The present invention relates to biaryl pyrazole compounds of Formula (I) [structure] methods of making them, pharmaceutical compositions containing them and their use as NRF2 regulators.

Description

80 parts

›This application is a 371 national stage entry…

This application is a 371 national stage entry of International Application No. PCT/IB2016/055996, filed Oct. 6, 2016, which claims the benefit of U.S. Provisional Application No. 62/237,655, filed Oct. 6, 2015, which is incorporated herein in its entirety.

›FIELD OF THE INVENTION

The present invention relates to biaryl pyrazole compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 regulators.

›BACKGROUND OF THE INVENTION · 1 of 2

NRF2 (NF-E2 related factor 2) is a member of the cap-n-collar family of transcription factors containing a characteristic basic-leucine zipper motif. Under basal conditions, NRF2 levels are tightly controlled by the cytosolic actin-bound repressor, KEAP1 (Kelch-like ECH associating protein 1), which binds to NRF2 and targets it for ubiquitylation and proteasomal degradation via the Cul3-based E3-ubiquitin ligase complex. Under conditions of oxidative stress, DJ1 (PARK7) is activated and stabilizes NRF2 protein by preventing NRF2 from interacting with KEAP1. Also, modification of reactive cysteines on KEAP1 can cause a conformational change in KEAP1 that alters NRF2 binding and promotes NRF2 stabilization. Thus, the levels of NRF2 in the cell are usually kept low in normal conditions but the system is designed to respond quickly to environmental stress by increasing NRF2 levels and thus downstream NRF2 activity.

Inappropriately low NRF2 activity in the face of on-going oxidative stress appears to be a pathological mechanism underlying chronic obstructive pulmonary disease (COPD). Yamada, K., et al. BMC Pulmonary Medicine, 2016, 16: 27. This may be a result of an altered equilibrium between NRF2 regulators with both inappropriate lack of positive regulators such as DJ1, and overabundance of negative regulators such as Keap1 and Bach1. Therefore, restoration of NRF2 activity in the lungs of COPD patients should result in repair of the imbalance and mitigation of deleterious processes such as apoptosis of structural cells (including alveolar epithelial and endothelial cells) and inflammation. The results of these effects would be enhanced cytoprotection, preservation of lung structure, and structural repair in the COPD lung, thus slowing disease progression. Therefore, NRF2 modulators may treat COPD (Boutten, A., et al. 2011. Trends Mol. Med. 17:363-371) and other respiratory diseases, including asthma and pulmonary fibrosis (Cho, H. Y., and Kleeberger, S. R. 2010. Toxicol. Appl. Pharmacol. 244:43-56).

The therapeutic potential of an NRF2 activator is exemplified in pulmonary macrophages from COPD patients where NRF2 pathway appears maladaptive. These cells have impaired bacterial phagocytosis compared with similar cells from control patients, and this effect is reversed by the addition of NRF2 activators in vitro. Therefore, in addition to the effects mentioned above, restoration of appropriate NRF2 activity could also rescue COPD exacerbations by reducing lung infection.

This is demonstrated by the NRF2 activator, Sulforaphane, which increases the expression of Macrophage Receptor with Collagenous structure (MARCO) by COPD macrophages and alveolar macrophages from cigarette smoke-exposed mice, thereby improving in these cells bacterial phagocytosis ( Pseudomonas aeruginosa , non-typable Haemophilus influenzae ) and bacterial clearance both ex vivo and in vivo. (Harvey, C. J., et al. 2011. Sci. Transl. Med. 3:78ra32).

The therapeutic potential of targeting NRF2 in the lung is not limited to COPD. Rather, targeting the NRF2 pathway could provide treatments for other human lung and respiratory diseases that exhibit oxidative stress components such as chronic asthma and acute asthma, lung disease secondary to environmental exposures including but not limited to ozone, diesel exhaust and occupational exposures, fibrosis, acute lung infection (e.g., viral (Noah, T. L. et al. 2014. PLoS ONE 9(6): e98671), bacterial or fungal), chronic lung infection, α1 antitrypsin disease, and cystic fibrosis (C F, Chen, J. et al. 2008. PLoS One. 2008; 3(10):e3367).

A therapy that targets the NRF2 pathway also has many potential uses outside the lung and respiratory system. Many of the diseases for which an NRF2 activator may be useful are autoimmune diseases (psoriasis, IBD, MS), suggesting that an NRF2 activator may be useful in autoimmune diseases in general.

In the clinic, a drug targeting the NRF2 pathway (bardoxolone methyl) has shown efficacy in diabetic patients with diabetic nephropathy/chronic kidney disease (CKD) (Aleksunes, L. M., et al. 2010. J. Pharmacol. Exp. Ther. 335:2-12), though phase III trials with this drug in patients with the most severe stage of CKD were terminated. Furthermore, there is evidence to suspect that such a therapy would be effective in sepsis-induced acute kidney injury, other acute kidney injury (AKI) (Shelton, L. M., et al. 2013. Kidney International . June 19. doi: 10.1038/ki.2013.248.), and kidney disease or malfunction seen during kidney transplantation.

In the cardiac area, bardoxolone methyl is currently under investigation in patients 30 with Pulmonary Arterial Hypertension and so a drug targeting NRF2 by other mechanisms may also be useful in this disease area. Oxidative stress is increased in the diseased myocardium, resulting in accumulation of reactive oxygen species (ROS) which impairs cardiac function [ Circ (1987) 76(2); 458-468] and increases susceptibility to arrhythmia [ J of Mol & Cell Cardio (1991) 23(8); 899-918] by a direct toxic effect of increased necrosis and apoptosis [ Circ Res (2000) 87(12); 1172-1179]. In a mouse model of pressure overload (TAC), NRF2 gene and protein expression is increased during the early stage of cardiac adaptive hypertrophy, but decreased in the later stage of maladaptive cardiac remodeling associated with systolic dysfunction [ Arterioscler Thromb Vasc Biol (2009) 29(11); 1843-5 1850; PLOS ONE (2012) 7(9); e44899]. In addition, NRF2 activation has been shown to suppress myocardial oxidative stress as well as cardiac apoptosis, fibrosis, hypertrophy, and dysfunction in mouse models of pressure overload [ Arterioscler Thromb Vasc Biol (2009) 29(11); J of Mol & Cell Cardio (2014) 72; 305-315; and 1843-1850 ; PLOS ONE (2012) 7(9); e44899]. NRF2 activation has also been shown to protect against cardiac I/R injury in mice 10 [Circ Res (2009) 105(4); 365-374 ; J of Mol & Cell Cardio (2010) 49(4); 576-586] and reduce myocardial oxidative damage following cardiac I/R injury in rat. Therefore, a drug targeting NRF2 by other mechanisms may be useful in a variety of cardiovascular diseases including but not limited to atherosclerosis, hypertension, and heart failure (Oxidative Medicine and Cellular Longevity Volume 2013 (2013), Article ID 104308, 10 pages), acute coronary 15 syndrome, myocardial infarction, myocardial repair, cardiac remodeling, cardiac arrhythmias, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction and diabetic cardiomyopathy.

›BACKGROUND OF THE INVENTION · 2 of 2

A drug activating the NRF2 pathway could also be useful for treatment of several neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) (Brain Res. 2012 Mar. 29; 1446:109-18. 2011.12.064. Epub 2012 Jan. 12) and multiple sclerosis (MS). Multiple in vivo models have shown that NRF2 KO mice are more sensitive to neurotoxic insults than their wild-type counterparts. Treatment of rats with the NRF2 activator tert-butylhydroquinone (tBHQ) reduced cortical damage in rats in a cerebral ischemia-reperfusion model, and cortical glutathione levels were increased in NRF2 wild-type but not KO mice after administration of tBHQ (Shih, A. Y., et al. 2005 . J. Neurosci. 25: 10321-10335). Tecfidera™ (dimethyl fumarate), which activates NRF2 among other targets, is approved in the U.S. to treat relapsing-remitting multiple sclerosis (MS). Activation of NRF2 may also help treat cases of Friedreich's Ataxia, where increased sensitivity to oxidative stress and impaired NRF2 activation has been reported (Paupe V., et al, 2009. PLoS One; 4(1):e4253. Omaveloxolone (RTA-408) is also in clinical trials for Friedreich's Ataxia.

There is preclinical evidence of the specific protective role of the NRF2 pathway in models of inflammatory bowel disease (IBD, Crohn's Disease and Ulcerative Colitis) and/or colon cancer (Khor, T. O., et al 2008 . Cancer Prev. Res . (Phila) 1:187-191).

Age-related macular degeneration (AMD) is a common cause of vision loss in people over the age of 50. Cigarette smoking is a major risk factor for the development of non-neovascular (dry) AMD and perhaps also neovascular (wet) AMD. Findings in vitro and in preclinical species support the notion that the NRF2 pathway is involved in the anti-oxidant response of retinal epithelial cells and modulation of inflammation in preclinical models of eye injury (Schimel, et al. 2011. Am. J. Pathol. 178:2032-2043). Fuchs Endothelial Corneal Dystrophy (FECD) is a progressive, blinding disease characterized by corneal endothelial cells apoptosis. It is a disease of aging and increased oxidative stress related to low levels of NRF2 expression and/or function (Bitar, M. S., et al. 2012. Invest Ophthalmol. Vis. Sci . Aug. 24, 2012 vol. 53 no. 9 5806-5813). In addition, an NRF2 activator may be useful in uveitis or other inflammatory eye conditions.

Non-alcoholic steatohepatitis (NASH) is a disease of fat deposition, inflammation, and damage in the liver that occurs in patients who drink little or no alcohol. In preclinical models, development of NASH is greatly accelerated in KO mice lacking NRF2 when challenged with a methionine- and choline-deficient diet (Chowdhry S., et al. 2010. Free Rad. Biol . & Med. 48:357-371). Administration of the NRF2 activators oltipraz and NK-252 in rats on a choline-deficient L-amino acid-defined diet significantly attenuated progression of histologic abnormalities, especially hepatic fibrosis (Shimozono R. et al. 2012. Molecular Pharmacology. 84:62-70). Other liver diseases that may be amenable to NRF2 modulation are toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, and cirrhosis (Oxidative Medicine and Cellular Longevity Volume 2013 (2013), Article ID 763257, 9 page).

Recent studies have also begun to elucidate the role of ROS in skin diseases such as psoriasis. A study in psoriasis patients showed an increase in serum malondialdehyde and nitric oxide end products and a decrease in erythrocyte-superoxide dismutase activity, catalase activity, and total antioxidant status that correlated in each case with disease severity index (Dipali P. K., et al. Indian J Clin Biochem. 2010 October; 25(4): 388-392). Also, an NRF2 modulator may be useful in treating the dermatitis/topical effects of radiation (Schafer, M. et al. 2010 . Genes & Devl. 24:1045-1058), and the immunosuppression due to radiation exposure (Kim, J. H. et al., J. Clin. Invest. 2014 Feb. 3; 124(2):730-41).

There are also data suggesting that an NRF2 activator may be beneficial in preeclampsia, a disease that occurs in 2-5% of pregnancies and involves hypertension and proteinuria ( Annals of Anatomy—Anatomischer Anzeiaer Volume 196, Issue 5, September 2014, Pages 268-277).

Preclinical data has shown that compounds with NRF2 activating activity are better at reversing high altitude-induced damage than compounds without NRF2 activity, using animal and cellular models of Acute Mountain Sickness (Lisk C. et al, 2013, Free Radic Biol Med. October 2013; 63: 264-273.)

›SUMMARY OF THE INVENTION · 1 of 3

In one aspect, this invention provides for biaryl pyrazole analogs, or a salt, particularly a pharmaceutically acceptable salt thereof, and pharmaceutical compositions containing them. In particular, the compounds of this invention include a compound of Formula (I).

In a second aspect, this invention provides for the use of the compounds of Formula (I) as NRF2 regulators.

Accordingly, the present invention is also directed to a method of regulating NRF2 which method comprises contacting a cell with a compound according to Formula (I), or a salt, particularly a pharmaceutically acceptable salt, thereof.

In another aspect, this invention provides for the use of the compounds of Formula (I) for treating and preventing conditions associated with NRF2 imbalance.

In one aspect, the invention is provides a pharmaceutical composition comprising a compound of the invention according to Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Particularly, this invention is directed to a pharmaceutical composition for the treatment of an NRF2 regulated disease or disorder, wherein the composition comprises a compound according to Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In a further aspect, this invention provides for a method of treating a respiratory or non-respiratory disorder, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, acute kidney injury (AKI), kidney disease or malfunction seen during kidney transplantation, Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodelling, cardiac arrhythmias, Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or other inflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topical effects of radiation, immunosuppression due to radiation exposure, Preeclampsia, and high altitude sickness, which comprises administering to a human in need thereof, a compound of Formula (I).

In one aspect, this invention relates to a method of treating COPD, which comprises administering to a human in need thereof, a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof.

In one aspect, this invention relates to a method of treating heart failure, which comprises administering to a human in need thereof, a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof.

In yet another aspect, this invention provides for the use of a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, for the treatment of a respiratory or non-respiratory disorder, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, acute kidney injury (AKI), kidney disease or malfunction seen during kidney transplantation, Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodelling, cardiac arrhythmias, Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or other inflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topical effects of radiation, immunosuppression due to radiation exposure, Preeclampsia, and high altitude sickness.

In one aspect, this invention relates to the use of a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, for the treatment of COPD.

In one aspect, this invention relates to the use of a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, for the treatment of heart failure.

In a further aspect, this invention relates to use of a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a respiratory or non-respiratory disorder, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, acute kidney injury (AKI), kidney disease or malfunction seen during kidney transplantation, Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodelling, cardiac arrhythmias, Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or other inflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topical effects of radiation, immunosuppression due to radiation exposure, Preeclampsia, and high altitude sickness.

›SUMMARY OF THE INVENTION · 2 of 3

In one aspect, this invention relates to use of a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COPD.

In a further aspect, this invention relates to a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, for use in medical therapy. This invention relates to a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, for use in therapy, specifically for use in the treatment of a respiratory or non-respiratory disorder, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, acute kidney injury (AKI), kidney disease or malfunction seen during kidney transplantation, Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodelling, cardiac arrhythmias, Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or other inflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topical effects of radiation, immunosuppression due to radiation exposure, Preeclampsia, and high altitude sickness.

In one aspect, this invention relates to a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, for use in the treatment of COPD.

In one aspect, this invention relates to a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure.

The compounds of Formula (I) and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of allergic disease, inflammatory disease, autoimmune disease, for example; antigen immunotherapy, anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast), iNOS inhibitors, tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g., sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate), bronchodilators (e.g., muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents; monoclonal antibody therapy such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies e.g. etanercept and similar agents; antigen non-specific immunotherapies (e.g. interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents).

Suitably, for the treatment of asthma, compounds or pharmaceutical formulations of the invention may be administered together with an anti-inflammatory agent such as, for example, a corticosteroid, or a pharmaceutical formulation thereof. For example, a compound of the invention may be formulated together with an anti-inflammatory agent, such as a corticosteroid, in a single formulation, such as a dry powder formulation for inhalation. Alternatively, a pharmaceutical formulation comprising a compound of the invention may be administered in conjunction with a pharmaceutical formulation comprising an anti-inflammatory agent, such as a corticosteroid, either simultaneously or sequentially. In one embodiment, a pharmaceutical formulation comprising a compound of the invention and a pharmaceutical formulation comprising an anti-inflammatory agent, such as a corticosteroid, may each be held in device suitable for the simultaneous administration of both formulations via inhalation.

Suitable corticosteroids for administration together with a compound of the invention include, but are not limited to, fluticasone furoate, fluticasone propionate, beclomethasone diproprionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide and prednisilone. In one embodiment of the invention a corticosteroids for administration together with a compound of the invention via inhalation includes fluticasone furoate, fluticasone propionate, beclomethasone diproprionate, budesonide, ciclesonide, mometasone furoate, and, flunisolide.

Suitably, for the treatment of COPD, compounds or pharmaceutical formulations of the invention may be administered together with one or more bronchodilators, or pharmaceutical formulations thereof. For example, a compound of the invention may be formulated together with one or more bronchodilators in a single formulation, such as a dry powder formulation for inhalation. Alternatively, a pharmaceutical formulation comprising a compound of the invention may be administered in conjunction with a pharmaceutical formulation comprising one or more bronchodilators, either simultaneously or sequentially. In a further alternative, a formulation comprising a compound of the invention and a bronchodilator may be administered in conjunction with a pharmaceutical formulation comprising a further bronchodilator. In one embodiment, a pharmaceutical formulation comprising a compound of the invention and a pharmaceutical formulation comprising one or more bronchodilators may each be held in device suitable for the simultaneous administration of both formulations via inhalation. In a further embodiment, a pharmaceutical formulation comprising a compound of the invention together with a bronchodilator and a pharmaceutical formulation comprising a further bronchodilator may each be held in one or more devices suitable for the simultaneous administration of both formulations via inhalation.

›SUMMARY OF THE INVENTION · 3 of 3

Suitable bronchodilators for administration together with a compound of the invention include, but are not limited to, β 2 -adrenoreceptor agonists and anticholinergic agents. Examples of β 2 -adrenoreceptor agonists, include, for example, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol. Suitable anticholinergic agents include umeclidinium (for example, as the bromide), ipratropium (for example, as the bromide), oxitropium (for example, as the bromide) and tiotropium (for example, as the bromide). In one embodiment of the invention, a compound of the invention may be administered together with a β 2 -adrenoreceptor agonist, such as vilanterol, and an anticholinergic agent, such as, umeclidinium.

The compounds may also be used in combination with agents for aiding transplantation including Cyclosporines, Tacrolimus, Mycophenolate mofetil, Prednisone, Azathioprine, Sirolimus, Daclizumab, Basiliximab and OKT3.

They may also be used in combination with agents for Diabetes: metformin (biguanides), meglitinides, sulfonylureas, DPP-4 inhibitors, Thiazolidinediones, Alpha-glucosidase inhibitors, Amylin mimetics, Incretin mimetics and insulin.

The compounds may be used in combination with antihypertensives such as diuretics, ACE inhibitors, ARBS, calcium channel blockers, and beta blockers.

Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 22

The present invention provides for compounds of Formula (I):

wherein:

R is hydrogen or —C 1-5 alkyl, wherein —C 1-5 alkyl is unsubstituted or substituted by one or two substituents independently selected from —OH, —OC(O)—C 1-5 alkyl, —OC(O)-phenyl, —OC(O)—O—C 1-5 alkyl,

R 1 is —CF 3 , —C 3-7 cycloalkyl, or —C 4-7 heterocycloalkyl, wherein the —C 3-7 cycloalkyl, or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-3 alkyl, phenyl, triazolyl, pyridyl, pyridazinyl, imidazolyl, pyrazolyl, isoxazolyl, halo, —NR 9 —C(O)—R 10 and —C(O)R 10 , and wherein each of the phenyl, triazolyl, pyridyl, pyridazinyl, imidazolyl, pyrazolyl and isoxazolyl is unsubstituted or substituted by one or two substituents independently selected from halo, phenyl, and —C 1-7 alkyl optionally substituted with phenyl, —N(CH 3 ) 2 , —CF 3 , —OH, —C 3-7 cycloalkyl optionally substituted with —C 1-3 alkyl, and

—C 3-7 heterocylcoalkyl optionally substituted with —C 1-3 alkyl or —C(O)—C 1-4 alkyl;

or R 1 is —C 2-3 alkyl-R 11 ;

R 2a is hydrogen, halo, or —C 1-3 alkyl;

R 2 is hydrogen, halo, —CN, —O—C 1-3 alkyl, —OH, or —C 1-3 alkyl;

G is CH or N;

A is

R 3 is —(CH 2 ) n —C(O)NR 5 R 6 , —(CH 2 ) n —C(R 14 )(R 15 )—NR 5 R 6 , —(CH 2 ) n —S(O)NR 5 R 6 ,

or R 3 is —O—C 1-6 alkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, —N—R 12 R 13 , —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —S—C 1-3 alkyl, —S—C 4-7 heterocycloalkyl, S—C 3-7 cycloalkyl, —S(O)—C 1-3 alkyl, —S(O)—C 4-7 heterocycloalkyl, —S(O)—C 3-7 cycloalkyl, —S(O) 2 —C 1-3 alkyl, —S(O) 2 —C 4-7 heterocycloalkyl, or —S(O) 2 —C 3-7 cycloalkyl, wherein each of —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —S—C 1-3 alkyl, —S—C 4-7 heterocycloalkyl, S—C 3-7 cycloalkyl, —S(O)—C 1-3 alkyl, —S(O)—C 4-7 heterocycloalkyl, —S(O)—C 3-7 cycloalkyl, —S(O) 2 —C 1-3 alkyl, —S(O) 2 —C 4-7 heterocycloalkyl, or —S(O) 2 —C 3-7 cycloalkyl, is unsubstituted or substituted by one or two substituents independently selected from —C 3-7 alkyl, —C 3-7 cycloalkyl, —OH, ═O, —O—C 1-5 alkyl, CF 3 , —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazolyl, and wherein each of —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-3 alkyl, —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl is unsubstituted or further substituted by one or more substituents independently selected from —C 1-5 alkyl, —CF 3 , —OC 1-3 alkyl, phenyl, —C(O)—O—C 1-5 alkyl and halo;

Each R 4 is independently hydrogen, halo or —C 1-3 alkyl;

R 5 and R 6 are independently H, —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl, wherein each of —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from F, —CH—F 2 , —CF 3 , —(CH 2 ) n —O—(CH 2 ) m —CH 3 , and —C 3-7 cycloalkyl;

or R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-8-membered ring, an 8-11-membered bicyclic ring or a 9-10-membered bridged bicyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one —S(O) 2 , one or more oxygen ring atoms or one or more nitrogen ring atoms, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from —C 1-5 alkyl, —C 3-7 cycloalkyl, —C 4-7 heterocycloalkyl, halogen, —CHF 2 , —CF 3 , and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

or R 5 and R 6 together with the nitrogen atom to which they are attached form 4-azaspiro[2.5]octane, 7-azaspiro[4.5]decane, 2-oxa-8-azaspiro[5.5]undecane, 6-oxa-9-azaspiro[4.5]decane, 2-oxa-8-azaspiro[5.5]undecane, 1-azaspiro[4.5]decane, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine or 2,3,4,5-tetrahydro-1H-benzo[c]azepine;

R 7 and R 8 are independently H, —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl, wherein each of —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or two substituents independently selected from F, —CHF 2 , —CF 3 , and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

or R 7 and R 8 together with the carbon atoms to which they are attached form a 5-8-membered ring, which optionally includes one or more oxygen or nitrogen atoms as ring atoms, and wherein the 5-8-membered ring is unsubstituted or substituted by one or two substituents independently selected from —C 1-5 alkyl, —C 3-7 cycloalkyl, —C 4-7 heterocycloalkyl, F, —CHF 2 , —CF 3 , ═O, and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

R 9 is H or —C 1-3 alkyl;

R 10 is —C 1-3 alkyl;

R 11 is aryl, triazolyl, pyridyl, pyridazinyl, imidazolyl, or pyrazolyl, wherein each of aryl, triazolyl, pyridyl, pyridazinyl, imidazolyl, or pyrazolyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-3 alkyl and halo;

R 12 and R 13 are independently C 4-7 heterocycloalkyl, —C 1-3 alkyl or —C 3-7 cycloalkyl, wherein each of the —C 4-7 heterocycloalkyl, —C 1-3 alkyl or —C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, —OH, ═O, —O—C 1-5 alkyl, —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazolyl, and wherein each of the —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-5 alkyl, —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl is further optionally substituted by one or more substituents independently selected from —C 1-5 alkyl and halo;

R 14 is hydrogen or —C 1-3 alkyl;

R 15 is hydrogen or —C 1-3 alkyl;

Each X is CR 4 or N provided only one X is N;

Each n is independently 0 or 1;

Each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

“Alkyl” refers to a monovalent saturated hydrocarbon chain having the specified number of carbon member atoms. For example, C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon member atoms. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl, (n-propyl and isopropyl), butyl (n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (n-pentyl, tert-pentyl, iso-pentyl), and hexyl (n-hexyl, isohexyl, ter-hexyl).

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 22

When used herein, the terms “5-8-membered ring or an 8-10-membered bicyclic ring or a 9-10-membered bridged bicyclic ring” include both saturated and unsaturated ring structures containing the indicated number of carbon atoms. The terms “8-10-membered bicyclic ring or a 9-10-membered bridged bicyclic ring” can be aryl or heteroaryl, and also encompass bicyclic aryl groups containing an aryl ring moiety fused to a cycloalkyl ring moiety.

“Cycloalkyl” refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of carbon member atoms. For example, C 3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 carbon member atoms. Unsaturated cycloalkyl groups have one or more carbon-carbon double bonds within the ring. Cycloalkyl groups are not aromatic. Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

“C 4-7 heterocycloalkyl” refers to a 4 to 7 membered ring that contains up to 4 hetero atoms, including, nitrogen, oxygen, and sulfur. Examples are azetidine, thietane, thietane 1-oxide, thietane 1,1-dioxide, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydrothiophene 1-oxide, tetrahydrothiophene 1,2-dioxide, piperidine, morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1-oxide, tetrahydrothiopyran 1-1 dioxide, piperidine-2-one, azepan-2-one, pyrrolidin-2-one, azepane, oxepane, oxazepane, thiepane, thiepane 1-oxide, thiepane 1,1-dioxide, and thiazepane.

When used herein, the terms ‘halogen’ and ‘halo’ include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.

“Substituted” in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e., one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

The term “independently” means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. That is, each substituent is separately selected from the entire group of recited possible substituents.

The invention also includes various isomers of the compounds of Formula (I) and mixtures thereof. “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). The compounds according to Formula (I) contain one or more asymmetric centers, also referred to as chiral centers, and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. All such isomeric forms are included within the present invention, including mixtures thereof.

Chiral centers may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula (I), or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

For compounds falling within the scope of the invention, the structural conventions used in the Examples are as follows: (a) absolute stereochemistry is defined by the structure; (b) when annotated by “or”, then stereochemistry is unknown but resolved; and (c) when annotated by “&” or “and”, then stereochemistry is relative, but racemic.

As used herein, “pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 22

The skilled artisan will appreciate that pharmaceutically acceptable salts of the compounds according to Formula (I) may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately treating the purified compound in its free acid or free base form with a suitable base or acid, respectively. It will be understood by the skilled artisan that when R of Formula (I) provides an ester, this compound can function as a prodrug and as such, provide the parent acid upon incubation with cells or in vivo.

In certain embodiments, compounds according to Formula (I) may contain an acidic functional group and are, therefore, capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base. Examples of such bases include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids. Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.

As used herein, the term “a compound of Formula (I)” or “the compound of Formula (I)” refers to one or more compounds according to Formula (I). The compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed from crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e., the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs.” The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.

Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H, 14 O are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of Formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 22

Representative Embodiments

In one embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen or —C 1-5 alkyl which is unsubstituted or substituted by one or two substituents independently selected from —OH, —OC(O)—C 1-5 alkyl, —OC(O)-phenyl, —OC(O)—O—C 1-5 alkyl,

R 1 is —CF 3 , —C 3-7 cycloalkyl, or —C 4-7 heterocycloalkyl, wherein the —C 3-7 cycloalkyl, or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-3 alkyl, phenyl, triazolyl, pyridyl, pyridazinyl, imidazolyl, pyrazolyl, isoxazolyl, halo, —NR 9 —C(O)—R 10 and —C(O)R 10 , and wherein each of the phenyl, triazolyl, pyridyl, pyridazinyl, imidazolyl, pyrazolyl and isoxazolyl is unsubstituted or substituted by one or two substituents independently selected from halo, phenyl, —C 1-7 alkyl optionally substituted with phenyl, —N(CH 3 ) 2 , —CF 3 , —OH, and —C 3-7 cycloalkyl optionally substituted with —C 1-3 alkyl, —C 3-7 heterocylcoalkyl optionally substituted with —C 1-3 alkyl or —C(O)—C 1-4 alkyl;

or R 1 is —C 2-3 alkyl-R 11 ;

R 2a is hydrogen, halo, or —C 1-3 alkyl;

R 2 is hydrogen, halo, —CN, —O—C 1-3 alkyl, —OH, or —C 1-3 alkyl;

G is CH or N;

A is

R 3 is —(CH 2 ) n —C(O)NR 5 R 6 , —(CH 2 ) n —C(R 14 )(R 15 )—NR 5 R 6 , —(CH 2 ) n —S(O)NR 5 R 6

or R 3 is —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, —N—R 12 R 13 , —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —S—C 1-3 alkyl, —S—C 4-7 heterocycloalkyl, —S—C 3-7 cycloalkyl, —S(O)—C 1-3 alkyl, —S(O)—C 4-7 heterocycloalkyl, —S(O)—C 3-7 cycloalkyl, —S(O) 2 —C 1-3 alkyl, —S(O) 2 —C 4-7 heterocycloalkyl, or —S(O) 2 —C 3-7 cycloalkyl, wherein each of —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —S—C 1-3 alkyl, —S—C 4-7 heterocycloalkyl, S—C 3-7 cycloalkyl, —S(O)—C 1-3 alkyl, —S(O)—C 4-7 heterocycloalkyl, —S(O)—C 3-7 cycloalkyl, —S(O) 2 —C 1-3 alkyl, —S(O) 2 —C 4-7 heterocycloalkyl, or —S(O) 2 —C 3-7 cycloalkyl, is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, —OH, ═O, —O—C 1-5 alkyl, CF 3 , —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazolyl, and wherein each of —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-5 alkyl, —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazolyl is unsubstituted or further substituted by one or more substituents independently selected from —C 1-5 alkyl, —CF 3 , —OC 1-3 alkyl, phenyl, —C(O)—O—C 1-5 alkyl and halo;

Each R 4 is independently hydrogen, halo or —C 1-3 alkyl;

R 5 and R 6 are independently H, —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl, wherein each of —C 1-6 alkyl, —C 3-7 cycloalkyl and —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from F, —CH—F 2 , —CF 3 , —(CH 2 ) n —O—(CH 2 ) m —CH 3 , and —C 3-7 cycloalkyl;

R 7 and R 8 are independently H, —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl, wherein each of —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or more substituents independently selected from F, —CHF 2 , —CF 3 , and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

or R 7 and R 8 together with the carbon atoms to which they are attached form a 5-8-membered ring, which optionally includes one or more oxygen atoms or one or more nitrogen atoms as ring atoms, and wherein the 5-8-membered ring is unsubstituted or substituted by one or two substituents independently selected from —C 1-5 alkyl, —C 3-7 cycloalkyl, —C 4-7 heterocycloalkyl, F,

—CHF 2 , —CF 3 , ═O, and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

R 9 is H or —C 1-3 alkyl;

R 10 is —C 1-3 alkyl;

R 11 is aryl, triazolyl, pyridyl, pyridazinyl, imidazolyl, or pyrazolyl, optionally substituted by one or more substituents independently selected from —C 1-3 alkyl and halo;

R 12 and R 13 are independently —C 4-7 heterocycloalkyl, —C 1-3 alkyl or —C 3-7 cycloalkyl, wherein each of —C 4-7 heterocycloalkyl, —C 1-3 alkyl or —C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, —OH, ═O, —O—C 1-5 alkyl, —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazolyl, and wherein each of —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-3 alkyl, —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl is further optionally substituted by one or more substituents independently selected from —C 1-5 alkyl and halo;

R 14 is hydrogen or —C 1-3 alkyl;

R 15 is hydrogen or —C 1-3 alkyl;

Each X is CR 4 or N, provided only one X is N;

Each n is independently 0 or 1;

Each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen or —C 1-5 alkyl wherein —C 1-5 alkyl is unsubstituted or substituted by one or more substituents independently selected from —OH, —OC(O)—C 1-5 alkyl, —OC(O)-phenyl or —OC(O)—O—C 1-5 alkyl;

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 22

R 1 is —CF 3 , —C 3-7 cycloalkyl, wherein the —C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from triazolyl, pyridyl and halo, and wherein each of the triazolyl or pyridyl is unsubstituted or substituted by one or two substituents independently selected from phenyl, halo, —N(CH 3 ) 2 , —CF 3 , —OH, —C 1-7 alkyl optionally substituted with phenyl, —C 3-7 cycloalkyl optionally substituted with —C 1-3 alkyl, and —C 3-7 heterocylcoalkyl optionally further substituted with one or two substituents selected from

—C 1-3 alkyl and —C(O)—C 1-4 alkyl;

or R 1 is —C 2-3 alkyl-R 11 ;

R 2a is hydrogen or —C 1-3 alkyl;

R 2 is hydrogen, halo or —C 1-3 alkyl;

G is CH or N;

A is

R 3 is —(CH 2 ) n —C(O)NR 5 R 6 , —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 ), or

or R 3 is —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, or —O—C 3-7 cycloalkyl, wherein each of —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, and —O—C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, ═O, —O—C 1-5 alkyl, and —C 4-7 heterocycloalkyl, and wherein each of the —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-5 alkyl, and C 4-7 heterocycloalkyl, is further substituted by one or two substituents independently selected from —C 1-5 alkyl, CF 3 , O—C 1-3 alkyl, phenyl and halo;

Each R 4 is independently hydrogen, halo or —C 1-3 alkyl;

R 5 and R 6 are independently H, —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl, wherein each of —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or two substituents independently selected from F, —CH—F 2 , —CF 3 , —(CH 2 ) n —O—(CH 2 ) m —CH 3 , and —C 3-7 cycloalkyl;

or R 7 and R 8 together with the carbon atoms to which they are attached form a 5-8-membered ring, which optionally includes one or more oxygen or one or more nitrogen atoms as ring atoms, and wherein the 5-8-membered ring is unsubstituted or substituted by one or two substituents independently selected from —C 1-5 alkyl, —C 3-7 cycloalkyl, —C 4-7 heterocycloalkyl, F, —CHF 2 , —CF 3 , ═O, or —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

R 11 is aryl or triazolyl;

R 14 is hydrogen or —C 1-3 alkyl;

R 15 is hydrogen or —C 1-3 alkyl;

Each X is CR 4 or N provided only one X is N;

Each n is independently 0 or 1;

Each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 1 is —C 3-7 cycloalkyl, wherein the —C 3-7 cycloalkyl may be unsubstituted or substituted by one substituent selected from triazolyl, pyridyl or pyridazinyl, and wherein the, triazolyl, pyridyl, and pyridazinyl is optionally substituted by —C 1-3 alkyl;

R 2a is hydrogen or methyl;

R 2 is hydrogen or F;

G is CH or N;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ), —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 ), or

R 4 is independently hydrogen or F;

R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-8-membered ring, an 8-11-membered bicyclic ring or a 9-10-membered bridged bicyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one —S(O) 2 , one or more oxygen ring atoms or one or more nitrogen ring atoms, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from —C 1-5 alkyl, —C 3-7 cycloalkyl, —C 4-7 heterocycloalkyl, halogen, —CHF 2 , —CF 3 , and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

R 7 and R 8 are independently H, —C 1-6 alkyl or —C 3-7 cycloalkyl, wherein each of —C 1-6 alkyl, or —C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from substituted by F, —CHF 2 , —CF 3 , and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 22

R 14 is hydrogen;

R 15 is hydrogen;

X is CH;

n is independently 0 or 1;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 1 is cyclopropyl, wherein the cyclopropyl ring is unsubstituted or substituted by one substituent selected from halo, triazolyl, pyridyl, and pyridazinyl, and wherein the triazolyl, pyridyl, and pyridazinyl is unsubstituted or substituted by —C 1-3 alkyl;

R 2a is hydrogen;

R 2 is hydrogen;

G is CH;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ), —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 );

or R 3 is —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, or —O—C 3-7 cycloalkyl wherein each of —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, and —O—C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, ═O, —O—C 1-5 alkyl, and —C 4-7 heterocycloalkyl, and wherein each of the —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-5 alkyl, and C 4-7 heterocycloalkyl, is further substituted by one or two substituents independently selected from —C 1-5 alkyl, CF 3 , O—C 1-3 alkyl, phenyl and halo;

R 4 is independently hydrogen or F;

R 14 is hydrogen;

R 15 is hydrogen;

X is CH;

n is 0;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In still another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 1 is —CF 3 , —C 3-7 cycloalkyl, wherein —C 3-7 cycloalkyl is substituted by one or two substituents independently selected from triazolyl, pyridyl and halo, and wherein each of triazolyl or pyridyl is unsubstituted or substituted by one or two substituents independently selected from halo, phenyl, —N(CH 3 ) 2 , —CF 3 , —OH, —C 1-7 alkyl optionally substituted with phenyl, —C 3-7 cycloalkyl optionally substituted with —C 1-3 alkyl, and —C 3-7 heterocylcoalkyl optionally substituted with one or two substituents selected from —C 1-3 alkyl and —C(O)—C 1-4 alkyl;

R 2a is hydrogen or methyl;

R 2 is hydrogen, halo or —C 1-3 alkyl;

G is CH;

A is

R 3 is —(CH 2 ) n —C(O)NR 5 R 6 or

Each R 4 is independently hydrogen, halo or —C 1-3 alkyl;

R 5 and R 6 are independently —C 1-6 alkyl or —C 3-7 cycloalkyl, wherein each of —C 1-6 alkyl, —C 3-7 cycloalkyl is unsubstituted or substituted by one or more substituents selected from F, —CH—F 2 , —CF 3 , —(CH 2 ) n —O—(CH 2 ) m —CH 3 , and —C 3-7 cycloalkyl;

or R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-8-membered ring, wherein said 5-8-membered ring optionally includes one or more oxygen ring atoms or another nitrogen ring atom, and wherein said 5-8-membered ring is unsubstituted or substituted by —C 1-5 alkyl;

R 7 and R 8 are independently H, —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl, wherein each of —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or more substituents independently selected from F, —CHF 2 , —CF 3 , and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

—CHF 2 , —CF 3 , ═O, and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

X is CH;

n is 0;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 1 is —C 3-7 cycloalkyl, wherein the C 3-7 cycloalkyl is unsubstituted or substituted by one substituent selected from triazolyl, pyridyl and pyridazinyl, and wherein the triazolyl, pyridyl, or pyridazinyl is unsubstituted or substituted by —C 1-3 alkyl;

R 2 is hydrogen or F;

R 2a is hydrogen;

G is CH or N;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ); —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 ), or

or R 3 is —O—C 1-3 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, or, —O—C 3-7 cycloalkyl, wherein each of —O—C 1-3 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, or, —O—C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, ═O, —O—C 1-5 alkyl, and —C 4-7 heterocycloalkyl, and wherein each of the —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-3 alkyl, or —C 4-7 heterocycloalkyl is unsubstituted or further substituted by one or two substituents independently substituted by —C 1-5 alkyl, —CF 3 , —O—C 1-3 alkyl, phenyl or halo;

›DETAILED DESCRIPTION OF THE INVENTION · 7 of 22

Each R 4 is independently hydrogen or F;

R 7 and R 8 are independently H, —C 1-6 alkyl or —C 3-7 cycloalkyl wherein each of —C 1-6 alkyl or —C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from F, —CHF 2 , —CF 3 and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

or R 7 and R 8 together with the carbon atoms to which they are attached form a 5-8 membered ring, which optionally includes one or more oxygen atoms or one or more nitrogen atoms as ring atoms, and wherein the 5-8-membered ring is unsubstituted or substituted by one or two substituents independently selected from —C 1-5 alkyl, F, —CHF 2 and —CF 3 ;

R 14 is hydrogen;

R 15 is hydrogen;

Each X is CH;

Each n is independently 0 or 1;

Each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In still yet another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 1 is cyclopropyl, wherein the cyclopropyl is unsubstituted or substituted by one substituent selected from triazolyl, pyridyl, and pyridazinyl, and wherein the triazolyl, pyridyl, or pyridazinyl is unsubstituted or substituted by —C 1-3 alkyl;

R 2 is hydrogen;

R 2a is hydrogen;

G is CH;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ); —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 ), —(CH 2 ) n —S(O)NR 5 R 6 or

or R 3 is —O—C 1-3 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl or —O—C 3-7 cycloalkyl, wherein each of —O—C 1-3 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl or —O—C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, ═O, —O—C 1-5 alkyl, and —C 4-7 heterocycloalkyl, and wherein the —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-3 alkyl, or —C 4-7 heterocycloalkyl is unsubstituted or further substituted by one or two substituents independently selected from —C 1-5 alkyl, —CF 3 , —O—C 1-3 alkyl, phenyl and halo;

Each R 4 is independently hydrogen or F;

R 7 and R 8 are independently H, —C 1-6 alkyl or —C 3-7 cycloalkyl, wherein —C 1-6 alkyl or —C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents selected from F, —CHF 2 , —CF 3 , and

—(CH 2 ) n —O—(CH 2 ) m —CH 3 ; or

R 7 and R 8 together with the carbon atoms to which they are attached form a 5-8-membered ring, which optionally includes one or more oxygen or one or more nitrogen atoms as ring atoms, and wherein the 5-8-membered ring is unsubstituted or substituted by one or two substituents independently selected from —C 1-5 alkyl, F, —CHF 2 , or —CF 3 ;

R 14 is hydrogen;

R 15 is hydrogen;

Each X is CH;

n is 0;

Each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 2a is —CH 3 ;

R 2 is hydrogen;

G is CH;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ), —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 );

or R 3 is —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, or —O—C 3-7 cycloalkyl wherein each of —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, and —O—C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, ═O, —O—C 1-5 alkyl, and —C 4-7 heterocycloalkyl, and wherein each of the —C 3-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-5 alkyl, and C 4-7 heterocycloalkyl, is further substituted by one or two substituents independently selected from —C 1-5 alkyl, CF 3 , O—C 1-3 alkyl, phenyl and halo;

R 4 is independently hydrogen or F;

›DETAILED DESCRIPTION OF THE INVENTION · 8 of 22

R 14 is hydrogen;

R 15 is hydrogen;

X is CH;

n is 0;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 2a is hydrogen;

R 2 is halo;

G is CH;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ), —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 );

R 4 is independently hydrogen or F;

R 14 is hydrogen;

R 15 is hydrogen;

X is CH;

n is 0;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 2a is CH 3 ;

R 2 is —C 1-3 alkyl;

G is CH;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ), —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 );

R 4 is independently hydrogen or F;

R 14 is hydrogen;

R 15 is hydrogen;

X is CH;

n is 0;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 2a is —CH 3 ;

R 2 is halo;

G is CH;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ), —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 );

›DETAILED DESCRIPTION OF THE INVENTION · 9 of 22

R 4 is independently hydrogen or F;

R 14 is hydrogen;

R 15 is hydrogen;

X is CH;

n is 0;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 2a is hydrogen;

R 2 is —C 1-3 alkyl;

G is CH;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ), —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 );

R 4 is independently hydrogen or F;

R 14 is hydrogen;

R 15 is hydrogen;

X is CH;

n is 0;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the compound of Formula (I) is substituted as follows:

R is hydrogen;

R 1 is —CF 3 ;

R 2a is hydrogen or methyl;

R 2 is hydrogen or F;

G is CH or N;

A is

R 3 is —(CH 2 ) n —C(O)N(R 5 )(R 6 ), —(CH 2 ) n —C(R 14 )(R 15 )—N(R 5 )(R 6 ), or

R 4 is independently hydrogen or F;

›DETAILED DESCRIPTION OF THE INVENTION · 10 of 22

R 14 is hydrogen;

R 15 is hydrogen;

X is CH;

n is independently 0 or 1;

m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention is as follows:

A compound of Formula (Ia):

wherein:

R 1 is —CF 3 , —C 3-7 cycloalkyl, or C 4-7 heterocycloalkyl, wherein the —C 3-7 cycloalkyl, or —C 4-7 heterocycloalkyl may be unsubstituted or substituted by one or two substituents independently selected from C 1-3 alkyl, phenyl, triazolyl, pyridyl, pyridazinyl, imidazolyl, pyrazolyl, isoxazolyl, halo, —NR 9 —C(O)—R 10 and —C(O)R 10 , and wherein the phenyl, triazolyl, pyridyl, pyridazinyl, imidazolyl, pyrazolyl and isoxazolyl is unsubstituted or substituted by one or two substituents selected from —C 1-3 alkyl and halo;

or R 1 is C 2-3 alkyl-R 11 ;

R 2a is hydrogen, halo, or —C 1-3 alkyl;

R 2 is hydrogen, halo, —CN, —O—C 1-3 alkyl, —OH, or C 1-3 alkyl;

G is CH or N;

A is

R 3 is (CH 2 ) n —C(O)NR 5 R 6 , (CH 2 ) n —C(R 14 )(R 15 )—NR 5 R 6 ,

or R 3 is O—C 1-6 alkyl, C 1-6 alkyl, C 4-7 heterocycloalkyl, O—C 4-7 heterocycloalkyl, N—R 12 R 13 ,

C 3-7 cycloalkyl, O—C 3-7 cycloalkyl, S—C 1-3 alkyl, S—C 4-7 heterocycloalkyl, S—C 3-7 cycloalkyl, S(O)—C 1-3 alkyl, S(O)—C 4-7 heterocycloalkyl, S(O)—C 3-7 cycloalkyl, S(O) 2 —C 1-3 alkyl, S(O) 2 —C 4-7 heterocycloalkyl, S(O) 2 —C 3-7 cycloalkyl, all of which except for N—R 12 R 13 may be substituted by one or two substituents chosen from: C 1-7 alkyl, C 3-7 cycloalkyl, OH, ═O, —O—C 1-5 alkyl, CF 3 ;

C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl, and the C 1-7 alkyl, C 3-7 cycloalkyl, —O—C 1-3 alkyl, C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl may be further substituted by

C 1-5 alkyl, CF 3 , —OC 1-3 alkyl, phenyl, —C(O)—O—C 1-3 alkyl or halo;

Each R 4 is independently hydrogen, halo or C 1-3 alkyl;

R 5 and R 6 are independently H, C 1-6 alkyl, C 3-7 cycloalkyl or C 4-7 heterocycloalkyl, all of which may be substituted by F, CH—F 2 , CF 3 , (CH 2 ) n —O—(CH 2 ) m —CH 3 , or C 3-7 cycloalkyl;

or R 5 and R 6 together with the nitrogen atom can form a 5-8 member ring or a 8-11 member bicyclic ring or a 9 or 10-membered bridged bicyclic ring, all of which can optionally include oxygen or another nitrogen as ring atoms, and all of which may be substituted by one or two

C 1-5 alkyl, C 3-7 cycloalkyl, C 4-7 heterocycloalkyl, F, CHF 2 , CF 3 , or (CH 2 ) n —O—(CH 2 ) m —CH 3 ; or

R 5 and R 6 together with the nitrogen atom can form 4-azaspiro[2.5]octane, 7-azaspiro[4.5]decane, 2-oxa-8-azaspiro[5.5]undecane, 6-oxa-9-azaspiro[4.5]decane, 2-oxa-8-azaspiro[5.5]undecane, 1-azaspiro[4.5]decane, or 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine; 2,3,4,5-tetrahydro-1H-benzo[c]azepine;

R 7 and R 8 are independently H, C 1-6 alkyl, C 3-7 cycloalkyl or C 4-7 heterocycloalkyl, of which the C 1-6 alkyl, C 3-7 cycloalkyl or C 4-7 heterocycloalkyl may be substituted by F, CHF 2 , CF 3 ,

(CH 2 ) n —O—(CH 2 ) m —CH 3 ; or

R 7 and R 8 together together with the carbon atoms to which they are attached form a 5-8 member ring, which can optionally include oxygen or nitrogen as ring atoms, which may be substituted by one or two C 1-5 alkyl, C 3-7 cycloalkyl, C 4-7 heterocycloalkyl, F, CHF 2 , CF 3 , ═O, or (CH 2 ) n —O—(CH 2 ) m —CH 3 ;

R 9 is H or C 1-3 alkyl;

R 10 is C 1-3 alkyl;

R 11 is aryl, triazolyl, pyridyl, pyridazinyl, imidazolyl, or pyrazolyl, all of which may be substituted by C 1-3 alkyl or halo;

R 12 and R 13 are independently C 4-7 heterocycloalkyl, C 1-3 alkyl or C 3-7 cycloalkyl all of which may be substituted by one or two substituents chosen from: C 1-7 alkyl, C 3-7 cycloalkyl, OH, ═O, —O—C 1-5 alkyl, C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl, and the C 1-7 alkyl, C 3-7 cycloalkyl, —O—C 1-3 alkyl, C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl may be further substituted by C 1-5 alkyl or halo;

R 14 is hydrogen and C 1-3 alkyl;

R 15 is hydrogen and C 1-3 alkyl;

Each X is CR 4 or N provided only one X is N;

Each n is independently 0 or 1;

Each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention is as follows:

A compound of Formula (Ia):

wherein:

R 1 is —CF 3 , —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl, wherein the —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or two substituents selected from —C 1-3 alkyl, phenyl, triazolyl, pyridyl, pyridazinyl, imidazolyl, pyrazolyl, isoxazolyl, halo, —NR 9 —C(O)—R 10 and —C(O)R 10 , and wherein the phenyl, triazolyl, pyridyl, pyridazinyl, imidazolyl, pyrazolyl and isoxazolyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-3 alkyl and halo;

or R 1 is —C 2-3 alkyl-R 11 ;

R 2a is hydrogen, halo, or —C 1-3 alkyl;

R 2 is hydrogen, halo, —CN, —O—C 1-3 alkyl, —OH, or —C 1-3 alkyl;

G is CH or N;

A is

R 3 is —(CH 2 ) n —C(O)NR 5 R 6 , —(CH 2 ) n —C(R 14 )(R 15 )—NR 5 R 6 ,

or R 3 is —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, —N—R 12 R 13 , —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —S—C 1-3 alkyl, —S—C 4-7 heterocycloalkyl, —S—C 3-7 cycloalkyl, —S(O)—C 1-3 alkyl, —S(O)—C 4-7 heterocycloalkyl, —S(O)—C 3-7 cycloalkyl, —S(O) 2 —C 1-3 alkyl, —S(O) 2 —C 4-7 heterocycloalkyl, —S(O) 2 —C 3-7 cycloalkyl, wherein —O—C 1-6 alkyl, —C 1-6 alkyl, —C 4-7 heterocycloalkyl, —O—C 4-7 heterocycloalkyl, —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, —S—C 3-7 alkyl, —S—C 4-7 heterocycloalkyl, —S—C 3-7 cycloalkyl, —S(O)—C 1-3 alkyl, —S(O)—C 4-7 heterocycloalkyl, —S(O)—C 3-7 cycloalkyl, —S(O) 2 —C 1-3 alkyl, —S(O) 2 —C 4-7 heterocycloalkyl, —S(O) 2 —C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, —OH, ═O, —O—C 1-5 alkyl, —CF 3 , —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazolyl, and wherein the —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-3 alkyl, C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl is unsubstituted or further substituted by one or two substitutents selected from —C 1-5 alkyl, —CF 3 , —OC 1-3 alkyl, phenyl, —C(O)—O—C 1-5 alkyl and halo;

›DETAILED DESCRIPTION OF THE INVENTION · 11 of 22

Each R 4 is independently hydrogen, halo or —C 1-3 alkyl;

R 5 and R 6 are independently H, —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl, wherein each of —C 1-6 alkyl, —C 3-7 cycloalkyl or —C 4-7 heterocycloalkyl is unsubstituted or substituted by one or two substituents independently selected from F, —CH—F 2 , —CF 3 , —(CH 2 ) n —O—(CH 2 ) m —CH 3 , and —C 3-7 cycloalkyl;

or R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-8-membered ring or an 8-11-membered bicyclic ring or a 9-10-membered bridged bicyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one or more oxygen ring atoms or another nitrogen ring atom, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one or two substituents independently selected from —C 1-5 alkyl, F, —CHF 2 , —CF 3 , and —(CH 2 ) n —O—(CH 2 ) m —CH 3 ;

R 9 is H or —C 1-3 alkyl;

R 10 is —C 1-3 alkyl;

R 11 is aryl, triazolyl, pyridyl, pyridazinyl, imidazolyl or pyrazolyl, wherein each of aryl, triazolyl, pyridyl, pyridazinyl, imidazolyl or pyrazolyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-3 alkyl or halo;

R 12 and R 13 are independently —C 4-7 heterocycloalkyl, —C 1-3 alkyl or —C 3-7 cycloalkyl, wherein each of the —C 4-7 heterocycloalkyl, —C 1-3 alkyl or —C 3-7 cycloalkyl is unsubstituted or substituted by one or two substituents independently selected from —C 1-7 alkyl, —C 3-7 cycloalkyl, —OH, ═O,

—O—C 1-5 alkyl, —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazolyl, and wherein each of the —C 1-7 alkyl, —C 3-7 cycloalkyl, —O—C 1-5 alkyl, —C 4-7 heterocycloalkyl, phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazolyl is further optionally substituted by one or more substituents independently selected from —C 1-5 alkyl and halo;

R 14 is hydrogen and —C 1-3 alkyl;

R 15 is hydrogen and —C 1-3 alkyl;

Each X is CR 4 or N provided only one X is N;

Each n is independently 0 or 1;

Each m is independently 0 or 1;

or a pharmaceutically acceptable salt thereof.

