The present invention relates to certain benzimidazole compounds, or

pharmaceutically acceptable salts thereof, that inhibit Janus kinase 1 (JAKl), pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat certain types of cancer.

The JAK kinases are a tyrosine kinase family that regulate tyrosine

phosphorylation of various effectors and initiate activation of downstream signaling path ways. JAKl is a member of this family that mediates the activation of signal transducer and activator of transcription 3, STAT3, Persistent STAT3 activation is tumorigenic and promotes cancer cell survival and proliferation. Aberrations in STAT3 activation have been also shown to disrupt tumor immune surveillance in the tumor microenvironment. Therefore, inhibition of JAKl can block STAT3 activation resulting in tumor growth inhibition and tumor immune surveillance. In addition, activating JAKl mutations have been identified in both T-lineage acute lymphoblastic leukemia and Asia hepatocellular carcinoma and have been demonstrated as oncogenic. These results suggest JAKl is a viable oncology target.

JAK2 is known to form homodimers that mediate EPO and TPO receptor-signaling to the STATS pathway, which regulates red blood cells and platelet production. Inhibition of JAK2 can result in anemia and thrombocytopenia, JAKl, however, does not exhibit these activities and, thus, suggests that compounds that selectively inhibit JAKl may have a better hematotoxicity and/or immunogenicity profile than compounds that selectively inhibit JAK 2 or JAK 1/2 dual inhibitors.

JAK kinase inhibitor compounds are known in the literature. For example, US 2015/0203455 discloses certain benzimidazole compounds that are JAK inhibitors.

There remains a need to provide alternative JA l inhibitors for treatment of cancer. Also, there remains a need to provide selective JAKl inhibitors that reduce or avoid JAK2 inhibition. Accordingly, the present invention provides certain inhibitors of JA l which may be useful for treating cancer. Additionally, the present invention provides certain selective JAKl inhibitors that may reduce JAK2 inhibition.

The present invention provides a compound of Formula I:

Formuia !

or a pharmaceutically acceptable salt thereof.

Preferably, the present invention provides a compound which is selected from the group consisting of (2S)-3 - {[cis-4-( {4- [( 1 ,5 -dimethyl- 1 H-pyrazoi-3-yl)amino] - 1 -methyl-ni-benziirddazol-6-yl}oxy)cyc3ohexy3]amino}-i,l,l-trifluoropiOpan-2-o2^

or a pharmaceutically acceptable salt thereof, and

(2R)-3 - { [cis~4~( {4- [( 1 ,5 -dimethyl- 1 H-pyrazol-3 -yl)amino] - 1 -methyl- 1 H-benzimidazol-6-yl}oxy)cyclohexyl]amino}-l,l,i-trifiuoropropan-2-ol:

or a pharmaceutically acceptable salt thereof.

Preferably, the present invention provides a compound which is (2S)-3-{[ars-4-( {4-[( 1 ,5 -dimethyl- 1 H-pyrazol-3 -yi)amino] - 1 -methyl- 1 H-benzimidazol-6-yl}oxy)cyclohexyl]amino} -1,1,1 -tTifluoropropan-2-o3:

or a pharmaceutically acceptable salt thereof. More preferably, the present invention provides a compound which is (2R)-3-{[c¾-4-({4-[(l,5-dimethyl-lH-pyrazol-3-y])amino]- 1 -methyl- 1 H-benzimidazol-6-y] }oxy)cyclohexyl]amino} - 1,1,1 -trifluoropropan- 2 -ol :

or a pharmaceutically acceptable salt thereof.

As a particular embodiment, the present invention provides a compound which is (2R)-3 - { [cisA-i {4- [( 1 ,5 -dimeth l - 1 H-pyrazol-3 -yl)amino] - 1 -methyl - 1 H-benzimidazol-6-yl } oxy)cyciohexy i] amino } - 1 , 1 , 1 -trifluoropropan-2 -ol.

As a particular embodiment, the present invention also provides a compound which is (2S)-3-{[cw-4-({4-[(1.,5-dimethyl-lH-pyrazol-3-yl)amino]-1.-methy]-'lH-benzimidazol-6-yl} oxy)cyclohexyl] amino} -1,1,1 -trifluoropropan-2 -ol.

The present invention provides a pharmaceutical composition comprising (2R)-3-{ [cis-A-{ {4-[( 1 ,5 -dimethyl- 1 H-pyrazol-3 -yl)amino] - 1 -methyl- 1 H-benzimidazol-6-yl}oxy)cyclohexyl]amino}-l ,lJ -trtfluoropropan-2-ol, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The present invention provides a pharmaceutical composition comprising (2R)-3-{[c¾"-4-({4-[(l,5-dimethyl-lH-pyrazol-3-y])aimno]-] -methyl-lH-benzimtdazol-6-yl}oxy)cyclohexyl]ammo}-l,l,l-trif!uoropropan-2~ol, and a pharmaceutically acceptable carrier, diluent, or excipient.

