacted. The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-4' -methoxy-biphenyl-2-carboxylic acid (6mg, 5%).¹H NMR(300MHz,DMSO-d₆)δ12.99(br s,1H),8.49(d,J＝7.7Hz,2H),8.33(s,1H),8.26(d,J＝8.3Hz,1H),8.09(d,J＝8.5Hz,1H),7.77(d,J＝8.3Hz,1H),7.42(d,J＝8.1Hz,1H),7.35(s,1H),7.23(s,2H),2.37(s,3H).

Example 144

2 '-chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -5' -methyl-biphenyl-2-carboxylic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2-chloro-5-methylphenylboronic acid (available from Combi-Blocks inc.; 85mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-5' -methyl-biphenyl-2-carboxylic acid (59mg, 50%).¹H NMR(400MHz,DMSO-d₆)δ13.00(br s,3H),8.51(d,J＝2.0Hz,1H),8.48(s,1H),8.34(d,J＝2.0Hz,1H),8.27(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.77(d,J＝8.1Hz,1H),7.44(d,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.19-7.24(m,1H),7.18(s,1H),2.34(s,3H).

Example 145

2- (2-chloro-thiophen-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-chlorothiophene-3-boronic acid (available from Combi-Blocks inc.; 65mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2- (2-chloro-thiophen-3-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Benzoic acid (42mg, 45%).¹H NMR(400MHz,DMSO-d₆)δ13.18(br s,1H),8.44-8.56(m,2H),8.33(d,J＝2.0Hz,1H),8.26(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.3,2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.45-7.61(m,2H),7.08(d,J＝5.5Hz,1H)

Example 146

2- (3-chloro-thiophen-2-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -benzoic acid

Using the conditions of general procedure C for Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 3-chlorothiophene-2-boronic acid (available from Combi-Blocks inc.; 81mg,0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2- (3-chloro-thiophen-2-yl) -5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Benzoic acid (14mg, 12%).¹H NMR(400MHz,DMSO-d₆)δ13.23(br s,1H),8.50(s,1H),8.47(d,J＝2.0Hz,1H),8.33(d,J＝2.0Hz,1H),8.27(dd,J＝8.0,2.0Hz,1H),8.09(dd,J＝8.5,2.0Hz,1H),7.74-7.81(m,2H),7.60(d,J＝8.0Hz,1H),7.15(d,J＝5.3Hz,1H),7.15(d,J＝5.3Hz,3H).

Example 147

4' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 63mg,0.2mmol) was reacted with 4-chlorophenylboronic acid (available from Combi-Blocks inc.; 56mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (27mg, 29%).¹H NMR(400MHz,DMSO-d₆)δ8.47(s,1H),8.37(s,1H),8.33(s,1H),8.22(d,J＝8.0Hz,1H),8.09(d,J＝8.5Hz,1H),7.76(d,J＝8.5Hz,1H),7.56(d,J＝8.0Hz,1H),7.51(d,J＝6.8Hz,2H),7.42(d,J＝6.8Hz,2H).

Example 148

2',5' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2, 5-dichlorophenyl boronic acid (available from Combi-Blocks inc.; 76mg,0.4 mmol). Hydrolyzing the resulting ester and purifying the acid to obtain 2',5' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (32mg, 32%).¹H NMR(400MHz,DMSO-d₆)δ13.18(br s,1H),8.56(s,1H),8.50(s,1H),8.34(s,1H),8.29(d,J＝8.0Hz,1H),8.10(d,J＝8.5Hz,1H),7.77(d,J＝7.3Hz,1H),7.54-7.57(m,1H),7.49(s,1H),7.47(s,2H).

Example 149

2',3',5' -trichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure A for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 111mg,0.25mmol) was reacted with 2,3, 5-trichlorophenylboronic acid (available from Alfa Aesar; 113mg,0.5 mmol). Hydrolyzing the resulting ester and purifying the acid to obtain 2',3',5' -trichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (2.5mg, 2%).¹H NMR(300MHz,DMSO-d₆)δ13.27(br s,1H),8.58(d,J＝1.9Hz,1H),8.50(s,1H),8.34(d,J＝2.1Hz,1H),8.30(d,J＝7.9Hz,1H),8.10(dd,J＝8.4,2.0Hz,1H),8.00(d,J＝2.4Hz,1H),7.88(d,J＝2.4Hz,1H),7.77(d,J＝8.5Hz,1H),7.64(d,J＝2.4Hz,1H),7.47-7.53(m,1H).

Example 150

2',4' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2, 4-dichlorophenyl boronic acid (available from Combi-Blocks inc.; 76mg,0.4 mmol). Hydrolyzing the resulting ester and purifying the acid to obtain 2',4' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (65mg, 65%).¹H NMR(400MHz,DMSO-d₆)δ13.15(br s,1H),8.55(s,1H),8.49(s,1H),8.34(s,1H),8.29(d,J＝7.8Hz,1H),8.09(d,J＝8.5Hz,1H),7.78(d,J＝8.3Hz,1H),7.70(s,1H),7.51(d,J＝8.0Hz,1H),7.46(d,J＝8.0Hz,1H),7.36-7.43(m,1H).