It is to be understood that the present invention covers all combinations of the embodiments and particular groups described hereinabove.

Specific examples of compounds of the present invention include the following:

5-Cyclopentyl-1-{3-[3-(dimethylcarbamoyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid 1-{3-[3-(Dimethylcarbamoyl)-2-fluorophenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1-(3-{3-[Cyclopentyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{2-fluoro-3-[methyl(2-methylpropyl)carbamoyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 1-(3-{3-[Cyclohexyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[3-(3,3-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid 1-{3-[3-(azepane-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 1-(3-{3-[Bis(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid 1-{3-[3-(Azepane-1-carbonyl)phenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1-(3-{3-[(Cyclopentylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-[(cis)-3-Acetamidocyclopentyl]-1-{3-[2-fluoro-3-(propan-2-yloxy)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid (cis racemate) 1-(3-{3-[(Cyclopentylmethyl)(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 1-(3-{2-Chloro-3-[(cyclopropylmethyl)(propyl)carbamoyl]phenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-methylphenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{2-fluoro-3-[3-(trifluoromethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 1-[3-(3-{4-Azaspiro[2.5]octane-4-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[2-fluoro-3-(piperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{3-[(2R,6S)-2,6-dimethylpiperidine-1-carbonyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(methoxymethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(3,3,3-trifluoropropyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[3-(2,5-dimethylpyrrolidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid 1-{3-[3-(2-Propylpiperidine-1-carbonyl)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpyrrolidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[2-fluoro-3-(3-propylmorpholine-4-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(2-methylpropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[2-fluoro-3-(4-methylazepane-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[3-(2,5-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[3-(decahydroquinoline-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-cyclopropyl-1-[3-(2-fluoro-3-{3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic acid 1-{3-[3-(2-Cyclopentylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 1-[3-(3-{9-azabicyclo[3.3.1]nonane-9-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 1-[3-(3-{7-Azaspiro[4.5]decane-7-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{2-fluoro-3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(3,3,3-trifluoropropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-cyclopropyl-1-{3-[2-fluoro-3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-5-[2-(pyridin-3-yl)cyclopropyl]-1H-pyrazole-4-carboxylic acid 1-[3′-(2-Propyl-piperidine-1-carbonyl)-biphenyl-3-yl]-5-(2-pyridazin-3-yl-cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-[2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-[3-(2-fluoro-3-{2-oxa-8-azaspiro[5.5]undecane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic acid 5-cyclopropyl-1-[3-(2-fluoro-3-{6-oxa-9-azaspiro[4.5]decane-9-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic acid 5-cyclopropyl-1-(3-{2-fluoro-3-[(2S,5R)-2-methyl-5-propylmorpholine-4-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-(1-Acetylpiperidin-4-yl)-1-{3-[3-dimethylcarbamoyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid 1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 5-cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid 1-{3-[3-(dimethylcarbamoyl)phenyl]phenyl}-5-(3-phenylcyclobutyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic acid 5-[(1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 5-[(1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid 1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-5-[2-(pyridin-3-yl)cyclopropyl]-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-[3′-(3,5-dimethyl-piperidine-1-carbonyl)-2′-fluoro-biphenyl-3-yl]-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-{3-[2-fluoro-3-((2-S)-2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid (R)-1-(2′-Fluoro-3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (R)-5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)ethyl)-1-(3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-Isopropoxy-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3′-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-cyclopropyl-1-(3′-(4,5,6,7-tetrahydro-1H-indazol-1-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3′-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(6-(3-Isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 5-(2,2-Difluorocyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate, Sodium salt Barium 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate hydroxide Calcium 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate hydroxide 1-(3′-((S)-1-Cyclohexylethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexylmethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((R)-1-Cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-ethyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1-Cyclobutyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1-(1-(tert-Butoxycarbonyl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-( 1 -(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1-Cyclohexyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1-(Azetidin-3-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1-Benzyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-isopropyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-phenyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1H-1,2,3-Triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-(1-methylazetidin-3-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1S,2S)-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-((1R,2R)-2-(1H-1,2,3-Triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1S,2S)-2-(1H-1,2,3-Triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(cis-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(3-hydroxypropyl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-cyclohexylethoxy)-2′-fluoro-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid Ethyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate 2-Oxotetrahydrofuran-3-yl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate 2-Hydroxyethyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate 2-Morpholinoethyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (Pivaloyloxy)methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate Acetoxymethyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (Benzoyloxy)methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate ((tert-Butoxycarbonyl)oxy)methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate rac-1-(3′-((E)-2-Cyclohexylvinyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid rac-1-(3′-(2-Cyclohexylethyl)-[1,1′-biphenyl]-3-yl)-5-(-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(3-methylisoxazol-5-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((R) or (S)-2-Cyclohexylpropyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((R) or (S)-2-Cyclohexylpropyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(2′-fluoro-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(3-methylisoxazol-5-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid Methyl 1-(3′-((3-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate 1-(3′-(((S)-3-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-3-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((S)-5-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 2) 1-(3′-(((S)-5-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 1) 1-(3′-((5-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((S)-5-Ethyl-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 1) 1-(3′-(((R)-5-Ethyl-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 2) 1-(3′-((4,4-dimethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((1-Ethyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-isopropyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-4-Methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((S)-8-Bromo-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-2′-fluoro-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((S)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((S)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((S)-8-bromo-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 1) 1-(3′-(((R)-8-bromo-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 2) 1-(3′-(((S)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((5-Ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)sulfonyl)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((2-propylpiperidin-1-yl)sulfonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-(piperidin-1-ylsulfonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((tetrahydro-2H-thiopyran-3-yl)methoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((4,4-Difluorocyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((3-(trifluoromethyl)cyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((2-(trifluoromethyl)cyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((tetrahydro-2H-thiopyran-4-yl)methoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-((4-Ethylcyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexylmethoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexylmethoxy)-2′-fluoro-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3′-(4-(1-methyl-1H-1,2,3-triazol-4-yl)butoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(5-methyl-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1R,2R)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(5-methyl-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid (isomer 1) 5-((1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(5-methyl-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid (isomer 2) 1-(3′-(1-Cyclohexyl-2,2,2-trifluoroethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(dimethylcarbamoyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-ethyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(2-(5-Methylisoxazol-4-yl)cyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(5-Chloro-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) 1-(3′-((1-Cyclohexylpropan-2-yl)oxy)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 1-(3′-((R)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexylmethoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(tert-Butoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((1-(tert-Butoxycarbonyl)piperid in-4-yl)methoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-Cyclohexyl-4-methoxybutoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((tetrahydro-2H-pyran-3-yl)methoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexylmethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2-Cyclohexylpentyl)oxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-Cyclohexylpropoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((tetrahydro-2H-pyran-4-yl)methoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((tetrahydro-2H-pyran-2-yl)methoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((1R,4S)-4-Methoxycyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2-Methoxycyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((3-Methoxycyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((Cyclohexylmethyl)thio)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((R)-1-((1R,4R)-4-(trifluoromethyl)cyclohexyl)ethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′-isopropoxy-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Ethoxy-2-methylpropyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclopentyl(methoxy)methyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Methoxy-2-methylpropyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((4-Chlorocyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2-chlorocyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((3-chlorocyclohexyl)methoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(cyclohexylmethoxy)-[1,1′-biphenyl]-3-yl)-3-methyl-5-((1,2-trans)-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(5-cyano-3′-(cyclohexylmethoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(cyclohexylmethoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-imidazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-ethyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-cyclohexylethoxy)-5-methoxy-[1,1′-biphenyl]-3-yl)-5-((1S,2S)-2-(1-ethyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-cyclohexylethoxy)-5-methoxy-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-ethyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-isopropyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(6-(3-((R)-2-propylpiperidine-1-carbonyl)phenyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3-(5-((R)-2-propylpiperidine-1-carbonyl)pyridin-3-yl)phenyl)-1H-pyrazole-4-carboxylic acid 1-(3′-Fluoro-5′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Isopropyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Ethyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 3-Methyl-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid (R)-5-Cyclopropyl-3-methyl-1-(3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(6-(3-(6,6-Dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3′-(6-methyl-6-propyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-(6-Butyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3′-(6-cyclopropyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-(6,6-Dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-5-((1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3′-(5-ethyl-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3′-(5-methyl-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-Cyclopropyl-1-(3′-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-(6,6-Dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-pyrazol-4-yl)cyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-Cyclohexylacetyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-Cyclohexyl-1-methoxyethyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-Cyclohexyl-1-hydroxyethyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((1-Cyclohexylpropan-2-yl)oxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexyl(hydroxy)methyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Benzyloxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2-Fluorobenzyl)oxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((4-Fluorobenzyl)oxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((3-Fluorobenzyl)oxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(3,3-Dimethylbutoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-(neopentyloxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Cyclopentylethoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexyloxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Cyclopropylethoxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((1-(tert-Butoxycarbonyl)piperidin-3-yl)oxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-Cyclohexylethyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′-((tetrahydro-2H-pyran-4-yl)oxy)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-(1-phenylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-((1,2-trans)-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-(pyrimidin-5-ylmethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(3′-([1,1′-Biphenyl]-4-ylmethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-([1,1′-Biphenyl]-3-ylmethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-([1,1′-Biphenyl]-3-yl)ethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-([1,1′-Biphenyl]-4-yl)ethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(4′-(1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(1-Cyclohexylpropoxy)-[1,1′-biphenyl]-3-yl)-5-((1,2-trans)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexanecarbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(Cyclohexyl(methoxy)methyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3-(5-(Cyclohexylmethoxy)pyridin-3-yl)phenyl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-(piperid in-1-ylmethyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 5-(trans-2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid 1-(6-(3-(1-Cyclohexylethoxy)phenyl)pyridin-2-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(6,6-Dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 1-(6-(3-(6,6-Dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)phenyl)pyridin-2-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((4-Ethyl-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2,2-Dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2,3-Dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((R)-2-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-4-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(trans-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′-(piperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′-(3,3-dimethylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′-(azepane-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2R,6S)-2,6-Dimethylpiperidine-1-carbonyl)-2′-fluoro-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((2R,6S)-2,6-dimethylpiperidine-1-carbonyl)-2′-fluoro-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(3,5-Dimethylpiperidine-1-carbonyl)-2′-fluoro-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-(2-(Methoxymethyl)piperidine-1-carbonyl)-2′-fluoro-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((Cyclopropylmethyl)carbamoyl)-2′-fluoro-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(2′-Fluoro-3′(isobutyl(methyl)carbamoyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((S)-2-(Ethoxymethyl)pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((R)-2-(Ethoxymethyl)pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid 1-(3′-((R)-2-(Ethoxymethyl)pyrrolidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid

›DETAILED DESCRIPTION OF THE INVENTION · 12 of 22

In one embodiment, the invention is directed to compounds which are as follows.

1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid. 1-(3′-((S)-1-Cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid. 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid. 1-(3′-(((S)-5-Ethyl-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 1). 1-(3′-(((R)-5-Ethyl-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 2). 1-(3′-(2-Cyclohexylethyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid. 5-[(1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid. 1-(3′-(((R)-8-bromo-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (isomer 2). 1-(3′-(6,6-Dimethyl-5,6-dihydrocyclopenta[c]pyrazol-(4H)-yl)-[1,1′-biphenyl]-3-yl)-5-((1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid.

Compound Preparation

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

The synthesis of the compounds of the general Formula (I) and pharmaceutically acceptable derivatives and salts thereof may be accomplished as outlined below in Schemes 1-12. In the following description, the groups are as defined above for compounds of Formula (I) unless otherwise indicated. Abbreviations are as defined in the Examples section. Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art.

An appropriately substituted ethyl 3-oxyester (1) is stirred with a N,N-dimethylamide acetal at room temperature to provide a dimethylamino-methylene-oxoester intermediate (2). The ethyl 2-((dimethylamino)methylene)-3-oxoester (2) in an alcohol solvent, preferably ethanol is treated with the appropriately substituted bromo-aryl hydrazine (3) along with an amine base such as triethylamine or diisopropylethylamine, to provide the pyrazole intermediate (4). The pyrazole (4) in dioxane is treated with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5) in the presence of a palladium catalyst such as PdCl 2 dppf and potassium acetate to give the boronic ester (6).

An appropriately substituted ethyl 3-oxyester (1) is treated with an alkyl acid chloride in methylene chloride along with MgCl 2 and pyridine to give intermediate (2A). The intermediate (2A) in acetic acid and water is treated with the appropriately substituted bromo-aryl hydrazine (3) to provide the pyrazole intermediate (4). The pyrazole (4) in dioxane is treated with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5) in the presence of a palladium catalyst such as PdCl 2 dppf and potassium acetate to give the boronic ester (6).

The substituted boronobenzoic acid (7) is dissolved in an appropriate solvent such as DCM, DMF or a mixture of DCM and DMF, and treated with a substituted amine (8) in the presence of a coupling agent like HATU or EDC and an amine base such as triethylamine, or diisopropylethylamine, to provide the boronobenzoic amide (9). The boronobenzoic amide (9) and the pyrazole bromide (4) is dissolved in a mixture of dioxane and water with an inorganic base, such as K 2 CO 3 , and treated with a catalytic amount of a palladium catalyst, such as PdCl 2 dppf, to give the pyrazole amide ethyl ester (10). Base hydrolysis of the ethyl ester (10) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol such as methanol or ethanol and water provides the pyrazole amide acid (11).

The substituted bromobenzoic acid (12) is dissolved in an appropriate solvent such as DCM, DMF or a mixture of DCM and DMF, and treated with a substituted amine (8) in the presence of a coupling agent like HATU or EDC and an amine base such as triethylamine or diisopropylethylamine, to provide the bromobenzoic amide (13). The bromobenzoic amide (13) and pyrazole boronic ester (6) is dissolved in a mixture of dioxane and water with an inorganic base, such as K 2 CO 3 , and treated with a catalytic amount of a palladium catalyst, such as PdCl 2 dppf, to give the pyrazole amide ethyl ester (10). Base hydrolysis of the ethyl ester (10) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole amide acid (11).

The bromophenyl alcohol (14) and an alkyl, cycloalkyl or heterocycloalkyl primary or secondary alcohol (15) is dissolved in an ethereal solvent like THF and treated with a diazodicarboxylate, such as DEAD or DIAD, in the presence of a trisubstituted phosphine, such as triphenylphosphine or tributylphosphine, to give the bromophenyl ether (16). The bromophenyl ether (16) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the pyrazole ether ethyl ester (17). Base hydrolysis of the ethyl ester (17) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole ether acid (18).

›DETAILED DESCRIPTION OF THE INVENTION · 13 of 22

The bromophenyl alcohol (14) and an alkyl, cycloalkyl or heterocycloalkyl chloride, bromide, iodide or mesylate (19) is dissolved in an appropriate solvent, such as DMF, THF or dioxane and treated with a base, such as NaH to give the bromophenyl ether (16). The bromophenyl ether (16) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the pyrazole ether ethyl ester (17). Base hydrolysis of the ethyl ester (17) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole ether acid (18).

The bromophenyl aldehyde (20) is dissolved in an ethereal solvent such as diethyl ether or THF and treated with an alkyl, cycloalkyl, heterocycloalkyl or triazolyl Grignard reagent (21) to give the bromophenyl alcohol (22). The bromophenyl alcohol (22) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf to give the pyrazole alcohol ethyl ester (23). Base hydrolysis of the ethyl ester (23) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole alcohol acid (24).

The bromophenyl alcohol (22) is oxidized to the corresponding bromophenyl ketone (25) using an appropriate oxidizing agent such as pyridium chlorochromate or pyridium dichromate in CH 2 Cl 2 . The bromophenyl ketone (25) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf to give the pyrazole ketone ethyl ester (26). Base hydrolysis of the ethyl ester (26) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole ketone acid (27).

The bromophenyl alcohol (22) is dissolved in THF, dioxane or DMF and treated with an alkyl chloride, bromide, iodide or mesylate (28) to provide the bromophenyl ether (29). The bromophenyl ether (29) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the pyrazole ether ethyl ester (30). Base hydrolysis of the ethyl ester (30) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole ether acid (31).

The bromophenyl hydrazine (32) is treated with di-tert-butyl dicarbonate in an appropriate solvent such as DCM, dioxane or t-butanol with a base such as triethyl amide or diisopropylethyl amine to give the protected bromophenyl hydrazine (34). The protected bromophenyl hydrazine (34) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the protected hydrazine pyrazole ethyl ester (35). The protected hydrazine pyrazole methyl ester (34) is treated under acidic conditions such as HCl in dioxane or TFA in CH 2 Cl 2 to give the hydrazine pyrazole ethyl ester (35). The ketone (36) is heated with 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine to give the dimethylamino ketone as a mixture of isomers (37). The hydrazine pyrazole ethyl ester (35) is heated with the dimethylamino ketone (37) in acidic acid to give the pyrazole pyrazole ester (38). Base hydrolysis of the ethyl ester (38) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole pyrazole acid (39).

The substituted bromobenzoic acid (12) is treated with CDI in THF followed by heating with t-butyl carbazate to give the Boc-protected bromobenzoylhydrazine carboxylate (40). The Boc-protected bromobenzoylhydrazine carboxylate (40) is treated with acid in an appropriate solvent such as HCl in dioxane or TFA in CH 2 Cl 2 to give the bromobenzoylhydrazine carboxylate (41). The bromobenzoylhydrazine carboxylate (41) is they heated with the appropriate orthoester to give the bromophenyl-1, 3, 4-oxadiazole (42). The bromophenyl-1, 3, 4-oxadiazole (42) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the pyrazole 1, 3, 4-oxadiazole ethyl ester (43). Base hydrolysis of the ethyl ester (43) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole 1, 3, 4-oxadiazole acid (44).

The substituted bromophenyl nitrile (45) in an alcohol solvent like methanol or ethanol is heated with hydroxylamine-hydrochloride in the presence of an inorganic base such as NaHCO 3 to give the bromo-N′-hydroxybenzimidamide (46). The bromo-N′-hydroxybenzimidamide (46) is dissolved in DMF along with an alkylcarboxylic acid such as acetic acid or propionic acid in the presence of CDI to give the bromophenyl-1,2,4-oxadiazole (47). The bromophenyl-1,2,4-oxadiazole (46) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the pyrazole 1,2,4-oxadiazole ethyl ester (48). Base hydrolysis of the ethyl ester (48) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole 1,2,4-oxadiazole acid (49).

The substituted bromophenyl nitrile (45) in DMF is heated with NaN3 and NH4Cl followed by aqueous HCl to give the bromophenyl tetrazole (50). The bromophenyl tetrazole (50) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the pyrazole tetrazole ethyl ester (51). Base hydrolysis of the ethyl ester (51) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole tetrazole acid (52).

›DETAILED DESCRIPTION OF THE INVENTION · 14 of 22

The pyrazole tetrazole ethyl ester (51) is dissolved in an appropriate solvent like THF, dioxane or DMF, with an alkyl bromide, iodide or mesylate in the presence of a base such as NaH to give the pyrazole alkyl tetrazole ethyl ester (53). Base hydrolysis of the ethyl ester (53) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole alkyl tetrazole acid (54).

The aldehyde (20) in acetic acid is treated with a 1,2-dicarbonyl containing compound and ammonium acetate to provide the imidazole (55). The imidazole (55) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the imidazole-pyrazole ester (56). Base hydrolysis of the ester (56) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the imidazole-pyrazole acid (57).

The hydrazine pyrazole ethyl ester (35) in THF is treated with a substituted N-(tosyloxy)imidamide (58) and ethanesulfonic acid in THF to give the triazole-pyrazole ester (59). Base hydrolysis of the triazole-pyrazole ester (59) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the triazole-pyrazole acid (60).

The appropriately substituted (3-bromophenyl)methanol (61) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the hydroxymethyl intermediate (62). The hydroxymethyl intermediate (62) is dissolved in dichloromethane and treated with thionylchloride at room temperature to give the corresponding chloride (63). The chloride (63) is added to a mixture of NHR 5 R 6 (8), K 2 CO 3 and NaI in DMF and the resulting reaction stirred at room temperature to provide ester (64). Base hydrolysis of the ester (64) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole acid (65).

The appropriately substituted (3-bromophenyl)methanol (61) is dissolved in a mixture of dioxane and water and treated with the pyrazole boronic ester (6) in the presence of an inorganic base, such as K 2 CO 3 and a palladium catalyst such as PdCl 2 dppf, to give the hydroxymethyl intermediate (62). The hydroxymethyl intermediate (62) is dissolved in dichloromethane and treated with thionylchloride at room temperature to give the corresponding chloride (63). The chloride (63) is added to a mixture of NHR 5 R 6 (8), NaH and NaI in DMF and the resulting reaction stirred at room temperature to provide the ester (64). Base hydrolysis of the ester (64) with an inorganic base such as LiOH or NaOH in a mixture of an alcohol, such as methanol or ethanol, and water provides the pyrazole acid (65).

Biological Activity

As stated above, the compounds according to Formula I are NRF2 regulators, and are useful in the treatment or prevention of human diseases that exhibit oxidative stress components such as respiratory and non-respiratory disorders, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, acute kidney injury (AKI), kidney disease or malfunction seen during kidney transplantation, Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodelling, cardiac arrhythmias, Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or other inflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topical effects of radiation, immunosuppression due to radiation exposure, Preeclampsia, and high altitude sickness.

The biological activity of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a NRF2 antagonist, as well as tissue and in vivo models.

The biological activity of the compounds of Formula (I) are demonstrated by the following tests.

BEAS-2B NQO1 MTT Assay

NAD(P)H:quinone oxidoreductase 1 (NQO1), also called DT diaphorase, is a homodimeric FAD-containing enzyme that catalyzes obligatory NAD(P)H-dependent two-electron reductions of quinones and protects cells against the toxic and neoplastic effects of free radicals and reactive oxygen species arising from one-electron reductions. The transcription of NQO1 is finely regulated by NRF2, and thus NQO1 activity is a good marker for NRF2 activation. On day one, frozen BEAS-2B cells (ATCC) are thawed in a water bath, counted, and re-suspended at a concentration of 250,000 cells/mL. Fifty microliters of cells are plated in 384 well black clear-bottomed plates. Plates are incubated at 37° C., 5% CO 2 overnight. On day two, plates are centrifuged and 50 nL of compound or controls are added to the cells. Plates are then incubated at 37° C., 5% CO 2 for 48 hours. On day four, medium is aspirated from the plate and crude cell lysates are made by adding 13 uL of 1× Cell Signaling Technologies lysis buffer with 1 Complete, Mini, EDTA-free Protease Inhibitor Tablet (Roche) for each 10 mL of lysis buffer. After lysis plates are incubated for 20 minutes at room temperature. Two microliters of lysate are removed for use in Cell Titer Glo assay (Promega) and MTT cocktail is prepared (Prochaska et. al. 1998) for measurement of NQO1 activity. Fifty microliters of MTT cocktail is added to each well, plate is centrifuged, and analyzed on an Envision plate reader (Perkin Elmer) using Absorbance 570 nm label for 30 minutes. Product formation is measured kinetically and the pEC 50 of NQO1 specific activity induction is calculated by plotting the change in absorbance (Delta OD/min) versus the log of compound concentration followed by 3-parameter fitting.

›DETAILED DESCRIPTION OF THE INVENTION · 15 of 22

pEC 50 is the negative log of the EC 50 .

All examples described herein possessed NQO1 specific enzyme activity in BEAS-2B cells with EC 50 s between >10 μM-<1 nM unless otherwise noted (see table below). EC 50 s<1 nM (+++++), EC 50 s 10 nM-1 nM (++++), EC 50 s 10-100 nM (+++), EC 50 s 100 nM-1 μM (++), EC 50 s 1-10 μM (+), EC 50 s>10 μM (−), or were not determined (ND).

All examples described herein possessed NQO1 specific enzyme activity in BEAS-2B cells with EC 50 s between >10 uM-<10 nM unless otherwise noted (see table below).

Ex # EC 50 1 + *2 + 3 + 4 + 5 + 6 + 7 + 8 ++ 9 + 10 + 11 + 12 + *13 + 14 ++ 15 + 16 + 17 ++ 18 + 19 + 20 + 21 ++ 22 + 23 + 24 + 25 + 26 + 27 + 28 ++ 29 ++ 30 ++ 31 ++ 32 + 33 ++ 34 ++ 35 ++ 36 + 37, 54d ++ 38 ++ 39 + 40 + 41 + 42 ++ 43 + 44 + 45 ++ 46 + 47 + 48 + 49 + *50 + *51g + 51h +++ 52 + 53 ++ 54e ++ *55 + *56 + 57 +++ *58 + 59 + *60 + *61 ++ 62 ++ 63 ++ # 64 +++ 65 ++ *66 + 67 ++ 68 ++++ 69 +++++ 70 +++++ *71 + 72 +++ 73 ++++ 74 +++ 75 ++++ 76 ++++ 77 +++ 78 ++++ 79 ++++ 80 +++ 81 +++ 82 +++ 83 ++++ 84 +++ 85 ++ 86 ++ 87 +++ 88 +++ 89 ++++ 90 +++ 91 ++++ 92 ++++ 93 ++++ 94 +++ 95 ++++ 96 ++ 97 ++++ 98 ++++ 99 ++++ 100 ++ 101 ++ 102 ++ 103 ++ 104 +++ 105 +++++ 106 ++ 107 ++ 108 +++ 109 ++++ 110 +++++ 111 ++++ 112 ++++ 113 +++ 114 +++ 115 ++ 116e ++++ 116f ++++ 117 +++ 118 ++ 119 ++ 120 +++ 121 +++ 122 +++ 123 +++ 124 +++ 125 ++++ 126 ++ 127 ++ 128 ++ 129 ++ 130 ++ 131 ++ 132 ++ 133 + 134 ++ 135 +++ 136 ++ 137 +++ 138 + 139 + 140 + 141 ++ 142 ++ 143 ++ 144 +++ 145 ++ 146 +++ 147 +++ 148 +++ 149 ++ 150 +++ 151 + 152 +++ *153 + 154 ++ 155 ++ 156 ++ 157 +++ *158 + 159 ++ 160 ++ *161 ++ 162 +++ 163 +++ 164 +++ 165 ++++ 166 ++ 167 ++ 168 +++ 169 + 170 ++ 171 +++ 172 ++ 173 +++ 174 + 175 + 176 ++ 177 ++ 178 ++ 179 ++++ 180 ++++ 181 + 182 ++ 183 ++ 184 ++ 185 +++ 186 +++ 187 +++ 188 ++ *189 + 190 + 191 ++ 192 ++++ 193 ++ 194 ++ 195 +++ 196 ++ 197 + 198 ++ 199 +++ 200 ++ 201 ++ 202 ++ 203 + 204 ++ 205 ++ *206 ++ 207 + 208 +++ *209 + *210 ++ *211 + 212 ++ 213 ++ 214 ++ 215 ++ 216 +++ 217 ++ 218 +++ 219 +++ 220 + 221 ++ 222 ++ 223 ++ 224 ++ 225 +++ 226 +++ 227 ++ 228 ++++ 229 +++ 230 ++++ 231 ++ 232 ++ 233 ++++ 234 + 235 ++ 236 + 237 ++ 238 ++ 239 ++ 240 ++ *241 + 242 +++ 243 ++ 244 ++ 245 +++ 246 + 247 + 248 + 249 ++++ 250 ++ 251 ++ 252 ++ 253 ++ *254 ++ ϕ255 ++ *256 + *257 + 258 ++ 259 ++ 260 ++ 261 +++ 262 +++ 263 ++ 264 ++ 265 + 266 ++ 267 ++ 268 ++ 269 + *in some determinations EC 50 values were >10 μM # in some determinations EC 50 values were <170 pM *in some determinations EC 50 values were >10 μM ϕin two determinations for Example 255 resulted in EC 50 >1 μM

NRF2-Keap1 FP Assay

One model for the NRF2-Keap1 interaction is through two binding sites in the Neh2 domain on NRF2. The two sites are referred to as the DLG binding motif (latch domain, uM affinity) and the ETGE binding motif (hinge domain, nM affinity). The Keap1 protein consists of an N-terminal region (NTR), a broad complex, tramtrack, and brick a′ brac domain (BTB), an intervening region (IVR), a double glycine repeat domain (DGR or Kelch), and a C-terminal region. The DLG and ETGE motifs of NRF2's Neh2 domain bind to the Kelch domain of Keap1 at different affinities. In the Keap1 Kelch fluorescence polarization (FP) assay, a TAMRA-labeled 16mer peptide (AFFAQLQLDEETGEFL) containing the ETGE motif of NRF2 and the Kelch domain (321-609) of Keap1 is used. The assay determines if a compound interferes with the binding between Keap1 (361-609) and the TAMRA-labeled peptide. Binding of TAMRA-labeled NRF2 peptide to Keap1 (321-609) results in a high FP signal. If a compound interferes with the binding between the peptide and the protein, it will cause the assay signal to decrease. Thus, assay signal is inversely proportional to binding inhibition.

FP Assay

100 nl of 100× compound dose response curves (serial 3-fold dilutions) in DMSO are stamped using an Echo liquid handling system (Labcyte) into 384-well low volume black assay plates (Greiner, #784076), with DMSO in columns 6 and 18. The top concentration of compound is located in columns 1 and 13. Keap1 (321-609) is diluted to 40 nM (2×) in 1× assay buffer (50 mM Tris, pH 8.0, 100 mM NaCl, 5 mM MgCl 2 , 1 mM DTT, 2 mM CHAPS, and 0.005% BSA) and 5 ul is added using a Multidrop Combi (Thermo Electron Corporation) equipped with a metal tip dispenser to all wells of the compound plate, except column 18. Column 18 receives only 5 ul of assay buffer. Immediately, 5 uL of 16 nM (2×) of Tamra labeled peptide (AFFAQLQLDEETGEFL, 21 st Century Biochemicals) is added to all wells of the plate. The plates are spun at 500 rpm for 1 min, incubated for 1 hr at room temperature, and read on an Analyst GT (Molecular Devices) equipped with excitation (530/25 nm) and emission (580/10 nm) filters designed for Tamra probes. A 561 nm dichroic mirror is also used in the Analyst. The final assay concentrations of Keap1 (321-609) and Tamra labeled peptide are 20 nM and 8 nM, respectively. Fluorescence measurements, represented as mP, are used in the transformation of the data. Compound activity is calculated based on percent inhibition, normalized against controls in the assay (Control 1 contains the Tamra peptide and Keap1 (321-609) together (0% response) and control 2 contains the Tamra peptide alone (100% response)). Data analysis is handled using the software package Abase XE (Surrey, United Kingdom. The % inhibition values are calculated by the equation:

100−(100*((compound response−average control 2)/(average control 1−average control2))).

For calculation of pIC 50 s, Abase XE uses a four parameter equation. pIC 50 is the negative log of the IC 50 .

All examples described herein possessed activity in the Keap1/Nrf2 FP assay as listed (see table below) unless otherwise noted. IC 50 s<1 nM (+++++), IC 50 s 1 nM-10 nM (++++), IC 50 s 10-100 nM (+++), IC 50 s 100 nM-1 mM (++), IC 50 s 1-10 mM (+), IC 50 s>10 mM (−), or were not determined (ND).

›DETAILED DESCRIPTION OF THE INVENTION · 16 of 22

Ex # IC 50 1 ++ 2 ++ 3 ++ 4 ++ 5 ++ 6 +++ 7 +++ 8 +++ 9 +++ 10 ++ 11 + 12 +++ 13 + 14 +++ 15 ++ 16 ++ 17 +++ 18 ++ 19 ++ 20 ++ 21 +++ 22 +++ 23 ++ 24 ++ 24 ++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 +++ 31 ++ 32 ++ 33 +++ 34 +++ 35 +++ 36 ++ 37, 54d +++ 38 +++ 39 ++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 + 47 ++ 48 ++ 49 ++ 50 + 51g ++ 51g ++ 51h +++ 52 ++ 53 +++ 54e ++ 55 +++ 56 +++ 57 +++ 58 +++ 59 ++ 60 + 61 ++ 62 ++ 63 ++ 64 +++ 65 +++ 66 + 67 +++ 68 +++ 69 ++++ 70 +++ 71 + 72 ++ 73 +++ 74 +++ 75 +++ 76 +++ 77 +++ 77 +++ 78 +++ 79 +++ 80 ++ 81 ++ 82 +++ 83 +++ 84 ++ 85 +++ 86 +++ 87 ++ 88 +++ 89 +++ 90 +++ 91 +++ 92 +++ 93 +++ 94 +++ 95 +++ 96 + *97 +++ 98 +++ 99 +++ 100 + *101 − 102 + 103 + 104 +++ 104 +++ *105 − 106 − *107 − *108 − 109 − 110 ++ 111 − 112 − 113 ++ 114 ++ 115 ++ 116e +++ 116f +++ 117 +++ 118 +++ 119 +++ 120 +++ 121 ++++ 122 +++ 123 +++ 124 +++ 125 +++ 126 ++ 127 +++ 128 +++ 129 +++ 130 +++ 130 +++ 131 +++ 132 +++ 133 ++ 134 +++ 135 +++ 136 +++ 137 +++ 138 +++ 139 +++ 140 +++ 141 +++ 142 +++ 143 +++ 144 +++ 145 +++ 146 +++ 147 ++ 148 +++ 149 ++ 150 ++ 151 + 152 +++ 153 + 154 +++ 155 +++ 156 ++ 157 ++ 158 ++ 159 +++ 160 +++ 161 + 162 ++ 163 ++ 164 +++ 165 +++ 166 +++ 167 +++ 168 +++ 169 ++ 170 +++ 171 +++ 172 ++ 173 +++ 174 +++ 175 +++ 176 +++ 177 ++ 178 +++ 179 +++ 180 ++ 181 ++ 182 +++ 183 +++ 184 +++ 185 ++ 186 ++ 187 ++ 188 ++ 189 − 190 + 191 ++ 192 +++ 193 ++ 194 ++ 195 ++ 196 +++ 197 +++ 198 +++ 199 +++ 200 +++ 201 +++ 202 +++ 203 + 204 ++ 205 ++ 206 ++ 207 ++ 208 +++ 209 + 210 − 211 − 212 +++ 213 +++ 214 +++ 215 +++ 216 +++ 217 ++ 218 +++ 219 +++ 220 +++ 221 ++ 222 +++ 223 ++ 224 ++ 225 +++ 226 ++ 227 +++ 228 +++ 229 +++ 230 +++ 231 +++ 232 ++ 233 ++ 234 +++ 235 +++ 236 ++ 237 ++ 238 ++ 239 ++ 240 ++ 241 − 242 +++ 243 +++ 244 +++ 245 +++ 246 ++ 247 ++ 248 ++ 249 +++ 250 ++ 251 +++ 252 +++ 253 +++ 254 +++ 255 +++ 256 +++ 257 +++ 258 +++ 259 +++ 260 +++ 261 +++ 262 +++ 263 +++ 264 +++ 265 +++ 266 +++ 267 +++ 268 +++ 269 ++ *in some determinations IC 50 values were >100 μM

NRF2-Keap1 TR-FRET Assay

In the NRF2-Keap1 TR-FRET (time-resolved fluorescence resonance energy transfer) assay, full length NRF2 protein and full length Keap1 protein (Keap1 exists a dimer) are used. The assay detects the ability of compound to displace the binding of FlagHis-tagged Keap1 with biotinylated, Avi-tagged NRF2 protein. Biotin-NRF2 binds to streptavidin-europium (a component of the detection mix) and Keap1-FlagHis is recognized by anti-Flag APC (allophycocyanin) antibody (also a component of the detection mix). If binding occurs between the two proteins, there will be an energy transfer from the Eu+3 (donor) at 615 nm to the APC (acceptor) at 665 nm. A potential Keap1 inhibitor will cause a reduction in the TR-FRET signal by interfering with the binding of Keap1 to NRF2.

One hundred nanoliters of 100× compound dose response curves (serial 3-fold dilutions) in DMSO are stamped using an Echo liquid handling system (Labcyte) into 384-well, low volume, black assay plates (Greiner, #784076), with DMSO in columns 6 and 18. The top concentration of compound is located in columns 1 and 13. All reagents are diluted in assay buffer (50 mM Tris, pH 8.0, 5 mM MgCl2, 100 mM NaCl, 0.005% BSA, 1 mM DTT, and 2 mM CHAPS). The BSA, DTT, and CHAPS are added to the assay buffer on the day of assay. Using a Multidrop Combi (Thermo Electron Corporation) equipped with a metal tip dispenser, 5 ul of 25 nM Keap1-FlagHis protein is added to all wells of the compound plate, with the exception of the wells in column 18. Wells in column 18 receive 5 ul of assay buffer instead. Plates are centrifuged at 500 rpm for 1 minute, covered with a plate lid, and incubated at 37° C. for 2.25 hours. Plates are then removed from the incubator and allowed to cool to RT for 15 minutes. Five microliters of 50 nM biotin-NRF2 protein is then added to all wells of the plates and the plates are spun at 500 rpm for 1 minute, followed by incubating at 4° C. for 1.25 hours. The plates are then allowed to warm to RT for 15 minutes, followed by the addition of 10 ul of detection mix (1 nM Streptavidin Eu+ W1024 and 5 ug/ml mouse anti-DYKDDDDK IgG conjugated to SureLight APC antibody; both from Columbia Biosciences) to all wells. Plates are spun at 500 rpm for 1 minute, incubated for 1 hour at RT, and read on an Envision plate reader using a 320 nm excitation filter and 615 nm and 665 nm emission filters. Compound response (% inhibition) and potency (pIC50) are calculated based on the ratio of the two emissions (665 nm/615 nm) and then the transformed data is normalized against controls in the assay (control 1=1% DMSO in the presence of NRF2 and Keap1 protein and control 2=1% DMSO in the absence of protein). Data analysis is handled using the software package Abase XE (Surrey, United Kingdom). The % inhibition values are calculated from the ratio (transformed) data by the equation:

100−(100*(compound response−average control 2)/(average control 1−average control2)).

For calculation of pIC50s, Abase XE uses a four parameter equation. pIC 50 is the negative log of the IC 50 .

All examples described herein possessed activity in the Nrf2/Keap1 TR-FRET assay as listed (see table below) unless otherwise noted. IC 50 s<10 nM (+++++), IC 50 s 10-100 nM (++++), IC 50 s 100 nM-1 μM (+++), IC 50 s 1-10 μM (++). & IC 50 s 10-100 μM (+), IC 50 s>100 μM (−), or were not determined (ND).

Ex # IC 50 1 + 2 ++ 3 ++ 4 ++ 5 ++ 6 +++ 7 ++ 8 +++ 9 ++ 10 ++ 11 + 12 +++ 13 + 14 +++ 15 ++ 16 ++ 17 +++ 18 ++ 19 ++ 20 ++ 21 +++ 22 ++ 23 ++ 24 ++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 ++ 31 ++ 32 ++ 33 +++ 34 +++ 35 +++ 36 ++ 37, 54d ++ 38 +++ 39 ++ 40 +++ 41 ++++ 42 ++++ 43 +++ 44 +++ 45 +++ 46 + 47 ++ 48 ++ 49 + *50 − 51g ++ 51h ++++ 52 ++ 53 +++ 54e ++ 55 ++++ 56 +++ 57 ++++ 58 +++ 59 +++ 60 + 61 ++ 62 ++ 63 +++ 64 ND 65 ND 66 − 67 +++ 68 ND 69 ND 70 ND 71 ND 72 ND 73 ND 74 ND 75 ND 76 ND 77 ND 78 ND 79 ND 80 ND 81 ND 82 ND 83 ND 84 ND 85 ND 86 ND 87 ND 88 ND 89 ND 90 ND 91 ND 92 ND 93 ND 94 ND 95 ND 96 ND 97 ND 98 ND 99 ND 100 ND 101 ND 102 ND 103 ND 104 ND 105 ND 106 ND 107 ND 108 ND 109 ND 110 ND 111 ND 112 ND 113 ND 114 ND 115 ND 116e ND 116f ND 117 ND 118 ND 119 ND 120 ND 121 ND 122 ND 123 ND 124 ND 125 ND 126 ND 127 ND 128 ND 129 ++++ 130 ND 131 ND 132 ND 133 ND 134 ND 135 ND 136 ND 137 ND 138 ND 139 ND 140 ND 141 ND 142 ND 143 ND 144 +++ 145 +++ 146 +++ 147 +++ 148 +++ 149 +++ 150 +++ 151 + 152 +++ 153 + 154 ++++ 155 ++++ 156 +++ 157 +++ 158 ++ 159 ++++ 160 ++++ 161 + 162 ND 163 ++ 164 +++ 165 ++++ 166 +++ 167 +++ 168 +++ 169 +++ 170 ND 171 +++ 172 ++ 173 +++ 174 +++ 175 +++ 176 +++ 177 +++ 178 +++ 179 +++ 180 ND 181 ++ 182 +++ 183 +++ 184 +++ 185 +++ 186 +++ 187 +++ 188 ++ 189 + 190 + 191 +++ 192 +++ 193 ND 194 ND 195 ND 196 ++++ 197 ++++ 198 ++++ 199 ++++ 200 ND 201 ++++ 202 ++++ 203 ++ 204 ++ 205 +++ 206 ++ 207 ++ 208 ++++ 209 + *210 − 211 + 212 ++++ 213 ++++ 214 ++++ 215 +++ 216 +++ 217 +++ 218 +++ 219 +++ 220 +++ 221 +++ 222 +++ 223 ++ 224 +++ 225 +++ 226 +++ 227 ++++ 228 +++ 229 +++ 230 ++++ 231 +++ 232 ++++ 233 +++ 234 +++ 235 +++ 236 ++ 237 ++ 238 ++ 239 +++ 240 ++ 241 ND 242 243 +++ 244 +++ 245 +++ 246 ++ 247 ++ 248 +++ 249 ++++ 250 + 251 ++++ 252 +++ 253 +++ 254 +++ 255 ND 256 ND 257 ND 258 ++++ 259 ++++ 260 ++++ 261 ++++ 262 ++++ 263 ++++ 264 ++++ 265 ++++ 266 ++++ 267 ++++ 268 ++++ 269 + *in some determinations IC 50 values were >100 μM

›DETAILED DESCRIPTION OF THE INVENTION · 17 of 22

NRF2-Keap1 TR-FRET Low Protein Assay

In the NRF2-Keap1 TR-FRET (time-resolved fluorescence resonance energy transfer) low protein assay, full length NRF2 protein and full length Keap1 protein (Keap1 exists a dimer) are used. The assay detects a compound's ability to displace the binding of Keap1 FlagHis with biotinylated Avi-NRF2 protein. Biotin-NRF2 binds to streptavidin-europium (a component of the detection mix) and Keap1 FlagHis is recognized by anti-Flag APC (allophycocyanin) antibody (also a component of the detection mix). If binding occurs between the two proteins, there will be an energy transfer from the Eu+3 (donor) at 615 nm to the APC (acceptor) at 665 nm. A potential NRF2 inhibitor will cause a reduction in the TR-FRET signal by interfering with the binding of Keap1 to NRF2.

Ten nanoliters of 100× compound dose response curves (serial 3-fold dilutions) in DMSO are stamped using an Echo liquid handling system (Labcyte) into 384-well, low volume, black assay plates (Greiner, #784076), with DMSO in columns 6 and 18. An additional 90 nl DMSO is added to each well, to bring the total volume to 100 nl per well. The top concentration of compound is located in columns 1 and 13, with the serial dilutions going across the row. All reagents are diluted in assay buffer (50 mM Tris, pH 8.0, 5 mM MgCl2, 100 mM NaCl, 0.005% BSA, 1 mM DTT, and 2 mM CHAPS. The BSA, DTT, and CHAPS are added to the assay buffer on the day of assay. Using a Multidrop Combi (Thermo Electron Corporation) equipped with a metal tip dispenser, 5 ul of 1.25 nM Keap1 FlagHis protein is added to all wells of the compound plate, with the exception of the wells in column 18. Wells in column 18 receive 5 ul of assay buffer instead. Plates are centrifuged at 500 rpm for 1 minute, covered with a plate lid, and incubated at 37° C. for 2.25 hours. Plates are then removed from the incubator and allowed to cool to RT for 15 minutes. Five microliters of 2.5 nM biotin-NRF2 protein is then added to all wells of the plates and the plates are spun at 500 rpm for 1 minute, followed by incubating at 4° C. for 1.25 hours. The plates are then allowed to warm to RT for 15 minutes, followed by the addition of 10 ul of detection mix (1 nM Streptavidin Eu+W1024 and 5 ug/ml mouse anti-DYKDDDDK IgG conjugated to SureLight APC antibody; both from Columbia Biosciences) to all wells. Plates are spun at 500 rpm for 1 minute, incubated for 1 hour at RT, and read on an Envision plate reader using a 320 nm excitation filter and 615 nm and 665 nm emission filters. Compound response (% inhibition) and potency (pIC50) are calculated based on the ratio of the two emissions (665 nm/615 nm) and then the transformed data is normalized against controls in the assay (control 1=1% DMSO in the presence of NRF2 and Keap1 protein and control 2=1% DMSO in the presence of only the NRF2 protein). Data analysis is handled using the software package Abase XE (Surrey, United Kingdom). The % inhibition values are calculated from the ratio (transformed) data by the equation:

100−(100*(compound response−average control 2)/(average control 1−average control2)).

For calculation of pIC50s, Abase XE uses a four parameter equation. pIC 50 is the negative log of the IC 50 .

All examples described herein possessed activity in the Nrf2/Keap1 Low Protein TR-FRET assay as listed (see table below) unless otherwise noted. IC 50 s<10 nM (+++++), IC 50 s 10-100 nM (++++), IC 50 s 100 nM-1 uM (+++), IC 50 s 1-10 uM (++). & IC 50 s 10 uM-100 uM (+), IC 50 s>100 uM (−), or were not determined (ND).