The present invention provides a method for treating cancer comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The present invention provides a method for treating cancer comprising administering to a patient in need thereof an effective amou t of (2R)-3 - { [cis-4-( {4- [( 1 ,5 -dimethyl - 1 H-pyrazol-3 -yl)amino] - 1 -methyl - 1 H-benzimidazol-6-yl} oxy)cyclohexyl] amino} -1,1,1 -trifluoropropan-2-ol, or a

pharmaceuticaliy acceptable salt thereof. The present invention provides a method for

treating cancer comprising administering to a patient in need thereof an effective amount of (2R)~3~ { [cis-4~( {4~[( 1 ,5-dimethyl- 1 H-pyrazol-3 -yl)amino] - 1 -methyl- 1 H-beiizimidazol-6-yl} oxy)cyclohexyi] amino} -1,1,1 -trifluoropropan-2-oL

The present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. The present invention provides (2R)-3-{[cis-4-( {4-[( 1 ,5-dimethyl- 1 H-pyrazol-3 -yi)amino] - 1 -methyl- 1 H-benzimidazol-6-y2}oxy)cyclohexyl]amino}-l,l,l-trifluoropropan-2-o3, or a pharmaceutically acceptable salt thereof, for use in therapy. The present invention provides (2R)-3-{[cw-4-({4-[(l ,5-dimethyl- 1 H-pyrazol-3-yl)amino] - 1 -methyl- 1 H-benzirnidazol-6-yl}oxy)cyc2ohexyl]amino} -l,l,l-trifiuoropropan-2-oi, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

The present invention provides a compound of Formula I for use in therapy. The present invention also provides (2R)-3 -{[cis-4-{ {4- [(1,5 -dimethyl- 1 H-pyrazol-3 -yl)amino ] - 1 -methyl- 1 H-benzirnidazol-6-yl} oxy)cyclohexyl]amino } - 1 , 1 , 1 -trifluoropropan-2-ol for use in therapy. The present invention provides (2R)-3-{[cis-4-( {4-[( 1 ,5 -dimethyl- 1 H-pyrazol-3 -yl)arnino] - 1 -methyl- 1 H-benzimidazol-6-yl}oxy)cyc2ohexyl]amino} -l,l,l-trifiuoropropan-2-oi for use in the treatment of cancer.

The present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. The present invention provides the use of (2R)-3- {[cis-4-({4-[(l,5-dimethyl- 1 H-pyrazol-3-y 3)amino] - 1 -methyl- 1 H -benzimidazol-6-yl}oxy)cyclohexyl]amino}-l ,l .,l-trifluoropropan-2-ol, or a pharmaceuttcally acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. The present invention also provides the use of (2R)-3-{[c/5,-4-({4-[(l,5-dimethyl-lH-pyrazo2-3-y 3)amino] - 1 -methyl- 1 H-benzimidazol-6-y 3 } oxy)cyc3ohexyl] amino } - 1 , 1 , 1 -trifluoropropan-2-ol in the manufacture of a medicament for the treatment of cancer.

The present invention provides the freebase of (2R)-3-{[cis>4-({4-[(l,5-dimethyl-1 H-pyrazol-3-y l)amino] - 1 -methyl- 1 H-benzimidazol-6-y 3} oxy)cyclohexyl]amino } - 1 , 1 , -trifluoropropan-2-ol in a crystalitne form. The present invention also provides the freebase of (2R)-3-{[cw-4-({4-[(l,5-dimethyl-lH-pyrazol-3-yl)amino]-l-methyl-lH-benzimidazo3-6-y3}oxy)cyc3ohexy3]amino}-l,l,l-triiluoropropan-2-o3 in a crystalline form characterized by an X-ray powder diffraction pattern having characteristic peaks, in

2Θ ± 0.2, occurring at 1.9.5° in combination with one or more of the peaks selected from the group consisting of 1 1.9°, 15.4°, and 17.6°.