Example 151

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Methyl 2-bromo-5- (4- (3, 4-dichlorophenyl) thiazol-2-yl) benzoate (177mg,0.4mmol) was absorbed in CH₂Cl₂In combination with Na₂CO₃And (4) washing with an aqueous solution. The organic layer was dried (MgSO₄) Filtered and evaporated. Dioxane (2mL) was added, and tetrakis (triphenylphosphine) palladium (0) (37mg,0.032mmol) and 3MK were added₂CO₃Aqueous solution (267 μ L,0.8mmol) and phenylboronic acid (available from ASDI Incorporated; 97.5mg,0.8 mmol). The vial was evacuated and filled with nitrogen, and then the mixture was heated at 100 ℃ for 20 hours. The mixture was purified on an ISCO Combiflash system using 0-15% ethyl acetate/hexanes as eluent. Fractions homogeneous for the product were evaporated and the material dissolved in THF (2 mL). Aqueous 1M NaOH (2mL) was added and the mixture was heated at 60 ℃ overnight. Aqueous 1m hcl was added to bring the pH to about 2, and the mixture was extracted 4 times with EtOAc. The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered, evaporated and purified by preparative HPLC using the conditions outlined in general procedure a for Suzuki coupling and hydrolysis in a parallel manner to give 4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (33mg, 20%) as a yellow solid.¹HNMR(400MHz,DMSO-d₆)δppm8.45(s,1H),8.32(d,J＝1.6Hz,2H),8.20(dd,J＝8.2,2.0Hz,1H),8.07(dd,J＝8.2,2.0Hz,1H),7.74(d,J＝8.6Hz,1H),7.55(d,J＝8.2Hz,1H),7.35-7.48(m,5H).

Example 152

2',3' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2, 3-dichlorophenyl boronic acid (available from Combi-Blocks inc.; 76mg,0.4 mmol). Hydrolyzing the resulting ester and purifying the acid to obtain 2',3' -dichloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (19mg, 19%).¹H NMR(400MHz,DMSO-d₆)δ13.13(br s,1H),8.56(d,J＝1.8Hz,1H),8.49(s,1H),8.34(d,J＝2.0Hz,1H),8.29(dd,J＝7.9,1.9Hz,1H),8.09(dd,J＝8.3,2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.66(dd,J＝8.0,1.5Hz,1H),7.47(d,J＝8.0Hz,1H),7.43(t,J＝7.8Hz,1H),7.33(dd,J＝7.7,1.4Hz,1H).

Example 153

2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid

Using the conditions of general procedure B for the Suzuki coupling and hydrolysis in a parallel manner, 2-bromo-5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]Methyl benzoate (which may be prepared as described for intermediate 6; 89mg,0.2mmol) was reacted with 2-chlorophenylboronic acid (available from Combi-Blocks inc.; 63mg,0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2' -chloro-4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl]-biphenyl-2-carboxylic acid (23mg, 25%).¹H NMR(400MHz,DMSO-d₆)δ13.04(br s,1H),8.53(s,1H),8.49(s,1H),8.34(s,1H),8.28(d,J＝8.0Hz,1H),8.09(d,J＝8.5Hz,1H),7.78(d,J＝8.5Hz,1H),7.33-7.56(m,5H).

Example 154

In vitro testing of compounds of the invention: human eIF4E/4G binding assay

Human eIF4E (aa28-217) (HH-eIF4E) with a C-terminal His tag was expressed in e.coli in inclusion bodies. The protein was solubilized with 8M urea and purified under denaturing conditions using a nickel-filled HisTrap HP column (GE Healthcare). Refolding the protein by: diluted to about 0.25mg/mL with 6M urea, 20mM hepespH7.0, 500mM NaCl, 1mM DTT, 1mM EDTA, and 0.5M arginine HCl, then dialyzed into the same buffer without urea overnight. The protein was further dialyzed into 20mM Hepes pH6.5,50mM NaCl, 1mM EDTA and 1mM DTT, filtered, and then concentrated using a Hitrap SP sepharose FF column (GE Healthcare). The protein was dialyzed into 20mM Hepes pH7.0, 500mM NaCl, 5mM DTT and 10% glycerol and stored at-80 ℃ until use. Test compounds (1.6 mM stock in DMSO) were serially diluted 3-fold in DMSO. The compound solution was diluted 4-fold in assay buffer (50mM sodium phosphate, pH6.5,50mM KCl,1mM DTT and 0.5mg/mL γ -globulin). Mu.l of compound solution per well and 12. mu.l of 187.5nM HH-eIF4E in assay buffer per well were added to 384-well polypropylene microplates (Matrix Technologies Corp.). Mu.l of biotin-labeled 4G2 peptide (Ac-Lys-Gln-Tyr-Asp-Arg-Glu-Phe-Leu-Leu-Asp-Phe-Gln-Phe-Met-Pro-Lys (Aha-Bio) -NH21:2TFA) was added at 187.5nM per well in assay buffer. The samples were incubated at room temperature for 20 minutes. Then 6 μ l per well of 4.8nM Eu-streptavidin (Columbia Biosciences) and 48nM allophycocyanin-anti-His antibody (Columbia Biosciences) in assay buffer (without DTT) were added and the samples were incubated for 30 min at room temperature. The assay signal was monitored by the following method: the emitted fluorescence was read at 665nm on an EnVision reader (Perkinelmer Life and Analytical Sciences). IC50 values were calculated using Condoseo software (Genedata AG).