Ex # IC 50 1 ND 2 ND 3 ND 4 ND 5 ND 6 ND 7 ND 8 ++++ 9 ND 10 ND 11 ND 12 ND 13 ND 14 ++++ 15 ND 16 ND 17 ++++ 18 ND 19 ND 20 ND 21 +++ 22 ND 23 ND 24 ND 25 ND 26 ND 27 ND 28 ++++ 29 ++++ 30 +++ 31 ++++ 32 ND 33 ++++ 34 ++++ 35 ++++ 36 ND 37, 54d ++++ 38 ++++ 39 ND 40 ND 41 +++++ 42 +++++ 43 ND 44 ND 45 ++++ 46 ND 47 ND 48 ND 49 ND 50 ND 51g +++ 51h +++++ 52 ND 53 ++++ 54e +++ 55 ++++ 56 ND 57 +++++ 58 ND 59 +++ 60 ND 61 ++ 62 +++ 63 ++++ 64 +++++ #65 +++++ 66 ND 67 ++++ 68 +++++ 69 +++++ 70 +++++ 71 ++ 72 +++ 73 +++++ 74 ++++ 75 +++++ 76 ++++ 77 ++++ 78 ++++ 79 +++++ 80 ++++ 81 +++ 82 ++++ 83 ++++ 84 ++++ 85 ++++ 86 ++++ 87 +++ 88 ++++ 89 ++++ 90 +++++ 91 ++++ 92 +++ 93 ++++ 94 ++++ 95 +++++ 96 +++ 97 ++++ 98 +++++ 99 +++++ 100 +++ *101 ++ 102 ++ 103 ++ 104 ++++ *105 ++ 106 ++ 107 ++ 108 ++ 109 +++ 110 ++++ 111 +++ 112 +++ 113 +++ 114 ++++ 115 +++ 116e ++++ 116f ++++ 117 +++++ 118 +++++ 119 +++++ 120 +++++ 121 +++++ 122 +++++ 123 ++++ 124 +++++ 125 +++++ 126 +++ 127 ++++ 128 +++++ 129 +++++ 130 ++++ 131 +++++ 132 +++++ 133 ++++ 134 +++++ 135 ++++ 136 +++++ 137 ++++ 138 +++++ 139 +++++ 140 ++++ 141 ++++ 142 ++++ 143 ++++ 144 ++++ 145 ++++ 146 ++++ 147 ++++ 148 +++++ 149 ++++ 150 ++++ 151 ND 152 ++++ 153 ND 154 +++++ 155 +++++ 156 ND 157 ++++ 158 ND 159 ND 160 +++++ 161 ++ 162 ++++ 163 +++ 164 ++++ 165 +++++ 166 ND 167 ++++ 168 ND 169 ND 170 ++++ 171 ++++ 172 ND 173 ND 174 ND 175 ND 176 ++++ 177 +++ 178 ++++ 179 ++++ 180 ++++ 181 ND 182 ND 183 ++++ 184 ND 185 ++++ 186 ++++ 187 ++++ 188 ++ 189 ND 190 ND 191 +++ 192 ++++ 193 +++ 194 ++++ 195 ++++ 196 +++++ 197 +++++ 198 ND 199 ND 200 +++++ #201 +++++ 202 +++++ 203 ND 204 +++ 205 ++++ 206 +++ 207 ND 208 +++++ *209 ++ 210 + 211 ND 212 +++++ 213 +++++ 214 +++++ 215 ++++ 216 ++++ 217 ++++ 218 ++++ 219 ++++ 220 ND 221 +++ 222 ++++ 223 +++ 224 +++ 225 ++++ 226 ND 227 ++++ 228 ++++ 229 ++++ 230 ++++ 231 ++++ 232 ++++ 233 ++++ 234 ++++ 235 ++++ 236 ND 237 +++ 238 +++ 239 +++ 240 +++ *241 − 242 ++++ 243 ++++ 244 ++++ 245 ++++ 246 +++ 247 ND 248 ND 249 +++++ 250 +++ 251 +++++ 252 ++++ 253 +++++ 254 ++++ #255 +++++ 256 ++++ 257 +++++ 258 +++++ 259 +++++ 260 +++++ 261 +++++ 262 +++++ 263 +++++ 264 +++++ 265 ND 266 +++++ 267 +++++ 268 +++++ 269 ND *in some determinations IC 50 values were >100 μM #in some determinations IC 50 values were <10 nM

Rat Model of Myocardial Ischemia and Prolonged Reperfusion

›DETAILED DESCRIPTION OF THE INVENTION · 18 of 22

Oxidative stress is increased in the diseased myocardium, resulting in accumulation of reactive oxygen species (ROS) which impairs cardiac function [ Circ (1987) 76(2); 458-468] and increases susceptibility to arrhythmia [ J of Mol & Cell Cardio (1991) 23(8); 899-918] by a direct toxic effect of increased necrosis and apoptosis [ Circ Res (2000) 87(12); 1172-1179]. The present study determines whether a small molecule activator of NRF2 that targets the Kelch-domain of Keap1, improves cardiac function in a rodent model of established cardiac dysfunction following myocardial ischemia/reperfusion (I/R) injury.

Cardiac dysfunction is established in rats by 30 minutes of myocardial ischemia induced by occlusion of the left anterior descending coronary artery (LAD) followed by 4 weeks of reperfusion. Compound is administered once a day via subcutaneous injection for 28 days starting 2 hours post-reperfusion at 0.5, 5 and 50 mg/kg/d. Ejection fraction (EF), a measure of cardiac function, is measured as well as cardiac antioxidant enzyme activity, left ventricular fibrosis] and oxidative damage in the heart.

Methods of Use

The compounds of the invention are NRF2 regulators, and are useful in the treatment or prevention of respiratory and non-respiratory disorders, including COPD, asthma, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, al antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, acute kidney injury (AKI), kidney disease or malfunction seen during kidney transplantation, Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodelling, cardiac arrhythmias, Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or other inflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topical effects of radiation, immunosuppression due to radiation exposure, Preeclampsia, and high altitude sickness.

Accordingly, in another aspect the invention is directed to methods of treating such conditions.

The methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof.

As used herein, “treat” in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

The skilled artisan will appreciate that “prevention” is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, “safe and effective amount” in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.

As used herein, “patient” refers to a human or other animal.

The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.

The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

›DETAILED DESCRIPTION OF THE INVENTION · 19 of 22

Typical daily dosages may vary depending upon the particular route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per day. Preferred dosages are 1-500 mg once daily, more preferred is 1-100 mg per person per day. IV dosages range form 0.1-000 mg/day, preferred is 0.1-500 mg/day, and more preferred is 0.1-100 mg/day. Inhaled daily dosages range from 10 ug-10 mg/day, with preferred 10 ug-2 mg/day, and more preferred 50 uug-500 ug/day.

Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a “prodrug” of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, ethers, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

Compositions

The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, “pharmaceutically-acceptable excipient” means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.

The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

›DETAILED DESCRIPTION OF THE INVENTION · 20 of 22

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

In another aspect, the invention is directed to a dosage form adapted for administration to a patient parenterally including subcutaneous, intramuscular, intravenous or intradermal. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

In another aspect, the invention is directed to a dosage form adapted for administration to a patient by inhalation. For example, the compound of the invention may be inhaled into the lungs as a dry powder, an aerosol, a suspension, or a solution.

Dry powder compositions for delivery to the lung by inhalation typically comprise a compound of the invention as a finely divided powder together with one or more pharmaceutically acceptable excipients as finely divided powders. Pharmaceutically acceptable excipients particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides.

The dry powder compositions for use in accordance with the present invention are administered via inhalation devices. As an example, such devices can encompass capsules and cartridges of for example gelatin, or blisters of, for example, laminated aluminum foil. In various embodiments, each capsule, cartridge or blister may contain doses of composition according to the teachings presented herein. Examples of inhalation devices can include those intended for unit dose or multi-dose delivery of composition, including all of the devices set forth herein. As an example, in the case of multi-dose delivery, the formulation can be pre-metered (e.g., as in Diskus®, see GB2242134, U.S. Pat. Nos. 6,032,666, 5,860,419, 5,873,360, 5,590,645, 6,378,519 and 6,536,427 or Diskhaler, see GB 2178965, 2129691 and 2169265, U.S. Pat. Nos. 4,778,054, 4,811,731, 5,035,237) or metered in use (e.g., as in Turbuhaler, see EP 69715, or in the devices described in U.S. Pat. No. 6,321,747). An example of a unit-dose device is Rotahaler (see GB 2064336). In one embodiment, the Diskus® inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing the compound optionally with other excipients and additive taught herein. The peelable seal is an engineered seal, and in one embodiment the engineered seal is a hermetic seal. Preferably, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the leading end portions is constructed to be attached to a winding means. Also, preferably the engineered seal between the base and lid sheets extends over their whole width. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the base sheet.

A dry powder composition may also be presented in an inhalation device which permits separate containment of two different components of the composition. Thus, for example, these components are administrable simultaneously but are stored separately, e.g., in separate pharmaceutical compositions, for example as described in WO 03/061743 A1 WO 2007/012871 A1 and/or WO2007/068896, as well as U.S. Pat. Nos. 8,113,199, 8,161,968, 8,511,304, 8,534,281, 8,746,242 and 9,333,310.

›DETAILED DESCRIPTION OF THE INVENTION · 21 of 22

In one embodiment an inhalation device permitting separate containment of components is an inhaler device having two peelable blister strips, each strip containing pre-metered doses in blister pockets arranged along its length, e.g., multiple containers within each blister strip, e.g., as found in ELLIPTA®. Said device has an internal indexing mechanism which, each time the device is actuated, peels opens a pocket of each strip and positions the blisters so that each newly exposed dose of each strip is adjacent to the manifold which communicates with the mouthpiece of the device. When the patient inhales at the mouthpiece, each dose is simultaneously drawn out of its associated pocket into the manifold and entrained via the mouthpiece into the patient's respiratory tract. A further device that permits separate containment of different components is DUOHALER™ of Innovata. In addition, various structures of inhalation devices provide for the sequential or separate delivery of the pharmaceutical composition(s) from the device, in addition to simultaneous delivery.

Aerosols may be formed by suspending or dissolving a compound of the invention in a liquefied propellant. Suitable propellants include halocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols comprising a compound of the invention will typically be administered to a patient via a metered dose inhaler (MDI). Such devices are known to those skilled in the art.

The aerosol may contain additional pharmaceutically acceptable excipients typically used with multiple dose inhalers such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.

Suspensions and solutions comprising a compound of the invention may also be administered to a patient via a nebulizer. The solvent or suspension agent utilized for nebulization may be any pharmaceutically acceptable liquid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropyl alcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof. Saline solutions utilize salts which display little or no pharmacological activity after administration. Both organic salts, such as alkali metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.

Other pharmaceutically acceptable excipients may be added to the suspension or solution. The compound of the invention may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or ascorbic acid. These may be used alone or together to stabilize the compound of the invention. Preservatives may be added such as benzalkonium chloride or benzoic acid and salts thereof. Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithin, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters.

The compounds of Formula (I) and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of allergic disease, inflammatory disease, autoimmune disease, for example; antigen immunotherapy, anti-histamines, corticosteroids, (eg fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g. montelukast, zafirlukast, pranlukast), iNOS inhibitors, tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g. sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate), bronchodilators (e.g., muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents; monoclonal antibody therapy such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies e.g. etanercept and similar agents; antigen non-specific immunotherapies (e.g. interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents).

The compounds may be used in combination with antihypertensives such as diuretics, ACE inhibitors, ARBS, calcium channel blockers, and beta blockers.

›DETAILED DESCRIPTION OF THE INVENTION · 22 of 22

One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents. It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates to optimize the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will readily be appreciated by those skilled in the art.

The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of the invention together with another therapeutically active agent.

›EXAMPLES · 1 of 2

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

All temperatures are given in degrees Celsius, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon (Ar) or nitrogen (N 2 ) atmosphere where necessary.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. The CombiFlash® system used for purification in this application was purchased from Isco, Inc. CombiFlash® purification was carried out using prepacked silica gel columns, a detector with UV wavelength at 254 nm and a variety of solvents or solvent combinations.

Preparative HPLC was performed using a Gilson Preparative System with variable wavelength UV detection or an Agilent Mass Directed AutoPrep (MDAP) system with both mass and variable wavelength UV detection or Waters Preparative System with UV/PDA detection or an Shimadzu PREP LC 20AP. A variety of reverse phase columns, e.g., Luna 5 m C18(2) 100 A, SunFire C18, XBridge C18, Atlantics T3 were used in the purification with the choice of column support dependent upon the conditions used in the purification. The compounds are eluted using a gradient of CH 3 CN and water. Neutral conditions used an CH 3 CN and water gradient with no additional modifier, acidic conditions used an acid modifier, 0.1% TFA (added to both the CH 3 CN and water) or 0.1% formic acid and basic conditions used a basic modifier, 0.1% NH 4 OH (added to the water) or 10 mM ammonium bicarbonate.

Analytical HPLC was run using an Agilent system, Shimadzu/Sciex LCMS with variable wavelength UV detection using reverse phase chromatography with a CH 3 CN and water gradient with a 0.02 or 0.1% TFA modifier (added to each solvent). LC-MS was determined using either a PE Sciex Single Quadrupole 150EX LC-MS, or Waters ZQ Single Quadrupole LC-MS or Agilent 1200 series SL (dectectors: Agilent 6140 single quadrupole and Agilent 1200 MWD SL) instruments. The compound is analyzed using a reverse phase column, e.g., Thermo Hypersil Gold C18, eluted using a gradient of CH 3 CN and water with a low percentage of an acid modifier such as 0.02% TFA or 0.1% formic acid or a base modifier such as 5 mM ammonium bicarbonate (adjusted to pH 10 with aqueous ammonia). When specified “acid method” refers to 0.1% formic acid in water and CH 3 CN gradient (1.8 min. 0.9 mL/min flow) with a Waters Acquity UPLC HSS C18; 1.8μ; 2.1×50 mm at 50° C.; “basic method” refers to 95:5 H 2 O+0.1% NH 4 OH:CH 3 CN (pH=9.4) and water gradient (1.8 min. 0.9 mL/min flow) with a Waters Acquity UPLC BEH C18; 1.7μ; 2.1×50 mm at 50° C. and “overnight basic method” refers to 95:5 H 2 O+0.1% NH 4 OH:CH 3 CN (pH=9.4) and water gradient (16 min. 0.8 mL/min flow) with a Waters Acquity UPLC BEH C18; 1.7μ; 2.1×50 mm at 50° C.

Preparative Chiral SFC was performed using a Thar/Waters Preparative SFC System with single wavelength UV detection system or PDA detector. A variety of chiral SFC columns, e.g. Chiralpak IA, IC, AY, AD. OD, OJ, C2 were used in the purification. The compounds are eluted using supercritical fluid CO 2 and co-solvents, such as MeOH, EtOH, IPA, and combination of these solvent in different ratio based on the compound selectivity. Modifiers (0.1% of TFA, NH 4 OH, DEA) would be used as needed.

Analytical Chiral SFC was run using a Thar/Waters SFC system with variable wavelength UV detection or PDA detector. A variety of chiral SFC columns, e.g. Chiralpak IA, IB, IC, ID, AY, AD, AS, CCL4 were used in the purification. The compounds are eluted using supercritical fluid CO 2 and co-solvents, such as MeOH, EtOH, IPA, and combination of these solvent in different ratio based on the compound selectivity. Modifiers (0.1% of TFA, NH 4 OH, DEA) would be used as needed.

Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colo. Isolute® is a functionalized silica gel based sorbent, and is a registered trademark of Biotage AB Corp., Sweden.

Nuclear magnetic resonance spectra were recorded at 400 MHz using a Bruker AVANCE 400 or Brucker DPX400 or Varian MR400 400 MHz spectrometer. CDCl 3 is deuteriochloroform, DMSO-D 6 is hexadeuteriodimethylsulfoxide, and MeOD is tetradeuteriomethanol, CD 2 Cl 2 is deuteriodichloromethane. Chemical shifts are reported in parts per million (δ) downfield from the internal standard tetramethylsilane (TMS) or calibrated to the residual proton signal in the NMR solvent (e.g., CHCl 3 in CDCl 3 ). Abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad. J indicates the NMR coupling constant measured in Hertz.

Heating of reaction mixtures with microwave irradiations was carried out on a Biotage Initiator® or CEM microwave reactor, typically employing the high absorbance setting.

Cartridges or columns containing polymer based functional groups (acid, base, metal chelators, etc) can be used as part of compound workup. The “amine” columns or cartridges are used to neutralize or basify acidic reaction mixtures or products. These include NH 2 Aminopropyl SPE-ed SPE Cartridges available from Applied Separations and diethylamino SPE cartridges available from United Chemical Technologies, Inc.

General Methods Used in Examples:

Acidic Method (Analytical)

HPLC System: Agilent 1200 series SL

Mass Spec Detector: Agilent 6140 single quadrupole

›EXAMPLES · 2 of 2

Second Detector: Agilent 1200 MWD SL

Eluent A: 0.1% Formic Acid in Water

Eluent B: CH 3 CN

Flow Rate: 0.9 ml/min

Column: Waters Acquity UPLC HSS C18; 1.8μ; 2.1×50 mm

Column T: 50° C.

Time (mins) % B 0.0 5 0.1 5 1.11 95 1.67 95 1.68 5 1.80 5

Capillary voltage: 3000V on ES pos (2700V on ES Neg)

Fragmentor/Gain: 190 on ES pos (160 on ES neg)

Gain: 1

Drying gas flow: 12.0 L/min

Gas Temperature: 345° C.

Nebuliser Pressure: 60 psig

Scan Range: 125-1000 amu

Ionisation Mode: ElectroSpray Positive-Negative switching

Basic Method (Analytical)

HPLC System: Agilent 1200 series SL

Mass Spec Detector: Agilent 6140 single quadrupole

Second Detector: Agilent 1200 MWD SL

Eluent A: 95:5 H2O+0.1% NH4OH:CH3CN (pH=9.4)

Eluent B: CH 3 CN

Flow Rate: 0.9 ml/min

Column: Waters Acquity UPLC BEH C18; 1.7μ; 2.1×50 mm

Column T: 50° C.

Time (mins) % B 0.0 5 0.1 5 1.11 95 1.67 95 1.68 5 1.80 5

Capillary voltage: 3000V on ES pos (2700V on ES Neg)

Fragmentor/Gain: 190 on ES pos (160 on ES neg)

Gain: 1

Drying gas flow: 12.0 L/min

Gas Temperature: 345° C.

Nebuliser Pressure: 60 psig

Scan Range: 125-1000 amu

Ionisation Mode: ElectroSpray Positive-Negative switching

Overnight Basic Method (Analytical)

HPLC System: Agilent 1200 series SL

Mass Spec Detector: Agilent 6140 single quadrupole

Second Detector: Agilent 1200 MWD SL

Eluent A: 95:5 H2O+0.1% NH4OH:CH3CN (pH=9.4)

Eluent B: CH 3 CN

Flow Rate: 0.8 ml/min

Column: Waters Acquity UPLC BEH C18; 1.7μ; 2.1×50 mm

Column T: 50° C.

Time (mins) % B 0.0 5 0.6 5 11.0 95 14.1 95 14.2 5 16 5

Capillary voltage: 3000V on ES pos (2700V on ES Neg)

Fragmentor/Gain: 190 on ES pos (160 on ES neg)

Gain: 1

Drying gas flow: 12.0 L/min

Gas Temperature: 345° C.

Nebuliser Pressure: 60 psig

Scan Range: 125-800 amu

Ionisation Mode: ElectroSpray Positive-Negative switching

Abbreviations are listed in the table below. All other abbreviations are as described in the ACS Style Guide (American Chemical Society, Washington, D.C., 1986).

Table of Abbreviations

[Rh(cod)Cl] 2 or [RhCl(cod)] 2 : di-μ-chlorido-bis[η 2 ,η 2 -(cycloocta-1,5-

diene)rhodium

®T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide

└C.: degree Celsius

AcOH: acetic acid

ADDP: (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone)

aq = aqueous

BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene

CDl: Carbonyl dimidazole

CH 2 Cl 2 : dichloromethane

CH 3 CN: acetonitrile

CHCl 3 : chloroform

Cs 2 CO 3 : cesium carbonate

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE: dichloromethane

DCM: dichloromethane

DIPEA or DIEA: diisopropylethyl amine

DME: dimethyl ether

DMF: N,N-dimethylformamide

DMF-DMA or DMF-dimethyl acetal: N,N-dimethylformaide-dimethyl

acetal

DMSO: dimethyl sulfoxide

EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et 2 O: diethyl ether

Et 3 N: triethylamine

EtOAc: ethyl acetate

EtOH: ethanol

g: gram(s)

h: hour(s)

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium

hexafluorophosphate

HBTU: N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium

hexafluorophosphate

HCl: hydrochloric acid

HOAt: 1-hydroxy-7-azabenzotriazole

HPLC: high performance liquid chromatography

IPA: isopropyl alcohol

K 2 CO 3 : potassium carbonate

KOAc: potassium acetate

LAH: lithium aluminum hydride

LC: liquid chromatography

LC-MS: liquid chromatography-mass spectroscopy

LiBH 4 : lithium borohydride

LiHMDS: lithium hexamethyldisilazane

LiOH: lithium hydroxide

M: molar

MeCN: acetonitrile

Mel: methyl iodide

MeOH: methanol

mg: milligram(s)

MgCl 2 : magnesium chloride

MgSO 4 : magnesium sulfate

MHz: megahertz

min: minute(s)

mL: milliliter(s)

mmol: millimole(s)

MS: mass spectroscopy

N 2 : nitrogen gas

Na 2 CO 3 : sodium carbonate

Na 2 SO 4 : sodium sulfate

NaBH 3 CN or NaCNBH 3 : sodium cyanoborohydride

NaCl: sodium chloride

NaH: sodium hydride

NaHCO 3 : sodium bicarbonate

NaHMDS: sodium hexamethyldisilazane

NaHSO 4 : sodium bisulfate

NaOAc: sodium acetate

NaOH: sodium hydroxide

NBS: N-bromosuccinimide

nBuLi: n-butyl lithium

NH 4 Cl: ammonium chloride

NMR: nuclear magnetic resonance

P(tBu) 3 : tri-t-butyl phosphine

Pd(PhP 3 ) 4 : tetrakistriphenylphosphine palladium

Pd/C: pallidium on carbon

Pd 2 (dba) 3 : tris(dibenzylideneacetone)-dipalladium(0)

PdCl 2 (dppf) or Pd(dppf)Cl 2 : [1,1′-bis(diphenylphosphino)-ferrocene]

dichloropalladium(II)

Petrol: petroleum ether

PS-PPh 3 : polymer supported triphenylphosphine

PtO 2 : platinum(IV) oxide

RT: room temperature

T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide

solution

TEA: triethylamine

TFA: trifluoroacetic acid

TFFH: tetrafluoroformamidinium hexafluorophosphate

THF: tetrahydrofuran

triflic anhydride: trifluoromethanesulfonic anhydride

TsOH: p-toluenesulfonic acid

wt %: weight percent

›INTERMEDIATES · 1 of 12

2-Bromo-N-(2-methylallyl)benzenesulfonamide

To a solution of 2-bromobenzene-1-sulfonyl chloride (25 g, 98 mmol) in dichloromethane (DCM) (250 mL) at 0° C. was added TEA (13.64 mL, 98 mmol) and 2-methylprop-2-en-1-amine (6.96 g, 98 mmol) and stirred for 10 min. Then it was stirred at RT for 16 h. The reaction mixture was quenched with ice cold water and extracted with DCM (2×200 mL). The combined organic layer washed with ice cold water (2×100 mL), washed with brine solution (100 mL), dried over anhydrous Na 2 SO 4 . It was filtered and concentrated to give the title compound (20 g, 68.3 mmol, 69.8% yield). LC-MS m/z 289.81 (M+H) + , 2.20 min (ret. time).

4-Methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

To a solution of 2-bromo-N-(2-methylallyl)benzenesulfonamide (16 g, 55.1 mmol) in toluene (160 mL) at RT was added AIBN (1.811 g, 11.03 mmol). The reaction mixture was heated to 75° C. and added tri-n-butyltin hydride (29.4 mL, 110 mmol). It was heated at 110° C. for 18 h. The reaction mixture was cooled to RT and diluted with ice water (500 mL) and extracted with EtOAc (2×300 mL). The combined organic layer was washed with chilled brine solution (200 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified on flash column chromatography eluting with 15% ethyl acetate in hexane. Desired fractions were concentrated to give the title compound (8.51 g, 39.9 mmol, 72.3% yield) as a white solid. LC-MS m/z 211.11 (M+H) + , 1.826 min (ret. time).

(S)-4-Methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide and (R)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

4-Methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (4000 mg, 18.93 mmol) was resolved by Chiral SFC (Column: Chiralpak AY 20×250 mm, 5 u; Co-solvent: 20% EtOH; Flow rate: 50 mg/min; Back pressure: 100 Bar) to give single enantiomerically pure (S)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (2.2996 g, 10.88 mmol, 57.5% yield) (chiral SFC ret. time: 1.85 min) LC-MS m/z 211.9 (M+H) + , 0.72 min (ret. time) and single enantiomerically pure (R)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (2.2195 g, 10.50 mmol, 55.5% yield) (chiral SFC ret. time: 2.5 min) LC-MS m/z 211.9 (M+H) + , 0.72 min (ret. time).

N-(4-Methoxybenzyl)-2-methylenebutan-1-amine

To a solution of (4-methoxyphenyl)methanamine (24.46 g, 178 mmol) in toluene (100 mL) was added 2-methylenebutanal (15 g, 178 mmol). It was heated at 95° C. for 48 h. The reaction mixture was concentrated and dissolved in ethanol (100.0 mL), NaBH 4 (6.75 g, 178 mmol) was added at 0° C. and stirred at RT for 4 h. The reaction mixture was concentrated, quenched with water, extracted with DCM twice. The organic layer was dried under anhydrous Na 2 SO 4 , filtered and concentrated. The crude product was purified on flash column chromatography eluting with EtOAc: ether (18:72). Desired fractions were concentrated to give the title compound (13 g, 30.1 mmol, 16.87% yield) as pale yellow liquid. LCMS m/z 206.05 (M+H) + , 3.70 min (ret. time).

2-Bromo-N-(4-methoxybenzyl)-N-(2-methylenebutyl)benzenesulfonamide

To a solution of 2-bromobenzene-1-sulfonyl chloride (7.60 g, 29.8 mmol) in dichloromethane (DCM) (130 mL) at 0° C. was added N-(4-methoxybenzyl)-2-methylenebutan-1-amine (13 g, 29.8 mmol) and TEA (8.30 mL, 59.5 mmol). The reaction mixture was stirred at RT for 6 h. The reaction mixture was quenched with cold water, extracted with twice DCM, brine solution. The organic layer was dried under anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with EtOAC:hexane (5:95). Desired fractions were concentrated to give the title compound (9 g, 21.21 mmol, 71.3% yield) as white solid. LCMS m/z 426.05 (M+H) + , 4.18 min (ret. time).

2-Bromo-N-(2-methylenebutyl)benzenesulfonamide

To a solution of 2-bromo-N-(4-methoxybenzyl)-N-(2-methylenebutyl)benzenesulfonamide (9 g, 19.67 mmol) in acetonitrile (90 mL) and water (30 mL) at 0° C. was added CAN (43.1 g, 79 mmol). It was stirred at RT for 6 h. The reaction mixture was concentrated, quenched with ice water, extracted with DCM twice. The organic layer was dried under anhydrous Na 2 SO 4 , filtered and concentrated. The crude compound was purified by column chromatography eluting with EtOAC:hexane (15:85). Desired fractions were concentrated. It was then dissolved in methanol (50 mL). NaBH 4 (0.744 g, 19.67 mmol) was added at 0° C. The reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was concentrated, quenched with ice water, extracted with DCM twice. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude compound was purified by column chromatography eluting with EtOAC:hexane (06:94) to give the title compound (3 g, 9.14 mmol, 46.5% yield) as white solid. LCMS m/z 303.96 (M+H) + , 2.31 min (ret. time).

4-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

To a solution of 2-bromo-N-(2-methylenebutyl)benzenesulfonamide (3 g, 9.07 mmol) in benzene (30 mL) was added AIBN (0.447 g, 2.72 mmol) and heated at 65° C., tributylstannane (2.90 g, 9.98 mmol) was added at this temperature. The reaction was stirred at 85° C. for 16 h. The reaction mixture was concentrated. The crude product was purified on grace column chromatography with 100-200 silica gel mesh by using EtOAc:hexane (23:77) as solvent. The eluted fractions were concentrated. The product was washed with n-pentane (23 mL) and diethyl ether (10 mL) to give the title compound (980 mg, 4.21 mmol, 46.4% yield) as white solid. LCMS m/z 226.11 (M−H) + , 2.04 min (ret. time) 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.77 (dd, J=7.78, 1.21 Hz, 1H) 7.55 (brt, J=6.47 Hz, 1H) 7.45-7.51 (m, 1H) 7.34-7.42 (m, 2H) 3.37 (br s, 1H) 3.04-3.28 (m, 3H) 1.56 (br s, 1H) 1.15 (br s, 2H) 0.87 (t, J=7.34 Hz, 3H).

(S)-4-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide and (R)-4-ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

›INTERMEDIATES · 2 of 12

4-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (1 g, 4.44 mmol) was resolved by Chiral SFC (Column: Chiralpak AY 20×250 mm, 5 u; Co-solvent: 25% EtOH; Flowrate: 50 g/min; Back pressure: 100 Bar) to give single enantiomerically pure (S)-4-ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (471 mg, 2.090 mmol, 47.1% yield) (chiral SFC ret. time: 1.86 min) LC-MS m/z 226.1 (M+H) + , 0.92 min (ret. time) and (R)-4-ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (472 mg, 2.095 mmol, 47.2% yield) (chiral SFC ret. time: 2.47 min) LC-MS m/z 226.1 (M+H) + , 0.92 min (ret. time).

2,5-Dibromo-N-(2-methylallyl)benzenesulfonamide

To a solution of 2,5-dibromobenzene-1-sulfonyl chloride (5 g, 14.95 mmol) in dichloromethane (50 mL) at 0° C. was added 2-methylprop-2-en-1-amine (1.063 g, 14.95 mmol) and TEA (2.084 mL, 14.95 mmol). It was stirred for 10 min and then stirred at RT for 16 h. The reaction mixture was quenched with ice cold water and extracted with DCM (2×50 mL). The combined organic layer washed with ice cold water (2×35 mL), washed with brine solution (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the title compound (3.4 g, 8.58 mmol, 57.4% yield) LC-MS m/z 367.8 (M+H) + , 2.58 min (ret. time).

8-Bromo-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

To a solution of 2,5-dibromo-N-(2-methylallyl)benzenesulfonamide (3.4 g, 9.21 mmol) in toluene (35 mL) at RT was added AIBN (0.303 g, 1.842 mmol). The reaction mixture was heated at 75° C. and tri-n-butyltin hydride (4.92 mL, 18.42 mmol) was added. It was stirred at 110° C. for 18 h. The crude residue was diluted with ethyl acetate (100 mL) and washed with brine solution (100 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified on flash column chromatography eluting with 15% ethyl acetate in hexane. Desired fractions were concentrated to give the title compound (600 mg, 1.991 mmol, 21.61% yield) as an off-white solid. LC-MS m/z 287.8 (M+H) + , 2.29 min (ret. time).

rel-(R or S)-8-Bromo-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide and rel-(R or S)-8-bromo-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

8-Bromo-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide was resolved by Chiral SFC (Column: Chiralpak AY 20×250 mm, 5 u; Co-solvent: 20% EtOH; Flow rate: 50 g/min; Back pressure: 100 Bar) to give single enantiomerically pure rel-(R or S)-8-bromo-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (195 mg, 0.672 mmol, 32.5% yield) (chiral SFC ret. time: 3.06 min) LC-MS m/z 289.8 (M+H) + , 0.94 min (ret. time) and single enantiomerically pure rel-(R or S)-8-bromo-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (190 mg, 0.655 mmol, 31.7% yield) (chiral SFC ret. time: 4.03 min) LC-MS m/z 289.8 (M+H) + , 0.95 min (ret. time).

2-Bromo-N-(2-methylallyl)-5-(trifluoromethyl)benzenesulfonamide

To a suspension of 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride (5 g, 15.46 mmol) in dichloromethane (DCM) (50 mL) at RT was added 2-methylprop-2-en-1-amine (1.231 g, 17.31 mmol) and triethylamine (4.31 mL, 30.9 mmol). It was stirred for 20 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine (100 mL) and dried over Na 2 SO 4 , filtered and concentrated to give the title compound (5 g, 13.88 mmol, 90% yield) as gummy liquid. LC-MS m/z 355.9 (M+H) + , 2.61 min (ret. time).

4-Methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

To a solution of 2-bromo-N-(2-methylallyl)-5-(trifluoromethyl)benzenesulfonamide (5 g, 13.96 mmol) in toluene (50 mL) was added AIBN (0.458 g, 2.79 mmol). The reaction mixture was heated to 60° C. and then tributylstannane (8.13 g, 27.9 mmol) was added. It was stirred at 100° C. for 20 h. The reaction mixture was cooled and concentrated. The crude residue was purified on flash column chromatography eluting with 25% EtOAc in hexane. Desired fractions were concentrated to give the title compound (720 mg, 2.52 mmol, 18.02% yield) as a white solid. LC-MS m/z 278.01 (M+H) + , 2.37 min (ret. time).

(S)-4-Methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide and (R)-4-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

4-Methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (650 mg, 2.327 mmol) was resolved by Chiral SFC (Column: Chiralpak AD 20×250 mm, 5 u; Co-solvent: 5% IPA in Hexane; Flowrate: 10 mL/min; Back pressure: 100 Bar) to give single enantiomerically pure (S)-4-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (219 mg, 0.784 mmol, 33.7% yield) (chiral HPLC ret. time: 15.171 min) LC-MS m/z 279.9 (M+H) + , 0.95 min (ret. time) and single enantiomerically pure (R)-4-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (126 mg, 0.451 mmol, 19.38% yield) (chiral HPLC ret. time: 17.076 min) LC-MS m/z 279.9 (M+H) + , 0.96 min (ret. time).

2-Bromo-N-(2-methylallyl)-4-(trifluoromethyl)benzenesulfonamide

To a solution of 2-bromo-4-(trifluoromethyl)benzene-1-sulfonyl chloride (5 g, 15.46 mmol) in dichloromethane (DCM) (50 mL) at 0° C. was added 2-methylprop-2-en-1-amine (1.209 g, 17.00 mmol) and TEA (4.31 mL, 30.9 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with cold water, extracted with DCM twice. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the title compound (4.2 g, 11.64 mmol, 75% yield). LC-MS m/z 357.98 (M+H) + , 2.254 min (ret. time).

4-Methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

To a solution of 2-bromo-N-(2-methylallyl)-4-(trifluoromethyl)benzenesulfonamide (4.2 g, 11.73 mmol) in toluene (40 mL) was added AIBN (0.385 g, 2.345 mmol) and heated to 75° C. Tributyltin hydride (3.75 g, 12.90 mmol) was added at 75° C. and the reaction mixture was stirred at 110° C. for 16 h. The reaction mixture was cool and concentrated. The crude residue was purified on flash column chromatography eluting with EtOAC:hexane (11:89). Desired fractions were concentrated to give the title compound (1.6 g, 5.61 mmol, 47.8% yield). LC-MS m/z 278.09 (M+H) + , 2.08 min (ret. time).

›INTERMEDIATES · 3 of 12

(R)-4-Methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide and (S)-4-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

4-Methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (1500 mg, 5.37 mmol) was resolved by Chiral SFC (Column: Chiralpak AD 20×250 mm, 5 u; Co-solvent: 4% IPA/Hexane; Flow rate: 10 mL/min; Back pressure: 30 Bar) to give single enantiomerically pure (R)-4-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (685 mg, 2.453 mmol, 45.7% yield) (chiral HPLC ret. time: 22.284 min) LC-MS m/z 280.0 (M+H) + , 0.98 min (ret. time) and single enantiomerically pure (S)-4-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (660 mg, 2.363 mmol, 44.0% yield) (chiral HPLC ret. time: 27.803 min) LC-MS m/z 280.0 (M+H) + , 0.98 min (ret. time).

(R)-1-Aminobutan-2-ol

To a solution of ammonium hydroxide (113 mL, 2912 mmol) was added (R)-2-ethyloxirane (21 g, 291 mmol) and the result reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was evaporated under vacuum on lyophilization to give the title compound (16 g, 180 mmol, 61.6% yield). It was carried to next step without further purification.

(R)-2-Chloro-N-(2-hydroxybutyl)pyridine-3-sulfonamide

To a solution of (R)-1-aminobutan-2-ol (13.45 g, 151 mmol) in tetrahydrofuran (THF) (50 mL) and water (10 mL) at RT was added K 2 CO 3 (13.03 g, 94 mmol) and 2-chloropyridine-3-sulfonyl chloride (20 g, 94 mmol). It was stirred for 15 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine solution (200 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the title compound (16 g, 48.5 mmol, 51.5% yield) as a gammy liquid. LC-MS m/z 265.16 (M+H) + , 2.61 min (ret. time).

(R)-4-Ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

To a solution of (R)-2-chloro-N-(2-hydroxybutyl)pyridine-3-sulfonamide (16 g, 60.4 mmol) in dimethyl sulfoxide (DMSO) (160 mL) at 0° C. was added potassium tert-butoxide (6.78 g, 60.4 mmol). It was stirred at 80° C. for 2 h. The reaction mixture was cooled and diluted with ice water (500 mL) and extracted with EtOAc (2×300 mL). The combined organic layer was washed with chilled brine solution (200 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified on flash column chromatography eluting with 50% EtOAc in hexane. Desired fractions were concentrated to give the title compound (5.4 g, 23.66 mmol, 39.1% yield) as a pale yellow solid. LC-MS m/z 228.99 (M+H) + , 1.424 min (ret. time).

(R)-4-Ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

To a solution of (R)-1-aminobutan-2-ol (14.66 g, 164 mmol) in tetrahydrofuran (THF) (200 mL) and water (60 mL) at RT was added K 2 CO 3 (14.20 g, 103 mmol) and 2-fluorobenzene-1-sulfonyl chloride (20 g, 103 mmol). It was stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine solution (200 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the title compound (14 g, 53.8 mmol, 52.3% yield) as a gammy liquid. LC-MS m/z 494.83 (2M−H) + , 1.660 min (ret. time).

(R)-4-Ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

To a solution of (R)-2-fluoro-N-(2-hydroxybutyl)benzenesulfonamide (14 g, 56.6 mmol) in dimethyl sulfoxide (DMSO) (140 mL) at 0° C. was added potassium tert-butoxide (6.35 g, 56.6 mmol). It was then heated at 80° C. for 4 h. The reaction mixture was cooled and neutralized with 1N HCl, diluted with ice water (500 mL) and extracted with EtOAc (2×400 mL). The combined organic layer was washed with chilled brine solution (200 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified on flash column chromatography eluting with 50% EtOAc in hexane. Desired fractions were concentrated to give the title compound (11.12 g, 48.9 mmol, 86% yield) as a white solid. LC-MS m/z 228.05 (M+H) + , 1.84 min (ret. time).

2,5-Difluoro-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide

To a solution of 2,5-difluorobenzene-1-sulfonyl chloride (10 g, 47.0 mmol) in tetrahydrofuran (THF) (10 mL) at 0° C. was added 1-amino-2-methylpropan-2-ol (4.19 g, 47.0 mmol) and potassium carbonate (6.50 g, 47.0 mmol). The reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was extracted with EtOAc (2×100 mL). The combined organic layer washed with brine solution (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude product was purified on flash column chromatography eluting with 60% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (7 g, 25.5 mmol, 54.2% yield) as off white solid. LCMS m/z 264 (M−H) + , 4.13 min (ret. time).

8-Fluoro-4,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

To a solution of 2,5-difluoro-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide (7 g, 26.4 mmol) in DMSO (50 mL) at 0° C. was added potassium tert-butoxide (5.92 g, 52.8 mmol). The reaction mixture was stirred at 100° C. for 6 h. The reaction mixture was neutralized with 1N HCl at pH 6-7. It was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine solution (80 mL) and dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified on flash column chromatography eluting with EtOAc:Hexane (6:4). Desired fractions were concentrated to give the title compound (2.9 g, 10.93 mmol, 41.4% yield) as an off-white solid. LCMS m/z 244.12 (M−H) + , 2.28 min (ret. time).

1-((1-(2-Fluorophenyl)propyl)amino)-2-methylpropan-2-ol

To a solution of 1-amino-2-methylpropan-2-ol (10.54 g, 118 mmol) in toluene (400 mL) was added 1-(2-fluorophenyl)propan-1-one (15 g, 99 mmol). It was heated at 120° C. for 48 h. NaBH4 (7.46 g, 197 mmol) was added and stirred at RT for 48 h. The reaction mixture was concentrated and quenched with 1 N NaOH solution (80 mL) solution and extracted with ethyl acetate (2×100 mL). The organic layer was concentrated and purified on flash column chromatography eluting with EtOAc:hexane (4:6). Desired fractions were concentrated under vacuum to give the title compound (3.8 g, 10.69 mmol, 10.85% yield) as gummy liquid. LC-MS m/z 226.1 (M+H) + , 3.872 min (ret. time).

›INTERMEDIATES · 4 of 12

5-Ethyl-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of 1-((1-(2-fluorophenyl)propyl)amino)-2-methylpropan-2-ol (3.5 g, 15.53 mmol) in dimethyl sulfoxide (DMSO) (20 mL) at 10° C. was added potassium tert-butoxide (8.72 g, 78 mmol). It was heated to 90° C. for 12 h. The reaction mixture was cooled to room temperature and poured in ice water (50 mL), then extracted with ethyl acetate (2×50 mL). The combined organic layer was concentrated. The crude residue was purified on flash column chromatography eluting with EtOAc:hexane (4:6). Desired fractions were concentrated to give the title compound (1.5 g, 4.79 mmol, 30.9% yield) as a gummy liquid. LC-MS m/z 206.2 (M+H) + , 3.255 min (ret. time).

Ethyl 3-(2-cyanophenyl)-2,2-dimethylpropanoate

To a solution of ethyl isobutyrate (4.74 g, 40.8 mmol) in tetrahydrofuran (THF) (80 mL) at −78° C. was added LDA (30.6 mL, 61.2 mmol). It was stirred at that temperature for 45 min, then a solution of 2-(bromomethyl)benzonitrile (8 g, 40.8 mmol) in tetrahydrofuran (THF) (30 mL) was added slowly and stirred for at −78° C. for 1 h. The reaction was then allowed to warm to ambient temperature for 3 h. The reaction mixture was quenched with saturated NH 4 Cl solution and extracted with DCM (2×30 mL). The combined organic layer was washed with brine solution (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with 12% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (6 g, 24.85 mmol, 60.9% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm: 1.11-1.31 (m, 9H) 3.10-3.23 (m, 2H) 4.15 (q, J=7.02 Hz, 2H) 7.26-7.37 (m, 2H) 7.44-7.53 (m, 1H) 7.62 (d, J=7.67 Hz, 1H).

3-(2-(Aminomethyl)phenyl)-2,2-dimethylpropan-1-ol

To a solution of ethyl 3-(2-cyanophenyl)-2,2-dimethylpropanoate (6 g, 25.9 mmol) in tetrahydrofuran (THF) (60 mL) at 0° C. was added LAH (78 mL, 78 mmol). It was stirred at 25° C. for 16 h. The reaction mixture was quenched with saturated Na 2 SO 4 solution (15 mL), filtered and the filtrate was extracted with ethyl acetate (3×50 mL). The combined organic layer dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the title compound (3 g, 14.88 mmol, 57.3% yield). LC-MS m/z 194.0 (M+H) + , 3.73 min (ret. time).

Ethyl 3-(2-cyanophenyl)-2,2-dimethylpropanoate

To a solution of 3-(2-(aminomethyl)phenyl)-2,2-dimethylpropan-1-ol (3 g, 15.52 mmol) in dichloromethane (DCM) (30 mL) was added Boc 2 O (3.60 mL, 15.52 mmol). It was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and purified by column chromatography eluting with 25% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (6 g, 24.85 mmol, 60.9% yield). LC-MS m/z 294.34 (M+H) + , 3.78 min (ret. time).

3-(2-(((tert-Butoxycarbonyl)amino)methyl)phenyl)-2,2-dimethylpropyl Methanesulfonate

To a solution of tert-butyl 2-(3-hydroxy-2,2-dimethylpropyl)benzylcarbamate (3 g, 10.22 mmol) in dichloromethane (DCM) (35 mL) at 0° C. was added TEA (3.56 mL, 25.6 mmol) and mesyl chloride (1.594 mL, 20.45 mmol). It was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine solution (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with 20% ethyl acetate in n-hexane. Desired fractions were concentrated under reduced pressure to give the title compound (3 g, 7.70 mmol, 75% yield). LC-MS m/z 372.21 (M+H) + , 2.48 min (ret. time).

tert-Butyl 4,4-dimethyl-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate

To a solution of 3-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,2-dimethylpropyl methanesulfonate (3 g, 8.08 mmol) in isopropanol (50 mL) was added Cs 2 CO 3 (7.89 g, 24.23 mmol) and copper(I) iodide (0.154 g, 0.808 mmol). The reaction mixture was heated to 95° C. for 72 h. The reaction mixture was filtered through celite pad and washed with 10% MeOH in DCM (80 mL). The filtrate was concentrated to afford crude residue. The crude residue was purified by column chromatography eluting with 4% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (1.5 g, 4.56 mmol, 56.5% yield). LC-MS m/z 276.62 (M+H) + , 5.55 min (ret. time).

4,4-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine Hydrochloride

To a solution of tert-butyl 4,4-dimethyl-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carboxylate (1.5 g, 5.45 mmol) in 1,4-dioxane (5 mL) at 0° C. was added 4M HCl in 1,4-dioxane (4 mL, 16.00 mmol). It was stirred at ambient temperature for 2 h. The reaction mixture was concentrated. Diethyl ether (20 mL) was added to the crude residue and stirred for 30 min. It was filtered and dried to give the title compound (1.05 g, 4.93 mmol, 90% yield). LC-MS m/z 176.19 (M+H) + , 1.26 min (ret. time).

Ethyl 2-(2-cyanobenzyl)butanoate

To a solution of ethyl butyrate (0.681 mL, 5.10 mmol) in tetrahydrofuran (THF) (10 mL) at −78° C., was added lithium diisopropylamide (2M in THF) (3.83 mL, 7.65 mmol) slowly. After 30 min, a solution of 2-(bromomethyl)benzonitrile (1 g, 5.10 mmol) in THF (2 mL) was added slowly. It was stirred at −78° C. for 3 h. The reaction mixture was quenched with ammonium chloride solution (50 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine solution (20 mL) and dried over Na 2 SO 4 , filtered and concentrated. The crude residue was purified by silica gel chromatography to give the title compound (600 mg, 2.360 mmol, 46.3% yield) as a colorless liquid. LCMS m/z: 232.17 (M+H) + , 3.716 min (ret. time).

2-(2-(Aminomethyl)benzyl)butan-1-ol

To a solution of ethyl 2-(2-cyanobenzyl)butanoate (600 mg, 2.59 mmol) in tetrahydrofuran (THF) (10 mL) at ambient temperature was added LAH (7.78 mL, 7.78 mmol) slowly. The reaction mixture was stirred for 3 h. The reaction mixture was quenched with ammonium chloride solution and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated. The crude residue was purified by silica gel chromatography to give the title compound (400 mg, 2.069 mmol, 80% yield). LCMS m/z: 194 (M+H) + , 3.036 min (ret. time).

›INTERMEDIATES · 5 of 12

(2-(2-(Chloromethyl)butyl)phenyl)methanamine

To a solution of 2-(2-(aminomethyl)benzyl)butan-1-ol (400 mg, 2.069 mmol) in 1,2-dichloroethane (DCE) (10 mL) at 5° C. was added sulfurous dichloride (0.302 mL, 4.14 mmol) slowly. The reaction mixture was allowed to stir at ambient temperature for 15 h. It was concentrated and quenched with saturated sodium bicarbonate and extracted with DCM (2×25 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude residue was purified by silica gel chromatography to give the title compound (300 mg, 1.417 mmol, 68.5% yield). LCMS m/z: 212 (M+H) + , 1.94 min (ret. time).

4-Ethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine

To a solution of (2-(2-(chloromethyl)butyl)phenyl)methanamine (300 mg, 1.417 mmol) in acetonitrile (2 mL) was added DIPEA (1.237 mL, 7.08 mmol). The reaction mixture was stirred at ambient temperature for 16 h. It was concentrated and extracted with DCM (2×50 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The crude residue was purified by silica gel chromatography to give the title compound (180 mg, 1.027 mmol, 72.5% yield). LCMS m/z: 176.22 (M+H) + , 1.33 min (ret. time).