The present invention provides the dimethane sulfonic acid salt of (2R)-3-{[c«-4-( {4-[ ( 1 ,5 -dimethyl- 1 H-pyrazol-3 -yl)amino] - 1 -methyl- 1 H-benzimidazol -6-yl}oxy)cyclohexyl]ammo}-l,l,l-trifluoropropan-2-ol in a crystalline form. The present invention also provides the dimethane sulfonic acid salt of (2R)-3- {[c/s-4-({4-[(l,5-dimethyl- 1 H-pyrazol-3-y l)amino] - 1 -methyl- 1 H -benzimidazol-6-yl}oxy)cyclohexyl]amino}-l ,1 ,l-trifluoropropan-2-ol in a crystalline form characterized by an X-ray powder diffraction pattern having characteristic peaks, in 2Θ ± 0.2°, occurring at 21.7° in combination with one or more of the peaks selected from the group consisting of 21.2°, 18.0°, and 15.7°.

Furthermore, the present invention provides preferred embodiments of the methods and uses as described herein, in which cancer is selected from the group consisting of lung cancer, including non-small cell lung cancer, small cell lung cancer, and lung adenocarcinoma, adenocarcinoma, hepatocellular carcinoma, including Asian hepatocellular carcinoma, colorectal cancer, breast cancer, lymphoma, and leukemia, including acute lymphocyte leukemia and T-lineage acute lymphoblastic leukemia. Preferred cancers are lung cancer, including non-small cell lung cancer and lung adenocarcinoma, adenocarcinoma, hepatocellular carcinoma, including Asian hepatocellular carcinoma, colorectal cancer, breast cancer, and leukemia, including acute lymphocyte leukemia. More preferred cancers are non-small cell lung cancer, lung adenocarcinoma, breast cancer, and Asian hepatocellular carcinoma.

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

A "pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans.

"Pharmaceutically acceptable salts" or "a pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic salt or salts of a compound of the present invention.

"Effective amount" means the amount of a compound, or pharmaceutically acceptable salt thereof, of the present invention or pharmaceutical composition containing a compound, or pharmaceutically acceptable salt thereof, of the present invention that will elicit the biological or medical response of or desired therapeutic effect on a tissue, system, animal, mammal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

The terms "treatment," "treat," "treating," and the like, are meant to include slowing or reversing the progression of a disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if

progression of the disorder or condition is not itself slowed or reversed.

A compound of the present invention is capable of reaction, for example, with a number of inorganic and organic acids to form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et aL, HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiiey-VCH, 2002); S.M. Berge, et aL, "Pharmaceutical Salts, " Journal of Pharmaceutical Sciences, Vol 66, No. 1 , January 1977.

A compound of the present invention is preferably formulated as a pharmaceutical composition using a pharmaceutically acceptable carrier, diluent, or excipient and administered by a variety of routes. Preferably, such compositions are for oral administration. Such phannaceutical compositions and processes for preparing them are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (A. Gennaro, et a , eds., 21st ed., Mack Publishing Co., 2005).

The amount of a compound of the present invention actually administered will be determined by a physician under the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the present invention administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. Dosages per day normally fall within the range of about 50 to 1000 mg per day, preferably 80 to 600 mg per day, most preferably 300 mg per day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed. Dosage levels can be determined by one of skill in the art.

A compound of the present invention, or pharmaceutically acceptable salt thereof, may be prepared by a variety of procedures known in the art, as well as those described in the Preparations and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways to prepare a compound of the invention, or pharmaceutically acceptable salt thereof.

The reagents and starting materials are generally readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry, techniques which are known to one of ordinary skill in the art, and the procedures described in the Examples which follow including any novel procedures. The following Preparations and Examples further illustrate the invention. Unless noted to the contrary, the compounds illustrated herein are named and numbered using IUPACNAME ACDLABS.

Individual isomers, enantiomers, or diastereomers may be separated or resolved by one of ordinar skill in the ait at any convenient point in the synthesis of compounds by methods such as selective crystallization techniques or chiral chromatography (See, e.g., Enantiomers, Racemates, and Resolutions (J. Jacques, et al, John Wiley and Sons, Inc., 1981)).

The skilled artisan will appreciate a compound of the present invention contains at least one chiral center. The present invention contemplates all individual enantiomers or diastereomers, as well as mixtures of the enantiomers and diastereomers of said compounds including racemates. it is preferred that a compound of the present invention exists as a single enantiomer or diastereomer. The single enantiomer or diastereomer may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, the single enantiomer or diastereomer may be isolated from mixtures by standard chiral chromatographic or crystallization techniques.

A compound of the present invention can be prepared according to synthetic methods well known and appreciated in the art. Suitable reaction conditions for the steps of these reactions are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may be isolated and/or purified by various well known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification.

Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical, The particular order of steps required to produce a compound of the present invention is dependent upon the particular compound being synthesized, the starting compound, and the relative liability of the substituted moieties, as is well appreciated by the skilled chemist. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art.