The results of in vitro testing of the activity of the compounds of the invention as eIF4E antagonists are shown in the following table:

Claims

1. A compound of formula I:

wherein R1 is selected fromBromothienyl, thienyl, pyridyl, phenyl, said groups being optionally selectedThe generation has one or two members selected from: fluoro, chloro, bromo, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, -S (O)₂-methyl, and cyano;

wherein R2 is selected from:

-NH-X2, wherein X2 is a member selected from: -CH (CH3) -phenyl, and

2. The compound of claim 1 and pharmaceutically acceptable salts thereof,

wherein R1 is selected fromBromothienyl, thienyl, pyridyl, phenyl, said groups being optionally substituted with one or two groups selected fromThe following members: fluoro, chloro, bromo, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, and cyano;

wherein R2 is selected from:

-NH-X2, wherein X2 is a member selected from: -CH (CH3) -phenyl, and

- (CH2) n-X4 wherein n is 1 or 2 and X4 is a member selected from: pyridyl, thienyl, and phenyl, said groups optionally substituted with a member selected from the group consisting of: methyl, methoxy, fluoro, and trifluoromethyl.

3. The compound of any one of claims 1-2, wherein R1 is phenyl optionally substituted with one or two members selected from the group consisting of: fluorine, chlorine, bromine, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, and cyano.

4. The compound of any one of claims 1-3, wherein R2 is phenyl optionally substituted with 1-3 members selected from the group consisting of:methyl, cyano, hydroxy, acetyl, C (O) NH2, methoxy, ethoxy, trifluoromethoxy, C (O) H, chloro, fluoro, trifluoromethyl, nitro, -C (O) OH, -C (O) -X1, wherein X1 is a member selected from:and-NH-X2, wherein X2 is a member selected from: -CH (CH3) -phenyl and- (CH2) n-X4, wherein n is 1 or 2 and X4 is a member selected from: pyridyl, thienyl, and phenyl, said groups optionally substituted with a member selected from the group consisting of: methyl, methoxy, fluoro, and trifluoromethyl.

5. The compound of any one of claims 1-4, wherein R1 is selected fromBromothienyl, thienyl, and pyridyl.

6. The compound of any one of claims 1-5, wherein R2 is selected from:

7. The compound of any one of claims 1-6, wherein R2 is nitrophenyl.

8. The compound of any one of claims 1-6, R1 is dichlorophenyl.

9. A compound according to any one of claims 1 to 8, selected from

4- [4- (4-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (4-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-chloro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (2-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-fluoro-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-bromo-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (4-bromo-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (3-cyano-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

4- [4- (4-cyano-phenyl) -thiazol-2-yl ] -2' -nitro-biphenyl-2-carboxylic acid,

2' -nitro-4- (4- (pyridin-2-yl) -thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4- (pyridin-3-yl) -thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4- (pyridin-4-yl) -thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4-p-tolyl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4- (thiophen-3-yl) -thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4-phenyl-thiazol-2-yl) -biphenyl-2-carboxylic acid,

2' -nitro-4- (4- (thiophen-2-yl) -thiazol-2-yl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (3- (morpholin-4-yl) -propylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2- (morpholin-4-yl) -ethylcarbamoyl) -biphenyl-2-carboxylic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -4' - (2- (pyridin-3-yl) -ethylcarbamoyl) -biphenyl-2-carboxylic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2-pyrimidin-5-yl-benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (pyridin-3-yl) -benzoic acid,

5- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -2- (pyridin-4-yl) -benzoic acid,

4- [4- (3, 4-dichloro-phenyl) -thiazol-2-yl ] -biphenyl-2-carboxylic acid,

10. Compounds according to any one of claims 1 to 9 for use as therapeutically active substances.

11. A pharmaceutical composition comprising a compound of any one of claims 1-9 and a therapeutically inert carrier.

12. Use of a compound according to any one of claims 1 to 9 for the treatment or prophylaxis of cancer in a human.

13. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment or prophylaxis of cancer in a human.

14. A compound according to any one of claims 1 to 9 for use in the treatment or prevention of cancer in a human.

15. A method for the treatment or prophylaxis of cancer in a human which comprises administering an effective amount of a compound as defined in any one of claims 1 to 9.

16. The invention as hereinbefore described.