1-((2-Bromobenzyl)amino)-2-methylpropan-2-ol

To a solution of 2-bromobenzaldehyde (25 g, 135 mmol) in methanol (250 mL) was added 1-amino-2-methylpropan-2-ol (12.04 g, 135 mmol) and NaOH (13.51 mL, 13.51 mmol). The reaction mixture was stirred under nitrogen atmosphere for 1 h. Then NaBH4 (4.09 g, 108 mmol) was added portion wise for 10 min. It was stirred at 25° C. for 40 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and washed with brine solution (300 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the title compound (28 g, 108 mmol, 80% yield). 1 H NMR (DMSO-d6, 400 MHz): δ=7.55 (ddd, J=19.7, 7.7, 1.1 Hz, 2H), 7.33-7.39 (m, 1H), 7.18 (td, J=7.6, 1.6 Hz, 1H), 4.19 (s, 1H), 3.78 (s, 2H), 2.40 (s, 2H), 1.99 (s, 1H), 1.03-1.13 ppm (m, 6H).

2,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of 2-((2-bromobenzyl)amino)propan-2-ol (2.0 g, 8.19 mmol) in isopropanol (12 mL) was added Cs 2 CO 3 (5.34 g, 16.38 mmol) and copper(I) iodide (0.156 g, 0.819 mmol). It was heated in microwave at 130° C. for 1 h. The reaction mixture was filtered through celite pad and washed with ethyl acetate. The filtrate was concentrated and the crude residue was purified by column chromatography eluting with 2% MeOH in DCM. Desired fractions were concentrated under reduced pressure to give the title compound (1.14 g, 4.97 mmol, 60.7% yield). LCMS m/z 178.19 (M+H) + , 2.82 min (ret. time).

tert-Butyl 2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of 2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (8 g, 45.1 mmol) in dichloromethane (DCM) (80 mL) was added TEA (9.44 mL, 67.7 mmol) and added Boc 2 O (15.72 mL, 67.7 mmol) slowly. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water and extracted with DCM (2×100 mL). The combined organic layer was washed with brine solution (150 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with 4% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (9 g, 32.4 mmol, 71.9% yield) 1 H NMR (CDCl 3 , 400 MHz): δ=7.11-7.22 (m, 2H), 6.99-7.06 (m, 1H), 6.90-6.97 (m, 1H), 4.36-4.46 (m, 2H), 3.55-3.64 (m, 2H), 1.38-1.45 (m, 9H), 1.20 ppm (s, 6H).

2,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine Hydrochloride

To a solution of tert-butyl 2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (9 g, 32.4 mmol) in 1,4-dioxane (50 mL) at 0° C. was added 4M HCl in 1,4-dioxane (16.22 mL, 64.9 mmol) slowly. The reaction mixture was allowed to stir at 25° C. for 2 h. The reaction mixture was concentrated. Diethyl ether was added to the residue and stirred for 30 min. Solid was precipitated out. The solid was filtered and dried to give the title compound (6.2 g, 28.2 mmol, 87% yield). LCMS m/z 178.32 (M+H) + , 2.78 min (ret. time).

1-((2,5-Difluorobenzyl)amino)-2-methylpropan-2-ol

To a solution of 2,5-difluorobenzaldehyde (8 g, 56.3 mmol) in methanol (80 mL) was added 1-amino-2-methylpropan-2-ol (5.02 g, 56.3 mmol) and 1 N sodium hydroxide (5.63 mL, 5.63 mmol). The reaction mixture was stirred for 4 h; sodium tetrahydroborate (2.130 g, 56.3 mmol) was added and then stirred for 16 h. The reaction mixture was concentrated. The crude residue was quenched with ice cold water (80 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layer was washed with brine solution (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography using 50% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (6 g, 27.9 mmol, 49.5% yield). LCMS m/z 215.90 (M+H) + , 1.91 min (ret. time).

7-Fluoro-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of 1-((2,5-difluorobenzyl)amino)-2-methylpropan-2-ol (6 g, 27.9 mmol) in dimethyl sulfoxide (DMSO) (50 mL) was added potassium tert-butoxide (7.82 g, 69.7 mmol). It was heated at 90° C. for 16 h. The reaction mixture was cooled and quenched with ice (10 g). It was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with ice cold water (3×30 mL) and brine solution (30 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with 70% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (2.8 g, 12.09 mmol, 43.4% yield). LCMS m/z 195.91 (M+H) + , 2.006 min (ret. time).

tert-Butyl 7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

›INTERMEDIATES · 6 of 12

To a solution of 7-fluoro-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (2.8 g, 14.34 mmol) in dichloromethane (DCM) (30 mL) at 25° C. was added TEA (1.999 mL, 14.34 mmol) and Boc-anhydride (3.33 mL, 14.34 mmol). It was stirred for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2×20 mL). The combined organic layer was washed with brine solution (30 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with 5% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (2.7 g, 8.83 mmol, 61.6% yield). LCMS m/z 240 (M−56) + , 2.794 min (ret. time).

7-Fluoro-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine Hydrochloride

To a solution of tert-butyl 7-fluoro-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (2.7 g, 9.14 mmol) in 1,4-dioxane (15 mL) at 0° C. was added 4M HCl in 1,4-dioxane (6.86 mL, 27.4 mmol). It was stirred 25° C. for 2 h. The reaction mixture was concentrated. Diethyl ether (20 mL) was added to the residue and stirred for 30 min then the solid was filtered, washed with hexane (5 mL) and dried to give the title compound (1.94 g, 8.27 mmol, 91% yield) as a white solid. LCMS 196.1 (M−HCl) + , 4.682 min (ret. time).

1-((5-Bromo-2-fluorobenzyl)amino)-2-methylpropan-2-ol

To a solution of 5-bromo-2-fluorobenzaldehyde (1 g, 4.93 mmol) in methanol (50 mL) was added 1-amino-2-methylpropan-2-ol (0.439 g, 4.93 mmol) and 1N sodium hydroxide (0.493 mL, 0.493 mmol). It was stirred for 4 h; sodium tetrahydroborate (0.186 g, 4.93 mmol) was added and stirred for 16 h. The reaction mixture was concentrated, quenched with ice cold water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine solution (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with 50% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (820 mg, 2.89 mmol, 58.6% yield). LCMS m/z 275.97 (M+H) + , 1.97 min (ret. time).

7-Bromo-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of 1-((5-bromo-2-fluorobenzyl)amino)-2-methylpropan-2-ol (6 g, 21.73 mmol) in dimethyl sulfoxide (DMSO) (40 mL) was added potassium tert-butoxide (6.10 g, 54.3 mmol). It was heated at 90° C. for 1 h. The reaction mixture was cooled and quenched with ice (10 g). It was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with ice cold water (3×30 mL) and brine solution (30 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with 70% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (2.4 g, 3.87 mmol, 17.82% yield). LCMS m/z 257.91 (M+2H) + , 3.42 min (ret. time).

tert-Butyl 7-bromo-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

To a solution of 7-bromo-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (7.2 g, 28.1 mmol) in dichloromethane (DCM) (50 mL) was added TEA (5.88 mL, 42.2 mmol) and Boc-anhydride (6.53 mL, 28.1 mmol). It was stirred at ambient temperature for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2×20 mL). The combined organic layer washed with brine solution (20 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by column chromatography eluting with 5% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (3.3 g, 9.08 mmol, 32.3% yield). LCMS m/z 299.91 (M−57) + , 4.26 min (ret. time).

7-Bromo-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine Hydrochloride

To a solution of tert-butyl 7-bromo-2,2-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (3.3 g, 9.26 mmol) in 1,4-dioxane (40 mL) at 0° C. was added 4M HCl in 1,4-dioxane (6.95 mL, 27.8 mmol). It was then stirred at ambient temperature for 2 h. The reaction mixture was concentrated. Diethyl ether (20 mL) was added and stirred for 30 min. Solid was filtered, washed with hexane (5 mL) and dried to give the title compound (2.1 g, 7.08 mmol, 76% yield) as off-white solid. LCMS m/z 256.04 (M−HCl) + , 1.48 min (ret. time).

2,2-Dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

A solution of 7-bromo-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride (100 mg, 0.342 mmol) in ethanol (13.7 mL) was go through a H-cube hydrogenation flow apparatus equipped with a pre-installed Pd/C cartridge (1 bar, RT). After 15 h and 25 min, the reaction was concentrated to give the title compound as yellow/green oil (83.7 mg). LC-MS m/z 178.1 (M+H) + , 0.49 min (ret. time). 1 H NMR (400 MHz, methanol-d4) δ ppm 1.35 (s, 6H) 3.41 (s, 2H) 4.33 (s, 2H) 7.05 (d, J=8.03 Hz, 1H) 7.12-7.20 (m, 1H) 7.31-7.40 (m, 2H).

1-(((3-Fluoropyridin-2-yl)methyl)amino)-2-methylpropan-2-ol

To a solution of 3-fluoropicolinaldehyde (10 g, 80 mmol) in methanol (100 mL) was added 1-amino-2-methylpropan-2-ol (7.13 g, 80 mmol) and Indium(III) trifluoromethanesulfonate (8.99 g, 15.99 mmol). It was stirred under nitrogen atmosphere for 1 h, then NaCNBH 4 (5.53 g, 88 mmol) was added portion wise for 10 min. It was stirred at RT for 24 h. It was concentrated and purified on flash column chromatography (Neutral alumina) by using MeOH:DCM (1:9) as solvent. Desired fractions were concentrated to give the title compound (4 g, 13.58 mmol, 16.99% yield) as a colorless liquid. LC-MS m/z 198.91 (M+H) + , 1.592 min (ret. time).

2,2-Dimethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine

To a solution of 1-(((3-fluoropyridin-2-yl)methyl)amino)-2-methylpropan-2-ol (4 g, 20.18 mmol) in dimethyl sulfoxide (DMSO) (10 mL) was added potassium tert-butoxide (2.264 g, 20.18 mmol). The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was poured in ice water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (2×40 mL), brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The crude residue was purified on flash column chromatography (Neutral alumina) using 45% ethyl acetate in hexane. The collected the fractions were concentrated to give the title compound (3.2 g, 15.59 mmol, 77% yield) a gummy liquid. LC-MS m/z 178.92 (M+H) + , 1.057 min (ret. time).

›INTERMEDIATES · 7 of 12

tert-Butyl 2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate

To a solution of 2,2-dimethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (3.2 g, 17.95 mmol) in dichloromethane (DCM) (5 mL) at 0° C. was added TEA (5.00 mL, 35.9 mmol) and Boc-anhydride (5.42 mL, 23.34 mmol). It was stirred at RT for 3 h. The crude residue was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified on flash column chromatography eluting with 3% ethyl acetate in hexane. Desired fractions were concentrated to give the title compound (3.1 g, 9.45 mmol, 52.6% yield) as a colorless liquid. LC-MS m/z 279.13 (M+H) + , 3.583 min (ret. time).

2,2-Dimethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine Hydrochloride

To a solution of tert-butyl 2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate (3.1 g, 11.14 mmol) in dichloromethane (DCM) (20 mL) at 10° C. was added 4 M HCl in 1,4-dioxane (3.34 mL, 13.36 mmol). It was stirred for 1 h. The obtained precipitation was filtered and the solid was washed with hexane, diethyl ether and dried to give the title compound (2.16 g, 9.85 mmol, 88% yield) as a brown solid. LC-MS m/z 179.1 (M−HCl) + , 4.040 min (ret. time)

(R)-1-((2-Bromobenzyl)amino)butan-2-ol

To a solution of 2-bromobenzaldehyde (10 g, 54.0 mmol) in methanol (100 mL) was added (R)-1-aminobutan-2-ol (4.82 g, 54.0 mmol) and NaOH (5.40 mL, 5.40 mmol). It was stirred under nitrogen atmosphere for 1 h. NaBH4 (0.818 g, 21.62 mmol) was added portion wise for 10 min and stirred at RT for 72 h. Solvent was concentrated. The crude product was purified on flash column chromatography (Neutral alumina) eluting with EtOAc:hexane (3:7). Combined fractions were concentrated to give the title compound (10 g, 28.9 mmol, 53.5% yield). as an off-white solid. LC-MS m/z 258.12 (M+H) + , 1.302 min (ret. time)

(R)-2-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

To a solution of (R)-1-((2-bromobenzyl)amino)butan-2-ol (3 g, 11.62 mmol) in isopropanol (30 mL) was added Cs 2 CO 3 (7.57 g, 23.24 mmol) and copper(I) iodide (0.443 g, 2.324 mmol). The reaction mixture was heated in microwave reactor at 130° C. for 1 h. The reaction mixture was filtered through celite, washed with isopropanol and concentrated. The crude residue was purified on flash column chromatography eluting with 2.5% MeOH in DCM. Desired fractions were concentrated to give the title compound (1.7 g, 8.77 mmol, 75% yield) as a gummy liquid. LC-MS m/z 178.18 (M+H) + , 1.27 min (ret. time).

(R)-2-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride

To a solution of (R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (5.5 g, 31.0 mmol) in dichloromethane (DCM) (20 mL) at 10° C. was added 4M HCl in 1,4-dioxane (9.31 mL, 37.2 mmol). It was stirred for 1 h. The obtained precipitates were filtered and the solid was washed with hexane and dried to give the title compound (5.1 g, 23.82 mmol, 77% yield) as an off-white solid. LC-MS m/z 178.1 (M+H) + , 1.563 min (ret. time).

Methyl 2-cycloheptylacetate

To a solution of 2-cycloheptylacetic acid (4.76 g, 30.5 mmol) in methanol (50 mL) was added sulfuric acid (2.99 g, 30.5 mmol) slowly. Then it was stirred at 70° C. for 16 h. After it was cooled to ambient temperature, the reaction mixture was added to 50 mL of water and extracted with ethyl acetate (3×50 mL), washed with brine, concentrated to obtain the title compound methyl 2-cycloheptylacetate (5.18 g, 28.3 mmol, 92.9% yield). LCMS m/z 171.2 (M+H) + , 1.82 min (Ret. time).

2-Cycloheptylethanol

To a solution of methyl 2-cycloheptylacetate (4.33 g, 25.4 mmol) in tetrahydrofuran (THF) (20 mL) was added lithium aluminum hydride (1.931 g, 50.9 mmol) slowly under nitrogen at 0° C. and stirred for 1 hour. Then the reaction mixture was stirred at 25° C. for 16 hours. Then 30 mL of HCl (3 M) was added, extracted with EtOAc (3×30 mL), washed with brine, dried over MgSO 4 and concentrated to obtain the title compound 2-cycloheptylethanol (3.28 g, 20.75 mmol, 82% yield) as a white oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 4.26 (t, J=4.9 Hz, 1H), 3.41 (q, J=5.9 Hz, 2H), 1.73-1.29 (m, 13H), 1.22-1.08 (m, 2H).

2-Cycloheptylacetaldehyde

To a solution of 2-cycloheptylethanol (3.28 g, 23.06 mmol) in dichloromethane (DCM) (50 mL) was added PCC (7.46 g, 34.65 mmol) and silica gel (15 g). The reaction mixture was stirred at 25° C. for 16 h. Then it was filtered through a pad of celite. The filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography (EtOAC:Hexane=1:5) to obtain the title compound 2-cycloheptylacetaldehyde (1.30 g, 8.81 mmol, 38.2% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.74 (s, 1H), 2.32-1.28 (m, 15H).

2-(Cycloheptylmethyl)-1H-imidazole

To a solution of 2-cycloheptylacetaldehyde (1.2 g, 8.56 mmol) in methanol (36 mL) and water (36 mL) was added oxaldehyde (0.993 g, 17.12 mmol) and ammonia hydrate (2.189 g, 62.5 mmol). The reaction mixture was stirred at 0° C. for 2 h, then it was stirred at ambient temperature for 18 h. The solid was filtered and dried under vacuum to obtain the title compound 2-(cycloheptylmethyl)-1H-imidazole (680 mg, 3.43 mmol, 40.1% yield) as a white solid. LCMS m/z 179.2 (M+H) + , 1.22 min (ret. time).

1-((1H-Imidazol-2-yl)methyl)piperidine

To a solution of 1H-imidazole-2-carbaldehyde (2 g, 20.81 mmol) in 1,2-dichloroethane (DCE) (100 mL), piperidine (1.772 g, 20.81 mmol) and acetic acid (0.5 mL) were added. After it was stirred at ambient temperature for 16 h, NaBH(OAc) 3 (8.82 g, 41.6 mmol) was added. The reaction mixture was stirred at 25° C. for a further 2 h. The solvent was removed and the residue was purified by reverse-phase HPLC (0.05% NH 4 HCO 3 /H 2 O: CH 3 CN=5%˜95%) to give the title compound 1-((1H-imidazol-2-yl)methyl)piperidine (1.6 g, 9.68 mmol, 46.5% yield) as a yellow solid. LC-MS m/z 166.2 (M+H) + , 1.27 min (ret. time).

›INTERMEDIATES · 8 of 12

Example 1. 5-Cyclopentyl-1-{3-[3-(dimethylcarbamoyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

1a) 3-Bromo-2-fluoro-N,N-dimethyl-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (1.50 g, 6.85 mmol), HATU (3.91 g, 10.3 mmol), dimethylamine (2M in THF, 6.85 mL, 13.7 mmol) and DIPEA (1.77 g, 13.7 mmol) in DMF (20 mL) was stirred for 3 h. Further dimethylamine, DIPEA and HATU was added. After 2 h, the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with water (×3) and brine before drying (MgSO 4 ), filtering, and concentrating to give the product (0.121 g, 7%), used without further purification. LC-MS m/z 246 (M+H) + , 1.12 (ret. time), basic method.

1b) 1-(3-Bromo-phenyl)-5-cyclopentyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred solution of diisopropylamine (8.23 g, 81.4 mmol) in dry THF (10 mL) under N 2 at 0° C. was treated with nBuLi (2.5M in hexane, 31.5 mL, 78.7 mmol). After 30 minutes the solution was cooled to −78° C. Dry EtOAc (7.69 mL, 78.7 mmol) was then added dropwise. After 5 min, a solution of cyclopentane carbonyl chloride (3.48 g, 26.2 mmol) in dry THF (2 mL) was added in one go. After 5 min, the cool bath was removed and the mixture was allowed to warm to room temperature. The mixture was diluted with 1N HCl (30 mL) and then extracted with Et 2 O (2×30 mL). The combined organic phase was dried (MgSO 4 ), filtered, and concentrated 7.8 g of crude 3-cyclopentyl-3-oxo-propionic acid ethyl ester. A mixture of this material (2.4 g, 13.0 mmol) and DMF-dimethyl acetal was stirred in a microwave reactor at 130° C. for 15 min. After cooling, the stirred mixture was diluted with EtOH (10 mL) and treated with 3-bromophenylhydrazine HCl (2.91 g, 13.0 mmol) followed by triethylamine (2.61 g, 26.1 mmol). After 16 h at room temperature the mixture was partitioned between EtOAc and water and then the organic phase washed with water, 0.5 N HCl, water and then brine before it was dried (MgSO 4 ), filtered, and concentrated to give the crude product (4.5 g, 12.4 mmol). LC-MS m/z 363 (M+H) + , 1.61 (ret. time), basic method.

1c) 5-Cyclopentyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A mixture of 1-(3-bromo-phenyl)-5-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.00 g, 8.26 mmol), bis(pinacolato)diboron (2.31 g, 9.08 mmol), KOAc (1.62 g, 16.5 mmol) and Pd(dppf)Cl 2 (0.332 g, 0.45 mmol) in dioxane (80 mL) was stirred under reflux for 3 hours. The mixture was then concentrated and partitioned between EtOAc and water. The organic phase was washed with water and then brine before it was dried (MgSO 4 ), filtered and concentrated. Purification by silica column, eluting 0-20% EtOAc in petrol gave the product (2.3 g, 5.61 mmol, 68%). LC-MS m/z 329 (M+H) + for boronic acid), 1.33 (ret. time), basic method. Boronate ester hydrolyses in LC-MS media—retention time is for corresponding boronic acid.

1d) 5-Cyclopentyl-1-{3-[3-(dimethylcarbamoyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-2-fluoro-N,N-dimethyl-benzamide (0.150 g, 0.61 mmol), 5-cyclopentyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.300 g, 0.73 mmol), Na 2 CO 3 (0.258 g, 2.44 mmol) and Pd(PPh 3 ) 4 (0.042 g, 0.04 mmol) in EtOH (2 mL) and toluene (7 mL) was heated at reflux for 18 h. After cooling the mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the organic phase was washed with water (20 mL) and brine (20 mL) before it was dried (MgSO 4 ), filtered, and concentrated. Purified by silica column (10-40% EtOAc in petrol) to give the product (148 mg, 83%). LC-MS m/z 450 (M+H) + , 1.49 (ret. time), basic method.

1e) 5-Cyclopentyl-1-{3-[3-(dimethylcarbamoyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopentyl-1-{3-[3-(dimethylcarbamoyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.122 g, 0.27 mmol) in EtOH (4 mL) was treated with a solution of NaOH (0.043 g) in water (1 mL). After 60 hours the mixture was acidified with 1N HCl and extracted into EtOAc (2×). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.048 g, 42%). LC-MS m/z 432 (M+H) + , 1.02 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.31 (1H, s), 7.99 (1H, s), 7.80-7.65 (3H, m), 7.63 (1H, s), 7.57-7.57 (1H, m), 7.57-7.48 (1H, m), 7.48-7.34 (2H, m), 3.27-3.11 (1H, m), 3.03 (3H, s), 2.89 (3H, s), 2.17-2.02 (2H, m), 1.90-1.70 (4H, m), 1.51 (2H, d).

Example 2. 1-{3-[3-(Dimethylcarbamoyl)-2-fluorophenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid

2a) 1-(3-Bromo-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred solution of 2-[1-ethoxy-meth-(Z)-ylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (3.09 g, 16.0 mmol) in EtOH (60 mL) was treated with 3-bromophenylhydrazine HCl (5.78 g, 24.0 mmol) followed by DIPEA (4.56 g, 35.3 mmol). After 16 h at room temperature the mixture was partitioned between EtOAc and water and then the organic phase washed with further water, 0.5 N HCl, water, and then brine before it was dried (MgSO 4 ), filtered and concentrated to give the product (6.64 g, quantative). LC-MS m/z 363 (M+H) + , 1.52 (ret. time), basic method.

2b) 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A mixture of 1-(3-bromo-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.00 g, 8.26 mmol), bis(pinacolato)diboron (2.31 g, 9.08 mmol), KOAc (1.62 g, 16.5 mmol) and Pd(dppf)Cl 2 (0.332 g, 0.45 mmol) in dioxane (80 mL) was stirred under reflux for 3 hours. The mixture was then concentrated and partitioned between EtOAc and water. The organic phase was washed with water and then brine before it was dried (MgSO 4 ), filtered, and concentrated. Purified by silica column, 25S, eluting 0-15% EtOAc in petrol to give the product (1.64 g, 48%).

›INTERMEDIATES · 9 of 12

2c) 1-{3-[3-(Dimethylcarbamoyl)-2-fluorophenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-2-fluoro-N,N-dimethyl-benzamide (0.150 g, 0.61 mmol), 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.300 g, 0.73 mmol), Na 2 CO 3 (0.194 g, 3 mmol) and Pd(PPh 3 ) 4 (0.042 g, 0.04 mmol) in EtOH (2 mL) and toluene (7 mL) was heated at reflux for 4 h. After cooling, the mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the organic phase was washed with water (20 mL) and brine (20 mL) before it was dried (MgSO 4 ), filtered, and concentrated. Purified by silica column (30-100% EtOAc in petrol) to give the product (109 mg, 40%). LC-MS m/z 450 (M+H) + , 1.40 (ret. time), basic method.

2d) 1-{3-[3-(Dimethylcarbamoyl)-2-fluorophenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-{3-[3-(dimethylcarbamoyl)-2-fluorophenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.109 g, 0.24 mmol) in EtOH (3 mL) was treated with a solution of NaOH (0.039 g) in water (0.75 mL). After 60 hours the mixture was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.068 g, 67%). LC-MS m/z 422 (M+H) + , 0.98 (ret. time). 1H NMR (400 MHz, DMSO-d6): 13.34 (1H, s), 8.27 (1H, s), 7.82-7.60 (5H, m), 7.50-7.34 (2H, m), 3.03 (3H, s), 2.89 (3H, s).

Example 3. 1-(3-{3-[Cyclopentyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

3a) 3-Bromo-N-cyclopentyl-2-fluoro-N-methyl-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (0.50 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), N-cyclopropentyl-N-methylamine (0.356 g, 2.63 mmol) and DIPEA (0.885 g, 6.85 mmol) in DCM (20 mL) was stirred for 3 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.905 g, quantative), used without further purification.

3b) 1-(3-Bromo-phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A mixture of ethyl 3-cyclopropyl-3-oxopropanoate (0.731 g, 4.69 mmol) and DMF-dimethyl acetal (0.614 g, 5.15 mmol) was stirred in a microwave reactor at 130° C. for 15 min. After cooling, the stirred mixture was diluted with EtOH (15 mL) and treated with 3-bromophenylhydrazine HCl (1.05 g, 4.69 mmol) followed by triethylamine (1.17 g, 11.7 mmol). After 16 h at room temperature the mixture was partitioned between EtOAc and water and then the organic phase washed with further water, 0.5 N HCl, water and then brine before it was dried (MgSO 4 ), filtered, and concentrated to give the product (1.48 g, 94%). LC-MS m/z no ion observed, 1.50 min (ret. time).

3c) 5-Cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A mixture of 1-(3-bromo-phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.20 g, 15.5 mmol), bis(pinacolato)diboron (4.33 g, 17.1 mmol), KOAc (3.04 g, 31.0 mmol) and Pd(dppf)Cl 2 (0.624 g, 0.85 mmol) in dioxane (75 mL) was stirred under reflux for 2 hours. The mixture was then concentrated and partitioned between EtOAc and water. The organic phase washed with water and then brine before it was dried (MgSO 4 ), filtered, and concentrated. It was then purified by silica column, 25S, eluting 3-20% EtOAc in petrol to give the product (6.60 g, quantative.).

3d) 1-(3-{3-[Cyclopentyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-N-cyclopentyl-2-fluoro-N-methyl-benzamide (0.150 g, 0.50 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.127 g, 0.33 mmol), aqueous Na 2 CO 3 (3M, 0.33 mL, 3.3 mmol) and Pd(PPh 3 ) 4 (0.029 g, 0.02 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the organic phase washed with water (20 mL) and brine (20 mL) before it was dried (MgSO4), filtered, and concentrated to give the product, used without further purification (0.207 g, quantative).

3e) 1-(3-{3-[Cyclopentyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-(3-{3-[cyclopentyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.207 g, 0.44 mmol) in EtOH (3 mL) was treated with aqueous NaOH (2M, 0.87 mL). After 18 hours the mixture was partitioned between EtOAc and water. The organic phase was discarded and then the aqueous was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, and the residue purified by preparative HPLC to give the product (0.028 g, 14%). LC-MS m/z 448 (M+H) + , 1.08 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.21 (1H, s), 7.97 (1H, s), 7.79 (1H, s), 7.72-7.58 (4H, m), 7.39 (2H, d), 4.98-4.85 (0.4H, m), 4.02-3.90 (0.6H, m), 2.90 (2H, s), 2.75 (1H, s), 2.20-2.09 (1H, m), 1.87-1.51 (7H, m), 1.41 (1H, s), 0.87 (2H, d), 0.57 (2H, d). Substituents adjacent to amide N are rotameric peaks.

Example 4. 5-Cyclopropyl-1-(3-{2-fluoro-3-[methyl(2-methylpropyl)carbamoyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

4a) 3-Bromo-2-fluoro-N-isobutyl-N-methyl-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (0.50 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), N-isobutyl-N-methylamine (0.229 g, 2.63 mmol) and DIPEA (0.590 g, 4.57 mmol) in DCM (15 mL) was stirred for 3 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.66 g, quantative), used without further purification. LC-MS m/z 288 (M+H) + , 1.43 (ret. time), basic method.

›INTERMEDIATES · 10 of 12

4b) 5-Cyclopropyl-1-(3-{2-fluoro-3-[methyl(2-methylpropyl)carbamoyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-2-fluoro-N-isobutyl-N-methyl-benzamide (0.226 g, 0.78 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.045 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography (EtOAc/petrol 20-60% gradient) to give the product (0.110 g, 60%). LC-MS m/z 464 (M+H) + , 1.53 (ret. time), basic method.

4c) 5-Cyclopropyl-1-(3-{2-fluoro-3-[methyl(2-methylpropyl)carbamoyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{2-fluoro-3-[methyl(2-methylpropyl)carbamoyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.110 g, 0.24 mmol) in EtOH (2 mL) was treated with aqueous NaOH (2M, 0.593 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was discarded and then the aqueous acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, to give the product (0.068 g, 66%). LC-MS m/z 436 (M+H) + , 1.09 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.44-12.08 (1H, m), 7.97 (1H, s), 7.79 (1H, d), 7.68 (4H, s), 7.44-7.35 (2H, m), 3.09-2.95 (2H, m), 2.87 (2H, s), 2.20-1.98 (2H, m), 0.97-0.79 (6H, m), 0.73 (2H, d), 0.64-0.52 (2H, m). Rotameric peaks around amide and 1 H underwater peak.

Example 5. 1-(3-{3-[Cyclohexyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

5a) 3-Bromo-N-cyclohexyl-2-fluoro-N-methyl-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (0.50 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), N-cyclohexyl-N-methylamine (0.297 g, 2.63 mmol) and DIPEA (0.590 g, 4.57 mmol) in DCM (15 mL) was stirred for 3 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.905 g, quantative), used without further purification. LC-MS m/z 314 (M+H) + , 1.50 (ret. time).

5b) 1-(3-{3-[Cyclohexyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-N-cyclohexyl-2-fluoro-N-methyl-benzamide (0.226 g, 0.78 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.045 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography (EtOAc/petrol 15-60% gradient) to give the product (0.114 g, 59%). LC-MS m/z 490 (M+H) + , 1.57 (ret. time), basic method.

5c) 1-(3-{3-[Cyclohexyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-(3-{3-[cyclohexyl(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.114 g, 0.23 mmol) in EtOH (2 mL) was treated with aqueous NaOH (2M, 0.582 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was discarded and then the aqueous acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, to give the product (0.084 g, 78%). LC-MS m/z 462 (M+H) + , 1.12 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.23 (1H, s), 7.97 (1H, d), 7.79 (1H, s), 7.67 (4H, s), 7.51-7.33 (2H, m), 4.42-4.31 (0.5H, m), 3.30-3.19 (0.5H, m), 2.91 (1.5H, s), 2.74 (1.5H, s), 2.21-2.06 (1H, m), 1.81 (1H, d), 1.75-1.45 (6H, m), 1.45-1.29 (1H, m), 1.01 (2H, m), 0.93-0.76 (2H, m), 0.69-0.50 (2H, m). Peaks close to amide are rotameric.

Example 6. 5-Cyclopropyl-1-{3-[3-(3,3-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

6a) (3-Bromo-2-fluoro-phenyl)-(3,3-dimethyl-piperidin-1-yl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.100 g, 0.46 mmol), HATU (0.174 g, 0.46 mmol), 3,3-dimethylpiperidine (0.059 g, 0.53 mmol) and DIPEA (0.118 g, 0.91 mmol) in DCM (15 mL) was stirred for 3 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.905 g, quantative), used without further purification. LC-MS m/z 314 (M+H) + , 1.44 (ret. time).

6b) 5-Cyclopropyl-1-{3-[3-(3,3-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-(3,3-dimethyl-piperidin-1-yl)-methanone (0.173 g, 0.55 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.03 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography (EtOAc/petrol 10-60% gradient) to give the product (0.119 g, 62%). LC-MS m/z 490 (M+H) + , 1.56 (ret. time).

6c) 5-Cyclopropyl-1-{3-[3-(3,3-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[3-(3,3-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.119 g, 0.24 mmol) in EtOH (2 mL) was treated with aqueous NaOH (2M, 0.608 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was discarded and then the aqueous acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.073 g, 65%). LC-MS m/z 462 (M+H) + , 1.12 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.21 (1H, s), 7.97 (1H, s), 7.79 (1H, d), 7.74-7.58 (4H, m), 7.45-7.34 (2H, m), 3.47 (1H, m), 3.21 (2H, m), 2.98 (1H, m), 2.20-2.08 (1H, m), 1.53 (2H, d), 1.41 (2H, m), 0.96 (3H, s), 0.92-0.83 (2H, m), 0.79 (3H, s), 0.57 (2H, d).

›INTERMEDIATES · 11 of 12

Example 7. 1-{3-[3-(azepane-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

7a) Azepan-1-yl-(3-bromo-2-fluoro-phenyl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.500 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), azepane (0.260 g, 2.63 mmol) and DIPEA (0.590 g, 4.57 mmol) in DCM (15 mL) was stirred for 3 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (1.11 g, quantative), used without further purification. LC-MS m/z 300 (M+H) + , 1.36 (ret. time), basic method.

7b) 1-{3-[3-(Azepane-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of azepan-1-yl-(3-bromo-2-fluoro-phenyl)-methanone (0.236 g, 0.78 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.045 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL). The organic phase was washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography (EtOAc/petrol 15-65% gradient) to give the product (0.093 g, 50%). LC-MS m/z 476 (M+H) + , 1.52 (ret. time), basic method.

7c) 1-{3-[3-(Azepane-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-{3-[3-(azepane-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.093 g, 0.20 mmol) in EtOH (2 mL) was treated with aqueous NaOH (2M, 0.489 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was discarded and then the aqueous was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, to give the product (0.061 g, 70%). LC-MS m/z 448 (M+H) + , 1.08 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.21 (1H, s), 7.97 (1H, s), 7.79 (1H, s), 7.72-7.59 (4H, m), 7.45-7.35 (2H, m), 3.60 (2H, s), 3.37-3.24 (2H, m), 2.19-2.08 (1H, m), 1.78-1.65 (2H, m), 1.55 (6H, s), 0.92-0.81 (2H, m), 0.63-0.52 (2H, m).

Example 8. 1-(3-{3-[Bis(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

8a) 3-Bromo-N,N-bis-cyclopropylmethyl-2-fluoro-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (0.500 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), N,N-bis-cyclopropylmethylamine (0.329 g, 2.63 mmol) and DIPEA (0.590 g, 4.57 mmol) in DCM (15 mL) was stirred for 3 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.904 g, quantative), used without further purification. LC-MS m/z 326 (M+H) + , 1.46 (ret. time), basic method.

8b) 1-(3-{3-[Bis(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-N,N-bis-cyclopropylmethyl-2-fluoro-benzamide (0.192 g, 0.59 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.034 g, 0.03 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL). The organic phase was washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated to dryness to give the product, used without further purification (0.213 g, quantative). LC-MS no ion observed, 1.57 (ret. time), basic method.

8c) 1-(3-{3-[Bis(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-(3-{3-[bis(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.213 g, 0.42 mmol) in EtOH (3 mL) was treated with aqueous NaOH (2M, 1.06 mL). After 60 hours the mixture was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, and the residue purified by preparative HPLC to give the product (0.044 g, 22%). LC-MS m/z 474 (M+H) + , 1.14 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.29 (1H, s), 7.97 (1H, s), 7.79 (1H, s), 7.73-7.56 (4H, m), 7.44-7.35 (2H, m), 3.68-3.39 (2H, m), 3.14 (2H, d), 2.19-2.08 (1H, m), 1.27-1.10 (1H, m), 0.98-0.79 (3H, m), 0.63-0.55 (2H, m), 0.50 (2H, d), 0.43 (2H, d), 0.33 (2H, d), 0.04 (2H, s).

Example 9. 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

9a) 3-Bromo-N-cyclopropylmethyl-2-fluoro-N-propyl-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (0.500 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), N-cyclopropylmethyl-N-propylamine (0.297 g, 2.63 mmol) and DIPEA (0.590 g, 4.57 mmol) in DCM (15 mL) was stirred for 3 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (1.23 g, quantative), used without further purification. LC-MS m/z 314 (M+H) + , 1.44 (ret. time), basic method.

9b) 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-N-cyclopropylmethyl-2-fluoro-N-propyl-benzamide (0.247 g, 0.78 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.045 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated to dryness to give the product, used without further purification (0.250 g, quantative). LC-MS m/z 490 (M+H) + , 1.56 (ret. time), basic method.

›INTERMEDIATES · 12 of 12

9c) 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.238 g, 0.49 mmol) in EtOH (3 mL) was treated with aqueous NaOH (2M, 1.215 mL). After 60 hours the mixture was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, and the residue purified by preparative HPLC to give the product (0.034 g, 15%). LC-MS m/z 462 (M+H) + , 1.15 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.31 (1H, s), 7.97 (1H, d), 7.79 (1H, s), 7.67 (4H, s), 7.44-7.35 (2H, m), 3.69-3.34 (2H, m), 3.21 (1H, t), 3.06 (1H, d), 2.19-2.08 (1H, m), 1.72-1.59 (1H, m), 1.54-1.41 (1H, m), 1.15-1.05 (0.5H, m), 0.96-0.78 (4.5H, m), 0.69 (1H, t), 0.57 (2H, d), 0.54-0.47 (1H, m), 0.43 (1H, d), 0.36-0.27 (1H, m), 0.05 (1H, d). Rotameric peaks around amide.

›Examples37

›Example 10. 1-{3-[3-(Azepane-1-carbonyl)phenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

10a) Azepan-1-yl-(3-bromo-2-fluoro-phenyl)-methanone

A solution of 3-bromobenzoic acid (0.500 g, 2.49 mmol), HATU (0.946 g, 2.49 mmol), azepane (0.284 g, 2.86 mmol) and DIPEA (0.643 g, 4.98 mmol) in DCM (15 mL) was stirred for 4 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (1.1 g, quantative), used without further purification. LC-MS m/z 282 (M+H) + , 1.36 (ret. time).

10b) 1-{3-[3-(Azepane-1-carbonyl)phenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of azepan-1-yl-(3-bromophenyl)-methanone (0.243 g, 0.81 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.155 g, 0.41 mmol), aqueous Na 2 CO 3 (3M, 0.405 mL) and Pd(PPh 3 ) 4 (0.047 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (15 mL) and water (15 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated to dryness to give crude product (0.33 g, quantative). LC-MS m/z 458 (M+H) + , 1.53 (ret. time).

10c) 1-{3-[3-(Azepane-1-carbonyl)phenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-{3-[3-(azepane-1-carbonyl)phenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.330 g, 0.72 mmol) in EtOH (3 mL) was treated with aqueous NaOH (2M, 1.80 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was discarded and then the aqueous acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, and the residue purified by silica chromatography eluting with EtOAc/petrol 50-100% followed by MeOH/EtOAc 0-10% to give the product (0.084 g, 27%). LC-MS m/z 430 (M+H) + , 1.10 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.31 (1H, s), 7.97 (1H, s), 7.95-7.89 (1H, m), 7.87-7.78 (2H, m), 7.71 (1H, s), 7.68-7.59 (2H, m), 7.55 (1H, t), 7.38 (1H, d), 3.58 (2H, t), 3.41-3.33 (2H, m), 2.23-2.12 (1H, m), 1.80-1.65 (2H, m), 1.56 (6H, s), 0.93-0.79 (2H, m), 0.63-0.52 (2H, m).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 1 of 18

11a) 1-{3-[3-(Propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 1-(3-bromo-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.08 g, 0.22 mmol), 3-isopropoxy-phenylboronic acid (0.050 g, 0.29 mmol), Na 2 CO 3 (0.095 g, 0.88 mmol) and Pd(PPh 3 ) 4 (0.025 g, 0.022 mmol) in DME/water 2:1 (3 mL) was heated at 95° C. for 5 h. After cooling, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO 4 ), filtered, and purified by SiO 2 chromatography (eluting with 50-100% EtOAc/hexanes) to give the product (0.040 g, 43%). LC-MS m/z 419 (M+H) + . 1.67 (ret. time).

11b) 1-{3-[3-(Propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid

1-(3′-Isopropoxy-biphenyl-3-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.040 g, 0.096 mmol) was dissolved in MeOH (3 mL) and treated with aqueous LiOH (1M, 1 mL). After 24 hours the mixture was concentrated under vacuum and partitioned between EtOAc and water. The aqueous layer was acidified with 5N aqueous HCl and the product was extracted with DCM (×3). The DCM layer was dried (MgSO 4 ), filtered and concentrated to dryness to give the product (0.009 g, 24%). LC-MS m/z 391 (M+H) + , 1.17 (ret. time). 1 H-NMR (400 MHz, d6-DMSO): 13.36 (1H, br), 8.26 (1H, s), 7.96-7.82 (2H, m), 7.65 (1H, t), 7.53 (1H, d), 7.39 (1H, t), 7.32-7.19 (2H, m), 6.97 (1H, dd), 4.81-4.68 (1H, m), 1.29 (6H, d).

Example 12. 1-(3-{3-[(Cyclopentylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

12a) 3-Bromo-N-cyclopentylmethyl-2-fluoro-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (1.00 g, 4.57 mmol), HATU (1.74 g, 4.57 mmol), cyclopentylmethylamine (0.712 g, 5.25 mmol) and DIPEA (1.77 g, 13.7 mmol) in DCM (15 mL) was stirred for 4 h. The mixture was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (1.40 g, quantative), used without further purification. LC-MS m/z 300 (M+H) + , 1.41 (ret. time).

12b) 3-Bromo-N-cyclopentylmethyl-2-fluoro-N-methyl-benzamide

A stirred solution of 3-bromo-N-cyclopentylmethyl-2-fluoro-benzamide (0.200 g, 0.67 mmol) in dry THF (5 mL) under N 2 at 0° C. was treated with NaH (0.019 g, 0.80 mmol). After 30 minutes MeI (0.104 g, 0.75 mmol) was added. After 1 h the reaction was quenched with water and extracted into EtOAc (×2). The combined organic phase was washed with water and brine before it was dried (MgSO4), filtered, and concentrated to give the product (0.124 g, 59%). LC-MS m/z 314 (M+H) + , 1.47 (ret. time).

12c) 1-(3-{3-[(Cyclopentylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-N-cyclopentylmethyl-2-fluoro-N-methyl-benzamide (0.123 g, 0.39 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.26 mmol), aqueous Na 2 CO 3 (3M, 0.262 mL) and Pd(PPh 3 ) 4 (0.023 g, 0.02 mmol) in EtOH (0.75 mL) and toluene (3 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water, (10 mL) and the organic phase was washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated to dryness. Purification by silica column eluting 5-50% EtOAc in petrol gave the product (0.056 g, 44%). LC-MS m/z 490 (M+H) + , 1.60 (ret. time), basic method.

12d) 1-(3-{3-[(Cyclopentylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-(3-{3-[(cyclopentylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.056 g, 0.11 mmol) in EtOH (1 mL) was treated with aqueous NaOH (2M, 0.286 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was discarded and then the aqueous acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give the product (0.043 g, 81%). LC-MS m/z 462 (M+H) + , 1.19 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.25 (1H, s), 7.97 (1H, s), 7.79 (1H, d), 7.73-7.59 (4H, m), 7.44-7.35 (2H, m), 3.45 (1H, s), 3.13 (1H, d), 3.01 (1H, s), 2.88 (2H, s), 2.38-2.24 (1H, m), 2.24-2.12 (1H, m), 1.74-1.49 (4H, m), 1.49-1.22 (3H, m), 1.07-0.92 (1H, m), 0.92-0.79 (2H, m), 0.57 (2H, d).

Example 13. 5-[(cis)-3-Acetamidocyclopentyl]-1-{3-[2-fluoro-3-(propan-2-yloxy)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid (Cis Racemate)

13a) 3-(3-tert-Butoxycarbonylamino-cyclopentyl)-3-oxo-propionic Acid Methyl Ester

A stirred mixture of 3-aminocyclopentanecarboxylic acid (4.00 g, 31.0 mmol) in THF (20 mL) was treated with NaOH (1M aqueous, 57 mL) followed by Boc anhydride (6.76 g, 31.0 mmol). After 16 h the mixture was acidified with 2N HCl and then extracted with EtOAc (2×70 mL). The organic phases were combined, dried (MgSO 4 ), filtered, and concentrated to dryness. The residue was taken up into dry THF (70 mL) and 1,1′-carbonyldiimidazole (2.86 g, 17.6 mmol) was added and the mixture stirred for 1 h. A solid, powdered mixture of MgCl 2 (2.10 g, 17.6 mmol) and potassium methyl malonate (5.05 g, 32.3 mmol) was added and the mixture stirred at room temperature for 18 h. The mixture was concentrated and then partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc before the combined organic phase was washed with brine, dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (5 g, quantative) used directly in the next step without purification.

13b) 1-(3-Bromo-phenyl)-5-((cis)-3-tert-butoxycarbonylamino-cyclopentyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A mixture of 3-(3-tert-butoxycarbonylamino-cyclopentyl)-3-oxo-propionic acid methyl ester (5.00 g, 17.5 mmol) and DMF-dimethyl acetal (2.30 g, 19.3 mmol) was stirred at room temperature for 16 h. A portion of the residue (3.00 g) was taken up into EtOH (50 mL) and treated with 3-bromophenylhydrazine HCl (1.97 g, 8.81 mmol) followed by triethylamine (2.64 g, 26.4 mmol). After 16 h at room temperature the mixture was partitioned between EtOAc and water and then the organic phase washed with further water, 0.5 N HCl, water and then brine before it was dried (MgSO 4 ), filtered, and concentrated to dryness. Purification by silica chromatography eluting with EtOAc/petrol 10-40% gave the cis product (2.70 g, 66%). LC-MS m/z 464 (M+H) + , 1.55 (ret. time), basic method. A small amount (100 mg) of the trans isomer was also isolated.

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 2 of 18

13c) 5-((cis)-3-Amino-cyclopentyl)-1-(3-bromo-phenyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred solution of 1-(3-bromo-phenyl)-5-((cis)-3-tert-butoxycarbonylamino-cyclopentyl)-1H-pyrazole-4-carboxylic acid methyl ester (2.70 g, 5.07 mmol) in DCM (40 mL) was treated with HCl (4M in dioxane, 6.34 mL). After 16 h the mixture was diluted with DCM and water, then brought to basic pH with 2M NaOH. The organic layer was dried (MgSO 4 ), filtered and concentrated to give the product (2.19 g, quantative). LC-MS m/z 364 (M+H) + , 1.26 (ret. time), basic method.

13d) 5-((cis)-3-Acetylamino-cyclopentyl)-1-(3-bromo-phenyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred solution of 5-((cis)-3-amino-cyclopentyl)-1-(3-bromo-phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (2.19 g, 6.01 mmol) in DCM (30 mL) was treated with acetic anhydride (0.737 g, 7.22 mmol). After 4 h the mixture was diluted with DCM and washed with water. The organic phase was dried (MgSO 4 ), filtered and concentrated to dryness to give the product (1.80 g, 74%). LC-MS m/z 406 (M+H) + , 1.31 (ret. time), basic method.

13e) 5-[(cis)-3-Acetamidocyclopentyl]-1-{3-[2-fluoro-3-(propan-2-yloxy)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred mixture of 2-fluoro-3-isopropoxyphenylboronic acid (0.081 g, 0.45 mmol), 5-((cis)-3-acetylamino-cyclopentyl)-1-(3-bromo-phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (0.153 g, 0.38 mmol), aqueous Na 2 CO 3 (3M, 0.377 mL) and Pd(PPh 3 ) 4 (0.026 g, 0.02 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated to dryness to give the product used without further purification (0.151 g, 84%). LC-MS m/z 480 (M+H) + , 1.47 (ret. time), basic method.

13f) 5-[(cis)-3-Acetamidocyclopentyl]-1-{3-[2-fluoro-3-(propan-2-yloxy)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid (Cis Racemate)

A stirred solution of 5-[(cis)-3-acetamidocyclopentyl]-1-{3-[2-fluoro-3-(propan-2-yloxy)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.151 g, 0.31 mmol) in EtOH (2 mL) was treated with aqueous NaOH (2M, 0.765 mL). After 60 hours the mixture was partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×3). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.055 g, 39%). LC-MS m/z 466 (M+H) + , 1.13 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 8.01 (1H, s), 7.90 (1H, d), 7.75-7.64 (2H, m), 7.55 (1H, s), 7.51-7.44 (1H, m), 7.27-7.18 (2H, m), 7.16-7.09 (1H, m), 4.72-4.62 (1H, m), 4.02-3.89 (1H, m), 3.28-3.18 (1H, m), 2.24-2.12 (1H, m), 2.09-1.97 (2H, m), 1.91-1.81 (2H, m), 1.79 (3H, s), 1.74-1.61 (1H, m), 1.32 (6H, d).

Example 14. 1-(3-{3-[(Cyclopentylmethyl)(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

14a) 3-Bromo-N-cyclopentylmethyl-N-cyclopropylmethyl-2-fluoro-benzamide

A stirred solution of 3-bromo-N-cyclopentylmethyl-2-fluoro-benzamide (0.300 g, 1.00 mmol) in dry THF (8 mL) under N 2 at 0° C. was treated with NaH (0.029 g, 1.20 mmol). After 30 minutes bromomethyl cyclopropane (0.1484 g, 1.10 mmol) was added. After a further 1 h the reaction was quenched with water and extracted into EtOAc (×2). The combined organic phase was washed with water and brine before it was dried (MgSO4), filtered, and concentrated to dryness followed by silica chromatography eluting with EtOAc/petrol 5-30% to give the product (0.193 g, 54%). LC-MS m/z 354 (M+H) + , 1.59 (ret. time).