As used herein, the following terms have the meanings indicated: "ATP" refers to adenosine 5 '-triphosphate; "BSA" refers to bovine serum albumin; "DMSO" refers to dimethyl sulfoxide; "EDTA" refers to ethylenediaminetetraacetic acid; "EGTA" refers to ethylene glycol tetraacetic acid; "FBS" refers to fetal bovine serum; "GFP" refers to green fluorescent protein; "HEPES" refers to 4~(2-hydroxyethyl)piperazine-l-ethanesulfonic acid; "HWB" refers to human whole blood; "IC50" refers to the concentration of compound that reduces a given response (ligand binding or enzyme response) by 50%; "IC50 relative" refers to the relative concentration giving half the compound's maximum response; "IVTI" refers to in vivo target inhibition; "JAK" refers to Janus kinase; "MS" refers to mass spectroscopy; "NMR" refers to nuclear magnetic resonance; "NSCLC" refers to non-small cell lung cancer; "PBS" refers to phosphate buffered saline; "RNase" refers to ribonuclease; "RT" refers to room temperature;

"SCLC" refers to small cell lung cancer; "STAT" refers to signal transducers and activators of transcription; "TED" refers to threshold effective dose; "TR-FRET" refers to time resolved fluorescence resonance energy transfer.

Preparation 1

(2R)-2-(Trifluoromethyl)oxirane

Add acetic acid (0.89 mL, 0.052 eq) to a solution of (l S,2S)-(+)-l,2~

cyclohexanediatnino-N, '-bis(3,5-di-t-butylsaiicylidene)cobalt (II) (0.90 g, 0.0050 eq) in toluene (16.65 mL). Stir at room temperature for 30 minutes. Remove the solvent in vacuo. Add toluene (20 mL) and concentrate in vacuo. Cool to 0UC and add 2-

(trifluoromethyl)oxirane (37.00 g, 330 mmol; 80.0% ee, (2R) is the major enantiomer). Stir for five minutes and add water (0.80 mL, 0.15 eq) dropwise. Allow to slowly warm to room temperature and stir overnight. Vacuum distill at room temperature, collecting the title compound in a cooled flask as a light yellow oil (28.10 g, 76%; 99.8% ee). lll NMR (CDC33) δ 2.92-2.94 (m, I H), 2,98-3.01 (m, IH), 3.41 -3.46 (m, 1 H).

Combine the title compound (0.13 g, 1.16 mmol) and methanol (1.3 mL). Cool to 0 C and add triethylamine (0.17 mL, 1.10 eq) and thtophenol (0.12 mL, 1.05 eq). Stir for 30 minutes. GCMS of an aliquot shows formation of l,l,l-trifluoro-3-phenylsulfanyl-propan-2-ol (from ring-opening of the title compound); m/z = 222, Chiral LC-MS shows 99.8% ee, (2S)-1 ,1,1 -trifluoro-3-pheny]sulfanyl-propan-2-ol is the major enantiomer.

Preparation 2

l-Bromo-3,5-difluoro-2 -nitrobenzene

Add nitric acid (fuming, 20 mL) dropwise to a solution of 1 -bromo-3,5-difluorobenzene (35.00 mL, 304 mmol) in sulfuric acid (50 mL) at 0 C, Allow to slowly warm to room temperature and stir overnight. Pour the reaction mixture into a mix of ice and water (600 mL). Allow to slowly warm to room temperature. Add ethyl acetate (200 mL) and hexanes (100 mL). Stir until all solids dissolve. Separate the layers. Wash the organics with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a yellow oil (57.37 g, 79%). GCMS m/z = 237,239 (Br).

P:

3-Bromo-5-fluoro-N-methyl-2-nitroaniline

Add 2 M monomethylamine in tetrahydrofuran (92 mL, 2.00 eq) to a solution of l-bromo-3,5-difluoro-2-nitrobenzene (21.90 g, 92 mmol) in 1,4-dioxane (92 mL). Stir at room temperature for 45 minutes. Add water and extract with ethyl acetate. Wash the organics with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 20-40% methylene chloride in hexanes gradient, to give the title compound as an orange solid (16.95 g, 74%). MS (ES) m/z = (79Br/8iBr) 249/251 (M+H).

Preparation 4

tert-Butyl {ci5-4-[3-bromo-5- methyiamino)-4-nitrophenoxy]cyc2ohexy2}carbamate

Combine 3-bromo-5-fluoro-N-methy]-2-nitroaniline (75.04 g, 301 mmol), tert-butyl (ci-f-4-hydroxycyclohexyl)carbamate (89.52 g, 1.38 eq), and tetra(n-butyl)ammonium bisulfate (15.58 g, 0.15 eq) in dichioromethane (975 mL) and 5 M aqueous sodium hydroxide (241 mL). Stir rapidly at 37 C under nitrogen for five days. Cool to room temperature. Dilute with dichioromethane (200 mL) and water (400 mL). Separate the layers. Extract the aqueous with dichioromethane (3 x 100 mL). Wash the combined organics with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 0-40% ethyl acetate in hexanes gradient, to give the title compound as an orange solid (68.57 g, 51%). MS (ES) m/z = (79Br/8iBr) 442/444 (M-H).

Preparation 5

tert-Butyl {ci5-4-[(4~bromo-i-methyl-lH-benzimidazol-6-yl)oxy]cyelohexyl}earbamate

Combine tert-butyl {ci -4-[3-bromo-5-(methylamino)-4-ni1rophenoxy]cyelohexyl}earbamate (76.92 g, 173 mmol) and platinum 5% on carbon (sulfided, 3.85 g) in tetrahydrofuran (923 mL) in a Parr reactor. Stir at room temperature under 414 kPa hydrogen for three days. Filter through diatomaceous earth. Wash with tetrahydrofuran. Add taimethylorthoformate (165 mL, 8.70 eq) to the combined

tetrahydrofuran filtrates. Stir for 22 hours at 63 C, Concentrate the majority of the reaction mixture in vacuo. Dilute with water (400 mL) and ethyl acetate (400 mL). Basify with aqueous sodium carbonate to adjust pH to 9. Separate the layers. Extract the aqueous with ethyl acetate (2 x 200 mL). Dry the combined organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Dilute with methyl fert-butyl ether (400 mL) and sonicate for 30 minutes. Filter, wash with methyl fert-butyl ether, and dry under vacuum to give the title compound as a light brown solid (52.02 g, 71%). MS (ES) m/z = (79Br/8!Br) 424/426 (M+H).

Preparation 6

czi-4-[(4-Bromo-l-methyl-lH-benzimidazol-6-yl)oxy]cyclohexanamine

Add trifluoroacetic acid (666 mL) slowly via addition funnel to a solution oi tert-butyl {cis~4~ [(4-bromo- 1 -methyl- 1 H-benzimidazol-6-yi)oxy]cyclohexyl } carbamate (222 g, 497 mmol) in dichloromethane (1110 mL) at 0 C. Allow to slowly warm to room

temperature and stir overnight. Concentrate the reaction mixture in vacuo. Add water (250 mL) and basify wit 50% aqueous sodium hydroxide to adjust pH to 10. Add water (250 mL). Extract with 20% methanol in dichloromethane (1500 mL, then 500 mL, then 250 mL). Wash the combined organics with 2 M aqueous sodium hydroxide, dry over anhydrous magnesium sulfate, filter, and concentrate to give the title compound as a brown solid (155 g, 91%). MS (ES) m/z = (79Br/8iBr) 324/326 (M+H).

Preparation 7

(2R)~3 ~( {cis-A- [(4-Bromo- 1 -methyl- 1 H-benzimidazol-6-yl)oxy]cyclohexyl} amino)- 1 ,1,1- trifluoropropan-2-ol

Add (2R)-2-(trif]uoromethyl)oxirane (73.29 g, 1.50 eq) to a solution of czs-4-[(4-bromo-1 -methyl- lH-benzimidazol-6-yl)oxy]cyclohexanamine (150.4 g, 436 mmol) in methanol (1053 mL). Stir at room temperature overnight. Concentrate the reaction mixture in vacuo. Purify by normal phase chromatography, eluting with a 0-10% ethanol in dic loromethane gradient, to give the title compound as an off-white solid (98.10 g, 52%). MS (ES) m/z = (79Br/8iBr) 436/438 (M+H).

Preparation 8

3 -( {cis- - [(4-Bromo- 1 -methyl- 1 H-benzimidazol-6-yl)oxy]cyclohexyl} amino)- 1,1,1- trifluoropropan-2-ol

Add 2-(trifluoromethyl)oxirane (2.13 mL, 1.02 eq; 80.0% ee, (2R) is the major enantiomer) to a solution of c«-4-[(4-bromo- 1 -methyl- lH-benzimidazol-6-y])oxy]cyclohexanamine (7.90 g, 24.37 mmol) in isopropanol (130 mL). Heat at 70 C overnight. Concentrate the reaction mixture in vacuo, Purify by normal phase chromatography, eluting with a stepwise gradient from 100% ethyl acetate to 2.5% to 5% to 7.5% to 10% methanol in ethyl acetate, to give the title compound (7.86 g, 74%). MS (ES) m/z = (79Br/8!Br) 436/438 (M+H).