14b) 1-(3-{3-[(cyclopentylmethyl)(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-N-cyclopentylmethyl-N-cyclopropylmethyl-2-fluoro-benzamide (0.110 g, 0.35 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.112 g, 0.29 mmol), aqueous Na 2 CO 3 (3M, 0.262 mL) and Pd(PPh 3 ) 4 (0.020 g, 0.02 mmol) in EtOH (0.75 mL) and toluene (3 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated to dryness to give the product, used without further purification (0.204 g, quantative). LC-MS m/z no mass ion observed, 1.68 (ret. time).

14c) 1-(3-{3-[(Cyclopentylmethyl)(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-(3-{3-[(cyclopentylmethyl)(cyclopropylmethyl)carbamoyl]-2-fluorophenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.204 g, 0.39 mmol) in EtOH (3 mL) was treated with aqueous NaOH (2M, 0.963 mL). After 60 hours the mixture was partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×3). The combined organic phases were dried (MgSO 4 ), filtered, concentrated under vacuum, and purified by HPLC. The residue was diluted with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.055 g, 39%). LC-MS m/z 502 (M+H) + , 1.24 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 7.97 (1H, s), 7.78 (1H, d), 7.72-7.61 (4H, m), 7.44-7.35 (2H, m), 3.72 (1H, br, m), 3.45 (1H, br, m), 3.20 (1H, br, m), 3.08 (1H, d), 2.41-2.28 (1H, m), 2.23-2.11 (1H, m), 1.77-1.51 (4H, m), 1.45-1.22 (3H, m), 1.16-0.94 (1H, m), 0.94-0.79 (3H, m), 0.62-0.54 (2H, m), 0.51 (1H, d), 0.48-0.38 (1H, m), 0.32 (1H, d), 0.03 (1H, s).

Example 15. 1-(3-{2-Chloro-3-[(cyclopropylmethyl)(propyl)carbamoyl]phenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

15a) 3-Bromo-2-chloro-N-cyclopropylmethyl-N-propyl-benzamide

A solution of 3-bromo-2-chloro-benzoic acid (0.500 g, 2.12 mmol), HATU (0.807 g, 2.12 mmol), N-cyclopropylmethyl propylamine (0.402 g, 2.63 mmol) and DIPEA (0.74 mL, 4.2 mmol) in DCM (20 mL) was stirred for 2 h. The mixture was diluted with DCM. The organic phase was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (1.21 g, quantative), used without further purification. LC-MS m/z 330 (M+H) + , 1.49 (ret. time).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 3 of 18

15b) 1-(3-{2-Chloro-3-[(cyclopropylmethyl)(propyl)carbamoyl]phenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-2-chloro-N-cyclopropylmethyl-N-propyl-benzamide (0.181 g, 0.55 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase was washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-50% to give the product (0.117 g, 59%). LC-MS m/z 506 (M+H) + , 1.61 (ret. time).

15c) 1-(3-{2-Chloro-3-[(cyclopropylmethyl)(propyl)carbamoyl]phenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-(3-{2-chloro-3-[(cyclopropylmethyl)(propyl)carbamoyl]phenyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.117 g, 0.23 mmol) in THF (3 mL) and MeOH (3 mL) was treated with LiOH (98 mg, 4.08 mmol) in water (3 mL). After 40 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.070 g, 63%). LC-MS m/z 478 (M+H) + , 1.17 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.15 (1H, br s), 7.96 (1H, d), 7.69-7.61 (3H, m), 7.59-7.47 (3H, m), 7.43-7.35 (1H, m), 3.70-3.35 (2H, m), 3.26-2.92 (2H, m), 2.18-2.08 (1H, m), 1.72-1.42 (2H, m), 1.09 (1H, d), 0.97-0.81 (4H, m), 0.71 (1H, t), 0.62-0.25 (5H, m), 0.19-0.04 (1H, m).

Example 16. 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-methylphenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

16a) 3-Bromo-2-methyl-N-cyclopropylmethyl-N-propyl-benzamide

A solution of 3-bromo-2-methyl-benzoic acid (0.250 g, 1.16 mmol), HATU (0.440 g, 1.16 mmol), N-cyclopropylmethyl propylamine (0.131 g, 1.16 mmol) and DIPEA (0.40 mL, 2.32 mmol) in DCM (10 mL) was stirred for 2 h. The mixture was diluted with DCM and the organic phase was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.58 g, quantative), used without further purification. LC-MS m/z 310 (M+H) + , 1.50 (ret. time).

16b) 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-methylphenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-2-methyl-N-cyclopropylmethyl-N-propyl-benzamide (0.170 g, 0.55 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase was washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-50% to give the product (0.107 g, 57%). LC-MS m/z 486 (M+H) + , 1.60 (ret. time).

16c) 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-methylphenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(propyl)carbamoyl]-2-methylphenyl}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.107 g, 0.22 mmol) in THF (2 mL) and MeOH (2 mL) was treated with LiOH (92 mg, 3.83 mmol) in water (2 mL). After 40 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.060 g, 60%). LC-MS m/z 458 (M+H) + , 1.18 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.20 (1H, br s), 7.95 (1H, d), 7.67-7.58 (2H, m), 7.56 (1H, d), 7.49-7.42 (1H, m), 7.38-7.26 (2H, m), 7.23-7.15 (1H, m), 3.67-3.56 (1H, m), 3.47-3.38 (0.4H, m), 3.28-2.98 (2H, m), 2.91 (0.4H, dd), 2.13 (4H, d), 1.66 (1H, dd), 1.56-1.39 (1H, m), 1.20-1.05 (1H, m), 0.97-0.78 (4H, m), 0.69 (1H, t), 0.62-0.25 (4H, m), 0.11-0.05 (1H, m).

Example 17. 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

17a) (3-Bromo-2-fluoro-phenyl)-(2-propyl-piperidin-1-yl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.500 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), 2-propylpiperidine (0.319 g, 2.51 mmol) and DIPEA (0.79 mL, 4.56 mmol) in DCM (20 mL) was stirred for 2 h. The mixture was diluted with DCM and the organic phase washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (1.33 g, quantative), used without further purification. LC-MS m/z 328 (M+H) + , 1.52 (ret. time).

17b) 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-(2-propyl-piperidin-1-yl)-methanone (0.180 g, 0.55 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.150 g, 0.39 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase was washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-50% to give the product (0.127 g, 65%). LC-MS m/z 504 (M+H) + , 1.63 (ret. time).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 4 of 18

17c) 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.127 g, 0.25 mmol) in THF (3 mL) and MeOH (3 mL) was treated with LiOH (106 mg, 4.41 mmol) in water (2 mL). After 40 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.070 g, 59%). LC-MS m/z 476 (M+H) + , 1.17 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers]12.31 (1H, br s), 7.97 (1H, s), 7.82-7.72 (1H, m), 7.72-7.60 (4H, m), 7.47-7.28 (2H, m), 4.78 (0.6H, br s), 4.44 (0.4H, br s), 3.62-3.52 (0.4H, m), 3.28-3.21 (0.7H, m), 3.20-3.06 (0.6H, m), 2.79 (0.4H, t), 2.19-2.09 (1H, m), 1.87-1.18 (10H, m), 1.01-0.81 (4H, m), 0.79-0.65 (1H, m), 0.58 (2H, d).

Example 18. 5-Cyclopropyl-1-(3-{2-fluoro-3-[3-(trifluoromethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

18a) (3-Bromo-2-fluoro-phenyl)-(3-trifluoromethyl-piperidin-1-yl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.500 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), 3-trifluoromethylpiperidine (0.402 g, 2.63 mmol) and DIPEA (0.885 g, 6.85 mmol) in DCM (10 mL) was stirred for 4 h. The mixture was diluted with DCM and the organic phase washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (1.89 g, quantative), used without further purification. LC-MS m/z 354 (M+H) + , 1.41 (ret. time).

18b) 5-Cyclopropyl-1-(3-{2-fluoro-3-[3-(trifluoromethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-(3-trifluoromethyl-piperidin-1-yl)-methanone (0.222 g, 0.63 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.120 g, 0.31 mmol), aqueous Na 2 CO 3 (3M, 0.314 mL) and Pd(PPh 3 ) 4 (0.036 g, 0.05 mmol) in EtOH (0.75 mL) and toluene (3 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated to dryness to give the product, used without further purification (0.204 g, quantative). LC-MS m/z 530 (M+H) + , 1.56 (ret. time).

18c) 5-Cyclopropyl-1-(3-{2-fluoro-3-[3-(trifluoromethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{2-fluoro-3-[3-(trifluoromethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.231 g, 0.44 mmol) in EtOH (3 mL) was treated with aqueous NaOH (2M, 1.09 mL). After 18 hours the mixture was partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, concentrated under vacuum, and purified by HPLC. The residue was diluted with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.027 g, 12%). LC-MS m/z 502 (M+H) + , 1.15 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.36-12.21 (1H, m), 7.97 (1H, s), 7.79 (1H, s), 7.69 (4H, s), 7.57-7.37 (2H, m), 4.54 (0.5H, d), 4.44-4.23 (0.5H, m), 3.64-3.54 (0.5H, m), 3.43 (0.5H, d), 3.27-3.00 (2H, m), 2.20-2.08 (1H, m), 1.99 (1H, s), 1.87-1.74 (1H, m), 1.74-1.53 (2H, m), 1.53-1.39 (1H, m), 0.87 (2H, d), 0.61-0.51 (2H, m). Peaks around amide are rotameric.

Example 19. 1-[3-(3-{4-Azaspiro[2.5]octane-4-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

19a) (4-Aza-spiro[2.5]oct-4-yl)-(3-bromo-2-fluoro-phenyl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.250 g, 1.16 mmol), HATU (0.440 g, 1.16 mmol), 4-azaspiro[2.5]octane hydrochloride (0.171 g, 1.16 mmol) and DIPEA (0.40 mL, 2.32 mmol) in DCM (10 mL) was stirred for 2 h. The mixture was diluted with DCM and the organic phase washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.828 g, quantative), used without further purification. LC-MS m/z 312 (M+H) + , 1.42 (ret. time).

19b) 1-[3-(3-{4-Azaspiro[2.5]octane-4-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of (4-Aza-spiro[2.5]oct-4-yl)-(3-bromo-2-fluoro-phenyl)-methanone (0.143 g, 0.46 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.125 g, 0.32 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-60% to give the product (0.094 g, 60%). LC-MS m/z 488 (M+H) + , 1.54 (ret. time).

19c) 1-[3-(3-{4-Azaspiro[2.5]octane-4-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-[3-(3-{4-azaspiro[2.5]octane-4-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.094 g, 0.193 mmol) in THF (2 mL) and MeOH (2 mL) was treated with LiOH (61 mg, 2.54 mmol) in water (2 mL). After 40 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.060 g, 68%). LC-MS m/z 460 (M+H) + , 1.13 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.18 (1H, br s), 7.97 (1H, s), 7.77 (1H, s), 7.70-7.62 (4H, m), 7.46-7.34 (2H, m), 3.70 (1H, br s), 2.18-2.09 (1H, m), 1.82-1.59 (4H, m), 1.59-1.38 (3H, m), 0.99-0.72 (4H, m), 0.62-0.43 (4H, m).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 5 of 18

Example 20. 5-Cyclopropyl-1-{3-[2-fluoro-3-(piperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

20a) (3-Bromo-2-fluoro-phenyl)-piperidin-1-yl-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.250 g, 1.16 mmol), HATU (0.440 g, 1.16 mmol), piperidine (0.099 g, 1.16 mmol) and DIPEA (0.40 mL, 2.32 mmol) in DCM (10 mL) was stirred for 2 h. The mixture was diluted with DCM and the organic phase washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.644 g, quantative), used without further purification. LC-MS m/z 286 (M+H) + , 1.34 (ret. time).

20b) 5-Cyclopropyl-1-{3-[2-fluoro-3-(piperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-piperidin-1-yl-methanone (0.130 g, 0.46 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.125 g, 0.32 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-60% to give the product (0.080 g, 54%). LC-MS m/z 462 (M+H) + , 1.51 (ret. time).

20c) 5-Cyclopropyl-1-{3-[2-fluoro-3-(piperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[2-fluoro-3-(piperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.080 g, 0.174 mmol) in THF (2 mL) and MeOH (2 mL) was treated with LiOH (74 mg, 3.08 mmol) in water (2 mL). After 60 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.057 g, 76%). 1 H NMR (400 MHz, DMSO-d6): 12.13 (1H, br s), 7.97 (1H, s), 7.79 (1H, s), 7.71-7.63 (4H, m), 7.45-7.36 (2H, m), 3.63 (2H, br s), 3.24 (2H, t), 2.19-2.10 (1H, m), 1.67-1.51 (4H, m), 1.46 (2H, s), 0.92-0.83 (2H, m), 0.61-0.53 (2H, m).

Example 21. 5-Cyclopropyl-1-(3-{3-[(2R,6S)-2,6-dimethylpiperidine-1-carbonyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

21a) (3-Bromo-2-fluoro-phenyl)-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.250 g, 1.16 mmol), HATU (0.440 g, 1.16 mmol), cis-2,6-dimethylpiperidine (0.131 g, 1.16 mmol) and DIPEA (0.40 mL, 2.32 mmol) in DCM (10 mL) was stirred for 2 h. The mixture was diluted with DCM and the organic phase washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (0.722 g, quantative), used without further purification. LC-MS m/z 314 (M+H) + , 1.45 (ret. time).

21b) 5-Cyclopropyl-1-(3-{3-[(2R,6S)-2,6-dimethylpiperidine-1-carbonyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-methanone (0.143 g, 0.46 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.125 g, 0.32 mmol), aqueous Na 2 CO 3 (3M, 0.392 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.04 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-60% to give the product (0.061 g, 39%). LC-MS m/z 490 (M+H) + , 1.56 (ret. time).

21c) 5-Cyclopropyl-1-(3-{3-[(2R,6S)-2,6-dimethylpiperidine-1-carbonyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{3-[(2R,6S)-2,6-dimethylpiperidine-1-carbonyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.061 g, 0.125 mmol) in THF (2 mL) and MeOH (2 mL) was treated with LiOH (52 mg, 3.08 mmol) in water (2 mL). After 60 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.032 g, 56%). LC-MS m/z 462 (M+H) + , 1.14 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.28 (1H, br s), 7.97 (1H, s), 7.79 (1H, d), 7.71-7.61 (4H, m), 7.47-7.34 (2H, m), 4.75 (1H, br s), 3.81 (1H, br s), 2.20-2.09 (1H, m), 1.83 (1H, br s), 1.71-1.43 (5H, m), 1.33-1.12 (6H, m), 0.93-0.82 (2H, m), 0.61-0.53 (2H, m).

Example 22. 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(methoxymethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

22a) 3-Bromo-2-fluoro-benzoic Acid Benzyl Ester

A stirred solution of 3-bromo-2-fluorobenzoic acid (3.00 g, 13.7 mmol) in DCM (40 mL) was treated with benzyl alcohol (1.48 g, 13.7 mmol), HOAt (2.23 g, 16.4 mmol), EDC (3.15 g, 16.4 mmol) and DIPEA (4.77 mL, 16.4 mmol). After 16 h the mixture was diluted with DCM, and washed sequentially with 5% aqueous citric acid, saturated NaHCO 3 and brine, dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (3.94 g, 93%) used without further purification. LC-MS m/z 326 (M+H) + , 1.54 (ret. time).

22b) 1-(3′-Benzyloxycarbonyl-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred mixture of 3-bromo-2-fluoro-benzoic acid benzyl ester (0.146 g, 0.47 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.125 g, 0.32 mmol), aqueous Na 2 CO 3 (3M, 0.340 mL) and Pd(PPh 3 ) 4 (0.028 g, 0.024 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-60% to give the product (0.114 g, 72%). LC-MS m/z 472 (M+H) + , 1.61 (ret. time).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 6 of 18

22c) 1-(3′-Carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Methyl Ester

A shaken mixture of 1-(3′-benzyloxycarbonyl-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.114 g, 0.242 mmol) and 10% Pd/C in EtOH (5 mL) and EtOAc (5 mL) was hydrogenated at atmospheric pressure for 16 h. The mixture was then filtered and concentrated to dryness under vacuum to give the product (0.073 g, 79%). LC-MS m/z 381 (M+H) + , 1.08 (ret. time).

22d) 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(methoxymethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.037 g, 0.098 mmol), HATU (0.037 g, 0.097 mmol), 2-methoxymethyl piperidine (0.014 g, 0.108 mmol) and DIPEA (0.033 mL, 0.22 mmol) in DCM (4 mL) was stirred for 16 h. The mixture was diluted with DCM, and the organic phase was washed with water and dried by passage through a phase separation cartridge. Concentration to dryness followed by silica purification eluting with EtOAc/hexane 0-80% gave the product (0.038 g, 79%). LC-MS m/z 492 (M+H) + , 1.48 (ret. time).

22e) 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(methoxymethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{2-fluoro-3-[2-(methoxymethyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (0.038 g, 0.077 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was treated with LiOH (18 mg, 0.77 mmol) in water (0.5 mL). After 60 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.030 g, 82%). LC-MS m/z 478 (M+H) + , 1.19 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.25 (1H, br s), 7.97 (1H, s), 7.79 (1H, br s), 7.71-7.61 (4H, m), 7.46-7.30 (2H, m), 4.92-4.84 (0.5H, m), 4.48-4.41 (0.5H, m), 3.80-3.47 (2H, m), 3.12 (2H, s), 2.18-2.10 (1H, m), 1.76 (1H, d), 1.53 (5H, s), 0.92-0.83 (2H, m), 0.61-0.53 (2H, m) [OMe signal 3H underwater peak].

Example 23. 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(3,3,3-trifluoropropyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

23a) 3-Bromo-2-fluoro-N-(3,3,3-trifluoro-propyl)-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (0.500 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), 3,3,3-trifluoropropylamine (0.297 g, 2.63 mmol) and DIPEA (1.19 mL, 6.85 mmol) in DCM (10 mL) was stirred for 4 h. The mixture was diluted with DCM and the organic phase washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness gave the crude product (1.58 g, quantative), used without further purification. LC-MS m/z 315 (M+H) + , 1.33 (ret. time).

23b) 3-Bromo-N-cyclopropylmethyl-2-fluoro-N-(3,3,3-trifluoro-propyl)-benzamide

A stirred solution of 3-bromo-2-fluoro-N-(3,3,3-trifluoro-propyl)-benzamide (0.500 g, 1.59 mmol) in dry THF (14 mL) under N 2 at 0° C. was treated with NaH (0.046 g, 1.91 mmol). After 30 minutes bromomethylcyclopropane (0.645 g, 4.78 mmol) was added. After 19 h additional bromomethylcyclopropane (0.645 g, 4.78 mmol) and NaH (0.046 g, 1.91 mmol) were added. After a further 24 h additional bromomethylcyclopropane (0.645 g, 4.78 mmol) was added. After a further 24 h the reaction was quenched with water and extracted into EtOAc (×2). The combined organic phase was washed with water and brine before it was dried (MgSO 4 ), filtered and concentrated, and the residue purified by silica chromatography eluting with EtOAc/petrol 0-60% to give the product (0.210 g, 37%). LC-MS m/z 368 (M+H) + , 1.46 (ret. time).

23c) 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(3,3,3-trifluoropropyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred mixture of 3-bromo-N-cyclopropylmethyl-2-fluoro-N-(3,3,3-trifluoro-propyl)-benzamide (0.125 g, 0.34 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.125 g, 0.34 mmol), aqueous Na 2 CO 3 (3M, 0.340 mL) and Pd(PPh 3 ) 4 (0.028 g, 0.024 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase was washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-60% to give the product (0.127 g, 71%). LC-MS m/z 530 (M+H) + , 1.55 (ret. time).

23d) 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(3,3,3-trifluoropropyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(3,3,3-trifluoropropyl) carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (0.127 g, 0.240 mmol) in THF (2 mL) and MeOH (2 mL) was treated with LiOH (58 mg, 2.4 mmol) in water (2 mL). After 24 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, and the residue purified by HPLC to give the product (0.024 g, 19%). LC-MS m/z 514 (M−H) − , 1.14 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.24 (1H, br s), 7.87 (1H, s), 7.69 (1H, s), 7.64-7.55 (4H, m), 7.37-7.28 (2H, m), 3.75-3.68 (2H, m), 3.47-3.39 (1H, m), 3.02 (1H, d), 2.69-2.58 (1H, m), 2.56-2.45 (1H, m), 2.08-2.00 (1H, m), 1.04-0.71 (3H, m), 0.50-0.33 (4H, m), 0.27-0.06 (2H, m).

Example 24. 5-Cyclopropyl-1-{3-[3-(2,5-dimethylpyrrolidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 7 of 18

24a) 5-Cyclopropyl-1-{3-[3-(2,5-dimethylpyrrolidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.037 g, 0.098 mmol), HATU (0.037 g, 0.097 mmol), dimethylpyrrolidine (0.010 g, 0.10 mmol) and DIPEA (0.033 mL, 0.22 mmol) in DCM (4 mL) was stirred for 16 h. The mixture was diluted with DCM, and the organic phase washed with water and dried by passage through a phase separation cartridge. Concentration to dryness followed by silica purification eluting with EtOAc/hexane 0-60% gave the product (0.038 g, 79%). LC-MS m/z 462 (M+H) + , 1.47 (ret. time).

24b) 5-Cyclopropyl-1-{3-[3-(2,5-dimethylpyrrolidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[3-(2,5-dimethylpyrrolidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.034 g, 0.074 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was treated with LiOH (18 mg, 0.74 mmol) in water (0.5 mL). After 36 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.026 g, 79%). 1 H NMR (400 MHz, DMSO-d6): 12.24 (1H, br s), 7.97 (1H, s), 7.79 (1H, s), 7.71-7.62 (4H, m), 7.47-7.35 (2H, m), 4.31-4.09 (1H, m), 3.92-3.65 (1H, m), 2.18-2.09 (2H, m), 1.99-1.92 (1H, m), 1.78-1.52 (2H, m), 1.34 (3H, d), 0.96 (3H, d), 0.91-0.81 (2H, m), 0.61-0.53 (2H, m).

Example 25. 1-{3-[3-(2-Propylpiperidine-1-carbonyl)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid

25a) [2-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-(2-propyl-piperidin-1-yl)-methanone

A solution of 2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (0.500 g, 1.9 mmol), HATU (0.725 g, 1.9 mmol), 2-propylpiperidine (0.242 g, 1.9 mmol) and DIPEA (0.66 mL, 3.8 mmol) in DCM (20 mL) was stirred for 4 h. The mixture was diluted with DCM and the organic phase was washed with aqueous NaHCO 3 and dried by passage through a phase separation cartridge. Concentration to dryness followed by silica chromatography eluting with EtOAc/petrol 0-30% gave the product (0.51 g, 75%). LC-MS m/z 358 (M+H) + , 1.59 (ret. time).

25b) 1-{3-[3-(2-Propylpiperidine-1-carbonyl)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 1-(3-bromo-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.170 g, 0.46 mmol), [2-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-(2-propyl-piperidin-1-yl)-methanone (0.125 g, 0.35 mmol), aqueous Na 2 CO 3 (3M, 0.351 mL) and Pd(PPh 3 ) 4 (0.030 g, 0.027 mmol) in EtOH (1 mL) and toluene (4 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 0-60% to give the product (0.127 g, 71%). LC-MS m/z 530 (M+H) + , 1.55 (ret. time).

25c) 1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.127 g, 0.248 mmol) in THF (2 mL) and MeOH (2 mL) was treated with LiOH (59 mg, 2.48 mmol) in water (2 mL). After 60 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.034 g, 28%). LC-MS m/z 486 (M+H) + , 1.20 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 13.34 (1H, br s), 8.27 (1H, s), 7.98-7.88 (2H, m), 7.81 (1H, d), 7.73-7.61 (2H, m), 7.61-7.52 (2H, m), 7.36 (1H, d), 4.92-4.16 (1H, m), 3.85-3.36 (1H, m), 3.21-2.74 (1H, m), 1.85-1.26 (10H, m), 1.01-0.54 (3H, m).

Example 26. 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpyrrolidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

26a) 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpyrrolidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.113 g, 0.294 mmol), HATU (0.114 g, 0.291 mmol), 2-propylpyrrolidine (0.034 g, 0.30 mmol) and DIPEA (0.099 mL, 0.66 mmol) in DCM (10 mL) was stirred for 16 h. The mixture was diluted with DCM, and the organic phase washed with water and dried by passage through a phase separation cartridge. Concentration to dryness followed by silica purification eluting with EtOAc/hexane 0-60% gave the product (0.052 g, 37%). LC-MS m/z 476 (M+H) + , 1.54 (ret. time).

26b) 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpyrrolidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[2-fluoro-3-(2-propylpyrrolidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.052 g, 0.109 mmol) in THF (1 mL) and MeOH (1 mL) was treated with LiOH (26 mg, 1.09 mmol) in water (1 mL). After 36 hours the mixture was concentrated to remove organic solvents and the residue was partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.041 g, 82%). LC-MS m/z 462 (M+H) + , 1.16 (ret. time). 1 H NMR (400 MHz, DMSO-d6): 12.29 (1H, brs), 7.97 (1H, s), 7.78 (1H, d), 7.72-7.62 (4H, m), 7.50-7.35 (2H, m), 4.16-4.08 (0.7H, m), 3.71-3.54 (0.6H, m), 3.50-3.41 (0.3H, m), 3.29-3.14 (1.3H, m), 2.20-2.09 (1H, m), 2.05-1.92 (1H, m), 1.91-1.61 (3.5H, m), 1.47-1.26 (2.5H, m), 1.16-1.04 (1H, m), 0.93 (2H, t), 0.90-0.81 (2H, m), 0.61-0.54 (2H, m), 0.54-0.48 (1H, m).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 8 of 18

Example 27. 5-Cyclopropyl-1-{3-[2-fluoro-3-(3-propylmorpholine-4-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

27a) 5-Cyclopropyl-1-{3-[2-fluoro-3-(3-propylmorpholine-4-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.050 g, 0.13 mmol), HATU (0.050 g, 0.13 mmol), 2-propylmorpholine (0.017 g, 0.13 mmol) and DIPEA (0.039 mL, 0.26 mmol) in DCM (5 mL) was stirred for 16 h. The mixture was diluted with DCM, and the organic phase washed with water and dried by passage through a phase separation cartridge. Concentration to dryness followed by silica purification eluting with EtOAc/hexane 0-80% gave the product (0.055 g, 85%). LC-MS m/z 492 (M+H) + , 1.48 (ret. time).

27b) 5-Cyclopropyl-1-{3-[2-fluoro-3-(3-propylmorpholine-4-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[2-fluoro-3-(3-propylmorpholine-4-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.055 g, 0.112 mmol) in THF (1 mL) and MeOH (1 mL) was treated with LiOH (27 mg, 1.12 mmol) in water (1 mL). After 36 hours the mixture was concentrated to remove organic solvents and the residue was partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.042 g, 79%). LC-MS m/z 478 (M+H) + , 1.08 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.32 (1H, br s), 7.97 (1H, s), 7.79 (1H, br s), 7.68 (4H, s), 7.52-7.33 (2H, m), 4.51 (1H, br s), 4.25 (1H, d), 3.91 (1H, dd), 3.82-3.62 (2H, m), 3.62-3.35 (2H, m), 3.21-3.05 (1H, m), 2.20-2.09 (1H, m), 1.90-1.26 (4H, m), 1.15-1.04 (1H, m), 0.99-0.81 (4H, m), 0.70 (1H, br s), 0.57 (2H, d).

Example 28. 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(2-methylpropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

28a) 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(2-methylpropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.050 g, 0.13 mmol), HATU (0.050 g, 0.13 mmol), 2-isobutylpiperidine (0.027 g, 0.15 mmol) and DIPEA (0.069 mL, 0.39 mmol) in DCM (1 mL) was stirred for 4 h. The mixture was diluted with DCM, and the organic phase was washed with water and dried by passage through a phase separation cartridge. Concentration to dryness followed by silica purification eluting with EtOAc/hexane 5-40% gave the product (0.052 g, 79%). LC-MS m/z 504 (M+H) + , 1.63 (ret. time), basic method.

28b) 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(2-methylpropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{2-fluoro-3-[2-(2-methylpropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (0.052 g, 0.10 mmol) in EtOH (1 mL) was treated with aqueous NaOH (2M, 0.246 mL). After 60 hours the mixture was partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give the product (0.038 g, 79%). LC-MS m/z 490 (M+H) + , 1.21 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.32 (1H, s), 7.97 (1H, s), 7.79 (1H, s), 7.71-7.59 (4H, m), 7.49-7.34 (2H, m), 4.87 (0.5H, m), 4.44 (0.5H, m), 3.68-3.57 (0.5H, m), 3.23 (0.5H, m), 3.15 (0.5H, m), 2.87-2.77 (0.5H, m), 2.19-2.11 (1H, m), 1.73-1.46 (7H, m), 1.39-1.25 (2H, m), 0.99-0.85 (6H, m), 0.65-0.56 (4H, m).

Example 29. 5-Cyclopropyl-1-{3-[2-fluoro-3-(4-methylazepane-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

29a) 5-Cyclopropyl-1-{3-[2-fluoro-3-(4-methylazepane-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.043 g, 0.11 mmol), HATU (0.043 g, 0.11 mmol), 4-methylazepane (0.015 g, 0.13 mmol) and DIPEA (0.039 mL, 0.23 mmol) in DCM (1 mL) was stirred for 4 h. The mixture was diluted with EtOAc, and the organic phase washed with water, dried (MgSO 4 ) and concentrated to dryness. Silica purification eluting with EtOAc/hexane 10-60% gave the product (0.043 g, 80%). LC-MS m/z 476 (M+H) + , 1.54 (ret. time).

29b) 5-Cyclopropyl-1-{3-[2-fluoro-3-(4-methylazepane-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[2-fluoro-3-(4-methylazepane-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.043 g, 0.09 mmol) in EtOH (1 mL) was treated with aqueous NaOH (2M, 0.226 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was extracted with water and then discarded. The combined aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give the product (0.028 g, 67%). LC-MS m/z 462 (M+H) + , 1.14 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.29 (1H, s), 7.97 (1H, s), 7.79 (1H, s), 7.67 (4H, m), 7.44-7.35 (2H, m), 3.88-3.79 (0.5H, m), 3.69 (0.5H, m), 3.52 (0.5H, m), 3.43-3.33 (1.5H, m), 3.28-3.17 (1H, m), 2.20-2.08 (1H, m), 1.90-1.76 (1H, m), 1.76-1.46 (4H, m), 1.31-1.12 (2H, m), 0.94 (1.5H, d), 0.91-0.78 (3.5H, m), 0.63-0.51 (2H, m). Azapane peaks are rotameric.

Example 30. 5-Cyclopropyl-1-{3-[3-(2,5-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

30a) 5-Cyclopropyl-1-{3-[3-(2,5-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.050 g, 0.13 mmol), HATU (0.050 g, 0.13 mmol), 2,5-dimethylpiperidine (0.015 g, 0.13 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DCM (4 mL) was stirred for 16 h. The mixture was diluted with EtOAc, and the organic phase was washed with water, dried (MgSO 4 ), and concentrated to dryness. Silica purification eluting with EtOAc/hexane 0-60% gave the product (0.060 g, 96%.). LC-MS m/z 476 (M+H) + , 1.56 (ret. time).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 9 of 18

30b) 5-Cyclopropyl-1-{3-[3-(2,5-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[3-(2,5-dimethylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.060 g, 0.126 mmol) in THF (1 mL) and MeOH (1 mL) was treated with LiOH (30 mg, 1.26 mmol) in water (1 mL). After 60 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.036 g, 62%). LC-MS m/z 462 (M+H) + , 1.13 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.27 (1H, br s), 7.97 (1H, s), 7.79 (1H, br s), 7.73-7.60 (4H, m), 7.45-7.30 (2H, m), 4.86 (0.4H, br s), 4.40-4.14 (0.5H, m), 3.85-3.65 (0.5H, m), 3.51-3.34 (0.3H, m), 3.20-2.96 (1H, m), 2.19-2.09 (1H, m), 1.91-1.76 (2H, m), 1.66-1.08 (6H, m), 1.08-0.71 (5H, m), 0.57 (2H, d).

Example 31. 5-Cyclopropyl-1-{3-[3-(decahydroquinoline-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

31a) 5-Cyclopropyl-1-{3-[3-(decahydroquinoline-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.050 g, 0.13 mmol), HATU (0.050 g, 0.13 mmol), decahydroquinoline (0.018 g, 0.13 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DCM (4 mL) was stirred for 16 h. The mixture was diluted with EtOAc, and the organic phase washed with water, dried (MgSO 4 ) and concentrated to dryness. Silica purification eluting with EtOAc/hexane 0-60% gave the product (0.061 g, 93%.). LC-MS m/z 502 (M+H) + , 1.60 (ret. time).

31b) 5-Cyclopropyl-1-{3-[3-(decahydroquinoline-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[3-(decahydroquinoline-1-carbonyl)-2-fluorophenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.061 g, 0.122 mmol) in THF (1 mL) and MeOH (1 mL) was treated with LiOH (29 mg, 1.22 mmol) in water (1 mL). After 48 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.033 g, 56%). LC-MS m/z 488 (M+H) + , 1.21 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.28 (1H, br s), 7.97 (1H, s), 7.78 (1H, br s), 7.71-7.61 (4H, m), 7.45-7.31 (2H, m), 4.61 (0.4H, d), 4.43 (0.3H, d), 3.51-3.33 (1H, m), 3.30-2.74 (2H, m), 2.20-2.06 (1H, m), 1.90-1.22 (12H, m), 0.91-0.82 (2H, m), 0.62-0.53 (2H, m).

Example 32. 5-cyclopropyl-1-[3-(2-fluoro-3-{3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid

32a) 5-Cyclopropyl-1-[3-(2-fluoro-3-{3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.043 g, 0.11 mmol), HATU (0.043 g, 0.11 mmol), 3-oxa-8-aza-bicyclo [3.2.1]octane (0.019 g, 0.13 mmol) and DIPEA (0.059 mL, 0.34 mmol) in DCM (1 mL) was stirred for 4 h. The mixture was diluted with DCM, and the organic phase was washed with sat. aqueous NaHCO 3 , dried (MgSO 4 ) and concentrated to dryness. Silica purification eluting with EtOAc/hexane 20-100% gave the product (0.055 g, quantative). LC-MS m/z 476 (M+H) + , 1.54 (ret. time), basic method.

32b) 5-Cyclopropyl-1-[3-(2-fluoro-3-{3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-[3-(2-fluoro-3-{3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.055 g, 0.12 mmol) in EtOH (1.5 mL) was treated with aqueous NaOH (2M, 0.289 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was further extracted with water and then discarded. The combined aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give the product (0.035 g, 63%). LC-MS m/z 462 (M+H) + , 1.02 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.25 (1H, s), 7.97 (1H, s), 7.81 (1H, s), 7.74-7.61 (4H, m), 7.56-7.47 (1H, m), 7.41 (1H, t), 4.59 (1H, s), 3.77 (1H, s), 3.66 (2H, m), 3.52 (2H, m), 2.20-2.09 (1H, m), 1.97-1.82 (4H, m), 0.93-0.80 (2H, m), 0.62-0.53 (2H, m).

Example 33. 1-{3-[3-(2-Cyclopentylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

33a) 2-Cyclopentyl-pyridine

PdCl 2 dppf (231 mg, 0.32 mmol) was added to a solution of 2-bromopyridine (1.0 g, 6.33 mmol) and cyclopentyl zinc bromide (0.5M in THF, 19 mL, 9.5 mmol) in dry dioxane (20 mL) under nitrogen and the reaction was heated to reflux for 2 h. The reaction mixture was concentrated and then partitioned between EtOAc (40 mL) and water (30 mL). The organic phase was washed with water, brine and then dried (MgSO 4 ), filtered and concentrated. Silica purification eluting with EtOAc/hexane 0-25% gave the product (0.93 g, 99%). LC-MS no mass ion observed, 1.30 (ret. time), basic method.

33b) 2-Cyclopentyl-piperidine

To a solution of 2-cyclopentylpyridine (0.93 g, 6.32 mmol) in ethanol (100 mL) was added HCl in dioxane (4M, 1.74 mL, 9.65 mmol) and PtO 2 (150 mg) and the mixture shaken under a hydrogen atmosphere for 4 h. The catalyst was removed by filtration and then the solution concentrated to dryness to give product (775 mg, 65%) as the HCl salt. 1 H NMR (400 MHz, DMSO-d6): 9.34-8.16 (2H, m), 3.17 (1H, d), 2.93-2.68 (2H, m), 2.11-1.91 (1H, m), 1.85-1.17 (14H, m).

33c) 1-{3-[3-(2-Cyclopentylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Methyl Ester

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 10 of 18

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.050 g, 0.13 mmol), HATU (0.050 g, 0.13 mmol), 2-cyclopentylpiperidine (0.030 g, 0.16 mmol) and DIPEA (0.069 mL, 0.39 mmol) in DCM (1 mL) was stirred for 2 h. The mixture was diluted with DCM, and the organic phase was washed with sat. aqueous NaHCO 3 , dried (MgSO 4 ) and concentrated to dryness. Silica purification eluting with EtOAc/hexane 10-60% gave the product (0.049 g, 72%). LC-MS m/z 516 (M+H) + , 1.65 (ret. time), basic method.

33d) 1-{3-[3-(2-Cyclopentylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-{3-[3-(2-cyclopentylpiperidine-1-carbonyl)-2-fluorophenyl]phenyl}-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.049 g, 0.10 mmol) in EtOH (0.75 mL) was treated with aqueous NaOH (2M, 0.238 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was further extracted with water and then discarded. The combined aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give the product (0.028 g, 59%). LC-MS m/z 502 (M+H) + , 1.25 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.27 (1H, s), 7.97 (1H, s), 7.78 (1H, s), 7.72-7.60 (4H, m), 7.48-7.24 (2H, m), 4.54-4.42 (1H, m), 3.27-3.07 (1.7H, m), 2.83 (0.3H, t), 2.20-2.08 (1H, m), 1.82-1.38 (11H, m), 1.38-1.13 (3H, m), 1.06-0.91 (1H, m), 0.87 (2H, d), 0.58 (2H, s). Peaks close to amide are rotameric.

Example 34. 1-[3-(3-{9-azabicyclo[3.3.1]nonane-9-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

34a) 1-[3-(3-{9-Azabicyclo[3.3.1]nonane-9-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.050 g, 0.13 mmol), HATU (0.050 g, 0.13 mmol), 9-aza-bicyclo[3.3.1] nonane (0.021 g, 0.17 mmol) and DIPEA (0.050 mg, 0.39 mmol) in DCM (4 mL) was stirred for 16 h. The mixture was diluted with DCM, and the organic phase was washed with sat. aqueous NaHCO 3 followed by brine, dried (MgSO 4 ), filtered, and concentrated to dryness. Silica purification eluting with EtOAc/hexane 0-60% gave the product (0.062 g, 97%). LC-MS m/z 488 (M+H) + , 1.53 (ret. time).

34b) 1-[3-(3-{9-Azabicyclo[3.3.1]nonane-9-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-[3-(3-{9-azabicyclo[3.3.1]nonane-9-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.062 g, 0.127 mmol) in THF (1 mL) and MeOH (1 mL) was treated with LiOH (30 mg, 1.27 mmol) in water (1 mL). After 60 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.044 g, 73%). LC-MS m/z 474 (M+H) + , 1.16 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.26 (1H, br s), 7.97 (1H, s), 7.79 (1H, s), 7.71-7.63 (4H, m), 7.46-7.36 (2H, m), 4.73 (1H, s), 3.60 (1H, s), 2.18-2.00 (3H, m), 1.90-1.53 (10H, m), 0.91-0.83 (2H, m), 0.61-0.54 (2H, m).

Example 35. 1-[3-(3-{7-Azaspiro[4.5]decane-7-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

35a) 1-[3-(3-{7-Azaspiro[4.5]decane-7-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.050 g, 0.13 mmol), HATU (0.050 g, 0.13 mmol), 7-azaspiro[4.5]decane (0.018 g, 0.13 mmol) and DIPEA (0.050 mg, 0.39 mmol) in DCM (4 mL) was stirred for 16 h. The mixture was diluted with DCM, and the organic phase washed with sat. aqueous NaHCO 3 followed by brine, dried (MgSO 4 ), filtered, and concentrated to dryness. Silica purification eluting with EtOAc/hexane 0-60% gave the product (0.060 g, 91%). LC-MS m/z 502 (M+H) + , 1.60 (ret. time).

35b) 1-[3-(3-{7-Azaspiro[4.5]decane-7-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-[3-(3-{9-azabicyclo[3.3.1]nonane-9-carbonyl}-2-fluorophenyl)phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.060 g, 0.120 mmol) in THF (1 mL) and MeOH (1 mL) was treated with LiOH (29 mg, 1.20 mmol) in water (1 mL). After 60 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.044 g, 73%). LC-MS m/z 488 (M+H) + , 1.21 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.29 (1H, br s), 7.97 (1H, s), 7.79 (1H, d), 7.72-7.63 (4H, m), 7.43-7.36 (2H, m), 3.59 (1H, d), 3.27-3.12 (1H, m), 3.01 (1H, s), 2.19-2.09 (1H, m), 1.70-1.41 (9H, m), 1.41-1.13 (4H, m), 0.92-0.82 (2H, m), 0.61-0.53 (2H, m).

Example 36. 5-Cyclopropyl-1-{3-[3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

36a) 1-(3-Bromo-phenyl)-5-methyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A mixture of ethyl acetoacetate (6.0 mmol) and DMF-dimethyl acetal (6.0 mmol) was stirred in a microwave reactor at 130° C. for 15 min. After cooling, the stirred mixture was diluted with EtOH (10 mL) and treated with 3-bromophenylhydrazine HCl (1.12 g, 5.0 mmol), followed by triethylamine (0.68 mL, 5.0 mmol) and heated at 80° C. for 3 h. After cooling, the mixture was concentrated to dryness and purified by silica eluting with EtOAc/petrol 10% to give the product (1.50 g, 97%). LC-MS m/z 309 (M+H) + , 1.47 (ret. time).

36b) 1-(3-Bromo-phenyl)-5-methyl-1H-pyrazole-4-carboxylic Acid

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 11 of 18

A stirred solution of 1-(3-bromo-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.50 g, 4.85 mmol) in MeOH (5 mL) was treated with aqueous NaOH (2M, 4.85 mL) and heated to 60° C. After 2 hours the mixture was partitioned between DCM and water. The aqueous layer was acidified with 1N HCl and extracted into DCM (×3) and IPA/CHCl 3 (×2). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give the product (0.792 g, 25%). LC-MS m/z 279 (M+H) + , 0.86 (ret. time).

36c) 1-(3-Bromo-phenyl)-5-methyl-1H-pyrazole

A stirred solution of 1-(3-bromo-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (0.372 g, 1.32 mmol) in quinoline (0.5 mL) was heated at 240° C. for 4 h. After cooling the solution was loaded onto a silica column and eluted with EtOAc/petrol 15% to give the product (0.362 g, quantative). 1H NMR (400 MHz, CDCl 3 ): 7.71-7.47 (3H, m), 7.47-7.34 (2H, m), 6.24 (1H, s), 2.38 (3H, s).

36d) 5-Cyclopropyl-1-{3-[3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred mixture of 1-(3-bromo-phenyl)-5-methyl-1H-pyrazole (0.130 g, 0.55 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.144 g, 0.66 mmol), aqueous Na 2 CO 3 (2M, 2.2 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.03 mmol) in DME (11 mL) was heated at 80° C. under N 2 for 16 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography eluting with EtOAc/petrol 30% to give the product (0.090 g, 41%). LC-MS m/z 399 (M+H) + , 1.48 (ret. time).

36e) 5-Cyclopropyl-1-{3-[3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.090 g, 0.23 mmol) in MeOH (1 mL) was treated with aqueous NaOH (2M, 0.5 mL) and heated to 60° C. After 16 hours the mixture was partitioned between DCM and water. The aqueous layer was acidified with 1N HCl and extracted into DCM (×4). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum, and the residue purified by HPLC to give the product (0.022 g, 25%). LC-MS m/z 385 (M+H) + , 1.07 (ret. time).

Example 37. 5-Cyclopropyl-1-(3-{2-fluoro-3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

37a) (R)-2-propyl-piperidine

A solution of racemic 2-n-propylpiperidine (3.00 g, 23.6 mmol) in dry MeOH (9.5 mL) was treated with (S)-(+)-mandelic acid (3.59 g, 23.6 mmol) with cooling in an ice bath. Dry ether (21 mL) was then added and the flask left in the fridge for 6 days. The solid was filtered off and rinsed with cold ether. The solid was then redissolved in dry MeOH (6.5 mL) and then dry ether (13 mL) added. Left in fridge overnight and then solid filtered off, again washing with cold ether to give 1.67 g of salt. The salt was dissolved in water (14 mL) and then solid KOH was added until basic. The mixture was extracted with Et 2 O (×3) before it was dried (MgSO 4 ) and filtered. HCl in Et 2 O (2M, 3 mL) was added and concentrated to give the product (0.965 g, 25%) as the HCl salt.

37b) (3-Bromo-2-fluoro-phenyl)-((R)-2-propyl-piperidin-1-yl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.090 g, 0.41 mmol), HATU (0.156 g, 0.41 mmol), (R)-2-propyl-piperidine hydrochloride (0.067 g, 0.41 mmol) and DIPEA (0.179 mL, 1.03 mmol) in DCM (2 mL) was stirred for 2 h. The mixture was diluted with DCM and the organic phase washed with aqueous NaHCO 3 and dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography (EtOAc/petrol 5-30% gradient) to give the product (0.115 g, 64%). Chiral HPLC rt 6.61 min.

37c) 5-Cyclopropyl-1-(3-{2-fluoro-3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-((R)-2-propyl-piperidin-1-yl)-methanone (0.103 g, 0.31 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.120 g, 0.31 mmol), aqueous Na 2 CO 3 (3M, 0.314 mL) and Pd(PPh 3 ) 4 (0.018 g, 0.02 mmol) in EtOH (1 mL) and toluene (3 mL) was heated at reflux for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (15 mL) and the organic phase was washed with water (15 mL) and brine (15 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness and purified by silica chromatography (EtOAc/petrol 20-70% gradient) to give the product (0.133 g, 84%). LC-MS m/z 504 (M+H) + , 1.64 (ret. time).

37d) 5-Cyclopropyl-1-(3-{2-fluoro-3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{2-fluoro-3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.133 g, 0.26 mmol) in EtOH (2 mL) was treated with aqueous NaOH (2M, 0.66 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was further extracted with water and then discarded. The combined aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.074 g, 59%). LC-MS m/z 476 (M+H) + , 1.18 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.30 (1H, s), 7.97 (1H, s), 7.82-7.72 (1H, m), 7.72-7.58 (4H, m), 7.48-7.26 (2H, m), 4.78 (0.6H, brs), 4.44 (0.4H, m), 3.56 (0.5H, s), 3.26-3.03 (1H, m), 2.79 (0.5H, t), 2.19-2.08 (1H, m), 1.88-1.39 (7H, m), 1.38-1.14 (3H, m), 1.02-0.81 (4H, m), 0.81-0.62 (1H, m), 0.58 (2H, d).

Example 38. 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(3,3,3-trifluoropropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

38a) 2-(3,3,3-Trifluoro-propyl)-pyridine

PdCl 2 dppf (231 mg, 0.32 mmol) was added to a solution of 2-bromopyridine (1.0 g, 6.33 mmol) and 3,3,3-trifluoropropyl zinc bromide (0.5M in Et 2 O, 19 mL, 9.5 mmol) in dry dioxane (20 mL) under nitrogen and the reaction heated to reflux for 2 h under N 2 (the reflux condenser was not turned on initially to allow loss of ether). The reaction mixture was concentrated and then partitioned between EtOAc (40 mL) and water (30 mL). The organic phase was washed with water, brine, and then dried (MgSO 4 ), filtered, and concentrated. Silica purification eluting with EtOAc/hexane 3-30% gave the product (0.495 g, 45%). LC-MS no mass ion observed, 1.22 (ret. time), basic method.

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 12 of 18

38b) 2-(3,3,3-Trifluoro-propyl)-piperidine

To a solution of 2-(3,3,3-Trifluoro-propyl)-pyridine (0.495 g, 2.93 mmol) in ethanol (40 mL) was added HCl in dioxane (4M, 0.78 mL, 3.11 mmol) and PtO 2 (60 mg) and the mixture shaken under a hydrogen atmosphere for 4 h. The catalyst was removed by filtration and then the solution concentrated to dryness to give product (480 mg, 78%) as the HCl salt. 1 H NMR (400 MHz, DMSO-d6): 9.39-8.72 (2H, m), 3.23 (1H, d), 3.06 (1H, s), 2.82 (1H, dd), 2.49-2.24 (2H, m), 2.01-1.82 (2H, m), 1.82-1.68 (3H, m), 1.68-1.50 (1H, m), 1.50-1.33 (2H, m).