Preparation 9

(5 S)~3 - {cis-4- [(4-Bromo- 1 -methyl- 1 H-benzimidazol -6-yl)oxy]cyclohexyl } -5- (trifluoromethyl)- 1 ,3 -oxazolidin-2-one

Combine 3 -( {cis-4- [(4-bromo- 1 -methyl- 1 H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-l,l,l-trifluoropropan-2-ol (3.34 g, 7.66 mmol: 80,0% ee, (2R) is the major enantiomer), Ι,Γ-carbonyldiimidazole (2.48 g, 2,00 eq), and 4-dimethylaminopyridine (0.094 g, 0.10 eq) in dichioromethane (38.3 mL). Stir at room temperature under nitrogen overnight. Concentrate the reaction mixture in vacuo. Purify by normal phase chromatography, eluting with a 0-5% methanol in dichioromethane

gradient, to give 3-{t¾'-4-[(4-bromo-l-methyl-lH-benzimidazol-6-yl)oxy]cyclohexyl}-5-(trifluoromethyl)-l,3-oxazolidin-2-one (3.28 g; 80.0% ee, (5R) is the major enantiomer),

Separate the above with the following chiral chromatography conditions to give the title compound (0.32 g, 9%). MS (ES) m/z = (79Br/8iBr) 462/464 (M+H): Enantiomer , >99% ee, 75%/25% C02/MeOH, 5 mL/min, 4.6 x 150 mm, Chiralpak AD-H.

Preparation 10

(2S)-3-( {cw-4-[(4-Bromo- 1 -methyl- 1. H-benzimidazx)l-6-y])oxy]cyclohexyl} amino)- 1,1 , 1- trifluoropropan-2-ol

Combine (5 S)-3 - {cis-4- [(4-bromo- 1 -methyl- 1 H-benzimidazol-6-yl)oxy]cyclohexyl}-5-(trif]uoromethyl)-l,3-oxazolidm-2-one (0.32 g, 0.69 mmol) and potassium trimethylsilanolate (0.36 g, 4.00 eq) in tetrahydrofuran (7 mL). Stir at room temperature under nitrogen for six days. Dilute with water. Filter, wash with water, and dry under vacuum to give the title compound as a white solid (0.22 g, 73%). MS (ES) m/z = (79Br/8iBr) 436/438 (M+H).

Example 1

(2R)-3- { [cis-4-( {4- [( 1 ,5 -Dimethyl- 1 H-pyrazol-3-yl)amino] - 1 -methyl- 1 H-benzimidazol- 6-y i } oxy)cyclohexyl] amino } - 1 , 1 , 1 -trifluoropropan-2-ol

Combine (2R)-3-( {ds-4-[(4-bromo-i -methyl- lH-benzimidazol-6-yl)oxy](^c]ohexy]}amino)-l ,l,l-trifluoropropan-2-ol (0.20 g, 0.46 mmol), 1,5-dimeftylpyrazol-3-amrne (0.056 g, 1.1 eq), potassium carbonate (0.158 g, 2.5 eq), 2-(di~ te^bu1ylphosphmo)-2',4',6'-lTiisopropyl-3,6-dimet oxy-l,r-biphenyl (0.046 g, 0,20 eq), tris(dibenzylideneacetone)dipalladium(0) (0.042 g, 0.10 eq), and acetic acid (0.01 mL) in tertAmtyl alcohol (5 ml,). Seal with a crimp cap. Heat in a microwave reactor at 120 C for 45 minutes. Concentrate the reaction mixture in vacuo. Purify by normal phase chromatography, elating with a stepwise gradient from 100% ethyl acetate to 1% to 2.5% to 5% methanol in ethyl acetate, to give the title compound (0.071 g, 33%). MS (ES) m/z = 467 (M+H).

Alternate Example 1

(2R)-3 - { [cis~4-( {4- [( 1 ,5 -Dimethyl- 1 H-pyrazol-3-yl)amino] - 1 -methyl- 1 H-benzimidazol- 6-yl} oxy)cyclohexyl] amino} - 1 , 1 ,1 -trifluoropropan-2-ol

Combine (2R)-3 -( {cis-4- [(4-bromo- 1 -methyl- 1 H-benzimidazol-6-yl)oxy]cyclohexyl}ammo)-l,l,l-trifluoropropan-2-ol (50 g, 115 mmol), 1 ,5-dimethylpyrazol-3-amine (18.25 g, 1.43 eq), and potassium carbonate (50 g, 3.16 eq) in 2-methylbutan-2-ol (400 mL). Stir and degas with a bubbling nitrogen line for 15 minutes. Add 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l, biphenyl (2.20 g, 0.034 eq) and tris(dibenzylideneacetone)dipalladiurn(0) (1.60 g, 0.015 eq). Stir and degas with a bubbling nitrogen line for five minutes. Add acetic acid (3 mL). Heat at reflux under nitrogen for twenty hours. Add 2-(dicycioliexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l ,l.'-biphenyl (1.10 g, 0.017 eq) and

tris(dibenzylideneacetone)dipalladium(0) (0.80 g, 0.0075 eq). Heat at reflux under nitrogen for three hours. Concentrate the reaction mixture in vacuo. Dilute with water (500 mL). Acidify with 35% aqueous hydrochloric acid to adjust pH to 1. Add ethyl acetate (100 mL) and stir for five minutes. Treat the stirring mixture with activated charcoal (5 g) and filter through diatomaceous earth. Separate the layers and discard the organics. Basify the aqueous layer with 30% w/w aqueous ammonium hydroxide to adjust pH to 10. Filter to obtain a solid. Purify by nonnal phase chromatography, eluting with 10% 2 M ammonia/ methanol in dichloromethane, to give the title compound (52 g, 95%). MS (ES) m/z = 467 (M+H).

Second Alternate Example 1

(2R)~3 - { [cis-4-( {4~ [( 1 ,5 -Dimethyl- 1 H-pyrazol -3 ~y l)amino] - 1 -methyl- 1 H-benzimidazol - 6-yl} oxy)cyc2ohexyl]amino} -l,l,l-trifluoropropan-2-ol, Crystalline Form I

A: Dissolve a portion of the normal phase chromatography product of Alternate Example 1 (1.60 g) in 9: 1 acetone:water (45 mL). Stir at room temperature for 15 minutes and add SiliaBond® DMT (0.42 g). Filter after five hours at room temperature. Concentrate the filtrate to remove all acetone, then dilute with water (10 mL). Filter and dry under vacuum to give crystalline material (1.37 g). MS (ES) m/z = 467 (M+H).

B: Slurry the normal phase chromatography product of Alternate Example 1 (47.0 g) in isopropanol (1.15 L). Heat the mixture to reflux to obtain a solution. Add glassy carbon (6 g). After one hour at reflux, filter through diatomaceous earth. Wash with isopropanol (50 mL) and seed the filtrate with crystalline material from Subsection A as provided directly above (0.20 g, portionwise). Stir and allow to cool to room temperature over two hours. Filter and dry under vacuum to give crystalline material (37.8 g). MS (ES) m/z = 467 (M+H).

Example 2

(2S)-3- {[ci5-4-({4~[(l,5-Dimethyl-lH"pyrazo2-3-yl)amino]-l-methyl-lH-benziniidazo yl}oxy)cyclohexyl]amino}-l ,1,1 -trifluoropropan-2-ol

Combine (2S)-3-({c/5-4-[(4-Bromo-l-methyl-lH-benzimidazol-6-yl)oxy]cyc]ohexy]}ammo)-l , l,l -1xif]uoropropan-2-ol (0.077 g, 0.18 mmol), 1,5-dimethylpyrazol-3-amine (0.030 g, 1.45 eq), potassium carbonate (0.060 g, 2.46 eq), 2-(di-tert"butylphosphmo)-2',4,,6'-triisopropyi-3,6-dimethoxy-l,r-biphenyl (0,022 g, 0.25 eq), tris(dibenz ]ideneacetone)dipalladium(0) (0,0080 g, 0.050 eq), and acetic acid (0,01 mL) in teri-butyl alcohol (2.5 niL). Seal with a crimp cap. Heat at 95 C overnight. Dilute with ethyl acetate and filter through diatomaceous earth. Concentrate the filtrate in vacuo. Purify by normal phase chromatography, eluting with a 5-100% B gradient (A: dichloromethane; B; 15% 0.75 M ammoniated methanol in dichloromethane). Further purify by reverse phase chromatography, eluting with a 5-100% B gradient (A: 10 nM aqueous ammonium bicarbonate with 10% methanol; B: acetonitrile). Concentrate clean fractions from ethanol, then again from dichloromethane, to give the title compound (0.054 g, 65%). MS (ES) m/z = 467 (M+H).