38c) (3-Bromo-2-fluoro-phenyl)-[2-(3,3,3-trifluoro-propyl)-piperidin-1-yl]-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.200 g, 0.91 mmol), HATU (0.347 g, 0.91 mmol), 2-(3,3,3-trifluoro-propyl)-piperidine (0.199 g, 0.91 mmol) and DIPEA (0.477 mL, 2.74 mmol) in DCM (5 mL) was stirred for 3 h. The mixture was diluted with DCM and the organic phase was washed with aqueous NaHCO 3 and dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (0.340 g, 97%), used without further purification. LC-MS m/z 382 (M+H) + , 1.50 (ret. time), basic method.

38d) 5-Cyclopropyl-1-(3-{2-fluoro-3-[2-(3,3,3-trifluoropropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-[2-(3,3,3-trifluoro-propyl)-piperidin-1-yl]-methanone (0.212 g, 0.55 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.170 g, 0.46 mmol), aqueous Na 2 CO 3 (3M, 0.462 mL) and Pd(PPh 3 ) 4 (0.032 g, 0.05 mmol) in EtOH (1.5 mL) and toluene (4.5 mL) was heated at reflux for 2 h. After cooling, the mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the organic phase was washed with water (20 mL) and brine (20 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography (EtOAc/petrol 10-50% gradient) to give the product (0.141 g, 56%). LC-MS m/z 544 (M+H) + , 1.56 (ret. time), basic method.

38e) 5-cyclopropyl-1-(3-{2-fluoro-3-[2-(3,3,3-trifluoropropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{2-fluoro-3-[2-(3,3,3-trifluoropropyl)piperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (0.141 g, 0.26 mmol) in EtOH (2 mL) was treated with aqueous NaOH (2M, 0.65 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was extracted ith further water and then discarded. The combined aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.093 g, 68%). LC-MS m/z 530 (M+H) + , 1.18 (ret. time), basic method. 1H NMR (400 MHz, DMSO-d6): 12.26 (1H, s), 7.97 (1H, s), 7.83-7.72 (1H, m), 7.72-7.60 (4H, m), 7.50-7.36 (2H, m), 4.84 (0.7H, s), 4.46 (0.3H, s), 3.67 (0.3H, s), 3.31-3.23 (0.9H, m), 3.15 (0.8H, d), 2.30 (1H, d), 2.22-2.01 (3H, m), 1.83-1.44 (6H, m), 1.44-1.23 (1H, m), 0.87 (2H, s), 0.57 (2H, d). Peaks close to amide are rotameric.

Example 39. 5-cyclopropyl-1-{3-[2-fluoro-3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

39a) 1-(3-chloro-2-fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A mixture of ethyl acetoacetate (2.01 mmol) and DMF-dimethyl acetal (2.01 mmol) was stirred in a microwave reactor at 130° C. for 15 min. After cooling, the stirred mixture was diluted with EtOH (5 mL) and treated with 3-chloro-2-fluorophenylhydrazine HCl (0.330 g, 1.68 mmol), followed by triethylamine (0.23 mL, 1.68 mmol) and heated at 80° C. for 3 h. After cooling, the mixture was concentrated to dryness and purified by silica eluting with EtOAc/petrol 10% to give the product (0.462 g, 97%). LC-MS m/z 283 (M+H) + , 1.44 (ret. time).

39b) 1-(3-Chloro-2-fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-(3-chloro-2-fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.462 g, 1.64 mmol) in MeOH (3 mL) was treated with aqueous NaOH (2M, 4 mL) and heated to 60° C. After 90 min. the mixture was partitioned between DCM and water. The aqueous layer was acidified with 1N HCl and cooled in an ice bath. The resulting precipitate was isolated by filtration, washed with water, and dried to give the product (0.403 g, 90%). LC-MS m/z 255 (M+H) + , 0.86 (ret. time).

39c) 1-(3-Chloro-2-fluoro-phenyl)-5-methyl-1H-pyrazole

A stirred solution of 1-(3-chloro-2-fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (0.40 3 g, 1.58 mmol) in quinoline (0.5 mL) was heated at 240° C. for 3 h. After cooling the solution was loaded onto a silica column and eluted with EtOAc/petrol 20%. Combined fractions containing the product were concentrated to ⅓ volume and washed with aqueous citric acid (5%), dried (MgSO 4 ), and concentrated to dryness to give the product (0.086 g, 26%). LC-MS m/z 211 (M+H) + , 1.31 (ret. time).

39d) 5-Cyclopropyl-1-{3-[2-fluoro-3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred mixture of 1-(3-chloro-2-fluoro-phenyl)-5-methyl-1H-pyrazole (0.86 g, 0.4 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.144 g, 0.66 mmol), aqueous Cs 2 CO 3 (0.156 g, 0.48 mmol) and Pd 2 dba 3 (0.018 g, 0.014 mmol), P( t Bu) 3 in dioxane (1 mL) under N 2 was heated in a microwave at 120° C. for 1 h. After cooling, the mixture was treated with aqueous NaOH (2M, 2 mL). After 16 hours the mixture was partitioned between DCM and water. The aqueous layer was acidified with 1N HCl and extracted into IPA/CHCl 3 (1:3 mix, ×4). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum, and the residue was purified by HPLC to give the product (0.007 g, 4%). LC-MS m/z 403 (M+H) + , 1.08 (ret. time).

Example 40. 1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-5-[2-(pyridin-3-yl)cyclopropyl]-1H-pyrazole-4-carboxylic Acid

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 13 of 18

40a) (E)-3-Pyridin-2-yl-acrylic Acid Methyl Ester

A stirred suspension of 60% sodium hydride (0.48 g, 12.0 mmol) in THF (62 mL) at 0° C. under nitrogen was treated dropwise with (EtO) 2 P(O)CH 2 CO 2 Me (3.97 mL, 24.0 mmol). After 30 min, pyridine-3-carboxaldehyde (1.00 g, 9.24 mmol) in 5 mL of THF was added dropwise. After a further 1.5 h at 0° C., the reaction mixture was partitioned between diethyl ether and water. The organic phase was dried, filtered, and concentrated under vacuum. Silica chromatography with EtOAc in petrol gave the product (1.46 g, 97%). LC-MS m/z 164 (M+H) + , 1.05 (ret. time) basic method.

40b) 2-Pyridin-2-yl-cyclopropanecarboxylic Acid Methyl Ester

Trimethyl sulfoxonium iodide (2.37 g, 10.7 mmol) was added slowly in small portions over a period of 20 min, to a stirred suspension of sodium hydride (0.43 g, 10.7 mmol) in dry DMSO (60 mL) at RT. After 1 h, a clear solution was formed and a solution of (E)-3-pyridin-2-yl-acrylic acid methyl ester (1.46 g, 8.95 mmol) in dry DMSO (50 mL) was added slowly dropwise. After 30 min, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice water (2×100 mL), brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness to give the product, used without further purification (0.810 g, 51%). LC-MS m/z 178 (M+H) + , 1.12 (ret. time) basic method.

40c) 2-Pyridin-2-yl-cyclopropanecarboxylic Acid

A stirred solution of 2-pyridin-2-yl-cyclopropanecarboxylic acid methyl ester (0.80 g, 4.51 mmol) in THF/MeOH (1:1, 23 mL) was treated with a solution of LiOH (0.967 g, 22.6 mmol) in water (23 mL). After 4 hours the reaction was diluted with water and the pH adjusted to pH4 (aqueous citric acid 5%). The mixture was extracted with IPA:CHCl 3 (1:3, ×3) and the combined organic layers washed with brine, dried over MgSO 4 , filtered, and concentrated to dryness. Purification by silica chromatography eluting with EtOAc/petrol gave the product (0.50 g, 68%). LC-MS m/z 164 (M+H) + , 0.20 (ret. time) basic method.

40d) 3-Oxo-3-(2-pyridin-2-yl-cyclopropyl)-propionic Acid Methyl Ester

1,10-carbonyldiimidazole (0.55 g, 3.37 mmol) was added portionwise over 5 min to a stirred solution of 2-pyridin-2-yl-cyclopropanecarboxylic acid (0.50 g, 3.06 mmol) in anhydrous THF (8 mL) under argon. After 1 h, a mixture of MgCl 2 (0.58 g, 6.13 mmol) and potassium hydrogen methyl malonate (1.44 g, 9.19 mmol) was added. After 7 h the mixture was concentrated under vacuum and diluted with ethyl acetate. The mixture was then washed with aqueous NaHSO 4 (1M) and brine, and the organic phase dried over Na 2 SO 4 , filtered, and concentrated to dryness to give the product, used without further purification (0.80 g, quantative). LC-MS m/z 220 (M+H) + , 1.10 (ret. time), basic method.

40e) 1-(3-Bromo-phenyl)-5-(2-pyridin-2-yl-cyclopropyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A mixture of 3-oxo-3-(2-pyridin-2-yl-cyclopropyl)-propionic acid methyl ester (0.80 g, 3.65 mmol) and DMF-dimethyl acetal (1.455 mL, 11.0 mmol) was stirred at room temperature for 24 h, then concentrated to dryness under vacuum. The residue was treated with toluene and again concentrated to dryness. The residue was taken up into MeCN (12 mL) and, with stirring at 0° C., treated with DIPEA (1.57 mL, 9.02 mmol) and, portionwise, 3-bromophenylhydrazine hydrochloride (0.905 g, 3.97 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h, then diluted with aqueous citric acid (5%) and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated to dryness. Silica purification eluting with EtOAc/petrol gave the product (0.293 g, 20%). LC-MS m/z 398 (M+H) + , 1.44 (ret. time).

40f) 1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-5-[2-(pyridin-2-yl)cyclopropyl]-1H-pyrazole-4-carboxylic Acid

A stirred mixture of 1-(3-bromo-phenyl)-5-(2-pyridin-2-yl-cyclopropyl)-1H-pyrazole-4-carboxylic acid methyl ester (0.060 g, 0.15 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-(2-propyl-piperidin-1-yl)-methanone (0.059 g, 0.17 mmol), aqueous Na 2 CO 3 (3M, 0.055 mL) and Pd(PPh 3 ) 4 (0.006 g, 0.008 mmol) in dioxane/water 1:1 (2 mL) was heated at 100° C. for 2 h. After cooling, the mixture was diluted with MeOH (3 mL) and treated with LiOH (1M, 3 mL). After 24 hours the mixture was acidified with citric acid (5% aqueous) and extracted into EtOAc (×3). The combined organic phases were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated under vacuum. The residue was purified by silica column eluting with EtOAc/MeOH 0-10% to give the product (0.066 g, 82%). LC-MS m/z 535 (M+H) + , 1.14 (ret. time). 1 H NMR (400 MHz, Me-d 3 -OD): 8.20 (1H, d), 8.06 (1H, s), 7.95 (1H, s), 7.78-7.69 (2H, m), 7.64-7.47 (5H, m), 7.41-7.30 (2H, m), 7.20 (1H, dd), 4.53 (0.5H, s), 3.82 (0.5H, d), 3.57-3.47 (0.5H, m), 3.23 (1H, br s), 2.94 (0.5H, br s), 2.53-2.45 (1H, m), 2.06 (1H, s), 1.95-1.54 (9H, m), 1.51-1.42 (2H, m), 0.98 (4H, s).

Example 41. 1-[3′-(2-Propyl-piperidine-1-carbonyl)-biphenyl-3-yl]-5-(2-pyridazin-3-yl-cyclopropyl)-1H-pyrazole-4-carboxylic Acid

41a) 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-(2-propyl-piperidin-1-yl)-methanone

A solution of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (1.00 g, 3.9 mmol), HBTU (1.97 g, 5.1 mmol), 2-propylpiperidine (0.550 g, 4.3 mmol) and DIPEA (1.02 mL, 5.9 mmol) in DCM (13 mL) was stirred for 16 h. The mixture was diluted with aqueous NaHCO 3 and extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO 4 ), and concentrated to dryness. The residue was purified by silica chromatography eluting with EtOAc/petrol 0-30% to give the product (1.10 g, 79%). LC-MS m/z 275 (M−82) + , 1.24 (ret. time).

41b) (E)-3-Pyridazin-3-yl-acrylic Acid Methyl Ester

A stirred suspension of 60% sodium hydride (0.48 g, 12.0 mmol) in THF (62 mL) at 0° C. under nitrogen was treated dropwise with (EtO) 2 P(O)CH 2 CO 2 Me (3.97 mL, 24.0 mmol). After 30 min, pyridazine-3-carboxaldehyde (1.00 g, 9.24 mmol) in 5 mL of THF was added dropwise. After a further 1.5 h at 0° C., the reaction mixture was partitioned between diethyl ether and water. The organic phase was dried, filtered, and concentrated under vacuum. Flash chromatography with 5% diethyl ether in petrol gave the product (0.86 g, 57%). LC-MS m/z 165 (M+H) + , 0.60 (ret. time).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 14 of 18

41c) 2-Pyridazin-3-yl-cyclopropanecarboxylic Acid

Trimethyl sulfoxonium iodide (1.38 g, 6.29 mmol) was added slowly in small portions over a period of 20 min, to a stirred suspension of sodium hydride (0.25 g, 6.29 mmol) in dry DMSO (35 mL) at RT. After 1 h, a clear solution was formed and a solution of (E)-3-pyridazin-3-yl-acrylic acid methyl ester (0.86 g, 5.24 mmol) in dry DMSO (29 mL) was added slowly dropwise. After 30 min, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice water (2×100 mL), brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness (0.18 g). A stirred solution of the ester (0.1 g, 0.56 mmol) in THF/MeOH (1:1, 3 mL) was treated with a solution of LiOH (0.12 g, 2.81 mmol) in water (3 mL). After 4 hours the reaction was diluted with water and the pH adjusted to pH4 (aqueous citric acid 5%). The mixture was extracted with IPA:CHCl 3 (1:3, ×3) and the combined organic layers washed with brine, dried over MgSO 4 , filtered, and concentrated to dryness. Purification by silica chromatography eluting with EtOAc/petrol gave the product (77 mg, 32%). LC-MS m/z 165 (M+H) + , 0.15 (ret. time).

41d) 3-Oxo-3-(2-pyridazin-3-yl-cyclopropyl)-propionic Acid Methyl Ester

1,1-carbonyldiimidazole (84 mg, 0.52 mmol) was added to a stirred solution of 2-pyridazin-3-yl-cyclopropanecarboxylic acid (77 mg, 0.47 mmol) in anhydrous THF (1 mL) under argon. After 1 h, a mixture of MgCl 2 (89 mg, 0.94 mmol) and potassium hydrogen methyl malonate (220 mg, 1.41 mmol) was added. After 14 h the mixture was concentrated under vacuum and diluted with ethyl acetate. The mixture was then washed with aqueous NaHSO 4 (1M) and brine, and the organic phase dried over Na 2 SO 4 , filtered, and concentrated to dryness to give the product, used without further purification (100 mg, 97%). LC-MS m/z 221 (M+H) + , 0.55 (ret. time).

41e) 1-(3-Bromo-phenyl)-5-(2-pyridazin-3-yl-cyclopropyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A mixture of 3-oxo-3-(2-pyridazin-3-yl-cyclopropyl)-propionic acid methyl ester (0.10 g, 0.45 mmol) and DMF-dimethyl acetal (0.181 mL, 1.36 mmol) was stirred at room temperature for 24 h, then concentrated to dryness under vacuum. The residue was treated with toluene and again concentrated to dryness. The residue was taken up into MeCN and, with stirring at 0° C., treated with DIPEA (2.17 mL, 1.24 mmol) and, portionwise, 3-bromophenylhydrazine hydrochloride (0.125 g, 0.55 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h, then diluted with aqueous citric acid (5%) and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated to dryness. Silica purification eluting with EtOAc/petrol gave the product (0.293 g, 20%). LC-MS m/z 399 (M+H) + , 1.27 (ret. time).

41f) 1-[3′-(2-Propyl-piperidine-1-carbonyl)-biphenyl-3-yl]-5-(2-pyridazin-3-yl-cyclopropyl)-1H-pyrazole-4-carboxylic Acid

A stirred mixture of 1-(3-bromo-phenyl)-5-(2-pyridazin-3-yl-cyclopropyl)-1H-pyrazole-4-carboxylic acid methyl ester (26 mg, 0.07 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-(2-propyl-piperidin-1-yl)-methanone (26 mg, 0.07 mmol), aqueous Na 2 CO 3 (3M, 0.05 mL) and Pd(PPh 3 ) 4 (3 g, 0.003 mmol) in dioxane/water 1:1 (1 mL) was heated at 100° C. for 2 h. After cooling, the mixture was diluted with MeOH (3 mL) and treated with LiOH (1M, 3 mL). After 24 hours the mixture was acidified with citric acid (5% aqueous) and extracted into EtOAc (×3). The combined organic phases were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated under vacuum. The residue was purified by silica column eluting with EtOAc/MeOH 0-10% to give the product (19 mg, 51%). LC-MS m/z 536 (M+H) + , 1.13 (ret. time). 1 H NMR (400 MHz, Me-d 3 -OD): [presence of rotamers] 8.84 (1H, d), 8.07 (1H, s), 7.76 (1H, s), 7.74-7.71 (1H, m), 7.63-7.49 (5H, m), 7.43-7.35 (2H, m), 7.23 (1H, dd), 4.61-4.47 (0.5H, m), 3.90-3.74 (0.5H, m), 3.58-3.53 (0.5H, m), 3.05-2.92 (0.5H, m), 2.92-2.85 (1H, m), 2.37-2.30 (1H, m), 1.94-1.39 (11H, m), 1.24-0.93 (3H, m), 0.81 (1H, br s)

Example 42. 5-[2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

42a) (E)-3-(1-Methyl-1H-[1,2,3]triazol-4-yl)-acrylic Acid Benzyl Ester

A mixture of 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (0.63 g, 5.67 mmol) and benzyl (triphenylphosphoranylidene)acetate (2.69 mL, 6.24 mmol) in toluene (14 mL) was stirred at 120° C. for 2 h. The mixture was then concentrated to dryness under vacuum, and the residue purified by silica chromatography eluting with EtOAc/petrol to give the product (0.764 g, 55%). LC-MS m/z 244 (M+H) + , 1.25 (ret. time).

42b) 2-(1-Methyl-1H-[1,2,3]triazol-4-yl)-cyclopropanecarboxylic Acid Benzyl Ester

Trimethyl sulfoxonium iodide (0.83 g, 3.77 mmol) was added slowly in small portions over a period of 20 min, to a stirred suspension of sodium hydride (0.151 g, 3.77 mmol) in dry DMSO (21 mL) at RT. After 1 h, a clear solution was formed and a solution of (E)-3-(1-methyl-1H-[1,2,3]triazol-4-yl)-acrylic acid benzyl ester (0.764 g, 3.14 mmol) in dry DMSO (17 mL) was added slowly dropwise. After 30 min, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice water (2×100 mL), brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness to give the product, used without further purification (0.60 g, 62%). LC-MS m/z 258 (M+H) + , 1.24 (ret. time).

42c) 2-(1-Methyl-1H-[1,2,3]triazol-4-yl)-cyclopropanecarboxylic Acid

A stirred solution of 2-(1-methyl-1H-[1,2,3]triazol-4-yl)-cyclopropanecarboxylic acid benzyl ester (0.60 g, 2.33 mmol) in THF/MeOH (1:1, 12 mL) was treated with a solution of LiOH (0.499 g, 11.7 mmol) in water (12 mL). After 24 hours the reaction was diluted with water and the pH adjusted to pH4 (aqueous citric acid 5%). The mixture was extracted with EtOAc (×3) and the combined organic layers washed with brine, dried over MgSO 4 , filtered, and concentrated to dryness to give the product (0.10 g, 26%). 1 H-NMR (400 MHz, Me-d3-OD): 7.75 (s, 1H), 4.05 (s, 3H), 2.51 (ddd, 1H), 1.95 (ddd, 1H), 1.52 (ddd, 1H), 1.42 (ddd, 1H).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 15 of 18

42d) 3-[2-(1-Methyl-1H-[1,2,3]triazol-4-yl)-cyclopropyl]-3-oxo-propionic acid methyl Ester

1,10-carbonyldiimidazole (0.109 g, 0.67 mmol) was added portionwise over 5 min to a stirred solution of 2-(1-methyl-1H-[1,2,3]triazol-4-yl)-cyclopropanecarboxylic acid (0.100 g, 0.61 mmol) in anhydrous THF (2 mL) under argon. After 1 h, a mixture of MgCl 2 (0.116 g, 1.22 mmol) and potassium hydrogen methyl malonate (0.285 g, 1.83 mmol) was added. After 24 h the mixture was concentrated under vacuum and diluted with ethyl acetate. The mixture was then washed with aqueous NaHSO 4 (1M) and brine, and the organic phase dried over Na 2 SO 4 , filtered, and concentrated to dryness to give the product, used without further purification (0.187 g, quantative). LC-MS m/z 224 (M+H) + , 0.68 (ret. time).

42e) 1-(3-Bromo-phenyl)-5-[2-(1-methyl-1H-[1,2,3]triazol-4-yl)-cyclopropyl]-1H-pyrazole-4-carboxylic Acid Methyl Ester

A mixture of 3-[2-(1-methyl-1H-[1,2,3]triazol-4-yl)-cyclopropyl]-3-oxo-propionic acid methyl ester (0.187 g, 0.50 mmol) and DMF-dimethyl acetal (0.20 mL, 1.51 mmol) was stirred at room temperature for 24 h, then concentrated to dryness under vacuum. The residue was treated with toluene and again concentrated to dryness. The residue was taken up into MeCN (2 mL) and, with stirring at 0° C., treated with DIPEA (0.218 mL, 1.25 mmol) and, portionwise, 3-bromophenylhydrazine hydrochloride (0.123 g, 0.55 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h, then diluted with aqueous citric acid (5%) and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated to dryness to give the product (0.200 g, 50%), used without further purification. LC-MS m/z 402 (M+H) + +, 1.26 (ret. time).

42f) 5-[2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred mixture of 1-(3-bromo-phenyl)-5-[2-(1-methyl-1H-[1,2,3]triazol-4-yl)-cyclopropyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.200 g, 0.25 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-(2-propyl-piperidin-1-yl)-methanone (0.098 g, 0.27 mmol), aqueous Na 2 CO 3 (3M, 0.029 mL) and Pd(PPh 3 ) 4 (0.010 g, 0.012 mmol) in dioxane/water 1:1 (2 mL) was heated at 100° C. for 2 h. After cooling, the mixture was diluted with MeOH (3 mL) and treated with LiOH (1M, 3 mL). After 24 hours the mixture was acidified with citric acid (5% aqueous) and extracted into EtOAc (×3). The combined organic phases were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated under vacuum. The residue was purified by HPLC to give the product (0.042 g, 31%). LC-MS m/z 539 (M+H) + , 1.15 (ret. time). 1 H-NMR (400 MHz, Me-d3-OD): 8.08 (1H, s), 7.81-7.76 (2H, m), 7.67-7.54 (5H, m), 7.45 (1H, s), 7.40 (1H, d), 4.60-4.43 (0.5H, m), 3.90 (3H, s), 3.89-3.81 (0.5H, m), 3.62-3.51 (0.5H, m), 3.24 (1H, s), 2.96 (0.5H, s), 2.61-2.54 (1H, m), 2.23-2.16 (1H, m), 1.93-1.52 (11H, m), 1.43-1.34 (2H, m), 1.04 (1H, s), 0.81 (1H, d).

Example 43. 5-Cyclopropyl-1-[3-(2-fluoro-3-{2-oxa-8-azaspiro[5.5]undecane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid

43a) 5-Cyclopropyl-1-[3-(2-fluoro-3-{2-oxa-8-azaspiro[5.5]undecane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.065 g, 0.17 mmol), HATU (0.065 g, 0.17 mmol), 2-oxa-8-azaspiro[5.5]undecane (0.032 g, 0.21 mmol) and DIPEA (0.060 mL, 0.34 mmol) in DCM (1.5 mL) was stirred for 18 h. The mixture was diluted with DCM, and the organic phase washed with aqueous NaHCO 3 , dried (MgSO 4 ), filtered, and concentrated to dryness. Silica purification eluting with EtOAc/hexane 20-70% gave the product (0.092 g, quantative). LC-MS m/z 518 (M+H) + , 1.45 (ret. time), basic method.

43b) 5-Cyclopropyl-1-[3-(2-fluoro-3-{2-oxa-8-azaspiro[5.5]undecane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-[3-(2-fluoro-3-{2-oxa-8-azaspiro[5.5]undecane-8-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.092 g, 0.18 mmol) in EtOH (1.5 mL) was treated with aqueous NaOH (2M, 0.444 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was extracted with further water and then discarded. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.071 g, 80%). LC-MS m/z 504 (M+H) + , 1.08 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.46-12.14 (1H, m), 7.97 (1H, s), 7.79 (1H, s), 7.73-7.60 (4H, m), 7.46-7.35 (2H, m), 3.84-3.59 (1H, m), 3.59-3.38 (3H, m), 3.30-3.02 (4H, m), 2.20-2.08 (1H, m), 1.77-1.61 (1H, m), 1.61-1.40 (4H, m), 1.40-1.15 (3H, m), 0.94-0.80 (2H, m), 0.63-0.52 (2H, m).

Example 44. 5-cyclopropyl-1-[3-(2-fluoro-3-{6-oxa-9-azaspiro[4.5]decane-9-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid

44a) (3-Bromo-2-fluoro-phenyl)-(6-oxa-9-aza-spiro[4.5]dec-9-yl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.200 g, 0.91 mmol), HATU (0.347 g, 0.91 mmol), 6-oxa-9-aza-spiro[4.5]decane (0.129 g, 0.91 mmol) and DIPEA (0.318 mL, 1.83 mmol) in DCM (5 mL) was stirred for 3 h. The mixture was diluted with DCM and the organic phase washed with aqueous NaHCO 3 and dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (0.380 g, quantative), used without further purification. LC-MS m/z 342 (M+H) + , 1.36 (ret. time).

44b) 5-Cyclopropyl-1-[3-(2-fluoro-3-{6-oxa-9-azaspiro[4.5]decane-9-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-(6-oxa-9-aza-spiro[4.5]dec-9-yl)-methanone (0.209 g, 0.61 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.150 g, 0.41 mmol), aqueous Na 2 CO 3 (3M, 0.407 mL) and Pd(PPh 3 ) 4 (0.035 g, 0.03 mmol) in EtOH (1 mL) and toluene (3 mL) was heated at reflux for 2 h. After cooling, the mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the organic phase was washed with water (20 mL) and brine (20 mL) before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica chromatography (EtOAc/petrol 5-80% gradient) to give the product (0.144 g, 70%). LC-MS m/z 504 (M+H) + , 1.50 (ret. time).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 16 of 18

44c) 5-Cyclopropyl-1-[3-(2-fluoro-3-{6-oxa-9-azaspiro[4.5]decane-9-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-[3-(2-fluoro-3-{6-oxa-9-azaspiro[4.5]decane-9-carbonyl}phenyl)phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.144 g, 0.29 mmol) in EtOH (2 mL) was treated with aqueous NaOH (2M, 0.715 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was further extracted with water. The combined aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.097 g, 69%). LC-MS m/z 490 (M+H) + , 1.12 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.28 (1H, s), 7.97 (1H, s), 7.80 (1H, d), 7.74-7.62 (4H, m), 7.49-7.37 (2H, m), 3.77-3.59 (2H, m), 3.59-3.43 (2H, m), 3.28 (1H, s), 3.23-3.15 (1H, m), 2.20-2.09 (1H, m), 1.78-1.53 (6H, m), 1.46 (1H, s), 1.38-1.23 (1H, m), 0.92-0.81 (2H, m), 0.62-0.52 (2H, m).

Example 45. 5-cyclopropyl-1-(3-{2-fluoro-3-[(2S,5R)-2-methyl-5-propylmorpholine-4-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

45a) (R)-2-((S)-2-Hydroxy-propylamino)-pentan-1-ol

To a solution of (R)-2-amino-pentanol (0.465 g, 4.51 mmol) in water (5 mL) cooled in an ice bath was added (S)-2-methyloxirane (0.288 g, 4.96 mmol) dropwise over 15 minutes. The solution was allowed to warm to rt and stirred for 18 h. The reaction mixture was concentrated to dryness to give the product (0.73 g, 100%) used directly in the next reaction.

45b) N—((R)-1-Hydroxymethyl-butyl)-N—((S)-2-hydroxy-propyl)-4-methyl-benzenesulfonamide

A mixture of (R)-2-((S)-2-Hydroxy-propylamino)-pentan-1-ol (0.73 g, 4.53 mmol), toluenesulfonyl chloride (1.726 g, 9.05 mmol) and triethylamine (13.6 g, 13.6 mmol) in DCM (18 mL) was stirred at rt for 18 h. The reaction mixture was partitioned between further DCM (50 mL) and aqueous Sodium bicarbonate (40 mL). The organic phase was washed with water and brine and then dried (MgSO 4 ), filtered, and concentrated to dryness. Silica chromatography, eluting with 15-60% EtOAc in petroleum ether gave the product (0.423 g, 30%). LC-MS m/z 316 (M+H) + , 1.27 (ret. time), basic method.

45c) (2S,5R)-2-Methyl-5-propyl-4-(toluene-4-sulfonyl)-morpholine

A mixture of N—((R)-1-Hydroxymethyl-butyl)-N—((S)-2-hydroxy-propyl)-4-methyl-benzenesulfonamide (0.423 g, 1.34 mmol) and tosyl imidazole (0.298 g, 1.34 mmol) was stirred at rt for 30 minutes in THF (10 mL). Cooled to 0° C. and sodium hydride (0.134 g, 3.35 mmol) was added. The reaction was stirred at rt for 60 h. The mixture was partitioned between EtOAc and water and then the organic phase was washed with water and brine before it was dried (MgSO 4 ), filtered, and concentrated. Silica chromatography, eluting with 0-40% EtOAc/petroleum ether gave the product (0.349 mg, 88%).

45d) (2S,5R)-2-methyl-5-propylmorpholine

Magnesium turnings (0.31 g, 12.9 mmol) were stirred under a nitrogen atmosphere for 18 h to activate the surface. Dry MeOH (6 mL) was added followed by a solution of (2S,5R)-2-methyl-5-propyl-4-(toluene-4-sulfonyl)-morpholine (0.349 g, 1.17 mmol) in dry MeOH (3 mL) in small batches. There were no initial signs of a reaction, so the flask was left in a room temperature water bath for 2 h. The clear solution had turned grey and the reaction was left to stir for 18 h. The mixture was partitioned between aqueous NH 4 Cl and EtOAc and then the aqueous phase extracted with further EtOAc. The combined organic layers were washed with brine, dried (MgSO 4 ), filtered, and concentrated to dryness to give product (0.175 g, quantative).

45e) 5-Cyclopropyl-1-(3-{2-fluoro-3-[(2S,5R)-2-methyl-5-propylmorpholine-4-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.050 g, 0.13 mmol), HATU (0.050 g, 0.13 mmol), (2S,5R)-2-methyl-5-propylmorpholine (0.028 g, 0.16 mmol) and DIPEA (0.057 mL, 0.33 mmol) in DCM (1 mL) was stirred for 2 h. The mixture was diluted with DCM, and the organic phase washed with aqueous NaHCO 3 , dried (MgSO 4 ), filtered, and concentrated to dryness. Silica purification eluting with EtOAc/petrol 15-60% gave the product (0.036 g, 54%). LC-MS m/z 506 (M+H) + , 1.50 (ret. time), basic method.

45f) 5-Cyclopropyl-1-(3-{2-fluoro-3-[(2S,5R)-2-methyl-5-propylmorpholine-4-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{2-fluoro-3-[(2S,5R)-2-methyl-5-propylmorpholine-4-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (0.036 g, 0.07 mmol) in EtOH (0.5 mL) was treated with aqueous NaOH (2M, 0.178 mL). After 60 hours the mixture was partitioned between EtOAc and water. The organic phase was extracted with further water and then discarded. The combined aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.016 g, 46%). LC-MS m/z 492 (M+H) + , 1.08 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.36-12.19 (1H, m), 7.97 (1H, s), 7.79 (1H, s), 7.74-7.61 (4H, m), 7.53-7.31 (2H, m), 4.56-4.45 (0.5H, m), 4.16-4.06 (0.5H, m), 4.00-3.75 (2H, m), 3.63-3.36 (2H, m), 3.28-3.17 (0.5H, m), 2.98 (0.5H, d), 2.20-2.08 (1H, m), 1.66-1.45 (1H, m), 1.45-1.25 (2H, m), 1.17-1.06 (3H, m), 1.02-0.81 (5H, m), 0.81-0.63 (1H, m), 0.58 (2H, d).

Example 46. 5-(1-Acetylpiperidin-4-yl)-1-{3-[3-dimethylcarbamoyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

46a) 5-(1-Acetyl-piperidin-4-yl)-1-(3-bromo-phenyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A mixture of 3-(1-acetyl-piperidin-4-yl)-3-oxo-propionic acid methyl ester (250 mg, 1.04 mmol) and dimethylformamide dimethylacetal (0.15 mL, 1.14 mmol) and TsOH (2 mg) was heated at 130° C. in the microwave for 15 min. The mixture was concentrated under vacuum and the residue dissolved in acetonitrile (2 mL). Diisopropylamine (0.271 mL, 1.55 mol) was added followed by 3-bromophenylhydrazine hydrochloride (260 mg, 1.14 mmol). The solution was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc and washed with water (×7). The organic phase was dried over MgSO 4 , filtered, and concentrated under vacuum to afford the title compound (160 mg, 38%) which was used without further purification. LC-MS m/z 406 (M+H) + , 1.26 (ret. time).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 17 of 18

46b) 5-(1-Acetylpiperidin-4-yl)-1-{3-[3-dimethylcarbamoyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A mixture of 5-(1-acetyl-piperidin-4-yl)-1-(3-bromo-phenyl)-1H-pyrazole-4-carboxylic acid methyl ester (160 mg, 0.39 mmol), N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (119 mg, 0.43 mmol), sodium carbonate (46 mg, 0.43 mmol) and tetrakistriphenylphosphine palladium (16 mg, 0.02 mmol) in degassed dioxane (2 mL) and water (2 mL) was heated at 100° C. for 4 hours. The reaction was allowed to cool and MeOH (3 mL) and LiOH (1M, 3 mL) were added. The mixture was stirred at room temperature for 16 hours. The aqueous was acidified with citric acid (5% aqueous). The product extracted with EtOAc (×3). The combined organic layers were washed with water, brine and dried over MgSO 4 . The product was filtered and evaporated to dryness. Purification by prep HPLC gave the title compound (50 mg, 28%). LC-MS m/z 164 (M+H) + , 0.97 (ret. time). 1 H NMR (400 MHz, Me-d3-OD): 8.07 (1H, s), 7.91 (1H, d), 7.84-7.80 (1H, m), 7.76 (2H, d), 7.72 (1H, t), 7.60 (1H, t), 7.50-7.45 (2H, m), 4.63-4.56 (1H, m), 4.01-3.93 (1H, m), 3.29-3.19 (1H, m), 3.15 (3H, s), 3.09-2.99 (4H, m), 2.58-2.34 (3H, m), 2.10 (3H, s), 1.83-1.67 (2H, m).

Example 47. 1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid

47a) 3-Bromo-N-cyclopropylmethyl-2-fluoro-N-methyl-benzamide

A solution of 3-bromo-2-fluoro-benzoic acid (0.50 g, 2.28 mmol), HATU (1.30 g, 3.42 mmol), cyclopropylmethyl-methylamine (0.42 g, 3.42 mmol) and DIPEA (0.89 g, 6.85 mmol) in DMF (9 mL) was stirred for 18 h. The mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases washed with water (×2) and brine before drying (MgSO 4 ), filtering, and concentrating to give the product (0.708 g, quantative), used without further purification. LC-MS m/z 573 (2M+H) + , 1.32 (ret. time), basic method.

47b) 1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-N-cyclopropylmethyl-2-fluoro-N-methyl-benzamide (0.140 g, 0.49 mmol), 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.201 g, 0.49 mmol), Na 2 CO 3 (3M, 0.489 mL) and Pd(PPh 3 ) 4 (0.028 g, 0.02 mmol) in EtOH (2 mL) and toluene (7 mL) was heated at reflux for 18 h. After cooling, the mixture was partitioned between EtOAc (150 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated to give the product (212 mg, 97%). LC-MS m/z 490 (M+H) + , 1.51 (ret. time), basic method.

47c) 1-(3-{3-[(Cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.212 g, 0.43 mmol) in EtOH (3 mL) was treated with a solution of NaOH (0.069 g) in water (0.75 mL). After 60 hours the mixture was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.048 g, 24%). LC-MS m/z 462 (M+H) + , 1.09 (ret. time). 1 H NMR (400 MHz, DMSO-d6): 13.36 (1H, s), 8.27 (1H, s), 7.86-7.57 (5H, m), 7.48-7.35 (2H, m), 3.45-3.35 (1H, m), 3.13-3.01 (2H, m), 2.98-2.89 (1H, m), 1.15-1.02 (1H, m), 0.95-0.83 (1H, m), 0.56-0.48 (1H, m), 0.44 (1H, d), 0.35-0.25 (1H, m), 0.07 (1H, s).

Example 48. 5-cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

48a) 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of 3-bromo-N-cyclopropylmethyl-2-fluoro-N-methyl-benzamide (0.141 g, 0.49 mmol), 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-5-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.188 g, 0.49 mmol), Na 2 CO 3 (3M, 0.492 mL) and Pd(PPh 3 ) 4 (0.028 g, 0.02 mmol) in EtOH (1.5 mL) and toluene (7 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the organic phase washed with water (20 mL) and brine (20 mL) before it was dried (MgSO 4 ), filtered, and concentrated to give the product (250 mg, quantative). LC-MS m/z 462 (M+H) + , 1.48 (ret. time), basic method.

48b) 5-Cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-(3-{3-[(cyclopropylmethyl)(methyl)carbamoyl]-2-fluorophenyl}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.250 g, 0.54 mmol) in EtOH (4 mL) was treated with aqueous NaOH (2M, 1.08 mL). After 60 hours the mixture was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.079 g, 34%). LC-MS m/z 434 (M+H) + , 1.05 (ret. time). 1 H NMR (400 MHz, DMSO-d6): 12.20 (1H, s), 7.97 (1H, s), 7.79 (1H, s), 7.76-7.57 (4H, m), 7.52-7.34 (2H, m), 3.47-3.36 (1H, m), 3.14-3.01 (2H, m), 2.94 (1H, s), 2.21-2.06 (1H, m), 1.14-1.01 (1H, m), 0.96-0.80 (3H, m), 0.62-0.53 (2H, m), 0.53-0.48 (1H, m), 0.44 (1H, d), 0.36-0.25 (1H, m), 0.07 (1H, d).

Example 49. 1-{3-[3-(dimethylcarbamoyl)phenyl]phenyl}-5-(3-phenylcyclobutyl)-1H-pyrazole-4-carboxylic Acid AT29349/GSK3180353A Astex Example 62

49a) 1-(3-Bromo-phenyl)-5-(3-phenyl-cyclobutyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

Under argon, 1,1-carbonyldiimidazole (552 mg 3.4 mmol) was added portionwise to a solution of 3-phenyl-cyclobutanecarboxylic acid (500 mg, 2.84 mmol) in anhydrous THF (9 mL) and the mixture was stirred at room temperature for 1 hour. Then, a well homogenised and powdered solid mixture of MgCl 2 (270 mg, 2.84 mmol) and potassium hydrogen methyl malonate (665 mg, 4.26 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. The reaction was concentred under vacuum, ethyl acetate was added, and the organic layer was washed with NaHSO 4 (1M, aqueous) and then brine. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated to dryness under vacuum to give 3-oxo-3-(3-phenyl-cyclobutyl)-propionic acid methyl ester (0.63 g). A mixture of 3-oxo-3-(3-phenyl-cyclobutyl)-propionic acid methyl ester (0.63 g), dimethylformamide-dimethylacetal (1.32 mL, 3.12 mmol) and TsOH (5 mg) was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and dissolved in acetonitrile (9 mL). Diisopropylamine (0.742 mL, 4.26 mmol) was added followed by 3-bromophenylhydrazine hydrochloride (712 mg, 3.12 mmol). The solution was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc and washed with water (×7). The organic phase was dried over MgSO 4 , filtered, and concentrated under vacuum to afford the title compound (800 mg, 69%) which was used without further purification. LC-MS m/z 411 (M+H) + , 1.61 (ret. time).

›Example 11. 1-{3-[3-(propan-2-yloxy)phenyl]phenyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 18 of 18

49b) 1-{3-[3-(dimethylcarbamoyl)phenyl]phenyl}-5-(3-phenylcyclobutyl)-1H-pyrazole-4-carboxylic Acid

A mixture of cis and trans 1-(3-bromo-phenyl)-5-(3-phenyl-cyclobutyl)-1H-pyrazole-4-carboxylic acid methyl ester (800 mg, 2.5 mmol), N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.86 mg, 3.12 mmol), sodium carbonate (331 mg, 3.12 mmol) and tetrakistriphenylphosphine palladium (117 mg, 0.142 mmol) in degassed dioxane (14 mL) and water (14 mL) was heated at 100° C. for 2 hrs. After cooling, the mixture was diluted with NaHCO 3 (sat., aqueous) and extracted with EtOAc (×3). The combined organic layers were washed with water and brine, dried over MgSO 4 , filtered and concentrated to dryness under vacuum. The residue was treated with MeOH (3 mL) and LiOH (1M, 3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was acidified with citric acid (5% aqueous) and the product extracted with EtOAc (×3). The combined organic layers were washed with water and brine, dried over MgSO 4 , filtered and concentrated to dryness under vacuum. Purification by preparative HPLC gave the title compound (361 mg, 27%). LC-MS m/z 466 (M+H) + , 1.09 (ret. time). 1 H NMR (400 MHz, Me-d 3 -OD): 8.09-8.05 (1H, m), 7.91-7.67 (5H, m), 7.63-7.56 (1H, m), 7.52-7.45 (2H, m), 7.28-7.08 (5H, m), 4.23-4.11 (0.3H, m), 3.99-3.88 (0.7H, m), 3.60-3.50 (0.3H, m), 3.14 (3H, d), 3.06 (3.7H, d), 2.68-2.50 (3.3H, m), 2.46-2.37 (0.7H, m).

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 1 of 12

50a) 3-Furan-2-yl-phenol

A stirred mixture of 2-bromofuran (0.533 g, 0.3.63 mmol), 3-hydroxyphenylboronic acid (0.500 g, 3.63 mmol), aqueous Na 2 CO 3 (3M, 3.63 mL, 10.9 mmol) and Pd(PPh 3 ) 4 (0.210 g, 0.18 mmol) in EtOH (4.5 mL) and toluene (15 mL) was heated at reflux for 3 h. After cooling, the mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the organic phase washed with water (20 mL) and brine (20 mL) before it was dried (MgSO 4 ), filtered and concentrated. The crude product was purified by silica chromatography (EtOAc/petrol 5-50% gradient) to give the product (0.326 g, 56%). LC-MS m/z 159 (M−H) − , 1.21 (ret. time), basic method.

50b) 3-(Tetrahydro-furan-2-yl)-phenol

To a solution of 3-furan-2-yl-phenol (0.326 g, 2.03 mmol) in ethanol (30 mL) was added Pd/C (10%, 0.050 g) and the mixture shaken under an atmosphere of hydrogen for 4 h. The catalyst was removed by filtration and the solution concentrated to dryness. The crude product was purified by silica chromatography (EtOAc/petrol 10-65% gradient) to give the product (0.076 g, 23%). LC-MS m/z 163 (M−H) − , 1.03 (ret. time), basic method.

50c) Trifluoro-methanesulfonic acid 3-(tetrahydro-furan-2-yl)-phenyl Ester

A solution of 3-(tetrahydro-furan-2-yl)-phenol (0.076 g, 0.46 mmol) and triethylamine (0.070 g, 0.69 mmol) in DCM (2 mL) at 0° C. was treated with triflic anhydride (0.509 mL, 1M in DCM, 0.51 mmol) and the reaction stirred at 0° C. for 1 h. The solution was partitioned between DCM and aqueous sodium bicarbonate and then the organic phase dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (0.137 g, 100%). LC-MS m/z 314 (M+NH 4 ) + , 1.49 (ret. time), basic method.

50d) 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of trifluoro-methanesulfonic acid 3-(tetrahydro-furan-2-yl)-phenyl ester (0.134 g, 0.45 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.115 g, 0.30 mmol), aqueous Na 2 CO 3 (3M, 0.30 mL, 0.90 mmol) and Pd(PPh 3 ) 4 (0.017 g, 0.02 mmol) in EtOH (1 mL) and toluene (3 mL) was heated at reflux for 2 h. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (10 mL) and the organic phase washed with water (10 mL) and brine (10 mL) before it was dried (MgSO 4 ), filtered, and concentrated. The crude product was purified by silica chromatography (EtOAc/petrol 10-30% gradient) to give the product (0.066 g, 55%). LC-MS m/z 403 (M+H) + , 1.59 (ret. time), basic method.

50e) 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid

A solution of 5-cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.066 g, 0.16 mmol) in EtOH (2.5 mL) was treated with aqueous NaOH (2M, 0.82 mL). After 18 hours the mixture was partitioned between EtOAc and water. The organic phase was extracted with water and then discarded. The combined aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.053 g, 86%). LC-MS m/z 375 (M+H) + , 1.10 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 12.45-12.12 (1H, m), 7.97 (1H, s), 7.86 (1H, t), 7.82-7.75 (1H, m), 7.68-7.55 (4H, m), 7.45 (1H, t), 7.36 (1H, d), 4.89 (1H, t), 4.03 (1H, q), 3.84 (1H, q), 2.42-2.29 (1H, m), 2.23-2.11 (1H, m), 2.02-1.92 (2H, m), 1.80-1.68 (1H, m), 0.91-0.78 (2H, m), 0.64-0.51 (2H, m).

Example 51. 5-[(1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic acid and 5-[(1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

51a) (R)-2-Propyl-piperidine

To a solution of racemic 2-propylpiperidine (3.00 g, 23.6 mmol) in dry MeOH (9.5 mL) was added (S)-(+)-mandelic acid whilst cooling in an ice bath. Dry diethyl ether (21 mL) was then added and the mixture left in a fridge for 6 days. The solid was removed by filtration and rinsed with cold ether. The solid was then redissolved in dry MeOH (6.5 mL) and then dry diethyl ether (13 mL) was added. The mixture was left in a fridge for 18 h and then the solid was collected by filtration, and washed with ether to give 1.67 g of the salt. The salt was then dissolved in water (14 mL) and solid KOH added until basic. The aqueous phase was extracted with diethyl ether (×3) and then the combined organic phase was dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (0.965 g, 32%).

51b) ((R)-2-Propyl-piperidin-1-yl)-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone

A solution of 3-(pinacolborane)benzoic acid (1.35 g, 5.44 mmol), HATU (2.07 g, 5.44 mmol), (R)-2-propyl-piperidine.HCl (0.891 g, 5.44 mmol) and DIPEA (1.76 g, 13.6 mmol) in DCM (20 mL) was stirred for 2 h. The mixture was washed with aqueous NaHCO 3 and dried (MgSO 4 ). Concentration to dryness followed by silica column purification (EtOAc/petrol 5-30% gradient) gave the product (1.23 g, 63%).

51c) N′-(3-Bromo-phenyl)-hydrazinecarboxylic Acid Tert-Butyl Ester

A mixture of (3-bromo-phenyl)-hydrazine (4.00 g, 21.4 mmol) and triethylamine (6.42 g, 64.2 mmol) in DCM (40 mL) was treated with di-tertbutyl-dicarbonate (4.67 g, 21.4 mmol) and the reaction stirred for 18 h. The mixture was partitioned between DCM and water and then the organic phase dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (5.77 g, 94%). LC-MS m/z 231 (M+H(− t Bu)+H) + , 1.37 (ret. time), basic method.

51d) N′-[3′-((R)-2-Propyl-piperidine-1-carbonyl)-biphenyl-3-yl]-hydrazinecarboxylic Acid Tert-Butyl Ester

A stirred mixture of N′-(3-bromo-phenyl)-hydrazinecarboxylic acid tert-butyl ester (1.19 g, 4.13 mmol), ((R)-2-propyl-piperidin-1-yl)-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.23 g, 3.44 mmol), aqueous Na 2 CO 3 (3M, 3.44 mL, 10.3 mmol) and Pd(PPh 3 ) 4 (0.199 g, 0.17 mmol) in EtOH (10 mL) and toluene (30 mL) was heated at reflux for 2 h. After cooling, the mixture was partitioned between EtOAc (80 mL) and water (40 mL) and the organic phase washed with water (30 mL) and brine (30 mL) before it was dried (MgSO 4 ), filtered, and concentrated. The crude product was purified by silica chromatography (EtOAc/petrol 10-50% gradient) to give the product (0.615 g, 41%). LC-MS m/z 438 (M+H) + , 1.54 (ret. time), basic method.

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 2 of 12

51e) (3′-Hydrazino-biphenyl-3-yl)-((R)-2-propyl-piperidin-1-yl)-methanone

A solution of N′-[3′-((R)-2-Propyl-piperidine-1-carbonyl)-biphenyl-3-yl]-hydrazinecarboxylic acid tert-butyl ester (0.615 g, 1.41 mmol) in DCM (15 mL) was treated with HCl in dioxane (4M, 1.76 mL, 7.0 mmol) and the reaction stirred for 18 h. Further DCM was added and water, and the mixture basified with 2M NaOH. The aqueous phase was extracted with further DCM before the combined organic phase was dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (0.455 g, 96%). LC-MS m/z 338 (M+H) + , 1.38 (ret. time), basic method.

51f) 5-[trans-2-(1-Methyl-1H-[1,2,3]triazol-4-yl)-cyclopropyl]-1-[3′-((R)-2-propyl-piperidine-1-carbonyl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid Methyl Ester

A mixture of 3-[2-(1-methyl-1H-[1,2,3]triazol-4-yl)-cyclopropyl]-3-oxo-propionic acid methyl ester (0.505 g, 1.35 mmol) and DMF-dimethyl acetal (0.20 mL, 1.51 mmol) was stirred at room temperature for 24 h, then concentrated to dryness under vacuum. The residue was treated with toluene and again concentrated to dryness to give 3-dimethylamino-2-[2-(1-methyl-1H-[1,2,3]triazol-4-yl)-cyclopropanecarbonyl]-acrylic acid methyl ester (0.375 g, 1.35 mmol). This was taken up in ethanol (20 mL), treated with (3′-hydrazino-biphenyl-3-yl)-((R)-2-propyl-piperidin-1-yl)-methanone (0.455 g, 1.35 mmol) and triethylamine (0.337 g, 3.37 mmol), and stirred at room temperature for 18 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The aqueous phase was extracted with further EtOAc and then the combined organic phase was washed with brine, dried (MgSO 4 ), filtered and concentrated to dryness. Purification by silica chromatography (EtOAC/petrol 25-100% gradient) gave the product (0.295 g, 40%). LC-MS m/z 553 (M+H) + , 1.45 (ret. time), basic method.

51g) 5-[(1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

and

51h) 5-[(1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

A solution of 5-[trans-2-(1-methyl-1H-[1,2,3]triazol-4-yl)-cyclopropyl]-1-[3′-((R)-2-propyl-piperidine-1-carbonyl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic acid methyl ester (0.275 g, 0.50 mmol) in EtOH (7.5 mL) was treated with aqueous NaOH (2M, 2.49 mL). After 18 hours the mixture was concentrated to dryness and then partitioned between EtOAc and water, acidifying with 1N HCl. The aqueous layer was extracted with further EtOAc. The combined organic phases were dried (MgSO 4 ), filtered, and concentrated to dryness. The two trans cyclopropyl diastereoisomers were separated by chiral preparative HPLC (with TFA modifier) and then concentrated to dryness.

51g) 5-[(1S,2S)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

TFA salt (0.104 g, 32%). LC-MS m/z 539 (M+H) + , 1.14 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 8.02 (1H, s), 7.86-7.73 (2H, m), 7.66-7.38 (6H, m), 7.33 (1H, d), 4.49-4.21 (1H, m), 3.81 (3H, s), 3.65 (0.5H, s), 3.49-3.23 (0.5H, m), 3.23-2.95 (0.5H, m), 2.95-2.71 (0.5H, m), 2.60-2.52 (1H, m), 2.18-2.08 (1H, m), 1.91-0.55 (15H, m).

51h) 5-[(1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl]-1-(3-{3-[(2R)-2-propylpiperidine-1-carbonyl]phenyl}phenyl)-1H-pyrazole-4-carboxylic Acid

TFA salt (0.093 mg, 28%). LC-MS m/z 539 (M+H) + , 1.13 (ret. time), basic method. 1 H NMR (400 MHz, DMSO-d6): 8.02 (1H, s), 7.86-7.74 (2H, m), 7.66-7.45 (6H, m), 7.33 (1H, d), 4.88-4.24 (2H, m), 3.81 (3H, s), 3.43-3.36 (0.5H, m), 3.18-3.01 (0.5H, m), 2.60-2.54 (1H, m), 2.17-2.08 (1H, m), 1.86-0.53 (15H, m).

Example 52. 1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-5-[2-(pyridin-3-yl)cyclopropyl]-1H-pyrazole-4-carboxylic Acid

52a) (E)-3-Pyridin-3-yl-acrylic Acid Methyl Ester

A stirred suspension of 60% sodium hydride (0.48 g, 11.9 mmol) in THF (61 mL) at 0° C. under nitrogen was treated dropwise with (EtO) 2 P(O)CH 2 CO 2 Me (3.93 mL, 23.8 mmol). After 30 min, pyridine-3-carboxaldehyde (1.00 g, 9.15 mmol) in 5 mL of THF was added dropwise. After a further 1.5 h at 0° C., the reaction mixture was partitioned between diethyl ether and water. The organic phase was dried, filtered, and concentrated under vacuum. Flash chromatography with 5% diethyl ether in petrol gave the product (1.39 g, 93%). LC-MS m/z 164 (M+H) + , 0.98 (ret. time).

52b) 2-Pyridin-3-yl-cyclopropanecarboxylic Acid Methyl Ester

Trimethyl sulfoxonium iodide (2.25 g, 10.2 mmol) was added slowly in small portions over a period of 20 min, to a stirred suspension of sodium hydride (0.41 g, 10.2 mmol) in dry DMSO (57 mL) at RT. After 1 h, a clear solution was formed and a solution of (E)-3-pyridin-3-yl-acrylic acid methyl ester (1.39 g, 8.52 mmol) in dry DMSO (47 mL) was added slowly dropwise. After 30 min, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice water (2×100 mL), brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness to give the product, used without further purification (0.60 g, 40%). LC-MS m/z 178 (M+H) + , 1.02 (ret. time).

52c) 2-Pyridin-3-yl-cyclopropanecarboxylic Acid

A stirred solution of 2-pyridin-3-yl-cyclopropanecarboxylic acid methyl ester (0.50 g, 2.82 mmol) in THF/MeOH (1:1, 14 mL) was treated with a solution of LiOH (0.604 g, 14.1 mmol) in water (14 mL). After 4 hours the reaction was diluted with water and the pH adjusted to pH4 (aqueous citric acid 5%). The mixture was extracted with IPA:CHCl 3 (1:3, ×3) and the combined organic layers washed with brine, dried over MgSO 4 , filtered, and concentrated to dryness. Purification by silica chromatography eluting with EtOAc/petrol gave the product (0.30 g, 65%). LC-MS m/z 164 (M+H) + , 0.24 (ret. time).

52d) 3-Oxo-3-(2-pyridin-2-yl-cyclopropyl)-propionic Acid Methyl Ester

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 3 of 12

1,10-carbonyldiimidazole (0.33 g, 2.02 mmol) was added portionwise over 5 min to a stirred solution of 2-pyridin-3-yl-cyclopropanecarboxylic acid (0.30 g, 1.84 mmol) in anhydrous THF (5 mL) under argon. After 1 h, a mixture of MgCl 2 (0.35 g, 3.68 mmol) and potassium hydrogen methyl malonate (0.86 g, 5.52 mmol) was added. After 7 h the mixture was concentrated under vacuum and diluted with ethyl acetate. The mixture was then washed with aqueous NaHSO 4 (1M) and brine, and the organic phase dried over Na 2 SO 4 , filtered, and concentrated to dryness to give the product, used without further purification (0.335 g, 83%). LC-MS m/z 220 (M+H) + , 0.99 (ret. time).

52e) 1-(3-Bromo-phenyl)-5-(2-pyridin-3-yl-cyclopropyl)-1H-pyrazole-4-carboxylic Acid Methyl Ester

A mixture of 3-oxo-3-(2-pyridin-3-yl-cyclopropyl)-propionic acid methyl ester (0.335 g, 1.53 mmol) and DMF-dimethyl acetal (0.609 mL, 4.58 mmol) was stirred at room temperature for 24 h, then concentrated to dryness under vacuum. The residue was treated with toluene and again concentrated to dryness. The residue was taken up into MeCN (5 mL) and, with stirring at 0° C., treated with DIPEA (0.635 mL, 3.65 mmol) and, portionwise, 3-bromophenylhydrazine hydrochloride (0.366 g, 1.60 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h, then diluted with aqueous citric acid (5%) and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated to dryness. Silica purification eluting with EtOAc/petrol gave the product (0.126 g, 21%). LC-MS m/z 398 (M+H) + , 1.37 (ret. time).

52f) 1-{3-[3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-5-[2-(pyridin-3-yl)cyclopropyl]-1H-pyrazole-4-carboxylic Acid

A stirred mixture of 1-(3-bromo-phenyl)-5-(2-pyridin-3-yl-cyclopropyl)-1H-pyrazole-4-carboxylic acid methyl ester (0.100 g, 0.25 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-(2-propyl-piperidin-1-yl)-methanone (0.099 g, 0.28 mmol), aqueous Na 2 CO 3 (3M, 0.029 mL) and Pd(PPh 3 ) 4 (0.010 g, 0.013 mmol) in dioxane/water 1:1 (3 mL) was heated at 100° C. for 2 h. After cooling, the mixture was diluted with MeOH (3 mL) and treated with LiOH (1M, 3 mL). After 24 hours the mixture was acidified with citric acid (5% aqueous) and extracted into EtOAc (×3). The combined organic phases were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated under vacuum. The residue was purified by silica column eluting with EtOAc/MeOH 0-10% to give the product (0.110 g, 82%). LC-MS m/z 535 (M+H) + , 1.18 (ret. time). 1 H NMR (400 MHz, Me-d 3 -OD): 8.84 (1H, d), 8.07 (1H, s), 7.76 (1H, s), 7.74-7.71 (1H, m), 7.63-7.49 (5H, m), 7.43-7.35 (2H, m), 7.23 (1H, dd), 4.61-4.47 (0.5H, m), 3.90-3.74 (0.5H, m), 3.58-3.53 (0.5H, m), 3.05-2.92 (0.5H, m), 2.92-2.85 (1H, m), 2.37-2.30 (1H, m), 1.94-1.39 (11H, m), 1.24-0.93 (3H, m), 0.81 (1H, br s).

Example 53. 5-Cyclopropyl-1-[3′-(3,5-dimethyl-piperidine-1-carbonyl)-2′-fluoro-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid

53a) 5-Cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic Acid Methyl Ester

A mixture of 1-(3-bromo-phenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (5.22 g, 16.26 mmol), bis(pinacolato)diboron (4.55 g, 17.88 mmol), KOAc (3.19 g, 35.52 mmol) and Pd(dppf)Cl 2 (0.595 g, 0.813 mmol) in dioxane (75 mL) was stirred under reflux for 2 hours, still starting material present 10% excess of reagents added stirred under reflux for further hour. The mixture was then concentrated and partitioned between EtOAc and water. The organic phase was washed with water and then brine before it was dried (MgSO 4 ), filtered, and concentrated. Purified by silica column, eluting 0-20% EtOAc/petrol to give the product (3.0 g, 50%). LC-MS m/z 286 [fragment] (M+H) + , 1.16 (ret. time).

53b) 3-Bromo-2-fluoro-benzoic Acid Benzyl Ester

A stirred solution of 3-bromo-2-fluorobenzoic acid (3.00 g, 13.7 mmol) in DCM (40 mL) was treated with benzyl alcohol (1.48 g, 13.7 mmol), HOAt (2.23 g, 16.4 mmol), EDC (3.15 g, 16.4 mmol) and DIPEA (4.77 mL, 16.4 mmol). After 16 h the mixture was diluted with DCM, and washed sequentially with 5% aq. citric acid, saturated NaHCO 3 and brine, dried (MgSO 4 ), filtered, and concentrated to dryness to give the product (3.94 g, 93%) used without further purification. LC-MS m/z 326 (M+H) + , 1.54 (ret. time).

53c) 1-(3′-Benzyloxycarbonyl-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Methyl Ester

A stirred mixture of 3-bromo-2-fluoro-benzoic acid benzyl ester (1.81 g, 5.85 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (1.55 g, 4.41 mmol), aq. Na 2 CO 3 (3M, 4.21 mL) and Pd(PPh 3 ) 4 (0.347 g, 0.3 mmol) in EtOH (12.4 mL) and toluene (49.6 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc and water and the organic phase washed with water and brine before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica column eluting with 0-60% EtOAc/petrol to give the product (1.31 g, 62%). LC-MS m/z 471 (M+H) + , 1.61 (ret. time).

53d) 1-(3′-Carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid Methyl Ester

A shaken mixture of 1-(3′-benzyloxycarbonyl-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (1.31 g, 2.78 mmol) and 10% Pd/C in EtOH (30 mL) and EtOAc (30 mL) was hydrogenated at atmospheric pressure for 16 h. The mixture was then filtered and fresh catalyst added and left further 24 h, the mixture was filtered then concentrated to dryness under vacuum to give the product (0.7 g, 67%). LC-MS m/z 381 (M+H) + , 1.08 (ret. time).

53e) 5-Cyclopropyl-1-[3′-(3,5-dimethyl-piperidine-1-carbonyl)-2′-fluoro-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid Methyl Ester

A solution of 1-(3′-carboxy-2′-fluoro-biphenyl-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (0.057 g, 0.131 mmol), HATU (0.050 g, 0.097 mmol), 3,5-dimethylpiperidine (0.015 g, 0.131 mmol) and DIPEA (0.046 mL, 0.26 mmol) in DCM (4 mL) was stirred for 16 h. The mixture was diluted with DCM, and the organic phase washed with saturated NaHCO 3 brine then dried (MgSO 4 ), concentrated to dryness and purified by silica column eluting with 0-60% EtOAc/hexane to give the product (0.059 g, 95%). LC-MS m/z 476 (M+H) + , 1.56 (ret. time).

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 4 of 12

53f) 5-Cyclopropyl-1-[3′-(3,5-dimethyl-piperidine-1-carbonyl)-2′-fluoro-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-[3′-(3,5-dimethyl-piperidine-1-carbonyl)-2′-fluoro-biphenyl-3-yl]-1H-pyrazole-4-carboxylic acid methyl ester (0.059 g, 0.124 mmol) in THF (1 ml) and MeOH (1 mL) was treated with LiOH (52 mg, 1.2 mmol) in water (0.5 mL). After 36 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give the product (0.042 g, 73%). LC-MS m/z 462 (M+H) + , 1.17 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers] 12.29 (1H, s), 7.97 (1H, s), 7.79 (1H, s), 7.68 (4H, s), 7.40 (2H, d), 4.51 (1H, d), 3.36 (1H, d), 2.62 (1H, s), 2.26 (1H, t), 2.19-2.09 (1H, m), 1.80 (1H, d), 1.57 (2H, s), 0.98-0.69 (9H, m), 0.61-0.53 (2H, m).

Example 54. 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

and

5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

54a) (3-Bromo-2-fluoro-phenyl)-(2-propyl-piperidin-1-yl)-methanone

A solution of 3-bromo-2-fluoro-benzoic acid (0.500 g, 2.28 mmol), HATU (0.868 g, 2.28 mmol), 2-propylpiperidine (0.319 g, 2.51 mmol) and DIPEA (0.79 mL, 4.56 mmol) in DCM (20 mL) was stirred for 2 h. The mixture was diluted with DCM and the organic phase washed with aq. NaHCO 3 and dried (MgSO 4 ), filtered and concentrated under vacuum to give the crude product (1.33 g, quantitative), used without further purification. LC-MS m/z 328 (M+H) + , 1.52 (ret. time).

54b) 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid Ethyl Ester

A stirred mixture of (3-bromo-2-fluoro-phenyl)-(2-propyl-piperidin-1-yl)-methanone (1 g, 3.03 mmol), 5-cyclopropyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid methyl ester (0.8 g, 2.17 mmol), aqueous Na 2 CO 3 (3M, 2.18 mL) and Pd(PPh 3 ) 4 (0.178 g, 0.154 mmol) in EtOH (5 mL) and toluene (20 mL) was heated at 80° C. for 2 h. After cooling, the mixture was partitioned between EtOAc and water (and the organic phase washed with water and brine before it was dried (MgSO 4 ), filtered, concentrated to dryness, and purified by silica column eluting with 0-50% EtOAc/petrol to give the product (0.75 g, 71%). LC-MS m/z 490 (M+H) + , 1.60 (ret. time).

54c) 5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

A stirred solution of 5-cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid methyl ester (0.75 g, 1.53 mmol) in THF (15 mL) and MeOH (15 mL) was treated with LiOH (0.64 g, 15.33 mmol) in water (15 mL). After 48 hours the mixture was concentrated to remove organic solvents and the residue partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl and extracted into EtOAc (×2). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated under vacuum to give the product (0.714 g, 98%). LC-MS m/z 476 (M+H) + , 1.18 (ret. time). 1 H NMR (400 MHz, DMSO-d6): [presence of rotamers]12.23 (1H, br s), 7.97 (1H, s), 7.82-7.71 (1H, m), 7.71-7.60 (4H, m), 7.47-7.28 (2H, m), 4.79 (0.6H, br s), 4.44 (0.4H, br s), 3.61-3.52 (0.4H, m), 3.29-3.21 (1H, m), 3.20-3.04 (0.6H, m), 2.79 (0.3H, t), 2.19-2.08 (1H, m), 1.88-1.21 (10H, m), 1.01-0.79 (4H, m), 0.79-0.65 (1H, m), 0.58 (2H, d).

54d) 5-Cyclopropyl-1-{3-[2-fluoro-3-((2R)-2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

and

54e) 5-Cyclopropyl-1-{3-[2-fluoro-3-((2-S)-2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic Acid

5-Cyclopropyl-1-{3-[2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid (580 mg) was separated into its enantiomers using the SFC system with a Chiralpak AY, 20×250 mm, 5 u column and 30% ethanol as co-solvent and a flow rate of 50 g/min and backpressure of 100 bar. The desired fractions were collected and dried by RotorVap. The dried samples were transferred to pre-weighed 20 mL vial with MeOH, and dried under nitrogen stream at 45° C. to yield 0.260 g of 5-cyclopropyl-1-{3-[2-fluoro-3-((2R)-2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid and 0.254 g of 5-cyclopropyl-1-{3-[2-fluoro-3-((2-S)-2-propylpiperidine-1-carbonyl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid. The absolute configuration of each enantiomer was confirmed by VCD analysis.

Example 55. (R)-1-(2′-Fluoro-3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylic Acid

55a) (R)-2-Propylpiperidine

To a solution of 2-propylpiperidine (1.322 mL, 23.58 mmol) in methanol (9.5 mL) at 0° C. was added (S)-(+)-mandelic acid (3.59 g, 23.58 mmol). Diethyl ether (21 mL) was added and the flask left in the fridge for 3 days. Solid was filtered off and rinsed with cold ether. Solid was then redissolved in dry MeOH (9.5 mL) and then ether (20 mL) was added. It was left in fridge for 18 h and solid was filtered off, washing with cold ether to give white solid. The white solid was filtered and washed with cool ether to obtain 2.54 g of salt. The salt was dissolved in water (20 mL) and then solid KOH added until basic. It was extracted with Et 2 O (×3). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (1.17 g, 9.20 mmol, 39.0% yield). LC-MS m/z 128.0 (M+H) + , 0.48 min (ret. time).

55b) (R)-(2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-propylpiperidin-1-yl)methanone and (R)-(2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl)boronic Acid

A solution of 50 wt % T 3 P in EtOAc (1.600 mL, 2.69 mmol) was added to a solution of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (550 mg, 2.067 mmol), (R)-2-propylpiperidine (276 mg, 2.170 mmol), and TEA (1.146 mL, 8.27 mmol) in DCM (10 mL) at RT. It was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO 3 , and extracted with DCM twice. The combined organic layer was washed with brine, and dried (Na 2 SO 4 ). It was filtered and concentrated to give a mixture of (R)-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-propylpiperidin-1-yl)methanone and (R)-(2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl)boronic acid (790 mg, 2.105 mmol, 102% yield). It was carried to the next step without purification. LC-MS m/z 376.2 (M+H) + , 1.27 min (ret. time) LC-MS m/z 274.1 (M+H) + , 0.86 min (ret. time).

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 5 of 12

55c) (R)-1-(2′-Fluoro-3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylic Acid

A mixture of (R)-(3-(2-propylpiperidine-1-carbonyl)phenyl)boronic acid and (R)-(2-propylpiperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (100 mg), methyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylate (80 mg, 0.205 mmol), Na 2 CO 3 (65.2 mg, 0.615 mmol) and PdCl 2 (dppf) (15.00 mg, 0.021 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed for 5 min and then heated under microwave for 15 min at 100° c. It was passed through a PL-Thiol MP SPE + and washed with ethyl acetate. It was then quenched with water and then extracted with ethyl acetate. The organic layer was washed with brine and then concentrated to give crude product. It was redissolved in MeOH (3 mL), and 2M LiOH (0.615 mL, 1.230 mmol) was added and heated under microwave for 30 min at 80° C. The reaction mixture was acidified with 1 N HCl to pH 1. 1 mL of DMSO was added and concentrated. It was purified with acidic reverse-phase HPLC to give the title compound (101 mg, 0.185 mmol, 90% yield). LC-MS m/z 545.3 (M+H) + , 1.00 min (ret. time).

Example 56. 1-(2′-Fluoro-3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylic Acid

56a) (2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-propylpiperidin-1-yl)methanone and (2-Fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl)boronic Acid

A solution of 50 wt % T 3 P in EtOAc (1.891 mL, 3.18 mmol) was added to a solution of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (650 mg, 2.443 mmol), 2-propylpiperidine (326 mg, 2.57 mmol), and TEA (1.355 mL, 9.77 mmol) in DCM (10 mL) at RT. It was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO 3 , and extracted with DCM twice. The combined organic layer was washed with brine, dried (Na 2 SO 4 ). It was filtered and concentrated to give a mixture of (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-propylpiperidin-1-yl)methanone and (2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl)boronic acid (1.1 g, 2.93 mmol, 120% yield). It was carried to the next step without purification. LC-MS m/z 376.4 (M+H) + , 1.25 min (ret. time) LC-MS m/z 294.1 (M+H) + , 0.82 min (ret. time).

56b) 1-(2′-Fluoro-3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylic Acid

A mixture of (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-propylpiperidin-1-yl)methanone and (2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl)boronic acid (85 mg, 0.226 mmol), methyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylate (0.075 mL, 0.205 mmol), Na 2 CO 3 (65.2 mg, 0.615 mmol) and PdCl 2 (dppf) (15.00 mg, 0.021 mmol), 1,4-Dioxane (3 mL) and water (1 mL) was degassed for 5 min and then heated under microwave for 15 min at 100° C. It was passed through Celite® and washed with ethyl acetate. It was then extracted with ethyl acetate twice. The combined organic layer was washed with brine and then concentrated to give the crude product. It was redissolved in MeOH (3 mL), 2M LiOH (0.615 mL, 1.230 mmol) was added and heated under microwave for 30 min at 80° C. The reaction mixture was acidified with 1 N HCl to pH around 1, 1 mL of DMSO was added and concentrated. It was purified with acidic reverse-phase HPLC to give the title compound (60.9 mg, 0.112 mmol, 54.5% yield). LC-MS m/z 545.5 (M+H) + , 0.98 min (ret. time).

Example 57. 1-(2′-Fluoro-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

57a) Ethyl 3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate

To a solution of 2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarboxylic acid (2 g, 11.96 mmol) in tetrahydrofuran (THF) (20 mL) stirred under nitrogen at room temp was added CDI (2.134 g, 13.16 mmol). The reaction mixture was stirred at RT for 1 h, then magnesium chloride (1.366 g, 14.36 mmol) and methyl potassium malonate (5.60 g, 35.9 mmol) were added and stirred at RT for 24 h. The reaction mixture was poured in ice water (30 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (20 mL) and concentrated under reduced pressure to give crude compound. The crude residue was purified with silica gel chromatography eluting with 2% MeOH in DCM to give the title compound (1.1 g, 4.47 mmol, 37.3% yield) as a gummy liquid. LC-MS m/z 237.9 (M+H) + , 2.83 min (ret. time).

57b) (E)-Ethyl 3-(dimethylamino)-2-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarbonyl)acrylate

To a solution of ethyl 3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate (2.4 g, 10.12 mmol) in DMF-DMA (4.06 ml, 30.3 mmol) under nitrogen was added p-TsOH (0.019 g, 0.101 mmol). The reaction mixture was stirred at 100° C. for 2 h. It was concentrated under reduced pressure, and co-distilled with toluene. The crude residue was purified with silica gel chromatography eluting with 2.5% MeOH in DCM to give the title compound (1.8 g, 5.85 mmol, 57.9% yield) as a gummy brown liquid. LC-MS m/z 292.9 (M+H) + , 2.74 min (ret. time).

57c) Ethyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

A mixture of (Z)-ethyl 3-(dimethylamino)-2-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarbonyl)acrylate (300 mg, 1.026 mmol), (3-bromophenyl)hydrazine, hydrochloride (275 mg, 1.231 mmol) and DIEA (0.538 mL, 3.08 mmol) in ethanol (6 mL) was stirred at RT for 19 h. Solid precipitated out from reaction mixture. Solid was filtered and washed with ether to give the title compound (380 mg, 0.913 mmol, 89% yield) as white solid. LC-MS m/z 416.2 (M+H) + , 0.91 min (ret. time).

57d) Ethyl 1-(2′-fluoro-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 6 of 12

A mixture of (R)-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-propylpiperidin-1-yl)methanone and (R)-(2-fluoro-3-(2-propylpiperidine-1-carbonyl)phenyl)boronic acid (79 mg, 0.211 mmol), ethyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (0.075 mL, 0.192 mmol), Na 2 CO 3 (61.1 mg, 0.577 mmol) and PdCl 2 (dppf) (14.06 mg, 0.019 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed for 5 min and then heated under microwave for 15 min at 100° C. It was passed through Celite® and washed with ethyl acetate twice. The combined organic layer was washed with brine and then concentrated to give the crude product. The reaction mixture was purified with reverse-phase HPLC under neutral conditions to give the title compound (74 mg, 0.127 mmol, 65.9% yield). LC-MS m/z 585.2 (M+H) + , 1.14 min (ret. time).

57e) 1-(2′-Fluoro-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of ethyl 1-(2′-fluoro-3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (74 mg, 0.127 mmol) in Methanol (2 mL) was added 2M LiOH (0.345 mL, 0.690 mmol). The mixture was heated under microwave for 30 min at 80° C. The reaction mixture was acidified with 1 N HCl to pH around 1, 1 mL of DMSO was added and concentrated. It was purified with reverse-phase HPLC under acidic conditions to give the title compound (62 mg, 0.111 mmol, 97% yield). LC-MS m/z 557.0 (M+H) + , 0.98 min (ret. time).

Example 58. (R)-5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)ethyl)-1-(3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

58a) (R)-(2-Propylpiperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone and (R)-(3-(2-propylpiperidine-1-carbonyl)phenyl)boronic Acid

A solution of 50 wt % T 3 P in EtOAc (1.560 mL, 2.62 mmol) was added to a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (500 mg, 2.015 mmol), (R)-2-propylpiperidine (269 mg, 2.116 mmol), and TEA (1.118 mL, 8.06 mmol) in DCM (10 mL) at 0° C. The ice bath was removed, and the reaction was stirred at room temperature for 1 h, storing in freezer for 76 h. The reaction was quenched with saturated NaHCO 3 , and extracted with DCM twice. The organic layer was washed with brine, dried (Na 2 SO 4 ). It was filtered and concentrated to give a mixture of (R)-(2-propylpiperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (650 mg, 1.819 mmol, 90% yield) and (R)-(3-(2-propylpiperidine-1-carbonyl)phenyl)boronic acid. It was carried to the next step without purification. LC-MS m/z 358.3 (M+H) + , 1.28 min (ret. time) LC-MS m/z 276.2 (M+H) + , 0.86 min (ret. time).

58b) (R)-5-(2-(1-Methyl-1H-1,2,3-triazol-4-yl)ethyl)-1-(3′-(2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

A mixture of (R)-(3-(2-propylpiperidine-1-carbonyl)phenyl)boronic acid and (R)-(2-propylpiperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (100 mg, 0.280 mmol), methyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl)-1H-pyrazole-4-carboxylate (109 mg, 0.280 mmol), Na 2 CO 3 (89 mg, 0.840 mmol) and PdCl 2 (dppf) (20.48 mg, 0.028 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed for 5 min and then heated under microwave for 15 min at 100° C. 30 mg of (R)-(3-(2-propylpiperidine-1-carbonyl)phenyl)boronic acid and (R)-(2-propylpiperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone was added and heated under microwave for 10 min at 100° C. It was passed through Celite® and washed with ethyl acetate twice. The combined organic layer was washed with brine and then concentrated to give crude product. It was redissolved in MeOH (3 mL), 2 M LiOH (0.840 mL, 1.679 mmol) was added and heated under microwave for 30 min at 80° C. The reaction mixture was acidified with 1 N HCl to pH around 1, 1 mL of DMSO was added and concentrated. It was purified with reverse-phase HPLC under acidic conditions to give the title compound (63.7 mg, 0.121 mmol, 43.2% yield) was obtained. LC-MS m/z 527.1 (M+H) + , 0.99 min (ret. time).

Example 59. 1-(3′-Isopropoxy-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

59a) Ethyl 1-(3′-isopropoxy-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

To a solution of ethyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (100 mg, 0.240 mmol) in tetrahydrofuran (THF) (5 mL) and water (1 mL) was added sodium carbonate (50.9 mg, 0.480 mmol), (3-isopropoxyphenyl)boronic acid (51.9 mg, 0.288 mmol). The reaction mixture was purged with nitrogen for 10 min, and Pd(Ph 3 P) 4 (27.8 mg, 0.024 mmol) was added. It was heated to 70° C. for 5 h. The crude residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine solution (10 mL) and dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The crude residue was purified with silica gel chromatography eluting with 15% ethyl acetate in hexane to afford the title compound (50 mg, 0.088 mmol, 36.8% yield) as white solid. LC-MS m/z 472.07 (M+H) + , 2.657 min (ret. time).

59b) 1-(3′-Isopropoxy-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of ethyl 1-(3′-isopropoxy-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (200 mg, 0.424 mmol) in Ethanol (5 mL) was added 1M NaOH in water (0.424 mL, 0.424 mmol). It was stirred at 25° C. for 5 h. The reaction mixture was concentrated. The residue was cooled and acidified with 1N HCl solution to pH 4. Solid was filtered, washed with water and dried to afford title compound (70 mg, 0.150 mmol, 35.4% yield) as off-white solid. LC-MS m/z 223.90 (M+H) + , 2.97 min (ret. time)

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 7 of 12

Example 60. 1-(3′-(1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

60a) Ethyl 5-cyclopropyl-1-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate

To a solution of ethyl 1-(3-bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (1 g, 2.98 mmol) in tetrahydrofuran (THF) (4 mL) was added (3-hydroxyphenyl)boronic acid (0.617 g, 4.47 mmol), sodium carbonate (0.632 g, 5.97 mmol) and water (1 mL). The reaction mixture was degassed with argon for 10 min and then added tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.298 mmol) was added and stirred at 80° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×80 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na 2 SO 4 and concentrated. The crude residue was purified with silica gel chromatography, eluting with 40% ethyl acetate in n-Hexane. Desired fractions were combined to give the title compound (900 mg, 2.58 mmol, 87% yield). 1 H NMR (400 MHz, CDCl 3 ) δ: 8.04 (s, 1H), 7.71 (t, J=1.9 Hz, 1H), 7.60 (dt, J=7.4, 1.7 Hz, 1H), 7.56-7.45 (m, 2H), 7.31 (t, J=7.9 Hz, 1H), 7.20-7.13 (m, 1H), 7.04 (t, J=2.0 Hz, 1H), 6.84 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 5.14 (s, 1H), 4.34 (q, J=7.1 Hz, 2H), 2.02 (tt, J=8.5, 5.5 Hz, 1H), 1.38 (t, J=7.1 Hz, 3H), 1.01-0.90 (m, 2H), 0.73-0.64 (m, 2H).

60b) (1-Chloroethyl)cyclohexane

To a solution of 1-cyclohexylethanol (1 g, 7.80 mmol) in dichloromethane (DCM) (15 mL) was added thionyl chloride (1.139 mL, 15.60 mmol) at 0° C. and stirred for 15 min. The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with saturated bicarbonate solution and extracted with DCM (3×30 mL). The combined organic layer was washed with water (50 mL) and brine solution (50 mL), dried over anhydrous Na 2 SO 4 , and concentrated to give the title compound (650 mg, 4.43 mmol, 56.8% yield). This material was carried to next step without further purification.

60c) Ethyl 1-(3′-(1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

To a solution of ethyl 5-cyclopropyl-1-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (450 mg, 1.292 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added cesium carbonate (842 mg, 2.58 mmol) and heated to 100° C. for 1 h in Microwave. The reaction mixture was diluted with ice water and extracted with ethyl acetate (3×40 mL). The combined organic layer was washed with chilled water (3×50 mL) and washed brine solution (100 mL), dried over anhydrous Na 2 SO 4 and concentrated. The crude residue was purified with silica gel chromatography eluting with 10% ethyl acetate in n-Hexane. Title compound (140 mg, 0.285 mmol, 22.06% yield) was obtained. LC-MS m/z 459.20 (M+H) + , 4.89 min (ret. time).

60d) 1-(3′-(1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

To a solution of ethyl 1-(3′-(1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (140 mg, 0.305 mmol) in ethanol (5 mL) was added 2 M NaOH (0.153 mL, 0.305 mmol). It was stirred 25° C. for 3 h. The reaction mixture was concentrated and then diluted with ice. It was acidified with 1N HCl solution till pH 2. It was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine solution (50 mL), and dried over anhydrous Na 2 SO 4 , and concentrated. The crude residue was purified with silica gel chromatography by eluting with MeOH:DCM (0.5:9.5) to give the title compound (60 mg, 0.135 mmol, 44.1% yield) as gummy solid. LC-MS m/z 431.25 (M+H) + , 3.17 min (ret. time).

60e) 1-(3′-(1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic Acid

A solution of 1-(3′-(1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (10 mM, 695 μL in DMSO) was concentrated on the V10 evaporator to afford the title compound (25.7 mg, 0.060 mmol). LC-MS m/z 431.4 (M+H) + , 1.39 min (ret. time)

Example 61: 5-Cyclopropyl-1-(3′-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

61a) 2-((Dimethylamino)methylene)cyclopentanone

To a solution of cyclopentanone (0.559 mL, 5.94 mmol) in toluene (2 mL) was added N,N-dimethylformamide dimethyl acetal (0.796 ml, 5.94 mmol). The reaction mixture was stirred at 100° C. for 19 hr. The reaction mixture was concentrated to afford the title compound 2-((dimethylamino)methylene)cyclopentanone (237.7 mg, 1.708 mmol, 28.7% yield) which was carried forward without further purification. LC-MS m/z 139.9 M+, 0.88 min (ret. time). 1H NMR (400 MHz, methanol-d4) δ ppm 1.89 (quin, J=7.50 Hz, 2H) 2.22 (t, J=7.91 Hz, 2H) 2.92 (t, J=7.15 Hz, 2H) 3.16 (s, 6H) 7.31 (s, 1H).

61b) Tert-butyl 2-(3-bromophenyl)hydrazinecarboxylate

To a solution of (3-bromophenyl)hydrazine hydrochloride (3.28 g, 14.66 mmol) and triethylamine (6.13 mL, 44.0 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (3.40 mL, 14.66 mmol). The reaction mixture was stirred at ambient temperature for 93 hr. The reaction mixture was quenched with water and extracted with DCM (2×). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound tert-butyl 2-(3-bromophenyl)hydrazinecarboxylate (4.1815 g, 14.56 mmol, 99% yield) which was carried forward without further purification. LC-MS m/z 287.0 (M+H) + , 0.96 min (ret. time).

61c) Ethyl 1-(3′-(2-(tert-butoxycarbonyl)hydrazinyl)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

To a solution of ethyl 5-cyclopropyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-4-carboxylate (1.00 g, 2.62 mmol) and tert-butyl 2-(3-bromophenyl)hydrazinecarboxylate (1.127 g, 3.92 mmol) in a mixture of 1,4-dioxane (12.00 mL) and water (4.00 mL) was added potassium carbonate (0.723 g, 5.23 mmol) and PdCl 2 (dppf) (0.191 g, 0.262 mmol). The reaction vessel was heated in a Biotage microwave at high absorption for 15 min at 100° C. The reaction was filtered, extracted with EtOAc (3×20 mL) and concentrated to afford the crude product. The crude product was purified by silica gel chromatography to afford the title compound ethyl 1-(3′-(2-(tert-butoxycarbonyl)hydrazinyl)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (650 mg, 1.405 mmol, 74.8% yield). LC-MS m/z 463.2 (M+H) + , 1.18 min (ret. time).

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 8 of 12

61d) Ethyl 5-cyclopropyl-1-(3′-hydrazinyl-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate Hydrochloride

To a solution of ethyl 1-(3′-(2-(tert-butoxycarbonyl)hydrazinyl)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (650 mg, 1.405 mmol) in dichloromethane (6 mL) was added 4 N HCl in dioxane (1.405 mL, 5.62 mmol). The reaction mixture was stirred at ambient temperature for 17 hr. The reaction mixture was concentrated to afford the crude product. Soluble impurities were removed from the crude product via trituration in ether to afford the title compound, ethyl 5-cyclopropyl-1-(3′-hydrazinyl-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate hydrochloride (260.2 mg, 0.718 mmol, 76.4% yield). LC-MS m/z 363.1 (M+H) + , 0.83 min (ret. time).

61d) 5-Cyclopropyl-1-(3′-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

To a solution of 2-((dimethylamino)methylene)cyclopentanone (30.7 mg, 0.221 mmol) and sodium acetate (18.11 mg, 0.221 mmol) in ethanol (1.5 mL) was added ethyl 5-cyclopropyl-1-(3′-hydrazinyl-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate hydrochloride (80 mg, 0.221 mmol). The reaction mixture was stirred at 70° C. under nitrogen atmosphere for 18 hr. The reaction mixture was concentrated to remove excess solvent. The crude product was dissolved in methanol (2 mL) and to the reaction mixture was added 2 M LiOH (0.441 mL, 0.883 mmol). The reaction vessel was heated in a Biotage microwave at high absorption for 10 min at 100° C. The reaction was neutralized with 1 N HCl (1 mL) and concentrated to afford the crude product. The crude product was dissolved in DMSO (2 mL), filtered through a 0.45 μm acrodisc, and purified with reverse-phase HPLC under acidic conditions to afford the title compound 5-cyclopropyl-1-(3′-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid (13.57 mg, 0.033 mmol, 14.98% yield). LC-MS m/z 411.1 (M+H) + , 1.10 min (ret. time). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 0.68 (d, J=5.27 Hz, 2H) 0.97 (d, J=8.03 Hz, 2H) 2.10-2.19 (m, 1H) 2.71 (m, J=15.90, 6.10 Hz, 4H) 3.09 (t, J=6.65 Hz, 2H) 7.43 (s, 1H) 7.57-7.73 (m, 5H) 7.86 (d, J=7.28 Hz, 1H) 7.91 (s, 1H) 7.98 (s, 1H) 8.05 (s, 1H).

Example 62: 5-cyclopropyl-1-(3′-(4,5,6,7-tetrahydro-1H-indazol-1-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

62a) 2-((Dimethylamino)methylene)cyclohexanone

1-Tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (533 mg, 3.06 mmol) was added drop wise to cyclohexanone (300 mg, 3.06 mmol). The reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 1.5 hr, then at 110° C. for 4 hr. The reaction mixture was diluted with water (1 mL) and extracted with EtOAc (3×1 mL). The combined organic layer was concentrated to afford the title compound 2-((dimethylamino)methylene)cyclohexanone (296.2 mg, 1.933 mmol, 63.2% yield). LC-MS m/z 154.9 (M+H) + , 0.67 min (ret. time).

62b) Tert-butyl 2-(3-bromophenyl)hydrazinecarboxylate

To a solution of (3-bromophenyl)hydrazine hydrochloride (3.28 g, 14.66 mmol) and triethylamine (6.13 mL, 44.0 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (3.40 mL, 14.66 mmol). The reaction mixture was stirred at ambient temperature for 93 hr. The reaction mixture was quenched with water and extracted with DCM (2×). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to afford the title compound tert-butyl 2-(3-bromophenyl)hydrazinecarboxylate (4.1815 g, 14.56 mmol, 99% yield) which was carried forward without further purification. LC-MS m/z 287.0 (M+H) + , 0.96 min (ret. time).

62c) Ethyl 1-(3′-(2-(tert-butoxycarbonyl)hydrazinyl)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

To a solution of ethyl 5-cyclopropyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-4-carboxylate (1.00 g, 2.62 mmol) and tert-butyl 2-(3-bromophenyl)hydrazinecarboxylate (1.127 g, 3.92 mmol) in a mixture of 1,4-dioxane (12.00 mL) and water (4.00 mL) was added potassium carbonate (0.723 g, 5.23 mmol) and PdCl 2 (dppf) (0.191 g, 0.262 mmol). The reaction vessel was heated in a Biotage microwave at high absorption for 15 min at 100° C. The reaction was filtered, extracted with ethyl acetate (3×20 mL) and concentrated to afford the crude product. The crude product was purified by silica gel chromotography to afford the title compound ethyl 1-(3′-(2-(tert-butoxycarbonyl)hydrazinyl)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (650 mg, 1.405 mmol, 74.8% yield). LC-MS m/z 463.2 (M+H) + , 1.18 min (ret. time).

62d) Ethyl 5-cyclopropyl-1-(3′-hydrazinyl-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate Hydrochloride

62e) Ethyl 5-cyclopropyl-1-(3′-(4,5,6,7-tetrahydro-1H-indazol-1-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate

To a solution of ethyl 5-cyclopropyl-1-(3′-hydrazinyl-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (80 mg, 0.221 mmol) in acetic acid (1.5 mL) was added 2-((dimethylamino)methylene)cyclohexanone (33.8 mg, 0.221 mmol). The reaction mixture was stirred at 100° C. for 3 hr. The reaction mixture was concentrated to afford the crude product. The crude product was dissolved in DMSO (2 mL) and purified with reverse-phase HPLC under neutral conditions to afford the title compound, ethyl 5-cyclopropyl-1-(3′-(4,5,6,7-tetrahydro-1H-indazol-1-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (33.6 mg, 0.074 mmol, 33.6% yield). LC-MS m/z 453.2 (M+H) + , 1.34 min (ret. time). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 0.65 (d, J=5.27 Hz, 2H) 0.97 (d, J=8.53 Hz, 2H) 1.41 (t, J=7.03 Hz, 3H) 1.86 (d, J=5.02 Hz, 4H) 2.10-2.20 (m, 1H) 2.60-2.67 (m, 2H) 2.77-2.85 (m, 2H) 4.35 (q, J=7.11 Hz, 2H) 7.49 (s, 1H) 7.53 (d, J=8.03 Hz, 1H) 7.58-7.71 (m, 3H) 7.75 (d, J=7.78 Hz, 1H) 7.81-7.88 (m, 2H) 7.90 (s, 1H) 8.05 (s, 1H).

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 9 of 12

62f) 5-Cyclopropyl-1-(3′-(4,5,6,7-tetrahydro-1H-indazol-1-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

To a solution of ethyl 5-cyclopropyl-1-(3′-(4,5,6,7-tetrahydro-1H-indazol-1-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (33.6 mg, 0.074 mmol) in methanol (1 mL) was added 2M LiOH (0.223 mL, 0.445 mmol). The reaction vessel was heated in a Biotage microwave at high absorption for 30 min at 80° C. The reaction mixture was neutralized with 1 N HCl (1 mL) and concentrated. The crude product was dissolved in DMSO (2 mL) and purified with reverse-phase HPLC under acidic conditions to afford the title compound 5-cyclopropyl-1-(3′-(4,5,6,7-tetrahydro-1H-indazol-1-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid (24.0 mg, 0.057 mmol, 76% yield). LC-MS m/z 425.4 (M+H) + , 1.08 min (ret. time). 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 0.67 (d, J=5.27 Hz, 2H) 0.95 (d, J=8.28 Hz, 2H) 1.86 (d, J=4.77 Hz, 4H) 2.08-2.17 (m, 1H) 2.61-2.66 (m, 2H) 2.77-2.82 (m, 2H) 7.51-7.55 (m, 2H) 7.58-7.71 (m, 3H) 7.75 (d, J=7.78 Hz, 1H) 7.83 (s, 2H) 7.89 (s, 1H) 8.04 (s, 1H).

Example 63: 5-Cyclopropyl-1-(3′-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

63a) 5-((Dimethylamino)methylene)-2,2-dimethylcyclopentanone

To a solution of 2,2-dimethylcyclopentanone (200 mg, 1.783 mmol) in toluene (1 mL) was added N,N-dimethylformamide dimethyl acetal (0.239 mL, 1.783 mmol). The reaction mixture was stirred at 100° C. for 22 hr. The reaction mixture was concentrated to afford the title compound 5-((dimethylamino)methylene)-2,2-dimethylcyclopentanone (288.8 mg, 1.727 mmol, 97% yield) which was carried forward without further purification. LC-MS m/z 167.9 (M+H) + , 0.69 min (ret. time).

63b) Tert-butyl 2-(3-bromophenyl)hydrazinecarboxylate

63c) Ethyl 1-(3′-(2-(tert-butoxycarbonyl)hydrazinyl)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

To a solution of tert-butyl 2-(3-bromophenyl)hydrazinecarboxylate (1.127 g, 3.92 mmol) and ethyl 5-cyclopropyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-4-carboxylate (1.00 g, 2.62 mmol) in a mixture of 1,4-dioxane (12 mL) and water (4.00 mL) was added potassium carbonate (0.723 g, 5.23 mmol) and PdCl 2 (dppf) (0.191 g, 0.262 mmol). The reaction vessel was heated in a Biotage microwave at high absorption for 15 min at 100° C. The reaction was filtered, extracted with ethyl acetate (3×20 mL), and concentrated to afford the crude product. The crude product was purified by silica gel chromatography to afford the title compound ethyl 1-(3′-(2-(tert-butoxycarbonyl)hydrazinyl)-[1,1′-biphenyl]-3-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (650 mg, 1.405 mmol, 74.8% yield). LC-MS m/z 463.2 (M+H) + , 1.18 min (ret. time).

63d) Ethyl 5-cyclopropyl-1-(3′-hydrazinyl-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate Hydrochloride

63e) Ethyl 5-cyclopropyl-1-(3′-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (N31313-1)

To a solution of 5-((dimethylamino)methylene)-2,2-dimethylcyclopentanone (23.07 mg, 0.138 mmol) in acetic acid (1.5 mL) was added ethyl 5-cyclopropyl-1-(3′-hydrazinyl-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (50 mg, 0.138 mmol). The reaction mixture was stirred at 100° C. for 3 hr. The reaction mixture was stirred at ambient temperature for an additional 16 hr. The reaction mixture was concentrated and the crude product was dissolved in DMSO (2 mL) and purified with reverse-phase HPLC under neutral conditions to afford the title compound ethyl 5-cyclopropyl-1-(3′-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (19.9 mg, 0.043 mmol, 30.9% yield). LC-MS m/z 467.2 (M+H) + , 1.39 min (ret. time).

63f) 5-Cyclopropyl-1-(3′-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

To a solution of ethyl 5-cyclopropyl-1-(3′-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (19.9 mg, 0.043 mmol) in MeOH (1 mL) was added 2M LiOH (0.085 mL, 0.171 mmol). The reaction vessel was heated in a Biotage microwave at high absorption for 30 min at 80° C. The reaction mixture was neutralized with 1 N HCl (1 mL) and concentrated to afford the crude product. The crude product was dissolved in DMSO (2 mL) and purified with reverse-phase HPLC under acidic conditions to afford the title compound, 5-cyclopropyl-1-(3′-(6,6-dimethyl-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid (3.53 mg, 8.05 μmol, 18.87% yield). LC-MS m/z 439.4 (M+H) + , 1.13 min (ret. time). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 0.67 (d, J=5.27 Hz, 2H) 0.95 (d, J=8.28 Hz, 2H) 1.30 (s, 6H) 2.44 (t, J=6.78 Hz, 2H) 2.65-2.73 (m, 3H) 7.38 (s, 1H) 7.52 (d, J=8.03 Hz, 1H) 7.60-7.73 (m, 3H) 7.78-7.87 (m, 3H) 7.90 (s, 1H) 8.04 (s, 1H).

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 10 of 12

Example 64. 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

64a) 4-(Diethoxymethyl)-1-methyl-1H-1,2,3-triazole

A solution of iodomethane (166 g, 1170 mmol) in tert-butanol (500 mL) was added to NaHCO 3 (98 g, 1170 mmol), copper(II) sulfate (12.45 g, 78 mmol), sodium azide (76 g, 1170 mmol) and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (30.9 g, 156 mmol) in water (500 mL) slowly at room temperature. Then 3,3-diethoxyprop-1-yne (50 g, 390 mmol) was added. The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was extracted with ethyl acetate (3×1000 mL). The combined organic layer was dried with MgSO 4 and concentrated to obtain the title compound 4-(diethoxymethyl)-1-methyl-1H-1,2,3-triazole (46 g, 236 mmol, 60.5% yield) which was carried over to next step without further purification. LC-MS m/z 186.1 (M+H) + , 1.46 min (ret. time).

64b) 1-Methyl-1H-1,2,3-triazole-4-carbaldehyde

To a solution of 4-(diethoxymethyl)-1-methyl-1H-1,2,3-triazole (46 g, 248 mmol) in water (200 mL), TFA (100 mL, 649 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The water was evaporated and dried under vacuum to get the title compound, 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (26 g, 234 mmol, 94% yield) as a yellow solid. LC-MS m/z 112.2 (M+H) + , 0.51 min (ret. time).