Example 3

(2R)-3 - { [cis~4-( {4- [( 1 ,5 -Dimethyl- 1 H-pyrazol-3-yl)amino] - 1 -methyl- 1 H-benzimidazol- 6-yl}oxy)cyc2ohexyl]amino}-l,l,l-trifluoropropan-2-ol; dimethane sulfonic acid

F3C O H

Combine (2R)-3-{[cw-4-({4-[(l,5-dimethyl-lH-pyrazol-3~yl)ammo]-l~methyl-lH-benziniidazol-6-yl}oxy)cyclohexyl]arnino}-l,l,l-trifluoiOpropan-2-o2 (1.00 g, 2,15 mmol) and acetone (35 mL). Heat at 51 C and add a solution of methanesulfonic acid (0.30 mL, 2,10 eq) in acetone (5 mL) dropwise. Stir at 51°C for one hour, and then cool to room temperature. Filter the resulting solid and dr in a vacuum oven at 70 C overnight to give the title compound (1 .25 g, 88%).

Obtain the XRD patterns of crystalline solids on a Broker D4 Endeavor X-ray-powder diffractometer, equipped with a Cu a source λ = 1.54060 A) and a Vantec detector, operating at 35 kV and 50 mA. Scan the sample between 4 and 40 in 2Θ, with a step size of 0.009 in 20 and a scan rate of 0.5 seconds/step, and with 0.6 mm divergence, 5.28 fixed anti-seatter, and 9.5 mm detector slits. Pack the dry powder on a quartz sample holder and obtain a smooth surface using a glass slide. Collect the crystal form diffraction patterns at ambient temperature and relative humidity. It is well known in the crystallography art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. , The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature or humidity at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present peak position variability of ± 0.2 in 2Θ will take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks (in units of ° 2Θ), typically the more prominent peaks. Adjust the crystal form diffraction patterns, collected at ambient temperature and relative humidity, based on IST 675 standard peaks at 8.853° and 26.774° 2Θ.

Characterize a prepared sample of the compound of Second Alternate Example 1 by an XRD pattern using CuKa radiation as having diffraction peaks (2 Θ values) as described in Table 1 below, and in particular having peaks at 19.5 in combination with one or more of the peaks selected from the group consisting of 1 1.9 , 15.4 , and 17.6 ; with a tolerance for the diffraction angles of 0.2 .

Table 1: X-ray powder diffraction peaks of Second Alternate Example 1

3 14.7 11.7%

4 15.4 41.9%

5 16.2 27.5%

6 16.9 24.9%

n ι 17.6 40.1%

8 19.5 100.0%

9 20.8 32.1%

10 21.5 19.6%

Characterize a prepared sample of the compound of Example 3 by an XRD pattern using CuKa radiation as having diffraction peaks (2Θ values) as described in Table 2 below, and in particular having peaks at 21.7 in combination with one or more of the peaks selected from the group consisting of 21.2 , 18.0 , and 15.7 ; with a tolerance for the diffraction angles of 0.2 .

WE CLAIM:

A compound of Formula I:

Formula

or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1 wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, and

or a pharmaceutically acceptable salt thereof.

3. The compound according to Claim 2 which is

or a pharmaceutically acceptable salt thereof. 4. The compound according to Claim 2 which is

5. A pharmaceutical composition comprising the compound or salt according to any one of Claims 1-4, and a pharmaceutically acceptable carrier, diluent, or excipient.

6. A method of treating cancer, comprising administering to a patient in need thereof, an effective amount of the compound or salt according to any one of Claims 1-4

7. The method according to Claim 6, wherein the cancer is selected from the group consisting of lung cancer, including non-small cell lung cancer and lung adenocarcinoma, adenocarcinoma, hepatocellular carcinoma, including Asian hepatocellular carcinoma, colorectal cancer, breast cancer, and leukemia, including acute lymphocyte leukemia.

8. The method according to Claim 7, wherein the cancer is non-small cell lung cancer.

9. The method according to Claim 7, wherein the cancer is lung adenocarcinoma.

10. The method according to Claim 7, wherein the cancer is breast cancer.

1 1. The method according to Claim 7, wherein the cancer is Asian hepatocellular carcinoma.

12. The compound or salt according to any one of Claims 1-4 for use in therapy.

13. The compound or salt according to any one of Claims 1-4 for use in the treatment of cancer.

14. The compound or salt for use according to Claim 13 wherein the cancer is selected from the group consisting of lung cancer, including non-small cell lung cancer and lung adenocarcinoma, adenocarcinoma, hepatocellular carcinoma, including Asian

hepatocellular carcinoma, colorectal cancer, breast cancer, and leukemia, including acute lymphocyte leukemia.

15. The compound or salt for use according to Claim 14, wherein the cancer is non-small cell lung cancer,

16. The compound or salt for use according to Claim 14, wherein the cancer is lung adenocarcinoma.

17. The compound or salt for use according to Claim 14, wherein the cancer is breast cancer.

18. The compound or salt for use according to Claim 14, wherein the cancer is Asian hepatocellular carcinoma.