64c) (Z)-Tert-butyl 3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylate

To a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (62.4 g, 248 mmol) in tetrahydrofuran (500 mL), sodium hydride (10.80 g, 270 mmol, 60%) was added at 0° C. The reaction mixture was stirred at 0° C. under N 2 for 10 min. Then a solution of 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (25 g, 225 mmol) in THF (500 mL) was added dropwise and the reaction mixture was stirred at 0° C. for 15 min. Water (500 mL) was added and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with water (2×100 mL) and brine (2×100 mL), dried over Na 2 SO 4 and concentrated. The crude product was purified by Combiflash chromatography (hexane:ethyl acetate=1:5) to give the title compound (Z)-tert-butyl 3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylate (40 g, 184 mmol, 82% yield) as an oil. LC-MS m/z 210.1 (M+H) + , 1.73 min (ret. time).

64d) tert-Butyl 2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarboxylate

To a solution of trimethylsulfoxonium iodide (126 g, 573 mmol) in dimethyl sulfoxide (300 mL), sodium hydride (16.06 g, 401 mmol) was added at 0° C. The reaction mixture was stirred at room temperature under N 2 for 1 h. Then a solution of (E)-tert-butyl 3-(1-methyl-1H-1,2,3-triazol-4-yl)acrylate (40 g, 191 mmol) in tetrahydrofuran (300 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hr and heated to 50° C. for another 1 h. Then 200 mL of ethyl acetate and 250 mL of water were added. The water layer was extracted with ethyl acetate (3×250 mol), the combined organic layer was dried with Na 2 SO 4 and concentrated to get tert-butyl 2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarboxylate (36 g, 144 mmol, 75% yield). LC-MS m/z 224.1 (M+H) + , 1.69 min (ret. time).

64e) 2-(1-Methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarboxylic Acid

A solution of tert-butyl 2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarboxylate (36 g, 161 mmol) in dichloromethane (400 mL), TFA (200 mL, 2596 mmol) was added slowly under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 h Then it was concentrated. 100 mL of ethyl acetate and 100 mL of water were added to residue. The water layer was extracted with ethyl acetate (3×100 mL). The combined organic phase was dried with MgSO 4 and concentrated to get title compound 2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarboxylic acid (24 g, 134 mmol, 83% yield) as a white solid. LC-MS m/z 168.1 (M+H) + , 1.16 min (ret. time).

64f) Methyl 3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate

To a solution of 2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarboxylic acid (24 g, 144 mmol) in tetrahydrofuran (700 mL), was added CDI (30.3 g, 215 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then potassium 3-methoxy-3-oxopropanoate (67.3 g, 431 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and re-dissolved in ethyl acetate (200 mL). Then it was washed with 1 M KHSO 4 (150 mL), saturated NaHCO 3 (150 mL) and brine (150 mL). The organic layer was dried with Na 2 SO 4 and concentrated to obtain the title compound methyl 3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate (20 g, 85 mmol, 59.3% yield) as an oil. LC-MS m/z 224.1 (M+H) + , 1.39 min (ret. time).

64 g) Methyl 2-(isopropylimino)-3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate

A mixture of methyl 3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-3-oxopropanoate (19 g, 85 mmol) 1,1-dimethoxy-N,N-dimethylmethanamine (11.16 g, 94 mmol) was stirred at 25° C. for 12 h. The reaction mixture was concentrated to obtain the title compound methyl 3-(dimethylamino)-2-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarbonyl)acrylate (24 g, 77 mmol, 90% yield) as an oil which was used in next step without further purification. LC-MS m/z 279.1 (M+H) + , 1.61 min (ret. time).

64h) Methyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

A solution of methyl 3-(dimethylamino)-2-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropanecarbonyl)acrylate (10 g, 35.9 mmol) in acetonitrile (100 mL) was added to (3-bromophenyl)hydrazine hydrochloride (9.64 g, 43.1 mmol) slowly under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 16 h. Then 200 mL of water was added and extracted with ethyl acetate (3×500 mL). The combined organic layer was dried with Na 2 SO 4 and concentrated. The crude product was purified by Combiflash chromatography (hexane:ethyl acetate=4:1) to give the title compound methyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (14 g, 34.8 mmol, 97% yield). LC-MS m/z 204.1 (M+H) + , 1.81 min (ret. time).

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 11 of 12

64i) Methyl 5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-4-carboxylate

To a solution of methyl 1-(3-bromophenyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (14 g, 34.8 mmol) in 1,4-dioxane (200 mL) was added potassium acetate (6.83 g, 69.6 mmol), bis(pinacolato)diboron (13.26 g, 52.2 mmol) and the reaction mixture was degassed with argon for 30 min and then PdCl 2 (dppf)-CH 2 Cl 2 adduct (2.84 g, 3.48 mmol) was added. The reaction mixture was stirred at 100° C. for 16 h. After it was cooled to room temperature, it was filtered through Celite pad and the filtrate was concentrated. The crude product was purified by Combiflash chromatography (hexane:ethyl acetate=2:1) to get the title compound methyl 5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-4-carboxylate (15 g, 23.37 mmol, 67.1% yield) as white solid. LC-MS m/z 450.1 (M+H) + , 1.69 min (ret. time).

64j) (3-(4-(Methoxycarbonyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic Acid

To a solution of methyl 5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-4-carboxylate (15 g, 33.4 mmol) in acetone (100 mL), ammonium acetate (100 mL, 100 mmol) was added, then sodium periodate (21.42 g, 100 mmol) in water (50 mL) was added slowly under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 16 h. Then it was extracted with ethyl acetate (3×100 mL). The combined organic phase was dried with Na 2 SO 4 and concentrated. The crude product was purified by Combiflash chromatography (DCM:MeOH=5:1) to obtain the racemate title compound (3-(4-(methoxycarbonyl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic acid (9.02 g, 26.1 mmol, 72% yield). Then it was separated by chiral column (Chiralpak AY 20×250 mm, 5 u, SFC) to get single isomer-title compound (3-(4-(Methoxycarbonyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic acid (4.303 g, 34.34%). LC-MS m/z 368.0 (M+H) + , 1.32 min (ret. time).

64k) (S)-1-Bromo-3-(1-cyclohexylethoxy)benzene

To a solution of 3-bromophenol (2.407 mL, 23.12 mmol) in THF (60 mL), (R)-1-cyclohexylethanol (3.83 mL, 27.7 mmol) DIAD (5.39 mL, 27.7 mmol) and Ph 3 P (7277 mg, 27.7 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and purified by Combiflash chromatography (hexane/ethyl acetate) to get the title compound (S)-1-bromo-3-(1-cyclohexylethoxy)benzene (4.8 g, 16.95 mmol, 73.3%). 1 H NMR (400 MHz, CDCl3) δ=7.16-7.05 (m, 3H), 6.84-6.82 (d, J=8.0 Hz 1H), 4.14 (t, J=8.0 Hz, 1H), 1.94-1.57 (m, 6H), 1.30-1.04 (m, 8H).

64l) Methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

To a solution of (3-(4-(methoxycarbonyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic acid (1.13 g, 3.08 mmol in a mixture of 1,4-Dioxane (18 mL) and water (6.00 mL), (S)-1-bromo-3-(1-cyclohexylethoxy)benzene (1.307 g, 4.62 mmol), potassium carbonate (1.276 g, 9.23 mmol) and PdCl 2 (dppf) (0.225 g, 0.308 mmol) were added. The reaction was heated in a microwave at 120° C. for 80 min. Then it was partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate (3×). The combined organic layer was dried with MgSO 4 and concentrated to get crude product which was purified by Combiflash chromatography (hexane/ethyl acetate) to get the title compound methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (1.28 g, 2.435 mmol, 79%). LC-MS m/z 526.4 (M+H) + , 1.44 min (ret. time).

64m) 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (1.28 g, 2.435 mmol) in a mixture of methanol (30.00 mL) and tetrahydrofuran (16.00 mL), LiOH (0.737 g, 30.8 mmol) and 6.0 mL of water were added. Then the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated. The residue was partitioned between ethyl acetate and 1N HCl. The water layer was extracted with ethyl acetate (3×). The combined organic phase was dried with MgSO 4 and concentrated to get crude product which was purified by reverse-phase HPLC under acidic condition to get the title compound 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (700 mg, 1.368 mmol, 44.5%). LC-MS m/z 512.6 (M+H) + , 1.34 min (ret. time).

Example 65. 1-(3′-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

65a) Methyl 1-(3′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

To a solution of (3-(4-(methoxycarbonyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic acid (200 mg, 0.545 mmol) and water (1.5 mL) (3-bromophenyl)methanol (153 mg, 0.817 mmol), K 2 CO 3 (226 mg, 1.634 mmol) and PdCl 2 (dppf) (39.9 mg, 0.054 mmol) were added. The reaction was heated in a microwave at 120° C. for 30 min. The solvent was evaporated and purified by Combiflash chromatography (hexane/ethyl acetate) to get the title compound methyl 1-(3′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (60 mg, 0.140 mmol, 25.6%). LC-MS m/z 430.0 (M+H) + , 0.88 min (ret. time).

›Example 50. 5-Cyclopropyl-1-[3′-(tetrahydro-furan-2-yl)-biphenyl-3-yl]-1H-pyrazole-4-carboxylic Acid · 12 of 12

65b) Methyl 1-(3′-(chloromethyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

To a solution of methyl 1-(3′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (60 mg, 0.140 mmol) in dichloromethane (2 mL), sulfurous dichloride (49.9 mg, 0.419 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated to obtain the title compound methyl 1-(3′-(chloromethyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (60 mg, 0.134 mmol, 96%) which was carried over to next step without further purification. LC-MS m/z 448.1 (M+H) + , 1.01 min (ret. time).

65c) Methyl 1-(3′-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

To a solution of methyl 1-(3′-(chloromethyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (60 mg, 0.134 mmolin N,N-dimethylformamide (2 mL), (R)-2-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (47.5 mg, 0.268 mmol), K 2 CO 3 (74.1 mg, 0.536 mmol) and sodium iodide (40.2 mg, 0.268 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried with MgSO 4 and concentrated to get the title compound methyl 1-(3′-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (60 mg, 0.102 mmol, 76%) which was carried over to next step without further purification. LC-MS m/z 589.1 (M+H) + , 0.89 min (ret. time).

65d) 1-(3′-(((R)-2-Ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of methyl 1-(3′-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (60 mg, 0.102 mmol) in a mixture of methanol (2.000 mL) and tetrahydrofuran (2.000 mL) LiOH (32.1 mg, 1.340 mmol) and 0.1 mL of water were added. The reaction mixture was stirred at RT for 48 h. The solvent was evaporated and 1 N HCl was added to reaction mixture to pH=1. The solvent was evaporated and purified by reverse-phase HPLC under neutral condition to get the title compound (39.2 mg, 0.068 mmol, 50.9%). LC-MS m/z 575.4 (M+H) + , 0.85 min (ret. time).

›Example 66. 1-(6-(3-Isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 1 of 6

66a) Ethyl 1-(6-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

To a mixture of 2-chloro-6-hydrazinylpyridine (0.5 g, 3.48 mmol) in ethanol (17 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (0.677 mL, 3.48 mmol). The result reaction mixture was heated at 80° C. for 1 h. The reaction mixture was evaporated down, diluted in EtOAc and then washed with brine. The organic layer was dried with MgSO 4 , filtered, and evaporated down to give the title compound (1.1350 g, 2.84 mmol, 82% yield). LC-MS m/z 320.0 (M+H) + , 1.16 min (ret. time).

66b) Ethyl 1-(6-(3-isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

To a mixture of ethyl 1-(6-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.188 g, 0.587 mmol) and (3-isopropoxyphenyl)boronic acid (0.16 g, 0.889 mmol) in 1,4-dioxane (2.2 mL) and water (0.733 mL) was added Pd(Ph 3 ) 4 (2.054 g, 1.778 mmol) and sodium carbonate (0.147 mL, 0.293 mmol). The result reaction mixture was heated with microwave at 130° C. for 30 min. The reaction mixture was filtered and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were evaporated down the purified with flash chromatograph to give the title compound (0.2125 g, 0.507 mmol, 57.0% yield). LC-MS m/z 420.2 (M+H) + , 1.45 min (ret. time).

66c) 1-(6-(3-Isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid (61.0 mg, 0.156 mmol, 66.7% Yield)

To ethyl 1-(6-(3-isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (98 mg, 0.234 mmol) was added to a mixture of sodium hydroxide (6 N) (0.195 mL, 1.168 mmol) in tetrahydrofuran (1 mL). The result mixture was stirred at room temperature for 21 h then was heated at 50° C. for 3 h. This reaction mixture was acidified with HCl (0.195 mL, 6 N), evaporated down under vacuum, purified by reverse phase HPLC (TFA modifier) to give the title compound (61.0 mg, 0.156 mmol, 66.7% yield). LC-MS m/z 392.1 (M+H) + , 1.13 min (ret. time).

Example 67. 5-(2,2-Difluorocyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

67a) Methyl 3-(2,2-difluorocyclopropyl)-3-oxopropanoate

To a solution of 2,2-difluorocyclopropanecarboxylic acid (5.00 g, 41.0 mmol) in Tetrahydrofuran (THF) (50 ml) was added CDI (7.97 g, 49.2 mmol), portionwise, and stirred at room temperature for 3 h. Then, the reaction was diluted with Tetrahydrofuran (THF) (25 ml) and magnesium chloride (5.15 g, 54.1 mmol) and potassium methyl malonate (12.79 g, 82 mmol) were added and the reaction was stirred for 18 h. Afterwards, the reaction was diluted with water (50.0 ml) and the pH was adjusted to pH=7 with 1M HCl (47.5 ml, 47.5 mmol). The aqueous layer was extracted with EtOAc (2×). The combined organics were washed with 1N HCl and brine, dried with MgSO 4 and the solvent was concentrated. The residue was re-dissolved in EtOAc and washed with sat. K 2 CO 3 (3×), brine, dried with MgSO 4 , and concentrated to provide the title compound (1.86 g, 25% yield). 1 H NMR (400 MHz, Chloroform-d) δ ppm 1.72-1.84 (m, 1H) 2.21-2.32 (m, 1H) 2.89-3.01 (m, 1H) 3.57-3.68 (m, 2H) 3.80 (s, 3H).

67b) (Z)-Methyl 2-(2,2-difluorocyclopropanecarbonyl)-3-(dimethylamino)acrylate

To a solution of methyl 3-(2,2-difluorocyclopropyl)-3-oxopropanoate (1.86 g, 10.44 mmol) in dichloromethane (DCM) (12 mL) was added DMF-DMA (1.678 mL, 12.53 mmol) and TsOH (0.020 g, 0.104 mmol) and stirred at room temperature for 18 hours. Additional DMF-DMA (0.419 mL, 3.13 mmol) was added and the reaction was and heated to 40° C. for 5 h. The solvent was concentrated and the residue was purified by flash chromatography eluting with 0-2% MeOH/DCM to provide the title compound (2.31 g, 74% yield). LC/MS m/z=234 (M+H) + , 0.60 min (ret. time).

67c) Methyl 1-(3-bromophenyl)-5-(2,2-difluorocyclopropyl)-1H-pyrazole-4-carboxylate

To a solution of (Z)-methyl 2-(2,2-difluorocyclopropanecarbonyl)-3-(dimethylamino)acrylate (2.31 g, 7.73 mmol) in Methanol (30 mL) was added triethylamine (1.615 mL, 11.59 mmol) and (3-bromophenyl)hydrazine, hydrochloride (1.727 g, 7.73 mmol) and stirred at room temperature for 4 h. Additional (3-bromophenyl)hydrazine, hydrochloride (0.086 g, 0.386 mmol) was added and stirred for 1.5 h. The solvent was concentrated and the residue was dissolved in EtOAc, washed with water (3×), brine, dried with MgSO 4 , and the solvent was concentrated. The residue was purified by flash chromatography eluting with 0-5% EtOAc/DCM to provide the title compound (2.63 g, 95% yield). LC/MS m/z=357 (M+H) + , 1.04 min (ret. time).

67d) Methyl 5-(2,2-difluorocyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate

A mixture of (R)-(2-propylpiperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (100 mg, 0.280 mmol), methyl 1-(3-bromophenyl)-5-(2,2-difluorocyclopropyl)-1H-pyrazole-4-carboxylate (116 mg, 0.325 mmol), and Na 2 CO 3 (89 mg, 0.840 mmol) were dissolved/suspended in 1,4-dioxane (3 mL) and water (1 mL) in a 10 mL microwave reaction vessel. The solvent was purged with nitrogen and then PdCl 2 (dppf)-CH 2 Cl 2 adduct (22.86 mg, 0.028 mmol) was added. The reaction was heated on microwave to 100° C. for 10 min. The reaction was heated a second time at 100° C. for 10 min. The reaction was filtered through a PL-Thiol-MP-SPE cartridge and the solvent was concentrated. The residue was purified by flash chromatography eluting with 0-10% EtOAc/DCM to provide the title compound (0.135 g, 90% yield). LC/MS m/z=508 (M+H) + , 1.27 min (ret. time).

67e) 5-(2,2-Difluorocyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

To a mixture of methyl 5-(2,2-difluorocyclopropyl)-1-(3′-((R)-2-propylpiperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate (135 mg, 0.266 mmol) in tetrahydrofuran (THF) (3 mL) and water (1 mL) was added LiOH (31.8 mg, 1.330 mmol) and stirred at room temperature for 18 h. The reaction was then heated to 45° C. for 9 hours. Additional LiOH (31.8 mg, 1.330 mmol) was added and the reaction was heated for 18 h. The temperature was increased to 60° C. and the reaction was heated for 26 h. The solvent was then concentrated and the reaction was diluted with water and acidified with 6N HCl. The aqueous layer was extracted with EtOAc (3×) and the combined organics were washed with water, brine and dried with MgSO 4 . The solvent was concentrated and the residue was purified by reverse phase preparative HPLC under neutral conditions to provide the title compound (0.071 g, 54% yield). LC/MS m/z=494 (M+H) + , 1.10 min (ret. time).

›Example 66. 1-(6-(3-Isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 2 of 6

Example 68. 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate, Sodium salt

1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (51 mg, 0.100 mmol) was weighed out and Water (1 mL) was added followed by 2M NaOH (0.050 mL, 0.100 mmol). The solution was stirred overnight and then concentrated. The crude product was dissolved in DMSO (2 mL) and purified with reverse-phase HPLC under neutral conditions to afford the title compound (53.49 mg, 101% yield). LC-MS m/z 512.3 (M+H) + , 1.25 min (ret. time). 1 H NMR (DMSO-de) δ: 7.81 (s, 1H), 7.68-7.73 (m, 2H), 7.48-7.60 (m, 3H), 7.33 (s, 1H), 7.12 (s, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.94 (s, 1H), 4.30-4.38 (m, 1H), 3.84 (s, 3H), 2.33-2.42 (m, 1H), 1.83-1.93 (m, 1H), 1.74 (d, J=10.3 Hz, 3H), 1.51-1.67 (m, 3H), 1.02-1.37 (m, 1 OH).

Example 69. Barium 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate Hydroxide

Water (1 mL) was added to 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (52.5 mg, 0.103 mmol), followed by barium hydroxide (16.19 mg, 0.051 mmol). Not much dissolved. The reaction was heated to 40° C. Added MeOH (1 mL) and, still not all went into solution, after heating for 2 hours. Added THF (1 mL) and all went into solution. The solution was heated overnight and then concentrated. The crude product was dissolved in DMSO (2 mL) and purified with reverse-phase HPLC under neutral conditions to afford the title compound (40.52 mg, 59.4% yield). LC-MS m/z 512.4 (M+H) + , 1.35 min (ret. time). 1 H NMR (DMSO-d 6 ) δ: 7.79 (br. s., 1H), 7.65-7.70 (m, 2H), 7.62 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 7.12 (br. s., 1H), 7.04 (d, J=7.5 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 4.34 (s, 1H), 3.83 (s, 3H), 2.59-2.70 (m, 1H), 2.24-2.35 (m, 1H), 1.84-1.93 (m, 1H), 1.68-1.82 (m, 5H), 1.60-1.67 (m, 1H), 1.49-1.59 (m, 1H), 1.30-1.36 (m, 1H), 1.01-1.25 (m, 8H).

Example 70. Calcium 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate Hydroxide

Water (1 mL) was added to 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (54.2 mg, 0.106 mmol), followed by calcium hydroxide (3.92 mg, 0.053 mmol). Not much dissolved. The reaction was heated to 40° C. Added MeOH (1 mL) and, still not all went into solution, after heating for 2 h. Added THF (1 mL) and all went into solution. The solution was heated overnight and then concentrated. The crude product was dissolved in DMSO (2 mL) and purified with reverse-phase HPLC under neutral conditions to afford the title compound (39.2 mg, 65.2% yield). LC-MS m/z 512.4 (M+H) + , 1.34 min (ret. time). 1 H NMR (DMSO-d 6 ) δ: 7.78-7.98 (m, 1H), 7.69 (br. s., 3H), 7.46-7.57 (m, 2H), 7.28-7.35 (m, 1H), 7.12 (br. s., 1H), 7.05 (d, J=6.8 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 4.29-4.40 (m, 1H), 3.82 (br. s., 3H), 3.18 (br. s., 1H), 2.32 (br. s., 1H), 1.87 (d, J=12.0 Hz, 1H), 1.50-1.76 (m, 6H), 1.39 (br. s., 1H), 0.99-1.26 (m, 8H). Theoretical Elemental Analysis: C, 63.47; H, 5.86; N, 12.34; Found Elemental Analysis: C, 63.82; H, 6.10; N, 12.04.

Example 71. 1-(3′-((S)-1-Cyclohexylethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

71a) (S)-1-Bromo-3-(1-cyclohexylethoxy)-2-methylbenzene

Dissolved 3-bromo-2-methylphenol (255 mg, 1.363 mmol) and Ph3P (429 mg, 1.636 mmol) in Tetrahydrofuran (THF) (5 mL). Added (R)-1-cyclohexylethanol (0.226 mL, 1.636 mmol) followed by DIAD (0.318 mL, 1.636 mmol). The reaction was stirred for 22 h and then concentrated. The compound was purified by flash chromatography with silica running from 100% Hex to 100% EtOAc. The desired fractions were concentrated to give the title compound (183.6 mg, 45.3% yield). LC-MS 1.70 min (ret. time).

71b) Methyl 1-(3′-((S)-1-cyclohexylethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

Weighed out (S)-1-bromo-3-(1-cyclohexylethoxy)-2-methylbenzene (182 mg, 0.612 mmol), (3-(4-(methoxycarbonyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic acid (158.7 mg, 0.432 mmol) and cesium carbonate (352 mg, 1.081 mmol). Added 1,4-dioxane (5 mL) followed by water (1.000 mL), then the flask was flushed with nitrogen. Tetrakis (49.9 mg, 0.043 mmol) was added and the reaction was sealed and heated to 80° C. for 15 h. The reaction was cooled to RT and more tetrakis (49.9 mg, 0.043 mmol) was added and reheated to 80° C. for 1 day. The reaction was concentrated and purified by flash chromatography on silica running from 100% Hex to 100% EtOAc. The desired fractions were concentrated to give the title compound (134.0 mg, 57.4% yield). LC-MS m/z 540.2 (M+H) + , 1.48 min (ret. time).

71c) 1-(3′-((S)-1-Cyclohexylethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of methyl 1-(3′-((S)-1-cyclohexylethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (134.0 mg, 0.248 mmol) in a mix of methanol (2 mL) and tetrahydrofuran (THF) (1.000 mL) was added LiOH (104 mg, 2.483 mmol) and water (0.400 mL). The reaction was heated to 50° C. for 2 h and then concentrated. To the residue was added acetonitrile (5 mL), then the reaction was acidified with 1 M HCl to pH=3. The reaction was concentrated. The crude product was dissolved in DMSO (5 mL) and purified with reverse-phase HPLC under acidic conditions to afford the title compound (82.9 mg, 63.5%). LC-MS m/z 526.2 (M+H) + , 1.36 min (ret. time). 1 H NMR (400 MHz, DMSO-d 6 ) δ=7.99 (s, 1H), 7.59 (s, 1H), 7.54 (s, 2H), 7.44 (s, 1H), 7.38 (d, J=5.8 Hz, 1H), 7.17 (t, J=7.9 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 6.62 (d, J=7.5 Hz, 1H), 4.29 (t, J=5.8 Hz, 1H), 3.91 (s, 3H), 2.26-2.16 (m, 1H), 2.00 (s, 3H), 1.90 (d, J=12.0 Hz, 1H), 1.74 (d, J=10.5 Hz, 3H), 1.69-1.53 (m, 2H), 1.39-1.32 (m, 1H), 1.30-1.05 (m, 10H).

›Example 66. 1-(6-(3-Isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 3 of 6

Example 72. 1-(3′-(Cyclohexylmethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

72a) 1-Bromo-3-(cyclohexylmethoxy)-2-methylbenzene

Dissolved 3-bromo-2-methylphenol (251 mg, 1.342 mmol) and Ph 3 P (422 mg, 1.610 mmol) in tetrahydrofuran (THF) (5 mL). Added cyclohexylmethanol (0.204 mL, 1.610 mmol) followed by DIAD (0.313 mL, 1.610 mmol). The reaction was stirred for 22 h and then concentrated. The compound was purified by flash chromatography with silica running from 100% Hex to 100% EtOAc. The desired fractions were concentrated to give the title compound (281.1 mg, 74.0% yield). LC-MS 1.67 min (ret. time).

72b) Methyl 1-(3′-(cyclohexylmethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

Weighed out 1-bromo-3-(cyclohexylmethoxy)-2-methylbenzene (278 mg, 0.982 mmol), (3-(4-(methoxycarbonyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic acid (236.6 mg, 0.644 mmol) and cesium carbonate (525 mg, 1.611 mmol). Added 1,4-dioxane (25 mL) followed by water (5.00 mL), then the flask was flushed with nitrogen. Tetrakis (74.5 mg, 0.064 mmol) was added and the reaction was sealed and heated to 80° C. for 18 h. Added more tetrakis (74.5 mg, 0.064 mmol) and reheated to 80° C. for 1 day. The reaction was concentrated and purified by flash chromatography on silica running from 100% Hex to 100% EtOAc. The desired fractions were concentrated to give the title compound (194.2 mg, 57.3% yield). LC-MS m/z 526.4 (M+H) + , 1.48 min (ret. time).

72c) 1-(3′-(cyclohexylmethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of methyl 1-(3′-(cyclohexylmethoxy)-2′-methyl-[1,1′-biphenyl]-3-yl)-5-(2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (194.2 mg, 0.369 mmol) in a mix of methanol (2 mL) and tetrahydrofuran (THF) (1.000 mL) was added LiOH (155 mg, 3.69 mmol) and Water (0.400 mL). The reaction was heated at 50° C. for 90 min and then concentrated. To the residue was added acetonitrile (5 mL), then the reaction was acidified with 1 M HCl to pH=3. The reaction was concentrated. The crude product was dissolved in DMSO (4 mL) and purified with reverse-phase HPLC under acidic conditions to afford the title compound (29.4 mg, 15.5%). LC-MS m/z 512.2 (M+H) + , 1.32 min (ret. time). 1 H NMR (400 MHz, DMSO-de) 6=7.99 (s, 1H), 7.57 (d, J=13.3 Hz, 3H), 7.44 (s, 1H), 7.38 (d, J=4.5 Hz, 1H), 7.22-7.15 (m, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 3.90 (s, 3H), 3.83 (d, J=5.5 Hz, 2H), 2.25-2.16 (m, 1H), 2.01 (s, 3H), 1.90-1.63 (m, 6H), 1.38-1.04 (m, 8H).

Example 73. 1-(3′-((S)-1-Cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

73a) (S)-(1-(3-Bromophenoxy)ethyl)cycloheptane

Dissolved 3-bromophenol (0.15 mL, 1.413 mmol) and Ph 3 P (446 mg, 1.700 mmol) in tetrahydrofuran (THF) (5 mL). Added (R)-1-cycloheptylethanol (245 mg, 1.722 mmol) followed by DIAD (0.33 mL, 1.697 mmol). The reaction was stirred for 19 h and then concentrated. The compound was purified by flash chromatography with silica running from 100% Hex to 60% Hex/40% EtOAc. The desired fractions were concentrated to give the title compound (229.8 mg, 54.7% yield). LC-MS 1.61 min (ret. time).

73b) Methyl 1-(3′-((S)-1-cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

Weighed out (S)-(1-(3-bromophenoxy)ethyl)cycloheptane (229.8 mg, 0.773 mmol), (3-(4-(methoxycarbonyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic acid (201 mg, 0.547 mmol) and cesium carbonate (447 mg, 1.372 mmol). Added 1,4-dioxane (8 mL) followed by water (1.600 mL). Then the flask was flushed with nitrogen. Tetrakis (190 mg, 0.164 mmol) was added and the reaction was sealed and heated to 80° C. for 18 h. The reaction was cooled to room temp and concentrated. The residue was taken back up in DCM (100 mL) and washed with water (25 mL). The organic layer was concentrated. The compound was purified by flash chromatography on silica running from 100% Hex to 100% EtOAc. The desired fractions were concentrated to give the title compound (302.8 mg, 102% yield). LC-MS m/z 540.2 (M+H) + , 1.46 min (ret. time).

73c) 1-(3′-((S)-1-Cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of methyl 1-(3′-((S)-1-cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (310 mg, 0.574 mmol) in a mix of Methanol (5 mL) and Tetrahydrofuran (THF) (2.500 mL) was added LiOH (245 mg, 5.84 mmol) and Water (1.000 mL). The reaction was stirred at RT for 19 h and then concentrated. The residue was partitioned between EtOAc (50 mL) and 1N HCl (25 mL). The water layer was extracted with EtOAc (25 mL) and the combined organics were dried MgSO 4 , filtered and concentrated in vacuo. The crude product was dissolved in DMSO and purified with reverse-phase HPLC under acidic conditions (0.1% formic acid) to afford the title compound. The compound was crystallized from EtOAc and hexane to give the title compound (85.5 mg, 28.3% yield). LC-MS m/z 526.4 (M+H) + , 1.29 min (ret. time). 1 H NMR (400 MHz, DMSO-d 6 ) δ: 12.42-12.32 (m, 1H), 8.01 (s, 1H), 7.81-7.72 (m, 2H), 7.57 (d, J=10.8 Hz, 2H), 7.47 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.14-7.07 (m, 2H), 6.94 (d, J=8.3 Hz, 1H), 4.47-4.37 (m, 1H), 3.82 (s, 3H), 2.15 (d, J=7.8 Hz, 1H), 1.86-1.64 (m, 5H), 1.59-1.25 (m, 9H), 1.20 (d, J=6.0 Hz, 3H).

Example 74. 1-(3′-((R)-1-Cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

74a) (R)-(1-(3-Bromophenoxy)ethyl)cycloheptane

Dissolved 3-bromophenol (0.15 mL, 1.413 mmol) and Ph 3 P (452 mg, 1.723 mmol) in tetrahydrofuran (THF) (5 mL). Added (S)-1-cycloheptylethanol (245 mg, 1.722 mmol) followed by DIAD (0.33 mL, 1.697 mmol). The reaction was stirred for 19 h and then concentrated. The compound was purified by flash chromatography with silica running from 100% Hex to 60% Hex/40% EtOAc. The desired fractions were concentrated to give the title compound (225.6 mg, 53.7% yield). LC-MS 1.61 min (ret. time).

›Example 66. 1-(6-(3-Isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 4 of 6

74b) Methyl 1-(3′-((R)-1-cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

Weighed out (R)-(1-(3-bromophenoxy)ethyl)cycloheptane (225.6 mg, 0.759 mmol), (3-(4-(methoxycarbonyl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazol-1-yl)phenyl)boronic acid (204 mg, 0.556 mmol) and cesium carbonate (462 mg, 1.418 mmol). Added 1,4-dioxane (8 mL) followed by water (1.600 mL). The flask was flushed with nitrogen. Tetrakis (193 mg, 0.167 mmol) was added and the reaction was sealed and heated to 80° C. for 18 h. The reaction was cooled to room temp and concentrated. The residue was taken back up in DCM (100 mL) and washed with water (25 mL). The organic layer was concentrated. The compound was purified by flash chromatography on silica running from 100% Hex to 100% EtOAc. The desired fractions were concentrated to give the title compound (293.3 mg, 98% yield). LC-MS m/z 540.2 (M+H) + , 1.46 min (ret. time).

74c) 1-(3′-((R)-1-Cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of methyl 1-(3′-((R)-1-cycloheptylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (310 mg, 0.574 mmol) in a mix of Methanol (5 mL) and Tetrahydrofuran (THF) (2.500 mL) was added LiOH (241 mg, 5.74 mmol) and Water (1.000 mL). The reaction was stirred at RT for 19 h and then concentrated. The residue was partitioned between EtOAc (50 mL) and 1N HCl (25 mL). The water layer was extracted with EtOAc (25 mL) and the combined organics were dried MgSO 4 , filtered and concentrated in vacuo. The crude product was dissolved in DMSO and purified with reverse-phase HPLC under acidic conditions (0.1% formic acid) to afford the title compound. The compound was crystallized from EtOAc and hexane to give the title compound (185.1 mg, 61.3% yield). LC-MS m/z 526.3 (M+H) + , 1.37 min (ret. time). 1 H NMR (400 MHz, DMSO-de) δ: 12.51-12.26 (m, 1H), 8.02 (s, 1H), 7.81-7.72 (m, 2H), 7.61-7.51 (m, 2H), 7.47 (s, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.15-7.06 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 4.47-4.39 (m, 1H), 3.82 (s, 3H), 2.19-2.12 (m, 1H), 2.08 (s, 1H), 1.85-1.63 (m, 5H), 1.59-1.25 (m, 10H), 1.19 (d, J=5.8 Hz, 3H).

Example 75. 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

75a) Ethyl 2-(2,2-dibromovinyl)cyclopropanecarboxylate

To a solution of triphenylphosphine (258 g, 985 mmol) in dichloromethane (DCM) (300 mL) was added a solution of carbon tetrabromide (163 g, 492 mmol) in dichloromethane (DCM) (300 mL) dropwise at 0° C. After addition, the mixture was stirred for 10 min, a solution of ethyl 2-formylcyclopropanecarboxylate (35 g, 246 mmol) in dichloromethane (DCM) (50 mL) was then added dropwise. After addition, the reaction mixture was stirred for 30 min at 0° C. The ice bath was removed and the reaction mixture was stirred for additional 30 min. The mixture was filtered and the filtrate was concentrated. The residue was triturated with hexanes and filtered through celite. The filtrate was filtered again through celite. To the filtrate was added isolute and concentrated. The isolute was loaded onto a cartridge and purified on the Torrent column chromatography (750 g silica gel, gold) eluting with a gradient of 0-5% ethyl acetate in hexanes. The title compound was obtained as clear colorless oil (43.7 g, 147 mmol, 59.6% yield). LC-MS m/z 296.9 (M+H) + , 1.14 min (ret. time).

75b) 2-(2,2-Dibromovinyl)cyclopropanecarboxylic Acid

To a solution of ethyl 2-(2,2-dibromovinyl)cyclopropanecarboxylate (43.7 g, 147 mmol) in tetrahydrofuran (THF) (70 mL) and methanol (70 mL) was added 6.0 N NaOH (73.3 mL, 440 mmol). The reaction mixture was stirred for 1.0 hour at room temperature. The mixture was acidified with 6.0 N HCl (aq) and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate. It was filtered and the filtrated was concentrated to give the title compound (37.6 g, 139 mmol, 95% yield) as white solid used in the next step without further purification. LC-MS m/z 268.5 (M+H) + , 0.86 min (ret. time).

75c) Methyl 3-(2-(2,2-dibromovinyl)cyclopropyl)-3-oxopropanoate

To a solution of 2-(2,2-dibromovinyl)cyclopropanecarboxylic acid (37.6 g, 139 mmol) in tetrahydrofuran (THF) (350 mL) was added CDI (33.9 g, 209 mmol). The mixture was stirred for 2 hours at room temperature, potassium 3-methoxy-3-oxopropanoate (65.3 g, 418 mmol) was added, followed by magnesium chloride (15.92 g, 167 mmol). The resulting reaction mixture was stirred overnight at room temperature. The mixture was neutralized with 6.0 N HCl and diluted with water, extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The residue was dissolved in DCM and purified on the Torrent flash column chromatography (750 g silica gel) eluting with a gradient of 0-25% ethyl acetate in hexanes. The title compound was obtained as clear yellow oil (45.4 g, 139 mmol, 100% yield). LC-MS m/z 324.8 (M+H) + , 1.0 min (ret. time).

75d) Methyl 2-(2-(2,2-dibromovinyl)cyclopropanecarbonyl)-3-(dimethylamino)acrylate

A mixture of methyl 3-(2-(2,2-dibromovinyl)cyclopropyl)-3-oxopropanoate (45.4 g, 139 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (24 ml, 180 mmol) in 1,4-Dioxane (24 mL) was stirred overnight at room temperature. The mixture was concentrated by rotavap. 1,4-dioxane (25 mL) was added and concentrated by rotavap (repeated one more time) to give the title compound (50 g, 131 mmol, 94% yield) as yellow oil used in the next step without further purification. LC-MS m/z 379.9 (M+H) + , 0.99 (ret. time).

75e) Methyl 1-(3-bromophenyl)-5-(2-(2,2-dibromovinyl)cyclopropyl)-1H-pyrazole-4-carboxylate

To a solution of methyl 2-(2-(2,2-dibromovinyl)cyclopropanecarbonyl)-3-(dimethylamino)acrylate (50 g, 131 mmol) in Ethanol (300 mL) was added (3-bromophenyl)hydrazine hydrochloride (32.3 g, 144 mmol). To the resulting suspension was added TEA (36.6 mL, 262 mmol). The mixture turned to clear solution and it was stirred for 2.0 hours at room temperature. The mixture was filtered and the solid was washed with ethanol, dried to give the clean title compound as white powder (43.23 g, 86 mmol, 65.2% yield). LC-MS m/z 502.9 (M+H) + , 1.37 min (ret. time).

›Example 66. 1-(6-(3-Isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 5 of 6

75f) rac-Methyl 1-(3-bromophenyl)-5-((1,2-E)-2-ethynylcyclopropyl)-1H-pyrazole-4-carboxylate

A mixture of methyl 1-(3-bromophenyl)-5-((1R,2R)-2-(2,2-dibromovinyl)cyclopropyl)-1H-pyrazole-4-carboxylate (10 g, 19.80 mmol) and cesium carbonate (16.13 g, 49.5 mmol) in dimethyl sulfoxide (DMSO) (100 mL) was stirred for 2 days at 115° C. After cooled to the room temperature, the mixture was diluted with 200 mL of ethyl acetate and hexanes (3:2, V:V). It was filtered through celite, washed with the solution of ethyl acetate and hexanes (3:2, V:V). The resulting mixture was diluted with water (200 mL). The layers were separated and the organic layer was washed with water (2×200 mL), dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated to give the crude product. The crude product was dissolved in dichloromethane (20 mL) and loaded onto a silica gel column (330 g, gold), purified by Combiflash eluting with a gradient of 0-20% ethyl acetate in hexanes. The title compound was obtained as clear light yellow oil (5.2 g, 15.06 mmol, 76% yield). LC-MS m/z 344.8 (M+H) + , 1.12 min (ret. time).

75 g) (S)-2-(3-(1-Cyclohexylethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of (S)-1-bromo-3-(1-cyclohexylethoxy)benzene (0.75 g, 2.65 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.009 g, 3.97 mmol), potassium acetate (0.520 g, 5.30 mmol), and PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.108 g, 0.132 mmol) in 1,4-dioxane (10 mL) was stirred for 2 hours at 100° C., the LCMS showed desired and little starting material. The mixture was stirred overnight at 80° C., the LCMS showed a complete reaction. After cooled to the room temperature, the mixture was filtered through celite, the filtrate was diluted with water and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The crude product was purified on the Combiflash column chromatography eluting with a gradient of 0-5% ethyl acetate in hexanes. The title compound was obtained as clear colorless oil (0.668 g, 2.023 mmol, 76% yield). LC-MS m/z 331.1 (M+H) + , 1.67 min (ret. time).

75h) Methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-ethynylcyclopropyl)-1H-pyrazole-4-carboxylate

A mixture of (S)-2-(3-(1-cyclohexylethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (550 mg, 1.665 mmol), rac-methyl 1-(3-bromophenyl)-5-((1R,2R)-2-ethynylcyclopropyl)-1H-pyrazole-4-carboxylate (575 mg, 1.665 mmol), tetrakis (96 mg, 0.083 mmol), and 10% Na 2 CO 3 (aq) (3530 mg, 3.33 mmol) in 1,4-dioxane (10 mL) was stirred for 20 min at 100° C. After cooled to the room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrate to give the crude product which was then purified on the Combiflash (silica gel column 120 g, gold) eluting with a gradient of 0-15% ethyl acetate in hexanes. The title compound was obtained as clear colorless oil (560 mg, 1.195 mmol, 71.8% yield). LC-MS m/z 469.1 (M+H) + , 1.64 min (ret. time).

75i) methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate

A mixture of rac-methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-((1R,2R)-2-ethynylcyclopropyl)-1H-pyrazole-4-carboxylate (60 mg, 0.128 mmol), iodomethane (0.020 mL, 0.320 mmol), sodium azide (22 mg, 0.338 mmol), copper(I) iodide (6.0 mg, 0.032 mmol) and DIPEA (0.022 mL, 0.128 mmol) in tert-butanol (2.0 mL) and water (1.0 mL) was irritated via microwave reactor for 40 min at 70° C. After cooled to the room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The crude product was purified on the Combiflash eluting with a gradient of 0-50% ethyl acetate in hexanes. The title compound was obtained as white solid (42 mg, 0.08 mmol, 62.4% yield). LC-MS m/z 526.1 (M+H) + , 1.43 min (ret. time).

75j) 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

A mixture of methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (42 mg, 0.080 mmol) and LiOH 50 mg/mL in water (0.765 mL, 1.598 mmol) in tetrahydrofuran (THF) (1.0 mL) and methanol (1.0 mL) was stirred for 18 hours at room temperature. The mixture was concentrated (still some water left) and neutralized with 1.0 N HCl. It was extracted with ethyl acetate. The solvent was evaporated and the crude product was then purified on the prep HPLC eluting with a gradient of 30-100% acetonitrile in water. The title compound was obtained as white solid (34 mg, 0.063 mmol, 79% yield). LC-MS m/z 512.1 (M+H) + , 1.30 min (ret. time).

The compounds in Table 1 were prepared by a method similar to the one described for the preparation of 1-(3′-((S)-1-Cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-methyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

Example 85. 5-(trans-2-(1-(Azetidin-3-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

A mixture of 5-(trans-2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.153 mmol) and TFA (0.5 mL, 6.49 mmol) in dichloromethane (DCM) (1.0 mL) was stirred for 1.0 hour at room temperature. The mixture was neutralized with saturated NaHCO 3 (aq) and the mixture was passed through a SCX cartridge flashed with methanol, followed by 2.0 M NH 3 in methanol solution. The NH 3 solution was collected and concentrated to give the title compound as white solid (80 mg, 0.138 mmol, 90% yield). LC-MS m/z 553.3 (M+H) + , 1.10 min (ret. time).

›Example 66. 1-(6-(3-Isopropoxyphenyl)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic Acid · 6 of 6

Example 86. 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1H-pyrazole-4-carboxylic Acid

To a solution of 5-(trans-2-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic acid (42 mg, 0.062 mmol) in dichloromethane (DCM) (0.6 mL) was added TFA (0.3 mL, 3.89 mmol). The reaction mixture was stirred for 1.0 hour at room temperature. The mixture was concentrated and the residue was diluted with water and neutralized with saturated NaHCO 3 (aq). The resulting mixture was passed through a SCX cartridge, flashed with methanol, followed by 2.0 M ammonia in methanol solution. The ammonia solution was collected and concentrated to give the title compound as white solid (31.5 mg, 0.052 mmol, 84% yield). LC-MS m/z 581.3 (M+H) + , 1.10 min (ret. time).

Example 87. 5-(trans-2-(1-Benzyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

87a) Methyl 5-(trans-2-(1-benzyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylate

A mixture of methyl 1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-5-(trans-2-ethynylcyclopropyl)-1H-pyrazole-4-carboxylate (100 mg, 0.213 mmol), (azidomethyl)benzene (71.0 mg, 0.534 mmol), copper(I) iodide (8.2 mg, 0.043 mmol), and DIPEA (12 μl, 0.069 mmol) in Tert-Butanol (2.0 mL) and Water (1.0 mL) was irritated via microwave reactor on high absorption for 50 min at 70° C. After cooled to the room temperature, the mixture was diluted with ethyl acetate and filtered through celite. The filtrate was diluted with brine and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrate to give the crude product which was then purified on the Combiflash eluting with a gradient of 0-40% ethyl acetate in hexanes. The title compound was obtained as white solid (102 mg, 0.17 mmol, 79% yield). LC-MS m/z 602.1 (M+H) + , 1.59 min (ret. time).

87b) 5-(trans-2-(1-Benzyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1′-biphenyl]-3-yl)-1H-pyrazole-4-carboxylic Acid

A mixture of methyl 5-(trans-2-(1-benzyl-1H-1,2,3-triazol-4-yl)cyclopropyl)-1-(3′-((S)-1-cyclohexylethoxy)-[1,1

›Tables in the description — 6

TABLE 13 — Retention

			LCMS	time
Example	Structure	Name	[M + H] +	(min)
217
1-(3′-(2-Cyclohexyl-1- hydroxyethyl)-[1,1′- biphenyl]-3-yl)-5-(2-(1- methyl-1H-1,2,3-triazol- 4-yl)cyclopropyl)-1H- pyrazole-4-carboxylic acid	512.36	2.45

TABLE 16 — Retention

			LCMS	time
Example	Structure	Name	[M + H] +	(min)
236
5-((1,2-trans)-2-(1- Methyl-1H-1,2,3-triazol- 4-yl)cyclopropyl)-1-(3′- (pyrimidin-5-ylmethoxy)- [1,1′-bipheny1]-3-yl)-1H- pyrazole-4-carboxylic acid	494.30	1.826

TABLE 17 — Retention

			LCMS	time
Example	Structure	Name	[M + H] +	(min)
238
1-(3′-([1,1′-Biphenyl]-3- ylmethoxy)-[1,1′- biphenyl]-3-yl)-5-((1,2- trans)-2-(1-methyl-1H- 1,2,3-triazol-4- yl)cyclopropyl)-1H- pyrazole-4-carboxylic acid	567.9	3.363

TABLE 7 — Retention

			LCMS	time
Example	Structure	Name	[M + H] +	(min)
240
1-(3′-(1-([1,1′-Biphenyl]- 4-yl)ethoxy)-[1,1′- biphenyl]-3-yl)-5-((1,2- trans)-2-(1-methyl-1H- 1,2,3-triazol-4- yl)cyclopropyl)-1H- pyrazole-4-carboxylic acid	582.30	2.775

TABLE 19 — Retention

			LCMS	time
Example	Structure	Name	[M + H] +	(min)
242
1-(3′-(1- Cyclohexylpropoxy)- [1,1′-biphenyl]-3-yl)-5- ((1,2-trans)-2-(1-methyl- 1H-1,2,3-triazol-4- yl)cyclopropyl)-1H- pyrazole-4-carboxylic acid	526.26	2.952

TABLE 20 — Retention

			LCMS	time
Example	Structure	Name	[M + H] +	(min)
244
1-(3′- (Cyclohexyl(methoxy) methyl)-[1,1′-biphenyl]- 3-yl)-5-(2-(1-methyl-1H- 1,2,3-triazol-4- yl)cyclopropyl)-1H- pyrazole-4-carboxylic acid	512.32	2.73

description truncated at 500,000 characters. 1 of 80 part labels are ours — the grant heads the rest

Stored text is truncated at the source; the tail of the description is not held.

Claims as granted

15 claims

Classifications

18 codes

IPC · International Patent Classification

Section A — Human necessities

A61K9/00
A61K31/41
A61K31/445
A61P11/00
A61K31/4196

Section C — Chemistry; metallurgy

C07D401/06
C07D401/12
C07D403/08
C07D401/14
C07D401/10
C07D405/14
C07D403/14
C07D417/14
C07D413/14
C07D401/04
C07D403/10
C07D413/08
C07D515/14

Claim changes

Soon

Coming soonHow the claims changed between publication and grant

See which claims were amended, added or cancelled during examination, with every added and removed word marked.

AmendedAddedCancelledUnchanged

The published claims of this application are not paired with the granted ones in what we hold.

File wrapper

⤢ drag to zoom

USPTOApplicanthover for detail · click to open

Pendency

2.8 y

1,027 days filing → grant

Office actions

none on record

Responses

2 RCE

Examiner

Alicia L Otton

art unit 1626 · TC 1600

Law firm

Law firm · Log in to unlock

Citations: 41 back · 1 forward

See the full prosecution history — every USPTO and applicant action on this file, in order.

Documents

Log in to open the documents of this file: the application as filed, every office action and response, the notice of allowance.

Chain of title

⤢ drag to zoom

Titlehover for detail · click to open

See the full assignment history — every owner this patent has passed through, with recordation dates and reel/frame numbers.